Method of refining valsartan comprising more than or equal to 10% D-isomers

Patent metadata

Field	Value
Publication number	US-9815801-B2
Application number	US-201515108209-A
Country	US
Kind code	B2
Filing date	Feb 15, 2015
Priority date	Feb 21, 2014
Publication date	Nov 14, 2017
Grant date	Nov 14, 2017

Abstract

The present invention relates to a method of refining valsartan comprising more than or equal to 10% D-isomers, the method comprising: adding a solvent to valsartan comprising more than or equal to 10% D-isomers to dissolve it, then adding a certain amount of inorganic base, separating solids out after salification, distilling a filtrate after filtration, and distilling the filtrate to remove the organic solvent; adjusting the pH of the filtrate with an acid, extracting with an organic solvent, concentrating most of the organic solvent, cooling to crystallize, and obtaining the product. The method enables isomers of the product to be below 0.5%, and produce a yield of more than or equal to 40%, being suitable for industrial production.

First claim

What is claimed is:

1. A method of refining valsartan comprising more than or equal to 10% D-isomers, characterized in that the method comprises the following steps:
1) adding a solvent to valsartan comprising more than or equal to 10% D-isomers to dissolve it, then adding a certain amount of inorganic base, separating solids out after salification, obtaining a filtrate after filtration, and distilling the filtrate to remove the solvent; and
2) adjusting the pH of the filtrate with an acid, extracting with an organic solvent, concentrating most of the organic solvent, cooling to crystallize, and obtaining the product.

2. The method of refining valsartan comprising more than or equal to 10% D-isomers according to claim 1 , characterized in that the solvent used in step 1) is a mixed solvent of water and a solvent selected from acetonitrile, butanone, acetone, methanol, or tetrahydrofuran.

3. The method of refining valsartan comprising more than or equal to 10% D-isomers according to claim 1 , characterized in that the inorganic base used in step 1) is selected from any one of NaOH, KOH, LiOH.H 2 O, Ba(OH) 2 .8H 2 O, and Ca(OH) 2 , or any combination thereof.

4. The method of refining valsartan comprising more than or equal to 10% D-isomers according to claim 1 , characterized in that the ratio of the solvent used in step 1) to valsartan is 1.0-8.0 ml/g.

5. The method of refining valsartan comprising more than or equal to 10% D-isomers according to claim 1 , characterized in that the molar ratio of the inorganic base used in step 1) to valsartan is 1.1-5.

6. The method of refining valsartan comprising more than or equal to 10% D-isomers according to claim 2 , characterized in that the ratio of water in the solvent used in step 1) to valsartan is 1.0-10.0 ml/g.

7. The method of refining valsartan comprising more than or equal to 10% D-isomers according to claim 1 , characterized in that the acid used in step 2) is selected from any one of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, methanoic acid, acetic acid, and oxalic acid, or any combination thereof.

8. The method of refining valsartan comprising more than or equal to 10% D-isomers according to claim 1 , characterized in that in step 2) the pH is adjusted to 0.5 -4.0.

9. The method of refining valsartan comprising more than or equal to 10% D-isomers according to claim 1 , characterized in that the organic solvent used in step 2) is any one of ethyl acetate, toluene, and dichloromethane, or any combination thereof.

10. The method of refining valsartan comprising more than or equal to 10% D-isomers according to claim 2 , characterized in that the solvent used in step 1) is any one of methanol/water, tetrahydrofuran/water, and butanone/water.

11. The method of refining valsartan comprising more than or equal to 10% D-isomers according to claim 4 , characterized in that the ratio of the solvent used in step 1) to valsartan is 1.0-5.0 ml/g.

12. The method of refining valsartan comprising more than or equal to 10% D-isomers according to claim 4 , characterized in that the ratio of the solvent used in step 1) to valsartan is 1.0-3.0 ml/g.

13. The method of refining valsartan comprising more than or equal to 10% D-isomers according to claim 5 , characterized in that the molar ratio of the inorganic base used in step 1) to valsartan is 1.1-3.0.

14. The method of refining valsartan comprising more than or equal to 10% D-isomers according to claim 5 , characterized in that the molar ratio of the inorganic base used in step 1) to valsartan is 1.1-1.8.

15. The method of refining valsartan comprising more than or equal to 10% D-isomers according to claim 6 , characterized in that the ratio of water in the solvent used in step 1) to valsartan is 2.0-10.0 ml/g.

16. The method of refining valsartan comprising more than or equal to 10% D-isomers according to claim 6 , characterized in that the ratio of water in the solvent used in step 1) to valsartan is 1.0-5.0 ml/g.

17. The method of refining valsartan comprising more than or equal to 10% D-isomers according to claim 6 , characterized in that the ratio of water in the solvent used in step 1) to valsartan is 1.0-2.0 ml/g.

18. The method of refining valsartan comprising more than or equal to 10% D-isomers according to claim 1 , characterized in that the valsartan comprises more than or equal to 20% D-isomers.

19. The method of refining valsartan comprising more than or equal to 10% D-isomers according to claim 1 , characterized in that the valsartan comprises more than or equal to 30% D-isomers.

Assignees

• Zhejiang Huahai Pharm Co Ltd
• Zhejiang Huahai Pharm Co Ltd

Inventors

• Chen Yongbi
• Zhang Wenling
• Wang Peng
• Chen Jian

Classifications

• C07D257/04 Primary

  Five-membered rings · CPC title

• C07B2200/09

  Geometrical isomers · CPC title