The use of multidentate sulfur-based silica scavengers 1, 2, and 3 as highly effective adsorbents for the removal of precious metals, specifically palladium residues in this paper, from highly functionalised synthetic intermediates and APIs is described. The synthesis and purification of the polar and electron-rich reaction products, containing multiple functional groups, from palladium-catalysed removals of commonly used protecting groups such as benzyl, benzyloxycarbonyl, and allyloxycarbonyl and Sonogashira, Suzuki, Heck, and Buchwald-Hartwig coupling reactions is reported. The significant levels of residual palladium species, typically associated with these reaction products, are successfully and rapidly removed to below acceptable regulatory levels, of less than 5 ppm, by simple, unoptimised treatment with the designed silica scavengers at room temperature. Performance aspects, including broad solvent compatibility, excellent stability, and high metal affinity, combined with large-scale availability, ease of handling, and minimal loss of API make these silica scavengers particularly useful to process development groups.

Functionalised silicas, used for selectively removing metal impurities in process streams, are packed in cartridges and inserted into multicartridge filters. The scavenging step that follows a catalytic reaction involves the single pass of the process stream through the multicartridge filter setup at a predetermined linear velocity and temperature. Efficiency in metal reduction as high as 98% has been so far achieved at tens of kilograms scale. Furthermore, the precious metal anchored onto the scavenger’s functionalities can be recovered and refined. Our chronological development of a versatile, general, and easily scalable format for metal scavenging at process scales is described, illustrated by application in real time to a range of projects passing through our Pharmaceutical Pilot Plant, employing a variety of metals (palladium, rhodium, iridium). Benefits of the cartridge format in terms of economics and environmental impact are also initially assessed.

The influence of four parameters (temperature, scavenging time, amount of scavenger, and concentration of palladium in the solution) on the efficiency of Pd removal from a cross-coupling reaction, using a commercially available Pd scavenger, SPM32, was studied. The DoE-based method employed yielded more information than is readily attainable from standard adsorption isotherms and kinetics experiments. The optimal regime of scavenging was identified; intuitive and nonintuitive effects of temperature, scavenging time, and scavenger amounts were highlighted; and a mathematical model quantifying predicted Pd removal from the synthetic intermediate was built.

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