The “Cyanoethyl Problem”

A known failure mode is formation of cyanoethyl adducts, e.g., reactions with nucleobase sites (commonly discussed for thymidine). This can create undesired modified full-length product and complicate QC/purification.

Common mitigation approaches

Two general strategies:

1. Add scavengers during C&D (e.g., thiol scavengers; specific options depend on protocol validation)

2. Remove cyanoethyl groups before cleavage

   • Example approach discussed internally: use a secondary amine (e.g., DEA) as a final step on the synthesizer to remove cyanoethyl groups quickly (minutes), then proceed with standard C&D.

Important: Specific reagents and timing should follow validated internal protocols and/or supplier recommendations for the chemistry/modifiers in use.

Suggested Visual: “Cyanoethyl problem” slide image with a short callout: “Mitigate with scavengers or pre‑deprotection step.”