RESUMO
R7128 is the prodrug of 2'-deoxy-2'-fluoro-2'-C-methylcytidine (PSI-6130), a potent and selective inhibitor of HCV NS5B polymerase. Currently, R7128 is in clinical trials for the treatment of HCV infection. To support clinical development efforts, we needed an efficient and scalable synthesis of PSI-6130. We describe an improved, diastereoselective synthetic route starting with protected d-glyceraldehyde. No chiral reagents or catalysts were used to produce the three new contiguous stereocenters. Introduction of fluorine at the C-2 tertiary carbon was accomplished in a highly regio- and stereoselective manner through nucleophilic substitution on a cyclic sulfate. Scale-limiting chromatographic purifications were eliminated through the use of crystalline intermediates.
Assuntos
Antivirais/síntese química , Química Farmacêutica/métodos , Desoxicitidina/análogos & derivados , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/química , Carbono/química , Química Orgânica/métodos , Cromatografia/métodos , Desoxicitidina/síntese química , Desoxicitidina/química , Desenho de Fármacos , Flúor/química , Gliceraldeído/química , Glicosilação , Lactonas , Modelos Químicos , Fosforanos/química , EstereoisomerismoRESUMO
A new synthesis of (-)-DAPD, suitable for large scale development, is described.
