Application of Thiol-Modified Dual-Pore Silica Beads as a Practical Scavenger of Leached Palladium Catalyst in C–C Coupling Reactions

Abstract

A practical and efficient method for scavenging palladium leached into the reaction mixture using thiol-modified dual-pore silica beads has been developed. Reducing the level of metal contamination, especially palladium, in pharmaceutical and bioactive compounds and fine chemicals to below the regulatory value is quite important for the quality assurance of industrial products. We have evaluated the performance of dual-pore silica beads as a palladium scavenger by investigating their ability to eliminate the divalent palladium ions in dilute palladium­(II) acetate in methanol (5 and 50 ppm) and ethyl acetate (5 ppm) solutions. The ability of the dual-pore silica beads to eliminate the palladium species leached from a 10% palladium on carbon (Pd/C) catalyst during the ligand- and copper-free 10% Pd/C-catalyzed Sonogashira-type coupling reaction was also investigated. The thiol-modified dual-pore silica beads exhibit a more rapid and effective elimination ability toward leached palladium species in the reaction mixture in comparison with commercially available conventional thiol-modified silica scavengers because of the effects of diffusion and perfusion due to the dual-pore skeleton of the silica beads. When methanol is used as a dilution and eluent solvent for the filtered reaction mixture, the leached palladium species were removed almost entirely (<1 ppm).

Impact of Cross-Coupling Reactions in Drug Discovery and Development

“…The Palladium-catalyzed amination using a benzophenone imine is widely used in medicinal chemistry. As an example, this methodology was applied in the SAR exploration for selective 5-HT 1F receptor agonists [34] (Scheme 3) that eventually led to the 2019 approved drug for acute migraine, Lasmiditan (38) [35]. Treatment of the key precursor halo-pyridinyl-(1-methyl-piperidin-4-yl)-methanone (34) with benzophenone imine, Pd 2 (dba) 3 , BINAP in the presence of tBuONa, led to the corresponding (6-((diphenylmethylene)amino)pyridin-2-yl) (1-methylpiperidin-4-yl) methanone derivative (35) in situ, that was hydrolyzed with hydrochloric acid to afford the desired amino-pyridine 36.…”

“…In particular, in process chemistry there are examples of specific cross-coupling reactions that are yield-efficient on a kilogram scale with cost-effective low catalyst loading. Purification of the desired product on a large-scale might become more complex, and the development of new technologies like metal scavenging or fixed-bed absorption processes enable the isolation of the desired cross-coupling product with minimal levels of palladium residue (<1 ppm) [38] to meet guidelines from regulatory agencies for active pharmaceutical ingredients (API). In addition of new methodology to remove traces of palladium or other catalysts, there is a strong trend to develop more "green" or environmentally friendly approaches to minimize potential toxicity to the ecosystem.…”

Nanowire Networks of Metal–Organosilicates as Reversible Pd(II) Reservoirs for Suzuki Coupling Reactions

“…Nevertheless, these supported Pd catalysts usually exhibit poor stability and recyclability due to the lack of ligands to stabilize Pd species. To circumvent such shortcomings, surface-modified solid supports are widely studied with P, N, and S atom-containing ligands, such as phosphine-based functional groups, thiol groups, amino groups, and N-heterocyclic carbene (NHC) in more recent investigations. ,− …”

Polyethyleneimine-Modified Polymer as an Efficient Palladium Scavenger and Effective Catalyst Support for a Functional Heterogeneous Palladium Catalyst

“…We have recently developed effective scavenging methods for the elimination of leached Pd species during the Pd/C-catalyzed Sonogashira-type reaction 13 using thiol-modified dual-pore silica beads as a Pd scavenger. 14 Because non-negligible amounts of both two and zero valent Pd species were leached from the heterogeneous Pd/C catalyst during the Pd/C-catalyzed Sonogashira-type reaction using 4′-iodoacetophenone and 3-butyn-1-ol due to the strong coordination of the alkyne moiety of 3-butyn-1-ol, 13 the reaction was suitable for evaluating the Pd scavenging abilities of chelate resins. The Pd scavenging abilities of the PEI-modified resins (TAs and TAm) from the diluted filtrate (23.8 μM of the leached Pd species) during the Sonogashira-type reaction were compared with those of commercially available Pd scavengers based on silica beads modified with propylamine or diethylenetriamine functionalities.…”