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

Abstract An efficient four step process for the preparation of 5′-O-(4,4′-dimethoxytrityl)-N 2-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 N 2-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.