Methyl iodide → HCID 86713813, compound

Participants

Reaction Steps

To a solution of 4-azido-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-3-ol, (Intermediate 57) (182 mg, 0.65 mmol) in anhydrous DMF (5 mL) under nitrogen was added sodium hydride (60% dispersion in mineral oil, 39 mg, 0.97 mmol) portionwise over 10 min. After a further 45 min, methyl iodide (0.06 mL, 0.97 mmol) was added dropwise and the mixture stirred for 18 hr at room temperature. Further sodium hydride (60% dispersion in mineral oil, 39 mg, 0.97 mmol) was added followed by methyl iodide (0.06 mL, 0.97 mmol) and the mixture stirred at room temperature for 48 hr. The mixture was quenched with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-50% EtOAc/isohexane) gave 5-(5-azido-6-methoxyoxepan-2-yl)-1-methyl-4-nitro-1H-pyrazole as an oil (100 mg). A solution of this oil (100 mg, 0.37 mmol) in THF/water (5 mL/1 mL) was treated with triphenylphosphine (97 mg, 0.37 mmol) and the reaction mixture heated at 70° C. behind a blast shield for 18 hr. The mixture was concentrated under reduced pressure. The residue was dissolved in dry DCM (3 mL) at 0° C. and di-tert-butyl-dicarbonate (89 mg, 0.4 mmol) and DIPEA (0.18 mL, 1.02 mmol) were added. The reaction mixture was warmed to room temperature and stirred for 3 hr. Water (10 mL) was added and the mixture extracted with DCM (20 mL). The organic layer was separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-50% EtOAc/isohexane) gave racemic tert-butyl-(3-methoxy-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (relative stereochemistry as shown above) as a clear oil (119 mg, 47% over three steps). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 5.39 (dd, J=10.6, 3.6 Hz, 1H), 4.75 (br s, 1H), 4.33 (dd, J=14.2, 1.9 Hz, 1H), 4.06 (s, 3H), 3.91-3.83 (m, 1H), 3.75 (dd, J=14.2, 3.2 Hz, 1H), 3.43 (s, 3H), 3.39-3.34 (m, 1H), 2.22-2.12 (m, 1H), 2.12-2.03 (m, 1H), 2.03-1.82 (m, 2H), 1.47 (s, 9H).

Provenance & Evidence