AG-3433
Chemical Name: 3(S)-[1-(4'-Cyanobiphenyl-4-yl)pyrrol-3-yl]-N-[4,4-dimethyl-2-oxotetrahydrofuran-3(S)-yl]succinamic acid
CAS No. 207118-71-6
项目整合开发状态: Preclinical
项目研究机构: Agouron (Originator), Roche Bioscience (Originator)
合成路线:The reaction of 2,5-dimethoxytetrahydrofuran-3-carbaldehyde (I) with 2-(trimethylsilyl)-1,3-dithiane (II) by means of BuLi in THF gives the expected condensation product (III),which is treated with HgCl2 and methanol in THF/water yielding 2-(2,5-dimethoxytetrahydrofuran-3-yl)acetic acid methyl ester (IV).The cyclization of (IV) with 4'-aminobiphenyl-4-carbonitrile (V) by means of CDE in hot trifluorocetic acid affords the biphenylylpyrrole (VI),which is hydrolyzed with LiOH and condensed with the chiral auxiliary 4(S)- benzyloxazolidin-2-one (VII) by means of pivaloyl chloride,BuLi and TEA in THF giving the acylated thiazolidine (VIII).The stereocontrolled reaction of (VIII) with benzyl bromoacetate (IX) by means of sodium hexamethyldisylazane (NaHMDS) in THF yields the succinamic ester (X),which is hydrolyzed with LiOH in THF/water to afford the succinic acid monoester (XI).The amidation of (XI) with 3(S)-amino-4,4-dimethyltetrahydrofuran-2-one (XII) by means of TBTU and NMM in DMF provides the succinamic ester derivative (XIII),which is debenzylated by hydrogenation with H2 over Pd/C in methanol.
📌 参考资料/链接：
参考文献标题:Heteroaryl succinamides and their use as metalloproteinase inhibitors
文献作者:Bender,S.L.; Castelhano,A.L.; Chong,W.K.M.; Abreo,M.A.; Billedeau,R.J.; Chen,J.J.; Deal,J.G.(Agouron Pharmaceuticals,Inc.; Syntex (USA),Inc.)
参考来源:EP 0937042; JP 2000511201; US 6008243; WO 9817643
📄 详细内容
合成路线:The reaction of 2,5-dimethoxytetrahydrofuran-3-carbaldehyde (I) with 2-(trimethylsilyl)-1,3-dithiane (II) by means of BuLi in THF gives the expected condensation product (III),which is treated with HgCl2 and methanol in THF/water yielding 2-(2,5-dimethoxytetrahydrofuran-3-yl)acetic acid methyl ester (IV).The cyclization of (IV) with 4'-aminobiphenyl-4-carbonitrile (V) by means of CDE in hot trifluorocetic acid affords the biphenylylpyrrole (VI),which is hydrolyzed with LiOH and condensed with the chiral auxiliary 4(S)- benzyloxazolidin-2-one (VII) by means of pivaloyl chloride,BuLi and TEA in THF giving the acylated thiazolidine (VIII).The stereocontrolled reaction of (VIII) with benzyl bromoacetate (IX) by means of sodium hexamethyldisylazane (NaHMDS) in THF yields the succinamic ester (X),which is hydrolyzed with LiOH in THF/water to afford the succinic acid monoester (XI).The amidation of (XI) with 3(S)-amino-4,4-dimethyltetrahydrofuran-2-one (XII) by means of TBTU and NMM in DMF provides the succinamic ester derivative (XIII),which is debenzylated by hydrogenation with H2 over Pd/C in methanol.
参考文献标题:Preparation of various P1'-heterocyclic succinamide inhibitors of matrix metalloproteases (MMP's)
文献作者:Deal,J.G.; Bender,S.L.; Chong,W.K.M.; et al.
参考来源:217th ACS Natl Meet (March 21 1999,Anaheim) 1999,Abst MEDI 197