The synthesis and the mechanism of a five-membered ring formation between an isothiocyanate and an amide leading to the yield of Enzalutamide anticancer API; a joint experimental and theoretical study

Abstract

This paper has been prepared to investigate the question "why the five-membered ring formation to give Enzalutamide, needs at least a portion of dimethyl sulfoxide (DMSO) as the solvent and a high level of temperature about 95 °C?". By understanding the role of DMSO as solvent in the mechanism of such ring closing, this question might be answered. In addition, with the aid of the potential energy surface (PES) (dE) calculations, and the density functional theory (DFT) investigations, the PES curves of the reaction were designed to find the probable energy valleys and barriers of the process. The results of the experimental as well as theoretical studies showed that by choosing a suitable catalyst in DMSO: Isopropyl acetate (IPOAC) as the solvent mixture, we could handle the synthesis of Enzalutamide anti-cancer active pharmaceutical ingredient (API) in a milder condition with a lower temperature (about 70 °C), and also a shorter time (about 18 h instead of 24 h). Also, the developed HPLC-UV method showed that after crystallization, the API powder would have a total purity profile up to 99%.