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
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- 作者：Fiona M. Adam ; Gerwyn Bish ; Frederick Calo ; Christopher L. Carr ; Nieves Castro ; Duncan Hay ; Paul B. Hodgson ; Peter Jones ; Craig J. Knight ; Michael Paradowski ; Gemma C. Parsons ; Katie J. W. Proctor ; David C. Pryde ; Filippo Rota ; Mya C. Smith ; Nicholas Smith ; Thien-Duc Tran ; James Hitchin ; Rachel Dixon
- 刊名：Organic Process Research & Development
- 出版年：2011
- 出版时间：July 15, 2011
- 年：2011
- 卷：15
- 期：4
- 页码：788-796
- 全文大小：875K
- 年卷期：v.15,no.4(July 15, 2011)
- ISSN：1520-586X
文摘
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.