CONCISE LARGE-SCALE SYNTHESIS OF THE HIGHLY-ACTIVE CEPHALOSPORIN CEFDALOXIME

Cefdaloxime (1a) is the bioactive principle of the 1-(S)-(pivaloyloxy) ethyl ester prodrug HR916K (Ib). To provide material for biological in vestigations a short and efficient large-scale synthesis of la was dev eloped, 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 thi oester in the presence of bis(trimethylsilyl)acetamide to yield trityl ated cefdaloxime, The trityl group is then removed by treatment with f ormic acid, followed by pa-adjusted precipitation of la. For a final p urification, which has to consider cefdaloxime specific side reactions ,crude la is dissolved in dimethyl sulfoxide and precipitated with met hanol to obtain la in 66% overall yield on a kilogram scale.