Method for purifying ropinirole hydrochloride

Patent metadata

Field	Value
Publication number	US-10961194-B2
Application number	US-201716623085-A
Country	US
Kind code	B2
Filing date	Jun 16, 2017
Priority date	Jun 16, 2017
Publication date	Mar 30, 2021
Grant date	Mar 30, 2021

Abstract

Provided is a method for purifying ropinirole hydrochloride (4-2-di-n-propylaminoethyl-1,3-dihydro-2H-indole-2-ketohydrochloride). The method comprises: adding ropinirole hydrochloride containing a monopropyl impurity A into water, adding organic solvent, stirring and dissolving at room temperature, adding alkali, stirring, standing, demixing, and removing an aqueous layer; optionally, drying the organic layer by using anhydrous magnesium sulfate, and filtering; and adding acyl chloride or acid anhydride into the organic layer, stirring, concentrating the organic layer to be dry, adding an organic solvent into the obtained oily matter, adding concentrated hydrochloric acid, and stirring, so as to obtain the ropinirole hydrochloride. By using the method, the impurity A in the ropinirole hydrochloride can be effectively removed, and the ropinirole hydrochloride can be obtained with a high yield and a high purity, so that the impurity A is controlled and the purity of the product reaches a medicinal standard.

First claim

The invention claimed is:

1. A method for purifying ropinirole hydrochloride, 4-(2-di-n-propylaminoethyl)-1,3-dihydro-2H-indol-2-one hydrochloride, represented by a structural formula (II), comprising the following steps:

wherein —R represents C 1 -C 6 alkyl or C 6 -C 10 aromatic group;
-L represents halogen —X, or acyloxy

(1) mixing ropinirole hydrochloride containing an impurity A, monopropyl ropinirole, represented by a structural formula (I) with water and an organic solvent, stirring and dissolving to obtain a clear solution at room temperature, adding an alkali, stirring, standing for demixing, and removing an aqueous layer, wherein the organic solvent is an aprotic solvent; and the alkali is a hydroxide, carbonate or bicarbonate of an alkali metal or alkaline earth metal, or an amine mono- or polysubstituted by C 1 -C 6 alkyl;
(2) drying an organic layer obtained over anhydrous magnesium sulfate and filtering; or subjecting the organic layer obtained directly to a next step without addition of anhydrous magnesium sulfate;
(3) adding acid halide or acid anhydride of a structural formula (IV) to the dried organic layer, stirring and concentrating; and
(4) after concentrating to dryness to obtain an oily substance, adding an organic solvent to the obtained oily substance, adding a concentrated hydrochloric acid, and stirring to obtain ropinirole hydrochloride, wherein the organic solvent is an alcohol.

2. The method according to claim 1 , wherein in step (1) the volume of the organic solvent in milliliters is 2 to 20 times of the mass of ropinirole hydrochloride in grams, and the volume of water in milliliters is 5 to 20 times of the mass of ropinirole hydrochloride in grams.

3. The method according to claim 1 , wherein the molar amount of the alkali in step (1) is 1.5 to 25 times of the molar amount of ropinirole hydrochloride.

4. The method according to claim 1 , wherein the organic solvent in step (1) is dichloromethane, n-hexane, cyclohexane, ethyl acetate, isopropyl acetate, toluene, xylene or methyl tert-butyl ether.

5. The method according to claim 1 , wherein the alkali in step (1) is selected from the group consisting of sodium carbonate, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium bicarbonate, triethylamine and diisopropylamine.

6. The method according to claim 1 , wherein the acid halide or acid anhydride in step (3) is selected from the group consisting of acetyl chloride, propionyl chloride, benzoyl chloride, acetic anhydride and benzoic anhydride, and the molar amount of the acid halide or acid anhydride is 1 to 5 times of the molar amount of impurity A.

7. The method according to claim 6 , wherein the acid halide or acid anhydride is selected from the group consisting of acetyl chloride, benzoyl chloride and acetic anhydride.

8. The method according to claim 1 , wherein the volume of the organic solvent in milliliters in step (4) is 2 to 20 times of the mass of ropinirole hydrochloride in grams.

9. The method according to claim 1 , wherein the molar amount of the concentrated hydrochloric acid in step (4) is 2 to 10 times of the molar amount of ropinirole hydrochloride.

10. The method according to claim 1 , wherein the organic solvent in step (4) is methanol, ethanol, isopropanol or n-butanol.

11. The method according to claim 2 , wherein the acid halide or acid anhydride in step (3) is selected from the group consisting of acetyl chloride, propionyl chloride, benzoyl chloride, acetic anhydride and benzoic anhydride, and the molar amount of the acid halide or acid anhydride is 1 to 5 times of the molar amount of impurity A.

12. The method according to claim 3 , wherein the acid halide or acid anhydride in step (3) is selected from the group consisting of acetyl chloride, propionyl chloride, benzoyl chloride, acetic anhydride and benzoic anhydride, and the molar amount of the acid halide or acid anhydride is 1 to 5 times of the molar amount of impurity A.

13. The method according to claim 11 , wherein the acid halide or acid anhydride is selected from the group consisting of acetyl chloride, benzoyl chloride and acetic anhydride.

14. The method according to claim 12 , wherein the acid halide or acid anhydride is selected from the group consisting of acetyl chloride, benzoyl chloride and acetic anhydride.

15. The method according to claim 2 , wherein the volume of the organic solvent in milliliters in step (4) is 2 to 20 times of the mass of ropinirole hydrochloride in grams.

16. The method according to claim 3 , wherein the volume of the organic solvent in milliliters in step (4) is 2 to 20 times of the mass of ropinirole hydrochloride in grams.

17. The method according to claim 2 , wherein the molar amount of the concentrated hydrochloric acid in step (4) is 2 to 10 times of the molar amount of ropinirole hydrochloride.

18. The method according to claim 3 , wherein the molar amount of the concentrated hydrochloric acid in step (4) is 2 to 10 times of the molar amount of ropinirole hydrochloride.

19. The method according to claim 2 , wherein the organic solvent in step (4) is methanol, ethanol, isopropanol or n-butanol.

20. The method according to claim 3 , wherein the organic solvent in step (4) is methanol, ethanol, isopropanol or n-butanol.

Assignees

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

Inventors

• Tu Guoliang
• Xu Zhongming
• Zhou Tao
• Huang Wenfeng
• Zhang Shiwen

Classifications

• C07D209/34 Primary

  in position 2 · CPC title