4-aminoquinolines, classically prepared via SNAr chemistry from an amine and 4-haloquinoline, are important scaffolds in medicinal chemistry. Interest in these compounds prompted us to explore palladium catalysis as an alternative to the existing methods for their preparation. Initial results followed by an iterative screening paradigm confirmed Pd(OAc)2/DPEphos/K3PO4 as a mild and convenient alternative for the formation of the C-N bond in 4-aminoquinolines. A description of the screen and the scope of this methodology are discussed herein.
The design, development,
and scale up of a continuous iridium-catalyzed
homogeneous high pressure reductive amination reaction to produce 6, the penultimate intermediate in Lilly’s CETP inhibitor
evacetrapib, is described. The scope of this report involves initial
batch chemistry screening at milligram scale through the development
process leading to full-scale production in manufacturing under GMP
conditions. Key aspects in this process include a description of drivers
for developing a continuous process over existing well-defined batch
approaches, manufacturing setup, and approaches toward key quality
and regulatory questions such as batch definition, the use of process
analytics, start up and shutdown waste, “in control”
versus “at steady state”, lot genealogy and deviation
boundaries, fluctuations, and diverting. The fully developed continuous
reaction operated for 24 days during a primary stability campaign
and produced over 2 MT of the penultimate intermediate in 95% yield
after batch workup, crystallization, and isolation.
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