Reaction Steps
Triethylamine (0.5 g, 5.3 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and 3,4-dichlorobenzoyl chloride (0.6 g, 2.9 mmol) in THF (30 mL) at 5-10° C. After stirring at 5° C. for 10 minutes, the mixture was stirred at room temperature overnight. The reaction was quenched with methanol (1 mL) and concentrated. The residue was stirred with 1N HCl (40 mL) for 1 hour then filtered. The solid was slurried with hot acetone (25 mL) to give 3,4-dichloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-benzamide (0.6 g, 62%) as a white solid: mp>260° C.; 1H NMR (DMSO-d6) δ 2.01-2.08 (m, 1H), 2.33-2.65 (m, 2H), 2.86-3.00 (m, 1H), 4.40-4.61 (m, 4H, 2CH2), 5.11-5.19 (dd, J=5.0 and 13.2 Hz, 1H, CH), 7.47-7.88 (m, 5H, Ar), 8.12 (d, J=1.9 Hz, 1H, Ar), 9.26 (t, J=5.6 Hz, 1H, NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.56, 31.16, 39.73, 46.25, 51.58, 121.78, 127.60, 128.34, 129.22, 130.73, 130.81, 131.27, 131.65, 134.16, 134.33, 140.23, 164.09, 168.01, 170.98, 172.81; Anal. calcd. for C21H17N3O4Cl2: C, 56.52; H, 3.84; N, 9.42; Cl, 15.89. Found: C, 56.42; H, 3.79; N, 9.21; Cl, 15.85.
