Over 200 million people worldwide have Hepatitis C (HCV) with an estimated 12,000 HCV related deaths in the U.S. alone.  Current therapies have numerous side effects and limited success rates, particularly for resistant strains.  Daclatasvir has shown significant promise in meeting this unmet medical need, demonstrating high SVR12 rates both in conjunction with current standard of care and in combination with other direct acting antivirals (DAAs).  As a result, an efficient, scalable synthesis for daclatasvir is required for commercial manufacture.  The most challenging and most critical step in the synthesis is the formation of the imidazole ring.  This structurally simplifying transform, using simple amino acid and a-halo ketone precursors, not only forms the imidazole ring, but also stitches together the hexacyclic core of daclatasvir in a single step.  This powerful transform does have a significant drawback in that the reaction mechanism is very complex, resulting in numerous impurities.  In the attempt to understand the first principles of this mechanism, a number of significant advancements have been made, resulting in improved purity, yield and efficiency.  The discovery, development and implementation of these advancements will be discussed.

Advances in the formation of 2,4-disubstitued imidazoles and its application towards the production of the HCV NS5A inhibitor Daclatasvir

244th National Meeting (2012)

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