WO2010082111A1

WO2010082111A1 - Preparation of 3-(2-hydroxy ethyl)-9-hydroxy-2-methyl-4h-pyrido-[1,2-a]-pyrimidin-4-one or its acid addition salt

Info

Publication number: WO2010082111A1
Application number: PCT/IB2010/000042
Authority: WO
Inventors: Keval Rameshchandra Sodagar; Vineet Malik; Bharat Ramchandra Desai; Sudhir Hukamchand Jain; Sanjay Natvarlal Parikh; Arun Omprakash Sharma; Uday Rajaram Bapat; Bakulesh Mafatlal Khamar
Original assignee: Cadila Pharmaceuticals Ltd.
Priority date: 2009-01-13
Filing date: 2010-01-12
Publication date: 2010-07-22

Abstract

The invention relates to an improved process for preparation of 3-(2-hydroxy ethyl)-9- hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one or its acid addition salt and its conversion to paliperidone or its acid addition salt without involving the use of an acid catalyst.

Description

PREPARATION OF 3-(2-HYDROXY ETHYL)-9-HYDROXY-2-METHYL-4H- PYRIDO-[1 ,2-a]-PYRIMIDIN-4-ONE OR ITS ACID ADDITION SALT

FIELD OF THE INVENTION The invention relates to an improved process for preparation of 9-hydroxy-3-(2- hydroxy ethyl)-2-methyl-4/-/-pyrido-[1 ,2-a]-pyrimidin-4-one or its acid addition salt and its conversion to paliperidone or its acid addition salt without involving the use of an acid catalyst.

BACKGROUND OF THE INVENTION

Paliperidone, chemically known as 3-[2-[4-(6-fluoro-1 ,2-benzisoxazol-3-yl)-piperidin-1- ylJ-ethyll-θ-hydroxy^-methyl-δJ.S.Θ-tetrahydro^H-pyrido-ti^-aJ-pyrimidin-^one is a benz- isoxazole derivative having the structural formula 1.

Paliperidone is also known as 9-hydroxy risperidone and useful for the treatment of schizophrenia. 9-hydroxy risperidone is a metabolite of risperidon.

US Patent No. 4,804,663 and 5,158,952 describes a variety of processes for the preparation of 3-piperidinyl-1 ,2-benzisoxazole derivatives along with their pharmaceutical compositions and methods of use. The processes for synthesizing paliperidone and related compounds are disclosed in U.S. Patent No. 5,158,952; 5,254,556 and 5,688,799.

9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[1 ,2-a]-pyrimidin-4-one is a key intermediate useful for preparation of paliperidone. The said pyrimidin-4-one compound is commonly prepared by using 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido-[1 ,2-a]- pyrimidin-4-one. i U.S. Patent Nos. 5,158,952 (hereinafter referred to as the '952 patent) and 5,254,556

(hereinafter referred to as the '556 patent) discloses the process for preparing of said pyrimidin-4-one compound by reacting an optionally protected corresponding 2- aminopyridine compound with 3-acetyldihydro-2(3H)-furanone in presence of activating agent, followed by treatment with ammonium hydroxide. The activating reagent includes halogenating reagent such as, phosphoryl chloride, phosphoryl bromide, phosphorous trichloride, thjonyl chloride and phosphoryl chloride is preferred for given reaction. The reaction mass is extracted with trichloromethane and then subjected to chromatographic purifications. The chromatographic putification process is not commercially viable.

9-hydroxy-3-(2-chloroethyl).-2-methyl-4H-pyrido[1 ,2-a]pyrimidin-4-one is prepared by the process as described in the '952 and the '556 patents. The processes are resulting in less purity containing product with significant impurities which are formed by the reaction of corresponding 2-aminopyridine with 3-acetyldihydro-2(3H)-furanone.

US Patent no. 5,688,799 (Example 1) describes preparation of 9-hydroxy-3-(2- hydroxy-ethyl)-2-methyl-4H-pyrido -[1 ,2-a]pyrimidin-4-one monohydrochloride comprising reaction of 2-amino-3-pyridinol,3-acetyIdihydro-2(3H)-furanone, 4-methylbenzenesulfonic acid in xylene at reflux temperature and involving the use of water separator overnight to provide the titled compound with 58.4 % yield. The use of xylene as a solvent requires high temperature and it is time consuming process.

The synthetic route for 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido[1 ,2- a]pyrimidin-4-one as described in the 799 patent involves multiple stages process. The end product is having low yield and purity. Moreover, the intermediate compound 9-hydroxy-3-(2- hydroxyethyl)-2-methyl- 4H-pyrido[1 ,2-a]pyrimidin-4-one is poorly soluble in xylene.

US Patent No. 5,919,788 (Example 5) discloses the preparation of 9-hydroxy-3-(2- hydroxy-ethyl)-2-methyl-4H-pyrido[1 ,2-a]pyrimidin-4-one monohydrochloride wherein 2- amino-3-pyridinol,3-acetyldihydro-2-(3H)-furanone, 4-methylbenzenesulfonic acid and xylene was stirred and refluxed overnight using a water separator. The mixture was cooled and the product was filtered off and dried. The product was converted to the hydrochloride acid salt using 2-propanol. The salt was filtered off and dried to yield 58.4 % of 9-hydroxy-3- (2-hydroxy-ethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one monohydrochloride.

WO2006/027370 discloses the preparation of 9-hydroxy-3-(2-hydroxyethyl)-2-methyi- 4H-pyrido-[1 ,2-a]pyrimidin-4-one by the reaction of 2-amino-3-hydroxypyridine in chlorobenzene with 2-Acetylbutyro lactone at room temperature followed by reaction with 7- toluenesulfonic acid monohydrate. 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido-[1 ,2-a]- pyrimidin-4-one is obtained with >97% purity and unreacted 2-amino-3-hydroxypyridine and 2-acetylbutyrolactone along with sum of other residual impurities. All the prior art processes describe the preparation of 3-(2-hydroxy ethyl)-9-hydroxy-

2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one or its acid addition salt that involve the use of solvents such as chlorobenzene or xylene and acid catalyst along with azeotropic water removal, produced during the reaction. The reaction mixture is treated with charcoal and filtered hot to remove the sticky black mass and the filtrate is allowed to cool resulting in the product in yield of less than 65 %. Therefore, there is a need in the art to provide an improved and commercially viable process to obtain 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido-[1 ,2-a3-pyrimidin-4-one or an acid addition salt with high yield and less environmental drawbacks.

We have surprisingly found that 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H- pyrido [1 ,2- a]pyrimidin-4-one (Formula - 5) or an acid addition salt can be prepared in high yields by reaction of 2-amino-3-pyridinol (Formula - 2) with 3-acetyldihydro-2(3H)-furanone (Formula - 3) without involving the use of an acid catalyst.

SUMMARY OF THE INVENTION The object of present invention is to provide an improved process for the preparation of 9-hydroxy-3-(2-hydroxy-ethyl)-2-methyl-4H-pyrido[1 ,2-a]pyrimidin-4-one or its acid addition salt without involving the use of an acid catalyst.

Another object of present invention is to provide an improved process for the , preparation of 9-benzyloxy-3-(2-hydroxy-ethyl)-2-methyl-4H-pyrido[1 ,2-a]pyrimidin-4-one compound.

Yet another object of the invention is to provide 9-hydroxy-3-(2-hydroxy-ethyl)-2- methyl-4H-pyrido[1 ,2-a]pyrimidin-4-one or its acid addition salt in >70% yield.

Yet another object of the invention is to provide 9-hydroxy-3-(2-hydroxy-ethyl)-2- methyl-4H-pyrido[1 ,2-a]pyrimidin-4-one or its acid addition salt in >98% purity. Yet another object of invention is to give paliperidone using process for the preparation of 9-hydroxy-3-(2-hydroxy-ethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one or its acid addition salt without involving the use of an acid catalyst.

DETAILED DESCRIPTION OF THE INVENTION The present invention discloses a process for preparing 9-hydroxy-3-(2- hydroxyethyl)-2-methyl-4H-pyrido[1 ,2-a]pyrimidin-4-one (Formula - 4) or its acid addition salt without involving the use of an acid catalyst. The title compound of formula 4 is obtained by condensation of 2-amino-3-pyridinol of formula - 2 with 3-acetyldihydro-2(3H)-furanone of formula - 3 in an inert solvent. The inert solvent is selected from n-butanol; chlorobenzene; mixture of n-butanol and toluene; mixture of o-dichlorobenzene and toluene; and like. The acid salt of product is isolated by addition of 2-propanollic HCI to hot reaction mixture and allow the mass to cool.

9-hydroxy-3-(2-hydroxy ethyl)-2-methyl-4H-pyrido[1 ,2-a]pyrimidin-4-one or its acid addition salt is further converted to 3-(2-ch!oroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro- 4H-pyrido[1 ,2-a]pyrimidin-4-one of formula - 6 or its acid addition . salt followed by catalytic reduction in presence of aq. Acetic acid. Thus obtain compound is further condensed with 2- benzisoxazole hydrochloride of formula 7 to give paliperidone. The present invention also provide process for the preparation of 9-benzyloxy-3-(2- hydroxy-ethyl)-2-methyI-4H-pyrido[1 ,2-a]pyrimidin-4-one compound without involving the use of an acid catalyst. The title compound of formula 4 is obtained by process as disclosed above. The benzyloxy compound of formula 4 is then converted to 3~(2-chloroethyl)-9- benzyloxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one of formula - 6a or its acid addition salt. The benzyloxy compound of formula 6a is deprotected by the known process in art to give compound of formula 6. The compound of formula 6 is further converted to paliperidone.

The processes are further depicted in scheme 1 and 2. Scheme 1

Formula 4 R = H or -CH₂C_βH₅ R = H Or-CH₂C₆H₅

In step-(1), the inert solvent used for the preparation of 9-hydroxy-3-(2-hydroxy ethyl)- 2-methyl-4H-pyrido[1 ,2-a]pyrimidin-4-one or its acid addition salt is selected from hydrocarbon solvents such as benzene, toluene, xylene, n-Butanol, chlorobenzene, decalin, orthodichlorobenzene, ethyl benzene, mesitylene, cyclohexane, methylcyclohexane, nitrobenzene, or any inert solvent or any combination of solvents mentioned herein above and like. The reaction is carried out at temperature ranging from 5O⁰C to 200⁰C. The reaction is providing an acid addition salt of 3-(2-hydroxy ethyl)-9-hydroxy-2-methyl-4H-pyrido[1,2- a]pyrimidin-4-one in over 70% yield with >98% purity. The substantially similar or more yield and purity is obtained for 9-benzyloxy 3-(2-hydroxyethyl)-2-methyl-4/-/-pyrido[1 ,2-a]pyrimidin- 4-one. The word "substantially" is defined as to give yield about 70% and purity about 98% or more.

In step (2), chlorinating agents are selected from thionyl chloride, sulfuryl chloride, oxalyl chloride, phosphorus trichloride, phosphorus oxychloride and cyanuril chloride. The solvent for the reaction is selected from halogenated solvents such as chloroform, dichloromethane, ethylene dichloride, aromatic hydrocarbon solvents such as benzene, toluene, xylene; aprotic polar solvents such as , N₁N dimethyl formamide, N₁N dimethyl acetamide, N-methyl 2-pyrrolidone, 1 ,3-dimethyl imidazolidin-2-one, 1 ,3 dimethyl propylene urea, tetramethyl urea; sulfolane; alicyclic hydrocarbons such as cyclohexane, methyl cyclohexane.

In step (3), the hydrogenation catalyst used for hydrogenation is selected from raney nickel or metal catalyst such as palladium, rhodium, ruthenium, platinum, iridium, palladium on charcoal. The solvent used in step (3) is selected from formic acid, acetic acid, water or mixtures thereof and like. The reaction is carried out at temperatures ranging from 4O⁰C to 14O⁰C under hydrogen pressure. The hydrogen pressure for instant reaction is ranging from 150 milibar to 10 bar. An aqueous acetic acid is used as solvent for preparation of hydrochloride salt of 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1 ,2- a]pyrimidin-4-one, for catalytic hydrogenation in presence of metal catalyst.

Deprotection

Paliperidone

Formula 6 Formula 7

The benzyloxy compound of formula 6a is deprotected by the known process in art to give compound of formula 6. A base such as potassium acetate, sodium acetate and like is used for the deprotection of benzyloxy compound. The crude is purified using oxalate salt to give acid salt of 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1 ,2-a]pyrimidin-4-one In step (4), N-alkylation reaction of (6-fluoro-3-piperidine-4-yl-1 ,2-benzisoxazole hydrochloride (Formula-7) with hydrochloride salt of 3-(2-chloroethyl)-9-hydroxy-2-methyl-

6,7,8,9-tetrahydro-4H-pyrido[1 ,2-a]pyrimidin-4-one (FormuIa-6) is carried out using solvent selected from ethers such as tetrahydro furan, dioxane, methyl tert. butyl ether, di-n-propyl ether; nitriles such as acetonitrile, propionitrile; aliphatic and alicyclic solvents such as hexane, heptane, cyclohexane, methyl cyclohexane; ketonic solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone, alcohols such as C₁ to C₅; benzotrifluoride, sulfolane; DMSO; N,N-dimethyl formamide; N, N- dimethyl acetamide; N-methyl 2- pyrrolidone; 1 ,3-dimethyl imidazolidin-2-one; 1 ,3 dimethyl propylene urea; tetramethyl urea. Also mixtures of above mentioned solvents can be used. The base used, in this reaction is selected from carbonates such as sodium carbonate, potassium carbonate, cesium carbonate; alkoxides of C₁ to C₄ alcohols; or organic tertiary amine bases such as C₁ to C₄ trialkyl amines; N-methyl morpholine; N-methyl pyrrolidine; N-methyl piperidine;

Diaza(1 ,3)bicyclo[5.4.0]undecane [DBU]; 1 ,5-Diazabicyclo[4.3.0]non-5-ene [DBN] and 1 ,4- diazabicyclo[2.2.2]octane [DABCO].

The reaction is carried out at 0 to 150°C, preferably at 10 to 100⁰C. N- Alkylation can also be carried out using a phase transfer catalyst. The compound of formula-6a can further be converted to paliperidone using following steps:

The compound of formula 6 is further purified by generating its oxalate salt which is then reacting with formula - 7 in presence of a base to give paliperidone.

In step (5), the obtained paliperidone is purified from solvent selected from acetonitrile; isopropyl alcohol; C₁ to C₄ alcohols; amides such as DMF; DMA; ethers such as 2-methyl THF, THF, dioxanes; esters such as alkyl acetates; water; benzotrifluoride; methyl cellosolve; or mixtures thereof. Paliperidone can also be purified by converting 9-hydroxy group to its acetate or benzoyl ester salt, followed by regenerating (optionally after recrystallization of formed ester) Paliperidone.

The invention is further illustrated by following non-limiting examples. Example - 1: Preparation of 9-hydroxy-3-(2-hydroxy-ethyl)-2~methyl-4H-pyrido [1,2- a]pyrimidin-4-one hydrochloride (Formula - 4):

10 gm of 2-amino-3-hydroxy pyridine, 13.94 gm acetyldihydro-2(3H)-furanone were taken in 100 ml n-butanol and mixed. The reaction mixture was heated to reflux temperature. Water was formed and separated from reaction mixture. The reaction mixture was cooled to 90°C-95°C and treated with charcoal, filtered and washed with butanol. The filtrate was treated with 2-propanolic HCI. The solid was formed. The reaction mass was cooled to ~10°C, stirred for about 30 minutes, filtered and washed with 2-propanol and dried. This material was treated with 50 ml 2-propanol, stirred at 50- 55⁰C for about half an hour. The reaction mixture was cooled to 25-30⁰C and stirred for about 30 minutes. The reaction mass was filtered, washed with 2-propanol and dried (Weight 17.2 gm, 73.78 %)

Example - 2: Preparation of 9-hydroxy-3-(2-hydroxy-ethyl)-2-methyI-4H-pyrido [1,2- a]pyrimidin-4-one hydrochloride (Formula - 4):

10 gm of 2-amino-3-hydroxy pyridine, 13.94 gm acetyldihydro-2(3H)-furanone were taken in 80 ml butanol and mixed. The reaction mixture was heated to reflux temperature. Water was formed and separated from reaction mixture. 27.5 ml of 2- propanolic HCI was added. The solid was formed. The reaction mass was cooled to

~10°C, stirred for about 30 minutes, filtered and washed with 2-propanol and dried. This material was treated with 50 ml 2-propanol, stirred at 50-55⁰C for about half an hour. The reaction mixture was cooled to 25-30⁰C and stirred for about 30 minutes. The solid was filtered, washed with 2-propanol and dried (Weight 16.2 gm, 69.49 %)

Example - 3: Preparation of 9-hydroxy-3-(2-hydroxy-ethyl)-2-methyl-4H-pyrido [1,2-a]- pyrimidin-4-one hydrochloride (Formula - 4):

10 gm of 2-amino-3-hydroxy pyridine, 13.94 gm of acetyldihydro-2(3H)-furanone and 110 m! of toluene and o-dichlorobenzene mixture were taken in to round bottom flask and heated to reflux temperature. Water was formed and separated from reaction mixture. The reaction mass was cooled up to 90-95⁰C and treated with charcoal. The mixture was filtered, washed with mixture of toluene and o-dichlorobenzene. The filtrate was treated with 27.5 ml of 2-propanolic HCI. The solid was formed and the reaction mixture was cooled to 25-30⁰C with stirring, filtered and washed with 2-propanol and dried. (Crude weight 17.5 gm, 75.07%)

This material was treated with 50 ml 2-propanol, stirred at 50-55⁰C for about 30 minutes, cooled to 25-30⁰C with stirring for about 30 minutes. The solid was filtered, washed with 2-propanol and dried (Weight 16.6 gm, 71.21%)

Example - 4: Preparation of 9-hydroxy-3-(2-hydroxy-ethyl)-2-methyl-4H-pyrido [1,2- a]pyrimidin-4-one hydrochloride (Formula - 4):

10 gm of 2-amino-3-hydroxy pyridine, 13.94 gm of acetyldihydro-2(3H)-furanone and

110 ml of chloro benzene were taken in round bottom flask and heated to reflux temperature. Water was formed and separated from reaction mixture. The reaction mass was cooled to 90°C-95°C, treated with charcoal, filtered and washed with chlorobenzene.

The filtrate was treated with 27.5 ml of 2-Propanolic HCI, solid formation was observed. The reaction mass was cooled to 25-30⁰C, stirred for about 30 minutes. The solid was filtered and washed with 2-propanol and dried. (Weight 17.0 gm, 72.93%)

This material was treated with 50 ml 2-propanol, stirred at 50-55⁰C for about 30 minutes, cooled to 25-30⁰C and stirred at same temperature for about 30 minutes. The reaction mass was filtered, washed with 2-propanol and dried (Weight 17.2 gm, 73.78%).

Example - 5: Preparation of 3-(2-chloroethyl)-9-hydroxy-2-methyl-4H-pyrido [1,2- a]pyrimidin-4-one HCI salt (Formula - 5):

A mixture of 9-hydroxy-3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1 ,2-a]pyrimidin-4-one hydrochloride (100 gm) and 400 ml of N.N-dimethyl formamide were charged in to RBF.

42.4 ml of Thionyl chloride was added drop wise into reaction mixture and heated up to

65 - 70⁰C for 3 hr. The reaction mixture was cooled to 50 - 55⁰C. Methanol was added to the reaction mass and the resultant mixture was allowed to stir for 30 min. 750 ml of

Ethyl acetate was added and the reaction mixture was allowed to cool down up to 30 - 35⁰C and stirred for 1 hr at about 30⁰C. The solid compound was filtered and the wet cake was washed twice with Acetone. The solid was dried under vacuum at 50⁰C to afford 92-95 gm of product (HPLC purity > 99%)

Example - 6: Preparation of 3-(2-chloroethyl)-9-hydroxy-2-methyI-6,7,8,9-tetrahydro- 4H-pyrido [1,2-a]pyrimidin-4-one HCI salt (Formula - 6):

100 gm of Hydrochloride salt of Formula-4 was dissolved in aq. CH₃COOH and heated up to 50 - 55⁰C followed by the addition of charcoal. The content was stirred for 30 min. The mass was filtered through hyflow and washed with aq. CH₃COOH. The filtered reaction mass was charged in to a 2L hydrogenator at 25-35⁰C followed by the addition of 10 gm of 10% Pd-C with H₂ pressure [4 to 4.5 Kg ] at 40-45⁰C. The reaction is filtered and filtrate is distilled to afford 100-105 gm crude product as oily mass and used in next step.

Example - 7: Preparation of 3-[2-[4-(6-Fluoro-1, 2-benzisoxazol-3-yl) piperidin-1-yl] ' ethyl]-9-hydroxy -2-methyI-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] -pyrimidin-

4 one (Formula - 1):

100 gm of 6-Fluoro-3-piperidin-4-yl-1 , 2-benzisoxazoIe hydrochloride was charged in acetonitrile along with molar excess potassium carbonate and potassium iodide in RBF at 30⁰C. The mixture was gradually heated up to 55-60⁰C and stirred for 1 hr. 100 gm of 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1 ,2-a]-pyrimidin-4-one

HCI in acetonitrile was charged drop wise in to the reaction mass in an hour. The reaction was maintained under stirring for 46 hr. The solvent was distilled under reduced pressure. The crude product was slurried in water and stirred at 25°C-30°C. The solid was filtered and washed with water and dried in vaccum at 60 - 65⁰C to afford 140 - 145 gm of crude Paliperidone (Purity >95%).

Example - 8: Purification of 3-[2-[4-(6-FIuoro-1,2-benzisoxazoI-3-yl)piperidin-1-yl ]ethy! ]-9-hydroxy -2-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] -pyrimidin-4-one (Formula - 1):

140 gm of Crude paliperidone was dissolved in previously heated lsopropyl alcohol and 8.8 gm of activated charcoal was charged. The content was stirred at about 80⁰C for 30 min and filtered through hyflow in hot condition. The hyflo bed was washed with hot lsopropyl alcohol. The filtered mass was gradually cooled up to O⁰C and stirred for 2 hr at 0-5⁰C. The solid product was filtered and repeatedly washed with chilled isopropyl alcohol. The product was dried in vaccum oven at 65-70⁰C for 24 hrs to obtain 85-90 gm product (Purity >99%). ,

Example - 9: Preparation of 9-Benzyloxy-3-(2-hydroxy-ethyl)-2-methyl-4H-pyrido [1,2- a]pyrimidin-4-one hydrochloride (Formula - 4):

9-Benzyloxy-3-(2-hydroxy-ethyl)-2-methyl-4H-pyrido[1 ,2-a]pyrimidin-4-one HCI

(Formula - 4) is prepared by the reaction of .2-amino-3-benzyloxypyridine of with 3- acetyldihydro-2(3H)-furanone in an inert solvent as per the process disclosed in example 1- 4.

Example - 10: Preparation of 3-(2-chloroethyl)-9-benzyloxy-2-methyl-4H-pyrido [1,2- a]pyrimidin-4-one HCI salt (Formula - 5): 3-(2-chloroethyl)-9-benzyloxy-2-methyI-4H-pyrido-[1 ,2-a]pyrimidin-4-one HCI salt

(Formula - 5) is prepared as per the process disclosed in example 5.

Example - 11 : Preparation of 3-(2-chloroethyl)-9-benzyloxy-2-methyl-6,7,8,9- tetrahydro-4H-pyrido [1,2-a]pyrimidin-4-one HCI salt (Formula - 6a) 3-(2-chloroethyl)-9-benzyloxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido [1 ,2-a]pyrimidin-

4-one HCI salt (Formula - 6aj is prepared as per the process disclosed in example 6..

Claims

We claim:

1 An improved process for the preparation of 9-hydroxy -3-(2-hydroxy-ethyl)-2-methyi-

4H-pyrido-[1,2-a]pyrimidin-4-one or its acid addition salt comprising: a. reaction of 2-arhino-3-hydroxy pyridine, with acetyidihydro-2(3H)-furanone in an organic solvent without using acid catalyst, b. treating the reaction mixture with an acid to give acid addition salt, c. separating the acid addition salt, d. washing the obtained compound followed by drying to yield 9-hydroxy-3-(2- hydroxy-ethyl)-2-methyl-4H-pyrido[1,2a]pyrimidin-4-one.

2. The process according to claim-1, wherein the organic solvent is selected from n- butanol; chlorobenzene; mixture of n-butanol and toluene or mixture of o- dichlorobenzene and toluene.

3. The process according to claim-2, wherein the organic solvent is n-butanol.

4. The process according claim-1 , wherein the acid used to prepare acid addition salt is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, formic acid or propionic acid.

5. The process according to claim-4, wherein the acid addition salt is taken in an alcohol medium, which is selected from C₁-C₄ alcohol, preferably 2-propanoI.

6. The process according to claim-1 , which is performed as a one pot reaction.

7. An improved process for the preparation of 9-benzyloxy-3-(2-hydroxy-ethyl)-2- methyl-4H-pyrido-[1 ,2-a]pyrimidin-4-αne or its acid addition salt as described in claim-1.

8. A process for the preparation of paliperidone comprising the process for the preparation of 9-hydroxy-3-(2-hydroxy-ethyl)-2-methyl-4H-pyrido-[1 ,2-a]pyrimidin-4- one or its acid addition salt involving the reaction of 2-amino-3-pyridinol of formula - 2 with 3-acetyldihydro-2(3H)-furanone of formula - 3 in an inert solvent.

9. A process for the preparation of paliperidone comprising the process for the preparation of 9-benzyloxy-3-(2-hydroxy-ethyl)-2-methyl-4H-pyrido-[1 ,2-a]pyrimidin-4- one or its acid addition salt involving the reaction of 2-amino-3-benzyloxypyridine of with 3-acetyldihydro-2(3H)~furanone in an inert solvent.

Date: 11 January 2010 For, Cadila Pharmaceuticals Ltd.,

Dr. Bakulesh M. Khamar Executive Director, Research