DESCRIPTION
The present invention provides a process for the preparation of 7-(4-chloro/bromobutoxy)-3,4-dihydrocarbostyril, which is useful as a key intermediate in the preparation of aripiprazole in presence of combination of bases.

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 and its intermediate 7-(4-chloro/bromobutoxy)-3,4-dihydrocarbostyril have been disclosed in application/patent No. US20060258869, US6995264, US20060079689, WO2007094009 and WO2007118923.

Subsequently, there is an ongoing need for the process of intermediate of aripiprazole, 7-(4-chloro/bromobutoxy)-3,4-dihydrocarbostyril, which is eco- friendly, cost-effective, and well suited for an industrial scale.

The present inventors found that the use of super base for preparing 7-(4-chloro/bromobutoxy)-3,4-dihydrocarbostyril of Formula II provides higher yield and reduces the formation of dimmer impurity in a shorter reaction period.

In one of the aspect, the present invention provides an improved process for the preparation of intermediate, 7-(4-chloro/bromobutoxy)-3,4-dihydrocarbostyril of Formula II

Formula II,
X=Cl, Br
which comprises reaction of hydroxy-3,4-dihydro-2(1H)-quinolinone of Formula III

Formula III
with 1-bromo-4-chlorobutane using super base in presence of water and a phase transfer catalyst.

In one of the embodiment of the present invention provides super base comprises combination of two or more bases. Suitable bases to prepare super base for conducting the reaction include, but are not limited to, ammonia, 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; organic bases such as triethyl amine, diisopropyl amine and the like.

In another embodiment of the present invention, the reaction may be performed using super base comprising combination of potassium bicarbonate and sodium hydroxide.

The mole ratio of super base that may be used in the reaction may vary depending upon the bases used. The molar ratio of two bases is in range from about 1-1.4 or vice-versa.

Suitable phase transfer catalyst that can be used for formation of 7-(4-chloro/bromobutoxy)-3,4-dihydrocarbostyril includes, but are not limited to, polyethylene glycols or quaternary ammonium salts such as tetrabutylammonium bromide, tetrabutylammoium iodide, tetrabutylammonium hydrogen sulfate, benyltriethylammonium chloride and the like.

Suitable temperature for performing the reaction may range from about 25 to about 100 °C or any temperature. The reaction may be carried out for a period of sufficient time, for example, for about 45 minutes to 2 hours.

The reaction can be performed not only in the presence of water, it may be performed in presence of organic solvent includes dimethylformamide (DMF), dimethyl acetamide (DMA), alcohol such as methanol, ethanol, isopropyl alcohol, and the like, or in combination of water thereof.

7-(4-chloro/bromobutoxy)-3,4-dihydrocarbostyril obtained from the present invention may have the purity greater than about 97% determined by high-performance liquid chromatography (HPLC), shorter reaction time.

7-(4-chloro/bromobutoxy)-3,4-dihydrocarbostyril obtained directly from the process of the present invention without involving any further purification has the content of dimmer impurity less than or equal to 1.0% by HPLC.

The intermediate, pure 7-(4-chloro/bromobutoxy)-3,4-dihydrocarbostyril, obtained from the present invention is subsequently utilized for the preparation of aripiprazole by the processes known in the prior art, for example, US5006528.

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 7-(4-chloro/bromobutoxy)-3,4-dihydrocarbostyril
A mixture of 7-hydroxy-3,4-dihydro carbostyril (10 gm), 1-bromo-4-chlorobutane (63.01 gm), potassium bicarbonate(8.56 gm), sodium hydroxide (3.4 gm), water (100 ml) and TBAB (1.0 gm) were stirred at a temperature of about 55-65 °C for a period of about 2 hour. After completion of the reaction, the reaction mixture was cooled to about 30-35 °C and then dichloromethane was charged (20 ml). The organic layer was separated and washed with water. The separated organic layer was concentrated and in the residue obtained cyclohexane (50 ml) was added and stirred for 60 minutes at a temperature of about 30-35 °C. The solid obtained was filtered, washed and dried to afford 7-(4-chloro/bromobutoxy)-3,4-dihydrocarbostyril.
Yield: 14 gm (90 %)
Purity by HPLC: 97.5% by HPLC
Dimer impurity: 0.7% by HPLC

We Claim:
1. A process for the preparation of 7-(4-chloro/bromobutoxy)-3,4-dihydrocarbostyril of Formula II

Formula II,
X=Cl, Br
which comprises reaction of hydroxy-3,4-dihydro-2(1H)-quinolinone of Formula III

Formula III
with 1-bromo-4-chlorobutane using super base in presence of water and a phase transfer catalyst.
2. The process according to claim 1, wherein said the super base comprising combination of two or more bases.
3. The process of claim2, wherein the molar ratio of two bases is in range from about 1-1.4 or vice-versa.
4. The process according to claim 2, wherein said bases are selected from hydroxides of alkali metals, carbonates of alkali metals, and bicarbonates of alkali metals or combination thereof.
5. The process according to claim 1, wherein said the super base comprising combination of potassium bicarbonate and sodium hydroxide.
6. The process according to claim 1, wherein said the phase transfer catalyst is selected from quaternary ammonium salts and polyethylene glycols.
7. The process according to claim 1, wherein said the phase transfer catalyst is tetrabutylammonium bromide.
8. The process according to claim 1, wherein said reaction is performed at a temperature of about 50 to 95°C.
9. The purity of 7-(4-chloro/bromobutoxy)-3,4-dihydrocarbostyril prepared according to the claim 1, is greater than or equal to 97.5% determined by HPLC.
10. The compound 7-(4-chloro/bromobutoxy)-3,4-dihydrocarbostyril prepared according to the process of claim 1, has the content of dimmer impurity less than or equal to 1.0% by HPLC.

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

(Mandar Kodgule)
Authorized Signatory