WO2013011518A1

WO2013011518A1 - Process for the preparation of retigabine of the formula i and pharmaceutically acceptable salts thereof

Info

Publication number: WO2013011518A1
Application number: PCT/IN2011/000639
Authority: WO
Inventors: Arun Kanti Mandal; Kamlesh Jayantilal Ranbhan; Sudhanshu Saxena; Sanjay Ramrao GAIKWAD; Pushpalata Balkrishna SARJEKAR
Original assignee: Arch Pharmalabs Limited
Priority date: 2011-07-21
Filing date: 2011-09-16
Publication date: 2013-01-24

Abstract

The invention relates to process for the preparation of 2-amino-4-(4- fluorobenzylamino)-l-ethoxycarbonylaminobenzene generically known as Retigabine of the formula (I) and its pharmaceutically acceptable salts e.g. Formula IA, particularly to the modification over the prior art processes-I and II disclosed therein in US5384330. The modifications are depicted in the scheme I and scheme II respectively. Disclosed herein are also the novel processes for the preparation of intermediates of formulae M, N and O of the process-I and of formulae R, S, T of process-II, those are used for preparation of Retigabine of the formula I and its pharmaceutically acceptable salts thereof.

Description

TITLE

Process for the preparation of Retigabine of the formula I and pharmaceutically acceptable salts thereof.

TECHNICAL FIELD OF THE INVENTION

The invention relates to a process for the preparation of 2-amino-4-(4- fluorobenzylamino)-l-ethoxycarbonylaminobenzene genetically known as Retigabine of the formula (I) and its pharmaceutically acceptable salts e.g. Formula IA, particularly to the modification over the prior art processes-I and II disclosed therein in US5384330. The modifications are depicted in the scheme I and scheme II respectively. Disclosed herein are also the novel processes for the preparation of intermediates of formulae M, N and O of the process-I and of formulae R, S, T of process-II, those are used for preparation of Retigabine of the formula I and its pharmaceutically acceptable salts thereof.

Formula (I)

Formula (IA)

 BACKGROUND OF THE INVENTION

Retigabine (INN) or Ezogabine (USAN), code named D-23129, is an anticonvulsant for the treatment for partial epilepsies and also for muscle relaxing, fever-reducing and as peripheral analgesic agent. The drug is being developed by Valeant Pharmaceuticals and Glaxo SmithKline with the proposed trade name Potiga. The FDA Peripheral and Central Nervous System Drugs Advisory Committee have unanimously recommended approval of Potiga. The ability of Retigabine to open potassium channels in neuronal cells differentiates from presently available anticonvulsant agents such as Phenytoin, Carbamazepine and Valproate. European Commission has granted the marketing authorization for Trobalt™ (retigabine) in the epilepsy therapy area. U.S. Food and Drug Administration (FDA) has approved as Potiga (ezogabine).The drug is known by ezogabine in the US and Canada.

Retigabine works primarily as a potassium channel opener that is, by activating a certain family of voltage-gated potassium channels in the brain. This mechanism of action is unique among antiepileptic drugs, and may hold promise for the treatment of other neurologic conditions, including migraine and neuropathic pain.

US5914425 (Meisel et al.) discloses polymorphic forms A, B and C of 2-amino-4-(4-fluorobenzylamino)- 1 -ethoxy-carbonylaminobenzene of formula (I) hereinabove and hereinbelow referred as Retigabine.

US 5849789 and US5852053 (both to Rostock et al.) disclose the use of Retigabine for the treatment of neurodegenerative disorders, including those associated with stroke. WO2011/012659 A2 (Medichem S.A.) discloses diethyl-4-(4- fluorobenzylamino)-l,2-phenylenedicarbamate and salts thereof of the formula given below, which are useful as reference markers and reference standards for analyzing samples comprising Retigabine or salts thereof.

Diethyl-4-(4-fluorobenzylamino)- 1 ,2-phenylenedicarbamate

US5384330 (hereinafter referred as '330) (Dieter et al.) discloses 1, 2, 4- triaminobenzene derivatives of the general formula:

and pharmaceutically acceptable acid addition salts thereof and their properties as anti-epileptic, muscle-relaxing, fever-reducing and peripheral analgesic agents.

'330 disclose particularly the processes for Retigabine as described below in process-I and process II. Process (I)

The process (I) has following drawbacks:

1) 2-Nitro-p-phenylenediamine of formula K also known as 2- nitrobenzene-l,4-diamine used as starting material in the process-I possessing two amino groups, when reacts with 4-fluorobenzaldehyde of formula L there remains a probability of the formation of two possible impurities of the formulae A and B respectively. Formation of these impurities not only reduces the yield and purity but also increase one unit operation to remove these impurities to obtain pure product meeting specifications. This makes the process inefficient for industrial scale.

Another drawback associated with this stage of condensation is the use of ion exchanger (e.g. Nation), water separators, techniques like azeotropic distillation using xylene as solvent to take the reaction towards completion during the preparation of 2-amino-5-(4- fluorobenzylideneamino)-nitrobenzene also known as (4- fluorobenzylidene)-3 -nitrobenzene- 1,4-diamine of formula M from reaction of 2-nitrobenzene- 1,4-diamine of formula K with 4- fluorobenzaldehyde of formula L. Compound of formula M is then further reacted with borohydride yielding compound of formula N with no mention of purity.

2) Another drawback associated with process-I, is the formation of mixture of products as undesired dicarbmates and other impurities of formulae C, D, E and F respectively, resulting from the interaction of both the amino groups of the compound of formula O with ethyl chloroformate. Formation of these undesired dicarbamates is overcome by process-II wherein, reaction with ethylchloroformate is done at earlier stage.

1) Use of hydrazine hydrate for the deprotection of phthaloyl group of the compound Q. Hydrazine hydrate is not only genotoxic, carcinogenic and potentially hazardous deprotection reagent but also forms phthalyl hydrazide of the formula G as a by-product in solid form obtained by the nucleophilic reaction between phthalimido group and hydrazine. This requires additional operational steps to remove impurity G thus makes the process industrially inefficient.

2. Common drawback associated with both the processes-I and II is the use of ion exchanger (e.g. Nafion)/catalyst, water separators, techniques like azeotropic distillation using xylene as solvent to take the reaction towards completion for the preparation of compounds of formulae M and S. Inventors of the present invention have successfully modified the reaction condition for both the processes-I and II for the preparation of compound of formulae M and S by simply heating the reactants in alcoholic solvents at a certain temperature and then isolating the products by simple filtration from the reaction mass.

3. Formation of impurity of formula U in process-II by transesterification during borohydride reduction using methanol as one of the solvents of the said solvent system comprising methanol and dioxane has been replaced by isopropanol and water combination. It has been observed by the inventors that selective choice of isopropanol does not undergo the transesterification. There is no such indications or teachings a person skilled in the art can ascertain from the prior art. These modifications over the prior art when implemented result into better purity and higher yield.

4. Moreover hydrogenation of compound of formula T using Raney nickel and 1 ,2-dimethoxyethane as solvent as reported in prior art results into the product with lesser yield and inferior purity, that requires additional operation for its purification.

In view of shortcomings and problems associated with the processes for the preparation of Retigabine disclosed therein the prior art, there remains a dire need for an efficient process which overcomes the problems in the processes of prior art and moreover meets current requirements for the environmental compatibility of production process by avoiding formation of secondary products and use of hazardous raw materials like hydrazine hydrate, solvents like dioxane, ether and xylene. It is also advantageous to reduce the number of operational process steps. Though there are drawbacks associated with processes-I and II but inventors of the present invention have successfully modified both the processes, therefore improvements over the processes-I and II remains under the scope of the invention.

TECHNICAL SOLUTIONS OVER THE PRIOR ART PROCESSES-I AND II

Disclose herein is an improved process which provide technical solutions to overcome the drawbacks of processes-I and II disclosed therein the prior art mentioned hereinabove.

1. Use of hazardous, genotoxic and carcinogenic hydrazine hydrate as deprotecting reagent in process-II has been replaced by novel set of compounds comprising ammonia, urea, thiourea, alkyl amines and the like. When methyl amine is used as deprotecting agent there exists a possibility of formation of the impurity of the formula H. However, the said impurity being soluble gets eliminated during filtration and goes directly into mother liquor without any extra efforts compared to precipitation of impurity of formula F while using hydrazine hydrate as reported in prior art, that requires additional operational step for its removal.

H

2. Common drawback associated with both the processes-I and II is the use of ion exchanger (e.g. Nafion)/catalyst, water separators, techniques like azeotropic distillation using xylene as solvent to take the reaction towards completion for the preparation of compounds of formulae M and S. Inventors of the present invention have successfully modified the reaction condition for both the processes-I and II for the preparation of compound of formulae M and S by simply heating the reactants in alcoholic solvents at a certain temperature and then isolating the products by simple filtration of the reaction mass.

3. Formation of impurity of formula U in process-II by transesterification during borohydride reduction using methanol as one of the solvents of the said solvent system comprising methanol and dioxane has been avoided by replacing methanol/dioxane solvent system with isopropanol and water combination. It has been observed by the inventors that selective choice of isopropanol does not undergo the transesterification. These modifications over the prior art when implemented result into better purity and higher yield.

4. Use of Raney Nickel and 1,2-dimethoxyethane has been replaced by Pd-C and alcohol-base combination as solvent system for the hydrogenation of compound of formula T is advantageous to produce Retigabine and its pharmaceutically acceptable salts with better yield and higher purity.

OBJECT OF THE INVENTION

First object of the present invention is to provide an efficient, economical and industrially viable process for the preparation of 2- amino-4-(4-fluorobenzylamino)- 1 -ethoxycarbonylaminobenzene of formula (I) hereinabove and hereinbelow referred as Retigabine and its pharmaceutically acceptable salts.

Second aspect of the invention is to provide the compounds of the formulae (I) and (IA) with improved yield and purity as compared to the prior art processes. Third aspect of the invention is to provide a novel process for the preparation of the Retigabine intermediate 5-amino-2- ethoxycarbonylamino-nitrobenzene of formula R comprising novel set of the compounds represented by RNH₂ to be used for the purpose of deprotection of the compounds comprising amino protecting groups.

Forth aspect of the invention is to provide a novel process for the preparation of Retigabine intermediate 2-ethoxycarbonylamino-5-(4- fluorobenzylideneamino)-nitrobenzene of formula S avoiding the use of any external catalyst/ion exchanger or water separator or water separator technique like azeotropic distillation.

Fifth aspect of the invention is to provide a novel process for the preparation of the Retigabine intermediate (4-fiuorobenzylidene)-3- nitrobenzene-l,4-diamine of formula M avoiding the use of any external catalyst/ion exchanger or water separator or water separator technique like azeotropic distillation.

Sixth aspect of the invention is to provide a novel process for the preparation of Retigabine intermediate 2-ethoxycarbonylamino-5-(4- fluorobenzylamino)-nitrobenzene of formula T in a single step by direct reductive amination of 5-amino-2-ethoxycarbonylamino nitrobenzene of formula R with 4-fluorobenzaldehyde of formula L and metal borohydride in aqueous solvent avoiding the formation/ isolation of the imine compound of the formula S. Presence of water in the solvent system does not allow the formation of imine which generally forms due to dehydration as described hereinabove thereby reducing one unit operation.

Seventh aspect of the invention is to provide a novel process for the preparation of Retigabine intermediate (4-fluorobenzyl)-3-nitrobenzene- 1 ,4-diamine of formula N in single step by direct reductive amination of 2-nitrobenzene-l,4-diamine of formula K with 4-fluorobenzaldehyde of formula L and metal borohydride in aqueous solvent avoiding the formation/ isolation of the imine compound of the formula M thereby reducing one unit operation .

Eighth aspect of the invention is to provide a novel process for the preparation of Retigabine intermediate 2-ethoxycarbonylamino-5-(4- fluorobenzylamino)-nitrobenzene of formula T in a single step by direct reductive amination of 5-amino-2-ethoxycarbonylamino nitrobenzene of formula R with 4-fluorobenzaldehyde of formula L and metal borohydride in non-aqueous solvent avoiding the formation/ isolation of the imine compound of the formula S. Thereby reducing one unit operation.

Ninth aspect of the invention is to provide a novel process for the preparation of Retigabine intermediate (4-fluorobenzyl)-3-nitrobenzene- 1 ,4-diamine of formula N in single step by direct reductive amination of 2-nitrobenzene-l,4-diamine of formula K with 4-fluorobenzaldehyde of formula L and metal borohydride in non-aqueous solvent avoiding the formation / isolation of the imine compound of the formula M thereby reducing one unit operation.

Tenth aspect of the invention is to provide a novel process for the preparation of Retigabine intermediate 2-ethoxycarbonylamino-5-(4- fluorobenzylamino)-nitrobenzene of formula T by indirect reductive amination of 5-amino-2-ethoxycarbonylamino nitrobenzene of formula R with 4-fluorobenzaldehyde of formula L forming imine compound of formula S with higher yield and better purity over the prior art, which gets further reduced with metal borohydride in a solvent system comprising water as one of the solvent resulting into the formation of compound of formula T with higher yield and better purity over the prior art. Eleventh aspect of the invention is to provide a novel process for the preparation of Retigabine intermediate (4-fluorobenzyl)-3-nitrobenzene- 1,4-diamine of formula N by indirect reductive amination of 2- nitrobenzene- 1,4-diamine of formula K with 4-fluorobenzaldehyde of formula L forming imine compound of formula M with higher yield and better purity over the prior art, which gets further reduced with metal borohydride in a solvent system comprising water as one of the solvent resulting into the formation of compound of formula N with higher yield and better purity over the prior art.

Twelfth aspect of the invention is to provide a novel process for the preparation of Retigabine intermediate 2-ethoxycarbonylamino-5-(4- fluorobenzylamino)nitrobenzene of formula T by indirect reductive amination of 5-amino-2-ethoxycarbonylamino nitrobenzene of formula R with 4-fluorobenzaldehyde of formula L forming imine compound of formula S with higher yield and better purity over the prior art, which gets further reduced with metal borohydride in a non-aqueous solvent resulting into the formation of compound of formula T.

Thirteenth aspect of the invention is to provide a novel process for the preparation of Retigabine intermediate (4-fluorobenzyl)-3-nitrobenzene- 1,4-diamine of formula N by indirect reductive amination of 2- nitrobenzene- 1,4-diamine of formula K with 4-fluorobenzaldehyde of formula L forming imine compound of formula M with higher yield and better purity over the prior art, which is further reduced with metal borohydride in non-aqueous solvent resulting into the formation of compound of formula N.

Fourteenth aspect of the invention is to provide a novel process for the preparation of Retigabine of formula I and its pharmaceutically acceptable salt comprising reduction of nitro group of 2- ethoxycarbonylamino-5-(4-fluorobenzylamino)-nitrobenzene of formula T by catalytic hydrogenation comprising alcohol-base combination as a solvent system resulting in better yield and high purity.

Fifteenth aspect of the invention is to provide a non-pressure reaction for the preparation of Retigabine of formula I and its pharmaceutically acceptable salt comprising reduction of nitro group of 2- ethoxycarbonylamino-5-(4-fluorobenzylamino)-nitrobenzene of formula T by pressure free catalytic transfer hydrogen reaction without using external source of hydrogen gas, optionally together with alcohol-base combination as a solvent system.

Sixteenth aspect of the invention is to convert 2-ethoxycarbonylamino-5- (4-fluorobenzylideneamino)-nitrobenzene of formula S directly into Retigabine acid addition salt of formula IA in a single step by reducing double bond and nitro group simultaneously by catalytic hydrogenation resulting into the formation of Retigabine base of formula I and then reacting the Retigabine base thus formed, optionally in-situ with pharmaceutically acceptable acid in solution to get Retigabine acid addition salt.

Seventeenth aspect of the invention is to provide a process for the preparation of Retigabine intermediate of formula T comprising the reaction of the compound 5-amino-2-ethoxycarbonylamino nitrobenzene of formula R with 4-fluorobenzaldehyde of formula L in an alcoholic solvent forming imine compound of formula S and in-situ reducing double bond by the addition of metal borohydride resulting into the formation of 2-ethoxycarbonylamino-5-(4-fluorobenzylamino)- nitrobenzene of formula T, thereby reducing the unit operations.

Eighteenth aspect of the invention is to provide a process for the preparation of compound of formula I comprising the reaction of the compound 5-amino-2-ethoxycarbonylamino nitrobenzene of formula R with 4-fluorobenzaldehyde of formula L in an alcoholic solvent forming imine compound of formula S and in-situ adding a base generating the alcohol-base combination as solvent system and hydrogenating double bond and nitro group simultaneously by catalytic hydrogenation resulting into the formation of Retigabine base of formula I and then reacting the Retigabine base thus formed, optionally in-situ with pharmaceutically acceptable acid in solution to get Retigabine acid addition salt thereby reducing the unit operations.

DETAILED MEANING OF THE TERMS USED HEREINABOVE AND HEREINBELOW:

DIRECT REDUCTIVE AMINATION: This reaction is described as a single step reaction between carbonyl compound and the amine with proper reducing agent without formation of the intermediate imine or iminium salt.

INDIRECT REDUCTIVE AMINATION: This reaction is described as a reaction wherein amine first reacts with carbonyl group to form a hydroxylamine species, which subsequently loses one water molecule to form imine. Simultaneous removal of water shifts the equilibrium towards imine, which can then be isolated and reduced with a suitable reducing agent.

CATALYTIC TRANSFER HYDROGEN REACTION: Selective reduction of several important functional groups by catalytic transfer hydrogen reaction using ammonium formate and the like together with catalyst selected from palladium, zinc or nickel and the like. SUMMARY OF THE INVENTION

The invention relates to process for the preparation of 2-amino-4-(4- fluorobenzylamino)-l-ethoxy-carbonylaminobenzene generically known as Retigabine of the formula (I) and its pharmaceutically acceptable salts e.g. Formula LA. The invention particularly relates to the modification over the prior art processes described hereinabove and also to the novel processes for the preparation of intermediates of formulae M, N and O of the process-I and R, S, T intermediates of process-II of prior art described hereinabove and use of said intermediates for the preparation of Retigabine of the formula I and its pharmaceutically acceptable salts thereof.

The entire summary including modifications over the prior art and new inventive features of the present invention can be depicted by the schemes I and II as given below:

SCHEME- 1

Formula (LA)

SCHEME- II

ADVANTAGES OF THE PRESENT INVENTION

1. Replacement of genotoxic and potentially hazardous hydrazine hydrate as a deprotecting agent by new set of deprotecting agents preferably selected from the set of ammonia, urea, thiourea, alkylamines and the like and thus avoiding the formation of by-products like phthaloyl hydrazide which is difficult to be removed from the product resulted into the isolation of product of formula R of higher purity in better yield.

2. Eliminating the use of catalyst or acid ion exchanger or water separator or azeotropic distillation technique while preparing Retigabine intermediates namely (4-fluorobenzylidene)-3-nitrobenzene- 1 ,4-diamine of formula M and 2-ethoxycarbonylamino-5-(4- fluorobenzylideneamino)-nitrobenzene of formula S comprising the condensation of respective amines with 4-fluorobenzaldehyde.

3. Eliminating the use of methanol as solvent during borohydride reduction of Retigabine intermediate of formula S, thus avoiding the formation of transesterified impurity of formula U namely 2-methoxy carbonylamin-5-(4-fluorobenzylamino)nitrobenzene. The solvent used for this reaction is IP A- water mixture.

4. Direct reductive amination of 5-amino-2-ethoxycarbonylamino- nitrobenzene of formula R or 2-nitrobenzene-l,4-diamine of formula K with 4-fluorobenzaldehyde of formula L in presence of borohydrides and aqueous solvent, thereby avoiding the formation/isolation of hygroscopic and comparatively less stable imine compound of formula S or M. However the concept remains under the scope of present invention. The said direct reductive amination is also performed using sodium triacetoxyborohydride in non-aqueous solvent. 5. Use of catalytic hydrogenation concept in presence of alcohol-base combination for simultaneous reduction of double bond (imine) and nitro group, thereby eliminating the use of metal borohydride for reduction, and Retigabine base or its acid addition salt of formula- I or IA is directly formed from the compound of formula S in single step without isolation/formation of compound of formula T, which is particularly advantageous as number of unit operations are reduced.

6. Use of transfer hydrogen reaction technique for the reduction of nitro group comprising ammonium formate in combination with hydrogenation catalyst is advantageous as it avoids pressure reaction and use of external source of hydrogen gas.

7. Use of alcohol-base combination as a solvent system for the reduction of the intermediates of the formulae S and T through catalytic hydrogenation results into the formation of Retigabine base and its pharmaceutically acceptable salt in higher yield and better purity.

DETAILED DESCRIPTION OF THE INVENTION

Disclosed herein is an efficient, economical and industrially viable process for the preparation of 2-amino-4-(4-fluorobenzylamino)-l- ethoxy-carbonylaminobenzene (Retigabine) of formula (I) and pharmaceutically acceptable salts thereof. The disclosure of the present invention has been described in detail under the following heads:

PROTECTION: In a general embodiment of the present invention disclosed herein is a process for the preparation of compound of formula Q' by contacting N-ethoxycarbonylamino-p-phenylenediamine of formula (P) with amine protecting reagent in a solvent and then contacting the reaction mixture with nitrating system comprising concentrated nitric acid replacing fuming nitric acid to produce compound of formula (Q') in higher yield.

P Q'

Wherein Pr is amine protecting group

Amine protecting group (Pr) is selected from carbobenzyloxy, tert- butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, acetyl, benzoyl, p- methoxybenzyl, 3, 4-dimethoxybenzyl, p-methoxyphenyl, tosyl, benzyl group, phthalimido group and the like. Preferably amine protecting group (Pr) is phthalimido group.

Nitrating system is selected from HN0₃/AcOH, HN0₃/H₂S0₄, aq. HN0₃ at 343 °K, HN0₃/Ac₂0/AcOH, potassium nitrate/H₂S0₄ and the like. Preferably nitrating system is cone. HN0₃/AcOH. Compound of formula of P can be prepared by the known methods as disclosed in US5384330 and Chemische Berichte, 1894, vol. 27, p-398, Justus Liebigs Annalen der Chemie, 1896, vol.293, page 374.

There is no particular restriction on the nature of the solvent to be employed; provided that it has no adverse effect on the reaction or on the reagents involved. Example of a compatible solvent is acetic acid.

Contacting hereinabove and hereinbelow comprises mixing, heating, stirring, refluxing or combination thereof.

In a preferred embodiment of the present invention 2-ethoxycarbonyl amino-5-phthalimido-nitrobenzene of formula Q is prepared by contacting N-ethoxycarbonylamino-p-phenylene diamine of formula (P) with phthalic anhydride in a solvent preferably acetic acid followed by optionally in-situ reaction with concentrated nitric acid as depicted below.

p

Q

DEPROTECTION: Deprotection of the amino protecting group of the compound of formula (Q/Q') is carried out by using compound of formula RNH₂ in a solvent to produce compound of formula (R) as depicted below that overcome the drawbacks associated with the use of hydrazine disclosed therein in'330, to produce highly pure product in good yield making the process technically and economically advanced.

R—NH₂

Wherein R is H, lower alkyl group, NH₂-CO-, NH₂-CS-, Ar-CH₂- wherein Ar is phenyl or optionally substituted phenyl.

The "lower alkyl group" means linear or branched chain alkyl group preferably having 1 to 12, more preferably 1 to 3, carbon atoms. Examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert. -butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, substituted alkyl and the like. Preferably R is H and methyl.

As per the third aspect of the invention in a general embodiment of the present invention disclosed herein is a novel process for the preparation of Retigabine intermediate 5-amino-2-ethoxycarbonylamino- nitrobenzene of formula R comprising contacting novel deprotecting agents represented by the formula RNH₂ preferably selected from the group comprising urea, thiourea, ammonia, methyl amine and the like with compounds of formula Q or Q\

In a preferred embodiment of the present invention 2-ethoxycarbonyl amino-5-phthalimido-nitrobenzene of formula Q is contacted with ammonia optionally in solvent resulting into the formation of 5-amino-2- ethoxycarbonylamino-nitrobenzene of formula R as depicted below:

Q R

Ammonia used herein could be in gaseous form or liquid ammonia or ammonium hydroxide or ammonia solution.

In another preferred embodiment of the present invention 5- phthaloylamino-2-ethoxycarbonylamino-nitrobenzene of formula Q is contacted with methyl amine optionally in solvent resulting into the formation of 5-amino-2-ethoxycarbonylamino-nitrobenzene of formula R as depicted below:

Methyl amine used herein could be in gaseous form or liquefied methyl amine or alcoholic methyl amine or aqueous methyl amine.

Solvent to be used for the embodiment should be compatible and should not react with any of the reactant.

CONDENSATION WITH 4-FLUOROBENZALDEHYDE: Referring to fourth and fifth aspects of the invention in a general embodiment herein is a novel process for the preparation of Retigabine intermediates comprising contacting an amine and a carbonyl compound in a solvent by heating the contents at a suitable temperature preferably at reflux temperature thereby generating a benzylidene compound without making any extra efforts for the removal of water or to proceed the reaction in forward direction by use of catalyst like acid ion exchanger or use of water separator or azeotropic distillation technique as disclosed in the prior art. The modified process results in better yield and higher purity of the product.

In a preferred embodiment of the present invention disclosed herein is a novel process for the preparation of Retigabine intermediate 2- ethoxycarbonylamino-5-(4-fluorobenzylideneamino)-nitrobenzene of formula S obtained by contacting 5-amino-2-ethoxycarbonylamino- nitrobenzene of formula R with 4-fluorobenzaldehyde in a solvent by heating at a suitable temperature avoiding the use of catalyst or acid ion exchanger or water separator or azeotropic distillation technique as disclosed in the prior art. The modified process results in higher yield about 95% and HPLC purity about 99.5%.

In another preferred embodiment of invention disclosed herein is a novel process for the preparation of Retigabine intermediate (4- fluorobenzylidene)-3 -nitrobenzene- 1,4-diamine of formula M by contacting 2-nitrobenzene- 1,4-diamine of formula K with 4-fluoro benzaldehyde in a solvent by just heating at a suitable temperature avoiding the use of catalyst or acid ion exchanger or water separator or azeotropic distillation technique for taking the reaction ahead as disclosed in the prior art. Thus isolating the product in better yield and higher purity.

Solvent used for the purpose may be any one that does not react with any of the reactant and is compatible. Preferably solvent is alcohol more preferably methanol.

Suitable temperature means any temperature that will not inhibit the reaction and will not impart the impurity formation. Preferably temperature range is between about 50°C to about 85°C. DIRECT REDUCTIVE AMINATION: Referring sixth, seventh, eighth and ninth aspect of the present invention in a general embodiment disclosed herein is a novel process for the preparation of Retigabine intermediates based on the concept of direct reductive amination comprising contacting an amine with carbonyl compound and a suitable reducing agent selected from borohydrides in a solvent system comprising water as one of the element. The main feature herein is the use of water that inhibits the formation of imine of formula S which actually forms due to dehydration as described under. Moreover it is observed that the use of isopropanol as selective solvent does not result into the formation of transesterified impurity of formula U, however methanol does form the impurity of formula U.

In a preferred embodiment disclosed herein is a novel process for the preparation of Retigabine intermediate 2-ethoxycarbonylamino-5-(4- fluorobenzylamino)-nitrobenzene of formula T comprising reaction of 5-amino-2-ethoxycarbonylamino-nitrobenzene of formula R with 4- fluorobenzaldehyde of formula L with sodium borohydride in aqueous isopropanol thus avoiding the formation/ isolation of intermediate of formula S.

The same reaction is also performed using sodium triacetoxyborohydride in non-aqueous solvent like halogenated solvent preferably methylenedichloride avoiding the formation/ isolation of compound of formula S.

e

In another preferred embodiment disclosed herein is a novel process for the preparation of Retigabine intermediate of formula N comprising contacting 2-nitrobenzene-l,4-diamine of formula K with 4- fluorobenzaldehyde of formula L and sodium borohydride in aqueous isopropanol thus avoiding the formation/ isolation of imine intermediate of formula M

The same reaction is performed by using sodium triacetoxyborohydride in non-aqueous solvent like halogenated solvent preferably methylenedichloride avoiding the formation/ isolation of compound of formula M.

The term "solvent system comprising water" used herein above and below in the specification is also referred as aqueous solvent.

INDIRECT REDUCTIVE AMINATION: Referring tenth, eleventh, twelfth and thirteenth aspect of the present invention in a general embodiment disclosed herein is a novel process for the preparation of Retigabine intermediates based on the concept of indirect reductive amination wherein it comprises first reaction of an amine with carbonyl compound generating a hydroxyl amine which on subsequent loss of water form an imine, simultaneous removal of water by physical or chemical means predominates the formation of imine which is then optionally isolated and further reduced by suitable reducing agent selected from borohydrides in a solvent system comprising water as a element.

In a preferred embodiment disclosed herein is a novel process for the preparation of Retigabine intermediates based on the concept of indirect reductive amination comprising contacting 5-amino-2- ethoxycarbonylamino-nitrobenzene of formula R with 4- fluorobenzaldehyde of formula L forming hydroxyl amine which subsequently looses water forming imine of the formula S. The compound of formula S is then optionally isolated and further reduced with sodium borohydride in a solvent system comprising water as one of the solvents resulting into the formation of compound of formula T.

Solvent is selected from group comprising of alcohol preferably ethanol and isopropanol.

In another preferred embodiment disclosed herein is a novel process for the preparation of Retigabine intermediates based on the concept of indirect reductive amination comprising contacting 2-nitrobenzene-l,4- diamine of formula K with 4-fluorobenzaldehyde of formula L forming hydroxyl amine which subsequently looses water forming imine of the formula M. The compound of formula M is then optionally isolated and further reduced with sodium borohydride in a solvent system comprising water as one of the solvents resulting into the formation of compound of formula N.

REDUCTION OF IMINE: In a preferred embodiment disclosed herein is a novel process for the preparation of Retigabine intermediate of formula T comprising contacting 2-ethoxycarbonylamino-5-(4- fluorobenzylideneamino)-nitrobenzene of formula S with metal borohydride in a solvent for the reduction of double bond.

In a more preferred embodiment disclosed herein is a novel process for the preparation of Retigabine intermediate (4-fluorobenzyl)-3- nitrobenzene-l,4-diamine of Formula N comprising contacting compound of formula M with metal borohydride in a solvent for reduction of double bond.

There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved. Examples of suitable solvents include protic solvents comprising water as one solvent and mixture thereof. Preferable solvent is isopropyl alcohol, water or mixture thereof. Moreover it is observed that the use of isopropanol as selective solvent does not result into the formation of transesterified impurity of formula U, however methanol does form the impurity of formula U. Metal borohydride used in specification hereinabove is selected from sodium borohydride, lithium borohydride, zinc borohydride, calcium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and the like. Preferably metal borohydride is sodium borohydride or sodium triacetoxyborohydride.

REDUCTION OF NITRO TO AMINE: Referring fourteenth and fifteenth aspect of the present invention in a preferred embodiment disclosed herein is a novel process for the preparation of Retigabine comprising reduction of nitro group of 2-ethoxycarbonylamino-5-(4- fluorobenzylamino)nitrobenzene of formula T to produce Retigabine base of formula (I) comprising catalytic hydrogenation using alcohol- base combination that enhances the yield and purity.

In another preferred embodiment disclosed herein is a novel process for the preparation of Retigabine base of formula I comprising reduction of nitro group of 2-ethoxycarbonylamino-5-(4- fluorobenzylamino)nitrobenzene formula T to produce Retigabine base of formula (I) comprising catalytic transfer hydrogen reaction with ammonium formate optionally in presence of alcohol-base combination as solvent system at atmospheric pressure avoiding external source of hydrogen gas and pressure reaction.

STEPS COMPRISING IN-SITU REACTIONS:

Referring sixteenth aspect of the present invention in a preferred embodiment disclosed herein is a novel process for the preparation of Retigabine and its pharmaceutically acceptable salts comprising reduction of nitro group and double bond of the compound of formula S simultaneously in a single step by catalytic hydrogenation as defined herein above using alcohol-base combination to directly produce the compound of formula I and optionally in-situ preparation of its acid addition salt of formula IA is advantageous in terms of reduction of process operational steps and also eliminate the use of metal borohydrides for reduction.

Reduction of nitro group and double bond of the compound of formula S simultaneously in a single step by catalytic hydrogenation as defined herein above using alcohol-base combination to directly produce the compound of formula I and optionally in-situ preparation of its acid addition salt of formula IA is advantageous in terms of reduction of unit operations. Referring seventeenth aspect of the present invention in a preferred embodiment disclosed herein is a novel process for the preparation of Retigabine intermediate of formula T comprising the reaction of the compound 5-amino-2-ethoxycarbonylamino nitrobenzene of formula R with 4-fluorobenzaldehyde of formula L in an alcoholic solvent forming imine compound of formula S and in-situ reducing double bond by the addition of metal borohydride resulting into the formation of 2- ethoxycarbonylamino-5-(4-fluorobenzylamino)-nitrobenzene of formula T, thereby reducing the unit operations.

Not isolated

Referring Eighteenth aspect of the present invention in a preferred embodiment disclosed herein is a novel process for the preparation of Retigabine and its pharmaceutically acceptable salts comprising the reaction of the compound 5-amino-2-ethoxycarbonylamino nitrobenzene of formula R with 4-fluorobenzaldehyde of formula L in an alcoholic solvent forming imine compound of formula S and in-situ adding a base generating the alcohol-base combination as solvent system and hydrogenating double bond and nitro group simultaneously by catalytic hydrogenation resulting into the formation of Retigabine base of formula I and then reacting the Retigabine base thus formed, optionally in-situ with pharmaceutically acceptable acid in solution to get retigabine acid addition salt thereby reducing the unit operations.

The base for the preparation of the alcohol-base combination is selected from ammonia, ammonia derivatives, organic bases selected from primary, secondary or tertiary alkyl amines, piperidine, optionally substituted pyridines, picolines and the like. Alcohol for the alcohol-base combination is selected from Q-C₇ aliphatic alcohols. Preferable alcohols are Q to C₃ alcohols.

Preferably alcohol-base combinations are Q to C₇ alcohol-ammonia or Ci to C₇ alcohol-triethylamine or d to C₇ alcohol-ethylene diamine or mixture thereof.

Reduction of nitro group can be carried out with nascent hydrogen or by catalytic hydrogenation or by catalytic transfer hydrogen reaction. For reduction, the hydrogen source is selected from metal/ mineral acid like zinc/hydrochloric acid, tin/hydrochloric acid, iron/hydrochloric acid or salts of hydrogen sulfide in alcohol/water or activated aluminum in aqueous ether or tin II chloride/hydrochloric acid or raney nickel- hydrazine or Pd/C-hydrazine or zinc dust-ammonium formate or Pd/C- ammonium formate system or NaH₂P0₂-Pd/C or Cr(II)Cl₂-HCl or Pd/C- triethylsilane or combinations thereof.

Catalyst for hydrogenation is selected from raney nickel, palladium, platinum, platinum dioxide and the like as well as compounds thereof, with and without carriers. Carrier is selected from barium sulphate, calcium sulphate, carbon and the like. For catalytic hydrogenation, preferably the catalyst is palladium with carbon as a carrier. While for catalytic transfer hydrogen reaction, preferred system is Pd/C- ammonium formate optionally together with alcohol-base combination.

The reduction is carried out by nascent hydrogen or by catalytic hydrogenation or by catalytic transfer hydrogen reaction. For reduction, the hydrogen source is selected from zinc/hydrochloric acid, tin/hydrochloric acid, iron/hydrochloric acid or salts of hydrogen sulfide in alcohol/water or activated aluminum in aqueous ether or tin II chloride/hydrochloric acid or raney nickel-hydrazine or Pd/C-hydrazine or zinc dust-ammonium formate or Pd/C-ammonium formate system or NaH₂P0₂-Pd/C or Cr(II)Cl₂-HCl or Pd/C-triethylsilane or by combinations thereof.

Preferably the catalyst is Pd/C and alcohol-base combinations are Q to C₇ alcohol-ammonia or Q to C₇ alcohol-triethylamine or d to C₇ alcohol-ethylene diamine or mixture thereof. While for catalytic transfer hydrogen reaction, preferably the system is Pd/C-ammonium formate optionally together with alcohol-base combination.

Catalytic hydrogen reaction is carried out at temperatures from about 20°C to about 100°C, and a pressure of about 1 bar to about 70 bars.

After reduction, the Retigabine base of formula (I) thus obtained is isolated or converted directly in-situ into its pharmaceutically acceptable acid addition salts of formula (IA) by contacting with pharmaceutically acceptable acids. The acid moiety is selected from inorganic or organic acids, in particular those which are suitable for forming pharmaceutically useful salts. Preferable acid moiety is hydrochloric acid.

The term alcohol-base used herein above and below in the specification is also referred as alkaline medium. The invention is explained in its best way by examples herein given below. It will be apparent to those skilled in the art that the various modifications and variations can be made in the present invention and specific examples provided herein without departing from the spirit or scope of the invention. Thus, it is intended that the present invention covers the modifications and variations of this invention that come within the scope of any claims and their equivalents.

The following examples are for illustrative purposes only and are not intended, or should they be interpreted to limit the scope of the invention.

EXAMPLE-1: Preparation of 2-ethoxycarbonylamino-5- phthalimidonitrobenzene from N-ethoxycarbonylamino-p- phenylenediamine.

Experiment- 1 : Phthalic anhydride (199 g) is added in 30 minutes in the stirred solution of N-ethoxycarbonylamino-p-phenylenediamine (220 g) in acetic acid (3740 ml) at room temperature under inert atmosphere. Reaction mass is heated to 90-95°C for 1 hour. Then cone. (69%) nitric acid (117.6 ml) is added in 30-45 minutes and the reaction mass is stirred at 100-105°C for 2-3 hrs. The reaction mass is cooled to RT and stirred at RT for 1.5 hrs. Solid appeared is filtered and washed with DM water and dried under vacuum at 60-65°C to produce 2- ethoxycarbonylamino-5-phthalimido nitrobenzene (392 g) as yellow colored solid. Yield: 90%; HPLC purity: 99.3%.

EXAMPLE-2: Preparation of l-ethoxycarbonylamino-4- phthalimidobenzene from N-ethoxycarbonylamino-p- phenylenediamine.

Experiment-2: Phthalic anhydride (9.04 g) is added in 30 minutes in the stirred solution of N-ethoxycarbonylamino-p-phenylenediamine (10 g) in DMF (30 ml) at room temperature under inert atmosphere. Reaction mass is heated to 90-95°C for 1 hour. Then reaction mass is cooled to RT and stirred for 1 hour at RT. Solid appeared is filtered, washed with DM water (10 ml) and dried under vacuum at 60-65 °C to produce 1- ethoxycarbonylamino-4-phthalimidobenzene (10.4 g) as off-white colored solid. Yield: 60.3%, HPLC purity: 99.06%.

EXAMPLE-3: Preparation of 5-amino-2-ethoxycarbonylamino nitrobenzene from 2-ethoxycarbonylamino-5-phthalimido nitrobenzene

Experiment-3: To the stirred solution of isopropyl alcohol (125 ml) and mono methyl amine (40% aqueous solution) (25 ml), 2- ethoxycarbonylamino-5-phthalimido nitrobenzene (25 g) is added at RT. Reaction mass is stirred at 60-65 °C for 2 hours and then cooled to RT and DM water (120 ml) is added in 30-45 minutes. The reaction mass is stirred at RT for 90 minutes, the solid appeared, is filtered, washed with DM water and dried under vacuum at 40-45°C to get 5-amino-2- ethoxycarbonylamino nitrobenzene (14.5 g) as dark red crystalline product. Yield: 91.5%; HPLC purity: 99.93%.

Experiment-4: To the stirred solution of isopropyl alcohol (75 ml) and DM water (100 ml), mono methyl amine (40% aqueous solution) (25 ml) is added at RT. Then 2-ethoxycarbonylamino-5-phthalimido nitrobenzene (25 g) is added and the reaction mass is stirred at 60-65°C for 2 hours. Then reaction mass is cooled to RT and DM water (75 ml) is added in 30-45 minutes. The reaction mass is stirred at RT for 90 minutes, then solid appeared is filtered, washed with DM water and dried under vacuum at 40-45°C to get 5-amino-2-ethoxycarbonylamino nitrobenzene (15.4 g) as dark red crystalline product. Yield: 97.2%; HPLC purity: 99.36%.

Experiment-5: To the stirred solution of isopropyl alcohol (50 ml) and liquor ammonia (50 ml) at 25-30°C, 2-ethoxycarbonylamino-5- phthalimido nitrobenzene (10 g) is added. The reaction mass is stirred at 60-65 °C for 5-6 hours. Then reaction mass is cooled to RT and DM water (120 ml) is added in 30-45 minutes through addition funnel. The reaction mass is stirred at RT for 90 minutes, then appeared solid is filtered, washed with DM water and dried under vacuum at 40-45°C to get 5-amino-2-ethoxycarbonylamino nitrobenzene (5.1 g) as dark red crystalline product. Yield: 80%; HPLC purity: 98.73%. EXAMPLE-4: Preparation of 2-ethoxycarbonylamino-5-(4- fluorobenzylideneamino)nitrobenzene from 5-amino-2- ethoxycarbonylamino nitrobenzene.

Experiment-6: To the stirred solution of 5-amino-2- ethoxycarbonylamino nitrobenzene (14 g) in methanol (70 ml), 4- fluorobenzaldehyde (7.3 ml) is added slowly through addition funnel in 10-15 minutes at RT. Reaction mass is refluxed for 16-18 hrs. Then reaction mass is cooled to 10-15°C and stirred at 10-15°C for 30 minutes. Solid appeared is filtered, washed with chilled methanol and dried under vacuum at 40-45°C to get 2-ethoxycarbonylamino-5-(4- fluorobenzylideneamino)nitrobenzene (19.8 g) as product. Yield: 96.16%; HPLC Purity: 99.28%.

Experiment-7: To the stirred solution of 5-amino-2- ethoxycarbonylamino nitrobenzene (10 g) in ethanol (50 ml), 4- fluorobenzaldehyde (5.18 ml) is added slowly through addition funnel in 10-15 minutes at RT. Reaction mass is stirred at 60-65°C for 16-18 hrs and then cooled to 10-15°C and stirred at 10-15°C for 30 minutes. Solid appeared is filtered, washed with chilled ethanol and dried under vacuum at 40-45°C to get 2-ethoxycarbonylamino-5-(4-fluorobenzylideneamino) nitrobenzene (14.4 g) as product. Yield: 97.9%; HPLC Purity: 99.17%

EXAMPLE-5: Preparation of 2-ethoxycarbonylamino-5-(4- fluorobenzylamino) nitrobenzene from 2-ethoxycarbonylamino-5-(4- fluorobenzylideneamino)nitrobenzene.

Experiment-8: In a mixture of isopropyl alcohol (1.59 L) and DM water (72 ml), 2-ethoxycarboriylamino-5-(4-fluorobenzylideneamino) nitrobenzene (265 g) is added at RT. The reaction mass is cool to 0-5°C and sodium borohydride (45.6 g) is added slowly in 2 hours in four equal lots at time interval of 30 minutes. The reaction mass is stirred at 25- 30°C for 14-16 hrs, then cooled to 0-5°C and the pH is adjusted to 1.5- 2.0 with 4N HC1 The reaction mass is stirred at 25-30°C and for 30 minutes. Again the pH is adjusted to 10-10.5 with liquor ammonia solution at 10-15°C. After Stirring at 10-15°C for 30 minutes, the solid is filtered, washed with DM water and dried under vacuum at 40-45°C to get 2-ethoxycarbonylamino-5-(4-fluorobenzylamino)nitrobenzene (256.2 g) as dark red colored crystalline product. Yield: 96.1%; HPLC Purity: 99.69%.

Experiment-9: In a mixture of isopropyl alcohol (284 ml) and DM water (19.3 ml), 2-ethoxycarbonylamino-5-(4-fluorobenzylideneamino) nitrobenzene (71 g) is added at RT. Then sodium borohydride (12.22 g) is added slowly in 2 hours in four equal lots at time interval of 30 minutes at RT and stirred at RT for 14-16 hrs. The pH is adjusted to 1.5- 2.0 with 4N HC1 maintaining temperature 25-30°C and stirred for 30 minutes at RT. The pH is again adjusted to 10-10.5 with liquor ammonia maintaining temperature 25-30°C. Reaction mass is stirred at 25-30°C for 30 minutes and the solid is filtered, washed with DM water and dried under vacuum at 40-45°C to get 2-ethoxycarbonylamino-5-(4- fluorobenzylamino)nitrobenzene (66.7 g) as dark red colored crystalline product. Yield: 93.4%; HPLC Purity: 99.87%.

Experiment- 10: 2-Ethoxycarbonylamino-5-(4-fluorobenzylideneamino) nitrobenzene (50 g) is taken in ethanol (300 ml) at RT. The reaction mass is cooled to 0-5°C and sodium borohydride (5.75 g) is added slowly in 2 hours in four equal lots at time interval of 30 minutes. The reaction mass is stirred at RT for 6-8 hrs, then cooled to 0-5°C and the pH is adjusted to 1.5-2.0 with 4NHC1. The reaction mass is stirred at 25- 30°C for 30 minutes and again the pH is adjusted to 10-10.5 with liquor ammonia solution at 10-15°C. The reaction mass is stirred for 30 minutes at RT and the solid that appeared is filtered, washed with DM water and dried under vacuum at 40-45°C to get 2- ethoxycarbonylamino-5-(4-fluorobenzylamino)nitrobenzene (48.3 g) as dark red colored crystalline product. Yield: 96.0%; HPLC Purity: 99.5%

EXAMPLE-6: Preparation of 2-ethoxycarbonylamino-5-(4- fluorobenzylamino)nitrobenzene from 5-amino-2- ethoxycarbonylamino nitrobenzene.

Experiment-11: 5-Amino-2-ethoxycarbonylamino nitrobenzene (10 g) and 4-fluorobenzaldehyde (5.9 ml) in isopropyl alcohol (84 ml) and DM water (3.8 ml) are mixed under stirring at RT. Then sodium borohydride (3.21 g) is added slowly in 2 hours in four equal lots at time interval of 30 minutes at RT and stirred at RT for 25-27 hrs. Then the pH of the reaction mixture is adjusted to 1.5-2.0 with 4N HC1 maintaining temperature 25-30°C and stirred for 30 minutes at RT. Again the pH is adjusted to 10-10.5 with liquor ammonia maintaining temperature 25- 30°C. The reaction mass is stirred at 25-30°C for 30 minutes and the solid appeared is filtered, washed with DM water and dried under vacuum at 40-45°C to get 2-ethoxycarbonylamino-5-(4- fluorobenzylamino)nitrobenzene (12.1 g) as dark red colored crystalline product. Yield: 81.7%; HPLC Purity: 99.08%

Experiment- 12: Acetic acid (12.3 ml) is added slowly in four hours to the stirred solution of sodium borohydride (2.57 g) in methylene dichloride (90 ml) at 25-30°C under inert atmosphere. The reaction mass is stirred for 15 hours, until evolution of hydrogen gas ceases. Then the mixture of 5-amino-2-ethoxycarbonylamino nitrobenzene (10 g) and 4- fluorobenzaldehyde (5.5 g) in methylene dichloride (50 ml) is added to the above mixture at RT and stirred for 27-29 hours at RT. The reaction mass is basified by adding liquor ammonia solution (19 ml) maintaining temperature at 10-15°C. DM water (100 ml) is added and layers are separated. Aqueous layer is extracted by methylene dichloride (50 ml X 2). Combine organic layer is washed with IN HC1 solution followed by brine solution and methylene dichloride is evaporated to get 2- ethoxycarbonylamino-5-(4-fluorobenzylamino)nitrobenzene (14.5 g) as crude product. This crude product is dissolved in isopropyl alcohol (58 ml) and recrystallised by adding water (58 ml) slowly in 30 minutes at RT. The reaction mass is stirred at 10-15°C for 30 minutes and filtered, washed with DM water and dried under vacuum at 40-45 °C to get 2- ethoxycarbonylamino-5-(4-fluorobenz lamino)nitrobenzene (11.4 g) as dark red colored crystalline product. Yield: 75.3%; HPLC purity: 98.4%

EXAMPLE-7: Preparation of 2-ethoxycarbonylamino-5-(4- fluorobenzylamino) nitrobenzene from 5-amino-2- ethoxycarbonylamino nitrobenzene

Experiment- 13: To the stirred solution of 5-amino-2- ethoxycarbonylamino nitrobenzene (10 g) in methanol (100 ml) is added 4-fluorobenzaldehyde (5.7 ml) slowly through addition funnel in 10-15 minutes at RT. Reaction mass is refluxed for 16-18 hrs. Then sodium borohydride (3.2 g) is added slowly in 2 hours in four equal lots at time interval of 30 minutes at RT and stirred at RT for 3-4 hrs. Then adjust the pH to 1.5-2.0 with 4N HCl maintaining temperature 25-30°C and stir for 30 minutes at RT. Again adjust the pH to 10-10.5 with liquor ammonia maintaining temperature 25-30°C. Stir at 25-30°C for 30 minutes and filtered the solid, washed with DM water and dried under vacuum at 40-45°C to get 2-ethoxycarbonylamino-5-(4- fluorobenzylamino) nitrobenzene (12.2 g) as dark red colored crystalline product. Yield: 82.4%; HPLC Purity: 93.7%

EXAMPLE-8: Preparation of Retigabine base from 2- ethoxycarbonylamino-5-(4-fluorobenzylamino) nitrobenzene

Experiment- 14: In an autoclave vessel, 2-ethoxycarbonylamino-5-(4- fluorobenzylamino) nitrobenzene (60 g) and 10% Pd-C (1.8 g) are added into methanolic ammonia solution (1% w/w) (1200 ml) under nitrogen atmosphere. The reaction mixture is hydrogenated at 3-4 Kg/cm pressure at 25-30°C for 2.5-3.5 hours. After completion of reaction, activated charcoal (5% w/w) is added and reaction mixture is stirred for 30 minutes at 25-30°C before filtration through hyflo bed under inert atmosphere. Methanolic ammonia is distilled upto 3 volumes under vacuum at 40-45 °C, then reaction mass is cooled to 0-5 °C and stirred at 0-5°C for 1 hour. Solid appeared is filtered, washed with chilled methanol and dried under vacuum at 40-45°C to get Retigabine base (45.6 g) as light grey to off-white coloured crystalline material. Yield: 83.5%; HPLC Purity: 99.95%, any single impurity < 0.1%.

Experiment- 15: In an autoclave vessel, 2-ethoxycarbonylamino-5-(4- fluorobenzylamino)nitrobenzene (14 g), methanol (280 ml), triethylamine (0.28 ml) and 10% Pd-C (0.42 g) are taken under nitrogen. The reaction mixture is hydrogenated at 3-4 Kg/cm pressure at 25-30°C for 3-3.5 hours. After completion of the reaction, activated charcoal (5% w/w) is added and stirred for 30 minutes at 25-30°C. The reaction mixture is filter through hyflo bed under inert atmosphere. Methanol is distilled upto 3 volumes and stirred at 0-5°C for 1 hour. Solid appeared, is filtered, washed with chilled methanol and dried under vacuum at 40- 45°C to get Retigabine base (10.5 g) as light grey to off-white colored crystalline material. Yield: 82.4%; HPLC Purity: 99.78%, any single impurity < 0.1%.

EXAMPLE-9: Preparation of Retigabine base from 2- ethoxycarbonylamino-5-(4-fluorobenzylamino)nitrobenzene by catalytic transfer hydrogenation.

Experiment- 16: 2-Ethoxycarbonylamino-5-(4-fluorobenzylamino) nitrobenzene (5.0 g) is stirred with 10% Pd-C (0.5 g), triethylamine (0.5 ml) and ammonium formate (4.73 g) under nitrogen atmosphere in methanol (100 ml) at 25-30°C for 5-6 hours. After completion of reaction, activated charcoal (5% w/w) is added and stirred for 30 minutes at 25-30°C then filtered through hyflo bed under inert atmosphere. Methanol is distilled upto 3 volumes under vacuum at 40- 45°C, then cooled to 0-5°C and stirred at 0-5°C for 1 hour. Solid appeared is filtered, washed with chilled methanol and dried under vacuum at 40-45°C to get Retigabine base (2:8 g). Yield: 61.5%; HPLC Purity: 96.78%.

Experiment- 17: 2-Ethoxycarbonylamino-5-(4-fluorobenzylamino) nitrobenzene (5.0 g) is stirred with 10% Pd/C (0.5 g) and ammonium formate (4.73 g) under nitrogen in methanol (100 ml) at 25-30°C for 5-6 hours. After completion of reaction, activated charcoal (5% w/w) is added and stirred for 30 minutes at 25-30°C then filtered through hyflo bed under inert atmosphere. Methanol is distilled upto 3 volumes under vacuum at 40-45°C, then cooled to 0-5°C and stirred at 0-5°C for 1 hour. Solid appeared is filtered, washed with chilled methanol and dried under vacuum at 40-45°C to get Retigabine base (2.68 g). Yield: 58.9%; HPLC Purity: 96.92%.

EXAMPLE-10: Preparation of Retigabine base from 2- ethoxycarbonylamino-5-(4-fluorobenzylideneamino)nitrobenzene.

Experiment- 18: In an autoclave vessel, 2-ethoxycarbonylamino-5-(4- fluorobenzylideneamino)nitrobenzene (15 g) in methanol (300 ml), triethylamine (3.0 ml) and 10% Pd-C (0.9 g) are taken under nitrogen atmosphere. The reaction mixture is hydrogenated at 3-4 Kg/cm² pressure at 25-30°C for 10-11 hours. After completion of reaction, activated charcoal (5% w/w) is added and stirred for 30 minutes at 25- 30°C then the reaction mass is filter through hyflo bed and washed with methanol under inert atmosphere. Methanol is distilled upto 3 volumes under vacuum at 40-45°C. Then reaction mass is cool to 0-5°C and stir at 0-5°C for 1 hour. Solid appeared is filtered, washed with chilled methanol and dried under vacuum at 40-45°C to get Retigabine base (8.8 g) as light grey to off-white colored crystalline material. Yield: 64.1%; HPLC purity: 98.2%.

EXAMPLE -11 : Preparation of Retigabine base from 5-amino-2- e

Experiment- 19: To the stirred solution of 5-amino-2- ethoxycarbonylamino nitrobenzene (7.0 g) in methanol (70 ml) is added 4-fluorobenzaldehyde (3.3 ml) slowly through addition funnel in 10-15 minutes at RT. Reaction mass is refluxed for 16-18 hrs. Then reaction mass is cooled to 25-30°C and stirred for 30 minutes and then transfer the reaction mass in an autoclave flask. To this was added methanol (125 ml), triethylamine (1.0 ml) and 10% Pd-C (0.29 g) under nitrogen. The reaction mixture is hydrogenated at 3-4 Kg/cm² pressure at 25-30°C for 10-11 hours. After completion of reaction activated charcoal (7% w/w) is charged and stirred for 30 minutes at 25-30°C then filter through hyflo bed and washed with methanol under inert atmosphere. Distill the methanol upto 3 volumes under vacuum at 40-45°C. Cool to 0-5 °C and stir at 0-5°C for 30 minutes. Solid appeared is filtered, washed with chilled methanol and dried under vacuum at 40-45 °C to get retigabine base (4.0 g) as crystalline material. HPLC purity: 91.72%

EXAMPLE-12: Preparation of Retigabine dihydrochloride from Retigabine base.

Experiment-20: Retigabine base (22 g) is taken in methanol (264 ml) and stirred for 20-30 minutes at RT. Then methanolic-HCl (23% w/w) (40.3 g) is added slowly through addition funnel in 20-30 minutes. The reaction mass is stirred to 25-30°C in 2 hours. Solid appeared is filtered, washed with methanol and dried under vacuum at 40-45°C to get Retigabine dihydrochloride (25.0 g) as off-white coloured crystalline material. Yield: 91.6%; HPLC Purity: 99.96%, any single impurity < 0.1%.

Experiment-21 : Retigabine base (15 g) is taken in ethanol (180 ml) and stirred for 20-30 minutes at RT. Then ethanolic-HCl (27% w/w) (23.4 g) is added slowly through addition funnel in 20-30 minutes. Reaction mass is cooled to 25-30°C and further stirred for 1 hour at 25-30°C. Solid appeared is filtered, washed with ethanol (15 ml) and dried under vacuum at 40-45°C to get the Retigabine dihydrochloride (14.8 g) as off- white coloured crystalline material. Yield: 80%; HPLC Purity: 99.5%, any single impurity < 0.1 %.

EXAMPLE-13: Preparation of Retigabine dihydrochloride from 2- ethoxycarbonyl amino-5-(4-fluorobenzylamino) nitrobenzene.

Experiment-22: In an autoclave vessel, 2-ethoxycarbonylamino-5-(4- fluorobenzylamino) nitrobenzene (15 g), methanol (300 ml), triethylamine (1.5 ml) and 10% Pd-C (0.45 g) are taken under nitrogen atmosphere. The reaction mixture is hydrogenated at 3-4 Kg/cm pressure at 25-30°C. After completion of the reaction, activated charcoal (5% w/w) is charged and stirred for 30 minutes at 25-30°C. Then filtered through hyflo bed and washed with methanol under inert atmosphere. Methanol is distilled upto 5 volumes under vacuum at 40-45°C. To this clear solution, methanolic HC1 (35.07 g, 23% w/w) is added slowly at 40-45°C in 20-30 minutes and the reaction mass is cooled to 25-30°C and stirred at 25-30°C for 1 hour, appeared solid is filtered, washed with methanol and dried under vacuum at 40-45 °C to get the Retigabine dihydrochloride (14.5 g) as off-white coloured crystalline material. Yield: 85.6%, HPLC Purity: 99.74%, any single impurity < 0.1%. Experiment-23: In an autoclave vessel, 2-ethoxycarbonylamino-5-(4- fluorobenzylamino)nitrobenzene (15 g) in methanolic ammonia 0.5% w/w (300 ml) and 10% Pd-C (0.45 g) are taken under nitrogen atmosphere. The reaction mixture is hydrogenated at 3-4 Kg/cm² pressure at 25-30°C. After completion of the reaction, activated charcoal (5% w/w) is added and reaction mixture is stirred for 30 minutes at 25- 30°C then filtered through hyflo bed and washed with methanol under inert atmosphere. Methanol is distilled upto 5 volumes under vacuum at 40-45°C and to this clear solution methanolic HCl (35.7 g, 23% w/w) is added slowly at 40-45°C. Reaction mass is then cooled to 25-30°C and stirred at 25-30°C for 1 hour. Solid is filtered, washed with methanol and dried under vacuum at 40-45°C to get the Retigabine dihydrochloride (15.0 g) as off-white coloured crystalline material. Yield: 88.5%; HPLC purity: 99.39%

EXAMPLE-14: Preparation of Retigabine dihydrochloride from 2- ethoxycarbonyl amino-5-(4-fluorobenzylamino)nitrobenzene by catalytic transfer hydrogenation.

Experiment-24: 2-Ethoxycarbonylamino-5-(4-fluorobenzylamino) nitrobenzene (5.0 g) is stirred with 10% Pd-C (0.5 g), triethylamine (0.5 ml) and ammonium formate (4.73 g) under nitrogen in methanol (100 ml) at 25-30°C for 5-6 hours. After completion of the reaction, activated charcoal (5% w/w) is added and stirred for 30 minutes at 25-30°C and then filtered through hyflo bed under inert atmosphere. Methanol is distilled upto 5 volumes under vacuum at 40-45°C then methanolic-HCl (23% w/w, 11.9 g) is added at 40-45°C in 20-30 minutes. Then reaction mass is cooled to 25-30°C and stirred for 1 hour. Solid appeared is filtered, washed with methanol and dried under vacuum at 40-45 °C to get Retigabine dihydrochloride (3.8 g) as off-white coloured crystalline solid. Yield: 67.7%; HPLC Purity: 97.86%.

Experiment-25 : 2-Ethoxycarbonylamino-5-(4-fluorobenzylamino) nitrobenzene (5.0 g) is stirred with 10% Pd-C (0.5 g) and ammonium formate (4.73 g) under nitrogen in methanol (100 ml) at 25-30°C for 5-6 hours. After completion of the reaction, activated charcoal (5% w/w) is added and stirred for 30 minutes at 25-30°C then filtered through hyflo bed under inert atmosphere. Methanol is distilled upto 5 volumes under vacuum at 40-45°C then methanolic-HCl (23% w/w, 11.9 g) is added at 40-45°C in 20-30 minutes. Then reaction mass is cooled to 25-30°C and stirred for 1 hour. Solid appeared is filtered, washed with methanol and dried under vacuum at 40-45°C to get Retigabine dihydrochloride (4.39 g) as off-white coloured crystalline solid. Yield: 77.83; HPLC Purity: 97.77%.

EXAMPLE-15: Preparation of Retigabine dihydrochloride from 2- ethoxycarbonyl amino-5-(4-fluorobenzylideneamino) nitrobenzene.

Experiment-26: In an autoclave vessel, 2-ethoxycarbonylamino-5-(4- fluoro benzylideneamino)nitrobenzene (18 g) in methanol (360 ml), triethylamine (1.8 ml) and 10% Pd-C (0.54 g) are taken under nitrogen atmosphere. The reaction mixture is hydrogenated at 3-4 Kg/cm pressure at 30-35°C for 8-9 hours. After completion of the reaction, activated charcoal (5% w/w) is added and stirred for 30 minutes at 25- 30°C then filter through hyflo bed and washed with methanol under inert atmosphere. Methanol is distilled upto 5 volumes under vacuum at 40- 45°C, to this clear solution, methanolic-HCl (30.02 g, 23% w/w) is added at 40-45°C. The reaction mass is cooled to 25-30°C and stirred for 1 hour. Solid appeared, is filtered, washed with methanol and dried under vacuum at 40-45°C to get the Retigabine dihydrochloride (16.08 g) as off-white coloured crystalline material. Yield: 78.2%; HPLC purity: 95.2%

EXAMPLE 16: Preparation of Retigabine dihydrochloride salt from 5-amino-2-ethoxycarbonylamino nitrobenzene

Experiment-27: To the stirred solution of 5-amino-2- ethoxycarbonylamino nitrobenzene (7.0 g) in methanol (70 ml) is added 4-fluorobenzaldehyde (3.3 ml) slowly through addition funnel in 10-15 minutes at RT. Reaction mass is refluxed for 16-18 hrs. Then reaction mass is cooled to 25-30°C and stirred for 30 minutes and then transfer the reaction mass in an autoclave flask. To this was added methanol (125 ml), triethylamine (1.0 ml) and 10% Pd-C (0.29 g) under nitrogen. The reaction mixture is hydrogenated at 3-4 Kg/cm2 pressure at 25-30°C for 10-11 hours. After completion of reaction activated charcoal (7% w/w) is charged and stirred for 30 minutes at 25-30°C then filter through hyflo bed and washed with methanol under inert atmosphere. Distill the methanol upto 5 volumes under vacuum at 40-45°C. Then charged methanolic -HCl 23% w/w (12.75 g) at 40-45°C. Cool to 25-30°C and stir at 25-30°C for 1 hour. Solid appeared is filtered, washed with methanol and dried under vacuum at 40-45 °C to get retigabine dihydrochloride (3.69 g) crystalline material. HPLC purity: 87.27%.

Example-17: Preparation of 2-amino-5-(4-fluorobenzylideneamino) nitrobenzene from 2-nitro-p-phenylenediamine

Experiment-28: To the stirred solution of 2-nitro-p-phenylenediamine (50 g) in methanol (300 ml) is added 4-fluorobenzaldehyde (38.6 ml) slowly through addition funnel in 10-15 minutes at RT. Reaction mass is refluxed for 16-18 hrs. Then reaction mass is cooled to 0-5°C and stirred for 30 minutes. Solid appeared is filtered, washed with chilled methanol and dried under vacuum at 40-45°C to get 2-amino-5-(4- fluorobenzylideneamino)nitrobenzene (83.2 g) as product. Yield: 98.3%; HPLC Purity: 98.64%

Example-18: Preparation of 2-amino-5-(4-fiuorobenzylamino) nitrobenzene from 2-amino-5-(4-fluorobenzylideneamino) nitrobenzene

Experiment-29: In a mixture of isopropyl alcohol (320 ml) and DM water (27.8 ml) is charged 2-amino-5-(4-fluorobenzylideneamino) nitrobenzene (80 g) at RT. Then sodium borohydride (17.6 g) is added slowly in 2 hours in four equal lots at time interval of 30 minutes at RT and stirred at RT for 14-16 hrs. Then adjust the pH to 1.5-2.0 with 4N HC1 maintaining temperature 25-30°C and stir for 30 minutes at RT. Again adjust the pH to 10-10.5 with liquor ammonia maintaining temperature 25-30°C. Stir at 25-30°C for 30 minutes and filtered the solid, washed with aqueous HC1 solution followed by DM water and dried under vacuum at 40-45°C to get 2-amino-5-(4-fluorobenzylamino) nitrobenzene (68.5 g) as product. Yield: 85%; HPLC Purity: 95.9%

Example-19: Preparation of 2-amino-5-(4-fluorobenzylamino) nitrobenzene from 2-nitro-p-phenylenediamine

Experiment-30: Charged 2-nitro-p-phenylenediamine (10 g) and 4- fluorobenzaldehyde (9.3 ml) in isopropyl alcohol (125 ml) and DM water (5.9 ml) mixture under stirring at RT. Then sodium borohydride (4.97 g) is added slowly in 2 hours in four equal lots at time interval of 30 minutes at RT and stirred at RT for 21-24 hrs. Then adjust the pH to 1.5-2.0 with 4N HC1 maintaining temperature 25-30°C and stir for 30 minutes at RT. Then filtered the residue, washed with plenty of DM water and residue was then taken in DM water and stirred for 20-30 minutes. The solid appeared is filtered, washed with DM water and dried under vacuum at 40-45°C to get 2-amino-5-(4-fluorobenzylamino) nitrobenzene (11.2 g) as product. Yield: 65.6%; HPLC Purity: 99.86%

Experiment-31 : Charged Acetic acid (23.1 ml) slowly in four hours to the stirred solution of sodium borohydride (5.04 g) in MDC (90 ml) at 25-30°C under inert atmosphere. Stir the reaction mass for 15 hours until evolution of hydrogen gas ceases. Then mixture of 2-nitro-p- phenylenediamine (10 g) and 4-fluorobenzaldehyde (7.0 ml) in methylene dichloride (50 ml) is added to the above mixture at RT. Stir for 48-56 hours at RT. Then basify by adding liquor ammonia solution (205 ml) maintaining temperature at 10-15°C. Add DM water (50 ml) and separated the layers. Aqueous layer is extracted by methylene dichloride (50 ml X 2); combine organic layer is washed with IN HCL solution followed by brine solution and methylene dichloride is evaporated under to get 2-amino-5-(4-fluorobenzylamino)nitrobenzene (12.79 g) as product. Yield: 75.0%; HPLC purity: 90.68%.

Claims

WE CLAIM:

1. A process for the preparation of the compound of formula (I)

Formula (I) and pharmaceutically acceptable acid addition salts thereof comprising: a) contacting N-ethoxycarbonylamino-p-phenylene diamine of formula (P) with amine protecting reagent in a solvent and then contacting the said reaction mixture with nitrating agent to produce compound of formula ');

Q'

wherein Pr is an amine protecting group as described hereinbefore specifications; b) contacting the compound of formula (Q') obtained above in step (a) with compound of formula RNH₂ to produce 5-amino-2- ethoxycarbonylamino-nitrobenzene of formula R;

Q" R wherein R selected from the group comprising of H, lower alkyl group, NH2-CO-, NH₂-CS-, Ar-CH₂- wherein Ar is phenyl or optionally substituted phenyl, lower alkyl group is linear or branched chain alkyl group having 1 to 12 carbon atoms. c) contacting 5-amino-2-ethoxycarbonylamino-nitrobenzene of formula R obtained above in step (b) with 4-fluorobenzaldehyde in a solvent to produce 2-ethoxy carbonylamino-5 -(4-fluorobenzylideneamino)- nitrobenzene of formula S optionally removing water formed during the react

d) contacting 2-ethoxycarbonylamino-5-(4-fluorobenzylideneamino)- nitrobenzene of formula S obtained above in step (c) with metal borohydride in a solvent system comprising water as one of the solvent to produce 2-ethoxycarbonylamino-5-(4-fluorobenzylamino)- nitrobenzene of formula T;

e) reducing 2-ethoxycarbonylamino-5-(4-fluorobenzylamino)- nitrobenzene of formula T obtained above in step (d), by catalytic hydrogenation comprising alcohol-base combination as solvent system or by catalytic transfer hydrogen reaction in presence of ammonium formate or formic acid optionally in alkaline medium to obtain substantially pure Retigabine base of formula (I) optionally isolating the base, contacting the said Retigabine base in-situ with an acid in a solvent to produce pharmaceutically acceptable Retigabine acid addition salt of formula (IA).

2. Process of claim 1 wherein amine protecting group selected from the group comprising carbobenzyloxy, tert-butyloxycarbonyl, 9- fluorenylmethyloxycarbonyl, acetyl, benzoyl, p-methoxybenzyl, 3,4- dimethoxybenzyl, p-methoxypheiiyl, tosyl, benzyl group, phthalimido group and preferably amine protecting group is phthalimido group.

3. Process of claim 1 wherein nitrating agent is selected from the group comprising HN0₃/AcOH, HN0₃/H₂S0₄, aq. HN0₃ at 343°K, HN0₃/ Ac₂0/AcOH, potassium nitrate/H₂S0₄ and preferably nitrating system is HN0₃ /AcOH.

4. Process of claim 1 wherein deprotecting agent is selected from the group comprising of formula RNH₂ wherein R is selected from the group comprising of H, lower alkyl group, NH₂-CO-, NH₂-CS-, Ar-CH₂- wherein Ar is phenyl or optionally substituted phenyl, lower alkyl group is linear or branched chain alkyl group having 1 to 12 carbon atoms

5. Process of claim 1, wherein solvent used in step c is selected from alcohols preferably methanol and ethanol.

6. Process of claim 1 wherein metal borohydride is selected from the group comprising sodium borohydride, lithium borohydride, zinc borohydride, calcium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and preferably metal borohydrides are sodium borohydride or sodium triacetoxyborohydride.

7. Process of claim 1, wherein solvent system used in step d comprising water as one solvent and alcohol as other element is preferably isopropanol.

8. Process of claim 1, wherein alcohol-base solvent system used in step e the base is selected from ammonia, ammonia derivatives, organic bases selected from primary, secondary or tertiary alkyl amines, piperidine, optionally substituted pyridines, picolines and the like preferably tertiary alkyl amine. Alcohol for the alcohol-base combination is selected from C C₇ aliphatic alcohols. Preferable alcohols are Q to C₃ alcohols.

9. A process for the preparation of 2-ethoxycarbonylamino-5-(4- fluorobenzylideneamino)-nitrobenzene of formula S used as a key intermediate for the preparation of Retigabine of the formula I, comprising contacting 5-amino-2-ethoxycarbonylamino-nitrobenzene of formula R with 4-fluorobenzaldehyde optionally in a solvent avoiding use of catalyst/ion-exchanger or water separator/ azeotropic distillation to take the reaction to completion.

10. A process for the preparation of intermediate 2- ethoxycarbonylamino-5-(4-fluorobenzylamino)-nitrobenzene of formula T used as a key intermediate for the preparation of Retigabine of formula I and its pharmaceutically acceptable salts as claimed in preceding claims comprising contacting 2-ethoxycarbonylamino-5-(4- fluorobenzylideneamino)-nitrobenzene of formula S with a metal borohydride in a solvent system comprising water as one of the solvent.

11. The process of claim 10 wherein the solvent system is selected from a mixture of water and alcohol preferably isopropanol.

12. A process for the preparation of Retigabine and its pharmaceutically acceptable salt comprising catalytic hydrogenation of the compound 2- ethoxycarbonylamino-5-(4-fluorobenzylamino)-nitrobenzene of formula T in presence of alcohol-base combination as solvent system resulting into the higher yield and better purity of Retigabine which is then optionally in-situ converted into its acid addition salt by contacting with pharmaceutically acceptable acid.

13. A process for the preparation of Retigabine and its pharmaceutically acceptable salt comprising catalytic transfer hydrogen reaction of the compound 2-ethoxycarbonylamino-5 -(4-fluorobenzylamino)- nitrobenzene of formula T at atmospheric pressure in presence of ammonium formate or formic acid optionally in alkaline medium.

14. The base for the preparation of the alcohol-base combination as per the claim 1,8 and 12 is selected from ammonia, ammonia derivatives, organic bases selected from primary, secondary or tertiary alkyl amines, piperidine, optionally substituted pyridines, picolines and the like preferably tertiary alkyl amine. Alcohol for the alcohol-base combination is selected from C C₇ aliphatic alcohols. Preferable alcohols are Q to C₃ alcohols.

15. A process for the preparation of the compound of formula (I)

Formula (I) and pharmaceutically acceptable acid addition salts thereof comprising: a) contacting N-ethoxycarbonylamino-p-phenylenediamine of formula (P) with amine protecting reagent in a solvent and then contacting the said reaction mixture with nitrating agent to produce compound of formula (Q');

wherein Pr is an amine protecting group as defined herein above; b) contacting the compound of formula (Q') obtained above in step (a) with compound of formula of RNH₂ to produce 5-amino-2- ethoxycarbonylamino-nitrobenzene of formula R

Q' R

wherein R is as defined herein above- c) direct reductive amination by contacting 5-amino-2- ethoxycarbonylamino-nitrobenzene of formula R with 4- fluorobenzaldehyde of formula L and metal borohydride in solvent system comprising water as one of solvents resulting into formation of 2- ethoxycarbonylamino-5-(4-fluoroberizylarnino)-nitrobenzene of formula T in a single step without formation/ isolation of imine of formula S

d) Reduction of 2-ethoxycarbonylamino-5-(4-fluorobenzylamino)- nitrobenzene of formula T in presence of alcohol-base either by catalytic hydrogenation or by catalytic transfer hydrogen reaction at atmospheric pressure in presence of ammonium formate or formic acid in alkaline medium resulting into the formation of Retigabine base of formula I and optionally isolating the base, contacting the said Retigabine base in-situ with an acid in a solvent to produce pharmaceutically acceptable Retigabine acid addition salt of formula (IA).

16. A process for the preparation of intermediate 2- ethoxycarbonylamino-5-(4-fluorobenzylamino)-nitrobenzene of formula T which is a key intermediate for the preparation of Retigabine of formula I and its pharmaceutically acceptable salts as claimed in claim 1 comprising contacting 2-ethoxycarbonylamino-5-(4- fluorobenzylideneamino)-nitrobenzene of formula S with a metal borohydride preferably sodium triacetoxyborohydnde in a non aqueous solvent preferably selected from the group of halogenated solvents.

17. Process of claim 15 wherein solvent system comprises aqueous alcohol selected from mixture of water and C1-C6 alcohol and preferably mixture of water and IP A.

18. Process of claim 15 and 16 wherein metal borohydride is selected from the group comprising sodium borohydride, lithium borohydride, zinc borohydride, calcium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and preferably metal borohydride is sodium borohydride or sodium triacetoxyborohydride.

19. A process for the preparation 2-ethoxycarbonylamino-5-(4r fluorobenzylamino)-nitrobenzene of formula T a key intermediate for the preparation of Retigabine and its pharmaceutically acceptable salts as claimed in claim 1 comprising direct reductive amination comprising contacting 5-amino-2-ethoxycarbonylamino-nitrobenzene of formula R with 4-fluorobenzaldehyde of formula L and sodium triacetoxyborohydride in a non-aqueous solvent selected from halogenated hydrocarbons.

20. A process for the preparation of the Retigabine of formula (I)

Formula (I) and pharmaceutically acceptable acid addition salts thereof in a single operational step comprising: a) contacting 5-amino-2-ethoxycarbonylamino-nitrobenzene of formula R with 4-fluorobenzaldehyde optionally in a solvent to obtain compound of formula S

b) simultaneous reduction of double bond and nitro group comprising catalytic hydrogenation of compound of formula S using alcohol-base combination as solvent system to obtain Retigabine base of formula (I) and optionally isolating the base and contacting the said Retigabine base in-situ with an acid in a solvent to produce pharmaceutically acceptable Retigabine acid addition salt of formula (IA).

21. A process for the preparation of the Retigabine intermediate of formula T

comprising: b) contacting 5-amino-2-ethoxycarbonylamino-nitrobenzene of formula R with 4-fiuorobenzaldehyde in an alcoholic solvent to obtain compound of formula S and in-situ contacting the reaction mass with metalbohydride resulting into the formation of the compound of formula T

22. A process for the preparation of the Retigabine of formula (I)

Formula (I) and pharmaceutically acceptable acid addition salts thereof in a single operational step comprising: contacting 5-amino-2-ethoxycarbonylamino-nitrobenzene of formula R with 4-fluorobenzaldehyde fluorobenzaldehyde in an alcoholic solvent to obtain compound of formula S and in-situ hydrogenating the reaction mass with hydrogenation catalyst selected from the group comprising Pd/C, Pt/C, raney nickel and adding a base generating alcohol base solvent system as described in the specification resulting into the formation of Retigabine base of formula (I) and optionally isolating the base and contacting the said Retigabine base in-situ with an acid in a solvent to produce pharmaceutically acceptable Retigabine acid addition salt of formula (IA).

J Formula I

Not isolated

23. A process for the preparation of the compound of formula (I)

and pharmaceutically acceptable acid addition salts thereof comprising: a) contacting 2-nitrobenzene-l,4-diamine of formula K with 4- fluorobenzaldehyde of formula L in a solvent just by heating at a suitable temperature resulting into formation of (4-fluorobenzylidene)-3- nitrobenzene-l,4-diamine of formula M

b) contacting (4-fluorobenzylidene)-3-nitrobenzene-l,4-diamine of formula M with metal borohydride in a solvent system comprising of water as one of the solvent preferably aqueous alcohol resulting into the formation of (4-fluorobenzyl)-3-nitrobenzene-l,4-diamine of formula N.

c) reduction of the compound of formula N obtained in step b into corresponding amino compound namely 2-amino-4-(4- fluorobenzylamino) aniline of formula O by catalytic hydrogenation or by catalytic transfer hydrogen reaction, which is then further converted to Retigabine of formula I and its pharmaceutically acceptable salts as described in the specification or by the methods known in the prior art ('330 or WO2011/012659)

24. A process for the preparation of the compound of formula (I)

Formula (I)

and pharmaceutically acceptable acid addition salts thereof comprising: a) direct reductive amination by contacting 2-nitrobenzene-l,4-diamine of formula K with 4-fluorobenzaldehyde of formula L and sodium borohydride in solvent system comprising water as one solvent resulting into the formation of (4-fluorobenzyl)-3-nitrobenzene-l,4-diamine of formula N; thus by avoiding the formation/isolation of compound of formula M thereby reducing one unit operation.

b) reduction of the compound of formula N obtained in step a into corresponding amino compound namely 2-amino-4-(4- fluorobenzylamino) aniline of formula O by catalytic hydrogenation or by catalytic transfer hydrogen reaction, which is then further converted to Retigabine of formula I and its pharmaceutically acceptable salts as described in the specification or by the methods known in the prior art ('330 or WO2011/012659).

25. A process for the preparation of intermediate (4-fluorobenzylidene)- 3 -nitrobenzene- 1,4-diamine of formula M to be used for the preparation of Retigabine and its pharmaceutically acceptable salts by contacting 2- nitrobenzene- 1,4-diamine of formula K with 4-fluorobenzaldehyde avoiding use of water separator, azeotropic distillation or use of catalyst/ion exchanger to drive the reaction in forward direction.

26. A process for the preparation of (4-fluorobenzyl)-3-nitrobenzene- 1 ,4-diamine of formula N to be used for the preparation of Retigabine and its pharmaceutically acceptable salts comprising contacting (4- fluorobenzylidene)-3-nitrobenzene- 1,4-diamine of formula M with metal borohydride in a solvent system comprising of water as one solvent preferably aqueous alcohol.

27. A novel process for the preparation of (4-fluorobenzyl)-3- nitrobenzene- 1,4-diamine of formula N to be used for the preparation of Retigabine and its pharmaceutically acceptable salt comprising direct reductive amination of 2-nitrobenzene- 1,4-diamine of formula K with 4- fluorobenzaldehyde of formula L and sodium borohydride in solvent system comprising water as one of solvent.

28. A novel process for the preparation of (4-fluorobenzyl)-3- nitrobenzene- 1,4-diamine of formula N to be used for the preparation of Retigabine and its pharmaceutically acceptable salt comprising direct reductive amination of 2-nitrobenzene- 1,4-diamine of formula K with 4- fluorobenzaldehyde of formula L using sodium triacetoxyborohydride in non-aqueous solvent selected from the group of halogenated solvents.