It is demonstrated that the acrylonitrile (AN) generated during the ammonolysis step of oligonucleotide manufacture selectively adds to thymine residue present in ISIS 2302 to give a fulllength oligonucleotide in which thymine is replaced by an N 3cyanoethylthymine residue. Treatment of support-bound ISIS 2302 with a solution of triethylamine in CH 3 CN before ammonolysis is sufficient to prevent formation of this class of impurity.

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A new process for the preparation of large amounts of thioate oligonucleotides in a quasi-classical solution condition is described. This method takes advantage of the use of poly(ethylene glycol) as a soluble, inert support during the synthesis. The quality and amount of the desired oligonucleotides are improved by the use of pre-formed dimeric phosphoramidite as synthons. The easy intermediate purification from moderate excess of reagents allows obtaining very high coupling yields, and, consequently, the efficient production of quite long sequences as those required for their pharmacological applications.