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Dabigatran etexilate intermediate synthesis method

A compound, haloformate technology, applied in the field of chemistry, can solve the problems of long reaction steps, low total yield of intermediates, and large amount of waste acid

Active Publication Date: 2016-04-27
CHONGQING PHARMA RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] This method mainly has the following problems: 1) 3-[(3-amino-4-methylaminobenzoyl) (pyridin-2-yl) amino] ethyl propionate and N-(4-cyanophenyl) When aminoacetic acid is condensed in the presence of EDCI and HOBT to generate corresponding benzimidazole derivatives, the yield is about 50%, which is on the low side, and column chromatography is required for purification; The reaction operation is cumbersome, and a large amount of waste acid will be produced
[0015] This method also has long reaction steps, especially the low yield when synthesizing benzimidazole derivatives, resulting in low overall yield of intermediate (D5)

Method used

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  • Dabigatran etexilate intermediate synthesis method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] Preparation of 2-chloromethyl-1-methyl-1H-benzimidazole-5-carboxylic acid:

[0070] Take 11 g of 3-amino-4-methylaminobenzoic acid, add 200 ml of ethyl acetate, stir well, then add dropwise the solution obtained by dissolving 12 g of chloroacetic anhydride in 52 g of ethyl acetate. The addition was completed in about 10 minutes. After the addition, it was reacted at room temperature for 30 minutes, and then heated to 65°C for 4 hours. TLC (developer: methanol: dichloromethane = 5:1) determined the end point of the reaction. After the reaction was completed, cool to room temperature, filter, wash the reaction flask and filter cake with 50ml ethyl acetate, and dry under reduced pressure at 65°C to obtain the target compound product with a yield of 91.5%.

Embodiment 2

[0072] Preparation of 2-chloromethyl-1-methyl-1H-benzimidazole-5-carboxylic acid:

[0073] Take 11g of 3-amino-4-methylaminobenzoic acid, add 200ml of ethyl acetate, stir well, add 20g of chloroacetic acid, heat up to 40°C and react for 8 hours, TLC (developing agent methanol:dichloromethane=5:1) to determine end point of the reaction. After the reaction was completed, cool to room temperature, filter, wash the reaction flask and filter cake with 50ml of ethyl acetate, and dry under reduced pressure at 65°C to obtain the target compound product with a yield of 78.6%.

Embodiment 3

[0075] Preparation of ethyl 2-chloromethyl-1-methyl-1H-benzimidazole-5-carboxylate:

[0076] Take 11.2g of the product obtained in Example 1 or 2, add 180ml of absolute ethanol, stir well, add 14.3g of thionyl chloride dropwise under cooling in an ice-water bath, and finish adding in about 10 minutes. After the addition, react in an ice-water bath for 30 minutes, and then heat up After reflux for 6 hours, TLC (developing solvent: dichloromethane: methanol = 10:1) determined the end point of the reaction. After the reaction is complete, add 2g of activated carbon, stir and decolorize for 0.5-1 hour, filter while hot, concentrate to dryness under reduced pressure, add 40ml of ethanol to reflux to dissolve, add 20mlg of ethyl acetate, cool and crystallize, filter after cooling in an ice-water bath, and store at 50°C Dry under reduced pressure to obtain the target compound product with a yield of 93.4%.

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PUM

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Abstract

The invention discloses dabigatran etexilate, an intermediate thereof with a formula (5), and a synthesis method of a derivative thereof. According to the synthesis method, a compound represented by a formula (2) is subjected to a compound represented by a formula (4), such that a compound represented by the formula (5) is obtained; the compound represented by the formula (5) is hydrolyzed, and is subjected to a reaction with 3-(pyridin-2-ylamino)ethyl propionate, such that dabigatran etexilate is prepared.

Description

technical field [0001] The invention belongs to the field of chemistry, and in particular relates to a synthetic method of dabigatran etexilate and its key intermediate. Background technique [0002] Dabigatran etexilate (dabigatranetexilate), the chemical name is N-[2-[4-[[(hexyloxycarbonyl)amidino]phenyl]amino]methyl-1-methyl-1H-benzimidazole-5 -Carbonyl]-N-(2-pyridyl)-3-aminopropionic acid ethyl ester methanesulfonate, the structure is shown in formula I. [0003] [0004] Dabigatran etexilate Pradaxa (dabigatranexilate) was developed by Boehringer Ingelheim, Germany, and was launched in Germany and the UK in April 2008, in the U.S. in 2010, and in Japan in 2011. It is used for patients with abnormal heart rhythm (atrial fiber tremors) to prevent strokes and blood clotting. [0005] Dabigatran etexilate is a new type of synthetic direct thrombin inhibitor, which is the prodrug of dabigatran and is a non-peptide thrombin inhibitor. After oral administration and gas...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D235/14C07D401/12
Inventor 邢乃果王丽蔡鹏飞郑德平
Owner CHONGQING PHARMA RES INST