反应详情

To a solution of 4-azido-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-3-ol (660 mg, 2.34 mmol, intermediate 57) in DCM (12 mL) was added deoxo-Fluor® (50% in THF, 2.12 mL) and the mixture was stirred at room temperature for 18 hr. The mixture was diluted with DCM (22 mL), cooled to 0° C. and saturated aqueous NaHCO3 (20 mL) was carefully added. The aqueous layer was extracted with DCM (3×20 mL) and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-30% EtOAc/isohexane) gave 5-(5-azido-6-fluorooxepan-2-yl)-1-methyl-4-nitro-1H-pyrazole as an oil (440 mg). A solution of this oil (440 mg, 1.54 mmol) in THF/water (15 mL/2.8 mL) was treated with triphenylphosphine (487 mg, 1.86 mmol) and the reaction mixture was heated at 70° C. behind a blast shield for 18 hr. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in dry DCM (15 mL), cooled to 0° C. and di-tert-butyl-dicarbonate (402 mg, 1.84 mmol) was added followed by DIPEA (0.8 mL, 4.62 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 18 hr. Water (20 mL) was added and the mixture extracted with DCM (100 mL). The organic layer was separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-35% EtOAc/isohexane) followed by chiral prep SFC gave tert-butyl N-[(3S,4R,7S)-3-fluoro-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-yl]carbamate as a white solid (223 mg, 27% over three steps). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 5.37 (dd, J=10.5, 3.0 Hz, 1H), 4.89 (br s, 1H), 4.61 (ddd, J=49.1, 7.7, 3.2 Hz, 1H), 4.44 (dd, J=22.2, 15.0 Hz, 1H), 4.07 (s, 3H), 3.98-3.80 (m, 1H), 3.49 (d, J=5.3 Hz, 1H), 2.15-1.90 (m, 4H), 1.47 (s, 9H).

1. temperaturecooled to 0° C.
2. extractionThe aqueous layer was extracted with DCM (3×20 mL)
3. dry with materialthe combined organic layers were dried over Na2SO4
4. concentrationconcentrated under reduced pressure
5. customPurification via silica gel column chromatography (0-30% EtOAc/isohexane)