4-Methylmorpholine → N-Benzyl-L-alaninamide

Participants

Reaction Steps

To a mechanically-stirred, 18° C. solution of 37.5 g (116 mmole) of BOC-β-benzyl-(L)-aspartic acid in 270 mL ethyl acetate is added a solution of 17.75 g (116 mmole) of hydroxybenzotriazole hydrate in 25 mL of dimethylformamide. A solution of 24.5 g (119 mmole) of dicyclohexylcarbodiimide in 50 mL of ethyl acetate is then added over 30 minutes, using a water bath to keep the reaction temperature at or below 25° C. The reaction mixture is stirred for 1 hour, then a syrup of 33 g (116 mmole) of 3-cyclohexyl-(L)-alanineamide ester mono (trifluoroacetate) in 25 mL of dimethylformamide is added at 23° C., followed by dropwise addition of neat N-methylmorpholine over 2 minutes. The reaction mixture is allowed to warm to 30° C. during the N-methylmorpholine addition. The reaction mixture is stirred at ambient temperature overnight. The reaction mixture is filtered to remove dicyclohexyl urea, and the filtrate is diluted with ethyl acetate, washed twice with water, once with brine, twice saturated aqueous sodium bicarbonate, and once with 1:1 0.5N citric acid/brine. The organic phase is dried with magnesium sulfate, filtered, and diluted with heptane. The mixture is allowed to stand overnight, and the resulting crystals are collected by filtration, washed twice with heptane, and dried under vacuum to give a first crop of 37.5 g and a second crop of 9.5 g. Both crops show acceptable HPLC purity and are physically combined to afford 47 g of N-[(1,1-dimethylethoxy)carbonyl]-(L)-α-aspartyl-3-cyclohexyl-(L-alanineamide phenylmethyl ester (85 yield). MS (FAB) m/7 476 (M+H)+.

Provenance & Evidence