Dr John Studley, Science Director at Scientific Update and
Dr William Goundry from Astra Zeneca got together ahead of our forthcoming Organic Process R&D Conference in Lisbon, Portugal on 23-25 September.
Q: Dr John Studley (JS) We are looking forward to your presentation ‘The Good, the Bad and the Ugly! Successes and Failures from the Scale-Up of AZD6738 ’- can you tell us a little more about what to expect?
A: Dr William Goundry (WG) The talk will give the history of our manufacture of AZD6738 to date spanning seven different campaigns. As the title hints, the talk will be a true account.
Q: (JS) Structurally AZD6738 looks like an interesting molecule- particularly the chiral sulfoximine and cyclopropane ring. Did these groups prove difficult to access using scalable chemistry?
A: (WG) We’ve faced many challenges in accessing the dense functionality of AZD6738 at scale, especially as AstraZeneca are striving for sustainable processes using the 12 principles of green chemistry. The chiral sulfoximine has been the greatest challenge. We tried accessing this from a chiral sulfoxide, using hydrazoic acid in flow but unfortunately the product was racemic (OPRD 2015, 19, 1062).
Q: (JS) It’s great to see from your recent paper (OPRD 2019, 23, 1333) that you used continuous processing- was that a conscious decision to take this approach or was batch processing not practical?
A: (WG)The application of flow to this project was identified by the Med. Chem. Team and first demonstrated in Lead optimisation, so yes, a very conscious decision! However the continuous processing was very difficult, generating both a gaseous byproduct and an inorganic salt. Since the reaction is under biphasic phase-transfer conditions at the start, the resulting product stream is quadriphasic!
Q: (JS) You mention in your paper that the manufacture of AZD6738 remains a challenge- how do you plan to tackle this going forward?
A: (WG) Work is underway in AstraZeneca to develop a new route and we would love to present this at an OPR&D conference in 2020.
Q: (JS) Biocatalytic oxidation of the thioether to chiral sulfoxide is an interesting reaction (OPR&D 2017, 21, 107). I’ve noticed that several AZ molecules have a sulfoxide or sulfoxide derivative in the structure (Esomeprazole, ZD7944, ZD3638 etc) – is this a coincidence or do you know something we don’t?
A: (WG) The glutamine synthase inhibitor methionine sulfoximine was discovered in 1949. A detailed study of its mechanism of action showed that the nitrogen of the sulfoximine was irreversibly phosphorylated in the enzyme active site, followed by binding and inhibition. Since then the use of the sulfoximine moiety in psuedopeptide drug candidate has steadily increased.
Q: (JS) The complexity of molecules entering development is, in general, increasing whilst development timeless are becoming shorter. Do you see a similar trend at AZ and how do you mitigate this paradigm?
A: (WG) Yes, this is certainly a trend we’re seeing at AZ. Increasing complexity of our portfolio includes: Bigger molecules; macrocycles; atropisomers; natural product derivatives. We are constantly pushed to deliver projects faster, however it’s an exciting time to be a process chemist. At AstraZeneca we are rising to the challenge by using both the latest chemistries and predictive science. We are ramping up our efforts in Biocatalysis and beginning to scale up photo redox processes. We have a bold aspiration to use AI to predict which reactions we should do and in what solvent.
Q: (JS) What’s the most interesting chemistry paper you’ve read this year (other than your own!)?
A: (WG) For a process chemist it’s important to know: Can I scale up a reaction; How sensitive is the reaction? The recent paper from Prof. Glorius and co-workers (https://doi.org/10.1002/anie.201901935) has sparked lots of discussion internally at AZ on this topic. They report a systematic process to obtain information that can be displayed in a useful reporting graphic to assess the sensitivity of a chemical reaction to key parameters. Adopting this approach may lead to an increased level of reproducibility in the chemical literature.
Q: (JS) Who inspired you to study chemistry?
A: (WG) From the age of 14 I was lucky to have a very inspiring Chemistry Teacher, Mr Jones, at Bishop Vesey’s Grammar School. He sparked a life long love of chemistry in me. I was then lucky to be tutored by Prof. George Fleet at Oxford University who really brought Organic Chemistry to life.