Vandetanib, AZD-6474, ZD-6474
凡德他尼Chemical Name: N-(4-Bromo-2-fluorophenyl)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazolin-4-amine
CAS No. 338992-00-0, 338992-48-6 (HCl), 338992-53-3 (monotrifluoroacetate)
项目整合开发状态: Phase II
项目研究机构: AstraZeneca (Originator)
合成路线:Ethyl isonipecotate (I) was protected as the N-Boc derivative (II) and then reduced to alcohol (III) using LiAlH4.Treatment of alcohol (III) with p-toluenesulfonyl chloride in the presence of DBU afforded the intermediate tosylate (IV).
合成路线:Nucleophilic substitution of the chloroquinazoline (V) with 4-bromo-2-fluoroaniline (VI) in refluxing isopropanol provided the anilino quinazoline (VII).Subsequent cleavage of the benzyl ether group of (VII) by treatment with hot trifluoroacetic acid gave phenol (VIII),which was condensed with tosylate (IV) to furnish the ether adduct (IX).Acid deprotection of the N-Boc group of (IX) gave piperidine (X).Finally,reductive methylation of (X) using formaldehyde and sodium cyanoborohydride yielded the corresponding N-methyl piperidine.
📌 参考资料/链接：
参考文献标题:Quinazoline derivs.as VEGF inhibitors
文献作者:Hennequin,L.F.A.; Stokes,E.S.E.; Thomas,A.P.(AstraZeneca AB; AstraZeneca plc)
参考来源:WO 0132651
📄 详细内容
合成路线:The condensation of 7-hydroxy-6-methoxy-3-(pivaloyloxymethyl)quinazolin-3(4H)-one (I) with N-(tert-butoxycarbonyl)piperidine-4-methanol (II) by means of DEAD and PPh3 in dichloromethane or K2CO3 in DMF gives the aryl ether (III),which is deprotected with TFA to yield the free piperidine (IV).The reductive methylation of (IV) with HCHO and NaBH3CN in methanol/THF affords the methylated piperidine (V),which is deprotected with NH3 in methanol to provide the quinazolinone (VI).The reaction of (VI) with SOCl2 in DMF gives the 4-chloroquinazoline (VII),which is finally condensed with 4-chloro-2-fluoroaniline (VIII) by means of NaH in DMF to yield the target quinazoline-4-amine.
参考文献标题:Novel 4-anilinoquinazolines with C-7 basic side chains: Design and structure activity relationship of a series of potent,orally active,VEGF receptor tyrosine kinase inhibitors
文献作者:Hennequin,L.F.; Stokes,E.S.; Thomas,A.P.; Johnstone,C.; Ple,P.A.; Ogilvie,D.J.; Dukes,M.; Wedge,S.R.; Kendrew,J.; Curwen,J.O.
参考来源:J Med Chem 2002,45(6),1300
产品链接: CAS No. 338992-00-0›› 产品链接: CAS No.338992-53-3››