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Preparation method of high-purity dabigatran etexilate

A dabigatran etexilate, high-purity technology, applied in the field of preparation of high-purity dabigatran etexilate, can solve problems such as undiscovered removal, and achieve economical and affordable effects

Inactive Publication Date: 2017-01-25
CHANGZHOU SUNLIGHT PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] No literature reports have been found to remove the above-mentioned by-product compound 7

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1）

[0018] The preparation method of the high-purity dabigatran etexilate of the present embodiment has the following steps:

[0019] ①Under nitrogen protection, add 2060mL of ethanol hydrochloric acid solution with a concentration of 8-10wt% to the reaction flask, stir and cool down to 0-10°C, add 171.8g of compound 2 to the reaction flask in batches at this temperature, and finish adding Raise the temperature to 20-30°C, and keep it warm for 14 hours.

[0020] After the reaction, it was concentrated under reduced pressure to about 553.2 g, which was directly used in the next reaction without purification.

[0021] ②Under nitrogen protection, add 1718mL of absolute ethanol to the reaction solution prepared in step ① under stirring, cool down to 0-10°C, add 410.6g of ammonium carbonate in batches at this temperature, and raise the temperature to 20-25°C after adding. ℃, heat preservation reaction for 12h.

[0022] After the reaction, filter with suction, rinse the filter cake wi...

Embodiment 2～ Embodiment 6）

[0027] The preparation method of each embodiment is the same as that of Example 1, except for step ④, see Table 1 for details.

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PUM

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Abstract

The invention discloses a preparation method of high-purity dabigatran etexilate, prepared by subjecting ethyl 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazole-5-yl]carbonyl]pyridine-2-ylamino]propanoate to alcoholysis and aminolysis to obtain a compound 4, and subjecting the compound to esterification reaction with hexyl chloroformate; recrystallization is performed after the esterification reaction; the recrystallization employs a recrystallization solvent that is ethyl acetate, isopropyl acetate or n-butyl acetate. The recrystallization solvent can decrease the content of the byproduct compound 7 in dabigatran etexilate to 1% and below, particularly to 0.5% and below for ethyl acetate, with the loss of dabigatran etexilate less than 5%; the purifying process is economical and practical and is suitable for industrial large-scale production.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and in particular relates to a preparation method of high-purity dabigatran etexilate. Background technique [0002] The chemical name of dabigatran etexilate is: 3-[[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl]phenyl]amino]methyl]-1- Methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester is an oral thrombin inhibitor developed by Boehringer Ingelheim Pharmaceutical Company in Germany, and it is dabigatran The prodrug of the drug, which is a non-peptide thrombin inhibitor, was approved for marketing in Europe in April 2008. [0003] The synthetic method of dabigatran etexilate was first seen in the world patent document WO9837075A1, the synthetic route disclosed in this document is 3-amino-4-methylamino-benzoic acid-N-(2-pyridyl)-N-(2- Ethoxycarbonyl ethyl)-amide (compound 9) and N-(4-cyanophenyl)-glycine (compound 10) as raw materials, fi...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 胡锦平胡国宜汪士金钱王科王江波倪海伟奚小金
Owner CHANGZHOU SUNLIGHT PHARMA
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