RO-1169132/238
Chemical Name: 4-(3,4-Dichlorobenzyl)-1-methyl-1-[3-methyl-2(R)-[3-(3,4,5-trimethoxyphenyl)ureido]butyl]piperidinium chloride
CAS No. 270572-42-4
项目整合开发状态: Preclinical
项目研究机构: Roche Bioscience (Originator)
合成路线:Condensation of 3,4-dichlorobenzyl bromide (I) with triphenylphosphine affords the phosphonium salt (II).The ylide obtained from (II) and butyllithium is then subjected to a Wittig reaction with N-Boc-4-piperidinone (III) to provide the benzylidene piperidine (IV).Catalytic hydrogenation of (IV) over PtO2 gives rise to the corresponding benzylpiperidine (V).After acidic Boc group cleavage in (V),the deprotected piperidine (VI) is coupled with N-Boc-D-valine (VII) in the presence of EDC to furnish amide (VIII).Further N-Boc group cleavage in (VIII) employing trifluoroacetic acid yields amino amide (IX),which is then reduced to diamine (X) by means of borane in THF.Coupling of amine (X) with 3,4,5-trimethoxyphenyl isocyanate (XI) leads to urea (XII).Finally,quaternization of the piperidine N of (XII) with iodomethane provides the title piperidinium salt.
📌 参考资料/链接：
参考文献标题:Piperidine CCR-3 receptor antagonists
文献作者:Kertesz,D.J.; Smith,D.B.; Hirschfeld,D.R.(F.Hoffmann-La Roche AG)
参考来源:DE 19955793; EP 1131290; GB 2343894; JP 2002530375; US 6342509; WO 0031033
📄 详细内容
合成路线:Condensation of 3,4-dichlorobenzyl bromide (I) with triphenylphosphine affords the phosphonium salt (II).The ylide obtained from (II) and butyllithium is then subjected to a Wittig reaction with N-Boc-4-piperidinone (III) to provide the benzylidene piperidine (IV).Catalytic hydrogenation of (IV) over PtO2 gives rise to the corresponding benzylpiperidine (V).After acidic Boc group cleavage in (V),the deprotected piperidine (VI) is coupled with N-Boc-D-valine (VII) in the presence of EDC to furnish amide (VIII).Further N-Boc group cleavage in (VIII) employing trifluoroacetic acid yields amino amide (IX),which is then reduced to diamine (X) by means of borane in THF.Coupling of amine (X) with 3,4,5-trimethoxyphenyl isocyanate (XI) leads to urea (XII).Finally,quaternization of the piperidine N of (XII) with iodomethane provides the title piperidinium salt.
参考文献标题:Cyclic amine derivs.-CCR-3 receptor antagonists
文献作者:Wilhelm,R.S.; Smith,D.B.; Talamas,F.X.; Gong,L.; tesz,D.J.(Syntex (USA) LLC)
参考来源:US 6339087