DESCRIPTION OF THE INVENTION
While this specification concludes with claims particularly pointing out and distinctly
'-·
claiming that, which is regarded as the invention, it is anticipated that the invention can
be more readily understood through reading the following detailed description of the
invention and study of the included examples.
The processes for the preparation of ezogabine, as disclosed in prior arts, struggle with
various impurities formation and thus needs purification to make ezogabine to meet
pharmacopeia! standards, wherein the required purifications leads to very low yield.
Understanding, the limitations of prior arts and for the need of an advantageous process
for the preparation of ezogabine, the present invention is directed to an improved process
of preparing ezogabine by careful selection of reaction conditions, reagents and solvents
wherein the said reaction conditions/reagents/solvent results in controlled formation of
undesired impurities which eventually produces ezogabine that requires purification with
very low volumes of solvent to achieve pharmacopeia! standards as compared to very
high solvent volume requirements for purification of ezogabine in prior arts, which
I
reduces the economic inputs in terms of lesser requirement of solvent and much better
yield of ezogabine along with improving the quality of ezogabine. Furthermore, the
process of present invention also reduces the effluent generation, making the process
environmentally efficient.
According to one embodiment of the present invention, there is provided an improved
process for the preparation of ezogabine, optionally without isolating the intermediates,
comprising the steps of:
a) protecting ethyl-4-aminophenyl carb·amate of Formula II with phthalic anhydride
in presence of acid to obtain ethyl-4-phthalimidophenyl carbamate of Formula Ill;
IPO DELHI 27-03-2015 17 ~6
0
HN)lO~
¢
NH2
Formula II
0 o-(
__! NH 0 ObN O
~ ~
~
Formula III
b) nitrating the compound of Formula III using nitrating agent to obtain ethyl(2-
nitro-4-phthalimidophenyl)carbamate of Formula IV;
Formula IV
c) de-protecting the amino group of ethyl(2-nitro-4-phthalimidophenyl)carbamate of
Formula IV using hydroxylamine in presence of base and solvent to obtain
ethy1(4-amino-2-nitrophenyl)carbamate of Formula V;
o~ro'-/
H2N N02
Formula V
d) reacting ethyl(4-amino-2-nitrophenyl)carbamate of Formula V with 4-
fluorobenzaldehyde m solvent and acid to obtain ethyl-4-( 4-
' fluorobenzylideneamino )-2-nitrophenylcarbamate of Formula VI;
IPO DEL.HI 27-03-2015 17 ~·~
Formula VI
e) reducing ethyl-4-(4-fluorobenzylideneamino)-2-nitrophenylcarbamate of Formula
VI using a reducing agent in solvent to obtain ethy1((4-fluorobenzylamino)-2-
nitrophenyl]carbamate of Formula VII; and
Formula VII
f) catalytically hydrogenating ethyl [ ( 4-fluorobenzylamino )-2-nitrophenyl]carbamate
of Formula VII in solvent to obtain ezogabine of Formula I.
According to the present invention, the reaction of ethyl-4-aminophenyl carbamate of
Formula II with phthalic anhydride is carried out in presence of acid. The acid is selected
from a group comprising inorganic and organic. The inorganic acid is selected from the
group comprising of hydrochloric acid, hydrobromic acid, sulfuric acid and the like. The
organic acid is selected from the group comprising of oxalic acid, fumaric acid, acetic
acid and the like, preferably acet_ic acid. In accordance with the present invention, the
reaction is carried out at temperature from about 70°C to reflux temperature for 1-5 hr.
The resulting compound ethyl-4-phthalimidophenyl carbamate of Formula Ill is either
taken as such for further reaction or is isolated by isolation techniques known in the art.
IPO OELHr 27-03-2015 17 ~G
r----------------------------------------------- ---
According to the present invention, the resulting compound ethyl-4-phthalimidophenyl
carbamate of Formula Ill from step (a) is nitrated using nitrating agent, wherein the
nitrating agent is selected from a group comprising of nitric acid-sulfuric acid mixture,
potassium nitrate-sulfuric acid mixture, nitric acid-glacial acetic acid mixture and the
like, preferably used nitrating agent is nitric acid-glacial acetic acid mixture. The nitration
reaction is carried out at temperature between 70°C to reflux temperature, for about I to 5
hrs.
According to the present invention, the resulting compound of Formula IV is deprotected
in presence of hydroxylamine, base and solvent, wherein the hydroxylamine used is
selected from hydroxylamine free base or hydroxylamine hydrochloride.
The base is selected from a group comprising of alkali and alkaline earth metal
hydroxide, carbonate, hydride and bicarbonate, wherein the alkali and alkaline earth
metal is selected from lithium, sodium, potassium, calcium, magnesium, barium and the
like, preferably sodium carbonate. The solvent used herein is selected from a group
comprising of alcohols such as methanol, ethanol, propanol and the like; esters such as
ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate and the like; water or
mixtures thereof. In accordance with the present invention, the de-protection is carried
out at about 30 to 50 ·c in about I 0-12 hrs.
According to the present invention, the resulting compound of Formula V from step (c) is
further reacted with 4-fluorobenzaldeyde in solvent in presence of acid, wherein the acid
used is selected from a group comprising of organic or inorganic. The inorganic acid is
selected from the group comprising of hydrochloric acid, hydrobromic acid, sulfuric acid
and the like. The organic acid is selected from the group comprising of oxalic acid,
fumaric acid, acetic acid and the like, preferably acetic acid. The solvent used herein is
selected from a group comprising ,of halogenated solvents such as ethylene dichloride,
chloroform, chlorobenzene, chlorotoluene, I ,2-dichlorobenzene, I ,3-dichlorobenzene and
the like; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate and
the like; hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the
like or mixtures thereof, preferably toluene. The reaction is carried out at temperature
I P 0 DE L HI 2 7 - 0 3 - 2 0 1 5 1 7 ~26
between 60oC to reflux temperature for 10-15 hrs. The resulting compound ethyl-4-(4-
fluorobenzylideneamino)-2-nitrophenylcarbamate of Formula VI is either isolated using
the isolation techniques known in the art or is used as such in-situ for the next reaction.
According to the present invention, the compound ethyl-4-(4-fluorobenzylideneamino)-2-
nitrophenylcarbamate of Formula VI is subjected to reduction using reducing agent in
solvent, wherein the reducing agent is selected from a group comprising of sodium
borohydride, potassium borohydride, vitride, arid the like, preferable sodium borohydride.
The solvent used herein is selected from a group comprising of alcohols such as
methanol, ethanol, propanol, butanol and the like; halogenated solvents such as
dichloromethane, ethylene dichloride, chloroform, chlorobenze~e, chlorotoluene, 1,2-
dichlorobenzene, 1 ,3-dichlorobenzene and the like; esters such as ethyl acetate, n-propyl
acetate, isopropyl acetate, butyl acetate and the like; hydrocarbons such as toluene,
xylene, n-hexane, n-heptane, cyclohexane and the like or mixtures thereof, preferable
mixture of ethanol and dichloromethane. The reduction reaction is carried out at
temperature between 20 to 40 °C. The process step of reduction during the preparation of
ezogabine is known to face the challenge of formation of trans-esterification impurity, the
process step of reduction according to the present invention involving selection of
mixture of ethanol and dichloromethane as solvent of choice, overcomes the challenge of
formation of trans-esterification impurity. Thus, the present invention provides a very
easy solution for overcoming the shortcoming of prior art and thereby enhancing the
purity of intermediate and reducing the overall costs which might arise due to
requirement of purification operations.
The resulting compound ethyl ((4-fluorobenzylamino)-2-nitrophenyl]carbamate of
Formula Vll is either isolated using the isolation techniques known in the art or is used as
such in-situ for the next reaction. The intermediate is known to contain descarbamate
impurity (represented as Formula V111) from the processes known in prior art. The
inventors of present invention very suitably selected use of isopropanol for the
purification of ethyl ((4-fluorobenzylamino)-2-nitrophenyl]carbamate of Formula Vll,
wherein the purification successfully leads to the control'of descarbamate impurity that
eventually leads to better control of impurities in final product.
I P 0 DE L H I 2 7 - 0 3 - 2 0 1. 5 1 7 ~6
Formula VIII
According to the present invention, the compound ethyl [(4-fluorobenzylamino)-2-
nitrophenyl)carbamate of Formula VII is subjected to catalytic hydrogenation in solvent,
the catalyst used is selected from a group comprising of Raney nickel, palladium on
carbon, platinum on carbon and the like. The solvent used herein is selected from a group
comprising of alcohols such as methanol, ethanol, propanol, butanol and the like; ethers
such as dioxane, tetrahydrofuran and the like; 'halogenated solvents such as
dichloromethane, ethylene dichloride, chloroform, chlorobenzene, chlorotoluene, I ,2-
dichlorobenzene, I ,3-dichlorobenzene and the like; aromatic hydrocarbons such as
toluene, xylene and the like, and mixtures 'thereof, preferably dichloromethane. The
catalytic hydrogenation reaction is carried out with or without additives such as
triethylamine, activated carbon and the like. The reduction reaction is carried out in a
hydrogenator using 3-8 kg/cm2 pressure of hydrogen at temperature between 20 to 40 "C
and the reaction is complete in about 3-7 hrs. The process of catalytic reduction of nitro
group of compound of Formula VII to amine to obtain ezogabine, is known to involve the
formation of dimer impurities during the reaction. The inventors of present invention,
successfully controls the formation of dimer impurities by use of additives such as
triethylamine, maintaining the reaction temperature and hydrogen gas pressure. The
careful selection of reaction conditions as are achieved in present invention re.duces the
dimer impurities to not detected level, thereby reducing the purification steps that may be
required to remove dimer impurities and making the process industrially feasible and
economical.
According to the present invention, the ezogabine of Formula I thus obtained is isolated
by isolation techniques known in the art or is optionally converted in-situ into its
pharmaceutically acceptable acid addition salts by contacting with pharmaceutically
IPO DELHI 27-03-2015 17 34
6
------------------------------------------------------------------------------ --
acceptable acids such as hydrochloric acid, methanesulfonic acid, oxalic acid, tartaric
acid, fumaric acid and the like.
Polymorph(s) present in the drug substance impacts the dissolution profile and
subsequently the bioavailability from the drug product. Hence, the consistency in the
polymorph I polymorphic mixture is of utmost importance. The use of ethanol reported as
isolation solvent for ezogabine in U. S. Pat. No. 5384330 provides different polymorphs
for ezogabine as is shown in Fig. 2, Fig. 3 and Fig. 4, thus enhancing the need for a
robust process for the preparation of a consistent polymorph of ezogabine. Further prior
art also discloses various methods for the preparation of ezogabine as mixture of various
crystalline ·forms, but none of them qualify as a simple and efficient process for the
preparation of desired stable mixture of crystalline forms fqr application on industrial
scale. In wake of the requirement of an efficient and industrial process for preparation of
desired stable mixture of polymorphs, the present invention provides a very simple,
efficient and novel process for the preparation of ezogabine in mixture of crystalline
modification A and modification C with enhanced purity of product and control on
impurities to make ezogabine of very high pharmacopeia! standards.
Accordingly, in another embodiment of present invention, there is provided a novel
process for the preparation of mixture of crystalline modification A and modification C
of ezogabine, comprising the steps of:
a) dissolving ezogabine in a solvent;
b) adding basic additive to the reaction. mixture;
c) optionally adding the seed material;
d) adding acidic additive to the reaction mixture;
e) precipitating ezogabine mixture of crystalline modification A and modification C;
and
f) isolating ezogabine mixture of crystalline modification A and modification C.
According to the present invention, the ezogabine is dissolved in a solvent to provide a
solution, wherein the solvent is selected from a group comprising of alcohols such as
methanol, ethanol, propanol, butanol and the like; ketones such as acetone, methyl ethyl
I P 0 0 E L HI 2 7 - 0 3 - 2 0 1. 5 1 7 !?s
ketone and the like; water and mixtures thereof, preferably a mixture of ethanol and water
in I 0: 18 ratio. The ezogabine is dissolved at a temperature of 60-80 ·c to obtain a clear
solution. According to the present invention, the solution of ezogabine obtained in step
(a) is treated with a basic additive, wherein the basic additive is selected from a group
comprising of organic and inorganic base, wherein organic base is selected from a group
comprising of triethylamine, diisopropylethylamine and the like. The inorganic base is
selected from a group comprising of sodium dithionite, ammonia and the like The
additive is optionally added as a diluted mixture with a solvent, wherein the solvent is
selected from a group comprising of alcohols such as methanol, ethanol, propanol,
butanol and the like; ketones such as acetone, methyl ethyl ketone and the like; water and
mixtures thereof, preferably ethanol. The dilution of basic additive is about 0.1-5%. The
resulting mixture is optionally seeded with pure seed of ezogabine mixture of crystalline
modification A and modification C.
According to the present invention, the reaction mixture is further treated with an acidic
additive, wherein the acidic additive is selected from a group comprising of organic and
inorganic acid, wherein the organic acid is selected from a group comprising of acetic
acid, formic acid, oxalic acid and the like. The inorganic acid is selected from a group
comprising of hydrochloric acid, hydrobromic acid and the like, preferably used acid is
acetic acid. The additive is optionally added as a diluted mixture with a solvent, wherein
the solvent is selected from a group comprising of alcohols such as methanol, ethanol,
propanol, butanol and the like; ketones such as acetone, methyl ethyl ketone and the like;
water and mixtures thereof, preferably water. The dilution of acidic additive is about 0.1-
5%.
According to the present invention, the ezogabine mixture of crystalline modification A
( and modification C is precipitated and isolated from the reaction mixture using
techniques known ih the art.
The crystallization of ezogabine known in pnor art m vanous solvents suffers the
drawback of formation of impurities viz. Dimer-1 and Dimer-11. The present inventors
have very successfully controlled the formation of said impurities by use of basic additive
IPO DELHI 27-03-2015 17 36
G
preferably triethylamine while ensuring the crystallization of ezogabine resulting in the
formation of mixture of crystalline modification A and modification C.
According to the present invention, ezogabine is obtained as mixture of crystalline
modification A and modification C with about I 0% crystalline modification A to 11bout
90% crystalline modification A relative to 90% crystalline modification C to about 10%
crystalline modification C.
According to the present invention, ezogabine obtained by following the process of
present invention is purity of not less than 99.5%.
The process of present invention has following advantages over prior art processes:
(a) The process is environment friendly in terms of devoid of use of carcinogenic
solvents like dioxane.
(b) The process is devoid of use of potential genotoxic and carcinogen hydrazine
hydrate used in prior art for deprotection of phthaloyl group, whereas involves a
user-friendly hydroxylamine hydrochloride.
(c) The process for preparation of desired mixture of crystalline modifications is
operationally very simple, as does not involve solvent-anti-solvent, salt
formation-hydrolysis like steps .and thus the work-up is very much simplified.
(d) The careful selection of reagents and reaction conditions has resulted in control of
formation of impurities at various stages, thereby reducing the requirement of
purification steps.
(e) The process reduces the generation of toxic waste, thereby making the process
. .
environment friendly.
EXAMPLES
• Example 1: Preparation of ethyl (2-nitro-4-phthalimidophenyl) carbamate
To a solution of ethyl (4-aminophenyl) carbamate (100 g) in acetic acid (1700 ml), added
phathalic anhydride (86.5 g) at 25-30 ·c. The temperature of reaction mixture is raised to
about 85-90 ·c and is maintained for about 2.5-3 hrs. The reaction was monitored using
HPLC/ TLC. While maintaining the temperature of reaction mass at about 85-90 ·c,
IPO DELHI 27-03-2015 17: 1~6
nitric acid (41.8 ml) was added to the reaction mass. The temperature of reaction mass
was then raised to about 90-100 oC and maintained for about 2.5-3 hrs. The reaction was
monitored using HPLC/ TLC, on completion of reaction the reaction mass was cooled to
room temperature. The solid mass was filtered and washed with water, collected the wet
cake and dried to obtain ethyl (2-nitro-4-phthalimidophenyl)carbamate (170 g).
Example 2: Preparation of ethyl (4-amino-2-nitrophenyl)carbamate
To a solution of ethyl (2-nitro-4-phthalimidophenyl)carbamate (100 g) tn isopropanol
(400 ml) at 25-30 oc, added hydroxylamine hydrochloride (60 g), sodium carbonate (60
g) and water (25 ml). The temperature of the reaction mass was raised to 45-50 oc and
stirred for about 10-12 hrs. The progress of reaction was monitored using HPLC, after the
completion of reaction, the reaction mass was cooled to about 25-30 oC, added water (800
ml) and stirred for some-time. The solid in reaction mass was filtered and washed with
water and dried to obtain ethyl (4-amino-2-nitrophenyl)carbamate (58 g).
Example 3: Preparation of ethyl (4-amino-2-nitrophenyl)carbamate
To a solution of ethyl (2-nitro-4-phthalimidophenyl)carbamate (100 g) tn isopropanol
(400 ml) at 25-30 oc, added hydroxylamine base solution (50%) (103 ml). The reaction
mass was stirred at 25-30oC for about 10-12 hrs. The progress of reaction was monitored
using HPLC, after the completion of reaction, water (800mL) was added to the reaction
mass and stirred for some-time. The solid in reaction mass was filtered and washed with
water and dried to obtain ethyl ( 4-amino-2-nitrophenyl)carbamate (52 g).
Example 4: Preparation of ethyl-4-[(4-fluorobenzylideneamino)-2-
nitrophenyllcarbamate
To a solution of ethyl (4-amino-2-nitrophenyl)carbamate (100 g) in toluene (500 ml),
added a catalytic amount of acetic acid and 4-fluorobenzaldehyde (60 g) at 25-30 °C. The
temperature of the reaction mass was raised to about 110 oc and the reaction was
performed azeotropically for about 14 hrs. The progress of reaction was monitored using
HPLC/TLC. On completion of reaction, solvent was completely distilled-off from the
reaction mass to obtain the title compound.
I P 0 DE L H I 2 7 - 0 3 - 2 0 1 5 1 7 ~86
I
I
Example 5: Preparation of ethyl 1(4-fluorobenzvlamino)-2-nitrophenyllcarbamate
A solution of ethyl-4-[(4-fluorobenzylideneamino)-2-nitrophenyl]carbamate (obtained in
Example 3) in ethanol (200 ml) was stirred for about 30-60 minutes at reflux temperature
and then cooled to 25-30 ·c. To the resulting reaction mass, charged sodium borohydride
(8.34 g), dichloromethane (100 ml) and stirred for about 4-5 hrs. The progress of reaction
was monitored using HPLC, after completion of reaction, the reaction mass was cooled to
room temperature and added dichloromethane (500 ml) and water (500 ml). The reaction
mass was stirred and layers were separated, washed organic layer with water and
removed solvent from organic layer. The reaction mass was then diluted with isopropanol
(100 ml) and the reaction mass was stirred at reflux for about 1-1.5 hr. The reaction mass
was then slowly cooled to room temperature and maintained for about 1.5-2 hr. The solid
obtained was filtered and dried to obtain ethyl [(4-fluorobenzylamino)-2-
nitrophenyl]carbamate (II 0 g).
Example 6: Preparation of ethyl 1(2-amino-4-(4-fluorobenzylamino)phenyll
carbamate (Ezogabine)
To a solution of ethyl [(4-fluorobenzylamino)-~-nitrophenyl]carbamate (100 g) in
dichloromethane (700 ml) in an autoclave, charged I 0% palladium on carbon (5 g),
activated carbon (5 g) ·and triethylamine (5 ml) at 25-30 ·c. The autoclave was then
flushed with 4-6 kg/cm2 pressure of hydrogen gas for about 5.5-6 hrs at 25-30 ·c for
reduction reaction. The progress of reaction was mon_itored using HPLC, after the
completion of reaction, filtered the reaction mass through diatomaceous material. The
filtrate was subsequently washed with dilute hydrochloric acid and water. The solvent
from organic layer was partially removed and the resulting reaction mass was stirred at
room temperature followed by 0-5 ·c for about I hr. The solid was filtered to obtain
ezogabine (80 g).
HPLC purity: 99.95%
Yield: 0.8 (w/w)
IPO DELHI 27-03-2015 17 ~6
I
I
Example 7: Preparation of mixture of crystalline modification Form-A and
modification Form-C of ezogabine
A suspension of ezogabine (80 g.) m ethanol (1080 ml), water (1160 ml) and
triethylamine (0.8 ml) was heated to a temperature.of about 75 ·c to obtain clear solution.
The reaction mass was then cooled to a temperature of about 65 ·c and maintained for I
hr. The temperature of reaction mass was then ·further reduced to 25-30 ·c over a period
of I hr and maintained at 25-30 ·c for about 6-7 hrs. The solid mass obtained was filtered
and dried to obtain ezogabine as mixture crystalline modification A and modification C.
HPLC purity: 99.6%
Yield: 0.71 (w/w)
XRD: Mixture of modification C and modification A
Example 8: Preparation of mixture of crystalline modification Form-A and
modification Form-C of ezogabine
A suspension of ezogabine (80 g) In ethanol (1080 ml), water' (1320 ml) and 1%
I
triethylamine solution in ethanol (40 ml) was heated to a temperature of about 75 ·c to
obtain clear solution. The reaction mass was then cooled to a temperature of about 65 ·c
and seeded with crystalline mixture of modification-A and modification-C. The
temperature of reaction mass was then further reduced to 25-30 ·c over a period of time
and added I% aqueous acetic acid and maintained at 25-30 ·c for about 6-7 hrs. The
solid mass obtained was filtered and dried to obtain ezogabine as mixture crystalline
modification A and modification C.
HPLC purity: 99.96%
Yield: 0.71 (w/w)
XRD: Mixture of modification C and modification A (Figure I)
Example 9: Process A for crystallization of ezogabine using ethanol
IPO DELHI 2 7 - 0 3- 2 0 1 5 1 7 : ~6
A solution of ezogabine (25 g) in ethanol (65 ·ml) was heated to reflux to get a clear
solution and then cooled to 25-30 oC and further to 5-10 °C. Stirred the reaction mass at
5-10 oc for about 30 minutes and then filtered and washed with chilled ethanol. The solid
so obtained was dried to obtain ezogabine. (8.5 g) as crystalline modification A as is
depicted in Figure.2.
Example 10: Process B for crystallization of ezogabine using ethanol
To ezogabine. (8 g), added ethanol (8 ml) and heated to reflux temperature and
maintained for I 0 minutes, ezogabine did not dissolved. To the reaction mixture added
ethanol (8 ml) at 78-80oC to get a clear solution and maintained for about 30 minutes.
The reaction mixture is then· very slowly cooled to 25-30 °C, while keeping the
temperature constant for about I 0 minutes at each I 0 OC interval. The reaction mixture is
then cooled further to 5-l 0 °C. Stirred the reaction mass at 5-l 0 OC for about 30 minutes
and then filtered and washed with chilled ethanol. The solid so obtained was dried to
obtain ezogabine (6 g) as crystalline modification Cas is depicted in Figure.3.
Example 11: Process C for crystallization of ezogabine using ethanol
To ezogabine (5 g), added ethanol (5 ml) and heated the reaction mixture to reflux
temperature and maintained for I 0 minutes, ezogabine did not dissolved. To the reaction
mixture added ethanol (8 ml) at 78-80oC to get a clear solution and maintained for about
30 minutes. The reaction mixture is then slowly cooled to 25-30 oc in about I hour and
stirred at 25-30oC for about 2 hours. The reaction mixture is then further cooled to 5-l 0
°C. Stirred the reaction mass at 5-l 0 oC for about 30 minutes and then filtered and
washed with chilled ethanol. The solid so obtained was dried to obtain ezogabine (6 g) as
mixture crystalline modification A, modification B and modification C as is depicted in
Figure.4.

CLAIMS
I. A process for the preparation of ezogabine, optionally without isolating the
intermediates, comprising the steps of:
a) protecting ethyl-4-aminophenyl carbamate of Formula II with phthalic anhydride
in presence of acid to obtain· ethyl-4-phthalimidophenyl carbamate of Formula III;
0
Formula II,
_l-\H
0 OON 0
~ ~
~
Formula III
b) nitrating the compound of Formula III using nitrating agent to obtain ethyl(2-
nitro-4-phthalimidophenyl)carbamate of Formula IV;
Formula IV
c) de-protecting the amino group of ethyl(2-nitro-4-phthalimidophenyl)carbamate of
Formula IV using hydroxylamine in presence of base and solvent to obtain
ethyl(4-amino-2-nitrophenyl)carbamate of Formula V;
H
. ~NI(o"-./
~0 H2N N02
Formula V
22.
IPO DELHI 27-03-2015 17 36
•
d) reacting ethyl(4-amino-2-nitrophenyl)carbamate of Formula V with 4-
fluorobenzaldehyde m solvent and acid to obtain ethyl-4-( 4-
fluorobenzylideneamino )-2-nitrophenylcarbamate of Formula VI;
Formula VI
e) reducing ethyl-4-(4-fluorobenzylideneamino)-2-nitrophenylcarbamate of Formula
. VI using a reducing agent in solvent to obtain ethyl[(4-fluorobenzylamino)-2-
nitropi}enyl]carbamate of Formula VII; and
Formula VII
f) catalytically hydrogenating ethyl [( 4-fluorobenzylam ino )-2-nitrophenyl]carbamate
of Formula VII in solvent to obtain ezogabine of Formula I.
2. The process according to claim I, wherein the acid used in step (a) is selected
from the group comprising of inorganic acid selected from hydrochloric acid,
hydrobromic acid, sulfuric acid; and organic acid selected from, oxalic acid,
fumaric acid and acetic acid.
3. The process according to claim I, wherein the nitrating agent used in step (b) is
selected from the group comprising of nitric acid-sulfuric acid mixture, potassium
nitrate-sulfuric acid mixture and nitric acid-glacial acetic acid mixture.
IPO DELHI 2 7 - 0 3 - 2•0 1 5 1 7 : ~ 6
4. The process according to claim I, wherein the base used in step (c) is selected
from the group comprising of alkali and alkaline earth metal hydroxide,
carbonate, hydride and bicarbonate, wherein the alkali and alkaline earth metal is
selected from lithium, sodium, potassium, calcium, magnesium and barium.
5. The process according to claim I, wherein the solvent used in step (c) is selected
from the group comprising of alcohols selected from .methanol, ethanol, propanol;
esters selected from ethyl acetate, n-propyl acetate, isopropyl acetate, butyl
acetate; water and mixtures thereof.
6. The process according to claim I, wherein the acid used in step (d) is selected
from the group comprising of organic acid selected from hydrochloric acid,
hydrobromic acid, sulfuric acid; and inorganic acid selected from oxalic acid,
fumaric acid and acetic acid.
7. The process according to claim I, wherein the solvent used in step (d) is selected
from the group comprising of halogenated solvents selected from ethylene
dichloride, chloroform, chi oro benzene, chlorotoluene, I ,2-dichlorobenzene, I ,3-
dichlorobenzene; esters selected from ethyl acetate, n-propyl acetate, isopropyl
acetate, butyl acetate; hydrocarbons selected from toluene, xylene, n-hexane, nheptane,
cyclohexane; and mixtures thereof.
8. The process according to claim I, wherein the reducing agent used in step (e) is
selected from the group comprising of sodium borohydride, potassium
borohydride and vitride.
9. The process according to claim I, wherein the solvent used in step (e) is selected
from the group comprising of alcohols selected from methanol, ethanol, propanol,
butanol; halogenated solvents selected from dichloromethane, ethylene dichloride,
chloroform, chlorobenzene, chlorotoluene, I ,2-dichlorobenzene, I ,3-
dichlorobenzene; esters selected from ethyl acetate, n-propyl acetate, isopropyl
acetate, butyl acetate; hydrocarbons selected from toluene, xylene, n-hexane, nheptane,
cyclohexane; and mixtures thereof.
I 0. The process according to claim I, wherein the catalyst used for hydrogenation in
step (f) is selected from the group comprising of Raney nickel, palladium on
carbon and platinum on carbon.
IP 0 D.EL HI 2 7 -8 3- 201 5 17 ~46 ';~;.
11. The process according to claim 1, wherein the solvent used in step (f) is selected
from the group comprising of alcohols selected from methanol, ethanol, propanol,
butanol; ethers selected from dioxane, tetrahydrofuran; halogenated solvents
selected from dichloromethane, ethylene dichloride, chloroform, chlorobenzene,
chlorotoluene, I ,2-dichlorobenzene, I ,3-dichlorobenzene; aromatic hydrocarbons
selected from toluene, xylene; and mixtures thereof.
12. A process for the preparation of mixture of crystalline modification A and
modification C of ezogabine, comprising the steps of:
a) dissolving ezogabine in a solvent;
b) adding basic additive to the reaction mixture;
c) optionally adding the seed material;
d) adding acidic additive to the reaction mixture;
e) precipitating ezogabine mixture of crystalline modification A and modification C;
and
\.
f) isolating ezogabine mixture of crystalline modification A and modification C.
13. The process according to claim 12, wherein the solvent used in step (a) is selected
from the group comprising of alcohols selected from methanol, ethanol, propanol,
butanol; ketones selected from acetone and methyl ethyl ketone; and mixtures
thereof along with water.
14. The process according to claim 12, wherein the basic additive used in step (b) is
selected from the group comprising of organic selected from triethylamine,
diisopropylethylamine and inorganic selected from sodium dithionite and
ammoma.
15. The process according to claim 12, wherein the acidic additive used in step (d) is
selected from the group comprising of organic acidic additive selected from acetic
acid, formic acid, oxalic acid and inorganic acidic additive selected from
hydrochloric acid and hydrobromic acid.
16. The process according to claim 12, wherein the basic and acidic additive are
optionally used as diluted mixture in a solvent, wherein the solvent is selected
from the group comprising of methanol, ethanol, propanol, butanol, acetone,
methyl ethyl ketone, water and mixtures thereof.
IPO DELHI 2·7-03-2015 17 ~6
17. The process according to claim 12, wherein ezogabine is obtained as mixture of
crystalline modification A and modification C with about I 0% crystalline
modification A to about 90% crystalline modification A relative to 90%
crystalline modification C to about I 0% crystalline modification C.
18. A process for the preparation of mixture of crystalline modification A and
modification C of ezogabine, optionally without isolating the intermediates,
comprising the steps of:
a) protecting ethyl-4-aminophenyl carbamate of Formula II with phthalic anhydride
in presence of acid to obtain ethyl-4-phthalimidophenyl carbamat~ of Formula Ill;
0
Formula II
_)o~H
0 ObN O
~ ~ -
Formula Ill
b) nitrating the compound of Formula Ill using nitrating agent to obtain ethyl(2-
nitro-4-phthalimidophenyl)carbamate of Formula IV;
Formula IV
c) de-protecting the amino group of ethy1(2-nitro-4-phthalimidophenyl)carbamate of
Formula IV using hydroxylamine in presence of base and solvent to obtain
ethyl(4-amino-2-nitrophenyl)carbamate of Formula V;
IPO DELHI 27-03-2015 17:~6
;:~((~
H2N N02
Formula V
d) reacting ethyl(4-amino-2-nitrophenyl)carbamate of Formula V with 4-
fluorobenzaldehyde m solvent and acid to obtain ethyl-4-( 4-
fluorobenzylideneamino )-2-nitrophenylcarbamate of Formula VI;
~oyo
('YNH
~N~ .. N02
F~ ,
Formula VI
e) reducing ethyl-4-(4-fluorobenzylideneamino)-2-nitrophenylcarbamate of Formula
VI using a reducing agent in solvent to obtain ethy1[(4-fluorobenzylamino)-2-
nitrophenyl]carbamate of Formula VII; and
~oyo
('YNH
~~~N02
F~
Formula VII
f) catalytically hydrogenating ethyl[(4-fluorobe':lzylamino)-2-nitrophenyl)carbamate
of Formula VII in solvent to obtain ezogabine of Formula I;
g) dissolving ezogabine in a solvent;
h) adding basic additive to the reaction mixture;
i) optionally adding the seed material;
IPO DELHI 27-03-2015 17:~6
j) adding acidic additive to the reaction mixture;
k) precipitating ezogabine mixture of crystalline modification A and modification C;
and
I) isolating ezogabine mixture of crystalline modification A and modification C.
wherein the resulting ezogabine mixture of crystalline modification A and modification B
comprises of purity not less than 99.5% with less than 0.05% of unknown impurity as
measured by HPLC.