Synthesis of silodosin glucuronide and its deuterated counterpart: solving a problematic O-glycosylation of a nitrogen-containing molecule

[摘要] We report here the first chemical synthesis of silodosin glucuronide, a metabolite of the α 1A -adrenoceptor antagonist silodosin, and its deuterium-labeled counterpart. As a key synthetic step, the incorporation of a glucuronosyl unit onto silodosin invariably led to either an undesired orthoester or a complex mixture under an array of standard glycosylation conditions. This problematic O -glycosylation may be attributed to the presence of multiple basic groups that could neutralize the acidic activators, decrease the nucleophilicity of a hydroxy group via hydrogen bond or even facilitate acyl migration side reactions. After elaborate tuning of reaction conditions, success was eventually achieved by using perbenzoylated d -glucuronosyl N -phenyltrifluroacetimidate (PTFA) as donor in combination with a procedure of sequential addition of TMSOTf. This protocol is potentially general for the glycosylation of other nitrogen-containing small molecule drugs.

[学科分类] 内科医学

[关键词] glucuronide;glycosylation;metabolite;silodosin