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.
Organisations
- University of Bristol, United Kingdom (Lead Research Organisation)
- AstraZeneca plc (Collaboration)
- GlaxoSmithKline (GSK) (Collaboration)
- Syngenta Ltd, United Kingdom (Project Partner)
- GlaxoSmithKline, United Kingdom (Project Partner)
- Novartis Pharma AG, Switzerland (Project Partner)
- AstraZeneca plc, United Kingdom (Project Partner)
Publications

Al-Hadedi AAM
(2022)
A flow electrochemistry-enabled synthesis of 2-substituted N-(methyl-d)piperidines.
in Journal of labelled compounds & radiopharmaceuticals

Bennett RM
(2021)
A new mode of cyclobutenedione ring opening for the synthesis of 2-oxobut-3-enamides and tetrasubstituted furans.
in Chemical communications (Cambridge, England)

Blackham EE
(2016)
Combining photochemistry and catalysis: rapid access to sp3 - rich polyheterocycles from simple pyrroles.
in Chemical science

Donnelly B
(2019)
Sequential Photochemical and Prins Reactions for the Diastereoselective Synthesis of Tricyclic Scaffolds
in Angewandte Chemie International Edition

Elliott L
(2016)
A Small-Footprint, High-Capacity Flow Reactor for UV Photochemical Synthesis on the Kilogram Scale
in Organic Process Research & Development

Elliott L
(2018)
Using batch reactor results to calculate optimal flow rates for the scale-up of UV photochemical reactions
in Reaction Chemistry & Engineering

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

Elliott LD
(2020)
Rational Design of Triplet Sensitizers for the Transfer of Excited State Photochemistry from UV to Visible.
in Journal of the American Chemical Society

Elliott LD
(2019)
Photochemically Produced Aminocyclobutanes as Masked Dienes in Thermal Electrocyclic Cascade Reactions.
in Organic letters

Folgueiras-Amador A
(2019)
The influence of non-ionic surfactants on electrosynthesis in extended channel, narrow gap electrolysis cells
in Electrochemistry Communications
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 | 08/2016 |
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 | 08/2019 |
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 | 09/2014 |
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 | A photoreactor is described, the reactor including a first end piece, a second end piece, a plurality of elongate reactor tubes extending between the first end piece and the second end piece, the reactor tubes being axially distributed so as to define a lamp receiving recess, and two or more fluid connectors connecting at least three of the reactor tubes. Usually, the reactor will include a coolant jacket surrounding the reactor tubes, the coolant jacket allowing circulating coolant to flow around and over the reactor tubes. Also described in a photochemical process using the photoreactor. The photoreactor may be used with high power lamps. |
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 |