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【结 构 式】 
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【分子编号】67986 【品名】ethyl 2,3,5,6,8,9-hexahydrobenzo[b][1,4,7,10]tetraoxacyclododecine-12-carboxylate 【CA登记号】 |
【 分 子 式 】C15H20O6 【 分 子 量 】296.3202 【元素组成】C 60.8% H 6.8% O 32.4% |
合成路线1
该中间体在本合成路线中的序号：(XVIIIb)The crown ether fused quinazoline precursor (VI) can be prepared as follows. Cyclization of either methyl (XVIIa) or ethyl (XVIIb) 3,4-dihydroxybenzoate with triethyleneglycol ditosylate (II) in the presence of K2CO3 in DMF provides the corresponding tetraoxacyclododecane derivatives (XVIIIa) and (XVIIIb), which by nitration with HNO3 in the presence of H2SO4 in AcOH afford the respective ortho-nitrobenzoates (XIXa) and (XIXb) . Reduction of the nitro group in compounds (XIXa) and (XIXb) by catalytic hydrogenation over Pd/C, optionally in the presence of methanolic HCl (generated from AcCl and MeOH), followed by acidification with HCl in MeOH result in the corresponding anthranilates (XXa) and (XXb) , which finally undergo cyclization with HCONH2 and HCOONH4 at 165 °C .
| 【1】 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. |
| 【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. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVIIa) | 11659 | methyl 3,4-dihydroxybenzoate | 2150-43-8 | C8H8O4 | 详情 | 详情 |
| (XVIIb) | 56439 | 3,4-Dihydrohybenzoic acid ethyl ester; Ethyl 3,4-dihydroxybenzoate; Ethyl Protocatechuate; Protocatechuic acid ethyl ester | 3943-89-3 | C9H10O4 | 详情 | 详情 |
| (XVIIIa) | 67985 | methyl 2,3,5,6,8,9-hexahydrobenzo[b][1,4,7,10]tetraoxacyclododecine-12-carboxylate | C14H18O6 | 详情 | 详情 | |
| (XVIIIb) | 67986 | ethyl 2,3,5,6,8,9-hexahydrobenzo[b][1,4,7,10]tetraoxacyclododecine-12-carboxylate | C15H20O6 | 详情 | 详情 | |
| (XIXa) | 67988 | methyl 13-nitro-2,3,5,6,8,9-hexahydrobenzo[b][1,4,7,10]tetraoxacyclododecine-12-carboxylate | C14H17NO8 | 详情 | 详情 | |
| (XIXb) | 67987 | ethyl 13-nitro-2,3,5,6,8,9-hexahydrobenzo[b][1,4,7,10]tetraoxacyclododecine-12-carboxylate | C15H19NO8 | 详情 | 详情 | |
| (XXa) | 67989 | methyl 13-amino-2,3,5,6,8,9-hexahydrobenzo[b][1,4,7,10]tetraoxacyclododecine-12-carboxylate hydrochloride | C14H19NO6.HCl | 详情 | 详情 | |
| (XXb) | 67990 | ethyl 13-amino-2,3,5,6,8,9-hexahydrobenzo[b][1,4,7,10]tetraoxacyclododecine-12-carboxylate hydrochloride | C15H21NO6.HCl | 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 |
| (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 |