Synthesis of hydroxy-substituted aza-analogues of antitumor anthrapyrazoles

Synthetic routes have been developed which lead to ring-hydroxylated aza-analogues of antitumor anthrapyrazoles, namely, 2,5-bis(aminoalkyI)amino] substituted 10-hydroxymdazolo3,4-fg]isoquinolin-6(2H)-ones 1 and 7-hydroxyindazolo4,3-gh]isoquinolin-6(2H)-ones 2 . The regiospecific synthesis of 6,9-dihalo-4-hydroxybenzg]isoquinolines 3 and 4 has been accomplished. Intermediate 3 was constructed in a multistep process involving Diels-Alder chemistry of benzoylacrylates whereas 4 was assembled using Ni(II) mediated coupling of methyl 3-chloro-5-methoxyisonicotinate ( 15b ) with the organic zinc reagent 18 derived from 2-fluoro-5-chlorobenzyl bromide ( 17 ). After protection of the hydroxy group with a p-methoxybenzyl moiety, the different nucleofugacities of the leaving groups present in 10 and 20 allowed sequential displacements by substituted hydrazines and amines, respectively, to lead to the desired p-methoxybenzyl protected analogues 12 and 22 . Deprotection led to the side arm modified compounds 1 and 2 . The displacements of 21a and 21b with N,N-dimethylethylenediamine also led to the tri(aminoalkyl)amino]substituted analogues 23a and 23b , respectively, which arose from further S_NAr substitutions of the p-methoxybenzyloxy group.