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【结 构 式】 
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【药物名称】Ofloxacin, Hoe-280, DL-8280, Exocin, Exocine, Ocuflox, Floxin, Tarivid 【化学名称】(±)-9-Fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid 【CA登记号】82419-36-1 【 分 子 式 】C18H20FN3O4 【 分 子 量 】361.3762 |
【开发单位】Daiichi Pharmaceutical (Originator), Allergan (Licensee), Aventis Pharma (Licensee), Ortho-McNeil (Licensee), Santen (Licensee) 【药理作用】Antibacterial Drugs, Antibacterial Ophthalmic Drugs, ANTIINFECTIVE THERAPY, Ocular Antiinflammatory and Antiinfective Agents, OCULAR MEDICATIONS, Ophthalmic Drugs, Quinolones |
合成路线1
The partial hydrolysis ot 2,3,4-trifluoronitrobenzene (I) with KOH in DMSO gives 2,3-difluoro-6-nitrophenol (II), which by condensation with chloroacetone (III) by means of K2CO3 - KI in refluxing acetone yields 2-acetonyloxy-3,4-difluoronitrobenzene (IV). The reductive cyclization of (IV) with H2 over Raney-Ni in ethanol affords 7,8-difluoro-2,3-dihydro-3-methyl-4H-benzoxazine (V), which is condensed with diethyl ethoxymethylenemalonate (VI) by heating at 145 C giving the malonic derivative (VII). The cyclization of (VII) by heating at 145 C with ethyl polyphosphate (PPE) yields ethyl 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylate (VIII), which is hydrolyzed with HCl in refluxing acetic acid affording the corresponding free acid (IX). Finally, this compound is condensed with N-methylpiperazine (X) in DMSO at 110 C.
| 【1】 Hayakawa, I.; Hiramitsu, T.; Tanaka, Y. (Daiichi Pharmaceutical Co., Ltd.); Benzoxazine derivs.. EP 0047005; US 4382892 . |
| 【2】 Serradell, M.N.; Blancafort, P.; Castaner, J.; DL-8280. Drugs Fut 1983, 8, 5, 395. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 30677 | 1,2,3-trifluoro-4-nitrobenzene; 2,3,4-trifluoronitrobenzene | 771-69-7 | C6H2F3NO2 | 详情 | 详情 |
| (II) | 30678 | 2,3-difluoro-6-nitrophenol | 82419-26-9 | C6H3F2NO3 | 详情 | 详情 |
| (III) | 15288 | 1-Chloroacetone; Chloroacetone | 78-95-5 | C3H5ClO | 详情 | 详情 |
| (IV) | 30679 | 1-(2,3-difluoro-6-nitrophenoxy)acetone | C9H7F2NO4 | 详情 | 详情 | |
| (V) | 30680 | 7,8-difluoro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine | C9H9F2NO | 详情 | 详情 | |
| (VI) | 14088 | Diethyl ethoxymethylenemalonate; Diethyl 2-(ethoxymethylene)malonate | 87-13-8 | C10H16O5 | 详情 | 详情 |
| (VII) | 30681 | diethyl 2-[(7,8-difluoro-3-methyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)methylene]malonate | C17H19F2NO5 | 详情 | 详情 | |
| (VIII) | 30682 | ethyl 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate | C15H13F2NO4 | 详情 | 详情 | |
| (IX) | 12058 | 9,10-Difluoro-3-methyl-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid; 8,9-Difluoro-3-me-6-oxo-2,3-dihydro-6h-1-oxa-3a-aza-phenalene-5-carboxylic acid | 82419-35-0 | C13H9F2NO4 | 详情 | 详情 |
| (X) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |