Reaction Steps
2-[1-(3-Ethoxy-4-methoxyphenyl)-2-(1,3,4-oxadiazol-2-yl)ethyl]isoindolin-1-one was prepared as described in Example 1. Reaction of 3-(3-ethoxy-4-methoxyphenyl)-3-(1-oxoisoindolin-2-yl)propanoic acid (1.50 g, 4.22 mmol), carbonyldiimidazole (0.80 g, 4.9 mmol) and formic hydrazide (310 mg, 5.16 mmol) in tetrahydrofuran (10 mL) yielded crude N-carbonylamino-3-(3-ethoxy-4-methoxyphenyl)-3-(1-oxoisoindolin-2-yl)propanamide (1.0 g, 2.2 mmol), which was then reacted with phosphorus pentoxide (2.32 g, 16.3 mmol) in chloroform (30 mL) at room temperature for 18 hours. The product was obtained as a white solid (250 mg, 16% overall yield): mp, 143.5-144.5° C.; 1H NMR (CDCl3); δ 1.43 (t, J=7.0 Hz, 3H, CH3), 3.65 (dd, J=6.1, 15.1 Hz, 1H, CHH), 3.85 (s, 3H, CH3), 3.87 (dd, J=9.9, 15.0 Hz, 1H, CHH), 4.01-4.12 (m, 3H, NCHH, CH2), 4.46 (d, J=16.6 Hz, 1H, NCHH), 5.99 (dd, J=6.1, 10.1 Hz, 1H, NCH), 6.83-6.87 (m, 1H, Ar), 6.94-7.01 (m, 2H, Ar), 7.34-7.52 (m, 3H, Ar), 7.78 (d, J=7.1 Hz,1H, Ar), 8.34 (s, 1H, NCH); 13C NMR (CDCl3) δ 14.60, 27.84, 46.19, 52.13, 55.86, 64.45, 111.32, 112.45, 118.98, 122.78, 123.72, 127.95, 129.95, 131.49, 131.98, 141.09, 148.66, 149.35, 153.31, 163.86, 168.25; Anal Calcd for C21H21N3O4+0.06 CH2Cl2: C, 65.79; H, 5.54; N, 10.93. Found: C, 65.87; H, 5.67; N, 10.89.
