Reaction Steps
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.4 mmol) and 4-chlorophenylacetic acid (0.4 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminlpropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight then was filtered. The solid was slurried with hot acetone (15 mL) to afford 2-(4-chloro-phenyl)-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-acetamide (0.8 g, 82%) as a white solid: mp 243-245° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=4.04 min. (86%); 1H NMR (DMSO-d6) δ 2.02-2.08 (m, 1H), 2.51-2.63 (m, 2H), 2.84-2.96 (m, 1H), 3.54 (s, 2H), 4.72 (d, J=5.9 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.8 Hz, 1H), 7.29-7.38 (m, 4H), 7.61-7.67 (m, 1H), 7.71-7.83 (m, 2H), 8.68 (t, J=5.8 Hz, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 21.95, 30.90, 37.86, 41.31, 48.83, 121.90, 127.13, 128.14, 130.94, 131.14, 131.52, 133.22, 134.69, 135.11, 139.95, 166.89, 167.42, 169.78, 170.24, 172.73; Anal. Calcd. for C22H18N3O5Cl: C, 60.08; H, 4.12; N, 9.55; Cl, 8.06. Found: C, 60.06; H, 3.85; N, 9.67; Cl, 8.07.
