Description:
<jats:title>Abstract</jats:title><jats:p>An efficient synthesis of HR 916 B (<jats:bold>4</jats:bold>), the orally active 1‐(<jats:italic>RS</jats:italic>)‐(pivaloyloxy)ethyl prodrug ester of the cephalosporin cefdaloxime, was developed and applied on a multi‐kg scale. AMCA (<jats:bold>8</jats:bold>) was prepared by exchange of the acetoxy group of fermentation product ACA (<jats:bold>7</jats:bold>) with the nucleophile methanol under acidic conditions. Its 7‐amino group was acylated with mixed anhydride <jats:bold>14</jats:bold> to give <jats:bold>15</jats:bold>. Carboxylic acid <jats:bold>15</jats:bold> was esterified with iodohydrin ester <jats:bold>27</jats:bold> or bromohydrin ester <jats:bold>30</jats:bold>, respectively, to provide the acylal <jats:bold>16</jats:bold>. Simultaneous removal of both the amino‐ and the oximo‐protecting group furnished the prodrug HR 916 <jats:bold>3</jats:bold>, which was purified and stabilized by precipitation of its tosylate salt <jats:bold>4</jats:bold>. The overall yield of <jats:bold>4</jats:bold> (ratio <jats:bold>5/6</jats:bold> = 0.65) was 39% relative to AMCA (<jats:bold>8</jats:bold>) (four steps), 15% relative to ACA (<jats:bold>7</jats:bold>) (five steps).</jats:p>