Chemical Modification of Sulfazecin. Synthesis of 4-Methoxycarbonyl-2-azetidinone-1-sulfonic Acid Derivatives

In the course of the chemical modification of sulfazecin, 3-[2-(2-aminothiazol-4-yl)-(Z)-2-(substituted oxyimino) acetamido]-4-methoxycarbonyl-2-azetidinone-1-sulfonic acids were synthesized starting from cis-1-(2, 4-dimethoxybenzyl)-4-methoxycarbonyl-3-phthalimido-2-azetidinone (2). These new 4-substituted derivatives showed more potent antimicrobial activities against gram-negative bacteria than did the corresponding 4-unsubstituted compounds, and the derivatives having 3, 4-cis stereochemistry were more active than the trans isomers, especially against P. aeruginosa and some β-lactamase-producing bacteria. The reported procedure for the cycloaddition reaction used to prepare 2 was investigated in detail ; by the use of a 20% excess of triethylamine, 2 was easily obtained in the yield of 72% as colorless crystals. A possible intermediate of β-lactam formation in this cycloaddition reaction, an acyl iminium salt (6), was isolated as crystals and converted into β-lactams by treatment with 1, 8-diazabicyclo [5. 4. 0]-7-undecene.