新产品编号:329565
Chemical Name: 5-Phenyl-2-[4-(pyridin-4-ylcarbonyl)phenylsulfonylmethyl]pentanohydroxamic acid hydrochloride
CAS No. 203248-89-9
项目整合开发状态: Preclinical
项目研究机构: Celltech (Originator)
合成路线:Alkylation of the sodium salt of dibenzyl malonate (I) with 1-bromo-3-phenylpropane (II) afforded the (phenylpropyl)malonate (III).The benzyl ester groups of (III) were removed by hydrogenolysis in the presence of Pd/C to produce the intermediate malonic acid (IV).Subsequent condensation of diacid (IV) with formaldehyde in the presence of piperidine proceeded with concomitant decarboxylation,yielding 2-methylene-5-phenylpentanoic acid (V).Addition of HBr to the unsaturated acid (V) gave bromide (VI).Condensation of (VI) with thiophenol (VIII),prepared by nucleophilic displacement of 4-(4-chlorobenzoyl)pyridine (VI) with sodium hydrogen sulfide,furnished the sulfide adduct (IX).This was oxidized to the corresponding sulfone (X) by treatment with Oxone(R).Conversion of (X) to the desired hydroxamic acid was carried out by coupling with O-tert-butyldimethylsilyl hydroxylamine,followed by deprotection of the resulting O-silyl hydroxamate (XI) with tetrabutylammonium fluoride.
📌 参考资料/链接：
参考文献标题:Hydroxamic and carboxylic acid derivs.having MMP and TNF inhibitory activity
文献作者:Owen,D.A.; Montana,J.G.; Keily,J.F.; Watson,R.J.; Baxter,A.D.(Celltech Group plc)
参考来源:EP 0968182; JP 2000517297; WO 9805635
📄 详细内容
合成路线:Alkylation of the sodium salt of dibenzyl malonate (I) with 1-bromo-3-phenylpropane (II) afforded the (phenylpropyl)malonate (III).The benzyl ester groups of (III) were removed by hydrogenolysis in the presence of Pd/C to produce the intermediate malonic acid (IV).Subsequent condensation of diacid (IV) with formaldehyde in the presence of piperidine proceeded with concomitant decarboxylation,yielding 2-methylene-5-phenylpentanoic acid (V).Addition of HBr to the unsaturated acid (V) gave bromide (VI).Condensation of (VI) with thiophenol (VIII),prepared by nucleophilic displacement of 4-(4-chlorobenzoyl)pyridine (VI) with sodium hydrogen sulfide,furnished the sulfide adduct (IX).This was oxidized to the corresponding sulfone (X) by treatment with Oxone(R).Conversion of (X) to the desired hydroxamic acid was carried out by coupling with O-tert-butyldimethylsilyl hydroxylamine,followed by deprotection of the resulting O-silyl hydroxamate (XI) with tetrabutylammonium fluoride.
参考文献标题:Arylsulphonyl hydroxamic acids: Potent and selective matrix metalloproteinase inhibitors
文献作者:Baxter,A.D.; Bhogal,R.; Bird,J.; Keily,J.F.; Manallack,D.T.; Montana,J.G.; Owen,D.A.; Pitt,W.R.; Watson,R.J.; Wills,R.E.
参考来源:Bioorg Med Chem Lett 2001,11(11),1465