FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
[Section 10 and Rule 13]
A PROCESS FOR THE PREPARATION OF PALIPERIDONE


Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near Dinesh
Hall, Ahmedabad 380 009, Gujarat, India

The following specification describes the invention:


A PROCESS FOR THE PREPARATION OF PALIPERIDONE
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Paliperidone.
BACKGROUND OF THE INVENTION
Paliperidone, 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl] ethyl]- 6,7.8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one, is a 5-HT antagonist belonging to the chemical class of benzisoxazole derivatives and a racemic mixture having the following structural formula (I):

Paliperidone is an active metabolite of the older antipsychotic risperidone (paliperidone is 9-hydroxy risperidone, i.e. risperidone with an extra hydroxy! group), marketed under the name, Invega® Paliperidone is a psychotropic agent approved in the United States for the treatment of schizophrenia.
A process for the preparation of Paliperidone is described in U.S. Patent No. 5,158,952.
The process comprises the reaction 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-piperidin-4-yl-1,2-
benzisoxazole or salt thereof in the presence of N-(l-methylethyl)-2-propanamine. The reaction mixture was stirred overnight at 60°C to obtain paliperidone. Furthermore,

paliperidone obtained required column chromatography and recrystallization from different solvents for purification, which ultimately resulted into the low yield i.e. 21.1% approximately. Methods involving column chromatographic purifications are generally undesirable for large-scale operations, thereby making the process commercially unfeasible.
International Pub.No.WO 2008/021346 A2 discloses various purification processes to obtain pure paliperidone.
We surprisingly found an improved process for the preparation of substantially pure paliperidone. The process is simple, industrially feasible and economical.
SUMMARYOF THE INVENTION
In one embodiment, the specification discloses a process for preparation of the compound of formula (I),

wherein the process comprises:
(a) condensing 3-(2-chloroethyl)-6.7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[ 1,2-a]-pyrimidin-4-one (II)



with 6-fluoro-3-piperidin-4-yl-l,2-benzisoxazole or salt thereof (III)
in the presence of base;
(b) dissolving the product of step (a) in a solvent;
(c) adding a reducing agent;
(d) isolating the compound of formula (I);
(e) optionally purifying the product of step (d).
In another embodiment, the specification discloses a crystalline Form X of Pahperidone as shown in Fig. 1.
In another embodiment, pahperidone obtained by the process of the present invention contains less than 0.15% of the impurity PLP-OXO.
DESCRIPTION OF THE DRAWINGS
Figure-l: An X-ray powder diffraction pattern of a crystalline Form X of Paliperidone.

DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term "PLP-OXO" refers to oxidized paliperidone impurity of the following structure:

In one embodiment, the specification discloses a process for preparation of the compound of formula (T),

wherein the process comprises:
(a) condensing 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l ,2-
a]-pyrimidin-4-one (II)



with 6-fluoro-3-piperidin-4-y[-1,2-benzisoxazole or salt thereof (III)
in the presence of base;
(b) dissolving the product of step (a) in a solvent;
(c) adding a reducing agent;
(d) isolating the compound of formula (I);
(e) optionally purifying the product of step (d).
The condensation reaction comprises reaction of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l,2-a]-pyrimidin-4-one (II) and 6-fluoro-3-piperidin-4-yl-1,2-benzisoxazole (III) in presence of base and suitable solvent followed by the addition of salt.
The salt such as potassium iodide, potassium bromide, sodium iodide and sodium bromide may be added in order to enhance the rate of reaction.
The base may be selected from organic base or inorganic base. The organic base may be selected from N,N-diethylethanamine, diisopropylethylamine, N-(l-methylethyI)-2-propanamine, 4-ethylmorpholine, l,4-diazabicyclo[2-2.2]octane or pyridine. The inorganic base may be selected from alkaline earth metal carbonate like sodium carbonate or potassium carbonate; hydrogen carbonate like sodium hydrogen carbonate; hydroxide like sodium hydroxide; alkoxide like sodium methoxide; or hydride like sodium hydride.
The solvent may be selected from inert solvent such as water; an aromatic solvent such as benzene, methylbenzene, dimethylbenzene, chlorobenzene, methoxybenzene and the like; a Ci.6 alkanol such as methanol, ethanol, 1-butanol and the like; a ketone such as 2-propanone, 4-methyl-2-pentanone and the like, an ester such as ethyl acetate and the like;

an ether such as I,l'-oxybisethane, tetrahydrofuran, 1,4-dioxane and the like; a dipolar
aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide,
dimethylsulfoxide, pyridine, l,3-dimethyl-3,4,5.6-tetrahydro-2(lH)-pyrimidinone, 1,3-
dimethyl-2-imidazoIidinone, 1,1,3,3-tetramethylurea, l-methyl-2-pyrrolidinone,
nitrobenzene, acetonitrile and the like; or a mixture of such solvents.
The condensation reaction may be carried out at a temperature in the range from about room temperature to about reflux. The heated mixture may be maintained for at least 15 to 20 hours and subsequently may be cooled to a temperature of about 25 °C to about 30°C to obtain the compound of formula (I).
The process further comprises the preparation of the compound of formula (I) having less than 0.15% of PLP-OXO by dissolving the compound of formula (I) in an organic solvent selected from methylene dichloride, ethylene dichloride, chloroform, carbon tetrachloride or tetrahydrofuran to obtain a solution; by adding a reducing agent selected from alkali borohydride like sodium borohydride or sodium triacetoxy borohydride; aluminium isopropoxide, sodium sulphate and the like; and isolating the compound of formula (I) having less than 0.15% PLP-OXO.
The process of purification of the compound of formula (I) comprises:
(a) treating the compound of formula (I) with an acid;
(b) adding solvent to the step (a);
(c) adding base to the step (b) and isolating the compound of formula (I).
The purification process comprises treating the compound of formula (I) with an acid. The acids may be selected from hydrochloric acid, formic acid, hydrobromic acid, tartaric acid, acetic acid and the like. The obtained acid solution is further washed with solvent such as cyclohexane, ethylacetate and the like and further subjected to carbon treatment. The impurities are removed from the solution, and are filtered out along with carbon. The carbon can be washed with water. The obtained aqueous layer is then added to the solvent such as alcohol like methanol, ethanol or isopropanol; ketone such as acetone or methyl

ethyl ketone; ester such as ethyl acetate and the like; aprotic solvent such as dimethylformamide, dimethyl sulfoxide, N-methyl pyrrolidine, N, N-dimethylacetamide and the like. The obtained mixture is then treated with base. The bases may be selected from sodium or potassium hydroxide., sodium or patassium casbonate or becarbonate, ammonia and the like. The resultant reaction mixture is then further cooled to about 5-10°C and filtered and washed with solvent such as isopropyl alcohol. Preferably, the compound of formula (I) is then dried. Any drying technique known to a person skilled in the art may be used.
In another embodiment, the specification discloses a crystalline Form X of Paliperidone, which is characterized by an x-ray powder diffraction spectrum having peaks expressed at about 7.43, 8.20, 9.68, 10.29, 10.83, 12.09, 12.45, 13.12, 13.79, 13.97, 14.56, 14.93, 15.75, 16.24, 17.56,18.67, 19.19,20.02,20.46,20.68,21.11,21.47,21.94,22.07,22.51, 23.18, 23.80, 24.66, 25.04, 25.81, 26.43, 26.95, 28.03, 28-56, 29.41, 30.94, 31.21, 33.64, 34.75, 35.62, 37.57, 38.56, 39.81 ± 0.2 degree two theta.
Paliperidone obtained by the process of the present invention have less than 0.15% of the impurity PLP-OXO, preferably less than 0.08%, more preferably, less than 0.05%.
Paliperidone obtained by the process of the present invention has a total purity of atleast about 98.5 %.
The following examples illustrate certain embodiments in greater detail, and are not intended to limit the scope of the invention.
Example-I 3-(2-chloroethyl)-9-benzyloxy-2-methyI-4H-pyrido[l,2-a]-pyrimidin-4-one
50 gm 3-benzyloxy-2-amino pyridine, 250 ml toluene, 35.30 gm 3-acetyl-4,5 dihydro-2(3H)-furan-one and 8.0 gm cone. HC1 were added into round bottom flask at 25-30°C. The reaction mass was heated at 110-115°C and maintained for 24 hours. The water was

removed through dean stark. The reaction mass was cooled at 70-75°C. 250 ml of toluene was charged into the reaction mass. 100 ml of R.O. water was added into the reaction mass and stirred for 15 minutes at 70-75°C. The layers were separated. The toluene layer was charged into the round bottom flask. 100 ml R.O. water was added and stirred for 15 minutes at 70-75°C. The layers were separated. The toluene layer was added into the round bottom flask. 100 ml R.O. water was added and stirred for 15 minutes at 70-75°C. The toluene layer was distilled out up to 250 ml. 250 ml of toluene was added into the reaction mass and the reaction mass was cooled to 60±5°C. The reaction mass was clear and no solid precipitate was observed. 38.30 gm phosphorous oxy chloride was added over a period of 30-40 minutes. The reaction mass was slowly heated to 95±2°C and maintained for 7-8 hours. The reaction mass was cooled to 25±5°C and was stirred for 4 hours. The solid was filtered and washed with 50 ml toluene. The solid was air dried at 25±5°C. 400 ml of water was added into the round bottom flask and cooled to 0-5°C. The air dried solid was added into the round bottom flask and stirred for 15 minutes at 10-15°C. The reaction mass was adjusted to pH 8.0-9.0 with ammonia solution at 10-15°C and was stirred for I hour at 10-15°C. The solid was filtered and washed with 100 ml of water. The wet cake was charged in to round bottom flask and 250 ml of water was charged and stirred at 25±5°C for 1 hour. The solid was filtered and washed with 100 ml of water. The solid was dried at 50-55°C.
Dry weight: 57 gm Yield: 65-70% HPLC purity: 88.30%
Example-II 3-(2-chloroethyl)-9-benzyloxy-2-methyl-4H-pyrido[l,2-a]-pyrimidin-4-one
500 ml toluene and 5.75 gm phosphorus oxychloride were charged into round bottom flask at 25-30°C. 100.0 gm 3-bezyloxy-2-amino pyridine and 70.5 gm of 3-acetyl-4,5 dihydro-2-(3H)-furan-one was charged into round bottom flask at 25±5°C. The reaction mass was heated to 110-115°C and maintained for 24 hours. The water was removed

through dean stark. The reaction mass was cooled at 70±5°C. 500 ml toluene was charged into the reaction mass. 500 ml of R.O. water was charged into reaction mass and stirred for 30 minutes at 70-75°C. The layers were separated. Toluene layer was charged into the round bottom flask. 500 ml of R.O. water was charged and stirred for 15 minutes at 70-75°C. The layers were separated. Toluene layer was charged into the round bottom flask. 500 ml of R.O. water was charged and stirred for 15 minutes at 70-75°C. The layers were separated. The toluene layer was taken and water traces were removed azeotropically. The reaction mass was cooled to 60±5°C. 77 gm phosphorus oxychloride was added through dropping funnel over a period of 30-40 minutes at 60±5°C. The reaction mass was heated to 95±2°C and maintained for 7-8 hours. The reaction mass was cooled to 25±5°C and stirred for 4 hours. The solid was filtered and washed with toluene. The solid was air dried at 25±5°C. 800 ml R.O. water was charged into round bottom flask and cooled to 5-10°C. The solid was charged into the round bottom flask and stirred for 15 minutes at 5-10°C. The pH was adjusted to 8.0-9.0 with ammonia solution at 5-10°C. The reaction mass was stirred for 1 hour at 10-15°C. The solid was filtered and washed with water. The wet cake and 500 ml water was charged into round bottom flask and was stirred at 25±5°C for 1 hour. The solid was filtered and dried at 50-55°C.
Dry weight: 115 gm Yield: 65-70% HPLC purity: 87.50%
Example-III
3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l,2-a]-
pyrimidin-4-one
600 ml of methanol and palladium slurry was charged into hydrogenator under nitrogen atmosphere at 25±5°C. 40 gm of 3-(2-chloroethyl)-9-benzyloxy-2-methyl-4H-pyrido[l,2-a]-pyrimidin-4-one and 200 ml of methanol was added into hydrogenator. 1.0 kg nitrogen pressure was applied and released. It was repeated twice. 0.5 kg hydrogen pressure was applied to hydrogenate and released which was repeated. 1.8±0.2 kg hydrogen pressure

was applied and the reaction mass was slowly heated to 38±2°C and maintained for 10-12 hours. The hydrogen pressure was released slowly. 1.0 kg nitrogen pressure was applied and released thrice. The reaction mass was filtered under nitrogen atmosphere through hyflow bed and washed with 80 ml of methanol. The filtrate was distilled out completely under vacuum at below 35°C. The reaction mass was cooled tc 3±2°C. 160 ml of chilled water was added into the reaction mass and stirred for 15 minutes at 3±2°C. 80 ml of ethyl acetate was charged and stirred for 15 minutes at below 15°C. The layers were separated at below 15°C. The aqueous layer was charged into round bottom flask at below 15°C. 80 ml of ethyl acetate was charged and stirred for 15 minutes at below 15°C. The layers were separated. The aqueous layer was charged into round bottom flask at below 15°C, 400 ml ethyl acetate was charged and maintained below 15°C. pH was adjusted to 8.0±0.2 with saturated sodium bicarbonate solution at below 15°C and stirred for 15 minutes. The layers were settled and separated at below 15°C. The aqueous layer was charged into round bottom flask and maintained at below 15°C. 200 ml of ethyl acetate was charged and stirred for 15 minutes at below 15°C. The layers were settled and separated at below 15°C. Both the organic layers were combined and charged into round bottom flask and maintained below at 15°C. 160 ml of R.O. water was charged and stirred for 15 minutes at below 15°C. The layers were separated. Ethyl acetate layer was charged into round bottom flask at 25±5°C. 8.0 gm activated charcoal was charged and stirred for 30 minutes at 25±5°C. The reaction mass was filtered through hyflow bed and washed with 40 ml of ethyl acetate. The clear filtrate was collected and ethyl acetate was distilled out completely under vacuum at below 35°C and was stripped out with 20 ml of isopropanol at below 35°C. 50 ml isopropanol was added into the reaction mass. The reaction mass was heated to clear solution at 75±5°C. The hot solution was filtered through hyflow bed and washed with 10 ml of hot isopropanol. The filtrate was cooled and stirred for 3 hour at 3±2°C. The solid was filtered and washed with 10 ml chilled isopropanol. The solid was dried under vacuum at 38±2°C for 12 hours.
Dry weight: 16.1 gm
Yield: 54.5%
HPLC purity: 97.73%

Example-IV
3-(2-chIoroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyI-4H-pyrido[l,2-a]-
pyrimidin-4-one
600 ml of methanol and palladium slurry was charged into hydrogenator under nitrogen atmosphere at 25±5°C. 40 gm of 3-(2-chlorotoethyI)-9-benzyloxy-2-methyl-4H-pyrido[l,2-a]-pyrimidin-4-one and 200 ml of methanol was added into hydrogenator. 1.0 kg nitrogen pressure was applied and released. It was repeated twice. 0.5 kg hydrogen pressure was applied to hydrogenate and released which was repeated. 1.8±0.2 kg hydrogen pressure was applied and the reaction mass was slowly heated to 38±2°C and maintained for 10-12 hours. The hydrogen pressure was released slowly. 1.0 kg nitrogen pressure was applied and released thrice. The reaction mass was filtered under nitrogen atmosphere through hyflow bed and washed with 80 ml of methanol. The filtrate was distilled out completely under vacuum at below 35°C. The reaction mass was cooled to 3±2°C. 160 ml of chilled water was added into the reaction mass and stirred for 15 minutes at 3±2°C. 80 ml of ethyl acetate was charged and stirred for 15 minutes at below 15°C. The layers were separated at below 15°C. The aqueous layer was charged into round bottom flask at below 15°C. 80 ml of ethyl acetate was charged and stirred for 15 minutes at below 15°C. The layers were separated. The aqueous layer was charged into round bottom flask at below 15°C. 400 ml ethyl acetate was charged and maintained below 15°C. pH was adjusted to 8.0±0.2 with saturated sodium bicarbonate solution at below 15°C and stirred for 15 minutes. The layers were settled and separated at below 15°C. The aqueous layer was charged into round bottom flask and maintained at below 15°C. 200 ml of ethyl acetate was charged and stirred for 15 minutes at below 15°C. The layers were settled and separated at below 15°C. Both the organic layers were combined and charged into round bottom flask and maintained below at 15°C. 160 ml of R.O. water was charged and stirred for 15 minutes at below 15°C. The layers were separated. Ethyl acetate layer was charged into round bottom flask at 25±5°C. 8.0 gm activated charcoal was charged and stirred for 30 minutes at 25±5°C. The reaction mass was filtered through hyflow bed and washed with 40 ml of ethyl acetate. The clear filtrate was collected and ethyl acetate was distilled out completely under vacuum at below 35°C and was stripped

out with n-hexane at below 35°C. 160 ml of n-hexane was charged into the reaction mass and stirred for 15 minutes. The reaction mass was cooled and stirred for 1 hour at 3±2°C. The solid was filtered and washed with 40 ml of n-hexane. The solid was dried under vacuum at 38±2°C for 12 hours.
Dry weight: 21.6 gm Yield: 72.97% HPLC purity: 96.36%
Example-V
3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yI)-l-piperidiiiyl] ethyl]- 6,7,8,9- tetrahydro-9-
hydroxy-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one [Pali peri do ne]
70 gm 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[ 1,2-a]-pyrimidin-4-one, 79 gm 6-fluoro-3-piperidino-l,2-benzisoxazol hydrochloride, 700 ml of methanol, 83 gm diisopropylethylamine and 4.4 gm potassium iodide were added into a round bottom flask at 25-30°C. The reaction mass was heated upto 64-68°C and maintained for 15-20 hours. The reaction mass was cooled to 25-30°C. 1050 ml of methylene dichloride was charged to the reaction mass and stirred to get the clear solution. 0.29 gm of sodium borohydride was and stirred for 1 hour at 25-30°C. The content of PLP-OXO was measured by HPLC. (Not more than 0.1%). The solvent was distilled out completely under vacuum at below 35°C. 140 ml methanol was charged and distilled out completely under vacuum at below 35°C. 700 ml methanol was charged and stirred for 2 hours at 25-30°C. The solid was filtered and washed with 70 ml of methanol. The solid was dried at 35-40°C under vacuum.
Yield: 85-90% HPLC purity: 98.80%

Exam pie-VI
Purification of Paliperidone
108 gm of paliperidone and 1080 ml of RO water were added into round bottom flask and cooled to 10-15°C. 110 ml 20% aqueous acetic acid solution was slowly added and stirred to get clear solution. The aqueous layer was washed with cyclohexane and the layers were separated. The aqueous layer was washed with ethyl acetate and the layers were separated. 11 gm of activated carbon was added and stirred for 30 minutes at 5-10°C. The reaction mass was filtered through hyflow bed and washed with water. 1250 ml of isopropanol was added to the clear filtrate into round bottom flask and cooled to 5-I0°C. 47 ml liquid ammonia solution was added at 5-10°C and pH was adjusted between 7.5-8.5. The reaction mixture was stirred for 2 hours at 5-10°C. The solid was filtered and wash with isopropanol. The solid was dried under vacuum at 35-40°C till water content was below 1.0%.
Yield: 80-85% HPLC Purity: 99.7%
Dated this 12th day of January, 2009