反应详情

To a solution containing racemic methyl 1-oxaspiro[2.5]octane-5-carboxylate (34.2 g, 201 mmol), dissolved in MeOH (540 mL) was added neopentyl amine (18.4 g, 211 mmol). The reaction was heated at reflux for 20 h. The reaction mixture was cooled to rt and concentrated to an oil. The crude material was dissolved in 1,4-dioxane (540 mL) and treated with CDI (42.3 g, 261 mmol). The reaction was again heated at reflux. After 14 h, the reaction was concentrated to a thick oil, taken up in water, and acidified to pH 3. The product was extracted into DCM (5×300 mL). The combined organics were washed with concentrated aqueous H3PO4 solution followed by brine. The organics were then dried over sodium sulfate, filtered, and concentrated to a waxy white solid. This solid was purified on a 330 g silica gel column (0-60% EtOAc/hexanes, 30 min gradient; 100 mL/min elution; 254 nm detection) to provide the title compound (40.8 g, 69.7%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 3.69 (s, 3H), 3.38 (dd, J=8.78, 13.05 Hz, 2H), 3.01 (dd, J=14.05, 25.35 Hz, 2H), 2.17-2.28 (m, 1H), 2.02-2.12 (m, 1H), 1.98 (dd, J=2.13, 13.68 Hz, 1H), 1.71-1.86 (m, 2H), 1.54-1.65 (m, 2H), 1.29-1.47 (m, 2H), 0.97 (s, 9H).

1. temperatureThe reaction was heated
2. temperatureat reflux for 20 h
3. concentrationconcentrated to an oil
4. dissolutionThe crude material was dissolved in 1,4-dioxane (540 mL)
5. temperatureThe reaction was again heated
6. temperatureat reflux
7. concentrationthe reaction was concentrated to a thick oil
8. extractionThe product was extracted into DCM (5×300 mL)
9. washThe combined organics were washed with concentrated aqueous H3PO4 solution
10. dry with materialThe organics were then dried over sodium sulfate
11. filtrationfiltered
12. concentrationconcentrated to a waxy white solid
13. customThis solid was purified on a 330 g silica gel column (0-60% EtOAc/hexanes, 30 min gradient; 100 mL/min elution; 254 nm detection)