Reaction Steps
2-[1-(3-Ethoxy-4-methoxyphenyl)-2-(5-methyl(1,3,4-oxadiazol-2-yl))ethyl]isoindolin-1-one was prepared by the procedure of Example 1. Reaction 3-(3-ethoxy-4-methoxyphenyl)-3-(1-oxoisoindolin-2-yl)propanoic acid (1.50 g, 4.22 mmol), carbonyldiimidazole (0.76 g, 4.7 mmol) and acetic hydrazide (381 mg, 5.16 mmol) in tetrahydrofuran (15 mL) gave crude N-carbonylamino-3-(3-ethoxy-4-methoxyphenyl)-3-(1-oxoisoindolin-2-yl)propanamide (1.22 9, 3.06 mmol), which (650 mg, 1.47 mmol) was then reacted with phosphorus pentoxide (2.0 g, 14 mmol) in chloroform (30 mL) at room temperature for 18 hours The product was obtained as a white solid (250 mg, 32% overall yield): mp, 125.5-128.0° C.; 1H NMR (CDCl3); δ 1.43 (t, J=7.0 Hz, 3H, CH3), 2.46 (s, 3H, CH3), 3.56 (dd, J=6.3, 15.1 Hz, 1H, CHH), 3.76 (dd, J=10.0, 15.0 Hz, 1H, CHH), 3.86 (s, 3H, CH3), 4.02-4.11 (m, 3H, NCHH, CH2), 4.46 (d, J=16.6 Hz, 1H, NCHH), 5.97 (dd, J=6.3, 9.9 Hz, 1H, NCH), 6.83-6.87 (m, 1H, Ar), 6.95-7.01 (m, 2H, Ar), 7.35-7.53 (m, 3H, Ar), 7.77-7.81 (m, 1H, Ar); 13C NMR (CDCl3) δ 10.89, 14.64, 28.04, 46.18, 52.08, 55.89, 64.47, 111.32, 112.51, 119.03, 122.81, 123.74, 127.95, 130.13, 131.48, 132.11, 141.17, 148.64, 149.31, 163.86, 164.23, 168.30; Anal Calcd for C22H23N3O4+0.28 EtOAc: C, 66.42; H, 6.08; N, 10.05. Found: C, 66.47; H, 5.98; N, 10.04. (1H NMR showed that the sample contained 28% of ethyl acetate).
