An Efficient Synthesis of the Potent Dopamine D₁ Agonist Dinapsoline by Construction and Selective Reduction of 2′-Azadimethoxybenzanthrone

8,9-Dihydroxy-2,3,7,11b-tetrahydro-1H-naphth[1,2,3-de]isoquinoline (dinapsoline, 1) is a potent dopamine D₁ receptor agonist with potential antiparkinsonian activity. A new synthesis was developed with the fully aromatic compound 2 as the key intermediate. The synthesis herein described is suitable for a larger scale preparation of dinapsoline compared to the previously known methods. Furthermore, the unproductive protection/deprotection step of the nitrogen is circumvented by maintaining a high oxidation state of the isoquinoline moiety throughout the synthesis. The construction of the framework was accomplished by Friedel-Crafts acylation and a Suzuki cross-coupling reaction between the commercially available 4-bromoisoquinoline and aryl boronic acid 5, the latter demanding the transformation of the lithiation-directing amide back to a carboxylic acid functionality. The selective reduction was carried out stepwise with sodium borohydride and sodium cyanoborohydride. The new synthesis is highly yielding and reduces the number of transformations in the previously reported methods.

regioselective reduction - boron - Suzuki cross-coupling - electrophilic aromatic substitution - acylation - hydrogenation - amide hydrolysis - cyclization