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 CH3CN (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-hydroxybenzenetriazole (0.35 g, 2.6 mmol) and 3,4-dichlorophenylacetic acid (0.49 g, 2.4 mmol) were added. The mixture was then added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.62 g, 3.2 mmol) and stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, and the residue was dissolved in CH2Cl2 (50 mL). The CH2Cl2 solution was washed with water (2×30 mL) and brine (30 mL), and dried over MgSO4. Solvent was removed in vacuo. The resulting oil solidified on standing and the mixture was stirred in acetone (10 mL) then in MeOH (10 mL). The resulting solid was filtered and dried in vacuum oven to afford 2-(3,4-dichloro-phenyl)-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-acetamide as an off-white solid (0.69 g, 67%): mp, 163-165° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=6.5 min. (98%); 1H NMR (DMSO-d6): δ 2.03-2.08 (m, 1H), 2.52-2.63 (m, 2H), 2.84-2.92 (m, 1H), 3.58 (s, 2H), 4.73 (d, J=6.0 Hz, 2H), 5.12-5.18 (dd, J=5, 12 Hz, 1H), 7.26-7.82 (m, 6H), 8.69 (t, J=6 Hz, 1H), 11.14 (s, 1H). 13C NMR (DMSO-d6) δ: 21.95, 30.90, 37.92, 40.80, 48.83, 121.95, 127.16, 129.13, 129.58, 130.29, 130.65, 131.15, 131.52, 133.31, 134.68, 137.19, 138.92, 166.88, 167.39, 169.77, 172.72. Anal Calcd for C22H17Cl2N3O5+0.2H2O: C, 55.29; H, 3.67; N, 8.79; Cl, 14.84. Found: C, 55.19; H, 3.33; N, 8.83; Cl, 14.71.
