IMPROVED PROCESS FOR THE PREPARATION
OF ARIPIPRAZOLE

IND-SWIFT LABORATORIES LIMITED,
S.C.O. NO. 850, SHIVALIK ENCLAVE,
NAC, MANIMAJRA,
CHANDIGARH-160 101
(AN INDIAN ORGANIZATION)

The following application particularly describes the invention and the manner in which is to be performed.

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of pure aripiprazole and in particular present invention relates to an improved and cost effective method for the preparation of highly pure aripiprazole, wherein each impurity specifically corresponding quinoline, impurity namely 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)quinolin-2(1H)-one is present in an amount of not more than 0.1%

BACKROUND OF THE INVENTION
Aripiprazole, of formula I, is marketed by Bristol Myers Squibb under trade name Abilify. Aripiprazole is an atypical antipsychotic and antidepressant used in the treatment of schizophrenia, bipolar disorder, and clinical depression and is chemically designated as 7-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy]-3,4-dihydroquinolin-2-one,

Formula I

Aripiprazole is broadly disclosed first time in US patent 4,734,416 and specifically in US patent 5,006,528 [ herein after US’528] . The process for the preparation of aripiprazole is well disclosed in US’528. and is shown in below Scheme:

The process involves reacting 7-hydroxy-3,4-dihydrocarbostyril with dibromobutane in water using potassium carbonate as base at reflux temperature. The product is isolated by extraction of reaction mixture with dichloromethane followed by purification using column chromatography as well as by recrystallization from hexane and ethanol. 7-(4-Bromobutoxy)-3,4-dihydrocarbostyril, thus obtained, is condensed with 1-2,(3-dichlophenyl)piperazine in acetone using sodium iodide as catalyst to obtain aripiprazole.
The intermediate, 7-(4-bromobutoxy)-3,4-dihydrocarbostyril is purified using column chromatography, which is known to be cumbersome and thus difficult to apply at industrial scale. Further, US'528 is silent about the process for the preparation of 7-hydroxy-3,4-dihydrocarbostyril and about the purity of aripiprazole. But in literature, several methods are reported, wherein process for preparation of 7-hydroxy-3,4-dihydrocarbostyril is disclosed. An article, namely, Berichte der Deutschen Chemischen Gesellschaft [Abteilung], Volume: 60B, Pages 858-64, Journal,1927 first time disclosed a process of preparation of 7-hydroxy-3,4-dihydrocarbostyril as shown below,

Later another article namely, Chemical & Pharmaceutical Bulletin, Volume: 9, Pages: 970-5, Journal, 1961 discloses that the above process of preparation of 7-hydroxy-3,4-dihydrocarbostyril comprises Friedel-Craft reaction of 3-chloro-3'-hydroxypropionilide gives a reaction product of melting point 230°C, the position of hydroxyl group of which remained ambiguous, whether in 5- or 7-position.
Therefore, in later article, a modified process by changing molar ratio's of 3-chloro-3'-hydroxypropionilide, aluminium chloride, sodium chloride and potassium chloride and reaction temperature has been presented.
Further, US application 2006/0079690 also discloses an alternate process to reduce undesired isomeric 5-position impurity by using high boiling point solvent for synthesizing pure 7-hydroxy-3,4-dihydrocarbostyril followed by recrystallization.
7-Hydroxy-3,4-dihydrocarbostyril is a key intermediate for synthesizing aripiprazole. The purity of 7-hydroxy-3,4-dihydrocarbostyril is very important as its corresponding impurities, if present, may carry forward to final product.

There are several disclosures such as US patents 7,884,205 and 7,77,039; US patent applications 2010/0130744; 2009/0198059; 2007/0032651; 2007/0213535; 2006/0079689 and PCT publications WO2013/020672; WO2008/001188; WO2007/094009; WO2007/118923; WO2007/148191, wherein 7-hydroxy-3,4-dihydrocarbostyril is used as key starting material. Most of these disclosures criticize the process for preparation of aripiprazole as disclosed in patent US’528, for low yielding of intermediates, which affect the yield of aripiprazole and also high level of impurities specifically dimer impurity.

The purity of final active pharmaceutical ingredient plays an important role for commercialization of a product.
Impurities in aripiprazole, or any active pharmaceutical ingredients. (“API”) are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing the API. Aripiprazole may contain impertinent compounds or impurities. These impurities may be, for example, starting materials; impurities carry forward from starting materials, by-products of the reaction, product of side reactions or degradation products.
The Regulatory authorities of all major countries like U.S. Food and Drug Administration (“FDA”); Medicines and Healthcare Products Regulatory Agency ("MHRA"), European Medicines Agency ("EMEA") require that impurities be maintained below set limits. For example, in ICH Q7A guidance for API manufacturers, preferred limits for the quality of raw materials that may be used are specified. The general impurities of aripiprazole reported in US and EP pharmacopeias are given below



Among these most important impurities are dimer impurity and corresponding quinoline impurity, namely 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)quinolin-2(1H)-one
as represented by compound of formula II,

Formula II

Various references such as Analytical chemistry, An Indian Journal, 2008, 7(7), 551-553; Heterocyclic Communications (2005), 11(6), 485-490; Czech Republic patent CZ300351 also disclose about corresponding quinoline impurity of formula II, its preparation and its removal process from aripiprazole.
Czech Republic patent CZ300351 discloses a process to control presence of corresponding quinoline impurity of formula II in aripiprazole by a process which involves preparation of pure 7-hydroxy-3,4-dihydro-1H-quinolin-2-one. The process comprises of reduction of 7-hydroxy-3,4-dihydro-1H-quinolin-2-one having 6% impurity of 7-hydroxyquinolin-2(1H)-one in the presence of palladium on charcoal and methanol as solvent to give pure 7-hydroxy-3,4-dihydro-1H-quinolin-2-one having 0.04% impurity of 7-hydroxyquinolin-2(1H)-one.
It is given that reaction can be carried out at 40-100°C, but in exemplified process reaction is carried out at 70-80°C and 7-hydroxy-3,4-dihydro-1H-quinolin-2-one is precipitated at -18°C. Therefore, the above process involves use of high temperature for reaction and very low temperature for precipitation of product, eventually increase burden on utility and finally increase cost burden. Further, the above process makes use of palladium on charcoal for purification of 7-hydroxy-3,4-dihydro-1H-quinolin-2-one, which is a very costly reagent, and enhance cost and hence not attractive option, being expensive.
An Indian patent application, 2738/MUM/2011 discloses a process for the preparation of corresponding quinoline impurity of formula II as shown in below scheme. Further discloses a methodology for the conversion of said corresponding quinoline impurity into aripiprazole by treating with palladium on carbon as shown below:

The above process suffer from several drawbacks like use of expensive reagent, and reduction step in final stage which is an additional step and would lead to loss in yield and would amount to extra cost.
A Chinese patent application CN102863377 discloses several impurities of aripiprazole including said corresponding quinoline impurity represented by formula II and process of purification of aripiprazole. The purification process comprises treatment of aripiprazole with organic acids to form acid addition salt of aripiprazole followed by hydrolysis using a suitable base.
The above process is not an industrial attractive process as the above process uses an additional step of acid-base treatment for purifying aripiprazole, which may result in loss of yield at final stage and amount to cost burden.
In view of the above and it is observed that when dihydro quinolin-2-one, namely 7-hydroxy-3,4-dihydro-1H-quinolin-2-one represented by compound of formula III,

Formula III

is contaminated with quinolin-2-one, namely 7-hydroxyquinolin-2(1H)-one represented by formula IV,

Formula IV
then, it leads to the formation of said corresponding quinoline impurity of formula II. The amount of said impurity varies depending on amount of quinolin-2-one impurity of formula IV, present in dihydro quinolin-2-one compound of formula III. It is found that quinolin-2-one impurity of formula IV is present upto 10% in dihydro quinolin-2-one compound of formula III and further leads to many side products including corresponding quinoline impurity of formula II.
It is very difficult to remove corresponding quinoline impurity of formula II from aripiprazole by using simple purification technique; it requires either reduction in final step or acid base treatment as discussed above which leads to considerable loss of yield and are not attractive choices to carried on industrial scale. Since corresponding quinoline of formula II is a process impurity and generate during the synthetic process, when dihydro quinolin-2-one compound of formula III is used as one of key starting material, therefore it is advisable to remove this impurity at intermediate stage itself to avoid further side product formation.
Therefore, there is a urgent need to develop an improved process for the preparation of highly pure aripiprazole having each impurity specifically corresponding quinoline impurity in less than 0.1%, which avoids use of expensive reagents and yield loss in final step. Thus, the present invention aims to solve the problems associated with prior art and provides an efficient, industrially feasible and cost effective process for the preparation of aripiprazole which solves impurity concern at intermediate stage only and improves the economics by providing the intermediate as well as final product in high yield and high purity by using inexpensive reagents.

OBJECT OF THE INVENTION
The principle object of the present invention is to provide an efficient and industrial advantageous process for the preparation of pure aripiprazole compound of formula I.
Another object of the present invention is to provide an efficient and industrial advantageous process for the preparation of pure aripiprazole compound of formula I, having corresponding quinoline impurity of formula II, in an amount less than 0.10%, measured by HPLC.
One another object of the present invention is to provide an cost-effective and industrial advantageous process for the preparation of pure dihydro quinolin-2-one compound of formula III.
One another object of the present invention is to provide an efficient and industrial advantageneous process for the preparation of pure aripiprazole compound of formula I comprising conversion of pure dihydro quinolin-2-one compound of formula III.

SUMMARY OF THE INVENTION
Accordingly, the present invention provide an efficient and industrially advantageous process for the preparation of pure aripiprazole compound of formula I,

Formula I
having impurity of corresponding quinoline impurity of formula II in an amount of less than about 0.1 area % as measured by HPLC,

Formula II
comprises the steps of:
a) reacting dihydro quinolin-2-one compound of formula III,

Formula III
having impurity of quinolin-2-one represented by formula IV in an amount greater than 0.4 area % as measured by HPLC,

Formula IV
with a suitable reducing agent under hydrogen, in the presence of a suitable organic solvent at a suitable temperature to obtain pure dihydro quinolin-2-one of formula III;
b) condensing resulting pure dihydro quinoline-2-one of formula III, having corresponding quinoline-2-one impurity of formula IV in an amount of less than 0.4 area % with a dihalo compound of formula V,
X-(CH2)3-X Formula V
wherein X can be halogen and independently selected from Cl or Br,
in the presence of a base in a suitable solvent to obtain 7-(3-halo-propoxy)-3,4-dihydro-1H-quinolin-2-one compound of formula VI,

Formula VI
wherein X is halogen and independently can be selected from Cl or Br.
c) reacting 7-(3-halo-propoxy)-3,4-dihydro-1H-quinolin-2-one compound of formula VI with 1-(2,3-dichloro-phenyl)-piperazine or salts thereof in the presence of base and optionally in the presence of metal halide, suitable solvent to give pure aripiprazole of formula I.
According to one another embodiment, the present invention provide an cost-effective and industrial advantageneous process for the preparation of pure dihydro quinolin-2-one of formula III,

Formula III
comprises of reacting dihydro quinolin-2-one of formula III having impurity quinolin-2-one represented by formula IV,

Formula IV
with a suitable reducing agent under hydrogen, in the presence of a suitable organic solvent at a suitable temperature to obtain pure dihydro quinolin-2-one compound of formula III.
According to one another embodiment, the present invention provide an efficient and industrial advantageneous process for the preparation of pure aripiprazole compound of formula I,


Formula I
having corresponding quinoline impurity of formula II in an amount of less than about 0.1area % as measured by HPLC,

Formula II
comprises the conversion of pure dihydro quinolin-2-one compound of formula III,

Formula III
having quinolin-2-one impurity of formula IV in an amount of less than 0.4 area %.

Formula IV

DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention provide an efficient and industrial advantageneous process for the preparation of pure aripiprazole by utilizing pure dihydro quinolin-2-one compound of formula III.
Pure dihydro quinolin-2-one compound of formula III is prepared by reducing dihydro quinolin-2-one compound of formula III having quinolin-2-one impurity of formula IV in a suitable organic solvent under mild reaction conditions. Generally, process involves reduction of dihydro quinolin-2-one compound of formula III having corresponding quinolin-2-one impurity of formula IV in the presence of a suitable reducing agent, under hydrogen, in a suitable solvent.
The suitable reducing agent used in the reaction can be selected from any suitable reducing agent which is capable of reducing double bond. In general, reducing agent can be selected from transition metal catalysts such as nickel, platinum; borohydride with additives such as sodium borohydride with additive selected from nickel chloride, cobalt chloride, copper chloride and the like; magnesium methanol etc. In particular, reducing agent can be selected from Raney nickel, an economical reducing agent and make the process cost-effective.
The solvent used in reaction can be selected from alcohols such as methanol, ethanol, propanol, isopropanol, tert-butanol and the like; halogenated solvents such as dichloromethane, 1,2-dichloroethane, chloroform and the like; ether solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane and the like or mixture thereof. Optionally, reaction can be carried out in the presence of a base.
The reaction can be accomplished at a temperature of 20oC to 80oC, under hydrogen pressure of 6-10 Kg/Cm2, for sufficient time, which can be 15 minutes to few hours or completion of reaction. The progress of reaction can be monitored by suitable chromatographic technique such as thin layer chromatography [TLC], high pressure liquid chromatography [HPLC], ultra pressure liquid chromatography [UPLC], gas chromatography [GC] and the like.
In particular, crude dihydro quinolin-2-one compound of formula III, having quinolin-2-one impurity of formula III is taken in a suitable solvent and treated with a suitable reducing agent under nitrogen and hydrogen gas. The resulting reaction mass is heated at suitable temperature and applying hydrogen pressure in an autoclave. The reaction mixture is maintained under specified conditions till the completion of reaction. Thereafter, reaction mixture is filtered to remove the catalyst. The resulting filterate is optionally purified by characoalization. Specifically, activated carbon is added to the filterate and the reaction mixture is stirred for sufficient time. Then, reaction mass is filtered and solvent is distilled from filterate to obtain pure dihydro quinolin-2-one compound of formula III. Optionally the resulting compound can be recrystallized in a suitable solvent to further enhance the purity of dihydro quinolin-2-one compound of formula III, if desired.
The starting compound dihydro quinolin-2-one of formula III, initially used in the reaction, contains more than 0.4 area % of quinolin-2-one impurity of formula IV, measured by HPLC.
The resulting pure dihydro quinolin-2-one compound of formula III obtained after reduction may have corresponding quinolin-2-one impurity of formula IV, in an amount of less than 0.4 area %, preferably less than 0.2 area %, more preferably less than 0.1 area % measured by HPLC.
The resulting pure dihydro quinolin-2-one compound of formula III is then condensed with dihalobutane of formula V, in the presence of a base in a suitable solvent to obtain 7-(3-halo-propoxy)-3,4-dihydro-1H-quinolin-2-one compound of formula VI. The halo group refers to halogens and can be independently selected from chloro or bromo.
The base used in the reaction can be inorganic base or organic base. Inorganic base can be selected from potassium carbonate, calcium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide and organic base can be selected from the group consisting of triethylamine, tripropylamine, pyridine, and quinoline.
The solvent used in reaction and purification can be selected from polar solvent such as water, dimethylformamide, dimethylsulfoxide, dimethylacetamide alcohols such as methanol, ethanol, propanol, isopropanol, tert-butanol and the like; halogenated solvents such as dichloromethane, 1,2-dichloroethane, chloroform and the like; ether solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane; N-methyl pyrrolidine and the like or mixture thereof.
Specifically, in one embodiment, pure dihydro quinolin-2-one compound of formula III is reacted with dibromobutane in the presence of a base in a suitable solvent to obtain7-(4-bromobutoxy)-3,4-dihydrocarbostyril.
In another embodiment, pure dihydro quinolin-2-one compound of formula III is reacted with 1-bromo-4-chlorobutane in the presence of a base in a suitable solvent to obtain 7-(4-chlorobutoxy)-3,4-dihydrocarbostyril.
The resulting halo compound of formula VI is then reacted with 1-(2,3-dichloro-phenyl)-piperazine or salts thereof in the presence of a suitable base, optionally in the presence of metal halide, in a suitable solvent to obtain pure aripiprazole compound of formula I. Optionally, aripiprazole of formula I can be purified by any method known in the prior art such as slurry washing, recrystallization with suitable solvents.
The base used in the reaction can be inorganic base or organic base. Inorganic base can be selected from potassium carbonate, calcium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide and organic base can be selected from the group consisting of triethylamine, tripropylamine, pyridine, and quinoline.
The suitable metal halide used in the reaction can be selected from sodium iodide, potassium iodide and the like or mixture thereof.
The solvent used in reaction and purification can be selected from polar solvent such as water, dimethylformamide, dimethylsulfoxide, dimethylacetamide; alcohols such as methanol, ethanol, propanol, isopropanol, tert-butanol and the like; halogenated solvents such as dichloromethane, 1,2-dichloroethane, chloroform and the like; ether solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane; and the like or mixture thereof.
The reaction can be carried out at temperature of 20oC to 80oC for 15 minutes to completion of reaction. The progress of reaction can be monitored by suitable chromatographic technique such as thin layer chromatography [TLC], high pressure liquid chromatography [HPLC], ultra pressure liquid chromatography [UPLC], gas chromatography [GC] and the like.
Pure aripiprazole compound of formula I prepared according to present invention has purity of greater than 99.5% more preferable greater than 99.8 % and have corresponding quinoline impurity, 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy) quinolin-2(1H)-one represented by compound of formula II , in an amount of less than 0.1 area % as measured by HPLC.
Major advantages realized in the present invention is that concerned impurity i.e. corresponding quinoline impurity of formula II is reduced in aripiprazole to an amount of less than 0.1 area % as measured by HPLC, by improving purity at an intermediate stage by using inexpensive reagent and mild reaction conditions and hence cost has been reduced many fold.
It is against this and other backgrounds, which shall be filed in a detailed manner in complete specifications, in due course, the present invention is brought out and explained in following non limiting examples.

EXAMPLES:
Example 1: Preparation of pure 7-hydroxy-3,4-dihydro-1H-quinolin-2-one [compound of formula III]
Method A: 7-Hydroxy-3,4-dihydro-1H-quinolin-2-one (20g) containing impurity 7-hydroxyquinolin-2(1H)-one of formula IV (0.48%) was dissolved in methanol (200ml) at room at 45ºC. To the resulting solution, Raney nickel (20g) was added, and reaction mixture maintained at a temperature of 45ºC under hydrogen pressure of 7-9 Kg/cm2 for 4 hours. After completion of reaction, the reaction mass was filtered to remove catalyst. The solvent was distilled off from filterate and ethanol (30ml) was added to resulting mass. The reaction mass was stirred at a temperature of 20-25 ºC for 1 hour and then filtered, dried to get 19.0g of pure 7-hydroxy-3,4-dihydro-1H-quinolin-2-one compound of formula III having purity 99.7% and 0.05% of 7-hydroxyquinolin-2(1H)-one, measured by HPLC.
Method B: 7-Hydroxy-3,4-dihydro-1H-quinolin-2-one (20g) containing impurity 7-hydroxyquinolin-2(1H)-one (0.48%) was dissolved in methanol (200ml) at room at 45ºC To the resulting solution, Raney nickel (12g) was added and reaction mixture was heated at a temperature of 45ºC under hydrogen pressure of 7-10 Kg/cm2 for further 4 hours. After completion of the reaction, the reaction mass was filtered. The solvent was distilled off from the resulting filterate to get crude 7-hydroxy-3,4-dihydro-1H-quinolin-2-one. n-Hexane (30ml) was added to the resulting reaction mass at room temperature, then cooled the reaction mass at 0-5ºC and maintained for 4 hours. Thereafter, the resulting solid, was filtered, washed with hexane, dried to get 17g of pure 7-hydroxy-3,4-dihydro-1H-quinolin-2-one compound of formula III having purity 99.9% and 0.03% of 7-hydroxyquinolin-2(1H)-one, measured by HPLC.
Method C: 7-Hydroxy-3,4-dihydro-1H-quinolin-2-one (50g) having impurity 7-hydroxyquinolin-2(1H)-one (0.89%) was dissolved in methanol (500ml) at 45ºC. To the resulting solution Raney nickel (25g) was added under nitrogen and reaction mixture was heated at 40-45ºC in an autoclave under hydrogen pressure of 7-10 Kg/cm2 for 7 hours. After completion of the reaction, the reaction mass was filtered, activated carbon (5g) was added to the resulting filterate and heated at a temperature of 55-60ºC for 30 minutes. The reaction mixture was filtered, and the solvent of resulting filtrate was distilled off to get a crude compound. The resulting crude compound was recrystallized with ethanol to obtain 43.5g of pure 7-hydroxy-3,4-dihydro-1H-quinolin-2-one compound of formula III having purity 99.9% and 0.05% impurity of 7-hydroxyquinolin-2(1H)-one, measured by HPLC.
Example 2: Preparation of 7-(4-halobutoxy)-3,4-dihydrocarbostyril
Method A: Preparation of 7-(4-chlorobutoxy)-3,4-dihydrocarbostyril
1-Bromo-4-chlorobutane (45ml) was added to a solution of pure 7-hydroxy-3,4-dihydrocarbostyril (30g) in dimethylformamide (45ml) at ambient temperature. Potassium carbonate (54g) was added to the reaction mixture and heated at a temperature of 55-60ºC for 4 hours. After completion of reaction, the reaction mixture was cooled at ambient temperature and demineralized water was added to it. The reaction mixture was further cooled to 5-10ºC. The resulting solid, was filtered and dried to obtain title compound.

Method B: Preparation of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril
1,4-Dibromobutane (52.5 ml) was added to a solution of pure 7-hydroxy-3,4-dihydrocarbostyril (35g) in N-methyl pyrrolidine (175ml) at ambient temperature. The reaction mixture was heated at 55-60ºC. followed by slow addition of potassium carbonate (63g) and further stirred for 4 hours. After completion of reaction, reaction mass was cooled to ambient temperature. Demineralized water, isopropyl ether and ethyl acetate were added and filtered the reaction mass. The organic layer was separated and washed with sodium hydroxide solution and then with brine solution. The organic layer was evaporated under reduced pressure to obtain residue. Hexane (140ml) was added to the resulting residue to give 44.5g of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril.
Example 3: Preparation of Aripiprazole
Method A: To a solution of 7-(4-chloro butoxy)-3,4-dihydrocarbostyril (13g) in N,N-dimethylformamide (40ml), sodium iodide (2.6g), 1-(2,3-dichlorophenyl)piperazine hydrochloride (12g) and triethyl amine were added at 20-30ºC. The reaction mixture was stirred at 20-30ºC for further 4 hours. After completion of reaction, purified water (40ml) was added slowly to the reaction mixture, stirred for 30 minutes. The resulting product was filtered, washed with purified water, was and dried at 45-55ºC under vacuum to give crude aripiprazole having 0.05% corresponding quinoline impurity of formula II measured by HPLC. The resulting product was recrystallized with acetone to give 16.5g of aripiprazole having purity 98.8% and 0.048.% of corresponding quinoline impurity of formula II, measured by HPLC.
Method B: To a solution of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril (40g) in N,N-dimethylformamide (120ml), sodium iodide (6.0g) , 1-(2,3-dichlorophenyl)piperazine hydrochloride (36g) and triethylamine (46.4ml) were added at 20-30ºC and the reaction mixture was further stirred at 20-30ºC for 4 hours. After completion of reaction, purified water (120ml) was added slowly to the reaction mixture, stirred for 30 minutes, filtered and washed with purified water to give crude aripiprazole having 0.07% corresponding quinoline impurity of formula II, measured by HPLC. The resulting product was recrystallized with acetone to give 47.2 g of aripiprazole compound formula I having purity 99.72% and 0.06% corresponding quinoline impurity of formula II, measured by HPLC.
Method C: To a solution of 7-(4-chloro butoxy)-3,4-dihydrocarbostyril (5.0 g) in N,N-dimethylformamide (20ml), sodium iodide (1.5g), 1-(2,3-dichlorophenyl)piperazine hydrochloride (4.6g) and potassium carbonate (10g) were added. The reaction mixture was stirred at 55-60ºC for further 24 hours. After completion of reaction, purified water (20ml) was added slowly to the reaction mixture, stirred for 1 hour. The solid, thus obtained, was filtered, washed with purified water and dried at 45-55ºC under vacuum to give crude aripiprazole having 0.08% corresponding quinoline impurity, measured by HPLC. The resulting crude compound was recrystallized using acetone to obtain 6.2 g of aripiprazole having purity 99.40% and 0.09% of corresponding quinoline impurity of formula II, measured by HPLC. ,

CLAIMS:WE CLAIM
1. A process for the preparation of pure aripiprazole compound of formula I,

Formula I
having impurity of corresponding quinoline impurity of formula II in an amount of less than about 0.1 area % as measured by HPLC,

Formula II
comprises the steps of:
a) reacting dihydro quinolin-2-one compound of formula III,

Formula III
having impurity of quinolin-2-one represented by formula IV in an amount greater than 0.4 area % as measured by HPLC,

Formula IV
with a suitable reducing agent under hydrogen, in the presence of a suitable organic solvent at a suitable temperature to obtain pure dihydro quinolin-2-one of formula III;
b) condensing resulting pure dihydro quinoline-2-one of formula III, having corresponding quinoline-2-one impurity of formula IV in an amount of less than 0.4 area % with a dihalo compound of formula V,
X-(CH2)3-X Formula V
wherein X can be halogen and independently selected from Cl or Br,
in the presence of a base in a suitable solvent to obtain 7-(3-halo-propoxy)-3,4-dihydro-1H-quinolin-2-one compound of formula VI,

Formula VI
wherein X is halogen and independently can be selected from Cl or Br.
c) reacting 7-(3-halo-propoxy)-3,4-dihydro-1H-quinolin-2-one compound of formula VI with 1-(2,3-dichloro-phenyl)-piperazine or salts thereof in the presence of base and optionally in the presence of metal halide, suitable solvent to give pure aripiprazole of formula I.
2. The process as claimed in claim 1, wherein in step a) suitable reducing agent is selected from transition metal catalysts such as nickel, platinum; borohydride with additives such as sodium borohydride and additive is selected from nickel chloride, cobalt chloride and copper chloride.
3. The process as claimed in claim 1, wherein in step a) suitable reducing agent is Raney nickel.
4. The process as claimed in claim 1, wherein in step a) suitable organic solvent is selected from alcohols such as methanol, ethanol, propanol, isopropanol, tert-butanol; halogenated solvents such as dichloromethane, 1,2-dichloroethane, chloroform; ether solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane and or mixture thereof.
5. The process as claimed in claim 1, wherein in step a) the temperature of the reaction is 20oC to 80oC, under hydrogen pressure of 6-10 Kg/Cm2.
6. The process as claimed in claim 1, wherein in step b) base is selected from inorganic base such as potassium carbonate, calcium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide or organic base such as triethylamine, tripropylamine, pyridine, and quinoline.
7. The process as claimed in claim 1, wherein in step b) solvent is selected from polar solvent such as water, dimethylformamide, dimethylsulfoxide, dimethylacetamide; alcohols such as methanol, ethanol, propanol, isopropanol, tert-butanol; halogenated solvents such as dichloromethane, 1,2-dichloroethane, chloroform; ether solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane; N-methyl pyrrolidine and or mixture thereof.
7. The process as claimed in claim 1, wherein in step c) the base is selected from inorganic base such as potassium carbonate, calcium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide or organic base; organic base such as triethylamine, tripropylamine, pyridine, and quinoline.
8. The process as claimed in claim 1, wherein in step c) the suitable metal halide used in the reaction is selected from sodium iodide, potassium iodide and or mixture thereof.
9. The process as claimed in claim 1, wherein in step c) the solvent used in reaction is selected from polar solvent such as water, dimethylformamide, dimethylsulfoxide, dimethylacetamide; alcohols such as methanol, ethanol, propanol, isopropanol, tert-butanol; halogenated solvents such as dichloromethane, 1,2-dichloroethane, chloroform; ether solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane; or mixture thereof and the reaction is carried out at temperature of 20oC to 80oC for 15 minutes to .....hours..
10. A process for the preparation of pure aripiprazole compound of formula I,


Formula I
having corresponding quinoline impurity of formula II in an amount of less than about 0.1area % as measured by HPLC,

Formula II
comprises the use of pure dihydro quinoline-2-one of formula III, having corresponding quinoline-2-one impurity of formula IV in an amount of less than 0.4 area %.

Dated this day 3rd January, 2014

...................
(Dr. Asha Aggarwal)
Head-IPM Department
Ind-Swift laboratories Limited