Synthesis of mono- and di-substituted 2,4,5-trifluorobenzoic acid synthons, key precursors for biologically active 6-fluoroquinolones

Abstract

In the search for new potent antiparasitical fluoroquinolones, a QSAR analysis by molecular connectivity led to the design of R5 (Me or Et)/R8 (MeO, Me or Et)-substituted analogs of the most powerful antibacterial or antiparasitical fluoroquinolones known so far. Unfortunately, the synthetic schemes that were elaborated in literature for 3- and 3,6-di-substituted 2,4,5-trifluorobenzoic acids, the key precursors of the target R5/R8-substituted 6-fluoroquinolones, led in our hands to poor yields and/or to inextricable mixtures of derivatives. This led us to reinvestigate the key alkylation steps of the 2,4,5-trifluorophenyl- oxazoline synthons and the subsequent deprotection of their oxazoline into acid with the aim of optimising the syntheses of 3- and 3,6-di-substituted 2,4,5-trifluorobenzoic acids, which constitute the entries to our target derivatives. © 2005 Elsevier Ltd. All rights reserved.