Reaction Steps
A stirred mixture of 5-ethoxy-pyridine-2-carboxylic acid (0.33 g, 2.00 mmol) and CDI (0.36 g, 2.20 mmol) in N,N-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 1 h, 5-aminomethyl-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.68 g, 2.00 mmol) was added and the mixture was heated at 40° C. for 1.5 h. The mixture was cooled to rt and water (40 mL) was added. The solids were filtered and dissolved in CH2Cl2 (10 mL). The crude product was purified by column chromatography (0-5% MeOH CH2Cl2, gradient, product eluted at 3% MeOH). The product fractions were combined and concentrated to give 5-ethoxy-pyridine-2-carboxylic acid[2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.69 g, 77% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 4.98 min (95.90%); mp: 145-147° C.; 1H NMR (DMSO-d6) δ 1.37 (t, J=7.2 Hz, 3H), 1.88 (s, 3H), 2.01-2.07 (m, 1H), 2.54 2.71 (m, 3H), 4.19 (dd, J=6.9, 13.8 Hz, 2H), 4.61 (d, J=6.3 Hz, 2H), 7.53 (dd, J=3.0, 8.7 Hz, 1H), 7.77-7.82 (m, 3H), 7.99 (d, J=8.7 Hz, 1H), 8.31 (d, J=2.4 Hz, 1H), 9.40 (t, J=6.3 Hz, 1H), 11.00 (s, 1H); 13C NMR (DMSO-d6) δ12.70, 19.30, 26.90, 27.40, 40.60, 57.00, 62.40, 119.60, 120.00, 121.40, 121.70, 127.80, 129.60, 131.80, 135.10, 14.050, 145.90, 155.30, 162.30, 166.10, 166.20, 170.40, 170.50; LCMS: MH=451; Anal Calcd for C23H22N4O6+0.5H2O: C, 60.13; H, 5.05; N, 12.19. Found: C, 59.95; H, 4.91; N, 12.04.
