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

Abstract

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.

Synthesis of Mepivacaine and Its Analogues by a Continuous‐Flow Tandem Hydrogenation/Reductive Amination Strategy

“…Reactions with secondary amines are generally more challenging. Nevertheless, reductive amination is increasingly employed also for the production of complex pharmaceutical targets, and the advantages of continuous‐flow processing to accomplish this transformation are well documented . An early pioneering study was the hydrogenation of preformed imines over Pd/C in a continuous‐flow high‐pressure hydrogenator (H‐Cube TM ) by Ley and coworkers .…”

Impact of continuous flow chemistry in the synthesis of natural products and active pharmaceutical ingredients

“…D&M Continuous Solutions, Eli Lilly and Lilly Research Laboratories (May et al 2016) have developed an efficient continuous iridiumcatalyzed homogeneous high pressure reductive amination reaction to produce the penultimate intermediate (172) in evacetrapib synthesis. The continuous process operated under GMP conditions for 24 days and produced over 2x10 6 tons of 172 in 95% yield after batch workup, crystallization, and isolation (Scheme 37).…”

Design and Comparison of Tubular and Pipes-in-Series Continuous Reactors for Direct Asymmetric Reductive Amination

“…Table 15 lists several of the continuous pipes in series reactors that have been used at Eli Lilly and Company for high pressure hydrogenations. As seen in the table, the reactors have been scaled down to 11 ml and scaled up to 360 L. 3 Pictures of the 11 mL and the 360 L reactors are shown in the Supporting…”

“…2 It was a scale down version of a 360 L vertical bubble flow pipes in series reactor in Lilly GMP manufacturing. 3 This continuous DARA paper is the documents the work that fills the gap between the previous papers on coiled tubes and pipes in series. This DARA chemistry was the project on which our reactor designs evolved from coiled tubes, to horizontal pipes in series, and finally to vertical pipes in series.…”