反应详情

温度

7 °C

A 22-L four-neck round bottom flask equipped with a mechanical stirrer, nitrogen inlet, 1-L addition funnel with nitrogen outlet, a temperature probe, and an external bath for cooling was purged with nitrogen overnight. A solution of the product of Step D (426 g, 1.57 mol) and acetone (8.1 L) was added, the flask was cooled to 7° C., and the addition funnel was charged with Jones reagent (710 mL). The oxidant was added dropwise over 1 h 20 min, keeping the temp between 7-9° C. After the first 200 mL was added, a green ball formed that made stirring very difficult. After about ½ of the oxidant was added, LCMS was run to follow the reaction. At the end of addition, olive green suspension resulted with a hint of red (excess Jones). The ice bath was removed, the reaction was stirred at rt for 1 h after which time the reaction was judged complete. Isopropyl alcohol (40 mL) was added, the reaction stirred for 25 min, and water (800 mL) was added, that caused a nice separation of green chunk from the acetone/water layer. The water/acetone was decanted off and evaporated. The green chunk was dissolved in water (1.5 L), transferred to a separatory funnel and extracted with CH2Cl2 (1 L). The aqueous layer was checked by TLC and found to contain no product, so it was discarded. The organic extract was saved for combining later. The green water/acetone concentrate was evaporated to about 5-7 L, until the solution looked hazy. The concentrate was transferred to a separatory funnel and extracted with CH2Cl2 (1×3 L, 3×1 L) and the aqueous layer checked after each extraction for the presence of product. The combined extracts were washed with brine (250 mL) which caused a terrible emulsion. The emulsion was broken by addition of water and EtOAc (˜500 mL). The organic layer was dried (Na2SO4) but not very effectively as some water came through during the filtration. Near the end of the evaporation, the distillation rate slowed, and a thick yellow oil resulted. MeCN (500 mL) was added to the pot, the rotary evaporator bath warmed to 50° C., and the contents seeded with reference material. A fine white solid slowly formed within 10 min or so. Seeding was done a second time, and continued swirling for another 10 min at 50° C. Crystallization was visually detected, the bath was drained and filled with ice, and the flask swirled at 0° C. for 30 min, resulting in a thick white solid. The solid was filtered, washed with ice-cold MeCN (2×100 mL) and the solid was air-dried overnight. The product of Step E was isolated as a white, free-flowing solid. 1H NMR (MeOH) δ: 4.43 (d, J=5.4 Hz, 1H), 4.00-4.13 (m, 1H), 3.89-3.98 (m, 1H), 3.63 (td, J=9.1, 5.7 Hz, 1H), 2.54 (ddd, J=12.6, 5.7, 3.2 Hz, 1H), 1.93-2.13 (m, 3H), 1.74-1.87 (m, 1H), 1.53-1.66 (m, 1H), 1.43 (s, 9H). Calculated for C13H21NO5: 294.1 (M+23). found: 294.1.

1. customA 22-L four-neck round bottom flask equipped with a mechanical stirrer, nitrogen inlet
2. temperaturea temperature probe, and an external bath for cooling
3. customwas purged with nitrogen overnight
4. additionThe oxidant was added dropwise over 1 h 20 min
5. custombetween 7-9° C
6. additionAfter the first 200 mL was added
7. customa green ball formed
8. additionAfter about ½ of the oxidant was added
9. customthe reaction
10. additionAt the end of addition, olive green suspension
11. customresulted with a hint of red (excess Jones)
12. customThe ice bath was removed
13. stirringthe reaction was stirred at rt for 1 h after which time the reaction
14. additionIsopropyl alcohol (40 mL) was added
15. stirringthe reaction stirred for 25 min
16. additionwater (800 mL) was added
17. customa nice separation of green chunk from the acetone/water layer
18. customThe water/acetone was decanted off
19. customevaporated
20. dissolutionThe green chunk was dissolved in water (1.5 L)
21. customtransferred to a separatory funnel
22. extractionextracted with CH2Cl2 (1 L)
23. extractionThe organic extract
24. concentrationThe green water/acetone concentrate
25. customwas evaporated to about 5-7 L, until the solution
26. customThe concentrate was transferred to a separatory funnel
27. extractionextracted with CH2Cl2 (1×3 L, 3×1 L)
28. extractionafter each extraction for the presence of product
29. washThe combined extracts were washed with brine (250 mL) which
30. additionThe emulsion was broken by addition of water and EtOAc (˜500 mL)
31. dry with materialThe organic layer was dried (Na2SO4)
32. filtrationnot very effectively as some water came through during the filtration
33. customNear the end of the evaporation
34. customa thick yellow oil resulted
35. temperaturewarmed to 50° C.
36. customA fine white solid slowly formed within 10 min
37. customCrystallization
38. additionfilled with ice
39. waitthe flask swirled at 0° C. for 30 min
40. customresulting in a thick white solid
41. filtrationThe solid was filtered
42. washwashed with ice-cold MeCN (2×100 mL)
43. customthe solid was air-dried overnight