Synthesis of 2' protected nucleosides
AssigneeHongene Biotech Corporation
InventorsWing C. Poon, Ruiming Zou, Aldrich N.K. Lau, David Yu, Gengyu Du, Yun-Chiao Yao, Gang Zhao
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Abstract
Embodiments of the present application relate to the preparation of 2′-O-protected nucleoside phosphoramidites and conjugation of the 2′-O-protected nucleoside to a solid support. More specifically, the present application relates to nucleosides having a hydroxy protecting group at the 2′ position that reduces migration to the 3′ position during RNA (e.g., mRNA) synthesis and can be readily removed under mild conditions without the use of toxic metal-containing reagents. Methods of using the nucleosides described herein in RNA synthesis are also disclosed.
Claims27
A compound of Formula (I):
- or a pharmaceutically acceptable salt thereof,
- wherein
- R1 is hydrogen or a hydroxy protecting group;
- R2 is hydrogen, a hydroxy protecting group, —C(═O)CH2CH2C(═O)R3, or —P(OR4)NR5R6;
- alternatively, R1 and R2 are joined together to form a 6-10 membered heterocyclic ring;
- RHet is optionally substituted 5-10 membered heteroaryl or optionally substituted 5-10 membered heterocyclyl;
- R3 is hydroxy, —OR7 or —NR8R9;
- each of R4, R5 and R6 is independently H, unsubstituted C1-C6 alkyl, or substituted C1-C6 alkyl;
- R7 is unsubstituted C1-C6 alkyl, substituted C1-C6 alkyl, or a hydroxy protecting group;
- each of R8 and R9 is independently H, unsubstituted or substituted C1-6 alkyl, or an amino protecting group;
- and
- B is a natural nucleobase, a modified natural nucleobase, or an unnatural nucleobase.
(canceled)
(canceled)
A method of deprotecting an oligonucleotide or polynucleotide comprising at least one 2′ protected nucleotide residue comprising the structure of Formula (II):
- wherein
- X is O or S;
- R4 is H, unsubstituted C1-C6 alkyl or substituted C1-C6 alkyl;
- B is a natural nucleobase, a modified natural nucleobase, or an unnatural nucleobase;
- and
- RHet is optionally substituted 5-10 membered heteroaryl or optionally substituted 5-10 membered heterocyclyl;
- the method comprising:
- contacting the oligonucleotide or polynucleotide with a composition comprising an amine or ammonia to deprotect the 2′ protected nucleotide residue.
24-34. (canceled)
A solid support bound oligonucleotide or polynucleotide comprising at least one 2′ protected nucleotide residue comprising the structure of Formula (II):
- wherein
- X is O or S;
- R4 is H, unsubstituted C1-C6 alkyl or substituted C1-C6 alkyl;
- B is a natural nucleobase, a modified natural nucleobase, or an unnatural nucleobase;
- and
- RHet is optionally substituted 5-10 membered heteroaryl or optionally substituted 5-10 membered heterocyclyl.
37-44. (canceled)
Dependencies are inferred from the claim text.