Optimization of an Aminothiazine Ring Formation: Integrating Modeling with Experiments to Maximize Yield by Minimizing Impurity Formation

The aminothiazine formation step is a key transformation in the process to synthesize a potent and selective inhibitor of Beta-Amyloid Cleaving Enzyme (BACE). There are several impurities formed during the telescoped process that impacted the overall yield of the transformation. In order to improve the overall yield and design the impurity control strategy, a mechanistic model was developed to understand the impact of different process parameters on yield and impurity levels. This work describes how mechanistic models were integrated with experiments to determine process conditions to maximize the yield by minimizing impurity formation.