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【结 构 式】 
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【分子编号】12053 【品名】3,5-Dinitrobenzoyl chloride 【CA登记号】99-33-2 |
【 分 子 式 】C7H3ClN2O5 【 分 子 量 】230.564 【元素组成】C 36.47% H 1.31% Cl 15.38% N 12.15% O 34.7% |
合成路线1
该中间体在本合成路线中的序号：(II)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 |
合成路线2
该中间体在本合成路线中的序号：(XXXI)Alternatively, derivative (XXIX) can be obtained in an analogous way as its enantiomer (XIX). Diastereoselective epoxidation of (XXIX) with trimethylsulfoxonium iodide and NaH in DMSO provides oxirane (XXX) (3). THP group removal by means of PPTS in EtOH, followed by reaction with 3,5-dinitrobenzoyl chloride (XXXI) and NaHCO3 in CH2Cl2, yields a diastereomeric mixture from which dinitrobenzoate derivative (2R,3R)-(XXXII) is obtained by recrystallization (1). Hydrolysis of (2R,3R)-(XXXII) in MeOH by treatment with aqueous NaOH gives compound (2R,3R)-(XXXIII), which is converted into ester (2R,3S)-(XXXIV) by Mitsunobu reaction with benzoic acid, Ph3P and DEAD in THF. Subsequent debenzoylation of (2R,3S)-(XXXIV) with NaOMe in MeOH affords oxiranyl ethanol derivative (2R,3R)-(XXXV), which is first converted into its triflate derivative by means of Tf2O and DIEA in CH2Cl2, and then into triazolone derivative (2S,3R)-(XXXVI) by reaction with intermediate (VII) and NaH in CH2Cl2/DMF. Finally, oxirane derivative (2S,3R)-(XXXVI) reacts with triazole (XXVI) and NaH in DMF to furnish the desired product.
| 【1】 Tasaka, A.; Tamura, N.; Matsushita, Y.; Teranishi, K.; Hayashi, R.; Okonogi, K.; Itoh, K.; Optically active antifungal azoles. I. Synthesis and antifungal activity of (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-butanol and stereoisomers. Chem Pharm Bull 1993, 41, 6, 1035-42. |
| 【2】 Tamura, N.; Okonogi, K.; Hayashi, R.; Matsushita, Y.; Kitazaki, T.; Tasaka, A.; Itoh, K.; Optically active antifungal azoles.VI. Synthesis and antifungal activity of N-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-N'-(4-substituted phenyl)-3(2H,4H)-1,2,4-triazolones and 5(1H,4H)-tetrazolones. Chem Pharm Bull 1996, 44, 2, 314. |
| 【3】 Itoh, K.; Okonogi, K.; Tamura, N. (Takeda Chemical Industries, Ltd.); Azole cpds., their production and use. EP 0567982; US 5371101 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXXIV) | 43518 | (1S)-1-[(2S)-2-(2,4-difluorophenyl)oxiranyl]ethyl benzoate | C17H14F2O3 | 详情 | 详情 | |
| (VII) | 43502 | 4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C11H9F4N3O2 | 详情 | 详情 | |
| (XXVI) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |
| (XXIX) | 13102 | (2R)-1-(2,4-Difluorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanone | C14H16F2O3 | 详情 | 详情 | |
| (XXX) | 13103 | (1R)-1-[(2R)-2-(2,4-Difluorophenyl)oxiranyl]ethyl tetrahydro-2H-pyran-2-yl ether; 2-([(1R)-1-[(2R)-2-(2,4-Difluorophenyl)oxiranyl]ethyl]oxy)tetrahydro-2H-pyran | C15H18F2O3 | 详情 | 详情 | |
| (XXXI) | 12053 | 3,5-Dinitrobenzoyl chloride | 99-33-2 | C7H3ClN2O5 | 详情 | 详情 |
| (XXXII) | 27874 | (1R)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]ethyl 3,5-dinitrobenzoate | C17H12F2N2O7 | 详情 | 详情 | |
| (XXXIII) | 27875 | (1R)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]-1-ethanol | C10H10F2O2 | 详情 | 详情 | |
| (XXXV) | 27877 | (1S)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]-1-ethanol | C10H10F2O2 | 详情 | 详情 | |
| (XXXVI) | 43519 | 2-[(1R)-1-[(2R)-2-(2,4-difluorophenyl)oxiranyl]ethyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one | C21H17F6N3O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)D-Threonine (I) was esterified by means of thionyl chloride in methanol, and the resultant amino ester (II) was subsequently acylated with 3,5-dinitrobenzoyl chloride (III) to afford amide (IV). Conversion of (IV) to the acetoacetate ester (VI) was effected by reaction with the diketene precursor 2,2,6-trimethyl-4H-1,3-dioxin-4-one (V) in boiling xylene. Treatment of keto ester (V) with ammonia in the presence of p-toluenesulfonic acid produced the aminocrotonate ester (VI). Dihydropyridine (IXa-b) was then obtained as a diastereomeric mixture by a modified Hantzsh condensation between enamine (VI), 2-trifluoromethylbenzaldehyde (VII) and nitroacetone. After chromatographic separation of the isomers, the chiral auxiliary group was removed by methanolysis in the presence of DBU. The desired (+)-(S)-dihydropyridinecarboxylic acid (X) was finally converted to the nitrooxyethyl ester by reaction with 2-bromoethyl nitrate (XI).
| 【1】 Shan, R.; Knaus, E.E.; Howlett, S.E.; Syntheses, calcium channel agonist-antagonist modulation activities, nitric oxide release, and voltage-clamp studies of 2-nitrooxyethyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylate enantiomers. J Med Chem 2002, 45, 4, 955. |
| 【2】 Knaus, E.E.; Shan, R.; The design of (-)-(S)-nitrooxyethyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylate: A cardioselective positive inotropic derivative of Bay K 8644. Bioorg Med Chem Lett 1999, 9, 17, 2613. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIII) | 30332 | 2-(trifluoromethyl)benzaldehyde | 447-61-0 | C8H5F3O | 详情 | 详情 |
| (IXa) | 59607 | (1S,2R)-2-[(3,5-dinitrobenzoyl)amino]-3-methoxy-1-methyl-3-oxopropyl (4S)-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-1,4-dihydro-3-pyridinecarboxylate | C27H24F3N5O11 | 详情 | 详情 | |
| (IXb) | 59608 | (1S,2R)-2-[(3,5-dinitrobenzoyl)amino]-3-methoxy-1-methyl-3-oxopropyl (4R)-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-1,4-dihydro-3-pyridinecarboxylate | C27H24F3N5O11 | 详情 | 详情 | |
| (I) | 28908 | L-Threonine; (2R,3S)-2-amino-3-hydroxybutyric acid | 632-20-2 | C4H9NO3 | 详情 | 详情 |
| (II) | 42026 | methyl (2S,3R)-2-amino-3-hydroxybutanoate | C5H11NO3 | 详情 | 详情 | |
| (III) | 12053 | 3,5-Dinitrobenzoyl chloride | 99-33-2 | C7H3ClN2O5 | 详情 | 详情 |
| (IV) | 59604 | methyl (2R,3S)-2-[(3,5-dinitrobenzoyl)amino]-3-hydroxybutanoate | C12H13N3O8 | 详情 | 详情 | |
| (V) | 13327 | 2,2,6-Trimethyl-4H-1,3-dioxin-4-one；2,2,6-trimethyl-1,3-dioxin-4-one；2,2,6-trimethyl-m-Dioxin-4-one;3-(1-hydroxy-1-methylethoxy)-d-lactone Crotonicacid | 5394-63-8 | C7H10O3 | 详情 | 详情 |
| (VI) | 59605 | methyl (2R,3S)-3-(acetoacetyloxy)-2-[(3,5-dinitrobenzoyl)amino]butanoate | C16H17N3O10 | 详情 | 详情 | |
| (VII) | 59606 | (1S,2R)-2-[(3,5-dinitrobenzoyl)amino]-3-methoxy-1-methyl-3-oxopropyl (E)-3-amino-2-butenoate | C16H18N4O9 | 详情 | 详情 | |
| (X) | 59609 | (4S)-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-1,4-dihydro-3-pyridinecarboxylic acid | C15H13F3N2O4 | 详情 | 详情 | |
| (XI) | 59610 | 1-bromo-2-(nitrooxy)ethane | C2H4BrNO3 | 详情 | 详情 |