Production of crosslinked artificial nucleoside

Abstract

To provide a new method for producing a spirocyclopropylene bridged nucleic acid (scpBNA) and its precursor.SOLUTION: The method for producing a compound represented by formula (III) comprises using a compound represented by formula (I) as a raw material.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for producing spirocyclopropylene-bridged nucleic acids (scpBNAs). More specifically, the present invention relates to a method for producing nucleosides of scpBNAs, compounds used in the method, and compounds obtained by the method. [Background technology]

[0002] In recent years, nucleic acid drugs have been attracting attention as a new molecular species for drug discovery. Because natural nucleic acids have problems such as being hydrolyzed by enzymes in the body, various studies have been conducted on modified nucleic acids. For example, it has been reported that scpBNA has high binding affinity to single-stranded RNA and excellent in vivo stability (Patent Document 1 and Non-Patent Documents 1-2). [Prior art documents] [Patent documents]

[0003] [Patent Document 1] WO2015 / 125783 [Non-patent literature]

[0004] [Non-Patent Document 1] Chem. Commun., 2015, Vol.51, p.9737-9740 [Non-patent document 2] J. Org. Chem., 2016, Vol.81, p.11000-11008 Summary of the Invention [Problem to be solved by the invention]

[0005] However, it was found that producing scpBNA using conventional techniques required multiple steps, leaving room for improvement in terms of production methods aimed at large-scale synthesis.

[0006] The present invention aims to provide a novel method for producing spirocyclopropylene-bridged nucleic acids (scpBNAs) and their precursors.

[0007] Another object of the present invention is to provide an efficient method for producing spirocyclopropylene-bridged nucleic acids (scpBNAs) and their precursors.

[0008] A further object of the present invention is to provide compounds that can be used in the above-mentioned production methods and methods for producing the same. [Means for solving the problem]

[0009] Therefore, the present inventors conducted extensive research to solve the above-mentioned problems and discovered that scpBNA can be efficiently synthesized via an intermediate compound represented by formula (I) described below, thereby completing the present invention.

[0010] That is, the present invention relates to the following [1] to

[37] . [1] A method for producing a compound represented by formula (II), comprising at least a step of intramolecularly cyclizing a compound represented by formula (I).

[0011] [ka]

[0012] (In the formula, X represents a nucleic acid base moiety which may have one or more optional substituents selected from group α, wherein the group α consists of a hydroxyl group, a hydroxyl group protected with a protecting group for nucleic acid synthesis, an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, a mercapto group, a mercapto group protected with a protecting group for nucleic acid synthesis, an alkylthio group having 1 to 5 carbon atoms, an amino group, an amino group protected with a protecting group for nucleic acid synthesis, an amino group substituted with an alkyl group having 1 to 5 carbon atoms, and a halogen atom; R 1 and R 2are each independently a hydrogen atom, a protecting group for a hydroxyl group in nucleic acid synthesis, an alkyl group having 1 to 7 carbon atoms which may be branched or cyclic, an alkenyl group having 2 to 7 carbon atoms which may be branched or cyclic, an aryl group having 3 to 10 carbon atoms which may have one or more optional substituents selected from the α group and which may contain a heteroatom, an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may have one or more optional substituents selected from the α group and which may contain a heteroatom, an acyl group which may have one or more optional substituents selected from the α group, a silyl group which may have one or more optional substituents selected from the α group, a phosphate group which may have one or more optional substituents selected from the α group, a phosphate group protected with a protecting group in nucleic acid synthesis, -P(R 3 )R 4 [In the formula, R 3 and R 4 each independently represents a hydroxyl group, a hydroxyl group protected with a protecting group for nucleic acid synthesis, a mercapto group, a mercapto group protected with a protecting group for nucleic acid synthesis, an amino group, an alkoxy group having 1 to 5 carbon atoms, an alkylthio group having 1 to 5 carbon atoms, a cyanoalkoxy group having 1 to 6 carbon atoms, or an amino group substituted with an alkyl group having 1 to 6 carbon atoms; R 5 represents a hydrogen atom; a halogen atom; an alkyl group having 1 to 7 carbon atoms which may be substituted with an aryl group having 3 to 12 carbon atoms which may contain a heteroatom and which may form a branched or cyclic ring; an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may contain a heteroatom; or a silyl group).

[0013] [ka]

[0014] (In the formula, X, R 1 , R 2 and R 5 is the same as above) [2] The production method according to [1] above, wherein the intramolecular cyclization is carried out in the presence of a base. [3] The production method according to [2] above, wherein the base is an alkoxide. [4] Group R of the compound represented by formula (IV) 6 The production method according to any one of the above [1] to [3], further comprising a step of deprotecting the compound represented by formula (I).

[0015] [ka]

[0016] (In the formula, X represents a nucleic acid base moiety which may have one or more optional substituents selected from group α, wherein the group α consists of a hydroxyl group, a hydroxyl group protected with a protecting group for nucleic acid synthesis, an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, a mercapto group, a mercapto group protected with a protecting group for nucleic acid synthesis, an alkylthio group having 1 to 5 carbon atoms, an amino group, an amino group protected with a protecting group for nucleic acid synthesis, an amino group substituted with an alkyl group having 1 to 5 carbon atoms, and a halogen atom; R 1 and R 2 are each independently a hydrogen atom, a protecting group for a hydroxyl group in nucleic acid synthesis, an alkyl group having 1 to 7 carbon atoms which may be branched or cyclic, an alkenyl group having 2 to 7 carbon atoms which may be branched or cyclic, an aryl group having 3 to 10 carbon atoms which may have one or more optional substituents selected from the α group and which may contain a heteroatom, an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may have one or more optional substituents selected from the α group and which may contain a heteroatom, an acyl group which may have one or more optional substituents selected from the α group, a silyl group which may have one or more optional substituents selected from the α group, a phosphate group which may have one or more optional substituents selected from the α group, a phosphate group protected with a protecting group in nucleic acid synthesis, -P(R 3 )R 4 [In the formula, R 3 and R 4each independently represents a hydroxyl group, a hydroxyl group protected with a protecting group for nucleic acid synthesis, a mercapto group, a mercapto group protected with a protecting group for nucleic acid synthesis, an amino group, an alkoxy group having 1 to 5 carbon atoms, an alkylthio group having 1 to 5 carbon atoms, a cyanoalkoxy group having 1 to 6 carbon atoms, or an amino group substituted with an alkyl group having 1 to 6 carbon atoms; R 5 represents a hydrogen atom; a halogen atom; an alkyl group having 1 to 7 carbon atoms which may be substituted with an aryl group having 3 to 12 carbon atoms which may contain a heteroatom and which may be branched or cyclic; an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may contain a heteroatom; or a silyl group; R 6 represents a protecting group for the hydroxyl group in nucleic acid synthesis) [5] R 6 is an acetyl group. [6] The production method according to any one of the above [1] to [5], comprising a step of producing a compound represented by formula (I) from a compound represented by formula (V) as a starting material.

[0017] [ka]

[0018] (In the formula, R 1 and R 2are each independently a hydrogen atom, a protecting group for a hydroxyl group in nucleic acid synthesis, an alkyl group having 1 to 7 carbon atoms which may form a branched or cyclic chain, an alkenyl group having 2 to 7 carbon atoms which may form a branched or cyclic chain, an aryl group having 3 to 10 carbon atoms which may have one or more optional substituents selected from the α group and which may contain a heteroatom, an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may have one or more optional substituents selected from the α group and which may contain a heteroatom, an acyl group which may have one or more optional substituents selected from the α group, a silyl group which may have one or more optional substituents selected from the α group, a phosphate group which may have one or more optional substituents selected from the α group, a phosphate group protected with a protecting group in nucleic acid synthesis, -P(R 3 )R 4 [In the formula, R 3 and R 4 each independently represents a hydroxyl group, a hydroxyl group protected with a protecting group for nucleic acid synthesis, a mercapto group, a mercapto group protected with a protecting group for nucleic acid synthesis, an amino group, an alkoxy group having 1 to 5 carbon atoms, an alkylthio group having 1 to 5 carbon atoms, a cyanoalkoxy group having 1 to 6 carbon atoms, or an amino group substituted with an alkyl group having 1 to 6 carbon atoms; wherein the α group consists of a hydroxyl group, a hydroxyl group protected with a protecting group for nucleic acid synthesis, an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, a mercapto group, a mercapto group protected with a protecting group for nucleic acid synthesis, an alkylthio group having 1 to 5 carbon atoms, an amino group, an amino group protected with a protecting group for nucleic acid synthesis, an amino group substituted with an alkyl group having 1 to 5 carbon atoms, and a halogen atom; R 6 and R 7are each independently a protecting group for a hydroxyl group in nucleic acid synthesis, an alkyl group having 1 to 7 carbon atoms which may form a branched or cyclic chain, an alkenyl group having 2 to 7 carbon atoms which may have one or more optional substituents selected from the α group and which may contain a heteroatom, an aryl group having 3 to 10 carbon atoms which may have one or more optional substituents selected from the α group and which may contain a heteroatom, an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may have one or more optional substituents selected from the α group and which may contain a heteroatom, an acyl group which may have one or more optional substituents selected from the α group, a silyl group which may have one or more optional substituents selected from the α group, a phosphate group which may have one or more optional substituents selected from the α group, or a phosphate group protected with a protecting group in nucleic acid synthesis; R 6 and R 7 together, -C(R 8 )(R 9 )-[where R 8 and R 9 each independently represents a hydrogen atom, an alkyl group having 1 to 7 carbon atoms which may be substituted with an aryl group having 3 to 12 carbon atoms which may contain a heteroatom and which may form a branched or cyclic ring, or an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may contain a heteroatom] [7] R 1 and R 2 is a benzyl group. [8] A method for producing a compound represented by formula (III), comprising a step of cyclopropanating a compound represented by formula (II), wherein the cyclopropanation step comprises a step of post-treating a reaction solution with ammonia.

[0019] [ka]

[0020] (In the formula, X, R 1 , R 2 and R 5 is the same as above, and R 5’ is R5 and independently R 5 (defined as [9] The method according to [8] above, wherein X is a group having a pyrimidine skeleton.

[10] A method for producing a compound represented by the formula (III) above, comprising at least a step of cyclopropanating a compound represented by the formula (II) above in the presence of an organic acid.

[11] The method according to

[10] above, wherein X is a group having a purine skeleton.

[12] A method for producing a compound represented by the formula (III), comprising at least a step of intramolecularly cyclizing a compound represented by the formula (I) to produce a compound represented by the formula (II), and a step of cyclopropanating the compound represented by the formula (II).

[13] The method according to

[12] above, comprising the step of preparing a compound represented by formula (I) by the method according to any one of [4] to [7] above.

[14] The method according to

[12] or

[13] above, wherein the intramolecular cyclization step is carried out by the method according to any one of [1] to [7] above.

[15] The production method according to any one of the above

[12] to

[14] , wherein the cyclopropanation step is carried out by the production method according to any one of the above [8] to

[11] .

[16] A compound represented by the above formula (IV) (wherein X is a 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl group, and R 1 and R 2 is a benzyl group, and R 6 is an acetyl group, and X is a 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl group, and R 1 , R 2 and R 6 is an acetyl group).

[17] R 6 The compound according to

[16] above, wherein is an acetyl group.

[18] The compound according to

[16] or

[17] above, wherein X is a group having a substituted uracil skeleton or a group having a substituted cytosine skeleton.

[19] The compound according to

[18] above, wherein the substituent is selected from the group consisting of a hydroxyl group and an alkyl group having 1 to 6 carbon atoms.

[20] The compound according to any one of

[16] to

[19] above, wherein the compound represented by formula (IV) is a compound selected from the following:

[0021] [ka]

[0022]

[21] The compound according to

[16] or

[17] above, wherein X is a group having a substituted purine skeleton.

[22] The compound according to

[21] above, wherein the substituent is selected from the group consisting of a hydroxyl group, an amino group, and an amino group protected with a protecting group.

[23] The compound according to any one of

[16] ,

[17] ,

[21] and

[22] above, wherein the compound represented by formula (IV) is a compound selected from the following:

[0023] [ka]

[0024]

[24] A compound represented by the above formula (I) (wherein X is a 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl group, and R 1 and R 2 is a benzyl group, and X is a 2-oxo-4-amino-1,2-dihydropyrimidin-1-yl group, and R 1 and R 2 is a hydrogen atom).

[25] The compound according to

[24] above, wherein X is a group having a substituted uracil skeleton or a group having a cytosine skeleton.

[26] The compound according to

[25] above, wherein the substituent is selected from the group consisting of a hydroxyl group and an alkyl group having 1 to 6 carbon atoms.

[27] The compound according to any one of

[24] to

[26] above, wherein the compound represented by formula (I) is a compound selected from the following:

[0025] [ka]

[0026]

[28] The compound according to

[24] above, wherein X is a group having a substituted purine skeleton.

[29] The compound according to

[28] above, wherein the substituent is selected from the group consisting of a hydroxyl group, an amino group, and an amino group protected with a protecting group.

[30] The compound according to any one of

[24] ,

[28] and

[29] above, wherein the compound represented by formula (I) is a compound selected from the following:

[0027] [ka]

[0028]

[31] A compound represented by the above formula (II) (wherein X is a 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl group, and R 1 is a naphthyl group, R 2 is a benzyl group, and X is a 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl group, and R 1 is a naphthyl group, R 2 is a hydrogen atom).

[32] The compound according to

[31] above, wherein X is a group having a substituted uracil skeleton or a group having a cytosine skeleton.

[33] The compound according to

[32] above, wherein the substituent is selected from the group consisting of a hydroxyl group and an alkyl group having 1 to 6 carbon atoms.

[34] The compound according to any one of

[31] to

[33] above, wherein the compound represented by formula (II) is a compound selected from the following:

[0029] [ka]

[0030]

[35] The compound according to

[31] above, wherein X is a group having a substituted purine skeleton.

[36] The compound according to

[35] above, wherein the substituent is selected from the group consisting of a hydroxyl group, an amino group, and an amino group protected with a protecting group.

[37] The compound according to any one of

[31] ,

[35] and

[36] above, wherein the compound represented by formula (II) is a compound selected from the following:

[0031] [ka] [Effects of the Invention]

[0032] According to the present invention, scpBNA can be produced efficiently. DETAILED DESCRIPTION OF THE INVENTION

[0033] The present invention is characterized by using an intermediate compound represented by formula (I) described below.

[0034] In the present invention, the use of the compound eliminates the need for the stereoinversion step of the 2'-hydroxyl group of the nucleoside sugar moiety, which increases the number of steps in conventional techniques, and is therefore presumed to enable a reduction in the number of steps, leading to efficient production of scpBNA. However, this presumption does not limit the present invention.

[0035] First, the terms used in this specification are defined.

[0036] The term "nucleobase moiety" refers to a hydrocarbon cyclic group, as well as any 5- to 20-membered heterocyclic group having a structure in which a carbon atom constituting the hydrocarbon ring is replaced with one or more heteroatoms such as nitrogen, sulfur, or oxygen atoms, and exhibiting aromaticity, including monocyclic and fused rings. Specific examples of hydrocarbon rings include benzene, naphthalene, anthracene, phenanthrene, indane, indene, tetrahydronaphthylene, and biphenylene. Examples of heterocyclic rings include purine nucleobases and pyrimidine nucleobases. Either ring may have one or more substituents selected from the following group α. Here, the purine nucleobases and pyrimidine nucleobases include bases commonly known as components of nucleic acids (e.g., guanine, adenine, cytosine, thymine, and uracil), as well as any chemical structures and tautomers thereof (e.g., keto-enol tautomers, imine-enamine tautomers) that can act as or substitute for bases in other similar nucleic acid components. Other examples include thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridazine, indolizine, indole, isoindole, isoquinoline, quinoline, naphthyridine, quinoxaline, quinazoline, pteridine, carbazole, phenanthridine, acridine, perimidine, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, pyrroline, imidazolidine, imidazoline, and pyrazolidine. Preferred are purine nucleobases or pyrimidine nucleobases, or purine nucleobases or pyrimidine nucleobases which may have one or more substituents selected from the following α group, and specifically preferred are a purin-9-yl group, a 2-oxo-pyrimidin-1-yl group, or a purin-9-yl group or 2-oxo-pyrimidin-1-yl group having a substituent selected from the following α group. α group: hydroxyl group, hydroxyl group protected by a protecting group for nucleic acid synthesis, alkyl group having 1 to 5 carbon atoms, alkoxy group having 1 to 5 carbon atoms, mercapto group, mercapto group protected by a protecting group for nucleic acid synthesis, alkylthio group having 1 to 5 carbon atoms, amino group, amino group protected by a protecting group for nucleic acid synthesis, amino group substituted with an alkyl group having 1 to 5 carbon atoms, and halogen atom

[0037] Preferred groups for the "purine nucleobase which may have a substituent" include 6-aminopurin-9-yl (i.e., adeninyl), 6-aminopurin-9-yl in which the amino group is protected with a protecting group for nucleic acid synthesis, 2,6-diaminopurin-9-yl, 2-amino-6-chloropurin-9-yl, 2-amino-6-chloropurin-9-yl in which the amino group is protected with a protecting group for nucleic acid synthesis, 2-amino-6-fluoropurin-9-yl, 2-amino-6-fluoropurin-9-yl in which the amino group is protected with a protecting group for nucleic acid synthesis, 2-amino-6-bromopurin-9-yl, The amino group is protected with a protecting group for nucleic acid synthesis, such as 2-amino-6-bromopurin-9-yl or 2-amino-6-hydroxypurin-9-yl (i.e., guaninyl), and one or both of the amino group and hydroxyl group are protected with a protecting group for nucleic acid synthesis, such as 2-amino-6-hydroxypurin-9-yl, 6-amino-2-methoxypurin-9-yl, 6-amino-2-chloropurin-9-yl, 6-amino-2-fluoropurin-9-yl, 2,6-dimethoxypurin-9-yl, 2,6-dichloroprolin-2-yl, or 6-mercaptopurin-9-yl.

[0038] Preferred groups for the "pyrimidine nucleobase which may have a substituent" include 2-oxo-4-amino-1,2-dihydropyrimidin-1-yl (i.e., cytosinyl), 2-oxo-4-amino-1,2-dihydropyrimidin-1-yl in which one or both of the amino group and the hydroxyl group are protected with a protecting group for nucleic acid synthesis, 2-oxo-4-amino-5-fluoro-1,2-dihydropyrimidin-1-yl, 2-oxo-4-amino-5-fluoro-1,2-dihydropyrimidin-1-yl in which the amino group is protected with a protecting group for nucleic acid synthesis, 4-amino-2-oxo-5-chloro-1,2-dihydropyrimidin-1-yl, 2- Examples of the oxo-4-methoxy-1,2-dihydropyrimidin-1-yl include oxo-4-mercapto-1,2-dihydropyrimidin-1-yl, 2-oxo-4-hydroxy-1,2-dihydropyrimidin-1-yl (i.e., uracinyl), 2-oxo-4-hydroxy-5-methyl-1,2-dihydropyrimidin-1-yl (i.e., thyminyl), 4-amino-5-methyl-2-oxo-1,2-dihydropyrimidin-1-yl (i.e., 5-methylcytosinyl), and a 2-oxo-4-amino-5-methyl-1,2-dihydropyrimidin-1-yl group in which the amino group is protected with a protecting group for nucleic acid synthesis.

[0039] Among the "purine nucleobases or pyrimidine nucleobases which may have a substituent", more preferred are 6-aminopurin-9-yl (i.e., adeninyl), 6-aminopurin-9-yl in which the amino group is protected with a protecting group for nucleic acid synthesis (e.g., 6-benzoylaminopurin-9-yl, 1-benzyloxymethyl-6-benzoylaminopurin-9-yl), 2-amino-6-hydroxypurin-9-yl (i.e., guaninyl), 2-amino-6-hydroxypurin-9-yl in which one or both of the amino group and the hydroxyl group are protected with a protecting group for nucleic acid synthesis (e.g., 2-isobutyrylamino-6-hydroxypurin-9-yl, 2-isobutyrylamino-6-diphenylcarbamoyloxypurin-9-yl), 2-oxo-4-amino-1,2-dihydropyrimidin-1-yl (i.e., cytosinyl), 2-oxo-4-amino-1,2-dihydropyrimidin-1-yl in which the amino group is protected with a protecting group for nucleic acid synthesis (e.g., 2-oxo-4-benzoylamino-1,2-dihydropyrimidin-1-yl), 2-oxo-4-hydroxy-1,2-dihydropyrimidin-1-yl (i.e., uracinyl), 2-oxo-4-hydroxy-5-methyl-1,2-dihydropyrimidin- 1-yl (i.e., thyminyl), 4-amino-5-methyl-2-oxo-1,2-dihydropyrimidin-1-yl (i.e., 5-methylcytosinyl), or 4-amino-5-methyl-2-oxo-1,2-dihydropyrimidin-1-yl in which the amino group is protected with a protecting group for nucleic acid synthesis (e.g., 2-oxo-4-benzoylamino-5-methyl-1,2-dihydropyrimidin-1-yl).

[0040] The protecting group in "amino group protecting group in nucleic acid synthesis," "hydroxyl group protecting group in nucleic acid synthesis," "amino group protected by a protecting group in nucleic acid synthesis," and "hydroxyl group protected by a protecting group in nucleic acid synthesis" is not particularly limited as long as it can stably protect an amino group or a hydroxyl group during nucleic acid synthesis. Specifically, it refers to a protecting group that is stable under acidic or neutral conditions and can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis, and photolysis. Examples of such protecting groups include formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, 3-methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl, 3,7-dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexanoyl, and the like. "Fatty acyl groups" such as alkylcarbonyl groups such as sadecanoyl, 1-methylpentadecanoyl, 14-methylpentadecanoyl, 13,13-dimethyltetradecanoyl, heptadecanoyl, 15-methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl, nonadecanoyl, 4-oxopentanoyl (levulinoyl), eicosanoyl, and heneicosanoyl, carboxylated alkylcarbonyl groups such as succinoyl, glutaroyl, and adipoyl, halogeno lower alkylcarbonyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl, and trifluoroacetyl, alkoxy lower alkylcarbonyl groups such as methoxyacetyl, phenoxyacetyl, and 2-(4-tert-butyl)phenoxyacetyl, and unsaturated alkylcarbonyl groups such as (E)-2-methyl-2-butenoyl;Arylcarbonyl groups such as benzoyl, α-naphthoyl, and β-naphthoyl; halogenoarylcarbonyl groups such as 2-bromobenzoyl and 4-chlorobenzoyl; lower alkylated arylcarbonyl groups such as 2,4,6-trimethylbenzoyl and 4-toluoyl; lower alkoxylated arylcarbonyl groups such as 4-anisoyl; carboxylated arylcarbonyl groups such as 2-carboxybenzoyl, 3-carboxybenzoyl, and 4-carboxybenzoyl; lower alkoxylated arylcarbonyl groups such as 2-(methoxycarbonyl)benzoyl; "Aromatic acyl groups" such as oxycarbonylated arylcarbonyl groups, nitrated arylcarbonyl groups such as 4-nitrobenzoyl and 2-nitrobenzoyl, and arylated arylcarbonyl groups such as 4-phenylbenzoyl; methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1 "lower alkyl groups" such as -methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, and 2-ethylbutyl; ethenyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-2-butenyl, 1-methyl-1-butenyl, and 3-methyl "lower alkenyl groups" such as 1-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 1-pentenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, and 5-hexenyl;"Halogeno lower alkyl groups" such as 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, 2,2,2-trifluoroethyl, and 2,2,2-trichloro-1,1-dimethylethyl; methyl groups substituted with 1 to 3 aryl groups such as benzyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, and 9-anthrylmethyl; 4-methylbenzyl, 2,4,6-trimethylbenzyl, and 3,4,5-trimethylbenzyl; "aralkyl groups" such as methyl groups substituted by 1 to 3 aryl groups in which the aryl ring is substituted by lower alkyl, lower alkoxy, halogen, or cyano groups, such as 4-chlorophenyl, 2-fluorophenyl, 4-methoxyphenyl, 4-nitrophenyl, 2-chlorobenzyl, 4-bromobenzyl, and 4-cyanobenzyl; "Aryl groups substituted with a halogen atom, a lower alkoxy group, or a nitro group" such as 4-dinitrophenyl; "silyl groups" such as tri-lower alkylsilyl groups such as trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl, and triisopropylsilyl, and lower alkylsilyl groups substituted with 1 to 2 aryl groups such as diphenylmethylsilyl, tert-butyldiphenylsilyl, diphenylisopropylsilyl, and phenyldiisopropylsilyl; "tetrahydropyranyl or tetrahydrothiopyranyl groups" such as tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-4-yl, and 4-methoxytetrahydrothiopyran-4-yl; "tetrahydrofuranyl or tetrahydrothiofuranyl groups" such as tetrahydrofuran-2-yl and tetrahydrothiofuran-2-yl;"Lower alkoxyalkyl groups" such as lower alkoxymethyl groups such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, and t-butoxymethyl, and lower alkoxyethyl groups such as 1-ethoxyethyl and 1-(isopropoxy)ethyl; "lower alkoxylated lower alkoxymethyl groups" such as 2-methoxyethoxymethyl; "halogeno lower alkoxymethyl groups" such as 2,2,2-trichloroethoxymethyl and bis(2-chloroethoxy)methyl; "aralkyloxymethyl groups in which the aryl ring may be substituted by one to two lower alkoxy or nitro groups" such as benzyloxymethyl, 4-methoxybenzyloxymethyl, and 2-naphthylmethoxymethyl; methoxycarbonyl, ethoxymethyl, and ethoxymethyl are examples of "lower alkoxymethyl groups" and "lower alkoxyalkyl groups" such as 2-methoxyethoxymethyl, 2-methoxyethoxymethyl, 4-methoxybenzyloxymethyl, and 2-naphthylmethoxymethyl; lower alkoxycarbonyl groups such as dicarbonyl, t-butoxycarbonyl, and isobutoxycarbonyl; lower alkoxycarbonyl groups substituted by halogen or tri-lower alkylsilyl groups such as 2,2,2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl; alkenyloxycarbonyl groups such as vinyloxycarbonyl and allyloxycarbonyl; aralkyloxycarbonyl groups in which the aryl ring may be substituted by 1 to 2 lower alkoxy or nitro groups, such as benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl; "oxycarbonyl groups" such as 9-fluorenylmethyloxycarbonyl;Examples of suitable carbamoyl groups include "carbamoyl groups which may be substituted on the nitrogen atom with an alkyl group, an aryl group, an alkenyl group, a lower alkoxy group, or an aralkyl group," such as dimethylcarbamoyl, diphenylcarbamoyl, methylphenylcarbamoyl, 1-pyrrolidinylcarbamoyl, and morpholinocarbamoyl. For example, in the case of "protecting groups for hydroxyl groups in nucleic acid synthesis," suitable examples include "aliphatic acyl groups," "aromatic acyl groups," "methyl groups substituted with 1 to 3 aryl groups," "methyl groups substituted with 1 to 3 aryl groups in which the aryl ring is substituted with a lower alkyl, lower alkoxy, halogen, or cyano group," and "silyl groups." More preferred examples include acetyl groups, benzoyl groups, and the like. The protecting group for the "hydroxyl group protected by a protecting group for nucleic acid synthesis" is preferably an "aliphatic acyl group," an "aromatic acyl group," a "methyl group substituted with 1 to 3 aryl groups," an "aryl group substituted with a halogen atom, a lower alkoxy group, or a nitro group," a "lower alkyl group," or a "lower alkenyl group," and more preferably a benzoyl group, a benzyl group, a 2-chlorophenyl group, a 4-chlorophenyl group, or a 2-propenyl group;

[0041] The protecting group for the "mercapto group protected by a protecting group for nucleic acid synthesis" is not particularly limited as long as it can stably protect the mercapto group during nucleic acid synthesis, but specifically refers to a protecting group that is stable under acidic or neutral conditions and can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis, or photolysis. Examples of the protecting group include those exemplified above as protecting groups for hydroxyl groups, as well as "groups that form disulfides" such as alkylthio groups such as methylthio, ethylthio, and tert-butylthio, and arylthio groups such as benzylthio, and are preferably "aliphatic acyl groups" or "aromatic acyl groups," and more preferably a benzoyl group.

[0042] The "protecting group" in "phosphate group protected by a protecting group in nucleic acid synthesis" is not particularly limited as long as it can stably protect the phosphate group during nucleic acid synthesis, but specifically refers to a protecting group that is stable under acidic or neutral conditions and can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis, or photolysis. Examples of such protecting groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethyl "Lower alkyl groups" such as propyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, and 2-ethylbutyl; "cyano lower alkyl groups" such as 2-cyanoethyl and 2-cyano-1,1-dimethylethyl; 2-methyldiphenylsilylethyl, 2-trimethylsilylethyl, and 2-triphenylsilyl. "silyl-substituted ethyl groups" such as 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, 2,2,2-trifluoroethyl, and 2,2,2-trichloro-1,1-dimethylethyl; "halogenated lower alkyl groups" such as ethenyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-2-butenyl, 1-methyl-1-butenyl, and 3-methyl -"lower alkenyl groups" such as 2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 1-pentenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, and 5-hexenyl;"Cycloalkyl groups" such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl; "cyanoated lower alkenyl groups" such as 2-cyanobutenyl; benzyl, α-naphthylmethyl, β-naphthylmethyl, indenylmethyl, phenanthrenylmethyl, anthracenylmethyl, diphenylmethyl, triphenylmethyl, 1-phenethyl, 2-phenethyl, 1-naphthylethyl, 2-naphthylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1-naphthylpropyl, 2-naphthylpropyl, 3-naphthylpropyl, 1-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, 4-phenylbutyl, 1-naphthylbutyl, 2-naphthylbutyl, 3-naphthylbutyl, 4-naphthylbutyl, 1-phenylpentyl, 2-phenylpentyl, and 3-phenyl "Aralkyl groups" such as pentyl, 4-phenylpentyl, 5-phenylpentyl, 1-naphthylpentyl, 2-naphthylpentyl, 3-naphthylpentyl, 4-naphthylpentyl, 5-naphthylpentyl, 1-phenylhexyl, 2-phenylhexyl, 3-phenylhexyl, 4-phenylhexyl, 5-phenylhexyl, 6-phenylhexyl, 1-naphthylpentyl, 2-naphthylpentyl, 3-naphthylpentyl, 4-naphthylpentyl, 5-naphthylpentyl, and 6-naphthylpentyl; "aralkyl groups in which the aryl ring is substituted with a nitro group or a halogen atom" such as 4-chlorobenzyl, 2-(4-nitrophenyl)ethyl, o-nitrobenzyl, 4-nitrobenzyl, 2,4-dinitrobenzyl, and 4-chloro-2-nitrobenzyl; "aryl groups" such as phenyl, indenyl, naphthyl, phenanthrenyl, and anthracenyl;Examples of "aryl groups substituted with a lower alkyl group, a halogen atom, or a nitro group" include 2-methylphenyl, 2,6-dimethylphenyl, 2-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2-bromophenyl, 4-nitrophenyl, and 4-chloro-2-nitrophenyl, and are preferably "lower alkyl groups," "lower alkyl groups substituted with a cyano group," "aralkyl groups," "aralkyl groups in which the aryl ring is substituted with a nitro group or a halogen atom," or "aryl groups substituted with a lower alkyl group, a halogen atom, or a nitro group," and more preferably a 2-cyanoethyl group, a 2,2,2-trichloroethyl group, a benzyl group, a 2-chlorophenyl group, or a 4-chlorophenyl group;

[0043] The term "alkyl group" generally refers to a linear or branched alkyl group having 1 to 20 carbon atoms, and includes, for example, linear or branched alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, and 2-ethylbutyl (also referred to as lower alkyl groups in this specification), as well as linear or branched alkyl groups having 7 to 20 carbon atoms such as heptyl, octyl, nonyl, and decyl. Furthermore, a portion of the alkyl group may form a ring.

[0044] The term "alkoxy group" generally refers to an alkoxy group having the above-mentioned alkyl group, and includes, for example, methyloxy (methoxy), ethyloxy (ethoxy), n-propyloxy (n-propoxy), isopropoxy, n-butyloxy (n-butoxy), isobutoxy, s-butoxy, tert-butoxy, n-pentyloxy (n-pentoxy), and the like.

[0045] The term "cyanoalkoxy group" generally refers to a group in which any number of cyano groups are substituted on the above-mentioned alkoxy group, and examples thereof include cyanomethoxy, 2-cyanoethoxy, 3-cyanopropoxy, 4-cyanobutoxy, 3-cyano-2-methylpropoxy, 1-cyanomethyl-1,1-dimethylmethoxy, 5-cyanopentyloxy, and 6-cyanohexyloxy.

[0046] The term "alkylthio group" generally refers to an alkylthio group having the above-mentioned alkyl group, and includes, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, s-butylthio, tert-butylthio, n-pentylthio, and the like.

[0047] The term "alkylamino group" generally refers to an alkylamino group having one or two of the above alkyl groups, and includes, for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, s-butylamino, tert-butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, di(s-butyl)amino, di(tert-butyl)amino, pentylamino, and the like.

[0048] The term "alkenyl group" generally refers to a linear or branched alkenyl group having 2 to 20 carbon atoms, and examples thereof include ethenyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-2-butenyl, 1-methyl-1-butenyl, 3-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3- Examples of alkenyl groups include linear or branched alkenyl groups having 2 to 6 carbon atoms such as butenyl, 1-pentenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, and 5-hexenyl (also referred to as lower alkenyl groups in this specification), as well as heptenyl, geranyl, farnesyl, etc. In addition, a part of the alkenyl group may form a ring.

[0049] The term "aryl group" generally refers to a monovalent substituent having 6 to 14 carbon atoms, formed by removing one hydrogen atom from an aromatic hydrocarbon group, and includes, for example, phenyl, indenyl, naphthyl, phenanthrenyl, anthracenyl, and the like. The aryl ring may be substituted with one or more groups, such as a halogen atom, a lower alkyl group, a hydroxyl group, an alkoxy group, an aryloxy group, an amino group, a nitro group, a trifluoromethyl group, or a phenyl group. Examples of such optionally substituted aryl groups include 2-methylphenyl, 2,6-dimethylphenyl, 2-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2-bromophenyl, 4-methoxyphenyl, 4-chloro-2-nitrophenyl, 4-nitrophenyl, 2,4-dinitrophenyl, and biphenyl. The aryl group may contain a heteroatom, including, for example, a heteroaryl in which at least one carbon atom constituting the ring structure of the aryl group is substituted with a heteroatom (e.g., a nitrogen atom, an oxygen atom, a sulfur atom, or the like). Heteroaryl includes pyridyl, pyrrolyl, quinolyl, indolyl, imidazolyl, furyl, thienyl and the like.

[0050] The term "aralkyl group" usually refers to an alkyl group having 1 to 6 carbon atoms substituted with an aryl group, and examples thereof include "methyl groups substituted with 1 to 3 aryl groups" such as benzyl, α-naphthylmethyl, β-naphthylmethyl, indenylmethyl, phenanthrenylmethyl, anthracenylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, and 9-anthrylmethyl, as well as 4-methylbenzyl, 2,4,6-trimethylbenzyl, and 3,4,5-trimethylbenzyl. In addition to "methyl groups substituted by 1 to 3 aryl groups in which the aryl ring is substituted by lower alkyl, lower alkoxy, halogen, or cyano groups," such as 1-phenylethyl, 2-phenethyl, 1-naphthylethyl, 2-naphthylethyl, 1-phenyl ... Phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1-naphthylpropyl, 2-naphthylpropyl, 3-naphthylpropyl, 1-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, 4-phenylbutyl, 1-naphthylbutyl, 2-naphthylbutyl, 3-naphthylbutyl, 4-naphthylbutyl, 1-phenylpentyl, 2-phenylpentyl, 3-phenylpentyl, 4-phenylpentyl, 5-phenylpentyl, 1-naphthylpentyl, 2 and "an alkyl group having 2 to 6 carbon atoms substituted with an aryl group," such as 1-naphthylpentyl, 3-naphthylpentyl, 4-naphthylpentyl, 5-naphthylpentyl, 1-phenylhexyl, 2-phenylhexyl, 3-phenylhexyl, 4-phenylhexyl, 5-phenylhexyl, 6-phenylhexyl, 1-naphthylpentyl, 2-naphthylpentyl, 3-naphthylpentyl, 4-naphthylpentyl, 5-naphthylpentyl, and 6-naphthylpentyl.

[0051] Examples of the "acyl group" include formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, 3-methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl, 3,7-dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, 1-methylpentadecanoyl, and 14-methylpentadecanoyl. alkylcarbonyl groups such as noyl, 13,13-dimethyltetradecanoyl, heptadecanoyl, 15-methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl, nonadecanoyl, eicosanoyl, and henaicosanoyl; carboxylated alkylcarbonyl groups such as succinoyl, glutaroyl, and adipoyl; halogeno lower alkylcarbonyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl, and trifluoroacetyl; methoxy Examples of "aliphatic acyl groups" include lower alkoxy-lower alkylcarbonyl groups such as acetyl, and unsaturated alkylcarbonyl groups such as (E)-2-methyl-2-butenoyl, and "aromatic acyl groups" include arylcarbonyl groups such as benzoyl, α-naphthoyl, and β-naphthoyl, halogenoarylcarbonyl groups such as 2-bromobenzoyl and 4-chlorobenzoyl, lower alkylated arylcarbonyl groups such as 2,4,6-trimethylbenzoyl and 4-toluoyl, lower alkoxylated arylcarbonyl groups such as 4-anisoyl, carboxylated arylcarbonyl groups such as 2-carboxybenzoyl, 3-carboxybenzoyl, and 4-carboxybenzoyl, nitrated arylcarbonyl groups such as 4-nitrobenzoyl and 2-nitrobenzoyl, lower alkoxycarbonylated arylcarbonyl groups such as 2-(methoxycarbonyl)benzoyl, and arylated arylcarbonyl groups such as 4-phenylbenzoyl.

[0052] Examples of the "silyl group" include "tri-lower alkylsilyl groups" such as trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl, and triisopropylsilyl, and "lower alkylsilyl groups substituted with 1 to 2 aryl groups" such as diphenylmethylsilyl, butyldiphenylbutylsilyl, diphenylisopropylsilyl, and phenyldiisopropylsilyl.

[0053] The "halogen atom" includes, for example, a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

[0054] Next, the present invention will be described in detail.

[0055] The method for producing the compound represented by formula (III) of the present invention may be any method using a compound represented by formula (I) below as a raw material, and includes at least a step using the compound represented by formula (I).

[0056] [ka]

[0057] (In the formula, X represents a nucleobase moiety which may have one or more optional substituents selected from group α; R 1 and R 2are each independently a hydrogen atom, a protecting group for a hydroxyl group in nucleic acid synthesis, an alkyl group having 1 to 7 carbon atoms which may be branched or cyclic, an alkenyl group having 2 to 7 carbon atoms which may be branched or cyclic, an aryl group having 3 to 10 carbon atoms which may have one or more optional substituents selected from the α group and which may contain a heteroatom, an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may have one or more optional substituents selected from the α group and which may contain a heteroatom, an acyl group which may have one or more optional substituents selected from the α group, a silyl group which may have one or more optional substituents selected from the α group, a phosphate group which may have one or more optional substituents selected from the α group, a phosphate group protected with a protecting group in nucleic acid synthesis, -P(R 3 )R 4 [In the formula, R 3 and R 4 each independently represents a hydroxyl group, a hydroxyl group protected with a protecting group for nucleic acid synthesis, a mercapto group, a mercapto group protected with a protecting group for nucleic acid synthesis, an amino group, an alkoxy group having 1 to 5 carbon atoms, an alkylthio group having 1 to 5 carbon atoms, a cyanoalkoxy group having 1 to 6 carbon atoms, or an amino group substituted with an alkyl group having 1 to 6 carbon atoms; R 5 represents a hydrogen atom; a halogen atom; an alkyl group having 1 to 7 carbon atoms which may be substituted with an aryl group having 3 to 12 carbon atoms which may contain a heteroatom and which may form a branched or cyclic ring; an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may contain a heteroatom; or a silyl group).

[0058] Examples of X in formula (I) include the above-mentioned nucleic acid base moieties. Among them, from the viewpoint of introduction into nucleic acid drugs, purine nucleic acid bases or pyrimidine nucleic acid bases which may have a substituent are preferred, for example, those represented by the following structural formula:

[0059] [ka]

[0060] and tautomers thereof, which are preferably 2-oxo-4-hydroxy-5-methyl-1,2-dihydropyrimidin-1-yl (thyminyl), 2-oxo-4-amino-1,2-dihydropyrimidin-1-yl (cytosinyl), 6-aminopurin-9-yl (adeninyl), 2-amino-6-hydroxypurin-9-yl (guaninyl), 4-amino-5-methyl-2-oxo-1,2-dihydropyrimidin-1-yl, and 2-oxo-4-hydroxy-1,2-dihydropyrimidin-1-yl (uracilyl), each represented by the following formula:

[0061] R in formula (I) 1 ~R 5 can be independently set appropriately with reference to the above-mentioned substituents. 3 )R 4 Suitable examples of the group represented by the formula include a group represented by the formula -P(OC2H4CN)(N(iPr)2) and a group represented by the formula -P(OCH3)(N(iPr)2), where iPr represents an isopropyl group.

[0062] An example of a production method using a compound represented by formula (I) as a starting material is a method using a compound represented by formula (II) obtained by intramolecular cyclization of the compound represented by formula (I). Thus, one embodiment of the present invention is a method including at least a step of intramolecular cyclization of the compound represented by formula (I). Hereinafter, this step may be referred to as step A.

[0063] The intramolecular cyclization can be carried out by a method known in the art, for example, an addition reaction of an alcohol to an alkyne. In the addition reaction, it is usually preferable to add a base to the substrate and carry out the reaction in a solvent or without a solvent, with cooling or heating as necessary.

[0064] Examples of bases include alkoxides such as sodium methoxide, sodium ethoxide, sodium t-butoxide, lithium methoxide, lithium ethoxide, lithium t-butoxide, potassium methoxide, potassium ethoxide, and potassium t-butoxide; carbonates such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; organometallic reagents such as methyllithium, ethyllithium, n-butyllithium, and methylmagnesium chloride; metal hydrides such as sodium hydride; metal amides such as lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, and lithium dicyclohexylamide; triethylamine, diisopropylethylamine, tributylamine, and t-butylamine; Examples of the base include organic bases such as N,N-dimethylaniline, N,N-diethylaniline, pyridine, 4-dimethylaminopyridine, pyrrolidine, piperidine, collidine, lutidine, morpholine, piperazine, diazabicycloundecene, diazabicyclononene, 1,4-diazabicyclo[2.2.2]octane, etc. These bases may be used alone or in combination and can be selected in consideration of the type of substrate, reactivity, and selectivity.

[0065] The amounts of substrate, base, etc. used in the reaction, the reaction temperature, the reaction time, etc. can be appropriately set according to known techniques. For example, the reaction temperature is −80 to 200° C., the reaction time is 1 to 24 hours, and the amount of base used is 1.0 equivalent to 30 equivalents. Furthermore, there are no particular limitations on the purification after the reaction.

[0066] The compound represented by formula (I) is 1 ~R 5 As long as the compound has X, it may be a commercially available product or one prepared according to a known method. For example, compounds in which X is a group having a uracil skeleton or a group having a cytosine skeleton, which may have a substituent (preferably a hydroxyl group, an amino group, or a hydroxyl group or amino group protected by a protecting group), and tautomers thereof may be used. Specific structures are shown below.

[0067] [ka]

[0068] Similarly, examples of the compound represented by formula (I) include compounds in which X is a group having a purine skeleton optionally having a substituent (preferably a hydroxyl group, an amino group, or a hydroxyl group or amino group protected by a protecting group), and tautomers thereof. Specific structures are shown below.

[0069] [ka]

[0070] In the present invention, the compound represented by formula (I) may be a compound in which X is a 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl group and R 1 and R 2 is a benzyl group, R 5 is a hydrogen atom, and X is a 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl group and R 1 , R 2 and R 5 A compound in which is a hydrogen atom may also be used.

[0071] The compound represented by formula (I) can be prepared by deprotecting a compound represented by formula (IV): Thus, one embodiment of the present invention can include a production method further comprising the step of deprotecting a compound represented by formula (IV) to produce a compound represented by formula (I).

[0072] [ka]

[0073] (In the formula, X represents a nucleobase moiety which may have one or more optional substituents selected from group α; R 1 and R 2are each independently a hydrogen atom, a protecting group for a hydroxyl group in nucleic acid synthesis, an alkyl group having 1 to 7 carbon atoms which may be branched or cyclic, an alkenyl group having 2 to 7 carbon atoms which may be branched or cyclic, an aryl group having 3 to 10 carbon atoms which may have one or more optional substituents selected from the α group and which may contain a heteroatom, an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may have one or more optional substituents selected from the α group and which may contain a heteroatom, an acyl group which may have one or more optional substituents selected from the α group, a silyl group which may have one or more optional substituents selected from the α group, a phosphate group which may have one or more optional substituents selected from the α group, a phosphate group protected with a protecting group in nucleic acid synthesis, -P(R 3 )R 4 [In the formula, R 3 and R 4 each independently represents a hydroxyl group, a hydroxyl group protected with a protecting group for nucleic acid synthesis, a mercapto group, a mercapto group protected with a protecting group for nucleic acid synthesis, an amino group, an alkoxy group having 1 to 5 carbon atoms, an alkylthio group having 1 to 5 carbon atoms, a cyanoalkoxy group having 1 to 6 carbon atoms, or an amino group substituted with an alkyl group having 1 to 6 carbon atoms; R 5 represents a hydrogen atom; a halogen atom; an alkyl group having 1 to 7 carbon atoms which may be substituted with an aryl group having 3 to 12 carbon atoms which may contain a heteroatom and which may be branched or cyclic; an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may contain a heteroatom; or a silyl group; R 6 represents a protecting group for the hydroxyl group in nucleic acid synthesis)

[0074] In particular, in a preferred embodiment of the present invention, the compound represented by formula (I) is 6 An example of an embodiment in which the compound is produced by deprotecting a compound represented by formula (IV), wherein represents a removable group.

[0075] R in formula (IV) 1 ~R 6and X can be independently set appropriately with reference to the above-mentioned substituents, and may be selected depending on the structure of the desired compound represented by formula (I).

[0076] The deprotection method can be appropriately selected according to the type of protecting group according to methods known in the art. For example, 6 When is an acetyl group, it is preferable to dissolve the compound in an organic solvent, add a base, and carry out the reaction by cooling or heating as necessary. For example, the reaction temperature is −80 to 200° C., the reaction time is 0.1 to 24 hours, and the amount of base used is 1.0 equivalent to 30 equivalents.

[0077] The compound represented by formula (IV) is 1 ~R 6 As long as the compound has R and X, it may be a commercially available product or one prepared according to a known method. 6 Examples of the compounds include compounds in which X is an acetyl group, and compounds in which X is a group having a uracil skeleton or a group having a cytosine skeleton which may have a substituent (preferably a hydroxyl group, an amino group, or a hydroxyl group or an amino group protected by a protecting group), as well as tautomers thereof. Specific structures are shown below.

[0078] [ka]

[0079] Similarly, examples of the compound represented by formula (IV) include compounds in which X is a group having a purine skeleton optionally having a substituent (preferably a hydroxyl group, an amino group, or a hydroxyl group or amino group protected by a protecting group), and tautomers thereof. Specific structures are shown below.

[0080] [ka]

[0081] In the present invention, the compound represented by formula (IV) is a compound in which X is a 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl group and R 1 and R 2 is a benzyl group, and R 6 is an acetyl group, and compounds in which X is a 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl group and R 1 , R 2 and R 6 A compound in which is an acetyl group may also be used.

[0082] Furthermore, the compound represented by formula (I) can be prepared, for example, from a compound represented by the following formula (V) as a raw material. Thus, one embodiment of the present invention can be a production method including a step of producing the compound represented by formula (I) from a compound represented by the following formula (V) as a raw material.

[0083] [ka]

[0084] (In the formula, R 1 and R 2 are each independently a hydrogen atom, a protecting group for a hydroxyl group in nucleic acid synthesis, an alkyl group having 1 to 7 carbon atoms which may form a branched or cyclic chain, an alkenyl group having 2 to 7 carbon atoms which may form a branched or cyclic chain, an aryl group having 3 to 10 carbon atoms which may have one or more optional substituents selected from the α group and which may contain a heteroatom, an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may have one or more optional substituents selected from the α group and which may contain a heteroatom, an acyl group which may have one or more optional substituents selected from the α group, a silyl group which may have one or more optional substituents selected from the α group, a phosphate group which may have one or more optional substituents selected from the α group, a phosphate group protected with a protecting group in nucleic acid synthesis, -P(R 3 )R 4 [In the formula, R 3 and R 4each independently represents a hydroxyl group, a hydroxyl group protected with a protecting group for nucleic acid synthesis, a mercapto group, a mercapto group protected with a protecting group for nucleic acid synthesis, an amino group, an alkoxy group having 1 to 5 carbon atoms, an alkylthio group having 1 to 5 carbon atoms, a cyanoalkoxy group having 1 to 6 carbon atoms, or an amino group substituted with an alkyl group having 1 to 6 carbon atoms; wherein the α group consists of a hydroxyl group, a hydroxyl group protected with a protecting group for nucleic acid synthesis, an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, a mercapto group, a mercapto group protected with a protecting group for nucleic acid synthesis, an alkylthio group having 1 to 5 carbon atoms, an amino group, an amino group protected with a protecting group for nucleic acid synthesis, an amino group substituted with an alkyl group having 1 to 5 carbon atoms, and a halogen atom; R 6 and R 7 are each independently a protecting group for a hydroxyl group in nucleic acid synthesis, an alkyl group having 1 to 7 carbon atoms which may form a branched or cyclic chain, an alkenyl group having 2 to 7 carbon atoms which may have one or more optional substituents selected from the α group and which may contain a heteroatom, an aryl group having 3 to 10 carbon atoms which may have one or more optional substituents selected from the α group and which may contain a heteroatom, an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may have one or more optional substituents selected from the α group and which may contain a heteroatom, an acyl group which may have one or more optional substituents selected from the α group, a silyl group which may have one or more optional substituents selected from the α group, a phosphate group which may have one or more optional substituents selected from the α group, or a phosphate group protected with a protecting group in nucleic acid synthesis; R 6 and R 7 together, -C(R 8 )(R 9 )-[where R 8 and R 9 each independently represents a hydrogen atom, an alkyl group having 1 to 7 carbon atoms which may be substituted with an aryl group having 3 to 12 carbon atoms which may contain a heteroatom and which may form a branched or cyclic ring, or an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may contain a heteroatom]

[0085] R in formula (V) 1 ~R 4 and R 6 ~R 7 can be independently set appropriately with reference to the above-mentioned substituents, and may be selected depending on the structure of the desired compound represented by formula (I).

[0086] The compound of formula (I) may be prepared from the compound of formula (V) by referring to a method known in the art. However, from the viewpoint of simplifying the production process, the compound of formula (I) may be prepared as follows.

[0087] Specifically, for example, the compound of formula (V) is first reacted in the presence of a reactant to prepare a 4-formyl compound of formula (VI). The reaction temperature is preferably −80 to 200° C., and the reaction time is preferably 0.1 to 24 hours.

[0088] [ka]

[0089] (In the formula, R 1 and R 2 are each independently a hydrogen atom, a protecting group for a hydroxyl group in nucleic acid synthesis, an alkyl group having 1 to 7 carbon atoms which may form a branched or cyclic chain, an alkenyl group having 2 to 7 carbon atoms which may form a branched or cyclic chain, an aryl group having 3 to 10 carbon atoms which may have one or more optional substituents selected from the α group and which may contain a heteroatom, an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may have one or more optional substituents selected from the α group and which may contain a heteroatom, an acyl group which may have one or more optional substituents selected from the α group, a silyl group which may have one or more optional substituents selected from the α group, a phosphate group which may have one or more optional substituents selected from the α group, a phosphate group protected with a protecting group in nucleic acid synthesis, -P(R 3 )R 4 [In the formula, R 3 and R 4each independently represents a hydroxyl group, a hydroxyl group protected with a protecting group for nucleic acid synthesis, a mercapto group, a mercapto group protected with a protecting group for nucleic acid synthesis, an amino group, an alkoxy group having 1 to 5 carbon atoms, an alkylthio group having 1 to 5 carbon atoms, a cyanoalkoxy group having 1 to 6 carbon atoms, or an amino group substituted with an alkyl group having 1 to 6 carbon atoms; wherein the α group consists of a hydroxyl group, a hydroxyl group protected with a protecting group for nucleic acid synthesis, an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, a mercapto group, a mercapto group protected with a protecting group for nucleic acid synthesis, an alkylthio group having 1 to 5 carbon atoms, an amino group, an amino group protected with a protecting group for nucleic acid synthesis, an amino group substituted with an alkyl group having 1 to 5 carbon atoms, and a halogen atom; R 6 and R 7 are each independently a protecting group for a hydroxyl group in nucleic acid synthesis, an alkyl group having 1 to 7 carbon atoms which may form a branched or cyclic chain, an alkenyl group having 2 to 7 carbon atoms which may have one or more optional substituents selected from the α group and which may contain a heteroatom, an aryl group having 3 to 10 carbon atoms which may have one or more optional substituents selected from the α group and which may contain a heteroatom, an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may have one or more optional substituents selected from the α group and which may contain a heteroatom, an acyl group which may have one or more optional substituents selected from the α group, a silyl group which may have one or more optional substituents selected from the α group, a phosphate group which may have one or more optional substituents selected from the α group, or a phosphate group protected with a protecting group in nucleic acid synthesis; R 6 and R 7 together, -C(R 8 )(R 9 )-[where R 8 and R 9 each independently represents a hydrogen atom, an alkyl group having 1 to 7 carbon atoms which may be substituted with an aryl group having 3 to 12 carbon atoms which may contain a heteroatom and which may form a branched or cyclic ring, or an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may contain a heteroatom]

[0090] The reactant may be any known oxidizing agent. Examples include Dess-Martin reagent, 2,2,6,6-tetramethylpiperidine-1-oxyl radical / sodium hypochlorite, oxalyl chloride / dimethyl sulfoxide, acetic anhydride / dimethyl sulfoxide, trifluoroacetic anhydride / dimethyl sulfoxide, dicyclohexylcarbodiimide / dimethyl sulfoxide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide / dimethyl sulfoxide, and sulfur trioxide-pyridine complex / dimethyl sulfoxide. Among these, sulfur trioxide-pyridine complex / dimethyl sulfoxide is preferred, as it requires mild reaction conditions. The amount of the reactant used is preferably 1.0 equivalent to 20 equivalents.

[0091] R in formula (VI) 1 ~R 4 and R 6 ~R 7 can be independently set appropriately with reference to the above-mentioned substituents, and may be selected depending on the structure of the desired compound represented by formula (I).

[0092] The resulting 4-formyl compound is then reacted according to known methods to prepare a 4-dibromoethenyl compound.

[0093] Next, the 4-dibromoethenyl compound is treated with R 5 Introduce R 5 or preparing a 4-ethynyl compound from a 4-dibromoethenyl compound, and further 5 By introducing R 5 To prepare a 4-ethynyl compound having the formula:

[0094] Thereafter, concentrated sulfuric acid is added to the resulting acetic acid-acetic anhydride solution of the 4-ethynyl compound to synthesize a compound represented by the following formula (VII), and a nucleobase moiety is introduced into the 1-position of the compound to prepare the compound of formula (I). The reaction temperature for preparing the compound of formula (VII) is preferably 0 to 40°C, the reaction time is preferably 0.1 to 24 hours, and the amount of concentrated sulfuric acid used is preferably 0.01 to 1.0 equivalents. Using these reaction conditions, a two-step reaction can be carried out in one step, thereby improving the efficiency of the synthesis.

[0095] [ka]

[0096] (In the formula, R 1 and R 2 are each independently a hydrogen atom, a protecting group for a hydroxyl group in nucleic acid synthesis, an alkyl group having 1 to 7 carbon atoms which may form a branched or cyclic chain, an alkenyl group having 2 to 7 carbon atoms which may form a branched or cyclic chain, an aryl group having 3 to 10 carbon atoms which may have one or more optional substituents selected from the α group and which may contain a heteroatom, an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may have one or more optional substituents selected from the α group and which may contain a heteroatom, an acyl group which may have one or more optional substituents selected from the α group, a silyl group which may have one or more optional substituents selected from the α group, a phosphate group which may have one or more optional substituents selected from the α group, a phosphate group protected with a protecting group in nucleic acid synthesis, -P(R 3 )R 4 [In the formula, R 3 and R 4 each independently represents a hydroxyl group, a hydroxyl group protected with a protecting group for nucleic acid synthesis, a mercapto group, a mercapto group protected with a protecting group for nucleic acid synthesis, an amino group, an alkoxy group having 1 to 5 carbon atoms, an alkylthio group having 1 to 5 carbon atoms, a cyanoalkoxy group having 1 to 6 carbon atoms, or an amino group substituted with an alkyl group having 1 to 6 carbon atoms; wherein the α group consists of a hydroxyl group, a hydroxyl group protected with a protecting group for nucleic acid synthesis, an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, a mercapto group, a mercapto group protected with a protecting group for nucleic acid synthesis, an alkylthio group having 1 to 5 carbon atoms, an amino group, an amino group protected with a protecting group for nucleic acid synthesis, an amino group substituted with an alkyl group having 1 to 5 carbon atoms, and a halogen atom; R 5 represents a hydrogen atom; a halogen atom; an alkyl group having 1 to 7 carbon atoms which may be substituted with an aryl group having 3 to 12 carbon atoms which may contain a heteroatom and which may be branched or cyclic; an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may contain a heteroatom; or a silyl group; R 6 and R 7 each independently represent a protecting group for a hydroxyl group in nucleic acid synthesis, an alkyl group having 1 to 7 carbon atoms which may be branched or cyclic, an alkenyl group having 2 to 7 carbon atoms which may be branched or cyclic, an aryl group having 3 to 10 carbon atoms which may have one or more optional substituents selected from the α group and which may contain a heteroatom, an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may have one or more optional substituents selected from the α group and which may contain a heteroatom, an acyl group which may have one or more optional substituents selected from the α group, a silyl group which may have one or more optional substituents selected from the α group, a phosphate group which may have one or more optional substituents selected from the α group, or a phosphate group protected with a protecting group in nucleic acid synthesis).

[0097] R in formula (VII) 1 ~R 7 can be independently set appropriately with reference to the above-mentioned substituents, and may be selected depending on the structure of the desired compound represented by formula (I).

[0098] The compound represented by formula (V) is 1 ~R 4 and R 6 ~R 7As long as it has the above formula, a commercially available product or one prepared according to a known method may be used.

[0099] The resulting compound represented by formula (I) may be purified appropriately according to known techniques.

[0100] Thus, in step A, a compound represented by the following formula (II) can be prepared from a compound represented by formula (I).

[0101] [ka]

[0102] (In the formula, X represents a nucleobase moiety which may have one or more optional substituents selected from group α; R 1 and R 2 are each independently a hydrogen atom, a protecting group for a hydroxyl group in nucleic acid synthesis, an alkyl group having 1 to 7 carbon atoms which may be branched or cyclic, an alkenyl group having 2 to 7 carbon atoms which may be branched or cyclic, an aryl group having 3 to 10 carbon atoms which may have one or more optional substituents selected from the α group and which may contain a heteroatom, an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may have one or more optional substituents selected from the α group and which may contain a heteroatom, an acyl group which may have one or more optional substituents selected from the α group, a silyl group which may have one or more optional substituents selected from the α group, a phosphate group which may have one or more optional substituents selected from the α group, a phosphate group protected with a protecting group in nucleic acid synthesis, -P(R 3 )R 4 [In the formula, R 3 and R 4each independently represents a hydroxyl group, a hydroxyl group protected with a protecting group for nucleic acid synthesis, a mercapto group, a mercapto group protected with a protecting group for nucleic acid synthesis, an amino group, an alkoxy group having 1 to 5 carbon atoms, an alkylthio group having 1 to 5 carbon atoms, a cyanoalkoxy group having 1 to 6 carbon atoms, or an amino group substituted with an alkyl group having 1 to 6 carbon atoms; R 5 represents a hydrogen atom; a halogen atom; an alkyl group having 1 to 7 carbon atoms which may be substituted with an aryl group having 3 to 12 carbon atoms which may contain a heteroatom and which may form a branched or cyclic ring; an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may contain a heteroatom; or a silyl group).

[0103] The substituents in formula (II) are appropriately set depending on the compound represented by formula (I) used.

[0104] Next, a method for preparing a compound represented by the following formula (III) from a compound represented by formula (II) will be described. Specifically, the compound can be prepared by cyclopropanating the compound represented by formula (II). Therefore, one embodiment of the present invention can be a method including a step of cyclopropanating the compound represented by formula (II). Hereinafter, this step may be referred to as step B.

[0105] [ka]

[0106] (In the formula, X represents a nucleobase moiety which may have one or more optional substituents selected from group α; R 1 and R 2are each independently a hydrogen atom, a protecting group for a hydroxyl group in nucleic acid synthesis, an alkyl group having 1 to 7 carbon atoms which may be branched or cyclic, an alkenyl group having 2 to 7 carbon atoms which may be branched or cyclic, an aryl group having 3 to 10 carbon atoms which may have one or more optional substituents selected from the α group and which may contain a heteroatom, an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may have one or more optional substituents selected from the α group and which may contain a heteroatom, an acyl group which may have one or more optional substituents selected from the α group, a silyl group which may have one or more optional substituents selected from the α group, a phosphate group which may have one or more optional substituents selected from the α group, a phosphate group protected with a protecting group in nucleic acid synthesis, -P(R 3 )R 4 [In the formula, R 3 and R 4 each independently represents a hydroxyl group, a hydroxyl group protected with a protecting group for nucleic acid synthesis, a mercapto group, a mercapto group protected with a protecting group for nucleic acid synthesis, an amino group, an alkoxy group having 1 to 5 carbon atoms, an alkylthio group having 1 to 5 carbon atoms, a cyanoalkoxy group having 1 to 6 carbon atoms, or an amino group substituted with an alkyl group having 1 to 6 carbon atoms; R 5 and R 5’ represents a hydrogen atom; an alkyl group having 1 to 7 carbon atoms which may be substituted with an aryl group having 3 to 12 carbon atoms which may contain a heteroatom and which may be branched or cyclic; or an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may contain a heteroatom).

[0107] Cyclopropanation can be carried out, for example, using the Simmons-Smith reaction. This reaction can be carried out in the presence of a zinc carbenoid, and methods using diethylzinc or CH2N2-ZnI2 reagents instead of zinc are also possible. For example, the amount of zinc carbenoid used in the reaction is preferably 1.0 to 20 equivalents.

[0108] The cyclopropanation reaction in step B may be carried out in the presence of an organic acid, since the reaction progress varies depending on the type of zinc carbenoid. The presence of an organic acid can suppress the formation of precipitation and side reactions. There are no limitations on the organic acid, as long as it is a known acid, and suitable examples include formic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, diphenylphosphoric acid, tosylic acid, and phenol. The amount of organic acid used is preferably, for example, 0.5 to 2.0 equivalents relative to the zinc carbenoid used.

[0109] The reaction in the presence of the organic acid can be applied to the compound represented by formula (II) without any particular limitation, but compounds in formula (II) where X has a purine skeleton and tautomers thereof are preferred.

[0110] The compound represented by formula (II) to be subjected to the reaction may be a commercially available product or may be prepared according to a known method. Alternatively, the compound may be prepared according to the above-mentioned step A.

[0111] Examples of the compound represented by formula (II) include compounds in which X is a group having a uracil skeleton or a group having a cytosine skeleton, which may have a substituent (preferably a hydroxyl group, an amino group, or a hydroxyl group or amino group protected by a protecting group), and tautomers thereof. Specific structures are shown below.

[0112] [ka]

[0113] Similarly, examples of the compound represented by formula (II) include compounds in which X is a group having a purine skeleton having a substituent (preferably a hydroxyl group, an amino group, or a hydroxyl group or amino group protected by a protecting group), and tautomers thereof. Specific structures are shown below.

[0114] [ka]

[0115] In the present invention, the compound represented by formula (II) is a compound in which X is a 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl group and R 1 is a naphthyl group, R 2 is a benzyl group, R 5 is a hydrogen atom, and X is a 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl group and R 1 is a naphthyl group, R 2 and R 5 A compound in which is a hydrogen atom may also be used.

[0116] Furthermore, from the viewpoint of improving the yield, the compound represented by formula (II) to be subjected to cyclopropanation may be a compound in which, for example, when the group X has active reactive groups, the active reactive groups are partially or entirely protected with known protecting groups. For example, when X is a compound having a purine skeleton to which a protecting group has been introduced, it is possible to suppress side reactions with X as a reaction site, thereby improving the yield.

[0117] The compound obtained in step B can be purified appropriately according to known techniques. For example, from the viewpoint of facilitating post-treatment of the reaction, a step of post-treating the reaction solution with ammonia may be included. Treatment with ammonia facilitates removal of reagent residues and is therefore preferred.

[0118] The post-treatment method can be applied to any compound represented by formula (III), but is preferably applied to a compound in which X in formula (III) has a pyrimidine skeleton, in which case the boundary between the organic layer and the aqueous layer becomes clear, enabling efficient separation.

[0119] Thus, the compound represented by formula (III) can be prepared from the compound represented by formula (II).

[0120] In one embodiment of the present invention, when a compound represented by formula (II) prepared according to step A is used, a method for producing a compound represented by formula (III) of the present invention can include at least steps A and B. It should be noted that the present invention also includes a method further comprising the step of preparing a compound represented by formula (I) in step A by the above-described method. The compound represented by formula (III) may be a compound having, as X, a group (e.g., a hydroxyl group, a mercapto group, an amino group) protected with a protecting group for nucleic acid synthesis, or a compound in which some or all of the groups protected with the protecting group for nucleic acid synthesis have been deprotected. The method for deprotecting a group (e.g., a hydroxyl group, a mercapto group, an amino group) protected with a protecting group for nucleic acid synthesis may be a known method [e.g., treatment with a weak acid (e.g., a carboxylic acid, silica gel, etc.)].

[0121] Furthermore, in the present invention, when preparing various compounds represented by formula (III), for example, a compound represented by formula (VII) can be commonly prepared, and then the desired nucleobase moieties can be introduced thereinto to prepare the compounds, thereby enabling efficient preparation.

[0122] The compound represented by formula (III) obtained by the present invention can be converted into an amidite by a known method. The obtained amidite derivative is expected to be useful as a raw material for synthesizing nucleic acid drugs (antisense nucleic acid drugs) that treat diseases by inhibiting the activity of specific genes. [Example]

[0123] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these. In the following examples, room temperature means 15 to 35°C.

[0124] Example 1: Synthesis of common intermediate compounds

[0125] [ka]

[0126] (1) Synthesis of Compound 2

[0127] [ka]

[0128] To a solution of compound 1 (20 g, 50 mmol) in anhydrous dichloromethane (167 mL), dimethyl sulfoxide (32 mL, 0.45 mol, 9.0 eq) and triethylamine (27.7 mL, 0.200 mol, 4.0 eq) were added. After cooling to an internal temperature of 7 °C, sulfur trioxide-pyridine complex (15.9 g, 0.100 mol, 2.0 eq) was added portionwise and stirred at room temperature for 21.5 h. City water (300 mL) was added to the reaction solution, which was then extracted with a mixture of ethyl acetate (200 mL) and hexane (100 mL). The mixture was then separated to give organic layer I and aqueous layer I. The organic layer I was washed with a mixture of city water (200 mL) and saturated aqueous ammonium chloride (100 mL), giving organic layer II and aqueous layer II. The organic layer II was further washed with a mixture of city water (100 mL) and saturated aqueous ammonium chloride (100 mL), giving organic layer III and aqueous layer III. The aqueous layers II and III were combined, extracted with ethyl acetate (100 mL), and washed with tap water (100 mL) to obtain organic layer IV. The organic layers III and IV were combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure to obtain crude compound 2 (20.24 g) as a pale orange oily liquid. The obtained compound 2 was not purified, and the yield was quantitative, so it was carried on to the next step. 1H NMR (600 MHz, CDCl3) δ: 9.91 (s, 1H), 7.37-7.26 (m, 8H), 7.25-7.21 (m, 2H), 5.84 (d, J=3.5 Hz, 1H), 4.71 (d, J=12.0 Hz, 1H), 4.59 (d, J=12.0 Hz, 1H), 4.60 (dd, J=4.4, 3.5 Hz, 1H), 4.52 (d, J=12.0 Hz, 1H), 4.46 (d, J=12.0 Hz, 1H), 4.37 (d, J=4.4 Hz, 1H), 3.67 (d, J=11.4 Hz, 1H), 3.61 (d, J=11.4 Hz, 1H), 1.60 (s, 3H), 1.35 (s, 3H)

[0129] (2) Synthesis of compound 3

[0130]

change

[0131] The crude product of compound 2 (20.24 g) obtained in the previous step was azeotropically distilled with toluene and then dissolved in anhydrous dichloromethane (250 mL). Carbon tetrabromide (33.1 g, 100 mmol, 2.0 eq) was added. Next, triphenylphosphine (52.4 g, 200 mmol, 4.0 eq) was added at an internal temperature of 20 °C or below, and the mixture was stirred at room temperature for 1.5 hours. Triethylamine (41.5 mL, 300 mmol, 6.0 eq) was then added at an internal temperature of 25 °C or below, and the mixture was stirred for an additional 2 hours. Hexane (200 mL) was added to the reaction solution, and the mixture was cooled on ice. Insoluble matter was filtered off and washed with ethyl acetate and dichloromethane (50 mL). The combined washings and filtrate were evaporated under reduced pressure. The resulting residue was loaded onto a silica gel pad (100 g of silica gel) using a 1 / 1 (v / v) mixture of dichloromethane and hexane. The resulting mixture was eluted with 300 mL of 1 / 2 (v / v) hexane and ethyl acetate, followed by 400 mL of ethyl acetate. The eluate was concentrated under reduced pressure, and the resulting residue was washed and suspended in 200 mL of 1 / 1 (v / v) hexane and ethyl acetate. The insoluble material was filtered off. The mother liquor was concentrated under reduced pressure, and the resulting residue was washed and suspended in 100 mL of 2 / 1 (v / v) hexane and ethyl acetate. The mother liquor was concentrated under reduced pressure to give a mixture of compound 3 and triphenylphosphine oxide (28.1 g) as a brown viscous liquid. The resulting compound 3 was quantitatively purified without further purification and was carried on to the next step. 1H NMR (600 MHz, CDCl3) δ: 7.39-7.26 (m, 8H), 7.26-7.22 (m, 2H), 7.11 (s, 1H), 5.76 (d, J=4.1 Hz, 1H), 4.72 (d, J=12.0 Hz, 1H), 4.60 (d, J=12.0 Hz, 1H), 4.59 (d, J=12.0 Hz, 1H), 4.53 (dd, J=4.7, 4.1 Hz, 1H), 4.42 (d, J=12.0 Hz, 1H), 4.21 (d, J=4.7 Hz, 1H), 3.83 (d, J=11.4 Hz, 1H), 3.40 (d, J=11.4 Hz, 1H), 1.59 (s, 3H), 1.30 (s, 3H)

[0132] (3) Synthesis of Compound 4

[0133] [ka]

[0134] Under a nitrogen atmosphere, a mixture (28.1 g) of compound 3 and triphenylphosphine oxide obtained in the previous step was azeotropically distilled with anhydrous tetrahydrofuran and then dissolved in anhydrous tetrahydrofuran. At an internal temperature of −50°C or below, n-butyllithium (1.6 M hexane solution, 71 mL, 110 mmol, 2.2 eq) was added dropwise over 30 minutes, followed by stirring at −70°C for 1 hour. Water (100 mL) was added at the same temperature, followed by extraction with ethyl acetate (400 mL), tap water (100 mL), and saturated brine (100 mL), yielding organic layer I and aqueous layer I. The resulting aqueous layer I was extracted with ethyl acetate (100 mL) to yield organic layer II. Organic layers I and II were combined, washed sequentially with saturated aqueous ammonium chloride (200 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield crude compound 4 (21.2 g) as a brown liquid. The obtained compound 4 was not purified and was used in the next step as the yield was quantitative. 1H NMR (600 MHz, CDCl3) δ: 7.41-7.27 (m, 8H), 7.22-7.19 (m, 2H), 5.70 (d, J=3.5 Hz, 1H), 4.77 (d, J=12.6 Hz, 1H), 4.69 (d, J=12.6 Hz, 1H), 4.55 (dd, J=4.7, 3.5 Hz, 1H), 4.52 (d, J=12.3 Hz, 1H), 4.44 (d, J=12.3 Hz, 1H), 4.16 (d, J=4.7 Hz, 1H), 3.70 (d, J=11.2 Hz, 1H), 3.55 (d, J=11.3 Hz, 1H), 2.65 (s, 1H), 1.72 (s, 3H), 1.33 (s, 3H)

[0135] (4) Synthesis of Compound 5

[0136] [ka]

[0137] A solution of the crude compound 4 (21.0 g) obtained in the previous step in acetic anhydride (94.5 mL, 1.00 mol) was added to a solution of concentrated sulfuric acid (255 mg, 2.60 mmol, 0.05 eq) in acetic acid (60 mL, 1.0 mol) and stirred at room temperature for 7 hours. Acetic acid (57.2 mL, 1.00 mol) was added to the reaction solution and stirred for an additional 15 hours. Under ice cooling, the reaction solution was poured into a mixture of ethyl acetate (200 mL) and saturated aqueous sodium bicarbonate (300 mL). The aqueous layer was extracted twice with ethyl acetate (100 mL). The combined organic layer was washed sequentially with saturated aqueous sodium bicarbonate (100 mL), tap water (100 mL), and saturated brine (100 mL). After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (silica gel: 100 g, hexane / ethyl acetate = 1 / 0 to 2 / 1 (v / v)) to obtain compound 5 (17.7 g, 40.4 mmol, 4-step yield 82%) as an orange viscous liquid. 1H NMR (600 MHz, CDCl3) δ: 7.36-7.27 (m, 8H), 7.26-7.16 (m, 2H), 6.19 (s, 1H), 5.29 (d, J=4.7 Hz, 1H), 4.72 (d, J=12.2 Hz, 1H), 4.59 (d, J=12.2 Hz, 1H), 4.50 (d, J=11.9 Hz, 1H), 4.46 (d, J=4.7 Hz, 1H), 4.39 (d, J=11.9 Hz, 1H), 3.67 (d, J=11.2 Hz, 1H), 3.56 (d, J=11.2 Hz, 1H), 2.65 (s, 1H), 2.15 (s, 3H), 1.80 (s, 3H)

[0138] Example 2: Synthesis of T-dibenzyl derivative

[0139] [ka]

[0140] (1) Synthesis of Compound 6

[0141] [ka]

[0142] Under a nitrogen atmosphere, thymine (3.79 g, 30.1 mmol, 3.0 eq), N,O-bis(trimethylsilyl)acetamide (7.15 mL, 49.9 mmol, 5.0 eq), and trimethylsilyl triflate (2.71 mL, 15.0 mmol, 1.5 eq) were added sequentially to a solution of compound 5 (4.38 g, 10.0 mmol) in anhydrous acetonitrile (50 mL), and the mixture was heated under reflux for 5 hours. The reaction mixture was allowed to cool to room temperature and poured into saturated aqueous sodium bicarbonate (300 mL) and extracted twice with ethyl acetate (300 mL, 200 mL). After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (silica gel: 80 g, hexane / ethyl acetate = 2 / 1 to 1 / 2 (v / v)) to obtain compound 6 (4.02 g, 7.97 mmol, 79.7%) as a pale yellow amorphous solid. 1H NMR (600MHz, CDCl3) δ: 8.45 (s, 1H), 7.37-7.29 (m, 9H), 7.26-7.22 (m, 2H), 6.28 (d, J=4.8 Hz, 1H), 5.26 (dd, J=6.0, 4.8 Hz, 1H), 4.67 (d, J=11.7 Hz, 1H), 4.62 (d, J=11.7 Hz, 1H), 4.50 (d, J=11.3 Hz, 1H), 4.46 (d, J=11.3 Hz, 1H), 4.40 (d, J=6.0 Hz, 1H), 3.85 (d, J=10.6 Hz, 1H), 3.62 (d, J=10.6 Hz, 1H), 2.68 (s, 1H), 2.11 (s, 3H), 1.54 (d, J=1.2 Hz, 3H)

[0143] (2) Synthesis of Compound 7

[0144] [ka]

[0145] To a solution (10 mL) of compound 6 (1.0 g, 2.0 mmol) in methanol, potassium carbonate (821 mg, 5.94 mmol, 3.0 eq) was added and stirred at room temperature for 20 minutes. Tap water (10 mL) and ethyl acetate (10 mL) were added, followed by extraction with ethyl acetate (60 mL). The resulting organic layer was washed with a mixture of tap water (30 mL) and a small amount of saturated brine, followed by saturated brine (10 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 7 (0.83 g, 1.8 mmol, 91%) as a white solid. 1H NMR (600 MHz, CDCl3) δ: 7.40-7.25 (m, 11H), 6.07 (d, J=5.3 Hz, 1H), 4.90 (d, J=11.4 Hz, 1H), 4.68 (d, J=11.4 Hz, 1H), 4.56 (d, J=12.0 Hz, 1H), 4.55 (d, J=12.0 Hz, 1H), 4.29 (dd, J=5.9, 5.3 Hz, 1H), 4.23 (d, J=5.9 Hz, 1H), 3.86 (d, J=10.6 Hz, 1H), 3.70 (d, J=10.6 Hz, 1H), 2.71 (s, 1H), 1.59 (d, J=0.9 Hz, 3H)

[0146] (3) Synthesis of Compound 8

[0147] [ka]

[0148] Under a nitrogen atmosphere, potassium tert-butoxide (303 mg, 2.70 mmol, 2.5 eq) was added to a solution of compound 7 (500 mg, 1.08 mmol) in anhydrous dimethyl sulfoxide (10 mL) and stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The resulting organic layer was washed twice with tap water (50 mL) and once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude compound 8 (435 mg) as a pale yellow amorphous solid. The crude compound 8 was carried on to the next step without further purification. 1H NMR (600MHz, CDCl3) δ: 9.21 (br s, 1H), 7.48 (d, J=1.2 Hz, 1H), 7.38-7.23 (m, 10H), 5.61 (s, 1H), 4.72 (s, 1H), 4.64 (d, J=10.9 Hz, 1H), 4.66 (d, J=12.0 Hz, 1H), 4.61 (d, J=10.9 Hz, 1H), 4.56 (d, J=12.0 Hz, 1H), 4.50 (d, J=3.1 Hz, 1H), 4.04 (d, J=3.1 Hz, 1H), 4.02 (s, 1H), 4.00 (d, J=11.3 Hz, 1H), 3.94 (d, J=11.3 Hz, 1H), 1.59 (d, J=1.2 Hz, 3H)

[0149] (4) Synthesis of Compound 9

[0150] [ka]

[0151] Under a nitrogen atmosphere, a solution of compound 8 (2.67 g, 5.77 mmol) in anhydrous dichloromethane (50 mL) was added dropwise to a solution of diiodomethane (7.73 g, 28.9 mmol, 5.0 eq) in anhydrous dichloromethane (15 mL) under ice cooling. After washing with anhydrous dichloromethane (5 mL), diethylzinc (1.0 M hexane solution, 28.9 mL, 28.9 mmol, 5.0 eq) was added dropwise over 15 min. The mixture was stirred at the same temperature for 2 h and then at room temperature for 20 h. At 10 °C or below, 25 wt% aqueous ammonia (20 mL) and water (50 mL) were added dropwise over 5 min, followed by extraction twice with ethyl acetate (150 mL). The resulting organic layer was washed with tap water and then saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (silica gel: 60 g, chloroform / methanol = 1 / 0 to 9 / 1 (v / v)) to obtain Compound 9 (2.16 g, 4.53 mmol, 78.5%) as a yellow solid. 1H NMR (600MHz, CDCl3) δ: 8.89 (br s, 1H), 7.51 (d, J=1.2 Hz, 1H), 7.38-7.27 (m, 10H), 5.74 (s, 1H), 4.70 (d, J=11.7 Hz, 1H), 4.57 (d, J=11.7 Hz, 1H), 4.56 (s, 2H), 4.53 (s, 1H), 4.04 (s, 1H), 3.62 (d, J=10.7 Hz, 1H), 3.50 (d, J=10.7 Hz, 1H), 1.62 (d, J=1.2 Hz, 3H), 1.03-0.96 (m, 1H), 0.96-0.89 (m, 1H), 0.75-0.65 (m, 2H)

[0152] Compound 9 can be synthesized from compound 1 through 11 conversion steps using the conventional synthesis method described in WO2015 / 125783. On the other hand, by using the methods of Examples 1 and 2, compound 1 can be converted to compound 9 in 8 steps, thereby reducing the number of steps.

[0153] Example 3: Synthesis of G-dibenzyl derivative (part 1)

[0154] [ka]

[0155] (1) Synthesis of Compound 10

[0156] [ka]

[0157] Under a nitrogen atmosphere, a solution of compound 5 (1.86 g, 4.24 mmol) and N,N-diphenylcarbamoyl-N-isobutyrylguanine (1.94 g, 4.66 mmol, 1.1 eq) in 1,2-dichloroethane (20 mL) was added with N,O-bis(trimethylsilyl)acetamide (1.5 mL, 8.3 mmol, 2.0 eq) and trimethylsilyl triflate (1.8 mL, 13 mmol, 3.0 eq) sequentially under ice cooling, and the mixture was heated to reflux for 2.5 hours. The reaction mixture was cooled to room temperature, cooled on ice, and saturated aqueous sodium bicarbonate (50 mL) was added. The mixture was extracted twice with chloroform (100 mL, 50 mL). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (silica gel: 45 g, chloroform / ethyl acetate = 1 / 0 to 85 / 15 (v / v)) to obtain Compound 10 (1.78 g, 2.24 mmol, 52.8%) as a pale yellow amorphous solid. 1H NMR (600 MHz, CDCl3) δ: 8.09 (s, 1H), 7.88 (s, 1H), 7.39-7.20 (m, 20H), 6.23 (d, J=3.8 Hz, 1H), 5.67 (dd, J=5.9, 3.8 Hz, 1H), 4.94 (d, J=5.9 Hz, 1H), 4.78 (d, J=11.7 Hz, 1H), 4.67 (d, J=11.7 Hz, 1H), 4.52 (d, J=12.1 Hz, 1H), 4.47 (d, J=12.1 Hz, 1H), 3.81 (d, J=10.9 Hz, 1H), 3.68 (d, J=10.9 Hz, 1H), 3.07-2.84 (m, 1H), 2.70 (s, 1H), 2.09 (s, 3H), 1.24 (d, J=6.8 Hz, 3H), 1.24 (d, J=6.8 Hz, 3H)

[0158] (2) Synthesis of Compound 12

[0159] [ka] Under a nitrogen atmosphere, potassium tert-butoxide (70.6 mg, 0.629 mmol, 5.0 eq) was added to a solution of compound 10 (100 mg, 0.126 mmol) in anhydrous dimethyl sulfoxide (1 mL) and stirred at room temperature for 30 min. Methanol (8.0 μL, 0.20 mmol, 1.6 eq) was added and the mixture was stirred for an additional 3 h. Methanol (4.0 μL, 0.10 mmol, 0.8 eq) and potassium tert-butoxide (37.5 mg, 0.334 mmol, 2.7 eq) were added and the mixture was stirred for an additional 16 h. Ethyl acetate (10 mL) and tap water (10 mL) were added, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed twice with 1 M aqueous hydrochloric acid (20 mL), then with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a mixture of compound 12 and diphenylamine (76.2 mg, purity 72% based on the H-NMR integral ratio, yield 78%) as a light brown amorphous solid. 1H NMR (600MHz, CDCl3) δ: 12.12 (br s, 1H), 9.48 (br s, 1H), 7.81 (s, 1H), 7.39-7.18 (m, 10H), 5.77 (s, 1H), 4.68 (d, J=12.3 Hz, 1H), 4.62 (d, J=12.3 Hz, 1H), 4.62 (s, 1H), 4.59 (d, J=11.7 Hz, 1H), 4.53 (d, J=11.7 Hz, 1H), 4.50 (d, J=2.9 Hz, 1H), 4.28 (s, 1H), 4.12 (d, J=2.9 Hz, 1H), 3.94 (d, J=11.4 Hz, 1H), 3.90 (d, J=11.4 Hz, 1H), 2.71-2.65 (m, 1H), 1.26 (d, J=6.2 Hz, 3H), 1.25 (d, J=6.2 Hz, 3H)

[0160] (3) Synthesis of Compound 13

[0161] [ka]

[0162] Under a nitrogen atmosphere, N,N-diisopropylethylamine (0.10 mL, 0.59 mmol, 3.0 eq) and N,N-diphenylcarbamoyl chloride (56 mg, 0.24 mmol, 1.2 eq) were added sequentially to a solution of compound 12 (110 mg, 0.197 mmol) in anhydrous pyridine (0.8 mL) and stirred at room temperature for 6 h. Tap water (0.1 mL) was added, and the solvent was evaporated under reduced pressure. The mixture was then azeotroped twice with toluene. The residue was dissolved in ethyl acetate and washed sequentially with 1 M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine. It was then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was azeotroped twice with toluene to obtain crude compound 13 (178 mg) as a red amorphous solid. The resulting compound 13 was carried on to the next step without further purification. 1H NMR (600 MHz, CDCl3) δ: 8.18 (s, 1H), 7.98 (br s, 1H), 7.50-7.14 (m, 20H), 5.95 (s, 1H), 4.97 (s, 1H), 4.67 (d, J=12.3 Hz, 1H), 4.62 (d, J=12.3 Hz, 1H), 4.59-4.55 (m, 2H), 4.52 (d, J=3.2 Hz, 1H), 4.28 (s, 1H), 4.12 (d, J=3.2 Hz, 1H), 3.94 (d, J=11.3 Hz, 1H), 3.89 (d, J=11.3 Hz, 1H), 3.06-2.90 (m, 1H), 1.26-1.24 (m, 6H)

[0163] (4) Synthesis of compound 14

[0164]

change

[0165] Under a nitrogen atmosphere, diethylzinc (1M hexane solution, 2.0 mL, 2.0 mmol, 10 eq) was added to ice-cooled anhydrous dichloromethane (3 mL). A solution of trifluoroacetic acid (230 mg, 2.02 mmol, 10 eq) in anhydrous dichloromethane (1 mL) was added dropwise over 5 min. After stirring at the same temperature for 30 min, a solution of diiodomethane (542 mg, 2.02 mmol, 10 eq) in anhydrous dichloromethane (1 mL) was added dropwise over 5 min. The mixture was stirred at the same temperature for an additional 30 min. To this solution, a solution of crude compound 13 (178 mg) in anhydrous dichloromethane (0.5 mL, washed in with an additional 0.5 mL) was added dropwise and the mixture was stirred at the same temperature for 3 h. 0.5 M aqueous hydrochloric acid (10 mL) and chloroform (15 mL) were added, and the mixture was stirred vigorously at room temperature for 1 h. The resulting solution was separated into aqueous and organic layers, and the aqueous layer was further extracted with chloroform. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (silica gel: 14 g, hexane / ethyl acetate / methanol = 90 / 5 / 5 to 75 / 20 / 5 (v / v / v)) to give compound 14 (86.4 mg, 0.113 mmol, 57.2%) as a reddish-brown viscous liquid. 1H NMR (600 MHz, CDCl3) δ: 8.19 (s, 1H), 7.97 (s, 1H), 7.51-7.20 (m, 20H), 6.10 (s, 1H), 4.78 (s, 1H), 4.62 (d, J=11.9 Hz, 1H), 4.59-4.53 (m, 1H), 4.55 (d, J=11.9 Hz, 1H), 4.30 (s, 1H), 3.64 (d, J=11.0 Hz, 1H), 3.54 (d, J=11.0 Hz, 1H), 3.08-2.95 (m, 1H), 1.25 (d, J=6.9 Hz, 3H), 1.25 (d, J=6.9 Hz, 3H), 1.01-0.91 (m, 2H), 0.88-0.83 (m, 1H), 0.76-0.70 (m, 1H)

[0166] (5) Synthesis of the compound represented by formula (a)

[0167] [ka]

[0168] It was confirmed that compound 14 can be easily converted to the compound represented by formula (a) by treating it with a weak acid (such as a carboxylic acid).

[0169] The compound shown in formula (a) below can be used as a precursor of scpBNA, similar to compound 14:

[0170] [ka]

[0171] can be synthesized from compound 1 through 12 conversion steps by using the conventional synthesis method described in WO2015 / 125783. On the other hand, by using the methods of Example 1 and Example 3, compound 1 can be converted to the compound represented by formula (a) in 9 steps, thereby reducing the number of steps.

[0172] Example 4: Synthesis of G-dibenzyl compound (part 2)

[0173] [ka]

[0174] (1) Synthesis of Compound 15

[0175] [ka]

[0176] Under a nitrogen atmosphere, N-isobutyrylguanine (1.94 g, 8.77 mmol, 1.2 eq), N,O-bis(trimethylsilyl)acetamide (3.14 mL, 21.9 mmol, 3.0 eq), and trimethylsilyl triflate (2.64 mL, 14.6 mmol, 2.0 eq) were added sequentially to a solution of compound 5 (4.0 g, 80% purity, 7.3 mmol) in 1,2-dichloroethane (100 mL) under ice cooling. The mixture was stirred at room temperature for 17 hours, then heated to 50 °C and stirred for 1 hour. N,O-bis(trimethylsilyl)acetamide (3.14 mL, 21.9 mmol, 3.0 eq) was added and the mixture was stirred at the same temperature for an additional hour. After heating to reflux for 2 hours, the mixture was allowed to cool to room temperature and stirred for an additional 3 hours. Saturated aqueous sodium bicarbonate (50 mL) was added under ice cooling, and the mixture was extracted three times with chloroform. The combined organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel: 60 g, hexane / ethyl acetate / chloroform / methanol = 3 / 3 / 1 / 0 to 3 / 3 / 1 / 0.4 (v / v / v / v)) to obtain a mixture of compound 15 and compound 16 (3.00 g, compound 15: compound 16 = 85:15 by H-NMR, 4.25 mmol, 58% yield) as a pale brown amorphous solid. 1H NMR (600 MHz, CDCl3) δ: 12.21 (s, 0.85H), 12.06 (s, 0.15H), 9.67 (br s, 0.15H), 8.19 (br s, 0.85H), 8.19 (s, 0.15H), 7.83 (s, 0.85H), 7.36 - 7.30 (m, 8H), 7.26 - 7.24 (m, 2H), 6.50 (d, J = 3.2 Hz, 0.15H), 6.16 (d, J = 5.0 Hz, 0.85H), 5.63 (dd, J = 6.0, 3.2 Hz, 0.15H), 5.61 (dd, J = 5.9, 5.0 Hz, 0.85H), 4.73 (d, J = 11.6 Hz, 0.85H), 4.64 (d, J = 11.4 Hz, 0.15H), 4.64 (d, J = 5.9 Hz, 0.85H), 4.59 (d, J = 11.6 Hz, 0.85H), 4.57 (d, J = 6.0 Hz, 0.15H), 4.56 (d, J = 11.4 Hz, 0.15H), 4.55 (d, J = 11.9 Hz, 0.85H), 4.49 - 4.47 (m, 0.30H), 4.48 (d, J = 11.9 Hz, 0.85H), 3.81 (d, J = 10.9 Hz, 0.15H), 3.79 (d, J = 10.9 Hz, 0.85H), 3.68 (d, J = 10.9 Hz, 0.85H), 3.58 (d, J = 10.9 Hz, 0.15H), 2.77 (dq, J = 6.9, 6.9 Hz, 0.85H), 2.71 (s, 0.85H), 2.70 (s, 0.15H), 2.50 (dq, J = 6.9, 6.9 Hz, 0.15H), 2.14 (s, 0.45H), 2.08 (s, 2.55H), 1.28 (d, J = 6.9 Hz, 0.45H), 1.27 (d, J = 6.9 Hz, 0.45H), 1.23 (d, J = 6.9 Hz, 2.55H), 1.22 (d, J = 6.9 Hz, 2.55H)

[0177] (2) Synthesis of Compound 17

[0178] [ [Chemical formula]

[0179] To a solution of a mixture of Compound 15 and Compound 16 (3.0 g, 5.0 mmol, Compound 15:Compound 16 = 85:15) in methanol (30 mL) was added potassium carbonate (2.07 g, 15.0 mmol, 3.0 eq) under ice cooling, and the mixture was stirred at the same temperature for 30 min. Potassium carbonate (0.50 g, 3.6 mmol, 0.72 eq) was added, and the mixture was stirred for an additional 15 min. After adding saturated aqueous ammonium chloride, the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with tap water and saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (silica gel: 30 g, chloroform / ethyl acetate = 1 / 0 to 4 / 1 (v / v)) to obtain a mixture of Compound 17 and Compound 17' (2.41 g, Compound 17:Compound 17' = 85:15, 4.32 mmol, 86% yield) as a white amorphous solid. 1H NMR (600 MHz, CDCl3) δ: 12.50 (br s, 0.15H), 12.25 (br s, 0.85H), 9.82 (br s, 0.15H), 8.99 (br s, 0.85H), 8.12 (s, 0.85H), 7.88 (s, 0.15H), 7.42 - 7.21 (m, 10H), 6.31 (d, J = 4.4 Hz, 0.85H), 6.02 (d, J = 4.7 Hz, 0.15H), 4.91 (d, J = 11.4 Hz, 0.15H), 4.82 (d, J = 11.4 Hz, 0.85H), 4.78 (d, J = 11.4 Hz, 0.15H), 4.70 (d, J = 11.4 Hz, 0.85H), 4.65 - 4.62 (m, 0.15H), 4.59 (d, J = 12.0 Hz, 0.85H), 4.55 (d, J = 12.0 Hz, 0.15H), 4.55 (d, J = 12.0 Hz, 0.85H), 4.55 - 4.53 (m, 0.15H), 4.54 (ddd, J = 6.6, 6.2, 4.4 Hz, 0.85H), 4.49 (d, J = 12.0 Hz, 0.15H), 4.40 (d, J = 6.2 Hz, 0.85H), 3.87 - 3.85 (m, 0.15H), 3.85 (d, J = 10.4 Hz, 0.85H), 3.78 (d, J = 10.9 Hz, 0.15H), 3.71 (d, J = 10.9 Hz, 0.15H), 3.69 (d, J = 10.4 Hz, 0.85H), 3.52 (d, J = 6.6 Hz, 0.85H), 2.81 (dq, J = 6.9, 6.9 Hz, 0.85H), 2.74 (s, 0.85H), 2.73 (s, 0.15H), 2.62 (dq, J = 6.9, 6.9 Hz, 0.15H), 1.26 (d, J = 6.9 Hz, 2.55H), 1.26 (d, J = 6.9 Hz, 2.55H), 1.22 (d, J = 6.9 Hz, 0.45H), 1.22 (d, J = 6.9 Hz, 0.45H)

[0180] (3) Synthesis of Compound 18

[0181] [ka]

[0182] Under a nitrogen atmosphere, potassium tert-butoxide (302 mg, 2.69 mmol, 1.5 eq) was added to a solution of a mixture of compound 17 and compound 17' (1.00 g, 1.79 mmol, compound 17: compound 17' = 85:15) in anhydrous dimethyl sulfoxide (20 mL) and stirred at room temperature for 1 hour. Potassium tert-butoxide (150 mg, 1.34 mmol, 0.75 eq) was added and stirred for 30 minutes, after which potassium tert-butoxide (273 mg, 2.43 mmol, 1.4 eq) was added and stirred for an additional 3 hours. Ethyl acetate (150 mL) and tap water (50 mL) were added under ice cooling, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed twice with tap water and then with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a crude mixture of Compound 18 and Compound 18' (904 mg, Compound 18:Compound 18'=85:15) as a pale brown amorphous solid. 1H NMR (600 MHz, CDCl3) δ: 12.29 (br s, 0.85H), 12.12 (br s, 0.15H), 9.96 (br s, 0.15H), 8.85 (br s, 0.85H), 8.20 (s, 0.15H), 7.82 (s, 0.85H), 7.37-7.16 (m, 10H), 6.15 (s, 0.15H), 5.75 (s, 0.85H), 4.71-4.47 (m, 6H), 4.26 (s, 0.85H), 4.18 (s, 0.15H), 4.11 (d, J=3.23 Hz, 0.85H), 4.06 (d, J=3.23, 0.15H), 3.96 (d, J=10.9 Hz, 0.15H), 3.93 (d, J=11.2 Hz, 0.85H), 3.90 (d, J=10.9 Hz, 0.15H), 3.89 (d, J=11.2 Hz, 0.85H), 2.78 (dq, J=6.9, 6.9 Hz, 0.15H), 2.67 (dq, J=6.9, 6.9 Hz, 0.85H), 1.28 (d, J=6.9 Hz, 2.55H), 1.27 (d, J=6.9 Hz, 0.45H), 1.27 (d, J=6.9 Hz, 2.55H), 1.25 (d, J=6.9 Hz, 0.45H)

[0183] (4) Synthesis of Compound 19 The reaction was carried out under the same conditions as in step (3) of Example 3.

[0184] (5) Synthesis of Compound 20 The reaction was carried out under the same conditions as in step (4) of Example 3.

[0185] As in Example 3, it can be seen that scpBNAs incorporating compounds having a guanine backbone can be obtained regardless of the presence or absence of a protecting group.

[0186] Example 5: Synthesis of A-dibenzyl compound (part 1)

[0187] [ka]

[0188] (1) Synthesis of Compound 21

[0189] [ka]

[0190] Under a nitrogen atmosphere, N6-benzoyladenine (1.60 g, 6.69 mmol, 1.1 eq) was added to a solution of compound 5 (3.32 g, 80% purity, 6.08 mmol) in acetonitrile (80 mL). N,O-bis(trimethylsilyl)acetamide (2.61 mL, 18.2 mmol, 3.0 eq) and trimethylsilyl triflate (1.65 mL, 9.12 mmol, 1.5 eq) were added sequentially under ice cooling, and the mixture was stirred at room temperature for 18 hours. After heating to reflux for 5.5 hours, the mixture was allowed to cool, stirred at room temperature for 18 hours, heated to reflux for 6 hours, cooled to room temperature again, and stirred at room temperature for 20 hours. Saturated aqueous sodium bicarbonate was added under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with tap water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (silica gel: 60 g, chloroform / ethyl acetate = 1 / 0 to 6 / 4 (v / v)) to obtain compound 21 (3.11 g, 5.04 mmol, yield 82.8%) as a pale brown amorphous solid. 1H NMR (600 MHz, CDCl3) δ: 8.95 (s, 1H), 8.74 (s, 1H), 8.21 (s, 1H), 8.04-8.00 (m, 2H), 7.64-7.59 (m, 1H), 7.56-7.51 (m, 2H), 7.38-7.27 (m, 8H), 7.23-7.19 (m, 2H), 6.40 (d, J=4.1 Hz, 1H), 5.82 (dd, J=5.6, 4.1 Hz, 1H), 4.76 (d, J=5.6 Hz, 1H), 4.72 (d, J=11.7 Hz, 1H), 4.66 (d, J=11.7 Hz, 1H), 4.49 (d, J=12.0 Hz, 1H), 4.44 (d, J=12.0 Hz, 1H), 3.81 (d, J=10.9 Hz, 1H), 3.63 (d, J=10.9 Hz, 1H), 2.72 (s, 1H), 2.11 (s, 3H)

[0191] (2) Synthesis of Compound 22

[0192] [ka]

[0193] Potassium carbonate (1.00 g, 7.24 mmol, 3.0 eq) was added to a methanol solution (20 mL) of compound 21 (1.50 g, 2.43 mmol) under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. Saturated aqueous ammonium chloride solution was added, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain crude compound 22 (1.50 g) as a pale orange amorphous solid. The resulting compound 22 was immediately used in the next reaction without further purification. 1H NMR (600 MHz, CDCl3) δ: 8.91 (s, 1H), 8.74 (s, 1H), 8.19 (s, 1H), 8.03-8.00 (m, 2H), 7.64-7.60 (m, 1H), 7.56-7.51 (m, 2H), 7.43-7.29 (m, 8H), 7.25-7.22 (m, 2H), 6.23 (d, J=4.4 Hz, 1H), 4.92 (d, J=11.4 Hz, 1H), 4.81 (ddd, J=6.7, 5.9, 4.4 Hz, 1H), 4.72 (d, J=11.4 Hz, 1H), 4.60 (d, J=5.9 Hz, 1H), 4.56 (d, J=12.0 Hz, 1H), 4.51 (d, J=12.0 Hz, 1H), 3.83 (d, J=10.6 Hz, 1H), 3.70 (d, J=10.6 Hz, 1H), 3.33 (d, J=6.7 Hz, 1H), 2.76 (s, 1H)

[0194] (3) Synthesis of Compound 23

[0195] [ka]

[0196] Under a nitrogen atmosphere, potassium tert-butoxide (545 mg, 4.85 mmol, 2.0 eq) was added to a solution (30 mL) of the crude compound 22 (1.50 g) obtained in the previous step in anhydrous dimethyl sulfoxide, and the mixture was stirred at room temperature for 2.5 hours. Saturated aqueous ammonium chloride and ethyl acetate were added, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed successively with tap water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified using a silica gel pad (NH silica gel, hexane / ethyl acetate / methanol = 8 / 8 / 1) to give compound 23 (1.18 g, 2.05 mmol, 84.4% yield over two steps) as a brown viscous liquid. 1H NMR (600 MHz, CDCl3) δ: 9.04 (s, 1H), 8.75 (s, 1H), 8.26 (s, 1H), 8.04 (d, J=7.5 Hz, 2H), 7.63 (t, J=7.6 Hz, 1H), 7.54 (dd, J=7.6, 7.5 Hz, 2H), 7.41-7.28 (m, 6H), 7.26-7.17 (m, 4H), 6.06 (s, 1H), 4.98 (s, 1H), 4.69 (d, J=12.2 Hz, 1H), 4.64 (d, J=12.2 Hz, 1H), 4.61 (d, J=12.0 Hz, 1H), 4.58 (d, J=12.0 Hz, 1H), 4.56 (d, J=3.2 Hz, 1H), 4.36 (s, 1H), 4.15 (d, J=3.2 Hz, 1H), 3.98 (d, J=11.2 Hz, 1H), 3.92 (d, J=11.2 Hz, 1H)

[0197] (4) Synthesis of compound 24

[0198]

change

[0199] To prepare the zinc carbenoid solution, diethylzinc (2.4 mL, 2.4 mmol, 10 eq) was added to 2.8 mL of ice-cooled anhydrous dichloromethane under a nitrogen atmosphere. A solution of trifluoroacetic acid (274 mg, 2.40 mmol, 10 eq) in 1 mL of anhydrous dichloromethane was added dropwise over 5 min. After stirring at the same temperature for 30 min, a solution of diiodomethane (643 mg, 2.40 mmol, 10 eq) in 1 mL of anhydrous dichloromethane was added dropwise over 5 min. The mixture was stirred at the same temperature for an additional 30 min. To prepare the zinc carbenoid solution, 720 μL of the zinc carbenoid solution was added dropwise to a solution of 23 (138 mg, 0.240 mmol) in 2.0 mL of anhydrous dichloromethane under a nitrogen atmosphere. After stirring at the same temperature for 1.5 hours, zinc carbenoid solution (720 μL) was added dropwise. After stirring for 1 hour, zinc carbenoid solution (720 μL) was added dropwise. After 30 minutes and 75 minutes, zinc carbenoid solution (1.5 mL each) was added dropwise and stirred for 1.5 hours. Saturated aqueous ammonium chloride and chloroform were added, and the mixture was stirred vigorously at room temperature for 30 minutes. The resulting solution was separated into aqueous and organic layers, and the aqueous layer was further extracted with chloroform. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a residue. The resulting residue contained a 3:1 ratio of compound 24 to compound 25 (as calculated by LC / MS and 1H-NMR).

[0200] Example 6: Synthesis of A-dibenzyl compound (part 2)

[0201] [ka]

[0202] (1) Synthesis of Compound 26

[0203] [ka]

[0204] Under a nitrogen atmosphere, a solution of adenine (1.01 g, 7.47 mmol, 2.5 eq) in bis(trimethylsilyl)amine (25 mL) was added with chlorotrimethylsilane (11 mL, 87.1 mmol, 29 eq) and heated to reflux for 5 h. The mixture was allowed to cool and concentrated under reduced pressure. The resulting residue was dissolved in 1,2-dichloroethane (5 mL) under a nitrogen atmosphere, and a solution of compound 5 (1.32 g, 3.00 mmol) in dichloroethane (10 mL) was added. Trimethylsilyl triflate (2.70 mL, 14.9 mmol, 5.0 eq) was then added and stirred at room temperature for 17.5 h. Saturated aqueous sodium bicarbonate (200 mL) was added, and the mixture was extracted twice with ethyl acetate (200 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (silica gel: 60 g, hexane / ethyl acetate / methanol = 75 / 20 / 5 to 45 / 50 / 5 (v / v / v)) to obtain compound 26 (1.32 g, 2.57 mmol, yield 85.7%) as a white waxy solid. 1H NMR (600 MHz, CDCl3) δ: 8.29 (s, 1H), 7.96 (s, 1H), 7.38-7.27 (m, 8H), 7.24-7.20 (m, 2H), 6.32 (d, J=4.1 Hz, 1H), 5.79 (dd, J=5.9, 4.1 Hz, 1H), 5.74 (br s, 2H), 4.76 (d, J=5.9 Hz, 1H), 4.70 (d, J=11.7 Hz, 1H), 4.65 (d, J=11.7 Hz, 1H), 4.50 (d, J=12.0 Hz, 1H), 4.44 (d, J=12.0 Hz, 1H), 3.80 (d, J=10.7 Hz, 1H), 3.63 (d, J=10.7 Hz, 1H), 2.71 (s, 1H), 2.10 (s, 3H)

[0205] (2) Synthesis of Compound 27

[0206] [ka]

[0207] To a solution of compound 26 (395 mg, 0.769 mmol) in tert-butyl alcohol (4 mL), potassium tert-butoxide (432 mg, 3.85 mmol, 5.0 eq) was added and stirred at room temperature for 1.5 h. Potassium tert-butoxide (480 mg, 4.28 mmol, 5.6 eq) was added and stirred for 1 h. Potassium tert-butoxide (300 mg, 2.67 mmol, 3.5 eq) was then added and stirred for an additional 1 h. Tap water (6 mL) and saturated brine (12 mL) were added, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give crude compound 27 (315 mg) as an orange amorphous solid. The crude compound 27 was carried on to the next step without further purification. 1H NMR (600 MHz, CDCl3) δ: 8.31 (s, 1H), 8.00 (s, 1H), 7.30-7.22 (m, 10H), 5.99 (s, 1H), 5.78 (br s, 2H), 4.97 (s, 1H), 4.69 (d, J=12.2 Hz, 1H), 4.63 (d, J=12.2 Hz, 1H), 4.59 (s, 2H), 4.54 (d, J=2.9 Hz, 1H), 4.35 (s, 1H), 4.14 (d, J=2.9 Hz, 1H), 3.97 (d, J=11.3 Hz, 1H), 3.92 (d, J=11.3 Hz, 1H)

[0208] (3) Synthesis of Compound 28

[0209] [ka]

[0210] Under a nitrogen atmosphere, sodium iodide (318 mg, 2.12 mmol, 10 eq) was added to a solution of compound 27 (100 mg, 0.212 mmol) in N,N-dimethylformamide (2 mL). Then, benzyl chloromethyl ether (300 μL, 2.16 mmol, 10 eq) was added under ice cooling and stirred at room temperature for 3 h. Saturated aqueous sodium bicarbonate (6 mL) and tap water (12 mL) were added, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed sequentially with 15 wt% aqueous sodium thiosulfate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give crude compound 28 (390 mg) as an orange oily liquid. The crude compound 28 was carried on to the next step without further purification.

[0211] (4) Synthesis of Compound 29

[0212] [ka]

[0213] Benzoyl chloride (120 μL, 1.03 mmol, 4.9 eq) was added to a pyridine solution (3 mL) of the crude compound 28 (390 mg) obtained in the previous step under a nitrogen atmosphere, and the mixture was stirred at room temperature for 5 h. After adding tap water (20 mL) and extracting twice with ethyl acetate, the combined organic layer was washed sequentially with 1 M aqueous hydrochloric acid, tap water, and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (NH silica gel: 20 g, hexane / ethyl acetate / methanol = 85 / 10 / 5 to 70 / 25 / 5 (v / v / v)) to obtain compound 29 (60.5 mg, 0.0870 mol, 41.0% yield) as a pale yellow oily liquid. 1H NMR (600 MHz, CDCl3) δ: 8.18-8.15 (m, 2H), 8.02 (s, 1H), 7.98 (s, 1H), 7.53-7.49 (m, 1H), 7.44-7.18 (m, 17H), 5.89 (s, 1H), 5.72 (d, J=10.7 Hz, 1H), 5.70 (d, J=10.7 Hz, 1H), 4.82 (d, J=12.0 Hz, 1H), 4.84 (d, J=12.0 Hz, 1H), 4.74 (s, 1H), 4.63 (d, J=12.6 Hz, 1H), 4.58 (d, J=12.6 Hz, 1H), 4.56 (d, J=12.0 Hz, 1H), 4.52 (d, J=12.0 Hz, 1H), 4.51 (d, J=3.1 Hz, 1H), 4.29 (s, 1H), 4.08 (d, J=3.1 Hz, 1H), 3.88 (d, J=11.2 Hz, 1H), 3.83 (d, J=11.2 Hz, 1H)

[0214] (5) Synthesis of compound 29

[0215]

change

[0216] Under a nitrogen atmosphere, sodium iodide (241 mg, 1.61 mmol, 2.2 eq) was added to a solution of compound 27 (345 mg, 0.732 mmol) in N,N-dimethylacetamide (1.5 mL). Benzyl chloromethyl ether (250 μL, 1.80 mmol, 2.5 eq) was then added under ice cooling and stirred at the same temperature for 2 hours. Benzyl chloromethyl ether (35 μL, 0.25 mmol, 0.34 eq) was added at the same temperature and stirred for an additional 1.5 hours. Triethylamine (2.0 mL, 14.4 mmol, 20 eq) and benzoyl chloride (400 μL, 3.44 mmol, 4.7 eq) were then added at the same temperature and stirred for 2 hours. After stirring, ethyl acetate (30 mL) and tap water (10 mL) were added and the mixture was separated into organic and aqueous layers. The organic layer was washed sequentially with 15 wt% aqueous sodium thiosulfate, tap water, and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (NH silica gel: 30 g, hexane / ethyl acetate / methanol = 90 / 5 / 5 to 85 / 10 / 5 (v / v / v)) to give compound 29 (462.6 mg, purity 70%, 0.465 mmol, yield 63.6%) as a pale yellow oil.

[0217] (6) Synthesis of Compound 30

[0218] [ka]

[0219] Diethylzinc (1M hexane solution, 0.25 mL, 0.25 mmol, 7.0 eq) was added to 0.25 mL of ice-cooled anhydrous dichloromethane under nitrogen. A solution of trifluoroacetic acid (30.0 mg, 0.263 mmol, 7.3 eq) in anhydrous dichloromethane (0.25 mL) was added dropwise over 1 min and stirred at the same temperature for 30 min. A solution of diiodomethane (67.4 mg, 0.259 mmol, 7.0 eq) in anhydrous dichloromethane (0.25 mL) was added dropwise over 1 min and stirred at the same temperature for an additional 30 min to prepare a zinc carbenoid solution. To this solution, a solution of compound 29 (25.0 mg, 0.0359 mmol) in anhydrous dichloromethane (0.5 mL, washed in with an additional 0.5 mL) was added dropwise and stirred at the same temperature for 4.5 h. Saturated aqueous ammonium chloride (20 mL) and chloroform (20 mL) were added, and the mixture was stirred vigorously at room temperature for 30 minutes. The resulting solution was separated into an aqueous and an organic layer, and the aqueous layer was further extracted with chloroform. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (silica gel: 10 g, hexane / ethyl acetate / methanol = 80 / 15 / 5 (v / v / v)) to obtain compound 30 (20.0 mg, 0.0282 mmol, 78.5% yield) as a pale yellow oily liquid. 1H NMR (600 MHz, CDCl3) δ: 8.19-8.15 (m, 2H), 8.03 (s, 1H), 7.97 (s, 1H), 7.52-7.48 (m, 1H), 7.44-7.21 (m, 17H), 6.04 (s, 1H), 5.72 (d, J=10.3 Hz, 1H), 5.70 (d, J=10.3 Hz, 1H), 4.84 (d, J=12.0 Hz, 1H), 4.82 (d, J=12.0 Hz, 1H), 4.59-4.52 (m, 4H), 4.52 (s, 1H), 4.27 (s, 1H), 3.54 (d, J=11.2 Hz, 1H), 3.47 (d, J=11.2 Hz, 1H), 1.02-0.65 (m, 4H)

[0220] (7) Synthesis of the compound represented by formula (b)

[0221] [ka]

[0222] It was confirmed that compound 30 can be easily converted to the compound represented by formula (b) by treating it with a weak acid (carboxylic acid, silica gel, etc.).

[0223] The compound shown in formula (b) below can be used as a precursor of scpBNA, similar to compound 30.

[0224] [ka]

[0225] can be synthesized from compound 1 through 12 conversion steps by using the conventional synthesis method described in WO2015 / 125783. On the other hand, by using the methods of Example 1 and Example 6, compound 1 can be converted to the compound represented by formula (b) in 9 steps, thereby reducing the number of steps. [Industrial Applicability]

[0226] INDUSTRIAL APPLICABILITY The present invention makes it possible to efficiently produce nucleosides of spirocyclopropylene-bridged nucleic acids (scpBNAs), and therefore can be suitably used in the field of nucleic acid medicines, for example.

Claims

1. A compound represented by formula (IV): 【Chemistry 1】 (In the formula, X represents a nucleic acid base moiety which may have one or more optional substituents selected from group α, wherein the group α consists of a hydroxyl group, a hydroxyl group protected with a protecting group for nucleic acid synthesis, an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, a mercapto group, a mercapto group protected with a protecting group for nucleic acid synthesis, an alkylthio group having 1 to 5 carbon atoms, an amino group, an amino group protected with a protecting group for nucleic acid synthesis, an amino group substituted with an alkyl group having 1 to 5 carbon atoms, and a halogen atom; R １ and R ２ are each independently a hydrogen atom, a protecting group for a hydroxyl group in nucleic acid synthesis, an alkyl group having 1 to 7 carbon atoms which may be branched or cyclic, an alkenyl group having 2 to 7 carbon atoms which may be branched or cyclic, an aryl group having 3 to 10 carbon atoms which may have one or more optional substituents selected from the α group and which may contain a heteroatom, an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may have one or more optional substituents selected from the α group and which may contain a heteroatom, an acyl group which may have one or more optional substituents selected from the α group, a silyl group which may have one or more optional substituents selected from the α group, a phosphate group which may have one or more optional substituents selected from the α group, a phosphate group protected with a protecting group in nucleic acid synthesis, -P(R ３ ) R ４ [In the formula, R ３ and R ４ each independently represents a hydroxyl group, a hydroxyl group protected with a protecting group for nucleic acid synthesis, a mercapto group, a mercapto group protected with a protecting group for nucleic acid synthesis, an amino group, an alkoxy group having 1 to 5 carbon atoms, an alkylthio group having 1 to 5 carbon atoms, a cyanoalkoxy group having 1 to 6 carbon atoms, or an amino group substituted with an alkyl group having 1 to 6 carbon atoms; R 5 represents a hydrogen atom; a halogen atom; an alkyl group having 1 to 7 carbon atoms which may be substituted with an aryl group having 3 to 12 carbon atoms which may contain a heteroatom and which may be branched or cyclic; an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may contain a heteroatom; or a silyl group; R ６ represents a protecting group for a hydroxyl group in nucleic acid synthesis; where X is a 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl group, and R １ and R ２ is a benzyl group, and R ６ is an acetyl group, and X is a 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl group, and R １ , R ２ and R ６ is an acetyl group)

2. R ６ The compound of claim 1 , wherein is an acetyl group.

3. 3. The compound according to claim 1, wherein X is a group having a substituted uracil skeleton or a group having a substituted cytosine skeleton.

4. 4. The compound according to claim 3, wherein the substituent is selected from the group consisting of a hydroxyl group and an alkyl group having 1 to 6 carbon atoms.

5. The compound according to any one of claims 1 to 4, wherein the compound represented by formula (IV) is a compound selected from the following: 【Chemistry 2】

6. The compound according to claim 1 or 2, wherein X is a group having a substituted purine skeleton.

7. 7. The compound according to claim 6, wherein the substituent is selected from the group consisting of a hydroxyl group, an amino group, and an amino group protected with a protecting group.

8. The compound according to any one of claims 1, 2, 6 and 7, wherein the compound represented by formula (IV) is a compound selected from the following: 【Transformation 3】

9. A compound represented by formula (I): 【Chemistry 4】 (In the formula, X represents a nucleic acid base moiety which may have one or more optional substituents selected from group α, wherein the group α consists of a hydroxyl group, a hydroxyl group protected with a protecting group for nucleic acid synthesis, an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, a mercapto group, a mercapto group protected with a protecting group for nucleic acid synthesis, an alkylthio group having 1 to 5 carbon atoms, an amino group, an amino group protected with a protecting group for nucleic acid synthesis, an amino group substituted with an alkyl group having 1 to 5 carbon atoms, and a halogen atom; R １ and R ２ are each independently a hydrogen atom, a protecting group for a hydroxyl group in nucleic acid synthesis, an alkyl group having 1 to 7 carbon atoms which may be branched or cyclic, an alkenyl group having 2 to 7 carbon atoms which may be branched or cyclic, an aryl group having 3 to 10 carbon atoms which may have one or more optional substituents selected from the α group and which may contain a heteroatom, an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may have one or more optional substituents selected from the α group and which may contain a heteroatom, an acyl group which may have one or more optional substituents selected from the α group, a silyl group which may have one or more optional substituents selected from the α group, a phosphate group which may have one or more optional substituents selected from the α group, a phosphate group protected with a protecting group in nucleic acid synthesis, -P(R ３ ) R ４ [In the formula, R ３ and R ４ each independently represents a hydroxyl group, a hydroxyl group protected with a protecting group for nucleic acid synthesis, a mercapto group, a mercapto group protected with a protecting group for nucleic acid synthesis, an amino group, an alkoxy group having 1 to 5 carbon atoms, an alkylthio group having 1 to 5 carbon atoms, a cyanoalkoxy group having 1 to 6 carbon atoms, or an amino group substituted with an alkyl group having 1 to 6 carbon atoms; R 5 represents a hydrogen atom; a halogen atom; an alkyl group having 1 to 7 carbon atoms which may be substituted with an aryl group having 3 to 12 carbon atoms which may contain a heteroatom and which may be branched or cyclic; an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may contain a heteroatom; or a silyl group; where X is a 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl group, and R １ and R ２ is a benzyl group, and X is a 2-oxo-4-amino-1,2-dihydropyrimidin-1-yl group, and R １ and R ２ is a hydrogen atom)

10. The compound according to claim 9, wherein X is a group having a substituted uracil skeleton or a group having a substituted cytosine skeleton.

11. 11. The compound according to claim 10, wherein the substituent is selected from the group consisting of a hydroxyl group and an alkyl group having 1 to 6 carbon atoms.

12. The compound according to any one of claims 9 to 11, wherein the compound represented by formula (I) is a compound selected from the following: 【Transformation 5】

13. The compound according to claim 9, wherein X is a group having a substituted purine skeleton.

14. 14. The compound according to claim 13, wherein the substituent is selected from the group consisting of a hydroxyl group, an amino group, and an amino group protected with a protecting group.

15. The compound according to any one of claims 9, 13 and 14, wherein the compound represented by formula (I) is a compound selected from the following: 【Transformation 6】

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