Development and Optimization of a Novel Synthetic Route for 2,4-Diamine-quinazoline Containing Ziresovir: A Drug Candidate for the Treatment of Respiratory Syncytial Virus (RSV) Infection

Ziresovir (AK0529) is a potent fusion (F) protein inhibitor featuring a quinazoline-2,4-diamine core and is currently a Phase III clinical drug candidate for the treatment of respiratory syncytial virus (RSV) infectious diseases. The existing synthetic routes to Ziresovir involve two consecutive nucleophilic substitutions on 2,4-dichloro-6-methylquinazoline with amines, which often result in undesired side products and require harsh conditions for the second chlorine substitution. In this study, we report the development and optimization of a streamlined, three-step synthesis of Ziresovir. The process begins with a copper-catalyzed ring closure reaction between 2-bromobenzoic acid and guanidine to form substituted quinazoline scaffolds. Subsequent chlorination with POCl3 produces intermediate 4-chloroquinazoline compound 19. Finally, nucleophilic substitution of compound 19 with 3-amino-3-oxetanylmethylamine yields the target molecule, Ziresovir. This chromatography-free process offers practical advantages, offering a viable pathway for the production of Ziresovir and other quinazoline analogs.