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Development and Manufacturing GMP Scale-Up of a Continuous Ir-Catalyzed Homogeneous Reductive Amination Reaction

 PROCESS, SYNTHESIS, Uncategorized  Comments Off on Development and Manufacturing GMP Scale-Up of a Continuous Ir-Catalyzed Homogeneous Reductive Amination Reaction
Oct 202016
 
Evacetrapib.svg

Evacetrapib

Abstract Image

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.

Figure

Development and Manufacturing GMP Scale-Up of a Continuous Ir-Catalyzed Homogeneous Reductive Amination Reaction

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States
Eli Lilly SA, Dunderrow, Kinsale, Cork, Ireland
D&M Continuous Solutions, LLC, Greenwood, Indiana 46113, United States
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.6b00148
Publication Date (Web): October 19, 2016
Copyright © 2016 American Chemical Society
*E-mail (Scott A. May): may_scott_a@lilly.com., *E-mail: (Martin D. Johnson): johnson_martin_d@lilly.com., *E-mail: (Declan D. Hurley):hurley_declan_d@lilly.com.

ACS Editors’ Choice – This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

 

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