63286-48-6Relevant academic research and scientific papers
Hydrolytic reactions of thymidine 5′-O-phenyl-N- alkylphosplioramidates, models of nucleoside 5′-monophosphate prodrugs
Ora, Mikko,Ojanperae, Jarno,Loennberg, Harri
, p. 8591 - 8599 (2007)
To obtain detailed data on the kinetics of hydrolytic reactions of triester-like nucleoside 5′-O-aryl-N-alkylphosphoramidates, potential prodrugs of antiviral nucleoside monophosphates, the hydrolysis of diastereomeric (Rp/Sp) thymidine 5′-{O-phenyl-N- [(1S)-2-oxo-2-methoxy-1-methylethyl]phosphoramidate) (3), a phosphoramidate derived from the methyl ester of L-alanine, has been followed by reversed-phase HPLC over the range from H0 = 0 to pH 8 at 90°C. According to the time-dependent product distributions, the hydrolysis of 3 proceeds at pH 5, the predominant reaction is hydrolysis of the carboxylic ester linkage followed by intramolecular displacement of a phenoxide ion by the carboxylate ion and hydrolysis of the resulting cyclic mixed anhydride into an acyclic diester-like thymidine 5′-phosphoramidate. The latter product accumulated quantitatively without any indication of further decomposition. Hydroxide-ioncatalyzed P-OPh bond cleavage of the starting material 3 occurred as a side reaction. Comparative measurements with thymidine 5′-{N-[(1S)-2- oxo-2-methoxy-1-methylethyl]phosphoramidate( (4) revealed that, under acidic conditions, this diester-like compound is hydrolyzed by P-N bond cleavage three orders of magnitude more rapidly than the triester-like 3. At pH > 5, the stability order is reversed, with 3 being hydrolyzed six times as rapidly as 4. Mechanisms of the partial reactions are discussed.
