The reaction development, process optimization, and pilot plant production of a key intermediate in the synthesis of Afimetoran (BMS-986256) are reported. A convergent Ni-catalyzed Negishi reaction was developed to achieve selective methyl-group installation on 3,5-dibromo-4-methylpyridin-2-amine (7) for the synthesis of a key triazole intermediate (4). The amidine directing group, which is later converted into a triazole ring, enabled selective methylation at the 3-bromo position. Careful selection of the inorganic base during aqueous workup prevented hydrolysis of the methylated intermediate (6) and effectively removed residual metal catalysts and inorganic salts (Ni, Zn, Mg). The amidine-to-triazole transformation using hydroxylamine-O-sulfonic acid (HOSA) was successfully implemented on a 130 kg input scale, delivering a high-quality triazole intermediate (4) suitable for downstream processing.
Kim et al. (Mon,) studied this question.