SB-683698, TR-14035

(S)-2-(2,6-二氯苯酰胺)-3-(2,6-二甲氧基-[1,1-联苯]-4-基)丙酸Chemical Name: 2(S)-(2,6-Dichlorobenzamido)-3-(2',6'-dimethoxybiphenyl-4-yl)propionic acid; N-(2,6-Dichlorobenzoyl)-3-(2',6'-dimethoxybiphenyl-4-yl)-L-alanine; N-(2,6-Dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine
CAS No. 232271-19-1
项目整合开发状态: Phase I
项目研究机构: Tanabe Seiyaku (Originator), GlaxoSmithKline (Licensee)
合成路线:Treatment of N-Boc-4-bromo-L-phenylalanine (I) with ethanolic or methanolic HCl gave aminoester (II).Subsequent condensation of (II) with 2,6-dichlorobenzoyl chloride (III) produced amide (IV).Lithiation of 1,3-dimethoxybenzene (V) with n-butyllithium,followed by reaction with trimethyl borate and aqueous hydrolysis yielded boronic acid (VI).Suzuki coupling of bromide (IV) with boronic acid (VI) in the presence of palladium catalyst furnished biphenyl derivative (VII).Finally,hydrolysis of the ethyl ester of (VII) with LiOH provided the title carboxylic acid.
📌 参考资料/链接:
参考文献标题:Inhibitors of alpha4 mediated cell adhesion
文献作者:Gudmundsson,K.S.; Sircar,I.; Martin,R.(Tanabe Seiyaku Co.,Ltd.)
参考来源:WO 9936393

📄 详细内容


合成路线:In an alternative procedure,N-Boc-L-tyrosine methyl ester (VIII) was treated with trifluoromethanesulfonic anhydride to afford triflate (IX).Suzuki coupling of (IX) with boronic acid (VI) produced biphenyl (X).After deprotection of the Boc group of (X) with trifluoroacetic acid,the resulting aminoester (XI) was acylated with acid chloride (III) to give amide (XII).The title compound was then obtained by hydrolysis of the methyl ester of (XII) with LiOH.

参考文献标题:Discovery of TR-14035: An orally active dual alpha4beta7/alpha4beta1 integrin antagonist
文献作者:Hattfield,L.D.; Sircar,I.; McNutly,A.; Naubauer,B.
参考来源:218th ACS Natl Meet (Aug 22 1999,New Orleans) 1999,Abst MEDI 59


合成路线:In an alternative procedure,N-Boc-L-tyrosine methyl ester (VIII) was treated with trifluoromethanesulfonic anhydride to afford triflate (IX).Suzuki coupling of (IX) with boronic acid (VI) produced biphenyl (X).After deprotection of the Boc group of (X) with trifluoroacetic acid,the resulting aminoester (XI) was acylated with acid chloride (III) to give amide (XII).The title compound was then obtained by hydrolysis of the methyl ester of (XII) with LiOH.

参考文献标题:SAR of TR-14035: An orally active dual alpha4beta7/alpha4beta1 integrin antagonist
文献作者:Sircar,I.; Liang,J.T.; Mart韓,R.; et al.
参考来源:218th ACS Natl Meet (Aug 22 1999,New Orleans) 1999,Abst MEDI 60


合成路线:Treatment of N-Boc-4-bromo-L-phenylalanine (I) with ethanolic or methanolic HCl gave aminoester (II).Subsequent condensation of (II) with 2,6-dichlorobenzoyl chloride (III) produced amide (IV).Lithiation of 1,3-dimethoxybenzene (V) with n-butyllithium,followed by reaction with trimethyl borate and aqueous hydrolysis yielded boronic acid (VI).Suzuki coupling of bromide (IV) with boronic acid (VI) in the presence of palladium catalyst furnished biphenyl derivative (VII).Finally,hydrolysis of the ethyl ester of (VII) with LiOH provided the title carboxylic acid.

合成路线:In an alternative procedure,N-Boc-L-tyrosine methyl ester (VIII) was treated with trifluoromethanesulfonic anhydride to afford triflate (IX).Suzuki coupling of (IX) with boronic acid (VI) produced biphenyl (X).After deprotection of the Boc group of (X) with trifluoroacetic acid,the resulting aminoester (XI) was acylated with acid chloride (III) to give amide (XII).The title compound was then obtained by hydrolysis of the methyl ester of (XII) with LiOH.
参考文献标题:Synthesis and SAR of N-benzoyl-L-biphenylalanine derivatives: Discovery of TR-14035,a dual alpha4beta7/alpha4beta1 integrin antagonist
文献作者:Sircar,I.; Gudmundsson,K.S.; Martin,R.; Liang,J.; Nomura,S.; Jayakumar,H.; Teegarden,B.R.; Nowlin,D.M.; Cardarelli,P.M.; Mah,J.R.; Connell,S.; Griffith,R.C.; Lazarides,E.
参考来源:Bioorg Med Chem 2002,10(6),2051


产品链接: CAS No. 232271-19-1››