Research On The Synthesis Of2'-O-methyl Nucleoside Derivatives

As a series of important materials of preparing the second generation antisense oligonucleotides, researching the property of ribonucleosides with2'-methoxy modified as pharmaceutical intermediate and modern method of synthesis have significant value in the field of anti-cancer and antibiotic.In this paper, synthesis procedures of2'-O-methyl-5'-O-(4,4'-dimethoxytriphenylmethyl)-N6-benzoyl adenosine and2'-O-methyl-5'-O-(4,4'-dimethoxytriphenylmethyl)-N2-isobutyryl guanosine are described in details. The final products were identited by IR and1H NMR.Adenosine using as raw material reacted with methyl iodide which reaction located at the2'-hydroxyl group of the sugar ring.After it was converted to2'-O-methyl adenosine,protection reaction were needed at the site of N6-amino of base with adenosine benzoyl chloride and the site of5'-hydroxyl group reacted with4,4'-dimethoxytriphenylmethyl chlide.The final yield rate of2'-O-methyl-5'-O-(4,4'-dimethoxytriphenylmethyl)-N6-benzoyl adenosine was31%.The raw material2,6-diamino purine nucleoside reacted with methyl iodide, and was catalyzed by adenosine deaminase, then it was converted into2'-O-methyl guanosine.After the reaction of isobutyl acylation, isobutyl chloride protected the N2-amino of base. The next,4,4'-dimethoxytriphenylmethyl chlide protected the5'-hydroxyl group. Finally we perpared the2'-O-methyl-5'-O-(4,4'-dimethoxytriphenyl methyl)-N2-isobutyl guanosine,with a total yield of37%.The route process above has the advantages in simple operation, low financial cost and being environmental protected. Also,this method could apply with middle to large scale manufacture.