Synthesis and properties of 1-(3-fluoroadamantan-1-yl)-3-R-ureas and 1,1′-(alkan-1,n-diyl)bis[3-(3-fluoroadamantan-1-yl)ureas], promising inhibitors of epoxide hydrolase sEH

A three-stage method for the preparation of 3-fluoro-1-isocyanatoadamantane in 76% yield was developed using the reaction of 3-hydroxyadamantane-1-carboxylic acid with Ishikawa's reagent and subsequent reaction with diphenylphosphoryl azide. The reaction of 3-fluoro-1-isocyanatoadamantane with a number of aliphatic diamines, fluorine-containing anilines, and trans-4-amino(cyclohexyloxy)benzoic acid afforded a new series of targeted inhibitors of epoxide hydrolase sEH in 43-89% yields. The absence of a methylene bridge between the adamantane and urea moieties led to an increase in the melting points of the synthesized compounds, while the introduction of a fluorine atom reduces their melting points compared to nonfluorinated analogs.

Automated summary

A method for the synthesis of 3-fluoro-1-isocyanatoadamantane and a new series of inhibitors were developed. The absence of a methylene bridge between adamantane and urea led to higher melting points, while the introduction of a fluorine atom reduced melting points.