Overcoming the Limitations of Diastereomeric Crystallisation of Chiral Amines

Chiral amines are important building blocks in pharmaceutical compounds. Being able to synthesise chiral amines in high yield and enantiopurity is highly desirable due to the different physiological activities exhibited by the opposite enantiomers. Classical resolution using chiral acids has been the main strategy in preparing enantiopure amines at industrial scale, however the processes often lead to high waste and intrinsically low yields.

To overcome the limitations of classical resolution of chiral amines, the research presented in this work has focused on the development of a resolution-racemisation-recycle (R3) process which couples diastereomeric crystallisation and catalytic racemisation of the undesired enantiomer in the mother liquor. The crystallisation was carried out in batch in a continuous-stirred tank reactor (CSTR) whilst the racemisation was carried out in flow with a packed-bed reactor (PBR) containing the racemisation SCRAM catalyst which was immobilised on a Wang resin support, enabling it to be recycled up to 130 times. The two steps were separated but linked with tubing and a pump to yield a continuous recirculation process. Unlike traditional approaches in asymmetric transformations in which the resolution and in-situ racemisation are carried out in one pot, the R3 process allows each step to be operated independently under its optimum conditions.

The success of the R3 process depends strongly upon the rate of racemisation, the absolute, and difference in, solubility of the diastereomeric salts, the rates of growth and dissolution of the less soluble and more soluble diastereomers respectively. The system was tested with primary, secondary and tertiary amines with up to 50-times improved resolvability observed. For one secondary amine, a 96% diastereopurity and 78% yield gave a resolvability of 1.5 compared to the classical resolution of 0.11. The R3 processes of the primary and tertiary amines were less successful, mainly due to the formation of undesired by-products. Racemisation of the amine substrates were studied with homogeneous and immobilised SCRAM catalysts to better understand the reaction kinetics and mechanism. A series of iron- and copper-based metal compounds were also screened in an attempt to search for low-cost alternatives of amine racemisation catalysts.