Preparation process for arotinolol hydrochloride with high purity

Abstract

The invention discloses a preparation process for arotinolol hydrochloride with high purity. The preparation process comprises the following steps: pouring an acid-binding agent into an alcohol-watercompounded solvent, adding a compound namely 5-(2-sulfhydryl-4-thiazole)-2-thiophenecarboxamide, then adding epichlorohydrin, carrying out a reaction at a room temperature, and carrying out filteringand drying so as to obtain an intermediate III; pouring tert-butylamine into anhydrous ethanol, adding the intermediate III, carrying out a micro-reflux reaction, carrying out concentration, adding purified water, carrying out dissolving under heating, carrying out cooling, adjusting the pH value of an obtained solution to be acidic, carrying out washing with an organic solvent, adding ethanol into an aqueous layer, carrying out dissolving under heating, and carrying out cooling crystallization, and carrying out filtering so as to obtain a crude product; and pouring the crude product into an alcohol-water compounded solvent, carrying out dissolving under heating, and carrying out cooling crystallization, filtering and drying so as to obtain the arotinolol hydrochloride with high purity. The preparation process provided by the invention can effectively remove impurities from arotinolol hydrochloride, can reach a purity of 99.95% or above, and has simple operation and high yield.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a preparation process of high-purity arololol hydrochloride. Background technique [0002] Alolol hydrochloride was developed by Sumitomo Pharmaceutical Co., Ltd. of Japan. It was first launched in Japan in 1985 and registered for domestic import in 1996. Alololol hydrochloride is the 4th generation of β receptor blocker, without intrinsic sympathomimetic activity, this product has β receptor block effect and moderate α receptor block effect, the ratio of the strength of the two is 8 : 1. It can increase curative effect, reduce adverse reactions, does not affect blood lipid and glucose metabolism, and has no adverse effect on renal function. It is mainly used clinically to treat mild to moderate essential hypertension, angina pectoris, tachycardia arrhythmia and essential vibration. [0003] J.Phmarmaceutical Sciences, 67 (9), 1978, EPO245835, JP0413918, Progress in P...

AI Technical Summary

Problems solved by technology

Because arolol hydrochloride has low solubility in various solvents, it is slightly soluble in methanol and water, very slightly soluble in absolute ethanol, almost insoluble in chloroform and ether, and only in high boiling point solvent dimethyl sulfoxide It is easy to dissolve, so it is difficult to remove the impurities of this product, and the recrystallization with water and alcohol composite solvent cannot effectively remove the impurities of this product

In order to improve the purity of this product, the existing patents and documents adopt a variety of different and complicated post-processing and refining methods. Documents such as CN 104356126A, CN 104370900A, CN 104530033A and the bachelor’s thesis of Hebei University of Science and Technology use methyl tertiary Butyl ether beating, the crude product of intermediate (Ⅳ) alolol is beating with toluene first, and finally the high boiling point solvent dimethyl sulfoxide is used to dissolve into salt, and acetone is added to disperse and cool down to crystallize. Toluene is a toxic solvent, and the high boiling point solvent dimethyl sulfoxide is easy to form residues; CN 104530033A uses methanol as a solvent for the preparation of intermediate (Ⅲ), Lewis acid as a catalyst to prepare a relatively pure intermediate (Ⅲ), and then acetonitrile as a solvent Open the ring with tert-butylamine, adjust the pH value with hydrochloric acid to form a salt, and finally recrystallize with alcohol and water composite solvent. This process is relatively simple to operate, but it has been proved that simple alcohol and water composite solvent recrystallization cannot effectively remove impurities and achieve the purity disclosed in the patent. And the preparation of intermediate (Ⅲ) introduces second-class toxic solvent methanol and Lewis acid, which easily causes metal ion residues, and the yield is low (about 78%)

[0007] Based on the pharmaceutical value and good market prospect of Alololol hydrochloride, and the process of removing impurities in the existing technology is relatively cumbersome, the yield is low, and a variety of toxic second-class solvents or high-boiling point solvents are used.

Images