Field of the Invention:
The invention relates to a novel process preparation of iloperidone (I).
Background of the Invention:
Iloperidone is chemically known as 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]
propoxy]-3-methoxyphenyl]ethanone (I) and it is used for the treatment of schizophrenia.

The method for preparation of iloperidone disclosed in the patent EP 0402644 and the
publication Drugs of Future 2000, 25(1):29 involves condensation of 6-fluoro-3-(4-
piperidinyl)-1,2-benzisoxazole hydrochloride (II) with 1-[4-(3-chloropropoxy)-3-
methoxyphenyl] ethanone (III a), in the presence of potassium carbonate in
dimethylformamide as solvent.

The patent application IN 1980/MUM/2007 describes the preparation of iloperidone by
condensation of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (II) with 1-[4-(3-
chloropropoxy)-3-methoxyphenyl] ethanone (IIIa) in the presence of inorganic base using
water as solvent.
Summary of the Invention:
The present invention relates to a novel process for the preparation of iloperidone that
comprises reaction of 6-fluoro-3-(piperidine-4-yl)-1,2-benzisoxazole hydrochloride (II) with
1-[4-(3- chloro / bromopropoxy)-3-methoxyphenyl]ethanone (III) in the presence of base and
phase transfer catalyst in an autoclave.
Detailed description of the invention:
The present invention relates to a novel process for the preparation of iloperidone that
comprises :
i) reaction of 4-hydroxy-3-methoxy acetophenone (IV) with 1-bromo-3-
chloropropane (V) in the presence of a base and phase transfer catalyst to obtain 1-[4-(3-chloro/bromo propoxy)-3-methoxyphenyl]ethanone (III a/ III b);
ii) reaction of 6-fluoro-3-(piperidine-4-yl)-1,2-benzisoxazole hydrochloride (II) with 1-[4-(3- chloro/ bromopropoxy)-3-methoxyphenyl]ethanone (III a / III b) in the
presence of base and phase transfer catalyst in an autoclave;
iii) isolation of iloperidone.
The present invention provides novel process for the preparation of iloperidone (1) as shown
below

The base used is an inorganic base selected from carbonates such as sodium bicarbonate,
potassium bicarbonate; bicarbonates such as sodium bicarbonate, potassium bicarbonate;
hydroxides such as sodium hydroxide, potassium hydroxide, ammonium hydroxide; alkali
amides such as sodium amide, potassium amide etc; the preferred inorganic base is potassium
carbonate. Potassium iodide can be optionally used in the steps (i) and (ii).
The solvent used is selected from nitriles such as acetonitrile, alcohols such as methanol,
ethanol, isopropanol; ketones such as diethyl ketone, dimethyl ketone, ethyl methyl ketone,
methyl isobutyl ketone, esters such as ethyl acetate, methyl acetate; ethers such dioxane,
hydrocarbons such as toluene, tetrahydrofuran and polar aprotic solvents such as dimethyl
sulfoxide, sulfolanes, 2-pyrrolidinone etc and mixtures thereof.
The most preferred solvent for step (i) is acetonitrile and for step (ii) is methanol.
The phase transfer catalyst used is selected from group comprising of
benzyltrimethylammonium chloride, hexadecyltributylphosphonium bromide,
methyltrioctylammonium chloride, tertiary butyl ammonium bromide (TBAB). The most
preferred catalyst is TBAB.
The pressure of the autoclave is maintained in the range of 0.1-4 Kg/cm2; preferably 1-2
Kg/cm2
Purification of iloperidone can be carried by crystallization from solvents selected from the
group comprising of nitriles such as acetonitrile, alcohols such as methanol, ethanol,
isopropanol; ketones such as diethyl ketone, dimethyl ketone, ethyl methyl ketone, methyl
isobutyl ketone, esters such as ethyl acetate, methyl acetate; ethers such dioxane,
hydrocarbons such as toluene or mixtures thereof. The most preferred solvents for
crystallization are methanol or acetone.
The aforementioned process uses less toxic and less hazardous solvents such as dimethyl
formamide thereby making ecofriendly process.
The principles, preferred embodiments, and modes of operation of the present invention have
been described in the foregoing examples.
Examples
Example 1: Preparation of 1-[4-(3-chloro/bromo propoxy)-3-mefhoxyphenyl] ethanone
(III)
Acetonitrile (1L) was charged to 4-hydroxy-3-methoxy acetophenone (IV) (0.5 kg, 3.009
moles). 1-Bromo-3-chloropropane (V) (1.89 Kg, 12.036 moles) was added to the reaction
mixture and was stirred followed by addition of TBAB (0.030 Kg, 0.0903 moles ). Potassium
carbonate (0.78 Kg, 5.657 moles) was added to the reaction mixture and heated to 80°C The
mixture was cooled and filtered. The solid obtained was charged to dichloromethane (2 liters)
and stirred. The reaction mixture was heated to 40-45°C and distilled. The reaction mixture
was cooled and methanol (0.5 liters) was added followed by the addition of water (5 liters).
The entire reaction mixture was added to chilled water and stirred. The reaction mixture was
filtered and washed with water and dried.
Yield: 0.779 Kg.
Purity: 99.35%
Example 2: Preparation of iloperidone (I)
6-Fluoro-3-(piperidinyl-4-yl)-1,2-benzisoxazole hydrochloride (II) (0.60 kg, 2.34 moles) and 1-[4-(3-chloro/bromo propoxy)-3-methoxyphenyl)ethanone (0.68 kg, 2.81 moles) were added
to methanol (6 liters ) in autoclave. To the mixture potassium carbonate (0.39 kg, 2.81 moles)
was added followed by the addition of TBAB (0.03 kg). The reaction was maintained in the
autoclave at 60-65°C for 15-16 hours. The reaction was then cooled and methanol was
distilled out for the mixture. Toluene was charged to the reaction mixture and heated to 50-
55°C. The reaction mixture was maintained for half an hour. Toluene was distilled out and
reaction mixture is cooled. The solid was filtered and washed with chilled toluene and dried.
Yield: 0.77kg
Purity: 98.18%
Example 3: Purification of iloperidone
Iloperidone (0.750 kg) was charged to methanol (1.688 liters). The mixture was heated to
reflux temperature. The solution was gradually cooled to 0 -5°C. The reaction mixture was
maintained for 2 hours and the solid was filtered. The wet solid was washed with chilled
methanol at 0-5°C and dried.
Yield: 0.71 kg
Purity: 99.25%
Example 4: Purification of iloperidone
Iloperidone obtained in example 3 (2.12 kg) was charged to acetone (10.6 liters) and charge
charcoal (0.11Kg). The mixture was heated to reflux temperature at 55-60°C and maintained
for an hour. The solution was filtered through hyflo bed and washed with acetone. The filtrate
was heated between 55-60°C to get a clear solution. The reaction was maintained for an hour
and cooled to 0-5°C. The solid was filtered and washed with chilled acetone. The solid was
dried for 5-6 hours.
Yield: 1.735 kg
Purity: 99.90%
We Claim:
1) A novel process for the preparation of iloperidone that comprises :
(i) reaction of 4-hydroxy-3-methoxy acetophenone (IV) with 1-bromo-3-
chloropropane (V) in the presence of a base and phase transfer catalyst to obtain
1-[4-(3-chloro/bromo propoxy)-3-methoxyphenyl]ethanone (IIIa / IIIb);
(ii) reaction of 6-fluoro-3-(piperidine-4-yl)-1,2-benzisooxazole hydrochloride (II)
with 1-[4-(3- chloro/ bromopropoxy)-3-methoxyphenyl]ethanone (IIIa / IIIb) in
the presence of base and phase transfer catalyst in an autoclave;
(iii) isolation of iloperidone.
2) Process according to claim 1 wherein, the base is selected from carbonates such as
sodium carbonate, potassium carbonate; bicarbonates such as sodium bicarbonate,
potassium bicarbonate; hydroxides such as sodium hydroxide, potassium hydroxide,
ammonium hydroxide; alkali amides such as sodium amide, potassium amide.
3) A process of claim 2 wherein, most preferred base is potassium carbonate.
4) Process according to claim 1 wherein, the phase transfer catalyst is selected from
benzyltrimethylammonium chloride, hexadecyltributylphosphonium bromide,
methyltrioctylammonium chloride, tertiary butyl ammonium bromide.
5) Process according to claim 4 wherein, the most preferred phase transfer catalyst used
is tertiary butyl ammonium bromide.
6) Process according to claim I wherein, step (i) and step (ii) are optionally carried out
in the presence of potassium iodide.
7) A process according to claim 1 wherein, the solvent in step (i) and (ii) is selected from
nitriles such as acetonitrile; alcohols such as methanol, ethanol, isopropanol; ketones
such as diethyl ketone, dimethyl ketone, ethyl methyl ketone, methyl isobutyl ketone;
esters such as ethyl acetate, methyl acetate; ethers such dioxane, tetrahydrofuran;
hydrocarbons such as toluene; and polar aprotic solvents such as dimethylformamide,
dimethyl sulfoxide, sulfolanes, 2-pyrrolidinone etc and mixtures thereof.
8) Process according to claim 7 wherein, the most preferred solvent for step (i) is
acetonitrile.
9) Process according to claim 7 wherein, the most preferred solvent for step (ii) is
methanol.
10) Process according to claim 1 wherein the pressure in step (ii) is maintained at 1-2
kg/cm2.
11) The process for the preparation of iloperidone as described by foregoing examples.

The present invention relates to a novel process for the preparation of iloperidone (I) that
comprises reaction of 1-[4-(3-halopropoxy)-3-methoxyphenyl] ethanone (IIIa / IIIb) with 6-
fiuoro-3-(piperidine-4-yl)-1,2-benzisoxazole hydrochloride (II) under pressure in an
autoclave.