A-71497

Chemical Name: (?-7-(3-Aminopyrrolidin-1-yl)-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxaldehyde hydrochloride
CAS No. 134762-03-1
项目整合开发状态: Preclinical
项目研究机构: Abbott (Originator)
合成路线: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.