Synthesising complex chiral amines through resolution-racemisation-recycle

Abstract

Chiral amines building blocks are present in 40% of pharmaceuticals, though synthesis remains a challenge. Traditional methods involving kinetic resolution and diastereomeric crystallisation are limited by low maximum yields (50%) which lead to costly and wasteful disposal of unwanted enantiomers. Coupling of in situ racemisation of undesired enantiomers can increase theoretical yield to 100%, although harsh conditions required for racemisations are incompatible with relatively mild conditions required for resolution. The Resolution-Racemisation-Recycle (R3) process overcomes the traditional limitations of diastereomeric crystallisation through spatial separation of resolution and racemisation steps. The diastereomeric resolution is conducted at optimal crystallisation temperatures (room temperature and below) and the racemisation at elevated temperatures (80 ºC). The process employs a continuous flow set-up coupling a continuously-stirred tank reactor (CSTR) for crystallisation and packed-bed reactor (PBR) containing immobilised iridium-based racemisation catalyst. Investigation of each process independently is required prior to coupling the two. Successful epimerisation conditions for a novel amino acid ester salt were demonstrated, and investigation of a mixture of sertraline diastereomers under unoptimised R3 conditions generated solid, of which 75% was sertraline. The mechanism of chiral amine racemisation using homogeneous iodo-iridium complex [IrCp*I2]2 was explored on-line using flowNMR, allowing real-time reaction monitoring. Coupled with mass spectrometry data, an iridium-hydride intermediate validating the originally proposed inner-sphere mechanism was observed. Triply bridged mono, di and trihydride dinuclear iridium intermediates were evidence through mass spectrometry, believed to be off-cycle species. An updated mechanistic cycle was proposed. Exploration of amine racemisation is often impeded by the need for analytical methods and enantiopure amine. Development of a hydrogen borrowing methodology, involving hydrogen-deuterium exchange, allowed circumvention of these issues. Iridium-catalysed generation of an imine or enamine intermediate followed by re-hydrogenation, or racemisation, with deuterium was investigated using 1H NMR and mass spectrometry. The integration decrease at α-chiral and adjacent β-centres, coupled with narrow isotopologue distribution patterns with sufficient mass difference to the non-deuterated amine was demonstrated for a number of pharmaceutically complex chiral amines