Date: 28 November 2024 | Category: News
Flow chemistry facilitates scale-up to 200 mmol, maintaining excellent stereoselectivity and yields
Martins Oderinde, Rajender Nallagonda and co-workers from the Bristol Myers Squibb Small Molecule Discovery Chemistry group have successfully used the Vapourtec UV-150 photochemical flow reactor to achieve stereoselective metallaphotoredox decarboxylative arylation. This set-up was used to truncate the synthesis of LNP023, an FDA-approved drug, from a reported 12-step racemic route to a 4-step enantioselective route.
We are grateful to Dr Martins Oderinde for the following introduction to this excellent research.
Despite the potential of Ni-metallaphotoredox decarboxylative arylation methodology as an enabling cross-coupling tool in industrial research laboratories, the difficulty in scaling up and providing multigram quantities of materials required for preclinical and early clinical studies has limited its adoption in process development and manufacturing. However, in a newly published article in ACS Catal. 2024, 14, 13439-13450, M. S. Oderinde and co-workers at Bristol Myers Squibb used the Vapourtec UV-150 photoreactor to scale up this reaction on a 200 mmol scale in a continuous flow mode. The Vapourtec UV-150 flow photoreactor overcame the poor light penetration that precluded scale-up in batch mode. The operational simplicity of the Vapourtec UV-150 allowed the industrial chemists to rapidly optimize the variable reaction parameters such as light wavelength, temperature, solvent, and residence time. Secondary reactions that lead to undesired side-products due to prolonged irradiation of reactants and product mixture in batch mode (flask reactions) were also avoided by carrying out the reaction in the flow photoreactor, where the product was collected and shielded from excessive light irradiation. The expedited 4-step synthesis of Iptacopan, LNP023, an FDA-approved drug, was also achieved by scaling up the key decarboxylative cross-coupling step on the Vapourtec UV-150 flow photoreactor. Collectively, this report demonstrates the power of the Vapourtec UV-150 instrument as a reliable flow platform for scaling up Ni-metallaphotoredox reactions and other photochemical processes.
In this work, the use of the UV-150 flow photochemical reactor:
- Allowed precise control of reaction conditions
- Facilitated screening of conditions (wavelength of light, temperature, residence time)
- Increased material throughput
- Provided excellent yield and diastereoselectivity reliably, even on 200 mmol (51.5 g) scale
References:
[1] Unveiling the Stereoselectivity Aspects of Metallaphotoredox Decarboxylative Arylation (R. Nallagonda, R. Quan, L. Grant, C. Jorge, S. Yip, D.-R. Wu, T. G. M. Dhar, J. Kempson, A. Mathur, and M. S. Oderinde, ACS Catalysis, 2024, 14, 13439–13450). https://doi.org/10.1021/acscatal.4c03818
[2] At the Speed of Light: The Systematic Implementation of Photoredox Cross-Coupling Reactions for Medicinal Chemistry Research. (N. J. Gesmundo, A. J. Rago, J. M. Young, S. Keess, Y. Wang, J. Org. Chem. 2024, ASAP). https://doi.org/10.1021/acs.joc.3c02351
[3] Decarboxylative Arylation of α-Amino Acids via the Merger of Photoredox and Nickel Catalysis. (Z. Zuo, H. Cong, W. Li, J. Choi, G. C. Fu, D. W. C. MacMillan, J. Am. Chem. Soc., 2016, 138, 6, 1832–1835). https://doi.org/10.1021/jacs.5b13211
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