Reaction Steps
A 25 mL round-bottom flask was charged with intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid, (0.991 g, 3.0 mmol), intermediate 39, 2-(aminomethyl)-5-fluoro-N-methylbenzamide trifluoroacetic acid salt (1.185 g, 4.0 mmol), 4-dimethylaminopyridine (DMAP, 1.1 g, 9.0 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 1.722 g, 4.5 mmol). Dimethylformamide (20 mL) was added and the mixture stirred for 1 h at ambient temperature. After this, the reaction mixture was diluted with ethyl acetate (100 mL) then washed with water (3×25 mL) and brine (25 mL). The organic layer was dried (Na2SO4), filtered, concentrated and purified by flash chromatography (SiO2), eluting with hexanes/ethyl acetate (1:1 to 1:3) followed by ethyl acetate, to afford the title compound as an off-white solid (1.48 g, 100% yield). 1H NMR (500 MHz, CDCl3) δ ppm: 8.49 (1H, t, J=6.1 Hz), 7.48-7.46 (2H, m), 7.43 (1H, dd, J=8.5, 5.5 Hz), 7.31-7.27 (3H, m), 7.12 (1H, dd, J=8.9, 2.7 Hz), 7.05 (1H, td, J=8.2, 2.7 Hz), 6.52 (1H, br s), 5.26 (2H, s), 4.53 (2H, d, J=6.4 Hz), 4.01 (2H, t, J=4.9 Hz), 3.96 (2H, t, J=4.9 Hz), 2.97 (3H, d, J=4.9 Hz), 1.62 (6H, s). HRMS (M+H) calcd for C26H28FN4O5: 495.2044; found: 495.2032.
