Development and Scale-Up of an Optimized Route to the ALK Inhibitor CEP-28122
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- 作者：Shawn P. Allwein ; Renee C. Roemmele ; James J. Haley ; Jr. ; Dale R. Mowrey ; Daniel E. Petrillo ; James J. Reif ; Diane E. Gingrich ; Roger P. Bakale
- 刊名：Organic Process Research & Development
- 出版年：2012
- 出版时间：January 20, 2012
- 年：2012
- 卷：16
- 期：1
- 页码：148-155
- 全文大小：354K
- 年卷期：v.16,no.1(January 20, 2012)
- ISSN：1520-586X
文摘
Evolution of the process strategies to prepare CEP-28122, an anaplastic lymphoma kinase (ALK) inhibitor, is presented. The initial medicinal chemistry route, used for the preparation of key supplies for biological screening, is reviewed. In addition, the process research and development of the final optimized process for manufacture of preclinical and clinical supplies is discussed. Details regarding a blocking group strategy for selective nitration; discovery of a one-pot transfer hydrogenation to effect a reductive amination, nitro group reduction, and dehalogenation; an enzymatic resolution of a critical intermediate; and the discovery of a novel, stable, in situ generated mixed mesylate hydrochloride salt of the API are disclosed.