Multistep Synthesis of Paracetamol in Continuous Flow

Abstract

p-Aminophenol (AP) is the key intermediate of the traditional synthesis of paracetamol. The method of obtaining AP included a selective reduction reaction of the generation of N-arylhydroxylamine (AHA) using nitrobenzene (NB) as the raw material, followed by a Bamberger rearrangement reaction to transfer AHA to the target product. The generation of AHA is a key step, but due to its structural instability and the incompatibility of the two reaction systems, one-pot synthesis of paracetamol faces great challenges. Considering that using flow reactors in series may avoid the problems faced by batch reactors, the article presents the strategy to obtain paracetamol via a continuous flow technology. In particular, we focus on condition screening in total synthesis experiments, including hydrogenation, Bamberger rearrangement, and amidation in flow. The continuous three-step synthesis process used NB as a raw material to generate AHA, which entered the downstream for timely conversion, achieving in situ on-demand preparation of the unstable intermediate AHA, avoiding cumbersome processing and storage processes. Moreover, each step of the reaction system exhibits excellent compatibility, and the work-up is simple.