Preparation method of arotinolol hydrochloride intermediate

High-purity 5-acetylthiophene-2-carboxylic acid was prepared by esterification, bromination and ethoxyvinylation of thiophene-2-carboxylic acid, which solved the problems of high equipment requirements, large amount of hazardous waste and insufficient safety in the existing technology, and realized the efficient industrial production of aprolol hydrochloride intermediate.

CN121471196AActive Publication Date: 2026-02-06JINAN GUODING PHARM TECH CO LTD
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Patent Information

Application Number
CN202610021422.X
Authority / Receiving Office
CN · China
Patent Type
Applications(China)
Current Assignee / Owner
Filing Date
2026-01-08
Publication Date
2026-02-06
Estimated Expiration
2046-01-08

AI Technical Summary

Technical Problem

Existing synthetic routes for aprololol hydrochloride intermediates suffer from problems such as high equipment requirements, large amounts of hazardous waste, and insufficient safety, making it difficult to achieve industrial-scale production and high yields.

Method used

5-Acetylthiophene-2-carboxylic acid was prepared by a four-step reaction involving esterification, selective bromination, Pd-catalyzed ethoxyvinylation, and acid-promoted hydrolysis of thiophene-2-carboxylic acid, using diethyl sulfate, an NBS/p-toluenesulfonic acid system, and a tetrakis(triphenylphosphine)palladium catalyst, avoiding the use of toxic or highly corrosive reagents, under mild conditions.

Benefits of technology

The preparation of high-purity, high-yield apronolol hydrochloride intermediates has been achieved, which is suitable for industrial scale-up and green production. The overall process is simple, with few by-products and a product purity of up to 99.0%.

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Abstract

The invention discloses a preparation method of an arotinolol hydrochloride intermediate. The preparation method comprises the following steps: S1, reacting thiophene-2-carboxylic acid with an esterification reagent under the action of carbonate to obtain thiophene-2-ethyl formate; s2, enabling the thiophene-2-ethyl acetate to react with a bromination reagent, so as to obtain 5-bromothiophene-2-ethyl formate; s3, the 5-bromothiophene-2-ethyl formate and tributyl (1-ethyoxyl ethylene) tin react under the action of a catalyst, and 5-ethyoxyl vinyl-2-ethyl formate is obtained; and S4, hydrolyzing the 5-ethoxy vinyl-2-ethyl formate under an acidic condition, so as to obtain the 5-acetyl thiophene-2-formic acid. Compared with the prior art, the method has the advantages that toxic or strong corrosive reagents are not used, the total yield is high, the product purity (gt, 99.0%) is high, and the method is suitable for industrial amplification and green production.
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