IRREVERSIBLE ENZYME INHIBITORS .151. ACTIVE-SITE-DIRECTED IRREVERSIBLE INHIBITORS OF DIHYDROFOLIC REDUCTASE DERIVED FROM 5-(P-AMINOPHENYLBUTYL)-2,4-DIAMINOPYRIMIDINES WITH A TERMINAL SULFONYL FLUORIDE

Wittig condensation of 2-acetamido-4-hydroxy-6-methylpyrimidiiie-5-propionaldehyde (5) with p-tiilrobeuzyl triphenylphosphonium bromide (6) proceeded in 69% yield to 2-acetamido-6-methyl-5-[4-(p-nitrophenyl)-3-buten-l-yl]-4-pyrimidinol (7) in DMF by use of 1,4-diazabicydo[4.3.0]non-5-ene (DBN) as the base. By further transformations, 7 was converted to the key intermediate, 5-(p-aminophenylbutyl)-2,4-diamino-6-methylpyrimidine (11). 2,4-Diacetamidopyrimidine-5-carboxaldehyde (14) condensed smoothly with p-nitrocinnamyltriphenylphosphonium bromide (15) with DBN as the base to give 2,4-diaoetamido-5-[4-(p-mtrophenyl)-1,3-butadien-l-yl] pyrimidine (16) in 84% yield. Catalytic reduction of 16 and hydrolysis afforded the key intermediate, 5-(p-aminophenylbutyl )-2,4-diaminopyrimidine (17) in 56%, yield. Acylation of the ary lamino group of 11 arid 17 with m-or p-fluorosulfonylbenzoyl chloride gave a series of candidate irreversible inhibitors of dihydrofolic reductase. Two of these were excellent irreversible inhibitors of the enzyme from L1210 mouse leukemia and showed good specificity by showing poor inactivation of the mouse liver enzyme; however, these compounds showed poor diffusion through the L1210 cell wall. © 1969, American Chemical Society. All rights reserved.