WO2002012216A1 - Procede ameliore de preparation de docetaxel - Google Patents

Procede ameliore de preparation de docetaxel Download PDF

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Publication number
WO2002012216A1
WO2002012216A1 PCT/IB2000/001107 IB0001107W WO0212216A1 WO 2002012216 A1 WO2002012216 A1 WO 2002012216A1 IB 0001107 W IB0001107 W IB 0001107W WO 0212216 A1 WO0212216 A1 WO 0212216A1
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WO
WIPO (PCT)
Prior art keywords
formula
docetaxel
iii
compound
group
Prior art date
Application number
PCT/IB2000/001107
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English (en)
Inventor
Subrahmanyam Duvvuri
Ramachandra Puranik
Original Assignee
Dr. Reddy's Research Foundation
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 Dr. Reddy's Research Foundation filed Critical Dr. Reddy's Research Foundation
Priority to AU2000261768A priority Critical patent/AU2000261768A1/en
Priority to PCT/IB2000/001107 priority patent/WO2002012216A1/fr
Publication of WO2002012216A1 publication Critical patent/WO2002012216A1/fr

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    • 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 an improved process for the preparation of 'Docetaxel'.
  • Docetaxel is also known as 'Taxotere', a trademark of Rhone-poulenc Rorer and it is a taxane derivative having potent anti-tumor activity.
  • the present invention more particularly relates to a short synthesis of docetaxel of formula (1) following a semi-synthetic route comprising C-13 esterification of a suitably protected 10-Deacetylbaccatin III with a suitably protected side chain acid and subsequent deprotections to produce docetaxel .
  • 'Paclitaxel' having the formula (2) widely known as 'TaxoF in chemical literature is a naturally occurring compound from the bark of Pacific as well as Himalayan Yew tree and exhibits a broad spectrum of anti-tumor activity. It has been approved in various countries for use in the treatment of ovarian and breast cancers and clinical trials are under progress in many countries for its use in several other types of cancers as well.
  • SAR Structure Activity Relationship
  • Docetaxel of the formula (1) is one such synthetic derivative of paclitaxel of the formula (2) which showed most promising anti-tumor activity in clinical trials. It was developed as an anti-cancer drug by Rhone-Poulenc Rorer for the treatment of cancer. Docetaxel has been approved in several countries for the treatment of breast cancer recently. Docetaxel has the molecular formula (1), which is similar to paclitaxel of the formula (2) except that a free hydroxyl group at C-10 position of baccatin part and a t-butoxycarbonyl (t-boc) group at C-3' nitrogen of the side chain acid part.
  • 10-deacetylbaccatin III (10- DAB III) of the formula (3) is a relatively abundant precursor molecule obtained from several species of the Yew tree (genus Taxus) grown in various parts of the world.
  • 10-DAB III of the formula (3) it is necessary to protect the C-7, & C-10 hydroxyl groups before undertaking the esterification of C-13 hydroxyl group in the compound of the formula (3) to produce docetaxel of the formula (1) or paclitaxel of the formula (2).
  • R 1 & R 2 independently represent hydrogen, lower alkyl, phenyl, substituted phenyl groups which corresponds to the side chain acid part of the docetaxel of the formula (1) and a cost effective method of the side chain acid preparation also accounts for a salient feature of a good synthesis of both docetaxel as well as paclitaxel.
  • the objective of the present invention is to provide an improved process for the preparation of 'Docetaxel' of the formula (1),
  • the starting compound 10-deacetylbaccatin III of the formula (3) has been isolated from the leaves of the plant 'Taxus baccata ' or 'Taxus wallichiana ' available in western ghats of India following the literature procedure.
  • the present invention provides an improved process for the preparation of docetaxel of the formula (1) which comprises, i) reacting 10-deacetylbaccatin III of the formula (3) with a compound of the formula (5)
  • R 1 & R 2 independently represent hydrogen, lower alkyl, phenyl, substituted phenyl groups, in the presence of a base, and a solvent to furnish the novel C-13 coupled product of the formula (7)
  • the compound of the formula (5) employed in the reaction step (i) is a heterocyclic compound, preferably an aromatic heterocyclic compound, more preferably the heterocyclic group is an imidazole.
  • the transformation of 10-deacetylbaccatin III of the formula (3) to 7,10- diprotected 10-deacetylbaccatin III of the formula (6) may be achieved in a single step by reacting .
  • CDI carbonyldiimidazole
  • the solvents employed in the reaction may be chosen from ethereal solvents such as 1,4-dioxane, dimethoxyethane, tetrahydrofuran or aromatic solvents such as benzene, toluene or chlorinated solvents such as dichloroethane, dichloromethane, chloroform but preferably chlorinated solvents.
  • ethereal solvents such as 1,4-dioxane, dimethoxyethane, tetrahydrofuran or aromatic solvents such as benzene, toluene or chlorinated solvents such as dichloroethane, dichloromethane, chloroform but preferably chlorinated solvents.
  • the appropriate compounds of the formula (6) obtained by the reaction may be purified by crystallization methods or column chromatography using silicagel preferably of 6-120 mesh.
  • R 1 and R 2 may preferably represent methyl group.
  • the base used in this reaction may be carbodiimide bases such as dicyclohexyl carbodiimide or carbonate bases such as dipyridylcarbonate along with 4-N,N- dimethylaminopyridine as a promoter of the reaction.
  • carbodiimide bases such as dicyclohexyl carbodiimide
  • carbonate bases such as dipyridylcarbonate along with 4-N,N- dimethylaminopyridine as a promoter of the reaction.
  • the solvents used in the reaction may be selected from chlorinated solvents such as dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride or aromatic solvents such as benzene, toluene, hexane, 1,2-dichlorobenzene, xylene or ethereal solvents such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane or amides such as dimethylformamide, dimethylacetamide.
  • chlorinated solvents such as dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride or aromatic solvents such as benzene, toluene, hexane, 1,2-dichlorobenzene, xylene or ethereal solvents such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane or amides such as dimethylformamide, di
  • the reaction may be carried out at a temperature in the range of 20 to 80 °C but preferably between 20- 40 °C.
  • the appropriate compounds of the formula (7) obtained by the reaction may be isolated by known methods and if required purified by crystallization or column chromatography using silicagel preferably of 100-120 mesh. We have observed that the crystallization of the compound of the formula (7) provides a high purity compound. For such crystallizations, solvents such as chloroform, acetone, diethyl ether, diisopropyl ether, pet-ether, hexane or cyclohexane were found to be preferable.
  • the deprotection of the protecting groups at C-7, C-10 carbons and the oxazolidine group present in the compound of the formula (7) may be carried out by the treatment with an acid to obtain the amino alcohol of the formula (8).
  • the acid used in the reaction may be selected from organic acids such as formic acid, acetic acid, trifluoroacetic acid either neat or in aqueous form.
  • the solvent used in the reaction may be selected from water, tetrahydrofuran, diethyl ether, 1,4-dioxane, acetonitrile, methanol, and ethanol.
  • the temperature employed for the reaction may be in the range of -10 to 30 °C but preferably in the range of -5 to 5 °C.
  • the amino alcohol of the formula (8) may be derivatised with tertbutoxycarbonyl (Boc) group using diter butyl dicarbonate in the presence of a base.
  • the base used in the reaction may be selected from sodium bicarbonate, sodium carbonate, and potassium carbonate.
  • the solvent employed in the reaction may be selected from tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane and ethyl acetate.
  • the chiral protected side chain acid of the formula (4) used in the present invention may be prepared in two steps from a known vinyl alcohol of the formula (9) ( A.E. Greene et.al., J.Org.Chem., 56, 6939(1991) following the method described in our US patent number 5,763,477.
  • the method of its preparation involves: (i) the reaction of vinyl alcohol of the formula (9) with a reagent of the formula (10) where R 1 & R 2 independently represents hydrogen, lower alkyl, phenyl, substituted phenyl groups under acidic reaction conditions to obtain an oxazolidine derivative of the formula (11),
  • lower alkyl denotes a univalent, branched or straight chain hydrocarbon containing 1 to 8 carbon atom.
  • Representative of the alkyl groups may be methyl, ethyl, propyl, isopropyl, butyl, sec.butyl, tertbutyl, pentyl, iso pentyl, tert. Pentyl, hexyl, isohexyl, octyl.
  • lower alkoxy denotes lower alkyl groups as defined above attached via oxygen linkage to the rest of the molecule. Representative of those groups are methoxy, ethoxy, isopropoxy, tertbutoxy, hexyloxy, heptoxy and octoxy.
  • 'halogen' represents chlorine, bromine or fluorine.
  • 'Ph' represents phenyl.
  • 'substituted' phenyl group used in the present invention refers to those substituents which can be selected from the groups such as hydroxyl, lower alkyl, halogen, lower alkoxy, amino, lower alkylamino.
  • substituents such as hydroxyl, lower alkyl, halogen, lower alkoxy, amino, lower alkylamino. Examples of such groups are 4-hydroxyphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-tert.butyl phenyl, 3-N, N- dimethylaminophenyl.
  • the process described in the present invention has significant advantages over the existing processes in terms of less number of steps, milder reaction conditions, inexpensive reagents, simple crystallization methods to obtain high purity compounds at each step and therefore, amenability for large scale preparation also the final compound docetaxel so obtained by following this process is of high purity as observed by the HPLC (High performance liquid chromatography) method. Accordingly the present invention provides an efficient route for the preparation of docetaxel on a commercial scale.
  • step (i) 5g of 7,10-Di (imidazolyl) carbonylyloxy- 10-deacetylbaccatin III of the formula (6) obtained in step (i) was treated with 5.5g of oxazolidine acid of the formula (4) where R 1 and R 2 are methyl, in the presence of 3.54g (2.5equiv.) of dicyclohexylcarbodiimide (DCC) and 0.8g (1 equiv.) of 4-dimethylaminopyridine (DMAP) suspended in 1L of toluene and stirred the contents at 25 °C until the starting baccatin derivative was consumed. At the end, reaction mixture was filtered and the filtrate was diluted with ethylacetate.
  • DCC dicyclohexylcarbodiimide
  • DMAP 4-dimethylaminopyridine
  • the novelty of the present invention includes (i) single step protection of both the C-7 & C-10 hydroxyl groups in 10-deacetylbaccatin III in high yields (ii) single step deprotection of three protecting groups at C-7, C-10 & oxazolidine moiety in step (iii) of the process.

Abstract

L'invention concerne un procédé amélioré de préparation de l'antitumoral « docetaxel ». Elle a plus particulièrement trait à une synthèse courte de docetaxel selon une méthode semi-synthétique comportant une estérification en C-13 d'une 10 désacétylbaccatine III protégée de manière adéquate avec un acide de chaîne latérale protégé de manière adéquate, et des déprotections ultérieures pour former le docetaxel. Le procédé décrit comporte les étapes consistant à : 1) faire réagir la 10 désacétylbaccatine III avec un composé hétérocyclique pour produire une nouvelle 10 désacétylbaccatine III à double protection en 7, 10 ; 2) estérifier le groupe hydroxyle en C-13 du composé de 10 désacétylbaccatine III à double protection en 7, 10 obtenu à l'étape 1) avec un acide de chaîne latérale d'oxazolidine pour former un nouveau composé d'addition couplé en C-13 ; 3) déprotéger les groupes de protection en C-7, C-10 et le groupe oxazolidine pour former un amino alcool intermédiaire ; 4) dérivatiser le groupe amine libre de l'amino alcool obtenu à l'étape 3) avec du ditert. butyl dicarbonate pour obtenir le composé de docetaxel voulu.
PCT/IB2000/001107 2000-08-08 2000-08-08 Procede ameliore de preparation de docetaxel WO2002012216A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2000261768A AU2000261768A1 (en) 2000-08-08 2000-08-08 An improved process for the preparation of docetaxel
PCT/IB2000/001107 WO2002012216A1 (fr) 2000-08-08 2000-08-08 Procede ameliore de preparation de docetaxel

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IB2000/001107 WO2002012216A1 (fr) 2000-08-08 2000-08-08 Procede ameliore de preparation de docetaxel

Publications (1)

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WO2002012216A1 true WO2002012216A1 (fr) 2002-02-14

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PCT/IB2000/001107 WO2002012216A1 (fr) 2000-08-08 2000-08-08 Procede ameliore de preparation de docetaxel

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AU (1) AU2000261768A1 (fr)
WO (1) WO2002012216A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007109654A3 (fr) * 2006-03-21 2007-12-13 Reddys Lab Ltd Dr Polymorphes de docétaxel et procédés
WO2009006590A3 (fr) * 2007-07-04 2009-03-12 Reddys Lab Ltd Dr Procédés de préparation de docétaxel et de polymorphes
EP2125765A1 (fr) * 2006-12-18 2009-12-02 Hanmi Pharm. Co., Ltd. Procede de preparation de derives de taxane et intermediaires utilises dans ce procede
WO2010138010A2 (fr) 2009-05-29 2010-12-02 Przedsiębiorstwo Produkcyjno-Wdrożeniowe Solvates du 4-acétoxy-2α-benzoyloxy-5β,20-époxy-1,7β,10β-trihydroxy-9-oxo-tax-11-en-13α-yl(2r,3s)-3-tert-butoxycarbonylamino-2-hydroxy-3-phénylpropionate
CN109836401A (zh) * 2017-11-28 2019-06-04 正大天晴药业集团股份有限公司 一种多西他赛的纯化方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2697522A1 (fr) * 1992-10-30 1994-05-06 Rhone Poulenc Rorer Sa Procédé de préparation de dérivés du taxane.
US5476954A (en) * 1990-11-23 1995-12-19 Rhone-Poulenc Rorer S.A. Process for preparing taxane derivatives, new derivatives obtained and pharmaceutical compositions containing them
EP0735036A1 (fr) * 1995-03-22 1996-10-02 Bristol-Myers Squibb Company Méthodes de préparation de taxanes utilisant des intermédiaires oxazolidine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5476954A (en) * 1990-11-23 1995-12-19 Rhone-Poulenc Rorer S.A. Process for preparing taxane derivatives, new derivatives obtained and pharmaceutical compositions containing them
FR2697522A1 (fr) * 1992-10-30 1994-05-06 Rhone Poulenc Rorer Sa Procédé de préparation de dérivés du taxane.
EP0735036A1 (fr) * 1995-03-22 1996-10-02 Bristol-Myers Squibb Company Méthodes de préparation de taxanes utilisant des intermédiaires oxazolidine

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007109654A3 (fr) * 2006-03-21 2007-12-13 Reddys Lab Ltd Dr Polymorphes de docétaxel et procédés
EP2125765A1 (fr) * 2006-12-18 2009-12-02 Hanmi Pharm. Co., Ltd. Procede de preparation de derives de taxane et intermediaires utilises dans ce procede
EP2125765A4 (fr) * 2006-12-18 2011-08-03 Hanmi Holdings Co Ltd Procede de preparation de derives de taxane et intermediaires utilises dans ce procede
WO2009006590A3 (fr) * 2007-07-04 2009-03-12 Reddys Lab Ltd Dr Procédés de préparation de docétaxel et de polymorphes
WO2010138010A2 (fr) 2009-05-29 2010-12-02 Przedsiębiorstwo Produkcyjno-Wdrożeniowe Solvates du 4-acétoxy-2α-benzoyloxy-5β,20-époxy-1,7β,10β-trihydroxy-9-oxo-tax-11-en-13α-yl(2r,3s)-3-tert-butoxycarbonylamino-2-hydroxy-3-phénylpropionate
CN109836401A (zh) * 2017-11-28 2019-06-04 正大天晴药业集团股份有限公司 一种多西他赛的纯化方法
CN109836401B (zh) * 2017-11-28 2023-02-14 正大天晴药业集团股份有限公司 一种多西他赛的纯化方法

Also Published As

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