|
【结 构 式】 
|
【分子编号】12054 【品名】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 【CA登记号】 |
【 分 子 式 】C22H15F2N3O10 【 分 子 量 】519.3721264 【元素组成】C 50.88% H 2.91% F 7.32% N 8.09% O 30.81% |
合成路线1
该中间体在本合成路线中的序号：(III)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 |