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Synthesis method of dabigatran etexilate

A dabigatran etexilate and synthetic method technology, applied in the direction of organic chemistry, etc., can solve the problems of cumbersome process and purification steps, difficult industrialization promotion, high cost, etc., and achieve avoidance of column chromatography separation, easy availability of raw materials, and route simple effect

Inactive Publication Date: 2015-05-27
QINGDAO HUANGHAI PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Because the process and purification steps of the synthetic dabigatran lipid intermediates are cumbersome, especially the method of column chromatography is used for purification, it is not easy to operate in industrial production, the cost is high, and it is difficult to promote industrialization

Method used

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  • Synthesis method of dabigatran etexilate
  • Synthesis method of dabigatran etexilate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Example 1. Intermediate 3-({2-[(4-cyano-phenylimine)-methylene]-1-methylene-1H-benzimidazole-5-carbonyl}-pyridine-2- Synthesis of ethyl imine) propionate (3)

[0022] Add 3.35g (18.98mmol) N-(4-cyanophenyl)glycine (2) into 40ml of dichloromethane, stir for 10 minutes and cool down to 0-5°C, add 2.57g (18.98mmol) N,N -Carbonyldiimidazole (abbreviated as HoBt), after stirring for 20 minutes, add 3.64g (18.98mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide salt (abbreviated as EDCl), and continue to stir for 1 hour , slowly warmed to room temperature.

[0023] Then 5g (14.6mmol) 3-[(3-amino-4-methylaminobenzoyl) (pyridin-2-yl) amino] ethyl propionate (1) was dissolved in 30ml of dichloromethane, 15- Add dropwise to the above solution for 20 minutes, stir overnight at room temperature, then evaporate the solvent to dryness, add ethyl acetate (analytical grade) and water for extraction, take the organic layer and dry it with anhydrous sodium sulfate, filter, and evapora...

Embodiment 2

[0030] Example 2. Intermediate 3-({2-[(4-cyano-phenylimine)-methylene]-1-methylene-1H-benzimidazole-5-carbonyl}-pyridine-2- Synthesis of ethyl imine) propionate (3)

[0031] Add 3.09g (17.52mmol) N-(4-cyanophenyl)glycine (2) into 40ml of dichloromethane, stir for 10 minutes and cool down to 0°C, add 2.37g (17.52mmol) N,N-carbonyl Diimidazole (abbreviated as HoBt), after stirring for 22 minutes, add 3.36g (17.52mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide salt (abbreviated as EDCl), continue to stir for 1 hour, slowly Bring to room temperature.

[0032] Then 5g (14.6mmol) 3-[(3-amino-4-methylaminobenzoyl) (pyridin-2-yl) amino] ethyl propionate (1) was dissolved in 30ml of dichloromethane, 15- Add dropwise to the above solution for 20 minutes, stir overnight at room temperature, then evaporate the solvent to dryness, add ethyl acetate (analytical grade) and water for extraction, take the organic layer and dry it with anhydrous sodium sulfate, filter, and evaporate the s...

Embodiment 3

[0039] Example 3. Intermediate 3-({2-[(4-cyano-phenylimine)-methylene]-1-methylene-1H-benzimidazole-5-carbonyl}-pyridine-2- Synthesis of ethyl imine) propionate (3)

[0040] Add 3.09g (17.52mmol) N-(4-cyanophenyl)glycine (2) into 40ml of dichloromethane, stir for 10 minutes and cool down to -5-0°C, add 2.37g (17.52mmol) N, N-carbonyldiimidazole (abbreviated as HoBt), after stirring for 20 minutes, add 3.36g (17.52mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide salt (abbreviated as EDCl), continue to stir for 1 hour, slowly warming to room temperature.

[0041] Then 5g (14.6mmol) 3-[(3-amino-4-methylaminobenzoyl) (pyridin-2-yl) amino] ethyl propionate (1) was dissolved in 30ml of dichloromethane, 15- Add dropwise to the above solution for 20 minutes, stir overnight at room temperature, then evaporate the solvent to dryness, add ethyl acetate (analytical grade) and water for extraction, take the organic layer and dry it with anhydrous sodium sulfate, filter, and evaporate ...

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Abstract

The invention relates to the technical field of medicine synthesis and purification, in particular to a synthesis method for preparing dabigatran etexilate. The method comprises the following steps: with N-(4-cyanophenyl) glycine and 3-[(3-amino-4-methylamino benzoyl) (pyridine-2-yl) amino] ethyl propionate as raw materials, carrying out dehydration-condensation reaction, sequentially introducing hydrogen chloride and an ammonia gas to the reactants in an ethanol solution; adding hexyl chloroformate, and carrying out condensation reaction; and carrying out recrystallization to obtain the dabigatran etexilate of which the purity is 99%. The method is simple, safe, easy to operate, short in reaction cycle, and relatively high in yield and purity; impurities are easy to remove; column chromatography isolation is not needed in purification; and the method is suitable for industrialized production.

Description

technical field [0001] The invention relates to the technical field of medicine synthesis and purification, in particular to a preparation and synthesis method of dabigatran etexilate. Background technique [0002] Dabigatran (Pradaxa) is an oral direct thrombin inhibitor developed and produced by Boehringer Ingelheim, Germany. It is a prodrug of Dabigatran (Dabigatran), and it is a non-peptide thrombin inhibitor. After oral administration and gastrointestinal absorption, it is transformed into Dabigatran with direct anticoagulant activity in the body. Dabigatran binds to the fibrin-specific binding site of thrombin, preventing fibrinogen from being cleaved into fibrin, thereby blocking the final step of the coagulation cascade network and thrombus formation. Dabigatran dissociates from the fibrin-thrombin complex and exerts a reversible anticoagulant effect. The drug was first launched in Germany and the UK in April 2008. Dabigatran has direct anticoagulant activity and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 刘志达李常青鲁大东陈晓涛王宝超张姗高永吉
Owner QINGDAO HUANGHAI PHARM CO LTD
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