反应详情

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 pentanoyl chloride (0.36 g, 3.00 mmol) in MeCN (20 mL), was added DIPEA (1.05 mL, 6.00 mmol) at room temperature under nitrogen. After 1 h, 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 for 18 h. The product was dried in vacuo to give pentanoic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.77 g, 35% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 2.71 min (95.58%); mp: 184-186° C.; 1H NMR (DMSO-d6) δ 0.81-0.95 (m, 3H, CH3), 1.28 (dq, J=7.3, 14.8 Hz, 2H, CH2), 1.41-1.64 (m, 2H, CH2), 1.97-2.13 (m, 1H, CHH), 2.17 (t, J=7.5 Hz, 2H, CH2), 2.53-2.70 (m, 2H, CHH, CHH), 2.77-2.99 (m, 1H, CHH), 4.43 (d, J=6.0 Hz, 2H, CH2), 5.15 (dd, J=5.4, 12.9 Hz, 1H, CH), 7.67-7.81 (m, 2H, Ar), 7.88 (d, J=7.7 Hz, 1H, Ar), 8.50 (t, J=5.9 Hz, 1H, NH), 11.13 (s, 1H, NH); 13C NMR (DMSO-d6) δ 13.68, 21.79, 21.99, 27.37, 30.93, 34.98, 41.87, 48.99, 121.78, 123.48, 129.71, 131.59, 133.28, 147.84, 166.97, 167.12, 169.82, 172.47, 172.73; LCMS: MH=372; Anal Calcd for C19H21N3O5: C, 61.45; H, 5.70; N, 11.31. Found: C, 61.12; H, 5.54; N, 11.15.

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