【结 构 式】 |
【分子编号】68870 【品名】3-ethynylimidazo[1,2-b]pyridazine 【CA登记号】 |
【 分 子 式 】C8H5N3 【 分 子 量 】143.14792 【元素组成】C 67.12% H 3.52% N 29.35% |
合成路线1
该中间体在本合成路线中的序号:(IX)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 |
合成路线2
该中间体在本合成路线中的序号:(IX)In a related way, Sonogashira coupling of 3-iodo-4-methylbenzoic acid (VII) with 3-ethynylimidazo[1,2-b]pyridazine (IX) in the presence of CuI, Pd(PPh3)4 and either Et3N in EtOAc or DIEA in DMF affords 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzoic acid (XIII). Finally, carboxylic acid (XIII) is chlorinated with (COCl)2 in the presence of NMM in CH2Cl2, followed by amidation with the aniline derivative (V) by means of DMAP at reflux .
【1】 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 |
---|---|---|---|---|---|---|
(V) | 68866 | 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline | 694499-26-8 | C13H18F3N3 | 详情 | 详情 |
(VII) | 68868 | 3-iodo-4-methylbenzoic acid | C8H7IO2 | 详情 | 详情 | |
(IX) | 68870 | 3-ethynylimidazo[1,2-b]pyridazine | C8H5N3 | 详情 | 详情 | |
(XIII) | 68873 | 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4- methylbenzoic acid | C16H11N3O2 | 详情 | 详情 |