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Preparation process of high-purity apixaban

A preparation process and technology of apixaban, applied in the field of preparation technology of high-purity apixaban

Active Publication Date: 2019-12-27
JIANGXI GUOYAO PHARMA LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Impurity A is an analogue of apixaban, and its existence is not conducive to the improvement of product quality. The existing technology has tried to reduce this impurity, but it cannot be greatly reduced

Method used

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  • Preparation process of high-purity apixaban
  • Preparation process of high-purity apixaban
  • Preparation process of high-purity apixaban

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] A preparation process for high-purity apixaban, comprising the following steps:

[0051] S1: Preparation of Compound (Ⅲ):

[0052] Add 80mL of acetonitrile, 20g (49.3mmol) of compound (Ⅳ), 7.4g (73.9mmol) of δ-valerolactone successively in the pressure reactor, seal it, and feed nitrogen to make the pressure to 3kg / cm 2 , heat up to 50-60°C, keep stirring for 4-5 hours, lower the temperature, decompress and concentrate under reduced pressure to remove acetonitrile, add 150mL dichloromethane and 12g (93mmol) diisopropylethylamine after cooling down to room temperature, and cool down to 0 -10°C, add 12g (63mmol) p-toluenesulfonyl chloride dichloromethane solution dropwise, keep the reaction for 2 hours, wash with 100mL water and 100mL saturated sodium chloride solution successively, concentrate the washed organic layer under reduced pressure, add 140mL acetic acid The ethyl ester was stirred and heated to reflux, filtered after clarification, cooled to 0-10°C for crystal...

Embodiment 2

[0060] S1: Preparation of Compound (Ⅲ):

[0061] Add 80mL of acetonitrile, 20g (49.3mmol) of compound (Ⅳ), 7.4g (73.9mmol) of δ-valerolactone successively in the pressure reactor, seal it, and feed nitrogen to make the pressure to 3kg / cm 2 , heat up to 50-60°C, keep stirring for 4-5 hours, lower the temperature, decompress and concentrate under reduced pressure to remove acetonitrile, add 150mL dichloromethane and 12g (93mmol) diisopropylethylamine after cooling down to room temperature, and cool down to 0 -10°C, add 12g (63mmol) p-toluenesulfonyl chloride dichloromethane solution dropwise, keep the reaction for 2 hours, wash with 100mL water and 100mL saturated sodium chloride solution successively, concentrate the washed organic layer under reduced pressure, add 140mL acetic acid The ethyl ester was stirred and heated to reflux, filtered after clarification, cooled to 0-10°C to crystallize, filtered, and vacuum-dried to obtain 26.7 g of off-white or off-white solid compound ...

Embodiment 3

[0069] S1: Preparation of Compound (Ⅲ):

[0070] Add 80mL of acetonitrile, 20g (49.3mmol) of compound (Ⅳ), 7.4g (73.9mmol) of δ-valerolactone successively in the pressure reactor, seal it, and feed nitrogen to make the pressure to 3kg / cm 2 , heat up to 50-60°C, keep stirring for 4-5 hours, lower the temperature, decompress and concentrate under reduced pressure to remove acetonitrile, add 150mL dichloromethane and 12g (93mmol) diisopropylethylamine after cooling down to room temperature, and cool down to 0 -10°C, add 12g (63mmol) p-toluenesulfonyl chloride dichloromethane solution dropwise, keep the reaction for 2 hours, wash with 100mL water and 100mL saturated sodium chloride solution successively, concentrate the washed organic layer under reduced pressure, add 140mL acetic acid The ethyl ester was stirred and heated to reflux, filtered after clarification, cooled to 0-10°C for crystallization, filtered, and vacuum-dried to obtain 26.4 g of off-white or off-white solid comp...

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Abstract

The invention discloses a preparation process of apixaban. The method comprises the following steps of: performing amidation on an initial raw material compound (IV) and delta-valerolactone under pressure; performing a one-pot reaction on the obtained hydroxyl amide and p-toluenesulfonyl chloride (PTSC)to obtain a compound (III); carrying out a reaction with tetrabutylammonium fluoride trihydrateto obtain a cyclization product compound (II); preparing a compound (I) from 2,4-dichlorobenzaldehyde and formamide under the action of sodium methoxide and a molecular sieve; refining the crude product by adopting an optimized ethanol / dichloromethane mixed solvent, so that impurity A is removed well; by means of the method, the apixaban product with high yield and high purity is prepared, whereinthe purity of the apixaban product is not lower than 99.5%, the impurity A does not exceed 0.05%, and any single impurity does not exceed 0.1%.

Description

technical field [0001] The invention relates to a preparation process of high-purity apixaban, which belongs to the field of drug synthesis. Background technique [0002] Apixaban, the English name is Apixaban (trade name: Eliquis), the Chinese chemical name is 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-1- Piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, CAS No. 503612-47-3, has the following chemical Structural formula: [0003] [0004] Apixaban is an antithrombotic drug. It is a direct factor Xa inhibitor jointly developed by Bristol-Myers Squibb and Pfizer. It was approved for marketing in the European Union in March 2011 and approved by the FDA in December 2012. The drug was launched in the United States. [0005] There are many reports on the synthesis route and preparation process of apixaban. Check the published synthesis route and preparation process. Many routes have a common feature, such as WO200304968, WO2010030983, etc., using p...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 杨建国万义斌葛友群左飞鸿杨明余承祥孟周钧柒伟超
Owner JIANGXI GUOYAO PHARMA LLC
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