WO2013175499A2 - Forme polymorphe du 5-(4-[4-(5-cyano-1h-indol-3-yl)butyl]pipérazin-1-yl)benzofurane-2-carboxamide - Google Patents

Forme polymorphe du 5-(4-[4-(5-cyano-1h-indol-3-yl)butyl]pipérazin-1-yl)benzofurane-2-carboxamide Download PDF

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WO2013175499A2
WO2013175499A2 PCT/IN2013/000262 IN2013000262W WO2013175499A2 WO 2013175499 A2 WO2013175499 A2 WO 2013175499A2 IN 2013000262 W IN2013000262 W IN 2013000262W WO 2013175499 A2 WO2013175499 A2 WO 2013175499A2
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formula
carboxamide
benzofuran
vilazodone
acid
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PCT/IN2013/000262
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English (en)
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WO2013175499A3 (fr
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Shriprakash Dhar DWIVEDI
Ramesh Chandra SINGH
Rajendra Gokalbhai CHAVDA
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Cadila Healthcare Limited
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Publication of WO2013175499A3 publication Critical patent/WO2013175499A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a process for the preparation of 5-(4-[4-(5- cyano-lH-indol-3-yl)butyl]piperazin-l-yl)benzpfuran-2-carboxamide of Formula (1) or its pharmaceutically acceptable salt, solvates ;or hydrates thereof.
  • the present invention provides a novel intermediate compound, 5-(4-substitutedpiperazin- l-yl)benzofuran-2-carboxamide of Formula (X).
  • the present invention further provides solid state form of 5-(4-[4-(5-cyano-lH- indol-3-yl) butyl]piperazin-l-yl)benzofuran-2-carboxamide of Formula (1) and process for its preparation.
  • U.S. Patent No. 5,532,241 discloses 5-(4-[4-(5-cyano-lH-indol-3- yl)butyl]piperazi -l-yl) benzofuran-2-carboxamide i.e. vilazodone of Formula (1)
  • the '241 patent discloses process for preparing vilazodone or its pharmaceutically acceptable salt thereof.
  • U.S. Patent No. 5,977,112 relates to process for preparing intermediate involved in the preparation of vilazodone or its pharmaceutically acceptable salt thereof.
  • U.S. Patent No. 6,509,475 Bl relates to process for preparing intermediate involved in the preparation of vilazodone or its pharmaceutically acceptable salt thereof.
  • U.S. Patent No. 7,834,020 B2 (the US ⁇ 20 B2) claims vilazodone hydrochloride anhydrate in crystalline modification IV (Form IV) characterized by XRD.
  • the US ⁇ 20 B2 discloses total 15 crystalline forms of Vilazodone HC1 designated as crystalline Form-I to Form-XI and Form-XIII to Form-XVI.
  • U.S. Patent No. 7,981 ⁇ 894 B2 claims vilazodone hydrochloride monohydrate in crystalline modification V (Form-V) having characteristic peaks in XRD.
  • the invention provides a new process for the preparation of 5- (4-[4-(5-cyano- 1 H-indol-3-yl)butyl]piperazin- 1 -yl)benzofuran-2-carboxamide of Formula (1) or its pharmaceutically acceptable salts, solvates or hydrates thereof.
  • the compound of Formula (1) is known as vilazodone.
  • the present invention provides vilazodone of Formula (1) or its pharmaceutically acceptable salts, solvates or hydrates thereof having a total purity of greater than about 99%, specifically greater than about 99.5%, most specifically greater than about 99.9%, as measured by FIPLC.
  • Another aspect of the present invention provides a novel intermediate compounds, 5-(4-substituted piperazin-l-yl)benzofuran-2-carboxamide of Formula
  • R is a suitable amino protecting group selected from, methansulfonamide, p- methoxybenzyl carbonyl, p-mluenesulfonamide, tert-mutyloxycarbonyl (BOC), 9- fluorenylmethyloxycarbonyl (FMOC), benzyl carbamate, acetamide, phthalimide, carbobenzyloxy (Cbz), acetyl, benzoyl, benzyl, carbamates, p-methoxybenzyl, p- methoxyphenyl and the like.
  • the present invention provides a novel intermediate compound, 5-(4-tosylpiperazin-l-yl)benzofuran-2-carboxamide of Formula (F).
  • the present invention provides the use of the novel intermediate ;5-(4-tosylpiperazin-l-yl)benzofuran-2-carboxamide of Formula (F) for the preparation of vilazodone.
  • Another aspect of present invention provides a process for the preparation of the novel intermediate 5-(4-tosylpiperazin-l-yl)benzofuran-2-carboxamide of Formula (F)
  • the present invention provides an improved process for preparing 5-aminobenzofuran-2-carboxamide of Formula (E),
  • Form-A In another aspect, the present invention provides a solid state Form-A of 5-(4-[4-(5- cyano-lH-indol-3-yl)butyl]piperazin-l-yl)benzofuran-2-carboxamide i.e. vilazodone of Formula (1) is characterized by XRD, DSC and TGA.
  • the present invention provides the use of solid state Form-A of 5-(4-[4-(5-cyano-lH ⁇ indol-3-yl)butyl]piperazin-l-yl)benzofuran-2-carboxamide i.e. vilazodone of Formula (1) in the preparation of vilazodone hydrochloride.
  • the present invention provides solid state form of hydrate or solvate of 5-(4-[4-(5-cyano-lH-indol-3-yl)butyl]piperazin-l-yl) benzofuran-2- carboxamide i.e. vilazodone of Formula (1).
  • the present invention provides solid state form of solvate of
  • the present invention provides solid state form of methanol solvate of 5-(4-[4-(5-cyano-lH-indol-3-yl)butyl]piperazin ⁇ -l-yl) benzofuran-2- carboxamide i.e. vilazodone of Formula (1) is characterized by XRD, DSC and TGA.
  • the present invention provides a solid state Form-A of vilazodone of Formula (1) having a total purity of greater than about 99%, specifically greater than about 99.5%, more specifically greater than about 99.9%, and most specifically greater than about 99.98% as measured by HPLC.
  • the present invention provides a process for preparing solid state Form-A of 5-(4-[4-(5-cyano-lH-indol-3-yl)butyl]piperazin-l-yl)benzofuran-2- carboxamide i.e. vilazodone of Formula (1).
  • the present invention provides the use of solid state Form-A of 5-(4-[4-(5-cyano-lH-indol-3-yl)butyl]piperazin-l-yl) benzofuran-2 -carboxamide i.e. vilazodone of Formula (1)
  • FIG. 1 Shows X-ray diffractogram (XRD) of solid state Form-A of vilazodone of Formula (1).
  • FIG. 2 Shows differential scanning calorimetry (DSC) of solid state Form-A of vilazodone of Formula (1).
  • FIG. 3 Shows thermal gravimetric analysis (TGA) of solid state Form-A of vilazodone of Formula (1).
  • FIG. 4 Shows X-ray diffractogram (XRD) of methanol solvate of vilazodone of Formula (1).
  • FIG. 5 Shows differential scanning calorimetry (DSC) of methanol solvate of vilazodone of Formula (1).
  • FIG. 6 Shows thermal gravimetric analysis (TGA) of methanol solvate of vilazodone of Formula (1).
  • the present invention provides a novel intermediate compounds, 5-(4-substitutedpiperazin-l-yl)benzofuran-2-carboxamide of Formula (X)
  • R is a suitable amino protecting group selected from, methansulfonamide, p- methoxybenzyl carbonyl, p-toluenesulfonamide, tert-butyloxycarbonyl (BOC), 9- fluorenylmethyloxycarbonyl (FMOC), benzyl carbamate, acetamide, phthalimide, carbobenzyloxy (Cbz), acetyl, benzoyl, benzyl, carbamates, p-methoxybenzyl, p- methoxyphenyl and the like. More particularly, the suitable protecting group is p- toluenesulfonamide (tosyl).
  • Another aspect of the invention provides a process for the preparation of the novel compounds of Formula (X) (X)
  • R is a suitable amino protecting group selected from, methansulfonamide, p- methoxybenzyl carbonyl, p-toluenesulfonamide, tert-butyloxycarbonyl (BOC), 9- fluorenylmethyloxycarbonyl (FMOC), benzyl carbamate, acetamide, phthalimide, carbobenzyloxy (Cbz), acetyl, benzoyl, benzyl, carbamates, p-methoxybenzyl or p- methoxyphenyl; comprising reacting 5-aminobenzofuran-2-carboxamide of Formula (E) or
  • the present invention provides the novel intermediate
  • Another aspect of the present invention provides, the novel intermediate, 5-(4- tosylpiperazin-l-yl)benzofuran-2-carboxamide of Formula (F) having purity higher than around about 95%, more particularly higher than around about 98%, more particularly higher than around about 99% and even more particularly higher than around about 99.5%.
  • Another aspect of the present invention provides the process for the preparation of vilazodone of Formula (I) or its pharmaceutically acceptable salts, solvates, hydrates thereof
  • R is a suitable amino protecting group selected from, methansulfonamide, p-methoxybenzyl carbonyl, p-toluenesulfonamide, tert-butyloxycarbonyl (BOC), 9- fluorenylmethyloxycarbonyl (FMOC), benzyl carbamate, acetamide, phthalimide, carbobenzyloxy (Cbz), acetyl, benzoyl, benzyl, carbamates, p-methoxybenzyl, p- methoxyphenyl, in the presence of a base in a suitable solvent to obtain 5-(4- substitutedpiperazin-l-yl)benzofuran-2-carboxamide of Formula (X);
  • the invention provides the process for the preparation of vilazodone of Formula (1) or its pharmaceutically acceptable salts, solvates or hydrates thereof,
  • 5-aminobenzofuran-2-carboxamide of Formula (E) is reacted with N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide of Formula ( ⁇ ') in the presence of a base in a suitable solvent to provide novel compound, 5-(4- tosylpiperazin-l-yl)benzofuran-2-carboxamide of Formula (F).
  • the suitable solvent for step (i) comprises one or more of hydrocarbons, nitriles, " amides, alcohol, ketones, ester and the like.
  • the suitable solvent comprises toluene, xylene, ethylbenzene dimethyl formamide, dimethyl acetamide, acetonitrile, CrC 4 straight chain or branched alcohols, acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, butyl acetate and the likes.
  • the solvent may be methanol.
  • the suitable base for step (i) comprises of an alkali and alkaline metal hydroxide and carbonate or organic base
  • the suitable alkali metal hydroxide comprises of sodium hydroxide, potassium hydroxide, lithium hydroxide, and the like
  • carbonate comprises of sodium carbonate, potassium carbonate, cesium carbonate and the like
  • organic base comprises of triethylamine, diisopropylethylamine, isopropyl amine.
  • the base may be Diisopropylethylamine or triethyl amine.
  • the novel compound, 5-(4-tosylpiperazin-l-yl)benzofuran-2-carboxamide of Formula (F) is further underwent deprotection.
  • the deprotection may be carried out by using acid.
  • the suitable acid in step (ii) may be selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, acetic acid, benzoic acid, p-hydroxy benzoic acid and like or a mixture thereof. More particularly the acid used is a mixture of Hydrobromic acid, acetic acid as well as p-Hydroxy benzoic acid or sulfuric acid.
  • the suitable solvent used in step (ii) for removal of amino group protection from 5-(4-tosylpiperazin-l-yl)benzofuran-2-carboxamide of Formula (F) is selected from one or more of water, hydrocarbons, nitriles, amides, alcohol, ketones, ester and the like.
  • the suitable solvent comprises water, toluene, xylene, ethylbenzene dimethyl formamide, dimethyl acetamide, acetonitrile, C1-C4 straight chain or branched alcohols, acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, butyl acetate and the likes.
  • the solvent may be water and ethyl acetate.
  • the 5-(l-piperazinyl) benzofuran-2-carboxamide of Formula (G) is isolated in the solid state form by reacting with a base in a suitable solvent.
  • the suitable base comprises of an alkali and alkaline metal hydroxide and carbonate, in particular the suitable alkali metal hydroxide comprises of sodium hydroxide, potassium hydroxide, lithium hydroxide, and the like, carbonate comprises of sodium carbonate, potassium carbonate, cesium carbonate and the like.
  • the base may be sodium hydroxide.
  • the suitable solvent for the isolation of 5-(l-piperazinyl) benzofuran-2- carboxamide of Formula (G) in solid state form comprises one or more of hydrocarbons, water, nitriles, amides, alcohol, ketones, ester and the like.
  • the suitable solvent comprises toluene, xylene, ethylbenzene dimethyl formamide, dimethyl acetamide, acetonitrile, C1-C4 straight chain or branched alcohols, acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, butyl acetate and the likes.
  • the solvent may be ethyl acetate.
  • the 5-(l-piperazinyl) benzofuran-2- carboxamide of Formula (G) or its salts is reacted with 3-(4-chlorobutyl)-lH-indole-5-carbonitrile of Formula (H) in the presence of a base in a suitable solvent, optionally in the presence of phase transfer catalyst to obtain vilazodone of Formula ( 1 ).
  • the suitable solvent comprises one or more of water, water miscible solvent, polar solvent, hydrocarbons, amide, sulfoxide, ester.
  • the solvent Comprises of toluene, xylene, ethylbenzene, dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, acetonitrile, C1-C4 straight chain or branched alcohols, acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, butyl acetate, N- methyl pyrrolidone.
  • the suitable base for step (iv) is selected from an organic or inorganic base;
  • an organic base may be a tertiary amine base such as trimethylamine, triethylamine, N- methylpiperidine,
  • an inorganic base may be an alkali and alkaline metal hydroxide and carbonate, preferably triethylamine.
  • phase transfer catalyst comprises of crown ethers, hexadecyltributylphosphonium bromide, tetra-n-butylammonium bromide, methyltrioctyl- ammonium chloride or other known phase transfer catalyst which facilitates the reaction, preferably the phase transfer catalyst may be crown ethers.
  • Another aspect of the present invention provides, a process for the preparation of a solid state form of 5-(4-[4-(5-cyano-lH-indol-3-yl)butyl]piperazin-l-yl) benzofuran-2-carboxamide i.e. vilazodone of Formula (1),
  • the suitable solvent for step (i) is one or more of solvent comprises of hydrocarbons, nitriles, amides, alcohol, ketones, ester and the like.
  • the suitable solvent comprises toluene, xylene, ethylbenzene dimethyl formamide, dimethyl acetamide, acetonitrile, C1-C4 straight chain or branched alcohols, acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, isopropyl acetate & butyl acetate and the like.
  • the base for step (i) comprises of an organic or inorganic base;
  • an organic base may be selected from diisopropylethylamine, diisopropylamine, trimethylamine, diethylamine, piperidine, morpholine, pyridine, DBU, DABCO and the like;
  • the inorganic base comprises of an alkali and alkaline metal hydroxide and carbonate, in particular the suitable alkali metal hydroxide comprises of sodium hydroxide, potassium hydroxide, lithium hydroxide, and the like, carbonate comprises of sodium carbonate, potassium carbonate, cesium carbonate and the like.
  • the base selected may be diisopropylethylamine.
  • the phase transfer catalyst comprises of crown ethers, hexadecyltributylphosphonium bromide, tetra-nrbutylammonium bromide, methyltrioctyl- ammonium chloride or other known phase transfer catalyst which facilitates the reaction, particularly the phase transfer catalyst may be crown ethers.
  • the solid state form of vilazodone of Formula (1) is isolated by treating with suitable solvent comprises of hydrocarbons, nitriles, amides, alcohol, ketones, ester and the like.
  • suitable solvent comprises toluene, xylene, ethylbenzene dimethyl formamide, dimethyl acetamide, acetonitrile, Cj-C 4 straight chain or branched alcohols, acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, isopropyl acetate and butyl acetate and the like.
  • the solvent may be methanol.
  • the present invention provides a solid state form of 5-(4-[4- (5-cyano-lH-indol-3-yl)butyl]piperazin-l-yl) benzofuran-2-carboxamide i.e. vilazodone of Formula (1), which is designated as Form-A.
  • a solid state Form-A of 5-(4-[4-(5-cyano-lH-indol-3-yl)butyl]piperazin-l-yl) benzofiiran-2-carboxamide i.e. vilazodone of Formula (1) is characterized by X-ray - powder diffraction having characteristic peaks at about 8.9, 11.4, 12.6, 14.3, 16.6, 18.7, 20.2, 21.5, 24.4, 27.1 and 28.0 ⁇ 0.2 degree 20.
  • a solid state Form-A of 5-(4-[4-(5-cyano-lH-indol-3-yl)butyl]piperazin-l-yl) benzofuran-2-carboxamide i.e. vilazodone of Formula (1) is further characterized by X-ray powder diffraction having characteristic peaks at about 13.7, 15.0, 16.0, 17.8, 20.8, 22.7, 23.5, 29.4, 30.0, 31.3 and 32.6 ⁇ 0.2 degree 20.
  • a solid state Form-A of 5-(4-[4-(5-cyano-lH-indol-3-yl)butyl]piperazin-l- yl)benzofuran-2-carboxamide i.e. vilazodone of Formula (1) is characterized by X-ray powder diffraction as depicted in FIG.1.
  • a solid state Form-A of 5-(4-[4-(5-cyano-lH-indol-3-yl)butyl]piperazin-l- yl)benzofuran-2-carboxamide i.e. vilazodone of Formula (1) is characterized by Differential Scanning Calorimetry (DSC) having peak at about 292°C respectively.
  • a solid state Form-A of 5-(4-[4-(5-cyano-lH-indol-3-yl)butyl]piperazin-l- yl)benzofuran-2-carboxamide i.e. vilazodone of Formula (1) is characterized by Differential Scanning Calorimetry as depicted in FIG.2.
  • a solid state Form-A of 5-(4-[4-(5-cyano-lH-indol-3-yl)butyl]piperazin-l- yl)benzofuran-2-carboxamide i.e. vilazodone of Formula (1) is characterized by Thermal gravimetric analysis (TGA) having water loss of less than 1%.
  • a solid state Form-A of 5-(4-[4-(5-cyano-lH-indol-3-yl)butyl]piperazin-l-yl) benzofuran-2-carboxamide i.e. vilazodone of Formula (1) is characterized by Thermal gravimetric analysis (TGA) as depicted in FIG.3.
  • a solid state Form-A of 5-(4-[4-(5-cyano-lH-indol-3-yl)butyl]piperazin-l- yl)benzofuran-2-carboxamide i.e. vilazodone of Formula (1) is an anhydrous form.
  • the present invention provides the usage of solid state Form- A of 5-(4-[4-(5-cyano-lH-indol-3-yl)butyl]piperazin-l-yl) benzofuran-2-carboxamide i.e. vilazodone of Formula (1) in the preparation of Vilazodone hydrochloride of Formula (2).
  • the present invention provides solid state form of hydrate or solvate of vilazodone of Formula (1).
  • the present invention provides solid state form of methanol solvate of vilazodone of Formula (1).
  • the present invention provides solid state form of methanol solvate of 5-(4-[4-(5-cyano-lH-indol-3-yl)butyl]piperazin-l-yl) benzofuran-2- carboxamide i.e. vilazodone of Formula (1) is characterized by X-ray powder diffraction having characteristic peaks at about 8.3, 12.3, 12.8, 16.0, 18.4, 19.0, 19.6, 21.0, 24.4, 25.2, 25.6, 26.2, 27.7 and 29.8 ⁇ 0.2 degree 20.
  • a solid state form of methanol solvate of 5-(4-[4-(5-cyano-lH-indoI-3- yl)butyl]piperazin-l-yl) benzofuran-2-carboxamide i.e. vilazodone of Formula (1) is further characterized by X-ray powder diffraction having characteristic peaks at about 8.9, 10.7, 11.4, 13.3, 14.4, 15.0, 16.8, 17.6, 20.1, 22.1, 22.4, 23.3, 27.2, 28.6, 29.4, 32.2 and 32.5 ⁇ 0.2 degree 20.
  • a solid state form of methanol solvate of 5-(4-[4-(5-cyano-lH-indol-3- yl)butyl]piperazin-l-yl)benzofuran-2-carboxamide i.e. vilazodone of Formula (1) is characterized by X-ray powder diffraction as depicted in FIG. 4.
  • a solid state form of methanol solvate of 5-(4-[4-(5-cyano-lH-indol-3- yl)butyl]piperazin-l-yl)benzofuran-2-carboxamide i.e. vilazodone of Formula (1) is characterized by Differential Scanning Calorimetry (DSC) having two peaks at about 113°C and 288°C respectively.
  • DSC Differential Scanning Calorimetry
  • a solid state form of methanol solvate of 5-(4-[4-(5-cyano-lH-indol-3- yl)butyl]piperazin-l-yl)benzofuran-2-carboxamide i.e. vilazodone of Formula (1) is characterized by Differential Scanning Calorimetry (DSC) as depicted in FIG. 5.
  • a solid state form of methanol solvate of 5-(4-[4-(5-cyano-lH-indol-3- yl)butyl]piperazin-l-yl)benzofuran-2-carboxamide i.e. vilazodone of Formula (1) is characterized by Thermal gravimetric analysis (TGA) having weight loss of more than 6.0%.
  • a solid state form of methanol solvate of 5-(4-[4-(5-cyano-lH-indol-3- yl)butyl]piperazin-l-yl) benzofuran-2-carboxamide i.e. vilazodone of Formula (1) is characterized by Thermal gravimetric analysis (TGA) as depicted in FIG. 6.
  • a solid state form of methanol solvate of Form-A of 5-(4-[4-(5-cyano-lH- indol-3-yl)butyl]piperazin-l-yl)benzofuran-2-carboxamide i.e. vilazodone of Formula (1) is a methanol solvate form.
  • the invention provides an improved process for the preparation of 5-aminobenzofuran-2-carboxamide of Formula (E),
  • the organic solvent for step (i) is selected from group comprising of water, aromatic hydrocarbons, C 3-8 ketones, C 3-4 esters, C 2-8 alcohols, ethers, or a mixture thereof, preferably water.
  • the base for step (i) is selected from group comprising of alkali and alkaline metal hydroxides, carbonates, bicarbonates, preferably sodium hydroxide.
  • the acid for step (ii) is selected from group comprising of sulfuric acid, nitric acid or both, preferably both sulfuric acid and nitric acid.
  • 5-nitrobenzofuran-2-carboxylic acid is converted to 5- nitrobenzofuran-2-carboxamide of Formula (D) by reacting with thionyl chloride in solvent comprises of aromatic hydrocarbons, dimethyl formamide (DMF), C 3- 8 ketones, C 3-4 esters, C 2-8 alcohols, ethers, or a mixture thereof, preferably toluene and DMF formation of 5-nitrobenzofuran-2-carbonyl chloride, which was reacted with ammonia to obtain 5-nitrobenzofuran-2-carboxamide of Formula (D.
  • solvent comprises of aromatic hydrocarbons, dimethyl formamide (DMF), C 3- 8 ketones, C 3-4 esters, C 2-8 alcohols, ethers, or a mixture thereof, preferably toluene and DMF formation of 5-nitrobenzofuran-2-carbonyl chloride, which was reacted with ammonia to obtain 5-nitrobenzofuran-2-carboxamide of Formula (D.
  • the suitable metal catalyst for reduction of 5-nitrobenzofuran-2-carboxamide of Formula (D) to 5-aminobenzofuran-2-carboxamide of Formula (E) in step (vi) is selected from the group comprising of Raney-Ni, zinc chloride, Fe/HCl, Pd/C, sodium dithionite, sodium formaldehyde sulphoxylate (Safolite) etc, preferably Raney-Ni.
  • the suitable organic solvent for reduction step (vi) is selected from Q-C5 alcohols, water or a mixture thereof, preferably methanol.
  • Another aspect of the present invention provides, a new process for the preparation of solid state form of 5-(l-piperazinyl) benzofuran-2-carboxamide of Formula (G)
  • step (iii) isolating the solid state form of 5-(l-piperazinyl) benzofuran-2-carboxamide of Formula (G) in presence of a base.
  • the suitable solvent for step (i) comprises one or more of hydrocarbons, nitriles, amides, alcohol, ketones, ester and the like.
  • the suitable solvent comprises toluene, xylene, ethylbenzene dimethyl formamide, dimethyl acetamide, acetonitrile, Ci-C4 straight chain or branched alcohols, acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, butyl acetate and the likes.
  • the solvent may be methanol.
  • the suitable base for step (i) comprises of an alkali and alkaline metal hydroxide and carbonate or organic base
  • the suitable alkali metal hydroxide comprises of sodium hydroxide, potassium hydroxide, lithium hydroxide, and the like
  • carbonate comprises of sodium carbonate, potassium carbonate, cesium carbonate and the like
  • organic base comprise of triethylamine, diisopropylethylamine, isopropylamine.
  • the base may be diisopropylethylamine.
  • the suitable solvent used in step (ii) for removal of amino group protection from 5-(4-tosylpiperazin-l-yl)benzofuran-2-carboxamide of Formula (F) is selected from one or more of hydrocarbons, nitriles, amides, alcohol, ketones, ester and the like.
  • the suitable solvent comprises toluene, xylene, ethylbenzene dimethyl formamide, dimethyl acetamide, acetonitrile, Ci-C 4 straight chain or branched alcohols, acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, butyl acetate and the likes.
  • the solvent may be water and ethyl acetate.
  • the suitable acid in step (ii) may be selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, acetic acid, benzoic acid, p-hydroxy benzoic acid and like or a mixture thereof. More particularly the acid used is sulfuric acid.
  • the suitable solvent for step (iii) for isolating a solid state form of 5-(l- piperazinyl) benzofuran-2-carboxamide of Formula (G) comprises one or more of hydrocarbons, water, nitriles, amides, alcohol, ketones, ester and the like.
  • the suitable solvent comprises toluene, xylene, ethylbenzene dimethyl formamide, dimethyl acetamide, acetonitrile, C1-C4 straight chain or branched alcohols, acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, butyl acetate and the likes.
  • the solvent may be ethyl acetate.
  • the suitable base employed in step (iii) comprises of an alkali and alkaline metal hydroxide and carbonate, in particular the suitable; alkali metal hydroxide comprises of sodium hydroxide, potassium hydroxide, lithium hydroxide, and the like, carbonate comprises of sodium carbonate, potassium carbonate, cesium carbonate and the like.
  • the base may be sodium hydroxide.
  • According to another aspect of the present invention is to provide a process for preparing vilazodone hydrochloride of Formula (2)
  • the solid state form of vilazodone of Formula (1) may be crystalline Form A or methanol solvate.
  • the suitable organic solvent for step (i) is selected from the group comprising of Cj-C 5 alcohols, hydrocarbons, acetonitrile, dimethyl formamide (DMF), preferably methanol.
  • the present invention provides vilazodone hydrochloride having particle size in terms of d95 is less than about 100 microns.
  • the present invention provides vilazodone hydrochloride having particle size in terms of d95 is less than about 50 microns.
  • the present invention provides vilazodone hydrochloride having particle size in terms of d95 is less than about 10 microns.
  • the present invention provides a process for controlling the particle size of vilazodone hydrochloride having particle size in terms of d95 is less than about 100 microns.
  • a process for preparing Vilazodone Hydrochloride having particle size in terms of d95 is less than about 50 microns, more particularly, less than about 10 microns comprising the steps of:
  • vilazodone of Formula (1) or its pharmaceutically acceptable salts, solvates, hydrates thereof having a total purity of greater than about 99%, specifically greater than about 99.5%, more specifically greater than about 99.9%, and most specifically greater than about 99.97% as measured by HPLC.
  • a pharmaceutical composition comprising of vilazodone of Formula (1) or its pharmaceutically acceptable salt and which includes one or more pharmaceutically acceptable excipients/diluents.
  • the pharmaceutical composition of the present invention may be in the form of a solid or liquid dosage forms for oral, parenteral or topical use and may have immediate or sustained release characteristics.
  • the dosage forms possible include tablets, capsules, powders, granules, creams, lotions, ointments, injectables, ophthalmic or optic solutions, suspensions, elixirs and the like.
  • Acetic anhydride (500 ml) and 2-(2-formyl-4-nitrophenoxy) acetic acid of Formula (B) (100 g) were added to a four-neck two liter round bottom flask at 35°C and stirred for 15 minutes.
  • Anhydrous sodium acetate (150 g) was added to the reaction mass and heated to 125°C and maintained for 8 hours.
  • the reaction mass was cooled to 100°C and further cooled to 80°C and toluene (200 ml) was added.
  • the reaction mass was stirred for 30 minutes and under vacuum up to 85°C and cooled to 35 35°C. Water (500 ml) was added and cone. HC1 (200 ml) was added to adjust pH 1-2.
  • the reaction mass was stirred for 60 minutes.
  • the product was washed with water (500 ml) and stirred for 30 minutes at 35°C.
  • the product was dried for 16 hours at 65°C.
  • Toluene (200 ml) was added to the product at 35°C and heated to 90°C and maintained for 30 minutes and cooled to 35°C, further cooled to 5°C and maintained for 30 minutes.
  • the product was washed with chilled toluene (2 x 25 ml) to afford 5-nitrobenzofuran-2- carboxylic acid of Formula (C).
  • Toluene (1200 ml) and 5-nitrobenzofuran-2-carboxylic acid of Formula (C) were added to a four-neck two litre round bottom flask at 35°C and stirred for 15 minutes.
  • DMF (10 ml) was added and heated to 70°C followed by addition of thionyl chloride (86.4 g) and heated to 115°C and maintained for 30 minutes.
  • Toluene was distilled out and reaction mass was cooled to 35°C and further cooled to 10°C. Ammonia gas was passed till pH was 8 to 9.
  • the product was washed with Toluene (2 X 100 ml) and dried for 60 minutes and dried in hot air oven at for 12.0 hrs at 65°C.
  • DMSO 1000 ml
  • 5-(l-piperazinyl) benzofuran-2-carboxamide of Formula (G) 100 g
  • 3-(4-chlorobutyl)-lH-indole-5-carbonitrile of Formula (H) 18-crown-6-ether
  • DIPEA diisopropylethyl amine
  • DMSO 1000 ml
  • 5-(l-piperazinyl) benzofuran-2-carboxamide of Formula (G) 100 g
  • 3-(4-chlorobutyl)-lH-indole-5-carbonitrile of Formula (H) 18-crown-6-ether
  • DIPEA diisopropylethyl amine
  • IPA 200 ml was added to vilazodone free base of Formula (1) (100 g) in a four-neck two litre round bottom flask at 35°C followed by addition of IPA HC1 (198.4 g) and stirred for 30 minutes. The reaction mass was heated to 80°C and stirred 30 minutes. The reaction mass was cooled to 35°C and further cooled to 5°C. The product was filtered and washed with IPA (2 x 25 ml) to afford vilazodone Hydrochloride.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention porte sur un procédé pour la préparation de 5-(4-[4-(5-cyano-1H-indol-3-yl)butyl]pipérazin-1-yl)benzofurane-2-carboxamide de formule (1) ou de son sel pharmaceutiquement acceptable ou de solvates ou d'hydrates de ceux-ci. En particulier, la présente invention porte sur un nouveau composé intermédiaire, 5-(pipérazin-1-yl 4-substitué)benzofurane-2-carboxamide de formule (X). La présente invention porte en outre sur une forme à l'état solide du 5-(4-[4-(5-cyano-1H-indol-3-yl)butyl]pipérazin-1-yl)benzofurane-2-carboxamide de formule (1) et sur un procédé pour sa préparation.
PCT/IN2013/000262 2012-04-20 2013-04-22 Forme polymorphe du 5-(4-[4-(5-cyano-1h-indol-3-yl)butyl]pipérazin-1-yl)benzofurane-2-carboxamide WO2013175499A2 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014061004A3 (fr) * 2012-10-19 2014-06-19 Ranbaxy Laboratories Limited Procédé pour la préparation de vilazodone ou de sel pharmaceutiquement acceptable de celui-ci
US20140179713A1 (en) * 2012-11-05 2014-06-26 Cadila Healthcare Limited Polymorphic form of 5-(4-[4-(5-cyano-1h-indol-3-yl) butyl] piperazin-1-yl) benzofuran-2-carboxamide and process for preparing thereof
CN104926804A (zh) * 2015-06-04 2015-09-23 天津渤海职业技术学院 一类具有抗肿瘤作用的化合物、其制备方法和用途
CN105541811A (zh) * 2016-01-08 2016-05-04 万特制药(海南)有限公司 一种抗抑郁药物维拉佐酮的精制方法
US9382233B2 (en) 2012-06-13 2016-07-05 Apotex Inc. Forms of vilazodone and processes for the preparation thereof
US9533949B2 (en) 2012-09-12 2017-01-03 Apotex Pharmachem Inc. Processes for the preparation of 3-alkyl indoles

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EP0738722A1 (fr) * 1995-04-20 1996-10-23 MERCK PATENT GmbH Dérivés d'acides 5-amino-benzofuran-2-carboxyliques
CN102267985A (zh) * 2011-06-15 2011-12-07 上海医药工业研究院 维拉佐酮或其盐酸盐的制备方法
WO2013114338A1 (fr) * 2012-02-01 2013-08-08 Ranbaxy Laboratories Limited Procédé pour la préparation de vilazodone ou de ses sels pharmaceutiquement acceptables

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EP0738722A1 (fr) * 1995-04-20 1996-10-23 MERCK PATENT GmbH Dérivés d'acides 5-amino-benzofuran-2-carboxyliques
CN102267985A (zh) * 2011-06-15 2011-12-07 上海医药工业研究院 维拉佐酮或其盐酸盐的制备方法
WO2013114338A1 (fr) * 2012-02-01 2013-08-08 Ranbaxy Laboratories Limited Procédé pour la préparation de vilazodone ou de ses sels pharmaceutiquement acceptables

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HEINRICH T ET AL: "Synthesis and Structure-Activity Relationship in a Class of Indolebutylpiperazines as Dual 5-HT1A Receptor Agonists and Serotonin Reuptake Inhibitors", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, vol. 47, no. 19, 1 January 2004 (2004-01-01), pages 4684-4692, XP002388367, ISSN: 0022-2623, DOI: 10.1021/JM040793Q *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9382233B2 (en) 2012-06-13 2016-07-05 Apotex Inc. Forms of vilazodone and processes for the preparation thereof
US9533949B2 (en) 2012-09-12 2017-01-03 Apotex Pharmachem Inc. Processes for the preparation of 3-alkyl indoles
WO2014061004A3 (fr) * 2012-10-19 2014-06-19 Ranbaxy Laboratories Limited Procédé pour la préparation de vilazodone ou de sel pharmaceutiquement acceptable de celui-ci
US20140179713A1 (en) * 2012-11-05 2014-06-26 Cadila Healthcare Limited Polymorphic form of 5-(4-[4-(5-cyano-1h-indol-3-yl) butyl] piperazin-1-yl) benzofuran-2-carboxamide and process for preparing thereof
CN104926804A (zh) * 2015-06-04 2015-09-23 天津渤海职业技术学院 一类具有抗肿瘤作用的化合物、其制备方法和用途
CN105541811A (zh) * 2016-01-08 2016-05-04 万特制药(海南)有限公司 一种抗抑郁药物维拉佐酮的精制方法

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