Thermally Hazardous 1,3-Dioxolane Coupling ReactionRequired for a Pharmaceutical Candidate Starting Material, Made Saferby Employing Process Safety Data as Key Design of Experiments OutputVariables

The optimization of a ruthenium-catalyzed catechol, terminal-alkyne coupling reaction to form a key benzodioxolane intermediate toward Lotiglipron is described. This transformation required the use of 3-butyn-2-ol, a valuable yet thermally hazardous reagent. Manual reaction condition optimization delivered a good yield but a poor process safety profile. Further reaction understanding was gained by performing a design of experiments (DoE) screening of relevant reaction conditions while using differential scanning calorimetry output data as well as productivity optimization parameters to strike a balance of process safety and chemical yield. To the best of our knowledge, this work represents the first report of using process safety data as DoE output to guide safe reaction condition selection. Finally, the optimal conditions were demonstrated in a lab-scale flow reactor with good translation of results from the batch reaction.