2-(2-amino-5-bromophenyl)propan-2-ol

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2-(2-amino-5-bromophenyl)propan-2-ol (18 g, 78 mmol) in dry THF (150 mL) was added 1,1′-carbonyldiimidazole (15.5 g, 94 mmol) under nitrogen. The reaction solution was heated at 50° C. overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (100 mL). The solution was washed with 1N aqueous hydrochloride solution (2×40 mL), brine (20 mL), and dried with MgSO4. After removal of solvent in vacuo, 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one was obtained as a white solid (20 g, 100%): mp 199-200° C.; 1H-NMR (DMSO-d6) δ10.32 (s, 1H, D2O exchangeable), 7.48 (d, 1H, J=2.1 Hz), 7.43 (dd, 1H, J=8.5, 2.1 Hz), 6.84 (d, 1H, J=8.4 Hz), 161 (s, 6H). The solvent was removed in vacuo the residue was dissolved in ethyl acetate (100 mL) The solution was washed with 1N aqueous hydrochloride solution (2×40 mL), brine (20 mL) dried with MgSO4 After removal of solvent 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 2-amino-5-bromobenzoic acid (10 g, 46 mmol) in dry THF (200 mL) was treated at −78° C. under nitrogen with a solution of methylmagnesium bromide in ether (3.0 M, 90 mL, 270 mmol). The reaction mixture was slowly warmed to ambient temperature, kept stirring for 48 hours under nitrogen and then poured into a cold 0.5 N aqueous hydrochloride solution (300 mL). The mixture was neutralized with aqueous 1 N sodium hydroxide solution and ethyl acetate (300 mL) was added. The organic layer was separated and aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine and dried (MgSO4). After removal of solvent in vacuo, the residue was purified by a silica gel flash chromatography (hexane:ethyl acetate/3:2) to give 2-(2-amino-5-bromophenyl)propan-2-ol as off-white solid (6 g, 57%): mp 62-63° C.; 1H-NMR (CDCl3) δ7.19 (d, 1H, J=2.3 Hz), 7.12 (dd, 1H, J=8.4, 2.3 Hz), 6.51 (d, 1H, J=8.4 Hz), 4.70 (s, 2H), 1.82 (s, 1H), 1.65 (s, 6H). was added The organic layer was separated aqueous layer was extracted with ethyl acetate (3×100 mL) The combined organic layers were washed with brine dried (MgSO4) After removal of solvent in vacuo the residue was purified by a silica gel flash chromatography (hexane:ethyl acetate/3:2)

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2-(2-amino-5-bromophenyl)propan-2-ol (18 g, 78 mmol) in dry THF (150 mL) was added 1,1′-carbonyldiimidazole (15.5 g, 94 mmol) under nitrogen. The reaction solution was heated at 50° C. overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (100 mL). The solution was washed with 1N aqueous hydrochloride solution (2×40 mL), brine (20 mL), and dried with MgSO4. After removal of the solvent in vacuo, 6-bromo-4,4-dimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one was obtained as a white solid (20 g, 100%): mp 199-200° C.; 1H-NMR (DMSO-d6) δ 10.32 (s, 1H, D2O exchangeable), 7.48 (d, 1H, J=2.1 Hz), 7.43 (dd, 1H, J=8.5, 2.1 Hz), 6.84 (d, 1H, J=8.4 Hz), 1.61 (s, 6H). The solvent was removed in vacuo the residue was dissolved in ethyl acetate (100 mL) The solution was washed with 1N aqueous hydrochloride solution (2×40 mL), brine (20 mL) dried with MgSO4 After removal of the solvent 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 2-amino-5-bromobenzoic acid (10 g, 46 mmol) in dry THF (200 mL) was treated at −78° C. under nitrogen with a solution of methylmagnesium bromide in ether (3.0 M, 90 mL, 270 mmol). The reaction mixture was slowly warmed to ambient temperature, kept stirring for 48 hours under nitrogen and then poured into a cold 0.5 N aqueous hydrochloride solution (300 mL). The mixture was neutralized with aqueous 1 N sodium hydroxide solution and ethyl acetate (300 mL) was added. The organic layer was separated and aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine and dried (MgSO4). After removal of solvent in vacuo, the residue was purified by a silica gel flash chromatography (hexane:ethyl acetate/3:2) to give 2-(2-amino-5-bromophenyl)propan-2-ol as an off-white solid (6 g, 57%): mp 62-63° C.; 1H-NMR (CDCl3) δ 7.19 (d, 1H, J=2.3 Hz), 7.12 (dd, 1H, J=8.4, 2.3 Hz), 6.51 (d, 1H, J=8.4 Hz), 4.70 (s, 2H), 1.82 (s, 1H), 1.65 (s, 6H). was added The organic layer was separated aqueous layer was extracted with ethyl acetate (3×100 mL) The combined organic layers were washed with brine dried (MgSO4) After removal of solvent in vacuo the residue was purified by a silica gel flash chromatography (hexane:ethyl acetate/3:2)

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

実験手順: A mixture of 2-(2-amino-5-bromo-phenyl)-propan-2-ol (5 g, 21.7 mmol), trifluoroacetaldehyde methyl hemiacetal (5 mL), and magnesium sulfate (10 g) in toluene (75 mL) was heated at 80° C. under nitrogen. After disappearance of the starting material, the reaction was filtered through a pad of silica gel and the filtrate dried over sodium sulfate and concentrated to give 6-bromo-4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazine as an amorphous solid: 1H-NMR (DMSO-d6) δ 7.31 (d, 1H, J=1.99 Hz), 7.19 (dd, 1H, J=8.73, 2.38 Hz), 6.88 (s, 1H), 6.74 (d, 1H, J=8.33 Hz), 5.32 (m, 1H), 1.52 (s, 6H). After disappearance of the starting material, the reaction was filtered through a pad of silica gel the filtrate dried over sodium sulfate concentrated

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

実験手順: A mixture of 2-(2-amino-5-bromo-phenyl)-propan-2-ol (5 g, 21.7 mmol), trifluoroacetaldehyde methyl hemiacetal (5 mL), and magnesium sulfate (10 g) in toluene (75 mL) was heated at 80° C. under nitrogen. After disappearance of the starting material, the reaction was filtered through a pad of silica gel and the filtrate dried over sodium sulfate and concentrated to give 6-bromo-4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazine as an amorphous solid: 1H-NMR (DMSO-d6) δ 7.31 (d, 1H, J=1.99 Hz), 7.19 (dd, 1H, J=8.73, 2.38 Hz), 6.88 (s, 1H), 6.74 (d, 1H, J=8.33 Hz), 5.32 (m, 1H), 1.52 (s, 6H). After disappearance of the starting material, the reaction was filtered through a pad of silica gel the filtrate dried over sodium sulfate concentrated

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

実験手順: To a solution of 2-(2-amino-5-bromophenyl)propan-2-ol (27 g, 125 mmol) in anhydrous toluene was added at ambient temperature under a blanket of nitrogen acetylaldehyde (10.5 mL, 187 mmol). After 10 minutes, the mixture was passed through a pad of silica gel and filtrate was concentrated to yield 6-bromo-2,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazine as off-white solid (25 g, 78%): 1H-NMR (DMSO-d6) δ 7.22 (d, 1H, J=2.2 Hz), 7.08 (dd, 1H, J=8.6, 2.3 Hz), 6.51 (d, 1H, J=8.6 Hz), 6.36 (s, 1H), 4.72 (m, 1H), 1.45 (s, 3H), 1.40 (s, 3H), 1.25 (d, 3H, J=5.5 Hz). was concentrated

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

実験手順: To a solution of 2-(2-amino-5-bromophenyl)propan-2-ol (27 g, 125 mmol) in anhydrous toluene was added at ambient temperature under a blanket of nitrogen acetylaldehyde (10.5 mL, 187 mmol). After 10 minutes, the mixture was passed through a pad of silica gel and filtrate was concentrated to yield 6-bromo-2,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazine as off-white solid (25 g, 78%): 1H-NMR (DMSO-d6) δ 7.22 (d, 1H, J=2.2 Hz), 7.08 (dd, 1H, J=8.6, 2.3 Hz), 6.51 (d, 1H, J=8.6 Hz), 6.36 (s, 1H), 4.72 (m, 1H), 1.45 (s, 3H), 1.40 (s, 3H), 1.25 (d, 3H, J=5.5 Hz). was concentrated

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

実験手順: A solution of 2-amino-5-bromobenzoic acid (10 g, 46 mmol) in dry THF (200 mL) was treated at −78° C. under nitrogen with a solution of methylmagnesium bromide in ether (3.0 M, 90 mL, 270 mmol). The reaction mixture was slowly warmed to ambient temperature, kept stirring for 48 hours under nitrogen and then poured into a cold 0.5 N aqueous hydrochloride solution (300 mL). The mixture was neutralized with aqueous 1 N sodium hydroxide solution and ethyl acetate (300 mL) was added. The organic layer was separated and aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine and dried (MgSO4). After removal of solvent in vacuo, the residue was purified by a silica gel flash column chromatography (hexane:ethyl acetate/3:2) to give 2-(2-amino-5-bromophenyl)propan-2-ol as off-white solid (6 g, 57%): mp 62-63° C.; 1H-NMR (CDCl3) δ 7.19 (d, 1H, J=2.3 Hz), 7.12 (dd, 1H, J=8.4, 2.3 Hz), 6.51 (d, 1H, J=8.4 Hz), 4.70 (s, 2H), 1.82 (s, 1H), 1.65 (s, 6H). was added The organic layer was separated aqueous layer was extracted with ethyl acetate (3×100 mL) The combined organic layers were washed with brine dried (MgSO4) After removal of solvent in vacuo the residue was purified by a silica gel flash column chromatography (hexane:ethyl acetate/3:2)