Date: 5 December 2024 | Category: News
Authors: K. Okamoto, T. Ueno, Y. Hato, Y. Kawaguchi, T. Hakogi, S. Majima, T. Ohara, M. Hagihara, N. Tanimoto, and T. Tsuritani
Okamoto and co-workers, from the Technology Development Division at Shionogi Pharma & Co., based in Japan, have used the Vapourtec UV-150 photochemical reactor within the Vapourtec R2 system to undertake photocatalytically-medicated decarboxylation, the final step in their improved synthesis of the drug baloxavir marboxil (BXM) (1). In particular, the new route has two fewer steps than the current approach, and overall yield is improved from 12% to 48%.
Avoiding lengthy chiral separation by using L-serine
Baloxavir marboxil, BXM, is an orally bioavailable prodrug that shows broad-spectrum inhibitory activity against seasonal, avian, and swine influenza viruses in vitro (2) that was approved by the FDA for use in October 2018. The current route to relies upon optical resolution to remove the undesired enantiomer, which requires installation and removal of a chiral auxiliary and results in losses of approximately half the material (3, 4). The final step of Okamoto and co-workers’ new approach relies upon photoredox decarboxylation, which removes the carboxylic acid residue installed through use of L-serine as a chiral starting material. The use of L-serine was key, as it facilitated selective cyclisation and attack of the Si face, giving the desired (R) conformation.
Flow facilitates scale-up
The photocatalytic step was initially optimised in batch, (5), where it was found that solvent, base, disulfide and photocatalyst all had substantial impact upon the reaction outcome, with some combinations halting the reaction entirely. Once optimal conditions were identified, the reaction was converted to flow. The use of flow provided significant advantage and reaction times were significantly reduced; 40 minutes residence time in flow versus 8 h in batch. In addition, the reported scale was larger in flow and 1.20 mmol of starting material was processed compared with 0.20 mmol starting material in batch.
Flow photochemistry: excellent yields, reliable outcomes
In this work, the use of a flow photoreactor significantly reduced reaction times and allowed more material to be processed, by virtue of the uniform reaction conditions. For further information about the photochemical UV-150 reactor and how it is revolutionising photocatalysis, please contact us.
References:
[1] Stereoselective Synthesis of Baloxavir Marboxil Using Diastereoselective Cyclization and Photoredox Decarboxylation of L‑Serine. (K. Okamoto, T. Ueno, Y. Hato, Y. Kawaguchi, T. Hakogi, S. Majima, T. Ohara, M. Hagihara, N. Tanimoto, and T. Tsuritani, J. Org. Chem., 2024, 89, 9937–9948). https://doi.org/10.1021/acs.joc.4c00799
[2] Baloxavir marboxil, a novel cap-dependent endonuclease inhibitor potently suppresses influenza virus replication and represents therapeutic effects in both immunocompetent and immunocompromised mouse models. (K. Fukao, Y. Ando, T. Noshi, M. Kitano, T. Noda, M. Kawai, R. Yoshida, A. Sato, T. Shishido and A. Naito, Plos One, 2019). https://doi.org/10.1371/journal.pone.0217307
[3] Substituted Polycyclic Pyridone Derivative and Pharmaceutical Composition Containing Prodrug Thereof. (M. Kawai, K. Tomita, T. Akiyama, A. Okano, and M. Miyagawa, WO2018030463A1, 2018). https://patents.google.com/patent/WO2018030463A1/en
[4] Producing Substituted Polycyclic Pyridone Derivative and Crystal of Same. (S. Shibahara, N. Fukui, T. Maki and K. Anan, WO2017221869A1, 2022). https://patents.google.com/patent/WO2017221869A1/en
[5] Hydrodecarboxylation of Carboxylic and Malonic Acid Derivatives via Organic Photoredox Catalysis: Substrate Scope and Mechanistic Insight. (J .D. Griffin, M. A. Zeller and D. A. Nicewicz, J. Am. Chem. Soc., 2015, 137 (35), 11340−11348). https://doi.org/10.1021/jacs.5b07770
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