Gefitinib, ZD-1839, Iressa
吉非替尼 4-(3-氯-4-氟苯基氨基)-7-甲氧基-6-[3-(4-吗啉基)丙氧基]喹唑啉二盐酸盐 Chemical Name: 4-(3-Chloro-4-fluorophenylamino)-7-methoxy-6-[3-(4-morpholinyl)propoxy]quinazoline
CAS No. 184475-35-2, 184475-56-7 (diHCl), 184475-55-6 (mono HCl salt)
项目整合开发状态: Launched-2002
项目研究机构: AstraZeneca (Originator), EORTC (Not Determined), M.D. Anderson Cancer Center (Not Determined), National Cancer Institute (Not Determined)
合成路线:Monodemethylation of 6,7-dimethoxyquinazolin-4(3H)-one (I) in refluxing methanesulfonic acid in the presence of L-methionine provides 6-hydroxy-7-methoxyquinazolin-4(3H)-one (II),which is acetylated with acetic anhydride and pyridine at 100 C to give the acetate (III).Treatment of compound (III) with refluxing SOCl2 and a catalytic amount of DMF yields chloride (IV),which by condensation with 3-chloro-4-fluoroaniline (V) in boiling isopropanol affords the anilinoquinazoline (VI).Hydrolysis of the acetate group of (VI) by treatment with NH4OH in refluxing MeOH gives the 6-hydroxyquinazoline derivative (VII),which finally is alkylated with 3-(4-morpholinyl)-propyl chloride (VIII) or 3-(4-morpholinyl)propyl bromide (IX).
📌 参考资料/链接：
参考文献标题:Quinazoline derivs.
文献作者:Gibson,K.H.(AstraZeneca plc)
参考来源:EP 0823900; JP 1999504033; US 5770599; WO 9633980
📄 详细内容
合成路线:Monodemethylation of 6,7-dimethoxyquinazolin-4(3H)-one (I) in refluxing methanesulfonic acid in the presence of L-methionine provides 6-hydroxy-7-methoxyquinazolin-4(3H)-one (II),which is acetylated with acetic anhydride and pyridine at 100 C to give the acetate (III).Treatment of compound (III) with refluxing SOCl2 and a catalytic amount of DMF yields chloride (IV),which by condensation with 3-chloro-4-fluoroaniline (V) in boiling isopropanol affords the anilinoquinazoline (VI).Hydrolysis of the acetate group of (VI) by treatment with NH4OH in refluxing MeOH gives the 6-hydroxyquinazoline derivative (VII),which finally is alkylated with 3-(4-morpholinyl)-propyl chloride (VIII) or 3-(4-morpholinyl)propyl bromide (IX).
参考文献标题:Studies leading to the identification of ZD1839 (Iressa(TM)): An orally active,selective epidermal growth factor receptor tyrosine kinase inhibitor targeted to the treatment of cancer
文献作者:Barker,A.J.; Gibson,K.H.; Grundy,W.; Godfrey,A.A.; Barlow,J.J.; Healy,M.P.; Woodburn,J.R.; Ashton,S.E.; Curry,B.J.; Scarlett,L.; Henthorn,L.; Richards,L.
参考来源:Bioorg Med Chem Lett 2001,11(14),1911
合成路线:Monodemethylation of 6,7-dimethoxyquinazolin-4(3H)-one (I) in refluxing methanesulfonic acid in the presence of L-methionine provides 6-hydroxy-7-methoxyquinazolin-4(3H)-one (II),which is acetylated with acetic anhydride and pyridine at 100 C to give the acetate (III).Treatment of compound (III) with refluxing SOCl2 and a catalytic amount of DMF yields chloride (IV),which by condensation with 3-chloro-4-fluoroaniline (V) in boiling isopropanol affords the anilinoquinazoline (VI).Hydrolysis of the acetate group of (VI) by treatment with NH4OH in refluxing MeOH gives the 6-hydroxyquinazoline derivative (VII),which finally is alkylated with 3-(4-morpholinyl)-propyl chloride (VIII) or 3-(4-morpholinyl)propyl bromide (IX).
参考文献标题:Iressa
文献作者:D'Souza,N.; Castar,J.; Levin,M.
参考来源:Drugs Fut 2002,27(4),339