|
【结 构 式】 
|
【分子编号】51459 【品名】2-Methoxyethyl bromide; 2-Bromoethyl methyl ether; 1-Bromo-2-methoxyethane; Methyl 2-bromoethyl ether 【CA登记号】6482-24-2 |
【 分 子 式 】C3H7BrO 【 分 子 量 】138.99198 【元素组成】C 25.92% H 5.08% Br 57.49% O 11.51% |
合成路线1
该中间体在本合成路线中的序号：(II)The condensation of allylmalonic acid diethyl ester (I) with 2-methoxyethyl bromide (II) by means of NaOEt in ethanol gives 2-allyl-2-(2-methoxyethyl)malonic acid diethyl ester (III), which is monodecarboxylated with LiCl in DMSO/DMF at 170 C to yield the pentenoic ester (IV). The reduction of the ester group of (IV) with LiAlH4 in dry ether affords the alcohol (V), which is oxidized to the corresponding aldehyde (VI) with (COCl)2 in dichloromethane. The protection of the aldehyde group of (VI) with ethyleneglycol (VII) and Ts-OH affords the cyclic ketal (VIII), which is treated with BH3/Me2S in dichloromethane to provide the primary alcohol (IX). The oxidation of (IX) with (COCl)2 as before gives the corresponding aldehyde (X), which is condensed with the indoloazepine (XI) in refluxing toluene, yielding the pyrrolocarbazole derivative (XII). The reductive ring opening of (XII) with NaBH4 in hot acetic acid affords the tricyclic intermediate (XIII), which is debenzylated with H2 over Pd/C in acetic acid to provide the secondary amine (XIV). The deprotection of the cyclic ketal group of (XIV) with HCl and HOAc, followed by treatment with NaOH, induces cyclization to the tetracyclic compound (XV), which is finally cyclized to the target compound in refluxing toluene.
| 【1】 Bandarage, U.K.; et al.; Total syntheses of racemic albifloranine and its anti-addictive congeners, including 18-methoxycoronaridine. Tetrahedron 1999, 55, 31, 9405. |
| 【2】 Glick, S.D.; Kuehne, M.E. (Albany Medical College; University of Vermont); Ibogamine congeners. US 6211360; WO 9705869 . |
| 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) | 51458 | Allylmalonic acid diethyl ester; Allyl malonic acid; Diethyl allylmalonate | 2049-80-1 | C10H16O4 | 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) | 51460 | diethyl 2-allyl-2-(2-methoxyethyl)malonate | C13H22O5 | 详情 | 详情 | |
| (IV) | 51461 | ethyl 2-(2-methoxyethyl)-4-pentenoate | C10H18O3 | 详情 | 详情 | |
| (V) | 51462 | 2-(2-methoxyethyl)-4-penten-1-ol | C8H16O2 | 详情 | 详情 | |
| (VI) | 51463 | 2-(2-methoxyethyl)-4-pentenal | C8H14O2 | 详情 | 详情 | |
| (VII) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
| (VIII) | 51464 | 2-[1-(2-methoxyethyl)-3-butenyl]-1,3-dioxolane; 3-(1,3-dioxolan-2-yl)-5-hexenyl methyl ether | C10H18O3 | 详情 | 详情 | |
| (IX) | 51465 | 4-(1,3-dioxolan-2-yl)-6-methoxy-1-hexanol | C10H20O4 | 详情 | 详情 | |
| (X) | 48474 | 4-(1,3-dioxolan-2-yl)-6-methoxyhexanal | C10H18O4 | 详情 | 详情 | |
| (XI) | 51466 | methyl 3-benzyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-5-carboxylate | C21H22N2O2 | 详情 | 详情 | |
| (XII) | 51468 | methyl (3aS,4R,11bR)-3-benzyl-4-[2-(1,3-dioxolan-2-yl)-4-methoxybutyl]-2,3,3a,4,5,7-hexahydro-1H-pyrrolo[2,3-d]carbazole-6-carboxylate | C31H38N2O5 | 详情 | 详情 | |
| (XIII) | 51467 | methyl (5R)-3-benzyl-5-[2-(1,3-dioxolan-2-yl)-4-methoxybutyl]-1,2,3,4,5,6,7,8-octahydroazonino[5,4-b]indole-7-carboxylate | C31H40N2O5 | 详情 | 详情 | |
| (XIV) | 51469 | methyl (5R)-5-[2-(1,3-dioxolan-2-yl)-4-methoxybutyl]-1,2,3,4,5,6,7,8-octahydroazonino[5,4-b]indole-7-carboxylate | C24H34N2O5 | 详情 | 详情 | |
| (XV) | 48482 | methyl (13R,15S)-17-(2-methoxyethyl)-1,11-diazatetracyclo[13.3.1.0(4,12).0(5,10)]nonadeca-4(12),5,7,9,17-pentaene-13-carboxylate | C22H28N2O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)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 |