DESCRIPTION

The present invention provides a process for the preparation of aripiprazole from 7-(4-halobutoxy)-3,4-dihydrocarbostyril by using solvent system comprising combination of two or more solvents, wherein formation of dimmer impurity is less than 0.15%.

Aripiprazole of Formula I is chemically known as 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydrocarbostyril.

Formula I
This compound is psychotropic drug that is available as tablets, orally disintegrating tablets, oral solution, injection, and a solution for intramuscular injection under the trade name ABILIFY®. Aripiprazole is approved specifically for the treatment of schizophrenia.

US 4,734,416 patent describes Aripiprazole generically. US 5006528 patent discloses Aripiprazole specifically and a process for the preparation thereof.

Various processes for aripiprazole have been disclosed in prior art references, for exmaple, Journal of Medicinal Chemistry, Vol.41, No.5, 658-667, (1988), US20060258869, US6995264, US20060079689, WO2007094009 and WO2007118923.

The present inventors while developing the process for the preparation of Aripirazole have found that the use of solvent system comprising combination of two or more solvents for preparing aripiprazole from the starting material, 7-(4-halobutoxy)-3,4-dihydrocarbostyril reduces the dimmer impurity with improved yield and process is found to be suitable at industrial scale up.

In one of the aspect of the present invention provides a process for the preparation of aripiprazole of formula I, which comprises condensation of 7-(4-halobutoxy)-3,4-dihydrocarbostyril of formula II

Formula II
X=Cl, Br
with 1-(2,3-dichlorophenyl)piperzine hydrochloride of formula III using base in presence of solvent comprising combination of two or more solvents.

Formula III

The intermediate, 7-(4-halobutoxy)-3,4-dihydrocarbostyril of formula II, used as starting material may be prepared by the processes known in the prior art via US 20060258869, US 20060079689, WO 2007094009 and WO2007118923. The halo compound or X defined as X chloro and bromo substituted compound of dihydrocarbostyril of formula II.

Suitable base for conducting the reaction include, but are not limited to, hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate, and the like; and bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate, and the like.

Further, the condensation of 7-(4-halobutoxy)-3,4-dihydrocarbostyril with 1-(2,3-dichlorophenyl)piperzine hydrochloride may be performed in presence of alkali metal iodide such as potassium iodide, sodium iodide and the like as the reaction accelerator.

Suitable solvent used for the combinations may be selected from polar aprotic solvents such as dimethyl formamide, dimethyl acetamide, dimethylsulfoxide, N-methylpyrrolidone (NMP); alcohol such as isopropyl alcohol, n-butanol and the like; nitriles such as acetonitrile, propionitrile, and the like.

The condensation reaction may be performed at a suitable temperature of about 20-100°C, depends on the solvent used; In one embodiment of the present condensation process is conducted at a temperature of about 70-80 °C.

Aripiprazole, obtained from the condensation, may have the purity greater than about 99% and the content of dimmer impurity of Formula IV less than or equal to 0.15% determined by HPLC.

Formula-IV
Aripiprazole, prepared by the process of the invention, may be treated with hydrochloric acid in presence of alcohol such as ethanol, isopropyl alcohol, and n-butanol to provide aripiprazole hydrochloride salt, which is further converted to aripiprazole by neutralization with base such as sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate and like to provide aripiprazole. Finally, the obtained aripiprazole is converted to crystalline Form B of aripiprazole.

In another aspect of the present invention provide a process for preparing anhydrous crystalline form B of aripiprazole the process includes the step of;
a) contacting of aripiprazole in alcohol,
b) isolating the solid from the reaction mixture thereof,
c) suspend the solid obtained in step b) in water and heated to temperature of about 50-90°C;
d) isolating the Aripiprazole Form-B from the reaction mixture thereof.

Any form of aripiprazole, such as any crystalline or amorphous form obtained by any method may be used for converting into Aripiprazole Form B. The aripiprazole include of aripiprazole obtained from its salts such as hydrochloride salt. The Aripiprazole is combined with C-1 to C-4 alcohols such as methanol, ethanol, and isopropyl alcohol at room temperature. Optionally, the obtained solution may be heated to temperature about 70 to 85°C or reflux and maintained for a suitable time period.

The solid may be isolated from the solution by techniques such as distillation of the solvent to a desired extent to produce a suspension, cooling to below 15°C or combination of both the techniques. The obtained suspension may be maintained at below 15°C for a suitable time period to increase the precipitation of solid.

The solid may be isolated by the techniques known in the art. For example, the solid may be isolated using filtration technique.

The obtained wet solid may be used further for preparing suspension in water at room temperature; optionally the solution may be heated to higher temperatures, such as about 30 to 90°C or reflux. The suspension may be maintained at about 30 to about 90°C for a period of about 30 minutes to about 3 hours or more.

The solid may be isolated by the techniques known in the art. For example, it may be isolated by using filtration, centrifugation or decanting.

The Aripiprazole is dried in tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like at about 50-90°C under reduced pressure. The drying may be carried out for any time periods, such as, for example, for about 1 to about 15 hours or longer, to provide desired crystalline anhydrous form B of aripiprazole.

The obtained anhydrous crystalline form B may have the purity greater than about 99.8% determined by HPLC.

The present invention is further illustrated by the following example, which does not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.

EXAMPLES
Preparation of aripiprazole
7- (4- chloro/bromobutoxy)-3,4-dihydro carbostyril (10 gm) and 1-(2,3-dichlorophenyl)piperazine hydrochloride(10 gm) are suspended in N,N-dimethylacetamide (50 ml) and acetonirile (50 ml) with simultaneous stirring and maintained for about 10 minutes. Potassium carbonate (15 gm) and potassium iodide (7.65 gm) are added to the reaction mixture and stirred at a temperature of about 70-75°C for a period of about 10 hours. After completion of the reaction, the reaction mixture cooled to a temperature of about 5-10°C, stirred for 60 minutes and filtered. The resultant wet solid is suspended into water (150 ml) at a room temperature and stirred for a 3 hours. The suspension obtained is filtered and subjected for drying at a temperature of about 75-80°C for about 8 hours to afford aripiprazole.
Yield: 15 gm (87%)
Purity by HPLC: 99.27%
Dimer impurity: 0.14% by HPLC
Other impurities: less than 0.05% by HPLC.

Purification of Aripiprazole
Aripiprazole (160.0 gm, dimmer impurity 0.5%) is suspended in isopropyl alcohol (1600.0 ml) with simultaneous stirring, heated to a temperature of about 70-80 °C and maintained for 30 minutes. Concentrated hydrochloric acid (14.7 gm) is added to the reaction mixture and then refluxed for 5 hours at the same temperature. The reaction mass is cooled to a temperature of about 5-10°C, stirred for 60 minutes and then filtered. The resultant solid is washed with chilled isopropyl alcohol (160 ml) and suck dried to get aripiprazole hydrochloride. The wet cake is suspended in dichloromethane (1600.0 ml) and water (320.0 ml), and then subjected to pH adjustment to about 8.4-8.8 by using 20% aqueous sodium carbonate solution (125.0 ml). Dichloromethane layer is separated, washed with water (320.0 ml) and concentrated to get residue. The wet cake obtained is suspended in water (1600.0 ml) and stirred for 3 hrs at about 75-80°C. The reaction suspension is filtered and washed with water (160.0 ml). The resultant solid is dried at about 75-80°C for about 6 hrs to get Aripiprazole.
Yield: 138 gm
Purity by HPLC: 99.8 %,
Single maximum impurity 0.05 %
Ethanol content: Not detected
Moisture content: 0.2 %
Dimmer Impurity: 0.02%

We Claim:
1. A process for the preparation of aripiprazole, which comprises condensation of 7-(4-halobutoxy)-3,4-dihydrocarbostyril of formula II

Formula II

X=Cl, Br
with 1-(2,3-dichlorophenyl)piperzine hydrochloride of formula III

Formula III
using base in presence of solvent comprising combination of two or more solvents.
2. The process of claim 1, wherein said base is selected from hydroxides of alkali metals, carbonates of alkali metals and bicarbonates of alkali metals.
3. The process of claim 1, wherein said base is selected from bicarbonates of alkali metals such as potassium bicarbonate.
4. The process of claim 1, wherein said condensation reaction is performed in presence of accelerator such as potassium iodide.
5. The process of claim 1, wherein said combination of solvents are selected from polar aprotic solvent, alcohol and nitriles.
6. A process for the purification of Aripiprazole, the process comprises of;
a) treating aripiprazole with hydrochloric acid in of alcohol ,
b) isolating aripiprazole hydrochloride from the reaction mixture thereof,
c) suspending isolated product of step b) in dichloromethane and treated with base,
d) isolating Aripiprazole from the reaction mixture thereof.
7. The process of claim 1 and 6 wherein isolating of aripiprazole always comprises of heating aripiprazole with water at temperature 50-90°C.
8. The compound aripiprazole prepared according to the process of claim 1 and 6, have the content of dimmer impurity less than or equal to 0.15% by HPLC.
9. A process for preparing anhydrous crystalline form B of aripiprazole the process comprises of;
a. contacting of aripiprazole in alcohol,
b. isolating the solid from the reaction mixture thereof,
c. suspend the solid obtained in step b) in water and heated to temperature of about 50-90°C;
d. isolating the Aripiprazole Form-B from the reaction mixture thereof.
10. The process of claim 7 and 9, wherein alcohol is one or more C-1 to C-4 alcohols.

Dated this 28th day of December, 2010 For Wockhardt Limited

(Mandar Kodgule)
Authorized Signatory