Synthesis of pyrido[1,2‐ a ]pyrimido[4,5‐ d ]pyrimidin‐5‐ones. Cyclization reaction of 4‐[(3‐hydroxy‐2‐pyridyl)amino]‐2‐phenyl‐5‐pyrimidinecarboxylic acid with acetic anhydride

Treatment of 4‐[(3‐hydroxy‐2‐pyridyl)amino]‐2‐phenyl‐5‐pyrimidinecarboxylic acid (X) with acetic anhydride under refluxing conditions afforded 10‐hydroxy‐2‐phenyl‐5 H ‐pyrido[1,2‐ a ]‐pyrimido[4,5‐ d ]pyrimidin‐5‐one acetate (IX). The intermediate X was prepared from 4‐chloro‐2‐phenyl‐5‐pyrimidinecarboxylic acid ethyl ester (V). The reaction of V with the sodium salt of 2‐amino‐3‐hydroxypyridine at room temperature gave 4‐(2‐amino‐3‐pyridyloxy)‐2‐phenyl‐5‐pyrimidinecarboxylic acid ethyl ester (VI). Treatment of VI with a hot aqueous sodium hydroxide solution and subsequent acidification gave X. Involvement of 4‐[(3‐hydroxy‐2‐pyridyl)amino]‐2‐phenyl‐5‐pyrimidinecaroboxylic acid ethyl ester (VIII) (Smiles rearrangement product) as an intermediate in the above alkaline hydrolysis reaction of VI to X was demonstrated by the isolation of VIII and its subsequent conversion into X under alkaline hydrolysis conditions. Acetylation of VIII with acetic anhydride in pyridine solution gave 4‐[(3‐hydroxy‐2‐pyridyl)amino]‐2‐phenyl‐5‐pyrimidinecarboxylic acid ethyl ester acetate (XI), which afforded IX on fusion at 220°. This alternative synthesis of IX from XI supported the structural assignment of IX. Fusion of VI gave 10‐hydroxy‐2‐phenyl‐5 H ‐pyrido[1,2‐ a ]pyrimido]4,5‐ d ]pyrimidin‐5‐one (VII). The latter was also obtained when VIII was fused at 210°. Acetylation of VII with acetic anhydride afforded IX.