反应详情

A mixture of 3-[4-(acetylamino)-1,3-dioxoisoindolin-2-yl]-3-(3-ethoxy-4-methoxyphenyl)propanoic acid (1.69 g, 3.96 mmol) and carbonyidiimidazole (0.71 g, 4.4 mmol) in acetonitrile (20 mL) was stirred at room temperature for 2 hours. To the solution was added formic hydrazide (289 mg, 4.81 mmol). The mixture was then stirred for 18 hours. To the resulting solution was added phosphorus oxychloride (1.0 mL, 10.7 mmol), and this mixture was heated at reflux for 2 hours. The solution was poured to water (10 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with aqueous sodium hydrogen carbonate (50 mL, sat), brine (50 mL) and then dried over magnesium sulfate. Chromatography followed by removal of solvent yielded an oil. The oil was stirred in ether (10 mL) to give a suspension. This suspension was filtered to yield N-[2-[1-(3-ethoxy-4-methoxyphenyl)-2-(1,3,4-oxadiazol-2-yl)ethyl]-1,3-dioxoisoindolin-4-yl]acetamide as a white solid (478 mg, 27% yield): mp, 141.0-143.0° C.; 1H NMR (CDCl3) δ 1.47 (t, J=6.9 Hz, 3H, CH3), 2.26 (s, 3H, CH3), 3.74 (dd, J=5.8, 15.8 Hz, 1H, CHH), 3.85 (s, 3H, CH3), 4.11 (q, J=7.1 Hz, 2H, CH2), 4.38 (dd, J=10.6, 15.8 Hz, 1H, CHH), 5.78 (dd, J=5.6, 10.6 Hz, 1H, NCH), 6.83 (d, J=8.9 Hz, 1H, Ar), 7.11-7.14 (m, 2H, Ar), 7.45 (d, J=7.2 Hz, 1H, Ar), 7.64 (d, J=7.5 Hz, 1H, Ar), 8.31 (s, 1H, Ar), 8.75 (d, J=8.4 Hz, 1H, Ar), 9.46 (br s, 1H, NH); 13C NMR (CDCl3) δ 14,70, 24.92, 27.60, 51.74, 55.92, 64.50, 111.40, 112.47, 115.15, 118.11, 120.15, 124.91, 129.87, 130.99, 136.01, 137.55, 148.49, 149.59, 153.07, 163.88, 167.44, 169.14, 169.75; Anal Calcd for C23H22N4O6: C, 61.33; H, 4.92; N, 12.44. Found: C, 61.37; H, 4.88; N, 12.11.

1. stirringThe mixture was then stirred for 18 hours
2. temperaturethis mixture was heated
3. temperatureat reflux for 2 hours
4. extractionThe aqueous layer was extracted with ethyl acetate (2×50 mL)
5. washThe combined organic layers were washed with aqueous sodium hydrogen carbonate (50 mL, sat), brine (50 mL)
6. dry with materialdried over magnesium sulfate
7. customChromatography followed by removal of solvent
8. customyielded an oil
9. customto give a suspension
10. filtrationThis suspension was filtered