Reaction Steps
1,8-Diazabicyclo[5.4.0]undec-7-ene (0.8 g, 5.0 mmol) was added to a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.0 mmol) in DMF (30 mL). After stirring for 10 minutes, 1-hydroxybenzenetriazole (0.3 g, 2.4 mmol) and indole-2-carboxylic acid (0.4 g, 2.2 mmol) were added. The reaction was initiated by adding 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.0 mmol) and stirred at room temperature overnight. The mixture was poured into cold water (120 mL) and extracted with EtOAc (3×50 mL). The combined EtOAc solution was washed with water (3×40 mL) and brine (40 mL), and dried (MgSO4). Solvent was removed, and the solid residue was slurried with hot acetone (20 mL) to give 1H-indole-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide (0.6 g, 70%) as a white solid: mp>260° C.; 1H NMR (DMSO-d6) δ 2.08-2.11 (m, 1H), 2.56-2.65 (m, 2H), 2.85-2.98 (m, 1H), 4.99 (d, J=5.5 Hz, 2H), 5.15-5.22 (dd, J=5.4 and 12.7 Hz, 1H), 7.05 (t, J=7.5 Hz, 1H), 7.16-7.22 (m, 3H), 7.42 (d, J=8.1 Hz, 1H), 7.62 (d, J=7.9 Hz, 1H), 7.75-7.83 (m, 3H), 9.15 (t, J=5.4 Hz, 1H), 11.15 (s, 1H), 11.64 (s, 1H); 13C NMR (DMSO-d6) δ 22.00, 30.34, 37.92, 48.89, 102.95, 112.31, 119.78, 121.54, 121.92, 123.45, 127.04, 127.14, 131.18, 131.57, 133.06, 134.33, 136.54, 139.29, 161.52, 166.97, 167.55, 169.83, 172.75; Anal. calcd. for C23H18N4O5+0.24H2O: C, 63.54; H, 4.28; N, 12.89. Found: C, 63.39; H, 4.38; N, 12.80.
