From Reaction Solvent to Crystallization Solvent, Membrane Assisted Reaction Workup and Interpretation of Membrane Performance Results by Application of Spiegler-Kedem Theory

Within practically all multistep synthetic sequences used to prepare molecular entities, a step can be found in which a change of solvent is required. Presently this is nearly always carried out by distillation process. Alternatives to distillation do, however, exist such as the nonthermal membrane based solvent exchange. Although highly efficient and useful in several circumstances, this technique is seldom carried out within an industrial setting, possibly due to some uncertainty as to the issues to be confronted. By making use of a practical example in which the Refametnib intermediate DIM-DAB (2) undergoes a solvent exchange from the reaction solvent THF to its crystallization solvent ethanol, these issues are illustrated and explained. Furthermore, the at first sight seemingly arbitrary rejection profile of DIM-DAB (2) over various membranes is explained by applying Spiegler Kedem theory. Use of this modeling leads to a more targeted membrane screening phase, in which solute rejection is determined in a particular solvent over a number of membranes. Moreover, this model can also be used to simulate membrane performance in a solvent exchange without necessarily requiring the experimental demonstration. The simulation increases the efficiency of the experimental work by allowing a more comprehensive view of membrane performance. This in turn leads to more informed decisions of which membrane is the most suited to the requirements of the process.