Preferential crystallization (AS3PC mode) of modafinic acid: an example of productivity enhancement by addition of a non-chiral base

Modafinic acid belongs to the minor fraction of chiral components whose racemic mixture crystallizes as a stable conglomerate. Preferential crystallization attempts were carried out on a two-litre scale via the AS3PC mode (auto seeded polythermic programmed preferential crystallization): the direct entrainments of modafinic acid resulted in a substantial yield (the final enantiomeric excess of the mother liquor eef reaches 10%). In a second step, the entrainment attempts were performed by addition of triethanolamine—a non-chiral base—in such a way that the solubility of the racemic mixture was increased and simultaneously the αmol ratio = s(±)/s(+) was decreased. The results show a clear robustness of the new process and an improved yield (+ 50 wt% with 30 mol% of triethanolamine) which appears to be a direct consequence of the increase of the racemic mixture concentration whereas the entrainment magnitudes are similar in both protocols (eef ≈ 10%). As the duration of the two processes is identical, the gain in productivity is proportional to the increase in yield.