1,4-dinitro-1H-imidazole -Drug Synthesis Database

【结构式】

【分子编号】57884

【品名】1,4-dinitro-1H-imidazole

【CA登记号】19182-81-1

【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%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(II)

Further nitration of the nitroimidazole (I) with HNO3, Ac2O gives the 1,4-dinitroimidazole (II), which is treated with KCN and NaHCO3 in methanol/water to yield 5-nitro-1H-imidazole-4-carbonitrile (III). The reaction of (III) with dihydropyran and Ts-OH in ethyl acetate affords the N-protected imidazole (IV). The reduction of (IV) with H2 over Pt/C in ethyl acetate provides the hydroxylamine (V), which is oxidized with NaIO4 in ethyl acetate/water to give the nitroso derivative (VI). The condensation of (VI) with phenyl 2-methylcarbazate (VII) by means of HOAc and TFA yields the triazene (VIII), which is treated with conc. HCL in ethyl acetate to afford the carboxamide (IX). Finally, this compound is cyclized to the target imidazo-tetrazinone by irradiation with daylight in acetone/MeOH, most probably through the non isolated cis intermediate (X).

参考文献中间体

合成目标

【1】 Wanner, M.J.; Koomen, G.J.; A new synthesis of temozolomide. J Chem Soc - Perkins Trans I 2002, 16, 1877.

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)	57883	5-Nitroimidazole		C₃H₃N₃O₂	详情	详情
(II)	57884	1,4-dinitro-1H-imidazole	19182-81-1	C₃H₂N₄O₄	详情	详情
(III)	57885	5-nitro-1H-imidazole-4-carbonitrile		C₄H₂N₄O₂	详情	详情
(IV)	57886	5-nitro-1-tetrahydro-2H-pyran-2-yl-1H-imidazole-4-carbonitrile		C₉H₁₀N₄O₃	详情	详情
(V)	57887	5-(hydroxyamino)-1-tetrahydro-2H-pyran-2-yl-1H-imidazole-4-carbonitrile		C₉H₁₂N₄O₂	详情	详情
(VI)	57888	5-nitroso-1-tetrahydro-2H-pyran-2-yl-1H-imidazole-4-carbonitrile		C₉H₁₀N₄O₂	详情	详情
(VII)	57889	phenyl 1-methyl-1-hydrazinecarboxylate		C₈H₁₀N₂O₂	详情	详情
(VIII)	57890	phenyl (E)-3-(4-cyano-1H-imidazol-5-yl)-1-methyl-2-triazene-1-carboxylate		C₁₂H₁₀N₆O₂	详情	详情
(IX)	57891	phenyl (E)-3-[4-(aminocarbonyl)-1H-imidazol-5-yl]-1-methyl-2-triazene-1-carboxylate		C₁₂H₁₂N₆O₃	详情	详情
(X)	57892	phenyl (Z)-3-[4-(aminocarbonyl)-1H-imidazol-5-yl]-1-methyl-2-triazene-1-carboxylate		C₁₂H₁₂N₆O₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

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 .

参考文献中间体

合成目标

【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

Extended Information