Triethylamine → tert-butyl ((1R,5S,6R)-5-(5-(((S)-1-(5-chloropyridin-2-yl)-2,2,2-trifluoroethyl)amino)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-yl)-carbamate

Participants

Reaction Steps

To a solution of tert-butyl((1R,5S,6R)-5-(5-amino-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-yl)carbamate (16i-B, 0.121, 0.326 mmol) and 1-(5-chloropyridin-2-yl)-2,2,2-trifluoroethanone (0.070 g, 0.33 mmol) in DCM (1.5 mL) at −78° C. were added triethylamine (0.135 mL, 0.969 mmol) and titanium chloride (1 M in DCM, 0.360 mL, 0.360 mmol). The cold bath was removed and the reaction mixture was allowed to stir at room temperature over 10 min. The reaction mixture was again cooled to −78° C. and lithium aluminium hydride (1.0 M in THF, 0.660 mL, 0.660 mmol) was added. The reaction mixture was stirred at −78° C. for 20 min and quenched with EtOAc. Saturated aqueous sodium potassium tartrate (5 mL) was added. The mixture was warmed to room temperature and stirred for 45 min. The mixture was transferred to a separatory funnel. The aqueous phase was extracted with EtOAc (2×). The combined organic extracts were washed with brine and dried over MgSO4. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (10% to 50% EtOAc in heptane) to give a 1:1 mixture of tert-butyl((1R,5S,6R)-5-(5-(((R)-1-(5-chloropyridin-2-yl)-2,2,2-trifluoroethyl)amino)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-yl)carbamate and tert-butyl((1R,5S,6R)-5-(5-(((S)-1-(5-chloropyridin-2-yl)-2,2,2-trifluoroethyl)amino)-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-yl)carbamate (0.070 g, 0.124 mmol, 38% yield combined yield) as a white solid. MS m/z=565.1 (M+H). Calculated for C24H23ClF6N4O3 564.1.

Provenance & Evidence