Method for producing monomer for single-stranded nucleic acid molecule

Patent metadata

Field	Value
Publication number	US-10308672-B2
Application number	US-201716085330-A
Country	US
Kind code	B2
Filing date	Apr 17, 2017
Priority date	Apr 26, 2016
Publication date	Jun 4, 2019
Grant date	Jun 4, 2019

Abstract

A compound represented by formula (3):

or an enantiomer thereof can be obtained by comprising:
reacting a compound represented by formula (1):

or an enantiomer thereof with 6-hydroxyhexanoic acid in a solvent in the presence of an additive such as 1-hydroxybenzotriazole and a condensing agent, and then mixing the resultant reaction mixture, water, and a base such as alkali metal hydroxide to produce a compound represented by formula (2):

or an enantiomer thereof; and
reacting the compound represented by formula (2) or an enantiomer thereof with 2-cyanoethyl-N,N,N′,N′-tetraisopropylphosphorodiamidite in a solvent in the presence of a coupling activator.

First claim

The invention claimed is:

1. A method for producing a compound represented by formula (3):

or an enantiomer thereof, comprising:
reacting a compound represented by formula (1):

or an enantiomer thereof with 6-hydroxyhexanoic acid in a solvent in the presence of an additive and a condensing agent selected from the group consisting of 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, N-hydroxysuccinimide, ethyl(hydroxyimino)cyanoacetate, N,N′-disuccinimidyl carbonate, N-hydroxyphthalimide, N-hydroxypiperidine, 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine and N-hydroxy-5-norbornene-2,3-dicarboxylic acid imide, and then mixing the resultant reaction mixture, water, and a base selected from the group consisting of alkali metal hydroxide, alkali metal carbonate, a bicyclic amidine compound, alkali metal alkoxide, and quaternary ammonium hydroxide to produce a compound represented by formula (2):

or an enantiomer thereof; and
reacting the compound represented by formula (2) and obtained in the production step or an enantiomer thereof with 2-cyanoethyl-N,N,N′,N′-tetraisopropylphosphorodiamidite in a solvent in the presence of a coupling activator to obtain the compound represented by formula (3) or an enantiomer thereof.

2. The production method according to claim 1 , wherein the base is an alkali metal hydroxide.

3. The production method according to claim 1 , wherein the condensing agent is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, N,N′-dicyclohexylcarbodiimide, N,N′-diisopropylcarbodiimide, 1,1-carbonyldiimidazole, 1-propylphosphonic anhydride cyclic trimer or 2-chloro-4,6-dimethoxy-1,3,5-triazine.

4. The production method according to claim 1 , wherein the additive is 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, N-hydroxysuccinimide, ethyl (hydroxyimino)cyanoacetate or N,N′-disuccinimidyl carbonate.

5. The production method according to claim 1 , wherein the coupling activator is diisopropylaminetetrazole salt, 1H-tetrazole, 5-(ethylthio)-1H-tetrazole, 5-(benzylthio)-1H-tetrazole or 4,5-dicyanoimidazole.

Assignees

• Sumitomo Chemical Co

Inventors

• Sato Kanako
• Ihara Hideki

Classifications

• C07H21/00

  Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids · CPC title

• C07F9/572 Primary

  Five-membered rings · CPC title

• C12N2330/30

  chemically synthesised · CPC title

• C12N15/113

  Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)} · CPC title