The two-step method for the preparation of adenosine cyclic 3′,3′-phosphoramidate diastereoisomers, which involves the activation of adenosine cyclic 3′,5′-monophos-phate (1) with an acid chloride and in situ aminolysis of the anhydride intermediate (Bentrude, W.G.; Tomasz, J. Synthesis 1984, 27; Bottka, S.; Tomasz, J. Tetrahedron Lett.1985, 24, 2909), has been improved. The best yields were attained when 1_ was reacted with 4.4 molar equivalents of phosphorus oxychloride in trimethyl phosphate at 0°C for 3 h, and the solution of phosphorus oxychloride in trimethyl phosphate was pretreated with 0.5 molar equivalent of water at room temperature for 20 min. Rp and Sp diastereoisomers of adenosine cyclic 3′,3′-N-methylphosphoramidate and N,N-dimethylphos-phoramidate have been synthesized under these experimental conditions.
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