Development of a Practical Synthesis of a TORC1/2 Inhibitor: A Scalable Application of Memory of Chirality

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• 作者：Frederick Hicks ; Yongquan Hou ; Marianne Langston ; Ashley McCarron ; Erin O鈥橞rien ; Tatsuya Ito ; Chunrong Ma ; Chris Matthews ; Colin O鈥橞ryan ; David Provencal ; Yuxin Zhao ; Jie Huang ; Qiang Yang ; Li Heyang ; Matthew Johnson ; Yan Sitang ; Liu Yuqiang
• 刊名：Organic Process Research & Development
• 出版年：2013
• 出版时间：May 17, 2013
• 年：2013
• 卷：17
• 期：5
• 页码：829-837
• 全文大小：445K
• 年卷期：v.17,no.5(May 17, 2013)
• ISSN：1520-586X

文摘

Progression toward a scalable synthesis of TORC1/2 inhibitor bulk drug, culminating in the first GMP manufacturing campaign, is described. Process research and development was needed to obtain the prerequisite stereocenter in high enantiomeric excess for kilogram-scale production. Through route selection, a six-linear step synthesis was developed which afforded the API in 20% overall yield. Development included an application of memory of chirality (MOC) to install a quaternary chiral center with near complete retention, a reductive cyclization to form a piperazinone core, and a palladium-catalyzed C鈥揅 bond-forming step.