WO2008092306A1 - Procédé d'hémisynthèse de taxol et de docétaxel - Google Patents

Procédé d'hémisynthèse de taxol et de docétaxel Download PDF

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Publication number
WO2008092306A1
WO2008092306A1 PCT/CN2007/000456 CN2007000456W WO2008092306A1 WO 2008092306 A1 WO2008092306 A1 WO 2008092306A1 CN 2007000456 W CN2007000456 W CN 2007000456W WO 2008092306 A1 WO2008092306 A1 WO 2008092306A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
semi
equation
docetaxel
Prior art date
Application number
PCT/CN2007/000456
Other languages
English (en)
Chinese (zh)
Inventor
Xiao He
Xin Shen
Lixin Liao
Huaxing Zhan
Fuxing Lin
Jidong Yang
Original Assignee
Shanghai Parling Pharma-Tech. Co, Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Parling Pharma-Tech. Co, Ltd. filed Critical Shanghai Parling Pharma-Tech. Co, Ltd.
Publication of WO2008092306A1 publication Critical patent/WO2008092306A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • 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 present invention relates to the field of pharmaceutical synthesis, and in particular to a novel semi-synthetic method for paclitaxel and docetaxel.
  • Paclitaxel and docetaxel are the most effective anticancer drugs discovered by humans to date, and are extracted from the genus Taxus, but these plants are protected by the state and are extracted from plants. Therefore, seek The chemical synthesis of paclitaxel and docetaxel has become the direction of many scientists. Summary of the invention
  • the technical problem to be solved by the present invention is to provide a novel semi-synthesis method of paclitaxel and docetaxel.
  • the principle of the present invention is: The present invention docks with a chiral side chain and a protected 10-deacetylbaccatin 10-DAB, and then removes the protection of the side chain hydroxyl group by oxazoline (synthesis of paclitaxel) or Mitsunobu reaction. (Synthesis of docetaxel) The configuration of the inverted side chain.
  • the semi-synthesis method of paclitaxel and docetaxel provided by the invention specifically comprises the following steps:
  • step 3 if the compound of formula 5 is removed by the 7-position protection, paclitaxel is obtained, and if 7 and 10 positions are simultaneously removed, docetaxel is obtained;
  • Equation 4 Equation 4
  • Equation 5 Equation 5
  • R1 is a hydroxy protecting group such as TBS (tert-butyldimethylsilyl), TES (triethylsilyl), EE (ethoxyethyl), THP (tetrahydropyran), Troc (trichloroethyl) Oxycarbonyl) or MOM (methoxymethyl);
  • R2 is Ac (acetyl) or a hydroxy protecting group such as TBS, TES, EE, THP, Troc or MOM;
  • R3 is a hydroxy protecting group such as TBS, TES, EE, THP, Troc or MOM;
  • R4 is Bz (benzoyl) or Boc (tert-butoxycarbonyl).
  • the compound of the formula 1 and the compound of the formula 2 in the step 1 are subjected to a condensation reaction, and the reagent used in the reaction is a carbonyl diimide-based condensing agent such as dicyclohexylcarbonyldiimide and DMAP; wherein the amount of the condensing agent and the dehydrating agent is 1-10.
  • the equivalent amount of the organic base is 1-10 equivalents (calculated as 10-deacetylbaccatin 10-DAB).
  • the temperature of the condensation reaction is between 30 and 40 degrees.
  • the inversion of the side chain hydroxyl configuration can be carried out by oxazoline (synthesis of paclitaxel) or Mitsunobu (methanol acesulfame) (synthesis of docetaxel).
  • the semi-synthetic method of the present invention employs a trans-chiral side chain, and the synthesis of the trans side chain is much less difficult than the cis side chain.
  • the method of the invention has mild reaction conditions and is suitable for industrial production. detailed description

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Epoxy Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

La présente invention concerne un procédé d'hémisynthèse de taxol ou de docétaxel au cours duquel les composés souhaités sont préparés par la connexion de chaînes latérales chirales avec la 10-désacétylbaccatine protégée, l'élimination de la protection du radical hydroxyle dans la chaîne latérale et l'inversion de la configuration de la chaîne latérale par réaction en présence d'oxazoline ou de Mitsunobu. Le procédé présente l'avantage d'être un procédé simple, à haut rendement et est approprié à la production industrielle.
PCT/CN2007/000456 2007-01-26 2007-02-09 Procédé d'hémisynthèse de taxol et de docétaxel WO2008092306A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200710036856A CN100586940C (zh) 2007-01-26 2007-01-26 紫杉醇和多烯紫杉醇的半合成方法
CN200710036856.4 2007-01-26

Publications (1)

Publication Number Publication Date
WO2008092306A1 true WO2008092306A1 (fr) 2008-08-07

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2007/000456 WO2008092306A1 (fr) 2007-01-26 2007-02-09 Procédé d'hémisynthèse de taxol et de docétaxel

Country Status (3)

Country Link
KR (1) KR20080070500A (fr)
CN (1) CN100586940C (fr)
WO (1) WO2008092306A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101525321B (zh) * 2008-03-06 2012-03-07 上海希迪制药有限公司 多烯紫杉醇倍半水结晶体及其制备方法
CN101972668B (zh) * 2010-09-27 2011-12-28 罗梅 一种手性双膦酰二胺噁唑啉的新用途
CN107936058B (zh) * 2017-11-20 2020-05-19 沈阳药科大学 多西紫杉醇衍生物及其制备方法和应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6596880B1 (en) * 1992-02-07 2003-07-22 Aventis Pharma S.A. Method for preparing taxane derivatives
WO2005037840A1 (fr) * 2003-10-16 2005-04-28 Mayne Pharma (Usa), Inc. Methode pour inverser le groupe hydroxyle c2' d'esters de taxane

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6596880B1 (en) * 1992-02-07 2003-07-22 Aventis Pharma S.A. Method for preparing taxane derivatives
WO2005037840A1 (fr) * 2003-10-16 2005-04-28 Mayne Pharma (Usa), Inc. Methode pour inverser le groupe hydroxyle c2' d'esters de taxane

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KANAZAWA A.M. ET AL.: "Highly stereocontrolled and efficient preparation of the protected, esterification-ready docetaxel (taxotere) side chain", JOURNAL OF ORGANIC CHEMISTRY, vol. 59, no. 6, 1994, pages 1238 - 1240, XP002238306 *
MANDAI T. ET AL.: "A semisynthesis of paclitaxel via a 10-deacetylbaccatin III derivative bearing a beta-kote ester appendage", TETRAHEDRON LETTERS, vol. 41, no. 2, 1999, pages 243 - 246, XP004185457 *

Also Published As

Publication number Publication date
KR20080070500A (ko) 2008-07-30
CN101020676A (zh) 2007-08-22
CN100586940C (zh) 2010-02-03

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