Solid-Phase Synthesis of Highly Diverse Purine-Hydroxyquinolinone Bisheterocycles

Abstract

Solid-phase synthesis of bisheterocyclic compounds that contain purine and the 3-hydroxyquinolin-4(1H)-one skeleton connected with an aliphatic spacer of a different length/structure is described. The reaction sequence started from the primary amines immobilized on aminomethylated polystyrene resin equipped with an acid-labile linker (4-(4-formyl-3-methoxyphenoxy)butyric acid). After the arylation of amines with 2,6-dichloropurine via its C(6), purine N(9) was alkylated and subsequently the chlorine at purine C(2) was substituted with aliphatic diamines. The resulting terminal amino group was used as the starting point for the synthesis of 3-hydroxyquinolin-4(1H)-one precursors based on the acylation with 3-amino-4-(methoxycarbonyl)benzoic acid followed by the saponification of the methyl ester and esterification of the resulting carboxylic acid with various haloketones. The intermediates were cleaved from the resin, and their cyclization to the target purine-hydroxyquinolinone bisheterocycles was accomplished by heating in acetic or trifluoroacetic acid.

Solid-Phase Synthetic Strategies for the Preparation of Purine Derivatives

“…In contrast, it is difficult to accomplish the subsequent substitution of the chlorine in the purine C 2 position. In the case of reactive nucleophiles (primary aliphatic amines, piperidines, or piperazines), the solid-phase amination can be accomplished using high boiling solvents, for example, DMSO, NMP, or diethylene glycol diethyl ether, at 150–200 °C. , To avoid these harsh conditions, an alternative approach was introduced by Brill who studied the possible C 2 substitution under Pd catalysis . He reported that the use of Pd 2 dba 3 as the promoter, P­( t -Bu) 3 as the coligand and K 3 PO 4 as a base furnished the desired products 48 in high yields (70–97%) at temperatures up to 100 °C.…”

Methods of Synthesis and Bioactivity of 3-Carboxy-quinolin-4(1H)-ones

“…A síntese orgânica em fase sólida (SOFS) [62][63][64][65] vem sendo uma alternativa viável na síntese de diferentes 3-carboxi-quinolin-4(1H)-onas. Srivastava et al, 66 preparam derivados da 3-carboxi-quinolin-4(1H)-ona a partir do tratamento da resina Merrifield (clorometilpoliestireno/divinilbenzeno) (41) com ácido 4-aminobenzóico (42) em presença de uma base (Cs 2 CO 3 ) para fornecer o intermediário (43).…”

Preparation of 2-phenyl-3-hydroxyquinoline-4(1H)-one-5-carboxamides as potential anticancer and fluorescence agents

“…Recently, a deeper attention has been paid to compounds bearing the carboxamide group located on a benzene ring of the quinolinone scaffold. For such compounds, a high-throughput solidphase synthesis concept has been developed [17][18][19] and targeted chemical libraries of 3HQs with the carboxamide group located in position 6, 7 and 8 were prepared. Both structurecytotoxicity 20,21 and structure-uorescence 22 relationships have been evaluated and derivatives with the most promising biological and uorescence properties were identied (Fig.…”