PL154877B1 - Method for manufacturing new derivatives of 3-hydrobutyric acid - Google Patents

Description

PATENT DESCRIPTION

154 877

OFFICE

PATENT

RP

Additional patent to patent no. - Applied: 88 05 21 / p. 272597 /

Int. Cl.5 C07F 9/30 C07F 9/38

Priority 87 05 22 United States of America

Application announced: 89 03 06

Patent description published: 1992 02 28

Inventors: Donald S. Karanewsky, Scott A. Biller, Erie M. Gordon

Covered by patent: E.R. S0UIBB and SONS, Inc., / United States. America /

METHOD OF TREATING NEW DERIVATIVES OF 3-HYDROXYBUTTER

OBJECT OF THE INVENTION There is a method for the preparation of new 3-hydroxyiethyl acid derivatives which inhibit the activity of 3-hydroxy-3-eetylgluarrylkkeenzeu A reductase, useful for inhibiting cholesterol biosynthesis and consuming the antichoesterolytic effect.

F.M. Singer et al., Proc. Soc. Exper. Biol. Mo., 102, 370 (1959-) and F. H. Hulcher, A-ch, Blochem. Biophys, 146, 422/1971, /, discloses that certain derivatives of eevalonate kw ^^ inhibit cholesterol biosynthesis.

In U.S. Pat. Nos. J. et al. Ae. Nos. 4,049,495, 4,137,322 and 3,983,140 disclose a fereenation product which is active in biosynthesis. This product was named coepaadn and Brown et al., J.CheeJ ^ c ^ c. Perkin I 1165 (1976) reported that it had a coeplex structure of eetvlonic acid lactone.

British Patent No. 1,586,152 discloses a group of synthetic compounds of the general formula 21 where E is a direct bond, Cj-aliίtenooy units or wieyleeoay units, and different R syrnhols represent different substituents. The activity of the compounds described in British Patent Specification is less than 1% of the coeepad activity.

V U.S. Patent Ae. No. 4375475 discloses hypocholesteΓOkeemlcenye and hypolipenic compounds of formula 22 in which A is hydrogen or eethyl, E is direct bond, -CH-- groups, -CH - CC2-, -OΗ2 "®2" ^ 2 " or -CH = CH-, R, R and R are selected from atoeu hydrogen, halogen, Cj-alkyl group, C _£ __ chloknkooaakilkwej, phenyl, phenyl substituted atornee halogen, Ci-zalkoksylową, C2_Qalkanoilkisrlooą C-alkylated or C1-haloalloyl and OR2 group in which R1 is hydrogen, C2-6alk: ankyl, benzoyl, phenyl, halogen: phenyl, phenyl-C1-alkyl, C1-6alkyl, cinnamyl, C1-chloroalkyl, alkyl , crkloalkyj: .oC -_-- aliilooa, adaIeneyro-Ccr-2kyl, or substituted group 154 877

154 877 Ci_.j phenyl-alkyl, wherein the substituents ^are selected J® t from halogen atoms, C ^ ZalkoksylcweJ, C alkiOowej or C ^ haloalkyl one corresponding dwAydroksykwasy, powwtające otwrcie by hydrolysis of the lactone ring and the pharmaceutically acceptable the salts of these acids and the C 1-6 alkyl and phenyl, dinethylamino or acetoamino substituted C 1-6 alkyl esters of d 2 H 6 dOxy acids, wherein these compounds are enricomtoam L having the configuration of 4r in the tetrahydropion portion of the general trans formula shown above.

In International Publication No. 0 84/02131 of the patent application PCT / PCT / EP 83/00308 / based on the patent applications in St. Zjdin.Am. No. 443 668, filed on November 22, 1982 and No. 548850, November 4, 1983 discloses heterocyclic analogs of mooralonolactone and its derivatives of general formula 23, in which one of the symtb> O and R and R "is a group of formula 24, and the other is primary or a secondary C 1-6 alkyl, C 1-6 cycloalkyl or phenyl group (CH 2) where in formula 24, R 1 is hydrogen, C 1-4 alkyl, C 1-4 alkoxy! (except tertiary butoxyl), trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy, Rj is hydrogen, C 1-6 alkyl, C 1-6 alkyl. _¢ trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy group, R, a is a hydrogen atom, C 1-12 HI, (1-2 alloxy, fluorine or chlorine atom, and m is the number 1, 2 or 3, provided that when R 5 is hydrogen, then both R, and R, a must be hydrogen when R, is a hydrogen atom R, a must be a disadvantage, not more than one of R, and R j is trifluoromethyl, not more than one of R, and R 1 is phenoxy and no more than one of R 1 and R 1 is benzyloxy, R 2 is voluntary, C 1, C, alkyl, C, alkyl, C 1, alkoxy. tΓÓjfluo] romethyl, fluorine, chlorine, phenoxy or benzyloxy

Iowa, Rj is hydrogen, Ci_aU ^ i ^, i.a_jaαkoxy, toyforomethyl, fluorine, chlorine, phenoxy or benzyloxy, with the proviso that when R2 is hydrogen then R, muui be hydrogen, no more than one of R2 and Rj is trio-ohmethyl, no more than one of Rg and Rj is phenoxy, and no more than one of R2 and R- is benzyloxy; X represents a "CC ^ / n- or -CH" CH / n = 0, 1, 2, 3 or / and Z is a group of formula 25 wherein Rg is hydrogen or C _l _ ^ £ ^ al ^ il; in free acid form, or in the form of a physiologically hydrolyzing and physiologically acceptable ester or lactose, or in the form of a salt.

British Patent Application No. 2162-179-A discloses naphthyl meevalactan analogs useful as inhibitors of cholesterol biosynthesis of the general formula 26 wherein R2 is C1-4alkyl, Z is the group of formula 27, or formula 28, wherein R represents a hydrogen atom, a hydroOizable ester group or a cation.

EP 164-698-A discloses the preparation of lactones of formula 30 useful as anti-hyoeocholesterolemic agents by tactooling an amide of formula 29 with an organic sulfonyl halide of formula RSO./ and removal of the Pr protection group as shown in Scheme 4. where X is a halogen atom, Po is • 1 3 4 a carbinol protecting group, R is hydrogen or meeyl, R and R are hydrogen, or phenyl-C, _ ^ '- ^ ϋ with a phenyl group toentιum substituted with C ^ _J ^^ and 60 ° C, alkoxy or halo Syl ^k c ^hl ooo> ^oca, R 'is ^g ou ^PE of formula 3 ^{or 31 2, and Q} ozna.l · - 6 connectors goup of formula 33 or 34, wherein where in the formulas R represents a hydrogen atom or a hydroxyl group, R represents a hydrogen atom or a meeyl atom, and, b, c and d are, optionally, double bonds, R represents a phenyl or benzyloxy group, with a ring - but only substituted with a alkyl group or a halogen atom, R and R are C1-121N1N1.1, or halogen, a r 'stands for ^C γ__a ^α keel ^{, f} en ^y l ^l ^ or one or two / CC - ^^ i.lo ^ enyl /.

In the published German patent application no 3525256 discloses a naphthyl analogs of MEWO ^α onollkton ^{o o} o Formula ²⁶ a ^inclu wherein R 'is Al ^k yl, Z is ^g ou 27 ^PE formula η

or 35, wherein R 'is hydrogen or a hydro-lysable ester group, useful as inhibitors of cholesterol biosynthesis and in the treatment of atherosclerosis.

154 877

In International Publication No. WO 8402-903 of PCT Application / based on US Patent Application. No. 460,600, filed January 24, 1983 / meroarnolaktonu discloses analogs useful as agents with hipoOipoporoteinemmicznjro of the general ozorze 36, wherein the two groups R _q together form a radical of roorze 37 or a -CCHg / w 37 wherein R2 is hydrogen, C 1-8 alkU, C 1-4 alkoxy (except tertiary butoxy), trifluoromethyl, fluorine, chlorine, phenoxy or benzyloxy group, Ra is valor, C 1-4 alkoxy, C 1-6 acoxy, trinoromethyl, fluorine. chOoru group, fenoksyOową Oub benzyloxy <hose with the proviso that no more than one of R ₂ and R represents trójfluororaaeyl, no more than one of the substituents R ₂ and Ra is phenoxy and not more than one of R ₂ and R represents a benzylSsyO group, R_ is a hydrogen atom,

C., GalcoO, fluorine, chlorine or benzyloxy group A, R is hydrogen, C.I.alkyl, C.sub.16. / ^I with the exception of potassium t -butoxy /, trójfurorometyl, aoom fluoro, chloro, fenoksylcwą Oub benzyO ^ c ^^ ^ lo ^ ks Et, R_ represents wodor ^ Ccaaalkśl, C. | _jalkslsyl, trójnuorometyl, fluoro, chloro, phenoxy or benzylS11 group, Ra _a is a hydrogen atom, C 1-8 alkyl, C 1-8 alkoxy, fluorine or chlorine atom, but not more than one of Ra and Ra is trinoromethyl, not more than one of Ra and Ra is a phenoxyl group and no more than one of Ra and Ra is benzyloxy, X is -CCH ₂ / n-O or a group of formula 38 in which n is 0, 1, 2 or 3, and both the symbols q represent the number 0 or One of them is the number 0 and the other the number 1, Z represents the group of formula 39, where Rg is hydrogen or Cjajalkyl, except that the group -Χ-Ζ and the substituent Ra with a phenyl group are each other in the ortho position, in the form of a free Oub loom in the form of a physiologically susceptible ester or its lactose or salt.

European Patent Application No. 127848-A discloses loom derivatives

2-hydroxy-4-thio-aoyloaScanosarboxylic compounds of the general formula where Z is a group of formula 41 or formula 42, n is 0, 1 or 2, E is a group -CH ₂ ~, -CH ₂ -CH ₂ - , -CH ₂ -CH ₂ -CH ₂ -, -CH = CH-CH2- or -CH ₂ -CH = CH-; R1, R2 and Rj are, for example, hydrogen, chlorine, bromine, fluorine, Body, phenyl, substituted phenyl or a group OR ', wherein R is, for example. hydrogen, C 2-8 ^ 1Sθnill, benzoyl, phenyl, substituted phenyl, CgalkiO, cinnamyl, C ₁ a_chllolwcclαkSl, allyl, cylSίoaakill CJ_j-alkyl, adaMniylo-Cl_j -alkyl or fenyOo-C.aj - lkil, RA, Rj and Rg are hydrogen, chlorine, bromine, fluoro or O ^ im, and X is e.g. hydrogen, Ci-j-alOk1, alkali metal or ammonium cation

These compounds Imja pozeciwhipeΓcholeΞterolemeczne action due to the ability inhibitory redu zy ^ 3-hldrlSsy-3-metylogluarloOsleinlm ^l l A / HMO Co-and / or antifungal activity ·

V French patent application No. 2596393 A discloses 3-patch karblSsy-2-hydolSslpolpanoflsfonowego and their salts, useful as hipolipaemiczne of the general formula 43 wherein R and R ₂ are hydrogen, lower alkyl or optionally substituted aralkyl; and R and Ra are hydrogen, lower alkyl, or we will make eronniular aryl or aralkyl. It has been found that these compounds provide a greater reduction in the level of cholesterol, yo-glieoides and phospholipids in the blood than meglutol.

European Patent Application No. 142-146A discloses mevonolyn compounds of the general formula 44, in which R is, for example, hydrogen or α-alkyl, E is -CH "CH", -CH = CH-O or -CCH "), and Z represents: (1) a group of the general formula in which X ^r QQ 7 is an -O- group or a -NR group in which R is a hydrogen atom or a C 1 -alkyl, R is a C "alkyl, and R is hydrogen or meeyl, 12.1 a group with a total chip of 46 where 10 12

R, R and R are independently, for example, hydrogen, halogen or <RTI ID = 0.0> 3-10-1, </RTI> a group represented by general formula 47.

Phosphorus-containing compounds are produced by the method according to the milk, eiιhibitl-ącg the enzyme ogdlktαzl 3-hydolSεl-3-meyylogUuaiyolslginlml A / HKG-CoA οο & ΛΙ ^ ϊζθ / and therefore useful as hlplcholgsygrillemic agents in which they contain 4 the group -O- or -NH-, n is 1 or 2 and Z is a hydrophobic anchor.

154 877

As used herein, the term hydrophobic anchor refers to a lipophilic group "which, when linked to the general side chain of an HM-poohine molecule via an appropriate linking group (X /), binds to a hydrophobic enzyme pocket not used to bind the HMC-Cd- substrate, resulting in a tightening of m > activity compared to compounds where Z is hydrogen.

The method according to the invention is used to prepare further new derivatives of 1-hrfrotoxylbutyric acid of the general formula 1, in which H is a hydroxyl group, lower alkoxy or lower alkyl "X represents an oxygen atom or a -NH- group, n represents a number 1 or 2, Z represents an anchor. hydrophobic 12 2 of the general formula II, in which R, R and R are the same or different and represent a hydrogen atom, a halogen atom, triluoromethyl, a lower alkyl, a haloalkyl, phenyl, a substituted phenyl or a group of the formula ORy in which R ^y is hydrogen, alkanone, beraon, phenyl, halophenyl, thi-rromethylphenyl, phenyl-lower alkyl, lower alkyl, cinnamyl, haloalkyl, allyl, cycloaakyl lower alkyl, adamatyl lower alkyl or substituted phenyl lower alkyl, and R ^x is a disor or lower alkyl, in the form of a valable acid or in the form of a physically hydrolysable and physiologically acceptable ester, optionally in the form of a salt, and also the salts of these compounds, especially pharmacologically acceptable salts.

Oxidation salt and salts refers to salts with bases formed with inorganic and organic bases. Such salts include ammonium salts, alkali metal salts such as lithium, sodium and potassium salts (which are preferred), alkaline earth metal salts such as calcium and magnesium salts, organic base salts such as amine salts and the like, e.g., Owlcyclo salt, benzathine, N-methyl-D-glycamine, hydrabamines, and salts with amino acids such as arginine, lysia ftp. The non-toxic fgrmagoOllically acceptable salts are preferred, although other salts are also useful, for example, in isolating or purifying the products.

Thus compounds of formula 1 include compounds of formula Ia and Ib.

The term lower alkyl or alkyl as used herein, alone or as part of another group, includes both straight and branched chain hydrocarbons having 1-12 carbon atoms in the normal chain, preferably 1-7 carbon atoms, especially 1-4 carbon atoms such as ethyl , propyl, isopropyl, butyl, 3rd order. butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, ^^ - diphenylpennyl, octyl, 2,2,4-tΓmstylpentyl, nonyl, decyl, undecyl, doclecy !, their various branched chain isomers and similar hydrocarbon chains as well as ^{There are} several groups containing a halogen substituent, such as a fluorine, bromine, chlorine or iodine atom, or a yeast atom: roeethyl, alkoxy substituent, αellvoy substituent, alkyaryl substituent, chrovoaryl substituent, cycloalkyl, alkylcycloalkyl, hydroxy, alkoxyl, alkoxyl, alkyl 'blnyl' amino, nitro, cyano, thio or alkyl.

The term cycloalkyl as used herein, alone or as part of another group, includes saturated cyclic hydrocarbon groups with 3-12 carbon atoms, preferably 3-8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, with each of these groups may be substituted with 1 or 2 halogens, 1 or 2 lower alkyl groups, 1 or 2 lower alkoxy groups, or 2 hydroxyl groups, 1 or 2 α1 and 2 α-amino groups, 1 or 2 alkanoylamino groups, 1 or 2 geylcarbonylamino groups, With 1 or 2 amino groups, 1 or 2 nitro groups, 1 or 2 cyaMWl4 groups, 1 or 2 thio groups and / or 1 or 2 alkylthio groups.

The term aryl or -r as used herein refers to eonilyl or owu: cyclic arcamtic groups having 6-10 carbon atoms in the ring portion, such as phenyl, naphthyl, substituted phenyl or substituted naphthyl, in which groups the substituents of the phenyl or iaphthyl group may be 1 , 2 or 3 lower alkyl groups, halogen atoms (Cl, Br or F), 1, 2 or 3 lower alkyl groups, 1, 2 or 3 hydroxyl groups, 1, or 3 phenyl groups, 1, 2 or 3 alkyloxy groups. 1, 2 or 3 bisoyloxy groups,

154 877

1, 2 or 3 haloalkyl groups, 1, 2 or 3 cloo and phenyl groups, 1, 2 or 3 cycloalkylalkyl groups, 1, 2 IrU 3 gorup adamney Porlkilrwe, 1, 2 IrU 3 gorun alliroaminrwe,

1, 2 O. or 3 groups aineroOloaoeLroee, 1, 2 units or 3 groups onylylouOiepyloanienoee ,, 1, 2 O. or 3 mine groups, 1, 2 Oru 3 nitro gorups, 1, 2 lru 3 cpjn new gorups, 1, 2 , lru 3 gorups of thiol and / or 1, 2 luu of 3 gorups of nolyllotii with tpa, that the loophary are lop's gorups containing 3 urnals! i.

The term used is aralkyl, aryl-allyl Ouu aogrlo-lower nllyl, snae Ouu Jolo part of another gouuy, dr-tpczp lower head ^ u aOl-yl-spoken u ^^ and ^ ei ^ i ^ ir, including chub uo & set Solid, tali Jnl uenzyl.

As used herein, rldesenle lower nOlrlsnl, allilspl, or arylolspl Ouu aralloxy, snae lru Jalo part of another group, means Itóoplolwl with the description of the lower stem nllili, allili, aralkili lru aoyli bound to the tether atom.

As used here ol ^ e ^: 51enie lower gorua allilrtio, gorun nllilotio, gouua aoplotio lru gorua aoalkilrtio, snao Ouu Jalo part of another gorup, ruejauje ltóoplolwiel z ouisau npch previously lower nlkili, allili, no singing nołaea nołaea nołaea

As used here, the term lower gorun allionaminown, gorua allirnaminowa, gorun aoyOaaminooa Ouu gorua noploalk Oramenowa, saae lru Jalo part of another mountain, ouejauje ltóoplolwiel with ouisaipch downstream of the lower allili, nlkili, nryl nryli nryli aryanpyl.

The term allanoyl jnlo part of another gorup means a lower nllyl arranged together with dr gnup laouoeylrw.

The term halogen, luu and halo, as used herein, means atm chloro, ugiau, iodine Oru Olroor, preferably ntoap chloou and Oluoro.

Compounds of formula 1 are preferred, in the form of formula 1, R with a significant amount of hpdrrlsplowy, R ^x denomination of hydrogen, or lithium, X of a significant amount of oxygen or gouua -NH-, n Z being the top of the formula 2, in literal R stands for Oenpl znwiewającp jalo urdstnwiiki allyl ή

1 / 1uu halogen, luu R ¹ means uenzpOolsplowy group containing uenzopolpol

2 _n n R and R are uniquely and represent halogeno lr lower than nllyl.

Suosóu wtwrzania new uochrdnpch lwisr 3-hpdrolspffiłsłrwego ooaz esters, and salts urlega by wyrealnzlr en tpa that eteo a ^ LOOwp r ogólrprn sea 3, ltóiprn X, Z and n Aaja above urdnne defined and R ^C oznnczn niższp allyl luu niższp nllrksyl. is subjected to the oozszczuinnin eteou si ^ lilw ^ i ^ gr and the second esteo r general sea 4, in ltóipro R ^x equals nllil, a R, X, ii With the above-mentioned meaning, tr is a connection to sea 1, in ltóopa R means lower lower allyl, lower lower allyl, R is lower, and X, n and Z have the meaning given below, possibly uozeproin. There is a general sea of 5, where R is lower allyl luu lower alloxyl, and X, n and Z have the meaning given below , w ltóipa rgóliprn formula 6, w ltóipa R, X, ni Z wound above the meaning, w salt r general sea 7, w ltóopa X, ni Z rises more uniquely the meaning of Ouu w ltóipa rgóliprn sea 8, w ltórprn X, I do not want the meaning given above,

Jnlo starting compound loreistically, a compound of sea 3 is used, in Ι ^ γ ^ Rc is nllrlsyl, X is oxygen atra top NH, n is 1 Ouu 2, especially 1, and Z significant gouuę r sea 2, in which R, R and R have a different meaning in ^ Lej. Związel r sea 3 urddaje the oenkcji oozszczeuianin ether gouup sillloiej, tonltując it rurjętn3a orzuuszczalnilr iogani ^ <^ Z ^ i ^ 5a waist JNL tetrahpdooOurai, lwasern rctowpro and Oluorliern czteoUluPolonronlOiym, rtozyrniując esteo y Formula 4 ltórprn R ^x rznaczn allyl.

Esteo r sea 4 spit then hydrolysis dr ldu corresponding, rot lwsr lru rnetal salt nllnlicziegi, tr is dr lt r sea 4, in ltoryra R ^x denoting ntoa water luu ntorn inetalr aOlal, by bathing it with a yearly base, dilennoul wado tetΓaladorfrranu luu other runegr orzuuszczalii.ll lognnicnegi, in atrnoopheosis of inert gas tnliegr Jal nogrn, at the temperature of 25 ° C, using strswel rolrwp rule: esteo r sea 4 and plating from about 1: 1 to rlso 1.1: ldu>: WOeS salt different6

154,877 to the alkali of Formula 5 wherein R is lower alkyl or lower alkoxy.

The compound of formula 5 can then be treated with a strong acid such as HCl to give the corresponding acid, a pg. 6.

The ester of formula IV, where R C is lower alkoxy, can be converted to the corresponding alkali metal dihydrate by treating it with a suitable base at 50-60 ° C with a Rasal ratio of base: 4 ester ranging from about 28 1 to about 4 8 1, yielding a compound with chip 7.

The two salt of alkaline solution 7 can be converted to the corresponding acid (compound of sea 7 in which R is hydroxyl) by treating it with a minor acid such as HCl to give the compound of formula 6.

The compounds of the present invention can be incorporated in the form of racemic mixtures and separated thereafter to isolate the S-isomer, which is preferred. However, these compounds can also be produced directly as the S-isomers as described in the description and in the examples.

The input compounds of formula 3 can be repeated as shown in Schemes 1-3, with the second part of Scheme 3 illustrating the preparation of compounds of Formula 1.

As shown in Scherote 1, the iodide of formula 10 will undergo a Arbuzow reaction by heating it with a phosphinite / phosphite of formula 11, wherein R ^a is lower alkyl or lower alkoxy, under typical Watermelon reaction conditions, forming a phosphinate / phosphonate of formula 11. general sack 9, being a new compound.

The phosphinate / phosphonate of formula 9 is then subjected to cleavage of the phosphorus-containing ester group by treating a solution of the compound of formula 9 in an inert organic solvent such as methylene chloride followed by bis (tΓOjeethyl8illfo / Orδjίlsoroaeetaeid / BSTFA) and bromide, trimethylsilyl gas. inert such as argon to give an acid Sosinowi of formula 12 wherein R ^a is lower alkyl, when R ^a compound of formula 9 ozmczało lower alkyl, i.e. the compound of formula 12a, or wherein R ^a is hydroxy, when Ra in porter 9 was lower alkoxy, ie the compound of Formula 12b. The compounds of formulas 12a and 12b are very useful intermediates.

In case of receiving kwisu phosphorus compound of formula 12b, it is esterified in anhydrous pirydynta tsraktując alkoholm of the formula R ^ OH, in ktarym R ^s is a lower alkyl, ^and dwcylkLohekSlloka Γbodwuleidee ^ CC ^ /, as shown in scherocie 2. R ^ IWS The reaction mixture is stirred under an inert gas such as argon to give the phosphorus alkyl eosiotter of Formula 13.

The reactions shown in Scheme 3 are then carried out. The ester of formula 13 or the k? S Sfsphinooyl of formula 12a is dissolved in an inert organic solvent such as γΐω chloride! benzene or yttΓahydrffuoan / 'ΓΗ' / »is treated with yrójeethylfsilSloWutethyfoaein and stirred under an inert gas such as argon, the mixture is then evaporated and the residue dissolved in methylene chloride or other suitable inert organic solvent. The resulting solution was cooled to about 0-25 ° C with treatment with oxalyl chloride and evaporated to give crude chlorine-sulfonate. This compound is dissolved in an inert organic solvent, such as titanium chloride, ^, benzene, pyridine or THF, the solution cooled to about -20 ° ^C to 0 ° C and treated with a compound of the formula / - / 02 - ^ 1 using the ratio the molar mole ratio of the compound of Formula 13 or Formula 12a or 12b to the compound of Formula Z-ZC4 / n-O1 yielding from about 0.5: 1 to about 3: 1, and preferably from about 1: 1 to about 2: 1 followed by the addition of triethyphaein and catalytically acting 4-diumeeylfaeinopyridine (DMA) to give an adduct of formula III wherein R ^c is lower alkyl or lower alkoxy.

The iodide 10 can be prepared from the bromide of formula 14 obtained as described in Teyhahtdrfy Lett. 26, 2951 (1985), which is dissolved in a solution in a dinettloffromide (DM) with Iidazflee and 4-diethylsaeiyfpioyl, and the resulting solution is then treated with with 3rd order chloride. butylphylphylphilyl into an inert gas naphthose, yielding lithium ether

154 877 15. A solution of formula allyl ether of formula 15 in an inert solvent such as methyl ethyl ketone or DM ^1, is treated with sodium iodide in the field of ato an inert gas such as argon to give the iodide of formula 10.

The compound of formula Z- / CH ₂ / _n -XH can be prepared as described below depending on the importance of Z and X.

Thus, a compound of formula Z- / CH ₂ / n-XH, in which Z is the group of formula 2 and X is oxygen, i.e. compounds of formula 16, can be prepared by treating the aldehyde of formula 17 with a reducing agent. such as iHonaluminum hydride or sodium borohydride.

Compounds of formula Z- / CH2 / n-XH »where X is nitrogen, i.e. compounds of formula 18, can be prepared by oxidizing the aldehyde of formula 17 by treating it in an acetone solution or p. Jones reagent to give an acid of formula 19, the methylene chloride suspension of which is treated with oxalyl chloride to give the corresponding acid chloride. This Cbh. Solution is dissolved in an inert organic solvent such as tetrahydrofuran and treated with a mixture of concentrated ammonium hydroxide with tetaahydrofuraneo to produce aidd of formula 20. This amide is then reduced to the corresponding amide of formula 18 by treatment with a reducing agent such as hydride l.iowł ^ g ^ h ^ c ^ wy.

As what if j in ^the mentioned compounds of the present invention includes balancing of the method are inhibitors of 3-hyOΓoksy-3-metyllglutaryOoleinzm ^lu A / HMJ-Co and / or they are thus useful in inhibiting cholesterol biosynthesis as demonstrated in the following tests.

1. Rat hepatic reductase HM-Co A.

Rat hepatic HIM-Co-A reductase activity was determined using a modified method described by Edwards / D.A. Edwards et al., J. Lipid Res. 20: 40.19 * 79 /. Rat liver micrasome was used as the source of the enzyme and the activity of the enzyme was determined by measuring the conversion of the C-IWG-Co A substrate to C-mevalonic acid.

a / Preparation of microsomes. Livers from 2 to 4, fed with cholestryraoin after decapitation, were removed and homogenized in phosphate A / potassium phosphate buffer, 0.04 m, pH 7.2; KC1 0.05 m; sucrose 0.1 m; EDTA 0.03 m; rirotiiiir, 500 Ki (volume) units. The homolenization product was centrifuged at 16,000 g for 15 minutes at 4 ° C. The supernatant was removed and centrifuged again under the same conditions. The supernatant from the second centrifugation was centrifuged for 70 minutes at 4 ° C at 100,000 g. The microsome tablet was resuspended in a minimum volume of A buffer (3-5 O. per liver) and homogenized in a glass / glass filter. Two thiotreitol (10 moles) was added and the formulation was divided into beehives aliquots which were quickly frozen in acetone / dry ice and stored at -80 ° C. The specific activity of the first microsomal preparation is 0.68 OhmU oevlonic acid / mg protein / minute.

b / Amaitic enzyme determination. Reductase was determined analytically in 0.25% samples containing the following components at the indicated end concentration: 0.04% potassium phosphate, pH 7.0; 0.05 m KCl; 0.10 by sucrose; 0.03 about EDTA; 0.01 for dictniitol;

3.5 mol of AaCl; 1% dw ^: obyliiuffotlirkf. ;; 50-200 µg of micro-somilic protein; 100 ug ¹ⁱ * ^C ~ / ^DL / AIMC-Co A / 0 ° ⁵ ° C Ci, ⁰ 30-6 OCI / 00% 2.7 ^on it and NADPH / ^phosphate wfnίkleoty ^d in nikotynoaoidu adenine /.

I incubate the reaction mixtures at 37 ° C. In the pathways described, the enzyme activity increased linearly to 300 µg of microsol protein per reaction imesanine and remained linear with respect to the incubation time up to 30 minutes. The standard incubation time selected for the study of the drug wimU 20 minutes, during which there was a 12-15% conversion of the HiW-Co A medium to q ^ su 00: ^ 0: 3 ^ 20. The substrate / D, L- / HKG-Co A was used with a ratio of 100 [mu] m, twice the concentration needed to saturate the enzymes in the sward described.

.1ADPH was used at a nadim of 2.7 times the concentration needed to achieve the oxoane enzyme rate.

Standard assays for evaluating inhibitors were performed according to the following procedure. The microsomal enzyme is incubated in the presence of AADPH for 15 minutes at 8 ° C

154 877 rd 37 ° C. DMSO containing or not containing the test compound was added as liquid carrier and the mixture was further incubated at 37 ° C for 15 minutes. The enzyme sample was activated by adding C-HMG-Co A medium. After 20-notes incutation at 37 ° C, the reaction was quenched with 25 µL of 33% KOH. 1 H-mevalonic acid 00.05 µCi was added and the reaction mixture was allowed to stand for 30 minutes at this time. 00 [mu] l was added to lactonize the-clonic acid. 5 N HCl. Bromo-phenol blue was added as a pH indicator to track the corresponding decrease in pH. Lactonization was allowed to proceed at room temperature for 30 minutes. The reaction mixture was centrifuged for 15 minutes at 2,800 rpm.

The superratants were coated in wraps on 2 g of AG 1-Χ8 anion exchange resin (Biorad form), poured into glass columns 0.7 cm in diameter and eluted with 2.0 -L H-O. The first 0.5 -L was discarded and the next 1.5 -L were collected and the amounts of both tritium and carbon were counted in 10 -L Optifluor scintillation fluid. The results were calculated as the amount of n-m methallonic acid formed in 20 minutes and knit / night for 100% tritium recovery. Efficacy of the drug was expressed as the value of Ι-wyw / drug concentration resulting in 50% inhibition of enzyme activity / obtained from the given reactions n combined dose within the indicated 95% certainty interval.

Conversion of the lactone drugs to their sodium salts was achieved by dissolving the lactone in DMSO, adding a 10 fold excess of NaOH, and allowing the mixture to stand for 15 minutes at room temperature. The mixture was then neutralized (pH 7.5-8.0) with IN HCl and diluted to obtain enzyme reaction mixture.

2. Cholesterol synthesis in freshly isolated rat hepatocytes.

Activity Mapping Compounds As HM3-Co A reductase inhibitors were evaluated for their ability to inhibit the incorporation of the C-octar group into cholesterol in a suspension of freshly isolated rat hepatotocytes using the method described by D.M. Capizzi and S. Margoois, Lipids, 6: 602, 1971.

a. Extraction of rat hepatocytes.

Spraąne Dawley rats (180-220 g) were anesthetized with Nem-btanol (50 m- / kg), after which their abdominal cavities were opened and the venous veins were clamped. Heparin was injected directly into the main vein of the abdominal cavity / 100-200 units /. A single clamping surgical suture was placed on the distal segment of the venous vein and the invertebrate vein was catheterized between the clamping suture and the first branching vein. The liver was perfused at 20 ra / min, warmed - previously to 37 ° C, oxidized - with A / HBSS buffer without induction or - magnesium containing 0.5 µl EDTA / after disconnection of the vena cava to allow drainage to drain. The liver was additionally perfused with 200 -L of pre-warmed B / HBSS buffer containing 0.0% bacterial collagenase. After perfusion with buffer B, the liver was excised and flushed in 60-L WeynmoutK! Medium, allowing free cells to disperse freely in the medium. Drained hepatntn by slow centrifugation for 3 minutes at room temperature under 50 g overload. The hepatocyte tablet was washed once with Weym-out !, the hepatocyte viability was counted and the viability of the hepatocytes was analyzed by trypan blue removal. Such enriched hepatocyte cell suspensions routinely have a viability of 70 - 90%.

b. C-acetate group to cholesterol

^N ^ hepatocytes flat ribbon zejrOwtoono in slings ^ pos ^ ce / h / s-the ^ NIU ⁵ ° θ 1 ^k omórek 2 - medium [0.02 - Tris - HC1 / pH 7, A / - KC1, 3 , 3 ml of sodium citrate, 6.7 ml of nicotinic acid alpha id, 0.23 ml of NADP, 1.7 ml of glucose phosphate-6 J.

Routine test compounds were dissolved in DMSO or in a DMSO: H-0/1: 3 mixture and added to the IM. The final DMSO concentration in IM was 1,% and had no significant effect on cholesterol synthesis.

^And the genre ^b ACJ ^{ę inicnowann,} adding C-acetate / 5 ⁸ m Ci / MMB 2 ^y u Ci / ml / placing the cell suspension / 2,0 -J for 2 hours ^at 37 ° C in the vials to tissue hodowwi diameter 35 mm. After incubation, the cell suspensions were transferred to glass tubes

Centrifuges and centrifuged at room temperature for 3 minutes at 50 g. Cell pellets were resuspended and lysed in 1.0 M HgO and placed in an ice bath.

Lipids were extracted essentially As described by E.C. Bligh and W.J.Dyer, ten. J. Biochem. and. PhyySol., 37: 911, 1959. The lower organic phase was removed and dried under a nitrogen stream and the residue was resuspended in 100 µl chloroform mixture. methanol (2: 1). The entire sample was spotted onto silica gel plates /ΊΧ.&! for the layer chromatography and developed with the hexane: ethyl ether mixture:

: acetic acid (75: 25: 1). Plates were examined and counted using a Bio Scan automated scanning system. The level of radiolabeled groups in the cholesterol peak (Rf 0.28) was determined and weighed as the total number of counts per peak and as the percentage of the groups labeled in total lipid extract. The cholesterol peaks in the control cultures routinely visualize 800-1000 cpm and contain 9-20% of the labeled groups present in the total of the 1st and 2nd extract; the results obtained by the method of Cajpizzi et al. show 9% of extracted groups labeled in cholesterol.

Drug performance (% inhibition of cholesterol synthesis) was determined by comparing the% content of cholesterol-labeled groups in control and drug treated cultures. Dose-response curves were plotted from two or more compound dose trials, and the results were weighted as values of Ι with a 95% confidence interval.

3. Cholesterol synthesis in human skin fibroblasts

A selectivity of a compound resulting in greater inhibitory activity in hepatic tissue would be a feature of a cholesterol synthesis inhibitor. Therefore, in addition to evaluating inhibitors in hepatocytes, these compounds were also tested for their activity as inhibitors of cholesterol synthesis in cultured fibroblasts.

a. Culture of human skin fibroblasts

Human skin fibroblasts (passage 7-27) were grown in Eagle's minimal basal medium (EM) containing 10% fetal calf serum. In each test cultures were subjected to primary trypsonizacji ^ dispersed to present the cell monolayer, counted, and placed in wells on a plate for hodowm ttenek having a diameter of 5 mm ^ ³ ^ .10 tomórek / ^{/ 2,} 0 m / sec. Cultures of iikuboaaio for 18 hours at 37 ° C in 5% COg air and 95% humidity. Cholesterol biosynthesis enzymes were induced by removing serum containing medium, washing cells with ionolWΓStay and adding 1.0m EN containing 1% fatty acid free bovine serum albumin, and incubating the cultures for an additional 24 hours.

b. Turning ^g u ^p C-acetate into cholesterol

Induced fibroblast cultures were washed with ΕΜΕΜΕΜΕΜΕΜΕΜ (Earle Minimum Medium Medium). The test compounds were dissolved in DMSO or in the DMSO: EM mixture (3: 1) (final DrMSO concentration in nodal cells ϊέ 1.0%), added to the nodes, and the culture was pre-incubated at 37 ° C for 30 minutes in room atmosphere 5% and 95% humidity. ^p in the initial incubation with drug, add ethyl 1- ^{£ 1Z} * C_7fJa / 2,0 / u ZilmumoOl and the cultures reincubated for 4 hours. After incutbation, the culture medium was removed and the cell monolayer (200 µg of cell protein per culture) was scraped to 1.0 ml &lt; 0 &gt; 0. The lipids contained in the lysed cell suspension were extracted with the chloroform: methanol mixture as described for the hepatocyte suspensions. The organic phase was dried under nitrogen and the residue was resuspended in chloroform: methanol / 2: 1 / / 100 / µl / and the whole sample was spotted onto silica gel plates (1KGD) for thin-layer chromotography, and then analyzed as described for hepatocytes.

The inhibition of cholesterol synthesis was determined by comparing the content of radiolabeled groups in the cholesterol peak with the control and culture treatment drug. The kynics are expressed as 1 ^^ and are derived from a plot of the composite dose response curves for two or more trials. The 95% memory interval was also calculated from these curves.

154 877

The compounds of the invention can be used in the form of pharmaceutical compositions consisting of at least one compound of formula I in association with a pharmacologically acceptable carrier or diluent. These compositions can be formulated using known solid or liquid carriers and pharmacological additives appropriate to the method desired for the administration. They can be administered orally, e.g. in the form of tablets, capsules, granules or powders, or by parenteral administration in the form of injectables, with dosage forms containing 1 - 2000 mg of active ingredient per donor being used for treatment. The workable dose depends on the unit dose, disease symptoms, age and body weight of the patient.

The compounds of baggage 1 can be administered in a similar manner to known compounds proposed for use in inhibiting cholesterol biosynthesis such as loyastatin, to mammals such as dogs, cats and the like, and to humans. Thus, the compounds of formula 1 may be administered in an amount of from about 4 - 2000 ml in a single dose or in the form of individual doses 1-4 times daily, preferably in an amount of 4 - 200 mm in partial doses of 1 - 100 mg, suitably in unit doses. 0.5 - 50 ml and 2 - 4 times a day, or in the form of sustained release of the active ingredient.

Wyyaaazek is illustrated by the following examples in which the abbreviation mt. means melting point, and TLC means friction chromatogram. C] M: · The flash was carried out on silicon: emiorOcoliim Merck 60 or Watmann LR5-1 gel.

^^ (^ roa ^ g ^ raa ^ e with reversed phase was carried out on CHP-20 MC gel resin, manufactured by Mitsubishi Ltd.

EXAMPLE 1 (S (-4-) 4ffluoro-3,3 ', 5'-trimeeyl-1,1'-biphenylyl-22) -methoxy-methoxy-3-pho-phinyl (-3ah) rtirl) salt monolayer salt.

A. N- (2,4-avlmethylbenzylidenoffelylaamine) (see description of IaιtenOovl). Aπκ! RlOii No. 4,375,475, p. 39 /.

A solution of 6.97 ml (50 mlirol) of freshly distilled 2,4-dalmethylobtnzaldehyde and 4.56 ml · (50 mmoH) (distilled aniline / Aldrich) in 80.0 ml of anhydrous toluene was heated under reflux for 3.0 ml. hours under argon in a Dean-Stark flask. The mixture was cooled and then Idparoaαnl under reduced pressure to give a yellow oil. The crude oil was purified by distillation using a ball condenser (67 Pa, 160-180 ° C) to afford 8.172 g (78.1%) of the desired title phenylamine as a light yellow oil, from which on standing, a low mp crystallized solid. TLC (4: 1 hexane-acetone / R f = 0.67 and 0.77) geometric isomers, UV and J 2.

B. The compound of formula 49 (see US Pat. No. US No. 4,375,475, p. 39 /. To a mixture of 6.9 g (28.7 mmol) of Part A phenylimine in 144 ML of glacial acetic oil was added 6.44 g (28.7 mmol) of palladium acetate (Ii), and the clear red homogeneous solution was heated under heating. under reflux under argon for 1 hour. The resulting cloudy mixture was filtered through a pad of celite 12.7 m thick into 900 mL of water. The precipitated red precipitate was filtered off and dried in vacuo at 65 ° C over P 8 ° C for 16 hours to afford 10.627 g (85%) of the desired title paUadium complex as an orange solid, m.p. 194-196 ° C (mp. the recrystallized uralitic sample according to the literature is 203-205 ° C).

C. 2-FormmlOl4'-fluoΓO-3,3 », 5-tΓmethylOlll, l * lbiphenyl / l / BΓorol4-flulΓO-3lmeeylphylnyo / mαgntz / see US Patent No. No. 4 3 75 475, pp. 37-38 /.

The title Grignard reagent from part c / l / was obtained in a dropwise manner with 22.5 g / 60.9 milliU / 5 l-bromol-2-fluorotlluene / Fairfield Chemical at a rate of PLN / e sufficient to keep the reaction mixture in the mixture / under a condensation cooler to a stirred suspension 1.35 g (55.4 [nilimooyl / 8.0 equation) of corneal flakes in 70.0 ml of anhydrous ethyl ether. The reaction was revealed in a search device. After the addition of bromide dropwise, the mixture was stirred for 1 hour under argon at room temperature, heated to reflux for 15 minutes and allowed to cool to room temperature.

154 877/2/2-Formmlo-4'-fluoro-3,3'-trimethyl-1,1'-biphenyl.

In a separate flask, a mixture of 3.0 g (6.92 mmol) of the duplex complex from Part B and 14.52 g (55.4 mmol, 8 eq) in 100 ml of anhydrous benzene was stirred at room temperature under argon for 30 minutes. To this solution was added in one portion via cannula a freshly prepared and filtered through a plug of glass wool with a Grignard reagent component / c / l /, then meszaninę stirred at room temperature for ^_ R five hours under argon. After adding 35 μm of 6.0 N HCl, the mixture was stirred for an additional hour at room temperature and then filtered through a celite pad 12.7 μm thick. The filtrate was extracted with 250 ml of diethyl ether, then the ethyl extract was washed with two 100 ml portions of brine, dried over anhydrous MgSO 4 and evaporated under reduced pressure to give 13.35 g of a viscous post-crude oil which crystallized on standing. The crude oil was purified by flash chromatography over 700 g of silica gel eluting with hexane followed by 95: 5 hexane-ethyl ether. Product fractions were evaporated to give 1.507 g (89%) of the desired title aldehyde as a light yellow solid with mp 72-75 ° C according to literature mp = 73-74 ° C. TLC / 95: 5 hexane-ethyl ether / Rf. 0.40 UV and PMA.

D. 2-Hyyroxymetyto-4'-fluoro-3,3'-trimethyl-1,1'-biphenyl.

To 15.0 ml of anhydrous diethyl ether, cooled in an ice bath to 0 ° C, 259 mg (6.82 mmol, 0.55 equiv / LiAlH) were added and a solution of 3.0 g was added dropwise to the resulting gray suspension over 15 minutes. (12.4 m / m / m 2/1/2) aldehyde from part C in 15 ml of anhydrous ethyl ether. The mixture was meshed at room temperature under argon for 30 minutes, cooled back to 0 ° C and quenched by successively trampling 260 µl of water, 260 µl of 15% NaOH and 780 µl of water. The slurry was diluted with ethyl acetate, filtered through anhydrous NagSO on a pad of Celite 6.4 cm thick, the colorless filtrate was evaporated under reduced pressure to give 2.99 g (98% white solid). After trituration of the crude material with cold hexane and drying under reduced pressure, 2.467 g (81%) of the desired title alcohol was obtained as a white solid, m.p. 102-103 ° C. TLC / 7: 1 hexane-ethyl acetate / Rf = 0.24, UV and PMA.

E. Kwisu methyl ester / s / -3- / /l,1-dw.ιmeeyloetyOoOdrWenylsilyloxy / -4- / 0rdroksm ^e toSsyfkεfinyk / eπBsOowegk / l / Mmi ^ lo acid ester / s / -4-bΓemo-3-OrOkskoemsowy l / / a / Strain salt hydrate of quise / R- / R ^X , R ^x / / -2,3,4-trihydrate. (see Carbohydrate Research 72, pp. 301-304 (1979).

g of calcium carbonate was added to a solution of 44.0 g (250 mmole) of D-isoascorbic acid in 625 ml of water, then the suspension was cooled to 0 ° C in an ice bath and 100 ml of 30% H 2 O 4 was added thereto in portions. The mixture was stirred at 30 ° -40 ° C in an oil bath for 30 minutes, then 10 g of Darco was added to it and the black suspension was heated on the steam bath until no oxygen was released. The slurry was filtered through celite and evaporated in a bath temperature of 40 ° C, using a bath temperature of 40 ° C. The residue was dissolved in 50 m. Vid, heated on a steam bath and added until the solution turned cloudy. In 0Γąckio ^white resin precipitate was filtered and air dried to give methyl 30.836 g ΙΊΪ.Ζ & Ι wipniowej the desired salt as a white powder. TLC / 7: 2: 1 isopropanol, 1M 4 OH - water / R = 0.19, PMA.

/ 1 / / b / Eetolkva ester of acid / SR ^x , S ^x , / / -2,4-duubΓomk-3-hydrosylate / see K. Bock et al., Acta Scandinavica / b / 37, pp. 341-344 / 1983 //.

g of the calcium salt from / 1 / lal part was dissolved in 210 ml of 30-3% HBr in acetic acid, and the mixture was stirred at room temperature for 24 hours. After adding 990 ml of methanol, the brown solution was stirred overnight. The mixture was evaporated to give a clear and pure oil which was taken up in 75 ml. The mixture was heated under reflux for 2.0 hours and evaporated. The residue is mixed with 100 ml of ethyl acetate and water, the organic phase is washed with 1O2 SO4 with water, once with brine, dried over anhydrous Na2SO4 and for 12

The 154,877 was evaporated to yield 22.83 g (90.5%) of crude-dbromide as a light phosphornamine oil. TLC. (1: 1 ethyl acetate-hexane) R _f = 0.69. UV and PMA.

hllzl / s / -4-rormo-3-hydroxy-tartaric acid mrtyl ester / see the same reference as in the synthesis / l / b /.

To a solution purged with argon of 20.80 g (75.mmol) dibromide and 21.0 g of anhydrous sodium acetate in 370 ml of ethyl acetate and 37 ml of glacial acetic acid was added 1.30 g of 5% Pd / c and the black suspension was stirred under 0.1 MIPi hydrogen pressure, tracing hydrogen uptake. After 2.0 hours uptake of hydrogen ceased and the mixture was filtered through celite and the filtrate was washed with saturated NaHCO3 and brine, dried over anhydrous MgSO4 and evaporated to give the crude dIbromrosteo as a brown oil. The crude oil was combined with oil from another batch of dibromide with 36.77 g of dibromide and tested under reduced pressure to give 25.77 g (61%) of the desired title bronoester as a clear 79% oil. ) ⁰ C under a pressure of 133 Pa. TLC / 1: 1 ethyl acetate-hexane / Rf = 0.0-4.

Elemental analysis for CejH ^ O ^ Br

Calculated C 30.48 H 4.60 Br 403> 56

It was found to be C 29.76 H 4 O Br 39.66 / 2 / M-ester of / s/-/-bfomo-3-/7l,l-dvulretylethyl / low-acid acid.

For a solution of 4.0 g (20.4 mmoles of broTOhydrin from part Eh), 6.94 g (5.0 eq. Of imidazole and 12 mm (0.005 eq.) / 4) dimreylarinopyridine (4-IMAP) by 40 m of anhydrous digunreylphyrarid (M) 5.84 m. (1.1 eq.) P (butyl chloride) U'enilosilyl chloride was added and the homogeneous mixture was stirred overnight under argon at room temperature. The mixture was mixed with 5% KHSO4 and ethyl acetate, then the organic phase was washed with water and milk, dried over anhydrous NaN2O4 and evaporated to give 9.32 g / L (0%) of crude silHoether as a clear viscous oil. TLC / 3: 2 hexane-ethyl acetate R ^ = 0.75 UV and PM./3 (Methyl ester (s/-/-jofo-3-Z'/l,l-dumιityloityl/ diphenylsilyloxy / butter).

To a solution of 9.32 g (201 g of crude bromide from part E (2) in a 60 ml of methyl, l, l, and tilte / ton dried over 0.4 mm sieves, 15.06 g (100.5 mmol, 5) were added. 0 equivalents / sodium iodide and the yellow suspension were heated to reflux for 5.0 hours under argon. The mixture was cooled, diluted with ethyl acetate, filtered then the filtrate was washed with dilute NaHSO · f until decolorizing and brine, dried over anhydrous Na ₂ SO 4 and evaporated under reduced pressure to give 10.17 g of a yellow oil. The crude oil was purified with flash chromatography on 600 g silica gel eluting with 3: 1 hexane-Cl 2 ClI. The product fractions were combined and evaporated to give 7.691 g (74%) total yield for both steps) of the desired title iodide as a clear, colorless, viscous oil. TLC / 3: 1 hexane-ethyl acetate / R f = 0.75, UV and PMA. / Note: the spots of iodide and starting bromide are in the same place /.

(4) (4) Methyl ester (i) -4-α < 0-dimethylxyflsfinyl) -3- / llmethylethyl (αO &lt; 2 &gt; phenyl) siiiloxymffl.

A solution of 7.691 e iodide in 20 ml triethyl phosphite was heated in an oil bath at 155 ° C for 3.5 hours under argon. The mixture was cooled and the excess phosphite was distilled off under a lowered οί ^π, ^^ ηίΜ (67 Pa, 75 ° C), yielding approximately 8.0 g of a yellow oil. The crude oil was purified by flash choline over 400 g of silica gel, eluting with 4: 1 hexane-acetone. Product fractions were evaporated to afford 3.222 g (41%) of the desired title phosphonate as a washed colorless viscous oil. TLC / 1: 1 hexane-acetone / R2 = 0.51, UV and P1MA. In addition, 2.519 g of starting iodide was recovered from part (3), so that the corrected yield was 61%.

154 877/5 / Methyl ester (S/-3-C./^- phosphonomic acid.

5.31 K (32.0 eilieols, 1.6 eq / bistrimethylsilllotróffluoroeethamide IBSTFA) and 6.60 m / were added successively to a solution of 9.85 g / 20.0 mlimoOi / phosphonate from part / 4 / in 60 KL of anhydrous CHgCl4. 50.0 mM1O [mu] m, 2.5 equilibrium of (Trimeeoyl bromide (TwS3R)), then the transparent m-eesanole was passed overnight under argon at room temperature. After the addition of 80 K SU KHOf, the mixture was extracted with ethyl acetate. The aqueous phase was saturated with ad and re-extracted with ethyl acetate. The organic layers were washed with brine, dried over anhydrous Ma ₂ SOf and evaporated under reduced pressure to give the crude title phosphonic acid in a viscous oil. / 7 * 2: 1 isopropane- ^ HfOH-'wudι /.

Rf - 0.30, UV and PMA.

/ 6 / Acid methyl ether / S / -3-2 /l,l-du^metyloethyl/-dw Ufnnloollyloxy^-4//lyirokSleetoxyphosphinyl/aa soybean

To about 20.0 /. Metίκαί of crude phosphonic acid from part / 5 / in 25 KL of anhydrous pyridine, 1.62 KL / 40.0 m-lim 3 ol., 2.0 equi ali / meto ul dried over 0.3 sieves were added. hm and 4.54 g (22.0 m [mu] lLimol and 1.10 equilibrium of (dvoyldLohexyliaΓbudbouleydu) (DCCi) and the resulting white suspension was stirred under argon at room temperature overnight. The pyridine was removed under reduced pressure, then the mLesoia was distilled with aztotrope with two 15m portions of benzene. The remaining oil was dissolved in ethyl acetate, filtered, washed with 1.0N HCl and brine, dried with anhydrous Nb ₂ SO 4. and evaporated under reduced pressure to give 8.272 g of the crude title ester as an oil containing a small amount of precipitated DCliU. TLC / 7: 2: 1 isopropKinol-lttbOH water / R _f - 0.60 UV and PMA.

F. (s) (-4-Z ') 4'-fluo acid, methyl ester: r-3,3'55-thΓΓmethyl-1,1'-bt-phecylUl2 - // teO] -lphosphyl, 7-3-III -Γzęd.-bulyUodwuftnylusilUloks / masUiiegu

6.595 g (about 14.7 µl) of the crude phosphonic acid ester of part E was dissolved in 30 ml of anhydrous CH ₂ Cl ₂ , followed by the addition of 5.60 m. (29.4 µl) ola, 2.0 equivalents of (distilled tΓ) and the mixture was stirred under argon at room temperature for 1 hour. The mixture was evaporated under pressure, dessylated with 30 ml of benzene and dried in vacuo. Pale yellow viscous oil was dissolved in 30 mL of anhydrous CH ₂ C1 ₂ with 2 drops of DMF dried over ertami ^0, 4 ME, followed by ^{p y} rzejrz January solution was cooled to -10 ° C in an ^ice-salt and treated dropwise via strzylawki 1.41K (16.2mmol, 1.1equoane), distilled oxalyl chloride. We observed intensive gas evolution and the color of the solution ^{st t} o Ala cramnożółta. ^M ieszaninę stirred under argon at -10 ° ^{C p} slaughter ¹ 5 einut ^then warmed to room temperature and stirred for 1 GOIZIN. The mixture was evaporated under reduced pressure, azeot distilled with 30 ml of benzene and dried in vacuo to give the crude fusfoouchlUidao as a yellow oil.

To a solution of approximately mile 14.7 / iola crude fusfonuchluridanu 10 mL of dry CH ₂ C1 ₂ wkroplLono R ⁶ twłir 2.0 g / 8.43 mmol / Mfenyloalkohollu of Part D in ¹ 5 rnl of anhydrous pyridine and the resulting mixture was stirred at at room temperature under argon for 16 hours. The mixture was evaporated to dryness and the residue was mixed with 5% KHSOf and ethyl acetate. The organic phase was washed with saturated KaHCO-j and brine, dried over anhydrous gSOf and evaporated under reduced pressure to give 8.290 g of a brown oil. The crude product was purified by flash chromatography of 370 g of silica gel eluting with 70:30 hexane-acetone. Product fractions were combined and evaporated to give 3.681 g (66%) of the desired title phosphonate as a pale yellow TLC oil / 3: 2 hexane-acetone / Rf = 0.59.

UV and PMA.

G. Est ethyl ^{er q} and ^s u / ^s / 4- / 74'-floro- ^{3,3 ', 5-trójeetylo-l,} l-bifeyylUlo- ^e / ^y eeUoks fusfin _7 ~ lu ^{s 3} - ^{h' yd} ru ^k s ^y easłuwe ^g u.

154 877

^ To a mixture of 103 g / 1.66 mmol / silyl ether from Part F in 20.0 ml of anhydrous tetrahydrofuran / THF / ^d of ^d ano 38 ° ^y L / 6.64 ^{mmol, 4.0} eq / lo ^d owatą ^g of acid in acetic oi 4.9 ^{g of 8 m} / 4.98 mmol, ^{3, the} Γ ⁰ (5κ ™ ^ ζηί ^ /, 1.0 - czterobutyooamoniowego fluoride solution, and the clear yellow solution was stirred overnight at room temperature under an atmosphere of Argon The mixture was mixed with cold water and ethyl acetate and the organic phase was washed with saturated aHCO and brine, dried over anhydrous NaSO and evaporated to give 1.174 g of a sticky yellow oil. Crude Hej was purified by flash chromatography. on 47 g of silica gel, eluting with a 85:15 mixture of C ^ C-acetone. product fractions were evaporated well, to give ⁶⁷⁹ m ^g / 9 ^3, 1% / tytHowego the desired alcohol as a clear viscous oil. TLC 1: 1 / Hexane ^h -acetone / = ^0, 4 ^1, UV and PMA.

H. ^S OL jedrnlKom Vasu ^k / s / ~ ⁴ - / / 4'-fluoro-3,3 * 5-trimethyl-l, l'-biphenyl ^l LO ^and / ox ⁱⁿ the metoksyfosfinylo ^f / 33 ^d-h duikyyraasal words ^g l.

To a solution of ¹⁸⁴ m ^g / 0.420 mmol / of methyl ester from Part G in 5.0 mL dioxa ^α n ^l was added ^0, 5 ⁰ ml / 1.2 ^ wnoiwtoi-ka / Li ^1.0 N ° ^H ^ mixed and stirred included at room temperature under argon for 3 hours. The mixture was diluted with water, filtered through a 0.4 µm poly-carbonate membrane and evaporated under reduced pressure. The residue was dissolved in 75 ml of water, frozen and lyophilized. The crude acid was dissolved in the main amount of water and treated with a 100m bed of HP-20 resin, eluting with a 1% concentration gradient of water-CH.C-. The product fractions were evaporated, dissolved in 50 m of water, the solution was filtered through a polycarbonate membrane of 0.4 and yim zliofilizotano to give ¹⁷⁴ m ^g / £ 59.1% / w, based on the lorry * ^hy a'tu / Z ^A of the title salt homogeneous in the form of a small solid. TIC / 7: 2: 1 isoprojanol-1H11H-vocha / R _f = 0.58, UV and PMA. Elementary aralysis for C ^ H ^^ PFLi. 1.95 H ₂ ⁰ / C Molecular weight 465.46 /.

Calculated: C 54.19, H 6.26, F 4.08, P 6.65

Found: C 54.19, H 621, F 4.29, P 6.43 ^{"H -} MR./4 ⁰⁰ m and /: <$ / pp ^ ^{1, 74} - ^2, 0 ^{8/2 H,} m, -P ^ OCH / CHg- / ^{2, 0} 3 / 3H, s, ^g roup methyl ^Getting pierocieniu aromatic ^{/, 2,} 3, ² / M, d, ^g roup methyl ^Getting an aromatic, OC ^s tosunku ^to F , ^{2, 2} Hz /, ^2, 3, ^5-2, 62/2 ^ ^{a, 2.46} / 75Ά, s, methyl gjrupa ^Getting pie ^ shade aromatic / ^3, 57 and ^3, 6 ^3/3 ^ 2 : χ <i— ^Ο ^ / (^ 1 ^^^^ / - ^{, 2} d ⁱ aytereoilomtr ^f , JH_ ^p - 10.3 Hz /, ^4, 28 / l ^ m, -CH ² CH / OH / CH ² CO2Li ^{/ 4,} 97/2 ^ m, C ^ CH ^ P / 0 ^ 0 ^ = /, ^{6, 87} - ^7, 25/5 ^H »m, ^H aromtyczne /.

Example II. ^S OL, dilithium toasu ^ / - 4 - // ^{4-3,3'--fllOΓO} 5-trimethyl-l, l 'and ^{b f f} tnylilo- ^2a metoksyh dru ^and syfos ^f in ^{f lo,} 7-3-hydΓo ^k syaαyłoot ^g u ^,

A solution of ³⁷⁴ mg / 0.853 mmol / diester from Ex ^yk order I 8 ⁰ ml dioxa ^ u, to which was added 2.6 mL / 3.0 onowożn r ^{r and} k ⁱ / l, ^{LiO 0} N ^H o ^ zewam in an oil bath at 5 ⁰ ° C for 5.0 hours under argon. ZtubseIoo> otnu white precipitate. The mixture was diluted with water and filtered. The aqueous solution was extracted once with ttyU01 / fra ether, the filtrates were pulped through a 0.4 [mu] m pulverized diaphragm and concentrated under reduced pressure. The crude product was chromatographed on a 100 ml bed of HP-20 resin, eluting with mixtures of water-CH wodaC- with a linear concentration gradient. The product fractions were evaporated under reduced pressure, dissolved in 50 ml of water. The solution was filtered through a polyethylene membrane pore ęrlanooą ^ = ^0.4 and zliofil ^ wwano afford 267 mg / 67% based on the mis ^{of E} [hydrate / dwilitowej desired title salt in the form of a small substance TLC / 7: 2: 1 ^ o ^ rol-CH.OH-water /

Rf = 0.47, UV and PMA.

Elemental analysis for ^ oH ^ OgPFLi · ,. 1.77 ^ 0

Calculated: C 52, Θβ, H 5.67, F 4118, P 6.82

Found: C 52.88, H 5.26, F 4.24, P 6.43.

¹ H -MR / 400 CD.OD /: cT / ppm / 1.69 / 2H, m, ^ P / o / C ^ CH / / Oh / - /, 2.26 ^- 2.42 / 2.42, ^m

154 877

CH-CO-Li /, 2.30 / 3H, s, methyl group on the aromatic ring // 2.31 / 3H, d, methyl group on the aromatic ring, <Z with respect to F./jj—, "= 1 , 9 Hz /, 2.38 / 3H, s, methyl group on the aromatic ring /, 4.22 / 1H, m, -CH / OH / CH - /, 4.75 / 2H, m, PhCHOP / / θ ("), 6.86-7.22 (5H, m, aroma, 1, 2, and 2) protons.

Example III. Acid monolithium salt / 3S / -4- / 74'-fluoro-3,3'-t-triMeeylool, 1'-biphenylyl-2 / methoxymethyl: fo8f and nyl <7 - ^ - yyi ^ i ^ <^ ls ^; mas3 ^ <^ wego.

A. i / tyl ester of / £> - ^ c _C , ^ orr ^ n ^ eJ ^ y ^^ (^ J ^^ i ^: fin ^ oo33 ^^ / lιl-Sw / ethylthylr / dw ^ rphenylsilioxy Jmslow .

The title compound is prepared as described in the first three portions of Part B of Example 6.

B. Methyl / 3S / -4 - / "4'oflurrr-3,3 ^', 5-tróJπ" Tyll / 0, l biftiylilo-2 / mttoksym / tylofosfiiylo _7-3-tert. butylrde. ^ fennlosillOokl / njsstr.

To a solution cooled in an ice bath to 0 ° C about 2.2 mmol of the compound from Part A i

429 mg / 2.2 mmoles, 1.0 ^ ί «» ιβίηα / biphenyl alcohol from part c / 2 / example 1 in 10 / anhydrous CHgCl 425 µu / 3.04 mmoles, 1.4 parallels / tramines and 27 mg were added (0.22 mmol) 4-DMAP and the orange solution was stirred at room temperature overnight under argon. The mixture was mixed with 5 KHSO- and ethyl acetate, then the organic layer was washed with brine, dried over anhydrous NagSO 4 and evaporated to yield 1.1 g of an orange oil. The crude oil was purified by flash chromatography on 44 g of UP5-1 silica gel eluting with 1: 1 ethyl acetate-hexane. Product fractions were combined and evaporated to afford 298 mm (21%) of the desired title coupling product as a light yellow oil. 460 mg of the starting bifenylalkrhol from Part C / 2 / Example 1 was also recovered such that the corrected yield had instilled in 67%. TLC / 1: 1 ethyl acetate-hexane / R- 0.18, UV and PMA.

C. (3S) -4-2 / 4'-fluoΓO-3,3′-5-aróJmethyl-1,1lbffylyl-2-methoxyoyl-ethylphosphinyl-1-hydroxybutyric acid methyl ester.

110 µl (1.84) µmla, 4.0 glacial acetic acid and 1.43 (3.1 eq / 1) were added to a solution of 298 mm (0.46 mmol) Part B silio ether in 6.0 anhydrous THF. 0.1% of a solution of tetra butyraminegrin fluoride in THF and the resulting solution was stirred overnight at room temperature under argon. The mixture was mixed with cold water and ethyl acetate and the organic phase was washed with saturated NaHCO- and brine, dried over anhydrous Na2SO- and evaporated to give 273m / yellow oil. The crude oil was purified with a m / m charl flash tube on 11 g LP3-1 silica gel, eluting with 1: 1 hexanacetone. Product fractions were combined and evaporated to afford 150 µl (80%) of the desired title alcohol as a viscous oil. TLC / 1: 1 hexane-acetone / Rf 0.23, UV and PMA.

D. The monohydrate salt of (3) - 4-) ^- 4 -fluoro ^^ ', 5-trimethyl (1,1' - 'bieinylyl - // teOoxy methylphosphilyl) 7-3ohldarkmaric acid.

To a solution of 150 µl / 0.367 mmol / of methyl ester from C part in 3.0 µl of dioxane was added 0.44 ml / 1.2 aówi:> rwjηika / 1.0 n LiOH and the resulting white suspension / was allowed to stir at room temperature under argon for 2 hours. The mixture was diluted with water, filtered through a 0.4 [mu] m pristrocarbonate membrane and evaporated under low pressure to give a colorless glassy solid.

The crude product was dissolved in the minimum amount of vidia and chromium in a 100 m bed of HP-20, eluting the mixture of / i water-CH-CN with a concentration gradient. The product fractions were evaporated, dissolved in 50 ml of water, the solution was filtered through a polycarbonate membrane of 0.4 / m and zliof ιΙ ς ^ ^ ι ^ afford 130 mg / ^{1 of} 7% based on the weight of hydrate / lioowej desired title salt in the form white solid. TLC / 7: 1: 1 -H2-12- (®taiol-acetic acid / Rf = 0.52, UV and PMA.

Elemental analysis for C- ^ H-O-FLiP. 1.73 H-O (MW 44.43).

Calculated: C 56.61, H 6.44, F 4.26, P 6.95

154 877

Found: C 56.67, H 6.36, F 4.31, P, 7.43 ¹ H NMR / 400MHz / C / ppm / 1.49 / 3H, d, -ΟΡ / Ο / Ο ^ - / -, 14.7 Hz /, 1.83-2.0 / 2H, m,

P / 0 / - ^ CH ^ / C ^ H ^ · 2.27-2.40 / 2Ά, m, a ^ gO / Li /, 2.30 / 6H, s, 2 methyl groups on the aromatic ring /, 2.44 / 3H, s, methyl group on the aromatic ring-rn /, 4.26 / lH, m, - ^ ΟΗ / ϋΗ / ^^ ϋ /, 4.87 / 2H, m, ArCH20P / 0 / CCH3 / - /, 6.90-7.20 (5H, m, H aromtite).

Example IV. Salt monolithic acid / s / -4- / 2,4-dwucthoro-6- (4-fluorophenylmethoxyphenylmethoxymethoxyfooSinyl) -3-hydroxybutyrate.

A. 2,4-diucl'-oro-6 - / - 4ol-α-oeeyyOmethoxy (benkaldehyde) see J.Mec. C-em. 1986, 29, 167- /.

While stirring a solution of 13.77 g (72.5 mmol) of 4,6-dwlC-loro-2-hydro-oxybenzaldehyde in 100 ml of DMF, 12.02 g (87 mmol) of K2CO3 was added thereto. The mixture was heated for 60 minutes at about 70 ° C and then 11.7 ml of 4 / 0ΊuoΓObenzyl bromide was added thereto. The resulting solution was stirred at 70 ° C for 3.5 hours and then poured into 1.5 liters of ice water. The solid was filtered off, washed with water, and recrystallized from diethyl ether-petroleum ether to afford 17.88 g (83%) of almost white crystals with a mp. 107-108 ° C.

B. 2,4-Dwιlh-lΓr-6- (4-0'luorophenes) -methoxybenzenemethanol.

158 mg (4.16 mmol, 0.6 equiv. Of LiALH) was added to 10.0 ml of cold, ice-bath-cooled to 0 ° C, solution 2 was added dropwise to the resulting gray suspension. 06 g (6.93 mmol) of Part A aldehyde in 10 mL of anhydrous THP. The mixture was warmed to room temperature and stirred for one hour under an argon atmosphere. The mixture was cooled back to 0 ° in an ice bath and the reaction was quenched by dripping successively 160 µl water, 160 µl 15% Na / H and 475 µl water. The precipitated salts were removed by filtering the mixture through anhydrous 2 SO 4 through a bed of Celite 6.4 mm thick. The clear filtrate was evaporated to give 2.052 g (98%) of the suaosec-alcohol as white crystals. After trituration with cold hexane, 1.892 g (91.2%) of pure title alcohol was obtained as a crystalline white solid 5.5 72-73 ° C. TLC / 4: 1 hexane-acetone / Rf 0.31, UV and PMA.

Elemental analysis for C1H210 (Cl8F) (low molecular 301.142).

Calculated: C 55.14, H 3, t?, Cl 23.55, F 6.31

Found: C 55.97, H 3.71 Cl 23.42, F 6.30

C. Kwisu methyl ester /s/-4-Z'2,4-diuchlor-6-/4-fluoxophene-methoxyOfetylmethoxymethoxyphosOinyl.7-3- first order-shoes-retortOentlsilyloxmIαιs.

To a solution of about 3.84 mmoles of the methyl ester from Part E / 6 / Example 1 in 10 ml of anhydrous CH 2 Cl 2 was added 1.46 m (7.68 mmole, 2.0 equiv. Distilled triethyl-yl-diamethylamine) and the solution was stirred at room temperature. under argon for 1.0 hour. The -dlarosan- mixture under reduced pressure was azeotrope distilled once with 20 ml of benzene and dried in vacuo to give the crude monomethyl ester of the silylated ohosphonic acid as a colorless oil.

A solution of about 3.84 mmoles of crude ester in 10 mL of anhydrous CH 2 Cl 2 with the addition of 1 drop of anhydrous DMF was cooled to -10 ° C in an ice-salt bath, and 368 µL (4.2.2 mmoles) was added dropwise thereto. , 1 equilateral / distilled oxoUl chloride. Gas evolution from the clear yellow mixture was observed. The mixture was stirred at room temperature under argon for 1 hour, then evaporated in vacuo and azeotropically distilled twice with 20 ml of benzene to give the crude Oosphonochloridate as a sticky yellow oil.

To approximately 3.84 ml of crude O-phosphonochlidane in 10 ml of anhydrous C 5 C 3 at 0 ° C in an ice bath, 1.15 g (3.84 mmol), 1.0 eq. from Part B followed by 805 [mu] l / 5.76 mils) 1a, 1.5 eq / triethyl amine and 47 mg / 0.384 mmol, 0.1 eq / 4-DMAP and the brown mixture was stirred overnight at room temperature in an argon atmosphere. The mixture was mixed with 5% KHSO4 and ethyl acetate and then Oaza

The organic was washed with brine, ^dried over anhydrous Na ₂ SO 3 and evaporated to give 3.197 g of a dark brown oil. The crude product was purified by flash chromatography over 160 g silica gel eluting with 7: 3 hexane-ethyl acetate. Product fractions were combined and evaporated to afford 594 mg (21.1%) of the desired title phosphonate as a yellow oil. In addition, 688 mm of starting alcohol from Part B were recovered, so that the corrected yield was 52.6%. TLC / 1: 1 hexane-acetone / Rf 0.29, UV and PMA.

D. (s) (4- (2,4-Dichhoro-6- (4-fluorophenylmethoxy) phenyl) methoxymeehyphosphinyl) -3-hydroxybutyric acid methyl ester.

To a solution of 578 mg (0.788 mmol) of Part C silio ether in 8 µl of anhydrous THF was added 180 µl (3.2 mmol, 4.0 equiv.Okr) of glacial acetic acid followed by 2.36 ml / 2.36 mmol, 3. ORIGINALS / 1.0 m / n-ZgHg / NF in THF and the resulting pale yellow solution was stirred overnight under argon at room temperature. The mixture was poured into a cold water and extracted twice with ethyl acetate. The organic phase was washed with saturated NaHCO 3 and brine, dried over anhydrous Na ₂ 50 g and evaporated to give 625 mg of a yellow oil. The crude product is purified by flash chromatography on 31 g of silica gel, eluting with 7: 3 hexane-acetone. Product fractions were combined and evaporated to give 339 mg (86%) of the desired title alcohol as a clear, colorless, viscous oil. TLC / 1: 1 hexane-acetone / Rg = 0.25 UV and PM.

E. Homogenous salt of the (s) -4- (2,4-diuclhLoro-6- (4-fluorophenylmethoxy) phenylmethoxymeorrifhosphoyl) -hydraxyribic salt.

To a solution of 132 mg / 0.267 mmol / phosphonate from part D in 2.5 mL of dioxane was added 0.32 ml / 1.2 equiv / 1.0% LIOH, and the mixture was stirred at room temperature for 4.0 hours under argon. . An inclusion of a white solid was observed. The mixture was diluted with water and filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was chilled onto a 100 mL bed of HP-20 resin, eluting with a linear gradient of water-CHgCN mixtures. The product fractions were combined and evaporated, dissolved in water, the solution was filtered through a 0.4 µm polycarbonate membrane and lyophilisophilized to give 108 mg (7 µm hydrate basin) of the desired title lithium salt as a white solid. TLC / 20: 1: 1 CHCl2-methanol-acetic acid / Rf = 0.41, UV and PMA.

Elemental analysis for C ₁ gHlgOfCl2FLi2P · 1.42 H ₂ O (molecular weight? 511.72).

Calculated: C 44I, 59 H 4.10 Cl 13.86 F 3.71 P 6.05

Found: C, Al 4.22 H 4.09 Cl 13.91 F 3.72 P 6 R 1 ¹ H NMR / 400 Mz / :( T / ppm ^{/ 1} 98-2. ¹¹ / 2H, m, OP / O / ^O (CH ^{3 (} CH ₂ (OH) -) ^, 2.26-2.45 (2H, and ^m

CH / 0H / CH2C0 ₂ Li / 3.63 and 3.62 / 3H, 2 xd, 2 difstereoiroraerf, 0P / o // CCHg / <H ₂ -, DRG = HH ^ /, 4.23 / 1H, m, //: c ₂ - / C / OC // - C ₂ / O ₂ Li /, 5.16 / 2H, s, F-PHH, 0 /, 5.24 / 2h, d, ArCHgOp ¹ , ^J HP ⁼ R, 2 Hz), 7.13-7.53 (6H, m, H aroma).

Example V. Salt Z ^ wιlitooa kaw su / 3S / -4- / 2,4-ZwJlhlloOr6- / 4-fluooofenflo-meOrkSf / fonyromeOrrsfhydrocryphosphioylr / -3-hfdrrkΞymasłooegr

To a mixture of 210 mg / 0.424 mmol / dl of BST-ru from part D of Example 4 in 4.0 ml of dioxane was added 1.30 ml / 3.0 mono-phosphor / 1.0 n LiOH and the colorless solution was heated in an oil bath at 50 ° C. C for 3.5 hours in argon aOmorfeosis. After 15 minutes, precipitation of a white solid was observed. The mixture of water and water was filtered and the filtrate evaporated under reduced pressure. The residue was dissolved in the minimum amount of water and chromatographed on a 100 mL HP-20 resin bed, eluting with a 10-N gradient concentration gradient of water-CCgCN mixtures. The product fractions were combined and evaporated. The residue was dissolved in 50 ml of the water, the solution was filtered through a 0.4 [mu] m and pore carbonate diaphragm to give 175 mg (81% by weight of hydrate) of the desired title lithium salt as a white solid. TLC. / 8: 1: 1 CHcC / ₂ -meetιno-acetic rosas / Rf = 0.7, UV and PMA.

154 877

Analysis calculated for C ₁ gH ₁ gO ^ C ^ l. ₂ FLi2P. ₁ , 70 H ₂ 0 (molecular weight 509.62).

Calculated: C 42.42 H 3.84 F 3.73 Cl 13.91 P 6.08

Found: C 44.46 H 3.90 F 3.93 Cl 17.42 P 5.66 ¹ H NMR (400 Mk): J7pp ^m (1.77-1.94 (4H, m) OR (o) OLi-CH ^ H / OHA-Z, 47 (iH.dd ,- CH / OH / C ^ COg Li, Jyjj- 8.8 kz !, 4.79 / 1 /, dd, - CH / O ^ -C (C 16 Li, 4.4 Hz), 4.46 µm, m, CH 4 CH (OH) CH 4

CO4L./, 5.08 / 4h, s, F-P — C (OAa), 7.07-7.57 (6), m, H aroma /.

EXAMPLE VI. Mtyl ester Z ^ su /4D/-4-/4,4-dwielU.o]ro-6-/4-fluoxo>eenylmetoZsy/phenylmethoZsymetyCiooafieyl J-S -butyrate

A. Zwisu methyl ester / sA * - ^ /l.l- dimethylethyl/dwilenelooSliloZsy ^ -A-eeoZkymethylphosphate

A mixture of 4.68 g (9.18 mmol) of iodine from the E1 ~ 7L portion of Example I by 5.0 g (76.7 mM1l) (meeyl-dd4nolyzes Co8fin (chemcaas strem). was heated at 100 ° C in an oil bath for 4.5 hours, then at 150 ° C for a further 7 hours under argon in a yellow solution, and a white precipitate was formed. The excess phosphine was distilled off under reduced pressure (67 Pa), and the crude product was purified with a c-romase flash on ZrzemionZodye gel, eluting with 65:75 hexane-acetone. The product fractions were combined and evaporated to give 1.590 g / 78 [mu] l of the desired titanium ester mixture of diastenolemerod as a clear viscous oil. TLC (7: 4-eZsane-acetone (Rf = 0.19 and 0.44 (4 diastereoisomers), UV and PMA.

B. Zwsu / 7S / -4 - / ^ 4,4-dduchloIr] -6- / 4-flιl) Γoneny0eeetoZsyineny0oentlZsymenyllyl8iinyll .7-3-III-radium methyl ester - UuCyloddlphenylsllileπa8lodego.

To a solution of 605 ml of h-.7 mmol / Part A ester in 6.0 ml of anhydrous CHgClg was added 480 µl / 1.05 mmol, 0.8 different dtneka / bis / thymethylsilyl / triUluoΓoaeeaemiOu / BSTFA / and 410 / ul / 1.57 miimoles, 1.4 miscellaneous dιtnelzl / bromine trieeeyColSlill, then the resulting solution was meshed at room temperature under an argon atmosphere overnight. After addition of 15 m. 5% KHSO ^ d the mixture ^{rel tΓt-S} l> given with ethyl acetate. The organic phase was washed with brine, dried over anhydrous Na 4 SO 4, and evaporated under reduced pressure to give the crude salt slurry as a colorless oil.

470 µl / 1.44 µmol, 1.1 equivolume / distilled trimethylsilylethylamine were added to a solution of 1.7 ml of crude slime in 6.0 ml of anhydrous CH4Cl ⁴ , and the clear mixture was combed at room temperature under argon. for 1.0 hour. The mixture was evaporated under reduced pressure, distilled, i.e. trapped once with 15 ml of benzene, and dried under reduced pressure.

To a solution of about 1.7 ml of a silildinium Silded Flush in 6.0 ml of anhydrous CH ⁴ Cl ⁴ with 1 drop of DMF was added dropwise using a cutter: L 170 / ii / 1.44 millimoles, cooled in an ice bath to 0 ° C. 1.1 from a variety of distilled c-lorZu oxalyl. Gas was observed in ^ ^ and ^ s ^^ in ^ and ^ iLe. The mixture mesh at poZojowej in atmisferze argon for 1 hour, then evaporated under reduced pressure, distilled tznltrlpowej once with 15 ml of benzene and df ^s, l ^s zlnl under zmlinjszonye pressure uzysZując surldc c-loreZ overhang phospha> owngl as a yellow oil.

D ° of a solution cooled to 0 ^° C in an ice bath of a solution of about 1.3 mmol of phosphinic acid chlorine and 392 mg (1.3 mmol) of alcohol from part E / 6 / Example 1 in 6.0 ml of anhydrous CH ² Cl ⁴ was added 275 µl (1.97 mmol, 1.5eq) triethylamine and 16mg (0.13mmol, 0.1eq) 4-DMAP to give a yellow mixture under argon at room temperature overnight. The mixture mesh with 5% KHSO ^ and ethyl acetate and the organic phase was washed with brine, dried over anhydrous Na ₂ S0 ^ and evaporated to give 908 mg of crude product as a dark yellow oil. The crude product was purified by flash chromaaoggaphy on 45g silica gel eluting with 3: 2 hexane-ethyl acetate. Product fractions were combined and evaporated to give 266 mg (28.3%) of the desired title

154 877 for the product in the form of a clear colorless oil. 197 mg of starting alcohol was also recovered, so that the corrected yield was 57%.

C. (3s) -4-'2.4dW _{V [} mu] l _C hioro-6- (4-i'lurrofeyyoo! Netoxy) (phenyo-methoxymeeylphosphinyl) J7-3_hydroxybutyric acid methyl ester.

To a solution of 275 mg (0.38 mmol) of part B siimeter ether in 6.0 ml of anhydrous THF was added 90 [mu] l (1.53 mmol, 0.0 equal to 1% of the total amount of glacial acetic acid and 1 , 2 m. / 3.1 eq. / 1.0 of a solution of tetrabutyaammonium fluoride in THF. the solution was stirred overnight in an argon atmosphere at room temperature. The mixture was mixed with cold water and ethyl acetate, the organic phase was washed with saturated NaHCO 3 and brine, dried over anhydrous 2 ° C and evaporated to give 258 mg of a yellow oil. The crude product was purified by chroma, flash and purification over 8 g of LPS-1 silica gel, eluting with 1: 1 hexanacetone. Product fractions were combined and evaporated to give 1/2 mg (77%) of the desired title alcohol as a clear, colorless oil.

TLC (1: 1 hexane-acetone) = 0.20, UV and PMA.

D. Kwisu / 3S / -4- ~ 2,4-Wwwchlorr-6 - / _- fluo-phenyo-methoisy-phenyophtoisy_ meeylphos / inyl salt J7-3_hydroxy phenytois.

To a solution of 1/2 mg / 0.296 mmol / Part C methyl ester in 3.0 ml of dioxane was added 0.36 m. / 1.2 eq / 1.0 n LiOH and the resulting white suspension was stirred under argon at room temperature. for 2.0 hours. The mixture was diluted with water, filtered through a 0.1 µm polycarbonate membrane, and the filtrate was evaporated under reduced pressure.

The crude product was dissolved in a m / m mixture of water and chrmtographs per 100 mL HP-20 resin bed, eluting with an Indwm water-CH2CN mixture gradient. The product fractions were combined and evaporated. The residue was dissolved in the view, the solution was filtered through a polycarbonate membrane and lyophilized to give 93 mg / 6% based on hydrate grade / the desired title lithium salt as a white solid TLC / 8: 1: 1 CH / g N-methane acetic acid / R - = 0.51, UV and PMA.

Elemental analysis for 1.38 H ₂ 0 (molecular weight 495.94).

Calculated: C 46.01 H 4.42 F 3.83 Cl 14.30 P

Found: C * / H 5.10 4, 99 F 3.22 Cl 14.32 P 6 * 3 ¹ N NMR // 00 // MM: ^{/ p} pm / ^1, 53 ^/ 3G, d _ OPA / CH / C ^ -J ^ p ^- 14.6 Hz /, ^1,87_2, 10/2 / m / OO ^ / ^ C /, 2.27 / H, dd, flight / OHlCH2CO4Li, J /../- ® , / Hz, J / _ _p _ 1.1 Hz /, 2.38 /iH.dd,- CH / OO / _CH2C02L .. J / _ / = /, 7 Hz, J / _p = 1.1 Hz / , //, 29 µm, m, _1H4CH / OH / CH2_lO2Li /, 5.16 + 5.18 // H, m, ArC1OP and F-PhC / O- /, 7.11_7.52 / 6H, m, aromatic /.

Example VII. Mono-polyol salt of k4 (4) / 4 -luoro-3.3 ', 5-trimethyl-1.1, 1'-li-fnylyl-4 (methylaminomethoryl-oinyl)) -hydroxybutyrate.

A. Kiws / '- fluoro-3; 3', _- tojymethyl-1,1'-biphenyakbrl: kkly0owl_2

To a solution of 1.0 g. 13 mmol / of the aldehyde from part of Example 1 in 10.0 ml of acetone, at 0 ° C in an ice bath, was added dropwise. 1 ml (excess). Jones reagent and the resulting brownish gray suspension were stirred overnight under argon at room temperature. The excess oxidant was destroyed by the addition of 10.0 m. Isopropanol and the precipitated chromium salts were removed by filtering the suspension through a bed of Celite 6.4 m thick. The filtrate was evaporated, taken up in ethyl acetate, the solution was washed 2 times with 1.0 N HCl, 2 times with saturated NH / d and once with brine, dried over anhydrous NH 2 SO 4 and evaporated to give 1.011 g of a green solid, mp. 153_15 / ° C.

The crude acid was purified through a salt with a cyclic rheisylamine salt. To a solution of the crude acid in 5.0 ml of ethyl acetate was added 823 [mu] l (1.0 equiv / dicyclic hexylaminl / DCT / a). The solution was diluted with hexane and the precipitated salt was separated to give 997 mg (5% lipid of the aldehyde) desired product as a crystalline off-white DC / A salt, m.p. 181_183 ° C.

The title free K / SO 4 salt was removed from the DCHA salt by mixing this salt with 5% K / SO 4 and ethyl acetate.

154 877 lu. The organic phase was washed with brine, dried over anhydrous Na ₂ SO 4, and evaporated under pressure to give 554 mg (52% yield from the aldehyde) of the desired title acid. TLC / 9: 1 CH ₂ C 12 meeanoo / R f = 0.37, UV and PMA.

B. 4'-Fluoro-3,3 *, 5-trδjmethyl-1,1 '-' binynylokaboramide-2. To a suspension of 554 mg / 2.14 mmol / of Part A acid in 6.0 mL of anhydrous CH ₂ Cl ₂ with 1 drop of anhydrous DMF cooled to 0 ° C in an ice bath, 205 / µl / 2.35 mmol was added dropwise via a syringe, 1.1 eq / distilled oxalyl chloride and the clear yellow solution were stirred under argon at room temperature for 1 hour. The mixture was evaporated under reduced pressure, distilled azeotroped with benzene and dried in vacuo to afford the crude acid chloride as a yellow oil.

A solution of the crude acid chloride in 3.0 mL of THF was added dropwise to a mixture of 3.0 mL of THF and 2.0 (excess / concentrated NH 4 OH) cooled in an ice bath to 0 ° C and the resulting light orange solution was stirred at room temperature under argon for 1.0 hour. The mixture was mixed with water and ethyl acetate and the organic phase was washed with saturated NaHCO 3, water and brine, dried over anhydrous Na 2 SO 4 and evaporated to give 528 mg (96.1%) of the crude amide as a light orange solid. One recrystallization from ethyl acetate-hexane gave 435 mg (79.1%) of the purified title amide as pale yellow needles, m.p. 197-198 ° C.

TLC / 1: 1 ethyl ether-acetone / R _f? 0.83, UV and PMA.

C. 2-Aminomethyl-4-fluoro-3,3,5-trimethylOol, 1'-biphenyl.

To 5.0 mL of anhydrous THF, cooled to 0 ° C in an ice bath, 125 mg (3.3 mmol) of solid LiAl = was added, and a solution of 424 mg (1.65 mmol / amide from Part B) was added dropwise to the gray suspension over 5 minutes. in 5.0 ml THF. The solid suspension was stirred at room temperature under argon for 2r5 hours and then heated under reflux for 45 minutes. The mixture was cooled to 0 ° C in an ice bath and quenched by the sequential addition of 125 µl water, 125 µl 15% NaOH, and 375 µl water. The precipitated gHncwe salts were removed by filtering a suspension through anhydrous Na ₂ SO 4 on a pad of celite. The clear filtrate was evaporated under winter pressure to give the crude amine as a clear oil. TLC / 7: 3 ethyl ether-acetone / Rj = 0.60, UY and PMA. The amine was purified via the hydrochloride salt.

To a solution of about 1.65 mmol of the crude amine in 8.0 ml of absolute ethanol was added 152 µl / 1.82 of concentrated HCl, and the resulting mixture was stirred for 15 minutes at room temperature under argon. The mixture was evaporated under reduced pressure to give a crystalline white solid. After trituration with cold diethyl ether, filtration and drying in vacuo, 426 mg (92.4%) of the title amine hydrochloride were obtained as fine white crystals.

D. Methyl ^ k su / S / -4 - // 4'-fluoro-3,3 ^', 5-trójeeeylOll, l'-bifenyli0o-2 / metylljminoπmto0sylolSioylo 7-3 -ΪII-Γzęd.-UulyOodwufeollltililoklmπaslowegl.

To a solution of about 2.0 mmoles of the methyl ester from part E / 6 / Example 1 in 5.0 ml of anhydrous CH 2 Cl 2 was added 758 µL / 4.0 mmoles, 2.0 eq of Oki (distilled triethylthlyl-dueyylaeiol) and the clear mixture was stirred at room temperature under argon for 1 hour. The mixture was evaporated under reduced pressure, subjected to an ionizing distillation with 15 ml of benzene and dried under reduced pressure.

192 µl / 2.2 eilimal, 1.1 of dethyl oxalyl chloride were poured into a 0 ° C solution of the crude thiloylo sulfonate in 7.0 ml anhydrous CH 2 Cl 2 with 1 drop of DMF. Evolution of gas was observed from the clear yellow mixture. The solution was stirred at room temperature for 1 hour, evaporated under reduced pressure, azeotroped with two portions of 15 ml of benzene, and dried under vacuum οϊί ^ ηϊι ^ ηϊη to give crude photfonochloridao as a viscous yellow oil.

To a 0 ° C solution of phosphorus terrace chloride and 416 [mu] g (1.49 eilol) Part C biphenylamol hydrochloride in 10 ml of dry CH ₂ Cl ₂ was added 641 µl / 4.6 mmol,

2,3 ^ ϋονΗηόΚβ / trieyllamol and 24 mg / 0.2 millimol, 0.1 different ηOka / 4-DMAP, then

The resulting clear yellow mixture was stirred overnight at room temperature under argon. The mixture was mixed with 5% KHSO 4 and ethyl acetate, the organic phase was washed with brine, dried over anhydrous N 2 SO 4 SO 4 and evaporated under reduced pressure to give 1.19 g of a yellow oil. The crude product was purified by flash chromatography on 60 g silica gel eluting with 7: 3 hexane-acetone. Product fractions were evaporated to afford 588 mg (59.%) of the desired title phosphoionamide as a viscous pale yellow oil. TLC: Rf = 0.20 (hexane-acetone 7: 3, UV and —M).

E. Cross-methyl ester (s (-4 -) "/ 4'-fluoro-3,3 ', 5-tΓΓmethyl-1,1--biienylSo2 / methylsaminomethoxyffofinyls" / -S-hydroxybutyrate.

To a solution of 588 mg / 0.888 mmol / eiliSoeteIjι from Part D in 10.0 mL of anhydrous THF was added 203 µl / 3.55 mmol, 4.0 eq / glacial acetic acid and 2.88 ml / 2.68 mmol. , 3.0 equiroanics / 1.0 M of a four-shoe-salt fluoride solution in Tlff, followed by stirring overnight under argon at room temperature. The mixture was poured into cold water and extracted with ethyl acetate. The organic phase was washed with saturated NaHCOp then brine, dried over anhydrous Na ₂ SO 4, and evaporated under reduced pressure to give 605 mg of an orange oil. The crude product was purified by flash flash on 38 g of silica gel, eluting with 1: 1 hexane-acetone. Product fractions were combined and evaporated to give 198 mg (50%) of the desired title alcohol as a pale microscopic oil.

TLC (1: 1 hexane-acetone (R f = 0.18, UV and W).

F. Salt monohoGNa krosu / 4'-fUuoro-3,3 *, 5-trimoyl-, l'-biinyliO-22 / methylsaminomethoxyphosphinyls _- 7-3-hydrsksy®asłowigs

288 µl / 1.2 tq / 1.0 n LiOH was added to a solution of 105 mg / 0.2140 milliral / Dvustru from Part E in 2.0 ml of dioxane and the white suspension was stirred under argon at room temperature for 4 hours. , 0 hours. The mixture was diluted with goose, filtered and the filtrate was evaporated under reduced pressure. The residue was chrroratographed on a 100 mL H-20 bed, eluting with a concentration gradient of water-CH-1CN mixtures. The product fractions were combined and evaporated. The residue was dissolved in 50 ml of water, the solution was filtered through a polycarbonate membrane with 0.4 µm pores and lyophilized to give the desired title lithium salt 70 mg (82% based on hydrate) / the desired title lithium salt as a white solid.

TLC / 20: 1: 1 CHCl2-methanol-acetic acid / Rf-0.19, UV and PMA.

Elemental Arrlysis for C8 ^ gNO ^ PFL1.E.a and HgO (MW 472.75).

Calculated: c 53.35, H 6.57, N 2.96, F 4.02, P 80.55

Found: C 53.35, H 6.52, N 2.98, F 4.05, P 6.59 ¹ H JAR / 400 Miz /: T / ppm / 1.79-1.97 / 2H, m, p / 0 / OOC3 / CH2 /, 2,29-2,44 / 2H, ^m, CH2C0 ₂ Li /, 2.29 / ^3H, g ^r spine ratylowy at ^p ierścieniu and ro has Stake NYM / ^{2 ,} 31 / 3H, Ar-CH DSW ratio ^{d F,} JH-l ^ l-Iz /, ^2, 4 ⁷ / ¾. ^3, 4 ^{9 3,} 5 ° / 3 ^ 2x <i, ² stereoisomers ^ <^ 1 = 10,5ΗζΛ ³ 9 ⁹ z'2H, m, C and ⁵ łCH2N ^^^ {Oj bCH3 / - /, 4.17 (1H, m, (-CH 2 CH) ° H (CH ₂ CO ₂ Li), 9.84-7.21 (5H, m, aromatic protons).

^Fr zykład VIII. Methyl ester ^k rosu / ^S / ^-4-p dłwuizopprp loksyfasoinylo-3 - / - / l ^d l wumetylootylo / dwufer ⁿ looilil.ocksy ./masłowego ²¹ ° 7 g / 4 ⁵ 1 mmol / iodide in Part E / ³ / it happens and I mix in very low-pressure holes for 30 minutes. After the addition in one portion 93.92 g / 0.451 mol, 113.37 mJ fresh distilled trójizoproyylowego phosphite the reaction mixture was stirred under an atmosphere of argon while warming in an oil bath at 1 ⁵⁵ ° C for 16.5 ^g odzin ^{y p} r ^s parts of ^d of cooled room temperature. Madrnia. - isopropyl tri phosphite and volatile reaction products were removed by distillation mletailarnej at a pressure of 1.33 kPa and then distillation using's lymphoma ^{d s} of the ball at one °° C ^{O p} o ^d cUśnieniern ⁹ 7 ^p and ^p slaughter 8 ^{g of} product for eye odzir .. ^y szczono chroraatogaaii by flash column having a diameter of 95 mm with a layer of Merck silica gel with a height of 15 mm °. The column was eluted with 9: 3: 1 hexane-acetone-toluene from shaft 22

154 977 with a linear bone of 50 m / min, collecting fractions of 50 Obtained 17.68 g / 33.96 mmoles,

75% yield of the title isopropylphosphouiant as a clear viscous oil.

TLC / silica gel, 6: 3: 1 hexane-acetone-toluene (R) = 0.32.

¹ H NMR (270 M! Z, CCCl - (: 7.70-7.65 "), bH? 7.45-7.35") ^, 6h), 4.57-4.44 ^m m, 3H), 3.59 / s, 3H /, 2.94+ 2.88 / 2xd, 1H, J = 3.7 Hz /, 2.65 + 2.60 / 2xd, 1H, J = 7.4 Hz /, 2 , 24-1.87 (m series, 2h), 1.19 + 1.12 (2xd, 12h, J? 6.3 Hz), 1.01 (s, 9H).

Example DC. Salt of the methyl ester k "su ms / -4hydroxymethoxyphosphinyl-3 - /" / ml, d-WummethylethyOodWvulfenylsilyloxy (ιαasOic and dimethylOhexylamino / 1: 1).

10.66 / 30.5 mmol / izopropylofosfoniant of Example XXI was stirred under argon at room temperature, 80 ml of anhydrous CHHgC ₂ · What this solution was added dropwise over 5 minutes 8.71 ml / 8.44 g, 32.8 (ill (oH) bistrimethylsilii.tritluoraccea (πlidt (BSTFA)) followed by the dropwise addition of 6.75 (7.84 g, 51.3 (11l) trimethylsilyl bromide (TMSSr) over 10 minutes. After stirring for 20 hours at room temperature, the reaction was quenched with 200 ml of 5% aqueous KHSO4 and vigorously stirred for 15 minutes. The aqueous layer was extracted 3 times with ethyl acetate. The organic extracts were combined, washed once with brine, dried over NagSO 4, and concentrated under reduced pressure. The residue was azeotroped twice with 50 ml of toluene each. The precipitate was dispersed in toluene and the suspension was filtered. The filtrate was concentrated and azeotropic distillation was performed again by filtration. The resulting filtrate was evaporated under reduced pressure and then dried for 5 hours under very low pressure using a vacuum pump. The resulting viscous, clear oil was mixed under argon at room temperature with 50 µl of anhydrous pyridine. Each of this solution was added 4.65 g (22.6 mmol) of dMuykl.ohethyl-carbodiimide (DCC) and then 1.67) in one portion. (1.31 g, 41.0 milli µl) methanol. After (sewing at room temperature for 20 hours), the reaction mixture was filtered through a cent pad on a splintered glass funnel. Celite was washed with ethyl acetate and the combined filtrates were evaporated under reduced pressure. The residue was redissolved in ethyl acetate and washed times with 5% aq. KHHO4 and once with brine. The organic extract was dried over Na ₂ SO 4, filtered and the filtrate was concentrated and azeotroped 2 times with toluene, dispersed in toluene and the suspension was filtered. The resulting filtrate was concentrated again, subjected to a purge azeot, filtered and the filtrate was evaporated under reduced pressure / m and placed under very low pressure / for 6 hours, yielding 10.2 g (over 10C% yield) of phosphono karst monoester as a clear viscous oil . TLC: Rf = 0.50 (silica gel, n (p / 11a, no- &lt; 2 &gt; HĄ-wldα 7: 2: 1). 1.21 g of phosphonic karst monoester sample was dried under very low pressure for 4 more hours using a vacuum pump to obtain 1.16 g (2.57) l / o / of the product which was dissolved in 10 l of anhydrous ether ethyl. The solution was bought in 0.528 µl (0.481 g, 2.65 ml / l / d) of hexane / ha. The repeated homogeneous solution was allowed to stand for 7 hours at room temperature as a result of which a significant amount of crystals formed. The mixture was allowed to stand for 16 hours at -20 ° ^C then warmed to room temperature and filtered. foyształy washed with cold anhydrous ether / light ityOow /> and dried under vacuum over P wsokim 0- ₂ for 18 hours. The crystals were then dried under very low pressure at 45 ° C for 4 hours to give 1.25 g / l, 98 mmoles, 77% of the title salt of the di-ticlohexstlore salt as a white powder, mp 155-156 ° C. . TLC silica gel, 20% methanol solution in (C ₂ Cl ₂ / R 2 = 0.57.

¹ H fJMR '270 MHz, CID1- /: 7,71-7,65 //.W, ^7,40-7, 32 // 6h /, 4.02 / m, M / ^3, 52 / a , 3hrs

3.28 + 3.22 d, 1h /, 3.11 (d, 3H, J = 11Hz), 2.77-2.64 (m, 2h), 2.62-2.56 //, 1H) , 1.92-1.08 (series / 22Η /, 1.00 (s, 9H).

* 'id / o / ^ words / FA3 /: 632 / m + H / +

IR / K ^ i //: 3466-3457 / broad /, 3046, 3016, 2997, 2937, 2858, 2336, 2798, 2721, 2704,

2633, 2533, 2447, 1736, 1449, 1435, 1426, 1379, 1243, 1231, 1191, 1107, 1074, 1061, 1051,

820 ^c n: ~ ¹ .

154 877

Elemental analysis for ^c 22 ^H 31 ° 6 ^PSi 'Cl2 ^H 23N

Calculated: C 64.63, H, 61, N 22.22

Found: C 64.51, H 8.49, N 2.18.

Claims (4)

Patent claims 6. The method of producing new 3-hydroxybutyric acid derivatives of the general value 6, in which R is a hydroxyl group, a lower alkoxy or a lower alkyl, X is an oxygen atom or a group ——Η—, n is a number 6 or 2, z is an anchor hydrophobic of general formula II, in which R, R and R are the same or different and represent a hydrogen atom, a halogen atom, trifluoromethyl, lower alkyl, haloalkyl, phenyl, substituted phenyl or a group of the formula ORy in which R5 is hydrogen, alkanoyl, bernoyl, phenyl, halophenyl, trifluoromeeylphenyl, phenyl-lower alkyl, lower alkyl, cinnamyl, halohydrocylkyl, allyl, cycloalkylγ - lower alkyl, adaιMlthyllower alkyl or substituted phenyl-lower alkyl, and R is hydrogen or lower alkyl, in the form of a free acid or in the form of a physiologically acceptable ester, optionally in the form of a salt, and the salts of these compounds, characterized by that a SiOo ether of general formula III, in which X, Z as defined above, and rc is lower alkyl or lower alkoxy, will undergo a silyl ether cleavage reaction and the same ester of general formula IV in which R is alkyl, and R, X, n and Z MJ a ^ ^e j defined ewentullnie- converted into a salt of formula 5, wherein R is lower alkyl or lower alkoxy, and X, n and Z are O & ^e j defined in acid of general formula 6 in which R, X, n and Z have the meaning given above, into a salt of general formula 7 in which X, n and Z have the meaning given above, or into an acid of general formula I, in which X , ni Z mj w ^ ^e j given meaning. 2. The method according to p. The process of claim 6, wherein R c is alkoxy, X is oxygen, n is 6 or 2 and Z is the group of formula 2. 3. The method according to p. The process of claim 6, wherein Rc is alkoxy, X is -NH-, n is 6 and Z is the group of formula 2. 9 9 RP CH ₂ C-CH? CCRR *? ÓH (ęH ₂ ) ⁿ From Formula 1 o Rf = CH CH-CHZ-0 CCR-OH (CH ₂₎ n Z Formula 1o R -6- CH2CH-CH2 -CO3NH4H (CH2) n Formula 1b Formula 2 154 877 ρ RCp —CH2 — ęH-CH2 CC ^ alkyl ^{χ δ} (CH ₂ ) _n / J-CCCtCj) » ^{Z ó} & ^H s ^C e ^H s Formula 3 C. R P-CHg-CH-CHgCOz alkali metal * OH ( ^C H ₂ ) " Formula 5 R ^c i-CH2-CH-C ^H r ^CC 2 ^RX X & H (CHa) n From Formula 4 p R- ^c> - ^ch 2 ^{ch - c H} 2 ~ ^CC 0 ^H x Ch (CH ₂ ) ⁿ 7 Pattern 6 sts alkoiczny o- ^d ~ ^C ~ H; RCH-CHCA (J ^ ⁰ ^ * OC (CHzin From Wóćr 7 ABOUT SS * - 5 CH 6 -? H -C? R every ₂ kits CH C • Si- C OCH ^ θδ ^Η 5 (^ 5 In ^ r 12 a C. RO- PCH ₂ CHCH ₂ aKil ÓH C Si-C ( ^CH 3) 3 CeH CeHs Formula 13 X CH ( ^C H0 « From Formula 8 C ^H ° - ζ> CH2-CH- ^CH 2- ^C ° ² a ^lk and ^l CH C ^ Si CHs CelHs Formula 12 b pH ^{Br CH} 2 ^Ch- HCCalkrt Formula 14 CHs ch ^XZ Z ^λ rci-CCCIHH ^ Br-CH 2 IC-CH 4 alkyl Formula 15 154 877 Formula 16 Formula 17 Ri R ^2a ~ O 5M ^CH 2 n NH ₂ 2 R ² Model 18 ^R 5a R5 Formula 2A 154 877 -CHCl2CHCH6COOfy OH OH Pattern 27 WHAT? OH Pattern 28 II ABOUT Pattern 35 8 7 6 5 OC-C; C W ^ daughter 31 # -CI ch '3 Pattern 33 R ⁶ CH Pattern 3z Rs R ₂ R3 Pattern 38 Pattern 37 4 fci 1 CH ₂ -C-ClYC00H OH Lox SO) n E. 1 Pattern 39 Pattern 40 154 877 ^ OR, rOoc-ch ₂ - c-ch ₂ - ³ OH Pattern * 3 ^x OR4 E. AND WITH Pattern 44 ABOUT II <? -f-CHjrCH-CH1-CO * OH (CHjln Pattern 48 R1O. R " Ce ^H 5 OSi-CęCH ^ | CgHs J-CC -C-CH CCalkyl H. Formula 10 R ^a - PfOalkyl) ₂ Formula 11 Λ Watermelon reaction p R ^a - P-CH ₂ pH-C 1 -C 6 alkyl 6 alkyl j 1 ShCC CH ₂ CfiHs 0θΗ ₅ 1 (CH ^ 3-S1 Br _from CH ₂ Cl ₂ 2. H ₂ 0 ~ Cleavage of the phosphinic / phosphonic acid ester O Pattern 9 R ^a - p-CH 2 · H-CH 6 CO 6 -alkyl OH 6 Śi-C (CH ₃ ) ₃ '6 ⁿ 5 «Ms Scheme 1 Formula 12 154 877 Compound of Formula 12b RhOH-DCC Pyridine (Esterification) Scheme 2 RhO PCHz CH-CH 6 CO 3 alkyl OH 9 H -CH ₆ Hs C ₆ Hs Pattern 13 ^Z —-- sj SSSSSŻr— Uch), Z G \ CHs CgHj Formula 3 z) oh; dioxane (hydrolysis) Scheme 3 (CH ^£ ) n WITH OH Sack 1 Ri Scheme 4 R * SO ° X 4/0 Pattern 30 Department of Publishing of the UP RP. Mintage 100 ega. Price: PLN 3,000