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Method for preparing docetaxel

A technology of docetaxel and deacetylation, applied in the field of preparation of docetaxel, can solve the problems of poor reaction selectivity, difficult to obtain high purity, low reaction temperature and the like, and achieves low cost, high reaction yield and high quality. Effect

Inactive Publication Date: 2009-01-28
重庆医科大学医药研究所
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0012] The weak point of this reaction is: (a) reaction temperature is too low, energy consumption is big; (b) reaction yield is only 80%; (c) because n-butyllithium is extremely strong, reaction selectivity is relatively poor , it is difficult to obtain high-purity C-7, C10-di-CBZ-10-deacetylbaccatin III even by column chromatography

Method used

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  • Method for preparing docetaxel
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  • Method for preparing docetaxel

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Experimental program
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Effect test

Embodiment 1

[0061] A. C-7, C-10-di-CBZ-10-deacetylbaccatin III(II)

[0062] The first esterification reaction:

[0063] 10-deacetylbaccatin III (I) and DMAP were dissolved in anhydrous tetrahydrofuran, and the amount of DMAP was 5 times the molar number of 10-deacetylbaccatin III (I); under stirring at room temperature, Benzyl chloroformate (15 times the number of moles of 10-deacetylbaccatin III (I)) was dropped into it, and after the addition was completed, it was reacted at 35-60°C for 0.5 hours, and the reaction solution was cooled to room temperature and then filtered. After adding an appropriate amount of water, adjust the pH of the solution to neutral with a common acid-base, extract with dichloromethane, combine the organic layers, dry with anhydrous sodium sulfate, filter, and evaporate the solvent to obtain C-7, C10-di-X -CBZ-10-deacetylbaccatin III (II) oil crude product; the oil was subjected to silica gel column chromatography (eluent ethyl acetate and n-hexane) to obtain a ...

Embodiment 2

[0074] A.C-7, C-10-di-NO 2 -CBZ-10-Deacetylbaccatin III(II)

[0075] The first esterification reaction:

[0076] Dissolve 10-deacetylbaccatin III (I) and DMAP in anhydrous tetrahydrofuran, the amount of DMAP is 5 times the molar number of 10-deacetylbaccatin III (I); under stirring at room temperature, chlorine Formic acid-4-nitrobenzyl ester (10 times the molar number of 10-deacetylbaccatin III (I)), drop into it, after the addition is completed, react at 35-60°C for 0.5 hours, and the reaction solution is cooled After reaching room temperature, filter, add an appropriate amount of water, adjust the pH of the solution to neutrality with a common acid-base, extract with dichloromethane, combine the organic layers, dry with anhydrous sodium sulfate, filter, and evaporate the solvent to obtain C-7. C10-di-NO 2 -CBZ-10-deacetylbaccatin III (II) oil crude product; the oil was subjected to silica gel column chromatography (eluent ethyl acetate and n-hexane) to obtain a white sol...

Embodiment 3

[0086] A.C-7, C-10-di-Cl-CBZ-10-deacetylbaccatin III(II)

[0087] The first esterification reaction:

[0088] Dissolve 10-deacetylbaccatin III (I) and DMAP in anhydrous tetrahydrofuran, the amount of DMAP is 5 times the molar number of 10-deacetylbaccatin III (I); under stirring at room temperature, chlorine 4-chlorobenzyl formate (10 times the number of moles of 10-deacetylbaccatin III (I)), was added dropwise, and reacted for 0.5 hours at 35-60°C after the addition, and the reaction solution was cooled to After filtering at room temperature, after adding an appropriate amount of water, adjust the pH of the solution to neutrality with common acid and base, extract with dichloromethane, combine the organic layers, dry with anhydrous sodium sulfate, filter, and evaporate the solvent to obtain C-7, C10 -two-no 2 -CBZ-10-deacetylbaccatin III (II) oil crude product; the oil was subjected to silica gel column chromatography (eluent ethyl acetate and n-hexane) to obtain a white so...

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Abstract

The invention relates to a new method for preparing Docetaxel which includes a new synthesizing method for forming 10-deacetyl baccatin III(II) for protecting C-7, C-10-carbobenzoxy by using the 10-deacetyl baccatin III(I) for reacting with a benzyl chloroformate compound, and a new method for forming a new compound of 2'-(1-ethoxyethyl)-N-debenzoyl-N-(boc)-C-7, C-10-II-X-CBZ-10-deacetyl paclitaxel(IV) by the reaction of (II) with 1-boc-(3R,4S)-4-phenyl azetidine-2-ketone(III) as well as the new compound. Simultaneously, the invention also provides a new method for preparing a new compound of 2'- (1-ethoxyethyl)-N-debenzoyl-N-(boc)-10-deacetyl paclitaxel(V) and a new method for removing the 1-ethoxyethyl from the (IV) to form the Docetaxel.

Description

technical field [0001] The present invention generally relates to the synthesis of docetaxel from precursor compounds. More specifically, the present invention relates to the preparation of docetaxel by the following reaction: [0002] Background technique [0003] Since 1992, paclitaxel has been widely used in the treatment of various cancers (LUNDBERGBB, RISOVIC V, RAMASWAMY M, et.al. A lipophilic paclitaxel derivative incorporated in a lipid emulsion for parenteral administration, J Controlled Release , 2003, 86(1): 93-100). In addition to being mainly used to treat breast cancer and ovarian cancer, paclitaxel also has obvious curative effects on non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) when it is used in combination. In addition, Yuan et al. have shown that paclitaxel has significant anti-human liver cancer activity (YUAN JH, ZHANG RP, ZHANG RG, et al, Growth-inhibiting efforts of taxolon human liver carcinoma in vitro and in nude mice, W...

Claims

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Application Information

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IPC IPC(8): C07D305/14A61P35/00
Inventor 李勤耕陈大海王涛田睿罗绪全继平郭彬谢守权
Owner 重庆医科大学医药研究所
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