7-bromo-4H-1,4-benzoxazin-3-one

反応条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of N-(4-bromo-2-fluorophenyl)-2-hydroxyacetamide (8.0 g, 32.3 mmol) in 50 ml dry DMF was added drop wise to a suspension of sodium hydride (5.2 g, 129 mmol) in 30 ml dry DMF and the mixture was stirred for 2 h under an atmosphere of nitrogen at 140° C. After cooling to ambient temperature water was added and the mixture was extracted several times with ethyl acetate. After washing the combined organic layers with brine and drying over MgSO4 the solvent was removed under reduced pressure and the crude product was obtained as a pale yellow solid. Purification by flash chromatography on silica gel (dichloromethane/methanol, 97/3, Rf=0.35) yielded 7-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (2.3 g, 10.1 mmol, 31%) as off-white solid. was added the mixture was extracted several times with ethyl acetate After washing the combined organic layers with brine drying over MgSO4 the solvent was removed under reduced pressure the crude product was obtained as a pale yellow solid Purification by flash chromatography on silica gel (dichloromethane/methanol, 97/3, Rf=0.35)

反応条件: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of 2-amino-5-bromophenol (51.3 g, 273 mmol) and NaHCO3 (68.8 g, 819 mmol) in water (200 mL) and DME (200 mL) was added 2-chloroacetyl chloride (46.2 g, 409 mmol) at 0° C. and the reaction mixture was stirred at 15° C. for 0.5 h then heated at 80° C. for 18 h. The reaction mixture was cooled to ambient temperature. The precipitate was collected by suction, washed with water and dried in vacuo to give 7-bromo-4H-benzo[1,4]oxazin-3-one (59.7 g, 96%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 10.83 (br s, 1H), 7.17 (s, 1H), 7.12 (d, J=8.4 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 4.59 (s, 2H). then heated at 80° C. for 18 h The reaction mixture was cooled to ambient temperature The precipitate was collected by suction washed with water dried in vacuo

反応条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of N-(4-bromo-2-fluorophenyl)-2-hydroxyacetamide (8.0 g, 32.3 mmol) in 50 ml dry DMF was added drop wise to a suspension of sodium hydride (5.2 g, 129 mmol) in 30 ml dry DMF and the mixture was stirred for 2 h under an atmosphere of nitrogen at 140° C. After cooling to ambient temperature water was added and the mixture was extracted several times with ethyl acetate. After washing the combined organic layers with brine and drying over MgSO4 the solvent was removed under reduced pressure and the crude product was obtained as a pale yellow solid. Purification by flash chromatography on silica gel (dichloromethane/methanol, 97/3, Rf=0.35) yielded 7-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (2.3 g, 10.1 mmol, 31%) as off-white solid. was added the mixture was extracted several times with ethyl acetate After washing the combined organic layers with brine drying over MgSO4 the solvent was removed under reduced pressure the crude product was obtained as a pale yellow solid Purification by flash chromatography on silica gel (dichloromethane/methanol, 97/3, Rf=0.35)

反応条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of N-(4-bromo-2-fluorophenyl)-2-hydroxyacetamide (8.0 g, 32.3 mmol) in 50 ml dry DMF was added drop wise to a suspension of sodium hydride (5.2 g, 129 mmol) in 30 ml dry DMF and the mixture was stirred for 2 h under an atmosphere of nitrogen at 140° C. After cooling to ambient temperature water was added and the mixture was extracted several times with ethyl acetate. After washing the combined organic layers with brine and drying over MgSO4 the solvent was removed under reduced pressure and the crude product was obtained as a pale yellow solid. Purification by flash chromatography on silica gel (dichloromethane/methanol, 97/3, Rf=0.35) yielded 7-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (2.3 g, 10.1 mmol, 31%) as off-white solid. was added the mixture was extracted several times with ethyl acetate After washing the combined organic layers with brine drying over MgSO4 the solvent was removed under reduced pressure the crude product was obtained as a pale yellow solid Purification by flash chromatography on silica gel (dichloromethane/methanol, 97/3, Rf=0.35)

反応条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of N-(4-bromo-2-fluorophenyl)-2-hydroxyacetamide (8.0 g, 32.3 mmol) in 50 ml dry DMF was added drop wise to a suspension of sodium hydride (5.2 g, 129 mmol) in 30 ml dry DMF and the mixture was stirred for 2 h under an atmosphere of nitrogen at 140° C. After cooling to ambient temperature water was added and the mixture was extracted several times with ethyl acetate. After washing the combined organic layers with brine and drying over MgSO4 the solvent was removed under reduced pressure and the crude product was obtained as a pale yellow solid. Purification by flash chromatography on silica gel (dichloromethane/methanol, 97/3, Rf=0.35) yielded 7-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (2.3 g, 10.1 mmol, 31%) as off-white solid. was added the mixture was extracted several times with ethyl acetate After washing the combined organic layers with brine drying over MgSO4 the solvent was removed under reduced pressure the crude product was obtained as a pale yellow solid Purification by flash chromatography on silica gel (dichloromethane/methanol, 97/3, Rf=0.35)

反応条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of N-(4-bromo-2-fluorophenyl)-2-hydroxyacetamide (8.0 g, 32.3 mmol) in 50 ml dry DMF was added drop wise to a suspension of sodium hydride (5.2 g, 129 mmol) in 30 ml dry DMF and the mixture was stirred for 2 h under an atmosphere of nitrogen at 140° C. After cooling to ambient temperature water was added and the mixture was extracted several times with ethyl acetate. After washing the combined organic layers with brine and drying over MgSO4 the solvent was removed under reduced pressure and the crude product was obtained as a pale yellow solid. Purification by flash chromatography on silica gel (dichloromethane/methanol, 97/3, Rf=0.35) yielded 7-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (2.3 g, 10.1 mmol, 31%) as off-white solid. was added the mixture was extracted several times with ethyl acetate After washing the combined organic layers with brine drying over MgSO4 the solvent was removed under reduced pressure the crude product was obtained as a pale yellow solid Purification by flash chromatography on silica gel (dichloromethane/methanol, 97/3, Rf=0.35)

反応条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of N-(4-bromo-2-fluorophenyl)-2-hydroxyacetamide (8.0 g, 32.3 mmol) in 50 ml dry DMF was added drop wise to a suspension of sodium hydride (5.2 g, 129 mmol) in 30 ml dry DMF and the mixture was stirred for 2 h under an atmosphere of nitrogen at 140° C. After cooling to ambient temperature water was added and the mixture was extracted several times with ethyl acetate. After washing the combined organic layers with brine and drying over MgSO4 the solvent was removed under reduced pressure and the crude product was obtained as a pale yellow solid. Purification by flash chromatography on silica gel (dichloromethane/methanol, 97/3, Rf=0.35) yielded 7-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (2.3 g, 10.1 mmol, 31%) as off-white solid. was added the mixture was extracted several times with ethyl acetate After washing the combined organic layers with brine drying over MgSO4 the solvent was removed under reduced pressure the crude product was obtained as a pale yellow solid Purification by flash chromatography on silica gel (dichloromethane/methanol, 97/3, Rf=0.35)

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

実験手順: Part 2. A solution of 2-amino-5-bromophenol (2.53 g, 18.2 mmol, 1.0 equiv) in 15 mL of isobutylmethyl ketone and 15 mL of water was cooled to 0° C., NaHCO3 (3.67 g, 2.4 equiv) and then chloroacetyl chloride (2.36 g, 1.67 mL, 1.15 equiv) were added. The mixture was heated to reflux overnight, then cooled to room temperature. The mixture was diluted with ethyl acetate, washed with water, dried over MgSO4, and concentrated in vacuo. Flash chromatography on silica gel gave 7-bromo-3,4-dihydro-2H-1,4-benzoxazin-3-one in 77% yield. LRMS found for C9H10NO3 (M+H)+: 180.1. The mixture was heated to reflux overnight washed with water dried over MgSO4 concentrated in vacuo

反応条件: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of 2-amino-5-bromophenol (51.3 g, 273 mmol) and NaHCO3 (68.8 g, 819 mmol) in water (200 mL) and DME (200 mL) was added 2-chloroacetyl chloride (46.2 g, 409 mmol) at 0° C. and the reaction mixture was stirred at 15° C. for 0.5 h then heated at 80° C. for 18 h. The reaction mixture was cooled to ambient temperature. The precipitate was collected by suction, washed with water and dried in vacuo to give 7-bromo-4H-benzo[1,4]oxazin-3-one (59.7 g, 96%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 10.83 (br s, 1H), 7.17 (s, 1H), 7.12 (d, J=8.4 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 4.59 (s, 2H). then heated at 80° C. for 18 h The reaction mixture was cooled to ambient temperature The precipitate was collected by suction washed with water dried in vacuo