【结 构 式】 |
【药物名称】Erlotinib hydrochloride, Ro-50-8231, R-1415, NSC-718781, OSI-774, CP-358774, Tarceva 【化学名称】4-(3-Ethynylphenylamino)-6,7-bis(2-methoxyethoxy)quinazoline hydrochloride 【CA登记号】183319-69-9, 183321-74-6 (free base) 【 分 子 式 】C22H24ClN3O4 【 分 子 量 】429.90728 |
【开发单位】OSI (Proprietary), Pfizer (Originator), Cleveland Clinic Foundation (Not Determined), M.D. Anderson Cancer Center (Not Determined), Chugai (Codevelopment), Genentech (Codevelopment), National Cancer Institute (Codevelopment), Roche (Codevelopment) 【药理作用】Brain Cancer Therapy, Breast Cancer Therapy, Cervical Cancer Therapy, Colorectal Cancer Therapy, Gastric Cancer Therapy, Glioblastoma MultiformeTherapy, Head and Neck Cancer Therapy, Liver Cancer Therapy, Lung Cancer Therapy, Non-Small Cell Lung Cancer Therapy, Oncolytic Drugs, Ovarian Cancer Therapy, Pancreatic Cancer Therapy, Renal Cancer Therapy, Solid Tumors Therapy, EGFR (erbB1) Inhibitors, Inhibitors of Signal Transduction Pathways, Tyrphostins |
合成路线1
【1】 Chandregowda V,Rao GV, et aL 2007. One-pot conversion of 2-nitrobenzonitriles to quinazolin-4 (3H)-ones and synthesis of gefitinib and erlotinib hydrochloride. Heterocycles, 71: 39~48 |
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) | 39749 | 3,4-dihydroxybenzaldehyde | 139-85-5 | C7H6O3 | 详情 | 详情 |
(II) | 66352 | 3,4-bis(2-methoxyethoxy)benzaldehyde | C13H18O5 | 详情 | 详情 | |
(III) | 66353 | 3,4-bis(2-methoxyethoxy)benzonitrile | C13H17NO4 | 详情 | 详情 | |
(IV) | 66354 | 4,5-bis(2-methoxyethoxy)-2-nitrobenzonitrile | 236750-65-5 | C13H16N2O6 | 详情 | 详情 |
(V) | 66355 | 2-amino-4,5-bis(2-methoxyethoxy)benzonitrile | C13H18N2O4 | 详情 | 详情 | |
(VI) | 56443 | 6,7-bis(2-methoxyethoxy)-4(3H)-quinazolinone | 179688-29-0 | C14H18N2O5 | 详情 | 详情 |
合成路线2
【1】 Jyothi Prasad R,Nageshwar Rao B,et al. 2007. A novel prcess for preparation of erlotinib. WO 2007060691 |
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) | 18684 | 6,7-dimethoxy-4(3H)-quinazolinone | 13794-72-4 | C10H10N2O3 | 详情 | 详情 |
(II) | 66356 | 6,7-dihydroxyquinazolin-4(3H)-one | C8H6N2O3 | 详情 | 详情 | |
(III) | 66357 | 4-oxo-3,4-dihydroquinazoline-6,7-diyl diacetate | C12H10N2O5 | 详情 | 详情 | |
(IV) | 66358 | 4-chloroquinazoline-6,7-diyl diacetate | C12H9ClN2O4 | 详情 | 详情 | |
(V) | 66359 | 4-((3-ethynylphenyl)amino)quinazoline-6,7-diyl diacetate | C20H15N3O4 | 详情 | 详情 | |
(VI) | 66360 | 4-((3-ethynylphenyl)amino)quinazoline-6,7-diol | C16H11N3O2 | 详情 | 详情 |
合成路线3
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 |