Solid-phase parallel synthesis of 4-beta-D-ribofuranosylpyrazolo[4,3-d]pyrimidine nucleosides.
The synthesis of pyrazolo[4,3-d]pyrimidine nucleoside library using solid-phase parallel synthesis methodology is described. Glycosylation of the trimethylsilyl (TMS) derivative of 1- and 2-(methyl)-1H and 2H-pyrazolo[4,3-d]pyrimidine-5,7-(4H, 6H)-dione (5) with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose in the presence of TMS triflate provided two novel protected nucleosides 6 and 7. The structures of 6 and 7 were assigned by 1H and 2D NMR experiments. Nucleosides 6 and 7 were then transformed to the key intermediates 12 and 15 respectively. Reaction of 12 and 15 with MMTCl resin in the presence of 2,6-lutidine afforded the necessary scaffolds B and C. Different amines (96) were introduced selectively by nucleophilic substitution on scaffolds B and C using solid-phase parallel semi-automated synthesizer. Cleavage of the products from the solid support with 30% HFIP in a parallel fashion yielded nucleoside libraries simultaneously, and they were analyzed and characterized by high-throughput LC-MS.
Ramasamy
Kanda S
KS
R & D Division, Valeant Pharmaceuticals, Costa Mesa, California 92626, USA. kramasamy@valeant.com
Amador
Roberto B
RB
Habib
Qazi
Q
Rong
Frank
F
Han
Xiaogang
X
Li
David Y
DY
Huang
Jingfan
J
Hong
Zhi
Z
An
Haoyun
H
D000493:Allopurinol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D015394:Molecular Structure; D012263:Ribonucleosides / Q000138:chemical synthesis* / Q000737:chemistry
D012263:Ribonucleosides; D000493:Allopurinol; C021958:allopurinol riboside