WO2002072858A2 - Degradation of epothilones and ethynyl substituted epothilones - Google Patents

Degradation of epothilones and ethynyl substituted epothilones Download PDF

Info

Publication number
WO2002072858A2
WO2002072858A2 PCT/EP2002/002105 EP0202105W WO02072858A2 WO 2002072858 A2 WO2002072858 A2 WO 2002072858A2 EP 0202105 W EP0202105 W EP 0202105W WO 02072858 A2 WO02072858 A2 WO 02072858A2
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
epothilone
scheme
process according
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/EP2002/002105
Other languages
French (fr)
Other versions
WO2002072858A3 (en
Inventor
Gerhard Hoefle
Usama Karama
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Helmholtz Zentrum fuer Infektionsforschung HZI GmbH
Original Assignee
Helmholtz Zentrum fuer Infektionsforschung HZI GmbH
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
Priority to BR0207675-6A priority Critical patent/BR0207675A/en
Priority to PL02362556A priority patent/PL362556A1/en
Priority to NZ527557A priority patent/NZ527557A/en
Priority to HU0303895A priority patent/HUP0303895A3/en
Priority to KR10-2003-7011281A priority patent/KR20030084952A/en
Priority to DE60211124T priority patent/DE60211124T2/en
Priority to IL15731202A priority patent/IL157312A0/en
Priority to US10/468,919 priority patent/US7157595B2/en
Priority to MXPA03007466A priority patent/MXPA03007466A/en
Application filed by Helmholtz Zentrum fuer Infektionsforschung HZI GmbH filed Critical Helmholtz Zentrum fuer Infektionsforschung HZI GmbH
Priority to JP2002571909A priority patent/JP2004522801A/en
Priority to EP02719946A priority patent/EP1364040B1/en
Priority to CA002437707A priority patent/CA2437707A1/en
Publication of WO2002072858A2 publication Critical patent/WO2002072858A2/en
Publication of WO2002072858A3 publication Critical patent/WO2002072858A3/en
Priority to NO20033784A priority patent/NO20033784D0/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed 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
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • 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
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages
    • 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
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/14—Nitrogen or oxygen as hetero atom and at least one other diverse hetero ring atom in the same ring
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
    • C12P17/181—Heterocyclic compounds containing oxygen atoms as the only ring heteroatoms in the condensed system, e.g. Salinomycin, Septamycin
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/62—Carboxylic acid esters
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/14—Heterocyclic carbon compound [i.e., O, S, N, Se, Te, as only ring hetero atom]
    • Y10T436/141111—Diverse hetero atoms in same or different rings [e.g., alkaloids, opiates, etc.]

Definitions

  • the invention concerns a process for a degradation of an epothilone C or an epothilone D, wherein an epothilone C or an epothilone D is subjected to an olefin metathesis in the presence of ethylene and subsequently an optional ester hydrolysis (scheme I) .
  • the epothilone C or D can be a fermentation product.
  • the invention concerns a process for the production of an epothilone of formula 9
  • reaction mixture was diluted with a saturated solution of NaHC0 3 (10 mL) .
  • the aqueous layer was extracted with ether and the combined organic extracts were washed with a brine and dried over MgS0 4 .
  • Concentration under vacuum, and flash column chromatography (silica gel, 10:1 petroleum ether/ethyl acetate), yielded 0.52 g (70.6%) a yellow oil.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Microbiology (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Silicon Polymers (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The invention concerns a process for a degradation of an epothilone C or a epothilone D, wherein an epothilone C or epothilone D is subjected to an olefin metathesis in the presence of ethylene and subsequently an optional ester hydrolysis. The invention further concerns (2-methyl-1,3-thiazol-4-yl)-ethynyl substitued epothilones (9). Formula (9).

Description

Our ref . : 12838-GBF
New International Patent Application
Gesellschaft fuer Biotechnlogische Forschung mbH (GBF)
Degradation of Epothilones
Epothilones of type C and type D belong to the art and are especially characterized by a C=C double bond at positions 12 and 13 and a hydrogen atom at position 12 (type C) or an alkyl group- (type D) .
According to one embodiment the invention concerns a process for a degradation of an epothilone C or an epothilone D, wherein an epothilone C or an epothilone D is subjected to an olefin metathesis in the presence of ethylene and subsequently an optional ester hydrolysis (scheme I) .
According to the invention the epothilone C or D can be a fermentation product.
According to another embodiment the invention concerns a process for the production of an epothilone of formula 9
Figure imgf000002_0001
9 wherein an epothilone of formula 2a (schemes I and II) is converted into compound of formula 3a (scheme II) , the compound of formula 3a is reacted with a compound of formula 6 (which has been formed by reacting a compound of formula 4 with a compound of formula 5; scheme II) to give a compound of formula 7 by esterification (scheme II) , the compound of formula 7 is reacted in the presence of a Grubbs catalyst to give a compound of formula 8a by deprotection (scheme II) , the compound of formula 8a is converted into a compound of formula 8b by deprotection (scheme II) , and compound of formula 8b is converted to a compound of formula 9 by epoxidation (scheme ID •
Alternatively to the reaction sequence depicted in scheme I synthetic intermediates of type 3 may be obtained according to scheme III by
1) cleavage of the lactone of epothilone C or D with e.g. pig liver esterase (PLE) or, after protection of the 3,7-hydroxyl groups, with aqueous base to give 10 (this conversion is described in U.S. Patent Application 09/811,808, March 19, 2001 by BMS/GBF) ,
2) optionally esterification with diazomethane and optionally protection of the 3 , 7-dihydroxyl groups to give 11,
3) olefin metathesis with an excess of an olefin, e.g. ethylene and a ruthenium or molybdenum metathesis catalyst and optionally protection of the 3, 7-dihydroxyl groups to give 3b.
Experimental Part
12,13-seco-Epothilone C (2a):
450 mg of epothilone C (1) (0.95 mmol) were dissolved in 250 mL of dichloromethane, saturated with ethylene and after addition of 60 mg of Grubb's catalyst (PhCHRuCl2 [P (Cy) 3] 2 stirred for 24 hours. After addition of further 60 mg of catalyst and stirring for 24 hours the dark solution was evaporated to dryness and the residue purified by chromatography on silica with the solvent system hexanes/tert . -butylmethylester/methanol 80:20:1. The first fraction contained 360 mg (75 %) of 2a, the second 100 mg (22 %) of recovered starting material 1.
2a: XH-NMR (CDC13) , 300 MHz): δ = 6.95 (s, 19-H) , 6.02 (s, 17- H) , 5.89 - 5.64 (m, 12-H, 13-H), 5.16 - 4.89 (m, 12a-H2, 13a- H2) , 5.37 (t, J = 7 Hz, 15-H) , 4.24 (ddd, J = 10, 3, 3.5 Hz, 3- H) , 3.36 (s, OH), 3.34 (d, J = 8 Hz, 7-H) , 3.25 (dq, J = 1.5, 7 Hz,~8-H), 3.21 (d, J = 3.8 Hz, OH), 2.70 (s, 21-H3) , 2.52 - 2.32 (m, 2-H2, 14-H2), 2.07 (d, J = 1.5 Hz, 16-Me) , 2.05 - 1.95 (m, 11-H2) , 1.8 - 1.1 (m, 6-H, 8-H, 9-H2, 10-H2) , 1.18 (s, 4- Me) , 1.10 (s, 4-Me), 1.04 (d, J = 7 Hz, 6-Me) , 0.83 (d, J = 7 Hz, 8-Me) .
ESI-MS (pos ions) m/z = 506 [M + H+] , CI - MS (NH3 pos . ions) m/z = 506 [M + H+] (22 %) , 380 (100 %) .
3,7-Di- [tert-buthyldimethyl-silyloxy] -4,4, 6, 8-tetramethyl-5- oxo-12-tridecenoic acid (3a)
To 330 mg (0.65 mmol) of 12 , 13-seco-epothilone C (2a) dissolved in 10 mL of THF were added with stirring 0.6 mL of NEt3 and 0.6 mL of tert-butyldimethylsilyltriflate . After one hour the solvent was evaporated in vacuo. The residue was dissolved in 10 mL of THF, 70 mg of LiOH dissolved in 0.5 mL of water were added and the mixture stirred for 16 hours. The solvents were evaporated and the residue distributed between phosphate buffer of pH 5 and ethyl acetate. The organic layer was dried with MgS04 and evaporated to dryness. Preparative HPLC on RP-18 with the solvent system methanol/20 mmol ammonium acetate buffer pH 7 gave 235 mg (67 %) of 3a as colorless viscous oil. Analytical HPLC on Nucleosil RP-18 (260 x 5 mm) solvent system methanol/20 mmol ammonium acetate buffer pH 7, 1 mL/min, light scattering detector: Rt = 5.5 min.
XH-NMR (CDC13, 300 MHz): δ = 5.78 (m, 12-H) , 4.99, 4.92 (m, 13- H2) , 4.39 (dd, J = 6.3, 3.4 Hz, 3-H) , 3.79 (dd, J = 7.2, 2.0 Hz, 7-H) , 3.12 (dq, J = 7.0 Hz, 8-H) , 2.49 (dd, J = 16.5, 3.5 Hz, 2 -Ha) , 2.32 (dd, J = 16.5, 6.2 Hz, 2-Hb) , 1.5 - 1.0 (m, 6- H, 8-H, 9-H2, 10-H2, 11-H2) , 1.2 (s, 4-Me), 1.07 (s, 4-Me) , 1.04 (d, J = 6.9 Hz, 6-Me) , 0.91 (d, J = 7.0 Hz, 8-Me) , 0.89 (s, tBuSi) , 0.88 (s, tBuSi) , 0.09 (s, MeSi) , 0.06 (s, MeSi) , 0.05 (s, 2 MeSi) . ESI - MS (neg. ions) m/z = 541 (M-H) .
4-Bromo-2-methyl-thiazole (4)
1 g (2.05 mmol) 2 , 4-Dibromothiazole was dissolved in 25 mL anhydrous ether and the resulting solution was stirred under N2 atmosphere at - 78°C. To the solution was added n-BuLi (1.1 equivalent, 4.52 mmol, 2.82 mL of 1.6 M solution in hexane) and the stirring was continued for 1 h. To the reaction mixture was then added dropwise a solution of dimethylsulfate 1.16 mL (12.34 mmol) in 1 mL ether. After stirring for 4 h at -78°C the reaction mixture was allowed to warm to room temperature and stirred for 14 h. The reaction mixture was diluted with a saturated solution of NaHC03 (10 mL) . The aqueous layer was extracted with ether and the combined organic extracts were washed with a brine and dried over MgS04. Concentration under vacuum, and flash column chromatography (silica gel, 10:1 petroleum ether/ethyl acetate), yielded 0.52 g (70.6%) a yellow oil.
IR (KBr) : 3122, 2923, 1485, 1441, 1252, 1178, 1085887, 834 cm-1.
XH-NMR (CDC13, 400 MHz) : δ = 7.02 (s, 1H) , 2.71 (s, 3H) . 13C-NMR (CDCI3, 100.6 MHz) : δ = 167.31, 124.18, 116.11, 19.40. EI-MS (70 eV) : m/z (%) : 179 (93) [M+2H]+, 177 (100) [M+H]+, 169 (30) , 164 (20) , 159 (15) . HRMS (El) : calcd for C4H4BrNS 176.9251, found 176.9248
1- (2-methyl-thiazol-4-yl) -hex-5-en-l-yn-3-ol (6)
480 mg (2.68 mmol) 4-Bromo-2-methyl-thiazole (4) in 4 mL Et3N was added to 131 mg (0.187 mmol) PdCl2(PPh3)2 and the suspension was stirred 15 minutes under N2 atmosphere at room temperature, then 117 mg ( 0.614 mmol) Cul was added under N2 atmosphere followed by dropwise addition of 283 mg alcohol 5 (A.B. Smith, III et al . JACS 120, 3935-3948 (1998)) in 1 mL Et3N. The mixture was stirred for 15 minutes at room temperature and heated to 80°C for 6 h. Concentration under vacuum, and flash column chromatography (silica gel, 3:2 petroleum ether/ethyl acetate), yielded 0.29 g (56 %) a yellow oil. [α] = - 29.1 (c= 1 in chloroform)
IR (KBr) : 3386, 3142, 2924, 1641, 1501, 1435, 1286, 1194, 1041, 993, 918 cm"1.
^Η- MR (CDCI3, 400 MHz) : δ = 7.26 (s, 1H) , 5.98-5.88 (m, 1 H) ,
5.23-5.16 (m, 2H) , 4.62 ( dd, J= 11.9, 5.8 Hz, 1H) , 2.68 (3H,
S) , 2.58-2.54 (2H, m) , 2.39 (d J= 6.1Hz, 1H, OH)
13C-NMR (CDC13, 75.5 MHz) : δ = 165.77, 136.20, 133.09, 122.48,
118.85, 89.53, 79.04, 61.84, 41.87, 19.10.
DCI-MS (NH3) : 211 [M+NH4 +] , 194 [M+H+] .
(IS) -1- [ (2-Methyl-thiazole-4-yl) -1-ethynyl] -3-butenyl (2S,6R,7S,8S) -3,7-di- [tert-butyldimethylsiloxy] -4,4,6,8- tetramethyl-5-oxo-12-tridecenoate (7)
99 mg (0.478 mmoDDCC was added at 0°C to a solution of acid 200 mg (0.368 mmol), alcohol 79 mg (0.405 mmol) and 12 mg (0.09 mmol) DMAP in 10 mL CH2C12 . The mixture was stirred for 15 min at 0°C and for 16 h at room temperature. Concentration under vacuum, and flash column chromatography (silica gel, 10:1 petroleum ether/ethyl acetate) , yielded 240 mg (91%) a yellow oil .
[α] = - 45.8 (c= 1 in CH2C12)
IR (KBr) : 2929, 2856, 1742, 1697, 1641, 1472, 1253, 989 cm"1.
^-NMR (CDC13, 400 MHz) : δ = 7.28 (s, 1H, thiazole H-5) , 5.91-
5.73 (m, 2H, H-12, H-3') ,
5.58 "(t, "= 6.1Hz, 1H, , H-l'), 5.20-4.90 (m, 4H, H-13, H-4"),
4.38 (dd, J= 6.3, 3.3 Hz, 1H, H-3) , 3.74 (dd, J= 6.8, 2.2 Hz,
1H, H-7) , 3.11 (dq, J= 6.8, 6.8 Hz, 1H, H-6) , 2.67 (s, 3H, thiazole CH3) , 2.60 (t, J= 6.6Hz, 1H, , H-2) , 2.55 (dd, J"= 16.7,
3.5 Hz, 1H, H-2') , 2.29 (dd, J= 17.0, 63 Hz, 1H, H-2') , 2.05-
1.95 (m, 2H, H-11) , 1.47-1.29 (m, 3H, ) 1.17-1.08 (m, 2H) (H-8, H-
9, H-10) , 1.21 (s, 3H, H-22), 1.05 (s, 3H, H-23) , 1.03 (d, J=
6.6Hz, 3H, C6-CH3) , 0.89 (d, J= 6.6Hz, 3H, C8-CH3) , 0.88, 0.87(
2s, 2x9H, OSiC(CH3)3) , 0.089 (s, 3H, OSi(CH3)2) , 0.032, 0.028,
0.024 (3S, 3x3H, OSi(CH3)2) .
13C-NMR (CDC13, 100.6 MHz) : 217.63, 170.84, 165.55, 138.97,
136.08, 132.23, 123.22, 118.91, 114.41, 85.67, 79.97, 73.76,
63.77, 53.38, 45.23, 40.20, 39.09, 38.87, 34.35, 34.00, 30.48,
27.11, 26.26, 26.07, 25.66, 24.97, 23.44, 19.89, 18.55, 17.66,
15.52, -3.61, -3.74, -4.20, -4.59
DCI-MS (NH3) : 735 [M+NH +] , 718 [M+H+] .
HRMS (DCI) : calcd for C39H70N2O5SSi2 735.4622, found 735.4675.
{4S, 7R,8S,9S, 16S) -4,8 -Di - tert-butyldimethylsilyloxy-5 , 5,7,9- tetramethyl- -6- [2- (2-methyl-l, 3-thiazol-4-yl) -1-ethynyl) -1- oxa-13-cyclohexadecen-2, 6-dione, mixture of Z and E isomeres (8a)
To a solution of 190 mg (0.264 mmol) diene 7 in 66 mL CH2C12 was added 44 mg (0.053 mmol) bis (tricyclohexylphosphine)benzylideneruthenium dichloride and the reaction mixture was stirred for 48 h at room temperature. Concentration under vacuum, and flash column chromatography (silica gel, 10:1 petroleum ether/ethyl acetate), yielded 95mg (52%) of a yellow oil.
{4S, 7R, 8S, 9S, 16S) -4 , 8-Dihydroxy-tert-5, 5, 7 , 9-tetra-methyl-1-6- [2- (2-methyl-l,3-thiazol-4-yl) -1-ethynyl) -l-oxa-13- cyclohexadecen-2, 6-dione (8b), mixture of cis and trans isomere
A solution of 95 mg (0.137 mmol) lactone X in 12 mL CH2C12 at - 20°C was treated with 2 mL trifluoroacetic acid, and the mixture was stirred for 2 h at 0°C. After concentration under vacuum, the residue was diluted with EtOAC , washed with saturated NaHC03 solution and dried over MgS0 . Concentration under vacuum, and separation by HPLC (80:20:3 hexane/t-BuOMe/ MeOH) , yielded 27 mg (42 %) of the cis-hydroxy lactone 8b and 27 mg (42 %) of the corresponding trans isomer. [α] = - 123 (c= 1 in CH2C12)
XH-NMR (CDC13, 400 MHz) : δ = 7.30 (s, 1H, H-19) , 5.65 (dd,J= 9.1, 2.9 Hz, 1H, H-15) , 5.55-5.41 (m, 2H, H-12, H-13), 4.20 (dd,J= 10.8, 2.7 Hz, 1H, H-3), 3.67-3.65 (m, 1H, H-7) , 3.12 (dq, ι7= 6.6, 2.0 Hz, 1H, H-6) , 2.88-2.77 (m, 1H, H-14) , 2.70 (s, 3H, H-21) , 2.51 ( dd, J= 15.0Hz, 10.9 Hz, 1H, H-2) , 2.27 (dd,J= 15.2, 2.8 Hz, 1H, H-2), 2.18-2.00 (m, 2H, H-11, H-14), 1.71-1.58 (m, 3H, H-8, H-9, H-10) , 1.32 (s, 3H, H-22), 1.30- 1.19 (3H, H-8, H-9, H-10), 1.18 (d, J= 6.7Hz, 3H, H-24), 1.07 (s, 3H, H-23), 0.98 (d, J= 6.9Hz, 3H, H-25)
13C-NMR (CDC13, 75.5 MHz) : δ = 220.81, 169.96, 164.44, 134.16, 134.27, 123.75, 123.00, 86.13, 80.00, 74.38, 72.03, 64.11, 53.31, 41.74, 39.37, 38.71, 32.87, 32.37, 27.63, 27.47, 22.69, 19.18, 18.37, 15.46, 13.70. 16,17-Didehydro-16-desmethyl-epothilone A (9)
To a solution of 27 mg (0.058) of lactone (8b) 4 mL CH2C12 was added dropwise at - 20°C a solution of dimethyl dioxirane in acetone ( 2 equiv) . Stirring was continued for 2 h at - 20°C . Concentration under vacuum, and separation by HPLC (80:20:3 hexane/t-BuOMe/ MeOH) , yielded 17 mg (60 %) of α-epoxide 9 and 9 mg (32 %) of β-epoxide.
α-epoxide
[α] = - 34 (c= 1 in CH2C12)
IR (KBr) : 3453, 2958, 2850, 1744, 1690, 1500, 1467, 1376, 1290, 1261, 1147, 979, 775 cm"1.
13C-NMR (CDC13, 100.6 MHz) : 220.55, 170.19, 166.12, 135.50, 123.28, 85.00, 80.56, 75.12, 73.59, 62.71, 57.17, 53.75, 52.67, 43.68, 38.69, 35.96, 32.67, 29.72, 26.56, 23.63, 21.12, 20.48, 19.16, 17.06, 14.46
EI-MS (70 eV) : m/z (%) : 477(27) [M+H]+, 421 (14) , 389 (19) , 378 (100) , 364 (28) , 346 (27) , 328 (15) .
β-epoxide
13C-NMR (CDC13, 75.5 MHz) : δ = 221.38, 170.03, 166.05,135.70 , 123.28, 85.13, 80.48, 73.24, 73.11, 62.24, 57.14, 55.31, 52.28, 42.89, 38.98, 37.53, 32.40, 31.82, 27.60, 27.01, 23.45, 20.62, 20.36, 16.38, 13.49.

Claims

Our ref . : 12827-GBFNew International Patent ApplicationGesellschaft fuer Biotechnlogische Forschung mbH (GBF)Claims
1. Process for a degradation of an epothilone C or an epothilone D, wherein an epothilone C or an epothilone D is subjected to an olefin metathesis in the presence of ethylene and subsequently an optional ester hydrolysis (scheme I) .
2. Process according to claim 1, wherein the epothilone C or D is a fermentation product.
3. Process for the production of an epothilone of formula 9
Figure imgf000010_0001
wherein (i) an epothilone of formula 2a (schemes I and II) is converted into compound of formula 3a (scheme II) , (ii) the compound of formula 3a is reacted with a compound of formula 6 (which has been formed by reacting a compound of formula 4 with a compound of formula 5; scheme II) to give a compound of formula 7 (scheme
ID, (iii) the compound of formula 7 is reacted in the presence of a Grubbs catalyst to give a compound of formula 8a
(scheme II) , (iv) the compound of formula 8a is converted into a compound of formula 8b (scheme II) , and (v) compound of formula 8b is converted to a compound of formula 9 (scheme II) .
4. Process according to claim 3, wherein at stop (i) first free hydroxy groups are protected and second an ester hydrolysis is carried out.
5. Process according to claim 3, wherein at step (iv) deprotection is carried out in an acidic medium preferably by means of trifluoro acetic acid.
6. Process for the production of a compound of formula 3b
R = H, Methyl
Figure imgf000011_0001
P = H, protecting group e.g. trialkylsilyl, p-methoxybenzyl wherein 3b (i) the lactone group of an epothilone C or an epothilone
D is cleaved, (ii) the cleavage product of formula 10 (scheme III) is optionally subjected to an esterificartion with diazomethane and the 3,7-hydroxy groups are optionally protected to give a compound of formula 11 (scheme III) and (iii) the compound of formula 11 is subjected to an olefin metathesis and the 3,7-hydroxy groups are optionally protected, to give a compound of formula 3b (scheme III) .
7. Process according to claim 6, wherein in step (i) the cleavage is carried out
- with pig liver esterase or
- after protection of the 3,7-hydroxy groups, with an aqueous base .
8. Process according to claim 6, wherein in step (iii) ethylene is used as olefin and/or a ruthenium or molybdenum catalyst is used as metathesis catalyst.
9. Process according to claim 3 or claim 6, wherein the 3,7- hydroxy groups are protected by trialkylsilyl or p-methoxybenzyl .
10. Process according to claim 6, wherein the compound of formula 3b is further processed in accordance to steps (ii) to (v) of claim 3.
11. Compounds of formula 2, 2a, 3, 3a, 3b, 4, 5, 6, 7, 8, 8a, 8b, 9, 10 and 11, obtainable according to a process according to one or more of the preceding claims .
PCT/EP2002/002105 2001-02-27 2002-02-27 Degradation of epothilones and ethynyl substituted epothilones Ceased WO2002072858A2 (en)

Priority Applications (13)

Application Number Priority Date Filing Date Title
MXPA03007466A MXPA03007466A (en) 2001-02-27 2002-02-27 Degradation of epothilones.
NZ527557A NZ527557A (en) 2001-02-27 2002-02-27 Degradation of epothilones and ethynyl substituted epothilones
HU0303895A HUP0303895A3 (en) 2001-02-27 2002-02-27 Degradation of epothilones
KR10-2003-7011281A KR20030084952A (en) 2001-02-27 2002-02-27 Degradation of epothilones and ethynyl substituted epotilones
DE60211124T DE60211124T2 (en) 2001-02-27 2002-02-27 Degradation of epothilones
IL15731202A IL157312A0 (en) 2001-02-27 2002-02-27 Processes for the preparation of epothilone derivatives and compounds produced thereby
US10/468,919 US7157595B2 (en) 2001-02-27 2002-02-27 Degradation of epothilones
BR0207675-6A BR0207675A (en) 2001-02-27 2002-02-27 Epothilone Degradation
JP2002571909A JP2004522801A (en) 2001-02-27 2002-02-27 Degradation of epothilone
PL02362556A PL362556A1 (en) 2001-02-27 2002-02-27 Degradation of epothilones and ethynyl substituted epothilones
EP02719946A EP1364040B1 (en) 2001-02-27 2002-02-27 Degradation of epothilones and ethynyl substituted epothilones
CA002437707A CA2437707A1 (en) 2001-02-27 2002-02-27 Degradation of epothilones and ethynyl substituted epothilones
NO20033784A NO20033784D0 (en) 2001-02-27 2003-08-26 Degradation of epothilones

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP01104448 2001-02-27
EP01104448.4 2001-02-27

Publications (2)

Publication Number Publication Date
WO2002072858A2 true WO2002072858A2 (en) 2002-09-19
WO2002072858A3 WO2002072858A3 (en) 2002-12-19

Family

ID=8176579

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2002/002105 Ceased WO2002072858A2 (en) 2001-02-27 2002-02-27 Degradation of epothilones and ethynyl substituted epothilones

Country Status (19)

Country Link
US (1) US7157595B2 (en)
EP (2) EP1564217B1 (en)
JP (1) JP2004522801A (en)
KR (1) KR20030084952A (en)
CN (1) CN1501980A (en)
AT (2) ATE335746T1 (en)
BR (1) BR0207675A (en)
CA (1) CA2437707A1 (en)
CZ (1) CZ20032291A3 (en)
DE (2) DE60213884T2 (en)
HU (1) HUP0303895A3 (en)
IL (1) IL157312A0 (en)
MX (1) MXPA03007466A (en)
NO (1) NO20033784D0 (en)
NZ (2) NZ527557A (en)
PL (1) PL362556A1 (en)
RU (1) RU2003128953A (en)
WO (1) WO2002072858A2 (en)
ZA (1) ZA200306034B (en)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6204388B1 (en) 1996-12-03 2001-03-20 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
CA2273083C (en) 1996-12-03 2012-09-18 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof
DE19826988A1 (en) * 1998-06-18 1999-12-23 Biotechnolog Forschung Gmbh Epothilone minor components
US20020058286A1 (en) * 1999-02-24 2002-05-16 Danishefsky Samuel J. Synthesis of epothilones, intermediates thereto and analogues thereof
US7649006B2 (en) 2002-08-23 2010-01-19 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
US6921769B2 (en) 2002-08-23 2005-07-26 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
EP2186811A1 (en) 2002-08-23 2010-05-19 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0057736B1 (en) 1981-02-05 1986-11-20 Phillips Petroleum Company Olefin disproportionation process and catalyst
JP4183099B2 (en) 1995-11-17 2008-11-19 ゲゼルシャフト・フュア・ビオテヒノロジッシェ・フォルシュング・ミット・ベシュレンクテル・ハフツング（ゲー・ベー・エフ） Epothilones C and D, production methods and compositions
AU716610B2 (en) * 1996-08-30 2000-03-02 Novartis Ag Method for producing epothilones, and intermediate products obtained during the production process
US5969145A (en) * 1996-08-30 1999-10-19 Novartis Ag Process for the production of epothilones and intermediate products within the process
ES2312695T3 (en) 1996-11-18 2009-03-01 Gesellschaft Fur Biotechnologische Forschung Mbh (Gbf) EPOTILONES E AND F.
US6380394B1 (en) * 1996-12-13 2002-04-30 The Scripps Research Institute Epothilone analogs
US6441186B1 (en) * 1996-12-13 2002-08-27 The Scripps Research Institute Epothilone analogs
JP2001513098A (en) * 1997-02-25 2001-08-28 ゲゼルシャフト フュア バイオテクノロギッシェ フォーシュンク エム ベー ハー（ゲー ベー エフ） Epothilone with modified side chains
US6605599B1 (en) 1997-07-08 2003-08-12 Bristol-Myers Squibb Company Epothilone derivatives
US6365749B1 (en) 1997-12-04 2002-04-02 Bristol-Myers Squibb Company Process for the preparation of ring-opened epothilone intermediates which are useful for the preparation of epothilone analogs
US6498257B1 (en) 1998-04-21 2002-12-24 Bristol-Myers Squibb Company 2,3-olefinic epothilone derivatives
US6211412B1 (en) * 1999-03-29 2001-04-03 The University Of Kansas Synthesis of epothilones
US6518421B1 (en) 2000-03-20 2003-02-11 Bristol-Myers Squibb Company Process for the preparation of epothilone analogs
US6593115B2 (en) * 2000-03-24 2003-07-15 Bristol-Myers Squibb Co. Preparation of epothilone intermediates

Also Published As

Publication number Publication date
BR0207675A (en) 2004-03-09
NO20033784L (en) 2003-08-26
RU2003128953A (en) 2005-03-10
ATE335746T1 (en) 2006-09-15
HUP0303895A3 (en) 2007-06-28
WO2002072858A3 (en) 2002-12-19
NO20033784D0 (en) 2003-08-26
HUP0303895A2 (en) 2004-03-29
EP1364040B1 (en) 2006-05-03
EP1564217A3 (en) 2005-08-31
DE60213884T2 (en) 2007-02-22
KR20030084952A (en) 2003-11-01
IL157312A0 (en) 2004-02-19
EP1364040A2 (en) 2003-11-26
DE60213884D1 (en) 2006-09-21
DE60211124D1 (en) 2006-06-08
EP1564217A2 (en) 2005-08-17
US20040092560A1 (en) 2004-05-13
PL362556A1 (en) 2004-11-02
CZ20032291A3 (en) 2004-02-18
NZ539204A (en) 2005-12-23
MXPA03007466A (en) 2003-12-08
JP2004522801A (en) 2004-07-29
ZA200306034B (en) 2004-08-05
ATE325201T1 (en) 2006-06-15
EP1564217B1 (en) 2006-08-09
NZ527557A (en) 2005-05-27
CN1501980A (en) 2004-06-02
US7157595B2 (en) 2007-01-02
DE60211124T2 (en) 2006-11-30
CA2437707A1 (en) 2002-09-19

Similar Documents

Publication Publication Date Title
US6288237B1 (en) Epothilons C and D, preparation and compositions
RU2201932C2 (en) Epotilons modified by by-side chain
Schinzer et al. Total synthesis of (−)‐epothilone A
Nicolaou et al. Total Synthesis of 16‐Desmethylepothilone B, Epothilone B10, Epothilone F, and Related Side Chain Modified Epothilone B Analogues
US6660758B1 (en) Epothilone analogs
AU5757798A (en) Epothilone analogs
EP1564217B1 (en) Process for the production of epothilones
AU2002251030A1 (en) Degradation of epothilones and ethynyl substituted epothilones
HK1066569A (en) Degradation of epothilones and ethynyl substituted epothilones
Zhang et al. Recent progress in the synthesis of epothilones
US8030503B2 (en) Process for the preparation of epothilones
US6376230B1 (en) Stereoselective process for producing intermediates of cryptophycins
EP1127055A2 (en) Stereoselective process for producing cryptophycins
EP0987268B1 (en) Pharmaceutical agents containing epothilone A-N-oxide and/or epothilone B-N-oxide

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
AK Designated states

Kind code of ref document: A3

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 2003/06034

Country of ref document: ZA

Ref document number: 200306034

Country of ref document: ZA

WWE Wipo information: entry into national phase

Ref document number: 2437707

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 157312

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 2002571909

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 527557

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: PA/a/2003/007466

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: PV2003-2291

Country of ref document: CZ

Ref document number: 2002719946

Country of ref document: EP

Ref document number: 028055349

Country of ref document: CN

Ref document number: 2002251030

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 1020037011281

Country of ref document: KR

WWP Wipo information: published in national office

Ref document number: 1020037011281

Country of ref document: KR

WWP Wipo information: published in national office

Ref document number: 2002719946

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 10468919

Country of ref document: US

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: PV2003-2291

Country of ref document: CZ

WWP Wipo information: published in national office

Ref document number: 527557

Country of ref document: NZ

WWG Wipo information: grant in national office

Ref document number: 527557

Country of ref document: NZ

WWG Wipo information: grant in national office

Ref document number: 2002719946

Country of ref document: EP