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【结 构 式】 
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【分子编号】67983 【品名】4-chloro-7,8,10,11,13,14-hexahydro-[1,4,7,10]tetraoxacyclododecino[2,3-g]quinazoline 【CA登记号】 |
【 分 子 式 】C14H15ClN2O4 【 分 子 量 】310.73688 【元素组成】C 54.11% H 4.87% Cl 11.41% N 9.02% O 20.6% |
合成路线1
该中间体在本合成路线中的序号：(VII)Cyclization of 4-[(3-bromophenyl)amino]-6,7-dihydroxyquinazoline (I) with ditosylate (II) [prepared by sulfonylation of triethylene glycol (III) with p-TsCl in the presence of NaOH in THF/H2O (1)] by means of K2CO3 in DMF at 80-90 °C yields the tetraoxacyclododecane derivative (IV), which is finally submitted to Sonogashira coupling with (trimethylsilyl)acetylene (V) using Pd(PPh3)4, CuI and K2CO3 in refluxing DMF .
The aryl bromide precursor (IV) can also be prepared by chlorination of the quinazolinone (VI) using POCl3 in the presence of a catalytic amount of DMF at reflux to afford the 4-chloroquinazoline derivative (VII), which is then coupled with 3-bromoaniline (VIII) in i-PrOH/DMF .
Alternatively, condensation of chloroquinazoline (VII) with 3-ethynyl-aniline (IX) in refluxing i-PrOH/DMF directly produces icotinib .
| 【1】 Wang, Y., Ding, L., Tan, F. et al. (Zhejiang Beta Pharma, Inc.). Icotinib hydrochloride, synthesis, crystallographic form, medical combination, and uses thereof. CN 10187818, EP 2392576, JP 2011527291, KR 2011031370, US 2011182882, WO 2010003313. |
| 【2】 Zhang, D., Xie, G., Davis, C., Cheng, Z., Chen, H., Wang, Y., Kamal, M.(Beta Pharma, Inc.). Fused quinazoline derivatives useful as tyrosine kinase inhibitors. US 2004048883, US 7078409, WO 2003082830. |
| 【3】 Hu, S., Xie, G., Zhang, D.X. et al. Synthesis and biological evaluation of crown ether fused quinazoline analogues as potent EGFR inhibitors. Bioorg Med Chem Lett 2012, 22(19): 6301-5. |
| 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) | 67978 | 4-[(3-bromophenyl)amino]-6,7-dihydroxyquinazoline | C14H10BrN3O2 | 详情 | 详情 | |
| (II) | 67980 | (ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl) bis(4-methylbenzenesulfonate) | 19249-03-7 | C20H26O8S2 | 详情 | 详情 |
| (III) | 67979 | 2,2'-(ethane-1,2-diylbis(oxy))diethanol;Triethylene glycol | 112-27-6 | C6H14O4 | 详情 | 详情 |
| (IV) | 67981 | N-(3-bromophenyl)-7,8,10,11,13,14-hexahydro-[1,4,7,10]tetraoxacyclododecino[2,3-g]quinazolin-4-amine | C20H20BrN3O4 | 详情 | 详情 | |
| (V) | 23897 | ethynyl(trimethyl)silane；trimethylsilyl acetylene | 1066-54-2 | C5H10Si | 详情 | 详情 |
| (VI) | 67982 | 7,8,10,11,13,14-hexahydro-[1,4,7,10]tetraoxacyclododecino[2,3-g]quinazolin-4(3H)-one | C14H16N2O5 | 详情 | 详情 | |
| (VII) | 67983 | 4-chloro-7,8,10,11,13,14-hexahydro-[1,4,7,10]tetraoxacyclododecino[2,3-g]quinazoline | C14H15ClN2O4 | 详情 | 详情 | |
| (VIII) | 19136 | 3-bromoaniline; 3-bromophenylamine; 3-bromobenzenamine | 591-19-5 | C6H6BrN | 详情 | 详情 |
| (IX) | 56445 | 3-Aminophenylacetylene; 3-Ethynylaniline; m-Aminophenylacetylene | 54060-30-9 | C8H7N | 详情 | 详情 |