This application claims priority to this Indian patent application 1406/CHE/2012 filed on April 09, 2012 and 2582/CHE/2012 filed on June 28, 2012

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Blonanserin intermediates and further conversion to Blonanserin. The present invention further relates to purification of Blonanserin.

BACKGROUND OF THE INVENTION

Blonanserin, 2-(4-Ethyl-l -piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine having the Formula-I is used as an antipsychotic. Blonanserin is marketed by Dainippon Pharmaceuticals as LONASEN® in Japan.
Formula-I

US 5,021,421 discloses Blonanserin and related compounds along with the synthesis of Blonanserin. US'421 discloses process for the preparation of 4-(4-Fluorophenyl) 5,6,7,8,9,10-hexahydrocyclooctane[b]pyridine-(lH)-ketone of Formula-II by hydrolyzing 4-Fluorobenzoyl acetonitrile in presence of Polyphosphoric acid and further reaction with Cyclooctanone and condensation with N-ethyl piperzene.

CN 102030707 discloses process for the preparation of 4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro cyclooctane[b]pyridine-(lH)-ketone of Formula-II by hydrolysis of 4-Fluorobenzoyl acetonitrile with sulfuric acid to get an intermediate compound 3-(4-Fluorophenyl)-3-oxo propanamide. This compound on reaction with Cyclooctanone gives 4-(4-Fluorophenyl)-5,6,7,8,9,10-hexahydro cyclooctane [b]pyridine-(lH)-ketone. CN 102093289 also discloses similar process for the preparation of 4-(4-Fluorophenyl) 5,6,7,8,9,10-hexahydro cyclooctane [b] pyridine-(lH)-ketone.

In prior art US 5021421 the hydrolysis of 4-Fluorobenzoyl acetonitrile is carried out in presence of Polyphosphoric acid. Handling of Polyphosphoric acid is very difficult at the large scale synthesis and the reaction mass colour will change into black at reaction temperature. The yield obtained by the prior art process is low. There is a need in the art to prepare Blonanserin with improved yield and quality.
Cryst.Eng.Comm, 2012, 14, 2367-2372 discloses Blonanserin Hydrochloride Monohydrate and process for the preparation of same by dissolving Blonanserin Hydrochloride in hot nitromethane. Isolation of Blonanserin Hydrochloride Monohydrate in the preparation of Blonanserin will enhance the purity of Blonanserin. Thus the present invention provides an improved and industrially viable process for the preparation of Blonanserin Hydrochloride and further conversion to Blonanserin.

OBJECT AND SUMMARY OF THE INVENTION

Principle object of the present invention is to provide an improved process for the preparation Blonanserin.

Another object of the present invention is to provide an improved process for the preparation of 2-halo-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocyclooctane [b] pyridine of Formula-HI which is an intermediate of Blonanserin.

Another object of the present invention is to provide an improved and industrially viable process for the preparation of Blonanserin Hydrochloride.

One aspect of the present invention is to provide a process for the preparation of 4-(4-Fluorophenyl)-5,6,7,8,9,10-hexahydro cyclooctane [b] pyridine-(lH) -ketone comprising the steps of:

a) hydrolyzing 4-Fluorobenzoyl acetonitrile in presence of an acid to give 3-(4-Fluorophenyl)-3-oxo propanamide,

b) reacting with Cyclooctanone; and

c) isolating 4-(4-Fluorophenyl)-5,6,7,8,9,10-hexahydro cyclooctane [b] pyridine-(lH)-ketone.
wherein, acid is selected from Methanesulphonicacid, Eaton's reagent or organic acid.
One more aspect of the present invention is to provide an improved process for the preparation of 2-halo-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro cyclooctane [b] pyridine comprising reacting 4-(4-Fluorophenyl)-5,6,7,8,9,10-hexahydro cyclooctane [b] pyridine-(lH)-ketone with halogenating agent to give corresponding halide compound.

One more aspect of the present invention is to provide an improved process for the preparation of Blonanserin comprising reacting 2-halo-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro cyclooctane [b] pyridine with N-ethyl piperazine in an organic solvent.
One more aspect of the present invention is to provide a process for the preparation of Blonanserin Hydrochloride comprising the steps of:

a) dissolving Blonanserin in water, water miscible organic solvent, or mixtures thereof,

b) adding HC1 source, and

c) isolating Blonanserin Hydrochloride.

One more aspect of the present invention is to provide pure Blonanserin from Blonanserin Hydrochloride comprising the steps of:

a) taking Blonanserin Hydrochloride in a solvent or mixture of solvents,

b) adjusting pH to basic with a base,

c) isolating Blonanserin, and

d) optionally converting into its pharmaceutically acceptable salts.

One more aspect of the present invention is to provide pure Blonanserin from Blonanserin Hydrochloride comprising the steps of:

a) taking Blonanserin Hydrochloride in a mixture of water and water immiscible organic solvent,

b) adjusting pH to basic with a base,

c) separating the organic layer, and

d) optionally extracting Blonanserin from aqueous layer, and

e) isolating the pure Blonanserin from organic layer.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for the preparation of 4-(4-Fluorophenyl)-5,6,7,8,9,10-hexahydro cyclooctane [b] pyridine-(lH)-ketone comprising the steps of hydrolyzing 4-Fluorobenzoyl acetonitrile in presence of an acid; reacting with Cyclooctanone; and isolating 4-(4-Fluorophenyl)-5,6,7,8,9,10-hexahydro cyclooctane [b] pyridine-(lH)-ketone. The present invention also relates to further conversion 4-(4- Fluorophenyl)-5,6,7,8,9,10-hexahydro cyclooctane [b] pyridine-(lH)-ketone into Blonanserin. The present invention also provides, process for the preparation of Blonanserin Hydrchloride and further conversion of Blonanserin Hydrchloride to pure Blonanserin.
The main aspect of the present invention is to provide an improved process for the preparation of 4-(4-Fluorophenyl)-5,6,7,8,9,10-hexahydro cyclooctane [b] pyridine-(lH)-ketone comprising the steps of:

a) hydrolyzing 4-Fluorobenzoyl acetonitrile in presence of an acid to give 3-(4-Fluorophenyl)-3-oxopropanamide, wherein, acid is selected from Methanesulphonicacid, Eaton's reagent or organic acid.

b) reacting with Cyclooctanone; and

c) isolating 4 -(4-Fluorophenyl)-5,6,7,8,9,10-hexahydro cyclooctane [b] pyridine-(lH)-ketone.

In one embodiment of the present invention, Eaton's reagent is 5.3 - 9.5 wt % of phosphorus pentoxide solution in methanesulfonic acid.

In another embodiment of the present invention, organic acid is selected from Trifluoroaceticacid, Trichloroacetic acid, preferably Trifluoroaceticacid.

In prior art US 5021421 the hydrolysis of 4-Fluorobenzoyl acetonitrile is carried out in presence of Polyphosphoric acid. Handling of Polyphosphoric acid is very difficult at the large scale synthesis and the reaction mass colour will change into black at reaction temperature. The yield obtained by the prior art process is low. Handling of Methanesulphonic acid or Eaton's reagent is easy at the large scale synthesis and quantities of Methanesulphonic acid and Eaton's reagents used for the reaction are very less compared to Polyphosphoric acid.

As per the present invention, of 4-Fluorobenzoyl acetonitrile is taken in an acid. Acid is selected from Methanesulphonicacid, Eaton's reagent or organic acid, preferably Methanesulphonicacid or Eaton's reagent. Reaction temperature was raised to 50-90 °C, preferably 65-75°C and maintained for 1-5 hrs, preferably 2-3 hrs. Then Cyclooctanone is added and temperature was raised to 90-120°C, preferably 110 °C and maintained for 1-4 hrs, preferably 2-4 hrs. To the reaction mass water immiscible organic solvent is added. Water immiscible organic solvent is selected from ester solvent such as ethyl acetate; hydrocarbon solvent such as toluene; halogenated solvent such as Dichloromethane, chloroform preferably dichlormethane. To this water is added and layers were separated.

Organic layer is washed with water and distilled out. The product was crystallized form solvent selected from Acetone, IPA, ethyl acetate or Cyclohexane.

Another aspect of the present invention provides further conversion of 4-(4-Fluorophenyl)-5,6,7,8,9,10-hexahydro cyclooctane [b]pyridine-(lH)-ketone to Blonanserin as depicted in scheme I comprising the steps of:

a) converting4-(4-Fluorophenyl)-5,6,7,8,9,10-hexahydrocyclooctane[b] pyridine-(lH)-ketone to 2-halo-4-(4-fluorophenyl) 5,6,7,8,9,10 hexahydro cyclooctane [b] pyridine,

b) condensing 2-halo-4-(4-fluorophenyl) 5,6,7,8,9,10 hexahydro cyclooctane [b] pyridine with N-ethyl piperazine to get Blonanserin.

As per the present invention, 4-(4-Fluorophenyl)-5,6,7,8,9,10-hexahydro cyclooctane [b] Pyridine-(lH)-ketone is converted to 2-halo-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro cyclooctane [b] pyridine by reacting with halogenating agent to give corresponding halide compound.

In one embodiment, halogenating agent is used for halogenation is selected from Phenyl phosphonic dichloride in presence of polar aprotic solvent like N-Methyl pyrrolidone.

Prior art processes doesn't involves the use of solvent in the preparation of 2-Chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro cyclooctane [b] pyridine. Handling of neat reaction is very difficult at the large scale synthesis and the reaction is exothermic. The sampling and in-process analysis is not consistent in neat reaction. Thus using of the organic solvent is easy at the large scale synthesis.
In one embodiment of the present invention, 2-halo-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro cyclooctane [b] pyridine is reacted with N-ethyl piperazine to get Blonanserin.

As per the present invention, 2-halo-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro cyclooctane [b] pyridine compound, preferably 2-Chloro-4-(4-fluorophenyl)-5,6,7,8,9,10- hexahydro cyclooctane [b] pyridine is reacted with N-ethyl piperazine in absence / presence of suitable solvent. The suitable solvent used in this reaction is selected from N-Methyl pyrrolidone, Dimethyl sulphoxide (DMSO), preferably N-Methyl pyrrolidone.

Prior art processes doesn't involves the use of solvent in the preparation of Blonanserin. Handling of neat reaction is very difficult at the large scale synthesis and the reaction is exothermic. The sampling and in-process analysis is not consistent in neat reaction. Thus using of the organic solvent is easy at the large scale synthesis.

Another aspect of the present invention is to provide an improved process for the preparation of Blonanserin Hydrochloride comprising the steps of:

a) dissolving Blonanserin in water, water miscible organic solvent, or mixtures thereof,

b) adding HC1 source, and

c) isolating Blonanserin Hydrochloride.

As per the present invention, Blonanserin is dissolved in water, water miscible organic solvent, or mixtures thereof. Water miscible organic solvent is selected from alcohol solvents such as methanol, ethanol and isopropanol, preferably methanol and ethanol, more preferably methanol. The most preferable solvent mixture used for dissolving Blonanserin is a mixture of methanol and water. To this HC1 source is added. HC1 source is selected from HC1 gas, Con HC1, alcholic HC1, preferably Con HC1. The reaction mass is optionally heated to 70-100°C, preferably 80-85°C. The reaction mass is cooled to 20-40°C, preferably 25-30°C. The resulting solid is filtered and crystallized in a mixture of methanol and purified water to get pure Blonanserin Hydrochloride. The obtained Blonanserin Hydrochloride may be in the form of hydrate, preferably Blonanserin Hydrochloride Monohydrate.

One more aspect of the present invention is to provide pure Blonanserin from Blonanserin Hydrochloride comprising the steps of:

a) taking Blonanserin Hydrochloride in a solvent or mixture of solvents,

b) adjusting pH to basic with a base,

c) isolating Blonanserin, and

d) optionally converting into its pharmaceutically acceptable salts.

In one embodiment, the solvent used in this reaction is selected from water miscible solvent, water immiscible solvent or mixtures thereof. Water miscible solvent is selected from alcohol solvents such as methanol, ethanol and isopropanol. Water immiscible solvents selected from halogenated solvent such as chloroform, dichloromethane; alkyl acetate such as ethyl acetate and isopropyl acetate. The suitable mixture of solvents is methanol and water or ethyl acetate and water.

In another embodiment, base used for adjusting pH to basic is selected from alkaline metal bicarbonates such as; sodium bicarbonate, potassium bicarbonate. And alkaline metal carbonates such as; potassium carbonate, sodium carbonate; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide; preferably sodium hydroxide.

As per the present invention, Blonanserin Hydrochloride, preferably Blonanserin Hydrochloride Monohydrate is taken in a solvent or mixtures of solvents. Solvent is selected from water miscible solvent is alcohol solvent such as methanol, ethanol and isopropanol; water immiscible solvent is halogenated solvent such as chloroform, dichloromethane; alkyl acetate such as ethyl acetate and isopropyl acetate; mixture of solvent is selected from methanol and water or ethyl acetate and water, preferably methanol and water. The reaction temperature is raised to 40-70 °C, preferably 50-60 °C, pH is adjusted to 7.5-11, preferably 8-8.5 with a base such as sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide and potassium hydroxide; preferably sodium hydroxide. The reaction mass is cooled to 20-40°C, preferably 25-30°C. The obtained solid is filtered and optionally crystallized in a mixture of water and methanol to get pure Blonanserin.

One more aspect of the present invention is to provide pure Blonanserin from Blonanserin Hydrochloride comprising the steps of:

a) taking Blonanserin Hydrochloride in a mixture of water and water immiscible organic solvent,

b) adjusting pH to basic with a base,

c) separating the organic layer, and

d) optionally extracting Blonanserin from aqueous layer, and

e) isolating the pure Blonanserin from organic layer.

In one embodiment, water immiscible organic solvent used in this reaction is selected from halogenated solvent such as chloroform, dichloromethane; alkyl acetate such as ethyl acetate and isopropyl acetate, preferably ethyl acetate.

In another embodiment, base used for adjusting pH to basic is selected from alkaline metal bicarbonates such as; sodium bicarbonate, potassium bicarbonate. And alkaline metal carbonates such as; potassium carbonate, sodium carbonate; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide; preferably sodium hydroxide.

As per the present invention, Blonanserin Hydrochloride, preferably Blonanserin Hydrochloride Monohydrate is taken in a mixture of water and water immiscible organic solvent. Water immiscible organic solvent is halogenated solvent such as chloroform, dichloromethane; alkyl acetate such as ethyl acetate and isopropyl acetate, preferably ethyl acetate. pH of the reaction mass is adjusted to 7.5-11, preferably 8.5-9 with a base such as sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide and potassium hydroxide; preferably sodium hydroxide. The layers were separated and aqueous layer is extracted with water immiscible organic solvent. The combined organic layer is distilled out completely under vacuum at 30-50°C, preferably 40-45°C to get residue. To this residue is dissolved in alcohol solvent such as isopropyl alcohol. The reaction mass is cooled to 0-10°C, preferably 0-5°C. The resulting solid is filtered and dried to get pure Blonanserin.

The following examples are provided to illustrate the process of the present invention. They, are however, not intended to limiting the scope of the present invention in any way and several variants of these examples would be evident to person ordinarily skilled in the art.

Experimental procedure:
Example-1: Process for the preparation of 4-(4-Fluorophenyl)-5,6,7,8,9,10-
hexahydro cyclooctane [b] pyridine-(lH)-ketone

A mixture of 4-Fluorobenzoyl acetonitrile (10 g), Methanesulphonic acid (23.6 g) and water (1.42 ml) were taken in a round bottom flask and heated at a temperature of 70°C for three hours. Methanesulphonic acid (0.7g), water (0.042 ml) were added and maintained at 70°C for 2-4 hours. To this Cyclooctanone (8.5 g) was added and temperature was raised to 110°C. The reaction mass was maintained at 110°C for two hours. The reaction mass was cooled to 30°C and Dichloromethane was added. The reaction mixture was poured into cold water and layers were separated. Aqueous layer was extracted with
Dichloromethane and organic layer was combined. The combined organic layers were washed with saturated Sodium bicarbonate solution followed by water. The organic layer was dried with sodium sulphate and Dichloromethane was distilled out completely under vacuum at 40°C. The product was crystallized form Acetone to get title compound (10-11 g).

Example-2: Process for the preparation of 4-(4-Fluorophenyl)-5,6,7,8,9,10-hexahydro cyclooctane [b] pyridine-(lH)-ketone

A mixture of 4-Fluorobenzoyl acetonitrile (10 g) and Eaton's reagent (18 ml) were taken in a round bottom flask and heated at a temperature of 70°C for four hours. To this Cyclooctanone (8.5 g) was added and temperature was raised to 110°C. The reaction mass was maintained at 110°C for two to four hours. The reaction mass was cooled to 30°C and Dichloromethane was added. The reaction mixture was poured into cold water and layers were separated. Aqueous layer was extracted with Dichloromethane and organic layers were combined. The combined organic layer was washed with saturated Sodium bicarbonate solution followed by water. The organic layer was dried with sodium sulphate and
Dichloromethane was distilled out completely under vacuum at 40°C. The product was crystallized form
Acetone to get title compound (10-11 g).

Example-3: Process for the preparation of 3-(4-Fluorophenyl)-3-oxopropanamide
A mixture of Trifluoroaceticacid (20 ml) and 4-Fluorobenzoyl acetonitrile (5 g) was taken in a round bottom flask and temperature was raised to 75°C. The reaction mass was maintained at the same temperature for 4 hours. After completion of the reaction mass was cooled to 35°C and poured into cold water. The solid was collected by filtration and washed with water. The residue was dried to get g title compound(14-16 g).

Example-4: Process for the preparation of 2-Chloro-4-(4 -fluorophenyl)-5,6,7,8,9,10-hexahydro cyclooctane [b] Pyridine

A mixture of 4-(4-Fluorophenyl)-5,6,7,8,9,10-hexahydro cyclooctane [b] pyridine-(lH)-ketone (10 g) and N-Methyl pyrrolidone (10 ml) was taken in a round bottom flask and to this Phenyl phosphonic dichloride ( 14.32 g) was added. The reaction mass temperature was raised to 170°C and maintained for four hours. The reaction mass was cooled to 30°C and Dichloromethane was added. The reaction mixture was poured into cold water and pH of reaction mass was adjusted to 8-8.5 with ammonia solution. The layers were separated and aqueous layer was extracted with Dichloromethane. The organic layer was dried with sodium sulphate and half of the Dichloromethane was distilled out under vacuum. To this ethanol was added and solvents were distilled out completely. The residue was crystallized form Acetonitrile to get title compound. The product was alternatively crystallized from Ethanol to get title compound (8.5-9.2 g).

Exampel-5: Process for the preparation of -2-Chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro cyclooctane [b] Pyridine
A mixture of 4-(4-Fluorophenyl)-5,6,7,8,9,10-hexahydro cyclooctane [b] pyridine-(lH)-ketone (100 g) was taken in a round bottom flask and to this Phenyl phosphonic dichloride (144.4 g) was added. The reaction mass temperature was raised to 165°C and maintained for Two hours. The reaction mass was cooled to 30°C and Dichloromethane was added. The reaction mixture was poured into cold water and pH of reaction mass was adjusted to 8-8.5 with ammonia solution. The layers were separated and aqueous layer was extracted with Dichloromethane. To the organic layer added activated charcoal and maintained for 20-30 minutes at room temperature. The reaction mass was filtered and washed with
Dichloromethane. Dichloromethane was distilled out under vacuum to get residue. To this acetone (200 ml) was added and distilled out under vacuum to remove traces of Dichloromethane. The residue was crystallized form Acetone to get title compound (80-90 g).

Example-6: Process for the preparation of Blonanserin
A mixture of 2-Chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro cyclooctane [b] Pyridine (10 g), N-Methyl pyrrolidone (10 ml), Potassium Iodide (5.5 g) and N-ethyl piperazine (12.36 g) was taken in a round bottom flask and the temperature was raised to 170°C. The reaction mass was maintained at the same temperature for 14 hours. The reaction mass was cooled to 30°C and mixture of ethyl acetate and water was added. The layers were separated and aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and Hydrochloric acid was added. The organic layer was extracted with Hydrochloric acid and aqueous layers were combined, ethyl acetate was added. The pH of reaction mass was adjusted to 8 with ammonia solution. Layers were separated and aqueous layer was extracted with ethyl acetate. Organic layers were combined and ethyl acetate was distilled out completely under vacuum. The residue was crystallized form Ethanol to get title compound (8.5-9.5 g).

Example-7: Preparation of Blonanserin Hydrochloride Monohydrate
A mixture of -2-Chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro cyclooctane [b] pyridine (50 g 0.173 mole), Potassium Iodide (27.5 g 0.165 mole) and N-ethyl piperazine (60.1 g 0.52 moles) was taken in a round bottom flask at ambient temperature. The temperature of the reaction mass was raised to 170°C and maintained for 16 hours. The reaction mass was cooled to 55-60°C and a mixture of ethyl acetate (1000 ml) and purified water (200 ml), was added, maintained for 20 minutes and gradually cool to 25-30°C. The organic layer was separated .The aqueous layer was extracted with ethyl acetate (250 ml).

Combined ethyl acetate layer was washed with purified water (2 x 250 ml). To the organic layer dilute Hydrochloric acid solution (55 ml Cone. HCL and 250 ml water) was added and maintained for 20 minutes. Layers were separated. The organic layer was extracted with dilute Hydrochloric acid solution (55 ml Cone. HCL and 250 ml water). Combined aqueous layer was washed with ethyl acetate (250 ml). Ethyl acetate was added to aqueous layer and, pH was adjusted to 8-8.5 with 30 % sodium hydroxide solution. Layers were separated. The aqueous layer was extracted with ethyl acetate (250 ml). Both ethyl acetate layers were combined and washed with purified water (250 ml). Combined organic layer was distilled out completely under vacuum at 45°C. To the residue left, a mixture of methanol (125 ml) and purified water (375 ml) was added. To this cone. Hydrochloric acid solution (17 g) was added and temperature was raised to 80-85°C to get homogeneous solution and maintained at same temperature for 30 minutes. The reaction mass was cooled to 25-30°C, maintained for 2 hours 25-30°C. Filtered the solid and washed with mixture of methanol (12.5 ml) and purified water (37.5 ml).The obtained solid was crystallized in a mixture of methanol (125 ml) and purified water (375 ml).The obtained solid was dried at 40-45°C for 10 hours to get title compound (42-50 g) with HPLC purity >99.8 %.

Example-8: Preparation of Blonanserin
A mixture of methanol (75 ml) and purified water (225 ml) was added to Blonanserin Hydrochloride monohydrate (30 g).The reaction mass temperature was raised to 80-85°C, maintained for 15-20 minutes and if reaction mass is not clear added 0.5 ml Cone. Hydrochloric acid to obtained clear solution. The hot reaction mass was filtered, added filtrate and temperature was raised to 50-55°C. pH was adjusted to 8-8.5 with 30 % Sodium hydroxide solution.The reaction mass was cooled to 25-30°C, maintained for 2 hours at 25-30°C. The solid was filtered and washed with purified water till filtrate showed negative test for chloride. The reaction mass was again washed with mixture of methanol (7.5 ml) and purified water (22.5 ml).The obtained solid was dried at 40-45°C for 10 hours to get Blonanserin(20-23 g) with HPLC purity >99.9%.

Example-9: Preparation of Blonanserin
A mixture of purified water (150 ml) and ethyl acetate (300 ml) was added to Blonanserin Hydrochloride monohydrate (30 g).The pH was adjusted to 8.5-9 with 30% Sodium hydroxide solution at 25-30°C. The layers were separated and aqueous layer was extracted with ethyl acetate (150 ml). The Combined organic layer was washed with purified water (150 ml). The organic layer was filtered to make it particle free. Ethyl acetate was distilled out completely under vacuum at 40-45°C. To the residue isopropyl alcohol (150 ml) was added and temperature was raised to 80-85°C, maintained for 15-20 minutes to obtained clear solution. The reaction mass was cooled to 0-5°C.The solid was filtered and washed with isopropyl alcohol. The obtained solid was dried at 40-45°C for 10 hours to get Blonanserin (20-25 g) with HPLC purity >99.8%.

We Claim:

1. An improved process for the preparation of 4-(4-Fluorophenyl)-5,6,7,8,9,10- hexahydro cyclooctane [b] pyridine-(lH)-ketone comprising the steps of:

a) hydrolyzing 4-Fluorobenzoyl acetonitrile in presence of an acid to give 3-(4- Fluorophenyl)-3-oxo propanamide, wherein, acid is selected from Methanesulphonicacid, Eaton's reagent or organic acid.,

b) reacting with Cyclooctanone; and

c) isolating 4-(4-Fluorophenyl)-5,6,7,8,9,10-hexahydro cyclooctane [b] pyridine-( 1 H)-ketone.

2. The process according to claim 1, wherein the obtained 4-(4-Fluorophenyl)-5,6,7,8,9,10-hexahydro cyclooctane [b] pyridine-(lH)-ketone is further converted into Blonanserin.

3. The process according to claim 2, wherein further process for the preparation of Blonanserin from 4-(4-Fluorophenyl)-5,6,7,8,9,10-hexahydro cyclooctane [b] pyridine-(lH)-ketone comprising the steps of;

a) converting the compound of Formula-II to Formula-Ill.
wherein X is Halo b) condensing the compound of Formula-Ill with N-ethyl piperazine; and

c) isolating the Blonanserin.

4. The process according to claim 3, wherein compound of Formula-II is converted into Formula-Ill in presence of halogenating agent.

5. The process according to claim 4, wherein halogenating agent is Phenyl phosphonic dichloride.

6. The process according to claim 3, wherein compound of Formula-Ill is condensed with N-ethyl piperazine in presence of organic solvent such as N-Methyl pyrrolidone ,Dimethyl sulphoxide (DMSO).

7. A process for the preparation of Blonanserin Hydrochloride comprising the steps of:

a) dissolving Blonanserin in water, water miscible organic solvent, or mixtures thereof,

b) adding HC1 source, and

c) isolating Blonanserin Hydrochloride.

8. The process according to claim 7, wherein Blonanserin is dissolved in a mixture of water and water miscible organic solvent selected from alcoholic solvent.

9. The process according to claim 8, wherein Blonanserin is dissolved in a mixture of water and methanol.

10. A process for the preparation of pure Blonanserin from Blonanserin Hydrochloride comprising the steps of:

a) taking Blonanserin Hydrochloride in a solvent or mixture of solvents,
b) adjusting pH to basic with a base,
c) isolating Blonanserin.

11. The process according to claim 10, wherein Blonanserin Hydrochloride is taken in a solvent selected from methanol, ethanol, isopropanol, and water or mixtures thereof.

12. The process according to claim 10, wherein solvent mixture is selected from methanol and water.

13. A process for the preparation of pure Blonanserin from Blonanserin Hydrochloride comprising the steps of:

a) taking Blonanserin Hydrochloride in a mixture of water and water immiscible organic solvent,

b) adjusting pH to basic with a base,
c) separating the organic layer, and
d) optionally extracting Blonanserin from aqueous layer, and
e) isolating the pure Blonanserin from organic layer.

14. The process according to claim 13, wherein water immiscible organic solvent is selected from chloroform, dichloromethane, ethyl acetate or isopropyl acetate.

15. The process according to claim 10 and 13, wherein base is selected from sodium bicarbonate, potassium bicarbonate, potassium carbonate, sodium carbonate, sodium hydroxide or potassium hydroxide.