The synthetic routes were investigated to four kinds of tetrapeptides made up of three usual amino acid residues and one N-carboxymethyl (Cm-) amino acid residue. The application of vacuum distillation made the isolation of a Cm-amino acid diester more convenient and efficient compared with the chromatographic methods which had been used previously. The efficiency of peptide bond formation at the imino group of a Cm-amino acid by the acid chloride method was remarkably improved under suitable reaction conditions. In the elongation of the peptide chain from a peptide containing a Cm-amino acid at the C-terminal position, the coupling efficiency was usually poorer than that in the case of the corresponding peptide composed only of the usual amino acid residues, and it depended greatly on the coupling methods, the 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide–1-hydroxybenzotriazole method being generally the most desirable.

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