Synthesis of Some Amino Acid Linked Nitrogen Mustard Derivatives

Dichlorophosphoramide is readily prepared by the reaction of bis(ß-chloroethyl)amine hydrochloride with phosphoryl chloride at elevated temperature. The crude product is pure without need for troublesome vacuum distillation. However, this reagent reacts only poorly with ethanol, propanol, and the methyl ester of valine. Thus, an alternative route was sought to amino acid linked derivatives of nitrogen mustards. This involved the synthesis of the appropriate alkyl phosphorodichloridate, and its reaction with bis(ß-chloroethyl)amine, followed by condensation with an amino acid carboxyl ester. Reactions proceed in high yield, under mild conditions. In all but the case of glycine derivatives, the presence of multiple chiral centres in the final product leads to the generation of diastereoisomers, which can be observed by spectroscopic and analytical (HPLC) methods.