WO2012063269A2 - Procédé de préparation d'iloperidone - Google Patents
Procédé de préparation d'iloperidone Download PDFInfo
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- WO2012063269A2 WO2012063269A2 PCT/IN2011/000785 IN2011000785W WO2012063269A2 WO 2012063269 A2 WO2012063269 A2 WO 2012063269A2 IN 2011000785 W IN2011000785 W IN 2011000785W WO 2012063269 A2 WO2012063269 A2 WO 2012063269A2
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- iloperidone
- peaks
- process according
- impurities
- substantially free
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- RUNPLXZHXLMWFP-UHFFFAOYSA-N CC(c(cc1)cc(OC)c1OCCCN(CC1)CCC1c1n[o]c2c1ccc(N(CC1)CCC1c1n[o]c3cc(F)ccc13)c2)=O Chemical compound CC(c(cc1)cc(OC)c1OCCCN(CC1)CCC1c1n[o]c2c1ccc(N(CC1)CCC1c1n[o]c3cc(F)ccc13)c2)=O RUNPLXZHXLMWFP-UHFFFAOYSA-N 0.000 description 2
- 0 CC(c(cc1)cc(OC)c1OCCC*)=O Chemical compound CC(c(cc1)cc(OC)c1OCCC*)=O 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Definitions
- the invention relates to an improved process for the preparation iloperidone. More particularly, it relates to a process for preparation of iloperidone and its pharmaceutically acceptable salts with suitable acids.
- the invention also relates to iloperidone substantially free from one or more of its impurities.
- the invention also relates pharmaceutical compositions that include iloperidone substantially free from impurities.
- Iloperidone is an antipsychotic, serotonin/dopamine receptor antagonist. Iloperidone is also known by the chemical name l -[4-[3-[4-(6-flouro-l ,2- benzoisoxazol-3-yl)piperidin-l -yl]propoxy]-3-methoxypropyl]ethanone, compound of Formula (I).
- the crystalline form obtained after recrystallization is designated herein as Form-I.
- Scheme-1 International (PCT) Publication No. WO 2010/031497 Al discloses a new process for the synthesis of iloperidone by condensation of 3-[l-(3-chloropropyl)-4- piperidinyl]-6-flouro-l ,2-benzisoxazole of Formula (IV) with 4-hydroxy-3-methoxy acetophenone of Formula (V) in presence of potassium carbonate in methyl ethyl ketone solvent.
- the European Patent No. EP 1 523 335 B l discloses an injectable depot formulation of crystals of iloperidone or its metabolite or a pharmaceutically acceptable salt, hydrate, solvate, polymorph and stereoisomer thereof, wherein the X50 value of the crystals is from 1 to 200 microns.
- U.S. Patent Application No. 2009/176739 Al discloses preparation of metabolite of iloperidone by reduction of iloperidone with boran complex of (3aR,7R)- l-methyI-3,3-diphenyl-tetrahydropyrrolo[l ,2c][l ,2,3]oxazaborole.
- the metabolite disclosed is (S)-l -[4-[3-[4-(6-flouro-l,2-benzoisoxazol-3-yl)piperidin-l -yl]propoxy]-3- methoxypropyl]ethanol as white crystals and melting point 138.2-138.8°C.
- Indian Patent Application No. IN 1980/MUM/2007 Al discloses a process for preparing iloperidone by condensing 6-fluoro-3-(4-piperidinyl)- l,2-benzisoxazole hydrochloride (II) and l-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (III) in water as a solvent in presence of water soluble or insoluble inorganic base.
- WO 201 1/061750 A2 discloses the process for the preparation of l -[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (III) via Grignard reaction over aldehyde compound.
- the WO '750 A2 also discloses the process for the preparation of iloperidone by condensing 6-fluoro-3-(4-piperidinyl)-l ,2- benzisoxazole hydrochloride (II) and l-[4-(3-chloropropoxy)-3-methoxyphenyl] ethanone (III) in presence of organic base.
- the cited prior art discloses crystalline form of iloperidone or optical isomer of its metabolite.
- none of the prior art reference discloses the method of obtaining iloperidone substance with higher purity in terms of one or more of its impurities like N-oxide, desflouro, dimer impurities or total impurities.
- iloperidone which is atleast substantially free from impurities and easily scalable, for industrial use.
- the iloperidone obtained by the process of present invention is crystalline.
- the process is simple, cost-effective, eco- friendly and commercially viable.
- iloperidone substantially free from one or more of its impurities like N-oxide, desflouro or dimer impurity and the like.
- the invention provides iloperidone or its pharmaceutically acceptable salts thereof, which are useful for achieving higher purity of iloperidone.
- An aspect of the invention provides the process for the preparation of iloperidone or its pharmaceutically acceptable salts thereof.
- An aspect of the invention provides crystalline iloperidone by using iloperidone or its pharmaceutically acceptable salts thereof, wherein the crystalline iloperidone is characterized by X-ray powder diffraction as depicted in Figure- 1.
- crystalline iloperidone or salts thereof having particle size distributions wherein the 10th volume percentile particle size (DIO) is less than about 50 um, the 50th volume percentile particle size (D50) is less than about 200 ⁇ , or the 90th volume percentile particle size (D90) is less than about 400 ⁇ , or any combination thereof.
- the present invention provides iloperidone containing less than about 0.2% of the impurity N-oxide and Desflouro.
- the present invention provides iloperidone containing less than about 0.2% of the dimer impurity.
- compositions comprising iloperidone substantially free of one or more of its corresponding impurities as measured by HPLC.
- compositions comprising a stable crystalline form of iloperidone together, with one or more pharmaceutically acceptable excipients.
- compositions comprising a stabilized crystalline solid dispersion of iloperidone together with one or more pharmaceutically acceptable carrier, optionally with one or more pharmaceutically acceptable excipients.
- FIG 1. shows the X-ray diffractogram (XRD) of crystalline iloperidone Form-I
- FIG 2. shows the X-ray diffractogram (XRD) of crystalline iloperidone hydrochloride
- FIG 3. shows the X-ray diffractogram (XRD) of crystalline iloperidone hydrogensulfate
- FIG 4. shows the X-ray diffractogram (XRD) of crystalline iloperidone phosphate
- FIG 5. shows the X-ray diffractogram (XRD) of crystalline iloperidone citrate
- FIG 6. shows the X-ray diffractogram (XRD) of crystalline iloperidone acetate
- FIG 7. shows the X-ray diffractogram (XRD) of crystalline iloperidone nitrate
- FIG 8. shows the X-ray diffractogram (XRD) of crystalline iloperidone succinate
- FIG 9. shows the X-ray diffractogram (XRD) of crystalline iloperidone maleate
- FIG 10. shows the X-ray diffractogram (XRD) of crystalline iloperidone fumarate
- FIG 1 1. shows the X-ray diffractogram (XRD) of crystalline iloperidone oxalate
- FIG 12. shows the X-ray diffractogram (XRD) of crystalline iloperidone salicylate
- FIG 13. shows the X-ray diffractogram (XRD) of crystalline ILK-Ial
- FIG.14. shows the Differential scanning calorimetry (DSC) of crystalline iloperidone Form-I
- FIG.15 shows the Differential scanning calorimetry (DSC) of crystalline iloperidone hydrochloride Form-I.
- the terms "suspending”, “slurrying” and “triturating” are interchangeable, and refer to a process carried out in a 1 heterogeneous mixture where complete dissolution does not occur. Also, heating the suspension or slurry can result in a homogenous mixture where complete or partial dissolution occurs at an elevated temperature or ambient temperature.
- heating means, heating the reaction mixture either heterogeneous or homogeneous is heated at a temperature from about 35°C to boiling point of solvent. More preferably from about 35°C to about 120°C.
- cooling used herein means, maintaining the reaction mixture either heterogeneous or homogeneous at a temperature from about 10°C to about 35°C of solvent.
- FBIP 6-flouro-3-(4-piperidiriyl)-l ,2- benzisoxazole or salt thereof of Formula (II)
- ILK-Ia as used herein means l-(4- (3-chloropropoxy)-3-methoxyphenyl)ethanone of Formula (III).
- stable Iloperidone includes either: crystalline Iloperidone that after exposure to a relative humidity of 75% at 40°C, for a period of at least three months contains less than about 0.1% (wt/wt) l-[4-[3-[4-(6-flouro-l,2-benzoisoxazol- 3-yl)piperidih-l -yl]propoxy]-3-methoxypropyl]ethanol (metabolite) or N-oxide or desflouro or dimer impurities by area percentage of HPLC.
- stable Iloperidone also includes either: crystalline iloperidone that after exposure to a relative humidity of 60% at 25°C, for a period of at least three months contains less than about 0.1% (wt/wt) l -[4-[3-[4-(6-flouro-l ,2-benzoisoxazol- 3-yl)piperidin-l -yl]propoxy]-3-methoxypropyl]ethanol (metabolite) or N-oxide or desflouro or dimer impurities by area percentage of HPLC.
- the term "substantially free” herein means, the iloperidone prepared by the process of the present invention contains less than about 0.2%, particularly less than about 0.1%, more particularly less than about 0.07% of one or more of impurities like N-oxide, desflouro or dimer impurity when measured by area percentage of HPLC.
- Suitable solvent means a single or a combination of two or more solvents.
- Impurity "Metabolite” is l -[4-[3-[4-(6-flouro-l ,2-benzoisoxazol-3-yl)piperidin-l-yl]- propoxy] -3 -methoxypropyl] ethanol
- N-oxide is l -[4-[3-[4-(6-flouro-l,2-benzoisoxazol-3-yl)piperidin-l-yl]- propoxy]-3-methoxypropyl]ethanone N-oxide.
- Impurity "FBIP” is 6-flouro-3-(4-piperidinyl)-l,2 benzisoxazole (II).
- Impurity "ILK-Ia” is l -[4-(3-chloropropoxy)-3-methoxyphenyl)ethanone (III)
- Impurity "Dimer” is l -(4-(3-(4-(6-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-l - yl)benzo-
- the invention provides iloperidpne dimer impurity of Formula (B).
- the invention provides iloperidone substantially free from one or more of its impurities like N-oxide, desflouro or dimer impurity.
- Iloperidone prepared by using prior art methods involves condensation of 6- flouro-3-(4-piperidinyl)-l,2-benzisoxazole hydrochloride (FBIP) or a salt thereof and l-[4-(3-chloropropoxy)-3-methoxyphenyl)ethanone (ILK-la).
- FBIP 6-flouro-3-(4-piperidinyl)-l ,2-benzisoxazole hydrochloride
- FBIP 6-flouro-3-(4-piperidinyl)-l ,2-benzisoxazole hydrochloride
- benzisoxazole dimer compound (A) i.e. 6-fluoro-3-(l -(3-(piperidin-4-yl)benzo[d]isoxazol-6-yl)piperidin-4- yl)benzo[d]isoxazole.
- the compound FBIP is obtained with purity of about 95.04% having 3.1% of compound of Formula (A) when measured by area percentage of HPLC.
- the iloperidone prepared by using FBIP or salt thereof, prepared by using prior art methods results in contamination of dimer impurity of Formula (B) to the level of more than 1% by area percentage of HPLC.
- the present inventors has developed the process for the preparation of FBIP or salts thereof with the purity of 99.9% by area percentage of HPLC, wherein the compound of Formula (A) is not in detectable amount.
- iloperidone prepared by using FBIP or salt thereof, prepared by process of the present invention results in reduced level of dimer impurity, particularly not in detectable amount.
- the present invention provides iloperidone substantially free from dimer impurity of formula (B).
- the present invention provides iloperidone containing less than about 0.5% of dimer impurity of Formula (B).
- the present invention provides iloperidone containing less than about 0.2% of dimer impurity of Formula (B). In another general aspect, the present invention provides iloperidone containing less than about 0.1 % of dimer impurity of Formula (B).
- the present invention provides iloperidone substantially free from N-oxide and desflouro impurities.
- the present invention provides iloperidone or its pharmaceutically acceptable salts thereof with suitable acids.
- the pharmaceutically acceptable salts selected from hydrochloride, hydrobromide, hydrogensulfate, phosphate, nitrate, citrate, acetate, succinate, fumarate, oxalate, maleate, salicylate, malate, besylate, mesylate, tosylate, napsylate, tartarate and the like.
- the pharmaceutically acceptable salts of iloperidone are crystalline.
- the present invention provides crystalline pharmaceutically acceptable salts of iloperidone characteristized by having atleast X- ray powder diffraction with characteristic peaks at 2-theta as below.
- iloperidone hydrogensulfate having an X-ray diffraction pattern comprising at least three peaks selected from peaks with 20 angles of about 7.8°, 12.5 °, 14.2 °, 15.3 °,
- iloperidone phosphate having an X-ray diffraction pattern comprising at least three peaks selected from peaks with 20 angles of about 4.8°, 10.5°, 12.9°, 19.1°, 20.8°, 26.0°, and 27.4 ⁇ 0.2° (20);
- iloperidone citrate having an X-ray diffraction pattern comprising at least three peaks selected from peaks with 20 angles of about 1 1.0°, 12.4°, 13.4°, 14.9°, 19.9°, 20.7°, 21.8°, 25.8°, 26.9°, and 28.5 ⁇ 0.2° (20);
- iloperidone acetate having an X-ray diffraction pattern comprising at least three peaks selected from peaks with 20 angles of about 12.5°, 14.2°, 16.7°, 17.0°, 18.2°, 20.6°, 21 .5°, 22.0°, and 23.8 ⁇ 0.2° (20);
- iloperidone nitrate having an X-ray diffraction pattern comprising at least three peaks selected from peaks with 20 angles of about 8.1°, 12.1°, 16.7°, 13.8°, 14.7°, 17.7°, 20.2°, 24.9°, and 27.1 ⁇ 0.2° (20);
- iloperidone succinate having an X-ray diffraction pattern comprising at least three peaks selected from peaks with 20 angles of about 8.5°, 1 1.3°, 13.3°, 16.2°, 18.1°, 22.4°, 24.2°, and 26.8 ⁇ 0.2° (2 ⁇ );
- iloperidone maleate having an X-ray diffraction pattern comprising at least three peaks selected from peaks with 2 ⁇ angles of about 9.3°, 1 1.5°, 13.9, 14.9, 15.6°,
- iloperidone fumarate having an X-ray diffraction pattern comprising at least three peaks selected from peaks with 20 angles of about 12.5°, 14.1°, 16.2°, 17.0°, 17.8°, 18.3°, 19.7, 21 .8°, 22.8°, 24.3°, 26.1°, and 28.1 ⁇ 0.2° (20);
- iloperidone oxalate having an X-ray diffraction pattern comprising at least three peaks selected from peaks with 20 . angles of about 6.9°, 9.1°, 10. , 13.3°, 14.0°, , 14.9°, 16.0°, 16.8°, 18.4°, 20.0°, 21.0°, 21.9°, 22.8°, 23.9°, 24.7°, and 27.3 ⁇ 0.2° (20);
- iloperidone salicylate having an X-ray diffraction pattern comprising at least three peaks selected from peaks with 20 angles of about 5.1°, 10.0°, 1 1.3°, 13.2°, 14.4°, 16.1°, 17.5°, 18.6°, 20.8°, 21.7°, 22.6°, 23.9°, 26.0°, and 26.5 ⁇ 0.2° (20);
- the present invention provides crystalline pharmaceutically acceptable salts of iloperidone characteristized by X-ray powder diffraction pattern as depicted in figures as below.
- the present invention provides iloperidone or its hydrochloride salt thereof characteristized by having atleast X-ray powder diffraction with characteristic peaks at 2-theta and/or X-ray powder diffraction pattern as shown herein after.
- the present invention provides an improved process for preparing iloperidone of Formula (I) substantially free from one or more of its impurities,
- X may be leaving group selected from chlorine, bromine, fluorine, iodine, mesylate or tosylate,
- iloperidone acid addition salts (c) neutralizing iloperidone acid addition salts with suitable base to obtain iloperidone substantially free from one or more of its impurities.
- suitable acid addition salts can be selected from hydrochloride, hydrobromide, hydrogensulfate, phosphate, nitrate, citrate, acetate, succinate, fumarate, oxalate, maleate, salicylate, malate, besylate, mesylate, tosylate, napsylate, tartarate and the like.
- a mixture of FBIP (II) or a salt thereof, ILK-Ia and an organic base are reacted.
- the reaction occurs in the presence of a suitable solvent.
- the suitable solvent comprises from one or more of polar solvents like water, C alcohols; polar aprotic solvents like acetonitrile, N-methylpyrrolidone, C 3-6 amides, C 3-6 ketones, C 2- 6 acetates; non-polar solvents like C 5 .] 2 aromatic hydrocarbons, and C 2-8 ethers.
- Ci -4 alcohols are methanol, ethanol, n-propanol, isopropanol
- IPA n-butanol
- the preferred C 3 . 6 amides are dimethylacetamide and dimethylformamide (DMF).
- the preferred C 3 - 6 ketones are acetone, methyl ethyl ketone (MEK) and methyl iso-butyl ketone (MIBK).
- the preferred C 6- 12 aromatic hydrocarbons are benzene, toluene, xylene, ethylbenzene.
- Preferred C 2-6 acetates are ethyl acetate, isopropyl acetate, isobutyl acetate and n-butyl acetate.
- Preferred C 2- 8 ethers are tetrahydrofuran (THF), diethoxymethane (DEM), isobutyl methyl ether, dibutyl ether and polyethylene glycol (PEG). More particularly, the solvent is water, acetonitrile, IPA or DMF. Even more particularly, the solvent is water.
- the organic base used may be in a ratio of about 1 to about 3 moles per mole of FBIP or salt thereof such as about 2.5 moles of the organic base per mole of FBIP or salt thereof.
- the amount of the organic base used is in a molar ratio of about 2, more particularly about 1.5 moles of the organic base per mole of FBIP, such as about 1.2 moles of the organic base per mole of FBIP.
- the ILK-Ia may be used in a ratio of about 1 to about 3 moles per mole of FBIP or salt thereof such as about 2.5 moles of the ILK-Ia may be used per mole of FBIP or salt thereof.
- the amount of ILK-Ia used particularly is in a molar ratio of about 2, more particularly about 1.5 moles of ILK-Ia per mole of FBIP, such as about 1.1 moles of ILK-Ia per mole of FBIP.
- the suitable organic base comprises from one or more of dimethyl amine, diethyl amine, dibutyl amine, triethyl amine, diisopropylethylamine, diisopropylamine, tert-butylamine, isobutylamine, pyridine, 4-dimethylaminopyridine (DMAP), imidazole, N-methylmorpholine, l,4-diazobicyclo-[2,2,2]octane (DABCO), l,8-diazabicyclo[4.3.0]non-5-ene (DBN) and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), particularly triethylamine or dibutylamine.
- DMAP 4-dimethylaminopyridine
- DVBCO 4-dimethylaminopyridine
- DVBCO 4-dimethylaminopyridine
- DBN 4-dimethylaminopyridine
- DBN
- reaction occurs under nitrogen, in order to avoid the color formation, attributed to impurities. This results in a final iloperidone that has higher purity.
- phase transfer catalyst may be present as well, in order to facilitate the reaction, which is performed in a two-phase system.
- the phase transfer catalyst is selected from the group consisting of tetraalkylammonium halides, tetraarylammonium halides, and tetra(alkyl)(aryl) ammonium halides, wherein the alkyl and aryl are the same or different.
- the alkyl is C 1-6 alkyl.
- the aryl is C6-io aryl.
- the halide is chloride, bromide or iodide.
- the phase transfer catalyst is particularly selected from the group consisting of tetrabutylmethylammonium bromide or tetrabutylmethyl- ammonium iodide.
- the obtained reaction mixture may be heated, particularly to a temperature from about 50°C to about reflux temperature of solvent, most particularly to a temperature of about 50°C to about 120°C.
- the reaction mixture is particularly heated at about 8Q°C to 85°C.
- the heated mixture may be maintained for at least about 10 hours, for the reaction to take place.
- the reaction mixture may be maintained for at least about 15 hours, and most particularly, for at least about 20 hours.
- the reaction mixture may be cooled prior to isolation of product.
- the cooling may be gradual to about ambient temperature, and then to a temperature of below 30°C.
- the preferred temperature may be from about 20°C to 30°C either relatively or quickly, e.g. over about 30 minutes, or alternatively, over a longer period of time, such as about 6-10 hours, especially for large quantities for industrial scale.
- solid iloperidone is formed, which is then recovered by methods known in the art. Particularly, the obtained iloperidone is first slurried with an 5 organic solvent, which is the organic solvent used in the reaction, such as water, acetonitrile, ethanol, acetone, dichloromethane or IPA, followed by filtration and washing. The solid Iloperidone obtained is dried. Preferably, the drying is performed at about 50°C to 55°C for about 12 hours.
- the embodiments of the process further includes, converting iloperidone to its acid additions salts.
- the suitable acid addition salts can be selected from wherein suitable acid addition salts can be selected from hydrochloride, hydrobromide, hydrogensulfate, phosphate, nitrate, citrate, acetate, succinate, fumarate, oxalate, maleate, salicylate, malate, besylate, mesylate, tosylate, napsylate, tartarate and the like.
- the acid addition salts may be neutralized with suitable base to obtain iloperidone.
- suitable base comprises of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, dimethyl amine, diethyl amine, dibutyl amine, triethyl amine, diisopropylethylamine, diisopropylamine, tert-butylamine, isobutylamine, pyridine and the like.
- triethylamine may be used.
- the purification of iloperidone may be performed by dissolving iloperidone in the suitable solvent as disclosed herein below, preferably by heating the reaction mixture to allow complete dissolution, followed by cooling of the obtained solution, whereby Iloperidone crystallizes.
- the preferred C3-6 ketones are acetone, methyl ethyl ketone (MEK) and methyl iso-butyl ketone (MIBK).
- the preferred C3-6 amides are dimethylacetamide and dimethylformamide.
- the preferred halo-substituted C6-12 aromatic hydrocarbons are chlorobenzene and dichlorobenzene.
- the preferred C alcohols are methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and 2- butanol.
- the preferred C 2- 6 acetates are ethyl acetate, isopropyl acetate, n-butyl acetate and isobutyl acetate.
- the preferred C 2-8 ethers are dibutyl ether, Methyl tert-butyl ether, diisopropyl ether and polyethylene glycol (PEG).
- the solvent is a mixture of ethanol and water or acetone and water.
- the ratio between the solvents is between about 1 : 1 to about 3: 1 by volume.
- the ratio of acetone to water is preferably about 3: 1 by volume.
- the obtained product is particularly recovered by filtering, washing of the obtained crystals, and drying, preferably overnight under reduced pressure.
- lloperidone obtained by the above process preferably contains N-oxide and desflouro impurities, each one in an amount of less than about 0.2%.
- the above crystallization process may be repeated in order to further purify the obtained lloperidone, so that the N-oxide and desflouro impurity levels may be reduced to less than about 0.07%.
- lloperidone obtained by above process is having purity greater than 99%, more particularly greater than 99.5% by HPLC.
- the present invention provides an improved process for preparing lloperidone or salts thereof by reacting 6-flouro-3-(4-piperidinyl)-l ,2- benzisoxazole (FBIP) or a salt thereof
- X may be leaving group selected from chlorine, bromine, fluorine, iodine, mesylate, or tosylate,
- phase transfer catalyst in the presence of an organic base optionally in presence of phase transfer catalyst.
- the organic base comprises one or more of dimethyl amine, diethyl amine, dibutyl amine, triethyl amine, diisopropylethylamine, diisopropylamine, tert- butylamine, isobutylamine, pyridine, 4-dimethylaminopyridirie (DMAP), imidazole, N- methylmorpholine, l,4-diazobicyclo-[2,2,2]octane (DABCO), 1 ,8- diazabicyclo[4.3.0]non-5-ene (DBN) and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
- phase transfer catalyst may be selected from one described hereinabove in the specification.
- the present invention provides a process for preparing lloperidone substantially free from dimer impurity (B),
- 2,4-diflourophenylpiperidin-4-yl methanone (VI) or salt thereof is reacted with hydroxylamine hydrochloride in presence of base selected from organic base selected from one or more of dimethyl amine, diethyl amine, dibutyl amine, triethyl amine, diisopropylethylamine, diisopropylamine, tert-butylamine, isobutylamine, pyridine, 4-dimethylaminopyridine (DMAP), imidazole, N-methylmorpholine, 1,4- diazobicyclo-[2,2,2]octane (DABCO), l,8-diazabicyclo[4.3.0]non-5-ene (DBN) and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), particularly triethylamine or dibutylamine.
- base selected from organic base selected from one or more of dimethyl amine
- the reaction of step (a) may be done in suitable organic solvent selected from one or more of C 3- 6 ketone or a mixture thereof with water, N-methylpyrrolidone, C 3-6 amides, halo-substituted C 6 -i 2 aromatic hydrocarbons propylene glycole, dimethyl sulfoxide, di-methyl carbonate, C alcohols, a mixture of a C alcohol and. water, acetonitrile or a mixture thereof with water, C 2-6 acetates.
- suitable organic solvent selected from one or more of C 3- 6 ketone or a mixture thereof with water, N-methylpyrrolidone, C 3-6 amides, halo-substituted C 6 -i 2 aromatic hydrocarbons propylene glycole, dimethyl sulfoxide, di-methyl carbonate, C alcohols, a mixture of a C alcohol and. water, acetonitrile or a mixture thereof with water, C 2-6 acetates.
- the solvent is methanol.
- the reaction is particularly done under heating conditions at about 60°C to 65°C followed by cooling and isolating oxime or its salt of formula (V).
- the oxime of formula (V) is neutralized by reaction with base selected from one or more of inorganic base like sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like.
- the base is sodium hydroxide.
- the reaction is in particular carried out in polar solvent selected from one or more of C alcohol, water, acetonitrile, N- methylpyrrolidone, C 3- 6 amides and the like, particularly water.
- the neutralization is done at elevated temperature of about 50°C to about 100°C, particularly at about 70°C to 75°C followed by gradual cooling at room temperature to isolate oxime free base of formula (IV).
- the oxime free base of formula (IV) is further reacted with suitable inorganic base selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like.
- suitable inorganic base selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like.
- the base is sodium hydroxide at an elevated temperature of about 60°C to 65°C in suitable organic solvent.
- the suitable organic solvent in reaction of step (c) may be selected from one or more of C 3-6 ketone or a mixture thereof with water, N-methylpyrrolidone, C 3-6 amides, halo-substituted C 6 -i 2 aromatic hydrocarbons, propylene glycole, dimethyl sulfoxide, dimethyl carbonate, C alcohols, a mixture of a C 1 -4 alcohol and water, acetonitrile or a mixture thereof with water, C 2- 6 acetates.
- the solvent is methanol to obtain FBIP (II).
- a mixture of FBIP (II) or a salt thereof, IL -Ia (Ilia) and an organic base are reacted.
- the reaction occurs in the presence of a solvent.
- the solvent is preferably selected from the group consisting of polar solvents like water, C alcohols; polar aprotic solvents like acetonitrile, N-methylpyrrolidone, C 3 . 6 amides, C 3 . 6 ketones, C 2-6 acetates; non-polar solvents like C 5- i aromatic hydrocarbons, and C 2-8 ethers.
- Examples of the organic base that can be used in the process for preparing iloperidone comprises one or more of dimethyl amine, diethyl amine, dibutyl amine, triethyl amine, diisopropylethylamine, diisopropylamine, tert-butylamine, isobutylamine, pyridine, 4-dimethylaminopyridine (DMAP), imidazole, N- methylmorpholine, 1 ,4-diazobicyclo-[2,2,2]octane (DABCO), 1,8- diazabicyclo[4.3.0]non-5-ene (DBN) and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Particularly, triethylamine or dibutylamine.
- DMAP 4-dimethylaminopyridine
- DVBCO 1,8- diazabicyclo[4.3.0]non-5-ene
- DBU 1,8
- a process for the purifying iloperidone comprises suspending iloperidone in one or more of suitable organic solvent, heating to allow complete dissolution and obtaining iloperidone substantially free from one or more of its impurities.
- the crystallization is preferably performed by dissolving iloperidone in the above solvent, preferably by heating the reaction mixture to allow complete dissolution, followed by cooling of the obtained solution, whereby iloperidone crystallizes.
- the preferred C 3- 6 ketones are acetone, methyl ethyl ketone (MEK) and methyl iso-butyl ketone (MIBK).
- the preferred C 3 - 6 amides are dimethylacetamide and dimethylformamide.
- the preferred halo-substituted C6-i 2 aromatic hydrocarbons are chlorobenzene and dichlorobenzene.
- the preferred Ci -4 alcohols are methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and 2-butanol.
- the preferred C 2- 6 acetates are ethyl acetate, isopropyl acetate, n-butyl acetate and isobutyl acetate.
- the preferred C 2-g ethers are dibutyl ether, methyl tert-butyl ether, diisopropyl ether and polyethylene glycol (PEG).
- the solvent is a mixture of ethanol and water or acetone and water. When a mixture is used (such as.
- the ratio between the solvents is between about 1 : 1 to about 3: 1 by volume.
- the ratio of acetone to water is preferably about 3: 1 by volume.
- Iloperidone obtained by the above process preferably contains dimer impurity (B), N-oxide and desflouro impurities, in an amount of less than about 0.2%.
- the above crystallization process may be repeated in order to further purify the obtained Iloperidone, so that the level of impurities may be reduced to less than about 0.1% when measured by HPLC.
- the present invention provides a process for purifying iloperidone comprises combining suspension of iloperidone in one or more of suitable solvent with a suitable anti-solvent to obtain iloperidone substantially free from N- oxide and desflouro impurities.
- the suitable solvent comprises one or more of methylene dichloride, chlorobenzene, chloroform, THF, acetone, acetonitrile, methanol and ethanol.
- the suitable anti-solvent comprises from one or more of methyl t-butyl ether (MTBE), diisopropyl ether, cyclohexane, hexane, heptane, toluene, benzene, xylene and water.
- MTBE methyl t-butyl ether
- the solution may be obtained by dissolving iloperidone in halogenated hydrocarbons like methylene dichloride, chlorobenzene, chloroform or THF, particularly at a reflux temperature.
- halogenated hydrocarbons like methylene dichloride, chlorobenzene, chloroform or THF, particularly at a reflux temperature.
- the obtained solution is then cooled, particularly to a temperature of about 0°C to about 30°C, and most particularly at about 25°C, followed by admixing with the anti-solvent described above.
- the admixing may be done in any order, for example, the anti-solvent may be added to the solution, or alternatively, the solution may be added to the anti-solvent.
- the temperature difference causes the fast crystallization.
- the addition may be added dropwise or in one volume.
- the obtained mixture may be then particularly maintained for at least about 5 minutes or till crystallization occurs, more particularly between about 5 minutes and about 6 hours, most particularly for about 1.5 hours, and suitably under stirring.
- the obtained product is particularly recovered by filtering.
- Iloperidone obtained by the above process particularly contains N-oxide in an amount of less than about 0.2% and desflouro in an amount of less than about 0.1%.
- the above crystallization process may be repeated in order to further purify the obtained iloperidone, so that the N-oxide and desflouro levels may be reduced to less than about 0.05%.
- a process for purifying iloperidone comprises slurrying iloperidone in one or more of suitable organic solvent to obtain iloperidone substantially free from N-oxide and desflouro impurities.
- the slurrying may be performed at a temperature of about 20°C to about 80°C, more particularly at a temperature of about 25°C to about 80°C.
- the slurrying may be performed for a period of time sufficient for purifying iloperidone, particularly from about 30 minutes to about 24 hours.
- the organic solvent comprises from one or more of Ci -4 alcohols like methanol, ethanol, isopropanol, butanol and the like, C 3- 5 ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone and the like, acetonitrile and water.
- Ci -4 alcohols like methanol, ethanol, isopropanol, butanol and the like
- C 3- 5 ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone and the like
- acetonitrile and water.
- Iloperidone obtained by the above process preferably contains N-oxide in an amount of less than about 0.2% and desflouro in an amount of less than about 0.1%.
- the above crystallization process may be repeated in order to further purify the obtained iloperidone, so that the N-oxide and desflouro levels may be reduced to less than about 0.05%.
- the total purity of iloperidone is about 99.0%, particularly about 99.5% or more.
- a process for purifying iloperidone comprises,
- the filtering step may be performed in order to remove the finely powdered carbon.
- the solution is obtained by dissolving iloperidone in one or more of organic solvent selected from mixture of acetone:water or ethanol :water.
- the organic solvent is preferably a mixture of acetone:water or ethano water.
- finely powdered carbon is an active carbon.
- the active carbon may be selected from the group consisting of HB ultra, CGP super, GBG, SX plus, ROX 0.8 and A super eur.
- the filtration is preferably done through hy-flow.
- Iloperidone obtained by the above process preferably contains N-oxide in an amount of less than about 0.15% and desflouro in an amount of less than about 0.10%.
- the above crystallization process may be repeated in order to further purify the obtained iloperidone, so that the N-oxide and desflouro impurity levels may be reduced to less than about 0.05%.
- the total purity of iloperidone is about 99.0%, particularly about 99.5% or more.
- iloperidone pharmaceutically acceptable salt from said suspension, wherein suitable acid can be selected from hydrochloride, hydrobromide, hydrogensulfate, phosphate, nitrate, citrate, acetate, succinate, fumarate, oxalate, maleate, salicylate, malate, besylate, mesylate, tosylate, napsylate, tartarate and the like.
- the suitable organic solvent comprises one or more of water, C ! -4 alcohols; polar aprotic solvents like acetonitrile, N-methylpyrrolidone, C 3-6 amides, C 3-6 ketones, C 2-6 acetates; non-polar solvents like C5.12 aromatic hydrocarbons, halogenated hydrocarbons and C 2-8 ethers or mixture thereof.
- the process comprises:
- reaction mixture (a) reacting 4-hydroxy-3-methoxy acetophenone and l -bromo-3-chloropropane in one or more of first organic solvent in presence of base to obtain reaction mixture;
- the first organic solvent comprises one or more of water, C alcohols like methanol, ethanol, isopropanol, n-butanol; polar aprotic solvents like acetonitrile, N-methylpyrrolidone, C 3- 6 amides like ⁇ , ⁇ -dimethylformamide, N,N- dimethylacetamide, C 3-6 ketones like acetone, methylisobutyl ketone, methyl ethyl ketone (2-butanone), C 2-6 acetates like ethylacetate, isopropyl acetate, n-butylacetate, isobutyl acetate etc or mixture thereof.
- polar aprotic solvents like acetonitrile, N-methylpyrrolidone, C 3- 6 amides like ⁇ , ⁇ -dimethylformamide, N,N- dimethylacetamide, C 3-6 ketones like acetone, methylisobutyl ketone, methyl ethy
- the reaction mixture may be heated at an elevated temperature preferably the boiling point of solvent.
- the most preferable temperature range is from 50°C to 90°C.
- the reaction mixture may be concentrated by usual method as reported in the art which includes but not limited to distillation under vacuum, distillation under atmosphere, decantation etc.
- the second organic solvent comprises one or more of toluene, xylene, ethylbenzene, methylene dichloride, chlorobenzene, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl tert-butyl ether, diisopropyl ether, n-hexane, n-heptane, cyclohexane or mixture thereof.
- the l-[4-(3-chloropropoxy)-3- methoxyphenyl)ethanone (ILK-Ia) compound isolated by the process of present invention is crystalline Form-I characterized by X-ray diffraction pattern substantially as depicted in Figure- 13.
- Form-I is characterized by having X-ray diffraction pattern comprising at least three peaks selected from peaks with 2 ⁇ angles of about 8.0°, 10.7°, 14.4°, 14.9°, 16.4°, 18.7°, 21.3°, 21.9°, 23.0°, 24.7°, 25.1°, 25.8°, 27.2°, 27.8°, and 28.9 ⁇ 0.2° (2 ⁇ ).
- the invention provides purification of l-[4-(3-chloropropoxy)-3- methoxyphenyl)- ethanone (ILK-Ia) in suitable organic solvent selected from methyl tert-butyl ether, diisopropyl ether, cyclohexane, methanol, ethanol, isopropanol, acetone, ethyl acetate, isopropyl acetate, butylacetate, N,N-dimethylformamide, acetonitrile and the like to obtain crystalline Form-I.
- suitable organic solvent selected from methyl tert-butyl ether, diisopropyl ether, cyclohexane, methanol, ethanol, isopropanol, acetone, ethyl acetate, isopropyl acetate, butylacetate, N,N-dimethylformamide, acetonitrile and the like to obtain crystalline Form-I.
- a stable crystalline iloperidone or salts thereof which is stored under nitrogen atmosphere and packed in a double polythene bag tied with a thread, keeping primary packing containing crystalline Iloperidone or salts thereof inside a black color polyethylene bag containing oxygen busters and sealing it, placing above the double polyethylene bag inside a triple laminated bag optionally containing oxygen busters and sealing it, and placing the sealed triple laminated bag inside a closed high density polyethylene (HDPE) container and storing in controlled environment chamber at about 25°C and/or 40°C.
- HDPE high density polyethylene
- the present invention provides crystalline iloperidone of formula (I) having an chemical purity of greater than about 90%, or greater than about 95%, or greater than about 98%, or greater than about 99%, or greater than about 99.5%, or greater than about 99.8%, or greater than about 99.9%, as determined using high performance liquid chromatography (HPLC).
- HPLC high performance liquid chromatography
- An aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of crystalline iloperidone substantially free of one or more of its corresponding impurities as measured by HPLC.
- An aspect of the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of crystalline iloperidone substantially free from N-oxide and desflouro, and one or more pharmaceutically acceptable carriers, excipients or diluents.
- An , aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of crystalline iloperidone substantially free from dimer impurity, and one or more pharmaceutically acceptable carriers, excipients or diluents.
- Crystalline Iloperidone is characterized as substantially depicted in XRD (FIG.l).
- Crystalline Iloperidone is characterized as substantially depicted in DSC (FIG.14) having endothermic peak at about 124.66°C.
- Another aspect of the invention provides crystalline iloperidone or salts thereof having particle size distributions wherein the 10th volume percentile particle size (D10) is less than about 50 ⁇ , the 50th volume percentile particle size (D50) is less than about 200 ⁇ , or the 90th volume percentile particle size (D90) is less than about 400 ⁇ , or any combination thereof.
- the purity of FBIP prepared by the process of the present invention may be tested by using following HPLC conditions.
- Diluent 0.1% orthophosphoric acid in water :Acetonitrile (50:50).
- the purity of iloperidone prepared by the process of the present invention may be tested by using following HPLC conditions.
- Diluent 0.1 % orthophosphoric acid in watenAcetonitrile (50:50).
- Powder X-ray Diffraction of crystalline Iloperidone form can be obtained under following conditions.
- Iloperidone can be prepared by the reaction
- compositions includes tablets, pills, powders, liquids, “ suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
- compositions containing the iloperidone of the invention may be prepared by using diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents, surface active agents, and lubricants.
- diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents, surface active agents, and lubricants.
- modes of administration of the pharmaceutical compositions of the invention can be selected depending on the therapeutic purpose, for example tablets, pills, powders, liquids, .suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
- reaction mass was poured into water, and the aqueous mixture was 078S extracted with ethyl acetate. The ethyl acetate was washed with water and dried oyer magnesium sulfate. The reaction mass was distilled under reduced pressure to obtain moist solid.
- the product was recrystallized in ethyl alcohol to obtain 5.0 g (58%) of 1- [4-[3-[4-(6-flouro-l ,2-benzoisoxazol-3-yl)piperidin-l -yl]propoxy]-3- methoxypropyl]ethanone as beige solid, m.p. 1 18-120°C.
- the product was characterized by X-ray powder diffraction pattern having peaks at about 7.0, 12.5, 14.2, 16.6, 17.0, 1 7.4, 19.8, 20.2, 20.5, 21.4, 21.9, 23.4, 23.8, 26.2, 28.8 and 30.6 degrees 20 (Form-I).
- Oxime hydrochloride (VI) 100. g was heated in water (1000 mL) at 75°C for 15 minutes. The reaction mixture was cooled to 55°C whereupon it was treated with 25% sodium hydroxide solution (82 mL) and stirred for 15 minutes. The reaction mixture was cooled. The precipitated product was filtered and washed with water. The product was dried to obtain 80 g (92%) oxime free base (V). (Dimer > 0.25%)
- the product was characterized by X-ray powder diffraction pattern having peaks at about 7.0, 12.5, 14.2, 16.6, 17.0, 17.4, 19.8, 20.2, 20.5, 21.4, 21.9, 23.4, 23.8, 26.2, 28.8 and 30.6 degrees 2 ⁇ (Form-1).
- Example 26 Purification of Iloperidone by slurrying in different solvent
- Iloperidone (25 g) and acetone (250 mL) were combined and stirred at 75°C for about 15 minutes to dissolve Iloperidone completely.
- Charcoal (2.0 g) was added and stirred at 75°C for 15 minutes.
- the solution was cooled to ambient temperature and filtered through a hyflow bed and washed with acetone (50 mL). The filtrate was distilled completely under reduced pressure at 45°C to afford 22.7 g of crystalline Iloperidone. Chemical purity 99.7% and N-oxide ⁇ 0.1 % and desflouro ⁇ 0.1 %
- the crystalline iloperidone is stored under nitrogen atmosphere and packed in a double polythene bag tied with a thread, keeping primary packing containing crystalline Iloperidone or salts thereof inside a black color polyethylene bag containing oxygen busters and sealing it, placing above the double polyethylene bag inside a triple laminated bag optionally containing oxygen busters and sealing it, and placing the sealed triple laminated bag inside a closed high density polyethylene (HDPE) container and storing in controlled environment chamber at about 25°C and/or.40°C.
- HDPE high density polyethylene
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Abstract
L'invention concerne l'iloperidone et son procédé de préparation, et notamment un procédé amélioré de préparation de l'iloperidone sous forme cristalline. L'invention concerne des compositions pharmaceutiques comprenant l'iloperidone cristalline sensiblement exempte d'impuretés telles que N-oxyde, desfluoro et dimère.
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IN1518/MUM/2011 | 2011-05-18 |
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CN102796090A (zh) * | 2012-08-30 | 2012-11-28 | 天津华津制药有限公司 | 一种伊潘立酮的制备方法 |
WO2012164516A1 (fr) * | 2011-06-03 | 2012-12-06 | Lupin Limited | Procédé pour la préparation d'ilopéridone |
CN103880828A (zh) * | 2012-12-24 | 2014-06-25 | 凌沛学 | 一种苯并异噁唑类化合物的氧化物 |
CN106831742A (zh) * | 2016-12-28 | 2017-06-13 | 北京医药集团有限责任公司 | 一种伊潘立酮中间体的制备方法 |
CN109438443A (zh) * | 2018-12-24 | 2019-03-08 | 浙江工业大学上虞研究院有限公司 | 利培酮的制备方法 |
US20220024905A1 (en) * | 2018-12-07 | 2022-01-27 | Nhwa Pharma. Corporation | Crystalline form of propanamide derivative and preparation method therefor |
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