Polymorphic form of 5-(4-[4-(5-cyano-1H-indol-3-yl) butyl] piperazin-l-yl)
`
`benzofuran-Z-carboxamide and process for preparing thereof
`
`FIELD OF THE INVENTION
`
`The present invention relates to polymorphic form of 5-(4-[4-(5-cyano-1H-indol-
`
`3-yl) butyl]piperazin-1-yl)benzofuran-2-carboxamide. The present
`
`invention
`
`relates to a process for preparing polymorphic form of 5-(4-[4-(5-cyano-1H-indol-
`
`3-yl)butyl]piperazin-1-yl)benzofuran-2-carboxamide.
`
`In
`
`particular
`
`present
`
`invention relates to use of polymorphic form of 5-(4-[4-(5-cyano-1H-indol-3-
`
`yl)butyl]piperazin-1-yl)benzofuran-2-carboxamide
`
`in the preparation of
`
`its
`
`pharmaceutically acceptable salts thereof.
`
`BACKGROUND OF THE INVENTION
`
`US. Patent No. 5,532,241 discloses 5-(4-[4-(5-cyano-1H-indol-3-
`
`yl)butyl]piperazin-1-yl) benzo- furan-2-carboxamide i.e. vilazodone of Formula
`
`(1)
`
`HN \
`
`CN
`
`//\ m0
`NJ
`/ NH2
`
`(1)
`
`or its pharmaceutically acceptable salt. Patent provides process for preparing
`
`vilazodone or its pharmaceutically acceptable salt thereof.
`
`US. Patent No. 5,977,112 relates to process for preparing intermediate involved
`
`in the preparation of vilazodone or its pharmaceutically acceptable salt thereof.
`
`US. Patent No. 6,509,475 B1 relates to process for preparing intermediate
`
`involved in the preparation of vilazodone or its pharmaceutically acceptable salt
`
`thereof.
`
`US. Patent No. 7,834,020 B2 claims vilazodone hydrochloride anhydrate in
`
`crystalline modification IV (Form IV) characterized by XRD. Patent discloses
`
`10
`
`15
`
`2O
`
`25
`
`30
`
`1
`
`Argentum EX1035
`Argentum EX1035
`Page 1
`
`Page 1
`
`

`

`total 15 crystalline forms of vilazodone hydrochloride designated as crystalline
`
`Form-I to Form-XI and Form-XIII to Form-XVI.
`
`US. Patent No. 7,981,894 B2 claims vilazodone hydrochloride monohydrate in
`
`crystalline modification V (Form-V) having characteristic peaks in XRD.
`
`SUMMARY OF THE INVENTION
`
`In one general aspect, there is provided a solid state form of 5-(4-[4-(5-cyano-1H-
`
`indol-3-yl)butyl]piperazin-1-yl) benzofuran-2-carboxamide i.e. vilazodone of
`
`Formula (1)
`
`CN
`
`(1)
`
`The solid state form of 5-(4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl)
`
`benzofuran-2-carboxamide i.e. vilazodone of Formula (1) has been designated as
`
`Form-Z.
`
`In another aspect, there is provided a solid state Form-Z of 5-(4-[4-(5-cyano-1H-
`
`indol-3-yl)butyl]piperazin-1-yl) benzofuran-2-carboxamide i.e. vilazodone of
`
`Formula (1) characterized by XRD, DSC and TGA.
`
`In another aspect, there is provided the use of solid state Form-Z of 5-(4-[4-(5-
`
`cyano-1H-indol-3 -yl)butyl]piperazin-1-yl)
`
`benzofuran-2-carboxamide
`
`i.e.
`
`vilazodone of Formula (1) in the preparation of vilazodone hydrochloride.
`
`In another aspect, there is provided a solid state form of hydrate or solvate of 5-(4-
`
`[4-(5 -cyano-1H-indol-3-yl)butyl]piperazin-1-yl) benzofuran-2-carboxamide
`
`i.e.
`
`vilazodone of Formula (1).
`
`10
`
`15
`
`20
`
`25
`
`Page 2
`
`Page 2
`
`

`

`In another aspect, there is provided a solid state form of solvate of 5-(4-[4-(5-
`
`cyano- lH-indol-3 -yl)butyl]piperazin- l-yl)
`
`benzofuran-2-carboxamide
`
`i.e.
`
`vilazodone of Formula (1).
`
`In another aspect, there is provided a solid state Form-Z 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.
`
`In another aspect, there is provided a process for preparing a Form-Z of 5-(4-[4-
`
`(5-cyano-lH-indol-3-yl)butyl]piperazin-l-yl)
`
`benzofuran-2-carboxamide
`
`i.e.
`
`vilazodone of Formula (1).
`
`In another aspect, there is provided the use of solid state Form-Z of 5-(4-[4-(5-
`
`cyano- lH-indol-3 -yl)butyl]piperazin- l-yl)
`
`benzofuran-2-carboxamide
`
`i.e.
`
`vilazodone of Formula (1)
`
`NpN/W
`
`O
`
`\J
`
`O
`
`NH2
`
`HN \
`
`CN
`
`10
`
`15
`
`20
`
`in the preparation of vilazodone hydrochloride of Formtfia (2)
`
`HN \
`
`o
`
`NON/WC
`
`CN
`
`(2)
`
`BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS
`
`FIG. 1: Shows X-ray diffractogram (XRD) of Form-Z of vilazodone of Formula
`
`25
`
`(1).
`
`Page 3
`
`Page 3
`
`

`

`FIG. 2: Shows differential scanning calorimetry (DSC) of Form-Z of vilazodone
`
`of Formula (1).
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`An embodiment of the present invention provides a solid state form of 5-(4-[4-(5-
`
`cyano-1H-indol-3 -yl)butyl]piperazin-1-yl)
`
`benzofuran-2-carboxamide
`
`i.e.
`
`vilazodone of Formula (1)
`
`o
`
`NON/WCNH2
`
`HN \
`
`CN
`
`10
`
`15
`
`2O
`
`25
`
`The present invention has designated the solid state form of 5-(4-[4-(5-cyano-1H-
`
`indol-3-yl)butyl]piperazin-1-yl) benzofuran-2-carboxamide i.e. vilazodone of
`
`Formula (1) as Form-Z and the term Form-Z will be used for describing the said
`
`form of vilazodone of Formula (1).
`
`A solid state Form-Z of 5-(4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl)
`
`benzofuran-2-carbo xamide i.e. vilazodone of Formula (1) is characterized by X-
`
`ray powder diffraction having characteristic peaks at about 5.5, 11.0, 15.9, 18.7,
`
`20.7, 22.5, 25.0, 26.1, and 27.0 i0.2 degree 20.
`
`A solid state Form-Z of 5-(4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl)
`
`benzofuran-2-carbo xamide i.e. vilazodone of Formula (1) is further characterized
`
`by X-ray powder diffraction having characteristic peaks at about 7.5, 14.2, 15.2,
`
`16.7, 17.7 28.6, 29.8, 30.8 and 32.2 i0.2 degree 20.
`
`A solid state Form-Z of 5-(4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-
`
`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-Z of 5-(4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-
`
`yl)benzofuran-2-carboxamide i.e. vilazodone of Formula (1) is characterized by
`
`Page 4
`
`Page 4
`
`

`

`Differential Scanning Calorimetry (DSC) having two endotherms at about 880C
`
`and 2100C respectively.
`
`A solid state Form-Z 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-Z of 5-(4-[4-(5-cyano-lH-indol-3-yl)butyl]piperazin-l-
`
`yl)benzofuran-2-carboxamide i.e. vilazodone of Formula (1)
`
`is having water
`
`10
`
`content of about 4%.
`
`A solid state Form-Z 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 monohydrate
`
`form.
`
`A solid state Form-Z of 5-(4-[4-(5-cyano-lH-indol-3-yl)butyl]piperazin-l-
`
`yl)benzofuran-2-carboxamide i.e. vilazodone of Formula (1) is substantially free
`
`from residual organic solvents.
`
`In another aspect, there is provided use of solid state Form-Z 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.
`
`In another aspect, there is provided solid state form of hydrate or solvate of 5-(4-
`
`[4-(5 -cyano- l H-indol-3-yl)butyl]piperazin- l -yl) benzofuran-2-carboxamide
`
`i.e.
`
`vilazodone of Formula (1).
`
`15
`
`20
`
`25
`
`In another aspect,
`
`there is provided solid state form of solvate of 5-(4-[4-(5-
`
`cyano- lH-indol-3 -yl)butyl]piperazin- l-yl)
`
`benzofuran-2-carboxamide
`
`i.e.
`
`30
`
`vilazodone of Formula (1).
`
`Page 5
`
`Page 5
`
`

`

`In another aspect, there is provided a new process for the preparation of 5-(l-
`
`piperazinyl) benzofuran-2-carboxamide of Formula (G),
`
`in the preparation of
`
`vilazodone of Formula (1)
`
`03%"
`/
`NH2
`
`(\N
`
`
`
`(E)
`
`HNJ
`
`(G)
`
`10
`
`15
`
`20
`
`i) reacting 5-Aminobenzofuran-2-carboxamide of Formula (E) with N,N-bis(2-
`
`chloroethyl)-4-methylbenzenesulfonamide of Formula (E’) in presence of solvent
`
`and base to obtain 5-(4-tosylpiperazin-l-yl)benzofuran-2-carboxamide of Formula
`
`(F);
`
`ii) deprotecting 5-(4-tosylpiperazin-l-yl)benzofuran-2-carboxamide of Formula
`
`(F) by reaction with a suitable acid or its hydrohalide salt and p-Hydroxy benzoic
`
`acid; and
`
`iii)
`
`isolating 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. In particular,
`
`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. Particularly, the solvent may be methanol.
`
`Page 6
`
`Page 6
`
`

`

`The suitable base for step (i) 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. Particularly, 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. In particular, 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. Particularly, the solvent may
`
`be water and ethyl acetate.
`
`The suitable acid in step (ii) may be selected from hydrochloric acid, hydrobromic
`
`acid, hydroiodic 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.
`
`The suitable solvent for step (iii)
`
`for isolating a solid state form of 5-(1-
`
`piperazinyl) benzofuran-2-carboxamide of Formula (G) comprises one or more of
`
`hydrocarbons, water, nitriles, amides, alcohol, ketones, ester and the like.
`
`In
`
`particular, 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. Particularly, 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
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Page 7
`
`Page 7
`
`

`

`like, carbonate comprises of sodium carbonate, potassium carbonate, cesium
`
`carbonate and the like. Particularly, the base may be sodium hydroxide.
`
`In another aspect, there is provided a process for preparing a solid state form-Z of
`
`5 -(4- [4-(5-cyano- lH-indol-3-yl)butyl]piperazin- l-yl) benzofuran-2-carboxamide
`
`i.e. vilazodone of Formula (1)
`
`o
`
`NON/WCNH2
`
`HN \
`
`ON
`
`the process comprising:
`
`i)
`
`reacting solid state form of 5-(l-piperazinyl) benzofuran-2-carboxamide
`
`Formula (G)
`
`or its salts with 3-(4-chlorobutyl)-lH-indole-5-carbonitrile of
`
`Formula (H)
`
`in an organic solvent
`
`in presence of a base to obtain crude
`
`vilazodone free base;
`
`HN
`
`()1
`
`G
`
`(
`
`)
`
`NH2 +
`
`(H) ON
`
`_.
`
`\J
`
`ON
`
`1
`H
`
`0
`
`O
`
`NH2
`
`ii) purifying the crude vilazodone free base of step (i) in an organic solvent;
`
`iii) treating the purified vilazodone free base of step (ii) with an acid and an
`
`organic solvent to obtain solid state form-Z of vilazodone of Formula (1).
`
`The suitable solvent for step (i) comprises one or more of solvent comprises of
`
`hydrocarbons, nitriles, amides, alcohol, ketones, ester and the like. In particular,
`
`the suitable solvent comprises toluene, xylene, ethylbenzene dimethyl formamide,
`
`dimethyl sulfoxide, dimethyl acetamide, acetonitrile, C1-C4 straight chain or
`
`branched alcohols, acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl
`
`acetate, isopropyl acetate and butyl acetate and the like. Particularly, the solvent
`
`may be dimethyl sulfoxide.
`
`10
`
`15
`
`20
`
`25
`
`Page 8
`
`Page 8
`
`

`

`The suitable 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. Particularly, the base may be diisopropylethylamine.
`
`The obtained crude vilazodone of step (i) is purified in step (ii) using one or more
`
`of solvent comprises of hydrocarbons, nitriles, amides, alcohol, ketones, ester and
`
`the like. In particular, the suitable solvent comprises toluene, xylene, ethylbenzene
`
`dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide, acetonitrile, C1-C4
`
`straight chain or branched alcohols, acetone, methyl isobutyl ketone, methyl ethyl
`
`ketone, ethyl acetate, isopropyl acetate and butyl acetate and the like. Particularly,
`
`the solvent may be acetone.
`
`The suitable acid for step (iii) may be selected from both organic and mineral
`
`acid, preferably acetic acid.
`
`The suitable solvent for step (iii) comprises one or more of solvent comprises of
`
`hydrocarbons, nitriles, amides, alcohol, ketones, ester and the like. In particular,
`
`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 and butyl acetate and the like. Particularly, the solvent may be methanol.
`
`In another aspect, there is provided a new process for preparing vilazodone of
`
`Formula (1) or its pharmaceutically acceptable salts thereof;
`
`10
`
`15
`
`20
`
`25
`
`Page 9
`
`Page 9
`
`

`

`O
`
`0W0
`
`HN \
`
`ON
`
`the process comprising:
`
`i) reacting 5-Aminobenzofuran-2-carboxamide of Formula (E) with N,N-bis(2-
`
`chloroethyl)-4-methylbenzenesulfonamide of Formula (E’) in an organic solvent
`
`in presence of
`
`a base
`
`to
`
`obtain
`
`5-(4-tosylpiperazin-l-yl)benzofuran-2-
`
`carboxamide of Formula (F);
`
`ii) deprotecting 5-(4-tosylpiperazin-l-yl)benzofuran-2-carboxamide of Formula
`
`(F) in the presence of acid;
`
`iii) isolating a solid state form of 5-(l-piperazinyl) benzofuran-2-carboxamide of
`
`10
`
`Formula (G) in an organic solvent in presence of a base;
`
`15
`
`20
`
`HNQ
`
`(G)
`
`iv) reacting 5-(l-piperazinyl) benzofuran-2- carboxamide of Formula (G) with 3-
`
`(4-chlorobutyl)-lH-indole-5-carbonitrile of Formula (H) in an organic solvent in
`
`presence of a base to obtain vilazodone of Formula (1);
`
`O
`O
`W
`NH2 +
`
`HN
`
`O
`
`HN \
`
`CI
`
`\
`
`HN
`
`G
`
`(
`
`)
`
`(H) CN
`
`O
`
`bN/QNO
`N
`\J
`NH2
`
`CN
`
`1
`()
`
`v) optionally converting vilazodone of Formula (1)
`
`into its pharmaceutically
`
`acceptable salts thereof.
`
`10
`
`Page 10
`
`Page 10
`
`

`

`The suitable solvent for step (i) comprises one or more of hydrocarbons, nitriles,
`
`amides, alcohol, ketones, ester and the like. In particular,
`
`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. Particularly, the solvent may be methanol.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`The suitable base for step (i) 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. Particularly, 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. In particular, 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. Particularly, the solvent may
`
`be water and ethyl acetate.
`
`The suitable acid in step (ii) may be selected from hydrochloric acid, hydrobromic
`
`acid, hydroiodic 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.
`
`The suitable solvent for step (iii)
`
`for isolating a solid state form of 5-(1-
`
`piperazinyl) benzofuran-2-carboxamide of Formula (G) comprises one or more of
`
`hydrocarbons, water, nitriles, amides, alcohol, ketones, ester and the like.
`
`In
`
`particular, 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,
`
`11
`
`Page 1 1
`
`Page 11
`
`

`

`isopropyl acetate, butyl acetate and the likes. Particularly, the solvent may be
`
`ethyl acetate.
`
`The suitable base for 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. Particularly, the base may be sodium hydroxide.
`
`The suitable solvent for step (iv) comprises one or more of solvent comprises of
`
`hydrocarbons, nitriles, amides, alcohol, ketones, ester and the like. In particular,
`
`the suitable solvent comprises toluene, xylene, ethylbenzene dimethyl formamide,
`
`dimethyl sulfoxide, dimethyl acetamide, acetonitrile, C1-C4 straight chain or
`
`branched alcohols, acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl
`
`acetate, isopropyl acetate and butyl acetate and the like. Particularly, the solvent
`
`may be dimethyl sulfoxide.
`
`The suitable base for step (iv) 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. Particularly, the base may be diisopropylethylamine.
`
`The suitable solvent for step (v) comprises one or more of solvent comprises of
`
`hydrocarbons, nitriles, amides, alcohol, ketones, ester and the like. In particular,
`
`the suitable solvent comprises toluene, xylene, ethylbenzene dimethyl formamide,
`
`dimethyl sulfoxide, dimethyl acetamide, acetonitrile, C1-C4 straight chain or
`
`branched alcohols, acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl
`
`acetate, isopropyl acetate and butyl acetate and the like. Particularly, the solvent
`
`may be acetone.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`12
`
`Page 12
`
`Page 12
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`

`

`In another aspect, there is provided vilazodone hydrochloride having particle size
`
`in terms of d95 is less than about 100 microns.
`
`In another aspect, there is provided vilazodone hydrochloride having particle size
`
`in terms of d95 is less than about 10 microns
`
`In another aspect,
`
`there is provided a process
`
`for preparing vilazodone
`
`hydrochloride having particle size in terms of d95 is less than about 10 microns;
`
`the process comprising:
`
`i) milling vilazodone hydrochloride having particle size in terms of d95 is greater
`
`than about 100 microns;
`
`ii) slurrying micronized vilazodone hydrochloride in one or more organic solvents
`
`to form a solution;
`
`iii) isolating vilazodone hydrochloride having particle size in terms of d95 is less
`
`than about 10 microns.
`
`In another aspect,
`
`there is provided vilazodone of Formula (1) or
`
`its
`
`pharmaceutically acceptable salts 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.
`
`In another aspect, there is provided a pharmaceutical composition comprising as
`
`its active ingredient of vilazodone of Formula (1). With the active ingredient, the
`
`pharmaceutical composition 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.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`13
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`Page 13
`
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`

`

`According to the present invention, the process for the preparation of vilazodone
`
`of Formula (1) can be illustrated by below mentioned Scheme-1, which should
`
`not be considered as limiting the scope of the invention.
`
`OH
`
`Chloroaceticacid
`—,
`CH0
`Base
`
`(A)
`
`HNo3
`
`H
`
`OVCOOH H2804 @OVCOO
`—>
`CHO
`02N
`CHO —> 02N
`(B)
`
`OH
`
`0
`
`0
`
`/
`
`(c)
`
`CI
`5
`\\
`O
`N
`3“ I
`/©/ 0
`(E)
`
`CI
`
`H2N
`
`o
`8“
`/©/ 0
`
`JCS—<0
`/
`NH2
`
`(‘N
`(F)
`
`Thionyl Chloride
`Ammonia gas
`
`0
`
`(E)
`
`NH2
`o
`
`NH2
`O
`'
`Rane
`y—NI
`.— W0
`(D)
`
`02N
`
`o
`
`2
`
`NH
`
`+
`
`O
`/
`(G)
`
`(\N
`HNJ
`
`HN \
`
`CN
`
`(H)
`
`HN \
`
`—>
`Cl
`
`Nd
`
`(1)
`
`10
`
`15
`
`20
`
`Examples
`
`While the present invention is described with respect to particular examples and
`
`preferred embodiments, it is understood that the present invention is not limited to
`
`these examples and embodiments. The present
`
`invention,
`
`therefore,
`
`includes
`
`variations form the particular examples embodiments described herein, as will be
`
`applicant to one of skill in the art.
`
`Example 1:
`
`Preparation of 2-(2-f0rmylphen0xy) acetic acid of Formula (A)
`
`Water (700 ml), salicyaldehyde (100 g), chloroacetic acid (77 g) and sodium
`
`hydroxide solution (165 ml) were added to a four-neck two litre round bottom
`
`flask at 300C. The reaction mass was heated to 100°C and maintained for 3 hours.
`
`Conc.HCl (100 ml) was added to adjust pH 1 to 2. The reaction mass was cooled
`
`to 300C and further cooled to 150C and stirred for 1 hour. The product was
`
`filtered and washed with chilled water (2 x 25 ml) to afford 2-(2-formylphenoxy)
`
`acetic acid of Formula (A).
`
`14
`
`Page 14
`
`Page 14
`
`

`

`Example 2:
`
`Preparation of 2-(2-formyl-4-nitrophenoxy) acetic acid of Formula (B)
`
`Sulfuric acid (550 ml) added to a four-neck two litre round bottom flask at 350C
`
`and cooled to 50C and added lot wise 2-(2-formy1phenoxy)acetic acid of Formula
`
`(A) (100 g). The reaction mass was stirred for 15 minutes. In another two litr
`
`e round bottom flask nitric acid (45 ml) was added at 350C. The reaction mass
`
`was cooled to 150C followed by addition of sulfuric acid (50 m1) and stirred for
`
`15 minutes. The reaction mass of second round bottom flask was added into first
`
`round bottom flask at 50C and stirred for 1 hour below 150C. In another round
`
`10
`
`bottom flask water (1500 ml) was added at 350C and cooled to 100C. The reaction
`
`mass of first round bottom flask was dumped into third round bottom flask having
`
`water and stirred for 1 hour. Finally the product was washed chilled water (2 x
`
`100 m1) at 350C to afford 2-(2-formy1—4-nitrophenoxy) acetic acid of Formula (B).
`
`15
`
`Example 3:
`
`2O
`
`25
`
`Preparation of S-nitrobenzofuran-2-carboxylic acid of Formula (C)
`
`Acetic anhydride (500 m1) and 2-(2-formy1-4-nitrophenoxy) acetic acid of
`
`Formula (B) (100 g) were added to a four-neck two litre round bottom flask at
`
`350C and stirred for 15 minutes. Anhydrous Sodium acetate (150 g) was added to
`
`the reaction mass and heated to 1250C and maintained for 8 hours. The reaction
`
`mass was cooled to 1000C and further cooled to 800C and toluene (200 ml) was
`
`added. The reaction mass was stirred for 30 minutes and under vacuum up to
`
`850C and cooled to 35 350C. Water (500 ml) was added and conc. HCl (200 ml)
`
`was added to adjust pH 1-2. The reaction mass was stirred for 60 minutes. The
`
`product was washed with water (500 m1) and stirred for 30 minutes at 350C. The
`
`product was dried for 16 hours at 650C. Toluene (200 ml) was added to the
`
`product at 350C and heated to 900C and maintained for 30 minutes and cooled to
`
`350C, further cooled to 50C and maintained for 30 minutes. The product was
`
`washed with chilled toluene (2 x 25 ml) to afford 5-nitrobenzofuran-2-carboxy1ic
`
`30
`
`acid of Formula (C).
`
`Example 4:
`
`Preparation of S-nitrobenzofuran-2-carboxamide of Formula (D)
`
`15
`
`Page 15
`
`Page 15
`
`

`

`Toluene (1200 ml) and 5-nitrobenzofuran-2-carboxylic acid of Formula (C) were
`
`added to a four-neck two litre round bottom flask at 350C and stirred for 15
`
`minutes. DMF (10 ml) was added and heated to 700C followed by addition of
`
`Thionyl chloride (86.4 g) and heated to 1150C and maintained for 30 minutes.
`
`Toluene was distilled out and reaction mass was cooled to 350C and further
`
`cooled to 100C. 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 650C. To the obtained product DMF (250 ml) was added at
`
`350C and heated to 1300C. The reaction mass was stirred for 30 minutes and
`
`10
`
`cooled to 950C followed by addition of water (2300 ml) and stirred for 30
`
`minutes. The reaction mass was cooled to 500C. The product was filtered and
`
`washed with water (2 x 100 ml) to afford 5-nitrobenzofuran-2-carboxamide of
`
`Formula (D).
`
`15
`
`Example 5:
`
`Preparation of 5-amin0benz0furan-2-carb0xamide of Formula (E)
`
`In a 5.0 lit Autoclave methanol (2000 ml) and 5-nitrobenzofuran-2-carboxamide
`
`of Formula (D) (100 g) and Raney Nickel (40.0 g) were added at 350C. The
`
`reaction mass was flushed with two times Nitrogen pressure (0.5-1.0 Kg) and
`
`released. Hydrogen pressure up to 5.0 Kg/cm2 was applied at 350C. The reaction
`
`mass was heated to 600C and maintained at 6.0 Kg/cm2 pressure for 14 hours at
`
`600C. The reaction mass was cooled to 350C and Hydrogen pressure was released.
`
`Organic layer was distilled out under vacuum at 600C. Hexane (50 ml) was added
`
`and stirred for 30 minutes and reaction was cooled to 350C. The product was
`
`washed with hexane (2 x 25 ml) to afford 5-aminobenzofuran-2-carboxamide of
`
`Formula (E).
`
`Example 6:
`
`Preparation of N,N-bis(2-chlor0ethyl)-4-methylbenzenesulfonamide (E’)
`
`To a reaction flask, 100 g. of bis(2-chloroethyl)amine hydrochloride and 500 ml.
`
`of MDC were added and stirred. To the reaction mass was added triethyl amine as
`
`a base and again stirred for 15 minutes at room temperature. p-Toluene
`
`sulfonylchloride solution (in MDC) was added to the reaction mass and heated to
`
`2O
`
`25
`
`30
`
`16
`
`Page 16
`
`Page 16
`
`

`

`400 C and maintained for 6 hours. TLC was checked for completion of reaction
`
`and treated with 250 ml of water and organic layer was separated. To this reaction
`
`mass, was added 250 ml of 10% HCl solution and stirred. The organic layer was
`
`separated, treated with sodium sulfate and washed thrice with MDC as the solvent
`
`was removed under vacuum. To this mass hexane was added and again removed
`
`under vacuum twice. Once again Hexane was added and reaction mass stirred for
`
`two hours and cooled which afforded the product N,N-bis(2-chloroethyl)-4-
`
`methylbenzene sulfonamide which was filtered, washed with hexane and dried.
`
`10
`
`Example 7:
`
`Preparation of 5-(4-t0sylpiperazin-1-yl)benzofuran-Z-carboxamide (F)
`
`1200 ml DIPEA as a base and 5-aminobenzofuran-2-carboxamide (E) were added
`
`to a reaction flask and stirred for 15 minutes to which 252 g of N,N-bis(2-
`
`chloroethyl)-4-methylbenzenesulfonamide was added, stirred, heated at 1200C
`
`and maintained for 10 hours. The completion of reaction was checked by TLC and
`
`cooled after which DIPEA was decanted and 1000 ml of Methanol was added to
`
`it. The mass was again heated to about 550 C and stirred for 1 hour after which it
`
`was cooled to afford us with 5-(4-tosylpiperazin-1-yl)benzofuran-2-carboxamide
`
`(F) which was filtered under vacuum, and washed with methanol and dried.
`
`Example 8:
`
`Preparation of 5-(1-piperazinyl) benzofuran-Z-carboxamide of Formula (G)
`
`To a mixture of 500 ml of hydrobromic acid in acetic acid was added portion wise
`
`169 g of p-hydroxy benzoic acid and stirred. To this mixture was added portion
`
`wise 100 g of 5-(4-tosylpiperazin-1-yl)benzofuran-2-carboxamide (F) and stirred
`
`for some time after which the temperature was raised to around 50 OC and the
`
`mass was stirred for 3 hours. After the completion of reaction was checked by
`
`TLC, it was slowly cooled at around 10 OC and 1.5 liters of cold water was added
`
`to it. The solid obtained was filtered and washed with Ethyl Acetate four times
`
`and the aqueous layer was then collected and the pH was adjusted to 10 by using
`
`sodium hydroxide solution. The mass was stirred for half an hour and the solid
`
`thus obtained was filtered, washed with water and dried to afford us with 5-(1-
`
`piperazinyl) benzofuran-2-carboxamide of Formula (G)
`
`15
`
`2O
`
`25
`
`30
`
`17
`
`Page 17
`
`Page 17
`
`

`

`Example 9:
`
`Preparation of Form-Z of Vilazodone of Formula (1)
`
`DMSO (1000 ml), 5-(1-piperazinyl) benzofuran-2-carboxamide of Formula (G)
`
`(100
`
`g),
`
`3-(4-chlorobutyl)-1H-indole-5-carbonitrile
`
`of Formula
`
`(H)
`
`and
`
`diisopropylethylamine (DIPEA) (1500 ml) were added to a four-neck two litre
`
`round bottom flask at 350C and reaction mass was heated to 800C and maintained
`
`for 30 hours. The reaction mass was cooled to 550C. The reaction mass was
`
`10
`
`15
`
`treated with EDTA (3 g) and charcoal (10 g). The residue was filtered and treated
`
`with DMSO (800 ml) at 80-850C and stirred for 15 minutes. The reaction mass
`
`was treated with acetone at 20-250C and stirred for 1 hour. The reaction mass was
`
`washed with acetone (2 x 100) and treated with acetic acid (720 ml) and methanol
`
`(500 ml) at 25-300C and stirred for 10 minutes. The reaction mass is heated to 80-
`
`810C and treated with activated charcoal (10 g) and stirred for 15-20 min. The
`
`reaction mass was cooled to 15-200C, filtered and washed with methanol (2 X 100
`
`ml). The product was dried in hot air oven at 60-650C for 12-14 hours. The
`
`product was further dried in oven at 1050C for 4 hours afforded Form-Z of
`
`Vilazodone of Formula (1). (HPLC purity >99.70%).
`
`XRD and DSC pattern is
`
`substantially as depicted in FIG.1 and FTG.2
`
`2O
`
`respectively.
`
`Example 10:
`
`Preparation of Vilazodone hydrochloride
`
`Form-Z of Vilazodone free base of Formula (1) (60 g) and acetone (1200 ml) were
`
`heated to 50-550C. An another assembly was arranged in a tub using diisopropyl
`
`ether (1000 ml) and conc. hydrochloric acid (16 ml) at 0-50C. First reaction mass
`
`was added into second reaction mass and stirred for 30 minutes. The reaction
`
`mass was filtered and washed with chilled DIPE (120 ml) at 0-50C afforded
`
`Vilazodone hydrochloride. (HPLC purity >99.80%).
`
`25
`
`30
`
`Example 11:
`
`Preparation of Vilazodone hydrochloride
`
`18
`
`Page 18
`
`Page 18
`
`

`

`Form-Z of Vilazodone free base of Formula (1) (60 g) and acetone (1200 ml) were
`
`heated to 50-550C. An another assembly was arranged in a tub using acetone (300
`
`ml) and conc. hydrochloric acid (16 ml) at 0-50C. First reaction mass was added
`
`into second reaction mass and stirred for 30 minutes. The reaction mass was
`
`filtered and washed with chilled acetone (120 ml) at 0-50C afforded Vilazodone
`
`hydrochloride. (HPLC purity >99.85%).
`
`19
`
`Page 19
`
`Page 19
`
`

`

`We Claim:
`
`1. A solid state Form-Z of 5-(4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl)
`
`benzofuran-2-carboxamide i.e. Vilazodone of Formula (1)
`
`O
`
`0W0NH2
`
`HN \
`
`CN
`
`which is characterized by one or more of the following properties:
`
`i) a powder X-ray diffraction pattern having characteristic peaks expressed in
`
`degrees 20 at about 5.5, 11.0, 15.9, 18.7, 20.7, 22.5, 25.0, 26.1, and 27.0 i0.2
`
`degree 20 substantially as depicted in FIG.1.
`
`ii) a powder X-ray diffraction pattern haVing additional peaks at about 7.5, 14.2,
`
`15.2, 16.7, 17.7 28.6, 29.8, 30.8 and 32.2 i0.2 degree 20 substantially as depicted
`
`in FIG.1.
`
`iii) a Differential Scanning Calorimetry (DSC) haVing two endotherms at about
`
`880C and 2100C substantially as depicted in FIG.2.
`
`10
`
`15
`
`2. The solid state Form-Z of Vilazodone as claimed in claim