Reaction Steps
To a suspension of 3-(4-methylaminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.60 g, 1.86 mmol) and 3-chloro-phenyl-isocyanate (0.27 mL, 2.23 mmol) in dry CH2Cl2 (80 ml), was added diisopropylethylamine (0.45 mL g, 2.60 mmol). The mixture was stirred at room temperature overnight. The mixture was quenched with MeOH and filtered. The resulting solid was rinsed with CH2Cl2 (5 mL) to give 3-(3-chloro-phenyl)-1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-urea (0.68 g, 82%): mp 193-195° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.29 (99%); 1H NMR (DMSO-d6): δ 2.00-2.04 (m, 1H), 2.32-2.38 (m, 1H), 2.56-2.63 (m, 1H), 2.85-2.92 (m, 1H), 2.98 (s, 3H), 4.38 (d, J=17.3 Hz, 1H), 4.45 (d, J=17.3 Hz, 1H), 4.65 (s, 2H), 5.10-5.18 (dd, J=4.5, 13.2 Hz, 1H), 7.00 (d, J=7.8 Hz, 1H), 7.26 (t, J=8.0 Hz, 1H), 7.46-7.41 (In, 2H), 7.53 (t, J=7.5 Hz, 1H), 7.64-7.67 (m, 2H), 8.65 (s, 1H), 11.13 (s, 1H). 13C NMR (DMSO-d6) δ: 22.57, 31.19, 34.76, 46.27, 48.37, 51.60, 118.00, 119.08, 121.42, 121.77, 128.48, 129.85, 129.92, 131.93, 132.69, 133.62, 140.15, 142.04, 155.34, 168.00, 171.01, 172.84. Anal Calcd for C22H21ClN4O4: C, 59.93; H, 4.80; N, 12.71, Cl, 8.04. Found: C, 59.30; H, 4.66; N, 12.33, Cl, 8.36.
