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 |
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Authors: | Taj Shabbir Ali S Gurumurthy P Suresh R Narayanan S Suman Meenakshi S Sanghvi Yogesh S |
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Institution: | Shasun Chemicals and Drugs Limited, Chennai, India. |
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Abstract: | 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. |
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