Phospholipidation of TLR7/8-active imidazoquinolines using a tandem phosphoramidite method.

A high-yielding and scalable phosphoramidite procedure was developed for the phospholipidation of TLR7/8-active imidazoquinolines. This method involves the reaction of a 1,2-diacyl- or dialkyl--glycerol or 3-chlolesterylalkanol with 2-cyanoethyl ,,','-tetraisopropylphosphordiamidite in the presence of -tetrazole followed by treatment of the resulting ,'-diisopropylphosphoramidite lipid in situ with 1-imidazoquinolinylalkanols. The resulting phosphite can be purified or directly oxidized with -butyl hydroperoxide. The cyanoethyl protecting group is then removed with triethylamine and the phospholipidated imidazoquinoline products isolated in good yield and purity by simple filtration.