Continuous Platinum‐Mediated Hydrogenation of Refametinib Iodo‐nitroaniline Key Intermediate DIM‐NA: The Combined Challenges of Selectivity and Catalyst Deactivation

Abstract

The chemoselective, continuous, multistep reduction of iodo‐nitroaromatics in a fixed‐bed hydrogenation reactor has been investigated. This transformation poses challenges upon both the catalyst and process conditions if high yields are to be achieved. First, the stability and selectivity of four flow‐compatible Pt catalysts, Pt(X)/C (X = Fe, V), were investigated by using 1‐iodo‐4‐nitrobenzene as the model substrate. Granular Pt(Fe) on carbon was identified as the most promising candidate. With this catalyst, iodo‐nitroaromatic API (active pharmaceutical ingredient) intermediate DIM‐NA [(2,3‐difluoro‐5‐methoxy‐6‐nitrophenyl)(2‐fluoro‐4‐iodophenyl)amine] could be converted into the corresponding aniline with high selectivity on a preparative scale. UV/Vis spectroscopy was successfully applied for online conversion control, proving to be highly useful for detecting the effects of catalyst deactivation.

Fixed Bed Continuous Hydrogenations in Trickle Flow Mode: A Pharmaceutical Industry Perspective

“…For use in the pharmaceutical industry, two figures for D t /D p have been reported: Bayer and Eli Lilly using a value ≥10, GSK using a value ≥15, and other industries use a value of ≥20. 17,19,76,80,127 At D t /D p ratios below these values, the risk of liquid maldistribution becomes more significant, as the increased void volume (porosity, space) between the particles and the walls gives a path of lower resistance at the column walls, which causes channelling, affecting the contact time with the catalyst and residence time distribution. 80,129 In addition, Mederos et al and Azrapour et al have reported reactors larger than 25.4 mm (1 in.)…”

“…Commercially available trickle bed reactors include the Ehrfeld Cartridge Reactor 240 (ID 10 mm, Figure ) from the Ehrfeld modular microreactor system range, which has been utilized by Bayer. − …”

“…Therefore, the maximum particle size of the catalysts in a pharmaceutical trickle bed reactor is limited by the laboratory-scale reactor ID size, as a minimum reactor to catalyst diameter ratio (tube-to-particle ( D t / D p ) ratio), must be maintained to ensure a reproducible performance at different scales and minimize risk of liquid maldistribution. For use in the pharmaceutical industry, two figures for D t / D p have been reported: Bayer and Eli Lilly using a value ≥10, GSK using a value ≥15, and other industries use a value of ≥20. ,,,, At D t / D p ratios below these values, the risk of liquid maldistribution becomes more significant, as the increased void volume (porosity, space) between the particles and the walls gives a path of lower resistance at the column walls, which causes channelling, affecting the contact time with the catalyst and residence time distribution. , In addition, Mederos et al and Azrapour et al have reported reactors larger than 25.4 mm (1 in.) will have significant liquid maldistribution; the authors have witnessed this issue with GSK’s model pilot scale reactors (ID > 24.4 mm), requiring the design of distribution plates to remove maldistribution issues. , The use of monolithic packing in trickle bed reactors would give a D t / D p ratio of 1; Bayer/Sanofi and Santolubes Manufacturing LLC have reported on their use. , Monoliths can allow mass-transfer enhancement over a fixed bed of catalyst particles. − …”

“…Argyle et al have reviewed heterogeneous catalyst deactivation; defined as the loss of catalyst activity or selectivity over time . The catalyst in a fixed bed reactor deactivates during operation over time for a variety of reasons: ,,,,,,− (1) poisoning, (2) fouling (coking), (3) thermal degradation and sintering (aging, hardening, or agglomeration), (4) metal leaching accompanied by transport from the catalyst surface or particle, (5) vapor formation, (6) vapor–solid or solid–solid reactions (chemical routes rather than thermal), and (7) attrition/crushing.…”

Evaluation and Screening of Spherical Pd/C for Use as a Catalyst in Pharmaceutical-Scale Continuous Hydrogenations

“…Continuous hydrogenation within trickle bed reactors (fixed, packed bed reactors) is a well-known technology in other industries such as fine chemicals, where hydrogenations are conducted in multitonne quantities. − Over the past 15 years micro scale continuous hydrogenations have become common place within industrial medicinal chemistry groups and academia following the introduction of commercially available cartridge-based (3 mm internal diameter × 30 mm height) ThalesNano H-Cube systems. , Pharma as a whole is developing the capability to perform continuous hydrogenations within trickle bed reactors to enable a more efficient delivery of active pharmaceutical ingredients (APIs). − Traditional pharmaceutical batch reactors tend to be limited to pressures of ≤10 bar with hydrogenation vessels limited to ≤5 bar and 100 °C (in GSK, varies between companies) for safety and economic reasons. , Motivation to develop continuous hydrogenations in a trickle bed platform to deliver APIs stems from the ability to access considerably higher temperatures and pressures with elevated catalyst loadings (up to 150 °C and 100 bar within GSK, in both laboratory and pilot plant trickle bed reactors). − This facilitates access to chemistry with improved quality and productivity, leading to process intensification. In addition, the trickle bed platform allows enhanced process control, reduced reactor size, reduced vessel cleaning time, and increased process safety, leading to greener processes. ,− …”