Novel Synthesis of Nucleoside 5'-Triphosphates and Their Derivatives

A process of preparing a nucleoside 5′-triphosphate of formula (I), or a derivative thereof, or a pharmaceutically acceptable salt of said nucleoside 5′-triphosphate or said derivative,

• wherein the Base of formula (I) is Adenine (A), Cytosine (C), Guanine (G), Thymine (T), Uracil (U), modified nucleobase or unnatural nucleobase;
• R1 is H or OH, R2 is H or OH, X is independently selected from the group consisting of O, S and Se;
• and Y is independently selected from the group consisting of O, B (borano, or BH3), S, and Se;
• comprising steps according to Scheme A:
• wherein in step (a), salicyl phosphorochloridite 1 or a derivative of said salicyl phosphorochloridite 1 is reacted with an suitable pyrophosphate reagent or a derivative of said pyrophosphate reagent under a suitable solvent and suitable temperature to provide a cyclic phosphite intermediate 2 (P2,P3-dioxo-P1-(salicyl)cyclotriphosphite), and then said intermediate 2 is reacted with a nucleoside under a suitable solvent and suitable temperature to provide an intermediate 3 (P2,P3-dioxo-P1-5′-(nucleosidyl-5′-O-)cyclotriphosphite);
• and in step (b), said intermediate 3 is converted to product 4 (nucleoside 5′-triphosphate) via oxidation with suitable oxidative reagent and then hydrolysis with or without a suitable base.