2-(chloromethyl)-1,3-difluorobenzene

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:22.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 10.25 g (158 mmol) of NaN3, 2.5 g (7.76 mmol) of tetrabutylammonium bromide and 25 g (154 mmol) of 2,6-difluorobenzyl chloride in 50 mL of isopropyl acetate was left stirring at 20-25° C. during 14 h until showing completion by TLC. The resultant mixture was washed with 10% NaCl aqueous solution at 0° C. to remove unreacted NaN3 and the organic phase was stirred with a solution of 17.26 g (246 mmol) of propiolic acid in 50 mL of water at 50° C. during 8 h. After cooling to 20-25° C., the pH was adjusted to 3.2-3.4 by addition of 30% aqueous solution of NaOH and, after one hour at 20-25° C., the suspension was filtered. The solid was further washed with 25 mL of isopropyl acetate precooled at 0-5° C., washed with 40 mL of water dried at 200 mbar and 50° C. to obtain 21.52 g (57.4%) of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid (purity by UPLC area: 99.94%, 3H-isomer: 0.06%). was left The resultant mixture was washed with 10% NaCl aqueous solution at 0° C. to remove unreacted NaN3 After cooling to 20-25° C. the suspension was filtered The solid was further washed with 25 mL of isopropyl acetate precooled at 0-5° C. washed with 40 mL of water dried at 200 mbar and 50° C.

Conditions: temp:22.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 0.200 g (1.23 mmol) of 2,6-difluorobenzyl chloride in 0.5 mL of DMSO was added dropwise to a mixture of 0.090 g (1.23 mmol) of NaN3 in 2 mL of DMSO at 20-25° C. The reaction was left stirring at 20-25° C. during 4 h. until showing completion by TLC. The crude was treated with 1.6 mL of water and 1.6 mL of cyclohexane and the organic phase was vacuum distilled to obtain 0.210 g (97%) of 2,6-difluorobenzyl azide as yellowish oil The reaction was left distilled

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of the compound obtained in Example 1 (157 mg, 0.53 mmol) in DMF (15 ml), potassium carbonate (80 mg, 0.58 mmol), 2,6-difluorobenzyl chloride (103 mg, 0.64 mmol) and potassium iodide (44 mg, 0.26 mmol) are added, followed by stirring at about 15 to 25° C. for 1 hour and stirring under heating at 80° C. for 1 hour. The brownish white crystalline substance obtained by concentration under reduced pressure of the reaction mixture is dispensed to ethyl acetate (30 ml) and water (30 ml). The water layer is extracted with ethyl acetate (10 ml), and the organic layers are combined and dried over sodium sulfate, after which the solvent is distilled off under reduced pressure to yield a crude brownish white crystalline product (204 mg), which is then purified by flush column chromatography to yield a white crystal (146 mg, 65%). stirring under heating at 80° C. for 1 hour The brownish white crystalline substance obtained by concentration under reduced pressure of the reaction mixture The water layer is extracted with ethyl acetate (10 ml) dried over sodium sulfate after which the solvent is distilled off under reduced pressure

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of the compound obtained in Example 1 (157 mg, 0.53 mmol) in DMF (15 ml), potassium carbonate (80 mg, 0.58 mmol), 2,6-difluorobenzyl chloride (103 mg, 0.64 mmol) and potassium iodide (44 mg, 0.26 mmol) are added, followed by stirring at about 15 to 25° C. for 1 hour and stirring under heating at 80° C. for 1 hour. The brownish white crystalline substance obtained by concentration under reduced pressure of the reaction mixture is dispensed to ethyl acetate (30 ml) and water (30 ml). The water layer is extracted with ethyl acetate (10 ml), and the organic layers are combined and dried over sodium sulfate, after which the solvent is distilled off under reduced pressure to yield a crude brownish white crystalline product (204 mg), which is then purified by flush column chromatography to yield a white crystal (146 mg, 65%). stirring under heating at 80° C. for 1 hour The brownish white crystalline substance obtained by concentration under reduced pressure of the reaction mixture The water layer is extracted with ethyl acetate (10 ml) dried over sodium sulfate after which the solvent is distilled off under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The titled compound (20 mg) as a white solid was prepared from the compound [4-6] obtained in the process (6) of Example 4 (100 mg) and 2,6-difluorobenzyl chloride according to the method of the process (7) of Example 4.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The titled compound (20 mg) as a white solid was prepared from the compound [4-6] obtained in the process (6) of Example 4 (100 mg) and 2,6-difluorobenzyl chloride according to the method of the process (7) of Example 4.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound (0.07 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 1 mmol) using 2,6-difluorobenzyl chloride (1.5 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also yielded 3-(4-chlorophenyl)-2-(2,6-difluoro-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C20H18ClF2N3, 373.12; found, m/z 374.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.34-7.30 (m, 5H), 6.93-6.90 (m, 2H), 5.34 (s, 2H), 3.59-3.57 (m, 2H), 3.39-3.37 (m, 4H), 2.94-2.92 (m, 2H).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound (0.07 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 1 mmol) using 2,6-difluorobenzyl chloride (1.5 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-(2,6-difluoro-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C20H18ClF2N3, 373.12. found, m/z 374.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.34-7.30 (m, 5H), 6.93-6.90 (m, 2H), 5.34 (s, 2H), 3.59-3.57 (m, 2H), 3.39-3.37 (m, 4H), 2.94-2.92 (m, 2H).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound (0.07 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 1 mmol) using 2,6-difluorobenzyl chloride (1.5 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-(2,6-difluoro-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C20H18ClF2N3, 373.12. found, m/z 374.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.34-7.30 (m, 5H), 6.93-6.90 (m, 2H), 5.34 (s, 2H), 3.59-3.57 (m, 2H), 3.39-3.37 (m, 4H), 2.94-2.92 (m, 2H).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The process comprises the preparation of Rufinamide by reacting 2,6-difluorobenzyl chloride and sodium azide in the presence of DMSO to obtain 2,6-difluoro benzyl azide, which is then treated with propiolic acid to give carboxylic acid intermediate which on further reaction with thionyl chloride to give corresponding acyl chloride. The acyl chloride intermediate is further reacted with methanolic ammonia to yield Rufinamide.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The process comprises the preparation of Rufinamide by reacting 2,6-difluorobenzyl chloride and sodium azide in the presence of DMSO to obtain 2,6-difluoro benzyl azide, which is then treated with propiolic acid to give carboxylic acid intermediate which on further reaction with thionyl chloride to give corresponding acyl chloride. The acyl chloride intermediate is further reacted with methanolic ammonia to yield Rufinamide.