【药物名称】A-71497
化学结构式(Chemical Structure):
参考文献No.114586
标题:Synthesis and biological properties of A-71497: A prodrug of tosufloxacin
作者:Swanson, R.N.; Pernet, A.G.; Marsh, K.C.; Chu, D.T.W.; Lico, I.M.; Plattner, J.J.
来源:9th Int Symp Fut Trends Chemother 1990,21
合成路线图解说明:

Treatment of ethyl 2,6-dichloro-5-fluoronicotinylacetate (I) with ethyl orthoformate in refluxing acetic anhydride and then with 2,4-difluoroaniline in methylene chloride at room temperature gives the enaminoketo ester derivative (II). Cyclization of (II) with sodium hydride in THF gives ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (III). Hydrolysis of (III) with hydrochloric acid yields 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (IV). Condensation of (IV) with 3-tert-butoxycarbonylaminopyrrolidine in pyridine in the presence of triethylamine yields 7-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (V). Sodium borohydride reduction of (V) in methanol followed by decarboxylation in the presence of toluenesulfonic acid yields the 7-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,2,3,4-tetrahydro-4-oxo-1,8-naphthyridine (VI). Acylation of (VI) with ethyl formate in THF in the presence of NaH and a catalytic amount of ethanol yields the 7-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-1-(2,4-difluorophenyl)-6-fluoro-3-formyl-4-hydroxy-1,2-dihydro-1,8-naphthyridine (VII). Oxidation of (VII) with manganese dioxide in methanol gives 7-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-1-(2,4-difluorophenyl)-6-fluoro-3-formyl-1,4-dihydro-4-oxo-1,8-naphthyridine (VIII). Hydrolysis of (VIII) in hydrochloric acid and dioxane gives A-71497.

参考文献No.147154
标题:A-71497
作者:Chu, D.T.W.
来源:Drugs Fut 1990,15(12),1171
合成路线图解说明:

Treatment of ethyl 2,6-dichloro-5-fluoronicotinylacetate (I) with ethyl orthoformate in refluxing acetic anhydride and then with 2,4-difluoroaniline in methylene chloride at room temperature gives the enaminoketo ester derivative (II). Cyclization of (II) with sodium hydride in THF gives ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (III). Hydrolysis of (III) with hydrochloric acid yields 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (IV). Condensation of (IV) with 3-tert-butoxycarbonylaminopyrrolidine in pyridine in the presence of triethylamine yields 7-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (V). Sodium borohydride reduction of (V) in methanol followed by decarboxylation in the presence of toluenesulfonic acid yields the 7-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,2,3,4-tetrahydro-4-oxo-1,8-naphthyridine (VI). Acylation of (VI) with ethyl formate in THF in the presence of NaH and a catalytic amount of ethanol yields the 7-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-1-(2,4-difluorophenyl)-6-fluoro-3-formyl-4-hydroxy-1,2-dihydro-1,8-naphthyridine (VII). Oxidation of (VII) with manganese dioxide in methanol gives 7-(3-tert-butoxycarbonylaminopyrrolidin-1-yl)-1-(2,4-difluorophenyl)-6-fluoro-3-formyl-1,4-dihydro-4-oxo-1,8-naphthyridine (VIII). Hydrolysis of (VIII) in hydrochloric acid and dioxane gives A-71497.

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