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Industrial preparation method of dabigatran

A technology of dabigatran etexilate and compounds, which is applied in the field of industrial preparation of dabigatran etexilate, can solve the problem of difficulty in realizing the industrial scale preparation of dabigatran etexilate and intermediates, the absence of established and perfect quality standards for raw materials and intermediates, Unable to guarantee the stability of the final product quality and other issues, to achieve the effect of mild conditions, less pollution and stable quality

Active Publication Date: 2017-03-29
CHENGDU LIKAI CHIRAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are many by-products during the reduction of oxime, and the raw materials are difficult to react completely. The product needs to be separated and purified by column chromatography, and the reduction yield is only 67%, which is not suitable for industrial scale-up.
[0037] In summary, although there are many synthetic methods of dabigatran etexilate reported in the literature, there are obvious defects in these methods, and it is difficult to realize the industrial scale preparation of dabigatran etexilate and intermediates
Especially for the preparation of the intermediate amidine, there is no safe, environmentally friendly, operable and stable and reliable method
On the other hand, in order to ensure the curative effect and safety of clinical medication, the quality standards that various countries formulate to pharmaceutical intermediates and raw materials are getting higher and higher, and the synthetic method of dabigatran etexilate reported in the above-mentioned documents all lacks the technical process. Research and control, without establishing a sound quality standard for raw materials and intermediates, can not guarantee the stability of the quality of the final product, it is difficult to be directly applied to the industrial preparation of dabigatran etexilate

Method used

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  • Industrial preparation method of dabigatran

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] A kind of industrial preparation method of dabigatran etexilate, concrete steps are:

[0069] (1), 3-(3-((2-(4-cyanophenyl)amino)acetamido)-4-(methylamino)-N-(pyridin-2-yl)benzamide) ethyl propionate Preparation of ester (4)

[0070] Pump 200kg of chloroform into the 500L reaction kettle, open the feeding port, and put in 11.3kg of (4-cyanoanilino) acetic acid and 12.2kg of CDI in sequence; ~5 o C, and heat preservation reaction for 3 hours; open the feeding port, slowly drop in 20kg of compound 3 under a slight negative pressure; after the addition is completed, after the refrigerant in the jacket is discharged, pour in tap water and gradually warm up to room temperature, stir and react for 24 hours, then sample HPLC detection, Compound 3 ≤ 1%, compound 4 ≥ 95.0%, stop the reaction; pump in 50kg of water, stir, inject hot water into the jacket for circulation, and recover chloroform (applicable) by vacuum distillation to dryness, and quickly stir the raffinate to dis...

Embodiment 2

[0078] A kind of industrial preparation method of dabigatran etexilate, concrete steps are:

[0079] (1), 3-(3-((2-(4-cyanophenyl)amino)acetamido)-4-(methylamino)-N-(pyridin-2-yl)benzamide) ethyl propionate Preparation of ester (4)

[0080] Pump 200kg of 1,4-dioxane into the 500L reactor, open the feeding port, and put in 11.3kg of (4-cyanoanilino)acetic acid, 13.5kg of EDCI-HCl, and 14.3kg of DMAP in sequence; after feeding, start stirring , the jacket is put into the coolant, and the temperature in the kettle drops to 0-5 o C, and heat preservation reaction for 3 hours; open the feeding port, slowly drop in 20kg of compound 3 under a slight negative pressure; after the addition is completed, after the refrigerant in the jacket is discharged, pour in tap water and gradually warm up to room temperature, stir and react for 24 hours, then sample HPLC detection, Compound 3 ≤ 1%, compound 4 ≥ 95.0%, stop the reaction; pump in 50kg of water, stir, inject hot water into the jacket, ...

Embodiment 3

[0088] A kind of industrial preparation method of dabigatran etexilate, concrete steps are:

[0089] (1) Ethyl 3-(3-((2-(4-cyanophenyl)amino)acetamido)-4-(methylamino)-N-(pyridin-2-yl)benzamide)propionate (4) Preparation

[0090] Pump 1000kg of dichloromethane into the 3000L reactor, open the feeding port, and put in 62kg of (4-cyanoanilino) acetic acid and 62kg of CDI in turn; after feeding, start stirring, put the jacket into the cooling liquid, and the temperature in the kettle will drop to 0 ~5 o C, and heat preservation reaction for 6 hours; open the feeding port, slowly drop into 100kg of compound 3 under a slight negative pressure; after the addition is completed, after the refrigerant in the jacket is discharged, tap water is gradually warmed up to room temperature and stirred for 24 hours, then the sample is detected by HPLC. Compound 3 ≤ 1%, compound 4 ≥ 95.0%, stop the reaction; pump in 250kg of water, stir, inject hot water into the jacket for circulation, distil...

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Abstract

The invention discloses an industrial preparation method of dabigatran, and belongs to the field of medicinal chemistry, wherein the preparation method sequentially comprises a condensation reaction, a closed cyclization reaction, a Pinner reaction, and other steps. According to the present invention, the hydrogen chloride / alcohol / ester solution is prepared by using acyl chloride and alcohol as raw materials, such that the problems of corrosion on equipment, high hidden safety danger, environmental pollution and the like caused by the use of hydrogen chloride gas in the prior art are solved; and the reactions in various steps are subjected to the industrial-scale-based optimization, the unnecessary distillation, extraction and re-crystallization process is reduced, the process is simplified, the purification method of the final product dabigatran is improved, the purification efficiency is increased in the case of the ensuring of the process yield and the product quality, the process reproducibility is good, the preparation cost is low, and the method is the ideal industrial preparation method of the dabigatran.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to an industrial preparation method of dabigatran etexilate. Background technique [0002] Dabigatran etexilate (Dabigatran Etexilate, 1), chemical name: 3-(2-(((4-(N'-((hexyloxy)carbonyl)formamidine)phenyl)amino)methyl)- 1-Methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamide) ethyl propionate is a new type of direct thrombin inhibitor. The drug is the prodrug of dabigatran (Dabigatran, 2), which has the characteristics of oral administration, high safety, few drug interactions, low bleeding risk, and wide application range. It is mainly used clinically to prevent thrombosis in the stroke system And orthopedic postoperative anti-thrombosis and other fields. [0003] [0004] Dabigatran etexilate was developed by Boehringer-Ingelheim (Boehringer-Ingelheim), Germany, and was first launched in Germany and the UK in April 2008 under the trade name of Pradaxa. Since its lau...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 袁伟成龙超久周鸣强徐小英雷三忠王川陈宇袁仕雪
Owner CHENGDU LIKAI CHIRAL TECH
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