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

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

実験手順: To a mixture of 6-bromo-7-fluoro-4H-benzo[1,4]oxazin-3-one (41.0 g, 167 mmol) and K2CO3 (23.0 g, 167 mmol) in acetone (300 mL) was added ethyl 2-bromopropanoate (75.0 g, 53.8 mL, 417 mmol) drop-wise at ambient temperature and the mixture was heated at reflux overnight. The mixture was cooled to ambient temperature and filtered. The filtrate was evaporated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 10% EtOAc in petroleum ether) to give 2-(6-bromo-7-fluoro-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (43.0 g, 75%). 1H NMR (CDCl3, 400 MHz): δ 6.97 (d, J=6.4 Hz, 1H), 6.85 (d, J=8.4 Hz, 1H), 5.25 (q, J=7.2 Hz, 1H), 4.59 (dd, J=15.2 Hz, 2H), 4.27 (m, 2H), 1.63 (d, J=7.2 Hz, 3H), 1.23 (t, J=7.2 Hz, 3H). the mixture was heated at reflux overnight filtered The filtrate was evaporated in vacuo the residue was purified by column chromatography on silica gel (eluting with 10% EtOAc in petroleum ether)

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

実験手順: To a 0° C. mixture of 2-amino-4-bromo-5-fluorophenol (38.0 g, crude from previous step) and K2CO3 (76.0 g, 553 mmol) in DMF (100 mL) was added 2-chloroacetyl chloride (23.0 g, 15.3 mL, 203 mmol) drop-wise. The reaction mixture was heated at 80° C. overnight then cooled to ambient temperature and poured into water (300 mL). The precipitate was collected by filtration, washed with water and dried to give 6-bromo-7-fluoro-4H-benzo[1,4]oxazin-3-one (41.0 g, 90%). 1H NMR (DMSO-d6, 400 MHz): δ 7.13 (m, 2H), 4.62 (s, 2H). The amide proton was not observed. then cooled to ambient temperature The precipitate was collected by filtration washed with water dried

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

実験手順: To a mixture of 6-bromo-7-fluoro-4H-benzo[1,4]oxazin-3-one (41.0 g, 167 mmol) and K2CO3 (23.0 g, 167 mmol) in acetone (300 mL) was added ethyl 2-bromopropanoate (75.0 g, 53.8 mL, 417 mmol) drop-wise at ambient temperature and the mixture was heated at reflux overnight. The mixture was cooled to ambient temperature and filtered. The filtrate was evaporated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 10% EtOAc in petroleum ether) to give 2-(6-bromo-7-fluoro-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (43.0 g, 75%). 1H NMR (CDCl3, 400 MHz): δ 6.97 (d, J=6.4 Hz, 1H), 6.85 (d, J=8.4 Hz, 1H), 5.25 (q, J=7.2 Hz, 1H), 4.59 (dd, J=15.2 Hz, 2H), 4.27 (m, 2H), 1.63 (d, J=7.2 Hz, 3H), 1.23 (t, J=7.2 Hz, 3H). the mixture was heated at reflux overnight filtered The filtrate was evaporated in vacuo the residue was purified by column chromatography on silica gel (eluting with 10% EtOAc in petroleum ether)

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

実験手順: To a 0° C. mixture of 2-amino-4-bromo-5-fluorophenol (38.0 g, crude from previous step) and K2CO3 (76.0 g, 553 mmol) in DMF (100 mL) was added 2-chloroacetyl chloride (23.0 g, 15.3 mL, 203 mmol) drop-wise. The reaction mixture was heated at 80° C. overnight then cooled to ambient temperature and poured into water (300 mL). The precipitate was collected by filtration, washed with water and dried to give 6-bromo-7-fluoro-4H-benzo[1,4]oxazin-3-one (41.0 g, 90%). 1H NMR (DMSO-d6, 400 MHz): δ 7.13 (m, 2H), 4.62 (s, 2H). The amide proton was not observed. then cooled to ambient temperature The precipitate was collected by filtration washed with water dried