ZD-4974
Chemical Name: 3-Cyano-N-[2(S)-(3,4-dichlorophenyl)-4-[4-[2-[(S)-methylsulfinyl]phenyl]piperidin-1-yl]butyl]-2-methoxy-N-methylnaphthalene-1-carboxamide citrate
CAS No. 263860-84-0, 263860-83-9 (free base)
项目整合开发状态: Preclinical
项目研究机构: AstraZeneca (Originator)
合成路线:3-Hydroxy-2-naphthoic acid (I) is iodinated by means of NaI and NaOCl to afford 3-hydroxy-4-iodo-2-naphthoic acid (II).Subsequent alkylation with dimethyl sulfate provides the methoxynaphthoate ester (III).Direct conversion of ester (III) to the corresponding nitrile (IV) is accomplished by treatment with dimethylaluminum amide in boiling xylene.Carbonylation of iodonaphthalene (IV) using carbon monoxide in the presence of Pd(OAc)2 and methanol yields the methyl naphthoate (V).Saponification of ester (V) using LiOH gives acid (VI),which is further activated as the acid chloride (VII) by treatment with oxalyl chloride and DMF
合成路线:Reductive amination of the N-Boc amino aldehyde (VIII) with (S)-4-(2-methylsulfinylphenyl)piperidine (IX) in the presence of NaBH3CN affords the Boc-protected diamine (X).Deprotection of (X) by means of trifluoroacetic acid yields amine (XI) (1).Acylation of (XI) with acid chloride (VII),followed by treatment with citric acid,gives rise to the title compound
📌 参考资料/链接：
参考文献标题:Naphthalenecarboxamides as tachykinin receptor antagonists
文献作者:Bernstein,P.R.; Russell,K.; Ohnmacht,C.J.; Dedinas,R.F.; Shewood,S.A.(AstraZeneca plc)
参考来源:EP 1119551; JP 2002526527; WO 0020389
📄 详细内容
合成路线:3-Hydroxy-2-naphthoic acid (I) is iodinated by means of NaI and NaOCl to afford 3-hydroxy-4-iodo-2-naphthoic acid (II).Subsequent alkylation with dimethyl sulfate provides the methoxynaphthoate ester (III).Direct conversion of ester (III) to the corresponding nitrile (IV) is accomplished by treatment with dimethylaluminum amide in boiling xylene.Carbonylation of iodonaphthalene (IV) using carbon monoxide in the presence of Pd(OAc)2 and methanol yields the methyl naphthoate (V).Saponification of ester (V) using LiOH gives acid (VI),which is further activated as the acid chloride (VII) by treatment with oxalyl chloride and DMF
合成路线:Reductive amination of the N-Boc amino aldehyde (VIII) with (S)-4-(2-methylsulfinylphenyl)piperidine (IX) in the presence of NaBH3CN affords the Boc-protected diamine (X).Deprotection of (X) by means of trifluoroacetic acid yields amine (XI) (1).Acylation of (XI) with acid chloride (VII),followed by treatment with citric acid,gives rise to the title compound
参考文献标题:Design,synthesis,and SAR of tachykinin antagonists: Modulation of balance in NK1/NK2 receptor antagonist activity
文献作者:Albert,J.S.; Aharony,D.; Andisik,D.; Barthlow,H.; Bernstein,P.R.; Bialecki,R.A.; Dedinas,R.; Dembofsky,B.T.; Hill,D.R.; Kirkland,K.M.; Koether,G.M.; Kosmider,B.J.; Ohnmacht,C.J.; Palmer,W.; Potts,W.; Rumsey,W.; Shen,L.; Shenvi,A.; et al.
参考来源:J Med Chem 2002,45(18),3972