Continuous Process Improvement in the Manufacture of Carfilzomib, Part 2: An Improved Process for Synthesis of the Epoxyketone Warhead

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.