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WO2010057378A1 - Procédé pour la préparation de docétaxel, ses intermédiaires et leurs procédés de préparation - Google Patents

Procédé pour la préparation de docétaxel, ses intermédiaires et leurs procédés de préparation Download PDF

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Publication number
WO2010057378A1
WO2010057378A1 PCT/CN2009/071939 CN2009071939W WO2010057378A1 WO 2010057378 A1 WO2010057378 A1 WO 2010057378A1 CN 2009071939 W CN2009071939 W CN 2009071939W WO 2010057378 A1 WO2010057378 A1 WO 2010057378A1
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Prior art keywords
compound
reaction
group
organic solvent
amount
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English (en)
Chinese (zh)
Inventor
沈鑫
詹华杏
杨继东
何晓
林复兴
武哨红
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SHANGHAI PARLING PHARMA-TECH Co Ltd
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SHANGHAI PARLING PHARMA-TECH Co Ltd
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Priority to JP2010543367A priority Critical patent/JP5238822B2/ja
Priority to US12/741,714 priority patent/US8658811B2/en
Publication of WO2010057378A1 publication Critical patent/WO2010057378A1/fr
Anticipated expiration legal-status Critical
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • 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 invention relates to a preparation method of an anticancer drug, an intermediate thereof and a preparation method thereof, and particularly relates to a preparation method of docetaxel, an intermediate thereof and a preparation method thereof.
  • Docetaxel (structural formula 1) is obtained by structural modification on the basis of paclitaxel. It has a broad spectrum of anti-leukemia and anti-solid tumor activity, and its anticancer activity is 1.3-12 times that of paclitaxel. It is considered to be one of the most significant anticancer drugs to date. Docetaxel is as complex as paclitaxel, with many functional groups and chiral centers, and it is extremely difficult to synthesize. Semi-synthetic methods are the most effective chemical method for producing docetaxel.
  • the semi-synthetic methods of docetaxel in the existing literature and patents can be roughly divided into two categories.
  • the first type is a side chain condensation of protected 10-deacetylbaccatin and pentazone oxalate, followed by hydrolysis deprotection to give docetaxel (eg US6900342); the second is protected 10-deacetylation
  • the baccatin gibberellin is reacted with a quaternary lactam at a very low temperature by a strong base such as butyllithium, and then hydrolyzed and deprotected to obtain docetaxel (for example, US2005288520). (See below)
  • the first type of method is mild in condensation, but a large amount of the condensation reagent DCC (dicyclohexylcarbodiimide) must be used, which is very difficult for subsequent purification.
  • the technical problem to be solved by the present invention is to provide a preparation method of docetaxel, an intermediate thereof and preparation thereof in order to overcome the defects of difficulty in purification, easy loss of raw materials and high production cost in the prior route for preparing docetaxel.
  • the method has the advantages that the protecting group used in the preparation method of the invention is simple and easy to be separated, and the intermediate products are easy to purify, low in cost, high in yield and purity, and suitable for industrial production.
  • the present invention relates to a method for preparing docetaxel according to Formula 1, which comprises the steps of: removing Compound 1 from an acetyl group (Ac) to obtain Compound 1;
  • Boc is a tert-butoxycarbonyl group
  • Ac is an acetyl group
  • Ph is a phenyl group.
  • the method and conditions for the reaction for removing an acetyl group can be the conventional methods and conditions for removing a hydroxy protecting group of a hydroxyl group; preferred methods and conditions are as follows: in an organic solvent, in sodium hydrogencarbonate Compound 6 can be reacted with deacetylation by the action of hydrogen peroxide.
  • the organic solvent is preferably one or more of dichloromethane, ethyl acetate, toluene, diethyl ether, diisopropyl ether, acetone, acetonitrile and tetrahydrofuran; more preferably tetrahydrofuran;
  • the volume of the solvent and the compound 6 is preferably 5 to 50 ml/g ;
  • the sodium hydrogencarbonate is preferably a 0.5% by mass saturated aqueous solution, more preferably a saturated aqueous solution of sodium hydrogencarbonate;
  • the amount of sodium hydrogen is preferably from 2 to 10 times; more preferably from 3 to 5 times the molar amount of the compound;
  • the hydrogen peroxide is preferably an aqueous solution of hydrogen peroxide, and the mass percentage thereof is preferably 10% ⁇ 70%; more preferably 30%;
  • the amount of hydrogen peroxide is preferably 2 to 10 times the molar amount of the compound 6; more preferably 3 to 5 times; the temperature of the
  • the present invention also relates to an intermediate compound 6 of docetaxel
  • Boc is a tert-butoxycarbonyl group
  • Ac is an acetyl group
  • Ph is a phenyl group.
  • the present invention further relates to a method for preparing compound 6, which comprises the steps of: removing compound 5 by removing a t-butoxycarbonyl group (Boc) to obtain compound 6;
  • Boc is a tert-butoxycarbonyl group
  • Ac is an acetyl group
  • Ph is a phenyl group.
  • the method and conditions for the reaction for removing a t-butoxycarbonyl group are all the methods and conditions for dehydrogenating a t-butoxycarbonyl protecting group in the art; preferred methods and conditions are as follows: organic solvent In the case, the compound 5 is reacted under the action of trifluoroacetic acid.
  • the organic solvent is preferably one or more of dichloromethane, ethyl acetate, toluene, diethyl ether, diisopropyl ether, acetone, acetonitrile and tetrahydrofuran; more preferably dichloromethane;
  • the volumetric mass of the organic solvent and the compound 5 is preferably 5 to 20 ml/g ; and the amount of the trifluoroacetic acid is preferably 0.1 to 2 times, more preferably 0.2 to 0.5 times, the molar amount of the compound;
  • the temperature of the reaction described below is preferably 0 ⁇ 50 ° C, more preferably of 20 ⁇ 35 ° C; the reaction time is preferred to detect the reaction is complete, usually 1 ⁇ 8 hours.
  • the present invention also relates to an intermediate compound 5 of docetaxel
  • Boc is a tert-butoxycarbonyl group
  • Ac is an acetyl group
  • Ph is a phenyl group.
  • the present invention further relates to a process for the preparation of compound 5, which comprises the steps of: deactivating a protecting group of a compound 4 to obtain a compound 5;
  • TBS tert-butyldimethylsilyl
  • SiEt 3 triethylsilyl
  • EE ethoxyethyl
  • THP tetrahydropyranyl
  • Troc trichloroethoxycarbonyl
  • MOM methoxymethyl
  • Troc trichloroethoxycarbonyl
  • SiEt 3 triethylsilyl
  • the method and conditions for the reaction of removing the hydroxyl group protecting group can be the methods and conditions for the conventional dehydroxylation group reaction in the art; preferred methods and conditions are as follows - when it is trichloroethoxycarbonyl (Troc), in the organic solvent and water, the compound 4 can be reacted under the action of acetic acid and zinc.
  • the organic solvent is preferably one or more of dichloromethane, ethyl acetate, toluene, diethyl ether, diisopropyl ether, acetone, acetonitrile, tetrahydrofuran, methanol and ethanol, more preferably methanol.
  • the volume ratio of the organic solvent to the mass of the compound 4 is preferably 5 to 20 ml/g ; and the amount of the acetic acid is preferably 5 to 20 times, more preferably 5 to 6 times the molar amount of the compound 4;
  • the zinc is zinc powder, and the amount thereof is preferably 2 to 20 times, more preferably 3 to 5 times, the molar amount of the compound;
  • the temperature of the reaction is preferably 0 to 80 ° C. More preferably, it is 50 to 70 ° C; the reaction time is preferably carried out to detect the completion of the reaction, and is usually from 2 to 12 hours.
  • ⁇ is a triethylsilyl group (SiEt 3 )
  • the compound 4 is reacted by the action of tetrabutylammonium fluoride.
  • the organic solvent is preferably one or more of dichloromethane, ethyl acetate, toluene, diethyl ether, diisopropyl ether, acetone, acetonitrile, tetrahydrofuran, methanol and ethanol, more preferably tetrahydrofuran;
  • the volume ratio of the organic solvent to the compound 4 is preferably from 5 to 20 ml/g ; and the tetrabutylammonium fluoride is preferably used in an amount of from 1 to 20 times, more preferably from 1.2 parts by mole of the compound. ⁇ 2.0 ⁇ ;
  • the temperature of the reaction is preferably 0 to 80 ° C, more preferably 0 to 10 ° C; the reaction time is preferably to detect the reaction is complete,
  • reaction can be carried out by the action of ammonium fluoride.
  • TBS tert-butyldimethylsilyl
  • compound 4 is in tetrabutyl
  • the reaction can be carried out by the action of ammonium fluoride.
  • Each of the reaction conditions is a conventional condition of the method.
  • ⁇ is an ethoxyethyl group (EE)
  • the compound 4 is reacted with a dilute acid using an alcohol and water as a solvent.
  • Each of the reaction conditions is a conventional condition of the method.
  • reaction conditions is a conventional condition of the method.
  • the present invention also relates to an intermediate compound 4 of docetaxel
  • TBS tert-butyldimethylsilyl
  • SiEt 3 triethylsilyl
  • EE ethoxyethyl
  • THP tetrahydropyranyl
  • Troc trichloroethoxycarbonyl
  • MOM methoxymethyl
  • Troc trichloroethoxycarbonyl
  • SiEt 3 triethylsilyl
  • the present invention further relates to a method for preparing a compound 4, which comprises the following steps: Compound 2 and 3 are subjected to acylation of a hydroxyl group to prepare a compound 4;
  • the method and conditions for the acylation reaction of the hydroxyl group may be the methods and conditions for acylation of a hydroxyl group conventionally in the art; preferred methods and conditions are as follows: In an organic solvent, the compound 2 is in 4-dimethylaminopyridine.
  • the organic solvent is preferably one or more of dichloromethane, ethyl acetate, toluene, diethyl ether, diisopropyl ether, acetone, acetonitrile, tetrahydrofuran, methanol and ethanol, more preferably toluene;
  • the volume ratio of the organic solvent to the compound 2 is preferably 5 to 20 ml/g ; and the amount of the compound 3 is preferably 1 to 10 times, more preferably 1.5 to 5 times the molar amount of the compound 2
  • the amount of the 4-dimethylaminopyridine (DMAP) is preferably 1.2 to 20 times the molar amount of the compound 2; more preferably 1.5 to 3 times; the amount of the triethylamine is preferably The amount of the organic solvent is preferably one or more of dichloromethane, ethyl acetate, toluene, diethyl ether, diisopropyl ether, acetone, ace
  • the optimal preparation method of docetaxel according to the present invention comprises the following steps:
  • tert-butyldimethylsilyl TBS
  • triethylsilyl SiEt 3
  • ethoxyethyl EE
  • tetrahydropyranyl TPS
  • trichloroethoxycarbonyl Troc Or methoxymethyl (MOM)
  • trichloroethoxycarbonyl Troc or triethylsilyl (SiEt 3 )
  • Boc is tert-butoxycarbonyl
  • Ac is acetyl
  • Ph phenyl.
  • the present invention also relates to an intermediate compound 3 of docetaxel; wherein, Boc is a tert-butoxycarbonyl group, Ac is an acetyl group, and Ph is a phenyl group.
  • the present invention further relates to a method for preparing a compound 3, which comprises the steps of: in an organic solvent, the compound 9 is subjected to a reaction of removing a benzyl protecting group of a hydroxyl group;
  • Boc is a tert-butoxycarbonyl group
  • Ph is a phenyl group
  • Ac is an acetyl group
  • Bn is a benzyl group.
  • the methods and conditions for the reaction of the dehydroxylated benzyl protecting group described herein are all conventional methods and conditions for the dehydroxylation of a benzyl protecting group in the art.
  • the preferred methods and conditions are as follows: Compound 9 can be hydrogenated under the action of palladium on carbon.
  • the pressure of the reaction is preferably from 1 to 10 atm; the mass fraction of palladium in the palladium carbon is preferably from 1 to 20%, more preferably from 2 to 10%;
  • the amount of the compound is preferably from 0.01 to 0.5 times, more preferably from 0.05 to 0.3 times the mass of the compound;
  • the temperature of the reaction is preferably from 0 to 60 ° C, more preferably from 10 to 30 ° C;
  • the reaction time is usually 2 to 24 hours until the reaction is detected to be complete.
  • the compound 9 can be obtained by the following method: in the organic solvent, the compound 8 is subjected to a reaction of a tert-butoxycarbonyl protecting group of an upper amino group;
  • Boc is tert-butoxycarbonyl
  • Ph is phenyl
  • Ac is acetyl
  • Bn is benzyl t
  • the method and conditions for the reaction of the tert-butoxycarbonyl protecting group of the above amino group are the conventional methods and conditions for the tert-butoxycarbonyl protecting group of the amino group in the art.
  • the preferred methods and conditions are as follows:
  • Compound 8 can be reacted with Boc 2 0 by the action of 4-dimethylaminopyridine (DMAP).
  • the organic solvent is preferably one or more of dichloromethane, ethyl acetate, toluene, diethyl ether, diisopropyl ether, acetone, acetonitrile and tetrahydrofuran, more preferably acetonitrile;
  • the volume of the solvent and the compound 8 is preferably 5 to 50 ml/g; and the amount of the N, N-dimethylpyridine is preferably 1 to 10 times, more preferably 1.2 to 8 parts by mole of the compound.
  • the amount of Boc 20 is preferably from 1 to 10 times, more preferably from 2 to 5 times the molar amount of the compound;
  • the temperature of the reaction is preferably from 0 to 80 ° C. More preferably, it is 50 to 60 ° C ;
  • the reaction time is until the reaction is completed, preferably 2 to 24 hours.
  • the compound 8 can be obtained by the following method: the compound 7 is subjected to a reaction of acetylation of a hydroxyl group;
  • Boc is a tert-butoxycarbonyl group
  • Ph is a phenyl group
  • Ac is an acetyl group
  • Bn is a benzyl group.
  • the methods and conditions for the acetylation reaction of the hydroxyl group are the conventional methods and conditions for the acetylation reaction of the hydroxyl group in the art.
  • Preferred methods and conditions are as follows:
  • the organic solvent is preferably one or more of dichloromethane, ethyl acetate, toluene, diethyl ether, diisopropyl ether, acetone, pyridine, acetonitrile and tetrahydrofuran, more preferably dichloromethane.
  • the volume ratio of the organic solvent to the compound 7 is preferably 5 to 50 ml/g, more preferably 5 to 10 ml/g; and the acetic anhydride is preferably used in an amount of 7 mol.
  • the amount of the reaction is 1 to 10 times, more preferably 1.5 to 3 times;
  • the temperature of the reaction is preferably 0 to 60 ° C, more preferably 0 to 25 ° C;
  • the reaction is completed, preferably 2 to 12 hours.
  • the present invention also relates to an intermediate compound 9 of docetaxel; wherein, Boc is a tert-butoxycarbonyl group, Ph is a phenyl group, Ac is an acetyl group, and Bn is a benzyl group.
  • the positive effect of the present invention is that the protecting group used in the preparation method of the present invention is simple and easy to remove, and the intermediate products are easy to purify, low in cost, high in yield and purity, and suitable for industrial production. detailed description
  • Example 1 2a, 4a, 2b, and 4b in Examples 3 to 9 are the same as those in Example 1 and Example 2.
  • Example 1 2a, 4a, 2b, and 4b in Examples 3 to 9 are the same as those in Example 1 and Example 2.
  • Steps 3 and 4 are the same as those in the first embodiment, and the identification data is the same as in the first embodiment.
  • step 1
  • Step 2 40 g of compound 4a (30.75 mmol) was dissolved in 9.2 g (153.75 mmol) of acetic acid, 50 ml of water, ethanol (50 ml), acetonitrile (50 ml), acetone (100 ml), and 4 g (61.5 mmol) of zinc powder was added. The reaction was carried out at 0 ° C, and the reaction was completed by TLC, and then neutralized to neutral with saturated sodium hydrogen carbonate, solvent was evaporated, and the residue was subjected to column chromatography to give 22.2 g of Compound 5 as a white solid. Yield: 75.9
  • step 1
  • step 1
  • step 1
  • the sodium sulfite solution was neutralized with an excess of hydrogen peroxide, extracted with dichloromethane, and subjected to conventional workup. After concentration, the residue was subjected to column chromatography to obtain 11.4 g of docetaxel. Yield: 80%.
  • Step 3 23 g of the compound 5 (24.21 mmol) was dissolved in a mixed solvent of toluene (2 ml), diethyl ether (2 ml), diisopropyl ether (5 ml), acetone (5 ml), dichloromethane (446 ml), and 5.5 g of trifluoroacetic acid was added.
  • step 1
  • N-Bocphenylisoserine benzyl ester (Compound 7, MW: 371) 371 g (1 mol) was dissolved in 500 ml of anhydrous pyridine, and 200 ml of cesium acetate (density: 1.08, 216 g, 2.1 mol) was added dropwise. Adding to 25-30 ° C, stirring to TLC, the disappearance of the starting material, pouring into 1000 liters of ice water, adjusting the pH to 5-6 with 6N hydrochloric acid, extracting with ethyl acetate, washing the extract with dilute hydrochloric acid, washing with saturated sodium hydrogen carbonate Washed with saturated brine, dried and concentrated.
  • the obtained oil was dissolved in 1 liter of acetonitrile, 300 g of Boc 2 O (1.38 mol) was added, and 4-dimethylaminopyridine (DMAP) was added in portions, 150 g, and the reaction was terminated by TLC. After acetonitrile is concentrated, the residue is subjected to column chromatography, and the obtained oil is dissolved in ethyl acetate. 50 g of 5% palladium carbon is added, hydrogenated at 3 atm to hydrogen, filtered, and concentrated. Ethyl ester, the residue was added to petroleum ether, and 350 g of product was precipitated as a white solid. The yield was 82.7 %.
  • N-Boc phenyl isserine benzyl ester (Compound 7, MW: 371) 371 g (lmol) was dissolved in acetone (500 ml), acetonitrile (500 ml) and tetrahydrofuran (855 ml), and 100 liters of acetic anhydride was added dropwise ( Density: 1.08, lmol). After adding 0 °C to TLC, the disappearance of the starting material was observed.
  • N-Boc phenyl isserine benzyl ester (Compound 7, MW: 371) 371 g (lmol) was dissolved in dichloromethane (10 L), ethyl acetate (4 L) and toluene (4.55 L), and acetic acid was added dropwise.
  • N-Boc phenyl isserine benzyl ester (Compound 7, MW: 371) 371 g (1 mol) was dissolved in diethyl ether (4000 ml) and isopropyl ether (4162 ml), and 500 liters of acetic anhydride was added dropwise (density: 1.08). , 5mol).

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract

L'invention porte sur un procédé pour la préparation de docétaxel de formule 1, comprenant : (1) l'acylation de l'hydroxyle du composé 2 avec le composé 3 pour obtenir le composé 4; (2) l'élimination du groupe protecteur d'hydroxyle R1 du composé 4 obtenu pour obtenir le composé 5; (3) l'élimination d'un groupe Boc du composé 5 obtenu à l'étape (2) pour obtenir le composé 6; (4) l'élimination d'Ac du composé 6 obtenu à l'étape (3) pour obtenir du docétaxel de formule 1, dans laquelle R1 représente tert-butyldiméthylsilyle, triéthylsilyle, éthoxyéthyle, tétrahydropyranyle, trichloroéthoxycarbonyle ou méthoxyméthyle. L'invention porte également sur les intermédiaires utilisés dans la préparation du docétaxel et sur leurs procédés de préparation.
PCT/CN2009/071939 2008-11-19 2009-05-22 Procédé pour la préparation de docétaxel, ses intermédiaires et leurs procédés de préparation Ceased WO2010057378A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2010543367A JP5238822B2 (ja) 2008-11-19 2009-05-22 ドセタキセル（Ｄｏｃｅｔａｘｅｌ）の合成プロセス、その中間体及びその合成法
US12/741,714 US8658811B2 (en) 2008-11-19 2009-05-22 Process for the preparation of docetaxel, its intermediates, and methods for preparation thereof

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CN200810202997.3 2008-11-19
CN200810202997A CN101735179B (zh) 2008-11-19 2008-11-19 一种多烯紫杉醇的制备方法，其中间体及制备方法

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CN103159704B (zh) * 2011-12-12 2015-06-10 上海佰霖国际贸易有限公司 卡巴他赛中间体及卡巴他赛中间体的制备方法
CN103242267B (zh) * 2012-02-03 2015-03-18 福建南方制药股份有限公司 卡巴他赛及其中间体的制备方法及卡巴他赛中间体
CN103086924A (zh) * 2013-01-17 2013-05-08 暨明医药科技（苏州）有限公司 一种多西他赛及其中间体的合成方法
CN119487014A (zh) * 2022-06-29 2025-02-18 石药集团中奇制药技术（石家庄）有限公司 紫杉醇类抗肿瘤化合物
CN115650882A (zh) * 2022-11-14 2023-01-31 肇庆学院 一种多西他赛杂质及其制备方法

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