Process Development for the Synthesis of 5′-O-(4,4′-Dimethoxytrityl)-N2-isobutyryl-2′-O-(2-methoxyethyl)-guanosine—A Potential Precursor for the Second Generation Antisense Oligonucleotides: An Improved Process for the Preparation of 2′-O-Alkyl-2,6-diaminopurine Riboside

An efficient four step process for the preparation of 5'-O-(4,4'-dimethoxytrityl)-N2-isobutyryl-2'-O-(2-methoxyethyl)-guanosine 1 was developed. Direct 2'-O-alkylation of 2,6-diaminopurine riboside 2 was accomplished via inexpensive and commercially available reagents such as KOH, DMSO and alkyl halides at room temperature in 4-6 hrs. Pure 2'-O-(2-methoxyethyl)-DAPR 3 was isolated by crystallization from methanol. Enzymatic deamination of 3 followed by selective N2-isobutyrylation and 5'-O-dimethoxytritylation furnished desired 1 in high yield and purity. Fully optimized four step synthetic process has been scaled up to the pilot plant level.