Method for refining dabigatran etexilate and method for controlling specific degradation impurities of dabigatran etexilate

A technology of dabigatran etexilate and refining method, which is applied in the field of medicine, can solve the problems of short reaction steps and no attention to the problem of product impurity content, and achieve the effects of easy operation, less solvent types and high yield

Inactive Publication Date: 2021-08-27
杭州国瑞生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The preparation method of the invention has mild reaction conditions, cheap and easy-to-obtain raw materials, short reaction steps, high atom utilization, simple and controll...

Method used

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  • Method for refining dabigatran etexilate and method for controlling specific degradation impurities of dabigatran etexilate
  • Method for refining dabigatran etexilate and method for controlling specific degradation impurities of dabigatran etexilate
  • Method for refining dabigatran etexilate and method for controlling specific degradation impurities of dabigatran etexilate

Examples

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Effect test

Embodiment 1

[0044] The refining method of embodiment 1 dabigatran etexilate:

[0045] Dissolve 10g of dabigatran etexilate in 50mL of acetone, raise the temperature to dissolve, then drop the temperature and add 60mL of water, continue to cool down to 10°C and stir for 1 hour, then filter, the filter cake is washed with acetone-water mixed solution, and the dry product is dissolved after vacuum drying. In 50mL of acetonitrile, heat up and stir to dissolve, then slowly cool down to 60°C and keep stirring for 1 hour, then continue to drop to 25°C, keep stirring for 1 hour, filter, wash the filter cake with acetonitrile, and dry it in vacuum at 40°C to obtain dabigatran etexilate 8.8g, yield 75.2%, purity 99.52%.

Embodiment 2

[0046] The refining method of embodiment 2 dabigatran etexilate:

[0047] Dissolve 30g of dabigatran etexilate in 150mL of acetone, heat up to dissolve, then drop the temperature and add 300mL of water, continue to cool down to 15°C and stir for 1 hour, then filter, the filter cake is washed with acetone-water mixed solution, dried in vacuum, and then dissolved In 198mL of acetonitrile, heat up to 70°C and stir to dissolve, then slowly cool down to 50°C and keep stirring for 2 hours, then continue to drop to 20°C, keep stirring for 2 hours, then filter, wash the filter cake with acetonitrile, and dry it under vacuum at 45°C to obtain Darby Gatran etexilate 25.6g, yield 72.9%, purity 99.65%.

Embodiment 3

[0048]The refining method of embodiment 3 dabigatran etexilate:

[0049] Dissolve 40g of dabigatran etexilate in 240mL of acetone, raise the temperature to dissolve, then drop the temperature and add 240mL of water, continue to cool down to 10°C and stir for 1 hour, then filter, wash the filter cake with acetone-water mixed solution, vacuum dry and dissolve the dry product In 394mL of acetonitrile, heat up to 70°C and stir to dissolve, then slowly cool down to 55°C and keep stirring for 1 hour, then continue to drop to 20°C, keep stirring for 1 hour, then filter, wash the filter cake with acetonitrile, and dry it under vacuum at 45°C to obtain the ratio Gatran etexilate 34.7g, yield 74.2%, purity 99.67%.

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Abstract

The invention provides a method for refining dabigatran etexilate and a method for controlling specific degradation impurities of dabigatran etexilate. The dabigatran etexilate compound is 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridine-2-yl-amino]-ethyl propionate mesylate, the invention also relates to a control method of specific degradation impurities in the refining process of the compound. The method comprises the following steps: stirring and mixing dabigatran etexilate and acetonitrile, then heating to a reflux state, carrying out heat preservation for 1-2 hours in the reflux state, then carrying out slow cooling, filter pressing, vacuum drying and other technological processes to obtain dabigatran etexilate, and salifying the dabigatran etexilate and methanesulfonic acid to obtain dabigatran etexilate mesylate. The dabigatran etexilate obtained by the refining method provided by the invention has the advantages of high purity, no solvent residue, mild reaction conditions and easiness in industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a method for refining dabigatran etexilate and a method for controlling specific degradation impurities thereof, in particular to 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl )-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester and its specific degradation impurity control. Background technique [0002] Dabigatran etexilate mesylate is a new type of direct thrombin inhibitor, a prodrug of dabigatran, and a non-peptide thrombin inhibitor. It is a new generation of oral anticoagulant direct thrombin inhibitors (DTIs), which is at the forefront of clinical practice, and is used to prevent stroke and systemic embolism in patients with non-valvular atrial fibrillation. Dabigatran etexilate can provide effective, predictable, and stable anticoagulant effect, and at the same time, there are few drug interactions, no drug-food inter...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 崔林芳赵胤钱刚张文灵田湘寅
Owner 杭州国瑞生物科技有限公司
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