Synthesis of 2β-Azidomethylpenicillin-1,1-Dioxides and 3β-Azido-3α-methylcepham-1,1-Dioxides

A convenient synthesis of the 2β-azidomethylpenicillin-1,1-dioxides, precursors of the active "YTR" class of β-lactamase inhibitors, is described starting with 6-aminopenicillanic acid (6-APA), which is converted to 6α-bromopenicillanic acid. Oxidation with peracetic acid in the presence of benzophenone hydrazone give benzhydryl 6α-bromopenicillanate-1-oxide in one step and reduction with zinc and acetic acid gave the 6,6-dihydropenicillanate-1-oxide. The unsymmetrical azetidinone disulfide was obtained by heating with 2-mercaptobenzothiazole, and reaction with copper(II) chloride or bromide gave the 2β-halomethylpenams. Reaction with sodium azide in aqueous dimethylformamide gave a mixture of the 2β-azidomethylpenam and the 3β-azidocepham. Oxidation with potassium permanganate gave a mixture of the 2β-azidomethylpenam-1,1-dioxide and the 3β-azidocepham-1,1-dioxide, which was easily separated by fractional crystallization.