Practical Synthesis and Molecular Structure of a Potent Broad-Spectrum Antibacterial Isothiazoloquinolone
2007-05-18T00:00:00Z (GMT) by
We report the synthesis of the new 2-sulfonylquinolone ethyl 1-cyclopropyl-6,7-difluoro-2-methanesulfonyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (<b>5</b>). Sulfone <b>5</b> is a key intermediate used in the optimized synthesis of the isothiazoloquinolone 9-cyclopropyl-6-fluoro-8-methoxy-7-(2-methylpyridin-4-yl)-9<i>H</i>-isothiazolo[5,4-<i>b</i>]quinoline-3,4-dione (<b>1</b>), a potent broad-spectrum antibacterial agent that is effective against clinically important resistant organisms such as methicillin-resistant <i>Staphylococcus aureus</i> (MRSA). Our synthetic method is free of chromatographic purification and amenable to large-scale synthesis. The molecular structures of <b>1</b>, 9-cyclopropyl-6,7-difluoro-8-methoxy-9<i>H</i>-isothiazolo[5,4-<i>b</i>]quinoline-3,4-dione (<b>4</b>), <b>5</b>, and ethyl 2-cyclopropylamino-6,7-difluoro-8-methoxy-4-oxo-4<i>H</i>-thiochromene-3-carboxylate (<b>10</b>) were established unambiguously using multinuclear NMR spectroscopy and X-ray crystallography.