A kind of preparation technology of high-purity arolol hydrochloride

Abstract

The invention discloses a preparation process of high-purity arololol hydrochloride, which comprises the following steps: putting an acid-binding agent into an alcohol-water composite solvent, adding compound 5-(2-mercapto-4-thiazole)-2-thienyl Amide, add epichlorohydrin, react at room temperature, filter, and dry to obtain intermediate III; in absolute ethanol, put tert-butylamine, add intermediate III, slightly reflux reaction, concentrate, add purified water, stir, heat and cool to room temperature, Adjust the pH to be acidic, wash with organic solvent, add ethanol to the water layer, heat to dissolve, cool and crystallize, and filter to obtain the crude product; put the crude product in the alcohol-water composite solvent, heat to dissolve, cool and crystallize, filter, and dry to obtain high purity Alolol hydrochloride. The invention can effectively remove the impurities of the arolol hydrochloride, the purity can reach more than 99.95%, and the operation is simple and the yield is high.

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 104356126 A, CN 104370900 A, CN 104530033 A and the bachelor's thesis of Hebei University of Science and Technology adopt intermediate (Ⅲ) Methyl tert-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. This process is cumbersome to operate, not only The second type of toxic solvent toluene is introduced, and the high boiling point solvent dimethyl sulfoxide is easy to form residues; CN 104530033 A uses methanol as a solvent and Lewis acid as a catalyst for the preparation of intermediate (Ⅲ) to prepare relatively pure intermediate (Ⅲ), Then acetonitrile is used as a solvent to open the ring with tert-butylamine, hydrochloric acid is used to adjust the pH value to form a salt, and finally recrystallized 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. The disclosed purity, and the preparation of intermediate (Ⅲ) introduces second-class toxic solvent methanol and Lewis acid, which is easy to cause 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.

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