Preparation method of terbutaline sulfate and B crystal form thereof

Abstract

The invention relates to a preparation method of terbutaline sulfate and a B crystal form thereof, which comprises the following steps: sequentially carrying out bromination, reduction reaction and substitution reaction to obtain 1-[3, 5-bis (benzyloxy) phenyl]-2-(tert-butylamino) ethanol; reacting 1-[3, 5-di (benzyloxy) phenyl]-2-(tert-butylamino) ethanol with a reducing agent and a catalyst, performing salifying with sulfuric acid to obtain a terbutaline sulfate crude product, and crystallizing the terbutaline sulfate crude product under a heating reflux condition to obtain the terbutaline sulfate medicinal B crystal form. Raw materials and auxiliary materials used in the method are cheap and easy to obtain, highly toxic and explosive reagents are avoided in the reaction process, the whole reaction route is short, operation is easy and convenient, reaction conditions are mild and safe, the yield of the obtained finished product terbutaline sulfate and the medicinal B crystal form thereof is high, the yield of terbutaline sulfate is 83% or above, and the yield of the medicinal B crystal form is 70% or above, and industrialized production can be achieved easily.

Description

technical field [0001] The invention relates to the technical field of chemical drug synthesis, in particular to a preparation method of terbutaline sulfate and its B crystal form. Background technique [0002] Terbutaline Sulfate, also known as hydroxyalbutaline, can selectively stimulate β2 receptors to relax bronchial smooth muscle. Clinically, it is mainly used for bronchial asthma, asthmatic bronchitis and chronic obstructive pulmonary disease. treatment of bronchospasm. It was first developed by AstraZeneca Pharmaceutical Co., Ltd., and it was produced and marketed abroad in 1988. This product is soluble in water, slightly soluble in methanol, almost insoluble in chloroform. [0003] At present, there are few literature reports on the synthesis routes of terbutaline sulfate, and these routes will have some problems in industrial application, such as expensive starting materials and difficult to obtain, lengthy process routes, cumbersome operations, and problems in un...

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Problems solved by technology

This route has fewer reaction steps and higher yield, but the unprotected hydroxyl group directly undergoes bromination reaction, the hydroxyl group is easy to oxidize and deteriorate, and the treatment after sodium borohydride reduction is also relatively cumbersome, so the industrial application prospect of this method is not great;

[0008] (4) Chinese patent application CN201310560213.5 uses commercially available bambuterol hydrochloride as a raw material, and terbutaline sulfate can be obtained only after hydrolysis and salification. The route is simple, the yield is high, the operation is convenient, and the environmental pressure is small , but the raw material bambuterol hydrochloride is expensive, the cost is too high, and the industrialized products are not competitive

At present, the reports on terbutaline sulfate are mainly based on the synthetic route, and there are few reports on the preparation of its medicinal B crystal form

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