"PROCESSES FOR THE PREPARATION OF 4'-[3-[4-(6-FLUORO-l,2-
BENZISOXAZOL-3-YL)PIPERIDINO]PROPOXY]-3'-METHOXYACETOPHENONE
AND INTERMEDIATES THEREOF"
PRIORITY
This application claims the benefit of Indian Provisional Applications with no.
2610/CHE/2010, filed on 07 September 2010 and 3959/CHE/2010, filed on 24 December,
2010, the contents of each of which are incorporated by reference herein.
BACKGROUND OF THE INVENTION
1. Technical Field
The present invention relates to processes for the preparation of 4'-[3-[4-(6-fluoro-l,2-
benzisoxazol-3-yl)piperidino]propoxy]-3'-methoxyacetophenone and intermediates thereof.
2. Description of the related art
Iloperidone is a neuroleptic and 5- hydroxytryptamine 2A antagonist to be used for the
treatment of schizophrenia and general psychosis. Iloperidone is available in the market under
the brand name FANAPT® in the form of tablets in the dosage strengths 1 mg, 2 mg, 4 mg, 6
mg, 8 mg, 10 mg, or 12 mg . Iloperidone is chemically known as 4'-[3-[4-(6-Fluoro-l,2-
benzisoxazol-3-yl)piperidino]propoxy]-3'-methoxyacetophenone (herein after referred by its
generic name Iloperdione) and represented by the structural formula I
I
U.S.Patent No. USRE39198 E (US 5,364,866) describes piperidinyl-benzisoxazole
derivatives, including iloperidone, a pharmaceutical composition, a method of treatment, and a
process for the preparation of iloperidone.
The described prior art processes uses expensive and hazardous chemicals rendering
the processes expensive and not viable on commercial scale thus prompting a need for an
improved process for the preparation of iloperidone and its intermediates, which avoids the use
of hazardous and expensive chemicals, the likely formation of process related impurities.
The preparation of intermediate compound of formula II from novel compounds of
formula III and V have not been reported in the literature as of now.
The reported prior art processes uses expensive and hazardous chemicals rendering
the processes expensive and not viable on commercial scale. Hence there is a need in the art to
provide an improved process for the preparation of iloperidone and its intermediates, which
avoids the use of hazardous and expensive chemicals, the likely formation of process related
impurities resulting in high yields and purities of the final products.
The applicant has now developed a new industrial synthesis which, in reproducible
manner and without requiring laborious purification, yields iloperidone having a purity that is
compatible with its use as a pharmaceutical active ingredient, starting from a intermediates
obtained from simple and cost effective processes.
The processes of present invention are simple, eco-friendly, inexpensive, reproducible,
robust and is well suited on an industrial scale.
SUMMARY OF THE INVENTION
The present invention relates to processes for the preparation of 4'-[3-[4-(6-fluoro-l , 2-
benzisoxazol-3-yl)piperidino]propoxy]-3'-methoxyacetophenone and intermediates thereof.
In one aspect, the present invention provides a process for preparing intermediate 4-(3'-
sub-propoxy)-3-methoxy acetophenone la (II),
(II)
Where X is a leaving group selected from halogen, methanesulphonate, benzene sulphonate, ptoluenesulphonate,
4- nitrobenzene sulphonate, 4-bromobenzene sulphonate and triiluoromethyl
sulphonate
comprising:
reacting a novel compound 1-[4-(3 -propoxy)-3-methoxy phenyl]ethanol of
formula (III),
(HI)
Where X is same as defined above.
with a suitable oxidizing agent optionally in the presence of an organic solvent.
In another aspect, the present invention provides another process for preparing
intermediate 4-(3 -sub-propoxy)-3-methoxy acetophenone compound of Formula II,
II
Where X is a leaving group selected from halogen, methanesulphonate, benzene
sulphonate, p-toluenesulphonate, 4- nitrobenzene sulphonate, 4-bromobenzene sulphonate arid
trifluoromethyl sulphonate.
comprising:
a) reacting a compound 4-(3 -sub-propo -3-methoxy benzaldehyde of Formula VI,
VI
Where X is same as defined above.
with a suitable reagent in the presence or absence of an organic solvent to give the
compound 4-(3 1-sub-propoxy)-3-methoxybenzonitrile of Formula V
V
Where X is same as defined above.
b) reacting the compound of formula V with a Grignard reagent followed by treating the
intermediate obtained with an acid to give the intermediate compound of formula II.
c) the conversion of compound of formula V to compound of formula II is also
carried out in the presence of catalyst cuprous (I) salts.
In another aspect, the present invention relates to a process for the preparation of
Iloperidone of formula I
I
compirising :
reacting the intermediate compound 4-(3'-sub-propoxy)-3-methoxy acetophenone of formula
(ID
II
Where X is same as defined above.
with a compound 6-fluoro-3(4-piperidinyl)-l,2-benzisoxazole or a salt thereof of formula (IV)
(IV)
in the presence of a base and a solvent.
In yet another aspect, the present invention provides an alternate process for
preparation of Iloperidone of formula I
compirising :
a) reacting the intermediate compound 4-(3 1-sub-propoxy)-3-methoxybenzonitrile of
Formula (V)
(V)
Where X is same as defined above,
with a compound 6-fluoro-3(4-piperidinyl)-l,2-benzisoxazole or a salt thereof of formula (IV)
(IV)
in the presence of a base and an organic solvent to give 4'-[3-[4-(6-Fluoro-l,2-benzisoxazol-3-
yl)piperidino]propoxy]-3'-methoxy benzonitrile of formula X
X
b) reaction of the compound of formula X with Grignard reagents in the presence of catalyst
cuprous (I) salts to afford compound of formula I.
In yet another aspect, the present invention provides a process for purifying iloperidone
thereof comprising: a) providing a solution or suspension of iloperidone in a solvent o a
mixture of solvents or their aqueous mixtures and b) precipitating the solid from the solution,
and c) recovering the iloperidone in pure form.
In yet another aspect, the present invention provides iloperidone obtained by the
processes herein described above having purity greater than about 98.0 area % to about 99.0
area % as measured by HPLC, preferably greater than about 99.0 area % to about 99.5 area%,
more preferably greater about 99.5 area % to about 99.9 area %.
In yet further aspect, the present invention provides iloperidone obtained by the
processes herein described above having individual impurities lower than about 0.15 area %,
preferably lower than about 0.1 % and total impurities lower than about 0.5 area % by HPLC.
In another aspect, the present invention provides Iloperidone having the compound 4-
hydroxy-3- methoxy benzaladehyde of structural formula VII
VII
amount less than or equal to 0.10 area % as measured by HPLC.
n another aspect, the present invention provides Iloperidone having the compound 4-
(3-chloropropoxy)-3- methoxy benzaladehyde of structural formula VIII
VIII
in an amount less than or equal to 0.10 area %, as measured by HPLC.
In yet another aspect, the present invention provides Iloperidone having the compound
4-(3-chloropropoxy) -3- methoxy acetophenone of structural formula IX
IX
in an amount less than or equal to 0. 0 area % as measured by HPLC.
In yet further aspect, the present invention provides Iloperidone having the compound
6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole or a salt thereof of structural formula IV
IV
. in an amount less than or equal to 0.10 area% as measured by HPLC.
BRIEF DESCRIPTION OF THE DRAWING
Fig. 1: is a schematic representation of the processes of present invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to processes for the preparation of 4'-[3-[4-(6-fluoro-l,2-
benzisoxazol-3-yl)piperidino]propoxy]-3'-methoxyacetophenone and intermediates thereof.
In one embodiment, the present invention provides a process for preparing intermediate 4-
(3'-sub-propoxy)-3-methoxy acetophenone compound of formula (II),
( )
Where X is a leaving group selected from halogen, methanesulphonate, benzene
sulphonate, p-toluenesulphonate, 4- nitrobenzene sulphonate, 4-bromobenzene sulphonate and
trifluoromethyl sulphonate
comprising:
reacting a novel compound l-[4-(3'-prbpoxy)-3-methoxy phenyl]ethanol of formula (III),
(III)
Where X is same as defined above
with a suitable oxidizing agent optionally in the presence of an organic solvent.
The oxidizing agents that can be used include but are not limited to pyridinium
dichromate, collin's reagent, pyridinium chlorochromate, pyridinium chlorochromate on
alumina, DMSO-DCC, DMSO-acetic anhydride and the like; or mixtures thereof. Preferably
DMSO-DCC or DMSO-acetic anhydride.
The molar ratio of oxidizing agent to the compound of formula (III) can be from about
5:1to about 1:1, preferably 1:1.
The solvents that can be used include but are not limited to water, halogenated solvents
such as dichloromethane, ethylene dichloride, chloroform, chlorobenzene and the like; esters
such as ethyl acetate, isopropyl acetate, tertiary butyl acetate and the like; hydrocarbon solvents
such as n-heptane, cyclohexane, n-hexane, toluene, xylene and the like; ethers such as
tetrahydrofuran, 1,4-dioxane and the like; aprotic polar solvents such as N,Ndimethylformamide
(DMF), dimethylsulfoxide (DMSO), ,-dimethylacetamide (DMA), Nmethyl
pyrrlolidine (NMP) and the like; or mixtures thereof in various proportions without
limitation. Preferably, water or halogenated solvent dichloromethane is being used.
The conversion of compound of formula III to the compound of formula II is optionally
carried out in the absence of solvents.
The conversion of compound of formula III to the compound of formula II is carried out
in the presence of an acid when DMSO-DCC is being used as oxidizing agent.
The acid that can be used include, but are not limited to hydrochloric acid, hydrobromic
acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like, and their aqueous
mixtures thereof, preferably ortho phosphoric acid or trifluoro acetic acid.
The oxidation of compound of formula III to the compound of formula II is carried out
using DMSO-DCC as oxidizing agent in the presence of pyridinium trifluoroacetate.
The reaction time and the temperature should be suitable to bring the reaction to
completion at a minimum time, without the production of unwanted side products. In general, it
is convenient to carry out the reaction at a temperature of from about 20°C to about 00°C,
preferably at a temperature of from about 25°C to about 35 °C. The time required for the
reaction may also vary widely, depending on many factors, notably the reaction temperature
and the nature of the reagent and solvent employed. However, provided that the reaction is
effected under the preferred conditions discussed above, a period of from about 1 hour to about
10 hours, preferably from about 1hour to 5 hours is sufficient.
The intermediate compound of formula II is optionally dried under conditions which
avoid degradation of the product, which can be from about 25°C to about 40°C in the presence
or absence of reduced pressure.
The processes reported for the preparation of Iloperdione or its intermediates results
formation of various impurities and bye products leading to several purification steps thus
resulting in very poor yields and purities of the intermediates and final product.
Advantageously, the processes of present invention provides the intermediate
compound of formula II from novel intermediate compound of formula III and also further
conversion to compound of formula I in higher yields and purities which inturn results in
higher yields and purities of final product.
The intermediate compound of formula II may be obtained in crystalline or amorphous
form.
The compound of formula III used herein can be prepared by the processes known in
the art.
The intermediate compound of formula II is purified by recrystallisation, using a
solvent or mixture of solvents; such as aqueous methanol, ethanol, isopropyl alcohol, n-hexane,
aqueous ,-dimethyl formamide, cyclohexane, acetone, acetonitrile and mixtures thereof.
In one embodiment of the present invention, there is provided a process for preparation
of intermediate l-[4-(3'-chloropropoxy)-3-methoxyphenyl] ethanone compound of Formula II,
II
Where X is a leaving group selected from halogen, methanesulphonate, benzene sulphonate, ptoluenesulphonate,
4- nitrobenzene sulphonate, 4-bromobenzene sulphonate and
trifluoromethyl sulphonate.
comprising:
a) reacting a compound 4-(3 1-Chloropropoxy)-3-methoxy benzaldehyde of Formula VI,
VI
Where X is same as defined above.
with a suitable reagent in the presence of an organic solvent to give the compound 4-(3 -
chloropropoxy)-3-methoxybenzonitrile of Formula V
Where X is same as defined above.
b) reacting the compound of formula V with a Grignard reagent followed by treating the
intermediate obtained with an acid in the present of an organic solvent to give the
desired intermediate compound of formula II.
c) The conversion of compound of formula V to compound of formula II is also carried
out in the presence of catalyst cuprous (I) salts.
The reagent that can be used in step a) include but are not limited to hydroxyl amine
hydrochloride or hydroxyl amine sulphate. Preferably hydroxyl amine hydrochloride.
The molar ratio of the reagent to the compound of formula (VI) can be from about 5:1
to about 1:1, preferably 1:1.
The intermediate obtained is treated with acetic anhydride or sodium formate and
formic acid or sodium acetate and acetic acid to give the compound of formula V.
The solvents that can be used in step a) include but are not limited to water, alcohols
such as methanol, ethanol, isopropyl alcohol, n-butanol and the like; 'halogenated solvents such
as dichloromethane, ethylene dichloride, chloroform, chlorobenzene and the like; esters such as
ethyl acetate, isopropyl acetate, tertiary butyl acetate and the like; hydrocarbon solvents such as
n-heptane, cyclohexane, n-hexane, toluene, xylene and the like; ethers such as tetrahydrofuran,
1,4-dioxane and the like; aprotic polar solvents such as ,-dimethylformamide (DMF),
dimethylsulfoxide (DMSO), ,-dimethylacetamide (DMA), N-methyl pyrrlolidine (NMP)
and the like; or mixtures thereof in various proportions without limitation. Preferably, ethanol
is being used.
The reaction time and the temperature should be suitable to bring the reaction to
completion at a minimum time, without the production of unwanted side products. In general, it
is convenient to carry out the reaction at a temperature of from about 35°C to about reflux
temperatures of the reaction mixture or the solvents used. Preferably at a temperature of from
about 45°C to about reflux temperatures. The time required for the reaction may also vary
widely, depending on many factors, notably the reaction temperature and the nature of the
reagent and solvent employed. However, provided that the reaction is effected under the
preferred conditions discussed above, a period of from about 30 minutes to about 10 hours,
preferably from about 1 hour to about 4 hours is sufficient.
The solvents that can be used in step b) grignard reaction include but are not limited to
hydrocarbon solvents such as n-heptane, cyclohexane, n-hexane, toluene, xylene and the like;
ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and the like; or mixtures thereof in
various proportions without limitation. Preferably, ether or toluene is being used.
The reaction time and the temperature should be suitable to bring the reaction to
completion at a minimum time, without the production of unwanted side products. In general, it
is convenient to carry out the reaction at a temperature of from about 35°C to about reflux
temperatures of the reaction mixture or the solvents used, preferably at a temperature of from
about 45°C to about reflux temperatures. The time required for the reaction may also vary
widely, depending on many factors, notably the reaction temperature and the nature of the
reagent and solvent employed. However, provided that the reaction is effected under the
preferred conditions discussed above, a period of from about 30 minutes to about 10 hours,
preferably from about 1 hour to about 6 hours is sufficient.
The conversion of intermediate compound of formula V to the intermediate compound
of formula II is also being performed using cuprous (I) salts as catalyst.
The cuprous (I) salts that can be used include but are not limited to cuprous chloride,
cuprous bromide, cuprous iodide, cuprous cyanide and cuprous bromide-dimethyl
sulphite.Preferably cuprous chloride.
The intermediate compound of formula II is optionally dried under conditions which
avoid degradation of the product, which can be from aboiit 25°C to about 40°C in the presence
or absence of reduced pressure.
The processes reported for the preparation of Iloperdione or its intermediates results in
the formation of various impurities and bye products leading to several purification steps thus
resulting in very poor yields and purities of the intermediates and the final product.
Advantageously, the process of present invention provides the intermediate compound
of formula II from novel intermediate compound of formula V and also further conversion to
compound of formula I in higher yields and purities which inturn results in higher yields and
purities of final product.
The intermediate compounds of formula II and V obtained by the process of present
invention can be crystalline or amorphous form or mixture thereof.
The intermediate compounds of formula II, V and final compound of formula I are
optionally purified by recrystallisation, using a solvent or mixture of solvents; such as
methanol, ethanol, isopropyl alcohol, ethyl acetate, diethyl ether, methyl tertiary butyl ether,
petroleum ether, n-hexane, n-heptane, cyclohexane, ,-dimethyl formamide, acetone,
acetonitrile or mixtures thereof or their aqueous mixtures.
The reaction time and the temperature should be suitable to bring the reaction to
completion at a minimum time, without the production of unwanted side products. In general, it
is convenient to carry out the reaction at a temperature of from about 35°C to about 100°C or
boiling point of the solvent(s) used, preferably at a temperature of from about 50°C to about
100 °C. The time required for the reaction may also vary widely, depending on many factors,
notably the reaction temperature and the nature of the reagent and solvent employed. However,
provided that the reaction is effected under the preferred conditions discussed above, a period
of from about 1 hour to about 10 hours, preferably from about 1 hour to 5 hours is sufficient.
After completion of the reaction, the desired compounds can be obtained from the
reaction mixture by conventional means known in the art. For example, the working-up of
reaction mixtures, especially in order to isolate desired compounds, follows customary
procedures, known to the organic chemists skilled in the norms of the art and steps, e.g.
selected from the group comprising but not limited to extraction, neutralization, crystallization,
chromatography, evaporation, drying, filtration, centrifugation and the like.
The intermediate compound of formula II can be alternatively prepared by the processes
as described in the examples herein.
The X in the compound of formula V is a leaving group selected from the group
consisting of halogen (CI, Br, I), methanesulphonate, benzene sulphonate, p-toluenesulphonate,
4- nitrobenzene sulphonate, 4-bromobenzene sulphonate and trifluoromethyl sulphonate.
Preferably the X is chloro.
In another embodiment, the present invention provides a process for the preparation of
Iloperidone of formula I
compinsmg
reacting the intermediate compound 4-(3'-propoxy)-3-methoxy acetophenone
of formula (II)
II
Where X is same as defined above.
with a compound 6-fluoro-3(4-piperidinyl)-l,2-benzisoxazole or a salt thereof of formula
(IV)
(IV)
in the presence of a base and a solvent.
The base that can be used include organic base or inorganic base. The organic base is
selected from the group consisting of triethylamine, tripropylamine, pyridine,
diisopropylamine, diisopropylethylamine or mixture thereof. Inorganic bases include
ammonia, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide,
potassium ethoxide, potassium tert-butoxide and the like; alkali metal carbonates such as
sodium carbonate, potassium carbonate, sodium hydrogen carbonate and the like; and alkali
metal hydroxides, such as sodium hydroxide, potassium hydroxide and the like or mixtures
thereof, preferably potassium carbonate.
The solvents that can be used include but are not limited to water, halogenated solvents
such as dichloromethane, ethylene dichloride, chloroform, chlorobenzene and the like; esters
such as ethyl acetate, isopropyl acetate, tertiary butyl acetate and the like; hydrocarbon solvents
such as n-heptane, cyclohexane, n-hexane, toluene, xylene and the like; ethers such as
tetrahydrofuran, 1,4-dioxane and the like; aprotic polar solvents such as N,Ndimethylformamide
(DMF), dimethylsulfoxide (DMSO), N,N-dimethylacetamide (DMA), Nmethyl
pyrrolidine ( MP) and the like; or mixtures thereof in various proportions without
limitation. Preferably, ,-dimethyl formamide (DMF) is being used.
The compound of formula IV can be used in the formed of acid addition salt preferably
hydrochloric acid salt form is being used.
The molar ratio of compound of formula II and IV can be from about 0.25 : 2.5,
preferably 1: 1 is being used.
The reaction temperature and time should be suitable to bring the reaction to completion
at a minimum time, without the production of unwanted side products. In general, it is
convenient to carry out the reaction at a temperature of from about 35°C to about 100°C or
boiling point of the solvent(s) used, preferably at a temperature of from about 50°C to about
100 °C. The time required for the reaction may also vary widely, depending on many factors,
notably the reaction temperature and the nature of the reagent and solvent employed. However,
provided that the reaction is effected under the preferred conditions discussed above, a period
of from about 1 hour to about 0 hours, preferably from about 1 hour to 5 hours is sufficient.
After completion of the reaction, the desired compounds can be obtained from the
reaction mixture by conventional means known in the art. For example, the working-up of
reaction mixtures, especially in order to isolate desired compounds, follows customary
procedures, known to the organic chemists skilled in the norms of the art and steps, e.g.
selected from the group comprising but not limited to extraction, neutralization, crystallization,
chromatography, evaporation, drying, filtration, centrifugation and the like.
In another embodiment, the present invention provides alternate process for the
preparation of Iloperidone of formula I
I
compirising :
a) reacting the intermediate compound 4-(3'-Chloropropoxy)-3-methoxybenzonitrile of
Formula
(V)
(V) ,
Where X is same as defined above.
with a compound 6-fluoro-3(4-piperidinyl)-l,2-benzisoxazole or a salt thereof of formula (IV)
(IV)
in the presence of a base and an organic solvent to give 4'-[3-[4-(6-Fluoro-l ,2-benzisoxazol-3-
yl)piperidino]propoxy]-3'-methoxy benzonitrile of formula X
b) reaction of the compound of formula X with Grignard reagent in the presence of catalyst
cuprous (I) salts to afford compound of formula I.
The solvents that can be used in step a) include but are not limited to alcohols such as
methanol, ethanol, isopropyl alcohol and the like; halogenated solvents such as
dichloromethane, ethylene dichloride, chloroform, chlorobenzene and the like; esters such as
ethyl acetate, isopropyl acetate, tertiary butyl acetate and the like; hydrocarbon solvents such as
n-heptane, cyclohexane, n-hexane, toluene, xylene and the like; ethers such as tetrahydrofuran,
1,4-dioxane and the like; aprotic polar solvents such as ,-dimethylformamide (DMF),
dimethylsulfoxide (DMSO), ,-dimethylacetamide (DMA), N-methyl pyrrlolidine (NMP)
and the like; or mixtures thereof in various proportions without limitation. Preferably, N,Ndimethyl
formamide (DMF) is being used.
The base may include organic base or inorganic base. The organic bases that can be
used include, but are not limited to triethylamine, tripropylamine, pyridine, diisopropylamine,
diisopropylethylamine and the like, Inorganic bases include ammonia, alkali metal alkoxides
such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide,
potassium ethoxide or potassium tert-butoxide; alkali metal carbonates such as sodium
carbonate or potassium carbonate, sodium hydrogen carbonate; and alkali metal hydroxides,
such as sodium hydroxide or potassium hydroxide and the like or mixtures thereof, preferably
potassium carbonate.
The reaction time and the temperature should be suitable to bring the reaction to
completion at a minimum time, without the production of unwanted side products. n general, it
is convenient to carry out the reaction at a temperature of from about 35°C to about 100°C or
boiling point of the solvent(s) used, preferably at a temperature of from about 50°C to about
100 °C. The time required for the reaction may also vary widely, depending on many factors,
notably the reaction temperature and the nature of the reagent and solvent employed. However,
provided that the reaction is effected under the preferred conditions discussed above, a period
of from about 1 hour to about 0 hours, preferably from about 1 hour to 5 hours is sufficient.
The solvents that can be used in step b) grignard reaction include but are not limited to
halogenated solvents such as dichloromethane, ethylene dichloride, chloroform, chlorobenzene
and the like; hydrocarbon solvents such as n-heptane, cyclohexane, n-hexane, toluene, xylene
and the like; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and the like; or mixtures
thereof in various proportions without limitation. Preferably, ether and toluene are being used.
The cuprous (I) salts that can be used in step b) include but are not limited to cuprous
chloride, cuprous bromide, cuprous iodide, cuprous cyanide and cuprous bromide-dimethyl
sulphite. Preferably cuprous chloride is being used.
The reaction temperature and time should be suitable to bring the reaction to completion
at a minimum time, without the production of unwanted side products. In general, it is
convenient to carry out the reaction at a temperature of from about 35°C to about reflux
temperatures of the reaction mixture or the solvents used preferably at a temperature of from
about 45°C to about reflux temperatures. The time required for the reaction may also vary
widely, depending on many factors, notably the reaction temperature and the nature of the
reagent and solvent employed. However, provided that the reaction is effected under the
preferred conditions discussed above, a periocf of from about 30 minutes to about 10 hours,
preferably from about 1 hour to about 6 hours is sufficient.
In yet another embodiment, the present invention provides a process for purifying
iloperidone comprising: a) providing a solution of iloperidone in a solvent or a mixture of
solvents or their aqueous mixtures and b) precipitating the solid from the solution, and c)
recovering the iloperidone in pure form.
The solvents include but are limited to water, alcohols such as methanol, ethanol,
isopropanol and the like; ketones such as acetone, methyl ethyl ketone, ethyl methyl ketone and
the like; nitriles such as acetonitrile, propionitrile and the like; hydrocarbons such as toluene,
n-hexane, n-heptane, cyclohexane and the like; aprotic polar solvents such as N,N-dimethyl
formamide (DMF), dimethyl sulfoxide (DMSO) and the like; ethers such as dimethyl ether,
diethyl ether, isopropyl ether, methyl tertiary butyl ether (MTBE), tetrahydrofuran, ,4-dioxane
and the like; esters such as ethyl acetate, isopropyl acetate, isobutyl acetate, t-butyl acetate and
the like; or mixtures thereof in various proportions without limitation. Preferably alcohols and
water mixture.
The temperature for dissolution can range from about 25 °C to about 100°C or reflux
temperatures of the solvents used, preferably at about 3Q°C. The time period for dissolution can
be range from about 30 minutes to about 5 hours, preferably 1 hour. The solution obtained is
optionally filtered through celite or diatamous earth to separate the extraneous matter present or
formed in the solution by using conventional filtration technique known in the art. The
precipitation of solid in b) above is achieved but not limited to evaporation, cooling, drying, by
adding antisolvent and the like.
The temperature range for precipitation of solid can be from about -10 °C to about
30°C, preferably about 0-5°C.
The time period for complete precipitation of solid can range from about 30 minutes to
about 5 hours, preferably 1 hour.
Iloperidone obtained by the processes described can be dried can be from about 25°C to
about 75°C, preferably at about 50°C and at reduced pressure of about e.g. 5 to 20 mbar, for a
period of about 1 to about 0 hours. Preferably 1 hour.
In another embodiment, the present invention provides iloperidone obtained by the
processes described herein above having purity greater than about 98.0 area % to about 99.0
area % as measured by HPLC, preferably greater than about 99.0 area % to about 99.5 area%,
more preferably greater about 99.5 area % to about 99.8 area .
In yet another embodiment, the present invention provides iloperidone obtained by the
processes described herein above having individual impurities lower than about 0.15 area ,
preferably lower than or equal to 0.1 area % and total impurities lower than about 0.5 area %,
preferably lower than 0.25 area % as measured by HPLC.
In another embodiment, the present invention provides Iloperidone having the
compound 4-hydroxy-3- methoxy benzaladehyde of structural formula VII
VII
in an amount less than or equal to 0. 0 area % as measured by HPLC.
In yet another embodiment, the present invention provides Iloperidone having the
compound 4-(3-chIoropropoxy) -3- methoxy benzaladehyde of structural formula VIII
VIII
in an amount less than or equal to 0.10 area % as measured by HPLC.
In a still further embodiment, the present invention provides Uoperidone having
compound l-[4-(3-chloropropoxy) -3- methoxy phenyl] ethanone of structural formula IX
IX
in an amount less than or equal to 0.10 area % as measured by HPLC.
In yet further embodiment, the present invention provides Uoperidone having the
compound 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole of structural formula IV
IV
in an amount less than or equal to 0.10 area % as measured by HPLC.
Advantageously, Uoperidone obtained by the processes described above has residual
organic solvents or organic volatile impurities comprises less than the amount recommended
for pharmaceutical products, as set forth for example in ICH guidelines and U.S.
pharmacopoeia; less than about 2000ppm of methanol, ethanol, isopropanol, acetone, ethyl
acetate, cyclohexane, diethyl ether, diisopropyl ether and dimetyl sulfoxide, less than about
500 pp of dichloromethane, toluene and ,-dimethyl fomamide.
While the present invention has been described in terms of its specific embodiments,
certain modifications and equivalents will be apparent to those skilled in the art and are
intended to be included within the scope of the present invention.
EXAMPLES
EXAMPLE -1: Preparation of 4(3 -chloropropoxy)-3-methoxy acetophenone
using collins reagent as oxidizing agent
(24.5g, 0.245moles) Chromium trioxide was added to a solution of 38.8g (0.49moles) of
dry pyridine in 200ml of dry dichloromethane and stirred for 5 minutes in a clean and dry 500
ml 4 neck R.B.Flask at about 30°C. A solution of the l-[4-(3'-chloropropoxy)-3-methoxy
phenyl]ethanol (lOg, 41mmoles) in 100ml of toluene was added in one portion. A tarry black
deposit was separated immediately, after stirring for an additional 15 minutes at about 30°C,
the solution was decanted from the residue, and washed with 100ml of dichloromethane. The
organic layers were combined and distilled completely under vacuum to obtain the residue. To
the residue ether (100ml) was added, filtered to remove insoluble chromium salts followed by
washing with 5% cold aqueous sodium hydroxide solution and saturated brine solution. The
solvent was evaporated under vacuum to afford the oily residue. To the oily residue 30ml of
diisopropyl ether was added and cooled to about 0°C and stirred for 30minutes. The solid
separated was filtered and washed with chilled diisopropylether (10ml) to give the title
compound.
Yield: 8.15 gms (% Yield: 82%).
EXAMPLE -2: Preparation of 4-(3 -methanesulfony-oxypropoxy)-3-methoxy
acetophenone using collin's reagent as oxidizing agent
Same procedure as described in Ex. 1 using l-[4-(3'-methanesulfonyloxypropoxy)-3-
methoxyphenyl] ethanol instead of l-[4-(3'-chloropropoxy)-3-methoxy phenyl]ethanol to
provide the title compound.
Yield: 2 gms (% Yield: 80%).
EXAMPLE -3: Preparation of 4(3 -chloropropoxy)-3-methoxy acetophenone using
DMSO-DCC as oxidizing agent
(5g, 20mmoles) of l-[4-(3'-chloropropoxy)-3-methoxy phenyl] ethanol in 20 ml of
dimethylsulfoxide (DMSO) and toluene (70ml) containing dicyclohexyl-carbodiimide (DCC)
(12,4g, 60mmoles) were charged into a clean and dry 500 ml 4 neck R.B.Flask. Anhydrous
orthophosphoric acid (0.4ml of a 5M solution in dimethylsulfoxide (DMSO), 2mmoles) was
added, and the resultant reaction mixture was kept at about 30°C for overnight. 100ml of water
was added and filtered after 30minutes. The Filtrate was taken and washed the organic layer
with 50ml of aqueous hydrochloric acid solution and 50ml of sodium bicarbonate solution and
50 ml of water. The solvent was distilled completely under reduced pressure and recrystallised
from diisopropyl ether to give the title compound.
Yield : 2.2 gms (% Yield: 44%).
EXAMPLE-4: Alternate process for the preparation of 4(3 -chIoropropoxy)-3-methoxy
acetophenone using DMSO-DCC as oxidizing agent
5g (20mmoles) of l-[4-(3'-chloropropoxy)-3-methoxyphenyl]ethanol was dissolved in
20 ml of dimethylsulfoxide (DMSO) (20ml) and toluene(70ml) containing dicyclohexylcarbodiimide
(DCC) (12.4g, 60mmoles) were charged into a clean and dry 500ml 4 neck
R.B.Flask. Pyridine (1.58g, 20mmoles) and trifluoroacetic acid (0.8ml, lOmmoles) were added
and the reaction mixture was kept at about 30°C for overnight. Workup same as described in
above example to afford the title compound.
Yield: 2.45 gms (% Yield: 49%).
EXAMPLE-5: Preparation of 4-(3 -benzenesulphonyloxy propoxy)-3-methoxy
acetophenone using DMSO-DCC as oxidizing agent
Same procedure as described in Ex. 4 using l-[4-(3'- benzenesulphonyloxy propoxy)-3-
methoxyphenyl]ethanol instead of l-[4-(3'-chloropropoxy)-3-methoxyphenyl]ethanol to
provide the title compound.
Yield: 2.45 gms (% Yield: 49%).
EXAMPLE -6: Preparation of 4(3 -chloropropoxy)-3-methoxy acetophenone using
DMSO-Acetic anhydride as oxidizing agent
5 g (20mmoles) of l-[4-(3'-chloropropoxy)-3-methoxyphenyl]ethanol dissolved in 130
ml of dimethyl sulfoxide (DMSO) and 40 ml of acetic anhydride were charged in a clean and
dry 500ml R.B.Flask and stirred at about 30°C for overnight, acetic anhydride was evaporated
under vacuum leaving a residue which was dissolved in ethyl acetate, washed with aqueous
sodium bicarbonate solution, and then with water, and dried over sodium sulphate. After
evaporation of the solvent the residue was crystallized from diisopropylether to give the title
compound.
Yield: 3.2 gms (% Yield: 64.5 %).
EXAMPLE -7: Preparation of 4-(3 -benzenesulphonyloxy propoxy)-3-methoxy
acetophenone using DMSO-Acetic anhydride as oxidizing agent
Same procedure as described in Ex. 6 using l-[4-(3 '-benzenesulphonyloxy propoxy)-3-
methoxyphenyl]ethanol instead of l-[4-(3 ,-chloropropoxy)-3rmethoxyphenyl]ethanol to give
the title compound.
Yield: 3.2 gms (%Yield: 64.5 %).
EXAMPLE-8: Preparation of l-[4-(3'- benzenesulphonyloxy propoxy)-3-methoxyphenyI]
ethanol
Magnesium turnings (4.8g, 0.2moles) and ether (100ml) were charged in a clean and
dry 500ml 4 neck R.B. Flask and stirred to make a suspension methyl iodide (35. 5g,
0.25moles) was added to the suspension by drop-wise. The resultant reaction mixture was
refluxed for 30minutes and cooled to about 0°C. 4-(3'-benzenesulphonyloxypropoxy)-3-
methoxy benzaldehyde (35g, O.lmoles) dissolved in 100ml toluene was added under cooling by
drop-wise. The resultant reaction mixture was raised heated to room temperature and stirred for
4 hours at 25-30°C. Decomposed the reaction mixture into ice and acidified with aqueous
sulfuric acid. Separated the organic layer and aqueous layer extracted into toluene (50ml><2).
The organic layer washed with water (50ml) followed by brine solution (50ml) and distilled
completely under reduced pressure to yield the title compound as yellow oil. Yield: 30 gms.
EXAMPLE-9: Preparation of 4(3 -chloropropoxy)-3-methoxy acetophenone using
pyridinium chlorochromate as oxidizing agent
(13.5g, 63mmol) pyridinium chlorochromate (PCC) and 100ml of anhydrous
dichloromethane were charged into a clean and dry 500 ml 4neck RB Flask. l-[4-(3'-
chloropropoxy)-3-methoxy phenyl] ethanol (lOg, 41mmol) in 100ml of toluene was charged at
about 30°C. The resultant reaction mixture was stirred for about lhour 30 minutes and 100ml
of dichloromethane was added and the supernatant solution was decanted from the black gum.
The solvent was distilled completely under vacuum to get an oily residue. To the residue 30ml
of diisopropylether was added to give the title compound.
Yield: 8 gms (% Yield: 80%).
EXAMPLE - 10: Preparation of 4-(3 -chloropropoxy)-3-methoxy acetophenone using
pyridinium chlorochromate as oxidizing agent.
23.1ml of 6M hydrochloric acid was charged in clean and dry 500ml 4 neck R.B.Flask
followed by addition of 12.5g of chromium (VI) oxide under stirring. After 5 min. the
homogenous solution was cooled to about 0°C and 12.25ml of pyridine was added over lOmin.
The orange-yellow precipitate was heated to about 30°C and l-[4-(3'-chloropropoxy)-3-
methoxy phenyl] ethanol (lOg) (41 mmol) in 200ml toluene was added at once. After 2 hours
of stirring at about 30°C, the organic phase was separated and the aqueous phase was extracted
with toluene (2x50ml). The organic layers were combined and washed with water (2x50ml).
The organic layer was separated and distilled completely to get an oily residue and
recrystallised from diisopropylether to give the title compound.
Yield: 7.8 gms
EXAMPLE -11: Preparation of 4-(3 -benzenesulfonyloxypropoxy)-3-methoxy
acetophenone using pyridinium chlorochromate as oxidizing agent.
Same procedure as described in Ex. 10 using l-[4-(3'-benzenesulfonyloxypropoxy)-3-
methoxy phenyl]ethanol (15g,4 1mmol) to give the title compound.
Yield : 12.5 gms (%Yield: 84%).
EXAMPLE -12: Preparation of 4-(3 ,-benzenesulfonyloxypropoxy)-3-methoxy
acetophenone using pyridinium chlorochromate on alumina as oxidizing
agent
(7.5gr., 6.1m.mol) pyridinium chlorochromate on alumina reagent was added to a flask
containing a solution of l-[4-(3'-chloropropoxy)-3-methoxyphenyl]ethanol (9.3gr., 38m.mol)
in 100ml. toluene and stirred for about 2 hrs. The reaction solution was filtered, and washed
with (3x 10ml.) of toluene. The combined filtrates were evaporated and recrystallized from
aqueous methanol to yield the title compound.
Example-13: Preparation of 4-(3'-chloropropoxy)-3-methoxy acetophenone using
pyridinium dichromate as oxidizing agent
30.75gr. (81.8m.mol) of pyridinium dichromate and 75ml. of dichloromethane were
charged into a clean and dry 500ml 4 neck R.B.Flask. 10gr.(41m.mol) of l-[4-(3'-
chloropropoxy)-3-methoxy phenyl]ethanol in 100ml. of toluene was added in one portion. The
resulted reaction mixture was stirred at about 30°C for about 4hrs. The chromium salts
separated were filtered and washed with 50ml. of toluene. The filtrate was washed with water
(2x50ml) and distilled completely under vacuum to furnish the oily residue. To the oily residue,
30ml. of di-isopropyl ether was added and cooled to about 0°C and stirred for about 30min.The
separated solid was filtered and the solid obtained was washed with 10ml. of chilled diisopropyl
ether to afford the title compound.
Yield : 7.72 gms (%Yield: 77%).
Example-14: Preparation of 4-(3'-p-toIuenesulfonylpropoxy)-3-methoxy acetophenone
using pyridinium dichromate as oxidizing agent
Same procedure as described in Ex. 3 using l-[4-(3'-p-toluenesulfonyloxypropoxy)-3-
methoxyphenyl]ethanol to provide 12gr. of the title compound as an off-white crystalline
powder.
Yield: 12 g (%Yield: 78%).
Example-15: Preparation of 4-(3 -Chloropropoxy)-3-methoxybenzonitriIe (V)
114.2gms (0.5moles) of 4-(3 -chloropropoxy)-3-methoxy benzaldehyde (VI) was
dissolved in 200ml. of preheated 95% alcohol in a clean and dry R.B. Flask. To the resultant
reaction solution a warm solution of 42gms (0.6mol.) of hydroxylamine hydrochloride in 50ml.
of water was added. The two solutions were mixed thoroughly, and a solution of 30gms
(0.75mol.) of sodium hydroxide in 40ml. of water was added drop-wise. The resultant reaction
mixture was stirred at about 30°C for about 2 hours 30 minutes. The separated white crystalline
solid was filtered and the solid was washed with copious amount of water. The obtained
intermediate oxime was suspended in lOOgms of acetic anhydride and heated to reflux for
about 30 minutes. After completion of the reaction, the reaction mixture was quenched by
adding to 300ml of ice-cold water slowly under stirring. The solid separated was filtered and
the solid obtained was washed with copious amount of water. The solid obtained was
recrystallised from 300ml of methanol using decolourising carbon to afford the title compound.
Yield : 84.5 gms (% Yield : 75%).
Example-16: Preparation of l-^-^'-ChloropropoxyJ-S-methoxyphenyl] ethanone (II)
(10.6gr., 0.44moles) Magnesium turnings and 100ml. diethyl ether were charged in a
clean and dry 1 lilt. 4 neck R.B.Flask. 78.7gms (0.55moles) of methyl iodide in 100ml. of ether
was added at about 20°C.(after addition of 4-5gr. Of methyl iodide initiation started). The
resultant reaction mixture was refluxed for about 30min. To the resultant suspension 1litre of
toluene was added and the solvent was distilled to a volume of about 200ml. Then 50gms
(0.22moles) of 4-(3'-chloropropoxy)-3-methoxybenzonitrile in 250 ml of toluene was added
and the resultant reaction mixture was refluxed for about 3hrs. The reaction mixture was cooled
to about 0°C and 800ml. of 10% HC1 solution was added drop-wise. The resultant reaction
mixture was refluxed for about 6hrs. The reaction mixture was cooled and the organic layer
was separated. The organic layer was washed with 200ml of 10%w/v sodium carbonate
solution followed by 200ml of water. The organic layer was separated and the solvent was
distilled-off completely under vacuum to afford the residue. The residue was re-crystallized
from 200ml of di-isopropyl ether to afford the title compound as an off-white crystalline solid.
Yield: 37.6 gms (% Yield: 75%).
Example-17: Preparation of l-^-^-p-ToluenesulfonyloxypropoxyJ-S-methoxy
phenyl] ethanone
Same procedure as described in Ex. 16 using 4-(3'-p-toluene sulfonyloxypropoxy)-3-
methoxybenzonitrile and the solid was recystallised from methanol to give the title compound.
Yield: 36.8 gms (%Yield: 70%).
Example-18: Alternate process for the preparation of l-^-^-ChloropropoxyJ-Smethoxyphenyl]
ethanone (II)
To a 3 molar solution of methyl magnesium iodide in diethyl ether (86.3 gms (0.26mol)
added 30 gms (0.13 mol) of 4-(3'-chloropropoxy)-3-rnethoxybenzonitrile in 300 ml of
anhydrous toluene and 230 mg (2.32 mmol) of cuprous chloride and the resultant mixture was
refluxed under nitrogen for about lhr.The reaction mixture was cooled to about 25-30 °C and
50 ml of water was added slowly for about 15 minutes followed by addition of 332 ml of (15%
v/v) sulphuric acid. The reaction mixture was stirred for about 2 hours under reflux, 100ml of
toluene was added. Organic and aqueous layers were separated and the aqueous layer was
extracted with 100 ml of toluene. The organic layers were combined and washed with 100 ml
of 10%w/v sodium carbonate solution and then with 100 ml of water. The solvent was distilled
completely under vacuum and the residue was re-crystallized from 200ml of di-isopropyl ether
to afford the title compound as an light brown coloured solid.
Yield: 25 gms (%Yield: 77.5%).
Example-19: Alternate process for the preparation of l-^-p'-Chloropropoxy)^-
methoxyphenyl] ethanone (II)
To a 3 molar solution of methyl magnesium iodide in diethyl ether (49.8 gms (0.15mol)
added 30 gms (0.13 mol) of 4-(3 1-chloropropoxy)-3-methoxybenzonitrile in 300 ml of
anhydrous toluene and 230 mg (2.32 mmol) of cuprous chloride and the resultant mixture was
refluxed under nitrogen for about 2hrs.The reaction mixture was cooled to about 25-30 °C and
50 ml of water was added slowly for about 15 minutes followed by addition of 332 ml of (15%
v/v) sulphuric acid. The reaction mixture was stirred for about 2 hours under reflux, 100ml of
toluene was added. Organic and aqueous layers were separated and the aqueous layer was
extracted with 100 ml of toluene. The organic layers were combined and washed with 00 ml
of 10%w/v sodium carbonate solution and then with 100 ml of water. The solvent was distilled
completely under vacuum and the residue was re-crystallized from 200ml of di-isopropyl ether
to afford the title compound as an light brown coloured solid. Yield: 24 gms (74.4%).
Example-20: Alternate process for the preparation of 4-(3 -Chloropropoxy)-3-
methoxy benzonitrile (V)
To 2.28gms (0.01 mole) of 4-(3'-Chloropropoxy)-3-methoxy benzaldehyde , 0.8gms
(0.015moles) of hydroxy 1amine hydrochloride, 1.25 gms of sodium formate and 15 ml (98-
100%) of formic acid were added and the resultant reaction mixture was refluxed for about
lhr.The title compound was obtained by dilution with water as a colourless crystals.
Yield: 2.1 gms (% Yield : 93%).
Example-21: Alternate process for the preparation of 4-(3 -Chloropropoxy)-3-
methoxybenzonitrile (V)
To 74.5 gms (0.5mol) of 4-Hydroxy-3-methoxybenzonitrile in 450ml. of acetone was
added 136gms ( 1 mole) of potassium carbonate and the resultant reaction mixture was stirred at
about 25-30°C for about 5min. To the reaction suspension 1 0 gms (0.7mol) of 3-Chloro-lbromo
propane was added drop-wise at about 25-35°C for about 30mins. The resultant reaction
mixture was refluxed for about 12hrs. The undissolved inorganic salts was filtered off and
washed with acetone. The solvent was distilled completely under vacuum and the residue was
re-crystallised from 300ml of isopropyl alcohol to afford the title compound as white
crystalline solid.
Yield: 92.5gms (% Yield : 82%).
Example-22: Preparation of 4-(3 -p-toIuenesulfonyloxypropoxy)-3-methoxy
benzonitrile
Step-1:
To 74.5gr.(0.5mol) of 4-Hydroxy-3-methoxy benzonitrile in 450ml. of acetone, was
added 136 gms ( 1 mol.) of potassium carbonate and stirred at about 25-30°C for about 5min.
To the resultant reaction suspension 97.3gms (0.7mol) by drop-wise at about 25-35°C and
refluxed the mixture for about 12hrs. The separated inorganic salts were filtered off and washed
with acetone. The solvent was distilled completely under vacuum and the solid obtained was
recrystallised from isopropyl alcohol to afford the intermediate compound.
Step-2:
To 50gms (0.24mol) of 4-(3'-Hydroxypropoxy)-3-methoxy benzonitrile in 200ml.of
cyclohexane was added 26gms (0.24 mol) of sodium carbonate and 46gms (0.24mol) of ptoluenesulfonyl
chloride was by drop-wise. The resultant reaction mixture was refluxed for
about 4-6hrs. After completion of the reaction, the reaction mass was cooled to about 25-30 °C
and the separated inorganic salts were filtered off. and washed with cyclohexane. The solvents
were distilled completely and solid obtained was recrystallised from 150 ml of ethyl acetate to
afford the title compound as white crystalline powder.
Yield: 60.5 gms (%Yield : 75%).
Example-23: Preparation of Iloperidone (I)
4-(3'-tosyloxypropoxy)-3-methoxy acetophenone (37.8g,0.1 moles), sodium carbonate
(42.4g,0.4moles) and 220ml of ,-dimethylformamide (DMF) were charged in a clean and
dry 500ml 4 neck R.B.Flask. 6-fluoro-3(4-piperidinyl)-l,2-benzisoxazole hydrochloride
(25.5g, O.lmoles) was added at about 65°C and stirred for about 8 hrs. The reaction mixture
was stirred at about 90°C for about 6 hours. After completion of the reaction, the reaction
mixture was quenched by pouring into water and filtered after 30minutes. The solid obtained
was recrystallised from aqueous methanol to get pure Iloperidone (I) as white crystalline
powder.
Example -24: Alternate process for the preparation of Iloperidone (I)
6-Fluoro-3-(4-piperidinyl)-l,2benzisoxazole hydrochloride (IV) (25.5gr., O.lmol.),
potassium carbonate (27.0gr.,0.2mol.) and 80ml. of ,-dimethyl formamide (DMF) were
charged into a clean and dry 500ml 4 neck R.B.Flask. 4-(3'-chIoropropoxy)-3-
methoxybenzonitrile (V) (20.0gr.,0.08mol.) and potassium iodide (680mg.) were added at
about 30°C . The resultant reaction mixture was heated to about 90°C and stirred for about
9hrs. After completion of the reaction, the reaction mixture was cooled to about 30°C and
400ml. of water was charged. After stirring for 30min., the separated solid was filtered and the
solid obtained and washed with 50ml. of water. Recrystallised from methanol and water (3:1)
using decolourising carbon to afford the title compound as an off-white crystalline powder.
Yield: 28.4gr (% Yield : 78%).
40.95gr.(0.1mol.) of 4'-[3-[4-(6-Fluoro-l,2-benzisoxazol-3-yl)-piperidino]-propoxy]-
3'-methoxy benzonitrile (X) in 400ml. of toluene was added to a 3.0 molar solution of methyl
magnesium iodide(66.4gr.,0.2mol.) in diethyl ether taken in a clean and dry 1 lit. 4 neck
R.B.Flask at once. 309gr. of cuprous chloride was added and the resultant reaction mixture was
quickly heated to reflux and stirred for about 2hrs. The reaction mixture was cooled to about
25°C, 50ml. of water was added followed by addition of 350ml. of 15% v/v sulphuric acid
solution. The resultant reaction mixture was heated to reflux for about 2hrs. The reaction
solution was cooled to about 30°C, and the organic layer was separated and the aqueous layer
was extracted with toluene (2x1 00ml.).The organic layers were combined and washed with
200ml. of 10%w/v sodium carbonate solution followed by 200ml. of water. The solvent was
distilled-off completely under vacuum to yield Iloperidone as yellow oil which was solidified
upon standing. Recrystallised from methanol and water (3:1) by using decolourising carbon to
afford Iloperidone as off-white crystalline powder.
Yield: 29.8gr.(% Yield: 70%).
PURIFICATION PROCESSES
Example -1: Purification of Iloperidone (I) using Methanol: Water (1:1)
42.5gms of crude Iloperidone was dissolved in a mixture of 744ml of methanol and 3 19
ml of water at reflux. 8gms of charcoal carbon was charged and filtered hot on celite. The
reaction solution was cooled to about 25-30°C and 425ml. of water was added followed by
stirring for about 30min.. The separated solid was filtered and the solid was washed with 50ml.
of methanol-water mixture (1:1) to afford pure form of Iloperidone as a cream-light yellow
solid.
Yield: 32 gms (% Yield: 75%); Purity by HPLC: 99.75%.
Example -2: Purification of Iloperidone (I) using Methanol: Water (3:1)
32gms of Iloperidone was dissolved in a mixture of methanol (600ml.) and water
(100ml) at reflux. 6gms of charcoal carbon was charged under reflux and the resultant
suspension was filtered hot on celite. The filtrate was cooled to about 25-30°C and stirred for
about 20min.. The solution was further cooled to 0-5°C and stirred for about 30min.The
separated solid was filtered and the solid was washed 50 ml of precooled methanol to afford
pure form of Iloperidone as a white solid.
Yield: 24 gms (% Yield: 56%); Purity by HPLC: 99.8%.
Example -3: Purification of Iloperidone (I) using Ethyl acetate
42.5gms of crude Iloperidone was dissolved in ethyl acetate (212.5ml.) at reflux. . 8gms
of charcoal carbon was charged under reflux. The suspension was filtered hot on celite. The
filtrate solution was cooled to about 0-5°C and stirred for 30min. The separated solid was
filtered and the solid obtained was washed with 40 ml of precooled ethyl acetate to afford 34
g s of pure form of Iloperidone as a light brown solid.
Yield: 34 gms; Purity by HPLC: 99.5%.
Example -4: Purification of Iloperidone (I) using Toluene
42.5gms of crude Iloperidone was dissolved in 212 ml of toluene at reflux. 8gms of
charcoal carbon was charged and the suspension was filtered hot on celite. The filtrate solution
was cooled to about 25-30°C followed by further cooling to about 0-5°C,stirred for 30min. The
separated solid was filtered and the solid washed with 40ml of precooled toluene to afford 29.7
gms of pure form of Iloperidone as a light-yellow solid.
Yield: 29.7 gms; Purity by HPLC: 99.5%.
Example -5: Purification of Iloperidone (I) using Dimethyl formamide-Water
42.5gms of crude Iloperidone was dissolved in a mixture of 212.5 ml of N,Ndimethylformamide
(DMF) and 212.5 ml of water by heating to about 90°C. 8gms of charcoal
carbon was charged and filtered hot and the filtrate was cooled to about 25-30°C and stirred for
about 30min. The separated solid was filtered and the solid was washed with a mixture of N,Ndimethyl
formamide (DMF) and water ( 1:1) (50ml.) to afford Iloperidine in pure form as a
light-brown solid.
Yield: 30.6 gms; Purity by HPLC: 99.7%.
Example -6: Purification of Iloperidone (I) using Acetone
42.5gms of crude Iloperidone was dissolved 170 ml of acetone at reflux. 8gms of
charcoal carbon was charged, the resultant suspension was filtered hot and the filtrate was
cooled to about 25-30°C and stirred for about 5min. The filtrate was further cooled to about 0-
5°C and stirred for about 30min. The separated solid was filtered and the solid was washed
with 40 ml of precooled acetone to afford 29.7 gms of Iloperidone in pure form as a lightyellow
crystals. Purity by HPLC: 99.5%.
Example -7: Purification of Iloperidone (I) using Methanol: Water (3:1)
29.7gms of Iloperidone was dissolved in a mixture of 556 ml of methanol and 188 ml of
water at reflux. 6 gms of charcoal carbon was charged and the resultant suspension was filtered
hot. The filtrate was cooled to about 25-30°C followed by further cooling to about 0-5°C and
stirred for about 30min. The separated solid was filtered and the solid was washed with 30 ml
of precooled methanol to afford Iloperidone in pure form as a white crystalline solid.
Yield : 22.2 gms ; Purity by HPLC: 99.4%.
Example -8: Purification of Iloperidone (I) using Ethanol
42.5gms of crude Iloperidone was dissolved 340ml of ethanol at reflux. 8gms of
charcoal carbon was charged and the resultant suspension was filtered hot on celite. The filtrate
was cooled to about 25-35°C followed by further cooling to about 0-5°C, stirred for about
30min. The separated solid was filtered and the solid was washed with 80 ml of precooled
ethanol to give 34gms of Iloperidone as a light-brown solid. Repeated the same crystallization
with 34gr. of iloperidone in 272ml. of ethanol to obtain pure Iloperidone as a white crystalline
solid.
Yield: 25.5gr.(% Yield : 60% based on theoretical weight); Purity by HPLC: 99.6%.
WO 2012/032532
We Claim:
1) A process for preparing intermediate 4-(3 1-propoxy)-3-methoxyacetopherione compound of
formula (II),
(II)
Where X is a leaving group selected from halogen, methanesulphonate, benzene sulphonate,
p- toluenesulphonate, 4- nitrobenzene sulphonate, 4-bromobenzene sulphonate and
trifluoromethyl sulphonate
comprising:
reacting a novel compound l-[4-(3'-propoxy)-3-methoxy phenyl]ethanoI of
formula (III),
(III)
Where X is as defined above
with a suitable oxidizing agent optionally in the presence of an organic solvent..
2) A process of claim 1, wherein the oxidizing agent is selected from the group consisting of
collin's reagent, pyridinium dichromate, pyridinium chlorochromate, pyridinium
chlorochromate on alumina, DMSO-DCC, DMSO-acetic anhydride or mixtures thereof.
Preferably DMSO-DCC or DMSO-acetic anhydride
3) A process of claim 1, wherein the organic solvent optionally used is selected from the group
consisting of water, halogenated solvents like dichloromethane, ethylene dichloride, •
chloroform, chlorobenzene, esters like ethyl acetate, isopropyl acetate, tertiary butyl acetate
hydrocarbon solvents like n-heptane, cyclohexane, n-hexane, toluene, xylene, ethers like
tetrahydrofuran, 1,4-dioxane, aprotic polar solvents like ,-dimethylformamide (DMF),
dimethylsulfoxide (DMSO), ,-dimethylacetamide (DMA), N-methyl pyrrolidine (NMP)
or mixtures thereof, preferably water or halogenated solvent.
4) A process of claim 1, wherein the reaction is carried out at a temperature of from about 20°C
to about 100°C and the time period for the reaction is from about 1 hour to about 0 hours.
5) The process of claim 1, wherein the reaction is carried out optionally in the presence of
an acid.
6) A process for preparing intermediate 4-(3 1-chloropropoxy)-3-methoxy acetophenone
compound of Formula II,
II
Where X is a leaving group selected from halogen, methanesulphonate, benzene sulphonate,
p-toluenesulphonate, 4- nitrobenzene sulphonate, 4-bromobenzene sulphonate and
trif!uoromethyl sulphonate.
comprising:
a) reacting a compound 4-(3 1-chloropro xy)-3-methoxy benzaldehyde of Formula VI,
VI
Where X is same as defined above.
with a suitable reagent in the presence of an organic solvent to give the compound 4-
chloropropoxy)-3-methoxybenzonitrile of Formula V
V
Where X is same as defined above.
b) reacting the compound of formula V with a Grignard reagent followed by treating the
intermediate obtained with an acid in the presence of an organic solvent to give the desired
intermediate compound of formula II.
c) the conversion of compound of formula V to compound of formula II is carried
out in the presence of cuprous (I) salts like cuprous chloride, cuprous bromide, cuprous
idodide, cuprous cyanide or cuprous bromide-dimethyl sulphate.
7) A process of claim 6, wherein the suitable reagent for the conversion of compound of
formula VI to V is selected from the group consisting of hydroxyl amine hydrochloride or
hydroxyl amine sulphate and the acid is acetic anhydride or sodium formate and formic acid
or sodium acetate and acetic acid.
8) A process of claim 6, wherein the organic solvent is selected from the group consisting of
water, alcohols such as methanol, ethanol, isopropanol and the like; halogenated solvents
such as dichloromethane, ethylene dichloride, chloroform, chlorobenzene and the like;
esters such as ethyl acetate, isopropyl acetate, tertiary butylacetate and the like;
hydrocarbon solvents such as n-heptane, cyclohexane, n-hexane, toluene, xylene and the
like; ethers such as tetrahydrofuran, 1,4-dioxane, aprotic polar solvents such as N,N
dimethylformamide (DMF), dimethylsulfoxide (DMSO), ,-dimethylacetamide (DMA),
N-methyl pyrrolidine (NMP) or mixtures thereof, preferably ethanol.
9) A process of claim 6, wherein the reaction step a) is carried out at a temperature from about
30°C to about reflux temperatures and the time period for the reaction is from about 30
minutes to about 10 hours.
WO 2012/032532
10) A process for the preparation of Iloperidone of formula I
I
comprising :
reacting the intermediate compound 4-(3'-propoxy)-3-methoxy acetophenone of formula
( )
II
Where X is same as defined above.
with a compound 6-fluoro-3(4-piperidinyl)-l,2-benzisoxazole or a salt thereof of formula
(IV)
(IV)
in the presence of a base and a solvent.
11) The process of claim 10, wherein the base is selected from the group consisting of organic
bases like triethylamine, tripropylamine, pyridine, diisopropylamine,
diisopropylethylamine, inorganic bases like sodium methoxide, sodium ethoxide, sodium
tert-butoxide, potassium methoxide, potassium ethoxide potassium tert-butoxide, alkali
metal carbonates like sodium carbonate, potassium carbonate, sodium hydrogen
carbonate, alkali metal hydroxides like sodium hydroxide, potassium hydroxide or mixtures
thereof, preferably potassium carbonate.
1 ) The process of claim 10, wherein the solvents used is selected from the group consisting of
water, halogenated solvents like dichloromethane, ethylene dichloride, chloroform,
chlorobenzene ,esters like ethyl acetate, isopropyl acetate, tertiary butyl acetate,
hydrocarbon solvents like cyclohexane, toluene, xylene, ethers like tetrahydrofuran, 1,4-
dioxane, aprotic polar solvents like ,-dimethylformamide (DMF), dimethylsulfoxide
(DMSO), ,-dimethylacetamide, N-methyl pyrrolidine (NMP) or mixtures thereof,
preferably, ,-dimethyl formamide (DMF).
13) The process of claim 10, wherein the reaction is carried out at temperature from about 35°C
to about 100°C or boiling point of the solvent(s) used, preferably at a temperature of from
about 50°C to about 100 °C. and the time period is from about 1 hour to about 10 hours,
preferably from about 1 hour to 5 hours is sufficient.
1 ) An alternate process for the preparation of Iloperidone of formula I
comprising :
a) reacting the intermediate compound 4-(3 I-propoxy)-3-methoxybenzonitrile of
Formula (V)
(V)
where X is same as defined above.
with a compound 6-fluoro-3(4-piperidinyl)-l,2-benzisoxazole or a salt thereof of formula
(IV)
in the presence of a base potassium carbonate and an organic solvent dimethyl formamide
to give 4'-[3- [4-(6-Fluoro-l,2-benzisoxazol-3-yl)piperidino]propoxy]-3'-methoxy
benzonitrile of formula X
X
b) reaction of the compound of formula X with Grignard reagents in the presence of
catalyst cuprous (I) salts to afford compound of formula I .
15) The process of claim 14, wherein the base used in step a) is selected from the group
consisting of organic bases like triethylamine, tripropylamine, pyridine, diisopropylamine,
diisopropylethylamine, inorganic bases include ammonia, sodium methoxide, sodium
ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tertbutoxide,
sodium carbonate, potassium carbonate, sodium hydrogen carbonate, sodium
hydroxide, potassium hydroxide, or mixtures thereof, preferably potassium carbonate.
16) The process of claim 14, wherein the solvents used in step a) is selected from alcohols like
methanol, ethanol, isopropyl alcohol, halogenated solvents like dichloromethane, ethylene
dichloride, chloroform, chlorobenzene, esters like ethyl acetate, isopropyl acetate, tertiary
butyl acetate, hydrocarbons like cyclohexane, toluene, xylene, ethers like tetrahydrofuran,
1,4-dioxane, aprotic polar solvents like ,-dimethylformamide (DMF), dimethylsulfoxide
(DMSO), ,-dimethylacetamide (DMA), N-methyl pyrrolidine (NMP) or mixtures
thereof, preferably, ,-dimethyl formamide (DMF).
17) The process of claim 14, wherein the reaction is carried out at temperature from about 35°C
to about 100°C or boiling point of the solvent(s) used, preferably at about 50°C to about
100 °C and the time required is from about 1 hour to about 0 hours, preferably from about
1 hour to 5 hours is sufficient.
18) The process of claim 1 , wherein the solvent used in step b) is selected from halogenated
solvents like dichloromethane, ethylene dichloride, chloroform, chlorobenzene,
hydrocarbons like cyclohexane, toluene, xylene ethers like diethyl ether, tetrahydrofuran,
,4-dioxane or mixtures thereof, preferably, ether and toluene are being used.
) The process of claim 14, where in cuprous (I) salts used in step b) is selected cuprous
chloride, cuprous bromide, cuprous iodide, cuprous cyanide and cuprous bromide-dimethyl
sulphite, preferably cuprous chloride.
20) The process of claim 14, wherein the reaction is carried out at temperature from about
35°C to about reflux temperatures of the reaction mixture or the solvents used, preferably
from about 45°C to about reflux temperatures and the period is from about 30 minutes to
about 0 hours, preferably from about 1 hour to about 6 hours.
21) A process for purifying iloperidone comprising: a) providing a solution or suspension of
iloperidone in a solvent or a mixture of solvents or their aqueous mixtures and
b) precipitating the solid from the solution, and c) recovering the iloperidone in
substantially pure form.
22) The process of claim 21, wherein the solvent is selected from methanol, ethanol, ethyl
acetate, acetone, toluene, ,-dimethyl formamide, acetonitrile, methyl
tertiary butyl ether, methyl tertiary butyl methyl ether, tetrahydrofuran, 1,4-dioxane,
methyl ethyl ketone, n-hexane and mixtures thereof, and mixtures of said organic solvents
and water.
23) Iloperidone of preceding claims has a purity of at least about 98 area % by HPLC.
24) Iloperidone of claim 23, has a purity of at least about 99.5 area % by HPLC.
25) Iloperidone of preceding claims has less than about 0.5 area % of total impurities by
HPLC.
26) Iloperidone of preceding claims has less than about 0.1 area % of any individual impurity
by HPLC.
27) Iloperidone of preceding claims having the compound 4-hydroxy-3-methoxy
benzaladehyde of structural formula VII
VII
in an amount less than or equal to 0. 0 area % by HPLC.
28) Iloperidone of preceding claims having the compound 4-(3-chloropropoxy) -3- methoxy
benzaladehyde of structural formula VIII
VIII
in an amount less than or equal to 0.10 area % by HPLC.
29) Iloperidone of preceding claims having the compound l-[4-(3-chloropropoxy) -3- methoxy
phenyl] ethanone of structural formula IX
IX
in an amount less than or equal to 0.10 area % by HPLC.
30) Iloperidone of preceding claims having the compound 6-fluoro-3-(4- piperidinyl)-l,2
benzisoxazole of structural formula IV
IV
amount less than or equal to 0.10 area % by HPLC