Preparation method of terbutaline sulfate

A technology of terbutaline sulfate and terbutaline, which is applied in the preparation of organic compounds, chemical instruments and methods, preparation of nitro compounds, etc., can solve the problems of increasing operational risks, low atom utilization, and complicated routes. , to achieve the effect of shortening working hours, conducive to research and control, and high total yield

Active Publication Date: 2020-07-28
SHANDONG MEITAI PHARMA CO LTD
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  • Claims
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Problems solved by technology

The entire synthetic route of terbutaline, due to the existence of two phenolic hydroxyl groups on the benzene ring structure, makes the route extremely cumbersome, so terbutaline sulfate is prepared through the synthetic route of 3,5-dihydroxyacetophenone as the key intermediate , total synthesis of more than 8 steps to prepare terbutaline, low atom utilization, high cost, use of bromine or selenium dioxide, increased operational risk

Method used

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  • Preparation method of terbutaline sulfate
  • Preparation method of terbutaline sulfate
  • Preparation method of terbutaline sulfate

Examples

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Embodiment 1

[0064] The present embodiment provides a kind of preparation method of terbutaline sulfate, comprises the following steps:

[0065] Step 1, acetophenone, sulfuric acid and nitric acid are subjected to nitration reaction, and intermediate 1 is obtained after water analysis and organic solvent crystallization and purification;

[0066] The preparation of intermediate one (3,5-dinitroacetophenone):

[0067] In a 2L three-necked flask, add concentrated sulfuric acid (1200ml), cool down to 0°C, start mechanical stirring, then add acetophenone (240.00g, 2.00mol) in batches, after the addition, nitric acid (320ml, density 1.42g / ml, the mass fraction is 69.2%) drop about 20ml into it to initiate the reaction, start to heat up, the temperature rises to 60-70°C, the color of the reaction solution becomes darker, turn off the heating, slowly add the remaining nitric acid, strictly control the rate of addition, to avoid reaction Vigorously, after dropping, raise the temperature to 140°C...

Embodiment 2

[0084] The difference between this example and Example 1 lies in the preparation of the intermediate tris(2-tert-butylamino-1-(3,5-dinitrophenyl)ethanol):

[0085] Add Intermediate II (40.00g, 0.15mol), tert-butylamine (16.22g, 0.22mol), and 500ml of absolute ethanol to a 2L three-necked flask at room temperature, and raise the temperature to reflux for 4h; add sodium borohydride (8.36g, 0.22mol) in batches ), a large number of bubbles are generated, and it takes about 1.5 hours to add, continue to reflux for 1 hour, until no bubbles are released, evaporate the solvent under reduced pressure, add 500ml dichloromethane to the concentrate, wash once with 200ml 1N hydrochloric acid, separate liquid, organic Wash once with 200ml of 5% aqueous sodium hydroxide solution, separate the liquids, wash the organic phase once with 200ml saturated brine, separate the liquids, dry the organic phase over anhydrous sodium sulfate, filter with suction, concentrate, add 30ml of dichloromethane a...

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Abstract

The invention relates to the field of preparation of chemicals, in particular to a preparation method of terbutaline sulfate. The invention provides a preparation method of terbutaline sulfate. With simple and low-cost acetophenone as an initial raw material, the terbutaline is prepared through five-step reaction; then the terbutaline is subjected to salifying and purification to obtain terbutaline sulfate. According to the method disclosed by the invention, the total synthesis route of terbutaline is effectively shortened, so that the method is simple in intermediate purification, single in reaction solvent, simple in process, mild in reaction condition, easy to operate, high in total yield and more suitable for industrial production; the burden of workshop waste liquid treatment and purification is relieved, the three wastes and reaction energy consumption are reduced, the whole route is combined, research and control of raw material medicine impurities are better facilitated, and working hours are shortened technically and the three wastes and reaction energy consumption are reduced technically.

Description

technical field [0001] The invention relates to the field of preparation of chemicals, in particular to a method for preparing terbutaline sulfate. Background technique [0002] Terbutaline is an adrenergic β2-receptor agonist that dilates the bronchi by selectively stimulating β2-receptors. Terbutaline accelerates the clearance of mucus secretions by increasing the mucociliary cleansing function decreased by obstructive lung disease. Inhaled terbutaline works within minutes and lasts for 6 hours. The metabolism of terbutaline is mainly through the combination of sulfuric acid and excretion in the form of sulfuric acid conjugates, and no active metabolites are produced. [0003] Terbutaline sulfate was first developed by AstraZeneca Pharmaceutical Co., Ltd., and it was produced and marketed abroad in 1988. It is mainly used clinically for the treatment of bronchospasm in bronchial asthma, asthmatic bronchitis and chronic obstructive pulmonary disease. At present, in addit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/08C07C215/60
CPCC07C201/08C07C201/12C07C213/02C07C213/08C07C205/45C07C215/34C07C215/60
Inventor 王瑛张文建张衍建王淑梅刘莉娜
Owner SHANDONG MEITAI PHARMA CO LTD
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