The one-pot, telescoped Miyaura borylation and Suzuki coupling reaction is a popular reaction used to synthesize pharmaceutical compounds. Due to the heterogeneous nature of the borylation step and the biphasic conditions under which the Suzuki coupling typically operates, ensuring robustness when scaling up is a key challenge. In our case, we had a one-pot, telescoped Miyaura borylation and Suzuki coupling reaction that required tight control of water concentration during the borylation and challenges with impurities after the Suzuki coupling. Scaling up the process led to further complications, underscoring the necessity to predict reaction results based on initial conditions (determined via Karl Fischer titration and in-process control samples). To address this, we developed a kinetic mechanistic model, which provided deeper insight into the reaction network and enabled the prediction of reaction performance under varying conditions. Unlike empirical approaches, our model allowed for a priori identification of rate-determining steps, optimal water concentrations, and impurity formation pathways, reducing the need for extensive experimental screening. The model successfully predicted the effects of water and the impurity profile under various simulated conditions, which were validated through experiments. By leveraging kinetic modeling, we optimized scale-up conditions to maximize yield while minimizing key impurities, ensuring a more robust and scalable process.
