FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
"A PROCESS FOR THE PREPARATION OF (S)-(+)-10, ll-DIHYDRO-10-HYDROXY-5H-DIBENZ [b, f] AZEPINE-5-CARBOXAMIDE"

Glenmark Generics Limited
an Indian Company, registered under the Indian company's Act 1957 and having its registered
office at
Glenmark House.,
HDO - Corporate Bldg, Wing -A,
B.D. Sawant Marg, Chakala, Andheri (East), Mumbai -400 099

The following specification describes the nature of the invention


FIELD OF THE INVENTION
The present invention relates to a process for the preparation of (S)-(+)-10, 1 1-dihydro-10-hydroxy-5H-dibenz [b, f] azepine-5-carboxamide (eslicarbazepine), its novel intermediates and their use in the synthesis thereof.
BACKGROUND OF THE INVENTION
Eslicarbazepine acetate is a novel, voltage-gated sodium channel blocker that has been studied to reduce the frequency of partial-onset seizures when used in combination with other anti-epileptic drugs. Eslicarbazepine acetate in the European Union under the name ZEBINIX® is under review for the treatment of partial-onset seizures with or without secondary generalization in combination with other anti-epileptic drugs. Eslicarbazepine acetate is chemically known as (S)-(-)-10-(acetyloxy)-10, 11- dihydro-5H-dibenz [b,f] azepine-5-carboxamide and represented by the formula as shown below:

U.S. Patent No. 5,753,646 describes dihydrodibenzo [b, f] azepines derivatives, including eslicarbazepine acetate or stereoisomer thereof, a pharmaceutical composition and method of treatment, and a process for the preparation of eslicarbazepine acetate.
J. Med. Chem., 42, 2582-2587 (1999) discloses the preparation of eslicarbazepine of formula (I) by esterification of racemic 10, I l-dihydro-10-hydroxy-5H-dibenz [b,f] azepine-5-carboxamide of formula (II) with mentyloxyacetic acid, separation of the resulting diastereomers and hydrolysis of the respective mentyloxyacetate which is illustrated below:

U.S. Patent Nos. 7,119,197, 7,189,846 and 7,241,886 also disclose processes for preparation of eslicarbazepine or eslicarbazepine acetate.

PCT Patent Publication WO2006056339 discloses a process for the preparation of (S)-(+)-10, 1 l-dihydro-10-hydroxy-5H-dibenz [b,f] azepine-5-carboxamide of formula (I) from racemic 5-cyano-10, 1 l-dihydro-10-hydroxy-5H-dibenz [b,f] azepine which is illustrated below:

U.S. Patent Publications 2006/0142566, 2008/0221320, 2008/0139807 and PCT Patent Publications 2007/117166 and 2007/012793 also disclose processes for preparation of eslicarbazepine or eslicarbazepine acetate.
There are evolving and more rigorous requirements demanded of drug manufacturers and with the prevailing disadvantages present with the prior art, there is a need for an improved process for the preparation of eslicarbazepine and its intermediates, which circumvents the use of potentially hazardous chemicals, the likely formation of isomeric and other process related impurities, while ensuring a target eslicarbazepine product with optimum yield and purity.
The processes, herein described, for the preparation of eslicarbazepine, eslicarbazepine acetate and intermediates of eslicarbazepine are simple, eco-friendly, inexpensive, reproducible, robust and well suited on industrial scale.
SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation of (S)-(+)-10, 1 J-dihydro-10-hydroxy-5H-dibenz [b,f] azepine-5-carboxamide of formula (I), its novel intermediates and their use in the synthesis thereof.

In a general aspect (as schematically shown in Fig, 1), the present invention provides a process for preparing eslicarbazepine of formula (I),

comprising:
a) reacting compound of formula (II),

(II)
with an aliphatic or aromatic dicarboxylic acid anhydride, in the presence of an organic solvent to form a compound of formula (B),

(B) wherein R comes from the corresponding aliphatic or aromatic dicarboxylic acid
anhydride, '
b) resolving the compound of formula (B) with (S)-l-phenylethylamine, in the presence of an organic solvent to form a diastereomeric mixture,
c) separating the compound of formula (C) from the diastereomeric mixture in b),

d) reacting the compound of formula (C) with an acid, in the presence of an organic solvent to form a compound of formula (D),

e) reacting the compound of formula (D) with a base, in the presence of an organic solvent.
In the subsequent particular aspects, the present invention provides a process for the preparation of eslicarbazepine of formula (I), as shown schematically in Fig.l, comprising the a) through e) as described directly above, wherein, the compounds of formulae (B), (C) and (D) are as would correspond to the aliphatic or aromatic dicarboxylic acid anhydride.
The present invention provides a process for preparing eslicarbazepine of formula (I), comprising: a) reacting compound of formula (II) with succinic acid anhydride, in the presence of an organic solvent to form a compound of formula (III),

b) resolving the compound of formula (III) with (S)-l-phehylethylamine, in the presence of an organic solvent to form a diastereomeric mixture,
c) separating the compound of formula (IV) from the diastereomeric mixture in b),

d) reacting the compound of formula (IV) with an acid, in the presence of an organic solvent to form a compound of formula ( V),

e) reacting the compound of formula (V) with a base, in the presence of an organic solvent.
The present invention provides a process for preparing eslicarbazepine of formula (I), comprising: a) reacting the compound of formula (II) with rnaleic acid anhydride, in the presence of an organic solvent to form a compound of formula (VI),

b) resolving the compound of formula (VI) with (S)-l-phenyiethylamine, in the presence of an organic solvent to form a diastereomeric mixture,
c) separating the compound of formula (VII) from the diastqreomeric mixture in b),

(VII) d) reacting the compound of formula (VII) with an acid, in the presence of an organic solvent to
form a compound of formula (VIII),



e) reacting the compound of formula (VIII) with a base, in the presence of an organic solvent.
The present invention provides a process for preparing eslicarbazepine of formula (I), comprising: a) reacting the compound of formula (II) with phthalic acid anhydride, in the presence of an organic solvent to form a compound of formula (IX),

b) resolving the compound of formula (IX) with (S)-l-phenylethylamine, in the presence of an organic solvent to form a diastereomeric mixture,
c) separating the compound of formula (X) from the ensuing diastereomeric mixture,

d) reacting the compound of formula (X) with an acid, in the presence of an organic solvent to form a compound of formula (XI),

e) reacting the compound of formula (XI) with a base, in the presence of an organic solvent.
The present invention provides a process for preparing eslicarbazepine acetate of formula (la), comprising:

(la) reacting the eslicarbazepine of formula (I) with an acylating agent, in the presence of an organic
solvent.
The present invention provides a process for purifying eslicarbazepine acetate of formula
(la), comprising:
(a) providing a solution of eslicarbazepine acetate in a solvent or a mixture of solvents or their aqueous mixtures and
(b) precipitating the solid from the solution, and
(c) recovering the eslicarbazepine acetate in substantially pure form.
The present invention provides eslicarbazepine of formula (I), prepared by the processes herein described, having a purity of at least about 99.9%.
The present invention provides eslicarbazepine acetate of formula (la), prepared by the processes herein described, having a purity of at least about 99.9%.
The present invention provides 4-[[5-(aminocarbonyl)-10,l l-dihydro-5H-dibenzo[b,f]azepin-10-yl] oxy]-4-oxobutanoic acid of formula (III) or a salt thereof.



The present invention provides 4-[[(10S)-5-(aminocarbonyl)-10,l l-dihydro-5H-dibenzo[b,f]azepin-10-yl]oxy]-4-oxobutanoic acid (S)-l-phenylethylamine salt of formula (IV).

The present invention provides 4-[[( 10S)-5-(aminocarbonyI)-10,11 -dihydro-5H-dibenzo[b,f]azepin-10-yl]oxy]-4-oxobutanoic acid of formula (V) or a salt thereof.

The present invention provides 4-[[5-(aminocarbonyl)-I0,l l-dihydro-5H-dibenzo[b,f]azepin-10-yI]oxy]-4-oxobut-2-enoic acid of formula (VI) or a salt thereof.

The present invention provides 4-[[(10S)-5-(aminocarbony/)-10, 11-dihydro-5H-dibenzo [b, fj azepin-lOyl] oxy]-4-oxobut-2-enoic acid, (S)-l-phenylethylamine salt of formula (VII).

The present invention provides 4-[[(10S)-5-(aminocarbonyl)-10, 11-dihydro-5H-dibenzo [b, f] azepin-lOyl] oxy]-4-oxobut-2-enoic acid of formula (VIII) or a salt thereof.

The present invention provides 2-[[[5-(aminocarbonyl)-10,l I-dihydro-5H-dibenzo[b,f]azepin-10yi]oxy] carbonyl] benzoic acid of formula (IX) or a salt thereof.

The present invention provides 2-[[[(10S)-5-(aminocarbonyl)-10, 1 l-dihydro-5H-dibenzo [b, f] azepin-10-yl] oxy] carbonyl] benzoic acid, (S)-l-phenylethylamine salt of formula (X).

The present invention provides 2-[[[(I0S)-5-(aminocarbonyl)-10, 1 l-dihydro-5H-dibenzo [b,f]azepin-10-yl]oxy]carbonyl]benzoic acid of formula (XI) or a salt thereof.

The present invention provides eslicarbazepine acetate of formula (la) having a median particle size less than about 20 microns.
The present invention provides a pharmaceutical composition comprising eslicarbazepine or eslicarbazepine acetate obtained by the processes herein described, having purity at least greater than about 99.0% as measured by HPLC and at least a pharmaceutically acceptable carrier.
BRIEF DESCRIPTION OF THE DRAWING
Fig. I: is a schematic representation of an embodiment of the process of present invention.



DETAILED DESCRIPTION OF THE INVENTION
As mentioned above, the present invention is directed to improved processes for the synthesis of eslicarbazepine of formula (I), its novel intermediates and their use in the synthesis thereof.
In one embodiment, the present invention provides a process for preparing eslicarbazepine of formula (I),

comprising:
a) reacting compound of formula (II),

(II)
with an aliphatic or a aromatic dicarboxylic acid anhydride, in the presence of an organic solvent to form a compound of formula (B),

(B) wherein R comes from the corresponding aliphatic or aromatic dicarboxylic acid
anhydride,
b) resolving the compound of formula (B) with (S)-l-phenylethylamine, in the presence of an organic solvent to form a diastereomeric mixture,
c) separating the compound of formula (C) from the diastereomeric mixture in b),



d) reacting the compound of formula (C) with an acid, in the presence of an organic solvent to form a compound of formula (D),

e) reacting the compound of formula (D) with a base, in the presence of an organic solvent.
The aliphatic dicarboxylic acid anhydride may be saturated or unsaturated and is, for example succinic acid, maleic acid, malic acid, 1, 2-cyclohexanedicarboxylic acid and the like. Preferably succinic acid and maleic acid. The aromatic dicarboxylic acid anhydride, for example phthalic acid and the like.
The molar ratio of compound of formula (II) to the aliphatic or aromatic dicarboxylic acid anhydride is suitably at least 1:2, preferably at least 1:1.5, more preferably 1:1.05.
The reaction time and the temperature are chosen so as to bring the reaction to completion at a minimum time without the production of unwanted side products. In general, it is convenient to carry out the reaction at a temperature of from about 25 °C to about 100 °C, preferably at a temperature from about 25 °C to about 50 °C
The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagent and solvent employed. However, provided that the reaction is effected under the preferred conditions discussed above, a period of from about 1 hour to about 10 hours, preferably from about 1 hour to 5 hours.
The reaction may preferably be effected in the presence of a 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 and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents that can be used include but are not limited to polar protic solvent such as formic acid, acetic acid, formamide, N, N-dimethyl formamide; polar

aprotic solvent such as tetrahydrofuran, acetonitrile, 1, 4-dioxane, N, N-dimethylacetamide, dimethylsulfoxide, acetone, ethyl acetate, diethyl ether, diisopropyl ether; non-polar aprotic solvent such as diisopropyl ether, methylisobutylketone, diisobutylketone, substituted 2-pyrrolidones, C1-C5 alcohol such as
methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol; aliphatic hydrocarbon such as hexane, heptane; aromatic hydrocarbon such as benzene, toluene, (mono-, di, tri-) substituted benzene, xylene; chlorinated hydrocarbon such as methylene chloride, ethylene chloride, trichloroethylene, chloroform, carbon tetrachloride, dichlorobenzene and mixtures thereof, and mixtures of said solvents and water, preferably methylene chloride.
The acid used in d) above may include organic acid or inorganic acid. The organic acid that can be used include, but are not limited to carboxylic acid, phosphonic acid, sulfonic acid, formic acid, maleic acid, acetic acid, succinic acid, citric acid, oxalic acid, benzoic acid, ascorbic acid and the like, and their aqueous mixtures thereof, preferably acetic acid.
The inorganic acid that can be used include, but are not limited to hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like, and their aqueous mixtures thereof, preferably hydrochloric acid.
The base in e) above may include organic base or inorganic base. The organic bases that can be used include, but are not limited to triethylamine, tripropyfamine, pyridine, diisopropylamine, diisopropylethylamine and the like, preferably triethylamine.
Inorganic bases include one or more of alkali metal alkoxides, such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide or potassium tert-butoxide; alkali metal carbonates, such as sodium carbonate or potassium carbonate, sodium hydrogen carbonate; and alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide; sodium hydride, potassium hydride and the like or mixtures thereof, preferably sodium hydroxide.
Racemic (±)-10, 1 l-dihydro-10-hydroxy-5H-dibenz [b, f] azepine-5-carboxamide of formula (II) was found to be the main metabolite of oxcarbazepine, which is synthesized by reduction of oxcarbazepine, and thus serve as a useful intermediate in the synthesis of (S)-(+)-10, 1 l-dihydro-10-hydroxy-5H-dibenz [b, f] azepine-5-carboxarnide of formula (I). Procedure for making oxcarbazepine is described in U.S. Patent No. 7,459,553 which is incorporated herein by reference, in its entirety.
After completion of the reaction, the desired compounds can be obtained from the reaction mixture by conventional means known in the art. For example, the working-up of

reaction mixtures, especially in order to isolate desired compounds, follows customary procedures, known to the organic chemists skilled in the norms of the art and steps, e.g. selected from the group comprising but not limited to extraction, neutralization, crystallization, chromatography, evaporation, drying, filtration, centrifugation and the like.
As previously described earlier, in the subsequent particular aspects, the present invention provides a process for the preparation of eslicarbazepine of formula (I), as shown schematically in Fig.l, comprising the a) through e) as described directly above, wherein, the compounds of formulae (B), (C) and (D) are as would correspond to the aliphatic dicarboxylic acid anhydride or aromatic dicarboxylic acid anhydride. Correspondingly, the process parameters are adjusted, in techniques, well known to organic chemist skilled in the art, to accommodate the particulars that would allow the synthesis to proceed in the manner, as described and contemplated herein.
In an embodiment, the present invention provides a process for preparing eslicarbazepine of formula (I) as previously described.
comprising: a) reacting compound of formula (II) with a dicarboxylic acid anhydride, wherein the dicarboxylic acid anhydride is succinic acid anhydride, in the presence of an organic solvent to form a compound of formula (III),

b) resolving the compound of formula (III) with (S)-l-phenylethylamine, in the presence of an organic solvent to form a diastereomeric mixture,
c) separating the compound of formula (IV) from the diastereomeric mixture of b),

d) reacting the compound of formula (IV) with an acid, in the presence of an organic solvent to form a compound of formula (V),

e) reacting the compound of formula (V) with a base, in the presence of an organic solvent.
In yet another embodiment, the present invention provides a process for preparing eslicarbazepine of formula (I), comprising: a) reacting the compound of formula (II) with a dicarboxylic acid anhydride, wherein the dicarboxylic acid anhydride is maleic acid anhydride, in the presence of an organic solvent to form a compound of formula(VI)

b) resolving the compound of formula (VI) with (S)- 1 -phenylethylamine, in the presence of an organic solvent to form a diastereomeric mixture,
c) separating the compound of formula (VII) from the diastareomeric mixture in b),

(VII) d) reacting the compound of formula (VII) with an acid, in the presence of an organic solvent to
forma a compound of formula (VIII),

(VIII) e) reacting the compound of formula (VIII) with a base, in the presence of an organic solvent.
In yet another embodiment, the present invention provides a process-for preparing
eslicarbazepine of formula (I), comprising: a) reacting the compound of formula (II) with a
dicarboxylic acid anhydride, wherein the dicarboxylic acid anhydride is phthalic acid anhydride,
in the presence of an organic solvent to form a compound of formula (IX),

b) resolving the compound of formula (IX) with (S)-l-phenylethy!amine. in the presence of an organic solvent to form a diastereomeric mixture,
c) separating the compound of formula (X) from the diastereomeric mixture in b),

d) reacting the compound of formula (X) with an acid, in the presence of an organic solvent to form a compound of formula (XI),

e) reacting the compound of formula (XI) with a base, in the presence of an organic solvent.
In yet another embodiment, the present invention provides a process for preparing eslicarbazepine acetate of formula (la), comprising:

(la) reacting the eslicarbazepine of formula (I), prepared by the processes herein described
previously, with an acylating agent, in the presence of an organic solvent, by the processes
known in the art.
The acylating agents that can be used include, but are not limited to acetyl chloride, acetic anhydride and the like.
The solvent that can be used include, but are not limited to methylene chloride, ethylene chloride pyridine, toluene and the like.
In yet another embodiment, the present invention provides a process for purifying eslicarbazepine acetate of formula (la), comprising:
(a) providing a solution of eslicarbazepine acetate), prepared by the process herein
described previously, in a solvent or a mixture of solvents or their aqueous mixtures and
(b) precipitating the solid from the solution in (a), and
(c) recovering the eslicarbazepine acetate in (c) in substantially pure form.
The solvent or mixture of solvents is selected from C2-C6 ether, a C2-C4 ester, a mixture orC2-C4 esler/H2O. a mixture of C2-C6 ether/C3-C5 ketone, a mixture of C2-C6 ether/C2-C4 ester, a mixture of C2-C6 ether/C1-C5 alcohol, cyclic ether, a C2-C9 aliphatic hydrocarbon, a C6-C9 aromatic hydrocarbon, a C3-C5 carbonate, dimethylformamide. dimelhylsulfoxide. acetonitrile. a


mixture of acetonitrile/H:0 and mixtures thereof, and mixtures of said organic solvents and water. More preferably the solvent is selected from acetone, diethyl ether, ethyl acetate, ethyl acetate/H20, diethyl ether/acetone, letrahydrofuran, hexane. toluene, dimethyl carbonate, acetonitrile. acetonitrile/H2O, and mixtures thereof.
The term "substantially pure", as used herein, is intended to mean eslicarbazepine or eslicarbazepine acetate having a purity at least equal to or greater than about 98%, preferably at least equal to or greater than about 99% and preferably at least equal to or greater than about 99.5% and also having a relatively low content of organic volatile impurities.
In yet another embodiment, the present invention provides eslicarbazepine of formula (I) or eslicarbazepine acetate of formula (la) obtained by the processes herein described, having purity at least greater than about 96.0% to about 99.9%, preferably at least greater than about 99.0% to about 99.8%, more preferably at least greater about 99.5% to about 99.8%.
In yet another embodiment, the present invention provides eslicarbazepine of formula (I) or eslicarbazepine acetate of formula (la) obtained by the processes herein described, having individual impurities lower than about 1.0 %, preferably lower than about 0.5%, more preferably lower than about 0.15%.
In yet another embodiment, the present invention provides pharmaceutical .compositions comprising eslicarbazepine of formula (I) or eslicarbazepine acetate of formula (la) obtained by the processes herein described, having a median particle size below at least about 20 microns, preferably below at least about 15 microns, more preferably below at least about 10 microns, still more preferably below at least about 5 microns. The particle size disclosed here can be obtained by, for example, any milling, grinding, micronizing or other particle size reduction method known in the art to bring the solid state eslicarbazepine or eslicarbazepine acetate into any of the foregoing desired particle size range.
Dissolution and bioavailability of poorly soluble drugs may be enhanced by practices known in the art as norms of formulation practice, which may include the use of small particles of these drugs, exhibiting a narrow particle size distribution. .
In yet another embodiment, the present invention provides 4-[[5~(aminocarbonyl)-10,l 1-dihydro-5H-dibenzo[b,f]azepin-I0-yl] oxy]-4-oxobutanoic acid of formula (III) or a salt thereof.



In yet another embodiment, the present invention provides 4-[[(10S)-5-(aminocarbonyl)-10,ll-dihydro-5H-dibenzo[b,f]azepin-10-yl]oxy]-4-oxobutanoic acid (S)-l-phenylethyl- amine salt of formula (IV).

In yet another embodiment, the present invention provides 4-[[(10S)-5-(aminocarbonyl)-10,1 l-dihydro-5H-dibenzo[b,f]azepin-10-yl]oxy]-4-oxobutanoic acid of formula (V) or a salt thereof.

In yet another embodiment, the present invention provides 4-[[5-(aminocarbonyl)-10,11-dihydro-5H-dibenzo[b,f|azepin-10-yl]oxy]-4-oxobut-2-enoic acid of formula (VI) or a salt thereof.

In yet another embodiment, the present invention provides 4-[[(10S)-5-(aminocarbonyl)-10, 11-dihydro-5H-dibenzo [b, f] azepin-lOyl] oxy]-4-oxobut-2-enoic acid, (S)-l-phenylethylamine salt of formula (VII).

(VII) In yet another embodiment, the present invention provides 4-[[(10S)-5-(aminocarbonyl)-
10, I l-dihydro-5H-dibenzo [b, fj azepin-lOyl] oxy]-4-oxobut-2-enoic acid of formula (VIII) or a
salt thereof.

In yet another embodiment, the present invention provides 2-[[[5-(aminocarbonyl)-10,l 1 dihydro-5H-dibenzo[b,f]azepin-10yI]oxy] carbonyl] benzoic acid of formula (IX) or a salt thereof.

In yet another embodiment, the present invention provides 2-[[[(10S)-5-(aminocarbonyl)-10, 11-dihydro-5H-dibenzo [b, f] azepin-10-yl] oxy] carbonyl] benzoic acid, (S)-l-phenylethylamine salt of formula (X).

In yet another embodiment, the present invention provides 2-[[[(10S)-5-(aminocarbonyI)-10, ll-dihydro-5H-dibenzo [b,f]azepin-10-y]]oxy]carbonyl]benzoic acid of formula (XI) or a salt thereof.

The compounds of formulae III, IV, V, VI, VII, VIII, IX, X and XI are novel and the present invention provides for use of any of these intermediates in the preparation of eslicarbazepine of formula (I).


While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
The present invention is particularly described below:
A) A process for the preparation of eslicarbazepine of formula (I),

comprising: a) reacting compound of formula (II),

with an aliphatic or aromatic dicarboxylic acid anhydride, in the presence of an organic solvent to form a compound of formula (B),

wherein R comes from the corresponding aliphatic or aromatic dicarboxylic acid anhydride,
b) resolving the compound of formula (B) with (S)-l-phenylethylamine, in the presence of an organic solvent to form a diastereomeric mixture,
c) separating the compound of formula (C) from the diastereomeric mixture in b),

d) reacting the compound of formula (C) with an acid, in the presence of an organic solvent to form a compound of formula (D),

e) reacting the compound of formula (D) with a base, in the presence of an organic solvent.
B) The process as described in 'A' above wherein compound of formula (I) is prepared by the
process comprising:
a) reacting compound of formula (II) with succinic acid anhydride, in the presence of an organic
solvent to form a compound of formula (III),

b) resolving the compound of formula (III) with (S)-l-phenylethylamine, in the presence of an organic solvent to form a diastereomeric mixture,
c) separating the compound of formula (IV) from the diastereomeric mixture in b),

d) reacting the compound of formula (IV) with an acid, in the presence of an organic solvent to form a compound of formula (V),

e) reacting the compound of formula (V) with a base, in the presence of an organic solvent.
C) The process as described in 'A' above wherein compound of formula (I) is prepared by the
process comprising:
a) reacting the compound of formula (II) with maleic acid anhydride, in the presence of an
organic solvent to form a compound of formula (VI),

b) resolving the compound of formula (VI) with (S)-l-phenylethylamine, in the presence of an organic solvent to form a diastereomeric mixture,
c) separating the compound of formula (VII) from the diastereomeric mixture in b),

d) reacting the compound of formula (VII) with an acid, in the presence of an organic solvent to forma a compound of formula (VIII),



e) reacting the compound of formula (VII I) with a base, in the presence of an organic solvent. D) The process as described in 'A' above wherein compound of formula (I) is prepared by the process comprising:
a) reacting the compound of formula (II) with phthalic acid anhydride, in the presence of an organic solvent to form a compound of formula (IX),

b) resolving the compound of formula (IX) with (S)-l-phenylethylamine, in the presence of an organic solvent to form a diastereomeric mixture,
c) separating the compound of formula (X) from the diastereomeric mixture in b),

d) reacting the compound of formula (X) with an acid, in the presence of an organic solvent to form a compound of formula (XI),

e) reacting the compound of formula (XI) with a base, in the presence of an organic solvent. E) The process for the preparation of eslicarbazepine acetate of formula (la), comprising:

(la) reacting the eslicarbazepine of formula (1), prepared by the processes described previously, with
an acylating agent, in the presence of an organic solvent.
F) A process for purifying eslicarbazepine acetate (la), obtained by process herein described,
comprising:
(a) providing a solution of eslicarbazepine acetate in a solvent or a mixture of solvents or their
aqueous mixtures and
(b) precipitating the solid from the solution, and
(c) recovering the eslicarbazepine acetate in substantially pure form.
G) The process as described in 'F' above wherein the solvent is selected from a C2-C6 ether, a
C2-C4 ester, a mixture of C2-C4 ester/H20, a mixture of C2-C6 ether/C3- C5 ketone, a mixture of
C2-C6 ether/C2-C4 ester, a mixture of C2-C6 ether/C1-C5 alcohol, cyclic ether, a C2-C9 aliphatic
hydrocarbon, a C6-C9 aromatic hydrocarbon, a C3-C5 carbonate, dimethylformamide,
dimethylsulfoxide, acetonitrile, a mixture of acetonitrile/H2O and mixtures thereof, and mixtures
of said organic solvents and water.
H) A compound 4-[[5-(aminocarbonyl)-10,l l-dihydro-5H-dibenzo[b,f]azepin-10-yl] oxy]-4-oxobutanoic acid of formula (III) or a salt thereof.



(III)
I) A compound 4-[[(10S)-5-(aminocarbonyl)-10,11-dihydro-5H-dibenzo[b,fjazepin-10-
yl]oxy]-4-oxobutanoic acid (S)-l-phenylethylamine salt of formula (IV).

J) A compound 4-[[(10S)-5-(aminocarbonyl)-10,l l-dihydro-5H-dibenzo[b,f|azepin-10-yl]oxy]-4-oxobutanoic acid of formula (V) or a salt thereof.

K) A compound 4-[[5-(aminocarbonyl)-10,l l-dihydro-5H-dibenzo[b,f]azepin-10-yl]oxy]-4-oxobut-2-enoic acid of formula (VI) or a salt thereof.



L) A compound 4-[[(10S)-5-(aminocarbonyl)-10, 1 l-dihydro-5H-dibenzo [b, f] azepin-lOyl] oxy]-4-oxobut-2-enoic acid, (S)-1 -pheny lethylamine salt of formula (VII).

M) A compound 4-[[(10S)-5-(aminocarbonyl)-10, 1 l-dihydro-5H-dibenzo [b, f] azepin-10yl] oxy]-4-oxobut-2-enoic acid of formula (VIII) or a salt thereof.

N) A compound 2-[[[5-(aminocarbonyl)-10,11-dihydro-5H-dibenzo[b,f]azepin-10yl]oxy] carbonyl] benzoic acid of formula (IX) or a salt thereof.

0) A compound 2-[[[(10S)-5-(aminocarbonyl)-10.1 l-dihydro-5H-dibenzo[b,f]azepin-10-yl]oxy]carbonyl]benzoic acid,(S)-l-phenylethylamine salt of formula (X).

(X) P) A compound 2-[[[( 10S)-5-(aminocarbonyl)-10, 11 -dihydro-5H-dibenzo[b,f]azepin-10-
y]]oxy]carbonyl]benzoic acid of formula (XI) or a salt thereof.

. (XI) Q) Eslicarbazepine acetate of formula (la) having a median particle size less than about 20
microns.
R) Use of any of the compounds of the formulae III, IV, V, VI, VII, VIII, IX, X and XI in the
preparation of eslicarbazepine.
S) Eslicarbazepine or eslicarbazepine acetate obtained by the processes herein described, having
purity greater than about 99.0% as measured by HPLC.
T) A pharmaceutical composition comprising eslicarbazepine or eslicarbazepine acetate obtained
by the processes herein described, having purity greater than about 99.0% as measured by HPLC
and at least a pharmaceutically acceptable carrier.
Dated this First (1st) day of April, 2009


(Signed).

DR. MADHAVI KARNIK
DY GENERAL MANAGER - IPM
Glenmark Generics Limited