DESCRIPTION
The present invention provides a process for the preparation of analogues of aripiprazole of Formula II or pharmaceutical acceptable salt thereof, which are present as impurities in the aripiprazole and use of theses impurities as reference marker to quantify the presence of these analogue in aripirazole.

Formula II
wherein –Cl group may be present at C2, C3, or C4 position

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.

The Journal of Medicinal Chemistry 1998, 41(5), 658-667 specifically discloses analogues of aripiprazole of Formula II, 7-(4-(4-(2-chlorophenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one, 7-(4-(4-(3-chlorophenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one and 7-(4-(4-(4-chlorophenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one.

Various processes for aripiprazole and its intermediates have been disclosed in prior art references, for example, Journal of Medicinal Chemistry, Vol.41, No.5, 658-667, (1988), US20060258869, US6995264, US20060079689, WO2007094009 and WO2007118923.

The present inventors found 7-(4-(4-(3-chlorophenyl)piperazin-1-yl)butoxy)-3,4-dihydro quinolin-2(1H)-one and 7-(4-(4-(2-chlorophenyl)piperazin-1-yl)butoxy)-3,4-dihydro quinolin-2(1H)-one are process impurities in aripiprazole and provide a simple process for the preparation of compound of formula II in a relatively pure state, which can be used as reference marker (reference standard) and as an intermediate for the preparation of aripiprazole.

In one of the aspect of the present invention relates to a process for preparing analogue of aripiprazole of formula II or its salt,

Formula II
wherein –Cl group may be present at C2, C3, or C4 position
the process includes of condensation of 7-(4-chlorobutoxy)-3,4-dihydrocarbostyril of formula III

Formula III
with phenylpiperzine derivative of formula IV or its salt

Formula IV
wherein –Cl group may be present at C2, C3, or C4 position
using base in presence of solvent.

The intermediate, 7-(4-chlorobutoxy)-3,4-dihydrocarbostyril of formula III, used as starting material may be prepared from the processes known in the prior art for example, US 20060258869, US 20060079689, WO 2007094009 and WO2007118923.

The condensation reaction is performed in the presence of base, includes, but are not limited to, inorganic base such as hydroxides of alkali metals, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like; carbonates of alkali metals, for example, sodium carbonate, potassium carbonate, and the like; and bicarbonates of alkali metals, for example, sodium bicarbonate, potassium bicarbonate, and the like; organic base such as pyridine, triethyl amine, dimethyl amine, monomethyl amine, and the like.

Further, the condensation of 7-(4-chlorobutoxy)-3,4-dihydrocarbostyril of formula III with phenylpiperzine derivative of Formula IV or its salt may be performed in presence of alkali metal iodide such as potassium iodide, sodium iodide and the like as the reaction accelerator.

Salt of compound of formula IV may be prepared by the treatment of formula IV with an acid. Acid may be selected from inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like; organic acid such as formic acid, acetic acid, methane sulfonic acid, p-toluene sulfonic acid, and the like.

The condensation reaction may be performed at a suitable temperature of about 20-100°C, depends on the solvent used; In one embodiment of the present condensation process is conducted at a temperature of about 70-80 °C.

After completion of the reaction, the reaction mixture concentrated and isolated solid by using suitable techniques such as slurry in a solvent, solvent-antisolvent technique and the like. Solvent such as water, alcohol for example, methanol, ethanol, isopropanol and the like, chlorinated solvents such as dichloromethane, chlorobenzene and the like.

Analogue of Formula II, obtained from the condensation, may have the purity greater than about 98% determined by HPLC. The obtained analogue of Formula II may be further purified by using conventional techniques such as recrystallization, slurry, column chromatography and the like.

Optionally, the resultant compound of Formula II may be dried untill the residual content of solvent reduced to desired levels. Drying may be suitably carried out in equipment such as a tray dryer, vacuum oven, air oven, or using a fluidized bed drier, spin flash dryer, flash dryer, and the like at a temperature of about 30°C to 100°C with or without vacuum.

In an embodiment of the present invention provides a process for the preparation of 7-(4-(4-(2-chlorophenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one or its salt, which includes the steps of condensation of 7-(4-chlorobutoxy)-3,4-dihydrocarbostyril of formula III

Formula III
with 1-(2-chlorophenyl)piperazine of Formula V or its salt

Formula V
using base in presence of solvent.

In another aspect, the present invention relates to a process for the preparation of 7-(4-(4-(3-chlorophenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one or its salt, which comprises condensation of 7-(4-chlorobutoxy)-3,4-dihydrocarbostyril of formula III

Formula III
with 1-(3-chlorophenyl)piperazine of Formula VI or its salt

Formula VI
using base in presence of solvent.

The resultant analogue of aripiprazole of Formula II may be converted into aripiprazole by using conventional prior art techniques.

The invention is further illustrated by the following example which is provided merely to be exemplary of the invention and do 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 invention.

Examples
Example-1: Preparation of 7-(4-(4-(3-chlorophenyl)piperazin-1-yl)butoxy)-3,4-dihydro quinolin-2(1H)-one

7-(4-chlorobutoxy)-3,4-dihydroquinolin-2(1H)-one (10 g; 0.0395 mol) was dissolved in dimethyl acetamide (35 ml). The solution of 1-(3-chlorophenyl)piperazine hydrochloride (9.16g; 0.0395 mol) in acetonitrile (40 ml), potassium bicarbonate (11.85 g; 0.118 mol) and potassium iodide (7.85 g; 0.047 mol) were added into the reaction solution simultaneously. The reaction mixture was heated at 80 °C and maintained for 10 h and then concentrated under vaccum to obtain residue. Distilled water (300 ml) was charged to the obtained residue, stirred and then filtered. The crude solid was charged on the silica column and purified using 2% Methanol in DCM to obtain the title compound.

Yield: 12.80 g (78.43 %)
Purity by HPLC: 99.4 %
Mass: (m/e): 414.3 (M+1)
1H NMR (400 MHz, DMSO): 1.50-1.60(2H,m), 1.64-1.74(2H,m), 2.28-2.41(4H,m),2.42-2.52(4H,m),2.75(2H,t, J=6.8 Hz),3.08-3.18(4H,m), 3.89(2H,t,J=6Hz), 6.41(1H,d, J=2Hz), 6.46 (1H,dd,J1=8 Hz,J2=2 Hz),6.74 (1H,d,J=7.6 Hz),6.85(1H,d, J=8.4 Hz), 6.89(1H,s), 7.01 (1H,d,J=8.4 Hz), 7.17(1H,t,J=8 Hz),9.94(1H,s).
13C NMR (400 MHz, DMSO): 23.4,24.7,27.3,31.4,48.3,53.1,58.0,67.9,102.4,108.2,114.2,115.1,116.1,118.6, 129.0, 31.0, 134.4, 139.8, 152.9, 158.5, 170.9.
IR in KBr : 3192 ,3087 ,2943 ,2821 ,2777 ,2468 ,1936 ,1679 ,1625 ,1595 ,1523 , 1482, 1376, 1235, 1178, 1029, 988, 861. cm –1.

Example-2: Preparation of 7-(4-(4-(2-chlorophenyl)piperazin-1-yl)butoxy)-3,4-dihydro quinolin-2(1H)-one

7-(4-chlorobutoxy)-3,4-dihydroquinolin-2(1H)-one (5 g; 0.0195 mol) was dissolved in 20 ml of dimethyl acetamide. The solution of 1-(2-chlorophenyl)piperazine hydrochloride (4.60 g; 0.0195 mol) in acetonitrile (20 ml), potassium bicarbonate (5.92 g; 0.0592 mol) and potassium iodide (3.93 g; 0.0237 mol) were added to the reaction solution simultaneously. The reaction mixture was heated to a temperature of about 80 °C and maintained for 10 h and then concentrated under vaccum. Distilled water (200 ml) was charged to the resultant residue, stirred and then filtered. The resultant crude solid was charged on the silica column and purified using 2% methanol in dichloromethane to afford the title compound.

Yield: 5.20 g (63.72 %)
Purity by HPLC: 98.5 %
Mass: (m/e): 414.2 (M+1)
1H NMR (400 MHz, DMSO): 1.50-1.60(2H,m), 1.65-1.75 (2H,m), 2.35-2.40(4H,m), 2.40-2.48(4H,m), 2.75(2H,t, J=7.2 Hz), 2.90-3.00(4H,m), 3.90(2H,t,J=6Hz), 6.41(1H,d, J=2Hz), 6.46 (1H,dd,J1=8 Hz,J2=2 Hz), 6.95-7.10 (2H,m), 7.12 (1H,d,J=7.6 Hz), 7.26(1H,t,J=8 Hz), 7.37(1H,d,J=8 Hz), 9.94(1H,s).
13C NMR (400 MHz, DMSO): 23.4, 24.7, 27.3, 31.4, 51.5, 53.5, 58.0, 67.9, 102.4, 108.2, 116.1, 121.4, 124.4, 128.2, 128.7, 129.0, 130.9, 139.8, 149.7, 158.5, 170.9.
IR in KBr : 3195, 3059, 2951, 2902, 2812, 2771, 2455, 1943, 1850, 1673, 1628, 1592, 1521, 1478, 1377, 1274, 1193, 1039, 949, 855 cm –1.

We claim:
1 A process for the preparation of analogue of aripiprazole of formula II or its salt,


Formula II
wherein –Cl group may be present at C2, C3, or C4 position
the process comprises of condensation of 7-(4-chlorobutoxy)-3,4-dihydrocarbostyril of formula III

Formula III
with phenylpiperzine derivative of formula IV or its salt

Formula IV
using base in presence of solvent.
wherein –Cl group may be present at C2, C3, or C4 position
2. The process according to claim 1, wherein said base is selected from inorganic base and organic base.
3. The process according to claim 1, wherein said base is selected from hydroxides of alkali metals, carbonates of alkali metals and bicarbonates of alkali metals.
4. The process according to claim 1, wherein said condensation reaction is performed in presence of accelerator such as metal iodide, for example, potassium iodide, sodium iodide and the like.
5. The process according to claim 1, wherein said solvents is selected from polar aprotic solvent, alcohol and nitriles or combination thereof.
6. The process according to claim 1, wherein said combination of solvents are selected from dimethyl acetamide and nitriles.
7. A process for the preparation of 7-(4-(4-(2-chlorophenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one or its salt, which comprises condensation of 7-(4-chlorobutoxy)-3,4-dihydrocarbostyril of formula III

Formula III
with 1-(2-chlorophenyl)piperazine of formula V or its salt

Formula V
using base in presence of solvent.
8. A process for the preparation of 7-(4-(4-(3-chlorophenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one or its salt, which comprises condensation of 7-(4-chlorobutoxy)-3,4-dihydrocarbostyril of formula III

Formula III
with 1-(3-chlorophenyl)piperazine of formula VI or its salt

Formula VI
using base in presence of solvent.

9. The purity of compound of 7-(4-(4-(2-chlorophenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one or its salt obtained according to the process of claim 7 is greater than about 98% by HPLC..
10. The purity of compound of 7-(4-(4-(3-chlorophenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one or its salt obtained according to the process of claim 8 is greater than about 99% by HPLC.