Making Complex Chiral Amines by Catalytic Resolution-Racemisation-Recycle (R3-Process)
Lead Research Organisation:
University of Leeds
Department Name: Sch of Chemistry
Abstract
This project aims to build-upon and move rapidly to exploit an exciting new process to make optically active amines that started with a current AZ supported CASE studentship (Blacker/Munday/Kwan). The method takes advantage of the benefits of diastereomeric crystal resolution - high selectivity, simple robust and scalable process, low cost and widely applicable, and overcomes the major limitation - maximum 50% yield with associated waste and cost issues. Thus far the scope has been evaluated with a series of 2o and 3o chiral amines, typically made in >80% yield and >95% e.e. We now wish to widen the scope of the R3-Process by researching optically active b-amino alcohols, and related chiral centres, that are frequently encountered in development compounds. A further aspect is to develop an understanding of diastereomer solubility to assist in solvent selection and predict salt pairs. The project addresses the AZ PhD Collaborations Call in developing a new more efficient method of product isolation.
| Description | - Investigation and further development of a rapid screening method for the investigation of amine racemisation - A hypothesis in a previously published paper has been disproved using experimental evidence - A further improved flow chemistry system since undertaking the project - Investigation of relatively complex chiral amines |
| Exploitation Route | - Further investigation of complex chiral amines in the R3 system |
| Sectors | Chemicals,Pharmaceuticals and Medical Biotechnology |
| Title | A rapid screening methodology for investigating chiral amine racemisation |
| Description | A hydrogen deuterium exchange method used to investigate the ability of chiral amines to racemise. |
| Type Of Material | Physiological assessment or outcome measure |
| Year Produced | 2017 |
| Provided To Others? | No |
| Impact | Avoids lengthy development of analytical methods for compounds which may not racemise readily. |
| Title | Resolution-Racemisation-Recycle Equipment |
| Description | Circulation of enantioriched mother liquors to a heated HPLC column containing immobilised racemisation catalyst. Return of mother liquors to initial vessel to crystallise as less soluble diastereomeric salt. |
| Type Of Material | Improvements to research infrastructure |
| Year Produced | 2014 |
| Provided To Others? | No |
| Impact | Increase in yields and enantiomeric excesses with a continuous system which requites minimal user interaction. |
| Description | AstraZeneca CASE |
| Organisation | AstraZeneca |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | Project is partly funded by AstraZeneca and has involved undertaking a 3 month work placement at the Macclesfield site. Work was conducted on one of their active pharmaceutical intermediates. |
| Collaborator Contribution | AstraZeneca partly fund the project. |
| Impact | Investigation of AstraZeneca relevent active pharmaceutical compounds. Multi-disciplinary in the sense that AstraZeneca employers people of various scientific backgrounds. |
| Start Year | 2017 |
| Description | University of Bath Dynamic Reaction Monitoring (DReaM) Facility |
| Organisation | University of Bath |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Use of FlowNMR facility. |
| Collaborator Contribution | Use of facility time and access to FlowNMR experts. |
| Impact | Observation of a catalytic intermediate species. |
| Start Year | 2018 |