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Preparation method of dabigatran etexilate mesylate

A technology for dabigatran etexilate mesylate and methanesulfonic acid, which is applied in the field of medicine and can solve the problems of short synthesis route, high cost, and unsuitability for industrial production and use.

Inactive Publication Date: 2016-05-11
HARBIN PHARMA GROUP TECH CENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The synthetic route used in this route is relatively short, and the yield is relatively ideal, but chloroacetic anhydride is used, which is more corrosive and toxic. Potassium iodide and tetrabutylammonium iodide are used at the same time, and the cost is relatively high, so it is not suitable for industrial production.

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
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Effect test

Embodiment 1

[0070] This embodiment provides a kind of preparation method of dabigatran etexilate mesylate, prepare according to the following steps:

[0071] 1. Preparation of intermediate S3

[0072] Take 0.38kg (2.3mol) of N,N'-carbonyldiimidazole and add it to 4.5L tetrahydrofuran, stir at room temperature and add 0.36kg (2mol) of N-(4-cyanophenyl)-aminoacetic acid, stir for 30 minutes, and then Add 0.62 kg (1.8 mol) of ethyl 3-[(3-amino-4-methylaminobenzoyl)pyridin-2-ylamino]propionate, and keep the reaction at room temperature for 10-12 hours. Add 0.05kg of purified water, stir for 10 minutes, concentrate under reduced pressure at 30-60°C, and dry in vacuo to obtain 0.85kg of intermediate (S3), with a yield of 93.8%.

[0073] 2. Preparation of intermediate S4

[0074] Add 0.80 kg (1.6 mol) of the intermediate (S3) obtained in step 1 to 2.5 kg of n-butyl acetate and 0.3 kg of glacial acetic acid, heat up to 85-90° C. and react for 3-4 hours. Subsequently, n-butyl acetate and glacia...

Embodiment 2

[0082] This embodiment provides a kind of preparation method of dabigatran etexilate mesylate, prepare according to the following steps:

[0083] 1. Preparation of intermediate S3

[0084] Take 0.38kg (2.3mol) of N,N'-carbonyldiimidazole and add it to 4.5L tetrahydrofuran, stir at room temperature and add 0.36kg (2mol) of N-(4-cyanophenyl)-aminoacetic acid, stir for 30 minutes, and then Add 0.62 kg (1.8 mol) of ethyl 3-[(3-amino-4-methylaminobenzoyl)pyridin-2-ylamino]propionate, and keep the reaction at room temperature for 10-12 hours. Add 0.05 kg of purified water, stir for 10 minutes, concentrate under reduced pressure at 30-60° C., and dry in vacuo to obtain 0.83 kg of intermediate (S3), with a yield of 91.6%.

[0085] 2. Preparation of intermediate S4

[0086] Add 0.80 kg (1.6 mol) of the intermediate (S3) obtained in step 1 to 2.5 kg of n-butyl acetate and 0.3 kg of glacial acetic acid, heat up to 85-90° C. and react for 3-4 hours. Subsequently, n-butyl acetate and gl...

Embodiment 3

[0094] This embodiment provides a kind of preparation method of dabigatran etexilate mesylate, prepare according to the following steps:

[0095] 1. Preparation of intermediate S3

[0096] Take 0.47kg (2.3mol) of dicyclohexylcarbodiimide and add it to 4.5L tetrahydrofuran, stir and add 0.36kg (2mol) of N-(4-cyanophenyl)-aminoacetic acid at room temperature, stir for 30 minutes, and then add 0.62 kg (1.8 mol) of ethyl 3-[(3-amino-4-methylaminobenzoyl)pyridin-2-ylamino]propionate was kept at room temperature for 10-12 hours. Add 0.05kg of purified water, stir for 10 minutes, concentrate under reduced pressure at 30-60°C, and dry in vacuo to obtain 0.81kg of intermediate (S3), with a yield of 89.4%.

[0097] 2. Preparation of intermediate S4

[0098] Add 0.75 kg (1.5 mol) of the intermediate (S3) obtained in Step 1 to 2.5 kg of ethyl acetate and 0.3 kg of glacial acetic acid, and heat up to reflux for 5-6 hours. Ethyl acetate and glacial acetic acid were then distilled off und...

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Abstract

The invention discloses a preparation method of dabigatran etexilate mesylate, and belongs to the technical field of medicine. The preparation method comprises the following steps: taking 3-[(3-amino-4-methylaminobenzoyl)pyridine-2-ylamino]ethyl propanoate and N-(4-cyanphenyl)amino acetic acid as the raw materials to synthesize an intermediate (S3); making the intermediate (S3) carry out ring-closure reactions to generate an intermediate (S4); subjecting the intermediate (S4) to acid splitting in the presence of a hydrogen chloride-ethanol solution at first, then carrying out ammonification in the presence of ammonia water to generate an intermediate (S5); carrying out reactions between the intermediate (S5) and n-hexyl chloroformate under an alkaline condition to generate an intermediate (S6); dissolving the intermediate (S6), and finally carrying out reactions between the intermediate (S6) and methylsulfonic acid to obtain dabigatran etexilate mesylate. The preparation method has the advantages of simpleness, controllable and mild conditions, high yield, high product purity, stable product property, and suitability for industrial production.

Description

technical field [0001] The invention relates to a preparation method of dabigatran etexilate mesylate, which belongs to the technical field of medicine. Background technique [0002] Dabigatran etexilate is the prodrug of dabigatran, and it is an oral thrombin inhibitor developed by Boehringer Ingelheim Pharmaceutical Company of Germany. It was approved in Europe in March 2008, which is 50 years after warfarin. The first new class of oral anticoagulant drugs on the market in many years is a major development and milestone in the field of anticoagulant therapy and the prevention of potentially fatal blood clots. [0003] Dabigatran etexilate is converted into dabigatran with direct anticoagulant activity in the body, and dabigatran binds to the fibrin-specific binding site of thrombin, preventing fibrinogen from being split into fibrin, thereby blocking the The final step of the coagulation network and thrombus formation, dabigatran can dissociate from the fibrin-thrombin co...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 袁淑杰杨新春李郑武齐岩刘磊张珊珊刘佳吉赵乐曹翊婕户巧芬丁辉于海涛魏涛曲学伟高晶赵华南关录凡
Owner HARBIN PHARMA GROUP TECH CENT
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