FIELD OF THE INVENTION
The present invention provides a novel process for preparation of flupirtine maleate (2)
and various methods to obtain crystalline Form A of flupirtine maleate.
BACKGROUND OF THE INVENTION
Flupirtine (1) is chemically known as 2-amino-6-[(4-flurobenzyl) amino]-3-
pyridinecarbamic acid ethyl ester and is represented by structure as shown in formula 1.
Flupirtine shows antipholgistic and analgesic activity. Flupirtine acts as an antipholgistic
drug by relieving inflammation and fever. Flupirtine also acts as an analgesic medication
as it reduces or eliminates pain.

Flupirtine (1) and its salts of pharmaceutically acceptable acids are generically disclosed
in patent GB 1191302 and flupirtine maleate (2) is specifically disclosed in patent GB
2084138.
There are several documents cited in the literature directed to the process for preparation
of flupirtine hydrochloride (7) and flupirtine maleate (2). These are discussed below.
The patent GB 1191302 describes the preparation of flupirtine hydrochloride (7)
comprising the steps: (a) coupling of 6-chloro-2-amino-3-nitro pyridine (3a) with 4-
flurobenzylamine (4) to give 2-amino-3-nitro-6-[(4-flurobenzyl)]amino pyridine (5), (b)
hydrogenation of compound 5 with hydrogen gas at high pressure in presence of Raney
Ni to obtain 2,3-diamino-6-[(4-flurobenzyl)]amino pyridine (6), and • (c)

ethoxycarbonylation of compound 6 with ethyl chloroformate as shown in the following
synthetic scheme 1.

The patent EP 199951 describes the preparation of flupirtine hydrochloride (7) as shown
in the synthetic scheme 1 wherein 2-amino-3-nitro-6-[(4-flurobenzyl)amino] pyridine (5)
is prepared by the coupling of 2-amino-3-nitro-6-methoxy pyridine (3b) with 4-
flurobenzyl amine (4) in water.
The patent EP 977736 describes preparation of flupirtine base (1) in a similar way as
shown in synthetic scheme 1. Flupirtine base (1) so obtained is treated with maleic acid to
obtain Form A of flupirtine maleate. All these steps, hydrogenation, ethoxycarbonylation
and salt formation are carried out in one pot in water soluble alcohols wherein
isopropanol, ethanol are preferred.
The patent GB 1191302 describes process for the preparation of flupirtine hydrochloride
(7) as shown in synthetic scheme 1 wherein reduction of 2-amino-3-nitro-6-[(4-
flurobenzyl)amino] pyridine (5) to 2,3-diamino-6-([4-flurobenzyl)amino] pyridine (6) is

achieved by using palladium, Zn/HCl, Sn/HCl, Fe/HCl, hydrogen sulfide in alcohol/water
or aluminum in aqueous ether and hydrogenation under pressure in presence of Raney Ni
at elevated temperature. The reducing reagents such as Zn/HCl, Sn/HCl, Fe/HCl are not
preferable due to requirement of highly acidic conditions which cause corrosion of the
reactors. Hydrogen sulfide is toxic, moreover, it has very strong smell like that of rotten
egg which makes its handling difficult on large scale and hence it is less preferable.
Another publication Choi et al, Journal of Labeled Compounds and
Radiopharmaceuticals, 24(1), (1987), 1-14 describes microscale preparation of [14C]
flupirtine maleate in a similar way as shown in synthetic scheme 1 from 6-chloro-2-
amino-3-nitro pyridine (3 a).
The publication, Stefan et al, Helvetica Chimica Acta, 77, (1994), 2175-2190 discloses
entirely different method for preparation of flupirtine maleate (2).
Most of the earlier methods for preparation of flupirtine involve hydrogenation reaction
under pressure which is required to be carried out in high pressure reactors. The high
pressure reactors in large scale production are having many disadvantages like difficulty
in handling of reactants, safety issues, high pressure drop, mass transfer limitations,
filtration of catalyst, mechanical stirring etc.
The novel process for preparation of flupirtine maleate (2) of the present invention not
only avoids drawbacks of the reduction step in the prior art methods as discussed above,
but also is easy and safe for large scale production.
There are several patent/ patent applications that are directed to the preparation of various
polymorphs of flupirtine maleate.
The publication D. Kaufmann et al, Tetrahedron Letters, 45, (2004), 5275-5278 describes
various methods of crystallization of flupirtine maleate (2) from isopropanol to obtain
Form A, Form B and isopropanol solvate.

The patent GB 2084138 describes preparation of crystalline form A and B of flupirtine
maleate by reaction of flupirtine base with maleic acid in isopropanol, ethanol under
various conditions.
This patent lists several parameters that shows crystalline Form A has high compatibility
over Form B in pharmaceutical preparations such as: '
i) Form A has better flow properties,
ii) Preparation of the various formulations of Form A by machine requires
considerably less lubricant, and
iii) Form A shows better wettability
The PCT application WO 2008110357 describes process for preparation of crystalline
Form B of flupirtine maleate by crystallization of flupirtine maleate (2) in solvent
selected from aromatic hydrocarbons, aromatic halogenated hydrocarbon, aliphatic esters,
aliphatic ketones or mixtures thereof with other solvents or water.
Another PCT application WO 2008007117 describes polymorphs V, W, X, Y and Z of
flupirtine maleate and process for their preparation.
SUMMARY OF THE INVENTION
The present invention provides a novel process for preparation of flupirtine maleate (2)
comprising the steps: (a) reduction of 2-amino-3-nitro-6-[(4-flurobenzyl)amino] pyridine
(5) using Raney Ni and hydrazine hydrate to give 2,3-diamino-6-[(4-flurobenzyl)amino]
pyridine (6), (b) ethoxycarbonylation of compound (6) to obtain flupirtine base (1) or its
acid addition salt, and (c) treatment of flupirtine base (1) or its acid addition salt with
maleic acid. The present invention further provides different methods to obtain crystalline
Form A of flupirtine maleate, these are:
i) crystallizing flupirtine maleate
or
ii) reacting flupirtine base with maleic acid
or

iii) reacting flupirtine hydrochloride with maleic acid
using suitable solvent selected from methanol or mixture of methanol and
ethyl acetate.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a novel process for preparation of flupirtine maleate (2)
comprising the steps:
(a) reduction of 2-amino-3-nitro-6-[(4-flurobenzyl)amino] pyridine (5) with Raney
Ni and hydrazine hydrate to 2,3-diamino-6-[4-flurobenzylamino] pyridine (6),
(b) ethoxycarbonylation of compound (6) to obtain flupirtine base (1) or its acid
addition salt,
(c) treatment of flupirtine base (1) or its acid addition salt with maleic acid.
The process for preparation of flupirtine maleate of the present invention is as shown in
synthetic scheme-2.


The starting compound, 2-amino-3-nitro-6-[(4-flurobenzyl)amino] pyridine (5) can be
prepared by the methods known in literature.
In the preferred embodiment, the compound, 2-amino-3-nitro-6-[(4-flurobenzyl)amino]
pyridine (5) was subjected to reduction by using aqueous hydrazine hydrate in presence
of Raney Ni as catalyst to obtain 2,3-diamino-6-[(4-flurobenzyl)amino] pyridine (6). The
process for reduction can be carried out in an organic solvent such as aromatic
hydrocarbon (e.g. toluene, xylene, benzene); cyclic ether (e.g. tetrahydrofuran, dioxan);
alcohols (e.g. methanol, ethanol). Preferred solvent for reduction is toluene. The
reduction can be carried out using 0.5 g to 10 g of Raney Ni per 50 g of 2-amino-3-
nitro-6-[(4-flurobenzyl)amino] pyridine (5), preferably 2 g to 3 g of Raney Ni per 50 g of
compound 5. The quantity of hydrazine hydrate can be in the range of 1 eq. to 20 eq. of
2-amino-3-nitro-6-[(4-flurobenzyl)amino] pyridine (5), preferably 2 to 5 eq.
The reaction mixture during reduction is a biphasic mixture when aromatic hydrocarbons
such as benzene, toluene, xylene are used. The reduction in aromatic hydrocarbon as
solvent were optionally carried out using phase transfer catalyst such as tri-n-butyl-
methylammonium chloride, phenyltrimethylammoniuni bromide, tetra-n-butylammonium
bromide, crown ethers e.g. diaza-18-crown-6.
Flupirtine base (1) or its acid addition salt was prepared by ethoxycarbonylation of 2,3-
diamino-6-[(4-flurobenzyl)amino] pyridine (6) with different reagents such as ethoxy
carbonyl pthalimide, diethoxycarbonyl anhydride, haloethylformate (e.g. ethyl
chloroformate) in organic solvent. The organic solvent is selected from aromatic
hydrocarbon e.g. toluene, xylene, benzene; cyclic ethers e.g. dioxan, tetrahydrofuran;
ketones e.g. acetone, methylethylketone; halogenated hydrocarbons e.g. dichloromethane,
chloroform; alcohols e.g. ethanol, isopropanol; amides e.g. dimethylformamide,
dimethylacetamide. Preferred solvent for ethoxycarbonylation is toluene.
The acid addition salts of flupirtine are converted to free base by treatment with organic
or inorganic base. Reaction of 2,3-diamino-6-[(4-flurobenzyl)amino] pyridine (6) with
ethyl chloroformate provide flupirtine hydrochloride (7).

In yet, another embodiment, the two steps, reduction and ethoxycarbonylation are carried
out in one pot without isolation of 2,3-diamino-6-[(4-flurobenzyl)amino] pyridine (6).
Treatment of flupirtine hydrochloride (7) with aqueous maleic acid solution afforded
flupirtine maleate (2). Alternatively, flupirtine hydrochloride (7) is converted to flupirtine
base (1) and flupirtine base is treated with maleic acid to obtain flupirtine maleate (2).
In yet, another embodiment, the present invention provides novel methods to obtain
crystalline Form A of flupirtine maleate. These are:
Method I: crystallizing flupirtine maleate,
Method II: reacting flupirtine base (1) with maleic acid, and
Method III: reacting flupirtine hydrochloride (7) with maleic acid.
using suitable solvent selected from methanol or mixture of methanol and ethyl acetate.
The solvent used in these methods is 5-20 times, preferably 8-10 times of the substrate.
When mixture of methanol-ethyl acetate is used, then the ratio of methanol to ethyl
acetate is 1:99 to 99:1, preferably 10:90 to 90:10, most preferably 90:10 to 80:20.
The above mentioned steps were carried out at temperature from 20 °C to 100 °C,
preferably at 50- 80 °C.
The process of the present invention for production of flupirtine maleate (2) is much
convenient compared to earlier methods, on large scale due to the following advantages:
i) the high pressure reactors are avoided,
ii) non-acidic conditions are employed,
iii) less toxic reagents are used,
iv) economical due to lesser time cycle, and
v) environment friendly due to non-polluting by product.
The crystalline Form A obtained by process of the present invention is characterized by
IR and PXRD. The IR spectrum exhibits peaks at 3427, 3224, 1703, 1623, 1568, 1517,
1386, 1361, 1278, 1224, 1166, 1124, 1074, 977, 862 cm-1. The PXRD shows peaks at
6.90, 9.22, 10.57, 12.46, 13.81,17.86, 18.56, 20.82,23.91, 24.17 at 26 degree.

EXPERIMENTAL
Example 1: Preparation of 2-amino-3-nitro-6-[4-flurobenzylamino] pyridine (5)
To the mixture of 150 g (0.86 mol) 2-amino-6-chloro-3-nitropyridine and 113.53 g (0.91
mol) 4-flurobenzylamine in 150 ml of isopropanol was added 113.68 g (1.12 mol)
triethylamine and heated at 80-85 °C for 3 hours. Cooled to 55- 60 °C and 450 ml of
water added. Further cooled to 0-5 °C. The precipitated yellow solid was filtered, washed
with chilled water and dried to obtain 2-amino-3-nitro-6-[(4-flurobenzy)lamino] pyridine.
Yield: 215 g, (94%)
Example 2: Preparation of flupirtine hydrochloride (7)
To the mixture of 50 g (0.19 mol) 2-amino-3-nitro-6-[(4-flurobenzyl)amino] pyridine (5)
in 500 ml toluene at nitrogen atmosphere was added 2.5 g Raney Ni and heated to 35- 40
°C. 51 g (0.762 mol) hydrazine hydrate (75%) was added to reaction mixture within 1
hour. Heated at 50- 60 °C for 1 hour and further at 80 °C for 30 minutes. The reaction
mixture was cooled to 60 °C and 26.2 g (0.232 mol) ethyl chloroformate was added
dropwise within 20 minutes. After completion of reaction, mixture of 650 ml isopropanol
and 100 ml water at 60- 65 °C was added, filtered and filtrate was cooled to 5 °C. The
precipitated solid was filtered, washed with chilled isopropanol and dried to obtain
flupirtine hydrochloride.
M.P: 202- 210 °C, yield: 40 g, (61.6 %)
Example 3: Preparation of flupirtine hydrochloride using phase transfer catalyst
To the mixture of 50 g (0.19 mol) 2-amino-3-nitro-6-[(4-flurobenzyl)amino] pyridine (5)
in 250 ml toluene was added 5g TBAB and 2.5 g Raney Ni along with 250 ml toluene at
nitrogen atmosphere and heated to 35- 40 °C. 51 g (0.762 mol) hydrazine hydrate (75%)
was added to reaction mixture within 1 hour. Heated at 50- 60 °C for 1 hour and further at
80 °C for 1 hour. The reaction mixture was cooled to 60 °C and 26.2 g (0.232 mol) ethyl
chloroformate was added. After completion of reaction, mixture of 325 ml isopropanol
and 100 ml water was added at 60- 65 C and filtered. The filtrate was cooled to 0- 5 °C.
The precipitated solid was filtered, washed with chilled isopropanol and dried to obtain
flupirtine hydrochloride.
M.P: 202- 210 °C, yield: 57.6 g, (90 %)

Example 4: Preparation of flupirtine base
To the solution of 55 g (0.018 mol) flupirtine hydrochloride in 110 ml isopropanol was
added 50 ml (0.111 mol) of 25% ammonium hydroxide under nitrogen atmosphere at 25-
30 °C and maintained for 30 minutes. 275 ml water was added and the reaction mixture
was maintained at 25- 30 °C for 2 hours. The precipitated solid was filtered, washed with
water and dried to obtain flupirtine base.
Yield: 41.5 g, (84%)
Example 5: Preparation of Form B of flupirtine maleate
To the solution of 19.4 g (0.167 mol) maleic acid in 380 ml water was added 38 g (0.111
mol) of flupirtine hydrochloride obtained in example 2 and heated at 55 °C to get clear
solution. Cooled to 25- 30 °C and precipitated crystals were filtered, washed with cold
water and dried to obtain crude flupirtine maleate. PXRD of crude flupirtine maleate was
matching with that of Form B described in EP 977736 Bl.
M.P: 170- 174 °C, yield: 37 g (80 %)
Example 6: Preparation of Form A flupirtine maleate using MeOH
Mixture of 32 g of crude flupirtine maleate in 320 ml methanol was heated to 65- 70 °C
to get a clear solution. Activated charcoal (0.6 g) was added to the reaction mixture,
filtered and charcoal washed with methanol. The combined filtrate heated to get a clear
solution and then cooled to 10 °C gradually. The precipitated solid was filtered, washed
with chilled methanol and dried to obtain pure flupirtine maleate Form A.
M.P: 174-176 °C, yield: 18 g
Example 7: Preparation of Form A flupirtine maleate using MeOH-EtOAc mixture.
To 40 g (0.095) of crude flupirtine maleate Form B in mixture of 333.2 ml methanol and
83.8 ml ethyl acetate was added activated charcoal (0.6 g) and heated to 65- 70 °C to get
a clear solution. The reaction mixture was filtered, washed with mixture of (1:5) ethyl
acetate: methanol. The combined filtrate heated to get a clear solution and then cooled to
10 °C gradually. The precipitated solid was filtered, washed with mixture of (1:5) ethyl
acetate: methanol and dried to obtain pure flupirtine maleate Form A.
M.P: 174- 176 °C, yield: 25 g (62.5%)

Example 8: Preparation of Form A flupirtine maleate from flupirtine base and
maleic acid by using MeOH.
To the mixture of 11.44 g (0.098) of maleic acid in 40 ml methanol was added 20 g
(0.06) flupirtine base and 200 ml methanol and heated to 65- 70 °C to get a clear solution.
Activated charcoal (1 g) was added, filtered and washed with hot methanol. The
combined filtrate heated to get a clear solution and was then cooled to 10 °C gradually.
The precipitated solid was filtered, washed with chilled methanol and dried to obtain pure
flupirtine maleate Form A.
M.P: 174-176 °C, yield: 22 g (81.4 %)
Example 9: Preparation of Form A flupirtine maleate from flupirtine base and
maleic acid by using MeOH-EtOAc mixture.
To 11.44 g (0.098 mol) of maleic acid in 50 ml (1:5) mixture of methanol: ethyl acetate
was added 20 g (0.06 mol) flupirtine base and 230 ml (5:1) methanol: ethyl acetate and
heated to 65 °C to get a clear solution. Activated charcoal (1 g) was added and filtered.
The combined filtrate heated to 65 °C to get a clear solution and was then cooled to 10 C
gradually. The precipitated solid was filtered, washed with mixture of chilled ethyl
acetate: methanol and dried to obtain pure flupirtine maleate Form A.
M.P: 174- 176 °C, yield: 22.5 g (81.4 %)
Example 10: Preparation of Form A flupirtine maleate from flupirtine
hydrochloride and maleic acid by using MeOH
To the mixture of 10.22 g (0.088 mol) of maleic acid in 50 ml methanol was added 20 g
(0.059) flupirtine hydrochloride and 150 ml methanol and heated to 65- 70 °C to get a
clear solution. Activated charcoal (1 g) was added, filtered and washed with hot
methanol. The combined filtrate was cooled to 10 °C gradually, water added and heated
the reaction mixture to 60-65 °C for 1 hour. The reaction mixture was cooled, seeded
with flupirtine maleate Form A and maintained for 5 hours at 10 °C. The precipitated
solid was filtered, washed with (1:1) chilled methanol: water and dried to obtain pure
flupirtine maleate Form A.
M.P: 172- 176 °C, yield: 10.2 g (41 %)

Example 11: Preparation of Form A flupirtine maleate from flupirtine
hydrochloride and maleic acid by using MeOH-EtOAc mixture.
To 10.22 g (0.088 mol) of maleic acid in 50 ml (1:5) mixture of ethyl acetate: methanol
was added 20 g (0.059) flupirtine hydrochloride and 150 ml (5:1) methanol: ethyl acetate
and heated to 65- 70 °C to get a clear solution. Activated charcoal (1 g) was added,
filtered and washed with (1:5) hot mixture of ethyl acetate: methanol. The combined
filtrate heated at 68 °C for 1 hour and gradually cooled to 25-30 °C. 200 ml of water
added and heated to 60-65 °C for 1 hour and gradually cooled to 10 °C. The reaction
mixture maintained for 5 hours at 10 C. The precipitated solid was filtered, washed with
(1:5) chilled mixture of ethyl acetate: methanol and dried to obtain pure flupirtine
maleate Form A.
M.P: 170- 174 °C, yield: 10.5 g (42.55 %)

We claim
1. A novel process for preparation of flupirtine maleate (2)

comprising the steps of:
a) reduction of 2-amino-3-nitro-6-[(4-flu'robenzyl)amino] pyridine (5) with
Raney Ni and hydrazine hydrate to 2,3-diamino-6-[4-flurobenzylamino]
pyridine (6),

b) ethoxycarbonylation of compound (6) to obtain flupirtine base (1) or its
acid addition salt,

c) treatment of flupirtine base (1) or its acid addition salt with maleic acid.

2. The process according to claim 1, wherein step a is carried out in an organic
solvent selected from aromatic hydrocarbon such as toluene, xylene, benzene;
cyclic ether such as tetrahydrofuran, dioxan; alcohols such as methanol, ethanol;
preferred solvent is toluene.
3. The process according to claim 1, wherein step a carried out using 0.01 g to 0.2 g
of Raney Ni (w/w); preferably 0.04 to 0.06 g (w/w).
4. The process according to claim 1, wherein quantity of hydrazine hydrate in step a
is in the range of 1 -20 molar equivalent; preferably 2-5 molar equivalent.
5. The process according to claim 1, wherein step b is carried out in organic solvent
selected from aromatic hydrocarbon such as toluene, xylene, benzene; cyclic
ethers such as dioxan, tetrahydrofuran; ketones such as acetone,
methylethylketone; halogenated hydrocarbons such as dichloromethane,
chloroform; alcohols such as ethanol, isopropanol; amides such as
dimethylformamide, dimethylacetamide; preferred solvent is toluene.
6. Process for obtaining crystalline Form A of flupirtine maleate by:
i) crystallizing flupirtine maleate
or
ii) reacting flupirtine base with maleic acid
or
iii) reacting flupirtine hydrochloride with maleic acid
using suitable solvent selected from methanol or mixture of methanol and ethyl
acetate.
7. The process according to claim 6, wherein solvent quantity is 5-20 times;
preferably 8-10 times of the substrate.
8. The process according to claim 6, wherein the ratio of methanol to ethyl acetate is
1:99 to 99:1; preferably 10:90 to 90:10; most preferably 90:10 to 80:20.

9. The process according to claim 1, wherein temperature in any of the step is in the
range of 20-100 °C; preferably at 50- 80 °C.
10. Flupirtine base (1) and flupirtine maleate (2) obtained by any of the preceding
claims.

The present invention provides a novel process for preparation of flupirtine maleate (2)
comprising the steps: (a) reduction of 2-amino-3-nitro-6-[(4-flurobenzyl)amino] pyridine
(5) using Raney Ni and hydrazine hydrate to give 2,3-diamino-6-[(4-flurobenzyl)amino]
pyridine (6), (b) ethoxycarbonylation of compound (6) to obtain flupirtine base (1) or its
acid addition salt, and (c) treatment of flupirtine base (1) or its acid addition salt with
maleic acid. The present invention further provides different methods to obtain crystalline
Form A of flupirtine maleate.