SC-964, SC-77964
Chemical Name: 1-Cyclopropyl-5-[4-[4-(trifluoromethoxy)phenoxy]phenylsulfonyl]piperidine-3-carbohydroxamic acid hydrochloride
CAS No. 226396-02-7, 308824-37-5 (free base)
项目整合开发状态: Preclinical
项目研究机构: Pfizer (Originator)
合成路线:Ethyl nipecotate (I) was protected as the tert-butyl carbamate (II) upon treatment with Boc2O in THF.The lithium enolate of ester (II) was then sulfenylated with the disulfide (IV),prepared by oxidation of 4-fluorothiophenol (III),yielding thioether (V).This was further oxidized to the corresponding sulfone (VI) using meta-chloroperbenzoic acid.Acid cleavage of the Boc protecting group of (VI) gave piperidine (VII),which was converted to the N-cyclopropyl amine (IX) by reductive alkylation with [(1-ethoxycyclopropyl)oxy]trimethylsilane (VIII) in the presence of NaBH3CN.Displacement of the aryl fluoride of (IX) with 4-(trifluoromethoxy)phenol (X) under basic conditions afforded the diaryl ether (XI).After saponification of the ester group of (XI),the resultant carboxylic acid (XII) was coupled to O-(tetrahydropyranyl)hydroxylamine by means of EDC to produce the protected hydroxamate (XIII).Finally,removal of the tetrahydropyranyl protecting group of (XIII) with HCl in dioxan afforded the title compound.
📌 参考资料/链接：
参考文献标题:Aromatic sulfone hydroxamic acid metalloprotease inhibitor
文献作者:Becker,D.P.; Mischke,D.A.; Villamil,C.I.; Bedell,L.J.; Fobian,Y.M.; Hanson,G.J.; Rico,J.G.; Barta,T.E.; Kolodziej,S.A.; Tollefson,M.B.; Stehle,N.W.; Howard,S.C.; Getman,D.P.; (Pharmacia Corp.)
参考来源:WO 0050396
📄 详细内容
合成路线:Ethyl nipecotate (I) was protected as the tert-butyl carbamate (II) upon treatment with Boc2O in THF.The lithium enolate of ester (II) was then sulfenylated with the disulfide (IV),prepared by oxidation of 4-fluorothiophenol (III),yielding thioether (V).This was further oxidized to the corresponding sulfone (VI) using meta-chloroperbenzoic acid.Acid cleavage of the Boc protecting group of (VI) gave piperidine (VII),which was converted to the N-cyclopropyl amine (IX) by reductive alkylation with [(1-ethoxycyclopropyl)oxy]trimethylsilane (VIII) in the presence of NaBH3CN.Displacement of the aryl fluoride of (IX) with 4-(trifluoromethoxy)phenol (X) under basic conditions afforded the diaryl ether (XI).After saponification of the ester group of (XI),the resultant carboxylic acid (XII) was coupled to O-(tetrahydropyranyl)hydroxylamine by means of EDC to produce the protected hydroxamate (XIII).Finally,removal of the tetrahydropyranyl protecting group of (XIII) with HCl in dioxan afforded the title compound.
参考文献标题:Design and synthesis of 4,4-disubstituted piperidine alpha-sulphone hydroxamates as potent and selective MMP inhibitors: The discovery of SC-77964
文献作者:Villamil,C.I.; et al.
参考来源:222nd ACS Natl Meet (Aug 26 2001,Chicago) 2001,Abst MEDI 258
产品链接: CAS No.308824-37-5››