化学
威尼斯人
班级(哲学)
比例(比率)
组合化学
认识论
内科学
白血病
哲学
物理
量子力学
医学
慢性淋巴细胞白血病
作者
Yi‐Yin Ku,Vincent Chan,Alan Christesen,Timothy Grieme,Mathew M. Mulhern,Yu‐Ming Pu,Michael Wendt
标识
DOI:10.1021/acs.joc.8b02750
摘要
The process development of a new synthetic route leading to an efficient and robust synthetic process for venetoclax (1: the active pharmaceutical ingredient (API) in Venclexta) is described. The redesigned synthesis features a Buchwald-Hartwig amination to construct the core ester 23c in a convergent fashion by connecting two key building blocks (4c and 26), which is then followed by a uniquely effective saponification reaction of 23c using anhydrous hydroxide generated in situ to obtain 2. Finally, the coupling of the penultimate core acid 2 with sulfonamide 3 furnishes drug substance 1 with consistently high quality. The challenges and solutions for the key Pd-catalyzed C–N cross-coupling will also be discussed in detail. The improved synthesis overcomes many of the initial scale-up challenges and was accomplished in 46% overall yield from 3,3-dimethyldicyclohexanone (6), more than doubling the overall yield of the first generation route. The new process was successfully implemented for producing large quantities of 1 with >99% area purity.
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