UK-356618
Chemical Name: 2(R)-[3-(2-Methylbiphenyl-4-yl)propyl]-N1-[2,2-dimethyl-1(S)-[N-[1(R)-phenylethyl]carbamoyl]propyl]-N4-hydroxysuccinamide
项目整合开发状态: Biological Testing
项目研究机构: Pfizer (Originator)
合成路线:Coupling of N-Boc-L-tert-leucine (I) with (R)-1-phenylethylamine (II) using EDC and HOBt gave amide (III) which,after acid cleavage of the N-Boc group,provided amino amide (IV).Acylation of amine (IV) with (R)-2-allylsuccinic acid 4-tert-butyl ester (V) afforded the diamide (VI).Biphenylyl bromide (IX) was prepared by the Suzuki coupling between 5-bromo-2-iodotoluene (VII) and phenylboronic acid (VIII).The biaryl group was then introduced via Heck reaction of biphenylyl bromide (IX) with olefin (VI),yielding adduct (X).Subsequent hydrogenation of the olefin double bond of (X) over Pd/C afforded (XI).Carboxylic acid (XII) was then obtained by trifluoroacetic acid-promoted cleavage of the tert-butyl ester group of (XI).Conversion of (XII) to the title hydroxamic acid was then achieved by coupling of carboxylic acid (XII) with O-allylhydroxylamine (XIII),followed by O-allyl group cleavage in the presence of ammonium formate and palladium catalyst.
📌 参考资料/链接：
参考文献标题:Discovery of potent and selective succinyl hydroxamate inhibitors of matrix metalloprotease-3 (stromelysin-1)
文献作者:Fray,M.J.; Dickinson,R.P.
参考来源:Bioorg Med Chem Lett 2001,11(4),571
📄 详细内容
合成路线:Coupling of N-Boc-L-tert-leucine (I) with (R)-1-phenylethylamine (II) using EDC and HOBt gave amide (III) which,after acid cleavage of the N-Boc group,provided amino amide (IV).Acylation of amine (IV) with (R)-2-allylsuccinic acid 4-tert-butyl ester (V) afforded the diamide (VI).Biphenylyl bromide (IX) was prepared by the Suzuki coupling between 5-bromo-2-iodotoluene (VII) and phenylboronic acid (VIII).The biaryl group was then introduced via Heck reaction of biphenylyl bromide (IX) with olefin (VI),yielding adduct (X).Subsequent hydrogenation of the olefin double bond of (X) over Pd/C afforded (XI).Carboxylic acid (XII) was then obtained by trifluoroacetic acid-promoted cleavage of the tert-butyl ester group of (XI).Conversion of (XII) to the title hydroxamic acid was then achieved by coupling of carboxylic acid (XII) with O-allylhydroxylamine (XIII),followed by O-allyl group cleavage in the presence of ammonium formate and palladium catalyst.
参考文献标题:Discovery of potent and selective succinyl hydroxamate inhibitors of matrix metalloprotease-3 (stromelysin-1)
文献作者:Fray,M.J.; et al.
参考来源:13th Noordwijkerhout-Camerino Symp Trends Drug Res (May 6 2001,Noordwijkerhout) 2001,Abst P8