FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
PROVISIONAL SPECIFICATION / COMPLETE
SPECIFICATION
(See section 10 and rule 13)

1. TITLE OF THE INVENTION
PREPARATION OF 3-(2-HYDROXY ETHYL)-9-HYDROXY-2-METHYL-4H-PYRIDO~[1.2-a]-PYRIMIDIN-4-ONE OR ITS ACID ADDITION SALT
2. APPLICANTS)
(a) NAME : CADILA PHARMACEUTICALS LIMITED
(b) NATIONALITY: An INDIAN Company
(c) ADDRESS : "Cadila Corporate Campus", Sarkhej - Dholka Road, Bhat, Ahmedabad
-382210, Gujarat, India
3. PREAMBLE TO THE DESCRITION
PROVISIONAL SPECIFICATION
The following specification describes the invention.
COMPLETE SPECIFICATION
The following cpocification do scribes and asoortains tho nature of this invontion and tho manner in which it is to be porformed
4. DESCRIPTION
(Description starts from next page)


FIELD OF THE INVENTION
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.
BACKGROUND OF THE INVENTION
Paliperidone, chemically known as S-p^-te-fluoro-l^-benzisoxazol-S-ylJ-piperidin-l-yl]-ethyl]-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]-pyrimidin-4-one is a benz-isoxazole derivative having the structural formula 1.

Paliperidone is 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 3-piperidinyl-1,2-benzisoxazole derivatives and their processes 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-hydroxyethyt)-2-methyl-4H-pyrido-[1,2-a]-pyrimidin-4-one.
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 said pyrimidin-4-one compound by reaction of 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, thionyl chloride and phosphoryl chloride is preferred for given reaction. The reaction mass is extracted with trichloromethane and then subjected to chromatographic purifications.
9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one prepared by the process as described in the '952 and the '556 patents. The processes are resulting in
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product with significant impurities which are formed by the reaction of corresponding 2-aminopyridine with 3-acetyidihydro-2(3H)-furanone.
US patent no. 5,688,799 (Example 1) describes preparation of 9-hydroxy-3-(2-hydroxy-ethyl)-2-methyl-4H-pyrido-[l,2-a]pyrimidin-4-one monohydrochloride comprising reaction of 2-amino-3-pyridinol,3-acetyldihydro-2{3H)-ftjranonel 4-methylbenzenesulfonic acid in xylene at reflux temperature and involving the use of water separator overnight to provide the title compound with 58.4 % yield.
The synthetic route for 3-(2-chloroethyl)-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-methyI-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-propanoi. 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-methyl-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-hydropyridine 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 involves the use of solvents such as chlorobenzene or xylene and acid catalyst along with azeotropically water removal produced during the reaction. The reaction mixture is treated with charcoal and then filtered hot to remove sticky black mass. The filtrate is allowed to cool to give product.
A need remains for an improved and commercially viable process of preparing 9-hydroxy-3-(2-chloroethyl)-2H7iethyl-4H-pyrido-[1,2-a]-pyrimidtn-4-one or an acid addition salt.
We surprisingly found that 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H- pyrido[1,2-aJpyrimidin-4-one or an acid addition salt is prepared by reaction of 2-amino-3-pyridinol with 3-acetyldihydro-2(3H)-furanone without involving the use of an acid catalyst. The inert solvents is used for the reaction which is selected from n-butanol or a mixture of n-butanol and toluene; or chlorobenzene; mixture of o-dichlorobenzene and toluene. The free base is
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isolated by allowing the reaction mixture to cool and the acid salt of product can optionally be isolated by addition of 2-propanol-HCI to hot reaction mixture.
SUMMARY OF THE INVENTION
The object o< present mwerttos\ te to prowidfe an improved process to toe preparation of 9-hydroxy-3-{2-nydroxy-ethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, its acid addition salt or corresponding 9-benzyl substituted compound without involving the use of acid catalyst.
Another object of invention is to provide the preparation of 9-hydroxy-3-(2-hydroxy-ethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one or its acid addition salt or its corresponding 9-benzyl substituted compound involving the reaction of 2-amino-3-hydroxy pyridine with
acetyldihydro-2(3HHuranone-
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 shorter reaction time.
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 high yield.
Yet another object of the invention is to provide 9-hydroxy-3-(2-hydroxy-ethyl)-2-methyMH-pyrido[1,2-aJpyrimidin-4-one or its acid addition salt in high purity.
Yet another object of the invention is to provide a novel and alternative process for producing 9-hydroxy-3-(2-hydroxy-ethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one or its acid addition salt.
DETAILED DESCRIPTION OF THE INVENTION
The present invention discloses a process for preparing 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one or an acid addition salt without involving the use of an acid catalyst. The title compound is obtained via condensation of 2-amino-3-pyridinol with 3-acetyldihydro-2(3H)-furanone in an inert solvent selected from n-butanol, chlorobenzene, mixture of n-butanol and toluene, mixture of o-dichlorobenzene and toluene. The free base is isolated by allowing the reaction mixture to cool and the acid salt of product may optionally be isolated by addition of 2-propanol-HCI to hot reaction mixture. The process is not involving the use of charcoal and hot filtration of reaction mixture.
The product of instant reaction i.e. 3-(2-hydroxy ethyl)-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one or its acid addition salt can further be converted to 3-(2-chloroethyO-Q-hydroxy^-methyl-e.T.S.g-tetrahydro^H-pyridoJI^-ajpyrimidin^-one or its acid addition salt followed by catalytic reduction and condensation with 2-benzisoxazole hydrochloride to provide paiiperidone in high yield.
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Further, the process is also be useful for preparing 3-(2-hydroxy ethyl)-9-benzyloxy hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one or its acid addition salt which is obtained by taking 2-amino-3-benzyloxypyridine in place of 2-Amino-3-hydroxypyridine. The reaction conditions and parameters are elaborated as under:
In step-(1), the solvent used for the preparation of 3-(2-hydroxy ethyl)-9-hydroxy-2-methyMtf-pyrido[1,2-aIpyrimidin-4-one or its acid addition salt; or 3-(2-hydroxy ethyl)-9-benzyloxy -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, chlorobenzene, decalin, orthodichlorobenzene, decalin, ethyl benzene, mesitylene , cyclohexane, methylcyclohexane, nitrobenzene or any inert solvent or any combination of solvents mentioned herein above. The reaction is carried out at temperature ranging from 50 °C to 200°C. The advantage of the present invention is to provide the acid addition salt of 3-(2-hydroxy ethyl)-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one or 3-(2-hydroxy ethyl)-9-benzyloxy -2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one in high yield and purity.
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 , 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; sulfolane; alicyclic hydrocarbons such as cyclohexane, methyl cyclohexane.
In step (3), the hydrogenation catalyst used for hydrogenation is selected from raney nickel or precious metal catalyst such as palladium, rhodium, ruthenium, platinum, iridium, palladium on charcoal. The solvent used in step (3) can be selected from formic acid, acetic acid, water or mixtures thereof. The reaction is carried out at temperatures ranging from 40 to 140 °C under 150 milibar to 10 bar hydrogen pressure. Compound of formula-3a can be converted to compound of formula-3 (free base) using a base such as potassium acetate and can be purified using oxalate salt. Further, 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 from hydrochloride salt of 9~benzyloxy-3-(2-hydroxyetnyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, using catalytic hydrogenation involving the use of metal catalyst.
In step (4), N-alkylation reaction of (6-fiuoro-3-piperidine-4-yM,2-benzisoxazole hydrochloride (formula-2) with hydrochloride salt of 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (formula-3a) is carried out using solvent selected from ethers such as tetrahydro furanfTHF], dioxane, methyl tert. butyl ether, di-n-
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propyl ethe; 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 Ci to C5; benzotrifluoride, sulfolane; DMSO; N.N-dimethyl formamide [DMF]; N,N- dimethyl acetamide [DMA]; N-methyl 2-pyrrolidone; 1,3-dimethyl imidazolidin-2-one; 1,3 dimethyl propylene urea; tetramethyl urea. Also mixtures of abovementioned 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 C, 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 100°C. N- alkylation can also be carried out using a phase transfer catalyst. The compound of formula-3a can further be converted to paliperidone using following steps: first converting to compound of formula 3a to compound of formula-3 (base), making a salt such as oxalate followed by regenerating free base and reaction of regenerated compound with compound of formula - 2 using a base to give paliperidone.
In step (5), the obtained paliperidone is purified from solvent selected from acetonitrile; isopropyl alcohol; Ct 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, followed by regenerating (optionally after recrystallization of formed ester) Paliperidone.


.N^^^CHa step2
HCI DMF/SOCfe

R = H or Bn

CH3 Stepl
(i)Heat,r Condensation,
Solvent (ii) MCI

OR

0
R = H or Bn
Step 3
Hydrogenation
H2-Aq. CH3COOH

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Crude 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]pyrirnidin-4-one hydrochloride
10 gm of 2-amino-3-hydroxy pyridine, 13.94 gm acetyldihydro-2(3H)-furanone wee take in 100 ml 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, 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 50-55°C for about half an hour. The reaction mixture was cooled to 25-30°C and stirred for about 30 minutes. The reaction mass was filtered, washed with 2-propanol and dried (Weight 17.2 gm)
Example-2 Preparation of 9-hydroxy-3-(2-hydroxy-ethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one hydrochloride 10 gm of 2-amino-3-hydroxy pyridine, 13.94 gm aceryldihydro-2(3H)-furanone wee take 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 50-55°C for about half an hour. The reaction mixture was cooled to 25-30°C and stirred for about 30 minutes. The solid was filtered, washed with 2-propano! and dried (Weight 16.2 gm)
Example-3 Preparation of 9-hydroxy-3-<2-hydroxy-ethyl)-2-methyl-4H-pyrido[1,2-a]-
pyrimidin-4-one hydrochloride
10 gm of 2-amino-3-hydroxy pyridine, 13.94 gm of acetyldihydro-2(3H)-furanone and
110 ml 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 90-95°C and treated with charcoal. The
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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 25-30°C with stirring, filtered and washed with 2-propanol and dried. (Crude weight 17.5 gm)
This material was treated with 50 ml 2-propanol, stirred at 50-55°C for about 30 minutes, cooled to 25-30°C with stirring for about 30 minutes. The solid was filtered, washed with 2-propanol and dried (Weight 16.6 gm) Example-4 Preparation of 9-hydroxy-3-(2-hydroxy-ethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one hydrochloride
10 gm of 2-amino-3-hydroxy pyridine, 13.94 gm of acety)dihydro-2(3H)-furanone and 110 ml of chloro benzene were taken in round bottom flask and heated till reflux temperature. Water was formed and separated from reaction mixture. The reaction mass was cooled to 90°C-95°C, treated with charcoal, filtered, washed with chlorobenzene. The filtrate was treated with 27.5 ml of 2-Propanol HCI, solid formation was observed. The reaction mass was cooled to 25-30°C, stirred for about 30 minutes. The solid was filtered and washed with 2-propanol and dried. (Weight 17.0 gm)
This material was treated with 50 ml 2-propanol, stirred at 50-55°C for about 30 minutes, cooled to 25-30°C and stirred at same temperature for about 30 minutes. The reaction mass was filtered, washed with 2-propanol and dried (Weight 17.2 gm). Example-5 Preparation of 3-{2-chloroethyl)-9-hydroxy-2-methyMH-pyrido[1,2-a]pyrimidin-4-one HCI salt (Formula-4a)
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 into a RBF. 42.4 ml of Thionyl chloride was added drop wise into reaction mixture and heated up to 65 - 70 °C for 3 hr. The reaction mixture was cooled to 50 - 55°C. Methanol was added to the reaction mass and the resultant mixture allowed to stir for 30 min. 750 ml of Etyl acetate was added and the reaction mixture was allowed to cool down up to 30 - 35 °C and stirred for 1 h at about 30°C. The solid compound was filtered and the wet cake washed twice with Acetone. The solid was dried under vacuum at 50 °C to afford 92-95 gm of product (HPLC purity > 99%) Example-6 Preparation of 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a]pyrimidin-4-one HCI salt (Formula-3a)
100 gm of Hydrochloride salt of Formula-4 was dissolved in aq. CH3COOH and heated up to 50 - 55 °C 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 into a 2L hydrogenator at 25-35 °C followed by the
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addition of 10 gm of 10% Pd-C with H2 pressure at 40-45 °C. The reaction is filtered and filtrate is distilled to afford 100-105 g 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-yQ
ethyQ-9-hydroxy -2-methyl-6, 7,8,9-tetrahydro-4H-pyrido [1,2-a] -pyrimidin-
4one (Formula-1) 100 gm of 6-Fluoro-3-piperidin-4-yl-1, 2-benzisoxazole hydrochloride was charged in acetonitrile along with molar excess potassium carbonate and potassium iodide in a RBF at 30 °C. The mixture was gradually heated up to 55-60°C and stirred for 1 hr. 100 gm 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1l2-a]-pyrimidin-4-one HCI in acetonitrile was charged drop wise into 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 - 65°C to afford 140 - 145 g of crude Paliperidone (Purity >95%).
Purification of 3-[2-[4-(S-Fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl ]ethyl ]-9-hydroxy -2-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] -pyrimidin-4-one
140 g of Crude paliperidone was dissolved in previously heated Isopropyl alcohol and 8.8 gm of activated charcoal was charged. The content was stirred at about 80 °C for 30 min and filtered through hyflow in hot condition. The hyflo bed was washed with hot Isopropyl alcohol. The filtered mass was gradually cooled up to 0 °C and stirred for 2 hr at 0-5 °C. The solid product was filtered and repeatedly washed chilled isopropyl alcohol. The product was dried in vaccum oven at 65~70°C for 24 Hrs. 85-90 g product (Purity >99%).

Dr. Bakulesh M. Khamar Executive Director, Research
Date: 9 January 2009 >^rff?^ ^or, Cadila Pharmaceuticals Ltd.,

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