新产品编号:1645789
Chemical Name: 4-[2(R),5(S)-Dimethyl-4-[3,3,3-trifluoro-2(R)-hydroxy-2-methylpropionyl]piperazin-1-ylcarbonyl]benzonitrile
项目整合开发状态: Preclinical
项目研究机构: Novartis (Originator)
合成路线:Alkylation of an equimolecular mixture of trans-2,5-dimethylpiperazine dihydrochloride (I) and the free base (II) with benzyl chloride produced the racemic monobenzyl piperazine,which was resolved using (-)-tartaric acid to yield the required (2R,5S)-isomer (III).(R)-3,3,3-Trifluoro-2-hydroxy-2-methylpropionic acid (IV) was protected as the silyl derivative (V) using bis(trimethylsilyl)urea,and subsequently converted to acid chloride (VI) by means of oxalyl chloride.Coupling of acid chloride (VI) with the chiral piperazine (III) afforded amide (VII),which was desilylated in methanolic HCl yielding (VIII).Hydrogenolysis of the N-benzyl group of (VIII) over Pd/C gave piperazine (IX).Finally,coupling of (IX) with 4-cyanobenzoyl chloride (X) furnished the corresponding bisamide.
📌 参考资料/链接：
参考文献标题:(R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionamides are orally active inhibitors of pyruvate dehydrogenase kinase
文献作者:Aicher,T.D.; Anderson,R.C.; Bebernitz,G.R.; Coppola,G.M.; Jewell,C.F.; Knorr,D.C.; Liu,C.; Sperbeck,D.M.; Brand,L.J.; Strohschein,R.J.; Gao,J.; Vinluan,C.C.; Shetty,S.S.; Dragland,C.; Kaplan,E.L.; DelGrande,D.; Islam,A.; Liu,X.; et al.
参考来源:J Med Chem 1999,42(15),2741