Development of a Practical Synthesis of Toll-like Receptor Agonist PF-4171455: 4-Amino-1-benzyl-6-trifluoromethyl-1,3-dihydroimidazo [4,5-c] pyridin-2-one

• Published in: Organic process research & development Vol. 15; no. 4; pp. 788 - 796
• Main Authors: Adam, Fiona M, Bish, Gerwyn, Calo, Frederick, Carr, Christopher L, Castro, Nieves, Hay, Duncan, Hodgson, Paul B, Jones, Peter, Knight, Craig J, Paradowski, Michael, Parsons, Gemma C, Proctor, Katie J. W, Pryde, David C, Rota, Filippo, Smith, Mya C, Smith, Nicholas, Tran, Thien-Duc, Hitchin, James, Dixon, Rachel
• Format: Journal Article
• Language: English
• Published: American Chemical Society 15.07.2011
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/op200021a

The development and implementation of a scalable process for the manufacture of the Toll-like receptor (TLR7) agonist PF-4171455 (1) is described. Initial routes used to synthesise 1 in milligram quantities were unsuitable for large-scale synthesis to provide bulk material. As part of the transfer between Medicinal Chemistry and Research-API, collaboration provided a fit for purpose route for the kilo-scale synthesis of 1. Key aspects of the synthesis included (i) a safe and practical synthesis of a key nitropyridone intermediate 7 over four steps, (ii) a sequential regioselective chlorination to selectively functionalise 7 and (iii) use of a carbamate as a tethered carbonyl group, allowing an efficient regiospecific synthesis of 1.