Practical Large-Scale Synthesis of the Hepatitis C Virus Protease Inhibitor BI 201335

A concise synthetic route for large‐scale manufacture of the hepatitis C virus (HCV) protease inhibitor BI 201335 has been developed. A convergent synthetic design was achieved by using three advanced intermediates: a densely functionalized thiazole‐quinoline, a hydroxyproline‐containing dipeptide acid, and an optically pure vinylcyclopropane. Only three subsequent synthetic steps were then required for the final assembly of this complex target. The first step is a critical CO bond formation to join the heterocycle and the peptidic portion of the molecule, which was done by using a newly‐designed heterocyclic sulfone. The second step uses an inexpensive peptide coupling of the aminocyclopropane and ester saponification, then recrystallization completes the route. This economical and practical process is suitable for large scale production of BI 201335, requires no protecting groups or chromatography, and every isolated intermediate is a crystalline solid. Upsizing: A large‐scale synthesis of BI 201335, which is a new drug for the treatment of hepatitis C infection, is described. BI 201335 has a molecular weight of 870, six rings, and five stereocenters. The synthetic route has high convergence, with a late‐stage SNAr reaction between a heterocyclic sulfone and a dipeptide acid. All of the peptide couplings were performed without protecting groups or hazardous reagents and without measurable racemization.