反应详情

温度

0 °C

Intermediate 85 (900 g, 1.0 eq, 1.0 wt) was charged to a solution of (S)-(−)-2-methyl-CBS-oxazaborolidine (198 g, 0.3 eq, 0.22 wt) in tetrahydrofuran (3.6 L, 4 vol) at 20° C., followed by a line rinse with tetrahydrofuran (0.9 L, 1 vol). The suspension was cooled to 0° C. and chilled (0° C.) 1M borane in tetrahydrofuran solution (4.82 L, 2 eq 5.35 vol) was added over 1 hour 35 minutes at <3° C. The mixture was stirred at 0° C. for 1 hour 20 minutes when complete dissolution was observed and sampled for completion by HPLC. Reaction was complete. The mixture was added into chilled (0° C.) methanol (3.6 L, 4 vol) at <5° C. over 40 minutes, followed by a line rinse with methanol (0.9 L, 1 vol). The mixture was warmed to 20° C. and stirred at this temperature for 1 hour 15 minutes when effervescence had ceased. Water (2.7 L, 3 vol) was added, followed by the addition of 5M aqueous hydrochloric acid (0.9 L, 1 vol) at <10° C. over 10 minutes. The mixture was warmed to 20° C. and stirred at this temperature for 1 hour when effervescence had ceased. To the mixture was added 48% w/w aqueous sodium hydroxide (0.99 L, 1.1 vol) at <30° C. over 15 minutes and the mixture stirred vigorously for 10 minutes at 20° C. The basic aqueous layer was separated. The organic phase was diluted with isopropylacetate (3.6 L, 4 vol) and washed with water (2.7 L, 3 vol). The aqueous phase was separated and the organic phase was concentrated by vacuum (100-200 mbar) distillation to 3.6 L/4 vol at 25° C. To the mixture was added isopropylacetate (5.4 L, 6 vol), followed by water (6 L, 6.7 vol) and the mixture stirred vigorously for 10 minutes at 20° C. The aqueous phase was separated and the organic phase was concentrated by vacuum distillation on a rotary evaporator. The solids were slurried in heptane (9 L, 10 vol) on the rotary evaporator at 40 C for 1 hour and stirred at this temperature for 16 hours. The solids were collected by vacuum filtration, washed with heptane (2×0.9 L, 2×1 vol) and dried in vacuo at 40° C. for 23 hours 30 minutes. Yield of the title compound obtained was 739 g/90% theory yield/82% w/w yield.

1. washrinse with tetrahydrofuran (0.9 L, 1 vol)
2. additionwas added over 1 hour 35 minutes at <3° C
3. dissolutionwhen complete dissolution
4. aliquotsampled for completion by HPLC
5. customReaction
6. additionThe mixture was added
7. washrinse with methanol (0.9 L, 1 vol)
8. temperatureThe mixture was warmed to 20° C.
9. stirringstirred at this temperature for 1 hour 15 minutes when effervescence
10. additionWater (2.7 L, 3 vol) was added
11. additionfollowed by the addition of 5M aqueous hydrochloric acid (0.9 L, 1 vol) at <10° C. over 10 minutes
12. temperatureThe mixture was warmed to 20° C.
13. stirringstirred at this temperature for 1 hour when effervescence
14. additionTo the mixture was added 48% w/w aqueous sodium hydroxide (0.99 L, 1.1 vol) at <30° C. over 15 minutes
15. stirringthe mixture stirred vigorously for 10 minutes at 20° C
16. customThe basic aqueous layer was separated
17. additionThe organic phase was diluted with isopropylacetate (3.6 L, 4 vol)
18. washwashed with water (2.7 L, 3 vol)
19. customThe aqueous phase was separated
20. concentrationthe organic phase was concentrated by vacuum (100-200 mbar) distillation to 3.6 L/4 vol at 25° C
21. additionTo the mixture was added isopropylacetate (5.4 L, 6 vol)
22. stirringthe mixture stirred vigorously for 10 minutes at 20° C
23. customThe aqueous phase was separated
24. concentrationthe organic phase was concentrated by vacuum distillation on a rotary evaporator
25. customThe solids were slurried in heptane (9 L, 10 vol) on the rotary evaporator at 40 C for 1 hour
26. stirringstirred at this temperature for 16 hours
27. filtrationThe solids were collected by vacuum filtration
28. washwashed with heptane (2×0.9 L, 2×1 vol)
29. customdried in vacuo at 40° C. for 23 hours 30 minutes