6-BROMO-2H-1,4-BENZOXAZIN-3(4H)-ONE

TEA (4.06 g, 0.04 mmol) was added to a solution of XXXV-1 (5 g, 27 mmol) in THF (150 mL). And then 2-chloroacetyl chloride (3.33 g, 0.03 mmol) was added in portions at 0°C. After 20 minutes, the mixture was stirred at rt for 2 hrs. The reaction mixture was cooled to 0°C and NaH (60percent, 2.2 g, 54 mmol) was added in portions. The reaction mixture was stirred at 0°C for 20 minutes then at rt for 2h before being quenched with water. The solvent was removed in vacuo and the resulting mixture diluted with water. The precipitate was filtered, washed with water and dried in vacuo to give XXXV-2 (5.5 g, 89percent yield).INTERMEDIATE 6; 6-Bromo-4HNEtTo a stirred solution of 2-amino-4-bromophenol (2.5 g, 13.3 mmol) in TηF (80 mL) at 0A mixture of 2-amino-4-bromophenol (10.15g, 354.29mmol), 2-chloroacetyl chloride (7.35g, 65.15mmol) and DCM (150mL) was cooled to 0 °C. DIEA (35.06g, 271.45mmol) was added dropwise, the resulting mixture was stirred at 20 °C for 5 hours. The reaction mixture was concentrated in vacuo and HWeigh 2-amino-4-bromophenol (2.5 g, 13 mmol) into a three-neck bottle.80 mL of tetrahydrofuran was added to the system, and triethylamine (2.4 mL, 17 mmol) was added thereto.The reaction system was cooled to 0 ° C, and chloroacetyl chloride (1.12 mL, 14 mmol) was added dropwise to the reaction system.After the addition was completed, the mixture was stirred at 0 ° C for 10 minutes, and further stirred at room temperature for 2 hours.The system was then lowered to 0 ° C and sodium hydride (1.05 g, 26 mmol) was added portionwise.The reaction system was lowered to 0 ° C for 20 minutes and then raised to room temperature for 2 hours.The reaction system was concentrated, and the reaction was quenched by adding 100 mL of water, and the precipitate was filtered and washed with water.Dry the filter cake. Get 2.5g red solidTo a solution of methyl (4-bromo-2-nitrophenoxy)acetate from step A (8.1 g, 27.9 mmol) in acetic acid (75 ml_) and ethanol (75 ml_) was added iron powder (94.7 g, 83.8 mmol) at room temperature. After refluxing overnight, the reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (300 ml_), The mixture filtered through a pad of Celite and the cake washed with ethyl acetate. The filtrate was concentrated to dryness to give the title compound (5.9 g, 93percent) as a solid. MS [(-)ESI, m/z]: 226 [M-H][Synthesis of Compound E3] (0130) Compound E2 (13.1 g, 68.8 mmol, 1 Eq) was dissolved in acetic acid (50 mL), and placed on an ice bath. Iron powder (15.0 g, 271 mmol, 6 Eq) was added divided over five times over 20 minutes. The reaction system was stirred for another 20 minutes at room temperature, then fresh acetic acid (50 mL) was added, and it was stirred for three hours while heating and refluxing. After the reaction had been completed, the reaction system was returned to room temperature, and the iron powder was filtered out under reduced pressure, and the filtrate was distilled off under reduced pressure. A small amount of methanol was added to the residue obtained, and the solid obtained was filtered under reduced pressure. The filtered material was washed with water and methanol, and the target compound E3 (9.02 g, 88percent) was obtained as light brown acicular crystals. (0131) To a solution of methyl 2-(4-bromo-2-nitrophenoxy)acetate (1.3 g, 4.5 mmol) in acetic acid (15 mL) was added powdered iron (1.25 g, 22.4 mmol). To a stirred solution of intermediate 1 (13.48g, 44. 33mmol) in glacial acetic acid (200mi) was added iron powder (10eq, 24.6g, 0. 44mol) at r. t. and the mixture was heated at 60°C for two days. The mixture was filtered through a pan of celite and washed through with EtOAc. The filtrate was evaporated under reduced pressure and the residue was poured into a saturated solution of NaHCO3 and extracted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4 and filtered. The solvent was evaporated under reduced pressure to give the title compound as a white solid (8.2g, 81percent) ; m. p. 220°C ;'H NMR (350 MHz; CDCl3) 8 : 10.79 (1H, br. s), 7.09-7. 01 (2H, m), 6.91 (1H, d), 4.59 (2H, s).Compound 7-1 (25g, 0.12mol) was dissolved in CH3CN (250ml), add K2CO3 (42g, 0.23mol) and ethyl 2-bromoacetate (30g, 0.18mol). The mixture was stirred at reflux for 2h, filtered, and the filtrate was concentrated to give crude product. The crude product was dissolved in acetic acid (250ml), was added Fe (20g, 0.36mol). The mixture was stirred at 80 2h, then poured into water, extracted with ethyl acetate (3x 200ml), then washed, separated and purified by silica gel column chromatography aq.NaHCO3 (6N) (EtOAc / PE = 1: 1) to give a yellow solid compound 7-2 (22.2g, 85percent).

It is used to construct the structural unit of pyrimidinyl substituted benzoxazinone and small molecule rennet inhibitor.

Molecular Weight:228.04
XLogP3:1.6
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Exact Mass:226.95819
Monoisotopic Mass:226.95819
Topological Polar Surface Area:38.3
Heavy Atom Count:12
Complexity:198
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes