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.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/P510555/1 30/09/2016 29/09/2021
1939694 Studentship EP/P510555/1 30/09/2017 31/12/2021 Nisha Pokar
EP/R51200X/1 30/09/2017 31/12/2022
1939694 Studentship EP/R51200X/1 30/09/2017 31/12/2021 Nisha Pokar
 
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