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Preparation method of dabigatran etexilate mesylate

A technology of dabigatran etexilate mesylate and dabigatran etexilate, applied in the field of preparation of dabigatran etexilate mesylate, to achieve the effects of reducing related substances, low price, and easy industrialization

Inactive Publication Date: 2017-07-04
NANJING LIFENERGY R & D
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the prior art does not record the use of diatomaceous earth to remove specific related substances in the synthesis of drugs to improve the purity of the product.

Method used

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  • Preparation method of dabigatran etexilate mesylate
  • Preparation method of dabigatran etexilate mesylate
  • Preparation method of dabigatran etexilate mesylate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] 5.0g (8.0mmol) dabigatran etexilate base (purity 95.73%, BIBR951: 0.12%, BIBR1087: 0.09%, the same below) and 100.0g ethyl acetate are joined in the 250ml there-necked flask, heated to 60 ℃ to Dissolved completely, filtered through 2.0g of diatomaceous earth (Celite STD: D50: 22μm, D90: 38μm), added dropwise 0.77g (8.0mmol) methanesulfonic acid to the obtained filtrate at 50°C, cooled to room temperature after the dropwise addition, and passed Filter, dry, pulverize to obtain dabigatran etexilate mesylate 5.3g, yield 91.9% (purity 99.50%, BIBR951: 0.02%, BIBR1087: 0.04%)

Embodiment 2

[0029] 5.0g (8.0mmol) dabigatran etexilate base and 100.0g ethyl acetate were added in a 250ml three-necked flask, heated to 60°C to dissolve completely, and passed through 2.0g diatomaceous earth (Celite 503: D50: 29.6 μm, D90: 64.2μm) hot filtration, the resulting filtrate was added dropwise with 0.77g (8.0mmol) methanesulfonic acid at 50°C, cooled to room temperature after the dropwise addition, filtered, dried and pulverized to obtain 5.2g of dabigatran etexilate mesylate , yield 90.2% (purity 99.30%, BIBR951: 0.07%, BIBR1087: 0.08%)

Embodiment 3

[0031] 5.0g (8.0mmol) dabigatran etexilate base and 100.0g ethyl acetate were added in a 250ml three-necked flask, heated to 60°C to dissolve completely, and passed through 2.0g diatomaceous earth (Celite 512: D50: 22.5 μm, D90: 38 μm) hot filtration, the resulting filtrate was added dropwise with 0.77g (8.0mmol) methanesulfonic acid at 50°C, cooled to room temperature after the dropwise addition, filtered, dried, and pulverized to obtain 5.1g of dabigatran etexilate mesylate, Yield 88.5% (purity 99.56%, BIBR951: 0.03%, BIBR1087: 0.03%)

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Abstract

The invention discloses a preparation method of dabigatran etexilate mesylate. The method comprises a, adding a dabigatran etexilate basic group into an organic solvent and heating to dissolve the solution, b, filtering the solution to obtain a dabigatran etexilate basic group solution, c, adding methylsulfonic acid into the filtrate drop by drop so that the dabigatran etexilate mesylate is formed through acidification, and d, carrying fluid exhaustion, drying and crushing to obtain a dabigatran etexilate mesylate product. The organic solvent used in the step a is ethyl acetate, and in the filtration process of the step b, diatomaceous earth as a filter aid is used. The method has simple processes and is suitable for industrial production. The product has low related substance content and high purity.

Description

technical field [0001] The invention relates to a thrombin inhibitor drug, in particular to a preparation method of dabigatran etexilate mesylate. Background technique [0002] Dabigatran etexilate is a new type of oral anticoagulant drug developed by Boehringer Ingelheim (Boehringer Ingelheim) in Germany. In April 2008, it was first launched in Germany and the United Kingdom under the trade name of Pradaxa. In October 2010, it was approved by the FDA to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation. Patent WO98 / 37075 first disclosed the structure of dabigatran etexilate and its preparation method, and its chemical structure is as follows: [0003] [0004] Due to the particularity of its structure (containing active groups such as ethyl propionate and carbamate), it is prone to hydrolysis to generate impurities such as the following structure: [0005] [0006] Its degradation process is shown in the figure below: ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 胡良明汤传飞王宁沙伟
Owner NANJING LIFENERGY R & D
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