新产品编号:903831
Chemical Name: 3(R)-(3,4-Difluorophenyl)-2(S)-(4-fluorophenyl)-4-hydroxy-N-[2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3(S)-yl]butyramide
CAS No. 376582-48-8 (stereoisomer)
项目整合开发状态: Biological Testing
项目研究机构: Merck Sharp & Dohme (Originator)
合成路线:3,4-Difluorocinnamic acid (I) is converted to the corresponding methyl ester (II) by treatment with iodomethane and K2CO3 in DMF.Subsequent reduction of ester (II) employing DIBAL in cold THF affords the cinnamyl alcohol (III).Esterification of (III) with 4-fluorophenylacetyl chloride (IV) gives rise to ester (V).This is then subjected to an asymmetric Ireland-Claisen rearrangement in the presence of the chiral catalyst (S,S)-1,2-bis[[3,5-bis(trifluoromethyl)phenyl]sulfonylamino]-1,2-diphenylethane to produce the diaryl pentenoic acid (VI).Coupling of acid (VI) with aminobenzodiazepinone (VII) furnishes amide (VIII).Finally,ozonolysis of the olefin double bond of (VIII) followed by reductive work up with NaBH4 leads to the desired 4-hydroxybutyramide derivative.(1,2)
📌 参考资料/链接：
参考文献标题:Benzodiazepine derivs.as APP modulators
文献作者:Teall,M.R.; Castro Pineiro,J.L.; Harrison,T.; Owens,A.P.; Guiblin,A.R.; Madin,A.; Williams,S.; Sparey,T.J.; Nadin,A.J.; Churcher,I.; Kerrad,S.(Merck Sharp & Dohme Ltd.)
参考来源:EP 1294702; JP 2003534333; WO 0190084
📄 详细内容
合成路线:3,4-Difluorocinnamic acid (I) is converted to the corresponding methyl ester (II) by treatment with iodomethane and K2CO3 in DMF.Subsequent reduction of ester (II) employing DIBAL in cold THF affords the cinnamyl alcohol (III).Esterification of (III) with 4-fluorophenylacetyl chloride (IV) gives rise to ester (V).This is then subjected to an asymmetric Ireland-Claisen rearrangement in the presence of the chiral catalyst (S,S)-1,2-bis[[3,5-bis(trifluoromethyl)phenyl]sulfonylamino]-1,2-diphenylethane to produce the diaryl pentenoic acid (VI).Coupling of acid (VI) with aminobenzodiazepinone (VII) furnishes amide (VIII).Finally,ozonolysis of the olefin double bond of (VIII) followed by reductive work up with NaBH4 leads to the desired 4-hydroxybutyramide derivative.(1,2)
参考文献标题:Design and synthesis of highly potent benzodiazepine gamma-secretase inhibitors: Preparation of (2S,3R)-3-(3,4-difluorophenyl)-2-(4-fluorophenyl)-4-hydroxy-N-((3S)-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]-diazepin-3-yl)butyramide by use of an
文献作者:Churcher,I.; Williams,S.; Kerrad,S.; Harrison,T.; Castro,J.L.; Shearman,M.S.; Lewis,H.D.; Clarke,E.E.; Wrigley,J.D.J.; Beher,D.; Tang,Y.S.; Liu,W.
参考来源:J Med Chem 2003,46(12),2275