WO2013080215A1 - An improved process for the preparation of flupirtine and pharmaceutically acceptable salts thereof - Google Patents

An improved process for the preparation of flupirtine and pharmaceutically acceptable salts thereof Download PDF

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WO2013080215A1
WO2013080215A1 PCT/IN2012/000300 IN2012000300W WO2013080215A1 WO 2013080215 A1 WO2013080215 A1 WO 2013080215A1 IN 2012000300 W IN2012000300 W IN 2012000300W WO 2013080215 A1 WO2013080215 A1 WO 2013080215A1
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formula
base
solvent
nitro
pyridine
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PCT/IN2012/000300
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French (fr)
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Vikram Sarjerao Jagtap
Ravindra Baburao Chache
Dayaghan Gangadhar Patil
Kamlesh Jayantilal Ranbhan
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Arch Pharmalabs Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates

Definitions

  • the invention relates to an improved process for the preparation of flupirtine of formula (I) and its pharmaceutically acceptable salts, particularly flupirtine maleate of formula (IA) preferably pure crystal modification A of flupirtine maleate.
  • Flupirtine is 2-amino-3-carbethoxyamino-6-(p-fluorobenzylamino) pyridine; CAS No: 56995-20-1 , an aminopyridine that functions as a centrally acting non-opioid analgesic. It first became available in Europe in 1984, and is sold mainly under the names atadolon, Trancolong, Awegal, Efiret, Trancopal Dolo, and Metanor. It is unique as a non- opioid, non-NSAID, non-steroidal analgesic. Flupirtine is used as an analgesic for acute and chronic pain, in moderate to severe cases.
  • Flupirtine has been noted for its neuro-protective properties, as well as its possible uses for Creutzfeld- Jakob disease, Alzheimer's disease, and multiple sclerosis are being investigated. It has also been proposed as a possible treatment for Batten disease. Flupirtine also acts as an antioxidant and prevent free radical- mediated structural damage.
  • US3481943 discloses the process for the preparation of flupirtine hydrochloride of formula (T) wherein p- fluorobenzylamine (formula R) is reacted with 2-amino-3-nitro-6- chloropyridine (Q) in n-propanol using potassium carbonate to prepare 2-amino-3-nitro-6-p-fluorobenzylamino-pyridine of formula (S) which is hydrogenated in dioxane using raney nickel at 50 C under a gauge pressure of 30 atmospheres. Solution is filtered off to remove the catalyst and then reacted with chloroformic acid ethyl ester (ethyl chloroformate) while stirring. The product is filtered off and recrystallized from water to give flupirtine hydrochloride salt of formula (T).
  • the process disclosed therein in '943 is depicted as given below
  • 2-amino-3-nitro-6-(4-fluorobenzylamino) pyridine of formula (S) is then hydrogenated in the presence of raney nickel at 5 bar at 60°C to give 2,3- diamino-6-(4-fluorobenzylamino) pyridine using 2-methoxy ethanol as hydrogenating solvent.
  • This is followed by acylation with ethyl chloroformate using triethylamine as a base under inert gas atmosphere to obtain flupirtine base of formula (I).
  • the catalyst is filtered off and filtrate containing dissolved triethyi amine hydrochloride is directly added to solution of maleic acid in isopropanol resulting into formation of crude flupirtine maleate (IA). It also discloses the importance of the exclusion of atmospheric oxygen by an intensive supply of inert gas and closed reactor system to avoid development of troublesome coloured complexes.
  • the purification of crude flupirtine maleate is carried out by converting crude flupirtine maleate into crude flupirtine base by contacting with ammonia or sodium hydroxide solution. Then the crude flupirtine base is recrystallized from isopropanol and, after contacting with activated carbon/kieselguh'r, it is reacted with a solution of maleic acid in isopropanol to give flupirtine maleate of formula (IA).
  • the reaction scheme of DE3133519 is depicted herein below.
  • ammonia gas Another disadvantage of using ammonia gas is that it is classified as a hazardous material and is subject to strict regulations and risk management procedures for transport, storage, and handling. These requirements result in additional costs and may generate local community concerns over transporting and storing hazardous materials. While aqueous ammonia used by the inventors requires minimal special handling, social and regulatory requirements.
  • US59591 15A discloses a process for the preparation of flupirtine maleate (IA) as discussed under DE3133519 (US4481205). It also discloses crystalline form "A" of flupirtine maleate by the use of water soluble alcohols (such as ethanol or isopropanol) during synthesis and/or purification.
  • process variant shows three proposed variants in ⁇ 15 as shown below:
  • process variant comprises synthesis of oxygen sensitive crude base in situ in process step A and it was converted by a "very rapid" suction filtration process into an aqueous maleic acid solution from which coloured crude flupirtine maleate (IA) is obtained, which is to be purified by recrystallization from isopropanol-water.
  • process step G in 2 nd variant represents substantially shorter alternative process in which the precipitation of crude flupirtine maleate from the flupirtine base formed in situ in isopropanol is effected by Alteration with suction into an aqueous maleic acid solution at 50-60°C and, after that without isolation of the crude maleate, colourless pure material is obtained.
  • the flupirtine base (I) is precipitated preferably in ethanol or water and is purified by recrystallization and than treated with maleic acid to prepare pure flupirtine maleate (IA).
  • ⁇ 15 disclose hydrogenation of ANFP (S), acylation and precipitation in water-soluble alcohols, such as ethanol or isopropanol.
  • 2 nd process variant also does not produce colorless pure maleate.
  • the flupirtine base is precipitated preferably in ethanol or water and is purified by recrystallization and than treated with maleic acid to prepare pure flupirtine maleate salt (IA).
  • US47851 10A discloses a process for the preparation of 2-amino-3-nitro- 6-fluorobenzylamino pyridine of formula (S) comprising reaction of 2- amino-3-nitro-6-methoxypyridine of formula (T) (1 mole) with 4-fluoro- benzylamine of formula R (2-4 mole) optionally as a mineral acid salt in water at a temperature between 70 ° C and 150°C; preferably between 90° and 120°C. The said condensation is also performed in autoclave as the temperature is above 100°C.It also discloses the necessity of using basic material suitably as an aqueous solution in case when acid addition salts of 4-fluoro-benzylamine of formula (R) is used to liberate the free base for the reaction.
  • aqueous ammonia preferably (20-25%) for the preparation of 2-amino-3-nitro-6-chloro pyridine replacing the use of gaseous ammonia or liquid ammonia as reported in the prior art not only minimizes the formation of the impurities of formulae X and Y but also needs minimum special handling and social and regulatory requirements.
  • Figure I represents impurities profile based on use of gaseous ammonia
  • Figure II represents impurities profile based on use of gaseous ammonia
  • Figure III represents impurities profile based on use of liquid ammonia
  • Figure IV represents use of aqueous ammonia
  • Another aspect of reducing nitro group of the said compound is by catalytic transfer hydrogenation using different formyl derivatives in the presence of metal catalyst without external hydrogen source.
  • First aspect of the invention is to provide an efficient, environmentally safe, economical and industrially viable process for the preparation of 2- amino-3-carbethoxyamino-6-(p-fluorobenzylamino pyridine of formula (I) hereinabove and hereinbelow referred as Flupirtine 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 processes reported therein in the prior art.
  • Third aspect of the invention is to provide an easy and economical process for the preparation of the Flupirtine intermediate 2-amino-3- nitro-6-chloro-pyridine of formula (Q) comprising the use of aqueous ammonia solution preferably (20-25%) thereby minimizing/eliminating the formation of impurities of formulae X and Y.
  • Forth aspect of the invention is to provide a novel, technically and economically advantageous and industrially safe process adopting more "green" methodology for the preparation of Flupirtine intermediate 2- amino-3-nitro-6-p-fluorobenzylamino-pyridine of formula (S) comprising contacting 2-amino-3-nitro-6-chloro-pyridine of formula (Q) with 4-fluorobenzylamine of formula (R) using water as a solvent which is ubiquitous, cheap, and environmental friendly thereby avoiding the use of volatile, toxic, flammable and non-renewable organic solvents which originate a significant portion of chemical processes waste as used in the prior art processes.
  • Fifth aspect of the invention is to use solvent base combination during the hydrogenation resulting into a smooth and complete hydrogenation reaction.
  • the present invention provides a novel, efficient, economical and industrially viable process for the preparation of 2-amino-3- carbethoxyamino-6-(p-fluorobenzylamino) pyridine also known as Flupirtine of the formula I and its pharmaceutically acceptable salts particularly maleate of Formula IA and its crystalline modification A comprising:
  • step (b) contacting said compound of formula (Q) produced in step (a) with p-fluorobenzylamine taking water as a solvent in presence of a base to produce 2-amino-3-nitro-6-p-fluorobenzylamino-pyridine of formula
  • step b reducing nitro group of 2-amino-3-nitro-6-p-fluorobenzylamino- pyridine of formula (S) produced in step b by catalytic hydrogenation in the presence of solvent-base combination as a solvent system or optionally by catalytic transfer hydrogenation optionally in the presence of solvent-base combination; or by catalytic hydrogenation in the presence of solvent optionally in the presence of carriers;
  • step c optionally insitu without isolation acylating the hydrogenated product produced in step c by contacting with ethyl chloroformate and base to produce flupirtine base of formula (I);
  • step (e) contacting the said flupirtine base of formula (I); produced in step (d) with acid solution to produce the corresponding acid addition salt.
  • step e contacting flupirtine acid addition salt produced in step e with alcoholic solvent and water and contents are heated to get clear solution which is then optionally seeded with crystalline modification A to produce flupirtine acid addition salt as crystalline modification A'
  • acid addition salt is maieate.
  • the subject invention discloses herein a novel process for the reduction of nitro group of the compound of formula (S) by catalytic hydrogenation using solvent-base combination; or by catalytic transfer hydrogenation optionally in the presence of solvent-base combination or by catalytic hydrogenation in the presence of solvent optionally in the presence of carriers to produce the compound of formula (I) and optionally in-situ preparation of its acid addition salt of formula (IA) which is advantageous in terms of reduction of process operational steps.
  • Flupirtine of formula (I) and its pharmaceutically acceptable salts e.g. flupirtine maleate of formula (IA) and flupirtine maleate crystal modification A.
  • the process has been summarized in the scheme-I given herein below.
  • solvent 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.
  • suitable solvents include Ci to C 6 alcohols.
  • Preferable solvent is isopropyl alcohol.
  • Aq. ammonia used is about 5% to about 32%. Preferably aq. ammonia is about 20% to about 25%.
  • step (b) contacting said compound of formula (Q) obtained in step (a) with p- fluorobenzylamine taking water as a solvent in the presence of a base to produce 2-amino-3-nitro-6-p-fluorobenzylamino-pyridine of formula
  • the base used for the said condensation reaction is selected from the group comprising inorganic as well as organic bases that can act as an acid schavanger.
  • base is water soluble base selected from the group comprising hydroxides, carbonate or bicarbonates of alkali metals or alkali earth metals, ammonia, ammonia derivatives, primary, secondary or tertiary alkyl amines, piperidine, optionally substituted pyridines, picolines and the like.
  • base is selected from organic bases. Still more preferably base is triethyl amine.
  • step b reducing nitro group of 2-amino-3-nitro-6-(p-fluorobenzylamino) pyridine of formula (S) produced in step b by catalytic hydrogenation in the presence of solvent-base combination optionally in the presence of carriers or by catalytic transfer hydrogenation optionally in the presence of solvent-base combination; or by catalytic hydrogenation in a solvent without using base optionally in the presence of carriers.
  • nitro group of 2-amino-3-nitro-6-(p-fluorobenzylamino) pyridine of formula (S) is reduced by catalytic hydrogenation in the presence of solvent-base combination
  • step c optionally insitu acylating the product obtained in step c comprising contacting said compound of formula (S) produced in step c with ethyl chloroformate in the presence of a base;
  • the base used in solvent-base combination to be used as a solvent system for the reaction comprising reduction of nitro group is selected from the group comprising ammonia, primary, secondary or tertiary alkyl amines, piperidine, optionally substituted pyridines, picolines and the like.
  • base is ammonia.
  • solvent used in solvent-base combination to be used as solvent system for the reaction comprising reduction of nitro group is selected from the group comprising of C1-C4 alcohols, cyclic ethers such as dioxane and tetrahydrofuran, ethoxyethanol, water, aromatic hydrocarbons as well as mixtures thereof.
  • solvent is dioxane.
  • solvent-base combinations comprise C
  • the carriers used for the catalytic hydrogenation is selected from the group comprising of barium sulphate, calcium sulphate, sodium sulphate, magnesium sulphate that makes ease in isolating the reduced product.
  • 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 selected from zinc/hydrochloric acid, tin/hydrochloric acid, iron/hydrochloric acid or tin II chloride/hydrochloric acid or hydrazine- raney nickel 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 triethylsilane-Pd/C 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.
  • preferred system is Pd/C-ammonium formate optionally together with solvent-base combination
  • Catalytic hydrogenation reaction is carried out at temperature about 75° to about 80°C, and pressure preferably of about 4-5 kg.
  • solvent-base used herein above and below in the specification is also referred as alkaline medium.
  • the base to be used during the acylation is selected from the group comprising primary, secondary or tertiary alkyl amines, piperidine, optionally substituted pyridines, picolines and the like preferably base is triethyl amine.
  • step (e) contacting the product obtained in step (d) with acid solution to produce the corresponding acid addition salt.
  • the acid used for the preparation of pharmaceutically acceptable acid salts is selected from the group comprising pharmaceutically acceptable acid selected from inorganic or organic acids, in particular those which are suitable for forming pharmaceutically useful salts.
  • suitable acids are maleic acid, oxalic acid, mandelic acid, methane sulphonic acid, benzene sulphonic acid, phosphoric acid, hydrohalides, sulphates, bi-sulphates and the like.
  • Preferable acid moiety is maleic acid.
  • Aq. ammonia used is about 5% to about 32%. Preferably aq. ammonia is about 20% to about 25%.
  • step (b) contacting compound of formula (Q) produced in step (a) with p- fluorobenzylamine taking water as a solvent in presence of triethylamine as a base to produce 2-amino-3-nitro-6-p-fluorobenzylamino-pyridine of formula (S);
  • step c reducing nitro group of 2-amino-3-nitro-6-(p- fluorobenzylamino)pyridine of formula (S) produced in step b by catalytic hydrogenation in the presence of dioxane as solvent and aq. ammonia) as a base resulting into the formation of 2,3-diamino-6-p- fluorobenzylamino pyridine & (d) optionally insitu acylating the product obtained in step c comprising contacting said compound of formula (S) produced in step c with ethyl chloroformate in the presence of a base;
  • step (e) contacting the said flupirtine base obtained in step (d) with maleic acid solution made in water to produce maleate salt.
  • step (b) contacting compound of formula (Q) produced in step (a) with p- fluorobenzylamine taking water as a solvent in presence of triethylamine as base to produce 2-amino-3-nitro-6-p-fluorobenzylamino-pyridine of formula (S);
  • step b reducing nitro group of 2-amino-3-nitro-6-(p- fluorobenzylamino)pyridine of formula (S) produced in step b by catalytic hydrogenation in the presence of dioxane as solvent and triethyl amine as base resulting into the formation of 2,3-diamino-6-p- fluorobenzylamino pyridine
  • step c optionally insitu acylating the product produced in step c comprising contacting said compound of formula (S) produced in step c with ethyl chloroformate in the presence of a base;
  • step (e) contacting the said flupirtine base produced in step (d) with maleic acid solution made in water to produce flupirtine maleate salt.
  • reaction mass 100 gm of 2-amino-3-nitro-6-chloro-pyridine is taken in 800 ml of water.
  • 90 gm of p-fluorobenzylamine is added dropwise into the reaction mixture at 20-25°C.
  • 87 gm triethylamine is also added dropwise into the reaction mixture at 20-25°C.
  • the reaction mass is stirred at 40-45°C for half an hour again the reaction mass is heated to 80-85°C and stirred at this temperature for 3-4 hours.
  • the reaction mass is cooled to 20-25°C and stirred at this temperature for 2-3 hours and then stirred at 15-20°C for 3-4 hours.
  • the solid mass is filtered and then washed with 200 ml of water and 100 ml isopropyl alcohol and then dried in air oven till constant weight to get 140-150 gm. of 2-amino-3-nitro-6-p- fluorobenzylamino-py ridine .
  • reaction mass is distilled up to 70-80% under vacuum. This concentrated reaction mass is added into aqueous solution of maleic acid (72 gm in 2000 ml DM water at 65-70°C and maintained at 65-70°C for 2 hours under nitrogen to get crude Flupirtine Maleate as a solid.
  • the reaction mass is cooled to 25-30°C in 5-6 hours and maintained at this temperature for next 2-3 hours then filtered. The wet cake is washed with 200 ml water and dried to get 145 gm of flupirtine maleate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to an improved process for the preparation of flupirtine (I) and its pharmaceutically acceptable salts, especially of flupirtine maleate (IA), and pure crystal modification A of flupirtine maleate.

Description

TITLE
An improved process for the preparation of Flupirtine and pharmaceutically acceptable salts thereof.
TECHNICAL FIELD OF THE INVENTION
The invention relates to an improved process for the preparation of flupirtine of formula (I) and its pharmaceutically acceptable salts, particularly flupirtine maleate of formula (IA) preferably pure crystal modification A of flupirtine maleate.
Figure imgf000002_0001
BACKGROUND OF THE INVENTION
Flupirtine is 2-amino-3-carbethoxyamino-6-(p-fluorobenzylamino) pyridine; CAS No: 56995-20-1 , an aminopyridine that functions as a centrally acting non-opioid analgesic. It first became available in Europe in 1984, and is sold mainly under the names atadolon, Trancolong, Awegal, Efiret, Trancopal Dolo, and Metanor. It is unique as a non- opioid, non-NSAID, non-steroidal analgesic. Flupirtine is used as an analgesic for acute and chronic pain, in moderate to severe cases. Its muscle relaxant properties make it popular for back pain and other orthopaedic uses, but it is also used for migraines, in oncology, postoperative care, and gynaecology. Flupirtine has been noted for its neuro-protective properties, as well as its possible uses for Creutzfeld- Jakob disease, Alzheimer's disease, and multiple sclerosis are being investigated. It has also been proposed as a possible treatment for Batten disease. Flupirtine also acts as an antioxidant and prevent free radical- mediated structural damage.
US3481943 (hereinafter referred as '943) discloses the process for the preparation of flupirtine hydrochloride of formula (T) wherein p- fluorobenzylamine (formula R) is reacted with 2-amino-3-nitro-6- chloropyridine (Q) in n-propanol using potassium carbonate to prepare 2-amino-3-nitro-6-p-fluorobenzylamino-pyridine of formula (S) which is hydrogenated in dioxane using raney nickel at 50 C under a gauge pressure of 30 atmospheres. Solution is filtered off to remove the catalyst and then reacted with chloroformic acid ethyl ester (ethyl chloroformate) while stirring. The product is filtered off and recrystallized from water to give flupirtine hydrochloride salt of formula (T). The process disclosed therein in '943 is depicted as given below
Figure imgf000003_0001
Drawbacks associated with the process disclosed in '943 are:
1) The yield of 2-amino-3-nitro-6-p-fluorobenzylamino-pyridine of formula S obtained is around 40% only. '943 does not disclose the preparation of maleate salt of flupirtine.
2) During the preparation hydrochloride salt of flupirtine on an industrial scale, intensely blue colored by products are formed which are either difficult to remove or can not be removed completely.
3) Use of n-propanol as reaction solvent is expensive. reaction mass thereby hindering the progress of the reaction. Another most probable reason attributed for getting poor yield of 40% in the said process could be masking of hydrochlorides of both the reactants of formulae (Q') and (R') (as both reactants are amino compounds and form hydrochlorides) over potassium carbonate making it unavailable for further reaction posing problem towards the completion of reaction thereby adversely affecting the yield.
Figure imgf000004_0001
DE3133519 (US4481205) discloses the preparation of flupirtine maleate of formula (IA), wherein 2-amino-3-nitro-6-chloro-pyridine of formula (S) is prepared by taking 2,6-dichloro-3-nitropyridine of formula (P) (90%, water wet) in isopropanol at 20°-30°C and purging ammonia gas (or dropping liquid ammonia) into the said reaction mixture and then resulting 2-amino-3-nitro-6-chloro-pyridine of formula (Q) is reacted with p-fluorobenzylamine (R) in isopropanol using triethyl amine as a base ; the reaction mixture is refluxed for 6 hours. Thereupon after addition of a large volume of water the compound 2-amino-3-nitro-6-(p- fluorobenzylamino)-pyridine of formula (S) precipitates.
2-amino-3-nitro-6-(4-fluorobenzylamino) pyridine of formula (S) is then hydrogenated in the presence of raney nickel at 5 bar at 60°C to give 2,3- diamino-6-(4-fluorobenzylamino) pyridine using 2-methoxy ethanol as hydrogenating solvent. This is followed by acylation with ethyl chloroformate using triethylamine as a base under inert gas atmosphere to obtain flupirtine base of formula (I). The catalyst is filtered off and filtrate containing dissolved triethyi amine hydrochloride is directly added to solution of maleic acid in isopropanol resulting into formation of crude flupirtine maleate (IA). It also discloses the importance of the exclusion of atmospheric oxygen by an intensive supply of inert gas and closed reactor system to avoid development of troublesome coloured complexes.
The purification of crude flupirtine maleate is carried out by converting crude flupirtine maleate into crude flupirtine base by contacting with ammonia or sodium hydroxide solution. Then the crude flupirtine base is recrystallized from isopropanol and, after contacting with activated carbon/kieselguh'r, it is reacted with a solution of maleic acid in isopropanol to give flupirtine maleate of formula (IA). The reaction scheme of DE3133519 is depicted herein below.
Figure imgf000005_0001
Drawbacks associated with the process disclosed in DE3133519 (US4481205) are:
1) Use of gaseous ammonia or liquid ammonia for the preparation of 2-amino-3-nitro-6-chloro-pyridine of formula (Q) starting from 2, 6- dichloro-3-nitropyridine of formula (P) contributes towards increased level of impurities of formulae X and Y as the gaseous ammonia and liquid ammonia as sources of ammonia are in concentrated forms and it is not easy to control the purging or addition in appropriate quantities and as a consequence it results in the formation of higher amounts of impurities and poor yield of the desired compound.
Figure imgf000006_0001
Another disadvantage of using ammonia gas is that it is classified as a hazardous material and is subject to strict regulations and risk management procedures for transport, storage, and handling. These requirements result in additional costs and may generate local community concerns over transporting and storing hazardous materials. While aqueous ammonia used by the inventors requires minimal special handling, social and regulatory requirements.
2) Preparation of 2-amino-3-nitro-6-(p-fluorobenzylamino)-pyridine of formula (S comprises reaction between 2-amino-3-nitro-6-chloro- pyridine of formula (Q) and p-fluorobenzylamine of formula (R) using isopropanol as solvent and triethyl amine as base. To induce separation of 2-amino-3-nitro-6-(p-fluorobenzylamino)-pyridine of formula (S from the reaction mixture in IP A a large volume of water is required which makes reaction mass highly voluminous therefore, not preferred at industrial scale. 3) Basification of crude flupirtine maleate comprising the process of liberating free flupirtine base using ammonia or sodium hydroxide produces an ammonium or sodium salt which pollutes the water.
4) Use of activated charcoal and kieselgulir during the purification of flupirtine base (that contains three amino groups known for their light and colour sensitive nature) takes prolonged time for filtration through filtering bed thereby exposing to environment producing high coloration.
5) The crude flupirtine maleate remains trapped with triethyl amine hydrochloride.
US59591 15A (hereinafter referred as Ί 15) discloses a process for the preparation of flupirtine maleate (IA) as discussed under DE3133519 (US4481205). It also discloses crystalline form "A" of flupirtine maleate by the use of water soluble alcohols (such as ethanol or isopropanol) during synthesis and/or purification. There are three proposed variants in Ί 15 as shown below: process variant:
Figure imgf000007_0001
A: ANFP (S)→hydrogenation→acylation→crude flupirtine base.
B: crude flupirtine base→maleic acid→crude flupirtine maleate
C-E (as shown in scheme-II): not applicable F: crude maleate→pure maleate.
1 s process variant comprises synthesis of oxygen sensitive crude base in situ in process step A and it was converted by a "very rapid" suction filtration process into an aqueous maleic acid solution from which coloured crude flupirtine maleate (IA) is obtained, which is to be purified by recrystallization from isopropanol-water.
2" process variant:
Figure imgf000008_0001
A: ANFP (S)→hydrogenation→acylation→crude flupirtine base.
B: flupirtine base→maleic acid→crude flupirtine maleate.
C-F (as shown in scheme-II): Not applicable.
G: without isolation of the crude maleate→pure maleate.
As compared to the process step F in 1st variant, process step G in 2nd variant represents substantially shorter alternative process in which the precipitation of crude flupirtine maleate from the flupirtine base formed in situ in isopropanol is effected by Alteration with suction into an aqueous maleic acid solution at 50-60°C and, after that without isolation of the crude maleate, colourless pure material is obtained.
3rd process variant:
Figure imgf000009_0001
A: ANFP (S)→hydrogenation→acylation→cmde flupirtine base (isolated)
B: pure flupirtine base→maleic acid→pure flupirtine maleate.
Herein, after acylation, the flupirtine base (I) is precipitated preferably in ethanol or water and is purified by recrystallization and than treated with maleic acid to prepare pure flupirtine maleate (IA).
Ί 15 disclose hydrogenation of ANFP (S), acylation and precipitation in water-soluble alcohols, such as ethanol or isopropanol.
1) In 1st process variant "very rapid" suction filtration process is a great limitation at plant scale.
2) 2nd process variant also does not produce colorless pure maleate.
3) In 3 process variant, after acylation, the flupirtine base is precipitated preferably in ethanol or water and is purified by recrystallization and than treated with maleic acid to prepare pure flupirtine maleate salt (IA).
Prior art processes disclosed hereinabove results in the formation of intensely colored impurities which makes the purification of the desired product very complex.
It also discloses that although the treatment of final product with activated carbon and recrystallization is known as a reasonably successful procedure to remove impurities. This approach is reluctantly accepted because of the losses in overall yield as it is applied in the last production step of a drug and particularly in the case of flupirtine, it is not a preferred/desirable procedure as it may result into the formation of colored impurities.
US47851 10A discloses a process for the preparation of 2-amino-3-nitro- 6-fluorobenzylamino pyridine of formula (S) comprising reaction of 2- amino-3-nitro-6-methoxypyridine of formula (T) (1 mole) with 4-fluoro- benzylamine of formula R (2-4 mole) optionally as a mineral acid salt in water at a temperature between 70°C and 150°C; preferably between 90° and 120°C. The said condensation is also performed in autoclave as the temperature is above 100°C.It also discloses the necessity of using basic material suitably as an aqueous solution in case when acid addition salts of 4-fluoro-benzylamine of formula (R) is used to liberate the free base for the reaction. It also discloses subsequent reduction of nitro group of 2-amino-3-nitro-6-methoxypyridine by various modes with preference to catalytic hydrogenation optionally in the presence of carriers selected from barium sulphate, calcium sulphate, magnesium sulphate, sodium sulphate etc.
Figure imgf000010_0001
The drawbacks associated with the process described in US47851 10A are: 1) As per the experimental section of the said process of condensation for the preparation of 2-amino-3-nitro-6-fluorobenzylamino pyridine of formula (S) discloses heating at boiling for ten hours. The temperature would be around 100°C as water is used as solvent. However, inventors of the subject invention disclose herein the same process comprising using 6-chlorpyridine instead of 6-methoxy pyridine and water as solvent', wherein the reaction is carried out at temperature much below boiling point of water and reaction gets completed in 3 hrs compare to 10 hrs at temperature of boiling water as in' 1 10. Furthermore, the said reaction disclosed herein in the present invention does not require autoclave. There is no teaching or anticipation on this aspect from Ί 10.
2) Excessive use of 2-4 moles of 4-fluoro-benzylamine of formula ( ) for the preparation of 2-amino-3-nitro-6-fluorobenzylamino pyridine of the formula (S) comprising the reaction of 2-amino-3-nitro-6- methoxypyridine of formula (T)with 4-fluoro-benzylamine of formula (R).Unreacted 4-fluoro-benzylamine is then removed by steam distillation which is not only time and energy consuming but also increase in an extra unit operation.
3) In case when acid addition salts of 4-fluoro-benzylamine are used that requires another additional operation of basification to liberate free base to enable 4-fluoro-benzylamine to be available to react further with 2- amino-3-nitro-6-methoxypyridine forming 2-amino-3-nitro-6- fluorobenzylamino pyridine of the formula (S) .
TECHNICAL SOLUTIONS OVER THE PRIOR ART PROCESSES:
Disclosed herein are improvements in process which provides technical solutions to overcome the drawbacks of processes disclosed therein in the prior art mentioned hereinabove. 1. Use of aqueous ammonia preferably (20-25%) for the preparation of 2-amino-3-nitro-6-chloro pyridine replacing the use of gaseous ammonia or liquid ammonia as reported in the prior art not only minimizes the formation of the impurities of formulae X and Y but also needs minimum special handling and social and regulatory requirements.
Figure imgf000012_0001
Experimental results details of contacting 2,6-dichloro-3-nitro pyridine of formula (P) with gaseous ammonia, liquid ammonia and aqueous ammonia solution to produce 2-amino-3-nitro-6-chloro-pyridine are given below in Table- 1.
Figure imgf000012_0002
The HPLC spectral graphs given herein below clearly indicate the clarity of reaction using aqueous ammonia over gaseous ammonia and liquid ammonia:
Figure I represents impurities profile based on use of gaseous ammonia Figure II represents impurities profile based on use of gaseous ammonia Figure III represents impurities profile based on use of liquid ammonia Figure IV represents use of aqueous ammonia
Figure imgf000013_0001
Figure imgf000014_0001
Figure imgf000015_0001
Experiment results of figures I, II and III in a vivid manner demonstrates that use of gaseous ammonia and liquid ammonia definitely results in the formation of higher proportion of impurities of formulae X and Y and low yield of desired product.
2) Use of water as a solvent for the preparation of 2-amino-3-nitro-6-p- fluorobenzylamine of formula S replacing alcoholic solvents such as costly n-propanol and isopropanol as reported in the prior art along with provision of using water soluble bases such as potassium carbonate selected from inorganic bases , triethyl amine selected from organic bases. These bases do not create heterogeneity when water is used as a solvent thereby giving good purity and higher yield around 96-99%. Furthermore, when alcoholic compound is used as a solvent then a large volume of water is used to precipitate the product making the reaction mass voluminous making it unacceptable at industrial scale. This issue gets addressed when alcoholic solvent is replaced with water.
Figure imgf000016_0001
3) Avoiding excessive use of 4-fluoro-benzylamine of formula (R) or its acid addition salt thereby avoiding the steam distillation thereby improving the time cycle of the process.
4) Avoiding use of 4-fluoro-benzylamine acid addition salt thereby avoiding basification step thereby reducing operational step.
5) Preference to the use of 2-amino-3-nitro-6-chloro pyridine of formula (Q) over the use of 2-amino-3-nitro-6-methoxypyridine of formula (T) since chloro group is a better leaving group than the methoxy group. Chloro group works with ease during condensation comprising 2-amino- 3-nitro-6-chloro pyridine and 4-fluoro-benzylamine at a temperature of 80-85 °C while use of methoxy compound requires heating at boiling at water boiling temperature for ten hours which requires auto clave. The temperature would be around 100°C as water is used as a solvent; therefore, autoclave is used for the said reaction when methoxy is a leaving group. There is no teaching or expectation from the prior art about the use of water as a solvent and accomplishment of reaction at temperature lower than 100°C for the said reaction when corresponding chloro substituted compound in place of methoxy substituted compound of formula (T) is used as a reactant.
6) The said condensation reaction comprising contacting 2-amino-3- nitro-6-chloro pyridine of formula (Q) with 4-fluoro-benzylamine of formula (R) in water as reaction medium and water soluble compound as a base proceeds at comparatively lower temperature in shorter time (about 80°C ; 4 hrs) compared to process disclosed in prior art comprising reaction between 2-amino-3-nitro-6-chloro pyridine of formula (Q) and 2-amino-3-nitro-6-mefhoxypyridine of formula (T) which requires higher temperature and longer time and also the reaction is carried out in an autoclave.
Figure imgf000017_0001
7) No charcoal treatment hence no time consuming filtration through filtering aid during the purification of final product and removal of color (as it is performed in the prior art) thereby avoiding the exposure to atmospheric oxygen thus minimizing the color development.
These technical solutions as described hereinabove are economically and technically very advantageous, as these avoids the problem of large reaction volume and chemical waste generated from organic solvents, time consuming operations and further contributes in the preparation of the high purity final product flupirtine maleate (IA) in excellent yield at low cost.
Moreover, inventors of the subject invention have observed that catalytic hydrogenation of 2-amino-3-nitro-6-fluorobenzylamino pyridine preferably using Raney nickel is not reproducible with expected success as the reaction does not get completed and some proportion of unreacted material always remains as an impurity. This issue of hydrogenation is solved by the use of solvent- base combination as solvent system. It has been observed that the reduction of nitro group of 2-amino-3-nitro-6- fluorobenzylamino pyridine proceeds to completion very smoothly when a few drops of a base like aq. ammonia are added to the hydrogenation mass.
Another aspect of reducing nitro group of the said compound is by catalytic transfer hydrogenation using different formyl derivatives in the presence of metal catalyst without external hydrogen source.
OBJECT OF THE INVENTION:
First aspect of the invention is to provide an efficient, environmentally safe, economical and industrially viable process for the preparation of 2- amino-3-carbethoxyamino-6-(p-fluorobenzylamino pyridine of formula (I) hereinabove and hereinbelow referred as Flupirtine 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 processes reported therein in the prior art.
Third aspect of the invention is to provide an easy and economical process for the preparation of the Flupirtine intermediate 2-amino-3- nitro-6-chloro-pyridine of formula (Q) comprising the use of aqueous ammonia solution preferably (20-25%) thereby minimizing/eliminating the formation of impurities of formulae X and Y.
Forth aspect of the invention is to provide a novel, technically and economically advantageous and industrially safe process adopting more "green" methodology for the preparation of Flupirtine intermediate 2- amino-3-nitro-6-p-fluorobenzylamino-pyridine of formula (S) comprising contacting 2-amino-3-nitro-6-chloro-pyridine of formula (Q) with 4-fluorobenzylamine of formula (R) using water as a solvent which is ubiquitous, cheap, and environmental friendly thereby avoiding the use of volatile, toxic, flammable and non-renewable organic solvents which originate a significant portion of chemical processes waste as used in the prior art processes.
Fifth aspect of the invention is to use solvent base combination during the hydrogenation resulting into a smooth and complete hydrogenation reaction.
SUMMARY OF THE INVENTION
The present invention provides a novel, efficient, economical and industrially viable process for the preparation of 2-amino-3- carbethoxyamino-6-(p-fluorobenzylamino) pyridine also known as Flupirtine of the formula I and its pharmaceutically acceptable salts particularly maleate of Formula IA and its crystalline modification A comprising:
(a) contacting 2,6-dichloro-3-nitro pyridine of formula (P) with aqueous ammonia solution in a compatible solvent to produce 2-amino-3-nitro-6- chloro-pyridine (
Figure imgf000019_0001
(b) contacting said compound of formula (Q) produced in step (a) with p-fluorobenzylamine taking water as a solvent in presence of a base to produce 2-amino-3-nitro-6-p-fluorobenzylamino-pyridine of formula
(S);
Figure imgf000020_0001
(c) reducing nitro group of 2-amino-3-nitro-6-p-fluorobenzylamino- pyridine of formula (S) produced in step b by catalytic hydrogenation in the presence of solvent-base combination as a solvent system or optionally by catalytic transfer hydrogenation optionally in the presence of solvent-base combination; or by catalytic hydrogenation in the presence of solvent optionally in the presence of carriers;
Figure imgf000020_0002
(d) optionally insitu without isolation acylating the hydrogenated product produced in step c by contacting with ethyl chloroformate and base to produce flupirtine base of formula (I);
Figure imgf000020_0003
(e) contacting the said flupirtine base of formula (I); produced in step (d) with acid solution to produce the corresponding acid addition salt.
Figure imgf000021_0001
f) contacting flupirtine acid addition salt produced in step e with alcoholic solvent and water and contents are heated to get clear solution which is then optionally seeded with crystalline modification A to produce flupirtine acid addition salt as crystalline modification A'
Preferably acid addition salt is maieate.
Figure imgf000021_0002
Entire schematic representation for the preparation of flupirtine and it pharmaceutically acceptable salt of the present invention is represented as follows:
Figure imgf000022_0001
ADVANTAGES OF THE INVENTION
The process of the present invention has following decisive advantages:
1 ) The use of aqueous ammonia solution (20-25%) for the preparation of 2-amino-3-nitro-6-chloro-pyridine (Q) needs minimum special handling or regulatory requirements and improves the impurity profile, resulting into high purity product in better yields.
2) Introducing more "green" methodology for the preparation of Flupirtine intermediate 2-amino-3-nitro-6-p-fluorobenzylamino-pyridine of formula (S) comprising contacting 2-amino-3-nitro-6-chloro- pyridine of formula (Q) with 4-fluorobenzylamine of formula (R) taking water as a solvent which is ubiquitous, cheap, and environmental friendly, and avoiding the use of organic solvents which generate a significant portion of chemical processes waste, is technically and economically very advantageous and further contributes in the preparation of the final product flupirtine maleate (IA) in excellent yield of 85%
3) The reaction mass of condensation reaction for the preparation of 2- amino-3-nitro-6-p-fluorobenzylamino-pyridine of formula (S) is not voluminous when water is used as a solvent compared to the process disclosed therein in the prior art wherein alcohols are used as a solvent for the same purpose.
4) The subject invention discloses herein a novel process for the reduction of nitro group of the compound of formula (S) by catalytic hydrogenation using solvent-base combination; or by catalytic transfer hydrogenation optionally in the presence of solvent-base combination or by catalytic hydrogenation in the presence of solvent optionally in the presence of carriers to produce the compound of formula (I) and optionally in-situ preparation of its acid addition salt of formula (IA) which is advantageous in terms of reduction of process operational steps.
5) The use of solvent-base combination during the reduction of 2-amino- 3-nitro-6-p-fluorobenzylamino-pyridine of formula (S) drives the reaction to completion which otherwise remains incomplete.
DETAILED DESCRIPTION OF THE INVENTION:
Disclosed herein is an efficient, economical - and industrially viable process for the preparation of 2-amino-3-carbethoxyamino-6-(p- fluorobenzylamino) pyridine herein above and herein below referred as Flupirtine of formula (I) and its pharmaceutically acceptable salts e.g. flupirtine maleate of formula (IA) and flupirtine maleate crystal modification A. The process has been summarized in the scheme-I given herein below.
Scheme (I):
Figure imgf000023_0001
Figure imgf000024_0001
In a general embodiment the process comprises:
(a) contacting 2, 6-dichloro-3-nitro-pyridine of formula (P) with aqueous ammonia solution in a compatible solvent to produce 2-amino-3-nitro-6- chloro-pyridine of formula (Q).
Figure imgf000025_0001
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. Examples of suitable solvents include Ci to C6 alcohols. Preferable solvent is isopropyl alcohol.
Aq. ammonia used is about 5% to about 32%. Preferably aq. ammonia is about 20% to about 25%.
(b) contacting said compound of formula (Q) obtained in step (a) with p- fluorobenzylamine taking water as a solvent in the presence of a base to produce 2-amino-3-nitro-6-p-fluorobenzylamino-pyridine of formula
(S);
Figure imgf000025_0002
The base used for the said condensation reaction is selected from the group comprising inorganic as well as organic bases that can act as an acid schavanger. Preferably base is water soluble base selected from the group comprising hydroxides, carbonate or bicarbonates of alkali metals or alkali earth metals, ammonia, ammonia derivatives, primary, secondary or tertiary alkyl amines, piperidine, optionally substituted pyridines, picolines and the like. More preferably base is selected from organic bases. Still more preferably base is triethyl amine.
(c) reducing nitro group of 2-amino-3-nitro-6-(p-fluorobenzylamino) pyridine of formula (S) produced in step b by catalytic hydrogenation in the presence of solvent-base combination optionally in the presence of carriers or by catalytic transfer hydrogenation optionally in the presence of solvent-base combination; or by catalytic hydrogenation in a solvent without using base optionally in the presence of carriers. Preferably nitro group of 2-amino-3-nitro-6-(p-fluorobenzylamino) pyridine of formula (S) is reduced by catalytic hydrogenation in the presence of solvent-base combination
&
(d) optionally insitu acylating the product obtained in step c comprising contacting said compound of formula (S) produced in step c with ethyl chloroformate in the presence of a base;
Figure imgf000026_0001
The base used in solvent-base combination to be used as a solvent system for the reaction comprising reduction of nitro group is selected from the group comprising ammonia, primary, secondary or tertiary alkyl amines, piperidine, optionally substituted pyridines, picolines and the like. Preferably base is ammonia.
The solvent used in solvent-base combination to be used as solvent system for the reaction comprising reduction of nitro group is selected from the group comprising of C1-C4 alcohols, cyclic ethers such as dioxane and tetrahydrofuran, ethoxyethanol, water, aromatic hydrocarbons as well as mixtures thereof. Preferably solvent is dioxane. Preferably solvent-base combinations comprise C| to C7 alcohol- ammonia or Ci to C7 alcohol-triethylamine or d to C7 alcohol-ethylene diamine or mixture thereof or dioxane-ammonia or dioxane- triethylamine or dioxane-ethylene diamine or mixture thereof. More preferably solvent-base combination is dioxane-triethylamine.
The carriers used for the catalytic hydrogenation is selected from the group comprising of barium sulphate, calcium sulphate, sodium sulphate, magnesium sulphate that makes ease in isolating the reduced product.
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 selected from zinc/hydrochloric acid, tin/hydrochloric acid, iron/hydrochloric acid or tin II chloride/hydrochloric acid or hydrazine- raney nickel 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 triethylsilane-Pd/C 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. For catalytic transfer hydrogen reaction, preferred system is Pd/C-ammonium formate optionally together with solvent-base combination Catalytic hydrogenation reaction is carried out at temperature about 75° to about 80°C, and pressure preferably of about 4-5 kg.
The term solvent-base used herein above and below in the specification is also referred as alkaline medium.
The base to be used during the acylation is selected from the group comprising primary, secondary or tertiary alkyl amines, piperidine, optionally substituted pyridines, picolines and the like preferably base is triethyl amine.
(e) contacting the product obtained in step (d) with acid solution to produce the corresponding acid addition salt.
Figure imgf000028_0001
The acid used for the preparation of pharmaceutically acceptable acid salts is selected from the group comprising pharmaceutically acceptable acid selected from inorganic or organic acids, in particular those which are suitable for forming pharmaceutically useful salts. Examples of suitable acids are maleic acid, oxalic acid, mandelic acid, methane sulphonic acid, benzene sulphonic acid, phosphoric acid, hydrohalides, sulphates, bi-sulphates and the like. Preferable acid moiety is maleic acid.
Contacting hereinabove and hereinbelow comprises mixing, heating, stirring, refluxing or combination thereof. In a preferred embodiment for the preparation of flupirtine maleate of formula 1 A process comprises:
(a) contacting 2, 6-dichloro-3-nitro-pyridine of formula (P) with aqueous ammonia solution in a compatible solvent to produce 2-amino- 3-nitro-6-chloro-pyridine of formula (Q).
Figure imgf000029_0001
Aq. ammonia used is about 5% to about 32%. Preferably aq. ammonia is about 20% to about 25%.
(b) contacting compound of formula (Q) produced in step (a) with p- fluorobenzylamine taking water as a solvent in presence of triethylamine as a base to produce 2-amino-3-nitro-6-p-fluorobenzylamino-pyridine of formula (S);
Figure imgf000029_0002
(c) reducing nitro group of 2-amino-3-nitro-6-(p- fluorobenzylamino)pyridine of formula (S) produced in step b by catalytic hydrogenation in the presence of dioxane as solvent and aq. ammonia) as a base resulting into the formation of 2,3-diamino-6-p- fluorobenzylamino pyridine & (d) optionally insitu acylating the product obtained in step c comprising contacting said compound of formula (S) produced in step c with ethyl chloroformate in the presence of a base;
Figure imgf000030_0001
(e) contacting the said flupirtine base obtained in step (d) with maleic acid solution made in water to produce maleate salt.
Figure imgf000030_0003
In another preferred embodiment for the preparation of crystalline modification A of flupirtine maleate of formula 1 A process comprises:
(a) contacting 2, 6-dichloro-3-nitro-pyridine of formula (P) with aqueous ammonia solution in a compatible solvent to produce 2-amino- 3-nitro-6-chloro-pyridine of formula (Q).
Figure imgf000030_0002
(b) contacting compound of formula (Q) produced in step (a) with p- fluorobenzylamine taking water as a solvent in presence of triethylamine as base to produce 2-amino-3-nitro-6-p-fluorobenzylamino-pyridine of formula (S);
Figure imgf000031_0001
(c) reducing nitro group of 2-amino-3-nitro-6-(p- fluorobenzylamino)pyridine of formula (S) produced in step b by catalytic hydrogenation in the presence of dioxane as solvent and triethyl amine as base resulting into the formation of 2,3-diamino-6-p- fluorobenzylamino pyridine
&
(d) optionally insitu acylating the product produced in step c comprising contacting said compound of formula (S) produced in step c with ethyl chloroformate in the presence of a base;
Figure imgf000031_0002
(e) contacting the said flupirtine base produced in step (d) with maleic acid solution made in water to produce flupirtine maleate salt.
Figure imgf000032_0001
(f) contacting said flupirtine maleate salt produced in step e with alcoholic solvent and water is added, contents are heated resulting into a clear solution which is cooled optionally seeded with crystalline modification A to produce flupirtine maleate as crystalline modification A.
Figure imgf000032_0002
EXAMPLES:
The invention is explained in its best mode as illustrated in the examples herein given below. The invention covers the modifications and variations of this invention that come within the scope of the 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-amino-3-nitro-6-chloro-pyridine.
A solution of 100 gm. 2, 6-dichloro-3-nitro-pyridine in 800 ml isopropyl alcohol is taken in round bottom flask. 300 ml of aqueous ammonia solution (20-25%) is added at 20-25°C. The reaction mass is stirred for 20-24 hours at 20-25°C. After completion of the reaction
The solid is filtered and washed with 100 ml isopropyl alcohol then dried to obtain 70-75 gm 2-amino-3-nitro-6-chloro-pyridine.
EXAMPLE 2: Preparation of 2-amino-3-nitro-6-p-fluorobenzylamino- pyridine.
100 gm of 2-amino-3-nitro-6-chloro-pyridine is taken in 800 ml of water. 90 gm of p-fluorobenzylamine is added dropwise into the reaction mixture at 20-25°C. Then 87 gm triethylamine is also added dropwise into the reaction mixture at 20-25°C. After complete addition, the reaction mass is stirred at 40-45°C for half an hour again the reaction mass is heated to 80-85°C and stirred at this temperature for 3-4 hours. After completion of the reaction, the reaction mass is cooled to 20-25°C and stirred at this temperature for 2-3 hours and then stirred at 15-20°C for 3-4 hours. The solid mass is filtered and then washed with 200 ml of water and 100 ml isopropyl alcohol and then dried in air oven till constant weight to get 140-150 gm. of 2-amino-3-nitro-6-p- fluorobenzylamino-py ridine .
EXAMPLE 3: Preparation of flupirtine maleate.
In an autoclave, 100 gm. 2-amino-3-nitro-6-p-fluorobenzylamino- pyridine is taken in 500 ml. 1, 4-dioxane and 20 ml aqueous ammonia solution. 10 gm of raney nickel is added under nitrogen atmosphere and hydrogenated at 75-80°C for 2-3 hours under 4-5 kg pressure. After completion of the reaction, the reaction mass is cooled and filtered at 40- 45°Cthen in filtrate 45 ml of ethyl chloroformate is added slowly at 5- 10°C. The temperature is raised to 25-30°C and 80 ml triethyl amine is added under nitrogen atmosphere. The reaction mass, is heated at 55- 60°C under stirring for 3-4 hours. After completion of the reaction, the reaction mass is distilled up to 70-80% under vacuum. This concentrated reaction mass is added into aqueous solution of maleic acid (72 gm in 2000 ml DM water at 65-70°C and maintained at 65-70°C for 2 hours under nitrogen to get crude Flupirtine Maleate as a solid. The reaction mass is cooled to 25-30°C in 5-6 hours and maintained at this temperature for next 2-3 hours then filtered. The wet cake is washed with 200 ml water and dried to get 145 gm of flupirtine maleate.
EXAMPLE 4: Preparation of pure flupirtine maleate crystalline modification A.
1 15 gm crude Flupirtine maleate obtained in example 3 is taken in 1 150 ml methanol and 58 ml water. This mixture is heated to reflux and 58 ml water is added slowly to get a clear solution and refluxed for about half an hour. The reaction mixture is cooled slowly to 60°C and seeded with crystals of modification A. Then it is cooled slowly to 20-25°C and maintained at this temperature for 2 hours. The crystalline mass is filtered and washed with 100 ml chilled methanol and dried to give 92 gm. flupirtine maleate crystalline modification A.

Claims

WE CLAIM:
1 ) A process for the preparation of the compound of formula (I)
Figure imgf000035_0001
and pharmaceutically acceptable acid addition salts thereof comprising the steps of:
(a) contacting 2, 6-dichloro-3-nitro pyridine of formula (P) with aqueous ammonia solution in a compatible solvent to produce 2-amino-3-nitro-6- chloro-pyridine of formula (Q);
Figure imgf000035_0002
(b) contacting said compound of formula (Q) with p-fluorobenzylamine taking water as a solvent in presence of a base to produce 2-amino-3- nitro-6-p-fluorobenzylamino-pyridine of formula (S);
Figure imgf000035_0003
(c) reducing nitro group of 2-amino-3-nitro-6-p-fluorobenzylamino- pyridine of formula (S) in a solvent base combination as solvent system in the presence of a catalyst;
Figure imgf000036_0001
(d) contacting 2,3-diamino-6-p-fluorobenzyl amino pyridine produced in step c with an ethyl chloroformate in presence of a base optionally insitu without isolation to produce flupritine base of formula (I);
Figure imgf000036_0002
(e) contacting the said flupritine base of formula (I) with acid solution to produce corresponding acid addition salt.
Figure imgf000036_0003
2. The process of claim 1 wherein compatible solvent for step a is selected from Q to C6 alcohols.
3. The process of claim 2 wherein compatible solvent is isopropyl alcohol.
4. The process of claim 1 wherein base for step b is selected from the group comprising hydroxides, carbonate or bicarbonates of alkali metals or alkali earth metals, ammonia, ammonia derivatives, primary, secondary or tertiary alkyl amines, piperidine, optionally substituted pyridines, picolines and the like.
5. The process of claim 4 wherein base is triethyl amine.
6. The process of claim 1 wherein solvent for solvent-base combination for the reduction of compound of (S) is selected from the group comprising C1 -C4 alcohols, cyclic ethers such as dioxane and tetrahydrofuran, ethoxyethanol, water, aromatic hydrocarbons and mixtures thereof.
7. The process of claim 6 wherein solvent is dioxane.
8. The process of claim 1 wherein the base or solvent-base combination is selected from the group comprising ammonia, primary, secondary or tertiary alkyl amines, piperidine, optionally substituted pyridines, picolines.
9. The process of claim 8 wherein the base 8 is ammonia.
10. The process of claim 1 wherein the solvent-base combination is selected from the group comprising d to C7 alcohol-ammonia or d to C7 alcohol-triethylamine or Q to C7 alcohol-ethylene diamine or mixture thereof or dioxane-ammonia or dioxane-triethylamine or dioxane- ethylene diamine or mixture thereof.
1 1. The process of claim 10 wherein the solvent base combination is dioxane-ammonia.
12. The process of claim 1 wherein catalyst for reduction of step c is selected from raney nickel, palladium, platinum, platinum dioxide.
13. The process of claim 12 wherein catalyst is raney Ni.
14. The process of claim 1 wherein base for step d is selected from the group comprising primary, secondary or tertiary alkyl amines, piperidine, optionally substituted pyridines, picolines.
15. The process of claim 14 wherein base is triethyl amine.
16. The process of claim 1 wherein the acid for step e is selected from the group comprising maleic acid, oxalic acid, mandilic acid, methane sulphonic acid, benzene sulphonic acid, phosphoric acid, hydrohalides, sulphates, bi-sulphates.
17. The process of claim 16 wherein the acid is maleic acid.
18. A process for the preparation of 2-amino-3-nitro-6-chloro of the formula (Q) comprising contacting 2,6-dichloro -3-nitro- of the formula (P) with aqueous ammonia .
Figure imgf000038_0001
19. A process for the preparation of 2-amino-3- nitro -6- (4- fluorbenzylamino)-pyridine of formula (S) an important flupirtine intermediate comprising contacting 2-amino-3-nitro-6-chloro of the formula (Q) with 4-fluorobenzylamine of formula (R) in water as a solvent at a temperature below 100°C.
Figure imgf000039_0001
20. A process for the preparation of flupirtine maleate of formula 1A and its pure crystal modification A
Figure imgf000039_0002
comprising:
(a) contacting 2, 6-dichloro-3-nitro pyridine of formula (P) with aqueous ammonia solution in a compatible solvent to produce 2-amino-3-nitro-6- chloro-pyridine of formula (Q);
Figure imgf000039_0003
(b) contacting said compound of formula (Q) with p-fluorobenzylamine taking water as a solvent in presence of a base to produce 2-amino-3- nitro-6-p-fluorobenzylamino-pyridine of formula (S);
Figure imgf000040_0001
(c) reducing nitro group of 2-amino-3-nitro-6-p-fluorobenzylamino- pyridine of formula (S) obtained in step c in a solvent base combination as solvent system in the presence of a catalyst;
Figure imgf000040_0002
(d) ) contacting 2,3-diamino-6-p-fluorobenzyl amino pyridine produced in step c with an ethyl chloroformate in presence of a base optionally insitu without isolation to produce flupritine base of formula (I);
Figure imgf000040_0003
(e) contacting the said flupritine base of formula (I) produced in step (d) with maleic acid solution to produce flupirtine maleate ;
Figure imgf000041_0001
f) contacting flupirtine maleate produced in step e with an alcoholic solvent and water is added to get suspension and the said suspension is heated to get clear solution which on cooling and optionally seeding with crystalline modification A give flupirtine maleate as crystalline modification A.
Figure imgf000041_0002
21. The process of claim 20 wherein alcoholic solvent for step f is selected from CI -C4 alcohols.
22. The process of claim 21 wherein alcoholic solvent is methanol.
23. The process of claim 20 step a wherein compatible solvent is isopropyl alcohol.
24. The process of claim 20 step b wherein base for step b is triethyl amine.
25. The process of claim 20 wherein the solvent base combination for step c is dioxane-ammonia.
26. The process of claim 20 wherein catalyst I for step c is raney Ni.
27. The process of claim 20 wherein base for step c is aqueous ammonia,
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Publication number Priority date Publication date Assignee Title
CN103333103A (en) * 2013-07-12 2013-10-02 南京正大天晴制药有限公司 Method for preparing flupirtine maleate by one-pot method
CN103333103B (en) * 2013-07-12 2015-07-22 南京正大天晴制药有限公司 Method for preparing flupirtine maleate by one-pot method
CN104086481A (en) * 2014-07-18 2014-10-08 四川新斯顿制药有限责任公司 Synthesis method of flupirtine maleate
CN104513197A (en) * 2014-11-28 2015-04-15 南京红太阳生物化学有限责任公司 2-aminonicotinic acid synthetic method
CN105541705A (en) * 2015-12-31 2016-05-04 山东罗欣药业集团股份有限公司 Synthesis method for flupirtine maleate compound
CN106397313A (en) * 2016-08-31 2017-02-15 安徽省润生医药股份有限公司 High efficient synthesis method of flupirtine maleate
CN109053563A (en) * 2018-07-20 2018-12-21 四川青木制药有限公司 A method of preparing hydrochloric acid Flupirtine
CN109053562A (en) * 2018-07-20 2018-12-21 四川青木制药有限公司 A method of preparing the flupirtine maleate of the high heap density of A crystal form
CN109053563B (en) * 2018-07-20 2022-03-29 四川青木制药有限公司 Method for preparing flupirtine hydrochloride
CN109053562B (en) * 2018-07-20 2022-05-27 四川青木制药有限公司 Method for preparing A-crystal-form flupirtine maleate with high bulk density

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