新产品编号:1732799
Chemical Name: 1-Cyclopentyl-7-[4-(4-hydroxypiperidin-1-yl)phenylamino]pyrimido[4,5-d]pyrimidin-2(1H)-one
项目整合开发状态: Biological Testing
项目研究机构: Pfizer (Originator)
合成路线:Condensation of S-methylisothiourea (I) and cyano acetate derivative (II) by means of NaOMe in MeOH affords pyrimidine derivative (III),whose hydroxy group is converted into chloro by means of refluxing POCl3,yielding derivative (IV).Alkylation of (IV) with cyclopentylamine (V) and Et3N in CH2Cl2 provides derivative (VI),whose nitrile group is then reduced by means of LiAlH4 in THF to afford aminomethyl compound (VII).Treatment of (VII) with 1,1-carbonyldiimidazole (CDI) in refluxing THF gives pyrimidopyrimidinone (VIII),whose methylsulfanyl group is oxidized with 3-phenyl-2-(phenylsulfonyl)oxaziridine (IX) in CHCl3 to afford methyl sulfoxide derivative (X).Displacement of the methyl sulfoxide group of (X) with substituted aniline (XI) in TFA/acetonitrile yields 3,4-dihydropyrimidopyrimidinone (XII),which is finally oxidized by means of KOtBu in THF or DMSO.
📌 参考资料/链接：
参考文献标题:Bicyclic pyrimidines and bicyclic 3,4-dihydropyrimidines as inhibitors of cellular proliferation
文献作者:Dobrusin,E.M.; Showalter,H.D.H.; Schroeder,M.C.; Toogood,P.; Kramer,J.B.; Trumpp-Kallmeyer,S.A.; Hamby,J.M.(Pfizer Inc.)
参考来源:WO 9961444
📄 详细内容
合成路线:Condensation of S-methylisothiourea (I) and cyano acetate derivative (II) by means of NaOMe in MeOH affords pyrimidine derivative (III),whose hydroxy group is converted into chloro by means of refluxing POCl3,yielding derivative (IV).Alkylation of (IV) with cyclopentylamine (V) and Et3N in CH2Cl2 provides derivative (VI),whose nitrile group is then reduced by means of LiAlH4 in THF to afford aminomethyl compound (VII).Treatment of (VII) with 1,1-carbonyldiimidazole (CDI) in refluxing THF gives pyrimidopyrimidinone (VIII),whose methylsulfanyl group is oxidized with 3-phenyl-2-(phenylsulfonyl)oxaziridine (IX) in CHCl3 to afford methyl sulfoxide derivative (X).Displacement of the methyl sulfoxide group of (X) with substituted aniline (XI) in TFA/acetonitrile yields 3,4-dihydropyrimidopyrimidinone (XII),which is finally oxidized by means of KOtBu in THF or DMSO.
参考文献标题:Synthesis and biological activity of a novel series of pyrimidopyrimidinones as inhibitors of cyclin-dependent kinases
文献作者:Kramer,J.B.; et al.
参考来源:219th ACS Natl Meet (March 26 2000,San Francisco) 2000,Abst MEDI 40