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The preparation method of n-(2-chloromethyl-1-methyl-1h-benzimidazole-5-acyl)-n-(pyridin-2-yl)-3-aminopropionic acid ethyl ester

A technology of ethyl aminopropionate and benzimidazole, which is applied in the field of preparation of N--N--3-ethyl aminopropionate (dabigatran etexilate intermediate), which can solve the problem of large quantities and solubility , low recovery rate and purity, to achieve the effect of cheap raw materials, low equipment requirements, and easy availability of raw materials

Active Publication Date: 2016-04-13
ABA CHEM CORP
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Problems solved by technology

[0002] N-(2-Chloromethyl-1-methyl-1H-benzimidazole-5-yl)-N-(pyridin-2-yl)-3-aminopropionic acid ethyl ester is a new type of product developed and marketed by BoehringerIngelheim, Germany. The important intermediate of anticoagulant dabigatran etexilate (DabigatranEtexilate), its literature report (WO2011061080, etc.) provides a synthetic method, we have carried out the synthesis, the main problem is that N-(pyridin-2-yl )-N-(4-methylamino-3-nitrobenzoyl)-3-aminopropionic acid ethyl ester solubility problem, resulting in the hydrogenation reaction requiring a large amount of solvent to dissolve, and the recovery rate and purity are low

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  • The preparation method of n-(2-chloromethyl-1-methyl-1h-benzimidazole-5-acyl)-n-(pyridin-2-yl)-3-aminopropionic acid ethyl ester

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[0022] The following are specific embodiments of the present invention, further describing the technical solution of the present invention, but the present invention is not limited to this embodiment.

[0023] (1) Synthesis of 2-chloromethyl-1-methyl-1H-benzimidazole-5-carboxylic acid (one)

[0024] Into a 1000mL reaction flask, add 61.2g of 3-amino-4-methylaminobenzoic acid hydrochloride and 400ml of DMF, slowly raise the temperature to 50°C for reaction, add dropwise 30ml of chloroacetyl chloride, react for 2h, and monitor and control the raw material <0.2% by HPLC; Add 400ml ethyl acetate (the reactant is dissolved in DMF, add ethyl acetate to precipitate the product), cool to 0°C, filter; get 2-chloromethyl-1-methyl-1H-benzimidazole- 5-Carboxylate hydrochloride crude product. The crude product was dissolved in a mixed solvent of 400ml of water and 400ml of acetonitrile, adjusted to pH 4-5 with 3N aqueous sodium hydroxide solution, and a solid was precipitated; filtered,...

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Abstract

The invention discloses a preparation method of a dabigatran etexilate intermediate. The method process is as follows: a) Using 3-amino-4-methylaminobenzoic acid as the starting material, 2-chloromethyl-1-methyl-1H-benzimidazole-5- carboxylic acid. b) 2-chloromethyl-1-methyl-1H-benzimidazole-5-carboxylic acid forms 2-chloromethyl-1-methyl-1H-benzimidazole-5formyl chloride under the action of oxalyl chloride. c) Condensation of 2-chloromethyl-1-methyl-1H-benzimidazole-5 formyl chloride with 3-(pyridin-2-yl) ethyl aminopropionate to give N-(2-chloromethyl-1- ethyl methyl-1H-benzimidazol-5-yl)-N-(pyridin-2-yl)-3-aminopropanoate. The synthetic route has not been reported in the literature, and the raw materials are cheap and easy to obtain; the unit operation is simple, the equipment requirements are low, and it is suitable for large-scale industrial production.

Description

technical field [0001] The present invention relates to a kind of N-(2-chloromethyl-1-methyl-1H-benzimidazole-5-acyl)-N-(pyridin-2-yl)-3-aminopropionic acid ethyl ester (darby Gatran etexilate intermediate) preparation method. Background technique [0002] N-(2-Chloromethyl-1-methyl-1H-benzimidazole-5-yl)-N-(pyridin-2-yl)-3-aminopropionic acid ethyl ester is a new type of product developed and marketed by BoehringerIngelheim, Germany. The important intermediate of anticoagulant dabigatran etexilate (DabigatranEtexilate), its literature report (WO2011061080, etc.) provides a synthetic method, we have carried out the synthesis, the main problem is that N-(pyridin-2-yl )-N-(4-methylamino-3-nitrobenzoyl)-3-alanine ethyl ester solubility problem, resulting in the hydrogenation reaction requires a large amount of solvent to dissolve, and the recovery rate and purity are low. Contents of the invention [0003] The technical problem to be solved by this invention is to provide a...

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 林志刚刘艳琴徐军江岳恒蔡彤
Owner ABA CHEM CORP
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