WO2012156987A2

WO2012156987A2 - A novel process for the preparation of eslicarbazepine

Info

Publication number: WO2012156987A2
Application number: PCT/IN2012/000323
Authority: WO
Inventors: Milind Moreshwar Gharpure; Dnyandev Rane; Sunil Sudhakar Zope; Krishna Baban NARAWADE; Amit Anant THANEDAR
Original assignee: Glenmark Generics Limited
Priority date: 2011-05-19
Filing date: 2012-05-02
Publication date: 2012-11-22
Also published as: WO2012156987A3

Abstract

The present invention relates to a process for the preparation of (S)-(+)-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide,(eslicarbazepine), (S)-(-)-10-(acetyloxy)-10,11-dihydro-5H-dibenz[b,f]-azepine-5-carboxamide (eslicarbazepine acetate) and novel compounds that may be useful intermediates in the preparation thereof.

Description

A NOVEL PROCESS FOR THE PREPARATION OF ESLICARBAZEPINE PRIORITY

[0001] This application claims the benefit of IN1533/MUM/201 1, filed on May

19, 201 1 , the content of which is incorporated herein by reference.

FIELD OF THE INVENTION

[0002] 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), (S)-(-)-10- (acetyloxy)-10,l l-dihydro-5H-dibenz[b,f]-azepine-5-carboxamide (eslicarbazepine acetate) and novel compounds that may be useful intermediates in the preparation thereof.

BACKGROUND OF THE INVENTION

[0003] Eslicarbazepine acetate is a 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, sold under the name ZEBINIX^® in the European Union, 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, 1 l-dihydro-5H-dibenz[b,f]azepine-5- carboxamide and represented by formula (I):

[0004] U.S. Patent No.

[b,f]azepines derivatives, including eslicarbazepine .acetate or stereoisomer thereof, a pharmaceutical composition, a method of treatment, and a process for the preparation of eslicarbazepine acetate.

[0005] Benes, J. et al., J. Med. Chem., 42, 2582-2587 ( 1999) disclose the preparation of

(S)-(+)-10, l l -dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide (eslicarbazepine) by esterification of racemic 10, 1 l-dihydro-10-hydroxy-5H-dibenz [b,f]azepine-5-carboxamide with mentyloxy acetic acid, then the separation of the resulting diastereomers and hydrolysis of the respective mentyloxyacetate.

[0006] U.S. Patent Nos. 7,1 19,197; 7, 189,846; 7,241,886; 7,834,177 and 7,858,778 also disclose processes for preparation of eslicarbazepine or eslicarbazepine acetate.

[0007] European Patent No. EP 1833798 describes a process for the preparation of (S)-

(+)-10, l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide (eslicarbazepine) from racemic 5-cyano-10, l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine.

[0008] U.S. Patent Publications 2006/0142566, 2009/203902 and 2010/173893 also disclose processes for preparation of eslicarbazepine or eslicarbazepine acetate.

[0009] The present invention presents a process for the preparation of eslicarbazepine acetate with optimum yield and purity by using less expensive reagents. The instant process provides a simple, eco-friendly, straightforward, robust and commercially viable process for eslicarbazepine acetate and intermediates thereof.

SUMMARY OF THE INVENTION

[0010] The present invention provides a process for the preparation of S-(+)- 10, 1 1 - dihydro-10-hydroxy-5H-dibenz [b,fj azepine-5-carboxamide compound of formula (II),

the process comprising reacting racemic (±)-10, l l -dihydro-10-hydroxy-5H-dibenz [b,fj azepine- 5-carboxamide, compound of formula (V), with (2S)-(+)-2-(4-isobutylphenyl)-propionic acid or derivative thereof, compound of formula (VIF) wherein R is selected from the group consisting of halogens, OR' and OCOR'; wherein R' is selected from the group consisting of H, CpCio linear or branched chain alkyl, cycloalkyl, aryl, alkylaryl and arylalkyl.

(VII')

[0011] The present invention provides a process for the preparation of S-(+)-10, l l- dihydro-10-hydroxy-5H-dibenz [b,f] azepine-5-carboxamide compound of formula (II), the process comprising:

(a) reacting racemic (±)-10,l l-dihydro-10-hydroxy-5H-dibenz [b,f] azepine-5-carboxamide, compound of formula (V), with (2S)-(+)-2-(4-isobutylphenyl)-propionyl halide, compound of formula (VIF), wherein R is halogen, to give a mixture of diastereoisomeric (2S)-(+)-2-(4- isobutylphenyl)-propionate esters, compound of formula (IV).

(b) precipitating the dias

from the mixture of diastereoisomeric (2S)-(+)-2-(4-isobutylphenyl)-propionate esters,

(c) hydrolyzing the compound of formula (III), to obtain S-(+)-10,l l-dihydro-10-hydroxy-5H- dibenz [b,f] azepine-5-carboxamide, compound of formula (II). [0012] The present invention provides a process for the preparation of compound of formula (Γ),

the process comprising:

reacting S-(+)-10, l l-dihydro-10-hydroxy-5H-dibenz [b,fj azepine-5-carboxamide, compound of formula (II),

with trialkyl silyl ester of formula

(VIII') wherein R and Rj is substituted or unsubstituted linear or branched CpCio alkyl group or C3-C12 cyclic group, to form compound of formula (Γ).

[0013] The present invention provides a process for the preparation of eslicarbazepine acetate, compound of formula (I),

the process comprising:

reacting S-(+)-10, l l-dihydro-10-hydroxy-5H-dibenz [b,f] azepine-5-carboxamide, compound of formula (II),

with trimethyl silyl acetate of formula (VIII),

in the presence of a suitable organic solvent.

[0014] The present invention provides a process for the preparation of eslicarbazepine acetate, compound of formula (I),

comprising:

with acetic acid in the presence of a coupling agent.

[0015] The present invention provides a compound of formula (IV).

(HI')

[0018] The present invention provides a pharmaceutical composition comprising eslicarbazepine or eslicarbazepine acetate obtained by the processes of the present invention and at least a pharmaceutically acceptable carrier. DESCRIPTION OF THE INVENTION

[0019] The present invention is directed to effective processes for the synthesis of S-

(-+-)- 10, 1 l-dihydro-10-hydroxy-5H-dibenz [b,fj azepine-5-carboxamide (eslicarbazepine), eslicarbazepine acetate and novel compounds which may be useful intermediates in the preparation thereof. [0020] The present invention provides a process for the preparation of S-(+)- 10, 1 1 - dihydro-10-hydroxy-5H-dibenz [b,fj azepine-5-carboxamide, compound of formula (II),

the process comprising reacting racemic (±)-10,l l-dihydro-10-hydroxy-5H-dibenz [b,f] azepine- 5-carboxamide, compound of formula (V), with (2S)-(+)-2-(4-isobutylphenyl)-propionic acid or derivative thereof, compound of formula (VIF) wherein R is selected from the group consisting of halogens; OR' and OCOR' wherein R' is selected from the group consisting of H, C_rCio linear or branched ch

(v) (vir)

[0021] The halogen, R, includes fluorine, chlorine, bromine and iodine. Preferably, chlorine. '

[0022] The C_rCi₀ alkyl group may be substituted or unsubstituted linear or branched and is, for example methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, secondary butyl or tertiary butyl, pentyl, hexyl and the like. Preferably, methyl, ethyl, isopropyl and tertiary butyl.

[0023] The cycloalkyl group may be substituted or unsubstituted and may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and their halo, nitro, amino derivatives and the like.

[0024] The aryl group may be substituted or unsubstituted and may include phenyl, naphthyl, anthracenyl, phenanthrenyl, and their halo, nitro, amino derivatives and the like.

[0025] The alkylaryl group may be substituted or unsubstituted and may include benzyl,

2-phenylethyl, 3-phenylpropyl, 2-naphth-2-ylethyl, and their halo, nitro, amino derivatives and the like. [0026] The arylalkyl group may be substituted or unsubstituted and may include tolyl, phenyl ethyl, phenyl propyl, phenyl butyl, phenyl tert.-butyl, and their halo, nitro, amino derivatives and the like.

[0027] More specifically, the present invention relates to a method for the preparation of S-(+)-10,l l-dihydro-10-hydroxy-5H-dibenz [b,f] azepine-5-carboxamide, compound of formula (II), the process comprising:

(a) reacting racemic (±)-10, l i-dihydro-10-hydroxy-5H-dibenz [b,f] azepine-5-carboxamide, compound of formula (V), with (2S)-(+)-2-(4-isobutylphenyl)-propionyl halide, compound of formula (VIP), wherein R is a halogen, to give a mixture of diastereoisomeric (2S)-(+)-2-(4- isobutylphenyl)-propionate esters, compound of formula (IV).

(b) precipitating the di

(III)

(c) hydrolyzing the compound of formula (III) to obtain S-(+)-10, l l-dihydro-10-hydroxy-5H- dibenz [b,fj azepine-5-carboxamide, compound of formula (II).

[0028] In one embodiment, the present invention relates to a method for the preparation of S-(+)-10, l l-dihydro-10-hydroxy-5H-dibenz [b,fj azepine-5-carboxamide, compound of formula (II) by resolution of racemic (±)- 10, 1 l-dihydro-10-hydroxy-5H-dibenz [b,f] azepine-5- carboxamide, compound of formula (V), the process comprising reacting racemic (±)-10,l l- dihydro-10-hydroxy-5H-dibenz [b,fj azepine-5-carboxamide, compound of formula (V), with (2S)-(+)-2-(4-isobutylphenyl)-propionyl halide, compound of formula (VII') wherein R is halogen, to give a mixture of diastereoisomeric (2S)-(+)-2-(4-isobutylphenyl)-propionate esters, compound of formula (IV).

[0029] In one embodiment, the present invention relates to a method for the preparation of S-(+)-10, l 1 -dihydro- 10-hydroxy-5H-dibenz [b,f] azepine-5-carboxamide, compound of formula (II) by resolution of racemic (±)-10,l 1 -dihydro- 10-hydroxy-5H-dibenz [b,f] azepine-5- carboxamide, compound of formula (V), the process comprising reacting the racemic (±)- 10, l 1 - dihydro- 10-hydroxy-5H-dibenz [b,f] azepine-5-carboxamide, compound of formula (V), with (2S)-(+)-2-(4-isobutylphenyl)-propionyl chloride compound of formula (VII'), wherein R is chlorine, to give a mixture of diastereoisomeric (2S)-(+)-2-(4-isobutyIphenyl)-propionate esters, compound of formula (IV).

[0030] In a) of the process described directly above for the preparation of compound of formula (II), the reaction of racemic (±)-10, l 1 -dihydro- 10-hydroxy-5H-dibenz [b,f] azepine-5- carboxamide, compound of formula (V), with (2S)-(+)-2-(4-isobutylphenyl)-propionyl chloride may be carried out in the presence of a solvent. The solvent may be selected from the group consisting of halogenated hydrocarbons such as methylene dichloride (MDC), chloroform, carbon tetrachloride, ethylene dichloride and the like; aromatic hydrocarbons such as hexane, heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like and mixtures thereof and mixtures of said solvents and water.

[0031] Furthermore in a), the reaption of racemic (±)-10, l 1 -dihydro- 10-hydroxy-5H- dibenz [b,f] azepine-5-carboxamide, compound of formula (V), with (2S)-(+)-2-(4- isobutylphenyl)-propionyl chloride may be carried out in the presence of a base The base may be selected from the group consisting Of triethylamine, tributylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, lutidine, collidine, and mixtures thereof. Preferably triethylamine, pyridine and 4-dimethylaminopyridine are used.

[0032] In one embodiment, the present invention provides a process for the preparation of S-(+)-10,l l-dihydro-10-hydroxy-5H-dibenz [b,fj azepine-5-carboxamide, compound of formula (II) by resolution of racemic (±)-10, l 1 -dihydro- 10-hydroxy-5H-dibenz [b,f] azepine-5- carboxamide, compound of formula (V), the process comprising reacting racemic (±)-10, l l- dihydro-10-hydroxy-5H-dibenz [b,fj azepine-5-carboxamide, compound of formula (V), with (2S)-(+)-2-(4-isobutylphenyl)-propionyl chloride in methylene chloride and in the presence of pyridine and 4-dimethylaminopyridine to give a mixture of diastereoisomeric (2S)-(+)-2-(4- isobutylphenyl)-propionate esters.

[0033] The mixture of diastereoisomeric (2S)-(+)-2-(4-isobutylphenyl)-propionate esters is structurally represented by compound of formula (IV).

[0034] The present invention provides the process described directly above, further comprising isolating the mixture of diastereoisomers (2S)-(+)-2-(4-isobutylphenyl)-propionate esters, compound of formula (IV) from the main reaction mixture by evaporating the solvent.

[0035] In one embodiment, the present invention further provides the isolation process described directly above comprising adding water to the main reaction mixture to obtain the mixture of diastereoisomers (2S)-(+)-2-(4-isobutylphenyl)-propionate esters, compound of formula (IV) separating the organic layer; and evaporating the organic layer.

[0036] In one embodiment, the present invention provides the said isolation process described directly above comprising evaporating the methylene chloride layer

[0037] In (b) of the method for the preparation of S-(+)-10, l l-dihydro-10-hydroxy-5H- dibenz [b,fj azepine-5-carboxamide, compound of formula (II), , the diastereoisomeric compound of formula (III),

is isolated by precip tat ng t rom t e astereo somer c m xture of (2S)-(+)-2-(4- isobutylphenyl)-propionate esters, compound of formula (1V).

[0038] . In one embodiment, the present invention provides the isolation process of compound of formula (III) described directly above comprising precipitating the diastereoisomeric compound of formula (III) by crystallizing the diastereoisomeric mixture of (2S)-(+)-2-(4-isobutylphenyl)-propionate esters, compound of formula (IV) in an organic solvent.

[0039] The present invention provides the isolation process described directly above comprising crystallizing of diastereoisomeric mixture of (2S)-(+)-2-(4-isobutylphenyl)- propionate esters, compound of formula (IV), the crystallization process comprising suspending the reaction mixture in an organic solvent; raising the temperature to the organic solvent's reflux temperature to obtain a clear solution; cooling the clear solution to about room temperature or below; then precipitating the less soluble diastereoisomeric compound of formula (III).

[0040] The differential solubility of the two diastereoisomers present in the diastereoisomeric mixture provides guidance in the choice of organic solvent that aids in their separation.

[0041] The organic solvent used for crystallization may be selected from the group consisting of C₁-C5 alcohols such as methanol, ethanol, isopropanol, n-propanol, butanol, isobutanol, 2-butanol and the like; C3-C9 ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone and the like; C₂-C₉ ester such as methyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate, n-butyl acetate, t-butyl acetate and the like; ethers such as diethyl ether, dimethyl ether, dimethoxymethane, dimethoxypropane, isopropyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran (THF), dioxane, furan, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, anisole and the like; aprotic polar solvents such as Ν,Ν-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), acetonitrile and the like.

[0042] In one embodiment, the present invention provides the isolation process of the compound of formula (III) described directly above further comprising precipitating the diastereoisomeric compound of formula (III) by crystallizing the diastereoisomeric mixture of (2S)-(+)-2-(4-isobutylphenyl)-propionate esters, compound of formula (IV) in an organic solvent selected from the group consisting of Q-C5 alcohols such as methanol, ethanol, isopropanol, n- propanol, butanol, isobutanol, 2-butanol and the like, C₃-C9 ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone and the like and mixtures thereof. Preferably, methanol and acetone.

[0043] In one embodiment, the present invention provides a process for the preparation of

S-(+)-10,l l -dihydro-10-hydroxy-5H-dibenz [b,f] azepine-5-carboxamide, compound of formula (II) by resolution of racemic (±)-10,l l-dihydro-10-hydroxy-5H-dibenz [b,f] azepine-5- carboxamide, compound of formula (V), the process comprising precipitating the diastereoisomeric compound of formula (III) by subjecting the diastereoisomeric mixture of (2S)- (+)-2-(4-isobutylphenyl)-propionate esters, compound of formula (IV) to crystallization in acetone.

[0044] In one embodiment, the present invention relates to a process for the preparation of S-(+)-10, l l -dihydro-10-hydroxy-5H-dibenz [b,f] azepine-5-carboxamide, compound of formula (II), by resolution of racemic (±)-10, l l-dihydro-10-hydroxy-5H-dibenz [b,f] azepine-5- carboxamide, compound of formula (V), the process comprising precipitating the diastereoisomeric compound of formula (III) by subjecting the diastereoisomeric mixture of (2S)- (+)-2-(4-isobutylphenyl)-propionate esters, compound of formula (IV) to crystallization in a mixture of acetone and methanol.

[0045] In one embodiment, the present invention relates to a process for the preparation of S-(+)-10, l l-dihydro-10-hydroxy-5H-dibenz [b,f] azepine-5-carboxamide, compound of formula (II) by resolution of racemic (±)-10, l l-dihydro-10-hydroxy-5H-dibenz [b,fj azepine-5- carboxamide, compound of formula (V), the process comprising precipitating the diastereoisomeric compound of formula (III) by subjecting the diastereoisomeric mixture of (2S)- (+)-2-(4-isobutylphenyl)-propionate esters, compound of formula (IV) to crystallization in methanol.

[0046] Optionally, the diastereoisomeric compound of formula III may be repeatedly recrystallized in the solvent to an enriched form.

[0047] In (c) of the process described above for the preparation of S-(+)-10, l 1-dihydro-

10-hydroxy-5H-dibenz [b,f] azepine-5-carboxamide, compound of formula (II)„ the compound of formula (I

(Ill) (II)

[0048] The hydrolysis of the compound of formula (III) may be effectuated with an acid or base in the presence of a suitable solvent to form a compound of formula (II).

[0049] The selection of acid or base is not critical. The acid can be an organic or inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, acetic acid, formic acid, citric acid, oxalic acid, maleic acid, fumaric acid, succinic acid, benzoic acid, sulfonic acid, methane sulfonic acid, paratoluene sulfonic acid, phosphoric acid, and the like; and their aqueous or alcoholic mixtures thereof.

[0050] The base can be an inorganic or organic. The inorganic bases are hydroxides, carbonates, bicarbonates, alkoxides and oxides of alkali or alkaline earth metals. The alkali metal compounds are those of lithium, sodium and potassium. The alkaline earth metal compounds are those of calcium and magnesium. Some example of these bases are sodium hydroxide, potassium hydroxide, magnesium hydroxide, magnesium oxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium tert.butoxide, potassium tert.butoxide and mixtures thereof and their aqueous or alcoholic mixtures. The preferred bases are sodium hydroxide and potassium hydroxide.

[0051] Suitable solvents include, but are not limited to, Ci-C₅ alcohol such as methanol, ethanol, isopropanol, n-propanol, butanol, isobutanol, 2-butanol and the like; hydrocarbon solvents and halogenated derivatives thereof such as pentane, hexane, heptane, cyclohexane, petroleum ether, toluene, benzene, cycloheptane, methylcyclohexane, ethylbenzene, m-,o-,or p- xylene, methylene dichloride (MDC), chloroform, carbon tetrachloride, ethylene dichloride and the like and mixtures thereof and mixtures of said solvents and water. Preferably, methanol, toluene or mixture thereof.

- [0052] In one embodiment, the present invention relates to a process for the preparation of S-(+)-10, l l-dihydro-10-hydroxy-5H-dibenz [b,f] azepine-5-carboxamide, compound of formula (II) by resolution of racemic (±)-10, l l-dihydro-10-hydroxy-5H-dibenz [b,f] azepine-5- carboxamide, compound of formula (V), the process comprising hydrolyzing the compound of formula (III) in C1-C5 alcohol or hydrocarbon solvent using alkali metal hydroxide.

[0053] In one embodiment, the present invention relates to a process for the purification of

S-(+)-10,l l-dihydro-10-hydroxy-5H-dibenz [b,f] azepine-5-carboxamide, compound of formula (II) , the process comprising washing the compound of formula (II) with water, followed by washing with toluene.

[0054] The compound of formula (VIF) represents S-(+)-ibuprofen and derivatives thereof; namely, (2S)-(+)-2-(4-isobutylphenyl)-propionic acid or derivative thereof.

[0055] In one embodiment, the present invention provides a process for the preparation of S-(+)-ibuprofen derivative of formula (VIP),

wherein R is halogen, the process comprising:

reacting S-(+)-ibuprofen of formula (VII),

(VII)

with a halogenating agent in the presence of a solvent.

[0056] The halogen, R, includes fluorine, chlorine, bromine and iodine. Preferably, chlorine.

[0057] The halogenating agent may be selected from the group consisting of oxalyl chloride, oxalyl fluoride, thionyl chloride, thionyl bromide, thionyl iodide, phosphorous pentachloride, phosphorous trichloride, phosphorous oxychloride, triphenylphosphine dichloride and the like. Preferably, oxalyl chloride and thionyl chloride.

[0058] The solvent is a halogenated hydrocarbon solvent such as methylene dichloride (MDC), chloroform, carbon tetrachloride, ethylene dichloride and the like. Preferably, MDC.

[0059] In one embodiment, the present invention provides a process for the preparation of compound of formula (Γ),

the process comprising:

reacting (S)-(+)-10, 1 l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide, compound of formula (II),

with trialkyl silyl ester of formula (VHP),

wherein R and Ri are not necessarily the same and can be either substituted or unsubstituted linear or branched Q-Cio alkyl group or C3-Q2 cyclic group.

[0060] The trialkyl silyl esters that can be used include, but are not limited to, triethyl silyl ester, trimethyl silyl ester and the like.

[0061] In one embodiment, the present invention provides a process for preparing compound of formula (Γ), wherein R is methyl comprising reacting S-(+)-10, l l-dihydro- 10- hydroxy-5H-dibenz [b,f] azepine-5-carboxamide, compound of formula (II), with trimethyl silyl acetate of formula (VIII),

(VIII)

[0062] In one embodiment, the present invention provides a process for the preparation of (S)-(-)-10-(acetyIoxy)-10, 1 l-dihydro-5H-dibenz [b, f] azepine-5-carboxamide compound of formula (I),

the process comprising:

reacting (S)-(+)-10, l l-dihydro-10-hydroxy-5H-dibenz[b,fJazepine-5-carboxamide, compound of formula (II),

(VIII) in the presence of a suitable organic solvent.

[0063] The solvent may be selected from the group consisting of hydrocarbon solvents and halogenated derivatives thereof, for example, pentane, hexane, heptane, cyclohexane, petroleum ether, toluene, benzene, cycloheptane, methylcyclohexane, ethylbenzene, m-,o-,or p- xylene, methylene dichloride (MDC), chloroform, carbon tetrachloride, ethylene dichloride and the like; C3-C9 ketones, for example, acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone and the like; Q-C5 alcohols, for example, methanol, ethanol, isopropanol (IPA), n- propanol, butanol, isobutanol, 2-butanol and the like; C2-C9 ester, for example methyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate, n-butyl acetate, t-butyl acetate and the like; ethers, for example, diethyl ether, dimethyl ether, dimethoxymethane, dimethoxypropane, isopropyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran (THF), dioxane, furan, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, anisole and the like; aprotic polar solvents, for example, N,N- dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), acetonitrile and the like and mixtures thereof and mixtures of said solvents and water. Preferably, methylene chloride, acetone and isopropanol.

[0064] The reaction of compound of formula (VIII) or (VHP) with (S)-(+)-10, l 1-dihydro-

10-hydroxy-5H-dibenz[b,fJazepine-5-carboxamide, compound of formula (II) may be carried out in the presence of a dehydrating agent.

[0065] The dehydrating agent may be selected from the group consisting of phosphorous pentoxide, phosphoryl chloride, calcium oxide and the like. [0066] The reaction of compound of formu la (VIII) or (VIIF ) with (S)-(+)- 10, 1 1 -dihydro- 10-hydroxy-5H-dibenz[b,f azepine-5-carboxamide, compound of formula (II) may be carried out in the presence of a metal halide.

[0067] The metal halide may be selected from the group consisting of metal iodide like calcium iodide, sodium iodide, potassium iodide, magnesium iodide, zinc iodide, cupric iodide, and manganese iodide and the like; metal bromide like potassium bromide, sodium bromide and the like.

[0068] In one embodiment, the present invention provides a process for the preparation of (S)-(-)- 1 O-(acetyloxy)- 10, 1 l-dihydro-5H-dibenz [b, f] azepine-5-carboxamide compound of formula (I), the process comprising reacting (S)-(+)-10, l l-dihydro-10-hydroxy-5H- ibenz[b,f]azepine-5-carboxamide (II) with trimethyl silyl acetate in the presence of phosphorous pentoxide.

[0069] In one embodiment, the present invention provides a process for the preparation of (S)-(-)-10-(acetyloxy)-10, 1 l-dihydro-5H-dibenz [b, f] azepine-5-carboxamide compound of formula (I), the process comprising reacting (S)-(+)-10,l l-dihydro-10-hydroxy-5H- ibenz[b,f]azepine-5-carboxamide (II) with trimethyl silyl acetate in the presence of phosphorous pentoxide and sodium iodide.

[0070] In one embodiment, the present invention provides a process for the preparation of (S)-(-)-10-(acetyloxy)-10, l l -dihydro-5H-dibenz [b,f]azepine-5-carboxamide, compound of formula (I),

(I)

the process comprising:

reacting (S)-(+)-10, l l-dihydro-10-hydroxy-5H-dibenz[b,fJazepine-5-carboxamide, compound of formula (II), with acetic acid in the presence of a coupling agent and a suitable organic solvent.

[0071] The coupling agents that can be use include, but are not limited to dicyclohexylcarbodiimide (DCC), diisopropylylcarbodiimide (DIC), carbonyldiimidazole, hydroxybenzotriazole (HOBT) and the like. Preferably, dicyclohexylcarbodiimide. [0072] Suitable solvents that can be used are as previously described.

[0073] In one embodiment, the present invention relates to a process for the purification of (S)-(-)-10-(acetyloxy)-10, 1 l-dihydro-5H-dibenz [b,f]azepine-5-carboxamide, compound of formula (I), by subjecting the compound of formula (I) to slurrying in acetone.

[0074] In one embodiment, the present invention relates to a process for the purification of (S)-(-)-10-(acetyloxy)-10, 1 l-dihydro-5H-dibenz [b,f]azepine-5-carboxamide, compound of formula (I), by subjecting the compound of formula (I), to recrystallization in an alcoholic solvent selected from the group consisting of methanol, ethanol, propanol, isopropanol and the like.

[0075] In one embodiment, the present invention provides (S)-(-)-10-(acetyloxy)- 10, 1 1- dihydro-5H-dibenz [b,f]azepine-5-carboxamide, compound of formula (I) having chiral purity as determined by high performance liquid chromatography (HPLC) greater than 99.0%, preferably greater than 99.5%.

[0076] In one embodiment, the present invention provides (S)-(-)-10-(acetyloxy)- 10, 1 1- dihydro-5H-dibenz [b,f]azepine-5-carboxamide, compound of formula (I) having chemical purity as determined by high performance liquid chromatography (HPLC) greater than 98.5%, preferably greater than 99.0%.

[0077] In yet another embodiment, the present invention provides 2(S)-(+)-2-(4- isobutylphenyl)-propionate esters, a compound of formula (IV) or a salt thereof.

[0078] In one es for preparation of

compound of formula (IV) as disclosed in the working examples (Examples 2,3,4,5, 6)

[0079] In one embodiment, the present invention provides a compound of formula (III) or a salt thereof.

[0080] In one embodiment, the present invention provides processes for the preparation of compound of formula (III) as disclosed in the working examples (Examples 7, 8, 9).

[0081] In one embodiment, the present invention provides a compound of formula (ΙΙΓ) or a salt thereof.

(ΙΙΓ)

[0082] The present invention provides a process for the preparation of a compound of formula- (IIP), comprising evaporating the mother liquor obtained after precipitating the compound of formula (III), to obtain the compound of formula (ΠΓ).

(IIP)

[0083] The present invention provides a process for the preparation of a compound of formula (III'), comprising separation of the two diastereoisomers present in the diastereoisomeric mixture (2S)-(+)-2-(4-isobutylphenyl)-propionate esters, compound of formula (IV) by adding the compound of formula (IV) in an organic solvent, precipitating out the compound of formula (III) from a solvent; separating the compound of formula (III) by filtration; and evaporating the mother liquor to obtain a solid, which is predominantly compound of formula (IIP). [0084] In one embodiment, the present invention provides a process for the preparation of a compound of formula (ΙΙΓ)_> the process comprising separating the two diastereoisomers present in the diastereoisomeric mixture (2S)-(+)-2-(4-isobutylphenyl)-propionate esters, compound of formula (IV), comprising adding the diastereoisomeric mixture of (2S)-(+)-2-(4- isobutylphenyl)-propionate esters, a compound of formula (IV) in an organic solvent selected from the group consisting of C1-C5 alcohols such as methanol, ethanol, isopropanol, n-propanol, butanol, isobutanol, 2-butanol and the like, C C₉ ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone and the like and mixtures thereof, preferably, methanol and acetone, separating the compound of formula (III) by filtration; and evaporating the mother liquor to obtain a solid, which is predominantly compound of formula (III').

[0085] In one embodiment, the present invention provides a process for the preparation of a compound of formula (IIF), the process comprising precipitating the diastereoisomeric compound of formula (III) comprising crystallizing the diastereoisomeric mixture of (2S)-(+)-2- (4-isobutylphenyl)-propionate esters, compound of formula (IV) in methanol; filtering to separate the compound of formula (III) by filtration; and evaporating the methanolic layer to obtain a compound of formula (III').

[0086] The present invention provides a process for the preparation of compound of formula (IF), R-(-)-10, l l-dihydro-10-hydroxy-5H-dibenz [b,fj azepine-5-carboxamide,

(Π')

comprising hydrolyzing the compound of formula (III').

[0087] The hydrolysis of compound of formula (IIF) may be effectuated with an acid or base in the presence of a suitable solvent to form a compound of formula (IF), R-(-)- 10, 1 1 - dihydro-10-hydroxy-5H-dibenz [b,fj azepine-5-carboxamide.

[0088] The acid or base for hydrolysis may be selected as defined earlier for hydrolysis of compound of formula (III).

[0089] The present invention provides a process for recycling the R-(-)-10, l l-dihydro-10- hydroxy-5H-dibenz [b,f] azepine-5-carboxamide, compound of formula (IF), to the racemic (±)- 10, 1 l-dihydro-10-hydroxy-5H-dibenz [b,fj azepine-5-carboxamide, compound of Formula (V).

[0090] The present invention provides a process for recycling R-(-)-10, l 1 -dihydro- 10- hydroxy-5H-dibenz [b,f] azepine-5-carboxamide, compound of formula (IV), to racemic (±)- 10, 1 1 -dihydro- 10-hydroxy-5H-dibenz [b,fj azepine-5-carboxamide, compound of Formula (V)

(IF) (V)

the process comprising:

(a) reacting the R-(-)- 10,l 1 -dihydro- 10-hydroxy-5H-dibenz [b,f] azepine-5-carboxamide, compound of formula (ΓΓ) with an oxidizing agent to obtain oxcarbazepine, compound of formula (VI), an

IF VI

(b) reducing oxcarbazepine, compound of formula (VI) to racemic (±)-10,l 1 -dihydro- 10- hydroxy-5H-dibenz [b,f] azepine-5-carboxamide, compound of formula (V).

[0091] The oxidation in (a) of compound of formula (II) to compound of Formula (VI) is carried out in a Jones reagent. A Jones reagent can either be a solution of chromium trioxide in dilute sulfuric acid and acetone, or a mixture of potassium dichromate and dilute sulfuric acid.

[0092] In one embodiment, the oxidation in (a) of compound of formula (II) to compound of Formula (VI) is carried out in a solution of chromium trioxide in dilute sulfuric acid and acetone. [0093] In (b) of the above process, the reduction of oxcarbazepine, . compound of formula (VI) reduced to racemic (±)-10, l l-dihydro-10-hydroxy-5H-dibenz [b,fj azepine-5- carboxamide, compound of Formula (V) uses reducing agents selected from the group consisting of sodium borohydride, potassium borohydride, lithium aluminum hydride and the like. Preferably, sodium borohydride.

[0094] In one embodiment, the present invention provides the recycling of R-(-)- 10, 1 1 - dihydro-10-hydroxy-5H-dibenz [b,fj azepine-5-carboxamide, compound of formula (IP) to the racemic (±)-10,l l-dihydro-10-hydroxy-5H-dibenz [b,fj azepine-5 -carboxamide, compound of formula (V), the process comprisingreacting the R-(-)-10, l l-dihydro-10-hydroxy-5H-dibenz [b,f] azepine-5-carboxamide, compound of formula (IP) with a solution of chromium trioxide in dilute sulfuric acid and acetone to obtain oxcarbazepine, compound of formula (VI); reacting oxcarbazepine, compound of formula (VI) with sodium borohydride to obtain the racemic (±)- 10, 1 l-dihydro-10-hydroxy-5H-dibenz [b,f] azepine-5 -carboxamide, compound of formula (V).

[0095] Racemic (±)-10, 1 l-dihydro-10-hydroxy-5H-dibenz [b, f] azepine-5- carboxamide, compound of formula (V), may be synthesized by reduction of oxcarbazepine. Procedures for making oxcarbazepine are found in literature. Illustratively, it is described in U.S. Patent No. 7,459,553, which is incorporated herein by reference, in its entirety.

[0096] The present invention provides a pharmaceutical composition comprising eslicarbazepine or eslicarbazepine acetate obtained by the processes of the present invention and at least a pharmaceutically acceptable carrier.

[0097] The processes, herein described, for the preparation of eslicarbazepine, eslicarbazepine acetate and novel compounds useful as intermediates of eslicarbazepine are simple, eco-friendly, inexpensive, reproducible, robust and well suited on industrial scale.

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. EXAMPLES

Example 1: Preparation of compound of formula (V) (racemic (±)-10, 1 l-dihydro-10- hydroxy-5H-dibenz [b,f] azepine-5-carboxamide)

Oxcarbazepine ( lOOgm, 0.393 mol) was suspended in a mixture of water (130ml) and methanol (400 ml). Sodium borohydride (10.5gm, 0.277mol) was added to this suspension in three equal portions for about over 15 minutes at about 25-30°C. The temperature of the reaction mixture was raised to about 40-45°C and stirring was continued at about 40-45°C for about 3hours. After completion of the reaction, the reaction mixture was cooled to about 10-15°C and then acetone (100ml) was added at about 10-15°C. The reaction mixture was concentrated at about 40-45°C under reduced pressure till 200 ml methanol distilled off and thereafter water (500ml) was added and methanol was distilled out completely under reduced pressure at about 40-45 °C. Then reaction mass was cooled to about 20-25°C and stirred at same temperature for about 2 hours. The solid obtained was washed with water, filtered and dried at about 40-45°C to obtain title compound (97gm).

Example 2: Preparation of compound of formula (IV) (mixture of diastereoisomeric (2S)-(+)- 2-(4-isobutylphenyl)-propionate esters)

The mixture of S-(+)-Ibuprofen (97.4gm, 0.472mol) and oxalyl chloride (75gm, 0.590 mol) was stirred in methylene chloride (500ml) at about 25-30°C for about 3 hours. Thereafter excess oxalyl chloride was distilled out from the reaction mass under reduced pressure at about 40-45°C. The obtained residue was dissolved in methylene chloride (200ml) and compound of formula (V) (l OOgm, 0.393mol), pyridine (46.6gm, 0.589mol) and 4-dimethylaminopyridine (5gm, 0.04mol) was added in methylene chloride (500ml). The reaction mixture was stirred at about 25-30°C for about 3hours and demineralized (DM) water (500ml) was added. The reaction mass was stirred at about 25-30°C for about 15-20minutes. The methylene chloride layer was separated and washed with dilute hydrochloric acid and then with 5% aqueous sodium bicarbonate solution. The organic layer was washed with brine solution. The methylene chloride was distilled out under reduced pressure at about 40-45°C to obtain title compound as solid product (170gm).

I H NMR (DMSO): 7.31-7.34 (d, 2H, Ar-H), 7.18-7.24 (m 6H, Ar-H), 7.09-7.1 1 (d 2H, Ar-H) 6.99-7.03(t lH,Ar-H),6.73-6.75(d,lH,Ar-H),6.14(bs,lH),5.86(s,2H,NH₂ ),3.73-3.80(q 1 H.-CH- ),3.01(bs lH,-CH-),2.40-2.48(ld, ls, 2H,-CH₂ -),1.75- 1.84(m , 1H -CH-), 1.39-1.4 l(d,3H, ,-CH₃), 0.82-0.85(d,6H, ,2-CH₃.)

SORs +26.0° to +27.0° (1.0 % in methylene dichloride at 20 °C). Example 3: Preparation of compound of formula (IV)

The mixture of S-(+)-ibuprofen (87.62gm, 0.424mol) and thionyl chloride (63.13gm, 0.590mol) was stirred in methylene chloride (180ml) at about 25-30°C for about 3 hours. Excess thionyl chloride was distilled out from reaction mass under reduced pressure at about 40-45°C. The residue was dissolved in methylene chloride (180ml) and then compound of formula (V) (90gm, 0.3539mol), pyridine (42gm, 0.53 lmol) and 4-dimethylaminopyridine (4.5gm, 0.0368mol) was added in methylene chloride (450ml). The reaction mixture was stirred at about 25-30°C for about 3hours and then demineralized (DM) water (450ml) was added. The reaction mass was stirred at about 25-30°C for about 15-20minutes and the methylene chloride layer was separated and washed with dilute hydrochloric acid and then with 5% aqueous sodium bicarbonate solution. The organic layer was washed with brine solution. Methylene chloride was distilled out under reduced pressure at about 40-45°C to obtain title compound as solid product (155gm). Example 4: Preparation of compound of formula (TV)

The mixture of S (+)-ibuprofen (4.45gm, 0.02 lmol) and oxalyl chloride (3.7gm, 0.029mol) was stirred in methylene chloride (25ml) at about 25-30°C for about 3hours. Excess oxalyl chloride was distilled out from reaction mass under reduced pressure at about 40-45°C. The residue was dissolved in methylene chloride (10 ml) and then compound of formula (V), prepared as in Example 1, (5gm, 0.393mol), triethyl amine (2.98gm, 0.029mol) and 4-dimethylaminopyridine (0.25gm, 0.0020mol) was added in methylene chloride (25ml). The reaction mixture was stirred at about 25-30°C for about 3 hours and then DM water (25ml) was added. The reaction mass was stirred at about 25-30°C for about 15-20minutes and the methylene chloride layer was separated and washed with dilute hydrochloric acid and then with 5% aqueous sodium bicarbonate solution. The organic layer was washed with brine solution. Methylene chloride was distilled under reduced pressure at about 40-45°C to obtain the title compound as a solid product (8.6gm)

Example 5: Preparation of compound of formula (IV)

The mixture of S (+)-ibuprofen (4.45gm, 0.021mol) and oxalyl chloride (3.71gm, 0.029 mol) was stirred in methylene chloride (25ml) at about 25-30°C for about 3hours. Excess oxalyl chloride was distilled out from the reaction mass under reduced pressure at about 40-45°C. The residue was dissolved in methylene chloride (10ml) and compound of formula (V), prepared as in Example 1, (5gm, 0.019mol), triethylamine (2.98gm, 0.029mol) was added in methylene chloride (25ml). The reaction mixture was stirred at about 25-30°C for about 3hours and then DM water (25ml) was added to it. The reaction mass was stirred at about 25-30°C for about 15- 20minutes and the methylene chloride layer was separated and washed with dilute hydrochloric acid and then with 5% aqueous sodium bicarbonate solution. The organic layer was washed with brine solution. Methylene chloride was distilled out under reduced pressure at about 40-45°C to obtain title compound as solid product (8.55gm).

Example 6: Preparation of compound of formula (IV)

The mixture of S (+)-ibuprofen (4.45gm, 0.022mol) and oxalyl chloride (3.71gm, 0.029 mol) was stirred in methylene chloride (25ml) at about 25-30°C for about 3hours. Excess oxalyl chloride was distilled out from reaction mass under reduced pressure at about 40-45°C. The residue was dissolved in methylene chloride ( 10ml) and compound of formula V, prepared as in Example 1, (5gm, 0.019mol), pyridine (2.33gm, 0.029mol) was added in methylene chloride (25ml). The reaction mixture was stirred^' at about 25-30°C for about 3 hours and then DM water (25ml) was added. The reaction mass was stirred at about 25-30°C for about 15-20minutes and the methylene chloride layer was separated and washed with dilute hydrochloric acid and then with 5% aqueous sodium bicarbonate solution. The organic layer was washed with brine solution. Methylene chloride was distilled out under reduced pressure at about 40-45°C to obtain title compound as solid product (7.5gm).

Example 7: Preparation of compound of formula (III)

Compound of formula (IV), prepared as described herein, (150gm, 0.316mol) was added to acetone (2.25L) and the reaction mass was heated to reflux temperature of 56°C for about one hour and the reaction mass was cooled for about 15-20°C for about 2hours. The solid was filtered and washed with acetone (150ml) and dried at about 45-50°C to obtain 41.5gm product. The acetone purification was repeated. The wet cake obtained (41gm) was added to acetone (1.16L) and the reaction mass was heated to reflux temperature of about 56°C for about an hour and then the reaction mass was cooled at about 15-20°C for about 2 hours. The solid was filtered, washed with acetone (41ml) and dried at about 45- 50°C to obtain 35gm of title product.

Chiral Purity 'S' Isomer = 99.73 %

SOR: +18.5° to +19.0° (1.0 % in methylene dichloride at 20° C)

I H NMR (DMSO): 7.31-7.34 (d, 2H, Ar-H), 7.18-7.24 (m 6H, Ar-H), 7.09-7.1 1 (d 2H, Ar-H) 6.99-7.03(t lH,Ar-H),6.73-6.75(d,lH,Ar-H),6.14(bs, lH),5.86(s,2H,NH₂ ),3.73-3.80(q 1H,-CH- ),3.01(bs lH,-CH-),2.40-2.48(ld, ls, 2H,-CH₂ -), 1.75- 1.84(m ,1H -CH-), 1.39-1.41(d,3H, ,-CH₃), 0.82-0.85(d,6H, ,2-CH₃.)

Example 8: Preparation of compound of formula (III)

Compound of formula (IV), prepared as described herein, (50gm, 0.1 13mol) was added to a mixture of acetone (350ml) and methanol (350ml) and reaction mass was heated to reflux temperature of about 56-60°C for about an hour and the reaction mass was cooled at about 15- 20°C for about 2hours. The solid was filtered and washed with mixture of acetone and methanol (50ml) and dried at about 45-50°C to obtain 15gm of title compound.

Example 9: Preparation of compound of formula (III)

Compound of formula (IV) (lOgm, 0.022mol) was added to methanol (10ml) and reaction mass was heated to reflux temperature of about 64°C for about an hour and the reaction mass was cooled at about 25-30°C for about an hour. The solid was filtered and washed with methanol (10 ml) and dried at about 45-50°C to obtain solid product. The methanol purification was repeated. The wet cake obtained was added to methanol (100 ml) and reaction mass was heated to reflux temperature of about 64°C for about an hour and then the reaction mass was cooled at about 25- 30°C for about an hour. The solid was filtered and washed with methanol (10ml) and dried at about 45-50°C to obtain 3.2gm of title compound.

Example 10: Preparation of compound of formula (III')

Compound of formula (IV), prepared as described herein, (150gm, 0.316mol) was added to acetone (2.25L) and reaction mass was heated to reflux temperature of about 56°C for about one hour and the reaction mass was cooled for about 15-20°C for about 2hours. The solid was filtered and washed with acetone (150ml) and dried at about 45-50°C to obtain 41.5gm product. The acetone purification was repeated. The wet cake obtained (41 gm) was added to acetone ( 1.16L) and the reaction mass was heated to reflux temperature of about 56°C for about an hour and then the reaction mass was cooled at about 15-20°C for about 2hours. The solid was filtered, washed with acetone (41ml). The filtrates were combined and concentrated under vacuum at about 45- 55°C to obtain 1 10 gm of solid.

Example 11: Preparation of compound of formula (II)

Compound of formula (III), prepared as described herein, (18gm) was added to methanol (270ml) and the reaction mass was stirred for about lOminutes at about 25-30°C, 3N aqueous sodium hydroxide solution (54ml) was added at about 25-30°C and the reaction mass was stirred at about 50-55°C for about 3hours. The methanol was distilled under reduced pressure till 135ml methanol was distilled off. DM water (90ml) was added to the reaction mass at about 25-30°C, the contents were stirred at about the same temperature for about lOminutes. The aqueous layer was extracted with methylene chloride (3x90ml). The methylene chloride layer was distilled out at about 35- 40°C to obtain title compound as white solid (9gm)

Example 12: Preparation of compound of formula (II)

Compound of formula (III), prepared as described herein, (50gm, 0.1 12mol) was added to toluene (200ml), methanol (10ml) and the reaction mass was stirred for about lOminutes at about 25- 30°C, then 50% aqueous sodium hydroxide solution (15ml) was added at about 25-30°C and the reaction mass was stirred at about 50-55°C for about an hour. The reaction mass was cooled at about 25-30°C and DM water (250 ml) was added to it. The reaction mass was cooled at about 15-20°C and (1 : 1) HC1 (43ml) was added at about the same temperature and reaction mass was stirred at about 5-10°C for about 4 hours. The solid was filtered, wash with DM water and toluene and dried at about 45- 50°C to obtain title compound as white solid (25.6 gm).

Example 13: Preparation of compound of formula (II)

Compound of formula (III), prepared as described herein, (50gm, 0.1 12mol) was added in toluene (200ml), methanol (10ml) and the reaction mass was stirred for about lOminutes at about 25- 30°C, 50% aqueous potassium hydroxide solution (15ml) was added at about 25-30°C and the reaction mass was stirred at about 50-55°C for about an hour. The reaction mass was cooled at about 25-30°C and DM water (250ml) was added. The reaction mass was cooled at about 15- 20°C and (1 : 1) HC1 (43ml) was added at same temperature and the reaction mass was stirred at about 5-10°C for about 4hours. The solid was filtered, washed with DM water and toluene and dried at about 45-50°C to obtain title compound as white solid (25.6gm).

Example 14: Preparation of compound of formula (IF)

Compound of formula (III'), prepared as described herein, (l l Ogm) was added to toluene (330ml), methanol (22ml) and the reaction mass was stirred for about lOminutes at about 25- 30°C, then aqueous sodium hydroxide solution (25ml) was added at about 25-30°C and the reaction mass was stirred at about 45-50°C for about an hour. The reaction mass was cooled at about 25-30°C and DM water (550ml) was added to it. The reaction mass was cooled at about 10- 15°C and (1 : 1) HC1 (99ml) was added at about the same temperature and reaction mass was stirred at about 5-10°C for about 3hours. The solid was filtered, washed with DM water and toluene and dried at about 50-55°C to obtain title compound as solid (55gm).

Example 15: Recycling of compound of formula (IP) to compound of formula (V)

Compound of formula (IF), prepared as in Example 14, (20gm) was suspended in acetone and stirred at about 25-30 °C. Jones reagent (20ml water, 4.5ml cone, sulfuric acid and about 5.4g chromium trioxide) was added to the reaction mass and stirred for about 2 hours. The temperature was raised to about 35-40 °C and the reaction was stirred for about an hour at about the same temperature. The solid was filtered, washed with water and acetone and the obtained solid was dried to obtain compound of formula (VI) (15.7gm). The compound of formula (VI) is converted into compound of formula (V) as exemplified in Example 1.

Example 16: Preparation of S-(-)-Eslicarbazepine acetate (compound of formula I)

Compound of formula (II), prepared as described herein, (lOgm, 0.039mol), methylene chloride (150ml) and acetic acid (4.72gm, 0.078mol) were stirred under an inert atmosphere for about 10- 15minutes at about 25-30°C. Dimethyl aminopyridine (3.34gm, 0.023mol) was added and the reaction mass was stirred for about 10-15minutes at about 25-30°C. The reaction mass was cooled at about 0°C and dicyclohexylcarbodiimide (8.92 gm, 0.043 mol) was added portionwise under an inert atmosphere at about 0-5°C in about 15-20 minutes and the reaction mass was maintained for about 3hours at about the same temperature. The reaction mass was stirred at about 25-30°C and the reaction mass was heated at about 35-40°C for about 2hours. The reaction mass was cooled at about 25-30°C then filtered and washed with (20ml) methylene chloride. The filtrate of methylene chloride was collected, washed with diluted hydrochloric acid (1x30ml) and 10% sodium bicarbonate solution (2x30ml) and methylene chloride was distilled out under reduced pressure at about 30-35°C to obtain off white product 12.8gm. To the solid product obtained, isopropyl alcohol (72.0ml) was added and heated to reflux for about an hour. The reaction mass was cooled at about 25°-30°C for about an hour, the slurry filtered and washed with isopropyl alcohol (20ml). The product was dried at about 45-50°C to obtain title compound as white solid (10.3gm).

Example 17: Preparation of S-(-)-Eslicarbazepine acetate (compound of formula I)

A mixture of trimethyl silyl acetate (6.24gm, 0.0471 mol) and anhydrous phosphorous pentoxide (3.34gm, 0.023mol) was heated at about 50-55°C for about 3hours. The reaction mass was cooled at about 25-30°C and compound of formula (II), prepared as herein described (8gm, 0.314mol) and methylene chloride (40ml) were added. The reaction mass was stirred for about 3-5hours at about 35-40°C. The reaction mass was cooled at about 25-30°C and the reaction mass quenched slowly in DM water (40 ml) and methylene chloride layer was washed with 5% aqueous sodium bicarbonate solution (2x40 ml) till neutral pH. The methylene chloride was distilled under reduced pressure at about 30-35°C to obtain off white solid product. Acetone (24 ml) was added to the solid product obtained, and stirred at about 10-15°C for about an hour. The product was filtered, washed with acetone (4 ml) and the product was dried at about 45-50°C to obtain title compound as white solid (6.8gm).

Example 18: Preparation of S-(-)-Eslicarbazepine acetate (compound of formula I)

A mixture of trimethyl silyl acetate (10.44gm,) and anhydrous phosphorous pentoxide (5.6gm) was heated at about 50-55°C for about 3hours. The reaction mass was cooled at about 25-30°C and compound of formula (II), prepared as herein described (lOgm,) and methylene chloride (60ml) were added. The reaction mass was stirred and sodium iodide (2.36 gm, 0.0157 mole) was added. Methylene chloride (60 ml) was added dropwise to the reaction mass at 40°-45°C. The reaction mass was stirred for about 1.0 hour at about 40-45°C. The reaction mass was cooled at about 25-30°C and the reaction mass quenched slowly in DM water (70 ml) and methylene chloride layer was washed with 7% sodium metabisulphate solution (2x70 ml), followed by washing with 7% sodium carbonate solution (2x70 ml). The methylene chloride layer was separated and was washed with 20% sodium chloride solution (70 ml). The methylene chloride layer was charcoalised. The reaction mass was stirred at about 25-30°C for 30 min and filtered through Hyflo and washed the Hyflo with methylene chloride (10 ml).The methylene chloride layer was concentrated under reduced pressure at about 30-35°C to obtain a white solid product. Thereafter isopropyl alcohol (100 ml) was added to the solid product, and stirred at about 80- 85°C for about 30 min. The reaction mass was further cooled to 25-30°C and stirred for about 1.0 hour. The product was filtered, and washed with isopropyl alcohol (20 ml) and the product was dried at about 50-55°C to obtain title compound as white solid (8.5gm).

Example 19: Purification of S-(-)-Eslicarbazepine acetate (compound of formula I)

Isopropyl alcohol (130 ml) was added to 9 g of S-(-)-Eslicarbazepine acetate compound of formula I, and the reaction mass was refluxed at about 80-85°C for about 30 min. Thereafter the reaction mass was cooled at about 60° 65°C. The reaction mass was filtered at 60°-65°C and was distilled out partly. The reaction mass further cooled gradually to about 25°-30°C and stirred for about 1.0 hour. The product was filtered, and washed with isopropyl alcohol and the product was dried at about 50-55°C to obtain title compound as white solid, 8.0gm.

Claims

1] A process for the preparation of S-(+)-10, l l-dihydro-10-hydroxy-5H-dibenz [b,f] azepine-5- carboxamide compound of formula (II),

the process comprising: reacting racemic (±)-10,l l-dihydro-10-hydroxy-5H-dibenz [b,fj azepine- 5-carboxamide,a compound of formula (V), with (2S)-(+)-2-(4-isobutylphenyl)-propionic acid or derivative thereof, a compound of formula (VIP) wherein R is selected from the group consisting of halogens, OR' and OCOR'; wherein R' is selected from the group consisting of H, Q-Cio linear or branched chain alkyl, cycloalkyl, aryl, alkylaryl and arylalkyl.

(VII')

2] A process for the preparation of S-(+)-10, l l-dihydro-10-hydroxy-5H-dibenz [b,f] azepine-5- carboxamide compound of formula (II), comprising:

(a) reacting racemic (±)- 10,1 l-dihydro-10-hydroxy-5H-dibenz [b,f] azepine-5-carboxamide, compound of formula (V), with (2S)-(+)-2-(4-isobutylphenyl)-propionyl halide, compound of formula (VIP), wherein R is a halogen, to give a mixture of diastereoisomeric (2S)-(+)-2-(4- isobutylphenyl)-propionate esters, compound of formula (IV)

formula (IV)

(b) precipitating the diastereoisomeric compound of formula (III),

(III)

from the mixture of diastereoisomeric (2S)-(+)-2-(4-isobutylphenyl)-propionate esters, compound of formula (IV); and

(c) hydrolyzing the compound of formula (III) to obtain S-(+)-10,l l-dihydro-10-hydroxy-5H- dibenz [b,f] azepine-5-carboxamide, compound of formula (II).

3] The process of claim 2, wherein in (a) the reaction is carried out in the presence of base. 4] The process of claim 2, wherein in (b), the diastereoisomeric compound of formula (III) is precipitated by recrystallizing the mixture of diastereoisomeric (2S)-(+)-2-(4-isobutylphenyl)- propionate esters, compound of formula (IV) in an organic solvent.

5] The process of claim 4 wherein the organic solvent is selected from the group consisting of C_r C₅ alcohols, C3-C9 ketones and mixtures thereof.

6] The process of claim 2, wherein hydrolysis of the compound of formula (III) may be carried out in presence of an acid or a base.

7] A process for the preparation of co ,

( )

comprising:

reacting S-(+)-10,l l-dihydro-10-hydroxy-5H-dibenz [b,f] azepine-5-carboxamide, compound of formula (II),

(II)

with trialkyl silyl ester of formula

VIII¹ wherein R and Ri are not necessarily the same and can be either substituted or unsubstituted linear or branched Q-Cio alkyl group or C3-C12 cyclic group, to form compound of formula ( ).

8] A process as claimed in claim 7, wherein R is methyl comprising reacting S-(+)-10, l l - dihydro-10-hydroxy-5H-dibenz [b,fj azepine-5-carboxamide, compound of formula (II), with trimethyl silyl acetate of formula (VIII),

(VIII)

9] A process as claimed in claim 7, wherein the reaction is carried out in presence of dehydrating agent.

10] A process as claimed in claim 7, wherein the reaction is carried out in the presence of a metal halide.

1 1] A process for the preparation of eslicarbazepine acetate, ci ompound of formula (I),

comprising:

reacting S-(+)-10, l l-dihydro-10-hydroxy-5H-dibenz [b,fj azepine-5-carboxamide compound of formula (II),

with trimethyl silyl acetate of formula (VIII),

(VIII) in the presence of a suitable organic solvent.

12] A process for the preparation of compound of formula (I),

(I) .

comprising:

(Π)

with acetic acid in the presence of a coupling agent.

13] The process of claim 10, wherein the coupling agent is selected from the group consisting dicyclohexylcarbodiimide, diisopropylylcarbodiimide, carbonyldiimidazole and

hydroxybenzotriazole.

14] A compound of formula (IV).

(IV)

15] A compound of formula (III) or a salt thereof.

(III)

16] A compound of formula (III^*) or a salt thereof.

(IIP)

17] A process for recycling R-(-)-10, l l-dihydro-10-hydroxy-5H-dibenz [b,f] azepine-5- carboxamide, compound of formula (ΙΓ), to racemic (±)-10,l l-dihydro-10-hydroxy-5H-dibenz [b,f] azepine-5-carboxamide, compound of formula (V) , the process

(IF) (V)

comprising

(a) reacting the R-(-)- 10, l l-dihydro-10-hydroxy-5H-dibenz [b,f] azepine-5-carboxamide, compound of formula (IF) with an oxidizing agent to obtain oxcarbazepine, compound of formula (VI), an

(IF) (VI)

(b) converting oxcarbazepine, compound of formula (VI) to racemic (±)- 10,1 1 -dihydro- 10- hydroxy-5H-dibenz [b,f] azepine-5-carboxamide, compound of formula (V).