Claims:We Claim:
1. An improved process for the preparation of Retigabine or its pharmaceutically acceptable salts, which comprises:
a) reacting compound of Formula III

Formula III
wherein R1 represents hydrogen (or) N-protecting group, R2 represents C1-6 alkyl, with sodium nitrate in the presence of an acid and optionally in a solvent to give compound of Formula IV,

Formula IV
wherein R1 and R2 are as defined above,
b) optionally deprotecting compound of Formula IV, when R1 represents a suitable N-protecting group, and
c) converting compound of Formula IV to Retigabine or its pharmaceutically acceptable salts.

2. An improved process as claimed in claim 1, further comprises wherein:
a) the compound of Formula IV is reacted with 4-fluoro benzaldehyde optionally in the presence of a base, followed by reducing with a suitable reducing agent to give compound of Formula V

Formula V
wherein R1 and R2 are as define above,
b) reducing compound of Formula V with a suitable reducing agent to give compound of Formula VI, and

Formula VI
wherein R1 and R2 are as define above, and
c) optionally deprotecting compound of Formula VI, when R1 represents a suitable protecting group to give Retigabine or its pharmaceutically acceptable salts.

3. An improved process for the preparation of compound of Formula IV, which comprises:
a) reacting compound of Formula III

Formula III
wherein R1 represents hydrogen (or) N-protecting group, R2 represents C1-6 alkyl, with sodium nitrate in the presence of an acid and optionally in a solvent to give compound of Formula IV,

Formula IV
wherein R1 and R2 are as defined above, and
b) optionally deprotecting compound of Formula IV, when R1 represents a suitable N-protecting group.

4. An improved process for the preparation of compound of Formula IV, which comprises:
a) reducing compound of Formula II

Formula II
wherein R2 represents C1-6 alkyl, in the presence of a suitable reducing agent to give compound of Formula III

Formula III
wherein R1 represents hydrogen (or) N-protecting group, R2 represents C1-6 alkyl,
b) reacting compound of Formula III

Formula III
wherein R1 and R2 are as defined above, with sodium nitrate in the presence of an acid and optionally in a solvent to give compound of Formula IV,

Formula IV
wherein R1 and R2 are as defined above, and
c) optionally deprotecting compound of Formula IV, when R1 represents a suitable N-protecting group.

5. An improved process for the preparation of Retigabine or its pharmaceutically acceptable salts, which comprises:
a) reducing compound of Formula II

Formula II
wherein R2 represents C1-6 alkyl, in the presence of a suitable reducing agent to give compound of Formula III

Formula III
wherein R1 represents hydrogen (or) N-protecting group, R2 represents C1-6 alkyl,
b) reacting compound of Formula III

Formula III
wherein R1 and R2 are as defined above, with sodium nitrate in the presence of an acid and optionally in a solvent to give compound of Formula IV,

Formula IV
wherein R1 and R2 are as defined above,
c) optionally deprotecting compound of Formula IV, when R1 represents a suitable N-protecting group,
d) reacting compound of Formula IV with 4-fluoro benzaldehyde optionally in the presence of a base, followed by reducing with a suitable reducing agent to give compound of Formula V

Formula V
wherein R1 and R2 are as define above,
e) reducing compound of Formula V with a suitable reducing agent to give compound of Formula VI, and

Formula VI
f) optionally deprotecting compound of Formula VI, when R1 represents a suitable protecting group to give Retigabine or its pharmaceutically acceptable salts.

6. An improved process for the preparation of compound of Formula IVA

Formula IVA

which comprises:
a) dissolving compound of Formula IIIA

Formula IIIA

in H2SO4,
b) cooling the reaction mass of step a) to -10 to 10ºC,
c) adding NaNO3 to the reaction mass of step b),
d) adjusting the pH of the reaction mass to 12-15 using a base, and
e) isolating compound of Formula IVA.

7. The process as claimed in any of the proceeding claims, wherein the acid is selected from hydrochloric, hydrobromic, sulfuric, phosphoric, oxalic, maleic, succinic, citric, acetic and p-toluenesulfonic acid.

8. The process as claimed in any of the proceeding claims, wherein R1 represents hydrogen (or) N-protecting group, N-protecting group is selected from Carbobenzyloxy (Cbz), tert-Butyloxycarbonyl (BOC), p-Methoxybenzyl carbonyl (Moz or MeOZ), 9-Fluorenylmethyloxycarbonyl (FMOC), Acetyl (Ac), Benzoyl (Bz), Benzyl (Bn), benzyl Carbamate, p-Methoxybenzyl (PMB), 3,4-Dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), Tosyl (Ts), sulfonamides. Preferably R1 represents hydrogen and R2 represents ethyl group.

9. The process as claimed in any of the proceeding claims, wherein the base is selected from either inorganic base like alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; Alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof; Alkali metal halide such as halides of Lithium, Sodium, Potassium, Rubidium, and Caesium. Alkaline earth metal halide is selected from halides of Beryllium, Magnesium, Calcium, Strontium, Barium, and Radium, nitrogen containing bases including ammonia, primary, secondary, tertiary amines.

10. The process as claimed in any of the proceeding claims, wherein the solvent is selected from water or "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol and the like or "hydrocarbon solvents" such as benzene, toluene, xylene, heptane, hexane and cyclohexane and the like or "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like or "esters solvents" such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, and the like or "nitrile solvents" such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile and the like or "ether solvents" such as di-tert-butylether, dimethylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 2-methoxyethanol and dimethoxyethane, or “Amide solvents” such as formamide, DMF, DMAC, N-methyl-2-pyrrolidone, N-methylformamide, 2-pyrrolidone, 1-ethenyl-2-pyrrolidone, haloalkanes such as dichloromethane, 1,2-dichloroethane and chloroform, “Amine solvents” selected from diethylenetriamine, ethylenediamine, morpholine, piperidine, pyridine, quinoline, tributylamine, diisopropyl amine and/or mixtures thereof.

11. The process as claimed in any of the proceeding claims, wherein the reducing agent is selected from Pd/C, Fe, Raney nickel, palladium hydroxide, platinum catalyst, rhodium, and ruthenium or hydride, diborane, NaBH4, LiBH4, NaCNBH3, sodium triacetoxyborohydride, hydrazine and its hydrates.

Dated this Ninth (9th) day of June 2016.
__________________________________
Dr. S. Padmaja
Agent for the Applicant
IN/PA/883 , Description:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&

THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

AN IMPROVED PROCESS FOR PREPARING ANTICONVULSANT AND ITS INTERMEDIATES

We, SUVEN LIFE SCIENCES LIMITED,
a company incorporated under the companies act, 1956 having address at 5th floor, Serene Chamber, Road No.5, Off Avenue No. 7, Banjara Hills, Hyderabad 500 034, Telangana State, India

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 an improved process for the preparation of an anticonvulsant compound.
The present invention particularly relates to an improved process for the preparation of Retigabine or its pharmaceutically acceptable salts.
The present invention further relates to an improved process for the preparation of Retigabine intermediates.
The present invention more particularly relates to an improved process for the preparation of Retigabine intermediates which is commercially feasible.

BACKGROUND OF THE INVENTION
Retigabine, or its USAN name Ezogabine is an Antiepileptic drug which is approved for the treatment of partial-onset seizures in patients aged 18 years and older. Ezogabine is approved by USFDA on Jun 10, 2011 which is marketed by GlaxoSmithKline under the brand name POTIGA®. The chemical name of Ezogabine is N-[2-amino-4-(4-fluorobenzylamino)-phenyl]carbamic acid ethyl ester, and it has the following structure:

Formula I

Retigabine is disclosed in US 5,384,330 and EP 0554 543. US 5,384,330 discloses a process for preparing Retigabine (D-23129). The process disclosed in US ‘330 is represented in the scheme given below:

Scheme I:

US ‘330 further discloses a process for preparing Retigabine intermediates which is shown in the scheme given below:
Scheme II:

The process disclosed in US ‘330 for Retigabine and its intermediates cannot be applied for industrial scale as this process involves more number of steps, the purity and yield of the resulted products are very low, the process enabled in US ‘330 suffers with the side reactions.

US 2014/0163252 A1 discloses a process for preparing Retigabine and its intermediates which is shown in the schemes given below:

Scheme III:

The process enabled in US ‘252 cannot be applied for industrial scale as the yield of the Retigabine intermediates formed in steps a & b accounts only 60-65% which is not suitable for industrial scale up.

There is consequently a need for a more advantageous alternative method of preparing Retigabine and its intermediates. Said novel method should in particular be simpler and involves less number of steps, more industrially scalable, involve the use of cheaper reagents, employ mild reaction conditions, and at the same time provide Retigabine and its intermediates with high yields, high chemical purity and efficiency.

The present inventors have surprisingly found an improved process for preparing Retigabine and its intermediates, which involves less number of steps, more industrially scalable with high yields.

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide an improved process for the preparation of Retigabine and its intermediates.

The preferred objective of the present invention is to provide an improved process for the preparation of Retigabine or its pharmaceutically acceptable salts, which is commercially feasible.
Another preferred objective of the present invention is to provide an improved process for the preparation of Retigabine intermediates, which is commercially feasible.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of Retigabine or its pharmaceutically acceptable salts, which comprises:
a) reacting compound of Formula III

Formula III
wherein R1 represents hydrogen (or) N-protecting group, R2 represents C1-6 alkyl, with sodium nitrate in the presence of an acid and optionally in a solvent to give compound of Formula IV,

Formula IV
wherein R1 and R2 are as defined above,
b) optionally deprotecting compound of Formula IV, when R1 represents a suitable N-protecting group, and
c) converting compound of Formula IV to Retigabine or its pharmaceutically acceptable salts.

In another preferred aspect, the present invention provides an improved process for the preparation of compound of Formula IV, which comprises:
a) reacting compound of Formula III

Formula III
wherein R1 represents hydrogen (or) N-protecting group, R2 represents C1-6 alkyl, with sodium nitrate in the presence of an acid and optionally in a solvent to give compound of Formula IV,

Formula IV
wherein R1 and R2 are as defined above,
b) optionally deprotecting compound of Formula IV, when R1 represents a suitable N-protecting group.

In yet another preferred aspect, the present invention provides an improved process for the preparation of compound of Formula IV, which comprises:
a) reducing compound of Formula II

Formula II
wherein R2 represents C1-6 alkyl, in the presence of a suitable reducing agent to give compound of Formula III

Formula III
wherein R1 represents hydrogen (or) N-protecting group, R2 represents C1-6 alkyl,
b) reacting compound of Formula III

Formula III
wherein R1 and R2 are as defined above, with sodium nitrate in the presence of an acid and optionally in a solvent to give compound of Formula IV,

Formula IV
wherein R1 and R2 are as defined above,
c) optionally deprotecting compound of Formula IV, when R1 represents a suitable N-protecting group.

In yet another preferred aspect, the present invention provides an improved process for the preparation of Retigabine or its pharmaceutically acceptable salts, which comprises:
a) reducing compound of Formula II

Formula II
wherein R2 represents C1-6 alkyl, in the presence of a suitable reducing agent to give compound of Formula III

Formula III
wherein R1 represents hydrogen (or) N-protecting group, R2 represents C1-6 alkyl,
b) reacting compound of Formula III

Formula III
wherein R1 and R2 are as defined above, with sodium nitrate in the presence of an acid and optionally in a solvent to give compound of Formula IV,

Formula IV
wherein R1 and R2 are as defined above,
c) optionally deprotecting compound of Formula IV, when R1 represents a suitable N-protecting group,
d) reacting compound of Formula IV with 4-fluoro benzaldehyde optionally in the presence of a base, followed by reducing with a suitable reducing agent to give compound of Formula V

Formula V
wherein R1 and R2 are as define above,
e) reducing compound of Formula V with a suitable reducing agent to give compound of Formula VI, and

Formula VI
f) optionally deprotecting compound of Formula VI, when R1 represents a suitable protecting group to give Retigabine or its pharmaceutically acceptable salts.

In a still another preferred aspect, the present invention provides an improved process for the preparation of compound of Formula IVA,

Formula IVA
which comprises:
a) providing a solution of compound of Formula IIIA

Formula IIIA
with H2SO4,
b) cooling the reaction mass of step a) to -10 to 10ºC,
c) adding NaNO3 to the reaction mass of step b),
d) adjusting the pH of the reaction mass to 12-15 using a base, and
e) isolating compound of Formula IVA.

DETAILED DESCRIPTION OF THE INVENTION
Accordingly the present invention provides an improved process for preparing Retigabine or its pharmaceutically acceptable salts.

The present invention further provides an improved process for preparing Retigabine intermediates.

In a preferred embodiment, the present invention provides an improved process for the preparation of Retigabine or its pharmaceutically acceptable salts, which is commercially feasible, does not involve any side reactions, and contains fewer impurities.

In another preferred embodiment, R1 represents hydrogen and R2 represents ethyl group, wherein compound of Formula II is reduced using a suitable reducing agent preferably palladium in an alcohol solvent or Fe powder/NH4Cl to give compound of Formula III.

In yet another preferred embodiment, R1 represents N-protecting group and R2 represents ethyl group, wherein compound of Formula II is reduced using a suitable reducing agent preferably palladium in an alcohol solvent or Fe powder/NH4Cl followed by protection to give compound of Formula III.

The present inventors have developed an improved process for preparing compound of Formula IV which yields more than 86% with a purity of 98.5%, wherein the process enabled in the prior art such as US 2014/0163252 A1 yields only 60% which cannot be used for industrial scale up.

The present inventors have developed an improved process for preparing compound of Formula III which yields more than 99% with a purity of 99.8%, wherein the process enabled in the prior art such as US 2014/0163252 A1 yields only 65% which cannot be used for industrial scale up.

In still another preferred embodiment, compound of Formula IV is prepared by nitrating compound of Formula III using sodium nitrate in the presence of sulfuric acid to give compound of Formula IV.

In still another preferred embodiment, compound of Formula IV is converted to Retigabine or its pharmaceutically acceptable salts by reacting compound of Formula IV with 4-fluorobenzaldehyde followed by reducing with a suitable reducing agent preferably sodium borohydride optionally in the presence of a solvent selected from alcohols to give compound of Formula V or its salts. Reducing compound of Formula V in the presence of a suitable reducing agent preferably palladium in the presence of an alcoholic solvent to give Retigabine or its pharmaceutically acceptable salts.

The process developed is simple, involves less number of steps, more industrially scalable, involve the use of cheaper reagents, employ mild reaction conditions, and at the same time provide Retigabine and its intermediates with high yields, high chemical purity and efficiency.

In another preferred embodiment, the compounds of Formulae II, III, IV, V, VI or their salts used in the present invention may be isolated or not. Any of the above reactions may be carried out in-situ reactions to obtain Retigabine or its pharmaceutically acceptable salts.

Accordingly, the present invention provides an improved process for the preparation of Retigabine its pharmaceutically acceptable salts, which comprises:
a) reacting compound of Formula IIIA

Formula IIIA
with sodium nitrate in the presence of an acid and optionally in a solvent to give compound of Formula IVA,

Formula IVA
b) converting compound of Formula IVA to Retigabine or its pharmaceutically acceptable salts.

In another preferred embodiment, the present invention provides an improved process for the preparation of compound of Formula IVA,

Formula IVA
which comprises:
a) reducing compound of Formula IIA

Formula IIA
in the presence of a suitable reducing agent to give compound of Formula IIIA,

Formula IIIA
b) reacting compound of Formula IIIA

Formula IIIA
with sodium nitrate in the presence of an acid optionally in a solvent to give compound of Formula IVA.

In yet another preferred embodiment, the present invention provides an improved process for the preparation of Retigabine or its pharmaceutically acceptable salts, which comprises:
a) reducing compound of Formula IIA

Formula IIA
using palladium on carbon in the presence of an alcoholic solvent to give compound of Formula IIIA,

Formula IIIA
b) reacting compound of Formula IIIA

Formula IIIA
with sodium nitrate in the presence of sulfuric acid to give compound of Formula IVA,

Formula IVA
c) reacting compound of Formula IVA with 4-fluoro benzaldehyde optionally in the presence of a base, followed by reducing with sodium borohydride optionally in a solvent to give compound of Formula VA,

Formula VA
d) reducing compound of Formula VA using palladium on carbon in the presence of an alcoholic solvent to give Retigabine,

e) treating Retigabine with methanolic hydrochloride to give Retigabine dihydrochloride, wherein Retigabine and Retigabine dihydrochloride contains any single impurity less than 0.1%.

In yet another preferred embodiment, the present invention provides an improved process for the preparation of compound of Formula IVA

Formula IVA
which comprises reacting compound of Formula IIIA

Formula IIIA
with sodium nitrate in the presence of sulfuric acid to give compound of Formula IVA.

In yet another preferred embodiment, the present invention provides an improved process for the preparation of compound of Formula IVA,

Formula IVA
which comprises:
a) dissolving compound of Formula IIIA,

Formula IIIA
in H2SO4,
b) cooling the reaction mass of step a) to -10 to 10ºC,
c) adding NaNO3 to the reaction mass of step b),
d) adjusting the pH of the reaction mass to 12-15 using a base, and
e) isolating compound of Formula IVA.

According to the present invention R1 represents hydrogen (or) N-protecting group, wherein N-protecting group is selected from Carbobenzyloxy (Cbz), tert-Butyloxycarbonyl (BOC), p-Methoxybenzyl carbonyl (Moz or MeOZ), 9-Fluorenylmethyloxycarbonyl (FMOC), Acetyl (Ac), Benzoyl (Bz), Benzyl (Bn), benzyl Carbamate, p-Methoxybenzyl (PMB), 3,4-Dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), Tosyl (Ts), sulfonamides and R2 represents ethyl group.

In yet another embodiment suitable base used in the present invention is selected from either inorganic base like alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; Alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof; Alkali metal halide such as halides of Lithium, Sodium, Potassium, Rubidium, and Caesium. Alkaline earth metal halide is selected from halides of Beryllium, Magnesium, Calcium, Strontium, Barium, and Radium, or organic base which is selected from the group consisting of quinine, cinchonidine, cinchonine, quinidine, 8-hydroxy-quinoline, 5- chloro-8-hydroxy-quinoline, benzathin, procain, N-methyl-D-glucamine, diethylamine, ethylenediamine, piperazine, ethanolamine, thiethanolamine, betaine, lysine and arginine and other basic and polar amino-acids, nitrogen containing bases including ammonia, primary, secondary, tertiary amines.

In yet another embodiment suitable solvents used in the present invention are selected from water or "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol and the like or "hydrocarbon solvents" such as benzene, toluene, xylene, heptane, hexane and cyclohexane and the like or "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like or "esters solvents" such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, and the like or "nitrile solvents" such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile and the like or "ether solvents" such as di-tert-butylether, dimethylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 2-methoxyethanol and dimethoxyethane, or “Amide solvents” such as formamide, DMF, DMAC, N-methyl-2-pyrrolidone, N-methylformamide, 2-pyrrolidone, 1-ethenyl-2-pyrrolidone, haloalkanes such as dichloromethane, 1,2-dichloroethane and chloroform, “Amine solvents” selected from diethylenetriamine, ethylenediamine, morpholine, piperidine, pyridine, quinoline, tributylamine, diisopropyl amine and/or mixtures thereof.

In yet another embodiment deprotection as defined in the presence invention is carried out in the presence of metal catalyst, hydrogen source, wherein the metal catalyst is selected from Pd, Ni, Pt, Rh or the deprotection may carried out in the presence of an acid which is selected from strong acids such as HCl or CF3COOH or the deprotection may carried out in the presence of a base, which is selected from primary or secondary amines.

In another embodiment of the present invention acid is selected from hydrochloric, hydrobromic, sulfuric, phosphoric, oxalic, maleic, succinic, citric, acetic and p-toluenesulfonic acid.

In another embodiment of the present invention reducing agent is selected from Pd/C, Fe, Raney nickel, palladium hydroxide, platinum catalyst, rhodium, and ruthenium or hydride, diborane, NaBH4, LiBH4, NaCNBH3, sodium triacetoxyborohydride, hydrazine and its hydrates.
In another embodiment of the present invention the term “pharmaceutical acceptable salts or salts” refers to acid addition salts such as hydrochloric, hydrobromic, sulfuric, phosphoric, oxalic, maleic, succinic, and citric.

In a preferred embodiment compound of Formula IIA can be prepared by reacting 4-nitroaniline with ethylchloroformate in the presence of a solvent, wherein the solvent is as defined above.

In a more preferred embodiment the compound of Formula IIA

Formula IIA
is prepared by reacting 4-nitroaniline with ethylchloroformate in the presence of a solvent selected from toluene, xylene, acetonitrile, amine solvent and/or mixtures thereof.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and is not intended to limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLES:
EXAMPLE 1: Preparation of 4-ethoxycarbonylamino nitrobenzene Formula IIA:

Formula IIA
To the stirred solution of 4-nitroaniline (100 g) in toluene (500 mL) diisopropyl amine (139 mL) was charged. The reaction mass was heated at 45-50ºC, ethylchloroformate (90 mL) was added slowly over 45-60 min maintaining the temperature at 45-50oC. The reaction mass was stirred for 5h at 45-50oC. Then the reaction mass was brought to RT and 500 mL 2N HCl was added over 10-15 min and stirred for further 2 h at 0-5oC. Thus the obtained solid was filtered, solid cake was washed with 500 mL water and dried in oven at 50oC for overnight. 4-Ethoxycarbonylamino nitrobenzene Formula IIA, obtained as light green colour solid in 98 % yield and 99.95 % HPLC purity.

EXAMPLE 2: Preparation of 4-ethoxycarbonylamino nitrobenzene Formula IIA:

Formula IIA
To the stirred solution of 4-nitroaniline (10 g) and acetonitrile (50 mL) diisopropyl amine (13.8 mL) was added at RT. Ethylchloroformate (8.2 mL) was added over 15-20 min at room temperature and the reaction mass was stirred at 45-50oC for 24h. Then the reaction mass was brought to RT, 2N HCl (100 mL) was added slowly over 10-15 min and stir for another 2h at 0-5oC. Light green colour solid (4-ethoxycarbonylamino nitrobenzene, Formula IIA) obtained was filtered, washed with water (50 mL) and dried in oven at 50oC for overnight. Yield: 83%; HPLC purity 96.50%.

EXAMPLE 3: Preparation of 4-ethoxycarbonylamino aniline Formula IIIA:

Formula IIIA
In an autoclave vessel 4-ethoxycarbonylamino nitrobenzene Formula IIA (140 g) and 3% Pd-C (4.2 g) in 1.4 Lt MeOH were added under N2 atmosphere. The reaction mass was hydrogenated at 10 Kg/cm2 pressure at RT. After completion of the reaction, the product formed was filtered through celite bed and washed with methanol. Solvent evaporated under reduced pressure, 4-ethoxycarbonylamino aniline Formula IIIA, obtained as light brown solid in 99% yield and 99.97% HPLC purity.

EXAMPLE 4: Preparation of 4-ethoxycarbonylamino aniline Formula IIIA:

Formula IIIA
4-Ethoxycarbonylamino nitrobenzene (10 g) was added to the stirred solution of Fe powder (7.99 g) and NH4Cl (7.6 g) in 100 mL water and the reaction mass was heated at 55-60oC for 5h. Then the reaction mass was brought to RT, hyflo (10 g) and EtOAc (80 mL) were added to the reaction mass and stirred for 10-15 min. The reaction mass was filtered and hyflo bed washed with 20 mL EtOAC. FMLs pH was adjusted to 2 using con.HCl. Organic layer separated and aqueous layer pH adjusted to 14 using 50% NaOH solution. Aqueous layer extracted with 2X50 mL MDC, combined organic layer dried over anhydrous Na2SO4, solvent evaporated under reduced pressure. Thus obtained oily crude stirred in 50mL hexanes. 4-Ethoxycarbonylamino aniline Formula IIIA obtained as brown colour solid in 86% yield and 99.74% HPLC purity.

EXAMPLE 5: Preparation of 5-amino-2-ethoxycarbonylamino nitrobenzene Formula IVA:

Formula IVA
4-Ethoxycarbonylamino aniline (105 g) was added to 525 mL of H2SO4 at temperature below 30oC. Reaction mass was cooled to 0-5oC, NaNO3 (57 g) was added in lot wise maintaining the temperature below 5oC and reaction mass was stirred for 2h at 0-5oC. Reaction mass was poured into ice water (3 kg) and stirred for 2h at RT. Reaction mass pH was adjusted to 14 using 30 % NaOH solution the temperature was maintained below 30oC. Reaction mass was stirred for 3-4 h at RT, filtered and the solid cake washed with water. 5-Amino-2-ethoxycarbonylamino nitrobenzene Formula IVA obtained as reddish brown solid in 86% yield and 98.56% HPLC purity.

EXAMPLE 6: Preparation of 5-amino-2-ethoxycarbonylamino nitrobenzene Formula IVA:

Formula IVA
4-Ethoxycarbonylamino aniline Formula IIIA (5 g) was added to 20 ml H2SO4 and the reaction mass was cooled to -5 to 0oC. 1.5 mL fumic HNO3 in 5 mL H2SO4 were added maintaining the temperature between -5 to 0oC. The reaction mass was stirred at 0-5oC for 1h, poured into 100 g ice. Stirred for 30 min at RT and cooled to 0-5oC. pH was adjusted to 14 with aq. NH3 solution with maintaining the temperature below 30oC. The reaction mass was stirred for 1h, filtered and the solid cake wash with 100 mL water. 5-Amino-2-ethoxycarbonylamino nitrobenzene Formula IVA obtained as reddish brown solid in 80 % yield and 91.49% HPLC purity.

EXAMPLE 7: Preparation of 5-amino-2-ethoxycarbonylamino nitrobenzene Formula IVA as enabled in US 2014/0163252 A1:

Formula IVA
4-Ethoxycarbonylamino aniline (20 g, 11.1 mmol) was dissolved in a 95% w/w solution of H2SO4 (100 mL) and water (20 mL), and the resulting mixture was maintained under stirring and cooled to -5°C. 65% w/w HNO3 (8.5 mL) was slowly added, and the reaction mixture was maintained under stirring in an inert atmosphere at 0°C. for 30 minutes. The reaction mixture was then quenched by slow dripping in water (500 mL) at the temperature of 5°C. The solid formed is filtered, and 15 g of product is obtained with complete selectivity, yield of 60%, and a purity of 98.6%, evaluated by HPLC.

EXAMPLE 8: Preparation of 2-ethoxycarbonylamino-5-(4-fluorobenzylamino) nitro-benzene Formula VA:

Formula VA
4-Fluorobenzaldehyde (55.4 mL) was added slowly over 30-45 min to the stirred solution of 5-amino-2-ethoxycarbonylaminonitrobenzene (105 g) in EtOH (840 ml) at 65-70oC. Then the reaction mass was stirred for 4h at RT, reaction mass was cooled to 0-5oC, NaBH4 (21.2 g) was added in lot wise over 45-60 min. Then the reaction mass stirred for 10h at room temperature (25-30oC). The reaction mass pH was adjusted to 2 with 4N HCl solution maintaining the temperature below 30oC and stirred for 1h at RT. Again the pH was adjusted to 14 using 20% NaOH solution maitaining the temperature below 30oC. The reaction mass was stirred at RT for 4h, filter and the solid cake washed with water several times. 2-Ethoxycarbonylamino-5-(4-fluorobenzylamino)nitrobenzene Formula VA obtained as reddish brown solid in 88 % yield and 97.79% HPLC purity.

EXAMPLE 9: Preparation of 2-ethoxycarbonylamino-5-(4-fluorobenzylamino) nitro-benzene Formula VA:

Formula VA
To the stirred solution of 5-amino-2-ethoxycarbonylaminonitrobenzene (5 g) in 50 ml IPA, 4-flurobenzaldehyde (2.61 mL) was added slowly over 10-15 min and the reactiom mass was refluxed for 20h. The reaction mass was cooled to 0-5oC, NaBH4 (1.6 g) added in lots wise over 30 min. Then the reaction mass stirred for 18 h at room temperature (25-30oC). The reaction mass was cooled to 0-5oC the pH was adjusted to 2 using 4N HCl solution and stirred for 30 min at RT. the pH was adjusted again to 14 with aq. NH3 solution maintaining the temperature below 30oC. The mass was stirred for 30 min, filtered and washed with water. 2-Ethoxycarbonylamino-5-(4-flurobenzylideneamino)nitrobenzene Formula VA was obtained reddish brown solid in 80 % yield and 94.2% HPLC purity

EXAMPLE 10: Preparation of N-[2-amino-4-(4-fluorobenzylamino)-phenyl]carbamic acid ethyl ester (Retigabine base):

Retigabine
In a 5 Lt autoclave vessel 2-ethoxycarbonylamino-5-(4-fluorobenzylamino) nitrobenzene Formula VA (105 g) and 10% Pd-C (3.15 g) in MeOH (2.1 Lt) and 5 mL Et3N were charged under N2 atmosphere. The reaction mass was hydrogenated at 1 Kg/cm2 pressure at RT. After completion of the reaction, filter through celite bed and washed with methanol. Charcoal was added to the FMLs, filter through celite bed, solvent evaporated under reduced pressure. N-[2-Amino-4-(4-fluorobenzylamino)-phenyl]carbamic acid ethyl ester (Retigabine base) obtained as as colourless solid in 98% yield and 99.53% HPLC purity.

EXAMPLE 11: Preparation of N-[2-amino-4-(4-fluorobenzylamino)-phenyl]carbamic acid ethyl ester (Retigabine base):

Retigabine
N2H4 was added over 30 min to the stirred solution of 2-ethoxycarbonylamino-5-(4-fluorobenzylamino) nitrobenzene Formula VA (10 g) and Raney Ni (500 mg) under N2 atm in 100 ml EtOH at 55-60oC. Stirred for 6h at 55-60oC for 6h, charcoal 5% w/w was added and stirred for 10min at RT. Filtered and washed with 50 mL EtOH, solvent evaporated under reduced pressure. N-[2-Amino-4-(4-fluorobenzylamino)-phenyl]carbamic acid ethyl ester (Retigabine base) obtained as colorless solid in 93% yield and 95.31% HPLC purity.

EXAMPLE 12: Preparation of 2-ethoxycarbonylamino-5-(4-fluorobenzylamino)aniline dihydrochloride (Retigabine.2HCl) Fromula I:

Formula I
MeOH.HCl (3.5eq.w/w) was added at RT to the stirred solution of N-[2-amino-4-(4-fluorobenzylamino)-phenyl]carbamic acid ethyl ester Formula VIA in MeOH. The reaction mass stirred for 5-6 h, filter and wash with MeOH. Retigabine.2HCl Formula I obtained in 87% yield and 99.89% HPLC purity (any single impurity is below 0.1%).

The process of the present invention is advantageous over the prior-art processes in terms of yield and purity as shown in the below table:

Product According to the present invention According to the Prior art (US 2014/0163252 A1)
Yield Purity Yield Purity
Formula IIIA 99% 99.84% 65% 98.7%
Formula IVA 86% 98.5% 60% 98.6%