反应详情

温度

40 °C

To 9-(tert-butoxycarbonyl)-4-(2,2-difluoroethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-2-carboxylic acid (418 mg, 1.15 mmol), 1-aminobutan-2-one (156 mg, 1.26 mmol) and propane phosphonic acid anhydride (T3P) (1.095 g, 1.0 mL of 50% w/w, 1.72 mmol) in 2-methyltetrahydrofuran (3.1 mL) was added triethylamine (640 μL, 4.59 mmol) at room temperature. The reaction mixture was then heated at 40° C. for 5 hours. The reaction mixture was cooled quenched with sat. aq. NaHCO3 and extracted with ethyl acetate. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo, then purified by silica gel column chromatography using 0-50% EtOAc in DCM to yield tert-butyl 4-(2,2-difluoroethyl)-2-((2-oxobutyl)carbamoyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (300 mg, 60%). 1H NMR (400 MHz, CDCl3) δ 7.40-7.30 (m, 1H), 6.09-5.64 (m, 1H), 4.31 (dd, J=11.0, 3.0 Hz, 1H), 4.21-4.05 (m, 2H), 3.77 (ddt, J=10.9, 7.5, 6.3 Hz, 2H), 3.39-3.17 (m, 2H), 3.14-2.95 (m, 1H), 2.80-2.63 (m, 3H), 2.50 (q, J=7.3 Hz, 2H), 2.41-2.27 (m, 1H), 2.25-2.11 (m, 2H), 1.67-1.51 (m, 3H), 1.46 (s, 9H), 1.13 (t, J=7.4 Hz, 3H). ESI-MS m/z calc. 433.2. found 434.5 (M+1)+; Retention time: 1.78 minutes (3 min run).

1. temperatureThe reaction mixture was cooled
2. customquenched with sat. aq. NaHCO3
3. extractionextracted with ethyl acetate
4. dry with materialThe combined organics were dried over Na2SO4
5. filtrationfiltered
6. concentrationconcentrated in vacuo
7. custompurified by silica gel column chromatography