反应详情

温度

10 °C

A 2-L, 3-neck, round bottom flask was equipped with a mechanical stirrer, a J-KEM temperature controller, a reflux condenser, and a nitrogen inlet. The flask was charged with 4-(methoxycarbonyl)bicyclo[2.2.1]heptane-1-carboxylic acid (100 g, 0.504 mol) and anhydrous toluene (500 mL). The flask was cooled to 10° C. and DIEA (175 mL, 1.008 mol) was slowly added over 5 min resulting in a mild exotherm up to 14° C. Diphenylphosphonic azide (130 mL, 0.605 mol) was slowly added to the reaction mixture. The mixture was heated to about 60° C. when off-gassing began. The reaction quickly generated a large amount of gas and exothermed to reflux. The reaction was stirred at reflux (110° C.) for 2 h, then cooled to 50° C. and slowly treated with benzyl alcohol (104 mL, 1.008 mol) over 5 min. The reaction was heated again to 110° C. and stirred for 40 h. The reaction mixture was concentrated to an oil in vacuo, dissolved in ethyl acetate (2 L), washed with brine (500 mL), and the brine layer was extracted with ethyl acetate (2×400 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to a crude oil which was transferred to a 5-L, 3-neck, round bottom flask equipped with a mechanical stirrer, a J-KEM temperature controller, and a nitrogen inlet. The flask was charged with methanol (2 L). The mixture was cooled to 10° C. and treated with 2N sodium hydroxide (500 mL) over 5 min resulting in an exotherm to 16° C. The reaction was stirred at 60° C. for 20 h when TLC analysis (20% methanol/ethyl acetate) indicated a complete reaction. The reaction was cooled to room temperature and methanol was removed in vacuo. With cooling, the reaction mixture was acidified using 2 N hydrochloric acid (480 mL) to pH 2-3. The aqueous mixture was extracted using ethyl acetate (2 L, then 500 mL). The combined organic layers were washed with brine (400 mL), dried over sodium sulfate, and concentrated to provide the crude product as a brown oil. The crude product was purified by silica gel chromatography (20-100% ethyl acetate/hexane) providing 132 g (91%) of 4-(benzyloxycarbonylamino)-bicyclo[2.2.1]heptane-1-carboxylic acid. 1H NMR (500 Hz, DMSO-d6) δ ppm 12.12 (s, 1H), 7.56 (s, 1H), 7.34-7.38 (m, 4H), 7.28-7.32 (m, 1H), 4.98 (s, 2H), 1.80-1.93 (m, 4H), 1.79 (s, 2H), 1.64 (t, J=9.1 Hz, 2H), 1.57 (t, J=8.8 Hz, 2H).

1. customresulting in a mild exotherm up to 14° C
2. temperatureThe mixture was heated to about 60° C. when
3. customThe reaction
4. temperatureto reflux
5. temperatureat reflux (110° C.) for 2 h
6. temperaturecooled to 50° C.
7. temperatureThe reaction was heated again to 110° C.
8. stirringstirred for 40 h
9. concentrationThe reaction mixture was concentrated to an oil in vacuo
10. dissolutiondissolved in ethyl acetate (2 L)
11. washwashed with brine (500 mL)
12. extractionthe brine layer was extracted with ethyl acetate (2×400 mL)
13. dry with materialThe combined organics were dried over sodium sulfate
14. filtrationfiltered
15. concentrationconcentrated to a crude oil which
16. custom3-neck, round bottom flask equipped with a mechanical stirrer
17. additionThe flask was charged with methanol (2 L)
18. temperatureThe mixture was cooled to 10° C.
19. additiontreated with 2N sodium hydroxide (500 mL) over 5 min
20. customresulting in an exotherm to 16° C
21. customa complete reaction
22. temperatureThe reaction was cooled to room temperature
23. custommethanol was removed in vacuo
24. temperatureWith cooling
25. extractionThe aqueous mixture was extracted
26. washThe combined organic layers were washed with brine (400 mL)
27. dry with materialdried over sodium sulfate
28. concentrationconcentrated
29. customto provide the crude product as a brown oil
30. customThe crude product was purified by silica gel chromatography (20-100% ethyl acetate/hexane)