Preparation method for terbutaline hemisulfate

Abstract

The invention discloses a preparation method for terbutaline hemisulfate. The method comprises the following steps: by adopting 3, 5-resacetophenone as a raw material, performing bromination reaction by directly using a bromination reagent without protecting hydroxide radical, then reducing carbanyl group; condensing with tert-butylamine, finally, forming salt with sulfuric acid, thereby obtaining terbutaline hemisulfate. The method can overcome the defects of deprotection after hydroxide radical protection, usage of various high-risk toxic reagents, long reaction steps and low yield in the present technology.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a preparation method of terbutaline sulfate. Background technique [0002] Terbutaline Sulfate (Terbutaline Sulfate), also known as hydroxyalbutaline, terbutaline, is an adrenergic agonist that can selectively activate β 2 Receptors can relax bronchial smooth muscle, inhibit the release of endogenous spasm-causing substances and edema caused by endogenous mediators, and improve the clearance ability of bronchial mucociliary epithelium. [0003] Terbutaline sulfate was first developed by AstraZeneca Pharmaceutical Co., Ltd., and it was produced and marketed abroad in 1988. Clinically, it is mainly used for the treatment of bronchospasm in bronchial asthma, asthmatic bronchitis and chronic obstructive pulmonary disease. At present, the methods for synthesizing terbutaline sulfate at home and abroad mainly contain the following. [0004] 1. The route adopted by the patent US3937...

AI Technical Summary

Problems solved by technology

[0004] 1. The route adopted by the patent US3937838 of the original manufacturer AstraZeneca Pharmaceuticals Co., Ltd. is: use 3,5-dihydroxybenzoic acid as the starting material, undergo esterification, benzyl protection, hydrolysis, acylation, bromination, condensation, Hydrodebenzylation, and finally salify with sulfuric acid to obtain terbutaline sulfate, this route uses highly toxic diazomethane, and the steps are long and the yield is low, so it is not suitable for industrial production

[0005] 2. Yin Dunxiang and others from the Shanghai Institute of Materia Medica, Chinese Academy of Sciences used 3,5-dihydroxybenzoic acid as the starting material, after esterification, benzyl protection, hydrolysis, acylation, oxidation, condensation, reduction, hydrogenation and debenzylation, and finally Salt with sulfuric acid to obtain terbutaline sulfate, this route has used the dangerous metal reagent methyllithium and highly toxic selenium oxide, also has the disadvantage of long steps and low yield

[0006] 3. Zhang Xueli of Shenzhen University and others used 3,5-dihydroxybenzoic acid as the starting material, after esterification, benzyl protection, hydrolysis, acylation, bromination, condensation, reduction, hydrogenation debenzylation, and finally formed with sulfuric acid Salt obtains terbutaline sulfate, and this route is actually the optimization of the above-mentioned route, and the yield has been greatly improved, but still does not avoid the dangerous metal reagent methyl lithium, and the steps are relatively long, so it is not suitable for industrial production

[0007] 4. Chinese patent CN201310560213.5 uses commercially available bambuterol hydrochloride as a raw material, undergoes alkaline hydrolysis, and then forms a salt with sulfuric acid to obtain terbutaline sulfate. This route has mild reaction conditions, convenient operation, and short steps. The environmental pollution is very small, but the price of the commercially available raw material is very high. If bambuterol hydrochloride can be synthesized at low cost, it will be a good industrialization route

[0008] 5. Chinese patent CN201510758230.9 uses 3,5-dihydroxyacetophenone as the starting material, undergoes acetyl group protection, bromination, reduction, condensation, and finally salts with sulfuric acid to obtain terbutaline sulfate. This route avoids The use of high-risk reagents and hydrogenation reactions solves the problems of long steps, difficult operation, and high cost in the previous process, but bromine is used as the bromine reagent, which causes great pollution to the environment

[0009] The above route has the disadvantages of using high-risk and highly toxic reagents, long steps, low yield, and great environmental pollution. The present invention aims to provide a preparation of terbusulfuric acid that is easy to operate, mild in reaction conditions, short in steps and low in cost, and suitable for industrial production. his method