(652d) Model Based Approach to Develop a Ring-Closure Reaction with High Product Selectivity

Authors: 
Andiappan, M., Eli Lilly and Company
McFarland, A. D., Eli Lilly and Company
Fennell, J., Eli Lilly and Company

An intramolecular nucleophilic aromatic substitution reaction promoted by strong base is a commonly used reaction to form pharmaceutically-relevant heterocycles in the industry.  In this contribution, modeling of this ring-closure reaction was used to achieve extremely high product selectivity over impurity formation by a competitive side reaction between the desired product and the strong base, potassium tert-butoxide. The elementary steps of this competitive reaction were investigated using in situ NMR techniques for raw data collection to derive a mechanistic kinetic model. Demonstration of the model findings, specifically removal of the byproduct t-butanol (t-BuOH) from the solution, resulted in reduced impurity formation.

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