Deracemization of Naproxenderived esters

Details

Supervisors

Leyssens, Tom

Faculty

Faculté des bioingénieurs

Degree label

Master [120] : bioingénieur en chimie et bioindustries, à finalité spécialisée

Abstract

Chirality is a fundamental concept in organic and pharmaceutical chemistry, referring to the property of a molecule that cannot be superimposed on its mirror image, that is, lacking a plane of symmetry. This molecular asymmetry plays a key role in biological interactions since, for reasons still unknown, enantiomers can have very different effects on biological systems. Various strategies and methods exist today to obtain enantiomerically pure mixtures. Some allow for favoring the synthesis of one enantiomer over the other, others allow for the “sorting” of racemic mixtures (chromatography or preferential crystallization). Still others allow for active deracemization by isolating the enantiomer of interest and inducing the transformation of the undesired enantiomer into its desired counterpart. Among deracemization approaches, the so-called Viedma ripening method, discovered in 2005, allows, from a racemic conglomerate subjected to racemization in solution and continuous stirring, to spontaneously achieve high enantiomeric excess, or even complete enantiopurity, without any external chiral input. More recently, studies have shown that this strategy could be transposed to the solid phase via mechanochemical processes, without solvent[1]. This is the case for Mechanochemical Deracemization by Abrasive Grinding (MCDR)[2]. successfully explored the feasibility of MCDR of naproxen methyl ester with NaOMe. The aim of this master thesis is to extend this technique to bases other than NaOMe and to test their effectiveness. Thirteen bases were tested for the deracemization of the same molecule (naproxen methyl ester), mainly carbonates, hydroxides, ethoxides, and tert-butoxides. The tertbutoxide bases (NaOtBu and KOtBu) proved to be the most effective (up to 73% ee, from 20%), with an optimal molar ratio lower than that used by [2] for NaOMe. However, traces of side transesterification reactions with naproxen esters were detected and discussed in this work, in varying proportions depending on the base used. The influence of the presence of water in the medium was also tested, as well as the risk of accidental back racemization after the end of the reaction. Finally, some parameters were also varied to test their influence on the ee. The interest of these MCDR approaches lies in the reduced use of solvents and thus the reduced production of waste, making them more sustainable methods and more aligned with the principles of green chemistry, increasingly adopted with the aim of making chemical engineering more environmentally friendly.