新产品编号:823149
Chemical Name: 4-[5-[1-(3-Chlorobenzyl)-2-oxopyrrolidin-3(S)-ylaminomethyl]-1H-imidazol-1-ylmethyl]benzonitrile
CAS No. 330185-25-6, 330182-86-0 (diHCl), 330185-24-5 (enantiomer)
项目整合开发状态: Preclinical
项目研究机构: Merck & Co. (Originator)
合成路线:4-(Hydroxymethyl)imidazole (I) was protected as the 1-trityl derivative (II) by treatment with triphenylmethyl chloride.The hydroxyl group of (II) was then esterified with Ac2O in pyridine to yield acetate (III).After N-alkylation of (III) with 4-cyanobenzyl bromide (IV),the intermediate imidazolium bromide was deprotected by refluxing in MeOH to give (V).Subsequent hydrolysis of the acetate ester with LiOH provided alcohol (VI),which was oxidized to aldehyde (VII) under Swern conditions employing DMSO in the presence of SO3-pyridine complex.
合成路线:Coupling of N-Boc-L-methionine (VIII) with 3-chlorobenzylamine (IX) using PyBOP provided amide (X).Methylation of the sulfide group of (X) with iodomethane gave rise to the sulfonium salt (XI),which was further cyclized to pyrrolidinone (XII) by treatment with lithium bis(trimethylsilyl)amide in cold THF.Acid deprotection of the Boc group of (XII) furnished amine (XIII).This was finally subjected to reductive alkylation with aldehyde (VII) in the presence of sodium cyanoborohydride to provide the corresponding (imidazolylmethyl)amine.
📌 参考资料/链接：
参考文献标题:Inhibitors of prenyl-protein transferase
文献作者:Beshore,D.C.; Bell,I.M.; Gallicchio,S.N.; Sisko,J.T.; Zartman,C.B.; Lumma,W.C.Jr.(Merck & Co.,Inc.)
参考来源:WO 0117992
📄 详细内容
合成路线:Coupling of N-Boc-L-methionine (VIII) with 3-chlorobenzylamine (IX) using PyBOP provided amide (X).Methylation of the sulfide group of (X) with iodomethane gave rise to the sulfonium salt (XI),which was further cyclized to pyrrolidinone (XII) by treatment with lithium bis(trimethylsilyl)amide in cold THF.Acid deprotection of the Boc group of (XII) furnished amine (XIII).This was finally subjected to reductive alkylation with aldehyde (VII) in the presence of sodium cyanoborohydride to provide the corresponding (imidazolylmethyl)amine.
参考文献标题:Design and biological activity of (S)-4-(5-{[1-(3-chlorobenzyl)-2-oxopyrrolidin-3-ylamino]methyl}imidazol-1-ylmethyl)benzonitrile,a 3-aminopyrrolidinone farnesyltransferase inhibitor with excellent cell potency
文献作者:Bell,I.M.; Gallicchio,S.N.; Abrams,M.J.; Beshore,D.C.; Buser,C.A.; Culberson,J.C.; Davide,J.; Ellis-Hutchings,M.; Fernandes,C.; Gibbs,J.B.; Graham,S.L.; Hartman,G.D.; Heimbrook,D.C.; Homnick,C.F.; Huff,J.R.; Kassahun,K.; et al.
参考来源:J Med Chem 2001,44(18),2933