【药物名称】
化学结构式(Chemical Structure):
参考文献No.480204
标题:Potent and selective bicyclic lactam inhibitors of thrombin: Part 2: P1 modifications
作者:Plummer, J.S.; Berryman, K.A.; Cai, C.; Cody, W.L.; DiMaio, J.; Doherty, A.M.; Edmunds, J.J.; He, J.X.; Holland, D.R.; Levesque, S.; Kent, D.R.; Narasimhan, L.S.; Rubin, J.R.; Rapundalo, S.T.; Siddiqui, M.A.; Susser, A.J.; St-Denis, Y.; Winocour, P.D.
来源:Bioorg Med Chem Lett 1998,8(23),3409
合成路线图解说明:

The condensation of 1-(benzyloxycarbonyl)piperidin-4-one with N-(tert-butoxycarbonyl)-2-phosphonoglycine trimethyl ester (II) by means of DBU in dichloromethane gives 2-[1-(benzyloxycarbonyl)piperidin-4-ylidene]-N-(tert-butoxycarbonyl)glycine methyl ester (III), which is selectively deprotected and reduced by hydrogenation with H2 over Pd/C in methanol yielding N-(tert-butoxycarbonyl)-2-(4-piperidyl)glycine methyl ester (IV). The reaction of (IV) with N,N'-di(tert-butoxycarbonyl)pyrazole-1-carboxamidine (V) by means of DIEA in dichloromethane gives the protected piperidine-1-carboxamidine (VI), which is treated with LiOH in methanol/water to obtain (VII) with a free carboxy group. The reaction of (VII) with O,N-dimethylhydroxylamine affords the hydroxamic ester (VIII), which is condensed with thiazole (IX) by means of butyllithium in THF yielding the fully protected intermediate (X). The deprotection of (X) with HCl in dioxane gives (XI) with free amino and amidino groups. The conddensation of (XI) with chiral acid (XII) by means of BOP and DIEA in acetonitrile yields amide (XIII) as a diastereomeric mixture that is resolved by preparative reverse-phase HPLC.

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