SYNTHESIS OF 2-METHYL-5-SUBSTITUTED PHENOXY-PRIMAQUINE AND ANTIMALARIALS ACTIVITY

In searching for efficient, safe and radically curative agen⁺ and causal prophylactics for malaria, seven 2-methyl-5-substituted phenoxy-6-methoxy-8-(1-methyl-4-aminobutylamino)-quinolines (Ⅱ_1～7) were synthesized and their antimalarial activities were compared with the corresponding 4-methyl substituted derivatives of primaquine.The starting material, 2-nitro-4-methoxy-5-bromo-acetanilide (Ⅲ),was prepared from p-methoxy aniline through acetylation, bromination and nitration. Ⅲ was then condensed with substituted phenols in the presence of potassium carbonate. The condensed products were subsequently hydrolyzed with dilute alcoholic hydrochloric acid to yield 2-nitro-4-methoxy-5-substituted phenoxy-aniline (Ⅴ) which underwent Skraup's reaction with 2-butenal to provide the key intermediates 2-methyl-5-substituted phenoxy-6-methoxy-8-nitroquinolines (Ⅵ). These 8-nitroquinoline derivatives were reduced to 8-aminoquinoline derivatives (Ⅶ). The latter were condensed with 4-bromo-1-phthalimido-pentane and then hydrolyzed with hydrazine hydrate, the final products were obtained as oxalate or succinate. The structure of the target compounds and unknown intermediates were confirmed by elementary and spectral analysis.Primary biolological evaluation showed that all compounds Ⅱ_1～7 were much less active than the 4-methyl substituted derivatives and slightly less active than primaquine in both causal prophylactic test against plasmodium yoelii and suppressive antimalarial test against P. berhei.