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【结 构 式】 
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【分子编号】68871 【品名】3-bromoimidazo[1,2-b]pyridazine 【CA登记号】18087-73-5 |
【 分 子 式 】C6H4BrN3 【 分 子 量 】198.022 【元素组成】C 36.39% H 2.04% Br 40.35% N 21.22% |
合成路线1
该中间体在本合成路线中的序号：(X)Bromination of 1-methyl-4-nitro-2-(trifluoromethyl)benzene (I) with NBS in the presence of AIBN in refluxing CCl4 gives the corresponding bromomethyl derivative (II), which is condensed with 1-methylpiperazine (III) by means of Et3N in CH2Cl2 to afford 1-methyl-4-[4-nitro-2-(trifluoromethyl)benzyl]piperazine (IV). Reduction of compound (IV) with Na2S2O4 in refluxing acetone/H2O yields the aniline (V), which by coupling with 3-iodo-4-methylbenzoyl chloride (VI) (prepared by chlorinating acid [VII] with SOCl2 at reflux) in the presence of DIEA and DMAP in THF provides the corresponding amide (VIII). Finally, the iodobenzene derivative (VIII) is submitted to Sonogashira coupling with 3-ethynylimidazo[1,2-b]pyridazine (IX) by means of CuI, Pd(PPh3)4 and DIEA in DMF .
Intermediate (IX) is prepared by Sonogashira coupling of 3-bromoimidazo[1,2-b]pyridazine (X) with trimethylsilyl acetylene (XI) in the presence of CuI, PdCl2(PPh3)4 and DCHA in acetonitrile at 80 °C or CuI, Pd(PPh3)4 and DIEA in DMF to give 3-[(trimethylsilyl)ethynyl]imidazo[1,2-b]pyridazine (XII), which is deprotected by cleaving the trimethylsilyl moiety by means of TBAF in THF .
| 【1】 Huang, W.S., Metcalf, C., Sundaramoorthi, R. et al. Discovery of 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a potent, orally active pan-inhibitor of breakpoint cluster region-Abelson (BCR-ABL) kinase including the T315I gatekeeper mutant. J Med Chem 2010, 53(12): 4701-19. |
| 【2】 Zou, D., Huang, W.-S., Thomas, R.M. et al. (Ariad Pharmaceuticals, Inc.).Bicyclic heteroaryl compounds. EP 1973545, JP 2009521462, US 2007191376, WO 2007075869. |
| 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) | 68863 | 1-methyl-4-nitro-2-(trifluoromethyl)benzene | C8H6F3NO2 | 详情 | 详情 | |
| (II) | 68864 | 1-(bromomethyl)-4-nitro-2-(trifluoromethyl)benzene | C8H5BrF3NO2 | 详情 | 详情 | |
| (III) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
| (IV) | 68865 | 1-methyl-4-(4-nitro-2-(trifluoromethyl)benzyl)piperazine | C13H16F3N3O2 | 详情 | 详情 | |
| (V) | 68866 | 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline | 694499-26-8 | C13H18F3N3 | 详情 | 详情 |
| (VI) | 68867 | 3-iodo-4-methylbenzoyl chloride | C8H6ClIO | 详情 | 详情 | |
| (VII) | 68868 | 3-iodo-4-methylbenzoic acid | C8H7IO2 | 详情 | 详情 | |
| (VIII) | 68869 | 3-iodo-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide | C21H23F3IN3O | 详情 | 详情 | |
| (IX) | 68870 | 3-ethynylimidazo[1,2-b]pyridazine | C8H5N3 | 详情 | 详情 | |
| (X) | 68871 | 3-bromoimidazo[1,2-b]pyridazine | 18087-73-5 | C6H4BrN3 | 详情 | 详情 |
| (XI) | 23897 | ethynyl(trimethyl)silane；trimethylsilyl acetylene | 1066-54-2 | C5H10Si | 详情 | 详情 |
| (XII) | 68872 | 3-[(trimethylsilyl)ethynyl]imidazo[1,2-b]pyridazine | C11H13N3Si | 详情 | 详情 |