FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
PROVISIONAL SPECIFICATION / COMPETE SPECIFICATION (See section 10 and rule 13)
1. TITLE OF THE INVENTION
AN IMPROVED PROCESS FOR THE PREPARATION OF PALIPERIDONE

2. APPLICANT(S)
(a) NAME : CADI LA PHARMACEUTICALS LTD
(b) NATIONALITY: An INDIAN Company
(cj ADDRESS : "Cadffa Corporate Campus" Sarkhoj - Dholka Road, Bhat, Ahmedabad -382210, Gujarat, India
3. PREAMBLE TO THE DESCRITION
PROVISIONAL SPECIFICATION
The following specification describes the invention.
COMPLETE SPECIFICATION
The following specification particularly describet the invention and the manner in which it is teo be performed
4. DESCRIPTION
{Description starts from next page)


FIELD OF THE INVENTION
The invention relates to an improved process for the preparation of paliperidone in high yield and purity. The purity of paliperidone is -99.7% by HPLC, wherein total impurity is less than about 0.3 % and each individual impurity is less than about 0.1 %. The invention also relates to provide the alcohol-water co-solvent for the purification of Paliperidone. The invention further provides a method to minimize the formation of N-oxide impurity in finished paliperidone.
BACKGROUND OF THE INVENTION
Paliperidone, chemically known as 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-piperidin-1-yll-ethyll^hydroxy^-methyl-e.y.S.Q-tetrahydro^H-pyrido-tl^-al-pyrimidin^-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. Paliperidone was first disclosed in US patent No. 5,158,952, and 5,254,556 (herein after designated as US '952 & US '556 patents respectively). US '952 patent describes process for the synthesis of paliperidone by condensation of 6-fluoro-3-piperidin-4-yl-1,2-benzisoxazole hydrochloride (formula-2) and 3-(2-chloroethyi)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]-pyrimidin-4-one (formula-3) in presence of organic base. Both the compounds of formula 2 and formula 3 are key intermediates useful in synthesis of Paliperidone. The benzisoxazole hydrochloride intermediate of formula-2 is commonly used for preparation of Risperidone and Paliperidone.
PCT applications WO 2008/140641 and WO2008/021346 provide processes for the purification of paliperidone. WO2008/021346 describes the purification of paliperidone wherein paliperidone is crystallized by combining a solution of paliperidone in a first solvent followed by addition of an anti solvent and discloses the use of CM alcohol as solvent followed by water as anti-solvent wherein water is used in large quantity. The first solvent is
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selected from group consisting of dichloromethane, dioxane,and C1 toc4 alkyl alcohols. The anti-solvent is selected from group consisting of C3 to £« ketones, C3 to C6 ethers, acetonitrile, C3 to C7 straight and cyclic carbohydrates and water
PCT applications WO 2008/021345 describes a process for preparing paliperidone comprising reacting 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hyt,roxy-2-metnyl-4H-Pyn'ido-[1.2-a]- pyrimidin-4-one or salt thereof and 6-fluoro-3-piperidino-1,2-benzisoxazole or salt thereof in the presence of an inorganic base.
US publication No. 2005/0232995 A1 in fig.-7 illustrates potential degradation pathways for paliperidone under stress conditions. As Palip^ridone. is reported to degrade under certain conditions, like pH, aerial exposure, it is preferable to avoid extensive purification at the finished product stage
The prior art processes described above, provide palip)eridone wn'C" is contaminated with several impurities, which are difficult to remove by purified'0" °f paliperidone.
SUMMARY OF THE INVENTION
The object of present invention is to provide industna"y scalable process for the preparation of paliperidone with high yield and purity.
Another object of the invention is to provide an alternative process for the preparation of paliperidone by reacting S^-chloroetnyO-S-hydroxy-a-methyf-e.Z.S.g-tetrahydro-4H-pyrido-[1,2-a]-pyrimidin-4-one or its acid addition salt with 6-fluoro-3-piperidin-4-yl-1,2-benzisoxazole or its acid addition salt in pre^ence °fan organic base.
Yet another object of the invention is to provide an improved process for purification of paliperidone having total impurity < 0.3 %.
Yet another object of the invention is to provide an improved process for purification of paliperidone having each individual impurity < 0.1 %.
Yet another object of the invention is to provide alcoh^-water mixture as an alternate solvent for purification of paliperidone.
Yet another object of the invention is to provide C5 *° °B alcohol-water mixture as solvent system for purification of paliperidone.
Yet another object of the invention is to provide palipendone free from corresponding N-oxide impurity.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved process for the preparation of paliperidone in high yield and purity comprising reaction of 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]-pyrimidin^-one o( its acid addition salt with 6-
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fluoro-3-piperidin-4-yl-1,2-benzisoxazole or its acid addition salt in presence of an organic base.
In accordance with the present invention, paliperidone is prepared comprising following steps:
a. reacting 3-(2-chloroethyl)-9-hydroxy-2-methyl-6I7,8,9-tetrahydro-4H-pyrido[1,2-a]-pyrimidin-
4-one or its acid addition salt with 6-fluoro-3-piperidin-4-yl-1,2-benzisoxazole or its acid
addition salt in organic solvent and involving the use of halogen exchange catalysis in
presence of an organic base. Thus obtained solid is washed by an organic solvent to give
crude paliperidone.
b. purifying crude paliperidone from with mixture of an alcohol and water to give pure
paliperidone having HPLC purity about 99.7 % and total impurity < 0.3 % wherein
specifically each impurity is < 0.1 %.
The N-alkylation process as described above involves use of an organic solvent which is preferably selected from Cu™ alcohol, more preferably methanol. The process is also carried out in presence of an organic base which is preferably nitrogen containing organic base selected from tertiary amines such as (Ri)(R2)(R3)N wherein R1,R2,R3 is preferably Ci_5 alkyl; N-d_4 alkyi, morpholine; N- C^ alkyl pyrrolidene; N-C^ alkyl piperidine; N-C^ alkyl aniline; preferably selected from trilakylamines such as diisopropyl ethyl amine. The halide of halogen exchange catalysis ion is Br or I, preferably iodide. The halogen exchange catalysis reagent is selected from sodium iodide, potassium iodide, cesium iodide, calcium iodide, ammonium iodide preferably potassium iodide. The reaction is carried at 25°C to 150°C, preferably at 50°C to 125°C more preferably at 60°C-65°C. The process involves use of water and / or an organic solvent for the washing of solid material wherein the suitable organic solvent is selected from ethyl acetate, 2-propanol, acetonitrile, alcohol, preferably methanol.
The crude paliperidone is purified with alcohol and water mixture wherein alcohol is preferred from Ci.10 alcohol preferably moderately water soluble alcohols optionally under nitrogen atmosphere. The more preferable alcohol water mixture is CM alcohol and water mixture. The present invention is exemplified using pentanol water mixture. The present invention provides a particular ratio of n-pentanol and water mixture wherein alcohol becomes miscible at high temperature and provides homogeneous solvent system wherein water acts as a co-solvent. The crystallization of paliperidone is earned out using instant co-solvent system. The n-pentanol-water composition varies from about 85 to 95 n-pentanol with water in 15 to 5 ratio. The preferable composition is n-pentanol: water is 90 : 10. The purification is optionally repeated upon requirement. The preferably n-Pentanol:water mixture is used in the ratio of varies from 85 to 95 :15 to 5 v/v. Use of nitrogen prevents the formation of N-oxide impurity, in finished product.
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Any other anti-oxidant compounds can also be used in catalytic quantities to prevent the formation of N-oxide impurity in finished paliperidone.
The paliperidone obtained by above process is having HPLC purity about -99.7% or more and chemical purity over 99.9%. The total impurity in end product is < 0.3 % and every impurity is < 0.1%.
The instant invention is further illustrated by following non-limiting example. Example-1 Preparation of Paliperidone
100 gm of 6-fluoro-3-piperidin-4-yl-1, 2-benzisoxazole hydrochloride, 125.8 gm diiso-propylethyl amine, potassium iodide and methanol were stirred at room temperature. The reaction mixture heated with stirring under nitrogen . 100 gm of 3-(2-chIoroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one was added with stirring. The reaction mass was cooled to room temperature and stirred for an hour. The reaction mass was filtered and washed with methanol. The wet cake was stirred with water under nitrogen at 50-55°C and washed with water. The product was dried under vacuum to give crude paliperidone (120-125 gm) (HPLC Purity > 97 %; Water content < 1 %)
Example-2 Purification of crude paliperidone:
Mixture of 2.160L n-pentanol and 240 ml water was heated to about 75°C. 120 gm of crude paliperidone was added with stirring under nitrogen . The reaction mass was cooled to about 0°C and stirred at 0 to -5°C. The reaction mass was filtered and washed with n-pentanol: water mixture. The wet cake was taken out and optionally purification is repeated to give 75-80 gm of purified Paliperidone.
Date: 29 January 2009
For, Cadila Pharmaceuticals Ltd.
Dr. Bakulesh M. Khamar
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