Analogs of tetrahydrofolic acid. XXVI. synthesis of some 5‐aryl and 5‐aralkyl pyrimidine‐6‐carboxylic acids and their effect on dihydrofolic reductase and thymidylate synthetase

摘要: 2-Amino-4-hydroxy-5-(4-phenylbutyl)pyrimidine-6-carboxylic acid (V) was synthesized from isopropyl 2-ethoxalyl-6-phenylhexanoate (XIII) by conversion to acyl guanide (XV) with guanidine followed anhydrous catalyzed ring closure ethyl 2-amino-α-(4-phenylbutyl)-4-oxo-2-imidazoline-Δ5,α-acetate (XXIII) and base rearrangement V; similarly, p-chlorophenylacetonitrile converted 5-(p-chlorophenyl)-2,4-diaminopyrimidine-6-carboxylic (VIII). Claisen condensation of 6-phenylhexanoate (XI) or trifluoroacetate afforded 2-amino-5-(4-phenylbutyl)-6-(trifluoromethyl)-4-pyrimidinol (XXVI) 5 - (p-chlorophenyl) -2,4 -diamino-6-(trifluoromethyl)pyrimidine (XXXIV). Evaluation V, VIII, XXVI, XXXIV as inhibitors dihydrofolic reductase showed that the 6-carboxyl, 6-trifluoromethyl, 6-carbethoxy groups greatly reduced effectiveness compared corresponding 6-methyl derivatives. The inhibition data appear make unlikely possibility pyrimidines binding enzyme four hydrogen bonds propounded Zakrzewski (19) through a charge-transfer complex, but supports concept (18) an anionic-cationic interaction for protonated 2,4-diaminopyrimidines; weak -weak non-protonated pyrimidine is stronger than bond also proposed.