A novel method for the synthesis of quinolones. Total synthesis of Norfloxacin.

Abstract

Quinolones are a class of synthetic compounds that are used as antibacterial agents since their discovery in the 1960s. Their chemical synthesis has mostly been based on ring-closing reactions, for instance the Gould-Jacobs cyclization reaction. This project demonstrates the synthesis of (fluoro)quinolones in general with a new and efficient method that employs halogenated ethyl diazoacetates in reaction with indole-derivatives; forming quinoline precursors that convert easily to quinolones. The key reaction in the new method is the synthesis of the quinoline precursor. The reaction was based on recent work in our group, and the proposed reaction mechanism was a cyclopropanation reaction between rhodium(II)-carbenoids (of α-halodiazoacetates) and indole-derivatives, followed by a ring expansion to quinoline structures. Cyclopropanation of heterocycles followed by ring expansion has historically been called the “abnormal” Reimer-Tiemann reaction. Because of its significance in this project, the reaction was investigated further by changing the catalyst and the reaction solvent. The results implicated that the original conditions still were the best for synthesis of quinoline structures, but changing the reaction solvent to toluene gave also good yields. Converting quinolines to 4-quinolones was done by alcoholysis according to a literature procedure. The halogenated ethyl diazoacetates were synthesized according to a new and safe procedure previously developed in our group. The reaction was quantitively analyzed during this project and verified quantitative conversion of ethyl diazoacetate to its halogenated-analogs. Without signs of dimerization, high yields of these species were obtained after purification by filtration through a pre-cooled silica plug. Optimization was attempted by using other methods for the synthesis of the α-halodiazoacetates that involved an extraction step rather than a filtration step. However, the original procedure still gave the best yield. The new and efficient method was used to synthesize 4-quinolone-3-carboxylic acid as a quinolone core structure, and ethyl 6,7-difluoro-4-quinolone-3-carboxylate as a fluoroquinolone key intermediate. The fluoroquinolone was reacted further in literature-based reactions to synthesize Norfloxacin as its hydrochloride salt.