Synthesis of hydroxy-substituted aza-analogues of antitumor anthrapyrazoles

Article abstract of DOI:10.1002/jhet.5570350419

Synthetic routes have been developed which lead to ring-hydroxylated aza-analogues of antitumor anthrapyrazoles, namely, 2,5- bis[(aminoalkyl)amino] substituted 10-hydroxyindazo[3,4-fg]isoquinolin- 6(2H)-ones 1 and 7-hydroxyindazolo[4,3-gh]isoquinolin-6(2H)-ones 2. The regiospecific synthesis of 6,9-dihalo-4-hydroxybenz[g]isoquinolines 3 and 4 has been accomplished. Intermediate 3 was constructed in a multistep process involving Diels-Alder chemistry of benzolacrylates 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 23s and 23b, respectively, which arose from further S(N)Ar substitutions of the p-methoxybenzyloxy group.