反应详情

温度

12.5 °C

As shown in step 3-iv of Scheme 3, 3-(difluoromethoxy)pyridin-2-ol (986 mg; 6.12 mmol) was dissolved in 25 mL of glacial acetic acid and sodium acetate (79 mg; 9.6 mmol) was added. The mixture was cooled in an ice bath and bromine (780 μL; 1.63 g; 10.22 mmol) in 10 mL of glacial acetic acid was added over 10 minutes. The reaction was stirred for 30 minutes at 10-15° C. The volatiles were removed under reduced pressure and the residue was partitioned between brine/saturated sodium carbonate solution and ethyl acetate. After the evolution of gas ceased, the organic and aqueous layers were separated and the aqueous solution extracted three additional times with EtOAc. The combined organics were dried over Na2SO4, filtered, and the volatiles removed under reduced pressure. The residue was purified twice by silica gel chromatography (first a DCM to 10% MeOH/DCM gradient then 1:1 EtOAc/hexanes) to provide 5-bromo-3-(difluoromethoxy)pyridin-2-ol as a light yellow powder (Compound 1009, 810 mg, 55% yield): ESMS (M+H) 241.9/243.9; 1H NMR (CDCl3) δ 13.2 (br m, 1H), 7.44 (d, 1H, J=2.1 Hz), 7.18 (d, 1H, J=2.1 Hz), 6.92 (t, 1H, J=75 Hz).

1. temperatureThe mixture was cooled in an ice bath
2. customThe volatiles were removed under reduced pressure
3. customthe residue was partitioned between brine/saturated sodium carbonate solution and ethyl acetate
4. customthe organic and aqueous layers were separated
5. extractionthe aqueous solution extracted three additional times with EtOAc
6. dry with materialThe combined organics were dried over Na2SO4
7. filtrationfiltered
8. customthe volatiles removed under reduced pressure
9. customThe residue was purified twice by silica gel chromatography (first a DCM to 10% MeOH/DCM