Acyl couplings between carboxylic acids and nucleophiles represents a ubiquitous strategy used in the fine chemical industry. This reaction class typically involves activation of carboxylic acids with activating agents such as CDI (carbonyldiimidazole) before coupling. Common challenges encountered throughout the development of these processes include inconsistent potency of the activating reagent, water reactivity, and variable activation times. A combination of process analytical technology (PAT) tools were deployed to interrogate a particularly challenging slurry to slurry acyl coupling (penultimate API step). By combining automated slurry sampling with in situ infrared (IR) spectroscopy, invaluable kinetic data was collected throughout the reaction’s progress. Improved conditions were identified and the reaction was successfully demonstrated on 60 L scale while monitoring with in situ IR.

Monitoring acyl couplings with orthogonal PAT: Temporal data from lab scale to scaleup

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