Nucleoside and nucleotide analogues form a major class of antiviral drugs used against herpesviruses, hepatitis B, and RNA viruses. A defining synthetic operation is attachment of a sugar or acyclic side chain to a purine base at the N-9 position, a coupling that is difficult because guanine and related purines dissolve poorly in common organic media. Dimethyl sulfoxide is the standard solvent for this transformation: it dissolves the purine base, sustains a homogeneous reaction, and maximizes the reactivity of the purine anion.
The N-9 Alkylation Step
The purine base is deprotonated with NaH, K₂CO₃, or DBU, then attacks a sugar or acyclic side chain bearing a leaving group such as acetate, halogen, or tosylate at the attachment carbon. Guanine forms strong hydrogen-bond networks in the solid state and stays undissolved in dichloromethane, acetonitrile, toluene, and even lower-boiling polar solvents, which would leave the reaction heterogeneous. DMSO breaks up that self-association through its sulfoxide oxygen, keeping deprotonation and alkylation at a predictable rate.
| API | Virus target | DMSO coupling |
|---|---|---|
| Acyclovir / ganciclovir | Herpes / CMV | Guanine N-9 + acyclic side chain |
| Entecavir | Hepatitis B | Stereoselective cyclopentyl N-9 coupling |
| Favipiravir | RNA viruses | Late-stage side-chain coupling |
Table 1: DMSO N-9 coupling across major nucleoside antivirals
Regioselectivity and Product Practice
Purines offer N-9 and N-7 nitrogens, and the N-7 isomer is inactive and hard to remove. DMSO favors N-9 alkylation because its solvation pattern stabilizes the transition state leading to the N-9 anion, typically holding the N-9:N-7 ratio above 90:10, with NaH giving the cleanest selectivity.
Ganciclovir and its prodrug valganciclovir use the same DMSO platform, and entecavir relies on it to preserve stereochemical fidelity on the chiral cyclopentyl side chain. Favipiravir uses DMSO in later-stage coupling steps; where these transformations are strongly exothermic, continuous-flow operation provides tight control over residence time and heat removal.
Why DMSO over DMF and NMP
DMSO combines solubilizing power with anion activation: its sulfoxide oxygen solvates the alkali-metal cation strongly while the purine anion stays bare and reactive, the bare-nucleophile effect. In a protic solvent, hydrogen bonding would tightly surround and deactivate that anion, slowing the coupling. Its 189 °C boiling point supports the 60–120 °C coupling range in atmospheric equipment, and unlike NMP it carries no REACH reproductive-toxin classification. As a Class 3 solvent it is readily reduced below the 5000 ppm ICH Q3C limit during aqueous workup, and pharmaceutical-grade DMSO is specified because these steps feed directly to the drug substance.
References
- Townsend, L.B. (Ed.) Chemistry of Nucleosides and Nucleotides, Vol. 1; Plenum: New York, 1988.
- Furuta, Y. et al. Antimicrob. Agents Chemother., 2005 (T-705 / favipiravir).
- ICH Harmonised Tripartite Guideline Q3C(R6), 2019.