Practical synthesis of the new carbapenem antibiotic ertapenem sodium

ORGN 73

J. M. Williams, K. M. J. Brands, K. M. Conrad, B. Pipik, K. A. Savary, F-R. Tsay, P. G. Houghton, R. T. Skerlj, R. B. Jobson, G. Marchesini, L. M. DiMichele, and U-H. Dolling. Department of Process Research, Merck Research Laboratories, P.O.Box 2000, Rahway, NJ 07065-0900
Ertapenem Sodium, a new parenteral carbapenem antibiotic, has been approved as a once daily IV or IM treatment for moderate to severe community acquired infections. Ertapenem presents significant synthetic challenges arising from the presence of acidic and basic functionality and the inherent instability of the product. An efficient synthesis was devised which minimizes the use of protecting groups. Tetramethylguanidine is used as base for the low temperature coupling of the thiol with the enol phosphate followed by hydrogenolysis of the p-nitrobenzyl ester. The use of bicarbonate in the hydrogenolysis is key in providing transient protection of the pyrrolidine amine as the sodium carbamate. Experimental evidence for the formation of the sodium carbamate will be provided. An expedient process for purification minimizing degradation relies on ion-pairing extraction and crystallization.

 

Process R&D
1:00 PM-5:00 PM, Sunday, September 7, 2003 Sheraton New York -- Royal Ballroom B, Oral

Division of Organic Chemistry
The 226th ACS National Meeting, New York, NY, September 7-11, 2003