FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"AN IMPROVED PROCESS FOR THE PREPARATION OF 1LOPERIDONE."
Enaltec Labs Pvt. Ltd. an Indian Company, having its Registered Office at 17th Floor, Kesar Solitaire, Plot No.5 Sector-19, Sanpada, Navi Mumbai Maharashtra, India. Pin Code: 400705
1. The following specification particularly describes the invention and the manner in which it is to be performed.

AN IMPROVED PROCESS FOR THE PREPARATION OF ILOPERIDONE
FIELD OF THE INVENTION:
The present invention relate to an improved process for the preparation of iloperidone compound of structural formula I comprises reacting 6-fluoro-3-(4-piperidinyl)-l, 2-benzisoxazole hydrochloride compound of structural formula II with l-[4-(3-chloropropoxy)-3-methoxyphenyl] ethanone compound of structural formula III in the presence of a base and a phase transfer catalyst.
BACKGROUND OF THE INVENTION:
Iloperidone is chemically 4'-[3-[4-(6-Fluoro-I, 2-benzisoxazol-3-yl) piperidino] propoxy]-3'-methoxyacetophenone and is known from U.S. Patent No. RE 39, 198 and is represented by compound of structural formula I.

Iloperidone has been approved in USA and sold in market under the proprietary name FANAPT. It is an atypical antipsychotic agent indicated for the treatment of schizophrenia in adults.

U.S. Patent No. RE 39, 198 describe a process for the preparation of iloperidone compound of structural formula I wherein, 6-fluoro-3-(4-piperidinyl)-l, 2-benzisoxazole hydrochloride compound of structural formula II was reacted with l-[4-(3-chloropropoxy)-3-methoxyphenyl] ethanone compound of structural formula III in dimethylformamide solvent in presence of base potassium carbonate to get iloperidone compound of structural formula I as described below in scheme no. 1.

Scheme no. 2
U.S. patent publication no. 2010/076196 describe a process for the preparation of iloperidone compound of structural formula I wherein, 3-[l-(3-chloropropyl)-4-piperidinyl]-6-fluoro-l, 2-benzisoxazole compound of structural formula IV was reacted with 4-hydroxy-3-methoxy acetophenone compound of structural formula V in methyl ethyl ketone solvent in presence of base potassium carbonate to get iloperidone compound of structural formula I as described below in scheme no. 2.


Chinese patent publication no. 101735208 describe a process for the preparation of iloperidone compound of structural formula I wherein, reaction of compound of structural formula VI with compound of structural formula III to get compound of structural formula VII followed by cyclization of compound of structural formula VII to get iloperidone compound of structural formula I as described below in scheme no. 3.

Scheme no. 3
Surprisingly, it has now been found that iloperidone can be prepared in good yields on an industrial scale by reacting 6-fluoro-3-(4-piperidinyl)-l, 2-benzisoxazole hydrochloride compound of structural formula II with l-[4-(3-chloropropoxy)-3-methoxyphenyl] ethanone compound of structural formula III in the presence of a base and a phase transfer catalyst.

SUMMARY OF THE INVENTION:
A first aspect of the present invention is to provide an improved process for the preparation of iloperidone compound of structural formula I comprises reacting 6-fluoro-3-(4-piperidinyl)-l, 2-benzisoxazole hydrochloride compound of structural formula II with l-[4-(3-chloropropoxy)-3-methoxyphenyl] ethanone compound of structural formula III in the presence of a base and a phase transfer catalyst.

The invention thus relates to an improved process for the preparation of iloperidone compound of structural formula I comprises reacting 6-fluoro-3-(4-piperidinyl)-l, 2-benzisoxazole hydrochloride compound of structural formula II with l-[4-(3-chloropropoxy)-3-methoxyphenyl] ethanone compound of structural formula III in the presence of base such as an alkali metal hydroxide and a phase transfer catalyst.
DETAIL DESCRIPTION OF THE INVENTION:
The compound of structural formula II used for present invention may be formed by methods disclosed in the art such as those described in U.S. Patent No. 4,804,663 which is incorporated herein by reference only.
The compound of structural formula III used for present invention may be formed by methods disclosed in the art such as those described in U.S. Patent No. 4,366,162 which is incorporated herein by reference only.

The iloperidone compound of structural formula I may be prepared by reacting a solution of 6-fluoro-3-(4-piperidinyl)-l, 2-benzisoxazole hydrochloride compound of structural formula II in water with l-[4-(3-chloropropoxy)-3-methoxyphenyl] ethanone compound of structural formula III in an aromatic hydrocarbon solvent in the presence of base such as an alkali metal hydroxide and a phase transfer catalyst at a temperature in the range of 20°C to 110°C for a period of 30 minutes to 8 hours to get iloperidone compound of structural formula I.
The examples of aromatic hydrocarbon solvents may include but not limited to benzene, toluene, cresol or xylene.
The examples of alkali metal hydroxide may include but not limited to lithium hydroxide, sodium hydroxide or potassium hydroxide.
The examples of phase transfer catalyst may include but not limited to
tetraethylammonium p-toluenesulfonate, tetrapropylammonium
trifluoromethanesulfonate, tetraphenylphosphonium hexafluoroantimonate,
cetylpyridinium bromide, triphenylmethyl tnphenylphosponium chloride,
benzyltriethylammonium chloride, benzyltrimethylammonium chloride,
benzyltriphenylphosphonium chloride, benzytributylammonium chloride,
butyltriethylammonium bromide, butyltriphenylphosphonium bromide, cetyltrimethyl
ammonium bromide, cetyltrimethyl ammonium chloride, ethyltriphenylphosphonium
bromide, ethyltriphenylphosphonium iodide, methyltrioctylammonium bromide,
methyltriphenylphosphonium bromide, methyltriphenylphosphonium iodide,
phenyltrimethylammonium chloride, tetrabutylammonium hydroxide,
tetrabutylammonium perchlorate, tetrabutylammonium bromide, tetrabutylammonium
hydrogensulphate, tetrabutylammonium iodide, tetrabutylammonium tetrafluoroborate,
tetrabutylammonium thiocyanate, tetraethylammonium hydroxide, tetraethylammonium
iodide, tetraethylammonium bromide, tetramethylammonium chloride,
tetramethylammonium iodide, tetramethylammonium chloride, tetraoctylammonium

bromide, tetraphenylphosphonium bromide, tetrapropylammonium hydroxide, tetrapropylammonium bromide or tributylmethylammonium chloride.
The iloperidone compound of structural formula I may be isolated by cooling the reaction mixture to 0-5°C and then stirred the reaction mixture for 30 minutes to 4 hours at same temperature, followed by the steps of centrifugation, filtration, washing, drying and the combination thereof.
The iloperidone compound of structural formula I may be dried at a temperature in the range of 40T to 80°C for 2 to 8 hours.
EXAMLE:
In the following example, the preferred embodiment of the present invention is described only by way of illustrating the processes of the invention. However, these are not intended to limit the scope of the present invention in any way.
Example 1: Preparation of iloperidone.
The solution of 6-fluoro-3-(4-piperidinyl)-l, 2-benzisoxazole hydrochloride (50gm) in water (500ml) was added 1 -[4-(3-chloropropoxy)-3-methoxyphenyl] ethanone (47.2gm), sodium hydroxide (24gm), tetrabutyl ammonium bromide (3gm), sodium chloride (55gm) and toluene (250ml) at 25°C then the reaction mixture was stirred at 90-95°C for 1 hour. The resulting reaction mixture was then slowly cooled to 0-5°C and stirred for 2 hours to get solids. The resulting solids were the filter, washed with water (100ml) and dried at 55-60°C for 6 hours to get title compound. Yield: 83.1 gm Purity: 99.96% (By HPLC)

WE CLAIM:
1. An improved process for preparing iloperidone compound of structural formula I comprises reacting 6-fiuoro-3-(4-piperidinyl)-l, 2-benzisoxazole hydrochloride compound of structural formula II with l-[4-(3-chloropropoxy)-3-methoxyphenyl] ethanone compound of structural formula III in the presence of a base and a phase transfer catalyst.

2. An improved process for the preparation of iloperidone compound of structural formula I comprises reacting 6-fluoro-3-(4-piperidinyl)-l, 2-benzisoxazole hydrochloride compound of structural formula II with 1 [4-(3-chloropropoxy)-3-methoxyphenyl] ethanone compound of structural formula III in the presence of base such as an alkali metal hydroxide and a phase transfer catalyst.

3. The process according to claim nos. 1 and 2 wherein reaction of 6-fluoro-3-(4-piperidinyl)-!, 2-benzisoxazole hydrochloride compound of structural formula II with l-[4-(3-chloropropoxy)-3-methoxyphenyl] ethanone compound of structural formula III is carried out in a mixture of water and aromatic hydrocarbon solvent.

4. The process according to claim nos. ] and 2 wherein reaction of 6-fluoro-3-(4-piperidinyl)-l, 2-benzisoxazole hydrochloride compound of structural formula II with l-[4-(3-chloropropoxy)-3-methoxyphenyl] ethanone compound of structural formula III is carried out in the presence of base.
5. The process according to claim no 3, wherein aromatic hydrocarbon solvent is selected from the group comprising of benzene, toluene, cresol or xylene.
6. The process according to claim no 4, wherein base is selected from the group comprising of lithium hydroxide, sodium hydroxide or potassium hydroxide.
7. The process according to claim nos. 1 and 2 wherein phase transfer catalyst is selected from the group comprising of tetraethylammonium p-toluenesulfonate, tetrapropylammonium trifluoromethanesulfonate, tetraphenylphosphonium hexafluoroantimonate, cetylpyridinium bromide, triphenylmethyl triphenylphosponium chloride, benzyltriethylammonium chloride, benzyltrimethylammonium chloride, benzyltriphenyiphosphoniurn chloride, benzytributylammonium chloride, butyltriethylammonium bromide, butyltriphenylphosphonium bromide, cetyltrimethyl ammonium bromide, cetyltrimethyl ammonium chloride, ethyltriphenylphosphonium bromide, ethyltriphenylphosphonium iodide, methyltrioctylammonium bromide, methyltriphenylphosphonium bromide, methyltriphenylphosphonium iodide, phenyltrimethylammonium chloride, tetrabutylammonium hydroxide, tetrabutylammonium perchlorate, tetrabutylammonium bromide, tetrabutylammonium hydrogensulphate, tetrabutylammonium iodide, tetrabutylammonium tetrafluoroborate, tetrabutylammonium thiocyanate, tetraethylammonium hydroxide, tetraethylammonium iodide, tetraethylammonium bromide, tetramethylammonium chloride, tetramethylammonium iodide, tetramethylammonium chloride, tetraoctylammonium bromide, tetraphenylphosphonium bromide,

tetrapropyl ammonium hydroxide, tetrapropylammonium bromide or tributylmethylammonium chloride.
8. The process according to claim nos. 1 and 2 wherein reaction of 6-fluoro-3-(4-piperidinyl)-l, 2-benzisoxazole hydrochloride compound of structural formula II with l-[4-(3-chloropropoxy)-3-methoxyphenyl] ethanone compound of structural formula III is carried out at a temperature in the range of 20°C to 110°C.
9. The process according to claim nos. 1 and 2 wherein reaction of 6-fluoro-3-(4-piperidinyl)-l, 2-benzisoxazole hydrochloride compound of structural formula II with l-[4-(3-chloropropoxy)-3-methoxyphenyl] ethanone compound of structural formula III is carried out for a period of 30 minutes to 8 hours.
10. The process according to claim nos. 1 and 2 wherein iloperidone compound of structural formula I is isolated by cooling the reaction mixture to 0-5 °C and then stirred the reaction mixture for 30 minutes to 4 hours at same temperature, followed by the steps of centrifugation, filtration, washing, drying and the combination thereof.