Plevitrexed, BGC-9331, ZD-9331, Vamidex
Chemical Name: 2(S)-[4-[N-(2,7-Dimethyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(2-propynyl)amino]-2-fluorobenzamido]-4-(1H-tetrazol-5-yl)butyric acid
CAS No. 153537-73-6, 153537-74-7 ((R)-isomer)
项目整合开发状态: Phase I/II
项目研究机构: AstraZeneca (Originator), BTG (Originator), Institute of Cancer Research (Originator)
合成路线:Cyclization of N-acetyl dimethylanthranilic acid (I) with acetic anhydride produced benzoxazinone (II) which,upon treatment with aqueous ammonia,furnished trimethylquinazolinone (III).Incorporation of the N-(pivaloyloxy)methyl (POM) protecting group of (III) gave (IV),and subsequent regioselective bromination with N-bromosuccinimide in the presence of AIBN yielded the 6-bromomethyl compound (V).Condensation of (V) with p-aminobenzoate derivative (VI) afforded tertiary amine (VII).After trifluoroacetic acid-promoted cleavage of the tert-butyl ester of (VII),coupling with pentafluorophenol in the presence of DCC provided pentafluorophenyl ester (VIII).The title compound was then obtained by condensation of (VIII) with the tetrazolyl aminoester (IX) in the presence of 1-hydroxybenzotriazole,followed by basic hydrolysis of both methyl ester and POM protecting group.
📌 参考资料/链接：
参考文献标题:Design and synthesis of potent non-polyglutamatable quinazoline antifolate thymidylate synthase inhibitors
文献作者:Marsham,P.R.; Wardleworth,M.; Boyle,F.T.; Hennequin,L.F.; Kimbell,R.; Brown,M.; Jackman,A.L.
参考来源:J Med Chem 1999,42(19),3809
📄 详细内容
合成路线:Cyclization of N-acetyl dimethylanthranilic acid (I) with acetic anhydride produced benzoxazinone (II) which,upon treatment with aqueous ammonia,furnished trimethylquinazolinone (III).Incorporation of the N-(pivaloyloxy)methyl (POM) protecting group of (III) gave (IV),and subsequent regioselective bromination with N-bromosuccinimide in the presence of AIBN yielded the 6-bromomethyl compound (V).Condensation of (V) with p-aminobenzoate derivative (VI) afforded tertiary amine (VII).After trifluoroacetic acid-promoted cleavage of the tert-butyl ester of (VII),coupling with pentafluorophenol in the presence of DCC provided pentafluorophenyl ester (VIII).The title compound was then obtained by condensation of (VIII) with the tetrazolyl aminoester (IX) in the presence of 1-hydroxybenzotriazole,followed by basic hydrolysis of both methyl ester and POM protecting group.
参考文献标题:Quinazoline antifolate thymidylate synthase inhibitors: replacement of glutamic acid in the C2-methyl series
文献作者:Marsham,P.R.; Jackman,A.L.; Barker,A.J.; Boyle,F.T.; Pegg,S.J.; Wardleworth,J.M.; Kimbell,R.; O'Connor,B.M.; Calvert,A.H.; Hughes,L.R.
参考来源:J Med Chem 1995,38(6),994-1004
产品链接: CAS No. 153537-73-6›› 产品链接: CAS No.153537-74-7››