Synthesis method of terbutaline and application of terbutaline in preparation of terbutaline sulfate

Abstract

The invention discloses a synthesis method of terbutaline, which is characterized by comprising the following steps: (1) reacting 3, 5-dimethoxyacetophenone with tetrabutylammonium tribromide to obtain 2-bromo-1-(3, 5-dimethoxyphenyl)ethanone; (2) reacting the 2-bromo-1-(3, 5-dimethoxyphenyl)ethanol with a reducing agent in methanol to obtain 2-bromo-1-(3, 5-dimethoxyphenyl)ethanol; (3) carrying out cyclization reaction on the 2-bromo-1-(3, 5-dimethoxyphenyl)ethanol under an alkaline condition to generate 2-(3, 5-dimethyloxy) ethylene oxide; (4) carrying out a reaction on the 2-(3, 5-dimethyloxy) ethylene oxide and tert-butylamine to generate 1-(3, 5-dimethoxyphenyl)-2-tert-butylamino-ethanol; and (5) hydrolyzing under an acidic condition to obtain a salt of 1-(3, 5-dihydroxyphenyl)-2-tert-butylamino-ethanol, namely terbutaline. The total molar yield is about 60% and is far higher than the yield in the prior art, and the synthesis method of terbutaline and the application of terbutaline in the preparation of terbutaline sulfate are suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of chemical pharmacy, and in particular relates to a synthesis method of terbutaline and its application in preparing terbutaline sulfate. Background technique [0002] Terbutaline sulfate, also known as hydroxyalbutaline and terbutaline, is a highly selective short-acting β2-receptor agonist dosage form developed by AstraZeneca. It has a bronchodilation effect and is clinically used for the treatment of Bronchial asthma, chronic and asthmatic bronchitis, emphysema and other diseases are clinically recommended drugs for patients with mild and moderate chronic obstructive pulmonary disease (COPD). Compared with other marketed short-acting β2-receptor agonists, terbutaline sulfate inhalation has lower dose-dependent side effects. At present, the synthetic route of terbutaline sulfate mainly contains following several kinds. [0003] The synthetic route of US Patent US3937838 is based on 3,5-hydroxybenzoic acid as the ...

AI Technical Summary

Problems solved by technology

The price of bambuterol hydrochloride is relatively high, and it is not suitable as a starting material for the preparation of terbutaline sulfate. At the same time, the reaction route is short, and it is not suitable as a declared process. The total molar yield is about 50%.

[0006] At present, the synthetic routes reported at home and abroad are similar, and most of the synthetic processes use highly toxic reagents, high-risk reactions of Pd / C hydrogenation, or expensive starting materials, etc.

At the same time, most of the preparation process of the final product of terbutaline sulfate adopts the method of concentrating the solvent at the end of the reaction and adding methanol to crystallize, which increases the difficulty of operation.

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