FORM 2
THE PATENTS ACT, 1970
(Act 39 of 1970)
&
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(See Section 10 & rule 13)
"A PROCESS FOR THE PREPARATION OF FLUPIRTINE
MALEATE"
ZCL CHEMICALS LIMITED
'A'- 806/807,
215 ATRIUM CHAKALA,
ANDHERI (EAST), MUMBAI-400 059,
MAHARASHTRA, INDIA.
(An Indian Organization)
The following specification particularly describes the invention and the manner in which it is to be performed.

A PROCESS FOR THE PREPARATION OF FLUPIRTINE MALEATE FIELD OF THE INVENTION
The present invention relates to a process for the preparation of flupirtine maleate of formula I thereof,

BACKGROUND OF THE INVENTION
Flupirtine with a chemical name 2-amino-3-carbethoxyamino-6-(p-fluorobenzylamino)pyridine is a centrally acting non-opioid analgesic without antipyretic or antiphlogistic properties. As reported in abstracts of Maedica (Buchar). 2012 June; 7(2): 163-166, J Anaesthesiol Clin Pharmacol. 2012 Apr-Jun; 28(2): 172-177 and Wikipedia. flupirtine is unique as a non-opioid. non-NSAID. non-steroidal analgesic and was first approved in Germany on a national level in 1989. This selective neuronal potassium channel opener evolved rapidly into one of the most preferred analgesics for the treatment of musculoskeletal pain in European countries. It is devoid of adverse effects of routinely used analgesic drugs, but is equally efficacious in reducing pain sensation. It has a distinctive mechanism of action, exerting a dual therapeutic effect with both analgesic and muscle relaxant properties that has utility in the treatment of pain, including that associated with muscle tension. Additional effects identified include neuro-protection, and anti-apoptotic action. Although it is not yet approved by United States Food and Drug Administration (US FDA), it is still used in many countries including India. Recently. US FDA granted permission to carry out phase II clinical trial with flupirtine for the treatment of fibromyalgia. More over that, flupirtine is in use for the last 25 years for the management of pain following surgery, trauma, dental extraction, pain associated

with muscle spasm, cancer, degenerative joint diseases, and conditions such as headache and dysmenorrhoea in Europe.
GB patent 1,191,302 discloses the process for the preparation of flupirtine hydrochloride by reacting 6-ch!oro-2-amino-3-nitro-pyridine with 4-fluorobenzylamine at 100°C to give 2-amino-3-nitro-6-[(4-fluorobenzyl)]amino pyridine followed by hydrogenation with hydrogen gas at 20 atmospheric pressure in dioxane, in the presence of Raney Ni and precipitated from filtrate on the addition of petroleum ether to give 2,3-diamino-6-[(4-fluorobenzyl)]amino pyridine. The obtained compound is undergone for ethoxycarbonylation with ethyl chloroformate in dioxane to give flupirtine base.
2,3-diamino-6-[(4-fluorobenzyl)]amino pyridine compound is highly oxygen sensitive and lead the product towards blue color. The use of dioxane in hydrogen pressure leads the reaction to impurity formation. Moreover that dioxane is not suitable from industrial point of view at large scale as generally it is considered typically unsafe and toxic.
GB patent 2,084,138 discloses flupirtine maleate and process for its preparation. It describes flupirtine maleate in polymorphic form "crystal modification A" having contamination of "crystal modification B". Flupirtine maleate "crystal modification A" is prepared by four slightly different processes in impure "crystal modification A". First process discloses flupirtine base dissolved in large amount of isopropanol reacted with maleic acid dissolved in isopropanol at 60°C and cooled to 25°C to give flupirtine maleate 80% "crystal modification A" and 20% "crystal modification B". Second process discloses reaction of maleic acid in ethanol with flupirtine base dissolved in large amount of ethanol and the seed crystals obtained by first process at 65°C and immediate cooled to 8°C to give 71% "crystal modification A" of flupirtine maleate. Third process discloses the flupirtine base in isopropanol treated with activated carbon in isopropanol at 70°C and filtered. The solution of

maleic acid in isopropanol is reacted with above obtained flupirtine base at 60°C and cooled to 18-20°C to give 84% "crystal modification A" of flupirtine maleate. Fourth process discloses maleic acid solution in isopropanol and flupirtine base in isopropanol and seed crystals obtained by first process reacted at 60°C and cooled to 18°C to give 77% "crystal modification A" of flupirtine maleate.
The above four disclosed processes are unable to make "crystal modification A" in pure crystal form. The quantity of solvents used is also very large; hence neither industrially viable nor plant feasible.
Journal of Labelled Compounds and Radiopharmaceuticals, 24 (1), (1987), 1-14, discloses micro scale preparation of [oC] flupirtine maleate. The reported process is of academic interest only and not for the industrial use.
EP patent 0 977 736 discloses the process for the preparation of flupirtine maleate by hydrogenating 2-amino-3-nitro-6-(p-fluorobenzylamino)pyridine in water soluble alcohols in the presence of 16% Raney-Ni and hydrogen pressure of 5 bar at 65°C temperature. After completion of hydrogenation, reaction mixture is treated with ethyl chloroformate in the presence of triethylamine at 60°C temperature. The hot solution is then sucked with stirring into a solution of maleic acid prepared in water and stirred at 20°C to give flupirtine maleate. Further obtained flupirtine maleate having 10% A modification and 90%) B modification is recrystallized from isopropanol to get pure A modification.
The disadvantages of the above process is reaction carried out in the presence of triethylamine with ethyl chloroformate, it forms flupirtine base which is very much oxygen sensitive, responsible for colored product and unstable with compare to flupirtine hydrochloride. Moreover that it is very difficult to recover the water soluble alcohols from the mother liquor and other by products; hence effluent generation is not in favor of environment when it has high percentage of ammonical nitrogen and

now a day's effluent treatment cost is also very high. All the above disadvantages cumulatively increase the cost of product as well as more operations.
PCT application 2008/110357 discloses the process to prepare crystal modification B of flupirtine maleate. Further the application discloses process to prepare pure crystal modification A by purifying flupirtine maleate with methanol in comparative example.
IN application 157/KOL/2010 discloses the process to prepare flupirtine maleate form A and form B. 2-amino-6-chloro-3-nitropyridine is reacted with 4-fluorobenzylamine in isopropanof in the presence of triethylamine, heated at 80-85°C and cooled to 55-60°C to obtain 2-amino-3-nitro-6-[(4-fluorobenzyI)amino]pyridine. Further it is undergone hydrogenation in the presence of hydrazine hydrate and Raney-Ni in toluene. The reaction mixture is heated to 50-60°C and further to 80°C. The reaction is cooled to 60°C followed by addition of ethyl chloroformate. After completion of reaction isopropanol and water is added, filtered and cooled to 5°C to get flupirtine hydrochloride. Another process discloses use of phase transfer catalyst in hydrogenation reaction. Further crystalline form A of flupirtine maleate is prepared by crystallizing flupirtine maleate. by reacting flupirtine base with maleic acid and by reacting flupirtine hydrochloride with maleic acid using solvent methanol or mixture of methanol and ethyl acetate.
Here in above process hydrazine hydrate is used which is known to be toxic, carcinogenic with long lasting effects. Hydrazine hydrate is very difficult to handle at plant scale. The reduction reaction in the presence of hydrazine hydrate and Raney Ni with 2-amino-3-nitro-6-[(4-fluorobenzyt)amino]pyridine is highly exothermic and generates high energy lead the reaction to runaway. Moreover that the use of combination of Raney Ni in toluene in reduction reaction is highly unsafe from the industrial point of view.

PCT application 2013/080215 discloses the condensation of 2-amino-6-chloro-3-nitropyridine with 1.25 mole equivalent 4-fluorobenzylamine in water in the presence of water soluble bases [triethylamine] to get 2-amino-3-nitro-6-[(4-fluorobenzyl)amino]pyridine. Then it is reduced in the presence of raney Ni and soivent-base combination [dioxane - aqueous ammonia]. In-situ acylation by contacting with ethyl chloroformate in the presence of triethylamine followed by distillation of reaction mass and subsequently reacted with maleic acid. Then purified in alcohol-water to get flupirtine maleate in crystalline modification A.
The use of triethylamine in large volume is disadvantageous as discussed above. The distillation of reaction mixture makes the process cumbersome and tedious. Moreover that the patent application is silent about the purity of flupirtine maleate.
EP application 2 046 749 discloses the polymorphic forms V, W, X, Y and Z of flupirtine maleate and EP application 2 206 699 discloses polymorph II of flupirtine base.
Thus, present invention fulfills the need of the art to provide an improved and industrially applicable process for preparation of flupirtine maleate by avoiding use of hazardous reagents, difficult process conditions, minimize the effluent generation, distillation at high vacuum, less unit operations and isolation of intermediates at various stages as well which makes the process plant friendly, environment friendly, non-hazardous and economically viable.
OBJECTIVE OF THE INVENTION
The principal objective of the present invention is to provide a process for preparation of flupirtine maleate to overcome or ameliorate one of the disadvantages of the prior art processes.

Another leading objective of the present invention is to provide the one-pot process for the preparation of flupirtine maleate from 2-amino-6-chloro-3-nitropyridine.
Another prime objective of the invention is to provide an efficient, improved and industrially advantageous process for preparation of flupirtine maleate which is conveniently applicable to industrial scale.
Yet another primary object of the present invention is to provide flupirtine maleate wherein hydrogenation. acylation and maleate salt formation are carried out in water immiscible alcohol.
Yet another leading objective of the present invention is to avoid use of hazardous reagents.
One more principal objective of the present invention is to provide a process for the preparation of 2-amino-3-nitro-6-[4-fluorobenzylamino] pyridine by condensing 2-amino-6-chloro-3-nitropyridine and 4-fluorobenzylamine in a water immiscible alcohol optionally in combination with water.
One more objective of the present invention is to provide pure "crystal modification A" of flupirtine maleate.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides a one-pot process for the preparation of flupirtine maleate,

comprises the steps of:
a), condensing formula II with 4-fluorobenzylamine to form compound of

b). hydrogenating compound of formula III to form compound of formula

c). acylating the compound of formula IV by ethyl chloroformate to form compound of formula V; and

d). treating compound of formula V with maleic acid to isolate flupirtine maleate.

Accordingly; the present invention provides an improved process for the preparation of pure "crystal modification A" of fiupirtine maleate.

comprises the steps of:
a), condensing formula II with 4-fluorobenzylamine in water immiscible
alcohol in the presence of inorganic base to form compound of formula
III; b). hydrogenating compound of formula 111 in water immiscible alcohol in
the presence of reducing agent and optionally in the presence of phase
transfer catalyst to form compound of formula IV in-situ; c). acylating the compound of formula IV in-situ by ethyl chloroformate in
water immiscible alcohol to form compound of formula V; d). treating compound of formula V with maleic acid in-situ to isolate
fiupirtine maleate; and e). purifying fiupirtine maleate to isolate pure "crystal modification A" of
fiupirtine maleate.
Accordingly, the present invention provides a process for the preparation of fiupirtine maleate, process comprises the steps of:
a), hydrogenating compound formula III in the presence of reducing agent and optionally in the presence of phase transfer catalyst to form compound of formula IV; b). acylating compound of formula IV by ethyl chloroformate to form compound of formula V; and

c). treating compound of formula V with maieic acid to isolate flupirtine maleate. wherein step a) to c) are carried out in water immiscible alcohol optionally in combination with water.
Accordingly, the present invention provides a process for the preparation of compound of formula III by treating formula II with 4-fluorobenzylamme in isobutanot in the presence of inorganic base.
Accordingly, the present invention provides an improved process for the preparation of flupirtine maleate as depicted in detailed description.
BRIEF DESCRIPTION OF DRAWINGS:
FIG. 1 is a powdered X-ray diffraction pattern for "crystal modification A" of flupirtine maleate having 2-theta values at 6.9°, 9.3°, 10.6°, 12.4°, 13.9°, 15.4°, 17.9°, 18.6°, 20.9°, 23.9°, 24.2° ±0.2.
DETAILED DESCRIPTION OF THE INVENTION
All ranges recited herein include the endpoints, including those that recite a range "between" two values. Terms such as "about", "generally" and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
The term ''in-situ' typically means "in the reaction mixture". The term "one-pot process" typically means "without isolating the intermediates".

According to the embodiment of the invention provides an industrially feasible and economically viable process for preparation of pure "crystal modification A" of flupirtine maleate of formula I from compound of formula II.
Stage 1:
Compound of formula II is reacted with 4-fluorobenzylamine to give compound of formula III. Generally the reaction involves condensing formula II with 4-flurorbenzylamine in water immiscible alcohol optionally in combination with water, in the presence of inorganic base. Wherein water immiscible alcohols include n-butanoL isobutanoL sec-butanol, 3-methylbutan-2-ol. panten-l-ol, 3-methyl-l-butanol, 2-methyl-l-butanoL 2,2-dimethylpropan-l-ol, 3-Pentanol, 2-PentanoL 3-methylbutan-2-ol, 2-methyl-2-butanol and the like or mixtures thereof. The inorganic base includes alkali or alkaline metal hydroxides, carbonates, bicarbonates: wherein inorganic base is preferably sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate; wherein inorganic base is more preferably sodium carbonate. The reaction mixture is heated to 70-130°C. preferably 80-110°C, more preferably 95-105°C for 1-24 hours, preferably 1-10 hours, more preferably 2-3 hours. The completion of the reaction can be monitored by high performance liquid chromatography or thin layer chromatography. After confirmation of reaction completion, the reaction mixture is cooled to 10-60°C, more preferably 50-55°C. The work up procedure can be followed by adding water and further cooled to 0-40°C, preferably 10-35°C; more preferably 25-30°C to form the compound of formula III, optionally isolating compound of formula III from the reaction mixture.
The major advantage of the stage 1 is to reduce the molar equivalent amount of 4-flurobenzylamine [present invention involves use of 1.05 mole equivalent amount] with compare to prior art processes, avoid use of costly bases like triethylamine and to introduce water immiscible alcohol as novel solvent. Moreover

that the present invention reports one-pot process for the preparation of flupirtine maleate from compound of formula II. wherein compound of formula III is not isolated. It is well known in the art that one-pot process has lots of advantages then multi-step process.
Stage 2:
The compound of formula III is hydrogenated in the presence of reducing agent in water immiscible alcohol. The reducing agent involves Raney Ni, Palladium on carbon. Rhodium complexes, Platinum based catalysts and the like, preferably Raney Ni. Wherein water immiscible alcohols include n-butanol, isobutanol, sec-butanol. 3-methylbutan-2-ol, panten-1-ol, 3-methyl-l-butanol, 2-methyl-l-butanol, 2,2-dimethylpropan-l-ol, 3-Pentanol, 2-Pentanol, 3-methyIbutan-2-ol, 2-methyI-2-butanol and the like or mixtures thereof, preferably isobutanol. Conventionally, a phase transfer catalyst may also be used to reduce the reaction time. Wherein the phase transfer catalyst include C3-C5 tetra alkyl ammonium chloride such as tetra propyl ammonium chloride, tetra butyl ammonium chloride, tetra pentyl ammonium chloride or C3-C5 tetra alkyl ammonium bromide such as tetra propyl ammonium bromide, tetra butyl ammonium bromide, tetra pentyl ammonium bromide, preferably tetra butyl ammonium bromide. The reaction can be carried out at 50-100°C, preferably at 50-55°C. For the hydrogenation reaction, hydrogen pressure can be applied l-10kg/cm2, preferably 5kg/cm2. The reaction mixture is stirred for till the completion of the reaction, preferably for 5-6 hours at 25-80°C preferably 45-50°C. The reaction completion can be monitored by high performance liquid chromatography or thin layer chromatography. After confirmation of reaction completion, the reaction mixture possesses compound of formula IV is carried forward in-situ for the acylation.
Acylation of formula IV in-situ by ethyl chloroformate in water immiscible alcohol to form compound of formula V. Wherein water immiscible alcohols include n-butanol. isobutanol, sec-butanol, 3-methylbutan-2-ol, panten-1-ol. 3-methyl-l-

butanol, 2-methyl-l-butanol, 2,2-dimethy!propan-l-ol, 3-Pentanol, 2-Pentanol, 3-methylbutan-2-ol, 2-methyl-2-butanol and the like or mixtures thereof, preferably isobutanol. The reaction mixture is maintained under stirring for 0.5-5 hours, preferably 0.5-1 hour at 25-70°C, preferably 50-60°C to form formula V in-situ. The reduction catalyst is filtered off from the reaction mixture.
The formed flupirtine hydrochloride of formula V is treated in-situ with maleic acid to form flupirtine maleate. It can be prepared by adding above resultant filtrate generated after filtering catalyst to the prepared solution of maleic acid in water. The reaction mixture is heated to 50-80°C, preferably 55-60°C for l-5hours, preferably 1 hour. More quantity of water is added to the reaction mixture; the reaction mixture is cooled to -5-10°C; preferably 0-5°C and stirred for 3-4 hours. The precipitated product is filtered, washed with the suitable solvent and dried to get flupirtine maleate.
The some of the advantages of stage 2 are as cited below:
- Avoids use of dioxane and water soluble alcohols; make the process safe from
the industrial point of view and recovery of solvent is possible due to use of
water immiscible alcohol. In this way process is being environment friendly
and economical;
Avoids use of hazardous and carcinogenic reagents like hydrazine hydrate; make the process safe, plant friendly:
- Avoids isolation or formation of flupirtine free base [i.e base like triethylamine is not used in the process: hence flupirtine hydrochloride will form], which is very oxygen sensitive and responsible for colored product; Rectifies critical conditions like exothermic reaction, hazardous reagent and incompetent solvents;
- Ameliorate lengthy work-up procedures:
- Avoids isolation of intermediates at various stages; and

- Cost effective, environment friendly, industrially viable and regulatory requirement efficient.
Stage 3:
The reaction involves purification of flupirtine maleate to give pure flupirtine maleate of formula I.
Particularly, flupirtine maleate is treated with methanol and heated to reflux, preferably at 64-65°C for 1-3 hours, preferably 1 hour. The reaction mixture is then filtered, cooled to -5-5°C, preferably at 0-5°C and maintained for 3-hours. The reaction mixture is filtered, washed with chilled methanol and dried to get pure '"crystal modification A" of flupirtine maleate of formula I having HPLC purity particularly >99.8%, more particularly >99.9%.
Moreover that, a one-pot synthesis is a strategy to improve the efficiency of a chemical reaction whereby a reactant is subjected to successive chemical reactions without isolating intermediates at various stages. It also avoids a lengthy isolation steps, filtration and drying at various stages, avoids use of large quantity of solvents and purification of the intermediate compounds would save time as well as resources while increasing product yield.
The invention is further defined by reference to the following examples describing in detail by the preparation of the compounds of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

EXAMPLES:
Example -1: Preparation of 2-amino-3-nitro-6-[4-fluorobenzylamino] pyridine
III)
The mixture of 200g (1.15 mol) 2-amino-6-chloro-3-nitropyridine (II) and 151.40g (1.21 mol) 4-fluorobenzylamine in 400 ml of isobutanol was added followed by addition of 183.18g (1.73 mol) sodium carbonate and heated to 95-105°C for 2 hours. The reaction mixture was cooled to 50-55°C and 1000 ml of water was added. Further cooled to 25-30°C to precipitate yellow solid was then filtered, washed with water and dried to get 288 g 2-amino-3-nitro-6-[4-fluorobenzylamino] pyridine (III) Molar vield: 95% HPLC purity: 99.60%
Example -2: Preparation of Flupirtine Maleate
200g (0.76 mol) 2-amino-3-nitro-6-[4-fluorobenzylamino] pyridine (III) was hydrogenated in a suspension of 20.0g Raney Ni, 10-0g tetrabutyl ammonium bromide in 1200 ml isobutanol at 50-55X. The pressure hydrogenator was purged two times with nitrogen (2.0 kg/cm2) and two times with hydrogen (2.0 kg/cm2) pressure. The reaction mixture was stirred for 6.0 hours at 50°C and 5.0 kg/cm2 hydrogen pressure to form compound of formula IV. After completion of hydrogenation, 104.57g (0.96 mol) ethyl chloroformate was added and the reaction maintained for half an hour at 50-60°C to form compound of formula V. The reaction mixture was sucked at 70-80°C to remove the reduction catalyst, washed with mixture of hot isobutanol and water (1:1). directly into a solution of 132.90g(1.14 mol) maleic acid in 300 ml of water, the solution was heated to 60°C for 1.0 hour. 3600 ml of water was charged in one lot, then cooled to below 5°C and stirred for 3.0 hours. The flupirtine maleate was filtered off at below 5°C. washed with mixture of chilled isobutanohwater (1:1) and dried to get 258 g flupirtine maleate. Molar yield: 80% HPLC purity: >98.5%

Example -3: Preparation of pure Flupirtine Maleate (I)
200.0g (0.48 mol) Flupirtine maleate in 2000 ml of methanol was heated at 65°C for 1 hour under nitrogen. The reaction mass was filtered under hot condition, followed by cooling at 0-5°C and maintained for 3.0 hours. The solid was filtered, wash with 400 ml chilled methanol and dried to get 168.0g pure "crystal modification A" of flupirtine Maleate (I) as depicted in fig. 1. Molar yield: 84.0% HPLC purity: 99.95%
Example 4: One-pot process to prepare flupirtine maleate
The mixture of lOO.Og (0.57mol) 2-amino-6-chloro-3-nitropyridine (II) and 75.60g (0.60mol) 4-fluorobenzyl amine in 500 ml isobutanol was added 45.80g (0.43mol) sodium carbonate in auto clave (pressure reactor) and heated to 95-105°C for 2 hours. 2-amino-6-chloro-3-nitropyridine (II) should be not more than 1.0% was checked by thin layer chromatography .The reaction mixture was cooled to 25-30°C to form 2-amino-3-nitro-6-[4-fluorobenzyIamino] pyridine (III). The reaction mixture was undergone for hydrogenation in a suspension of 15.0g Raney Ni, 7.5g tetrabutyl ammonium bromide in 400 ml isobutanol at 50-55°C. The pressure was applied two times with nitrogen gas (2.0 Kg/cm2) and two times with hydrogen gas (2.0 Kg/cm2). The reaction mixture was stirred for 6.0 hours at 50°C and 5.0 Kg/cm2 hydrogen pressure to form compound of formula IV. After completion of hydrogenation, 78.00g (0.72mol) ethyl chloroformate was added and the reaction maintained for half an hour at 50-60°C to form compound of formula V. The reaction mixture was sucked at 75-80°C to remove the reduction catalyst and directly filtrate dropped into a solution of 99.68g (0.85 mol) maleic acid in 225ml of water, the solution was heated to 60°C for 1.0 hour. 2700 ml of water was charged in one lot, then cooled to below 5°C and stirred for 3.0 hours. The flupirtine maleate was filtered off at below 5°C,

washed with mixture of chilled isobutanol: water (1:1) and dried to get 194 g flupirtine maleate. Molar yield: 80% HPLC purity: >98.5 %

WE CLAIM:
1. A one-pot process for the preparation of flupirtine maleate from compound of formula II.
2. The process according to claim 1, wherein process for the preparation of flupirtine maleate,

comprising the steps of: a), condensing formula II with 4-fluorobenzylamine to form compound of

b). hydrogenating compound of formula III to form compound of formula

c). acylating the compound of formula IV by ethyl chloroformate to form compound of formula V;


d). treating compound of formula V with maleic acid to isolate flupirtine maleate.
3. An improved process for the preparation of pure "crystal modification A" of flupirtine maleate formula 1,

comprising the steps of: a), condensing formula II with 4-fluorobenzyIamine in water immiscible
alcohol in the presence of inorganic base to form compound of formula
III; b). hydrogenating compound of formula III in water immiscible alcohol in
the presence of reducing agent and optionally in the presence of phase
transfer catalyst to form compound of formula IV in-situ: c). acylating the compound of formula IV in-situ by ethyl chloroformate in
water immiscible alcohol to form compound of formula V; d). treating compound of formula V with maleic acid in-situ to isolate
flupirtine maleate; and e). purifying flupirtine maleate to isolate pure "crystal modification A" of
flupirtine maleate.

4. The process according to claim 3. wherein
in step a) inorganic base is selected from alkali or alkaline metal hydroxides,
carbonates, bicarbonates; wherein inorganic base is preferably sodium
hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate.
potassium carbonate, lithium carbonate, sodium bicarbonate, potassium
bicarbonate, lithium bicarbonate; wherein inorganic base is more preferably
sodium carbonate;
in step b) reducing agent is selected from Raney Ni, palladium on carbon,
rhodium complexes, platinum based catalysts and the like, preferably Raney
Ni;
in step b) phase transfer catalyst is selected from C3-C5 tetra aikyl ammonium
chloride such as tetra propyl ammonium chloride, tetra butyl ammonium
chloride, tetra pentyl ammonium chloride or C3-C5 tetra alkyl ammonium
bromide such as tetra propyl ammonium bromide, tetra butyl ammonium
bromide, tetra pentyl ammonium bromide, preferably tetra butyl ammonium
bromide; and
in step a), b), c) water immiscible alcohol solvent is selected from n-butanol.
isobutanol, sec-butanol 3-methylbutan-2-ol, panten-1-ol, 3-methyl-l-butanol,
2-methyl-I-butanoI. 2,2-dimethylpropan-l-ol. 3-Pentanol, 2-Pentanol. 3-
methytbutan-2-ol, 2-methyl-2-butanol or mixtures thereof.
5. A process for the preparation of flupirtine maleate, process comprises the
steps of:
a). hydrogenating compound formula HI in the presence of reducing agent and optionally in the presence of phase transfer catalyst to form compound of formula IV;
b). acylating compound of formula IV by ethyl chloroformate to form compound of formula V; and

c). treating compound of formula V with maleic acid to isolate flupirtine
maleate. wherein step a) to c) are carried out in water immiscible alcohol optionally in combination with water.
6. The process according to claim 5, wherein
in step a) reducing agent is selected from Raney Ni, palladium on carbon, rhodium complexes, platinum based catalysts and the like, preferably Raney Ni;
in step a) optionally phase transfer catalyst is selected from C3-C5 tetra alkyl ammonium chloride such as tetra propyl ammonium chloride, tetra butyl ammonium chloride, tetra pentyl ammonium chloride or C3-C5 tetra alkyl ammonium bromide such as tetra propyl ammonium bromide, tetra butyl ammonium bromide, tetra pentyl ammonium bromide, preferably tetra butyl ammonium bromide; and
in steps a) to c) water immiscible alcohol solvent is selected from n-butanol, isobutanol, sec-butanol, 3-methylbutan-2-ol, panten-l-ol, 3-methyl-l-butanol, 2-methyl-l-butanol, 2,2-dimethylpropan-l-ol, 3-Pentanoi, 2-Pentanol, 3-methylbutan-2-ol, 2-methyl-2-butanol or mixtures thereof.
7. A process for the preparation of compound of formula 111 by treating formula II with 4-fiuorobenzylamine in isobutanol optionally in combination with water in the presence of inorganic base.
8. The process according to claim 7, wherein inorganic base is selected from alkali or alkaline metal hydroxides, carbonates, bicarbonates; wherein inorganic base is preferably sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium

bicarbonate, potassium bicarbonate, lithium bicarbonate; wherein inorganic base is more preferably sodium carbonate.