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.

中文翻译：

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卡非佐米生产中的连续工艺改进，第2部分：合成环氧酮战斗部的改进方法

描述了改进的合成卡菲佐米环氧酮战斗部的方法的发展和千克规模的演示。该过程成功的关键在于：（1）开发可扩展的不对称环氧化方案；（2）鉴定具有改善的物理性质的结晶中间体以进行分离；（3）发现和优化差向异构化条件以设定目标立体化学；（4）引入晶种床共结晶，以促进最终低熔点目标的分离。共享了公斤级示范运行的结果，包括安全执行放热的Barbier型格氏试剂的连续过程的详细信息。