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 (0.50 g, 1.40 mmol) and 4-(trifluoromethoxy)phenylisocyanate (0.20 mL, 1.40 mmol) in N,N-dimethylformamide (10 mL), was added triethylamine (0.38 mL, 2.7 mmol) at room temperature under nitrogen. After 2 h, 1 N aq. HCl (15 mL) was added and the solids were isolated by filtration and washed with water (30 mL). The crude solids were slurried in EtOAc (15 mL) for 4 h then filtered, washed with EtOAc (15 mL) and dried in vacuo to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-(4-trifluoromethoxy-phenyl)-urea as an off-white solid (0.43 g, 67% 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, 8.87 min (98.89%); mp: 269-271° C.; 1H NMR (DMSO-d6) δ 1.85-2.13 (m, 1H, CHH), 2.25-2.47 (m, 1H, CHH), 2.60 (d, J=17.2 Hz, 1H, CHH), 2.79-3.08 (m, 1H, CHH), 4.22-4.38 (d, J=17.4 Hz, 1H, CHH), 4.38-4.57 (m, 3H, CHH, CH2), 5.11 (dd, J=5.0, 13.1 Hz, 1H, CH), 6.81 (t, J=5.9 Hz, 1H, NH), 7.23 (d, J=8.7 Hz, 2H, Ar), 7.45 (d, J=7.9 Hz, 1H, Ar), 7.48-7.60 (m, 3H, Ar), 7.70 (d, J=7.7 Hz, 1H, Ar), 8.87 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.49, 31.18, 42.79, 47.12, 51.56, 120.08 (q, M03), 118.80, 120.08 (q, J=250 Hz), 121.56, 121.86, 122.93, 126.88, 130.30, 139.71, 142.07, 142.38, 144.69, 155.10, 167.93, 170.99, 172.85; LCMS: MH=477; Anal Calcd for C22H19N4O5F3: C, 55.47; H, 4.02; N, 11.76; F, 11.96. Found: C, 55.27; H, 3.88; N, 11.73; F, 11.99.

1. customthe solids were isolated by filtration
2. washwashed with water (30 mL)
3. waitThe crude solids were slurried in EtOAc (15 mL) for 4 h
4. filtrationthen filtered
5. washwashed with EtOAc (15 mL)
6. customdried in vacuo