Continuous Process Improvement in the Manufacture of Carfilzomib, Part 2: An Improved Process for Synthesis of the Epoxyketone Warhead
Matthew G. Beaver, Xianqing Shi, Jan Riedel, Parth Patel, Alicia Zeng, Michael T. Corbett, Jo Anna Robinson, Andrew T. Parsons, Sheng Cui, Kyle D. Baucom, Michael A. Lovette, Elçin Içten, Derek B. Brown, Ayman D. Allian, Tawnya G. Flick, Wendy Chen, Ning Yang, Shawn D. Walker
Abstract
The development and kilogram-scale demonstration of an improved process for the synthesis of the epoxyketone warhead of carfilzomib is described. Critical to the success of this process was: (1) development of a scalable asymmetric epoxidation protocol; (2) identification of a crystalline intermediate with improved physical properties for isolation; (3) discovery and optimization of epimerization conditions to set the target stereochemistry; and (4) introduction of a seeded-bed coaddition crystallization to facilitate isolation of the final low-melting target. The results of kilogram-scale demonstration runs are shared, including details of a continuous process for the safe execution of an exothermic Barbier-type Grignard process.