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Improved method for preparing Dabigatran etexilate

A technology of dabigatran etexilate and molar ratio, applied in the field of preparation of dabigatran etexilate, can solve problems such as waste acid treatment and industrial production troubles

Active Publication Date: 2016-02-24
BENGBU BBCA MEDICINE SCI DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] In the preparation method of dabigatran etexilate described in the current patent WO98 / 37075, WO2012 / 152855, a large amount of hydrogen chloride ethanol solution is used in the process of nitrilation amidine, which brings great trouble to industrial production, and Causes a large amount of waste acid to be disposed of

Method used

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  • Improved method for preparing Dabigatran etexilate
  • Improved method for preparing Dabigatran etexilate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Add 250mL of absolute ethanol to the reaction bottle, add 72.4g of the compound of formula 1 under stirring, add 15.6g of hydroxylamine hydrochloride after dissolving, then raise the temperature to 58°C, slowly add 72.9g of 21% sodium ethylate in ethanol solution dropwise, and dropwise Afterwards, keep the reaction at 58°C for 23 hours, lower the temperature to 0-5°C and stir for 1 hour, filter, and wash the filter cake with 30 mL of absolute ethanol to obtain the compound of formula 2.

[0031] Add the above solid (that is, the compound of formula 2) into the reaction flask, add 300mL of purified water, stir and add 1.0g of 10% Pd / C, heat up to 70°C, slowly add 9.0g of glacial acetic acid dropwise, and stir for 3 hours after the drop is complete , filtered, added 16.8mL of concentrated hydrochloric acid to the mother liquor, concentrated until solids precipitated, added 180mL of acetone, stirred and cooled to below 5°C for crystallization for 1 hour, filtered, and vacuu...

Embodiment 2

[0034] Add 250mL of absolute ethanol to the reaction bottle, add 72.4g of the compound of formula 1 under stirring, add 15.6g of hydroxylamine hydrochloride after dissolving, then raise the temperature to 58°C, slowly add 72.9g of 21% sodium ethylate in ethanol solution dropwise, and dropwise Afterwards, keep the reaction at 58°C for 23 hours, lower the temperature to 0-5°C and stir for 1 hour, filter, and wash the filter cake with 30 mL of absolute ethanol to obtain the compound of formula 2.

[0035] Put the above solid into the reaction bottle, add 300mL of purified water, stir and add 21.0g of reduced iron powder, raise the temperature to 70°C, slowly add 9.0g of glacial acetic acid dropwise, stir and react for 3 hours after dropping, filter, add 16.8mL of mother liquor Concentrated hydrochloric acid, concentrated until solids precipitated, added 180mL of acetone, stirred and cooled to below 5°C for crystallization for 1 hour, filtered, and vacuum dried at 50°C to obtain 60...

Embodiment 3

[0038] Add 250mL of methanol to the reaction flask, add 72.4g of the compound of formula 1 under stirring, add 10.4g of hydroxylamine hydrochloride after dissolving, then raise the temperature to 55°C, slowly add 38.6g of 21% methanol solution of sodium methoxide dropwise, and keep React at 55°C for 25 hours, lower the temperature to 0-5°C and stir for 1 hour, filter, wash the filter cake with 30 mL of methanol, and obtain the compound of formula 2.

[0039] Add the above solid (that is, the compound of formula 2) into the reaction flask, add 300mL of purified water, stir and add 8.4g of reduced iron powder, raise the temperature to 50°C, slowly add 9.0g of glacial acetic acid dropwise, and stir for 5 hours after the dropwise reaction. Filtrate, add 16.8mL of concentrated hydrochloric acid to the mother liquor, concentrate until solid precipitates, add 160mL of acetone, stir and cool down to below 5°C for crystallization for 1 hour, filter, and vacuum dry at 50°C to obtain 61.2...

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Abstract

The invention relates to a method for preparing Dabigatran etexilate. The method comprises the specific steps of enabling a compound represented by a formula 1 shown in the description, i.e., 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl] pyrid-2-ylamino]ethyl propionate to subject to addition reaction with hydroxylamine hydrochloride in the presence of a catalyst in an alcoholic solution, so as to obtain a compound represented by a formula 2 shown in the description, reducing the compound represented by the formula 2 so as to obtain a compound represented by a formula 3 shown in the description, and enabling the compound represented by the formula 3 to subject to amidation reaction with n-hexyl chloroformate in the presence of a catalyst, thereby obtaining a compound represented by a formula 4 shown in the description, i.e., Dabigatran etexilate. Compared with the prior art, the preparation process disclosed by the invention has the advantages that the generation of a large volume of waste acid in the prior art is avoided, the reaction conditions are mild, the control is easy, the yield is high, and the product quality is good, thereby being applicable to industrial production.

Description

technical field [0001] The invention relates to the field of compound synthesis, in particular to an improved method for preparing dabigatran etexilate. Background technique [0002] Dabigatran (Dabigatran) was first disclosed in the international patent WO98 / 37075, and was later developed and marketed by the German company Boehringer Ingelheim (Boehringer Ingelheim). It is a new type of oral anticoagulant drug. The drug was first launched in Germany and the UK in April 2008, and was approved by the US FDA in October 2010 to reduce the risk of stroke and provincial embolism in patients with non-valvular atrial fibrillation. The drug has the characteristics of oral administration, strong potency, no need for special drug monitoring, and few drug interactions, so the market demand is relatively large. [0003] In the preparation method of dabigatran etexilate described in the current patent WO98 / 37075, WO2012 / 152855, a large amount of hydrogen chloride ethanol solution is use...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 李立标张瑾郑爱张杰胡媛
Owner BENGBU BBCA MEDICINE SCI DEV
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