Design and optimization of a shared synthetic route for multiple active pharmaceutical ingredients through combined computer aided retrosynthesis and flow chemistry

Abstract

This study investigates the synergistic integration of Computer-Aided Retrosynthesis (CAR) and continuous flow chemistry to identify and optimise shared synthetic pathways for multiple active pharmaceutical ingredients (APIs). CAR was employed to identify shared synthetic routes across 11 different APIs, leveraging a Hantzsch thiazole synthesis as a shared reaction step for all investigated targets. The results showed that transitioning from traditional batch synthesis to continuous flow led to significant enhancements, including a 95% isolated yield under optimized conditions at 50°C and a residence time of only 10 minutes. The optimized reaction recipes and conditions also enhanced the environmental footprint of the process, improving the overall GreenMotion score by 25% and nearly doubling the 'Process' category score. Additionally, the study introduced a pH-induced crystallization method for purification, which streamlined the process and reduced resource intensity. The combined CAR and flow chemistry approach demonstrated enhanced flexibility and scalability, and reduced environmental impact, underlining its potential to transform API production through more holistic Green-by-Design strategies. • Combined Computer Aided Retrosynthesis (CAR) and flow chemistry delivers greener and more efficient processes or API synthesis. • Smarter and faster pharmaceutical design compared to traditional trial-and-error approaches. • Multi-target CAR optimizes shared synthetic routes for multiple APIs and ensures a more holistic approaches to optimize the synthetic routes of the chemicals • The integration of CAR with continuous flow chemistry enhances process flexibility, scalability, and yield, providing a more efficient alternative to traditional batch-based manufacturing.

Topics & Concepts