摘要
目的改进克拉霉素合成工艺。方法分离、鉴定红霉素A肟的醚化、硅烷化的一锅煮副产物。结果主产物为E-2′,4-″O-双(三甲基硅)红霉素A 9-O-(1-异丙氧基环己基)肟;4个副产物按含量从高到低依次为Z-2′,4-″O-双(三甲基硅)红霉素A 9-O-(1-异丙氧基环己基)肟、E-4-″O-三甲基硅-红霉素A 9-O-(1-异丙氧基环己基)肟、Z-4-″O-三甲基硅-红霉素A 9-O-(1-异丙氧基环己基)肟和E-2-′O-三甲基硅-红霉素A 9-O-(1-异丙氧基环己基)肟。结论六甲基二硅氨烷在酸性下生成三甲基硅正离子和NH3,由于3′-叔胺基在酸性下带正电,有排斥作用,硅烷化容易先发生在4-″OH上,该反应为SN1机制,相应的4-″OH比2-′OH表现出较高的活性。但由于NH3等碱性物质的干扰,提高了2-′OH的活性,硅烷化的区域选择性不高,却有助于得到2′-、4″-OH的双硅烷化产物。
Aim To improve the synthesis of clarithromycin.Method The products of etherification and silyla-tion of erythromycin A oxime in one-pot synthesis were separated and identified.Result E-2",4'20-bis(trimethylsilyl)erythromycin A 9-O-(1-isopropoxycyclohexyl)oxlme was obtained with four by-products,i.e,Z-2",4"-O-bis(trimethylsilyl)erythromycin A 9-O-(1-isopropoxycyclohexyl)oxime,E-4"-O-(trimethylsilyl)erythromycin A 9-0-(1-isopropoxycyclohexyl)oxime,Z-4"-O-(trimethylsilyl)erythromycin A 9-O-(1-1sopropoxycyclohexyl)oxime,and E-T-O-(trimethylsilyl)erythromycin A 9-O-(1-isopropoxycyclohexyl)oxime in the decreasing content.Conclusion 4"-OH is more liable to be silylated than 2′-OH in the presence of 1,1,1,3,3,3-hexamethyldisilazane(HMDS)and acidic reagent whereby(CH3)3Si^+and NH3 would be produced.In SN1 mechanism(CH3)3Si+probably attached to 2'-or 4"-hydroxyl group,and preferred to 4"-hydroxyl group due to the exclusion by the neighboring 3′-N(CH3)2 of the desosamlne moiety under acidic condition.Low regloselectlvity occurred for the existence of base such as NH3,however as made contribution to disilylation at both 2′-OH and 4"-OH.
作者
梁建华
姚国伟
LIANG Jian-hua;YAO Guo-wei(School of Life Science and Technology,Beijing Institute of Technology,Beijing 100081,China)
出处
《中国药物化学杂志》
CAS
CSCD
2006年第1期27-32,共6页
Chinese Journal of Medicinal Chemistry
基金
国家经贸委技术创新项目(01BK-009)
北京理工大学基础研究项目(200506B4223)
关键词
药物化学
药物制备
化学合成
克拉霉素
肟
硅烷化
反应机制
medicinal chemistry
drug preparation
chemical synthesis
clarithromycin
oxime
silylation
reaction mechanism
