VRC-4307
Chemical Name: N1-(2-Cyclopentylethyl)-N2-(4,5-dimethylthiazol-2-yl)-N1-(N-hydroxycarbamoylmethyl)pyrrolidine-1,2(S)-dicarboxamide
CAS No. 345890-26-8
项目整合开发状态: Preclinical
项目研究机构: Novartis (Originator), Vicuron Pharmaceuticals (Originator)
合成路线:The condensation of ArgoGel-OH resin (I) with N-(Fmoc)-glycine (II) by means of DIC and DMAP gives the resin-bound Fmoc-glycine (III),which is deprotected with piperidine to yield the resin-bound glycine (IV).The reaction of (IV) with 2-nitrophenylsulfonyl chloride (V) affords the sulfonamide (VI),which is alkylated with 2-cyclopentylethanol (VII) by means of DIAD and PPh3 to provide the N-alkylated sulfonamide (VIII).The reaction of (VIII) with Ph-SH,DBU and pyridine gives the N-alkylated resin-bound glycine (IX),which is condensed with 1-(chlorocarbonyl)-L-proline tert-butyl ester (X) to yield the resin-bound dipeptide tert-butyl ester (XI).Hydrolysis of the ester group of (XI) with TFA affords the free resin-bound dipeptide (XII),which is condensed with 4,5-dimethylthiazole-2-amine (XIII) by means of PyBOP and DMAP to provide the corresponding prolinamide (XIV).Finally,this compound is treated with hydroxylamine in order to cleave the title compound from the resin by formation of the desired hydroxamic acid.
📌 参考资料/链接：
参考文献标题:Novel urea cpds.,compsns.and methods of use and preparation
文献作者:Patel,D.V.; Jacobs,J.W.; Lewis,J.; Ni,Z.-J.(Versicor,Inc.)
参考来源:WO 0144178
📄 详细内容
合成路线:The condensation of ArgoGel-OH resin (I) with N-(Fmoc)-glycine (II) by means of DIC and DMAP gives the resin-bound Fmoc-glycine (III),which is deprotected with piperidine to yield the resin-bound glycine (IV).The reaction of (IV) with 2-nitrophenylsulfonyl chloride (V) affords the sulfonamide (VI),which is alkylated with 2-cyclopentylethanol (VII) by means of DIAD and PPh3 to provide the N-alkylated sulfonamide (VIII).The reaction of (VIII) with Ph-SH,DBU and pyridine gives the N-alkylated resin-bound glycine (IX),which is condensed with 1-(chlorocarbonyl)-L-proline tert-butyl ester (X) to yield the resin-bound dipeptide tert-butyl ester (XI).Hydrolysis of the ester group of (XI) with TFA affords the free resin-bound dipeptide (XII),which is condensed with 4,5-dimethylthiazole-2-amine (XIII) by means of PyBOP and DMAP to provide the corresponding prolinamide (XIV).Finally,this compound is treated with hydroxylamine in order to cleave the title compound from the resin by formation of the desired hydroxamic acid.
参考文献标题:Iterative parallel synthesis-derived N-alkyl urea hydroxamic acids: A new class of peptide deformylase inhibitors
文献作者:Lewis,J.G.; Wu,C.; Jacobs,J.; et al.
参考来源:41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001,Chicago) 2001,Abst F-358