Time‐Dependent Resolution of an Atropisomeric 1‐Arylpyrrole by a Novel 1‐Arylethylamine Saltforming Agent

This study represents a special, time‐dependent resolution strategy of an atropisomeric, bifunctional 1‐phenylpyrrole derivative, using the nonactive enantiomer of the key amine intermediate Apremilast as an efficient resolving agent. Among the solvents investigated, ethyl acetate was identified as the optimal solvent, allowing rapid crystallization and high enantiomeric purity (> 99% ee ). A detailed study of kinetic behavior revealed that early‐stage crystallization and timely separation of diastereomeric salt are critical to achieving high enantiopurity and avoiding recrystallization to lead to a racemic product. Time‐dependent studies suggest that solvate formation of enantiomers and ethyl acetate plays a crucial role in the resolution mechanism. This resolution process enables the direct separation of racemic 2‐(2‐carbamoyl‐1 H ‐pyrrol‐1‐yl)‐3‐(trifluoromethyl) benzoic acid suitable for further applications, such as resolving agents for amine‐type compounds. Significantly, this approach recycles an amine‐type drug intermediate that is typically discarded during the large‐scale production of Apremilast, thus being in line with green chemistry principles by minimizing waste and enabling resource recovery.