Acetonide protection of dopamine for the synthesis of highly pure N-docosahexaenoyldopamine

Direct acetonide protection of the catechol of dopamine has proven to be problematic due to the formation of Pictet–Spengler isoquinolines. Here we report an efficient method for acetonide protection of dopamine, allowing the preparation of a dopamine prodrug without complications from the Pictet–Spengler reaction. Acetonide-protected dopamine was first synthesized by pre-protecting the amino group with phthaloyl followed by refluxing with 2,2-dimethoxypropane in the presence of TsOH. Further work demonstrated that Fmoc and trifluoroacetyl were also suitable N-protective groups, while Boc-protected dopamine gave an isoquinoline product. Acetonide-protected dopamine was coupled to DHA (all cis-4,7,10,13,16,19-docosahexaenoic acid) to produce the N-DHA-dopamine prodrug with high purity.