Improved Process for the Preparation of Palioeridone
Field of the Invention:
The present invention relates to an improved process for the preparation of paliperidone. Paliperidone is chemically known as 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-1 -yl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido-[ 1,2-a] pyrimidin-4-one, which is represented by formula-1.

Paliperidone is an active metabolite of risperidone, widely prescribed antipsychotic drug used for the treatment of schizophrenia and bipolar disorder. Paliperidone marketed under the name Invega® acts as a dual antagonist of dopamine D2 receptors in the mesolimbic pathway and 5-HT2A receptors in the prefrontal cortex. Its ability to bind to these receptors in corresponds with its antipsychotic effect and stabilization of some of the antisocial behaviors in patients with schizophrenia. It has been approved in the United States for the treatment of schizophrenia.
Background of the Invention:
Paliperidone is an active metabolite of risperidone. Risperidone is metabolized by cytochrome P-450 IID6 to produce 9-hydroxy-risperidone also known as paliperidone. EP 196132 Bl and US Patent No 4804663 describe certain l,2-benzisoxazol-3-yl derivatives having psychotic and anti-serotonin activity including 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido-[l,2-a] pyrimidin-4-one (Risperidone) which is a mixed 5-HT2/D2-receptor antagonist and a typical neuroleptic drug. They exemplify the process for the preparation of risperidone, which includes the condensation of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one mono hydrochloride and 6-fluoro-3-(4-piperidinyl)-l,2-

i
benzisoxazole hydrochloride in presence of N,N-dimethylformamide, sodium carbonate and catalytic amount of potassium iodide. The crude risperidone was crystallized from a mixture of DMF and isopropanol. 9-hydroxy risperidone, its enantiomeric forms and the C2.20 alkanoic acid esters thereof are described in EP 0,368,388. Said esters are considered to be potentially valuable prodrugs of paliperidone.
Risperidone is a highly potent drug having a relatively narrow therapeutic index. It may produce undesirable side effects on over dosage most notably extrapyramidal side effects such as tardive dyskinesia. The most frequently observed adverse reactions include orthostatic hypotension and dizziness, drowsiness, palpitations, weight gain, erectile dysfunction, and a significant increase in rashes and rhinitis. Accordingly, an antipsychotic agent having the efficacy of risperidone, but causing fewer side effects, would be desirable. It would be desirable to find a compound that has the advantages of risperidone while providing a more predictable dosage regimen in the patient population and decreasing the chances for drug-drug interactions.
Paliperidone was found to overcome some of the problems associated with risperidone. It possesses a longer elimination half life. It has a potent activity in the treatment of psychotic disorders and other conditions, including those that would benefit from an anti diarrheal, an inhibitor of gastro-esophageal reflux and /or an anti emetic, especially in cancer patients receiving chemotherapy and radiation. It is also used in combating autism, hypertension, vascular disorders, obesity, and the withdrawal symptoms associated with cessation of drinking and smoking. It provides a more predictable dosage regimen in the patient population and decreases the chances of drug-drug interactions by avoiding oxidative metabolism for which the cytochrome P4502D6 enzyme system is required.
A process for the synthesis of paliperidone is described in US Patent No 5,158,952 according to scheme-1. The preparation involves the condensation of 3-(2-chIoroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one with 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole monohydrochloride in the last step.


When paliperidone was prepared according to this process using diisopropylamine base in methanol for the condensation of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l ,2-a]pyrimidin-4-one with 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole monohydrochloride, the starting material was left over in the reaction which resulted in the low yield (16%) of paliperidone. So in order to enhance the yields, we executed the above reaction with similar reagents and raw material under pressure condition which provided paliperidone with moderate yields (up to 36%) but there was an increase in the level of impurities (example-4).
It was felt that the base was not able to break the 6-fluoro-3-(4-piperidinyI)-l,2-benzisoxazole monohydrochloride salt and release the free base, hence the reaction did not proceed properly and the yield was very poor. In order to over come this, we thought of using pure free base of 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole, in the place of the hydrochloride salt, in the condensation reaction which provided paliperidone with good yields (85%) and also of high purity (example-5).

A process for the synthesis of intermediate 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one is also described in US Patent No 5,688,799. The processes described in the above publications are lengthy, time consuming and result in low yields, making their application in the industry very difficuh.
Based on the above teachings, we developed a process which overcomes the shortfalls of the prior art processes. The present invention provides an improved process for the preparation of paliperidone, which improved the yields, purity and also provides a crystalline form of an intermediate.
Brief Description of the Invention:
The first aspect of the present invention encompasses a novel process for the preparation of paliperidone, chemically known as 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido-[l,2-a] pyrimidin-4-one, which is represented by formula-1. The process comprises the following steps;
a) Condensing 3-(2-chloroethyl)-9-oxo-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[l,2-a]pyrimidin-4-one, compound of formula-2 with 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole, crystalline solid compound of formula-3, in presence of a base in a suitable solvent, to provide 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-9-oxo-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[l,2-a]pyrimidin-4-one, compound of formula-5,
b) treating the compound 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-9-oxo-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[l ,2-a]pyrimidin-4-one compound of formula-5 obtained in step a) with suitable reducing agent to obtain paliperidone,
c) purifying the paliperidone obtained in step b) crystallizing it from alcohol, followed by treatment with acid and subsequent treatment with a base in presence of an alcohol to obtain pure paliperidone compound of formula-1.
The second aspect of the present invention encompasses an improved process for the preparation of paliperidone, which comprises of the following steps;

a) Condensing 3 -(2-chioroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[l,2-a]pyrimidin-4-one, compound of fonnula-4, with 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole, crystalline solid compound of formula-3 in presence of organic base in a suitable solvent, to provide 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[l,2-a]pyrimidin-4-one, compound of formula-1,
b) treating the paliperidone, compound of formula-1 obtained in step a) with sodium borohydride, to convert any amount of the 3-[2-[4-(6-fluoro-l,2-benzisoxazol -3-yl)piperidin-1 -yl]ethyl]-9-oxo-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[ 1,2-a] pyrimidin-4-one compound of formula-5, formed and present as an impurity, into 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-9-hydroxy-2-methyl-6,7, 8,9 -tetrahydro-4H-pyrido-[l,2-a]pyrimidin-4-one, compound of formula-1 ,
c) purifying the paliperidone obtained in step-b, by crystallizing it from alcohol, followed by treatment with acid and subsequent treatment with a base in presence of an alcohol to obtain pure paliperidone.
The third aspect of the present invention encompasses a process for the preparation of crystalline 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole, compound of formula-3, which comprises of the following steps;
a) treating 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole monohydrochloride, compound of formula-6, with an aqueous base to convert it into its free base,
b) isolating the obtained solid from water or extracting the free base, compound of formula-3, from the reaction mixture with a suitable solvent and concentrating the solvent to provide a crystalline solid of compound of formula-3.
Brief Description of the Drawings:
Figure-1: Illustrates the powder X-ray diffraction pattern of 6-fIuoro-3-(4-piperidinyl)-
1,2-benzisoxazole.
Figure-2: Illustrates the photograph of paliperidone as seen through a microscope.
Figure-3: Illustrates the photograph of paliperidone obtained as per the prior art process
as seen through the microscope

Detailed Description of the Invention:
The present invention encompasses a novel process for the preparation of paliperidone, chemically known as 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido-[l,2-a] pyrimidin-4-one, which is represented by formula-1.

Formula-1 Accordingly the first aspect of the present invention encompasses a novel process for the preparation of paliperidone compound of formula-1, which comprises of the following steps;
a) Condensing 3-(2-chloroethyl)-9-oxo-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[l,2-
a]pyrimidin-4-one, compoimd of formula-2 with 6-fluoro-3-(4-piperidinyl)-l,2-
benzisoxazole, crystalline solid compound of formula-3 in presence of a base in a
suitable solvent, to provide 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-
yl]ethyl]-9-oxo-2-methyI-6,7,8,9-tetrahydro-4H-pyrido-[l,2-a]pyrimidin-4-one,
compound of formula-5,
b) treating the compound 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-
9-oxo-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[ 1,2-a]pyrimidin-4-one compound of
formula-5 obtained in step a) with suitable reducing agent in a suitable solvent to
obtain paliperidone,
c) purifying the crude paliperidone formed in step-b, by crystallizing it from alcohol,
followed by treatment with acid, washing the aqueous layer with a suitable solvent
and subsequent treatment with a base in presence of an alcohol to obtain pure
paliperidone compound of formula-1.

In step a) the base used for the condensation may be a suitable inorganic base which is selected from a group which includes but is not limited to hydroxides of alkali and alkaline earth metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like and bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate and the like; or may be an organic base which is selected from a group which includes but is not limited to triethyl amine, tributyl amine, N-(l-methylethyl)-2-propanamine,4-ethylmorpholine,4-dimethylaminopyridine, diisopropyl ethyl amine, 4-dimethylaminopyridine, l,8-diazabicyclo[5.4.0]undec-7-ene, l,4-diazabicyclo[2.2.2]octane, pyridine and the like. The solvent used is selected without limitation, from water, aliphatic hydrocarbons like hexane, cyclohexane, petroleum ether; or aromatic hydrocarbons like xylene, toluene; or halogenated hydrocarbons like dichloromethane, chloroform, 1,2-dichloroethane; or ethers like diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxy ethane; or ketones like acetone, methyl ethyl ketone, diethyl ketone; or acetates like ethyl acetate, propyl acetate, butyl acetate; alcohol like methanol, ethanol,l-propanol, isopropyl alcohol, n-butanol ; or nitriles like acetonitrile and propionitrile and the like.
In the step b) the 9-oxo group of 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl) piperidin-1 -yl]ethyl]-9-oxo-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[ 1,2-a]pyrimidin-4-one, compound of formula-5, is reduced to hydroxy group using a reducing agent selected from sodium borohydride, sodium cyanoborohydride, diborane, and hydrogen in presence of a catalyst. The reduction can be performed using a number of catalysts. These include, without limitation heterogeneous catalysts containing from about 0.1% to about 20% by weight of transition metals such as Ni, Pd, Pt, Rh, Re, Ru and Ir, including oxides and combination thereof, which are typically supported on various materials including AI2O3. C, CaCOs, SrCOa, BaS04. MgO, SiOa, TiOa, ZrOa and the like. Many of these metals including Pd may be doped with an amine, sulfide or a second metal such as Pb, Cu and Zn. Useful catalysts include raney nickel, palladium catalyst such as Pd/C, Pd/SrCOa. Pd/ AI2O3, Pd/MgO, Pd/CaCOs, Pd/ BaS04, PdO, Pd Black, PdCh and the like. Other useful catalysts Rh/C, Ru/C, Re/C, Pt02, Rh/C, RUO2. The reaction is typically

carried out in the presence of one or more solvents including without limitation water, alcohols, ethers, ester, acids and hydrocarbon solvents such as, methanol, ethanol, isopropyl alcohol, tetrahydofuran, ethyl acetate, acetic acid, dichloromethane and the like. The preferred reducing agent in the present embodiment is sodium borohydride.
In the step c) the paliperidone is recrystallised using alcohol solvent selected from methanol, ethanol, 1-propanol, 2-propanol and the like; and recrystallised product is subjected to treatment with an acid. Washed the obtained aqueous mass with a suitable solvent selected from ester solvents like ethyl acetate and/or ketone solvents like methyl isobutyl kotone to remove the impurities, followed by treatment with base to obtain paliperidone of very high purity. The acid used is an organic acid which is selected from formic acid, acetic acid, propionic acid and the like or an inorganic acid like hydrochloric acid and sulfuric acid. The base used for neutralization may be ammonia or is an inorganic base which is selected from group which includes but is not limited to hydroxides of alkali and alkaline earth metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like and bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate and the like, in the presence of alcohol solvent selected from methanol, ethanol, 1-propanol, isopropanol and the like.
The starting material 3-(2-chloroethyl)-9-oxo-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[l,2-a]pyrimidin-4-one, compound of formula-2 can be prepared by oxidizing 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[l,2-a]pyrimidin-4-one, compound of formula-4 using oxalyl chloride in the presence of dimethyl sulfoxide.
The first aspect of the present invention is represented in Scheme-2.


0 ^^ T
Formula-3

Scheme-2
0
+

,N^CH3

CI
0 Formula-2
Formula-1 PALIPERIDONE(PURE)

base
solvent
purificarion

Formula-1 PALIPERIDONE

The second aspect of the present invention encompasses an improved process for the preparation of paliperidone, comprising the following steps;
a) Condensing 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[l,2-a]pyrimidin-4-one, compound of formula-4 with 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole, crystalline solid compound of formula-3 in presence of organic base in an alcohol solvent, to provide 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[l,2-a]pyrimidin-4-one (paliperidone), compound of formula-1,
b) treating the paliperidone, compound of formula-1 obtained in step a) with sodium borohydride, to convert any amount of the 3-[2-[4-(6-fluoro-l,2-benzisoxazol -3-yl)piperidin-l-yl]ethyl]-9-oxo-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[l,2-a] pyrimidin-4-one compound of formula-5, formed and present as an impurity, into 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-9-hydroxy-2-methyl -6,7,8,9-tetrahydro-4H-pyrido-[l,2-a]pyrimidin-4-one, compound of formula-1 ,
c) purifying the crude paliperidone formed in step-b, by crystallizing it from alcohol, followed by treatment with acid, washing the aqueous layer with a suitable solvent and subsequent treatment with a base in presence of an alcohol to obtain pure paliperidone.

In step a) the condensation of 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[l,2-a]pyrimidin-4-one, compound of formula-2 with 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole, crystalUne solid compound of formula-3 is carried out using an organic base, such as, e.g. triethyl amine, tributyl amine, N-(l-methylethyl)-2-propanamine, 4-ethylmorpholine, 4-dimethylaminopyridine, l,4-diazabicyclo[2.2.2] octane, l,8-diazabicyclo[5,4.0]undec-7-ene, diisopropyl ethyl amine, 4-dimethylamino pyridine, pyridine and the like. The reaction can be carried out by mixing the reactants optionally in Ci. 6 alcohols; tetrahydrofuran and acetonitrile and their mixtures thereof
In the US Patent No 5,158,952 also exemplifies the above process, but the condensation is carried out using 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole monohydrochloride. The yields reported are poor i.e. around 21 %, which were confirmed when these reactions were repeated in the laboratory. When the reactions were carried out using 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole free base, compound of formula-3 which is a pure crystalline solid, the yields improved substantially to 80-85%. Also the purity of the product was enhanced to provide paliperidone of >99.5% purity when measured using HPLC.
In the step b) the paliperidone formed in step a), containing 9-oxo impurity in low concentrations is treated with sodium borohydride to convert the oxo compound into paliperidone so that the purity of the final product improves substantially. The reaction is carried out in an alcohol solvent selected from methanol, ethanol, 1-propanol, 2-propanol and the like.
In the step c) the paliperidone is recrystallised using an alcohol solvent selected from methanol, ethanol, 1-propanol, 2-propanol and the like; and the recrystallised product is subjected to treatment with an acid. Washed the obtained aqueous mass with a suitable solvent selected from ester solvents like ethyl acetate and/or ketone solvents like methyl isobutyl ketone to remove the impurities, followed by treatment with base to obtain paliperidone of very high purity. The acid used is an organic acid which is selected from formic acid, acetic acid, propionic acid and the like or an inorganic acid like hydrochloric acid and sulfuric acid. The base used may be ammonia or an inorganic base

which is selected from group which includes but is not limited to hydroxides of alkali and alkaline earth metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like and bicarbonates of alkali metals such as sodium bicarbonate, potassiimi bicarbonate and the like, in the presence of an alcohol solvent selected from methanol, ethanol, 1-propanol, isopropanol and the like.
The particles of paliperidone obtained as per the process of the present invention have porous texture and irregular shape morphology, when seen through the microscope (as shown in Figure-2).The porous nature of the particles may impart greater solubility to the drug substance.
The particles of paliperidone prepared as per the process of the process disclosed in prior art (i.e., recrystallisation from isopropyl alcohol) have been obtained in the form of flakes with nonporous morphology, as seen through the microscope (Figure-3)
The second aspect of the present invention is represented in Scheme-3
Scheme-3



organic,^ I i
hace ^— I'
base
0 "^ F
Formula-3
Formula-5 Impurity (1-2 %)
Formula-1 N-Q '^"
PALIPERIDONE
NaBH^

purification

Formula-1 N-Q PAUPERIDONE(pure)

Formula-1 N-Q PALIPERIDONE(crude)

The third aspect of the present invention encompasses a process for the preparation of crystalline 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole, compound of formula-3, which comprises of the following steps;

a) treating 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole monohydrochloride, compound of formula-6, with an aqueous base to convert it into its free base,
b) isolating the obtained solid from water or extracting the free base, compound of formula-3 from the reaction mixture, with a suitable solvent and concentrating the solvent to provide a crystalline solid compound of formula-3.
In the step a) of the present embodiment the salt of formula-6 is converted into its free base i.e. compound of formula-3, using aqueous base of alkali metal or alkaline metal carbonate, hydrogen carbonate, hydroxide, oxide, e.g. sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide etc.
In the step b) the free base is extracted from the reaction mixture using a aliphatic hydrocarbons like hexane, cyclohexane; or aromatic hydrocarbons like xylene, toluene; or halogenated hydrocarbons like dichloromethane, chloroform, 1,2-dichloroethane; or ester solvents like ethyl acetate, propyl acetate, butyl acetate; and the like.
The present invention also provides a crystalline 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole. The crystalline 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole, compound of formula-3 is characterized by strong X-ray peaks at about 5.4,10.5,15.7, 17.3, 18.2, 18.8,19.4,20.1,20.8,21.5,22.2,22.8, 24.4, 26.2, ± 0.2 degrees two theta.
The third aspect of the present invention is represented in Scheme-4 Scheme-4



.HCI 2. Dichloromethane
1 .Aqueous NaOH

XRD analysis of crystalline 6-f[uoro-3-(4-piperidinyl)-l,2-benzisoxazole was carried out using SIEMENS/D-5000 X-Ray diffractometer using Cu, Ka radiation of wavelength 1.54 A° and continuous scan speed of 0.0457min.
Morphology of crystalline paliperidone was recorded in the following method: The samples are moulded on alumina stubs using double adhesive tape, coated with gold using HUS-5GB vacuum evaporator and observed in Hitachi S-520 Scanning Electron Microscope at an acculation voltage of 10 KV.
The related substance of paliperidone was analyzed by HPLC using the following conditions:
Column: ACE phenyl 250 x 4.6 mm; Flow rate: 1 ml/min; wavelength: 238 nm PDA; Temperature: 25°C; Load: 10 p,l; Run time: 45 min; and using acetonitrile and methanol in 1:1 ratio as a diluent

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples:
ExampIe-1: Preparation of 3-(2-chIoroethyl)-9-oxo-2-methyl-6,7,8,9-tetrahydro-4H-
pyrido[l,2-a] pyriinidin-4-one.
A solution of oxalyl chloride (8.8 ml) in dichloromethane (20 ml) was cooled to -65°C and a solution of dimethyl sulfoxide (6.5 ml) dissolved in dichloromethane (20 ml) was added to it slowly and stirred for 30 min. keeping the temperature at -65°C a solution of 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[ 1,2-a]pyrimidin-4-one (5 g) dissolved in dichloromethane (30 ml) was added to it very slowly and stirred for 40 min. Triethyl amine was added to the reaction mixture and then quenched with water. The organic layer was separated, washed with aqueous sodium carbonate and water. The solvent from the organic layer was distilled off under reduced pressure to provide the title compound. Yield: 4.0 g
Exaniple-2: Preparation of crystalline 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole:
To the suspension of 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole hydrochloride (25 g) dissolved in water (100 ml),added aqueous sodium hydroxide (4.8 g in 20 ml water). Stirred for 20 min and filtered the precipitated solid. Washed the solid with cold water and dried to obtain the title compound. Yield: 19 g
Example-3: Preparation of crystalline 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole:
To the suspension of 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole hydrochloride (25 g) dissolved in water (100 ml),added aqueous sodium hydroxide (4.8 g in 20 ml water). Stirred for 20 min and extracted with dichloromethane. Washed the organic layer with water, distilled off the solvent under reduced pressure to obtain the title compound. Yield: 21 g

Example-4: Preparation of Paliperidone.
3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[ 1,2-a] pyrimidin-4-one (5.2 g) and diisopropyl ethyl amine (12.56 g) was added to 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole (5.0 g) in methanol (75 ml) taken in autoclave and then heated to 60-65°C. 0.8 Kg pressure was applied and maintained for 16 hours. The reaction mixture cooled and then distilled under reduced pressure. Isopropyl alcohol was added to the obtained residue and stirred for 15 minutes and then distilled off under reduced pressure to get the title compound. Heated the reaction mixture to reflux temperature and stirred for 20 hrs at same temperature. Cooled the reaction mixture to 20°C and stirred for 90 minutes at the same temperature. Filtered the solid precipitated. Washed the solid with chilled methanol and dried the compound. Yield: 3.0 g
Example-5: Preparation of Paliperidone.
Step-A : Preparation of 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-
9-oxo-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[l,2-a]pyrimidin-4-one:
To the solution of 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole (0.62 g) taken in methanol added 3 -(2-chloroethyl)-9-oxo-2-methyl-6,7,8,9-tetrahydro-4H-pyrido [ 1,2-a] pyrimidin-4-one (0.94 g), diisopropyl ethyl amine(0.75 g) and refluxed the reaction for 23 hrs. Cooled the reaction mixture to 26°C and stirred for 15 minutes. Filtered the precipitated solid. Washed the solid with chilled methanol and dried. Separated the compound with column chromatography using chloroform/methanol as an elluent. Yield: 0.3 g Step-B: Preparation of Paliperidone.
To a solution of 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-9-oxo-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[l,2-a]pyrimidin-4-one (0.3 g) taken in a mixture of methanol (1.5 ml )and dichloromethane (3ml ) added sodium borohydride (0.008 g) and stirred for 1 hour at 30°C. the solvent was distilled off under reduced pressure. Methanol (1.5 ml) was added to it and heated to reflux for 30 min. the reaction mixture was cooled to 20°C and stirred for Ihour. Filtered the solid, washed with methanol and dried. Yield: 0.2 g

£xample-6: Preparation of Paliperidone.
Step-A: To the solution of 6-fluoro-3-(piperidin-4-yI)benzo[d]isoxazole (5.0 g) in methanol (25 ml) added 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-4-one (5.5 g) and diisopropyl ethyl amine (4.5 g). Heated the reaction mixture to reflux temperature and stirred for 20 hrs at same temperature. Cooled the reaction mixture to 20°C and stirred for 90 minutes at the same temperature. Filtered the solid precipitated. Washed the solid with chilled methanol and dried the compound. Yield: 6.9 g
Step-B: To the paliperidone obtained in step a) added dichloromethane (65 ml) and methanol (32.5 ml), stirred for 10 minutes and added sodium borohydride (0.03 g) to it. Stirred the reaction mixture for 90 minutes at 20°C. Distilled off the solvent completely under reduced pressure. Methanol (65 ml) was added to the reaction mixture and heated to reflux, cooled the reaction mixture to 20°C and stirred for 90 minutes. Filtered the crystallized compound. Washed the compound with methanol and dried the compound to obtain paliperidone. Yield: 5.5 g
Example-7: Preparation of Paliperidone (one pot process).
To the solution of 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole (10.0 g) in methanol (50 ml), 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido [l,2-a]pyrimidin-4-one (11 g) and diisopropyl ethyl amine (9 g) were added. The reaction mixture heated to 70°C and stirred for 24 hrs at the same temperature. The reaction mixture was cooled. Dichloromethane (100 ml) and sodium borohydride (0.086 g) were added to it and stirred for 60 minutes at the same temperature. The solvent was distilled off under reduced temperature. Methanol was added to the residue and heated to reflux for 30 min. The reaction mixture was cooled to 20°C stirred for 1 hour. Filtered the solid precipitated. Washed the solid with chilled methanol and dried the compound. Yield: 12.5 g
£xampIe-8: Purification of paliperidone.
Paliperidone (10 g) was taken in isopropyl alcohol (650 ml) and heated the reaction mixture to 80-85 °C. After getting clear solution it was cooled to 50°C and neutral carbon (2 g) was added to it. The reaction mixture was heated to 85°C for 20
17

min and filtered through hyflow. The filtrate was cooled to 0°C and filtered the
precipitated solid. The wet solid was taken in water (50 ml) and acidified with acetic
acid. Washed the reaction mixture with ethyl acetate and the aqueous layer was filtered.
Hydrose (Ig) and isopropyl alcohol (8 ml) were added to the filtrate and the reaction
mixture was basified with ammonia solution. Stirred the reaction for 1 hr, filtered the
solid precipitated and washed with water. Dried the solid to obtain pure paliperidone.
Yield: 8.0 g (Purity by HPLC 99.90%)
Particle Size Distribution:
Before micronisation: D(0.1):3.3nm; D(0.5): 28.4 ^m; D(0.9): 14.8 ^im; D[4,3]:
46.02 |xm.
After micronisation: D(0.1):0.7 ^im; D(0.5): 3.91 ^im; D(0.9): 11.3 ^im; D[4,3]: 5.4 \i
ExampIe-10: Purification of paliperidone.
Paliperidone (10 g) was taken in isopropyl alcohol (650 ml) and heated the reaction mixture to 80-85°C. After getting clear solution it was cooled to 50°C and neutral carbon (2 g) was added to it. The reaction mixture was heated to 85°C for 20 min and filtered through hyflow. The filtrate was cooled and filtered the precipitated solid. The wet solid was taken in water (50 ml) and adjusted acidified with acetic acid. Washed the reaction mixture with methyl isobutyl ketone and the aqueous layer was filtered. Hydrose (Igm) and isopropyl alcohol (8 ml) were added to the filtrate and basified with ammonia solution. Stirred the reaction for 1 hr, filtered the solid precipitated and washed with water. Dried the solid to obtain pure paliperidone. Yield: 7.6 g (Purity by HPLC 99.60%)
Example-U: Purification of paliperidone.
Paliperidone (12 g) was taken in isopropyl alcohol (780 ml) and heated the reaction mixture to 80-85°C. After getting clear solution it was cooled to 50°C and neutral carbon (2.4 g) was added to it. The reaction mixture was heated to 85°C for 20 min and filtered through hyflow. The filtrate was cooled to 0°C and fihered the precipitated solid. The wet solid was taken in water (120 ml) and acidified with acetic acid. Washed the reaction mixture with ethyl acetate followed by methyl isobutylketone and the aqueous layer were filtered. Hydrose (1.2 gm) and isopropyl alcohol (12 ml) were

added to the filtrate and the basified with ammonia solution. Stirred the reaction for
1 hr, filtered the solid precipitated and washed with water. Dried the solid to obtain pure
paliperidone.
Yield: 8.5 g (Purity by HPLC 99.68%)

We Claim:
1. A novel process for the preparation of paliperidone, comprising the following steps;
a) Condensing 3-(2-chloroethyl)-9-oxo-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[ 1,2-
a]pyrimidin-4-one, compound of formula-2,

b) treating the 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-9-oxo-
2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[l ,2-a]pyrimidin-4-one compound of
formula-5 obtained in step a) with suitable reducing agent in a suitable solvent to
obtain paliperidone,
c) purifying the crude paliperidone formed in step-b, by crystallizing it from alcohol,
followed by treatment with acid, washing the aqueous mass with a suitable
solvent and subsequent treatment with a base in presence of an alcohol to obtain
pure paliperidone compound of formula-1.

2. The process according to claim-1 ,wherein,
i) in step a) the base used is selected from a group which includes hydroxides of alkali and alkaline earth metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like and bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate and the like; or may be an organic base which is selected from a group which includes but is not limited to triethyl amine, tributyl amine, N-(l-methylethyl)-2-propanamine, 4-ethylmorpholine, 4-dimethylamino pyridine, diisopropyl ethyl amine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5.4.0]undec-7-ene, l,4-diazabicyclo[2.2.2]octane, pyridine and the like. The solvent used is selected from water, aliphatic hydrocarbons like hexane, cyclohexane, or aromatic hydrocarbons like xylene, toluene; or halogenated hydrocarbons like dichloromethane, chloroform, 1,2-dichloroethane; or ethers like diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxy ethane; or ketones like acetone, methyl ethyl ketone, diethyl ketone; or acetates like ethyl acetate propyl acetate, butyl acetate; alcohols like methanol, ethanol,l-propanol, isopropyl alcohol, n-butanol; or nitriles like acetonitrile and propionitrile and the like, ii) in step b) the reducing agent is selected from sodium borohydride, sodium cyanoborohydride, diborane, and hydrogen in presence of a catalyst, which include heterogeneous catalysts containing from about 0.1% to about 20% by weight of transition metals such as Ni, Pd, Pt, Rh, Re, Ru and Ir, including oxides and combination thereof, which are typically supported on various materials including AI2O3, C, CaCOs. SrCOj, BaS04, MgO, SiOa, TiOi, ZrOz and the like. Many of these metals including Pd may be doped with an amine, sulfide or a second metal such as Pb, Cu and Zn. Usefril catalysts include raney nickel, palladium catalyst such as Pd/C, Pd/SrCOa, Pd/ AI2O3. Pd/MgO, Pd/CaCOs, Pd/ BaS04, PdO, Pd Black, PdCb ,Rh/C, Ru/C, Re/C, Pt02, Rh/C, RUO2 and the like; and the suitable solvent is selected from water, alcohols, ethers, esters, acids and hydrocarbon solvents such as, methanol, ethanol, isopropyl alcohol, tetrahydrofiaran, ethyl acetate, acetic acid, dichloromethane and the like.

iii) in the step c) the alcohol solvent is selected from methanol, ethanol, l-propanol, 2-propanol, n-butanol and the like; the acid used is an organic acid which is selected from formic acid, acetic acid, propionic acid and the like or an inorganic acid like hydrochloric acid and sulfuric acid; suitable solvent is selected from ester solvent like ethyl acetate; ketone solvents like methyl isobutyl ketone; and the base used may be ammonia or an inorganic base which is selected from group which includes but is not limited to hydroxides of alkali and alkaline earth metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like and bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate and the like, in the presence of alcohol solvent selected from methanol, ethanol, l-propanol, isopropanol, n-butanol and the like.
3. A novel process for the preparation of paliperidone, comprising the following steps; a) Condensing 3-(2-chloroethyl)-9-oxo-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[l ,2-a]pyrimidin-4-one, compound of formula-2,

to provide 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-9-oxo-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[l ,2-a]pyrimidin-4-one, compound of formula-5,


b) treating the 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-9-oxo-
2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[ 1,2-a]pyrimidin-4-one compound of
formula-S obtained in step a) with sodium borohydride in methanol to obtain
crude paliperidone,
c) purifying the crude paliperidone formed in step b) by crystallizing it from
isopropyl alcohol, followed by treatment with acetic acid, washing the aqueous
mass with ethyl acetate or methyl isobutyl ketone and subsequent treatment with
ammonia solution in the presence of isopropyl alcohol to obtain pure paliperidone
compound of formula-1,
4. 3-(2-chloroethyl)-9-oxo-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[l,2-a]pyrimidin-4-one, compovmdof formula-2.

with 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole, crystalline solid compound of formula-3,


in presence of organic base selected from triethyl amine, tributyl amine, N-(l-methylethyl)-2-propanamine, 4-ethylmorpholine, 4-dimethylamino pyridine, 1,4-diazabicyclo[2.2.2]octane, diisopropyl ethyl amine, 4-dimethylaminopyridine, pyridine, in an solvent selected from Ci. 6 alcohols like methanol, ethanol, 1-propanol, isopropanol, n-butanol and the like; tetrahydrofuran and acetonitrile and their mixtures thereof, to provide 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-1 -yl]ethyl]-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[ 1,2-a]pyrimidin-4-one, compound of formula-1 (paliperidone),
b) treating the paliperidone obtained in step a) with sodium borohydride, to convert any amount of the 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-9-0X0-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[l,2-a]pyrimidin-4-one compound of formula-S, formed and present as an impurity, into 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[l,2-a]pyrimidin-4-one compound of formula-1 ,
c) purifying the crude paliperidone formed in step-b, by crystallizing it from alcoholic solvent selected from methanol, ethanol, 1-propanol, isopropanol , n-butanol and the like, followed by treatment with acid selected from formic acid, acetic acid, propionic acid; or an inorganic acid like hydrochloric acid and sulfuric acid; and subsequent treatment with a base selected from group which includes ammonia or an inorganic base like hydroxides of alkali and alkaline earth metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like and bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate and the like, in the presence of alcohol solvent selected from methanol, ethanol, 1-propanol, isopropanol, n-butanol and the like to obtain pure paliperidone compound of formula-1.

6. An improved process for the preparation of paliperidone, comprising of;
a) Condensing 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-

in presence of diisopropyl ethylamine in methanol, to provide 3-[2-[4-(6-fluoro-
1,2-benzisoxazol-3-yl)piperidin-1 -yl]ethyl]-9-hydroxy-2-methyl-6,7,8,9-
tetrahydro-4H-pyrido-[l,2-a]pyrimidin-4-one,compound of formula-1
(paliperidone),
b) treating the paliperidone obtained in step a) with sodium borohydride in
methanol, to convert any of the 3-[2-[4-(6-fIuoro-l,2-benzisoxazol-3-yl) piperidin
-l-yl]ethyl]-9-oxo-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[l,2-a]pyrimidin-4-one
compound of formula-5, formed and present as an impurity, into
3-[2-[4-(6-fluoro-1,2-benzisoxazol-3 -yl)piperidin-1 -yl]ethyl]-9-hydroxy-2-methyl
-6,7,8,9-tetrahydro-4H-pyrido-[l,2-a]pyrimidin-4-one compound of Formula-1,
c) purifying the crude paliperidone formed in step-b, by crystallizing it from
isopropyl alcohol, followed by treatment with acetic acid, washing the aqueous
mass with ethyl acetate or methyl isobutyl ketone and subsequent treatment with
ammonia solution in the presence isopropanol, to obtain pure paliperidone,
compound of Formula-1.


characterized by its strong X-ray peaks at about 5.4,10.5,15.7, 17.3, 18.2, 18.8, 19.4, 20.1,20.8,21.5,22.2,22.8,24.4,26.2, ± 0.2 degrees two theta.
8. A process for the purification of paliperidone, which comprises of treating the
paliperidone containing 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl) piperidin-1-
yl]ethyl]-9-oxo-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[l ,2-a]pyrimidin-4-one with a
suitable reducing agent in a suitable solvent to provide highly pure paliperidone.
9. A process according to claim 8, wherein the suitable reducing agent is sodium
borohydride and the suitable solvent is alcohol solvent selected from methanol,
ethanol, isopropanol and butanol.
10. A process for the purification of crude paliperidone comprising of,
a) dissolving the paliperidone in an aqueous acid,
b) washing the mixture obtained in step a) with suitable solvents,
c) treating the aqueous mass with a base in the presence of suitable alcohol to obtain pure paliperidone.
11. The process according to claim 10, wherein,
i) in step a) the acid is an organic acid selected from formic acid, acetic acid, propionic acid and the like or an inorganic acid selected from hydrochloric acid and sulfuric acid and the like, ii) in step b) the suitable solvents selected from ester solvents like ethyl acetate, methyl acetate, isopropyl acetate or ketone solvents like methyl isobutyl ketone.

iii) in step c) the base is selected from ammonia or an inorganic base like hydroxides of alkali and alkaline earth metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like and bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate and the like suitable alcohol selected from methanol, ethanol, isopropanol and butanol.
12. A process for the purification of crude paliperidone comprising of,
a) dissolving the paliperidone in aqueous acetic acid,
b) washing the mixture obtained in step a) with ethyl acetate or methyl isobutyl
ketone,
c) treating the aqueous mass with a ammonia in the presence of isopropanol or
methanol to obtain pure paliperidone.
13. Paliperidone having porous texture and irregular shape morphology, seen through the
microscope as shown in figure-2.