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A kind of synthesis method of terbutaline and its application in preparing terbutaline sulfate

A technology of terbutaline and a synthesis method, which is applied in the application field of preparing terbutaline sulfate, can solve the problems of high price of bambuterol hydrochloride, expensive starting materials, increased operation difficulty and the like, and achieves reaction conditions. More, low production cost, convenient operation effect

Active Publication Date: 2022-03-04
YANGZHOU ZHONGBAO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The price of bambuterol hydrochloride is relatively high, and it is not suitable as a starting material for the preparation of terbutaline sulfate. At the same time, the reaction route is short, and it is not suitable as a declared process. The total molar yield is about 50%.
[0006] At present, the synthetic routes reported at home and abroad are similar, and most of the synthetic processes use highly toxic reagents, high-risk reactions of Pd / C hydrogenation, or expensive starting materials, etc.
At the same time, most of the preparation process of the final product of terbutaline sulfate adopts the method of concentrating the solvent at the end of the reaction and adding methanol to crystallize, which increases the difficulty of operation.

Method used

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  • A kind of synthesis method of terbutaline and its application in preparing terbutaline sulfate
  • A kind of synthesis method of terbutaline and its application in preparing terbutaline sulfate
  • A kind of synthesis method of terbutaline and its application in preparing terbutaline sulfate

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Embodiment 1

[0055] A kind of preparation method of terbutaline sulfate, refer to figure 1 Shown synthetic route, concrete steps are as follows:

[0056] (1) Add 100g (MW: 180.20, 0.55mol) of 3,5-dimethoxyacetophenone into a three-necked flask, add 300mL tetrahydrofuran and 100mL methanol, add 294g (MW: 482.18, 0.61mol) tetrabutyltri Ammonium bromide, stirred at room temperature for 2h. After the reaction was completed, 1L of isopropanol and 1L of purified water were added to the system, stirred and crystallized in an ice-water bath for 2h, filtered under reduced pressure, and the filter cake was air-dried at 50°C for 8h to obtain 129g of a light yellow solid (molar yield 90% ).

[0057] (2) Add 120g of 2-bromo-1-(3,5-dimethoxyphenyl)ethanone (MW: 259.10, 0.46mol) into a three-necked flask, add 600mL of methanol, and add boron in batches under an ice-water bath Add 8.76 g of sodium hydride (MW: 37.83, 0.23 mol). After the addition, stir at room temperature for 2 h. After the reaction, ...

Embodiment 2

[0061] Embodiment 2: the terbutaline sulfate synthetic route in the present invention has been fully optimized for parameters, and the parameter optimization results are as follows:

[0062] 1. Bromination reaction

[0063] (1) bromination reaction solvent type optimization result is as follows (table 1), and other parameters are with step (1) in embodiment 1:

[0064] Table 1

[0065]

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Abstract

The invention discloses a synthetic method of terbutaline, which is characterized in that it comprises the following steps: (1) reacting 3,5-dimethoxyacetophenone with tetrabutylammonium tribromide to obtain 2- Bromo-1-(3,5-dimethoxyphenyl)ethanone; (2) react it with a reducing agent in methanol to give 2-bromo-1-(3,5-dimethoxyphenyl ) ethanol; (3) it is carried out ring-forming reaction under alkaline condition, generates 2-(3,5-dimethyloxyl) oxirane; (4) it is reacted with tert-butylamine, generates 1-( 3,5-dimethoxyphenyl)-2-tert-butylamino-ethanol; (5) demethylating it under acidic conditions to give 1-(3,5-dihydroxyphenyl)-2-tert-butyl The salt of amino-ethanol is terbutaline. In the present invention, the total molar yield is about 60%, which is much higher than that of the prior art, and is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the field of chemical pharmacy, and in particular relates to a synthesis method of terbutaline and its application in preparing terbutaline sulfate. Background technique [0002] Terbutaline sulfate, also known as hydroxyalbutaline and terbutaline, is a highly selective short-acting β2-receptor agonist dosage form developed by AstraZeneca. It has a bronchodilation effect and is clinically used for the treatment of Bronchial asthma, chronic and asthmatic bronchitis, emphysema and other diseases are clinically recommended drugs for patients with mild and moderate chronic obstructive pulmonary disease (COPD). Compared with other marketed short-acting β2-receptor agonists, terbutaline sulfate inhalation has lower dose-dependent side effects. At present, the synthetic route of terbutaline sulfate mainly contains following several kinds. [0003] The synthetic route of US Patent US3937838 is based on 3,5-hydroxybenzoic acid as the ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C213/00C07C213/08C07C213/10C07C215/60C07C213/04C07C217/70C07D301/26C07D303/22C07C41/26C07C43/23C07C45/63C07C49/84
CPCC07C213/00C07C213/08C07C213/10C07C213/04C07D301/26C07D303/22C07C41/26C07C45/63C07C49/84C07C43/23C07C217/70C07C215/60
Inventor 郭晓东张广明张冠亚裴章宏韩晓秋
Owner YANGZHOU ZHONGBAO PHARMA
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