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WO1998008849A1 - Procede de fabrication d'epothilones, et composes intermediaires obtenus au cours de ce procede - Google Patents

Procede de fabrication d'epothilones, et composes intermediaires obtenus au cours de ce procede Download PDF

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Publication number
WO1998008849A1
WO1998008849A1 PCT/DE1997/000111 DE9700111W WO9808849A1 WO 1998008849 A1 WO1998008849 A1 WO 1998008849A1 DE 9700111 W DE9700111 W DE 9700111W WO 9808849 A1 WO9808849 A1 WO 9808849A1
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WO
WIPO (PCT)
Prior art keywords
mmol
solution
methyl
hydrogen
mixture
Prior art date
Application number
PCT/DE1997/000111
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German (de)
English (en)
Inventor
Dieter Schinzer
Anja Limberg
Oliver M. BÖHM
Armin Bauer
Martin Cordes
Original Assignee
Novartis Aktiengesellschaft
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 claimed from DE19636343A external-priority patent/DE19636343C1/de
Priority claimed from DE19645362A external-priority patent/DE19645362A1/de
Priority claimed from DE19645361A external-priority patent/DE19645361A1/de
Application filed by Novartis Aktiengesellschaft filed Critical Novartis Aktiengesellschaft
Priority to AU21493/97A priority Critical patent/AU716610B2/en
Priority to EP97914077A priority patent/EP0923583A1/fr
Priority to NZ334821A priority patent/NZ334821A/xx
Priority to JP10511141A priority patent/JP2001500851A/ja
Publication of WO1998008849A1 publication Critical patent/WO1998008849A1/fr

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • 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
    • 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
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to processes for the production of epothilones and intermediates within the process.
  • Epothilone 1 (DE 41 38 042 C2) represent a new class of tubulin-stabilizing natural products with T.axol-like activity. Their cytotoxic activity against drug-resistant tumor cell lines is of enormous importance for potential use in cancer therapy [G. Höfle , N. Bedorf, H. Steinmetz, D. Schomburg, K. Gerth, H. Reichenbach Angew. Chem. 1996, 108, 1671; Appl. Chem. Int. Ed. Engl. 1996, 35, 1567; D. Schinzer "Epothiiones - New Promising Microtubule-stabilizing Natural Products with Taxol-like Biological Activity", Eur. Chem. Chron. 1996, 1, 7; D.M.
  • Epothilones 1 are accessible in a convergent reaction from the three building blocks 2, 3 and 4.
  • building blocks 2 and 3 are linked in a stereoselective aldol reaction.
  • Esterification with fragment 4 provides the almost fully functionalized fragment 17, which is in A cyclization metathesis to deoxy-epothilone A 19 is cyclized.
  • a final epoxidation finally provides 1
  • the key step in the synthesis is the stereoselective aldol reaction of fragments 2 and 3 (obtainable from the commercially available heptenic acid).
  • 70 is obtained % Yield exclusively the desired compound 5 with the four correctly placed asymmetry centers.
  • Double stereodifferentiation obviously leads to a chiral override of the preferred Cra selectivity of the aldehyde 3, since both reactants are optically active Form are used
  • ERSATZBI_ATT (RULE 26) The invention thus relates to a process for the preparation of epitholone A or B of the general formula 1
  • R hydrogen (A) or a methyl group (B), a thiazole alkyl die ⁇ alcohol derivative of the formula 4th
  • B benzyl, tetrahydropyranyl and / or a silyl protecting group (s) and
  • R hydrogen or methyl, is esterified, the ester obtained is ring-closed by means of an open metathesis in the presence of a noble metal catalyst, optionally the hydroxyl protective groups
  • REPLACEMENT BI ATT (RULE 26) are cleaved, the newly formed double bond is epoxidized and, if necessary, the hydroxyl protective groups are cleaved.
  • Suitable as silyl protective groups B are generally all different trialkyl or diaryl-alkyl silyl protective groups, in particular the tert-butyl-diethyl, trimethylsilyl and diphenyl-tert-butyl-silyl groups.
  • the epoxidation of the newly formed double bond is preferably carried out using peracid, e.g. B. perchloric acid, or peroxide, e.g. B. cumene hydroperoxide or dimethyldioxirane.
  • peracid e.g. B. perchloric acid
  • peroxide e.g. B. cumene hydroperoxide or dimethyldioxirane.
  • the invention further includes deoxy-epothilones according to general formula 19a
  • B benzyl, tetrahydropyranyl and / or a silyl protective group ( ⁇ ) and
  • R hydrogen or methyl, and the meaning of B in the molecule can be different, and compounds of the general formula 4a
  • the (S) alcohol 10 [D. Schinzer, A. Limberg, OM Böhm, Chem. Eur. J. 1996, 2, 1477] was first silylated with TBSCI, then ozonized to methyl ketone 12 and converted to the tricyclic olefin 13 in a stereoselective Horner-Wadsworth-Emmons reaction ⁇ A selective desilylation with HF in acetonitrile gives compound 14. The desilylation to 14 only works in the presence of some glass splinters; the reaction is apparently catalyzed by H2SiF6. Dess-Martin oxidation followed by a Wittig
  • ERSATZB.LATT (RULE 26) Olefination generates compound 16, which in a final desilylation with TBAF in THF segment 4 yields.
  • the 3 - [(terf-butyldimethylsilyl) oxy] propanal 42 is prepared starting from propane-1,3-diol 40 by first using a method of P.G. McDougal, J.G. Rico, Y. Oh, B.D. Condon, J. Org. Chem. 1986, 51, 3388-3390, is monosilylated to 3 - [(tert-butyldimethylsilyl) oxy] -1-propanol 41, which is then oxidized with DMSO / oxalyichloride to form aldehyde 42 (A. Jenmalm , W. Berts, Y. Li, K. Luthmann, I. Csöregh, U. hacksell, J. Org. Chem. 1994, 59, 1139-1148).
  • the THF is then pumped off at RT (14 mm Hg / 1 h), (0.5 mm / 2 h) and the residue is dissolved in 10.5 ml of diethyl ether.
  • the solution is cooled to -78 ° C. and 1,382 g (7.34 mmol, 1 equiv) aldehyde 42 are added dropwise.
  • the mixture is stirred for 12 h at -78 ° C. and then allowed to warm to RT.
  • the reaction mixture is mixed with 10.7 ml of 3N NaOH solution, then with 4.4 ml of 30% H2O2 solution and heated under reflux for 2 h.
  • the organic phase is separated off, saturated with 15 ml of H2O and 15 ml.
  • Diastereomer 1 30.04 (q), 25.73 (t), 24.64 (t), 20.03 (q), 19.25 (q), 15.99 (q), 11.67
  • Diastereomer 2 30.02 (q), 25.41 (t), 25.08 (t), 20.85 (q), 20.30 (q), 18.90 (q), 11.95
  • the sodium 6-hydroxyhexanoate is produced according to a regulation by Wulff, Krüger and Röhle Chem. Ber. 1971, 704, 1387-1399 made from ⁇ -caprolactone.
  • reaction solution is then reduced to a quarter in vacuo. It is diluted with 130 ml of sat. NaCI solution and adjust to pH 4-5 with 1 M KHS04 solution. It is extracted with diethyl ether. The combined organic phases are dried over MgSO4 and the solvent is distilled off on a rotary evaporator. This gives 2.01 g (8.17 mmol) of 6 - [(terr-rutvlriimethvlsilvhoxvl-hexanoic acid, corresponding to a yield of 90%.
  • 2H26 ⁇ 3Si, FG 246.42 g / mol
  • aqueous phase is extracted with ether, the combined organic phases are dried over MgSO 4 and the solvent is distilled off on a rotary evaporator.
  • Connection 22a is established analogously. From 2.03 g (8.0 mmol) 21a, 1.56 g (5.84 mmol, 73%) are obtained.
  • Connection 23a is established analogously. From 748 mg (2.80 mmol) 22a. you get
  • Connection 3a is established analogously. 199 mg (1.42 mmol, 71%) 3a are obtained from 284 mg (2.00 mmol) 23a.
  • Ozone in 02 is passed at -78 ° C through a solution of 1, 610 g (4.67 mmol) H in 200 ml absolute dichloromethane (dry ice / acetone cooling bath). If starting compound H can no longer be detected by thin layer chromatography, 3.89 g (14.83 mmol) of triphenylphosphine are added and the cooling bath is removed. The reaction mixture is allowed to slowly come to room temperature and the solvent is distilled off in vacuo. Flash chromatography of the residue through a silica gel column with pentane / Et2 ⁇ (50: 1) gives 1.135 g (3.27 mmol, 70%) 12.
  • ERSATZB.LATT Diethyl (2-methylthiazol-4-yl) methane phosphonate
  • ERSATZB.LATT (RULE 26) (S, 4 ⁇ -4- [3- (fert-Butyldimethylsiiyloxy) -2-methyl-hexa-1,5-dienyl] -2-methyl-thiazole 16
  • B stands for benzyl, p-methoxybenzyl, tetrahydropyranyl or a silyl protective group; e.g. trialkyl or diaryl alkyl silyl protective groups, in particular tert.-butyl-dimethyl, trimethylsilyl and diphenyl-tert.-butyl- silyl groups
  • Connection 5a is made analogously. From 238 mg (1.70 mmol) 3a, 386 mg (1.09 mmol, 64%) 5a are obtained.
  • Connection 6a is established analogously. 96 mg (0.270 mmol) 5a gives 77 mg (0.246 mmol, 91%) ⁇ a.
  • Pentane: diethyl ether 30: 1 purified. 462 mg (0.719 mmol, 96%) of the trisilylated product 7 are obtained as a colorless oil.
  • Connection 7a is established analogously. From 204 mg (0.650 mmol) 6a 423 mg (0.644 mmol, 99%) are obtained.
  • Connection 8a is established analogously. From 152 mg (0.232 mmol) 7a, 101 mg (0.186 mmol, 80%) 8a are obtained.
  • REPLACEMENT BI ATT (RULE 26)
  • General data: C29H58 ⁇ sSi2, FG 542.94 g / mol, compound 2a is prepared analogously. From 320 mg (0.590 mmol) ⁇ a one obtains 273 mg (0.490 mmol, 83%) Sa
  • ERSATZB.LATT (RULE 26) (4S, 7H, 8S, 9S, 16S, 13Z) -4,8-di-fert-butyldim ⁇ thylsilyloxy-5 ⁇ 5,7,9-t ⁇ tra-methyl-16- [(£) -1-methyl-2- ( 2-methylthiazol-4-yl) vinyl] -1-oxa-cyclohexadec-13-ene-2,6-dione 18 and
  • the invention also relates to stereoisomers of the compounds according to the claims, as are usually obtained during synthesis.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention porte sur un procédé de fabrication d'épothilones et sur les composés intermédiaires obtenus au cours de ce procédé. Epothilone A et B sont des substances naturelles pouvant être fabriquées par les microorganismes et possédant des propriétés analogues au taxol, d'où l'intérêt qu'elles présentent pour la chimie pharmaceutique.
PCT/DE1997/000111 1996-08-30 1997-01-15 Procede de fabrication d'epothilones, et composes intermediaires obtenus au cours de ce procede WO1998008849A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU21493/97A AU716610B2 (en) 1996-08-30 1997-01-15 Method for producing epothilones, and intermediate products obtained during the production process
EP97914077A EP0923583A1 (fr) 1996-08-30 1997-01-15 Procede de fabrication d'epothilones, et composes intermediaires obtenus au cours de ce procede
NZ334821A NZ334821A (en) 1996-08-30 1997-01-15 Method for producing epothilones
JP10511141A JP2001500851A (ja) 1996-08-30 1997-01-15 エポシロンの製造法および製造過程中に得られる中間生産物

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
DE19636343A DE19636343C1 (de) 1996-08-30 1996-08-30 Zwischenprodukte innerhalb der Totalsynthese von Epothilon A und B
DE19645362.3 1996-10-28
DE19645362A DE19645362A1 (de) 1996-10-28 1996-10-28 Verfahren zur Herstellung von Epothilon A und B und Derivaten
DE19645361.5 1996-10-28
DE19645361A DE19645361A1 (de) 1996-08-30 1996-10-28 Zwischenprodukte innerhalb der Totalsynthese von Epothilon A und B, Teil II
DE19636343.8 1996-10-28

Publications (1)

Publication Number Publication Date
WO1998008849A1 true WO1998008849A1 (fr) 1998-03-05

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EP (1) EP0923583A1 (fr)
JP (1) JP2001500851A (fr)
AU (1) AU716610B2 (fr)
NZ (1) NZ334821A (fr)
WO (1) WO1998008849A1 (fr)

Cited By (147)

* Cited by examiner, † Cited by third party
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WO1998022461A1 (fr) * 1996-11-18 1998-05-28 GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) Epothilone c, d, e et f, mode de preparation et application comme agents cytostatiques et phytosanitaires
WO1999007692A3 (fr) * 1997-08-09 1999-05-14 Schering Ag Nouveaux derives d'epothilone, leur procede de fabrication et leur utilisation pharmaceutique
WO1999059985A1 (fr) * 1998-05-18 1999-11-25 Novartis Ag Intermediaires pour la synthese d'epothilones et procede de preparation desdits intermediaires
WO1999067253A3 (fr) * 1998-06-22 2000-04-20 Novartis Ag Desmethylepothilones
WO1999065913A3 (fr) * 1998-06-18 2000-04-20 Biotechnolog Forschung Gmbh Constituants secondaires d'epothilone
WO2000031247A2 (fr) 1998-11-20 2000-06-02 Kosan Biosciences, Inc. Matieres et procedes recombinants destines a la production d'epothilone et de derives d'epothilone
EP0977563A4 (fr) * 1996-12-03 2001-04-25 Sloan Kettering Inst Cancer Synthese d'epothilones, intermediaires utilises dans leur synthese, analogues et utilisations de celles-ci
US6262094B1 (en) 1999-02-22 2001-07-17 Bristol-Myers Squibb Company C-21 modified epothilones
US6288237B1 (en) 1995-11-17 2001-09-11 Gesellschaft Fur Biotechnologische Forschung Mbh (Gbf) Epothilons C and D, preparation and compositions
US6291684B1 (en) 1999-03-29 2001-09-18 Bristol-Myers Squibb Company Process for the preparation of aziridinyl epothilones from oxiranyl epothilones
US6316630B1 (en) 1996-12-03 2001-11-13 Sloan Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
US6320045B1 (en) 1997-12-04 2001-11-20 Bristol-Myers Squibb Company Process for the reduction of oxiranyl epothilones to olefinic epothilones
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
US6380394B1 (en) 1996-12-13 2002-04-30 The Scripps Research Institute Epothilone analogs
US6380395B1 (en) 1998-04-21 2002-04-30 Bristol-Myers Squibb Company 12, 13-cyclopropane epothilone derivatives
US6410301B1 (en) 1998-11-20 2002-06-25 Kosan Biosciences, Inc. Myxococcus host cells for the production of epothilones
US6441186B1 (en) 1996-12-13 2002-08-27 The Scripps Research Institute Epothilone analogs
WO2002072858A3 (fr) * 2001-02-27 2002-12-19 Biotechnolog Forschung Gmbh Degradation d'epothilones
US6498257B1 (en) 1998-04-21 2002-12-24 Bristol-Myers Squibb Company 2,3-olefinic epothilone derivatives
US6518421B1 (en) 2000-03-20 2003-02-11 Bristol-Myers Squibb Company Process for the preparation of epothilone analogs
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US6593115B2 (en) 2000-03-24 2003-07-15 Bristol-Myers Squibb Co. Preparation of epothilone intermediates
US6596875B2 (en) 2000-02-07 2003-07-22 James David White Method for synthesizing epothilones and epothilone analogs
US6605599B1 (en) 1997-07-08 2003-08-12 Bristol-Myers Squibb Company Epothilone derivatives
WO2003078411A1 (fr) 2002-03-12 2003-09-25 Bristol-Myers Squibb Company Derives de c3-cyano epothilone
US6660758B1 (en) 1996-12-13 2003-12-09 The Scripps Research Institute Epothilone analogs
US6670384B2 (en) 2001-01-25 2003-12-30 Bristol-Myers Squibb Company Methods of administering epothilone analogs for the treatment of cancer
US6683100B2 (en) 1999-01-19 2004-01-27 Novartis Ag Organic compounds
US6686380B2 (en) 2001-02-20 2004-02-03 Bristol-Myers Squibb Company Treatment of refractory tumors using epothilone derivatives
US6689802B2 (en) 2000-08-16 2004-02-10 Bristol-Myers Squibb Company Polymorphs of an epothilone analog
US6727276B2 (en) 2001-02-20 2004-04-27 Bristol-Myers Squibb Company Epothilone derivatives for the treatment of refractory tumors
US6780620B1 (en) 1998-12-23 2004-08-24 Bristol-Myers Squibb Company Microbial transformation method for the preparation of an epothilone
US6800653B2 (en) 2001-06-01 2004-10-05 Bristol-Myers Squibb Compnay Epothilone derivatives
US6867305B2 (en) 1996-12-03 2005-03-15 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
US6936628B2 (en) 2002-04-04 2005-08-30 Bristol-Myers Squibb Company Oral administration of epothilones
US7001916B1 (en) 1999-02-11 2006-02-21 Schering, Ag Epothilon derivatives, method for the production and the use thereof as pharmaceuticals
US7008936B2 (en) 2002-06-14 2006-03-07 Bristol-Myers Squibb Company Combination of epothilone analogs and chemotherapeutic agents for the treatment of proliferative diseases
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US7312237B2 (en) 2001-03-14 2007-12-25 Bristol-Myers Squibb Co. Combination of epothilone analogs and chemotherapeutic agents for the treatment of prolilferative diseases
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