Continuous Reactors for Homogeneous Catalysis in Pharmaceutical Manufacturing

2017 Spring Symposium

Martin D Johnson, Scott A May, Joel R Calvin, Kevin P Cole
Eli Lilly and Company, Indianapolis, IN

Abstract – Continuous flow chemistry for metal catalyzed organic reactions offers several advantages in the pharmaceutical industry. Capital cost was lower than batch for the high pressure reactors described in this presentation. The 1000 psig rated hydrogenation reactors ranged from 7 L to 360 L, and capital cost for just the reactor ranged from $4000 to $120,000. Quality assurance was higher compared to batch because the inexpensive reactors were dedicated to specific types of catalysis. For example, individual plug flow reactors (PFRs) were dedicated to Ir, some for Rh/Ru, some for Pd/Pt, and each was not used for other metals. Safety was improved compared to batch, because the continuous reactors were smaller, less reagent gas was in the reactor at any one time, and in some cases the hydrogenation reactors operated outside. A 73L PFR was used for asymmetric reduction of a tetrasubstituted enone, producing 144 kg penultimate with 95% EE. Reaction conditions were Rh(COD)2OTf, diphosphine ligand, 2000:1 S:C, 5 mol% Zn(OTf), 30% MeOH in EtOAc (10 volumes), 1000 psig H2, 1.3 molar eq H2 in flow, 70 °C, 12 h mean residence time (τ). The pipes in series PFRs proved to be superior to the coiled tubes for gas/liquid high pressure reactions in terms of scalability, gas/liquid mixing rate, % liquid filled, and inspectability. A direct asymmetric reductive amination (DARA) was run in a 32L horizontal pipes in series reactor, producing 15 kg advanced intermediate. Reaction conditions were [Ir(cod)Cl]2 and (S)-Xyl-BINAP, 4000 S:C,ketal , aminotetrazole (1.1 eq), CSA (0.02 eq), TBAI (0.01 eq), H2 (1000 psig), 12 h τ. A reductive amination was run in a 360 L vertical pipes in series reactor in GMP manufacturing, producing 2000 kg penultimate. Reaction conditions were [Ir(cod)Cl]2, no ligand, S:C 1100, 800 psig H2, 3 molar equivalents H2 in flow, 0.5 equiv TBAI wrt Ir, 1.05 eq HOAc, 1.4 eq aldehyde wrt amine, 1 volume water, 9 volumes THF, 1 volume MeTHF, 12 h τ. The reactor operated outside, and H2 was stripped from product solution before flowing back inside. A 32L oscillating flow tube reactor was used for a selective hydroformylation in which the catalyst and ligand precipitated from solution in the reactor, as they were less soluble in the product aldehyde than the methyl methacrylate reagent. Reaction conditions were (PPh)3HRhCO, S:C 1000, catalyst is dissolved in neat methyl methacrylate, 1000 psi 50:50 CO:H2, 24 h τ. The back and forth flow and custom methods of pressure control kept the reactor from fouling for the entire 314 h continuous run to produce 180 kg advanced intermediate with high selectivity of the branched aldehyde.

Biography – Martin D. Johnson works for Eli Lilly and Company in Small Molecule Design and Development.  He received his dual doctorate in chemical engineering and environmental engineering from the University of Michigan in 2000, and his undergraduate in Chemical Engineering from Virginia Tech.  Prior to joining Eli Lilly in 2005, he worked as a process research engineer at Union Carbide and The Dow Chemical Company in the Engineering Sciences and Market Development department, focusing on process development and separations.  At Eli Lilly, Dr. Johnson leads a group of engineers who focus on design and development of continuous processes.  He has applied process technologies from the chemical industry to increase efficiency, decrease waste, and increase the types of chemistries that Eli Lilly can safely scale up from research to production of small molecule pharmaceutical compounds.  Dr. Johnson’s group has used continuous reactions in the manufacture of active pharmaceutical ingredients for highly exothermic and hazardous reactions, high pressure reactions with hazardous gas reagent like hydrogenations, chemistries at extreme temperatures and pressures, and process separations including distillation, extraction, crystallization, and filtration.  Eli Lilly has implemented his continuous processes for the production of active pharmaceutical ingredient in cGMP manufacturing both internally at the Lilly facility in Ireland and externally in multiple contract manufacturing organizations.  Dr. Johnson was awarded the 2016 ACS Award for Affordable Green Chemistry, and the 2016 AIChE Award for Outstanding Contribution to QbD for Drug Substance.