Computer-Aided Retrosynthesis for Greener and Optimal Total Synthesis of a Helicase-Primase Inhibitor Active Pharmaceutical Ingredient

Abstract

This study leverages and upgrades the capabilities of computer-aided retrosynthesis (CAR) in the systematic development of greener and more efficient total synthetic routes for the active pharmaceutical ingredient (API) IM-204, a helicase-primase inhibitor that demonstrated enhanced efficacy against Herpes simplex virus (HSV) infections. Using various CAR tools, several total synthetic routes were uncovered, evaluated, and experimentally validated, with the goal to maximize selectivity and yield and minimize the environmental impact. The CAR tools revealed several synthetic options under different constraints, which can overperform the patented synthetic route used as a reference. The selected CAR-based route demonstrated a significant improvement of the total yield from 8% (patented route) to 26%, along with a moderate improvement in the overall green performance. It was also shown that a human-in-the-loop approach can be synergistically combined with CAR to drive further improvements and deliver greener synthetic alternatives. This strategy further enhanced the green metrics by substituting solvents and merging two steps into one. These changes led to a significant improvement in the overall yield of IM-204 synthesis from 8 to 35%. Additionally, the green performance score, based on the GreenMotion metrics, was improved from 0 to 18, and the total cost of the building blocks was reduced by 550-fold. This work demonstrates the potential of CAR in drug development, highlighting its capacity to streamline synthesis processes, reduce environmental footprint, and lower production costs, thereby advancing the field toward more efficient and sustainable practices.