[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[C:9][C:10]([OH:12])=O.Cl.[CH2:14]([O:16][C:17](=[O:21])[CH2:18][NH:19][CH3:20])[CH3:15].CN1CCOCC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[C:9][C:10]([N:19]([CH2:18][C:17]([O:16][CH2:14][CH3:15])=[O:21])[CH3:20])=[O:12]To a 0° C. slurry of 3-(2-fluorophenyl)prop-2-ynoic acid (151 g, 0.92 mol) in CH2Cl2 (3L) was added DMAP (118 g, 0.96 mol, 1.05 equiv), followed by sarcosine ethyl ester hydrochloride (148 g, 0.96 mol, 1.05 equiv), and NMM (233 g, 2.3 mol, 2.5 equiv). The resulting clear solution was allowed to warm to room temperature and was maintained for 17 h. The reaction mixture was washed with a 2N HCl solution (4×500 mL). The aqueous layers were combined and the mixture was adjusted to pH 2 using conc. H2SO4, then back-extracted with CH2Cl2 (2×500 mL). The organic layers were combined, washed with a 10% H2SO4 solution (2×500 mL), dried (Na2SO4) and concentrated under reduced pressure to give ethyl 2-[3-(2-fluorophenyl)-N-methylprop-2-ynoylamino]acetate (174 g, 72%) as a brown oil: TLC (40% EtOAc/hex) Rf 0.61; 1H NMR (CDCl3; of rotomeric mixture) δ 1.27 (t, J=7.2 Hz, 3H), 3.07 (s, 1.4H, N—CH3), 3.36 (s, 1.6H, N—CH3), 4.17-4.27 (m, 3.2H), 4.41 (s, 0.8H, N—CH2), 7.06-7.17 (m, 2H), 7.37-7.58 (m, 2H); 13C NMR (CDCl3; of rotomeric mixture) δ 14.00, 14.03, 33.5, 37.2, 48.0, 52.5, 61.3, 61.5, 83.6, 84.3, 85.7 (d, JC−F=9.9 Hz, 1C), 108.9 (d, JC−F=15.5 Hz, 1C), 109.1, (d, JC−F=15.5 Hz, 1C), 115. (d, JC−F=10.4 Hz, 1C), 115.6 (d, JC−F=10.4 Hz, 1C), 124.2, 132.0 (d, JC−F=7.8 Hz, 1C), 132.1 (d, JC−F=7.8 Hz, 1C), 134.10, 134.15, 154.6, 163.3 (d, JC−F=254.4 Hz, 1C), 168.1, 168.5; HPLC ES-MS m/z (rel abundance) 264 (MH+, 75%).
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