反应详情

TEA (0.28 ml, 2 mmol) was added to a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (0.37 g, 1 mmol) and 1-chloro-2-isocyanato-4-trifluoromethyl-benzene (0.15 ml, 1 mmol) in acetonitrile (10 mL) under nitrogen. The mixture was stirred at ambient temperature for 1 h, during which time it remained a suspension. The reaction was then monitored and determined to be complete. A 3.5% aqueous HCl solution (10 mL) was added, and the mixture stirred for 10 minutes. The solid was isolated by filtration, and the solid was washed with additional 3.5% aq. HCl (20 mL) and acetonitrile (20 mL), yielding the 1-(2-chloro-5-trifluoromethyl-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (240 mg, 49%). HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 CH3CN 0.1% H3PO4 in H2O: tR=7.88 min (99%); mp. 240-242° C.; 1H NMR (DMSO-d6) δ 1.93-2.06 (m, 1H, CHH), 2.39 (qd, J=4.3, 13.2 Hz, 1H, CHH), 2.63 (br. s., 1H, CHH), 2.82-3.02 (m, 1H, CHH), 4.24-4.55 (m, 4H, CH2+CH2), 5.12 (dd, J=5.0, 13.1 Hz, 1H, NCH), 7.30 (dd, J=1.6, 8.4 Hz, 1H, Ar), 7.47 (d, J=7.9 Hz, 1H, Ar), 7.55 (s, 1H, Ar), 7.69 (dd, J=8.0, 15.4 Hz, 2H, Ar), 7.78 (t, J=5.7 Hz, 1H, Ar), 8.49 (s, 1H, NH), 8.66 (s, 1H, NH), 10.99 (s, 1H, NH). 13C NMR (DMSO-d6) δ 22.49, 31.20, 42.80, 47.13, 51.58, 116.19, 116.25, 118.54, 122.07, 123.06, 124.60, 125.64, 127.02, 127.90, 128.32, 130.23, 130.49, 137.51, 142.49, 143.95, 154.67, 167.89, 170.98, 172.85. LCMS MH=495; Anal Calcd for: C22H18ClF3N4O4+0.05 HCl: C, 53.20; H, 3.66; N, 7.49; Cl, 11.28. found: C, 53.08; H, 3.39; N, 7.64; Cl, 11.29.

1. stirringthe mixture stirred for 10 minutes
2. customThe solid was isolated by filtration
3. washthe solid was washed with additional 3.5% aq. HCl (20 mL) and acetonitrile (20 mL)