FORM 2
THE PATENT ACT, 1970
(39 of 1970)
& The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"A NOVEL PROCESS FOR THE PREPARATION OF ESLICARBAZEPINE"
Enaltec Labs Pvt. Ltd. an Indian Company, having its Registered Office at 17th Floor, Kesar Solitaire, PlotNo.5 Sector-19, Sanpada, Navi Mumbai Maharashtra, India. Pin Code: 400705
1. The following specification particularly describes the invention and the manner in which it is to be performed.

A NOVEL PROCESS FOR THE PREPARATION OF ESLICARBAZEPINE
FIELD OF THE INVENTION:
The present invention relates to a novel process for the preparation of eslicarbazepine, eslicarbazepine acetate and novel compounds that may be useful as intermediates in the preparation thereof.
BACKGROUND OF THE INVENTION:
Eslicarbazepine acetate is a dibenz [b, f| azepine-5-carboxamide derivative and is chemically defined as (S)-lO-Acetoxy-lO, ll-dihydro-5H-dibenz [b, f] azepine-5-carboxamide. It is known from U.S. Patent No. 5,753,646 and is represented by compound of structural formula I.
Eslicarbazepine acetate is sold in USA under the proprietary name "APTIOM" and is indicated as adjunctive treatment of partial-onset seizures.
U.S. Patent No. 5,753,646 describes a process for the preparation of eslicarbazepine acetate compound of structural formula I as shown below in scheme no. I.

U.S. Patent No. 7,119,197 describes a process for the preparation of eslicarbazepine acetate compound of structural formula I as shown below in scheme no. II.

PCT Publication No. 2011/091131 describes a process for the preparation of eslicarbazepine acetate compound of structural formula I as shown below in scheme no. III.
PCT Publication No. 2011/117885 describes a process for the preparation of eslicarbazepine acetate compound of structural formula I as shown below in scheme no. IV.

PCT Publication No. 2011/138795 describes a process for the preparation of eslicarbazepine acetate compound of structural formula I as shown below in scheme no. V.
PCT Publication No. 2012/121701 describes a process for the preparation of eslicarbazepine acetate compound of structural formula I as shown below in scheme no. VI.

PCT Publication No. 2012/156987 describes a process for the preparation of eslicarbazepine acetate compound of structural formula I as shown below in scheme no. VII.

There is still need in the art to develop a simple, ecofriendly, straightforward and commercially viable process for the preparation of eslicarbazepine acetate compound of structural formula I.
The present invention provides a novel process for the preparation of eslicarbazepine acetate compound of structural formula I, which is simple, ecofriendly, straightforward and commercially viable.
SUMMARY OF THE INVENTION:
A first aspect of the present invention is to provide a novel process for the preparation of eslicarbazepine compound of structural formula II.

A second aspect of the present invention is to provide a novel process for the preparation of eslicarbazepine compound of structural formula II comprising the steps of:
(a) reacting compound of structural formula III with compound of structural formula XIV to give a mixture of diastereoisomeric compound of structural formula XV,
wherein, R' is -C1 to C3 alkyl or substituted or unsubstituted phenyl or -O-C1-C3 alkyl (b) separating diastereoisomeric compound of structural formula XVI, and
(c) hydrolyzing the diastereoisomeric compound of structural formula XVI to get eslicarbazepine compound of structural formula II.

A third aspect of the present invention is. to provide a novel process for the preparation of eslicarbazepine compound of structural formula II comprising the steps of:
(a) reacting compound of structural formula III with (2S,3S)-2,3-dimethoxysuccinic acid
compound of structural formula XVII to give a mixture of diastereoisomeric compound
of structural formula XVIII,
(b) separating diastereoisomeric compound of structural formula XIX, and
(c) hydrolyzing the diastereoisomeric compound of structural formula XIX to get eslicarbazepine compound of structural formula II.

A fourth aspect of the present invention is to provide a novel process for the preparation of eslicarbazepine compound of structural formula II comprising the steps of:
(a) reacting compound of structural formula III with (2S,3S)-2,3-dimethylsuccinic acid compound of structural formula XX to give a mixture of diastereoisomeric compound of structural formula XXI,
(b) separating diastereoisomeric compound of structural formula XXII, and
(c) hydrolyzing the diastereoisomeric compound of structural formula XXII to get eslicarbazepine compound of structural formula II.

Another aspect of the present invention is to provide a novel process for the preparation of eslicarbazepine compound of structural formula II comprising the steps of:
(a) reacting compound of structural formula III with (2S,3S)-(+)-2,3-diphenylsuccinic acid
compound of structural formula XXIII to give a mixture of diastereoisomeric compound
of structural formula XXIV,
(b) separating diastereoisomeric compound of structural formula XXV, and
(c) hydrolyzing the diastereoisomeric compound of structural formula XXV to get eslicarbazepine compound of structural formula II.

Another aspect of the present invention is to provide a novel process for the preparation of eslicarbazepine acetate compound of structural formula I comprising the steps of:
(a) reacting compound of structural formula III with compound of structural formula XIV to give a mixture of diastereoisomeric compound of structural formula XV,
wherein, R' is -C1to C3 alkyl or substituted or unsubstituted phenyl or -O-C1-C3 alkyl. (b) separating diastereoisomeric compound of structural formula XVI,
(c) hydrolyzing the diastereoisomeric compound of structural formula XVI to get eslicarbazepine compound of structural formula II, and

(d) converting eslicarbazepine compound of structural formula II in to eslicarbazepine acetate compound of structural formula I.
Another aspect of the present invention is to provide a novel compound of structural formula XV.
wherein, R' is -C1 to C3 alkyl or substituted or unsubstituted phenyl or -O-C1-C3 alkyl
Another aspect of the present invention is to provide a novel compound of structural formula XVIII, XXI or XXIV.

Another aspect of the present invention is to provide a novel compound of structural formula XVI.
Another aspect of the present invention is to provide a novel compound of structural formula XIX, XXII or XXV.

DETAIL DESCRIPTION OF THE INVENTION:
The compound of structural formula III used herein may be prepared by the processes known in the art such as those described in U.S. Patent No. 7,119,197; PCT Publication Nos. 2011/091131 and 2011/138795, which are incorporated herein by reference only.
The reaction of compound of structural formula III with compound of structural formula XIV may be carried out in presence of acetic anhydride and organic base in halogenated aliphatic hydrocarbon solvent.
The reaction of compound of structural formula III with compound of structural formula XIV may be carried out at a temperature in the range of 10°C to 80°C for a period of 30 minutes to 12 hours.
The reaction of compound of structural formula III with compound of structural formula XIV, may involve treatment of compound of structural formula XIV with acetic anhydride in presence of sulphuric acid and then resulting reaction mass reacted with compound of structural formula III in presence of organic base in halogenated aliphatic hydrocarbon solvent to get a mixture of diastereoisomeric compound of structural formula XV.

The examples of organic base may include but not limited to triethylamine, diisopropylamines, imidazole, pyridine, pyridazine, pyrimidine, lithium diisopropylamide, potassium bis(trimethylsilylamide), potassium tert-butoxide, 4-dimethylaminopyridine, 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) or l,5-Diazabicyclo[4.3.0]non-5-ene(DBN) etc.
The examples of halogenated aliphatic hydrocarbon solvent may include but not limited to dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixture(s) thereof.
The reaction mixture containing mixture of diastereoisomeric compound of structural formula XV may be treated with water at 20°C to 30°C for period of 2 hour to 12 hours, during this period the precipitation of less soluble diastereoisomeric compound of structural formula XVI occurs.
The precipitated diastereoisomeric compound of structural formula XVI may be separated by steps of filtration, washing with water and drying to get diastereoisomeric compound of structural formula XVI.
The hydrolysis of diastereoisomeric compound of structural formula XVI may be carried out in presence of aqueous solution of inorganic base in an alcohol solvent at a temperature in the range of 20°C to 35°C for a period of 20 minutes to 6 hours to get eslicarbazepine compound of structural formula II.
The examples of an alcohol solvent may include but not limited to methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, t-butyl alcohol or mixture(s) thereof.
The examples of inorganic base may include but not limited to sodium hydroxide, potassium hydroxide or lithium hydroxide.

The eslicarbazepine compound of structural formula II may be isolated by filtering reaction mixture to get filtrate, concentrating resulting filtrate under reduced pressure to get residue, adding water to the resulting residue and mixture is allow standing for 2 to 12 hours, during this period eslicarbazepine compound of structural formula II crystallizes from reaction mixture. The resulting solids were filtered, washed with water and dried at 60-70°C for 2 hours to 12 hours under reduced pressure to get eslicarbazepine compound of structural formula II.
The examples of compound of structural formula XIV may include (2S,3S)-2,3-dimethoxysuccinic acid compound of structural formula XVII, (2S,3S)-2,3-dimethyIsuccinic acid compound of structural formula XX or (2S,3S)-2,3-diphenylsuccinic acid compound of structural formula XXIII.
The examples of compound of structural formula XV may include compound of structural formula XVIII, compound of structural formula XXI or compound of structural formula XXIV.

The examples of compound of structural formula XVI may include compound of structural formula XIX, compound of structural formula XXII or compound of structural formula XXV.
The eslicarbazepine compound of structural formula II may be converted in to eslicarbazepine acetate compound of structural formula I by the processes known in the art such as those described in U.S. Patent Nos. 5,753,646 or 7,119,197 and PCT Publication Nos. 2011/091131; 2011/117885; 2011/138795; 2012/121701 or 2012/156987, which are incorporated herein by reference only.
EXAMPLE:
In the following example, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.
Example 1: Preparation of eslicarbazepine compound of structural formula II. Step 1: (2S,3S)-2,3-dimethylsuccinic acid compound of structural formula XX (30 gm) was added acetic anhydride (41.9 gm) at 25-30°C and then sulphuric acid (96%, 2 ml) was added and heated to 70°C for 15 minutes and then cooled to 25-30°C. The resulting reaction mixture was

added dichloromethane (600 ml) followed by 10,ll-dihydro-10hydroxy-5H-dibenz/b,f/azepine-5-carboxamide compound of structural formula III (50 gm) and triethylamine (20 gm) were added and stirred for 1 hour at 25-30°C to get reaction mixture containing mixture of diastereoisomeric compound of structural formula XXI.
The reaction mixture containing mixture of diastereoisomeric compound of structural formula XXI was added water (400 ml) and stirred for 10 hours at 20-25°C. The precipitated solid was filtered, washed with water (4x50 ml) and dried up to constant weight to get diastereoisomeric compound of structural formula XXII. Yield: 75.2 gm Purity: 99% (By HPLC)
Step 2: A solution of diastereoisomeric compound of structural formula XXII (75 gm) in methanol (450 ml) was added aqueous sodium hydroxide solution (3N, 260 ml) and the reaction mixture was stirred for 40 minutes at 25-30°C. The resulting reaction mixture was filtered and washed with methanol (70 ml) to get filtrate. The resulting filtrate was concentrated under reduced pressure to get residue and water (700 ml) was added to the residue. After standing at 20°C for 10 hours, the crystalline product was filtered, washed with water (2x70 ml) and dried at 60-65 °C for 8 hours under reduced pressure to get eslicarbazepine compound of structural formula II. Yield: 49.8 gm Purity: 99% (By HPLC)

WE CLAIM:
1. A novel process for the preparation of eslicarbazepine compound of structural formula II comprising the steps of:
(a) reacting compound of structural formula III with compound of structural formula -XIV to give a mixture of diastereoisomeric compound of structural formula XV,
wherein, R' is ~Cj to C3 alkyl or substituted or unsubstituted phenyl or -O-C1-C3 alkyl (b) separating diastereoisomeric compound of structural formula XVI, and
(c) hydrolyzing the diastereoisomeric compound of structural formula XVI to get eslicarbazepine compound of structural formula II.

2. The process according to claim no. 1, wherein the reaction of compound of structural formula III with compound of structural formula XIV is carried out in presence of acetic anhydride and organic base in halogenated aliphatic hydrocarbon solvent at a temperature in the range of 10°C to 80°C for a period of 30 minutes to 12 hours to get a mixture of diastereoisomeric compound of structural formula XV.
3. The process according to claim no. 2, wherein the examples of organic base is selected from the group comprising of triethylamine, diisopropylamines, imidazole, pyridine, pyridazine, pyrimidine, lithium diisopropylamide, potassium bis(trimethylsilylamide), potassium tert-butoxide, 4-dimethylaminopyridine, l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) or l,5-Diazabicyclo[4.3.0]non-5-ene(DBN).
4. The process according to claim no. 2, wherein the examples of halogenated aliphatic hydrocarbon solvent is selected from the group comprising of dichloromethane, dichforoethane, chloroform, carbon tetrachloride or mixture(s) thereof.
5. The process according to claim no. 1, wherein the reaction mixture containing mixture of diastereoisomeric compound of structural formula XV is treated with water at 20°C to 30°C for period of 2 hour to 12 hours, during this period the precipitation of less soluble diastereoisomeric compound of structural formula XVI occurs and then the precipitated diastereoisomeric compound of structural formula XVI is separated by steps of filtration, washing with water and drying to get diastereoisomeric compound of structural formula XVI.
6. The process according to claim no. 1, wherein the hydrolysis of diastereoisomeric compound of structural formula XVI is carried out in presence of aqueous solution of inorganic base in an alcohol solvent at a temperature in the range of 20°C to 35°C for a period of 20 minutes to 6 hours to get eslicarbazepine compound of structural formula II.

7. The process according to claim no. 6, wherein, the examples of an alcohol solvent is selected from the group comprising of methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, t-butyl alcohol or mixture(s) thereof; The examples of inorganic base is selected from the group comprising of sodium hydroxide, potassium hydroxide or lithium hydroxide.
8. A novel compound of structural formula XV.
wherein, R' is -Ci to C3 alkyl or substituted or unsubstituted phenyl or -O-C1-C3 alkyl 9. A novel compound of structural formula XVI.
wherein, R' is -Ci to C3 alkyl or substituted or unsubstituted phenyl or -O-C1-C3 alkyl

10. A novel process for the preparation of eslicarbazepine acetate compound of structural formula I comprising the steps of:
(a) reacting compound of structural formula III with compound of structural formula XIV to give a mixture of diastereoisomeric compound of structural formula XV,
wherein, R' is -Ci to C3 alkyl or substituted or unsubstituted phenyl or -O-C1-C3 alkyl. (b) separating diastereoisomeric compound of structural formula XVI,
(c) hydrolyzing the diastereoisomeric compound of structural formula XVI to get eslicarbazepine compound of structural formula II, and

(d) converting eslicarbazepine compound of structural formula II in to eslicarbazepine acetate compound of structural formula I.