Continuous, on-demand generation and separation of diphenylphosphoryl azide

Abstract Diphenylphosphorylazide (DPPA) has been synthesized in microfluidics with near-100% yield in sub-3 minute residence time, affordably, and with a process design that minimizes hazards associated with hydrazoic acid (HN 3 ) production. A pilot-plant scale continuous process for the on-demand synthesis of diphenylphosphoryl azide (DPPA) that can readily be integrated with subsequent transformations was designed, built, and validated. Using Corning's Low Flow reactor system coupled to a membrane separator and in-line Fourier Transform Infrared (FTIR), DPPA was safely produced at a rate of 1 mol/hr as a 2.0 M anhydrous toluene stream. Continuous FTIR was able to reliably monitor product quality, purity and concentration, showcasing the ease and utility of this continuous flow process for manufacturing common, safe pharmaceutical precursors.