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Synfacts 2012; 8(1): 0001
DOI: 10.1055/s-0031-1289917
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of MK-7655

Contributor(s):
Philip Kocienski
Mangion IK, * Ruck RT, Rivera N, Huffman MA, Shevlin M. Merck and Co., Inc., Rahway, USA
A Concise Synthesis of a β-Lactamase Inhibitor.

Org. Lett. 2011;
13: 5480-5483
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Further Information

Publication History

Publication Date:
19 December 2011 (online)

 
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Key words

MK-7655 - β-lactamase inhibitors - iridium-catalyzed N–H insertion - sulfoxonium ylides

Significance

MK-7655 is a potent β-lactamase inhibitor. It is in clinical trials for the treatment of bacterial infections in conjunction with β-lactam antibiotics. The bicyclic urea is highly reactive and a major challenge was to find conditions for its formation and preservation during the construction of the aminoxy sulfate. This work features the first practical application of the N–H insertion of a sulfoxonium ylide (D → E) in a complex synthesis.


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Comment

The synthesis depicted delivered multikilogram quantities of API in twelve steps and 10% overall yield. MK-7655 is only stable in the pH range of 4–8; therefore, removal of the Boc group in the final step cannot be achieved under the usual acidic conditions. After extensive experiments, 1.4 equivalents of HBF4·OEt2 in trifluoroethanol successfully removed the Boc group.


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