Development of an Effective Palladium Removal Process for VEGF Oncology Candidate AG13736 and a Simple, Efficient Screening Technique for Scavenger Reagent Identification

Abstract

AG13736 (Axitinib), an inhibitor of vascular endothelial growth factor (VEGF) under investigation as an oncology drug, is currently manufactured via a three-step process that utilizes two palladium-mediated cross-couplings. Historically, removal of residual heavy metals from the active pharmaceutical ingredient has been a persistent issue. The development of a much improved process for palladium removal and a useful screening technique developed to rapidly identify the most efficient reagents for this purpose are outlined. The performance of the new endgame process in pilot-plant scale-up is also discussed.

Process Intensification of Alkynol Semihydrogenation in a Tube Reactor Coated with a Pd/ZnO Catalyst

“…A slightly higher leaching under H 2 -lean conditions is well in line with the literature observations of a decreased leaching in the presence of hydrogen [61]. However, it should be noted that in both of the cases, leaching was orders of magnitude below the acceptable level that is an order of 1000 ppb [62]. A possible reason for such a low difference in leaching levels is likely that even under H 2 -lean condition, the major part of the tube length is still operating in hydrogen excess.…”

Polymer Cocktail: A Multitask Supported Ionic Liquid‐Like Species to Facilitate Multiple and Consecutive CC Coupling Reactions

“…In most cases where the use of heterogeneous catalysts for C À C coupling reactions has been reported, [11] a careful study of the reaction mechanism revealed that, under the conditions employed, the supported species acted as "Trojan horses", [12,13] servng as reservoirs of the "soluble" active species generated in the course of the reaction. [14] This very often leads to a contamination of the final products with metals, [15] which is a key factor for the pharmaceutical industry. [16] Furthermore, the reaction requires the use of a base to neutralize the acid formed giving rise to the formation of salts that complicate the downstream processing and the scaleup.…”

High‐Performance Isocyanide Scavengers for Use in Low‐Waste Purification of Olefin Metathesis Products

“…If not removed, these residues can causet he decomposition or isomerization of the product over time or negatively affect the yield of subsequent steps of the synthesis. Additionally,t hey preclude the use of such products in the synthesis of active pharmaceutical ingredients (API), [4][5][6][7][8][9][10] which are subjectt os trict legal limits on heavy-metal contamination (less than 10 ppm). [11] Thanks to the discoveryo fw ell-defined ruthenium catalysts Ru1-Ru6 (Figure 1), [12][13][14][15][16][17] olefin metathesis (OM) became av ery useful tool in organic synthesis.…”

“…The resultant product 4b contained 40 ppm of ruthenium (Table 1, entry 5). Scavengers I-III gave much better results (Table 1, entries [7][8][9][10][11][12][13][14][15][16][17][18][19]. The use of II (4.4 equiv) reduced the residual ruthenium content by two orders of magnitudew ith respect to the control experiment, down to 1.6 ppm ( Table 1, entry 12).…”

“…[7] Therefore, we investigated whether II contaminated the product.W ev erifiedt hat II produced ad istinct peak in GC chromatograms. GC analysis of the reaction mixture before filtration through silica gel showedt he Scheme4.Model RCM reaction used to benchmark the performance of isocyanides I, II,and D1 in the removal of residues of selectedcommercial OM catalysts.…”