The development and kilogram-scale demonstration of a high-temperature continuous-flow racemization process to recycle the off-enantiomer of an atropisomeric sotorasib intermediate is described. Part 1 of this two-part series details the design and execution of a classical resolution to generate atropisomer M-1 from a racemic precursor (rac-1). In parallel, the team sought to develop a racemization process to enable recycling of the classical resolution waste stream and maximize productivity and sustainability. Computational and experimental methods revealed a high barrier to rotation (ca. 42 kcal/mol) prompting the design of a high-temperature (>300 °C) racemization protocol for recovery of the racemic compound. Described herein are the determination of the barrier to rotation, optimization of conditions to enable racemization, proof-of-concept for a continuous-flow process to execute the process, and kilogram-scale demonstration, including (1) recovery of the undesired atropisomer as a crystalline solid from the classical resolution waste stream, (2) thermal racemization by a high-temperature continuous-flow process, and (3) isolation of the racemic compound by crystallization directly from the reaction stream.
We have developed a convenient development-scale reactor (0.44 mol/h) to prepare diazomethane from N-methyl-N-nitroso-p-toluenesulfonamide (MNTS) in ∼80% yield. Diazomethane (CH 2 N 2 ) made with this reactor is extracted into nitrogen gas from the liquid reaction mixture, effectively removing it from reagents and byproducts that may interfere in subsequent reactions. Vertically oriented tubular reactors were used to produce and consume diazomethane in situ. Key features of this reactor include high productivity and correspondingly low reactor volume (reactor volume/liquid flow rate = 6.5 min) and a commercially available gas/liquid separator equipped with a selectively permeating hydrophilic membrane. The design of the reactor keeps the inventory below 53 mg of CH 2 N 2 during normal operation. The reactor was demonstrated by generating CH 2 N 2 that was used in a connected continuous reactor. We evaluated esterification reactions and a continuous Pd-catalyzed cyclopropanation reaction with the reactor and achieved high conversion with 1.5 and 4.1 equiv of MNTS precursor, respectively.
In this article, we describe the process development efforts to improve the final methylation step in the AMG 397 drug substance process, culminating in the execution of a Good Manufacturing Practice (GMP) continuous manufacturing process. During the development, batch kinetic studies and detailed NMR analysis of the final step identified that rapid base addition and the presence of stoichiometric water were critical to ensure consistent levels of reaction conversion and to obtain the desired active pharmaceutical ingredient (API) in high purity. As a result, a continuous process was developed to facilitate the rapid base addition and short deprotonation residence time, ensuring reliable process performance on a multi-kilogram scale. The AMG 397 GMP manufacture, comprised of the continuous reaction process and semi-batch isolation, delivered the final API in high purity (>99%) and yield (76%), exceeding the API specifications. The lessons learned from the manufacturing campaign, which include equipment clogging and loss of tubing integrity, are discussed and drove the development of a second-generation continuous process to improve reaction processing for future deliveries. The second-generation process has not encountered the challenges of the GMP campaign due to the implementation of important equipment modifications, and the improved process has been successfully demonstrated on a 100 g scale.
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