|
【结 构 式】 
|
【药物名称】Icotinib 【化学名称】N-(3-Ethynylphenyl)-7,8,10,11,13,14-hexahydro[1,4,7,10]tetraoxacyclododecino[2,3-g]quinazolin-4-amine hydrochloride 【CA登记号】 【 分 子 式 】C22H21N3O4.HCl 【 分 子 量 】427.8808 |
【开发单位】Zhejiang Beta Pharma, Inc. (CN) 【药理作用】EGFR Inhibitor;Oncolytic |
合成路线1
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 |
合成路线2
Chlorination of 4,5-dimethoxy-2-nitrobenzoic acid (X) with SOCl2, followed by reaction with aqueous ammonia yields the nitrobenzamide (XI), which is reduced to the corresponding aminobenzamide (XII) by means of NaBH4 in the presence of catalytic amounts of CuSO4. Anthranilamide (XII) is then cyclized to quinazolinone (XIII) by refluxing in formic acid . Alternatively, cyclization of 4,5-dimethoxyanthranilic acid (XIV), either by heating with formamide at 190 °C or with formamidine hydrochloride at 210 °C , gives rise to quinazolinone (XIII) . Subsequent chlorination of compound (XIII) to the corresponding 4-chloroquinazoline (XV) is accomplished by treatment with either POCl3 , SOCl2 or (COCl)2 in the presence of catalytic amounts of DMF. Chloroquinazoline (XV) is then condensed with 3-bromoaniline (VIII) in refluxing EtOH or i-PrOH to produce anilinoquinazoline (XVI) , which is finally demethylated by either treatment with BBr3 in THF or by heating with pyridinium chloride at 205 °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】 Uckun, F.M., Narla, R.K., Liu, X.-P. (Parker Hughes Institute). Quinazolines for treating brain tumor. EP 1082311, JP 2002516823, US 6316454, WO 1999061428. |
| 【3】 Barker, A.J. (AstraZeneca plc). Quinazoline derivatives. CA 2086968, EP 0566226, JP 1994073025, US 5457105, US 5616582. |
| 【4】 Johnström, P., Fredriksson, A., Thorell, J.-O., Stone-Elander, S. Synthesis of [methoxy-11C]PD153035, a selective EGR receptor tyrosine kinase inhibitor. J Label Compd Radiopharm 1998, 41(7): 623-9. |
| 【5】 Bridges, A.J., Zhou, H., Cody, D.R. et al. Tyrosine kinase inhibitors. 8. An unusually steep structure-activity relationship for analogues of 4-(3-bromoanilino)-6,7-dimethoxyquinazoline (PD 153035), a potent inhibitor of the epidermal growth factor receptor. J Med Chem 1996, 39(1): 267-76. |
| 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 | |
| (VIII) | 19136 | 3-bromoaniline; 3-bromophenylamine; 3-bromobenzenamine | 591-19-5 | C6H6BrN | 详情 | 详情 |
| (X) | 31789 | 4,5-dimethoxy-2-nitrobenzoic acid | 4998-07-6 | C9H9NO6 | 详情 | 详情 |
| (XI) | 31791 | 4,5-dimethoxy-2-nitrobenzamide | 4959-60-8 | C9H10N2O5 | 详情 | 详情 |
| (XII) | 31792 | 2-amino-4,5-dimethoxybenzamide | 5004-88-6 | C9H12N2O3 | 详情 | 详情 |
| (XIII) | 18684 | 6,7-dimethoxy-4(3H)-quinazolinone | 13794-72-4 | C10H10N2O3 | 详情 | 详情 |
| (XIV) | 23763 | 2-amino-4,5-dimethoxybenzoic acid | 5653-40-7 | C9H11NO4 | 详情 | 详情 |
| (XV) | 23765 | 4-chloro-6,7-dimethoxyquinazoline; 4-chloro-6-methoxy-7-quinazolinyl methyl ether | C10H9ClN2O2 | 详情 | 详情 | |
| (XVI) | 67984 | N-(3-bromophenyl)-6,7-dimethoxyquinazolin-4-amine hydrochloride | 183322-45-4 | C16H14BrN3O2.HCl | 详情 | 详情 |
合成路线3
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 |