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Preparation method of dabigatran etexilate mesylate

A technology of dabigatran etexilate mesylate and dabigatran etexilate, which is applied in the field of preparation of new oral anticoagulant drug dabigatran etexilate mesylate, can solve the problems of restricting mass production, restricting popularization and application, Low reaction temperature and other problems, to achieve good practical value and significance of popularization and application, shorten the process flow, and achieve the effect of high purity

Inactive Publication Date: 2018-11-23
TOPFOND PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, analysis and research shows that in the existing preparation process, there are defects such as low reaction temperature, long reaction time, complicated operation, silica gel column chromatography for purification, low yield, low purity, and long cycle, which limit mass production. Limiting the promotion and application of the drug

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] The preparation method of dabigatran etexilate mesylate provided by the application, its operation process is specifically introduced as follows.

[0031] (1) 3-[[[2-[[(4-amidinophenyl)amino]methyl]-1-methyl-1H-benzimidazole-5-carbonyl](pyridin-2-yl)amino ]-Ethyl propionate p-toluenesulfonate and potassium carbonate are added to the dissolving agent and mixed uniformly;

[0032] In terms of specific dosage, 3-[[[2-[[(4-amidinophenyl)amino]methyl]-1-methyl-1H-benzimidazole-5-carbonyl](pyridin-2-yl)amino ]-ethyl propionate p-toluenesulfonate consumption is 40g, and potassium carbonate consumption is 56g;

[0033] During the mixing operation, the dissolving agent is an acetone-water system; the acetone-water system is specifically prepared by uniformly mixing 1000ml of acetone and 550ml of water to form a solution.

[0034] The 3-[[[2-[[(4-amidinophenyl)amino]methyl]-1-methyl-1H-benzimidazole-5-carbonyl](pyridin-2-yl)amino]- Ethyl propionate p-toluenesulfonate, prepared...

Embodiment 2

[0048] The preparation method of the dabigatran etexilate mesylate provided by the present embodiment, concrete process is roughly the same as embodiment 1, only adjusts part reaction parameter as follows:

[0049] In step (1):

[0050] When dissolving and mixing operations: in terms of specific dosage, 3-[[[2-[[(4-amidinophenyl)amino]methyl]-1-methyl-1H-benzimidazole-5-carbonyl](pyridine- 2-base) amino]-propionic acid ethyl ester p-toluenesulfonate consumption is 40g, and potassium carbonate consumption is 58g;

[0051] Preparation of 3-[[[2-[[(4-amidinophenyl)amino]methyl]-1-methyl-1H-benzimidazole-5-carbonyl](pyridin-2-yl)amino]-propane For ethyl acetate p-toluenesulfonate:

[0052] In step A, the amount of methanol added is 320g, 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl] Pyridin-2-yl amino] ethyl propionate consumption is 50g;

[0053] In step C, add 320 g of methanol to dissolve after evaporating to dryness under reduced pressure;

...

Embodiment 3

[0064] The preparation method of the dabigatran etexilate mesylate provided by the present embodiment, concrete process is roughly the same as embodiment 1, only adjusts part reaction parameter as follows:

[0065] In step (1):

[0066] When dissolving and mixing operations: in terms of specific dosage, 3-[[[2-[[(4-amidinophenyl)amino]methyl]-1-methyl-1H-benzimidazole-5-carbonyl](pyridine- 2-base) amino]-propionic acid ethyl ester p-toluenesulfonate consumption is 40g, and potassium carbonate consumption is 56g;

[0067] Preparation of 3-[[[2-[[(4-amidinophenyl)amino]methyl]-1-methyl-1H-benzimidazole-5-carbonyl](pyridin-2-yl)amino]-propane For ethyl acetate p-toluenesulfonate:

[0068] In step A, the amount of methanol added is 300g, 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl] Pyridin-2-yl amino] ethyl propionate consumption is 50g;

[0069] In step C, add 320 g of methanol to dissolve after evaporating to dryness under reduced pressure; ...

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Abstract

The invention belongs to the technical field of medicine preparation, and in particular relates to a preparation method of a novel oral anticoagulant drug dabigatran etexilate mesylate; the method comprises the following steps: (1) adding and mixing 3-[[[2-[[(4-amidino-ylphenyl)amino]methyl]-1-methyl-1H-benzimidazole-5-carbonyl](pyridine-2-yl)amino]-ethyl propionate tosilate and potassium carbonate in a solvent; (2) adding hexyl chloroformate for reaction; (3) adding a refining solvent to dissolve to obtain dabigatran etexilate; 4) adding a reactive solvent for dissolving, and dropwise addingmethanesulfonic acid for reaction; in general, the preparation method of the dabigatran etexilate mesylate provided by the application has mild reaction conditions, short reaction period, and no toxicand harmful substance in purification process of a finished product, and the yield of the final product dabigatran etexilate mesylate is high, so the preparation method has better practical value andpopularization and application significance.

Description

technical field [0001] The invention belongs to the technical field of medicine preparation, and in particular relates to a preparation method of a novel oral anticoagulant drug dabigatran etexilate mesylate. Background technique [0002] Dabigatran etexilate, whose trade name is Pradaxa, is a new type of oral anticoagulant drug developed by Boehringer Ingelheim, Germany, and belongs to non-peptide direct thrombin inhibitors. It was first approved for marketing by the EU EMA, and was approved by the FDA for marketing in the United States on September 20, 2010. It is used for the prevention of thrombosis after hip and knee replacement and the prevention of stroke caused by atrial vibration (AF). When used, dabigatran etexilate acts as a prodrug, which is converted into active dabigatran in vivo, which exerts anticoagulant effect by directly inhibiting thrombin. Due to the characteristics of oral administration, strong potency, no need for medication monitoring, and few drug ...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07C303/44C07C303/32C07C309/04
CPCC07D401/12
Inventor 乔向勇李卫民马国旺马奇耿电光赵臻罗峰王迎举张念程亚丽周香莹
Owner TOPFOND PHARMA CO LTD
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