Method for synthesizing tulobuterol

A technique for synthesizing appropriate compounds, which is applied in the field of drug synthesis, can solve problems such as high reaction temperature, unfavorable industrial production, and low yield, and achieve the effect of simple operation

Active Publication Date: 2019-12-20
HANGZHOU BIO SINCERITY PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] This route prepares tulobuterol through olefination reaction, ring-forming reaction and ring-opening reaction. When compound 8 is prepared by olefination reaction, the reaction temperature is between 180°C-210°C, the reaction temperature is high, there are many by-products, and the yield Low, not conducive to industrial production

Method used

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  • Method for synthesizing tulobuterol
  • Method for synthesizing tulobuterol
  • Method for synthesizing tulobuterol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Put 100.0 g of the mixture of compound 3 and compound 10 into the three-necked flask (converted to 0.40 mol of compound 2), add 500 ml of ethanol, add 227.2 g of anhydrous sodium sulfate, add 116.8 g of tert-butylamine, and react at 30 ° C for 4 h under nitrogen protection. Cool down to -10°C, add 9.1g of sodium borohydride in portions, control the temperature at -10°C-10°C, add sodium borohydride, react at 10°C for half an hour, heat up, reflux for 6 hours, the reaction is over, concentrate the reaction solution to dryness , then add 300ml of dichloromethane and 300ml of 5% sodium hydroxide solution, extract and layer, take the dichloromethane layer, add 300ml of 4% hydrogen chloride solution, extract and separate, take the water layer, add 300ml of dichloromethane and 300ml of 5% hydroxide to the water layer Sodium solution, extraction and separation, the dichloromethane layer was extracted once with 150 ml of purified water, and concentrated to obtain 70.8 g of tulobu...

Embodiment 2

[0036] Put 100.0 g of the mixture of compound 3 and compound 10 into the three-necked flask (converted to 0.40 mol of compound 2), add 250 ml of ethanol, add 113.6 g of anhydrous sodium sulfate, add 58.4 g of tert-butylamine, and react at 30 ° C for 4 h under nitrogen protection. Cool down to -10°C, add 6.1g of sodium borohydride in portions, control the temperature at -10°C-10°C, add sodium borohydride, react at -10°C for half an hour, heat up, reflux for 8 hours, and complete the reaction, according to Example 1 After the post-processing method, 67.9 g of tulobuterol was obtained with a total molar yield of 75%.

Embodiment 3

[0038] Put 100.0 g of the mixture of compound 3 and compound 10 into the three-necked flask (converted to 0.40 mol of compound 2), add 300 ml of ethanol, add 170.4 g of anhydrous sodium sulfate, add 87.6 g of tert-butylamine, and react at 30 ° C for 3 h under nitrogen protection. Cool down to -10°C, add 7.6g of sodium borohydride in portions, control the temperature at -10°C-10°C, add sodium borohydride, react at 0°C for half an hour, heat up, reflux for 6 hours, and complete the reaction, according to the method in Example 1 After post-processing, 68.5 g of tulobuterol was obtained with a total molar yield of 75%.

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Abstract

The invention discloses a method for synthesizing tulobuterol. According to the method, 1-(2-chlorophenyl)-2-bromoethanone (compound 3) and 1-(2-chlorophenyl)-2,2-dibromoethanone (compound 10) can besimultaneously utilized to synthesize the tulobuterol. In an original route, the compound 10 is a by-product of synthesis of the compound 3, and about 10-15% of the compound 10 is not fully utilized.The method provided by the invention can improve the synthesis yield of the tulobuterol, is simple to operate, is environmentally friendly, is low in cost and is suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a method for synthesizing tulobuterol. Background technique [0002] Tulobuterol is a selective β2-receptor agonist, which has a strong and long-lasting expansion effect on bronchial smooth muscle and a weak excitability on the heart. It is mainly used for the prevention and treatment of bronchial asthma, asthmatic bronchitis and chronic bronchitis. Tulobuterol hydrochloride was approved for marketing as an anti-asthma drug in Japan in 1981. The active ingredient is tulobuterol hydrochloride. In 1998, tulobuterol patch was approved for the treatment of COPD. The active ingredient is Tulobuterol is currently used as a patch for the treatment of childhood asthma. [0003] Bibliographical reports are less about the method for synthesizing tulobuterol, mainly contain the following several: [0004] Synthetic route 1 (original research route) [0005] [0006] This route ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/00C07C215/30
CPCC07C45/63C07C213/00C07C49/80C07C215/30
Inventor 吴俊平叶鑫杰李召勇王传东李艳芹
Owner HANGZHOU BIO SINCERITY PHARMA TECH CO LTD
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