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Synthesis of hydroxy‐substituted aza‐analogues of antitumor anthrapyrazoles
Author(s) -
Krapcho A. Paul,
Gallagher Cynthia E.,
Hammach Abdelhakim,
Hacker Miles P.,
Menta Ernesto,
Oliva Ambrogio,
Di Domenico Roberto,
Da Re Giovanni,
Lotto Andrea,
Spinelli Silvano
Publication year - 1998
Publication title -
journal of heterocyclic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.321
H-Index - 59
eISSN - 1943-5193
pISSN - 0022-152X
DOI - 10.1002/jhet.5570350419
Subject(s) - chemistry , moiety , reagent , bromide , ring (chemistry) , stereochemistry , medicinal chemistry , combinatorial chemistry , organic chemistry
Synthetic routes have been developed which lead to ring‐hydroxylated aza‐analogues of antitumor anthrapyrazoles, namely, 2,5‐bis[(aminoalkyI)amino] substituted 10‐hydroxymdazolo[3,4‐ fg ]isoquinolin‐6(2 H )‐ones 1 and 7‐hydroxyindazolo[4,3‐ gh ]isoquinolin‐6(2 H )‐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 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 N Ar substitutions of the p ‐methoxybenzyloxy group.