op7b00070_si_001.pdf (3.77 MB)

Development of a Process Route to the FAK/ALK Dual Inhibitor TEV-37440

Download (3.77 MB)
journal contribution
posted on 25.04.2017, 00:00 by Shawn P. Allwein, Dale R. Mowrey, Daniel E. Petrillo, James J. Reif, Vikram C. Purohit, Karen L. Milkiewicz, Roger P. Bakale, Michael A. Christie, Mark A. Olsen, Christopher J. Neville, Gregory J. Gilmartin
The development of a scalable route to TEV-37440, a dual inhibitor of focal adhesion kinase (FAK) and anaplastic lymphoma kinase (ALK), is presented. The medicinal chemistry route used to support this target through nomination is reviewed, along with the early process chemistry route to support IND (inversigational new drug) enabling activities within CMC (Chemistry, Manufacturing, and Controls). The identification and development of an improved route that was performed in the pilot plant to supply early phase clinical supplies are discussed. Details surrounding the use of a novel ring expansion, a selective nitration through a para-blocking group strategy, a single-pot amination–hydrogenation, a diastereomeric salt resolution, a through-process step to avoid a hazardous intermediate, and a practical formation of a trihydrochloride dihydrate salt are disclosed.

History

Exports