Macrocycles in Medicine: Vaniprevir (MK-7009)

by Diana Stoianova on January 9, 2013

Kong, J.; Chen; C.; Balsells-Padros; J., Cao, Y.; Dunn, R. F.; Dolman, S. J.; Janey, J.; Li, H.; and Zakuto, M.J. “Synthesis of the HCV Protease Inhibitor Vaniprevir (MK-7009) Using Ring-Closing Metathesis Reaction” J. Org. Chem. 2012, 77, 3820.

Several years ago the chemical development group at Boehringer Ingelheimused a ring closing metathesis (RCM) step to produce hundreds of kilos of the HCV protease inhibitor BILN 2061 for clinical trials, showing that RCM is a great way to generate a macrocycle on large scale. Recently, the process research group at Merck has developed a practical scalable route to the HCV protease inhibitor Vaniprevir utilizing a RCM reaction to form the 20-membered macrocyclic core of the molecule. The simultaneous slow addition of catalyst and substrate allowed them to avoid the high dilution conditions necessary for macrocyclization and sustain the catalyst activity during the reaction. Addition of 10 mol% 2,6-dichloroquinone suppressed the isomerization of the allylic diene to a styrene double bond and the formation of a 19-membered ring as a side product. Under these conditions the methyl ester 3 was formed in 91% yield. Hydrogenation of the crude product followed by crystallization gave the saturated macrocycle in 89% overall yield and excellent purity. It’s noteworthy that the metal content (both Ru and Pd) was <10 ppm in the product after the hydrogenation.

Unfortunately the success of the RCM reaction with low catalyst loadings was highly dependent on the purity of the starting material, and the ester 1 was an oil with limited options for purification. But the easily accessible free acid 2 was a nice crystalline solid and could be isolated consistently in high purity. The RCM of the free acid 2 worked under the same conditions used for the ester 1 and gave the macrocyclic acid 4 in great yield and purity.

1Farina, V., Shu; C.; Zeng; X.; Wei, X.; Han, Z.; Yee, N. K.; and Senanayake, C. H. “Second Generation Process for the HCV Protease Inhibitor BILN 2061: A Greener Approach to Ru-Catalyzed Ring-Closing Metathesis” Org. Process Res. Dev. 2009, 13, 250.

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