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【结 构 式】 
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【药物名称】Nadifloxacin, OPC-7251, Nadoxin, Acuatim Ointment, Acuatim Lotion, Acuatim Cream 【化学名称】(±)-9-Fluoro-8-(4-hydroxy-1-piperidinyl)-5-methyl-1-oxo-6,7-dihydro-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid 【CA登记号】124858-35-1, 81962-84-7 (undefined isomer), 86826-12-2 (undefined isomer;monoNa salt) 【 分 子 式 】C19H21FN2O4 【 分 子 量 】360.38862 |
【开发单位】Otsuka (Originator), Ferrer (Licensee), Galderma (Licensee) 【药理作用】Acne Therapy, Antibacterial Drugs, ANTIINFECTIVE THERAPY, DERMATOLOGIC DRUGS, Quinolones |
合成路线1
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.
| 【1】 Kano, M.; Nakagawa, K.; Ishikawa, H.; Uno, T. (Otsuka Pharmaceutical Co., Ltd.); Antibacterial agents. JP 1983090511 . |
| 【2】 Bernauer, K.; Borgulya, J.; Bruderer, H.; Da Prada, M.; Zurcher, G. (F. Hoffmann-La Roche AG); 3,5-Disubstituted pyrocatechol derivs. EP 0237929; US 5389653; US 5476875 . |
| 【3】 Ishikawa, H.; Tabusa, F.; Miyamoto, H.; Kano, M.; Ueda, H.; Tamaoka, H.; Nakagawa, K.; Synthesis of substituted 6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acids. Chem Pharm Bull 1989, 37, 8, 2103-8. |
| 【4】 Prous, J.; Castaner, J.; OPC-7251. Drugs Fut 1990, 15, 7, 685. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 12076 | 4-Piperidinol; 4-Hydroxypiperidine | 5382-16-1 | C5H11NO | 详情 | 详情 | |
| (I) | 10869 | 6-Fluoro-2-methylquinoline | 1128-61-6 | C10H8FN | 详情 | 详情 |
| (II) | 10870 | 5-Bromo-6-fluoro-2-methylquinoline | C10H7BrFN | 详情 | 详情 | |
| (III) | 10871 | 5-Bromo-6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline | C10H11BrFN | 详情 | 详情 | |
| (IV) | 10872 | diethyl 2-[(E)-ethoxymethylidene]succinate | C11H18O5 | 详情 | 详情 | |
| (V) | 10873 | 8-Bromo-9-fluoro-5-methyl-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acid | C14H11BrFNO3 | 详情 | 详情 |