This application claims priority to Indian patent application no 493/CHE/2011 filed on Feb 21, 2011, the contents of which are incorporated by reference in their entirety.

FIELD OF THE INVENTION;

The present invention relates to an improved process for the preparation of Iloperidone or its pharmaceutically acceptable salt.

BACK GROUND OF THE INVENTION:

Iloperidone, an anti psychotropic agent is a monoamine directed towards acting upon and antagonizing specific neurotransmitters, particularly multiple dopamine and serotonin.

It is chemically known as l-[4-[3-[4-(6-Fluoro-l, 2-benzisoxazol-3-yl)-l- piperidinyl] propoxy]-3- methoxy phenyl] ethanone having the structure of formula I.

US. patent 5364866, disclosed Iloperidone or its salts, according to which it was prepared by the condensation of 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole hydrochloride and l-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, in the presence of potassium carbonate as a base in dimethylformamide (DMF), followed by extraction with organic solvent, to give the moist solid Iloperidone, which was further recrystallized from the ethyl alcohol to produce iloperidone as a beige (i.e. light brown) as shown in Scheme-1.

Journal of medicinal chemistry 1995, vol.38, No. 7, 1119-1131 discloses general synthesis of pharmaceutically active piperidine-l-yl-benzioxazole derivative including Iloperidone which is depicted in Scheme-2;

Drugs of future 2000, 25(1):29 discloses the preparation of iloperidone comprising the condensation of l-[4-(3-chloropropoxy)-3-methoxyphenyI] ethanone with 6-fluoro-3-(4-piperidinyl)-l, 2-benzisoxazole hydrochloride in the presence of hot dimethylformamide and potassium carbonate which is depicted in scheme-3;

IN1980/MUM/2007 application discloses the preparation of iloperidone in the presence of water and water soluble inorganic base, which is depicted in scheme-4;

The entire prior art processes involves hazardous solvents like dimethylformamide and extraction procedures. Thus there is a need of an alternative simple, less time consuming, cost effective and commercially feasible process for the preparation of Iloperidone. The present process is involves simple filtration and no extractive and evaporative workup is required.

OBJECT OF THE INVENTION

The main object of the present invention is to provide an improved process for the preparation of Iloperidone or its pharmaceutically acceptable salt.

SUMMARY OF THE INVENTION

One aspect of the present invention is to provide a process for the preparation of iloperidone, which comprises reacting a compound of formula III with compound of formula II in the presence of an organic base in a solvent. Another aspect of the present invention is to provide a process for the preparation of Iloperidone, comprising the steps of:

a) reacting a compound of formula III with compound of formula II in the presence of an organic base in water at 50-100°C,

b) cooling the solution of step a) to room temperature, and

c) isolating the Iloperidone.

Yet another aspect of the present invention is to provide a process for the preparation of Iloperidone of comprising the steps of:

a) reacting a compound of formula III with compound of formula II in the presence of a base in water at 50-100°C;

b) cooling the reaction mass to 20-35°C,

c) extracting in to an organic solvent, and

d) isolating the Iloperidone.

Yet another aspect of the present invention is to provide Iloperidone having the particle size dgo is less than 250 microns, dso is less than 100 microns and dio is less than 20microns.

Yet another aspect of the present invention Iloperidone having the purity is greater than 99.8%.

The entire process for the preparation of iloperidone is depicted in scheme-5 below:

DETAILED DESCRIPTION OF THE INVENTION

The present relates to an improved process for the preparation of Iloperidone or its pharmaceutically acceptable salt by reacting l-[4-(3-chloropropoxy)-3-methoxyphenyl] ethanone of formula III with 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole of formula II or its salt in presence of organic base in a solvent.

In one embodiment, the present invention provides an improved process for the preparation of Iloperidone, which comprises reacting a compound of formula III in the presence of an organic base in a solvent.

According to the present invention l-[4-(3-chloropropoxy)-3-methoxyphenyl] ethanone of formula III is suspended in a solvent at ambient temperature, organic base is added followed by 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole of formula II or it salt. The resulting mixture is heated to 50-100°C, preferably 75-85°C for about 4-50hrs. The reaction mass is cooled to ambient temperature and filtered the obtained solid. The obtained solid is recrystallized from alcohol solvent to get pure Iloperidone.

According to the present invention the solvent used for condensation reaction is selected from water, acetonitrile, methanol, ethanol, isopropyl alcohol, acetone, toluene or mixture thereof. The organic base in the present invention is selected from triethylamine, pyridine, disiopropyl amine, diethyl amine, methyl amine or imidazole. Alcoholic solvent used for the recrystallization is selected from methanol, ethanol, isopropyl alcohol or butanol.

According to the present invention the reaction is also carried out using inorganic base selected from sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate or potassium carbonate.

Another embodiment of the present invention is to provide an improved process for the preparation of Iloperidone comprising the steps of; a) reacting a compound of formula III in the presence of a base in water at 50-100°C,

b) cooling the reaction mass to 20-35°C,

c) extracting in to an organic solvent, and

d) isolating the Iloperidone.

According to the present invention l-[4-(3-chloropropoxy)-3-methoxyphenyl] ethanone of formula III is suspended in water at ambient temperature, base is added followed by 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole of formula II or it salt. The resulting mixture is heated to 50-100°C, preferably 75-80°C for about 4-lOhrs. The reaction mass is cooled to ambient temperature and product is extracted with an organic solvent, evaporated to get the residue. Alcoholic solvent is added to the residue and stirred to get solid. The obtained solid is filtered.

According to the present invention the base is selected from triethyl amine, pyridine, diisopropyl amine, diethyl amine, methyl amine, imidazole, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate or potassium carbonate.

According to the present invention the organic solvent for extraction of the compound is selected from methylene chloride, chloroform, toluene, ether or ethyl acetate.

Alcoholic solvent is selected from methanol, ethanol, isopropyl alcohol or butanol.

Yet another embodiment of the present invention is to provide an improved process for the preparation of Iloperidone comprising the steps of; a) reacting a compound of formula III

in the presence of an organic base in water at 50-100°C,

b) cooling the solution of step a) to room temperature, and

c) isolating the Iloperidone.

According to the present invention l-[4-(3-chloropropoxy)-3-methoxyphenyl] ethanone of formula III is suspended in water at ambient temperature, organic base is added followed by 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole of formula II or it salt. The resulting mixture is heated to 50-100°C, preferably 75-85°C for about 4-lOhrs. The reaction mass is cooled to ambient temperature and filtered the obtained solid. The obtained solid is recrystallized from alcohol solvent to get pure Iloperidone.

According to the present invention organic base is selected from triethylamine, pyridine, disiopropyl amine, diethyl amine, methyl amine or imidazole. Alcoholic solvent used for the recrystallization is selected from methanol, ethanol, isopropyl alcohol or butanol.

Yet another embodiment of the present invention is to provide Iloperidone having the particle size dgo is less than 250 microns, dso is less than 100 microns and dio is less than 20microns.

Yet another embodiment of the present invention iloperidone having the purity is greater than 99.8%

The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention in any way.

Examples

Example 1: Preparation of l-(4-(3-chloropropoxy)-3-methoxyphenyl) ethanone.

Potassium carbonate (62.3g) and l-(4-hydroxy-3-methoxyphenyl) ethanone (50gm) were added to acetonitrile (500 ml) into a RB flask. The mixture was heated to 65-70°C a solution of l-bromo-3-chloropropane (83.5g) in acetonitrile (167 ml) was added slowly to the mixture for 2 hours. The reaction mass maintained at 65-70°C for 8 hours, solid was filtered and washed with acetonitrile. Filtrate was concentrated, cyclohexane was added (250 ml), maintained for 2 hours, solid was filtered and dried under vacuum to yield l-(4-(3-chloropropoxy)-3-methoxyphenyl) ethanone (60 g).

Example 2: Preparation of l-(4-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl) piperidin-1-yl) propoxy)-3-methoxyphenyI) ethanone.

l-(4-(3-chloropropoxy)-3-methoxyphenyl) ethanone (20g) of example 1 was taken into a RB flask at room temperature. Purified water (200ml), Sodium bicarbonate (17.4 g) and 6-Fluoro-3-piperidin-4-yl-benzo[c/] isoxazole (19.9gm) were added at room temperature and reaction was maintained at 80-85°C for 6 hours. After completion of reaction cooled to room temperature, product extracted with dichloromethane (100 ml) and distilled the solvent, Solid obtained by adding isopropyl alcohol (100 ml.) was filtered and washed with isopropyl alcohol (20ml) to yield crude Iloperidone (30g). HPLC purity: 99.33%

Example 3: Preparation of l-(4-(3-(4-(6-fluorobenzo[d]isoxazol-3-yI) piperidin-1-yl) propoxy)-3-methoxyphenyl) ethanone.

l-(4-(3-chloropropoxy)-3-methoxyphenyl) ethanone (l0g) of example 1 was taken into a RB flask at room temperature. Isopropyl alcohol (l00ml), Sodium carbonate (10.9 g) and 6-Fluoro-3-piperidin-4-yl-benzo[£f]isoxazole (10 gm) were added at room temperature and reaction was maintained at 75-80°C for 45 hours. After completion of reaction cooled to room temperature and Solid obtained was fihered, washed with isopropyl alcohol (10 ml). The wet material was subjected to slurry wash with Purified water (100ml) to yield crude Iloperidone (15g). HPLC purity: 99.42%

Example 4: Preparation of l-(4-(3-(4-(6-fluorobenzo[d]isoxazoI-3-yl) piperidin-1-yl) propoxy)-3-methoxyphenyl) ethanone.

l-(4-(3-chloropropoxy)-3-methoxyphenyl) ethanone (5g) was taken into a RB flask at room temperature. Purified water (50ml), Triethylamine (6g) and 6-Fluoro-3-piperidin-4-yl-benzo[£/]isoxazole (5g) were added at room temperature and reaction was maintained at 75-80°C for 6 hours. After completion of reaction cooled to room temperature and product extracted with dichloromethane (30ml) and distilled the solvent, Solid obtained by adding isopropyl alcohol (30ml.) was filtered and washed with isopropyl alcohol (5ml) to yield crude Iloperidone (7.5g). HPLC purity: 99.41%

Example 5: Preparation of l-(4-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl) piperidin-1-yl) propoxy)-3-methoxyphenyI) ethanone.

l-(4-(3-chloropropoxy)-3-methoxyphenyl) ethanone (5g) was taken into a RB flask at room temperature. Purified water (50ml), Triethylamine (6g) and 6-Fluoro-3-piperidin-4-yl-benzo[£/]isoxazole (5g) were added at room temperature and reaction was maintained at 75-80°C for 6 hours. After completion of reaction cooled to room temperature and product obtained by filtration and slurry with isopropyl alcohol (30 ml.) was filtered and washed with isopropyl alcohol (5 ml) to yield crude Iloperidone (7.5g). HPLC purity: 99.78%

Example 6: Preparation of l-(4-(3-(4-(6-fluorobenzo[dlisoxazol-3-yl) piperidin-1-yl) propoxy)-3-methoxyphenyl) ethanone.

l-(4-(3-chloropropoxy)-3-methoxyphenyl)ethanone (5g) was taken into a RB flask at RT. 10% aqueous isopropyl alcohol (50ml),Triethylamine (5.2g) and 6-Fluoro-3-piperidin-4-yl-benzo[c(lisoxazole (5g) were added at room temperature and reaction was maintained at 75-80°C for 45 hours. After completion of reaction (Limit of 1-(4-(3-chloropropoxy)-3-methoxyphenyl) ethanone NMT 5%), cooled to room temperature and product obtained by filtration and slurry with isopropyl alcohol (25 ml.) was filtered and washed with isopropyl alcohol (5 ml) to yield crude Iloperidone (7.0g). HPLC purity: 97.68%

Example 7: Preparation of l-(4-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl) piperidin-1-yl) propoxy)-3-methoxyphenyl) ethanone.

l-(4-(3-chloropropoxy)-3-methoxyphenyl) ethanone (5 g) was taken into a RB flask at room temperature. 90% aqueous isopropyl alcohol (50ml), Triethylamine (5.2 g) and 6-Fluoro-3-piperidin-4-yl-benzo[£flisoxazole (5g) were added at room temperature and reaction was maintained at 75-80°C for 10 hours. After completion of reaction (Limit of l-(4-(3-chloropropoxy)-3-methoxyphenyl) ethanone NMT 5%), cooled to room temperature and product obtained by filtration and slurry with isopropyl alcohol (25 ml.) was filtered and washed with isopropyl alcohol (5ml) to yield crude Iloperidone (7.5g). HPLC purity: 99.90%

Example 8: Preparation of l-(4-(3-(4-(6-fluorobenzo[d]isoxazoI-3-yI) piperidin-1-yl) propoxy)-3-raethoxyphenyl) ethanone.

l-(4-(3-chloropropoxy)-3-methoxyphenyl) ethanone (5 g) was taken into a RB flask at room temperature. 50% aqueous isopropyl alcohol (50ml), Triethylamine (5.2 g) and 6-Fluoro-3-piperidin-4-yl-benzo[c/]isoxazole (5g) were added at room temperature and reaction was maintained at 75-80°C for 20 hours. After completion of reaction (Limit of l-(4-(3-chloropropoxy)-3-methoxyphenyl) ethanone NMT 5%), cooled to room temperature and product obtained by filtration and slurry with isopropyl alcohol (25 ml.) was filtered and washed with isopropyl alcohol (5ml) to yield crude Iloperidone (7.5g). HPLC purity: 99.84%

Example 9: Preparation of l-(4-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl) piperidin-1-yl) propoxy)-3-methoxyphenyl) ethanone.

l-(4-(3-chloropropoxy)-3-methoxyphenyl) ethanone (15 g) was taken into a RB flask at room temperature. Purified water (150ml), Triethylamine (25g) and 6-Fluoro-3-piperidin-4-yl-benzo[<5Qisoxazole hydrochloride (17.5g) were added at room temperature and reaction was maintained at 75-80°C for 6-7 hours. After completion of reaction cooled to room temperature and product obtained by filtration and slurry with isopropyl alcohol (90 ml.) was filtered and washed with isopropyl alcohol (15 ml) to yield crude Iloperidone (22.5 g). HPLC purity: 99.50%

Example 10: Preparation of l-(4-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl) piperidin-1-yl) propoxy)-3-methoxyphenyl) ethanone.

l-(4-(3-chloropropoxy)-3-methoxyphenyl) ethanone (5 g) was taken into a RB flask at room temperature. Purified water (50ml), diisopropylethylamine (10.6 g) and 6-Fluoro-3-piperidin-4-yl-benzo[