Concise Large-Scale Synthesis of the Highly Active Cephalosporin Cefdaloxime

Abstract

Cefdaloxime (1a) is the bioactive principle of the 1-(S)-(pivaloyloxy)ethyl ester prodrug HR916K (1b). To provide material for biological investigations a short and efficient large-scale synthesis of 1a was developed, which avoids chromatographic purification steps. Commercially available (6R,7R)-7-amino-3-(methoxymethyl)-3-cephem-4-carboxylic acid (AMCA) (2) is acylated with trityl-protected mercaptobenzothiazole thioester in the presence of bis(trimethylsilyl)acetamide to yield tritylated cefdaloxime. The trityl group is then removed by treatment with formic acid, followed by pH-adjusted precipitation of 1a. For a final purification, which has to consider cefdaloxime specific side reactions, crude 1a is dissolved in dimethyl sulfoxide and precipitated with methanol to obtain 1a in 66% overall yield on a kilogram scale.