ABSTRACT
Continuous-flow multistep synthesis is combined with quasi-continuous final-product purification to produce pure products from crude reaction mixtures. In the nucleophilic aromatic substitution of 2,4-difluoronitrobenzene with morpholine followed by a heterogeneous catalytic hydrogenation, the desired monosubstituted product can be continuously separated from the co- and by-products in a purity of over 99 % by coupling a flow reactor sequence to a multiple dual-mode (MDM) centrifugal partition chromatography (CPC) device. This purification technique has many advantages over HPLC, such as higher resolution and no need for column replacement or silica recycling, and it does not suffer from irreversible adsorption.
ABSTRACT
Recent advances in the field of continuous flow chemistry allow the multistep preparation of complex molecules such as APIs (Active Pharmaceutical Ingredients) in a telescoped manner. Numerous examples of laboratory-scale applications are described, which are pointing towards novel manufacturing processes of pharmaceutical compounds, in accordance with recent regulatory, economical and quality guidances. The chemical and technical knowledge gained during these studies is considerable; nevertheless, connecting several individual chemical transformations and the attached analytics and purification holds hidden traps. In this review, we summarize innovative solutions for these challenges, in order to benefit chemists aiming to exploit flow chemistry systems for the synthesis of biologically active molecules.
