Moxifloxacin hydrochloride, Bay-12-8039, Vigamox, Proflox, Octegra, Actira, Avalox, Avelox
盐酸莫西沙星 莫西沙星 莫西沙星盐酸盐一水合物Chemical Name: (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
CAS No. 186826-86-8, 151096-09-2 (free base), 192927-63-2 (hydrate)
项目整合开发状态: Launched-1999
项目研究机构: Bayer (Originator), Alcon (Not Determined), Schering-Plough (Marketer), Shionogi (Marketer), Esteve (Licensee), Recordati (Licensee), Vita (Licensee)
合成路线: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.
📌 参考资料/链接：
参考文献标题:Synthesis and in vitro activity of BAY 12-8039,a new 8-methoxy-quinolone
文献作者:Petersen,U.; Bremm,K.-D.; Dalhoff,A.; Endermann,R.; Heilmann,W.; Krebs,A.; Schenke,T.
参考来源:36th Intersci Conf Antimicrob Agents Chemother (Sept 15-18,New Orleans) 1996,Abst.F1.
📄 详细内容
合成路线: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.
参考文献标题:Bay-12-8039
文献作者:Martel,A.M.; Leeson,P.A.; Castar,J.
参考来源:Drugs Fut 1997,22(2),109
合成路线: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.
参考文献标题:Synthesis of carbon-14 labelled moxifloxacin hydrochloride
文献作者:Seidel,D.; Conrad,M.; Brehmer,P.; Mohrs,K.; Petersen,U.
参考来源:J Label Compd Radiopharm 2000,43(8),795