反应详情

温度

80 °C

3-Bromo-5-(2,4-difluoro-phenoxy)-2-methyl-phenylamine (5.31 g, 16.9 mmol) was dissolved in 50 mL dry benzene, and acetic anhydride (5.17 g, 50.7 mmol) and potassium acetate (1.69 g, 17.2 mmol) were added. The reaction mixture was placed under nitrogen atmosphere and heated to 80° C. with stirring for 10 minutes. Isoamyl nitrate (3.39 mL, 25.4 mmol) was added dropwise over 30 minutes, after which the reaction mixture was stirred at 80° C. under nitrogen for 17 hours. The reaction mixture was cooled and filtered, and the filtrate was concentrated under reduced pressure. Water (8 mL) and concentrated HCl (16 mL of 6N aqueous solution) were added, and the mixture was heated to 55° C. Methanol (100 mL) was added, and the mixture was heated to 80° C. The mixture was cooled and concentrated under reduced pressure, and the residue was partitioned between water and ethyl acetate. The organic layer was separated and concentrated under reduced pressure. The residue was partitioned betwee methylene chloride and saturated sodium bicarbonate. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was chromatographed through silica (0%-25% EtOAc in hexanes) to give 3.18 g of 4-bromo-6-(2,4-difluoro-phenoxy)-1H-indazole.

1. stirringafter which the reaction mixture was stirred at 80° C. under nitrogen for 17 hours
2. temperatureThe reaction mixture was cooled
3. filtrationfiltered
4. concentrationthe filtrate was concentrated under reduced pressure
5. additionWater (8 mL) and concentrated HCl (16 mL of 6N aqueous solution) were added
6. temperaturethe mixture was heated to 55° C
7. additionMethanol (100 mL) was added
8. temperaturethe mixture was heated to 80° C
9. temperatureThe mixture was cooled
10. concentrationconcentrated under reduced pressure
11. customthe residue was partitioned between water and ethyl acetate
12. customThe organic layer was separated
13. concentrationconcentrated under reduced pressure
14. customThe residue was partitioned betwee methylene chloride and saturated sodium bicarbonate
15. customThe organic layer was separated
16. washwashed with brine
17. dry with materialdried (MgSO4)
18. filtrationfiltered
19. concentrationconcentrated under reduced pressure
20. customThe residue was chromatographed through silica (0%-25% EtOAc in hexanes)