反应详情

温度

17.5 °C

To (S)-(−)-α,α-diphenyl-2-pyrrolidinemethanol (2.71 g, 10.70 mmol) was added THF (80 mL) at 23° C. The very thin suspension was treated with trimethyl borate (1.44 g, 13.86 mmol) over 30 seconds, and the resulting solution was mixed at 23° C. for 1 h. The solution was cooled to 16-19° C., and N,N-diethylaniline borane (21.45 g, 132 mmol) was added dropwise via syringe over 3-5 min (caution: vigorous H2 evolution), while the internal temperature was maintained at 16-19° C. After 15 min, the H2 evolution had ceased. To a separate vessel was added 1,4-Bis(4-nitrophenyl)butane-1,4-dione (22.04 g, 95 wt %, 63.8 mmol), followed by THF (80 mL), to form an orange slurry. After cooling the slurry to 11° C., the borane solution was transferred via cannula into the dione slurry over 3-5 min. During this period, the internal temperature of the slurry rose to 16° C. After the addition was complete, the reaction was maintained at 20-27° C. for an additional 2.5 h. After reaction completion, the mixture was cooled to 5° C. and methanol (16.7 g, 521 mmol) was added dropwise over 5-10 min, maintaining an internal temperature <20° C. (note: vigorous H2 evolution). After the exotherm had ceased (ca. 10 min), the temperature was adjusted to 23° C., and the reaction was mixed until complete dissolution of the solids had occurred. Ethyl acetate (300 mL) and 1 M HCl (120 mL) were added, and the phases were partitioned. The organic phase was then washed successively with 1 M HCl (2×120 mL), H2O (65 mL), and 10% aq. NaCl (65 mL). The organics were dried over MgSO4, filtered, and concentrated in vacuo. Crystallization of the product occurred during the concentration. The slurry was warmed to 50° C., and heptane (250 mL) was added over 15 min. The slurry was then allowed to mix at 23° C. for 30 min and filtered. The wet cake was washed with 3:1 heptane:ethyl acetate (75 mL), and the orange, crystalline solids were dried at 45° C. for 24 h to provide (1R,4R)-1,4-bis(4-nitrophenyl)butane-1,4-diol (15.35 g, 99.3% ee, 61% yield), which was contaminated with 11% of the meso isomer (vs. dl isomer).

1. additionthe resulting solution was mixed at 23° C. for 1 h
2. temperaturewhile the internal temperature was maintained at 16-19° C
3. customto form an orange slurry
4. temperatureAfter cooling the slurry to 11° C.
5. waitDuring this period
6. customrose to 16° C
7. additionAfter the addition
8. temperaturethe reaction was maintained at 20-27° C. for an additional 2.5 h
9. customAfter reaction completion
10. temperaturethe mixture was cooled to 5° C.
11. temperaturemaintaining an internal temperature <20° C. (note: vigorous H2 evolution)
12. custom(ca. 10 min)
13. customwas adjusted to 23° C.
14. additionthe reaction was mixed until complete dissolution of the solids
15. customthe phases were partitioned
16. washThe organic phase was then washed successively with 1 M HCl (2×120 mL), H2O (65 mL), and 10% aq. NaCl (65 mL)
17. dry with materialThe organics were dried over MgSO4
18. filtrationfiltered
19. concentrationconcentrated in vacuo
20. customCrystallization of the product
21. concentrationoccurred during the concentration
22. temperatureThe slurry was warmed to 50° C.
23. additionheptane (250 mL) was added over 15 min
24. additionto mix at 23° C. for 30 min
25. filtrationfiltered
26. washThe wet cake was washed with 3:1 heptane
27. dry with materialethyl acetate (75 mL), and the orange, crystalline solids were dried at 45° C. for 24 h