反应详情

In an apparatus fitted with a Dean Stark trap, reflux a solution of 1.0 kg (6.75 mol) of benzylacetone, 725 g (6.75 mol) of benzylamine and 5.0 g of p-toluenesulfonic acid hydrate in 7 liters of benzene for 14 hours. Remove the solvent in vacuo, and dissolve the residue in 6.5 liters of methanol. With cooling and stirring, carefully add 125 g of NaBH4 and stir the mixture for 16 hours at room temperature. Remove the methanol in vacuo, and add 2 liters water and 4 liters benzene, and extract the product into the benzene. After drying (MgSO4), filter and distill (b.p. 145°-150° C./0.5 mm). Dissolve 1,028 g (4.288 mol) of the distillate and 1.23 kg (4.328 mol) of N-p-toluenesulfonyl-(L)-leucine in 7.2 liters of boiling ethanol and allow to cool to room temperature without agitation. Wash the precipitate with a small amount of ice-cold ethanol, recrystallize from 4.8 liters of ethanol, wash with ice-cold ethanol and filter off the solid product that is highly enriched with the salt of the undesired S enantiomer. Combine the mother liquor from the original precipitation and that from the recrystallization, remove the solvent and recover the free base by basifying with 500 ml of 20% aqueous NaOH and extracting with benzene. After drying (MgSO4), filtering and removing the benzene, dissolve the residue [487 g (2.04 mol)] and 346 g (2.06 mol) of N-acetyl-(L)-leucine in 2.0 liters of boiling ethanol and allow the solution to cool to room temperature. Filter and recrystallize once from 1.8 liter of ethanol followed by recrystallization from 4.0 liters of acetonitrile to obtain the desired R salt, m.p. 151°-152° C. Basify with 400 ml of aqueous 2.5N NaOH, extract with ether, dry (MgSO4), filter and remove the solvent in vacuo to obtain the product (2), [α]26D =+4.5° (c=5.0, ethanol).

1. customIn an apparatus fitted with a Dean Stark trap
2. customRemove the solvent in vacuo
3. dissolutiondissolve the residue in 6.5 liters of methanol
4. temperatureWith cooling
5. stirringcarefully add 125 g of NaBH4 and stir the mixture for 16 hours at room temperature
6. customRemove the methanol in vacuo
7. additionadd 2 liters water and 4 liters benzene
8. extractionextract the product into the benzene
9. dry with materialAfter drying (MgSO4)
10. filtrationfilter
11. distillationdistill (b.p. 145°-150° C./0.5 mm)
12. washWash the precipitate with a small amount of ice-cold ethanol
13. customrecrystallize from 4.8 liters of ethanol
14. washwash with ice-cold ethanol
15. filtrationfilter off the solid product that
16. customfrom the original precipitation
17. customthat from the recrystallization
18. customremove the solvent
19. customrecover the free base
20. extractionextracting with benzene
21. dry with materialAfter drying (MgSO4)
22. filtrationfiltering
23. customremoving the benzene
24. temperatureto cool to room temperature
25. filtrationFilter
26. customrecrystallize once from 1.8 liter of ethanol
27. customfollowed by recrystallization from 4.0 liters of acetonitrile
28. customto obtain the desired R salt, m.p. 151°-152° C
29. extractionBasify with 400 ml of aqueous 2.5N NaOH, extract with ether
30. dry with materialdry (MgSO4)
31. filtrationfilter
32. customremove the solvent in vacuo