Continuous flow synthesis of chiral amines

The synthesis of chiral amines is important due their presence in a range of active pharmaceutical ingredients (APIs). Chiral resolution processes are common in the pharmaceutical industry as they are cheaper and easier than the alternatives; however, the maximum yield is only 50%. Crystallisation induced diastereomeric transformation (CIDT) is a variant of resolution, where a racemic amine is converted into a diastereomeric salt pair by reaction with a chiral acid, forming a pair of diastereomers, which have different solubilities. This process allows a single diastereomer to crystallise whilst the undesired diastereomer remains in solution. The undesired product can be racemised by iridium catalysis, either in- or ex-situ, forming more of the racemic starting material, which is then available for further crystallisation. This diastereomeric resolution/racemisation recycling process has been carried out in a continuous flow process. Conventionally, flow systems are unable to handle multiphase systems; however, the AMTech Coflore agitated tube reactor (ATR) addresses this problem. We present a continuous diastereomeric crystallisation/racemisation process of a model amine substrate using the Coflore ATR, which can give a theoretical 100% yield of a single enantiomer. To our knowledge, this is the first time such a process has been successfully achieved in flow.