A Concise Synthesis of a β-Lactamase Inhibitor

Department of Process Research, Merck and Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, USA.
Organic Letters (Impact Factor: 6.36). 09/2011; 13(20):5480-3. DOI: 10.1021/ol202195n
Source: PubMed


MK-7655 (1) is a β-lactamase inhibitor in clinical trials as a combination therapy for the treatment of bacterial infection resistant to β-lactam antibiotics. Its unusual structural challenges have inspired a rapid synthesis featuring an iridium-catalyzed N-H insertion and a series of late stage transformations designed around the reactivity of the labile bicyclo[3.2.1]urea at the core of the target.

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    • "MK-7655, a novel DBO that is structurally similar to AVI except for an additional piperidine ring, exhibits synergy in combination with imipenem against KPC-producing K. pneumoniae and P. aeruginosa expressing AmpC (Figure 2; Mangion et al., 2011; Hirsch et al., 2012). Studies show that at a concentration of 4 mg/L, MK-7655 lowers imipenem MICs for Enterobacteriaceae with KPC carbapenemases from 16–64 mg/L to 0.12–1 mg/L (Livermore et al., 2013). "
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