反应详情

To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.37 g, 1.0 mmol) and 4-cyanophenylisocyanate (0.14 g, 1.0 mmol) in acetonitrile (10 mL), was added triethylamine (0.28 mL, 2.0 mmol) at room temperature under nitrogen. After 18 h, 1 N aq. HCl (15 mL) was added and the solids were isolated by filtration, washed with water (40 mL). The crude product was purified by prep-HPLC (MeCN/H2O, 10/90 to 90/10 gradient over 15 min). The product fractions were combined, triturated in Et2O then filtered and dried in vacuo to give 1-(4-cyano-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.16 g, 38% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 to 90/10 CH3CN/0.1% H3PO4 gradient over 15 mins, 7.31 min (97.64%); mp: 258-260° C.; 1H NMR (DMSO-d6) δ 1.86-2.06 (m, 1H, CHH), 2.27-2.47 (m, 1H, CHH), 2.60 (d, J=17.0 Hz, 1H, CHH), 2.78-3.03 (m, 1H, CHH), 4.31 (d, J=17.2 Hz, 1H, CHH), 4.38-4.59 (m, 3H, CHH, CH2), 5.11 (dd, J=4.9, 13.2 Hz, 1H, CH), 7.00 (t, J=5.7 Hz, 1H, NH), 7.45 (d, J=7.9 Hz, 1H, Ar), 7.52 (s, 1H, Ar), 7.56-7.63 (m, 2H, Ar), 7.64-7.82 (m, 3H, Ar), 9.23 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.49, 31.20, 42.79, 47.12, 51.56, 102.50, 117.56, 119.40, 121.89, 122.96, 126.91, 130.36, 133.15, 142.39, 144.39, 144.84, 154.68, 167.92, 170.98, 172.85; LCMS: MH=418; Anal Calcd for C22H19N5O4: C, 62.76; H, 4.64; N, 16.63. Found: C, 62.65; H, 4.55; N, 16.69.

1. customthe solids were isolated by filtration
2. washwashed with water (40 mL)
3. customThe crude product was purified by prep-HPLC (MeCN/H2O, 10/90 to 90/10 gradient over 15 min)
4. customtriturated in Et2O
5. filtrationthen filtered
6. customdried in vacuo