A Journey through Process Development Enhanced by Kinetic Modeling: An Efficient Manufacturing Route to Balcinrenone

Abstract

This work focuses on the accelerated development of a versatile process for synthesizing a key amide intermediate en route to the active pharmaceutical ingredient balcinrenone. The process development was facilitated by the implementation of predictive kinetic models at the early stages of development. The predictive kinetic models effectively guided and expedited route design, process design, and process optimization for both batch and continuous manufacturing of a telescoped asymmetric reduction/amidation process using methylamine in methanol. The implementation of the telescoped batch process led to significant enhancements in throughput, sustainability, and economic efficiency of the synthesis of balcinrenone, resulting in the successful manufacture of the key amide intermediate. Additionally, the utilization of a multilinear regression (MLR)-Kinetics hybrid model enabled the rapid development of an alternative process using methylamine in water, providing a contingency plan for manufacturing campaigns in the event of shortage of methylamine in methanol. In addition to the primary focus, this study expanded the application of kinetic modeling to guide process design and optimization for a second intermediate obtained via pH-controlled addition/cyclization, thereby enhancing understanding and throughput for this step. Finally, the use of a structured experimentation design involving initial kinetic studies led to the discovery of improved conditions for the final amide bond formation to produce balcinrenone.