4-bromo-2,6-dichloroaniline

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

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

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Bromo-2,6-dichloroaniline (5, 80 g) was dissolved in acetone (640 mL), and a 48% hydrogen bromide aqueous solution (120 mL) was added, followed by stirring at 0° C. A sodium nitrite (32 g) aqueous solution (160 ml,) was added dropwise thereto, the mixture was stirred for 30 minutes, and methyl acrylate (200 nit), and water (200 mL) were added, followed by stirring for 1 hour. At room temperature, cuprous oxide (2 g) was added, followed by stirring for 2 hours. The reaction solution was extracted with ethyl acetate, and purified by column chromatography to obtain methyl (E)-3-(4-bromo-2,6-dichlorophenyl)acrylate (48.5 g). Methyl (E)-3-(4-bromo-2,6-dichlorophenyl)acrylate (48.5 g) was dissolved in dichloromethane, an ozone gas was introduced at −70° C., and ozone oxidization was performed. To the reaction solution was added dimethyl sulfide (40 mL), and this was extracted with ethyl acetate to obtain 4-bromo-2,6-dichlorobenzaldehyde (6, 37.2 g). the mixture was stirred for 30 minutes by stirring for 1 hour by stirring for 2 hours The reaction solution was extracted with ethyl acetate purified by column chromatography

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

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-azido-5-fluoropyridine-3-carbaldehyde (10.0 g, 60.0 mmol) and 4-bromo-2,6-dichlorophenylamine (14.4 g, 60.0 mmol) in DCM (200 mL) was cooled to 0° C., under an atmosphere of nitrogen. Triethylamine (25 mL, 180 mmol) was added, followed by dropwise addition of titanium (IV) chloride solution (1 N in DCM, 36 mL, 36 mmol). The reaction mixture was stirred at 0° C. then allowed to reach room temperature overnight. The resultant mixture was concentrated under reduced pressure and the residue was suspended in toluene and filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to afford the title compound (quantitative yield). This was used in the next step without further purification. The resultant mixture was concentrated under reduced pressure filtered through a pad of Celite® The filtrate was concentrated under reduced pressure

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

Procedure: 2,6-Dichloro-4-bromoaniline (15.6 g, 64.8 mmol) was gradually added to concentrated sulfuric acid (40 ml). The mixture was then stirred at room temperature for 20 minutes. The mixture was then cooled to 0° C. To the mixture was then added gradually sodium nitrite (4.9 g, 71.22 mmol). The mixture was then stirred at a temperature of 0° C. to 5° C. for 2.5 hours. The mixture thus obtained was then added to ice-water (200 g). To the mixture was then added an aqueous solution of potassium iodide (12.9 g, 77.76 mmol) at 5° C. The mixture was then allowed to stand at 5° C. for 15 minutes and at room temperature for 1 hour. The mixture was then extracted with diethyl ether. The extract was washed with an aqueous solution of sodium thiosulfate, and then dried over magnesium sulfate. The solvent was then distilled off. The crude product thus obtained was then extracted with hexane (200 ml). The solvent was then distilled off. As a result, a crude product was obtained in an amount of 18.62 g. The crude product was then recrystallized from ethanol (75 ml). As a result, 2,6-dichloro-4-bromoiodobenzene was obtained (14.8 g; yield: 65%). The mixture was then cooled to 0° C The mixture was then stirred at a temperature of 0° C. to 5° C. for 2.5 hours The mixture thus obtained to stand at 5° C. for 15 minutes and at room temperature for 1 hour The mixture was then extracted with diethyl ether The extract was washed with an aqueous solution of sodium thiosulfate dried over magnesium sulfate The solvent was then distilled off The crude product thus obtained was then extracted with hexane (200 ml) The solvent was then distilled off As a result, a crude product was obtained in an amount of 18.62 g The crude product was then recrystallized from ethanol (75 ml)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Bromo-2,6-dichloroaniline (5, 80 g) was dissolved in acetone (640 mL), and a 48% hydrogen bromide aqueous solution (120 mL) was added, followed by stirring at 0° C. A sodium nitrite (32 g) aqueous solution (160 ml,) was added dropwise thereto, the mixture was stirred for 30 minutes, and methyl acrylate (200 nit), and water (200 mL) were added, followed by stirring for 1 hour. At room temperature, cuprous oxide (2 g) was added, followed by stirring for 2 hours. The reaction solution was extracted with ethyl acetate, and purified by column chromatography to obtain methyl (E)-3-(4-bromo-2,6-dichlorophenyl)acrylate (48.5 g). Methyl (E)-3-(4-bromo-2,6-dichlorophenyl)acrylate (48.5 g) was dissolved in dichloromethane, an ozone gas was introduced at −70° C., and ozone oxidization was performed. To the reaction solution was added dimethyl sulfide (40 mL), and this was extracted with ethyl acetate to obtain 4-bromo-2,6-dichlorobenzaldehyde (6, 37.2 g). the mixture was stirred for 30 minutes by stirring for 1 hour by stirring for 2 hours The reaction solution was extracted with ethyl acetate purified by column chromatography

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Bromo-2,6-dichloroaniline (5, 80 g) was dissolved in acetone (640 mL), and a 48% hydrogen bromide aqueous solution (120 mL) was added, followed by stirring at 0° C. A sodium nitrite (32 g) aqueous solution (160 mL) was added dropwise thereto, the mixture was stirred for 30 minutes, and methyl acrylate (200 mL), and water (200 mL) were added, followed by stirring for 1 hour. At room temperature, cuprous oxide (2 g) was added, followed by stirring for 2 hours. The reaction solution was extracted with ethyl acetate, and purified by column chromatography to obtain methyl (E)-3-(4-bromo-2,6-dichlorophenyl)acrylate (48.5 g). Methyl (E)-3-(4-bromo-2,6-dichlorophenyl)acrylate (48.5 g) was dissolved in dichloromethane, an ozone gas was introduced at −70° C., and ozone oxidization was performed. To the reaction solution was added dimethyl sulfide (40 mL), and this was extracted with ethyl acetate to obtain 4-bromo-2,6-dichlorobenzaldehyde (6, 37.2 g). the mixture was stirred for 30 minutes by stirring for 1 hour by stirring for 2 hours The reaction solution was extracted with ethyl acetate purified by column chromatography

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

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Bromo-2,6-dichloroaniline (5, 80 g) was dissolved in acetone (640 mL), and a 48% hydrogen bromide aqueous solution (120 mL) was added, followed by stirring at 0° C. A sodium nitrite (32 g) aqueous solution (160 mL) was added dropwise thereto, the mixture was stirred for 30 minutes, and methyl acrylate (200 mL), and water (200 mL) were added, followed by stirring for 1 hour. At room temperature, cuprous oxide (2 g) was added, followed by stirring for 2 hours. The reaction solution was extracted with ethyl acetate, and purified by column chromatography to obtain methyl (E)-3-(4-bromo-2,6-dichlorophenyl)acrylate (48.5 g). Methyl (E)-3-(4-bromo-2,6-dichlorophenyl)acrylate (48.5 g) was dissolved in dichloromethane, an ozone gas was introduced at −70° C., and ozone oxidization was performed. To the reaction solution was added dimethyl sulfide (40 mL), and this was extracted with ethyl acetate to obtain 4-bromo-2,6-dichlorobenzaldehyde (6, 37.2 g). the mixture was stirred for 30 minutes by stirring for 1 hour by stirring for 2 hours The reaction solution was extracted with ethyl acetate purified by column chromatography

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

Procedure: The title compound (0.4 g) was prepared from 4-bromo-2,6-dichloroaniline (0.5 g, 2.1 mmol) and 2-chlorophenylboronic acid (0.421 g, 2.7 mmol) as a white solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.55-7.50 (m, 1H), 7.40-7.32 (m, 3H), 7.29 (s, 2H), 5.72 (s, 2H).

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

Procedure: The title compound (0.367 g) was prepared from 4-Bromo-2,6-dichloro aniline (0.5 g, 1.9 mmol) and 2-fluorophenylboronic acid (0.363 g, 2.6 mmol) as a white solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.50 (t, J 6.3, 1H), 7.43 (s, 2H), 7.39-7.31 (m, 1H), 7.29-7.21 (m, 2H), 5.73 (s, 2H).