Enoxacin, PD-107779, CI-919, AT-2266, Almitil, Enoxor, Penetrex, Comprecin, Flumark

依诺沙星Chemical Name: 1-Ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid
CAS No. 74011-58-8
项目整合开发状态: Launched-1986
项目研究机构: Dainippon Pharmaceutical (Originator)
合成路线:The reaction of 2,6-dichloro-3-nitropyridine (I) with N-ethoxycarbonylpiperidine (II) by means of triethylamine in CHCl gives 6-chloro-2-(4-ethoxycarbonyl-1-piperazinyl)-3-nitropyridine (III),which is treated with ethanolic NH3 at 120 C in a sealed tube to afford 6-amino-2-(4-ethoxycarbonyl-1-piperazinyl)-3-nitropyridine (IV).The acetylation of (IV) with acetic anhydride - acetic acid at 90 C yields the corresponding 6-acetamido derivative (V),which is reduced with H2 over Pd/C in acetic acid giving 3-amino-6-acetamido-2-(4-ethoxycarbonyl-1-piperazinyl)pyridine (VI).The diazotation of (VI) with isoamyl nitrite (A) and tetrafluoroboric acid in ethanol affords 6-acetylamino-2-(4-ethoxycarbonylpiperazinyl)-3-pyridine diazonium tetrafluoroborate (VII),which by heat treatment at 120 C in toluene is converted into 6-acetylamino-2-(4-ethoxycarbonylpiperazinyl)-3-fluoropyridine (VIII).The hydrolysis of (VIII) with HCl in methanol yields the corresponding 6-aminopyridine derivative (IX),which is condensed with diethyl ethoxymethylenemalonate (X) by heating at 130 C to afford diethyl N-[2-(4-ethoxycarbonyl-1-piperazinyl)-3-fluoro-6-pyridinyl]aminomethylenemalonate (XI).The cyclization of (XI) by heating at 255 C yields ethyl 7-(4-ethoxycarbonyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (XII),which is N-alkylated by means of ethyl iodide and K2CO3 in hot DMF to afford ethyl 7-(4-ethoxycarbonyl-1-piperazinyl)-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (XIII).Finally,this compound is hydrolyzed by means of NaOH in refluxing ethanol.