4-bromo-3-methylbenzene-1,2-diamine

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 3-bromo-2-methyl-6-nitroaniline (0.45 g, 1.95 mmol) in EtOH (6 mL) was added tin(II) chloride (1.48 g, 7.8 mmol), and the resulting solution was stirred at 70° C. for 4 hours. The mixture was cooled to room temperature and poured into water, and 1 N aq. NaOH was added to adjust to pH>7. The resulting mixture was extracted with CH2Cl2 (2×), and the combined extracts were dried over Na2SO4. The drying agent was filtered off and solvent was removed in vacuo to give the title compound as an oil (0.34 g, 88%). The mixture was cooled to room temperature was added The resulting mixture was extracted with CH2Cl2 (2×) the combined extracts were dried over Na2SO4 The drying agent was filtered off solvent was removed in vacuo

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 3-bromo-2-methyl-6-nitroaniline (0.45 g, 1.95 mmol) in EtOH (6 mL) was added tin(II) chloride (1.48 g, 7.8 mmol), and the resulting solution was stirred at 70° C. for 4 hours. The mixture was cooled to room temperature and poured into water, and 1 N aq. NaOH was added to adjust to pH>7. The resulting mixture was extracted with CH2Cl2 (2×), and the combined extracts were dried over Na2SO4. The drying agent was filtered off and solvent was removed in vacuo to give the title compound as an oil (0.34 g, 88%). The mixture was cooled to room temperature was added The resulting mixture was extracted with CH2Cl2 (2×) the combined extracts were dried over Na2SO4 The drying agent was filtered off solvent was removed in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 4-bromo-3-methylbenzene-1,2-diamine (prepared according to the procedure of PCT Pat. Appl. WO 2008/021851, 400 mg, 1.989 mmol) in DCM (10 mL) was treated with TEA (0.693 mL, 4.97 mmol), then was treated dropwise with 4-fluorobenzoyl chloride (0.282 mL, 2.387 mmol). The mixture was stirred at rt for 70 min, then was concentrated. The residue was suspended in ethanol (25 mL), treated with concentrated hydrochloric acid (3 mL, 36.5 mmol) and heated at 90-95° C. After 42.5 h, the mixture was cooled to rt and the ethanol was removed under vacuum. The residual paste was suspended in water and the pH was adjusted to ca. 8 with NaHCO3 (aq). The precipitate was collected by filtration, washed with water and dried under vacuum to provide 6-bromo-2-(4-fluorophenyl)-7-methyl-1H-benzo[d]imidazole as a pale pink solid (636 mg, 95%). 1H NMR (400 MHz, DMSO-d6) δ 8.24 (2H, dd, J=8.9, 5.4 Hz), 7.33-7.45 (4H, m), 2.57 (3H, s). Mass spectrum m/z 305, 307 (M+H)+. was concentrated heated at 90-95° C After 42.5 h the mixture was cooled to rt the ethanol was removed under vacuum The precipitate was collected by filtration washed with water dried under vacuum

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 156 (28 g, 140 mmol), formic acid (240 mL) and 37% concentrated HCl (400 mL) was heated to 60° C. for 12 h, cooled in an ice-water bath, and the pH slowly adjusted to 8-9 with 28% concentrated NH4OH. The solid was collected by filtration, washed with water and dried in air to afford 25 g (98%) of 5-bromo-4-methyl-1H-benzo[d]imidazole (158) as a yellow solid: MS (ESI) m/z=213 [M+1]+. cooled in an ice-water bath The solid was collected by filtration washed with water dried in air

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 154 (40 g, 154 mmol), SnCl2.2H2O (208 g, 920 mmol), EtOAc (300 mL) and EtOH (150 mL) was heated to 80° C. for 12 h, cooled to RT, poured into crushed ice (2 Kg) and the pH adjusted to pH 7-8 with solid NaHCO3. The solid was filtered and washed with EtOAc. The filtrate was thrice extracted with EtOAc. The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (10 to 50% EtOAc) to afford 28 g (91%) of 4-bromo-3-methyl-1,2-benzenediamine (156) as a brown oil: MS (ESI) m/z=202 [M+1]+. cooled to RT poured The solid was filtered washed with EtOAc extracted with EtOAc The combined extracts were washed with brine dried (Na2SO4) filtered concentrated in vacuo The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (10 to 50% EtOAc)

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 154 (40 g, 154 mmol), SnCl2.2H2O (208 g, 920 mmol), EtOAc (300 mL) and EtOH (150 mL) was heated to 80° C. for 12 h, cooled to RT, poured into crushed ice (2 Kg) and the pH adjusted to pH 7-8 with solid NaHCO3. The solid was filtered and washed with EtOAc. The filtrate was thrice extracted with EtOAc. The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (10 to 50% EtOAc) to afford 28 g (91%) of 4-bromo-3-methyl-1,2-benzenediamine (156) as a brown oil: MS (ESI) m/z=202 [M+1]+. cooled to RT poured The solid was filtered washed with EtOAc extracted with EtOAc The combined extracts were washed with brine dried (Na2SO4) filtered concentrated in vacuo The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (10 to 50% EtOAc)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 4-bromo-3-methylbenzene-1,2-diamine (prepared according to the procedure of PCT Pat. Appl. WO 2008/021851, 400 mg, 1.989 mmol) in DCM (10 mL) was treated with TEA (0.693 mL, 4.97 mmol), then was treated dropwise with 4-fluorobenzoyl chloride (0.282 mL, 2.387 mmol). The mixture was stirred at rt for 70 min, then was concentrated. The residue was suspended in ethanol (25 mL), treated with concentrated hydrochloric acid (3 mL, 36.5 mmol) and heated at 90-95° C. After 42.5 h, the mixture was cooled to rt and the ethanol was removed under vacuum. The residual paste was suspended in water and the pH was adjusted to ca. 8 with NaHCO3 (aq). The precipitate was collected by filtration, washed with water and dried under vacuum to provide 6-bromo-2-(4-fluorophenyl)-7-methyl-1H-benzo[d]imidazole as a pale pink solid (636 mg, 95%). 1H NMR (400 MHz, DMSO-d6) δ 8.24 (2H, dd, J=8.9, 5.4 Hz), 7.33-7.45 (4H, m), 2.57 (3H, s). Mass spectrum m/z 305, 307 (M+H)+. was concentrated heated at 90-95° C After 42.5 h the mixture was cooled to rt the ethanol was removed under vacuum The precipitate was collected by filtration washed with water dried under vacuum

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 3-bromo-2-methyl-6-nitroaniline (0.45 g, 1.95 mmol) in EtOH (6 mL) was added tin(II) chloride (1.48 g, 7.8 mmol), and the resulting solution was stirred at 70° C. for 4 hours. The mixture was cooled to room temperature and poured into water, and 1 N aq. NaOH was added to adjust to pH>7. The resulting mixture was extracted with CH2Cl2 (2×), and the combined extracts were dried over Na2SO4. The drying agent was filtered off and solvent was removed in vacuo to give the title compound as an oil (0.34 g, 88%). The mixture was cooled to room temperature was added The resulting mixture was extracted with CH2Cl2 (2×) the combined extracts were dried over Na2SO4 The drying agent was filtered off solvent was removed in vacuo

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 3-bromo-2-methyl-6-nitroaniline (0.45 g, 1.95 mmol) in EtOH (6 mL) was added tin(II) chloride (1.48 g, 7.8 mmol), and the resulting solution was stirred at 70° C. for 4 hours. The mixture was cooled to room temperature and poured into water, and 1 N aq. NaOH was added to adjust to pH>7. The resulting mixture was extracted with CH2Cl2 (2×), and the combined extracts were dried over Na2SO4. The drying agent was filtered off and solvent was removed in vacuo to give the title compound as an oil (0.34 g, 88%). The mixture was cooled to room temperature was added The resulting mixture was extracted with CH2Cl2 (2×) the combined extracts were dried over Na2SO4 The drying agent was filtered off solvent was removed in vacuo

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 3-bromo-2-methyl-6-nitroaniline (0.45 g, 1.95 mmol) in EtOH (6 mL) was added tin(II) chloride (1.48 g, 7.8 mmol), and the resulting solution was stirred at 70° C. for 4 hours. The mixture was cooled to room temperature and poured into water, and 1 N aq. NaOH was added to adjust to pH>7. The resulting mixture was extracted with CH2Cl2 (2×), and the combined extracts were dried over Na2SO4. The drying agent was filtered off and solvent was removed in vacuo to give the title compound as an oil (0.34 g, 88%). The mixture was cooled to room temperature was added The resulting mixture was extracted with CH2Cl2 (2×) the combined extracts were dried over Na2SO4 The drying agent was filtered off solvent was removed in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 4-bromo-3-methylbenzene-1,2-diamine (prepared according to the procedure of PCT Pat. Appl. WO 2008/021851, 400 mg, 1.989 mmol) in DCM (10 mL) was treated with TEA (0.693 mL, 4.97 mmol), then was treated dropwise with 4-fluorobenzoyl chloride (0.282 mL, 2.387 mmol). The mixture was stirred at rt for 70 min, then was concentrated. The residue was suspended in ethanol (25 mL), treated with concentrated hydrochloric acid (3 mL, 36.5 mmol) and heated at 90-95° C. After 42.5 h, the mixture was cooled to rt and the ethanol was removed under vacuum. The residual paste was suspended in water and the pH was adjusted to ca. 8 with NaHCO3 (aq). The precipitate was collected by filtration, washed with water and dried under vacuum to provide 6-bromo-2-(4-fluorophenyl)-7-methyl-1H-benzo[d]imidazole as a pale pink solid (636 mg, 95%). 1H NMR (400 MHz, DMSO-d6) δ 8.24 (2H, dd, J=8.9, 5.4 Hz), 7.33-7.45 (4H, m), 2.57 (3H, s). Mass spectrum m/z 305, 307 (M+H)+. was concentrated heated at 90-95° C After 42.5 h the mixture was cooled to rt the ethanol was removed under vacuum The precipitate was collected by filtration washed with water dried under vacuum

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 156 (28 g, 140 mmol), formic acid (240 mL) and 37% concentrated HCl (400 mL) was heated to 60° C. for 12 h, cooled in an ice-water bath, and the pH slowly adjusted to 8-9 with 28% concentrated NH4OH. The solid was collected by filtration, washed with water and dried in air to afford 25 g (98%) of 5-bromo-4-methyl-1H-benzo[d]imidazole (158) as a yellow solid: MS (ESI) m/z=213 [M+1]+. cooled in an ice-water bath The solid was collected by filtration washed with water dried in air