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【结 构 式】

【分子编号】67525

【品名】(5-((4-bromo-2-fluorophenyl)amino)-4-fluoro-1-methyl-1H-benzo[d]imidazol-6-yl)(1H-imidazol-1-yl)methanone

【CA登记号】 

【 分 子 式 】C18H12BrF2N5O

【 分 子 量 】432.227

【元素组成】C 50.02% H 2.80% Br 18.49% F 8.79% N 16.20% O 3.70%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(XIX)

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
Extended Information