Process for the manufacture of aripiprazole by using purified carbostyril compounds such as 7-(4-halobutoxy)-3,4-dihydro-2(1H)-quinolinones

Abstract

The present invention provides a process for purifying carbostyril derivatives such as 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone and 7-(4-chlorobutoxy)-3,4-dihydro-2(1H)-quinolinone and aripiprazole by passing a solution of the material in an organic solvent through a suitable absorbing material.

Description

Claims

1. A process for preparing aripiprazole comprising admixing a solution containing a purified carbostyril compound, such as 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone or 7-(4-chlorobutoxy)-3,4-dihydro-2(1H)-quinolinone with 1-(2,3-dichlorophenyl)piperazine mono hydrochloride and a base, e.g., potassium carbonate and optionally also a phase transfer catalyst e.g., tetra-butylammonium bromide to obtain aripiprazole.

2. A process for purifying carbostyril compounds comprising the steps of: a) passing a solution containing the carbostyril compound in an organic solvent through a suitable absorbing material;b) washing the absorbing material with a solvent;c) combining the wash solvent with the a solution containing the carbostyril compound; andd) optionally using the obtained solution in the next step to make aripiprazole.

3. The process of claim 2, wherein the carbostyril compound is 7-(4-halobutoxy)-3,4-dihydro-2(1H)-quinolinone, that is 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone or 7-(4-chlorobutoxy)-3,4-dihydro-2(1H)-quinolinone.

4. The process of claim 2, wherein the organic solvent is selected from the group consisting of toluene, ethyl benzene, xylenes, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, and mixtures thereof.

5. The process of claim 4, wherein the organic solvent is toluene.

6. The process of claim 2, wherein the suitable absorbing material is selected from the group consisting of aluminium oxide, Florisil®, Celite®, fumed silica gel, colloidal silica gel, chromatography grade silica gel, and combinations thereof.

7. The process of claim 6, wherein the suitable absorbing material is silica gel 60, which has an average particle size in the range of 40-200 microns.

8. The process of claim 7, wherein the silica gel 60 has a particle size in the range of 40-63 microns.

9. The process of claim 8, wherein the ratio between the carbostyril derivative and the silica gel is less than 1:10 (w/w).

10. The process of claim 9, wherein the ratio between the carbostyril derivative and the silica gel is less than 1:5 (w/w).

11. The process of claim 10, wherein the ratio between the carbostyril derivative and the silica gel is about 1:1 (w/w).

12. The process of claim 2, wherein the purification is carried out at ambient temperature.

13. A process for purifying aripiprazole comprising the steps of: a) passing a solution containing aripiprazole in an organic solvent through a suitable absorbing material;b) washing the absorbing material with a solvent;c) combining the wash solvent with the solution containing aripiprazole; andd) isolating aripiprazole.

14. The process of claim 13, wherein the organic solvent is selected from the group consisting of toluene, ethyl benzene, xylenes, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, and mixtures thereof.

15. The process of claim 14, wherein the organic solvent is toluene.

16. The process of claim 13, wherein isolating aripiprazole can be achieved by evaporating the solvent.

17. The process of claim 1, wherein aripiprazole is obtained having a purity of at least 98.5% (by HPLC).

18. The process of claim 17, wherein aripiprazole is obtained having a purity equal to or higher than 99.5% (by HPLC).