Design and operation of a filter reactor for continuous production of a selected pharmaceutical intermediate

A novel filter reactor system for continuous production of selected pharmaceutical intermediates is presented and experimentally verified. The filter reactor system consists of a mixed flow reactor equipped with a bottom filter, to retain solid reactant particles, followed by a conventional plug flow reactor, where residual reactant is converted by titration. A chemical case study, production of the pharmaceutical intermediate allylcarbinol by a reaction between allylmagnesium chloride and 2-chloro-thioxanthone, in the presence of a side reaction is considered. The synthesis is conducted in tetrahydrofuran solvent. The use of the filter reactor design was explored by examining the transferability of a synthesis step in a present full-scale semi-batch pharmaceutical production into continuous processing. The main advantages of the new continuous minireactor system, compared to the conventional semi-batch operation, are reduced impurity formation and the use of much lower reactor volumes (factor of 1000 based on the laboratory reactor) and less solvent consumption (from 5.8 to 2.3 L/kg reactant). Added challenges include handling of continuous solid powder feeding, stable pumping of reactive slurries, and a possibility of continuous control.

► Paradigm shift of a present pharmaceutical batch synthesis into a continuous process.
► Continuous production of selected pharmaceutical intermediate.
► Continuous reactor retaining solid starting material in excess.
► Grignard alkylation with increased selectivity of target product.
► Flow chemistry with most soluble reactant as limiting parameter for concentration.