Solution stability and degradation pathway of deoxyribonucleoside phosphoramidites in acetonitrile |
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Authors: | Krotz Achim H Rentel Claus Gorman Dennis Olsen Phil Gaus Hans J McArdle James V Scozzari Anthony N |
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Institution: | Drug Substance Manufacturing, Isis Pharmaceuticals, Inc., Carlsbad, California 92008, USA. akrotz@isisph.com |
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Abstract: | The impuritiy profiles of acetonitrile solutions of the four standard O-cyanoethyl-N,N-diisopropyl-phosphoramidites of 5'-O-dimethoxytrityl (DMT) protected deoxyribonucleosides (dG(ib), dA(bz), dC(bz), T) were analyzed by HPLC-MS. The solution stability of the phosphoramidites decreases in the order T, dC>dA>dG. After five weeks storage under inert gas atmosphere the amidite purity was reduced by 2% (T, dC), 6% (dA), and 39% (dG), respectively. The main degradation pathways involve hydrolysis, elimination of acrylonitrile and autocatalytic acrylonitrile-induced formation of cyanoethyl phosphonoamidates. Consequently, the rate of degradation is reduced by reducing the water concentration in solution with molecular sieves and by lowering the amidite concentration. Acid-catalyzed hydrolysis could also be reduced by addition of small amounts of base. |
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