FORM 2
THE PATENT ACT 1970 (39 of 1970)
& The Patents Rules, 2003 COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"An improved process for synthesis and isolation of Aripiprazole."
2. APPLICANT (S)
(a) NAME: Centaur chemicals Pvt. ltd
(b) NATIONALITY: An Indian Company incorporated under the Indian Companies ACT 1956
(C) ADDRESS:
Centaur chemicals Pvt. ltd.
Centaur House, shanti Nagar.Vakola,
Santacruz (e) Mumbai 400055.
Tel No. 022-66499144
Fax No. 022-66499108/112
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

An improved process for synthesis and isolation of Aripiprazole.
Field of Invention:
The present invention mainly relates to an improved and commercially viable process for synthesis of Aripiprazole, 7-[4-[4-(2, 3-dichlorophenyl)-l-piperazinyl] butoxy]-3, 4-dihydro-2 (IH)-quinolinone having good yield and purity. Furthermore relates to the simple isolation for Aripiprazole over the existing prior art.
Background of Invention:
Aripiprazole, 7-[4-[4-(2,3-dichlorophenyl)-l-piperazinyl] butoxy]-3,4-dihydro-2 (1H)-quinolinone is used for treating schizophrenia and its preparation is firstly described in European Patent EP 367, 141 (1990) and use of Aripiprazole as anti-psychotic agent is mentioned in J.Med.Chem. Vol.41, PP.658-667 (1998).
The process for preparation of Aripiprazole (I) referred as title compound as described in
the European Patent EP 367, 141 (1990) is reproduced in scheme-I:
Scheme-I:

The above said process involves reaction of 7-hydroxy-3, 4-dihydro-2 (lH)-quinolinone (II) with 1, 4-dibromobutane (III) in water using potassium carbonate as base at reflux temperature. The product was isolated by extraction of reaction mixture with methylene chloride. The isolated product was purified by column chromatography and was recrystallized from hexane and ethanol. 7-(4-bromobutoxy)-3, 4-dihydro-2 (1H)-quinolinone (IV) thus obtained was condensed with l-(2, 3-dichlorophenyl) piperazine hydrochloride (V) in acetonitrile using sodium iodide as catalyst and triethylamine as base to obtain crude aripiprazole. The crude aripiprazole was further crystallized from ethanol twice to obtain pure aripiprazole pure.
The drawback in the above process is the yield and the purity of the first stage product obtained from condensation of 7-hydroxy-3, 4-dihydro-2- (lH)-quinolinone with 1, 4-dibromobutane. The crude product obtained from the reaction is very impure and hence purified by column chromatography followed by crystallization from hexane and ethanol.
According to our preferred embodiment, the methodology was developed for the purification of intermediate 7-(4-bromobutoxy)-3, 4-dihydro-2 (lH)-quinolinone (IV) such that the tedious and cumbersome operation on large-scale separation by column chromatography was eliminated which has been well depicted in example. Further the modification in isolation process of crude aripiprazole offered a distinct advantage in obtaining better purity of final product.
According to WO 2006/038220, the key intermediate used in the preparation of aripiprazole, 7-hydroxy-3, 4-dihydro-2- (lH)-quinolinone (II) is prepared from 3-hydroxy aniline (VI) and 3-chloropropionyl chloride (VII)

In this preparation method for compound II, besides the required product, the other unwanted isomer of the formula (VIII) is also forms, which in turn reacts similarly to that of 7-hydroxy-3, 4-dihydro-2- (lH)-quinolinone. The impurity emanating from this compound continues to be present in the final drug aripiprazole. The purification process employed for removal of this impurity result in lowering of overall yield of aripiprazole.
In our embodiment, the aripiprazole prepared from the intermediate 7-hydroxy-3, 4-dihydro-2- (lH)-quinolinone (II) (which is depicted in following example) shows the percentage of undesired analogue emanating from formula(VIII) well within usual pharmaceutical limits of 0.05%.
Objective of Invention:
The main object of present invention is to provide an industrially applicable and commercially feasible process for the preparation of Aripiprazole. Furthermore, another object of present invention is to provide aripiprazole with desired purity and yield. Another object of present invention is to provide simple method of isolation for aripiprazole over the existing prior art.

Summary of Invention:
The present invention mainly concern with industrially feasible and cost effective concomitant with green chemistry process for preparation of aripiprazole. The invented process has added advantage of the improved purity of Aripiprazole.
This method further provides substantial benefits relative to previously used or suggested production methods. For example, the starting materials, intermediates, liquid media, and catalysts used are relatively easy to handle and to dispose off, if necessary. Importantly, the present method provides high yields of the desired product or products so that substantial process efficiencies are achieved.
The present invention carried out in two steps which has been briefly summarize below
and elaborately in forgoing example.
Step-1
Preparation of 7-(4-bromobutoxy)-3, 4-dihydro-2(lH)-quinolinone.
7- hydroxy -3,4-dihydro -2(lH)-quinolinone was reacted with 1,4- dibromobutane in
presence of potassium carbonate and water at 80 °C to obtain crude 7-(4-bromobutoxy )-
3,4-dihydro-2(lH) quinolinone which was purified by treatment of silica gel charcoal
mixture in methylene dichloride to obtained pure 7-(4-bromobutoxy)-3,4-dihydro -2(1 H)-
quinolinone
Step-2
Preparation of Aripiprazole.
The purified 7-(4-bromobutoxy)-3, 4-dihydro-2(lH)-quinolinone was reacted with sodium
iodide in acetonitrile followed by reaction with l-(2, 3-dichlorophenyl) piperazine
hydrochloride in presence of triethylamine at reflux temperature. The isolated crude

aripirazole was purified & recrystallised from ethanol to obtain a pure title compound (Aripiprazole).
Detail description of Invention:
According to present invention, the preparation of aripiprazole involves two steps, which
has been depicted as follows.
Step I:
In step I, the 7-hydroxy-3, 4-dihydro-2(lH) quinolinone is reacted with 1, 4-
dibromobutane in water at 75-85°C using potassium carbonate as base. After completion
of reaction, the crude 7-(4-bromobutoxy)-3, 4-dihydro-2(lH) quinolinone is isolated after
addition of hexane.

The isolated crude 7-(4-bromobutoxy)-3, 4-dihydro-2(lH) quinolinone (IV) was dissolved
in methylene chloride and was cooled to 0-5°C. The solution obtained was stirred with
charcoal and silica at 0-5°C for 45 min. and filtered. The charcoal-silica bed was washed
with cold methylene chloride. The procedure of charcoal - silica was repeated two times
on the methylene chloride solution. The HPLC purity of 7-(4-bromobutoxy)-3, 4-dihydro-
2(1H) quinolinone obtained after isolation from methylene chloride was found to be >
99%. The details of the isolation process are given in example.

Step II:
In step II, 7-(4-bromobutoxy)-3, 4-dihydro-2(lH) quinolinone (IV) is reacted with sodium iodide in acetonitrile followed by l-(2, 3-dichlorophenyl piperazine) hydrochloride (V) in presence of triethylamine.

SCHEME IV ARIPIPRAZOLE
The reaction was carried out by heating at reflux temperature for 4 hrs. After completion of reaction, it was cooled to room temperature and filtered. The isolated solids were again re-suspended in acetonitrile and triethyl amine and were heated to reflux temperature for 30 min. The reaction mixture was cooled to room temperature and solids were isolated by filtration. The isolated solids were suspended in methylene chloride and water mixture. The mixture was basified using liquor ammonia. The organic layer was separated and evaporated to obtain the solid residue, which was crystallized twice from ethanol to obtain pure aripiprazole. The modifications in isolation procedure offered an advantage in improving the purity of aripiprazole.
The aripiprazole isolated from this improved process has the HPLC purity more than 99.9%.
Following example is offered to provide the person skill in the art with sufficiently clear and complete explanation of this invention but should not consider as a limitation to the essential aspect of object thereof, as they have been explained below.

Example:
Stage I:
Preparation of 7-(4-bromobutoxy)-3, 4-dihydro-2(lH) quinolinone:
A mixture of 7-hydroxy-3,4-dihydro-2(lH) quinolinone (50g, 0.3moles), 1,4-dibromobutane (292.5 ml, 2.45 moles), potassium carbonate (83.7g, 0.6moles) and water (25 ml) was heated to 80°C for 36 hrs. The reaction mixture thus obtained was washed with hot water (65-70°C, 200 ml) for three times. The reaction mixture was cooled to room temperature. Hexane (585 ml) was added and the reaction mixture was stirred at 0-5°C for 2 hrs. The precipitated solids were filtered and washed with 2 x 100 ml of hexane. Yield - 73 - 75 gms (HPLC purity - 86-87%). Stage I material (73 - 75 gms, crude) obtained was dissolved in methylene chloride (525 ml). The solution was cooled to 0 -5°C. Charcoal (15 gms) was added to it and stirred at 0 - 5°C for 15 min. Silica gel (18.7 gms) was added and stirred for 30 min. The reaction mass was filtered and washed with cold methylene chloride (0-5°C). The charcoal and silica gel treatment was repeated two more times. Methylene chloride was degassed and the solids were separated after addition of hexane at room temperature. The second crop was isolated from mixture of charcoal and silica gel obtained from second and third treatment by treating it with methylene chloride/methanol mixture (75:25). The second crop obtained was recycled. Yield: 62.5 gms. (HPLC purity - 98%).
Stage II:
Preparation of Aripiprazole:
A suspension of 62.5 gms (0.209 moles) of 7-(4-bromobutoxy)-3, 4-dihydro-2(lH) quinolinone and 46.87 gms (0.312moles) of sodium iodide in 468 ml of acetonitrile was refluxed for 30 min. The reaction mixture was cooled to 35 - 40°C, 66.8 gms (0.249

moles) of l-(2, 3-dichlorophenyl) piperazine hydrochloride and 43.75 ml (0.314 moles) of triethylamine was added and further refluxed for 4 hrs. The reaction mixture was cooled to room temperature and stirred for 2 hrs. The solids were filtered and washed with cold (10°C) acetonitrile (30 ml). (Wet weight - 109 - 111 gms).
The solid product was taken in 328 ml of acetonitrile and 21.9 ml of triethylamine. The reaction mass was refluxed for 30 min., cooled to room temperature and stirred at room temperature for 1 hr. The solids were filtered and washed with cold acetonitrile (54 ml). The solids were dried in oven at 60°C. (Yield: 88 gms).
The solid product (88 gms) was taken in water (440 ml). The pH was adjusted to 8-9 with liquor ammonia. The reaction mass was stirred at 50-55°C for 30 min. The reaction mass was extracted with methylene chloride (10 parts) at 35-38°C. The organic phase was washed with water (2 x 100 ml), dried over anhydrous sodium sulfate and concentrated to obtain crude Aripiprazole. The crude aripiprazole thus obtained was recrystallized from ethanol twice to yield 67.0 gms of pure aripiprazole having HPLC purity > 99.9%.

Claims:
1) An improved method for the isolation of 7-(4-bromobutoxy)-3, 4-dihydro-2 (1H)-quinolinone, an intermediate of aripiprazole. Comprising the steps of
a) Forming a solution of isolated product obtained from the reaction of 7-hydroxy-3, 4-dihydro-2(lH) quinolinone and 1, 4-dibromobutane in methylene dichloride and cooling to 0-5°C.
b) Stirring with charcoal and silica gel for 45 min. at 0-5°C followed by filtration of charcoal and silica gel, washing the filtered charcoal and silica gel with methylene chloride.
c) Repeating the operation (b) followed by concentrating the combined methylene chloride layer obtained from filtration and washings.
d) Isolation of 7-(4-bromobutoxy)-3, 4-dihydro-2 (lH)-quinolinone after addition of hexane.
2) Improved method for the isolation of aripiprazole, prepared as described in base patent route wherein 7-(4-bromobutoxy)-3, 4-dihydro-2 (lH)-quinolinone and l-(2, 3-dichloro phenyl piperazine) hydrochloride is reacted in acetonitrile using triethylamine as base, Comprises of following steps
a. Isolation of solid product formed after reaction in acetonitrile by filtration.
b. Re-suspending the isolated product in 2 parts of acetonitrile and 0.75 parts
of triethyl amine, heating the mixture at reflux temperature for 30 min.
c. Isolating the product by filtration after cooling at room temperature.
d. Basification of product with liquor ammonia.

3) The process as claimed in claim 1 (d) wherein, isolation of 7-(4-bromobutoxy)-3, 4-dihydro -2(1 H) quinolinone from methylene dichloride at ambient temperature with addition of hexane in dropwise manner.
4) The process as claimed in claim 2 (c) wherein, wet solid cake obtained which was basified at pH 7-10 by using ammonia solution and concomitantly stirred at 50-60 °C up to 1 hour and extracted by methylene dichloride to get title compound.
5) The process as claimed in claim 2 wherein, pure title compound (Aripiprazole) obtained by twice crystallization with ethanol.
6). The process claimed as 1 a-d and 2 a-c forms the aripiprazole with comparable yield w. r. to prior art and purity of > 99.9%.
7) An improved process for synthesis of aripiprazole as substantially described herein with reference to forgoing example-1.

Abstract:
An improved process for the synthesis of aripiprazole and furthermore an isolation process of 7-(4-bromobutoxy)-3, 4-dihydro-2 (lH)-quinolinone (IV) is simplified. The aripiprazole prepared from this improved process has a better purity and comparable yields with respect to prior art.