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US 2025/0325575 A2Published application
Synthesis of 3 -rna oligonucleotides
AssigneeAlnylam Pharmaceuticals, Inc.
InventorsJayaprakash K. NAIR, Juan C. SALINAS, John Frederick BRIONES, Mark K. SCHLEGEL, Shigeo MATSUDA, Alexander V. KEL’IN, Ligang ZHANG, Martin A. MAIER
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Abstract
The disclosure is directed to monomers and methods for synthesizing oligonucleotides comprising at least one nucleoside comprising a 3′-hydroxyl group.
Claims22
A method for synthesizing oligonucleotides having at least one nucleoside with a 3′-OH group, the method comprising:
- (i) coupling a free 5′-hydroxyl group on a nucleoside or oligonucleotide with a nucleoside phosphoramidite monomer having (i-a) a 2′-phosphoramidite group and (i-b) a triisopropylsilylether (TIPS) protected 3′-hydroxyl group to form a phosphite triester intermediate;
- (ii) oxidizing or sulfurizing said phosphite triester intermediate to form a protected intermediate;
- and
- (iii) deprotecting the protected intermediate with a base, wherein said treating with the base is at a temperature of 30° C. or higher,
- wherein the nucleoside phosphoramidite monomer has the structure of Formula (I):
- wherein:
- B is a modified or unmodified nucleobase;
- R1 is a hydroxyl protecting group;
- R2 is —Si(R4)3;
- R3 is —P(NR5R6)OR7;
- each R4 is independently isopropyl;
- R5 and R6 are independently optionally substituted alkyl, or wherein R5 and R6 are linked to form a heterocyclyl;
- and
- R7 is β-cyanoethyl.
11 more elements
(canceled)
(canceled)
A nucleoside monomer having the structure of Formula (I):
- wherein:
- B is a modified or unmodified nucleobase;
- R1 is a hydroxyl protecting group;
- R2 is —Si(R4)3;
- R3 is —P(NR5R6)OR7;
- each R4 is isopropyl;
- R5 and R6 are independently optionally substituted alkyl, or wherein R5 and R6 are linked to form a heterocyclyl;
- and
- R7 is β-cyanoethyl.
6 more elements
-30. (canceled)
Dependencies are inferred from the claim text.