Indian Patents. 279496:AN IMPROVED PROCESS FOR THE PREPARATION OF ARIPIPRAZOLE

Title of Invention	AN IMPROVED PROCESS FOR THE PREPARATION OF ARIPIPRAZOLE
Abstract	The present invention provides a process for the preparation of Aripiprazole, which comprise reacting 7-hydroxy-3,4dihydro-2(1H)quinolinone, 1,4-dichlorobutane, a base and dimethyl acetamide to obtain 7-(4-bromobutoxy)-3,4-dihydro-2-(1H)-quinolone; and reacting 7-(4-bromobutoxy-3,4-dihydro-2-(1H)-quinolone, 1-(2,3-dichloropheny1) piperizine, a base and sodium iodide in dimethy1 acetamide

Full Text	In another embodiment of the present invention, the step (e) is performed by using alkali iodide such as sodium iodide, potassium iodide and the like, preferably sodium iodide. In yet another embodiment of the present invention, the step (c) is performed by using an alkali solution, which is selected from the group comprising sodium hydroxide solution, potassium hydroxide solution, sodium carbonate solution, potassium carbonate solution, sodium hydrogen carbonate solution and the like, most preferably sodium hydroxide solution. In still another embodiment of the present invention step (a) and (e) is performed at the temperature in the range of 20°C to 100°C, most preferred temperature range for step (a) is 90°C to 95°C and for step (e) is 90°C to 97°C. The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway. Examples Preparation ofStaee 1 A mixture of dimethylacetamide (16.8L), 7-hydroxy-3,4-dihydrocarbostyril (2.4Kg), 1,4-dichlorobutane (16.8Kg) and potassium carbonate (2.04Kg) were heated to 90°C to 95°C under stirring for 15 to 16 hrs. On completion of the reaction, the reaction mass was cooled, filtered and the residue was washed with 2 x 2.4 L of dimethyl acetamide. The filtrate was distilled to 3 to 4 Vol under reduced pressure (wherein temperature should be less than 110 °C). The reaction mass was cooled to 60°C to 70 °C and 10 L (10 Vol) of sodium hydroxide (0.5%) solution was charged portion wise. The reaction mass was further cooled to 25°C to 30 °C and was stirred for 1 to 2 hrs. The solid product formed was filtered, washed with water up to neutral pH 7) and dried at 45 °C to 50°C under vacuum for 10 to 16 hours to obtain 2.9 - 3.6Kg of 7-(4-chlorobutoxy)-3,4- dihydrocarbostyril. (Yield = 75- 95 % and HPLC Purity > 90 %). loco Ah &/ax>£?4 Preparation of Staee 2 A mixture of 7-(4-chlorobutoxy)-3,4-dihydrocarbostyril (50g) obtained from stage I, l-(2,3-dichlorophenyl)piperazine hydrochloride (50.lg), potassium carbonate (54.45g) and sodium iodide (32.48g,) in dimethyl acetamide (500 mL) were heated to 90°C to 97 °C under stirring for 1 to 2 hrs. On completion of the reaction, the reaction mixture was cooled to room temperature and was diluted with 1.2L of dichloromethane. The organic layer was washed with 3 x 500mL of 0.5 % sodium hydroxide solution. The organic layer was evaporated to 5 Vol under reduced pressure. The reaction mixture was cooled to 0°C to 5 °C and was stirred for 2hrs. The solid obtained was filtered and was washed with 2 x lOOmL of ethyl acetate. The crude product thus obtained was recrystallized from ethanol to obtain Aripiprazole (50-70 g) in pure form (Yield = 56-80 % and HPLC Purity > 99 %). Advantages (1) Simple method of Isolation of compound of formula (III) without using any additional solvent (s) for extraction (s). (2) Use of 1,4-dichlorobutane is cost effective and comparatively less hazardous and less irritant as compared to 1,4-dibromobutane and l-bromo-4-chlorobutane. (3) The recovered dimethylacetamide solvent, which contained 1,4 dichlorobutane can be recycled and used in subsequent batches. (4) 1,4 dichlorobutane is selected as a reactant for the preparation of a compound of formula (III), since its boiling point is relatively close to that of dimethylacetamide and can be co-distilled and reused. (4) A process according to claim 1 wherein, the said alkali iodide is selected from the group comprising sodium iodide, potassium iodide and the like, most preferably sodium iodide. (5) A process according to claim 1 wherein, the said alkali solution is selected from the group comprising sodium hydroxide solution, potassium hydroxide solution, sodium carbonate solution, potassium carbonate solution, sodium hydrogen carbonate solution and the like, most preferably sodium hydroxide solution. (6) A process according to claim 1 wherein, step (a) and (e) are performed at a temperature in the range of 20°C to 100°C. (7) A process according to claim 6 wherein most preferred temperature range for step (a) is 90°C to 95°C and for step (e) is 90°C to 97°C.

Full Text

In another embodiment of the present invention, the step (e) is performed by using alkali iodide such as sodium iodide, potassium iodide and the like, preferably sodium iodide.
In yet another embodiment of the present invention, the step (c) is performed by using an alkali solution, which is selected from the group comprising sodium hydroxide solution, potassium hydroxide solution, sodium carbonate solution, potassium carbonate solution, sodium hydrogen carbonate solution and the like, most preferably sodium hydroxide solution.
In still another embodiment of the present invention step (a) and (e) is performed at the temperature in the range of 20°C to 100°C, most preferred temperature range for step (a) is 90°C to 95°C and for step (e) is 90°C to 97°C.
The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.
Examples
Preparation ofStaee 1
A mixture of dimethylacetamide (16.8L), 7-hydroxy-3,4-dihydrocarbostyril (2.4Kg), 1,4-dichlorobutane (16.8Kg) and potassium carbonate (2.04Kg) were heated to 90°C to 95°C under stirring for 15 to 16 hrs. On completion of the reaction, the reaction mass was cooled, filtered and the residue was washed with 2 x 2.4 L of dimethyl acetamide. The filtrate was distilled to 3 to 4 Vol under reduced pressure (wherein temperature should be less than 110 °C). The reaction mass was cooled to 60°C to 70 °C and 10 L (10 Vol) of sodium hydroxide (0.5%) solution was charged portion wise. The reaction mass was further cooled to 25°C to 30 °C and was stirred for 1 to 2 hrs. The solid product formed was filtered, washed with water up to neutral pH 7) and dried at 45 °C to 50°C under vacuum for 10 to 16 hours to obtain 2.9 - 3.6Kg of 7-(4-chlorobutoxy)-3,4- dihydrocarbostyril. (Yield = 75- 95 % and HPLC Purity > 90 %).
loco Ah &/ax>£?4
Preparation of Staee 2
A mixture of 7-(4-chlorobutoxy)-3,4-dihydrocarbostyril (50g) obtained from stage I, l-(2,3-dichlorophenyl)piperazine hydrochloride (50.lg), potassium carbonate (54.45g) and sodium iodide (32.48g,) in dimethyl acetamide (500 mL) were heated to 90°C to 97 °C under stirring for 1 to 2 hrs. On completion of the reaction, the reaction mixture was cooled to room temperature and was diluted with 1.2L of dichloromethane. The organic layer was washed with 3 x 500mL of 0.5 % sodium hydroxide solution. The organic layer was evaporated to 5 Vol under reduced pressure. The reaction mixture was cooled to 0°C to 5 °C and was stirred for 2hrs. The solid obtained was filtered and was washed with 2 x lOOmL of ethyl acetate. The crude product thus obtained was recrystallized from ethanol to obtain Aripiprazole (50-70 g) in pure form (Yield = 56-80 % and HPLC Purity > 99 %).
Advantages
(1) Simple method of Isolation of compound of formula (III) without using any additional solvent (s) for extraction (s).
(2) Use of 1,4-dichlorobutane is cost effective and comparatively less hazardous and less irritant as compared to 1,4-dibromobutane and l-bromo-4-chlorobutane.
(3) The recovered dimethylacetamide solvent, which contained 1,4 dichlorobutane can be recycled and used in subsequent batches.
(4) 1,4 dichlorobutane is selected as a reactant for the preparation of a compound of formula (III), since its boiling point is relatively close to that of dimethylacetamide and can be co-distilled and reused.

(4) A process according to claim 1 wherein, the said alkali iodide is selected from the group comprising sodium iodide, potassium iodide and the like, most preferably sodium iodide.
(5) A process according to claim 1 wherein, the said alkali solution is selected from the group comprising sodium hydroxide solution, potassium hydroxide solution, sodium carbonate solution, potassium carbonate solution, sodium hydrogen carbonate solution and the like, most preferably sodium hydroxide solution.
(6) A process according to claim 1 wherein, step (a) and (e) are performed at a temperature in the range of 20°C to 100°C.
(7) A process according to claim 6 wherein most preferred temperature range for step (a) is 90°C to 95°C and for step (e) is 90°C to 97°C.

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Patent Number

279496

Indian Patent Application Number

1050/CHE/2006

PG Journal Number

04/2017

Publication Date

27-Jan-2017

Grant Date

24-Jan-2017

Date of Filing

20-Jun-2006

Name of Patentee

Orchid Chemicals & Pharmaceuticals Ltd.

Applicant Address

Orchid Towrs, 313, Valluvar Kottam High Road Nungambakkam, Chennai -600 034.

Inventors:

#	Inventor's Name	Inventor's Address
1	Siripragada Mahender Rao	Orchid Chemicals & Pharmaceuticals Ltd, 476/14, Old Mahablipuram Road, Sholinganallur, Chennai-600 119.
2	Nagabushanam Nagamani	Orchid Chemicals & Pharmaceuticals Ltd, 476/14, Old Mahablipuram Road, Sholinganallur, Chennai 600 119,
3	Santhosh Unni	Orchid Chemicals & Pharmaceuticals Ltd, 476/14, Old Mahablipuram Road, Sholinganallur, Chennai 600 119,
4	Manoharan Muthu Tamizh	Orchid Chemicals & Pharmaceuticals Ltd, 476/14, Old Mahablipuram Road, Sholinganallur, Chennai 600 119,

PCT International Classification Number

A61K9/20

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA