Quest for the ring – Synthesis of Vaniprevir (old)

I was trying to think of a very catchy title to get readers to visit my website and take a look at my latest posting, and I thought, gees, what if I could portray the principal investigator/author and his team as a group of adventurers.  If you get a chance to use an analogy that mimics “Lord of The Rings”, you should do it, so I did.  Why did I pick Lord of the Rings ?  Because in Lord of The Rings, it was the quest about seeking out the one Ring, the ring that would rule all.  What if the ring was, let’s say, a potential HCV candidate, a 22-membered macrocycle, a possible treatment for hepatitis C.  I would say that was a mighty powerful ring, indeed.



The paper I am drawing my analogy from is “Synthesis of Vaniprevir (MK-7009): Lactamization To Prepare A 22-Membered Macrocycle”, by Z.J. Song & D.M Tellers et al, J. Org. Chem., 2011, 76, 7804-15.  But as discussed in the paper, the final step, the formation of the macrocycle became their primary focus, before proceeding to develop their process.  Although I have never worked on macrocycles myself,  I could see that you wouldn’t want to go to a lot of in-depth research to build part of the macrocycle and then find your final step, the ring-formation to be of poor yield, conversion, purity, etc.


Scheme 1.  Medicinal chemistry route to Vaniprevir, MK-7009.

 What was wrong with using Neolyst or Zhan 1B ?  (what are these, by the way  ?? Ruthenium catalysts)  The authors mentioned that catalyst load and reaction solvent dilution were high.  Upon decreasing catalyst load or increasing reaction concentration led to reduced product yield.  Purification of product was an issue.  I can see why a lot of effort was put into improving ring closure.

The colleagues at Merck tried three different approaches to form the macrocycle needed.  They were 1) Pd-catalyzed intramolecular cross-coupling reactions, 2) ring-closing metathesis and 3) macrolactamization.  I will just say that they did try some palladium cross-coupling reactions (you can refer to this paper if you are interested).  The ring-closing metathesis was avoided due to a lot of the catalysts needed are under patent protection and with the approaching timeline were not feasible.

I liked that this paper included the results from the Pd-catalyzed intramolecular cross-coupling reactions.  The final process looked like the following:


Scheme 2.  Process Development of Vaniprevir

With the final step, they found out that EDC/hydroxypyridine N-oxide provided good yield and provided an alternative to more expensive HATU.  I didn’t find a yield from the Sonogashira product 17, going forward.  The “zipper” reaction of 13 to form 14 is pretty interesting.  I thought it was a pretty good process development paper in JOC.

Originally posted on PHARMNBIOFUEL.COM on 2011-11-07


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