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.

中文翻译：

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通过动力学建模增强的工艺开发之旅：通往 Balcinrenone 的高效制造路线


这项工作的重点是加速开发一种多功能工艺，用于合成关键的酰胺中间体，然后用于生产活性药物成分巴辛利酮。在开发的早期阶段实施预测动力学模型促进了工艺开发。预测动力学模型有效地指导和加快了使用甲醇中甲胺的伸缩式不对称还原/酰胺化工艺的批量和连续制造的路线设计、工艺设计和工艺优化。伸缩间歇工艺的实施显著提高了 balcinrenone 合成的通量、可持续性和经济效率，从而成功生产了关键的酰胺中间体。此外，利用多线性回归 （MLR）-动力学混合模型，能够快速开发使用水中甲胺的替代工艺，在甲醇中甲胺短缺的情况下为生产活动提供应急计划。除了主要关注点之外，本研究还扩展了动力学建模的应用，以指导通过 pH 控制添加/环化获得的第二中间体的工艺设计和优化，从而增强对此步骤的理解和通量。最后，使用涉及初始动力学研究的结构化实验设计导致发现最终酰胺键形成以产生巴辛酮的改进条件。