Method for preparing pregabalin intermediate 3-isobutylglutaric acid monoamide

Patent metadata

Field	Value
Publication number	US-10577309-B2
Application number	US-201716313262-A
Country	US
Kind code	B2
Filing date	Jun 21, 2017
Priority date	Jun 30, 2016
Publication date	Mar 3, 2020
Grant date	Mar 3, 2020

Abstract

Provided is a method for preparing a pregabalin intermediate 3-isobutylglutaric acid monoamide. The method comprises: 1) adding 3-isobutylglutaric acid and urea into a first organic solvent; 2) keeping warm and refluxing when heated to 100-140° C.; 3) adding water when cooled to 70-90° C.; 4) adding an ion membrane alkaline when cooled to 40-60° C., adjusting the pH to 11.0-14.0, then keeping warm at 40-60° C.; 5) when finished keeping warm, removing an organic layer; 6) adding an acid into the water layer to adjust the pH to 1.0-3.0; 7) extracting the solution acquired in step 6) by using a second organic solvent of a total volume of V, vacuum distilling 0.5-0.6 V of the organic solvent from an organic layer acquired by extraction; and 8) cooling to 0-15° C. and crystallizing to acquire 3-isobutylglutaric acid monoamide.

First claim

The invention claimed is:

1. A method for preparing a pregabalin intermediate 3-isobutylglutaric acid monoamide, comprising:
1) adding 3-isobutylglutaric acid and urea to a first organic solvent;
2) heating to a temperature of 100-140° C., and refluxing while maintaining the temperature;
3) cooling the mixture obtained in step 2) to 70-90° C., then adding water;
4) cooling the mixture obtained in step 3) to a temperature of 40-60° C., then adding an ion-exchange membrane caustic soda solution to adjust the pH value of the mixture to 11.0-14.0, while maintaining the temperature of 40-60° C.;
5) separating an organic layer after maintaining the temperature;
6) adding an acid into the aqueous layer to adjust the pH value of the aqueous layer to 1.0-3.0;
7) extracting the aqueous solution obtained in step 6) with a second organic solvent of a total volume of V, distilling the second organic layer obtained by extraction under reduced pressure to remove 0.5V-0.6 V of the second organic solvent; and
8) cooling the distilled second organic layer to 0-15° C. and crystallizing to obtain 3-isobutylglutaric acid monoamide.

2. The method according to claim 1 , wherein the ratio of the volume of the first organic solvent in step 1) in milliliters to the mass of 3-isobutylglutaric acid in grams is 2:1 to 6:1; and the mass ratio of urea to 3-isobutylglutaric acid is 0.2:1 to 0.6:1.

3. The method according to claim 1 , wherein the first organic solvent in step 1) is selected from the group consisting of toluene, xylene and octane.

4. The method according to claim 1 , wherein the duration of refluxing and maintaining the temperature in step 2) is 2.0 h to 5.0 h.

5. The method according to claim 1 , wherein the mass of water added in step 3) is 1.5 to 4.0 times as much as the mass of 3-isobutylglutaric acid.

6. The method according to claim 1 , wherein step 4) further comprises stirring and maintaining the temperature of the mixture at 40-60° C. for 0.5 h to 4.0 h.

7. The method according to claim 1 , wherein the second organic solvent in step 7) is selected from the group consisting of ethyl acetate, dichloromethane and toluene.

8. The method according to claim 1 , wherein the duration of crystallizing in step 8) is 1.0 h to 6.0 h.

9. The method according to claim 1 , further comprising centrifuging, filtering and drying the 3-isobutylglutaric acid monoamide after crystallizing in step 8).

Assignees

• Zhejiang Huahai Pharm Co Ltd
• Zhejiang Huahai Zhicheng Pharmaceutical Co Ltd
• Zhejiang Huahai Pharmaceuticals Co Ltd

Inventors

• Guo Pan
• Liu Musong
• Zhou Zengle
• Zhang Wenling
• Wang Peng

Classifications

• C07C231/02

  from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines · CPC title

• C07C231/10 Primary

  from compounds not provided for in groups C07C231/02 - C07C231/08 · CPC title

• C07D211/88

  attached in positions 2 and 6, e.g. glutarimide · CPC title

• C07C233/05

  having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms · CPC title