The Process Development of a Scaleable Route to the PDE5 Inhibitor UK-357,903
| Autor: | Peter J. Dunn, Philip Charles Levett, Albert Shaw Wood, Farhat Hussain, John Draper, Gordon Ward, David J. Dale, Hughes Michael Leslie |
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| Rok vydání: | 2002 |
| Předmět: | |
| Zdroj: | Organic Process Research & Development. 6:767-772 |
| ISSN: | 1520-586X 1083-6160 |
| DOI: | 10.1021/op0200468 |
| Popis: | A case history is outlined for the development of a scaleable route to the drug candidate UK-357,903. Despite the partial structural similarities to those of sildenafil (Viagra), the introduction of the central pyridine moiety within UK-357,903 had a significant impact on the commercial process. In particular, the triply activated 2-alkoxypyridyl moiety of UK-357,903 is much more susceptible to nucleophilic attack than the 2-ethoxyphenyl moiety of sildenafil, necessitating the development of new chemistry. Particular items of note are (i) the new six-step route to the advanced 2-ethoxy-5-(4-ethylpiperazinylsulfonyl)nicotinic acid intermediate and the subsequent telescoping to a two-pot process, (ii) the telescoping of the two steps from N-[3-carbamoyl-5-ethyl-1-(2-pyridylmethyl)-1H-pyrazol-4-yl]-2-ethoxy-5-(4-ethyl-1-piperazinylsulfonyl)nicotinamide to UK-357,903 to a single step, with the additional use of a hydroxide trapping agent to give an ambient pressure process yielding clinical quality product, a... |
| Databáze: | OpenAIRE |
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