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【结 构 式】 
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【分子编号】24710 【品名】4-fluoro-3-nitroaniline 【CA登记号】364-76-1 |
【 分 子 式 】C6H5FN2O2 【 分 子 量 】156.1163832 【元素组成】C 46.16% H 3.23% F 12.17% N 17.94% O 20.5% |
合成路线1
该中间体在本合成路线中的序号：(I)The reduction of 4-fluoro-3-nitroaniline (I) with SnCl2.2H20 in concentrated aqueous HCl gives 4 fluoro-m-phenylenediamine (II), which is condensed with diethyl ethoxymethylenemalonate (III) in refluxing ethanol to afford diethyl 4-fluoro-3-aminoanilinomethylenemalonate (IV). The cyclization of (IV) by means of acetic anhydride in diphenyl oxide at 250 C yields ethyl 7-acetamido-4-hydroxy-6-fluoroquinoline-3-carboxylate (V), which is alkyiated with ethyl bromide and NaOH in refluxing ethanol to give 7-amino-6-fluoro-1-ethyl-1,4 dihydro-4-oxoquinoline-3-carboxylic acid (VI). Finally, this compound is condensed with 2,5-dimethoxytetrahydrofuran (VII) in hot acetic acid.
| 【1】 Esteve Soler, J. (Provesan SA); 7-(1-Pyrrolyl) derivs. of 1-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acids and 1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids and their use as antimicrobial agents. EP 0134165; FR 2548664; FR 2559484; US 4552882 . |
| 【2】 Prous, J.; Castaner, J.; Irloxafin. Drugs Fut 1986, 11, 10, 839. |
| 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) | 24710 | 4-fluoro-3-nitroaniline | 364-76-1 | C6H5FN2O2 | 详情 | 详情 |
| (II) | 24711 | 3-amino-4-fluorophenylamine | C6H7FN2 | 详情 | 详情 | |
| (III) | 14088 | Diethyl ethoxymethylenemalonate; Diethyl 2-(ethoxymethylene)malonate | 87-13-8 | C10H16O5 | 详情 | 详情 |
| (IV) | 24713 | diethyl 2-[(3-amino-4-fluoroanilino)methylene]malonate | C14H17FN2O4 | 详情 | 详情 | |
| (V) | 24714 | ethyl 7-(acetamido)-6-fluoro-4-hydroxy-3-quinolinecarboxylate | C14H13FN2O4 | 详情 | 详情 | |
| (VI) | 24715 | 7-amino-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C12H11FN2O3 | 详情 | 详情 | |
| (VII) | 12132 | 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether | 696-59-3 | C6H12O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)Formylation of 2-methoxy-5-nitroaniline (I) with formic acid (II) in Ac2O/THF yields formamide (III), whose nitro group is then hydrogenated over Pd/C in MeOH to provide aniline (IV). Treatment of (IV) with pentafluorophenylsulfonyl chloride (V) in acetone in the presence of 2,6-lutidine affords sulfonamide (VI), which is then deformylated to hydrochloride (VII) by treatment with acetyl chloride and HCl in EtOH. The target compound is finally obtained by reaction of (VII) with potassium cyanate (KCNO) in H2O/HOAc. An analogous route can be also followed for the synthesis of the target product: Treatment of 3-nitro-4-fluoroaniline (VIII) with sodium methoxide (NaOMe) in refluxing MeOH furnishes 4-methoxy-3-nitroaniline (IX), which is then condensed with pentafluorophenylsulfonyl chloride (V) in MeOH to give sulfonamide (X). Reduction of the nitro moiety of (X) by hydrogenation over Pd/C in EtOH yields aniline (XI), which is finally treated with potassium cyanate (KCNO) in H2O/HOAc.
| 【1】 Houze, J.; Medina, J.; Gergely, J.; et al.; T900607: Design and evaluation of a second-generation irreversible binder of beta-tubulin. Clin Cancer Res 2000, 6, Suppl., Abst 562. |
| 【2】 Houze, J.B. (Tularik Inc.); Arylsulfonanilide ureas. EP 1115701; US 6214880; WO 0017159 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII), (XI) | 46684 | N-(3-amino-4-methoxyphenyl)-2,3,4,5,6-pentafluorobenzenesulfonamide | C13H9F5N2O3S | 详情 | 详情 | |
| (I) | 46680 | 2-methoxy-5-nitrophenylamine; 2-methoxy-5-nitroaniline | 99-59-2 | C7H8N2O3 | 详情 | 详情 |
| (II) | 14590 | Formic acid | 64-18-6 | CH2O2 | 详情 | 详情 |
| (III) | 46681 | 2-methoxy-5-nitrophenylformamide | C8H8N2O4 | 详情 | 详情 | |
| (IV) | 46682 | 5-amino-2-methoxyphenylformamide | C8H10N2O2 | 详情 | 详情 | |
| (V) | 20482 | 2,3,4,5,6-pentafluorobenzenesulfonyl chloride | 832-53-1 | C6ClF5O2S | 详情 | 详情 |
| (VI) | 46683 | 2,3,4,5,6-pentafluoro-N-[3-(formylamino)-4-methoxyphenyl]benzenesulfonamide | C14H9F5N2O4S | 详情 | 详情 | |
| (VIII) | 24710 | 4-fluoro-3-nitroaniline | 364-76-1 | C6H5FN2O2 | 详情 | 详情 |
| (IX) | 46685 | 4-methoxy-3-nitroaniline; 4-methoxy-3-nitrophenylamine | C7H8N2O3 | 详情 | 详情 | |
| (X) | 46686 | 2,3,4,5,6-pentafluoro-N-(4-methoxy-3-nitrophenyl)benzenesulfonamide | C13H7F5N2O5S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Conversion of 4-fluoro-3-nitroaniline (I) into the N-methyl derivative (III) was achieved via formation of the corresponding p-toluenesulfonamide (II), which was further N-alkylated with dimethyl sulfate in the presence of NaOH, followed by sulfonamide hydrolysis with concentrated sulfuric acid. Displacement of the fluoride group of (III) with phenethylamine (IV) in hot NMP gave rise to the p-phenylenediamine (V). After selective protection of the methylamino group of (V) as the N-Boc derivative (VI), the nitro group was reduced to amine (VII) by catalytic hydrogenation over Pd/C. Condensation of (VII) with benzoyl isothiocyanate to yield (VIII), and subsequent cyclization in the presence of EDC, produced the benzimidazole (IX). Acidic cleavage of the Boc protecting group of (IX) gave amine (X). This was finally condensed with isopropyl isocyanate to furnish the title urea.
| 【1】 Akwabi-Ameyaw, A.; et al.; Synthesis and SAR of substituted 5-acylamino benzimidazoles as potent neuropeptide Y Y5 antagonists. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 33. |
| 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) | 24710 | 4-fluoro-3-nitroaniline | 364-76-1 | C6H5FN2O2 | 详情 | 详情 |
| (II) | 53116 | N-(4-fluoro-3-nitrophenyl)-4-methylbenzenesulfonamide | n/a | C13H11FN2O4S | 详情 | 详情 |
| (III) | 53117 | 4-fluoro-N-methyl-3-nitroaniline; N-(4-fluoro-3-nitrophenyl)-N-methylamine | n/a | C7H7FN2O2 | 详情 | 详情 |
| (IV) | 18333 | Phenethylamine; 2-Phenyl-1-ethanamine | 64-04-0 | C8H11N | 详情 | 详情 |
| (V) | 53118 | N-methyl-N-[3-nitro-4-(phenethylamino)phenyl]amine; N~4~-methyl-2-nitro-N~1~-phenethyl-1,4-benzenediamine | n/a | C15H17N3O2 | 详情 | 详情 |
| (VI) | 53119 | tert-butyl methyl[3-nitro-4-(phenethylamino)phenyl]carbamate | n/a | C20H25N3O4 | 详情 | 详情 |
| (VII) | 53120 | tert-butyl 3-amino-4-(phenethylamino)phenyl(methyl)carbamate | n/a | C20H27N3O2 | 详情 | 详情 |
| (VIII) | 53121 | tert-butyl 3-{[(benzoylamino)carbothioyl]amino}-4-(phenethylamino)phenyl(methyl)carbamate | n/a | C28H32N4O3S | 详情 | 详情 |
| (IX) | 53122 | tert-butyl 2-(benzoylamino)-1-phenethyl-1H-benzimidazol-5-yl(methyl)carbamate | n/a | C28H30N4O3 | 详情 | 详情 |
| (X) | 53123 | N-[5-(methylamino)-1-phenethyl-1H-benzimidazol-2-yl]benzamide | n/a | C23H22N4O | 详情 | 详情 |