FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
"PROCESS FOR PREPARATION OF RETIGABINE"
Glenmark Generics Limited an Indian Company, registered under the Indian company's Act 1957 and having its
registered office at
Glenmark House,
HDO- Corporate Bldg, Wing-A,
B. D. Sawant Marg, Chakala, Andheri (East), Mumbai- 400 099
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to a process for the preparation of retigabine, its intermediate compounds and pharmaceutically acceptable salts thereof. BACKGROUND OF THE INVENTION
Retigabine or ezogabine, also known as ethyl N-[2-amino-4-(4-fluorobenzy!amino)phenyl] carbamate, is represented by the structure of formula 1.

Retigabine is an anticonvulsant indicated for the adjunctive treatment of adult epilepsy patients with partial onset seizures. Retigabine is marketed under the brand name POT1GA® in the United States (approved in June 2011) and under the brand name TROBALT® in Europe (approved in March 2011).
United States Patent No. 5384330 (the '330 patent) discloses retigabine and its salts. The '330 patent discloses the preparation of retigabine in Example 1 with two alternatives, Variant A and Variant B, as schematically represented by Scheme I.

In Variant A of Example 1 of the '330 patent, 2-amino-5-(4-fluorobenzylamino)nitrobenzene or 2-amino-4-{4-fluoroberizylarnino)nitrobenzene is hydrogenated

in presence of Raney nickel in dioxane. On completion of hydrogenation, the catalyst is filtered off and the filtrate is treated with ethyl chloroformate in the presence of diisopropylethylamine to give retigabine. The starting material 2-ammo-5-(4-fluorobenzylamino)nitroberizene is prepared by reducing 2-amino-5-(4-fluorobenzylideneamino)nitrobenzene using sodium borohydride as schematically represented by Scheme n.

In Variant B of Example 1 of the '330 patent, ethyl N-[4-(4-fluorobenzylamLno)-2-nitrophenyl] carbamate is hydrogenated in the presence of Raney nickel to give retigabine. The starting material ethyl N-[4-(4-fluorobenzylamino)-2-nitrophenyl] carbamate is prepared by reducing ethyl N-[4-(4-fluorobenzylideneamino)-2-nitrophenyl] carbamate using sodium borohydride as schematically represented by Scheme III.

The processes known in the art to prepare retigabine as represented in Scheme I-Variant B and Scheme III involve two-step reduction wherein in the first step, the imine group of ethyl Ar-[4-(4-fluorobenzylideneamino)-2-nitrophenyl] carbamate is reduced using sodium borohydride to give ethyl N-[4-(4-fiuorobenzylamino)-2-nitrophenyl] carbamate and in the second step, the nitro group of ethyl N-[4-(4-fluorobenzylamino)-2-nitrophenyl] carbamate is reduced by catalytic hydrogenation using Raney nickel to give retigabine.
There is no teaching in the art for the preparation of retigabine wherein the inline group and the nitro group are reduced in a single step.
The object of the present invention is to provide a one-step reduction process for the preparation of retigabine wherein the imine group and the nitro group are reduced in a single step.
The '330 patent discloses that catalytic hydrogenation using Raney nickel or precious metals like palladium or platinum as catalyst as particularly suitable for the reduction of the nitro group, as represented in Scheme I- Variant A and Variant B. The '330 patent discloses that the said reduction step may also be carried out using zinc/hydrochloric acid, tin/hydrochloric acid, iron/hydrochloric acid, stannous chloride, stannous chloride/hydrochloric acid, ammonium formate,

activated aluminium, salts of hydrogen sulfide. However, the reduction of the nitro group taught in the '330 patent uses costly, harmful, environment unfriendly heavy metal reducing agents.
There is a need in the art, therefore, for an inexpensive, safe, environmentally benign reagent/s, for the reduction of the nitro group in the synthesis of retigabine, which would be advantageous over the reported reagents of the '330 patent.
The '330 patent discloses the preparation of ethyl N-[4-(4-fluoroben2ylideneamino)-2-nitrophenyl] carbamate as schematically represented by Scheme IV.

Correspondingly, the object of the present invention is to further provide a novel method for the preparation of ethyl N-[4-(4-fluorobenzy]ideneamino)-2-nitrophenyl] carbamate which is more convenient and more efficient than the previously known method.
The synthesis of retigabine known in the art involves reaction steps, each requiring different conditions, solvents, temperature, thereby needing isolation at each step. This results in a discontinuous process entailing longer processing time, lower yields, increased solvent usage.
The.object of the present invention is to avoid multiple isolation steps and to provide an economical synthetic route with minimum isolation steps suitable for industrial application.
SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of retigabine, a compound of formula 1,

and pharmaceutically acceptable salts thereof, the process comprising:
(a) reducing ethyl N-(4-nitrophenyl) carbamate, a compound of formula VI, to give ethyl N-
(4-aminophenyl) carbamate, a compound of formula VII;

(b) reacting the compound of formula VII with phthalic anhydride to give ethyl N-(4~ phthalimidophenyl) carbamate, a compound of formula VIII;

(c) nitrating the compound of formula VIII to give ethyl N-(2-nitro-4-phthatimidophenyl) carbamate, a compound of formula IX;

(d) reacting the compound of formula IX with hydrazine hydrate to give ethyl Ar-(4-amino-2-nitrophenyl) carbamate, a compound of formula IIIb;

(e) reacting the compound of formula IIIb with 4-fluorobenzaIdehyde to give ethyl Af-[4-(4-fluorobenzylideneamino)-2-nitrophenyl] carbamate, a compound of formula IIb;


(f) reducing the compound of formula IIb to give ethyl N-[4-(4-fluorobenzylamino)-2-nitrophenyi] carbamate, a compound of formula IIIa;

(g) reducing the nitro group of the compound of formula IIIa to give retigabine; wherein either or all of the products of steps (a),.(b) and (e) are not isolated.
DETAILED DESCRIPTION OF THE INVENTION The present invention provides a process for the preparation of retigabine, a compound of formula I,

and pharmaceutically acceptable salts thereof, the process comprising:
(a) acylating 2-amino-5-(4-fluorobenzy!ideneamino)nitrobenzene, a compound of formula IIa,
to give ethyl N-[4-{4-fluorobenzylideneamino)-2-nitrophenyl] carbamate, a compound of formula IIb;

(b) reducing the compound of formula IIb to give retigabine;
(c) and optionally, converting to pharmaceutically acceptable salts thereof.
In the present application, the term "room temperature" means a temperature of about 25°C to about 30°C. The term "one-pot" means the reaction is carried out in the same reaction

vessel without the isolation of the intermediate compounds. The term "one-step reduction" means the reduction of the imine group (or Schiff base) and the nitro group in a single step.
The compound of formula IIa is obtained by reacting l,4-diamino-2-nitrobenzene with 4-fluorobenzaldehyde in the presence of a suitable solvent.
The suitable solvent includes, but is not limited to diethyl carbonate; alcohols such as methanol, ethanol, 1-propanol, isopropyl alcohol, 1-butanoi, 2-butanol, 1-pentanol, 1-octanol and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene and the like; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; NN-Methyl-2-pyrrolidone; water or mixtures thereof. Preferably the solvent selected is diethyl carbonate, methanol, isopropyl alcohol.
The reaction may be carried out at a temperature in the range of about 25°C to about 70°C. The reaction is carried out for a period of about 2 hours to about 8 hours. Preferably the reaction is carried out at a temperature of about room temperature for a period of about 2 hours to about 4 hours.
In (a) of the process for the preparation of retigabine, a compound of formula I, the compound of formula 11a is acylated to give the compound of formula lib.
A suitable acylating agent includes, but is not limited to diethyl carbonate; ethyl haloformate such as ethyl chloroformate, ethyl bromoformate, ethyl iodoformate; ethyl haloformate/hydroxybenzotriazole; ethyl haloformate/N-hydroxysuccinirnide; ethyl halofonriate/N,N'-carbonyldiimidazole. Preferably the acylating agent selected is diethyl carbonate.
The reaction may be carried out in the presence of a suitable base. The suitable base includes, but is not limited to alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkaline earth metal hydroxides; alkali metal carbonates such as sodium carbonate, potassium carbonate, caesium carbonate; alkaline earth metal carbonates; alkali metal bicarbonates such as sodium bicarbonate; alkali metal hydrides such as sodium hydride, potassium hydride; alkali metal alcoholates such as lithium methoxide, sodium methoxide, potassium methoxide, rubidium methoxide, caesium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, sodium pentoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide; alkaline earth metal alcoholates such as calcium ethoxide, magnesium iso-propoxide; alkyl lithium such as n-butyl lithium; alkali metal acetates, tertiary amines such as triethylamine, N,N'-diisopropylethylamine; ammonia, pyridine, piperidine, 4-dimethylaminopyridine, l,4-diazabicyclo[2.2.2]octane, l,8-diazabicyclo[5.4.0]undec-7-ene, potassium bis(trimethylsilyl)amide. Preferably the base selected is sodium ethoxide, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide.
The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes, but is not limited to diethyl carbonate; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like;

alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; hydrocarbons such as toluene, xylene and the like; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide;N-Methyl-2-pyrrolidone; water or mixtures thereof. Preferably the solvent selected is diethyl carbonate, dioxane.
The reaction may be carried out at a temperature in the range of about 25°C to about 100°C. The reaction is carried out for a period of about 2 hours to about 6 hours. Preferably the reaction is carried out at a temperature of about 45°C to about 55°C for a period of about 2 hours to about 3 hours.
In one embodiment, the present invention provides a process for the preparation of the compound of formula lib, the process comprising (i) reacting l,4-diamino-2-nitrobenzene with 4-fluorobenzaldehyde in methanol to give the compound of formula IIa, (ii) isolating the compound of formula Ila, and (iii) acylating the compound of formula IIa using diethyl carbonate and sodium ethoxide to give the compound of formula IIb.
In one embodiment, the present invention provides a one-pot process for the preparation of the compound of formula IIb, the process comprising (i) reacting l,4-diamino-2-nitrobenzene with 4-fluorobenzaldehyde to give the compound of formula IIa, and (ii) acylating the compound of formula IIa to give the compound of formula IIb, wherein the compound of formula IIa is not isolated.
In one preferred embodiment, the present invention provides a one-pot process for the preparation of the compound of formula IIb, the process comprising (i) reacting l,4-diamino-2-nitrobenzene with 4-fiuorobenzaldehyde in diethyl carbonate to give the compound of formula Ila, and (ii) acylating the compound of formula IIa using diethyl carbonate and sodium ethoxide to give the compound of formula IIb, wherein the compound of formula IIa is not isolated.
In (b) of the process for the preparation of retigabine, a compound of formula I, the compound of formula IIb is reduced to give retigabine.
A suitable reducing agent includes, but is not limited to alkali metal borohydride/alkali metal halide such as sodium borohydride/lilhium chloride, sodium borohydride/lithium bromide, sodium borohydride/lithium iodide, potassium borohydride/lithium chloride, potassium borohydride/lithium bromide, potassium borohydride/lithium iodide; alkaline earth metal borohydride/alkali metal halide; transition metal borohydride/alkali metal halide; alkali metal borohydride/alkaline earth metal halide; alkaline earth metal borohydride/alkaline earth metal halide; transition metal borohydride/alkaline earth metal halide; alkali metal borohydride/transition metal halide; alkaline earth metal borohydride/transition metal halide; transition metal borohydride/transition metal halide; lithium borohydride; lithium aluminium hydride; sodium cyanoborohydride; sodium triacetoxyborohydride; zinc/calcium chloride dihydrate; zinc/hydrochloric acid, iron/hydrochloric acid, sodium dithionite.
The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes, but is not limited to alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, l-octanol and the like; ethers such as dimethyl ether, diethyl ether,

diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; haloalkanes such as dichloromethane, chloroform and the like; dimethyl formamide; dimethyl acetamide; water or mixtures thereof. Preferably the solvent selected is tetrahydrofuran-water mixture.
The reaction may be carried out at a temperature in the range of about 25°C to about ]00°C. The reaction is carried out for a period of about 2 hours to about 10 hours. Preferably the reaction is carried out at a temperature of about 70°C to about 90°C for a period of about 4 hours to about 5 hours.
In one embodiment, the present invention provides a process for the preparation of retigabine, the process comprising reducing the compound of formula IIb using alkali metal borohydride/alkali metal halide to give retigabine, wherein the imine group and The nitro group are reduced in a single step.
In one preferred embodiment, the present invention provides a process for the preparation of retigabine, the process comprising reducing the compound of formula IIb using sodium borohydride/lithium chloride to give retigabine.
In (b) of the process for the preparation of retigabine, a compound of formula 1, the compound of formula IIb is reduced to give retigabine comprising:
(i) reducing the compound of formula IIb to give ethyl N-[4-(4-fluorobenzylamino)-2-nitrophenyl] carbamate, a compound of formula IIIa;

(ii) reducing the nitro group of the compound of formula IIIa to give retigabine.
In (i) of the above process, the compound of formula IIb is reduced to give the compound of formula IIIa.
A suitable reducing agent includes, but is not limited to lithium borohydride, sodium borohydride, potassium borohydride, sodium cyanoborohydride, lithium aluminium hydride. Preferably, the reducing agent selected is sodium borohydride.
The reaction may be carried out in the presence of a suitable solvent The suitable solvent includes, but is not limited to alcohols such as methanol, elhanol, 1-propanol, 2-propanol, l-butanol, 2-butanol, I -pentanol, I -octanol and the tike; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-buryl methyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; dimethyl formamide; dimethyl acetamide; water or mixtures thereof. Preferably the solvent selected is tetrahydrofuran-watier mixture, ethanol-water mixture.
The reaction may be carried out at a temperature in the range of about 25°C to about 100°C. The reaction is carried out for a period of about 2 hours to about 6 hours. Preferably the reaction is carried out at a temperature of about 50°C to about 60°C for a period of about 2 hours to about 4 hours.

In (ii) of the above process, the compound of formula IIIa is reduced to give retigabine.
A suitable reducing agent includes, but is not limited to sodium dithionite, zinc/hydrochloric acid, tin/hydrochloric acid, iron/hydrochloric acid, stannous chloride, stannous chloride/hydrochloric acid, ammonium formate, activated aluminium, salts of hydrogen sulfide, hydrazine hydrate/Raney nickel, hydrazine hydrate/palladium on carbon, hydrazine hydrate/platinum on carbon, zinc/calcium chloride dihydrate, zinc/ammonium chloride, alkali metal borohydride/alkali metal halide, alkaline earth metal borohydride/alkali metal halide, transition metal borohydride/alkali metal halide, alkali metal borohydride/alkaline earth metal halide, alkaline earth metal borohydride/alkaline earth metal halide, transition metal borohydride/alkaline earth metal halide, alkali metal borohydride/transition metal halide, alkaline earth metal borohydride/transition metal halide, transition metal borohydride/transition metal halide, lithium aluminium hydride, sodium cyanoborohydride, sodium triacetoxyborohydride, or reduction by catalytic hydrogenation using Raney nickel, palladium, platinum catalyst. Preferably, the reducing agent selected is sodium dithionite, zinc/calcium chloride dihydrate.
The reaction may be carried out in the presence of a suitable solvent The suitable solvent includes, but is not limited to alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1 -pentanol, 1-octanol and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyi acetate and the like; dimethyl formamide; dimethyl acetamide; water or mixtures thereof. Preferably the solvent selected is tetrahydrofuran-water mixture, ethanol-water mixture.
The reaction may be carried out at a temperature in the range of about 30°C to about 100°C. The reaction is carried out for a period of about 2 hours to about 10 hours. Preferably the reaction is carried out at a temperature of about 40°C to about 5 0°C for a period of about 2 hours to about 4 hours.
In one embodiment, the present invention provides a process for the preparation of retigabine, the process comprising (i) reducing the compound of formula IIb to give the compound of formula IIIa, (ii) isolating the compound of formula IIIa, and (iii) reducing the compound of formula IIIa to give retigabine.
In one preferred embodiment, the present invention provides a process for the preparation of retigabine, the process comprising (i) reducing the compound of formula IIb using sodium borohydride to give the compound of formula IIIa, (ii) isolating the compound of formula IIIa, and (iii) reducing the compound of formula IIIa using sodium dithionite to give retigabine.
In one preferred embodiment, the present invention provides a process for the preparation of retigabine, the process comprising (i) reducing the compound of formula lib using sodium borohydride to give the compound of formula IIIa, (ii) isolating the compound of formula Ilia, and (iii) reducing the compound of formula IIIusing zinc/calcium chloride dihydrate to give retigabine.
In one embodiment, the present invention provides a one-pot process for the preparation of retigabine, the process comprising (i) reducing the compound of formula IIb to

give the compound of formula IIIa, and (ii) reducing the compound of formula IIIa to give retigabine, wherein the compound of formula IIIa is not isolated.
In one preferred embodiment, the present invention provides a one-pot process for the preparation of retigabine, the process comprising (i) reducing the compound of formula IIb using sodium borohydride to give the compound of formula IIIa, and (ii) reducing the compound of formula IIIa using zinc/calcium chloride dihydrate to give retigabine, wherein the compound of formula IIIa is not isolated.
In (b) of the process for the preparation of retigabine, a compound of formula I, the compound of formula IIb is reduced to give retigabine comprising: (i) reducing the compound of formula IIb to give the compound of formula IIe;

(ii) reducing the imine group of the compound of formula IIe to give retigabine.
In one embodiment, the present invention provides a process for the preparation of retigabine, the process comprising (i) reducing the compound of formula IIb using sodium dithionite to give the compound of formula IIe, and (ii) reducing the compound of formula IIe using sodium borohydride to give retigabine.
The present invention provides a process for the preparation of retigabine comprising a one-step reduction of a compound of formula II,

wherein R is selected from the group consisting of-NH2, -NO2, -NH-C(=O)-OCH2CH3; R' is selected from the group consisting of -NH2 or -NO2;
provided that at least one of R and R is -NO2; the process comprising using a reducing agent selected from the group consisting of alkali metal borohydride/alkali metal halide, alkaline earth metal borohydride/alkali metal halide, transition metal borohydride/alkaii metal halide, alkali metal borohydride/alkaline earth metal halide, alkaline earth metal borohydride/alkaline earth metal halide, transition metal borohydride/alkaline earth metal halide, alkali metal borohydride/transition metal halide, alkaline earth metal borohydride/transition metal halide, tr ansition metal borohydride/transition metal halide, lithium borohydride, lithium aluminium hydride, sodium cyanoborohydride, sodium triacetoxyborohydride, zinc/calcium chloride dihydrate, sodium dithionite. The alkali metal borohydride/alkali metal halide is selected from the group consisting of sodium borohydride/lithium chloride, sodium borohydride/lithium bromide, sodium

borohydride/lithium iodide, potassium borohydride/lithium chloride, potassium borohydride/lithium bromide, potassium borohydride/lithium iodide. Preferably, sodium borohydride/lithium chloride is used.
The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes, but is not limited to alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol. l-octanol and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; dimethyl formamide; dimethyl acetamide; water or mixtures thereof. Preferably the solvent selected is tetrahydrofuran-water mixture.
The reaction may be carried out at a temperature in the range of about 30°C to about 100°C. The reaction is carried out for a period of about 2 hours to about 8 hours. Preferably the reaction is carried out at a temperature of about 50°C to about 60°C for a period of about 2 hours to about 3 hours.
In one embodiment, the present invention provides a process for the preparation of retigabine, the process comprising reducing the compound of formula II, wherein R is -NH-C(=0)-OCH2CH3 and R' is -NO2, using sodium borohydride/lithium chloride to give retigabine.
In one embodiment, the present invention provides a process for the preparation of retigabine, the process comprising reducing the compound of formula II, wherein R is either -NH2 or -N02 and R' is either -NH2 or -NO2, provided that at least one of R and R' is -NO2, using sodium borohydride/lithium chloride to form an intermediate compound of formula IV,

and converting the compound of formula IV to give retigabine.
The present invention provides a process for the preparation of retigabine comprising the step of reduction of one or more nitro groups of acompound of formula III,

wherein R is selected from the group consisting of -NH2, -NO2,-NH-C(=0)-OCH2CH3; R' is selected from the group consisting of-NH2 or -NO2;
R" is selected from the group consisting of-NH2, -NO2, -NH-CH2-(4-f1uorophenyl); provided that at least one of R, R1 and R" is -N02; wherein said reduction is carried out using sodium dithionite.
The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes, but is not limited to alcohols such as methanol, ethanol, 1 -propanol, 2-propanol, 1 -butanol,

2-butanol, 1-pentanol, 1-octano! and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; dimethyl formamide; dimethyl acetamide; water or mixtures thereof. Preferably the solvent selected is methanol-water mixture.
The reaction may be carried out at a temperature in the range of about 30oC to about 70°C. The reaction is carried out for a period of about 2 hours to about 8 hours. Preferably the reaction is carried out at a temperature of about 50°C to about 60°C for a period of about 2 hours to about 3 hours.
In one embodiment, the present invention provides a process for the preparation of retigabine, the process comprising reducing the compound of formula III, wherein R is -NH-C(=0)-OCH2CH3, R' is -NO2 and R" is -NH-CH2-(4-fluorophenyl), using sodium dithionite to give retigabine.
In one embodiment, the present invention provides a process for the preparation of retigabine, the process comprising reducing the compound of formula III, wherein R is either -NH2 or -N02, R' is either -NH2 or -N02 and R" is -NH-CH2-(4-fluorophenyl), provided that at least one of R and R1 is -N02, using sodium dithionite to form an intermediate compound of formula IV,

and converting the compound of formula IV to give retigabine.
In one embodiment, the present invention provides a process for the preparation of retigabine, the process comprising reducing the compound of formula III, wherein R is -NH-C(=O)-OCH2CH3, R' is either -NH2 or -N02 and Rn" is either -NH2 or -N02, provided that at least one of R' and R" is -N02, using sodium dithionite to form an intermediate compound of formula V,

and converting the compound of formula V to give retigabine.
The present invention provides a process for the preparation of retigabine, a compound of formula 1,

and pharmaceuticallly acceptable salts thereof, the process comprising:
(a) reducing ethyl N-(4-nitrophenyl) carbamate, a compound of formula VI, to give ethyl N-
(4-aminophenyl) carbamate, a compound of formula VII;

(b) reacting the compound of formula VII with phthalic anhydride to give ethyl N-(4-phthalimidophenyi) carbamate, a compound of formula VIII;

(c) nitrating the compound of formula VIII to give ethyl N-(2-nitro-4-phthalimidophenyl) carbamate, a compound of formula IX;

(d) reacting the compound of formula IX with hydrazine hydrate to give ethyl N-{4-amino-2-nitrophenyl) carbamate, a compound of formula IIIb;

(e) reacting the compound of formula IIIb with 4-fluorobenzaldehyde to give ethyl N-[4-(4-fluorobenzylideneamino)-2-nitrophenyl] carbamate, a compound of formula IIb;


(f) reducing the compound of formula IIb to give ethyl N-[4-(4-fluorobenzylamino)-2-nitrophenyl] carbamate, a compound of formula IIIa;

(g) reducing the nitro group of the compound of formula IIIa to give retigabine; wherein either or all of the products of steps (a), (b) and (e) are not isolated.
In (a) of the above process, the compound of formula VI is reduced to give the compound of formula VII. The reducing agent is selected from the group consisting of sodium dithionite, zinc/hydrochloric acid, tin/hydrochloric acid, iron/hydrochloric acid, stannous chloride, stannous chloride/hydrochloric acid, ammonium formate, activated aluminium, salts of hydrogen sulfide, hydrazine hydrate/Raney nickel, hydrazine hydrate/palladium on carbon, hydrazine hydrate/platinum on carbon, zinc/calcium chloride dihydrate, zinc/ammonium chloride, alkali metal borohydride/alkali metal halide, alkaline earth metal borohydride/alkali metal halide, transition metal borohydride/alkali metal halide, alkali metal borohydride/alkaline earth metal halide, alkaline earth metal borohydride/alkaline earth metal halide, transition metal borohydride/alkaline earth metal halide, alkali metal borohydride/transition metal halide, alkaline earth metal borohydride/transition metal halide, transition metal borohydride/transition metal halide, lithium aluminium hydride, sodium cyanoborohydride, sodium triacetoxyborohydride, or reduction by catalytic hydrogenation using Raney nickel, palladium, platinum catalyst. Preferably the compound of formula VI is reduced to the compound of formula VII by catalytic hydrogenation using palladium on carbon catalyst.
The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes, but is not limited to alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; dimethyl formamide; dimethyl acetamide; acetic acid; water or mixtures thereof. Preferably the solvent selected is acetic acid.

In one embodiment, the present invention provides a process for the preparation of retigabine wherein the product of step (a) is not isolated.
In (b) of the above process, the compound of formula VII is reacted with phthalic acid to give the compound of formula VIII. The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes, but is not limited to alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; dimethyl formamide; dimethyl acetamide; acetic acid; water or mixtures thereof. Preferably the solvent selected is acetic acid.
In one embodiment, the present invention provides a process for the preparation of retigabine wherein the product of step (b) is not isolated.
In one embodiment, the present invention provides a process for the preparation of retigabine wherein the products of steps (a) and (b) are not isolated.
In (c) of the above process, the compound of VIII is nitrated using concentrated nitric acid to give the compound of formula IX.
In one embodiment, the present invention provides a process for the preparation of retigabine wherein steps (a), (b) and (c) are carried out in the same reaction vessel.
In (d) of the above process, the compound of formula IX is reacted with hydrazine hydrate to give the compound of formula (IIIb). The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes, but is not limited to alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; dimethyl formamide; dimethyl acetamide; water or mixtures thereof. Preferably the solvent selected is ethyl acetate.
In (e) of the above process, the compound of formula IIIb is reacted with 4-fluorobenzaldehyde to give the compound of formula IIb. The suitable solvent includes, but is not limited to diethyl carbonate; alcohols such as methanol, ethanol, 1-propanol, isopropyl alcohol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene and the like; dimethyl sulfoxide; dimethyl formamide; dimethyl acetamide; Af-methyl-2-pyrrolidone; water or mixtures thereof. Preferably the solvent selected is isopropyl alcohol.
In one embodiment, the present invention provides a process for the preparation of retigabine wherein the product of step (e) is not isolated.
In one embodiment, the present invention provides a process for the preparation of retigabine wherein all of the products of steps (a), (b) and (e) are not isolated.

In one embodiment, the present invention provides a process for the preparation of retigabine wherein either of the products of steps (a), (b) and (e) are not isolated.
In one embodiment, the present invention provides a process for the preparation of retigabine wherein the products of steps (a) and (b) are not isolated and the product of step (e) is isolated.
In (f) of the above process, the compound of formula IIb is reduced to give the compound of formula IIIa. The reducing agent is selected from the group consisting of lithium borohydride, sodium borohydride, potassium borohydride, sodium cyanoborohydride, lithium aluminium hydride. Preferably, the reducing agent selected is sodium borohydride.
The reaction may be carried out in the presence of a suitable solvent. The suitable solvent includes, but is not limited to alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate arid the like; dimethyl formamide; dimethyl acetamide; water or mixtures thereof. Preferably the solvent selected is isopropyl alcohol.
In one embodiment, the present invention provides a process for the preparation of retigabine wherein steps (e) and (f) are carried out in the same reaction vessel.
In (g) of the above process, the compound of formula IIIa is reduced to give retigabine. The reducing agent is selected from the group consisting of sodium dithionite, zinc/hydrochloric acid, tin/hydrochloric acid, iron/hydrochloric acid, stannous chloride, stannous chloride/hydrochloric acid, ammonium formate, activated aluminium, salts of hydrogen sulfide, hydrazine hydrate/Raney nickel, hydrazine hydrate/palladium on carbon, hydrazine hydrate/platinum on carbon, zinc/calcium chloride dihydrate, zinc/ammonium chloride, alkali metal borohydride/alkali metal halide, alkaline earth metal borohydride/alkali metal halide, transition metal borohydride/alkali metal halide, alkali metal borohydride/alkaline earth metal halide, alkaline earth meta! borohydride/alkaline earth metal halide, transition metal borohydride/alkaline earth metal halide, alkali metal borohydride/transition metal halide, alkaline earth metal borohydride/transition metal halide, transition metal borohydride/transition metal halide, lithium aluminium hydride, sodium cyanoborohydride, sodium triacetoxyborohydride, or reduction by catalytic hydrogenation using Raney nickel, palladium, platinum catalyst. Preferably the compound of formula IIIa is reduced to give retigabine by catalytic hydrogenation using palladium on carbon catalyst.
The reaction may be carried out in the presence of a. suitable solvent. The suitable solvent includes, but is not limited to alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the; like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; dimethyl formamide; dimethyl acetamide; acetic acid; water or mixtures thereof. Preferably the solvent selected is ethyl acetate.

The present invention provides retigabine free of compound of formula X.

The present invention provides a polymorphic mixture of retigabine, comprising about 0.5 weight % to about 99.5 weight % of polymorph Form A of retigabine and about 99.5 weight % to about 0.5 weight % of polymorph Form B of retigabine.
In one embodiment, the present invention provides a polymorphic mixture of retigabine comprising about 90 weight % (± 5%) of polymorph Form A of retigabine and about 10 weight % (± 5%) of polymorph Form B of retigabine.
In one embodiment, the present invention provides a polymorphic mixture of retigabine comprising about 80 weight % (± 5%) of polymorph Form A of retigabine and about 20 weight % (± 5%) of polymorph Form B of retigabine.
In one embodiment, the present invention provides a polymorphic mixture of retigabine comprising about 70 weight % (± 5%) of polymorph Form A of retigabine and about 30 weight % (± 5%) of polymorph Form B of retigabine.
In one embodiment, the present invention provides a polymorphic mixture of retigabine comprising about 60 weight % (± 5%) of polymorph Form A of retigabine and about 40 weight % (± 5%) of polymorph Form B of retigabine.
In one embodiment, the present invention provides a polymorphic mixture of retigabine comprising about 50 weight % (± 5%) of polymorph Form A of retigabine and about 50 weight % (± 5%) of polymorph Form B of retigabine.
In one embodiment, the present invention provides a polymorphic mixture of retigabine comprising about 40 weight % (± 5%) of polymorph Form A of retigabine and about 60 weight % (± 5%) of polymorph Form B of retigabine.
In one embodiment, the present invention provides a polymorphic mixture of retigabine comprising about 30 weight % (± 5%) of polymorph Form A of retigabine and about 70 weight % (± 5%) of polymorph Form B of retigabine.

In one embodiment, the present invention provides a polymorphic mixture of retigabine comprising about 20 weight % (± 5%) of polymorph Form A of retigabine and about 80 weight % (± 5%) of polymorph Form B of retigabine.
In one embodiment, the present invention provides a polymorphic mixture of retigabine comprising about 10 weight % (± 5%) of polymorph Form A of retigabine and about 90 weight % (± 5%) of polymorph Form B of retigabine.
In one embodiment, the present invention provides polymorphic form B of retigabine with a small amount of polymorphic form A.
In one embodiment, the present invention provides a polymorphic mixture of retigabine with polymorphic form B of retigabine is in major amount and polymorphic form A of retigabine is in minor amount.
The present invention provides a polymorphic mixture of retigabine, comprising about 0.5 weight % to about 99.5 weight % of polymorph Form B of retigabine and about 99.5 weight % to about 0.5 weight % of polymorph Form C of retigabine.
In one embodiment, the present invention provides a polymorphic mixture of retigabine comprising about 90 weight % (± 5%) of polymorph Form B of retigabine and about 10 weight % (± 5%) of polymorph Form C of retigabine.
In one embodiment, the present invention provides a polymorphic mixture of retigabine comprising about 80 weight % (± 5%) of polymorph Form B of retigabine and about 20 weight % (± 5%) of polymorph Form C of retigabine.
In one embodiment, the present invention provides a polymorphic mixture of retigabine comprising about 70 weight % (± 5%) of polymorph Form B of retigabine and about 30 weight % (± 5%) of polymorph Form C of retigabine.
In one embodiment, the present invention provides a polymorphic mixture of retigabine comprising about 60 weight % (± 5%) of polymorph Form B of retigabine and about 40 weight % (± 5%) of polymorph Form C of retigabine.
In one embodiment, the present invention provides a polymorphic mixture of retigabine comprising about 50 weight % (± 5%) of polymorph Form B of retigabine and about 50 weight % (± 5%) of polymorph Form C of retigabine.
In one embodiment, the present invention provides a polymorphic mixture of retigabine comprising about 40 weight % (± 5%) of polymorph Form B of retigabine and about 60 weight % (± 5%) of polymorph Form C of retigabine,
In one embodiment, the present invention provides a polymorphic mixture of retigabine comprising about 30 weight % (± 5%) of polymorph Form B of retigabine and about 70 weight % (± 5%) of polymorph Form C of retigabine.

In one embodiment, the present invention provides a polymorphic mixture of retigabine comprising about 20 weight % (± 5%) of polymorph Form B of retigabine and about 80 weight % (± 5%) of polymorph Form C of retigabine,
In one embodiment, the present invention provides a polymorphic mixture of retigabine comprising about 10 weight % (± 5%) of polymorph Form B of retigabine and about 90 weight % (± 5%) of polymorph Form C of retigabine.
In one embodiment, the present invention provides a polymorphic mixture of retigabine comprising about 2 weight % (± 0.5%) of polymorph Form B of retigabine and about 98 weight % (± 0.5%) of polymorph Form C of retigabine.
The present invention provides a polymorphic mixture of retigabine, comprising about 0.5 weight % to about 99.5 weight % of polymorph Form A of retigabine and about 99.5 weight % to about 0.5 weight % of polymorph Form C of retigabine.
In one embodiment, the present invention provides a polymorphic mixture of retigabine comprising about 90 weight % (± 5%) of polymorph Form A of retigabine and about 10 weight % (± 5%) of polymorph Form C of retigabine.
In one embodiment, the present invention provides a polymorphic mixture of retigabine comprising about 80 weight % (± 5%) of polymorph Form A of retigabine and about 20 weight % (± 5%) of polymorph Form C of retigabine.
In one embodiment, the present invention provides a polymorphic mixture of retigabine comprising about 70 weight % (± 5%) of polymorph Form A of retigabine and about 30 weight % (± 5%) of polymorph Form C of retigabine.
In one embodiment, the present invention provides a polymorphic mixture of retigabine comprising about 60 weight % (± 5%) of polymorph Form A of retigabine and about 40 weight % (± 5%) of polymorph Form C of retigabine.
In one embodiment, the present invention provides a polymorphic mixture of retigabine comprising about 50 weight % (± 5%) of polymorph Form A of retigabine and about 50 weight % (± 5%) of polymorph Form C of retigabine.
In one embodiment, the present invention provides a polymorphic mixture of retigabine comprising about 40 weight % (± 5%) of polymorph Form A of retigabine and about 60 weight % (± 5%) of polymorph Form C of retigabine.
In one embodiment, the present invention provides a polymorphic mixture of retigabine comprising about 30 weight % (± 5%) of polymorph Form A of retigabine and about 70 weight % (± 5%) of polymorph Form C of retigabine.
In one embodiment, the present invention provides a polymorphic mixture of retigabine comprising about 20 weight % (± 5%) of polymorph Form A of retigabine and about 80 weight % (± 5%) of polymorph Form C of retigabine.

In one embodiment, the present invention provides a polymorphic mixture of retigabine comprising about 10 weight % (± 5%) of polymorph Form A of retigabine and about 90 weight % (± 5%) of polymorph Form C of retigabine.
The present invention provides a process for the preparation of a polymorphic mixture of Form A and Form B of retigabine, the process comprising recrystallizing retigabine in a solvent selected from the group consisting of alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol, ethylene glycol and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone and methyl isobutyl ketone and the like; hydrocarbons such as hexane, heptane, cyclohexane, toluene, xylene; acetic acid; water or mixtures thereof. Preferably the solvent selected is ethyl acetate-cyclo hexane mixture.
The present invention provides a process for the preparation of a polymorphic mixture of Form B and Form C of retigabine, the process comprising recrystallizing retigabine in a solvent selected from the group consisting of alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanoi, I-penlanoi, I-octanoI, ethylene glycol and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone and methyl isobutyl ketone and the like; hydrocarbons such as hexane, heptane, cyclohexane, toluene, xylene; acetic acid; water or mixtures thereof. Preferably the solvent selected is ethyl acetate-heptane mixture, ethanol-isopropyl alcohol mixture, methanol-water mixture.
The present invention provides a process for the preparation of a polymorphic mixture of Form A and Form C of retigabine, the process comprising recrystallizing retigabine in a solvent selected from the group consisting of alcohols such as methanol, ethanol, i-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol, ethylene glycol and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone and methyl isobutyl ketone and the like; hydrocarbons such as hexane, heptane, cyclohexane, toluene, xylene; acetic acid; water or mixtures thereof.
The present invention provides retigabine having 90% of particles with particle size less than 200 μm, 50% of particles with particle size less than lOOμm and 10% of particles with particle size less than 50μm. Preferably, 90% of particles have particle size less than lOOum, more preferably less than 50um. Preferably, 50% of particles have particle size less than 50um. Preferably, 10% of particles have particle size less than 25 μm.
The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.

EXAMPLES
EXAMPLE 1 Preparation of 2-amino-5-(4-fluorobenzylideneamino)nitrobenzene
4-Fluorobenzaldehyde (23g) was slowly added to a stirred solution of 1,4-diamino-2-
nitrobenzene (25g) in methanol (200mL). The reaction mixture was stirred for about 5h at
about room temperature and then water (l00mL) was added to the reaction mixture. The
reaction mixture was cooled to about 10°C to about 15°C and was stirred for about 2h at
about the same temperature. The solid obtained was filtered and dried under vacuum at about
45°C to about 50°C. Yield: 40g
EXAMPLE 2 Preparation of ethyl N-[4(4-fluorobenzylideneamino)-2-nitrophenyl]
carbamate
To a stirred mixture of 2-amino-5-(4-fluorobenzylideneamino)nitrobenzene (30g) prepared as
in Example 1, and diethyl carbonate (420mL) was added sodium ethoxide (78.74g) and the
reaction mixture was stirred for about 2h at about 60°C to about 65°C. The reaction mixture
was concentrated under vacuum at about 50°C to about 55°C to give a residue. Water was
added to the residue and the mixture was stirred at about room temperature. The solid
obtained was filtered and dried under vacuum.
EXAMPLE 3 Preparation of ethyl N'-[4-(4-fluorobenzylideneamino)-2-nitrophenyl|
carbamate
4-Fluorobenzaldehyde (9.72g) was slowly added to a stirred mixture of l,4-diamino-2-
nitrobenzene (10g) in diethyl carbonate (70mL) and the reaction mixture was stirred for
about 3h at about 50°C to about 55°C. The reaction mixture was cooled to about room
temperature and sodium ethoxide (35.36g) and diethyl carbonate (70mL) was added to the
reaction mixture. The reaction mixture was stirred for about 2h at about 50°C to about 55°C.
The reaction mixture was concentrated under vacuum at about 50°C to about 60°C to give a
residue. Water was added to the residue and the mixture was stirred for about lh at about
room temperature. The solid obtained was filtered and dried under vacuum at about 45°C to
about 50°C for about 12h to give a dark brown solid (15g).
EXAMPLE 4 Preparation of ethyl N-[4-(4-fluorobenzylamino)-2-nitrophenyl|
carbamate
Sodium borohydride (I6g) was added to a solution of ethyl N-[4-(4-fluorobenzylideneamino)-2-
nitrophenyl] carbamate (20g) prepared as in Example 3, in ethanol (160mL) and water (40mL).
The reaction mixture was stirred for about 2h at about 65°C to about 70°C and water (200mL)
was added to it. The reaction mixture was stirred for about lh at 60°C to about 70°C. The
reaction mixture was cooled to about 10°C to about 15°C and was stirred for about lh at about
the same temperature. The solid obtained was filtered, washed with water (l00mL) and dried
under vacuum at about 50°C to about 55°C for about 12h to give a brown solid (17g),

EXAMPLE 5 Preparation of retigabine
Zinc dust (9.81 g) and calcium chloride dihydrate (22.05g) was added to a solution of ethyl N-[4-(4-fluorobenzylamino)-2-nitrophenyl] carbamate (l0g) prepared as in Example 4, in ethanol (l00mL) and water (25mL). The reaction mixture was stirred for about 2h at about 70°C to about 75°C. The reaction mixture was filtered over Hyflo bed. The filtrate was concentrated under vacuum at about 50°C to about 55°C to give a residue which was crystallized from isopropyl alcohol and ethyl acetate to give retigabine (6g). EXAMPLE 6 Preparation of retigabine
Sodium borohydride (1.86g) was added to a solution of ethyl Af-[4-(4-fluorobenzylideneamino)-2-nitrophenyl] carbamate (6.5g) prepared as in Example 3, in ethanol (39mL) and water (26mL) and the reaction mixture was stirred for about 2h at about 65 °C to about 70°C. Zinc dust (6.4g) and calcium chloride dihydrate (14.4g) was added to the reaction mixture. The reaction mixture was stirred for about 2h at about 70°C to about 75°C and was filtered over Hyflo bed. The filtrate was concentrated under vacuum at about 50°C to about 55°C to give a residue which was crystallized from isopropyl alcohol and ethyl acetate to give retigabine (6g). EXAMPLE 7 Preparation of retigabine
Sodium borohydride (0.45g) was added to a solution of ethyl N-[4-{4-fJuorobenzylideneamino)-2-nitrophenyl] carbamate (l.0g) prepared as in Example 2, in tetrahydrofuran (7mL) and water (5mL) and the reaction mixture was stirred for about 2h at about 50°C to about 55°C. Zinc dust (0.98g) and calcium chloride dihydrate (2.2g) was added to the reaction mixture. The reaction mixture was stirred for about 12h at about 75°C to about 80°C and was filtered over Hyflo bed. The filtrate was concentrated under vacuum at about 50°C to about 55°C to give a residue which was crystallized from ethyl acetate to give retigabine (0.8g). EXAMPLE 8 Preparation of retigabine
Sodium borohydride (2g) was added to a solution of ethyl N-[4-(4-fluorobenzylideneamino)-2-nitrophenyl] carbamate (5.0g) prepared as in Example 2, in tetrahydrofuran (15mL) and water (l5mL) and the reaction mixture was stirred for about 2h at about 70°C to about 80°C. Sodium borohydride (2g) and lithium chloride (0.2g) was added to the reaction mixture and stirred at about 70°C to about 80°C for about 30min. The reaction mixture was concentrated to give a residue. Water (50mL) was added to the residue and the mixture was stirred for about 2h at about room temperature. The solid obtained was filtered and dried under vacuum to give retigabine (3g). EXAMPLE 9 Preparation of retigabine
Sodium dithionite (83.56g) was added to a solution of ethyl N-[4-{4-fluorobenzylamino)-2-nitrophenyl] carbamate (32.0g) prepared as in Example 4, in methanol (160mL) and water (160mL) and the reaction mixture was stirred for about 2h at about 50°C to about 60°C. The reaction mixture was cooled to about room temperature and water (224mL) and dichloromethane (160mL) was added to it. The reaction mixture was stirred for about 30min at about room temperature and the

two layers were separated. The aqueous layer was extracted thrice with dichloromethane. The combined organic layer was washed thrice with water, treated with Norrit charcoal and filtered over Hyflo bed. The Hyflo bed was washed with dichloromethane. The combined filtrate and washings were collected together and concentrated under vacuum at about 50°C to about 60°C to give crude retigabine (16g). The crude retigabine was dissolved in a mixture of isopropyl alcohol and ethyl acetate and the mixture was heated at about 80°C to about 85°C under stirring to get a clear solution. The solution was gradually cooled to about room temperature and stirred for about 2h at about room temperature. The solid obtained was filtered under vacuum and dried at about 50°C to about 55°C to give retigabine. Yield: 6.8g; Purity (HPLC): >99% EXAMPLE 10
Retigabine (0.5g) was dissolved in ethyl acetate (2mL) at about 70°C to about 75°C to give a clear solution which was then added to cyclohexane (5mL) at about room temperature. The mixture was stirred for about 30min at about room temperature and the solid obtained was filtered. Yield: 0.4g; PXRD2θ values: 4.96,6.97, 15.01, 19.17, 19.55±0.2° EXAMPLE 11
Retigabine (0.5g) was dissolved in ethyl acetate (2mL) at about 70°C to about 75°C to give a clear solution which was then added to heptane (5mL) at about room temperature. The mixture was stirred for about 30min at about room temperature and the solid obtained was filtered. Yield: 0.45g;PXRD2θ values: 4.84,5.0,9.72, 15.06, 15.31,19.24, 19.53,21.76±0.2° EXAMPLE 12
Retigabine (0.5g) was dissolved in isopropyl alcohol (2mL) at about 70°C to about 80°C to give a clear solution and acetic acid (4mL) was added to it at about the same temperature. The solution was then gradually cooled to about room temperature and water was added to the clear solution at about room temperature. The mixture was stirred for about 30min at about room temperature and the solid obtained was filtered. Yield: 0.45g EXAMPLE 13 Preparation of ethyl N-(4-nitrophenyl) carbamate To a stirred suspension of 4-nitroaniline (lOOg) in THF (500mL), diisopropylethylamine (187.07g) was added at about room temperature. The reaction mixture was cooled to about 10°C to about 15°C and ethyl chloroformate (156.89g) was slowly added to it. The reaction mixture was stirred at about 10°C to about 15°C for about lh and at about room temperature for about 6h. The reaction mixture was concentrated under vacuum at about 45°C to about 50°C to give a residue. Water was added to the residue and the mixture was stirred for about lh at about room temperature. The solid obtained was filtered, washed with water and dried under vacuum at about 50°C to about 55°C. Yield: 150.6g; Purity (HPLC): >99 % EXAMPLE 14 Preparation of ethyl N-(2-nitro-4-phthalimidophenyl) carbamate To a solution of ethyl N-(4-nitrophenyl) carbamate (150g) in acetic acid (750mL) was added 10% palladium on carbon (6g). The reaction mixture was hydrogenated under hydrogen pressure

of about 3 kg/cm2 to about 4 kg/cm2 at about 25°C to about 50°C for about 5h to about lOh. The reaction mixture was filtered through a Hyflo bed to remove the catalyst and the Hyflo bed was washed with acetic acid. Phthalic anhydride (126.8g) was added to the filtrate and the reaction mixture was stirred at about 90°C to about 100°C for about 2h to about 5h. The reaction mixture was cooled to about room temperature and concentrated nitric acid (75mL) was added to it. The reaction mixture was stirred at about 90°C to about 100°C for about 6h. The reaction mixture was cooled to about 10°C to about 15°C and stirred for about lh at the same temperature. The solid obtained was filtered, washed with water and dried. Yield: 173g; Purity (HPLC): >98% EXAMPLE 15 Preparation of ethyl N-(4-amino-2-nitrophenyi) carbamate To a solution of ethyl N-(2-nitro-4-phthalimidophenyl) carbamate (60g) prepared as in Example
14, in ethyl acetate (600mL) was added hydrazine hydrate (12.95g). The reaction mixture was
heated to about 70°C to about 80°C and stirred for about 2h to about 4h at the same temperature.
The reaction mixture was cooled to about room temperature and stirred for about lh. The
reaction mixture was filtered through a Hyflo bed and the Hyflo bed was washed with ethyl
acetate. The filtrate and the washings were collected together and concentrated under vacuum at
about 50°C to about 55°C to give a residue. To the residue, water was added and the mixture was
stirred for about lh at about room temperature. The solid obtained was filtered and washed with
water. The solid was dissolved in toluene at about 80°C to about 90°C and the solution was
stirred for about lh at the same temperature. The hot solution was filtered through a Hyflo bed
and the Hyflo bed was washed with toluene. The filtrate and the washings were collected
together and concentrated under vacuum at about 60°C to about 70°C to give a residue. To the
residue, water was added and the mixture was stirred for about lh at about room temperature.
The solid obtained was filtered, washed with water and dried. Yield: 40g; Purity (HPLC): >97%
EXAMPLE 16 Preparation of ethyl N-[4-(4-fluorobenzylamino)-2-nitrophenyl]
carbamate
To a suspension of ethyl N-(4-amino-2-nitrophenyl) carbamate (35g) prepared as in Example
15, in isopropyl alcohol (350mL) was added 4-fluorobenzaldehyde (23.12g) at about room
temperature and the reaction mixture was stirred for about 5h. Sodium borohydride (23.62g)
was then added to the reaction mixture and stirred for about lOmin. Aqueous hydrochloric acid
(135mL) was slowly added and stirred for about 2h to about 5h at about room temperature.
Water was then added to the reaction mixture and the solid obtained was stirred for about lh at
about room temperature. The solid was filtered, washed with water and dried. Yield: 40g
EXAMPLE 17 Preparation of ethyl N-[4-(4-fluorobenzylideneamino}-2-nitrophenyl]
carbamate
To a suspension of ethyl N-(4-amino-2-nitrophenyl) carbamate (35g) prepared as in Example 15, in isopropyl alcohol (350mL) was added 4-fluorobenzaldehyde (23.12g) at about room temperature and the reaction mixture was stirred for about 5h. Water was added to the

reaction mixture and the solid obtained was stirred for about Ih at about room temperature.
The solid was filtered, washed with water and dried. Yield: 45g
EXAMPLE 18 Preparation of ethyl N-[4-(4-fluorobenzylamino)-2-nitrophenyl|
carbamate
To a solution of ethyl N-[4-(4-fluorobenzylideneamino)-2-nitrophenyl] carbamate (45g) prepared as in example 17, in isopropylalchol was added sodium borohydride (23.62g) and the reaction mixture was stirred for about lOmin. Aqueous hydrochloric acid (135mL) was slowly added and stirred for about 2h to about 5h at about room temperature. Water was then added to the reaction mixture and the solid obtained was stirred for about lh at about room temperature. The solid was filtered, washed with water and dried. Yield: 38g EXAMPLE 19 Preparation of retigabine
To a solution of ethyl N-[4-(4-fluorobenzylamino)-2-nitrophenyl] carbamate (30g) prepared as in Example 16, in ethyl acetate (150mL) was added 10% palladium on carbon (1.5g). The reaction mixture was hydrogenated under hydrogen pressure at about 2 kg/cm2 to about 3 kg/cm2 for about 5h. The reaction mixture was filtered and washed with ethyl acetate. The filtrate and the washings were collected together and concentrated under vacuum at about 45°C to about 50°C to give a residue. The residue was dissolved in acetone at about room temperature to give a clear solution and water was added slowly to the solution. The solid obtained was stirred for lh at about room temperature. The solid was filtered, washed with water and dried. Yield: 22.6g EXAMPLE 20
Retigabine (lOg) was dissolved in a mixture of ethanol and isopropyl alcohol (25:75) at about 80°C to about 85°C to give a clear solution and the clear solution was stirred for about 30min. The solution was gradually cooled to about room temperature and then stirred for about lh at the same temperature. The solid obtained was filtered, washed with a mixture of ethanol and IPA (25:75) and dried to give polymorphic mixture of retigabine Form B+C. EXAMPLE 21
Retigabine (2g) was dissolved in a mixture of ethyl acetate and heptane (50:50) at about 70°C to about 80°C to give a clear solution and the clear solution was stirred for about 15min. The solution was gradually cooled to about room temperature and then stirred for about lh at the same temperature. The solid obtained was filtered, washed with a mixture of ethyl acetate and heptane (50:50) and dried to give polymorphic mixture of retigabine Form B+C. EXAMPLE 22
Retigabine (3g) was dissolved in methanol (7mL) at about 60°C to about 65 °C to give a clear solution. Water (9mL) was added to the clear solution and the temperature was raised to about 70°C to about 80°C. The solution was gradually cooled to about 50°C to about 55°C and water (36mL) was added to it. The solution was cooled to about room temperature and the solid obtained was filtered, washed with water and dried to give polymorphic mixture of retigabine Form B+C.

WE CLAIM
1. A process for the preparation of retigabine, a compound of formula 1,

and pharmaceuticaliy acceptable salts thereof, the process comprising:
(a) reducing ethyl N-(4-nitrophenyl) carbamate, a compound of formula VI,

to give ethyl N-(4-aminophenyl) carbamate, a compound of formula VII;

(b) reacting the compound of formula VII with phthalic anhydride to give ethyl JV-(4-phthalimidophenyl) carbamate, a compound of formula VIII;

(c) nitrating the compound of formula VIII to give ethyl N-(2-nitro-4-phthalimidophenyl) carbamate, a compound of formula IX;


(d) reacting the compound of formula IX with hydrazine hydrate to give ethyl jV-(4-amino-2-nitrophenyl) carbamate, a compound of formula IIIb;

(e) reacting the compound of formula Mb with 4-fluorobenzaldehyde to give ethyl N-[4-(4-fluorobenzylideneamino)-2-nitrophenyl] carbamate, a compound of formula IIb;

(f) reducing the compound of formula lib to give ethyl iV-[4-{4-fluorobenzylamino)-2-nitrophenyl] carbamate, a compound of formula IIIa;

(g) reducing the nitro group of the compound of formula Ilia to give retigabine; wherein either or all of the products of steps (a), (b) and (e) are not isolated.
2. The process as claimed in claim 1, wherein in (a), comprising reduction by catalytic
hydrogenation using palladium on carbon catalyst.

3. The process as claimed in claim 1, wherein in (c), comprising nitration using concentrated nitric acid.
4. The process as claimed in claim 1, wherein in (f), comprising adding a reducing agent selected from the group consisting of lithium borohydride, sodium borohydride, potassium borohydride, sodium cyanoborohydride, lithium aluminium hydride.
5. The process as claimed in claim 1, wherein in (g), comprising reduction by catalytic hydrogenation using palladium on carbon catalyst.
6. The process as claimed in claim 1, wherein all of the products of steps (a), (b) and (e) are not isolated.
7. The process as claimed in claim 1, wherein the products of steps (a) and (b) are not isolated and the product of step (e) is isolated.