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Preparation method for docetaxel impurity

A docetaxel and impurity technology, applied in the field of pharmaceutical preparation, can solve problems such as undetected impurities, and achieve the effects of reducing reaction steps, high reaction yield and few steps

Inactive Publication Date: 2018-12-07
无锡紫杉药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

No relevant literature reports on the synthesis of this impurity have been found yet

Method used

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  • Preparation method for docetaxel impurity
  • Preparation method for docetaxel impurity
  • Preparation method for docetaxel impurity

Examples

Experimental program
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Effect test

Embodiment 1

[0025] (1) Dissolve 7-triethylsilyl-10-deacetylbaccatin III (6.5g) in 32.5ml of dichloromethane and 65ml of pyridine, stir in a low-temperature bath, and dropwise add chloroformic acid-2 , 2-dichloroethyl ester (7.8g), continue to react at 0°C for 60min after dropping. Add 10ml of water to the reaction solution to quench the reaction, add hydrochloric acid to neutralize until the water phase becomes acidic, collect the organic phase and concentrate it under reduced pressure at 45°C until it is evaporated without solvent, add 30ml of toluene, continue to concentrate until a large amount of solids are precipitated, filter with suction, and dry Product I (7.5 g) was obtained with a yield of 95.0%.

[0026] (2) Product I (7.5g) was dissolved in 75ml toluene, and 4-dimethylaminopyridine (0.7g), dorsic acid (4.5g) and N,N-dicyclohexylcarboimide ( 3.3g, 1.7 equivalents), reacted at 15°C for 2h. The reaction solution was suction filtered, and the filtrate was washed with dilute hydr...

Embodiment 2

[0029] (1) Dissolve 7-triethylsilyl-10-deacetylbaccatin III (6.5g) in 32.5ml of dichloromethane and 13ml of pyridine, stir in a low-temperature bath, and dropwise add chloroformic acid-2 , 2-dichloroethyl ester (15.6g), continue to react at 0°C for 15min after dropping. Add 10ml of water to the reaction solution to quench the reaction, add hydrochloric acid to neutralize until the water phase becomes acidic, collect the organic phase and concentrate it under reduced pressure at 45°C until it is evaporated without solvent, add 30ml of toluene, continue to concentrate until a large amount of solids are precipitated, filter with suction, and dry Product I (7.8 g) was obtained with a yield of 98.9%.

[0030] (2) Dissolve the product I (7.8g) in 78ml of dichloromethane, add 4-dimethylaminopyridine (0.7g), dorsic acid (3.9g) and N,N-diisopropylcarbodi Imine (1.8g, 1.5eq) was reacted at 25°C for 1.5h. The reaction solution was suction filtered, and the filtrate was washed with dilu...

Embodiment 3

[0033] (1) Dissolve 7-triethylsilyl-10-deacetylbaccatin III (6.5g) in 32.5ml of dichloromethane and 30ml of pyridine, stir in a low-temperature bath, and dropwise add chloroformic acid-2 , 2-dichloroethyl ester (12.5g), continue to react at 0°C for 15min after dropping. Add 10ml of water to the reaction solution to quench the reaction, add hydrochloric acid to neutralize until the water phase becomes acidic, collect the organic phase and concentrate it under reduced pressure at 45°C until it is evaporated without solvent, add 30ml of toluene, continue to concentrate until a large amount of solids are precipitated, filter with suction, and dry Product I (7.3 g) was obtained with a yield of 92.5%.

[0034] (2) Dissolve the product I (7.3g) in 73ml toluene, add 4-dimethylaminopyridine (0.7g), dorsic acid (14.6g) and 1-ethyl-(3-dimethylamino Propyl)carbodiimide hydrochloride (3.5g, 2eq), react at 20°C for 1h. The reaction solution was suction filtered, and the filtrate was washe...

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Abstract

The invention provides a preparation method for a docetaxel impurity, namely, 10-dichloroethoxycarbonyl docetaxel. The preparation method comprises the following steps: (1) taking 7-triethyl silicon-10-deacetylbaccatin III as a raw material and reacting with chloroformic-2,2-dichloro ethyl ester, thereby acquiring a product I; (2) triggering the product I to react with polysillic acid under the effect of a condensing agent, thereby acquiring a product II; (3) triggering the product III to react under the effect of hydrochloric acid, thereby acquiring the 10-dichloroethoxycarbonyl docetaxel. The method is simple in operation, high in yield and high in product purity. The acquired product has a great significance in researching docetaxel quality.

Description

technical field [0001] The invention relates to the technical field of medicine preparation, in particular to a preparation method of docetaxel impurity 10-dichloroethoxycarbonyl docetaxel. Background technique [0002] Docetaxel, a taxane drug, its pharmacological action is to promote the assembly of microtubule dimers into tubules, and at the same time stabilize the tubules by preventing depolymerization, arresting cells in G2 and M phases , thereby inhibiting the mitosis and proliferation of cancer cells. With the development of technology, USP41 has updated some docetaxel impurities, 6-Dichloroethoxy carbonyldocetaxel (ie 10-dichloroethoxycarbonyl docetaxel in the present invention) is one of them. In order to be better in line with international standards, in-depth research on this impurity is also required in the quality research of docetaxel, so it is necessary to prepare high-purity 10-dichloroethoxycarbonyl docetaxel. No relevant literature reports on the synthesi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D305/14
CPCC07D305/14
Inventor 高友新黄春汤伟彬须星怡
Owner 无锡紫杉药业股份有限公司
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