Synthesis of alpha-aminoacyl(1) derivatives of melphalan for use in antibody directed enzyme pro-drug therapy

L-Alanyl-, D-alanyl-, L-prolyl-, L-pyroglutamyl- and D-phenylalanylmelphala n were synthesized in 8 steps, with the reactive nitrogen mustard moiety fo rmed at the penultimate step. After protection of p-nitrophenylalanine with benzyl ester and N-t-butyloxycarbonyl (BOC) groups, the aromatic nitro was reduced to an amine which was reacted with ethylene oxide to give a produc t with a bis(2-hydroxyethyl)amino moiety. After removal of BOC, it was coup led to the relevant N-benzyloxycarbonyl-alpha-amino acid. Chlorination of h ydroxyethyl yielded the bis(2-chlorethyl)amino compound. Final removal of p rotecting groups was by catalytic hydrogenolysis. (C) 1999 Elsevier Science Ltd. All rights reserved.