Sulfuric Acid → (4S,6S)-4-(5-((3-chloro-1,7-naphthyridin-8-yl)amino)-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine

Participants

Reaction Conditions

Reaction Steps

A sealable vial was charged with crude (4S,6S)-4-(5-amino-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (345 mg, 1.116 mmol, step 1) and 3,8-dichloro-1,7-naphthyridine (Intermediate 2; 233 mg, 1.171 mmol). iPrOH (8 mL) was added and the suspension was briefly sonicated. Sulfuric acid (0.059 mL, 1.116 mmol, Aldrich) was added and the vial was sealed. The reaction was heated to 55° C. in an oil bath for one hour then cooled to RT and stirred for additional 16 hours. The reaction was diluted with water and EtOAc. The aqueous layer separated was basified to pH=12 by the addition of 1N NaOH. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude material was purified via silica gel chromatography using a gradient of 0-50% EtOAc:Hexanes to afford the title compound as a white solid. (130.8 mg, 0.277 mmol, 24.85% yield). MS m/z=472.0 [M+H]+. Calculated for C20H15ClF5N5O: 471.811

Provenance & Evidence