Preparation method for terbutaline hemisulfate

A technology of terbutaline sulfate and sulfuric acid, which is applied in the field of medicine, can solve problems such as difficult operation, long steps, low yield, and large environmental pollution, and achieve the effect of avoiding high-risk and highly toxic reagents and solving long steps and low yield

Inactive Publication Date: 2017-06-13
HANGZHOU BIO SINCERITY PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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 met

Method used

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Effect test

Embodiment 1

[0029] A preparation method of terbutaline sulfate, comprising.

[0030] (1) Add 45.8g of copper bromide to 200ml of ethyl acetate, stir at room temperature, dissolve 15.5g of 3,5-dihydroxyacetophenone in 90ml of chloroform, add it dropwise to the reaction flask, and heat up to 70°C , After reacting for 8 hours, it was lowered to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain 17.8 g of 2-bromo-1-(3,5-dihydroxyphenyl)ethanone.

[0031] (2) Dissolve 11.6g of 2-bromo-1-(3,5-dihydroxyphenyl)ethanone in 100ml of ethanol, cool in an ice-water bath to 10°C, add 2.1g of sodium borohydride in batches, and then rise to 25 ℃ for 2 hours, add 50ml of ammonium chloride solution, add 100ml of ethyl acetate for extraction, then extract the aqueous layer with 100ml of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 2-bro...

Embodiment 2

[0035] A preparation method of terbutaline sulfate, comprising.

[0036] (1) Add 82.3g of copper bromide to 320ml of ethyl acetate, stir at room temperature, dissolve 26.6g of 3,5-dihydroxyacetophenone in 150ml of chloroform, drop into the reaction flask, and heat up to 60°C , After reacting for 10 hours, it was lowered to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain 25.5 g of 2-bromo-1-(3,5-dihydroxyphenyl)ethanone.

[0037] (2) Dissolve 32.5g of 2-bromo-1-(3,5-dihydroxyphenyl)ethanone in 250ml of ethanol, cool in an ice-water bath to 5°C, add 7.5g of sodium borohydride in batches, and then rise to 25 ℃ for 4 hours, add 120ml of ammonium chloride solution, add 200ml of ethyl acetate for extraction, then extract the aqueous layer with 180ml of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 2-bromo- 1-...

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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...

Claims

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Application Information

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IPC IPC(8): C07C213/00C07C215/30
CPCC07C213/00C07C37/002C07C45/63C07C213/02
Inventor 刘晓锋罗瑾杨旭傅华锋衣丽娜
Owner HANGZHOU BIO SINCERITY PHARMA TECH CO LTD
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