Efficient synthesis of 2,9-disubstituted 8-hydroxyadenine derivatives

Abstract

An efficient and general method for the synthesis of 2,9-disubstituted 8-hydroxyadenines, which are expected to have various biological activities, was realized. 5-Amino-4-cyano-2-hydroxyimidazoles(1) were prepared from aminomalononitrile and isocyanates as key intermediates. The condensation of 1a with amidines, imidates, guanidine, urea and thioureas afforded 8-hydroxyadenines (2-6) possessing various substituents at the 2-position. Furthermore, selective alkylation of 2-amino- and 2-hydroxyadenines (4 and 6) successively proceeded to give the corresponding 2-alkylamino- and 2-alkoxyadenines (5 and 7), respectively. 2-Alkylthioadenines (15) were prepared by an analogous reaction of 1a with benzoyl isothiocyanate and subsequent S-alkylation. The imidazoles 1 are most useful intermediates for the synthesis of 8-hydroxyadenine derivatives.

Methods for the synthesis of 1-substituted 1H-imidazol-2(3H)-ones

“…93,94 We should note that the effectiveness of reaction strongly depended on the amount of (i-Pr) 2 NEt. The reaction proceeded smoothly with 0.8 equiv of (i-Pr) 2 NEt.…”

Facile syntheses of functionalized toll-like receptor 7 agonists

“…Potent small molecule TLR7 agonists have been discovered, including imidazoquinolines such as compound 1 5 and substituted adenine derivatives such as compound 2 6–8 (Figure 1). Unfortunately, the clinical utilization of these compounds is significantly limited by side-effects resulting from the overwhelming generation of cytokines subsequent to systemic administration.…”

“…The synthesis of the known 6–8 non-functionalized TLR agonist 4a was initially explored. Benzylation of commercially available chloroadenine 5 (which can also be conveniently synthesized on a large scale by amination of 2,6-dichloropurine 18 ) proceeded smoothly, affording the desired product in good yield by simple precipitation (Scheme 1).…”