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【结 构 式】

【分子编号】31223

【品名】tert-butyl 1-[8-(2,4-difluorophenyl)-3-fluoro-6-formyl-5-hydroxy-7,8-dihydro[1,8]naphthyridin-2-yl]-3-pyrrolidinylcarbamate

【CA登记号】

【 分 子 式 】C24H25F3N4O4

【 分 子 量 】490.4822696

【元素组成】C 58.77% H 5.14% F 11.62% N 11.42% O 13.05%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(VII)

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.

1 Swanson, R.N.; Pernet, A.G.; Marsh, K.C.; Chu, D.T.W.; Lico, I.M.; Plattner, J.J.; Synthesis and biological properties of A-71497: A prodrug of tosufloxacin. 9th Int Symp Fut Trends Chemother 1990, 21.
2 Chu, D.T.W.; A-71497. Drugs Fut 1990, 15, 12, 1171.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 19462 2,4-difluoroaniline; 2,4-difluorophenylamine;2,4-Difluoro-benzenamine;1-Amino-2,4-difluorobenzene 367-25-9 C6H5F2N 详情 详情
(B) 21310 tert-butyl 3-pyrrolidinylcarbamate 99724-19-3 C9H18N2O2 详情 详情
(I) 15228 ethyl 3-(2,6-dichloro-5-fluoro-3-pyridinyl)-3-oxopropanoate C10H8Cl2FNO3 详情 详情
(II) 15229 ethyl (Z)-2-[(2,6-dichloro-5-fluoro-3-pyridinyl)carbonyl]-3-(2,4-difluoroanilino)-2-propenoate C17H11Cl2F3N2O3 详情 详情
(III) 31219 ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,2,3,4-tetrahydro[1,8]naphthyridine-3-carboxylate C17H12ClF3N2O3 详情 详情
(IV) 31220 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,2,3,4-tetrahydro[1,8]naphthyridine-3-carboxylic acid C15H8ClF3N2O3 详情 详情
(V) 31221 7-[3-[(tert-butoxycarbonyl)amino]-1-pyrrolidinyl]-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,2,3,4-tetrahydro[1,8]naphthyridine-3-carboxylic acid C24H25F3N4O5 详情 详情
(VI) 31222 tert-butyl 1-[8-(2,4-difluorophenyl)-3-fluoro-5-oxo-5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl]-3-pyrrolidinylcarbamate C23H25F3N4O3 详情 详情
(VII) 31223 tert-butyl 1-[8-(2,4-difluorophenyl)-3-fluoro-6-formyl-5-hydroxy-7,8-dihydro[1,8]naphthyridin-2-yl]-3-pyrrolidinylcarbamate C24H25F3N4O4 详情 详情
(VIII) 31224 tert-butyl 1-[8-(2,4-difluorophenyl)-3-fluoro-6-formyl-5-oxo-5,8-dihydro[1,8]naphthyridin-2-yl]-3-pyrrolidinylcarbamate C24H23F3N4O4 详情 详情
Extended Information