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.