A-188925
Chemical Name: 11-Amino-11-N-[3-(4-aminophenyl)-2(E)-propenylamino]-11-N,12-O-carbonyl-3-des(hexopyranosyloxy)-11-deoxy-6-O-methyl-2,3-didehydroerythromicin A
项目整合开发状态: Biological Testing
项目研究机构: Abbott (Originator)
合成路线:Treatment of clarithromycin (I) with ethylene carbonate in refluxing triethylamine followed by dilute hydroalcoholic HCl removed the cladinose unit and dehydrated the C-11 hydroxyl to afford enone (II).Selective acetylation with acetic anhydride and triethylamine in dichloromethane gave the 2'-acetate (III),which was then mesylated at the 3-hydroxyl with methanesulfonic anhydride in pyridine to yield sulfonate (IV).Reaction of IV with carbonyldiimidazole (CDI) in DMF-THF,followed by NaH effected elimination of the methylsulfonyl group and gave the acylimidazole (V).Subsequent treatment of V with hydrazine in DMF,followed by methanolysis of the 2'-acetate gave a mixture of the epimeric carbazates (VI and VII) and the pyrazoline (VIII).
合成路线:Chromatographic separation of the mixture afforded the desired 10(R)-carbazate (VII),which was reductively alkylated with 4-nitrocinnamaldehyde (IX) in the presence of sodium cyanoborohydride and acetic acid to yield the title compound.
合成路线:Treatment of clarithromycin (I) with ethylene carbonate in refluxing triethylamine followed by dilute hydroalcoholic HCl removed the cladinose unit and dehydrated the C-11 hydroxyl to afford enone (II).Selective acetylation with acetic anhydride and triethylamine in dichloromethane gave the 2'-acetate (III),which was then mesylated at the 3-hydroxyl with methanesulfonic anhydride in pyridine to yield sulfonate (IV).Reaction of IV with carbonyldiimidazole (CDI) in DMF-THF,followed by NaH effected elimination of the methylsulfonyl group and gave the acylimidazole (V) (1).Subsequent treatment of V with hydrazine in DMF,followed by methanolysis of the 2'-acetate gave a mixture of the epimeric carbazates (VI and VII) and the pyrazoline (VIII).
合成路线:Chromatographic separation of the mixture afforded the desired 10(R)-carbazate (VII),which was reductively alkylated with 4-nitrocinnamaldehyde (IX) in the presence of sodium cyanoborohydride and acetic acid to yield the 4-nitrocinnamyl compound (X).Finally,reduction with zinc dust in methanolic HCl gave the target aminocompound.
📌 参考资料/链接：
参考文献标题:Anhydrolide macrolides.2.Synthesis and antibacterial activity of 2,3-anhydro-6.O-methyl 11,12-carbazate erythromycin A analogues
文献作者:Elliott,R.L.; Pireh,D.; Griesgraber,G.; Nilius,A.M.; Ewing,P.J.; Bui,M.H.; Raney,P.M.; Flamm,R.K.; Kim,K.; Henry,R.F.; Chu,D.T.; Plattner,J.J.; Or,Y.S.
参考来源:J Med Chem 1998,41(10),1651-1659
📄 详细内容
合成路线:Treatment of clarithromycin (I) with ethylene carbonate in refluxing triethylamine followed by dilute hydroalcoholic HCl removed the cladinose unit and dehydrated the C-11 hydroxyl to afford enone (II).Selective acetylation with acetic anhydride and triethylamine in dichloromethane gave the 2'-acetate (III),which was then mesylated at the 3-hydroxyl with methanesulfonic anhydride in pyridine to yield sulfonate (IV).Reaction of IV with carbonyldiimidazole (CDI) in DMF-THF,followed by NaH effected elimination of the methylsulfonyl group and gave the acylimidazole (V).Subsequent treatment of V with hydrazine in DMF,followed by methanolysis of the 2'-acetate gave a mixture of the epimeric carbazates (VI and VII) and the pyrazoline (VIII).
合成路线:Chromatographic separation of the mixture afforded the desired 10(R)-carbazate (VII),which was reductively alkylated with 4-nitrocinnamaldehyde (IX) in the presence of sodium cyanoborohydride and acetic acid to yield the title compound.
合成路线:Treatment of clarithromycin (I) with ethylene carbonate in refluxing triethylamine followed by dilute hydroalcoholic HCl removed the cladinose unit and dehydrated the C-11 hydroxyl to afford enone (II).Selective acetylation with acetic anhydride and triethylamine in dichloromethane gave the 2'-acetate (III),which was then mesylated at the 3-hydroxyl with methanesulfonic anhydride in pyridine to yield sulfonate (IV).Reaction of IV with carbonyldiimidazole (CDI) in DMF-THF,followed by NaH effected elimination of the methylsulfonyl group and gave the acylimidazole (V) (1).Subsequent treatment of V with hydrazine in DMF,followed by methanolysis of the 2'-acetate gave a mixture of the epimeric carbazates (VI and VII) and the pyrazoline (VIII).
合成路线:Chromatographic separation of the mixture afforded the desired 10(R)-carbazate (VII),which was reductively alkylated with 4-nitrocinnamaldehyde (IX) in the presence of sodium cyanoborohydride and acetic acid to yield the 4-nitrocinnamyl compound (X).Finally,reduction with zinc dust in methanolic HCl gave the target aminocompound.
参考文献标题:Anhydrolide macrolides.2.Synthesis and antibacterial activity of 2,3-anhydro-6.O-methyl 11,12-carbazate erythromycin A analogues
文献作者:Griesgraber,G.; Kramer,M.J.; Elliott,R.L.; Nilius,A.M.; Ewing,P.J.; Raney,P.M.; Bui,M.H.; Flamm,R.K.; Chu,D.T.; Plattner,J.J.; Or,Y.S.
参考来源:J Med Chem 1998,41(10),1660-1670