反应详情

温度

40 °C

A stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.37 g, 1.00 mmol) and CDI (0.18 g, 1.10 mmol) in N,N-dimethylformamide (10 mL) was heated to 40° C. under nitrogen overnight. 1-(3,4-Dichloro-phenyl)-ethylamine (0.19 g, 1.00 mmol) was then added and the mixture was heated at 40° C. overnight. Water (60 mL) was added, solid precipitated, was filtered, washed with water (30 mL) and was purified by preparative HPLC (gradient: CH3CN/H2O: 10/90 for 5 min, to 100/0 in 10 min, 100/0 for 5 min). Solvent was evaporated and the residue was triturated in ether (20 mL) for 1 h. The product was then isolated by filtration and dried in vacuo to give 1-[1-(3,4-Dichloro-phenyl)-ethyl]-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.084 g, 17% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, gradient: CH3CN/0.1% H3PO4: 10/90 to 90/10 in 10 min. 90/10 (5 min): 8.57 min (96.68%); mp: 200-202° C.: 1H NMR (DMSO-d6) δ 1.32 (d, J=7.0 Hz, 3H, CH3), 1.88-2.13 (m, 1H, CHH), 2.28-2.47 (m, 1H, CHH), 2.55-2.70 (m, 1H, CHH), 2.79-3.04 (m, 1H, CHH), 4.18-4.55 (m, 4H, CH2, CH2), 4.74 (quin, J=7.0 Hz, 1H, CH), 5.11 (dd, J=4.9, 13.2 Hz, 1H, CH), 6.51 (s, 1H, NH), 6.66 (d, J=7.9 Hz, 1H, NH), 7.20-7.46 (m, 3H, Ar), 7.48-7.62 (m, 2H, Ar), 7.65 (d, J=7.7 Hz, 1H, Ar), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.51, 22.80, 31.20, 42.86, 47.07, 48.18, 51.55, 121.61, 122.81, 126.28, 126.70, 127.78, 128.79, 130.14, 130.38, 130.77, 142.26, 145.29, 147.41, 157.20, 167.95, 170.98, 172.85; LCMS: MH=489, 491: Anal Calcd for C23H22N4O4Cl2+0.9H2O: C, 54.64; H, 4.75; N, 11.08. Found: C, 54.27; H, 4.66; N, 10.98.

1. temperaturethe mixture was heated at 40° C. overnight
2. customsolid precipitated
3. filtrationwas filtered
4. washwashed with water (30 mL)
5. customwas purified by preparative HPLC (gradient: CH3CN/H2O: 10/90 for 5 min, to 100/0 in 10 min, 100/0 for 5 min)
6. customSolvent was evaporated
7. customthe residue was triturated in ether (20 mL) for 1 h
8. customThe product was then isolated by filtration
9. customdried in vacuo