An alternative synthesis of piritrexim, a lipophilic inhibitor of human dihydrofolate-reductase

Article abstract of DOI:10.1002/jhet.5570360321

An alternative synthesis of the lipophilic antifolate piritrexim (1) is outlined. Starting from ketone 2, treatment with phosphorus oxychloride and dimethylformamide gave the β-chlorocrotonaldehydes 3E/Z, which were reacted with cyanoacetamide (6) in the presence of sodium hydride to yield a 3- cyano-2-pyridone derivative 7. Chlorination of 7 with thionyl chloride and subsequent reaction with guanidine (9) gave rise to piritrexim (1). The reaction of β-chlorocrotonaldehydes 3E/Z, with 2,4,6-triaminopyrimidine (4) yielded iso-piritrexim (5).