|
【结 构 式】 
|
【分子编号】56439 【品名】3,4-Dihydrohybenzoic acid ethyl ester; Ethyl 3,4-dihydroxybenzoate; Ethyl Protocatechuate; Protocatechuic acid ethyl ester 【CA登记号】3943-89-3 |
【 分 子 式 】C9H10O4 【 分 子 量 】182.176 【元素组成】C 59.34% H 5.53% O 35.13% |
合成路线1
该中间体在本合成路线中的序号：(I)Erlotinib can be obtained by three related ways: 1) Alkylation of 3,4-dihydroxybenzoic acid ethyl ester (I) with 2-bromoethyl methyl ether (II) by means of K2CO3 and tetrabutylammonium iodide (TBAI) in refluxing acetone gives 3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester (III), which is nitrated with HNO3 in acetic acid to yield 4,5-bis(2-methoxyethoxy)-2-nitrobenzoic acid ethyl ester (IV). Reduction of ester (IV) with H2 over PtO2 in ethanol/HCl affords the corresponding aniline derivative (V), which is cyclized with ammonium formate (VI) in formamide at 165 C to provide 6,7-bis(2-methoxyethoxy)-quinazolin-4(3H)-one (VII). Reaction of quinazoline (VII) with oxalyl chloride in refluxing chloroform gives the expected 4-chloroquinazoline derivative (VIII), which is finally condensed with 3-ethynylaniline (IX) in refluxing isopropanol containing pyridine. 2) Reaction of the 4-chloroquinazoline derivative (VIII) with 4-(3-aminophenyl)-2-methyl-3-butyn-2-ol (X) in refluxing acetonitrile gives the secondary amine (XI), which is finally treated with anhydrous solid NaOH in refluxing either 1-butanol, 2-butanol, isopropanol or 2-methoxyethanol. 3) Reaction of 3-bromonitrobenzene (XII) with trimethylsilylacetylene (XIII) by means of a Pd catalyst and Cu2I in hot TEA gives 3-(trimethylsilylethynyl)nitrobenzene (XIV), which is reduced with H2 over Pt/Al2O3 in isopropanol to provide 3-(trimethylsilylethynyl)aniline (XV). Condensation of the aniline (XV) with the quinazoline derivative (VIII) in refluxing isopropanol affords the silylated quinazoline derivative (XVI), which is finally deprotected with TBAF in THF.
| 【1】 Bayes, M.; Castaner, J.; Sorbera, L.A.; Silvestre, J.S.; Erlotinib Hydrochloride. Drugs Fut 2002, 27, 10, 923. |
| 【2】 Schnur, R.C.; Arnold, L.D. (Pfizer Inc.); Alkynyl and azido-substd. 4-anilinoquinazolines. US 5747498 . |
| 【3】 Schnur, R.C.; Arnold, L.D. (Pfizer Inc.); Quinazoline derivs.. EP 0817775; EP 1110953; JP 1998506633; WO 9630347 . |
| 【4】 Santafianos, D.P.; Norris, T.; Lehner, R.S. (Pfizer Inc.); Processes and intermediates for preparing anti-cancer cpds.. EP 1044969; JP 2000290262; US 6476040 . |
| 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) | 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 |
| (II) | 51459 | 2-Methoxyethyl bromide; 2-Bromoethyl methyl ether; 1-Bromo-2-methoxyethane; Methyl 2-bromoethyl ether | 6482-24-2 | C3H7BrO | 详情 | 详情 |
| (III) | 56440 | ethyl 3,4-bis(2-methoxyethoxy)benzoate | 183322-16-9 | C15H22O6 | 详情 | 详情 |
| (IV) | 56441 | ethyl 4,5-bis(2-methoxyethoxy)-2-nitrobenzoate | 179688-26-7 | C15H21NO8 | 详情 | 详情 |
| (V) | 56442 | ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate | 179688-27-8 | C15H23NO6 | 详情 | 详情 |
| (VII) | 56443 | 6,7-bis(2-methoxyethoxy)-4(3H)-quinazolinone | 179688-29-0 | C14H18N2O5 | 详情 | 详情 |
| (VIII) | 56444 | 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline; 4-chloro-6-(2-methoxyethoxy)-7-quinazolinyl 2-methoxyethyl ether | 183322-18-1 | C14H17ClN2O4 | 详情 | 详情 |
| (IX) | 56445 | 3-Aminophenylacetylene; 3-Ethynylaniline; m-Aminophenylacetylene | 54060-30-9 | C8H7N | 详情 | 详情 |
| (X) | 56446 | 4-(3-aminophenyl)-2-methyl-3-butyn-2-ol | C11H13NO | 详情 | 详情 | |
| (XI) | 56447 | 4-(3-{[6,7-bis(2-methoxyethoxy)-4-quinazolinyl]amino}phenyl)-2-methyl-3-butyn-2-ol | C25H29N3O5 | 详情 | 详情 | |
| (XII) | 56448 | 1-Bromo-3-nitrobenzene; 3-Bromonitrobenzene; 3-Nitrobromobenzene; m-Bromonitrobenzene; m-Nitrobromobenzene | 585-79-5 | C6H4BrNO2 | 详情 | 详情 |
| (XIII) | 23897 | ethynyl(trimethyl)silane；trimethylsilyl acetylene | 1066-54-2 | C5H10Si | 详情 | 详情 |
| (XIV) | 56449 | trimethyl[2-(3-nitrophenyl)ethynyl]silane | C11H13NO2Si | 详情 | 详情 | |
| (XV) | 56450 | 3-[2-(trimethylsilyl)ethynyl]aniline; 3-[2-(trimethylsilyl)ethynyl]phenylamine | C11H15NSi | 详情 | 详情 | |
| (XVI) | 56451 | N-[6,7-bis(2-methoxyethoxy)-4-quinazolinyl]-N-{3-[2-(trimethylsilyl)ethynyl]phenyl}amine; 6,7-bis(2-methoxyethoxy)-N-{3-[2-(trimethylsilyl)ethynyl]phenyl}-4-quinazolinamine | C25H31N3O4Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVIIb)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 |