WO2008080265A1 - Procédé de synthèse du docétaxel - Google Patents

Procédé de synthèse du docétaxel Download PDF

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Publication number
WO2008080265A1
WO2008080265A1 PCT/CN2007/000225 CN2007000225W WO2008080265A1 WO 2008080265 A1 WO2008080265 A1 WO 2008080265A1 CN 2007000225 W CN2007000225 W CN 2007000225W WO 2008080265 A1 WO2008080265 A1 WO 2008080265A1
Authority
WO
WIPO (PCT)
Prior art keywords
docetaxel
side chain
formula
compound
structural formula
Prior art date
Application number
PCT/CN2007/000225
Other languages
English (en)
Chinese (zh)
Inventor
Lixin Liao
Xin Shen
Huaxing Zhan
Fuxing Lin
Xiao He
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 WO2008080265A1 publication Critical patent/WO2008080265A1/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

Definitions

  • the present invention relates to the field of pharmaceutical synthesis, and in particular to a semi-synthetic method for an anticancer drug docetaxel.
  • the docetaxel (structural formula 1) is obtained by structural modification on the basis of paclitaxel. It has a broad spectrum of anti-leukemia and anti-tumor activity, and its anticancer activity is 1. 3 -12 times that of paclitaxel. It is considered to be one of the most significant anticancer drugs to date. Docetaxel is as complex as paclitaxel, with numerous functional groups and chiral centers, making it difficult to synthesize. Semi-synthetic methods are the most effective chemical method for producing docetaxel.
  • the semi-synthetic methods of docetaxel in the existing literature and patents can be roughly divided into two categories.
  • the first type is a side chain condensation of protected 10-deacetyloside gibberellin 10-DAB and five-membered oxazolidine acid, followed by hydrolysis deprotection to give docetaxel (eg US6900342); 10-Deacetylbaccatin 10-DAB is reacted with a quaternary lactam at a very low temperature under the action of a strong base such as butyllithium, and then hydrolyzed and deprotected to give docetaxel (for example, US2005288520) ). (See below)
  • the second category is a first category:
  • the first type of method is mild in condensation, but a large amount of condensation reagent DCC (dicyclohexylcarbonyl) must be used. Amine), this reagent poses great difficulties for subsequent purification.
  • the conditions of the second type of method are harsh, and due to the use of a strong base, a slight inadvertent decomposition of the 10-deacetylbaccatin 10-DAB which causes the protection of the raw material causes an expensive loss of raw materials;
  • the method must use a side chain that is many times in excess, which not only increases the difficulty for subsequent purification, but also increases the production cost. Summary of the invention
  • the technical problem to be solved by the present invention is to provide a method for synthesizing docetaxel to solve the defects in the prior art.
  • the method for synthesizing docetaxel provided by the present invention is specifically produced by a condensation reaction of 10-deacetylbaccatin 10-DAB of structural formula (2) and a C-13 side chain of structural formula (3);
  • TBS tert-butyldimethylsilyl
  • TES triethylsilyl
  • EE ethoxyethyl
  • Troc Trichloroethyloxycarbonyl
  • MOM methoxymethyl
  • the C-13 side chain of the structural formula (3) is (5);
  • R4 is succinimide (Su);
  • R4 is H or succinimide (Su) );
  • R 3 is an anisyl ketal or an acetone ketal.
  • the compounds of structural formulas (2) and (3) which are raw materials, were purchased from Xi'an Bailing Biotechnology Co., Ltd., and the product batch numbers were 905-0601003 and 918-0602001, respectively.
  • reaction formula (1) is:
  • reaction formula (2) is:
  • the reaction formula (1) in the present invention is a compound (5) obtained by condensation of a protected 10-deacetylbaccatin 10-DAB (2) and a novel chiral side chain (4), and the side chain is removed. Protection affords compound (6), and finally the protection of the 7 and 10 positions is removed to give docetaxel (Do Ce ta X ol).
  • the reaction formula (2) is a compound (7) obtained by condensation of a protected 10-deacetylbaccatin 10-DAB (2) and a novel chiral side chain (5), and the side chain is removed to obtain a compound ( 8), then the chirality of the 2' position is reversed (wherein R4' is p-toluenesulfonyl or formamylsulfonyl), and the protection of the 7 and 10 positions is finally removed to obtain docetaxel (Doceta X ol).
  • reaction intermediate or final product can be further purified by chromatography.
  • the synthesis method of the present invention is characterized by: 1.
  • the reaction formula 1 adopts different novel chiral side chains, which makes the docking reaction conditions milder, and avoids the use of the condensation reagent DCC which is difficult to purify; 2.
  • the reaction formula 2 adopts a clever strategy, and the 2'-position configuration is reversed. The side chains are docked and then flipped to get the correct configuration.
  • the process of the invention is suitable for industrial production.
  • step 1
  • Step 3 '

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Procédé de synthèse du docétaxel. On obtient le docétaxel en condensant la 10-déacétylbaccatine III avec une chaîne latérale en C-13 chirale synthétisée. Le procédé est facile, les conditions de la réaction sont modérées et le procédé convient pour une production industrielle.
PCT/CN2007/000225 2006-12-28 2007-01-22 Procédé de synthèse du docétaxel WO2008080265A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200610148365.4 2006-12-28
CN2006101483654A CN101020672B (zh) 2006-12-28 2006-12-28 多烯紫杉醇的合成方法

Publications (1)

Publication Number Publication Date
WO2008080265A1 true WO2008080265A1 (fr) 2008-07-10

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2007/000225 WO2008080265A1 (fr) 2006-12-28 2007-01-22 Procédé de synthèse du docétaxel

Country Status (2)

Country Link
CN (1) CN101020672B (fr)
WO (1) WO2008080265A1 (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
CN106632297A (zh) * 2016-12-28 2017-05-10 吉林医药学院 多烯紫杉醇侧链2′‑衍生的新型紫杉烷类抗肿瘤化合物及其合成方法与应用
CN111138386A (zh) * 2019-12-30 2020-05-12 重庆市碚圣医药科技股份有限公司 一种多西他赛的半合成方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997000870A1 (fr) * 1995-06-20 1997-01-09 Pharmacia & Upjohn S.P.A. Procede de preparation du taxol et de ses derives
US5686623A (en) * 1992-10-30 1997-11-11 Rhone-Poulenc Rorer, S.A. Method for preparing taxane derivatives
US6143902A (en) * 1999-06-21 2000-11-07 Napro Biotherapeutics, Inc. C-2 hydroxyl protected-N-acyl (2R,3S)-3-phenylisoserine N-imido activated esters and method for production thereof
WO2004056790A1 (fr) * 2002-12-19 2004-07-08 Agropharm S.A. Procede de production de produits semi-finis utiles dans la synthese du paclitaxel

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5686623A (en) * 1992-10-30 1997-11-11 Rhone-Poulenc Rorer, S.A. Method for preparing taxane derivatives
WO1997000870A1 (fr) * 1995-06-20 1997-01-09 Pharmacia & Upjohn S.P.A. Procede de preparation du taxol et de ses derives
US6143902A (en) * 1999-06-21 2000-11-07 Napro Biotherapeutics, Inc. C-2 hydroxyl protected-N-acyl (2R,3S)-3-phenylisoserine N-imido activated esters and method for production thereof
WO2004056790A1 (fr) * 2002-12-19 2004-07-08 Agropharm S.A. Procede de production de produits semi-finis utiles dans la synthese du paclitaxel

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
COMMERCON A. ET AL.: "Improved Protection and Esterification of a Precursor of the Taxotere and Taxol Side Chains", TETRAHEDRON LETTERS, vol. 32, no. 36, 1992, pages 5185 - 5188 *
DENIS ET AL.: "Taxotere by Esterification with Stereochemically "Wrong" (2S,3S)-Phenylisoserine Derivatives", TETRAHEDRON LETTERS, vol. 35, no. 1, 1994, pages 105 - 108 *

Also Published As

Publication number Publication date
CN101020672A (zh) 2007-08-22
CN101020672B (zh) 2010-08-25

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