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Blog Post: Scaling up is no small feat: the challenges with industrial commercialization of Pd-catalysts and ligands

  • Time of issue:2022-01-20 20:16

Blog Post: Scaling up is no small feat: the challenges with industrial commercialization of Pd-catalysts and ligands

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Organometallic chemistry has been crucial to the evolution of cross-coupling reactions over the past 20 years, largely due to advances in ancillary ligand design. In this four-part blog series, we talk about the rise of bulky adamantyl-containing phosphine ligands and their suitability for industrial applications. For our first blog, we give an overview of Pd-catalysts and ligand design for industry, and the challenges of scale-up.

 

The field of Pd-catalyzed C-C and C-X bond formation reactions has progressed remarkably over the past few decades. In fact, two of the most frequently used synthetic tools to produce materials for drug discovery programmes are the Suzuki-Miyaura reaction and aromatic nucleophilic substitutions. However, there are limitations when translating these methodologies from research labs to industrial applications.

Developing a production route – what needs to be considered?

While showing excellent promise for large-scale applications in industry, a catalyst or ligand for production processes needs to meet certain requirements to be appropriate for this use:

1) It should ideally be free of IP that belongs to another institution.

2) All the reagents must be readily available in bulk to ensure that the supply chain is secure even when the process is further scaled up.

3) The cost needs to be minimised. However, this may not be a deterrent if a particular process is very efficient based on other parameters such as E-factor (sustainability), chemo- and/or stereoselectivity.

There are already effective processes in place, but researchers are looking at new catalytic systems to expand previously unexplored chemical space and to facilitate more cost-effective scale-up.

Developing new catalysts and ligands

There are hundreds of existing ligands and catalytic systems for cross-coupling reactions. Unfortunately, it isn’t ‘one size fits all’ when it comes to catalysis. This means it is important to invest time into finding the optimum catalyst/ ligand and reaction conditions for each specific reaction and substrate combinations.

There are some privileged ligands (those acting as a good starting point by offering a high chance of success, giving at least a small amount of any desired cross-coupling product). Innovative ligands are always needed for optimal product synthesis, and new ligands are continuously reported year on year. However, very few survive the process of elimination to eventually make it to commercial scale.

Commercialization of catalysts and ligands

While a catalyst may work brilliantly at a small scale, commercializing a catalyst or ligand requires collaboration. For successful scale-up, academia and relevant companies including pharma-, agro- and fine chemicals need to communicate effectively. Ligand and catalyst manufacturers can help here by enabling small-scale technologies to become viable for manufacturing – but how do we determine which ones are suitable for commercialization?

There are many intertwining factors involved in identifying suitable catalysts and ligands for scale:

  • Is there a demand from relevant companies for a particular ligand or catalyst?
  • Is there a supplier for this ligand to secure the supply chain even when ramping up production?
  • If there is no ligand supplier, is any catalyst/ligand manufacturer able to develop it into a product?
  • When developed, can it be supplied at a cost that makes the eventual process for its application commercially viable?

 

If a catalyst or ligand can meet these requirements, then it shows good promise for effective commercialization.

Adamantyl-containing ligands – a future in manufacturing?

The adamantane scaffold, with its three fused cyclohexane rings, could be a potential candidate for commercialization of new ligands and catalysts. Compared to the privileged phosphine ligands, adamantane is extremely bulky, which can show interesting effects in catalytic systems. In 2016, Williams and co-workers reviewed adamantyl-containing ligands and catalysts, showing their promise.

So, there are many considerations when deciding which ligands and catalysts are appropriate for scale-up and wider use in industry. While new catalysts and ligands are being constantly developed, very few make it past all the barriers to commercialization. In our next blog, we’ll be discussing physical factors such as steric bulk that make a promising ligand. Additionally, we’ll highlight how the relatively simple large-scale preparation of the starting material adamantane improves the prospects of adamantyl-containing ligands in industry.  

Download our white paper here to learn more about advanced adamantyl-containing phosphine ligands for challenging cross-coupling reactions.

 


1 J. Boström, D. G. Brown, R. J. Young, G. M. Keserü, Nat. Rev. Drug Discov. 2018, 17, 709-727.

2 Selected privileged ligands: a) Amphos: A. S. Guram, A. O. King, J. G. Allen, X. Wang, L. B. Schenkel, J. Chan, E. E. Bunel, M. M. Faul, R. D. Larsen, M. J. Martinelli, P. J. Reider. Organic Lett., 2006, 8, (9),1787-1789; b) PtBu3: K. H. Shaugnessy, Curr. Org. Chem. 2020, 24, 231-264; c) Buchwald ligands: B. T. Ingoglia, C. C. Wagen, and S. L. Buchwald, Tetrahedron 2019, 75(32), 4199- 4211; d) ferrocene ligands: S. Dey, R. Pietschnig, Coord. Chem. Rev. 2021, 437, 213850.

3 K. A. Agnew-Francis, C. M. Williams, Adv. Synth. Catal. 2016, 358, 675-700.