红霉素A肟多羟基硅醚化反应研究
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摘要
目的研究红霉素A肟(EAO)的2',4''-羟基和9-肟羟基硅醚化反应。探索多羟基硅醚化反应影响因素,分步和"一锅煮"反应效果等,揭示EAO多羟基硅醚化反应规律。方法用HMDS进行2',4''-羟基硅醚化反应,用叔丁基二甲基氯硅烷、三苯基氯硅进行9-肟羟基硅醚化反应。研究溶剂、硅醚化试剂和催化剂等对多羟基硅醚化影响。研究单溶剂、组合溶剂和混合溶剂条件下分步硅醚化反应和"一锅煮"硅醚化反应的规律。通过IR、~1H NMR、FAB和单晶XRD确证分子结构。结果通过11种途径探索分步和"一锅煮"合成EAO多羟基硅醚化产物2',4''-O-二(三甲基硅)红霉素A9(O-叔丁基二甲基硅)肟(TMSi-TBDMSiEAO)和2',4''-O-二(三甲基硅)红霉素A9(O-三苯基硅)肟(TMSi-TPSi-EAO)的方法。结果表明,9-肟羟基优先硅醚化反应效果好,分步反应时,THF用于9-肟羟基,CH_3CN用于2',4''-羟基硅醚化转化率高。单溶剂CH_3CN、组合THF-CH_3CN或混合溶剂THF/CH_3CN对多羟基"一锅煮"硅醚化反应有利。TMSi-TBDMSi-EAO稳定性高于TMSi-TPSi-EAO,E构型化合物反应活性高于Z构型。TMSi-TBDMSi-EAO单晶结构显示2',4''-羟基和9-肟羟基硅醚化使红霉素内酯环上C6-OH突出,进一步的MM2和AM1量子化学计算表明,多羟基硅醚化提高了C6-OH甲基化的选择性。结论"一锅煮"红霉素A肟多羟基硅醚化反应简便、平稳、可控,有利于EAO选择性合成克拉霉素
Objective The reaction of erythromycin A oxime(EAO)2',4''-hydroxyl and 9-oxime hydroxyl silicon etherifi cation was studied.To explore the effects of multiple silicon hydroxyl etherifi cation reaction and the effects of the separate and"one-pot"silicon etherification reaction and to reveal the reactionproperties of EAO hydroxyl silicon etherifi cation.Methods 2',4''-hydroxyl and 9-oxime hydroxyl of EAO were reacted with HMDS and tertbutyl methyl chlorosilane or triphenyl silicon chloride,respectively.Impacts of the solvent,silicon reagents,and catalystson multiple silicon hydroxyl etherifi cation were investigated.The rules of the separate and"one-pot"silicon etherification under the conditions of single solvents,combination or mixed solvents were studied.The molecular structures were identifi ed by IR,~1H NMR,FAB,and single crystal XRD.Results 11 synthetic methods were used to explore multi-step and"one-pot"synthesis of EAO hydroxyl silicon etherifi cation,and to obtain two target molecules2',4'-O-Bis(Trimethylsilyl)erythromycin A9(O-t-Butyl-dimethylsilyl)oxime(TMSi-TBDMSi-EAO)and 2',4''-O-Bis(Trimethylsilyl)erythromycin A9(O-Triphenylsilyl)oxime(TMSi-TPSi-EAO).The results showed that the separate9-oxime hydroxyl silicon etherifi cation showed better reaction effects.A better silicon etherifi cation conversion rate occurred in THF with the 9-oxime hydroxyl and CH_3CN with 2',4''-hydroxyl when performing reactions using the multi-step method.Single solvent CH_3CN,combination of THF-CH_3CN or mixed solvent THF/CH_3CN allowed good"one-pot"reaction of multiple hydroxyl silicon etherifi cation.The stability of TMSi-TBDMSi-EAO was better than TMSi-TPSi-EAO.The reactivity of E isomer was better than Z,The single crystal structure of TMSi-TBDMSiEAO showed that 2′,4″-hydroxyl and 9-oxime hydroxyl silicon etherifi cation made erythromycin lactone ring C6-OH more prominent.Further quantum calculationsusing MM2 and AM1 showed that the hydroxyl silicon etherifi cation increased the selectivity of C6-OH methylation.Conclusion"One-pot"hydroxyl silicon etherifi cation reaction of EAO was simple,stable and controllable.It is conducive to the selective synthesis of clarithromycin from EAO.
Objective The reaction of erythromycin A oxime(EAO)2',4''-hydroxyl and 9-oxime hydroxyl silicon etherifi cation was studied.To explore the effects of multiple silicon hydroxyl etherifi cation reaction and the effects of the separate and"one-pot"silicon etherification reaction and to reveal the reactionproperties of EAO hydroxyl silicon etherifi cation.Methods 2',4''-hydroxyl and 9-oxime hydroxyl of EAO were reacted with HMDS and tertbutyl methyl chlorosilane or triphenyl silicon chloride,respectively.Impacts of the solvent,silicon reagents,and catalystson multiple silicon hydroxyl etherifi cation were investigated.The rules of the separate and"one-pot"silicon etherification under the conditions of single solvents,combination or mixed solvents were studied.The molecular structures were identifi ed by IR,~1H NMR,FAB,and single crystal XRD.Results 11 synthetic methods were used to explore multi-step and"one-pot"synthesis of EAO hydroxyl silicon etherifi cation,and to obtain two target molecules2',4'-O-Bis(Trimethylsilyl)erythromycin A9(O-t-Butyl-dimethylsilyl)oxime(TMSi-TBDMSi-EAO)and 2',4''-O-Bis(Trimethylsilyl)erythromycin A9(O-Triphenylsilyl)oxime(TMSi-TPSi-EAO).The results showed that the separate9-oxime hydroxyl silicon etherifi cation showed better reaction effects.A better silicon etherifi cation conversion rate occurred in THF with the 9-oxime hydroxyl and CH_3CN with 2',4''-hydroxyl when performing reactions using the multi-step method.Single solvent CH_3CN,combination of THF-CH_3CN or mixed solvent THF/CH_3CN allowed good"one-pot"reaction of multiple hydroxyl silicon etherifi cation.The stability of TMSi-TBDMSi-EAO was better than TMSi-TPSi-EAO.The reactivity of E isomer was better than Z,The single crystal structure of TMSi-TBDMSiEAO showed that 2′,4″-hydroxyl and 9-oxime hydroxyl silicon etherifi cation made erythromycin lactone ring C6-OH more prominent.Further quantum calculationsusing MM2 and AM1 showed that the hydroxyl silicon etherifi cation increased the selectivity of C6-OH methylation.Conclusion"One-pot"hydroxyl silicon etherifi cation reaction of EAO was simple,stable and controllable.It is conducive to the selective synthesis of clarithromycin from EAO.
引文
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[3]Jeli?D,Antolovi?R.From erythromycin to azithromycin and new potential ribosome-binding antimicrobials[J].Antibiot,2016,5(3):29-41.
[4]张森林,曹胜华.酮内酯类抗生素-泰利霉素和喹红霉素的化学合成[J].中国抗生素杂志,2009,34(12):709-716.
[5]Patel H H.Chemical synthesis of 6-O-alkyl erythromycin A:US,5,852,180[P].1998-12-22.
[6]孙京国,梁建华,邓志华,等.克拉霉素的合成进展[J].有机化学,2002,22(12):951-963.
[7]邓志华,梁建华,孙京国,等.红霉素A肟的新合成方法[J].中国药物化学杂志,2003,13(2):89-92.
[8]孟祥燕,李娜,彭凤,等.9-(E)-红霉素A肟杂质的分离与鉴定[J].中国抗生素杂志,2016,41(4):280-284.
[9]冯玉玲,孙京国,王丽君,等.2',4''-O-二(三甲基硅)红霉素A肟的合成研究[J].中国药物化学杂志,2004,14(3):150-153.
[10]孙京国.三苯基氯硅烷对红霉素A肟的保护研究[J].河北师范大学学报(自然科学版),2007,31(3):359-364.
[11]Adachi T,Morimoto S,Watanabe Y,et al.Crystal and molecular structure of(14 R)-14-hydroxy-6-Omethylerythromycin A[J].J Antibiot,1989,42(6):1012-1014.
[12]Iwasaki H,Sugawara Y,Adachi T,et al.Structure of6-O-methylerythromycin A(clarithromycin)[J].Acta Crystallogr Sect C:Cryst Struct Commun,1993,49(6):1227-1230.
[2]智会静,尤启冬.第三代大环内酯类抗生素的结构改造及合成方法[J].中国抗生素杂志,2011,36(7):492-501.
[3]Jeli?D,Antolovi?R.From erythromycin to azithromycin and new potential ribosome-binding antimicrobials[J].Antibiot,2016,5(3):29-41.
[4]张森林,曹胜华.酮内酯类抗生素-泰利霉素和喹红霉素的化学合成[J].中国抗生素杂志,2009,34(12):709-716.
[5]Patel H H.Chemical synthesis of 6-O-alkyl erythromycin A:US,5,852,180[P].1998-12-22.
[6]孙京国,梁建华,邓志华,等.克拉霉素的合成进展[J].有机化学,2002,22(12):951-963.
[7]邓志华,梁建华,孙京国,等.红霉素A肟的新合成方法[J].中国药物化学杂志,2003,13(2):89-92.
[8]孟祥燕,李娜,彭凤,等.9-(E)-红霉素A肟杂质的分离与鉴定[J].中国抗生素杂志,2016,41(4):280-284.
[9]冯玉玲,孙京国,王丽君,等.2',4''-O-二(三甲基硅)红霉素A肟的合成研究[J].中国药物化学杂志,2004,14(3):150-153.
[10]孙京国.三苯基氯硅烷对红霉素A肟的保护研究[J].河北师范大学学报(自然科学版),2007,31(3):359-364.
[11]Adachi T,Morimoto S,Watanabe Y,et al.Crystal and molecular structure of(14 R)-14-hydroxy-6-Omethylerythromycin A[J].J Antibiot,1989,42(6):1012-1014.
[12]Iwasaki H,Sugawara Y,Adachi T,et al.Structure of6-O-methylerythromycin A(clarithromycin)[J].Acta Crystallogr Sect C:Cryst Struct Commun,1993,49(6):1227-1230.