Synthesis of substituted 2-heteroarylbenzazol-5-ol derivatives as potential ligands for estrogen receptors

• Published in: Tetrahedron Vol. 69; no. 30; pp. 6076 - 6082
• Main Authors: Rezazadeh, Sina, Navidpour, Latifeh, Shafiee, Abbas
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 29.07.2013; Elsevier
• Subjects: 17β-Estradiol; Breast; Chemistry; Chemistry, Organic; Chlorides; Derivatives; ERB-041; Estrogens; Non-quinone forming ligands; Physical Sciences; Pyrazole; Reduction; Risk; Science & Technology; Toxicity; 17β-Estradiol; Non-quinone forming ligands; ERB-041; OXIDATION; QUINOIDS; EQUINE ESTROGEN; ANTIESTROGENS; QUINONES; MECHANISM; INITIATION; BETA SELECTIVE LIGANDS; PHYTOESTROGENS; CANCER; 17 beta-Estradiol
• ISSN: 0040-4020; 1464-5416
• DOI: 10.1016/j.tet.2013.05.084

Exposure to estrogen is associated with increased risk of breast and other types of human cancer. One therapeutic goal would be the creation of new molecules that would retain hormonal potency while incorporating features to retard or prevent quinone toxicity. Hence, new structures closely related to ERB-041, a known ERβ selective agonist, were synthesized whereas the phenol ring is substituted with non-quinone forming rings such as pyrazole, 2-pyrimidine-2(1H)-one or pyridine-2(1H)-one. 2-Methyl-5-methoxy-1,3-benzoxazoles (or 1,3-benzothiazole) are key intermediates for the production of the pyrazole and pyrimidine-2(1H)-one analogs. The required 1,3-benzoxazoles were synthesized starting from reduction of 2-nitro-4-methoxyphenols, followed by condensation with trimethyl orthoacetate. Then, the diiminium perchlorate intermediates were prepared from the latter compounds by Vilsmeier–Haack reaction. The reaction of the resulting intermediates with hydrazine hydrate and guanidium chloride afforded the title pyrazole and pyrimidine-2(1H)-ones, respectively. The pyridine analogs were synthesized starting from the reaction of 2-amino-4-methoxyphenols with 6-bromopyridine-3-carboxaldehyde followed by oxidation with DDQ to afford bromopyridines. These compounds were next treated with benzyl alcohol in the presence of potassium tert-butoxide to afford 2-benzyloxypyridine, which in subsequent dealkylation with boron tribromide produced the title pyridine-2-(1H)-ones. [Display omitted]