Rebimastat, D-2163, BMS-275291
(2S)-3,3-二甲基-2-甲基氨基-N-[(2S)-4-甲基-2-[[(2S)-2-硫基-4-(3,4,4-三甲基-2,5-二氧代-咪唑烷-1-基)丁酰基]氨基]戊酰]丁酰胺Chemical Name: N-[2(S)-Sulfanyl-4-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)butyryl]-L-leucyl-L-tert-leucine methylamide
CAS No. 259188-38-0, 189443-54-7 (no stereoch. at 2)
项目整合开发状态: Phase II/III
项目研究机构: Celltech (Originator), Bristol-Myers Squibb (Codevelopment)
合成路线:1,5,5-Trimethylhydantoin (I) was alkylated with tert-butyl 4-bromobutyrate (II) in the presence of NaH in DMF to afford (III).The tert-butyl ester group of (III) was then cleaved by treatment with trifluoroacetic acid to yield carboxylic acid (IV).Bromination of (IV) under Hell-Volhard-Zelinskii conditions furnished the alpha-bromoacid (V),which was condensed with potassium thioacetate to give the thioacetate ester (VI).Subsequent EDC-promoted coupling of (VI) with L-leucyl-L-tert-leucine-N-methylamide (VII) provided amide (VIII) as an epimeric mixture.The thioacetate ester of (VIII) was then hydrolyzed by means of methanolic ammonia to give thiol (IX) (1).The title diastereoisomer was finally isolated by using preparative HPLC.
📌 参考资料/链接：
参考文献标题:Thio-substd.peptides as inhibitors for metalloproteinases and TNF liberation
文献作者:Baxter,A.D.; Montana,J.G.; Owen,D.A.(Celltech Chiroscience Ltd.)
参考来源:JP 1999512733; WO 9712902
📄 详细内容
合成路线:1,5,5-Trimethylhydantoin (I) was alkylated with tert-butyl 4-bromobutyrate (II) in the presence of NaH in DMF to afford (III).The tert-butyl ester group of (III) was then cleaved by treatment with trifluoroacetic acid to yield carboxylic acid (IV).Bromination of (IV) under Hell-Volhard-Zelinskii conditions furnished the alpha-bromoacid (V),which was condensed with potassium thioacetate to give the thioacetate ester (VI).Subsequent EDC-promoted coupling of (VI) with L-leucyl-L-tert-leucine-N-methylamide (VII) provided amide (VIII) as an epimeric mixture.The thioacetate ester of (VIII) was then hydrolyzed by means of methanolic ammonia to give thiol (IX) (1).The title diastereoisomer was finally isolated by using preparative HPLC.
参考文献标题:Selective MMP inhibitors having reduced side-effects
文献作者:Wills,R.E.; Baxter,A.D.; Bird,J.; Montana,J.G.; Owen,D.A.(Darwin Discovery Ltd.)
参考来源:WO 9839024
产品链接: CAS No. 259188-38-0››