FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention - An improved process for preparing Iloperidone
2. Applicant(s)
(a) NAME: ALEMBIC LIMITED
(b) NATIONALITY: An Indian Company.
(c) ADDRESS: Alembic Campus, Alembic Road,
Vadodara-390, 003, Gujarat, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be
performed:

Field of the invention:
The present invention relates to an improved process for preparing I loperidone of formula CD-

Background of the invention:
The chemical name of Iloperidone is l-[4-[3-[4-(6-Fluoro-l,2-benzisoxazol-3-yI)-l-piperidinyl]propoxy]-3-methoxyphenyl]ethanone. The current pharmaceutical product containing this drug is being sold by Novartis using the tradename Zomaril, in the form of tablets.
Iloperidone is used as Antipsychotic. It is combined dopamine (D2) and serotonin (5HT2) receptor antagonist. It is used in the treatment of Schizophrenia.
US patent RE39198 describes a process for the preparation of Iloperidone which is shown in the scheme-I.


Scheme-I
The first process involves reacting 6-Fluoro-3-(4-piperidinyI)-l,2-benzisoxazol hydrochloride with l-(4-(3-chloropropoxy-3-methoxyphenyl]ethanone in the presence of potassium carbonate and N,N' dimethyl formamide to give Iloperidone whereas in the second process the reaction is carried out with free base 6-Fluoro-3-(4-piperidinyI)-l,2-benzisoxazol in the presence of acetonitrile. This process affords crude iloperidone which is purified by flash chromatography and then recrystallized from ethanol. The above process is not normally preferred at industrial scale as it requires chromatographic purification.
US4366162 describes a process for the preparation of intermediate as follows

The process involves alkylating hydroxyl group of l-(4-hydroxy-3-methoxyphenyl) ethanone with l-bromo-3-chloropropane in the presence of potassuim carbonate and acetone at reflux temperature for 20h to give l-(4-(3-chloropropoxy-3-

methoxyphenyl]ethanone. The product obtained as residual oil is purified by high vacuum distillation at 141-143°C.
The above process involves long reaction time which results in formation of dimer impurity. The crude product needs to be purified by high vacuum distillation. The high vacuum distillation is always a cumbersome process at industrial scale and requires special apparatus and skill. It requires high temperature which further contributes to degradation or charring of some portion of product and result in loss of yield. The unwanted dimer impurity is having structural formula as shown below.

This dimer impurity is difficult to remove by conventional purification methods.
It is therefore, a need to develop a smooth, industrially feasible process or preparing Iloperidone. Further, this process should ensure the formation of dimer impurity to a minimum desirable level. The present invention addresses these needs.
Present inventors have directed their research work towards developing a process for the preparation of Iloperiodne which is devoid of the above disadvantages. The present inventors used methylethyl ketone (MEK) as solvent as well as Phase transfer catalyst (PTC) in the reaction for preparation of l-(4-(3-chloropropoxy-3-methoxyphenyl]ethanone. This change in reagents reduced the reaction time and thereby formation of dimer impurity which in turn increase the yield and purity of Iloperidone. Further, the present inventors isolated the compound by trituration method and avoided high vacuum distillation.
Summary of the invention:
Accordingly, it is an object of the present invention to provide an improved process for the preparation of Iloperidone.

Another object of the present invention is to provide a process which gives Iloperidone with high purity.
Yet another object of the present invention is to provide a process which gives l-(4-(3-chIoropropoxy-3-methoxyphenyl]ethanone with minimum formation of unwanted dimer impurity.
Another object of the present invention is to provide a process which is operationally simple and cost effective.

comprising a step of reacting l-(4-hydroxy-3-methoxyphenyl) ethanone (II)

with l-bromo-3-chloropropane(III)

Accordingly, present invention provides an improved process for preparation of Iloperidone (I)
in the presence of base, organic solvent and phase transfer catalyst to give l-(4-(3-chloropropoxy-3-methoxyphenyl]ethanone (IV)


Accordingly, present invention provides an improved process for preparation of Iloperidone (I)
comprising steps of
with l-bromo-3-chloropropane (III)

reacting l-(4-hydroxy-3-methoxyphenyl) ethanone (II)

reacting l-(4-(3-chloropropoxy-3-metnoxyphenyl]ethanone (IV)
in the presence of base, organic solvent and phase transfer catalyst to give l-(4-(3-chloropropoxy-3 -methoxyphenyl] ethanone (IV)


with hydrochloride salt of 6-Fluoro-3-(4-piperidinyl)-l,2-benzisoxazol (V)


in the presence of base, solvent and alkali metal salt to give Iloperidone (I)
Accordingly, present invention provides Iloperidone having dimer impurity content less than 4.0%.
A compound of following .formula which is dimer impurity

Detailed description of the invention:
The present invention provides an improved process for preparation of Iloperidone (I)

comprising steps of
with l-bromo-3-chloropropane (III)
reacting l-(4-hydroxy-3-methoxyphenyl) ethanone (II)

in the presence of base, organic solvent and phase transfer catalyst to give l-(4-(3-chloropropoxy-3 -methoxyphenyl] ethanone (IV)

reacting l-(4-(3-chloropropoxy-3-methoxyphenyl]ethanone (IV)

with hydrochloride salt of 6-Fluoro-3-(4-piperidinyl)-l,2-benzisoxazol (V)

in the presence of base, solvent and alkali metal salt to give Iloperidone (I) The synthetic reaction scheme of the present invention is shown in the scheme-Ill.


In the process of present invention, a mixture of 4-hydroxy-3-methoxy acetophenone, 1-bromo-3-chloropropane, base, solvent and phase transfer catalyst (PTC) is heated at about 75 to 80°C for time sufficient to complete the reaction.
Base is selected from the group comprising alkali or alkaline earth metal hydroxide, carbonate, bicarbonate. The base is selected from NaOH, KOH, LiOH, NaHC03, KHCO3, LiHC03, Na2C03, K2C03, Li2C03, Mg(0H)2, Ca(OH)2, CaC03s MgC03, Ba(OH)2, Be(OH)2, BaC03; SrC03 and the like or mixtures thereof. The preferred base is K2C03.
The examples of solvent are selected from a group comprising ketones, nitriles, acetates, aromatic hydrocarbons and the like or mixtures thereof. Ketones used herein above are selected from methyl ethyl ketone, acetone, metyl isobutyl ketone, 3-heptanone. Acetates used herein above are selected from isopropyl acetate, ethyl acetate, methyl acetate, n-butyl acetate, t-butyl acetate. Nitriles used herein above are selected from acetonitrile, benzonitrile. Aromatic hydrocarbons used herein above are selected from toluene, xylene. The preferred solvent is methyl ethyl ketone or isopropyl acetate.

The example of the PTC as mentioned hereinabove includes but not limited to benzyl triethyl ammonium chloride, tetrabutyl ammonium bromide (TBAB), tetrabutyl ammonium chloride, Tetra Propyl Ammonium Bromide, Tri butyl Benzyl Ammonium Chloride, Tetra Ethyl Ammonium Bromide, Tetra Octyl Ammonium Bromide, Tetra Butyl Ammonium Hydrogen Sulphate, Benzyl Trimethyl Ammonium Chloride, Benzyl Triethyl Ammonium Chloride, Tetra Butyl Ammonium Acetate, Tetra Butyl Ammonium Iodide, Ethyl Triphenyl Phosphonium Bromide, tetrahexylammonium chloride, Tetra-n-butylammonium fluoride, phenyltrimethylammonium chloride and the like or the mixture thereof.
Generally the reaction completes within 1.5 to 2 hours. The progress of the reaction is monitored on thin layer chromatography (TLC). After completion of reaction, the reaction mixture is cooled at ambient temperature and DM Water is added to the reaction and extracted. The organic phase is separated and washed with 5% sodium chloride solution. The organic phase is distilled out under vacuum at 50°C. Non-polar aliphatic hydrocarbon solvent such as Cyclohexane is added to the oily residue and stirred to give solid. The other non-polar aliphatic hydrocarbon solvents are selected from a group comprising cyclopentane, cyclooctane, pentane, heptane, hexane, iso-octane, petroleum ether or mixtures thereof. The solid is filtered, washed with cyclohexane and suck dried. The solid is dried in oven at 45°C to give l-[4-(3-chloropropoxy)-3- methoxyphenyl]ethanone.
In second step a mixture of 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazoIe hydrochloride. 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, base, alkali metal salt, solvent mixture with DM Water is heated at about 70 to about 75°C for about 20 to 22 hours.
Alkali metal salt is selected from the group comprising sodium Bromide, potassium bromide, sodium chloride, potassium chloride and the like or mixtures thereof.
Base is selected from the group comprising alkali or alkaline earth metal hydroxide, carbonate, bicarbonate. The base is selected from NaOH, KOH, LiOH, NaHC03, KHC03,

LiHC03, Na2C03, K2C03, Li2C03, Mg(OH)2, Ca(OH)2, CaC03, MgC03, Ba(OH)2, Be(OH)2, BaC03, SrC03 and the like or mixtures thereof. The preferred base is K2C03.
Solvents are selected from the group comprising dimethyl sulfoxide, N-methyl pyrrolidone, dimethyl acetamide, N,N'-dimethyl formamide (DMF), propylene carbonate, acetonitrile, acetone, 1,4-dioxane, 2-butanone, methyl ethyl ketone, methyl n-propyl ketone, ethyl acetate, toluene, xylene, water and the like or mixtures thereof. The solvent and water is generally taken in the ratio of about 2-10:1-3. The suitable solvent mixtures are DMF: Water (2:1), Acetonitrile: Water (2:1), Toluene: Water (10:3).
After completion of the reaction, DM Water is added slowly to the reaction mixture. The reaction mixture is cooled to 30°C and stirred for 1 hour. The resulting precipitates are filtered and suck dried. The solid is added to DM Water and heated at 50°C for 30mins. The reaction mixture is filtered and washed first with DM Water and then with Ethyl acetate. The solid is suck dried and then dried in oven at 50°C to give Iloperidone as a crude product.
The crude product is optionally purified by methods known in the art. For example, methods such as charcoalization, crystallization or leaching process are used to remove impurities. The crude product can be purified by crystallization or leaching from alcohol solvents such as methanol, ethanol, isopropanol, butanol. The Iloperidone crude was dissolved in methanol at about 60 to about 65°C. Activated carbon is added and heated at the same temperature for 30 mins. The mixture is filtered through hyflo bed. The bed is washed with hot methanol. The filtrate is distilled approximately to half volume of the original at elevated temperature. The precipitation occurs while removing solvent. The slurry is cooled to 30°C and stirred for 1h. The precipitated solid is filtered and washed with methanol. The solid is dried in oven at 45 to 50°C to give pure Iloperidone.
The major advantage of this process is that the dimer impurity formation is very less in the first step compare to prior art process. Using prior art process, unwanted isomer is formed in more than 10%, whereas in present invention dimer impurity is formed only 3-4% in 1-

[4-(3-chloropropoxy)-3- methoxyphenyl]ethanone. The advantage of the present invention can be understand from the following data depicted in Table-1
Table-1

l-[4-(3-chloropropoxy)-3-
methoxyphenyl]ethanone
(crude) Prior art process (without PTC) Present invention (with PTC)
HPLC purity 88% 97%
% of dimer impurity 10-12% 3-4%
Yield 70-80% 90%
l-[4-(3-chloropropoxy)-3- methoxyphenyl]ethanone (crude) refers here the product obtained without doing high vacuum distillation.
The process of the present invention has following advantages: (i) Short reaction time for condensation in first step. (ii) Dimer impurity is less formed. (iii) High vacuum distillation of l-[4-(3-chloropropoxy)-3- methoxyphenyl]ethanone
is avoided. (iv) Easy isolation process. (v) Comparative quality and good yield is obtained.
The following examples illustrate the invention further. It should be understood, however, that the invention is not confined to the specific limitations set forth in the individual examples but rather to the scope of the appended claims.
Example-1
Preparation of l-(4-(3-chloropropoxy-3-methoxyphenyI]ethanone (IV)

A mixture of Methyl ethyl ketone (300 ml), Benzyl triethylammonium chloride (5.0 g), Potassium Carbonate (83.2 g), 4-hydroxy-3-methoxy acetophenone (100 g) and l-bromo-3-chloropropane (190 g) was heated at 78°C for 1.5 h. After completion of reaction, the reaction mixture was cooled to 30°C and DM Water (300 ml) was added to the reaction and extracted. The organic phase was separated and washed with 5% sodium chloride solution. The organic phase was distilled out under vacuum at 50°C. Cyclohexane (500 ml) was added to the oily residue and stirred to give solid. The solid was filtered, washed with cyclohexane (100ml) and suck dried. The solid was dried in oven at 45°C to give the title product (133.0 g) Dimer impurity content: 3.0% Purity by HPLC: 97%
Example-2
Preparation of Iloperidone (I)
A mixture of 6-fluoro-3-(4-piperidinyl)-l,2-b'enzisoxazole hydrochloride (105.76 g), l-[4-(3-chloropropoxy)-3- methoxyphenyl]ethanone (100 gm) (obtained from example 1), Potassium carbonate (71.16 g), Sodium Bromide (42.4 g), DMF (200 ml) and DM Water (100 ml) was heated at 70°C for 20 hours. After completion of the reaction, DM Water (500 ml) was added slowly to the reaction mixture. The reaction mixture was cooled to 30°C and stirred for 1 hour. The resulting precipitates were filtered and suck dried. The solid was added to DM Water (300 ml) and heated at 50°C for 30mins. The reaction mixture was filtered and washed first with DM Water (100 ml) and then with Ethyl acetate (140 ml). The solid was suck dried and then dried in oven at 50°C to give the title product (150.0 g) Purity by HPLC: 99.4%
Example-3
Purification of Iloperidone (I)
Iloperidone crude (100 g) was dissolved in methanol (800 ml) at 64°C. activated carbon (5 g) was added and heated at the same temperature for 30 mins. The mixture was filtered through hyflo. The bed was washed with hot methanol (100 ml). The filtrate was distilled

out (-550 ml methanol) at 64°C. The slurry was cooled to 30°C and stirred for lh. The solid was filtered and washed with methanol (50ml). The solid was dried in oven at 45°C to give the title product (88.0 g) Purity by HPLC: 99.85%

We claim:
1. A process for preparation of Iloperidone (I)

with l-bromo-3-chloropropane (III)

comprising a step of reacting l-(4-hydroxy-3-methoxyphenyl) ethanone (II)

A process for preparation of Iloperidone (I)

in the presence of base, organic solvent and phase transfer catalyst to give l-(4-(3-chloropropoxy-3-meth6xyphenyl]ethanone (IV)

comprising steps of
reacting l-(4-hydroxy-3-methoxyphenyl) ethanone (II)


with l-bromo-3-chloropropane(III)

in the presence of base, organic solvent and phase transfer catalyst to give l-(4-(3-chloropropoxy-3-methoxyphenyl]ethanone (IV)

reacting l-(4-(3-chloropropoxy-3-methoxyphenyl]ethanone (IV) with hydrochloride salt of 6-Fluoro-3-(4-piperidmyl)-l,2-benzisoxazol (V)

in the presence of base, solvent and alkali metal salt to give Iloperidone (I)
A process according to claim 1 or 2, wherein base is selected from NaOH, KOH, LiOH, NaHC03, KHC03, LiHC03, Na2C03, K2C03, Li2C03, Mg(OH)2, Ca(OH)2, CaC03, MgC03, Ba(OH)2, Be(OH)2) BaC03, SrC03 or mixtures thereof.
A process according to claim 1 or 2 step (i) wherein solvent is selected from a group comprising ketones, nitriles, acetates, aromatic hydrocarbons or mixtures thereof.

5. A process according to claim 3 wherein solvent is selected from ketones such as methyl ethyl ketone, acetone, metyl isobutyl ketone, 3-heptanone; acetates such as isopropyl acetate, ethyl acetate, methyl acetate, n-butyl acetate, t-butyl acetate; nitriles such as acetonitrile, benzonitriie; aromatic hydrocarbons such as toluene, xylene or mixtures thereof.
6. A process according to claim 1 or 2, wherein phase transfer catalyst is selected from benzyl triethyl ammonium chloride, tetrabutyl ammonium bromide (TBAB), tetrabutyl ammonium chloride, Tetra Propyl Ammonium Bromide, Tri butyl Benzyl Ammonium Chloride, Tetra Ethyl Ammonium Bromide, Tetra Octyl Ammonium Bromide, Tetra Butyl Ammonium Hydrogen Sulphate, Benzyl Trimethyl Ammonium Chloride, Benzyl Triethyl Ammonium Chloride, Tetra Butyl Ammonium Acetate, Tetra Butyl Ammonium Iodide, Ethyl Triphenyl Phosphonium Bromide, tetrahexylammonium chloride, Tetra-n-butylammonium fluoride, phenyltrimethylammonium chloride or mixtures thereof.
7. A process according to claim 2, wherein solvent for step (ii) is selected from dimethyl sulfoxide, N-methyl pyrrolidone, dimethyl acetamide, N,N'-dimethyl formamide (DMF), propylene carbonate, acetonitrile, acetone, 1,4-dioxane, 2-butanone, methyl ethyl ketone, methyl n-propyl ketone, ethyl acetate, toluene, xylene, water or mixtures thereof.
8. A process according to claim 2, wherein solvent for step (ii) is selected from solvent system DMF: Water (2:1), Acetonitrile: Water (2:1), Toluene: Water (10:3).
9. A process according to claim 2, wherein alkali metal salt is selected from sodium Bromide, potassium bromide, sodium chloride, potassium chloride or mixtures thereof.
10. A compound of following formula


11. lloperidone having dimer impurity content less than 4.0%.