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【结 构 式】 
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【分子编号】67523 【品名】4-bromo-2-fluoro-1-iodobenzene 【CA登记号】105931-73-5 |
【 分 子 式 】C6H3BrFI 【 分 子 量 】300.897 【元素组成】C 23.95% H 1.00% Br 26.56% F 6.31% I 42.17% |
合成路线1
该中间体在本合成路线中的序号：(XVII)Condensation of methyl 5-amino-4-fluoro-1-methylbenzimidazole-6-carboxylate (XVI) with 4-bromo-2-fluoro-1-iodobenzene (XVII) by means of Pd2dba3, Cs2CO3 and xantphos in toluene/dioxane gives the 5-phenylamino-benzimidazole derivative (IX), which is hydrolyzed with KOSiMe3 in DMF/THF to provide the potassium salt (XVIII). Compound (XVIII) is activated as its imidazolide (XIX) by treatment with carbonyl diimidazole (XX) in the presence of imidazole hydrochloride in THF/optionally DMF at 50 °C. Alternatively, hydrolysis of methyl ester (IX) by means of NaOH in H2O affords carboxylic acid (X), which is further activated as its imidazolide (XIX) under the same conditions mentioned above. Condensation of intermediate (XIX) with O-(2-tert-butoxyethyl)hydroxylamine (XXI) in H2O provides amide (XXII), which is finally O-deprotected by means of H3PO4 in aceto nitrile .
| 【1】 Krell, C.M., Misun, M., Niederer, D.A. et al. (Array BioPharma, Inc., Novartis AG). Preparation of and formulation comprising a MEK inhibitor. WO 2014063024; US 2014128442. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 67516 | methyl 5-((4-bromo-2-fluorophenyl)amino)-4-fluoro-1-methyl-1H-benzo[d]imidazole-6-carboxylate | C16H12BrF2N3O2 | 详情 | 详情 | |
| (X) | 67517 | 5-((4-bromo-2-fluorophenyl)amino)-4-fluoro-1-methyl-1H-benzo[d]imidazole-6-carboxylic acid | C15H10BrF2N3O2 | 详情 | 详情 | |
| (XVI) | 67522 | methyl 5-amino-4-fluoro-1-methylbenzimidazole-6-carboxylate | C10H10FN3O2 | 详情 | 详情 | |
| (XVII) | 67523 | 4-bromo-2-fluoro-1-iodobenzene | 105931-73-5 | C6H3BrFI | 详情 | 详情 |
| (XVIII) | 67524 | potassium 5-((4-bromo-2-fluorophenyl)amino)-4-fluoro-1-methyl-1H-benzo[d]imidazole-6-carboxylate | C15H9BrF2KN3O2 | 详情 | 详情 | |
| (XIX) | 67525 | (5-((4-bromo-2-fluorophenyl)amino)-4-fluoro-1-methyl-1H-benzo[d]imidazol-6-yl)(1H-imidazol-1-yl)methanone | C18H12BrF2N5O | 详情 | 详情 | |
| (XX) | 11353 | 1,1'-Carbonyldiimidazole; Di(1H-imidazol-1-yl)methanone; N,N-Carbonyldiimidazole; 1,1'-Carbonylbis(1H-imidazole) | 530-62-1 | C7H6N4O | 详情 | 详情 |
| (XXI) | 67526 | O-(2-tert-butoxyethyl)hydroxylamine | 1023742-13-3 | C6H15NO2 | 详情 | 详情 |
| (XXII) | 67527 | 5-((4-bromo-2-fluorophenyl)amino)-N-(2-(tert-butoxy)ethoxy)-4-fluoro-1-methyl-1H-benzo[d]imidazole-6-carboxamide hydrate | C21H23BrF2N4O3.H2O | 详情 | 详情 |