新产品编号:82773
Chemical Name: 4-[3,5-Bis(trifluoromethyl)benzyloxymethyl]-1-(2-methyl-5-thiazolylmethyl)-4-phenylpiperidine dihydrochloride
CAS No. 160377-16-2, 160376-22-7 (free base)
项目整合开发状态: Preclinical
项目研究机构: Merck & Co. (Originator)
合成路线:This compound can be obtained by two related ways:1.- The reduction of 4-phenylpiperidine-4-carboxylic acid (I) with LiAlH4 in THF gives the corresponding methanol derivative (II),which is treated with tert-butoxycarbonyl anhydride in THF to yield the N-protected piperidine (III).The acylation of (III) with 3,5-bis(trifluoromethyl)benzyl bromide (IV) by means of NaH in DMF affords the corresponding ether (V),which is deprotected with HCl in ethyl ether to afford the free piperidine (VI) (1,2).Finally,(VI) is reductocondensed with 2-methylthiazole-5-carbaldehyde (VII) by means of sodium cyanoborohydride in methanol/acetic acid.2.- The piperidine derivative (VI) can also be condensed with 5-(bromomethyl)-2-methylthiazole (VIII) by means of K2CO3 in DMF.
📌 参考资料/链接：
参考文献标题:4-Arylmethyloxymethyl piperidines as tachykinin antagonists
文献作者:Harrison,T.; Mcleod,A.M.; Stevenson,G.I.; Williams,B.J.(Merck Sharp & Dohme Ltd.)
参考来源:EP 0666856; JP 1996502510; US 5620989; WO 9410165
📄 详细内容
合成路线:This compound can be obtained by two related ways:1.- The reduction of 4-phenylpiperidine-4-carboxylic acid (I) with LiAlH4 in THF gives the corresponding methanol derivative (II),which is treated with tert-butoxycarbonyl anhydride in THF to yield the N-protected piperidine (III).The acylation of (III) with 3,5-bis(trifluoromethyl)benzyl bromide (IV) by means of NaH in DMF affords the corresponding ether (V),which is deprotected with HCl in ethyl ether to afford the free piperidine (VI) (1,2).Finally,(VI) is reductocondensed with 2-methylthiazole-5-carbaldehyde (VII) by means of sodium cyanoborohydride in methanol/acetic acid.2.- The piperidine derivative (VI) can also be condensed with 5-(bromomethyl)-2-methylthiazole (VIII) by means of K2CO3 in DMF.
参考文献标题:4,4-Disubstituted piperidine high-affinity NK1 antagonists: Structure-activity relationships and in vivo activity
文献作者:Stevenson,G.I.; Huscroft,I.; Macleod,A.M.; Swain,C.J.; Cascieri,M.A.; Chicchi,G.G.; Graham,M.I.; Harrison,T.; Kelleher,F.J.; Kurtz,M.; Ladduwahetty,T.; Merchant,K.J.; Metzger,J.M.; MacIntyre,D.E.; Sadowski,S.; Sohal,B.; Owens,A.P.
参考来源:J Med Chem 1998,41(23),4623