Hydrazine → 4,6-Difluoro-1H-indazole

Temperature

50 °C

To a solution of 2,4,6-trifluorobenzaldehyde (0.80 g, 5.0 mmol) in 1,2-dimethoxyethane (10 mL) were added potassium carbonate (1.04 g, 7.5 mmol) and O-methylhydroxylamine hydrochloride (438 mg, 5.25 mmol). The reaction mixture was heated at 50° C. for 5 h then cooled to room temperature and filtered, rinsing with dichloromethane. The filtrate was concentrated. The residue was dissolved in 1,2-dimethoxyethane (10 mL) and hydrazine (0.17 mL, 5.5 mmol) was added. The reaction mixture was heated at 100° C. for 1.5 h. Additional hydrazine (0.17 mL, 5.5 mmol) was added and heating was continued for 30 min. Thereaction was cooled to room temperature, poured into water, and extracted with ethyl acetate. The organic layer was washed with sat LiCl and brine then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 20% to 50% EtOAc/heptane to provide 358 mg (47%) of 4,6-difluoro-1H-indazole as a light yellow solid. 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 13.47 (br. s., 1H), 8.19 (s, 1H), 7.22 (d, J=9.1 Hz, 1H), 6.96 (td, J=10.0, 1.9 Hz, 1H).

1. temperaturethen cooled to room temperature
2. filtrationfiltered
3. washrinsing with dichloromethane
4. concentrationThe filtrate was concentrated
5. dissolutionThe residue was dissolved in 1,2-dimethoxyethane (10 mL)
6. temperatureThe reaction mixture was heated at 100° C. for 1.5 h
7. temperatureheating
8. temperatureThereaction was cooled to room temperature
9. extractionextracted with ethyl acetate
10. washThe organic layer was washed with sat LiCl and brine
11. dry with materialthen dried over MgSO4
12. concentrationconcentrated
13. customThe residue was purified by silica gel chromatography with 20% to 50% EtOAc/heptane

ORD record

ord-51aa280d41a4479bbf5df72d87dbe67d

Source dataset

uspto-grants-2014_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08658646B2