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Production process of pradaxa mesylate

A technology for dabigatran etexilate mesylate and a production process, which is applied in the field of drug synthesis, can solve the problems of difficult separation of final products and intermediates, unfavorable industrialization of column chromatography separation, and difficulty in accurate quantification of solution concentration, and shortens the production cycle. , good color, low moisture content

Active Publication Date: 2018-11-02
JIANGXI GUOYAO PHARMA LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The total yield of this synthetic route is low, the total yield is 36.6%, the separation of the final product and the intermediate is difficult, and a large amount of hydrogen chloride gas is needed to synthesize the benzamidine intermediate, which seriously corrodes the equipment and causes environmental pollution
The second step uses thionyl chloride, which is not conducive to pilot production; the third step uses palladium carbon hydrogenation, the cost is relatively high, and the risk is strong; in the literature, the product of each step is mostly separated by column chromatography, which is also Not conducive to pilot production
[0007] 3. The synthetic condition of dabigatran etexilate intermediate amidinization reported in the document "Xing Songsong et al. The synthesis of dabigatran etexilate. Chinese Journal of Pharmaceutical Industry, 2010, 41 (5): 321-325. Hydrogen chloride gas and ammonia gas are cumbersome to post-process, and the yield is about 70%, and they need to be purified by column chromatography, which is not suitable for industrial production;
[0008] 4. The synthesis condition used in the literature "Zhu Jinjin et al. Chinese Medicinal Chemistry, 2012, 22(3): 204-208" is to react with hydroxylamine hydrochloride and then reduce the amidine product with ammonium formate and Pd / C. This condition needs to be Catalyzed by precious metal palladium under nitrogen protection, the cost is high, and column chromatography purification is also required, and the yield is 67%
[0009] 5. The literature "Cai Zhiqiang et al. Synthetic process improvement of dabigatran etexilate. Fine Chemical Industry. 2015, 32(3): 308-311" uses chemical compound Ⅰ as the starting material, and uses zinc chloride Lewis acid to catalyze the Pinner reaction , the cyano alcoholysis, to obtain the intermediate (II), the intermediate II through aminolysis of ammonia ethanol solution to obtain the amidinated product III, intermediate III and n-hexyl chloroformate acylation to obtain dabigatran etexilate IV, although using Hydrogen chloride ethanol solution, but the preparation of the solution also requires the operation of passing hydrogen chloride gas, and the solution concentration is difficult to accurately quantify
In addition, the operation of column chromatographic separation is obviously not conducive to industrialization

Method used

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  • Production process of pradaxa mesylate
  • Production process of pradaxa mesylate
  • Production process of pradaxa mesylate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] A kind of production technique of dabigatran etexilate mesylate, comprises the following steps:

[0072] Preparation of S1 intermediate PR-I

[0073] Add 1 kg of organic solvent a, 1 kg of SM2, and 1 kg of CDI to the reaction kettle in turn, stir and react at 10-50 ° C for 2.5 hours, then add 1 kg of SM1 and 1 kg of organic solvent b in sequence, continue to stir and react for 11 hours, evaporate the solvent under reduced pressure at 35 ° C, and transfer to the reaction kettle Put acetic acid into the kettle, heat to 100°C to react for 4.5 hours, evaporate the solvent under reduced pressure below 100°C, add dichloromethane and stir to dissolve, wash with water, recover the solvent under reduced pressure in the organic phase, add ethyl acetate to the obtained residue and stir Until dissolved, add a solution containing oxalic acid dihydrate, stir and crystallize at 20°C for 1.5 hours, centrifuge filter, wash the filter cake with ethyl acetate, and dry the filter cake unde...

Embodiment 2

[0099] A kind of production technique of dabigatran etexilate mesylate, comprises the following steps:

[0100] Preparation of S1 intermediate PR-I

[0101] Add 1 kg of organic solvent a, 1.5 kg of SM2, and 1.2 kg of CDI to the reaction kettle in sequence, stir and react at 10-50 ° C for 3 hours, then add 1 kg of SM1 and 1 kg of organic solvent b in sequence, continue to stir and react for 12 hours, evaporate the solvent under reduced pressure at 40 ° C, Put acetic acid into the reaction kettle, heat to 110°C and react for 5 hours, evaporate the solvent under reduced pressure below 100°C, then add dichloromethane and stir to dissolve, wash with water, recover the solvent under reduced pressure in the organic phase, add ethyl acetate to the obtained residue Stir the ester until dissolved, add a solution containing oxalic acid dihydrate, stir and crystallize at 22°C for 2 hours, centrifugally filter, wash the filter cake with ethyl acetate, dry the filter cake under reduced pres...

Embodiment 3

[0126] A kind of production technique of dabigatran etexilate mesylate, comprises the following steps:

[0127] Preparation of S1 intermediate PR-I

[0128] Add 1 kg of organic solvent a, 1.8 kg of SM2, and 1.3 kg of CDI to the reaction kettle in sequence, stir and react at 10-50 °C for 4 hours, then add 1 kg of SM1 and 1 kg of organic solvent b in sequence, continue to stir and react for 11.5 hours, evaporate the solvent under reduced pressure at 45 °C, Put acetic acid into the reaction kettle, heat to 105°C and react for 5 hours, distill off the solvent under reduced pressure below 100°C, add dichloromethane and stir to dissolve, wash with water, recover the solvent under reduced pressure in the organic phase, add ethyl acetate to the obtained residue Stir the ester until dissolved, add a solution containing oxalic acid dihydrate, stir and crystallize at 23°C for 2 hours, centrifugally filter, wash the filter cake with ethyl acetate, dry the filter cake under reduced pressur...

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Abstract

The invention discloses a production process of pradaxa mesylate. The production process comprises the following steps: (1) preparing an intermediate PR-I; (2) preparing an intermediate PR-II; (3) preparing pradaxa PR-III; (4) refining the pradaxa PR-III; and (5) preparing pradaxa mesylate. The production process is mild in reaction condition, simple in reaction route, convenient in operation, high in selectivity, and capable of shortening the production period; and the obtained pradaxa intermediate is low in water content, the prepared pradaxa mesylate is high in yield and purity, and the maximum impurity is low in impurity content; and the production process is less in emission of three wastes, environmentally friendly, free from requiring the columnar chromatography purification, suitable for the industrialized production, capable of avoiding the requirement of palladium-on-carbon high-pressure hydrogenation on equipment and capable of reducing the risk.

Description

technical field [0001] The invention relates to a production process of dabigatran etexilate mesylate, which belongs to the field of drug synthesis. Background technique [0002] Dabigatran etexilate mesylate 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. In October 2010, it was approved by the FDA to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation. Dabigatran etexilate is the first new oral direct anticoagulant drug marketed in 50 years after warfarin. The launch of dabigatran etexilate mesylate is a major breakthrough in the field of anticoagulation therapy and the prevention of potentially fatal thrombosis, which is a milestone. The chemical structural formula of dabigatran etexilate mesylate is as follows: [0003] [0004] Several synthetic methods about the preparation of dabigatran etexilate ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 李恒农万义斌葛友群左飞鸿余承祥杨明李进进于莲欣刘林华姚文涛柒伟超
Owner JIANGXI GUOYAO PHARMA LLC
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