反应详情

温度

-75 °C

(A. K. Ghosh, S. P. McKee, and W. J. Thompson, J. Org. Chem. 56, 6500 (1991)). Under a nitrogen atmosphere, a solution of 1943 g (6.32 mol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-dihydrofuran-2-(3H)-one in 12.0 l of THF and 1.9 l of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone is cooled to -75° C., at an internal temperature of below -70° C. 14000 ml of lithium bis(trimethylsilyl)amide (IM) in THF (Aldrich) are added, and the mixture is then stirred for 20 min at -75° C. Over a period of 1 h, 835 ml (7.00 mol) of benzyl bromide are added thereto, the internal temperature not being allowed to exceed -70° C., and the mixture is stirred for 30 min at -75° C. to complete the reaction. There are then added to the clear solution at from -75 to -70° C. 2320 ml of propionic acid (90 min) followed by 2320 ml of water (1 h), the temperature being allowed to rise to -10° C. The reaction mixture is poured onto 30 l of ethyl acetate and 35 l of 10% citric acid solution, and the aqueous phase is removed and re-extracted twice with 10 l of ethyl acetate each time. The organic phases are washed three times with 12 l of sat. sodium bicarbonate solution each time, with 20 l of brine and twice with 20 l of water each time, and concentrated, and the oily residue is taken up in 10 l of toluene and concentrated by evaporation to a residual volume of approximately 5 1. Filtration of the evaporation residue through 4 kg of Merck silica gel (0.063-0.200 mm), subsequent washing with toluene and crystallisation of the crude product from hexane (4 l of hexane/kg of crude product) yields the title compound: TLC Rf (D)=0.54; FAB-MS (M+H)+ =414.

1. waitOver a period of 1 h
2. customto exceed -70° C.
3. stirringthe mixture is stirred for 30 min at -75° C.
4. customthe reaction
5. additionThere are then added to the clear solution at from -75 to -70° C
6. customto rise to -10° C
7. customthe aqueous phase is removed
8. extractionre-extracted twice with 10 l of ethyl acetate each time
9. washThe organic phases are washed three times with 12 l of sat. sodium bicarbonate solution each time
10. concentrationwith 20 l of brine and twice with 20 l of water each time, and concentrated
11. concentrationconcentrated by evaporation to a residual volume of approximately 5 1
12. filtrationFiltration of the evaporation residue through 4 kg of Merck silica gel (0.063-0.200 mm)
13. washsubsequent washing with toluene and crystallisation of the crude product from hexane (4 l of hexane/kg of crude product)