Nadifloxacin, OPC-7251, Nadixa, Nadoxin, Acuatim
那氟沙星 9-氟-6,7-二氢-8-(4-羟基-1-哌啶基)-5-甲基-1-氧基-1H,5H-苯并[ij]喹喹喹啶-2-羧酸 8-氟-5,6-二氢-7-(4-羟基哌啶)-4-甲基-1-氧-4H-3a-氮-1H-苯甲苯-2-羧酸钠盐Chemical Name: (?-9-Fluoro-8-(4-hydroxy-1-piperidinyl)-5-methyl-1-oxo-6,7-dihydro-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid
CAS No. 124858-35-1, 81962-84-7 (undefined isomer), 86826-12-2 (undefined isomer, monoNa salt)
项目整合开发状态: Launched-1993
项目研究机构: Otsuka (Originator), Ferrer (Licensee), Galderma (Licensee), Dr. R. Pfleger (Distributor)
合成路线:The bromination of 5-fluoro-2-methylquinoline (I) with Br2 and Ag2SO4 in H2SO4 or with Br2 and AlCl3 gives 5-bromo-6-fluoro-2-methylquinoline (II),which is reduced with H2 over PtO2 in acetic acid,yielding 5-bromo-6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline (III).The cyclization of (III) with diethyl ethoxymethylenemalonate (IV) and polyphosphoric acid (PPA) at 150 C affords 8-bromo-9-fluoro-5-methyl-1-oxo-6,7-dihydro-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid (V),which is finally condensed with 4-hydroxypiperidine (VI) by heating at 160 C in HMPT.
📌 参考资料/链接：
参考文献标题:Antibacterial agents
文献作者:Kano,M.; Nakagawa,K.; Ishikawa,H.; Uno,T.(Otsuka Pharmaceutical Co.,Ltd.)
参考来源:JP 1983090511
📄 详细内容
合成路线:The bromination of 5-fluoro-2-methylquinoline (I) with Br2 and Ag2SO4 in H2SO4 or with Br2 and AlCl3 gives 5-bromo-6-fluoro-2-methylquinoline (II),which is reduced with H2 over PtO2 in acetic acid,yielding 5-bromo-6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline (III).The cyclization of (III) with diethyl ethoxymethylenemalonate (IV) and polyphosphoric acid (PPA) at 150 C affords 8-bromo-9-fluoro-5-methyl-1-oxo-6,7-dihydro-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid (V),which is finally condensed with 4-hydroxypiperidine (VI) by heating at 160 C in HMPT.
合成路线:The synthesis of Ro 40-7592 is carried out as follows:Addition of 4-bromotoluene (I) to 4-(benzyloxy)-3-methoxybenzaldehyde (II) in the presence of butyllithium in THF at -78 C gives 4-(benzyloxy)-3-methoxy-4'-methylbenzhydrol (III).Oxidation of this compound with pyridinium chlorochromate in CH2Cl2 yields the corresponding 4-(benzyloxy)-3-methoxy-4'-methylbenzophenone (IV).Debenzylation of (IV) with 30% aqueous hydrobromic acid in acetic acid affords 4-hydroxy-3-methoxy-4'-methylbenzophenone (V).Regioselective nitration of (V) with 65% aqueous nitric acid in acetic acid gives 4-hydroxy-3-methoxy-4'-methyl-5-nitrobenzophenone (VI).Hydrolysis of the methoxy group in (VI) with 30% aqueous hydrobromic acid in boiling acetic acid affords 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone,Ro 40-7592.
参考文献标题:3,5-Disubstituted pyrocatechol derivs
文献作者:Bernauer,K.; Borgulya,J.; Bruderer,H.; Da Prada,M.; Zurcher,G.(F.Hoffmann-La Roche AG)
参考来源:EP 0237929; US 5389653; US 5476875
合成路线:The bromination of 5-fluoro-2-methylquinoline (I) with Br2 and Ag2SO4 in H2SO4 or with Br2 and AlCl3 gives 5-bromo-6-fluoro-2-methylquinoline (II),which is reduced with H2 over PtO2 in acetic acid,yielding 5-bromo-6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline (III).The cyclization of (III) with diethyl ethoxymethylenemalonate (IV) and polyphosphoric acid (PPA) at 150 C affords 8-bromo-9-fluoro-5-methyl-1-oxo-6,7-dihydro-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid (V),which is finally condensed with 4-hydroxypiperidine (VI) by heating at 160 C in HMPT.
参考文献标题:Synthesis of substituted 6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acids
文献作者:Ishikawa,H.; Tabusa,F.; Miyamoto,H.; Kano,M.; Ueda,H.; Tamaoka,H.; Nakagawa,K.
参考来源:Chem Pharm Bull 1989,37(8),2103-8
合成路线:The bromination of 5-fluoro-2-methylquinoline (I) with Br2 and Ag2SO4 in H2SO4 or with Br2 and AlCl3 gives 5-bromo-6-fluoro-2-methylquinoline (II),which is reduced with H2 over PtO2 in acetic acid,yielding 5-bromo-6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline (III).The cyclization of (III) with diethyl ethoxymethylenemalonate (IV) and polyphosphoric acid (PPA) at 150 C affords 8-bromo-9-fluoro-5-methyl-1-oxo-6,7-dihydro-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid (V),which is finally condensed with 4-hydroxypiperidine (VI) by heating at 160 C in HMPT.
参考文献标题:OPC-7251
文献作者:Prous,J.; Castar,J.
参考来源:Drugs Fut 1990,15(7),685