A diatrizoic acid derivative for N-acylation of amino acids

3,5-Bis(acetamido)-2,4,6-triiodobenzoic acid, aka diatrizoic acid (DTZOH), is a major compound for the radiopaque material research. Iodine elements at the 2,4,6-positions are the origin of the radiopacity, but the bulkiness of iodine frequently inhibits the nucleophilic attack to the 1-carboxylic carbon, resulting in a low yield when DTZOH is used as an acylation agent. In this study, the authors hypothesized that the 1-carboxylic oxygen is utilized as a nucleophile because of its freedom from iodine-shielding. The base-catalyzed esterification using tert-butyl α-bromoacetate and DTZOH formed the diatrizoyloxyacetic acid tert-butyl ester (DTZAc-OtBu) and subsequent removal of the tBu group using trifluoroacetic acid yielded the diatrizoyloxyacetic acid (DTZAcOH) in quantitative yield. Acylation of the primary amino groups of the β-alanine ethyl ester or Nα-tert-butyloxycarbonyl-l-lysine tert-butyl ester using isobutyl chloroformate were satisfactory in about 85 mol% yields. Conformer search calculations suggested that among the three classes of condensation reagents, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide monohydrochloride, 1,1′-cabonyldimidazole, and isobutyl chloroformate, the mixed anhydride generated by the condensation of DTZAcOH and isobutyl chloroformate has the highest freedom in the nucleophile approach direction and the lowest hindrance to the nucleophilic center. DTZAcOH is a feasible acylating agent of primary amino groups and inspires new designs of the functional X-ray shielding materials.