CLIAMS:We Claim:

1. An improved process for paliperidone free from its keto impurity, which comprises reacting 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole or its pharmaceutically acceptable salt with 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one or its pharmaceutically acceptable salt in a mixture of alcohol and chlorinated solvent in presence of base.

2. The process of claim 1, wherein said chlorinated solvent is selected from group of dichloromethane, dichloroethane, chloroform and chlorobenzene.

3. A process for preparing pure paliperidone, which comprises reacting 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole or its pharmaceutically acceptable salt with 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one or its pharmaceutically acceptable salt in presence of base and a mixture of alcohol and dichloromethane.

4. The process of claim 1, wherein said to paliperidone is containing less than about 0.1% of keto impurity.

5. The process of claim 1, wherein said pharmaceutically acceptable salt is hydrochloride salt.

6. The process of claim 1, wherein said base is selected from organic base or inorganic base.

7. The process of claim 1, wherein said base is diisopropyl amine.

8. The process of claim 1, wherein said alcohol is methanol.

Dated this 14th day of Jan, 2013 For Wockhardt Limited
(Dr Mandar Kodgule) Authorized Signatory
,TagSPECI:DESCRIPTION

The present invention provides an improved process for the preparation of Paliperidone free from its impurities, for example, keto impurity. The structure of keto impurity is depicted as formula A.

Formula A

Paliperidone (Invega) of Formula I is chemically known as ((±)-3-[2-[4-(6-fluoro-1,2benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4Hpyrido[1,2-a]pyrimidin-4-one.

Formula I

Paliperidone is a second generation antipsychotic drug developed by Janssen Pharmaceutical. Invega is an extended release formulation of Paliperidone that uses the Osmotic Release Oral Systems extended release system to allow for once-daily dosing. It is marketed for the treatment of schizophrenia and bipolar mania.

US patent No. 5,158,952 describes various processes for the synthesis of paliperidone in which one route involves condensation of 3-(2-chloroethy))-6,7,8,9-tetrahydro-9-hydroxy-2-methyl- 4H-pyrido[1 ,2-a]pyrimidin-4-one with 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride in the presence of a base followed by purification using column chromatography and recrystallization in a suitable solvent.

PCT application No. 2008/140641 describes purification of paliperidone by crystallization or by slurring paliperidone in an organic solvent.

PCT application No. 2008/021345 discloses a process for preparing paliperidone comprising reacting 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l,2-a]-pyrimidin-4-one or a salt thereof with 6-fluoro-3-piperidino-l,2-benzisoxazol or a salt thereof in a solvent in the presence of an inorganic base in the presence of metal iodide and/or phase transfer catalyst. This process with the dimethylformamide solvent produces paliperidone with 90% purity, which further requires multiple purifications/crystallizations to provide high purity paliperidone, thus resulting in low overall yields of the product.

PCT application No. 2011/06638 describes preparation of paliperidone and its purification. The process of ‘638 involves condensing 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazol hydrochloride with 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one using dry diisopropylamine in presence of methanol and water wherein the pH of the reaction medium is between 6 and 4. Further, purification of paliperidone is achieved by crystallization in the presence of active charcoal having neutral pH value and the content of individual metal cations less than 200 ppm.

WO 2009/118655 describes purification of crude paliperidone by contacting it with reducing agent. The reducing agents include metal hydrides, specifically sodium borohydride.

PCT application No. 2010/003703 describes preparation, isolation of keto impurity and its further use in the preparation of paliperidone. Keto impurity is converted into paliperidone by reduction using hydride, specifically sodium borohydride.

PCT application No. 2010/004578 discloses various processes for preparation of paliperidone. It also describes conversion of any amount of keto impurity that is formed and present as an impurity with sodium borohydride into paliperidone.

PCT application No. 2012/164242 describes preparation of paliperidone and purification to reduce the keto impurity. The process involves condensing 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]-pyrimidin-4-one with 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride in the presence of acetonitrile, base and inhibiting agent such as sodium borohydride at 65°C for 25 hours.

Various other patent application Nos. WO 2008/021346, WO 2009/010988, WO 2009/060297, WO 2011/030224 and WO2012042368 disclose process for preparation and purification to reduce the level of keto impurity in Paliperidone.

The above prior art references discloses preparation and purification processes to reduce the level of keto impurity in paliperidone. However, these methods are lengthy and tedious, requiring dissolution in a solvent, refluxing for several hours, further isolation and crystallization. The methods are also costly as they involve the use of additional solvents and reagents.

Therefore, there is need to develop an improved process for paliperidone to prepare paliperidone free from its impurity and to provide improved yield. The present inventors developed an improved process for paliperidone to reduce the formation of keto impurity.

In one aspect of the present invention relates to an improved process for paliperidone free from its keto impurity, which comprises reacting 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole or its pharmaceutically acceptable salt with 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one or its pharmaceutically acceptable salt in a mixture of alcohol and chlorinated solvent in presence of base.

The chlorinated solvent used for the reaction of present invention may be selected from dichloromethane, dichloroethane, chloroform, chlorobenzene and the like.

In another aspect of the present invention relates to a process for preparing pure paliperidone, which comprises reacting 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole or its pharmaceutically acceptable salt with 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one or its pharmaceutically acceptable salt in presence of base and a mixture of alcohol and dichloromethane.

The term pure paliperidone used in the present invention refers to paliperidone containing less than about 0.1% of keto impurity or less than about 0.05% keto impurity.

Both of starting materials, 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole and 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one, can be in the form of a base or acid addition salts. For example, salt is a hydrochloride salt. Both starting materials may be obtained by any method known in the art, such as EP 0 368 388, WO 2008/024415, WO 2008/140646, WO 2009/010988, WO 2009/045489, WO 2009/047499, EP 0 196 132, EP 0 428 437, EP 0 081 104 and the like.

The base used is selected from organic base or inorganic base. The inorganic base is selected from group comprising of potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, magnesium hydroxide, lithium hydroxide, and like. The organic base is selected from diisopropyl ethyl amine, di-isopropyl amine, pyridine, triethyl amine and the like.

The alcohol used for conducting the reaction may be selected from methanol, ethanol, n-propanol, isopropanol, 2-butanol, 1-butanol and the like or mixtures thereof.

The reaction may be performed at a reflux temperature, for example the temperature is above 35°C, depends on the solvent used. The reflux temperature may be maintained till to the completion of the reaction, for example, the time period may range from about 10 hours to about 25 hours.

In one embodiment of the present invention the reaction between 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride and 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one is conducted in presence of methanol (MeOH) and dichloromethane (DCM) at a reflux temperature, for example, at about 40°C for a period of 20 to 25 hours.

The use of chlorinated solvent in the present invention improves quality and yield of the paliperidone as well as reduction in the formation of keto impurity. The amount of chlorinated solvent used for the reaction may be in the range of about 0.5 to about 2 times with respect to 6-Fluoro-3-(4-pyridinyl)-1,2-benzisoxazole hydrochloride.

After completion of the reaction, the reaction mixture may be subjected to solid separation by using known techniques such as concentration by distillation, performing slurry, cooling to below room temperature, using anti-solvent or any combination thereof.

In another aspect of the present invention provides a process for purification of paliperidone using alcohol and chlorinated solvent.

The purification of paliperidone comprises providing a solution in a solvent mixture of chlorinated solvent and alcohol, treating the solution with activated charcoal and then subjecting the solution for the precipitation of pure paliperidone having purity greater than 99.5% by HPLC. The chlorinated solvent is selected from dichloromethane, chloroform and chlorobenzene. The alcohol is selected from methanol, ethanol, n-propanol, isopropyl alcohol and n-butanol.

The solution of paliperidone in a solvent mixture may be provided at elevated temperature ranging from about room temperature to about boiling point of the solvent. The temperature may be at about 35 °C to about 55°C.

The resultant solution is treated with activated charcoal and then filtered to remove the carbon. The solution may be filtered by passing through paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as Celite. Depending upon the equipment used, as well as the concentration and temperature of the solution, the filtration apparatus may need to be heated or cooled to avoid undesired crystallization.

The reaction solution obtained may be distilled till to reach certain amount which affects the precipitation of solid and cooled to below room temperature or to below 10°C and stirred for 20 minutes to 1 hour or more to affect the purity of the solid. In embodiments, the reaction mass may be cooled to temperatures about 0°C to about 5°C.

The obtained solid may be dried and then subjected for the development of pharmaceutically acceptable salt of paliperidone or its derivative, for example, paliperidone palmitate. The drying may be suitably carried out using any of equipment at atmospheric pressure or under reduced pressures, at temperatures less than about 40°C, less than about 30°C, less than about 20°C and any other suitable temperatures. The drying may be carried out for any time periods required for obtaining a desired quality, such as from about 15 minutes to several hours, or longer.

The present invention is further illustrated by the following example, which does not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.

EXAMPLES
Example –1: Preparation of Paliperidone

A mixture of 100 gm of 6-Fluoro-3-(4-pyridinyl)-1,2-benzisoxazole hydrochloride, 137 ml of di-isopropyl amine and 104 gm of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one in a mixture of 800 ml methanol and 50 ml dichloromethane was refluxed for 20-25 hours. After complete reaction, reaction mixture was one time (100 ml) distilled out. The reaction mass was cooled to 5-10°C, filtered and the solids thus obtained was washed with 200 ml chilled methanol. The wet solid was again washed with 200 ml DM water. The wet material was purified by acid base treatment using (375 ml -375 ml – 750 ml) DCM-Acetone-water solvents. Wet material so obtained was washed with 100 ml acetone followed by 200 ml water. The wet material was dried at 75-80°C under vacuum. (Dry Wt= 130 to 150 gm)

Yield: 130 to 150 gm
Keto Impurity: 0.04 to 0.05 %

140 gm dry Paliperidone crude dissolved into 1680 ml methanol and 700 ml dichloromethane at 40 to 45°C temperature. 14 gm activated carbon was charged to the clear solution and stirred for 30 minutes. The reaction mass was filtered through hyflo bed and washed with 280 ml dichloromethane. 1680 ml reaction mass was distilled out and cooled to a temperature of about 0 to 5°C temperature. The resultant solid was filtered, washed with 280 ml chilled methanol and dried under vacuum at 75 to 80°C.

Yield: 115 to 125 gm
Purity: 99.7 to 99.9 %
Keto Impurity: 0.04 to 0.05 %