Method for the enantiomoeric separation of optical active amlodipine

• US 7,678,921 B2
• Filed: 12/03/2004
• Issued: 03/16/2010
• Est. Priority Date: 12/05/2003
• Status: Active Grant

• Current Assignee: Shijiazhuang Pharmaceutical Group Huasheng Pharma Company Limited (CSPC Pharmaceutical Group Limited)
• Original Assignee: Shijiazhuang Pharmaceutical Group Huasheng Pharma Company Limited (CSPC Pharmaceutical Group Limited)
• Inventors: Ma, Hui, Chen, Yujie, Zhao, Xianfeng, Zhong, Nanping
• Primary Examiner(s): NORTHINGTON DAVIS, ZINNA
• Application Number:
  US10/596,209
• Publication Number:
  US 20070093661A1
• Time in Patent Office: 1,929 Days
• Field of Search: None
• US Class Current: 546/321
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 211/90 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Abstract

The present invention relates to the preparation of the (S)-(−)-amlodipine and (R)-(+)-amlodipine by means of enantiomeric separation of racemic amlodipine mixture, in which, L- or D-tartaric acid is used as resolution agent, and organic solvent containing 2-butanone is used as solvent. The 2-butanone used in the present invention has the advantage of low boiling point, low toxicity, litter pollution, and the method is suitable for large-scaled production.

Claims

1. A method for preparing (S)-(−

)-amlodipine comprising;

dissolving racemic amlodipine and L-(+)-tartaric acid in an organic solvent containing 2-butanone to yield (S)-(−

)-amlodipine-L-(+)-tartrate precipitate by reaction;

separating the precipitate;

recrystallizating the precipitate by using a lower alcohol solvent to obtain a solid;

adding a lower alkyl halide into the solid; and

neutralizing with an aqueous alkali to give (S)-(−

)-amlodipine.

2. The method for preparing (S)-(−

)-amlodipine according to claim 1, wherein said organic solvent is 2-butanone or mixture of 2-butanone with a cosolvent.

3. The method for preparing (S)-(−

)-amlodipine according to claim 2, wherein said cosolvent is selected from the group consisting of methanol, ethanol, n-butanol, acetone, 2-pentanone, ethyl ether, methyl ethyl ether, ethyl acetate, ethyl formate, dichloromethane and chloroform.

4. The method for preparing (S)-(−

)-amlodipine according to claim 1, wherein the molar ratio of racemic amlodipine to L-(+)-tartaric acid is 1;

0.25˜

0.8.

5. The method for preparing (S)-(−

)-amlodipine according to claim 4, wherein the molar ratio of racemic amlodipine to L-(+)-tartaric acid is 1;

0.5.

6. The method for preparing (S)-(−

)-amlodipine according to claim 1, wherein said lower alcohol solvent is selected from the group consisting of ethanol, methanol and isopropanol.

7. A method for preparing (R)-(+)-amlodipine comprising:

dissolving racemic amlodipine and D-(−

)-tartaric acid in an organic solvent containing 2-butanone to yield (R)-(+)-amlodipine-D-(−

)-tartrate precipitate by reaction;

separating the precipitate;

recrystallizating the precipitate by using a lower alcohol solvent to obtain a solid;

adding a lower alkyl halide into the solid; and

neutralizing with an aqueous alkali to give (R)-(+)-amlodipine.

8. The method for preparing (R)-(+)-amlodipine according to claim 7, wherein said organic solvent is 2-butanone or mixture of 2-butanone with a cosolvent.

9. The method for preparing (R)-(+)-amlodipine according to claim 8, wherein said cosolvent is selected from the group consisting of methanol, ethanol, n-butanol, acetone, 2-pentanone, ethyl ether, methyl ethyl ether, ethyl acetate, ethyl formate, dichloromethane and chloroform.

10. The method for preparing (R)-(+)-amlodipine according to claim 7, wherein the molar ratio of racemic amlodipine to D-(−

)-tartaric acid is 1;

0.25˜

0.8.

11. The method for preparing (R)-(+)-amlodipine according to claim 10, wherein the molar ratio of racemic amlodipine to D-(−

)-tartaric acid is 1;

0.5.

12. The method for preparing (R)-(+)-amlodipine according to claim 7, wherein said lower alcohol solvent is selected from the group consisting of ethanol, methanol and isopropanol.