FIELD OF THE INVENTION
The present invention relates to a process for the preparation of Eslicarbazepine acetate.
BACKGROUND OF THE INVENTION
Eslicarbazepine acetate (Aptiom®), chemically known (S)-10-acetoxy-10,l l-dihydro-5H-dibenz[b,f]azepine-5-carboxamide, is a third generation dibenz[b,fjazepine antiepileptic drugs represented by the following formula I.
US 5,753,646 of Portela & Ca., S.A discloses Eslicarbazepine or pharmaceutically acceptable salts thereof. US !646 discloses the process for the preparation of Eslicarbazepine acetate generically as follows:
The key step of the synthesis of compounds Eslicarbazepine acetate (BIA 2-093) and R-licarbazepine acetate (BIA 2-059) involves the formation of chiral alcohol in turn is obtained by the resolution of racemic 10,1 l-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide ((±)-MHD) or by the resolution of 10,1 l-dihydro-5H-dibenz/b,f/azepine-IO-o! into its separate, optically pure stereoisomers, which are the key intermediates.
Benes, J. et ah, J. Med. Chem., 42, 2582-2587 (1999) and Volosov, A. et al., Epilepsia, 41(9), 1107-1111 (2000)) discloses the resolution of the racemic alcohol, (±)-MHD, wherein these

methods involve the formation of diastereoisomeric menthoxyacetate-ester derivatives of (±)-MHD.
US 7,119,197 B2 of Portela & Ca., S.A. discloses the preparation of (S)-(+)-10,11 -dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide by the resolution of racemic alcohol ((±)-MHD) with substituted tartaric acid anhydride.
WO 2011117885 Al discloses the resolution of racemic alcohol ((±)-MHD) with acetyl mandelic acid.
WO 2004/031155, US 9,206,135 B2 discloses the asymmetric reduction of Oxcarbazepine in the presence of hydride source and Ruthenium catalyst.
Tetrahedron Letters 54 (2013) 2841-2844 discloses the enantioselective approach towards the synthesis of eslicarbazepine acetate by using (R)-(+)-2-Methyl-CBS-oxazaborolidine in the asymmetric reduction of ketone and thereafter carboxamidation.
The present inventors have found that the use of the expensive resolving agents, (+) and (-)-menthoxyacetic acid requires activation in order to react with (±)-MHD which requires an

additional step and involves the use of coupling agent thereby enhancing the formation of by products and results in low yield.
Further the present inventors have found that the use of resolving agents like substituted tartaric acid anhydrides involves exothermic reactions in the reagent preparation and hence is industrially difficult to handle it in large scale.
The major disadvantage of the prior art processes is the removal of residual content of ruthenium metal which therefore makes unsuitable for use as active pharmaceutical ingredient as per the Regulatory guidance.
The stereo selective process for the reduction of keto group with (R)-(+)-2-Methyl-CBS-oxazaborolidine and Borane DMS to its (S)-hydroxy derivative is expensive. Storage and handling of (R)-(+)-2-Methyl-CBS-oxazaborolidine is found to be risk because it's unstable and is flammable in nature. (R)-(+)-2-Methyl-CBS-oxazaborolidine is available as molar solutions in toluene and other solvents.
The present inventors have found that the prior art processes involves expensive reagents and also involves tedious work up thereby not suitable for large scale production of Eslicarbazepine acetate.
The present inventors have provided a convenient, cheap and efficient method for making an intermediate used in the manufacturing of Eslicarbazepine acetate.
OBJECTIVE OF THE INVENTION
The objective of the present invention is to provide a process for the preparation of Eslicarbazepine acetate, which is commercially and industrially feasible.
Another objective of the present invention is to provide a process for the preparation of (R)-(+)-a,a-Diphenyl-2-pyrrolidine methanol from the filtrate of the reaction mass.

SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation of Eslicarbazepine acetate compound of formula I,
—^
which comprises:
a. reducing the compound of formula II,
wherein R is selected from Hydrogen, -CONH2
with hydride source and catalyst selected from (R)-(+)-a,a-Diphenyl-2-pyrrolidine
methanol, to obtain a compound of formula III;
wherein R is selected from Hydrogen, -CONH2 b. optionally converting the compound of formula III to eslicarbazepine or its
pharmaceuticaily acceptable salts thereof; wherein step a is carried out optionally in
the presence of borates.
In other embodiment the present invention relates to process for preparing (R)-(+)-a,a-Diphenyl-2-pyrrolidine methanol which comprises: a. reducing the compound of formula II,

wherein R is selected from Hydrogen, -CONH2
with hydride source and catalyst selected from (R)-(+)-2-Methyl-CBS-oxazaborolidine, (R)-(+)-a,a-Dipheny]-2-pyrrolidine methanol, I H,3H-Pyrrolo[ 1,2-c][ I ,3,2]oxazaborole, tetrahydro-l-methoxy-3,3-diphenyl-, (R)- to obtain a compound of formula III;
wherein R is selected from Hydrogen, -CONH2
b. isolating (R)-(+)-a,a-Diphenyl-2-pyrrolidine methanol from the filtrate of the reaction mass.
In another embodiment the present invention relates to the process for the preparation of Eslicarbazepine acetate by using (R)-(+)-a,a-Diphenyl-2-pyrrolidine methanol.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect the present invention relates to a process for the preparation of Eslicarbazepine acetate compound of formula I, which comprises: reducing the compound of formula II, with (R)-(+)-a,a-Diphenyl-2-pyrrolidine methanol in the presence of hydride source selected from borane dimethylsulfide and optionally in the presence of borates selected from trialkylborates, triarylborates to obtain a compound of formula III; optionally converting the compound of formula III to eslicarbazepine by acyiation and/or followed by carboxamidation to yield the compound of formula I.
In other aspect the present invention, relates' to a process for the preparation of (R)-(+)-a,a-Diphenyl-2-pyrrolidine methanol from the filtrate of the reaction mass of eslicarbazepine which comprises: reducing the compound of formula II with hydride source selected from

borane dimethylsulfide in the presence of a catalyst selected from (R)-(+)-2-Methyl-CBS-oxazaborolidine, (R)-(+)-a,a-Diphenyl-2-pyrrolidine methanol, lH,3H-Pyrrolo[l,2-c][l,3,2]oxazaborole tetrahydro-l-methoxy-3,3-diphenyl-, (R)- and optionally in the presence of borates selected from trialkylborates, triarylborates to obtain a compound of formula III; isolating (R)-(+)-a,a-Diphenyl-2-pyrrotidine methanol from the filtrate of the reaction mass wherein isolation is carried out by concentrating the reaction mass by distillation, fractional distillation.
In other aspect of the present invention, reduction of compound of formula II is carried out in the presence of solvents selected from toluene, methylene dichloride, ketones, esters, nitriles, ethers, dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide or mixtures thereof.
In other aspect of the present invention, borate is selected from the group comprising of trialkyl borates selected from trimethylborate, triethyl borate, tri n-propylborate, tri-isopropyl borate, tri-n-butylborate, tri-sec-butyl borate, tri-tert-butyl borate, triamyl borate; triaryl borates selected from borates of phenol, m-cresol and 8-naphthol.
In another aspect of the present invention, the equivalents of compound of formula II and (R)-(+)-a,a-Diphenyl-2-pyrrolidine methanol is in the range of I : 0.05 - 1.
In another aspect of the present invention, the equivalents of compound of formula II and borane dimethylsulfide is in the range of 1 : 0.9 - 2.
In another aspect of the present invention, the equivalents of compound of formula II and borates is in the range of I : 1-3.
In other aspect of the present invention, acylation of compound of formula III when R is Hydrogen can be done prior to carboxamidation or vice versa.
In other aspect of the present invention, acylation of compound of formula III is carried out by the reaction of acylating agents selected from acetic anhydride, acetyl chloride.

In other aspect of the present invention, carboxamidation is performed with Chlorosulfony! isocyanate.
In another aspect of the present invention, ketones are aliphatic ketones selected from the group comprising acetone, diethyl ketone, methyl ethyl ketone, methyl isobutyl ketone and methyl propyl ketone, cyclobutanone, cyclopentanone, cyclohexanone or mixtures thereof; esters are aliphatic esters or aromatic esters wherein aliphatic esters are selected from ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate or mixtures thereof; nitriles are selected from the group comprising of aliphatic nitriles such as C2-C8 nitrile; ethers are selected from the group comprising of symmetrical or asymmetrical ethers or cyclic ethers selected from diethyl ether, methyl tert-butyl ether, diisopropyl ether, dioxane, tetrahydrofuran, tetrahydropyran or mixtures thereof;
In the following section embodiments are described by way of examples to illustrate the process of invention. However, these do not limit the scope of the present invention. Variants of these examples would be evident to persons ordinarily skilled in the art.
EXAMPLES
Reference example
Preparation of Esclicarbazepine acetate
Preparation of (10S)-10-[(2R)-(acetyIoxy)(phenyl)ethanoate]-10,ll- dihydro-5H-
dibenzo[b,f] azepine -5-carboxamide
Dichloromethane 2160 ml, 164.96 g (R)-(-)-acetyl mandelic acid, 180 g racemic licarbazepine,
86.48 g 4-dimethylamino pyrimidine and 175.28g dicyclohexylcarbodiimide were mixed in a
round bottom flask and the resultant reaction mixture was refluxed for one hour. After
completion of reaction the reaction mixture was filtered and the filtrate was washed with
aqueous acetic acid and aqueous sodium bicarbonate solution. The organic layer was collected
and it was concentrated. To the residue thus obtained 1620 ml of methyl isobutylketone was
added. The resultant reaction mixture was heated at 60 - 65 °C for one hour and filtered at the

same temperature. The solid thus obtained was again purified by. using methyl isobutylketone at 60 - 65 °C to get title compound with 97.6% of optical purity.
Preparation of (10S)-10-hydroxy-10,ll-dihydro-5H-dibenzo [b,f)azepine-5-carboxamide (Eslicarbazepine)
250 ml water, 50 g compound obtained form example I and 50 g sodium hydroxide were mixed in a round bottom flask. The resultant reaction mixture was heated at 80 -85 °C for I hour. After completion of reaction the reaction mixture was cooled to ambient temperature and the pH of the reaction mixture was adjusted to acidic to get 26 g of title compound.
Preparation of (10S)-5-carbamoyl-10,ll-dihydro-5H-dibenzo[b,f]azepin-10yl-acetate (Esclicarbazepine acetate)
240 ml dichloromethane, 5.29 g, acetic acid, 20 g esclicarbazepine, 9.6 g 4- dimethylamino pyridine and 19.47 g dicyclohexylcarbodiimide were charged in a round bottom flask. The reaction mixture was refluxed for 1 hour, after completion of reaction the reaction mixture was filtered, and the filtrate was washed with aqueous acetic acid and aqueous sodium bicarbonate solution. The organic layer was separated and it was concentrated, to the residue thus obtained isopropyl alcohol (140 ml) was added. The resultant mixture was heated to reflux for 30 minutes followed by cooling to 25 - 30 °C. The product thus separated and filtered to obtain 17g of title compound with 99.6% optical purity.
Preparation of Eslicarbazepine acetate Example 1.
Charged (R)-(+)-a,ct-Diphenyl-2-pyrrolidine methanol (24 gm), Trimethylborate (55 gm), toluene and heated the reaction mixture to 40 - 45°C for 1.5 hours to 2 hours. The reaction mixture was cooled to 0 - 5°C and added borane dimethylsulfide (47.2 gm) slowly at below 5°C. Added 5,1 l-dihydro-10H-dibenzo[b,f]azepin-10-one (100 gm) dissolved in methylene dichloride slowly for 1 hour to 2 hours at 0 - 5°C. The reaction mass was stirred for 3 hours -4 hours and then slowly added methanol. Charged water, separated the layers and extracted the aqueous layer with methylene dichloride. Distilled off the combined organic layers and the residue thus obtained was added methanol. Added water, filtered the solid and washed with

water and toluene to yield 86 gm of (S)-10, 1 l-dihydro-5H-dibenzo[b,f]azepin-10-ol (HPLC Purity: > 99%, Chiral HPLC purity: > 98 %).
Recovery process in the presence of tri alkyl borate:
Charged Trimethyl borate to the toluene mi's of the reaction mass obtained from example 1 and heated the reaction mixture to 40 - 45°C for 1.5 hours to 2 hours. The reaction mixture was cooled to 0 - 5°C and added Borane dimethylsulfide slowly over a period of I. 5 hours to 2 hours at below 5°C. Added 5,1 l-dihydro-10H-dibenzo[b,f]azepin-10-one (80 gm) dissolved in methylene dichloride slowly for 1 hour to 2 hours at 0 - 5°C. The reaction mass was stirred for 3 hours 30 minutes to 4 hours at 0-5°C, added slowly methanol. Charged water, separated the layers and extracted aqueous layer with methylene dichloride. Distilled off the combined organic layers and the residue thus obtained was added methanol. Added water, filtered the solid, washed with water and dried to yield 69 gm (83%) (HPLC Purity: > 99%, Chiral HPLC purity: > 98 %.).
Recovery process in absence of tri alkyl borate:
Charged Borane dimethylsulfide to the toluene mi's of the reaction mass obtained from example 1 at 0-5°C and stirred for 1.5 hours to 2 hours. Added 5,1l-dihydro-IOH-dibenzo[b,f]azepin-10-one (80 gm) dissolved in methylene dichloride slowly for 1 hour to 2 hours at 0-5°C. The reaction mass was stirred for 3 hours 30 minutes to 4 hours at 0-5°C, added slowly methanol. Charge water, separated the layers and extracted aqueous layer with methylene dichloride. Distilled off the combined organic layers and the residue thus obtained was added methanol. Added water, filtered the solid and washed with water and dried the material to yield 67 gm (83%) (HPLC Purity: > 99%, Chiral HPLC purity: > 98 %.).
Preparation of Eslicarbazepine acetate:
Charged (S)-l0,ll-dihydro-5H-dibenzo[b,f]azepin-l0-ol (130 gm) and methylene dichloride and heated the reaction mass temperature to 25 - 35°. Added Triethyl amine (125 gm) into the reaction mass and stirred the reaction mass for 10 minutes at 25 - 35°. Acetic anhydride was added to the reaction mixture, stirred for 5 - 10 minutes. The reaction mixture was heated to reflux and stirred for 10 hours. Cooled the reaction mass temperature to 5.0 ± 5.0°C and

charged methylene dichloride. Added acetic acid into the reaction mass at 5.0 ± 5.0°C. Slowly added Chlorosulfonyl isocyanate (100 ml) into the reaction mass at 5.0 ± 5.0°C and stirred the reaction mass for I hour at 10 ± 5 °C. Added water to the reaction mass, stirred and separated the layers. Extracted the aqueous layer with methylene dichloride and distilled off the solvent from combined organic layers. Added water and the pH of the reaction mass was adjusted to 7.5. Charged hexane, stirred and filtered. Added isopropyl alcohol to the wet material thus obtained and distilled off the solvent completely under vacuum. Cooled the reaction mass and added ethyl acetate at below 35°C. Charged isopropyl alcohol and heated reaction mass temperature to 70 ± 5°C. Given carbon treatment, filtered through hyflo and charged isopropyl alcohol, cooled the reaction mass temperature to 40 ± 5 °C. Charged Eslicarbazepine acetate at 40 ± 5 °C and cooled the reaction mass temperature to 0 - 5°C and stirred the reaction mass for 3 hours 30 minutes ± 30 minutes. Charged isopropyl alcohol, stirred, filtered and dried under vacuum to yield 90 gm of title compound.
Example 2.
Preparation of Eslicarbazepine acetate:
Charged (S)-IO,ll-dihydro-5H-dibenzo[b,f]azepin-IO-ol (300 gm), methylene dichloride and stirred for 10-15 minutes. Added Triethyl amine (399 ml), acetic anhydride (400 ml) into the reaction mass and stirred the reaction mass for 10 minutes at 25 - 35°. The reaction mixture was heated to reflux and stirred for 6 hours to 8 hours. Added water, stirred and separated the organic layer. Organic layer was washed with water and distilled off the solvent. Added hexane and stirred for 1 - 2 hours. The solid thus separated was filtered, washed with hexane and dried to yield 288 gm of (S)-10,1 l-dihydru-5H-dibenzo[b,fJazepinc-10-yl-acetate.
Charged (S)-10,l l-dihydro-5H-dibenzo[b,fJazepine-10-y[-acetate (300 gm), methylene dichloride and stirred for 10 minutes. Added chlorosulfonyl isocyanate (120 ml) at 10 -15 °C, and stirred for 10-15 minutes. Added water, stirred for 3 - 4 hours and separated the organic layer. Organic layer was washed with water and the distilled off the solvent. To the residue was added ethylacetate, stirred for I -2 hours. The solid thus obtained was filtered, washed with ethylacetate and dried to yield 270 gm of title compound.

Example 3.
Preparation of (S)-(-)-10,ll-dihydro-5H-dibenzo[b,f]azepin-10-ol
Step (a): Charged Dichloromethane and borane dimethyl sulfide (58.5 ml) stirred and cooled to 0-5'C. (R)-(+)-2-Methyl-CBS-oxazaborolidine (94 ml) (1M in toluene) was added at below 0°C and stirred for 10 min. A solution of SH-dibenzo^fjazepin-IOtlH^one (100 gm) in dichloromethane was added to the reaction mixture and stirred for 3 hours to 4 hours. After completion of the reaction, methanol and water were added to the reaction mixture at below 10°C and stirred. Separated the layers and aqueous layer was extracted with methylene dichloride. Total organic layer was distilled off and the residue thus obtained was added methanol and water, stirred and filtered. The solid was taken in toluene, stirred and filtered and dried at below 55°C to yield (S) (-)-IO, 1 l-dihydro-5H-dibenzo[b,f]azepin-10-ol (82.5gm).
Step (b): Extracted the Methanol + Water Mi's obtained during isolation with toluene obtained in step (a). Combined toluene extracts obtained in step (a) and extracted toluene ML's of methanol water were distilled off completely. The residue thus obtained was cooled to 25-30°C and added toluene. Stirred for 10 minutes to 15 minutes and charged trimethyl borate (36 gm) to the organic layer under nitrogen atmosphere. Heated to 40-45°C and maintained for 1 hour 30 minutes to 2 hours.Added Borane DMS(30.6 gm) slowly over a period of 1 hour 30 minutes to 2 hours at below 5°C. Added 5H-dibenzo[b,f]azepin-10(lH)-one (65 gm) solution dissolved in dichloromethane slowly for 1 hour to 2 hours at below 0-5°C and stirred for 3 hours 30 minutes to 4 hours at 0-5°C. After completion of the reaction, methanol and water were added to the reaction mixture at below I0°C and stirred. Separated the layers and aqueous layer extracted with methylene dichloride. Total organic layer was distilled off and the residue thus obtained was added methanol and water, stirred and filtered. The solid was taken in toluene, stirred and filtered and dried at below 55°C to yield (S) (-)-10,l l-dihydro-5H-dibenzo[b,f]azepin-10-ol (57.5gm).
We claim:
1. The process for the preparation of Eslicarbazepine acetate compound of formula I,
which comprises:
a. reducing the compound of formula II,
wherein R is selected from Hydrogen, -CONH2
with hydride source and catalyst selected from (R)-(+)-a,a-Diphenyl-2-pyrrolidine
methanol, to obtain a compound of formula III;
wherein R is selected from Hydrogen, -CONH2 b. optionally converting the compound of formula IN to eslicarbazepine or its
pharmaceutically acceptable salts thereof; wherein step a is carried out optionally in
the presence of borates.
2. The process for the preparation of Eslicarbazepine acetate according to claim I, wherein hydride source is selected from borane dimethylsulfide.

3. The process for the preparation of Eslicarbazepine acetate according to claim 1, wherein borates are selected from the group comprising of trialkylborates, triarylborates.
4. The process for the preparation of Eslicarbazepine acetate according to claim I, wherein the equivalents of compound of formula II and (R)-(+)-a,a-Diphenyl-2-pyrrolidine methanol is in the range of 1 : 0.05 - I.
5. The process for the preparation of Eslicarbazepine acetate according to claim 1, wherein the equivalents of compound of formula II and borane dimethylsulfide is in the range of I : 0.9-2.
6. The process for the preparation of Eslicarbazepine acetate according to according to claim 1, wherein the equivalents of compound of formula II and borates is in the range of
1:1-3.
7. The process for the preparation of Eslicarbazepine acetate according to claim 1, wherein
reduction of compound of formula II is carried out in the presence of solvents selected
from toluene, methylene dichloride, ketones, esters, nitriles, ethers, dimethyl sulfoxide,
dimethyl formamide, dimethyl acetamide or mixtures thereof.
8. The process for preparing (R)-(+)-a,a-Diphenyl-2-pyrrolidine methanol which comprises: a. reducing the compound of formula II,
wherein R is selected from Hydrogen, -CONH2
with hydride source and catalyst selected from (RH+)-2-Methyl-CBS-oxazaborolidine, (R)-(+)-a,ct-Diphenyl-2-pyrrolidine methanol, 1 H,3H-Pyrrolo[ 1,2-c][ 1,3,2]oxazaborole, tetrahydro-l-methoxy-3,3-diphenyl-, (R)- to obtain a compound of formula III;

wherein R is selected from Hydrogen, -CONH2
b. isolating (R)-(+)-a,a-Diphenyl-2-pyrrolidine methanol from the filtrate of the reaction mass.
9. The process for the preparation of Eslicarbazepine acetate by using (R)-(+)-ot,a-Diphenyl-2-pyrrolidine methanol.