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【结 构 式】 
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【分子编号】12058 【品名】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 【CA登记号】82419-35-0 |
【 分 子 式 】C13H9F2NO4 【 分 子 量 】281.2156064 【元素组成】C 55.52% H 3.23% F 13.51% N 4.98% O 22.76% |
合成路线1
该中间体在本合成路线中的序号：(IX)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 |
合成路线2
该中间体在本合成路线中的序号：(VII)9,10-Difluoro-3-(hydroxymethyl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid ethyl ester (I), a racemic intermediate in the synthesis of racemic ofloxacin, is esterified with 3,5-dinitrobenzoyl chloride (II) in the usual way to give the racemic ester (III), which is resolved into its optical isomers by HPLC over a SUMIPAX OA-4200 column, using hexane-1,2-dichloroethane-ethanol as carrier solvent. The (-)-optical isomer (IV) is partially hydrolyzed with ethanolic aqueous NaHCO3 to afford the (-)-alcohol (V), which is treated with triphenylphosphite methiodide in DMF giving the corresponding (-)-iodomethyl derivative (VI). The reduction and simultaneous hydrolysis of (VI) with tributyltin hydride in ethanol yields (-)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (VII), which is finally treated with N-methylpiperazine (VIII) to give (-)-ofloxacin.
| 【1】 Yoneda, N.; Kato, J.; Hayashi, K.; Ochiani, T.; Kinashi, K. (Tanabe Seiyaku Co., Ltd.); Quinolinecarboxylic acid derivs. and method for their preparation. EP 0095163; ES 8603427; US 4508727 . |
| 【2】 Böshagen, H.; Stoltefuss, J.; Berschauer, F.; De Jong, A.; Scheer, M. (Bayer AG); Pure enantiomeric 1,8-bridged-4-quinolo-3-carboxylic acids, process for their preparation and medicaments containing them, and their use in the preparation of medicaments. DE 3543513; EP 0225552; JP 1987145088 . |
| 【3】 Egawa, H.; Miyamoto, H.; Matsumoto, J. (Dainippon Pharmaceutical Co., Ltd.); Method for the preparation of pyridobenzoxazin derivs. and their intermediates. JP 1987215591 . |
| 【4】 Gershon, N.; Wizel, S.; Niddam-Hildesheim, V.; Amir, E. (Teva Pharmaceutical Industries Ltd.; Teva Pharmaceuticals USA, Inc.); Preparation of levofloxacin and forms thereof. WO 0328664 . |
| 【5】 Sharma, P.N.; Pernet, A.G.; Shen, L.L.; Mitscher, L.A.; Chu, D.T.W.; Chiral DNA gyrase inhibitors. 2. Asymmetric synthesis and biological activity of the enantiomers of 9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (ofloxacin). J Med Chem 1987, 30, 12, 2283-6. |
| 【6】 Prous, J.; Castaner, J.; Levofloxacin. Drugs Fut 1992, 17, 7, 559. |
| 【7】 Hayakawa, I.; Atarashi, S.; Yokohama, S.; Imamura, M.; Sakano, K.-I.; Furukawa, M.; Synthesis and antibacterial activities of optically active ofloxacin. Antimicrob Agents Chemother 1986, 29, 1, 163-4. |
| 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) | 12052 | ethyl 9,10-difluoro-3-(hydroxymethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate | C15H13F2NO5 | 详情 | 详情 | |
| (II) | 12053 | 3,5-Dinitrobenzoyl chloride | 99-33-2 | C7H3ClN2O5 | 详情 | 详情 |
| (III) | 12054 | ethyl 3-[[(3,5-dinitrobenzoyl)oxy]methyl]-9,10-difluoro-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate | C22H15F2N3O10 | 详情 | 详情 | |
| (IV) | 12055 | ethyl 3-[[(3,5-dinitrobenzoyl)oxy]methyl]-9,10-difluoro-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate | C22H15F2N3O10 | 详情 | 详情 | |
| (V) | 12056 | ethyl 9,10-difluoro-3-(hydroxymethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate | C15H13F2NO5 | 详情 | 详情 | |
| (VI) | 12057 | ethyl 9,10-difluoro-3-(iodomethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate | C15H12F2INO4 | 详情 | 详情 | |
| (VII) | 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 |
| (VIII) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |