Sodium Bicarbonate → 4-azido-5-fluoro-1-(1-ethyl-4-nitro-1H-pyrazol-5-yl)azepane

Participants

Reaction Steps

To a solution of 5-azido-1-(1-ethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ol (1.25 g, 4.2 mmol) in dry DCM (20 ml) was added dropwise deoxo-Fluor® (3.8 mL, 10.6 mmol, 50% in THF) and the mixture was stirred at room temperature for 16 hr. The mixture was cooled in an ice bath, saturated aqueous NaHCO3 solution (40 mL) was added slowly (effervescence observed) and the mixture was extracted with DCM (2×20 mL). The organic layer was washed with saturated aqueous NaHCO3 solution (2×10 mL), passed through a phase separation cartridge and concentrated under reduced pressure. The residue was purified via silica gel column chromatography (0-100% EtOAc/isohexane) to give 4-azido-5-fluoro-1-(1-ethyl-4-nitro-1H-pyrazol-5-yl)azepane as a yellow gum (0.91 g). A solution of this gum (0.9 g, 3.0 mmol) in THF/water (20 mL/4 mL) was treated with triphenylphosphine (0.8 g, 3.0 mmol) and the mixture was heated at 60° C. for 16 hr. The mixture was cooled and concentrated to 4 mL under reduced pressure, diluted with EtOAc (30 mL) and extracted with 1M HCl (4×10 mL). The combined aqueous extracts were washed with EtOAc (20 mL) and then basified with 6N NaOH and extracted with DCM (3×20 mL) The combined organic layers were separated, dried over MgSO4 and concentrated under reduced pressure to give 5-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-amine as a yellow oil (0.82 g). To a solution of this oil (0.8 g, 2.9 mmol) and DIPEA (0.77 mL, 4.4 mmol) in DCM (25 mL) was added di-tert-butyl-dicarbonate (0.97 g, 4.4 mmol) and the mixture stirred at room temperature for 16 hr. Water (15 mL) was added and the organic phase separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave tert-butyl 1-(1-ethyl-4-nitro-1H-pyrazol-5-yl)-5-fluoroazepan-4-ylcarbamate as a yellow solid (1.1 g, 70% over three steps). 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 4.96 (s, 1H), 4.74 (td, J=7.4, 3.6 Hz, 1H), 4.65-4.58 (m, 1H), 4.16-4.05 (m, 3H), 3.42-3.29 (m, 2H), 3.16 (d, J=11.4 Hz, 2H), 2.31-2.18 (m, 2H), 2.20-2.06 (m, 2H), 1.94-1.82 (m, 1H), 1.60-1.45 (m, 10H).

Provenance & Evidence