Synthesis of polyamide oligomers based on 14-amino-3,6,9, 12-tetraoxatetradecanoic acid

A series of oligomers of polyamides based on 14-amino-3,6,9, 12-tetraoxatetradecanoic acid monomers (ATTAn) was synthesized. These materials were designed as monodisperse analogues of poly(ethylene glycol) for use in biomedical applications where reproducible behavior is important. Synthesis of the monomer was evaluated using two routes. For small-scale preparations, tetraethylene glycol (TEG) was monoprotected with dihydropyran, converted to an alkoxide, and alkylated with ethyl bromoacetate. On larger scales, TEG was alkylated directly by treatment with sodium, followed by ethyl bromoacetate. The amine function was introduced by mesylation followed by treatment with sodium azide. Reduction of the azide to amino groups was performed over Pd/C using either hydrogen or formic acid as proton sources. Assembly of the oligomers was accomplished using standard DCC/NHS chemistry and an iterative dimerization sequence after appropriate deprotection of a pair of monomers. The amino group was protected by retaining the azido group as a latent amine. A series of ATTAn oligomers was prepared (n = 1-8). A lipid conjugate of the octamer, ATTA8-DSPE, was synthesized.