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

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:; See reaction.notes.procedure_details.

実験手順: Triethylamine (2.4 mL, 17 mmol) was added to 2-amino-4-bromophenol (2.5 g, 13 mmol) in THF (80 mL). The reaction was cooled in ice and chloroacetyl chloride (1.12 mL, 14 mmol) added portionwise. It was stirred with cooling for 10 min then allowed to warm to r.t. and stirred for a further 2 h. The reaction mixture was cooled in ice and sodium hydride (1.05 g of a 60% suspension in oil, 26 mmol) was added portionwise. The mixture was stirred with ice-bath cooling for 20 min then at r.t. for 2 h before being quenched with water (20 mL). The THF was removed in vacuo and the resulting mixture diluted with water (100 mL). The precipitate was filtered off, washed with water (3×50 mL) and dried in vacuo to yield the title compound as a beige solid (2.14 g, 70%). δH (DMSO-d6) 4.60 (2H, s), 6.92 (1H, d, J 8.5 Hz), 7.02 (1H, d, J 2.3 Hz), 7.08 (1H, dd, J 8.5, 2.3 Hz), 10.81 (1H, br s). The reaction was cooled in ice with cooling for 10 min stirred for a further 2 h The reaction mixture was cooled in ice The mixture was stirred with ice-bath cooling for 20 min at r.t. for 2 h before being quenched with water (20 mL) The THF was removed in vacuo the resulting mixture diluted with water (100 mL) The precipitate was filtered off washed with water (3×50 mL) dried in vacuo

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

実験手順: 2-Amino-4-bromophenol (2.1 g, 11 mmol) and bromo acetyl bromide (1.4 mL, 16.5 mmol) were reacted according to the procedure for Intermediate 60 to afford product as a solid, 2.1 g (85%). to afford product as a solid, 2.1 g (85%)

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

実験手順: 2-Amino-4-bromophenol (2.1 g, 11 mmol) and bromo acetyl bromide (1.4 mL, 16.5 mmol) were reacted according to the procedure for Intermediate 60 to afford product as a solid, 2.1 g (85%). to afford product as a solid, 2.1 g (85%)

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The suspension of 9.87 g of 6-bromo-4H-benzo[1,4]oxazin-3-one [24036-52-0], 9.40 g of 1-chloro-3-methoxypropane, potassium fluoride on alumina (Fluka 60244), 0.144 g of potassium iodide in 500 ml of acetonitrile is stirred at 100° C. over 40 hours. The reaction mixture is cooled to room temperature and filtered through Hyflo, and the filtrate is concentrated by evaporation to dryness. The title compound is obtained as a slightly yellowish solid from the residue by crystallization from ethyl acetate. Rf=0.43 (1:1 EtOAc-heptane). Rt=4.27 (gradient I). m.p. 193-195° C. The reaction mixture is cooled to room temperature filtered through Hyflo the filtrate is concentrated by evaporation to dryness

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The suspension of 9.87 g of 6-bromo-4H-benzo[1,4]oxazin-3-one [24036-52-0], 9.40 g of 1-chloro-3-methoxypropane, potassium fluoride on alumina (Fluka 60244), 0.144 g of potassium iodide in 500 ml of acetonitrile is stirred at 100° C. over 40 hours. The reaction mixture is cooled to room temperature and filtered through Hyflo, and the filtrate is concentrated by evaporation to dryness. The title compound is obtained as a slightly yellowish solid from the residue by crystallization from ethyl acetate. Rf=0.43 (1:1 EtOAc-heptane). Rt=4.27 (gradient I). m.p. 193-195° C. The reaction mixture is cooled to room temperature filtered through Hyflo the filtrate is concentrated by evaporation to dryness

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: NEt3 (2.4 mL, 17 mmol) was added to 2-amino-4-bromophenol (2.5 g, 13 mmol) in THF (80 mL). The reaction mixture was cooled to 0° C., chloroacetyl chloride (1.12 mL, 14 mmol) was added portionwise and then stirred at 0° C. for 10 minutes before being allowed to warm to r.t. and stirred for a further 2 h. The reaction mixture was cooled to 0° C. and NaH (1.05 g, 60% dispersion in oil, 26 mmol) was added portionwise. The reaction mixture was stirred at 0° C. for 20 minutes then at r.t. for 2 h before being quenched with water (20 mL). The solvent was removed in vacuo and the resulting mixture diluted with water (100 mL). The precipitate was filtered, washed with water (3×50 mL) and dried in vacuo to give the title compound (2.14 g, 70%) as a beige solid. δH (DMSO-d6) 10.81 (1H, br. s), 7.08 (1H, dd, J 8.5 and J 2.3 Hz), 7.02 (1H, d, J 2.3 Hz), 6.92 (1H, d, J 8.5 Hz), 4.60 (2H, s). to warm to r.t. stirred for a further 2 h The reaction mixture was cooled to 0° C. The reaction mixture was stirred at 0° C. for 20 minutes at r.t. for 2 h before being quenched with water (20 mL) The solvent was removed in vacuo the resulting mixture diluted with water (100 mL) The precipitate was filtered washed with water (3×50 mL) dried in vacuo

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: NEt3 (2.4 mL, 17 mmol) was added to 2-amino-4-bromophenol (2.5 g, 13 mmol) in THF (80 mL). The reaction mixture was cooled to 0° C., chloroacetyl chloride (1.12 mL, 14 mmol) was added portionwise and then stirred at 0° C. for 10 minutes before being allowed to warm to r.t. and stirred for a further 2 h. The reaction mixture was cooled to 0° C. and NaH (1.05 g, 60% dispersion in oil, 26 mmol) was added portionwise. The reaction mixture was stirred at 0° C. for 20 minutes then at r.t. for 2 h before being quenched with water (20 mL). The solvent was removed in vacuo and the resulting mixture diluted with water (100 mL). The precipitate was filtered, washed with water (3×50 mL) and dried in vacuo to give the title compound (2.14 g, 70%) as a beige solid. δH (DMSO-d6) 10.81 (1H, br. s), 7.08 (1H, dd, J 8.5 and J 2.3 Hz), 7.02 (1H, d, J 2.3 Hz), 6.92 (1H, d, J 8.5 Hz), 4.60 (2H, s). to warm to r.t. stirred for a further 2 h The reaction mixture was cooled to 0° C. The reaction mixture was stirred at 0° C. for 20 minutes at r.t. for 2 h before being quenched with water (20 mL) The solvent was removed in vacuo the resulting mixture diluted with water (100 mL) The precipitate was filtered washed with water (3×50 mL) dried in vacuo

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Under argon atmosphere, sodium carbonate (11.2 mg, 0.11 mmol), water (0.7 mL), and 6-bromo-3,4-dihydro-2H-1,4-benzoxazin-3-one (24.2 mg, 0.11 mmol) were added to a solution of ethyl 2-(tert-butoxy)-2-[2,5-dimethyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-3-yl]acetate (28f) (48 mg, 0.10 mmol) in N,N-dimethylformamide (2.1 mL). The solution was degassed under argon and palladium tetrakis(triphenylphosphine) (23.4 mg, 0.02 mmol) was added. The mixture was heated at 100° C. for 15 hours. The mixture was then cooled at room temperature, water was added and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by preparative TLC (cyclohexane/ethyl acetate 70/30) to afford the desired product (35a) (14 mg, 0.03 mmol, 33%). The solution was degassed under argon The mixture was then cooled at room temperature the aqueous layer was extracted with ethyl acetate The organic layer was washed with brine dried over sodium sulfate filtered evaporated under reduced pressure The residue was purified by preparative TLC (cyclohexane/ethyl acetate 70/30)

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-4H-benzo[1,4]oxazin-3-one (59 g, 259 mmol) in anhydrous THF (800 mL) was added KHMDS solution (1M in THF, 259 mL, 259 mmol) drop-wise at 0° C. and the reaction mixture was stirred for 30 min. (S)-2-trifluoromethanesulfonyloxy-propionic acid ethyl ester (Preparation #10, Step B, 117 g, 466 mmol) was added. The reaction mixture was warmed to ambient temperature and stirred for 2 h. The reaction mixture was quenched by the addition of water (1000 mL). The organic phase was separated and the aqueous solution was extracted with EtOAc (4×500 mL). The combined organic phase was washed with brine (1 L), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 5-10% EtOAc in petroleum ether) to give (R)-2-(6-bromo-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (82.4 g, 97%) as a brown liquid. 1H NMR (400 MHz, CDCl3) δ 7.12 (d, J=8.8 Hz, 1H), 6.97 (s, 1H), 6.92 (d, J=8.8 Hz, 1H), 5.23 (q, J=6.8 Hz, 2H), 4.67-4.58 (d, J=14.8 Hz, 2H), 4.26-4.20 (m, 2H), 1.60 (d, J=6.8 Hz, 3H), 1.23 (t, J=7.6 Hz, 3H). SFC (Table 1, Method 29) Rt=4.146 min.; [α]D20=31.45 (C=0.002 g/mL in methanol). was added The reaction mixture was quenched by the addition of water (1000 mL) The organic phase was separated the aqueous solution was extracted with EtOAc (4×500 mL) The combined organic phase was washed with brine (1 L) dried over Na2SO4 concentrated in vacuo The residue was purified by column chromatography on silica gel (eluting with 5-10% EtOAc in petroleum ether)

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-4-bromophenol (50 g, 266 mmol) and NaHCO3 (67.0 g, 798 mmol) in water (200 mL) and DME (200 mL) was added 2-chloroacetyl chloride (45.1 g, 399 mmol) at 0° C. The mixture was stirred at 15° C. for 0.5 h and then stirred at 80° C. overnight. The mixture was cooled to ambient temperature and quenched with water (400 mL). The precipitate was collected by suction filtration, washed with water (200 mL) and petroleum ether (300 mL) in turn, and dried to give 6-bromo-4H-benzo[1,4]oxazin-3-one (59 g, 97%) as a gray solid. 1H NMR (DMSO-d6, 400 MHz): δ 7.07 (d, J=8.4 Hz, 1H), 7.02 (s, 1H), 6.90 (d, J=8.4 Hz, 1H), 4.59 (s, 2H). stirred at 80° C. overnight The mixture was cooled to ambient temperature quenched with water (400 mL) The precipitate was collected by suction filtration washed with water (200 mL) and petroleum ether (300 mL) in turn dried