Investigation of Pd Catalyst for Key Coupling Reaction in Asciminib Synthesis and Impurity Characterization

Abstract

Asciminib, marketed as Scemblix, is approved for treating adults with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP), as well as for those previously treated with two or more tyrosine kinase inhibitors (TKIs). Existing literature on Asciminib manufacturing processes involves considerable quantities of preformed Pd complex catalysts for the key coupling reaction. We optimized the commercial production process by identifying dichlorobis[ditert-butyl(4-dimethylaminophenyl)phosphine]palladium(II) PdCl₂(Amphos)₂ as the most effective catalyst for the key coupling reaction. By fine-tuning the Pd complex quantity to a 0.0035 weight ratio relative to the key starting material─approximately one-third of the previously reported amount─we achieved complete conversion and obtained the desired coupling product in high yield. Additionally, we developed a highly effective and commercially viable method combining l-cystine and activated carbon to efficiently remove Pd metal impurities from the final product. The optimized process was successfully validated under GMP conditions at the multikilogram level and has proven to be easily scalable for larger quantities. This report also addresses the lack of detailed information on potential process and degradation impurities of Asciminib. We identified and synthesized potential process impurities (P-1 to P-5) and degradation impurities (DP-1 to DP-3), confirming their structures using ¹H NMR, ¹³C NMR, mass spectrometry, and IR spectroscopy. This comprehensive impurity identification enhances the quality and safety of Asciminib and supports the development of robust analytical methods for impurity quantification and validation.