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US 2025/0154191 A1Published application
Oligonucleotide production method
AssigneeLiid Pharmaceuticals, Inc.
InventorsYoshiyuki Hari, Yasufumi Fuchi, Yuta Ito, Kazuki Yamamoto
Life of this patent
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Abstract
As a solid phase synthesis method of an oligonucleotide that enables cleavage of a synthesized oligonucleotide even under mild conditions, a solid phase synthesis method of an oligonucleotide, including a step of carrying a nucleotide derivative represented by the formula (I): wherein each symbol is as described in the specification, on a solid phase support via a universal linker, and the like are disclosed.
Claims9
A solid phase synthesis method of an oligonucleotide, comprising a step of subjecting an oligonucleotide having, at the 3′-terminus of an oligonucleotide sequence thereof, a nucleotide derivative represented by the formula (II):
- wherein * is a bonding position to the universal linker;
- ** is a bonding position to the nucleotide or oligonucleotide;
- RZ is O or S;
- X is methoxy, ethoxy, isopropoxy, isobutoxy, neopentyloxy phenyl-oxy, or methyl;
- R1 is a hydrogen atom, a halogen atom, an optionally protected hydroxy group, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkenyloxy group, or an optionally substituted alkynyloxy group;
- R2 is a hydrogen atom, a halogen atom, an optionally protected hydroxy group, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkenyloxy group, or an optionally substituted alkynyloxy group;
- R3 is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkoxy group, or an optionally substituted alkylthio group, or
- R2 and R3 are bonded to each other to form a group represented by the following formula (shown in the order of —R2—R3—):
- —O—C(Ra)2—, —O—C(Rb)2—C(Rc)2—, —O—C(Rd)2—O—, —N(Re)—C(Rf)2—, —N(Rg)—CO—,—S—C(Rh)2—, or —C(Ri)2—C(Rj)2—
- in the above-mentioned formulas, Ra to Rj are each independently a hydrogen atom or an optionally substituted alkyl group;
- and
- Base is an optionally modified nucleobase,
- which oligonucleotide is carried on a solid phase support via a universal linker and synthesized by a nucleotide elongation reaction in a solid phase synthesis method of an oligonucleotide,
- to a reaction for cleaving the oligonucleotide from the solid phase support and the universal linker.
11 more elements
A solid phase synthesis method of an oligonucleotide, comprising
- (1) a step of carrying a nucleotide derivative represented by the formula (I):
- wherein X is methoxy, ethoxy, isopropoxy, isobutoxy, neopentyloxy, phenyl-oxy, or methyl;
- Y is a hydrogen atom or a hydroxy-protecting group;
- Z1 and Z2 are each independently an optionally substituted alkyl group;
- R1 is a hydrogen atom, a halogen atom, an optionally protected hydroxy group, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkenyloxy group, or an optionally substituted alkynyloxy group;
- R2 is a hydrogen atom, a halogen atom, an optionally protected hydroxy group, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkenyloxy group, or an optionally substituted alkynyloxy group;
- R3 is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkoxy group, or an optionally substituted alkylthio group, or
- R2 and R3 are bonded to each other to form a group represented by the following formula (shown in the order of -R2-R3-):
- —O—C(Ra)2—, —O—C(Rb)2—C(Rc)2—, —O—C(Rd)2—O—, —N(Re)—C(Rf)2—, —N(Rg)—CO—, —S—C(Rh)2—, or —C(Ri)2—C(Rj)2—
- in the above-mentioned formulas, Ra to Rj are each independently a hydrogen atom or an optionally substituted alkyl group;
- and
- Base is an optionally modified nucleobase,
- on a solid phase support via a universal linker,
- (2) a step of sequentially condensing nucleic acid monomers according to the desired oligonucleotide sequence to elongate the nucleotide (one or two or more nucleotide derivatives represented by the above-mentioned formula (I) may also be used as the nucleic acid monomers),
- (3) a step of subjecting the obtained oligonucleotide having the desired sequence to a reaction for cleaving from the solid phase support and the universal linker.
12 more elements
A nucleotide derivative represented by the formula (Ia):
- wherein Xa is isobutoxy or neopentyloxy;
- Y is a hydrogen atom or a hydroxy-protecting group;
- Z1 and Z2 are each independently an optionally substituted alkyl group, or
- R2 is a hydrogen atom, a halogen atom, an optionally protected hydroxy group, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkenyloxy group, or an optionally substituted alkynyloxy group;
- R2 is a hydrogen atom, a halogen atom, an optionally protected hydroxy group, an optionally substituted alkyl group, an optionally substituted alkoxy group, an optionally substituted alkenyloxy group, or an optionally substituted alkynyloxy group;
- R3 is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkoxy group, or an optionally substituted alkylthio group, or R2 and R3 are bonded to each other to form a group represented by the following formula (shown in the order of —R2—R3—):
- —O—C(Ra)2—, —O—C(Rb)2—C(Rc)2—, —O—C(Rd)2—O—, —N(Re)—C(Rf)2—, —N(Rg)—CO—,—S—C(Rh)2—, or —C(Ri)2—C(Rj)2—
- in the above-mentioned formulas, Ra to Rj are each independently a hydrogen atom or an optionally substituted alkyl group;
- and
- Base is an optionally modified nucleobase.
7 more elements
Use of a 1,2-diol derivative represented by the formula (III):
- Y1—O—C(X1)(X2)C(X3)(X4)—O—Y2 (III)
- wherein X1-X4 are each a hydrogen atom;
- and
- Y1 and Y2 are each a hydrogen atom or a hydroxy-protecting group, as a universal linker for oligonucleotide solid phase synthesis.
1 more element
Dependencies are inferred from the claim text.