Analogs of tetrahydrofolic acid. XXI. Synthesis of 6‐bromomethyl‐5‐( p ‐chlorophenyl)‐2,4‐diaminopyrimidine and its evaluation as a dihydrofolic reductase inhibitor

The title compound (IV) has been synthesized from p ‐chlorophenylacetonitrile by Claisen condensation with ethyl ethoxyacetate, conversion to an enol ether, then reaction with guanidine to give the key intermediate 5‐( p ‐chlorophenyl)‐2,4‐diamino‐6‐ethoxymethyl‐pyrimidine (V). Cleavage of the ethyl ether of V with hydrogen bromide in acetic acid gave IV. The bromomethylpyrimidine (IV) was a good reversible inhibitor of dihydrofolic reductase from pigeon liver, but IV was not an irreversible inhibitor of the enzyme.