新产品编号:861117
Chemical Name: 4(S)-[3-(3,4-Difluorophenyl)-2(S)-[3-(5-methylisoxazol-3-ylcarboxamido)-2-oxo-1,2-dihydropyridin-1-yl]propionamido]-5-[2-oxopyrrolidin-3(S)-yl]-2(E)-pentenoic acid isopropyl ester
CAS No. 343566-12-1
项目整合开发状态: Preclinical
项目研究机构: Agouron (Originator)
合成路线:Catalytic hydrogenation of 2-hydroxy-3-nitropyridine (I) in the presence of Pd/C affords 3-amino-2-hydroxypyridine (II).This is then acylated by 5-methylisoxazole-3-carbonyl chloride (III) to furnish the corresponding amide (IV).(1)
合成路线:Deprotection of N-Boc-D-3,4-difluorophenylalanine (V) by means of HCl in dioxane yields aminoacid (VI).Subsequent diazotization of (VI) with NaNO2/H2SO4 leads to hydroxyacid (VII).After esterification of (VII) with methanolic HCl,the hydroxyester (VIII) is converted into triflate (IX) upon treatment with trifluoromethanesulfonic anhydride and 2,6-lutidine.Condensation of hydroxypyridine (IV) with triflate (IX) in the presence of NaH gives rise to the N-alkylated pyridone (X).The methyl ester group of (X) is then hydrolyzed to the corresponding carboxylic acid (XI) by means of either NaOH or LiI in pyridine.(1,2)
合成路线:Treatment of the Boc-protected aminoalcohol (XII) with trifluoroacetic acid furnishes (XIII).This is then coupled with acid (XI) in the presence of HATU to afford the amide alcohol (XIV).Oxidation of (XIV) with the Dess-Martin periodinane (DMP) reagent gives rise to aldehyde (XV).Finally,Wittig condensation of aldehyde (XV) with isopropoxycarbonylmethylene triphenylphosphorane provides the target unsaturated ester.(1,2)
📌 参考资料/链接：
参考文献标题:Antipicornaviral cpds.and compsns.,their pharmaceutical uses,and material for their synthesis
文献作者:Dragovich,P.S.; Prins,T.J.; Zhou,R.; Johnson,T.O.Jr.(Agouron Pharmaceuticals,Inc.)
参考来源:JP 2003515591; US 2001047006; US 6514997; WO 0140189
📄 详细内容
合成路线:Deprotection of N-Boc-D-3,4-difluorophenylalanine (V) by means of HCl in dioxane yields aminoacid (VI).Subsequent diazotization of (VI) with NaNO2/H2SO4 leads to hydroxyacid (VII).After esterification of (VII) with methanolic HCl,the hydroxyester (VIII) is converted into triflate (IX) upon treatment with trifluoromethanesulfonic anhydride and 2,6-lutidine.Condensation of hydroxypyridine (IV) with triflate (IX) in the presence of NaH gives rise to the N-alkylated pyridone (X).The methyl ester group of (X) is then hydrolyzed to the corresponding carboxylic acid (XI) by means of either NaOH or LiI in pyridine.(1,2)
合成路线:Treatment of the Boc-protected aminoalcohol (XII) with trifluoroacetic acid furnishes (XIII).This is then coupled with acid (XI) in the presence of HATU to afford the amide alcohol (XIV).Oxidation of (XIV) with the Dess-Martin periodinane (DMP) reagent gives rise to aldehyde (XV).Finally,Wittig condensation of aldehyde (XV) with isopropoxycarbonylmethylene triphenylphosphorane provides the target unsaturated ester.(1,2)
参考文献标题:Structure-based design,synthesis,and biological evaluation of irreversible human rhinovirus 3C protease inhibitors: 6.Structure-activity studies of orally bioavailable,2-pyridone-containing peptidomimetics
文献作者:Dragovich,P.S.; Prins,T.J.; Zhou,R.; Brown,E.L.; Maldonado,F.C.; Fuhrman,S.A.; Zalman,L.S.; Tuntland,T.; Lee,C.A.; Patick,A.K.; Matthews,D.A.; Hendrickson,T.F.; Kosa,M.B.; Liu,B.; Batugo,M.R.; Gleeson,J.-P.R.; Sakata,S.K.; et al.
参考来源:J Med Chem 2002,45(8),1607