Manufacture of chiral amines using catalytic and flow processing methods
Lead Research Organisation:
University of Liverpool
Department Name: Chemistry
Abstract
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People |
ORCID iD |
| Jianliang Xiao (Principal Investigator) |
Publications
Talwar D
(2015)
Frontispiece: A Simple Iridicycle Catalyst for Efficient Transfer Hydrogenation of N-Heterocycles in Water
in Chemistry - A European Journal
Talwar D
(2015)
Regioselective acceptorless dehydrogenative coupling of N-heterocycles toward functionalized quinolines, phenanthrolines, and indoles.
in Angewandte Chemie (International ed. in English)
Wang C
(2017)
Iridacycles for hydrogenation and dehydrogenation reactions.
in Chemical communications (Cambridge, England)
| Description | Chiral amines are common building blocks in bioactive molecules. However, they are frequently unavailable in large quantities, costly and have long lead times. Furthermore production methods, particularly for secondary and tertiary chiral amines are complex, inefficient and wasteful, often giving low yields and purities. This project has addressed cross-sectoral industry needs (pharma, agro and fine chemical), by assessing the commercial potential of some existing methods, evaluating application to real systems and developing viable efficient processes. The project involved collaboration of two universities (Liverpool and Leeds) and six companies (AstraZeneca, Pfizer, Dr Reddy's, Syngenta, AMT and YProtech). The first process evaluated was the R3 Method (resolution, racemisation and recycle) and this was carried out by Prof John Blacker's group at Leeds. The second process studied at Liverpool was reductive amination using iridium catalysts under hydrogenation or transfer hydrogenation conditions. The aim was to develop a promising family of chiral isoxazoline ligands found at Liverpool which had given a best enantiomeric excess of 82% and increase this to the levels of >95% ee required for a commercial process. The key work revolved around the understanding of the chiral catalyst and the synthesis and testing of the new ligands and complexes. The project prepared a wide range of chiral ligand and catalyst candidates. This included investigating a new family of ligand types and immobilised versions of the catalysts. We also screened solvents, additives and substrate scope. The best chiral catalysts were also tested at two of the industry partners. Unfortunately no major improvement on the original system was obtained. However, a large body of data was generated for future ligand and catalyst development, as well as a promising start on an immobilised catalyst flow system based on a known chiral TsDPEN ligand. The project accelerates the transfer of Liverpool knowledge in imine hydrogenation catalysts to industry and furthers our knowledge of industrial need in chiral amine technology. The project trained a PDRA in asymmetric catalysis and included the involvement of two PhD researchers. |
| Exploitation Route | The project contributed to the funding of a three-year Innovate UK KTP project (2019-2022) on asymmetric reduction of N-heterocycles. The knowledge gained will help develop new chiral catalysts for the KTP project. The project also contributed to our continuous effort in developing new chiral Cp*Ir(III) catalysts, one of which was recently published (ACS Catal. 2018, 8, 8020-8026), which was highlighted by Nature Reviews Chemistry on 17 August 2018, and by X-MOL at https://www.x-mol.com/news/15049 The achiral version of our target Cp*Ir(III) catalysts has been used by a number of research groups worldwide, e.g. Nobel Laureate Grubbs (Chem. Sci., 2014, 5, 101) and more recently Hartwig of UC Berkeley (Angew. Chem. Int. Ed. 2019, 58, 3368), demonstrating the utility of the catalyst in chemical synthesis while highlighting the need for a more effective chiral version. |
| Sectors | Chemicals,Education,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology |
| Description | Collaboration with YProTech (now Apexmolecular: https://apexmolecular.com/our-services/xiao-reduction-catalysts/) on "Xiao Reduction Catalysts" is ongoing to further develop the catalysts. The finding contributed to the founding of the spinout company Liverpool ChiroChem at Liverpool and Taizhou, China. The project also contributed to the funding of a three-year KTP project by Innovate UK, which started January 2019, and to our continuous effort in developing new chiral Cp*Ir(III) catalysts, one of which was recently published (ACS Catal. 2018, 8, 8020), which was highlighted by Nature Reviews Chemistry (Nat. Rev. Chem., 2018, 2, 201), and by X-MOL at https://www.x-mol.com/news/15049 |
| Sector | Chemicals,Education,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology |
| Impact Types | Economic |
| Description | AstraZeneca case PhD studentship |
| Amount | £25,200 (GBP) |
| Funding ID | 89244 |
| Organisation | AstraZeneca |
| Sector | Private |
| Country | United Kingdom |
| Start | 10/2015 |
| End | 09/2019 |
| Description | KNOWLEDGE TRANSFER PARTNERSHIP between The University of Liverpool and Liverpool ChiroChem Limited |
| Amount | £192,866 (GBP) |
| Funding ID | KTP11214 |
| Organisation | Innovate UK |
| Sector | Public |
| Country | United Kingdom |
| Start | 01/2019 |
| End | 01/2022 |
| Description | Collaboration with AstraZeneca on asymmetric hydrogantion |
| Organisation | AstraZeneca |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | The university provided a PhD studentship. |
| Collaborator Contribution | AZ provided a case award to top-up the studentship. |
| Impact | The reseach is ongoing. |
| Start Year | 2015 |
| Company Name | Liverpool ChiroChem |
| Description | The company supplies specialist building blocks and chiral small molecules for pharmaceutical and biotech research/development and draws upon state-of-the-art synthetic methods in asymmetric catalysis developed at the University of Liverpool in collaboration with Pfizer. |
| Year Established | 2014 |
| Impact | The company has recently won top prize in the 2015 Merseyside Innovation awards (http://www.merseysideinnovationawards.co.uk/news/liverpool-chirochem-take-the-2015-grand-prize/) and the Bionow Start Up of the Year Award 2015 (http://www.bionow.co.uk/news/the14thbionowannualawardssuccessfullyshowcas.aspx). |
| Website | http://www.liverpoolchirochem.com/ |