Synthesis of nucleoside 5'-triphosphates and their derivatives

Abstract

Disclosed are nucleoside 5'-triphosphates modified at the α, (β, and/or γ phosphate to substitute one or more of the phosphate oxygen atoms with a borano, seleno, and/or thio group. Derivatives and pharmaceutically acceptable salts are also contemplated herein. Also disclosed are processes for preparing nucleoside 5′-triphosphates. Non-limiting, exemplary processes can include first reacting salicyl phosphorochloridite with a pyrophosphate reagent to provide P2, P3-dioxo-P1-(salicyl) cyclotriphosphite, and then reacting P2, P3-dioxo-P1-(salicyl) cyclotriphosphite with a nucleoside, followed by oxidation of the nucleoside-phosphite intermediate and hydrolysis to form the modified nucleoside 5′-triphosphate. Nucleoside 5′-triphosphates can be useful in nucleic acid replication, transcription, and translation. Processes disclosed herein are not limited to nucleoside 5′-triphosphates having a native base moiety, such as 9-adeninyl, 1-cytosinyl, 9-guaninyl, 1-thyminyl, or 1-uracilyl, and are also effective for the preparation of nucleoside 5′-triphosphates having a modified nucleobase or unnatural nucleobase.