Modular continuous flow synthesis of zidovudine (AZT): a two-stage integrated process enabling safe azidation and enhanced sustainability in HIV drug manufacturing

Abstract

AIDS is one of the deadliest global epidemics. Zidovudine (AZT), the first FDA-approved HIV treatment, is a key component of antiretroviral therapy. The current industrial synthesis of AZT exhibits several drawbacks: low selectivity of hydroxyl protection, hazardous azidation, and prolonged reaction times/extended processing durations, contributing to suboptimal efficiency, safety hazards, and environmental burden. To address these limitations, we developed a modular continuous flow process for the synthesis of AZT. We actively addressed the solvent and reagent compatibility issues and balanced the yield of integrated reactions. This process integrated hydroxyl protection and cyclization in module A, followed by azidation and hydroxyl deprotection in module B, with seamless filtration connecting the two modules. The integrated platform achieves a 69% overall yield across four transformations, reducing the batch time of 2550 minutes to a residence time of 108 minutes. Compared to traditional batch processes, the continuous flow system enhances the selectivity of hydroxyl protection, enables safer handling of azidation reactions, significantly reduces the E-factor from 375 to 210 while increasing the space–time yield (STY) to 17.39 g L⁻¹ h⁻¹, resulting in a 289-fold performance gain over the batch process.