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Enoxacin, PD-107779, CI-919, AT-2266, Almitil, Enoxor, Penet

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摘 要:Enoxacin, PD-107779, CI-919, AT-2266, Almitil, Enoxor, Penetrex, Comprecin, Flumark,74011-58-8,C15-H17-F-N4-O3,1-Ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid
  • 【药物名称】Enoxacin, PD-107779, CI-919, AT-2266, Almitil, Enoxor, Penetrex, Comprecin, Flumark
  • 【化学名】1-Ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid
  • 【CAS登记号】74011-58-8
  • 【结构式】Enoxacin, PD-107779, CI-919, AT-2266, Almitil, Enoxor, Penet--药物合成数据库
  • 【分子式】C15-H17-F-N4-O3
  • 【分子量】320.326
  • 【原研厂家】Dainippon Pharmaceutical (Originator)
  • 【作用类别】Antibacterial Drugs, ANTIINFECTIVE THERAPY, Quinolones
  • 【研发状态】Launched-1986
  • 【合成情况】 
  • 〖来源〗Drugs Fut
  • 〖合成路线〗
  • 〖标题〗AT-2266
  • 〖合成方法〗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.
  • 〖作者〗Blancafort, P.; Serradell, M.N.; Mealy, N.E.; Castaer, J.; Leeson, P.A.
  • 〖参考〗Blancafort, P.; Serradell, M.N.; Mealy, N.E.; Castaer, J.; Leeson, P.A.; AT-2266. Drugs Fut 1981, 6, 3, 129
  • 〖出处〗Drugs Fut1981,6,(3):129
  • 〖备注〗Synthesis of AT-2266 (EN:90031): 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), wich is treated with ethanolic NH3 at 120?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?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 and tetrafluoroboric acid in ethanol affords 6-acetylamino-2-(4-ethoxycarbonylpiperazinyl)-3-pyridine diazonium tetrafluoroborate (VII), which by heat treatment at 120?in toluene is converted into 6-acetylamino-2-(4-ethoxy-carbonylpiperazinyl)-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?to afford diethyl N-[2-(4-ethoxycarbonyl-1-piperazinyl)-3-fluoro-6-pyridinyl]aminomethylenemalonate (XI). The cyclization of (XI) by heating at 255?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 (1). (Scheme 09003101a) Description Crystals, m.p. 220-4? HCl salt, m.p. >300? methanesulfonic salt, m.p. >300?(decomp.); acetic acid salt, m.p. 228-9? Manufacturer Dainippon Pharmaceutical Co. (Japan). Reference 1. Matsumoto, J. et al. (Dainippon Pharm. Co.); EP 9425, JP 8031042.
  • 〖来源〗EP 0009425; ES 483629; US 4359578
  • 〖合成路线〗
  • 〖标题〗Novel naphthyridine derivatives, intermediates thereof, processes for preparation thereof and use thereof
  • 〖合成方法〗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.
  • 〖作者〗Matsumoto, J.; et al. (Aventis Pharma SA; Dainippon Pharmaceutical Co., Ltd.)
  • 〖参考〗Matsumoto, J.; et al. (Aventis Pharma SA; Dainippon Pharmaceutical Co., Ltd.); Novel naphthyridine derivatives, intermediates thereof, processes for preparation thereof and use thereof. EP 0009425; ES 483629; US 4359578
  • 〖出处〗EP 0009425; ES 483629; US 4359578,,():
  • 〖备注〗Synthesis of 090031: 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), wich is treated with ethanolic NH3 at 120?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?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 and tetrafluoroboric acid in ethanol affords 6-acetylamino-2-(4-ethoxycarbonylpiperazinyl)-3-pyridine diazonium tetrafluoroborate (VII), which by heat treatment at 120?in toluene is converted into 6-acetylamino-2-(4-ethoxy-carbonylpiperazinyl)-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?to afford diethyl N-[2-(4-ethoxycarbonyl-1-piperazinyl)-3-fluoro-6-pyridinyl]aminomethylenemalonate (XI). The cyclization of (XI) by heating at 255?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. (Scheme 09003101a) Description Crystals, m.p. 220-4? HCl salt, m.p. >300? methanesulfonic salt, m.p. >300?(decomp.); acetic acid salt, m.p. 228-9?
 
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