Enabling amidation in water: micellar catalysis approach for sustainable synthesis of iopamidol

Abstract

Micellar catalysis is becoming an increasingly versatile tool to carry out a wide range of organic transformations using water as the reaction medium. The approach was recently found to be effective also in the case of water sensitive organics such as acyl chlorides. This finding is of great relevance for the manufacturing of challenging substrates such as the known iodinated contrast agent iopamidol, requiring the use of aprotic dipolar solvents (DMF, NMP, DMAc) in the key amidation step of an acyl dichloride intermediate with serinol. These solvents are subjected to an increasing regulatory pressure due to safety and environmental concerns. We show that the amidation step can be straightforwardly performed in water containing the industrial surfactant Triton X-100, provided that the employed amine is not water soluble. Accordingly, we developed suitable lipophilic serinol derivatives that, after amidation and hydrolysis, directly gave iopamidol in a one-pot process.