DESC:The present invention relates to a commercially available methods for preparing and separating a compound 1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethanone (1a) from the reaction mixture of compound 1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethanone (1a) and compound 1-(2-chlorophenyl)-2-(1H-tetrazol-2-yl)ethanone (1b). This method achieves improved selectivity by using base treatment,

One embodiment of the present invention provides a method for preparing a compound of formula 1a, which comprises the steps of:

a) reacting 2-bromo-1-(2-chloro phenyl) ethanone (II) with tetrazole in presence of a base and a suitable solvent to obtain mixture of 1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethanone (1a) and 1-(2-chlorophenyl)-2-(1H-tetrazol-2-yl)ethanone (1b); and

b) separating the compound of formula (1a) from a mixture obtained by the reaction of step a) by using base treatment to obtain 1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethanone (1a).

In an embodiment of the present invention provides, a method for improving the productivity of a compound of formula (1a). The method comprises reacting the compound 2-bromo-1-(2-chloro phenyl) ethanone (II) with tetrazole in presence of a base and a suitable solvent to obtain mixture of 1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethanone (1a) and 1-(2-chlorophenyl)-2-(1H-tetrazol-2-yl)ethanone (1b). Further, separating the compound of formula (1a) from the reaction mixture by treating with base at room temperature for 20-30 minutes to obtain 1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethanone.

In one embodiment, the present invention provides a method for improving the productivity of a compound of formula (1a). The method involves reacting the compound 2-bromo-1-(2-chlorophenyl)ethanone (II) with tetrazole in the presence of a base and a suitable solvent to obtain a mixture of 1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethanone (1a) and 1-(2-chlorophenyl)-2-(1H-tetrazol-2-yl)ethanone (1b). Subsequently, the compound of formula (1a) is separated from the reaction mixture by treating it with base at room temperature for 20-30 minutes to obtain 1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethanone.

Another embodiment of the present invention provides a method for separating a compound of formula 1a from a mixture comprising compounds of formulas 1a and 1b using base treatment.

In one embodiment, the present invention provides a method for separating a compound of formula 1a from a mixture comprising a compound of formula 1a and a compound of formula 1b using acid-base treatment at room temperature for 20-30 minutes.

Another embodiment of the present invention provides a method of preparing Cenobamate, which comprises;
a) reacting 2-bromo-1-(2-chloro phenyl) ethanone (II) with tetrazole in presence of a base and a suitable solvent to obtain mixture of 1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethanone (1a) and 1-(2-chlorophenyl)-2-(1H-tetrazol-2-yl)ethanone (1b);

b) separating the compound of formula (1a) from a mixture obtained by the reaction of step a) by using base treatment a to obtain 1-(2-chlorophenyl)-2-(2H- tetrazol-2-yl)ethanone (1a); and

c) converting the compound of formula (1a) into Cenobamate.

In one embodiment, the present invention provides a method for improving the productivity of a compound of formula (1a). The method involves reacting the compound 2-bromo-1-(2-chlorophenyl)ethanone (II) with tetrazole in the presence of a base and a suitable solvent to obtain a mixture of 1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethanone (1a) and 1-(2-chlorophenyl)-2-(1H-tetrazol-2-yl)ethanone (1b). The compound of formula (1a) is separated from the reaction mixture obtained in step a) by treating with base at room temperature for 20-30 minutes, resulting in 1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethanone (1a), which is further converted into Cenobamate (I).

According to an embodiment of the present invention, wherein the suitable solvent is selected sulfoxides such as dimethyl sulfoxide and diethyl sulfoxide; alcohols such as methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, isobutanol, tert-butanol; nitriles such as acetonitrile and propionitrile; ether solvent such as tetrahydrofuran, diisopropylether, diethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, 1,4-dioxane; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; and aromatic hydrocarbons such as toluene, anisole, heptane and xylene; esters such as ethylacetate, methylacetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate; ketones such as acetone, methylisobutyl ketone, 2-pentanone, ethylmethylketone, diethylketone; halogenated hydrocarbons such as chloroform, dichloromethane; water; cyclohexane and N-methyl-2-pyrrolidone and or mixtures thereof.

According to an embodiment of the present invention, wherein the base in step a) is selected from inorganic bases such as sodium hydride, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, calcium carbonate, lithium carbonate; and organic bases such as pyridine, diethyl amine, diisopropylethylamine, and trimethylamine, triethyl amine, diethylamine and isopropylamine.

According to an embodiment of the present invention, wherein the amine base is selected from triethyl amine, diisopropylethylamine, diethylamine, isopropylamine.

According to an embodiment of the present invention, the base treatment and acid-base treatment in step b) are selected from 40% monomethylamine, 25% aqueous ammonia, 50% sodium hydroxide solution, Trimethylamine, and diisopropylethylamine. The acid is selected from hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, and citric acid.

The compound of formula (1a) prepared by the processes herein described above is having a purity of greater than about 99 area % as measured by HPLC.

In another embodiment, the purity of compound of formula (1a) produced by the process herein described above is greater than about 98 % area % as measured by HPLC.

Advantages of the Present Invention
The present invention offers an improved method for synthesizing the compound of formula (1a), which is a valuable intermediate in the production of Cenobamate. This new method provides several advantages over the prior art:
? Improved Selectivity: By utilizing a base treatment, the process more selectively synthesizes the compound of formula (1a);
? Enhanced Productivity: The new method increases the overall yield of the desired compound (1a), making the production process more efficient and commercially viable;
? Reduced Reaction Time: Unlike the prior method that requires 24 hours, the improved process significantly cuts down the reaction time, thus enhancing productivity;
? Lower Temperature Requirements: The base treatment method operates at lower temperatures compared to the 150°C required in the prior art, resulting in energy savings and a safer reaction environment.
? Scalability: The improved method is better suited for large-scale production, providing a more practical and cost-effective solution for manufacturing the carbamate intermediate

The following examples illustrate the present invention but should not be construed as limiting the scope of the invention.

EXAMPLES

Example-1
Preparation of 1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethanone
1,4-Dioxane (2000 ml), 1H-tetrazole (35 g), and 30% sodium methoxide solution (70 g) were added to a reaction flask, and the temperature was raised to 60-65°C. The mixture was stirred for 2 hours. Following this, 2-bromo-2-chloroacetophenone (100 g) was added to the reaction mixture, and stirring continued for 5-6 hours at 70-75°C. Purified water (500 ml), sodium hydroxide flakes (40 g), and n-heptane (300 ml) were added to the reaction mixture. After cooling to room temperature, the mixture was stirred for 10-20 minutes, allowed to settle, and the two layers were separated. The aqueous layer's pH was adjusted to 3.0-6.0 with hydrochloric acid (70 ml), and it was then extracted with toluene (1000 ml); the two layers were separated. The resultant toluene layer was mixed with 40% monomethylamine solution (300 ml) in a reaction flask. After stirring for 10-20 minutes and settling, the two layers were separated, and the toluene layer was extracted with monomethylamine solution in toluene (2 x 1000 ml). The total obtained toluene layer was washed with hydrochloric acid (2 x 200 ml) and purified water (200 ml); the two layers were separated and concentrate the toluene layer under reduced pressure at below 60°C.

Isopropyl alcohol (70.0 ml) and purified water (30.0 ml) were added to the obtained product after distillation at below 60°C. The mixture was cooled to 25-30°C and stirred for 120-180 minutes, then further cooled to 15-20°C and stirred for 20-30 minutes. The resulting product was filtered and washed with a mixture of isopropyl alcohol (21 ml) and purified water (9 ml), and dried at 40-45°C for 12 hours to obtain 1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethanone.
Yield: 52.6% (50 gm)
HPLC purity: 99.6%
Unwanted impurity: 0.3%

Example-2

Preparation of 1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethanone
1,4-Dioxane (200 ml), 1H-tetrazole (3.5 g), and 30% sodium methoxide solution (7.0 g) were added to a reaction flask. The temperature was raised to 60-65°C and the mixture was stirred for 2 hours. 2-Bromo-2-chloroacetophenone (10.0 g) was then added to the reaction mixture, which was stirred for an additional 5-6 hours at 70-75°C. Purified water (50 ml), sodium hydroxide flakes (4.0 g), and n-heptane (30 ml) were added to the reaction mixture, which was then cooled to room temperature and stirred for 10-20 minutes. The mixture was allowed to settle, and the two layers were separated. The pH of the aqueous layer was adjusted to 3.0-6.0 with hydrochloric acid (7.0 ml), and it was extracted with toluene (100 ml). The two layers were separated. Purified water and the resultant toluene layer (30 ml), along with 25% aqueous ammonia solution (10 ml), were added into the reaction flask. The mixture was stirred for 10-20 minutes, allowed to settle, and the two layers were separated. This process was repeated three times, extracting with aqueous ammonia solution in toluene (2 x 100 ml). The obtained toluene layer was then washed with hydrochloric acid (2 x 20 ml) and purified water (20 ml), and the two layers were separate and concentrate the toluene layer under reduced pressure at below 60°C.
Isopropyl alcohol (7.0 ml) and purified water (3.0 ml) were added to the obtained product after distillation at below 60°C. The mixture was cooled to 25-30°C and stirred for 120-180 minutes, then further cooled to 15-20°C and stirred for 20-30 minutes. The resulting product was filtered and washed with a mixture of isopropyl alcohol (2.1 ml) and purified water (0.9 ml), and dried at 40-45°C for 12 hours to obtain 1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethanone.
Yield: 40.0% (3.8 gm)
HPLC purity: 98.30%

Example-3
Preparation of 1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethanone
1,4-Dioxane (200 ml), 1H-tetrazole (3.5 g), and 30% sodium methoxide solution (7.0 g) were added to a reaction flask. The temperature was raised to 60-65°C, and the mixture was stirred for 2 hours. This was followed by the addition of 2-bromo-2-chloroacetophenone (10.0 g) to the reaction mixture, which was stirred for an additional 5-6 hours at 70-75°C. Purified water (50 ml), sodium hydroxide flakes (4.0 g), and toluene (50 ml) were added to the reaction mixture. The mixture was cooled to room temperature, stirred for 10-20 minutes, and allowed to settle. The two layers were then separated. The pH of the aqueous layer was adjusted to 3.0-6.0 with hydrochloric acid (7.0 ml), and it was extracted with toluene (100 ml). The two layers were separated. Purified water, the resultant toluene layer (20 ml), and triethylamine (10 ml) were added to a reaction flask. The mixture was stirred for 10-20 minutes and allowed to settle, and the two layers were separated. The obtained toluene layer was then washed with hydrochloric acid (2 x 20 ml) and purified water (20 ml), and the two layers were separated and concentrated the toluene layer under reduced pressure at below 60°C.

Isopropyl alcohol (7 ml) and purified water (3 ml) were added to the obtained product after distillation. The mixture was cooled to 25-30°C and stirred for 120-180 minutes, then further cooled to 15-20°C and stirred for 20-30 minutes. The resulting product was then filtered, washed with a mixture of isopropyl alcohol (2.1 ml) and purified water (0.9 ml), and dried at 40-45°C for 12 hours to obtain 1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethanone.
Yield: 42.10 % (4.0 gm)
HPLC purity: 96.47 %

Example-4
Preparation of 1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethanone
1,4-Dioxane (200 ml), 1H-tetrazole (3.5 g), and 30% sodium methoxide solution (7.0 g) were added to a reaction flask. The temperature was raised to 60-65°C, and the mixture was stirred for 2 hours. Subsequently, 2-bromo-2-chloroacetophenone (10.0 g) was added to the reaction mixture, and stirring was continued for 5-6 hours at 70-75°C. Purified water (50 ml), sodium hydroxide flakes (4.0 g), and toluene (50 ml) were added to the reaction mixture. After cooling to room temperature, the mixture was stirred for 10-20 minutes and allowed to settle. The two layers were then separated. The pH of the aqueous layer was adjusted to 3.0-6.0 with hydrochloric acid (7.0 ml) and extracted with toluene (100 ml). The two layers were separated. To the resultant toluene layer (20 ml), diisopropylethylamine (10 ml) and purified water were added. After stirring for 10-20 minutes and allowing to settle, the two layers were separated. The obtained toluene layer was washed with hydrochloric acid (2 x 20 ml) and purified water (20 ml). The two layers were separated and concentred the toluene layer under reduced pressure at below 60°C.

Isopropyl alcohol (7.0 ml) and purified water (3.0 ml) were added to the obtained product after distillation. The mixture was cooled to 25-30°C and stirred for 120-180 minutes, then further cooled to 15-20°C and stirred for 20-30 minutes. The mixture was filtered and washed with a mixture of isopropyl alcohol (2.1 ml) and purified water (0.9 ml). The solid product was dried at 40-45°C for 12 hours to obtain 1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethanone.
Yield: 47.36% (4.5 gm)
HPLC purity: 82.0%

Example-5
Preparation of 1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethanone
1,4-Dioxane (200 ml), 1H-tetrazole (3.5 g), and 30% sodium methoxide solution (7.0 g) were added to a reaction flask. The temperature was raised to 60-65°C, and the mixture was stirred for 2 hours. Subsequently, 2-bromo-2-chloroacetophenone (10.0 g) was added to the reaction mixture, and stirring was continued for 5-6 hours at 70-75°C. Purified water (50 ml), sodium hydroxide flakes (4.0 g), and n-heptane (30 ml) were added to the reaction mixture. After cooling to room temperature, the mixture was stirred for 10-20 minutes and allowed to settle. The two layers were then separated. The pH of the aqueous layer was adjusted to 3.0-6.0 with hydrochloric acid (7.0 ml), and it was extracted with toluene (100 ml). The two layers were separated. 50% sodium hydroxide solution and the resultant toluene layer were added into the reaction flask, stirred for 10-20 minutes, and allowed to settle. The two layers were separated. The obtained aqueous layer was extracted with toluene (3 x 90 ml) and ethyl acetate (3 x 10 ml). The two layers were separated. The obtained toluene layer was washed with purified water (20 ml), and the two layers were separated and concentrated the toluene layer under reduced pressure at below 60°C

Isopropyl alcohol (7.0 ml) and purified water (3.0 ml) were added to the obtained product after distillation. The mixture was cooled to 25-30°C and stirred for 120-180 minutes, then further cooled to 15-20°C and stirred for 20-30 minutes. The mixture was then filtered and washed with a mixture of isopropyl alcohol (2.1 ml) and purified water (0.9 ml). The solid product was dried at 40-45°C for 12 hours to obtain 1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethanone.
Yield: 35.79% (3.4 gm)
HPLC purity: 99.0%

Example-6
Preparation of (R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethanol
Formic acid-triethylamine complex (30.0 ml), 1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethanone (10.0 g), and chloro{[(1S,2S)-(+)-2-amino-1,2-diphenylethyl] (pentafluorophenylsulfonyl)amido}(p-cymene)ruthenium(II) (0.1 g) were added to a flask at 25-35ºC. The reaction mixture was stirred at the same temperature. After the reaction was complete, purified water (60.0 ml) and ethyl acetate (70.0 ml) were added to the reaction mixture. It was stirred at room temperature to separate the layers, and then 10% sodium carbonate solution (20.0 ml) was added. The mixture was stirred at room temperature and the layers were separated. The organic layer was concentrated under reduced pressure at below 50ºC. The resultant precipitate was filtered, washed with purified water, and dried to isolate the title compound.
Yield: 99.0% (10 g)
Chiral purity: 95.0%

Example-7
Preparation of Cenobamate
Methylene chloride (100 ml) and (R)-1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethanol (10 g) were added to a flask at room temperature, followed by the addition of 1,1'-carbonyldiimidazole (10 g). The mixture was stirred for 2 hours. After the reaction was complete, aqueous ammonia was added to the reaction mass and stirred for 4 hours. Upon completion of the reaction, purified water (50 ml) was added to the mixture, and the layers were separated. The obtained organic layer was washed with 10% sodium chloride solution and then concentrated. The resultant precipitate was isolated with isopropyl alcohol (20 ml), washed with isopropyl alcohol (2.5 ml), and dried to isolate the title compound.
Yield: 84.0% (10.0 gm)
,CLAIMS:1. A method for preparing a compound of formula 1a, which comprises the steps of:
a) reacting 2-bromo-1-(2-chloro phenyl) ethanone (II) with tetrazole in the presence of a base and a suitable solvent to obtain mixture of 1-(2-chlorophenyl)-2-(2H-tetrazol-2-yl)ethanone (1a) and 1-(2-chlorophenyl)-2-(1H-tetrazol-2-yl)ethanone (1b); and

b) separating the compound of formula (1a) from a mixture obtained in step a) by using base treatment to obtain 1-(2-chlorophenyl)-2-(2H- tetrazol-2-yl)ethanone (1a).

2. A method of preparing Cenobamate, which comprises.
a) reacting 2-bromo-1-(2-chloro phenyl) ethanone (II) with tetrazole in the presence of a base and a suitable solvent to obtain mixture of 1-(2-chloro phenyl)-2-(2H-tetrazol-2-yl)ethanone (1a) and 1-(2-chlorophenyl)-2-(1H-tetrazol-2-yl)ethanone (1b);

b) separating the compound of formula (1a) from the mixture obtained in step a) by using base treatment to obtain 1-(2-chloro phenyl)-2-(2H- tetrazol-2-yl)ethanone (1a);

c) converting the compound of formula (1a) into Cenobamate.

3. A method for improving the productivity of a compound of formula (1a) from a mixture comprising a compound of formula (1a) and a compound of formula (1b), by using base treatment.

4. The process as claimed in claim 1 or claim 2 for step (a), wherein the base is selected from inorganic bases such as sodium hydride, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, calcium carbonate, and lithium carbonate; and organic bases such as pyridine, diethylamine, diisopropylethylamine, trimethylamine, triethylamine, diethylamine, and isopropylamine.

5. The process as claimed in any one of claims 1, 2, or 3 wherein the suitable solvent is selected from the group consisting of dimethyl sulfoxide, methanol, ethanol, isopropyl alcohol, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, N,N-dimethylformamide, toluene, heptane, ethyl acetate, isopropyl acetate, acetone, chloroform, dichloromethane, water, cyclohexane, N-methyl-2-pyrrolidone, and mixtures thereof.

6. The process as claimed in any one of claims 1, 2, or 3, wherein in step (b), the base is selected organic bases such as aqueous monomethylamine, aqueous ammonia, sodium hydroxide solution, trimethylamine, diisopropylethylamine, diethylamine, and isopropylamine.

7. The process as claimed in any one of claims 1, 2, or 3, wherein the separation of a compound of formula 1a includes purification using isopropyl alcohol (IPA) and water.

8. The process according as claimed in any one of claims 1, 2, or 3, wherein compound of formula (1a) is obtained with a HPLC purity greater than 98%.