Synthesis of the β-Lactamase Indicators Cefesone and Nitrocefin

The synthesis of the β-lactamase indicators Cefesone [(6R,7R)-3-(2,4-dinitrostyryl)-7-(phenylacetamido)ceph-3-em-4-carboxylic acid] and Nitrocefin [(6R,7R)-3-(2,4-dinitrostyryl)-7-(2-thienylacetamido)ceph-3-em-4-carboxylic acid] from tert-butyl (1S,6R,7R)-3-bromomethyl-1-oxo-7-(phenylacetamido)ceph-3-em-4-carboxylate is reported. Phosphonylation of the latter compound with triphenylphosphine gave the corresponding phosphonium derivative in 93% yield. Reduction followed by Wittig coupling with 2,4-dinitrobenzaldehyde gave a 1 : 12 mixture of E- and Z-isomers in 83% yield. The tert-butyl protecting group was removed with titanium tetrachloride to give Cefesone as the pure crystalline E-isomer in 63% yield. De-acylation was achieved by enzymatic hydrolysis in 77% yield. Finally the 2-thienylacetyl side chain was introduced to give crystalline Nitrocefin in 67% yield.

Cefesone - cephalosporin - Nitrocefin - β-lactamase indicator - penicillin acylase