Synthesis of 7α-Methoxy-7-(4-phenyl-1<i>H</i>-1,2,3-triazol-1-yl)acetamino-3′-arylthio-cephalosporic Acid Derivatives from 7-Aminocephalosporic Acid

Abstract

The aim of this project was to develop a synthetic protocol for the preparation of a cephamycin scaffold that would readily allow the synthesis of its analogues with variations at the C-7 amino group and the C-3′ position. We also aimed to develop a method that avoided the use of toxic and potentially explosive diphenyldiazomethane. These aims were achieved via the synthesis of the novel α-bromo acetamide 18 which allowed functionalization at the α-bromo acetamide position by azide and then the introduction of a 4-phenyl-1H-1,2,3-triazol-1-yl moiety via a Cu(I)-catalysed azide–alkyne cycloaddition reaction with phenylacetylene. Palladium-catalyzed arylthioallylation reactions then allowed the introduction of 3′-arylthiol substituents. We also report for the first time the synthesis of the 4-methoxybenzyl ester of (6R,7S)-3-[(acetyloxy)methyl]-7-amino-7-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and the use of diphenyl trichloroacetimidate, instead of diphenyldiazomethane, and 4-methoxybenzyl trichloroacetimidate to prepare related 4-methoxybenzyl esters. The chemistry described, and several of the synthetic intermediates reported here, are potentially valuable methods and scaffolds, respectively, for further development of β-lactam antibiotics.

Keywords

• cephamycin
• cefotetan
• antibiotics
• triazole
• thioallylation