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

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Green Chemistry

Background:

• Herpes simplex virus (HSV) infections necessitate effective antiviral treatments.
• IM-204, a helicase-primase inhibitor, shows promise against HSV.
• Developing efficient and sustainable synthetic routes for APIs is crucial.

Purpose of the Study:

• To systematically develop greener and more efficient total synthetic routes for IM-204 using computer-aided retrosynthesis (CAR).
• To evaluate and experimentally validate CAR-generated synthetic options against the patented route.
• To explore the synergistic combination of CAR with a human-in-the-loop approach for further optimization.

Main Methods:

• Utilized various CAR tools to identify and analyze potential synthetic routes for IM-204.
• Experimentally validated selected CAR-derived synthetic pathways.
• Implemented a human-in-the-loop strategy to refine the synthesis, including solvent substitution and step merging.

Main Results:

• CAR identified routes outperforming the patented synthesis, increasing yield from 8% to 26%.
• The human-in-the-loop approach further boosted IM-204 yield to 35%.
• Green performance score improved from 0 to 18, and building block costs decreased 550-fold.

Conclusions:

• CAR is a powerful tool for streamlining API synthesis, reducing environmental impact, and lowering production costs.
• Combining CAR with human expertise accelerates the development of sustainable pharmaceutical manufacturing processes.
• This study demonstrates significant advancements in the efficient and eco-friendly synthesis of IM-204.