Continuous Flow Synthesis of Nitrofuran Pharmaceuticals Using Acetyl Nitrate

Abstract

Nitrofurfural is a key building block for the synthesis of antimicrobial nitrofurans as active pharmaceutical ingredients. Its synthesis involves the nitration of furfural, a substrate derived from biobased resources. However, furfural has a delicate heteroaromatic backbone. Typical nitrations involve harsh reaction conditions, which often compromise this structure, resulting in poor reproducibility and low yields. Although acetyl nitrate, a mild nitrating agent, is suitable for this task, major deterrents remain. First, its conventional preparation method involves conditions that are not compatible with furfural. Second, significant safety concerns are associated with the unstable and explosive nature of acetyl nitrate. These critical issues are addressed herein. A safe and robust continuous flow platform featuring in situ generation of acetyl nitrate for the nitration of furfural to nitrofurfural is reported. The high level of integration and automation enables remote process operation by a single operator. Key furfural-based pharmaceutical intermediates were synthesized with favorable metrics and high reproducibility. The efficiency of this flow platform is demonstrated using a selection of best-selling nitrofuran pharmaceuticals (nifuroxazide, nifurtimox, nitrofurantoin, and nitrofural), which were obtained with excellent isolated yields in under five minutes.