PREPARATION OF PALIPERIDONE

INTRODUCTION

Aspects of the present invention relate to processes for the preparation of paliperidone.

The drug having the adopted name "paliperidone" has a chemical name (±)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. The structural formula of paliperidone can be represented as (I).

The drug was approved for sale in the United States in December 2006, for the treatment of schizophrenia. INVEGA® is the brand name for paliperidone products marketed by Ortho-McNeil-Janssen Pharmaceuticals, Inc. Paliperidone is an active metabolite of risperidone.

U.S. Patent No. 5,158,952 discloses paliperidone, processes for preparing paliperidone, pharmaceutical compositions containing paliperidone, and a method of treating warm-blooded animals suffering from psychotic diseases with an antipsychotic effective amount of paliperidone. The chemical pathway exemplified for paliperidone in this patent is summarized in Scheme I. Crude paliperidone obtained from the reaction is purified by twice by column chromatography and the resulting residue is crystallized from acetone and recrystalized from 2-propanol.

Scheme I

International Application Publication Nos. WO 2008/021346 A1, WO 2008/024415 A1, WO 2008/021345 A1, WO 2009/016653 A1, WO 2009/044413 A1, WO 2009/144288 A1, WO 2010/004578 A1, and WO 2010/014047 A1 disclose processes for the preparation of paliperidone involving the use of the intermediate compound (II) and intermediate compound (III).

International Application Publication Nos. WO 2008/144073 A1, WO 2009/010988 A1, WO 2009/047499 A1, WO 2009/074333 A1, WO 2009/091962 A1, WO 2009/015828 A1, WO 2010/003702 A1, WO2010064134 A1 and WO2010082111 A1 disclose processes for the preparation of paliperidone or its intermediates.

The processes for the preparation of paliperidone described in the literature are lengthy, costly, or technically difficult to practice at an industrial scale, or result in low yields or quality of the product.

There remains a need to provide economically and industrially viable processes, which avoid column chromatography and the resulting lengthy work-ups for the preparation of paliperidone with the desired quality for use directly to prepare pharmaceutical formulations.

SUMMARY

In an aspect, the invention provides processes for the preparation of paliperidone, embodiments comprising:

(i) reacting 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, or a salt thereof, with 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole, or a salt thereof, in the presence of a base and optionally in the presence of hydrose in a solvent, to produce paliperidone;

(ii) purifying paliperidone obtained in step (i) by recrystallization in a solvent or a mixture of solvents, optionally in the presence of hydrose and/or activated carbon, to produce pure paliperidone; and

(iii) optionally, repeating step (ii) to produce a more purified paliperidone.

BRIEF DESCRIPTION OF THE DRAWING

Figure 1 depicts a powder X-ray diffraction (PXRD) pattern of paliperidone obtained by the procedure of Example 6.

DETAILED DESCRIPTION

In an aspect, the invention provides processes for the preparation of paliperidone, embodiments comprising:

(i) reacting 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, or a salt thereof, with the 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole, or a salt thereof, in the presence of a base and optionally in the presence of hydrose in a solvent, to produce paliperidone;

(ii) purifying paliperidone obtained in step (i) by recrystallization in a solvent or a mixture of solvents, optionally in the presence of hydrose and/or activated carbon, to produce pure paliperidone; and

(iii) optionally, repeating step (ii) to produce a more purified paliperidone.

A process disclosed in the present application can be illustrated as depicted in Scheme 2.

Scheme 2

According to the present invention, 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one of formula (II), or a salt thereof, which is one of the starting materials for the preparation of paliperidone, may be prepared according to any of the processes disclosed in the art. In the present application, the compound of formula (II) is designated as the "chloro compound". Optionally, the compound of formula (II) may be converted into its acid-addition salt by reacting it with a pharmaceutically acceptable acid. Examples of such acids include: inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, and the like; and organic acids such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, and the like. The salt of the compound of formula (II) may be converted to free base of the compound of formula (II) using a suitable base by the methods known in the art.

According to the present invention, 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole of formula (III), or a salt thereof, which is one of the two starting materials for the preparation of paliperidone, may be prepared according to any of the processes disclosed in the art. In the present application, the compound of formula (III) is designated as the "fluoro compound". Optionally, the compound of formula (III) may be converted into an acid-addition salt by reacting it with a pharmaceutically acceptable acid. Examples of such acids include: inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, and the like; and organic acids such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, and the like. A hydrochloride salt of the fluoro compound is a representative starting material. The salt of the compound of formula (III) may be converted to free base of the compound of formula (III) using a suitable base by the methods known in the art.

According to the present invention, the reaction of the chloro compound or a salt thereof with the fluoro compound or a salt thereof in step-(i) is carried out in the mole ratio of 1:0.7 to 1:1.3 respectively.

Preferably, chloro compound and fluoro hydrochloride compound carried out in a mole ratio of 1:1.

According to the present invention, the reaction of the chloro compound, or a salt thereof, with the fluoro compound, or a salt thereof in step-(i), is carried out in the presence of a base, which include an organic base or an inorganic base, for the preparation of paliperidone. Bases that are useful in the reaction include, but are not limited to: inorganic bases such as alkali metal or alkaline earth metal carbonates, hydrogen carbonates, hydroxides, oxides, carboxylates, and alkoxides, e.g., sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, calcium oxide, sodium acetate, sodium methoxide, and the like; and organic bases such as, for example, tertiary amines, e.g., triethylamine, N,N-diethylethanamine, N- (1-methylethyl)-2-propanamine, 4-ethylmorpholine, 1,4-diazabicyclo[2.2.2]-octane, N-methyl morpholine, diisopropylamine, pyridine, and the like.

According to the present invention, the reaction of the chloro compound, or a salt thereof, with the fluoro compound, or a salt thereof in step-(i), is carried out optionally in the presence of hydrose (sodium hydrosulphite), wherein hydrose can be used in amounts about 0.1% to 5% of the weight of the chloro compound, for the preparation of paliperidone.

According to the present invention, the reaction of the chloro compound, or a salt thereof, with the fluoro compound, or a salt thereof in step—(i), is carried out in the presence of a solvent. Solvents that may be utilized for this step include, but are not limited to: alcohols such as methanol, ethanol, isopropyl alcohol and n-propanol; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and carbon tetrachloride; ketones such as acetone, ethyl methyl ketone and methyl isobutyl ketone; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, and t-butyl acetate; ethers such as diethyl ether, dimethyl ether, di-isopropyl ether, methyl tertiary-butyl ether, 1,1'-oxybisethane, tetrahydrofuran, and 1,4-dioxane; hydrocarbons such as n-heptane, cyclohexane, and n-hexane; aromatic compounds, such as benzene, toluene, xylene, chlorobenzene, and methoxybenzene; nitriles such as acetonitrile and propionitrile; dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF) and N,N-dimethylacetamide; pyridine; 1,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone; 1,3-dimethyl-2-imidazolidinone; 1,1,3,3-tetramethylurea; 1 -methyl-2-pyrrolidinone; nitrobenzene; water; and mixtures thereof.

According to the present invention, the reaction of the chloro compound, or a salt thereof in step-(i), with the fluoro compound, or a salt thereof, is carried out at temperatures about 0°C to the reflux temperature of the solvent used, for the preparation of paliperidone.

According to the present invention, the reaction of the chloro compound, or a salt thereof in step-(i), with the fluoro compound, or a salt thereof, is carried out reacted for about 1 hour to about 50 hours, or longer, for the preparation of paliperidone with desired yield and purity. As is known to those skilled in the art, the reaction time varies upon reactant concentrations and temperatures, among other factors.

in embodiments, after the reaction of the chloro compound, or a salt thereof, and the fluoro compound, or a salt thereof, paliperidone obtained can be isolated using techniques known in the art, such as decantation, filtration by gravity or suction, centrifugation, and the like, and optionally washing with a solvent.

In embodiments, paliperidone that is isolated can be dried at suitable temperatures, such as about 40-100°C and suitable pressures, using drying equipment known in the art, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like. Drying temperatures and times will be sufficient to achieve desired product purity.

According to the present invention, the solvent or a mixture of solvents used for recrystallization of paliperidone in step—(ii) include, but not limited to: alcohols such as methanol, ethanol, isopropyl alcohol and n-propanol; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and carbon tetrachloride; ketones such as acetone, ethyl methyl ketone and methyl isobutyl ketone; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate and t-butyl acetate; ethers such as diethyl ether, dimethyl ether, diisopropyl ether, methyl tertiary-butyl ether, 1,1'-oxybisethane, tetrahydrofuran, and 1,4- dioxane; hydrocarbons such as n-heptane, cyclohexane and n-hexane; aromatic compounds such as. benzene, toluene, xylene, chlorobenzene, and methoxybenzene; nitriles such as acetonitrile and propionitrile; dimethylsulfoxide (DMSO), N.N-dimethylformamide (DMF) and N.N-dimethylacetamide; pyridine; 1,3- dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone; 1,3-dimethyl-2-imidazolidinone;

1,1,3,3-tetramethylurea; 1-methyl-2-pyrrolidinone; nitrobenzene; water; and mixtures thereof. Preferably mixtures of dichloromethane and isopropyl alcohol can be used for the purification of paliperidone. More preferably a mixture of dichloromethane and isopropyl alcohol in about a 1:2 volume ratio is used for the purification of paliperidone.

In embodiments, paliperidone can be heated in a solvent at temperatures up to the reflux temperature, to produce a clear solution. The solution can be obtained by dissolving paliperidone in solvents mentioned herein, or the solution can be directly obtained, with or without isolating paliperidone, from step (i). In embodiments, paliperidone and a mixture of dichloromethane and isopropyl alcohol are heated to reflux, or to about 40-60°C, to achieve a clear solution. Optionally, the reaction mass can be filtered to remove the insoluble material, if any.

According to the present invention, the solution of paliperidone is treated with hydrose in step—(ii), in about 0.1% to 5% of the weight of paliperidone employed, for the purification of paliperidone. Preferably about 0.5% hydrose, with respect to the weight of paliperidone employed.

In embodiments, after treatment with hydrose and/or activated carbon in step-(ii), the paliperidone solution can be filtered and washed with a solvent. The techniques which are known in the art can be used for filtration. The solvent used for washing can be selected from any of the solvents listed above or the solvent or the mixture of solvents used for the dissolution.

In embodiments, paliperidone may be isolated from a solution by removal of the solvent or by cooling the reaction mass. The solvent may be removed using any suitable methods, such as evaporation, atmospheric distillation, or distillation under vacuum. Distillation of the solvent may be conducted under vacuum, such as below about 100 mm Hg to below about 600 mm Hg, at elevated temperatures such as about 40°C to about 100°C. Any temperature and vacuum conditions may be used, as long as they do not affect the nature of the product. Suitable vacuum and the temperatures used for the removal of the solvent depend on parameters such as the boiling point of the solvent, and may readily be determined by persons skilled in the art. In embodiments, solvent removal is conducted only to remove a portion of the solvent, then the residue is cooled to promote crystallization of paliperidone. Smaller final volumes usually improve product recovery.

In embodiments, after the completion of distillation and subsequent cooling of the residue, paliperidone obtained can be isolated using techniques known in the art such as decantation, filtration by gravity or suction, centrifugation, and the like, and optionally washing with the solvent.

in embodiments, paliperidone that is isolated can be dried at suitable temperatures, such as about 40-100°C and suitable pressures, using drying equipment known in the art, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like. Drying temperatures and times will be sufficient to achieve desired product purity.

Paliperidone produced by a method of present invention can be chemically pure paliperidone having purity greater than about 99%, or greater than about 99.5%, or greater than about 99.8%, as determined using high performance liquid chromatography (HPLC).

Paliperidone produced by a method of present invention can be chemically pure paliperidone having purity greater than about 99% and containing no single impurity in amounts greater than about 0.5%, by HPLC. Impurities described in the present application include PLP-NO, PLP-car, keto, oxazole, the fluoro compound, and the chloro compound.

Chloro compound

Fluoro compound can also have isomeric impurities wherein the fluoro group is attached to other vacant positions in the benzene ring. These isomeric impurities of fluoro compound are also possible impurities in paliperidone. The possible impurities of the fluoro compound include: (1) 4-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole; (2) 5-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole; (3) 7-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole; and (4) 3-(4-piperidinyl)-1,2-benzisoxazole. The fluoro compound may also contain impurities, which include the intermediates used for its preparation or byproducts obtained during its preparation.

The chloro compound may also contain impurities which include the intermediates used for its preparation or by products obtained during its preparation.

Paliperidone produced by a process of the present invention can be chemically pure paliperidone having purity greater than about 99.5% and no single impurity present in amounts greater than about 0.1%, by HPLC.

Paliperidone produced by a method of present invention can be chemically pure paliperidone having purity greater than about 99.8% and no single impurity present in amounts greater than about 0.05%, by HPLC.

Paliperidone and its impurities can be analyzed using high performance liquid chromatography (HPLC), such as with a liquid chromatography equipped with variable wavelength UV detector and the parameters described below:

Paliperidone produced by a method of present invention can consistently have a polymorphic form at isolated intermediate stages and in the final stage having a powder X-ray diffraction (PXRD) with peaks at about 7.4, 8.2, 10.3, 12.5, 13.1, 13.8, 14.5, 14.9, 16.2, 16.5, 17.6, 18.7, 19.3, 20.1, 20.6, 21.5, 22.1, 22.4, 23.2, 24.2, 24.7, 25.1, 26.4, 28.0, 28.6 and 31.2, ± 0.2° two-theta. The X-ray powder diffraction patterns described herein were determined using a Broker AXS D8 Advance powder X-ray diffractometer with a copper K-alpha radiation source.

Paliperidone obtained according to the processes of the present application can be milled or micronized by any process known in the art, such as ball milling, jet milling, wet milling etc., to produce a desired particle size distribution. Paliperidone obtained according to certain processes of the present application has a particle size distribution wherein: d(0.5) is less than about 250 urn, or less than about 200 urn; and d(0.9) is less than about 500 urn, or less than about 450 urn. Particle size distributions can be determined using any means, including laser light diffraction equipment sold by Malvern Instruments limited, Malvern, Worcestershire, United Kingdom, Coulter counters, microscopic procedures, etc. The term d(x) means that a particular fraction has particles with a maximum size being the value given; 0.5 represents 50% of the particles and 0.9 represents 90% of the particles.

In an embodiment of the present invention, Paliperidone produced by a method of present application has any morphology. In an embodiment of the present invention, Paliperidone produced by a method of present application has a brick like morphology.

In an embodiment of the present invention, Paliperidone produced by a method of present application has specific surface area ranging from about 0.1 m2/g to about 5 m2/g.

An aspect of the present invention provides pharmaceutical compositions containing a therapeutically effective amount of paliperidone, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable excipients.

The pharmaceutical compositions comprising paliperidone or its pharmaceutically acceptable salt of the invention together with one or more pharmaceutically acceptable excipients may be formulated as: solid oral dosage forms, such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, but not limited to, solutions, dispersions, and freeze-dried compositions. Formulations may be in the form of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate-controlling substances to form matrix or reservoir systems, or combinations of matrix and reservoir systems. The compositions may be prepared using any one or more of techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated.

Pharmaceutically acceptable excipients that are useful in the present invention include, but are not limited to, any one or more of: diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches, and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; and release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes, and the like. Other pharmaceutically acceptable excipients that are useful include, but are not limited to, film-formers, plasticizers, colourants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present application.

EXAMPLES

Example 1: Paliperidone process

3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (35.0 g), 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (29.7 g), methanol (350 ml_), hydrose (0.35 g), and triethylamine (37.8 g) are charged into a reaction flask at 27°C. The mass is stirred for 10 minutes and then is heated to 65°C and maintained at that temperature for 38 hours. The mass is then cooled to 45°C and stirred at that temperature for 2 hours. The solid is filtered at the same temperature and washed with methanol (70 ml_). The solid is suction dried for 30 minutes and then dried in an oven at 75°C for 4 hours. Paliperidone HPLC purity: 99.02%.

Dried paliperidone, dichloromethane (460 mL) and isopropyl alcohol (920 mL) are charged into a round bottom flask at 27°C and stirred for 15 minutes. The mass is then heated to 50°C and maintained at that temperature for 10 minutes to obtain a clear solution. Hydrose (0.23 g) and activated carbon DX ultra (2.3 g) are charged into the solution at 50°C and the solution is maintained at the same temperature for 45 minutes. The mass is filtered through a Hyflow (flux-calcined diatomaceous earth) bed at the same temperature and the bed is washed with a mixture of dichloromethane (46 mL) and isopropyl alcohol (46 mL). The filtrate is charged into a round bottom flask and distilled untill the temperature reaches 81 °C. The mass is maintained at that temperature for 45 minutes and then cooled to 50°C. The mass is stirred at that temperature for 2 hours and filtered. The solid is washed with isopropyl alcohol (92 mL). The white solid is suction dried and then dried in an oven at 75°C for 4 hours. Product weight: 41.4 g; HPLC purity: 99.64%.

Example 2: Paliperidone purification

Paliperidone (10.0 g) obtained from Example 1, dichloromethane (100 mL) and isopropyl alcohol (200 mL) are charged into a round bottom flask at 27°C and stirred for 15 minutes. The mass is then heated to 48°C and maintained at that temperature for 15 minutes to form a clear solution. Hydrose (0.05 g) and activated carbon DX ultra (0.5 g) are charged into the solution at 48°C and the solution is maintained at that temperature for 45 minutes. The mass is filtered through a Hyflow bed at the same temperature and the bed is washed with a mixture of dichloromethane (10 mL) and isopropyl alcohol (10 mL). The filtrate is charged into a round bottom flask and distilled under atmospheric pressure until the temperature reaches 81 °C. The mass is maintained at that temperature for 45 minutes and then cooled to 48°C. The mass is stirred at that temperature for 2 hours and filtered. The solid is washed with isopropyl alcohol (20 mL). The white solid is dried in an oven at 75°C for 4 hours. Product weight: 9.1 g; HPLC purity: 99.80%.

Example 3: Paliperidone process

3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (300.0 g), 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (317.4 g), methanol (3300 mL), triethylamine (324.7 g), and hydrose (3.0 g) are charged into a round bottom flask at 28°C, stirred for 10 minutes, and then heated to 65°C and maintained at that temperature for 37 hours. The mass is then cooled to 45°C and stirred at that temperature for 2 hours. The solid is filtered at the same temperature and washed with methanol (600 mL). The solid is suction dried for 30 minutes at 28°C and then dried in an oven at 75°C for 5 hours. Dried material (paliperidone) has 98.96% purity by HPLC.

Dried paliperidone (450.6 g), dichloromethane (4500 mL) and isopropyl alcohol (9000 mL) are charged into a round bottom flask at 28°C and stirred for 15 minutes. The mass is then heated to 47°C and maintained at that temperature for 15 minutes, to obtain a clear solution. Hydrose (2.25 g) and activated carbon DX ultra (22.5 g) are charged into the solution at 47°C and the solution is maintained at that temperature for 50 minutes. The mass is filtered through a Hyflow bed at the same temperature and the bed is washed with a mixture of dichloromethane (450 mL) and isopropyl alcohol (450 mL). The filtrate is charged into a round bottom flask and distilled until the temperature reaches 81 °C. The mass is maintained at that temperature for 1 hour and then cooled to 48°C. The mass is stirred at that temperature for 2 hours and filtered. The solid is washed with isopropyl alcohol (900 ml_). The white solid is dried in an oven at 75°C for 5 hours. Product weight: 409.5 g; HPLC purity: 99.74%.

Example 4: Paliperidone purification

Paliperidone (400.0 g) obtained from Example 3, dichloromethane (4000 mL), and isopropyl alcohol (8000 mL) are charged into a round bottom flask at 28°C and stirred for 15 minutes. The mass is then heated to 47°C and maintained at that temperature for 15 minutes to form a clear solution. Hydrose (2.0 g) and activated carbon DX ultra (20.0 g) are charged into the solution at 48°C and the mixture is maintained at the same temperature for 45 minutes. The mass is filtered through a Hyflow bed at the same temperature and the bed is washed with a mixture of dichloromethane (400 mL) and isopropyl alcohol (400 mL). The filtrate is charged into a round bottom flask and distilled under atmospheric pressure until the temperature reaches 81 °C. The mass is maintained at that temperature for 45 minutes and then cooled to 48°C. The mass is stirred at that temperature for 2 hours and filtered. The solid is washed with isopropyl alcohol (800 mL). The white solid is dried in an oven at 75°C for 5 hours. Product weight: 364.0 g; HPLC purity: 99.8%; PXRD pattern as shown in Figure 1.

Example 5: Paliperidone process

3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (5 Kg), 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (5.3 Kg), methanol (60 L), hydrose (0.05 Kg), and triethylamine (5.41 Kg) are charged into a reactor at 32-33°C. The mass is stirred for 10 minutes at the same temperature and then is heated to reflux and maintained at that temperature for 38 hours. The mass is then cooled to 44°C and stirred at that temperature for 2 hours. The solid is filtered at the same temperature and washed with methanol (10 L). The solid is suction dried for 2 hours and then dried under vacuum at 60 to 64°C for 10 hours 40 minutes. Yield: 6.90 (78.41%); HPLC purity: 98.80%; Loss on drying: 0.35% w/w.

Example-6: Purification of Paliperidone Paliperidone (4 kg), dichloromethane (40 L) and methanol (80 L) are charged into a reactor and stirred for 15 minutes. The mass is then heated to 40.9°C, maintained at 40.9 to 42.5°C for 15 minutes to obtain a clear solution and cooled the reaction mass to 34.2°C. Hydrose (0.02 Kg) and activated carbon DX ultra (0.40Kg) are charged into the solution and the solution is maintained at 33.2 to 34.2°C for 45 minutes. The mass is filtered through a candy and micro filters into a crystallization reactor. Dichloromethane (8 L) and methanol (8 L) also passed through candy and micro filters into the crystallization reactor. The solvent is distilled from the reaction mass till the temperature reaches to 64°C. The mass is maintained at reflux for 30 minutes and then cooled to 31.5°C. The mass is stirred at 28.4 to 31.5°C for 2 hours and filtered. The solid is washed with methanol (15 L). The white solid is suction dried and then dried under vacuum of at 65 to 68°C for 9 hours 30 minutes. Yield : 3.4 Kg (85.00%); Purity by HPLC: 99.56%; Loss on drying : 0.24%w/w; Shape : brick like morphology; Surface area : 0.2225m2/g.

CLAIMS:

1. A process for the preparation of paliperidone, comprising the steps of:

(i) reacting 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H- pyrido[1,2-a]pyrimidin-4-one, or a salt thereof, with 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole, or a salt thereof, in the presence of a base and hydrose in a solvent to produce paliperidone;

(ii) purifying paliperidone obtained in step (i), in the presence of hydrose and/or activated carbon by recrystallization in a solvent to produce pure paliperidone; and

(iii) optionally repeating step (ii), to produce a more purified paliperidone.

2. The process according to claim-1, wherein the base is selected from an organic or an inorganic base.

3. The process according to claim-2, wherein base is selected from triethylamine, N,N-diethylethanamine, N-(1-methylethyl)-2-propanamine, 4-ethylmorpholine, 1,4-diazabicyclo[2.2.2]-octane, N-methyl morpholine, diisopropylamine and pyridine.

4. The process according to claim-1, wherein the solvent in step (i) is selected from the group consisting of alcohols, halogenated hydrocarbons, ketones, ethers, hydrocarbons, aromatic compounds, nitriles, water and mixtures thereof.

5. The process according to claim-4, wherein the solvent is isopropanol or methanol.

6. The process according to claim-1, wherein the solvent in step (ii) is selected from alcohols, halogenated hydrocarbons, ketones, ethers, hydrocarbons, aromatic compounds, nitriles, water or their mixtures thereof.

7. The process according to claim-6, wherein solvent is a mixture of dichloromethane and methanol.

8. A process for the preparation of paliperidone, comprising the steps of:

(i) reacting 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido-[1,2-a]pyrimidin-4-one with 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride in the presence of hydrose, triethyl amine in methanol to produce Paliperidone (ii) Purifying the Paliperidone obtained in step 1, by recrystallization using dichloromethane and methanol

9. Paliperidone according to any of the preceding claims, which is in crystalline form having the PXRD pattern as in Figure 1.

10. A pharmaceutical composition comprising paliperidone prepared according to any of the preceding claims.