Catalyst Cascade Reactions in ‘One-Flow’ within a Compartmentalized, Green-Solvent ‘Digital Synthesis Machinery’ – End-to-End Green Process Design for Pharmaceuticals

Project Information

One-Flow

Grant agreement ID: 737266

DOI

10.3030/737266

Project closed

EC signature date 13 December 2016

Start date 1 January 2017

End date 30 June 2021

Funded under

• EXCELLENT SCIENCE - Future and Emerging Technologies (FET)

Total cost

€ 3 896 827,50

EU contribution

€ 3 896 827,50

Coordinated by

TECHNISCHE UNIVERSITEIT EINDHOVEN
Netherlands

Periodic Reporting for period 2 - One-Flow (Catalyst Cascade Reactions in ‘One-Flow’ within a Compartmentalized, Green-Solvent ‘Digital Synthesis Machinery’ – End-to-End Green Process Design for Pharmaceuticals)

Reporting period: 2019-01-01 to 2021-06-30

Summary of the context and overall objectives of the project

The aim of ONE-FLOW was to create a technological equivalent of the biochemical assembly lines in nature. From a process engineering point of view this required the adaptation of continuous processing conditions that allow the use of 1 solvent, 1 temperature, 1 pressure and fine-tuned synthesis and control. In order to achieve these ambitious goals we set up a program that consisted out of the following work packages:
WP1: ‘The Compartmentalized Smart Factory’. We developed and introduced compartmentalization approaches for flow: (i) polymersomes composed of block copolymers, (ii) Pickering emulsions stabilized by solid particles, (iii) structured microfluidic multiphases, and (iv) chemisorption-anchored catalysts.
WP2: ‘The Green-Solvent Spaciant Factory’. Pharmacy likes to largely minimize use of non-green solvents and has banned the ones with environmental damage. Our approach was to use functional green solvents, which allowed to open and close interim reaction spaces alike reactors do, but more elegantly; thus, being named spaciants.
WP3: ‘The Systemic Operations Factory’. If full orthogonality is provided alike in the (bio )chemical assembly line, unit operations of chemical engineering virtually vanish to a systemic operation in the flow cascade. We envisioned the ultimate level of harmonization to be continuous “One-Flow” processing.
WP 4: ‘The Digital Machine-to-Machine Factory’. The “Internet of Chemical Things” is poised to alter the landscape of chemical synthesis, enabling simple machine-to-machine data transfer and relegation of process monitoring to central computer systems under the oversight of chemists.
WP5: ‘The Fully Continuous Integrated Factory’. To ensure right process selection and to avoid dead-end scenarios, a process-design evaluation was performed, using life-cycle assessment and cost analysis to monitor sustainability. This together with a ‘critical process parameter map’ resulted in a foundation towards a commercial platform technology.

With the ONE-FLOW programme we demonstrated a novel approach in chemical synthesis by executing multiple processes in a continuous flow system without intermediate work up steps. The benefits for society of this approach are that processes are intensified and hence require less chemicals (such as extraction solvents) and energy (for intermediate purification). This contributes to a greener production of fine chemicals. We have shown this concept for four important intermediates used by the pharmaceutical industry. Furthermore, using smart compartmentalization techniques, we were able to enlarge the process window, which allowed novel chemical pathways which are not possible in classical batch type processes. The achieved innovations were a result of the integrative approach regarding reaction, compartmentalization and reactor design, facilitated by automation.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Our ONE FLOW concept was tested with the multistep synthesis of four pharmaceutically relevant compounds, which all had the necessity to compartmentalize subsequent reaction steps. The feasibility of ONE-FLOW was fully demonstrated for two of the four compounds. The other two compounds were especially explored to investigate the scope of the compartmentalization strategies we have implemented. The general applicability of the concept was demonstrated also for the production of sialic acid derivatives, and the ONE-FLOW synthesis of Rufinamide.

The second innovative aspect was compartmentalization. Segmented flow systems were developed in which liquid droplets were effectively separated by interspersed gas droplets. The level of control makes this process directly translatable to flow production. The spaciant flow factory, in which solubility of the reaction components is highly controlled and can be effectively varied throughout the process, was instrumental for the execution of the synthesis of Rufinamide. As the solvent of choice can be efficiently selected via computational methods, this process holds great promise for process intensification.
We successfully explored Pickering emulsions in flow. These particle-stabilized emulsions are very stable, but can, under the right circumstances be efficiently separated, allowing for effective catalyst separation and recycling. This was also the case for newly developed catalytic nanoparticles, crosslinked enzyme nano-aggregates (nCLEnA). The in-depth life cycle analysis of this process indicated how many recycling steps are required to make this form of compartmentalization economically feasible.
The final level of innovation was in the area of process control and integration, using microprocessors for control and reaction monitoring. Through a workshop and through development of the system, even more interactions were achieved. Our open-access Tutored Discourse (10.1039/C9RE00407F) further allows all interested parties to use the machine-assisted approach to aid their research. Furthermore, using the automated process control in flow, we were able to identify novel processing windows and therefore could synthesize classes of molecules that were not attainable by classic batch chemistry. Finally we constructed tailor made ONE-FLOW reactors. Using a 3D printed steel reactor, we could successfully execute part of the synthesis of one of our pharmaceutical intermediates.

The research activities have led to the publication of 34 open access research papers. Furthermore, we have presented the results of the program at a wide range of conferences (45 oral and poster presentations. Specifically worth mentioning is the dedicated session on the ONE-FLOW concept held at the 2019 Dutch chemistry conference CHAINS.
Dissemination to the non-scientific public was addressed by articles in the popular press. To achieve this more effectively, the ONE-FLOW consortium participated in the Future Tech week and prepared a youtube video explaining the ONE-FLOW concept (https://www.youtube.com/watch?v=oV0dDMgq0FA&feature=youtu.be). Also, via our website we have informed the general audience about our program.
The ONE FLOW concept was brought under the attention to many companies via work shops, consultations and site visits. A brochure with the main highlights on innovation within ONE FLOW was prepared and distributed among pre-selected company contacts. As part of the dissemination and innovation potential, Microinnova constructed a ONE-FLOW prototype reactor made by 3D printing in steel. This prototype can be used to demonstrate to companies in the field of the fine chemicals and pharmaceuticals sectors how continuous production with in-flow work up can be achieved.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The integrative approach followed in the ONE FLOW program has shown that incompatibilities in reaction sequences can be overcome by smart compartmentalization. Furthermore, continuous flow is extremely suited for fast automation procedures. It also allows chemists to be more focused on the design of the molecules rather than having to spend most of their time in optimizing their syntheses. In combination with reactor design, factories of the future can be created which are more flexible in their usage and are green. This will tremendously increase the innovative potential of the chemical industry, which will be a great profit for society as it will lead to a faster development of useful molecules. We expect that ONE FLOW contributes to the gradual transition from batch to flow in the fine chemical industry

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