Investigation into an Unexpected Impurity: a Practical Approach to Process Development for the Addition of Grignard Reagents to Aldehydes Using Continuous Flow Synthesis

This work presents a case study of process development using continuous flow synthesis. In developing a process for manufacturing drug substances in batch reactors, we unexpectedly obtained a significant amount of a trimerized byproduct on addition of MeMgBr to an aldehyde. Consideration of a plausible generation mechanism for the byproduct indicated that it arose from a reaction between the starting material and the Mg salt of the target product. This led us to try applying continuous flow synthesis to the process to shorten the time during which the starting material coexists with the Mg salt of the target product. This led to drastic suppression of the byproduct under very mild conditions and the establishment of a more robust process than that for batch reactors.