Ammonium Hydroxide → 5-Bromo-1-methyl-1H-indazol-4-ol

A solution of 5-bromo-4-methoxy-1-methyl-1H-indazole (86.1 mg, 0.357 mmol) in methylene chloride (1.74 mL) was treated with boron tribromide (0.0405 mL, 0.428 mmol) at 0° C. The reaction mixture was warmed to RT and stirred at RT for 16 h, after which time the reaction mixture was cooled to 0° C., treated with additional boron tribromide (0.0405 mL, 0.428 mmol), warmed to RT and stirred at RT for 1.5 h. The reaction mixture was cooled to 0° C., treated with more boron tribromide (0.0405 mL, 0.428 mmol), and stirred for 2 h. The reaction mixture was then cooled to 0° C. and quenched carefully with saturated sodium bicarbonate (30 mL) and extracted with dichloromethane (2×30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield a crude mixture. This mixture was re-subjected to the initial reaction conditions. The crude mixture was suspended in 1,2-dichloroethane (1.74 mL), cooled to 0° C., treated with boron tribromide (0.0810 mL, 0.857 mmol), warmed to RT and stirred at RT for 2 h. The reaction mixture was cooled to 0° C. and quenched carefully with saturated solution of sodium bicarbonate (30 mL) and extracted with dichloromethane (2×30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product. This material was diluted with methanol (2.0 mL), treated with ammonium hydroxide (0.278 mL, 7.14 mmol), and stirred for 15 min. The resultant suspension was diluted with saturated ammonium chloride (30 mL) and extracted with dichloromethane (2×30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give the desired product (73 mg, 90%) as a yellow solid. LCMS calculated for C8H8BrN2O (M+H)+: m/z=227.0, 229.0. found: 226.9, 228.9.

1. temperatureafter which time the reaction mixture was cooled to 0° C.
2. temperaturewarmed to RT
3. stirringstirred at RT for 1.5 h
4. temperatureThe reaction mixture was cooled to 0° C.
5. stirringstirred for 2 h
6. temperatureThe reaction mixture was then cooled to 0° C.
7. customquenched carefully with saturated sodium bicarbonate (30 mL)
8. extractionextracted with dichloromethane (2×30 mL)
9. washThe combined organic layers were washed with brine
10. dry with materialdried over sodium sulfate
11. filtrationfiltered
12. concentrationconcentrated in vacuo
13. customto yield a crude mixture
14. customreaction conditions
15. temperaturecooled to 0° C.
16. temperaturewarmed to RT
17. stirringstirred at RT for 2 h
18. temperatureThe reaction mixture was cooled to 0° C.
19. customquenched carefully with saturated solution of sodium bicarbonate (30 mL)
20. extractionextracted with dichloromethane (2×30 mL)
21. washThe combined organic layers were washed with brine
22. dry with materialdried over sodium sulfate
23. filtrationfiltered
24. concentrationconcentrated in vacuo
25. customto give the crude product
26. stirringstirred for 15 min
27. extractionextracted with dichloromethane (2×30 mL)
28. washThe combined organic layers were washed with brine
29. dry with materialdried over sodium sulfate
30. filtrationfiltered
31. concentrationconcentrated

ORD record

ord-93afcec7daaf41129b5bb3c55cf28a65

Source dataset

uspto-grants-2016_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09399640B2