Development and optimization of a new general thermodynamic deracemization method : co-crystallization Induced Spontaneous Deracemization

In pharmaceutical industry, 50% of the marketed drug compounds contain a chiral center, essential to their functioning. Where one enantiomer has the desired pharmacological effect, the other might be inactive, equally active or have adverse effects. For this reason, development of enantiopure drugs is strongly recommended by regulation authorities to industries. The industrially most prominent way to enantiopure drugs still involves formation of a racemic compound, followed by a chemical or physical resolution. Such a resolution implies a maximum yield of 50%, as the unwanted enantiomer is discarded upon separation. However, if the compound is racemizable, in principle the unwanted enantiomer can be transformed into the desired one, leading to a so-called deracemization process, which finally can lead to a 100% maximum yield. Such processes exist for compounds that either are intermediates (Dynamic Kinetic resolution), can form salts (Crystallization Induced Diastereomer Transformation) or conglomerates (Viedma Ripening). However, there are still a considerable amount of racemizable molecules that don’t meet either criteria and therefore cannot be deracemized. In this work, the aim is to develop a novel tool within the library of deracemization techniques in order to touch a larger range of compounds, with the ultimate goal to develop a physical thermodynamic deracemization technique applicable to all racemizable compounds. To do so, crystal engineering and crystal growth tools are combined to develop a Co-crystallization Induced Spontaneous Deracemization method (CoISD). This process is based on co-crystallization in order to induce an imbalance in solution by precipitation of only one enantiomer while racemizing the excess of the other one in solution. Doing so, we first identified a suitable system on which to develop the CoISD process by synthetizing a series of analog compounds and submitting them to a co-crystal screening. A suitable co-crystal system composed
(SC - Sciences) -- UCL, 2020