Pyridine → 3-(2-fluoro-1-fluoromethyl-ethyl)-7-methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine

Temperature

0 °C

A mixture of 1,3-difluoro-propan-2-ol (0.697 mL, 9.00 mmol) and pyridine (0.910 mL, 11.2 mmol) in acetonitrile (42.3 mL, 810 mmol) was cooled at 0° C. and trifluoromethanesulfonic anhydride (1.59 mL, 9.45 mmol) was added dropwise. The mixture was stirred for 30 minutes and then potassium carbonate (1.24 g, 9.00 mmol) and 7-methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.00 g, 4.50 mmol) were added. The reaction was heated at 50° C. overnight and then cooled to room temperature and concentrated under reduced pressure. The residue was taken up in DCM (75 mL) and washed with water (75 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-100% EtOAc/hex as the eluting solvent to obtain 3-(2-fluoro-1-fluoromethyl-ethyl)-7-methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow amorphous solid (679 mg, 50%). LCMS (m/e) 301 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 7.67 (s, 1H), 6.83 (s, 1H), 4.75-4.65 (m, 2H), 4.63-4.54 (m, 2H), 3.96 (s, 3H), 3.29-3.11 (m, 1H), 2.99-2.93 (m, 2H), 2.93-2.82 (m, 6H).

1. temperatureThe reaction was heated at 50° C. overnight
2. temperaturecooled to room temperature
3. concentrationconcentrated under reduced pressure
4. washwashed with water (75 mL)
5. dry with materialThe organic layer was dried over sodium sulfate
6. filtrationfiltered
7. concentrationconcentrated under reduced pressure
8. customPurification by silica gel chromatography

ORD record

ord-8630d40be7eb4828990af5fd6008553b

Source dataset

uspto-grants-2013_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08552186B2