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WO2008074178A1 - Nouveau procédé de préparation de paclitaxel semi-synthétique - Google Patents

Nouveau procédé de préparation de paclitaxel semi-synthétique Download PDF

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Publication number
WO2008074178A1
WO2008074178A1 PCT/CN2006/003150 CN2006003150W WO2008074178A1 WO 2008074178 A1 WO2008074178 A1 WO 2008074178A1 CN 2006003150 W CN2006003150 W CN 2006003150W WO 2008074178 A1 WO2008074178 A1 WO 2008074178A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound represented
protecting group
paclitaxel
ketal
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/CN2006/003150
Other languages
English (en)
Chinese (zh)
Inventor
Xin Shen
Lixin Liao
Huaxing Zhan
Fuxing Lin
Xiao He
Jidong Yang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SHANGHAI BAILING PHARMACEUTICAL TECHNOLOGY Co Ltd
Original Assignee
SHANGHAI BAILING PHARMACEUTICAL TECHNOLOGY 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 BAILING PHARMACEUTICAL TECHNOLOGY Co Ltd filed Critical SHANGHAI BAILING PHARMACEUTICAL TECHNOLOGY Co Ltd
Priority to PCT/CN2006/003150 priority Critical patent/WO2008074178A1/fr
Publication of WO2008074178A1 publication Critical patent/WO2008074178A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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 invention relates to a novel semi-synthetic method of the anticancer drug paclitaxel. Background technique
  • Paclitaxel is considered to be the most effective anticancer drug ever discovered by humans and is extracted from the genus Taxus.
  • the extraction of paclitaxel from plants has not been possible due to its low content and the extraction of plants belonging to national conservation plants. Since the discovery of paclitaxel, its all-in-one achievement has become the synthetic target of many chemists. Due to the complex structure of paclitaxel, its fully synthetic route is long and the yield is low.
  • Semi-synthesis is relatively easy. Semi-synthesis mainly uses 10-deacetylbaccatin III and paclitaxel C13 side chain as raw materials. The chemical semi-synthesis method of paclitaxel not only helps to protect scarce plant resources, but also has great significance and huge economic benefits for expanding its clinical application and reducing treatment costs.
  • paclitaxel The strategy for semi-synthesis of paclitaxel is to dock with protected bacatein and chiral side chains and then deprotect to obtain paclitaxel as follows:
  • the side chain synthesis step is lengthy and the reagents used are expensive and cost prohibitive.
  • the present invention employs a third type of chiral side chain: 3-phenylisoserine type.
  • the invention has the following features: 1. Using different novel chiral side chains, the protected buckhaming III can be prepared by 10-deacetylbaccatin III extracted from the leaves of the yew, and the docking reaction condition is mild, at 0 ⁇ Reaction between 40 ° C for 1 ⁇ 12 h ; 2. Using a clever strategy to flip the 2 '' position of the C13 position side chain to get the correct configuration.
  • the process of the invention is suitable for industrial production.
  • the synthetic route of the present invention is as follows:
  • the R1 protecting group is a hydroxy protecting group such as tert-butyldimethylsilyl (TBS), triethylsilyl (TES), ethoxyethyl (EE), tetrahydropyran (THP), trichloroethyl Oxycarbonyl (Troc), methoxymethyl (MOM), etc.
  • R2 protecting group is a hydroxy protecting group such as TBS, TES, EE, THP, Troc, MOM, etc.
  • R3 is H; or R2, R3 are ketal protection
  • the ketal may be, for example, an anisyl ketal, an acetone ketal, or the like; and the dehydrating agent may be a thionyl chloride, a phosphorus pentachloride, a trifluoromethanesulfonic anhydride, a Vi lsmeier reagent or the like.
  • the invention condenses the protected bicalatin 111 (1) and the novel chiral side chain (2) under the action of cyclohexyl carbodiimide (DCC) / 4-dimethylaminopyridine (DMAP) to obtain a compound ( 3), removing the side chain protection to obtain the compound (4), dehydration while completing the side chain 2, chiral inversion to obtain the compound (5), and finally hydrolyzing the oxazoline to obtain the compound (6), removing the 7-position protection Paclitaxel (Taxol) was obtained.
  • DCC cyclohexyl carbodiimide
  • DMAP 4-dimethylaminopyridine

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Epoxy Compounds (AREA)

Abstract

L'invention concerne un nouveau procédé de préparation de taxol semi-synthétique par condensation du précurseur à chaîne latérale C-13 synthétique de 2-épipaclitaxel à l'aide de baccatine III protégée. Le paclitaxel obtenu présente une configuration totalement identique à celle de l'if.
PCT/CN2006/003150 2006-11-23 2006-11-23 Nouveau procédé de préparation de paclitaxel semi-synthétique Ceased WO2008074178A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CN2006/003150 WO2008074178A1 (fr) 2006-11-23 2006-11-23 Nouveau procédé de préparation de paclitaxel semi-synthétique

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2006/003150 WO2008074178A1 (fr) 2006-11-23 2006-11-23 Nouveau procédé de préparation de paclitaxel semi-synthétique

Publications (1)

Publication Number Publication Date
WO2008074178A1 true WO2008074178A1 (fr) 2008-06-26

Family

ID=39535958

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2006/003150 Ceased WO2008074178A1 (fr) 2006-11-23 2006-11-23 Nouveau procédé de préparation de paclitaxel semi-synthétique

Country Status (1)

Country Link
WO (1) WO2008074178A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011134067A1 (fr) * 2010-04-29 2011-11-03 6570763 Canada Inc. Nouvelle molécule d'acides aminés et ses utilisations

Citations (2)

* 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
CN1646512A (zh) * 2002-04-12 2005-07-27 因德纳有限公司 制备n－脱苯甲酰基紫杉醇的半合成方法

Patent Citations (2)

* 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
CN1646512A (zh) * 2002-04-12 2005-07-27 因德纳有限公司 制备n－脱苯甲酰基紫杉醇的半合成方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DENIS ET AL.: "Taxotere by Esterification with Stereochemically "Wrong" (2S,3S)-Phenylisoserine Derivatives", TETRAHEDRON LETTERS, vol. 35, no. 1, 1994, pages 105 - 108 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011134067A1 (fr) * 2010-04-29 2011-11-03 6570763 Canada Inc. Nouvelle molécule d'acides aminés et ses utilisations

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