以肌苷为原料合成水粉蕈素

Synthesis of nebularine from inosine

肌苷通过乙酰化和氯代反应得到了2′,3′,5′-三-O-乙酰基-6-氯嘌呤核苷(Ⅳ);接着,化合物Ⅳ与三苯基膦反应,得到了2′,3′,5′-三-O-乙酰基-6-三苯基膦嘌呤核苷(Ⅴ);最后,中间体Ⅴ在碳酸钾作用下断裂C—P键,同时脱掉乙酰基,以4步反应得到产物水粉蕈素,其总分离收率为62%。考察了C—P键的生成和断裂对产物分离收率的影响。C—P键生成的最佳反应条件为1.0 mmolⅣ,2.0 mL甲苯,140℃下反应20 h,在该条件下,中间体Ⅴ的分离收率为82%;C—P键断裂的最佳反应条件为1mmolⅤ,10mL混合溶剂[V(乙醇)∶V(H_(2)O)=1∶1],n(化合物Ⅴ)∶n(K_(2)CO_(3))=1.0∶1.5,120℃下反应8h,在该条件下,水粉蕈素的分离收率为85%。反应规模(即分别对应中间体Ⅳ和Ⅴ的质量)可以扩大到200 g。以重水和氘代乙醇为混合溶剂,得到6-氘代水粉蕈素,其基于中间体Ⅴ的分离收率为82%。

2′,3′,5′-Tri-O-acetyl-6-chloropurine nucleoside (Ⅳ) was obtained from inosine via acetylation and chlorination,followed by reacting with triphenylphosphine to give 2′,3′,5′-tri-O-acetyl-6-triphenylphosphonine nucleoside (Ⅴ).Finally,C—P bond in intermediateⅤwas broken in the presence of potassium carbonate and acetyl group was removed at the same time,and the targeting product nebularine was obtained in four steps and the overall separation yield was 62%.The effects of the formation and cleavage of C—P bond on the separation yield of product were investigated.The optimized reaction conditions for the formation of C—P bond were obtained as follow:1.0 mmolⅣ,2.0 m L toluene,reaction temperature 140℃and reaction time 20 h.Under the above-mentioned conditions,the separation yield of intermediateⅤwas 82%.The optimized reaction conditions for the cleavage of C—P bond were obtained as follow:1 mmolⅤ,10 m L mixed solvent[V(ethanol)∶V(H_(2)O)=1∶1],n(Ⅴ)∶n(K_(2)CO_(3))=1.0∶1.5,reaction temperature 120℃and reaction time 8 h.Under these conditions,the separation yield of nebularine was 85%.The reaction scale (the mass corresponding to intermediateⅣandⅤ,respectively) could reach 200 g.6-Deuterated nebularine was obtained in 82%separation yield from intermediateⅤin deuterated water and deuterated ethanol.