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【结 构 式】 
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【分子编号】38393 【品名】1H-imidazol-4-ylmethanol 【CA登记号】 |
【 分 子 式 】C4H6N2O 【 分 子 量 】98.10452 【元素组成】C 48.97% H 6.16% N 28.55% O 16.31% |
合成路线1
该中间体在本合成路线中的序号：(XI)The reaction of N-(tert-butoxycarbonyl)-L-norleucine (I) with N,O-dimethylhydroxylamine (II) by means of EDC, HOBT and TEA in DMF gives the methoxyamide (III), which is reduced with LiAlH4 to the corresponding aldehyde (IV). The reductocondensation of (IV) with 3-(trifluoromethoxy)aniline (V) by means of NaBH(OAc)3 affords the secondary amine (VI), which is acylated with chloroacetyl chloride (VII) and NaHCO3 to the chloroacetamide (VIII). The cyclization of (VIII) by means of Cs2CO3 in DMF gives the piperazinone (IX), which is finally reductocondensed with 1-(4-cyanobenzyl)imidazole-5-carbaldehyde (X) by means of NaBH(OAc)3. The intermediate 1-(4-cyanobenzyl)imidazole-5-carbaldehyde (X) has been obtained as follows: The tritylation of 1H-imidazole-4-methanol (XI) with trityl chloride and TEA in DMF gives the corresponding 1-trityl derivative (XII), which is acetylated with Ac2O and pyridine yielding the acetate (XIII). The condensation of (XIII) with 4-(bromomethyl)benzonitrile (XIV) in hot ethyl acetate affords 4-(5-acetoxyimidazol-1-ylmethyl)benzonitrile (XV), which is hydrolyzed with LiOH in THF/water providing the carbinol (XVI). Finally, this alcohol is oxidized to the target aldehyde (X) by means of SO3 and pyridine in DMSO.
| 【1】 Bergman, J.M.; Brashear, K.; Williams, T.M.; et al.; N-Arylpiperazinone inhibitors of farnesyltransferase: Discovery and biological activity. J Med Chem 1999, 42, 19, 3779. |
| 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) | 20398 | (2S)-2-[(tert-butoxycarbonyl)amino]hexanoic acid | C11H21NO4 | 详情 | 详情 | |
| (II) | 13361 | (Methoxyamino)methane; N,O-Dimethylhydroxylamine | 1117-97-1 | C2H7NO | 详情 | 详情 |
| (III) | 38382 | tert-butyl (1S)-1-[[methoxy(methyl)amino]carbonyl]pentylcarbamate | C13H26N2O4 | 详情 | 详情 | |
| (IV) | 38383 | tert-butyl (1S)-1-formylpentylcarbamate | C11H21NO3 | 详情 | 详情 | |
| (V) | 38384 | 3-(trifluoromethoxy)phenylamine; 3-(trifluoromethoxy)aniline | 1535-73-5 | C7H6F3NO | 详情 | 详情 |
| (VI) | 38385 | tert-butyl (1S)-1-[[3-(trifluoromethoxy)anilino]methyl]pentylcarbamate | C18H27F3N2O3 | 详情 | 详情 | |
| (VII) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (VIII) | 38386 | tert-butyl (1S)-1-[[(2-chloroacetyl)-3-(trifluoromethoxy)anilino]methyl]pentylcarbamate | C20H28ClF3N2O4 | 详情 | 详情 | |
| (IX) | 38387 | tert-butyl (2S)-2-butyl-5-oxo-4-[3-(trifluoromethoxy)phenyl]-1-piperazinecarboxylate | C20H27F3N2O4 | 详情 | 详情 | |
| (X) | 38388 | 4-[(5-formyl-1H-imidazol-1-yl)methyl]benzonitrile | C12H9N3O | 详情 | 详情 | |
| (XI) | 38393 | 1H-imidazol-4-ylmethanol | C4H6N2O | 详情 | 详情 | |
| (XII) | 38392 | (1-trityl-1H-imidazol-4-yl)methanol | C23H20N2O | 详情 | 详情 | |
| (XIII) | 38391 | (1-trityl-1H-imidazol-4-yl)methyl acetate | C25H22N2O2 | 详情 | 详情 | |
| (XIV) | 14200 | 4-(Bromomethyl)benzonitrile; alpha-Bromo-p-tolunitrile | 17201-43-3 | C8H6BrN | 详情 | 详情 |
| (XV) | 38390 | [1-(4-cyanobenzyl)-1H-imidazol-5-yl]methyl acetate | C14H13N3O2 | 详情 | 详情 | |
| (XVI) | 38389 | 4-[[5-(hydroxymethyl)-1H-imidazol-1-yl]methyl]benzonitrile | C12H11N3O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The condensation between 5-acetamido-2-fluoro-4-nitrobenzotrifluoride (I) and 4-(hydroxymethyl)imidazole (II) in acetonitrile at 120 C in a sealed vessel furnished aryl imidazole (III). Subsequent acetamide hydrolysis in (III) with aqueous HCl provided nitro amine (IV), which was further reduced to phenylenediamine (V) by catalytic hydrogenation over Pd/C. Quinoxaline (VII) was prepared by condensation of phenylenediamine (V) with diethyl oxomalonate (VI) in boiling EtOH. The primary hydroxyl group of (VII) was then condensed with ethyl 4-isocyanatobenzoate (VIII) yielding carbamate (IX). Finally, both ethyl ester groups of (IX) were hydrolyzed by means of KOH to produce the target dicarboxylic acid.
| 【1】 Takano, Y.; Takadoi, M.; Ando, N.; Anraku, T.; Shiga, F.; Uchiki, H.; Asano, J.; Fukuchi, K.; Uda, J. (Kyorin Pharmaceutical Co., Ltd.); 6,7-Asymmetrically disubstd. quinoxalinecarboxylic acid derivs., addition salts thereof, and processes for the preparation of both. EP 1020453; JP 2000080085; US 6348461; WO 9911632 . |
| 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) | 58742 | N-[4-fluoro-2-nitro-5-(trifluoromethyl)phenyl]acetamide | C9H6F4N2O3 | 详情 | 详情 | |
| (II) | 38393 | 1H-imidazol-4-ylmethanol | C4H6N2O | 详情 | 详情 | |
| (III) | 58743 | N-[4-[4-(hydroxymethyl)-1H-imidazol-1-yl]-2-nitro-5-(trifluoromethyl)phenyl]acetamide | C13H11F3N4O4 | 详情 | 详情 | |
| (IV) | 58744 | {1-[4-amino-5-nitro-2-(trifluoromethyl)phenyl]-1H-imidazol-4-yl}methanol | C11H9F3N4O3 | 详情 | 详情 | |
| (V) | 58745 | {1-[4,5-diamino-2-(trifluoromethyl)phenyl]-1H-imidazol-4-yl}methanol | C11H11F3N4O | 详情 | 详情 | |
| (VI) | 58746 | Diethyl ketomalonate; Diethyl mesoxalate; Diethyl oxomalonate; Mesoxalic acid diethyl ester | 609-09-6 | C7H10O5 | 详情 | 详情 |
| (VII) | 58747 | ethyl 7-[4-(hydroxymethyl)-1H-imidazol-1-yl]-3-oxo-6-(trifluoromethyl)-3,4-dihydro-2-quinoxalinecarboxylate | C16H13F3N4O4 | 详情 | 详情 | |
| (VIII) | 23979 | ethyl 4-isocyanatobenzoate | 30806-83-8 | C10H9NO3 | 详情 | 详情 |
| (IX) | 58748 | ethyl 7-{4-[({[4-(ethoxycarbonyl)anilino]carbonyl}oxy)methyl]-1H-imidazol-1-yl}-3-oxo-6-(trifluoromethyl)-3,4-dihydro-2-quinoxalinecarboxylate | C26H22F3N5O7 | 详情 | 详情 |