EP1087955A1 - Semi-synthese de baccatine iii - Google Patents

Semi-synthese de baccatine iii

Info

Publication number
EP1087955A1
EP1087955A1 EP99915408A EP99915408A EP1087955A1 EP 1087955 A1 EP1087955 A1 EP 1087955A1 EP 99915408 A EP99915408 A EP 99915408A EP 99915408 A EP99915408 A EP 99915408A EP 1087955 A1 EP1087955 A1 EP 1087955A1
Authority
EP
European Patent Office
Prior art keywords
iii
compound
acetyl
baccatin iii
paclitaxel
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.)
Withdrawn
Application number
EP99915408A
Other languages
German (de)
English (en)
Inventor
Lolita Zamir
Gaétan Caron
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.)
Individual
Original Assignee
Individual
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 Individual filed Critical Individual
Publication of EP1087955A1 publication Critical patent/EP1087955A1/fr
Withdrawn legal-status Critical Current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
    • 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
    • Y02P20/582—Recycling of unreacted starting or intermediate materials

Definitions

  • the present invention relates to a semi-synthetic process to convert a naturally occurring taxane into a suitable starting material for the synthesis of paclitaxel and related compounds Specifically, the present invention relates to a process for the conversion of 9-dihydro-13- acetylbaccatin III into baccatin III which can then be used as starting material for the synthesis of taxane derivatives such as paclitaxel, docetaxel, cephalomannine and other taxanes structurally related to baccatin III
  • the method as described uses a preparative scale technique which is amenable to commercial scale-up
  • taxane family of terpenes is considered to be an exceptionally promising group of cancer chemotherapeutic agents
  • Many taxane derivatives, including paclitaxel, docetaxel, taxcultine canadensol are highly cytotoxic and possess strong in vivo activities in a number of leukemic and other tumor systems Paclitaxel, and a number of its derivatives, have been shown to be effective against advanced breast and ovarian cancers in clinical trials (W P MacGuire et al ,
  • Taxanes are believed to exert their antiproliferative effect by inducing tubulin polymerization, which forms extremely stable and nonfunctional microtubules (Schiff, et al , Promotion of Microtubule Assembly in vitro by Paclitaxel Nature, 277, 665-667, 1979)
  • paclitaxel also known as taxolTM
  • TaxolTM paclitaxel
  • paclitaxel The only available natural source of paclitaxel to date are several species of a slow growing yew (genus Taxus), wherein paclitaxel is found in very low concentrations (less than 400 parts per million) in these trees Furthermore the extraction is difficult, the process is expensive and the yield of paclitaxel is low (Huang et al, J. Nat Prod 49 665, 1986, reported a yield of 0 00025% of a crude paclitaxel fraction from Tax s brevifolia bark)
  • Paclitaxel can be isolated from the bark of Taxus brevifolia. the pacific yew tree, or from Taxus baccata, its European relative. Since removal of the bark destroys the trees and endangers the species, isolation of taxanes from the stems and needles of various Taxus species offers hope that the supply of taxanes, in particular paclitaxel, would become more abundant.
  • paclitaxel derivatives some of which have been reported to demonstrate enhanced chemotherapeutic activity, ultimately depends upon the supply of the parent compound - baccatin III
  • the structure of baccatin III has the basic diterpenoid structure of paclitaxel without the side chain at the C-13 position
  • Baccatin III is an important starting material in paclitaxel semi-synthesis Therefore the significance of baccatin III will likely increase as more clinical studies are performed using paclitaxel One such reason is that it appears that water soluble paclitaxel-like compounds with slightly modified C-13 side chains may be more desirable as cancer chemotherapeutic agents than the naturally occurring less water soluble paclitaxel This increases the urgent need for baccatin III as a starting material to synthesize both paclitaxel and second or third generation paclitaxel-like compounds There is, therefore, a need for an improved method of isolating and/or synthesizing Baccatin III
  • 10- deacetylbaccatin III The conversion of 10-deacetylbaccatin III into paclitaxel is typically achieved by protecting the hydroxy at C-7, attachment of an acetyl group at the C-10 position, attachment of a C- 13 ⁇ -amido ester side chain at the C-13 position through esterification of the C-13 alcohol with the ⁇ -lactam moiety, and deprotecting C-7 Since the supply of 10- deacetylbaccatin III is limited, other sources should be pursued
  • the present invention provides such a method, describing the conversion of a known taxane (9-dihydro-13-acetylbaccatin III), which is produced as a major metabolite in a certain species of taxus, into a paclitaxel precursor which produces relatively large amounts of a 7-protected baccatin III
  • the yield of 9-dihydro-13-acetylbaccatin III can vary from 2 0 to 2 5g per kilogram of dry plant and this taxane can be chemically transformed, by the present invention, into 7-
  • the present invention is directed towards a new method of producing baccatin III. from a naturally occuring taxane (9-dihydro-13-acetylbaccatin III) which is produced in high yields in Taxus canadensis.
  • the baccatin III can be used as a starting material for the synthesis of paclitaxel and paclitaxel derivatives.
  • Still a further object is to provide a simple, inexpensive method of preparing baccatin III that proceeds at room temperature.
  • the present invention provides a process for the preparation of Baccatin III from a compound of formula (X)
  • the present invention provides a process for the preparation of a 7-protected-9-dihydro-13- acetylbaccatin of formula I.
  • P is a hydroxy protecting group, which comprises the step of reacting 9-dihydro-13- acetylbaccatin III with a hydroxy protecting group to form a compound of formula I.
  • the present invention also provides a process for the preparation of a compound of formula II
  • the present invention further provides aprocess for the preparation of a compound of formula III from a compound of formula II wherein P is a hydroxy protecting group, which comprises converting a 13 -acetyl group to 13- hydroxyl group of a compound of compound of formula II.
  • 7-protected-9-dihydro-13-acetylbaccatin is formed by reacting 9- dihydro-13-acetylbaccatin III with a silylhalide, benzylhalide or alkylhalide, the halide is selected from Cl, Br, or I.
  • Preferred protecting reagents are t-butyldiphenylsilylchloride, t- butyldimethylsilylchloride, triethylsilylchloride or triisopropylsilylchloride.
  • the oxidation is facilitated by Jones' reagent, pyridinium dichromate, a Swern oxidation, a permanganate ion or Sarret's reagent.
  • deacylation is facilitated by reaction with an alkylalkalimetal or arylalkalimetal reagent.
  • an alkylalkalimetal or arylalkalimetal reagent Most preferred regent for deacylation is H-butyllithium.
  • figure 1 shows NMR spectra of an example of Compound 2, 9-dihydro-13-acetyl-7-t- butyldiphenylsilyl-baccatin III
  • figure 2 shows NMR spectra of an example of Compound 3, -acetyl-7-t-butyldiphenyl-silyl-baccatin III
  • figure 3 shows NMR spectra of an example Compound 4, 7-tert-butyldiphenylsilylbaccatin III.
  • the present invention relates to a high yield process for converting 9-dihydro- 13- acetylbaccatin III (an abundant taxane found in T. canadensis needles), into a 7-protected baccatin III, and baccatin III itself, which can subsequently be used as starting material for the synthesis of paclitaxel and related compounds
  • Taxus canadensis is a preferred source for use in the semi-synthetic method claimed in the present invention and differs from other yews both in its physical appearance (it is a small ramping evergreen bush), and in the composition of some of its taxanes Paclitaxel, cephalomannine and 10-deacetylbaccatin III can be isolated from Taxus canadensis which are also found in most if not all other yews. Taxus canadensis is, however, the only yew presently known which accumulates a significant quantity of 9-dihydro-
  • 9-dihydro- 13 -acetylbaccatin III as starting material is that it can be isolated by simple recrystallisations instead of the numerous silica gel column and HPLC techniques commonly used Hence 9-dihydro- 13- acetylbaccatin III can be obtained in relatively high yield, rendering it an ideal starting material for many semi-synthetic pathways
  • Compound 2 the 7-protected intermediate, is then oxidized by the use of reagents such as Jones' reagent (chromium trioxide and sulphuric acid), pyridinium dichromate (PDC), pyridinium chlorochromate (PCC), Swern oxidation (C 2 O 2 Cl 2 /DMSO), potassium permanganate (KMnO 4 ) or Sarret's agent (CrO 3 /pyridine)
  • Jones' reagent chromium trioxide and sulphuric acid
  • PDC pyridinium dichromate
  • PCC pyridinium chlorochromate
  • Swern oxidation C 2 O 2 Cl 2 /DMSO
  • potassium permanganate KMnO 4
  • Sarret's agent Sarret's agent
  • the 7-protected baccatin III can then be used as starting material for the semi- synthesis of known and novel taxanes by derivatization at C-13 This can be achieved by the use of a range of side chains (Ojima, I et al , Tetrahedron, 48, 6985-7012, 1992; and Ojima, I et a ⁇ .. Tetrahedron Letters, 34, 4149-4152, 1992)
  • Example 6 SCHEME D Conversion of the major taxane from Taxus canadensis to baccatin III
  • the first step consists of benzylating 13-Acetyl-9(R)-dihydrobaccatin III. This results in a major product (47% yield) of a benzyl adduct at position 9 (designated as compound 1) and two minor products.
  • Compound 2 (10% yield) has the benzyl also at position 9 but the acetyl group at position C-10 has been removed while compound 3 (6% yield) has the benzyl attached at position C-7.
  • Compound 4 (90% yield) is produced when compound 1 is acetylated to protect the C-7 position. The further removal of the benzyl group at the C-9 position, followed by the oxidation of compound 4 leads to compound 5.
  • THF potassium phosphate buffer, pH 7.0 (2:1) resulting in a slightly turbid solution.
  • NaBH 4 4.5 mg; 0.118 mmol
  • This reaction is monitored by HPLC. Three more subsequent additions of NaBH 4 over a 24 h period gives a compound with the same retention time on the HPLC as compound 6.
  • the reaction is quenched with acetone, diluted with ethyl acetate, and finally washed with brine. The resulting organic phase is dried over MgSO 4 , filtered and evaporated.
  • the compound 7-Acetylbaccatin HI 6 is dissolved in 0.60 ml THF. This is then treated with 0.60ml of 50% aqueous CF 3 COOH, followed by a solution of NaBH 4 (4.5 mg; 0.118 mmol). Two more subsequent additions of the NaBH 4 over a 24 h period produced the completed conversion of 7 acetylbaccatin III to baccatin III, which is monitored by HPLC.
  • This method entails using a protecting group which will react only with the hydroxyl group at the C7 position and not at the C9 position
  • the C7 protecting group will be stable to acid conditions during the subsequent oxidation step, and can be easily removed
  • 13-acetyl-9 (R)-dihydrobaccatin III is acetylated at the C-7 position
  • a successful method for acetylating 13-acetyl-9 (R)-dihydrobaccatin II is achieved by adding this compound dropwise to the acetylating mixture After approximately 4 hours reaction time, one can obtain 30% of an acetylated product and recover almost 70% of the starting material
  • the mixture is oxidized to generate two compounds' the major one corresponding to a rearranged diketone (which can be obtained from oxidation of the starting material) and another compound which is found to correspond to compound 5 (Scheme I) following high performance liquid chromatography
  • the yield of the acetylated product can be improved by leaving the reaction mixture overnight at room temperature, after which two major compounds can be obtained Preparative thin layer chromatography can be employed to separate the two compounds, which can improves the yield to approximately 60% monoacetylated product and 40% recovered starting material The monoacetylated product can be analysed by NMR to demonstrate pure compound 1 '
  • scheme III entails few steps and provides excellent yields in the conversion of 13- acetyl-9(R)-dihydrobaccatin III to baccatin III and therefore to paclitaxel and other bioactive taxanes

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Epoxy Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

L'invention concerne un procédé de préparation de baccatine III à partir d'un composé représenté par la formule (X), qui comporte les étapes consistant à: (1) protéger le groupe hydroxy situé sur un composé représenté par la formule X à la position 7 ou C9, ou aux positions C7 et C9 séquentiellement; (2) oxyder le groupe obtenu à la position C9; (3) soit (a) désacyler séquentiellement les esters aux positions C13 et C7, soit (b) désacyler simultanément les esters aux positions C13 et C7.
EP99915408A 1998-04-20 1999-04-20 Semi-synthese de baccatine iii Withdrawn EP1087955A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CA2235356 1998-04-20
CA2235356 1998-04-20
PCT/CA1999/000328 WO1999054322A1 (fr) 1998-04-20 1999-04-20 Semi-synthese de baccatine iii

Publications (1)

Publication Number Publication Date
EP1087955A1 true EP1087955A1 (fr) 2001-04-04

Family

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Family Applications (1)

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EP99915408A Withdrawn EP1087955A1 (fr) 1998-04-20 1999-04-20 Semi-synthese de baccatine iii

Country Status (4)

Country Link
EP (1) EP1087955A1 (fr)
AU (1) AU3402699A (fr)
NZ (1) NZ508257A (fr)
WO (1) WO1999054322A1 (fr)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT1178979E (pt) * 1999-05-17 2004-04-30 Bristol Myers Squibb Co Novas condicoes de reaccao para a clivagem de eteres de sililo na preparacao de paclitaxel (taxol(r)) e analogos de paclitaxel
US6812356B2 (en) * 2002-09-26 2004-11-02 John Findlay Conversion 9-dihydro-13-acetylbaccatin III into 10-deacetylbaccatin III
EP2091932B1 (fr) * 2004-04-23 2013-12-11 Chatham Biotec Ltd. Semi-synthese et isolement d'intermediaires du taxane a partir d'un melange de taxanes
US7893283B2 (en) 2004-06-04 2011-02-22 Chatham Biotec, Limited Semi-synthesis of taxane intermediates and their conversion to paclitaxel and docetaxel
US20050288520A1 (en) 2004-06-25 2005-12-29 Phytogen Life Sciences Inc. One pot synthesis of taxane derivatives and their conversion to paclitaxel and docetaxel
US20050288521A1 (en) 2004-06-29 2005-12-29 Phytogen Life Sciences Inc. Semi-synthetic conversion of paclitaxel to docetaxel
CA2599888C (fr) 2005-03-31 2010-06-15 Bioxel Pharma Inc. Preparation de taxanes a partir de la 9-dihydro-13-acetylbaccatine iii
CN1314675C (zh) * 2005-07-01 2007-05-09 中国科学院上海有机化学研究所 紫杉醇衍生物
CN100417649C (zh) * 2006-04-05 2008-09-10 云南思摩贝特生物科技有限公司 一种多西他赛的制备方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2188190A1 (fr) * 1996-10-18 1998-04-18 Sarala Balachandran La semi-synthese d'une composition bacatin iii protegee
CA2204197A1 (fr) * 1997-05-01 1998-11-01 Jian Liu Methode pour convertir la 9-dihydro-13-acetylbaccatine iii en taxol et en ses derives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9954322A1 *

Also Published As

Publication number Publication date
WO1999054322A1 (fr) 1999-10-28
AU3402699A (en) 1999-11-08
NZ508257A (en) 2003-04-29
WO1999054322B1 (fr) 1999-12-16

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