WO2016098015A1 - Nouveaux procédés efficaces pour la synthèse de dérivés de type taxane tels que le docétaxel et leurs analogues structuraux, et procédé de préparation de ces derniers - Google Patents

Nouveaux procédés efficaces pour la synthèse de dérivés de type taxane tels que le docétaxel et leurs analogues structuraux, et procédé de préparation de ces derniers Download PDF

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Publication number
WO2016098015A1
WO2016098015A1 PCT/IB2015/059675 IB2015059675W WO2016098015A1 WO 2016098015 A1 WO2016098015 A1 WO 2016098015A1 IB 2015059675 W IB2015059675 W IB 2015059675W WO 2016098015 A1 WO2016098015 A1 WO 2016098015A1
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WIPO (PCT)
Prior art keywords
hrs
docetaxel
reaction
dried
heptane
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PCT/IB2015/059675
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English (en)
Inventor
Khashayar Karimian
Hatam SAFARI
Hamid MOFAKHAM
Saber NAZARI
Elias EISAPOUR
Hosein Ali AZIMI
Ali Reza ROSTAMIAN
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Khashayar Karimian
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Publication of WO2016098015A1 publication Critical patent/WO2016098015A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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

  • a novel process is outlined for the synthesis and preparing an anticancer medicine and it's intermediate.
  • This invention generally relates the synthesis of Docetaxel, its intermediates and methods for preparation thereof with using a suitably protected 10-deacetyl baccatin III (10-DAB), which is esterified with a suitably protected side chain acid to produce an intermediate that may be further deprotected to produce Docetaxel.
  • 10-DAB 10-deacetyl baccatin III
  • Docetaxel is a diterpene taxane found in very low concentration in the bark of Pacific yew tree Taxus brevifolia.
  • a number of semi-synthetic strategies have been developed for its synthesis from more readily available 10-DAB.
  • the taxane nucleus is highly prone to degradation and semi- synthetic crude materials are often contaminated with structurally similar impurities.
  • elaborate purification procedure using HPLC are required to produce pharmaceutical grade material.
  • US patent 5,688,977 teaches a process for preparing of Docetaxel by reaction of a protecting acid and a suitably protected 10-deacetyl baccatin III and selective removal of protecting groups. Furthermore, the procedure described by US patent 5,688,977 requires three steps for removal of protecting groups to convert to Docetaxel. The described method requires Pearlman's catalyst which is very expensive. Also, esterification preferably employs an excess of the hydroxyl function protecting group, such as six equivalents of the side chain for each equivalent of protected 10-deacetyl baccatin III.
  • US patent 6,900,342 disclose a process for preparing Docetaxel, wherein a protected 10- deacetylbaccatin III and five-membered oxazolidine side chain is de-protected through hydrolysis to yield Docetaxel. Furthermore, the procedure described by US patent 6,900,342 requires a large excess of condensation reagent DCC (N,N'-dicyclohexyl carbodiimide), which causes considerable difficulty in the following purification step.
  • DCC N,N'-dicyclohexyl carbodiimide
  • US patent 7,550,608 disclosed a method for the preparation Docetaxel with esterification of ⁇ -lactam under very low temperature in the presence of strong base.
  • strong base will cause decomposition of the protected 10-deacetylbaccatin III, waste of the expensive raw material and considerable problems in the following purification steps.
  • Our method is devoid of these problems.
  • US patent 5,476,954 discloses a process for preparing Docetaxel that involves reacting protected 10-deacetylbaccatin III and with (4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4- phenyl-5-oxazolidinecarboxylic acid in the presence of DCC, DMAP, and toluene and in continuation deprotection of the hydroxyl protecting group, 2,2,2-trichloroethoxycarbonyl, using zinc in the presence of acetic acid and methanol to obtained Docetaxel.
  • excess molar equivalents of di-tert-butyl dicarbonate about 16 equivalents
  • the reported yield is lower than the yield obtained in our process using 1.2 equivalents of di-tert-butyl dicarbonate.
  • the object of this invention is a novel process for the preparation of Docetaxel and its intermediates which minimize degradation during the process and thereby increase yield and purity of the target product.
  • Our process also circumvents the use of expensive reagents as well as large molar excess of the same. Furthermore, our process does not resort to chromatography of the process intermediates or the product. Accordingly, the process described herein is eco-friendly, cost-effective, and well suited for an industrial scale production of Docetaxel and its intermediates.
  • the present invention consists of a process for the preparation of Docetaxel, its intermediates comprising of subjecting 7, 10-di-O-chloroacetyl- 10-deacetylbaccatin III (2) to coupling with (4S,5R)-3-(tert-butoxycarbonyl)-2-(4-methoxyphenyl)-4- phenyloxazolidine-5-carboxylic acid (3) in the presence of a condensation agent and an activating agent at a temperature between 50 and 80° C to obtain coupled product 4, that may thereafter be deprotected.
  • the de-protection of haloacyl and paramethoxy phenyl (PMP) groups affords Docetaxel.
  • This route solves the technical problems of purification, waste of raw material, low yield, use of high temperature, use of chromatography, and reduces the high cost of manufacturing Docetaxel encountered in previously reported methods.
  • the present invention provides a process for the preparation of Docetaxel 1, which is prepared by removing two protecting groups Rl and one protecting group R2 from compound 4,
  • Rl is chloroacetyl chloride
  • R2 is paramethoxy phenyl (PMP)
  • R3 is tert- butoxycarbonyl.
  • Deprotection of haloacyl groups can be carried out in the intermediate 4 under mild alkaline condition in two steps, first in the presence of an aliphatic acid or perhalo aliphatic acids such as triflouroacetic acid for deprotecting paramethoxy phenyl (PMP) group and secondly in the presence of ammonia or aliphatic or aromatic amines or a combination thereof, preferably ammonia and pyridine (1:5) for deprotecting haloacyl groups.
  • PMP paramethoxy phenyl
  • the reactionin both steps are carried out at 0-5° C, preferably at 2° C.
  • the reaction time is decided by detection of the completion of the reaction, usually 6-24 hours, preferably 12 h, to obtain Docetaxel.
  • hydroxy-protecting groups include, without limitation, formyl, acetyl (Ac), benzyl (PhCH2), 1-ethoxyethyl (EE), methoxymethyl (MOM), (methoxyethoxy)methyl (MEM), (p-methoxyphenyl)methoxymethyl (MPM), tert- butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBPS), tert-butoxycarbonyl (t-Boc, t- Boc, t-BOC, t-BOC), tetrahydropyranyl (THP), triphenylmethyl (Trityl, Tr), 2- methoxy-2- methylpropyl, benzyloxycarbonyl (Cbz), chloroacetyl, dichloroacetyl, trichloroacetyl (OCCHyClX), 2,2,2-trichloroethoxycarbonyl (Troc),
  • protected hydroxy group refers to a hydroxy group that is bonded to a hydroxy-protecting group.
  • protected hydroxy groups include, without limitation, - O-alkyl, -O-acyl, acetal, and -O-ethoxyethyl, where some specific protected hydroxy groups include, formyloxy, acetoxy, propionyloxy, chloroacetoxy, bromoacetoxy, dichloroacetoxy, trichloroacetoxy, trifluoroacetoxy, methoxyacetoxy, phenoxyacetoxy, benzoyloxy, benzoylformoxy, p-nitro benzoyloxy, ethoxycarbonyloxy, methoxycarbonyloxy, propoxycarbonyloxy, 2,2,2- trichloroethoxycarbonyloxy, benzyloxycarbonyloxy, tert-butoxycarbonyloxy, 1- cyclopropylethoxy
  • the methods and conditions of removing protection group of the hydroxyl group described can be the common methods and conditions of deprotection group of the hydroxyl group known to men of art in the field.
  • Rl is a hydrogen atom of a suitable hydroxyl -protecting group
  • R2 is paramethoxy phenyl (PMP)
  • R3 is a hydrogen atom, a linear C1-C20 alkyl, a branched C3-C50 alkyl group, a C1-C50 acyl group, a CI -C50 halogenated acyl group, a C3- C50 cycloalkyl, a C1-C50 heterocyclyl, a C2 -C50 alkenyl, a C2 -C50 alkynyl, a C6 -C20 aryl, a C6-C50 aralkyl, a C1-C50 alkyloxy C6-C50 alkylaryl, a C1-C50 heteroaryl, a C2 -C50 alkylheterocyclyl or a C2-C50 alkylheteroaryl, said alkyl,
  • protected hydroxy group refers to a hydroxy group that is bonded to a hydroxy-protecting group.
  • protected hydroxy groups include, without limitation, - O-alkyl, -O-acyl, acetal, and -O-ethoxyethyl, where some specific protected hydroxy groups include, formyloxy, acetoxy, propionyloxy, chloroacetoxy, bromoacetoxy, dichloroacetoxy, trichloroacetoxy, trifluoroacetoxy, methoxyacetoxy, phenoxyacetoxy, benzoyloxy, benzoylformoxy, p-nitro benzoyloxy, ethoxycarbonyloxy, methoxycarbonyloxy, propoxycarbonyloxy, 2,2,2- trichloroethoxycarbonyloxy, benzyloxycarbonyloxy, tert-butoxycarbonyloxy, 1- cyclopropylethoxy
  • Rl is chloroacetyl chloride and R2 is paramethoxy phenyl (PMP)
  • the deprotection of compound 4 is performed under mild alkaline condition to remove haloacyl groups , for example in the presence of ammonia or aliphatic amines or aromatic amines or their combinations, preferably ammonia and pyridine (1:5).
  • the reaction is performed at temperature between 0-5° C, preferably at temperature between -3° to 0° C.
  • the reaction time is decided by detection of the completion of the reaction, 6-24 hours, preferably 12 h.
  • the deprotection of compound 4 is performed under acidic condition to remove paramethoxy phenyl (PMP) group, for example in the presence of halo-acetic acid and preferably trifluoro acetic acid.
  • the present invention further relates to a process for preparing compound 4, including the following steps: compound 4 was prepared from condensation reaction between compounds 3 and 2 in the presence of a condensation agent and an activating agent, wherein, compound 4 is obtained from reaction of 7, 10-di-O-protected-lO- deacetylbaccatin III 2 with protected side chain acid 3 in the presence of a condensation agent and an activating agent in organic solvent to obtain compound 4.
  • the organic solvent is preferably one or several chosen from dichloromethane, ethyl acetate, toluene, diethyl ether, isopropyl ether, acetone, acetonitrile, tetrahydrofuran, methanol and ethanol or a mixture thereof, preferably toluene.
  • the reaction is performed by dissolving the two compounds in the above-said organic solvent(s), preferably toluene, followed by the addition of the condensation agents.
  • the sequence of addition of the compounds and reagents may be changed as is known to the men of art.
  • the condensation agents used is, among other agents known in the art, dimethylamine pyridine (DMAP) and dialkylcarbodiimide.
  • the dialkylcarbodiimide is preferably in equal proportion to the amount of the side chain compound.
  • This dialkylcarboiimide is selected from a group consisting of a diisopropylcarbondiimide and dicyclohexylcarbodiimide or other analogues thereof.
  • the reaction is carried out at temperature between 0-100° C, preferably at 25-70° C, and most preferably at 60° C. Among aromatic hydrocarbons, toluene is found to be the most suitable.
  • the reaction time is determined by detection of the completion of the reaction, usually 12-36 hours.
  • Rl in formula (4) is a hydrogen atom of a suitable hydroxyl- protecting group
  • R2 and R3 can be hydrogen atoms, a linear C1-C20 alkyl, a branched C3-C50 alkyl group, a C1-C50 acyl group, a C1-C50 halogenated acyl group, a C3- C50 cycloalkyl, a C1-C50 heterocyclyl, a C2-C50 alkenyl, a C2-C50 alkynyl, a C6 -C20 aryl, a C6-C50 aralkyl, a C1-C50 alkyloxy C6-C50 alkylaryl, a C1-C50 heteroaryl, a C2-C50 alkylheterocyclyl or a C2-C50 alkylheteroaryl, said alkyl, cycloalkyl, heterocyclyl, alken
  • Compound 4 is obtained from 7, 10-di-O-(2-chloroacetyl)- 10-deacetylbaccatin III (2, 100 g, 0.143 mol), (4S,5R)-3-(tert-butoxycarbonyl)-2-(4-methoxyphenyl)-4-phenyloxaz- olidine-5-carboxylic acid (5, 71.53 g, 179 mmol), DCC (36.9 g, 179 mmol) and 4- dimethyl- aminopyridine (4.80 g, 31.54 mmol) in toluene (1.0 L) and stirred for 5-8 h at 60° C , followed by the separation of the resulting dicyclohexylurea by filtration.
  • Anhydrous Docetaxel is obtained from 7, 10-Di-O-(2-chlroacetyl) Docetaxel (5, 80 g, 0.08 mol) using 25% ammonia (510 ml) in pyridine (2.5 L) and stirred at 0-5 °C for 2 h.
  • 1.6 L ethyl acetate and 0.8 L water is used for extraction of the product.
  • After extraction the organic layer is successively washed with 3 M HC1, saturated sodium bicarbonate, brine and then dried over anhydrous sodium sulfate.
  • the organic layer is treated by activated charcoal and the organic solvent was removed under a reduced pressure. The residue is added into 1.2 L n-heptane. The resulting fine solid is filtered and then washed with 200 ml of heptane to afford Docetaxel 1 (51.7 g, 0.06 mol, 80%) which is used in the next step without any purification.
  • the precipitate was filtered and washed with 150 ml of n-heptane and dried in an oven at 50°C to the constant weight to yield 40 g (80%) the anhydrous Docetaxle as a white powder with HPLC purity of > 95%.

Abstract

La présente invention concerne un nouveau procédé pour la préparation de taxanes tels que le Docétaxel, un médicament anticancéreux très important. Le Docétaxel 1 est un médicament chimiothérapeutique de type anti-mitotique bien établi cliniquement, utilisé principalement pour le traitement du cancer du sein, du cancer de l'ovaire et du cancer du poumon non à petites cellules. Dans ce travail, nous présentons un procédé efficace et simple de production du Docétaxel 1 (voir ci-dessous), comprenant les étapes suivantes : a) réaction d'hydroxyl acylation de 10-DAB-III avec de l'acide chloracétique pour obtenir le composé 2; b) réaction de condensation des composés 2 et 3 pour obtenir le composé 4; c) levée de la protection du groupe protecteur paramethoxy phényl (PMP) pour obtenir le composé 5; d) levée de la protection du groupe protecteur R1 du composé 5 pour préparer le Docétaxel 1; R1 étant, parmi d'autres réactifs d'acétylation, du chlorure de chloroacétyle, R2 étant, parmi d'autres cétones et aldéhydes, du paramethoxy phényl (PMP), et R3 étant, parmi d'autres alcanes, du tert-butyl; e) soumission du Docétaxel brut à une filtration rapide sur un court filtre de gel de silice pour obtenir du Docétaxel anhydre de pureté > 95 %; f) cristallisation du Docétaxel anhydre de l'étape e) pour obtenir du trihydrate de Docétaxel de qualité pharmaceutique. Dans les procédés de préparation de la présente invention, les groupes protecteurs utilisés sont facilement retirés, la purification des intermédiaires est pratique, le coût de production est moindre, les étapes de réaction sont moins nombreuses, le rendement et la pureté sont plus élevés, et les procédés peuvent être redimensionnés pour une production à échelle industrielle. Un autre aspect important de la présente invention est que le Docétaxel de qualité pharmaceutique est préparé sans devoir recourir à la chromatographie.
PCT/IB2015/059675 2014-12-16 2015-12-16 Nouveaux procédés efficaces pour la synthèse de dérivés de type taxane tels que le docétaxel et leurs analogues structuraux, et procédé de préparation de ces derniers WO2016098015A1 (fr)

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IR139350140003010249 2014-12-16
IR13933010249 2014-12-16

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Citations (5)

* 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
US6130336A (en) * 1996-08-27 2000-10-10 Hanmi Pharm., Co. Ltd. Process for preparing paclitaxel
US6500966B1 (en) * 1999-03-02 2002-12-31 Indena S.P.A. Process for the preparation of taxanes from 10-deacetylbaccatin III
US6900342B2 (en) * 2002-05-10 2005-05-31 Dabur India Limited Anticancer taxanes such as paclitaxel, docetaxel and their structural analogs, and a method for the preparation thereof
US7759494B2 (en) * 2002-05-07 2010-07-20 Dabur India Limited Method of preparation of anticancer taxanes using 3-[(substituted-2-trialkylsilyl)ethoxy-carbonyl]-5-oxazolidine carboxylic acids

Patent Citations (5)

* 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
US6130336A (en) * 1996-08-27 2000-10-10 Hanmi Pharm., Co. Ltd. Process for preparing paclitaxel
US6500966B1 (en) * 1999-03-02 2002-12-31 Indena S.P.A. Process for the preparation of taxanes from 10-deacetylbaccatin III
US7759494B2 (en) * 2002-05-07 2010-07-20 Dabur India Limited Method of preparation of anticancer taxanes using 3-[(substituted-2-trialkylsilyl)ethoxy-carbonyl]-5-oxazolidine carboxylic acids
US6900342B2 (en) * 2002-05-10 2005-05-31 Dabur India Limited Anticancer taxanes such as paclitaxel, docetaxel and their structural analogs, and a method for the preparation thereof

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