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Method for recovering and preparing dabigatran etexilate mesylate from production mother liquor

A technology of dabigatran etexilate mesylate and dabigatran etexilate, which is applied in the field of preparing dabigatran etexilate mesylate, can solve problems such as difficult to purify dabigatran etexilate products and many impurities, and achieve Fewer types of solvents, reduced waste emissions, and milder reactions

Pending Publication Date: 2022-07-08
TOPFOND PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, more impurities are also enriched in the mother liquor for the preparation of crude dabigatran etexilate mesylate and the refined crystallization, so it is difficult to further purify the dissolved dabigatran etexilate product from the mother liquor

Method used

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  • Method for recovering and preparing dabigatran etexilate mesylate from production mother liquor
  • Method for recovering and preparing dabigatran etexilate mesylate from production mother liquor
  • Method for recovering and preparing dabigatran etexilate mesylate from production mother liquor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Get dabigatran etexilate mesylate and concentrate to dryness under reduced pressure at 50 ° C of the mother liquor, get 50 g of evaporated dry matter (its HPLC spectrogram is as follows: figure 1 shown), put it into a 1000ml three-necked flask, add 300g of acetonitrile, stir and heat up to 55-60°C. Adjust the pH of the system to 8 with ammonia water, keep stirring for 1 hour, slowly add 150 g of purified water, continue to keep stirring for 30 minutes after adding water, and cool down. The crystals were crystallized for 4 hours, filtered and dried to obtain 35 g of dabigatran etexilate free base.

[0062] Put 35g of dabigatran etexilate free base into a 500ml three-necked bottle, add 210g of ethyl acetate, stir and heat up to dissolve until the solution is clear, the temperature of the solution is 55-60°C, keep stirring for 30min, stop heating, cool down naturally, and observe crystal precipitation. After that, the temperature at the time of crystal precipitation was m...

Embodiment 2

[0066] Get dabigatran etexilate mesylate and concentrate to dryness under reduced pressure at 50 ° C of the mother liquor, get 50 g of evaporated dry matter (its HPLC spectrogram is as follows: figure 1 shown), put it into a 1000ml three-necked flask, add 350g of acetonitrile, stir and heat up to 55-60°C. Adjust the pH of the system to 8 with triethylamine, keep stirring for 1 hour, slowly add 180 g of purified water, continue to keep stirring for 30 minutes after adding water, and cool down. , crystallized for 5 hours, filtered, and dried to obtain 34.6 g of dabigatran etexilate free base.

[0067] Put 34.6g of dabigatran etexilate free base into a 500ml three-necked flask, add 230g of ethyl acetate, stir and heat up to dissolve until the solution is clear, the temperature of the solution is 55-60°C, keep stirring for 30min, stop heating, cool down naturally, and observe the crystals. After the precipitation, the temperature at the time of crystal precipitation was maintaine...

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Abstract

The invention provides a method for recovering and preparing dabigatran etexilate mesylate from production mother liquor, and relates to the technical field of preparation of dabigatran etexilate mesylate. The method specifically comprises the following steps: carrying out reduced pressure distillation on the dabigatran etexilate mesylate production mother liquor until the weight is constant, sequentially adding acetonitrile, a pH regulator and purified water into an obtained solid mixture, and carrying out cooling crystallization to obtain dabigatran etexilate free alkali; then adding ethyl acetate, purifying and crystallizing to obtain refined dabigatran etexilate free alkali; the method comprises the following steps: dissolving refined dabigatran etexilate free alkali in acetone, salifying with methanesulfonic acid to prepare dabigatran etexilate mesylate, crystallizing, and finally further refining the dabigatran etexilate mesylate through an alcohol-acetone system to obtain a high-quality dabigatran etexilate mesylate refined product. The method is simple in process, mild in reaction and few in solvent category, only cooling crystallization is needed in the purification step, column chromatography purification is not needed, the dabigatran etexilate mesylate production mother liquor can be effectively recycled, the production cost is reduced, and waste discharge is reduced.

Description

technical field [0001] The invention belongs to the technical field of preparing dabigatran etexilate mesylate, in particular to a method for recovering and preparing dabigatran etexilate mesylate from a production mother liquor. Background technique [0002] Dabigatran etexilate is a new oral anticoagulant drug developed by the German company Boehringer Ingelheim. It was first launched in Germany and the United Kingdom in 2008; Prevention of stroke and systemic thromboembolism in patients with non-valvular atrial fibrillation; launched in my country in 2013. Dabigatran etexilate mesylate is a prodrug of dabigatran, which itself has no activity. After oral absorption through the gastrointestinal tract, it is rapidly hydrolyzed by esterases in the liver and further converted into active dabigatran. Dabigatran etexilate exerts its anticoagulant effect by binding to the fibrin-specific site of thrombin, preventing the cleavage of fibrinogen into fibrin. Dabigatran etexilate me...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07C303/44C07C303/32C07C309/04
CPCC07D401/12C07C303/44C07C303/32C07C309/04
Inventor 马国旺王俊臣耿电光徐文斌吴戈亮王文华刘培养年蓓蕾赵臻刘学威贾秧秧勾旭陈秋实刘继方廖付齐
Owner TOPFOND PHARMA CO LTD
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