Indian Patents. 278241:PROCESS FOR THE PREPARATION OF PALIPERIDONE

Title of Invention	PROCESS FOR THE PREPARATION OF PALIPERIDONE
Abstract	ABSTRACT The present invention relates to a novel and improved process for the preparation of 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 (Paliperidone) represented by formula-1.

Full Text	Process for the Preparation of Paliperidone Field of the Invention: The present invention relates to a novel process for the preparation of paliperidone. Paliperidone is chemically known as 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-I-yl]ethyl]-6,7,8,9terahydro-9-hydroxy-2-methyl-4H-pyrido-[l,2-a] pyrimidin-4-one, which is represented by formula-1. It also relates to an improved process for the preparation of paliperidone. 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-HTVD2-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-benzisoxazole 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-hydroxyrisperidone, 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 gastroesophageal 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 of paliperidone via the intermediate 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l,2-a]pyrimidin-4- one (CMHTP) is depicted in the last step of the scheme. A process for the synthesis of intermediate 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyI-4H-pyrido[l,2-a]pyrimidin-4-one (CMHTP) is also described in US Patent No 5,688,799. The processes described in the above publications are long, time consuming and result in low chemical yields, making their application in the industry very difficult. Brief Description of the Invention: The first embodiment 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]pyri-midin-4-one, which is represented by formula-l.The process comprises the following steps; a) Condensing 3-benzyloxy-2-aminopyridine, compound of formula-2 with 3-acetyldihydrofuran-2(3H)-2-one, compound of formula-3 in presence of toluene to obtain a condensed compound of formula-4, which on in-situ treatment with acid, leading to deprotection of benzyl group to provide 3-(2-chloroethyI)-9-hydroxy-2-methyl-4H-pyrido-[l,2-a]pyrimidin-4-one, which is converted into hydrochloride salt, compound of formula -5, b) condensing compound of formula-5 with 6-fluoro-3-(4-piperidinyl> 1,2-benz-isoxazoie monohydrochloride, compound of formuIa-6 in presence of sodium carbonate in acetonitrile, to provide 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl) piperidin-l-yl]ethyt]-9-hydroxy-2-methyl-4H-pyrido-[l,2-a]pyrimidin-4-one, compound of formula-7, c) reducing compound of formula-7 by hydrogenation in the presence of palladium or platinum catalyst in acidic conditions to obtain paliperidone, d) purifying the crude paliperidone formed in step-c by crystallizing from isopropyl alcohol to obtain pure paliperidone. 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-benzyIoxy-2-aminopyridine, compound of formula-2 with 3-acetyldihydrofuran-2(3H)-2-one, compound of formula-3 in presence of an aromatic solvent, followed by treatment with acid to obtain 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido-[l,2-a]pyrimidin-4-one, which is converted into hydrochloride salt, compound of formula -5, b) reducing 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido-[l,2-a]pyrimidin-4-one hydrochloride, compound of formula-5 by hydrogenation in the presence of palladium catalyst in acidic conditions to obtain 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-4-one compound of formuIa-8, c) condensing compound of formula-8 with 6-fluoro-3-(4-piperidinyl)-l,2-benz-isoxazole monohydrochloride, compound of formula-6 in presence of base and aprotic solvent to obtain paliperidone, d) Purifying the crude paliperidone formed in step-c, by crystallizing form a suitable solvent to obtain pure paliperidone. Brief Description of the Drawings: Figure-1: Illustrates the powder X-ray diffraction pattern of crystalline paliperidone. Figure-2: Illustrates the IR spectrum of crystalline paliperidone. Figure-3: Illustrates the DSC of crystalline paliperidone. Detailed Description of the Invention: The first embodiment of the present invention encompasses to a novel process for the preparation of paliperidone. chemically known as 3-[2-[4-(6-fluoro-l,2-benzisoxazoI-3-yI)piperidin-l-yl]ethyI]-6,7,8,9-tetrahydro-9-hydroxy-2-methyI-4H-pyrido-[l,2-a]pyrimidin-4-one. which is represented by formula-1. The process comprises the following steps; a) Condensing 3-benzyloxy-2-aminopyridine, compound of formula-2 with 3-acetyldihydrofuran-2(3H)-2-one, compound of formula-3 in toluene to obtain a condensed compound of formuIa-4, which on in-situ treatment with acid, leading to deprotection of benzyl group, to provide 3-{2-chloroethyl)-9-bydroxy-2-methyl-4H-pyrido-[l,2-a]pyrimidin-4-one, which is converted into hydrochloride salt, compound of formula-5, b) condensing compound of formula-5 with 6-fluoro-3-(4-piperidinyl)-1,2-benz-isoxazole monohydrochloride, compound of formula-6 in presence of sodium carbonate in acetonitrile, to provide 3-[2-[4-(6-fluoro-I,2-benzisoxazol-3-yl) piperidin-1 -yl]ethyl]-9-hydroxy-2-rnethyl-4H-pyrido-[l,2-a]pyrimidin-4-one, comp -ound of formula-7, c) reducing compound of formula-7 by hydrogenation in the presence of palladium or platinum catalyst in acidic conditions to obtain paliperidone, d) purifying the crude paliperidone formed in step-c by crystallizing from isopropyl alcohol to obtain pure paliperidone. In step-a, the deprotection of the benzyl group is carried out by using an acid. The acid which can be used in the deprotection can be selected from hydrochloric acid, hydrobromic acid or sulfuric acid. In the preferred embodiment of the invention the acid used is hydrochloric acid. The 3-(2-chloroethyI)-9-hydroxy-2-methyl-4H-pyrido-[l,2- a]pyrimidin-4-one formed is obtained as its hydrochloride salt compound of formula-5, which is of substantially high purity. This enhances the yields in the subsequent reactions. In the step-b, 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido-[l,2-a]pyrimidin-4-one hydrochloride is condensed with 6-fluoro-3-(4-piperidinyl)-l,2-benz- isoxazole monohydrochloride, compound of formula-6 in presence of sodium carbonate in acetonitrile, to provide 3-[2-[4-(6-ftuoro-l,2-benzisoxazol-3-yI) piperidin-l-yI]ethyl]-9-hydroxy-2-methyl-4H-pyrido-[l,2-a]pyrimidin-4-one, compound of formula-7. The appropriate base which can be used for the condensation can be selected from a group such as for example, an alkali metal or alkaline metal carbonate, hydrogen carbonate, hydroxide, oxide, carboxylate, alkoxide, hydride or amide e.g. sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, sodium methoxide, sodium ethoxide sodium hydride, sodium amide and the like, or an organic base such as for example a tertiary amine, e.g. N,N-diethylethanamine, N-(l-methylethyl)-2-propanamine, 4-ethyl morpholine, l,4-diazabicyclo[2.2.2]octane, diisopropyl ethyl amine, pyridine and the like. The reaction can be carried out by mixing the reactants optionally in solvents such as aromatic solvents,C1-6, alcohols, ketones, an ester, an ether, a dipolar aprotic solvent e.g N,N-dimethyl formamide, N,N-dimethylacetamide, dimethyl sulfoxide, pyridine, acetonitrile and the like; or a mixture of such solvents. The reaction can be carried out in the presence or absence of a phase transfer catalyst which is selected from the group consisting of but not limited to tetra butyl ammonium bromide, tetra propyl ammonium bromide, tributyl benzyl ammonium bromide, tetra octyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium hydrogen sulfate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl ammonium iodide, ethyl triphenyl phosphonium bromide, more preferably tetra butyl ammonium bromide or alkali iodides like sodium iodide, potassium iodide and lithium iodide. In the step-c, the pyridine ring of 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl) piperidin-l-yl]ethyl]-9-hydroxy-2-methyl-4H-pyrido-[l,2-a]pyrimidin-4-one, compound of formula-7, is reduced by hydrogenation using palladium or platinum catalyst in acidic conditions. In the preferred embodiment the reaction was performed by hydrogenation using palladium catalyst in presence of acetic acid to provide paliperidone. The crude paliperidone formed in step-c, is purified by crystallizing from isopropyl alcohol to obtain pure paliperidone. The present embodiment of the invention is represented in Scheme-2. The second embodiment of the present invention encompasses an improved process for the preparation of paliperidone, which comprises of the following steps: a) Condensing 3-benzyloxy-2-aminopyridine, compound of formula-2 with 3-acetyldihydrofuran-2(3H)-2-one, compound of formula-3 in toluene to obtain a condensed compound of formula-4, which on in-situ treatment with acid, leading to deprotection of benzyl group to provide 3-(2-chloroethyl)-9-hydroxy-2-methyI-4H-pyrido-[l,2-a]pyrimidin-4-one, which is converted into hydrochloride salt, compound of formula-5, b) reducing 3-(2-chIoroethyl)-9-hydroxy-2-methy]-4H-pyrido-[l,2-a]pyrimidin-4-one hydrochloride, compound of formula-5 by hydrogenation in the presence of palladium or platinum catalyst in acidic conditions to obtain 3-(2-chloroethyI)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[ 1,2-a]pyrimidin-4-one compound of formula-8, c) condensing compound of formula-8 with 6-fluoro-3-(4-piperidinyl)-l,2-benz-isoxazole mo no hydrochloride, compound of formula-6 in presence of sodium carbonate in acetonitrile to obtain paliperidone, d) purifying the crude paliperidone formed in step-c by crystallizing from isopropyl alcohol to obtain pure paliperidone. In step-a, the deprotection of the benzyl group is carried out by using an acid. The acid which can be used in the deprotection can be selected from hydrochloric acid, hydrobromic acid or sulfuric acid. In the preferred embodiment of the invention the acid used is hydrochloric acid- The 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido-[l,2-a]pyrimidin-4-one formed is obtained as its hydrochloride salt compound of formula-5. In the step-b, the pyridine ring of 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido-[l,2-a]pyrimidin-4-one hydrochloride, compound of formula-5 is reduced by hydrogenation using palladium or platinum catalyst in acidic conditions. In the preferred embodiment the reaction was performed by hydrogenation using palladium catalyst in presence of acetic acid to provide 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one, compound of formula-8. In the processes disclosed in the prior art the hydrogenation is performed in the presence of palladium catalyst in alcohol solvent, which to partially may lead to the hydrogenolysts of the chlorine atom which is replaced by hydrogen. The dehalogenated product does not undergo the condensation reaction in the next step, which leads to decrease in the purity and yields of the intermediates and it may be present as impurity. In the present invention the hydrogenation by palladium catalyst in acidic conditions prevents the dechlorination which increases the purity and yield of the intermediates, as well as the yield of the paliperidone formed. In step-c the condensation of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one, compound of formula-8 and 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole mono hydrochloride, compound of formula-6 in presence of sodium carbonate and catalytic amount of potassium iodide in acetonitrile to provide paliperidone, which is purified in step-d, by crystallization from isopropyl alcohol. In the US Patent No 5,158,952 in the exemplified process the condensation step is carried out in the presence of organic base i.e., diisopropyl amine to provide paliperidone. But it also teaches that appropriate base such as for example, an alkali metal or alkaline metal carbonate, hydrogen carbonate, hydroxide, oxide, carboxylate, alkoxide hydride or amide e.g. sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide etc: can be used for the condensation. The reaction can be carried out by mixing the reactants optionally in solvents such as aromatic solvents,C1-6 alcohols, ketones, an ester, an ether, a dipolar aprotic solvent e.g N,N-dimethyl formamide, N,N-dimethyl acetamide, dimethyl sulfoxide, pyridine, acetonitrile and the like; or a mixture of such solvents. In the prior art above condensation step has been disclosed for the synthesis of analogous compounds especially risperidone and its analogues. US Patent No 4804663 exemplifies 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]pyrimi-din-4-one and 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole monohydrochloride 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. A monograph in European pharmacopoeia on risperidone, lists five impurities and paliperidone is one of them. Thus in the synthesis of paliperidone there is a possibility of formation of the similar impurities reported for risperidone. The present invention is schematically represented in Scheme-3; Scheme-3 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: Example-1: Preparation of 3-(2-chIoroethyl)-9-hydroxy-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one hydrochloride (5). A mixture of 3-benzyloxy-2-aminopyridine (2) (100 grams), toluene (3.5 L) and P0C13(139 ml) was heated to 50°C. 3-acetyldihydrofuran-2(3H)-2-one (3) (218 grams) was added to the reaction mixture, heated to 95°C and stirred for 18 hrs. The solvent was distilled off under reduced pressure to obtain a residue which was cooled to 40°C and toluene (500 ml) was added to it. A solution of concentrated hydrochloric acid (600 ml) was added to the reaction mixture, heated to 60°C and stirred for 6 hrs. The reaction mixture was cooled to 0°C. A solid crystallized out which was filtered, washed with toluene and dried at 50aC to yield the title compound. Yield: 95 grams. ExampIe-2: Preparation of 3-(2-chloroethyl)-9-hydro xy-2-methy 1-6,7,8,9-tetrahydro-4H-pyrido [l,2-a]pyrimidin-4-one (8). A mixture of 3-(2-chloroethyI)-9-hydroxy-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one hydrochloride (5) (40 grams), acetic acid (200 ml) and palladium carbon (40 grams) was taken in an autoclave. Hydrogen gas with a pressure of 3.0-3.5 Kg/cm was applied to the above mixture at 35°C for 6 hrs. The reaction was quenched with water and filtered the resultant mixture through a hyflow bed. The pH of the filtrate was adjusted to 6 using aqueous sodium hydroxide solution The reaction mixture was cooled to 0°C and stirred for lhr.The solid formed was filtered, washed with water and dried to yield the title compound. Yield: 22 grams. Example-3: Preparation of 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl\|-9-hydroxy-2-methyl-4H-pyrido-\|l,2-a\|pyrimidin-4-one(7). A mixture of 3-(2-chIoroethyl)-9-hydroxy-2-methyl-4H-pyrido[l,2-a] pyrimidin-4-one (11.1 grams), 6-fluoro-3-(4-piperidinyl)-l,2-benzoisoxazole mono hydrochloride (6) (10 grams), sodium carbonate (7.5 grams), potassium iodide (0.64 grams) in acetonitrile (100 ml) was heated to 80-85° C. The reaction mixture was refluxed for 17 hrs under nitrogen. Then it was cooled to -10° C and stirred for 30 min. The solid obtained was filtered and washed with cool acetonitrile. The solid was taken in water and treated with sodium hydro sulphite (hydrose) (2.0 grams). The solid was filtered and washed with water and dried at 50°C to provide the title compound. Yield: 12 grams. Example-4: Preparation of Paliperidone. A mixture of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yI)piperidin-1 -yl]ethyl]-9-hydroxy-2-methyl-4H-pyrido-[l,2-a]pyrimidin-4-one (7) (5 grams), acetic acid (25 ml) and palladium carbon (4 grams) was taken in an autoclave. Hydrogen gas with a pressure of 3.0 Kg/cm2 was applied to the above mixture at 32°C for 9 hrs. The reaction mixture was filtered through a hyflow bed. The filtrate was treated with water (100 ml) and the pH of the filtrate was adjusted to 10 using aqueous sodium hydroxide solution. The solid formed was filtered, washed with water and dried at 50°C to yield the title compound. Yield: 1.7 grams Example-5: Preparation of Paliperidone. A mixture of 3-(2-chloroethyl)-9-hydroxy-2-methy]-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-4-one (8) (170.1 grams), 6-fluoro-3-(4-piperidinyl)-l,2-benzoisoxazole monohydrochloride (6) (150 grams), sodium carbonate (113.3 grams), and potassium iodide (9.7 grams) in acetonitrile (1.5 L) was heated to 85°C. The reaction mixture was heated at 85°C for 6 hrs. The reaction mixture was then cooled to -10°C and stirred for 1.5 hrs. The solid obtained was filtered, washed with cold acetonitrile. The wet solid was taken in water, and acetic acid was added to the mixture to adjust the pH to 4.0. The reaction mixture was treated with acidic carbon and filtered through hyflow bed. The filtrate was treated with sodium hydrosulphite (hydrose). The pH of the reaction mixture was adjusted to 12 by adding aqueous sodium hydroxide solution and stirred for 45 min. The solid obtained was filtered, washed with water and dried to provide the title compound. Yield: 224 grams. ExampIe-6: Purification of paliperidone. The crude paliperidone (20 grams) obtained in example-3 was taken in isopropyl alcohol (1300 ml) and heated to reflux for 30 min. Basic carbon (10 grams) was added to the reaction mixture and refluxed further for 30 min. The reaction mixture was filtered through hyflow bed. The filtrate was cooled to 5°C and stirred for 30 min. the solid obtained was filtered, washed with cold isopropyl alcohol and dried at 50°C to provide pure paliperidone (1). Yield: 16 grams. We Claim: 1. A novel process for the preparation of paliperidone comprising the following steps; a) Condensing 3-benzyloxy-2-aminopyridine, compound of formula-2 with 3-acetyldihydrofuran-2(3H)-2-one, compound of formula-3 in presence of toluene to obtain a condensed compound of formula-4, which on in-situ treatment with acid, leading to deprotection of benzyl group to provide 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido-[l,2-a]pyrimidin-4-one, which is converted into hydrochloride salt, compound of formula -5, b) condensing compound of formula-5 with 6-fluoro-3-(4-piperidinyl)-l,2-benz-isoxazole monohydrochloride, compound of formula-6 in presence of sodium carbonate in acetonitrile, to provide 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl) piperidin-l-yl]ethyl]-9-hydroxy-2-methyl-4H-pyrido-[l,2-a]pyrimidin-4-one, compound of formula-7, c) reducing compound of formula-7 by hydrogenation in the presence of palladium or platinum catalyst in acidic conditions to obtain paliperidone, d) purifying the crude paliperidone formed in step-c by crystallizing from isopropyl alcohol to obtain pure paliperidone. 2. A process for deprotection of benzyl group of 3-(2-chloroethyl)-9-benzyloxy-2-methyMH-pyrido-1,2-a]pyrimidin-4-one, compound of formula-4 by treatment with hydrochloric acid to provide 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido-[l,2-a]pyrimidin-4-one hydrochloride, compound of formula 5. 3. 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-9-hydroxy-2-methyl-4H-pyrido-[l,2-a]pyrimidin-4-one, compound of formula-7 4. An improved process for preparation of paliperidone comprising of the following steps; a) Condensing 3-benzyloxy-2-aminopyridine, compound of formula-2 with 3-acetyldihydrofuran-2(3H)-2-one, compound of formula-3 in presence of toluene to obtain a condensed compound of formula-4, which on in-situ treatment with an acid, leading to deprotection of benzyl group to provide 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido-[l ,2-a]pyrimidin-4-one which is converted into hydrochloride salt, compound of formula -5, b) reducing 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido-[ 1,2-a]pyrimidin-4-one, compound of formula-5 by hydrogenation in the presence of palladium catalyst in acidic conditions to obtain 3-(2-chloroethyl)-9-hydroxy-2-rnethyl-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-4-one compound of formula-8, c) condensing compound of formula-8 with 6-fluoro-3-(4-piperidinyl)-l,2-benzoisoxazole monohydrochloride, compound of formula~6 in presence of sodium carbonate in acetonitrile to obtain paliperidone, d) purifying the crude paliperidone formed in step-c by crystallizing from isopropyl alcohol to obtain pure paliperidone. 5. A process of claim-4, wherein in step-a) the acid used for the deprotection of the benzyl group is selected from hydrochloric acid, hydrobromic acid or sulfuric acid. 6. A process of claim-4, wherein in step-a) the acid used for the deprotection of the benzyl group is hydrochloric acid. 7. A process of claim-4, wherein in step-a) the acid used for the deprotection of the benzyl group is hydrobromic acid. 8. A process of claim-4, wherein in step-b) the reduction is carried out by hydrogenation using palladium or platinum catalyst in acidic conditions. 9. A process of claim-4, wherein in step-b) the reduction is carried out by hydrogenation using palladium catalyst in presence of acetic acid. 10. A process of reduction of 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido-[l,2-a] pyrimidin-4-one hydrochloride, compound of formula-5 by hydrogenation in the presence of palladium catalyst in acetic acid to obtain 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[ 1,2-a]pyrimidin-4-one compound of formula-8.

Full Text

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

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-HTVD2-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-benzisoxazole 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-hydroxyrisperidone, 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 gastroesophageal 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 of paliperidone via the intermediate 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-
one (CMHTP) is depicted in the last step of the scheme.

A process for the synthesis of intermediate 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyI-4H-pyrido[l,2-a]pyrimidin-4-one (CMHTP) is also described in US Patent No 5,688,799. The processes described in the above publications are long, time consuming and result in low chemical yields, making their application in the industry very difficult.
Brief Description of the Invention:
The first embodiment 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]pyri-midin-4-one, which is represented by formula-l.The process comprises the following steps;
a) Condensing 3-benzyloxy-2-aminopyridine, compound of formula-2 with 3-acetyldihydrofuran-2(3H)-2-one, compound of formula-3 in presence of toluene to obtain a condensed compound of formula-4, which on in-situ treatment with acid,

leading to deprotection of benzyl group to provide 3-(2-chloroethyI)-9-hydroxy-2-methyl-4H-pyrido-[l,2-a]pyrimidin-4-one, which is converted into hydrochloride salt, compound of formula -5,
b) condensing compound of formula-5 with 6-fluoro-3-(4-piperidinyl> 1,2-benz-isoxazoie monohydrochloride, compound of formuIa-6 in presence of sodium carbonate in acetonitrile, to provide 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl) piperidin-l-yl]ethyt]-9-hydroxy-2-methyl-4H-pyrido-[l,2-a]pyrimidin-4-one, compound of formula-7,
c) reducing compound of formula-7 by hydrogenation in the presence of palladium or platinum catalyst in acidic conditions to obtain paliperidone,
d) purifying the crude paliperidone formed in step-c by crystallizing from isopropyl alcohol to obtain pure paliperidone.
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-benzyIoxy-2-aminopyridine, compound of formula-2 with 3-acetyldihydrofuran-2(3H)-2-one, compound of formula-3 in presence of an aromatic solvent, followed by treatment with acid to obtain 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido-[l,2-a]pyrimidin-4-one, which is converted into hydrochloride salt, compound of formula -5,
b) reducing 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido-[l,2-a]pyrimidin-4-one hydrochloride, compound of formula-5 by hydrogenation in the presence of palladium catalyst in acidic conditions to obtain 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-4-one compound of formuIa-8,
c) condensing compound of formula-8 with 6-fluoro-3-(4-piperidinyl)-l,2-benz-isoxazole monohydrochloride, compound of formula-6 in presence of base and aprotic solvent to obtain paliperidone,
d) Purifying the crude paliperidone formed in step-c, by crystallizing form a suitable solvent to obtain pure paliperidone.

Brief Description of the Drawings:
Figure-1: Illustrates the powder X-ray diffraction pattern of crystalline paliperidone.
Figure-2: Illustrates the IR spectrum of crystalline paliperidone.
Figure-3: Illustrates the DSC of crystalline paliperidone.
Detailed Description of the Invention:
The first embodiment of the present invention encompasses to a novel process for the preparation of paliperidone. chemically known as 3-[2-[4-(6-fluoro-l,2-benzisoxazoI-3-yI)piperidin-l-yl]ethyI]-6,7,8,9-tetrahydro-9-hydroxy-2-methyI-4H-pyrido-[l,2-a]pyrimidin-4-one. which is represented by formula-1. The process comprises the following steps;
a) Condensing 3-benzyloxy-2-aminopyridine, compound of formula-2 with 3-acetyldihydrofuran-2(3H)-2-one, compound of formula-3 in toluene to obtain a condensed compound of formuIa-4, which on in-situ treatment with acid, leading to deprotection of benzyl group, to provide 3-{2-chloroethyl)-9-bydroxy-2-methyl-4H-pyrido-[l,2-a]pyrimidin-4-one, which is converted into hydrochloride salt, compound of formula-5,
b) condensing compound of formula-5 with 6-fluoro-3-(4-piperidinyl)-1,2-benz-isoxazole monohydrochloride, compound of formula-6 in presence of sodium carbonate in acetonitrile, to provide 3-[2-[4-(6-fluoro-I,2-benzisoxazol-3-yl) piperidin-1 -yl]ethyl]-9-hydroxy-2-rnethyl-4H-pyrido-[l,2-a]pyrimidin-4-one, comp -ound of formula-7,
c) reducing compound of formula-7 by hydrogenation in the presence of palladium or platinum catalyst in acidic conditions to obtain paliperidone,
d) purifying the crude paliperidone formed in step-c by crystallizing from isopropyl alcohol to obtain pure paliperidone.
In step-a, the deprotection of the benzyl group is carried out by using an acid. The acid which can be used in the deprotection can be selected from hydrochloric acid, hydrobromic acid or sulfuric acid. In the preferred embodiment of the invention the acid used is hydrochloric acid. The 3-(2-chloroethyI)-9-hydroxy-2-methyl-4H-pyrido-[l,2-

a]pyrimidin-4-one formed is obtained as its hydrochloride salt compound of formula-5, which is of substantially high purity. This enhances the yields in the subsequent reactions.
In the step-b, 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido-[l,2-a]pyrimidin-4-one hydrochloride is condensed with 6-fluoro-3-(4-piperidinyl)-l,2-benz- isoxazole monohydrochloride, compound of formula-6 in presence of sodium carbonate in acetonitrile, to provide 3-[2-[4-(6-ftuoro-l,2-benzisoxazol-3-yI) piperidin-l-yI]ethyl]-9-hydroxy-2-methyl-4H-pyrido-[l,2-a]pyrimidin-4-one, compound of formula-7. The appropriate base which can be used for the condensation can be selected from a group such as for example, an alkali metal or alkaline metal carbonate, hydrogen carbonate, hydroxide, oxide, carboxylate, alkoxide, hydride or amide e.g. sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, sodium methoxide, sodium ethoxide sodium hydride, sodium amide and the like, or an organic base such as for example a tertiary amine, e.g. N,N-diethylethanamine, N-(l-methylethyl)-2-propanamine, 4-ethyl morpholine, l,4-diazabicyclo[2.2.2]octane, diisopropyl ethyl amine, pyridine and the like. The reaction can be carried out by mixing the reactants optionally in solvents such as aromatic solvents,C1-6, alcohols, ketones, an ester, an ether, a dipolar aprotic solvent e.g N,N-dimethyl formamide, N,N-dimethylacetamide, dimethyl sulfoxide, pyridine, acetonitrile and the like; or a mixture of such solvents.
The reaction can be carried out in the presence or absence of a phase transfer catalyst which is selected from the group consisting of but not limited to tetra butyl ammonium bromide, tetra propyl ammonium bromide, tributyl benzyl ammonium bromide, tetra octyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium hydrogen sulfate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl ammonium iodide, ethyl triphenyl phosphonium bromide, more preferably tetra butyl ammonium bromide or alkali iodides like sodium iodide, potassium iodide and lithium iodide.
In the step-c, the pyridine ring of 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl) piperidin-l-yl]ethyl]-9-hydroxy-2-methyl-4H-pyrido-[l,2-a]pyrimidin-4-one, compound

of formula-7, is reduced by hydrogenation using palladium or platinum catalyst in acidic conditions. In the preferred embodiment the reaction was performed by hydrogenation using palladium catalyst in presence of acetic acid to provide paliperidone.
The crude paliperidone formed in step-c, is purified by crystallizing from isopropyl alcohol to obtain pure paliperidone. The present embodiment of the invention is represented in Scheme-2.

The second embodiment of the present invention encompasses an improved process for the preparation of paliperidone, which comprises of the following steps:
a) Condensing 3-benzyloxy-2-aminopyridine, compound of formula-2 with 3-acetyldihydrofuran-2(3H)-2-one, compound of formula-3 in toluene to obtain a condensed compound of formula-4, which on in-situ treatment with acid, leading to deprotection of benzyl group to provide 3-(2-chloroethyl)-9-hydroxy-2-methyI-4H-pyrido-[l,2-a]pyrimidin-4-one, which is converted into hydrochloride salt, compound of formula-5,
b) reducing 3-(2-chIoroethyl)-9-hydroxy-2-methy]-4H-pyrido-[l,2-a]pyrimidin-4-one hydrochloride, compound of formula-5 by hydrogenation in the presence of palladium or platinum catalyst in acidic conditions to obtain 3-(2-chloroethyI)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[ 1,2-a]pyrimidin-4-one compound of formula-8,
c) condensing compound of formula-8 with 6-fluoro-3-(4-piperidinyl)-l,2-benz-isoxazole mo no hydrochloride, compound of formula-6 in presence of sodium carbonate in acetonitrile to obtain paliperidone,
d) purifying the crude paliperidone formed in step-c by crystallizing from isopropyl alcohol to obtain pure paliperidone.
In step-a, the deprotection of the benzyl group is carried out by using an acid. The acid which can be used in the deprotection can be selected from hydrochloric acid, hydrobromic acid or sulfuric acid. In the preferred embodiment of the invention the acid used is hydrochloric acid- The 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido-[l,2-a]pyrimidin-4-one formed is obtained as its hydrochloride salt compound of formula-5.
In the step-b, the pyridine ring of 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido-[l,2-a]pyrimidin-4-one hydrochloride, compound of formula-5 is reduced by hydrogenation using palladium or platinum catalyst in acidic conditions. In the preferred embodiment the reaction was performed by hydrogenation using palladium catalyst in presence of acetic acid to provide 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one, compound of formula-8.

In the processes disclosed in the prior art the hydrogenation is performed in the presence of palladium catalyst in alcohol solvent, which to partially may lead to the hydrogenolysts of the chlorine atom which is replaced by hydrogen. The dehalogenated product does not undergo the condensation reaction in the next step, which leads to decrease in the purity and yields of the intermediates and it may be present as impurity.
In the present invention the hydrogenation by palladium catalyst in acidic conditions prevents the dechlorination which increases the purity and yield of the intermediates, as well as the yield of the paliperidone formed.
In step-c the condensation of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one, compound of formula-8 and 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole mono hydrochloride, compound of formula-6 in presence of sodium carbonate and catalytic amount of potassium iodide in acetonitrile to provide paliperidone, which is purified in step-d, by crystallization from isopropyl alcohol.
In the US Patent No 5,158,952 in the exemplified process the condensation step is carried out in the presence of organic base i.e., diisopropyl amine to provide paliperidone. But it also teaches that appropriate base such as for example, an alkali metal or alkaline metal carbonate, hydrogen carbonate, hydroxide, oxide, carboxylate, alkoxide hydride or amide e.g. sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide etc: can be used for the condensation. The reaction can be carried out by mixing the reactants optionally in solvents such as aromatic solvents,C1-6 alcohols, ketones, an ester, an ether, a dipolar aprotic solvent e.g N,N-dimethyl formamide, N,N-dimethyl acetamide, dimethyl sulfoxide, pyridine, acetonitrile and the like; or a mixture of such solvents.
In the prior art above condensation step has been disclosed for the synthesis of analogous compounds especially risperidone and its analogues. US Patent No 4804663 exemplifies 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]pyrimi-din-4-one and 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole monohydrochloride 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.
A monograph in European pharmacopoeia on risperidone, lists five impurities and paliperidone is one of them. Thus in the synthesis of paliperidone there is a possibility of formation of the similar impurities reported for risperidone. The present invention is schematically represented in Scheme-3; Scheme-3

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:
Example-1: Preparation of 3-(2-chIoroethyl)-9-hydroxy-2-methyl-4H-pyrido
[1,2-a] pyrimidin-4-one hydrochloride (5).
A mixture of 3-benzyloxy-2-aminopyridine (2) (100 grams), toluene (3.5 L) and P0C13(139 ml) was heated to 50°C. 3-acetyldihydrofuran-2(3H)-2-one (3) (218 grams) was added to the reaction mixture, heated to 95°C and stirred for 18 hrs. The solvent was distilled off under reduced pressure to obtain a residue which was cooled to 40°C and toluene (500 ml) was added to it. A solution of concentrated hydrochloric acid (600 ml) was added to the reaction mixture, heated to 60°C and stirred for 6 hrs. The reaction mixture was cooled to 0°C. A solid crystallized out which was filtered, washed with toluene and dried at 50aC to yield the title compound. Yield: 95 grams.
ExampIe-2: Preparation of 3-(2-chloroethyl)-9-hydro xy-2-methy 1-6,7,8,9-tetrahydro-4H-pyrido [l,2-a]pyrimidin-4-one (8).
A mixture of 3-(2-chloroethyI)-9-hydroxy-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one hydrochloride (5) (40 grams), acetic acid (200 ml) and palladium carbon (40 grams) was taken in an autoclave. Hydrogen gas with a pressure of 3.0-3.5 Kg/cm was applied to the above mixture at 35°C for 6 hrs. The reaction was quenched with water and filtered the resultant mixture through a hyflow bed. The pH of the filtrate was adjusted to 6 using aqueous sodium hydroxide solution The reaction mixture was cooled to 0°C and stirred for lhr.The solid formed was filtered, washed with water and dried to yield the title compound. Yield: 22 grams.

Example-3: Preparation of 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl|-9-hydroxy-2-methyl-4H-pyrido-|l,2-a|pyrimidin-4-one(7).
A mixture of 3-(2-chIoroethyl)-9-hydroxy-2-methyl-4H-pyrido[l,2-a] pyrimidin-4-one (11.1 grams), 6-fluoro-3-(4-piperidinyl)-l,2-benzoisoxazole mono hydrochloride (6) (10 grams), sodium carbonate (7.5 grams), potassium iodide (0.64 grams) in acetonitrile (100 ml) was heated to 80-85° C. The reaction mixture was refluxed for 17 hrs under nitrogen. Then it was cooled to -10° C and stirred for 30 min. The solid obtained was filtered and washed with cool acetonitrile. The solid was taken in water and treated with sodium hydro sulphite (hydrose) (2.0 grams). The solid was filtered and washed with water and dried at 50°C to provide the title compound. Yield: 12 grams.
Example-4: Preparation of Paliperidone.
A mixture of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yI)piperidin-1 -yl]ethyl]-9-hydroxy-2-methyl-4H-pyrido-[l,2-a]pyrimidin-4-one (7) (5 grams), acetic acid (25 ml) and palladium carbon (4 grams) was taken in an autoclave. Hydrogen gas with a pressure of 3.0 Kg/cm2 was applied to the above mixture at 32°C for 9 hrs. The reaction mixture was filtered through a hyflow bed. The filtrate was treated with water (100 ml) and the pH of the filtrate was adjusted to 10 using aqueous sodium hydroxide solution. The solid formed was filtered, washed with water and dried at 50°C to yield the title compound. Yield: 1.7 grams
Example-5: Preparation of Paliperidone.
A mixture of 3-(2-chloroethyl)-9-hydroxy-2-methy]-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-4-one (8) (170.1 grams), 6-fluoro-3-(4-piperidinyl)-l,2-benzoisoxazole monohydrochloride (6) (150 grams), sodium carbonate (113.3 grams), and potassium iodide (9.7 grams) in acetonitrile (1.5 L) was heated to 85°C. The reaction mixture was heated at 85°C for 6 hrs. The reaction mixture was then cooled to -10°C and stirred for 1.5 hrs. The solid obtained was filtered, washed with cold acetonitrile. The wet solid was taken in water, and acetic acid was added to the mixture to adjust the pH to 4.0. The reaction mixture was treated with acidic carbon and filtered through hyflow bed. The

filtrate was treated with sodium hydrosulphite (hydrose). The pH of the reaction mixture was adjusted to 12 by adding aqueous sodium hydroxide solution and stirred for 45 min. The solid obtained was filtered, washed with water and dried to provide the title compound. Yield: 224 grams.
ExampIe-6: Purification of paliperidone.
The crude paliperidone (20 grams) obtained in example-3 was taken in isopropyl alcohol (1300 ml) and heated to reflux for 30 min. Basic carbon (10 grams) was added to the reaction mixture and refluxed further for 30 min. The reaction mixture was filtered through hyflow bed. The filtrate was cooled to 5°C and stirred for 30 min. the solid obtained was filtered, washed with cold isopropyl alcohol and dried at 50°C to provide pure paliperidone (1). Yield: 16 grams.

We Claim:
1. A novel process for the preparation of paliperidone comprising the following steps;
a) Condensing 3-benzyloxy-2-aminopyridine, compound of formula-2 with 3-acetyldihydrofuran-2(3H)-2-one, compound of formula-3 in presence of toluene to obtain a condensed compound of formula-4, which on in-situ treatment with acid, leading to deprotection of benzyl group to provide 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido-[l,2-a]pyrimidin-4-one, which is converted into hydrochloride salt, compound of formula -5,
b) condensing compound of formula-5 with 6-fluoro-3-(4-piperidinyl)-l,2-benz-isoxazole monohydrochloride, compound of formula-6 in presence of sodium carbonate in acetonitrile, to provide 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl) piperidin-l-yl]ethyl]-9-hydroxy-2-methyl-4H-pyrido-[l,2-a]pyrimidin-4-one, compound of formula-7,
c) reducing compound of formula-7 by hydrogenation in the presence of palladium or platinum catalyst in acidic conditions to obtain paliperidone,
d) purifying the crude paliperidone formed in step-c by crystallizing from isopropyl alcohol to obtain pure paliperidone.

2. A process for deprotection of benzyl group of 3-(2-chloroethyl)-9-benzyloxy-2-methyMH-pyrido-1,2-a]pyrimidin-4-one, compound of formula-4 by treatment with hydrochloric acid to provide 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido-[l,2-a]pyrimidin-4-one hydrochloride, compound of formula 5.
3. 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-9-hydroxy-2-methyl-4H-pyrido-[l,2-a]pyrimidin-4-one, compound of formula-7

4. An improved process for preparation of paliperidone comprising of the following steps;
a) Condensing 3-benzyloxy-2-aminopyridine, compound of formula-2 with 3-acetyldihydrofuran-2(3H)-2-one, compound of formula-3 in presence of toluene to obtain a condensed compound of formula-4, which on in-situ treatment with an acid, leading to deprotection of benzyl group to provide 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido-[l ,2-a]pyrimidin-4-one which is converted into hydrochloride salt, compound of formula -5,
b) reducing 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido-[ 1,2-a]pyrimidin-4-one, compound of formula-5 by hydrogenation in the presence of palladium catalyst in acidic conditions to obtain 3-(2-chloroethyl)-9-hydroxy-2-rnethyl-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidin-4-one compound of formula-8,
c) condensing compound of formula-8 with 6-fluoro-3-(4-piperidinyl)-l,2-benzoisoxazole monohydrochloride, compound of formula~6 in presence of sodium carbonate in acetonitrile to obtain paliperidone,
d) purifying the crude paliperidone formed in step-c by crystallizing from isopropyl alcohol to obtain pure paliperidone.

5. A process of claim-4, wherein in step-a) the acid used for the deprotection of the benzyl group is selected from hydrochloric acid, hydrobromic acid or sulfuric acid.
6. A process of claim-4, wherein in step-a) the acid used for the deprotection of the benzyl group is hydrochloric acid.
7. A process of claim-4, wherein in step-a) the acid used for the deprotection of the benzyl group is hydrobromic acid.
8. A process of claim-4, wherein in step-b) the reduction is carried out by hydrogenation using palladium or platinum catalyst in acidic conditions.
9. A process of claim-4, wherein in step-b) the reduction is carried out by hydrogenation using palladium catalyst in presence of acetic acid.

10. A process of reduction of 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido-[l,2-a] pyrimidin-4-one hydrochloride, compound of formula-5 by hydrogenation in the presence of palladium catalyst in acetic acid to obtain 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[ 1,2-a]pyrimidin-4-one compound of formula-8.

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Patent Number

278241

Indian Patent Application Number

1451/CHE/2008

PG Journal Number

53/2016

Publication Date

23-Dec-2016

Grant Date

19-Dec-2016

Date of Filing

16-Jun-2008

Name of Patentee

MSN LOBORATORIES LIMITED

Applicant Address

FACTIRTY ; NO 317 & 323 RUDRARAM VIL , ANDIRA PREDESH

Inventors:

#	Inventor's Name	Inventor's Address
1	SAJJA ESWARAIAH	MSN LABORATORIES LIMITED , RUDRARAM , PATANCHERU
2	MANNE SATYANARAYANA REDDY	MSN LOBOURATORIES LIMITED, RUDRARAM, PATANCHERU, ANDIRA PREDESH

PCT International Classification Number

CO7D471/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA