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【结 构 式】

【分子编号】68872

【品名】3-[(trimethylsilyl)ethynyl]imidazo[1,2-b]pyridazine

【CA登记号】  

【 分 子 式 】C11H13N3Si

【 分 子 量 】215.33

【元素组成】C 61.36% H 6.08% N 19.51% Si 13.04%

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:(XII)

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
Extended Information