Dicyclohexylcarbodiimide → benzyloxycarbonyl-L-valyl-L-proline t-butyl ester

Participants

Reaction Steps

N-Benzyloxycarbonyl-L-valine (121.3 g), 1-hydroxybenzotriazole (130.5 g) and dry dimethylformamide (DMF) (800 ml) were placed in a 5 liter, 3-necked flask equipped with a mechanical stirrer, thermometer, and a calcium sulfate drying tube, under nitrogen atmosphere. The mixture was cooled to 0° for 15 min and proline t-butyl ester (82.6 g) in dry DMF (800 ml) was added at a fast dropwise rate over 2 h while the temperature of the reaction mixture was maintained at 0°. Dicyclohexylcarbodiimide (109.4 g) in dry DMF (400 ml) then was added in one portion to the reaction mixture. The reaction was stirred at 0° for 3 h, allowed to warm to room temperature gradually over 1 h, and stirred for 48 h, whereupon the reaction was shown to be complete by TLC [Rf =0.55, chloroform:ethyl acetate (85:15)]. The reaction mixture was chilled in ice/water and filtered cold to remove the precipitated dicyclohexyl urea. The DMF was evaporated using a mechanical vacuum pump and at a maximum bath temperature of 40°. The remaining oil was diluted with ethyl acetate (2 liter), chilled, and refiltered to remove additional dicyclohexyl urea. The ethyl acetate solution was washed (20% (w/v) citric acid solution (twice), saturated sodium chloride solution, saturated sodium bicarbonate solution (twice), and saturated sodium chloride solution), dried (MgSO4), and evaporated to afford crude benzyloxycarbonyl-L-valyl-L-proline t-butyl ester as an amber oil (208.3 g, 100%).

Provenance & Evidence