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A kind of method that enzymatic reaction prepares main intermediate of dabigatran etexilate

A technology of dabigatran etexilate and enzymatic reaction, which is applied in the fields of chemical industry and chemical medicine, can solve the problems of affecting the yield, cumbersome operation, and low yield, and achieve the advantages of simple operation, improved reaction yield, and strong selectivity Effect

Active Publication Date: 2017-08-11
BENGBU BBCA MEDICINE SCI DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The traditional method of this step is cumbersome to operate, and the yield is generally not high
The catalysts used, such as CDI or EDCl, have high activity and are not easy to store and open for a long time. They are easy to deteriorate and affect the yield of this step.

Method used

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  • A kind of method that enzymatic reaction prepares main intermediate of dabigatran etexilate
  • A kind of method that enzymatic reaction prepares main intermediate of dabigatran etexilate
  • A kind of method that enzymatic reaction prepares main intermediate of dabigatran etexilate

Examples

Experimental program
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Effect test

Embodiment 1

[0032] The intermediate 3-[4-methylamino-3-amino-N-(2-pyridyl)-benzamido]-acrylic acid ethyl ester 100g and the intermediate 2-(4-cyanoanilino)acetic acid 51.4 The molar ratio of g is 1:1. Add it into tetrahydrofuran to dissolve, add 30g of immobilized enzyme Novozym435 into the reaction solution, and stir at room temperature for 24h. Liquid phase detection raw material reaction is complete.

[0033] Remove the immobilized enzyme Novozym435 by filtration, distill off the solvent tetrahydrofuran, add 400ml of ethyl acetate and 200ml of purified water to wash, distill off the ethyl acetate, add the obtained oil to 200ml of glacial acetic acid and react at 110°C for 2 hours after the reaction is complete, distill off the acetic acid, add Wash with 400 ml of ethyl acetate and 200 ml of purified water, and evaporate the ethyl acetate to obtain the product. The yield was 75%, and the purity by liquid phase detection was 92%.

Embodiment 2

[0035] The intermediate 3-[4-methylamino-3-amino-N-(2-pyridyl)-benzamido]-acrylic acid ethyl ester 100g and the intermediate 2-(4-cyanoanilino)acetic acid 51.4 The molar ratio of g is 1:1. Add it into 400ml of dichloromethane to form a suspension, add 30g of immobilized enzyme Novozym435 into the reaction solution, and stir at room temperature for 24h. Liquid phase detection raw material reaction is complete.

[0036] Remove the immobilized enzyme Novozym435 by filtration, wash with 200ml of purified water, distill off the dichloromethane, add the obtained oil to 200ml of glacial acetic acid at 110°C for 2 hours, and after the reaction is complete, evaporate the acetic acid, add 400ml of ethyl acetate and wash with 200ml of purified water. Ethyl acetate was evaporated to obtain the product with a yield of 78% and a liquid phase detection purity of 94%.

Embodiment 3

[0038] The intermediate 3-[4-methylamino-3-amino-N-(2-pyridyl)-benzamido]-acrylic acid ethyl ester 100g and the intermediate 2-(4-cyanoanilino)acetic acid 51.4 The molar ratio of g is 1:1. Add it to 300ml of dichloromethane to form a suspension, add 100ml of ionic liquid [bmim]BF4 and add 30g of immobilized enzyme Novozym435 to the reaction solution, and stir at room temperature for 10h. Liquid phase detection raw material reaction is complete.

[0039] Remove the immobilized enzyme Novozym435 by filtration, evaporate the solvent dichloromethane, add 400ml of ethyl acetate to separate the organic layer, wash the organic layer with 200ml of purified water, evaporate the ethyl acetate, add the obtained oil to 200ml of glacial acetic acid and react at 110°C After 2 hours of reaction, evaporate the acetic acid, add 400ml of ethyl acetate and 200ml of purified water for washing, and evaporate the ethyl acetate to obtain the product. The yield was 81%, and the purity by liquid pha...

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Abstract

The invention discloses a method for preparing a main intermediate of dabigatran etexilate through enzymatic reaction. The main steps are as follows: first, 3-[4-methylamino-3-amino-N-(2-pyridyl)-benzamido]-ethyl acrylate and 2-(4-cyano aniline) acetic acid are added in a reaction solvent, mixed and dissolved; immobilized enzyme Novozym 435 is added and reaction is carried out; second, after the reaction is finished, the immobilized enzyme Novozym 435 is removed through filtration, an organic phase layer and a filtrate are obtained; third, the obtained organic layer is subjected to solvent evaporation, and an oil-like substances are obtained, acetic acid is added and a reflux reaction is carried out; fourth, after the reaction is finished, acetic acid is evaporated, ethyl acetate and an alkaline solution are added, washing and extraction are carried out, the obtained organic layer is subjected to drying by distillation, and 3-[[[2-[[(4-cyano phenyl)amino] methyl]-1-methyl-1H-benzimidazole-5-group] carbonyl] pyridine-2-group amino] ethyl propionate ethyl ester. The method has simple operations and mild reaction conditions, the product with high purity is easy to obtain, the yield is high and the method is suitable for industrial amplification production.

Description

technical field [0001] The invention relates to a preparation method of an important intermediate of dabigatran etexilate. It belongs to the field of chemical industry and chemical medicine. Background technique [0002] Dabigatran etexilate is a new oral anticoagulant drug developed by Boehringer Ingelheim, Germany. In April 2008, it was first launched in Germany and the UK under the trade name of Pradaxa, and its chemical structure is as follows: [0003] [0004] At present, many documents and patents have introduced the synthesis of dabigatran etexilate. In these synthetic routes, most of 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1- Methyl-1H-benzimidazol-5-yl]carbonyl]pyridin-2-ylamino]ethyl propionate is an important intermediate in the synthesis of dabigatran etexilate. [0005] Such as: US Patent WO2012152855 and WO2010045900, the steps are as follows [0006] [0007] Such as US Patent WO2009111997, the steps are as follows: [0008] [0009] 3-[[[2-[[(4-c...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12P17/16
CPCY02P20/54
Inventor 郑爱孙建华张瑾陈昀
Owner BENGBU BBCA MEDICINE SCI DEV
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