Enzymatic synthesis of 4′-ethynyl nucleoside analogs
AssigneeMerck Sharp & Dohme Corp.
InventorsMark A. Huffman, Anna Fryszkowska, Joshua N. Kolev, Paul N. Devine, Kevin R. Campos, Matthew Truppo, Christopher C. Nawrat
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Abstract
The present invention relates to an enzymatic synthesis of 4′-ethynyl-2′-deoxy nucleosides and analogs thereof, for example EFdA, that eliminates the use of protecting groups on the intermediates, improves the stereoselectivity of glycosylation and reduces the number of process steps needed to make said compounds. It also relates to the novel intermediates employed in the process.
Claims27
A method for synthesizing a 4′-ethynyl 2′-deoxy nucleoside or an analog thereof comprising combining compound 6.5:
- with purine nucleoside phosphorylase and a nucleobase or an analog thereof, in a buffered solution containing a manganese (II) salt,
- and wherein 2X+ is (a) two protons, (b) one proton and one monovalent cation, (c) two monovalent cations wherein each cation is the same or different, or (d) one divalent cation.
A method for synthesizing a 4′-ethynyl 2′-deoxy nucleoside or an analog thereof comprising combining compound 5
- acetaldehyde and a nucleobase or an analog thereof,
- with deoxyribose-phosphate aldolase, phosphopentomutase and purine nucleoside phosphorylase,
- in a buffered solution containing a manganese (II) salt,
- wherein 2X+ is (a) two protons, (b) one proton and one monovalent cation, (c) two monovalent cations wherein each cation is the same or different, or (d) one divalent cation.
Dependencies are inferred from the claim text.