Continuous process improvement in the manufacture of Carfilzomib, part 2: an improved process for synthesis of the Epoxyketone warhead
MG Beaver, X Shi, J Riedel, P Patel… - … Process Research & …, 2020 - ACS Publications
MG Beaver, X Shi, J Riedel, P Patel, A Zeng, MT Corbett, JA Robinson, AT Parsons, S Cui…
Organic Process Research & Development, 2020•ACS PublicationsThe 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 …
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 …
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.
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