Factory in a Fumehood: Reagentless Flow Reactors as Enabling Techniques for Manufacture

Lead Research Organisation: University of Bristol
Department Name: Chemistry

Abstract

This proposal aims to bring together a unique team of scientists from academia and industry to develop new enabling manufacturing techniques for the reagentless synthesis of high value chemical products. Why reagentless? In traditional chemical processes once a reagent has performed its task it needs to be removed from the product stream. Unless the spent reagent can be reactivated then the waste stream must be dealt with. Most processes require large amounts of reagent, placing a heavy financial and environmental burden on manufacturing of high value products such as pharmaceuticals. The Holy Grail would be to avoid reagents altogether. Photochemisty, electrochemistry and thermochemistry are reagentless techniques, requiring only electrical energy as a primary input and will be the focus of this project in order to provide new enabling techniques for manufacturing. By the use of flow chemistry techniques these three areas can be connected together to provide rapid access to complex, high value products - this is conceptualized as a 'Factory in a Fumehood' - where scale-up can be achieved with a small footprint and with greatly reduced operating costs and waste.

Planned Impact

Manufacturing in the UK and Europe has suffered enormously over the past decade. The availability of cheap labour and the proliferation of CRO's in Asia has resulted in the outsourcing of both R&D and Manufacture. This has been particularly acute in the Pharmaceutical and Fine Chemical industries, in both of which the UK are world leading. The key problem is the high operational and depreciation costs associated with R&D labs and fixed manufacturing plants. Development of the reagentless flow chemistry techniques described herein will generate small footprint, portable reactors that can be housed in fumehoods. The 'Factory in a Fumehood' concept has been inspired by Berry and GSK colleagues who recently built a plant that is capable of manufacturing a product worth £6Bn per annum. This continuous process has a footprint of just 4-fumehoods and will shortly be reduced to manufacturing practice at an estimated cost of £5M. With such relatively trivial set-up and operating costs why outsource? Indeed, the recent GSK developments have the manufacturing capability of a conventional chemical manufacturing plant. The 'Factory in a Fumehood' concept has the real potential to create both jobs (in science and engineering and supporting areas) and wealth in the UK. At a fundamental level ready access to turnkey technologies that embody our reagentless techniques will have a profound impact on the chemical design philosophies of industrial chemists. This in turn will lead to the manufacture of new high value chemical products, creating new IP space. An added benefit will be the creation of commercial opportunities for UK based equipment design and manufacture to support the chemical manufacturing objectives.

Publications

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Donnelly BL (2019) Sequential Photochemical and Prins Reactions for the Diastereoselective Synthesis of Tricyclic Scaffolds. in Angewandte Chemie (International ed. in English)

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Elliott LD (2014) Batch versus flow photochemistry: a revealing comparison of yield and productivity. in Chemistry (Weinheim an der Bergstrasse, Germany)

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Gerry CJ (2016) Real-Time Biological Annotation of Synthetic Compounds. in Journal of the American Chemical Society

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Green R (2015) A Microflow Electrolysis Cell for Laboratory Synthesis on the Multigram Scale in Organic Process Research & Development

 
Description We have successfully developed operating flow photochemical and electrochemical reactors and have demonstrated their potential to synthesise over a kilogram of material in 24h. The electrochemical reactor has been commercialised and a number of units sold to date by Cambridge Reactor Design. A patent application has been filed for the photochemical reactor.
Exploitation Route Once fully developed and implemented the new reactors will enable the scale up of photochemistry and electrochemical synthesis in process and manufacture in pharma and agrochemical industries. The electrochemical reactor will be commercialised on 1/5/16 (see narrative) and the photochemical reactor is currently being patented. The photochemical reactor can contribute to our Photodiversity spin-out company by making large quantities of complex products available for drug discovery library production.
Sectors Agriculture, Food and Drink,Chemicals,Education,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

 
Description 'The Ammonite', a commercial continuous flow electrochemical reactor will be launched by Cambridge Reactor Design on 1/11/16. This reactor was developed by Brown, Green, Harrowven and Pletcher at Southampton University Chemistry Department as a key objective of the award. The successful development of the Firefly represents the first research laboratory scale photochemical reactor capable of producing over a kg of product per day. This capability and products produced by the Firefly photochemical reactor may be of interest to clients through our recently launched Photodiversity spin-out company. A patent was filed in July 2016 and published in Feb 2018 The reactors have been used to investigate some select GSK and AZ processes and further followups are being discussed.
Sector Agriculture, Food and Drink,Chemicals,Pharmaceuticals and Medical Biotechnology
Impact Types Economic

 
Description Cambridge Reactor Design
Amount £33,000 (GBP)
Organisation Cambridge Reactor Design 
Sector Private
Country United Kingdom
Start 09/2016 
End 09/2020
 
Description EPSRC Centre for Doctoral Training in Technology Enhanced Chemical Synthesis
Amount £6,610,129 (GBP)
Funding ID EP/S024107/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 09/2019 
End 03/2028
 
Description Eli Lilly CASE award
Amount £40,000 (GBP)
Funding ID EP/G036764/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 10/2014 
End 12/2017
 
Description Lilly Research Awards Programme
Amount $265,000 (USD)
Organisation Eli Lilly & Company Ltd 
Sector Private
Country United Kingdom
Start  
 
Description Photo-Electro: Transforming Chemical Synthesis, Discovery and Manufacture
Amount £6,486,390 (GBP)
Funding ID EP/P013341/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 02/2017 
End 02/2022
 
Title Development of New Reactors for Chemical Synthesis 
Description This grant has resulted in two new reactors for chemical synthesis. 1. The Ammonite is high capacity (kg/day) flow reactor for electrochemical synthesis and is currently available for sale by Cambridge Reactor Design 2. The Firefly is a high capacity (>kg/day) flow reactor for photochemical synthesis. A Patent has been filed and is currently under assessment. 
Type Of Material Improvements to research infrastructure 
Year Produced 2017 
Provided To Others? Yes  
Impact Commercialisation of Ammonite reactors. Firefly reactor impact on Photodiversity start-up company (Booker-Milburn) 
 
Description Factory in a Fumehood Project 
Organisation AstraZeneca
Department Research and Development AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution Reactor engineering advice. Scale-up of photochemistry and electrochemistry.
Collaborator Contribution Chemistry Face to Face meeting venues. In-house chemistry projects/outsourcing/ reactor trialling
Impact Publications, reactor development, reactor commercialisation, patent preparation
Start Year 2013
 
Description Factory in a Fumehood Project 
Organisation GlaxoSmithKline (GSK)
Department GlaxoSmithKline Medicines Research Centre
Country United Kingdom 
Sector Private 
PI Contribution Reactor engineering advice. Scale-up of photochemistry and electrochemistry.
Collaborator Contribution Chemistry Face to Face meeting venues. In-house chemistry projects/outsourcing/ reactor trialling
Impact Publications, reactor development, reactor commercialisation, patent preparation
Start Year 2013
 
Title Photochemical Reactor 
Description The development of a highly compact and powerful reactor for synthetic organic photochemistry is described, with up to 30% more power efficiency than previous fluorinated ethylene propylene tube reactors. The reactor consists of a succession of quartz tubes connected together in series and arranged axially around a variable power mercury lamp. This compact and relatively simple device can be safely operated in a standard fumehood. 
IP Reference WO2018011550 
Protection Patent application published
Year Protection Granted 2018
Licensed No
Impact Start-up company Photodiversity are looking at licensing the Patent from UoB.
 
Title The Ammonite continuous electrochemical reactor 
Description 'The Ammonite', a commercial continuous flow electrochemical reactor was launched by Cambridge Reactor Design on 1/5/17. This reactor was developed by Brown, Green, Harrowven and Pletcher at Southampton University Chemistry Department as a key objective of the award. 
Type Of Technology New/Improved Technique/Technology 
Year Produced 2017 
Impact 3 (?) Ammonite Reactors have been sold to date 
URL http://www.cambridgereactordesign.com/ammonite/
 
Company Name Photodiversity Limited 
Description A start up company to serve the Pharma, Biotech and Agrochem industries by production of novel and proprietary fragment, focussed and diversity libraries for use in drug discovery, in collaboration and for commercialisation. USP: Photochemically-derived moelcules produced using novel technologies and chemistries. Two part model: Universities of Bristol and Sussex 
Year Established 2015 
Impact Since trading started in November 2015, £125k in sales have been generated and £2.5m in contracts are in place.
 
Description FiaF Presentation to Process Development at Astra Zeneca Macclesfield 18/1/17 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Industry/Business
Results and Impact Lecture to update on AZ staff (not involved in FiaF) of the outputs of the grant
Year(s) Of Engagement Activity 2017
 
Description FiaF Presentation to Process Development at GSK Stevenage 22/4/16 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Presentation of outputs and know-how from grant to ~80 Process Chemists
Year(s) Of Engagement Activity 2016
 
Description Final FiaF Presentation to Process Development at GSK Stevenage 3/2/17 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Industry/Business
Results and Impact Dissemination of final outputs of FiaF grant to a wider GSK audience (with 2 other speakers in a mini-symposium)
Year(s) Of Engagement Activity 2017
 
Description Flow Chemistry Conference Southampton 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact A one day international Flow Chemistry conference organised by Southampton University Chemistry Department as part of their INTEREG CDT-type training program.
Year(s) Of Engagement Activity 2019
 
Description Hans Schutszy Symposium Salford 29/4/16 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Invited speaker at Synthetic Chemistry Symposium held in Honour of late Professor Hans Schutszy
Year(s) Of Engagement Activity 2016
 
Description Invited lecture to Beilstein Conference -Advancing Chemical Synthesis through Automation, Processes and Thinking Conference - Potsdam 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited lecture entitled: "Flow Photochemistry in Organic Synthesis - Generating Molecular Complexity on the Gram and Kilogram Scales"
Year(s) Of Engagement Activity 2017
 
Description Invited lecture to Charles River - Saffron Walden 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Lecture entitled:"Generating Molecular Complexity by Synthetic Photochemistry: From Grams to Kilograms"
Year(s) Of Engagement Activity 2017
 
Description Invited lecture to Evotec - Abbingdon 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Lecture entitled: "Generating Molecular Complexity by Synthetic Photochemistry: From Grams to Kilograms"
Year(s) Of Engagement Activity 2017
 
Description Invited lecture to Flow Chemistry Society Europe 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Lecture entitled:"Complexity Generation by Photochemistry In Flow : From Grams to Kilograms'
Year(s) Of Engagement Activity 2017
 
Description Invited lecture to: Bayer - Photochemistry for the Life Sciences Conferences: The Future is Bright- Dusseldorf 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Lecture entitled: "Generating Molecular Complexity by Synthetic Photochemistry: From Grams to Kilograms"
Year(s) Of Engagement Activity 2017
 
Description Presentation and Research Collaboration Discussion at Syngenta Stein (Switzerland) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact A research lecture on Photochemical Synthesis followed by a round table discussion on future collaboration in this area
Year(s) Of Engagement Activity 2016
 
Description Presentation to Flow Chemistry Europe Cambridge 7/2/17 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited Presentation to two day Flow Chemistry Europe conference in Cambridge 7/2/17
Year(s) Of Engagement Activity 2017
 
Description Presentations to Eli Lilly Chemists on Photochemical Technology and Synthesis 27/4/16 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Delivered 2 lectures to Lilly Chemists (UK) on Photochemical Synthesis and then Photochemical Technology and Methods. Video link to another site in Spain.
Year(s) Of Engagement Activity 2016
 
Description UKASF Invited Lecture 7/11/16 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Invited lecture on Photochemical technology to UK Automated Synthesis Forum
Year(s) Of Engagement Activity 2016