Phase Separation Macrocyclization in a Complex Pharmaceutical Setting: Application toward the Synthesis of Vaniprevir
A phase separation/continuous flow strategy employing an oxidative Glaser-Hay coupling of alkynes has been applied toward the synthesis of the macrocyclic core of complex pharmaceutical vaniprevir. The phase separation/continuous flow strategy afforded similar yields at 100-500 times the concentration and at shorter reaction times than common slow addition/high dilution techniques. In addition, dendritic PEG cosolvents were employed in the phase separation strategy for the first time and shown to allow productive macrocyclization at concentrations up to 200 mM.
Godin, éric,Bédard, Anne-Catherine,Raymond, Micha?l,Collins, Shawn K.
p. 7576 - 7582
(2017/07/26)
Synthesis of the HCV protease inhibitor Vaniprevir (MK-7009) using ring-closing metathesis strategy
Figure Persented: A highly efficient synthesis of Vaniprevir (MK-7009) has been accomplished in nine linear steps and 55% overall yield. The key features of this synthesis include a cost-effective synthesis of the isoindoline subunit and efficient construction of the 20-membered macrocyclic core of Vaniprevir (MK-7009) utilizing ring-closing metathesis technology. A high-performing ring-closing metathesis protocol has been achieved by simultaneous slow addition of the ruthenium catalyst (0.2 mol %) and the diene substrate at a concentration of 0.13 M.
Kong, Jongrock,Chen, Cheng-Yi,Balsells-Padros, Jaume,Cao, Yang,Dunn, Robert F.,Dolman, Sarah J.,Janey, Jacob,Li, Hongmei,Zacuto, Michael J.
p. 3820 - 3828
(2012/06/29)
Synthesis of vaniprevir (MK-7009): Lactamization to prepare a 22-membered macrocycle
Development of a practical synthesis of MK-7009, a 22-membered macrocycle, is described. A variety of ring-closing strategies were evaluated, including ring-closing metathesis, intermolecular palladium-catalyzed cross-couplings, and macrolactamization. Ri
Song, Zhiguo J.,Tellers, David M.,Journet, Michel,Kuethe, Jeffrey T.,Lieberman, David,Humphrey, Guy,Zhang, Fei,Peng, Zhihui,Waters, Marjorie S.,Zewge, Daniel,Nolting, Andrew,Zhao, Dalian,Reamer, Robert A.,Dormer, Peter G.,Belyk, Kevin M.,Davies, Ian W.,Devine, Paul N.,Tschaen, David M.
p. 7804 - 7815
(2011/12/14)
HCV NS3 PROTEASE INHIBITORS
The present invention relates to macrocyclic compounds of formula (Ia) that are useful as inhibitors of the hepatitis C virus (HCV) NS3 protease, their synthesis, and their use for treating or preventing HCV infections.
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Page/Page column 67
(2010/07/04)
Discovery of vaniprevir (MK-7009), a macrocyclic hepatitis C virus NS3/4a protease inhibitor
A new class of HCV NS3/4a protease inhibitors which contain a P2 to P4 macrocyclic constraint was designed using a molecular-modeling derived strategy. Exploration of the P2 heterocyclic region, the P2 to P4 linker, and the P1 side chain of this class of
McCauley, John A.,McIntyre, Charles J.,Rudd, Michael T.,Nguyen, Kevin T.,Romano, Joseph J.,Butcher, John W.,Gilbert, Kevin F.,Bush, Kimberly J.,Holloway, M. Katharine,Swestock, John,Wan, Bang-Lin,Carroll, Steven S.,Dimuzio, Julian M.,Graham, Donald J.,Ludmerer, Steven W.,Mao, Shi-Shan,Stahlhut, Mark W.,Fandozzi, Christine M.,Trainor, Nicole,Olsen, David B.,Vacca, Joseph P.,Liverton, Nigel J.
experimental part
p. 2443 - 2463
(2010/09/03)
HCV NS3 PROTEASE INHIBITORS
The present invention relates to macrocyclic compounds of formula (I) that are useful as inhibitors of the hepatitis C virus (HCV) NS3 protease, their synthesis, and their use treating or preventing HCV infections.
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Page/Page column 37
(2008/12/05)
HCV NS3 protease inhibitors
The present invention relates to macrocyclic compounds of formula (I) that are useful as inhibitors of the hepatitis C virus (HCV) NS3 protease, their synthesis, and their use for treating or preventing HCV infections.
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Page/Page column 70
(2008/06/13)
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