The present invention provides novel compounds of Formula III, isomers or pharmaceutically acceptable salts thereof, and use of said compounds as intermediates in the preparation of cenobamate of Formula I or pharmaceutically acceptable salt thereof.

The present invention further provides substantially pure cenobamate and its process of preparation wherein said process is cost effective, simple and economically feasible.

BACKGROUND OF THE INVENTION
Cenobamate having a chemical name; (R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethyl carbamate is represented with structure as follows:
.

Cenobamate is being investigated for the potential treatment of partial-onset seizures (also known as “focal seizures”) in adult patients.

Cenobamate is disclosed in US 7,598,279 B2 which further discloses the process for preparation of racemic as well as R and S isomer of cenobamate as mentioned in scheme 1 and 2 below:

Scheme 1 Scheme 2

US 8,501,436 B2 discloses process for the preparation of cenobamate by enantioselective reduction of keto-intermediate using oxidoreductase in presence of phosphate buffer saline containing 5% glycerol. US’436, further discloses process for the preparation of cenobamate by enantioselective ketoreduction using chiral ruthenium catalyst followed by carbamate formation using sodium cyanate as mentioned in the scheme below:
Scheme 3:

US 8,404,461 B2 (US’ 461) discloses the enzymatic process for the preparation of cenobamate and its intermediates by enantioselective enzyme reduction of an arylketone as mentioned in the scheme below:
Scheme 4:

As it is apparent from above disclosure(s), that there are certain processes known from prior published references, however these processes suffer from drawbacks such as use of chiral catalyst and expensive biocatalyst for chiral reduction of keto-intermediate. Moreover, these known processes suffer from another drawback of forming a positional isomer (result of reaction with IN tetrazole instead of 2N tetrazole) during coupling of bromoacetophenone with tetrazole which act as an undesired isomer and results into drastic decrease in overall yields.

Hence, the present invention is focussed towards the development of a novel process for the preparation of cenobamate and pharmaceutically acceptable salts thereof, wherein said process is simple, cost effective and results into preparation of pure cenobamate with high yields.

OBJECT OF THE INVENTION
The main object of the present invention is to provide a novel process for the preparation of cenobamate or pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a novel compounds used as intermediates for the preparation of cenobamate or pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a process for the preparation of stable cenobamate or pharmaceutically acceptable salt thereof, wherein said cenobamate or its salt is stable for atleast six months at 40oC and 75% RH and can be formulated easily for administering to patients.

Another object of the present invention is to provide a pharmaceutical composition comprising cenobamate or its pharmaceutically acceptable salts, along with pharmaceutically acceptable excipients.

SUMMARY OF THE INVENTION
In one aspect, the present invention provides a process for the preparation of cenobamate of Formula I or pharmaceutically acceptable salt thereof, wherein said process comprising the steps of:
a) converting compound of Formula XIII to compound of Formula III,

wherein, R1 is selected from –CHO, -CN, -COX, -COOR5, -CONR3R4, -NH2, –NO2, and -SO2R2;
R2 is selected from (un)substituted aryl, (un) substituted alkyl;
R3 and R4 are independently selected from hydrogen, alkyl, heteroalkyl, or R3 and R4 together forms saturated or unsaturated cyclic ring containing one or more heteroatoms;
R5 is selected from hydrogen or (un) substituted alkyl;
X is halogen;
provided that when dotted bond represents a full bond, then R is absent, and when dotted bond is absent, then R represents hydrogen or -CONH2; and
b) converting compound of Formula III to cenobamate or its pharmaceutically acceptable salts.

In another aspect, the present invention provides novel compound of Formula III, isomers and pharmaceutically acceptable salts thereof,

wherein, R1 is selected from –CHO, -CN, -COX, -COOR5, -CONR3R4, -NH2, –NO2, and -SO2R2;
R2 is selected from (un)substituted aryl, (un) substituted alkyl;
R3 and R4 are independently selected from hydrogen, alkyl, heteroalkyl, or R3 and R4 together forms saturated or unsaturated cyclic ring containing one or more heteroatoms;
R5 is selected from hydrogen or (un) substituted alkyl;
X is halogen;
provided that when dotted bond represents a full bond, then R is absent, and when dotted bond is absent, then R represents hydrogen or -CONH2.

In another aspect, the present invention provides compound of Formula III, represented by following Formulae;
, , , , ,
, , , ,
, , , ,
, and .

In another aspect, the present invention provides a process for the preparation of cenobamate of Formula I or pharmaceutically acceptable salt thereof, wherein said process comprising the steps of:
a) converting compound of Formula III to compound of Formula XI in presence of suitable solvent (s),
;
wherein R1 is as defined above and R is either absent or hydrogen; and
b) converting compound of Formula XI to cenobamate of Formula I or pharmaceutically acceptable salt thereof;

wherein R is either absent or hydrogen.

In another aspect, the present invention provides process for the preparation of cenobamate of Formula I or pharmaceutically acceptable salt thereof, wherein said process comprising the steps of:
a) ketoreduction of compound of Formula XIa in presence of alcohol dehydrogenase, and NADH or NADPH to give compound of Formula XII;
; and
b) converting compound of Formula XII to cenobamate or pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides process for the preparation of cenobamate of Formula I or pharmaceutically acceptable salt thereof, wherein said process comprising the steps of:
a) resoluting compound of Formula XIb in presence of suitable resoluting agent in suitable solvent to give compound of Formula XII;
; and
b) converting compound of Formula XII to cenobamate or pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a process for the preparation of cenobamate of Formula I or pharmaceutically acceptable salt thereof, wherein said process comprising the steps of:
a) reacting compound of Formula XIII with (R)-2-chlorostyrene oxide to give compound of Formula XIV,

wherein R1 is as defined above; and
b) converting compound of Formula XIV to cenobamate or its pharmaceutically acceptable salts.

In another aspect, the present invention provides a process for the preparation of cenobamate of Formula I or pharmaceutically acceptable salt thereof, by use of novel compounds of Formula III, wherein said process comprising the steps of:
a) reacting compound of Formula XIII with haloacetophenone of formula XV to give compound of Formula XVI,

wherein R1 is as defined above;
b) b1) reducing compound of Formula XVI in presence of suitable reducing agent in suitable solvent to give compound of Formula XVII,
,
wherein R1 is as defined above;
or
b2) ketoreduction of compound of Formula XVI in presence of alcohol dehydrogenase, and NADH or NADPH to give compound of Formula XIV;
,
c) resoluting compound of Formula XVII in present of suitable reducing agent in suitable solvent to give R-isomer of Formula XIV,

wherein R1 is as defined above; and
d) converting compound of Formula XIV of step b2) or c) to cenobamate or pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION
Definitions:
The terms “pharmaceutically acceptable salt” or “salt” are used interchangeably in the context of the present invention. “Pharmaceutically acceptable salts” or “salts” as used in the context of the present invention refers to inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid salt, carbonate salts; organic acids such as succinic acid, formic acids, acetic acid, diphenyl acetic acid, palmoic acid, triphenylacetic acid, caprylic acid, dichloroacetic acid, trifluoro acetic acid, propionic acid, butyric acid, lactic acid, citric acid, gluconic acid, mandelic acid, tartaric acid, malic acid, adipic acid, aspartic acid, fumaric acid, glutamic acid, maleic acid, malonic acid, benzoic acid, p-chlorobenzoic acid, dibenzoyl tartaric acid, oxalic acid, nicotinic acid, o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxy-naphthalene-2-carboxylic acid, hydroxynaphthalene-2-carboxylic acid, ethanesulfonic acid, ethane-1,2-disulfonic acid, 2-hydroxyethane sulfonic acid, methanesulfonic acid, (+)-camphor-10-sulfonic acid, benzenesulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid and the like. The inorganic salts may further includes alkali metal and alkaline earth metal salts such as sodium, potassium, barium, lithium, calcium, magnesium, rhodium, zinc, cesium, selenium, and the like or, benethamine, benzathine, diethanolamine, ethanolamine, 4-(2-hydroxy-ethyl)morpholine, 1-(2-hydroxyethyl)pyrrolidine, N-methyl glucamine, piperazine, triethanol amine or tromethamine and the like.

The “suitable solvent” as used in the context of the present invention, is selected from the group comprising of, but not limited to, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, benzene, toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, ethyl acetate, n-propyl acetate, n-butyl acetate, iso propyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, acetonitrile, propionitrile, butanenitrile, water and mixture thereof.

The present invention will now be explained in details. While the invention is susceptible to various modifications and alternative forms, specific embodiment thereof will be described in detail below. It should be understood, however that it is not intended to limit the invention to the particular forms disclosed, but on the contrary, the invention is to cover all modifications, equivalents, and alternative falling within the scope of the invention as defined by the appended claims.

The present invention provides a novel process by using novel compounds as intermediates wherein the preparation of undesired S-isomer of Formula I-1 and the positional isomer of Formula I-2 is restricted to increase the yields and quality of desired R-isomer of cenobamate, referred herein as “cenobamate” and is represented by Formula I below:

The prior art processes provide aryl ketone of Formula XV, which is used as starting material and reacted with tetrazole of Formula 3 to give compounds of 4, and 4a as mentioned below. The only advantage of the prior art process is availability of raw materials, however the prior art processes suffer from serious drawback of uncontrolled impurity formation. It requires purification process to provide desired compound of formula 4 which is obtained with yields of 40-45% only. It is observed that when compound of formula 2 is reacted with tetrazole, reaction with 1N-tetrazole is more favoured resulting into formation of undesired isomer 4a in large amount (more than 50%).

The present invention is focussed to provide starting material and reaction conditions that reduces the formation of undesired position isomers as well as undesired S-isomer. It is analysed that the reaction of 2N-tetrazole with aryl ketone is increased to upto 85% and more, by using the intermediate of Formula XIII.

Accordingly, in one embodiment, the present invention provides a process for the preparation of cenobamate of Formula I or pharmaceutically acceptable salt thereof, wherein said process comprising the steps of:
a) converting compound of Formula XIII to compound of Formula III,

wherein R1 is as defined above; and
b) converting compound of Formula III to cenobamate or its pharmaceutically acceptable salts.

In main embodiment, the present invention provides novel compounds of Formula III, isomers and pharmaceutically acceptable salts thereof,

wherein, R1 is selected from –CHO, -CN, -COX, -COOR5, -CONR3R4, -NH2 and –NO2, and -SO2R2;
R2 is selected from (un)substituted aryl, (un) substituted alkyl;
R3 and R4 are independently selected from hydrogen, alkyl, heteroalkyl, or R3 and R4 together forms saturated or unsaturated cyclic ring containing one or more heteroatoms;
R5 is selected from hydrogen or (un) substituted alkyl;
X is halogen;
provided that when dotted bond represents a full bond, then R is absent, and when dotted bond is absent, then R represents hydrogen.

In another embodiment, the present invention provides a process for the preparation of novel compounds of Formula III, that are used for the preparation of cenobamate of Formula I, as mentioned in the scheme 5 below:
Scheme 5
,
wherein R and R1 are as defined above.

In another embodiment, the present invention provides a process for the preparation of cenobamate of Formula I or pharmaceutically acceptable salt thereof, wherein said process comprising the steps of:
a) converting compound of Formula III to compound of Formula XI in presence of suitable solvent (s),
;
wherein R1 is as defined above and R is either absent or hydrogen; and
b) converting compound of Formula XI to cenobamate of formula I or pharmaceutically acceptable salt thereof;

wherein R is either absent or hydrogen.

In another embodiment, the present invention provides process for the conversion of compound of Formula III to compound of Formula XI, wherein said process involves elimination of group R1 from compound of Formula III, which is represented in the reaction schemes 6-8 below:

Scheme 6:
When R1 in compound of Formula III is represented as –COOH, then compound of Formula III is represented as compound of Formula IIIA, wherein said compound of Formula IIIA is decarboxylated by heating at a temperature in the range of 50oC to 200oC. The decarboxylation reaction is preferably carried out in an inert conditions such as under argon atmosphere,
.

Scheme 7:
When R1 in compound of Formula III is represented as ester, then compound of Formula III is represented as compound of Formula IIIB, wherein said compound of Formula IIIB is first hydrolyzed in presence of suitable base selected from the group comprising of alkali and alkaline earth metal hydroxides, alkali and alkaline earth metal carbonates, hydrides and the like. The hydrolyzed compound of formula IIIA is then decarboxylated at a temperature in the range of 50oC to 200oC to give compound of Formula XI,
.

Scheme 8:
When R1 in compound of Formula III is represented as cyano, then compound of Formula III is represented as compound of Formula IIIC, wherein said compound of Formula IIIC is first hydrolyzed in presence of suitable base selected from the group comprising of alkali and alkaline earth metal hydroxides, alkali and alkaline earth metal carbonates, hydrides and the like to give compound of Formula IIIA which then decarboxylated to give compound of Formula XI,
.

In one more embodiment, the present invention provides elimination of R1 group at various stages wherein said elimination can be performed either before keto-reduction and resolution, or after resolution of chiral alcohol compound. It is observed that the removal of R1 group can also be performed at final stage after carbamate formation.

In another embodiment, the present invention provides a process for the preparation of cenobamate of Formula I or pharmaceutically acceptable salt thereof, wherein said process comprising the steps of:
a) ketoreduction of compound of Formula XIa in presence of alcohol dehydrogenase, and NADH or NADPH to give compound of Formula XII;
; and
b) converting compound of Formula XII to cenobamate or pharmaceutically acceptable salt thereof.

In another embodiment, the enzymatic enantioselective keto-reduction of compound of Formula XIa (R is absent), is carried out in presence of alcohol dehydrogenase optionally in combination with oxidoreductase such as hydroxysteroid dehydrogenase isolated from Escherichia coli, Candida magnolia, Candida vaccinii, and Oryctolagus cuniculus. The enzymatic enantioselective reduction is carried out in presence of NADH or NADPH as cofactor that is oxidized during the process is regenerated by oxidation of secondary alcohols that are used as substrates. The enzymatic enantioselective reduction may further involve the use of co-substrates selected from esters, CH3COCH2COOR3 wherein R3 is selected from C1-C5 alkyl chain.

In another embodiment, the present invention provides a process for the preparation of cenobamate of Formula I or pharmaceutically acceptable salt thereof, wherein said process comprising the steps of:
a) resoluting compound of Formula XIb in presence of suitable resoluting agent in suitable solvent to give compound of Formula XII or its salt;
; and
b) converting compound of Formula XII or its salt to cenobamate or pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula IXa (wherein R is absent) is reduced conventionally in presence of suitable reducing agent selected from sodium borohydride, lithium hydride, and the like to give a compound of Formula IXb (wherein R is hydrogen). Said alcohol compound of Formula IXb thus formed is resolved in presence of suitable resoluting/resolving agent selected from, but not limited to, tartaric acid, camphor-10-sulfonic acid, camphor-3-sulfonic acid, 3-bromo-camphor-9-sulfonic acid, 2-keto-gulonic acid, a-methoxyphenylacetic acid, 2-Nitroanthranilic acid, malic acid, 2-phenoxypropionic acid, N-acetylleucine, N- (a-methylbenzyl) succinamic acid, N- (a-methylbenzyl) phthalamic acid, quinic acid, di-O- Isopropylidene-2-oxo-L-gulonic acid, 2-hydroxy-4-isopropenyl-1-methyl-cyclohexane-1-sulfonic acid, mandelic acid, and derivatives thereof, preferably (L)-tartaric acid, O, O'-di-p-toluoyl-(L)-tartaric acid, O, O'-dibenzoyl-(L)-tartaric acid, (R)-mandelic acid, (R)-3-chloro-mandelic acid and (R)-3-bromo-mandelic acid.

In another embodiment, the compound of formula XII is optionally isolated as salt wherein said salts are selected from, but not limited to, tartaric acid, camphor-10-sulfonic acid, camphor-3-sulfonic acid, 3-bromo-camphor-9-sulfonic acid, 2-keto-gulonic acid, a-methoxyphenylacetic acid, 2-Nitroanthranilic acid, malic acid, 2-phenoxypropionic acid, N-acetylleucine, N- (a-methylbenzyl) succinamic acid, N-(a-methylbenzyl) phthalamic acid, quinic acid, di-O- Isopropylidene-2-oxo-L-gulonic acid, 2-hydroxy-4-isopropenyl-1-methyl-cyclohexane-1-sulfonic acid, mandelic acid, and derivatives thereof.

In another embodiment, the cenobamate prepared as per the process of the present invention is enantiomerically enriched R-isomer containing R-stereoisomer of more than 75%, preferably more than 80%, preferably more than 85%, preferably more than 90%, and most preferably greater than 95%.

In another embodiment, the present invention provides a process for the preparation of cenobamate of Formula I or pharmaceutically acceptable salt thereof, wherein said process comprising the steps of:
a) reacting compound of Formula XIII with (R)-2-chlorostyrene oxide to give compound of Formula XIV,

wherein R1 is as defined above; and
b) converting compound of Formula XIV to cenobamate or its pharmaceutically acceptable salts.

In another embodiment, the present invention provides a process for the preparation of cenobamate of Formula I or pharmaceutically acceptable salt thereof, by use of novel intermediates of Formula III, wherein said process comprising the steps of:
a) reacting compound of Formula XIII with haloacetophenone of formula XV to give compound of Formula XVI,
,
wherein R1 is as defined above;
b) b1) reducing compound of Formula XVI in presence of suitable reducing agent in suitable solvent to give compound of Formula XVII,
,
wherein R1 is as defined above;
or
b2) ketoreduction of compound of Formula XVI in presence of alcohol dehydrogenase, and NADH or NADPH to give compound of Formula XIV or its salt;
,
c) resoluting compound of Formula XVII in present of suitable resolving agent in suitable solvent to give R-isomer of formula XIV or salt thereof,

wherein R1 is as defined above; and
d) converting compound of Formula XIV or its salt of step b2) or c) to cenobamate or pharmaceutically acceptable salt thereof.

In one another embodiment, the compound of Formula XIV is converted to cenobamate by carbamating compound of Formula XIV which comprises either hydrolysing the compound obtained after reacting compound of Formula XIV with isocyanate selected from chlorosulfonic isocyanate, trichloroacetyl isocyanate and trimethylsilyl isocyanate, or by reacting with CDI and excess of ammonium hydroxide, or by any conventional method known in the literature.
In another embodiment, the compound of Formula XVII is resolved in presence of suitable resoluting/resolving agent selected from, but not limited to, tartaric acid, camphor-10-sulfonic acid, camphor-3-sulfonic acid, 3-bromo-camphor-9-sulfonic acid, 2-keto-gulonic acid, a-methoxyphenylacetic acid, 2-Nitroanthranilic acid, malic acid, 2-phenoxypropionic acid, N-acetylleucine, N- (a-methylbenzyl) succinamic acid, N- (a-methylbenzyl) phthalamic acid, quinic acid, di-O- Isopropylidene-2-oxo-L-gulonic acid, 2-hydroxy-4-isopropenyl-1-methyl-cyclohexane-1-sulfonic acid, mandelic acid, and derivatives thereof, preferably (L)-tartaric acid, O, O'-di-p-toluoyl-(L)-tartaric acid, O, O'-dibenzoyl-(L)-tartaric acid, (R)-mandelic acid, (R)-3-chloro-mandelic acid and (R)-3-bromo-mandelic acid.

In another embodiment, the compound of Formula XIV is optionally isolated as a salt wherein said salt is selected from, but not limited to, tartaric acid, oxalic acid, camphor-10-sulfonic acid, camphor-3-sulfonic acid, 3-bromo-camphor-9-sulfonic acid, 2-keto-gulonic acid, a-methoxyphenylacetic acid, 2-Nitroanthranilic acid, malic acid, 2-phenoxypropionic acid, N-acetylleucine, N- (a-methylbenzyl) succinamic acid, N-(a-methylbenzyl) phthalamic acid, quinic acid, di-O- Isopropylidene-2-oxo-L-gulonic acid, 2-hydroxy-4-isopropenyl-1-methyl-cyclohexane-1-sulfonic acid, mandelic acid, and derivatives thereof.

In another embodiment, the present invention provides substantially pure cenobamate or a salt thereof, wherein said cenobamate or salt thereof is having a purity of atleast 99% by HPLC, or atleast 99.5% by HPLC, or atleast 99.9% by HPLC.

In another embodiment, the present invention provides substantially pure cenobamate or a salt thereof, wherein said cenobamate or salt thereof is substantially free of impurities of Formula I-1 and I-2, wherein each impurity is less than about 0.3%w/w.

In another embodiment, the cenobamate or salt thereof, obtained by the process of the present invention is characterized by particle size distribution of less than about 300µm, preferably less than about 200µm and most preferably about 100µm.

Now, the present invention will be explained in details through experimentations. However, the examples are provided as one of the possible way to practice the invention and should not be considered as limitation of the scope of the invention.

EXAMPLES

EXAMPLE 1: Preparation of (R)-2-(2-(2-chlorophenyl)-2-hydroxyethyl)-2H-tetrazole-5-carboxylic acid of Formula Va
To a solution of 2H-tetrazole-5-carboxylic acid of Formula XIIIa was added 2.5eq of sodium carbonate followed by addition of (R)-2-chlorostyrene oxide in DMF (dimethyl formamide) at room temperature. Heated the reaction to 120oC for 3-3.5h and then cooled to 25oC. After completion of reaction, quenched the reaction with water and extracted the compound in ethyl acetate. Dried the organic layer and distilled under vacuum to give desired compound. (Position undesired IN-tetrazole isomer: 10-20%)

EXAMPLE 2: Preparation of (R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethan-1-ol of Formula XII
Heated the (R)-2-(2-(2-chlorophenyl)-2-hydroxyethyl)-2H-tetrazole-5-carboxylic acid of Formula Va in dimethyl sulfoxide at 150oC under argon atmosphere for 2-3h. After completion of reaction, cooled the reaction to room temperature and isolated the compound by diluting the reaction mixture with ethyl acetate and washing the organic layer with brine. Dried the organic layer and distilled under vacuum to give desired compound. (Yield: 90%)

EXAMPLE 3: Preparation of cenobamate
Added (R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethan-1-ol of Formula XII to methylene chloride and added CDI (1,1’-carbonyl diimidazole). Stirred the reaction mixture at room temperature and added ammonium hydroxide at room temperature. Stirred the reaction for 5h. After completion of reaction, added water and separated the methylene chloride layer. Dried the organic layer and distilled under vacuum, purified in dichloromethane and hexane to give desired compound.

EXAMPLE 4: Preparation of 2-(2-(2-chlorophenyl)-2-oxoethyl)-2H-tetrazole-5-carboxylic acid of Formula IV
To a solution of 2-bromo-2’-chloroacetophenone and sodium carbonate was added 2H-tetrazole-5-carboxylic acid of Formula XIIIa in toluene. Refluxed the reaction for 4h and then cooled the reaction to room temperature. After completion of reaction, distilled the toluene and added ethyl acetate. Washed the organic layer with brine and the distilled the organic layer under vacuum to give desired compound.

EXAMPLE 5: Preparation of (R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethan-1-ol of Formula XII
Charged 70ml of DM water and 2.0 gm of dipotassium hydrogen phosphate in round bottom flask and adjusted the pH of the buffer solution to 7.0 by 10% potassium dihydrogen phosphate at 20-30oC. Charged magnesium chloride hexahydrate (0.02g) and took 40ml of above buffer solution in another round bottom flask. Added 2-(2-(2-chlorophenyl)-2-oxoethyl)-2H-tetrazole-5-carboxylic acid of Formula IV (40mg) to above 40ml of buffer solution. To remaining buffer solution was added hydroxysteroid dehydrogenase, alcohol dehydrogenase and NAD and stirred the enzyme slurry so obtained for 30 min. Charged enzyme slurry to the reaction mass containing compound of Formula IV and added 5.0 ml of Ethyl acetoacetate or methyl acetoacetate. Flushed the enzyme round bottom flask with buffer solution and added to the reaction mass. Stirred the reaction mass for 2-3 at 15-25oC. Cooled the reaction mass at 10oC and adjusted the pH of the reaction mass to 1.0 by hydrochloric acid solution. Stirred the reaction mass for 30 min at 10-20oC and then filtered and washed the wet cake with DM water (500ml). Distilled acetone and charged isopropyl alcohol (30ml) to the wet cake in a round bottom flask and heated the mass to reflux for 45-60 min at 50-60oC and then added 100ml of DM water and stirred the mass for 60-45 min at 50-60oC. Cooled the mass to 15-22oC. Filtered the mass and washed the wet cake with DM water to give desired compound.

CLAIMS:WE CLAIM:
1. Compound of Formula III, isomers and pharmaceutically acceptable salts thereof,

wherein, R1 is selected from –CHO, -CN, -COX, -COOR5, -CONR3R4, -NH2 and –NO2, and -SO2R2;
R2 is selected from (un)substituted aryl, (un) substituted alkyl;
R3 and R4 are independently selected from hydrogen, alkyl, heteroalkyl, or R3 and R4 together forms saturated or unsaturated cyclic ring containing one or more heteroatoms;
R5 is selected from hydrogen or (un) substituted alkyl;
X is halogen;
provided that when dotted bond represents a full bond, then R is absent, and when dotted bond is absent, then R represents hydrogen.

2. A process for the preparation of cenobamate of Formula I or pharmaceutically acceptable salt thereof, wherein said process comprising the steps of:
a) converting compound of Formula XIII to compound of Formula III,

wherein R1 is as defined in claim 1;
R is either absent or hydrogen; and
b) converting compound of Formula III to cenobamate or its pharmaceutically acceptable salts.

3. The process as claimed in claim 2, wherein said process further comprising the steps of:
a) converting compound of Formula III to compound of Formula XI in presence of suitable solvent (s),
;
wherein R1 and R, are as defined above;
b) converting compound of Formula XI to cenobamate of Formula I or pharmaceutically acceptable salt thereof;

wherein R is as defined above.

4. A process for the preparation of cenobamate of Formula I or pharmaceutically acceptable salt thereof, wherein said process comprising the steps of:
a) reacting compound of Formula XIII with (R)-2-chlorostyrene oxide to give compound of Formula XIV,

wherein R1 is as defined in claim 1; and
b) converting compound of Formula XIV to cenobamate or its pharmaceutically acceptable salts.

5. A process for the preparation of cenobamate of Formula I or pharmaceutically acceptable salt thereof, wherein said process comprising the steps of:
a) reacting compound of Formula XIII with haloacetophenone of Formula XV to give compound of Formula XVI,
,
wherein R1 is as defined in claim 1;
b) b1) reducing compound of Formula XVI in presence of suitable reducing agent in suitable solvent to give compound of Formula XVII,
,
wherein R1 is as defined above;
or
b2) ketoreduction of compound of Formula XVI in presence of alcohol dehydrogenase, and NADH or NADPH to give compound of Formula XIV or its salt;
,
c) resoluting compound of Formula XVII in present of suitable resolving agent in suitable solvent to give R-isomer of Formula XIV or salt thereof,

wherein R1 is as defined above; and
d) converting compound of Formula XIV or its salt of step b2) or c) to cenobamate or pharmaceutically acceptable salt thereof.

6. The process as claimed in claim 5, wherein said resolving agent selected from the group comprising of tartaric acid, camphor-10-sulfonic acid, camphor-3-sulfonic acid, 3-bromo-camphor-9-sulfonic acid, 2-keto-gulonic acid, a-methoxyphenylacetic acid, 2-Nitroanthranilic acid, malic acid, 2-phenoxypropionic acid, N-acetylleucine, N- (a-methylbenzyl) succinamic acid, N- (a-methylbenzyl) phthalamic acid, quinic acid, di-O- Isopropylidene-2-oxo-L-gulonic acid, 2-hydroxy-4-isopropenyl-1-methyl-cyclohexane-1-sulfonic acid, mandelic acid, and derivatives thereof, preferably (L)-tartaric acid, O, O'-di-p-toluoyl-(L)-tartaric acid, O, O'-dibenzoyl-(L)-tartaric acid, (R)-mandelic acid, (R)-3-chloro-mandelic acid and (R)-3-bromo-mandelic acid.

7. The process as claimed in claim 5, wherein said compound of Formula XIV is optionally isolated as salt wherein said salt is selected from tartaric acid, oxalic acid, camphor-10-sulfonic acid, camphor-3-sulfonic acid, 3-bromo-camphor-9-sulfonic acid, 2-keto-gulonic acid, a-methoxyphenylacetic acid, 2-Nitroanthranilic acid, malic acid, 2-phenoxypropionic acid, N-acetylleucine, N- (a-methylbenzyl) succinamic acid, N- (a-methylbenzyl) phthalamic acid, quinic acid, di-O- Isopropylidene-2-oxo-L-gulonic acid, 2-hydroxy-4-isopropenyl-1-methyl-cyclohexane-1-sulfonic acid, and mandelic acid.

8. The process as claimed in any of the preceding claim, wherein said cenobamate is substantially free of impurities of Formula I-1 and I-2, wherein each impurity is less than about 0.3%w/w.