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

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Abstract
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.