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【结 构 式】

【分子编号】15230

【品名】ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylate

【CA登记号】

【 分 子 式 】C17H10ClF3N2O3

【 分 子 量 】382.7259896

【元素组成】C 53.35% H 2.63% Cl 9.26% F 14.89% N 7.32% O 12.54%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(I)

Ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (I) is reacted with 3-aminopyrrolidine dihydrochloride (II), and then the resulting mixture is reacted with potassium hydroxide and p-toluenesulfonic acid monohydrate in order to obtain (rac)-7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-(2,4-difluorophenyl)- 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid p-toluenesulfonate hydrate.

1 Soejima, R.; Shimada, K.; TOSUFLOXACIN TOSYLATE < Prop INNM >. Drugs Fut 1989, 14, 6, 536.
2 Kokei, T.; et al.; Chemical structure and physicochemical properties of (rac)-7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-(2,4-difluorophenyl)-1,4- dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid p-toluensulfonate hydrate (T-3262). Iyakuhin Kenkyu 1988, 19, 682.
3 Narita, H.; et al.; Pyridonecarboxylic acids as antibacterial agents IV. Yakugaku Zasshi 1986, 106, 795.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 15230 ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylate C17H10ClF3N2O3 详情 详情
(II) 20938 3-pyrrolidinamine; 3-pyrrolidinylamine C4H10N2 详情 详情
(III) 20939 ethyl 7-(3-amino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylate C21H19F3N4O3 详情 详情

合成路线2

该中间体在本合成路线中的序号:(III)

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-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (III). Hydrolysis of (III) with hydrochloric acid yields 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (IV). Condensation of (IV) with 3-tert-butoxycarbonyl-L-norvalyl-L-norvalylaminopyrrolidine (V) in pyridine yields 7-(3-tert-butoxycarbonyl-L-norvalyl-L-norvalylaminopyrrolidin-1-yl)- 1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (VI). Hydrolysis of (VI) in trifluoroacetic acid gives A-70826.

1 Chu, D.T.W.; A-70826. Drugs Fut 1992, 17, 3, 179.
2 Chu, D.T.W.; Pernet, A.G.; Plattner, J.J.; Hallas, R.; Shipkowitz, N.; Marsh, K.C.; Synthesis and biological properties of A-70826: A prodrug of tosufloxacin. 31st Intersci Conf Antimicrob Agents Chemother (Sept 29-Oct 2, Chicago) 1991, Abst 1440.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
19462 2,4-difluoroaniline; 2,4-difluorophenylamine;2,4-Difluoro-benzenamine;1-Amino-2,4-difluorobenzene 367-25-9 C6H5F2N 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) 15230 ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylate C17H10ClF3N2O3 详情 详情
(IV) 15231 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid C15H6ClF3N2O3 详情 详情
(V) 15232 tert-butyl N-[(1S)-1-[([(1S)-1-[(tetrahydro-1H-pyrrol-3-ylamino)carbonyl]butyl]amino)carbonyl]butyl]carbamate C19H36N4O4 详情 详情
(VI) 15233 7-(3-[[(2S)-2-([(2S)-2-[(tert-butoxycarbonyl)amino]pentanoyl]amino)pentanoyl]amino]-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid C34H41F3N6O7 详情 详情

合成路线3

该中间体在本合成路线中的序号:(XI)

Trovafloxacin can be obtained by two related ways: 1) The cyclization of ethyl diazoacetate (I) with N-benzylmaleimide (II) in ethyl ether gives 5-benzyl-4,6-dioxo-1,3a,4,5,6,6a-hexahydropyrrolo[3,4-c]pyrazole-3-carboxylic acid ethyl ester (III), which by thermolysis at 185 C is converted into (1alpha,5alpha,6alpha)-3-benzyl-2,4-dioxo-3-azabicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester (IV). The reduction of (IV) with LiAlH4 in refluxing THF affords (1alpha,5alpha,6alpha)-3-benzyl-6-(hydroxymethyl)-3-azabicyclo[3.1.0] hexane (V), which is debenzylated by hydrogenolysis with H2 over Pd/C in methanol to the free azabicyclo compound (VI) (1, 2). The reaction of (VI) with benzyl chloroformate and NaHCO3 in doxane/water yields the corresponding N-benzyloxycarbonyl compound (VII), which is oxidized with the Jones reagent to (1alpha,5alpha,6alpha)-3-(benzyloxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (VIII). The reaction of (VIII) with diphenylphosphoryl azide (DPA) and triethylamine in refluxing tert-butanol gives (1alpha,5alpha,6alpha)-3-(benzyloxycarbonyl)-6-(tert-butoxycarbonylamino)-3-azabicyclo[3.1.0]hexane (IX), which is submitted to hydrogenolysis with ammonium formate over Pd/C to afford (1alpha,5alpha,6alpha)-6-(tert-butoxycarbonylamino)-3-azabicyclo[3.1.0] hexane (X). The condensation of (X) with 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid ethyl ester (XI) by means of triethylamine in hot acetonitrile gives (1alpha,5alpha,6alpha)-7-[6-(tert-butoxycarbonylamino)-3-azabicyclo [3.1.0]hex-3-yl]-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid ethyl ester (XII) (1-3), which is finally deprotected with refluxing 6N HCl (1) or methanesulfonic acid in dioxane/water. The cyclization of 1-(benzyloxycarbonyl)-2,5-dihydro-1H-pyrrole (XIII) with ethyl diazoacetate (I) gives 5-(benzyloxycarbonyl)-1,3a,4,5,6,6a-hexahydropyrrolo[3,4-c]pyrazole-3-carboxylic acid ethyl ester (XIV), which by thermolysis is converted into (1alpha,5alpha,6alpha)-3-(benzyloxycarbonyl)-2,4-dioxo-3-azabicyclo [3.1.0]hexane-6-carboxylic acid ethyl ester (XV). Finally, this compound is hydrolyzed to the desired carboxylic acid (VIII). 2) The carboxylic acid (VIII) can also be obtained as follows:

1 Fromtling, R.A.; Castaner, J.; Trovafloxacin Mesylate. Drugs Fut 1996, 21, 5, 496.
2 Brighty, K.E. (Pfizer Inc.); Azabicyclo quinolone carboxylic acids. AU 9161042; EP 0413455; JP 1991086875; US 5164402; WO 9102526 .
3 Gootz, T.D.; Brighty, K.E.; Anderson, M.R.; Haskell, S.L.; Sutcliffe, J.A.; Castaldi, M.J.; Miller, S.A.; In vitro activity and synthesis of CP-99,219, a novel 7-(3-azabicyclo[3.1.0]hexyl)naphthyridone. 32nd Intersci Conf Antimicrob Agents Chemother (Oct 11-14, Anaheim) 1992, Abst 751.
4 Brighty, K.E.; Gootz, T.D.; Girard, A.; et al.; 7-(3-Azabicyclo[3.1.0]hexyl)quinolone antibacterial agents: Synthesis and biological evaluation resulting in identification of CP-99,219. 33rd Intersci Conf Antimicrob Agents Chemother (Oct 17-20, New Orleans) 1993, Abst 1509.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(I) 15911 Ethyldiazoacetate; ethyl 2-diazoacetate 623-73-4 C4H6N2O2 详情 详情
(II) 15912 N-Benzylmaleimide; 1-benzyl-1H-pyrrole-2,5-dione 1631-26-1 C11H9NO2 详情 详情
(III) 15913 ethyl 5-benzyl-4,6-dioxo-1,3a,4,5,6,6a-hexahydropyrrolo[3,4-c]pyrazole-3-carboxylate C15H15N3O4 详情 详情
(IV) 15914 ethyl 2-[(1R,5S)-3-benzyl-2,4-dioxo-3-azabicyclo[3.1.0]hex-6-yl]acetate C16H17NO4 详情 详情
(V) 15915 [(1R,5S)-3-benzyl-3-azabicyclo[3.1.0]hex-6-yl]methanol C13H17NO 详情 详情
(VI) 15916 (1R,5S)-3-azabicyclo[3.1.0]hex-6-ylmethanol C6H11NO 详情 详情
(VII) 15917 benzyl (1R,5S)-6-(hydroxymethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate C14H17NO3 详情 详情
(VIII) 15918 (1R,5S)-3-[(benzyloxy)carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxylic acid C14H15NO4 详情 详情
(IX) 15919 benzyl (1R,5S)-6-[(tert-butoxycarbonyl)amino]-3-azabicyclo[3.1.0]hexane-3-carboxylate C18H24N2O4 详情 详情
(X) 15920 tert-butyl (1R,5S)-3-azabicyclo[3.1.0]hex-6-ylcarbamate C10H18N2O2 详情 详情
(XI) 15230 ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylate C17H10ClF3N2O3 详情 详情
(XII) 15922 ethyl 7-[(1R,5S)-6-[(tert-butoxycarbonyl)amino]-3-azabicyclo[3.1.0]hex-3-yl]-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylate C27H27F3N4O5 详情 详情
(XIII) 15923 1-Benzyloxycarbonyl-3-pyrroline;3-Pyrroline-1-carboxylicacid, benzyl ester ;N-(Benzyloxycarbonyl)-3-pyrroline;Benzyl 3-pyrroline-1-carboxylate;2H,5H-Pyrrole-1-carboxylicacid benzyl ester;2,5-Dihydropyrrole-1-carboxylic acid benzyl ester;benzyl 2,5-dihydro-1H-pyrrole-1-carboxylate 31970-04-4 C12H13NO2 详情 详情
(XIV) 15924 5-benzyl 3-ethyl 3a,4,6,6a-tetrahydropyrrolo[3,4-c]pyrazole-3,5(1H)-dicarboxylate C16H19N3O4 详情 详情
(XV) 15925 3-benzyl 6-ethyl (1R,5S)-3-azabicyclo[3.1.0]hexane-3,6-dicarboxylate C16H19NO4 详情 详情
Extended Information