DESC:Field of the Invention:
The present application relates to an improved process for the preparation of
cenobamate, which is represented by the following structural formula-I.
5
Formula-I
Background of the Invention:
The chemical name of cenobamate is [(1R)-1-(2-Chlorophenyl)-2-(tetrazol-2-yl) ethyl]
10 carbamate, with molecular formula of C10H10ClN5O2 is approved in US and Europe as tablet
oral for the treatment of partial-onset seizures in adult patients with the brand name of
XCOPRI ®
.
The US patent US7598279B2 discloses cenobamate as product and various processes for
cenobamate. US’279 further disclosed a purification process for cenobamate in 1:1 ratio of
15 dichloromethane and ethyl ether using column chromatography.
The US patent US8501436B2 (US’ 436) discloses a process for cenobamate by selective
asymmetric reduction through biological asymmetric reduction or chemical asymmetric
reduction using various reagents.
The US patent US9068207 B2 (US’ 207) discloses a enzymatic process for the preparation of
20 cenobamate and its intermediates. US’ 207 also disclosed a purification process for
cenobamate in a mixture of isopropanol and heptane.
There are various processes reported for cenobamate and salts thereof using different
solvents, reagents.
3
Based on the drawbacks in the prior art processes, there is a need for providing an improved process for the preparation of cenobamate, which involves simple experimental procedures, well suited to industrial production, which avoids the use of column chromatography purification, and which affords high pure cenobamate. The present invention provides an improved processes for preparation of cenobamate 5 and salts thereof, is efficient, industrially viable and cost effective for commercial purposes.
Brief Description:
The first aspect of the present invention is to provide an improved process for the preparation of cenobamate compound of formula-I. 10
The second aspect of the present invention is a compound of formula-2.
Brief description of the drawings:
Figure 1: Illustrates the PXRD pattern of crystalline Form of [(1R)--1--(2--Chlorophenyl)--2--(tetrazol--2--yl) ethyl] carbamate compound of formula-- I 15
Figure 2: Illustrates the IR of crystalline Form of [(1R)--1--(2--Chlorophenyl)--2--(tetrazol--2--yl) ethyl] carbamate compound of formula-- I
Figure 3: Illustrates the DSC of crystalline Form of [(1R)--1--(2--Chlorophenyl)--2--(tetrazol--2--yl) ethyl] carbamate compound of formula-- I
20
Detailed Description:
As used herein the term “suitable solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, petether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like; “ether solvents” such as 25 dimethoxymethane, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2-dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic 30 solvents such as 2-dimethylacetamide (DMA), dimethylformamide (DMF), dimethyl
4
sulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; “polar-protic solvents such as formic acid , hydrogen fluoride, acetic acid ,trifluoroacetic acid and the like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbontetra chloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; 5 “alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, l,2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar solvents” such as water or mixtures thereof. 10
As used herein the present invention the term “suitable base” refers to inorganic or organic base. Inorganic base refers to “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal 15 alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert-butoxide, lithium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; and organic bases such as like dimethylamine, diethylamine, diisopropyl amine, diisopropyl 20 ethylamine, diisobutylamine, triethylamine, pyridine, piperidine, 4-dimethyl amino pyridine (DMAP), N-methyl morpholine (NMM), or mixtures thereof.
The term “reducing” agent used in the present invention refers suitable reducing reagents are selected from Lithium aluminum hydride, sodium borohydride, BF3 etherate solution, 25 Borane–tetrahydrofuran, Pd/C, Ray-nickel;
The term “protecting” agent used in the present invention refers to a suitable protecting reagents that are selected selected from di-tert-butyl dicarbonate, 4-toluenesulfonyl(Tosyl), chlorobenzyl formate, benzylbromide, benzylchloride, acetylchloride, fluorenyl methyloxy carbonyl chloride; The term “phase transfer catalyst (PTC)” used in the present invention 30
5
refers are selected from triethylbenzyl ammonium chloride, tetrabutyl ammoniumbromide,
tetrabutyl ammonium chloride, tetrabutyl ammonium acetate, methyl tributyl ammonium
chloride, tetrabutyl ammonium hydroxide, tributylbenzylammonium chloride;
5
The first aspect of the present invention provides an improved process for the preparation of
compound of formula-I Comprising of:
a) Reacting compound of formula-1
10
Formula-1
with tetrazole using suitable reagent and solvent to provide a compound of formula-2
15 Formula-2
b) reducing the compound obtained in step-a) with suitable reagent, solvent to provide a
compound of formula -3,
Formula-3
6
c) reacting the compound obtained in step-b) with suitable reagent, solvent to provide a
compound of formula-I,
Formula-I
d)optionally purifying 5 the compound obtained in step-c) with suitable solvent to provide
Cenobamate.
Wherein in step-a,b,c,d) the suitable solvent is selected from hydrocarbon solvents, chloro
solvents, ether solvents, ketone solvents, nitrile solvents, ester solvents, polar protic solvents,
polar aprotic solvents, alcohol solvents, water and any mixture thereof;
10 wherein in step-a) the suitable reagents is selected from thionyl chloride, oxalyl chloride,
EDC, HATU, TBTU; organic base
wherein in step-b) the reduction is carried out using reducing agent selected from sodium
borohydride, iodine, potassium borohydride, lithium borohydride, sodium bis (2-methoxy
ethoxy) aluminum hydride, borane-dimethylsulfide, boron trifluoride-etharete and mixture
15 thereof.
wherein in step-c) the suitable reagent CDI, ammonia, methane sulfonic acid, sodium
cyanate, chlorosulfonyl isocyanate and mixture thereof.
The second aspect of the present invention is a compound of formula-2.
20
Formula-2
The process of the present invention can be represented schematically as follows:
Scheme-I:
7
An alternative process of the present invention can be represented schematically as follows:
5 Scheme-II
10
8
An alternative process of the present invention can be represented schematically as follows:
Scheme-III
5
An alternative process of the present invention can be represented schematically as follows:
Scheme-IV
10
An alternative process of the present invention can be represented schematically as follows:
9
Scheme-V
5
The other aspect of the present invention provides an improved process for the preparation of
compound of formula-I Comprising of:
10
a)Reacting compound of formula-9
Formula-9
with ketoreductase enzyme using suitable reagent and pH to provide a compound of
15 formula-8
10
Formula-2
b)cyclizing the compound obtained in step-a) with suitable reagent, solvent to provide (R)-2-
(2-chlorophenyl)oxirane, without isolation 5 further treating tetrazole to provide compound of
formula-3
Formula-3
c)reacting the compound obtained in step-b) with suitable reagent, solvent to provide a
10 compound of formula-I,
Formula-I
d)optionally purifying the compound obtained in step-c) with suitable solvent to provide
Cenobamate.
15 Wherein in step-a,b, c) the suitable solvent is selected from hydrocarbon solvents, chloro
solvents, ether solvents, ketone solvents, nitrile solvents, ester solvents, polar protic solvents,
polar aprotic solvents, alcohol solvents, water and any mixture thereof;
Step-a) suitable reagents are buffer solutions, NAD+. NAD++, NADP, NADPH, chemical
asymmetric hydride reducing agents such as chiral borane agents, conducting asymmetric
20 catalytic hydrogenation in presence of chiral auxiliary, or ketoreductase enzymes, metal
catalyst such as palladium, platinum, rhodium and ruthenium.
wherein in step-b) the suitable base are organic bases, inorganic base,
11
wherein in step-c) the suitable reagent CDI, ammonia, methane sulfonic acid, sodium
cyanate, chlorosulfonyl isocyanate and mixture thereof. Suitable temperature 20-100°C.
The other aspect of the present invention is a purification process for cenobamate the
5 compound of formula-I
comprising:
a) Dissolving cenobamate compound of formula-1 in suitable solvents,
b) strring at a suitable temperature,
c) isolating the pure crystalline form of cenobamate .
10 the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether solvents,
ketone solvents, nitrile solvents, ester solvents, polar protic solvents, polar aprotic solvents,
alcohol solvents, water and any mixture thereof; suitable temperature 0-100°C.
An alternative process of the present invention can be represented schematically as follows:
15 Scheme-IV
The process for the preparation of cenobamate, its salt developed by the present
inventors produces highly pure cenobamate with good yield. All the related substances and
20 residual solvents are controlled well within the limits as suggested by ICH guidelines and
most of the related substances are controlled in non-detectable levels.
The compound of formula-1a produced by the process of the present invention is
having purity of greater than 99.5%, preferably greater than 99.7%, more preferably greater
than 99.9% by HPLC and chiral HPLC
25 cenobamate and its polymorphs produced by the present invention can be further
micronized or milled to get the desired particle size to achieve desired solubility profile based
12
on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
PXRD analysis of cenobamate was carried out using BRUKER D8 5 ADVANCED/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min. IR spectra were recorded on a Perkin-Elmer FTIR spectrometer.
The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not 10 be construed as limitation of the scope of the invention.
Examples:
Example-1: Preparation of the compound of formula-2(((R)-2-(2-chlorophenyl)-2-hydroxy-1-(2H-tetrazol-2-yl)ethanone)).
A round bottom flask was charged with compound of formula--1 (50 g), tetrazole (18.8 g), 15 EDC (51.3 g) and HOBT (36.2 g) in DMF (250 mL) stirred at 25--35°C for 10 hr. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined ethyl acetate layer was dried and evaporated to get the title compound.
Yield: 38.0 g.
Example--2: Preparation of the compound of formula--3 ((R)--1--(2--chlorophenyl)--2--(2H--20 tetrazol--2--yl)ethanol.)
A round bottom flask was charged with compound of formula--2 (35 g), THF (350 mL) was stirred for 10 min. The reaction mixture was cooled to 0 to --10°C, charged borane--THF solution (1.2 eq) slowly and stirred for 8 hr at refluxed temperature. Cooled the reaction mixture to 0--5°C, quenched with cold methanol and dil HCl and stirred for 2 hr at 50--60°C. 25 Further, the reaction mixture was diluted with water and ethyl acetate and stirred for 30 min. The both layers were separated and the organic layer was dried and evaporated to get the title compound.
Yield: 20.0 g.
Example--3: Preparation of the compound of formula--I 30
13
A round bottom flask was charged with compound of formula--3 (5 g), methylene chloride (50 ml) and was added 1,1'--carbonyl diimidazole (4 moles) and the reaction mixture was stirred at room temperature for 4 hr. The reaction mixture was charged with excess ammonium hydroxide (50 ml) and stirred for 4 h at room temperature. The organic layer was separated and washed with brine solution. The resulting organic layer was dried and concentrated to get 5 the title compound.
Yield: 3.5 g.
Purity by HPLC: >99.9 %.
Example--4: Preparation of the compound of formula--10 (1--(2--chlorophenyl)--2--(2H--tetrazol--2--yl)ethanone) 10
A round bottom flask was charged with 2-bromo-1-(2-chlorophenyl) ethanone (25 g), sodium carbonate (1.2 eq), tetrazole (1.2 eq) and acetonitrile (5 V) stirred at 25-35°C. The reaction mixture was heated to 45-50°C for 1 hr and after completion of reaction, distilled-off solvent completely. The obtained crude compound dispersed in ethyl acetate and the obtained solid was filtered. The filtrate solution washed with water and dil. HCl solution. The organic layer 15 was distilled-off completely at 50 °C, the obtained residue was dispersed in methyl t-butyl ether and stirred for 30 min at 25-35°C. Filtered the solid, the resulting filtrate solution was distilled- off completely and crude compound was purified in isopropyl alcohol. The obtained compound was dried to get the title compound.
Yield: 18.2 g 20
Example--5: Preparation of the ( 1--(2--chlorophenyl)--2--(2H--tetrazol--2--yl)ethanol)
A round bottom flask was charged with 1--(2--chlorophenyl)--2--(2H--tetrazol--2--yl)ethanone (8 g), methanol (5 Vol) at 25--35°C. Cooled the reaction mixture to 0--5 °C, slowly added sodium borohydride (0.5 eq) and stirred for 1 hr at same temperature. The reaction mixture was quenched with water and charged dichloromethane and stirred for 10 min at 25--35°C. 25 Separated two layers, aqueous layer was extracted with dichloromethane, the combined organic layer was dried and evaporated to get the title compound.
Yield: 7.8 g
Example--6: Preparation of the racemic cenobamate( 1--(2--chlorophenyl)--2--(2H--tetrazol--
14
2--yl)ethyl carbamate)
A round bottom flask was charged with 1--(2--chlorophenyl)--2--(2H--tetrazol--2--yl)ethanol (10 g), CDI (1.2 eq) and dichloromethane (5 V) and stirred for 2 hr at 25--35°.C. The reaction mixture quenched slowly with ammonium hydroxide and stirred for 2 hr. The reaction mixture two layers were separated, and the aqueous layer was extracted with 5 dichloromethane, washed with sodium chloride solution and distilled--off solvent completely. The obtained residue was charged with methyl t--butyl ether and stirred for 2 hr . Filtered the solid, and washed with MTBE and dried to get the title compound.
Yield: 8.2 g
Example--7: Preparation of the (R)--1--(2--chlorophenyl)--2--(2H--tetrazol--2--yl)ethanol 10
A round bottom flask was charged with 1--(2--chlorophenyl)--2--(2H--tetrazol--2--yl)ethanone (5 g), ruthenium catalyst (0.01%) and methanol (5 Vol) at 25--35°C stirred under hydrogen atmosphere for 6 h at 25--35°C. Cooled the reaction mixture, and filtered the catalyst and the resulting filtrate solution was evaporated and dried to get the title compound.
Yield: 2.8 g 15
Example--8: Preparation of the 2--bromo--1--(2--chlorophenyl)ethanone (compound of formula--9 )
A round bottom flask was charged with 1--(2--chlorophenyl)ethanone (100 g), acetic acid (400 mL) followed by charged bromine solution (144 g in acetic acid 100 mL) and stirred for 2 hr at 25--30°C. The reaction mixture was quenched with water (500 mL) and sodium sulphite 20 (163 g) and stirred for 3 hr. Further, charged with dichloromethane to the reaction mixture and stirred for 15 min and separated the both layers. Again the aqueous layer was charged with dichloromethane and stirred for 15 min and separated the both layers. The combined organic layer was washed with sodium bicarbonate solution and sodium chloride solution and dried under sodium sulfate and distilled--off the solvent to get the title compound. 25
Yield: 115 g.
Example--9: Preparation of the 1--(2--chlorophenyl)--2--(2H--tetrazol--2--yl)ethanone (compound of formula--10 )
A round bottom flask was charged with compound of formula--9 (100 g), acetonitrile (1000 mL), 1H--tetrazole (45 g) and potassium carbonate (88.7 g) and stirred for 12 hr at 50--60°C. 30
15
The reaction mixture was filtered and evaporated the solvent to get the crude compound. The crude compound was charged with dichloromethane and washed with sodium metabisulphate solution and distilled--off the organic solvent to get the crude compound. The obtained crude compound was charged with methyl tert butyl ether and stirred for 3 hr at 25--35°C. The precipitated solid was filtered and washed with MTBE solvent and distilled--off the filtrate 5 layer. The obtained compound was charged with methanol (50 mL) and stirred at 0--5°C for 3 hr. Filtered the obtained compound and washed with cold methanol and dried to get the title compound.
Yield: 28.5 g. Purity by HPLC: > 96 %
Example--10: Preparation of the 1--(2--chlorophenyl)--2--(2H--tetrazol--2--yl)ethanone 10 (compound of formula--10 )
A round bottom flask was charged with compound of formula--9 (50 g), acetonitrile (500 mL), 1H--tetrazole (25 g) and potassium carbonate (45 g) and stirred for 12 hr at 50--60°C. The reaction mixture was filtered and evaporated the solvent to get the crude compound. The crude compound was charged with dichloromethane and washed with sodium metabisulphate 15 solution and distilled--off the organic solvent to get the crude compound. The obtained crude compound was charged with methyl tert butyl ether and stirred for 3 hr at 25--35°C. The precipitated solid was filtered and washed with MTBE solvent and distilled--off the filtrate layer. The obtained compound was charged with methanol (30 mL) and water (10 mL) stirred at 0--5°C for 3 hr. Filtered the obtained compound and washed with cold methanol and 20 dried to get the title compound.
Yield: 15.2 g. Purity by HPLC: 96.5 %
Example--11: Preparation of the 1--(2--chlorophenyl)--2--(2H--tetrazol--2--yl)ethanone (compound of formula--10 )
A round bottom flask was charged with compound of formula--9 (50 g), ethyl acetate (500 25 mL), DMF (50 mL), 1H--tetrazole (25 g) and potassium carbonate (45 g) and stirred for 8 hr at 50--60°C. The reaction mixture was charged with water and stirred for 30 min and separated the both layers. The organic layer was washed with sodium metabisulphate solution and distilled--off the organic solvent to get the crude compound. The obtained crude compound was charged with methyl tert butyl ether and stirred for 3 hr at 25--35°C. The 30
16
precipitated solid was filtered and washed with methyl tert butyl ether and distilled--off the filtrate layer. The obtained compound was charged with methanol (30 mL) and water (10 mL) stirred at 0--5°C for 3 hr. Filtered the obtained compound and washed with cold methanol and dried to get the title compound.
Yield: 12.8 g. 5
Example--12: Preparation of the 1--(2--chlorophenyl)--2--(2H--tetrazol--2--yl)ethanone (compound of formula--10 )
A round bottom flask was charged with compound of formula--9 (50 g), ethyl acetate (500 mL), 1H--tetrazole (25 g) and potassium carbonate (45 g) and stirred for 8 hr at 50--60°C. The reaction mixture was charged with water and stirred for 30 min and separated the both layers. 10 The organic layer was washed with sodium metabisulphate solution and distilled--off the organic solvent to get the crude compound. The obtained crude compound was charged with methyl tert butyl ether and stirred for 3 hr at 25--35°C. The precipitated solid was filtered and washed with methyl tert butyl ether and distilled--off the filtrate layer. The obtained compound was charged with methanol (30 mL) and stirred at 0--5°C for 3 hr. Filtered the 15 obtained compound and washed with cold methanol and dried to get the title compound.
Yield: 13.2 g.
Example--13: Preparation of the 1--(2--chlorophenyl)--2--(2H--tetrazol--2--yl)ethanone (compound of formula--10 )
A round bottom flask was charged with compound of formula--9 (50 g), ethyl acetate (500 20 mL), 1H--tetrazole (25 g) and potassium carbonate (45 g) and stirred for 8 hr at 50--60°C. The reaction mixture was charged with water and stirred for 30 min and separated the both layers. The organic layer was washed with sodium metabisulphate solution and distilled--off the organic solvent to get the crude compound. The obtained crude compound was charged with tetrahydrofuran and stirred for 3 hr at 25--35°C. The precipitated solid was filtered and 25 washed with tetrahydrofuran and distilled--off the filtrate layer. The obtained compound was charged with methanol (30 mL) and stirred at 0--5°C for 3 hr. Filtered the obtained compound and washed with cold methanol and dried to get the title compound.
Yield: 14.6 g.
Example--14: Preparation of the (R)--1--(2--chlorophenyl)--2--(2H--tetrazol--2--yl) ethanol 30
17
(compound of formula--3)
A round bottom flask was charged with compound of formula--10 (30 g), tetrahydrofuran (450 mL) and stirred for 15 min at 25--35°C. Cooled the reaction mixture to 0--5°C, charged with formic acid (18.6 g) and trimethylamine (40.9 g) under nitro gas purging for 1 hr. The reaction mixture was gradually heated to 25--35°C, charged with ruthenium catalyst (0.18 g) 5 and stirred for 15 hr at same temperature. The reaction mixture was distilled--off and quenched with water, followed by addition of methyl tert butyl ether, stirred the solution for 2 hr and separated the both layers. The aqueous layer was extracted with methyl terty butyl ether and separated the both layers. The combined organic layers were charged with carbon, stirred for 30 min and filtered through hyflow bed, further methyl terty butyl ether was 10 distilled--off. Cooled the obtained compound and charged with isopropanol and heptane stirred for 2 hr at 0--5°C and filtered the solid compound and washed with n--heptane to get the title compound.
Yield: 24.5 g, purity by HPLC: 98 %
Example--15: Preparation of the (R)--1--(2--chlorophenyl)--2--(2H--tetrazol--2--yl) ethanol 15 (compound of formula--3)
A round bottom flask was charged with compound of formula--10 (50 g), methanol (500 ml) and buffer solution (100 ml) heated to 55--60°C. NADP monosodium salt (0.1 g), Ketoreductase enzyme (1.0 g) and buffer solution (50 ml), NAD (0.02 g), ethyl acetate (10 mL) added and stirred at the same temperature about 6 hr. The reaction mixture was diluted with ethyl acetate 20 and stirred for 1 hr . The organic layer was separated and washed with water and brine solution, the combined organic layer was dried and distilled--off to get the crude title compound.
Yield: 45 g. HPLC: 98.8 %
Example--16: Preparation of the (R)--1--(2--chlorophenyl)--2--(2H--tetrazol--2--yl)ethyl carbamate (Cenobamate ) 25
A round bottom flask was charged with compound of formula--3 (25 g), dichloromethane (250 mL) and stirred for 15 min at 25--35°C. Cooled the reaction mixture to 0--5°C, charged 1,1'--carbonyldiimidazole (27 g) in lot wise over a period of 1 hr and stirred at same temperature for 3 hr. Further, the reaction mixture was purged with ammonia gas slowly at 0--5°C for about 1 hr and stirred for 2 hr at same temperature. The reaction mixture was 30
18
quenched with water at 0--5°C and stirred for 15 min and separated the both layers. The aqueous layer was extracted with dichloromethane and the combined organic layer was washed with brine solution. The organic layer was charged with carbon, stirred for 30 min and filtered and dried, distilled--off to get the crude compound. The crude compound was charged with isopropanol (50 mL) followed by n--heptane (150 mL) at 25--35°C and stirred 5 for 30 min at same temperature. Filtered the obtained solid and washed with n--heptane, dried to get the title compound.
Yield: 24.0 g. HPLC: 99.8 %
The obtained compound PXRD was depicted in figure 1.
Example--17: Purification of (R)--1--(2--chlorophenyl)--2--(2H--tetrazol--2--yl) ethyl 10 carbamate (Cenobamate)
A round bottom flask was charged with cenobamate (14 g), isopropanol (28 mL) and stirred for 15 min at 25--35°C. The reaction mixture was heated to 60--65°C and charged with n--heptane (84 mL) and stirred at same temperature about 30 min. The reaction mixture was cooled to 25--35°C, stirred for 30 min at same temperature and filtered the obtained solid and 15 washed with n--heptane and dried to get the title compound.
Yield: 13 g.
Purity by HPLC: 99.95%
The obtained compound PXRD was similar to the figure 1.
Example--18: Preparation of the (R)--2--bromo--1--(2--chlorophenyl) ethanol (formula--8) 20
A round bottom flask was charged with buffer solution (100 ml), enzyme (2.5 g) and NAD+ (0.1 g) at 25--35°C, slowly charged compound of formula--9 [2--bromo--1--(2--chlorophenyl)ethanone] (100g) in IPA (400 ml) at 25--35°C and stirred for 6 h at the same temperature. Filtered the reaction mass through hyflo bed and washed with IPA (50 ml) at 25--35°C and the filtrate solution was charged with carbon (10 g) and stirred the reaction 25 mass for 30 min. Filtered the reaction mass through hyflo bed and washed with IPA (50 ml), and the filtrate solution was distilled--off under vacuum. Cooled the reaction mass to 25--35°C and charged with water (100 ml), dichloromethane (100 ml) and stirred for 30 min at 25--35°C and separated the two layers. The aqueous layer was charged with dichloromethane (100 ml), stirred the reaction mass for 30 min and separated into two layers. The combined 30
19
organic layer was washed with water and distilled--off the solution under vacuum and cooled the reaction mass to 25--35°C to obtain the title compound.
Yield: 90.3 g. HPLC purity: 98.5 %
Example--19: Preparation of the (R)--1--(2--chlorophenyl)--2--(2H--tetrazol--2--yl)ethanol (formula--3) 5
A round bottom flask was charged with N--Methyl--2--Pyrrolidine (300 ml), formula--8 (100 g) DIPEA (164.6 g) at 25--35°C and heated the reaction mass to 95--105°C, maintained for 6 h at same temperature. Cooled the reaction mass to 35--45 °C to get the compound of (R)--2--(2--chlorophenyl)oxirane and in--situ, The reaction mixture was charged with tetrazole (44.6 g), and heated to 80--90°C and stirred for 2 hr at the same temperature. Cooled the reaction 10 mixture, charged with water (500 ml), ethyl acetate (300 ml) and stirred for 30 min at the same temperature and separated into two layers. The aqueous layer is charged with ethyl acetate (300 ml) at 25--35°C stirred the reaction mass for 30 min and separated into two layers. The combined organic (Ethyl acetate) layer was taken into another RB flask at 25--35°C, charged with water at the same temperature, stirred for 30 min at 25--35°C and 15 separated into two layers. The ethyl acetate layer was dried and distilled--off under vacuum to obtain the title compound.
Yield: 30 g.
Example--20: Purification of (R)--1--(2--chlorophenyl)--2--(2H--tetrazol--2--yl) ethyl carbamate (Cenobamate) 20
A round bottom flask was charged with cenobamate (10 g), isopropanol (20 mL), n--heptane (60 mL) and stirred for 15 min at 25--35°C. The reaction mixture was heated to 60--65°C and stirred at same temperature about 2 hr. The reaction mixture was cooled to 25--35°C, stirred for 30 min at same temperature and filtered the obtained solid and washed with n--heptane and dried to get the title compound. 25
Yield: 8.5 g ; Purity by HPLC: 99.97%.
PXRD pattern of obtained compound was similar to the figure-1.
Example--21: Preparation of the 1--(2--chlorophenyl)--2--(2H--tetrazol--2--yl)ethanone (compound of formula--10 )
A round bottom flask was charged with compound of formula--9 (100 g), DMF (100 mL), 30
20
acetonitrile (100 mL), 1H--tetrazole (36 g) were heated to 35--45°C and charged potassium carbonate (44.5 g) stirred at same temperature for 4 hr. Cooled the reaction mixture, filtered the salts, washed with ethyl acetate and the filtrate solution was distilled off completly. The obtained crude compound was charged with water, ethyl acetate and stirred for 1 hr and separated the both layers. The aqueous layer was charged with ethyl acetate and stirred for 15 5 min and separated the both layers. The combined organic layer was washed with sodium metabisulphate solution, water and brine solution and distilled--off the organic solvent to get the crude compound. The obtained crude compound was charged with methyl tert butyl ether and stirred at 40--45°C, cooled the solution and the precipitated solid was filtered and washed with methyl tert butyl ether. The filtrate solution was distilled off completely and cooled to 10 25--35°C, charged with methanol, water and stirred for 1 hr at 0 to 5°C. The obtained compound was filtered and washed with methanol dried to get the title compound.
Yield: 17 g.
Example--22: Preparation of the 1--(2--chlorophenyl)--2--(2H--tetrazol--2--yl)ethanone (compound of formula--10 ) 15
A round bottom flask was charged with compound of formula--9 (100 g), DMF (100 mL), methyl tert butylether (100 mL), tetrazole (33 g) and potassium carbonate (44.5 g) stirred at 35--45°C for 4 hr. Cooled the reaction mixture, charged with water, MTBE and stirred for 1 hr and filtered the obtained solid. Separated the filtrate solution and the aqueous layer was extracted with methyl tert butyl ether. The combined methyl tert butyl ether layer was washed 20 with sodium metabisulphate solution, water and brine solution and distilled--off completely to get the crude compound. The obtained crude compound was charged with methanol and stirred for 1 hr at 0 to 5°C. The obtained compound was filtered and washed with methanol dried to get the title compound.
Yield: 33 g. 25
Example--23: Preparation of the 1--(2--chlorophenyl)--2--(2H--tetrazol--2--yl)ethanone (compound of formula--10 )
A round bottom flask was charged with compound of formula--9 (10 g), DMF (10 mL), methyl tert butylether (10 mL), tetrazole (3.5 g) and potassium carbonate (4.5 g) stirred at 35--45°C for 2 hr. Cooled the reaction mixture, charged with water, MTBE and stirred for 1 hr 30
21
and filtered the obtained solid. Separated the filtrate solution and the aqueous layer was extracted with methyl tert butyl ether. The combined methyl tert butyl ether layer was washed with sodium metabisulphate solution, water and brine solution and distilled--off completely to get the crude compound. The obtained crude compound was charged with methanol, water and stirred for 1 hr at 0 to 5°C. The obtained compound was filtered and washed with 5 methanol dried to get the title compound.
Yield: 2.8 g. ,CLAIMS:We claim:
1.An improved process for cenobamate the compound of formula-I.
a)Reacting the compound of formula-9
5
Formula-9
with ketoreductase enzyme using suitable reagent to provide a compound of formula-8,
10 Formula-8
b)cyclizing the compound obtained in step-a) with suitable reagent, solvent to provide (R)-2-
(2-chlorophenyl)oxirane, in-situ further reacting with tetrazole to provide compound of
formula-3,
15
Formula-3
c)reacting the compound obtained in step-b) with suitable reagent, solvent to provide a
compound of formula-I,
20 Formula-I
23
d)optionally purifying the compound obtained in step-c) with suitable solvent to provide Cenobamate.
2. The process as claimed in claim 1, wherein step-a, b, c and d) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether solvents, ketone solvents, nitrile solvents, ester solvents, polar protic solvents, polar aprotic solvents, alcohol solvents, water 5 and any mixture thereof;
Step-a) suitable reagents are buffer solutions, NAD+. NAD++, NADP, NADPH, chemical asymmetric hydride reducing agents such as chiral borane agents, conducting asymmetric catalytic hydrogenation in presence of chiral auxiliary, or ketoreductase enzymes, metal catalyst such as palladium, platinum, rhodium and ruthenium. 10
wherein in step-b) the suitable base are organic bases, inorganic base,
wherein in step-c) the suitable reagent CDI, Liq. ammonia, ammonia (gas), methane sulfonic acid, sodium cyanate, chlorosulfonyl isocyanate and mixture thereof.
3. A purification process for cenobamate the compound of formula--I 15
comprising:
a) Dissolving cenobamate compound of formula-1 in suitable solvents,
b) strring at a suitable temperature,
c) isolating the pure crystalline form of cenobamate .
20
4. The process as claimed in claim 3, wherein the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether solvents, ketone solvents, nitrile solvents, ester solvents, polar protic solvents, polar aprotic solvents, alcohol solvents, water and any mixture thereof; suitable temperature 0-100°C.