Reaction Steps
To a mixture of 2-amino-2-(3-ethoxy-4-methoxyphenyl)ethanenitrile acetate (4.1 g, 14.6 mmol) and 3-acetamidophthalic anhydride (3.0 g, 14.6 mmol) in glacial acetic acid (60 mL), was heated to reflux for 17 hours. The mixture was concentrated in vacuo to provide an oil. The oil was dissolved in EtOAc and washed with water, brine and dried over MgSO4. Solvent was removed, and the residue was purified by chromatography (SiO2, Hexane:EtOAc 6:4) to give 4.9 g (83%) of N-{2-[cyano(3-ethoxy-4-methoxyphenyl)methyl]-1,3-dioxoisoindolin-4-yl}acetamide as a white solid; mp 118-120° C.; 1H NMR (CDCl3) δ 9.43 (s, 1H), 8.76 (d, J=8.4 Hz, 1H), 7.67 (t, J=7.7 Hz, 1H), 7.51 (d, J=7.2 Hz, 1H), 7.05-6.82 (m, 3H), 5.60-5.54 (dd, J=6.63 and 10.0 Hz, 1H), 4.10 (q, J=6.8 Hz, 2H), 3.81 (s, 3H), 3.81-3.74 (m, 1H), 3.29-3.20 (dd, J=6.2 and 16.8 Hz, 1H), 2.27 (s, 3H), 1.46 (t, J=7 Hz, 3H); 13C NMR (CDCl3) δ 169:56, 169.12, 167.19, 149.92, 148.64, 137.73, 136.30, 130.87, 128.70, 125.11, 119.92, 118.29, 116.76, 114.94, 112.14, 111.98, 64.56, 55.94, 51.08, 24.92, 21.04, 14.68. Aanly. Calculated for C22H21N3O5: C, 64.86; H, 5.20; N, 10.31. Found: C, 65.01; H, 5.10; N, 10.19.
