The last chemical step in standard oligonucleotide synthesis, the acid-catalyzed removal of 4,4‘-dimethoxytrityl (DMTr) protecting groups from the 5‘-terminus of oligonucleotides is accompanied by hydrolysis of purine nucleoside glycosidic linkages (depurination). A mild procedure for controlled DMTr removal using NaOAc (10 mM, pH 3.0) under a fixed set of conditions has been developed. The calculation of the reaction time is based on a t 1/2 versus pH profile, specifically determined for each individual oligonucleotide sequence. The effect of various solvent components on the reaction kinetics has been evaluated. As a result, oligonucleotides with improved impurity profile are obtained consistently from laboratory scale to production scale.
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Krotz et al. (2003) studied this question.
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