FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"PROCESS FOR PREPARATION OF ARIPIPRAZOLE USING PURIFIED1-
(2,3-DICHLOROPHENYL) PIPERAZINE HYDROCHLORIDE AND 7-(4-
BROMOBUTOXY) 3,4-DIHYDRO-2 (1H) QUINOLINONE"
2. APPLICANT:
(a) NAME: AARTI DRUGS LIMITED
(b) NATIONALITY: Indian Company incorporated under the Indian Companies
Act, 1956
(c) ADDRESS: Mahendra Industrial Estate, Ground Floor, Plot No. 109-D,
Road No. 29, Sion (East), Mumbai - 400 022, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it has to be performed.

Technical field of Invention:
The present invention relates to an improved process for the preparation of 7-[4-[4-[-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-,3,4-dihydro-2-(1H)quinolinone(Aripiprazole),of formula-Ill ,having purity more than 99.5% with a single major individual impurity not more than 0.1%

Formula III Particularly, the present invention relates to an improved process for the preparation of 1-(2, 3-dichlorophenyl) piperazine or salt of formula (I) having purity not less than 99.8%.

Formula 1 The present invention also relates to an improved process for the preparation of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril of formula (lI) having purity not less than 95.0% and dimer content not more than 4.5%.

Formula II
Background and Prior Art:
The chemical name of Aripiprazole is 7-[4-[4-[-(2,3-dichlorophenyl)-l-piperazinyl] butoxy]-3,4-dihydro-2- (IH) quinolinone, with a molecular formula C23H27Cl2N3O2 and

molecular weight 448.39.Aripiprazole is represented by structural formula (III).

Formula HI Aripiprazole is marketed by Bristol Myers Squibb under trade name Ability and indicated for the treatment of Alzheimer's dementia, antipsychotic disorders and bipolar disorders. U.S.Pat.No.5,006,528 describes the process for preparation of 7-[4[-(2, 3-dichlorophenyl)-l-piperazinyl] butoxy]-3, 4-dihydro-2-(lH) quinolinone.
Several synthetic methods for Aripiprazole preparation are described in U.S.Patent No. 5,006,528, including method illustrated in Scheme-1
Scheme-1


7-(4-bromobutexy)-3,4-dihydrocarbostyril
2,3-dichloroaniline Bischloro ethylamine HCI 1-(2,3-dichle rophenyl)piperazine or salt


Aripiprazole
According to this synthetic route, Aripiprazole is prepared in two-steps. The first step comprises of alkylating hydroxy group of 7-hydroxy-3,4-dihydro-

2(lH)quinolinone(hereinafter referred as7-HQ) of formula(V) with 1,4-dibromobutane in a mixture of potassium carbonate and water to obtain 7-(4-bromobutoxy)3,4-dihydro-2(lH)quinolinone(hereinafter referred as 7-BBQ) of formula(III). The second step involves reacting l-(2, 3 dichlorophenyl)piperazine or its salt of formula (IV) to give Aripiprazole.
However,7-(4-bromobutoxy)-3J4-dihydrocarbostyril(7HQ) obtained by this process involves the formation of high level of dimer impurity, which causes low yield and also affects the purity of intermediate as well as purity of the final product.
Further, the said Patent also provides a process for the preparation of l-(2, 3-dichlorophenyl) piperazine with a purity less than 99%, which causes low yield and also affects the purity of intermediates as well as purity of final product.
Oshiro Y. et al in J.Medicinal Chemistry 1998,41,658-667, describes the preparation of 7-BBQ, wherein 7-BBQ is obtained by reaction of 7-HQ with 3 molar equivalents of 1,4-dibromobutane in N, N-dimethyl-formamide (DMF) in presence of potassium carbonate with an isolated yeild of 75%.. However this process involves the formation of dimer impurity in the range of 5-8%, which causes low yield and also affects the purity of the final product.
U.S.Pat. No. 2006/0258869 provides an improved process for the preparation of 7-(4-Chlorobutoxy)-3,4-dihydrocarbostyril having dimer impurity less than 0.5%.comprising reacting 7-hydroxy-tetrahydroquinolinone with 1-bromo-4-chlorobutane in the presence of abase in a solvent.
WO2008146156 describes a process for preparation of 7-(4-bromobutoxy) 3,4-dihydro-2(1H) quinolinone wherein 7-hydroxy-3,4-dihydro-2(lH)quinolinone is reacted with 1,4-dibromo butane in potassium carbonate solution in DM water. After completion of the reaction the organic layer containing the dimer was washed with pre-cooled sodium hydroxide to remove unreacted 7-hydroxy-3,4-dihydro-2(lH)quinolinone. The organic layer is further concentrated and the concentrated mass was diluted with xylene, added silica gel, filtered, diluted further with xylene and the combined filtrate concentrared

under reduced pressure, washed with cyclohexane to give the product having purity of 97% and yield 88%.
The inventors repeated the synthetic procedure described in US'528 Patent. Relatively large amounts of impurities were obtained along with7-(4-bromobutoxy) 3,4-dihydro-2(1H) quinolinone (7-BBQ).Among these impurities, the following were isolated and identified;

Formula-IV

Formula-V
1,4-Bis [3,4-dihydro-2 (lH)-quinolinone-7-oxy] butane (BQB)

Formula-VI
In a specific run it was found that 7-BBQ prepared by procedure described in the US Patent.,5,006,528 contained 10% of BQB, which could not be eliminated.

Thus most of the processes known in the art utilizes 7-(4-bromobutoxy) 3,4-dihydro-2 (1H) quinolinone(7-BBQ) as an intermediate by the method known in the art having high content of dimer impurity (5-8%).
In short the process described in the prior art for the preparation 7-(4-bromobutoxy) 3,4-dihydro-2 (IH) quinoJinone formula (II) is tedious and causes the low yield.
Therefore, there is still a need in the art for an improved, low-cost process for preparing intermediate carbostyril such as 7-(4-bromobutoxy) 3,4-dihydro-2 (IH) quinolinone or 7-(4-chlorobutoxy) 3,4-dihydro-2 (IH) quinolinone, which will be suitable for large scale preparation in terms of simplicity, yield and purity of Aripiprazole.
Also, it is necessary to develop an improved, low-cost process, using 2,3-dichloroaniline and bischloroethylamine hydrochloride, to prepare l-(2, 3-dichlorophenyl) piperazine or its salt of formula (I), which will be suitable for large scale preparation in terms of simplicity, chemical yield, and purity of the product. .
Object of the invention:
Therefore, the object of the present invention is to provide an improved process for the preparation of Aripiprazole with a dimer content less than 0.1%
Another object of the invention is to provide a process for the preparation of an intermediate I-(2,3 dichlorophenyl) piperazine HC1 having purity more than 99.8% with single unknown purity less than 0.15%.
A further object of the current invention is to prepare 7-(4-bromobutoxy) 3,4-dihydro-2 (IH) quinolinone having purity not less than 95% and dimer content not more than 4.5%.
Summary of the invention:
The invention relates to the preparation of 7-[4-[4-[-(2,3-dichlorophenyl)-l-piperazinyl]butoxy]-3,4-dihydro-2-(lH) quinolinone(Aripiprazole) of formula-Ill having purity more than 99.5% and dimer content less than 0.1%,




comprising condensation of l-(2,3dichlorophenyl) pjperazine of formula I
with 7-(4-bromobutoxy) 3,4-dihydro-2 (1H) quinolinone of formula II
The invention further relates to a process for preparation of l-(2,3dichlorophenyl) piperazine (I),by reacting 2,3-dichloroaniline and biscbloroethylamine hydrochloride in presence of orthodichlorobenzene having purity of 99.8%.
The invention also relates to preparation of 7-(4-bromobutoxy) 3,4-dihydro-2 (1H) quinolinone by reacting 7-hydroxy tetrahydroquinolinone of formula (VII) and 1,4 dibromobutane in presence of a base in solvent wherein the dimer impurity is not more than 4.5% which results in producing Aripiprazole in high yield and purity.
Detailed description of the invention:
The present invention discloses an improved process for the preparation of I-(2, 3-dichlorophenyl) piperazine or its salt of formula (I) having purity not less than 99.8%. According to the process 2,3-dichloroaniline is reacted with bischloroethylamine hydrochloride in presence of orthodichlorobenzene as solvent.

Various solvents such as methanol, ethanol, isopropanol, DMF, DMSO, DMA, water toluene and xylene were also used, but the reaction was found to be slow and formed more impurities than that of orthodichlorobenzene.
The above material having purity more than 97% by HPLC is further purified in methanol to give l-(2, 3-dichlorophenyl) piperazine HC1, having purity more than 99.8% with single unknown impurity less than 0.15%.
The present invention also relates to an improved process for the preparation of 7-(4-bromobutoxy) 3,4-dihydro-2 (1H) quinolinone(H) having dimer impurity less than 4.5%, comprising a step of reacting 7-hydroxy tetrahydroquinolinone of formula (VII) and 1,4 dibromo butane in presence of base in a solvent. Sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate can be used as base. The preferable base being sodium hydroxide. The solvent is selected from methanol, ethanol, isopropyl alcohol, dimethylformamide, dimethyl sulfoxide, acetonitrile, dimethylacetamide or mixture thereof. The solvent dimethylformamide and unreacted 1,4-dibromobutane is distilled off completely and the product is isolated by precipitation in methanol and slurry washed with hexane.
In another embodiment of the present invention, Aripiprazole is prepared by condensation of (2, 3-dichlorophenyl) piperazine HC1 of formula (1) and 7-(4-bromobutoxy) 3,4-dihydro-2 (1H) quinolinone of FormuIa-(II)in presence of potassium carbonate,tetrabutyl ammonium bromide and sodium iodide in acetonitrile as solvent.
The reaction mixture is refluxed and maintained at reflux until complete conversion and the reaction mass is cooled to room temperature. Water is added to the reaction mass and stirred at ambient temperature. The mass is filtered and washed with water till pH of filtrate is 7.0 to 7.5.
During condensation, the use of 7-(4-bromobutoxy) 3,4-dihydro-2 (1H) quinolinone (formula-II) having dimer content less than 4.5% gives crude Aripiprazole having dimer content less than 1.5%.

Above material is subjected to toluene, ethanol or both or mixture thereof for purification, which gives Aripiprazole having dimer content less than 0.1%. The above material is finally subjected to ethanol or reducer (Ethanol-95%, and Acetone-5%) purification gives Aripiprazole having ICH purity. The above process is found to be simple, environment friendly, economical and leads to enhanced purity.
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.
Examples
Example 1
Preparation of (2,3-dichIorophenyl) piperazine HCI (Formula-I)
2,3-dichloroaniline (200 gm), bischloroethylamine HCI (678 gm) and orthodichlorobenzene was heated at 155-160°C for 24-30 hr for complete conversion of 2,3-dichioroaniline. Reaction mixture was cooled to an ambient temperature and stirred for 1 hr. Material was filtered at ambient temperature and suck dried well. Above crude material (425-450 gm) having purity NLT 97% was dissolved in 2.25 lit methanol at reflux temp and stirred for 30 min and filtrate slowly cooled to 5-10°C and stirred for 1 hr and filtered and washed with 200 ml chilled methanol. Above material was dried at 55-60°C for 6-8hr. Yield: >72-75% % HPLC purity: >99.80 % LOD:<0.5%
Example 2
Preparation of 7-(4-bromobutoxy) 3,4-dihydro-2 (1H) quinolinone (FormuIa-II)
1,4-dibromobutane (400ml) was added to a stirred solution of 7-hydroxy-3,4 dihydrocarbostyril (lOOgm) in dimethyl formamide (400ml) at 30-35°C. Sodium hydroxide (28.8gm) was added to reaction mixture at the interval of 60 min (Complete addition of sodium hydroxide in equal fraction in 6.0 hours) at 30-35°C. The reaction mixture was cooled at 25-30°C and filtered and suck dried well. Dimethyl formamide and

1,4-dibromobutane was distilled out completely under vacuum below 80°C from filtrate. The residue was cooled to 35-40°C and 400 ml methanol was charged and the reaction mixture was stirred at 30-35°C for 1 hr, cooled to 10-15°C for 1 hr and the solid filtered and washed with 100 ml chilled methanol. The wet solid was charged in 400ml of n-hexane at 25-30°C and stirred for I hr and filtered and material was dried at 60-70°C under vacuum for 6-8 hr. Yield: 145-150 gm (79-80%) Dimer content: 4.0-4.5%
Example 3
Preparation of 7-[4-[4-(2,3-dichlorophenyl)l-piperazinyl-] butoxy]-,3,4-dihydro-2-
(lH)quinoltnone (Aripiprazo1e)(Formula-HI)
The mixture of 100 gm of 7-(4-bromobutoxy) 3,4-dihydro-2 (1H) quinolinone from Example-2 in 600ml acetonitrile with potassium carbonate (109gm), sodium iodide (88.6gm) tetrabutylammonium bromide (0.5 gm) and (2, 3-dichlorophenyl) piperazine HC1 (l00gm) was stirred at 25-30°C.Then the reaction mixture was refluxed and maintained until reaction completes. The reaction mixture was cooled at 25-30°C and DM water (500 ml ) was added and stirred at 25-30°C for 30 min.The mass was filtered and washed with water till pH of the filtrate came to 7.0-7.5.
The above wet solid was dissolved in toluene (600ml) at 70-75°C to get clear solution. The solution was filtered at 70-75oC and washed with hot toluene. Filtrate was cooled to 25-30°C and stirred for 2 hr and filtered and suck dried well.
The wet solid was further dissolved in 800ml reducer (EthanoI-95%, and Acetone-5%) at
75-80°C to get clear solution. The solution was filtered at 75-80°C and washed with hot
reducer (Ethanol-95%, and Acetone-5%). Filtrate was cooled to 25-30°C and stirred for 2
hr and filtered and suck dried well.
Further material was dried at 60-65°C to give Aripiprazole.
Yield: 100 gm (60%)
Purity by HPLC >99.5
Dimer content: 0.07%

Example 4
Preparation of 7-[4-[4-(2,3-dichIorophenyl)l-piperazinyl]butoxy]-3,4-dihydro-2-
(lH)quinolinone (Aripiprazole) (Formula-Ill)
The mixture of 100 gm of 7-(4-bromobutoxy) 3,4-dihydro-2 (1H) quinolinone from Example-3 in 600ml acetonitrile with potassium carbonate(109gm) sodium iodide (88.6gm) tetrabutylammonium bromide(0.5 gm) and (2, 3-dichlorophenyl) piperazine HC1 (l00gm) was stirred at 25-30°C.Then the reaction mixture was refluxed and maintained until reaction completes. The reaction mixture was cooled at 25-30°C and DM water (500 ml ) was added and stirred at 25-30°C for 30 min.The mass was filtered and washed with water till pH of the filtrate is 7.0-7.5.
The above wet solid was dissolved in toluene (500ml) at 70-75°C to get clear solution. The solution was filtered at 70-75°C and washed with hot toluene. Filtrate was cooled to 25-30°C and stirred for 2 hr and filtered and suck dried well.
The wet solid was dissolved in 800m reducer (Ethanol-95%, and Acetone-5% at 75-80°C to get clear solution. The solution was filtered at 75-80°C and washed with hot reducer. Filtrate was cooled to 25-30°C and stirred for 2 hr and filtered and suck dried well.Further material was dried at 60-65°C to give Aripiprazole. Yield; 120 gm (71.0-72.0%) Purity by HPLC >99.5 Dimer content: 0.05%

We claim,
1. A process for preparation of (2, 3-dichlorophenyl) piperazine HC1 or its salt (formula-!) having purity not less than 99.8%

comprising a step of reacting 2,3-diehloroaniline and bischloroethylamine hydrochloride in presence of orthodichlorobenzene followed by purification in a solvent,
comprising a step of reacting 7-hydroxy tetrahydroquinolinone of formula (VII)

2. A process according to claim-1, wherein orthodichlorobenzene is used as solvent for reaction and methanol is used as solvent for purification.
3. A process according to claim-1, wherein temperature is in the range of 155-160°C.
4. A process for preparation of 7-(4-bromobutoxy) 3,4-dihydro-2 (1H) quinolinone of formula (II) having purity not less than 95% and dimer content not more than 4.5%.

with 1, 4-dibromobutane in presence of a base in solvent at 30-35° C for 60 min. 5. The process according to claim 4, wherein said base is selected from the group comprising NaOH, KOH, sodium carbonate, potassium carbonate or sodium bicarbonate.

6. The process according to claim 4, wherein the solvent is selected from group of solvent like methanol, ethanol, isopropyl alcohol, dimethylformamide, dimethyl sulfoxide, acetonitrile, dimethylacetamide or mixture thereof.
7. The process according to claim4 wherein, the solvent and unreacted 1,4-dibromobutane is distilled off completely to get dimer content not more than 4.5%.
8. A process for preparation of 7-[4-[4-(2,3-dichlorophenyl) 1- piperazinyl] butoxy]-3,4-dihydro-2-(IH)quinolinone (Aripiprazole) of formula(III) having impurity less than 0.1%

comprising step of
a) reacting 2,3-dichloroaniline and bis chloroethylamine hydrochloride in presence of orthodichlorbenzene at 155-160°C for 24-30 hr and purifying the above crude in methanol as solvent to get (2, 3-dichlorophenyl) piperazine HC1 or other salt of formula (I) having purity not less than 99.8% b)reacting 7-hydroxy-tetrahydroquinolinone of formula (VII)

with 1,4-dibromobutane in presence of base in solvent to obtain 7-(4-bromobutoxy) 3,4-dihydro-2 (1H) quinolinone of formula (II) having purity not less than 95% and dimer content less than 4.5%.
c ) condensing (2, 3-dichlorophenyl) piperazine HC1 or other salt of formula (I) having purity not less than 99.8% with 7-(4- bromobutoxy) 3,4-dihydro-2 (IH) quinolinone of formula (II) having purity not less than 95% and dimer content less

than 4,5% in presence of base, a phase transfer catalyst and sodium iodide in
solvent. 9. The process according to claim 8, wherein the said solvent in step (a) is
orthodichlorobenzene and solvent used for purification is selected from group
comprising methanol, isopropanol, and ethanol. 10.The, process, according to claim. 8, wherein the, said base in step (b) is selected
from group comprising sodium hydroxide, potassium hydroxide, sodium
carbonate, potassium carbonate or sodium bicarbonate.
11. The process according to claim 8, wherein the said solvent in step (b) is selected from group comprising methanol, ethanol, isopropyl alcohol, dimethylformamide, dimethyl sulfoxide, acetonitrile, dimethylacetamide or mixture thereof.
12. The process according to claim 8, wherein the said base in step (c) is selected from group comprising sodium carbonate, potassium carbonate or sodium bicarbonate sodium hydroxide, potassium hydroxide.
13. The process according to claim 8, wherein the said solvent in step (c) is selected from group comprising methanol, ethanol, isopropyl alcohol, dimethylformamide, dimethyl sulfoxide, acetonitrile, dimethylacetamide or mixture thereof.
14. Aripiprazole containing dimer impurity less than 0.15%
15. Aripiprazole containing dimer impurity less than 0.05%