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【结 构 式】 
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【分子编号】56023 【品名】2,4-dinitro-1H-imidazole 【CA登记号】5213-49-0 |
【 分 子 式 】C3H2N4O4 【 分 子 量 】158.07344 【元素组成】C 22.8% H 1.28% N 35.44% O 40.49% |
合成路线1
该中间体在本合成路线中的序号：(I)Condensation of 2,4-dinitroimidazole (I) with the silyl-protected (S)-glycidol (II) gave the N-substituted imidazole (III). The free hydroxyl group of (III) was then protected as the tetrahydropyranyl ether (IV) by treatment with dihydropyran and pyridinium tosylate. Desilylation of (IV) by means of tetrabutylammonium fluoride proceeded with concomitant nitro group displacement to afford the pyranoimidazole derivative (V). The tetrahydropyranyl group of (V) was then removed by acidic hydrolysis to provide alcohol (VI). Finally, condensation of (VI) with 4-(trifluoromethoxy)benzyl bromide (VII) under Williamson's ether synthesis conditions provided the title compound.
| 【1】 Baker, W.R.; Shaopei, C.; Keeler, E.L. (PathoGenesis Corp.); Nitroimidazole antibacterial cpds. and methods of use thereof. EP 0866793; JP 1999508270; WO 9701562 . |
| 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) | 56023 | 2,4-dinitro-1H-imidazole | 5213-49-0 | C3H2N4O4 | 详情 | 详情 |
| (II) | 42416 | tert-butyl(dimethyl)[(2S)oxiranylmethoxy]silane; tert-butyl(dimethyl)silyl (2S)oxiranylmethyl ether | 123237-62-7 | C9H20O2Si | 详情 | 详情 |
| (III) | 56024 | (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-3-(2,4-dinitro-1H-imidazol-1-yl)-2-propanol | C12H22N4O6Si | 详情 | 详情 | |
| (IV) | 56025 | 1-[(2S)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-(tetrahydro-2H-pyran-2-yloxy)propyl]-2,4-dinitro-1H-imidazole; tert-butyl(dimethyl)silyl (2S)-3-(2,4-dinitro-1H-imidazol-1-yl)-2-(tetrahydro-2H-pyran-2-yloxy)propyl ether | C17H30N4O7Si | 详情 | 详情 | |
| (V) | 56026 | (6S)-2-nitro-6-(tetrahydro-2H-pyran-2-yloxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine; (6S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl tetrahydro-2H-pyran-2-yl ether | C11H15N3O5 | 详情 | 详情 | |
| (VI) | 56027 | (6S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-ol | C6H7N3O4 | 详情 | 详情 | |
| (VII) | 20308 | 4-(bromomethyl)phenyl trifluoromethyl ether; 1-(bromomethyl)-4-(trifluoromethoxy)benzene | 50824-05-0 | C8H6BrF3O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)The nitration of imidazole (I) with HNO3 and H2SO4 at 100 °C gives 4-nitroimidazole (II) , which by a second nitration with HNO3 and Ac2O, and optionally AcOH, affords 1,4-dinitroimidazole (III) . Rearrangement of dinitroimidazole intermediate (III) in refluxing xylene or chlorobenzene generates 2,4-dinitroimidazole (IV), which then undergoes selective nitro group displacement with HCl in refluxing chlorobenzene/water to yield 2-chloro-4-nitroimidazole (V) . Condensation of imidazole (V) with epoxide (VI) by means of Et3N in hot ethyl acetate gives the adduct (VII), which is hydrolyzed using K2CO3 in MeOH providing the vicinal diol (VIII). Selective monomesylation of diol (VIII) by means of MsCl in the presence of pyridine affords the primary mesylate (IX), which is then treated with DBU in ethyl acetate to give epoxide (X). Finally, this compound is cyclized with the 4-substitutedphenol (XI) by means of NaH in DMF .
| 【1】 Wuellner, G., Herkenrath, F.-W., Juelich, A., Yamada, Y., Kawabe, S.(Dynamit Nobel GmbH Explosivstoff- and Systemtechnik; Asahi Kasei Chemicals Corp.; Otsuka Pharmaceutical Co., Ltd.). Methods for the production of 2-halo-4-nitroimidazole and intermediates thereof. CN 102131787, EP 2323990, JP 2012500183, WO 2010021409. |
| 【2】 Wüllner, G., Herkenrath, F.-W., Jülich, A. (Dynamit Nobel GmbH Explosivstoff-and Systemtechnik). Method for the production of 2-halogeno-4-nitroimidazole. WO 2010143007. |
| 【3】 Tsubouchi, H., Sasaki, H., Haraguchi, Y. et al. Synthesis and antituberculous activity of a novel series of optically active 6-nitro-2,3-dihydroimidazo[2,1-b]oxazoles. 45th Intersci Conf Antimicrob Agents Chemother (ICAAC) (Dec 16-19, Washington, D.C.) 2005, Abst F-1473. |
| 【4】 Tsubouchi, H., Itoya, M., Hasegawa, T. et al. (Otsuka Pharmaceutical Co., Ltd.). 2,3-Dihydroimidazo[2,1-b]oxazole compounds. CN 10253262, EP 1555267, JP 2004149527, US 006094767, US 7262212, WO 2004033463. |
| 【5】 Sasaki, H., Haraguchi, Y., Itotani, M. et al. Synthesis and antituberculosis activity of a novel series of optically active 6-nitro-2,3-dihydroimidazo[2,1-b]oxazoles. J Med Chem 2006, 49(26): 7854-60. |
| 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) | 10255 | Imidazole; 1H-Imidazole | 288-32-4 | C3H4N2 | 详情 | 详情 |
| (II) | 35764 | 4-nitro-1H-imidazole | 3034-38-6 | C3H3N3O2 | 详情 | 详情 |
| (III) | 57884 | 1,4-dinitro-1H-imidazole | 19182-81-1 | C3H2N4O4 | 详情 | 详情 |
| (IV) | 56023 | 2,4-dinitro-1H-imidazole | 5213-49-0 | C3H2N4O4 | 详情 | 详情 |
| (V) | 67892 | 2-Chloro-4-nitroimidazole;2-Chloro-4-nitro-1H-imidazole | 57531-37-0 | C3H2ClN3O2 | 详情 | 详情 |
| (VI) | 67893 | (S)-(2-methyloxiran-2-yl)methyl 4-nitrobenzoate | 118200-96-7 | C11H11NO5 | 详情 | 详情 |
| (VII) | 67895 | (S)-3-(2-chloro-4-nitro-1H-imidazol-1-yl)-2-hydroxy-2-methylpropyl 4-nitrobenzoate | C14H13ClN4O7 | 详情 | 详情 | |
| (VIII) | 67897 | (S)-3-(2-chloro-4-nitro-1H-imidazol-1-yl)-2-methylpropane-1,2-diol | C7H10ClN3O4 | 详情 | 详情 | |
| (IX) | 67896 | (S)-3-(2-chloro-4-nitro-1H-imidazol-1-yl)-2-hydroxy-2-methylpropyl methanesulfonate | C8H12ClN3O6S | 详情 | 详情 | |
| (X) | 67898 | (S)-2-chloro-1-((2-methyloxiran-2-yl)methyl)-4-nitro-1H-imidazole | C7H8ClN3O3 | 详情 | 详情 | |
| (XI) | 67894 | 4-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)phenol | C18H18F3NO3 | 详情 | 详情 |