Preparation method of terbutaline sulfate

A technology of terbutaline sulfate and sulfuric acid, which is applied in the field of medicine, can solve the problems of low yield of step factory, low yield of long step, and low yield, so as to avoid high-risk and highly toxic reagents and solve the problem of low yield of long step Effect

Active Publication Date: 2020-04-10
浙江赛默制药有限公司 +1
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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, finally salting with sulfuric acid to obtain terbutaline sulfate, this route uses highly toxic diazomethane, and the yield of the step plant 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 it is possible to synthesize bambuterol hydrochloride 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

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  • Preparation method of terbutaline sulfate

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Experimental program
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Effect test

Embodiment 1

[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 cooled to room temperature, filtered with diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain 21.6 g of 5-bromoacetyl resorcinol;

[0031] (2) Dissolve 20.5g of 5-bromoacetyl resorcinol in 200ml of ethanol, cool in an ice-water bath to 10°C, add 3.1g of sodium borohydride in batches, then rise to 25°C for 2 hours, add 10% hydroxide 22ml of sodium solution, react at room temperature for 3h, cool down to 5°C, add 100ml of dilute hydrochloric acid to quench the reaction, add 200ml of dichloromethane for extraction, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 2-(3,5 -dihydroxyphenyl) oxirane 11.6g;

[0032] (3) Dissolve...

Embodiment 2

[0035] (1) Add 65.2g of copper bromide to 250ml of ethyl acetate, stir at room temperature, dissolve 30.8g of 3,5-dihydroxyacetophenone in 200ml of chloroform, add it dropwise to the reaction flask, and heat up to 70°C After reacting for 6 hours, it was cooled to room temperature, filtered with diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain 37.2 g of 5-bromoacetyl resorcinol;

[0036] (2) Dissolve 35.2g of 5-bromoacetyl resorcinol in 260ml of methanol, cool in an ice-water bath to 5°C, add 5.2g of sodium borohydride in batches, then rise to 25°C for 3 hours, add 15% hydroxide Potassium solution 30ml, react at room temperature for 3h, cool down to 5°C, add 120ml of dilute hydrochloric acid to quench the reaction, add 280ml of dichloromethane for extraction, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 2-(3,5 -dihydroxyphenyl)oxirane 18.1g;

[0037] (3) Dissolve...

Embodiment 3

[0040] (1) Add 58.3g of copper bromide to 250ml of ethyl acetate, stir at room temperature, dissolve 23.6g of 3,5-dihydroxyacetophenone in 120ml of chloroform, add it dropwise to the reaction flask, and heat up to 75°C After reacting for 5 hours, it was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain 31.8 g of 5-bromoacetyl resorcinol;

[0041] (2) Dissolve 30.1 g of 5-bromoacetyl resorcinol in 200 ml of isopropanol, cool in an ice-water bath to 5°C, add 6.9 g of potassium borohydride in batches, then rise to 20°C for 3.5 hours, add 10 % Potassium hydroxide solution 28ml, react at room temperature for 4h, cool to 5°C, add 100ml of dilute hydrochloric acid to quench the reaction, add 200ml of dichloromethane for extraction, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 2-( 3,5-dihydroxyphenyl) oxirane 14.3g;

[0042] (...

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Abstract

The invention discloses a preparation method of terbutaline sulfate, wherein the method comprises the following steps: carrying out a bromination reaction on 3,5-dihydroxyacetophenone as a raw material by using a bromination reagent without hydroxyl protection, carrying out reduction and ring closing, carrying out a ring-opening reaction with tert-butylamine, and finally forming a salt with sulfuric acid to obtain terbutaline sulfate. According to the method, the defects of requirement of deprotection after hydroxyl protection, use of various high-risk highly toxic reagents, long reaction stepand low yield in the prior art are overcome.

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 method of synthesizing terbutaline sulfate at home and abroad mainly contains following several kinds: [0004] 1. The route adopted by the pate...

Claims

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Application Information

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IPC IPC(8): C07C215/52C07C213/08
CPCC07C45/63C07C213/02C07D301/02C07C49/825C07C215/52Y02P20/55
Inventor 刘晓锋杨旭方传祥李艳芹
Owner 浙江赛默制药有限公司
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