Scale-up of N-alkylation reaction using phase-transfer catalysis with integrated separation in flow

A continuous phase-transfer catalysis process for N-alkylation integrated with separation was developed. This approach circumvents the heat and mass transfer limitations encountered in batch scale-up, enabling a safer process and yielding a higher-quality product. Two continuous flow approaches are analyzed: a) an automated fill–empty reactor with an integrated gravity separator and b) a tubular flow reactor with an inline membrane separator. The fill–empty platform enabled the direct technology transfer from batch, achieving conversions >99% (by HPLC) and purities >90%. The tubular flow reactor allowed the reduction of the base solution requirements, yielding conversions of 91% and purities >88%. Both the setups provide a small process footprint with downstream integrated separation. The on-demand scale-up was efficiently and safely demonstrated using the fill–empty approach for the production of various substrates at the multigram scale.