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

An alternative synthesis of the lipophilic antifolate piritrexim (1) is out lined. Starting from ketone 2, treatment with phosphorus oxychloride and di methylformamide gave the beta-chlorocrotonaldehydes 3E/Z, which were reacte d with cyanoacetamide (6) in the presence of sodium hydride to yield a 3-cy ano-2-pyridone derivative 7. Chlorination of 7 with thionyl chloride and su bsequent reaction with guanidine (9) gave rise to piritrexim (1). The react ion of beta-chlorocrotonaldehydes 3E/Z, with 2,4,6-triaminopyrimidine (4) y ielded isa-piritrexim (5).