Periodic Reporting for period 3 - H-CCAT (Solid Catalysts for activation of aromatic C-H bonds)
Reporting period: 2020-01-01 to 2021-06-30
C-H activation on aromatic compounds, and develops innovative procedures to produce and shape these catalytic materials in an economically and environmentally beneficial way. The catalysts will allow sustainable production of pharmaceutically relevant compounds or other specialty chemicals. The targeted reactions comprise:
• (i) Oxidative C-H/C-H couplings, in which an organic molecule is linked via its C-H bond to an aromatic reactant with another C-H bond, and
• (ii) Non-oxidative C-H/C-X couplings, in which an organic molecule with a hetero-atom (X) is coupled to the C-H bond of the aromatic reactant.
• Depending on the reaction, catalysts are selected and developed starting from two material classes:
• (i) Metal-Organic Framework (MOF) materials: these are porous, crystalline and sometimes flexible hybrid materials, made from an inorganic metal-(oxo) cluster (e.g. Zr, Al, Fe,...) and organic linkers. These MOFs will be used for C-H/C-H coupling and for C-H/C-X coupling;
• (ii) Porous hybrid silicas, which are hybrid materials made from a silicate scaffold with organic surface groups, and which acquire porosity by templating with organic surfactant micelles. These will be used for C-H/C-X coupling.
• The active catalytic sites will be designed in these porous hybrid host materials using combinations of active metals and organic ligands, all linked with robust bonds to the host matrix with engineered porosity. Shaping processes will be developed in function of catalytic demonstration at pilot scale. Shaping will be up-scaled to pilot capacities to demonstrate the relevance and performance of the obtained materials in terms of properties (activity, absence of metal leaching, selectivity), reproducibility, quality control and costs and benefits for industrial applications in pharmaceutical production. Greening of the reactants, solvents and processes will be studied, strictly avoiding toxic compounds, and LCA will be performed to demonstrate the environmental benefits both in materials preparation and in pharmaceuticals production.
Material robustness. Rather than classical polymers (e.g. polystyrene based ones) H-CCAT uses robust materials, with strong Si-C and Si-O-Si bonds in the hybrid silica, or with the particularly stable coordinative bonds in Zr4+ and Cr3+ MOF materials. These readily withstand temperatures ≥ 150°C, which is the required temperature for e.g. the dehydrogenative processes.
The academic partners are world-leading groups in the field of catalysis and nanoporous materials. This will allow to go well beyond the state-of-the-art and to achieve important breakthroughs. The (industrial) partners are key players in the value chain; this will decrease the time-to-market for the new catalysts and speed up adoption of the catalytic processes in pharmaceutical production.
Some of the key molecules for which J&J could use C-H activation technology include Rilpivirine in the first place, and also Ibrutinib and VX-787. All the key molecules are APIs with a massive societal and economic importance, with potentially 107-108 treatments per year worldwide for Rilpivirine and VX-787, or even more.
H-CCAT will overcome the main bottlenecks in current API production.
First, the catalysts of H-CCAT will reach much higher TON, because of their intrinsic resistance against deactivation; consequently, they can also be used at higher temperatures (e.g. for C-H/C-X coupling), which raises TOF. In fact, other factors than catalyst cost then start to dominate process economics, both regarding cost of goods and regarding cost of operation. In the synthesis of a typical API, overall costs are ~ equally split in goods and raw materials (50%) and operational costs (50%). These can be significantly reduced by reducing the cost of goods and reducing operational costs by reaching higher step economy and reducing the number of unit operations by making the process heterogeneous. Additionally, H-CCAT will reinforce its positive economic benefits through the minimisation of downtime of the plants and flexibilisation of the production (with respect to temporal planning).
Finally, H-CCAT will have several positive environmental impacts:
1) Synthesis via C-H/C-H coupling or C-H/C-X coupling will produce significantly less waste (halides, borates, …), or even no waste at all (for the C-H/C-H coupling under oxygen). 2) Efficient metal immobilization strongly reduces the production of metal-contaminated wastes (e.g. liquids), and also makes the APIs much safer for the patient to ingest;
3) Some of the more toxic intermediates can be avoided.
4) H-CCAT will devote specific efforts to realize flow, reducing the environmental impact of the synthesis.
5) Preference will be given to use less harmful reagents and solvents.
The positive environmental impacts will be demonstrated through an LCA assessment.