WO2008092307A1 - Hemi-synthèse de paclitaxel et docetaxel - Google Patents

Hemi-synthèse de paclitaxel et docetaxel Download PDF

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Publication number
WO2008092307A1
WO2008092307A1 PCT/CN2007/000457 CN2007000457W WO2008092307A1 WO 2008092307 A1 WO2008092307 A1 WO 2008092307A1 CN 2007000457 W CN2007000457 W CN 2007000457W WO 2008092307 A1 WO2008092307 A1 WO 2008092307A1
Authority
WO
WIPO (PCT)
Prior art keywords
paclitaxel
compound
formula
docetaxel
semi
Prior art date
Application number
PCT/CN2007/000457
Other languages
English (en)
Chinese (zh)
Inventor
Huaxing Zhan
Xin Shen
Lixin Liao
Xiao He
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 WO2008092307A1 publication Critical patent/WO2008092307A1/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 semi-synthetic novel of 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 semi-synthetic method of paclitaxel and docetaxel to solve the defects of the prior art.
  • the principle of the present invention is that the chiral trans four-membered side chain and the protected 10-deacetylbaccatin 10-DAB are docked, then the side chain protection is removed, the chiral flip of the 2' position is performed, and finally the In addition to the protecting group, paclitaxel or docetaxel is obtained.
  • the method for semi-synthesis of paclitaxel and docetaxel specifically comprises the following steps:
  • a compound of formula 4 is obtained by inversion of the 25 position of the side chain to give a compound of formula 5;
  • 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 3 is:
  • Equation 4 Equation 4
  • 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 an Ac (acetyl) or 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 are subjected to a condensation reaction, and the reagent used for the reaction is an organic base such as butyllithium in an amount of from 1 to 1.2 equivalents (protected 10-deacetylbaccatin) 10—DAB shall prevail).
  • organic base such as butyllithium in an amount of from 1 to 1.2 equivalents (protected 10-deacetylbaccatin) 10—DAB shall prevail).
  • the temperature of the condensation reaction is between -70 and 0 °C.
  • the inversion of the side chain hydroxyl configuration in step 2 can be carried out by oxazoline (synthesis of paclitaxel) or Mitsunobu (metaacetamide) (synthesis of docetaxel).
  • the process of the invention has mild reaction conditions and is suitable for industrial production. It opens a new route for the synthesis of paclitaxel and docetaxel. detailed description

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

Abstract

L'invention concerne une hemi-synthèse de paclitaxel et docetaxel consistant à condenser une chaîne latérale de trans cycles chiraux à quatre éléments et la 10-déacétylbaccatine (10-DAB) protégée, assurer le renouvellement de 2'-chiralité, puis déprotéger la chaîne latérale et finalement obtenir du paclitaxel ou docetaxel par retrait des groupements protecteurs. Le procédé de cette invention est doux dans des conditions rédactionnelles et trouve une application commerciale.
PCT/CN2007/000457 2007-01-26 2007-02-09 Hemi-synthèse de paclitaxel et docetaxel WO2008092307A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CNB200710036855XA CN100554258C (zh) 2007-01-26 2007-01-26 紫杉醇和多烯紫杉醇的半合成方法
CN200710036855.X 2007-01-26

Publications (1)

Publication Number Publication Date
WO2008092307A1 true WO2008092307A1 (fr) 2008-08-07

Family

ID=38708562

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2007/000457 WO2008092307A1 (fr) 2007-01-26 2007-02-09 Hemi-synthèse de paclitaxel et docetaxel

Country Status (2)

Country Link
CN (1) CN100554258C (fr)
WO (1) WO2008092307A1 (fr)

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
FARINA V. ET AL.: "A SIMPLE CHIRAL SYNTHESIS OF THE TAXOL SIDE-CHAIN", SYNLETT., 1992, pages 761 - 763, XP002064430 *
HOLTON R.A. ET AL.: "A simple synthesis of 10-deacetoxytaxol derivatives", TETRAHEDRON LETTERS, vol. 35, no. 11, 1994, pages 1665 - 1668 *
HOLTON R.A. ET AL.: "First total synthesis of taxol. 2. Completion of the C and D rings", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 116, 1994, pages 1599 - 1600 *
KANT J. ET AL.: "Diastereoselective addition of grignard reagents to azetidine-2,3-dione: Synthesis of novel Taxol(R) analogues", TETRAHEDRON LETTERS, vol. 37, no. 36, 1996, pages 6495 - 6498, XP004030726 *
MORIHIRA K. ET AL.: "Enantioselective total synthesis of taxol", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 120, 1998, pages 12980 - 12981, XP000788257 *
NICOLAOU K.C. ET AL.: "Novel chemistry of taxol. Retrosynthetic and synthetic studies", JOURNAL OF THE CHEMICAL SOCIETY-CHEMICAL COMMUNICATIONS, 1994, pages 295 - 296 *
NICOLAOU K.C. ET AL.: "Total synthesis of taxol", NATURE, vol. 367, 1994, pages 630 - 634, XP000652074 *
NICOLAOU K.C. ET AL.: "Total synthesis of taxol. 4. The final stages and completion of the synthesis", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 117, 1995, pages 653 - 659, XP000485655 *

Also Published As

Publication number Publication date
CN101020675A (zh) 2007-08-22
CN100554258C (zh) 2009-10-28

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