WO2013011518A1 - Procédé de préparation de rétigabine de formule i et de ses sels pharmaceutiquement acceptables - Google Patents

Procédé de préparation de rétigabine de formule i et de ses sels pharmaceutiquement acceptables Download PDF

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WO2013011518A1
WO2013011518A1 PCT/IN2011/000639 IN2011000639W WO2013011518A1 WO 2013011518 A1 WO2013011518 A1 WO 2013011518A1 IN 2011000639 W IN2011000639 W IN 2011000639W WO 2013011518 A1 WO2013011518 A1 WO 2013011518A1
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formula
nitrobenzene
retigabine
ethoxycarbonylamino
preparation
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PCT/IN2011/000639
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English (en)
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Arun Kanti Mandal
Kamlesh Jayantilal Ranbhan
Sudhanshu Saxena
Sanjay Ramrao GAIKWAD
Pushpalata Balkrishna SARJEKAR
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Arch Pharmalabs Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/24—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds
    • C07C209/28—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds by reduction with other reducing agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/30—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds
    • C07C209/32—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups
    • C07C209/36—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups by reduction of nitro groups bound to carbon atoms of six-membered aromatic rings in presence of hydrogen-containing gases and a catalyst
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/44—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers
    • C07C209/52—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers by reduction of imines or imino-ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C249/02—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of compounds containing imino groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups

Definitions

  • 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.
  • 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 TrobaltTM (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.
  • US 5849789 and US5852053 disclose the use of Retigabine for the treatment of neurodegenerative disorders, including those associated with stroke.
  • WO2011/012659 A2 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.
  • the process (I) has following drawbacks:
  • process-I 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.
  • 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 RNH 2 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.
  • 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.
  • 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.
  • 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.
  • amine protecting group (Pr) is phthalimido group.
  • Nitrating system is selected from HN0 3 /AcOH, HN0 3 /H 2 S0 4 , aq. HN0 3 at 343 °K, HN0 3 /Ac 2 0/AcOH, potassium nitrate/H 2 S0 4 and the like.
  • nitrating system is cone.
  • 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.
  • Example of a compatible solvent is acetic acid.
  • Contacting hereinabove and hereinbelow comprises mixing, heating, stirring, refluxing or combination thereof.
  • 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.
  • R is H, lower alkyl group, NH 2 -CO-, NH 2 -CS-, Ar-CH 2 - 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.
  • R is H and methyl.
  • 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:
  • Ammonia used herein could be in gaseous form or liquid ammonia or ammonium hydroxide or ammonia solution.
  • 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.
  • 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%.
  • Solvent used for the purpose may be any one that does not react with any of the reactant and is compatible.
  • 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.
  • 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.
  • solvent system comprising water
  • aqueous solvent used herein above and below in the specification
  • 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.
  • 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.
  • 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.
  • solvents 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.
  • suitable solvents include protic solvents comprising water as one solvent and mixture thereof.
  • Preferable solvent is isopropyl alcohol, water or mixture thereof.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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-C 7 aliphatic alcohols. Preferable alcohols are Q to C 3 alcohols.
  • alcohol-base combinations are Q to C 7 alcohol-ammonia or Ci to C 7 alcohol-triethylamine or d to C 7 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.
  • 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 NaH 2 P0 2 -Pd/C or Cr(II)Cl 2 -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.
  • 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.
  • 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 NaH 2 P0 2 -Pd/C or Cr(II)Cl 2 -HCl or Pd/C-triethylsilane or by combinations thereof.
  • the catalyst is Pd/C and alcohol-base combinations are Q to C 7 alcohol-ammonia or Q to C 7 alcohol-triethylamine or d to C 7 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.
  • 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.
  • EXAMPLE-1 Preparation of 2-ethoxycarbonylamino-5- phthalimidonitrobenzene from N-ethoxycarbonylamino-p- phenylenediamine.
  • EXAMPLE-2 Preparation of l-ethoxycarbonylamino-4- phthalimidobenzene from N-ethoxycarbonylamino-p- phenylenediamine.
  • 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.
  • 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.
  • EXAMPLE-6 Preparation of 2-ethoxycarbonylamino-5-(4- fluorobenzylamino)nitrobenzene from 5-amino-2- ethoxycarbonylamino 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.
  • EXAMPLE-9 Preparation of Retigabine base from 2- ethoxycarbonylamino-5-(4-fluorobenzylamino)nitrobenzene by catalytic transfer hydrogenation.
  • EXAMPLE-10 Preparation of Retigabine base from 2- ethoxycarbonylamino-5-(4-fluorobenzylideneamino)nitrobenzene.
  • 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-12 Preparation of Retigabine dihydrochloride from Retigabine base.
  • EXAMPLE-13 Preparation of Retigabine dihydrochloride from 2- ethoxycarbonyl amino-5-(4-fluorobenzylamino) nitrobenzene.
  • EXAMPLE-14 Preparation of Retigabine dihydrochloride from 2- ethoxycarbonyl amino-5-(4-fluorobenzylamino)nitrobenzene by catalytic transfer hydrogenation.
  • 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.
  • Example-18 Preparation of 2-amino-5-(4-fiuorobenzylamino) nitrobenzene from 2-amino-5-(4-fluorobenzylideneamino) nitrobenzene
  • 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%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

Cette invention concerne un procédé de préparation de 2-amino-4-(4- fluorobenzylamino)-l-éthoxycarbonylaminobenzène connu sous le nom générique de Rétigabine de formule (I) et de ses sels pharmaceutiquement acceptables, par ex. Formule IA, en particulier, la modification par rapport aux procédés I et II de la technique antérieure décrits dans le brevet US5384330. Les modifications sont illustrées sur le schéma I et le schéma II respectivement. Les nouveaux procédés de préparation des intermédiaires de formules M, N et O du procédé I et de formules R, S, T du procédé II, ceux utilisés pour préparer la Rétigabine de formule I et ses sels pharmaceutiquement acceptables sont également décrits.
PCT/IN2011/000639 2011-07-21 2011-09-16 Procédé de préparation de rétigabine de formule i et de ses sels pharmaceutiquement acceptables WO2013011518A1 (fr)

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Publication number Priority date Publication date Assignee Title
CN103193657A (zh) * 2013-04-16 2013-07-10 石家庄度恩医药科技有限公司 一种合成依佐加滨中间体的方法
CN103336046A (zh) * 2013-04-17 2013-10-02 中国医药研究开发中心有限公司 一种瑞替加滨化合物的含量测定方法
CN103342648A (zh) * 2013-07-22 2013-10-09 北京科莱博医药开发有限责任公司 瑞替加滨中间体的制备方法和瑞替加滨的制备方法
CN103724231A (zh) * 2014-01-27 2014-04-16 南京工业大学 一种瑞替加滨的合成方法
ITMI20131371A1 (it) * 2013-08-08 2015-02-09 Dipharma Francis Srl Procedimento per la preparazione di un composto ad attivita' anticonvulsiva

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US5849789A (en) 1995-10-26 1998-12-15 Asta Medica Aktiengesellschaft Use of 4-amino-4-(4-fluorobenzylamino)-1-ethoxy-carbonylaminobenzene for the prophylaxis and treatment of reduced cerebral blood supply
US5914425A (en) 1997-01-20 1999-06-22 Asta Medica Aktiengesellschaft Modifications of 2-amino-4-(4-5fluorobenzylamino)-1-ethoxycarbonylaminobenzene, and processes for their preparation
WO2011012659A2 (fr) 2009-07-28 2011-02-03 Medichem S.A. 4-(4-fluorobenzylamino)-1,2-phénylèridicarbonate de diéthyle et ses sels
WO2011089126A2 (fr) * 2010-01-20 2011-07-28 Glaxo Group Limited Nouvelle composition

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US5849789A (en) 1995-10-26 1998-12-15 Asta Medica Aktiengesellschaft Use of 4-amino-4-(4-fluorobenzylamino)-1-ethoxy-carbonylaminobenzene for the prophylaxis and treatment of reduced cerebral blood supply
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103193657A (zh) * 2013-04-16 2013-07-10 石家庄度恩医药科技有限公司 一种合成依佐加滨中间体的方法
CN103193657B (zh) * 2013-04-16 2015-08-05 石家庄度恩医药科技有限公司 一种合成依佐加滨中间体的方法
CN103336046A (zh) * 2013-04-17 2013-10-02 中国医药研究开发中心有限公司 一种瑞替加滨化合物的含量测定方法
CN103342648A (zh) * 2013-07-22 2013-10-09 北京科莱博医药开发有限责任公司 瑞替加滨中间体的制备方法和瑞替加滨的制备方法
ITMI20131371A1 (it) * 2013-08-08 2015-02-09 Dipharma Francis Srl Procedimento per la preparazione di un composto ad attivita' anticonvulsiva
CN103724231A (zh) * 2014-01-27 2014-04-16 南京工业大学 一种瑞替加滨的合成方法

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