Novel, efficient, and alternative synthesis of a dual endothelin receptor antagonist – macitentan

A concise and efficient synthetic route to Macitentan (1), a potent endothelin receptor antagonist, has been developed. The strategy involves mono mesylation of 5-(4-bromophenyl) pyrimidine-4,6-diol (2), followed by O-alkylation with O-substituted ethylene chloride (13) to generate a key novel intermediate 14, which is on nucleophilic substitution with n-propyl sulfamide (15), furnishes macitentan, effectively suppressing the generation of the highly potent disubstitution product. This approach involves the key novel intermediates, hydroxy O-mesyl (11), O-substituted ethylene chloride (13), and O-mesyl ethoxy pyrimidine (14). This approach enables complete control over disubstitution product formation, resulting in a significant improvement in overall yield (73%). The developed process offers operational simplicity and scalability, making it suitable for commercial manufacturing of macitentan.