4-Methylmorpholine → [N-(t-butyloxycarbonyl)statine]-glutamic acid dibenzyl ester

Participants

Reaction Conditions

Reaction Steps

N-hydroxybenzotriazole (324 mg., 2.4 mmoles), N-methyl-morpholine (202 mg., 2 mmoles), L-glutamic acid dibenzyl ester p-toluenesulfonate (995 mg., 2 mmoles), N-(t-butyloxycarbonyl)-statine (660 mg., 2.4 mmoles) and 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho p-toluene sulfonate (1271 mg., 80% pure, 2.4 mmoles) were sequentially dissolved in methylene chloride (100 ml.) at 0° C. and the resulting solution stirred for 19 hours at 20° C. The reaction mixture was then washed consecutively with 5.5% aqueous HCl, saturated aqueous NaHCO3 solution and brine, and dried over anhydrous MgSO4After filtration and evaporation, 1269 g. of crude [N-(t-butyloxycarbonyl)statine]-glutamic acid dibenzyl ester was obtained as an oil (lH NMR, CDCl3, 5.2 delta, 2H s [benzyl CH2 ]). This oil (1269 g.) was dissolved in 10 ml. of 3.7N HCl/dioxane and the resulting solution allowed to stand for one hour at room temperature. The solution was then evaporated under high vacuum to a residue, which was triturated in ether and dried with nitrogen to yield 900 mg. of statine-glutamic acid dibenzyl ester hydrochloride as a foam (lH NMR, CDCl3, 5.2 delta, 2H s [benzyl CH2 ]). N-hydroxybenzotriazole (186 mg., 1.38 mmoles), N-methyl-morpholine (116 mg., 1.15 mmoles), a quantity of the statine-glutamic acid dibenzyl ester hydrochloride foam formed above (600 mg., 1.15 mmoles), N-(t-butyloxycarbonyl)-L-alanine (261 mg., 1.38 mmoles) and 1-cyclohexyl-3-(2-morpholinoethyl)-carbodiimide metho p-toluene sulfonate (732 mg., 80% pure, 1.38 mmoles) were sequentially dissolved in methylene chloride (60 ml.) at 0° C. and the resulting solution stirred for 19 hours at 20° C. The reaction mixture was then washed consecutively with 5.5% aqueous HCl, saturated aqueous NaHCO3 solution and brine, and dried over anhydrous MgSO4After filtration and evaporation, 743 mg. of crude product was obtained as a foam (lH NMR, CDCl3, 5.2 delta, 2H s [benzyl CH2 ]).

Provenance & Evidence