Development of 5-Amino-2,4,6-triiodoisophthalic Acid Derivatives for Carbamoylation of Amino Acids

Abstract

Herein, 5-amino-2,4,6-triiodoisophthalic acid (ATIIPA) is used as a nucleophile to produce the corresponding 1,3-diesters. Two types of 1,3-diesters, i) diethyl 5-amino-2,4,6-triiodoisophthalate (DEtTIIP) and ii) diacetoxyethyl 5-amino-2,4,6-triiodoisophthalate (DAcOEtTIIP), are mostly prepared in quantitative yields. The 1,3-esters are tested as a carbamoylation agent toward the amino groups of the βAla esters via isocyanation of the 5-amino group. The addition reaction of DEtTIIP-NCO and βAla-OEt yields DEtTIIP:CO-βAla-OEt, and the 1,3-diethyl ester is highly resistant to alkaline hydrolysis due to the steric shielding by the adjacent 2,4,6-iodines, while the α-ethyl ester of the βAla substructure is easily removed. Alkaline hydrolysis of another adduct, DAcOEtTIIP:CO-βAla-O^tBu, removes only the 1,3-acetoxy ethyl groups to form the product DAcOHTIIP:CO-βAla-O^tBu, and the acidic fission of the -O^tBu ester is quantitative to give DAcOEtTIIP:CO-βAla. These results indicate that the DAcOEtTIIP is a feasible precursor for the N-carbamoylation of the amino acid esters, preserving the freedom for selective ester deprotection, which further inspires the design of contrast molecules using amino acids and peptides.

Keywords: carbamoylation; di(acetoxyethyl) 5‐amino‐2,4,6‐triiodoisophthalate; diethyl 5‐amino‐2,4,6‐triiodoisophthalate; radiopaque material; selective deprotection.