Reaction Steps
2-[1-(3-Ethoxy-4-methoxyphenyl)-2-(1,3,4-oxadiazol-2-yl)ethyl]-5-methylisoindoline-1,3-dione was prepared by the procedure of Example 1. Reaction of 3-(3-ethoxy-4-methoxyphenyl)-3-(5-methyl-1,3-dioxoisoindolin-2-yl)propanoic acid (1.81 g, 4.72 mmol), carbonyldiimidazole (0.92 g, 5.7 mmol) and formic hydrazide (375 mg, 6.2 mmol) in ethyl acetate (20 mL) gave crude N-carbonylamino-3-(3-ethoxy-4-methoxyphenyl)-3-(5-methyl-1,3-dioxoisoindolin-2-yl)propanamide (0.93 g, 2.2 mmol), which was then treated with phosphorus oxychloride (0.4 mL, 4.3 mmol) in acetonitrile (12 mL). The product was obtained as a white solid (371 mg, 19% overall yield): mp, 122.0-124.0° C.; 1H NMR (CDCl3) δ 1.45 (t, J=6.9 Hz, 3H, CH3), 2.48 (s, 3H, CH3), 3.80 (dd, J=6.0, 15.6 Hz, 1H, CHH), 3.84 (s, 3H, CH3), 4.10 (q, J=6.9 Hz, 2H, CH2), 4.35 (dd, J=10.3, 15.6 Hz, 1H, CHH), 5.79 (dd, J=6.0, 10.2 Hz, 1H, NCH), 6.82 (d, J=8.1 Hz, 1H, Ar), 7.12-7.17 (m, 2H, Ar), 7.47 (d, J=7.5 Hz, 1H, Ar), 7.59 (s, 1H, Ar), 7.68 (d, J=7.6 Hz, 1H, Ar), 8.28 (s, 1H, Ar); 13C NMR (CDCl3) δ 14.61, 21.86, 27.67, 51.71, 55.83, 64.36, 111.29, 112.49, 120.22, 123.27, 123.88, 128.97, 130.23, 131.95, 134.58, 145.39, 148.33, 149.34, 152.93, 163.97, 167.91, 168.04; Anal Calcd for C22H21N3O5: C, 64.86; H, 5.20; N, 10.31. Found: C, 64.77; H, 5.07; N, 10.30.
