反应详情

温度

60 °C

1-(5-Chloro-4-fluoro-2-hydroxyphenyl)ethanone (e.g., from Example 13, step 1) (20.0 g, 101 mmol, 1.00 eq) and a 50% aqueous sulfuric acid (120 mL) were added to the flask. The resulting mixture was heated to 60° C. in a water bath with stirring. N-Bromosuccinimide (21.52 g, 120.9 mmol, 1.20 eq) was added in three portions [7.0 g+7.0 g+7.52 g] in 8 minute intervals. After the reaction mixture was heated at 60° C. for 3 hours, the reaction was complete. The reaction mixture was diluted with water (160 ml) and dichloromethane (DCM) (300 ml), and the mixture was stirred for 0.5 hour. The organic layer was separated and the aqueous layer was extracted with dichloromethane (100 ml). The combined organic layers were washed with 1 N HCl (100 ml×2), water (100 ml), brine (60 ml), and concentrated under reduced pressure to afford the crude product (29.1 g) as a yellowish solid. The crude product was dissolved in HOAc (100 ml) and then diluted with water (200 ml) under stirring. The resulting mixture was stirred for 20 min at room temperature and the product was collected by filtration and dried to give 1-(3-bromo-5-chloro-4-fluoro-2-hydroxyphenyl)ethanone (21.8 g, 80.9%) as a yellowish solid. 1H-NMR (300 MHz, CDCl3) δ 13.18 (s, 1H, —OH), 7.78 (d, J=7.78 Hz, 1 H), 2.63 (s, 3 H).

1. temperatureAfter the reaction mixture was heated at 60° C. for 3 hours
2. stirringthe mixture was stirred for 0.5 hour
3. customThe organic layer was separated
4. extractionthe aqueous layer was extracted with dichloromethane (100 ml)
5. washThe combined organic layers were washed with 1 N HCl (100 ml×2), water (100 ml), brine (60 ml)
6. concentrationconcentrated under reduced pressure
7. customto afford the crude product (29.1 g) as a yellowish solid
8. stirringunder stirring
9. stirringThe resulting mixture was stirred for 20 min at room temperature
10. filtrationthe product was collected by filtration
11. customdried