Reaction Steps
6-(4-Chloro-2-fluoro-3-methoxyphenyl)-4-oxo-1,4,5,6-tetrahydropyridine-2-carboxylic acid methyl ester (16, 5.19 g, 16.5 mmol) was slurried in methanol (160 mL). Hydroxylamine hydrochloride (3.35 g, 48.3 mmol) was added, followed by pyridine (10.0 mL, 123 mmol). The reaction mixture was stirred at reflux for 120 min. Methanol was evaporated under vacuum. H2O (200 mL) was added, and the residue was extracted into ether (4×150 mL). The combined extracts were washed with brine, dried (MgSO4) and evaporated under vacuum to give 6-(4-chloro-2-fluoro-3-methoxyphenyl)-4-hydroxyimino-1,4,5,6-tetrahydropyridine-2-carboxylic acid methyl ester (18; 4.54 g, 80%) as a white solid: mp 136-138° C. A 1:1 mixture of syn and anti isomers was observed by NMR spectroscopy and HPLC. 1H NMR (400 MHz, C6D6) δ 8.34 (br, 1H, NOH), 8.25 (br, 1H, NOH), 7.00 (s, 1H, H3), 6.71 (dd, JF-H=1.5 Hz, JH-H=9 Hz, 1H, aromatic), 6.69 (dd, JF-H=1.8 Hz, JH-H=9 Hz, 1H, aromatic), 6.57 (dd, JF-H=JH-H=7.5 Hz, 1H, aromatic), 6.53 (s, 1H, H3), 6.50 (dd, JF-H=JH-H=7.5 Hz, 1H, aromatic), 4.72 (s, 1H, NH), 4.52 (s, 1H, NH), 4.38 (dd, JH-H=3.6, 10.2 Hz, 1H, H6, isomer A), 4.23 (dd, JH-H=3.9, 11.4 Hz, 1H, H6, isomer B), 3.53 (s, 6H, CO2Me), 3.24 (s, 3H, OMe), 3.23 (s, 3H, OMe), 3.30 (dd, JH-H=4.2, 16.8 Hz, 1H, H5, isomer B), 2.63 (dd, JH-H=4.2, 15.3 Hz, 1H, H5, isomer A), 2.44 (dd, JH-H=10.5, 15.3 Hz, 1H, H5, isomer A), 2.33 (dd, JH-H=11.1, 16.8 Hz, 1H, H5, isomer B); 13C{1H} NMR (CDCl3) δ 164.2 (CO2Me), 163.9 (CO2Me), 153.7 (d, JF-C=250 Hz, C2′), 153.6 (d, JF-C=251 Hz, C2′), 152.6 (C4), 149.6 (C4), 144.3 (d, JF-C=3 Hz, C3′), 144.1 (d, JF-C=3 Hz, C3′), 139.2, 138.3, 128.6 (d, JF-C=12 Hz), 127.9 (d, JF-C=11 Hz), 127.8 (d, JF-C=3 Hz), 127.7 (d, JF-C=3 Hz), 125.3, 121.7, 101.7 (C3), 92.6 (C3), 61.42, 61.38, 52.7, 52.6, 49.3, 48.3, 33.6 (C5), 28.7 (C5). HRMS-ESI (m/z) calcd for C14H14ClFN2O4, 328.0621. found, 328.0620. Anal. Calcd for C14H14ClFN2O4: C, 51.15; H, 4.29; N, 8.52. Found: C, 51.31; H, 4.34; N, 8.40.
