期刊
ORGANIC PROCESS RESEARCH & DEVELOPMENT
卷 24, 期 4, 页码 490-499出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.oprd.0c00052
关键词
asymmetric epoxidation; continuous manufacturing; carfilzomib
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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