FORM-2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION (See Section 10 and Rule 13)
PROCESS FOR THE PREPARATION OF ESLICARBAZEPINE ACETATE
M/S AMOLI ORGANICS PVT. LTD,
407 Dalamal House, J.B.Road,
Nariman Point, Mumbai-400021,
INDIA
The following specification particularly describes the invention and the manner in
which it is to be performed

PROCESS FOR THE PREPARATION OF ESLICARBAZEPINE ACETATE
OBJECT OF THE INVENTION
The main object of the invention is to provide an improved process for thepreparation of eslicarbazepine of formula I from racemic (±) licarbazepine of formula III by using (R)-(-)-acetylmandeloyl chloride, and further for the preparation of eslicarbazepine acetate of formula V from eslicarbazepine of formula I.
BACKGROUND OF THE INVENTION
Racemic(±)-10,11 -dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide of (formula III) i.e. racemic licarbazepine, is a known substance which has been shown to possess anticonvulsant activity (Schutz, H. et al., Xenobiotica, 16, 7691778 (1986)), and was found to be the principal metabolite of the established anti-epileptic drug oxcarbazepine of formula IV. In addition to its anti-convulsant activity, racemic alcohol of formula III can be readily synthesized in high yield by reduction of oxcarbazepine of formula IV, and thus serves as a useful intermediate for the preparation of optically pure (S)-(-)-10-acetoxy-10,11 -dihydro-5H-dibenz[b,f]azepine-5-carboxamide of formula V and (R)-(+)-l0-acetoxy-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamideformula VI, i.e. eslicarbazepine acetate and rlicarbazepine acetate respectively. The (S)-(-)-enantiomer of formula V in particular has been shown to display a very favorable anti-convulsant profile.



A key step in the synthesis of either of the optically pure individual acetate esters of eslicarbazepine (formula V) or rlicarbazepine or (formula VI) involves the resolution of racemic licarbazepine (formula III) into its individual, optically pure stereoisomers, eslicarbazepine (formula I) or rlicarbazepine (formula II) which are the principal intermediates for synthesis of eslicarbazepine acetate (formula V) or rlicarbazepine acetate (formula VI)
Benes, J. et al., J. Med. Chem., 42; 2582-2587 (1999) and Volosov A. et. al., Epilepsia, 41 (9), 1107-1111 (2000) discloses resolution of racemic (±)-10,ll-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxainide into its separate optically pure stereoisomers i.e. (S)-(+)-10-hydroxy-10, 11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide, and (R)-(-)-10-hydroxy-10,11-dihydro-5H-dibenz[b,f)azepine-5-carboxamide. These methods involve the formation of diastereomeric separation of methoxyacetoacetate ester derivatives by fractional crystallization and subsequent hydrolysis to afford the individually pure stereo isomers. However, this method was utilized for the preparation of only small quantities of each stereoisomer and is not suitable for industrial production. The optically pure resolving agents (+) and (-)-methoxyacetic acid are expensive and are not readily available in commercially required quantity. A further limitation of above method is relatively low yield obtained of the optically pure rnethoxyacetate ester which is isolated after crystallization; it yields usually only marginally 20%.

US7119197 B2 discloses process to prepare optically pure (S)-(+)-10,l 1-dihydro-10-hydroxy-5H-diben.z[b,f]azepine-5-carboxamide and (R)-(-)-10,11-dihydro-10-hydroxy-5H-dibenz[b,flazepine-5-carboxamide by resolution of racemic (±)-10,l l-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxainide using diacetyl tartaric anhydride. Diacetyl tartaric anhydride is not readily available in commercial quantity and is also unstable, thus it needs to be prepared. In addition even after a complicated purification process of eslicarbazepine, ee value is still not high enough.
WO2011091131 discloses resolution of racemic (±)-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxainide by using suitable chiral reagents including but not limited to (+) mandelic acid, (+) naproxen, (-) camphor sulfonic acid, (+) ibuprofen, lactic acid.
IN 803/MUM/2010 demonstrates process to prepare eslicarbazepine or rlicarbazepine using optically active acetyl mandelic acid comprising the steps of reacting licarbazepine with (R)-(-)-acetyl mandelic acid or (S)-(+)-acetyl mandelic acid in the presence of coupling agent for example N,N'-Dicyclohexylcarbodiimide to give mixture of esters[(S,R)-acetyl mandelate and (R,R)-acetyl mandelate or (R,S)-acetyl mandelate and (S,S)-acetyl mandelate which are separated into individual esters by treating with solvent and then hydrolyzed using a base to gives licarbazepine or rlicarbazepine. The coupling agent for example N,N'-dicyclohexylcarbodiimide is expensive; additionally it is difficult to manipulate due to its low melting point and is indicated as a potent skin irritant, thus posing health risks for workers. Often there are encountered difficulties in removing completely the dicyclohexylurea by-product from the wanted product
The processes for the preparation of eslicarbazepine or its salts described in the prior art discussed above suffer from various disadvantages, such as tedious and cumbersome work-up procedures, use of not so environment friendly solvents,

reactions under pressure and high temperature, longer reaction times, column chromatographic purifications and thus resulting in low overall yields of the product.
The process of present application is simple, cost effective and industrially viable which uses readily available reagents for resolution of licarbazepine and for acetylation of individual isomer.
SUMMARY OF THE INVENTION
In an aspect, the present application provides preparation of eslicarbazepine of formula I from racemic (±) licarbazepibne of formula III by using (R)-(-)-acetylmandeloyl chloride, which includes one or more of the following steps
a) reacting D-(-)-mandelic acid with an acylating agent to obtain (R)-(-)-acetyl mandelic acid,
b) converting (R)-(-)-acetyl mandelic acid to (R)-(-)-acetylmandeloyl chloride,
c) reacting compound of formula III with (R)-(-)-acetylmandeloyl chloride,
d) separating of the desired ester (S)-acetyl mandelate of formula VII,
e) hydrolyzing of desired ester of (S)-acetyl mandelate of formula VII to provide optically pure eslicarbazepine and
f) converting of eslicarbazepine of formula (I) to eslicarbazepine acetate of
formula V.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved process for the preparation of eslicarbazepine of formula I by reacting racemic (±) licarbazepine of formula III with (R)-(-)-acetylmandeloyl chloride to form mixture of esters and then separating the desired ester and hydrolyzing it.
In an aspect, the present invention provides process for the preparation of eslicarbazepine acetate of formula V from eslicarbazepine of formula I

comprising the steps of
a) reacting D-(-)-mandelic acid with an acylating agent to obtain (R)-(-)-acetyl mandelic acid,
b)converting (R)-(-)-acetyl mandelic acid to (R)-(-)-acetylmandeloyl chloride,
c) reacting compound of formula III with (R)-(-)-acetylmandeloyl chloride,
d) separating of the desired ester (S)-acetyl mandelate of formula VII,
e) hydrolyzing of desired ester of (S)-acetyl mandelate of formula VII to provide optically pure eslicarbazepine and
f) converting of eslicarbazepine of formula (I) to eslicarbazepine acetate of formula V.
In another aspect of the invention, steps a) to d) are carried out in-situ; thereby avoiding a lengthy separation process and purification of the intermediate chemical compounds and thus saving time and resources while increasing chemical yield.
In an embodiment of the invention, (R)-(-)-acetyl mandelic acid may be synthesized from D-(-)-mandelic acid by using acetylating agent selected from acetyl chloride, acetic anhydride or acetic acid; preferably acetyl chloride, and by using organic solvents selected from methylene dichloride, toluene, xylene, n-hexane, n-heptane or cyclohexane; preferably methylene dichloride. In one aspect of the present invention, reaction is carried out at a temperature of about 25 to 50° C; preferably 35 to 45°C.
In another embodiment of the invention, (R)-(-)-acetylmandeloyl chloride can be prepared from (R)-(-)-acetyl mandelic acid by using chlorinating agent selected from thionyl chloride, oxalyl chloride; preferably thionyl chloride, and by using catalyst dimethylformamide. Organic solvents that can be used may be selected from methylene dichloride, toluene, xylene, n-hexane, n-heptane or cyclohexane;

preferably methylene dichloride. In another aspect of the present invention, reaction is carried out at a temperature of about 25 to 50° C; preferably 35 to 45°C.
In further embodiment of the invention, acetyl mandelate esters of formula VII and VIII can be synthesized by reaction of racemic licarbazepine of formula III with (R)-(-)-acetylmandeloyl chloride by using base selected from pyridine, tertiary amines like N,N-diisopropylethylamine, triethylamine, or the like and by using 4-dimethylaminopyridine as catalyst. Best results were obtained by using combination of N,N-diisopropylethylamine and 4-dimethylaminopyridine. The reaction was conducted in presence of solvent selected from chlorinated solvents such as methylene dichloride, dichloroethane, chloroform; ether such as tetrahydrofuran, diethyl ether or diisopropyl ether; preferably methylene dichloride. In one aspect of the present invention, reaction is carried out at a temperature of about 0-5°C.
In an embodiment of the invention, after completion of reaction, impurities and catalyst can be removed by adding water and strong acid such as hydrochloric acid and separating the lower organic layer. In further embodiment of the invention, the desired ester can be very easily isolated by evaporation of the reaction solvent from lower organic layer, and replacement with a suitable crystallization solvent such as for example, lower aliphatic alcohols such as methanol, ethanol or isopropanol, with or without addition of water, esters including ethyl acetate and isopropyl acetate or ketones including acetone and methyl ethyl ketone. The desired ester is then recovered by filtration and, if preferred, can be further purified by slurring or recrystallisation from suitable solvents, such as, for example, lower aliphatic alcohols such as methanol, ethanol or isopropanol, with or without addition of water, esters including ethyl acetate or isopropyl acetate or ketones including acetone and methyl ethyl ketone.
In another embodiment of the invention, eslicarbazepine is prepared by hydrolysis of desired ester of (S)-acetyl mandelate of formula VII by using base

selected from triethylamine, pyridine, alkali hydroxides such as sodium hydroxide or potassium hydroxide, alkali carbonates such as sodium carbonate or potassium carbonate and the like; preferably sodium hydroxide and by using solvents such as water; alcohol solvents, such as, for example, methanol, ethanol, propanol, 1-propanol, 2-propanol, butanol, pentanol, ethylene glycol, glycerol, or the like; ketone solvents, such as, for example, acetone, butanone, pentanone, methyl isobutyl ketone, or the like; ester solvents, such as, for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like. According to the present invention, hydrolysis is carried out at a temperature of about 20 to 50° C, preferably 25 to 40°C.
In further embodiment of the invention, acetylation of eslicarbazepine of formula I to form eslicarbazepine acetate of formula Vmay be carried out by using acetylating agents like acetyl chloride, acetic anhydride, acetic acid etc in presence of base selected from pyridine, tertiary amines like N,N-diisopropylethylamine, triethylamine, or the like and by using 4-dimethylaminopyridine as catalyst. Organic solvents that can be used may be selected from methylene dichloride, toluene, xylene, n-hexane, n-heptane or cyclohexane; preferably, methylene dichloride. After completion of reaction, impurities and catalyst can be removed by adding water, separating the lower organic layer and treatment of the lower organic water with strong acid such as hydrochloric acid and water. In another embodiment of the invention, purification is then performed by evaporation of the reaction solvent from lower organic layer, and replacement with a suitable crystallization solvent such as for example, lower aliphatic alcohols such as methanol, ethanol or isopropanol and optionally adding activated carbon. According to further embodiment of the invention, eslicarbazepine acetate obtained by this method has optical purity in the range 92% to 98% or 99%.
The process of the present invention is summarized in the following scheme:


The present invention can be illustrated by the following examples, which do not limit the scope of invention.

EXAMPLES
Example 1: Synthesis of (R)-(-)-acetyI mandelic acid
350 ml methylene dichloride and 75 gm D (-) mandelic acid were charged in clean and dry four necked round bottom flask at 25-35°C. The reaction mixture was stirred for 10-15 minutes at 25-35°C. 46.5 gm Acetyl chloride was slowly added at 25-35°C and temperature was slowly raised up to 38-42°C. The reaction mixture was maintained for 4 hours at 38-42°C. After completion of the reaction, methylene dichloride was distilled out completely at 38-42°C atmospherically. Vacuum was applied and oily mass obtained was then degassed for 1-2 hours for complete removal of acetyl chloride traces at below 40°C.
Example 2: Synthesis of (R)-(-)-acetyl mandeloyl chloride from (R)-(-)-acetyl mandelic acid
The reaction mass obtained in example 1 was cooled to 25-35°C. 450 ml methylene dichloride was charged at 25-35°C and the reaction mixture was stirred for 10-15 min at 25-35°C. 0.75 ml dimethylformamide and 82 gm thionyl chloride was then charged at 25-35°Cand temperature was slowly raised up to 38-42°C. The reaction mixture was maintained for 2 hours at 38-42°C.After completion of reaction methylene dichloride was distilled out completely at 38-42°C atmospherically. Reaction mass was then cooled to 25-35°C: Titled compound is obtained in-situ as oil.
Example 3: Synthesis of (S)-acetyl mandelate salt of licarbazepine
1200 ml methylene dichloride and 100 gm licarbazepine were charged in clean and dry four necked round bottom flask at 25-35°C.The reaction mixture was stirred for 10-15 minutes at 25-35°C. 5 gm 4-dimethylaminopyridine and 102 gm N,N-diisopropylethylamine were then charged at 25-35°Cand reaction mixture was stirred for 10-15 minutes at 25-35°C. Reaction mixture was chilled to 0-5°C and acid chloride oil obtained in example 1 was slowly added into the reaction mixture at 0-

5°C. Reaction mixture was then maintained for 4 hrs at 0-5°C. After completion of reaction, 350 ml water was added at 0-10°C. 50 ml HC1 was slowly added and reaction mixture was stirred for 25-30 min at 25-35°C.Reaction mixture was allowed to settle for 15-30 minutes at 25-35°C. The lower organic layer was then separated in to the conical flasks. Organic layer and hydrochloric acid solution was then charged in round bottom flask at 25-35°C. The reaction mixture was stirred for 25-30 minutes at 25-35°C.Reaction mixture was allowed to settle for 15-30 min at 25-35°C. The lower organic layer was then separated in to the conical flasks. Dichloromethane was distilled out completely at 35-42°C and 100 ml ethyl acetate was then added at below 40°C. Reaction mixture was stirred for 10-15 min at below 40°C. Residual methylene dichloride and ethyl acetate was then distilled out under vacuum up to thick slurry reaction mass at below 50°C. 1000 ml ethyl acetate was charged at below 40°C. The reaction mixture was heated at 75-80°C and stirred for 25-30 minutes. Reaction mixture was cooled to 30-35°C. The reaction mixture was stirred at 30-35°C for 1 hour.The reaction mass was filtered and washed with 50 ml ethyl acetate. The solid thus obtained was again purified using ethyl acetate by heating and stirring the reaction mixture containing solid and 1000 ml ethyl acetate at 75-80°C for 25-30 min, cooling to 30-35°C and stirring the reaction mixture at 30-35°C for 1 hr. The titled compound was then filtered, washed with 50 ml ethyl acetate and suck dried completely to get the titled compound in 85% yield.
Example 4: Synthesis of Eslicarbazepine
300 ml methanol and 100 gm (S)-acetyl mandelate of licarbazepine were charged in clean and dry four necked round bottom flask at 25-35°C. Reaction mixture was stirred for 10-15 minutes at 25-35°C. Sodium hydroxide solution (28%) was added drop wise at 25-35°C.After addition, the reaction mixture was maintained for 1 hr at 25-35°C.After completion of reaction, methanol was distilled out under vacuum at below 60° C. The reaction mixture was cooled to 25-35°C. 800 ml of water was then charged in to the residue at 25-35°Cand mass was stirred for 3-4 hours at 25-

35°C.The reaction mixture was filtered though buckner funnel and solid obtained was washed with 200 ml water. Wet product was unloaded and dried at 60-65°C for 8 hours to get titled compound in 80% yield.
Example 5: Synthesis of Eslicarbazepine acetate
500 methylene dichloride and 100 gm eslicarbazepine were charged in clean and dry four necked round bottom flask at 25-35°C. Reaction mixture was stirred for 10-15 minutes at 25-35°C. Triethylamine 51.8 and 4-dimethylaminopyridine 0.5 gm were then added in to the round bottom flask at 25-35°C. Reaction mixture was cooled to 20-25°C. The reaction mixture was stirred for 10-15 min at 20-25°C. 44.2 gm Acetic anhydride was then added in to the reaction mixture at 20-25°C.The reaction mixture was maintained for 2 hours at 20-25°C.Reaction mixture was cooled to below 10°C 500 ml of water was charged in to the reaction mass at below 10°C.The temperature of the reaction mass was raised up to 25-35°C.The reaction mixture was stirred for 25-30 minutes at 25-35°C. Reaction mixture was allowed to settle for 15-20 minutes at 25-35°C.The lower organic layer was separated in to the conical flask.Organic layer and 200 ml of HC1 solution were charged at 25-35°C.The reaction mixture was stirred for 25-30 min at 25-35°C. Reaction mixture was again allowed to settle for 15-20 minutes at 25-35°C and the lower organic layer was separated. After treatment of organic layer with 200 ml of water, lower organic layer was separated and organic layer was charged at 25-35°C. Methylene dichloride was distilled out completely at 38-42 C atmospherically first and then by applying vacuum. The mass was degassed for 1-2 hrs at below 40°C. 350 ml of methanol was charged in to the round bottom flask at 25-35°C.The reaction mixture was heatedup to 55-60°C and stirred at 55-60 C. 2 gm activated carbon was then charged into the reaction mixture and reaction mixture was stirred for 30-40 min at 55-60°C. The reaction mass was filtered while hot trough hyflo bed at 55-60°C & washed with 50 ml hot methanol. The clear filtrate was collected into the round bottom flask. The filtrate was then heated up to 60-65°C and maintained for 10-15 min at 60-65°C. The reaction mass

was then cooled up to 25-35°C.The reaction mass was cooled further to 0-5°C and maintained for 1 hour. The reaction mass was filtered and washed with 50 ml chilled methanol. The obtained solid was purified further with methanol and dried at 60-65°C for 10 hours to get the titled compound with 70 % yield.

We Claim:
1. A process for the preparation of eslicarbazepine acetate comprising the steps of
a) reacting D-(-)-mandelic acid with an acylating agent to obtain (R)-(-)-acetyl mandelic acid,
b) converting (R)-(-)-acetyI mandelic acid to (R)-(-)-acetylmandeloyl chloride,
c) reacting compound of formula III with (R)-(-)-acetylmandeloyl chloride,
d) separating of the desired ester (S)-acetyl mandelate of formula VII,
e) hydrolyzing of desired ester of (S)-acetyl mandelate of formula VII to provide optically pure eslicarbazepine and
f) converting of eslicarbazepine of formula (I) to eslicarbazepine acetate of
formula V.
2. The process as claimed in claim 1, wherein steps 1) to 4) are carried out in-situ
3. A process for the preparation of (S)-acetyl mandelate of formula VII, comprising the steps of

a) reacting D-(-)-mandelic acid with an acylating agent to obtain (R)-(-)-acetyl mandelic acid,
b) converting (R)-(-)-acetyl mandelic acid to (R)-(-)-acetylmandeloyl chloride,
c) reacting compound of formula III with (R)-(-)-acetylmandeloyl chloride and
d) separating of the desired ester (S)-acetyl mandelate of formula VII.

4. The process as claimed in claim 3, wherein all steps are carried out in-situ
5. The process as claimed in claim 1 and 3, wherein in step 1) acetylation is carried out using acetylating agent such as acetyl chloride, acetic anhydride or acetic acid and solvents may be selected from methylene dichloride, toluene, xylene, n-hexane, n-heptane or cyclohexane; preferably, methylene dichloride.
6. The process as claimed in claim 1 and 3, wherein in step 2) chlorinating agent used may be selected from thionyl chloride, oxalyl chloride and solvents may be selected from methylene dichloride, toluene, xylene, n-hexane, n-heptane or cyclohexane.

7. The process as claimed in claim 1 and 3, wherein in step 3) base used may be selected from pyridine, tertiary amines like N,N-diisopropylethylamine, triethylamine and solvent may be selected from chlorinated solvents selected from methylene dichloride, dichloroethane, chloroform, ether such as tetrahydrofuran, diethyl ether or diisopropyl ether.
8. The process as claimed in claim 1 and 3, wherein in step 4) strong acids comprises hydrochloric acid or sulphuric acid which may be optionally diluted.
9. The process as claimed in claim 1, wherein in step 5) base used may be selected from triethylamine, pyridine, alkali hydroxides such as sodium hydroxide or potassium hydroxide, alkali carbonates such as sodium carbonate or potassium carbonate.
10. The process as claimed in claim 1, wherein in step 6) acetylating agents used may
be selected from acetyl chloride, acetic anhydride, acetic acid.