Potential Anticancer Agents——Ⅲ.Preparation of Amino Acid Derivatives of Bis(β-chloroethyl)-Phosphoramidic Dichloride

In order to examine the feasibility that whether N-phosphorylated amino acid moiety would function as a carrier of the transport form of nitrogen mustard derivatives with the desired specificity in cancer chemotherapy, a number of amino acid derivatives of bis (β-chloroethyl)-phosphoramidic dichloride were prepared. Treatment of bis (β-chloroethyl)-phosphoramidic dichloride (Ⅰ) with two equivalents of the ethyl ester (Ⅱ) of glycine, alanine, valine, leucine, phenylalanine, aspartic acid, and glutamic acid in an inert solvent in the presence of triethylamine afforded the corresponding derivatives of N, N-bis(β-chloroethyl)-N', N"-di-(carboethoxymethyl)-phosphorotriamide (Ⅲ—Ⅸ). Similarly, reaction of the dichlorophophoramide (Ⅰ) with equivalent ethyl ester of serine (Ⅹ) yielded a cyclic derivative, 2-bis (β-chloroethyl)amino-4-carboethoxy-1, 3, 2-oxazophospholidine, 2-oxide (Ⅺ). The compounds derived from glycine, phenylalanine and glutamic acid were crystalline solids, while those from the remaining amino acids were less stable oily substances. The results of screening tests of the above compounds against transplanted tumours will be published in a separate paper.