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Novel preparation method of terbutaline sulfate

A technology of terbutaline sulfate and terbutaline, which is applied in the field of pharmaceutical technology, can solve problems such as danger and complicated hydrogenation debenzylation operation, and achieve the effect of cheap reagents and mild reaction conditions

Inactive Publication Date: 2020-02-25
HARVEST PHARMA HUNAN CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route uses hydrogenation debenzylation to operate complex and has certain risks

Method used

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  • Novel preparation method of terbutaline sulfate
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  • Novel preparation method of terbutaline sulfate

Examples

Experimental program
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Effect test

Embodiment 1

[0040] (1) Add 3,5-dihydroxybenzaldehyde (138g, 1.0mol) and dichloromethane (500mL) to a 1L reaction kettle, stir to dissolve, add acetic anhydride (190mL, 2.0mol), and cool to 0℃ Anhydrous aluminum trichloride (267g, 2.0mol) was added in batches, the reaction temperature was controlled between 0-10°C, the addition was completed within 1 hour, and the reaction was conducted at 5-10°C for 2 hours. After the reaction is completed, slowly pour into ice water (300mL), stir for 30min, separate the layers, wash the organic phase with water (300mL) and concentrate under reduced pressure at 40°C to obtain a light yellow-brown solid, and dry under reduced pressure at 40°C to obtain compound I (180g) , Yield 81.0%).

[0041] (2) Add trimethyl thionyl chloride (141g, 1.1mol), potassium tert-butoxide (124g, 1.1mol) to a 3L reaction kettle, and then add compound I (222g, 1.0mol) dimethylsulfoxide The sulfone (1L) solution was stirred to dissolve and then stirred for another 20 minutes, then ...

Embodiment 2

[0045] (1) Add 3,5-dihydroxybenzaldehyde (138g, 1.0mol) and dichloromethane (500mL) to a 1000ml reactor, stir to dissolve, add acetic anhydride (217mL, 2.3mol), and cool to 10°C Anhydrous aluminum trichloride (307g, 2.3mol) was added in batches, the reaction temperature was controlled between 20-30°C, the addition was completed within 1 hour, and the reaction was conducted at 20-30°C for 2 hours. After the reaction is completed, slowly pour into ice water (300mL), stir for 30min, separate the layers, wash the organic phase with water (300mL) and concentrate under reduced pressure at 40°C to obtain a light yellow-brown solid, and dry under reduced pressure at 40°C to obtain compound I (198g) , The yield is 89.1%).

[0046] (2) Add trimethyl sulfoxide bromide (260g, 1.5mol), potassium tert-butoxide (168g, 1.5mol) to a 3L reaction kettle, and then add compound I (222g, 1.0mol) dimethylsulfoxide The sulfone (900 mL) solution was stirred for dissolution and then stirred for another 2...

Embodiment 3

[0050] (1) Add 3,5-dihydroxybenzaldehyde (138g, 1.0mol) and dichloromethane (500mL) to a 1000ml reaction kettle, stir to dissolve, add acetic anhydride (236mL, 2.5mol), and cool to 10℃ Anhydrous aluminum trichloride (333g, 2.5mol) was added in batches, the reaction temperature was controlled between 10-20°C, the addition was completed within 1h, and the reaction was carried out at 10-20°C for 2h. After the reaction is completed, slowly pour into ice water (300mL), stir for 30min, separate the layers, wash the organic phase with water (300mL) and concentrate under reduced pressure at 40°C to obtain a light yellow-brown solid, and dry under reduced pressure at 40°C to obtain compound I (182g) , 81.9%).

[0051] (2) Add trimethyl sulfoxide iodide (264g,), potassium tert-butoxide (135g, 1.2mol) to a 3L reaction kettle, and then add compound I (222g, 1.0mol) of dimethyl sulfoxide ( 600mL) solution, stirred for dissolution and then stirred for another 20min, then heated to 50°C and co...

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Abstract

The invention belongs to the field of organic synthesis of medicines, and concretely relates to a novel preparation method of a medicine terbutaline sulfate for treating bronchial spasm caused by bronchial asthma, chronic bronchitis, emphysema and other lung diseases. The synthesis route of the preparation method comprises the following steps: reacting 3,5-dihydroxybenzaldehyde with acetic anhydride to generate a compound I; reacting the compound I with trimethyloxosulfonium halide to generate a compound II; reacting the compound II with tert-butylamine to generate terbutaline; and salifying the terbutaline to generate the terbutaline sulfate. The method has the advantages of avoiding of dangerous chemical reagents, low price of adopted reagents, mild reaction conditions, and suitablenessfor industrial amplification.

Description

Technical field [0001] The invention relates to the technical field of medical technology, in particular to a new preparation method of terbutaline sulfate. Background technique [0002] Terbutaline sulfate, molecular formula C 24 H 40 N 2 O 10 S; Molecular weight: 548.65, structural formula: [0003] [0004] Terbutaline sulfate, also known as terbutaline sulfate, was developed by AstraZeneca. It was first marketed in Denmark in 1970 and in the United States and Japan in 1974. It is a selective short-acting β2-adrenergic receptor. Body agonists have anti-asthmatic, expectorant and bronchial relaxation effects. They can be used to relieve bronchial spasm caused by bronchial asthma, chronic bronchitis, emphysema and other lung diseases, and can also be used to prevent premature birth and fetal asphyxia. [0005] The main existing process routes of terbutaline sulfate are as follows: [0006] The original AstraZeneca patent US3937838 uses 3,5-dihydroxybenzoic acid as the starting mater...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/08C07C215/60
CPCC07C213/08C07C67/08C07D301/02C07D303/16C07C213/04
Inventor 袁金桥秦敏晏瑾懿刘虎
Owner HARVEST PHARMA HUNAN CO LTD
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