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SSPC Impact Case Study: Small Molecule

SSPC Impact Case Study: Sustainability

Cyanide-free cyanation reactions in continuous flow mode

Project Lead:

Dr Marcus Baumann, University College Dublin

Project Partner:


Areas of Impact:

Environmental, Formulation, Societal

Scientific Domains:

Small Molecule / Drug Substance

The pharmaceutical and fine chemical industry continues to innovate and as new chemical identities (NCEs) are selected, contract and development manufacturing organisations (CDMOs) like Almac need to have an armoury of technologies at their disposal to be able to synthesise these NCEs from gram to potential multi-tonne manufacture efficiently and effectively. Technologies like chemo- and biocatalysis are the ‘norm’ (and indeed are expected). Flow assisted technologies are now becoming more and more prevalent in technical packages that are received from our customers. For many of our customers it is now simply a requirement that flow chemistry is an integrated service offering. As an established player in the CDMO space, Almac must continue to be at the forefront of the current state-of-the-art in this space, in order to utilise the optimal available technology for our customers’ demanding processing needs today, tomorrow and into the future. Almac’s focus is on identifying opportunities for our customers where we can crucially unlock more secure supply chains (given a renewed focus in light of the pandemic), as well as enhancing processing efficiencies, reducing waste and thereby costs as well. We want to access new synthetic routes which may not have been possible using batch processing, making the processes safer and increasing control of quality.

The Partnership

Almac’s collaboration with Dr Baumann commenced in 2020 with a prestigious Science Foundation Ireland (SFI) Industry Fellowship. The Industry Fellowship Programme has significantly enhanced our industry­ academia collaboration through funding of research projects focused on knowledge exchange to drive excellence and innovation throughout Ireland. The project CATCH – derived from continuous biocatalysed chemicals – underlines a commitment to develop new sustainable methodologies that enables the competitive, and environmentally friendly, manufacture of chemical intermediates and active pharmaceutical ingredients (APls) via the synergetic marriage of continuous flow and biocatalytic processes.

Flow chemistry is a disruptive innovation within the pharma industry and the cross disciplinary approach is resulting in new avenues in reaction chemistry. Accessing chemistries, which were previously deemed too difficult or hazardous to scale in batch, has been a major win for flow chemistry, in particular high-energy transformations such as the Curtius rearrangement. The success of the collaboration with Dr Baumann has been disseminated particularly effectively, with six peer reviewed publications since 2020, multiple oral talks, poster presentations in Ireland, UK & Japan and has allowed us to showcase the methodology on a global stage.

The Solution

Despite the challenges of the pandemic, Almac Sciences and the link with Dr Baumann and UCD has strengthened, indeed we are actively pursuing new avenues to develop this further. This includes other Irish opportunities (such as IRC fellowships), UK-Ireland programmes (where we are forging an introduction between QUB and UCD) and wider into the EU mechanisms under Horizon Europe (e.g. Marie Curie Fellowships and Doctorates). We have also just announced our further collaboration through the SFI Research Centre for Pharmaceuticals (SSPC) over the next 4 years to investigate flow­ based oxidation processes and additionally a SFI Frontiers in collaboration with Cornell University for 2 PhD’s and 1 Postdoc is set to commence before year-end.

Building networks with academic groups and equipment manufacturers have been imperative for the development of flow capabilities at Almac Sciences. Academic collaborations are essential to securing a pipeline of competent, expertly trained flow chemists with a crucial understanding of industry requirements. Almac has identified that it is critical that academic institutions and industry engage, to tailor undergraduate chemistry courses to ensure that continuous flow is a core discipline (akin to that of biocatalysis for example). The so-called CDMO “cultural change” will be accelerated if students are already exposed to new technologies and novel strategies for synthesis, building a deep understanding of the core principles.

The Impact:

Dr Baumann has a strong focus and desire to maximise impact of world-class knowledge developed within Irish research bases and to share this with industrial collaborators. The innovations demonstrated by the collaboration showcases the world class scientific expertise present in the island of Ireland enabling us to compete at the highest level with our global counterparts for innovation, production solutions and cost competitive manufacture, now and in the future. Biocatalysis and flow chemistry are truly 21st century technologies readily available to all chemists worldwide. It brings many benefits, including new route options, process simplification, increased speed of delivery and no heavy metals to control. Through the successful application of technology solutions, Almac and UCD are truly at the heart of the necessary drive for green pharmaceutical manufacture.

Research References:

Interrupted Curtius Rearrangements of Quaternary Proline Derivatives: A Flow Route to Acyclic Ketones and Unsaturated Pyrrolidines
Baumann, M.; Moody, TS; Smyth, M. Wharry, S. Oct 15 2021 | JOURNAL OF ORGANIC CHEMISTRY 86 (20), pp.14199-14206.

Evaluating the Green Credentials of Flow Chemistry towards Industrial Applications
Baumann, M.; Moody, TS; Smyth, M. Wharry, S. Nov 3 2021 | Jun 2021 (Early Access) | SYNTHESIS-STUTTGART 53 (21) , pp.3963-3976.

Tandem Continuous Flow Curtius Rearrangement and Subsequent Enzyme-Mediated Impurity Tagging
Baumann, M.; Leslie, A; Moody, TS; Smyth, M. Wharry, S
Mar 19 2021 | ORGANIC PROCESS RESEARCH & DEVELOPMENT 25 (3) , pp.452-456

Coupling biocatalysis with high-energy flow reactions for the synthesis of carbamates and beta-amino acid derivatives
Leslie, A; Moody, TS; Smyth, M. Wharry, S; Baumann, M

A Perspective on Continuous Flow Chemistry in the Pharmaceutical Industry
Baumann, M.; Moody, TS; Smyth, M.; Wharry, S
Oct 16 2020 | ORGANIC PROCESS RESEARCH & DEVELOPMENT 24 (10), pp.1802-1813.

Overcoming the Hurdles and Challenges Associated with Developing Continuous Industrial Processes
Baumann, M.; Moody, TS; Smyth, M.; Wharry, S. Dec 31 2020 | Oct 2020 (Early Access) | EUROPEAN JOURNAL OF ORGANIC CHEMISTRY 2020 (48), pp.7398-7406.

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