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Method for purifying glycopyrronium bromide intermediate 2-cyclopentyl-2-hydroxyphenylacetic acid

A kind of technology of hydroxyphenylacetic acid and purification method, applied in the field of recrystallization and purification of glycopyrronium bromide intermediate 2-cyclopentyl-2-hydroxyphenylacetic acid I, can solve problems such as low crude product purity and many by-products, and achieve Improve product purity, improve the effect of purity

Inactive Publication Date: 2018-12-11
SHANGHAI AOBO PHARMTECH INC LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are many by-products in this reaction, and the obtained crude product has low purity

Method used

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  • Method for purifying glycopyrronium bromide intermediate 2-cyclopentyl-2-hydroxyphenylacetic acid
  • Method for purifying glycopyrronium bromide intermediate 2-cyclopentyl-2-hydroxyphenylacetic acid
  • Method for purifying glycopyrronium bromide intermediate 2-cyclopentyl-2-hydroxyphenylacetic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Purification of 2-cyclopentyl-2-hydroxyphenylacetic acid

[0042] Prepare the cyclopentyl Grignard reagent first, then add 495g of acetophenone acid and 2.5LTHF into a 20L four-necked bottle, add 2.1eq of the cyclopentyl Grignard reagent dropwise at 15°C to 25°C, and use it after the reaction is completed. Quenched with 4N hydrochloric acid, then extracted with MTBE, washed with alkali and brine, and concentrated to obtain 563 g of the intermediate 2-cyclopentyl-2-hydroxyphenylacetic acid oil.

[0043] Add 150g of ethanol and 300g of purified water to the oil obtained from the above reaction, heat up to 55-65°C to dissolve, then slowly cool down to 0-5°C, keep warm for 1 hour, and filter with suction to obtain a brown-yellow solid; Then use 227g of ethanol and 300g of purified water, heat up to 70-80°C to dissolve, then slowly cool down to 0-5°C, keep warm for 1 hour, and then filter with suction to obtain a light yellow solid; use 300g of ethanol and 160g of purified w...

Embodiment 2

[0045] Prepare 578g of 2-cyclopentyl-2-hydroxyphenylacetic acid oil by the method in Example 1, add 160g of ethanol, 640g of purified water, heat up to 70-80°C to dissolve, then slowly cool down to 0-5°C , after heat preservation for 1 hour, suction filtration to obtain brown-yellow solid; add 327g of ethanol and 300g of purified water to the wet product, heat up to 75-80°C to dissolve, then slowly cool down to 0-5°C, hold heat for 1 hour, and then suction-filter, Obtain 204g of a light yellow solid; warm the crude product to 60-80°C with 2000ml of toluene and dissolve it, then slowly cool it down to -5-0°C, keep stirring for 1 hour, and then filter with suction to obtain a off-white solid. After dissolving at 80-110°C, slowly lower the temperature to 0-5°C, keep warm for 1 hour, filter with suction, and dry to obtain 156.8g of off-white solid with a yield of 21.6% and an HPLC purity of 98.2%.

Embodiment 3

[0047]Prepare 552g of 2-cyclopentyl-2-hydroxyphenylacetic acid oil by the method of Example 1, add 200g of ethanol and 350g of purified water, heat up to 50-70°C to dissolve, then slowly cool down to -5-0 ℃, keep warm for 1 hour, and filter with suction to obtain brown-yellow solid; add 227g of ethanol and 300g of purified water to the wet product, heat up to 75-85℃ to dissolve, then slowly cool down to 0-5℃, keep warm for 1 hour, and then suction-filter , to obtain 201g of a light yellow solid; warm the crude product to 60-80°C with 1300ml of toluene to dissolve it, then slowly cool it down to 0-5°C, keep stirring for 1 hour and then filter it with suction to obtain a off-white solid. After dissolving at 80-110°C, slowly lower the temperature to 0-5°C, keep warm for 1 hour, filter with suction, and dry to obtain 161.9 g of off-white solid with a yield of 22.3% and an HPLC purity of 98.4%.

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Abstract

The invention discloses a method for purifying a glycopyrronium bromide intermediate 2-cyclopentyl-2-hydroxyphenylacetic acid. The method comprises the following steps: (1) heating and dissolving crude 2-cyclopentyl-2-hydroxyphenylacetic acid in a mixed solvent of ethanol and water, cooling, crystallizing, and filtering to obtain a solid; (2) heating and dissolving the solid obtained in the step (1), cooling, crystallizing, and filtering, thereby obtaining the solid 2-cyclopentyl-2-hydroxyphenylacetic acid. According to the method, the various impurities can be effectively removed, the productpurity is obviously improved, the purity of HPLC (High Performance Liquid Chromatography) is more than 98.0%, the loss of the 2-cyclopentyl-2-hydroxyphenylacetic acid is reduced to the greatest degree, the yield is improved, and the method is suitable for industrial production.

Description

technical field [0001] The invention relates to a method for recrystallization and purification of glycopyrronium bromide intermediate 2-cyclopentyl-2-hydroxyphenylacetic acid I. [0002] technical background [0003] Chronic obstructive pulmonary disease (COPD) is a common respiratory disease, its morbidity and mortality are increasing year by year, and as many as 600 million people suffer from it every year. By 2020 COPD will become the third leading cause of death in the world. [0004] As a new type of long-acting anticholinergic drug, glycopyrronium bromide can produce longer-lasting bronchoprotective and bronchodilation effects, with a quick onset, and the bronchodilation effect can last for more than 24 hours. Glycopyrronium bromide can reduce shortness of breath, condition deterioration and emergency drug use in patients with chronic obstructive pulmonary disease, effectively improve lung function, quality of life and exercise tolerance. Glycopyrrolate was shown...

Claims

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Application Information

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IPC IPC(8): C07C51/43C07C59/54
CPCC07C51/43C07C59/54
Inventor 樊海生季翔郭效文黄鲁宁陈茜安建国顾虹
Owner SHANGHAI AOBO PHARMTECH INC LTD
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