RESUMO
Dasabuvir (1) is an HCV polymerase inhibitor which has been developed as a part of a three-component direct-acting antiviral combination therapy. During the course of the development of the synthetic route, two novel coupling reactions were developed. First, the copper-catalyzed coupling of uracil with aryl iodides, employing picolinamide 16 as the ligand, was discovered. Later, the palladium-catalyzed sulfonamidation of aryl nonaflate 33 was developed, promoted by electron-rich palladium complexes, including the novel phosphine ligand, VincePhos (50). This made possible a convergent, highly efficient synthesis of dasabuvir that significantly reduced the mutagenic impurity burden of the process.
Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Hepacivirus/efeitos dos fármacos , Paládio/química , Sulfonamidas/farmacologia , Uracila/análogos & derivados , Proteínas não Estruturais Virais/antagonistas & inibidores , 2-Naftilamina , Antivirais/síntese química , Antivirais/química , Catálise , Desenvolvimento de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Hepacivirus/enzimologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Sulfonamidas/síntese química , Sulfonamidas/química , Uracila/síntese química , Uracila/química , Uracila/farmacologia , Proteínas não Estruturais Virais/metabolismoRESUMO
[reaction: see text]. A highly diastereoselective coupling reaction between TBSOP (3) and trityl sulfenimine 4 was developed which provided influenza neuraminidase inhibitor intermediate 7 in 80% yield and >99% de after crystallization. The reaction was shown to be reversible with the high diastereoselectivity resulting from a favorable H-bonding interaction in the major diastereomer.
