Development of a continuous melt reactor for an acid-mediated decarboxylation

Abstract

Midazolam, a sterile injectable sedative, was in high demand during the COVID-19 pandemic. We developed a synthetic process where the final decarboxylation step provided high yield and excellent midazolam/isomidazolam selectivity when conducted as a hot-melt in the presence of a strong acid. Herein, we describe a new continuous reactor to conduct the acid-mediated high-temperature melt decarboxylation reaction. In particular, we will present a novel melt reactor composed of heated stacked aluminum plates that accepts a solid feed, melts the feed, and conveys the melt through a reaction zone using gravity. Several aspects of the plate reactor required design iteration and optimization, including the melting zone, the specific shape of the liquid outlet of each plate, control of the flow rate and residence time using the temperature of the melting zone, and powder feeding strategy. After optimization, a small-scale prototype was constructed, and the robustness was assessed with two production campaigns lasting approximately 13 and 28 hours. The reactor consistently produced midazolam with a >95% instantaneous yield and produced 691 g of crude midazolam across the two runs. Moreover, the melt reaction suppresses the formation of isomidazolam, a common and difficult to purge impurity, to levels below 0.3 liquid chromatography area percent.