反应详情

温度

40 °C

To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and 4-chlorobenzoyl chloride (0.53 g, 3.30 mmol) in THF (20 mL), was added DIPEA (1.05 mL, 6.00 mmol) at room temperature under nitrogen. The mixture was heated to 40° C. for 18 h then cooled to rt. The solvent was removed in vacuo and the residue was dissolved in EtOAc (100 mL). The organic layer was washed with dil. aq. HCl (2×150 mL), water (100 mL), dried (MgSO4) and then concentrated. The crude product was purified by column chromatography (0-5% MeOH/CH2Cl2). The product fractions were combined, concentrated and triturated in Et2O (50 mL) for 18 h. The product was isolated by filtration and dried in vacuo to give 4-chloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-benzamide as a white solid (0.80 g, 63% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 4.97 min (97.05%); mp: 178-180° C.; 1H NMR (DMSO-d6) δ 1.92-2.15 (m, 1H, CHH), 2.54-2.71 (m, 2H, CHH, CHH), 2.77-3.02 (m, 1H, CHH), 4.65 (d, J=5.9 Hz, 2H, CH2), 5.15 (dd, J=5.5, 12.8 Hz, 1H, CH), 7.53-7.63 (m, 2H, Ar), 7.74-7.87 (m, 2H, Ar), 7.87-8.03 (m, 3H, Ar), 9.31 (t, J=5.9 Hz, 1H, NH), 11.13 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.93, 42.67, 48.99, 122.01, 123.55, 128.50, 129.21, 129.84, 131.62, 132.64, 133.47, 136.30, 147.38, 165.40, 166.96, 167.10, 169.80, 172.72; LCMS: MH=426/428; Anal Calcd for C21H16N3O5Cl: C, 58.98; H, 3.82; N, 9.83. Found: C, 58.67; H, 3.67; N, 9.53.

1. temperaturethen cooled to rt
2. customThe solvent was removed in vacuo
3. dissolutionthe residue was dissolved in EtOAc (100 mL)
4. washThe organic layer was washed with dil. aq. HCl (2×150 mL), water (100 mL)
5. dry with materialdried (MgSO4)
6. concentrationconcentrated
7. customThe crude product was purified by column chromatography (0-5% MeOH/CH2Cl2)
8. concentrationconcentrated
9. customtriturated in Et2O (50 mL) for 18 h
10. customThe product was isolated by filtration
11. customdried in vacuo