Functionalization of 2,4-Dichloropyrimidines by 2,2,6,6-Tetramethylpiperidyl Zinc Base Enables Modular Synthesis of Antimalarial Diaminopyrimidine P218 and Analogues

Two routes to the antimalarial diaminopyrimidine <b>P218</b> were developed based on the C-6 metalation of suitable 2,4-dichloro-5-alkoxy pyrimidines using (TMP)₂Zn·2MgCl₂·2LiCl base. One approach involves a late-stage modification of the C-6 position, while the other allows for tail fragment modification of <b>P218</b>. Both routes have proven reliable in synthesizing <b>P218</b>, as well as eight analogues. These innovative strategies have the potential to contribute to the search for new antimalarial drugs.