合成路线: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.
参考文献标题:Alkynyl and azido-substd.4-anilinoquinazolines
文献作者:Schnur,R.C.; Arnold,L.D.(Pfizer Inc.)
参考来源:US 5747498
合成路线: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.
参考文献标题:Processes and intermediates for preparing anti-cancer cpds.
文献作者:Santafianos,D.P.; Norris,T.; Lehner,R.S.(Pfizer Inc.)
参考来源:EP 1044969; JP 2000290262; US 6476040
合成路线: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.
参考文献标题:Erlotinib Hydrochloride
文献作者:Bay閟,M.; Castar,J.; Sorbera,L.A.; Silvestre,J.S.
参考来源:Drugs Fut 2002,27(10),923
产品链接: CAS No. 183319-69-9›› 产品链接: CAS No.183321-74-6››