Palladium Extraction Following Metal-Catalyzed Reactions: Recent Advances and Applications in the Pharmaceutical Industry

Abstract

Palladium-catalyzed cross-coupling reactions are used extensively in the pharmaceutical industry. Therefore, the potential contamination of products with elemental impurities is an issue that any process chemist must consider in the design of a plant process. This is not only to meet regulatory limits, which is unequivocally the primary reason for metal scavenging, but also due to the high cost and limited supply of palladium, driving the need for recovery to recycle. This Review addresses the current approaches for palladium removal from organic solutions, with selected examples of their successful application in industrial-scale processes for pharmaceutical production. Palladium scavengers have been categorized based on their mode of action, i.e., adsorption, extraction/precipitation, and crystallization, to provide a summary of the current state-of-the-art in metal removal. Practical considerations when choosing metal removal methods are briefly discussed, illustrating their intrinsic advantages and drawbacks.

Building a Quaternary Stereogenic Center on Dihydroazaindole Carboxylic Acid through Scalable Process Development

“…To avoid overuse of the second starting material, 0.75 equiv of the coupling partner 4 was added and stirred for 3 h at 80 °C. The crude mixture was treated by N -acetyl- l -cysteine to reduce the Pd content from >200 to 77 ppm, and the product was isolated as an HCl salt (entries 1 and 2). PdCl 2 (dppf) complex was used for subsequent optimization and scaling up since a similar efficiency was obtained with higher atom economy, and the acid in the isolation process was changed to sulfuric acid (H 2 SO 4 ) to improve the reaction rate of the next step (entries 3 and 4, see the cyclization optimization for details).…”

Organic Solvent Nanofiltration in Pharmaceutical Applications

“…However, since most catalysts are not water soluble, they cannot be removed by extraction if the product is not water soluble. Extra steps, such as the addition of a chelating reagent, are required to facilitate the transfer of the catalyst into aqueous phase . Adsorption is a widely used technique; however, the adsorbent may unselectively adsorb the product, resulting in huge API product loss.…”

“…Adsorption is a widely used technique; however, the adsorbent may unselectively adsorb the product, resulting in huge API product loss. Also, it might leak new impurities which contaminate the final product, requiring further purification steps . Compared with other catalyst recovery techniques, OSN can selectively separate the catalyst from the product without phase transition and biphasic operation, which makes the recovery and reuse of homogeneous catalysts easier and greener. , A technological evaluation showed that significant energy and cost savings of up to 85% and 75%, respectively, can be achieved by OSN, compared to that of distillation …”

Reaction-Based Multisignal Detection of Palladium with High Sensitivity, Selectivity, and Reliability

“…However, Pd-catalyzed reactions often generate products with Pd residue contamination even after purification. The presence of palladium in drugs has received increasing attention as the maximum limits of residual Pd catalysts acceptable in the pharmaceutical industry is 0.5 ppm . In addition, the wide application of palladium has resulted in its accumulation in the environment. , Pd matrices in the environment are found in ultratrace levels, and the recovery of the precious metal requires the efficient detection of ultratrace Pd .…”