反应详情

温度

0 °C

Diethyl 3-(5-bromopyridin-2-yloxy)benzylphosphonate (2.00 g, 5.00 mmol) from Step 3 and 1,4,7,10,13-pentaoxacyclopentadecane (15-Crown-5, 0.025 mL, 0.13 mmol) were combined in THF (7 mL). The mixture was cooled to 0° C. and sodium hydride (210 mg, 60% dispersion in mineral oil, 5.25 mmol) was added. The reaction was warmed to room temperature, stirred for 30 min and then cooled back to 0° C. A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1.05 g, 5.25 mmol) in THF (4 mL) was added and the reaction was warmed to room temperature. After 16 h, an additional amount of sodium hydride (spatula tip) was added and the mixture was stirred an additional 6 h. Water was added and the mixture was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to a yellow oil. This material was crystallized from hot isopropyl ether/heptane. The supernatant was decanted and the solid was washed with heptane and dried in vacuo to afford the title compound (1.37 g, 62% yield) as an off-white solid. MS (APCI) M−100=345.0; 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (s, 9H) 2.30-2.37 (m, 2H) 2.44-2.50 (m, 2H) 3.38-3.44 (m, 2H) 3.48-3.54 (m, 2H) 6.35 (s, 1H) 6.85 (dd, J=8.77, 0.58 Hz, 1H) 6.94-7.00 (m, 2H) 7.03-7.07 (m, 1H) 7.35 (t, J=7.80 Hz, 1H) 7.78 (dd, J=8.67, 2.63 Hz, 1H) 8.23 (dd, J=2.53, 0.58 Hz, 1H).

1. temperatureThe reaction was warmed to room temperature
2. temperaturecooled back to 0° C
3. temperaturethe reaction was warmed to room temperature
4. waitAfter 16 h
5. stirringthe mixture was stirred an additional 6 h
6. extractionthe mixture was extracted twice with ethyl acetate
7. dry with materialThe combined organic layers were dried over anhydrous sodium sulfate
8. filtrationfiltered
9. concentrationconcentrated to a yellow oil
10. customThis material was crystallized from hot isopropyl ether/heptane
11. customThe supernatant was decanted
12. washthe solid was washed with heptane
13. customdried in vacuo