期刊
ORGANIC PROCESS RESEARCH & DEVELOPMENT
卷 6, 期 6, 页码 767-772出版社
AMER CHEMICAL SOC
DOI: 10.1021/op0200468
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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)nicotin- amide 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, and (iii) the introduction of process modifications to allow for the use of teratogenic 2-methoxyethanol, as both reagent and solvent, in the penultimate process step.
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