High-purity fasudil hydrochloride preparation method

Abstract

The invention discloses a high-purity fasudil hydrochloride preparation method which comprises the following steps: using homopiperazine and isoquinoline-5-sulphonyl chloride hydrochloride as raw materials, and using absolute ethyl alcohol to dissolve homopiperazine; using dichloromethane to dissolve isoquinoline-5-sulphonyl chloride hydrochloride, adding anhydrous sodium sulfate and solid sodium bicarbonate, reacting on a homopiperazine ethanol solution with an isoquinoline-5-sulfonyl chloride solution, performing concentration and crystallization under reduced pressure for many times, and finally performing filtration and drying to prepare high-purity fasudil hydrochloride. The high-purity fasudil hydrochloride prepared through the preparation method disclosed by the invention has an impurity content less than 0.1% and a purity more than 99.9%. The preparation method has the advantages of safety, environmental protection, low production cost, high production quality, convenience in operation and the like.

Description

technical field [0001] The invention relates to a preparation method of high-purity fasudil hydrochloride, and belongs to the technical field of medicine. Background technique [0002] Fasudil hydrochloride, chemical name: hexahydro-1-(5-isoquinolinesulfonyl)-1H-1,4-diazepine hydrochloride, molecular formula: C 14 H 17 N 3 O 2 S·HCl, molecular weight is 327.83, English name: Fasudil Hydrochloride. [0003] Its chemical structure is as follows: [0004] [0005] Fasudil hydrochloride is an isoquinoline sulfonamide drug developed by Japan's Asahi Kasei (Asahi Kasei) Co., Ltd. in the 1980s. It is a protein kinase RHO inhibitor (intracellular calcium ion antagonist), which blocks vasoconstriction by The final stage of the process, that is, by increasing the activity of myosin hydrogen chain phosphatase, dilating blood vessels (inhibiting vasospasm), and reducing the tension of endothelial cells, it exerts its medicinal effect, thereby improving the microcirculation of br...

AI Technical Summary

Problems solved by technology

[0007] 1. After alkalization, isoquinoline-5-sulfonyl chloride hydrochloride is extremely unstable in water and easily hydrolyzed, affecting the yield of the finished product and bringing impurities into the finished product;

[0008] 2. Homopiperazine is easy to degrade and produce a small amount of impurities during the storage process. When dichloromethane is used as a solvent to dissolve homopiperazine solids, violent polymerization reactions are likely to occur, and a large amount of heat is released to cause an explosion and cause a safety accident;

[0009] 3. Isoquinoline-5-sulfonyl chloride dichloromethane solution and homopiperazine react one-step impurity and are difficult to remove; although Chinese patent CN102020636A relates to the purification method of Fasudil hydrochloride in the prior art, that is, first pass Treat 5-isoquinolinesulfonic acid under SOCl2 / DMF conditions to prepare 5-isoquinolinesulfonic acid chloride hydrochloride, adjust the pH to neutral with NaHCO3 aqueous solution, extract with dichloromethane, and react dichloromethane solution with homopiperazine Dichloromethane solution of Fasudil

Chinese patents CN102002036, CN101812051, CN101962379, CN1183782, CN101092413, US5942505, etc. all relate to how to purify and refine Fasudil hydrochloride, specifically including methods such as changing column chromatography purification eluent, changing recrystallization solvent, resin adsorption, etc., but these methods will Increase working hours and produce a large amount of organic waste liquid;

[0010] 4. In order to avoid generation of side reaction product dimer in the synthetic process of fasudil hydrochloride, prior art such as CN201010558960.1 adopts to improve the feeding ratio of homopiperazine to prevent the generation of side reaction product dimer, homopiperazine and iso The mass ratio of quinoline-5-sulfonyl chloride is as high as 2-4:1, and the amount of homopiperazine input is very large, but the price of homopiperazine is relatively high, resulting in high production costs

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