F O R M 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. – “A process for the preparation of Aripiprazole”
2. Applicant(s)
(a) NAME : ALEMBIC LIMITED
(b) NATIONALITY : An Indian Company
(c) ADDRESS : Alembic Campus, Alembic Road, Vadodara-390 003, Gujarat, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed :

Field of the Invention:
The present invention relates to an improved process for the preparation of 7-[4[-(2, 3-dichlorophenyl)-l-piperazinyl] butoxy] 3, 4-dihydro-2-(lH) quinolinone (Aripiprazole), particularly, the present invention relates to the preparation of 7-(4-bromobutoxy)-3, 4-dihydrocarbostyril of formula (I)

Background of the invention:
The chemical name of Aripiprazole is 7-[4[-(2, 3-dichlorophenyl)-l-piperazinyl] butoxy] 3, 4-dihydro-2-(lH) quinolinone and molecular formula is C23H27C12N3O2 and molecular weight is 448.39. Aripiprazole is represented by structural formula (II)

Aripiprazole is marketed by Bristol Myers Squibb under tradename Ability and is indicated for the treatment of Alzheimer's dementia, antipsychotic disorders and bipolar disorders.
7-[4-[4-(2,3-dichlorophenyl)piperazin-l-yl]butoxy]-l,2,3,4-tetrahydroquinolin-2-one exhibits high affinity for dopamine D2 and D3, serotonin 5-HT1A and 5- HT2A receptors, moderate affinity for dopamine D4, serotonin 5-HT2C and 5-HT7, alpha-1-adrenergic and histamine Hi receptors. Aripiprazole functions as a partial agonist at the dopamine D2 and the serotonin 5-HTIA receptors, and as an antagonist at serotonin 5-HT2A receptor.
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7-(4-bromobutoxy)-3, 4-dihydrocarbostyril of formula (I) is a useful intermediate for the preparation 7-[4-[4-(2, 3-dichlorophenyl) piperazin-1-yl] butoxy]-l, 2, 3, 4-tetrahydroquinolin-2-one of formula (II), which is also known as Aripiprazole and is useful for the treatment of Schizophrenia.
7-[4-[4-(2, 3-dichlorophenyl) piperazin-1-yl] butoxy]-l, 2, 3, 4-tetrahydroquinolin-2-one is broadly disclosed in US patent no. 4,734,416 and specifically disclosed in US patent no. 5,006,528. The process for the preparation of 7-[4-[4-(2, 3-dichlorophenyl) piperazin-1-yl] butoxy]-l, 2, 3, 4-tetrahydroquinolin-2-one is well disclosed in US Patent no. 5,006,528.

l-(2,3-dichlorophenyl) piperazine or salt

Scheme-1
3
US Patent no. 5,006,528 provides a process for the preparation of 7-(4-bromobutoxy)-3, 4-dihydrocarbostyril of formula (I) in water in basic conditions. Water can often be difficult to remove from reaction mixtures.

Journal of Medicinal Chemistry, Vol. 41, No.5, 658-667, 1998 discloses the preparation of 7-(4-bromobutoxy)-3, 4-dihydrocarbostyril by alkylation of 7-hydroxy-tetrahydroquinolinone with 1,4-dibromobutane in the presence of potassium carbonate in N,-N-dimethylformamide (DMF). The recovery of DMF can be very difficult. Moreover, DMF is harmful by inhalation, ingestion or skin contact. It may act as a carcinogen and long-term exposure may result in kidney or liver damage.
In summary, process disclosed in prior art for the preparation of 7-(4-bromobutoxy)-3, 4-dihydrocarbostyril, are tedious and requires laborious column chromatography. Therefore, there is a need to develop a process for preparing 7-(4-bromobutoxy)-3, 4-dihydrocarbostyril, which should be free from the above mentioned drawbacks and should be simple, economical and does not involve laborious column chromatography.
With an objective of preparing more than 90% pure 7-(4-bromobutoxy)-3, 4-dihydrocarbostyril, the present inventors has directed the research, work towards developing a process for preparing of 7-(4-bromobutoxy)-3, 4-dihydrocarbostyril.
The present inventors had tried several solvent such as dimethylformamide, methylene dichloride, water or tetrahydrofuran to achieve the desired purity of 7-(4-bromobutoxy)-3, 4-dihydrocarbostyril but the present inventors did not get desired purity. Surprisingly, when present inventors had carried out the reaction of 7-hydroxy-tetrahydroquinolinone with 1, 4-dibromobutane in the presence of base and selectively using dimethylacetamide as solvent to obtain 7-(4-bromobutoxy)-3, 4-dihydrocarbostyril, compound obtained i.e. 7-(4-bromobutoxy)-3, 4-dihydrocarbostyril with more than 90% of purity.
Therefore, unexpectedly the present inventors have found that when 7-hydroxy-tetrahydroquinolinone is reacted with 1, 4-dibromobutane in the presence of base in dimethylacetamide, it gives 7-(4-bromobutoxy)-3, 4-dihydrocarbostyril with significantly improved purity (>90%). Moreover, this makes the process for the preparation of Aripiprazole operationally simple and easily applicable at an industrial scale.
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Surprisingly, because of the selective use of dimethylacetamide as a solvent removes the unwanted impurity and provides 7-(4-bromobutoxy)-3, 4-dihydrocarbostyril of formula (I) with purity of more than 90% which in turn helps in improving the resultant compound i.e. Aripiprazole.
OBJECT OF THE INVENTION:
Therefore, it is an object of the invention is to provide improved process for the preparation of 7-(4-bromobutoxy)-3, 4-dihydrocarbostyril.
Another object of the invention is to provide process for the preparation of 7-[4-[4-(2, 3-dichlorophenyl) piperazin-1-yl] butoxy]-l, 2, 3, 4-tetrahydroquinolin-2-one.
A further object of the present invention is to provide an improved process for preparing preparation of 7-(4-bromobutoxy)-3, 4-dihydrocarbostyril, which is operationally simple, easy to handle and feasible at commercial scale.
Another object of the present invention is to provide cost effective process for the preparation of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril.
Yet another object of the present invention is to provide 7-(4-bromobutoxy)-3, 4-dihydrocarbostyril with high purity.
A furthermore object of the present invention is to provides a process for the preparation of Aripiprazole comprising a step of, reacting 7-hydroxy-tetrahydroquinolinone of formula (III)
HO

(III)
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with 1,4-dibromobutane in the presence of base in dimethylacetamide to obtain 7-(4-bromobutoxy)-3,4-dihydrocarbostyril of formula (I)

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the preparation of Aripiprazole comprising a step of, reacting 7-hydroxy-tetrahydroquinolinone of formula (III)

Scheme-2
6
with 1,4-dibromobutane in the presence of base in dimethylacetamide to obtain 7-(4-bromobutoxy)-3,4-dihydrocarbostyril of formula (I)


Base is selected from NaOH, KOH, Ca (OH)2, Na2C03, K2C03 or NaHC03. Preferably, the base is NaOH, KOHor K2C03.
The reaction of 7-hydroxy-tetrahydroquinolinone with 1, 4-dibromobutane in the presence of base in dimethylacetamide is carried out at ambient temperature.
After completion of the reaction, the reaction mixture was cooled at ambient temperature and D.M water was added to it. The reaction mixture was extracted with ethylacetate. Organic layer was separated and washed with 5% brine and finally dried over sodium sulphate. The organic layer was evaporated to dryness optionally under reduced pressure at 45°C to obtain residue. Residue is treated with cyclohexane to give precipitates of 7-(4-bromobutoxy)-3, 4-dihydrocarbostyril.
The present invention relates to an improved process for the preparation of 7-[4-[4-(2, 3-dichlorophenyl) piperazin-1-yl] butoxy]-!, 2, 3,4-tetrahydroquinolin-2-one of formula (II)

comprising the steps of,
a) reacting 7-hydroxy-tetrahydroquinolinone of formula (III)
HO

(III)
with 1, 4-dibromobutane in the presence of base in solvent dimethylacetamide to obtain 7-(4-bromobutoxy)-3,4-dihydrocarbostyril of formula (I)
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b) condensing 7-(4-bromobutoxy)-3, 4-dihydrocarbostyril of formula (I)

with l-(2, 3-dichlorophenyl) piperazine of formula (IV)

in the presence of triethylamine and sodium iodide in solvent acetonitrile to obtain 7-[4-[4-(2, 3-dichlorophenyl) piperazin-1-yl] butoxy]-l0 2, 3, 4-tetrahydroquinolin-2-one of formula (II)

The condensation of 7-(4-bromobutoxy)-3, 4-dihydrocarbostyril with l-(2, 3-dichlorophenyl) piperazine in the presence of triethylamine and sodium iodide in acetonitrile is carried out at reflux temperature.
The reaction mass is stirred at 55°C for 3.5 to 4.5 hours. D.M water is added to reaction mass and stirred for 30 min at ambient temperature. The mass is filtered and washed with 50% aqueous acetonitrile and water till pH of filtrate comes to 7.0-7.5. The solid is dried in hot air oven at 60 °C to give Aripiprazole, subsequently is purified using ethanol.
The present invention provides process of preparation of 7-(4-bromobutoxy)-3, 4-dihydrocarbostyril of formula (I), which is simple, environment friendly, economical and leads to an enhanced purity.
Following are the experiments which did not give the 7-(4-bromobutoxy)-3, 4-dihydrocarbostyril of desired purity.
Experiment-I
7-hydroxy-3, 4-dihydrocarbostyril was reacted with 1, 4-dibromo butane in dimethylformamide solvent using base at 60 °C for 5 hours.
Result: Purity of 7-(4-bromobutoxy)-3, 4-dihydrocarbostyril was 80.7% and Dimer 11.34%. Conclusion: Purity of the compound was substantially less than desired.
Experiment-II
7-hydroxy-3, 4-dihydrocarbostyril was reacted with 1, 4-dibromo butane in methylene dichloride solvent using base at 35-40 °C for 4 - 5 hours.
Result: Conversion on in process TLC analysis was only 50-60%. Discontinued reaction. Conclusion: Reaction did not occur.
Experiment-III
7-hydroxy-3, 4-dihydrocarbostyril was reacted with 1, 4-dibromo butane in water solvent using
NaOCH3 at 35-40 °C for 4 - 5 hours.
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Result: Reaction not proceeded and end-up with starting material. Conclusion: Reaction did not occur.
Experiment-IV
7-hydroxy-3, 4-dihydrocarbostyril was reacted with 1, 4-dibromo butane in THF solvent using
base at 60 °C for 8 hours.
Result: Purity of 7-(4-bromobutoxy)-3, 4-dihydrocarbostyril was 82%.
Conclusion: Purity of the compound was substantially less than desired.
The process of the present invention is described by the following examples, which are illustrative only and should not be construed so as to limit the scope of the invention in any manner.
Example 1:
Preparation of 7-(4-bromobutoxy)-3, 4-dihydrocarbostyril:
1, 4-dibromo butane (509ml) was added to a stirred solution of. 7-hydroxy-3, 4-dihydrocarbostyril (100 gm) in dimethylacetamide (500 ml) at ambient temperature. The reaction mixture was heated at 36° to 40°C. Sodium hydroxide (33.1 gm) was added to the reaction mixture at the interval of 30 min (Complete the addition of Sodium hydroxide in 9 equal fractions in 4.0 hours). The reaction mixture was cooled at ambient temperature and D.M Water was added to it. The reaction mixture was extracted with ethylacetate. Organic layer was separated and washed with 5% brine and finally dried over sodium sulphate. The organic layer was evaporated to dryness under reduced pressure (10 mm) at 45°C to obtain residue. To the residue cyclohexane (1000 ml) was added to give precipitates of 7-(4-bromobutoxy)-3, 4-dihydrocarbostyril.
Yield: 127 gm (69.78%)
Purity by HPLC ~ 92%
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Example 2:
Preparation of 7-[4-[4-(2, 3-dichlorophenyl) piperazin-1-yl] butoxy]-l,2,3,4-tetrahydro
quinolin-2-one (Aripiprazole):
A mixture of 7-(4-bromobutoxy)-3, 4-dihydrocarbostyril (100 gm) and sodium iodide (75.5 gm) in acetonitrile (600 ml) was stirred at ambient temperature and refluxed for 60 min. Reaction mass was cooled to 50° to 60°C. Triethylamine (50 ml) was added to the reaction mass followed by addition of solution of l-(23 3-dichlorophenyl) piperazine (100 gm) in acetone. The reaction mass was stirred at 55°C for 3.5 to 4.5 hours. DM Water (800 ml) was added to reaction mass and stirred for 30 min at ambient temperature. The mass was filtered and .washed with 50% aqueous acetonitrile and water till pH of filtrate came to 7.0-7.5. The solid was dried in hot air oven at 60 °C to give Aripiprazole, subsequently is purified using ethanol. Yield: 122 gm (81.33%) Purity by HPLC - >99%
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We Claim:
1. A process for the preparation of Aripiprazole comprising a step of, reacting 7-hydroxy-tetrahydroquinolinone of formula (III)

with 1,4-dibromobutane in the presence of base in dimethylacetamide to obtain 7-(4-bromobutoxy)-3,4-dihydrocarbostyril of formula (I) having purity more than 90%.

2. A process according to claim 1, wherein the said base is selected from the group comprising of from NaOH, KOH, Ca (OH)2, Na2C03, K2C03 or NaHC03.
3. A process for the preparation of 7-[4-[4-(2, 3-dichlorophenyl) piperazin-1-yl] butoxy]-l, 2, 3, 4-tetrahydroquinolin-2-one of formula (II)

comprising the steps of,
a) reacting 7-hydroxy-tetrahydroquinolinone of formula (III)
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with 1,4-dibromobutane in the presence of base in dimethylacetamide to obtain 7-(4-bromobutoxy)-3,4-dihydrocarbostyril of formula (I) having purity more than 90%.
b) condensing 7-(4-bromobutoxy)-3, 4-dihydrocarbostyril of formula (I)

with l-(2, 3-dichlorophenyl) piperazine of formula (IV)

in the presence of triethylamine and sodium iodide in solvent acetonitrile to obtain 7-[4-[4-(2, 3-dichlorophenyl) piperazin-l-yl] butoxy]-l, 2, 3, 4-tetrahydroquinolin-2-one of formula (II)

Dated this 27th day of March 2006.

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ABSTRACT:
The present invention relates to an improved process for the preparation of Aripiprazole comprising a step of, reacting 7-hydroxy-tetrahydroquinolinone of formula (III)
HO

with 1,4-dibromobutane in the presence of base in dimethylacetamide to obtain 7-(4-bromobutoxy)-3,4-dihydrocarbostyril of formula (I) having purity of more than 90%.

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