Reaction Steps
6-(4-Chloro-2-fluoro-3-methoxyphenyl)-4-oxo-5,6-dihydro-4H-pyridine-1,2-dicarboxylic acid 2-methyl ester 1-phenyl ester (15; 7.213 g, 0.0166 mol) was slurried in MeOH (80 mL). The suspension was cooled in an ice bath, and solid sodium methoxide (NaOMe; 1.08 g, 0.02 mol) was added. After 1 h, the reaction was quenched with saturated aqueous NH4Cl solution (80 mL) and H2O (50 mL) and then cooled in ice. The precipitate was filtered, washed with H2O followed by cold MeOH and dried in air to give 6-(4-chloro-2-fluoro-3-methoxyphenyl)-4-oxo-1,4,5,6-tetrahydropyridine-2-carboxylic acid methyl ester (16; 4.93 g, 94%) as a white powder: mp 164.9-166.2° C.; 1H NMR (300 MHz, CDCl3) δ 7.20 (dd, JF-H=1.8 Hz, JH-H=8.7 Hz, 1H, aromatic), 7.10 (dd, JF-H=6.9 Hz, JH-H=8.7 Hz, 1H, aromatic), 5.84 (d, J=0.9 Hz, 1H, H3), 5.68 (br s, 1H, NH), 5.10 (t, J=9.3 Hz, 1H, H6), 3.98 (d, JF-H=1.5 Hz, 3H, OMe), 3.91 (s, 3H, CO2Me), 2.71 (d, J=9 Hz, 2H, H5); 13C{1H} NMR (75.4 MHz, CDCl3) δ 193.0 (C4), 163.6 (CO2Me), 153.8 (d, JF-C=251 Hz, C2′), 147.9 (C2), 144.6 (d, JF-C=13 Hz, C3′), 128.6 (d, JF-C=3 Hz, C1′/C4′), 126.8 (d, JF-C=11 Hz, C1′/C4′), 125.5 (d, JF-C=3 Hz, C5′), 121.5 (d, JF-C=4 Hz, C6′), 102.0 (C3), 61.6 (d, JF-C=5 Hz, OMe), 53.4, 50.8, 42.0; HRMS-ESI (m/z): calcd for C14H13ClFNO4, 313.0512. found, 313.0511; Anal. Calcd for C14H13ClFNO4: C, 53.60; H, 4.18; N, 4.46. Found: C, 53.30; H, 4.14; N, 4.35.
