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【结 构 式】

【药物名称】Moxifloxacin hydrochloride, Bay-12-8039, Vigamox, Proflox, Octegra, Actira, Avalox, Avelox

【化学名称】(1'S,6'S)-1-Cyclopropyl-7-(2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride
      (4aS,7aS)-1-Cyclopropyl-6-fluoro-8-methoxy-7-(octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride

【CA登记号】186826-86-8,354812-41-2,151096-09-2 (free base), 192927-63-2 (hydrate)

【 分 子 式 】C21H25ClFN3O4

【 分 子 量 】437.9025

【开发单位】Bayer (Originator), Alcon (Not Determined), Shionogi (Marketer), Esteve (Licensee), Recordati (Licensee), Vita (Licensee)

【药理作用】Antibacterial Drugs, Antibacterial Ophthalmic Drugs, ANTIINFECTIVE THERAPY, Ocular Antiinflammatory and Antiinfective Agents, OCULAR MEDICATIONS, Ophthalmic Drugs, DNA Gyrase Inhibitors, DNA Topoisomerase IV Inhibitors, Quinolones

合成路线1

 

1 Masuzawa K. 1987.8-Alkoxyquinolone carboxlic acids and salts there of excellent in the selective toxicity and process of preparing the same. EP 0230259(本专利为Kyorin Pharmaceutical Co Ltd所有)
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) 12255 3-Bromo-2,5,6-trifluorophenyl methyl ether; 1-Bromo-2,4,5-trifluoro-3-methoxybenzene C7H4BrF3O 详情 详情
(II) 12256 2,4,5-Trifluoro-3-methoxybenzonitrile C8H4F3NO 详情 详情
(III) 12257 2,4,5-Trifluoro-3-methoxybenzamide C8H6F3NO2 详情 详情
(IV) 12258 2,4,5-Trifluoro-3-methoxybenzoic acid 112811-65-1 C8H5F3O3 详情 详情
(V) 12259 2,4,5-Trifluoro-3-methoxybenzoyl chloride C8H4ClF3O2 详情 详情
(VI) 12260 diethyl 2-(2,4,5-trifluoro-3-methoxybenzoyl)malonate C15H15F3O6 详情 详情
(VII) 12261 ethyl 3-oxo-3-(2,4,5-trifluoro-3-methoxyphenyl)propanoate C12H11F3O4 详情 详情

合成路线2

The anhydrization of pyridine-2,3-dicarboxylic acid (I) with acetic anhydride gives the corresponding anhydride (II), which by treatment with benzylamine (III) is converted into the benzylimide (IV). The hydrogenation of (IV) with H2 over Pd/C yields 8-benzyl-2,8-diazabicyclo[4.3.0]nonane-7,9-dione (V), which is further hydrogenated with LiAlH4, affording (?-cis-8-benzyl-2,8-diazabicyclo[4.3.0]nonane (VI) (1). The optical resolution of (VI) by separation of the cis-(R,R)-isomer as crystalline L-(+)-tartrate and further purification of the cis-(S,S)-isomer (VII) as the D-(-)-tartrate affords enantiomerically pure (S,S)-8-benzyl-2,8-diazabicyclo[4.3.0]nonane (VII). The debenzylation of (VII) by hydrogenolysis with H2 over Pd/C gives (S,S)-2,8-diazabicyclo[4.3.0]nonane (VIII), which is condensed with 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (IX) in basic medium and finally salified with HCl. The 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (IX) has been obtained as follows: The reaction of 2,4,5-trifluoro-3-methoxybenzoyl chloride (X) with malonic acid monoethyl ester monopotassium salt (XI) by means of triethylamine gives 2-(2,4,5-trifluoro-3-methoxybenzoyl)acetic acid ethyl ester (XII), which is condensed with triethyl orthoformate yielding the corresponding ethoxymethylene derivative (XIII). The reaction of (XIII) with cyclopropylamine affords the cyclopropylaminomethylene derivative (XIV), which is finally cyclized to (IX) by means of NaF in DMF.

1 Martel, A.M.; Leeson, P.A.; Castañer, J.; Bay-12-8039. Drugs Fut 1997, 22, 2, 109.
2 Petersen, U.; Bremm, K.-D.; Dalhoff, A.; Endermann, R.; Heilmann, W.; Krebs, A.; Schenke, T.; Synthesis and in vitro activity of BAY 12-8039, a new 8-methoxy-quinolone. 36th Intersci Conf Antimicrob Agents Chemother (Sept 15-18, New Orleans) 1996, Abst. F1..
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) 17246 2,3-pyridinedicarboxylic acid; Quinolinic Acid 89-00-9 C7H5NO4 详情 详情
(II) 17247 furo[3,4-b]pyridine-5,7-dione; 2,3-Pyridinedicarboxylic anhydride 699-98-9 C7H3NO3 详情 详情
(III) 15147 Benzylamine; Phenylmethanamine 100-46-9 C7H9N 详情 详情
(IV) 17249 6-benzyl-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione C14H10N2O2 详情 详情
(V) 17250 6-benzyltetrahydro-1H-pyrrolo[3,4-b]pyridine-5,7(2H,6H)-dione C14H16N2O2 详情 详情
(VI) 17251 6-benzyloctahydro-1H-pyrrolo[3,4-b]pyridine C14H20N2 详情 详情
(VII) 17252 (4aS,7aS)-6-benzyloctahydro-1H-pyrrolo[3,4-b]pyridine C14H20N2 详情 详情
(VIII) 17253 (4aS,7aS)octahydro-1H-pyrrolo[3,4-b]pyridine C7H14N2 详情 详情
(IX) 12266 1-Cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid 112811-72-0 C14H11F2NO4 详情 详情
(X) 12259 2,4,5-Trifluoro-3-methoxybenzoyl chloride C8H4ClF3O2 详情 详情
(XI) 14338 potassium 3-ethoxy-3-oxopropanoate 6148-64-7 C5H7KO4 详情 详情
(XII) 12261 ethyl 3-oxo-3-(2,4,5-trifluoro-3-methoxyphenyl)propanoate C12H11F3O4 详情 详情
(XIII) 12262 ethyl (Z)-3-ethoxy-2-(2,4,5-trifluoro-3-methoxybenzoyl)-2-propenoate C15H15F3O5 详情 详情
(XIV) 12264 ethyl (E)-3-(cyclopropylamino)-2-(2,4,5-trifluoro-3-methoxybenzoyl)-2-propenoate C16H16F3NO4 详情 详情

合成路线3

The condensation of 2,4,5-trifluoro-3-methoxybenzoyl chloride (I) with 14C-labeled diethyl malonate (II) by means of MgCl2 and TEA gives the benzoylmalonate (III), which is monodecarboxylated with TsOH in refluxing water, yielding the benzoylacetate (IV). The reaction of (IV) with triethyl orthoformate and Ac2O at 140 C affords the benzoylacrylate (V), which is treated with cyclopropylamine (VI) in cyclohexane to provide ethyl 3-(cyclopropylamino)-2-(2,4,5-trifluoro-3-methoxybenzoyl)acrylate (VII). The cyclization of (VII) by means of K2CO3 in hot N-methylpyrrolidone gives the quinolone carboxylate (VIII), which is hydrolyzed with NaOH in hot methanol, affording the carboxylic acid (IX). Finally, this compound is condensed with (S,S)-2,8-diazabicyclo[4.3.0]octane (X) by means of 1,4-diazabicyclo[2.2.2]octane (DABCO) in refluxing acetonitrile.

1 Seidel, D.; Conrad, M.; Brehmer, P.; Mohrs, K.; Petersen, U.; Synthesis of carbon-14 labelled moxifloxacin hydrochloride. J Label Compd Radiopharm 2000, 43, 8, 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) 12259 2,4,5-Trifluoro-3-methoxybenzoyl chloride C8H4ClF3O2 详情 详情
(II) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(II) 45330 diethyl malonate C7H12O4 详情 详情
(III) 12260 diethyl 2-(2,4,5-trifluoro-3-methoxybenzoyl)malonate C15H15F3O6 详情 详情
(III) 45331 diethyl 2-(2,4,5-trifluoro-3-methoxybenzoyl)malonate C15H15F3O6 详情 详情
(IV) 12261 ethyl 3-oxo-3-(2,4,5-trifluoro-3-methoxyphenyl)propanoate C12H11F3O4 详情 详情
(IV) 45332 ethyl 3-oxo-3-(2,4,5-trifluoro-3-methoxyphenyl)propanoate C12H11F3O4 详情 详情
(V) 12262 ethyl (Z)-3-ethoxy-2-(2,4,5-trifluoro-3-methoxybenzoyl)-2-propenoate C15H15F3O5 详情 详情
(V) 45333 ethyl (Z)-3-ethoxy-2-(2,4,5-trifluoro-3-methoxybenzoyl)-2-propenoate C15H15F3O5 详情 详情
(VI) 12263 Cyclopropylamine; Cyclopropanamine 765-30-0 C3H7N 详情 详情
(VII) 12264 ethyl (E)-3-(cyclopropylamino)-2-(2,4,5-trifluoro-3-methoxybenzoyl)-2-propenoate C16H16F3NO4 详情 详情
(VII) 45334 ethyl (Z)-3-(cyclopropylamino)-2-(2,4,5-trifluoro-3-methoxybenzoyl)-2-propenoate C16H16F3NO4 详情 详情
(VIII) 12265 ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate C16H15F2NO4 详情 详情
(VIII) 45335 ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate C16H15F2NO4 详情 详情
(IX) 12266 1-Cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid 112811-72-0 C14H11F2NO4 详情 详情
(IX) 45336 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid C14H11F2NO4 详情 详情
(X) 17253 (4aS,7aS)octahydro-1H-pyrrolo[3,4-b]pyridine C7H14N2 详情 详情
Extended Information