PH26578A - Intermediate for preparing phosphorous-containing HMG-CoA reductase inhibitors - Google Patents

Intermediate for preparing phosphorous-containing HMG-CoA reductase inhibitors Download PDF

Info

Publication number
PH26578A
PH26578A PH38673A PH38673A PH26578A PH 26578 A PH26578 A PH 26578A PH 38673 A PH38673 A PH 38673A PH 38673 A PH38673 A PH 38673A PH 26578 A PH26578 A PH 26578A
Authority
PH
Philippines
Prior art keywords
alkyl
solution
mixture
mmole
hx10b
Prior art date
Application number
PH38673A
Inventor
Donald Steven Karanewsky
Michael Christopher Badia
Scott Adams Biller
Eric Michael Gordon
Original Assignee
Squibb & Sons Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Squibb & Sons Inc filed Critical Squibb & Sons Inc
Publication of PH26578A publication Critical patent/PH26578A/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
    • C07F9/301—Acyclic saturated acids which can have further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
    • C07F9/302—Acyclic unsaturated acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
    • C07F9/303—Cycloaliphatic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
    • C07F9/306—Arylalkanephosphinic acids, e.g. Ar-(CH2)n-P(=X)(R)(XH), (X = O,S, Se; n>=1)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
    • C07F9/32—Esters thereof
    • C07F9/3205—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/3211—Esters of acyclic saturated acids which can have further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
    • C07F9/32—Esters thereof
    • C07F9/3205—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/3217—Esters of acyclic unsaturated acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
    • C07F9/32—Esters thereof
    • C07F9/3205—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/3241—Esters of arylalkanephosphinic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings
    • C07F9/5728—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503—Five-membered rings
    • C07F9/65031—Five-membered rings having the nitrogen atoms in the positions 1 and 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503—Five-membered rings
    • C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

~ - \ C” | , . Oo -1- ; oo PHOSPHORUS—-CONTAINING HMG-CoA REDUCTASE
INHIBITORS, NEW INTERMEDIATES AND METHOD
This application is a continuation-in-part oo - of application Serial No. 109,681, filed ” - October 19, 1987, which is a continuation-in-part of application Serial No. 053,238, filed May 22, 1987, now abandoned. . 10 . : : © The present invention relates to new phosrhorus- containing compounds which inhibit the activity of =. 3-hydroxy-3-methylglutaryl-coenzyme A reductase and thus are useful in inhibiting cholesterol biosynthesis, to hypocholesterolemic compositions containing such mei ~~ .- compounds;- to- new intermediates formed in_the a - preparation of such compounds and to a method of - using such compounds for such purposes. : 20 :
Co eon F. M. Singer et al., Proc. Scc. Exper. : Biol..Med., 102, 370 (1959) and F. H. Hulcher,
Arch. Biochem. Biophys:, 146, 422 (1971) disclose
E 25 that certain mevalonate derivatives inhibit the biosynthesis of cholesterol. : 1osynthe | BAD ORIGINAL . . : * So nabs a pm =
} HX10b ~2-
Endo et al in U. S. Patents Nos. 4,049,495, : 4,137,322 and 3,983,140 disclose a fermentation . - product which is active in the inhibition of - cholesterol biosynthesis. This product is called compactin and was reported by Brown et al., © (J. Chem. Soc. Perkin I. 1165 (1976)) to have a complex mevalonolactons structure.
GB 1,586,152 discloses a group of synthetic compounds of the formula.
CH 0
R,0 0 a Re 25 . . i + 4 in which E represents a direct bond, a C,_, alkylene bridge or a vinylene bridge and the : - various R's represent a variety of substituents.
The activity reported in the U.K. patent is less than 1% that of compactin.
U. S. Patent No. 4,375,475 to Willard et al discloses hypocholesterolemic and hypolipemic -compounds having the structure
Ho 2 0
Gr
S
: 30 £ 62 °N2 - HA RL I Ra BAD ORIGINAL + Co 5 NL 3 , i no 4 Dentin aanmalt . 35 : Ry -
HX10b -3- ‘ " wherein A is H or methyl; E is a direct bond, -CH,-, -CH,-CH,~, -CH,-CH,-CH, = or -CH=CH~; Ry. R, and ‘R, are each selected from H, halogen, C;_, alkyl, Cc, , haloalkyl, phenyl, phenyl substituted by halogen, Ci-2 alkoxy, Cs.8 alkanoyloxy,
C,_gq alkyl, or Cy _, haloalkyl, and OR, 1n which R, is H, C,_g alkanoyl, benzoyl, phenyl, halophenyl, phenyl Ci 3 alkyl, C,_g alkyl, cinnamyl, Ci-2 haloalkyl, allyl, cycloalkyl-C, j-alkyl,
Lo. . 10 adamantyl-C,_5-alkyl, or substituted phenyl
C,_3-alkyl in each of which the substituents are selected from halogen, Ci.4 alkoxy, Ci-4 alkyl, or
Ci-a haloalkyl; and the corresponding dihydroxy . acids resulting from the hydrolytic opening of the lactone ring, and the pharmaceutically acceptable salts of said acids, and the C,.3 alkyl and phenyl, dimethylamino or acetylamino substituted The
C,_3-alkyl esters of the dihydroxy acids; all of - the compounds being the enantiomers having a 4 R configuration in the tetrahydropyran moiety of the : trans racemate shown in the above formula.
CO WO 84/02131 (PCT/EP83/00308) (based on
U. S. application Serial No. 443,668, filed
November 22, 1982, and U. S. application Serial
No. 548,850, filed November 4, 1983), filed in the name of Sandoz AG discloses heterocyclic analogs of . mevalono lactone and derivatives thereof having the structure
R, R 4 5 \ 5 X-2 6 N 1
Cail hs BAD ORIGINAL 3 CL °
HX10b -4- . | R, ~ wherein one of R and R, is” and the - | Rg © Rgy other is primary or secondary Ci_6 alkyl, Ci_g cycloalkyl or phenyl-(CH,) -, wherein Ry is hydrogen, Ci 4 alkyl, Ci a E alkoxy, (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy,
See - 10 Rg is hydrogen, Ci_3 alkyl, Ci_3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or ’ benzyloxy,
Co R;, is hydrogen, C,_, alkyl, C;_, alkoxy, fluoro or chloro, and mis 1, 2 or 3, oo Co , Co with the provisos that both Rg and Rg, must be hydrogen when Ry is hydrogen, Rg, must be
Co hydrogen when Rg is hydrogen, not more than one of . } R, and Rg is trifluoromethyl, not more than one of
R, and Rg is phenoxy and not more than one of Ry and Rg is benzyloxy,
Ry is hydrogen, Ci a alkyl, Cig cycloalkyl, Ci_a alkoxy (except t-butoxy), ’ trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, ’ . . Ry is hydrogen, C,_3 alkyl, Ci.3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the provisos that Ry must be hydrogen when R, is hydrogen, not more than one of
R, and R, is trifluoromethyl, not more than one of
R, and Ry is phenoxy, and not more than one of R,
IE ~ and Ry is benzyloxy.
Gee) oe BAD ORIGINAL . ’ | n— senarbmemaiid
HX10b -5- X is -(CH,) - or -CH=CH- (n=0, 1, 2 or 3), . Rg a : 5 4 3 2 1 to
Z is -CH-CH,~-C—CH,-COOH II
I 2° 2 ; 5 OH " OH wherein Rg is hydrogen or C13 alkyl in free' acid form or in the form of a physiologically- hydrolysable and -acceptable ester or a § lactone thereof or in salt form.
Coo TTT GB 2162-179-A discloses naphthyl analogues °° - of mevalolactone useful as cholesterol biosynthesis inhibitors having the structure le Me is qr
CCT oo
Ry wherein Ry = 1=-3C alkyl; : 2 is a gp. of formula 2 or Z,:
H OH
- (HCH, CHCH, COOR, ot “H
OH OH 0 ’ 0 (24) (z,) : : : R, = H, a hydrolysable ester gp. or a cation. :
BAD ORIGINAL
. oo Co : mt re or pimp = 24 1:4
HX10b 6
European Patent No. 164-698-A discloses To preparation of lactones useful as anti-hyper- : cholesterolemic agents by treating an amide with - i . an organic sulphonyl halide R®SO,X, then removing ) the protecting group Pr. rl R ' 0 S 1 . PrOem; 3.4 RSOX How! 0
H R-R — : i OH H i 10 0 : . rR? i : : wherein X = halo; oo
Pr = a carbinol-protecting group; .
R' = H or CH,; : rR, rR? = H, 1-3C alkyl or phenyl-(1-3C . : alkyl), the phenyl being optionally substituted by 1-3C alkyl, 1-3C alkoxy or halo;
R® = a group of formula (A) or (B): : . . 0 ’ } — ~~ ny | J .
CH, IH ; z q : Hy R R fides (A) ] (B) r?
I
: Q = R®-c- or r®-cH ;
Can Vo! (
CL cH, BAD ORIGINAL - - = id
HX10b -7- r® = H or OH; : : Le R = Hor CHy; : LL a, b, ¢c and d = optional double bonds; : - ’ Rr’ = phenyl ox benzyloxy, the ring in each case being optionally substituted by 1-3C alkyl or : halo;
R8, rR? = 1-3C alkyl or halo; - rR = 1-3C alkyl, phenyl or mono- or di-(1-3C alkyl)phenyl. °°. . 10 ..-... Anderson, Paul Leroy, Ger. Offen. oo " DE 3,525,256 discloses naphthyl analogs of mevalonolactones of the structure
Me 2) Me
H OH
H 2 _ 7 . Se=c” SHCH,QHCH, COR ° .
NK Se
OH OH
1 0
R Q
Q' . 1. = 1.7 _ wherein R™ is alkyl, 2 =9Q, Q ; R =H, or a hydrolyzable ester group useful as inhibitors of : cholesterol biosynthesis and in treatment of . atherosclerosis. ) 25 . WO 8402-903 (based on U.S. application serial No. 460,600, filed January 24, 1983) filed in the name of Sandoz AG discloses mevalono-lactone analogues useful as hypolipoproteinaemic agents - having the structure : -
X-2 Rea
Ro 1 R 2 5 ‘ I
Co 3 BAD ORIGINAL : | RS L : meee 4 1 N
HX10b -8- wherein the two groups Ro together form a radical
Id of formula a - 8 7 6 5 oo -+-C=C=~C=2¢C or =(CH,) ,~
Ry Ry : . wherein R, is hydrogen, C, , alkyl,
Crm “10 ¢,, alkéxy; (except t-butoxy), trifluoromethyl, . =. fluoro, chloro, phenoxy or benzyloxy, . : R, is hydrogen, Ci.3 alkyl, Ci.3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or ot benzyloxy, with the provisos that not more than one of R, and R, is trifluoromethyl, not more than : one of R, and Ry is phenoxy, and not more than one .
Co of R, and R, is benzyloxy,
Ry is hydrogen, Ci-6 alkyl, fluoro, chloro or benzyloxy,
Ry is hydrogen, Ci-a alkyl, Ci-4 alkoxy, : (except t-butoxy), trifluoromethyl, fluoro, : chloro, phenoxy or benzyloxy,
Rg is hydrogen, Ci_3 alkyl, Ci_3 alkoxy, . trifluoromethyl, fluoro, chloro, phenoxy or . 25 benzyloxy,
Reo is hydrogen, Ci-2 alkyl, Ci-2 alkoxy, : fluoro or chloro, and with the provisos that not } more than one of R, and Re is trifluoromethyl, not more than one of R, and Rg is phenoxy and not more than one of Ry and Rg is benzyloxy, : H CH } \ A 2'q
X is -(CH,) -, JE = “W . =(CHy)q BAD ORIGINAL Co
HX10b : : -9- wherein n is 0, 1, 2 or 3 and both g's are 0 or ‘ one is 0 and the other is 1, Te
Z is '
Re :
Co 5 4 3 2 1 -CH-CH.,—C-CH,-COOH I1
Co 2 | "2
OH OH: wherein Re is hydrogen or Ci.3 alkyl, with
RE, 10 the general proviso that -X-Z and the R, bearing - phenyl group are ortho to each other; : in free acid form or in the form of a physiologically-hydrolysable and acceptable . ester or a § lactone thereof or in salt form.
U. S. Patent No. 4,613,610 to Wareing (assigned to Sandoz) discloses a series of Co 7-pyrazolo-3,5~dihydrohept-6-emnoic acid HMG-COA = oo reductase inhibitors of the structure
Rg
Rg R,
Rj Ry 4
X-2
N~ S .
R
R, 1 - wherein.
Ry is C;_g2lkyl not containing an asymmetric carbon atom, each of R, and Rg is independently . hydrogen, C,_zalkyl, n-butyl, i-butyl, t-butyl, pr ORIGINAL . an intima
HX10b -10-
Cc; _jalkoxy, n-butoxy, i-butoxy, trifluoromethyl, fluoro, chloro, phenyl, phenoxy or benzyloxy,.- each of Ry and R'is independently : hydrogen, C,_zalkyl, C,.zalkoxy, trifluoromethyl, - fluoro, chloro, phenoxy or benzyloxy, each of R, and R, is independently hydrogen, C,_palkyl, C,.p2alkoxy, fluoro or chloro, : with the provisos that not more than one of R, and
Ry is trifluoromethyl, not more than one of R, and
A N 4 "Ry is phenoxy, not more than one of R, and Ry is - : : benzyloxy, not more than one of Rg and Re is . trifluoromethyl, not more than one of Rg and Rg is phenoxy, and not more than one of Rg and Rg is . benzyloxy, :
X is = (CH, ) =» -CH=CH-, -CH=CH-CH,- or -CH,-CH=CH~, wherein m is 0, 1, 2 or 3, and
Z is
CHa OH
Rio -CH SC ’ . ~CH-CH,~G~CH,-COOR, or | | Riot ‘ OH OH Oo CH ~ . NLS 2 c :
R wherein Rio is hydrogen or C;_3alkyl, and R;q is hydrogen, Ri, or M, wherein : R,, is a physiologically acceptable and : hydrolyzable ester group, and . 30 . Mis a cation, with the provisos that (i) the -X-Z group is in the 4- or 5-position of the pyrazole ring,
BAD ORIGINAL
Se MS cota tasters
HX10b ) -11-~ and (ii) the Ry group and the -X-2 group are ortho to each other. i
WO 8607-054A (Sandoz-Erfindungen) discloses imidazole analogues of mevalonolactone, uscful for. treating hyperlipoproteinaemia and : atherosclerosis, which have the formula . Ry X-2 - . mn ee me = 10 - ) — ( . i N N-R, (1) . hd
Ry = alkyl, cycloalkyl, adamantyl-l or Ryo : Rg, Rg-substituted phenyl (gp. A); y R, = alkyl, cycloalkyl, adamantyl-1l or R., )
Rg, Rg-substituted phenyl (gp. B): : : Ry = H, alkyl, cycloalkyl, adamantyl-1, styryl or Rig Rye R,,-substituted phenyl (gp, C);
X = = (CH, ) p= -CH=CH-, -CH=CH-CH, - or -CH,~-CH=CH~; . m= 0-3; z = -CH(OH)-CH,-C(R, 5) (OH)~CH,-COOR, , (gp. a), -Q-CH,-C(R; 5) (OH)-CH,-COOR, 4 (gp. c) or a gp. , . of formula (b):
HX10b -12- - CH, : : ~~ } : —CH CN -
SS | | R13 \ Se :
G
I! : o : © Q = CO or -C(OR; 5),
Rig = primary or sec. alkyl; each Rg being : . the same; . or Rig + Rg = (CH, ), or (CH, ) 4;
Ri, = H or 1-3C alkyl: :
Rig = H, Rig or M; .
Rie = ester gp.:;
M = cation; ° ’ provided that Z may be gp. (c) only when X Co is CH=CH or CH, -CH=CH and/or when Rig = 1-3C alkyl;
Ry. R, and Rig = 1-3C alkyl, n-, i- or t-butyl, 1-3C alkoxy, n- or i-butoxy, CF, F, Cl,
Br, phenyl, phenoxy or benzyloxy; i
Rg. Rg and Ry = H, 1-3C alkyl, 1-3C alkoxy, CFs, F, Cl, Br, COCR, 4, N(Ryg) 5 phenoxy or benzyloxy: .
R;;, = H, Ryg or M;
Rig = 1-3C alkyl, n, i- or t-butyl or benzyl; : Rig = alkyl;
Rg. Ry and Ris = H, 1-2C alkyl, 1-2C alkoxy, F or Cl; provided that ayia G0
: HX10b -13~- . (1) not more than one substituent of each. of gps. A, B and C is CFs, not more than one Co substituent of each of gps. A, B and C is phenoxy, and not more than one substituent of each of gps,
A, B and C is benzyloxy: : : (2) when Zz is gp. (cc; Q = C(OR,g)5) the compound is in free base form and either (i) Rig : is Rie and each Ry is independently R; 4 or (ii) .
Rig is M and each Rin is independently Rig or M;
Ce 10 and oo (3) when R;, and/or at least one Ry is M, the compound is in free base form.
Unless otherwise stated, all "alkyl" gps.
Lt are 1-6C and do not contain an asymmetric C; and "cycloalkyl" has 3-7C. To , WO 8603-488-A (Sandoz AG) discloses indene
ToT Co analogues of mevalolactone; useful as EE wo . . hypolipoproteinaemia and anti-atherosclerotic agents, in free acid form or in the form of an ester or delta-lactone or in salt form which have the formula
R .
Co 3 R o (I) i
X-2Z . R R
Ry 1
R = H or primary or secondary 1-6C alkyl;
Ry = primary or secondary 1-6C alkyl; } or R + Ry = (CH, ) pn or (Z2)-CH,-CH=CH-CH,;
BAD ORIGINAL ae . — —
HX10b -14- m= 2-6; .
R, = 1-6C alkyl, 3-7C cycloalkyl or Rys Reg, : Ro-substituted phenyl; ~ 3 Ry, Ry = H, 1-4C alkyl, 1-4C alkoxy (except : 5 t-butoxy), CFy, F, Cl, phenoxy or benzyloxy; oo Ry and Re = H, 1-3C alkyl, 1-3C alkoxy, . CF,, F, Cl, phenoxy or benzyloxy;
R, = H, 1-2C alkyl, 1-2C alkoxy, F or Cl; provided that there may only be one each of
Co 10 CFq, phenoxy or benzyloxy on each of the phenyl ; and indene rings; :
X = (CH), or -(CH,) (-CH=CH(CH,) o~; n= 1-3; : both g's = 0, or one is 0 and the other is 1; : 2 = -Q-CH,-C(R,,)(OH)-CH,COQH, in free acid form or in the form of an ester or delta-lactone or salt; . : Q = CO, -C(OR,),- or CHOH; - 20 R'og = the same primary or secondary 1-6C alkyl, or together are (CH,), or (CH, ) 3:
Rig = H or 1-3C alkyl; . provided that Q may be other than CHOH only when X is CH=CH or CH, ~CH=CH and/or Rig is 1-3C alkyl.
U. S. Patent No. 4,647,576 to Hoefle et al (Warner Lambert) discloses new C- and N-substituted to pyrrole(s), useful as hypolipidaemic and hypocho- lesterolaemic agents, which have the formula
HX10b -15~- - H_ (OH i R x" * ' 2A > a ° 0 (ry
Rs R4 . H OH mn 1 X COOH | i
R X 2 rN a CORY” (I1) —_— H © a R3 Rg : ! ! a } | X = -CH,~, CH, CH, = or ~CH(CH4 )CH,-; Cel ' Ry = 1- or 2-naphthyl; cyclohekyl; tn A oo ’ norbornenyl; phenyl optionally substituted by F, cl, OH, CF, 1-4C alkyl, 1-4C alkoxy or 2-8C i" 20 alkanoyloxy; 2-, 3- or 4-pyridinyl or their
N-oxides; or o
R..hal : : , ® 5 . “+ 7 >N +
Rg = 1-4C alkyl; hal = chloride, bromide or iodide; - Lo R, and Ry = H, Cl, Br, CN, CF,, phenyl, 1-4C alkyl, 2-8C carboalkoxy, -CH,ORg or -CH,OCONHR.,, ;
Rg = H or 1-6C alkanoyl;
HX10b -16- . } R, = alkyl or phenyl optionally substituted " by Cl, Br or 1-4C alkyl; Lo : or R, and Ry together = -(CH,) =, tL -CH,OCH,~, -CON(Rg)CO- or -CON(Ry)N(R,,)CO-; : n= 3 or 4;
Rg = H, 1-6C alkyl, phenyl or benzyl;
Ry and Rio = H, 1-4C alkyl or benzyl;
Ry = 1-4C alkyl, cyclopropyl, cyclobutyl or
CFy.
European patent application 0 221 025 Al Co (Sandoz AG) discloses heterocyclic analogs of ~ mevalonolactone and derivatives thereof having the formula
Rc Rb / A
Y
Rd Ra : - wherein
Ra is a group -X~2Z, Rb is R,, Rc is Ry. Rd is R, and Y is a group -N- or
Ra is R,. Rb is a group -X-2, Rc is R,, Rd . is R, and Y is 0, S or a group -N-i
Ry Co
La Ry, Ry and R, independently are Cig alkyl not containing an asymmetric carbon atom,
C,_ncycloalkyl or a ring
HX10b -17-
Rg | : - | 5 Co . 5 2 R. . or in the case of R; and Ry additionally hydrogen or for R, when Y is O or S ~ Fis 10 . : } 7° = Np 17 19 whereby Ry4 is hydrogen or C,_3alkyl and Rig and .
Rig are independently hydrogen, C,.3alkyl or . phenyl; each Rg is independently hydrogen,
C,.32lkyl, n-butyl, i-butyl, t-butyl, C,_zalkoxy, n-butoxy, i=butoxy, trifluoromethyl, fluoro, ) ) chloro, bromo, phenyl, phenoxy or benzyloxy; @ach' = ‘ Co ‘Ry is independently hydrogen, C,_jalkyl,
C,_3alkoxy, trifluoromethyl, fluoro, chloro, bromo, phenoxy or benzyloxy and each R, is independently hydrogen, C,.palkyl, C,_,alkoxy, : fluoro or chloro with the proviso that there may only be one each of trifluoromethyl, phenoxy or benzyloxy in each ring A present. X is (CH, ) py or (CH, ) (CH=CH(CH,) 4. mis 0, 1, 2 or 3 and both q's are 0 or one is 0 and the other is 1.
Rg
K: is ~CH-CH, -(~CH, ~COOH - OH OH wherein Ry is hydrogen or C,_3alkyl, : in free acid form or in the form of an ester of
B-lactone thereof or in salt form as appropriate
HX10b -18- which compounds are indicated for use as hypolipo- oC proteinemic and anti-atherosclerotic agents. . } Tetrahedron Letters, 29, 929, 1988, : discloses the synthesis of a 3-Hydroxy-3-methyl- glutaryl coenzyme A reductase inhibitor of the structure
F
OH OH ©
R ore To . F Hy CH, : where R 1s Na or C,Hg- } . European patent application 127,848-A (Merck & Co, Inc.) discloses derivatives of 3-hydroxy-5- thia-w-aryl-alkanoic acids having the structural formula:
HO 0 . , % $00), :
E
. 7 ~ . wherein Z is: :
HX10b -19- . ~~ gr® r? | : “C3 ’ oC
RS
’ R® . nis 0, 1 or 2;
E is -CH,-, -CH,-CH, =, -CH,-CH,-CH =, -CH=CH-CH, =; or -CH,-CH=CH-; : or To
Ry, R, and Ry are, e.g., hydrogen, chloro, bromo, fluoro, C,-alkyl, phenyl, substituted phenyl or OR, in which R, is, e.g., hydrogen, . C,_galkanoyl, benzoyl, phenyl, substituted phenyl, C,_galkyl, cinnamyl, C,.4haloalkyl, allyl, :
Ce Co cycloalkyl-C,_salkyl, adamantyl-C, salkyl, = phenyl C,_3 21kyls 6 ’ : “R*, R’ and R° are hydrogen, chloro, bromo, fluoro or Ci-3 alkyl; and
X is, e.g., hydrogen, Ci.3 alkyl, a cation derived from an alkali metal or is ammonium.
Those compounds have antihypercholesterolemic activity by virtue of their ability to inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and antifungal activity. " French patent application 2,596,393 A filed on April 1, 1986 (Sanofi SA) discloses 3-carboxy-2-hydroxy-propane-phosphonic acid = derivatives including salts thereof which are useful as hypolipaemic agents and have the formula: i ’
HX10b } : ~20- 9
R,00C-CH,~C~-CH,~-P . : 1 277727 : OH OR, 5 . wherein Ry and R, = H, lower alkyl or optionally substituted aralkyl;
R, and Ry = H, lower alkyl or optionally substituted aryl or aralkyl. : These comounds are disclosed as giving = greater reductions in cholesterol, triglyceride . and phospholipid levels than meglutol.
European patent application 142,146-A (Merck
Co & Co., Inc) discloses mevinolin-like compounds of the structural formula: . HO o or! , Z0
E } : 7 : wherein: rl is, e.g., hydrogen or Cy _4alkyl;
E is -CH,CH,, -CH=CH-, or -(CH,) = and
Z is
HX10b -21- 0 :
Co vo Co
Rg © © © TT 10 ‘wherein X is -0- or -NR? wherein R® is hydrogen or ;
C1-zalkyls
R" is C,_galkyl; and
R® is hydrogen or CH 5; . 2) i 15 ate : rl? wherein r'O, rll and r12 are independently, e.g., hydrogen, halogen or C,_galkyl; } . 3)
HX10b -22~ ’ wherein n is 0-2 and R'* is halo or C,_gqalkyl; or 4) -, | - B . o so A . rR’ Oo . : H
So 10 : (RY) >
These compounds are HMG-CoA reductase . inhibitors. 15 . : In accordance with the present invention, " there is provided phosphorus-containing compounds which inhibit the enzyme 3-hydroxy-3-methylglutaryl- : coenzyme A reductase (HMG-CoA Reductase) and thus are useful as hypocholesterolemic agents and
Co include the following moiety : 25 0 -P-CH,-CH-CH,-CO- ’
X bu ' 2 wherein X is ~(CH,) = ~CH=CH-, -C=C- or -CH,0- (where O is linked to 2), "a" is 1, 2 or 3, and Z is an "hydrophobic anchor".
The term hydrophobic anchor as employed herein refers to a lipophilic group which when
HX10b -23- : " linked to the HFMG-like upper side chain of the - " molecule by the appropriate linker ("X"}, binds to Co i a hydrophobic pocket of the enzyme not utilized in binding the substrate HMG CoA, resulting in : - 5 enhanced potency relative to compounds where Z=H.
In preferred embodiments, the compounds of : the invention have the formula I
SO i x } eee eee 10 LL R-P-CH,-G-CH,=CO,R i i — . 1 OH . wherein R is OH or lower alkoxy:
R* is H or lower alkyl; :
X is CH,, ~CH, CH, =, -CH,CH,CH,-, -CH=CH-, -C=C- or -CH,0- (where O is linked ta Z); Co
Z is a hydrophobic anchor; ‘ and including pharmaceutically acceptable salts thereof. :
The terms "salt" and "salts" refer to basic salts formed with inorganic and organic bases.
Such salts include ammonium salts, alkali metal ~ salts like, lithium, sodium and potassium salts (which are preferred), alkaline earth metal salts ljike the calcium and magnesium salts, salts with organic bases, such as amine like salts, e.g., dicyclohexylamine salt, benzathine, N-methyl-D- - glucamine, hydrabamine salts, salts with amino acids like arginine, lysine and the like. The nontoxic, pharmaceutically acceptable salts are preferred, although other salts are also useful, e.g., in isolating or purifying the product.
HX10b i -24- : " Examples of hydrophobic anchors which may be ‘ included in accordance with the present invention include, but are not limited to - al r2 :
Co { E : 3 p22 : 8
R i r3
Co N
R r4 : . . 3 4 3 . R 7 R r3 or we R ~~ / / a N ’ —_— N ’ : N= 0 ri0 rH R
HX10b -25- - i 8 ) . . 3 4 .. R oF .
R R 4 12 27 RANT A _ , \ ¢ , || , 210 R11 glo Z9 . rR2 R . | 10 me - - EE ) 3 = - ae en i Ca -
R3 N r?
Tr JL ec” als R16 N 50
R r23 : oo . g23a : 20 . . r® : 0 : alkyl ; . 5 1 or k 6a ] RY (R77) q
HX10b : -26- wherein the dotted lines represent optional double bonds, for example, oo 6
RS R
: 0 0 : alkyl alkyl 1 . rR RO :
EE 10 ‘ '
R> 6a R 6a ‘ (R Vg - 6 (R Yq r® R™ . 0 alkyl alkyl r> gS" . " RY (R%%) rR’ | (R%%) i r® r® ] o - 0 alkyl’ alkyl , or 5 6a RS g62 ’
R (R Vg ( Yq -
BAD ORIGINAL
HX10b -27-
RS . oo : alkyl . :
I
R (r%2) q wherein rl, grZ, rR%2 and r2P may be the same or different and are each independently selected from
H, halogen, lower alkyl, haloalkyl, phenyl, substituted phenyl or orY wherein RY is H, . alkanoyl, benzoyl, phenyl, halophenyl, phenyl-lower alkyl, lower alkyl, cinnamyl, haloalkyl, allyl, cycloalkyl-lower alkyl, " ~adamantyl-lower alkyl or substituted phenyl-lower : alkyl. .
Where Z is . RS ’ 0 alkyl ’ : rR’ 6a
R
( 'q
R® and R>' are the same or different and ’ are H, lower alkyl or OH; ete alte wi FP
HX10b -28- 0 0 , 6 ] n i! “R” 1s lower alkyl-C such as CH,-CH,-C-C-, 3 TN 7 oe CHj R .or arylCHj-; So
R®2 is lower alkyl, hydroxy, oxo or halogen; qis 0, 1, 2 or 3, and rR’ is H or lower alkyl. i:
Soros 0 10777. Where 2 is gd ; * (0 . | | K
Co Co rd 3 4 3 4
R R 3 4 pg R : z AR? FY / / \ : . N —N r — N ! — N 4. 0
R10 RO r10 . 4 3 4 r3 / _r? r3 AN R R N R
N \ _ . or \ / - 0 5 16 r10 all R R R
ARTS
: | . BAD ORIGINAL
Woes ce ona anadng. mh 2 M "
HX10b -29-~ p13 one of r3 and r? is ~X and : | | — gl4 pléa the other is lower alkyl, cycloalkyl or phenyl-(CH,) -, p is 0, 1, 2, 3 or 4; wherein R is hydrogen, lower alkyl, lower © alkoxy, (except t-butoxy), halogen, phenoxy or benzyloxy; :
Coot 710 rl? is hydrogen, lower alkyl, lower alkoxy, oo . halogen, phenoxy or benzyloxy; r142 is hydrogen, lower alkyl, lower alkoxy, or halogen; and with the provisos that both p14 and gl4a must ’ 15 be hydrogen when g13 is hydrogen, rid? must be hydrogen when rl is hydrogen, not more than one of p13 and rl% is trifluoromethyl, not mére than one of : . r!3 and R'* is phenoxy and not more than one of r13 and rl? is benzyloxy; 20 . r® is hydrogen, C;_, alkyl, Cy _¢ © cycloalkyl, Cig alkoxy (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy; : ’ RY is hydrogen, Cy _3 alkyl, C;_, alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the provisos that r® must be hydrogen when R® is hydrogen, not more than one of RS and rR? is trifluoromethyl, not more than 1
BAD ORIGINAL ihe eminem
Co HX10b -30-
Lo one of R® and R® is phenoxy, and not more than one of R® and Rr? is benzyloxy. Le
RYO and pil are independently selected from " . } hydrogen, alkyl, cycloalkyl, adamaniyl-1l or 13 -(CH,) _ : 2'qg 1 X gl4 : gléa ; 10 - i where r13, p14 and rl4a are as defined above and . .q@=0, 1, 2, 3 or 4.
Y is 0, S or N-r1O.
Where Z is : R 12 | :
RS 2 RP : :
Co i
R? is H or primary or secondary 1-6C alkyl;
RP is primary or secondary 1-6C alkyl; or R? + RP is (CH,), or (cis)-CH,-CH=CH-CH,; ~ r =2, 3, 4, 5 or 6;
BAD ORIGINAL
Co . . se ma iano vrs 8h -
HX10b : -31- 12
R is lower alkyl, cycloalkyl or : gl3 / rl4
R 4a ~ a. ~ 10 wherein r®, r?, r1?, rR! and rR? are as defined : above. : when 2 is 3 4
LN
37 15 16
R and R are both H, Cl, Br, CN, CE, phenyl, 1-4C alkyl, 2-8C alkoxycarbonyl, ~cH, or’ or ~CH,,0CONHR%; 817 is H or -1-6C alkanoyl;
R18 is alkyl or phenyl optionally : substituted by F, Cl, Br or 1-4C alkyl; or r1® and r16 taken together are -(CH,) -, ~CH,OCH,-, -CON(R*?)c0-, or -coN(R2%)N(r?1)co-;
Oh oY Tan
HX10b ~-32-
S = 3 or 4; Co r9 = H, 1-6C alkyl, phenyl or benzyl; oo r20 and R21 are H, 1-4C alkyl or benzyl; : : with the added proviso that when Z is oo ~ -10 rlS BN rl6
X can only be -CH,-, -CH,CH,~ or -CH,CH, CH, .
Co Where Z is : 23 ,
PE 20 r232a ee,
Bb (0) = - : : r23 . p23a :
HX10b -33- : 22 : R is lower alkyl, cycloalkyl, adamantyl-1 i or -(ct;) 0) + " : t =1, 2, 3 or 4; r*3 and R?32 are the same or different and are each independently selected from hydrogen, lower alkyl, lower alkoxyl (except t-butoxy), halogen, phenoxy or benzyloxy; and . with the provisos that R232 nust be
Co : hydrogen when R23 is hydrogen, not more than one of r?3 and g23a is trifluoromethyl, not more than : one of r23 and r23a is phenoxy, and not more than . one of r?3 and R332 jg benzyloxy. Co
Where X is -CH,0~ (carbon attached to P and
O attached to 2), the hydrophobic anchor 2 will be : a phenyl or naphthalene type anchor such as . or 2a ~ 1 r rR? R or (oc; 2b 2 : R R p22
HX10Db -34- i Thus, the compounds of formula I encompass . 0 Tos
H xX . Ia R-P-CH,-CH-CH,-CO,R Co
C OH ,
Hn .
C : 1
Z - oO . Ib R-P CH, ~CH~CH, CO, RX . R-B-CH,-CH-CH,-CO,
TTYL TTI CH OH ' cH (cis) . ’ 2 . 0 . I x
Ic R-P-CH,-CH-CH,~CO,R
CH OH '
CH (trans) : 2 - . 9 : x .
Id R-P-CH,-CH-CH,~CO,R : : | CH, OH ro
CH, . 2
HX10b -35-~
Ie R-P-CH,-CH-CH,-CO,R Co
CH, OH = CL, : z o
If R-P~CH.,~CH~CH., CORY i 2 = 2 2 (CH) 3 Cii , : Z oo 10 i . 0 1g R-P-CH. ~CH-CH,-CO,R® i 2 3 2 2
CH, OH | ' . 0 4
The term "lower alkyl" or "alkyl" as employed herein alone or as part of another group includes both straight and branched chain hydrocarbons, containing 1 to 12 carbons in the normal chain, preferably 1 to 7 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethyl- pentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, . undecyl, dodecyl, the various branched chain isomers thereof, and the like as well as such groups including a halo-substituent, such as F, Br,
Cl or I or CE, an alkoxy substituent, an aryl substituent, an alkyl-aryl substituent, a haloaryl - substituent, a cycloalkyl substituent, an alkyl- cycloalkyl substituent, hydroxy, and alkylamino substituent, an alkanoylamino substituent, an aryl- Co carbonylamino substituent, a nitro substituent, a
HX10b -36- "cyano substituent, a thiol substituent or an alkylthio substituent.
The term:"cycloalkyl" as employed herein . alone or as part of another group includes ’ saturated cyclic hydrocarbon groups containing 3 to 12 carbons, preferably 3 to 8 carbons, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyulooctyl, cyclodecyl and cyclododecyl, any of which groups may be substi- oo 10 tuted with 1 or 2 halogens, 1 or 2 lower alkyl .
Co groups, 1 or 2 lower alkoxy groups, 1 or 2 hydroxy groups, 1 or 2 alkylamino groups, 1 or 2 alkanoyl- amino groups, 1 or 2 arylcarbonylamino groups, 1 or . 2 amino groups, 1 or 2 nitro groups, 1 or 2 cyano groups, 1 or 2 thiol groups, and/or 1 or 2 alkyl- } thio groups.
The term "aryl" or "Ar" as employed herein refers to monocyclic or bicyclic aromatic groups containing from 6 to 10 carbons in the ring 200 portion, such as phenyl, naphthyl, substituted phenyl or substituted naphthyl wherein the substituent on either the phenyl or naphthyl may " be 1, 2 or 3 lower alkyl groups, halogens (Cl, Br or F), 1, 2 or 3 lower alkoxy groups, 1, 2 or 3 hydroxy groups, 1, 2 or 3 phenyl groups, 1, 2 or 3 alkanoyloxy group, 1, 2 or 3 benzoyloxy groups, 1, 2 or 3 haloalkyl groups, 1, 2 or 3 halophenyl . groups, 1, 2 or 3 allyl groups, 1, 2 or 3 cyclo- ~- alkylalkyl groups, 1, 2 or 3 adamantylalkyl groups, 1, 2 or 3 alkylamino groups, 1, 2 or 3 alkanoyl- amino groups, 1, 2 or 3 arylcarbonylamino groups,
CL, 2 or 3 amino groups, 1, 2 or 3 nitro groups, 1,
ERLE SPA cyano groups, 1, 2 or 3 thiol groups, and/or
BAD Orica 1
Cee da
: HX10b -37- © 1, 2 or 3 alkylthio groups with the aryl group ; : preferably containing 3 substituents.
Co + The term “aralkyl”, "aryl-alkyl" or . . "aryl-lower alkyl" as used herein alone or as part of another group refers to lower alkyl groups as discussed above having an aryl substituent, such as benzyl. : The term "lower alkoxy", "alkoxy", or varyloxy" or "aralkoxy" as employed herein alone or
Cee 10 as part of another group includes any of the above EE lower alkyl, alkyl, aralkyl or aryl groups linked to an oxygen atom.
The term "lower alkylthio", "alkylthio", . "arylthio" or "aralkylthio" as employed herein alone or as part of another group includes any of the above lower alkyl, alkyl, aralkyl or aryl groups linked to a sulfur atom. : Co } The term "lower alkylamino", "alkylamino", "arylamino", "arylalkylamino" as employed herein alone or as part of another group includes any of : the above lower alkyl, alkyl, aryl or arylalkyl - groups linked to a nitrogen atom.
The term "alkanoyl" as used herein as part of another group refers to lower alkyl linked to a carbonyl group.
The term "halogen" or "halo" as used herein refers to chlorine, bromine, fluorine, iodine and
CF, with chlorine or fluorine being preferred. - Preferred are those compounds of formula I which have the following structure
BAD ORIGINAL
. Jy anes CE
HX10b -38- 11 RQ CH, H CH, , p” “Nc” "Sco r® ) = 2
X ~ ’ { = : 2 OH . ‘ .
Bh wherein R is OH, OLi or CHO; R® is Li or H; : X 1s -CH,-, -CH,CH,-, -CH,CH, CH, , -CH=CH-, - =C=C- or -CH,0-; and
Z is 1 2 : 1.
R R wherein Ris phenyl or phenyl which includes an alkyl and/or halo substitutent, | R23 rR! is cycloalkylalkyl such as cyclohexylmethyl, . or r! is benzyloxy which includes a halo substituent; rR? and r?2 are the same and are hydrogen, halogen or lower alkyl; : 1 . . R
Z may also preferably be * 06 wherein rR: and rR? are as defined immediately above “ with respect to the compound of formula II; "30 r3
Z may be also preferably be .-. ) * 4 vo
RO
HX10b -39- wherein rR3 is substituted phenyl, lower alkyl, ‘ cycloalkyl or phenylalkyl and R* is substituted . phenyl, lower alkyl, such as isopropyl, cycloalkyl } + or phenylalkyl; or - : 6
No : zw
Z may also preferably be to me ee 210 J . . | | RS wherein R° is H, CH; or OH and R® is :
Oo . Co _- CH, oo
CH, ¢ or (substituted)phenylmethyl “3 Rr’ wherein R’ is H or CH, . to : Z may also preferably be \ , 3 3
R 3 4, R
R z R J oF R \ AY .
N
/ 3 a ' A . 10 | ] 0 rl wherein at least one of r3 and r? are phenyl or substituted phenyl and the remaining r3 or rt is - lower alkyl.
The compounds of formula I of the invention may be prepared according to the following reaction sequence and description thereof. . . ] Pa
~40-. HX10p : .
Q . : . ~~ . 7 > : :
Ad QQ u ~ Q od : Lis) « Q 5a ‘ Oo ™ ~ = oO x Q =r . © l Q o o u oN ~~ wn od -— ] oo . I) ee] Q e+] ~ ~ co 0 i © a > :
CE i HH _~0 > a 0
Swng = . HH y | «“ , o ND \m i a - 0 — . a Q oO > ’
E 1 CM § O=a4—0 = o . oO oN ~m
Bu —~ oO ~~ - o — ~ O wn he! QO Q. oO
E = “° > 3 OnQO=tn" °
Q cS 1 Nn . o oe x A=] .
QO ™ + Q Q — O |! = 3 | 5 of ° 2 0 o — x
Qo . © > . 3 Sul 48 . x a al ]5 CN
Cy 2 + — 9 ¥ v ; >
Q < ~ x
Jo) as} — " Q q ™ [21 oN — . ~~ ~ Oo ™ ‘ Zz Cs 3 N 5 nn = — H 0 = = m o ™ ns m ov 0 Q 0 0 — oN ol | I Q a ™ oO 0 0 x - go = wn OQ ™ 3 OMQO-wn i” = OO I 1 — “0 v nn
Foo= wo Mo oo ~ \ = >
Q O—V-0 =&m 5 o~ co xX wo a 1 0 =! =m | ab 0 v od 1 n a I = : a @ = : ov 0=a~-0 0 © Smmm— () . . ~~ 1 2 i ~~ ~N mo 0 + oN — 0 = > 9 0 &
Q { > — (+7 HH — . © .
-41- HX10b —- . po ~~
A > ~~ : a ’ a om —~ oN — [1+
Oo Sm oN ™
RY) x Oo -_~ } o~ Q wn Q a) m =~ m i m
Cv CE og 2 So . = ~/ > Q 0 © 0
Uno = 1 » 1 | Q : i 0 U3 o “A / =
CN \\ = Omo-o > je] o ! \n
Q Q oN = : § —~t x 0 -
O=/-0 © oO 0 Oo=—0Q . — o Co it > o Oo 0O-n ’ 4 of ~~ . —~ Eo! > og © Aq co —~
Q J . . ’ oo ’ . 0
Ls] -{ . 0 1 Po. 0 J Fr4 ~ m O x ’ o 1 oN = — al oa 1 ’ oN £5 ~ 0 $+ ° Qu —_~ ~~ - = . =] Q ~~ HJ OQ =z . 3 wn mm QQ = — | 0
BE co . 2 0 — 0 , ~~ oN . o~ . —_ NY Lo «o 0 Is] m oo m=O Eg oO - +
NNN 1] = PA ox 0 xX = gg 2 HH =z 4 © > oe oO 0 wn NO Yd oe Q
MN —~ o ood -~ mo mo 8 9 oo mL A o A oO nu ov - 59 © CI 2 § nO a = ~ or 9 T Q - = sc ~ . . 1) - 0 = : ~~ Qa 2 OU 0 :
Q
. ~- oN ‘ : H
QO la. ’ = foo ln > O-1 > , x ’
HX10b -42= . a oO . . [o] > . . , d A . Q . —t .
Q
: QU © . £00 rd : <n -
QO > ~~ —~ 0 > MN ] : ~~ TT > nv = .
FR =. ] a) . oO — ~~ . oO ~ oN . on : . 0 . r~
In >
OmoO [od RS : - ’ 1 [=] — o I] ™ xo oN — :
QO . oO ™ i - . Q x
O-A—-0U=0U-N oN 0 uy . x ~~ om
Q . oO oO \0 x i A 0 a) . . ’ jos VA —
UniO=-01 > : 1 uw . . - o foe}
Q Q x : ° o=a=0 } fy cs Q Nm 0 x [o] ~~ QO .A = x > I © . 0 ~ nN — . - oped — 0 = o no
OQ
8 O ~ » OU x © ™ Qo = 0 = rd Q ~ O 1 -
Q ~ + :
Cos 0 =
HO n =3 oN 0 = od : © Oo 0 0 n [i] Q ©
Po 5, H \ E ! ’ Q ah ~ TT + oN - = 0 0 [oH a 3: 3% >| ? > 0 om 0 ~ > + o xn - a x 0 ~ ~ Ln QO m wn Qo x 1 La —{ -~ QO oN —_ —_ v ~Q = — oN 0 =o = 0 1 x
O= A= Y= — =n — : Le. Q NG or
-43- HX10b a on Co, oS ' > } . od to
[4] : ' — } . 0 . . u . - vu 0 o£
How . a > ~ . ~~ 0 > M ~ gg .
Dy nn x — — . >
A . ¢ rel o ™~N ™ . - Q -
QO ™ . . 1 x wn ~ QO = x ~ ©
FT 9,° w x w/ - .
Co OnyO =n wn — 1 \ 5 > oN 0 x oO
Q oN o=d-5_ 1 N=
Oo U— nN oo > .
RS
— . . [}:] . 4 foo oN
QO A i 0 Q
T oN co By x - 0 = © a " i Nd wn ! = +J Qo n= 0 — - om 3 E po. i 9 ~NQ jo] o on = QO ~N o=d-3 1 N= = Q Oe 3
I] x . ’ >
-44- HX10b — = . } a 0 : 0 rd _ A + ] oH 3 } foo] 1 © wn x <td H OT oO UO YH © 1 | Q > Q ! - ox Q
Q - “ o a o i o - A o
A ™ — ~ om = . oO -—0 >
O NE = ~ 0-8
Q x
Hu 0 0
Q 1 —~ ou = . £ mE 0 0 = ole « .H Q i © $n . . + ol H I 5 _ 5 0 =~ ’ g _1 m gs c O=a-0 Q oN
Q QO 0-8 i Qu = g 0 un 0 A = wo o . oO © om £ = g © 0 ! = od - a =
Pon = 0 oo ’
Ho© n-o : ! dM NE - [u} h Hon a A . = a. . * 0 - m a 5 Re of qq < |) - Q g it g eg mm] o 5 6 —~ N - a + op o n & oO Jl = 5 Hoo | =z oT | [es] c > 8 4 0 on os . i 2
Q - 3 m-OUSU-8 :
Q - [
~ 45- HX10b o . o o . > o o — Q. © | 5
Y » 0
Q 0 = Au . 0 a > =. 3 i — oo > oT —~ Dy am : — ~ . _ oo be ie ~ ™ : . o —~ oN ™M oO mm un - *
OO 0 = oN ~~ 0 . £3
Lal,
Omo\=_ 0 =
Oo - — H O n HH oN - = > =o
VS ? a oN = + mon oe
QO — OoMmMmo a 1 = i H U =" N= aL = o O—03 0 : — t =
Oo=f~0
Z . I = — Q O—t3 : < fae) :
-46- HX10b
Co~ — — o> 0] : ~ 5 —~ oo — Co n
Jus] MN co
Oo + H [is] [}} ~— ~— > Iv o 1 oN : ~ ~ fs] H
I N= o=a-~-0U > -~ U—e2 | \ Sd — : Q oo] ~— O03 > > ’ x [03 ~ .
H . Ly) 0 : . 2H i — Tg & : o o } o~ A
T 3 0 —_ 58 -~ own . a 2 <] om wu
OE o oN I
Q. 0 = = pO QO . EO ~o OQ ~ gq 0 E 0 o £3 ~~
QO ~ ~ E co “NN . n ~ a ow HH ~
WA m0 N wW OBE o~ . . 0 Qu co —~ ZZ 0 ~ + @ ~~ M0 Qo Q = m 0 on = O° ~ ox UH —- foo} :
J g~— ~~ oO + ot [LI oN 0 . “un —~ eq o~ oc ~
Qo > ]
ON A op — } . — n ns 0 n oO oN o
CO = m m > Oo a—0Q) > ow I" ~~ } 4 TQ + +1 oi -- H 25 po i. BC
Hon / Q Nz EX ax Q , O—0a = & : ~~ | } <q ~~ oN , — . = og] om 0 0 ~ Oo i] —~ Q n -~
Q » 9 Jo + J
Q g O © © o . co 0 ~~ ~ Se 0 c . - [}] a oxy 1 ~~ 3 o = 9 ~ : 0 Q » oa J I ~ H QU Oo
Q o QL fry T° 9 of i 0 Q Ao foo! > Oo © oO 3 e+ mo a
Q rf
Bs) } . ] 0 — . . } 9 2 H HH
H > o UOm—e3 > >
’ | —47- HX10b a a:
Et o vu «= Qo gx tn
Tm jo2} 221 J 8 = ~ om
Xu . = 9 i} b 5-5 °
Qa 1 - Q } ~ ml oN > _1 = = 5 O=TN= o=9 od o O—-t3 ; o oN . 5 =a-9
OFT “ oO Ome + 0 } % ‘3 —~ : 2 Q 3 3 5 3 8 : o > . > ; ' 2 3 ® . & 0-0 ~ i © py a Vx 0 oN oO © 0 } 5 ~ Ya oe oO / | om 8 o=-U . 5 § Ng o zz 0 0 EH o-t 3 ~ ty joo] HH
P=
O=0=—
Lan] WE £8 5 2 o
-48- HX10b o . Q 7 -~ : . + S g 3 - 5 y = 1 [8 0 0 - QO . ~ sm Sm 0 }
Oo o Uo o o
Cg . og x = |o Co oA n dg MN . ot 0 oO ~ ~ > v ~ 0 A
NS NO ~ 0 Ho ~ d + £7 ~~ d oN 0 = Q A QO . o 1 nw O Uu © : 2 mE OO ! + : 0 . q o . . . I — = mle om P=0 HH 2 ~ g : So
Ga o~ ] ; > . . —_ O=—-0—N . “ ~ ! = 0 > Q o —~ 0 -~ Pa a | © —~ ~4 goo yh Oo HH ~ 3m - m > ©
O=f—~0—t3 5 2 - > £m oe oo QQ
OO o — wo) 5 01 - ~ . cu 0, o
S 0 = ©
Po o © Q@ / o om SH 7S oo ow . © O oH \ a or . . Qo ~ ~ H gs 1 3 on © a vis! - / Er pel @ 2 o-uU 0 = } \ 0 BE a ~~ o [Ls] Ps] Jao] 0 — © 0 oN n MN > . c ~ Xn —H 0 XK
Q U—-0—t3 >< -- = = SAN & -— o .
Q a = 0) © oN
I jos] + o O=—0 —8 +4 o | > 0 i. > * © 0 H 4 0 = HH : ~ : fed 0) —~03 > << ’
-49- HX10b
T, } oO : .
Q
[3 7 mom N om : =p Lh l
NN do —_— ~~ ’ 5 mf e ARR
O=Q—U-n . o } om } - . ! jae] : : n oO or 0 > wu —~ 3 0 Q
MN Q o 3 > o . ] ja] is} : ~~ >
A
—{ [} ™~ -
OQ
O
~ wm 9 : xn x —_ ~~ : o—0 NN ~H Mm i ! nono ” EAL Gt © o “ be ~~ — ar 0 «~ 1 — ~~
O=0L-0- 0 Kf
I~ H oH HH : Oo —
Sy
A
— o
~50- HX10b : 1 .
Q . o~ . ’ oi :
Q
1 cl ~ . 0 —~ 0 rH QO -r4 + ni . 0] Q ’ =< BE . . ~ a - .
Q — 0 oF NN) fy
H — ww oH ~~ |=
Q > m ~~ 10 . = £4 ~~ ZZ 0 mm me =z — vw oO . © = 0 + . . — oO Tg BH ~~ [os
[10] SOX Q —~ ~~ ~~ OAM Q gd —~
J | 0 £ Yd Nl :
H [=] m ' Oo ~~ QO x >| ’ - MO . “ ~~ 0 = 0 E oO ™ . 0 oO a 5
Tg 1 N i. = Q O—n HH — »S 0 > > [eR A > : E joo » — . } 0 O-n I. o oO >
Pe
Ww
EB 0 . je] . o Q
Q — 0 -~ ol < of 3 + Hm n om
Pd Un od > 0 Q - 0 0 - 3 co . . < a> D> 00 3 - . oo, ~~ ~~ QO x i) — 0 <3 0
MN oo 4 > oO - [oN eo moo © : I. > . . Hm . 0 © . Mm > Q
OU -~ 0 @® gx [iM]
Q MO | Mm ~ . . « o— .
Q —t : — = . . Sy o — ~ ~ .
Q — tn oO ~ } co ~ ~ > - 8-5 : o tq — +9 = = N
Q U-n > O—n o
Q ox ]
HX10b . o g . ef : ¥ = 0 9] O 3m 1 gm | m
Q or ol = QO om , o~
Q
~-1 “ > m
A Q |b) 2, 55 8 ? ™ x mw ©) © oO 1 oi _ i O= — o=0 I. 1 N o t+ 2 = . m oi 0 ~ 3
In " o=e—0 . ° No—w . . & a
MM Kal @ = n ct . - o- EEN ~
Io > ied ’ Co 4 " 0 Q ~~ Hof od > ov o|m™ ou > z - = § 8
HD / O . ¢ 0-0 ° ’ © ot 0 Nm = > c oO ! A ; ! ojo / ~
YoY wu " © 0 Ng = 0 oO 0 u ~ we 7 . mo . —_
O—0) to ~. 0 o~ h ) i mn Oe
O=0r—0U H Pom ] 1 \N H O=0+-U)
Q Oo—er ) N
J 2 S oO—tl . > > z o A jo — o os
Co HX10b -52~ SL
As seen in the above Reaction Sequence "A", * compounds of Formula I may be prepared by subjecting iodide A to an Arbuzov reaction by heating iodide A CL oo Fels 0-5i-C(CHz)4
A I-CH,-C-CH,-CO,alkyl and phosphite III : i 111 P(Oalkyl), So i. : employing standard Arbuzov conditions and procedures to form the phosphonate IV ’ 0 . ’
Iv alkylo-p——CH,—CH-CH,-CO,alkyl
I
Oalkyl ~~ 0si-C(CHy)y : Clg CgHg oo " (a novel intermediate) . ’
Phosphonate IV is then subjected to a phosphorus ester cleavage by treating a solution of phosphonate IV in an inert organic solvent, such . as methylene chloride, sequentially with bis(trimethylsilyl)trifluoroacetamide (BSTFA) and trimethylsilyl bromide, under an inert atmosphere such as argon, to form the phosphonic acid V
Co : . BAD ORIGINAL
HX10b -53-~ o i .
V HO-P-CH, ~CH-CH, ~CO, alkyl . OH 0 } __si-e(eny)y
CeHg CeHg (a novel intermediate)
Phosphonic acid V is esterified by treating V in dry pyridine with a lower alkyl alcohol (such as methanol) and dicyclohexyl carbodiimide and the resulting reaction mixture is stirred under an } inert atmosphere, such as argon, to form phosphonic . monoalkyl ester VI (a novel intermediate).
Phosphonic monoester VI is then dissolved in an inert organic solvent, such as, methylene chloride, benzene or tetrahydrofuran (THF) and treated. with trimethylsilyldiethylamine and stirred under an inert atmosphere such as argon, the mixture is evaporated and then dissolved in methylene chloride : : (or other appropriate inert organic solvent). The resulting solution is cooled to a temperature } within the range of from about -10°C to about 0°C, treated with oxalyl chloride and catalytic dimethyl- formamide and then evaporated to give crude phosphonochloridate VII (a novel inter- mediate). The phosphonochloridate VII is dissolved : in inert organic solvent such as methylene chloride, - benzene, pyridine or THF, the solution is cooled to a temperature within the range of from about -90°C to about 0°C and preferably from about -85°C to
HX10b . ~54- : "about -30°C and treated with a cooled (same range as solution of phosphonochloridate VII) solution of : the lithium anion of" acetylene X formed by treating
Lo with a lithium source such as n-butyllithium in hexane or other inert solvent,
X C=CH
Zz employing a molar ratio of VII:X of within the range of from about 3:1 to about 1:1 and : preferably from about 1.5:1 to about 2:1 to form the acetylenic phosphinate XI : 15 . 0
XI alkyl0-P——CH, ——CH-CH,-COjalkyl - Co § e ¢ _Si-C(CH3)y 2 CeHg CeHg (a novel intermediate) : Acetylenic phosphinate XI may then be’ . employed to prepare the various compounds of the present invention as follows.
Acetylenic phosphinate XI is converted to acetylenic phosphinate ial by subjecting XI to silyl ether cleavage by treating XI in an inert - organic solvent such as tetrahydrofuran, with glacial acetic acid and tetrabutylammonium oo fluoride to form ester iat
BAD ORIGINAL . [SUR
HX10b : -55= 2 a : - ial alkylO-E-CH,-CH-CH,~CC,alkyl - .
C OH ih ¢ Ce
Zz : which may then be hydrolyzed to the corresponding basic salt or acid, that is, where RX is R*? which cee 010 is ammonium, alkali metal, alkaline earth metal, _ an amine and the like, by treatment with strong ; base such as lithium hydroxide in the presence of ‘dioxane, tetrahydrofuran or other inert organic . solvent under an inert atmosphere such as argon, at . 25°C, employing a molar ratio of base:ester al of : within the range of /from about 1:1 to about 1.1:1 to form the corresponding basic salt . 0 1A2 alkylO-P~CH.,-CH-CH, CO, -RX? yl10-p-CH,-CH-CH,-C0,
Cc OH 1]
Cc : l 2
Compound 1A2 may then be treated with strong acid such as HCl to form the corresponding acid 3
IA :
HX1Ub -56- ! 1a%. alkylo-B-cH,-gH-CH,-CO,H : Cc OH ; n
S Cc { 2 : The ester IAL may be converted to the corresponding di-basic salt by treating ester al with strong base at 50-60°C employing a molar ratio of base:ester ial of within the range of from about 2:1 to about 4:1 to form 1a : : oo 9 1at R*20-P-CH,-CH-CH,,-CO, R i oo27E 27-72 : Cc OH i .
Cc
I . - a
The dibasic salt ad may be converted to the } corresponding acid by treatment with strong acid. such as HCl to form acid IA.
Phosphinate compounds of the invention where X'is (cis) -CH=CH-, that is, IB are formed by subjecting acetylenic phosphinate XI to selective reduction, for example by treating XI with H, in the presence of a reduction catalyst such as palladium on carbon, palladium on barium carbonate and an inert organic solvent such as methanol to form the silyl ether XII
HX10b -57- - 0 : . XII alkylO-P-CH,—CH-CH,CO,~alkyl
Co ; CH 0
CH _RimC(CH;)5 :
Z CgHg CcHg (a novel intermediate) } 10 ° Silyl ether XII may then be subjected to silyl - ether cleavage and hydrolysis as described above to form the ester IB! : . 9 1B! alkyl0-P-CH,-CH-CH,=CO,-alkyl
CH OH Co . (cis) GH : 2 , i the basic salt 182 12 alkylo-F-CH,~CH-CH,-CO,R"" ; CH OH (cis) GH 2 the acid 1e3
. HX10b -58- . 0 . IB alkylO-§-CH,-CH-CH,-CO,H ) " cH OH (cis) CH
A the dibssic metal salt 184 9 1% R¥*%0-F-CH, -CH-CH, ~CO,R™?
CH OH
(cis) CH «0 Z : oo 15 CL and the corresponding diacid IB. :
Cl Phosphinate compounds of thé invention where X is ~CH,-CH,~, that is, ID are formed by subjecting acetylenic phosphinate XII to catalytic reduction, for example by treating XII with H, in : the presence of a reduction catalyst such as palladium on carbon and an inert organic solvent such as methanol at 50 psi to form the silyl ether ‘ XIII 25 . 0
XIII alkylO-p-CH,—CH-CH,CO,-alkyl
Hy ©
CH, _-Si-c(cH, )3 2 CegHg CeHg (a novel intermediate) :
HX10b -59-
Silyl ether XIII may then be subjected to silyl a : ether cleavage and hydrolysis as described above : : to form the ester 1p? . 0 0 : ip? alkylO-P-CH,-CH-CH,~CO,=alkyl
GH OH
[H2 oo 2 : the basic salt 1D? : 0 l . 1D? alkylo-b-cH,-CH-CH,-CO,R*®
CH OH
12 oo
Re) :
Z . . 3 ’ ’ the acid ID 0 3 1ky10-P-CH,, ~CH~CH, ~CO_H
ID alky O-P- 27 -CH,-CO,
CH, OH
CH, 2 the dibasic salt 1p? - ! 1? R*30-P-CH,~CH~CH,~CO,R"*
GH, OH
CH,
: HX10b -60- and the corresponding diacid ID. )
Referring now to Reaction Sequence "B", - : compounds of Formula I wherein the X linking group between the phosphorus atom and the hydrophobic. anchor Z is (trans) -CH=CH- may be prepared by " treating a mixture of acetylene X and n-C,HySnH with a radical initiator such as azobisiso- butyrylnitrile ¢ .iBN), hydrogen peroxide, benzoyl peroxide and the like, and heating the resulting solution to a temperature of within the range of from about 100 to about 140°C under an inert atmosphere such as argon to form the vinyl stannane XV Co
Sn(n-C Hg), a.
Xv CH :
CH : 2 vinyl stannane XV dissolved in an organic solvent ‘ such as ethyl ether, methylene chloride or } chloroform is treated with iodine and stirred under an inert atmosphere such as argon to form vinyl iodide XVI } '
I
XVI CH
CH
3 oo . A cooled solution of vinyl iodide XVI (-78 : ph © to 40°C) in dry organic solvent such as tetra- hydrofuran, or ethyl ether is treated with a
BAD ORIGINAL j HX10b -61- " metallating agent such as n-blityllithium in an i inert organic solvent such as hexane and the : mixture is cooled at a temperature of from -78 to -40°C under an inert atmosphere such as argon.
The anion is added to a cooled (-78 to -40°C) solution of phosphoncchloridate VII at a molar ratio of XVI:VII of within the range of from about 1:1 to about 2:1 and preferably from about 1:1 to about 1.5:1 in dry inert organic solvent such as tetrahydrofuran, or ethyl ether to form the silyl ether XVII 0
XVII alkylo-F-CH,~CH-CH,-CO alkyl
A : (trans) CH _Osi-C(CHy),
CH Cells CeHg . z (a novel intermediate)
The silyl ether XVII is subjected to silyl ether i cleavage by treating a solution of XVII in an inert organic solvent such as tetrahydrofuran, or acetonitrile with glacial acetic acid and a solution of (n-C, Hy) NF in’ an inert organic solvent such as tetrahydrofuran to form the hydroxy diester ict
Co ct alkylo-P-CH,-CH-CH,~CO, alkyl . (trans) CH Su
CH
: —~
GAD ORIGINAL
HX10b -62-
Diester ict may then be hydrolyzed as described : above to form the basic salt 1c?, : 0 Co 2 i xa
IC alkylo-P-CH,-CH-CH,CO,R ' ' 2 3 2 2 (trans) CH OH < i the acid 1c’ a 3
IC alkylO-§-CH,-CH-CH,-CO,H ,
CH OH cH z the basic salt 1ct : 0 1c? rR*30-P-CH, -CH-CH,-CO,R*®
TT r2T 27-%2!
CH OH
~ . a . b and the corresponding diacid IC 9
I
IC HO-P-CH, -CH-CH, -CO,H
CH OH
Zz
HC oo 2 ; gq
BAD ORIGINAL
. HX10b -63- . In an ‘alternative process, as shown in
Reaction Sequence "C", compounds of Formula I : wherein the X linking group between the - phosphorus atom and the hydrophobic anchor Z is (trans )-CH=CH- may be prepared by subjecting aldehyde VIII
CHO
VIII Z oo 10 to a condensation reaction with a cooled (~90 to } 0°C) solution of dialkyl methylphosphonate and butyl lithium (LiCH,PO(alkyl),) in the presence of an organic solvent such as tetrahydrofuran or . ethyl ether to form the p-hydroxyphosphonate XX : 9 . , P(Oalkyl),
XX HO-CH~CH, : 2
The B-hydroxyphosphonate XX is then treated with p-toluenesulfonic acid in the presence of benzene ‘or toluene while heating to a temperature within the range of from about 50 to about 120°C, preferably ’ at reflux, to eliminate water and form the trans-olefin XXI ) . P(Oalkyl),
XXI (trans) CH - CH b which is hydrolyzed by treating with aqueous 14 alkali metal hydroxide, such as LiOH, in the . vo —
BAD ORIGINAL
HX10b -64- - presence of dioxane or other inert organic solvent and then with acid such as hydrochloric acid to form the monoacid ester XXII . : I alkylO-P-OH
XX11 (trans) CH ch
Z .
A solution of the monoacid ester XXII in dry methylene chloride is treated with trimethyl- } silyldiethylamine. The mixture is evaporated and the resulting oil is taken up in dry methylene . chloride cooled to 0°C and treated with oxalyl chloride and a catalytic amount of dimethyl formamide under an inert atmosphere such as argon ’ to form phosphonochloridate XXIII 0
B alkylo-P-Cl
XXIII (trans) CH . CH :
I
: Zz
Phosphonochloridate XXIII is condensed with an alkyl acetoacetate dianion such as methyl acetoacetate dianion in the presence of an inert organic solvent such as tetrahydrofuran at reduced temperature of -90 to -40°C employing a molar ratio . of phosphonochloridate:dianion of within the range of from about 1:1 to about 0.75:1 to form the ketophosphonate XXIV - . BAD ORIGINAL
] HX10b © -65- 8 9 ]
XXIV alkyl0-P-CH,-C-CH,=CO, alkyl : (trans) CH : }
A
(a novel intermediate) - which is reduced by treatment with a reducing agent such as sodium borohydride in the presence of
TT © 10 an alkanol such as ethanol to form the phosphinate Cee
Q . ict alkyl0-P-CH,-CH-CH,=CO alkyl . (trans) CH OH ~~ 1 . : Diester ict may then be hydrolyzed as described “above to form the basic salt 1c?, 20 . ‘ 0 2 Xa
IC alkylO-P-CH,-CH-CH,CO,R ' (trans) CH OH
CH z : 3 the acid IC . . D ‘ . 3
IC alkylo-P-CH,-CH-CH,-CO,H ’ (trans) CH OH ci oo A
ETE : nt
La
: HX10b -66- the basic salt 1c? : 0 1c? R*20-F -ci,~CH-CH, -CO,R™ : 5 : (trans) ps: OH
CH i ! and the corresponding diacid IC.
Referring to Reaction Sequence D, compounds of Formula I wherein X is -(CH,) = and ais 1,.2 or 3, that is -CH,-, -CH,CH,~- or -CH,CH,CH,- may ' be prepared starting with aldehyde VIII which is . converted to halide VIIIa using conventional procedures. For example, the aldehyde VIII may be reduced with NaBH, in the presence of ethanol and : ether to form the corresponding alcohol
Vila CH, OH
Zz which is treated with mesyl chloride in the presence of an organic base such as triethylamine and a solvent such as methylene chloride to form the chloride XXV (a=1). ’
The chloride XXV is subjected to a conden- _sation reaction where XXV is treated with : phosphite III employing a molar ratio of III:XXV of within the range of from about 1:1 to about 10:1 and a temperature within the range of from about 100 to about 150°C to form phosphonate diester XXVI. A solution of the phosphonate diester XXVI in a solvent such as dioxane is treated with a strong base such as an alkali metal hydroxide, for example, LiOH, to form a corre-
. HX10b -67- sponding monoester which is treated with oxalyl chloride in the presence of an inert organic : : solvent such as dimethylformamide to form the ° : ’ corresponding’ phosphonochloridate XXVII. XXVII is condensed with an alkyl acetoacetate dianion such as methylacetoacetate dianion in the presence of an inert organic solvent such as tetrahydrofuran at reduced temperatures of from about -90 to about -40°C employing a molar ratio of phosphono- chloridate XXVII:dianion of within the range of oo from about 1:1 to 0.75:1 to form the ketophos- phinate XXVII which is a novel intermediate.
Ketophosphinate XXVII may then be reduced to the . corresponding phosphinate pt, 1e! and IFY which may be hydrolyzed to form the corresponding ’ diacids ID, 1E and IF following procedures as described with respect to Reaction Sequence C.
Referring to Reaction Sequence E, compounds of formula I wherein X is -CH,0~- may be prepared starting with aldehyde VIII which is subjected to ' : a Baeyer-villiger oxidation by reacting VIII with : meta-chloroperbenzoic acid (MCPBA) in the presence of an inert organic solvent such as methylene chloride and followed by a strong base such as an alkali metal hydroxide like KOH or NaOH and a solvent such as tetrahydrofuran to form the corresponding alcohol XXIX. The alcohol XXIX is alkylated by treating XXIX with sodium hydride in the presence of an inert organic solvent such as | dimethyl formamide under an inert atmosphere such as argon and a solution of a dialkyl tosyloxymethyl- phosphonate XXX employing a molar ratio of XXX:XXIX of within the range of from about 1:1 to about 3:1 to form the corresponding dialkyl ester XXXI. The
HX10b -68-~ . remainder of the synthesis described in Reaction
Sequence E that is forming the monoester XXXII,
So chloride XXXIII, ketophosphinate XXXIV (a new intermediate), diester ict and diacid IG is similar to that set out hereinbefore with respect to in’ " Reaction Sequence D.
The acetylene starting material X may be prepared from the ccrresponding aldehyde VIII vIII CHO . Z . by subjecting VIII to a Wittig reaction, for . example, by treating a cooled solution of VIII : (-25°C to 0°C) in triphenylphosphine, and an inert organic solvent such as methylene :
Co chloride, with a solution of tetrabromomethane (CBr,) in an inert organic solvent such as : methylene chloride to form vinyl dibromide IX
IX CH=CBI, z :
Compound IX is subjected to dehydrohalogenation by ‘ treatment with n-butyllithium in an inert organic solvent such as hexane under an inert atmosphere to give X.
Alternatively, aldehyde VIII may be converted directly to acetylene X by treatment with dimethyl diazomethylphosphonate in the presence of potassium t-butoxide in an inert solvent such as tetrahydrofuran (-78°C to 25°C) under an inert atmosphere. . The iodide starting material A may be : prepared starting with the bromide C BAD ORIGINAL —
’ HX10b -69- : - ~CH- 1 o Br-CH,~CH-CH,C0,alkyl Co (which is prepared by employing procedures as described in Tetrahedron Lett. 26, 2951 (1985)) : which is dissolved in solution in dimethylformamide oo 10 (DMF) with imidazole and 4-dimethylamino pyridine and the resulting solution is treated with t-butyldiphenyl silyl chloride under an inert atmosphere such as argon to form the silyl ether D : 15 : Cells Celg psi-C(CH;)4
D Br-CH,-CH-CH,CO, alkyl
A solution of silyl ether D in an inert organic solvent such as methyl ethyl ketone or DMF is treated with sodium iodide under an inert atmosphere such as argon, to form iodide A.
The starting aldehyde compounds VIII, that is
VIII HO
2 are known compounds.
The various intermediates IV, V, VI, VII,
XI, XII, XIII, XVII and XXIV also are part of the - present invention. These novel intermediates may be represented by the following generic formulae:
Athen BAD ORIGINAL . | tenn
© HX10b -70~- . 1 0 . | - » : XXXV Ry ~F ClpqH-CHy=COalkyl oo 0 R}, PAE .
CeHg CgHg including all stereoisomers thereof, wherein RL is alkoxy or hydroxy and Ry is alkoxy, hydroxy, Cl, -CH,-2, -CH,CH,CH,-2, -CH,0-2, -C=C-Z, -CH=CH-Z, —= 10 “=CH,CH,~Z, wherein 2 is a hydrophobic anchor as defined above; provided that where Ry is hydroxy.
RL is preferably hydroxy or alkoxy; and 0 . XXXVI alky10-F-CH,-C-Ci,-C0,alkyl :
X 0 2 . . : : wherein 2 is as defined above, including all : stereoisomers thereof. B
The compounds of the invention may be . prepared as racemic mixtures and may later be resolved to obtain the S-isomer which is preferred. However, the compounds of the invention may be prepared directly in the form of" their S-isomers as described herein and in the working examples set out hereinafter.
The compounds of the invention are inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme
A (HMG-CoA) reductase and thus are useful in inhibiting cholesterol biosynthesis as demonstrated by the following tests.
BAD ORIGINAL
— | oe
HX10i, -71- 1) Rat Hepatic HMG-CoA Reductase
Rat hepatic HMG-CoA reductase activity is measured using a modification of the method described by Edwards (Edwards, P.A., et al.,
J. Lipid Res. 20:40, 1979). Rat hepatic microsomes are used as a source of enzyme, and the enzyme activity is determined by measuring the conversion of the 14¢_mmc-coa substrate to 14¢_mevalonic acid. a. Preparation of Microsomes
Livers are removed from 2-4 ‘cholestyramine-fed, decapitated, Sprague Dawley . rats, and homogenized in phosphate buffer A : 15 (potassium phosphate, 0.04 M, pH 7.2; KCl, 0.05 M; sucrose, 0.1 M; EDTA, 0.03 M; aprotinin, 500 KI : units/ml). The homogenate is spun at 16,000 x g for 15 minutes at 4°C. The supernatant is removed and recentrifuged under the same conditions a second time. The second 16,000 x g supernatant is spun at 100,000 x g for 70 minutes at 4°C.
Pelleted microsomes are resuspended in a minimum volume of buffer A (3-5 ml per liver), and homogenized in a glass/glass- homogenizer.
Dithiothreitol is added (10 mM), and the preparation is aliquoted, quick frozen in acetone/dry ice, and stored at -80°C. The specific activity of the first microsomal preparation was 0.68 nmole mevalonic acid/mg protein/minute. ) a BAD ARICINAL
HX10b ' -72- b. Enzyme Assay
The reductase is assayed in ‘0.25 ml which - contains the following components at the indicated final concentrations: B N 0.04 M Potassium phosphate, pH 7.0 oo 0.05 M KCl 0.10 M Sucrose 0.03 M EDTA
CT 10 0.01 M Dithiothreitol . 3.5 mM NaCl . 1% Dimethylsulfoxide 50-200 pg Microsomal protein . 100 uM 14. [DL ]HMG-CoA (0.05 uci, : 30-60 mCi/mmole) i 2.7 mM NADPH (nicotinamide adenine ) dinucleotide phosphate) )
Reaction mixtures are incubated at 37°C. Under conditions described, enzyme activity increases . linearly up to 300 pg microsomal protein per reaction mixture, and is linear with respect to : incubation time up to 30 minutes. The standard incubation time chosen for drug studies is 20 minutes, which results in 12-15% conversion of
HMG-CoA substrate to the mevalonic acid product. [DL-]HMG-CoA substrate is used at 100 pM, twice the concentration needed to saturate the enzyme under the conditions described. NADPH is used in excess at a level 2.7 times the concentration required to achieve maximum enzyme velocity.
HX10b -73-
Standardized assays for the evaluation of inhibitors are conducted according to the following procedure. Microsomal enzyme is incubated in the presence of NADPH at 37°C for 15 minutes. DMSO vehicle with or without test : compound is added, and the mixture further incubated for 15 minutes at 37°C. The enzyme : assay is initiated by adding 140 _mmG-coa substrate. After 20 minutes incubation at 37°C the reaction is stopped by the addition of 25 ul
CT of 33% KOH. 3y-mevalonic acid (0.05 pci) is added, and the reaction mixture allowed to stand at room temperature for 30 minutes. Fifty pul SN
HCl is added to lactonize the mevalonic acid. : 15 Bromophenol blue is added as a pH indicator to ; monitor an adequate drop in pH. Lactonization is ’ . allowed to proceed for 30 minutes at room : - _ temperature. Reaction mixtures are centrifuged ‘ for 15 minutes at 2800 rpm. The supernatants are layered onto 2 grams AG 1-X8 anion exchange resin (Biorad, formate form) poured in 0.7 cm (id) glass columns, and eluted with 2.0 ml H,0. The first : 0.5 ml is discarded, and the next 1.5 ml is collected and counted for both tritium and carbon 14 in 10.0 ml Opti-fluor scintillation fluid.
Results are calculated as nmoles mevalonic acid produced per 20 minutes, and are corrected to 100% recovery of tritium. Drug effects are expressed _ as Igo values (concentration of drug producing 507% inhibition of enzyme activity) derived from composite dose response data with the 95% confidence interval indicated. — :
LD ORIGINAL
-
HX10b ~74- ~ Conversion of drugs in lactone form to their sodium salts is accomplished by solubilizing the lactone in DMSO, adding a 10-fold molar excess of NaOH, and allowing the mixture to stand at room temperature for 15 minutes. The mixture is then partially neutralized (pH 7.5-8.0) using 1N HCI, and diluted into the enzyme reaction mixture. 2) Cholesterol Synthesis in Freshly Isolated Rat oC 10 Hepatocytes ce
Compounds which demonstrate activity as inhibitors of HMG-CoA reductase are evaluated for their ability to inhibit 140 _ acetate incorporation . into cholesterol in freshly isolated rat hepatocyte suspensions using methods originally described by
Capuzzi et al. (Capuzzi, D.M. and Margolis, S.,
Lipids, 6:602, 1971). ’ : a a. Isolation of Rat Hepatocytes -
Sprague Dawley rats (180-220 grams).are anesthetized with Nembutol (50 mg/kg). The abdomen is opened and the first branch of the portal vein is tied closed. Heparin (100-200 units) is injected directly into the abdominal vena cava. A single closing suture is placed on the distal section of the portal vein, and the . portal vein is canulated between the suture and the first branching vein. The liver is perfused ‘at a rate of 20 ml/minute with prewarmed (37°C), : oxygenated buffer A (HBSS without calcium or magnesium containing 0.5 mM EDTA) after severing the vena cava to allow drainage of the effluent.
The liver is additionally perfused with 200 ml °baL ORIGINAL : oo RE ' 4 .
HX10b -75~ prewarmed buffer B (HBSS containing 0.05% Er bacterial collagenase). Following perfusion with ~ buffer B, the 'liver is excised and decapsulated in 60 ml Waymouth's medium allowing free cells to CT : disperse into the medium. Hepatocytes are isolated by low speed centrifugation for 3 minutes at 50xg at room temperature. Pelleted hepatocytes . are washed once in Waymouth's uiedium, counted and assayed for viability by trypan blue exclusion.
These hepatocyte enriched cell suspensions : ‘ - routinely show 70-90% viability. b. 14¢_ acetate Incorporation into . Cholesterol
Hepatocytes are resuspended at 5x10° cells per 2.0 ml in incubation medium (IM) [0.02 M ) N
Tris-HCl (pH 7.4), 0.1 M KCl, 3.3 mM sodium citrate, 6.7 mM nicotinamide, 0.23 mM NADP, 1.7 mM glucose-6-phosphate]. .
Test compounds are routinely dissolved in
DMSO or DMSO:H,0 (1:3) and added to the IM. Final
DMSO concentration in the IM is < 1.0%, and has no significant effect on cholesterol synthesis. Lo
Incubation is initiated by adding 25. 140 acetate (58 mCi/mmol, 2 pCi/ml), and placing the cell suspensions (2.0 ml) in 35 mm tissue culture dishes, at 37°C for 2.0 hours. Following incubation, cell suspensions are transferred to = glass centrifuge tubes and spun at 50xg for 3 minutes at room temperature. Cell pellets are resuspended and lysed in 1.0 ml H,0, and placed in an ice bath. :
HX10b -76=- ) Lipids are extracted essentially as described by Bligh, E. G. and W. J. Dyer, Can. J.
Biochem. and Physiol., 37:911, 1959. The lower -organic phase is removed and dried under a stream of nitrogen, and the residue resuspended in (100 pl) chloroform:methanol (2:1). The total sample is spotted on silica gel (LK6D) thin-layer plates and developed in hexane:ethyl ether:acetic acid (75:25:1). Plates are scanned and counted using a
BioScan automated scanning system. Radiolabel in the cholesterol peak (RF 0.28) is determined and expressed at total counts per peak and as a percent of the label in the total lipid extract. . ‘Cholesterol peaks in control cultures routinely contain 800-1000 ¢pm, and are 9-20% of the label
Co present in the total lipid extract; results compatable with Capuzzi, et al., indicating 9% of ‘extracted label in cholesterol.
Drug effects (% inhibition of cholesterol synthesis) are determined by comparing % of label in cholesterol for control and drug treated cultures. Dose response curves are constructed , from composite data from two or more studies, and ‘results are expressed as Iso values with a 95% confidence interval. . 3) Cholesterol Synthesis in Human Skin Fibroblasts
Compound selectivity favoring greater inhibitory activity in hepatic tissue would be an attribute for a cholesterol synthesis inhibitor.
Therefore, in addition to evaluating cholesterol synthesis inhibitors in hepatocytes, these compounds are also tested for their activity as : BAD ORIGINAL
HX10b -77- inhibitors of cholesterol synthesis in cultured fibroblasts. : : a. Human Skin Fibroblast Cultures "Human skin fibroblasts (passage 7-27) are grown in Eagles' minimal essential medium (EM) containing 10% fetal calf serum. For each exririment, stock cultures are trypsonized to disperse the cell monolayer, counted, and plated
Ce 10 in 35 mm tissue culture wells (5%10° cells/2.0 ml). Cultures are incubated for 18 hours at 37°C : in 5% Co,/95% humidified room air. Cholesterol biosynthetic enzymes are induced by removing the . serum containing medium, washing the cell monolayers, and adding 1.0 ml of EM containing 1.0% fatty acid free bovine serum albumin, and 7 incubating the cultures an additional 24 hours. b. 14-_Acetate Incorporation into
Cholesterol
Induced fibroblast cultures are washed with
EMEM, (Earle's minimal essential medium). Test compounds are dissolved in DMSO or DMSO:EM (1:3) (final DMSO concentration in cell cultures < 1.0%), added to the cultures, and the cultures preincubated for 30 minutes at 37°C in 5% Co,/95% humidified room air. Following preincubation with drugs, (1-t4ciNa acetate (2.0 pCi/ml, 58 mCi /mmole) - is added, and the cultures reincubated for 4 hours.
After incubation, the culture medium is removed, and the cell monolayer (200 pg cell protein per : culture) is scraped into 1.0 ml of H,O. Lipids in the lysed cell suspension are extracted into
HX10b : -78- chlorofo:m:methanol as described for hepatocyte ‘ suspensions. The organic phase is dried under nitrogen, and the. residue resuspended in chloroform: methanol (2:1) (100 pl), and the total sample spotted on silica gel (LK6D) thin-layer plates, and analyzed as described for hepatocytes.
Inhibition of cholesterol synthesis is deternined by comparing the percent of label in the cholesterol peak from control and drug-treated : 10 cultures. Results are expressed as Ig, values, a and are derived from composite dose response curves from two or more experiments. A 95% confidence interval for the Igo value is also calculated from . the composite dose response curves. ° A further aspect of the present invention is a pharmaceutical composition consisting of at least one of the compounds of formula I in association with a pharmaceutical vehicle or diluent. The pharmaceutical composition can be formulated employing conventional solid or liquid vehicles of diluents and pharmaceutical additives of a type appropriate to the mode of desired administration. The compounds can be administered by an oral route, for example, in the form of tablets, capsules, granules or powders, or they can be administered by a parenteral route in the form of injectable preparations, such dosage forms containing from 1 to 2000 mg of active compound per dosage, for use in the treatment. The dose to be administered depends on the unitary dose, the symptoms, and the age and the body weight of the patient.
Phe AE Lhd
BAD ORIGINAL a. atti]
HX10b =79-
The cowpounds of formula I may be administered in a similar manner as known compounds suggested for use in inhibiting cholesterol hiosynthesis, such as lovastatin, in mammalian species such as humans, dogs, cats and : " the like. Thus, the compounds of the invention may be administered in an amount from about 4 to 2000 mg in a single dose or in the form of individual doses from 1 to 4 times per day, preferably 4 to = ..-----10 -200 mg in divided dosages of 1 to 100 mg, suitably 0.5 to 50 mg 2 to 4 times daily or in sustained release form. : BAD ORIGINAL
Ae me mt
~ HX10b -80-
The following working Examples represent tC preferred embodiments of the present invention. = Unless otherwise indicated, all temperatures are
B expressed in degr=es’ Centigrade. Flash 7 chromatography was per formed on either Merck 60 or whatmann LPS-I silica gel. Reverse phase chromatography was performed on CHP-20 MCI gel resin supplied hy Mitsubishi, Ltd.
As used in the following Examples, the abbreviations "Et, 0", "EtOAc", "MeOH" and "EtOH"
Co refer to ethyl ether, ethyl acetate, methanol and ethanol, respectively. : . Example 1 - ‘15 (s)-4-[[[4'-Fluoro-3,3',5-trimethyl{1,1'-biphenyl]}- 2-y1]methoxy]methoxyphosphinyl]-3-hydroxy-butanoic , acid, monolithium salt
A. N-(2,4-Dimethylbenzylidene )benzeneamine i
Ref. Merck U. S. Patent No. 4,375,475, pg. 39.
A solution of freshly distilled 2,4-dimethylbenzaldehyde (Aldrich, 6.97 ml, 50 mmole) and distilled aniline (Aldrich, 4.56 ml, 50 mmole) in dry toluene (80.0 ml) was refluxed for : 3.0 hours under argon in a flask equipped with a . 25 Dean-Stark apparatus. The mixture was cooled, then evaporated in vacuo to a yellow oil. The crude oil was purified by Kugelrohr distillation (0.5 mm Hg, 160-180°C) to give 8.172 g (78.1%) of desired title benzeneimine as a light yellow oil which crystallized on standing to a low melting } solid. TLC (4:1) Hex-acetone, Rf=0.67 and 0.77 ; (geometric isomers), U.V. and I,.
BAD ORIGINAL ermine
HX10b -81- “97 oo =,
H,C Pa- :
OCCH,
Oo . ) CH, 2
Ref. Merck U.S. Patent No. 4,375,475, pg. 39. ’ A mixture of Part A benzeneimine (6.0 g, 28.7 mmol) in glacial HOAc (144 ml) was treated with palladium (II) acetate (6.44 g, 28.7 mmole) . and the clear, red homogeneous solution refluxed under argon for one hour. The resulting turbid mixture was filtered warm through a packed %" bed of Celite into 900 ml of HO: Precipitated orange } solid was“collected by filtration and dried ‘ in vacuc at 65°C over P,0¢ for 16 hours to give 10.6 g (85.5%) of desired title palladium : complex as an orange solid with m.p. = 194°-196°C. (Literature m.p. of a recrystallized analytical sample = 203°-205°C). Co _C. 4'-Fluoro-3,3',5-trimethyl(1,1'- biphenyl]-2-carboxaldehyde (1) Bromo [4-fluoro-3-methylphenyl]- magnesium —- Ref. Merck U. S. Patent No. 4,375,475, pp- 37 and 38.
The title Part C(1) Grignard reagent was prepared by adding S-bromo-2-fluorotoluene (22.5 ’ g, 60.9 mmole, Fairfield Chemical Co.) dropwise
HX10b -82- . at a rate sufficient to maintain the reaction at reflux to stirred magnesium turnings (1.35 g, 55.4 Te : mmole, 8.0 eq.) in dry Et,0 (70.0 ml). The nL reaction was initiated in an ultrasound device. .
After bromide addition was complete, the mixture was stirred for one hour under argon at room temperature, refluxed for 15 minutes and then allowed to cool to room temperature. meme 10 (2) 4'-Fluoro-3,3',5-trimethyl- ~~ . [1,1'-biphenyl]-2-carboxaldehyde
In a second flask, a mixture of the Part B dipalladium complex (3.0 g, 6.92 mmole) and . triphenylphosphine (14.52 g, 55.4 mmole, 8.0 eq.) - in dry benzene (100 ml) was stirred at room . temperature under argon for 30 minutes. Freshly
Lov ‘prepared and filtered (glass wool” plug) Part'C ‘(1) -
Grignard reagent was then added in one portion by means of a cannula to this solution and the mixture was stirred for 1.5 hours at room ‘ temperature under argon. 6.0 N HCl (35 ml) was added, the mixture stirred an additional hour at - room temperature, then filtered through packed
Celite (%" bed). The filtrate was extracted with
Et,0 (250 ml), the extract washed with brine (2 x . ‘100 ml), dried over anhydrous MgSO, and evaporated in vacuo to give 13.35 g of a viscous orange oil which crystallized on standing. The crude orange solid was purified by flash chromatography on : 30 silica gel (700 g) eluting with hexane, followed by ' (95:5) hexane-Et,O. Product fractions were combined and evaporated to give 1.507 g (89.9%) of desired title aldehyde as a light yellow solid with
Hn BAD ORIGINAL eee ee et
HX10b } -83~ " m.p. = 72°-75°C) (Literature reports m.p. = . 73°=74°C). : . TLC: (95:5) Hex-Et,0, Rf = 0.40, U.V. and PMA. : D. 2-(2,2-Dibromoethenyl)-4'-fluoro- : 3,3',5-trimethyl[1,1'~biphenyl] : : A cooled (-10°C, salt/ice bath) solution of the Part C biphenyl aldehyde (242 mg, 1.0 mmole) and triphenylphosphine (787 mg, 3.0 mmole, 3.0 eq) “ 10 in dry CH,C1, (10 ml) was treated dropwise with a solution of CBr, (497 mg, 1.5 mmole, 1.5 eq) in :
CH,C1, (5.0 ml) over a 5 minute period. After 30 minutes at 0°C the red-orange solution was . partitioned between CH,C1, and saturated NaHCO,.
The organic phase was washed with saturated NaHCO, and brine, then dried over anhydrous Na,SO, and hes © evaporated to give 1.478 § of a 1ight brown ™ ~~ © 7 solid. The crude solid was purified by flash i ) : chromatography on silica gel (50:1) eluting with (9:1) Hex-CH,Cl,. Product fractions were combined and evaporated to give 392 mg (99%) of pure title vinyl dibromide as a pale yellow oil. : . TLC (95:5) Hex-EtOAc, RE = 0.51, UV and PMA.
E. 2-Ethynyl-4'-fluoro-3,3',65-trimethyl- [1,1'-biphenyl] oo A -78°C (dry ice/acetone) solution of the
Part D vinyl dibromide (336 mg, 0.844 mmole) in ~ | dry THF (5 ml) was treated dropwise via syringe with a 1.6 M solution of n-BuLi in hexanes (1.06 ml, 1.7 mmole, 2.0 eq) and the mixture stirred at -78°C under argon for one hour. During the n-BuLi addition color changes from colorless to deep
EE BAD ORIGINAL
To HX10b : -84~ yellow to pale yellow to deep blue-purple were i evident. The mixture was quenched at -78°C by the dropwise addition of saturated NH, Cl (4 ml), . allowed to warm to room temperature, extracted with Et,0, the ethereal layer washed with brine, : dried over anhydrous MgSO, and evaporated to give 191 mg of a green oil. The crude oil was purified by flash chromatography on LPS-1 silica gel (60:1) eluting with hexanes. Product fractions were
CT ~~ 10" combined and evaporated to give 185 mg (92%) of : desired title acetylene as a colorless oil which eventually turned deep blue on standing at -20°C under argon. © . TLC hexane, Rf = 0.18 UV and PMA. Co -
F. (S)-3-[[(1,l-Dimethylethyl)diphenyl- | LG silyl]oxy]-4-(chloromethoxyphosphinyl)- butanoic acid, methyl ester (1) (S)-4-Bromo-3-hydroxybutanoic acid, methyl ester _ oo : (1)(a) [R-(R*,R*)]-2,3,4-trihydroxy- : : butanocic acid, calcium salt, oo hydrate
Ref. carbohydrate Research 72, pp. 301-304 (1979). , Calcium carbonate (50 g) was added to a : . . solution of D-isoascorbic acid (44.0 g, 250 mmol) . in H,0 (625 ml), the suspension cooled to 0°C (ice bath) and treated portionwise with 30% H,0, (100 ml). The mixture was stirred at 30°-40°C (oil oo 30 bath) for 30 minutes. Darco (10 g) was added and the black suspension heated on a steam bath until evolution of 0, ceased. The suspension was filtered through Celite, evaporated in vacuo (bath
J Won -/ ) BAD ORIGINAL
HX10b : -85- temperature 40°C). The residue was taken up in
H,0 (50 ml), warmed on a steam bath and CH, OH was C : added until the solution was turbid. The gummy vo precipitated solid was collected by filtration and B 5. air dried to give 30.836 g (75.2%) of desired calcium salt as a powdery white solid.
TLC (7:2:1) iPrOH-NH,OH-H,0, Rf = 0.19, PMA. (1)(b) [S-(R*,S*)]-2,4-Dibromo-3-
REE 10 ~ hydroxybutanoic acid, methyl ester
Ref. Bock, K. et al., Acta Scandinavica (B) 37, pp. 341-344 (1983) . Part (1)(a) calcium salt (30 g) was . 15 dissolved in 30-32% HBr in acetic acid (210 ml) and stirred at room temperature for 24 hours.
Methanol (990 ml) was then added to the brown solution and it was stirred overnight. The mixture was evaporated to an orange oil, taken up in CH, OH (75 ml), refluxed for 2.0 hours and evaporated.
The residue was partitioned between EtOAc (100 ml) and H,0, the organic phase washed with H,0 (2x) and brine then dried over anhydrous Na,SO, and evaporated to give 22.83 g (90.5%) of crude . dibromide as a light orange oil. TLC (1:1) .
EtOAc-Hex, Rf = 0.69, UV & PMA. (1)(c) (S)-4-Bromo-3-hydroxybutanoic - : acid, methyl ester
Ref. the same as for preparation of (1)(b). ’
Co An argon purged solution of the dibromide
Le (20.80 g, 75.4 mmol) and anhydrous NaOAc (21.0 g) in
EtOAc (370 ml) and glacial HOAc (37 ml) was ; : BAD ORIGINAL
HX10b -86- treated with 5% Pd/C (1.30 g) and the black . suspension stirred under of H, (1 atm) . while monitoring H, uptake. After 2.0 oo ‘ hours H, uptake was complete, the mixture was filtered through Celite, the filtrate washed with saturated NaHCO, and brine then dried over - anhydrous MgSO, and evaporated to give crude dibromoestesr as a brown 0il. The crude oil was ~ ) combined with another batch (starting from 36.77 g oo 10 of the dibromide) and vacuum distilled to give - = : 25.77 g (61.3%) of desired title bromoester as a colorless oil with b.p. = 79°-80°C (1.0 mm Hg).
TLC (1:1) EtOAc-Hex, Rf = 0.44, PMA.
Anal Calcd for C.HyO,Br: C, 30.48; H, 4.60;
Br, 40.56
Found: C, 29.76; H, 4.50; Br, 39.86 ) (2) (s)-4-Bromo-3-[[(1,1-dimethylethyl)- - diphenylsilyl]oxylbutanoic acid, methyl - ester
A solution of part F(1l) bromchydrin (4.0 g, : 20.4 mmol), imidazole (6.94 g, 5.0 eq.), and 4-dimethylamino pyridine (4-DMAP) (12 mg, 0.005 eg.) in dry DMF (40 ml) was treated with t-butyl- diphenylsilyl chloride (5.84 ml, 1.1 eq.) and the homogeneous mixture stirred overnight under argon at room temperature. The mixture was partitioned : between 5% KHSO, and EtOAc, the organic phase washed with H,0 and brine, dried over anhydrous
Na,SO, and evaporated to give 9.32 g (100%) of ’ crude silyl ether as a colorless, viscous oil. : im mn
= .
HX10b -87-
TLC (3:1) Hex-EtOAc, Rf silyl ether = 0.75, U.V. and PMA. - : (3) (S)-4-Icde-3-[[(1,1-dimethylethyl)- diphenylsilyl]oxy]butanoic acid, : methyl ester
A solution of the crude Part F(2) bromide (9.32 g; 201 mmole) in methyl ethyl ketone (60 ml, dried over 4& sieves) was treated with sodium 10 . iodide (15.06 g, 100.5 mmole, 5.0 eq.) and the - yellow suspension refluxed for 5.0 hours under argon. The mixture was cooled, diluted with EtOAc, filtered, the filtrate washed with dilute NaHSO, . (until colorless) and brine then dried over Co oo 15 anhydrous Na,SO, and evaporated in vacuo to give go ooow yo 10.179 of a yellow oil. The crude oil was purified by flash chromatography on silica gel (600 gn : g) eluting with (3:1) Hexane-CH,Cl,. Product
Q fractions were combined and evaporated to give . 50 7.691 g (74.2%, overall yield for both steps) of desired title iodide as a clear, colorless, viscous : oil. TLC (3:1) Hex-EtOAc, product. Rf = 0.75, U.V. : and PMA. (Note: product iodide co-spots with , starting bromide). i (4) (S)-4-(Diethoxyphosphinyl)=3-{[(1,1- dimethylethyl)diphenylsilyl]oxy]- butanoic acid, methyl ester - A solution of the iodide (7.691 g) in triethyl phosphite (20 ml) was heated at 155°C .
Co (oil bath) for 3.5 hours under argon. The mixture was cooled and excess phosphite distilled off : in vacuo (0.5 mm Hg, 75°C) to leave a yellow oil . BAD ORIGINAL
HX10b i ~88- oo (~8.0 g). The crude oil was purified by flash chromatography on silica gel (400 g) eluting with -, (4:1) Hexane-acetone. Product fractions were . evaporated to give 3.222 g (41.1%) of desired title - : 5 phosphonate as a clear, colorless, viscous oil.
TLC (1:1) Hex-acetone, Rf = 0.51, U.V. and PMA.
Additionally 2.519 g (61.1% corrected yield) of starting Part (3) iodide was recovered. i0 (5) (S)-3-[[(1,1-Dimethylethyl)diphenyl- To silyl]oxy]-4-phosphonobutancic acid, methyl ester
A solution of the Part F(4) phosphonate (9.85 g, 20.0 mmole) in dry CHCl, (20 ml) was treated sequentially with bistrimethylsilyltri- fluoroacetamide (BSTFA) (5.31 ml, 32.0 mmole, 1.6 : eq.) and trimethylsilyl bromide (TMSBr) (6.60 ml . 50.0 mmole, 2.5 eq.) and.the clear mixture stirred overnight under argon at room temperature. 57 : 20 KHSO,, (80 ml) was added and the mixture was extracted with EtOAc. The agueous phase was : saturated with NaCl and re-extracted with EtOAc. ’ The combined organic layers were washed with brine, dried over anhydrous Na,SO, and evaporated , © 25 in vacuo to give crude title phosphonic acid as a . : viscous oil. TLC (7:2:1) iPrOH-NH,OH-H,O0, Rf = 0.30, U.V. and PMA. oo . (6) (S)-3-[[(1,1-Dimethylethyl)diphenyl- silyl]oxy]-4-(hydroxymethoxyphosphinyl)- butanoic acid, methyl ester ~~
Part F(5) crude phosphonic acid (~20.0 mmole) in dry pyridine (25 ml) was treated with dried
AT :
FREES i
BAD ORIGINAL
—
HX10b -89-
CH,0H (over 38 sieves, 1.62 ml, 40.0 mmole, 2.0 . eq.) and dicyclohexyl carbodiimide (DCC) (4.54 gm, 22.0 mmole, 1.10 eq.) and the resulting white . suspension stirred under argon at room temperature : oo 5 overnight. Pyridine was removed in vacuo, then * azeotroped with benzene (2 x 15 ml). The residual . 0il was dissolved in EtOAc, filtered and washed . with 1.0 N HCl and brine, dried over anhydrous
Na,SO, and evaporated in vacuo to give 8.272 g of crude title ester as an oil containing ) a small amount of precipitated dicyclohexyl urea (DCU). TLC (7:2:1) iPrOH-NH,-OH H,0, Rf = 0.60,
U.V. and PMA. (7) (S)-3-[[(1-Dimethylethyl)diphenylsilyl]- : oxy] -4- (chloromethoxyphosphinyl)- : butanoic acid, methyl ester : Part F(6) crude phosphonic acid mono methyl ester (6.595 gm, ~14.7 mmole) was dissolved in dry © 20 CH,CL, (30 ml), treated with distilled trimethyl- "silyldiethylamine (5.60 ml, 29.4 mmole, 2.0 eq.) : i and stirred under argon at room temperature for 1 as : hour. .The mixture was evaporated in vacuo, chased with benzene (1 x 30 ml) and dried in vacuo. oo 25 The light yellow viscous oil was dissolved in dry . CH,CI, (30 ml) and DMF (dried over 48 sieves, 2 co drops), the clear solution cooled to -lo°C (salt/ice bath) and treated dropwise via syringe - with distilled oxalyl chloride (1.41 ml, 16.2 mmole, 1.1 eqg.). Vigorbdus gas evolution was evident and the solution became deeper yellow in : color. The mixture was stirred under argon at -10°C for 15 minutes then allowed to stir at room
BAD ORIGINAL
Co . . mit .
HX10b -90- temperature for 1 hour. The mixture was evaporated in vacuo, chased with benzene (1 x 30 ml) and dried : in vacuo to give crude phosphonochloridate as a : : : yellow oil. ~ ] ; | | :
G. (S)-4-=[[2-[4'~-Fluoro-3,3',5~trimethyl- } (1,1'-biphenyl]-2-yl]ethynyl]methoxy- : ~ phosphinyl]-3-t-butyldiphenylsilyloxy- butanoic acid, methyl ester
A -78°C (CO, /acetone) solution of the Part : .
E acetylene (2.678 g, 11.2 mmole) in dry THF (20 ml) was treated dropwise with a 1.6 M solution of n-BuLi in hexanes (7 ml, 11.2 mmole, 1.0 eq). The . © purple mixture was stirred under argon at -78°C for one hour, briefly warmed to 0°C, recoocled to -78°C, transferred by cannula into an addition funnel and added dropwise to a =-78°C (CO, /acetone) ‘ solution of the Part F phosphonochloridate (8.27 g, 18.4 mmole, 1.6 eq) in dry THF (20 ml). After one hour at -78°C the mixture was quenched with saturated NH,C1, then allowed to warm: to room temperature and extracted with Et,0. The ethereal : layer was washed with saturated NaHCO, and brine ; then dried over anhydrous Mgso, and evaporated to give 11.705 g of a brown oil. The crude oil was purified by flash chromatography on silica gel eluting with (7:3) Hex-EtOAc. Product fractions were combined and evaporated to give 4.246 g (56%) of desired title acetylenic phosphinate as a light Co brown oil. Additionally, 457 mg (68% corrected . yield) of Part E biphenyl acetylene was recovered.
TLC (7:3) Hex-Acetone, Rf = 0.20, uv and PMA. oo BAD ORIGINAL : ee oom
HX10b ) : -91-
H. (S)-4-[(2-[4'~Fluoro-3,3",S-trinethyl- [1,1'-biphenyl]-2-yl]ethyl]methoxyphos-= : phinyl]~-3-t-butyldiphenylsilyloxy- - ) butanoic acid, methyl ester : ~
An argon purged solution of the Part G acetylenic phosphinate (333 mg) in CH, OH (5 ml) was treated with 10% Pd/C (121 mg, 36% by weight) and shaken on a Parr apparatus under H, (40 psi) for 30 hours. Catalyst was removed by filtration
Co - 10 through packed Celite and the filtrate evaporated : to a pale yellow oil. The crude oil was purified : by flash chromatography on silica gel eluting with (1:1) EtOAc-Hex. Product fractions were evaporated ) . to give 250 mg (75%) of the title saturated phosphinate as a clear oil.
TLC (4:1) EtOAc-Hex, Rf = 0,33, UV and PMA. a LL “t B Ce CL ten fy Tt
J. (s)-4-[[2-(4'~Fluoro-3,3',5-trimethyl- : [1,1'-biphenyl]-2-yl]ethyllmethoxyphos- phinyl]-3-hydroxybutanoic acid, methyl ester
A solution of the Part H silyl ether (330 mg, 0.489 mmole) in dry THF (6 ml) was treated : with glacial HOAc (115 pl, 1.96 mmole, 4.0 eq) followed by a 1.0 M tetrabutylammonium fluoride solution in THF (1.47 ml, 1.47 mmole, 3.0 eq) and the resulting mixture stirred overnight at room temperature under argon. The mixture was diluted - with 10 ml of ice water and extracted with EtOAc (2X). The organic phase was washed with saturated
NaHCO, and brine then dried over anhydrous Na,SO, : and evaporated to give 364 mg of a pale yellow 0il. The crude oil was purified by flash
. HX10b : -92- chromatography on silica gel eluting with (6:4) - Acetone-Hexane. Product fractions were evaporated } to give 205 mg (96%) of desired title free alcohol : as a clear oil whliich slowly crystallized on standing. " TLC (7:3) Acetone-hexane, Rf = 0.28, UV and PMA. : Example 2 ($)-4-[[2-[4'-Fluoro-3,3',5-trimethyl]1,1"'~ biphenyl]-2-yl]ethyl]lhydroxyphosphinyl]~-3-hydroxy- = = butanoic acid, dilithium salt '
A solution of the Example 1 diester (187 mg, 0.429 mmole) in dioxane (5 ml) was treated . with a 1.0 N LiOH solution (1.29 ml, 1.29 mmole, 3.0 eq) and the mixture heated at 55°C (oil bath) - under argon for 2.5 hours. , The mixture was cooled, diluted with H,0, filtered and evaporated - } in vacuo. The residue was dissolved in a minimum amount of H,O and chromatographed on HP-20 resin (25 mm column diameter, ~15 cm bed) eluting with H,0 followed by a (1:1) CH;OH-H,0 mixture. - Collected product fractions were evaporated, dissolved in H,0 (50 ml), filtered, and lyophilized : to give 175 mg (91%, based on hydrate weight) of desired title dilithium salt as a white, co electrostatic solid.
TLC (8:1:1) CH,Cl,-CH;0H-HOAC, Rf = 0.1, UV and
PMA and (7:2:1) iPrOH-NH,OH-H,O, Rf = 0.45, UV and
PMA.
Microanalysis for C,H, ,05FPLi, and 1.7 moles H,0 (MW 450.90) :
: HX10b ~93- © Caled: C, 55.93; H, 6.13; F, 4.21; P, 6.87
Found: C, 55.91; H, 5.84; F, 3.92; P, 6.89 : lyomm (200 MHz, CDOD LT
Cs 51.34 - 1.56 ppm (4H, multiplet) } 2.22 - 2.31 ppm (2H, multiplet) 2.25 + 2.37 ppm (6H, two singlets) 2.29 ppm (3H, doublet, J, po = 1.4 Hz) 2.75 ppm (2H, multiplet) ; 10 4.13 ppm (1H, multiplet) : : 6.73 - 7.10 ppm (5H, multiplet) : Example 3 (s)-4-[[2-(4'-Fluoro-3,3"',5-trimethyl(1,1'~ : biphenyl]-2-yl]ethynylImethoxyphosphinyl]-3-
Co hydroxybutanoic acid, methyl ester : :
Ten oo A mixture of the Example 1 Part G SLLyl mewn. fo ninae : ether (455 mg, 0.678 mmole) and glacial acetic ’ : acid (155 pl, 2.71 mmole, 4.0 eq.) in dry THF (7 ) 20 ml) was treated with a 1.0 M tetrabutylammonium fluoride solution in THF (2.0 ml, 2.0 mmole, 3.0 eq.) and the resulting solution stirred overnight
Co under argon at room temperature. The mixture was : oo i poured into ice cold H,0 (10 ml) and extracted ! * with EtOAc (2X). The organic phase was washed ‘ with saturated NaHCO, and brine, ‘then dried over anhydrous Na,SO, and evaporated to give 498 mg of a yellow oil. The crude product was purified by i flash chromatography on silica gel eluting with : 30 (3:2) Hexane-Acetone. Product fractions were : evaporated to give 217 mg (74%) of title alcohol as a colorless oil.
TLC (7:3) Hexane-Acetone, Rf = 0.10, U.V. and PMA. : BAD ORIGINAL
HX10b -94-
Example 4 Ce (S)-4-[[2-[4'-Fluorn-3,3',5-trimethyl(1,1'- ) biphenyl]-2-yl]ethy.iyl]hydroxyphosphinyl]-3-~ - hydroxybutanoic acid, dilithium salt
A mixture of the Example 3 diester (203 mg, © 0.469 mmole) in dioxane (6 ml) was treated with a ) © 1.0 N LiOH (1.6 m! 1.6 mmole, 3.5 eq.) and the solution heated at 55° (oil bath) under argon for 30 minutes. The mixture was cooled, diluted with
H,0, filtered, evaporated, taken up in H,0 (30 ml) and lyophilized. The white lyophilate was dissolved in a minimum amount of H,0 and chroma- . tographed on HP-20 resin (25 mm diameter column, 10 cm resin bed), eluting with H,0 followed by (50:50)
H,0-CH,OH. Product fractions were combined and ~ evaporated, the residue taken up in H,0 (30 ml) : and lyophilized to give 199 mg (97%, based on _ hydrate, MW = 435.36) of the title di-lithium salt as a white solid. : TLC (8:1:1) CH,Cl,-CH;OH-HOAc, Rf = 0.13, U,V. and
PMA. "Microanalysis for C,,H,,05FPLi, + 1.06 moles H,0 (MW 435.36) : . calcd: C, 57.93; H, 5.12; F, 4.36; P, 7.11
Found: C, 57.91; H, 4.89; F, 4.22; P. 6.89 oo ld MMR (400 MHzCD,OD): §1.76-1.82 ppm (2H, multiplet) 2.32 (3H, doublet, Jygp=1-8 Hz) : 2.34 (3H, singlet) : oo 5 Cone : BAL ORIGINAL
NB
HX10b -95- : 2.37 (1H, dd, J=8.4 Hz) ) : 2.41 (1H, dd, J=4.1 Hz) : 2.49 (3H, singlet) 4.27. (1H, multiplet) - 5 6.98-7.37 (5H, m) ; Example 5 : (S,2)-4-[[2-[4'-Fluoro-3,3',5- rimethyl[1l,1'- : biphenyl]-2-yl]ethenyl Jmethoxyphosphinyl]-3- : hydroxybutanoic acid, ‘methyl ester
A. (S,Z)-4-[[2-[4'-Fluoro-3,3',5~ trimethyl(l,1'-biphenyl]-2-yl]ethenyl]- methoxyphosphinyl]-3-t-butyldiphenyl- + silyloxy-butanoic acid, methyl ester oo
A degassed solution of the Example 1 Part G :
Co acetylenic phosphinate (498 mg, 0.742 mmole) in . CH,O0H (10 ml) was treated with 10% Pd/C (50 mg; " 10% by weight) and the black suspension stirred -
CC under an H, atmosphere (1 atm) for 2 hours. Co catalyst was removed by filtration through : _ Celite and.the filtrate evaporated to give
S00 mg of a yellow oil. The crude product was
Lo : purified by flash chromatography on silica gel eluting with (3:2) Hexane-EtOAc. :
Product fractions were combined and evaporated to give 498 mg (100%) of desired olefin as a colorless oil.
TLC (4:1) EtOAc-Hexane, Rf diastereomers = 0.44 and - 0.51, U.V. and PMA. : . 30
PE BAD ORIGINAL
: . emt ee ttre = : :
HX10b -96-
B. (S,2)-4-[[2-[4'-Fluoro-3,3',5-
CL. trimethyl[1,1'-biphenyl]-2-yl]ethenyl]-
Co methoxyphosphinyl]-3-hydroxybutanoic : : ~ acid, methyl ester :
A solution of the Part A silyl ether (498 : mg, 0.74 mmole) in dry THF (6 ml) was treated with glacial acetic acid (170 pl, 2.96 mmole, 4.0 eq.) followed by a 1.0M tetrabutylammonium fluorida solution in THF (2.2 ml, 2.2 mmole, 3.0 eq.) and
EE A the clear, colorless mixture stirred at room temperature under argon for 16 hours. TLC : indicated a small amount of remaining starting material. Additional HOAc (40 pl, 1.0 eq.) and . n-Bu,NF (0.74 ml, 1.0 eq.) were added and stirring continued for 6 more hours. The mixture was Co : . diluted with ice cold H,0 (10 ml) and extracted with : EtOAc (2X). The combined extracts were washed with : " saturated NaHCO, and brine, dried over anhydrous oo Na,SO, and evaporated to give 468 mg of a pale - 20 yellow oil. The crude product was purified by os flash chromatography on silica gel eluting with (7:3) Hexane-Acetone. Product fractions were i e combined and evaporated to give 243 mg (76%) of Lo title alcohol as a colorless oil.
TLC (7:3) Hexane-Acetone, Rf = 0.19, U.V. and PMA.
Example 6 (S,2)-4~([2-[4'~-Fluoro-3,3',5-trimethyl(1,1"'- : biphenyl]-2-yl]ethenyl Jhydroxyphosphinyl]}-3- hydroxybutanoic acid, dilithium salt
A solution of the Example 5 diester (240 mg, 0.552 mmole) in dioxane (7 ml) was treated with a 1.0 N LiOH solution (1.9 ml, 1.9 mmole, 3.5 eq.)
BAD ORIGINAL
HX10b : _97- . and the stirred mixture heated under argon at 50° . (oil bath) for 3 hours. A white precipitate Le
So was evident. The mixture was cooled, diluted with ' . | H,0, filtered and evzporated in vacuo to a white ; 5 solid. The crude solid was dissolved in a minimum
To amount of H,0 and chromatographed on HP-20 resin, eluting with H,0 followed by (50:50) H,0:CH,OH. : Product fractions were combined and evaporated, taken up in H,0 (50 ml), filtered, and lyophilized o 10 ‘to give 255 mg (100%, based on hydrate weight; MW... ...
Co 457.58) of title di-lithium salt as a white electrostatic solid. :
TLC (8:1:1) CH,Cl,-CH;0H-HOAc, Rf = 0.26, . U.V. and PMA. : 1s | i oo : Microanalysis for C,,H,,05FPLi, + 2.18 moles H,0 . (457.58): i Crh ee Aart ae SA ] Calcd: C, 55.12; H, 5.81; F, 4.15; P, 6.77 oo Found: C, 55.35; H, 5.68; F. 4.27; P, 7.09 . | ln NMR (400 MHz, CD4OD): 51.24 ppm (2H, multiplet) : ~ 2.09 (2H, doublet, J=6.2 Hz) 2.27 (3H, doublet, Jpp=1-8 Hz) 2.30 (34, singlet) : : 2.38 (3H, singlet) 4.06 (1H, multiplet) 5.87 (1H, 4d doublet, Ja=12.4 Hz, - | Jgp=14.3 Hz) 6.87 (1H, s) . 6.91 (1B, 4 doublet, Jgp=43.4 Hz) 6.98 (2H, triplet) 7.22 (2H, multiplet)
BAL ORIGINAL an
HX10b : _98- :
Example 7. - © (S)-4-[[2-[3-(4-Fluorophenyl)-1~(l-methylethyl)- 1H-indol-2-yl]ethyl Jmethoxyphosphinyl]-3-hydroxy- butanoic acid, methyl ester
Bh 5 A. 2-[(4-Fluorophenyl )methyl]-3- oxobutanoic acid, ethyl ester ; Sodium pellets (8.31 g, 362 mmole) were : dissolved with mechanical stirring in absolute :
EtOH (1 liter) and distilled ethyl acetoacetate } 10 (47 g, 362 mmole, 1 eq.) was added to_the clear " solution under argon. The pale yellow mixture was Co refluxed for 1 hour, cooled to room temperature, ‘ treated with 4-fluorobenzyl bromide (75 g, 398 . mmole, 1.1 eq.) &nd the light orange mixture stirred under argon at room temperature for 2.5 hours.- The mixture was concentrated in vacuo. I oo . The residue was partitioned between EtOAc-H,0; - the organic phase washed with H,0 (2X) and brine, ~ - dried over anhydrous Na,SO, and evaporated to : . 20 give an orange oil. The crude product was purified BN by vacuum distillation (5 mm Hg) to give 46.47 g (54%) of alkylated product as a clear, colorless liquid with b.p. 142°-144°C.
TLC (7:3) Hex-Et,0, Rf product = 0.31. : ln MR (cDC1,): 61.20 (3H, t), 2.19 (3H, s), 3.13 (2H, d), 3.73 (1H, t), 4.14 (2H, q). 6.95 (2H, t), 7.13 (2H, m) ppm. : 3c mmr (cpgoN): 614.4, 29.7, 33.7, 62.1, 62.3, 115.3, 116.8, 131.4, 131.9, 145.1 (J,_,=284 Hz), 170.1, 203.5 ppm. oo BAL LHIGINAL
- — -
HX10b -99-
B. 2-(4-Fluorophenyl)-1H~indole-2- ' = carboxylic acid, ethyl ester . Ref. Chemical Abstracts Vol. 33, p. 587 } : Ref. Helmuth R. et al. J. Chem. Society pp. 6-7, LL (1927) - : " Ref. Preparative Organic Chemistry 4th Ed. p. 582 (1972)
A solution of the part A ester (46.4 g, 185 mmole) in absolute EtOH (290 ml) at 0°C (ice bath) was treated with an aqueous NaOH solution (23.4 g; in 58 ml H,0), then treated immediately with a benzenediazonium chloride solution (Prep. Org. :
Chem, 4th Ed. p. 582 (1972) prepared from aniline . (17.8 ml), conc HCl (88 ml), H,0 (98 ml) and NaNo,, : (13.5 g)) to give a deep orange-red biphasic . solution. The mixture was stirred for 1 hour at : = room temperature, poured into ice cold H,0 (500 ml) . and extracted with EtOAc (3 x 300 ml). The organic phase was washed with brine, (500 ml), dried over anhydrous Na,SO, and evaporated in vacuo to give 55.62 g of crude hydrazone intermediate as an orange oil. TLC (7:3) Hex-Et,O, Rf hydrazone =
Co 0.22, UV and PMA. Crude material was used as is for subsequent Fischer cyclization. ) : ,. 25 A solution of the hydrazone in absolute
EtOH (200 ml) was treated with gaseous, bubbling
HCl for 30 minutes with intermittent ice bath cooling. The brownish mixture was poured into ice - cold H,0 (600 ml) and extracted with EtOAc (3X).
The organic phase was washed with H,0 (2X) and brine, dried over anhydrous Na,S0, and evaporated in vacuo to a brownish-tan solid. Trituration with ice cold hexane and filtration afforded 26.74 g
Lo paw. uriGINAL
Ty
HX10b ’ -100- © (49%) of desired title indole as tan, granular : crystals with m.p. = 129°-130°C. | -
TLC (7:3) Hex-Et,0, Rf = 0.26, U.V. and PMA.
Microanalysis for C,H; 4FNO,:
Calcd: C, 72.07; H, 4.98; F, 6.71; N, 4.94
Found: C, 72.38; H, 5.05; F, 6.87; N, 5.01 : lg mmr (CDCl): 61.22 ppm (3H, t), 4.29 (2H, q), memes sep 7,107.62 (8H, m), 9.21 (1H, bs) ppm. Te . : 13c mm (cDCl,): 614.1, 60.9, 111.8, 114.5, 114.8, - 120.9, 121.4, 122.9, 123.1, 125.9, 127.9, 129.5, a. 132.2 (J,_g=7.6 Hz), 135.7, 162.0, 162.2 (J_p=244 . Hz) ppm. ) 15
Cc. 3-(4-Fluorophenyl)-1-(l-methylethyl)-1H- oo indole-2-carboxylic acid; ethyl ester ~ Ref. Sandoz International Patent #158675 p. 35 (1984)
A solution of the Part B indole (26.74 gq,
LT 20 94.4 mmole) in dry, distilled dimethyl acetamide ] (100 ml) at 0°C (ice bath) was treated portionwise oo (vigorous gas evolution) with 607 NaH dispersion - in mineral 0il (4.53 g, 113.3 mmole, 1.2 eq.) and
Co the mixture stirred under argon at 0°C for 1 hour. 2-Iodopropane (85 g, 500 mmole, 5.3 eq.) was added and the mixture allowed to warm to room température under argon and stirred for 1 hour. The mixture was re-cooled to 0°C, treated with another 1.2 eq. of NaH, allowed to stir at room terperature for 1 hour. This procedure was repeated two more times. _ The final mixture was cooled to 0°C (ice bath) and excess NaH quenched by careful dropwise addition of absolute EtOH (30 ml). The mixture was diluted : . : BAD ORIGINAL re ntl
HX10b <101- with EtOAc, washed with 5% KHSO,, the aqueous phase’ pack extracted once with EtOAc, the combined EtOAc . layers washed with H,0, and brine (2X), dried over : . anhydwvous Na, SO, and evaporated to give 38.54 g cf a brown solid. The solid was taken up in hot
CH,Cl, and starting indole crystallized out with the addition of hexane. 13.88 g of the starting irdole was recovered. The mother liquor was evaporated in vacuo to give 22.32 g of a brown oil. "10 The crude product was purified by flash chroma- - ' tography on silica gel eluting with hexane followed by (95:5) Hex-Acetone. Product fractions were evaporated to give 6.55 g (21%) (62% - ~ corrected yield) of desired title N-isopropyl 15 indole as a yellow oil. :
TLC (4:1) Hexane-Acetoné, Rf 0.57, U.V. and BMA: "hoo H . 1g MR (CDCl): 61.04 (3H,t), 1.20 (6H, d), 4.17 } 20 (2H, gq), 5.40 (1H, m), 7.10-7.7 (8H, m) ppm. : 13c nur (cDCl,): 613.6, 21.5, 48.7, 53.3, 60.8, no 112.7, 114.5, 114.8, 120.3, 121.4, 122.4, 124.3, . * 125.9, 127.6, 130.8, 131.7 (Jo g=7-3 Hz), 136.2, 25 162.3 (Jo_p=144 Hz), 163.0 ppm.
D. 3-(4-Fluorophenyl)-1-(1l-methylethyl)- 1H-indole-2-methanol - © Lithium aluminum hydride (1.12 g, 29.6 : 30 mmole, 1.5 eq.) was carefully added to a 0°C (ice " bath) solution of dry, distilled Et,0 (30 ml).
The resulting suspension was treated dropwise over minutes with an ethereal solution of the Part C . : } ww VRIGINAL
HX10b -102- indole ester (6.42 g, 19.7 mmole in 20 ml of Et,0).
After stirring for 30 minutes at 0°C under argon, : the mixture was quenched by sequential dropwise addition of 1,0 (1.1 ml), 15% NaOH (1.1 ml) and : 5 H,0 (3.4 ml). The resulting suspension was filtered through packed Celite, dried over anhydrous MgSO, ‘and evaporated in vacuo to give 5.1 g »f a yellow foam. The crude product was purified by flash chromatography on silica gel eluting with (85:15) Hex-Acetone to give 5.08 y oo (91%) of pure title-alcohol as a pale yellow foam. .
TLC (7:3) Hex-Acetone, Rf= 0.38, U.V. and PMA. A
Co small sample was crystallized from hexanes to give
A 15 the title alcohol as white crystals with m.p. = 101°-103°C. | ,
Microanalysis for C, gH, ,NOF: i calcd: C, 76.30; H, 6.40; F, 6.71; N, 4.94 J
Found: C, 76.49; H, 6.46; F, 6.84; N, 4.88
Co lg MMR (CDC1,): 6 1.60 (1H, t),,1.69 (6H, d), 4.76 : (2H, d), 4.93 (1H, m), 7.05-7.62 (8H, m) ppm. 13c NMR (CDCl,): 6 20.9, 47.3, 54.8, 113.0, 115.9, 116.3, 116.6, 120.2, 120.6, 122.9, 128.5, 131.6, 132.4, 135.1, 135.7, 163.0 (Jo_p=245 Hz) ppm.
E. 3-(4-Fluorophenyl)-1-(1l-methylethyl)-1H- } indole-2-carboxaldehyde
A solution of Dess-Martin periodinane (5.9 g, 13.9 mmole, 1.2 eq.) in dry, CH,Cl, (30 ml) was
BAD ORIGINAL
. a imal
HX10b -103- - treated with dry t-butanol (1.3 ml, 13.9 mmole, 1.2 eq.) and the mixture stirred at room 3 temperature under argon for 15 minutes. Part D oo indole alcohol (3.28 g. 11.6 mmole, 1 eq) in dry
CH,Cl, (12 ml) was added dropwise over 5 minutes ’ and the yellow mixture stirred under argon at room temperature for 1 hour. The reaction mixture was added to a stir: .d solution of sodium : : thiosulfate (15.3 g, 97 mmol, 7 eq.) in freshly ieee = 10 prepared 1.0N NaHCO, (40 ml) and the resulting : mixture stirred vigorously for 5 minutes. The organic phase was separated, washed with 1.0N
NaHCO, H,0 and brine, dried over anhydrous : . Na,sO, and evaporated to give 3.69 g of a yellow oil. The crude product was purified by flash chromatography on silica gel eluting with (40:1)
Hexane-Et,O0 £0 give 2.7 g (83%) of pure title aldehyde as a white crystalline solid with m.p. = 88°-89°C. .
TLC (7:3) Hex-Acetone, Rf = 0.56, U.V. and PMA.
Microanalysis for C, gH; ¢FNO: calcd: C, 76.85; H, 5.73; N, 4.98; F. 6.75
Found: C, 76.91; H, 5.71; N, 4.95; F, 6.76 : lg NMR (CDCL,): 61.69 (6H, d), 5.92 (1H, m), - . 7.10~-7.70 (8H, m), 9.80 (1H, s) ppm. 13¢ NMR (CDCl): 521.4, 48.0, 112.5, 113.2, 115.4, 115.7, 120.8, 122.1, 126.9, 127.0, 132.0, 132.6 (Jop=7-3 Hz), 183.6 ppm. : : BAD ORIGINAL
HX10b -104-
F. 3-(4~Fluorcophenyl)-1-(l-methylethyl)-2- (2,2-dibromoethenyl)-1H-indole : : A cooled (-15°C, ice/salt bath) solution of "the Part E indole aldehyde (1.84 g, 6.54 mmole) and triphenylphosphine (5.14 g, 19.6 mmole, 3 eq.) : in dry CH,C1, (30 ml) was treated dropwise over 5 minutes with a dry CH,Cl, (10 ml) solution of CBr, } (3.25 g, 9.8 mmole, 1.5 eq.) and the vellow : mixture stirred at 15°C under argon for 15 : 10 minutes. The mixture was partitioned between saturated NaHCO; and CH,C1,, the organic phase washed with saturated NaHCO, and brine, dried ‘ over anhydrous Na, SO, and evaporated to give 9.44 ‘ g of a brown oil. The crude product was purified . 15 - by flash chromatography on silica gel eluting with (95:5) Hexane-CH,Cl,. Product fractions were evaporated to give 2.87 g (100%) of desired title ) vinyl dibromide as a yellow oil which crystallized } on standing. One recrystallization from ethyl ether gave 2.46 g (86%) of purified product as pale " yellow, granular crystals with m.p. 135-137°C. i TLC (7:3) Hex-CH,Cl,, Rf = 0.45, U.V. and PMA.
Microanalysis for C,H, NF Br,: : Caled: C, 52.20; H, 3.69; N, 3.20; Br, 36.56
Found: C, 52.25; H, 3.68; N, 3.20; Br, 36.58 lg mr (cDCl,): 6 1.15 (6H, d), 4.67 (1H, m), 7.10-7.70 (9H, m) ppm.
WET BAD ORIGINAL
: oo HX1:. -105- 3c mm (¢pcly): 6 21.9, 48.6, 98.6, 111.6, 115.3, 115.6, 115.9, 119.9 (Jo_p=7-6 Hz), 122.4, 127.5, . . 129.3, 130.5, 130.7, 130.9, 135.2, 161.5 (Jo_p=246 : iz) ppm. .
G. 3-(4-Fluorophenyl)-1-(l-methylethyl)-2- : : ethynyl-1H-indole
A -78°C solution (dry ice/acetone) of the
Part F vinyl dibromide (2.395 g, 5.48 mmole) in
Lo dry THF (10 ml) under argon was treated dropwise . with a 1.6M solution of n-BuLi in hexanes (6.9 ml, 10.96 mmole, 2 eq.). The resulting mixture was stirred at -78°C for 1 hour then quenched by : . . dropwise addition of saturated NH,Cl (5 ml). The ‘ 15 mixture was allowed to warm to room temperature ! then extracted with E£,0 (2X). The ethereal layers ¢ were washed with brine, dried over anhydrous «MgSO, Le and evaporated in vacuo to give 1.893 of a dark 3 brown oil. The crude product was purified by ) 20 flash chromatography on silica gel (80:1) eluting with (200:1) Hexane-Et,0 to give 1.12 g of purified product as a (3.3:1) mixture of acetylene to ’ terminal olefin. This mixture was separated by c chromatography on alumina (neutral, activity = II) column eluting with (200:1) Hexane-Et,0.
Evaporation of product fractions gave 900 mg of off-white crystals. One recrystallization from hot hexane gave 700 mg (46%) of purified title - acetylene as white needles with m.p. = 105-106°C.
TLC, (95:5) Hex-Et,0, Rf acetylene = 0.44, Rf olefin = 0.49, U.V. and PMA.
BER . BAD ORIGINAL . : a
HX10b -106- : " Microanalysis for Cy gH; NE: :
Calcd: C, 82.28; H, 5.81; N, 5.05; F, 6.85 ’ :
Found: C, 82.70; H, 5.85; N, 5.10; F, 6.62 . s lm mr (coer): 81.70 (6H, 4), 3.5 (1H, s), 5.06 - (1H, m), 7.10-7.75 (8H, m) ppm. :
H. (S)-4-[[2-[3-(4-Fluorophenyl)-1-(1- : methylethyl)-1H-indol-2~yl]ethynyl]- 710 methoxyphosphinyl]-3-(t-butyldiphenyl- EE : silyloxy)butanoic acid, methyl ester
A -78°C (dry ice/acetone) solution of the : Part G acetylene (678 ng, 244 mmole, 1.0 eq.) in . 2. " - .dry THF (6 ml) under argon was treated dropwise N with a 1.6M solution of n-BuLi in hexanes (1.53
Co ml, 2.44 mmole, 1.0 eq.). After 30 minutes at re 1989¢, the mixture was transferred By Eanhuia-t8a Pe : -78°C solution of Example 1 Part F phosphono- chloridate (~4.3 mmole, 1.75 eq.) in dry THF (5 20. ml). The dark brown mixture was stirred at -78°C - for 30 minutes then quenched by dropwise addition of saturated NH,C1 (5 ml) and allowed to warm to - room temperature. The mixture was extracted with
Et,0 (2X), washed with saturated NH,Cl and brine, ) dried over anhydrous MgsO, and evaporated in vacuo to give 2.567 g of a brown-red oil. The crude oil : was purified by flash chromatography on silica gel eluting with (3:2) Hexane-EtOAc to give 756 mg (44%) of desired title acetylenic phosphinate as a dark yellow oil.
TLC (7:3) Hex-Acetone, Rf = 0.27, U.V. and PMA. : : BAD ORIGINAL beter
. HX10b -107- ld NMR (cDC1,): 6 1.0 (9H, s), 1.64 (6H, d), 2.10-2.90 (4H, m), 3.56 (3H, s), 3.58 (3H, 4d), oo 4.6 (1H, bm), 4.90 (1H, m), 7.05-7.55 (18H, m) ppm. 1c NMR (cDely): 6 14.2, 19.1, 21.0, 26.7, 27.8, oo 37.5, 39.2, 42.2, 45.1, 49.2, 51.4, 51.9, 60.3, 65.5 (Jo_p=15.1 Hz), 88.1], 91.2, 98.3, 111.3, 115.3, 115.6, 120.8 (J=5.7 Hz), 122.3, 124.9, : 125.9, 126.4, 127.6, 129.2, 130.7, 133.0, 135.7, oo © 10 136.1, 170.9 ppm. - :
J. (S)-4-([2-[3~(4-Fluorophenyl)-1-(1- methylethyl)-1H-indol~-2-yl}ethyl]- . methoxyphosphinyl]-3-(t-butyldiphenyl- - 15 silyloxy)butanoic acid, methyl ester Co . Co , An argon purged solution of the Part H oo acetylenic phosphinate (422 mg) in CH, OH (9 ml) | " was treated with 10% Pt/C (420 mg) and the : 4 resulting mixture shaken on a Parr apparatus for 2 hours under 40 psi of hydrogen. Catalyst was ‘removed by filtration through Celite and the filtrate evaporated to give 380 (90%) of title
Lo indole phosphinate as a yellow foam. ’ TLC (4:1) EtOAc-Hex, Rf = 0.27 U.V. and PMA. lg Mm (CDCl): 6 1.00 (9H, 5), 1.63 (6H, 4d), 1.5-2.0 (2H, m), 2.20 (1H, m), 2.58-3.00 (5H, m), 3.44 (3H, d4, Jgq.p=10-6 Hz), 3.61 (3H, s), 4.52 - (2H, m), 7.07-7.66 (18H, m) ppm. :
BAY ORIGINAL
. . ~ CL —
HX10b -108- . }
Co 3c mm (cpcl,): 612.6, 16.8, 17.2, 19.1, 21.5, Co 26.7, 36.0, 42.1, 47.2, 50.9, 51.4, 65.8; 111.8, . 115.3, 119.1, 121.1, 127.7, 128.3, 129.9, 131.2, 131.3, 132.8, 133.4, 134. . 134.8, 135.7, 171.3 ppm. - : K. ($)-4-[[2-(3-(4-Fluorophenyl)-1-(1- oo methylethyl }- 'H-indol-2-yl]ethyl]- ' methoxyphosphinyl]-3-hydroxybutanoic oo . acid, methyl ester Cee
A solution of the Part J silyl ether (379 oo mg, 0.531 mmole) in dry THF (5 ml) was treated oo successively with glacial HOAc (120 pl, 2.12
Co. mmole, 4 eq.) and a 1.0M tetrabutylammonium . 15 fluoride solution in THF (1.6 ml, 1.6 mmole, 3 eq.) and the resulting solution stirred overnight . 0 oe } - under argon at room temperature. The mixture was oo diluted with ice cold H,0 (10 ml), extracted with
TL EtOAc (2X), the organic phase washed with saturated - 20 NaHCO, and brine then dried over anhydrous Na, sO, : and evaporated to give 408 mg of a yellow oil. The : } crude product was purified by flash chromatography
K n : on silica gel eluting with (7:3) Acetone-Hexane.
EE Product fractions were evaporated to give 197 mg oc , 25 (78%) of desired title alcohol as a white foam.
A : ? TLC (1:1) Hexane-Acetone, Rf = 0.09 U.V and PMA. - lg NMR (CDCl): 6 1.68 (6H, d), 1.80-2.0 (2H, m), 2.10 (2H, m), 2.58 (2H, m), 3.08 (2H, m), 3.63 (3H, dd, Jgp=10-1 Hz), 3.70 (3H, d), 3.96 (1H, : t), 4.35 + 4.49 (1H, 2 broad multiplets), 4.67 ’ (1H, m), 7.0-7.6 (8H, m) ppm. fo | BAD ORIGINAL e—— ed ~ t
HX10b ” : -109- 13¢ nmr (cDCly): 617.6, 17.7, 21.4, 29.2, 29.4, 33.2, 33.3, 34.6, 41.6, 41.8, 42.0, 42.2, 47.3, 50.9, 51.7, 63.4, 111.8, 113.5, 115.2, 115.5, . 119.0, 119.4, 121.1, 128.3, 131.3, 131.5, 134.2, SE 134.8, 161.5 J,_.=244.1 ws), 172.1 ppm.
Example 8 (S)-4-[[2-[3-(4-Fluorophenyl)~-1-(l-methylphenyl)- 1H-indol-2-yl]ethyl Jhydroxyphosphinyl]-3-hydroxy-
Ce "10 butanoic acid, dilithium salt oo :
A stirred solution of the Example 7 diester . : (197 mg, 0.414 mmole) in dioxane (5 ml) was : treated with 1.0N LiOH (1.45 ml, 3.5 eq.) and the . resulting white suspension was heated at 55°C (oil bath) under argon for 40 minutes. The mixture : was cooled, diluted with H,O0, filtered, evaporated B in vacuo. The residue was taken up in a minimum amount of H,0 and chromatographed on HP-20 resin, . eluting with H,0 followed by (50:50) H,0-CH;OH.
Product fractions were combined and evaporated. : The glassy residue was taken up in H,0 (50 ml), filtered and lyophilized to give 178 . mg (85%, based on hydrate weight) of pure title di-lithium salt as a white solid.
Microanalysis for C,H, NFP: 2L1 + 2.52 moles H,0 (MW 504.71): .
Calcd: C, 54.73; H, 6.00; N, 2.78; F, 3.76; P, 6.14
Found: C, 54.62; H, 5.67; N, 2.90; F, 3.61; P, 6.06 i rv ORIGINAL : } SE —
11X10b oo | -110- 14 NMR (400 MHz, cDCly): ” 6 1.69 ppm (6H, dd, J=5.8 Hz) i . 1.71 (2H, multiplet)
Lo | 1.93 (2H, multiplet) 2.38 (2H, multiplet) oT 3.06 (2H, quartet) ’ 4.32 (1H, multiplet) 4.87 (1H, multiplet) : 6.97 (1H, dt, J=0.7 E> 7.07 (1H, dt, J=1.1 H=} - 7.16 (2H, t) oo 7.41 . (3H, m) : 7.57 (1H, 1/2 AB quartet) . 15 Example 9 : (S)-4-[[2-[(1,1'-Biphenyl]}-2-yl]ethyl]methoky- oo phosphinyl ]-3-hydroxybutanoic acid, methyl ester : A. Biphenyl-2-carboxaldehyde =
Dess-Martin periodinane (27.64 g, 65.2 : 20 mmol) was stirred under argon atmosphere with 150 vo ml of CH,C1,. Dry t-BuOH (8.0 ml) was added to the stirring solution, and this mixture was oo stirred for 10 minutes at room temperature. A oT CH,Cl, solution (20 ml) of biphenyl-2-methanol (10 g, 54.3 mmol) was added dropwise over 15 minutes.
After the addition was complete, the reaction was allowed to stir at room temperature. After stirring for 1 hour at room temperature, 600 ml of - Et,0 (anhydrous) was added to the reaction followed by 1N NaOH (225 ml). After 10 minutes, the resulting slurry was filtered, and the filter
So cake was washed with Et,0. The filtrate was » washed 2X with 250 ml portions of 1N NaOH. The » A BAD ORIGINAL
Coin
: .10b -111- organic layer was dried over MgSO, and filtered to give a yellow oil (10 g) after solvent removal.
Purification by flash (silica gel, Lo . © 1:10/Et,O0:Hexane) provided title aldehyde (9.58 g, 97%) as a colorless oil.
TLC (1/9 EtOAc/Hexane, silica gel) Rf = 0.29
IR (film) 3065, 3025, 2850, 2760, 1685, 1700, oo 1600, 1470, 1450, 1395 cm : ‘ lp NMR (270 MHz) (CDCly) 58.00 (4d, 1, J=70. Hz), 7.60 (m, 1), 7.40 (m, 7). ; Mass Spec m/e 183 mt+H). ) } : ) : B. 2=(2,2-Dibromoethenyl)-[1,1'-biphenyl] y oo A solution of Part A aldehyde (2.0 g, 11 mmol) in CH,Cl, (60 ml) was placed under argon atmosphere and cooled to -10°C. Triphenylphosphine i © 20 (9.21 g, 35 mmol) was added, and this mixture was : stirred until all of the solid dissolved. To the resulting solution at -10°C was added over 15 . minutes a CH,Cl, (40 ml) solution of CBr, (5.5 g, 16.5 mmol). The reaction was stirred at -10°C for 1 hour 15 minutes, and then it was quenched at -10°C with 50 ml of saturated aqueous NaHCO, solution. The CH,Cl, and aqueous layers were separated and the aqueous layer was extracted 1X : ” with CH,Cl,. The combined CH,Cl, extracts were - washed 1X with saturated aqueous NaHCO, solution and 1X with saturated agueous NaCl solution. The
CH,Cl, extract was dried over Na,SO, and , evaporated to dryness. The crude product was ae BAD ORIGINAL ee"
. HY 1 Or. -112- purified by flash chromatography eluting with .
Ls hexane to give the title dibromide as an off
Co white solid (2.45 g, 66%). oo
TLC (5:95/EtOAc:Hexane silica gel) Rf = 0.47.
IR (CEC1,) 3064, 3011, 1596, 1473, 1450, 1435, . 889, 860, 702 cm © oo 10 1g aR (270 MHZ) (cpcly) Co 67.75 (m, 1), 7.35 (m, 8), 7.20 (s, 1) 13 : C NMR (67.0 MHz) (CDCl,)
ES 5141.06, 140.08, 137.49, 133.83, 129.81, 129.45,
Co 15 129.17, 128.61, 128.22, 127.50, 127.08, 90.78 . ot Mass Spec m/e 337/339/341 (M'+H) a C. 2-Ethynyl-[1,1'-biphenyl] eB 20 ‘A THF (35 ml) solution of Part B vinyl - oo ~~ dibromide (2.31 g, 6.9 mmol) was cooled to -78°C : under an argon atmosphere. With stirring at
Co -78°C, n-BuLi (5.52 ml of 2.5 M solution in oo ] hexane) was added over 10 minutes to the vinyl . 25 dibromide. On completion of the n-BuLi addition, the reaction mixture became deep purple. After oo stirring at -78°C' for 2 hours 45 minutes, the reaction was quenched with saturated aqueous NH, Cl : : solution. After the quenched reaction was warmed to room temperature, the THF was removed from the reaction mixture and the resulting material was : diluted with H,0 and extracted 3X with 1:
Et,O/hexane. The organic extract was dried over
BAD ORIGINAL
L0b -113-
MgSO, and filtered to give 1.3 g of a yellow oil. :
Purification by flash chromatography eluting with ’ : 1% Et,0/hexane provided the desired title ) acetylene (1.04 g, 88%).
TLC (100% Hexane, silica gel) Rf = 0.16
IR (film) 3287, 3061, 3026, 1474, 1449, 1432, 1008, 775, 758, 728 cm lg MR (270 MHZ) | | : (cDCly) 6 7.68 (m, 3), 7.35 (m, 6), 3.00 (s, 1) ) 13c mm (67.8 MHz) (CDCl,) oo 6144.40, 140.22, 133.83, 129.56, 129.20, 128.92; b ime 127.95, 127.49, 126.94, 120.44, 83.08, 80.15 - Cres hit : : - ph ta
Mass Spec m/e 179 (mt +H).
D. (S)-4-[[2-[{1,1'-Biphenyl]-2-yl]- ethynyl Jmethoxyphosphinyl]-3-(t-butyl- dipehnylsilyloxy)butanoic acid, methyl } ester :
Part C acetylene (0.332 g, 1.86 mmol) was stirred at -78°C (under argon atmosphere and in 10 ml of THF. Over 5 minutes, n-BuLi (0.75 ml of a 2.5 M solution in hexane) was added to the acetylene solution. The reaction was stirred at - - -78°C for 1 hour warmed to 0°C and stirred for 10 minutes and then recooled to -78°C. The . acetylenic anion solution was then added dropwise over 8 minutes to a 10 ml THF solution of the Co
Example 1 Part F phosphonochloridate (2.98 mmol) 0 ORIGINAL . ae
HX10b : -114- ) which had been cooled to -78°C under an argon : atmosphere. After the addition was complete, the : reaction was stirred at -78°C for 1 hour and then ‘quénched by the addition of saturated aqueous NH,Cl solution. The quenched reaction was warmed to room temperature, diluted with half-saturated aqueous
NaCl solution and extracted 3X with Et,0. The combined Et,0 extracts were washed with saturated aqueous NaHCO, and saturated aqueous NaCl ~ +e 10 -solutions. The Et,0 layer was dried over MgSO, oo : and evaporated to give 1.5 g of a yellow oil. . purification by flash chromatography eluting with - 5:1:4 hexane:toluene:EtOAc gave the title . ‘acetylenic phosphinate (0.543 gq, 48%). : : . : :
TLC (5:1:4 hexane:toluene:EtOAc, silica gel) Rf = 0.20.
IR (CHCL,) 3070, 3053, 3035, 3000, 2952, 2934, in 2896, 2859, 2178, 1735, 1474, 1448, 1436, 1429 cm lg MIR (270 MHz) CDCl.) co ” . 57.65 (m, 3), 7.65-7.28 (m, 16), 4.55 (m, 1), 3.55
CL (4, 3), 3.40 (dd, 3), 2.80 (m, 1), 2.55 (m, 1), 2.35 (m, 1) 2,08 (m, 1), 1.00 (s, 9) . 3c (67.8 Mz) (cDC1y) 5170.83, 145.29, 145.19, 139.22, 135.95, 135.59, 133.86, 133.75, 133.16, 132.86, 130.57, 129.56, : : 30 129.34, 128.81, 127.92, 127.75, 127.44, 127.39, 126.94, 117.90, 100.91, 100.38, 100.18, 84.51, cud BAD ORIGINAL
HX10b -115- oC ' 81.60, 65.53, 65.42, 60.06, 51.61, 51.50, 51.11, - ) 42.07, 41.90, 38.86, 37.16, 26.56, 20.75, 18.97, 13.97 : CL - 5 Mass Spec m/e 611 (it +H) ; E. (S)-4-[[(2-[[1,1'-Biphenyl]-2-yl]ethyl]- : methoxiynhosphinyl]-(t-butyldiphenyl- silyi::y)butanoic acid, methyl ester i 10 Argon was bubbled through a methanol (8 ml) : solution of Part D acetylenic phosphinate (0.515 g, 0.85 mmol) for 10 minutes. Addition of 10% oo
Pd/C (0.190 g) to the acetylene solution was . followed by Parr hydrogenation at 43 psi. After i shaking for 25 hours at 43 psi, the methanol solution was filtered through Celite and the filtrated evaporated to give the title phosphinate (0.510 g, 98%) as a colorless oil. . 20 TLC (4:1 EtOAc: hexane) Rf = 0.21.
IR (CHC1,) 3071, 3054, 2998, 2954, 2934, 2902, . 2859, 1734, 1477, 1462, 1448, 1438, 1428 cm lu mm (270 MHz) (CDCl) ‘ 67.65 (m, 3), 7.55-7.00 (m, 16), 4.45 (m, 1), 3.58 (s, 3), 3.30-3.20 (2 doublets, 3, J = 11 Hz), 2.88 : (m, 1), 2.60 (m, 3), 2.17-1.80 ({m, 1), 1.80-1.30 " . {m, 1), 1.00 (s, 3). oo : 13; NMR (67.8 MH) (Diagnostic peaks) (CDCl;) 6171.33, 65.78, 51.36, 42.24, 26.75
AD ORIGINAL
- ' ee tine -
HX10b -116-
Mass Spec m/e 615 (M" +H) : - F. (S)-4-[2-[([l,1'-Biphenyl]-2-yl]ethyl]-" methoxyphosphi- 1 ]-3-hydroxybutanoic oC acid, methyl euisr : A THF (10 ml) solution of Part E phosphinate (0.500 g, 0.82 mmol) was stirred under an argon atmosphere witli .iOAc (0.19 m1, 3.3 mmol). At room temperature, nBu, NF (2.45 ml, 1.0 - 10 M solution THF) was added dropwise. The reaction was stirred at room temperature for 23 hours and then quenched with 15 ml of ice water. The :
SL aqueous layer was extracted 3X with EtOAc. The
Coe combined organic solutions were washed 2X with
Co 15. saturated aqueous NaHCO, solution and 1X with :
Co °° saturated aqueous NaCl solution. The organic ,
Co layer was dried over Na,SO, and evaporated to give 0.437 g of a colorless oil. Purification }
Co by flash chromatography eluting with 7:3
BEE. 20 acetone:hexane gave the title. alcohol (0.247 gq, 81%) as a colorless oil. - TLC (7:3 acetone:hexane, silica gel) Rf = 0.22 - . 25 IR (CHC1,) 3600-3171 (br), 3064, 3009, 2954, 1731, 1479, 1439, 1237, 1180, 1042, 999 em”! : lg mm (270 MHz) (CDCl,) 5 7.50-7.10 (m, 9), 4.50-4.15 (m, 1), 3.70 (s, 3), 3.53 & 3.50 (2 doublets, 3, J=11 Hz), 2.88 (m, 2), 2.50 (m, 2), 2.00-1.60 (m, 4) 3 oo : BAD ORIGINAL
Ce cam
HX10b -117- ; 3c mur (67.8 MHz) (CDCI) 6171.55, 171.49, 141.39, 141.00, 138.10, 137.88, Le } 129.95, 128.81, 128.06, 127.53, 26.83, 126.22, t 63.08, 63.02, 62.85, 51.39, 50.58, 50.47, 42.35, . 42.15, 42.07, 41.87, 34.31, 33.06, 33.00, 30.77, 30.52, 29.49, 29.21, 25.41 :
Mass Spec m/e 377 (MY +H) :
CTI oo Example 10 (S)-4-[2-[1,1'-Biphenyl-2-yl]ethyl)hydroxyphos- phinyl]-3-hydroxybutanoic acid, dilithium salt
Example 9 diester (0.239 g, 0.64 mmol) was . stirred in dioxane (6.5 ml) under argon : "15 atomsphere. At room temperature, 1.9 ml of 1.0 M , LiOH solution was added. This mixture was stirred at 55°C. After stirring for 2.5 hours, the Cie reaction was cooled to room temperature, and the . ’ dioxane and most of the H,0 were removed by rotary evaporation. Purification by HP-20 chromatography (18 cm x 2.5 cm) eluting first with 100% H,0 and then with 1:1 MeOH:H,O gave the title dilithium - salt (0.180 g, 79%) as a white solid. .
TLC (8:1:1 CH, Cl, : MeOH: AcOH) Rf = 0.16 . (7:2:1 nPrOH: NH, :H,0) Rf = 0.37
LE BAL ORIGINAL i ‘b -118- oo Example 11 (R)-4-[[(E)-2-[4'-Fluoro-3,3',5-trimethyl(1,1'~ : : : biphenyl]-2-yl]ethenyl Jhydroxyphosphinyl]-3- : hydroxybutanoic acid, dilithium salt -
A. (E)-Tributyl[2-(4'-fluorc-3, 7", 5= ) trimethyl [1l,1'-biphenyl]-2-yl]ethenyl]- tin : Ref. Miftakov, M.A. et al. Synthesis {Clomm. ) : pp. 496-499 (1985). A mixture of 2-ethynyl-4'-
Sa 10 fluoro-3,3',5-trimethyl[1,1'-biphenyl] (1.7 g, 7.13 mmole) and (n-C,Hy),SnH (2.9 ml, 10.7 mmole, 1.5 eq.) was treated with AIBN (7.0 mg, 0.426 mmole) -.
EE and the solution heated rapidly to 120°C (oil bath) : under argon. After 15 minutes at 120°C an - 15 additional quantity of (n-C4Hg) 5SnH (0.39 m1, 1.43
Bh mmole, 0.2 eg.) was added and heating continued for ; a total of 3 hours. The yellow mixture was cooled and purified by Kugelrohr distillation at 0.1 mmHg, ; 240°C to give 3.073 g (81%) of title vinyl stannane ’ as a colorless liquid. : oo
TLC hexane, Rg product = 0.45, UV & PMA. Product is unstable on silica gel (streaks to baseline). oo 13; mm (67.5 MHz, CDCly): 9.5, 13.6, 14.5, 20.9, 21.1, 27.2, 27.6, 114.0, 114.3, 123.6, 123.9, 128.8, 130.4, 133.0, 135.6, 136.1, 138.1, 140.0, 144.4, 160.3 (J p=244 H,) ppm.
BAD ORIGINAL
BX10b i -119-
H MR: 60.8-1.5 ppm (27 H, m, Sn(Bu),) . . 2.27, 2.31, 2.36 (9H, 3 singlets, aromatic. : | cr, 's) | : 6.05 (1H, d, J=20 Hz, PhCH=CHSn) 6.68 (1H, d, J=20 Hz, PhCH=CHSn) 6.90-7.13 (5H, m, aromatic protons) - B. (E)-4'-Fluoro-2-(2-iodoethenyl)-3,3',5- _ trimethyl[l,1'-biphenyl] . A solution of the Part A vinyl stannane (1.537 g, 2.89 mmole) in dry Et,0 (20 ml) was treated with iodine (734 mg, 2.9 mmole, 1 eq.) and the brownish solution stirred at room temperature oo : 15 under argon for 2 hours. The mixture was washed : with saturated sodium thiosulfate, 10% NH, OH and : bp . brine, dried over anhydrous. MgSO, and evaporated.to . i... give 1.639 g of a yellow oil. The crude product was purified by flash chromatography on silica gel . 20 (160 gm) eluting with hexane. Combined product. . fractions gave 832 mg (65%) of desired pure title trans vinyl iodide as a pale yellow oil which slowly crystallized on standing, m.p,. 53-55°C.
TLC (hexane) Re trans olefin = 0.31, (Rg cis olefin .= 0.26), UV & PMA 1 ly NR (270 MHZ): oo 52.30 & 2.32 ppm (9H, 2 singlets, aromatic methyls) © 30 6.05 (1H, d, J=15 Hz, -HC=CHI) 6.92-7.10 (5H, m, aromatic H's) 7.24 © (1H, d, J=15 Hz, PhCH=CHI)
BAD ORIGINAL eT .
~ HX10b -120- 13c NMR (67.5 MHz): 14.6, 21.0, 21.1, 81.0 (=CH-I), 114.4, 114.7, 124.2, 124.5, 128.5, 128.7, 130.5, 132.7, 132.8, 133.2, 135.8, 137.2, 140.1, - 143.1 (PhCH=CHI), 161.0 (J. =244 Hz) ppm. 5 .
Note: An lH NMR (CDCl,, 270 MHz) on mixed : fractions indicated the close running impurity to oo be the cis vinyl iodide. - 66.54 ppm (1H, d, Jy = 7.9 Hz (PhCH =CE -%)) i 1 :
C. (R)-3-[[(1,l-Dimethylethyl)diphenyl- © sgilylloxyl-4-[[(E)-2-[4'-fluoro-3,3"',5~ :
Co trimethyl(1,1'-biphenyl]-2-yl]ethenyl]- oe ’ methoxyphosphinyl Jbutanoic acid, methyl : ] 15 ester : - A -78°C (dry ice/acetone) solution of the part B vinyl iodide (812 mg, 2.22 mmole) in dry
THF (6 ml) was treated dropwise via syringe with a Co 1.6 M n-BuLi solution in hexanes (1.4 ml, 2.2 mmole, 1 eq.) and the pale yellow mixture stirred : under argon at -78°C for 45 minutes. The anion was then transferred by cannula dropwise over 10 , minutes directly into a -78°C solution of the
Example 1 Part F phosphonochloridate (~3.5 mmole, , 25 1.58 eq) in dry THF (6 ml). The yellow mixture was stirred for 30 minutes at -78°C then warmed to room temperature. The mixture was quenched at room temperature by the addition of saturated
NH, Cl (5 ml): The mixture was diluted with Et,O, the ethereal layer washed with saturated NH, C1 and brine, then dried over anhydrous Mgso, and CL oo evaporated to give 2.083 g of a yellow oil. The #7 © + crude product was purified by flash chromatography
BAD ORIGINAL
HX10b -121- on silica gel eluting with (85:15) Hex-acetone.
L Product fractions were combined and evaporated to tL give 249 mg (17%) of the desired trans olefinic - . phosphinate as a pale yellow oil. NMR indicated : ‘ approximataly at (1:1) mixture of diastereomers at " phosphorus. TLC (7:3) Hex-acetone, Re = 0.35, UV &
PMA. } . lq NMR: | Co 0
Co : 63.27 ppm (3H, d, Jy p = 11.6 Hz, ~POCH, ) 3.57 & 3.60 (3H, 2 singlets, diastereomers, -CO,CH;) . 4.33 & 4.50 (1H, 2 multiplets, diastereomers, -CH,CH(0SiR,)CH,~) . : 4.84 & 5.25 (1H, 2 dd's, diastereomers, : SE Jyamp = 17-9 Hz, Jy, p=25:3 Hz, Co 0
PhCH, =CH_-P~) : :
D. (R)-4-[[(E)-2-[4'~Fluoro-3,3',5~ trimethyl[l,1'-biphenyl]}-2-yl]ethenyl]- methoxyphosphinyl]-3-hydroxybutanoic - acid, methyl ester
A solution of the Part C silyl ether (249 mg, 0.370 mmole) in THF (5.0 ml) was treated successively with glacial HOAc (85 pl, 1.48 mmoles, 4.0 eq.) and a 1.0 M (n-C Hy) NF solution in - THF (1.1 ml, 1.1 mmole, 3.0 eq) and the yellow mixture was stirred overnight at room temperature under argon. The mixture was diluted with cold : H,0 (10 ml) and extracted with EtOAc. The organic phase was washed with saturated NaHCO, and bringap ORIGINAL ect cenit
CL HX10b : -122- : ." then dried over anhydrous Na, SO, and evaporated to : give 243 mg of a yellow oil. The crude product was ’ . purified by flash chromatography on silica oo : ‘ ; gel eluting with (55:45) Hex-acetone. .
Product fractions were combined and evaporated to = : - give 121 mg (75%) of desired title hydroxy diester ; ~~ as a colorless viscous oil.
TLC (6:4) Aceton=-iex, Re = (0.26, UV & PMA. . Ce — io - “1g NMR : . . | 0 . - 6§1.8-2.06 ppm (2H, m, CH, 0-FCH,-)
Ce | 2.30, 2.35, oo 15 2.40 (9H, 3 singlets, aromatic
CL s CH,;'s) - ; 2.40-2.60 (2H, m, -CH(OH)CH,CO,CH,) 3.50+3.55 (3H, 2 doublets, diastereomers, }
Co | 0 : 20 -POCH,, Jy p=12 Hz) .
EE 3.64 (3H, s, -CO,CH;) oF 3.77+3.84 (1H, 2 doublets, : . TT : diastereomers, -CH(OH)-) 4.28+4.38 (1H, 2 broad multiplets, ~CH(OH)-) 5.52 (1H, 2 dd's, diastereomers
So Igy coupling | :
Co & Jip coupling, 9 :
PhCH=CH-P (OCH) -)
Co ’ Co oo | BAD ORIGINAL — remo, ed }
HX10b -123~- ‘ 6.90-7.10 (5H, aromatic protons) ‘ 7.50 (1H, multiplet, diastereomers & : : Jpg coupling | :
Jip coupling,
Co 2 :
PhCH=CH-P (OCH, )~)
E. (R)-4-[((E)-2-[4'-Fluoro-3,3',5~
Saha 10 trimethyl({1l,1'-biphenyl]-2-yl]ethenyl]- hydroxyphosphinyl]-3-hydroxybutanoic ’ acid, dilithium salt
A solution of Part D hydroxy diester (121 . mg, 0.279 mmole) in dioxane (2 ml) was treated with excess 1.0 N LiOH (0.98 mg, 0.98 mmole, 3.5 eq) and the clear pale yellow mixture stirred oo under argon at 50°C (oil bath). for 1.5 hours... The - _ . = mixture was cooled, diluted with H,0, filtered and evaporated in vacuo. The residue was taken up in a minimum amount of H,0 and chromatographed on
HP-20 resin (8 cm bed, 25 mm column diameter) eluting sequentially with H,0 (200 ml), (80:20) ; H,0-CH;0H, and finally (60:40) H,0-CH,OH. Product fractions were evaporated in vacuo, taken up in
H,0 (50 ml) and lyophilized to give 91 mg of pure title dilithium salt product as a hygroscopic, white lyophilate.
TLC (8:1:1) CH, CH, -CH,OH-HOAC, Rf = 0.19, UV & PMA.
BAD ORIGINAL
. . and .
HK10b -124-
Examples 12 to 24 Co
Lae Following the procedures as outlined . : ve heretofore and as described in the previous ‘ : working Examples, the following additional ) So compounds may be prepared. oo 0 H ; : iL x oo : R-P-CH,-C-CH,-C0,-R . - oo X OH = 10 Z - “9
BAU ORIGINAL
[RATES NY
} : - 125- "HX10b
Ex. . . = . - xX ! , No. R Zz x = __R_ Co 12. -Ct -
OH {o)—c, CH, CH, H . : oo 0
Cr : Hs 13. —CH=CH~
CHO " CH=CH CH,
CH, cl 14. OH © -C=C- H
SRE =O, oo a H
EA EE . © 5 Ce - : Co Saat as Cou . 15. ori Qt ~CH CH, = Li . . - 16. OH 1 -CH=CH- H 17. oui (0) -C=C- Li en oni ORIGINAL.
L <0) mmm ’
: ~ 126- HX10 b : ) ’ Ex. xX
No. rR zx BR : 18. "ocH -C - CH, 3. -CH, CH, 3 _ } \ q cy 19. OK CH=CH -CH=CH~ OK . - c=0 } , . 0 .
Co CH, :
Lo 20. ONa (0) - -czc- Na . 2 . - - a . 21. OH (Oca, -cnjcu,- HM ‘
CH oo nL - o . ’ : :
BAD ORIGINAL
' \ aint ennti foot -
=~ 127- © HX10b .
Ex. hd «
No. R z x R . : + . ’
C Hg ~C—C—0 22. OH J \ 5 ~CH,CH,- H . - : CH, CH .
C,Hg -
OH : a 23. CHO (o)- -CH=C CH,
~ HX10b -128- : . Example 25 (S)-4-(Hydroxymethoxyphosphinyl)-3=-[[(1,1-di- methylethyl)diphenylsilyl]oxylbutanoic acid, . | methyl ester, dicyclohexylamine (1:1) salt .
Co 5 A. (S)-4-Diisopropyloxyphesphinyl)-3- [[(1,1-dimethylethyl)diphenylsilyl] : Bh oxv]-butanoic acid, methyl ester -
The E-.le 1, Part F(2) iodide (45.1 mmol.,. 21.70 g) was stirred under high vacuum for 30 —TTTU 7 7907 minutes. Freshly distilled triisopropyl phosphite EE (0.451 mol., 93.92 g, 113.37 ml.) was added in one portion and the reaction mixture was stirred under - argon and heated in a 155°C oil bath for 16.5 : . hours. The mixture was then cooled to room “ © 15 temperature. Excess triisopropyl phosphite and volatile reaction products were removed by short - } path distillation (10 mm Hg) followed by Kugelrohr
Co distillation (0.50 mm Hg, 100°C, 8 hours). The - i . : product was further purified via flash chromato- — graphy (95 mm diam. column, 6" /Merck : : silica gel, 6/3/1 Hexane/acetone/toluene eluent, 2"/min flow rate, 50 ml fractions) to afford . oo 17.68 g (33.96 mmol, 75% yield) of the title CL ‘ . ; isopropylphosphonate as a clear viscous oil:
TLC: Silica gel R.=0.32 (6:3:1 Hexane/acetone toluene) lav: (270 MH,, cDCl,) 8 7.70-7.65 (m,4H) 7.45-7.35 (m,6H) : 4.57-4.44 (m,3H) oo oo 3.59 (s,3H) 2.94 and 2.88 (2xd, 1H J=3.7 Hz) oe BAD ORIGINAL
: HX10b : -129- : 2.65 and 2.60 (2xd, 1H J=7.4 Hz) : '
Co 2.24-1.87 (Series of m, 2H)
Co 1.19 and 1.12 (2xd, 12H J=6.3 Hz) : . 1.01 (s, 9H) oo -- ’ B. (S)-4~(Hydroxymethoxyphosphinyl)-3- © ([(1,1-dimethylethyl)diphenylsilyl]- : : oxylbutanoic acid, methyl ester, dicyclohexylamine (1:1) salt
The Part A isopropyl phosphonate (30.5. : ‘mmol, 10.66 g) was stirred under argon, at room temperature, in 80 ml of dry CH,C1,. This solution was treated dropwise (5 min) with : bistrimethylsilyltrifluoroacetamide (BSTFA) (32.8 : 15 mmol, 8.44 g, 8.71 ml), followed by dropwise
So addition (10 min) of trimethylsilylbromide (TMSBr) (51.3 mmol, 7.84 g, 6.75 ml). After stirring at. oo room temperature for 20 hours, the reaction mixture was quenched with 200 ml of 5% aqueous . 20 KHSO, and stirred vigorously for 15 minutes. The aqueous layer was extracted 3 times with ethylacetate. The organic extracts were combined, washed once with brine, dried over Na,S0, and “concentrated in vacuo. The residue was azeotroped 2 times with 50 ml of toluene. The precipitate which formed was suspended in toluene and filtered. The filtrate was concentrated and the azeotrope/filter process repeated. The resulting
B filtrate was evaporated in vacuo and then pumped under high vacuum for 5 hours. The resulting viscous clear oil was stirred under argon, at room temperature, in 50 ml of dry pyridine. This solution was treated in one portion with
AIT BAD oRGINALY . . } Co ssttareremand] A
" HX10b -130- : dicyclohexylcarbodiimide (DCC) (22.6 mmol, 4.65 g), followed by addition of methanol (41.0 mmol, 1.31 - 2 'g, 1.67 ml). After stirring at room temperature for 20 hours, the reaction mixture was filtered through a celite pad in a sintered glass funnel.
The celite was washed with ethyl acetate and the combined filtrates were evaporated in vacuo. The : residue was redissolved in ethyl acetate and : : washed 2 times with 5% aqueous KHSO, and once with
Te 10 brine. The organic extract was dried over Na,S0,. filtered, the filtrate concentrated and azeotroped 2 times with toluene, suspended in toluene and filtered. The resulting filtrate was again : . concentrated, azeotroped, filtered and the Co © 15 filtrate evaporated in vacuo and placed under high = : vacuum for 6 hours to afford the phosphonate Co - monoester as a clear viscous oil (10.2 g, >100% oo yield). TLC: silica gel R;=0.50 (7:2:1 )
Co nProH/NH,OH/H,0). The phosphonate monoester [1.21 g was pumped under high vacuum for 4 hours, Co : affording 1.16 g (2.57 mmol)] was dissolved in 10 oo ml of dry ethyl ether and treated dropwise with - ‘ dicyclohexylamine (2.65 mmol, 0.481 g, 0.528 ml).
The resulting homogeneous solution sat at room’ ' 25 temperature for 7 hours resulting in significant crystal formation. The mixture was stored at -20°C for 16 hours and then warmed to room temperature and filtered. The crystals were oo washed with cold, dry ethyl ether and then pumped under high vacuum over P,0g for 18 hours. The . crystals were subsequently pumped under high Co vacuum at 45°C for 4 hours, affording 1.25 g (1.98 . : Co 1 .
Co | BAD ORIGINAL een
. +0b : -131- : : mmol, 77% yield) of the title dicyclohexylamine salt as a white powdery solid, m.p. 155-156°C. :
TLC: Silica gel R.=0.57 (20% MeOH/CH,CL,) 'H NMR: . ; (270 MH, , CDC1,) : : 5 6 7.71-7.65 (m, 4H) 7.40-7.32 (m, 6H) i 4.02 (m, 1H) 3.52 (s, 3H) 3.28 and 3.22 (m, 1H)
Co 10 3.11 (d, 3H J=11 Hz) ~~ 2.77-2.64 (m, 2H) 2:62-2.56 (m, 1H) 1.92-1.08 (Series of m, 22H) . 1.00 (S, 9H) . . 15 Mass Spec: (FAB) 632 (Mss) ¥
IR: (KBr) 3466-3457 (broad) ’ 3046, 3016, 2997, 2937, 2858, 2836, 2798, 2721, 2704, 2633, 2533, 2447, 1736, 1449, 1435, 1426, 1379, 1243, 1231, 1191, 1107, 1074, 1061, 1051, 820 CM-1
Anal .Calcd for C,oHa, OgPSi-C,,H,N: c,64.63; H,8.61; N,2.22
I. Found: C, 64.51; H, 8.49; N, 2.18
Example 26 (E)-4-[[2-[4'-Fluoro-3,3',5-trimethyl{1,1'- biphenyl ]-2-yl]ethenyl]hdroxyphosphinyl]-3- hydroxybutanoic acid, dilithium salt . A. ([2-[4'-Fluoro-3,3',5~trimethyl(1l,1'- biphenyl]-2-yl]-2-hydroxyethyl]- phosphonic acid, dimethyl ester :
A -78°C (co, /acetone) solution of dimethylmethylphosphonate (1.8 ml, 16.5 mmole, 1.6 — we BAD ORIGINAL
HX10b . -132- eq) in dry THF (20 ml) was treated dropwise over 20 oo minutes with a 1.6 M n-butylithium solution in : ' hexanes (9.7 ml, 15.5 mmole, 1.5 eq) and the - resulting white suspension stirred under argon at -78°C for 60 minutes. Example 1, Part C biphenyl : aldehyde (2.5 g, 10.3 mmole, 1 eq) in dry THF (10 ml) was then added dropwise over 15 minutes at . -78°C to give a pale orange suspension. After 30 ‘minutes at -78°C, the mixture was quenched by dropwise addition of sat'd NH,C1 (10 ml.) and - ~~ °° I allowed to warm to room temperature. <The mixture : was partitioned between ethyl acetate and H,0, the organic phase washed with brine, dried over: . anydrous Na, SO, and evaporated in vacuo to give Cl
J © 15 4.127 g of a yellow oil which slowly crystallized Yo - on standing. The crystals were triturated with: ' _hexanes to give after filtration and drying in. ro . vacuo 3.38 g (89.4%) of pure title hydroxy oC Bh phosphonate as white needles with mp = 98°-100°C.
An additional 233 mg (3.613 g total, yield = 95.6%) of pure title compound was recovered by a . : flash chromatography of the mother liquor (603 mg)
To on LPS-1 silica gel (40:1) eluting with (7:3) - ° hexane-acetone. TLC (1:1) hexane-acetone,
R.=0.33, UV + PMA. a - Anal Calcd for C19Hp404FF: | : : : C, 62.29; H, 6.60; F, 5.19; P, 8.45 =
Found: C, 62.66; H, 6.56; F, 5.03; P, 8.68 ] oo oo BAD ORIGINAL a . | Co re . i. ’ tian fe EN t
HX10b : -133-
B. [(2-[4'-Fluoro-3,3', 5-trimethyl(1l,1'~ * .biphenyl]-2-yl]ethenyl]phosphonic + acid, dimethyl ester . to : A solution of the Part A hydroxy phosphonate (3.513 g, 9.6 umole) in dry (48 sieves) toluene (15 ml) was treated with pTsOH-1
H,0 (91 mg, 0.48 mmole, 0.05 eq) and refluxed through a Soxhlet apparatus c.i:taining 4A sieves for 16 hours under argon. Acditional pTsOH-H,0 - © 10 was added during the course of the reaction at the following time intervals: 3.5 hours (91 mg), 5.0 hours (91 mg), and 6.5 hours (91 mg). The mixture was cooled, diluted with ethyl acetate and washed . with sat'd NaHCO, to give an aqueous phase, an organic phase and an oily layer between phases.: : : The aqueous phase ‘and oily layer were collected, . washed with ethyl acetate, the ethyl acetate layer" Co washed with sat'd NaHCO, and put aside. The 2 bicarbonate washes were acidified with conc. HCl, extracted with ethyl acetate, the organic phase - washed with brine, dried over anhydrous Na, SO, and ! evaporated to give 520 mg of recovered phosphonic tL acid, mono methyl ester. The diester was \ regenerated by dissolving the oil in trimethyl orthoformate (5 ml) and refluxing the mixture under argon for 4 hours. Excess formate was removed in vacuo to give a yellow oil which was taken up in ethyl acetate and combined with the - - original neutral organic phase. The ethyl acetate layer was washed with brine, dried over anhydrous
Na, so, and evaporated to give 3.396 g of a yellow 0il. The crude oil was purified by flash «+. chromatography on LPS-1 silica gel (40:1) eluting
BAD ORIGINAL
. od A
HX10b : . ~134-~ , with (75:25) Hexane-acetone. Product fractions were evaporated to give 2.987 g (89.4%) of .the Ca title trans-vinyl dimethyl phosphonate as a ‘golden vo oil. TLC (1:1) Hex-acetone, R. = 0.44, UV & PMA. =. = . 5 ly mR (CDCl): 8 2.27 (3H, d, Jy _p=1.6 Hz) 2.33 (3H, s) 2.39 (3H, s) : 3.61 (6H, d, Jy p= 11 Hz) .
S10 5.51 (1H, dd, Jy p = 18 Hz, Jy p = 20.6 Hz) =... : 6.95-7.09 (5H, m) : 7.48 (1H, dd, Jg-H = 17.9 Hz, Ig-p=23.7 Hz) Co . ppm. 15. 13 c NMR (cpely): oo 8 14.4, 20.9, 52.0 (J._p=5.7 Hz) oo i 114.4, 114.7, 119.2 (Jo_p=185.5 Hz) i } 124.3, 124.5, 128.4, 128.5 129.0 130.6 130.9 132.6, 132.7, 134.6, 137.1, 141.0, oo 148.2, 148.2 (J,_p=5.7 Hz) Co 160.5 (Jaf = 244.1 Hz) . : | c. [2-{4'-Fluoro-3,3',5-trimethyl[1,1'- : biphenyl]-2-yl]ethenyl]phosphonic oo acid, monomethyl ester _ : ' A solution of Part E vinyl dimethylphosphonate (2.895 g, 8.31 mmole) in dioxane (20 ml) was treated with a 1.0 N LiOH : : 30 solution (12.5 ml, 12.5 mmole, 1.5 eq) and the : resulting mixture stirred at 75°C (oil bath) for 70 minutes under argon. After 15 minutes of heating, the mixture became homogeneous. The mixture was :
So | ©. ,BADORIGINAL =
Cy .
HX10b
Lo _135- cooled to room temperature, acidified. to pH 1 with 1.0 N HCl (~15 ml), extracted (2X) with ethyl . acetate, the organic phase washed with brine, - dried over anhydrous Na;SO, and evaporated in vacuo to give 2.663 g (55.8%) of desired title monomethyl ester as a clear, colorless oil. TLC: (8:1:1) CH, C1, CH; OH-HOAC, Rg=0.57, UV & PMA.
Mass Spec (M+H =335 observed). lu mr (cpc1y):
Coo 100 06 2.25 (3H, 4, JH-F =. 1.6 Hz) . . 2.33 (3H, s) . 2.39 (3H, s) © 3.53 (3H, d, Jy_p = 11 Hz)
EN 5.61 (1H, dd, Jg-g = 18 Hz, Jg.p=20-6 Hz) . 15 6.90-7.12 (5H, m) . 7.38 (1H, 44, Jy_,=18 Hz, Jy-p> 24 Hz) ppm.
D. 4-[[2-[4'-Fluoro-3,3', 5-trimethyl(1l,1'- biphenyl]}-2-yl}ethenyl]methoxyphosphinyl]- 20 . 3-oxobutanoic acid, methyl ester
Distilled methyl acetoacetate (420 pl, 3.9 : mmole, 1.3 eq) was added dropwise over 15 minutes
So ] to a stirred suspension of 60% NaH dispersion in mineral oil (168 mg, 4.2 mmole, 1.4 eq) in dry THF (10 ml) at 0°C (ice bath) under argon. The ‘ resulting clear solution was stirred 15 minutes at 0°C, then treated with 1.6 M n-butyllithium solution in hexanes (2.25 m, 3.6 mmole, 1.2-eq) " over 10 minutes. The yellow dianion solution was stirred for 15 minutes at 0°C, then cooled to -78°C in preparation for treatment with a phosphonochloridate.
BAD ORIGINAL
. eS
: HX10b . -136-
Phosphonochloridate was prepared from title
Part C mono methyl ester according to the following : method. A solution of the part C phosphonic mono methyl ester (960 mg, 2.87 mmole) in dry CH,C1, (8 - ml) was treated with distilled i:rimethylsilyl- : ~~ diethylamine (750 ul, 5.98 mmole, 2 eq) and the clear mixture stirred under argon at room temperature for 1 hour. The mixture was evaporated - in vacuo, azeotroped with benzene (2 x 15 ml) and oo ~ 10 -.-the viscous oil left on the vacuum pump for 15 IEEE minutes. The oil was taken up in dry CH,C1, (8 ml) and dry DMF (1 drop), cooled to 0°C (ice bath) and " treated with distilled oxalyl chloride (290 ul, - 3.3 mmole, 1.1 eq) dropwise over 5 minutes under : ; 15 argon. After 15 minutes at o°c, the mixture was - : - stirred at room temperature for 45 minutes then ) evaporated in vacuo. The crude oil was azeotroped Co . with dry benzene (2 x 15 ml) to give after evaporation and drying on the vacuum pump for 15 : : minutes crude phosphonochloridate as a pale : yellow oil. | CL BE
Phosphonochloridate (~2.9 mmole, 1 eq) in oo dry THF (8 ml) at -78°C was transferred via -. cannula dropwise over 30 minutes to a -78°C ! oC 25 solution of methyl acetoacetate dianion. After 30 : minutes at -78°C the orange brown reaction mixture was quenched by dropwise addition of saturated oo : NH,C1 (8 ml) and allowed to warm to room temperature. The mixture was diluted with ethyl acetate, washed with sat'd NaHCO, and brine, then dried over anhydrous Na,SO, and evaporated in } . vacuo to give 1.481 g of an orange oil. The crude oil was purified by flash chromatography on Merck
BAD ORIGINAL oo
Co. nat
HX10b . oo -137-
Co silica gel eluting with (9:1) Hexane-Acetone, ’ followed by (1:1) Hexane-Acetone. Product - fractions were combined and evaporated to give 813 - -
Co mg (62.9%) of desired title vinyl phosphinic - : : 5 disster as a viscous, pale yellow oil. TLC (1:1) : Hax-Acetone, R.=0.42, Uv & PMA. a mmr (cDC1y): | . 6 2.28 (3H, s) - 2.34 (3H, s)
Ce ___.. 10 2.40 (3H, s) Co . 3.15 (2H, dd, Jy _,=4.7 Hz, Jy ,=18.2 Hz) 3.54 (3H, d, Jy p = 11.6 Hz) 3.63 (2H, s)
Lo 3.72 (3H, s) 5.57 (1H, dd, Jy _=17.9 Hz, Jy p 25.3 Hz) | : 6.95-7.09 (5H; m) | Co 0 7.52 (1H, 4d, Jy_,=17.9 Hz, Jy p=22.7 Hz) 3 ppm.
Par (cpeiy): 6 14.0 (J,_p=3.9 Hz),
A 20.6, 45.3 (Jo.p™85-.9 Hz), oo ] 49.6, 50.9 (J,_p=5.8 Hz), 5.18, 113.6, 115.0 121.4 (Jo.p=128.9 Hz), 123.6, 124.7, 128, 187.7, 129.5, 130.3, . 130.8, 132.1, 132.4, 136.4, 136.8, 138.2, 140.7, 149.2 (Jo_p=4-° Hz), 160.3 (J,_p=245.1 Hz), : . 166.7, 194.4 (Jo_p=4-9 Hz) ppm. : 30
BAD ORIGINAL
: : ~ HX10b ~-138- . E. (E)-4-[[2-[4'-Fluoro-3,3', 5-trimethyl- [1,1'-biphenyl]-2-yl]ethenyl]methoxy~ ; : phosphinyl]-3-hydroxybutanoic acid, - methyl ester : “A 0°C (ice bath) soluticn of the Part D,
Ketone (585 mg, 1.35 mmole) in dry THF (4 ml) was : treated with solid NaBH, (51 mg, 1.35 mmole, 1 : molzs eq.) followed by dropwise addition of dry
CH4O0H (1 ml, 3A sieves) and the yellow mixture :
To 10 stirred under argon at 0°C for 30 minutes. The mixture was quenched at 0°C by addition of reagent acetone (6.5 ml) followed by addition of CC-4 - silica gel (500 mg). The suspension was warmed to * Co room temperature, filtered through sintered glass, } rinsed with ethyl acetate and evaporated in vacuo to give 607 mg of a yellow oil. The crude oil was purified by flash chromatography on Merck silica gel (30:1) eluting with neat ethyl acetate. i
Product fractions were evaporated to give 340 mg (57.6%) of desired title alcohol as a pale yellow "oil. oo
TLC (neat EtOAc), Rg=0.19, UV + PMA. . Mass, Spec (M+H'=435 observed) - ls MR (CDCl): 6 - 1.90 (2H, m) - 2.27 + 2.28 (3H, 2 singlets) © 2.34 (3H, s) : $2.39 + 2.40 (3H, singlets) 2.56 (2H, 4d), © 3.52 (3H, d, Jy p=11.1 Hz) 3.69 + 3.70 (3H, 2 singlets) 3.79 + 3.90 (1H, 2 doublets) 5.52 + 5.54 (1H, 244, Ip-g-18. Hz, Jy-p=2-48 - Ge Hz) - i
BAD ORIGINAL i cite!
: HX10b : -139- 6.95 = 7.02 (SH, m) : : , 7.52 - 7.54 (1H, 2dd, Jyg=18 Hz, Jy =21.6 °° : Co : Hz) ppm. Pe 13 nvr (CDC14)(R,S mixture): Co 6 - 14.3 (Jo_p=3.9 Hz) - ’ 20.8, 35.4 + 35.8 (J._p=100.6 Hz) 42.0 (Jy_p=12.7 Hz) 5¢.7 (J,_p=6.8 Hz) | : : 56.5, 63.2 (J,_p=3.9 Hz) cee me —=30 113.8, 115.3, 122.9 + 123.2 (J, _p=122.1 Hz) BE 123.8, 128.2, 128.7, 129.0, 130.4, 131.4, . 132.3, 132.7, 136.6, 137.0, 138.2, 140.8, 148.2 + 148.8 (J,_p=4.9 Hz) i 160.5 (J,_p=245.1 Hz) Co © 15 171.8 ppm.
F. (E)-4-[[2-[4'-Fluoro-3,3',5-trimethyl-, , [1,1'-biphenyl]-2-yl]ethenyl]hydroxy- phosphinyl]-3-hydroxybutanoic acid, dilithium salt
A solution of the Part E diester (339 mg, 0.781 mmole) in dioxane (8 ml) was treated with * excess 1.0 N LioOH (2.3 ml, 2.3 mmole, 3 eq) and oo the mixture heated at 50°C (oil bath) for 1.5 “ ; hb 25 hours under argon. A white precipitate was evident after 15 minutes. While still warm, the mixture was diluted with H,0 until all solids dissolved then filtered. The filtrate was - evaporated in vacuo, taken up in a minimum amount of H,0 and chromatographed on HP-20 resin eluting with a neat H,0 + neat CH;0H linear gradient.
Product fractions were evaporated, the white
AD ORIGINAL,
HX10b ~140- residue taken up in H,0 (50 ml), filtered and . lyophilized to give 270 mg (82.7%) of desired) Le title dilithium salt as a hygroscopic, white Lo lyophilate. :
TLC (8:1:1) CH,CL,-CH,OH-HOAC, R,=0.33, UV + PMA.
Anal for C, H,,05FP-2Li + 0.63 moles H,O (MW 429.57): Calcd: C, 58.71; H, 5.46; F, 4.42; : P, 7.21
Found: C, 58.71; H, 5.70; F, 4.18, P, 6.96 mm (cociy) C0 5 1.59 (2H, multiplet) ‘ 2.24-2.37 (2H, 3 multiplet, Ju_g=8:3 Hz + : 4.4 Hz) . 2.28 (3H, doublet, Jy .=1.8 Hz) 2.30 + 2.39 (6H, 2 singlets) : 4.14 (1H; multiplet) 5.78 (1H, Jy ,=17.9 Hz, Jy p=20.5 Hz) 6.88-7.21 (6H, multiplet) -
Example 27 i _4-[[2-[4'-Fluoro-3,3',5-trimethyl(1,1'-biphenyl]- 2-y1]ethyl]hydroxyphosphinyl]-3-hydroxybutanoic : “ acid, dilithium salt . A. 4-[[2-[4'-Fluoro-3,3'-trimethyl{1,1'- biphenyl]-2-yl]ethyl]methoxyphosphinyl]- 3-hydroxybutanoic acid, methyl ester ‘An argon purged solution of the Example 6 ,
Part E trans vinyl phosphinate (297 mg) in CH,OH (6 ml) was treated with 10% Pd/c (74 mg, 25% by i 30 weight) and the black suspension shaken on a Parr apparatus under 40 psi H, for 3 hours. Catalyst was removed by filtration through packed Celite and the filtrate evaporated in vacuo to an oil. :
EE Co BAD ORIGINAL
’ HX10b -141- ;
The oil crystallized from hexanes giving, after ’ - filtration and drying in VRCUT, 267 mg (89.5%) of title saturated phosphinate as a white crystalline
Co solid. TLC (EtOAc), R,=0.20, UV + PMA. ~ s lm NMR (cDCl,, 270 LEz), IR (KBr pellet)
Mass Spec (mtu =437" chserved). ‘a NMR (cDC1,): : 5 1.55-1.87 (217, m) 2.29 + 2.30 + 2.31 (6H, 3 singlets) | 2.35 (3H, d, Jy p=2.1 Hz) Co 2.52 (2H, m) 2.78 (2H, m) 3.50 + 3.55 (3H, 2 doublets J_,=4.3 Hz) : 3.71 (3H,s) : ; 15 3.86 + 3.91 (1H, 2 singlets) 4.25 + 4.39 (1H, 2 broad multiplets) ppm. wv ! a A ate A
B. 4-[[2-[4'-Fluoro-3,3',5-trimethyl{1,1'- biphenyl]-2-yl]ethyl]hydroxyphosphinyl}- 3-hydroxybutanoic acid, dilithium salt
A solution of the Part A diester (250 mg, 0.573 mmole) in dioxane (6 ml) was treated with ’ excess 1.0 N LiOH (1.72 ml, 3 eq) and the mixture - heatéd at 50°C (oil bath) under argon for 1.5 hours. A white precipitate was evident after 15 . minutes. The mixture was diluted with H,0, while still warm until all solids dissolved and then - filtered. The filtrate was evaporated in vacuo, } the white residue dissolved in a minimum amount of
H,0 and chromatographed on HP-20 resin eluting with neat H,0 (until neutral), followed by neat
CH;OH. Product fractions were evaporated in vacuo : to a white solid which was azeotroped (2X) with , ER
BAD ORIGINAL
HX10b ~142- . .CH,CN and dried in vacuo to give 131 mg (55%) of - desired title dilithium salt as a white solid. : . TLC (8:1:1) CH,Cl,-CHjOH-acetic acid, Rg=0.34, -
So : _ Uv + PMA. :
Anal Calcd for C, H,,O.FPLi, + 0.95 moles H,0 (MW . 437.30): Cc, 57.67; H, 5.97; F, 4.34; P, 7.08 . : Found: C, 57.67; H, 5.90; F, 3.92; P. 7.39 b lg NMR (CD,OD + D,0): : : 5 1.39-1.57 (4H, mul=-iiplet) ppm 2.22-2.37 (2H, multiplet) Lo 2.26 + 2.38 (6H, 2 singlets) 2.31 (3H, doublet, Jy _.=1.8 Hz) : - 2.71-2.77 (2H, multiplet) ; . .4.13-4.20 (1H, multiplet) . 6.73-7.11 (5H, multiplet, aromatic H's) | . vl . Example 28... . - Cen mane — : (E)-4-[[2-[3-(4-Fluorophenyl)-1-(1-methylethyl)- - 1H-indol-2-yl]ethenyl)hydroxyphosphinyl]-3- - 20 hydroxybutanoic acid, dilithium salt
A. [2-[3-(4~Fluorophenyl)-1-(1- methylethyl)-1H-indol-2-yl]}-2-
Lo hydroxyethyl }phosphonic acid, : dimethyl ester ’ ’
A -78°C (acetone/CO,) solution of methyl dimethylphosphonate (1.35 ml, 12.42 mmole, 1.6 eg.) in dry THF (20 ml) was treated dropwise over 15 minutes with a 1.6 M n-BuLi solution in hexanes (7.3 ml, 11.6 mmole, 1.5 eq.) and the resulting white suspension stirred under argon at -78°C for 1 hour. The Example 7 Part E indole aldehyde (2.183 g, 7.76 mmole) in dry THF (8 ml) was added dropwise over 10 minutes to the anion at -78°C and
BAD ORIGINAL
110b -143- the resulting light orange suspension stirred for 30 minutes at -78°C. The mixture was quenched by » : dropwise addition of saturated NH Cl (10 ml), oo . warmed to room temperature, partitioned between :
H,0 and ethyl acetate, the organic phace washed with brine, dried over anhydrous Na, 50, and : evaporated to give 3.19 g of a white solid. The : crude solid was triturated with warm hexane to : give 2.967 g (94.3%) of pure title Lydroxy phosphonate as a white solid with m.p.=161-162°C. Ce
I TLC (1:1) Hex-Acetone, R;=0.29, UV + PMA. oo ’ Anal Calcd for C,1HygOy NPE: Cc, 62.21; H, 6.22; } . N, 3.46; F, 4.69; P. 7.64 v Found: C, 62.34; H, 6.32; N, 3.30; F, 4.61; P. 7.32 : 15 1m NMR (cel): 6 1.69 + 1.74 (6H, 2 doublets)
SL 2.18 + 2.56 (2H, 2 multiplets) - = nuit 3.61 (1H)
B 3.67 + 3.71 (6H, 2 doublets, Jgp=11 Hz) 5.32 (1H, m) 5.50 (1H, m) : 7.04-7.25 (4H, m) 7.33-7.39 (2H quartet) ; 7.52 (2H, AB quartet) ppm. 3c mm (cpely): 6 21.1, 21.3, 33.1 (J,_p=136.3 Hz) 48.3, 52.6 + 52.7 (Jo.p=5-7 Hz) 62.1 (J,_p=3.8 Hz) 112.5, 114.3, 115.1, 115.4, 119.5, 120, 122, 128.1, 130.6, 131.9, 132.0, 134.8, 134.9, 135.2, 161.8 (J,_p=246.1 Hz) ppm. .
BAD ORIGINAL
HX10b -144- : B. (trans)-[2-[3-(4-Fluorophenyl)-1- (1-methylethyl)-1H-indol-2-yl]- . ethenyl Jphosphonic acid, dimethyl : : : ester - 5 The Part A hydroxy phosphonate (2.60 gq, ) 6.43 mmole) dissolved in warm benzene (20 ml) was : : treated with PTSOH-H,0 (122 mg, 0.1 eq.) and the mixture refluxed through a Soxhlet containing 44 : sieves for 1 hour under argon. The yellow . 7 10 “solution was cooled, diluted with ethyl acetate, : the organic phase washed with saturated NaHCO, (2X) and brine then dried over anhydrous Na,SO, : and evaporated to give 2.47 g of crude olefin as a . : yellow solid. One recrystallization from ethyl ; 15 acetate-hexanes gave 2.238 g (89.9%) of pure oo title trans vinyl phosphonate as pale yellow plates with m.p.=153-155°C.
TLC (1:1) Hex-Acetone, R, =0.33, UV + PMA
Mass Spec (m+a' 388" observed). . : 20 Anal Calcd for C,1H,30,5FNF: Cc, 65.11; H, 5:98;
N, 3.62; F, 4.90; P. 7.99
Found: C, 65.27; H, 6.03; N, 3.48; F, 5.11; P. 7.98
Rg 'm,MMR(cDCL) : 1.67 (6H, doublet) 3.68 (6H, d, Jgp=11.6 Hz) : 4.90 (lH, septet) 5.73 (1H, dd, Jy.gltrans)=18 Hz, Jgp-p=18.2 Hz) i 7.05-7.56 (8H, m) 7.64 (1H, dd, Jy .=17.9 Hz, Jy p=23.7 Hz) ppm. : | BAD ORIGINAL
HX10b -145- an 13¢ yur (CDCl): : 21.7, a7.8, 52.2 (J,_,=5.7 Hz) : 111.8, 115.4, 115.7, 118.5 (Jo.p=43.5 H) . 120.1, 120.2, 123.4, 128.2, 130.5, 130.7, Co 5 131.1, 131.7, 135.9, 137.9 (Jo_p=7.6 Hz) ) 161.9 (Jo_p=246 Hz) ppm. . : Cc. (trans)-[2-[3-(<-Fluorophenyl)-1- (1-methylethyl)-1H-indol-2-y1]- ethenyl ]Jphosphenic acid, ‘monomethyl Ce : ester
The Part B vinyl dimethylphosphonate (1.787
Co g, 4.61 mmole) was dissolved in warm dioxane (12 : . ml), treated with 1.0 N LiOH (6.9 ml, 6.9 mmole, 1.5 eq.) and heated at 75°C (oil bath) under argon for 30 minutes. The mixture was cooled, acidified Co i. with 1.0 N HC1 (8 ml), extracted with ethyl acetate : (2X), washed with H,0 (2X) and brine, dried over anhydrous Na,so, and evaporated to give 1.859 g of ’ - 20 a yellow oil. The oil was dissolved in warm : hexane, cooled, and crystallized to give 1.657 g (96.1%) of mono acid as a pale yellow solid with m.p.=181-183°C. }
B Anal Caled for C,(H, O.PNF: C, 64.02; H, 5.70; 25 . N, 3.73; F, 5.06; P, 8.25
Found: C, 64.02; H, 5.87, N, 3.64, F, 5.26, P. 7.90
TLC (20:1:1) CH,Cl,-CH,OH-acetic acid, Re =0.26, -
UV + PMA } 'n mmr (cel): 5 1.66 (6H, doublet) 3.64 (3H, doublet, Jyg-p=11.6 Hz) 4.89 (1H, septet) . : ’ oe - BAD ORIGINAL
HX10b : ~146- . 5.81 (1H, dd, J, _,=17.9 Hz, J, .=18.5 Hz) 7.06 -7.64 (9H, multiplet) ppm. ‘ co Pc mmr (opely): oo 8 21.8, 47.9, 52.1 (J,_p=5.7 Hz) 112.0, 115.5, 115.8, 116.1, 119.0 (Jo_p=9-5
Hz) ’ 120.2, 120.4, 123.5, 128.3, 130.4, 130.8, 131.2, 131.8, 131.9, 136.2, 136.8 i (Jo_p=7-6 Hz) ‘10 161.9 (Jo.p=246 Hz) ppm. - -
D. 4-[[2-[3~-(4-Fluorophenyl)-1~-(l1-methyl- ethyl)-1H-indol-2-yl]ethenyl Jmethoxy- . phosphinyl]-3-oxobutanoic acid, : 15 methyl ester ji Phosphonochloridate was prepared according to the following method. A solution of Part C oo phosphonic mono methyl ester (1.564 g, 4.19 mmole, l eq) in dry CH,Cl, (10 ml) was treated with : distilled diethylamino trimethylsilane (1.05 ml; 8.38 mmole, 2 eq) and the mixture stirred under - argon at room temperature for 1 hour. The mixture oo was evaporated in vacuo, taken up in benzene .
To (20 ml), evaporated in vacuo and the viscous oil left on the vacuum pump for 15 minutes. A solution of the crude silylated acid in dry CH,C1, (10 ml) and dry DMF (1 drop) was cooled to 0°C, treated dropwise with distilled (cocl), (400 ml, : 4.61 mmole, 1.1 eq), stirred 15 minutes at 0°C, } 30 then at room temperature for 45 minutes under ~ argon. The yellow mixture was evaporated oo in vacuo, taken up in benzene (20 ml), evaporated in vacuo and left on the vacuum pump .
BAD ORIGINAL
BX. -147- for 15 minutes to give crude phosphonochloridate ° Co oC . as a viscous yellow oil. A solution of the phosphonochloridate in dry THF (8 ml) at -78°C was ~ ’ ’ transferred by cannula dropwise over 20 minutes to - , - 5 a -~78°C solution of the methyl acetoacetat:.: dianion ~ prepared as described in Example 26 from methyl ; acetoacetate(590 pl, 5.45 mmole, 1.3 eq), 60% NaH 0il dispersion (235 mg, 5.87 mmole, 1.4 cq), 1.6 M : n-butyllithium (3.1 ml, 5.03 mmole, 1.2 eq), THF
Se 10. (10 ml). The orange reaction mixture was stirred _. _ 30 minutes at -78°C then quenched by dropwise addition of saturated NH,Cl and allowed to warm to : room temperature. The mixture was partitioned . between ethyl acetate and H,0, the organic phase washed with saturated NaHCO, and brine then dried over andhydrous Na,sO, and evaporated to give 2.080 g of a yellow oil. The crude oil was purified by flash chromatography on Merck silica gel eluting with (7:3) CH,Cl,-EtOAc. Product fractions were combined and evaporated to give 519 mg (26.3%) of : desired title trans phosphinate as a light yellow oil. : i TLC (1:1) Hex-Acetone, R.=0.48, UV + PMA. i Mass Spec (ME =472% observed). : 25m NMR (cDCl,): 6 1.66 + 1.71 (6H, 2 doublets) - 1.68 (2H, m) . oo 3.23 (2H doublet) : 3.54 (3H, d) 3.72 (3H, s) 4.90 (1H, septet) - 5.76 (1H, dd, Jy _,=18 Hz) ' BAD ORIGINAL
. HX10b -148- 7.10-7.58 (8H, m) . 7.66 (1H, dd, J, .=18 Hz) ppm. oo : 13 .
CL C MMR (CDCl;): : } 8 21.8, 45.7 (Jo_p=87-1 Hz) ~ s 47.9, 50.0, 51.5 (Jo p=5-7 Hz) . 52.3, 111.9, 115.5, 118.8 (Jo p=104.1 Hz) 119.8, 120.2, 120.3, 123.6, 128.2, 130.4, 130.8, 131.8, 131.9, 136.1, 139.2 - (Jo p=5-6 Hz) mime 10 161.9 (J,_p=246 Hz) - | : 167.0, 194.6 (J,_p=3.8 Hz) ppm.
E. (E)-4-[[2-[3-(4-Fluorophenyl)-1-(1- : . methylethyl)-1H-indol-2-yl]ethenyl]- methoxyphosphinyl]-3-hydroxybutanoic acid, methyl ester
A -15°C (salt/ice bath) solution of the
Part D ketone (519 mg, 1.1 mmole) in dry absolute ‘ }
EtOH (3R sieves, 8 ml) was treated with solid
NaBH, (42 mg, 1.1 mmole) and the yellow mixture . stirred under argon at -15°C for 20 minutes. The mixture was quenched by addition of acetone (0.5
SU ml) followed by CC-4 silica gel (500 mg). The 3 ‘ mixture was warmed to room temperature, filtered, : rinsed with ethyl acetate and evaporated in vacuo to give 512 mg of a yellow foam. The crude foam was purified by flash chromatography on Merck silica gel eluting with (4:1) ethyl acetate-acetone followed by neat acetone. Product fractions were evaporated to give 317 mg (60.9%) k of desired title alcohol as a yellow oil. : . TLC (4:1) EtOAc-Acetone, R.=0.21, Uv + PMA.
BAD ORIGINAL
HK10b ’ : -149-
Mass Spec (M+H'=2.74" observed) : 'n MR (cpely): CL 1.68 (6H, doublet) : - 1.97 (2H, m) : Co 5 2.58 (2H, d) : 3.61 (3H, d, Jgp=11 Hz) 3 . 3.68 (3H, s) 3.95 + 4.04 (1H, 2 doublets) or 4.40 (1H, bm) 4.95 (1H, septet) oT } 5.78 (1H, dd, Jy .=17.4 Hz, Jg_,=23.2 Hz) . 7.05-7.77 (9H, m) ppm. 12 mm (cpcl,): . 6 21.7, 34.9 + 36.3 (Jo_p=20.8 Hz) 42.0 (Jop=13.2 Hz) i - . 47.8, 50.8 (Jo_p=5.6.Hz) , . Cag eee eae " Tan 51.6, 63.1 (Jo_p=15.1 Hz) 111.8, 115.4, 115.7, 118.6, 119.9 + 121.8 - (Jo_p=18.9 Hz) 120.1, 123.4, 128.2, 130.6, 130.7, 131.1, 131.7, 131.9, 135.8, oo 138.0 + 138.5 (J,_p=5.7 Hz) 161.8 (Jo_p=246.1 Hz) 171.7, 171.8 ppm. oo
F. (E)~4-[[2-[3-(4~Fluorophenyl)-1-(1- . methylethyl)-1H-indol-2-yl]ethenyl]- hydroxyphosphinyl]-3-hydroxybutanoic acid, dilithium salt
A stirred solution of the Part E hydroxy " 30 diester (264 mg, 0.558 mmole) in dioxane (6 ml) was treated with 1.0 N LiOH (1.95 ml, 3.5 eq) and - heated at 70°C (oil bath) for 20 minutes under argon. The mixture was allowed to cool, diluted
Sa gap ORIGINAL
HX10b -150~ © with H,0, filtered, evaporated in vacuo, taken up in a small amount of H,0 (1-2 mls) and : chromatographed on HP-20 eluting with H,0 (until : . neutral, 3-4 cclumn volumes) followed by (75:25) - 5 CH,OH-H,0. Product fractions were evaporated, i taken up in H,0 (50 ml), filtered and lyophilized : to give 217 mg (85.1%) of desired title dilithium : . salt as a white lyophilate.
TLC (8:1:1) CH,Cl,-CHjOH-acetic acid, R;0.08,
Ce 10 - UV + PMA SRE oo
Co Anal Calcd for C, H,; ONPF-2 Li + 1.62 moles H,0 i (MW 486.46): : :
Cc, 56.78; H, 5.44; N, 2.88; F, 3.91;.P, 6.37 . . Found: C, 56.76; H, 5.64; N, 2.58; F, 3.60; P, 6.77 'H MMR (400 MHz, CDCl): | : 6 1.67 (6H, doublet) 1.73 (2H, multiplet) 2.38 (2H, doublet of AB quartet, Jap=15 Hz, . Jax=8 Hz, Jpx=4-8 Hz) 4.24 (1H, multiplet) . : . 5.06 (1H, septet) Cs 6.09 (1H, Jur=17-6 Hz, Jgp=19.4 Hz) . : ; 7.02-7.61 (9H, multiplet)
Example 29 (S)-4-[[2-([1-(4-Fluorophenyl)-3-(l-methylethyl)- 1H-indol-2-yl]ethyllhydroxyphosphinyl]-3-hydroxy- . butanoic acid, dilithium salt
A. 4-Methyl-2-oxopentanoic acid, ethyl ester 4-Methyl-2-oxopentanoic acid, sodium salt (25 g) was dissolved in a minimum amount of H,0, “acidified to pH 1 with concentrated HCl and then
BAD ORIGINAL
_ i
‘ HX10b -151~ : "extracted several times with CH,cl,. The aqueous . phase was saturated.with NaCl and back extracted o (2X) with CH,C1,. The combined organic phases were washed with brine, dried over 2nhydrous :
Na, SO, and evaporated to give 17.7 g of the free - acid as a viscous oil. :
A mixture of the acid (17.7 g, 136 mmole) oo in dry benzenz= (200 ml) was ticated with : diazabicycloundecane (DBU) (20.4 ml, 136.2 mmole,
To 77107 "1 eq.) giving an exothermic reaction and a gel-like Ce crystalline salt formed. The mixture was treated : with ethyl iodide (10.9 ml, 1 eq.) and mechanically stirred under argon for 3 hours. Precipitated . salts were removed by filtration, the filtrate washed once with a small amount of H,0 (50 ml) and brine then dried over anhydrous Na, so, . Benzene was removed by distillation at atmospheric pressure Co : and the yellow liquid remaining was vacuum A distilled to give 6.46 g (35.1%) of desired title ester as a clear, pale yellow liquid with bp = ) 65-66°C (5 mmHg). TLC (9:1) Hexane-acetone,
R.=0.55, PMA (pale blue) Mass Spec (M+H'=159% observed). }
B. 4-Methyl-2-(2Z-phenylhydrazono)- pentanoic acid, ethyl ester . A solution of the Part A ethyl ester (5 gq, 31.6 mmole) in dry CH,Cl, (30 ml) was treated with phenylhydrazine (3.3 ml, 33.2 mmole, 1.05 eq) . - 30 dropwise over 5 minutes and the resulting yellow mixture stirred under argon at room temperature over 4& sieves for 3 hours. The mixture was dried over anhydrous Na,S0,, filtered and evaporated \
BAD ORIGINAL
: HX10b -152- in vacuo to give 8.105 g of an orange oil. The ; oil was purified by flash chromatography on LPS-1 silica gel eluting with Hexane-ethyl acetate. oo 2 : Product fractions were evaporated to give 6.8 g : (86.7%) of pure title hydrazone and 848 mg (10.8%) of the geometrical isomer of the title hydrazone. ”
Total yield=97.5% :
TLC {9:1) Hexane-Acetone, Re geometrical Co : iscuwers=0.42 + 0.64, UV + PMA 7777710 Mass Spec (M+H"=249" observed). ~~ - - -
C. 3-(1-Methylethyl)-1H-indole-2- : carboxylic acid, ethyl ester «0 Gaseous HCl was bubbled (gas dispersion : 15 tube) into an absolute ethanolic (50 ml, over 3 & : sieves) solution of the Part B hydrazone (6.8 gq, - - 27.4 mmole) for 30 minutes at rodm €émperatike. " :
The exothermic reaction was characterized by color . changes from yellow to red to deep green followed : by precipitation of NH, Cl. The suspension - was stirred an additional 20 minutes under
Drierite, then dumped into ice cold H,0 (50 ml). - . Ethanol was removed in vacuo and the residue partitioned between ethyl acetate and H,O0. The aqueous layer was extracted with ethyl acetate (2X), the combined organic phases washed with H,0 and brine, then dried over anhydrous MgSO, and evaporated to give 4.969 g of a green solid. The crude solid was dissolved in hot hexane, treated with Darco, filtered through packed Celite, concentrated to a 30-50 ml volume and the yellow solution allowed to crystallize. Precipitated : crystals were collected by filtration, rinsed with
Co | BAD ORIGINAL ct ton to Allin
HX10b -153-~ cold hexane and dried to give 4.34 g (68.5%) of .
Co pure title indole as white needles with mp80-81°C Lv and with consistent 14 NMR (¢pcl,, 270 MHz).
TLC (9:1) iixane-Acetone, Ry = 0.42, UV + PMA.
Note: Re +f hydrazone and indole are identical but indole has bright purple fluorescence. (M+H" = 232% observed). .
Anal C.l..! for Cy4H,,N0,: C, 72.70; H, 7.41, )
N, 6.06 ~~~ 10 Found: c, 72.67; H, 7.57; N, 6.00 Co
D. 1-(4-Fluorophenyl-3-(l-methylethyl)- E 1H-indole-2-carboxylic acid, ethyl . ester .
A solution of the Part C indole (3:937 gq, "17 mmole) and 1-bromo-4-fluorobenzene 9.34 ml, 85 ,
Co mmole, 5 eq) in dry DMF (15 ml) was treated with : cuprous oxide (245 mg, 1.7 mmole, 0.1 eq) and } " - refluxed under argon for 17 hours. Additional bromide (9.34 ml, 5 eq) and Cu,0 (245 mg, 0.1 eq) were added, refluxing continued for 6 hours, more
Cu,0 added (730 mg, 5.1 mmole) and refluxing : : continued for 60 more hours. DMF and excess } bromide were distilled off in vacuo and the orange residual oil taken up in ethyl acetate, filtered through packed Celite, washed with saturated © NaHCO, and brine then dried over anhydrous Na,s0, and evaporated to give 5.385 g (97.2%) of desired . crude title indole as an orange oil. So
TLC (9:1) Hexane-Acetone, Rg=0.29, UV + PMA, 14
L
Ce oo | BAD omaN® .
: HX10b -154-
E. 1-(4~Fluorophenyl)-3-(l-methylethyl)- 1H-indole-2-methanol - To
To cold (0°C, ice bath) dry ether (24 ml) ) under argon was added solid LiALH, (907 mg, 23.9 mmole, 1.5 molar equivalint) followed by dropwise addition of the Part D indole ester (5.185 g, 15.9 : mmole) in dry Et,0 (10 ml) over 10 minutes. The : ~ ~ mixture was stirred for 1 hour at 0°C, then : quenched at 0°C by sequential dropwise addition of
CL } ..10 -H,0 (910 pl), 15% NaOH (910. pl) and H,0 (2.73 ml).
The suspension was filtered through anhydrous : MgsO, over packed Celite and the filtrate : , evaporated .to a clear, colorless oil. The oil
CL gradually crystallized from hexane to give in 2 crops (3.771 g + 0.333 g) 4.10 g (90.9%) of purée title indole alcohol as white, granular crystals B with mp = 81-82°C..
Mass Spéc (mat =284" observed).
Anal Calcd for C, gH, gNOF: Cc, 76.30; H, 6.40; . 20 N, 4.94; F, 6.71
Found: C, 76.59; H, 6.31; N, 4.93; F, 6.49 - F. 1-(4-Fluorophenyl)-3-(l-methylethyl)- 1H-indole-2-carboxaldehyde ]
A solution of Dess-Martin periodinane (6.46 g, 15.24 mmole) in dry CH,Cl, (30 ml) was treated with dry t-butanol (48 sieves, 1.44 ml, 15.24 mmole, 1 eq.) and the mixture stirred under argon : for 15 minutes at room temperature. A solution of the Part E indole alcohol (3.599 g, 12.7 mmole) in dry CH,Cl, (13 ml) was added dropwise over 10 minutes and the pale yellow mixture stirred under . argon at room temperature for 30 minutes. The
SA BAD ORIGINAL ' ; emma .
) HX10b -155- * reaction mixture was added to a solution of sodium © thiosulfate (14.06 g, 89 mmole, 7 eq) in freshly . : prepared 1N NaHCO, (40 ml) and stirred for 10 : : minutes. The aqueous phase was drawn off, the - : 5 organic phase washed with 1.0 N NaHCO, (2X), H,0 - and brine, then dried ovér anhydrous Na,so, and : evaporated to give 3.877 g of a yellow oil. The crude oil was purified by flash chromatography on
LPS-1 silica gel eluting with (40:1) ++. - 10 Hexane-ether. Product fractions were evaporated Co Co to give 3.118 g (87.3%, crude yield) of crude : product. One recrystallization from hot hexane : gave 2.643 g (74%) of pure title aldehyde as ) . white fluffy needles with mp = 114-116°C.
Mass Spec (M+H'=282" observed). TLC (7:3)
Hex-Et,0, R.=0.51, UV + PMA oo ‘ Anal Calcd for CN, NOF: C; 76.85; 'H, 5.733% ~~ "v= °°
N, 4.98; F, 6.75
Found: C, 76.87; H, 5.63; N, 4.89; F, 6.88 - . G. 2-(2,2-Dibromoethenyl)-1-(4-fluoro- phenyl)-3-(1l-methylethyl)~1H-indole
A -15°C (salt/ice bath) solution of the ~ Part F aldehyde (1.615 g, 5.74 mmole) and - 25 triphenylphosphine (4.52 g, 17.22 mmole, 3 eq) in dry CH,C1, (25 ml) was treated dropwise over 10 i ‘ minutes with a CBr, (2.86 g, 8.61 mmole, 1.5 eq) solution in dry CH,Cl, (10 ml) and the resulting dark orange red solution stirred under argon at © 30 -15°C for 15 minutes. The mixture was quenched at -15°C by the addition of saturated NaHCO, diluted » with CH,CL,, the organic phase washed with saturated NaHCO, and brine then dried over 1
BAD ORIGINAL . . . ’ J “ fo
‘ HL: -156- Lo anhydrous Na,S0, and evaporated to give 8.9 g of a
Co red solid. The crude solid was purified by flash : chromatography on LPS-1 silica gel eluting . with (100:1) Hexane-ether. Product fractions were evaporated to give 2.017 g (80.6%) of pure title : vinyl dibromide as pale yellow crystals with . mp=123°-124°C .
C TLC (9:1) Hexane-ether, R, = 0.67, UV < PMA. .
Mass Spec (Ms&H =438" observed). )
Ce 10 Anal Calcd for CoH, gNFBI,: C; 52.20; H, 3:69; . N, 3.20; F, 4.35; : : Br, 36.56 : :
Co Found: C, 52.25; H, 3.69; N, 3.18; F, 4.24;
SE Br, 36.59
SE : oo H. 2-Ethynyl-1-(4-fluorophenyl)-3-(1- methylethyl)-1H-indole ~~ =
A -78°C (CO, /acetone) solution of dry THF ; (10 ml) was treated with a 1.6 M n-butyl lithium solution in hexanes (5.5 ml, 8.8 mmole, 2.2 eq) and. : a solution of Part G vinyl dibromide (1.749 g, 4 mmole) in dry THF (10 ml) was added dropwise over
N 15 minutes under argon. The yellow mixture was - ’ stirred 20 minutes at =-78°C, then quenched by the addition of sat'd. NH,Cl (10 ml). After warming - to room temperature, the mixture was diluted with : ethyl acetate, the organic phase washed with sat'd. NH,Cl and brine, then dried over anhydrous :
Na,SO, and evaporated to give 1.216 g of a dark green-brown oil. The crude oil was purified by flash chromatography on Merck silica gel eluting with (300:1) Hexane-ether. Product fractions were evaporated to give 1.084 g (97.5%) we ER eg . Le 3
BAD ORIGINAL
HX10b ~157- of title indole acetylene as a fluorescent : green oil. Iq NMR (cDC1,, 270, MHZ) indicated an ; - (18:1) mixture of desired acetylene to undesired terminal olefin. "TLC (50:1) Hex-Et,0, R.=0.55, . 5 Uv & PMA.
J. (S8)-4-[[2-[1-(4-Fluorophenyl)-1- } ~ (1-methylethyl)-1H-indol-2-y1]- ethynyl Imethoxyphosphinyl]--2.-
LT 0 TT [[(1,1-dimethylethyl)diphenylsilyl]- oxy]butanoic acid, methyl ester
Phosphonochloridate was prepared from the
Example 25 phosphonic mono methyl ester, . dicylohexylamine salt by the following procedure. . 15 = The free acid was regenerated from the : dicyclohexylamine salt (4.32 g, 6.83 mmole, 1.75 eq) by partitioning between 1.0 N HC1 and ethyl acetate, washing the organic phase with 1.0 HCl (2X) and brine then drying over anydrous Na,so, and 2Q evaporating in vacuo to give the free acid (6.8 mmole) as a clear, viscous oil. The phosphonic oo acid, mono methyl ester (6.8 mmole) in dry CH,C1, (10 ml) was treated with distilled trimethylsilyl : ) diethylamine (1.72 ml, 13.7 mmole, 2 eq) and the ° clear solution stirred under argon at room temp. for 1 hour. The mixture was evaporated in vacuo, chased with dry benzene (2 X 20 ml) and left . on the vacuum pump for 15 minutes. The crude silylated acid in dry CH,C1, (10 m1) and dry DMF (1 drop) was cooled to 0°C (ice bath) and treated dropwise over 5 minutes with distilled (coci), (655 vl, 7.5 mmole, 1.1 eq). The yellow mixture was stirred at 0°C for 15 minutes and 45 minutes at
BAD ORIGINAL
HX10b -158- room temp. under argon. The mixture was : evaporated in vacuo, chased with benzene (2 x 20 nm) and left on the vacuum pump for 15 minutes : giving crude phosphonochloridate as a yellow, viscous oil. : A -78°C solution (CO,/acetone) of the Part H } indole acetylene (1.084 g, 3.90 mmole, 1 eq) in ; dry THF (10 ml) was treated dropwise over 10 Co minutes with a 1.6 M n-butyllithium in hexanes 777 10 solution (2.44 ml, 3.9 mmole, 1 eq) and the purple see suspension stirred under argon at -78°C for 30 . ~ minutes. The anion was added dropwise via cannula : over 30 minutes at -78°C to a -78°C solution of . the phosphonochloridate in dry THF (10 ml). The dark brown mixture was stirred at -78°C for 30 | . minutes then quenched by dropwise addition of sat'd NH, C1 (10 ml). The mixture was warmed to } oo room temperature, partitioned between ethyl : . acetate, and sat'd NH, C1, washed with brine, dried i. : 20 over anhydrous Na, SO, and evaporated to give 1.968 g (71.1%) of title acetylenic phosphinate as a oo light yellow oil. oo TLC (7:3) Hexane-Acetone, R.=0.25, UV & PMA. . Mass Spec. (m+H =710" observed). oo 25 : Co
K. (S)-3-[[(1,1-Dimethylethyl)diphenyl- . silylloxyl-4-([2~[1-(4-fluorophenyl)~3- (1-methylethyl)-<1H~-indol-2-yl}ethyl]- : methoxyphosphinyl]butanoic acid, : methyl ester
An argon purged solution of Part J acetylene (950 mg) in CH,OH (10 ml) was treated with 10% Pt/C (238 mg, 25% by weight) and the
Co ‘BAD ORIGINAL
11X10b ; -159- black suspension stirred under an H, atmosphere (1 Co atm) overnight. Catalyst was removed by filtration through a Millipore polycarbonate
Co filter (0.4 um) and prefilter and the filtrate evaporated in vacuo to a yellow oil. The crude : . oil was purified by flash chromatography on Merck silica gel eluting with (8:2) Hexane-ethyl . acetate. Product fractions were evaporated to . give 915 mg (86.7%) of pure title saturated .. 10 'phosphinate as a white foam. Co mm ee
TLC (4:1) EtOAc-Hexane, Re = 0.39, ) : UV + PMA. Mass Spec (M+H =714" observed). . L. (S)-4-[[2-(1-(4-Fluorophenyl)-3-(1- -methylethyl)-1H-indol-2-yl]ethyl]- : methoxyphosphinyl]-3-hydroxybutanoic acid, methyl ester de ; A solution of the Part K silyl ether (915 : : mg, 1.22 mmole) in THF (10 ml) was treated - 20 successively with glacial acetic acid (280 pl, 4.88 mmole, 4 eq) and a 1.1 M n-C, Ho NF solution in THF (3.3 ml, 3.66 mmole, 3 eq) and the mixture stirred \ under argon at room temperature overnight. Ice : cold H,0 (8 ml) was added, the mixture extracted with ethyl acetate, the organic phase washed with 5% KHSO, (2X), saturated NaHCO, and brine then dried over anhydrous Na,so, and evaporated in vacuo to give 955 mg of a yellow oil. The . . crude oil was purified by flash chromatography on
Merck silica gel eluting with (1:1)
Hexane-Acetone. Product fractions were evaporated to give 521 mg (85.5%) of desired title alcohol as a pale yellow oil.
Co AD ORIGINAL
: HX10b - -160-
TLC (3:2) Acetone-Hexane, Rg=0.21, Uv + PMA. - Mass Spec (M+H'=476" observed). Co : - M. (S)-4-[[2-[1-(4-Fluorophenyl)=3~(1~ oo methylethyl)-1H-indol-2-yllethyl }-
CL hydroxyphosphinyl[-3-hydroxybutanoic .- : acid, dilithium salt
A solution of Part L diester (505 mg, 1.06 mmole) in dioxane (10 ml) was treated with: excess ..- 10 1.0 N LiOH (3.7 ml, 3.7 mmole, 3.5 eq) and the oo mixture heated at 65°C (oil bath) under argon for 1.5 hours. The mixture was diluted with H,O, filtered, and evaporated in vacuo to a light . yellow solid. The crude solid was suspended in a : small amount of H,0 and chromatographed on HP-20
Co resin (15 cm bed; 25 mm dia. column) eluting with
Co H,0 until neutral followed by CH,OH. Product . fractions were combined, evaporated, taken up in } ’ H,0 (50 ml) and lyophilized to give 484 mg (95.4%) of desired title dilithium salt as a white lyophilate. : : oo TLC (8:1:1) CH,Cl,-CH,OH-acetic acid, Rg=0.39, + UV + PMA. i . Anal Calcd for C,,H,cNOGFP-2Li + 1.03 moles H,O +25 (Mw=477.91): C, 57.80; H. 5.72; N, 2.93; F, 3.97; }
P, 6.48
Found: C, 57.80; H, 6.01, N. 3.01; F, 3.93, P, 6.41. oo Bro CiuGINAL )
HX10b : -161- -
Example 30 (S)-4-[[2-(1-(4-Fluorophenyl)-3-(1l-methylethyl)- 3 1B-indol-2-yl]ethynyl]hydroxyphosphinyl]-3-: ~ hydroxybutanoi~ acid, dilithium salt oo
A. (5)-4-[[2-[1-(4-Fluorophenyl)-3-(1- . methylethyl)-1H-indol-2-yl]ethynyl]- methoxyphosphinyl]-3-hydroxybutanoic ; acid, methyl ester n
A solution of the Example 30 Part J silyl - ether (987 ng, 1.39 mmole) in dry THF (12 ml) was Te - ~ treated successively with glacial acetic acid (320 : pl, 5.6 mmol, 4 eq) followed by a 1.1 M n-C,H NF : : solution in THF (3.8 ml, 4.17 mmole, 3 eq) and the : mixture stirred overnight under argon at room temperature. The mixture was diluted with ice
Co cold H,0 (10 ml) and extracted with ethyl : acetate. The organic phase was washed with 5% oo KHSO,, (3X), saturated NaHCO, and brine then dried over anhydrous Na, so, and evaporated to give 1.0 g of a yellow oil. TLC indicated formation of some ) mono acid which was converted back to the methyl ester by treatment with ethereal solution of : CH,N,. Excess CH,N, was quenched with glacial acetic acid and the mixture evaporated in vacuo to give 1.012 g of a brown oil. The crude oil ‘was purified by flash chromatography on Merck silica ~ gel eluting with (8:2) Hexane-Acetone (600 ml) followed by (1:1) Hexane-Acetone. Product fractions were evaporated to give 516 mg (78.7 %) of free title alcohol as a light brown oil. TLC (9:1) CH, C1, ~CH,OH, R=0.41, UV + PMA. Mass Spec (M+H =472 observed).
BAD ORIGINAL
’ HX10b . =16.. i oo B. (S)-4~([2-([1-(4-Fluorophenyl)-3-(1- ‘ : methylethyl)-1H-indol-2~yl]ethynyl]- ;
So hydroxyphosphinyl]-3-hydroxybutanoic . © acid, dilithium salt "A solution of the Part A diester (516 mg, a 1.09 mmole) in dioxane (10 ml) was treated with a : 1.0 N LiOH solution (3.8 ml, 3.8 mmole, 3.5 eq) : and the clear mixture heated and stirred at 60°C (oil bath) for 1.5 hours under argon. The mixture
Como 10 was diluted with H,0, filtered, evaporated . .. _ in vacuo, the residual oil taken up in a minimum amount of H,0 and chromatographed on HP-20 resin (15 cm béd, 25 mm column diameter) eluting with . neat H,0 (until neutral) followed by (1:1) } 15. H,0-CH,OH. Product fractions were evaporated.
Co in vacuo, taken up in H,0 (50 ml), filtered and lyophilized to give 447 mg (82.3%) of desired title di-lithium salt as a white lyophilate.
TLC (8:1:1) CH,C1,-CH,OH-acetic acid, R.=0.39,
Uv + PMA. : :
Anal Calcd for C,4H,,0gPNF-2L1+2.27 moles H,0" (MW 496.19): C, 55.67; H, 5.19; N, 2.82; F, 3.83; ~ . Pp. 6.24
Found: C, 55.69; H, 5.37; N, 2.82;, F, 3.85;
P, 6.19
Example 31 (S)-4-[[[2,4-Dimethyl-6-[(4-fluorophenyl )methoxy]- phenyl ]ethynyl Jhydroxyphosphinyl]-3-hydroxybutanoic acid, dilithium salt :
A. 1-(Methoxymethoxy)=-3,5-dimethylbenzene :
A THF solution (12 ml) of 3, 5-dimethylphenol (10.42 g, 85.3 mmol) was added dropwise over 10 “pan Amma
HX10b -163- minutes to a Suspension of NaH (85.3 mmol) -, (prewashed with pentane) in THF (150 ml) under an » argon atmosphere and cooled to 0°c. After ! - completion of the addition of the phenol, the reaction was stirred at 0°C for 10 minutes warmed to room temperature and stirred for 20 minutes. To the alkoxide solution was added 42 ml of dry DMF followed by the slow addition of a 10 ml THF solution of bromomethyl methyl ether (11.19 g, 89.6 "777710 mmol). aA white precipitate formed. After stirring : for 2.5 hours at room temperature, the reaction was . quenched by the slow addition of 25 ml of 1N NaOH.
The THF was removed from the reaction mixture by . rotary evaporation and the resulting solution was oo diluted with saturated NaCl solution and then extracted 3 times with ether. The combined ether ; ’ extracts were dried over Na,so, and filtered.
Solvent removal gave an orange oil. Purification ’ by flash chromatography eluting with 5% ether/hexanes gave the title methoxymethyl (MoM) : ether (12.0 gq, 85% yield) as a clear oil,
TLC R=0.45 (15% Et,O/Hexane, silica gel) ’
Mass Spec m/e 166 (M'), 165 (M*-m)" ’ . . 25 B. 2-(Methoxymethoxy)-4, 6-dimethyl- benzaldehyde
Tetramethylethylenediamine (7.70 g, 79.45 : mmol) was added slowly to a solution of ’ n-butyllithium (26.5 ml, of a 2.5 M solution of hexane) in cyclohexane (30 ml) under argon atmosphere. The solution was cooled to 0°C and
Co. the Part A MOM-ether (11.00 g, 66.21 mmol) was added. dropwise over 20 minutes. After the SAD ORIGINAL
} ha ’ -164- addition was complete, the reaction was stirred at ’ o°cC for 30 minutes, warmed to room temperature and : stirred for 10 minutes. The anion was then added via addition funnel to a 100 ml dry cycloii:iiane oC solution of DMF (5.81 g, 79.45 mmol) urnid=r argon atmosphere and at room temperature. The reaction : was stirred at room temperature for 2 hours then quenched with methanol. The reaction =~Ivent was removed on the rotava;, and the resulting orange © mei = 10 0il was dissolved in a 1:1 ether/water mixture. ~~ -
The water layer was extracted 3 times with ether and the combined ether extracts were dried over :
MgSO, . Filtration and solvent removal gave an * orange oil. Purification of the oil by flash chromatography eluting with 20% ether/Hexane gave the desired title aldehyde (7.7 g, 60%) as a clear oil.
TLC R=0.14 (15% Et,O/Hexane, silica gel). . Mass Spec. m/e 195 (M+H)', 179 (M-cHy)", ~ oo 20 163 (M-OCH,)", 149 (m-0,cHg)"
Cc. 2-Hydroxy-4,6-dimethylbenzaldehyde
A 1M HCl solution (35.5 ml) was added to a a dioxane (130 ml) solution of the Part B MOM-ether (6.89 g, 35.5 mmol) at room temperature. The reaction was warmed to a gentle reflux and stirred for 30 minutes. The reaction was cooled to room temperature, and the dioxane was removed via rotary evaporation. The resulting aqueous solution was diluted with H,0 and extracted with ether. The aqueous layer was then saturated with
NaCl and reextracted 2 times with ether. The
Pl ether extracts were combined and then dried over
BAD ORIGINAL
HX10b -165-~
MgSO, . Filtration and solvent removal gave a ' greenish solid which was purified by . recrystallization from hexane (4.01 g, 75%).
TLC R=0.48 (25% Et,0/Hexane, silica gel) mp - ° 46-48°C. lass Spec. m/e 151 (M+H)', 135 (M-cH)* ’ D. 2-[(4-Fluorophenyl Jmethoxy]-4, 6- dimethylbenzaldehyde
A solution of the Part C phenol (4.0 g, 26.7 mmol) and dry DMF (30 ml) was stirred under Cm ee argon atmosphere. At room temperature, solid }
K,CO0, (4.43 g, 32 mmol) was ‘added to the phenol solution and then warmed to 60°C for 35 minutes. . + The resulting orange solution was cooled to room temperature and the p-fluorobenzyl bromide oo | (5.55 g, 29.3 mmol) was added. The reaction was : warmed to 60°C and stirred for 2 hours. The " reaction mixture was poured into 50 ml of ice water ’ and this mixture was extracted several times with ether. The combined ether extracts were dried over
Mgso, and filtered to give a yellow solid after solvent removal. Purification by flash chromatography eluting with 15% ether/Hexane gave " the title benzyl ether (4.48 g, 60%) as a white solid.
TLC R.=0.34 (25% Et,0/Hexane, silica gel)
Mass Spec. m/e 259 (M+H) , 231 (M-CHO) , 109 (M-c. HF)"
E. 1-(2,2-Dibromoethenyl)-2,4-dimethyl-6- (phenylmethoxy)benzene ~~
A 170 ml dry CH,Cl, solution of the Part D aldehyde (4.42 g, 17.13 mmol) under argon .
BAD ORIGINAL oo 26578 oo : | HX10b 166- atmosphere was cooled in an ice-salt bath. To the - , ) cooled solution was added triphenyl phosphine : . (14.4 g, 55.0 mmol) and the mixture was stirred oC until all of the solid dissolved. A 50 ml CH,CL, solution of CBr, (8.52 g, 25.7 mmol) was added via an addition funnel over a 12 minute period. : : : After the addition was complete, the orange reaction solution was stirred at 0°C for 1 hour 15 : - minutes. The reaction was quenched with 60 ml of : 10 saturated aqueous NaHCOz solution and stirred----- - - = vigorously. The aqueous layer was removed and - extracted 2 times with CH,Cl,. The combined oo oo CH,C1, solutions were washed once with saturated :
Co aqueous NaHCO; solution, dried over MgsO, and filtered to give the title dibromide in the form - oo of a tan solid (13 g). The title dibromide was purified by flash chromatography eluting with 2% ) " ether/hexane providing 5.49 g, 77% yield of the
To title dibromide.
TLC R.=0.28 (2% Et,0/Hexane, silica gel). - Mass Spec. m/e 413 (M+H)', 333, 335 (M-Br)", 317 (M-CH,F), 109 (MC) GHgOBE,) ‘ i * «
F. 1-Ethynyl-2-[(4-fluorophenyl )methoxy]- . 25 4,6-dimethylbenzene :
A 70 ml THF solution of the Part G dibromide (5.48 g, 13.3 mmol) under argon atmosphere was cooled to -78°C. n-Butyllithium . (10.6 ml of a 2.5 M solution in hexane, 26.5 mmol) was added to the dibromide solution over 10 . minutes. The reaction was stirred at -78°C for 1 oo hour and then quenched at -78°C with saturated aqueous NH,Cl solution. After the reaction was } | BAD ORIGINAL
RE
HX10b warmed to room temperature, it was diluted with 60 ml of H,0, and the aqueous layer was extracted 2 EK times with ether. All of the ‘organic layers were : combined and dried over 1gso, . Filtration and "5 solvent removal gave 3.8 g of title benzyloxyacetylene in the form of a yellow solid.
The title benzyloxyacetylene was purified by flash chromatography eluting with 3% ether/hexane.
Title acetylene was obtained in 85% yield (2.76 q) -——-~——- 10 . as a white solid. Cee
TLC Re=0.17 (2% Et,0/Hexane, silica gel)
Mass Spec. m/e 255 (M+H)', 159 (M-C.H,F)Y, 109 (M-c, JH 0)" : 15 G. (S)-4-[[[2,4~-Dimethyl-6-[(4-fluoro~- : - phenyl )methoxy Jphenyl Jethynyl J hydroxy- CL
SR ’ phosphinyl]-3-(t-butyldiphenylsilyloxy)- : butanoic acid, dilithium salt : A 40 ml THF solution of the Part F acetylene (2.76 g, 11 mmol) under argon atmosphere . Was cooled to -78°C. At -78°C, n-butyllithium (4.4 ml of a 2.5 M solution in hexane) was added over 8 minutes. The reaction was stirred at -78°C : for 40 minutes.
The Example 25 phosphonylchloridate (17.4 mmol), in 60 ml of THF and under argon atmosphere ‘ was cooled to -78°C. The above generated acetylenic anion was then added over 8 minutes. _ After stirring for 1 hour at -78°C, the reaction : was quenched at -78°C with saturated aqueous NH, C1 . solution and allowed to warm to room temperature. i
The aqueous layer was diluted with H,0 and extracted 2 times with ether. The THF was removed
ORIGINAL
BROT a
HY
-168- from the THF reaction layer, and the resulting orange oil was taken up in ether. All of the ; } ether solutions were combined and washed once with oo saturated aqueous NaHCO, solution and oncn with’ : saturated NaCl solution. The organic layer was Co dried over MgSO, and filtered leaving 9.4 g of : title acetylenic phosphinic acid in the form of an . orange gum after solvent removal. The title - acetylenic phosphinic acid was purifis=d by flash
Cor 10 chromatography by eluting with a 5/1/44 ..... = .. _ . _ ' hexane/toluene/ethyl acetate mixture. Title acetylenic phosphinic acid (4.23 g) was obtained in 56% yield as a clear gum. . : TLC R;=0.28 (5/1/4 Hexane/toluene/ethylacetate silia gel) : oo
Mass Spec. m/e 609 (M+H-C HS)”, 255 (Cy H; oSi0)"
H. (S)-4-[[[2,4-Dimethyl-6-[(4-fluoro- . i. phenyl )methoxy]phenyl]ethynyl Jmethoxy- phosphinyl]}-3-hydroxybutanoic acid, : . methyl ester :
Part G acetylenic phosphinate (0.455 gq, } 0.66 mmol) was stirred in 10 ml of THF under argon ’ atmosphere. Acetic acid (0.16 g, 2.66 mmol) was - 25 added at room temperature followed by the dropwise addition over 5 minutes of n-C, H NF (1.8 ml of a oo 1.1 M THF solution, 2.0 mmol). After stirring for "24 hours at room temperature, the reaction was quenched by the addition of 30 ml of ice-water. . 30 The aqueous layer was removed and extracted 2 : times with ethyl acetate. The THF was removed
Co from the reaction organic layer, and the resulting
ES 0il was dissolved in ethyl acetate and combined : SE oo : BAD ORIGINAL : | ee
: : HX10b : -169- a with the extracts of the aqueous layer. This : ethyl acetate solution was washed 2 times with Co Co saturated aqueous NaHCO, solution and once with : saturated NaCl solution and then dried over .
Na,SO,. Filtration and solvent removal gave 0.40 g of title hydroxy acetylenic phosphinate in the form of an oil. The title hydroxy acetylenic - phosphinate was purified by flash chromatography : eluting with 100% ethyl acetate. Title hydroxy . acetylenic phosphinate was obtained in 79% yield. :
TLC R.=0.56 (7:3 acetone/Hexane, silica gel).
Mass Spec. m/e 449 (M+H)*, 431 (M-om)*, 417 . (m-ocuy)*
Co J. (s)-4-[([2,4-Dimethyl-6-[(4-fluoro- phenyl )methoxy]lphenyl]ethynyl]hydroxy- phosphinyl]-3-hydroxybutanoic acid, ’ dilithium salt r To a 6.0 ml dioxane solution of Part H acetylenic phosphinate (0.191 g, 0.43 mmol) at room temperature was added 1.4 ml of 1N LiOH solution. The reaction was warmed to 55°C and : stirred for 2 hours. The reaction was cooled to room temperature and evaporated to dryness to obtain the title compound. The title compound was purified on a 130 mm x 30 mm diameter column of
HP-20 eluting first with 100 ml of H,0 then with a 1:1 MeOH/H,0 mixture. Title compound was obtained - in 91% yield (0.170 g) as a white lyophilate.
TLC Rg=0.37 (7:2:1 nPrOH/NH, OH/H,0, silica gel). : ’ Mass Spec (FAB) m/e 421 (M+H) , 427 (M+Li) , 433 (M+2Li)?
BAD ORIGINAL ee
10b -170-
Anal Calcd for C,H, O.FPLi,-1.4 H,0: C, 55.09;
H, 4.98; F, 4.15; P, 6.78 : s
Found: C; 55.13; H, 5.25; F, 4.08; P, 6.91 oo 3 Example 32 - - "(S)~4-[[[2,4-Dimethyl-6-[(4~fluoroph=nyl)methoxy]- :
I phenyl ]ethyl Jhydroxyphosphinyl]-3-hydroxy- : . butanoic acid, dilithium salt oo : g
A. (S)-3-[[(1,1-Dimethylethyl)diphenyl-
So 10 - silyl]oxy]-4-[[2~[2-[(4-fluorophenyl)- Co To : methoxy]~4, 6-dimethylphenyl]ethyl]~- methoxyphosphinyl ]butanoic acid, oo methyl ester . The Example 31 of Part G acetylenic :
A 15 phosphinate (1.34 g, 1.95 mmole) was stirred in oo methanol (12 ml) and PtO, (0.040 g) was added - Hydrogen gas was bubbled through the methanol
A solution for 10 minutes and then a H, (9) . atmosphere was maintained with a balloon. After 5 - 20 hours, 15 minutes at room temperature, the - : Bh reaction was complete and argon was bubbled ' oo through the reaction solution. The reaction was co filtered through a celite pad in a fine sintered - . glass funnel, and the catalyst was washed with methanol. Solvent was removed from the filtrate to give 1.4 g of a title saturated phosphinate in the form of a clear gum. The title saturated phosphinate was purified by flash chromatography : eluting with 60% ethyl acetate/hexane and then’ . rechromatographing material from slightly impure - fractions with 6/2.5/1.5 hexane/acetone/toluene.
Title saturated phosphinate was obtained in 86% oo ‘yield (1.17 g). i _ ER BAD ORIGINAL * . . acl
HX10b . -171- i TLC R.=.045 (80% ethyl acetate/hexane, silica gel). ‘
Mass Spec. m/e 691 (m+u)*, 659 (M-0CH,)™; 635 . i (M-CH, josi)* : : an . . ro
B. (S)-4-[([2,4-Dimethyl-6-[(4-fluoro~ phenyl )methoxy]lphenyl]lethyl Jmethoxy- phosphinyl]-3-hydroxy-butanoic acid, methyl ester on ; - The Part A phosphinate (1.16 g, 1.63 mmol) wm drm 10 was stirred in THF (25 ml) under argon atmosphere and at room temp. Glacial acetic acid (0.40 ml) : : was added dropwise to the phosphinate solution, and then n-C,N NF (4.6 ml of ‘a 1.1 M THF solution) . was added dropwise over 5 minutes. The reaction : 1s was stirred at room temperature overnight (18 hours) . 3 and then quenched with 50 ml of ice-water. After wee - stirring for several minutes, sat'd NaCl solution was added, and the layers were separated. The organic layer was rotary evaporated to remove the - THF, and the resulting residue was dissolved in : ethyl acetate. The aqueous layer was extracted 2 ) times with ethyl acetate, and all of the ethyl : acetate solutions were combined and washed 2 times with sat'd aqueous NaHCO, solution and once with sat'd NaCl solution, then dried over Na,So,.
Filtration and solvent removal gave 1.13 g of title hydroxy phosphinate in the form of a clear oil. " The title hydroxy phosphinate was purified by flash ; . chromategraphy eluting with 100% ethyl acetate and : : gave the title hydroxy phosphinate as a clear oil in 83% yield.
TLC Re = 0.27 (6:4 Acetone hexane, silica, gel). .
Mass Spec. m/e 453 (M+H) , 343 (M-C HF)
BAD ORIGINAL
: : HX10b -172-
C. (S)-4-[[{2,4~Dimethyl-6-[(4~ . ; co fluorophenyl )methoxy]phenylJethyl]- . hydroxyphosphinyl]-3-hydroxy-butanoic
Co acid, dilithium salt - The Part B phosphinate (0.594 g, 1.3 mmole) h was stirred in 19 ml of dioxane at room . temperature 1¥ LiOH (4.0 ml) was added with stirring at room temp. 2nd the reaction was warmed to . 55°C. After 20 minutes at 55°C, a white thick
ER: precipitate formed and 4.0 ml of dioxane was added, and the resulting suspension was stirred at 55°C. =
After 2.5 at 55°c, 3 ml of H,0 were added and the
Co : reaction mixture became clear. After 3 hours at . . 55°C, the reaction was cooled to room temperature, and the dioxane and water were removed by rotary. 3 evaporation leaving title diacid in the form of : white solid which was placed under high vacuum for ; 15 minutes. The title diacid was purified by HP-20 : chromatography eluting first with 100 ml of H,0 followed by elution with 1:1 MeOH/H,0 solution.
Title diacid was obtained as a white lyophilate in 67% yield. TLC R=0.36 (7:2:1 n-propanol/NH, OH/H,0, ~ silica gel). ; :
Mass Spec. m/e (FAB), 425 (M+H)", 437 (M+m+2 Li)". : . oo Anal Calcd for C,1H,y40gFP-1.15 H,0: C, 55.19; co H, 5.80; F, 4.16; P, 6.78 } Found: C, 55.19; H, 5.80; F, 4.29; P. 6.83 - BAD ORIGINAL . - * rn ——
HX10b -173- : . Example 33 (8)-4-[{[2-[[1,1'~-Biphenyl]-2-yl]ethynyl] hydroxy- : phosphinyl]-3-hydroxybutanoic acid, dilithium salt a _ : : SE
A. (S)-4~({2-[[1,1' -Biphenyl]-2-y1]- - ethynyl]hydroxy-phosphinyl]-3~hydroxy butanoic acid, methyl ester : oo
The Example 9, Part D phosphinate (1.61 : mmole, 0.985 g) was stirred under argon, at room cee =e 10 temperature in 19.6 ml of dry THF. This solution was treated dropwise with glacial acetic acid Co (6.44 mmol, 0.386 g, 0.368 ml), followed by ] : dropwise addition (8 min) of n-C, H, NF (4.84 mmol, 4.40 ml of a 1.1 M solution in THF). After stirring at room temp. for 18 hours, the reaction. mixture was quenched with 30 ml of ice water. The aqueous ‘layer was extracted with ethyl acetate. ~~ = = : The organic extracts were combined, washed 2 times with saturated aqueous NaHCO,, once with brine, dried over: Mgso,, filtered and evaporated. The : product was isolated via flash chromatography (50 mm column, 6" Merck silica gel, 40% acetone/hexane . ~ eluent, 2"/min flow rate). Product fractions were . concentrated, azeotroped with toluene, and v 25 evaporated in vacuo to afford (0.369 g, 0.991 mmol, 62% yield) of the title alcohol as a viscous yellow oil. (Also obtained 0.098 g, 0.263 mmol, 16% of slightly impure product) TLC: Silica gel Re = - 0.35 (50% acetone/hexane).
Mass Spec. CI m/e 373 (M+) " gap ORIGINAL
HX10b -174-
Co B. (S)-4-[[2-[[l,1'-Biphenyl]-2-yl]~- " ethynyl Jhydroxyphosphinyl]-3- Co hydroxybutanoic acid, dilithium : oh : salt : . 5 The Part A diester (0.739 mmol, 0.275 g) -
So was stirred under argon in 7.57 ml of dioxane and
Lo treated with 1M LiOH (2.22 mmol, 2.22 ml). This
Co cloudy reaction mixture was heated in a 55°C oil > bath for 45 minutes. The mixture was cooled to room temp. The solvents were removed via rotary Lo . ‘evaporation and high vacuum (90 minutes). The ~ resulting yellow foam was dissolved in 4 ml of distilled H,0 and eluted through an HP-20 . chromatography column (2.5 cm x 19 cm), collecting . . 15 10 ml fractions every 1.4 minutes. The column was . eluted with H,0 until 15 fractions were collected ’ (no longer basic) and then elution with 45/55 methanol/H,0 afforded (after lyophilization (2X) 3
Co and high vacuum pump over P,0¢ for 16 hours) 0.231 g (0.649 mmol, 88% yield) of the title diacid as a i white lyophilate TLC: Silica gel R.=0.55 (7:2:1 oo n-propanol/NH,OH/H,0) A .\
Ce ~ Mass Spec. (FAB m/e 345 (M+H) , 351 (M+Li) , 357 (M+2 Li)T.
Anal Calcd for C, gH, 505PLi, + 1.42 moles H,O0 .
Mw=381.75: C, 56.63; H, 4.71; P, 8.07
Found: C, 56.62; H, 4.70; P, 8.07 1
BAD ORIGINAL :
: HX10b : : -175-
Example 34 : Co - (S)-4-[[2-[3,5-Dimethyl{1,1'-biphenyl]- 2-yl]- : ethyl Jhydroxyphosphinyl]-3-hydroxybutanoic acid, ’ ; oo dilithium salt =
A. 3,5-Dimethyl (1, 1'-lziphenyl]~2~ carboxaldehyde : : : Phenylmagnesium bromide was obtained from - : Aldrich (Cat. No. 17, 156-5) as a 3M solution in g ethyl ether. } A mixture of Example 1, Part B dipalladium me complex (4.48 mmol, 3.35 g) and triphenylphosphine (35.85 mmol, 9.40 g) was stirred at room temperature under argon in 67.2 ml of anhydrous toluene for 30 i . minutes. This reaction mixture was cooled to 0°C and phenylmagnesium bromide Grignard reagent (Aldrich) (35.84 mmol, 11.95 ml of a 3M solution in ether was added portionwise (quickly). The ~~‘ ce resulting mixture was stirred at room temp. for : 1.5 hours. The mixture was then cooled at 0° and - 20 treated in one portion with 22.4 ml of 6.0 N HC1, and stirred at room temp. for 1 hour. The aqueous . layer was separated and extracted with ether. The . organic extracts were combined, filtered through
Celite (washed with ether) and the filtrate washed with brine, azeotroped with toluene, and evaporated in vacuo to afford a yellow solid.
Attempted product purification via (2X) flash Co chromatography (95 mm diameter column, 6" Merck - silica gel, 100% Hexane + 3% ether/Hexane eluent, 2"/min flow rate afforded 2.95 g of a yellow solid (1.88 g, 8.96 mmol 100% yield of the title aldehyde and 1.06 g of triphenylphosphine). This compound mixture was used directly in the - BAD ORIGINAL imation :
: © Halob : -176- preparation of the Part B compound. .TLC: Silica : gel, R=0.30 (5% ether/Hexane) - I : Mass Spec. (CI) m/e 211 (M+H)', 263 (M,+H)", 473 (My +M, +H) * : :
M,= Part A aldehyde, M, = triphenylphcsihine. :
B. 2-(2,2-Dibromoethenyl)-3,5-dimethyl- {1,1'-biphenyl) Lo ;
A mixture of Part A aldehyde (8.96 mmol, "].88 g") and triphenylphosphine (26.4 mmol, 6.90 SE g) was stirred in 88 ml of dry CH,CH, at -5°C for 10 minutes. This reaction mixture was maintained at -5°C as a solution of CBr, (13.2 mmol, 4.38 g) . in 32 ml of dry CH,C1, was added dropwise (20 : min). The resulting reaction mixture was stirred - at -5°C for 1 hour and became progressively . darker orange with time. The mixture was then
So quenched with 85 ml of saturated aqueous NaHCO, . ) ol The aqueous layer was extracted with CH,Cl,. The organic extracts were combined, washed once with a saturated NaHCO, (aqueous), and once with brine, on i dried over MgSO, , filtered and evaporated in
Lo vacuo. The product was purified by preabsorbing .
Co : the crude product in CH,Cl, onto 25 g of Merck silica gel and applying this to a flash chromatography column (50 mm diameter, 6" Merck silica gel, 4% CH,Cl,/Hexane eluent, 2"/min flow rate), affording 2.18 g (5.96 mmol, 68% yield) of - | the title vinyl dibromide as a viscous colorless oo oil. TLC: Silica gel R.=0.37 (4% CHpCly Hexane)
Mass Spec. (CI) m/e 365/367/369 (M+H) . oo BAD ORIGINAL ! ee erat tnt trite
HX10D -177- 3 } C. 3,5-Dimethyl-2~(l-propynyl)(1,1'- . : biphenyl]
A solution of the Part B vinyl dibromide ) : (5.74 mmol, 2.10 g) in 29.11 ml of anhydrous THF
So 5 w.g stirred under argon and cooled to -78°C. This solution was treated dropwise (20 minutes) with n~butyllithium (11.47 mmol, 4.59 ml of a 2.5 M solution in hexanes) resulting in a deep urple solution. After stirring at -78°C for a: eee... 10 additional hour, the reaction mixture was quenched ’ at -78°C with 25 ml of saturated NH, Cl (aqueous), warmed to room temp. diluted with H,0, and the aqueous layer extracted with 1:1 ether/hexane. . The organic extracts were combined, dried over
MgsO,, filtered, and evaporated in vacuo. The : product was isolated via flash chromatography (50 CL to mm column, 6" Merck silica gel, 1% ether /hexane B eluent) to afford 1.08 g (5.23 mmol, 91% yield) of the title acetylene as a colorless oil which became blue when stored 16 hours at -20°C. .TLC:
Silica gel R.=0.32 (100% hexane) .
Mass spec. (CI) m/e 207 (M+H) .
D. (S)-3-[[(1,1-Dimethylethyl)diphenyl- silylloxyl-4-[[2-[3,5~-dimethyl[1,1"'~ . biphenyl]-2-yl]lmethoxyphosphinyl]- butanoic acid, methyl ester
A solution of the Part C acetylene (4.61 ~ mmol, 0.950 g) in 27.3 ml of dry THF was stirred under argon and cooled to -78°C. .n-Butyllithium (4.61 mmol,. 1.84 ml of a 2.5 M solution in hexanes) was added dropwise (20 min) resulting in = - 4 a dark purple/brown solution. The reaction AD ORIGINAL
Lo : HX10b -178- mixture was stirred at -78°C for 1 hour (reaction
Cl ‘mixture became a slurry) warmed to 0°C and stirred . ’ 15 min. (reaction mixture returned to a dark :
Co purple homogeneous solution) and finally recooled a 5 to -40”¢ {remained homogeneous). This acetylenic . anion solution at -40°C was then added dropwise .
Lo (25 min) to a solution of the Example 1, Part F : phospirinyl chloridate (8.12 mmol) in 27.3 ml of : - ‘dry LHF which had been cooled to -78°C as it was ©... .10 stirred under argon. After the addition of the ) acetylenic anion solution to the phosphinyl chloridate solution was complete, the dark orange ]
Co : reaction mixture was stirred at -78°C for 1 hour . and then quenched at -78°C with 50 ml of saturated
NH, C1, warmed to room temp. and diluted with H,0. » The aqueous layer was extracted with ether. The
So organic extracts were combined, washed once with saturated NaHCO, (aqueous), once with brine, dried + over MgSO, , filtered and evaporated in vacuo. The
So 20 . product was isolated via flash chromatography (50 mm diameter column, 6" Merck silica gel, 50% ethyl acetate/hexane eluent, 2"/min flow rate) to afford 0.609 g (0.945 mmol, 21%) of the title phosphinate as a golden orange oil.
TLC: Silica gel R.=0.32 (50% ethyl acetate/Hexane)
Co Mass Spec. (CI) m/e 639 (M+H)' oo _ E. (S)-4-[[2-(3,5-Dimethyl[1,1'-biphenyl]- " 2-yl)ethyl lhydroxyphosphinyl]-3-(t- butyldiphenylsilyloxy)butanoic acid, dilithium salt
Argon was bubbled through a methanol (13 oe By ml) solution of the Part D acetylenic PhosPR Ing ORIGINAL o Loa hy .
: } HX10b ‘ . -179-
CL (1.37 mmol, 0.876 g) for 10 minutes. 10% Pd/C . (0.315 g) was added and the reaction mixture was subjected to Parr hydrogenation at 40 psi. After d . shaking for 24 hours, the reaction mixture was : ) : 5 filtered through a Celite pad in a sintered glass funnel. The Celite was washed with methanol and the filtrate was evaporated in vacuo to afford 0.896 ¢g of a yellow oil which was purified via . flash chromatocgr-phy (50 mm diameter column, 6"
Merck silica gel, 40% + 50% ethyl acetate/Hexane eluent) to afford 0.680 g (1.06 mmol, 77% yield) of Co the title saturated phosphinate as a pale yellow foam. Stripping the flash column by eluting
Co. with methanol produced an additional 0.087 g of slightly impure product. TLC: Rg =0.27, Silica : gel (50% acetone/hexane). so : : : Mass Spec. (CI) m/e 643 (M+). Cte Co : F. (S)-4-[[2-[3,5-Dimethyl[1,1'-biphenyl]- 2-y1]ethyl]hydroxyphosphinyl]-3- ] : hydroxybutanoic acid, dilithium salt
The Part E phosphinate (1.03 mmol, 0.66 gq) ; was stirred under argon at room temp. in 12.65 ml of dry THF. This solution was treated dropwise with glacial acetic acid (4.12 mmol, 0.247 g, 0.236 ml), followed by dropwise addition of n-C, NgNF (3.09 mmol, 2.81 ml of a 1.1M solution of THF). oo After stirring at room temperature for 16 hours, the reaction mixture was quenched with 25 ml of jce water. The aqueous layer was extracted with ethyl acetate. The organic extracts were a _ combined, washed 2 times with saturated aqueous : BAD ORIGINAL
HX10b oo . ~180- . NaHCO, once with brine, dried over MgSO, , Co filtered and evaporated in vacuo. The product was . purified via flash chromatography (40 mm column, : 6" Merck silica gel, 50% aceton=/Hexane eluent) to .. - afford 0.363 g (0.898 mmole, 37. yield) of the : "title alcohol as a white solid. TLC: Silica gel, : Rg=0.30 (50% acetone/Hexane) . -
Mass Spec (FAB) m/e 405 (M+H) .
G. (S)-4-[[2-(3,5-Dimethyl(1,1'-biphenyl]- : 2-yllethyl lhydroxyphosphinyl]}-3- hydroxybutanoic acid, dilithium : : | salt : :
Co The Part F diester (0.878 mmol, 0.355 g) : was stirred under argon in 9 ml of dioxane and "
Co treated with IM LiOH (2.63 mmol, 2.63 ml). This §
Co : homogeneous reaction mixture was heated in a 55°C
So . oil bath. After stirring at 55°C for 10 minutes, Co
CL the reaction mixture became a white suspension. oo
An additional 9 ml of dioxane and 2 ml of H,O0 were : ;
Bh : added, and the suspension was heated at 55°C for : 45 minutes, then cooled to room temperature. The. . solvents were removed by rotary evaporation and high vacuum (1 hour). The resulting white solid was eluted through an HP-20 chromatography column, : (18 cm x 2.5 cm). 10 ml fractions were collected every 1.4 minutes. The column was eluted with H,0 to until 15 fractions were collected and then elution with 1:1 methanol/H,0 afforded [after lyophiliza- tion (3X) and high vacuum pump over PO; (4 x 8 hours)] 0.289 g (0.744 mmol, 85% yield) of the title diacid as a white lyophilate.
BAD ORIGINAL.
11X10b -181- .
TLC: silica gel, R.=0.56 (7:2:1, ’ n-propanol/NH, OH/H,0).
Anal Calcd for C,oHy305PL1, + 0.34 moles of H,0 : . M.W.=394.31: C, 60.92; H, 6.05 } : : : 5 Found: C, 60.95; H, 6.18 . Mass Spec. (FAB) m/e 389 (M+H) -
Example 35 (S)-4-[[2-[4'~Fluoro-3,5-dimethyl[1,1'-biphenyl]-2- y1]ethyl]hydroxyphosphinyl]-3-hydroxybutanoic Cee ee “acid, dilithium salt } A. = Bromo(4-fluorophenyl)magnesium
Magnesium metal turnings (44.35 mmol, 1.08 ) . g) were flame dried, then stirred under argon in 40 ml of anhydrous ether. With vigorous stirring, l-bromo-4-fluorobenzene (40.3 mmol) was added, dropwise to the magnesium. The reaction was . initiated in an ultrasound device and then the halide was added dropwise at a rate sufficient to maintain reflux. After addition of the bromide. was complete, the reaction mixture was stirred at room temperature for 20 minutes, then heated to reflux and finally cooled to room temperature. This procedure yielded a golden orange transparent
Grignard solution containing 40.32 mmol of title
Grignard as a 0.91 M solution in ether. : B. 4'-Fluoro-3,5-dimethyl(1l,1'-biphenyl]- - 2-carboxaldehyde
Reference: Stockker et al, Journal of
Med. Chem., 29, 170-181 (1986).
A mixture of the Example 26 Part B palladium complex (4.35 mmol, 3.20 g) and SAD ORIGINAL
HX10b -182- triphenylphosphine (40.32 mmol, 10.58 g) -was . ‘ . stirred at room temperature under argon in 67.2 ml .: "of anhydrous toluene for 30 minutes. Then this reaction mixture was cooled to 0°C and the Part A = 5 Grignard reagent (40.32 mmol, 44.43 ml) was added portionwise (quickly). The resulting mixture was stirred at room temperature for 1.5 hours. The ; mixture was then cooled to 0°C and treated. in one porticn with 21.75 ml of 6.0 N HCl and stirred at : room temperature for 1. hour. The aqueous layer fe om was separated, extracted with ether and the combined ‘organic extracts filtered through
Celite. The celite was washed with ether and ; the combined filtrates were washed with brine, : ‘azeotroped 2 times with toluene, and stripped, to. afford an orange-yellow solid. Attempts at Ch isolating the title aldehyde by flash a. chromatography using a 95 mm diameter column; 6" = oo Merck silica gel, hexane eluent followed by 39 ’ - oo 20 Et,0/hexane eluent, 2"/min flow rate, resulted in : a final reaction product mixture of the desired oo title aldehyde and triphenylphosphine as a pale yellow solid (3.70 g - assume this contains 8.7 : mmol, 1.99 g, 100% yield of title aldehyde + 1.70 : n 25 g of triphenylphosphine). This compound mixture oo was used directly in the preparation of Part C compound.
TLC: silica gel R.=0.25 (5% ether/Hexane) hE la mm: (270 Mz, cDCly) : : ——— a
AI .
’ EX10b . -183- ) oo . C. 2-(2,2-Dibromoethenyl)-4'-fluoro-3,5- dimethyl[1l,1'-biphenyl]
A mixture of the Part B aldehyde (8.70 ) mmol, "1.¢3 g") and triphenylphosphine (26.1 mmol, ’ 6.85 g) ws stirred in 87 ml of dry CH, C1, at -5°C for 10 minutes. This reaction mixture was - maintained at -5°C as a solution of CBr, (13.05 mmol, 4.23 g) in 43 ml of dry CH,C1, was added - dropwise over 25 minutes. The resulting reaction + ----10--- mixture was stirred at -5°C for 1 hour producing a SL dark orange solution which was then quenched with 80 ml of saturated aqueous NaHCO, . The aqueous layer was extracted 4 times with CH,Cl,. The . combined organic extracts were washed once with saturated aqueous NaHCO, and once with brine. The ~ CH,Cl, extract was dried over MgSO, , filtered and Lo the filtrate combined with 25 g of Merck silica : gel. The solvent was evaporated and the: preabsorbed product was purified via flash chromatography (50 mm diameter column, 6" Merck silica gel, 4% CH,Cl,/Hexane eluent, 2" /min flow rate) to afford 2.32 g (6.04 mmol, 69% yield) of . the title vinyl dibromide as a colorless oil.
TLC: silica gel, R.=0.43 (5% CH,Cl,/Hexane). : 25 Mass Spec. (CI) m/e 383/385/387 (M+H) . .
SE D. 4'-Fluoro-3,5-dimethyl-2-(1-propynyl)- [1,1'-biphenyl] = A solution of the Part C vinyl dibromide (5.99 mmol, 2.30 g) in 33 ml of anhydrous THF was stirred under argon and cooled to -78°C. This solution was treated dropwise (25 minutes) with : : n-butyllithium (11.97 mmol, 4.79 ml of a 2.5 M : BAD ORIGINAL
‘ HX10b ’ -184 " solution in hexanes), resulting in a deep. purple oo : solution. After stirring at -78°C for an : additional hour, the reaction mixture was quenched at -78°C with 25 ml saturated aqueous NH,CI, - warmed to room temperature and diluted with 25 ml «oo of H,O. The aqueous layer was extracted 4 times ; . with 1:1 ether/hexane. The organic extracts were
Co | combined, dried over Mgso,, filtered and : _ evaporated. The product was isolated via flash
SR —— 4 chromatography (50 mm column, 6" Merck silica gel, Co ’ 0.50% ether/hexane eluent, 2"/mm flow rate) to )
Co afford 1.25 g (5.57 mmol, 93% yield) of the title : ce acetylene, as a colorless oil which turns blue . when stored at 20°C. ’
TLC: silica gel, R.=0.25 (100% hexane) :
Co Co Mass Spec. (CI) m/e 225 (M+H) Co
E. (S)-4-[[2-[4'-Fluoro-3,5~dimethyl- [1,1'-biphenyl]-2-yl]ethynyl]hydroxy- . phosphinyll-3-(t-butyldiphenylsilyloxy)- - butanoic acid, methyl ester - Co A solution of the Part D acetylene (5.24 tA mmol, 1.18 g) in 28 ml of dry THF was stirred . under argon and cooled to -78°C. n-Butyllithium (5.24 mmol, 2.10 ml of a 2.5 M solution in hexane) co was added dropwise( 25 min) as the reaction mixture became dark purple/brown. The reaction mixture was then stirred at -78°C for 1 hour, + warmed to 0°C, stirred for 10 minutes, and ’ recooled to -78°C. This acetylenic anion solution at -78°C was then added dropwise (20 minutes) to a solution of the Example 1 Part F phosphinyl chloridate (8.32 mmol) in 28 ml of anhydrous THAD ORIGINAL
HX10b : : ~185~ : . which had been cooled to -78°C as it was stirred i under argon. After the addition was complete,’ the ~ a dark orange reaction mixture was stirred at -78°C J for 1 hour and then quenched at: -78°C with J saturated aqueous NH C1, warmed to room : temperature and diluted with E,O. The aqueous layer was extracted 4 times with ether. The . i organic extracts were combined and washed once : "with saturated aqueous NaHCO, once with brine, . ©1000 dried over MgSO, , filtered, and evaporated. The - product was isolated via flash chromatography (50 . mm diameter column, 6" Merck silica gel, 40% ethyl acetate/hexane eluent, 2"/min flow rate) to afford
Lo 0.730 g (1.11 mmol, 21% yield) of the title acetylenic phosphinate as a green viscous oil. 7
TLC: silica gel R.=0.36 (50% ethyl acetate/hexane) -
Mass Spec (CI) m/e 657 (m+E) SA to
F. (5)-4-[[2-[4'~Fluoro-3,5-dimethyl- - [1,1'-biphenyl]-2-yl]ethyl]hydroxy- phosphinyl]-3-(t-butyldiphenylsilyloxy)- : butanoic acid, methyl ester
Argon was bubbled through a methanol 9.9 ml solution of the Part E acetylenic phosphinate ; 25, (1.04 mmol, 0.685 g) for 10 minutes. 10% Pd/C 0.239 g was added and the reaction mixture was subjected to Parr hydrogenation at 40 psi. After shaking for 24 hours, the reaction mixture was - filtered through a Celite pad in a sintered glass funnel, the Celite was washed with methanol, and the filtrate was evaporated to afford 0.638 g of a . green oil. The product was purified via flash oo chromatography (40 mm diameter column, 6" Mere AD ORIGINAL
: 110b : -186- silica gel, 45% ethyl acetate/hexane eluent, 2"/min flow rate) to afford 0.530 g (0.802 mmo 1 77% yield) of the title saturated phosphinaté as a pale yellow foam. Also obtained 0.09 g (0:136 . | . mmol, 13%) of slightly impure product. Co
TLC: silica gel. R.=0.30 (50% ethyl acetate/hexane).
Mass spec. (CI) m/e 661 (M+H)*
G. (s)-4~([2-[4'-Fluoro-3,5~dimethyl- oo [1,1'-biphenyl]-2-~yl]ethyl]methoxy~- : phosphinyl ]-3-hydroxybutanoic acid, : methyl ester
The Part F phosphinate (0.794 mmol, 0.525
LT g) was stirred under argon at room temperature in 9.74 ml of anhydrous THF. This solution was treated dropwise with glacial acetic acid (3.18 oo mmol, 0.191 g, 0.182 ml), followed by dropwise ;
SE addition of n-C, Hy NF (2.38 mmol, 2.17 ml of a 1.1 oo
Ea M solution in THF). After stirring at room temperature for 16 hours, the reaction mixture was . quenched with 15 ml of ice water. The aqueous
Co layer was extracted 3 times with ethyl acetate. ar The organic extracts were combined, washed 2 times de with saturated aqueous NaHCO,, 1 time with brine,
EEL 25 dried over MgSO, , filtered and evaporated. The a. product was purified via flash chromatography (40 . mm diameter column, 6" Merck silica gel, 50% acetone/hexane eluent, 2"/min flow rate). : Product fractions were concentrated and azeotroped to dryness with toluene to afford 0.281 g (0.665 : : mmol, 84% yield) of the title alcohol as a white i solid. An impurity visible by 270 MHz lp NMR was
NK not separable/visible in various TLC systems.
BAD ORIGINAL
A cme
-187- | ” ‘ : TLC: Silica gel, Rg=0.31 (50% acetone/hexane) oo H NMR: (270 MHz, CDClg). :
Mass Spec. (CI) m/e 423 (M+H)" :
H. (S)-4-[[2-[4'-Fluoro-3,5~-dime=thyl- .[1,1'-biphenyl]~2-yl]lethyl]hvdroxy- phosphinyl]-3-hydroxybutanoic acid, dilithium salt
The Part G diester (0.473 mmoi, ~.20 g) was stirred under argon in dioxane (4.84 wl) and .- .... Coe oe treated with 1M LiOH (1.42 mmol, 1.42 ml). This homogeneous reaction mixture was heated in a 55°C : oil bath. After stirring at 55°C for 10 minutes, . the reaction mixture became a white suspension.
The mixture was maintained at 55°C for an : ’ additional 45 minutes, then cooled to room - témperature. The solvents weré removed by rotary ’ evaporation and high vacuum (1 hour). The resulting white foam was dissolved in 4 ml of distilled H,0 and eluted through an HP-20 : chromatography column (16 cm x 2.5 cm). 10 ml fractions were collected every 1.4 minutes. . The , column was eluted with H, until 15 fractions were collected and then elution with 1:1 methanol/H,0 afforded (after lyophilization (2X) and high vacuum pump over P05 for 11 hours) 0.158 g (0.389 mmol, 82% yield) of the title diacid as a white . lyophilate. ~ : TLC: silica gel Rg=0.59 (7:2:1, n-propanol/NH,OH/H,0) | .
Mass Spec (FAB) m/e 395 (M+H) :
Anal Calcd for C, Hy, FOgPLi,+0.39 moles H,0 . ] rr Te oe . BAD ORIGINAL
} HX1CH: ~188- oo Co MW=413.25; C, 58.12; H, 5.56
Found: C, 58.14; H, 6.09 oo oo 5 Example 36 =. | Lo (S)-4-[[2-[5-(4-Fluorophenyl)-3—(l-methylethyl)-1- : phenyl-1H-pyrazol-4-yl]ethynyl Imethoxyphosphinyl]- i oo 3-hydroxybutanoic acid, methyl ester ) - A. 4-Fluoro-B-oxobenzeriepropanoic E - acid, ethyl ester
Co 10 60% Sodium hydride in mineral oil (17.4 g,.. ... .. . 0.43 mmole) was washed twice with dry hexane,
Lo "dried in vacuo then treated with neat diethylcarbonate (44.3 ml, 0.36 mmole) followed by
CL the dropwise addition of p-fluoro-acetophenone (22 . oo 15 ml, 0.18 mole). After about 10% of the ketone . had been added, 4 drops of ethanol was added to
Co initiate refluxing and the remainder of the oo . p-fluoro-acetophenone was added over 1.0 hour at a : : rate that maintained reflux conditions. The
Co 20 yellow solid which formed was slurried in dry “ ether (250 ml) and refluxed for an additional 3.0 . hours under argon.
CL . - The reaction mixture was cooled in an ice co bath, diluted with ether (200 ml) and treated : slowly with water (1.3 liters) until all the solids dissolved. The aqueous phase was separated from oo the organic phase, acidified with 12N HCl (32 ml) to pH 1.0 and extracted with ether (2 x 500 ml).
The combined organic extracts were washed with brine (200 ml), dried (anhydrous MgsoO,), filtered oo and evaporated to dryness. The crude product . : (44.0 g) was distilled under reduced pressure (3.5 . mm) to give title compound as a homogeneous oil
Ch BAD ORIGINAL oo Ly E - " — bial
HX10b - -189- i (24.88 g, 65.8%).
TLC: Re 0.46 (Silica gel; CH,Cl,:hexane-4:1). -
B. 4-Fluoro-a-(2-methyl-1-oxopropyl)-f~ oxobenzenepropanoic acid, ethyl ester : : - €0% Sodium hydride in mineral oil (10.3 gq, © 0.26 mmole) was washed twice with dry hexane, dried in vacuo, suspended in dry tetrahydrofuran : (245 wl) and cooled down to 0° (ice water bath} 7 ——10- under argon. The suspension was treated dropwise Cel with Part A compound (24.5 g, 0.12 mole) over a 20-minute period, warmed to room temperature and : stirred for another 30 minutes. The reaction . mixture was cooled down to 0° (ice water bath), treated dropwise with isobutyryl chloride (18.62 : g, 0.17 mole), warmed to room temperature and oo stirred for 3.0 hours. The mixture was cooled = : : down to 0° (ice water bath), quenched with water (200 ml) to produce a homogeneous solution and . 20 evaporated on a rotary evaporator to remove most of the tetrahydrofuran. The aqueous phase was acidified with 10% HCl (37 ml) to pH 1.0 and . extracted with ether (3 x 100 ml). The combined - . organic extracts were washed with brine (50 ml), dried (anhydrous MgSO, ), filtered- and evaporated to dryness, to give an oil (36.85 g) which was a mixture of starting material and two other: products,
TLC: Re 0.46, 0.33, 0.20 (Silica gel;
CH,Cl,:hexane-4:1, uv). - BAD ORIGINAL
HX10b =190- i . C. 5-(4-Fluorophenyl)-3-(l-methylethyl)-1- phenyl-1H-pyrazole-4-carboxylic acid, : : ethyl ester oo Crude rart B. compound (36.85 g, ~ 0.12 - 5° mole) was dissolved in glacial acetic acid (151 " ml), treated portionwise with 97% phenylhydrazine : © (18.1 ml, 0.18 mole) under nitrogen and stirred at room tempera‘ure for 19 hours. The reaction : ., ‘mixture was poured into water (350 ml), extracted : ...10 with ether (3 x 100 ml) and the combined organic : : extracts were washed with saturated NaHCO, until : the aqueous layer was basic, brine (500 ml), dried (anhydrous MgSO, ), filtered and evaporated to . + dryness. Co o 15 . The dark orange oil was evaporated once ot from petroleum ether (300 ml) to obtain a yellow : A solid. This crude product was triturated with
LL " petroleum ether (100 ml) to give a crude product :
Lo (15.3 g) which in turn was chromatographed on a silica gel column (LPS-1), eluting the column with : - ~ CH,Cl,:hexane (2:1) to give 11.53 g of pure’
EE product. The mother liquor (26.4 g) on : chromatography on a silica gel column (LPS-1) and
Lo trituration of the compound obtained gave an oo 25 additional 7.12 g of desired product (total yield: 18.65 g or 44.1%). A small amount of title compound was recrystallized from Et,0:hexane to
Lo give homogeneous solid, m.p. 92-93°C. oo TLC: Ry 0.35 (Silica gel: CH,Cl,:hexane-4:1) 30 . Anal Caled: C, 71.57; H, 6.01; N, 7.95; F, 5.39
Found: C, 71.62; H, 5.99; N, 7.91; F, 5.54.
Ce y . . : BAD ORIGINAL :
N | _.
: HX10b -191- .
D. 5-(4-Fluorophenyl)-3-(l-methylethyl )-1- s : } phenyl-1H-pyrazole-4-methanol : . :
A solution of Part C compound (11.53 .g, : . : 32.7 mmole) in anhydrous ether (142 ml) was added } drepvise over a period of 1.5 hours to a cooled © (0°; ice-salt bath) suspension of lithium aluminum : hydride (3.67 gq, 96.7 mmoles) in anhydrous ether (7C ml) under argon. The greenish suspension was allowed to warm up to room temperature over a : oo 10 period of 1.5 hours, cooled back down to 0° - (ice-salt bath) and quenched by the dropwise - addition of water (20 ml) until gas evolution ceased. The thick slurry was diluted with ether . (100 ml) and filtered, washing the precipitates well with ethyl acetate (3 x 150 ml). The : - combined organic extracts were washed with brine , X (50 ml), dried (anhydrous Mgso,), filtered and evaporated to dryness to give a cream-colored : solid (10.3 g, 100% crude yield). 100 mg of the crude product was recrystallized from Et,0:hexane to give title compound (58 mg) as white crystals, m.p. 138-140°.
TLC: Rg 0.01 (Silica gel; CH,CL,) | .
Anal Calcd: C, 73.52; H, 6.17; F, 6.12; N, 9.03 } 25 Found: C, 73.16; H, 6.15; F, 6.12; N, 8.90
Ms (M+H) =311
E. 5-(4-Fluorophenyl)-3-(1l-methylethyl)- : - 1-phenyl-1H-pyrazole-4-carboxaldehyde
A solution of crude Part D compound (10.2 g, ~32.7 mmole) in dry dichloromethane (85 ml) was added rapidly to a solution of pyridinium chlorochromate (21.23 g, 98.4 mmoles) in dry .
BAD ORIGINAL
. Co HX10b -192- - Co ‘dichloromethane (125 ml) and the resulting dark : brown solution was stirred at room temperature oe : under nitrogen fer 4.0 hours, The mixture was : diluted with ethsr (750 ml) and stirred for 10 minutes. The supernatant solution was decanted from the tar-like residue and the residue was triturated with dichloromethane (2 x 100 ml). The dichloromethane :xtracts were diluted with ether : : (750 ml) and t!..: combined extracts filtered +10 through a silica gel pad. The clear filtrate was RS ) evaporated to dryness to give a crude product (10.0 g). .
The crude product was chromatographed on a : "silica gel column (Baker, 60-200 mesh, 400 ml), - 15 eluting the column with CH,Cl,:hexane (4:1) to . ; : give title compound as a solid (9.6 g, 95.2%). An ; analytical sample (72 mg, m.p. 108-110°) was + obtained by recrystallizing 100 mg from hexane.
Co TLC: Ry 0.58 (silica gel; CH,Cl,; UV).
Anal Calcd: C, 74.01; H, 5.56; N, 9.09; F, 6.16 . Found: C, 74.10; H, 5.52; N, 9.12; F, 6.29
Ms (M+E) =309
F. 4-(2,2-Dibromoethenyl)-5-(4~fluoro~ phenyl )-3-(1l-methylethyl)-1l-phenyl- 1H-pyrazole
Co : A mixture of Part E compound (2.0 g, 6.48 : : mmole) and triphenylphosphine (5.10 g, 19.2 ‘ mmoles) in dry dichloromethane (30 ml) was cooled down to -5° to -10° (ice-salt bath) under argon . and treated dropwise over a period of 5 minutes
CL with a solution of carbon tetrabromide (3.22 gq,
CL 9.61 mmoles) in dry dichloromethane (10 ml). The
BEATIN : i Cary Th} .
BAD ORIGINAL
. - oe aly,
HX10b -193~ } - reaction mixture was stirred at 15°-20° for 15 | ; minutes then poured onto saturated NaHCO, (10 ml) : and extracted with dichloromethane (3 x-50 ml). oo ‘The combined organic extracts were washed with
Co 5 saturated NaHCO, (10 ml), brine (25 ml), dried : (anhydrous MgSO, ), filtered and evaporated to oo dryness.
The crude product mixture (9.33 g) was | oo : chromatographed on a silica gel column (LPS-1) eluting the column with CH,Cl,:hexane mixtures Ce : (1:9, 1:1; 4:1) to give title compound as a solid : (2.75 g, 91.6%). Recrystallization of a small sample of title compound gave white crystals, m.p. . 88-90°. i : . 15 TLC: Rg 0.85 (silica gel; CH,Cl,:hexane-4:1) . L , Anal Calcd: C, 51.75; H, 3.69; N, 6.04; F, 4.09; i - Br, 34.43 - co To ’ Found: C, 51.96; H, 3.51; N, 5.97; F, 4.22; :
Br, 34.77
Ms (M+H) =465. :
G. 4-Ethynyl-5-(4-fluorophenyl)-3-(1- methylethyl)-1-phenyl-1H-pyrazole’ ’ A solution of Part F compound (2.64 g, 5.67 mmole) in dry tetrahydrofuran (10.5 ml) was cooled down to -78° (dry ice-acetone) under argon and treated dropwise with 1.6M n-BuLi/hexane (7.16 ml, 11.37 mmoles). The resulting suspension was ~ stirred at -78° for 1 hour and 20 minutes, quenched by the dropwise addition of 25% NH, Cl (10 ml) and allowed to warm up to room temperature. -
The reaction mixture was extracted with ether (3 x . 50 ml) and the combined organic extracts were
BAD ORIGINAL oo HX10b -194- oo : washed with brine (20 ml), dried (anhydrous .- :
Mgso,), filtered and evaporated to dryness to give 3 title compound as a light brown solid (1.79 gq). : y The crude product was chromatographed on a ; © 5 silica gel column, eluting the column with
Et,0:hexane (5:95) to give title compound as a : ’ light gold-colored solid (1.08 g, 97.4%). : Recrystallization of a small sample from hexane : - gave white, fluffy crystals, ..p. 106-108°. ©. 10 TLC: Re 0.70 (silica gel; Et,G:hexane-1:9; =. . _ _..._ developed 2X). --
Anal Calcd: C, 78.92; H, 5.63; N, 9.21; F, 6.24
Co Found: C, 79.22; H, 5.53; N, 9.28; F, 6.23
CL | Ms (M+H) =305 oo : . ~ : - . H. (S)-3-[[(1,1-Dimethylethyl )diphenyl- - to silyl}oxy]-4-[[[5-(4-fluorophenyl)-3-
Lo. oo (1-methylethyl)-1-phenyl-1H-
Lo . pyrazol-4-yl)ethynyl Jmethoxyphos- :
SE 20 . phinyl]butanoic acid, methyl ester
A mixture of the crude Example 1 Part F phosphonic monomethyl ester (2.77 g, 5.55 mmoles) and trimethylsilyldiethylamine (2.1 ml, 11.05 mmoles) in dry dichloromethane (10 ml) was stirred at room temperature under argon for 1.0 hour. ’ The mixture was evaporated to dryness, azeotroped with dry benzene (20 ml) and dried . in vacuo (pump) for 15 minutes. The viscous oil was re-dissolved in dry dichloromethane (10 ml), treated with one drop of DMF, cooled down to -10° (ice-salt bath) and treated dropwise with oxalyl chloride (530 pl, 6.08 mmoles). Vigorous gas evolution was observed and the dark yellow p | BAD ORIGINAL . fro fe OD -195- solution was stirred at -10° for 15 minutes, then at room temperature for 1.0 hour. The reaction mixture was evaporated to dryness, azsotroped with benzene (20 ml) and dried in vacuo. _ A solution of Part G compound (1.12 g, 3.67 mmoles) in dry tetrahydrofuran (9.0 wl) was cooled down to -78° (dry ice-acetone) under argon and : treated with 1.6M n-BuLi/hexane (2.3 ul, 3.67 mmoles) and stirred at -78° for 30 minutes. The ewe w=. 10__.above phosphochloridate-was dissolved in dry . . . tetrahydrofuran (6.5 ml), cooled down to -78° ’ : (dry ice-acetone) under argon and treated dropwise ’ by cannula with the solution of the acetylene . anion, both solutions being kept at -78° : 15 throughout the addition. The reaction mixture was stirred at -78° for 30 minutes, quenched by the dropwsie addition of 25% NH,Cl (6.0 ml) then = warmed to room temperature. The mixture was extracted with ether (3 x 100 ml) and the combined organic extracts were washed with 25% NH, C1 (10. ml), brine (25 ml), dried (anhydrous MgSO, ), filtered and evaporated to dryness. - The crude product mixture (~4.2 g) was . : chromatographed on a silica gel column, eluting the column with hexane:acetone (9:1) to give title compound as a light brown oil (1.54 g, . 57.0%).
TLC: Re 0.33 (silica gel; hexane:acetone-7:3)
I. (S)-4-[[2-(5-(4-Fluorophenyl)-3- : (1-methylethyl)-l-phenyl-1H-pyrazol-4- . yl]ethynyl Jmethoxyphosphinyl]-3- ) hydroxybutanoic acid, methyl ester or - BAD ORIGINAL
HX10b -196- - A solution of Part H compound (593.9 mg; oo 0.81 mmole) in dry tetrahydrofuran (8.0 ml) was Co : treated successively with glacial acetic acid (190 : : a. pl, 3.24 mmoles) and 1M Bu, NF (2.54 ml, 2.54 . - :
Co 5 mmoles) and stirred overnight at room temperature : oo under argon. The reaction mixture was cooled down to 0°C (ice water bath), treated with 5% KHSO, : : - (8.5 ml) and extracted with ethyl acetate (3 x 75 : ml). The combined organic extracts were washed - - 7-10 with 5% KHSO, (10 ml), brine (20 ml), dried (anhydrous ‘MgSO, ), filtered and evaporated to Co dryness. oo oo : The crude product was dissolved in a oo mixture of ether (14 ml) and dry tetrahydrofuran . 15 (10 ml),. cooled down to 0° (ice-salt bath), Co : So treated with excess diazomethane in ether and | - ) stirred at 0° for 3.0 hours. The reaction mixture was quenched by the dropwise addition of glacial to acetic acid, evaporated to dryness and dried in vacuo. The crude product was chromatographed on a silica gel column eluting the column with acetone:hexane (1:2) to give title compound as a : oC } semi-solid (325.6 mg, 80.6% yield). :
Example 37 . oo (S)-4-[[2-[5-(4-Fluorophenyl)-3-(l-methylethyl)-1- : phenyl-1H-pyrazol-4-yl]ethynyl Jhydroxyphosphinyl]-3- hydroxybutanoic acid, dilithium salt ’ A solution of Example 36 compound (325 mg, - "30 0.65 mmole) in dioxane (7.7 ml) was treated with : : 1N LiOH (2.25 ml, 2.25 mmole) stirred at 55° (oil
Lo bath) under nitrogen for 1.5 hours then at room : oo - temperature for 16 hours. The reaction mixture
Ll Co | | - BAD ORIGINAL -
- a To TT . ’ HX10b -197- a. was evaporated to dryness and dried in vacuo. The = : crude product was chromatographed on an HP-20 column (1" x 5"), eluting the column with : steam-distilled water (400 ml) and 50% aqueous
CH, OH (500 ml). The desired fractions were combined, evaporated to dryness and dried : in vacuo. The solid product was dissolved in . steam-distilled water and lyophilized to give title product =s a fluffy solid lyophilate (317.1 - mg, 96.4%).
TLC: Rg 0.33 (silica gel; i-PrOH:NH,OH:H,0-8:1:1).
Anal Calcd for Cp aHy , FN, OP 2 Li-1.3 H,0 (Eff. ) i
Mol. Wt.=505.861): C, 56.99, H, 4.90;, N, 5.54; . F, 3.75; P, 6.12 oo
Found: C, 56.98; H, 5.17; N, 5.46; = oo ~ F, 3.90; P, 6.26
H-NMR Spectrum (400 MHz, CD,OD): oo 6 1.40 (d, 6H, J=7 Hz) ’ 1.81-1.98 (m, 2H) 2.35 (dd, 1H, J=9, 15 Hz) - 2.48 (dd, 1H, J=4, 15 Hz) : 3.35 (septet, 1H, J=7 Hz) . 4.42 (m, 1H) . . 7.08-7.41 (m, SH).
IR(KBr): 2173 cm” (C=C).
Example 38 } (E)-4-[[2-[5-(4-Fluorophenyl)-3-(1-methylethyl)-1- phenyl-1H-pyrazol-4-yl]ethenyl Jmethoxyphosphinyl]-3- hydroxybutanoic acid, methyl ester :
CL BAD ORIGINAL
:
= ron, -198~ oe A. [2-[5-(4-Fluorophenyl)-=3-(l-mathyl- ethyl)-l-phenyl-1H-pyrazol-4-yl]- ~ oo ;
Lo 2-hydrokyethyl ]Jphosphonic acid, i dimethyl ester SE
A -78°C (CO, /acetone) solution of dimethyl methylphosphonate (2.81 ml, 25.9 mmole) in dry THF : (50 ml) was treated with a 1.6M n-BuLi sdlution in . hexanes (15.2 ml, 24.3 mmole) dropwise over 15 - : minutes and the white suspension (after ~15 minutes) stirred under argon at -78°C for one
Loe hour. Example 36 Part E pyrazole aldehyde (5.0 g,. } 16.2 mmole) in dry THF (15 ml) was added dropwise over 10 minutes and the yellow mixture stirred at : . - - -78°C for 30 minutes. The mixture was quenched - 15 with saturated NH, Cl (20 ml) and allowed to warm : to room temperature. The mixture was partitioned - between H,0 and EtOAc, the organic Phase washed with brine, dried over anhydrous Na,S0, and evaporated to give 7.158 g of crude title . 20 B-hydroxyphosphonate as a yellow foam. A small : : sample was crystallized from hexanes to give pure oo title compound as white crystals with m.p. =
Co | 126°-128°C. : p ; Co TLC (1:1) hexane-acetone, Re = 0.27. eo ‘ 25 Mass Spec. (m+Ht=433" observed). : ) | Anal Calcd for C,,H,cO,N,PF: C, 61.10; H, 6.06; . . N, 6.48; F, 4.39; P, 7.16
Found: C, 60.95; H, 6.06; N, 6.41; F, 4.22; P, 7.27
Co BAU URIGINAL
HX10b oo -199-
RTE (CDCl): ;
BE) 1.42 (6H, 4d)
Co 1..94-2.40 (2H, m) To . : 3.29 (1H, septet) 3.62+3.63 (2 doublets, J, ,=11.1 Hz) oo 3.91 (1H, s) ) 5.11 (1H, bm) : Co ~~ 6.90-7.30 (9H, m) ppm. oo 10 lc MMR (cpCl,): 6 22.6, 26.5, 32.8 (J._,=136.3
Hz), 52.1 (Jop=5-7 Hz), 60.8, 115.0, 115.4, 119.3, 119.5, 124.7, 126.3, 126.6, 128.5, 132.2, 132.3, 139.4, 139.5, 156.7, 164.5 (Jo p=265 Hz) . ppm. to
B. (E)-[2-[5-(4-Fluorophenyl)-3-(1- . : methylethyl)-1-phenyl-1H-pyrazol-4- yl]ethenyl phosphonic acid, dimethyl ester ‘A solution of the crude Part A hydroxy phosphonate (7.158 g) in dry benzene (40 ml) was " treated with pTsOH-H,0 (304 mg, 1.6 mmole) and the : mixture refluxed through a Dean Stark trap containing 4& sieves for 2 hours under argon. The mixture was cooled, diluted with EtOAc, the organic phase washed with saturated NaHCO, (2X) and brine then dried over anhydrous Na,SO, and - evaporated in vacuo to give 6.893 g of a yellow 0il. The crude oil was triturated with hexane to give 5.692 g of nearly pure vinyl phosphonate as off-white crystals. One recrystallization from
EtOAc-hexane gave in 2 crops 5.655 g (84.29%, total
RE BAD ORIGINAL
: HX10b -200- Lo yield from aldehyde) of pure title trans vinyl phosphonate as white needles with m.p. 143-144°C.
TLC (1:1) hexane-acetone, Ry = 0.40 :
Mass. Spec. (M+H' = 415% observed).
Anal Calcd for C,,H, O;PN,F: C, 63.76; H, 5.84;
N, 6.76; F, 4.58, Pp, 7.47. :
Found: C, 63.99; H, 5.95; N, 6.76; F, 4.54;
Pp, 7.31. la mm (cpely): § 1.42 (6H, d) : © 3.27 (1H, septet) : ’ 3.70 (6H, d, Jy p=11.0 Hz) 5.67 (1H, dd, Jpg=18.4 Hz, Jyp=18.5 Hz) oo 7.02-7.30 (9H, m) . .15 7.34 (1H, dd, J;=18 Hz, J,=24.3 Hz) ppn.
Pc NMR (cpely): 621.8, 27.1, 52.1 (J,_p=5.7 Hz), 110.4 (J,_p=193.1 Hz), 114.7 (J _p=24.6 Hz), 115.9, 116.2, 122.2, 124.9, 125.5, 127.3, 128.8, a 132.0, 139.2, 140.2 (J,_p=7.6 Hz), 142.1, 158.0, - 163.4 (Jo_p=249.8 Hz) ppm. : : a _ C. (E)-[2-[5-(4=Fluorophenyl)-3-(1-methyl-
Co oo ethyl )-l-phenyl-1H-pyrazol-4-yl}-= - 25 ethenyl ]phosphonic acid, monomethyl ’ ester : ip A solution of the Part B dimethylphosphonate ' (2.0 g, 4.83 mmole) in dioxane (15 ml) was treated : with 1.0N LiOH (7.3 ml) and the mixture refluxed for one hour under argon. The mixture was cooled to room temperature, acidified to pH 1 with 1.0N
HCl, extracted with EtOAc (2X), the organic phase : washed with 1.0N HCl and brine then dried over oo | bru URIGINAL oo mat ttm
Cn oo
HX1GL -201-~ : anhydrous Na,S0, and evaporated in vacuo to give crude mono acid which slowly crystallized on standing from hexane. Crystals were collected by : filtration and dried. in vacuo to give 1.918 (99%) : of title mono acid as a white crystalline solid oo vith m.p. 168-170°C. An analytical sample was prepared by recrystallization from EtOAc-hexane.
TLC (8:1:1) CH, C1 ,~CH3OH-HOAC, Rg=0.40. : :
Miss Spec (M+H =401" observed).
Anal Calcd. for C,H, ,05N, PE: Cc, 62.99; H, 5.54; :
RE : N, 7.00; F, 4.75; P. 7.74
Found: C, 62.95; H, 5.57; N, 6.87; F, 4.58; P, 7.58 1g amr (coelg): : - ~ 8 1.40 (6H, d) " 15 3.26 (1H, septet)" : 3.65 (3H, d, Jy ,=11.6 Hz) : 5.74 (1H, d4, Jg-g~17-9 Hz, Jyp=19.5 Hz) 7.00-7.36 (10H, m) ~ oo 8.65 (1H, bs) ppm. : : 13¢ mmr (cpcly): 6 21.8, 27.0, 51.8 (Jo_p=6.3 Hz), 111.7 (J;_p=198.7 Hz), 114.6 (Jo_p=24.6 Hz), 115.8, 116.2, 124.9, 125.4, 127.3, 128.7, 131.9, } | 132.1, 138.8 (J,.,=7.6 Hz), 139.2, 142.0, 157.9, 162.9 (Jo_p=249.8 Hz) ppm.
D. (E)-4-[[2-[5-(4~Fluorophenyl)-3-(1- methylethyl)-l-phenyl-1H-pyrazol-4- . yl]ethenyl Jmethoxyphosphinyl]-3- © 30 oxobutanoic acid, methyl ester
The dianion of methyl acetoacetate was prepared according to the method described in
Example 26 using the following quantities: . methyl acetoacetate (815 pl, 7.53 - cl BAD ORIGINAL
BE HX10b -202- mmole) 60% NaH dispersion in oil (324 mg, 8.11 : mmole), 1.6 M N-BuLi in hexanes (4.3 ml, 6.95 : oo mmole), THF (15 ml). : . A solution of phosphonic monomethyl ester ©. 5 (2.317 g, 5.79 mmole) and trimethylsilyldiethylamine v : (TMSDEA) (1.45 ml, 11.6 mmole) in CH,Cl, (15 ml) was stirred at room temperature for 1 hour. The oo mixture w.s evaporated to dryness, chased with benzene (20 ml) and dried in vacuo. The residue ei e210 - -was taken up in. dry CH,C1, (15 ml) treated with (cocl), (555 ul, 6.37 mmole) and DMF (1 drop), ’ : "and stirred at room temperature for 1 hour. The ‘mixture was evaporated to dryness, chased with } . : benzene (20 ml) and dried in vacuo. oo .15 A -78°C (CO,/acetone) solution of the : above phosphonochloridate in dry THF (10 ml) was : transferred dropwise via cannula over 20 minutes * to a -78°C solution of the methyl acetoacetate
Co dianion in dry THF (15 ml). The brown mixture was oo stirred for 30 minutes at -78°C then quenched by : dropwise addition of saturated NH,Cl (10 ml) and Co ~ allowed to warm to room temperature. The mixture . was partitioned between H,0 and EtOAc, the aqueous , : phase back-extracted with EtOAc, the combined ’ organic phases washed with saturated NaHCO, and "brine then dried over anhydrous Na,SO, and : evaporated in vacuo to give 3.080 g of an orange foam. The crude product was purified by flash ‘chromatography on Merck silica gel eluting with i (5:3:2) hexane-acetone-toluene. . ~The product fractions were combined and . evaporated to give 1.247 g (43.2%) of the desired title p-ketophosphonate as a pale yellow oil. oo ' TLC (4:4:2) acetone-hexane-toluene, R=0.29. bAL URIGINAL
Mass Spec (M+H'=499" observed). TT ee—
: HX10b 203- : i (cDCly): CL 8 1.42&1.43 (6H, 2 doublets) Co 3.24 (2H, m) 3.27 (1H, septet) . oo : ) 3.63 (2H, in) ; 3.66&3.67 (3H, 2 doublets, Jg_p=11.6 Hz) 3.72 (3H, s) 5.72 (1H, dd, Jg=18.7 Hz, Jp=24.3 Hz) 7.08-7.30 (9H, m) el... 10 oo 7.37 (1H, dd, Jpp=18.0 Hz, Jgp-22.7 Hz) ppm. | . 3c mm (cDCl,): 621.8, 27.1, 46.1 (J p=84.1 Hz), Co 50.0, 51.2 (Jo_p=5-9 Hz), 52.3, 112.6 (Jop=135.0 . Hz), 114.5 (Jop=23.5 Hz), 116.0, 116.3, 124.9, 125.4, 127.4, 128.8, 132.0, 132.1, 139.1, 141.4 (Jop=5-.9 Hz), 142.5, 158.2, 163.1 (Jop=250.4 Hz), 167.1, 194.9, 195.0 ppm. Ce pa Co :
E. (E)-4-[[2-[5-(4-Fluorophenyl}-3-(1- : methylethyl)-1-phenyl-1H-pyrazol-4-yl]- ethenyl Imethoxyphosphinyl]-3-hydroxy- : " butanoic acid, methyl ester : A -15° (salt/ice bath) solution of the Part
D ketone (1.304 g, 2.62 mmole) in absolute EtOH (15 ml) was treated with NaBH, (100 mg, 2.62 mmole) and the mixture stirred for 15 minutes under argon at -15°C. The reaction was quenched by addition of reagent acetone (0.3 ml) followed by CC-4 silica gel (600 mg), allowed to warm to room temperature, diluted with EtOAc, filtered and evaporated in vacuo to give 1.46 g of a yellow
J foam. The crude product was purified by flash -
BAD ORIGINAL
HX10b -20: ~ chromatography on Merck silica gel eluting a with (85:15) EtOAc-acetone. Product fractions . were evaporated to give 388 mg of pure title R alcohol as a white foam plus 228 mg of slightly : ’ impure product. Total yizld was 616 mg (47%).
TLC (7:3) EtOAc-~acetone, Re = 0.31.
Mass Spec. (m+at=s01" observed). :
Ht MR (cDClg): 8 1.42 (6H, 4d) ee 10 2.00 (2H, m) 2.60 (2H, 4) 3.27 (1H, 4) 3.64 (3H, d, Jyp=11.1 Hz) . 3.69 (3H, s) Co 3.93&4.02 (1H, 2 doublets) 4.42 (1H, 2 broad singlets) 5.72 (1H, dd, J;=18.0 Hz, J, 23.2 Hz) i} 7.04-7.47 (10H, m) ppm.
Mc wr (cpcl,): 6 21.8, 27.1, 35.7 & 36.5 (J,p=100.3 Hz), 42.0, 42.2, 50.8 (J-p=5.7 Hz), : 51.6, 63.4 (Jop=20.8 Hz), 114.2 & 114.4 (Jop=128.7 - Hz), 114.6 (Jop=20.8 Hz), 115.9, 116.3, 124.9, , 125.4, 127.3, 128.8, 131.9, 132.1, 139.1, 140.14&140.6 (Jop=5-7 Hz), 142.1, 158.0, 163.0 (Jp=251.6 Hz), 171.2, 171.9 ppm.
Co Example 39 (S)-4-[[2-[5-(4~-Fluorophenyl)<3~(l-methylethyl)- l-phenhyl-1H-pyrazol-4-yl]ethenyl Jhydroxyphosphinyl]-- 3-hydroxybutanoic acid, dilithium salt
A solution of the Example 38 diester (487 mg, 0.973 mmole) in dioxane (10 ml) was treated
BAD ORIGINAL
. HX10b ~205- with 1.0N. LiOH (3.4 ml, 3.4 mmole) and the . resulting mixture was heated and stirred at 70°C for 30 minutes. The mixture was cooled, diluted with H,0, filtered and evaporated in vacuo to an . 5 off-white solid. The crude product was dissolved in a minimum amount of H,0 and chromatographed on . : HP-20 resin (15 cm bed, 25 mm diameter column) : eluting with H,0 followes by (1:1) CH,OH-H,O. :
Product fractions were evaporated in vacuo, a lo dissolved in 75 ml of H,0, filtered and lyophilized to give 429 mg (87.3%) of pure title dilithium salt as a fluffy, white lyophilate. : TLC (8:1:1) CH,Cl,-CH,OH-HOAC, 'R.=0.14
Co. - Anal Calcd for C, 4H, 405N, PF Li, + 1.16 moles H,0 (MW 505.233): Cc, 57.05; H, 5.25; N, 5.55; ’
F, 3:76; P, 6.13 : a Found: C, 57.05; N, 5.18; N, 5.75; F, 3.89; P, .6.47 'r MR (400 MHz, CD,OD): » 6 1.39 (6H, doublet) 1.71 (2H, m) l . 2.35 (2H, m) : 3.36 (1H, septet)
Co 4.24 (1H, m) . i 6.00 (1H, dd, Jgp=17.6 Hz, J,=19.4 Hz) 7.07-7.35 (10H, m)
Example 40 (E)-4-[[2-[5-(4-Fluorophenyl)-3-(1l-methylethyl)-1- . phenyl-1H-pyrazol-4-yl]ethyl Jmethoxyphosphinyl}-3- : hydroxybutanoic acid, methyl ester ©
BAD ORIGINAL
HX10b -206-
A. ($)-3-[[(1,1-Dimethylethyl )diphenyl- silyl]oxy]-4-[[2-[5~(4-fluorophenyl)- 3-(1-methylethyl)-1-phenyl-1H-pytazol- 4-yl]ethyl Jmethoxyphosphinyl]butanoic : acid, methyl ester - }
A solution of Example 36 Parit H compound (912.0 mg, 1.24 mmole) in dry methanol (50 ml) was treated with 10% Pd/C and hydrogenated at 50 psi on a Parr hydrogenator overnight. The suspension was filtered through Celite and the filtrate was oo evaporated to dryness and dried in vacuo to give title compound as a homogeneous oil (908.3 mg, 99.1%). :
TLC: Re 0.23 (silica gel; Hexane:Acetone-7:3).
B. (S)-4-[[2-[5-(4-Fluorophenyl)-3-(1- : methylethyl )-1-phenyl-1H-pyrazol-4-yl]- ethyl Jmethoxyphosphinyl]-3-hydroxy- butanoic acid, methyl ester
A solution of Part A compound (908.3 mg, 1.23 mmole) in dry tetrahydrofuran (12 ml) was stirred under argon at room temperature and treated successively with glacial acetic acid }
R (0.29 ml, 4.94 mmoles) and 1.0 M Bu,NF/hexane (3.89 ml, 3.89 mmoles). The reaction mixture was stirred at room temperature for 20 hours, diluted with ice water (25 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic - extracts were washed with saturated NaHCO, (15 : 30 ml), brine (25 ml), dried (anhydrous MgSO, ), filtered and evaporated to dryness. oo
The crude product mixture (1.0 g) was chromatographed on a silica gel column (LPS-1; 1" . : : BAD ORIGINAL
. .0b -207-
Xx 9.5"), eluting the column wtih EtOAc:Hexane mixtures (4:1; 9:1), EtOAc and acetone to give title compound as an oil (529.1 mg, 85.6% yield). a
TLC: Rg 0.17 (silica gel; EtOAc:hexane-4:1). oo - :
Example 41 : (S)-4-[[2-[5-(4-Fluorophenyl)-3-(1l-mesthylethyl)-1- phenyl-1H-pyrazol-4-yl]ethyl lhydro::nhosphinyl]-3- hydroxybutanocic acid, dilithium sali,
Co 10. —— .—. A solution of Example 40 compound (529.0 mg, 1.05 mmoles) in dioxane (12.5 ml) was treated with 1.0 N LiOH (3.7 ml, 3.7 mmoles) and stirred at 55°C (oil bath) under nitrogen for 3.0 hours then at : . room temperature for 20 hours. The reaction mixture was evaporated to dryness and dried in vacuo. The crude product was chromatographed on oe an HP-20 column (1" x 6"), eluting the column with : steam-distilled water (750 ml), 10% aqueous CH,OH (500 ml), 20% aqueous CH5CH (500 ml) and 50% aqueous CH,OH (500 ml). The desired fractions were } combined, evaporated to dryness and dried in vacuo.
The solid obtained was dissolved in steam-distilled . water (35 ml) and lyophilized to give title
N compound as a fluffy white solid (510.0 mg, 92.4%). = 25 TLC: R, 0.38 (silica gel; i-PrOH:NH,OH: H,0-8:1:1).
Anal Calcd for ChyHygFLi, NOP 2.2 H,0 (Eff. Mo. wt. = 525.899): C, 54.81; H, 5.83; N, 5.33;
F, 3.61; P, 5.88 - } Found: C, 54.81; H, 5.61; N, 5.53; F, 4.06; P, 5.80 : 30 IR (KBr) (1596 cm™Y, C=0 of COO”).
CL ! BAD ORIGINA
IT Ge -208-
H'-NMR Spectrum (400 MHz, CD,OD): g 1.36 (d, 6H, J=7) : 1.60-1.72 (m, 4H) - © 2.32 (m, 2H) oo :
Ss 2.74 (m, 2H) - 3.21 (septet, 1H, J=7) 4.23 (m, 1B) . 7.06~7.32 (m, SH). . : ] e000 Example 42 (S)-4-[[2-[3-(4-Fliorophenyl)-5-(1l-methylethyl)-1- phenyl-1H-pyrazol-4-yl]ethynyl Jmethoxyphosphinyl]-3- : hydroxybutanoic acid, methyl ester ’ . . A. -4-Fluorobenzoic acid, 2-phenylhydrazide Lo
A mixture of phenylhydrazine (25 ml, 0.25 mmole) and triethylamine (35 ml, 0.25 mmole) in anhydrous ether (500 ml) was tooled down to -5° to ~10°C (ice-salt bath) under nitrogen and treated ‘ dropwise, over a 30 minute period, with 4-fluorobenzene carbonyl chloride (30 ml, 0.25 mole). The reaction mixture was warmed to room temperature, stirred for 3.0 hours, then filtered, : washing the solids well with ether (200 ml). The solids were dissolved in dichloromethane (600 ml), ’ “ 25 stripped to near dryness, suspended in hexane (600 ml) and filtered. The clear filtrate was evaporated to dryness, triturated with tetrahydrofuran (700 ml) and filtered, washing the solids well with tetrahydrofuran (100 ml). The filtrate was evaporated to dryness and dried oo in vacuo to give a crude product (34.6 g) : contaminated with two other components.
BAD ORIGINAL
HX10b : ~209-
The crude product was recrystallized from acetone to give title compound as white crystals (22.36 g, 38.8%), m.p..182-184°C. B i . The filtrate and mother liquor werd : combined, chromatographed on a silica gel column " (Baker, 60-200 mesh, 400 ml), eluting the column with EtOAc:CH,Cl, (1:9) to give an additional 9.78 g of tit. compound (55.87%).
TLC: R. ©.63 (silica gel: EtOAc: CH,Cl, -1:4). ~~ .....10 Anal caled for C,H, FN,0: C, 67.81; H, 4.82; . N, 12.17, F, 8.25. ’
Found: C, 67.86; H, 4.88; N, 12.14; F, 8.10 Co “Ms (m+H) =231. : 15 B. 4-Fluoro-N-phenylbenzenecarbohydrazo- co noyl chloride _ $s meee mete eA golution of Part A compotihd (6116 gh re smi ese 26.8 mmole) in anhydrous ether (46 ml) was treated with phosphorus pentachloride (6.6 g, 31.7 mmoles) and the reaction mixture was refluxed under i nitrogen for 16.0 hours. The reaction mixture was Co cooled to room temperature, treated with a - “ ; solution of phenol (11.5 g, 122.2 mmoles) in ether -- (15 ml), stirred for 5 minutes then treated : 25 dropwise with methanol (11.4 ml). The mixture was concentrated at ~75° in a rotary evaporator and the resulting oil cooled at 5°. The solid obtained was triturated with 5% aqueous acetone ” (20 ml) and filtered, washing the precipitates well with 5% aqueous acetone (30 ml). The ’ precipitates were dried in vacuo to give title compound as a solid (2.2 g), m.p. 118-120°. : BAD ORIGINAL
HX10b -210-
The clear filtrate was evaporated to . dryness and the product mixture chromatographed twice on a silica gel column (Baker, 60-200 mesh, © 400 ml), eluting the column with CH,Cl,:Hexane : mixtures (1:3; 1:1), to give more title compound (total amount = 5.66 g of 85%).
TLC: Rp 0.90 (silica gel; CH,Cl,:Hexane-4:1).
Anal Cal~ for C13H FN, Cc, 62.78; H, 4.05;
N, 11.27; F, 7.64; Cl, 14.26
S10 Found: C, 62.87; H, 3.97: N, 11.34; ~
F, 7.51; Cl, 13.95 CL
MS (M+H)'=249. . . . Cc. 3-(4-Fluorophenyl)-5-(1l-methylethyl)-
Co 15 1-phenyl-1H-pyrazole-4-carboxylic ) no acid, ethyl ‘ester -
CL A solution of sodium ethoxide (from 0.28 g : ‘of 12 mmoles of sodium metal and 40 ml of absolute ethanol) is treated dropwise under nitrogen with
CL 20 ethyl isobutyrylacetate (2.0 ml, 12 mmoles),
Ue stirred for 15 minutes. at room temperature then ” treated with Part B compound (3.0 g, 12 mmoles). oo oe "The mixture was stirred at. room temperature for 4.0 - ‘hours, quenched with 10% HCl (10 ml), evaporated ; 25 to dryness and the resulting solid triturated with ether (3 x 100 ml). The combined organic extracts were washed with brine (25 ml), dried (anhydrous
MgsO, ), filtered and evaporated to dryness. The } crude product (4.3 g) was chromatographed on a : . 30 silica gel column, eluting the column with
CH,C1,:hexane (1:1) to give title compound as a reddish-brown syrup (3.27 g, 77.3%).
TLC: Re 0.42 (silica gel; CH,Cl,:hexane-4:1).
BAD ORigIna
© HX10b ~11-
D. 3-(4-Fluorophenyl)-5-(1~methylethyl}~-1~ v . . phenyl-1H-pyrazolé-4-methanol :
Co ‘A solution of Part C compound (3.26 g, 9.25
Co mmoles) in dry ether -(22 ml) was added to a cooled Co _ 5 (0°, ice-salt bath) suspension of lithium aluminum : hydride (0.71 g, 18.7 mmoles) in dry ether (32 ml) oo and the reaction mixture was stirred at 0° under nitrogen for 3.0 hours. The mixture was quenched - at 0° by the dropwise addition of ethyl acetate oo 10 (5.0 ml), followed by 10% HCL (11 ml), decanted : and the residue triturated with ether (2 x 100 - ml). The combined organic extracts were washed with brine (20 ml), dried (anhydrous Mgso,)., . : filtered and evaporated to dryness to give title . compound (2.87 g, 94.4%). : 100 mg of title compound was recrystallized oo “a from ether to afford an analytical sample (57 mg, m.p. 145-147°). | oT h .
TLC: Re 0.17 (silica gel; CH,Cl,:hexane-4:1; . © 20 developed 2X). : » oo Anal Calcd for CoH, FN,0: C, 73.52; H, 6.17;
N, 9.03; F, 6.12 . | Found: C, 73.26; H, 6.11; N, 8.96; EF, 6.09 - MS (M+H) =311.
Co 25
E. 3-(4-Fluorophenyl)-5-(1-methylethyl)- 1-phenyl-1H-pyrazole-4-carboxaldehyde
A solution of Part D compound (2.59 4, 8.34 . ~ mmoles) in dry dichloromethane (22.0 nl) was added rapidly to a stirred suspension of pyridinium chlorochromate (5.41 g, 25.1 mmoles) in dry dichloromethane (32 ml) and stirred at room
BAD ORIGINAL
HX10b -212- : . temperature under nitrogen for 4.0 hours. The . reaction mixture was diluted with ether (190 ml), oo stirred for 20 minutes then decanted. The tarry : oo residue was triturated with ether (100 ml) and dichloromethane (30 ml) and the coxhined organic : " extracts were filtered through a silica gel pad. a ‘ The clear filtrate was evaporated to dryness and the crude product chromatographed on a silica gel column (Baker, 60-200 mesh, 300 =i) eluting the column with CH,Cl,:hexane (4:1) to give title Co i : compound (2.40 g, 93.4%) as a sclid product. 100 mg of title compound was recrystallized ’ from hexane to give an analytical sample (50 mg, . © m.p. 103-105°).
TLC: Rp 0.67 (silca gel; CH,CL,). Co
Anal calcd for C,g H,,FN,0: C, 74.01; H, 5.56;
N, 9.09; F, 6.16
Found: C, 74.18; H, 5.35; N, 9.11; F, 6.12
Ms (M+H) =309. } _ F. 4-(2,2-Dibromoethenyl)-3-(4-fluoro- phenyl)-5-(l-methylethyl)-1-phenyl- - . 1lH-pyrazole :
A mixture of Part E compound (2.296 gq, 7.45 mmoles) and triphenylphosphine (5.86 g, 22.1 mmoles) in dry dichloromethane (35.0 ml) was cooled down to -5° to -10°C (ice-salt bath) under : argon, treated dropwise, over a 5 minute period, with a solution of carbon tetrabromide (3.70 g, . 30 11.0 mmoles) in dry ‘dichloromethane (12 ml) and stirred at -10° for 20 minutes. The reaction mixture was warmed up to room temperature, poured into saturated NaHCO, (12 ml) and extracted with
BAD ORIGINAL
. HX10b -213- dichloromethane (3 x 60 ml). The combined organic } extracts were washed with saturated NaHCO, (12 : ~~ ml), brine (10 ml), dried (anhydrous MgSO, ), ~ filteved and evaporated to dryness. :
The crude product (11.0 g, solid) was chromatographed on a silica gel column, eluting the column with CH,Cl,:hexane mixtures (1:1, 4:1) to give title compound (2.96 g, ©6.0% oo corrected yield) and unrzacted starting material : . __._._. 10 (250.6 mg). ;
Co. © 100 mg of title compound was recrystallized from Et,O:hexane to give an analytical sample (36.5 mg, m.p. 93.5°). . + TLC: Rg 0.57 (silica gel; CH,Cl,:hexane-4:1). “15 Anal Calcd for C,H; 7BT Fly: Cc, 51.75; H, 3.69;
N, 6.04; Br, 34.43; F, 4.09 "a Found: C, 51.78; H, 3.54; N, 6.07; Br, 34.40; BN
F, 3.92 | ~ ‘Ms (M+H)=465
G. 4-Ethynyl-3-(4-fluorophenyl)-5-(1- methylethyl)-1l-phenyl-1H-pyrazole
Co A solution of Part F compound (2.87 g, 6.18 * mmoles) in dry tetrahydrofuran (11.44 ml) was cooled down to -78° (dry ice-acetone), treated dropwise with 1.6 M n-BuLi/hexane (11.7 ml, 18.6 mmoles) under argon then stirred at -78° for 2 : "hours and 20 minutes. The reaction mixture was } : quenched at -78° with 25% NH,CL (16.5 ml), warmed up to room temperature and extracted with ether (3 . x 60 ml). The combined organic extracts were washed with brine (22 ml), dried (anhydrous : MgSO, ). filtered and evaporated to dryness. The :
BAD ORIGINAL
HX10b . -214- crude product (1.9 g) was chromatographed on a . silica gel column, eluting the column with .
Et,O:hexane (5:95). The desired fractions were combined and evaporated to dryness to give title ccmpeurnd (1.88 g, 100% yield) as a solid product. 100 mg of title compound was recrystallized from hexane to give an analytical sample (63.5 mg, m.p. 117-118°)."
TLC: Re 0.37 (silica gel; Et,0:hexane-1:9). oe... ...10 . Anal Caled for CoH 7 Ny: Cc, 78.92; H, 5.83; ’ . F, 6.24; N, 9.21 :
Found: C, 79.12; H, 5.60; F, 6.02; N, 9.12
MS (M+H) =305. : " 15 H. (S)-3-[[(1,1-Dimethylethyl)diphenyl- : silyl)oxy]-4-(([3-(4-fluorophenyl)-5- ) oo (1-methylethyl)-1-phenyl-1H-pyrazol-4- '
Le yl]ethynyl Jmethoxyphosphinyl]butanoic
SE acid, methyl ester
EE 20 A solution of (S)-3-[[(1,1-dimethylethyl)- . diphenylsilyl]oxy]-4-(hydroxymethoxyphosphinyl)- : butanoic acid, methyl ester (prepared in Example 1
RE. ] Part F) (2.77 g, 5.55 mmoles) in dry dichloromethane (10 ml) was treated with - trimethylsilyldiethylamine (2.1 ml) and stirred at room temperature for 1.0 hour under argon. The reaction mixture was evaporated to dryness, azeotroped with dry benzene (20 ml) and dried in vacuo. The syrup was re-dissolved in dry dichloromethane (10 ml), cooled down to -10° Co (ice-salt bath), treated with 1 drop of DMF followed by the dropwise addition of oxalyl chloride (530 pl), stirred at -10° for 15 minutes
BAD ORIGINAL
HX10b -215- : then at room temperature for 1.0 hours. The mixture was evaporated to dryness, azeotroped with E benzene (20 ml) and dried in’ vacuo. ©
Part G compound (1.12'g, 3.67 mmoles), was dissolved in dry tetrahydrofuran (9.0 ml), cooled down to -78° (dry ice-acetone bath), treated with 1.6 M n-BuLi/hexane (2.3 ml, 3.68 mmoles) under argon and =tirred at -78° for 45 minutes. The 5 above phosphonochloridate was dissolved in dry © tetrahydrofuran (6.5 ml), cooled to -78° and } treated dropwise, by cannula, with the solution of Co the acetylene anion both solutions being kept at : -78° throughout the addition. The reaction : mixture was stirred at -78° for 30 minutes then ’ 15 quenched by the dropwise addition of 25% NH, C1 (6.0 ml) and allowed to warm up to room : i apd temperature. The mixture was extracted with ether es (3 x 100 ml) and the combined organic extracts - were washed with 25% NH,C1 (10 ml), brine (25 ml), dried (anhydrous MgSO, )., filtered and evaporated oo to dryness.
The crude product mixture (4.0 g) was i chromatographed on a silica gel column, eluting the column with acetone:hexane mixtures (1:9; 3:7) } to give title compound (1.76 gq, 65.2%) as an oil.
TLC: Re 0.40 (silica gel; hexane:acetone-7:3). oo
I. (S)-4-[[2-[3-(4~Fluorophenyl)-5-(1- methylethyl)-1-phenyl-1H-pyrazol-4-yl]- - 30 ethynyl |methoxyphosphinyl]-3-hydroxy- butanoic acid, methyl ester === } .
BAD ORIGINAL
HX10b -216-
A solution of Part H compound (700 mg, 0.95 : : mmoles) in dry tetrahydrofuran (9 ml) was treated successively with glacial HOAc (224 pl, oo | 3.82 mmoles) and 1.0 M (C4Hg) NF (3.0 ml, 3.0 . mmoles) and stirred overnight at room temperature : : under argon. The solution was cooled down to 0° (ice-salt bath), treated dropwise with 5% KHSO, a (10 ml) and extracted with ethyl acetate (3 x 75 : 'ml). The combined organic extracts were washed oo
CC . © 10 with 5% KHSO, (10 ml), brine (25 ml), dried .. : Lol (anhydrous MgSO, ), filtered and evaporated to dryness.
The crude product (890 mg) was dissolved : in a mixture of ether (16 ml) and tetrahydrofuran : 15 (12 ml), cooled down to 0° (ice-salt bath) and treated with excess diazomethane in ether. The : reaction mixture was stirred at 0° for ~3 hours, : quenched by the dropwise addition of glacial - oo acetic acid and evaporated to dryness. The crude Lo product mixture (764 mg) was chromatographed on . a silica gel column, eluting the column - with EtOAc:hexane mixtures (1:1; 4:1; 9:1) to give title compound as a semi-solid (347 mg, 73.2%).
TLC: Re 0.28 (silica gel; EtOAc:hexane-4:1).
Example 43 (S)-4-[[2-[3-(4-Fluorophenyl)-5-(1l-methylethyl)-1- phenyl-1H-pyrazol-4-yl]ethynyl]Jhydroxyphosphinyl]-3- hydroxybutanoic- acid, dilithium salt ' 30 | A solution of Example 42 compound (347 oo mg; 0.7 mmoles) in dioxane (8.3 ml) was treated with 1.0 N LiOH (2.4 ml, 2.4 mmoles) and stirred at 55°C (oil bath) under nitrogen for 45 minutes. ho | : :
BAD ORIGINAL
. HX10b ~217- oo The reaction mixture was evaporated to dryness and
EE dried in .vacuo. The resulting semi-solid was - "chromatographed on an HP-20 column (1" Xx avy; eluting the column with steam-distilled water (350 ml), 50% aqueous methancl (250 ml). The desired fractions were combined, evaporated to dryness and . dried in vacuo. The product was dissolved in steam-distilled water and lyophilized to give title compound as a “hite solid lyophilate (338 mg, 97.5%). ee
TLC: Rg 0.50 (silica gel; i-PrOH:NH,OH:H,0-7:2:1).
Anal Calcd for C, 4H, FLi, N,OgP 1.95 H,O: Cc, 55.71; :
H, 5.04; N, 5.42; F, 3.67; P, 5.99
Found: C, 55.90; H, 5.46; N, 5.30; F, 3.95; P, 5.96. } 15 H-NMR Spectrum (400 MHz, CD,OD): 6 1.45 (4d, 6H, J=7) 1.89-2.05 (m, 2H) Co
BE 2.38 (dd, 1H, J=9, i5) Lo ce : 2.52 (dd, 1H, J=4, 15) 3.06 (septet, 1H, J=7) 4.48 (m, 1H) 7.16-8.11 (m, 9H) } Example 44 * (S)-4-[[2-[3-(4-Fluorophenyl)-5-(1l-methylethyl)- 1-phenyl-1H-pyrazol-4-yl]lethyl]methoxyphosphinyl]- 3-hydroxybutanoic acid, methyl ester .
A. (S)-3-[((1,1-Dimethylethyl)diphenyl- silyl]oxy}-4-[[2-[3-(4-fluorophenyl)- - 30 5-(l-methylethyl)-1l-phenyl-1H-pyrazole- : : 4-yl]ethyl Jmethoxyphosphinyl)butanoic acid, methyl ester ~~ 7 opp ORIGNA
.HX10b
D3
A solution of Example 42 Part I compound ‘ (1.0 gm, 1.36 mmole) in dry methanol (72 ml) was . . treated with 10% Pd/C (250 mg) and hydrogenated in a Parr hydrogenator overnight at ~40 psi. The : reaction mixture was filtered through Celite and the clear filtrate was evaporated to dryness to give title compound as a homogeneous oil (1.0 gm, Lo 100% crude yield). So
TLC: Re 0.27 (silica gel; hexane:acetone =- 7:3). : me me 10 LL Lo : : oo B. (S)-4-[[2-[3~(4-Fluorophenyl)-5-(1- methylethyl )-1-phenyl-1H-pyrazol-4-yl]- ethyl Jmethoxyphosphinyl]-3-hydroxy- . butanoic acid, methyl ester
A solution of Part A compound (1.05 g, 1.41 :
Lo ~~ mmoles) in dry tetrahydrofuran (14.0 ml) was . treated successively with glacial acetic acid (334 : ul, 5:83 mmoles) and 1.0 M (C,H,),NF/THF (4.46 ml, 4.46 mmoles) and stirred at room temperature under argon for ~19 hours. The reaction mixture was aE diluted with ice-water (28 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic
To extracts were washed with saturated NaHCO, (15 : ] ml), brine (25 ml), dried (anhydrous MgSO, ), filtered and evaporated to dryness. The crude product mixture (1.14 g) was chromatographed on a oo silica gel column (Baker, 60-200 mesh, 150 ml), eluting the column with EtOAc:hexane mixtures (2:1; 4:1, 9:1), ethyl acetate and acetone to give title compound as a semi-solid (623.5 mg, 88.0%).
TLC: Re 0.18 (silica gel; EtOAc:hexane -4:1).
BAD ORGINAL
. . LE :
HX10b -21¢%- ~ Example 45 (S}-4-[[2-[3-(4-Fluorophenyl)-5-(l-methylethyl)-1- phenyl-1H-pyrazol-4-yl]ethylhydroxyphosphinyl]-3- hydroxybutanoic acid, dilithium salt
A solution of Example 44 compound (623.5 : mg, 1.24 mmoles) in dioxane (14.7 ml) was treated with 1.0 N LiOH (4.28 ml, 4.27 mmoles) under nitrogen, heated at 55°C (oil bath) for 2 hours then stirred at room temperature for ~20 hours. oo ee... 10 The reaction mixture was evaporated to dryness, oo dried in vacuo and chromatographed on an HP-20 "column (1" x 6"), eluting the column with steam~-distilled water (750 ml), 10% aqueous CH, OH, . 20% aqueous CH,OH (500 ml) and 50% aqueous CH,OH (500 ml). The desired fractions were combined and evaporated to dryness to give the desired product (560 mg, 92.8%). TLC: Rg 0.42 (silica gel; : i~ProH:NH,OH:H,0 - 8:1:1). : Anal Calcd for C,,H, FLi N,O;P-1.16 H)O: (Eff.
M.W. = 507.197): C, 56.83; H, 5.62; N, 5.52;
F, 3.74; P, 6.11
Found: C, 56.83; H, 5.80; N, 5.76; F, 3.46; P, 6.19. . H-NMR Spectrum (400 MHz, CD40D): : 6 1.30 (d, 6H, J=7) 1.60-1.78 (4d, 4H) 2.36 (m, 2H) . 2.96-2.99 (m, 2H) 3.14 (m, 1H) 4.26 (m, 1H) . = 30 7.14-7.68 (m, 9H) oo BAD ORIGINAL
. HX10b a. -220-
Example 46 : ’ (S)-4-[[[4-(4-Fluorophenyl)-1-(l-methylethyl)-3- phenyl-1H-pyrazol-5-yl]ethynyl Jmethoxyphosphinyl]- ' 3-hydroxybutanoic acid, methyl ster _ :
A. 2-(4-Fluorophenvl}-1l-phenylethanone
A suspension of magnesium turnings (928 mg, 38 mmoles) in dry ether (38 ml) under argon was i treated dropwise with 4-fluorobenzylbromide (5.3 - oo ml, 42 mmoles) over a period of 45 minutes at a - 10 rate maintaining gentle reflux. When addition was completed, the mixture was refluxed for another 30 " minutes, cooled down to room temperature and treated with a solution of benzonitrile (2.96 ml, . 29 mmoles) in dry ether (5 ml). The mixture was stirred at room temperature for 4.5 hours, poured slowly into cold 10% HCl (40 ml) and the resulting suspension was extracted with ether (5 x 50 ml) and ethyl acetate (2 x 100 ml). The combined organic extracts were washed with saturated NaHCO, (50 ml), brine (50 ml), dried (anhydrous Mgso,)., : filtered and evaporated to dryness.
The crude product (9.8 g) was : chromatographed on a silica gel column (Baker, ‘ 60-200 mesh, 400 ml), eluting the column with
Co 25 CH,Cl,:hexane mixtures (1:4, 1:2). The desired fractions were combined and evaporated to dryness to give title compound as a white solid (3.29 gq, m.p. 106-8°). (An additional 2.60 g was obtained from other fractions containing a trace of starting material to give a total yield of 94.8%.) - TLC: Ry 0.60 (silica gel; CH,Cl,:hexane - 1:1). : BAD ORIGINAL
_ Har -221- : oo Anal Calcd for C,H, FO: C, 78.49; H, 5.18; F, 8.87 oo
Found: C, 78.22; H, 5.22; F, 9.21 ms (M+H)'=215 oo
B. 2-(4-Fluorophenyl)-l-phenylethanone, - : (1-methylethyl)hydrazone
A solution of Part A compound (4.45 g, 21 mmoles) in a mixture of 95% ethanol (34 ml) and : : glacial acetic acid (0.74 ml) was treated with : 10 isopropylhydrazine (3.63 ml, ~42 mmoles) and
So heated at 80° (oil bath) under N, for 1.4 hours. :
Thin layer chromatography indicated that some starting material was still present so the : reaction mixture was treated with additional oT 15 isopropylhydrazine (2.0 ml, ~23 mmoles) and heated a0 di aiene wear... at 80° (oil bath) for another hour. The reaction co le
SE mixture was cooled down to room temperature, evaporated in a rotary evaporator to remove most of : the solvent then diluted with dichloromethane (200 ) 20 ml). The organic solution was washed with brine (25 ml), dried (anhydrous MgsO,), filtered and So : evaporated to dryness. The yellow oil obtained was . evaporated once from toluene (150 ml) to give title compound as a crude product (5.63 g) contaminated ’ with some starting material and traces of two other ; components. ’
TLC: Re 0.28 (silica gel; CH,Cl,:hexane-1:1).
Isopropylhydrazine was prepared as follows:
Co lodopropane (10.3 ml, 0.10 mole) was added
B 30 over a period of 2.0 hours to hydrazine hydrate (48.4 ml, 1.0 mole) under N,. The mixture was then stirred at 60° (oil bath) under N, for 3 . hours, cooled and extracted with ether (250 ml)
BAD ORIGINAL
HX10b . ~222- for 20 hours (liquid-liquid extractor). The - ethereal extract was evaporated to give isopropylhydrazine (5.63 ml or 5.3 g). : oo : C. Acetic acid, 2-[2-(4-fluorophenyl)--1- : phenylethylidene]-1-(l-methylethyl)~ hydrazide
Co A mixture of crude Part B compound (5.63 , : i oo 221 nwoles) and triethylamine (5.85 ml, 42 mmoles) ee... 10 in dry toluene. (210 ml) was cooled down to 0° Comme : (ice-salt bath) under N, and treated with acetyl . chloride (1.86 ml, 26.3 mmoles). The reaction - mixture was stirred with gradual warming to room . . temperature for 1.5 hours, diluted with ether (700 . 15 ml) and filtered. The clear filtrate was dried oo (anhydrous Na,S0,), filtered, evaporated to
Cl dryness and evaporated once from toluene (300 :
Co ml). The semi-solid obtained (7.1 g) was - chromatographed on a silica gel column (Baker, 60-200 mesh, 400 ml), eluting the column with : CH,C1,:hexane mixtures (1:1, 2:1), CH,C1, and
CH,Cl,:CH30H (9:1) to give title compound as a
Co crude product (4.11.g). The crude product was rechromatographed on another silica gel column, eluting the column with EtOAc:hexane (4:1). The desired fractions were combined and evaporated to dryness to give title compound as a : thick yellow oil (3.89 g).
TLC:Rg 0.47 (silica gel:EtOAc:hexane-1:1). : 30 oo - | BAD ORIGINAL
HX10b -223- : Dp. 4-(4-Fluorophenyl)-5-methyl-1-(l-methyl-
E ethyl)-3-phenyl-1H-pyrazole : A solution of Part C compound (1.50 g, 4.80
Co mmoles) in bis (2-methoxyethyl)ether (48 ml) was treated with solid potassium hydroxide (615 mg, 10.96 mmoles) and heated at 80° (oil bath) under
N, for 2.0 hours. The reaction mixture was treated with » second batch of potassium hydroxide (700 mg, 12.5 mmoles), heated at 80° for 2 hours and then stirred at room temperature for 16 i» : hours. The mixture was poured into water (300 ml) : and extracted successively with ether (3 x 150 ml) and ethyl acetate (200 ml). The organic solutions . were combined, washed with cold 3% HCl (500 ml), brine (2 x 100 ml), dried (anhydrous Mgso,), filtered and evaporated to dryness. The crude : product (3.5 g) was chromatographed on a silica’ : gel column (Baker, 60-200 mesh, 500 ml), eluting the column with EtOAc:hexane (1:4) to give title compound as a cream-colored solid (1.33 g, 94.3%), m.p. 135-=7°.
TLC: Rg 0.63 (silica gel; EtOAc:hexane - 1:4). " E. 4-(4-Fluorophenyl)-1-(l-methylethyl)- 3-phenyl-1H-pyrazole-5-carboxaldehyde : © A mixture of Cus0, * SH,0 (2.21 g, 8.85 mmoles) and potassium persulfate (9.53 gq, 35.3 mmoles) in acetonitrile (65 ml) and water (39 ml) was heated to 65° (oil bath) under N, and treated with Part D compound (2.6 g, 8.83 mmoles). The bath temperature was slowly raised to 75°, kept at 75° for 40 minutes then cooled to room temperature, using a water bath. The reaction mixture was
Lt BAD ORIGINAL -
HX10b -224- : : . diluted with dichloromethane (45 ml), stirred for 10 minutes and decanted, extracting the aqueous - suspension with more dichloromethane (3 X 45 ml). .
The combined organic extracts were washed with : brine (2 x 30 ml), dried (auhydrous MgSO, ). B filtered and evaporated to dryness. The crude product (2.75 g) was chromatographed on a silica ) gel column (LPS-1), eluting the column with : "EtOAc:hexane (1:9) to give~ title compound as a : 10... solid (1.57 g, 57.7%).
TLC: Re 0.72 (silica gel; EtOAc;hexane - 1:4). :
F. 5-(2,2-Dibromoethenyl)-4-(4-fluoro- ) phenyl)-1-(l-methylethyl)-3-phenyl- to 15 1H-pyrazole ’
A mixture of Part E compound (1.75 g, 5.68 : mmoles) and triphenylphosphine (4.6 g, 16.8 oo mmoles) in dry dichloromethane (27.0 ml) was oo ) cooled down to -5° to -10° (ice-salt bath) under
Ce 20 argon, treated dropwise, over a 5 minute period - with a solution of carbon tetrabromide (2.82 g, . 8.42 mmoles) in dry dichloromethane (9 ml) and
Co stirred at -10° for 20 minutes. The reaction ‘ - mixture was warmed up to room temperature, poured ° . 25 onto saturated NaHCO, (9.0 ml) and extracted with dichloromethane (3 x 50 ml). The combined organic. extracts were washed with saturated NaHCO, (10 ) ~ ml), brine (10 ml), dried (anhydrous MgSO, ), filtered and evaporated to dryness. : 30 The crude product was chromatographed on silica gel eluting with CH,Cl1,:hexane mixtures
CL oo DAD ORIGINAL
£1X10b -225~ (1:0, 1:4). The desired fractions were combined to give title compound (2.35 g, 91.4%) as an oil. i
TLC:R¢ 0.32 (silica gel:CH,Cl,:hexane - 1:1).
G. 5-Ethynyl-4-(4~-fluorcphenyl)=1-(1- methylethyl)-3-phenyl-1lH~pyrazole
A solution of Part F compound (1.89 g, 4.08 mmoles) in dry tetrahydrofuran (7 5 ml) was cooled down to -78° (dry ice-acetone), ticated dropwise : . 10 with 1.6 M BulLi/hexane (5.2 ml, 8.18 mmoles, 2 eq.) under argon and stirred at ~78° for 1 hour and 20 = : minutes. The reaction mixture was quenched at : -78° with 25% NH, C1 (11.0 ml), warmed up to room
Co temperature and extracted with dichloromethane (3
X 50°'ml). The combined organic extracts were : washed with brine (15 ml), dried (anhydrous - ’ MgsO,), filtered and evaporated to dryness. The ‘ crude product (1.77 g) was chromatographed on a silica gel column, eluting the column with : 20 CH,Cl,:hexane mixtures (1:4; 1:1) to give title compound (648 mg) along with mixed fractions containing title compound and Part F compound. - The mixed fractions were combined with the product ’ from another run (490 mg from 1.1 mmoles of Part F compound) and chromatographed on a second column, eluting the column with CH,Cl, :hexane . (1:9). The desired fractions were combined and evaporated to dryness to give title compound as an 0il (1.02 g, 71.5% corrected for recovered ” 30 starting material).
TLC: Re (silica gel; CH, C1, :hexane - 1:1).
Se BAD ORIGINAL
: . : HX1: -226-
H. {(S)-3-[[(1,1-Dimethylethyl)diphenyl- ‘
Co silyl]oxy]-4-[[[4-(4-fluorophenyl)-1- (1-methylethyl)-3-phenyl-1H-pyrazol-5- so Co yl]ethynyl Jmethoxyphosphinyl]hutanoic - | ~~ acid, methyl ester oS
A solution of the Example 1 Part F phosphonic monomethyl ester (2.341 g, 5.01 mmoles) | - : : and trimethylsilylethylamine (1.90 ml, "O mmoles) oo in dry dichloromethane (9.5 ml) was stirred at . Se 10 room temperature under argon for 1 hour. The 3 mixture was evaporated to dryness, azeotroped with dry benzene (15 ml) and dried in vacuo. The : viscous oil was re-dissolved in dry . dichloromethane (9.5 ml), treated with one drop of
DMF, cooled down to -10 to 0° (ice-salt bath) and : treated dropwise with oxalyl chloride (480 pl, 5.47 mmoles). Vigorous gas evolution was observed and the dark yellow solution was stirred at -10° to 0° for 15 minutes then at room temperature for 1.0 hour. The reaction mixture was evaporated to - dryness, azeotroped with benzene (18 ml) and dried in vacuo. : : - i A solution of Pait G compound (1.016 g, 3.34 mmoles) in dry tetrahydrofuran (8 ml) was cooled down to -78° (dry ice-acetone) under argon and treated with 1.6 M n-BuLi/hexane (2.1 ml, 3.36 " mmoles) and stirred at -78° for 1.0 hour. The above phosphonochloridate was dissolved in dry tetrahydrofuran (8 ml), cooled down to -78° (dry ice-acetone) under argon and treated dropwise by cannula with the solution of the acetylene anion both solutions being kept at -78° throughout the . addition. The reaction mixture was stirred at to BAD — ad
} HX10b -227-
To -78° for 1.0 hour, quenched by the dropwise addition of 25% NH, C1 (9 ml) then warmed up to ; room temperature. The mixture was extracted with ether (3°x 100 ml) and the combined organic extracts were washed with 25% NH,Cl (10 ml), brine x (25 ml), dried (anhydrous Mgso, ), filtered and evaporated to dryness. .
The crude product was chromatographed on a | : : silica gel column, eluting the column with acetone:hexane mixtures (1:9, 1:4) to give title Lo compound as an oil (1.595 g, 64.8%). -
TLC: Rp 0.43 (silica gel; acetone:hexane - 3:7). . I. (S)-4-[[[4-(4-Fluorophenyl)-1-(1- ’ 15 methylethyl)-3-phenyl-1H-pyrazol-5-yl}- - ethynyl ]methoxyphosphinyl}~-3-hydroxy- butanoic acid, methyl ester , -
A solution of Part H compound (1.0 g, 1.36 | oo : mmoles) in dry tetrahydrofuran (13 ml) was ’ treated successively with glacial acetic acid (320 ul, 5.46 mmoles) and 1 M (C,Hg),NF (4.26 ml; 4.26 mmoles) and stirred overnight at room temperature . under argon. The reaction mixture was cooled down
So to 0° (ice-salt bath), treated with 5% KHSO, (15 ml) and extracted with ethyl acetate (3 x 125 ml). The combined organic extracts were washed : with 5% KHSO, (2 x 25 ml), brine (25 ml), dried (anhydrous Mgso,). filtered and evaporated to - dryness. ~ 30 The crude product (1.06 g) was dissolved in a mixture of ether (23 ml) and tetrahydrofuran (18 ml), cooled down to 0° (ice-salt bath), : treated with excess diazomethane in ether and ce ee -
BAD ORIGINAL
HX10b -228- .. stirred at 0° for 4 hours. The reaction mixture . ' was quenched by the dropwise addition of glacial : acetic acid, evaporated to dryness and dried : oo : © in vacuo. The crude product was chromatographed :
Co 5 on a silica gel column, eluting the column with acetone:hexane (1:2). The desired fractions were } : combined and evaporated to dryness to give title compour.l as an oil (330 mg, 48.7%). | oo
TLC: Rg 0.23 (silica gel; EtCAc:hexane - 4:1). o 10 : .
Example 47 : (s)-4-[[[4-(4-Fluorophenyl)-1-(1l-methylethyl)-3- phenyl-1H-pyrazol-5-yl]ethynyl]hydroxyphosphinyl)- co 3-hydroxybutanoic acid, dilithium salt
A solution of Example 46 compound (330 mg, hk 0.66 mmole) in dioxane (7.8 ml) was treated with Co
EA "IN LiOH (2.29 ml, 2.29 mmole) stirred at 55° (oil } bath) under argon for 1.5 hours then at room
CT temperature for 16 hours. The reaction mixture was . 20 evaporated to dryness and dried in vacuo. The oo crude product was chromatographed on an HP-20 . column (1" x 10"), eluting the column with steam-~ oo distilled water (750 ml), 10% aqueous CH,0H (500
Co ml), 20% aqueous CH,0H (500 ml) and 507 aqueous
CH,OH (500 ml). The desired fractions were : _ combined, evaporated to dryness and dried : in vacuo. The solid product was dissolved in po | steam-distilled water and lyophilized to give title compound as a fluffy solid lyophilate (275 mg, 99.5%).
TLC: Rg 0.57 (silica gel; i-PrOH;NH,OH:H,O = 8:1:1).
BAD ORIGINAL ! : ce
HX10b -229-
Anal Calcd for Cp gH, FLipN,O5F 2.28 (Eff. mol. wt | Co = 523.310): C, 55.08; H, 5.11; N, 5.35; F, 3.63; oo
P, 5.92 :
Found: C, 55.08; H, 4.98; N, 5.47; F, 3.66; P, 5.99 .
IR (KBr): 2172 cm } (c=C) ’ al-NMR spectrum (400 MHz, CD30D): 5. 1.57 (4, 6H, J=7 Hz) ) ©1.86-2.01 (m, 2H) : 2.37 (dd, 1H, J=8) - 2.50 (dd, 1H, J=4) . ) © 4.40 (m, 1H) 5.01 (septet, 1H, J=7) : 7.04-7.39 (m, 9H) . 15 Example 48 Co N (S)-4-[[2-[4-(4-Fluorophenyl)-1-(1l-methylethyl)-3- phenyl-1H-pyrazol-5-yl]ethyl]methoxyphosphinyl)-3- - hydroxybutanoic acid, methyl ester. CL
A. (S)-3-[{(1,1-Dimethylethyl)diphenyl- silyl]oxy]-4-[[2-[4-(4-fluorophenyl)-1- . (1-methylethyl)-3-phenyl-1H-pyrazol-5- y1l]ethyl]methoxyphosphinyl]butanoic : acid, methyl ester :
A solution of Examplé 47, Part H compound (608 mg, 0.85 mmole) in dry methanol (63 ml) was treated with 10% Pd/C (155 mg) and hydrogenated at room temperature on a Parr hydrogenator at ~40 psi overnight. The suspension was diluted with methanol (50 ml) and filtered through a celite pad - 30 in a millipore unit, washing the pad well with methanol. The clear filtrate was evaporated to dryness and dried in vacuo to give title compound
Lo | BAD ORIGINAL
Co : HX10b : -230- as a homogeneous oil (559 mg, 90.9%) with ‘ consistent rl-NvR and c13-NMR spectral data. Co . " RC: Re 0.20 (silica gel:acetone: hexane 3:7; UV).
B. (S)-4-[[2-[4-(4-Fluorophenyl)-1-(1- . : methylethyl)-3-phenyl-1H-pyrazol-5-yl]- ethyl ]methoxyphosphinyl]-3-hydroxy- : butaiciz acid, methyl ester
A solution of Part A compound (559 mg, 0.75 sem 10 minole) in dry tetrahydrofuran (7.5 ml) was treated - oo successively with glacial acetic acid (176 pl, 3.0 " mmoles, 4 eq) and 1.0 M (CgHg)y NF/hexane (2.34 ml, : 2.34 mmoles, 3.1 eq) under nitrogen and stirred at . room temperature for ~20 hours. The reaction : mixture was diluted with ice-water (20 ml), extracted with ethyl acetate (3 x 70 ml), and the combined organic extracts were washed and saturated NaHCO, (10 ml), brine (20 ml), dried : (anhydrous MgSO, )., filtered and evaporated to dryness. The crude product (580 mg) was : chromatographed on a silica gel column, eluting the column with EtOAc:hexane (1:4), EtOAc and
So acetone:hexane (4:1). The desired fractions were combined, evaporated to dryness and dried in vacuo to give title compound as a homogeneous oil (337 mg, 89.4%). Co ’ TLC: Re 0.18 (silica gel; acetone:hexane - 1:1; uv). So : vo BAD ORIGINAL . a
HX10b -231 . Example 49 Co (s)-4-[[2-[4-(4-Fluorophenyl)-1-(l-methylethyl)-3- phenyl-1H-pyrazol-5-yl]ethyl]hydroxyphosphinyl]-3- oh : hydroxybutanoic acid, dilithium salt oo : 5 A solution of Example 48 compound (337.0 : mg, 0.67 mmole) in dioxane (8.0 ml) was treated with 1.0 N LiOH (2.32 ml, 3.5 eq) under argon, stirred at 55° (oil ba*h) for 3.0 hours then at room temperature for 20 hours. The reaction : ~ 10 mixture was evaporated to dryness and dried
Co in vacuo (pump) for 1.0 hour. The crude product "was chromatographed on an HP-20 column (1"x8"),
Ye eluting the column with steam-distilled water (500
LT ml), 10% aqueous CH,OH (500 ml), 20% aqueous CH,OH (500 ml) and 50% aqueous CH,0H. The desired fractions were combined, evaporated to dryness and ‘ dried in, vacuo. The resulting solid was dissolved in steam-distilled water, frozen and lyophilized overnight to give title compound as a fluffy white lyophilate (280.4 mg, 82.4%) with consistent analytical, mass spectrum, IR and al-NMR spectral data. : TLC: Re 0.45 (silica gel; i-Pron: NH, OH: H,0 - 8:1:1; UV). An additional 24 mg of slightly impure product was obtained from other fractions. . : Anal calcd for Co 4H, gFLi, NOP 1.19 H,0 (Effective mol weight) = 507.733: C, 56.77; H, 5.63; N, 5.51;
F, 3.74; P, 6.10
Found: C, 52.77; H, 5.69; N, 5.49; F, 3.91; P, 6.50 - | 30 IR (KBr) #69377 (1589 CM, C=0 of C00") ce ’ BAD ORIGINAL
‘ HX10b -232- : ul_NMR Spectrum (400 MHz, CD,0D) : - 8 1.55 (d, 6H, J=7, H;) : .- 1.64-1.84 (m, 4H, -, H_ + Hy) : 2.34 (m, 2H, -, H)) . = 2.91 (pseudo quartet, 2H, -, Hy) 4.25 (m, 1H, =, Hg)
Co : 4.77 (septet, 1H, partially buried under : HOD signal, -, H,) ) ‘ 7.05-7.32 (m, 9H, aromatic protons)
Co 10 oo Example 50 : (S)-4-[[{1-(4-Fluorophenyl)-4-(1-methylethyl)-2- : : phenyl-1H-imidazol-5-yl]ethynyl Jmethoxyphosphinyl]- - 3-hydroxybutanoic acid, methyl ester : oo "15 "A. N-Benzoylvaline : :
Co . A solution of valine (20 g, 0.17 mQle) in
Lo tetrahydrofuran (20 ml) and 2 N NaOH (111 ml) was cooled down to 10° (ice-water bath) under nitrogen : and treated dropwise with benzoyl chloride (23.8 ml, 0.21 mole). The reaction mixture was warmed up to room temperature, stirred for 3.0 hours then cooled back down to 0° (ice-salt bath) and treated . with concentrated,sulfuric acid (8.0 ml). The ] mixture was extracted with ethyl acetate (3 x 200 ml). The combined organic extracts were washed . with water (100 ml), brine (50 ml), dried ° (anhydrous MgSO, ), filtered and evaporated to dryness to give title compound as a solid (41.97 gq, 100% crude yield). }
A small amount (260 mg) of the product was recrystallized from ethyl acetate and petroleum ether to give title compound as an analytical sample (205 mg, m.p. 132-3°). N : BAD ORIGINAL ed
....1ob -233-
TLC: Rg 0.10 (silica gel; acetone:hexane - 1:1). i Anal Calcd: C, 65.14; N, 6.83: N, 6.33 zo ’ : .
Found: C, 64.81; N, 6.79; N, 6.2¢ :
Ws (meE)'=222° Lo : ~ B. N-(L-Acetyl-2-methylprepyl)benzanide oo
A mixture of part A compound {41.7 g, 20.17 mole) and triethylamine (47.3 ml, 0.34 mole) in acetic anhydride (48 ml) was treated with two
Co 10 portions of 4-dimethylaminopyridine (2.07 g, 0.017 wena } mole) and stirred at room temperature for 16 hours under nitrogen. The reaction mixture was cooled down to 0° (ice-salt bath), quenched with methanol . and stirred for 30 minutes. The light brown precipitates that formed were filtered off, washed well with water (1.1 1.) and re-dissolved in
Co dichloromethane (750 ml). The solution obtained : was dried (anhydrous Mgso,); filtered and wee E. : evaporated to dryness to give a crude product (35.9 9). : | oo
The crude product was dissolved in ether (1.3 1.), filtered to remove the insoluble solids and the clear filtrate was concentrated down to a : volume of ~300 ml and cooled in an ice-bath.
Title compound in the form of a cream colored precipitate (21.35 g, m.p- 88-90°) was filtered - off. purification of the solid obtained by evaporation of the filtrate on a silica gel column - (Baker, 600-200 mesh, 600 ml), eluting the column . 30 with EtOAc:hexane mixtures (1:7, 1:4) gave an additional 4.77 g of title compound. A small amount of title compound was recrystallized from ether, m.p. gg-89°C.
Le BN .
BAD ORIGINAL
HX10b -234- : TLC: Rg 0.75 (silica gel; acetone:hexane - 1:1). Co
Anal Calcd: C¢, 70.20; H, 7.81; N, 6.39 k
Found: C, 70.79; H, 7.68; N, 6.31 : 0 MS (M+H) =220. | -
Rk ’ C. N-[1-[1-[(4-Fluorophenyl)imino]ethyl]- 2-methylpropyl]benzamide
A solution of Part B compound (25.0 g, 0.114 mole) in dry toluene (250 ml) was treated with 4-fluoroaniline (12 ml, 0.127 mole; 1.11 ca.) pee : and p-toluenesulfonic acid hydrate (125 mg) and oo the reaction mixture was refluxed under N, with a
Dean-Starke distilling receiver for 20 hours. The
Co reddish-brown solution was cooled down to -10°C : 15 (ice-salt bath) and used as is for the next step ) in the sequence. } oo D. 1-(4-Fluorophenyl)-5-methyl-4-(1-
T : methylethyl)-2-phenyl-1H-imidazole : 20 The cooled solution of Part C compound : (20.114 mole) was diluted at -10° (ice-salt bath) with dry dichloromethane (200 ml) and treated : portionwise with phosphorus pentachloride (47.5; 0.228 mole). The cream-colored slurry was warmed up, refluxed for 2.5 hours under N,, cooled down . . to room temperature and poured slowly into a mixture of ice (400 g) and 50% NaOH (105 ml). The
To organic phase was separated and the aqueous phase oo : extracted with dichloromethane (2 x 200 ml). The , 30 combined organic extracts were washed with brine (2 x 100 ml), dried (anhydrous MgSO, )., filtered and evaporated to dryness. :
BAD ORIGINAL
SL ’ Ur TE
HX10b : -235= !
The crude product mixture (35.0 g) was chromatographed on a silica gel column (Baker, } 60-200 mesh, 600 ml), eluting with EtOAc:hexane oo mixtures (1:9, 1:4) to give title compound as Lo white needles (29.24 g, m.p. 146-8°, 87%). ;
TLC: Rg 0.40 (silica gel; EtOAc:hexane - 1:4)
Anal Calcd: C, 77.52; H, 6.51; N, 9.52; F, 6.45
Found: C, 77.48; H, 6.69; N, 9.40, F, 6.45
Ms (M+H)' = 29%
C210 "E. 1-(4-Fluorophenyl)-4-(1-methylethyl)- 2-phenyl-1H-imidazole-5-carboxaldehyde
A mixture of cupric sulfate hydrate (8.50
Co g, 34.0 mmoles) and potassium persulfate (36.8 g, 0.136 mole) in a solvent mixture of acetonitrile © (250 ml) and water (150 ml) was heated to 65° (oil oo bath) under N, and treated with Part D compouund (10 g, 34.0 mmoles).. The reaction mixture was slowly heated up to 75°, kept there for 40 minutes then cooled to room temperature. The solution was decanted from the solids, extracting both agueous . phase and solid with dichloromethane (3 x 200 . : ml). The combined organic extracts were washed with brine (2 x 100 ml), dried (anhydrous MgsO,), filtered and evaporated to dryness. The crude , product (17.0 g) was chromatographed on a silica a gel column (Baker, 60-200 mesh, 600 ml) eluting the column with EtOAc:hexane mixtures (5:95, 1:7) to give title compound as a solid (6.27 g, 59.8%). ” 30 200 mg of title compound was recrystallized from Et,O:hexane to give an analytical sample (76 mg, m.p. 160-1°). : i
BAD ORIGINAL
© HX10b ~231 . TLC: Re 0.34 (silica gel; EtOAc:hexane 1:4). .
CU - Anal Calcd: C,.74.01; H, 5.56; N, 9.09; F, 6.16
Found: C, 73.98; H, 5.68; N, 9.04; F, 6.09
R. MS (M+NT)=309 | : g : > 5 : oo )
F. 5-(2,2-Dibromoethenyl)-1-(4-fluoro- phenyl )-4- (1-methylethyl)-2-phenyl- ; oo 1H-imidazole
A solution of Part E compound (1.75 §, 5.68
Ce 10 mmoles) and triphenylphosphine (4.46 g, 16.8 - mmoles) in dry dichloromethane (27.0 ml) was cooled down to -5° to =10° (ice-salt bath) under argon and treated dropwise over a period of 5 . minutes with a solution of carbon tetrabromide oo : : 15 (2.82 g, 8.42 mmoles) in dry dichloromethane (9 oo ml). The mixture was stirred at -10° for 20 : oo : minutes then poured onto saturated sodium bicarbonate (9.0 ml) and extracted with
CT dichloromethane (3 x 50 ml). The combined organic oo 20 extracts were washed with saturated NaHCO, (10 . ml), brine (10 ml), dried (anhydrous MgSO, ). . filtered and evaporated to dryness. The crude ] product (8.07 g) was chromatographed on a silica gel column, eluting the column with CH,C1,:héxane mixtures (1:7; 1:4) to give title compound as a ‘ : solid (2.35 g, 91.4%). ‘ - . 100 mg of Part F compound was - recrystallized from Et,O:hexane to give an analytical sample (49 mg, m.p. 164-5°).
TLC: R0.32 (silica gel; CH, C1, :hexane - 1:1).
Anal Calcd: C, 51.75; H, 3.69: N, 6.04; F, 4.09;
Br, 34.43 © 7% Found: C, 51.80; H, 3.71; N, 6.02; F, 4.08;
BAD ORIGINAL
Cd .
HX10b . i ~237-
Co Br, 34.25 ms (M#H)T = 465. . :
Lo G. S-Ethynyl-1-(4-fluorophenyl)-4-(1- methylethyl)-2-phenyl-1lH-imidazole
A solution of Part F compound (3.065 g, "6.60 mmoles) in dry tetrahydrofuran (12.5 ml) was cooled down to -78° (dry ice-ac=tone) and treated ~ with 1.6 M n-BuLi/héexane (8.4 =’, 13.4 mmoles) under argon. The reaction mixture was stirred at -78° for 1 hour and 20 minutes, quenched by the dropwise addition of 25% NH, C1 (18 ml), warmed up to room temperature and extracted with ether (3 Xx 100 ml). The combined organic extracts were washed with brine (25 ml), dried (anhydrous MgSO, ), filtered and evaporated to dryness: The crude
Co product (2.08 g) was chromatographed on a silica gel column (Baker, 60-200 mesh, 400 ml), eluting: Ct . the column with EtOAc:hexane mixtures (1:9, 1:4).
The desired fractions were combined and evaporated to dryness to give title compound as a solid (1.97 g, 97.8%). : 92 mg of Part G compound was recrystallized : from hexane to give an analytical sample (59 mg, * : m.p. 148-150°).
TLC: Re 0.60 (silica gel; EtOAc:hexane - 1:4). v Anal Calcd: C, 78.92; H, 5.63; N, 9.21; F, 6.24
Found: C, 78.95; H, 5.83; N, 9.07; F, 6.63 _ Ms (M-H) = 303. i BAD ORIGINAL . ean %
: Bis ’ -238-
H. (S)-3-[[(1,1-Dimethylethyl)diphenyl- : © y silyl]oxyl-4-[[[1=(4-fluorophenyl)- ’
Vo 4-(1-methylethyl)-2-phenyl-1H-imidazol- - 5-y1]ethynyl Jmethoxyphosphinyliutanoic Lo acid, methyl ester ~~ : : A mixture of the Example 1 Part F crude phosphonic monomethyl ester (3.54:g, 7.86 mmoles) and trimethylsilyldiethylamine (2.70 ml, 14.21 mmoles) in dry dichloromethane was stirred at room _ temperature under argon for 1.0 hour. The mixture : . was evaporated to dryness, azeotroped with dry benzene (26 ml) and dried in vacuo. The viscous : oil was re-dissolved in dry dichloromethane (14
So. ml), treated with 2 drops of DMF, cooled down to -10° (ice-salt bath) and treated dropwise with : : oxalyl chloride (0.68 ml, 7.79 mmoles). Vigorous gas evolution was observed and the yellowish brown solution was stirred at -10° for 15 minutes then oo at room temperature for 1.0 hours. The reaction mixture was evaporated to dryness, azeotroped with
Co dry benzene (26 ml) and dried in vacuo. : a A solution of Part G compound (1.43 g, 4.7
CT mmoles) in dry tetrahydrofuran (11.5 ml) was . . - cooled down to -78° (dry ice-acetone) under argon . 25- and treated with 1.6 M n-BuLi/hexane (2.94 ml, 4.7 5 mmoles) and stirred at -78° for 30 minutes. The above phosphonochloridate was dissolved in dry
Co tetrahydrofuran (11.5 ml), cooled down to -78° "oo : (dry ice-acetone) under argon and treated dropwise by cannula with a solution of the acetylenic : anion, both solutions being kept at -78° "throughout the addition.- The reaction mixture was
Ce stirred at -78° for 30 minutes, quenched by the , = - BAD ORIGINAL ——ee oa
: : HX10b -239- dropwise addition of 25% NH,C1 (13 ml), allowed to - wakm up to room temperature then extracted with : ' ether (3 x 130 ml). The combined organic extracts . were washed with 25% NH,C1 (15 ml), brine (30 ml), . ‘- 5 dried (anhydrous MgSO, ) filtered and evaporated : to dryness. . ‘The crude product mixture (4.3 g) was : chromatographed on a silica gel column, : eluting the column with acetone:hexane mixtures oo 10 (5:95; 1:4). The desired fractions were combined... - «nd evaporated to dryness to give title compound as a light brown syrup (2.18 g, 62.9%) oo TLC: Rg 0.13 (silica gel; hexane:acetone - 7:3). :
I. (S)-4-[[[1-(4-Fluorophenyl)-4-(1- : methylethyl)-2-phenyl-1H-imidazol-5-yl]- oo ethynyl Jmethoxyphosphinyl]-3-hydroxy- : " - putanoic acid, fethyl ester Ca Lo - A solution of Part H compound (974 mg, 1.32 mmoles) in dry tetrahydrofuran (13.0 ml) was treated successively with glacial acetic acid (310 pl, 5.29 mmoles) and 1 M (CaHg) NF (4.14 ml, 4.14 ” mmoles) and stirred overnight at room temperature . under argon. The reaction mixture was cooled down to 0° (ice-water bath), treated with 5% KHSO, (14 ml) and extracted with ethyl acetate (3 Xx 125 ml). The combined organic extracts were washed ~ with 5% KHSO, (16 ml), brine (35 ml), dried . (anhydrous MgSO, ), filtered and evaporated to dryness.
The crude product (1.48 g) was dissolved in a mixture of ether (22 ml) and dry tetrahydrofuran (17 ml), cooled down to 0° (ice-water bath),
BAD ORIGINAL
HX10b . -240- treated with excess diazomethane in ether and . ) stirred at 0° for 4.0 hours. The reaction mixture : oo was quenched by the dropwise addition of glacial "acetic acid, evaporated to dryness and dried oo
In vacuo. The crude product was chromatographed on a silica gel column, eluting the column with EtOAc:hexane mixtures (1:1; 4:1). The desired fr- tions were combined to give title compound as a solid (304 mg, 46.2%). : _ "10 - TLC: R; 0.33 (silica gel; EtOAc:hexane - 4:1) - —— ee : Example S51 (S)-4-[[[1l-(4-Fluorophenyl)-4-(l-methylethyl)-2- - . phenyl-1H-imidazol-5-yl]ethynyl]hydroxyphosphinyl]- . 15 3-hydroxybutanoic acid, dilithium salt : :
Co : " A solution of Example 50 compound (304 mg, 0.6 mmole) in dioxane (7.1 ml) was treated with 1 N LiOH (2.03 ml, 2.08 mmoles), stirred at 55° - (oil bath) under argon for 1.5 hours then at room nL 20 . temperature for 24 hours. The reaction mixture : was evaporated to dryness and dried in vacuo. The : crude product was chromatographed on an HP-20 . column (1" x 7"), eluting the column with steam-
Co distilled water (750 hl), 10% aqueous CH, 0H (500 ml), 20% aqueous CH40H (500 ml) and 50% aqueous
CH,OH (500 ml). The desired fractions were combined, evaporated to dryness and dried .
Co in vacuo. The solid product was dissolved in : steam-distilled water and lyophilized to give. title comopund as a fluffy solid lyophilate (257
Co mg, 84.1 %).
Other fractions: TLC: Re 0.38 (silica gel; i-PrOH:NH,OH:H,0 - 8:1:1). : : BAD ORIGINAL © _ » oo
: HX10b -241- : Anal Calcd for Cj gly FLiN,O5P 1.52 H,0: C, 56.56; . H, 4.95;, N, 5.49; F, 3.73; P, 6.08 :
Found: C, 56.56; H, 4.94; N, 5.32; F, 3.89; P, 5.99.
H-NMR spectrum (400 MHz, CD4OD): 3 & 1.37 (d, 68, J=7 Hz) 1.79 (m, 2H) 2.31 (dd, 1H, J=9.15 Hz) : 2.43 (dd, 1H, J=4.15 Hz) - 3.24 (septet, 1H, J=7 Hz) 4.26 (m, 1H) 7.17-7.35 (m, 9H).
IR(KBr) 2163 (C=C), 1590 (C=0) cm™T. . Example 52 15 . (S)-4-[[2-{1-(4-Fluorophenyl)-4-(1l-methylethyl)-2- phenyl-1H-imidazol-5-yl)ethyl]methoxyphosphinyl]-3-
Pg hydroxybutanoic acid, methyl ester en A. (S)-3-[[{(1,1-Dimethylethyl)diphenyl= ae silyl]oxy)-4-[[2-(1-(4-fluorophenyl)-4- : 20 (1-methylethyl)-2-phenyl-1H-imidazol-5- . yl]ethyl]methoxyphosphin-ylbutanoic acid, methyl ester : . A solution of Example 50 Part H compound (839 mg, 1.14 mmoles) in dry methanol (86 ml) was } treated with 10% Pd/C (213 mg) and hydrogenated at room temperature on a Parr hydrogenator overnight : at ~40 psi. The suspension was filtered through celite, the clear filtrate was evaporated to dryness and dried in vacuo to give title compound - 30 as a thick syrup (853 mg, 100% yield).
TLC: Re 0.17 (silica gel; hexane:acetone - 7:3). : BAD ORIGINAL
. HX10b \ -242- : : . B. (S)-4-[[2~[1~(4-Fluorophenyl)-4-(1- ‘ methylethyl )-2-phenyl-1H-imidazol-5-yl]- : ethyl Jmethoxyphosphinyl]-3~hydroxy- oC :
Lo butanoic acid, methyl ester :
A solution of Part A compound (853 mg, oo ~1.14 mmoles) in dry tetrahydrofuran (11.0 ml) was oo treated successively with glacial acetic acid (270 )
Be pl, 4.60 mmoles) and 1.0 M (C4Hg) NF/hexane (3.62 ml, : 3.62 mmoles) and stirred cvernight at room ees = 10 temperature under argon. The reaction mixture was diluted with ice-water (25 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic extracts were washed with saturated NaHCO, {15 - . ml), brine (25 ml), dried (anhydrous Mgs0,),
SE : 15 filtered and evaporated to dryness. ’ oo
EE The crude product (958 mg) was chromato- ] oo " graphed on a silica gel column, eluting the column co ‘ with acetone:hexane mixtures (1:1, 4:1). The
Co Co desired fractions were combined, evaporated to
Co oo 20 dryness and dried in vacuo to give title compound
N as a solid (443 mg, 77.0%). . TLC: Rg 0.13 (silica gel; acetone:hexane - 1:1). to Example 53 (S)-4-[[2-[1-(4-Fluorophenyl)-4-(1-methylethyl)-2- phenyl-1H-imidazol-5-yl]ethyl jhydroxyphosphinyl]-3- hydroxybutanoic acid, dilithium salt
A solution of Example 52 compound (443 mg, 0.88 mmole) in dioxane (10.5 ml) was treated with : : 30 1.0 N LiOH (3.05 ml, 3.09 mmoles) and stirred at 55° (oil bath) under argon for 3.0 hours then at room temperature for ~20 hours. The reaction . mixture was evaporated to dryness and dried
Cn | BAD ORIGINAL
. : HX10b -243- } in vacuo. The crude product was chromatographed : i on an HP-20 column (1" x 8"), eluting the column . “with steam-distilled water (750 ml), 10% aqueous
CH,OH (500 ml), 20% aqueous CH,OH (500 ml) and 50% - aqueous CH,OH. The desired fractions were combined and evaporated to dryness. The resulting - solid was dissolved in steam~-distilled water (30 : ml) and lyophilized to give title compound as a ’ fluffy white solid (376.4 wg, 83.9%). lo TIC: Re 0.40 (silica gel; i-PrOH:NH,OH:H,0 - 8:1:1)
Anal Calcd for C, 4H, gFLIH,N,05P 0.84 H,0 (Eff. ’ mol. wt.=501.46): C, 57.43; H, 5.76; N, 5.69;
F, 3.99; P, 6.08 Co
Found: C, 57.48; N, 5.56; N, 5.59; F, 3.79; P, 6.18 a. 15 IR(KBr) (1587 cmt, C=0 COO") ) ul-NMR spectrum (400 MHz, CD,OD): 8 1.33 (4, 6H, J=7 Hz) : oo | 1.46-1.61 (m, 4H) = ~~ oo. es i» 2.30 (m, 2H) 2.76 (m, 2H) © 3.13 (septet, 1H, J7 Hz) 4.14 (m, 1H)
CL 7.17-7.30 (m, 9H). . “ .
Example 54 (s)-4-[[[2-(Cyclohexylmethyl)-4, 6-dimethylphenyl]- ethynyl]hydroxyphosphinyl]-3-hydroxybutanoic acid, dilithium salt . A. N-(2,4-Dimethylbenzylidene)benzeneanine ~ 30 Ref. Merck U. S. Patent No. 4,375,475, P9- 39.
The title compound was prepared as described in Example 1 Part A.
BAD ORIGINAL :
J,
: HX10b oo -244-
B. tL N : : : . ~ + . ) HG pd- ‘ -
Tog | } 0 : ) : CH, 2 . 5
Ce 10 Ref. Merck U.S. Patent No. 4,375,475, pg. 39. -.- ce - ’ The title Pd-complex was prepared as : described in Example 1 Part B. . Cc. 2-[(Cyclohexylmethyl)-4,6-dimethylbénz- aldehyde - . _ Magnesium turnings (1.44 g, 59.45 mmol) under argon atmosphere were covered with 15 ml of dry Et,0 and sonicated for 5 minutes. Cyclohexyl- methylbromide (1.5 ml) was added to the Mg°-turnings and sonication was continued (refluxing began : within minutes). Simultaneously via addition - funnel 60 ml of dry Et,0 and a 5S ml Et,0 solution " of the remainder of the cyclohexylmethylbromide was } - added with continued sonication (a total of 9.12 ml, 65.3 mmole qf cyclohexylmethylbromide was : : added). After addition was complete, sonication was continued for 15 minutes and then the reaction was refluxed for 40 minutes. This Grignard : reagent was cooled to room temperature and then } 30 added via cannula to a solution of the Part B - Pd-complex (5.55 g, 7.43 mmol) and triphenylphosphine
So (15.59 g, 59.45 mmol) which had been stirring for oo 30 minutes under argon atmosphere and at room
CL ne : : BAD ORIGINAL
HX10b -245- - temperature. Upon the addition of the Grignard reagent the reaction became green and a precipitate Ty formed. This reaction solution was stirred at room - ’ temperature for 2 hours followed by the addition of 37 ml of 6¥ HCl. This mixture was stirred for 1 a hour and then filtered through a celite pad in a : - , sintered glass funnel in order to remove solids. no The solid was washed with Et,0 and the filtrate was Lo rotavapped to remove volatiles. The resulting
Co - eee = 10 residue was stirred in Et,0 and filtered as above. So
The filtrate was washed once with saturated NaCl solution, and the organic layer was dried over
MgSO, ; 14.5 g of a brown oil was obtained.
To. purification by flash chromatography, eluting with 4% Et,O/hexane gave 1.70 g of a clear oil, 99% yield. I oo ’ TLC: R=0.30 (5% Et,0/hexane, silica gel). : IR (CHC1,) 3030, 3008, 2926, 2853, 1679, 1606, . oo . jase, 1147 cmt »0 lm MMR (270 MHz-CDCl,) : 8 10.51 (s, 1) oo 6.90 (s, 1) ’ 6.85 (s, 1) 2.80 (4, 2, J = 6.0 Hz) : 2.55 (s, 3) . 2.30 (s, 3) 1.80-1.55 (m, 5) 1.55-1.30 (m, 1) 1.30-0.80 (m, 5) | -
Mass Spec (CI) m/e 231 (m+H) : BAL ORIGINAL : mmm
HX10b -246- Co
D. 1-(Cyclohexylmethyl)-2-(2,2-dibromo- oC - Co ethenyl)-3,5-dimethylbenzene °
Part C aldehyde (1.68 g, 7.30 mmol) in 65 + ml of dry CH,Cl, under argon atmosphere was cooled ° to 0°C. To this solution was added triphenyl- : phosphine (6.13 g, 23.4 mmol) and the solution was - stirred until all of the solid was dissolved. At : : o°c, CBr, (3.63 g, 11.0 mmol) was added as a 20 ml
CH,Cl, solution. The reaction solution became . om =---10 © orange.” The reaction was stirred at-0°C for-1:5 -- : ’ ’ hours, then quenched with saturated NaHCO, solution ce no and stirred vigorously. The aqueous layer was
Co removed and extracted 2 times with CH,Cl,. The : . organic solutions were combined, washed once with : 15 saturated NaHCO, solution, and dried over MgSO, - oo © Filtration and solvent removal gave 9.6 g of a
Co oo | brown solid. Purification by flash chromatography
ET eluting with 100% hexane gave 2.52 g, 907% yield, : - of a clear oil.
TLC 0.62 (5% Et,0/hexane, silica gel) PMA. . IR (CHCl) 2925, 2852, 1608, 1472, 869 cm™t lmnMr (270 MHz, CDCl) ol 8 7.39 (s, 1) 6.87 (s, 1) : 6.80 (s, 1) : 2.37 (d, 2, J=6.3 Hz) : : 2.27 (s 3) 2.24 (s, 3) 1.70 (m, 5) oo , 30 1.45 (m, 1) : : 1.38-1.10 (m, 3) 0.90 (m, 2)
Ce BAD ORIGINAL
: HX10b -247-
Mass. Spec. (CI) m/e 387 (+H) " : E.. 1-(Cyclohexylmethyl)-2-ethynyl-3,5- - - dimethylbenzene . - The Part D vinyl dibromide (2.51 g, 6.5 © mmol) under argon atmosphere was stirred with THF ~ . (30 ml) and cooled to -78°C. To the dibromide . solution at -78°C was added n-butyllithium. (5.20 ” ml cf 2.5 M solution in Hexane) over 3 minutes. ~~. _ _..10 The resulting pink reaction mixture was stirred at -78°C. After 1.5 hours at -78°C, the reaction was - quenched with saturated aqueous NH, Cl solution and then warmed to room temperature. The aqueous . : layer was removed and extracted twice with Et,0 and 15 once with hexane. All of the organic layers were combined and dried over Mgso, to give 1.65 g of a © brown oil after filtration and solvent removal. purification by flash chromatography eluting with co hexane gave 1.39 g, 95% yield, of title acetylene. ’ 20 TLC 0.50 (5% toluene/hexane, silica gel), PMA.
IR (CHCl) 330% 3007, 2924, 2852, 2096, 1607, } 1470, 1448 cm.
CL lg mm (270 MHz, CDCl) 6.86 (s, 1) : ? 6.79 (s, 1) 3.39 (s, 1) : 2.63 (d, 2, J=6.9 Hz) 2.63 (m, 6) 1.20 (m, 3) - 30 1.00 (m, 2) ) .
Mass Spec(CI) m/e 227 (M+H) ’ BAD ORIGINAL
. COBXL ~248- . F. (S)-4-[[[2-(Cyclohexylmethyl)-4,6- : . - dimethylphenyl]ethynyl Imethoxyphos- : - phinyl]-3-[[(1,1-dimethylethyl)diphenyl- oo ) : silyl]oxylbutandic acid, methyl ester
Part E acetylene (1.36 g, 6.0 mmol) in 30 ml of dry THF under argon atomosphere was cooled to -78°C. To this solution was added n-BuLi (2.4 : ml, of 2.5 M solution in hexane); the . 10 reaction solution became a burgundy color, stirred for 1 hour at ~78°C. Example 1 Part F : phosphonochloridate (4.68 g, 9.6 mmol) was stirred ; with 30 ml of dry THF and cooled to -78°C. The
Co acetylenic anion was then cannulated into the : phosphonochloridate solution over 15 minutes. : After the transfer was complete, the reaction was . stirred at -78°C for 1 hour, then quenched with Lo saturated. aqueous NH,C1 and warmed to room Co - temperature. The THF was removed from the oo 20 reaction mixture, and the resulting material was dissolved with EL,0 and H,0. The aqueous layer was extracted 3 times with Et,0. All the Et,O0
Co extracts were combined and washed once with Co
Co saturated NaHCO, solution and once with brine, . 1’ 25 then dried over MgsO,. Filtration and solvent removal gave an orange oil which was purified by } flash chromatography eluting with 3.5:5.5:1/-
EtOAc:Hexane:toluene. The title acetylenic : phosphinate (2.80 g, 70% yield) was obtained as a - 30 clear oil. - | ) : TLC R=0.37 (5:1:4/Hexane: toluene:EtOAc, silica gel) PMA.
Lo | BAD ORiGInaL
HX10b - -249- :
IR (CHCl) 3025, 3001, 2929, 2856, 2164, 1736, i 1607, 1240, 1112, 1039, 823 cm : lg NMR (270 MHz, CDCl,) 6 7.66 (m, 4) ‘ i sl | 7.30 (m, 6), 6.87 (s, 1), 6.81 (s, 1) ] 4.66 (m, 1) : : : 3.70583.66 (d's, 3, J=14.3 Hz) 3.56 (s, 3) SE 72.95 (m, 1) 2.69 (m, 1) ) 2.50 (m, 3)
A 2.32 (m, 2) 2.30 (s, 3) 2.27 (s,. 3) ’ nr 1.60 (m, 6) | : 1.03 (m, 3) Bh mm or .o- 1.02 (s, 9) } 0.95 (m, 2)
Mass Spec (CI) m/e 659 (m+H) . i . . GG. (s)-4-[[[2-(Cyclohexylmethyl)-4,6- } : : dimethylphenyl]ethynyl Jmethoxyphos- phinyl]-3-hydroxybutanoic acid, methyl ester
The Part F acetyleneic phosphinate (0.633 g, 0.96 mmol) was stirred under argon atmosphere at room temperature with 14.0 ml of dry THF. - 30 Glacial acetic acid (0.22 ml, 3.84 mmol) was added to the phosphinate solution followed by the : dropwise addition over 5 minutes of n-Bu, NF (2.62 ml of 1.1 M THF solution). After stirring for 19 : BAD ORIGINAL ad
HX10b : Co -250- : : hours at room temperature, the reaction was ) quenched with ice water, and the aqueous layer was
BE extracted 3 times with EtOAc. The combined : . ~~ organic solutions were washed 2 times with saturated aqueous NaHCO, solution and once with saturated NaCl solution. The organic layer was : Co dried over Na,SO, and filtered to give a yellow gum (0.658 g) after solvent removal. Purification oo by flash chromatography eluting with EtOAc
FO 10 . provided the title alcohol. .(0.23 g, 65%) asa: Co ’ ~ clear oil. i
TLC Rg=0.51 (6:4 Acetone/hexane, silica gel) PMA
IR (CHC1,) 3450 (br), 3005, 2926, 2852, 2164, . : 1733, 1607, 1448, 1439, 1039 cm 1. Co 15 .'m mR (270 MHz, CDCl,) }
SE 6 6.89 (s, 1) 6.82 (s, 1)
Co 4.63 (m, 1) : 3.88&3.87 (2d's, 3, J=12 Hz) Co oo 20 3.69 (s, 3) : : 2.70 (s, 2) 2.62 (4, 2, J=6.3 Hz) -
La 2.43 (s, 3) : 2.32 (s, 3) : 2.27 (m, 2) 1.65 (m, 6) 1.19 (m, 3) 1.00 (m, 2)
Mass Spec (CI) m/e 421 (m+H)" : : oo BAD ORiGiNaL
HX10b “24 ;
H. (s)-4-[[[2-(Cyclohexylmethyl)-4,6- . : - dimethylphenyl]ethynyl}hydroxyphos- } phinyl]-3-hydroxybutanoic acid, dilithium salt . Lo
The Part G diester (0.212 g; 0.51 mmol) was stirred in dioxane (7 ml) and 1.5 ml of 1N LiOH (1.5 mmol) was added at room temperature. The Co reaction was warmed to 55°C and after 20 minutes the resulting precipitate was solubilized by adding 5 ml of dioxane and 4 ml of H;0:~ After 2 hours 30 oo ’ minutes at 55°C, the reaction was cooled to room . temperature, the solvent was removed under reduced pressure, and the resulting white solid was placed . under vacuum for 15 minutes. The product was purified on a 3.0 x 19 cm column of HP-20 resin eluting first with 100 ml of H,0 followed by 1:1
MeOH/H,0. Lyophilization of product Fr's gave
Co 0.145 g (71%) of a white lyophilate » Co : Re = 0.39 (7:2:1 nPrOH/NH,OH/H,0, silica gel) PMA.
IR (KBr) 3700-3100 (br), 2922, 2850, 2167, 1590, 1447, 1179, 1076 cml. lg NMR (400 MHz, D,0) : 5 = 6.99 (s, 1) : 6.94 (s, 1), ’ 4.53 (m, 1), 2.64 (m, 1), ’ 6.22 (4, 2, J=6.2 Hz) 2.39 (s, 3) 2.37 (m, 1) ’ © 30 2.26 (s, 3)
BAD ORIGINAL
’ seis . a
HX10b : -252- Co 2.02 (m, 2) I : 1.60 (m, 6) Le CL : 1.14 (m, 3) Co : : 1.00 (m, 2) Co a
Mass Spec (FAB) m/e 409 (x+H)¥, 397 (M-2 Li +H)"
Anal Calcd for C,H, OCP Li,-1.72 Hy0: C, 57.96;
H, 7.05; p, 7.12 : . Found: C, 57.96; H, 7.18; P, 6.96 me (gn Cee - Exam le 55 ~ . 4-[[2-[2-(Cyclohexylmethyl)-4,6-dimethylphenyl]- : ethenyl ]hydroxyphosphinyl]-3-hydroxybutanoic acid, . dilithium salt . A. (E)-[2-[2-(Cyclohexylmethyl)-4,6- 15. dimethylphenyljethenyl]phosphonic - i acid, dimethyl ester : ’
Dimethylméthylphosphonate (1.64 g, 13.2
Co mmol) in dry THF (20 ml) under argon atmosphere . was cooled to -78°C. To this solution at -78°C - was added n-butyl lithium (5.0 ml, 2.5 M solution
Co in hexane, 12.4 mmol) over 5 minutes. After the ' addition was complete, the milky white reaction es '- mixture was stirred for 1 hour. To the anion ] oF : solution at -78°C, a 10 ml THF solution of the
IE 25 Example 54 Part A aldehyde (1.9 g, 8.26 mmol) was added via addition funnel over 10 minutes. After
Co stirring for 35 minutes at -78°C, the reaction was
Co : quenched with saturated aqueous NH,Cl (8 ml) and then allowed to warm to room temperature. The . 30 organic layer was removed and ‘the aqueous layer : ~~ was extracted 3 times with EtOAc. The organics were combined and washed once with brine and dried
BAD ORIGINAL a i . HX10b ~253- . over Na,SO,. Filtration and. solvent removal gave : 3.25 g of a yellow oil.
The above yellow oil (3.25 g) was dissolved ; in dry toluene ‘and refluxed through a soxhlet : ) extractor containing 48 molecular sieves. p-Toluenesulfonic acid-H,0 (0.080 g, 0.42 mmol) : was added at time 0, 3.5 and 18 hours. After 22 : hours at reflux, the reaction was cooled to room temperature, and the toluene was removed : ’ ~~-~ =~ 10 in vacuo. The resulting yellow residue in EtOAc SE was washed twice with saturated NaHCO, solution, dried over Na,SO, and filtered to give a yellow : oil (A) after solvent removal. oo The aqueous solution was acidified with g . 15 concentrated HCl, extracted 3 times with EtOAc, , dried over MgS0,, filtered and solvent removed to ] give 0.535 g of a yellow oil. This yellow oil was then refluxed in 6.0 ml of HC(OCH), for 24 hours : followed by removal of excess HC(OCH;4)4 under ) : 20 vacuum. This material was combined with yellow : . oil (A) and purified by flash chromatography eluting with 80% EtOAc/hexane. The title vinyl } phosphonate (2.07 g, 73%) was obtained as a white : solid.
TLC R=0.45 (1:1 Acetone/hexane, silica gel) PMA.
IR(KBr) 2921, 2851, 1623, 1447, 1243, 1186, 1060, 1027 cmt. ly NMR (270 MHz, CDCl,) 6 7.65 (dd, 1, J=23.6 Hz, 18.1 Hz) - .30 6.88 (s, 1) Co 6.82 (s, 1) 5.80 (dd, 1, J=21.0 Hz, 18.1 Hz) 3.79 (4, 6, J=11.5 Hz)
Al
Co | a0 ORE
1.{10b : : ~254- 2.49 (d, 2, J=7.2 Hz) . 2.29 (s, 3) : 2.28 (s, 3) - 1.65 (m, 5) CL Co : 5 1.45 (m, 1) oo 1.25-0.80 (m, 5) -
Co ; Mass Spec (CI) m/e 337 (m+H)
B. (E)-[2~[2-(Cyclohexylmethyl)-4,6- . 10 dimethylphenyl]ethenyl phosphonic acid, - Cn ee methyl ester } )
Part A vinyl phosphonate (2.07 g, 6.16 : mmol) was stirred with 14 ml of dioxane at room . temperature. To this solution was added 1.0 N
LiOH (9.24 ml, 9.24 mmol), and this mixture was - warmed to 75°C. After 3.5 hours at 75°C, the reaction was cooled to room temperature, and the dioxane was removed in vacuo. The resulting BN ‘residue was stirred with H,0 and acidified to pH~2 with IN HCl. The aqueous solution was extracted 3 oo times with EtOAc, dried over Na,SO,, filtered and. solvent removed to give 1.95 g of off-white solid. oo } TLC Ry = 0.58 (8:1:1/CH, Cl, :CH;0H: ACOH, silica : : gel), PMA. ‘ lm NMR (270 MHz, CDCl,) 8 12.11 (s,1) oo 7.61 (dd, 1, J=24.17 Hz, 17.58 Hz) 6.87 (s, 1) 6.81 (s, 1) . } 30 5.88 (dd, 1, J=21.43 Hz, 17.58 Hz) 3.78 (d, 3, J=11.54 Hz) - oo 2.47 (4, 2, J=6.6 Hz) 2.29 (s, 3) : BAD ORIGINAL
Go —— om.
HX10b -255-
RE 2.28 (s, 3) : ) . 1.65 (m, 5) : 1.45 (m, 1) ©. 1.15 (m, 3) Co i . 5 0.95 (m, 2) . c. (E)-4-[[2-[2-(Cyclohexylmethyl)-4,6- dimethylphenyl]ethenyl]methoxyphos= phinyl]-3-oxobutanoic acid; methyl
Cm 10 ester Ce
The Part B monomethyl phosphonate (1.95 g, 6.06 mmol) in 50 ml of dry CH,Cl, was stirred at : room temperature under argon atmosphere with . (C, Hg), NSi(CH;) 4 (1.76 g, 12.1 mmol) for 1 hour 25 : 15 minutes. The CH,Cl, was removed in vacuo, and the "resulting yellow oil was azeotroped once with
To benzene and placed under high vacuum for 20 . Co minutes. This oil was then dissolved in dry ‘ CH,C1, (50ml) under argon atmosphere and cooled to 0°Cc. Two drops of dry DMF were added followed by : slow dropwise addition of oxalylchloride (0.92 g, 7.27 mmol):gas evolution was observed. The . ; reaction was,stirred for 15 minutes at 0°C then warmed to room temperature and stirred for 1 hour. The CH,C1, was removed in vacuo from the reaction mixture, and the resulting orange oil was azeotroped twice with dry benzene and pumped under high vacuum for 1 hour thus giving the - phosphonochloridate. :
The dianion of methylacetoacetate was ’ prepared as follows. Pentane washed NaH (0.25 g oil dispersion, 8.7 mmol) in dry THF (10 ml) under argon atmosphere was cooled to 0°C. Methyl
So BAD ORIGINAL
Co SE
HX10b I ~256- oo acetoacetate (0.92 gq, 7.9 mmol) was added to the .
NaH suspension as a 10 ml THF solution and Ce : stirred for 20 minutes, and then n-butyllithium oC (2.90 ml, 2.5 M in hexane, 7.3 mmol) was added Co : 5 followed by stirring for 45 minutes. The dianion solution was cooled to -78°C and a 10 ml THF solution of the above prepared phosphonochloridate was cooled to -78°C and added to the dianion . solution over 15 minutes. After stirring at -78°C
Te 10 for 30 minutes, the reaction was quetiched with : : “saturated aqueous NH, Cl solution and warmed to : room temperature. The THF was removed from the : reaction mixture, and the resulting orange oil was . taken up in 1:1 EtOAc/H,0. The aqueous layer was : extracted 3 times with EtOAc. The combined EtOAc
Co extracts were combined and washed Z times with oo . saturated NaHCO, solution and once with saturated oo NaCl solution, then dried over Na,SO,- oo Purification of the crude product (2.75 g) by .- 20 flash chromatography eluting with EtOAc gave the oo E : title keto ester (0.97 g, 42%) as. a yellow oil.
TLC R, = 0.24 (EtOAc, silica gel) PMA. } | lg NMR (270 MHz, CDCly) . oC 8 7.71 (dd, 1, J=22.52 Hz, 18.13 Hz) 6.89 (s, 1) Co, 6.83 (s, 1) : 5.89 (dd, 1, J=26.37 Hz, 17.58 Hz) 3.79 (s, 2) : 3.73 (s(br), 6) 3.36 (dd, 2, J=18.68 Hz, 5.5 Hz) 2.50 (m, 2) 2.30 (s, 3) . ’ 2.29 (s, 3)
SE BAU ORIGINAL
——
f. 10b -257- : 1.70 (m, 5) . 1.45 (m, 1) .1.10-0.80 (m, 5) ] 'D. 4-[[2-[2-(Cyclohexylmethyl)-4,6- ’ dimethylphenyl]ethenyl Jmethoxyphos- phinyl}-3-hydroxybutanoic acid, methyl ester } gy :
The Part C p-keto phosphonate (0.97 g, 2.31 . 10 “ mmol) was stirred in THF (10 ml) under argon - atmosphere and cooled to 0°C. Solid NaBH, (0.087 g, 2.31 mmol) was added to the THF solution : followed by the dropwise addition of 2 ml of . CH,OH; gas evolution resulted. After stirring for 50 minutes. at 0°C, the reaction was quenched with 2 ml of acetone followed by the addition of CC-4 silica gel. The reaction was warmed to room temperature and filtered through sintered glass. :
The solvent was removed from the filtrate to give a yellow oil which was purified by flash . chromatography eluting with EtOAc. The title alcohol was obtained as a clear oil (0.65 g, 66%). - ; TLC Re = 0.29 (50% Acetone/hexane, silica gel),
PMA. °
M.P. 80-83°C.
IR (KBr) 3282 (br), 2923, 2918, 2848, 1743, 1614, 1450, 1442, 1080, 1045 cml. lg WR (270 MHz, CDCly) 6 7.68 (m, 1) 6.88 (s, 1) ’ 6.82 (s, 1) oo 5,89 (m, 1)
BAD ORIGINAL
- ! ath oo © HX10b -258- _ 4.50 (m, 1) J x EI 4.00 (m, 1) Co So > 3.7763.74 (2 d's, 3, J=11.0 Hz) Co i 3.6953.68 (2 s's, 3) - ' : : 2.65 (d, 2, J=6.0 Hz) : 2.50 (m, 2) . : 2.30 (s(br),3) - | - .- 2.28 (s, 3) | | : 2.15 (m, 2) .
CTT 10 1.68 (m, 5) EE ) 1.45 (m, 1) | - 1.30 to 0.80 (m, 5) 3 oo Mass Spec (CI) m/e 423 (+E) * | ~ oo
E. 4-[[2-[2-(Cyclohexylmethyl)-4,6- : . dimethylphenyl]ethenyl ]Jhydroxyphos- phinyl]-3-hydroxybutanoic acid,’ Co ' dilithium salt Co
Part D diester (0.565 g, 1.33 mmol) was ! stirred with 14 ml of dioxane until all of the - solid went into solution. 1.0 N LiOH (4.0 ml) was = added and the solution warmed to 55°C... After 30
Ct oo minutes, the reaction became turbid. .After 2 to . 25 hours at 55°C, the reaction was cooled to room temperature, and the solvent was removed on the rotavap to give a white solid. The crude product was purified on a 3.0 x 15 cm column of HP-20
Co resin eluting first with 100 ml of H,0 followed by : } 30 75% MeOH/H,O. Lyophilization of product fractions ‘ gave title compound in the form of a white lyophilate (0.524 g, 98%). -
Lo. : ' " ) . den : LL
BAD ORIGINAL
HX10b : -259-
TLC Rp = 0.41 (7:2:1 nPrOH/NH,OH/H,0, silica gel) :
PMA. »
IR (KBr) 3700-3100 (br), 2921, 2851, 1591, 1446, oo 1222, 1195, 1161, 1051 cm . - lm NMR (400 lHz, D,0) 5 7.25 (dd, 1, J=18.68 Hz) : 6.98 (s, 1) Co 6.94 (s, 1) - 6.00 (dd, 1, J=17.95 Hz)
So 10 4.33 (m, 1) oo © 2.53 (dd, 1, J=15.0 Hz, 4.4 Hz) 2.49 (4, 2, J=7.0 Hz) : 2.36 (dd, 1, J=15.0 Hz, 8.43 Hz) . oo 2.27 (s, 3) 2.25 (s, 3) oo 1.89 (4d, 2, J=14.3 Hz, 6.6 Hz)
Seid 1.60 (m, 5) oo aden
To 1.45 (m, 1) re 1.13 (m, 3) 0.95 (m, 2)
Mass Spec. (FAB) m/e 407 (M+H)*, 327 (M'-2 Lit + 2m). oo Anal Calcd for C, H,gOgPLi,0.38 H)0: C, 61.03; "H, 7.45; P, 7.49
Found: C, 61.03; H, 7.63; P, 7.66 . Example S6 (S)-4-[[2-[2-(Cyclohexylmethyl)-4,6-dimethylphenyl]- ethyl ]hydroxyphosphinyl]-3-hydroxybutanoic acid, dilithium salt ~ © 30 A. 4-[[[2-(Cyclohexylmethyl)-4,6-dimethyl- phenyl ]ethyl Jmethoxyphosphinyl]-3- : [[(1,1-dimethylethyl)diphenylsilyljoxy]- butanoic acid, methyl ester ~ | | pap ORIGINAL
HX10b : -260- "Argon was bubbled through a 45 ml methanol oo : solution of Example 54 Part F acetylenic ; : phosphinate (1.33 g, 2.02 mmol) for 10 minutes. oo
So To this methanol solution in a Parr bottle was : added 10% Pd/C (0.34 g). Hydrogenation on a Parr " apparatus at 40 psi for 20 hours gave 1.39 g of an ) . oil after filtration through a celite pad in a : sintered glass funnel. Purification by flash chromatography eluting with 1:1 EtOAc/hexane gave K _ the title phosphinate (1.25 g, 94%) as a clear oil. | oo
TLC Re = 0.21 (5/4/1 Hexane/EtOAc/toluene, silica . ~~ gel) PMA. g oo IR (CHC1,) 3600-3200 (br), 3003, 2925, 2853, 1731, . : © 1448, 1440, 1247, 1233, 1179, 1044 cm *. lm NMR (270 MHz, CDCl) | Co EN 5 6.83 (s, 1) - A - 6.78 (s, 1) BE : : oo 4.50 (m, 1) Lo - | 3.80&3.77 (2 d's, 3, J=6.3 Hz) © 20 3.7263.71 (2 s's, 3) - oo
Co : 3.38 (m, 1) : 2.87 (m, 1) oo . 2.60 (m, 2) 2.45 (d, 2, J=6.9 Hz) © 2.29&2.28 (2 s's, 3) 2.25 (s, -3) 2.00 (m, 4) ’ 1.70 (m, 6) 1.45 (m, 1) Co : 30 .1.30-0.90 (m, 6) aE
Mass Spec (EI) m/e 424 mm”
NEA, nT . -
Co a Ln i BAD ORIGINAL ese
. ‘ HX10b -261~
B. (S)-4-[[2-([2~-(Cyclohexylmethyl)-4,66- ” ' : 'dimethylphenyl Jethyl Jmethoxyphosphinyl]- ~ 3-hydroxybutanoic acid, methyl ester
A solution of the Part A silyl ether (1.2 " g, 1.8 mmol) in THF (20 ml) was stirred under argon atmosphere at room temperature. To this Co solution was added sequentially 0.41 ml of glacial acetic acid and v-Lu,NF (5.0 ml of a 1.1 M THF soluiton, 5.44 mmol) which was added dropwise over
Co 10 5 minutes. After stirring for 23 hours at room --- - - - temperature, the reaction was quenched with 50 ml of ice water and stirred vigorously. The THF was removed in vacuo, .and the resulting material was . diluted with water and extracted 3 times with
EtOAc. The EtOAc extract was washed 2 times with saturated NaHCO, solution and once with brine then dried over Na,sO,. Filtration and solvent removal A © gave a clear oil (1.3 g). The product was = mE : purified by flash chromatography with 100% EtOAc to give the title alcohol (0.55 g, 72%) as a clear } oil. : oo
R¢=0.22 (EtOAc, silica gel) PMA . IR (CHCl,) 2999, 2950, 2929, 2858, 173% 1244, : 1195, 1183, 1112, 1105, 1065, 1043 cm ~. * lm wR (270 MHz, cDCly) 6 7.65 (m, 4) - 7.28 (m, 6) 6.81 (s, 1) 6.76 (s, 1) 4.51 (m, 1) 3.62&3.60 (2 d's, 3, J=5.3 Hz) 3.4983.46 (2 s's, 3) "BAD ORIGINAL . ’ [a J .
Are :
HX10b -262= 2.97 (m, 1) 2.65 (m, 2) ER Co 2.3562.33 (2 d's, 2, J=6.9 Hz) 2.25 (2 s's, 3) - oo 2.16 (2 s's, 3) 1.84 (m, 1) . : 1.68 (m, 6) Co 1.55 (m, 1) | a. 1.18 (m, 2) 1 "1.15 (m, 3) 1.00&0.99 (2 s's, 9) oo 0.91 (m, 2) ol
Mass Spec (CI) m/e 663 (u+r)" Co
C. (S)-4-[[2-[2-(Cyclohexylmethyl)-4,6~ . L ’ dimethylphenyl]ethyl]hydroxyphosphinyl]- | 3 3-hydroxybutanoic acid, dilithium salt . So : part B diester (0.552 g, 1.3 mmol) was } | ) stirred in 14 ml of dioxane at room temperature.
To this solution was added 1.0 N LiOH (3.9 ml, 3.9 . mmol) and then the reaction was warmed to 55°C.
After stirring for 30 minutes a cake-like precipi- i . tate formed which was solubilized by adding 5 ml of H,0. After 2 hours 15 minutes at 55°C, the reaction was cooled to room temperature, and the : volatiles were removed in vacuo leaving a white : solid. The product was purified on a 3.0 x 30 cm - | HP-20 column eluting first with 100 ml of H,O followed by 1:1 CH50H/H,0.- Product fractions were lyophilized to give 0.482 g, 92% yield of white : © lyophilate. : TLC R¢=0.36 (7:2:1 n-PrOH/NH,OH/H,0, silica gel) :
PMA. oo - BAD ORIGINAL ioub : -263-
IR (KBr) 3700-3100 (br), 2923, 2852, 1588, 1446, 1410, 1159, 1132, 1048 cm ©. oo oo ly NMR (400 MHz, D,O) oo § = 6.93 (s, 1) : 5 6.91 (s, 1) 4.34 (m, 1) ‘ . 2.80 (m, 2) 2.50 (dd, 1, J=14.7 Hz, 4.4 Hz) 2.48 (d, 2, J=5.12 Hz)
Cee 10 2.38 (dd, 1, J=15.0 Hz, 6.6 Hz) oo 2.29 (s, 3) 2.26 (s, 3) 1.84 (m, 2) . } 1.65 (m, 7) 1.48 (m, 1) 1.15 (m, 3) * 1.00 (m, 2) | : : Mass Spec (FAB) m/e 397 - (M+H-2L7) 4. 409 (ME) bor een : Anal Caled for C, Hy OgPLi, 0.76 HO: C, 59.76; 20 .° H, 7.77; P, 7.34 * Found:. C, 59.76; H, 7.91; B, 7.53 - : Example 57 . 4-[[[[4'-Fluoro-3,3', 5-trimethyl[1,1'-biphenyl]- 2-y1]oxy methyl ]hydroxyphosphinyl]-3-hydroxy= pbutanoic acid, dilithium salt
A. 4'-Fluoro-3,3',5-trimethyl(1,1'- | } biphenyl}-2-carboxaldehyde
Ref. Metck U. S. patent No. 4,375,475, PP. 37 and - 30 38.
The title compound was prepared as described in Example 1 Parts A to C. - } 1 { baw URIGINAL a amtnaesoi
HX10b ~-264-
B. 4'-Fluoro-3,3',5-trimethyl(1,1'- oo 'biphenyl]-2-methanol Fy : "part A aldehyde (1.03 g, 4.26 mmol) was : stirred in 30 ml of dry CH,CL, under argon atmosphere. A 20 ml CH,Cl, solution of m-Cl- perbenzoic acid (1.06 g, 5.11 mmol) was added dropwise over 15 minutes to the aldehyde solution : at room temperature. After stirring for 58 hours at room temperature, the reaction mixture was
SR 10 rotavapped to dryness, and the resulting yellow solid was dissolved in THF and treated with 6.4 ml i of 2N KOH. This mixture was stirred at room temperature for 5.5 hours, then the THF was . : removed from the reaction. The resulting residue was diluted with H,0 and the aqueous solution was extracted 3 times with Et,0 which was then dried over MgSO, . The crude yellow oil obtained after filtration and solvent removal was purified by i flash chromatography eluting with. 5% Et,0/hexane. .
The title phenol was obtained as white solid (0.843 g, 100%). :
TLC Rp = 0.37 (10% Et,0/hexane, silica gel) PMA - | M.P. 83-86°C. }
IR (KBr) 3512, 3500 (br), 2950, 1504, 1482, 1238, 1231, 1215 cml. lg NMR (270 MHz, CDCl,) 8 7.20 (m, 2) 7.07 (t, 1, J=9.0 Hz) 6.92 (s, 1) oo 6.82 (s, 1) . 4.95 (s, 1) 2.31 (s, 3) 2.25 (s, 6)
BAD ORIGINAL
&. ci,
HX10b ~265- "* Mass Spec (CI) m/e 231 (M+H)' )
Cc. [[[4'-Fluoro-3,3',5-trimethyl(1l,1'- ) : L:iphenyl]-2-yl]oxylmethyl]phosphonic } acid, diethyl ester
A suspension of pentane washed NaH (0.30 g 80% oil disp, 10.3 mmol) in 15 ml of dry DMF under : - argon &'wosphere was cooled in an ice bath. A 10 ml DMF solution of the Part B ph=nol (2.36 g, 10.3 7 710 mmol) was added to the NaH suspension over 15 : ee . min:gas evolution was observed. After the addition was complete, the reaction was warmed to - room temperature and stirred for 35 minutes. At . room temperature, an 11 ml DMF solution of the © 15 diethyl tosyloxy methylphosphonate (3.31 g, 10.26 . : mmol, for prep. see Holy, A., Rosenberg, I., IEEE
Collection Czechoslovak Chem. Commun., Vol. 47, oo 1982) was added dropwise over 10 minutes. After 22 hours at room temperature, the reaction was +20 quenched with saturated aqueous NH,Cl solution and So the DMF was removed in vacuo. The resulting solid : was dissolved in EtOAc and H,O, and the agueous layer was- washed 2 times with EtOAc. The combined
EtOAc extracts were washed with saturated aqueous
NaHCO, solution and brine then dried over MgSO,.
Filtration and solvent removal gave 4.3 g of crude ) title ether compound which was purified by flash chromatography eluting with 70% EtOAc/hexane. The : title ether (3.2 g, 82%) was obtained as a clear - 30 oil.
TLC 0.52 (50% Acetone/hexane, silica gel) PMA. - IR (Film) 2983, 2925, 2910, 1504, 1474, 1213, 1032, 971 em” lt. . eh BAD ORIGINAL : oo
HX10b -266- - ly NMR (270 MHz, CDCl;) : 8 7.33 (m, 2) e : 7.01 (t, 1, J=10.0 Hz) . i 6.96 (s, 1) | - 6.91 (s, 1) : : 4.07 (m, 4) - 3.69 (4, 2, J=9.3 Hz) 2.34 (s, 3) . i 2.31 (4, 3, J=1.7 Hz) eee 10 2.29 (8, 3) oo . | 1.31 (t, 6, J=7.0 Hz)
Mass Spec (CI) m/e 381 (M+H)', 242 (mc 8, 0s)" . D. [[{4'-Fluoro-3,3,5'-trimethyl(1,1'- biphenyl]-2-yl]oxy]methyl]phosphonic acid, monoethyl ester oo oo part C diester (3.21 g, 8.45 mmol) in 40 ml of dioxane was stirred with 12.7 ml of 1N LiOH (12.67 mmol) at 70°C. After 3 hours at 70°C, the reaction was cooled to room temperature and the dioxane was removed in vacuo. The aqueous solution was diluted with H,0 and cooled in an ice bath, then acidified to pH+1 with 6N HCl leaving a milky white solution. This solution was then extracted 3 times with EtOAc; the EtOAc extract was dried over MgSO, and filtered to give 3.12 g ’ of a clear gum.
TLC Rg=0.20 (9/0.5/0.5 CH,Cl,/AcOH/MeOH, silica gel) PMA : 1H NMR (270 MHz, CDCly) 6 10.26 (s, 1) 7.35 (2) 6.96 (m, 3) . br ORIGINAL - ay
HX10b -267-
N 4.05 (dq, 2, J=7.14 Hz, 14.8 Hz) . 3.63 (d, 2, J=9.34 Hz) 2.31 (s, 3) : : : 2.29 (s, 3) So 2.28 (d, 3, J=2.2 Hz) 1.28 (t, 3, J=7.14 Hz)
E. 4-[Ethoxy([(4'-fluoru 3,3',5-trimethyl- [1,1'-biphenyl]-2-yl]oxy]methyl]phos- ..10 . phinyl]-3-oxobutanoic acid, methyl ester -
Co The Part D phosphonic acid (2.96 g, 8.42 mmol) in 75 ml of dry CH,Cl, under argon atmosphere was stirred at room temperature with . (C,Hg),Si(CHy), (2.44 g, 16.84 mmol). After stirring for 1 hour 10 min, the CH,Cl, was removed in vacuo and the resulting oil was azeotroped once k . © _ with benzene, then placed under high vacuum f£or.15.. -. .. minutes. This oil was dissolved in 75 ml of dry ; . CH,Cl, and cooled to 0°C under argon atmosphere.
Three drops of dry DMF were added to the cooled : solution followed by dropwise addition of oxalyl chloride (1.18 g, 9.26 mmol). The reaction . oo was stirred at 90°C for 20 minutes, warmed to room temperature and stirred for an additional hour.
The reaction solvent was removed in vacuo and the ’ maroon oil phosphonochloridate was azeotroped 2 times with benzene then placed under high vacuum for 1 hour. : The dianion of methylacetoacetate was ~ 30 prepared as described in Example 55 Part C [methyl- acetoacetate (1.27 gq, 10.95 mmol), NaH (0.350 g oil disp., 12.05 mmol), n-butyllithium (4.0 ml of ks Co N AL
BAD ORIGIN,
Raman .
HX10b -268- 2.5 M solution in hexane, 10.07 mmol), THF (35 mi)]. a | Co
The above prepared phosphonochloridate .in 10 ml of THF, cooled to -78°C, was added dropwise over 20 minutes to the dianion solution also at - ’ + _78°C. After stirring at -78°C for 40 minutes, the reaction was quenched at -78°C with saturated - ) - aqueous NH,C1 and allowed to warm to oom temperature. The THF was removed in vacuo, and
Co 10 ~ “the resulting residue was dissolved in EtOAc and we
H,0. The aqueous layer was extracted 2 times with
EtOAc, and all of the EtOAc solutions were combined and washed once with saturated NaHCO, ol . solution and once with brine then dried over :
Na,SO,. Crude title phosphinate was obtained as g an orange oil (4.0 g) which was purified by flash chromatography eluting with 75% EtOAc/hexane. Lo - Title phosphinate (1.4 g, 42%) was obtained as a oo ) . yellow oil. .
TLC R;=0.25 (75% EtOAc/hexane, silica gel), PMA. oo
IR(CHCl,) 3004, 2954, 2925, 1744, 1718, 1643, 1541, 1503, 1472, 1449, 1438, 1425, 1236, 1037 : cm™L. . ] ) lg NMR (270 MHz, CDCl) 6 7.30 (m, 2) 6.95 (m, 3) . 4.05&3.90 (2 m's, 2) © 3.75 (m, 2) 3.73&3.66 (2 s's, 3) : 3.55 (m, 1) © 3.25 (m, 1) 2.33&2.29 (2 s's (br), 9) - BAD ORIGINAL
HX10b ’ : -269- } . 1.28&1.12 (2 t's, 3, J=7.1 Hz)
Mass Spec (CI) m/e 451 m+)" a oo F. 4-[[[[4'-Fluoro-3,3',5-trimethyl[1,1'- ~ biphenyl ]-2-yl]oxy methyl ]ethoxyphos- -
Co phinyl]-3-hydroxybutanoic acid, methyl : : ester oo :
A solution of Part E ketone (1.39 g, 3.09 ) mmol) in THF (15 ml) under argon atmosphere was
CTT 10 cooled to 0°C. To the cooled solution was added... oo © NaBH, (0.12 g, 3.09 mmol) followed by slow : dropwise addition of 'CH,OH (2.8 ml). After 1 hour at 0°C, the reaction was quenched with acetone . followed by 1.4 g of CC-4 silica gel and then : 15 warmed to room temperature. The reaction was , filtered, and the filtrate was rotavapped to give wewmon zee eB Yellow oil. The oil wag flash chromatographed, eluting with 90% EtOAc/hexane and product - : containing fractions were combined and solvent was . 20 removed in vacuo. The resulting yellow oil was crystallized from Et,O/hexane and the resulting crystals were triturated with Et,0/hexane to give - white crystals (0.320 g) of title alcohol.
Lo TLC R¢=0.38 (90% EtOAc/hexane, silica gel) PMA.
M.P. 116-119°C. : . ; IR (KBr) 3288 (br), 3000, 2950, 2920, 1735, 1503, 1473, 1440, 1311, 1232, 1195 cml. lg nvr (270 MHz, CDCl.) : 6 7.28 (m, 2) ” 30 7.05 (t, 1, J=6.0 Hz) 6.98 (s, 1) 6.90 (s, 1) i . 4.42 (m, 1)
BAD ORIGINAL eh ead
HX10U ow. -270~- © 4.0553.85 (m, 2) : 3.75 (4, 2, J=6.0 Hz) 3.70 (s, 3) 2.55 (m, 2) : 2.32 (s, 6) 2.30 (s, 3) ‘ 2.00 (m, 2) 1.30 (t, 3, J=7.0 Hz)
Macs Spec (CI) m/e 453 (Mi) , 435 (M-H,0)" : : G. 4-[[[[4'-Fluoro-3,3",5-trimethyl(1,1'- diphenyl]-2-ylJoxy]methyl]hydroxyphos- phinyl}-3-hydroxybutanoic acid, : dilithium salt =
At room temperature 1N LioH (2.0 ml) was added to a 13 ml dioxane solution of Part F diester (0.293 g, 0.65 mmol). The reaction ) mixture was warmed to 55°C and stirred for 1 hour
Lo . 45 minutes, then cooled to room temperature. The reaction mixture was rotavapped to dryness and - So gave a white solid which was then placed under high vacuum for 10 minutes. The crude product was " } purified by chromatography on a 15 cm x 3.0 cm column of HP-20 eluting first with 100 ml of H,0 followed by elution with 50% CH,OH/H,0. Pure title dilithium salt was obtained as a white lyophilate (0.295 g, 88%). oo TLC R;=0.38 (7:2:1 n-PrOH/NH, OH/H,0, silica gel)
PMA
IR (KBr) 3400 (br), 3021, 3011, 2981, 2958, 2924, 1575, 1503, 1475, 1446, 1430, 1401, 1231, 1175, ’ 1087 em Lt.
BAD ORIGINAL w ——
HX10b -271- : : ’ lg mur (270 MHz, D,0) J 8 7.20 (m, 2) 7.07 (d, 1, J=9.9 Hz) “7.03 (s, 1) Co 6.86 (s, 1) : 4.03 (m, 1) . ~3.40 (d, 2, J=8.3 Hz) : 2.24 (s, 3) - 2.21 (s, 3) - e100 2.20 (m, 2) : 2.17 (s, 3) . : :
Lo © 1.45 (m, 2). | : : Mass Spec (FAB) m/e 423 (M+H)" . Anal Calcd for CooH206FPL, 0-95 Hy0: C, 54.67;
H, 5.48; F, 4.32; P, 7.05
Found: C, 54.37; H, 5.03; F, 4.31; P, 7.55 fa Example 58 4-[[[4'-Fluoro-3,3',5-trimethyl[1,1'-biphenyij-2= oo y1]methyl]hydroxyphosphinyl]-3-hydroxybutanoic acid, dilithium salt -
A. 4'-Fluoro-3,3',5-trimethyl[l,1'- biphenyl]-2-methanol
To a 9 ml EtOH (Abs) solution of NaBH, (0.12 g, 3.18 mmol) was added the Example 57 part A aldehyde (0.70 g, 2.89 mmol) as an . Et,0-EtOH (4.5 m1/3.0 ml) solution. This reaction mixture was stirred at room temperature for 2 hours ' and then quenched with saturated NH,Cl solution.
The resulting solid precipitate was removed by ’ filtration. The filtrate was rotavapped to dryness and the resulting solid was dissolved in Et,0 and
H,O. The aqueous layer was washed 2 times with
BAD ORIGINAL
HX10b : -272-
Et,0, and the combined Et,0 solutions were dried ove: +igSOy . Sot ’ : After filtration and solvent removal 0.70 g ) of = white solid was obtained. The solid was purified by flash chromatography eluting with 337%
Et,0/hexane giving 0.675 g@ (100% yield) of title alcohol. . Tr. 0.11 (15% Et,0/hexane, silica gel) PMA. v.25, 101-102°C. - 10 IR (KBr) 3351, 3293, 3267, 3260, 3024, 3016, 2980, 2939, 2921, 1605, 1601, 1502, 1451, 1355, 1243, ‘ 1236, 1228, 1189, 1118, 999 cm . ly NMR (270 MHz, CDCl) oo > 8 7.15 (m, 2) 7.03 (m, 2) oo 6.90 (s, 1) 4.55 (d, 2, J=6.0 Hz) : © 2.48 (s, 3) ) Co . 2.33 (s, 6)
Mass Spec (CI) m/e 244 (M'), 227 (m+ 0H) | | oo : B. [[4'-Fluoro-3,3',5-trimethyl(1,1"- Co . biphenyl]-2-yllmethyl]phosphonic acid, diethyl ester ‘
A 50 ml CH,Cl, solution of Part A alcohol (1.94 g, 7.95 mmol) under argon atm. was cooled to 0°C. To this cooled solution was added Et,N (0.965 g, 9.54 mmol) followed by dropwise addition of MsCl (1.00 g, 8.75 mmol). The reaction was stirred at 0°C for 30 minutes and then warmed to room temperature and stirred overnight. The reaction was quenched with saturated NaHCO, : solution and stirred vigorously. The organic
BAD ORIGINAL
HX10b -273-~ : © layer was washed with saturated NaHCO, solution : and then dried over MgSO,. Filtration and solvent : removal gave 2.1 g of 2-(chloromethyl)-4'-fluoro- 3,3',5~trimethyl[1,1'-biphenyl] as a clear oil. .
TLC Rg = 0.68 (50% Et,0/hexane, silica gel) PMA. lg NMR (270 MHz, CDCl) . 5 7.22 (m, 2) . 7.03 (m, 2) 6.90 (s, 1) co 10 4.50 (s, 2) 2.48 (s, 3) 2.33 (s, 6) without further purification the above . ~ chloride (2.1 g) was stirred with P(OC, Hg), (30 ml) at 150°C under argon atomosphere for 3 hours. The reaction was cooled to room temperature and the oo excess P(OC, He) was removed by distillation. The
Lo - crude product was purified by flash chromatography eluting with 70% EtOAc/hexane. Title phosphonate” (2.40 g, 83%) was obtained as a clear oil.
TLC Re = 0.37 (70% EtOAc/hexane, silica gel) PMA.
IR(CHCl,) 2992, 2928, 2909, 1501, 1474, 1455, : . 1443, 1392, 1245, 1239, 1119, 1053, 1029, 970, 963 ' © em”L. : lH MR (270 MHz, CDCly) 6 7.15 (m, 2) : ‘ 7.00 (m, 2) 6.83 (s, 1) . | 3.83 (m, 4) 3.22 (d, 2, J=22.52 Hz) . 2.47 (s, 3) 2.29 (s, 6) 1.16 (t, 6, J=7.14 Hz)
HAD ORIGINAL
HX10b -274-
Mass spec (CI) m/e 365 (m+H)" E
Co C. [[4'-Fluoro-3,3',5-trimethyl(1,1'- : biphenyl]-2-yl]methvllghosphonic acid, monoethyl ester
Part B phosphonate diester (2.40 g, 6.59 mmol) was stirred in 30 ml of dioxane at room temperature. To this dioxane solution was added
IN LiOH (9.9 ml) and the reaction was warmed to a . 10 . reflux. Additional 1N LiOH (9.9 ml) was added at each of the 18 hour and 44 hour time points.
After 55 hours at reflux the reaction was cooled to room temperature and the dioxane was removed on . the rotavap. The resulting aqueous solution was : : 15 diluted with H,0 and extracted 2 times with Et,0 : oo to remove any remaining diester. The aqueous . layer was then cooled in an ice bath and acidified to pH~1 with 6N HCl. The milky white solution was ) extracted 3 times with EtOAc, the EtOAc extract was dried over MgSO, , filtered, and the solvent was removed to give 1.89 g, 85% yield of a clear : oil. oo TLC Rp = 0.26 (9/0.5/0.5, CH,Cl,/MeOH/ACOH, silica gel) PMA. . 25 IR (CHC1,) 3029, 3023, 3005, 2983, 2925, 1710, 1605, 1500, 1234, 1042, 988 cm TL. la NMR (270 MHZ, cDCly) 6 11.07 (s, 1) 7.05 (m, 2) 6.95 (m, 2) 6.80 (s, 1) : 3.71 (dq, 2, J=7.15 Hz, 14.83 Hz) . 3.13 (4, 2, J=23.0) i BAD ORIGINAL
HX10b : -275- . : 2.38 (s, 3) 2.27 (s, 6) = : 01.13 (t, 3, J=7.2 Hz). . oo . Mass Spec (CI) m/e 337 (M+H)"
CT 5 oo
D. 4-[Ethoxy[([4'-flucro-3,3',5-trimethyl- [1,1'-biphenyl]-2-yl]jmethyl]phos- oo phinyl]-3-oxobutanoic acid, methyl ester
A 50 ml CH,Cl, solutic: of Part C half acid . (1.85 g, 5.50 mmol) under argon atmosphere was : Ce stirred with (C,Hg),NSi(CH;); (1.60 g, 11.0 mmol) at room temperature for 1 hour 15 minutes. The
CH,C1, was removed from the reaction mixture and . the resulting yellow oil was azeotroped once with ’ 15 benzene and placed under high vacuum for 20 minutes. This oil under argon atmosphere was dissolved in 50 ml of dry CH,CL, and cooled to . 0°C. Two drops of dry DMF were added to the = cooled solution followed by the dropwise addition Co of oxalyl chloride (0.768 g, 6.06 mmol):gas x evolution was observed. The reaction was stirred at 0°C for 20 minutes, warmed to room temperature and stirred for an additional 1 hour 40 minutes; } the reaction turned deep burgundy. The CH,Cl, was removed from the reaction and the resulting oil was azeotroped 2 times with dry benzene then placed under high vacuum for 1 hour.
The dianion of methylacetoacetate was prepared as described in Example 57 Part E [methylacetoacetate (0.830 g, 7.16 mmol); NaH ’ } | (0.230 g oil disp., 7.88 mmol); n-BuLi (2.64 ml of 2.5 M solution in hexane, 6.59 mmol) ; 20 ml of
THE] . : C3
BAD ORIGINAL es tmnt
.10b -276-
The above prepared phosphonochloridate in ] 10 ml of dry THF cooled to -78°C was added via : cannula over 20 minutes to the dianion solution cooled to -78°C. After stirring for 40 minutes at -78°C, the reaction was quenched at -78°C with to " saturated NH,CL solution, and warmed to room temperature; the reaction mixture was diluted with H,0 in order to dissolve solid: and the THF ; was removed on ihe rotavap. The resulting mixture was extracted 3 times with EtOAc. The EtOAc extract was washed once with saturated NaHCO,, once with brine, dried over MgSO, and filtered to : give 2.6 g of crude orange oil after solvent . removal. The crude product was purified by flash chromatography eluting with 75% EtOAc/hexane. The
Part D ketone (0.43 g, 23%) was obtained as an orange foam.
TLC R=0.32 (50% acetone/hexane, silica gel), PMA. N
IR (KBr) 2952, 2925, 1739, 1718, 1654, 1529, 1503, 1472, 1234, 1206, 1166, 1119, 1035 emt. la MR (270 MHz, cDCl,) § 7.20-6.70 (aromatic H's, 5) 4.00-3.70 (m, 2) } 3.70&3.55 (2 s's, 3) 3.35 (m, 2) Lo X i 3.35 (4, 2, J=15 Hz) ‘ : 2.92 (m, 1) 2.45&2.35 (2 s's, 3) 2.25 (s, 6) . . 30 1.15&0.95 (2 t's, 3, J=7.0 Hz)
Mass Spec (CI) m/e 435 (M+H)Y = 5 . BAD ORIGINAL
HX10b : -277-
E. 4-[Ethoxy[[4'-fluoro-3,3',5-trimethyl- ’ ) [1,1'-biphenyl]-2-yl]methyl]phosphinyl]- : 3-hydroxybutanoic acid, methyl ester : . "Solid NaBH, (0.035 g, 0.92 mmol) was added
S to a 5 ml THF solution of the Part D ketone (0.40 g, 0.92 mmol) under argon atmosphere. Methanol (0.80 ml) was added to the THF solution at room temperature. After 1 hour at room temperature, the reaction was quenched with acetone follow=d by wmemmoow --10 the addition of 0.4 g of CC-4 silica gel. The reaction mixture was filtered and the solvent was removed. The reaction product still retained some ketone starting material; therefore, the above . reaction product was resubjected to the identical oo ] 15 reduction conditions described above; however, CO, (g) was bubbled through the solution prior to the addition of the NaBH, . Workup as before gave 0.250 g of a yellow oil which was purified by flash chromatography eluting with EtOAc. Pure title alcohol was obtained as a clear oil. . TLC R.=0.26 (50% acetone/hexane, silica gel) PMA. lH NMR (270 MHz, CDCl) : 6 7.10 (m, 2) . * © 7.00 (m, 2) 6.85 (s, 1) .4.28&4.03 (2 m's, 1) 4.10-3.70 (m, 2) 3.67 (s, 3) 3.33 (m, 2) 2.47 (s, 3) ’ , © 2.40 (m, 2) 2.30 (s, 6)
BAD ORIGINAL ser . : nd
HX10b -278- 1.63 (m, 2)
Co 1.17 (t, 3, J=6.6 Hz) :
F. 4-[[[4'-Fluoro-3,3',5-trimethyl(1,1'~ : biphenyl]-2-yl]methyl Jhydroxyphosphinyl]~- 3-hydroxybutanoic acid, dilithium salt
Part E diester (0.110 g. 0.252 mmol) in ds : CH,Cl, (5.5 ml) under argon atmosphere was cooled : 10 to 0°C and treated with collidine (0.046 g, 0.38 mmol) followed by dropwise addition of : trimethylsilyl iodide (TMSI) (0.182 g, 0.88 mmol). The reaction was stirred at 0°C for 2 . . hours then warmed to room temperature. After 24 hours an additiorial aliquot of both collidine (0.023 g) and TMSI (0.091 g) was added. After stirring for 48 hours at room temperature, the
CH,Cl, was removed, and 6 ml of dioxane was added to the oil followed by 1.7 ml of 1N LiOH. This mixture was refluxed for 16 hours, cooled to room temperature and the dioxane was removed to leave an orange gum. The gum was dissolved in H,0 and filtered through sintered glass to remove a solid. The filtrate was lyophilized to give an ’ . 25 off-white lyophilate which was purified on a 1.5 cm x 15 cm column of HP-20. The column was eluted i first with 150 ml of H,0 then with 50% MeOH/H,0.
Product fractions were lyophilized to give title compound in the form of a white lyophilate (88 mg, 80%)
TLC R,=0.38 (7:2:1 n-PrOH/NH,OH/H,0, silica gel), . PMA.
IR (KBr) 3700-3100 (br), 2923, 1591, 1501, 1234, t
BAD ORIGINAL
. | Sd
HX10b : -279- : - 1147 emt. lg avr (270 MHZ, D,0) - ) § 7.20-7.00 (m, 4) : 6.82 (s, 1) . SE : 3.76 (m, 1) © 3.11 (m, 2) 2.35 (s, 3) 2.22 (s, 3) : 2.21 (s, 3) ” 2.05 (m, 2) oo ‘ : 1.16 (4d, 2, J=12.32 Hz, 6.45 Hz)
Mass Spec (FAB) m/e 407 (m+) T.
Anal Calcd for C, Hy, FOgPLi, "0.80 H,0: Cc, 57.11; ’ . H, 5.65; F, 4.52; P. 7.36
Found: C, 57.11; H, 6.63; F, 4.44; Pp, 7.70
Example 59 (S)-4-[[ [1-(4-Fluorophenyl)-3-methyl-2-naphtha- x lenyl]ethynylhydroxyphosphinyl]-3-hydroxybutanoig . acid, dilithium salt -
A. 1-Methoxy-2-naphthalene carboxylic acid
Reference: J. Organomet. Chem., 20 (1969)
Pp. 251-252 .n~Buli (208.60 mmol, 83.44 ml of a 2.5 M solution in hexane, Aldrich) was stirred under argon in 42 ml of dry cyclohexane. This solution : was cooled to 0°C and treated dropwise (10 ; : min.) with distilled tetramethylethylenediamine (TMEDA) (208.6 mmol, 24.24 g, 31.48 ml). The . resulting slurry was stirred at 0°C for 30 minutes, then treated dropwise (20 minutes) with a solution - : of 1-methoxynaphthalene (208.60 mmol, 33 g. 30.28 ml) (Aldrich Chem. Co., used without further purification) in 84 ml of dry cyclohexane. The —
BAD ORIGINAL at .
HX10b : -280- " resulting bright red homogeneous reaction mixture . was warmed to room temperature and stirred for 2 : hours. The reaction mixture was cooled to 0°C and added portionwise over 30 minutes via cannula to a -J8°C solution of dry Et,0 (250 ml) saturated with co, (g) (co, pellets sublimed through drying tube containing $i0,, bubbled into dry Et,0 at -78°C).
The resulting white slurry was warmed to "7° over - 45 minutes and then treated with 450 ml of 5% HCl ‘ 10 (aqueous). The Et,0 layer was separated and the : aqueous layer extracted three times with Et,0.
The organic extracts were combined and extracted with 3 x 150 ml saturated NaHCO, (aqueous). The . aqueous layer was filtered through a sintered ’ 15 glass funnel to remove insolubles and the filtrate was cooled to 0°C and acidified slowly with concentrated HCl until pH=1. The resulting precipitate was filtered, azeotroped with 2°x 150 . ml of toluene, dried under high vacuum at 50°C for 5 hours to afford 32.52 g (0.161 mol, 77% yield) of the l-methoxy-2-naphthalene carboxylic acid as an off-white powder, m.p. 118-121.5°C.
TLC: Silica gel, R.=0.35 94:5:1/CH,Cl, : MeOH: CH;CO,H lg NMR: (270 MHz, CDCl,) consistent to 3c mm: (67.8 MHz, CDCl,) consistent
Mass Spec: CI m/e 203 (M+H)
IR: KBr consistent. :
B. N-(2-Hydroxy-1,1-dimethylethyl)-1- methoxy-2-naphthalenecarboxamide ’
The l-methoxy-2-naphthalene carboxylic acid (155.22 mmol, 31.4 g) was stirred under argon in 155 ml of dry CH,Cl,. The solution was then . oo BAD ORIGINAL
HX10b . -281- - treated with SOCl, (310.44 mmol, 36.94 g, 22.63 ml). The reaction mixture was stirred at room Co temperature for 45 minutes then heated to reflux : in a 55°C oil bath for 45 minutes. The reaction ) mixture was cooled to room temperature and treated - with an additional 15 g, 22 mmol (18.47 g, 11.32 ml) of thionyl chloride and again heated to reflux . for 45 minutes. The reaction mixture was cooled : to room temperature, the excess soCl, and CH,Cl, removed via rotary evaporation at 35°C (venting to - argon atmosphere) and the resulting mustard yellow " golid dissolved under argon in 155 ml dry CH,CL,.
This solution was transferred via cannula to an addition funnel and added dropwise (40 minutes) to ; 15 a solution of 2-amino-2-methyl propanol (310.44 : mmol, 27.67 g) in 155 ml dry CH,CL, which had been stirring under argon at 0°C. The resulting a reaction mixture was warmed to room temperature and stirred for 18 hours. The reaction mixtuke "’ v was then filtered, the precipitate washed with
CH,Cl,, the filtrate evaporated in vacuo. The residue was redissolved in 350 ml EtOAc and washed ) } with 1 x 250 ml H,0, 1 x 250 ml 5% HCl, 1 X 250 ml 5% NaOH and 1 x 250 ml brine. The aqueous ’ extracts were each back-extracted once with
EtOAc. The organic extracts were combined, dried . over MgSO, , filtered, and evaporated in vacuo to afford an orange oil which was azeotroped with 250 ml toluene and pumped under high vacuum at 55°C ” 30 for 8 hours to afford 38.2 g (139.76 mmol, 90% . yield) of the title naphthalamide as a light yellow solid. 520 ORIGINAL \
A
HX10b -282- :
TLC: Silica gel, Re = 0.65 100% EtOAc
H NMR (270 MHz, CDCl,) : 6 8.19 (s, br, 1H) : 8.14 (m, 1H) CL
S 8.03 (d, 1H, J=8.7 Hz) 7.83 (m, 1H) : 7.66 (4d, 1H, J=8.7 Hz) 7.55 (m, 2H) 4.00 is 3H) 3.74 (s, 2H) . 1.47 (s, 6H)
Mass Spec: CI m/e 274 (m+H) :
IR: (CHCl, solution) . ‘ 3365, 3063, 3024, 3005, 2971, 2938, 2873, 1641, ’ - 15 1597, 1540, 1456, 1446, 1387, 1371, 1344, 1291, 1256, 1238, 1223, 1210, 1199, 1183, 1168, 1145, 1079, 981, 833 cm I.
C. 4,5-Dihydro-2-(1l-methoxy-2-naphthalenyl)- 4,4-dimethyloxazole
The Part B naphthalamide (139 mmol, 38.2 g) was stirred under argon. and cooled to 0°C as thionyl chloride (0.556 mol, 66.15 g, 40.56-ml) ’ was added dropwise (15 minutes). The resulting dark brown oil was stirred at room temperature for 45 minutes. Dry Et,0 (500 ml) was added, and the reaction mixture was stirred mechanically for 2.5 hours. The resulting yellow crystalline precipitate was filtered, washed with Et,0 and then suspended in 250 ml Et,0. The suspension was cooled to 0°C and basified with ~200 ml 10% NaOH.
The aqueous layer was extracted 3 times with Et,0 and once with EtOAc. The organic extracts were 84p CRIGINA,
: . HX10b -283- Lo " combined, washed once with brine, concentrated, * dried over MgSO, and filtered. The filtrate was azeotroped with toluene in vacuo and the residue iE pumped under high vacuum at 55°C for 8 hours to afford 32.10 g (0.126 mol, 90% yield) of the title oxazoline as a golden powder.
TLC: Silica gel R;=0.37 50% EtOAC Co lu MMR: (270 MHz, opel)
Bb Co 5 8.25 (m, 1H) .
So 10 } 7.84 (4d, 1H, J=8.7 Hz) 7.84 (m, 1H) 7.60 (d, 1H, J=8.7 Hz) 7.54 (m, 2H) : 4.19 (s, 2H) ’ 15 4.04 (s, 3H) 1.46 (s, 6H) oo
Mass Spec: CI m/e 256 (m+g)* '
IR: 2969, 2935, 2896, 1642, 1465, 1447, 1386, 1372, 1349, 1255, 1109, 1074, 991 em bt. =
D. 2~(1-(4-Fluorophenyl)-2-~naphthalenyl)]- . 4,5-dihydro-4,4-dimethyloxazole } The Part C oxazoline (117.52 mmol, 30.0 g) was stirred under argon in 352.5 ml of dry THF.
This solution was warmed to 45°C in an oil bath.
The heat source was removed and a 2M solution of ) } 4-fluorophenyl magnesium bromide in Et,0 (Aldrich) (158.65 mmol, 79.33 ml) was added dropwise (30 minutes) at a rate sufficient to maintain the . ’ 30 reaction temperature at ~45°C. After addition was complete, the reaction temperature was maintained ~ at 45°C as the reaction mixture was stirred for 18 hours. The reaction mixture was cooled to 0°C and
BAD ORIGINAL
“
HX10b -284- quenche =~" 200 ml saturated NH,C1 (aqueous), diluted - © : 200 ml H,0 and 200 ml EtOAc. The E aqueous layer was extracted 4 times with EtOAc.
The organic extracts were combined, concentrated, : dried over MgSO, and filtered. The filtrate was evaporated in vacuo to afford 39 g of a dark golden solid. The product was purified via flash chromatography (95 mm diameter column, 7" Merck : a silica gel, 25% EtOAc/hexane eluent, 2"/min flow - 10 rate) to afford 30.42 g (95.25 mmol, 81% yield) of - the title 4-fluorophenyl substituted naphthalene as a pale yellow solid, m.p. 94-96°C. Also obtained was 3.38 g (10.58 mmol, 9%) of slightly . impure product. oo
TLC: silica gel Rg=0.45 50% EtOAc/hexane lm NMR: (270 MHz, cDpCl,) 6 7.93-7.13 (aromatic, 10H) 3.77 (s, 2H) . 1.27 (s, 6H)
Mass Spec: CI m/e 320 (M+H)'
IR: (KBr) 3060, 2966, 2927, 2884, 1667, 1603, 1508, 1462, 1383, 1354, 1335, 1293, 1219, 1185, 1160, 1119, 1083, 978, 842, 830 cm I.
E. 2-[l1-(4-Fluorophenyl)-3-methyl-2- : naphthalenyl)]-4,5-dihydro-4, 4- : : dimethyloxazole
The Part D 1-4-fluorophenyl-2-oxazoline- naphthyl compound (87.67 mmol, 28 g) was stirred under argon in 585 ml dry Et,0. This solution was cooled to -25°C and treated dropwise (1 hour) with Co n-BuLi (140.27 mmol, 56.1 ml of a 2.5 M solution in hexane). The reaction mixture transformed
SAD ORIGIN, —
HX10b : -285- : : during this hour i-ng addition from a yellow ‘ homogeneous soli .n to a dark red/orange solution to an orange/green solution with a precipitate.
Ce : The reaction mixture was stirred at -25°C for an additional 2.5 hours and was then treated with : iodomethane (263.01 mmol, 37.33 g, 16.4 ml) added dropwise over 15 minutes. The resulting dark . purgundy solution was stirred at -25°C for 4.5 hours, warmed to 0°C and stirred for 16 hours and
SR 10 _ _ finally warmed to room temperature and stirred for 7 hours. The resulting yellow transparent solution was quenched with 500 ml of ice cold. : brine. The aqueous layer was extracted 4 times oo Co with EtOAc. The organic extracts were combined, . . 15 concentrated, dried over MgSO, and filtered through Florisil (300 ml glass sintered funnel 2/3 ot full). The Florisil was washed with CH,Cl,. The : filtrate was concentrated, azeotroped with toluene and evaporated in vacuo and pumped under high: ' *-- : vacuum at 55°C for 3 hours to afford 30.32 g ("90.94 mmol", 100% yield) of the title methylated naphthalene as a yellow solid.
TLC: Silica gel R¢=0.50 50% EtOAc/hexane : ly NMR: (270 MHz, CDCl,) 5 7.79-7.07 (aromatic, 9H) 3.80 (s, 2H) 2.54 (s, 3H) 1.13 (s, 6H) . Mass Spec: CI m/e 334 m+H)"
IR: (CHCl, solution) : . 3013, 2967, 2931, 2895, 2870, 1667, 1605, 1513, 1497, 1461, 1299, 1280, 1235, 1190, 1158, 1041, 965, 841 cm 1. . BAD ORIGINAL
HX10b : -286-~
F. 2-{1-(4-Fluorophenyl)-3-methyl-2- } naphthalenyl)]-4,5-dihydro-3,4,4- trimethyloxazolium iodide
The Part E oxazoline (87.67 mmol, 29.23 gq) was stirred under argon in 140.28 ml nitromethane. This solution was treated in cne portion with iodomethane (0.789 mol, 112 g, 49.2 ml). The resulting brown reaction mixture vss heated in a 60°C oil bath for 1 hour 20 minutes in the absence of light. The iodomethane was removed : via simple distillation. The nitromethane was removed via rotary evaporation followed by pumping ) under high vacuum for 45 minutes. The resulting . burgundy solid was stirred mechanically in 250 ml dry Et,0 for 1 hour. The red filtrate was decanted and the solid was again triturated from
Et,0 as above. The resulting yellow solid was filtered and pumped under high vacuum for 4 hours (in the absence of light) to afford the title oxazolinium iodide 44 g ("92.63" mmol, 100% yield) as a mustard yellow solid. The title compound was stored in the absence of light at -30°C for 18 hours and was .then used directly in the preparation } of the Part G ‘compound. *
TLC:Silica gel R¢=0.30 10% MeOH/CH,C1, .
G. 1-(4-Fluorophenyl)-3-methyl-2- naphthalenecarboxaldehyde : The Part F oxazolinium iodide (87.67 mmol, 41.67 g) was stirred under argon in 526 ml of dry
THF and 210 ml absolute EtOH (dried over 4& molecular sieves). This solution/suspension was cooled to -15°C and treated protionwise with NaBH,
BAD ORIGINAL
: : HX10b -287- over a one hour period. After addition was complete, the reaction solution was stirred at - -10°C to -15°C for 2.5 hours. Then, the solution i} was diluted with 210 ml absolute EtOH and the - reaction mixture stirred at -15°C as 2N HCl (438 ml, 876 mmol) was added dropwise over 45 minutes (add very slowly initially). After addition was complete, the reaction mixture was warmed to room ° temperature and stirred for 4 hours. Then, © 10 dilution with 500 ml H,0 was followed by aqueous extraction with Et,0. The organic extracts were combined, concentrated, dried over MgsSO,, filtered, concentrated, azeotroped with toluene (2 . x 120 ml) and stripped in vacuo to afford 12.9 4g, (48.81 mmol, 56% yield) of the title aldehyde as a pale yellow solid. :
TLC: Silica gel R=0.66 50% EtOAc/hexane - ’ lg NMR: (270 MHz, CDCL,) 8 10.0 (s, 1H) ae Sat 7.83-7.18 (aromatic, 9H) 2.81 (s, 3H) Co
Mass Spec: CI m/e 265 (M+H)
IR: (CHCl, solution) : , 1685, 1512, 1422, 1237, 862 cm ~.
H. 2-(2,2-Dibromoethenyl)-1-(4-fluoro- phenyl )-3-methylnaphthalene
The part G aldehyde (11.35 mmol, 3.0 g) was . stirred under argon in 113.5 ml dry CH,Cl,. This solution was cooled to 0°C and then treated in one - portion with triphenylphosphine (36.32 mmol, 9.53 'g). The reaction mixture was stirred at 0° for 20 minutes and then treated dropwise (20 min) with a : BAD ORIGINAL ; ’ me - ’
HX10b : -288- : solution of carbon tetrabromide (18.16 mmol, 6.02 g) in 41 ml dry CH,CL,. The resulting dark orange CL solution became dark burgundy as it was stirred at ; 0°C for 1% hours. Then the reaction mixture was - quenched wiil 150 ml saturated NaHCO, (aqueous).
The aqueous layer was extracted 4 times with
CH,Cl,. The organic extracts were combined, concentrats’ in vacuo, washed once with brine, . dried over 350, and filtered. The filtrate was ~ ] 10 preabsorbed onto Merck silica gel (~28 g) and then - applied to a 50 mm diameter flash chromatography column containing 6" Merck silica gel and eluted with 7% EtOAc/hexane eluent, 2"/min flow rate to . afford 4.23 g of the title dibromo-olefin as a slightly impure pale yellow solid. Subsequent recrystallization from hexane afforded 3.68 g (8.77 mmol, 77% yield) of the title dibromo-olefin as a white powdery solid. m.p. = 134.5-135.5.
TLC: silica gel R=0.60 20% EtOAc/hexane 'u NMR: (270 MHz, CDCl) 8 7.79-7.11 (aromatic olefinic, 10H) . 2.48 (s, 3H)
Mass Spec: CI m/e 419/421/423 (M+H)"
IR: (CHCl, solution) 3016, 1604, 1512, 1496, 1234, 1220, 1208, 1158, ] 886, 858 cm Ll.
I. 2-Ethynyl-1-(4-fluorophenyl)-3- methylnaphthalene ’ 30 The Part H dibromo olefin (8.7 mmol, 3.69 g) was stirred under argon in 47.9 ml dry THF.
This solution was cooled to -78°C and then treated dropwise (15 min) with n-BuLi (17.4 mmol, 6.96 ml
BAD ORIGINAL }
HX10b ~289- : i of a 2.5 M solution in hexane - Aldrich). The - reaction mixture was stirred at -78°C for 1 hour : and then was quenched with 40 ml saturated NH, Cl . (aqueous). After warming to 0°C, the reaction mixture was diluted with 40 ml of H,0 and 40 ml of © Et,0. The aqueous phase was extracted 2 times . with Et,0 and once with EtOAc. The organic : extracts were combiied, dried over MgSO,, filtered : and the solvent evaporated in vacuo. Initial purification via flash chromatography (50 mm ~~ ~~ ~~ ~~ . : diameter column, 6" Merck silica gel, 7% .
EtOAc/hexane eluent, 2"/min flow rate) afforded 2.32 ) 'g of a green oil/solid. 270 MH, 14 NMR evidenced . impure product. Repurification via flash chromatography (75 mm diameter column, 6" Merck Co : silica gel, 1% EtOAc/hexane eluent, 2"/min flow rate) afforded 2.11 g (8.11 mmol, 93% yield) of - ; the title acetylene as a pale blue solid (pumped under high vacuum 8 hours) m.p. = 91.5-94:5: "rene eee iw
TLC: Silica gel, PMA Rg = 0.56 20% EtOAc/hexane , ly NMR: (270 MHz, CDCl,) - ’ § 7.77-7.13 (aromatic, 9H) : 3.18 (s, 1H) : 2.62" (s, 3H) -
Mass Spec: CI m/e 260 M'
IR: (CH,Cl, film) 3291, 1604, 1512, 1494, 1383, 1222, 1158, 1150, © 1092, ssa, 871, 853, 825 cm. ’ 30 J. (s)-3-[[(1,1-Dimethylethyl)diphenyl- : silyl]oxy]-4-[[(1-(4-fluorophenyl)-3- : methyl-2-naphthalenyljethynyl]methoxy- —
BAD ORIGINAL oo HX10b -290-
The Example 25 dicyclohexylamine salt (8.82 "mmol, 5.57 g) was partitioned between a 1:1 mixture of EtOAc/5Y% KHSO,, (150 ml ea.) and shaken h oe : vigorously. The layers were separated and the 5S EtOAc layer was washed with 2 x 100 ml fresh 5% . KHSO, . Finally, the organic phase was dried over
MgSO, , filtered and the solvent removed in vacuo.
The resulting residue was az: -troped with 2 x 120 ml benzene, evaporated and p:wmped under high © 7 "7 "10 ~ ¥dcuum for 2 hours to afford "4.33 g", “i09%" ~~ ~~ = yield, of the phosphonate monoester as a viscous pale yellow oil. This oil was stirred under argon in 24.8 ml dry CH,Cl, and treated dropwise (8 ) B . . minutes) with distilled diethyltrimethylsilylamine (17.64 mmol, 2.56 g, 3.34 ml). This solution was ~~ stirred at room temperature for 2 hours. Then, the volatiles were removed on the rotavap (vent to argon) and the resulting residue azeotroped with 1
Xx 60 ml dry benzene, evaporated in vacuo and pumped under high vacuum for 45 minutes. The residue was then stirred under argon in 24.8 ml of dry CH,Cl,. Two drops of DMF were added and the : } solution cooled to 0°C. Oxalyl chloride (10.58 n mmol, 1.34 g, 0.923 ml) was added dropwise (10 min). The resulting amber solution was stirred at 0°C for 30 minutes, warmed to room temperature and stirred for 2 hours. The volatiles were removed, the residue azeotroped and pumped under high vacuum as above. Finally, the residue was stirred under argon in 27.7 ml dry THF. This solution was cooled to -78°C and treated dropwise (15 minutes) with a -78°C THF solution of the acetylenic anion eo BAD ORIGINAL
HX10b : -291- : "formed and added to the phosphonochloridate as follows. - :
The Part I acetylene (5.19 mmol, 1.35 gq) ; was stirred under argon in 27.7 ml of dry THF and - - 5 cooled to -78°C. This solution was treated . dropwise (10 minutes) with n-BuLi (5.19 mmol, 2.08 . ml of a 2.5 M solution in hexane). The resulting : green solution was stirred at -78°C for 1.5 hours, warmed to 0°C for 15 minutes and recooled to - : 10 -78°C. This solution was maintained at -78°C as : it was transferred portionwise to an addition funnel and added dropwise to the -78°C THF : solution of the phosphonochloridate formed above. ’ . After completion of addition, the reaction mixture was stirred at -78°C for 1 hour, then quenched with 50 ml saturated NH,Cl (aqueous) and warmed to 0°C. The reaction mixture was then diluted with 40 ml H,0 and 40 ml Et,0. The aqueous layer was extracted with 4 x S50 ml Et,0. The organic extracts were combined, concentrated, dried over . Mgso,, filtered, and the solvent removéd in vacuo. . The product was isolated via flash chromatography (75 mm diameter column, 6" Merck silica gel, 5:4:1 hexane :EtOAc: toluene eluent, 2"/min flow rate) to afford 1.53 g (2.21 mmol 437% yield) of the title acetylenic phosphinate as a ’ yellow foam. Also recovered 0.589 g of impure starting material. :
TLC:Silica gel, PMA R.=0.26 5:4:1 : : 30 Hexane:EtOAc: toluene
BAD oraiNA- . =
HX10b -292- y lg NMR: (270 MHz, cel) - : - 6 7.82-7.09 (aromatic, 19H) : } 4.52 (m, 1H) : ; 3.60&3.59 (2 x s, 3H) - 5 3.36&3.31 (2 x d, 3H, J=11.5 Hz) 2.54&2.49 (2 x s, 3H) : ; 2.87-2.73 (m, 1H)
So 2.61-2.56 (m, 1H) - 2.39-2.22 (m, 1H) Co
Co 10 2.12-2.00 (m, 1H) - 1.02 (s, 9H)
Mass Spec: CI m/e 693 (M+H)"
IR: (CHCI, solution) -
Co 3004, 2951, 2932, 2858, 2164, 1735, 1605, 1512, 1494, 1472, 1437, 1427, 1237, 1197, 1182, 1158, : 1151, 1138, 1110, 1105, 1093, 1038, 1017, 951, i 885, 834 cm” Ll. : oN K. (S)-4-[{[[1-(4-Fluorophenyl)-3-methyl-
Co 20 2-naphthalenyl Jethynyl jmethoxyphos-
EN phinyl]-3-hydroxybutanoic acid,
Lo methyl ester - . ‘The Part J acetylenic phosphinate (0.866 p mmol,’ 0.60 g) was stirred under argon in 10.5 ml : oo 25 dry THF and treated with glacial acetic acid (3.46
To mmol, 0.208 g, 0.198 ml) followed by dropwise addition of tetrabutylammonium fluoride (2.60 mmol, 2.36 ml of a 1.1 M solution in THF). The : reaction mixture was stirred at room temperature for 24 hours, then quenched with 25 ml ice water . and diluted with EtOAc. The aqueous layer was extracted 3 times with EtOAc. The organic : extracts were combined, washed once with saturated
Fen ORIGINAL
HX10b -293- ‘ NaHCO, (aqueous) and once with brine, dried over
Mgso, » filtered and evaporated in vacuo. The product was purified via flash chromatography . ‘using a. 30 mm diameter column; 35:1 Merck silica
S gel, 100% EtOAc eluent, 2"/min flow rate to afford : 0.267 g (0.588 mmol, 68% yield) of the title
B-hydroxyphosphinate as a pale yellow foam:
Tr.C-Silica gel, PMA R¢=0.28 100% EtOAc 'u NMR: (270 MHz, CDCl) 4 5 7.81-7.18 (aromatic, 9H) . - 4.38 (m, 1H) . 3.71 (s, 3H) 3.59&3.58 (2 x 4, 3H, J=12 Hz) . 2.66&2.65 (2 x s, 3H) 2.62-2.52 (m, 2H) : 2.19-1.92 (m, 2H) } ‘Mass Spec: CI m/e 455 (m+a)*
IR: (film) 3380 (broad), 3065, 3048, 2993, 2951, 2166, 1738, 1604, 1513, 1495, 1457, 1438, 1423, 1401, 1385, : 1378, 1334, 1299, 1222, 1179, 1160, 1138, 1095, 1035, 951, 887, 836 cmt
L. (S)-4-[[[1-(4-Fluorophenyl)-3-methyl~2- A \ naphthalenyl]ethynyl]hydroxyphosphinyl]- 3-hydroxybutanoic acid, dilithium salt
The Part K diester (0.583 mmol, 0.265 g) was stirred under argon in 6 ml dioxane and treated with IN LiOH (1.75 mmol, 1.75 ml). The reaction mixture was heated in a 70°C oil bath for ~ 45 minutes. The reaction mixture was cooled to room temperature. The solvents were removed via rotary evaporation followed by pumping under high —-
BAD ORGINAL
HX10b . : -294- !
Co vacuum for 1 hour. The resulting white solid was : dissolved in 4 ml of distilled H,0 and applied to 4 : an HP-20 chromatography column (2.5 cm x 17.0 cm, te equilibrated with H,0). The column was eluted - Te with 250 ml H,0 followed by eluting with 45:55
MeOH: H,O. Fractions were collected every 1.3 m (+10 ml). Product fractions were evaporated in vacuo xt 35°C, lyophilized, and pumped under oo high vaccum over P,Og for 8 hours to afford 0.237 g (0.541 mmol, 93% yield) of the title phosphinic acid dilithium salt as a white lyophilate.
TLC:Silica gel, PMA R=0.40 7:2:1 n-C,H,OH/NH,OH/H,0 i lg NMR: (200 MHZ, D,0) . 6 7.88 (d, 1H, J=8.43 Hz) 7.80 (s, 1B) - , 7.58-7.29 (aromatic, 7H) i 4.14-4.05 (m, 1H) 2.61 (s, 3H) : 2.43 (dd, 1H, J=3.67, J=15.39) 2.21 (4d, 1H, J=9.16, J=15.39) 1.84-1.67" (m, 2H) .
Mass Spec: FAB m/e 439 (M+2 Li)* ’ IR: (KBr) 3443-3260 (broad), 3066, 2164, 1594, 1512, 1495, 1434, 1222, 1183, 1160, 1071, 834 cml.
Anal Calcd for C,3H; gFO PL1,+0.66 moles H,0 .
M.W.=450.14: C, 61.38; H, 4.33; F, 4.22; P, 6.88
Found: C, 61.38; H, 4.07; F. 4.42; P, 6.80 s Go BAD ORIGINAL k ; . . “orm or ritalin nnd
HX10b : -295- :
Example 60 ; : . ~ (E)-4-((2-(1-(4-Fluorophenyl)-3-methyl-2-naphth- : } alenyl]ethenyl]hydroxyphosphinyl]}-3-hydroxy-
Ss butanoic acid, dilithium salt
A. [2-(1l-(4-Fluorophenyl)-3-methyl-2- naphthalenyl]-2-hydroxyethyl phosphonic : : acid, dimethyl ester : Dimethv! =thyl phosphonate (24.21 mmol, : - 3.0 g, 2.62 ml} .as stirred under argon in dry THF ce 10 + (47 ml). This solution was cooled to -78°C and - : ~ then treated dropwise (15 min) with n-BuLi (22.70 : mmol, 9.08 ml of a 2.5 M solution in hexane).
This reaction mixture was stirred at -78°C for 1.5 n hours and then the resulting milky solution was treated dropwise (15 minutes) with a solution of the Example 59 Part G aldehyde (15.13 mmol, 4.0 g) : ’ in dry THF (14 ml). This reaction mixture was . stirred at -78°C for 45 minutes. Finally, the reaction mixture was quenched with saturated NH Cl (aqueous) (50 ml), warmed to room temperature, diluted with H,0 (50 ml) and EtOAc (50 ml). The oo aqueous layer was extracted 4 times with EtOAc.
The organic extracts were combined, dried over oo MgSO, , filtered, concentrated, azeotroped 2 times with toluene, evaporated in vacuo, and pumped ‘ under high vacuum to afford 5.90 g (15.13 mmol, 100% yield) of the title phosphonate as a yellow solid which was used directly in the preparation : of Part B compound. : " 30 TLC:Silica gel, PMA R=0.37 50% acetone/hexane } . Chota ; Co
HX10b -296-
B. (E)-[2-[1-(4-Fluorophenyl)-3-methyl-2- ©, naphthalenyl Jethenyl Jphosphonic acid, vo dimethyl ester . . The Part A f-hydroxyphosphonate (14.16 mmol, 5.5 g) was stirred under argon in 66.5 ml of . dry toluene. This solution was treated with paratoluene sulfonic acid monohydrate (TsOH-H,0) (3.54 mmol, 0.673 g). The reaction mixture was heated to reflux in a 135°C oil bath. The
TTT 710 condensate was passed through a soxhlet containing : dry 4R molecular sieves. After 16 hours at reflux additional TsOH-H,0 (2.12 mmol, 0.404 g) was added and the reaction mixture heated as above for an
Co . additional 8.5 hours. The reaction mixture was cooled to room temperature and diluted with 100 ml : _- oo ] of EtOAC. The mixture was then washed with 100 ml re Si of saturated NaHCO, (aqueous). “The aqueous layer
Lo was extracted 4 times with EtOAc. The organic
So extracts were combined, dried over MgsO,, filtered and evaporated in vacuo to afford 4.22 g of crude . vinyl phosphonate as a brown solid. The aqueous
CL layer was acidified with 5% HCl and then extracted i . 3 times with EtOAc. The organic extracts were : oo combined, dried over MgSO, filtered and ’ evaporated to afford 1.4 g ("3.92 mmol") of the vinyl phosphonate monoester as a light brown solid. This solid was stirred under argon in trimethyl orthoformate (15 ml) and heated to oo reflux in a 120°C oil bath for 16 hours. The : reaction mixture was cooled to room temperature.
The excess trimethyl orthoformate was removed in vacuo and the residue combined with the 4.22 g of crude vinyl phosphonate (above). The product
BAD ORIGINAL
HX10b : -297- was purified +» .: flash chromatography (75 mm diameter ccivi. 6" Merck silica gel, 100% EtOAc -, . Co eluent, 2"/ miu £low rate) to afford 3.70 g (9.99 ' mmol, 71% vield} of the title vinyl phosphonate as a peach solid.
TLC:Silica gel, PMA R=0.48 100% EtOAc oo
H NMR: (270 MHz, CDCl,) : 6 7.79 (4, 1H, J=8.4 Hz) 7.72 (s, 1H) . ” “10 "7.56-7.13 (m, 8H) ) 5.54 (dd, 1H, J=17.93 Hz, J=20.6 Hz) : 3.57 (d, 6H, J=11 Hz) : 2.54 (s, 3H) . Mass Spec: CI m/e 371 (M+H)* ; IR:(CHCl, solution) 3016, 2956, 2857, 1617, 1521, 1500, 1245, 1188, . 1162, 1071, 1047, 834 cmt.
Cc. (E)-[2-[1-(4-Fluorophenyl)-3-methyl-2- v naphthalenyl]ethenyl phosphonic acid, monomethyl ester : : The Part B vinyl phosphonate (9.72 mmol, "3.60 g) was stirred under argon in dioxane (23.5 ml) and treated with 1N LiOH (23.32 mmol, 23.32 ml). The reaction mixture was heated in a 75°C oil bath for 1 hour. Then, the reaction mixture ’ was cooled to room temperature and the solvents removed in vacuo. .The resulting residue was . diluted with 15 ml of H,0, cooled to 0°C and . acidified to pH=1 with 5% HCl (aqueous). The ” : aqueous layer was extracted 4 times with EtOAc.
The organic extracts were combined, dried over
MgSO, , filtered, concentrated, azeotroped 2 times
Bro ORIGINAL we LE a
_HX10b oo -298- : : . with benzene and evaporated in vacuo to afford . 3.38 g (9.48 mmol, 98% yield) of the title : phosphonate monoester as a peach solid. : - TLC:Silica gel, PMA R.=0.41 10:1:1 -
CH, Cl,/MeOH/ CH, COpH
H NMR: (270 MHz, CDCl,) - : 8 7.76 (d, 1H, J=8.4 Hz) 7.68 (s, 1H) BE 7.47-7.09 (m, 8H) - : 10 5.61 (dd, 1H, J=18.47 Hz, J=20.58 Hz) oo CT 3.48 (d, 3H, J=10.96 Hz) 2:52 (s, 3H) :
Mass Spec: FAB m/e 357 m+)" : IR: (CHCl, solution) . : 3025, 3008, 2951, ‘1614, 1605, 1511, 1494, 1235, SL . ‘1210, 1188, 1158, 1050, 987, 833 cm . } D. (E)-4-[[2-[1-(4-Fluorophenyl-3-methyl-2-
Lt naphthalenyl]ethenyl Jmethoxyphosphinyl]-
Co 20 3-oxobutanoic acid, methyl ester - oo
The Part C phosphonate monoester (9.12 ’ mmol, 3.29 g) was stirred under argon in dry : - : CH,Cl, (60 ml) and treated dropwise (10 minutes) with trimethylsilyldiethyl amine (TMSDEA) (18.24 mmol, 2.65 g, 3.45 ml, distilled). The reaction mixture was stirred at room temperature for 1.5 hours. The volatiles were removed on the rotavap - (vent to argon) and the residue pumped under high- : vacuum 40 minutes. Then, the residue was stirred under argon in dry CH,Cl, (25 ml). This solution tL was cooled to 0°C, treated with 2 drops of dry DMF, followed by dropwise addition (15 minutes) of : oxalyl chloride (10.94 mmol, 1.39 gq, 0.955 mol). , . ’ oo BAD ORIGINAL reo . . :
- [—
BX14, ~299-
The reaction mixture was stirred at 0°C for 20 ‘* minutes then warmed to room temperature and stirred "for 1 hour. The volatiles were removed and the : residue pumped as above. Finally, the residue was stirred under argon in dry THF (25 ml), cooled to © -78°C and maintained at -78°C as this solution was transferred via cannula to an addition furnel and : added dropwise (20 minutes) to a -78°C TH! solution of the dianion of methyl acetoacetate. This
Co 10 dianion was generated in the following manner: NaH (13.22 mmol, 0.317 g, 0.397 g of 80% mineral oil dispersion) was washed once with pentane, dried under an argon stream, and then stirred under argon * in dry THF (20 ml). This suspension was cooled to - 0°C and treated dropwise (10 minutes) with a - solution of methylacetoacetate (12.31 mmol, 1.43 gq, 1.33 ml) in dry THF (10 ml). The resulting clear solution was stirred at 0°C 8 for 20 minutes and was then treated dropwise (10 minutes) with n-BuLi (11.40 mmol, 4.56 ml of a 2.5 " M solution in hexane). The resulting yellow solution was stirred at 0°C for 45 minutes then ’ cooled to -78°C and treated dropwise with the . . -78°C THF solution of the phosphonochloridate » formed above. After the addition was complete, the reaction mixture was stirred at -78°C for 45 minutes. Then, the reaction was quenched with - saturated NH, C1 (aqueous) (50 ml), warmed to room . temperature, diluted with H,O .(50 ml) and EtOAc oo (50 ml). The aqueous layer was extracted 3 times " I with NaHCO, (aqueous) and once with CH,Cl,. The ‘organic extracts were combined, washed 3 times with } saturated NaHCO, (aqueous) and once with brine,
BAD ORIGINAL erred
CL i
HX10b - =-300- dried over MgsoO,, filtered and evaporated in vacuo oo to afford 4.0 g of a rust colored foam. Initial* purification via flash chromatography {40 mm BE diameter column, 20:1 Merck silica gel, 100% EtOAc eluent, 2"/min flow rate) afforded 2.0 g of slightly impure title keto-phosphinate as an orange } oil. Subsequent chromatography (30 mm diameter column, 25:1 Merck silica gel, 95% EtOAc/hexane eluent, 2"/min flow rate) afforded 1.95 g (4.29 > ~~ 10 - mmol 47% yield) of the title ketophosphinate as an orange foam. . .
TLC:Silica gel, PMA Rg=0.29 100% EtOAc R Lo
Ee: NMR: (270 MHz, cDCl,) Co ce oo . § 7.78-7.13 (aromatic, olefinic, 10H) ho 5.62 (dd, 1H, J=17.93 Hz, J=25.84 Hz) ; 3.71 (s, 3H)
BE 3.63 (s, 2H) 3.48 (4, 3H, J=11.6 Hz) 3.14&3.13 (2 x d, 2H, J=18.46 Hz) ’ } 2.44 (s, 3H) hE Mass Spec: CI m/e 455 (m+u)?
IR: (film) 1749, 1717, 1623, 1614, 1604, 1511, 1328, 1223, 1159, 1031, 834 cmt -25 .
E. (E)-4-[[2-[1-(4-Fluorophenyl)-3-methyl- 2-naphthalenyl ]ethenyl Jmethoxyphos- phinyl]-3-hydroxy-butanoic acid, methyl ester
The Part D ketophosphonate (2.82 mmol, 1.28 g) was stirred under argon in dry THF (12 ml).
This solution was cooled to 0°C and treated with -
NaBH, (2.82 mmol, 0.107 g), followed by dropwise ) BAD ORIGINAL ) ee pom meee :
: HX10b -301- : " addition of methanol (2.45 ml, dried over 44 - ’ molecular sieves). The reaction mixture was g stirred at 90°C for 1 hour, then quenched with 2.5 : ml of acetone. 1.3 g of CC-4 silica gel = (Mallinckrodt) were added and the reaction mixture ! was stirred as it was warmed to room temperature. : . Finally, the suspension was filtered through a : : fritted funnel, washed 2 times with EtOAc and 2 L times with CH,Cl,. The filtrate was evaporated - } 10 in vacuo to afford 1.3 g of an orange foam which Sees ~ crystallized upon addition of .EtOAc. The product was purified via flash chromatography (30 mm . - diameter column 30:1 Merck silica gel, 3% . MeOH/CH,Cl, eluent, 2"/min flow rate). Product fractions were combined, evaporated, and azeotroped one time with benzene to afford 0.653 g (1.43 mmol, 51% yield) of the title hydroxyphosphinate as a pale yellow solid. This : pure product was triturated from 7:3 EtOAc/hexane to afford 0.516 g of the hydroxyphosphinate as a : white solid. m.p.=132-134.5°C ’ N
TLC:Silica gel, PMA R=0.38 4% MeOH/CH, C1, 'H NUR: (270 MHz, CDCI) § 7.79-7.16 (aromatic, olefinic, 10H) 5.59 (2 x 4d, 1H, J=17.94 Hz, J=24.27 Hz) : 4.35&4.24 (2 x m, 1H) 3.70 (s, 3H) 3.49&3.47 (2 x 4, 3H, J=11 Hz) 2.58-2.53 (m, 2H) oo " 30 2.54&2.53 (2 x s, 3H) ~ 2.01-1.74 (m, 2H)
Mass Spec:CI m/e 457 (M+H)"
BAD ORIGINAL a
GO bl
. HX10b -302-
IR: (KBr) ~ Lo
IR 3422-3382, 3062, 3U51, 2951, 2926, 2913, 1738, : "1613, 1604, 1511, 1494, 1457, 1438, 1399, 1373, TE - 1330, 1311, 1307, 1286, 1220, 1194, 1177, 1160, Co 1092, 1077, 1035, £83, 833 cm Ll.
F. (E)-4-[[2-[1-(4-Fluorophenyl )-3-methyl- : 2-paphthalenyl ]ethenyl Jhydroxyphos- - phinyl]}-3-hydroxy-butancic acid;
To 10 dilithium salt B
The Part E diester (1.1 mmol, 0.50 g) was + stirred under argon in dioxane (10.45 ml) and . ~ treated with IN LiOH (3.3 mmol, 3.3 ml). The : .reaction mixture was heated in a 70°C oil bath for 45 minutes. The resulting white slurry was
Co dissolved in ~100 ml 9:1 H,0/MeOH and rotavapped to dryness at 35°C. The white solid was pumped under high vacuum for 1 hour, then redissolved in 100 m1 9:1 H,0/MeOH and rotavapped to a volume of ~8 ml. This turbid solution was applied directly Co a. oC to an HP-20 chromatography column (17.5 cm x 2.5 cm, equilibrated with H,0) and eluted with 250 ml - : - of H,0, followed by 45:55 MeOH/H,0. Fractions . CL oo were collected every 1.3 minutes (~10 ml). “ 25. Product fractions were combined, rotavapped at : 35°C, redissolved in H,0, lyophilized 16 hours and pumped under high vacuum over P,0g for 16 hours to afford 0.449 g, 1.02 mmol, 93% yield of the title dilithium salt as a white lyophilate. ’
TLC:Silica gel, PMA Rg=0.49 7:2:1 : - | (n-CyH,OH/NH, OH/H,0) :
CL Co BAD ORIGINAL
HX10b : : -303- : 1g NMR: (400 MH», -,0) ’ § 7.73 (4, Li, J=8.06 Hz) ; 7.64 (s, 1H) : ; :
Bh 7.43-7.39 (m, 1H) - : 7.25-7.13 (m, 4H) -
Bh 7.05-6.95 (m, 3H) . 5.62 (dd, 1H, J=17.96 Hz, J=21.2 Hz) ) 2.43 (s, 3H) . . 2.38 (dd, 1H, J=4.03 Hz, J=15.39 Hz) - ee 10 - 2.22 (dd, 1H, J=9.16 Hz, J=15.39 Hz) 1.59-1.51 (m, 2H)
Mass Spec:FAB m/e 429 (M+H)', 235 (M+rLi)™, 441 (M+20i)” : IR: (KBr) 3431 (br), 1603, 1593, 1511, 1494, 1423, 1221, 1158, 1050 cm”: | oo
Anal calcd for C, 3H, oFOgPLi, 0.87 moles H,0 i M.W.= 455.94: C, 60.60; H, 4.80; F, 4.17; P, 6.79
Found: C, 60.60; H, 4.73; F, 4.24; P, 6.83 B Co i 20 .
Example 61 (S)-4-[[2-[1-(4~-Fluorophenyl)-3-methyl-2-naphth- ’ alenyl ethyl Jhydroxyphosphinyl]-3-hydroxybutanoic oo acid, dilithium salt
Co 25 A. (S)-3-[[(1,1-Dimethylethyl)diphenyl-
Co | silyljoxy]-4-([2-(1-(4-fluorophenyl)-3- methyl-2-naphthalenyl]ethynyl jmethoxy-. phosphinyl Jbutanoic acid, methyl ester : } The Example 59 Part J acetylenic n 30 phosphinate (0.974 mmol, 0.675 g) was dissolved in methanol (14.3 ml). Argon was bubbled through : - this solution for 10 minutes, then 10% Pd/C (0.270 g) was added and the reaction mixture was shaken i Spo oo BAD ORIGINAL .
Co HX10b - a on a Parr hydrogenato: :'. 40 psi H, for 24 hours.
The reaction mixture was filtered through a celite : pad, washed through with methanol, and the oo filtrate evaporated in vacuo to afford a white foam. The product was purified via flash " chromatography (50 mm diameter column, 4.5" Merck . silica gel, 70% EtOAc/hexane eluent, 2"/min flow g rate) to afford 0.556 g (0.798 mmol, 82% yield) of the title saturated phosphinate as a white foam. -——————-- 10 Elution of the column with methanol afforded an CT additional 0.101 g. (0.145 mmol, 15%) of product.
TLC:Silica gel, PMA R.=0.24 60% EtOAc/hexane ’ a NMR: (270 MHz, CDCl;) . § 7.78-7.14 (aromatic, 19H) oo 4.44 (m, 1H) : 3.61 (s, 3H) 3.35&3.23 (2 x d, 3H, J=10.6 Hz) ; 2.92-2.83 (m, 1H) 2.63-2.54 (m, 3H) 2.21-1.27 (m, 4H) } 2.4582.42 (2 x s, 3H) SE 1.00 (s, 9H) . ‘ oo : Mass Spec: CI m/e 697 (+H) ¥ " IR:(CHCl, solution) 3028, 3019, 3007, 2997, 2953, 2933, 2859, 1735, 1510, 1497, 1472, 1463, 1439, 1428, 1378, 1364, 1314, 1236, 1197, 1157, 1142, 1112, 1091, 1073, 1065, 1043, 823 cml.
Co BAD ORIGINAL oo HX10b -305- : :
B. (S)-4-[[2-[l-(4-F}' .. phenyl)-3-methyl- -
Ca . 2-naphthalenyl jeth: i :methoxyphosphinyl]- oi oo 3-hydroxybutanoic acid, methyl ester :
B The Part A silyl ether (0.775 mmol; 0.540" oo g) was stirred under argon in 9.45 ml of dry THF and treated with glacial acetic acid (3.10 mmol, Co 0.186 g, 0.177 ml), followed by dropwise addition : of tetrabutylammonium fluoride (2.33 mmol, 2.1 ml of a 1.1 M solution in THF). The reaction mixture 10 ...was stirred at room temperature for 16 hours. The Lo i reaction mixture was quenched with 30 ml of ice water and diluted with EtOAc. The aqueous layer was extracted 3 times with EtOAc. The organic . extracts were combined, washed once with saturated : 15 NaHCO, (aqueous), one, time with brine, dried over ~ no MgsoO,, filtered and evaporated in vacuo. Initial - . : purification via flash chromatography .(40 mm . i diameter column, 6" Merck silica gel, 4% I Ca -
MeOH/CH, Cl, eluent, 2"/min flow rate afforded 0.40 : 20 g of a white solid. This solid was triturated . . - from 100% hexane, filtered and pumped under high vacuum (8 hours) to afford 0.317.g (0.691 mmol, . 89% yield) of the title hydroxyphosphinate as a white solid, m.p.=120-122°C. ‘ . ) 25 TLC:Silica gel Rg=0.12 2% MeOH/CH, Cl, lg MR: (270 MHz, cDCl,) - 8 7.76 (d, 1H, J=7.9 Hz) 7.69 (s, 1H) 7.42-7.16 (m, 7H) : " 30 4.4264.26 (2 x m, 1H) . 3.9263.84 (2 x d, 1H, J=3.16 Hz) 3.72 (s, 3H)
Cen ‘ BAD ORIGINAL
J
HX10b : ~306- 3.58&3.54 (2 x d, 3H, J=3.69 Hz) B 2.89-2.76 (m, 2H) . 2.56 (s, 3H) - 2.63-2.41 (m, 2H) - : - 1.92-1.61 (m, 4H) Co
Mass Spec:CI m/e 459 (+a)
IR: (KBr) : § 3428 (br), 3287 (br), 3064, 3050, 23017, 2989, - . 2952, 2921, 1737, 1603, 1510, 1497, 1458, 1438, - ew 10-1334, 1221, 1191, 1175, 1159, -1042, 826 cm 1. - Co
Cc. (S)-4~-{[2-[1-(4-Fluorophenyl)-3-methyl- . 2-naphthalenyl]ethyl Jhydroxyphosphinyl]- 3-hydroxybutanoic acid, dilithium salt. ’ 15 The Part B diester (0.687 mmol, 0.315 g) : was stirred under argon in dioxane (6.9 ml). The oe solution was treated with 1N LiOH (2.06 mmol, 2.06
Co ml). The reaction mixture was heated in a 70°C
SE oil bath for 45 minutes. The reaction mixture was co 20 cooled to room temperature. The solvents were removed on the rotavap at 35°C and the resulting
Co white solid pumped under high vacuum for 1 hour.
Then, the solid was dissolved in ~8 ml of distilled H,O and applied to an HP-20 , 25 chromatography column (16 cm x 2.5 cm equilibrated with H,0). The column was eluted with 250 ml of
H,0 followed by 45:55 MeOH/H,0. Fractions were a ‘ collected every 1.4 minutes (~10ml). Product . fractions (37-47) were combined, evaporated on the rotavap at 35°C, lyophilized 16 hours, and pumped under high vacuum over P,0g for 8 hours to afford : 0.286 g (0.647 mmol, 94% yield) of the title dilithium salt as a white lyophilate. . osu URIGINAL
HX10b -307-
TLC: «1.ica gel, PMA R.=0.42 7:2:1 : {n=CH;03i/NH, OF /8,0) : . : H NMR: (400 MHZ, D,0) . . 8 7.82 (d, 1H, J=8.06 Hz) Cd 7.76 (s, 1H) > 7.46-7.42 (m, 1H) Ce 7.30-7.25 (m, 3H) 7.18-7.13 (m, 3H) : 5 4.06 (m, 1H)
TT T10¢ '2.72-2.66 (m, 2H) oo 2.54 (s, 3H) ’ 2.34 (dd, 1H, J=4.4 Hz, J=15.22 Hz) 2.22 (dd, 1H, J=8.43 Hz, J=15.02 Hz)
Co. 1.59-1.51 (m, 2H)
CL 15. 1.44-1.39 (m, 2H) SE . Mass Spec: FAB m/e 443 (M+H)"
IR: (KBr) 3451-3426 (br), 3151, 3124, 1620, 1593, 1509, 1439, 1422, 1403, 1218, 1159, 1050 em™L. 0 Cee
Anal Calcd for C,H, ,FOgPLi, 0.60 moles H,O oo .
M.W. =453.09: C, 60.96; H, 5.16; F,. 4.19; P, 6.83
Found: C, 60.96; H, 5.29; F, 4.12; P, 6.82 : Example 62 4-[[3-[4'-Fluoro-3,3',5-trimethyl(1,1'-biphenyl]}-2- 41]propyl ]hydroxyphosphinyl]-3-hydroxybutanoic acid, dilithium salt
A. 3-[4'-Fluoro-3,3'5-trimethyl[1,1'- . biphenyl]-2-yl]-2-propenoic acid, 30 .- ethyl ester - Sodium hydride (4.96 mmol, 0.119 g, 0.149 g of an 80% mineral oil dispersion) was washed under ’ argon once with hexane and dried under an argon
BAD ORIGINAL
Ct ed Do iL
HX10b -308-~ : : " stream. Ti.., the NaH was stirred under argon in - © dry THF. {2.i ml). This suspension was cooled to . © 0°C and treated dropwise (5 minutes) with a - : solution of triethylphosphonoacetate {4,96 mmol, 1.11 g, 0.983 ml) in dry THF (2.2 ml). The . resulting clear solution was stirred at 0°C for 15 : minutes, then warmed to room temperature and ~ . stirred for 30 minutes. Finally, a solution of -
Example 1 Part C aldehyde (4.13 mmol, 1.0 g) in dry © iewwm—... 10 THF (2.5 ml) was added dropwise (8 minutes). The . ’ reaction mixture was stirred at room temperature , for 1 hour. The mixture was quenched with H,0 and the aqueous layer extracted 2 times with EtOAc and .- : 2 times with Et,0. The organic extracts were combined, washed once with brine, dried over }
Co MgSO, , filtered and evaporated in vacuo. The - product was purified via flash chromatography (50 : mm diameter column, 6" Merck silica gel, 6% ’ EtOAc/hexane eluent, 2"/min flow rate) to afford 1.19 g (3.79 mmol, 92% yield) of the title vinylic a. ester as a.pale yellow foam. Co
TLC:Silica gel, PMA Re=0.22 4% EtOAc/hexane lu Mm (270 MHz, cpCly) 6 7.64 (d, 1H, J=16.35 Hz) * 7.09-6.93 (m, SH) : oo 5.81 (d, 1H, J=16.35 Hz) 4.17 (q, 2H, J=7.12 Hz) 2.42 (s, 3H) 2.33 (s, 3H) oo ’ 30 2.28 (s, 3H) : ‘1.25 (t, 3H, J=7.12 Hz)
Mass Spec: CI m/e 313 (m+H)¥
Fe BAD ORIGINAL ; } . citi. 4
: HX10b - -309- : . B. 4'-Fluoro~-3,3',5-trimethyl{1l,1'- biphenyl}-2-butanocic acid, ethyl : oo ester L ; The Part A vinylic ester (3.68 mmol, 1.15 od g) was dissolved in absolute EtOH (36 ml). Argon was bubbled through the solution for 10 minutes. oe 10% Pd/C (230 mg) was added and H,(g) was bubbled : through the solution for 10 minutes. The reaction ) mixture was stirred under an atmosphere of H, for a + ein oo . --10.__2 hours. The reaction mixture was diluted with - SE
EtOH and filtered through a Lm Ccelite pad in a 60 : ml fritted funnel. The Celite was washed with
EtOH. The filtrate was evaporated in vacuo to
X afford 1.12 g (3.56 mmol, 97% yield) of the title . 15 saturated ester as a white solid. : v
TLC:Silica gel, PMA R.=0.29 5% EtOAc/hexane a mm (270 MHz, cpcly) 6 7.09-6.97 (m, 4H) : 6.84 (s, 1H) . 20 4.06 (q, 2H, J=7.12 Hz) | : 2.90-2.84 (m, 2H) : oo oo | 2.37 (s, 3H) 2.30 (2 x s, 6H) 2.32-2.27 (m, 2H) 1.20 (t, 3H, J=7.12 Hz)
Mass Spec: CI m/e 315 (+H) " ’
C. 4'-Fluoro-3,3',5-trimethyl(1,1'- : "biphenyl]-2-propanol ’ 30 Lithium aluminum hydride (3.5 mmol, 0.133 . 9) was stirred under argon in dry Et,0 (3.5 ml). -
This suspension was cooled to 0°C and treated dropwise (8 minutes) with a solution of the Part B —. pap ORIGINAL
’ HX10b -310- ester (3.5 mmol, 1.1 g) in J > %t,0 (3.5 ml). The a : reaction mixture was stirred at 0°C for 15 minutes, then warmed to rcom temperature and ’ stirred for 45 minutes. The mixture was again < cooled to 0°C and treated dropwise with 0.133 ml of H,0, followed by 0.133 ml of 15% NaOH and oo finally 0.399 ml of H,0. The suspension was warmed to room temperature over 30 minutes. The resulting white powdery solid was filtered and ; } ..... .. 10 washed with dry Et,0. The filtrate was - Sm me concentrated, azeotroped once with benzene and - stripped in vacuo to afford 0.950 g of alcohol : which was purified via flash chromatography (50 mm - diameter column, 6" Merck silica gel, 35% } ’ © 15 EtOAc/hexane eluent, 2"/min flow rate) to afford } 0.906 g (3.33 mmol, 95% yield) of the title alcohol as a colorless oil. : : ’ TL.C:Silica gel, PMA R.=0.18 20% EtOAc/Hexane a mm (270 MHz, cpcly) . 6 7.08-6.93 (m, 4H)
Co : ) 6.82 (s, 1H) oo © 3.45-3.40 (m, 2H) } 2.60-2.54 (m, 2H) * ‘ 2.34 (s, 3H) ’ 25 2.28 (2 x s, 6H) } 1.63-1.52 (m, 2H)
Mass Spec: Cl m/e 273 (M+H)" .
D. 2-(3-Bromopropyl)-4'-fluoro-3,3',5- trimethyl[l,1'-biphenyl] : A solution of triphenylphosphine (10.1 mmol, 2.65 g) in dry THF (27.5 ml) was cooled to 0°C and treated dropwise with a solution of carbon
BAD ORIGINAL | i
: . HX10b -311- tetrabromide (10.71 mmol, 3.55 g) i: --y THF (5.5 ml). The resulting yellow/white sluviy was E
B stirred at 0°C for 2 hours. The complex was CL . n ‘treated dropwise with a solution of the Part Cc - ; 5 alcohol (4.04 mmol, 1.1 g) in dry THF (8.2 ml). :
So oo The reaction mixture was stirred at 0°C for 1 hour, then warmed to room temperature and stirred - 16 hours. The reaction mixture was diluted with :
Et,0, filtered through a fritted funnel and the .
EO - 10 precipitate washed with Et,0. The filtrate was - Ce washed once with brine, dried over MgSO, , filtered, and evaporated in vacuo. The product : 3 was purified via flash chromatography (50 mm diameter, 6" Merck silica gel, 2Y% EtOAc/hexane ’ 15 . eluent, 2"/min flow rate) to afford 1.35 g (4.05 Co “ mmol, 100% yield) of the title bromide as a pale , yellow oil.
TLC:Silica gel, PMA R.=0.22 100% hexane Co : po oo ly NMR (270 MHz, cDC1,) 65 7.07-6.99 (m, 4H) : oo 6.82 (s, 1H) : . 3.22 (m, 2H) 2.69-2.63 (m, 2H) . 2.36 (s, 3H) 2.30 (s, 3H) : Co 2.28 (s, 3H) 1.90-1.80 (m, 2H)
Mass Spec: CI m/e 235 (M+H)'
Lo BAD ORIGINAL saanatil
PY10b -312~" : : E. [3-[4'-Fluoro-3,3',5-trim-:' , [1,1'~- biphenyl]-2-yl]propyl]phosj:honic : a acid, dimethyl ester _ : " The Part D bromide (3.88 mmol, 1.3 g) was stirred under argon in trimethylphosphite (38.8 " ml). The reaction mixture was heated to reflux in a 135°C oil bath for 36 hours. The excess (CH30),P was removed via short path distillation and the residue pumped under high vacuum at 100°C for 1 ~—s-ms= 0 = 10-"hour. The resulting yellow oil was subjected to Ce flash chromatography purification (50 mm diameter column, 6" Merck silica gel, 85% EtOAc/hexane eluent, 2"/min flow rate) to afford 1.13 g (3.10
CL | mmol, 80% yield) of the title dimethylphosphonate as a colorless oil: -
TLC:Silica gel, PMA, R.=0.28 100% EtOAc . la mm (270 MBz, cDCl,) +6 7.08-6.97 (m, 4H) : 6.81 (s, 1H) 3.65 (d, 6H, J=11 Hz) - 2.63-2.56 (m, 2H) . 2.34 (s, 3H)
C 2.30 (2 x s, 3H) - oo 2.28 (s, 3H) oo 25 1.68-1.50 (m, 4H) .
Co Mass Spec: CI m/e 365 (M+H)* ne ~ F. [3-[4'-Fluoro-3,3',5-trimethyl{l,1'-
Co : biphenyl ]-2-yl]propyl lphosphonic : no © 30 ~acid, monomethyl ester oo The Part E phosphonate (3.43 mmol, 1.25 g) . | was stirred under argon in dioxane (8.23 ml). oo - This solution was treated with 1N LiOH (5.15 mmol, . BAD ORIGINAL
: HX10b i -313- Co 5.15 ml) and heated in a 95°C oil bath. after 1 | : oo hour, an additional 3.43 mmol of LiOH were added : : and the reaction mixture again heated to 95°C for co 3.5 hours.- The reaction mixture was cooled to ] room temperature. The solvents were removad L . in vacuo. The white solid residue was diluted ; : with 25 ml of H,0, the slurry cooled to 0°C and ) acidified to pH=1 with 5% HCl (aqueous). The So - aqueous layer was extracted 4 times with EtOAc. i - 10 The organic extracts were combined, dried over -~—-- ~~ -
Co MgSO, filtered, and the filtrate concentrated. : The residue was azeotroped 2 times with benzene and the resulting viscous oil pumped under high : . vacuum for 4 hours to afford 1.18 g (3.37 mmol, i 98% yield) of the phosphonate mono-methyl ester as . a yellow oil. -
TLC:Silica gel, PMA, R.=0.46 10:1:1 ‘
CH,C1p/MeOH CH COR Lo ) :
H NMR (270 MHz, CDCl,) . 20 57.06-6.95 (m, 4H) 6.81 (s, 1H) Co 3.56 (d, 3H, J=11 Hz) 2.62-2.53 (m, 2H) . 2.32 (s, 3H) * : 2.27 (2 x s, 6H) 1.69-1.48 (m, 4H)
Mass Spec: FAB m/e 351 m+)" : G. 4-[[3-(4'-Fluoré-3,3',5-trimethyl(1,1'- " . 30 biphenyl]}-2-yllpropyl Imethoxyphosphinyl]- } . - 3-oxobutanoic acid, methyl ester
The Part F phosphonate monoester (3.22 mmol, 1.13 g) was stirred under argon in dry oo = BAD ORIGINAL
HX!cb -314- -
CH,C1, (12.9 ml). This solution was tre~i-=d dropwise (8 minutes) with TMSDEA .(6.44 m.cl, 0.918 : g, 1.20 ml freshly distilled). ‘This solution was stirred at room temperature for 1.5 hours. The : ~ 5 volaties were removed in vacuo (venting to oo argon). The residue was azeotroped once with 70 oo ml of dry benzene and evaporated in vacuo (venting : to argon). Finally, the residue was pumped under high vacuum for 50 minutes. Then, the residue was “ ——--- -—-- 10 stirred under argon in.dry CH,CI, (12.9 ml)... Two.. .. oo rom drops of dry DMF were added and the solution cooled to 0°C and treated dropwise (8 minutes) : with oxalyl chloride (3.70 mmol, 0.470 g, 0.323 : . ml). This reaction mixture was stirred at 0°C for - minutes, then warmed to room temperature and stirred for 1-3/4 hours. The volatiles were : removed; the residue azeotroped and pumped under ) high vacuum as above. The rust colored oil was
Co then stirred under argon in dry THF (9.0 ml).
RE 20 This solution was cooled to -78°C and maintained at -78°C as it was added dropwise (20 minutes) to : a -78°C THF solution of the dianion of : methylacetoacetate generated in the following . manner: Sodium hydride (4.85 mmol, 0.116 g, 0.145 g of an 80% mineral oil dispersiqn) was washed ~ once with hexane and dried under a stream of : ‘ argon... The solid was then stirred under argon in dry THF (7.1 ml) and this suspension was cooled to 0°C. A solution of methyl acetoacetate (4.36 mmol, 0.506 g, 0.471 ml) in dry THF (3.6 ml) was added dropwise (8 minutes) and the resulting clear solution stirred at 0°C for 25 minutes. Then, the reaction mixture was treated dropwise (10 minutes)
E | : BAD ORIGINAL . ud
( 3 HX10b -315~- : : with n-i.:Li (4.04 mmol, 1.62 ml of a 2.5 M soluticn in hexane, Aldrich). The resulitng yellow solution was stirred at 0°C for 35 minutes, . then cooled to -78°C and treated dropwise (20 min) - with the -78°C THF solution of the : " phosphonochloridate formed above. The reaction = mixture was stirred at -78°C for 1 hour, then quenched with saturated NH, Cl (aqueous) (45 ml) . and warmed to room temperature. The mixture was - _diluted with H,0 (45 ml) and EtOAc. The aqueous . a layer was extracted 4 times with EtOAc. The organic extracts were combined, washed once with saturated NaHCO, (aqueous) and once with brine, no . - dried over MgSO, , filtered and evaporated } in.vacuo to afford 2.0 g of a rust oil. The product was isolated via flash chromatography (40 mm diameter column, 35:1) Merck silica gel, 100% © EtOAc to 5% MeOH/CH,C1, "eluent, 2"/min flow rate to Loe afford 0.220 g (0.491 mmol, 15% yield) of the title p-ketophosphinate as a rust oil.
TLC: Silica gel, PMA R.=0.19 100% EtOAc ly wR (270 MHz, CDCL,) § 7.08-6.98 (m, 4H) " . 6.81 (s, 1H) : 3.73 (s, 3H) 3.65 (d, 3H, J=11 Hz) 3.64 (s, 2H) 3.10 (dd, 2H, J=5.27 Hz, J=17.41 Hz) 2.67-2.57 (m, 2H) oo 2.35 (s, 3H) ) - 2.30&2.28 (2 x s, 3H) 2.29 (s, 3H)
BAD ORIGINAL
: HX10b : -316- 1.72-1.56 {m, 4H) J = . Mass Spec: Ci w/e 449 (+H) oo oe H. 4-[[3-[4'-Fluoro-3,3',S-trimethyl(1,1"'~ | ) biphenyl]-2-yl]propyl Jmethoxyphosphinyl]- oo ~ : 3-hydroxybutanoic acid, methyl ester : : : The Part G:p-ketophosphinate (0.223 mmol, ) © 0.10 g) was stirred under argon in dry THF (1.9 a ml). This solution was cooled to 0°C and then " .. . 10 __treated with NaBH, (0.223 mmol, 0.008 g), followed So by dropwise addition of MeOH (0.194 ml, dried over ". 48 mol sieves). The reaction mixture was stirred : . at 0°C for 1 hour, then quenched with acetone oo. © (0.194 ml) followed by 0.10 g of CC-4 silica gel - oo 15 (Mallinckrodt). The suspension was stirred as it was warmed to room temperature, then filtered through a fritted funnel. The silica was washed ’
EE with EtOAc. The filtrate was evaporated in vacuo oo to afford 0.108 g of a golden oil. Two reaction oo 20 products were isolated via flash chromatography ) N (10 mm diameter column, 35:1 Merck silica gel, 4%
Lo MeOH/CH,Cl, eluent, 2"/min flow rate). The desired title B-hydroxyphosphinate was obtained in oo 58% yield (0.058 g, 0.129 mmol) as a pale yellow : 25 0il. Also obtained were 0.019 g (0.043 mmol 20% E : yield) of the 1,3-butandiol phosphinate. a TLC:Silica gel PMA Ry =0.19 3.5% MeOH/CH, C1, lH NMR (270 MHz, cDCl,) 5 7.08-6.98 (m, 4H) : 6.82 (s, 1H) : 4.44&4.32 (2 x m, 1H) 3.63 &3.62 (2 x d, 3H, J=10.55 Hz)
BAD ORIGINAL
HX10b -317- . ; : 3.70 (s, 3H) . 2.65-2.50 (m, 4H) : Cy EK 2.35 (s, 3H) - . 2.30 (2 x s, 3H) = 2.29 (s, -3H) Co 1.89-1.76 (m, 2H) : 1.71-1.59 (m, 4H) | -
Mass Spec: CI m/e 451, (M+H)' i eee 10 I. 4-[[3-[4'-Fluoro=-3;3';S=trimethyl{1l,1'=" ~~ biphenyl ]-2-yl]propyl]hydroxyphosphinyl]- + 3-hydroxybutanoic acid, dilithium salt -
The Part H diester (0.122 mmol, 0.055 g) 3 . was stirred under argon in dioxane (2 ml) and . 15 treated with 1N LiOH (0.366.mmol, 0.366 ml). The ; reaction mixture was heated in a 80°C oil bath for B 45 minutes. The reaction mixture was cooled to room temperature and the solvents. were removed on, the rotavap. The resulting yellow solid was pumped under high vacuum for 2 hours to afford the title dilithium salt as a yellow solid.
TLC:Silica gel, PMA R;=0.29 8:1:1
CH, C15/MeOH/CH; COR ]
H NMR (270 MHz, D,0) : 5 7.08-7.05 (m, 4H) \ 6.80 (s, 1H) ’ 4.13 (m, 1H) 2.54-2.47 (m, 2H) . 2.38-2.28 (m, 2H) 2.30 (s, 3H) » 2.22 (s, 3H) 2.20 (s, 3H) oo
BAD ORIGINAL
Co HX10b oo © =318- : 1.59-1.50 (m, 2H) ) oo 1.42-1.29 (m, 4H) : - So Example 63 - : [1S-[1<a(R*),2<a,4a<b,8<b,8a<a]]-4-[[2-[8-(2,2- - ’ Dimethyl-1l-oxobutoxy)decahydro-2-methyl-1-naphtha- lenyl]ethyl)hydroxyphosphinyl]-3-hydroxy butanoic { ; acid, dilithium salt ) ;
A. [1S-(l<a,2<a,4ac<b,8<b,8a<a)]-8-[[(1,1-
Tm TTT Dimethylethyl)dimethylsilyl]oxy}-- - Cee . Co 1,2,4a,5,6,7,8,8a~-octahydro-=2-methyl-1- naphthalenemethanol | ~
To dry Et,0 (5 ml) at 0°C (ice bath) was
R : added lithium aluminum hydride (132 mg, 1 molar Sn : 15 eq) followed by the dropwise addition of } oo [1S-(1<a,2<a,%a<b,8<b,8a<a)]-8-[[(1,1-dimethylethyl)- : dimethylsilylloxyl-1,2,4a,5,6,7,8,8a-octahydro-2- ‘ methyl-l-naphthalenecarboxylic, acid, methyl ester, . i R. L. Funk et al., Tetrahedron Lett. 25, 1655 : 20 (1984) (1.175 g, 3.47 mmole) in dry Et,0 (5 ml) and the resulting grey suspension stirred overnight under argon at room temperature. The mixture was quenched by the sequential dropwise addition of So ? * H,0 (130 pl), 15% NaOH (130 pl) and H,0 (390 pl).
Precipitated salts were removed by filtration : : through anhydrous MgSO, over packed Celite.
Evaporation in vacuo gave 1.112 g of -a clear oil : which was purified by flash chromatography on silica gel eluting with (95:5) Hexane-EtOAc to give 902 mg (85.7%) of desired title alcohol as a clear ’ oil which crystallized on standing, m.p. = 79-81°C. : TLC (9:1) Hexane-EtOAc, Rg=0.21.
TA
Lo BAD ORIGINAL
HX10b © =319- nl ' Anal Calcd for CygH,,0,Si: C, 69.61; H, 11.04 . 3 . Found: C, 69.64; H, 11.04
Co la nm (CDCL,) oo : ’ 8 0.00 (s, 6H) Lo :
Co 5 0.82 (s, 9H) oo : gy 0.83 (4, 3H) : ) : 0.94-1.05 (m, 2H) : 1.18 (s, 1H) oo ; 1.2-1.42 (m, 2H) i = 10 1.67 (m, 3H) ~~ © ~~ T= 1.89 (m, 1H) : - 2.25&2.37 (2H, 2 multiplets) 3.42 (bt, 1H) | N . . 3.80 (dd, 1H) . 3.93 (bs, 1H) | LL 5.29 (d, 1H) 5.48 (dq, 1H) ppm. :
B. [1S-(1<a,2<a,da<b,8<b,8a<a)]-8-[[(1,1- oo . 20 Dimethylethyl)dimethylsilyl]oxy]- 1,2,4a,5,6,7,8,8a-octahydro-2-methyl-1- naphthalenecarboxaldehyde
A solution of Dess-Martin periodinane (895 : mg, 2.11 mmole) in dry CH,Cl, (6 ml) was treated with dry t-C,H 0H (200 pl) and the white suspension stirred under argon at room temperature for 15 ’ minutes. A solution of the alcohol (596 mg, 1.92 mmole) in dry CH,Cl, (6 ml) was added dropwise . : over 5 minutes and the mixture stirred under argon at room temperature for 20 minutes. The mixture was added to a solution of sodium thiosulfate (2.12 g) in 1.0 N NaHCO, (12 ml) and the resulting mixture stirred until all solids dissolved. The
R
BAD ORIGINAL
. : i ; .
MX10b -320- Po
Co . organic phase was washed with saturatod NaHCO,
Vl. H,0 and brine then dried over aphydrous Na,SO, and : . evaporated in vacuo to give 1.005 g cf a colorless Ch oil. The crude product was combined with a : Co smaller run (1.306 g total) and then purified by Lo flash chromatography on silica gel eluting with Lo (98:2) hexane-EtOAc. Product fractions were : hE evaporated in vacuo to give 667 mg (75.7%) of i desired title aldehyde as a colorless oil. Ca
TIC (7:3) Hexane-Et,0, R.=0.70 PMA ~~ ~~ ©. lm mm (cpc1y): Lo | Co & 0.07 (s, 3H) Lo 0.00 (s, 3H) bo . | 0.85 (s, 9H) 0.89 (d, 3H) : Lo
EE 0.93-1.10 (m, 2H)
So 1.38-1.52.(m, 2H) : a
BR .1.58-1.78 (m, 4H) i a 2.31 (m, 1H) oo : 20 2.66 (m, 1H) : : 2.78 (m, 1H) oo 4.30 (s, 1H) 5.40 (d, 1H) oo 5.50 (m, 1H) 9.74 (d, 1H)
C. [1S-(l<a,2<a,da<b,8<b,8a<a)}-1-(2,2-
Dibromoethenyl)-8-{{(1,1-dimethylethyl)- dimethylsilyljoxy]}-1,2,4a,5,6,7,8,8a- - 30 octahydro-2-methylnaphthalene
A -15°C (salt/ice bath) solution of the -
Part B aldehyde (667 mg, 2.16 mmole) and triphenylphosphine (1.7 g, 6.48 mmole) in dry
BAD ORIGINAL
HX10b : - -321- : - ti,Cl, (10 ml) was treated dropwise over 5 wiiutes : with a CH,Cl, (5 ml) solution of carbon . tetrabromide (1.7 g, 6.48 mmole) and the deep oo reddish brown mixture stirred under argon at -15°C : 5 for 30 minutes, at 0°C for 2 hours and finally ~ overnight at room temperature. The mixture was recooled to 0°C, treated with additional : triphenylphosphine (567 mg, 216 mmol) followed by
CBr, (358 mg, 1.08 mmole) and stirred for 4 hours
CT 10 at room temperature. The mixture was quenched - ... Ce with saturated NaHCO, (10 ml), diluted with
CH,Cl,, the organic phase filtered through sintered glass, washed with saturated NaHCO, and : brine, dried over anhydrous Na,s0, and evaporated } : in vacuo to give 3.578 g of a brown solid. The : crude product was purified by flash chromatography ‘ on silica gel eluting with neat hexanes. Product B . fractions were evaporated to give 677 mg (67.3%) of pure title vinyl dibromide as a colorless oil.
TLC (9:11 Hexane-acetone, R=0.73 UV+PMA). la NMR (CDCl) 6 0.08&0.10 (2 singlets, 6H) 0.85 (d, 3H) . 0.90 (s, 9H) 0.98 (m, 2H) 1.25-2.52 (m, 5H) 1.74 (m, 1H) 1.82 (m, 1H) 2.39 (m, 1H) : . 30. 2.56 (m, 1H) : ] oo 2.66 (m, 1H) . 3.95 (s, 1H) 5.48 (4d, 1H) oo BAD ORIGINAL
: } HX10b : -322- Co 5.52 (w. 1H) ” ) 6.37 (<, 1H) ppm. : © D. [1S-(1l<a,2<a,4a<b,8<b,8aca)]-8-[[(1,1- * Dimethylethyl)dimethylsilyl]oxy]-1- : N ’ ethynyl-1,2,4a,5,6,7,8,8a-octahydro-2- ” . methylnaphthalene - . A -78°C (dry ice/acetone) solution of the .
Part C vinyl dibromide (495 mg, 1.07 mmole) in dry N “ome 10 THF (6 ml) was treated dropwise over 5 minutes _. . . with a 1.6 M n-BuLi in hexanes solution (1.34 ml, 2.14 mmole) and the clear, colorless mixture stirred for 30 minutes under argon at -78°C. The . mixture was quenched at -78°C by addition of : saturated NH, Cl (5 ml), allowed to warm to room Co temperature, diluted with EtOAc, the organic phase Ea washed with brine, dried over anhydrous Na,S0, and evaporated in vacuo to give 291 mg (89.6%) of : r : crude title acetylene as a colorless oil. o © 20 TLC hexanes R,=0.43, UV + PMA . la NMR (cDC1,) RE 5 0.08&0.12 (2 singlets, 6H) oo 0.90 (s, 9H) oo : © 0.99 (m, 1H) ? . 1.09 (4, 3H) : . 1.19 (m, 1H) 1.46 (m, 2H) 1.74 (m, 3H) oo | 2.12 (4, 1H) | oo oo 30 2.30 (m, 1H)
CL 2.41 (m, 1H) 2.71 (m, 1H) So . : : 4.37 (m, 1H) + BAD ORIGINAL ema cnn tn aa
‘ HX10b . -323- : 5.38 (4d, 1: 5.55 (m, 1H) :pm. i - :
E. (S)-4~(Chloromethoxyphosphinyl)-3- To : {{(1,1-dimethylethyl)diphenylsilyl]- - oxylbutanoic acid, methyl ester
Phosphonochloridate was prepared from the : -
Example 25 Part B dicyclohexylamine salt by the . : following procedure. The free acid was So ee 10 regenerated by partitioning the dicyclohexyl amine - salt (1.3 g, 2.05 mmole) between EtOAc and 5%
KHSO, , the organic layer was washed with 5% KHSO, : (4 times) and brine then dried over anhydrous
Na,so, and evaporated ‘in vacuo to give the free acid as a clear viscous oil.
The phosphonic acid monomethyl ester (2.05 mmole) was taken up in dry CH,Cl, (5 ml), treated . with distilled N,N-diethyltrimethylsilylamine (515 pl, 4.1 mmole) and the clear, colorless solution : stirred at room temperature under argon for 1 hour. Excess reagent and solvent was removed in vacuo, the residual oil chased with benzene (2 x 10 ml). : : The crude silyl ester (~2.05 mmole) in dry
CH,Cl, (5 ml) and dry DMF (1 drop) was cooled to 0°C (ice bath) and treated dropwise with distilled oxalyl chloride (195 pl, 2.26 mmole) and the yellow mixture stirred under argon at 0°C for 15 minutes and at room temperature for 45 minutes. ’ 30 The mixture was evaporated in vacuo, chased with dry benzene (2 x 10 ml) to give crude title phosphonochloridate as a viscous yellow oil.
AD ORIGINAL
HX10b . - F. [1s-[1<a(R*}.<a,4a<b,8<b,B8a<ca]]-4- } [[{8-[[(1,!-<imethylethyl)dimethyl- : : silylloxy}-1.2,4a,5,6,7,8,8a~octahydro- - oo 2-methyl-l-naphthalenyl]ethynyl]- oo 5 methoxyphosphinyl]-3-[[(1,1-dimethyl- ethyl)diphenylsilyl]}oxy]butanoic acid, a methyl ester : ; A -78°C solution of the Part D acetylene oo (356 mg, 1.17 mmole) in dry THF (5 ml) was treated ~~. 10 dropwise with a 1.6 M n-BuLi in hexanes solution - - - mr —oun oo : (730 pl, 1.17 mmole) and the clear mixture stirred 3 under ‘argon at -78°C for 30 minutes. The acetylenic anion was then transferred via cannula . dropwise over 15 minutes to a -78°C solution of ; 15 the Part E phosphonochloridate in dry THF (6 ml). :
The yellow mixture was stirred 30 minutes at -78°C ‘ then quenched by dropwise addition of saturated )
I NH, Cl (5 ml) and allowed to warm to room : : temperature. The mixture was partitioned between - 20 EtOAc and H,0; the organic phase washed with brine, dried over anhydrous Na,SO, and evaporated in vacuo to give 1.282 g of a pale yellow oil.
The crude product was purified by flash :
Ce chromatography on silica gel eluting with (7:3) = hexane-EtOAc. Product fractions were evaporated to give 624 mg (72.4%) of title acetylenic : phosphinate as a colorless glass.
TLC (7:3) Hexane-acetone, R.=0.49, Uv + PMA.
BAD ORIGINAL trsnicelt
HX10b -325-~ :
G. [1s-[1<a(R*),2<~,#:.<b,8<b,8a<al}-4-[[2~ ‘ (8-[[(1,1-Dimeti:;:-thyl)dimethylsilyl]- : oxy]decahydro-2-methyl-1-naphthalenyl]- ethyl Jmethoxyphosphinyl]-3=[[(1, 1- : dimethylethyl)diphenylsilyl)oxy]butanoic - acid, methyl ester
A solution of Part F acetylene phosphinate : oo "(498 mg) in CHLOH (6 ml) was treated with 10% Pt/C (200 mg) and the black suspension shaken on a Parr _ .... _..10 apparatus under H, (40 psi) for-48-hours. -.The - — .' catalyst was removed by filtration through Celite, : the reaction mixture charged with new catalyst " (150 mg) and shaken on the Parr apparatus under H, (40 psi) for an additional 24 hours. Catalyst was . 15 removed by filtration through Celite and the filtrate evaporated in vacuo to give 448 mg of a : . clear glass. The crude product was purified by flash chromatography on silica gel eluting with (8:2) Hexane-EtOAc. Product fractions were 3 evaporated in vacuo to give 334 mg (66.5%) of - title compound as a colorless glass. . TLC (7:3) EtOAc-Hexane, Re 3 diastereomers as one spot=0.42, Re 4th diastereomer as one spot=0.49, . + UV + PMA. ”5 .
H. [1S-[1<a(R*),2<a,4a<b,8<b,8a<al]-4- ‘ [[2-(Decahydro-8-hydroxy-2-methyl-1- naphthalenyl)ethyl ]methoxyphosphinyl]- 3-[[(1,1-dimethylethyl)diphenylsilyl]- . 30 oxy ]butanoic acid, methyl ester
A solution of Part G compound (248 mg, "- 0.334 mmole) in CH4CN (4 ml) was treated with 48%
HF in H,0 (36 pl, 1 mmole) and the mixture stirred
AL
Ch BAD ORIGIN a
HX10b : -326- " for 6.5 hours under argon at :r... Lemperature.
The mixture was partitioned bei. ..n EtOAc and : E . saturated NaHCO, the organic phase washed with brine, dried over anhydrous Na, So, and evaporated in vacuo to give 227 mg of a colcrless glass. The crude product was purified by flash chromatography . on silica gel eluting with (4:1) Hexane-EtOAc followed by neat EtOAc. Product fractions were evaporated in vacuo to give 159 mg (75.8 %) of + ——- -——-10 pure title mono alcohol -as a colorless oil. Cn
TLC (7:3) Acetane-Hexane, R;=0.5 (UV (weak) + PMA.
I. [1S-[l<a(R*),2<a,4a<b,8<b,8a<a]]-3- ; [[(1,1-Dimethylethyl)diphenylsilyl]oxy]- ’ 15 . 4-((2-(8~(2,2~dimethyl-1-oxobutoxy)- decahydro-2-methyl-l-naphthalenyl]ethyl]- ) methoxyphosphinyl]butanoic acid, methyl . ester
A solution of the Part H alcohol (147 mg, : 20 0.234 mmole) in dry pyridine (1.5 ml) was treated
Ce with 2,2-dimethylbutyryl choride (160 pl, 1.17
Sr : mmole, 5 eq.) followed by 4-dimethylaminopyridine
CL . (3 mg, 0.1 eq) and the pale yellow mixture heated os = so at 100°C under argon for 4 hours. The mixture was *
CL 25 cooled, partitioned between 1.0 N HCl and EtOAc,
CL the organic phase washed with 1.0 N HCl (2 times) oo and brine, dried over anhydrous Na,s0, and : evaporated to give 255 mg of a pale, yellow brown oil. The crude product was purified by flash "30 chromatography on silica gel eluting with (55:45)
Hexane-EtOAc. Product fractions were evaporated in vacuo to give 112 mg (65.9%) of desired title - dimethyl butyryl ester as a colorless oil. -
BAD RENAL
HX10b -327-
Hexane-acetcr: +, 0.62, UV + PMA.
J. [1s8-[l<a(R*),2<a,4a<b,8<b,8a<al]-4- oo [[2-[8~{2,2-Dimethyl-1-oxobutoxy)- - decahydro-2-methyl-l-naphthalenyl]ethyl]- methoxyphosphinyl]-3-hydroxy-butanoic acid, methyl ester : A solution of the Part I silyl ester (130 mg, 0.179 mmole) in THF (2 ml) was treated succes- :
To "10 ‘sively with glacial acetic acid (HOAc) (41 pl, 0.716 _ mmole) and a 1.1 M (n-C,Hy) NF solution in THF (490 pl, 0.537 mmole) and the mixture stirred overnight under argon. The mixture was partitioned between . no EtOAc and 5% KHSO, , the organic phase washed with
H,0 and brine, dried over anhydrous Na,sO, and evaporated in vacuo to give 115 mg of a colorless oil. The crude product was purified by flash : chromatography on silica gel eluting with (1:1) hexane-acetone. Product fractions were evaporated in vacuo to give 72 mg (82.4%) of desired title alcohol as a colorless oil.
TLC (1:1) Hexane-acetone, R¢=0.20, Uv + PMA. : K. [lS-[l<a(R*),2<a,4ac<b,b8<b, 8aca]l]-4- [[2-[8-(2,2-Dimethyl-1-oxobutoxy)~- decahydro-2-methyl-l-naphthalenyl]ethyl]- hydroxyphosphinyl]-3-hydroxy-butanoic acid, dilithium salt
A solution of Part J alcohol (72 mg, 0.147 30. mmole) in dioxane (1.5 ml) was treated with 1.0 N © LiOH (0.52 ml) and the mixture heated at 55°C (oil bath) under argon for 1.5 hours. The mixture was cooled, diluted with H,0, filtered and evaporated : BAD ORIGINAL ar
: HX10b -328- - in vacuo to a: il. The crude product was - chromatographs=u on HP-20 resin (3 cm bed, 15 mm sv diameter colwn:j eluting with H,0 followed by : (70:30) H,0-CijCH. Product fractions were : 5 evaporated in vacuo, dissolved in H,0 (20 ml) and lyophilized to give 55 mg (74%) of desired title : dilithium salt as a white solid. : TLC (8:1:1) CH,Cl,-CH,OH-CH COOH, R.=0.05, PMA. . Anal Calcd for C,3H340,PLI,+1.78 moles H,0 (MW meee . 10 504.53): C, 54.75; H, 8.50; P, 6.14 EE
Found: C, 54.75; H, 8.64; P, 5.93 :
Example 64 . (S)-4-[[[3'-(4~Fluorophenyl )spiro[cyclopentane- . 15 1,1'-[1H]indene}-2-yl]ethynyl Jhydroxyphosphinyl}-3- hydroxybutanoic acid, dilithium salt
A. 3-(4-Fluorophenyl)-1H-indene . To a sblution of solution of 4-fluorophenyl- magnesium bromide (prepared from 6.43 ml of = 4-fluorobromobenzene and 1.71 g of Mg in 50 ml of ether) at room temperature under argon was added dropwise over 40 minutes a solution of l-indanone . (6.61 g, 50 mmole) in dry ether (20 ml). After ) stirring at room temperature for 1 hour, the reaction was quenched by the dropwise addition of
Co saturated NH,Cl solution (15 ml). The mixture was diluted with Et,0, washed with saturated NaCl solution, dried (MgSO, ) and evaporated.
The residue was taken up in glacial acetic : 30 acid (15 ml) and refluxed under argon for 30 minutes. The acetic acid was evaporated off and chased twice with toluene. The residue (9.45 g) was purified by flash chromatography on silica gel
I i Tet . }
Co BAL urlINAL \ Cn
SE :
oo HX10b " eluting with hexane tc i e title compound (8.174 . g, 78%) as a colorless -!1 which crystallized:.on standing, m.p. 38-40°C ii.C (hexane) Rg=0.21." :
B. 3'-(4-Fluorophenyl)spiro[cyclopentane- 1,1'~-[1H]indene] : } . To a solution of Part A compound (10.676 gq, 50.8 mmole) in dry THF (90 ml) at 0°C under argon was added, in porticns, solid potassium t-butoxide (12.2 g, 109 mmole). After stirring at 0°C for 30 minutes, 1,4-dibromobutane (6.50 ml, 101 mmole) was added dropwise. The resulting mixture was "allowed to warm to room temperature, stirred for 2 . hours, then partitioned between EtOAc-5)% KHSO, } (150 ml each). The organic phase was washed with saturated NaCl solution, dried (Na,SO,,) and evaporated to: dryness. The crude product was purified by flash chromatography on silica gel, eluting with hexane to give title compound (9.439, 70%) as a colorless oil. TLC (Et,0-hexane; 1:9) i } R.=0.69 (Rg of Part A compound = 0.63). . C. 3'-(4-Fluorophenyl)spiro[cyclopentane- 1,1'-{1H]indene}-2"'-carboxaldehyde
To a solution of Part B compound (9.30,49, 35.2 mmole) in dry CH,Cl, (50 ml) at 0°C under argon was added a 1.0 M solution of TiCl, in
CH,C1, (70 ml, 70 mmole). The resulting dark . green solution was treated dropwise with. 1,l-dichloromethyl methyl ether (3.50 ml, 38.7 : mmole). After stirring at 0°C for 1 hour and at room temperature for 1 hour, the mixture was poured onto cold, saturated NaHCO, solution. The oo gaD ORIGINA : ey
J Ce
. . HX10b ~33: : organic phase was separatcd, sried (Na,S0,) and : . evaporated to dryness. Th= «iude product was : purified by flash chromatography on silica gel : eluting with Et,O-hexane (5:95) to give title ) compound (8.233 g,; 80%) as a yellow oil.
Crystallization of the oil from hexane gave pure title compound (6.778 g, 66%) as pale yellow : crystals, 116-117°C. ;
TLC (Et,O-hexane; 15:85) R;=0.56. . . eevieeo.. 10 Anal Calcd for C, H,.OF: C, 82.17; H, 5.86; F, 6.50 See
Found: C, 83.13; H, 5.82; F, 6.29
D. 2'-Ethynyl-3'-(4-fluorophenyl)spiro- [cyclopentane~1,1'-[1H]indene : v oT 15 To a solution of potassium t-butoxide : © (0.672 g, 6.00 mmol) in dry THF (8 ml) at -78°C h under argon was added dropwise a solution of :
LT dimethyl diazomethylphosphonate (0.960 g, 6.40
YL mmole, prepared as in J. Org. Chem. 36, 1379 :
PEE 20 (1971)) in THF (4 ml). After stirring at -78°C for 5 minutes, a solution of Part C compound (1.168 gq, . Co 4.00 mmole) in THF (8 ml) was added dropwise over minutes. After stirring at -78°C for 3 hours, y -45°C for 1.5 hour and at room temperature for 1 - 25 hour, the mixture was diluted with hexane (50 ml) and washed with 5% KHSO, solution. The organic . phase was washed with saturated NaCl solution, dried (Na,S0,) and concentrated to a small volume . (not to dryness). The yellow solution was flash chromatgraphed on silica gel eluting with hexane.
The product containing fractions were combined, ~ treated with butylated hydroxytoluene (BHT) (0.080 g, 0.36 mmole) and concentrated to a small volume : oo : BAD ORIGINAL oo a etme posses rn mn mmm mmr mn nT - : .
: HX10b -331- (5-10 ml) which was used immedi... ‘y as a solution nl -, for the next step. TLC (Et,0-heruie; 1:9) Rg=0.57. .e H NMR (270 MHz, CDCl,) using BHT as an internal
Co standard (1.45 ppm, 18H, s) shows the presence of . 3.10 mmoles (77.5% yield) of the desired acetylene (3.32 ppm, 1H, s).
E. (S)-4-(Chloromethoxyphosphinyl)-3- - [[(1l,1-dimethylethyl)diphenylsilyl]}-
CT L100 ee oxy]butanoic-acid, methyl ester
Title phosphonochloridate was prepared from ) the Example 25 Part B dicyclohexylamine salt (3.44 : g, 54.4 mmole) as described in Example 29, Part J . using the following quantities; trimethylsilyl- diethylamine (1.36 ml, 10.85 mmole), CH,Cl, (15 ’ ml); oxalyl choride (0.50 ml, 5.73 mmole), DMF (1 drop), CH,Cl, (15 ml).
F. (S)-3-[[(1,1-Dimethylethyl)diphenyl- silyl]oxy]-4-[([{3'-(4-fluorophenyl)- spiro[cyclopentane-1,1'-(1H]indene]-2- yl]ethynyl Imethoxyphosphinyl]butanoic i acid, methyl ester _
The hexane solution of the Part D acetylene . (3.10 mmole + 0.36 mmole of BHT) was diluted with dry ’ THF (15 ml) and cooled to .-78°C under argon. The solution was then treated with a 1.6 M solution of n-BuLi in hexane (2.16 ml, 3.46 mmole) dropwise via syringe. After stirring at -78°C for 45 minutes, the anion solution was transferred via cannula-to a -78°C solution of Part E phosphonochloridate (54.4 mmole) in dry THF (15 ml). After stirring at -78°C for 1 hour, the reaction was quenched by the 4 : aes
HX100 ) : -332- : . dropwise addition of saturated NH, Cl (i% .:) and . allowed to warm to room temperature. The iiixture Le ’ was extracted with EtOAc, the extracts washed with ne 59% KHSO,, , saturated NaHCO, and saturated NaCl : - solutions, dried (Na,S0,) and evaporated to dryness. The crude product was purified by flash: chromatography on silica gel eluting with ]
EtOAc-hexane (25:75) to give title compound (1.781 g, 80% based on Part D compound) as a pale
TTT TTT 10 TTyellow glass. co oC
TLC (acetone-hexane; 1:1) Re=0.46.
G. (S)-4-[[[3'-~(4-Fluorophenyl)spiro[cyclo- . pentane-1,1'-[1H]indene]-2-yl]ethynyl]- . methoxyphosphinyl }-3-hydroxybutanoic - acid, methyl ester _
To a solution of Part F compound (1.00 gq, oo 1.39 mmole) in dry THF (5 ml) at room temperature } : under argon was added glacial acetic acid (0.32 ml, : 5.59 mmole) and a 1.1 M solution of (n-C,Hy),NF in oo
THF (3.80 ml, 4.18 mmole). After stirring at room temperature for 18 hours, the mixture was diluted ’ with EtOAc (50 ml) washed successively with 1N HCl (3 x 30 ml) and saturated NaCl solutions, dried (Na,s0,) and evaporated to dryness. The residue . was taken up in Et,0 (20 ml), cooled in an ice bath and treated with excess etheral diazomethane.
The residue obtained by evaporation of the ether was purified by flash chromatography on silica gel : 30 eluting with acetone~hexane (3:7) to give title ! compound (0.595 g, 89%) as a colorless glass. ; TLC (acetone-~hexane; 1:1) Re =0.29. } : po | BAD ORIGINAL
SL a
HX10H -333-
H. (S)-4-(([3'-(4-Fluorophenyl)spirn- [cyclopentane-1,1'~[1H]indene]}-2~ : yllethynyl]hydroxyphosphinyl]-2- hydroxybutanoic acid, dilithium salt
To a solution of Part G compound (0.580 g, : 1.20 mmole) in dioxane (6 ml) at room temperature : under argon was added 1N LiOH solution (2.2 ml, 4.2 mmole). After stirring at room temperature
U7 10 for 3 hours, the mixture was diluted with — - = acetonitrile (20 ml), the white preciiptate was - collected, washed with acetonitrile and dried in vacuo to give crude title product (0.670 g) . : as a white solid. The crude product was suspended : 1s in water (10 ml) and applied to a short pad of i
HP-20 (15 ml bed volume, 1 inch diameter), eluted with water (300 ml) followed by MeOH (300 ml). . The product containing fractions were combined and evaporated to dryness. The solid residue was . triturated with acetonitrile to give pure title product (0.550 g, 98%) as a white solid, mp : 301-303°C (decomp). :
TLC (i-C3HjOH-concentrated NH,OH-H,0; 7:2:1) Rg=0.48.
AD ORIGINAL
Lo : amet -
So a
Co : : es Ede . . oo —_— 24 : CFR So cat eno . : - i ; SE eT aia et
E “3: 3 3 ’ : Co I Alf 0 AL Lt Ne ey . Te . - Le 3 Le 5% 1 pa yg rd ria Sa Akan oH Api Add hair Eh Ae dud) kl Lg rt ca i LE eye 4 igs ® SAR [EE a B
Examples 65 to 122
Following the procedures as outlined heretofore and as described in the previous i ‘ working Examples, the following additional i 5 compounds may be prepared. . ty lo] H :
No x - R-P-C p-S-CHy=C0p7R : x OH :
Cb 10 z . - ’ i oh pb 1 § ’ - - 8 ll : i : | . . i ! : : .
A :
Al : oo : ’ . ’ ’ . . ; oo BAD ORIGINAL
. ~-33 HX10b
Ex. ’ : ‘ 65 OCH F CH_-CH cH 0. 3 ToL -Hp TCH, 3 er cL : cL 66. OH 0) c1 -czc- H ve
C,H : CH, CH, 67. OLi : -CH,CHCH,~ Li cH,
Oa : 68. OH ~CH,0- H
GINAL pAD OR! .
-336- HX10b . . Ex. . : © xX ’ No. _R zo X R 69. oLi 0) : ~CH CH CH, = Li ol, = NX
CH, CH, fs } Lo
CH-CH, . 70. OCH, Cr -CH,CH,CH,- CH,
NO : . . F ‘ - } 3 ; - -CH,_- OK : . 71 OK C,H cx CH,
C=0 1 oo 0° . - " - ’ ’ co : . H CH,
Lo . CH,
LA 72. ONa CH. - Na 2 }
J wr ORIGINAL ] ’ } ied
- 337- 1X10b
Ex. ’
No. __R ___z x R"
Ce . 73. oH (0)—cuyo ~CH CH, H. : ‘ cd 74. OH FAT GO ~CH,CH, CH, ~ H
ER ce ch. cu, © oo 3 3 C H . : : 2"s a HO . 75. CH,0 (o)- -CH,,~ CH, 76. CH 0 -CH,0- H
BN r . . “ 77. 7 oH : CH,CH, H : BAD ORIGINAL . Ce yo as .
. - 338- - EXIoD
IX. ) : a x
Oe R Zz _. . no ve - __ RR : 7 ) ~CH=CH- . . 8. OH oo H.C CH, CH H : ‘ F CH CH H 79. OH - = ’
TL /H3 22 ~ : NSH, BN ‘ . . . * F . 80. Nao ’ $ CH -CH=CH~ Na : i ” - : ' . -— N CH, . ) 81. 0 F - -c=c- Ca ) £3 rE 0
CH, . .
Co BAD ORIGINAL
- 339- HX10b
Ex. ’ “No. on z Xx Ho
Le +. 82. HO F ~-C=C- H :
Al fo a 3 N C-CH, : 83. Nao CH -C=C- Na : N\_c-cH ys nu 3 . CH 7 \
CH, CH, : 84. CH,0 CH, -CH=CH- H
FH
. 3 CH \ 3
H,C H . . }
A CH, " CH 85. CH.O - _ 3 ©) o / 3 CH,CH, NH, c CCH, :
Hy Vs H pa
Co HX10b
Ex.
No. R Co ns ® —E
CH Sc 86. HO 3 FH Ha” ‘ | } . I / 3 2 . ~~ — C-CH Ce [ H 3
Teme eee CF, . © re . or on, CH,CH, CH, ca : © y— c-cH
Ys H 3 : oo Fi Co - wo. cro (DON Nden, cn, —C-CH,,
CH, + 89. H gr / -CH_- H
C-CH a 3
BAD ORIGINAL eee a asd
- 300 HX10b ’ Ex. ’
No. _R__ ___ 7 x __R - 90. CH,0 ©) Is JRE © —-CH=CH- H . : : NX (en
C91. HO F 2 Fis ~CH=CH~- H
Y—c-ch, :
CH,
F Hy . 92. CH,0 0 NIE ~CH,,~ CH, . Ws +H 3 . CH 0 i * . F | CH, . Li 93. LiO 20 eo 7 ~CH,CH,,CH,~
C-CH
Wg g 3 cl : BAD ORIGINAL ttl
Coin bd
- 342- b.10b
Co Ex. ’ = . . Nn. __ RR _____ 0 z 0. x _R_ . oN . * } i
Co : RE } -CH_CH..- Po. . 94 KO «FH CH,CH,, K j
C-CH :
Ws #3 ; : : : CHy 95. HO .F CH ~CH=CH- H : ~ / 3 )
CH, : Wed 3 : CH :
Cot i c | oo
B ~ . of, CH, - F . 96. HO © FHy -c=C- H ~ / : : C-CH :
Vs H 3 to - Le - * CH ; co | 3 . 97. HO CHA -csc- H : . / 7 — — F + CH, (=
LCE } ’ : CH CH, 3
Cp to .
REE . BAD ORIGINAL a IN . forme es meen _ = - ce . : .
~ 343 HX10b . C.-. - © vw. RR _ ___ oz 0X RT
Ce ] : , ’ CH, 98. Lio -Cc=C- LE a-aca
CH, | N
Co 99, Lio ® 5 F ~CH,- Bi - \
N
CH
. / NN
CH, . CH,
Hy 100. HO on ~CH, - H / ’\
CH, © f - ~ . F 101. HO ~CH, CH, - H
Clo : . cl
CH
~N } 4 CH, 3 . i Lee s
BAD ORIGINAL
VHA =r Ca | ’
LIARTT te
; T 344- HX10b .
Ex. : ) .
SNe. _ Roz % RE r } 102. Nao Co -cHcH- va : So CH,0,C
CH,0,C : cH CH, : CH, . oo
F . : 103. Lio -CH, CH, ~ Li i . ’ Br : . ~ N- . Br
Gi chy . : , } CH,
Co F 104. HO cH, - H
SEER oo
Bh n Br \ . “fo CH,
Cr. CH, . * ’ : F ' ) . 105. CH, ~CH, CH, - ch, ) CH}0,C_ . ~,N-
CH.0.C : Lo 32 CH— CH . 3 . i | /
Co : CH,
DE BAD ORIGINAL
: - 345- HX10b :
Ex.
No. _R__ zx __R 106 HO /F : -CH_CH,~- H ’ 272
N- : CH— CH ; 3 : /
CH, . } F } 107. HO -CH,CH,CH, - H cl . cl . : CH — CH 3 /
CH,
F } 108. KO -CH,CH,- K ; cl “Y- cl
CH, - - .
F
. 109. HO ~CH,CH, = H
Br ~ N- . By
CH — cH, : 2 . / 7
CH
2 . +
RATS ITE a BAD ORIGINAL d .
= 346- HX10b
Ex. ’ : go. Roz 0000 x RB . } ’ + . :
F = Co } 110. Lio ©) ~CH=CH ~ Li c=Cc :
Nien 13%
Cn x0 QL TCH, CH= K _ el oo : © i-C3H, cH, oo
F
112. rio © -CH=CH- Li [3 . 7 . =C ] : * } Ne u : 2"s cL . or F : CH, : CH,0 113. cH TQ “CH=CH- cH, c=c Lo i Neon : 3 : : CH, oo - ae BAD ORIGINAL fT ’ . .. — se . i .
— HX10b
Ex.
No. Rex RE . CL F } : 114. OH . -CH.- - = H :
Pe . 2 ’
CH. > o 3 pp . F or 115. Lio Jou a -czc- Li . : cH, N° cH, ‘ 116 LiO F Li . . i ~ CH, ~CH,CH,- Li
CHy 117. LiO -C=C- Li a
CH NTN ~~ 3 CH . CH, 118. LiO SL -CH_CH_- Li - 2772
CH, N-3y~ CH \cH 3
BAD ORIGINAL
> . Cw sb
— — Lo — - 348- HX10b } Ex. ’ . ‘ ‘No. _R ze Xx _R oo | o : 119. Lio ToL CH -czC- Li oe . way cl . ~~ oo F oo 120. LiO ToL . CH, ~CH,CH,- Li
Co yA CH oo CH . . : ’ F. R oo : 121. LiO _CHy =CZc— = Li
PL
. : S “CH i . = N 3 : } a. GS 122. LiO F CH, ~-CizC- Li . i | TL CH, = . : N Ar CH ~cu : cn ,0 ; \ -
ER | BAD ORIGINAL

Claims (1)

  1. CLAIMS . 1. An intermediate having the structure: 0 0 } . or . . I R a”P-CHp CH CHp 005 (01 ~Crp Tatil rl, A Cg CgHs including all stereoisomers thereof, where RY, is C1-Cyo alkoxy or hydroxy; rly is hydrexy, Cl, -C=C-Z, -CH,-Z, -CHyCH,yCHy-Z, -CH,0-Z, -CH=CH-Z or -CH,CH,-Z, wherein Z is a hydrophobic anchor which is 1 , p22 at i R R (074 ba Rg? r2 RR” ~ i ‘ rE oo 3 R : iI N Co
    R |. r 3 4 4 3 4 R R 3 rt NOY CE Fo Y=u : —n aD ORIGINAL R 0 } R 0 rio | . asl r3 r* 4 CR RY 7 “nT R N R : 2) = Ny = ’ bo 0 N11 Ao R R R rR? a b
    —— . . i A 23 BE of SI p?ia c=C - 16 = R*” R NN 22 Lo (0) : ; : 223 Co ) r232 . a A So : 0 : . . . : : alkyl } - SORA BE © or oo : ’ 5 ca . . : cL | RS (Rg BAD ORIGINAL vo wherein Rl, R2, R2a and R2bh are the same or different and are each independently selected from H, halogen, lower alkyl, haloalkyl, phenyl, substituted phenyl or ORY, wherein RY is H, Co-Cya alkanoyl, benzoyl, phenyl, halophenyl, phenyl-lower alkyl, - lower alkyl, ecinnamyl, haloalkyl, allyl, eycloalkyl-lower alkyl, adamantyl- lower alkyl or substituted phenyl-lower alkyl; . ‘where Z is 26 boo alkyl 3 : (R62, q / rR? and RY’ are the same or different and are H, lower alkyl or OH; . o Co I R” is lower alkyl-C or a monocyclic or bicyclic aromatic group comprising 6 to 10 carbon atoms in the ring portion; pha is lower alkyl, hydroxy, oxo or halegen; q is 0, 1, 2 or 3, and . , ’ r’ is H or lower alkyl; Lo BAD ORIGINAL oo at
    . ~. : where Z is rE : ] 3 . R ’ . = CR r? R R “a3 4 3 4 : a ~ oo yr NY : : NN —N ! = N oo! \—n : 4 0 : : 3 = 23 NR N R . 0 7 . glo gl | R rL3 ae BAD ORIGINAL pl? one of Rr? and rt is ay and 14 pl4a R : ’ the other is lower alkyl, C3-Cyo cycloalkyl or phenyl- (CHg) pH-) p is 0, 1, 2, 3 or 4; wherein rl3 is hydrogen, lower alkyl, lower alkoxy, {except "t-butoxy), halogen, phenoxy or henzyloxy; rlé is hydrogen, lower alkyl, lower alkoxy, halogen, phenoxy or benzyloxy; . plia is hydrogen, lower alkyl, lower alkoxy, or halogen; and . p? is hydrogen, C;_4 alkyl, Cj_g cycloalkyl, C;_4 alkoxy (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy; RY is hydrogen, Cy-a alkyl, Ci-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or pl? and pl! are independently selected from hydrogen, Cy-Cyg alkyl, C3-Cyo cycloalkyl, adamantyl-1 ar ) : 13 EX 14 R plé4a BAD ORIGINAL where R13, RI and R142 are as defined ahove and q = 0,
    1, 2, 3 or 4; Y is 0, Ss or N-R!®; . where Z is . ! } 8 ~ : rl2 - 9 : R Rr? RP <0 R? is H or primary or secondary 1-8C alkyl; . RP is primary or secondary 1-6C alkyl; ] or R® + R” is (CH,)_ or (cis)-CHy-CH=CH-CH,; oo : r =2, 3, 4, 5 or 6; pl? is lower alkyl, Ca-Cqo cycloalkyl or : | r:3 7X > rl : - _ Rr 4a oo wherein rR, RY, pl? pld and pléa are as defined above; where 7 is oo oR BAD ORIGINAL rl3 p16
    R1% and R1® are hoth H, Cl, Br, CN, CF,, phenyl, 1-4C alkyl, 2-8C alkoxycarbonyl, -cH,oRT or ~CH,0CONHR®; ’ rRl7 is H or 1-6C alkanoyl; : SE ELE C;-Cyg alkyl or phenvl optionally substituted hy F, Cl, Br or 1-4C alkyl; or pl? and rl® taken together are -(CHy)_-, —cHy0cH,-, -CON(R®)co-, or -coN(REY)N(R?!)co-; S = 3 or 4; r!? = H, 1-6C alkyl, phenyl or benzyl; p20 and rll are H, 1-4C alkyl or henzyl; . and X is -CHy-, -CHyCHy- or -CHyCHoCHo where Z is . LEN Bp : N22 223
    To . r232 R22 is lover alkvl, C3-Cqy cycloalkyl, adamantyvl-1 or -(CHy)y {O) ; oo BAD ORIGINAL t = 1, 2, 3 or 4; _—— p23 and p23 are the same or different sand are each independently selected from hydrogen, lower alkyl, lower alkoxy (except t-butoxy), halogen, phenoxy or benzyloxy; and Ta : where X is ~CHy0- {carbon attached to P. and 0 attached to Z), the hydrophobic Anchor Z will be Co 2a 1 rl RZ R O5- : or . 2 2a R b r2 . R wherein R* is hydrogen or lower alkyl in free acid ~ farm or in the form of a physionlogically-hydrolysable Co and -acceptable ester or in salt form. Bh
    2. An intermediate having the structure:
    : . 0
    ] . . t X 0 oo z : ‘ including all stereoisomers thereof wherein X is (CH, ) -CH=CH-, -C=C- or -CHy-0- and a is 1, 2 ar 3 and Z is a . hydrophobic anchor which is defined as in claim 1. Inventors: DONALD STEVEN KARANEWSKY ET SCOTT ADAMS BILLER BAL urIGINAL . ‘ ERIC MICHAEL GORDON :
    \ CO) Abstract : ' ! PHOSPHORUS—CONTALNI HMG-CoA REDUCTASE . INHIBITORS, NEW INTERMEDIATES AND METHOD . Abstract of the Disclosure : Compounds which are useful as inhibitors of cholesterol biosynthesis and thus as hypocholesterolemic agents are provided which have : the structure 0 " H 1" \ x R-P-CH,-C-CH,-CO,R X OH ’ Z wherein R is OH, or salts thereof or lower alkoxy; R* is H or alkyl; Co oC ’ I GN §-] ~CH,-, -CH,~CH,~, ~-CH=CH-, -C=C-, : -CH, CH, CH, ~ or -CH,0- (vhere O is linked to 2); 7 is a hydrophobic anchor, such as r22 rY rl Rr? o gAD ORIGINAL . ’ ’ ant
    7 . 5 nn ”
    a . rR rR? . re
    - 364 - en . R : . N ) - R : - r RY RY 3 xf 4 v ] R 7 NT.
    NON - / } A N ’ == N ’ N= RO RO RY te or . oe a . hoa bl Cy ¥ Sate Ce Me . . iN Ed ar : orp ty dn AR et 3 4 Co rR” R R 4 7 “Nn R [oR R'Z - _ CoN ) glo Ri! RHO 9 o ) - R Rr? R= . \ : 23 : | 4 R N R Ti 23a - ~ 1s 16 R c=c R R N 22 . - R r23 B | r23a 1 Co BAD ORIGINAL
    ~ 365 - . HX10b : r® ~ 0 ~ | alkyl 5° or te . *, - i ca R> (R77) wherein the dotted lines represent optional . double bonds.
    New intermediates used in preparing the above compounds, pharmaceutical compositions containing such compounds and a method for using such compounds to inhibit cholesterol biosynthesis are also provided.
    BAD ORIGINAL ft
PH38673A 1987-05-22 1989-05-19 Intermediate for preparing phosphorous-containing HMG-CoA reductase inhibitors PH26578A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US5323887A 1987-05-22 1987-05-22
US10968187A 1987-10-19 1987-10-19

Publications (1)

Publication Number Publication Date
PH26578A true PH26578A (en) 1992-08-19

Family

ID=26731613

Family Applications (2)

Application Number Title Priority Date Filing Date
PH36953A PH25581A (en) 1987-05-22 1988-05-20 PHOSPHORUS-CONTAINING HMG-CoA REDUCTASE
PH38673A PH26578A (en) 1987-05-22 1989-05-19 Intermediate for preparing phosphorous-containing HMG-CoA reductase inhibitors

Family Applications Before (1)

Application Number Title Priority Date Filing Date
PH36953A PH25581A (en) 1987-05-22 1988-05-20 PHOSPHORUS-CONTAINING HMG-CoA REDUCTASE

Country Status (24)

Country Link
JP (1) JPH01139589A (en)
KR (1) KR880013959A (en)
CN (1) CN1030761A (en)
AU (2) AU610174B2 (en)
BE (1) BE1002251A3 (en)
CH (3) CH678625A5 (en)
DE (1) DE3817298C2 (en)
DK (1) DK277388A (en)
ES (1) ES2009919A6 (en)
FI (1) FI87927C (en)
FR (1) FR2615516B1 (en)
GB (1) GB2205838B (en)
GR (1) GR880100332A (en)
HU (1) HU201085B (en)
IE (1) IE63715B1 (en)
IL (1) IL86463A (en)
IT (1) IT1217684B (en)
NL (1) NL8801331A (en)
NO (1) NO882219L (en)
NZ (1) NZ224734A (en)
PH (2) PH25581A (en)
PL (1) PL157761B1 (en)
PT (1) PT87540B (en)
SE (3) SE501541C2 (en)

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU610591B2 (en) * 1987-05-22 1991-05-23 E.R. Squibb & Sons, Inc. Phosphorus-containing hmg-coa reductase inhibitors, new intermediates and method
US5112819A (en) * 1989-10-10 1992-05-12 Glaxo Group Limited Imidazole derivatives, pharmaceutical compositions and use
US5025000A (en) * 1990-03-02 1991-06-18 E. R. Squibb & Sons, Inc. Phosphorus-containing HMG-CoA reductase inhibitor compounds
US5124453A (en) * 1990-03-02 1992-06-23 E. R. Squibb & Sons, Inc. Process for preparing certain 5,6,7,8-tetrahydroindolizinyl (ethyl or ethynyl)-hydroxy or methoxy-phosphinyl-3-hydroxy-butanoates and derivatives thereof
CA2042526A1 (en) * 1990-06-11 1991-12-12 Adeoye Y. Olukotun Method for preventing a second heart attack employing an hmg coa reductase inhibitor
CA2043525A1 (en) * 1990-06-24 1991-12-25 Donald S. Karanewsky Phosphorus-containing hmg-coa reductase inhibitors, new intermediates and method
DE4023308A1 (en) * 1990-07-21 1992-01-23 Bayer Ag SUBSTITUTED PYRIDO OXAZINE
DE4025818A1 (en) * 1990-08-16 1992-02-20 Bayer Ag PHENYL SULPHONAMIDE SUBSTITUTED PYRIDINALKEN AND -AMINOOXYALKANCARBONE ACID DERIVATIVES
NZ241574A (en) * 1991-02-22 1993-08-26 Ishihara Sangyo Kaisha Substituted phenyl derivatives of hydrazone and pesticidal compositions
US5202327A (en) * 1991-07-10 1993-04-13 E. R. Squibb & Sons, Inc. Phosphorus-containing hmg-coa reductase inhibitors
US5256692A (en) * 1992-01-07 1993-10-26 E. R. Squibb & Sons, Inc. Sulfur-containing HMG-COA reductase inhibitors
US20010006644A1 (en) 1997-07-31 2001-07-05 David J. Bova Combinations of hmg-coa reductase inhibitors and nicotinic acid and methods for treating hyperlipidemia once a day at night
WO2003076409A1 (en) * 2002-03-14 2003-09-18 Syngenta Participations Ag Derivatives of 1-phenyl-3-phenylpyrazole as herbicides
JP4407237B2 (en) * 2002-12-24 2010-02-03 三菱化学株式会社 Non-aqueous electrolyte and non-aqueous electrolyte secondary battery using the same
JP4485169B2 (en) 2003-05-16 2010-06-16 花王株式会社 Intestinal mineral absorption capacity improver
CN1760363B (en) * 2004-10-14 2010-04-28 蒋继宏 Coded sequence of reductase enzyme protein of eucommia 3-hydroxy-3-coenzyme of methyl glutaryl A
WO2007081019A1 (en) * 2006-01-16 2007-07-19 Sankyo Agro Company, Limited (3-sulfur-substituted phenyl)pyrazole derivative

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR339233A (en) * 1903-12-23 1905-01-26 Cyanidgesellschaft Mit Beschra New process for obtaining explosives
DE803645C (en) * 1949-10-11 1951-04-05 Dynamit Act Ges Vormals Alfred Firedamp proof detonator in connection with electric igniters
DE918196C (en) * 1952-12-23 1954-09-20 J G W Berckholtz Fa Mass for producing colored smoke
US3274035A (en) * 1964-06-15 1966-09-20 Lohr A Burkardt Metallic composition for production of hygroscopic smoke
US3862866A (en) * 1971-08-02 1975-01-28 Specialty Products Dev Corp Gas generator composition and method
DE2841815C2 (en) * 1978-09-26 1985-02-21 Buck Chemisch-Technische Werke GmbH & Co, 7347 Bad Überkingen Method for producing a floor filling
US4438700A (en) * 1982-07-19 1984-03-27 The United States Of America As Represented By The Secretary Of The Army White smoke spotting composition for training ammunition
FR2596393B1 (en) * 1986-04-01 1988-06-03 Sanofi Sa HYDROXY-3 DIHYDROXYOXOPHOSPHORIO-4 BUTANOIC ACID DERIVATIVES, THEIR PREPARATION PROCESS, THEIR USE AS MEDICAMENTS AND THE COMPOSITIONS CONTAINING THEM
AU610591B2 (en) * 1987-05-22 1991-05-23 E.R. Squibb & Sons, Inc. Phosphorus-containing hmg-coa reductase inhibitors, new intermediates and method

Also Published As

Publication number Publication date
CH678625A5 (en) 1991-10-15
PT87540B (en) 1992-09-30
GB2205838B (en) 1991-12-11
AU7126691A (en) 1991-05-02
IL86463A (en) 1994-10-07
SE9201587D0 (en) 1992-05-20
PH25581A (en) 1991-08-08
HU201085B (en) 1990-09-28
SE9201587A0 (en) 1992-05-14
IL86463A0 (en) 1988-11-15
GB2205838A (en) 1988-12-21
DE3817298A1 (en) 1988-12-01
AU643501B2 (en) 1993-11-18
JPH01139589A (en) 1989-06-01
NL8801331A (en) 1988-12-16
SE8801904L (en) 1988-11-23
GR880100332A (en) 1989-02-23
DE3817298C2 (en) 1997-02-13
FI882385L (en) 1988-11-23
KR880013959A (en) 1988-12-22
NO882219L (en) 1988-11-23
PL157761B1 (en) 1992-06-30
AU610174B2 (en) 1991-05-16
CN1030761A (en) 1989-02-01
IT8820681A0 (en) 1988-05-20
PT87540A (en) 1989-05-31
SE9201588D0 (en) 1992-05-20
IT1217684B (en) 1990-03-30
CH678626A5 (en) 1991-10-15
GB8811931D0 (en) 1988-06-22
HUT47123A (en) 1989-01-30
FR2615516B1 (en) 1991-04-12
FI87927B (en) 1992-11-30
ES2009919A6 (en) 1989-10-16
FI87927C (en) 1993-03-10
DK277388D0 (en) 1988-05-20
BE1002251A3 (en) 1990-11-06
NZ224734A (en) 1991-04-26
SE8801904D0 (en) 1988-05-20
IE63715B1 (en) 1995-06-14
DK277388A (en) 1988-11-23
AU1650288A (en) 1988-11-24
SE501541C2 (en) 1995-03-06
NO882219D0 (en) 1988-05-20
SE9201588A0 (en) 1992-05-20
CH675582A5 (en) 1990-10-15
FR2615516A1 (en) 1988-11-25
IE881544L (en) 1988-11-22
FI882385A0 (en) 1988-05-20

Similar Documents

Publication Publication Date Title
US5091378A (en) Phosphorus-containing HMG-CoA reductase inhibitors, new intermediates and method
PH26578A (en) Intermediate for preparing phosphorous-containing HMG-CoA reductase inhibitors
CA2036407A1 (en) Phosphorus-containing hmg-coa reductase inhibitors, new intermediates and method
HU205125B (en) Process for producing phosphorous compounds and pharmaceutical compositions comprising same
US4918212A (en) Arylphosphorus derivatives
US5202327A (en) Phosphorus-containing hmg-coa reductase inhibitors
US4904646A (en) Phosphorus-containing HMG-COA reductase inhibitors
US5017716A (en) Phosphorous-containing HMG-CoA reductase inhibitors, new intermediates and method
WO2008005565A2 (en) Antiviral phosphinate compounds
CH676848A5 (en)
JPH08501794A (en) Arylmethylphosphonates and phosphonic acids useful as anti-inflammatory agents
DE3805789C2 (en) Intermediates and process for the preparation of antihypercholesterolemic tetrazole compounds
EP0463456A1 (en) Phosphorus-containing HMG-CoA reductase inhibitors, new intermediates and their use
US5298625A (en) Process for the preparation of 4-phosphinyl-3-keto-carboxylate and 4-phosphonyl-3-keto-carboxylate intermediates useful in the preparation of phosphorus containing HMG-CoA reductase inhibitors
GB2238545A (en) Intermediates for phosphorus-containing HMG-CoA reductase inhibitors
IE63403B1 (en) Phosphorus-containing hmg-coa reductase inhibitors new intermediates and method
US5124453A (en) Process for preparing certain 5,6,7,8-tetrahydroindolizinyl (ethyl or ethynyl)-hydroxy or methoxy-phosphinyl-3-hydroxy-butanoates and derivatives thereof
DD281605A5 (en) METHOD FOR PRODUCING PHOSPHORUS-BASED HMG-COA REDUCTASE INHIBITORS OF GENERAL FORMULA I
US4939265A (en) Intermediates and process for the preparation of antihypercholesterolemic tetrazole compounds
US5274155A (en) Intramolecular arbuzov process for the preparation of intermediates useful in the preparation of phosphorus containing HMG-COA reductase inhibitors
AT401263B (en) Process for the preparation of novel tetrazole compounds
MXPA04007798A (en) Alpha-substituted arylalkyl phosphonate derivatives.
PH26228A (en) An intermediate for the preparation of phosphorous containing CoA reductase inhibitors
DD297818A5 (en) NEW TETRAZOL INTERMEDIATES, THEIR PREPARATION AND THEIR USE OF THE PREPARATION OF ANTIHYPERCHOLESTERINA MIXTURES