2′,4″-O-双(三甲基硅)红霉素A9-O-(1-异丙氧环己基)肟甲基化反应的副产物研究

A side-product in the methylation of 2′,4″-O-bis(trimethylsilyl)erythromycin A 9-O-(1-isopropoxycyclohexyl) oxime

目的改进克拉霉素合成工艺。方法鉴定甲基化反应的副产物并研究其影响因素。结果主要的副产物为E-2′-O-三甲基硅-6-O-甲基红霉素A 9-O-(1-异丙氧基环己基)肟(1)。高温、反应时间的延长、三乙胺的加入、过量的去质子试剂均会导致副产物(1)的大量生成;而投料次序为先甲基化试剂后去质子试剂、甲基化试剂过量、THF/DMSO和toluene/DMSO混和溶剂不利于1的生成。结论通过优化甲基化工艺条件,甲基化反应收率最高可达100.2%,其中副产物1仅含0.76%。

Aim To improve the synthesis of clarithromyein. Methods Identify a side-product of methylation and investigate the influenee of the reaction condition on it. Results The side-product is E-2′-O-trimethylsilyl-6- O-methylerythromyein A 9- O- （1-isopropoxyeyelohexyl） oxime （ 1 ）. Higher temperature, longer reaction time, the addition of triethylamine, and an excessive deproton reagent will lead to the increase of 1, whereas the order of adding methylating reagents followed by deproton reagents, an excessive methylating reagent, the mixture of THF/DMSO and toluene/DMSO are detrimental to the production of 1. Conclusion By optimizing the reaction condition, the yield of the methylation was 100.2 % with 0.76 96 of 1.