A mixture of 2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4-aminoisoindoline-1,3-dione (0.80 g, 1.9 mmol) and 2-bromopropionyl chloride (0.8 mL, 7.9 mmol) was heated at 100° C. for 30 min. The mixture was cooled to room temperature. Methanol (10 mL) was added to the mixture. The solvent was removed in vacuo to give an oil. The oil was stirred in ether (10 mL) for 1 day. The resulting suspension was filtered and the solid washed with ether to give 3-bromo-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl}propanamide as a yellow solid (0.84 g, 80% yield). A portion of the isolated bromide (620 mg, 1.2 mmol) and dimethylamine (2 mL, 2M in methanol, 4 mmol) was stirred at room temperature for 3 h. The resulting suspension was filtered and washed with methanol to yield the crude product as a yellow solid. The solid was purified by column chromatography to give 3-(dimethylamino)-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl}propanamide as a white solid (180 mg, 30% yield): mp, 163-165° C.; 1H NMR (CDCl3) δ1.47 (t, J=6.9 Hz, 3H, CH3), 2.38 (s, 6H, CH3), 2.59 (t, J=5.7 Hz, 2H, CH2), 2.70 (t, J=5.9 Hz, 2H, CH2), 2.82 (s, 3H, CH3), 3.78-3.85 (m, 1H, CHH), 3.86 (s, 3H, CH3), 4.10 (q, J=7.0 Hz, 2H, CH2), 4.49 (dd, J=9.8, 14.6 Hz, 1H, CHH), 5.86 (dd, J=4.9, 9.7 Hz, 1H, NCH), 6.82-6.85 (m, 1H, Ar), 7.10-7.13 (m, 2H, Ar), 7.48 (d, J=7.2 Hz, 1H, Ar), 7.63 (t, J=7.5 Hz, 1H, Ar), 8.82 (d, J=8.4 Hz, 1H, Ar), 11.36 (s, 1H, NH); 13C NMR (CDCl3) δ14.62, 34.85, 41.49, 44.65, 48.74, 54.31, 55.01, 55.88, 64.44, 111.43, 112.52, 115.99, 117.93, 120.39, 120.08, 129.52, 131.42, 135.59, 137.33, 148.55, 149.67, 168.00, 168.16, 171.86; Anal Calcd for C25H31N3O7S: C, 58.01; H, 6.04; N, 8.12. Found: C, 57.75; H, 5.86; N, 7.91.
