Remibrutinib Drug Substance Synthesis to Reduce Nitrosamine Impurities

The patent removes the problematic intermediate INT 3 (5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline) from the synthesis pathway. By replacing INT 3 with alternative intermediates that do not contain the boronic acid ester structure prone to nitrosation, the process eliminates the source of nitrosamine impurity formation while maintaining remibrutinib production capability

The patent modifies the chemical parameters of the synthesis process by changing the intermediate structures and reaction conditions. Specifically, it alters the molecular structure of intermediates to avoid those that form nitrosamines, and adjusts reaction parameters such as using alternative coupling reagents and purification conditions to reduce nitrosamine levels below 1000 ppb

The patent extracts and eliminates the genotoxic intermediate INT 3 from the synthesis pathway. By designing alternative synthetic routes that use different intermediates without the boronic acid ester moiety, the process removes the source of mutagenicity while preserving the ability to synthesize remibrutinib effectively

The patent converts the harmful genotoxic property of INT 3 into a design criterion for selecting alternative intermediates. By deliberately choosing intermediates that lack the nitrosation-prone structural features of INT 3, the process transforms the problem of genotoxicity into a guiding principle for safer chemical design, resulting in a synthesis pathway that is both effective and safe