FORM 2 THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(SECTION 10)
IMPROVED PROCESS FOR THE PREPARATION OF AN INTERMEDIATE OF PALIPERIDONE
UNICHEM LABORATORIES LIMITED,
A COMPANY REGISTERED UNDER THE INDIAN COMPANY
ACT, 1956, HAVING ITS REGISTERED OFFICE LOCATED AT
UNICHEM BHAVAN, PRABHAT ESTATE, OFF S. V. ROAD,
JOGESHWARI (WEST), MUMBAI - 400 102,
MAHARASTRA, INDIA
The following specification particularly describes the invention and the manner in which it is to be performed.
IMPROVED PROCESS FOR THE PREPARATION OF AN INTERMEDIATE OF PALIPERIDONE

TECHNICAL FIELD
The present invention describes an improved and economic process for the synthesis of 3-(2-chloroethyl)-2-methyi-9-hydroxy-4H-pyrido[l ,2-a]pyrimidine-4-one, an intermediate used in the synthesis of Paliperidone and also the process for the synthesis of pure Paliperidone.
BACKGROUND OF THE INVENTION
Paliperidone, chemically known as 3-[2-[4-(6-fIuoro-l,2-benzisoxazole-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l:2-a]pyrimidine-4-one. It is 9-hydroxy risperidone, a metabolite of risperidone. It is antipsychotic agent and belongs to the chemical class of benzisoxazole derivatives used in the treatment of psychotic disorders mainly schizophrenia and is marketed in United States under the brand name INVEGA.
Paliperidone (I) is first reported in US Patent No 5,158,952 (equivalent patent EP 0368 388). The synthetic scheme described in the patent is described as follows.


In the process described 2-amino-3-benzyloxy pyridine is condensed with 2-acetyl gamma butyrolactone to give 3-(2-chloroethyl)-2-methyl-9-(phenylmethoxy)-4H-pyrido[l,2-a]pyrimidine-4-one, an intermediate, which on hydrogenation gives 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-4H-pyrido[l,2-a]pyrimidine-4-one. Subsequently, this intermediate is reacted with 6-fluro-3-(4-piperidinyl)-l, 2-benzisoxazole monohydrochloride (FBIP) in presence of base, diisopropyl amine in methanol to yield crude Paliperidone (1).
The crude Paliperidone was purified by column chromatography first and later crystallisation in acetone followed by recrystallisation in 2-propanol to achieve Paliperidone. Further in this synthetic process, the intermediate obtained was impure, oily mass which required column chromatography to purify it. During hydrogenation process, lots of unwanted impurities were generated which were carried forward till the final stage. Use of column chromatography and repeated crystallizations made this process time consuming and expensive resulting in poor yields.
US2008/0171875A1 (Ini, Santiago, et al, 2008) describes process for the synthesis of Paliperidone. According to this process, Paliperidone was synthesized by the reaction of 3-(2-chloroethyl)-6, 7, 8, 9-tetrahydro-2-methyl-9-hydroxy-4H-pyrido [1, 2-a]

pyrimidine-4-one (CMHTP) with 6-fluoro-3-piperidino-l,2-benzisoxazol (FBIP) or its salt in presence of inorganic base. The said process does not describe the synthesis of key intermediate, CMHTP.
US 2008/0200676A1 (Dolitzky, et al., 2008) also describe a process for the synthesis of 3-(2-chloroethyl)-6, 7, 8, 9-tetrahydro-2-methyl-9-hydroxy-4H-pyrido [1, 2-a] pyrimidine-4-one (CMHTP) in which first 3-benzyloxy-2-aminopyridine was reacted with 3-acetyi-4,5-dihydro-3H-2-furanone by using water absorbents such as para-toluene sulphonic acid, sulphuric acid in one or more aromatic solvents such as xylene or toluene. The product thus obtained was isolated, crystallized and it was further treated with excess phosphorous oxychloride to get the 3-(2-chloroethyl)-2-methyl-9-(benzyloxy)-4H-pyrido [1, 2-a] pyrimidine-4-one. The reduction of this intermediate was done by using Pd/C in methanol and aqueous HC1. This process involved the isolation and crystallization of intermediate by which the throughput is decreased and the operations increased.
WO 2009/010988A1 (Ravi, et al., 2009) also describe process in which the condensation of 3-(phenylmethoxy)-2-aminopyridine and 3-acetyl-4,5-dihydro-3H-2-furanone was done in cyclohexane in presence of sulphuric acid to obtain 3-(2-hydroxyethyl)-2-methyl-9-(phenylmethoxy)-4H-pyrido[l,2-a]pyrimidine-4-one,which was further treated with phosphorous oxy chloride to obtain 3 -(2-chloroethyl)-2-methyl-9-(phenylmethoxy)-4H-pyrido[ 1,2-a]pyrimidine-4-one.The chloro derivative thus obtained was debenzylated by using aqueous hydrochloric acid and finally hydrogenated over Pd/C to get CMHTP. The process described involves the isolation of intermediate stage and for debenzylation, acidic conditions at elevated temperature is utilized by which during reaction degradation occurs and the product obtained requires purification steps.
WO 2009/045489A2 (Ini, Santiago, et al., 2009) describe a process for the synthesis of CMHTP in which 3-(2-chIoroethyl)-2-methyl-9-hydroxy-4H-pyrido[l,2-a]pyrimidine-4-one or 3-(2-chloroethyl)-2-methyl-9-benzyloxy-4H-pyrido[] ,2-a]pyrimidine-4-one was hydrogenated by utilizing chemical compound as hydrogen source, wherein the hydrogen source is selected from cyclohexene, cyclohexadiene or ammonium formate mixed with formic acid and a hydrogenation catalyst. The process

described is not advantageous since some of the hydrogenation catalysts disclosed is very expensive.
In view of above prior art facts, there is a need and scope for improved, more economical and efficient synthetic process for Paliperidone and its intermediate with better yield and quality.
OBJECT OF THE INVENTION
The main object of the present invention is to provide an improved and economical process which provides high yield and purity of Paliperidone.
Another object of the present invention is to provide an efficient and industrially scalable and advantageous process for the preparation of pure paliperidone intermediates.
Yet another object of the present invention is to provide an eco friendly process for the preparation of paliperidone and its intermediates.
SUMMARY OF THE INVENTION
The present invention provides an improved process for the preparation of 3-(2-chloroethyl)-6, 7, 8, 9-tetrahydro-2-methyl-9-hydroxy-4H-pyrido [1, 2-a] pyrimidine-4-one (CMHTP) of formula (VI)

Which comprises
a. condensation of 2-amino-3-benzyloxy pyridine of formula (II) with 2-acetyl gamma butyrolactone of formula (III) in presence of dehydrating agent and a solvent and subsequent in situ chlorination gives 3-(2-chloroethyl)-2- methyl -9-(phenylmethoxy)-4H-pyrido[l,2-a]pyrimidine-4-one of formula (IV);

b. debenzylation of 3-(2-chloroethyl)-2-methyl-9-(phenylmetrioxy)-4H-pyrido|; 1 ,2-a]pyrimidine-4-one of formula (IV) in presence of hydrogen pressure with a catalyst in a polar solvent and subsequent in-situ treatment with acid gives the corresponding acid addition salt e.g. 3-(2-chloroethyl)-2-methyl-9-(hydroxy)-4H-pyrido[l?2-a]pyrimidine-4-one hydrochloride of formula (V);

c. reduction of 3-(2-chloroethyl)-2-methyl-9-(hydroxy)-4H-pyridoLl,2-a]pynmidine-4-one hydrochloride of formula (V) under hydrogen pressure with catalyst in presence of polar solvent gives 3-(2-chloroethyI)-6, 7, 8, 9-tetrahydro-2-methyl-9-hydroxy-4H-pyrido [1, 2-a] pyrimidine-4-one (CMHTP) of formula (VI).
Further the present invention also, relates to an improved process the preparation of Paliperidone of formula (I) which comprises

a. N-alkylation of CMHTP of formula (VI)
with FBIP HC1 of formula (VII)

in presence of base and an activator in a solvent to obtain Paliperidone. b. crystallization of Paliperidone from a solvent to obtain pure Paliperidone.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for the preparation of 3-(2-chloroethyl)-6, 7, 8, 9-tetrahydro-2-methyl-9-hydroxy-4H-pyrido [1, 2-a] pyrimidine-4-one (CMHTP), an intermediate used for the preparation of paliperidone.
The present invention also relates to an improved and economical process which involve in-situ operation for the synthesis of Paliperidone (represented in Scheme-II) with high yield and purity. Also, the present invention is to eliminate the use of

column chromatography and multiple crystallization processes to get the final product.
The process for preparation of 3-(2-chloroethyl)-6,1, 8, 9-tetrahydro-2-methyl-9-hydroxy-4H-pyrido [1, 2-a] pyrimidine-4-one (CMHTP), comprises condensation of 2-amino-3-benzyloxy pyridine of formula (II) with 2-aceryl gamma butyrolactone of formula (III) in presence of dehydrating agent and solvent under azeotropic conditions.
The completion of the reaction is monitored by checking the presence of 2-amino-3-benzyloxy pyridine by HPLC. The solvent is removed and in situ a chlorination agent is added to the reaction mass. After chlorination, the reaction mass is poured into a mixture of ice and water and pH is adjusted to neutral. The product is extracted with methylene chloride, methylene chloride is distilled off and isopropyl alcohol is added to the residue. The reaction mixture is heated to get a clear solution and cooled. The precipitated product is filtered and washed with isopropyl alcohol to get pure 3-(2-chloroethyl)-2-methyl-9-(pheny!methoxy)-4H-pyrido[l,2-a]pyrimidine-4-one. The dehydrating agents used in the condensation step are selected from boric acid, cyanuric chloride or Eaton's reagent, preferably Eaton's reagent. The solvent used is selected from hydrocarbon solvents like toluene, xylene, cyclohexane, methylene chloride, monochlorobenzene and like. The chlorinating agents used are selected from phosphorous oxychloride, phosphorous trichloride, phosphorous pentachloride, thionyl chloride or mixture thereof, preferably phosphorus oxychloride. The condensation reaction is done starting from room temperature to reflux temperature of the solvent used, preferably at reflux temperature. The water formed in the reaction can be removed azeotropically. The dehydrating agents used are in the range of 0.2 to 0.5 molar equivalent, preferably 0.2 molar equivalent.
The debenzylation reaction was carried out under hydrogen pressure in presence of a catalyst. The catalysts used are selected from Raney nickel, Pd/C, Pt/C and like, preferably Pd/C. The solvents used for debenzylation are polar solvents selected from methanol, ethanol, isopropyl alcohol, or mixture thereof, preferably methanol. After the debenzylation is over, the catalyst is filtered off and the solvent is removed by distillation, acid was added to the residue to make the acid addition salt. The acids which can be used are hydrochloric acid or hydrobromic acid, sulphuric acid in water or in organic solvent preferably aqueous hydrochloric acid is added to the residue

obtained and stirred. The salt obtained is filtered and washed to give 3-(2-chloroethyl)-2-methyl-9-(hydroxy)-4H-pyrido [1, 2-a] pyrimidine-4-one hydrochloride.
Further, in an embodiment of the present invention, 3-(2-chloroethy])-2-methyl-9-(hydroxy)-4H-pyrido[l,2-a]pyrimidine-4-one hydrochloride is hydrogenated over Pd/C catalyst in presence of hydrogen pressure to get the 3-(2-chloroethyl)-6, 7, 8, 9-tetrahydro-2-methyl-9-hydroxy-4H-pyrido [1, 2-a] pyrimidine-4-one (CMHTP), • The amount of catalyst used is 10% palladium charcoal in the range of 20-30% (w/w), preferably 22% (w/w) and hydrogen pressure is in the range 0.1 kg to 1.0 kg, preferably 0.1 kg to 0.2 kg. The polar solvent for this step is selected from methanol, ethanol, preferably methanol.
In another embodiment of the present invention, paliperidone of formula 1 is synthesized by condensation of CMHTP of (formula VI) with FBIP monohydrochloride of (formula VII) to give crude Paliperidone. The reaction is carried out in a solvent in presence of a base and an activator. The solvents used are selected from acetone, acetonitrile, dimethylformamide and aliphatic alcohols such as methanol, ethanol, isopropanol, preferably methanol. The base used is selected from a group of alkali metal carbonates such as sodium carbonates, potassium carbonate, cesium carbonate preferably cesium carbonate. The activator used is selected from Cul or mixture of cesium iodide and Cul. The amount of this activator is in the range of 2-10% w/w preferably 5%. This reaction is carried out at 25-30oC to reflux temperature of the solvent.
Yet another embodiment of the present invention, paliperidone obtained in the process is crystallized to obtain pure Paliperidone. The pure Paliperidone obtained after crystallization meets the criteria of ICH quality material, where any individual impurity is less than 0.10%. The solvent which is used for crystallization is aqueous tetrahydroftiran. If the desired purity is not achieved then crystallization is repeated till the desired purity is achieved. The present invention is illustrated as given in the below scheme, Scheme-II:


Having described the invention with reference to certain preferred embodiments, the other embodiments will become apparent to one skilled in the art from consideration of the specification.
Examples:
The following examples are presented for illustration only and are not intended to limit the scope of the invention or appended claims.

Example 1:
3-(2-chloroethyl)-2-methyl-9-(phenylmethoxy)-4H-pyrido[l,2-a]pyrimidine-4-one (1st method):
50 gm of 2-amino 3-benzyloxy pyridine (formula II) (0.249 mole) and 750 ml of toluene was charged into clean and dry reaction assembly at 25-30 °C, stirred for 10-15 min to dissolve it completely. 33.7 gm of 2-acetyl gamma butyrolactone (formula III) (0.262 mole) was charged and stirred for 5 min and 1.75 gm of cyanuric chloride was added. The reaction mass was stirred at refiuxing temperature and water was removed azeotropically by using Dean-Stark apparatus. After 15.0 hrs of refiuxing, another lot, 10.92 gm of 2-acetyl gamma butyrolactone and 0.75 gm of cyanuric chloride was added to the reaction mass and refluxed for another 15.0 hrs. The progress of the reaction was monitored by HPLC. After completion of the reaction, toluene was evaporated completely from the reaction mass to get an oily residue. 112.5 ml of POCl3 (1.207 mole) was charged into the reaction assembly at 25-30 °C, the reaction mass heated to 75-80 °C for 4 hours. After completion of the reaction which was monitored by HPLC, the reaction mass was cooled to 15-20 °C and quenched by slowly pouring over ice-water mixture, high exotherm observed. 250 ml of Methylene dichloride was added to the reaction mass, neutralized with 450 ml of 25% aq ammonia solution and separated the layers. The, water layer was again extracted with 250 ml Methylene dichloride. The combined Methylene dichloride layer was washed with water and evaporated to get residue. 100 ml of 2-propanol was added to the residue, the product precipitated out filtered and crystallised from 2-propanol to get 48.0 gm of the product with purity by HPLC (99.7%)
Example 2:
3-(2-chloroethyl)-2-methyl-9-(phenylmethoxy)-4H-pyrido [1, 2-a] pyrimidine-4-
one (2nd method)
50 gm of 2~amino 3-benzyloxy pyridine (formula II) (0.249 mole) and 750 ml of toluene was charged into clean and dry reaction assembly at 25-30 °C, stirred for 10-15 min to dissolve it completely. 33.7 gm of 2-acetyl gamma butyrolactone (formula III) (0.262 mole) was charged to the reaction mass, stirred for 5 min and 2.5 gm of

Eaton reagent is added. The reaction mass stirred at refluxing temperature and water was removed azeotropically using Dean-Stark apparatus. The progress of the reaction was monitored by HPLC, after completion of the reaction, toluene was evaporated completely from the reaction mass to get an oily residue, 112.5 ml of POCl3 (1.207 mole) was charged into the reaction assembly at 25-30 °C and the reaction mass heated to75-80 °C for 4 hours. After completion of reaction which was monitored by HPLC, reaction mass was cooled to 15-20 °C and quenched by slowly pouring over ice-water mixture, high exotherm observed, 250 ml of methylene chloride was added to the reaction mass, neutralized with 530 ml of 25% aq ammonia solution and the layers are separated. The water layer was again extracted with 250 ml Methylene chloride. The combined Methylene chloride layer was washed with water and evaporated to get residue. 100 ml of 2-propanol was added to the residue, the product precipitated out was filtered and crystallised from 2-propanol to get 40.0 gm of the product.
Example 3:
3-(2-chloroethyl)-2-methyl-9-(pheny]methoxy)-4H-pyrido[l,2-a]pyrimidine-4-one (3rd method)
50 gm of 2-amino 3-benzyloxy pyridine (formula II) (0.249 mole) and 750 ml of toluene was charged into clean and dry reaction assembly at 25-30 °C, stirred for 10-15 min to dissolve it completely. 33.7 gm of 2-acetyl gamma butyrolactone (formula III) (0.262 mole) was charged, stirred for 5 min and 2.5 gm of boric acid was added. The reaction mass was stirred at refluxing temperature and water removed azeotropically using Dean-Stark apparatus. After 15.0 hrs of refluxing, another lot, 10.92 gm of 2-acetyl gamma butyrolactone was added to the reaction and continued refluxing for another 15.0 hrs. The progress of the reaction was monitored by HPLC. After completion of the reaction, toluene was evaporated completely from the reaction mass to get an oily residue. 112.5 ml of POCI3 (1.207 mole) was charged into the reaction assembly at 25-30 °C and the reaction mass is heated to75-80 °C for 4 hours. After completion of the reaction monitored by HPLC, the reaction mass was cooled to 15-20 °C and quenched by slowly pouring over ice-water mixture, 250 ml of methylene chloride was added and reaction mass was neutralized with 450 ml of 25% aq ammonia solution and the layers were separated. The water layer was again

extracted with 250 ml of Methylene chloride. The combined methylene chloride layer washed with water and evaporated to get a residue. 100 ml of 2-propanol was added, the product precipitated out, was filtered and crystallised from 2-propanol to get 37.0 gm of the product.
Example 4:
3-(2-chloroethyl)-2-methyl-9-(hydroxy)-4H-pyrido[l,2-a]pyrimidine-4-one hydrochloride
60 gm of 3-(2-chloroethyl)-2-methyl9-(phenylmethoxy)-4H-pyrido[l ,2-a]pyrimidine-4-one (0.183 mole), 750 ml of methanol and 3 gm 5% palladium charcoal catalyst were charged in an autoclave reactor, the reaction mass was stirred at 60-65 °C under 3-4 kg constant hydrogen pressure for 4.0 hours. After completion of the reaction which was monitored on TLC (ethyl acetate: methanol (9.9: 0.1), the reaction mass was filtered through celite bed and washed with 120 ml of methanol. Methanol was distilled till approx 135 ml left in the reaction assembly. 34.5 ml of aqueous hydrochloric acid was added slowly drop wise at 25-30 °C to the reaction mass and stirred for 5 hours at 25-30 °C. It was cooled at 5-10 °C, filtered, washed the product with chilled methanol, suck dried and dried in an air oven at 100-105 °C for 6 hours to get 37.0 gm of the product with HPLC purity of 97.9%.
Example 5:
3-(2-chlo roethy l)-6,7,8,9-tetra hy d ro-9- hyd roxy-4H-py r ido [1,2-a] py ri m idine-4-one: (CMHTP)
40 gm of 3-(2-chloroethyl)-2-methyl-9-(hydroxy)-4H-pyrido[l,2-a]pyrimidine-4-one hydrochloride ( 0.145 mole), 400 ml of methanol and 8.8 gm of palladium charcoal (10%) were charged into an autoclave reactor at 25-30 °C and stirred the reaction mass at 40-45 °C by maintaining 0.1-0.2 kg hydrogen pressure for 3-4 hours. After completion of the reaction which was monitored by HPLC, the reaction mass was

cooled to 25-30 °C, 0.6 gm of thiophene was added to it and stirred for 15-20 minutes. The reaction mass was filtered through hyflo bed and washed with methanol. Methanol was evaporated completely from the filtrate and washed to get a thick oily mass. 140 ml water was added to this oil with stirring, the reaction mass neutralized with the addition of aqueous potassium acetate solution, cooled to 0-5 °C and stirred for 2 hours at 0-5 °C. CMHTP precipitated out in the reaction mass, filtered, washed with 80 ml water and dried in an air oven at 60-65° C. Wt of the crude CMHTP obtained was 22 gm. It is crystallised from ethyl acetate to get 13.0 gm of pure CMHTP having purity 99.5% by HPLC.
Example 6:
3-[2-[4-(6-fluoro-l,2-benzisoxazole-3-yl)-l-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l,2-a]pyrimidine-4-one (Paliperidone):
25 gm of FBIP (0.097mole) (formula VII), 27.15 gm CMHTP (formula VI) (0.112 mole) and 150 ml of methanol were charged into a clean and dry reaction assembly under nitrogen atmosphere at 25-30 °C, stirred for 15 minutes and charged 34.1gm of sodium carbonate (0.321 mole), 1.25 gm of copper iodide and stirred at 50-55 °C for 45-50 hrs under nitrogen atmosphere. The reaction was monitored by HPLC. After completion of the reaction, the reaction mass cooled to 25-30 °C, filtered and the crude Paliperidone washed with 50 ml of methanol, 150 ml of water and dried in an air oven at 100 °C for 6 hours to get 35 gm product having Purity by HPLC 98.5 %.
Example 7:
Crystallisation of Paliperidone:
25 gm of crude Paliperidone and 563 ml of aqueous THF (1:1) wass charged into clean dry assembly at 25-30 °C. The reaction mass was refluxed and stirred for 20-25 minutes at reflux temperature to dissolve the crude Paliperidone completely. It was gradually cooled from reflux temperature to 25-30 °C first, then 5-10 °C and stirred for 30-40 min. Paliperidone crystallized out, filtered, washed with 50 ml of THF, unloaded and dried in an air oven at 100-105 °C for 6-8 hours to get 21.0 gm of pure Paliperidone, purity 99.45% by HPLC.

We claim:
1. An improved process for the preparation of 3-(2-chloroethyl)-6, 7, 8, 9-tetrahydro-2-methyl-9-hydroxy-4H-pyrido [1, 2-a] pyrimidine-4-one (CMHTP) of formula (VI)

which comprises
a. condensation of 2-amino-3-benzyloxy pyridine of formula (II) with 2-acetyl gamma butyrolactone of formula (III) in presence of dehydrating agent and a solvent and subsequent in situ chlorination gives 3-(2~chloroethyl)-2- methyl -9-(phenylmethoxy)-4H-pyrido[l,2-a]pyrimidine-4-one of formula (IV);

b. debenzylation of 3-(2-chloroethyl)-2-methyl-9-(phenyImethoxy)-4H-pyrido[l ,2-a]pyrimidine-4-one of formula (IV) in presence of hydrogen pressure with a catalyst in a polar solvent and subsequent in-situ treatment with acid gives the corresponding acid addition salt e.g. 3-(2-chloroethyl)-2-methyl-9-(hydroxy)-4H-pyrido[l,2-a]pyrimidine-4-one hydrochloride of formula (V);

c. reduction of 3-(2-chloroethyl)-2-methyl-9-(hydroxy)-4H-pyrido[l,2-a]pyrimidine-4-one hydrochloride of formula (V) under hydrogen pressure with catalyst in presence

of polar solvent gives 3-(2-chloroethyl)-6, 7, 8, 9-tetrahydro-2-methyl-9-hydroxy-4H-pyrido [1, 2-a] pyrimidine-4-one (CMHTP) of formula (VI).
2 An improved process of claim la, wherein the dehydrating agent selected from
boric acid, cyanuric chloride or Eaton's reagent, preferably Eaton;s reagent.
3 An improved process of claim la, wherein solvent is selected from hydrocarbons like toluene, xylene, monochlorobenzene, methylene chloride, cyclohexane, preferably toluene or mixture thereof.
4 An improved process of claim la, wherein chlorinating agents are selected from such as POCI3 PCI3, PCI5 or thionyl chloride, or mixtures thereof, preferably POCI3.
5 An improved process according to claim la, wherein the reaction temperature is room temperature to reflux temperature, preferably at reflux temperature of the solvent.
6 An improved process of claim lb, wherein debenzylation is done under hydrogen pressure in presence of Pd/C, Pt/C, Raney Ni catalyst preferably Pd/C.
7 An improved process of claim lb, wherein the debenzylation reaction is done in methanol, ethanol, isopropanol or mixture thereof, preferably methanol.
8 An improved process of claim lb, wherein the acids used for in-situ salt formation are hydrochloric acid, hydrobromic acid, sulphuric acid in water or organic solvent preferably aqueous hydrochloric acid.
9 An improved process of claim lc, wherein catalyst is 10% palladium charcoal in the range of 20-30% (w/w), preferably 22% (w/w).
10 An improved process of claim lc, wherein hydrogen pressure is in the range 0.1 kg to 1.0 kg, preferably 0.1 kg to 0.2 kg.
11 An improved process of claim lc, wherein the polar solvent is selected from methanol, ethanol, preferably methanol.
12 An improved process of claim 1, wherein the preparation of Paliperidone of formula (I) comprises

b. N-alkylation of CMHTP of formula (VI)

with FB1P HC1 of formula (VII)

in presence of base and an activator in a solvent to obtain Paliperidone. b. crystallization of Paliperidone from a solvent to obtain pure Paliperidone.
13 An improved process of claim 12a, wherein the base selected from sodium carbonate, potassium carbonate, cesium carbonate, preferably cesium carbonate.
14 An improved process of claim 12a, wherein the solvent selected from acetone, acetonitrile, dimethylformamide and alcohols like methanol, ethanol, isopropanol, preferably methanol.

15 An improved process of claim 12a, wherein activator is selected from copper iodide or mixture of cesium iodide and Cul, and used is in the range of 2-10 % w/w preferably 5%.
16 An improved process of claim 12a, wherein the reaction temperature is 25-30 °C to reflux temperature of the solvent.
17 An improved process of claim 12b, wherein the solvent for crystallization of Paliperidone is aqueous tetrahydrofuran.
18 A process according to claim 12, wherein pure paliperidone has any individual impurity less than 0.1% by HPLC.
19 An improved process according to any of the preceding claims substantially as herein described with reference to the examples.