A facile synthesis of certain 4‐ and 4,5‐disubstituted 1‐β‐d‐ribofuranosylpyrazoles

Abstract

Abstract A number of pyrazole ribonucleosides, structurally related to AICA riboside and ribavirin have been prepared and evaluated for their biological activity in vitro . Deisopropylidenation of 5‐amino‐1‐(2,3‐ O ‐isopropylidene‐β‐D‐ribofuranosyl)pyrazole‐4‐carbonitrile ( 6 ) with aqueous trifluoroacetic acid gave 5‐amino‐1‐(β‐D‐ribofuranosyl)pyrazole‐4‐carbonitrile ( 7 ). Conventional transformation of the carbonitrile function of 7 gave the AICA riboside congener ( 2 ) and related 5‐amino‐1‐(β‐D‐ribofuranosyl)‐pyrazoles ( 8–10 ). Acetylation of 7 at low temperature gave the versatile intermediate 5‐amino‐1‐(2,3,5‐tri‐ O ‐acetyl‐β‐D‐ribofuranosyl)pyrazole‐4‐carbonitrile ( 15 ). Non‐aqueous diazotization of 15 with isoamylnitrite in dibromomethane or diiodomethane gave the corresponding C 5 ‐bromo 13 and C 5 ‐iodo 16 derivatives. Compounds 13 and 16 were subsequently transformed into 5‐bromo‐1‐(β‐D‐ribofuranosyl)pyrazole‐4‐carboxamide ( 11 ) and the 5‐iodo analog 25 . However, a similar nonaqueous diazotization of 15 in dichloromethane afforded the deaminated product 1‐(2,3,5‐tri‐ O ‐acetyl‐β‐D‐ribofuranosyl)pyrazole‐4‐carbonitrile ( 22 ). Treatment of 22 with ammonium hydroxide/hydrogen peroxide gave the ribavirin congener 1‐(β‐D‐ribofuranosyl)pyrazole‐4‐carboxamide ( 18 ). Similar treatment of 22 with hydrogen sulfide in pyridine or hydroxylamine in ethanol gave the 4‐thiocarboxamide 19 and 4‐carboxamidoxime 20 derivatives, respectively. Catalytic hydrogenation of 20 afforded 1[β‐D‐ribofuranosyl)pyrazole‐4‐carboxamidine ( 21 ). These pyrazole nucleosides are devoid of any significant antiviral or antitumor activity in vitro .