DESCRIPTION
The present invention provides a process for the preparation of 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)quinolin-2(1H)-one, compound of formula II or pharmaceutical acceptable salts thereof, which may present in aripiprazole as an impurity.

Formula II
Aripiprazole of Formula I is chemically known as 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydrocarbostyril.

Formula I
Aripiprazole is a psychotherapic 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 patents 4,734,416 and 5,006,528 disclose Aripiprazole and its process for the preparation.

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. 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.

The U.S. Food and Drug Administration (“FDA”) requires that process impurities be maintained below set limits. For example, in its ICH Q7A guidance for API manufacturers, the FDA specifies the quality of raw materials that may be used.

Gutta et.al. Analytical chemistry An Indian Journal, 2008,7(7), 551-553 and Satyanarayana et.al. in Heterocyclic Communications (2005), 11(6), 485-490 disclosed about the impurity of 7-(4(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)quinolin-2(1H)-one.

The present inventor while working on the process for the preparation of aripiprazole comes across the impurity present in the Aripiprazole. The 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)quinolin-2(1H)-one (compound of formula II), which is a process impurity in aripiprazole and generate during the synthetic process of Aripiprazole. It is difficult to removes without considerable loss of yield. The inventor has developed a simple process for the preparation of compound of formula II in a relatively pure state, which can be used as reference marker of Aripiprazole.

As such, its presence could be quantified in Aripiprazole and undue purification for its removal could be avoided. The 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)quinolin-2(1H)-one may be used as an intermediate for the preparation of aripiprazole.

In one aspect of the present invention provides a process for 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)quinolin-2(1H)-one of formula II or its salt,

formula II

which includes the steps of,
i) condensation of 7-hydroxyquinolin-2(1H)-one with 1-bromo-4-chloro butane, in presence of a base and phase transfer catalyst in water to provide 7-(4-chlorobutoxy)quinolin-2(1H)-one,

ii) treating 7-(4-chlorobutoxy)quinolin-2(1H)-one with 1-(2,3-dichloro phenyl)piperazine or its salts in presence of a base and reaction accelerator in a solvent to provide 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)quinolin-2(1H)-one.


7-hydroxyquinolin-2(1H)-one undergoes condensation reaction with 1-bromo-4-chloro butane in presence of base and phase transfer catalyst in a water at temperature 50-90°C. After completion of the reaction, the reaction mixture is cooled to room temperature and extracted in halogenated solvent. The solvent is concentrated under reduced pressure to get residue of 7-(4-chlorobutoxy)quinolin-2(1H)-one which is optionally crystallized by using one or more suitable solvent/ solvents selected from cyclohexane, hexanes, heptane and methanol, ethanol, isopropanol or mixture thereof.

7-(4-chlorobutoxy)quinolin-2(1H)-one is reacted with 1-(2,3-dichloro phenyl)piperazine or its salts in presence of base and reaction accelator in solvent like dimethyl acetamide,dimethyl formamide, dimethyl sulfoxide, acetonitrile and the like or a mixture thereof at temperature between 60-100°C for 6-10 hours. After completion of reaction the product is filtered and further purified over column of silica gel or alumina.

The bases used in the step i) and ii) 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 or mixture thereof; organic base such as pyridine, triethyl amine, dimethyl amine, monomethyl amine or mixture thereof.

The phase transfer catalyst may includes, but are not limited to quaternary ammonium salts such as tetrabutyl ammonium bromide, tetrabutyl ammonium chloride and tetrabutyl ammonium fluoride or mixture thereof.

The term halogenated solvent includes one or more of dichloromethane, chloroform, ethylene dichloride, carbon tetra chloride and mixture thereof.

The term reaction accelerator may include of Sodium iodide and Potasium iodide.

The term salt includes of commonly known pharmaceutically accepted salt of the compounds which may be prepared by the treating compound 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 compound of Formula II may purified by using conventional techniques such as recrystallization, column chromatography and the like to obtained purity greater than 98% when measured by HPLC.

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, rotavapour and the like at a temperature of about 30°C to 100°C with or without vacuum.

In the embodiment of the invention wherein the 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)quinolin-2(1H)-one is further converted into Aripiprazole in presence of hydrogen and catalyst palladium on carbon in alcoholic solvents.

7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)quinolin-2(1H)-one dissolved in alcoholic solvents and hydrogenated over 5% Palladium on carbon at less than 100 psi hydrogen gas pressure. After completion of reaction, catalyst is filtered and filtrate is distilled under reduced pressure and obtained residue, which is optionally crystallized by using one or more suitable solvent/ solvents selected from methanol, ethanol, isopropanol or mixture thereof.

The term alcoholic solvents include one or more of methanol, ethanol, isopropanol or mixture thereof.

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-chlorobutoxy)quinolin-2(1H)-one

5 g of 7-hydroxyquinolin-2(1H)-one was dissolved in 100 ml of distilled water. To this was added 4.34 g of potassium bicarbonate, followed by 1.55 g of Sodium hydroxide, 0.5 g of Tetrabutyl ammonium bromide and 31 g of 1-bromo-4-chlorobutane. The reaction mixture was heated at 900 C for 6 h. The reaction mixture was cooled to room temperature and extracted with Dichloromethane. The Dichloromethane layer was washed with water and concentrated under reduced pressure. The crude solid was recrystallized using Cyclohexane. The amount obtained was 5.50 g.

Yield: 5.50g (70.60 %)
Mass: (m/e): 252.0 (M+1)

1H NMR (400 MHz, DMSO): 1.80-1.94(4H,m), 3.70(2H,t, J=6.4Hz), 4.02(2H,t, J=6Hz), 6.27(1H,d, J=9.2Hz), 6.76-6.78(2H,m), 7.53(1H,d, J=9.2Hz), 7.77(1H,d, J=9.2Hz), 11.54(1H,s).

Example-2: Preparation of 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)quinolin-2(1H)-one
5 g of 7-(4-chlorobutoxy)quinolin-2(1H)-one was dissolved in 20 ml of dimethyl acetamide. To this was added 5.29 g of 1-(2,3-dichloro phenyl)piperazine hydrochloride dissolved in 50 ml of acetonitrile followed by 5.97 g potassium bi carbonate and 4.76 g potassium iodide . The reaction mixture was heated at 800 C for 10 h. The reaction mixture was cooled to 10 0 C and filtered. The crude solid was charged on the silica column and purified using 2-4 % Methanol in Dichloromethane. The amount obtained was 5 g.

Yield: 5.0 g (56.43 %)
Purity by HPLC: 98.3 %
Mass: (m/e): 446.3 (M+1)

1H NMR (400 MHz, DMSO): 1.54-1.66(2H,m), 1.70-1.82(2H,m), 2.39(2H,t,J=6.8Hz), 2.49-2.52(4H,m), 2.90-3.02(4H,m), 4.02(2H,t, J=6.4Hz), 6.27 (1H,d,J=9.2Hz), 6.76-6.79(2H,m), 7.09-7.11(1H,m), 7.26-7.30(2H,m), 7.53(1H,d, J=9.2Hz), 7.78(1H,d, J=9.6Hz), 11.54(1H,bs).

13C NMR (DMSO): 23.3, 27.2, 51.6, 53.4, 57.9, 68.3, 99.3, 111.5, 113.9, 119.1, 120.1, 124.9, 126.6, 129.1, 129.9, 133.3, 140.6, 141.3, 151.8, 161.1, 162.9.

IR (KBr): 3140, 3079, 2947, 2826, 1655, 1577, 1557, 1515, 1473, 1446, 1415, 1375, 1323, 1269, 1241, 1222, 1182, 1140, 1098, 1047, 1022, 1001, 963, 945 cm-1.

We claim:
1 A process for the preparation of 7-(4(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)quinolin-2(1H)-one of formula II or its salt,

which comprises
i) condensation of 7-hydroxyquinolin-2(1H)-one with 1-bromo-4-chloro butane, in presence of a base and phase transfer catalyst in water and isolated 7-(4-chlorobutoxy)quinolin-2(1H)-one,

ii) treating 7-(4-chlorobutoxy)quinolin-2(1H)-one with 1-(2,3-dichloro phenyl)piperazine in presence of a base and reaction accelerator in a solvent to provide 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)quinolin-2(1H)-one.
2. The process of claim 1, wherein the base is selected from hydroxides of alkali metals, carbonates of alkali metals and bicarbonates of alkali metals and the like or mixture thereof.
3. The process of claim 1, wherein the phase transfer catalyst is selected from tetrabutyl ammonium bromide, tetrabutyl ammonium chloride or tetrabutyl ammonium fluoride or mixture thereof.
4. The process of claim 1, where in the solvent is one or more dimethyl acetamide,dimethyl formamide, dimethyl sulfoxide, acetonitrile and a mixture thereof.
5. The process of Claim 1, wherein reaction accelerators is sodium iodide, potassium iodide or a mixture thereof.
6. The process of claim1, wherein step i) product isolation technique involve removal of halogenated solvent and crystallized by using hydrocarbon and alcoholic solvents.
7. The process of claim 6, wherein hydrocarbon solvent is one or more cyclohexane, hexanes, heptanes or mixture thereof and alcoholic solvents is one or more methanol, ethanol, isopropanol or mixture thereof.
8. The purity of compound of 7-(4(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)quinolin-2(1H)-one is more than 98% when measured by HPLC.
9. The process of conversion of 7-(4(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)quinolin-2(1H)-one into Aripiprazole by using 5% palladium on carbon in presence of hydrogen gas in alcoholic solvent.
10. The process of claim 9, wherein the alcoholic solvent is one or more of methanol, ethanol, isopropanol or mixture thereof.