4-Fluoroaniline → Methyl 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate

To a solution of methyl 2-oxo-2H-pyran-3-carboxylate (10.0 g, 65 mmol, Aldrich) in DMF (80 mL) at ice bath temperature was added a solid of 4-fluoroaniline (7.21 g, 65 mmol), stirred for 15 min. and the reaction mixture was warmed to rt, stirred for 3 h at rt. To the 4-fluoroaniline adduct intermediate formed via Michael addition was added in situ solids of EDCI.HCl (14.8 g, 77 mmol) and DMAP (1.80 g) at rt. The reaction mixture was stirred at rt overnight. Most of DMF was removed in vacuo, and to the residue were added 1N aq HCl (150 mL) and EtOAc (400 mL), the EtOAc layer was separated, and the aqueous layer was washed with EtOAc (2×200 mL), the combined EtOAc layer was washed with brine (150 mL), dried over MgSO4 and concentrated in vacuo. The residue was triturated with iPrOH (180 mL) to obtain the 1st crop of product (8.5 g) as a yellow solid. The mother liquor was concentrated, and the residue was triturated with a small amount of ether to obtain the 2nd crop of product (2.5 g, total 11 g, 68%). 1H NMR (CDCl3) δ 8.23 (dd, 1H, J=7.2, 2.2 Hz), 7.57 (dd, 1H, J=6.6, 1.7 Hz), 7.32-7.34 (m, 2H), 7.17 (t, 2H, J=8.8 Hz), 6.32 (t, 1H, J=7.1 Hz), 3.89 (s, 3H); MS(ESI+) m/z 248.2 (M+H)+.