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Preparation method of dabigatran etexilate intermediate

A technology for dabigatran etexilate and intermediates, which is applied in the field of preparation of dabigatran etexilate intermediates, can solve the problems that the reaction is easily affected by moisture, the problems of product quality and yield, and the yield is not high, and the operation is achieved. Reduced steps, easy operation and strong selectivity

Active Publication Date: 2015-03-25
BENGBU BBCA MEDICINE SCI DEV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Its synthesis is prepared by chemical synthesis, the operation is cumbersome, the yield is generally not high, and the reaction is easily affected by moisture, which leads to problems in product quality and yield

Method used

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  • Preparation method of dabigatran etexilate intermediate
  • Preparation method of dabigatran etexilate intermediate
  • Preparation method of dabigatran etexilate intermediate

Examples

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Embodiment 1

[0039] Dabigatran etexilate intermediate β-alanine-N-[[1-methyl-1H-benzimidazole-2-chloromethyl]-5-carbonyl]-N-2-pyridine- The preparation method of ethyl ester comprises the following steps:

[0040] (1) Intermediate 3-[4-methylamino-3-amino-N-(2-pyridyl)-benzamido]-ethyl acrylate 100g and ethyl chloroacetate 35.8g (molar ratio is 1 : 1) Add to 300ml of acetone and stir to dissolve, add 30g of immobilized enzyme Novozym435 into the reaction solution, stir at 25°C for 15h, and the liquid phase detection raw material reaction is complete;

[0041] (2) Remove the immobilized enzyme Novozym435 by filtration, evaporate the reaction solvent acetone, add 400 ml of ethyl acetate and 200 ml of purified water to wash and extract, and collect the organic layer;

[0042] (3) The ethyl acetate of the organic layer was evaporated, and the obtained oil was added to 200ml of glacial acetic acid and reacted at 105°C for 2h;

[0043] (4) After the reaction is complete, remove glacial acetic ...

Embodiment 2

[0045] The difference between this example and Example 1 is that the acetone in step (1) is replaced by tetrahydrofuran, the yield of the product obtained is 76%, and the purity of the liquid phase test is 94%.

Embodiment 3

[0047] The difference between this example and Example 1 is that the acetone in step (1) is replaced by dichloromethane, the yield of the product obtained is 79%, and the purity of the liquid phase detection is 93%.

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Abstract

The invention discloses a preparation method of a dabigatran etexilate intermediate. The method comprises the major steps of (1) adding 3-[4-methylamino-3-amino-N-(2-pyridyl)-benzamido]-ethyl acrylate and ethyl chloroacetate to a reaction solution to mix and dissolve, and then adding immobilized enzyme to react; (2) removing immobilized enzyme after the reaction is finished to obtain organic layers; (3) distilling the organic layers to remove a reaction solvent so as to obtain an oily substance, and then adding acetic acid for reflux reacting; (4) distilling to remove glacial acetic acid after the reaction is finished, adding ethyl acetate and purified water, extracting, drying all obtained organic layers by distilling to obtain beta-alanine-N-[[1-methyl-1H-benzimidazole-2-chloromethyl]-5-carbonyl]-N-2-pyridine-ethyl ester. The method is simple to operate, mild under reaction conditions, easy to prepare a high-purity product, and high in product yield; in addition, the enzyme can be recycled, so that the preparation method has a good industrial application prospect.

Description

technical field [0001] The invention relates to the fields of chemical industry and chemical medicine, in particular to a preparation method of a dabigatran etexilate intermediate. Background technique [0002] Dabigatran etexilate, a new oral anticoagulant drug developed by Boehringer Ingelheim, Germany, is the most cutting-edge new generation of oral anticoagulant direct thrombin inhibitors (DTIs), used to prevent non- Stroke and systemic embolism in patients with valvular atrial fibrillation can provide effective, predictable, and stable anticoagulant effects, and at the same time have the advantages of less drug interactions and no drug-food interactions. Its chemical structure is as follows: [0003] [0004] Boehringer Ingelheim, Germany, disclosed an improved method for preparing dabigatran etexilate in patent CN 102612517 in 2012. The synthetic route is as follows: [0005] [0006] [0007] In the above synthetic route, β-alanine-N-[[1-methyl-1H-benzimid...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 鲍鹤龄孙建华李立标郑爱林文龙
Owner BENGBU BBCA MEDICINE SCI DEV
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