Process Intensified Flow Synthesis of 1<i>H</i>-4-Substituted Imidazoles: Toward the Continuous Production of Daclatasvir

Abstract

Herein we present a high-temperature/high-pressure continuous flow synthesis of 1H-4-substituted imidazoles starting from α-bromoacetophenones and carboxylic acids. 1H-4-aryl imidazoles are key building blocks in the synthesis of NS5A inhibitors, including daclatasvir as the most prominent example. The reaction sequence started with the generation of the α-acyloxy ketone from α-bromoacetophenone and the carboxylic acid. The subsequent condensation to the 1H-4-substituted imidazole was performed with ammonium acetate in a high-temperature stainless steel coil reactor. High-temperature operation (> ∼ 150 °C) was essential for this reaction to form the desired imidazole in high purity. Intensification of chemical reactions in continuous flow reactors has emerged as key enabling technology for process enhancement and for reducing the environmental impact of chemical processes. The continuous flow setup allowed rapid heating of the reaction mixture to the desired temperature. Furthermore, operation at elevated pressure (∼17 bar) eliminated headspace and increased the concentration of volatile compounds in the liquid phase. The imidazole formation was completed in the coil reactor after residence times of only 2 to 5 min. The products were isolated after the two step reaction sequence in high purity by a simple extraction procedure. Imidazoles derived from chiral amino acids were obtained as the optically pure compounds.