FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
PROVISIONAL SPECIFICATION /COMPLETE SPECIFICATION (See section 10 and rule 13)
1. TITLE OF THE INVENTION
Novel process for preparing pure 6-F!uoro-3-piperidin-4-yl-1,2-benzisoxazole hydrochloride
and its conversion to Paliperidone

2. APPLICANT(S)
(a) NAME : CADILA PHARMACEUTICALS LIMITED
(b) NATIONALITY: An INDIAN Company
(c) ADDRESS : "Cadiia Corporate Campus", Sarkhej - Dhoika Road, Bhat,
Ahmedabad - 382210, Gujarat, India
3. PREAMBLE TO THE DESCRITION
PROVISIONAL SPECIFICATION
The following specification describes the invention.

COMPLETE SPECIFICATION
The following specification describes and accertainc tho nature of this invention and tho manner in which it i6 to bo performod

4. DESCRIPTION
(Description starts from next page)


FIELD OF THE INVENTION
The invention relates to novel process for providing pure 6-Fluoro-3-piperidin-4-yl-1,2-
benzisoxazole hydrochloride and its conversion to substantially pure Paliperidone containing
less than 0.1 % of dimer impurity having structural formula compound offormula-1A. OH


Formula 1a [Dimer impurity] BACKGROUND OF THE INVENTION
Paliperidone, chemically known as 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-piperidin-1-yl]-ethyl]- 9-hydroxy -2-methyl-6,7,8,9-tetrahydro-4H-pyrido41,2-a]-pyrimidin-4-one is a benz-isoxazole derivative having the structural formula 1.
OH
Formula I
.N. ^CH3
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 is disclosed as an antipsychotic agent in US patent No. 4,804,663. 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.
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-yM ,2-benzisoxazole hydrochloride (formula-2) and 3-{2-chloroethyl)-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 compounds of formula 2 and formula 3 are key intemnediates useful in synthesis of Paliperidone. The benzisoxazole hydrochloride intermediate of formula-2 is commonly used for preparation of Risperidone and Paliperidone.
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International publications WO 2008/140641 and WO2008/021346 provide pure Paliperidone and processes for preparing thereof.
International publication WO 2008/021345 describes a process for preparing paliperidone from its intermediate 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l,2-a]- pyrimidin-4-one
The prior art processes as disclosed above for preparation of Paliperidone involves reaction of S^-chloroethyO-e./.S.Q-tetrahydro-Q-hydroxy^-methyMH-pyrridoII^-a]-pyrimidin-4-one (formula-3) with 6-fluoro-3-piperidin-4-yl-1, 2-benzisoxazole hydrochloride (fformula-2), which is resulting into the formation of impurities and those impurities are difficult to remove by purification of Paliperidone.
Paliperidone is reported to degrade under certain conditions like pH, aerial exposure etc. It is therefore preferable to avoid extensive purification at the finished product stage.
Thus, there is a need to have a robust process for synthesis of Paliperidone which does not involve the formation of impurities.
SUMMARY OF THE INVENTION
The object of present invention is to provide industrially scalable process for the preparation of pure Paliperidone.
Another object of present invention is to provide novel process for preparing pure 6-fluoro-3-piperidin-4-yl-1, 2-benzisoxazole or its acid addition salt.
Yet another object of present invention is to provide novel acid addition salts of 6-fluoro-3-piperidin-4-yl-1,2-benzisoxazole.
Yet another object of the invention is to provide process for the purification of 6-fluoro-3-piperidin-4-yl-1,2-benzisoxazole in order to reduce the impurity having structural formula-2a.
Yet another object of the invention is to provide a process for getting purified Paliperidone containing reduced levels of dimer impurity having structural formula-1a.
Yet another object of the invention is to provide, a novel compound having structural formula present in paliperidone as an impurity.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to novel process for purification of 6-Fluoro-3-piperidin-4-yl-1, 2-benzisoxazole via acid salt. The purified salt is reacting with 3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]-pyrimidin-4-one to give pure Paliperidone.
The commercially available 6-fluoro-3-piperidin-4-yl-1,2-benzisoxazole hydrochloride (formula-2) contains compound formula-2a as an impurity which possess reactive amino group. The same is formed during N-alkylation reaction with compound of formula-3 and
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generates N-alkylated dimer impurity having structural formula-la [Herein referred to as "Dimer" impurity].
Formula 1a [Dimer impurity]

Formula 2a
Once the compound of formula 1a is formed, it becomes difficult to remove / separate from Paliperidone even after repeated crystallization. The pure compound of formula-2 is converted to corresponding acid addition salt. Paliperidone is prepared by the salt having less than 0.5% of dimer impurity, preferably less than 0.15 % of dimer impurity more preferably less than 0.1 % of dimer impurity. An organic acid is selected for preparing acid addition salt. The preferable organic acid are mono basic acid such as acetic acid, formic acid, propionic acid; dibasic acid such as oxalic acid, fumaric acid, succinic acid, glutaric acid, tartaric acid, malonic acid, maleic acid; tribasic acid such as citric acid, benzene sulfonic acid. The inorganic acids such as sulfate, nitric acid, phosphoric acid can also be useful for the formation of an acid addition salt. The tartaric acid is preferred for the formation of an acid addition salt of compound of formula 2.
The compound of formula-2 is dissolved in water, followed by an addition of dichloromethane and treatment with a base (preferably ammonia) and dichloromethane layer is separated and dried over anhydrous sodium sulfate. Tartaric acid in methanol is added to provide tartarate salt of 6-fiuoro-3-piperidin-4-yl-1,2-benzisoxazole in the dried organic layer. The salt is formed and separated by filtration. Free base is prepared by treatment with suitable base like sodium hydroxide, ammonia, sodium carbonate. The process is optionally repeated, to improve the purity of 6-fluoro-3-piperidin-4-yl-1,2-benzisoxazole. 6-fluoro-3-piperidin-4-yl-1, 2-benzisoxazofe, is converted to its hydrochloride salt and reacted with compound of formula-3, using a base, in solvents) to give crude paliperidone, which after purification results in pure
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Paliperidone with an HPLC purity > 99.7, with reduced level of dimmer impurity in finished Paliperidone.
The pure 6-f!uoro-3-piperidin-4-yl-1,2-benzisoxazole or its hydrochloride [formula-2], is reacted with compound of formula-3 using a base optionally in presence of iodide source compounds like potassium iodide. The crude is purified using solvent to give paliperidone containing less than 0.5 % of dimer impurity, preferably less than 0.15 % ,more preferably less than 0.1 % of dimer impurity. The paliperidone thus obtained has a purity > 99.7 %.
The base is selected from carbonates such as sodium carbonate, potassium carbonate, cesium carbonate; alkoxides of d to C4 alcohols; or organic tertiary amine bases such as Ci to C4 tria\ky\ amines, N-methyl morpholine, N-methyl pyrrolidine, N-methyl piperidine, Diaza(1,3)bicyclo[5.4.0]undecane [DBU], 1,5-DiazabicycIo[4.3.0]non-5-ene [ DBN ] and 1,4-diazabicyclo[2.2.2]octane [DABCO]. The solvent is selected from water, methanol, benzotrifluoride, suifolane, isoamyl alcohol, amyl alcohol, isopropyl alcohol, acetone or mixtures thereof.

Formula-2a
The invention is further illustrated by following non-limiting examples. Example-1 Purification of 6-Fluoro-3-piperidin-4-yl-1,2-benzisoxazole HCI
200 gm of 6-Fluoro-3-piperidin-4-yl-1,2-benzisoxazole HCI with water and DCM was stirred at ambient temperature. 200 ml of aqueous ammonia was added stirred further till dichloromethane layer was separated. The organic layer was washed with water and dried over anhydrous sodium sulfate. A solution of tartaric acid in methanol was added and stirred. The tartrate salt was filtered, washed with methanol and dried. If required optionally the process is repeated to get pure 6-Fluoro-3-piperidin-4-yl-1, 2-benzisoxazole HCI.
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255 gm of tartrate salt of 6-Fluoro-3-piperidin-4-yl-1,2-benzisoxazole obtained by above proves was stirred with water and dichloromethane and treated with aqueous ammonia. Dichloromethane layer was separated, dried over sodium sulfate and treated with 2-propanolic HCI and stirred for 3CM5 minutes. The solid was filtered, washed with methanol and dried to give S-Fiuoro^-piperidin^-yi-l, 2-benzisoxazoie HCi. (HPLC purity >99.7%; compound of formula-2ais <0.1 %).
Example-2 Preparation of 3-[2-[4-(6-Fluoro-1, 2-benzisoxazol-3-yl) piperidin-1-yl] ethyI]-9-hydroxy -2-methy 1-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] -pyrimidin-4-one(Formula-1)
100 gm of 6-R|uoro-3-piperidin-4-yl-1, 2-benzisoxazole hydrochloride (Formula-2), and 143.4 gm potassium carbonate, 6.5 gm potassium iodide in 900 ml of acetonitrile was charged at 30°C. The mixture was heated upto 55-60°C and stirred for 1 hr. The previously prepared solution of 3-(2-chloroethy!)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (Formula-3) dissolved into 600 ml acetonitrile and charged drop wise into the reaction mass at about 60°C followed by stirring for 46 h. The acetonitrile was distilled at 50°C- 55°C under reduced pressure. The crude product was obtained and slurried in water with stirring for 1 hr at 25°C-30°C. If required water wash is repeated. The solid product was dried in vacuum oven at 60 - 65 C to brovide crude Paliperidone (purity >98%, dimer impurity <0.1 %) Purification of 3-fc-[4-(6-Fluoro-1,2-benzisoxazoI-3-yl)piperidin-1-yl ]ethyl ]-9-hydroxy -2-methy 1-6,7,8,9-tet»-ahydro-4H-pyrido [1,2-a] -pyrimidin-4-one (Formula-1)
140 g of Crude paliperidone obtained in previous step was dissolved in hot Isopropyl alcohol and activated charcoal was charged. The content was stirred for 30 min and filtered through hyflow in hot condition and washed with previously heated Isopropyl alcohol. The filtered mass was gradually cooled up to 0-5 °C and stirred for 2 hr. The solid product was filtered and washed wjth IPA. The purification is repeated if required and the obtained product was dried in vacuum <3ven at 65-70 °C to give product with >99% purity.
Date: 7 January 2009
For, Cadila Pharmaceuticals Ltd.,


Dr. Bakulesh M. Khamar Executive Director, Research

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