A kind of production technology of dabigatran etexilate mesylate

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 ...

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

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