Advances in the stereoselective synthesis of antifungal agents and ...

Chapter 1 30In vivo tests of compounds 18a-g proved to reduce the estradiol levelfrom 98% to 82% and also to have higher activities than AG 14a.CompounR IC 50 (nM) Relative Potencyd18a 4-CN 3 243618b 4-Cl 7.7 94918c 4-F 7.3 100118e 2-Me 7.9 92518d 4-Me 8.8 83118e 2-Cl 19.5 37518f 4-Ph 242 30.214a AG 7310 1Table 1.1: relative potencies of compounds 18a-g in comparison with the AG 14a.The 4-fluoro derivatives 18c have been separated by analytical chiralHPLC into the two enantiomers and their activity has been tested: the (+)-enantiomer was 15 fold more active than the (-)-enantiomer 141a , and the 4-cloro derivative 18b has been separated in single enantiomers by fractionalcrystallization of their dibenzoyltartrate salt, and also for this molecule the(+)-enantiomer was 15 fold more active than the (-)-enantiomer 141b .Molecular Modelling using the approches of Furet et al. 142 for thestudy of the binding of fadrozole to Aromatase provided a satisfactoryexplanation for these observations 141 .1.6. Aim of this thesis.Aim of the thesis was the synthesis of enantiopure benzhydryl azoles.This target was chosen both for its industrial importance where products ofthis kind are under development as racemates, and because it is considereda chemistry field not yet explored in depth. In order to achieve this goalthree different strategies were chosen (Fig. 1.17):1) Synthesis and separation of diasteroisomers.2) Enantioselective synthesis3) Crystallization of diasteroisomeric salts.