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DE60211124T2 - Abbau von Epothilonen - Google Patents

Abbau von Epothilonen Download PDF

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Publication number
DE60211124T2
DE60211124T2 DE60211124T DE60211124T DE60211124T2 DE 60211124 T2 DE60211124 T2 DE 60211124T2 DE 60211124 T DE60211124 T DE 60211124T DE 60211124 T DE60211124 T DE 60211124T DE 60211124 T2 DE60211124 T2 DE 60211124T2
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DE
Germany
Prior art keywords
formula
compound
epothilone
scheme
degradation
Prior art date
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Expired - Lifetime
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DE60211124T
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English (en)
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DE60211124D1 (de
Inventor
Gerhard Hoefle
Usama Karama
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Helmholtz Zentrum fuer Infektionsforschung HZI GmbH
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Helmholtz Zentrum fuer Infektionsforschung HZI GmbH
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Publication of DE60211124T2 publication Critical patent/DE60211124T2/de
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Expired - Lifetime legal-status Critical Current

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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
    • 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
    • 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.]

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

Description

  • Abbau von Epothilonen
  • Epothilone vom Typ C und Typ D gehören zum Stand der Technik und sind besonders durch eine C=C Doppelbindung an den Positionen 12 und 13 und einem Wasserstoffatom an der Position 12 (Typ C) oder einer Alkylgruppe (Typ D) gekennzeichnet.
  • Gemäß einer Ausführungsform betrifft die Erfindung ein Verfahren zum Abbau von einem Epothilon C oder einem Epothilon D, bei dem man das Epothilon C oder das Epothilon D einer Olefin-Metathese in Gegenwart von Ethylen und danach einer fakultativen Esterhydrolyse unterwirft (Schema 1).
  • Erfindungsgemäß kann das Epothilon C oder D ein Fermentationsprodukt sein.
  • Experimenteller Teil
  • 12,13-Seco-Epothilon C (2a):
  • 450 mg Epothilon C (1) (0,95 mmol) wurden in 250 ml Dichlormethan gelöst, mit Ethylen gesättigt und nach Zugabe von 60 mg Grubb's Katalysator (PhCHRuCl2]P(Cy)3]2) 24 Stunden lang gerührt. Nach Zugabe von weiteren 60 mg Katalysator und 24-stündigem Rühren wurde die dunkle Lösung zur Trockne eingedampft und der Rückstand durch Chromatographie über Kieselgel mit dem Lösungsmittelsystem Hexan/tert.-Butylmethylester/Methanol 80:20:1 gereinigt. Die erste Fraktion enthielt 360 mg (75%) an 2a, die zweite 100 mg (22%) an wiedergewonnenem Ausgangsmaterial 1.
    2a: 1H-NMR (CDCl3), 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 (positive Ionen) m/z = 506 [M + H+], CI-MS (NH3 positive Ionen) m/z = 506 [M + H+] (22%), 380 (100%).

Claims (3)

  1. Verfahren zum Abbau von einem Epothilon C oder einem Epothilon D, bei dem man das Epothilon C oder das Epothilon D einer Olefin-Metathesis in Gegenwart von Ethylen und danach einer fakultativen Esterhydrolyse unterwirft (Schema I).
  2. Verfahren nach Anspruch 1, bei dem Epothilon C oder Epothilon D ein Fermentationsprodukt sind.
  3. Verbindung der Formel 2a, erhältlich nach einem Verfahren gemäß einem oder mehreren der vorhergehenden Ansprüche.
DE60211124T 2001-02-27 2002-02-27 Abbau von Epothilonen Expired - Lifetime DE60211124T2 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP01104448 2001-02-27
EP01104448 2001-02-27
PCT/EP2002/002105 WO2002072858A2 (en) 2001-02-27 2002-02-27 Degradation of epothilones and ethynyl substituted epothilones

Publications (2)

Publication Number Publication Date
DE60211124D1 DE60211124D1 (de) 2006-06-08
DE60211124T2 true DE60211124T2 (de) 2006-11-30

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Family Applications (2)

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DE60211124T Expired - Lifetime DE60211124T2 (de) 2001-02-27 2002-02-27 Abbau von Epothilonen
DE60213884T Expired - Lifetime DE60213884T2 (de) 2001-02-27 2002-02-27 Verfahren zur Herstellung von Epothilonen

Family Applications After (1)

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DE60213884T Expired - Lifetime DE60213884T2 (de) 2001-02-27 2002-02-27 Verfahren zur Herstellung von Epothilonen

Country Status (19)

Country Link
US (1) US7157595B2 (de)
EP (2) EP1364040B1 (de)
JP (1) JP2004522801A (de)
KR (1) KR20030084952A (de)
CN (1) CN1501980A (de)
AT (2) ATE335746T1 (de)
BR (1) BR0207675A (de)
CA (1) CA2437707A1 (de)
CZ (1) CZ20032291A3 (de)
DE (2) DE60211124T2 (de)
HU (1) HUP0303895A3 (de)
IL (1) IL157312A0 (de)
MX (1) MXPA03007466A (de)
NO (1) NO20033784L (de)
NZ (2) NZ539204A (de)
PL (1) PL362556A1 (de)
RU (1) RU2003128953A (de)
WO (1) WO2002072858A2 (de)
ZA (1) ZA200306034B (de)

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 (de) * 1998-06-18 1999-12-23 Biotechnolog Forschung Gmbh Epothilon-Nebenkomponenten
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
PT1506203E (pt) * 2002-08-23 2007-04-30 Sloan Kettering Inst Cancer Síntese de epotilonas, seus intermediários, seus análogos e suas utilizações
US6921769B2 (en) 2002-08-23 2005-07-26 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0057736B1 (de) * 1981-02-05 1986-11-20 Phillips Petroleum Company Olefin-Disproportionierungs-Verfahren und Katalysator
PT1186606E (pt) 1995-11-17 2004-08-31 Biotechnolog Forschung Mbh Gbf Derivados do epotilone sua preparacao e utilizacao
NZ334821A (en) * 1996-08-30 2000-12-22 Novartis Ag Method for producing epothilones
US5969145A (en) 1996-08-30 1999-10-19 Novartis Ag Process for the production of epothilones and intermediate products within the process
DK0941227T5 (da) 1996-11-18 2009-10-05 Biotechnolog Forschung Gmbh Epothilon D, dens fremstilling samt dens anvendelse som cytostatisk middel og som plantebeskyttelsesmiddel
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
CN1128803C (zh) * 1997-02-25 2003-11-26 生物技术研究有限公司(Gbf) 环氧噻嗪酮b－n－氧化物及其制备方法
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
DE60213884T2 (de) 2007-02-22
EP1364040B1 (de) 2006-05-03
BR0207675A (pt) 2004-03-09
IL157312A0 (en) 2004-02-19
WO2002072858A3 (en) 2002-12-19
CA2437707A1 (en) 2002-09-19
ATE335746T1 (de) 2006-09-15
EP1364040A2 (de) 2003-11-26
EP1564217A2 (de) 2005-08-17
DE60213884D1 (de) 2006-09-21
NO20033784D0 (no) 2003-08-26
KR20030084952A (ko) 2003-11-01
NZ539204A (en) 2005-12-23
HUP0303895A2 (hu) 2004-03-29
CN1501980A (zh) 2004-06-02
CZ20032291A3 (cs) 2004-02-18
EP1564217B1 (de) 2006-08-09
NZ527557A (en) 2005-05-27
MXPA03007466A (es) 2003-12-08
PL362556A1 (en) 2004-11-02
ZA200306034B (en) 2004-08-05
US7157595B2 (en) 2007-01-02
DE60211124D1 (de) 2006-06-08
RU2003128953A (ru) 2005-03-10
EP1564217A3 (de) 2005-08-31
NO20033784L (no) 2003-08-26
ATE325201T1 (de) 2006-06-15
JP2004522801A (ja) 2004-07-29
US20040092560A1 (en) 2004-05-13
WO2002072858A2 (en) 2002-09-19
HUP0303895A3 (en) 2007-06-28

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