Application of Isayama–Mukaiyama cobalt catalyzed
hydroperoxysilylation for the preparation of ritonavir hydroperoxide


Sharon Gazal, Teva Pharmaceutical Industries. KS, Israel
Priya Gupta, AMRI (Albany Molecular Research Inc.)
Siva Ramakrishna Gunturu, AMRI (Albany Molecular Research Inc.)
Matthew Isherwood, AMRI (Albany Molecular Research Inc.)
Matthew E. Voss, AMRI (Albany Molecular Research Inc.)

We report the preparation of thiazol-5-ylmethyl ((2S,3S,5S)-5-((S)-2-(3-((2-(2-hydroperoxypropan-2-yl) thiazol-4-yl)methyl)-3-methylureido)-3-methylbutanamido)-3-hydroxy-1,6-diphenylhexan-2-yl)carbamate, a hydroperoxide impurity of ritonavir also known as ritonavir USP impurity F. In many cases, though listed in USP, impurity standards are not available either from USP or from other commercial sources. This also applied to ritonavir USP F. Due to the complexity of ritonavir’s structure and abundance of oxidation susceptible functional groups, forced degradation was found to be a non-selective and inadequate tactic. Therefore, a multistep synthesis was applied. The overall strategy involved initial introduction of a propenyl moiety to the terminal thiazole which enabled selective oxidation using Co(thd)2 (0.1 equiv)/O2 (Isayama–Mukaiyama cobalt catalyzed hydroperoxysilylation) following structural assembly.


Abstract Reference & Short Personal Biography of Presenting Author

S. Gazal et al. / Tetrahedron Letters 57 (2016) 5099–5102
Sharon Gazal Ph.D
Dr. Sharon Gazal received his BSc in Chemistry at 1995 from the Hebrew university of Jerusalem (HUJI). His master degree and Ph.D (1998 and 2003 respectively) were also awarded from HUJI at the Department of Organic Chemistry. Between 2003-2005 was a post-doc fellow at the University of Minnesota. His industrial experience includes, among all, Medicinal Chemistry research in drug discovery companies which comprised design and synthesis of peptide and small molecules drug candidates. In addition to drug discovery, he also took part in Nanotechnology field which included deign and preparation of molecular imprinted polymers applications. Currently, Dr. Gazal holds a Principal Scientist position at Teva Pharmaceutical industries (generic R&D).

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