Development and validation of a GC method for a key nemtabrutinib intermediate: Implementation of an in-situ free base sample preparation protocol

• Published in: Journal of pharmaceutical and biomedical analysis Vol. 241; p. 116002
• Main Authors: Rivera, Nelo R., Zewge, Daniel, Arvary, Rebecca, Lin, Mingxiang, Lohani, Sachin
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 15.04.2024
• Subjects: Ambersep 900 hydroxide form resin; Cyrene amine; GC analysis; Nemtabrutinib intermediate; Toluenesulfonic acid salt; Ambersep 900 hydroxide form resin; Toluenesulfonic acid salt; Cyrene amine; GC analysis; Nemtabrutinib intermediate
• ISSN: 0731-7085; 1873-264X
• DOI: 10.1016/j.jpba.2024.116002

A novel synthetic approach to nemtabrutinib (MK-1026) was recently developed in our laboratories. The chemistry goes through a cyrene amine intermediate which does not contain any chromophore. As a result, analysis of this key chiral intermediate by HPLC-UV is not feasible. Initial attempts to develop a HPLC-CAD method were unfruitful; therefore, a gas chromatography method was developed and optimized to effectively monitor the cyrene amine free base and related impurities generated during the process. As the synthetic process continued to be optimized, the toluene sulfonic acid salt (p-TsOH) of the cyrene amine intermediate was later identified by our process chemistry group to be beneficial in terms of ease of isolation and purity upgrade. However, repeated injections of the cyrene amine p-TsOH intermediate resulted in rapid GC column deterioration. After identifying p-TsOH as the main cause of the issue, we developed a straightforward and practical procedure that involves using a resin to remove the p-TsOH counterion in-situ, which converts cyrene amine salt to its neutral form in sample solutions. This protocol was successfully demonstrated and proven to be an efficient solution. This methodology may find applications with other analytes containing counterions that need to be neutralized prior to analysis. •GC method development and validation for a key amine intermediate for the synthesis of nemtabrutinib.•The presence of p-toluenesulfonic acid (TsOH) counterion led to rapid decline in column performance and peak broadening.•A simple and practical in-situ free base method using a commercially available resin was developed to ensure column robustness.•Demonstrated the utility of this resin treatment protocol with other model amine-TsOH substrates.