Scale-Up of a Vilsmeier Formylation Reaction:  Use of HEL Auto-MATE and Simulation Techniques for Rapid and Safe Transfer to Pilot Plant from Laboratory

Abstract

The application of reaction calorimetry and process modelling to allow for the rapid and safe scale-up of a Vilsmeier formylation reaction to the pilot plant will be described. This transformation was a key step in the preparation of the backbone amide linker (the so-called “BAL” handle) for solid-phase chemistry. In particular, use was made of Auto-MATE equipment from Hazard Evaluation Laboratories (HEL) and “Reaction Simulator” software to derive a thermokinetic model which allowed us to simulate heat-flow data on-scale. The model was then refined using a HEL SIMULAR 1-L calorimeter, and a direct comparison of the data showed there to be a 20% error in the enthalpy data gathered from the smaller Auto-MATE. The use of a preformed Vilsmeier reagent and dichloromethane as a reaction solvent gave a “square-wave” profile typical of a feed-controlled reaction. These conditions were successfully scaled to a 50-L pilot-plant vessel.