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【结 构 式】 
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【分子编号】67517 【品名】5-((4-bromo-2-fluorophenyl)amino)-4-fluoro-1-methyl-1H-benzo[d]imidazole-6-carboxylic acid 【CA登记号】 |
【 分 子 式 】C15H10BrF2N3O2 【 分 子 量 】382.164 【元素组成】C 47.14% H 2.64% Br 20.91% F 9.94% N 11.00% O 8.37% |
合成路线1
该中间体在本合成路线中的序号：(X)Nitration of 2,3,4-trifluorobenzoic acid (I) using HNO3 and H2SO4 gives 2,3,4-trifluoro-5-nitrobenzoic acid (II), which by displacement with NH4OH in H2O at 0 °C yields 4-amino-2,3-difluoro-5-nitrobenzoic acid (III). Fisher esterification of acid (III) with Me3SiCHN2 in THF/MeOH at 0 °C affords 4-amino-2,3-difluoro-5-nitrobezoic acid methyl ester (IV), which is condensed with 2-fluoroaniline (V) in xylene at 140 °C to provide methyl 4-amino-3-fluoro-2-(2-fluorophenylamino)-5-nitrobenzoic acid methyl ester (VI). Reduction and cyclization of intermediate (VI) using formic acid and Pd(OH)2/C in EtOH at 95 °C generates methyl 4-fluoro-5-(2-fluorophenylamino)-benzimidazole-6-carboxylate (VII), which by bromination with NBS and p-TsOH in DMF produces the bromo derivative (VIII). N-Methylation of compound (VIII) with methyl iodide by means of K2CO3 in DMF at 75 °C gives compound (IX), which is hydrolyzed with NaOH in THF/H2O to yield the free carboxylic acid (X). Condensation of carboxylic acid (X) with O-[2-(vinyloxy)ethyl]hydroxylamine (XI) using HOBt, Et3N and EDC in DMF affords amide (XII), which is finally treated with HCl in EtOH (1).
Intermediate O-[2-(vinyloxy)ethyl]hydroxylamine (XI) is prepared by Mitsnoubu reaction of 2-(vinyloxy)ethanol (XIII) with N-hydroxy - phthalimide (XIV) using PPh3 and DEAD in THF at 0 °C to give 2-[2-(vinyloxy)ethoxy]-1H-isoindole-1,3(2H)-dione (XV), which is finally treated with MeNHNH2 in CH2Cl2 .
| 【1】 Barrett, S.D., Biwersi, C., Warmus, J.S., Tecle, H., Kaufman, M. (Pfizer, Inc.). Oxygenated esters of 4-iodo phenylamino benzhydroxamic acids. WO 2002006213; EP 1301472; CA 2416685; US 2004054172; US 6960614. |
| 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) | 34622 | 2,3,4-trifluorobenzoic acid | 61079-72-9 | C7H3F3O2 | 详情 | 详情 |
| (II) | 67510 | 2,3,4-trifluoro-5-nitrobenzoic acid | C7H2F3NO4 | 详情 | 详情 | |
| (III) | 67511 | 4-amino-2,3-difluoro-5-nitrobenzoic acid | C7H4F2N2O4 | 详情 | 详情 | |
| (IV) | 67512 | 4-amino-2,3-difluoro-5-nitrobezoic acid methyl ester | 284030-58-6 | C8H6F2N2O4 | 详情 | 详情 |
| (V) | 22296 | 2-fluorophenylamine; 2-fluoroaniline | 348-54-9 | C6H6FN | 详情 | 详情 |
| (VI) | 67513 | methyl 4-amino-3-fluoro-2-(2-fluorophenyl-amino)-5-nitrobenzoic acid methyl ester | C15H13F2N3O4 | 详情 | 详情 | |
| (VII) | 67514 | methyl 4-fluoro-5-(2-fluorophenylamino)-benzimidazole-6-carboxylate | C15H11F2N3O2 | 详情 | 详情 | |
| (VIII) | 67515 | methyl 5-((4-bromo-2-fluorophenyl)amino)-4-fluoro-1H-benzo[d]imidazole-6-carboxylate | C15H10BrF2N3O2 | 详情 | 详情 | |
| (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 | |
| (XI) | 67518 | O-[2-(vinyloxy)ethyl]hydroxylamine | 391212-29-6 | C4H9NO2 | 详情 | 详情 |
| (XII) | 67519 | 5-((4-bromo-2-fluorophenyl)amino)-4-fluoro-1-methyl-N-(2-(vinyloxy)ethoxy)-1H-benzo[d]imidazole-6-carboxamide | C19H17BrF2N4O3 | 详情 | 详情 | |
| (XIII) | 67520 | 2-(vinyloxy)ethanol | 764-48-7 | C4H8O2 | 详情 | 详情 |
| (XIV) | 13505 | N-Hydroxyphthalimide; 2-Hydroxy-1H-isoindole-1,3(2H)-dione | 524-38-9 | C8H5NO3 | 详情 | 详情 |
| (XV) | 67521 | 2-[2-(vinyloxy)ethoxy]-1H-isoindole-1,3(2H)-dione | C12H11NO4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)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 |