Citric Acid → 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-phenylmethyldihydrofuran-2-(3H)one

Participants

Reaction Conditions

Reaction Steps

(see, also, A. K. Ghosh, S. P. McKee, and W. J. Thompson, J. Org. Chem. 56, 6500 (1991)). Under an N2 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 down to -75° C. and treated, at an internal temperature of below -70° C., with 14000 ml of a 1M solution of lithium bis(trimethylsilyl)amide in THF (Aldrich), and this mixture is subsequently stirred at -75° C. for 20 min. 835 ml (7.00 mol) of benzyl bromide are added dropwise to it over the space of 1 h, during which time the internal temperature is not allowed to exceed -70° C., and the mixture is then thoroughly stirred at -75° C. for 30 min. 2320 ml of propionic acid (90 min) and then 2320 ml of water (1 h) are subsequently added to the clear solution, with 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 separated off and reextracted 2× with 10 l of ethyl acetate. The organic phases are washed with 3× 12 l of sat. sodium bicarbonate solution, 20 l of saline and 2× 20 l of water, and then concentrated. The oily residue is taken up in 10 l of toluene, and this mixture is evaporated down to a residue volume of approximately 5 l. Filtering the evaporation residue through 4 kg of Merck silica gel (0.063-0.200 mm), washing with toluene and crystallizing the crude product from hexane (4 l of hexane/kg of crude product) affords the title compound: TLC Rf (D)=0.54; FAB-MS (M+H)+ =414.

Provenance & Evidence