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Method for preparing pregabalin intermediate

A technology for pregabalin and intermediates, applied in the field of preparing R-3-isobutylglutaric acid monoamide, achieving the effects of shortening time, taking less times, and lowering doses

Active Publication Date: 2015-07-29
ZHEJIANG HUAHAI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage of this process is that the separated intermediate compound 2 needs to be centrifuged and then dried. In the process, a large amount of chloroform waste gas will be generated, which is very harmful to the environment and operators.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

[0025] Add 1000mL of chloroform, 20ml of ethanol, and 300g of 3-isobutylglutaric acid monoamide into a 1L four-neck flask, stir and raise the temperature to 45°C, then keep stirring for 10 minutes, and start to add 110g of the resolving agent R-phenylethylamine dropwise. After the dropwise addition, keep stirring for 2 hours. After the heat preservation, start to cool down to 25° C. to crystallize for 1 hour, and filter with suction. Transfer the filter cake to a 500ml four-necked flask, add 350g of water, stir and then separate to remove the chloroform layer, add dropwise hydrochloric acid to the water layer to adjust the pH to 2, lower the temperature to 3°C and keep it warm for 2 hours for crystallization, then filter and dry to obtain R - 3-isobutyl glutaric acid monoamide, weighing: 114.0g, yield: 38.0%, isomer 0.32%.

example 2

[0027] Add 1000mL of chloroform, 15ml of ethanol, and 250g of 3-isobutylglutaric acid monoamide into a 1L four-neck flask, stir and raise the temperature to 40°C, then keep stirring for 10 minutes, and start to add 130g of the resolving agent R-phenylethylamine dropwise. After the dropwise addition, keep stirring for 1.5 hours. After the heat preservation, start to cool down to 20° C. to crystallize for 1 hour, and filter with suction. Transfer the filter cake to a 500ml four-neck flask, add 300g of water, stir and then separate to remove the chloroform layer, add dropwise hydrochloric acid to the water layer to adjust the pH to 3, lower the temperature to 5°C and keep it warm for 2 hours for crystallization, then filter and dry to obtain R - 3-isobutyl glutaric acid monoamide, weighing: 97.5g, yield: 39.0%, isomer 0.27%.

example 3

[0029] Add 1000mL of chloroform, 35ml of ethanol, and 200g of 3-isobutylglutaric acid monoamide into a 1L four-neck flask, stir and raise the temperature to 45°C, then keep stirring for 10 minutes, and start to add 60g of the resolving agent R-phenylethylamine dropwise. After the dropwise addition, keep stirring for 2 hours. After the heat preservation, start to cool down to 25° C. to crystallize for 1 hour, and filter with suction. Transfer the filter cake to a 500ml four-neck flask, add 400g of water, stir and then separate to remove the chloroform layer, add dropwise hydrochloric acid to the water layer to adjust the pH to 4, lower the temperature to 0°C for 2 hours, keep warm and crystallize for 2 hours, filter and dry to obtain R - 3-isobutyl glutaric acid monoamide, weighing: 74.6g, yield: 37.3%, isomer 0.21%.

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Abstract

The invention discloses a method for preparing a pregabalin intermediate, namely, R-3-isobutyl glutaric acid monoamide. The method comprises the following steps: (1) adding 3-isobutyl glutaric acid monoamide into a system of chloroform and an alcohol solvent; (2) heating to 40-50 DEG C, dropwise adding a resolving agent, namely, R-phenylethylamine, and starting to preserve heat; (3) cooling to 20-30 DEG C for devitrification, and performing suction filtration; (4) adding water into a filter cake for delamination; (5) adding acid into a water layer for adjusting the pH to 1-4; (6) cooling to 0-5 DEG C for devitrification, and performing suction filtration and drying to obtain R-3-isobutyl glutaric acid monoamide, wherein the alcohol solvent is methanol or ethanol. The method has remarkable advantages in the current environmental protection pressure form, the intermediate containing chloroform does not need to be dried, so that waste gas of chloroform can be reduced; meanwhile, the time of a whole procedure can be shortened remarkably, and the yield is increased.

Description

technical field [0001] The invention provides a method for preparing R-3-isobutyl glutaric acid monoamide, which belongs to the field of medicine and chemical industry. Background of the invention [0002] Pregabalin is a GABA receptor agonist developed by Priser. In July 2004, it was first approved by the European Union for the treatment of partial seizures in adult patients. The trade name is Lyrica. Approved in June 2005 for the auxiliary treatment of partial-onset epilepsy in adults, it is the most promising drug among the epilepsy drugs that have been developed. The number of times is less, and it has the advantages of anti-anxiety effect and no drug-drug interaction with existing antiepileptic drugs, so it is convenient to be used in combination with other antiepileptic drugs to synergize the antiepileptic effect. At the same time, this product is also used as a therapeutic drug for diabetic peripheral neuropathy-related neuralgia, shingles neuralgia, fibromyalgia,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C233/05C07C231/20
Inventor 刘幕松张靖东乔旭慧张文灵王鹏
Owner ZHEJIANG HUAHAI PHARMA CO LTD
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