The Synthesis Of 8-Alkoxy-6-Alkylamino-2-Alkylthio Purine Nucleoside Compounds

Purine bases, as the basic structural units in RNA and DNA, play paramount roles in numerous biological processes. Purine nucleosides decorated at N9 position with sugar ring draw extensive attention since they exhibit broad bioactivities in biochemistry and medicinal chemistry. Recently, purine derivatives are found to have anti-cancer, anti-viral and anti-bacterial activities, especially outstanding anti-platelet aggregation activities represented by N6-phenethyl-2-ethylthiopurien nucleosides. Thus, the chemical synthesis and structural modification of purines have attracted people’s attention for many years.At first, we investigated the effect of different sequences of functionalization on the synthesis and successfully developed a rapid and efficient approach for the preparation of 8-alkoxy-6-alkylamino-2-alkylthiopurine nucleosides, providing a promising way to modify the structure of purine nucleoside on all three positions (2-,6-, and 8-positions).This method was using guanosine (1) as the starting material, and reacted with bromine to obtain 8-bromo-guanosine (2). Then compound (2) reacted with acetic anhydride to afford 2-amino-8-bromo-6-hydroxy-9-(2’,3’, 5’-tri-O-acetyl-β-D-ribofuranosyl)purine (3). Subsquently, 2-amino-8-bromo-6-chloro-9-(2’,3’,5’-tri-O-acetyl-β-D-ribofuranosyl)purine (4) was synthesized with POCl3 as the halogenating reagent, and then (4) reacted with isoamyl nitrite and dialkyl sulfide to afford (5a-5b). Next, compounds (5a-5b) reacted with different sodium alkyloxide to get corresponding products (6a-6d). At last, the novel 8-alkoxy-6-alkylamino-2-alkylthio-9-β-D-ribofuranosylpurines (7a-7u) were generated from compounds (6a-6d) by amination. The final compounds (7a-7u) were characterized with 1H NMR、13C NMR、IR and HRMS, and provided in experimental section.