Production of (<i>S</i>)-1-Benzyl-3-diazo-2-oxopropylcarbamic Acid <i>tert</i>-Butyl Ester, a Diazoketone Pharmaceutical Intermediate, Employing a Small Scale Continuous Reactor

Abstract

N-Boc-(1S)-benzylhydroxy-3-chloropropylamine (6) is a precursor to pharmaceutically active compounds that act as human immunodeficiency virus (HIV) protease inhibitors. It is currently being produced via a batch process which includes a homologation step with diazomethane. This article considers the challenges faced when converting a traditional batch process to a continuous flow system for the production of the key intermediate (S)-1-benzyl-3-diazo-2-oxopropylcarbamic acid tert-butyl ester (4). A continuous flow reactor was designed, built, and used to carry out a two step reaction sequence: the formation of a temperature sensitive mixed anhydride intermediate (3) and the subsequent reaction of that intermediate (3) with trimethylsilyldiazomethane (8) to yield the diazoketone intermediate (4). By modifying the chemistry and maximizing the mixing and heat transfer, the batch process was successfully converted to a continuous flow process.