WO2011055188A1 - An improved process for the preparation of iloperidone - Google Patents

An improved process for the preparation of iloperidone Download PDF

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Publication number
WO2011055188A1
WO2011055188A1 PCT/IB2010/002712 IB2010002712W WO2011055188A1 WO 2011055188 A1 WO2011055188 A1 WO 2011055188A1 IB 2010002712 W IB2010002712 W IB 2010002712W WO 2011055188 A1 WO2011055188 A1 WO 2011055188A1
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acid
iloperidone
salt
pxrd
ray diffraction
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PCT/IB2010/002712
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French (fr)
Inventor
Buchi Reddy Reguri
Muthulingam Arunagiri
Prasada Chari Yarroju
Saravanakumar Kasiyappan Gurusamy
Kondalarao Ponnapalli
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Orchid Chemicals And Pharmaceuticals Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems

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  • the present invention relates to an improved process for the preparation of Iloperidone of formula (I).
  • the present invention also provides a novel polymorph of acid addition salts of Iloperidone of formula (I).
  • Iloperidone is a psychotropic agent belonging to the chemical class of piperidinyl-benzisoxazole derivatives. Its chemical name is 4'-[3-[4-(6-Fluoro- 1 ,2-benzisoxazol-3 -yl)piperidino]propoxy]-3 '-methoxyacetophenone and is marketed under the brand name Fanapt®.
  • US RE 39,198 patent discloses a process for preparing Iloperidone by condensing 6-fluoro-3-piperidin-4-yl-benzo[d] isoxazole hydrochloride and 1- (4-(3-chloropropoxy)-3-methoxyphenyl)ethanone in a solvent such as dimethylfonnamide, acetonitnle or butanol and in the presence of a base such as potassium carbonate.
  • a solvent such as dimethylfonnamide, acetonitnle or butanol
  • a base such as potassium carbonate.
  • US 20050250813 Al publication provides an injectable depot formulation comprising crystals of Iloperidone or its metabolite or a pharmaceutically acceptable salt, hydrate, solvate, polymorph and stereoisomer thereof.
  • the main objective of the present invention is to provide an improved process for the preparation of Iloperidone of formula (I) from its acid addition salt, which would be more simple, economical and easy to implement on large scale preparation.
  • Another objective of the present invention is to provide a novel polymorph of Iloperidone acid addition salts and its process for the preparation.
  • Yet another objective of the present invention is to provide an improved process for the isolation of Iloperidone of formula (I) directly from the reaction mixture with high purity.
  • One more objective of the present invention is to provide an improved process for the purification of Iloperidone of formula (I).
  • the present invention provides an improved process for the preparation of Iloperidone of formula (I) or its acid addition salt comprising the steps of:
  • the present invention further provides an improved process for the purification of Iloperidone of formula (I), which comprises the steps of: a) obtaining a solution of Iloperidone of formula (I) in first organic solvent; b) optionally treating the solution obtained in step a) with activated carbon; c) optionally removing the first organic solvent from the solution obtained in step a) or b);
  • step d) mixing the solution obtained in step a) or b) or c) with second organic solvent;
  • FIG-1 The powder X-ray diffraction pattern of Iloperidone hydrochloride.
  • FIG-2 The powder X-ray diffraction pattern of Iloperidone hydrobromide.
  • FIG-3 The powder X-ray diffraction pattern of Iloperidone phosphate.
  • FIG-4 The powder X-ray diffraction pattern of Iloperidone bisulphate.
  • FIG-5 The powder X-ray diffraction partem of Iloperidone malonate.
  • FIG-6 The powder X-ray diffraction pattern of Iloperidone succinate.
  • FIG-7 The powder X-ray diffraction pattern of Iloperidone benzene sulphonate.
  • FIG-8 The powder X-ray diffraction pattern of Iloperidone methane sulphonate.
  • FIG -9 The powder X-ray diffraction pattern of Iloperidone oxalate.
  • FIG-10 The powder X-ray diffraction pattern of Iloperidone fumarate.
  • FIG-11 The powder X-ray diffraction pattern of Iloperidone p-toluene sulphonate.
  • FIG-12 The powder X-ray diffraction pattern of Iloperidone of formula (I).
  • FIG-13 The powder X-ray diffraction pattern of l-(4-(3-chloropropoxy)-3- methoxyphenyl) ethanone of formula (II).
  • the polar solvent used in step (i) is selected from ⁇ , ⁇ -dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetone, acetonitrile, propionitrile, methanol, ethanol, propanol, isopropanol, butanol, or a mixture of such solvents.
  • the base used in step (i) is selected from sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, calcium oxide, sodium acetate, sodium methoxide, sodium hydride, sodium amide, triethylamine, piperidine, diethylamine, N- ethyldiisopropylamine, N-(l-methylethyl)-2-propanamine, morpholine, 4- ethylmorpholine, l,4-diazabicyclo[2.2.2]octane, pyridine and the like.
  • the compound of formula (III) used for condensation is as its free base or its acid addition salt selected from hydrochloride, hydrobromide, hydrogen sulphate and the like; more preferably as its hydrochloride salt.
  • (iv) for preparing the acid addition salt of compound of formula (I), is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, o- phosphoric acid, fumaric acid, oxalic acid, succinic acid, tartaric acid, citric acid, lactic acid, malonic acid, maleic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, benzoic acid, formic acid, acetic acid and the like; more preferably hydrochloric acid .
  • the acid addition salt of compound of formula (I) is isolated by optionally removing the solvent from the reaction mixture by distillation and treating the residue with the corresponding acid in the same or different solvent selected from methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, dichloromethane, dichloroethane and the like.
  • the isolated acid addition salt of formula (I) is neutralized with base selected from sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, calcium oxide, sodium acetate, sodium methoxide, sodium hydride, sodium amide, pyridine, aniline, 4-ethylmorpholine, 1 ,4-diazabicyclo[2.2.2]octane, methylamine, ethylamine, propylamine, isopropylamine, triethylamine diethylamine, N-ethyldiisopropylamine and the like; more preferably triethylamine (TEA).
  • base selected from sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, calcium oxide, sodium acetate, sodium methoxide, sodium hydride, sodium amide, pyridine, aniline, 4-ethylmorpholine, 1 ,4-diazabicyclo[2.2.2]octane, methylamine, ethylamine
  • the isolated acid addition salt of formula (I) is neutralized in the presence of solvent selected from methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, dichloromethane, dichloroethane and the like.
  • the solid isolated in step (iii) is optionally recrystallized using solvent selected from methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, dichloromethane, dichloroethane ethyl acetate, isopropyl acetate and the like.
  • quenching the reaction mixture with water in step ii) means that addition of water to the reaction mixture or vice versa.
  • the first organic solvent used in step a) is selected from acetone, acetonitrile, chloroform, dichloromethane, dichloroethane and the like or mixtures thereof; more preferably acetone.
  • obtaining a solution of Iloperidone in first organic solvent is by directly from the reaction mixture or by dissolving Iloperidone in the corresponding organic solvent.
  • removing the first organic solvent either in step a) or b) is by conventional technique such as distillation under atmospheric pressure, distillation under vacuum and the like.
  • the second organic solvent used in step d) is selected from methanol, ethanol, isopropanol, n- propanol, butanol, water and the like or mixtures thereof; more preferably methanol.
  • the product obtained in step d) is optionally cooled and isolated by, filtration, washing and drying.
  • the present invention provides crystalline
  • Iloperidone hydrochloride is characterized by powder X-ray diffraction having 2 ⁇ values at 10.71, 16.77, 17.71, 18.27, 19.42, 19.73, 21.60, 22.06, 23.74, 24.95, 25.55, +0.2 ⁇ .
  • the present invention provides crystalline
  • Iloperidone hydrochloride is further characterized by powder X-ray diffraction having 2 ⁇ values at 9.83, 13.82, 14.57, 15.74, 16.0, 18.54, 20.54, 24.16, 27.90, 29.43, 29.73, 30.82, 31.23 +0.2 ⁇ .
  • the present invention provides crystalline Iloperidone hydrobromide is characterized by X-ray powder diffraction having 2 ⁇ values at 7.78, 11.34, 15.61, 16.83, 17.70, 18.16, 19.28, 19.55, 19.84, 21.25, 22.14, 23.50, 24.15, 25.14, 27.21, 29.52 ⁇ 0.20.
  • the present invention provides crystalline Iloperidone hydrobromide is further characterized by powder X-ray diffraction having 2 ⁇ values at 13.05, 13.66, 14.64, 15.79, 18.42, 20.67, 21.82, 23.83, 24.60, 26.56, 27.57, 27.81, 28.07, 30.91, 31.11, 31.49, 32.20, 33.02, 34.89 +0.2 ⁇ .
  • the present invention provides crystalline Iloperidone phosphate is characterized by X-ray powder diffraction having 2 ⁇ values at 4.66, 9.02, 10.31, 12.80, 14.12, 17.06, 18.13, 19.03, 20.64, 21.40, 22.70, 23.29, 24.45, 26.69, 27.47, 28.35, 30.80, 31.67, 39.90 +0.2 ⁇ .
  • the present invention provides crystalline Iloperidone bisulphate is characterized by X-ray powder diffraction having 2 ⁇ values at 9.6, 14.24, 16.52, 16.79, 23.42, 24.15 +0.2 ⁇ .
  • the present invention provides crystalline Iloperidone bisulphate is further characterized by X-ray powder diffraction having 2 ⁇ values at 6.26, 12.58, 13.35, 13.81, 18.54, 19.27, 25.37 +0.2 ⁇ .
  • the present invention provides crystalline Iloperidone malonate is characterized by X-ray powder diffraction having 2 ⁇ values at 13.36, 17.67, 20.77, 23.20, 25.48, 28.47 +0.2 ⁇ .
  • the present invention provides crystalline Iloperidone malonate is further characterized by X-ray powder diffraction having 2 ⁇ values at 9.59, 10.52, 14.38, 15.09, 15.42, 16.29, 21.11, 22.14, 24.30, 25.12, 26.45, 26.87, 27.28, 28.13, 30.59 +0.2 ⁇ .
  • the present invention provides crystalline Iloperidone succinate is characterized by X-ray powder diffraction having 2 ⁇ values at 8.18, 8.72, 11.47, 13.50, 13.73, 16.41, 16.79, 17.42, 18.00, 18.35, 18.58, 19.15, 24.04, 24.38, 26.57, 26.99 +0.2 ⁇ .
  • the present invention provides crystalline Iloperidone succinate is further characterized by X-ray powder diffraction having 2 ⁇ values at 11.95, 14.33, 20.08, 20.47, 21.01, 22.80, 24.77, 25.37, 25.91, 27.77, 29.05, 29.62, 31.20 ⁇ 0.20.
  • the present invention provides crystalline Iloperidone benzene sulphonate is characterized by X-ray powder diffraction having 2 ⁇ values at 9.22, 13.66, 14.75, 15.52, 15.86, 16.16, 17.24, 18.45, 18.62, 19.15, 20.42, 21.57, 24.99, 25.88 +0.2 ⁇ .
  • the present invention provides crystalline Iloperidone benzene sulphonate is further characterized by X-ray powder diffraction having 2 ⁇ values at 12.87, 16.84, 17.53, 20.83, 21.11, 22.05, 22.64, 23.20, 23.65, 24.02, 25.53, 27.09, 30.74 +0.2 ⁇ .
  • the present invention provides crystalline Iloperidone methane sulphonate is characterized by X-ray powder diffraction having 2 ⁇ values at 9.47, 13.95, 14.23, 15.94, 16.80, 17.06, 17.55, 18.99, 19.68, 21.67, 23.04, 23.74, 24.30, 24.80 +0.2 ⁇ .
  • the present invention provides crystalline Iloperidone methane sulphonate is further characterized by X-ray powder diffraction having 20 values at 11.81, 13.66, 14.80, 19.24, 22.06, 27.83 ⁇ 0.20.
  • the present invention provides crystalline Iloperidone oxalate is characterized by X-ray powder diffraction having 2 ⁇ values at 6.67, 6.99, 9.19, 10.14, 13.38, 14.06, 14.94, 16.12, 16.92, 20.12, 20.63, 21.10, 21.41, 22.01, 22.80, 23.06, 24.00, 24.80, 25.76, 27.02, 27.39, 28.36, 31.39, 31.87, 35.48 +0.20.
  • the present invention provides crystalline Iloperidone oxalate is further characterized by X-ray powder diffraction having 2 ⁇ values at 8.18, 10.77, 11.25, 17.4, 18.44, 19.03, 19.66, 26.18, 27.92, 30.13, 32.75, 33.22, 36.62, 36.80, 38.09, 38.48, 42.81, 43.67 ⁇ 0.20.
  • the present invention provides crystalline Iloperidone fumarate is characterized by X-ray powder diffraction having 2 ⁇ values at 8.48, 12.57, 14.23, 16.32, 16.58, 17.01, 17.91, 18.35, 19.74, 21.92, 24.32, 24.62, 24.97, 25.47, 25.89, 26.15 ⁇ 0.20.
  • the present invention provides crystalline Iloperidone fumarate is further characterized by X-ray powder diffraction having 2 ⁇ values at 8.14, 10.67, 12.11, 17.43, 20.34, 20.67, 22.89, 26.86, 27.55, 28.13, 30.25, 34.26, 42.60 +0.20.
  • the present invention provides crystalline Iloperidone p-toluene sulphonate is characterized by X-ray powder diffraction having 2 ⁇ values at 7.47, 12.46, 13.06, 13.87, 15.95, 17.25, 17.73, 18.15, 18.64, 19.87, 20.68, 22.11, 22.57, 23.31, 23.42, 23.66, 25.11, 26.07, 27.50 ⁇ 0.29.
  • the present invention provides crystalline Iloperidone p-toluene sulphonate is further characterized by X-ray powder diffraction having 2 ⁇ values at 6.73, 11.04, 11.45, 12.74, 15.06, 18.90, 19.47, 21.52, 24.00, 24.33, 24.54, 26.31, 26.93, 28.01, 29.31, 30.21, 31.98 +0.2 ⁇ .
  • the present invention provides crystalline Iloperidone of formula (I), is characterized by X-ray powder diffraction having 2 ⁇ values at 10.13, 11.89, 14.32, 16.75, 17.19, 17.54, 18.22, 19.93, 20.37, 20.69, 21.56, 22.11, 23.26, 23.61, 23.92, 26.31, 30.75 +0.2 ⁇ , which is matching with that of product obtained by following the process disclosed in example-3 of US RE 39,198.
  • the present invention provides crystalline l-(4-(3- chloropropoxy)-3-methoxyphenyl) ethanone of formula (II), is characterized by X-ray powder diffraction having 2 ⁇ values at 7.8, 8.1, 10.6, 14.76, 16.30, 21.12, 21.79, 22.92, 24.64, 25.06 +0.2 ⁇ .
  • the present invention provides crystalline 1- (4-(3-chloropropoxy)-3-methoxyphenyl) ethanone of formula (II), is further characterized by X-ray powder diffraction having 2 ⁇ values at 14.22, 18.58, 21.49, 22.46, 25.69, 27.12, 27.75, 28.78, 29.49, 29.84, 30.41 ⁇ 0.20.
  • the present invention provides Iloperidone of formula (I) having 50 % (d 50 ) of particle size is preferably below 300 micron, more preferably below 200 micron, most preferably below 50 micron.
  • the PSD of Iloperidone can be reduced by using conventional techniques such as milling, micronization, etc., to achieve desired effect.
  • the present invention provides Iloperidone of formula (I) having 10 % (d 10 ) of particle size are in the range of 10-50 microns, 50 % (d 50 ) of particles size are in the range of 60-230 microns and 90 % (d 90 ) of particles size are in the range of 100-350 microns.
  • the Iloperidone thus obtained is micronized to yield pharmaceutically acceptable level for example d 90 in the range below 50 microns, preferably below 20 micron, more preferably below 10 microns.
  • the Iloperidone prepared according to the process of the present invention does not contain or contain in pharmaceutically acceptable level of following impurities that are otherwise present in higher amount in Iloperidone of formula (I) obtained by following the prior art processes.
  • the starting materials are prepared according to the process disclosed in the prior art or by following the process given in scheme-2.
  • Example 1 Process for preparing Iloperidone hydrochloride:
  • Example 2 Process for preparing Iloperidone from Iloperidone
  • Triethylamine was added to a mixture of Iloperidone hydrochloride and methanol. The clear solution was filtered through hyflo bed and washed with methanol. The filtrate was distilled under vacuum to remove the solvent. To the residue was added isopropanol and heated to 50-55° C. The reaction mass was cooled to 15-35° C. The crystallized product was filtered, washed with isopropanol and dried to afford the title compound. Purity by HPCL: 99.95 %
  • Example 3 Process for preparing Iloperidone from Iloperidone acid addition salt:
  • Example 4 Process for preparing Iloperidone: A mixture of 6-Fluoro-3-piperidin-4-yl-benzo[d]isoxazole hydrochloride, l-(4-(3-chloropropoxy)-3-methoxyphenyl) ethanone and potassium carbonate in dimethyl formamide was heated at 70-95° C until the reaction gets completed and the reaction mixture was cooled to 15-35° C. The resulting reaction mass was poured into water and heated to 60-70° C and cooled to 15-35° C. The precipitated product was filtered, washed with water and dried.
  • the wet product was purified by recrystallization using methanol, ethanol, acetone, ethyl methyl ketone or mixtures thereof. M.pt. 121-124 °C.
  • the PXRD of Iloperidone obtained is as shown in Fig- 12. Purity by HPCL: 99.9 %; content of compound of formula (X): ⁇ 0.05 % and more than 0.3 % in product obtained by prior art processes.
  • Example 5 Purification of Iloperidone:
  • Example 6 Process for preparing Iloperidone hydrochloride:
  • Example 7 Process for preparing Iloperidone hydrobromide: Hydrobromic acid was added to Iloperidone in ethanol, the mixture was heated to reflux. The reaction mass was cooled to 25-30° C, filtered and dried to afford Iloperidone hydrobromide. The PXRD of the product is as shown in Fig- 2.
  • Example 8 Process for preparing Iloperidone phosphate:
  • Example 9 Process for preparing Iloperidone bisulphate:
  • Example 10 Process for preparing Iloperidone malonate:
  • Example 11 Process for preparing Iloperidone succinate; Succinic acid was added to Iloperidone in ethanol, the mixture was heated to reflux. The reaction mass was cooled to 25-30° C, filtered and dried to obtain Iloperidone succinate. The PXRD of the product is as shown in Fig-6.
  • Example 12 Process for preparing Iloperidone oxalate:
  • Oxalic acid dihydrate was added to Iloperidone in ethanol, the mixture was heated to reflux.
  • the reaction mass was distilled and crude salt was isolated in ethyl acetate, filtered and dried to obtain Iloperidone oxalate.
  • the PXRD of the product is as shown in Fig-9.
  • Example 13 Process for preparing Iloperidone fumarate:
  • Example 14 Process for preparing Iloperidone benzene sulphonate:
  • Example 15 Process for preparing Iloperidone methane sulphonate: Methane sulphonic acid was added to Iloperidone in ethanol, the mixture was heated to reflux. The reaction mass was cooled to 25-30° C, filtered and dried to obtain Iloperidone methane sulphonate. The PXRD of the product is as shown in Fig-8.
  • Example 16 Process for preparing Iloperidone p-toluene sulphonate: p-Toluene sulphonic acid was added to Iloperidone in ethanol, the mixture was heated to reflux.
  • the reaction mass was distilled and crude salt was isolated in ethyl acetate at 25-30° C, filtered and dried to obtain Iloperidone p- toluene sulphonate.
  • the PXRD of the product is as shown in Fig- 11.
  • Reference Example (1) Process for preparing l-(4-(3-chloropropoxy)-3- methoxyphenvDethanone (Compound of formula (ID) To a mixture of l-(4-hydroxy-3-methoxyphenyl)ethanone in acetone were added potassium carbonate and l-bromo-3-chloropropane . The mixture was refluxed until completion of reaction. The resulting reaction mass was cooled to 25-35° C, filtered and washed the solid with acetone. The filtrate was concentrated under vacuum to remove solvent and cooled to 15-30° C. To the residue was added non-polar solvent such as n-heptane and cooled to 0-5° C. The precipitated product was filtered, washed with n-heptane and dried to afford pure title compound. M.pt 63-66 °C. The PXRD pattern is as shown in Fig-13.

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Abstract

The present invention relates to an improved process for the preparation of Iloperidone of formula (I). Further the present invention also provides a novel polymorph of acid addition salts of Iloperidone of formula (I). (I)

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF
ILOPERIDONE
Field of the Invention
The present invention relates to an improved process for the preparation of Iloperidone of formula (I). The present invention also provides a novel polymorph of acid addition salts of Iloperidone of formula (I).
Figure imgf000002_0001
0)
Background of the Invention Iloperidone is a psychotropic agent belonging to the chemical class of piperidinyl-benzisoxazole derivatives. Its chemical name is 4'-[3-[4-(6-Fluoro- 1 ,2-benzisoxazol-3 -yl)piperidino]propoxy]-3 '-methoxyacetophenone and is marketed under the brand name Fanapt®. US RE 39,198 patent discloses a process for preparing Iloperidone by condensing 6-fluoro-3-piperidin-4-yl-benzo[d] isoxazole hydrochloride and 1- (4-(3-chloropropoxy)-3-methoxyphenyl)ethanone in a solvent such as dimethylfonnamide, acetonitnle or butanol and in the presence of a base such as potassium carbonate. US 20050250813 Al publication provides an injectable depot formulation comprising crystals of Iloperidone or its metabolite or a pharmaceutically acceptable salt, hydrate, solvate, polymorph and stereoisomer thereof. Though this publication mentioned crystal of Iloperidone or its metabolite or a pharmaceutically acceptable salt, hydrate, solvate, this publication does not provide the X-ray diffraction pattern of the said crystal. Further, the said publication does not provide any scope for the preparation of crystalline Iloperidone acid addition salts. All the prior art processes for the preparation of Iloperidone involves the isolation as its free base directly from the reaction mixture resulted in low yield and the quality of the isolated product is also less.
Objective of the Invention
The main objective of the present invention is to provide an improved process for the preparation of Iloperidone of formula (I) from its acid addition salt, which would be more simple, economical and easy to implement on large scale preparation.
Another objective of the present invention is to provide a novel polymorph of Iloperidone acid addition salts and its process for the preparation.
Yet another objective of the present invention is to provide an improved process for the isolation of Iloperidone of formula (I) directly from the reaction mixture with high purity.
One more objective of the present invention is to provide an improved process for the purification of Iloperidone of formula (I). Summary of the Invention
Accordingly, the present invention provides an improved process for the preparation of Iloperidone of formula (I) or its acid addition salt comprising the steps of:
Figure imgf000004_0001
(I)
(i) reacting l-(4-(3-chloropropoxy)-3-methoxyphenyl)ethanone of formula (II)
Figure imgf000004_0002
(Π)
with 6-fluoro-3-piperidin-4-yl-benzo [d] isoxazole or its acid addition salt of formula (III)
Figure imgf000004_0003
(III)
in the presence of base in a polar solvent;
(ii) quenching the reaction mixture with water; (iii) isolating compound of formula (I) by filtration; and
(iv) coverting the compound of formula (I) into its crystalline acid addition salts by treating with an acid wherein the improvement consists of 1) direct isolation o Iloperidone from the reaction mass by filtration 2) preparation of crystalline acid addition salt of Iloperidone.
The above process for the preparation of compound of formula (I) is illustrated b the following reaction scheme- 1.
Figure imgf000005_0001
Scheme-1
Accordingly, the present invention further provides an improved process for the purification of Iloperidone of formula (I), which comprises the steps of: a) obtaining a solution of Iloperidone of formula (I) in first organic solvent; b) optionally treating the solution obtained in step a) with activated carbon; c) optionally removing the first organic solvent from the solution obtained in step a) or b);
d) mixing the solution obtained in step a) or b) or c) with second organic solvent; and
e) isolating the product obtained in step d). Brief Description of the Drawings
The invention will be further described with reference to the following non limiting figure.
FIG-1: The powder X-ray diffraction pattern of Iloperidone hydrochloride.
FIG-2: The powder X-ray diffraction pattern of Iloperidone hydrobromide.
FIG-3: The powder X-ray diffraction pattern of Iloperidone phosphate.
FIG-4: The powder X-ray diffraction pattern of Iloperidone bisulphate.
FIG-5: The powder X-ray diffraction partem of Iloperidone malonate.
FIG-6: The powder X-ray diffraction pattern of Iloperidone succinate.
FIG-7: The powder X-ray diffraction pattern of Iloperidone benzene sulphonate.
FIG-8: The powder X-ray diffraction pattern of Iloperidone methane sulphonate.
FIG -9: The powder X-ray diffraction pattern of Iloperidone oxalate.
FIG-10: The powder X-ray diffraction pattern of Iloperidone fumarate.
FIG-11: The powder X-ray diffraction pattern of Iloperidone p-toluene sulphonate.
FIG-12: The powder X-ray diffraction pattern of Iloperidone of formula (I). FIG-13: The powder X-ray diffraction pattern of l-(4-(3-chloropropoxy)-3- methoxyphenyl) ethanone of formula (II).
PXRD analyzed by X-Ray Powder Diffractometer of following features:
Figure imgf000006_0001
Detailed Description of the Invention
In an embodiment of the present invention, the polar solvent used in step (i) is selected from Ν,Ν-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, acetone, acetonitrile, propionitrile, methanol, ethanol, propanol, isopropanol, butanol, or a mixture of such solvents.
In another embodiment of the present invention, the base used in step (i) is selected from sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, calcium oxide, sodium acetate, sodium methoxide, sodium hydride, sodium amide, triethylamine, piperidine, diethylamine, N- ethyldiisopropylamine, N-(l-methylethyl)-2-propanamine, morpholine, 4- ethylmorpholine, l,4-diazabicyclo[2.2.2]octane, pyridine and the like. In still another embodiment of the present invention, the compound of formula (III) used for condensation is as its free base or its acid addition salt selected from hydrochloride, hydrobromide, hydrogen sulphate and the like; more preferably as its hydrochloride salt. In yet another embodiment of the present invention, the acid used in step
(iv) for preparing the acid addition salt of compound of formula (I), is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, o- phosphoric acid, fumaric acid, oxalic acid, succinic acid, tartaric acid, citric acid, lactic acid, malonic acid, maleic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, benzoic acid, formic acid, acetic acid and the like; more preferably hydrochloric acid .
In one more embodiment of the present invention, the acid addition salt of compound of formula (I) is isolated by optionally removing the solvent from the reaction mixture by distillation and treating the residue with the corresponding acid in the same or different solvent selected from methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, dichloromethane, dichloroethane and the like. In another embodiment of the present invention, the isolated acid addition salt of formula (I) is neutralized with base selected from sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, calcium oxide, sodium acetate, sodium methoxide, sodium hydride, sodium amide, pyridine, aniline, 4-ethylmorpholine, 1 ,4-diazabicyclo[2.2.2]octane, methylamine, ethylamine, propylamine, isopropylamine, triethylamine diethylamine, N-ethyldiisopropylamine and the like; more preferably triethylamine (TEA).
In still another embodiment of the present invention, the isolated acid addition salt of formula (I) is neutralized in the presence of solvent selected from methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, dichloromethane, dichloroethane and the like.
In yet another embodiment of the present invention, the solid isolated in step (iii) is optionally recrystallized using solvent selected from methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, dichloromethane, dichloroethane ethyl acetate, isopropyl acetate and the like.
In another embodiment of the present invention, quenching the reaction mixture with water in step ii) means that addition of water to the reaction mixture or vice versa.
In another embodiment of the present invention, the first organic solvent used in step a) is selected from acetone, acetonitrile, chloroform, dichloromethane, dichloroethane and the like or mixtures thereof; more preferably acetone.
In one more embodiment of the present invention, obtaining a solution of Iloperidone in first organic solvent is by directly from the reaction mixture or by dissolving Iloperidone in the corresponding organic solvent.
In yet another embodiment of the present invention, removing the first organic solvent either in step a) or b) is by conventional technique such as distillation under atmospheric pressure, distillation under vacuum and the like.
In still another embodiment of the present invention, the second organic solvent used in step d) is selected from methanol, ethanol, isopropanol, n- propanol, butanol, water and the like or mixtures thereof; more preferably methanol.
In yet another embodiment of the present invention, the product obtained in step d) is optionally cooled and isolated by, filtration, washing and drying. In still another embodiment, the present invention provides crystalline
Iloperidone hydrochloride is characterized by powder X-ray diffraction having 2Θ values at 10.71, 16.77, 17.71, 18.27, 19.42, 19.73, 21.60, 22.06, 23.74, 24.95, 25.55, +0.2Θ. In yet another embodiment, the present invention provides crystalline
Iloperidone hydrochloride is further characterized by powder X-ray diffraction having 2Θ values at 9.83, 13.82, 14.57, 15.74, 16.0, 18.54, 20.54, 24.16, 27.90, 29.43, 29.73, 30.82, 31.23 +0.2Θ. In another embodiment, the present invention provides crystalline Iloperidone hydrobromide is characterized by X-ray powder diffraction having 2Θ values at 7.78, 11.34, 15.61, 16.83, 17.70, 18.16, 19.28, 19.55, 19.84, 21.25, 22.14, 23.50, 24.15, 25.14, 27.21, 29.52 ±0.20.
In yet another embodiment, the present invention provides crystalline Iloperidone hydrobromide is further characterized by powder X-ray diffraction having 2Θ values at 13.05, 13.66, 14.64, 15.79, 18.42, 20.67, 21.82, 23.83, 24.60, 26.56, 27.57, 27.81, 28.07, 30.91, 31.11, 31.49, 32.20, 33.02, 34.89 +0.2Θ.
In still another embodiment, the present invention provides crystalline Iloperidone phosphate is characterized by X-ray powder diffraction having 2Θ values at 4.66, 9.02, 10.31, 12.80, 14.12, 17.06, 18.13, 19.03, 20.64, 21.40, 22.70, 23.29, 24.45, 26.69, 27.47, 28.35, 30.80, 31.67, 39.90 +0.2Θ.
In another embodiment, the present invention provides crystalline Iloperidone bisulphate is characterized by X-ray powder diffraction having 2Θ values at 9.6, 14.24, 16.52, 16.79, 23.42, 24.15 +0.2Θ.
In yet another embodiment, the present invention provides crystalline Iloperidone bisulphate is further characterized by X-ray powder diffraction having 2Θ values at 6.26, 12.58, 13.35, 13.81, 18.54, 19.27, 25.37 +0.2Θ.
In still another embodiment, the present invention provides crystalline Iloperidone malonate is characterized by X-ray powder diffraction having 2Θ values at 13.36, 17.67, 20.77, 23.20, 25.48, 28.47 +0.2Θ. In another embodiment, the present invention provides crystalline Iloperidone malonate is further characterized by X-ray powder diffraction having 2Θ values at 9.59, 10.52, 14.38, 15.09, 15.42, 16.29, 21.11, 22.14, 24.30, 25.12, 26.45, 26.87, 27.28, 28.13, 30.59 +0.2Θ.
In yet another embodiment, the present invention provides crystalline Iloperidone succinate is characterized by X-ray powder diffraction having 2Θ values at 8.18, 8.72, 11.47, 13.50, 13.73, 16.41, 16.79, 17.42, 18.00, 18.35, 18.58, 19.15, 24.04, 24.38, 26.57, 26.99 +0.2Θ.
In still another embodiment, the present invention provides crystalline Iloperidone succinate is further characterized by X-ray powder diffraction having 2Θ values at 11.95, 14.33, 20.08, 20.47, 21.01, 22.80, 24.77, 25.37, 25.91, 27.77, 29.05, 29.62, 31.20 ±0.20.
In another embodiment, the present invention provides crystalline Iloperidone benzene sulphonate is characterized by X-ray powder diffraction having 2Θ values at 9.22, 13.66, 14.75, 15.52, 15.86, 16.16, 17.24, 18.45, 18.62, 19.15, 20.42, 21.57, 24.99, 25.88 +0.2Θ.
In yet another embodiment, the present invention provides crystalline Iloperidone benzene sulphonate is further characterized by X-ray powder diffraction having 2Θ values at 12.87, 16.84, 17.53, 20.83, 21.11, 22.05, 22.64, 23.20, 23.65, 24.02, 25.53, 27.09, 30.74 +0.2Θ.
In still another embodiment, the present invention provides crystalline Iloperidone methane sulphonate is characterized by X-ray powder diffraction having 2Θ values at 9.47, 13.95, 14.23, 15.94, 16.80, 17.06, 17.55, 18.99, 19.68, 21.67, 23.04, 23.74, 24.30, 24.80 +0.2Θ. In another embodiment, the present invention provides crystalline Iloperidone methane sulphonate is further characterized by X-ray powder diffraction having 20 values at 11.81, 13.66, 14.80, 19.24, 22.06, 27.83 ±0.20. In yet another embodiment, the present invention provides crystalline Iloperidone oxalate is characterized by X-ray powder diffraction having 2Θ values at 6.67, 6.99, 9.19, 10.14, 13.38, 14.06, 14.94, 16.12, 16.92, 20.12, 20.63, 21.10, 21.41, 22.01, 22.80, 23.06, 24.00, 24.80, 25.76, 27.02, 27.39, 28.36, 31.39, 31.87, 35.48 +0.20.
In still another embodiment, the present invention provides crystalline Iloperidone oxalate is further characterized by X-ray powder diffraction having 2Θ values at 8.18, 10.77, 11.25, 17.4, 18.44, 19.03, 19.66, 26.18, 27.92, 30.13, 32.75, 33.22, 36.62, 36.80, 38.09, 38.48, 42.81, 43.67 ±0.20.
In another embodiment, the present invention provides crystalline Iloperidone fumarate is characterized by X-ray powder diffraction having 2Θ values at 8.48, 12.57, 14.23, 16.32, 16.58, 17.01, 17.91, 18.35, 19.74, 21.92, 24.32, 24.62, 24.97, 25.47, 25.89, 26.15 ±0.20.
In yet another embodiment, the present invention provides crystalline Iloperidone fumarate is further characterized by X-ray powder diffraction having 2Θ values at 8.14, 10.67, 12.11, 17.43, 20.34, 20.67, 22.89, 26.86, 27.55, 28.13, 30.25, 34.26, 42.60 +0.20.
In still another embodiment, the present invention provides crystalline Iloperidone p-toluene sulphonate is characterized by X-ray powder diffraction having 2Θ values at 7.47, 12.46, 13.06, 13.87, 15.95, 17.25, 17.73, 18.15, 18.64, 19.87, 20.68, 22.11, 22.57, 23.31, 23.42, 23.66, 25.11, 26.07, 27.50 ±0.29. In another embodiment, the present invention provides crystalline Iloperidone p-toluene sulphonate is further characterized by X-ray powder diffraction having 2Θ values at 6.73, 11.04, 11.45, 12.74, 15.06, 18.90, 19.47, 21.52, 24.00, 24.33, 24.54, 26.31, 26.93, 28.01, 29.31, 30.21, 31.98 +0.2Θ.
In yet another embodiment, the present invention provides crystalline Iloperidone of formula (I), is characterized by X-ray powder diffraction having 2Θ values at 10.13, 11.89, 14.32, 16.75, 17.19, 17.54, 18.22, 19.93, 20.37, 20.69, 21.56, 22.11, 23.26, 23.61, 23.92, 26.31, 30.75 +0.2Θ, which is matching with that of product obtained by following the process disclosed in example-3 of US RE 39,198.
In another embodiment, the present invention provides crystalline l-(4-(3- chloropropoxy)-3-methoxyphenyl) ethanone of formula (II), is characterized by X-ray powder diffraction having 2Θ values at 7.8, 8.1, 10.6, 14.76, 16.30, 21.12, 21.79, 22.92, 24.64, 25.06 +0.2Θ.
In yet another embodiment, the present invention provides crystalline 1- (4-(3-chloropropoxy)-3-methoxyphenyl) ethanone of formula (II), is further characterized by X-ray powder diffraction having 2Θ values at 14.22, 18.58, 21.49, 22.46, 25.69, 27.12, 27.75, 28.78, 29.49, 29.84, 30.41 ±0.20.
In still another embodiment, the present invention provides Iloperidone of formula (I) having 50 % (d50) of particle size is preferably below 300 micron, more preferably below 200 micron, most preferably below 50 micron. The PSD of Iloperidone can be reduced by using conventional techniques such as milling, micronization, etc., to achieve desired effect. In one more embodiment, the present invention provides Iloperidone of formula (I) having 10 % (d10) of particle size are in the range of 10-50 microns, 50 % (d50) of particles size are in the range of 60-230 microns and 90 % (d90) of particles size are in the range of 100-350 microns. The Iloperidone thus obtained is micronized to yield pharmaceutically acceptable level for example d90 in the range below 50 microns, preferably below 20 micron, more preferably below 10 microns.
In yet another embodiment, the Iloperidone prepared according to the process of the present invention does not contain or contain in pharmaceutically acceptable level of following impurities that are otherwise present in higher amount in Iloperidone of formula (I) obtained by following the prior art processes.
Figure imgf000014_0001
In the present invention the starting materials are prepared according to the process disclosed in the prior art or by following the process given in scheme-2.
Figure imgf000015_0001
Scheme-2 Advantages of the process:
The process of the present invention for preparing Iloperidone through its acid addition salt has the following advantageous
1. Simple,
2. Economical,
3. Easy to implement on large scale preparation.
4. Good purity.
5. Good yield.
The present invention is illustrated with the following example, which should not be construed for limiting the scope of the invention.
Example 1; Process for preparing Iloperidone hydrochloride:
A mixture of 6-Fluoro-3-piperidin-4-yl-benzo[d]isoxazole hydrochloride, l-(4-(3-chloropropoxy)-3-methoxyphenyl) ethanone and potassium carbonate in acetonitrile was heated at 60-85° C until the reaction gets completed. The reaction mixture was cooled to 15-35° C, the by-product formed was filtered and washed with acetonitrile. The mother liquor was concentrated under vacuum to remove solvent and cooled to 15-30° C. To the residue was added isopropanol and aqueous hydrochloric acid. The reaction mass cooled to 0-10° C. The crystallized product was filtered, washed with isopropanol and drying afforded the title compound. The PXR of the product is as shown in Fig-1. IB2010/002712
Example 2: Process for preparing Iloperidone from Iloperidone
hydrochloride:
Triethylamine was added to a mixture of Iloperidone hydrochloride and methanol. The clear solution was filtered through hyflo bed and washed with methanol. The filtrate was distilled under vacuum to remove the solvent. To the residue was added isopropanol and heated to 50-55° C. The reaction mass was cooled to 15-35° C. The crystallized product was filtered, washed with isopropanol and dried to afford the title compound. Purity by HPCL: 99.95 %
Example 3: Process for preparing Iloperidone from Iloperidone acid addition salt:
Sodium hydroxide in water was added to Iloperidone acid addition salt in water. The mixture was stirred at 25-30° C for 30-45 minutes, filtered and washed with water. The Iloperidone obtained was recrystallized from methanol.
Example 4: Process for preparing Iloperidone: A mixture of 6-Fluoro-3-piperidin-4-yl-benzo[d]isoxazole hydrochloride, l-(4-(3-chloropropoxy)-3-methoxyphenyl) ethanone and potassium carbonate in dimethyl formamide was heated at 70-95° C until the reaction gets completed and the reaction mixture was cooled to 15-35° C. The resulting reaction mass was poured into water and heated to 60-70° C and cooled to 15-35° C. The precipitated product was filtered, washed with water and dried. Optionally the wet product was purified by recrystallization using methanol, ethanol, acetone, ethyl methyl ketone or mixtures thereof. M.pt. 121-124 °C. The PXRD of Iloperidone obtained is as shown in Fig- 12. Purity by HPCL: 99.9 %; content of compound of formula (X): < 0.05 % and more than 0.3 % in product obtained by prior art processes. Example 5: Purification of Iloperidone:
A mixture of activated carbon and Iloperidone in acetone was heated to 50-55° C and the reaction mixture was cooled to 15-35° C. The reaction mass was filtered through hyflo bed and washed with acetone. The filtrate was distilled under vacuum to remove the solvent. Methanol was optionally added to the residue and heated to 60-65° C. The reaction mass was cooled to 0-35° C. The crystallized product was filtered, washed with acetone or methanol and dried to afford the pure Iloperidone. M.pt. 121-124 °C.
Example 6: Process for preparing Iloperidone hydrochloride:
Hydrochloric acid was added to Iloperidone in methanol, the mixture was heated to reflux. The reaction mass was cooled to 25-30° C, filtered and dried to obtain Iloperidone hydrochloride. The PXRD of the product is as shown in Fig- 1.
Example 7: Process for preparing Iloperidone hydrobromide: Hydrobromic acid was added to Iloperidone in ethanol, the mixture was heated to reflux. The reaction mass was cooled to 25-30° C, filtered and dried to afford Iloperidone hydrobromide. The PXRD of the product is as shown in Fig- 2. Example 8: Process for preparing Iloperidone phosphate:
Ortho phosphoric was added to Iloperidone in isopropanol, the mixture was heated to reflux. The reaction mass was cooled to 25-30° C, filtered and dried to afford Iloperidone phosphate. The PXRD of the product is as shown in Fig-3. 2010/002712
Example 9: Process for preparing Iloperidone bisulphate:
Sulphuric acid was added to Iloperidone in ethanol, the mixture was heated to reflux. The reaction mass was cooled to 25-30° C, filtered and dried to afford Iloperidone bisulphate. The PXRD of the product is as shown in Fig-4.
Example 10: Process for preparing Iloperidone malonate:
Malonic acid was added to Iloperidone in ethanol, the mixture was heated to reflux. The reaction mass was cooled to 0-5° C, filtered and dried to obtain Iloperidone malonate. The PXRD of the product is as shown in Fig-5.
Example 11: Process for preparing Iloperidone succinate; Succinic acid was added to Iloperidone in ethanol, the mixture was heated to reflux. The reaction mass was cooled to 25-30° C, filtered and dried to obtain Iloperidone succinate. The PXRD of the product is as shown in Fig-6.
Example 12: Process for preparing Iloperidone oxalate:
Oxalic acid dihydrate was added to Iloperidone in ethanol, the mixture was heated to reflux. The reaction mass was distilled and crude salt was isolated in ethyl acetate, filtered and dried to obtain Iloperidone oxalate. The PXRD of the product is as shown in Fig-9.
Example 13: Process for preparing Iloperidone fumarate:
Fumaric acid was added to Iloperidone in ethanol, the mixture was heated to reflux. The reaction mass was cooled to 25-30° C, filtered and dried to obtain Iloperidone fumarate. The PXRD of the product is as shown in Fig-10. Example 14: Process for preparing Iloperidone benzene sulphonate:
Benzene sulphonic acid was added to Iloperidone in ethanol, the mixture was heated to reflux. The reaction mass was cooled to 25-30° C, filtered and dried to obtain Iloperidone benzene sulphonate. The PXRD of the product is as shown in Fig-7.
Example 15: Process for preparing Iloperidone methane sulphonate: Methane sulphonic acid was added to Iloperidone in ethanol, the mixture was heated to reflux. The reaction mass was cooled to 25-30° C, filtered and dried to obtain Iloperidone methane sulphonate. The PXRD of the product is as shown in Fig-8. Example 16: Process for preparing Iloperidone p-toluene sulphonate: p-Toluene sulphonic acid was added to Iloperidone in ethanol, the mixture was heated to reflux. The reaction mass was distilled and crude salt was isolated in ethyl acetate at 25-30° C, filtered and dried to obtain Iloperidone p- toluene sulphonate. The PXRD of the product is as shown in Fig- 11.
Reference Example (1): Process for preparing l-(4-(3-chloropropoxy)-3- methoxyphenvDethanone (Compound of formula (ID) To a mixture of l-(4-hydroxy-3-methoxyphenyl)ethanone in acetone were added potassium carbonate and l-bromo-3-chloropropane . The mixture was refluxed until completion of reaction. The resulting reaction mass was cooled to 25-35° C, filtered and washed the solid with acetone. The filtrate was concentrated under vacuum to remove solvent and cooled to 15-30° C. To the residue was added non-polar solvent such as n-heptane and cooled to 0-5° C. The precipitated product was filtered, washed with n-heptane and dried to afford pure title compound. M.pt 63-66 °C. The PXRD pattern is as shown in Fig-13.
Reference Example (2): Process for preparing l-(4-(3-chloropropoxy)-3- methoxyphenvDethanone
To a mixture of l-(4-hydroxy-3-methoxyphenyl)ethanone in dimethyl formamide were added potassium carbonate and l-bromo-3-chloropropane . The mixture was stirred at ambient temperature until completion of reaction. To the reaction mass was added purified water. The crystallized product was filtered, washed with water and dried to afford pure title compound. M.pt 63-66 °C.

Claims

We claim:
1. A process for the preparation of Iloperidone of formula (I) or its acid addition salt com rising the step of:
Figure imgf000021_0001
(I)
(i) reacting l-(4-(3-chloropropoxy)-3-methoxyphenyl) ethanone of formula (Π)
Figure imgf000021_0002
(II)
with 6-fluoro-3-piperidin-4-yl-benzo [d] isoxazole or its acid addition salt of formula (III)
Figure imgf000021_0003
(HI)
in the presence of base in a polar solvent;
(ii) quenching the reaction mixture with water;
(iii) isolating the Iloperidone of formula (I) by filtration; and
(iv) converting the compound of formula (I) into its crystalline acid addition salts by treating with an acid; wherein the improvement consists of 1) direct isolation o Iioperidone from the reaction mass by filtration 2) preparation of crystalline acid addition salt of Iioperidone.
2. A process for the purification of Iioperidone of formula (I), which comprises the steps of:
a) obtaining a solution of Iioperidone of formula (I) in a first organic solvent;
b) optionally treating the solution obtained in step a) with activated carbon; c) optionally removing the first organic solvent from the solution obtained in step a) or b);
d) mixing the solution obtained in step a) or b) or c) with second organic solvent; and
e) isolating the product obtained in step d).
3. A process according to the claim 1, further comprising converting the acid addition salt of compound of formula (I) into Iioperidone by treating with base selected from comprising sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide; optionally in the presence of solvent.
4. A process according to the claim 1, wherein the base used in condensation step is selected from sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, calcium oxide, sodium acetate, sodium methoxide, sodium hydride, sodium amide, methyl amine, ethyl amine, propyl amine, isopropyl amine, triethylamine, diethylamine, piperidine, N-ethyldiisopropylamine, N-( 1 -methylethyl)-2-propanamine, morpholine, 4-ethylmorpholine, l,4-diazabicyclo[2.2.2]octane, and pyridine.
5. A process according to the claim 1, wherein the polar solvent used in condensation step is selected from Ν,Ν-dimethylformamide, N,N- dimethylacetamide, dimethylsulphoxide, acetone, methyl ethyl ketone, acetonitrile, propionitrile, methanol, ethanol, propanol, isopropanol, butanol, or mixture of thereof.
6. A process according to the claim 1, wherein the acid used in step (iv) for making the acid addition salt which is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, o-phosphoric acid, fumaric acid, oxalic acid, succinic acid, tartaric acid, citric acid, lactic acid, malonic acid, maleic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, benzoic acid, formic acid and acetic acid; more preferably hydrochloric acid.
7. A process according to the claim 2, wherein the first organic solvent used in step 1) is selected from acetone, methyl ethyl ketone, acetonitrile, propionitrile, chloroform, dichloromethane, and dichloroethane.
8. A process according to the claim 2, wherein the second organic solvent used in step 4) is selected from acetone, methanol, ethanol, isopropanol, n- propanol, and water.
9. Crystalline Iloperidone acid addition salts.
10. Crystalline Iloperidone Hydrochloride.
11. The Iloperidone acid addition salts according to claim 9, are selected from hydrochloride, hydrobromide, hydroiodide, phosphate, sulphate, tartrate, citrate, lactate, formate, acetate, benzoate, malonate, maleate, succinate, oxalate, fumarate, benzene sulphonate, methane sulphonate, ethane sulphonate, and p-toluene sulphonate.
12. Crystalline Iloperidone hydrochloride salt having one or more of the following
a) substantially same powder X-ray diffraction (PXRD) pattern as shown in Figure- 1.
b) having characteristic peaks at 10.71, 16.77, 17.71, 18.27, 19.42, 19.73, 21.60, 22.06, 23.74, 24.95, 25.55, +0.2Θ.
13. Crystalline Iloperidone hydrobromide salt having one or more of the following
a) substantially same powder X-ray diffraction (PXRD) pattern as shown in Figure-2.
b) having characteristic peaks at 7.78, 11.34, 15.61, 16.83, 17.70, 18.16, 19.28, 19.55, 19.84, 21.25, 22.14, 23.50, 24.15, 25.14, 27.21, 29.52 +0.2Θ.
14. Crystalline Iloperidone phosphate salt having one or more of the following a) substantially same powder X-ray diffraction (PXRD) pattern as shown in Figure-3
b) having characteristic peaks at 4.66, 9.02, 10.31, 12.80, 14.12, 17.06, 18.13, 19.03, 20.64, 21.40, 22.70, 23.29, 24.45, 26.69, 27.47, 28.35, 30.80, 31.67, 39.90 +0.2Θ.
15. Crystalline Iloperidone bisulphate salt having one or more of the following a) substantially same powder X-ray diffraction (PXRD) pattern as shown in Figure-4 b) having characteristic peaks at 9.6, 14.24, 16.52, 16.79, 23.42, 24.15 ±0.2Θ.
16. Crystalline Iloperidone malonate salt having one or more of the following a) substantially same powder X-ray diffraction (PXRD) pattern as shown in Figure-5
b) having characteristic peaks at 13.36, 17.67, 20.77, 23.20, 25.48, 28.47 +0.2Θ. 17. Crystalline Iloperidone succinate salt having one or more of the following a) substantially same powder X-ray diffraction (PXRD) pattern as shown in Figure-6
b) having characteristic peaks at 8.18, 8.72, 11.47, 13.50, 13.73, 16.41, 16.79,
17.42, 18.00, 18.35, 18.58, 19.15, 24.04, 24.38, 26.57, 26.99 +0.20.
18. Crystalline Iloperidone benzene sulphonate salt having one or more of the following
a) substantially same powder X-ray diffraction (PXRD) pattern as shown in Figure-7
b) having characteristic peaks at 9.22, 13.66, 14.75, 15.52, 15.86, 16.16, 17.24, 18.45, 18.62, 19.15, 20.42, 21.57, 24.99, 25.88 ±0.20. 19. Crystalline Iloperidone methane sulphonate salt having one or more of the following
a) substantially same powder X-ray diffraction (PXRD) pattern as shown in Figure-8 b) having characteristic peaks at 9.47, 13.95, 14.23, 15.94, 16.80, 17.06, 17.55, 18.99, 19.68, 21.67, 23.04, 23.74, 24.30, 24.80 +0.2Θ. 20. Crystalline Iloperidone oxalate salt having one or more of the following a) substantially same powder X-ray diffraction (PXRD) pattern as shown in Figure-9
b) having characteristic peaks at 6.67, 6.99, 9.
19, 10.14, 13.38, 14.06, 14.94, 16.12, 16.92, 20.12,
20.63, 21.10, 21.41, 22.01, 22.80, 23.06, 24.00, 24.80, 25.76, 27.02, 27.39, 28.36, 31.39, 31.87,
35.48 +0.2Θ.
21. Crystalline Iloperidone fumarate salt having one or more of the following a) substantially same powder X-ray diffraction (PXRD) pattern as shown in Figure- 10
b) having characteristic peaks at 8.48, 12.57, 14.23, 16.32, 16.58, 17.01, 17.91, 18.35, 19.74, 21.92, 24.32, 24.62, 24.97, 25.47, 25.89, 26.15 +0.2Θ. 22. Crystalline Iloperidone p-toluene sulphonate salt having one or more of the following
a) substantially same powder X-ray diffraction (PXRD) pattern as shown in Figure- 11
b) having characteristic peaks at 7.47, 12.46, 13.06, 13.87, 15.95, 17.25, 17.73, 18.15, 18.64, 19.87, 20.68, 22.11,
22.57, 23.31,
23.42, 23.66, 25.11, 26.07, 27.50 +0.2Θ.
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WO2012063269A2 (en) 2010-11-12 2012-05-18 Cadila Healthcare Limited Process for preparing iloperidone
WO2012063269A3 (en) * 2010-11-12 2013-03-14 Cadila Healthcare Limited Process for preparing iloperidone
WO2012090138A1 (en) * 2010-12-27 2012-07-05 Ranbaxy Laboratories Limited Processes for the preparation of iloperidone
WO2012164516A1 (en) * 2011-06-03 2012-12-06 Lupin Limited Process for the preparation of iloperidone
CN102276594B (en) * 2011-06-17 2013-10-23 吉林大学 Iloperidone medicinal cocrystal and preparation method thereof
CN102276594A (en) * 2011-06-17 2011-12-14 吉林大学 Novel iloperidone medicinal cocrystal and preparation method thereof
CN102659771A (en) * 2012-04-18 2012-09-12 吉林三善恩科技开发有限公司 Novel lloperidone pharmaceutical co-crystal and preparation method thereof
CN102633785A (en) * 2012-04-18 2012-08-15 吉林三善恩科技开发有限公司 Novel iloperidone pharmaceutical cocrystal and preparation method thereof
CN102633786A (en) * 2012-04-18 2012-08-15 吉林三善恩科技开发有限公司 Novel iloperidone pharmaceutical cocrystal and preparation method thereof
CN102633786B (en) * 2012-04-18 2013-11-27 吉林三善恩科技开发有限公司 Iloperidone pharmaceutical cocrystal and preparation method thereof
CN102633785B (en) * 2012-04-18 2014-07-30 吉林三善恩科技开发有限公司 Novel iloperidone pharmaceutical cocrystal and preparation method thereof
CN103044411A (en) * 2013-01-09 2013-04-17 吉林三善恩科技开发有限公司 Iloperidone drug cocrystal and preparation method thereof
CN103044411B (en) * 2013-01-09 2015-02-18 吉林三善恩科技开发有限公司 Iloperidone drug cocrystal and preparation method thereof
CN107033133A (en) * 2017-04-05 2017-08-11 上海华源医药科技发展有限公司 A kind of preparation method of Iloperidone
CN107513060A (en) * 2017-09-22 2017-12-26 山东金城医药化工有限公司 The synthetic method of Iloperidone

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