(ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl) bis(4-methylbenzenesulfonate) -Drug Synthesis Database

【结构式】

【分子编号】67980

【品名】(ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl) bis(4-methylbenzenesulfonate)

【CA登记号】19249-03-7

【分子式】C₂₀H₂₆O₈S₂

【分子量】458.554

【元素组成】C 52.39% H 5.71% O 27.91% S 13.99%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(II)

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 .

参考文献中间体

合成目标

【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

合成路线2

该中间体在本合成路线中的序号：(II)

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 .

参考文献中间体

合成目标

【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

Extended Information