FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patent Rules, 2006
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. TITLE OF THE INVENTION: A CONTINUOUS GREEN PROCESS FOR THE
PREPARATION OF ALKYL-(AMINOPHENYL)-CARBAMATE OF FORMULA-L
2. APPLICANT:
(a) NAME: ARCH PHARMALABS LIMITED
(b) NATIONALITY: INDIAN
(c) ADDRESS: ARCH HOUSE, 541-A,
MAROL- MAROSHI ROAD, MUMBAI, 400059, INDIA
PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

TITLE:

A continuous green process for the preparation of alkyl-(aminophenyl)-carbamate of formula-I.

FIELD OF TECHNOLOGY:

The subject invention relates to a continuous green process for the preparation of alkyl-(aminophenyl)-carbamate of formula-I. The process for the production of alkyl-(aminophenyl)-carbamate of formula-I comprises reaction of substrate diaminobenzene (also known as phenylenediamine) of formula-II with alkyl haloformate of formula-III in water as a reaction medium with out using a base; dialkyl-phenylenedicarbamate of formula-IV is obtained as a major by-product along with desired monocarbamate of formula-I. In the subject invention the by-product is processed so as to recover substrate phenylenediamine, which is recycled and reused for the preparation of alkyl-(aminophenyl)-carbamate of formula-I.

The process of the instant subject invention comprises a) continuously contacting substrate of formula-II in water; b) continuously contacting the substrate of step a with substrate of formula-III to affect the formation of the product of formula-I; c) continuously separating the by-product of formula-IV; d) continuously subjecting the mother liquor of step c for basification and separating the product of formula-I; e) continuously contacting by-product of formula-IV with water and a base to recover the substrate of formula-II; f) continuously separating the substrate of formula-II; g) continuously recycling the substrate of formula-II obtained from step f for step a to form the product of the formula-I.
The entire process summarized hereinabove is pictorially represented as given hereinbelow in process flow diagram.

BACKGROUND OF THE INVENTION:

Alkyl-(4-aminophenyl)-carbamates of formula-I wherein free NH2 group and carbamate group are located at para position are used as important pharmaceutical intermediate used for the preparation of drug molecules which intern are used for various medicaments. Particularly alkyl-(4-aminophenyl)-carbamate of formula-IA wherein R is ethyl group is used for the preparation of active medicaments against Helicobacter pylori, bacterial agent associated with the generation of gastric cancer. More specifically the invention refers to compounds behaving as antibacterial agents and in specific against the polymerization of tubulin, basic element in the constitution of Helicobacter pylori.

The compound of formulae- I or IA is a key intermediate for the preparation of 1,2,4-triaminobenzene derivatives of general formula-X which are used as potent openers of KCNQ family potassium channels. Examples are Retigabine of formula-V and its analogues as depicted hereinbelow.

wherein R1: hydrogen, C1-C6-alkyl, C2-C6 alkanoyl or the radical Ar;
R2: hydrogen or C1-C6 alkyl
R3: C1-C6-alkoxy, NH2,, C1-C6-alkylamino, C1-C6-dialkylamino, amino substituted by the radical Y, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, the radical Y, or the radical Y-O-;
R4: Hydrogen; C1-C6-alkyl or the radical Ar
R5: Hydrogen; C1-C6-alkyl or the radical Ar
Alk: Straight or branched alkylene group containing 1-9 carbon atoms, which can also be substituted by the radical Ar,
n is 0(when CO is absent) or 1
Ar: a phenyl radical substituted by the radicals R6, R7 and/or R8 where these radicals R6, R7 and R8 are the same or different and represent C1-C6-alkyl, C3-C7-cycloalkyl, hydroxy, C1-C6-alkoxy, C2-C6-alkanoyloxy, halogen, hydroxy, C1-C6-halogenoalkyl, -CN, -NH2, -NH-C1-C6-alkyl, -N(C1-C6-alkyl)2, -CO2H, -CO-C1-C6-alkyl, -CO-O-C1-C6-alkyl, -COAr, -CO-OAr, -CONH2, -CONH-C1-C6-alkyl, -CON(C1-C6-alkyl)2, -CONHAr, -NH-CO-C1-C6-alkyl, -NHCO-Ar, -NHCO-C1-C6-alkoxy, -NH-CO-OAr, -NHCO-NH2, -NHCO-N(C1-C6-alkyl)2, -NHCO-NHAr, -NH-SO2-C1-C6-alkyl, -NH-SO2Ar, -NH-SO2-nitrophenyl, -SO2-OH, -SO2-C1-C6-alkyl, -SO2-Ar, -SO2-C1-C6-alkoxy, -SO2-OAr, -SO2-NH2, -SO2-NH-C1-C6-alkyl, -SO2-N(C1--C6-alkyl)2, -SO2-NHAr, -SO2-C1-C6-alkoxy;

.

Wherein W is S or O, m is 0,1,2 or 3, n is 0, 1, 2, 3 or 4, p is 0 or 1 and R is independently selected from the group consisting of C1-C6 alk(en/yn)yl, C3-C8-cycloalk(en)yl, aryl, C3-C8-cycloalk(en)yl- C1-C6 alk(en/yn)yl, aryl-C1-C6 alk(en/yn)yl, acyl, halogen, halo-C1-C6-alk(en/yn)yloxy, cyano, nitro etc.

The compound of formula- I or IA is a key intermediate for compounds of formula-X. Some examples of compounds of formula-X are given hereinbelow. These compounds are anticonvulsant being investigated as a possible treatment for partial epilepsies and also for muscle relaxing, fever-reducing and as peripheral analgesic agent. For example 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 neurological conditions, including migraine and neuropathic pain.

Ethyl(2-amino-4-(4-fluorobenzyl)amino)phenylcarbamate (Retigabine)

Propyl {2-amino-4-[(1-benzothiophen-2-ylmethyl)amino]phenyl}carbamate

Ethyl (2-amino-4-{[(5-fluoro-1-benzothiophen-3yl)methyl]amino}phenyl)carbamate

Ethyl (2-amino-4-{[(5-bromo-2-thienyl)methyl]amino}phenyl)carbamate

Ethyl [2-amino-4-({[5-(dimethylamino)-1-benzothiophen-3yl]methyl}amino)phenyl] carbamate

Ethyl (2-amino-4-{[(5-chloro-2-thienyl)methyl](methyl)amino}phenyl)carbamate

Ethyl {2-amino-4-[(3,5-dichlorobenzyl)amino]phenyl}carbamate

Ethyl (2-amino-4-{[4-(trifluoromethyl)benzyl]amino}phenyl)carbamate

Ethyl [2-amino-4-(benzylamino)phenyl]carbamate

Other compounds of interest (includes their pharmaceutically acceptable analogues or salts) and some examples are given below:
{2-Amino-4-[(5-chloro-thiophen-2-ylmethyl)-methyl-amino]-phenyl}-carbamic acid ethyl ester;
{2-Amino-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic acid ethyl ester;
{2-Amino-4-[(5-methyl-thiophen-2-ylmethyl)-methyl-amino]-phenyl}-carbamic acid ethyl ester;
{2-Amino-4-[(5-bromo-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic acid ethyl ester;
{2-Amino-4-[(6-chloro-3-methoxy-benzo[b]thiophen-2-ylmethyl)-amino]-phenyl} carbamic acid ethyl ester;
{2-Amino-4-[(benzo[b] thiophen-2-ylmethyl)-amino]-phenyl}-carbamic acid ethyl ester;
{2-Amino-4-[(5-methyl-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic acid ethyl ester;
{2-Amino-4-[(4-bromo-3-methoxy-thiophen-2-ylnethyl)-amino]-phenyl}-carbamic acid ethyl ester;
{2-Amino-4-[(5-phenyl-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic acid ethyl ester;
{2-Amino-4-[(3-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic acid ethyl ester;
(2-Amino-4-{[4-(4-chloro-benzenesulfonyl)-3-methyl-thiophen-2-ylmethyl]-amino} phenyl)-carbamic acid ethyl ester;
{2-Amino-4-[(3-methyl-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic acid ethyl; ester;
{2-Amino-4-[(5-fluoro-benzofuran-3-ylmethyl)-amino]-phenyl}-carbamic acid ethyl ester;
{2-Amino-4-[(thiophen-2-ylmethyl)-amino]-phenyl}-carbamic acid ethyl ester;
{2-Amino-4-[(4-bromo-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic acid ethyl ester;
{2-Amino-4-[(5-ethyl-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic acid ethyl ester;
{2-Amino-4-[(thiophen-3-ylmethyl)-amino]-phenyl}-carbamic acid ethyl ester;
{2-Amino-4-[(5-chloro-thiophen-2-ylmethyl)-ethyl-amino]-phenyl}-carbamic acid ethyl ester;
{2-Amino-4-[(benzo[b] thiophen-3-ylmethyl)-amino]-phenyl}-carbamic acid ethyl ester;
{2-Amino-4-[(5-dimethyl-amino-benzo[b]thiophen-3-ylmethyl)-amino]-pllenyl} carbamic acid ethyl ester;
{2-Amino-4-[(5-dimethyl-amino-3-methyl-benzo[b]thiophen-2-ylmethyl)-amino] phenyl}-carbamic acid ethyl ester;
{2-Amino-4-[(5-fluoro-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic acid ethyl ester;
{2-Amino-4-[(benzo[b]thiophen-2-ylmethyl)-amino]-phenyl}-carbamic acid propyl ester;
{2-Amino-4-[(benzo[b]thiophen-3-ylmethyl)-amino]-phenyl}-carbamic acid propyl ester;
{2-Amino-4-[(5-chloro-thiophen-2-ylmethyl)-methyl-amino]-phenyl}-carbamic acid ethyl ester;
{2-Amino-4-[(5-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic acid ethyl ester;
{2-Amino-4-[(5-methyl-thiophen-2-ylmethyl)-methyl-amino]-phenyl}-carbamic acid ethyl ester;
{2-Amino-4-[(5-bromo-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic acid ethyl ester;
{2-Amino-4-[(6-chloro-3-methoxy-benzo[b]thiophen-2-ylmethyl)-amino]-phenyl} carbamic acid ethyl ester;
{2-Amino-4-[(benzo[b] thiophen-2-ylmethyl)-aminol-phenyl}-carbamic acid ethyl ester;
{2-Amino-4-[(5-methyl-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic acid ethyl I ester;
{2-Amino-4-[(4-bromo-3-methoxy-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic acid ethyl ester;
{2-Amino-4-[(5-phenyl-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic acid ethyl ester;
{2-Amino-4-[(3-chloro-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic acid ethyl ester;
(2-Amino-4-{[4-(4-chloro-benzenesulfonyl)-3-methyl-thiophen-2-ylmethyl]-amino} phenyl)-carbamic acid ethyl ester;
{2-Amino-4-[(3-methyl-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic acid ethyl ester;
{2-Amino-4-[(5-fluoro-benzofuran-3-ylmethyl)-amino]-phenyl}-carbamic acid ethyl ester;
{2-Amino-4-[(thiophen-2-ylmethyl)-amino]-phenyl}-carbamic acid ethyl ester;
{2-Amino-4-[(4-bromo-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic acid ethyl ester;
{2-Amino-4-[(5-ethyl-thiophen-2-ylmethyl)-amino]-phenyl}-carbamic acid ethyl l ester;
{2-Amino-4-[(thiophen-3-ylmethyl)-amino]-phenyl}-carbamic acid ethyl ester,
{2-Amino-4-[(5-chloro-thiophen-2-ylmethyl)-ethyl-amino]-phenyl}-carbamic acid ethyl ester and the like.
In the instant subject invention bis-carbamate of the formula-IV is formed as a by-product along with monocarbamate of formula-I; when diaminobenzene of the formula-II is reacted with alkyl haloformate of formula-III. In the subject invention the said by-product is processed in aqueous base to recover diaminobenzene of the formula-II, which is then recycled to get the compound of formula-I.

GENERAL SCHEME OF THE INVENTION:

Process disclosed herein comprises contacting phenylenediamine of formula-II with alkyl haloformate of formula-III in water without using a base to obtain a mixture of monocarbamate of formula-I and bis-carbamate of formula-IV. The monocarbamate of formula-I interacts with outgoing hydrogen halide molecule and results into the formation of water soluble hydrogen halide salt of formula-I, which goes into mother liquor (hereinabove and hereinbelow referred as MLR), while bis-carbamate of formula-IV being insoluble in water is obtained as solid. The said bis-carbamate of formula-IV is hydrolysed using a base in water to regenerate the diaminobenzene of formula-II which is then recycled to prepare the monocarbamate of formula-I.

The subject invention is to be understood by the following chemical scheme and process flow diagram wherein p-phenylenediamine also known as 1,4-diaminobenzene of formula-IIA is shown to react with ethyl chloroformate of formula-IIIA in water without using a base to produce the mixture of monocarbamate of formula-IA and bis-carbamate of formula-IVA. The bis-carbamate of formula-IVA formed as a by-product is hydrolysed to regenerate p-phenylenediamine/ 1,4-diaminobenzene of formula-IIA, which is then recycled to prepare the desired product monocarbamate of formula-IA.

CHEMICAL SCHEME:

PROCESS FLOW DIAGRAM:
Recovered PPDA
Water
Ethyl chloroformate
Fresh PPDA

Aq.
NaOH

NaHCO3 for pH adjustment

Dry product of formula-IA

To Effluent Plant

PPDA: p-phenylenediamine/ 1,4-diaminobenzene

US7368472 discloses the process for the preparation of compound of formula-IA by the process as depicted in the scheme-I. The process comprises the reaction of 4-nitroaniline (starting material) with ethyl chloroformate in ethyl acetate as reaction solvent in the presence of Hunnig’s base chemically known as N,N-diisopropylethylamine to produce ethyl-(4-nitrophenyl)carbamate as an intermediate followed by its catalytic hydrogenation using Pd/C.

Scheme-I

US7906537 disclose the process for the preparation of compound of formula-IA by the process as depicted in the scheme-II. The said process comprises the reaction of 4-nitroaniline (starting material) with ethyl chloroformate in ethyl acetate as reaction solvent, in presence magnesium oxide resulting into the formation of ethyl-(4-nitrophenyl)-carbamate as an intermediate followed by its reduction using zinc and acetic acid. The said patent neither mentions yield nor purity.

Scheme-II

The prior art methods for the preparation of monocarbamate of formula-I A comprises the use of 4-nitroaniline as starting material and involves reduction of the nitro intermediate later in the process either by catalytic reduction or by metal acid reduction.

WO2010/142956 discloses the process for the preparation of (4-amino-phenyl)-carbamic acid benzyl ester comprising the reaction of p-phenylenediamine as starting material with benzyl chloroformate in MDC as a solvent, in presence of N,N-diisopropylethylamine as a base as depicted in the Scheme-III. The reaction is conducted for 16 hrs at room temperature. Crude product is purified by column chromatography.

Scheme-III

US2005/277652 discloses the process for the preparation of (4-aminophenyl)-carbamic acid benzyl ester comprising the reaction of p- phenylenediamine with benzyl chloroformate using tetrahydrofuran as solvent and triethylamine as base, as depicted in scheme-IV. Crude product is purified by column chromatography followed by its re-crystallization using hexane: ethyl acetate yielding 45% of product. The patent does not mention the purity of the product.

Scheme-IV

US7709517, US2007/0004753A1 disclose the process for the preparation of (4-aminophenyl)carbamic acid tert.butylester comprising the reaction of three times excess molar quantity of p-phenylenediamine against di-tert.butylpyrocarbonate in DMF-THF solvent system in presence of potassium carbonate as a base as depicted in scheme-V. The resulting carbmate is purified by flash chromatography. The reported yield is only 31.6%. Moreover it is conducted on small scale.

Scheme-V

WO2007/58927 discloses the process for the preparation of (4-aminophenyl)carbamic acid tert.-butyl ester comprising the reaction of p- phenylenediamine as starting material with di-tert.butylpyrocarbonate in DMF as solvent yielding 65% with no mention for purity as depicted in scheme-VI. Moreover it is conducted on small scale

Scheme-VI

Prior art methods disclosed therein for the preparation of various monocarbamates comprising phenylenediamine compound of formula-II (wherein diamino compound is 1,4-diaminobenzene also known as p-phenylenediamine) as starting material with different haloformates or di-tert.butylpyrocarbonate results into the formation of carbamates that require purification by techniques like column chromatography or flash chromatography.

None of the prior arts cited hereinabove comprising the use of diamino benzenes as a starting material teaches or motivates a person of ordinary skill to use water as a solvent nor gives an idea that bis-carbamate, which is formed as a by-product is treated further regenerating diamino benzene ready for recycling for the preparation of monocarbamate of formula-I or formula-IA during the said process.

Journal of organic chemistry vol. 59, No.5 (1994) discloses the preparation of monocarbamate comprising the reaction of aniline hydrochloride with ethyl chloroformate in water as a solvent and NaOH as a base, as depicted in the scheme-VII.

Scheme-VII

Although the said non-patent reference introduces the concept of green chemistry by using water as solvent, the said non-patent reference discloses use of hydrochloride salt of aniline, which is soluble in water. The process disclosed therein further comprises the use of sodium hydroxide as a base. The concept of green chemistry using water as a solvent wherein commercially available phenylenediamine is used as a starting material and not its HCl salt, that too without using any external base for the preparation of monocarbamates in a continuous process can neither be anticipated from the prior art references nor yet has been explored for the preparation of compound of formula-I or formula-IA.

Zhurnal Organicheskoi Khimii; vol. 22; nb. 5; (1986); p. 1092-1095, 981–983, Journal of the American Chemical Society; vol. 74; (1952); p. 3029-3031 (use of pyridine), Journal of the Chemical Society; (1954); p. 2649 (sodium acetate, acetic acid) disclose the processes for the preparation of bis-carbamate as depicted in the scheme-VIII.

Scheme-VIII

Although the non-patent literature references as cited hereinabove discloses dimethyl-1,4-phenylenedicarbamate formation comprising the reaction of p-phenylenediamine compound with methyl chloroformate in the presence of a base. It neither teaches nor motivates and also a person skilled in the art can not anticipate that undesired bis-carbamate formed as a one of the major product which is used in a continuous process by treatment of the said bis-carbamate with a base in water to regenerate starting material diaminobenzene also referred as phenylenediamine that can be recycled in the process.

OBJECT AND SUMMARY OF THE INVENTION:

Accordingly, first general aspect of the subject invention is to provide a continuous process for the production of compound of the formula-I.

Second aspect of the subject invention is to provide the various unit operations of the continuous process for the preparation of compound of formula-I.

Third aspect of the subject invention is to provide a reactor system which will provide a means to isolate the compound of formula-I.

Fourth aspect of the invention is to provide a reactor system which will provide the continuous recycle of diaminobenzene of formula-II.

Fifth aspect is to regenerate compound of formula-II from the byproduct compound of formula-IV.

Sixth aspect is the green chemistry to prepare a compound of formula-I without using a base.

A specific aspect of the invention is to provide a continuous process for the production of compound of formula-IA.

Seventh aspect of the invention is to use the compound of formula-I made by the continuous process of the subject invention for the preparation of carbamic acid alkyl esters of formula-X.

A specific aspect of the invention is to use the compound of formula-IA made by the continuous process of the subject invention for the preparation of carbamic acid alkyl esters like Retigabine and its analogues.

Other objects and advantages of the subject invention will become apparent from the following summary of the invention and description of its preferred embodiments.

The subject invention in one aspect provides a continuous process for the preparation of compound of formula-I, the process comprises a) continuously contacting substrate of formula-II in water; b) continuously contacting the substrate of step a with substrate of formula-III to affect the formation of the product of formula-I without using a base; c) continuously separating the by-product of formula-IV; d) continuously subjecting the MLR for basification to adjust pH to isolate and separate the product of formula-I; e) continuously contacting by-product of formula-IV with water and a base to regenerate the substrate of formula-II for reuse for step a; f) continuously separating the substrate of formula-II recycling the substrate of formula-II obtained from step f for step a to form the product of the formula-I.

Another aspect of the subject invention provides an apparatus for conducting a continuous process for the preparation of compound of formula-I. The apparatus comprises a) means of holding substrate of formula-II; b) reactor means for holding the substrate of formula-II and water; c) means for feeding the substrate of formula-III from holding means to the reactor to produce the reaction product mixture (desired product and by-product); d) means for separating the by-product of formula-IV; e) means for isolating the desired product of formula-I by pH adjustment; f) means for separating the desired product of formula–I; g) reactor means for holding and heating the substrate of formula-IV and a base in water to regenerate compound of formula-II, cooling the contents; h) means for separating the substrate of formula-II; i) means for feeding the regenerated substrate of formula-II into reactor means for preparing the product of formula–I.

PROCESS FLOW DIAGRAM:
Recovered PPDA
Water
Ethyl chloroformate
Fresh PPDA

Aq.
NaOH

NaHCO3 for pH adjustment

Dry product of formula-IA

To Effluent Plant

GLR stands for glass lined reactor
SSR stands for stainless steel reactor
PPDA: p-Phenylenediamine or 1,4-Diaminobenzene

In the subject invention:
GLR-1 represents reactor means for holding the substrate of formula-II and water and reacting it with substrate of formula-III producing the mixture of monocarbamate of formula-I (desired product) and bis-carbamate of formula-IV (by-product);
centrifuge-1 represents means for separating the MLR and collecting the bis-carbamate (by-product) of the formula-IV;
GLR-2 represents means used for the isolation of compound of formula-I after pH adjustment using a base;
centifuge-2 represents the means separating the compound of formula-I;
dryer represent the means for drying the desired product of formula-I;
SSR represent the means for converting the bis-carbamate of formula-IV into substrate of formula-II;
centrifuge-3 represents the means for separating the substrate of formula-II.
However it is to be noted that GLR-1and 2 will be only one GLR used for the two purposes as mentioned hereinabove;
Centrifuge- 1, 2 and 3 will be only one centrifuge used for three purposes as mentioned hereinabove

In the subject invention, substrate diaminobenzene of formula-II is contacted with substrate haloformate of formula-III in water as a solvent without using any base to obtain product mixture (desired product of formula-I and by-product of formula-IV). Hydrogen halide an outgoing molecule produced during the reaction reacts with desired product of formula-I making it water soluble, which goes into mother liquor and is later taken for pH adjustment to isolate the desired product of formula-I as solid. The by-product of formula-IV being insoluble in water separates out in solid form from the reaction mass which is further heated with a base in water to regenerate the substrate diaminobenzene of formula-II, which is then recycled for the preparation of compound of formula-I.

DETAILED DESCRIPTION OF THE INVENTION:

In accordance to the subject invention the process disclosed herein provides the desired product of formula-I with purity of at least 99%. It also provides the regenerated substrate diaminobenzene of formula-II with a purity of not less than 98.5% that is continuously recycled for the preparation of desired product of formula-I.

In a general embodiment of the subject invention substrate diaminobenzene of formula-II is contacted with substrate haloformate of formula-III in water as green solvent without using a base to obtain product mixture comprising desired product of formula-I and by-product of formula-IV. Outgoing hydrogen halide formed during the reaction interacts with desired product of formula-I making its water soluble salt which remains in mother liquor. Mother liquor containing hydrogenhalide salt of formula-I is then taken for the pH adjustment using a base to isolate the monocarbamate of formula-I as desired product. This is best understood by the chemistry depicted hereinbelow in scheme-general. On the other hand by-product of formula-IV being insoluble in water gets separated from mother liquor as solid, which on further contacting with a base in water as green solvent regenerates substrate of formula-II which intern is reused as a starting material for the preparation of compound of formula-I.

Scheme-general:

The term contacted used thereinabove and hereinbelow mean mixing, reacting, heating, treating and the like.

Substrate diaminobenzene of formula-II as defined in general embodiment of the invention described hereinabove and hereinbelow is selected from group comprising 1,2-diaminobenzene, 1,3-diaminobenzene and 1,4-diaminobenzene.

Another substrate haloformate of the formula-III as defined in general embodiment of the invention described hereinabove and hereinbelow is selected from alkyl haloformate, aryl haloformate. Alkyl haloformate is further selected from group wherein halo group is selected from chloro, bromo, iodo and alkyl group is selected from C1 to C4 branched or straight chain alkyl groups. Aryl haloformate is further selected from group wherein halo group is selected from chloro, bromo, iodo aryl formates and aryl group is selected from group comprising substituted or unsubstituted phenyl, benzyl and the like.

Base as defined in general embodiment of the invention for the pH adjustment of the MLR to isolate the desired product of formula-I is selected from alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, rare earth metal hydroxide, rare earth metal carbonates and rare earth metal bicarbonates.

Base as defined in general embodiment of the invention described hereinabove and hereinbelow is any base that can cleave the bis-carbamate of formula-IV to regenerate compound of formula-II and is selected from alkali metal hydroxide and alkali metal carbonates.

In a preferred embodiment of the subject invention 1,4-diaminobenzene of formula-IIA in water is contacted with ethyl chloroformate of formula-IIIA without using a base to obtain ethyl-(4-aminophenyl)-carbamate of formula-IA (desired product) and diethyl-1,4-phenylenedicarbamate of formula-IVA (by-product). Hydrogen chloride produced during the reaction reacts with ethyl-(4-aminophenyl)carbamate of formula-IA and forms water soluble ethyl-(4-aminophenyl)carbamate hydrochloride salt, which goes into the mother liquor. On the other hand diethyl-1,4-phenylenedicarbamate (by-product) of formula-IVA being insoluble in water precipitated as solid, which is separated from the reaction mass. Mother liquor containing hydrochloride salt of ethyl-(4-aminophenyl)-carbamate is contacted with sodium bicarbonate to adjust the pH to isolate desired product ethyl-(4-aminophenyl)-carbamate of formula-IA as a solid.

In the mean time, diethyl-1,4-phenylenedicarbamate (by-product) of formula-IVA isolated as solid is contacted with sodium hydroxide using water as a solvent and regenerating the 1,4-diaminobenzene of formula-IIA as a solid which being a starting material is recycled to prepare the desired product ethyl-(4-aminophenyl)-carbamate of formula-IA.

In a general embodiment of the subject invention the compound of the formula-IA is converted into compound of formula-X comprising:

a) contacting compound of the formula-IA with a amino protecting agent in presence of a solvent to get a protected amino derivative of compound of formula-IA followed by its nitration resulting into amino protected nitro derivative of compound of formula-IA as depicted herein below;
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 HNO3/AcOH, HNO3/H2SO4, aq. HNO3 at 343˚K, HNO3/Ac2O/AcOH, potassium nitrate/H2SO4 and the like. Preferably nitrating system is conc. HNO3/AcOH.

b) contacting amino protected nitro derivative compound of formula-IA obtained from step a with a deprotecting agent optionally in presence of a solvent to get nitro derivative of the compound of formula-IA as depicted herein below:

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.
Deprotection of the amino protecting group of the compound of formula is carried out by using compound of formula RNH2,(optionally diluted with a solvent) wherein R is hydrogen, lower alkyl group, NH2-CO-, NH2-CS-, Ar-CH2- wherein Ar is phenyl or optionally substituted phenyl.

c) contacting nitro derivative of the compound of formula-IA obtained in step b with an aryl aldehyde in a solvent at a suitable temperature resulting into the condensed product as depicted herein below:

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.

d) subjecting condensed product obtained in step c for reduction using a solvent at a suitable temperature resulting into formation of compound of formula-X as a free base as depicted herein below:

Solvent used for the purpose may be any one that does not react with any of the reactant and is compatible.

Suitable temperature means any temperature that will not inhibit the reaction and will not impart the impurity formation.

e) contacting compound of formula-X obtained as a free base in step d with pharmaceutically acceptable acid using a solvent resulting into pharmaceutically acceptable salts of compound of formula-X as depicted hereinbelow:

Solvent used for the purpose may be any one that does not react with any of the reactant and is compatible.

In a specific embodiment of the subject invention the compound of the formula-IA is converted into Retigabine of formula-V comprising:

a) contacting compound of the formula-IA with phthalic anhydride using acetic acid as solvent to get a phthaloyol amino derivative of compound of formula-IA followed by its nitration resulting into phthaloylnitro derivative of compound of formula-IA as depicted hereinbelow;

b) contacting phthaloylnitro derivative of compound of formula-IA obtained from step a, with methyl amine diluted with alcohol to get nitro derivative of the compound of formula-IA as depicted hereinbelow:

c) contacting nitro derivative of the compound of formula-IA obtained in step b, with an 4-fluorobenzaldehyde using methanol as solvent heating at room temperature resulting into the condensed product as depicted hereinbelow:

d) subjecting condensed product obtained in step c for reduction first using sodium borohydride in isopropanol to reduce the double bond and followed by catalytic reduction of nitro group resulting into formation of Retigabine base of formula-V as depicted hereinbelow:

e) contacting Retigabine of formula-V obtained as a base in step d with hydrochloric acid resulting into Retigabine dihydrochloride as depicted hereinbelow.

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.
The invention is best understood by the following examples:

Experiment-1: 1,4-Diaminobenzene (p-Phenylenediamine) (350 g) is charged in DM water (4200 ml) under stirring at RT in 10-15 minutes. Then ethyl chloroformate (463 ml) is added slowly through addition funnel in 45-60 minutes, reaction temperature increases to 40-45ºC due to exotherm. Reaction mass is stirred at 40-45ºC for 30-60 minutes. The solid appeared is filtered and washed with DM water and dried. This is a by-product of this reaction (a di-carbamate derivative, Diethyl-1,4-phenylenedicarbamate 368 g). Solid sodium bicarbonate is added into the filtrate to adjust pH to 5.4-6.0. Then reaction mass is stirred at 0-5ºC for 1 hour and solid appeared is filtered, washed with DM water and dried under vacuum at 40-45ºC to get Ethyl-(4-aminophenyl)carbamate (251 g) as brown to grey colored solid. HPLC purity: 99.94%

Recovery of 1,4-diaminobenzene: Diethyl-1,4-phenylenedicarbamate (100 g) obtained as by-product is refluxed at 95-100ºC with aqueous sodium hydroxide solution (6.6%, 1200 ml) for 12-15 hrs. Then cooled the reaction mass to 0-5ºC and stirred at 0-5ºC for 2-3 hrs. Solid appeared is filtered, washed with chilled DM water and dried under vacuum at 60-65ºC to get p-phenylenediamine (34.3 g) as solid. HPLC purity: 99.44%

Experiment-2: p-Phenylenediamine (25 g) is charge in DM water (300 ml) under stirring at RT in 10-15 minutes. Then ethyl chloroformate (33 ml) is added slowly through addition funnel in 45-60 minutes maintaining temperature at 25-30ºC. Reaction mass is stirred at 25-30ºC for 30-60 minutes. The solid appeared is filtered and washed with DM water and dried. This is a by-product of this reaction (a di-carbamate derivative, Diethyl-1,4-phenylenedicarbamate 26 g). Solid sodium bicarbonate is added in the filtrate to adjust pH to 5.4-6.0. Then reaction mass is stirred at 0-5ºC for 1 hour and solid appeared is filtered, washed with DM water and dried under vacuum at 40-45ºC to get Ethyl (4-aminophenyl)carbamate (19.68 g) as brown to grey colored solid. HPLC purity: 99.74%

Recovery of 1,4-diaminobenzene: Diethyl-1,4-phenylenedicarbamate (100 g) obtained as by-product is refluxed at 95-100ºC with aqueous sodium hydroxide solution (6.6%,1200 ml) for 12-15 hrs. Then cooled the reaction mass to 0-5ºC and stirred at 0-5ºC for 2-3 hrs. Solid appeared is filtered, washed with chilled DM water and dried under vacuum at 60-65ºC to get p-phenylenediamine (34.3 g) as solid. HPLC purity: 99.44%

Experiment -3:

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

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 conc. (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%.

Experiment-4: Preparation of 5-amino-2-ethoxycarbonylamino nitrobenzene from 2-ethoxycarbonylamino-5-phthalimido nitrobenzene

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

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

In a mixture of isopropyl alcohol (1.59 L) and DM water (72 ml), 2-ethoxycarbonylamino-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 HCl 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-7: Preparation of Retigabine base from 2-ethoxycarbonylamino-5-(4-fluorobenzylamino)nitrobenzene

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/cm2 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-8: 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%.

CLAIMS:

We claim:

1. A process for the preparation of compound of formula-I, the process comprising the steps:

a) contacting substrate of formula-II in water;

b) contacting the substrate of step a, with substrate of formula-III to obtain the product mixture of compounds of formulae- I and IV;

c) separating the by-product of formula-IV ;

d) contacting the mother liquor of step c, with base to adjust pH to obtain the product of formula-I in solid form;
e) contacting by-product of formula-IV with water and a base to regenerate the substrate of formula-II;
f) separating the substrate of formula-II;
g) recycling the regenerated substrate of formula-II obtained from step f for step a, to form the product of the formula-I.

2. A process for the preparation of compound of formula-IA, the process

comprising the steps:
a) contacting substrate of formula-IIA in water;

b) contacting the substrate of step a, with substrate of formula-IIIA to obtain the product mixture of compounds of formulae- IA and IVA;

c) separating the by-product of formula-IVA;

d) contacting the MLR with base to adjust pH to obtain the product of formula-IA in solid form;
e) contacting by-product of formula-IVA with water and a base to regenerate the substrate of formula-IIA;
f) separating the substrate of formula-IIA;
g) recycling the regenerated substrate of formula-IIA obtained from step f for step a to form the product of the formula-IA.

3. A process of claims 1 and 2; wherein the compounds of formulae- I and IA are used for the preparation of pharmaceutical compounds and salts thereof of formula-X described in the specifications.

4. A process of the claim 2; wherein the compound of formula-IA is used or the preparation of Retigabine of formula-V and salts thereof.

Ethyl(2-amino-4-((4-fluorobenzyl)amino)phenyl)carbamate (Retigabine)