PREPARATION OF RETIGABINE AND ITS SALTS

INTRODUCTION

The present application relates to processes for the preparation of retigabine and Its salts.
The drug compound having the adopted name retigabine, has a chemical name 2-amino-4-(4-fluorobenzylamino)-1-ethoxycarbonyl-aminobenzene, and is represented by structure of formula (I).

U.S. Patent No. 5,384,330 discloses retigabine and its pharmaceutically acceptable salts.
In addition, it discloses their properties as anti-epileptic, muscle relaxing, fever reducing and peripheral analgesic agent or anti convulsive. Further, it discloses process for the preparation of retigabine and its pharmaceutically acceptable salts in two different processes, designated as process a) and process b)

Process a) involves the reaction of 4-fluorobenzaldehyde with 2-nitro-p-phenylenediamine to isolate imine intermediate followed by reduction with sodium borohydride to produce 2-amino-5-(4-fluorobenzylamino)-nitrobenzene. This intermediate upon further reduction with Raney™ nickel produces amine intermediate which on reaction with ethyl chloroformate followed by treatment with ethanolic hydrochloride to produce retigabine dihydrochloride. Process b) involves the protection of amino group in N-ethoxycarbonyl-p-phenylenediamine with phthalic anhydride followed by nitration with nitric acid and glacial acetic acid to give 2-ethoxycarbonylamino-5-phthalimido-nitrobenzene. This intermediate upon deprotection, followed by reaction with 4-fluorobenzaldehyde produces nitro intermediate of retigabine. Reduction of this intermediate with Raney® nickel followed by treatment with hydrochloric acid gives retigabine dihydrochloride.

U.S. Patent publication No. US 2003023111 A1 discloses process for preparation of retigabine by reaction of 4-(4-fluorobenzylamino)-1,2-phenylenediamine with pyrocarbonic acid ethyl ester.

These processes suffer from one or more drawbacks such as low purity, yield, and involving protection and deprotection of amino groups and lengthy workup.

Hence, there is a need to provide simple, economical, cost effective, scalable and robust processes for the preparation of retigabine and its salts.

SUMMARY

In the first embodiment, the present application relates to process for the preparation of retigabine of formula I, or its salts thereof, which comprises one or more of the following steps:

(a) reacting 4-halo aniline with a suitable reagent to provide N-carbamic ester of formula (II); Formula (IV)

(d) reducing the compound of formula (IV) with a suitable reducing agent to provide retigabine of formula (I); and

(e) optionally, converting the retigabine into a salt thereof.

In second embodiment, the present application relates to an improved process for the preparation of retigabine of formula I, or salts thereof, which comprises one or more of the following steps:

(a) reacting 2-nitrobenzene-1, 4-diamine with 4-fluorobenzaldehyde to provide a compound of formula (V); NO2 ,NH2 Formula (V) (b) reducing the compound of formula (V) with a suitable reducing reagent to provide a compound of formula (VI);

Formula (VI) (c) reducing the compound of formula (VI) with a suitable reducing reagent to provide triamine compound of formula (VII); NH, Formula (VII)

(d) converting the compound of formula (VII) to retigabine of formula (I); and

(e) optionally, converting the retigabine into a salt thereof.

In third embodiment, the present application relates to an improved process for the preparation of retigabine of formula I, which comprises one or more of the following steps:

(a) reacting 2-nitrobenzene-1,4-diamine with 4-fluorobenzaldehyde to provide a compound of formula (V) and in-situ reducing the compound of formula (V) to produce compound of formula (VI);

(b) reducing the compound of formula (VI) with a suitable reducing reagent to provide triamine compound of formula (VII); and

(c) converting the compound of formula (VII) to retigabine of formula (I);

In fourth embodiment, the present application relates to an improved process for the preparation of retigabine of formula I, which comprises one or more of the following steps:

(a) reacting 2-nitrobenzene-1,4-diamine with 4-fluorobenzaldehyde to provide
a compound of formula (V) and in-situ reducing the compound of formula (V) to
produce compound of formula (VI);

(b) reducing the compound of formula (VI) with sodium dithionite to provide
triamine compound of formula (VII); and

(c) converting the compound of formula (VII) to retigabine of formula (I);

In fifth embodiment, the present application relates to an improved process for the preparation of retigabine of formula I, which comprises one or more of the following steps:

(a) reacting 2-nitrobenzene-1,4-diamine with 4-fluorobenzaldehyde to provide a compound of formula (V) and in-situ reducing the compound of formula (V) with sodium borohydride to produce compound of formula (VI);

(b) reducing the compound of formula (VI) with a suitable reducing reagent to provide triamine compound of formula (VII); and

(c) converting the compound of formula (VII) to retigabine of formula (I);

DETAILED DESCRIPTION

In the first embodiment, the present application relates to process for the preparation of retigabine of formula I, or salts thereof, which comprises one or more of the following steps:

(a) reacting 4-halo aniline with a suitable reagent to provide N-carbamic ester of formula (II);

Formula (II) wherein X is F, CI, Br, or I;

(b) nitration of the N-carbamic ester of formula (II) to provide nitro compound
of formula (III); Formula (III) wherein X is F, CI, Br, or I;

(c) reacting nitro compound of formula (III) with 4-fluorobenzylamine to provide a compound of formula (IV); Formula (IV)

(d) reducing the compound of formula (IV) with a suitable reducing agent to provide retigabine of formula (I); and

(e) optionally, converting the retigabine into a salt thereof.

Step (a) involves reacting 4-halo aniline with a suitable reagent to provide N-carbamic ester of formula (II).

Suitable reagents that may be used in step (a) include but not limited to ethyl chloroformate, pyrocarbonic acid esters such as for examples, pyrocarbonic acid ethyl ester or the like, or any other suitable reagent.

Step (a) may be optionally carried out in presence of a base. Suitable bases that may be used in step (a) include, but are not limited to: organic bases, such as for example, triethylamine, tributylamine, N-methylmorpholine, N,N-diisopropylethylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole, or the like; inorganic bases, such as for example, alkali metal hydrides, such as for example, lithium hydride, sodium hydride, potassium hydride, or the like; sodamide; n-butyl lithium; lithium diisopropylamide; alkali metal hydroxides, such as for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide; alkaline metal hydroxides, such as for example, aluminum hydroxide, magnesium hydroxide, calcium hydroxide, or the like; alkali metal carbonates, such as for example, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, or the like; alkaline earth metal carbonates, such as for example, magnesium carbonate, calcium carbonate, or the like; alkali metal bicarbonates, such as for example, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, or the like; and ion exchange resins including resins bound to ions, such as for example, sodium, potassium, lithium, calcium, magnesium, substituted or unsubstituted ammonium ions, or the like; or any other suitable bases.

Step (a) may be carried out in a suitable solvent. Suitable solvents that may be used include, but are not limited to: water; alcohols, such as for example, methanol, ethanol, propanol, butanol, pentanol, ethylene glycol, glycerol, or the like; ketones, such as for example, acetone, butanone, pentanone, methyl isobutyl ketone, or the like; esters, such as for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like; ethers, such as for example, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like; aliphatic or alicyclic hydrocarbons, such as for example, hexane, heptane, pentane, cyclohexane, methylcyclohexane, or the like; halogenated hydrocarbons, such as for example, dichloromethane, chloroform, 1,1,2-trichloroethane, 1,2-dichloroethene, or the like; aromatic hydrocarbons, such as for example, toluene, xylene.

chlorobenzene, tetralin, or the like; nitriles, such as for example, acetonitrile, propionitrile, or the like; polar aprotic solvents, such as for example, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulphoxide, sulpholane, formamide, acetamide, propanamide, or the like; nitromethane; or any mixtures thereof.

Suitable temperatures for the reaction of step (a) may be about 0°C to about the reflux temperature of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed.

The reaction mixture obtained in step (a) may be optionally filtered to remove any insoluble solids, or particles may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other technique for the removal of solids.

The product of step (a) may be isolated directly from the reaction mixture itself after the reaction is complete in step (a), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction or the like.

Isolation of compound of formula (II) may involve methods including removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent, or the like. Stirring or other alternate methods, such as for example, shaking, agitation, or the like, that mix the contents may also be employed for isolation.

Suitable solvents that may be used for isolation compound of formula (II) include, but are not limited to: ketones, such as for example, acetone, methyl isobutyl ketone or the like; esters, such as for example, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like; ethers, such as for example, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, 1,2-dimethoxyethane, anisole, or the like; aliphatic or alicyclic hydrocarbons, such as for example, hexane, heptane, pentane, cyclohexane, methylcyclohexane, or the like; halogenated hydrocarbons, such as for example, dichloromethane, chloroform, 1,1,2-trichloroethane, 1,2-dichloroethene, or the like; aromatic hydrocarbons, such as for example, toluene, xylene, chlorobenzene, tetralin, or the like; nitromethane; and any mixtures thereof.

The recovered solid may be optionally further dried at suitable temperatures, and atmospheric or reduced pressures, for about 1-50 hours, or longer, using any types of drying equipment, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer or the like.

Step (b) involves nitration of N-carbamic ester of formula (II) to provide nitro compound of formula (III).

Suitable nitrating agents that may be used in step (b) include, but not limited to nitric acid, metal nitrates, alkyl nitrates, acyl nitrates or the like; and any other suitable nitrating reagents.

Suitable catalysts that may be used in step (b) include, but not limited to sulfuric acid, acetic acid, or the like.

Step (b) may be carried out in a suitable solvent. Suitable solvents that may be used include, but are not limited to: halogenated hydrocarbons, such as for example, dichloromethane, carbon tetrachloride or the like; nitriles, such as for example, acetonitrile, propionitrile, or the like; acids such as for example acetic acid or the like; acid anhydrides such as for example, acetic anhydride or the like; nitromethane; and any mixtures thereof.

Suitable temperatures for the reaction of step (a) may be about 0°C to about the reflux temperature of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed.

The product of step (b) may be isolated directly from the reaction mixture itself after the reaction is complete in step (c), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction or the like.

Isolation of nitro compound of formula (III) may involve methods including removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent, or the like. Stirring or other alternate methods, such as for example, shaking, agitation, or the like, that mix the contents may also be employed for isolation.

Suitable solvents that may be used for isolation of compound of formula (III) include, but are not limited to: ketones, such as for example, acetone, methyl isobutyl ketone or the like; esters, such as for example, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like; ethers, such as for example, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, 1,2-dimethoxyethane, anisole, or the like; aliphatic or alicyclic hydrocarbons, such as for example, hexane, heptane.

pentane, cyclohexane, methylcyclohexane, or the like; halogenated hydrocarbons, such as for example, dichloromethane, chloroform, 1,1,2-trlchloroethane, 1,2-dichloroethene, or the like; aromatic hydrocarbons, such as for example, toluene, xylene, chlorobenzene, tetralin, or the like; nitromethane; or any mixtures thereof.

The recovered solid may be optionally further dried at suitable temperatures, and atmospheric or reduced pressures, for about 1-50 hours, or longer, using any types of drying equipment, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer or the like.

The obtained nitro compound of formula (III) may be optionally further purified by recrystallization or by slurrying in a suitable solvent or by column chromatography or any other suitable technique.

Step (c) involves reacting nitro compound of formula (III) with 4-fluorobenzyl amine to provide a compound of formula (IV).

Suitable reagents that may be used in step (c) include, but not limited to alkali metal carbonates, such as for example, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, or the like; alkaline earth metal carbonates, such as for example, magnesium carbonate, calcium carbonate, or the like; alkali metal bicarbonates, such as for example, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, or the like; metal halides such as for example, copper chloride, copper bromide, copper iodide, silver chloride, silver bromide, silver iodide, or the like, amino acid derivatives such as for example, L-proline, or the like, or any mixtures thereof.

Step (c) may be carried out in a suitable solvent. Any of the solvents described in step (a) may be used for this step.

Suitable temperatures for the reaction of step (a) may be about 0°C to about the reflux temperature of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed.

The reaction mixture obtained in step (c) may be optionally filtered to remove any insoluble solids, or particles may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other technique for the removal of solids.

The product of step (c) may be isolated directly from the reaction mixture itself after the reaction is complete in step (c), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction or the like.

Isolation of compound of formula (IV) may involve methods including removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent, or the like. Stirring or other alternate methods, such as for example, shaking, agitation, or the like, that mix the contents may also be employed for isolation.

Suitable solvents that may be used for isolation compound of formula (IV) include, but are not limited to: ketones, such as for example, acetone, methyl isobutyl ketone or the like; esters, such as for example, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like; ethers, such as for example, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, 1,2-dimethoxyethane, anisole, or the like; aliphatic or alicyclic hydrocarbons, such as for example, hexane, heptane, pentane, cyclohexane, methylcyclohexane, or the like; halogenated hydrocarbons, such as for example, dichloromethane, chloroform, 1,1,2-trichloroethane, 1,2-dichloroethene, or the like; aromatic hydrocarbons, such as for example, toluene, xylene, chlorobenzene, tetralin, or the like; nitromethane; and any mixtures thereof.

The recovered solid may be optionally further dried at suitable temperatures, and atmospheric or reduced pressures, for about 1-50 hours, or longer, using any types of drying equipment, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer or the like.

The obtained compound in step (c) may be optionally further purified by recrystallization or by slurrying in a suitable solvent or by column chromatography or any other suitable technique.

Step (d) involves reducing nitro group of formula (IV) with suitable reducing reagent to provide retigabine of formula (I).

Step (d) may be carried out in a suitable reducing reagent. Suitable reducing reagent that may be includes but not limited to catalytic hydrogenation using palladium-on-carbon, platinum (IV) oxide, or Raney™ nickel, or the like; metal mediated reduction such as zinc and acetic acid, zinc and hydrochloric acid, tin and hydrochloric acid, sodium amalgam in ethanol, or iron and acetic acid; tin chloride (II), titanium (III) chloride, or the like; alkali metal hydrides, such as lithium aluminum hydride, sodium borohydride, sodium dihydro-bis-(2-methoxyethoxy) aluminate solution (VITRIDE®), diisobutyl aluminium hydride, sodium cyanoborohydride or the like; sodium dithionite in alkaline medium; any combination thereof; or any other suitable reducing agent known in the art. Optionally reaction may be carried out under an atmosphere of hydrogen.

Step (d) may be carried out in a suitable solvent. Suitable solvents that may be used include, but are not limited to: alcohols such as for examples, methanol, ethanol, isopropyl alcohol, 1-propanol, 1-butanol, 2-butanol, or the like; ketones such as for example, acetone, ethyl methyl ketone, methyl isobutyl ketone, or the like; hydrocarbons such as for examples, toluene, xylene, hexanes, heptanes, cyclohexane, or the like; halogenated hydrocarbons such as for example dichloromethane, ethylene dichloride, chloroform, or the like; esters such as for example, ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate, or the like; ethers such as for examples diethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran, dioxane, or the like; polar aprotic solvents such as for examples, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, sulpholane, N-methylpyrrolidone, or the like; nitriles such as for example, acetonitrile, propionitrile, or the like; water; and mixtures thereof, and any other suitable solvent.

Suitable temperatures for the reaction of step (a) may be about 0°C to about the reflux temperature of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed.

The reaction mixture obtained in step (d) may be optionally filtered to remove any insoluble solids, or particles may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other technique for the removal of solids.

The product of step (d) may be isolated directly from the reaction mixture itself after the reaction is complete in step (d), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction or the like.
Optionally the obtained crude product may be directly used for the step (e) or may be isolated as solid.

The isolation in step (d) may involve methods including removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, extraction with solvent, or the like. Stirring or other alternate methods, such as for example, shaking, agitation, or the like, that mix the contents may also be employed for isolation.

Step (e) involves optionally, converting a retigabine into its salt.

Suitable salts that may be prepared in step (e) include, but not limited to, e.g., water-soluble and water-insoluble salts, such as the acetate, aluminum, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzathine (N,N'-dibenzylethylenediamine), benzenesulfonate, benzoate, bicarbonate, bismuth, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate (camphorsulfonate), carbonate, chloride, choline, citrate, clavulariate, diethanolamine, dihydrochloride, diphosphate, edetate, edisylate (camphorsulfonate), esylate (ethanesulfonate), ethylenediamine, fumarate, gluceptate (glucoheptonate), gluconate, glucuronate, glutamate, hexafluorophosphate, hexylresorcinate, hydrabamine (N, N'-bis(dehydroabietyl)ethylenediamine), hydrobromide, hydrochloride, hydroxynaphthoate, 1-hydroxy-2-naphthoate, 3-hydroxy-2-naphthoate, iodide, isothionate (2-hydroxyethanesulfonate), lactate, lactobionate, laurate, lauryl sulfate, lithium, magnesium, malate, maleate, mandelate, meglumine (1-deoxy-1-(methylamino)-D-glucitol), mesylate, methyl bromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, palmitate, pamoate (4,4'-methylenebis-3-hydroxy-2-naphthoate, or embonate), pantothenate, phosphate, picrate, polygalacturonate, potassium, propionate, p-toluenesulfonate, salicylate, sodium, stearate, subacetate, succinate, sulfate, sulfosallculate, suramate, tannate, tartrate, teoclate (8-chloro-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione), triethiodide, tromethamine (2-amino-2-(hydroxymethyl)-1,3-propanediol), valerate, zinc salts, and 2-fluoroethyl quaternary ammonium trifluoroacetates.

Step (e) may be carried out in a suitable solvent. Any of the solvents described in step (a) may be used for this step. Suitable solvents that may be used include, but are not limited to: water; alcohols, such as for example, methanol, ethanol, propanol, butanol, pentanol, ethylene glycol, glycerol, or the like; ketones, such as for example, acetone, butanone, pentanone, methyl isobutyl ketone, or the like; esters, such as for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like; ethers, such as for example, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like; aliphatic or alicyclic hydrocarbons, such as for example, hexane, heptane, pentane, cyclohexane, methylcyclohexane, or the like; halogenated hydrocarbons, such as for example, dichloromethane, chloroform, 1,1,2-trichloroethane, 1,2-dichloroethene, or the like; aromatic hydrocarbons, such as for example, toluene, xylene, chlorobenzene, tetralin, or the like; nitriles, such as for example, acetonitrile, propionitrile, or the like; polar aprotic solvents, such as for example, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulphoxide, sulpholane, formamide, acetamide, propanamide, or the like; nitromethane; and any mixtures thereof.

Retigabine or its salt of formula (I) may be isolated by any techniques known in the art. For example, useful techniques include but are not limited to: decantation, centrifugation, gravity filtration, suction filtration, concentrating, cooling, stirring, shaking, evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying, freeze-drying, or the like.

The resulting solid may be optionally washed with a suitable solvent to remove occluded mother liquor in order to reduce some of the impurities trapped in the wet cake. The wet cake may be optionally dried by conventional drying techniques such as a tray dryer, cone vacuum dryer, fluidized bed dryer, thin film dryer, or the like, at atmospheric pressure or under reduced pressure.

The obtained retigabine or its salt of formula (I) in step (d) or step (e) may be optionally further purified by recrystallization or by slurrying in a suitable solvent or acid base treatment or column chromatography or by treating with adsorbent materials include, but not limited to silica gel, aluminium oxide, and synthetic resin or the like; or any other suitable technique.

Suitable solvents that may be used for purification of retigabine or its salt of formula (I) include any of the solvents or their mixture described in step e) i.e., to produce salt of Retigabine.

The resulting retigabine or its salt of formula (I) may be recovered as a solid using conventional methods, including decantation, centrifugation, gravity filtration, suction filtration, or other techniques known in the art for the recovery of solids. The retigabine or its salt of formula (I) may be in crystalline or amorphous form, or mixtures thereof.

The resulting solid may optionally be dried at suitable temperatures, and atmospheric or reduced pressures, for about 1-50 hours, or longer, using any types of drying equipment, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer or the like and in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium.

Optionally steps (a) to (d) may be carried out in-situ i.e. without isolating the intermediates in each stage.

In the second embodiment, the present invention relates to an improved process for the preparation of retigabine of formula I, or salts thereof, which comprises one or more of the following steps:

(a) reacting 2-nitrobenzene-1, 4-diamine with 4-fluorobenzaldehyde to provide a compound of formula (V);

Formula (V) (b) reducing the compound of formula (V) with a suitable reducing reagent to provide a compound of formula (VI);

Formula (VI) (c) reducing the compound of formula (VI) with a suitable reducing reagent to provide a compound of formula (VII);

Formula (VII) (d) converting the compound of formula (VII) to retigabine of formula (I); and

(e) optionally, converting the retigabine into a salt thereof.
Step (a) involves reacting 2-nitrobenzene-1, 4-diamine with 4-fluorobenzaldehyde to provide compound of formula (V).

Step (a) may be carried out in a suitable solvent. Suitable solvents that may be used include, but are not limited to: water; alcohols, such as for example, methanol, ethanol, propanol, butanol, pentanol, ethylene glycol, glycerol, or the like; ketones, such as for example, acetone, butanone, pentanone, methyl isobutyl ketone, or the like; esters, such as for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like; ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like; aliphatic or alicyclic hydrocarbons, such as for example, hexane, heptane, pentane, cyclohexane, methylcyclohexane, or the like; halogenated hydrocarbons, such as for example, dichloromethane, chloroform, 1,1,2-trichloroethane, 1,2-dichloroethene, or the like; aromatic hydrocarbons, such as for example, toluene, xylene, chlorobenzene, tetralin, or the like; nitriles, such as for example, acetonitrile, propionitrile, or the like; polar aprotic solvents, such as for example, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulphoxide, sulpholane, formamide, acetamide, propanamide, or the like; nitromethane; and any mixtures thereof.

Suitable temperatures for the reaction of step (a) may be about 0°C to about the reflux temperature of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed.

The reaction mixture obtained in step (a) may be optionally filtered to remove any insoluble solids, or particles may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other technique for the removal of solids.

Optionally the product of step (a) may be isolated or used directly for the next step from the reaction mixture itself after the reaction is complete in step (a), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction or the like. Unlike prior art process, the product of step (a) can be used directly i.e., in situ for the next step which reduces the cycle time and cost.

Step (b) involves reducing the compound of formula (V) with a suitable reducing reagent to provide compound of formula (VI);

Step (b) may be carried out in a suitable reducing reagent. Suitable reducing reagent that may be includes but not limited to alkali metal hydrides, such as lithium aluminum hydride, sodium borohydride, sodium dihydro-bis-(2-methoxyethoxy) aluminate solution (VITRIDE®), diisobutyl aluminium hydride, sodium cyanoborohydride or the like; any combination thereof; or the like or any other suitable reducing agent known in the art.

Step (b) may be carried out in a suitable solvent. Suitable solvents that may be used include, but are not limited to: alcohols such as for examples, methanol, ethanol, isopropyl alcohol, 1-propanol, 1-butanol, 2-butanol, or the like; hydrocarbons such as for examples, toluene, xylene, hexanes, heptanes, cyclohexane, or the like; halogenated hydrocarbons such as for example dichloromethane, ethylene dichloride, chloroform, or the like; ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like; polar aprotic solvents such as for examples, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, sulpholane, N-methylpyrrolidone, or the like; nitriles such as for example, acetonitrile, propionitrile, or the like; water; and mixtures thereof, and any other suitable solvent.

Suitable temperatures for the reaction of step (a) may be about 0°C to about the reflux temperature of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed.

The reaction mixture obtained in step (b) may be optionally filtered to remove any insoluble solids, or particles may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other technique for the removal of solids.

The product of step (b) may be isolated directly from the reaction mixture itself after the reacfion is complete in step (b), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extracfion or the like.

Isolation of compound of formula (VI) may involve methods including removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, extracfion with a solvent, or the like. Sfirring or other alternate methods, such as for example, shaking, agitation, or the like, that mix the contents may also be employed for isolation.

Suitable solvents that may be used for isolation of compound of formula (VI) include, but are not limited to: ketones, such as for example, acetone, methyl isobutyl ketone or the like; esters, such as for example, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like; ethers, such as for example, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, 1,2-dimethoxyethane, anisole, or the like; aliphatic or alicyclic hydrocarbons, such as for example, hexane, heptane, pentane, cyclohexane, methylcyclohexane, or the like; halogenated hydrocarbons, such as for example, dichloromethane, chloroform, 1,1,2-trichloroethane, 1,2-dichloroethene, or the like; aromatic hydrocarbons, such as for example, toluene, xylene, chlorobenzene, tetralin, or the like; nitromethane; water and any mixtures thereof.

The recovered solid may be optionally further dried at suitable temperatures, and atmospheric or reduced pressures, for about 1-50 hours, or longer, using any types of drying equipment, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer or the like.

The obtained compound in step (b) may be optionally further purified by recrystallization or by slurrying in a suitable solvent or by column chromatography or any other suitable technique.

Step (c) involves reducing the compound of formula (VI) with a suitable reducing reagent to provide compound of formula (VII);

Step (c) may be carried out in a suitable reducing reagent. Suitable reducing reagent that may be includes but not limited to catalytic hydrogenation using palladium-on-carbon, platinum (IV) oxide, or Raney™ nickel, or the like; metal mediated reduction such as zinc and acetic acid, zinc and hydrochloric acid, tin and hydrochloric acid, sodium amalgam in ethanol, or iron and acetic acid; tin chloride (II), titanium (III) chloride, or the like; sodium dithionite in alkaline medium; any combination thereof; or any other suitable reducing agent known in the art. Optionally reaction may be carried out under an atmosphere of hydrogen.

Step (c) may be carried out in a suitable solvent. Any of the solvents described in step (b) may be used for this step.

Suitabie temperatures for the reaction of step (a) may be about 0°C to about the reflux temperature of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed.

The reaction mixture obtained in step (c) may be optionally filtered to remove any insoluble solids, or particles may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other technique for the removal of solids.

Optionally the product of step (c) may be isolated as solid or used directly for the next step from the reaction mixture itself after the reaction is complete in step (c), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction or the like. The product of step (c) can be used directly i.e., in situ for the next step which reduces the cycle time and cost.

Step (d) involves converting the compound of formula (VII) to retigabine of formula (I):
The said conversion may be carried out by reacting the compound of fonnula (VII) with a suitable reagent, which includes but not limited to ethyl chloroformate, pyrocarbonic acid esters such as pyrocarbonic acid ethyl ester or the like, or any other suitable reagent.

Step (d) may be optionally carried out in presence of a base. Any of the bases described for step (a) of the first embodiment may also be used for this step.

Step (d) may be carried out in a suitable solvent. Any of the solvents described for step
(a) of the first embodiment may also be used for this step.

Suitable temperatures for the reaction of step (a) may be about O'C to about the reflux temperature of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed.

The reaction mixture obtained in step (d) may be optionally filtered to remove any insoluble solids, or particles may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other technique for the removal of solids.

The product of step (d) may be isolated directly from the reaction mixture itself after the reaction is complete in step (d), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction or the like.

Optionally the obtained crude product may be directly used for the step (e) or may be isolate as solid.

The isolation in step (d) may involve methods including removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent, or the like. Stirring or other alternate methods, such as for example, shaking, agitation, or the like, that mix the contents may also be employed for isolation.

Step (e) involves optionally, converting a retigabine into its salt.

Suitable retigabine salts that may be prepared in step (e) include, but are not limited to those described in the present application or any other pharmaceutically acceptable salts. The retigabine salts can be prepared by the methods described in the present application or any other method known in the art.

Optionally steps (a) to (d) may be carried out as in-situ i.e. without isolating the intermediates in each stage.

In third embodiment, the present application relates to an improved process for the preparation of retigabine of formula I, which comprises one or more of the following steps:

(a) reacting 2-nitrobenzene-1,4-diamine with 4-fluorobenzaldehyde to provide a compound of formula (V) and in-situ reducing the compound of formula (V) to produce compound of formula (VI);

(b) reducing the compound of formula (VI) with a suitable reducing reagent to provide triamine compound of formula (VII); and

(c) converting the compound of formula (VII) to retigabine of formula (I);

In fourth embodiment, the present application relates to an improved process for the preparation of retigabine of formula I, which comprises one or more of the following steps:

(a) reacting 2-nitrobenzene-1,4-diamine with 4-fluorobenzaldehyde to provide
a compound of formula (V) and in-situ reducing the compound of formula (V) to
produce compound of formula (VI);

(b) reducing the compound of formula (VI) with sodium dithionite to provide
triamine compound of formula (VII); and

(c) converting the compound of formula (VII) to retigabine of formula (I);

In fifth embodiment, the present application relates to an improved process for the preparation of retigabine of formula I, which comprises one or more of the following steps:

(a) reacting 2-nitrobenzene-1,4-dJamine with 4-fluorobenzaldehyde to provide a compound of formula (V) and in-situ reducing the compound of formula (V) with sodium borohydrlde to produce compound of formula (VI);

(b) reducing the compound of formula (VI) with a suitable reducing reagent to provide triamine compound of formula (VII); and

(c) converting the compound of formula (VII) to retigabine of formula (I);

The procedures that can be used for the third embodiment, fourth embodiment and fifth embodiment can be according to the process or procedures described as per second embodiment of the present application.

Retigabine obtained according to the processes of the present application can be milled or micronized by any process known in the art, such as ball milling, jet milling, wet milling etc., to produce desired particle sizes and particle size distributions. The bulk density, particle size and hausner ratio of the retigabine produced according to the processes of the present application will vary depending upon the conditions used. These properties of retigabine will vary from the product directly produced according to the processes disclosed in this application and after milling / micronization step.

The retigabine obtained according any of the processes of the present application may be crystalline or amorphous or solvate or hydrate or mixture of the crystalline modifications (any mixture of modification A or modification B or modification C).

The starting materials of the present application can be produced according to any of the processes known in the literature. The starting materials may be purified according to the known methods before using for the reaction.

The 2-nitro-p-phenylenediamine used in the present application can be prepared by acetylating p-phenylenediamine to produce N,N'-(1,4-phenylene)diacetamide which is nitrated to produce N,N'-(2-nitro-1,4-phenylene)diacetamide which upon hydrolysis gives 2-nitro-p-phenylenediamine.

The 4-fluorobenzaldehyde can be prepared by chlorinating 4-fluorotoluene to provide 1-(dichloromethyl)-4-fluorobenzene which is hydrolyzed to get 4-fluorobenzaldehyde.

In embodiments, prepared retigabine or its pharmaceutically acceptable salts can be substantially pure having a chemical purity greater than about 99%, or greater than about 99.5%, or greater than about 99.9%, by weight, as determined using high performance liquid chromatography (HPLC). Retigabine or its pharmaceutically acceptable salts produced by methods of present application can be chemically pure retigabine having purity greater than about 99.5% and containing no single impurity in amounts greater than about 0.15%, by HPLC. Retigabine or its pharmaceutically acceptable salts produced by methods of present application can be chemically pure retigabine having purity greater than about 99.8% and containing no single impurity in amounts greater than about 0.1%, by HPLC.

Potential impurities possible in retigabine or its pharmaceutically acceptable salts are the unreacted starting materials and intermediates, described in the present application. Possible impurities in retigabine or its pharmaceutically acceptable salts, in addition to unreacted starting materials or intermediates described in the present application, can have structural formulas as illustrated below.

N-acetyl impurity

Desfluoro impurity

In another aspect, the application relates to substantially pure retigabine or its pharmaceutically acceptable salts having less than about 0.1% of the N-acetyl impurity, the desfluoro impurity, the 2-fluoro impurity, the 3-fluoro impurity, the 1,4-dicarbamate impurity, the Methylene dimer, the Dimer-1, the Dimer-2 impurity. In another aspect, the application provides processes for preparing retigabine or its pharmaceutically acceptable salts having less than about 0.1% of the N-acetyl impurity, the desfluoro impurity, the 2-fluoro impurity, the 3-fluoro impurity, the 1, 4-dicarbamate impurity, the Methylene dimer, the Dimer-1 and the Dimer-2 impurity.

In an embodiment, it was found that, the source of the desfluoro impurity, the 2-fluoro impurity and the 3-fluoro impurity is from the starting material i.e., 4-fluorobenzaldehyde. If the corresponding impurities i.e., benzaldehyde, 2-fluorobenzaldehyde and 3-fluorobenzaldehyde are controlled at the starting material that will reduce the levels of corresponding impurities less than 0.1% at retigabine or its salt stage.

DEFINITIONS

The following definitions are used in connection with the present application unless the context indicates othenwise. Raney® nickel is a sponge-metal catalyst produced when a block of nickel-aluminum alloy is treated with concentrated sodium hydroxide. Raney® is a registered trademark of W. R. Grace and Company.

The phrase "nitrating agent" refers to a compound that introduces a nitro group (O2N-) onto a carbon atom of another compound. Examples of a nitrating agent include, tetranitromethane, nitric acid; mixtures of nitric acid and another acid, such as sulfuric acid or acetic acid; nitric acid and acetic anhydride; N2O5 in the presence of drying agent such as P2O5; esters of nitric acid, including, but not limited to, methyl nitrate and ethyl nitrate, in the presence of alkaline media, a protic acid, or a Lewis acid; metallic nitrites, such as sodium nitrite or potassium nitrite, in the presence of an acid, such as trifluoroacetic acid or sulfuric acid; N2O4; and nitronium salts such as NOaBpA", N02*PF6", N02*CF3S03'. Other suitable nitrating agents are summarized in Schofield, "Aromatic Nitration," (Cambridge University Press, Cambridge, 1980); and Hogget, et al., "Nitration and Aromatic Reactivity," 122-145, 163-222 (Cambridge University Press, London, 1971); each of which is incorporated herein by reference in its entirety.

Certain specific aspects and embodiments of the present invention are described in further detail by the examples below, which are provided only for the purpose of illustration and are not intended to limit the scope of the invention in any manner.

EXAMPLES

Example 1: Preparation of ethyl 4-iodophenvlcarbamate: 4-lodo aniline (20 g) is added to the reaction mixture containing toluene (120 mL) and sodium carbonate at 28°C and stirred for 15 minutes. Ethyl chloroformate (10.8 mL) is added to the reaction mixture at 28°C and stirred for 1 hour. Filtered the reaction mixture, washed unwanted wet compound with ethyl acetate and filtrate is washed with water. Organic layer is dried with anhydrous sodium sulfate and solvent is evaporated completely at 52°C under vacuum. To the resultant residue, n-hexane is added and stirred until complete solid separation. Separated solid is collected by filtration, washed with n-hexane. The wet solid was dried at 40°C under reduced pressure for 2 hours to afford the title compound. Yield: 22.32 g.

Example 2: Preparation of ethyl 4-iodo-2-nitrophenvlcarbamate: A 10 g portion of ethyl 4-iodophenylcarbamate and acetic anhydride (100 mL) are charged into round bottom flask and cooled to 3°C. Mixture of nitric acid (70%, 2.7 mL) and acetic acid (2 mL) is added to the reaction mass at 3°C over 10 minutes. Reaction mixture temperature is increased to 27°C and stirred for 24 hours. Reaction mixture is poured into ice cold water, aqueous layer is extracted with ethyl acetate, organic layer washed with water and dried with sodium sulfate. Solvent is evaporated completely at 52''C under vacuum. The resultant compound is purified using column chromatography to afford the title compound. Yield: 4.71 g.

Example 3: Preparation of ethyl 4-(4-fluorobenzvlannino)-2-nitrophenvl-carbamate: Cesium carbonate (50.8 g), copper iodide (21.23 g), L-proline (2.5 g) and dimethylsulfoxide (150 mL) are charged into round bottom flask and stirred for 20 minutes. Ethyl 4-iodo-2-nitrophenylcarbamate (15 g) and 4-fluorobenzylamine (10.24 mL) are charged into the reaction mixture and stirred at 80°C for 2 hours. Reaction mixture cooled to 28°C, water and ethyl acetate is added to the reaction mixture at 28°C. Reaction mixture is filtered, washed with ethyl acetate. Aqueous and organic layers were separated; organic layer is washed with pre-cooled water and brine solution. The resultant organic layer is dried with sodium sulfate and distilled of solvent completely at 52''C under reduced pressure. The obtained compound is further purified using column chromatography to afford title compound. Yield: 5.182 g.

Example 4: Preparation of retiqabine dihvdrochloride: Raney™ nickel (2.55 g) is charged into round bottom flask under nitrogen atmosphere. Ethyl 4-(4-fluorobenzylamino)-2-nitrophenylcarbamate (8.5 g) and ethanol (425 mL) is charged into the reaction mixture. Hydrogen pressure is applied and stirred the reaction mixture at 28°C for 8 hours. Reaction mixture is filtered, washed with ethanol and the filtrate evaporated at 52°C under reduced pressure. Ethanolic HCI is added to the resultant solid in ethanol at 3°C and stirred at 3°C for 2 hours. Reaction mixture temperature is increased to 28°C and stirred for 2 hours. Separated solid is collected by filtration, washed with pre cooled ethanol and n-pentane. The wet solid is dried for 4 hours to afford title compound. Yield: 5.5 g.

Example 5: Preparation of 2-amino-5-(4-fluorobenzvlamino)-nitrobenzene: 2-nitro-p-phenylenediamine (125 g), methanol (375 mL), 1,4-dioxane (1500 mL), 4-fluorobenzaldehyde (114.4 g) and dry Tulsion® T-66 MP (9.37 g) are charged into round bottom flask, heated to 75°C and stirred at 75°C for 4 hours 15 minutes. The resultant reaction mixture is filtered at 70°C and washed with mixture of methanol (30 mL) and 1,4-dioxane (120 mL). To the filtrate sodium borohydride (46.31 g) is added portion wise at below 15°C over a period of 75 minutes and the mixture is stirred at 24°C for 3 hours. Reaction mixture is distilled at below 50°C under reduced pressure, water (1.5 L) and dichloromethane (2.5 L) is added at 24°C and stirred for 5 minutes. Reaction mixture is filtered, washed with dichloromethane (500 mL).

Aqueous and organic layers are separated, organic layer is washed with water (1.0 L) and brine solution (1.0 L). The resultant organic layer is dried over sodium sulfate and solvent is evaporated at 45°C under reduced pressure. Toluene (375 mL) is added to the resultant compound at 24°C and stirred for solid separation. Separated solid is collected by filtration, washed with n-hexane (625 mL). The wet solid is dried at 40°C under reduced pressure to afford 136.0 g of title compound. Purity by HPLC: 99.53%

Example 6: Preparation of retigabine: 2-amino-5-(4-fluorobenzylamino)-nitrobenzene (100 g), methanol (1 L) and Raney™ nickel (60 g) are charged into vessel under nitrogen atmosphere. Hydrogen pressure is applied and stirred the reaction mixture at 28''C for 2 hours 30 minutes. Reaction mixture is filtered, washed with methanol (300 mL). Diethyl carbonate (58.9 g) is added to the filtrate at 4''C and stirred at 9°C for 30 minutes. Reaction mixture is distilled at below 40°C under reduced pressure and cooled to 24°C. Isopropyl alcohol (200 mL) is added to the resultant compound and stirred for 15 minutes. Separated solid is collected by filtration, washed with isopropyl alcohol (100 mL) and dried. The obtained dry compound, dichloromethane (8.5 L) and silica gel (20 g) are charged into flask and stirred for 15 minutes. Reaction mixture is filtered, washed with dichloromethane (500 mL) and filtrate solvent is evaporated at below 40°C under reduced pressure. Isopropyl alcohol (150 mL) is added to the resultant compound at 24°C and stirred for 15 minutes. Separated solid is collected by filtration, washed with isopropyl alcohol (50 mL) and dried to afford 77.0 g of title compound. Purity by HPLC: 99.83%

Example 7: Preparation of Hydrochloride salt of 4-(4-Fluorobenzylamino)-1. 2-phenvlene diamine: 2-amino-5-(4-fluorobenzylamino)-nitrobenzene (20 g), methanol (200 mL) and Raney™ nickel (12 g) are charged into vessel under nitrogen atmosphere. Hydrogen pressure is applied and stirred the reaction mixture at 28°C for 2 hours. Reaction mixture is filtered, washed with methanol (75 mL) and filtrate solvent is evaporated at below 40''C under reduced pressure. Methyl tertiary butyl ether (MTBE) (100 mL) is added to the resultant crude at 24''C and stirred for 15 minutes. Separated solid is collected by filtration, washed with MTBE (25 mL). The obtained wet compound and MTBE (100 mL) are charged into flask. MTBE HCI (40 mL) is slowly added to the reaction mixture at 4''C and stirred for 30 minutes. Separated solid is collected by filtration, washed with MTBE (30 mL) and dried to afford 10 g of title compound.

Example 8: Preparation of Hydrochloride salt of 4-(4-Fluoroben2vlamino)-1. 2-phenvlene diamine: 2-amino-5-(4-fluorobenzylamino)-nitrobenzene (20 g), methanol (200 mL) and Raney™ nickel (4.5 g) are charged into vessel under nitrogen atmosphere. Hydrogen pressure is applied and stirred the reaction mixture at 27°C for 14 hours 30 minutes. Reaction mixture is filtered, washed with methanol (40 mL) and filtrate solvent is evaporated at below 34°C under reduced pressure to afford 16.6 g of 4-(4-Fluorobenzylamino)-1, 2-phenylene diamine as residue. The resultant residue (2.0 g), methanol (20 mL) are charged into round bottom flask and cooled to 4°C. Diethyl pyrocarbonate (1.3 mL) is slowly added to the reaction mixture at 4°C and stirred for 15 minutes. Reaction mixture solvent is evaporated at below 34°C and stirred for 45 minutes. Separated solid is collected by filtration, washed with isopropyl alcohol (2 mL). The wet solid is dried at 26°C under reduced pressure to afford 0.5 g of title compound.

Example 9: Preparation of 2-amino-5-(4-fluorobenzviamino)-nitrobenzene: 2-nitro-p-phenylenediamine (50 g), methanol (400 mL) and N, N-dimethylformamide (100 mL) are charged into round bottom flask and stirred for 10 minutes. 4-fluorobenzaldehyde (38.5 mL) is added to the reaction mixture and stirred at 29°C for 60 minutes. Sodium borohydride (16 g) is added portion wise at below 15°C over a period of 90 minutes and the mixture is stirred at 24°C for 60 minutes. Water (500 mL) is slowly added to the reaction mixture at 10-15°C and stirred at 15-20°C for 80 minutes. Separated solid is collected by filtration, washed with water (500 mL). The wet solid is dried at 26°C under reduced pressure to afford 77.0 g of title compound.

Example 10: Preparation of 4-(4-Fluorobenzvlamino)-1. 2-phenvlene diamine: 2-amino-5-(4-fluorobenzylamino)-nitrobenzene (5 g), methanol (40 mL), water (40 mL) and zinc powder (4 g) are charged into round bottom flask and stirred for 20 minutes. Ammonium chloride (5 g) is charged into the reaction mixture, heated to 80°C and stirred at 80°C for 4 hours. Water (50 mL) and ethyl acetate (100 mL) are charged into reaction mixture at 47°C and stirred at 45°C for 30 minutes. Organic layer from the reaction mixture is separated, washed with 10% sodium chloride solution (50 mL). The resultant organic layer is distilled at below 40°C under reduced pressure to afford 4.5 g of the title compound.

Example 11: Preparation of 2-amino-5-(4-fluorobenzvlamino)-nitrobenzene: 2-nitro-p-phenylenediamine (10 g), methanol (50 mL) and N, N-dimethylformamide (50 mL) are charged into round bottom flask at 25°C under stirring and cooled the reaction mass to 20X for 15 minutes. 4-fluorobenzaldehyde (7.7 mL) is added to the reaction mass at 20°C. The resultant reaction mass is stirred for 30 minutes at 30°C. After completion of the reaction, the reaction mass is cooled to 5°C in 15 minutes. Sodium borohydride (3.45 g) is added portion wise to the reaction mass at 5°C and maintained for 30 minutes at 5°C. The temperature of the reaction mass is further raised to 30°C and maintained for 30 minutes at the same temperature. Water (100 mL) is charged in another flask and cooled to 17°C. After completion of the reaction, reaction mass is added slowly to the water at 17°C in 30°C. The obtained reaction mass is stirred for 30 minutes at 35°C. The precipitated solid is collected by filtration and washed with water (50 mL) and dried under suction at 35°C. The wet material is further dried at 60°C to afford 15.1 g; of the title compound. HPLC purity: 99.41%.

Example 12: Preparation of retiqabine: Dichloromethane (375 mL), 2-amino-5-(4-fluorobenzylamino)-nitrobenzene (75 g), sodium dithionite (225 g) and triethylamine (168.75 mL) are charged into a round bottom flask at 26°C. The reaction mass is stirred and cooled to 0°C. Water (375 mL) is added slowly to the reaction mass at 0 to 5''C in 35 minutes. The temperature of the reaction mass is slowly raised to 34°C in 45 minutes and stirred for 1 hour 45 minutes at the same temperature. After completion of the reaction, water (750 mL) is added to the reaction mass and stirred for 15 minutes at 34°C. Aqueous and organic layers are separated. The aqueous layer is extracted with dichloromethane (187.5 mL) and combined the organic layers (about 1800 g).

The organic layer (600 g) from the above obtained is charged into a round bottom flask at 26°C and cooled to -5°C. Dimethylaminopyridine (1.17 g) and potassium carbonate (13.2 g) are charged into the reaction mass at -5°C. The solution of ethylchloroformate (prepared by diluting 8.33 mL of ethylchloroformate in 62.5 mL dichloromethane) is slowly added to the reaction mass at -5°C in 40 minutes and stirred for 45 minutes at the same temperature. After completion of the reaction, Hydrochloric acid 10% solution 125 mL (prepared by diluting 12.5 ml concentrated hydrochloric acid in 125 mL water) is added to the reaction mass at -5°C. The reaction mass is stirred for 45 minutes at 5°C. The temperature of the reaction mass is raised to 25°C and 10% potassium carbonate solution (100 mL) is added. The reaction mass is stirred for 20 minutes at 25°C. Aqueous and organic layers are separated. The organic layer is washed with water (125 mL). The activated carbon (1.25 g) is added to the organic layer at 25°C and stirred for 20 minutes. The resulting suspension is filtered on hyflo and washed with dichloromethane (50 mL). Distilled out the dichloromethane under vacuum at 30°C and Isopropyl alcohol (100 mL) is added. The obtained solution is further distilled to remove the traces of dichloromethane at 35°C and cooled to 28°C and stirred for 40 minutes. The precipitated solid product is obtained by filtration and washed with Isopropyl alcohol (37.5 mL). The product is dried under suction at 27°C. The wet solid (15.1 g) and N, N-dimethylformamide (15 mL) are charged into a round bottom flask at 26°C. The obtained suspension is heated to 30°C to get clear solution and Isopropyl alcohol (150 mL) added to the clear solution at 30°C. The obtained suspension is stirred for 15 minutes at 30°C and cooled to 5°C. The resulted slurry is stirred for 30 minutes at 5°C. The solid is obtained by filtration and washed with Isopropyl alcohol (22.5 mL), dried under suction to obtained the title compound. The product is dried under vacuum at 33°C for 5 hours. Yield: 12.7 g; HPLC purity: 99.83%. N-acetyl impurity: not detected; Desfluoro impurity: 0.017%; 2-fluoro impurity: not detected; 3-fluoro impurity: 0.033%; 1, 4-Dicarbamate impurity: 0.036%, Methylene Dimer: 0.023%; Dimer-1: 0.015%; Dimer-2: not detected:

We Claim:

1. A process for preparing retigabine or its pharmaceutically acceptable salts comprising:

a) reacting 4-iialo aniline with a suitable reagent to provide N-carbamic ester of formula (II);

wherein X is F, CI, Br, or I; b) nitration of the N-carbamic ester of formula (II) to provide nitro compound of formula (III);

wherein X is F, CI, Br, or I; c) reacting the nitro compound of formula (III) with 4-fluorobenzyl amine to provide a compound of formula (IV);
Formula (IV)

d) reducing the compound of formula (IV) with a suitable reducing agent to provide retigabine of formula (I); and

e) optionally, converting the retigabine into a salt thereof.

2. A process for preparing retigabine or its pharmaceutically acceptable salts comprising:

a) reacting 2-nitrobenzene-1,4-diamine with 4-fluorobenzaldehyde to provide a compound of formula (V);

Formula (V) b) reducing the compound of formula (V) with a suitable reducing reagent to
provide a compound of formula (VI);

3. Formula (VI) c) reducing the compound of formula (VI) with a suitable reducing reagent to provide triamine compound of formula (VII);
Formula (VII)

(d) converting the compound of formula (VII) to retigabine of formula (I); and

(e) optionally, converting the retigabine into a salt thereof. 3. A process for preparing retigabine comprising:

(a) reacting 2-nitrobenzene-1,4-diamine with 4-fluorobenzaldehyde to provide a compound of formula (V) and in-situ reducing the compound of formula (V) to produce compound of formula (VI);

(b) reducing the compound of formula (VI) with a suitable reducing reagent to provide triamine compound of formula (VII); and

(c) converting the compound of formula (VII) to retigabine of formula (I);

4. A process for preparing retigabine comprising:

(a) reacting 2-nitrobenzene-1,4-diamine witli 4-fluorobenzaldehyde to provide
a compound of formula (V) and in-situ reducing tlie compound of formula (V)
to produce compound of formula (VI);

(b) reducing the compound of formula (VI) with sodium dithionite to provide
triamine compound of formula (VII); and

(c) converting the compound of formula (VII) to retigabine of formula (I);

5. A process for preparing retigabine comprising:

(a) reacting 2-nitrobenzene-1,4-diamine with 4-fluorobenzaldehyde to provide
a compound of formula (V) and in-situ reducing the compound of formula (V)
with sodium borohydride to produce compound of formula (VI);

(b) reducing the compound of formula (VI) with sodium dithionite to provide
triamine compound of formula (VII); and

(c) converting the compound of formula (VII) to retigabine of formula (I);

6. A process according to claim 2 to 5, wherein the solvent used for preparing the compound of formula (V) from 2-nitrobenzene-1,4-diamine is methanol and N,N-dimethyl formamide or their mixture.

7. A process according to claim 2 to 5, wherein the compound of formula (V) is used in next step without isolation.

8. A process according to claim 2 to 5, wherein the compound of formula (VII) is used in the next step without isolation.

9. A process according to claim 2 to 5, wherein the compound of formula (VI) is isolated by adding water to the reaction mass or reaction mass to the water.

10. A process according to any of the preceding claims wherein the retigabine obtained is having HPLC purity greater than 99.5%.