Preparation of cross-linked artificial nucleoside

Abstract

The invention relates to preparation of cross-linked artificial nucleoside. The invention provides a preparation method of a compound represented by a formula (III), which takes a compound represented by a formula (I) as a raw material. # imgabs0 #

Description

[0001] The present invention is a divisional application of Chinese patent application with application number 202080026954.3, application date March 31, 2020, and invention name “Preparation of cross-linked artificial nucleosides”. This application claims the priority of Japanese patent application No. 2019-073073 filed in Japan on April 5, 2019. Technical Field

[0002] The present invention relates to a method for preparing spirocyclopropene bridged nucleic acid (scpBNA). More specifically, the present invention relates to a method for preparing nucleosides of scpBNA, compounds used in the preparation method, and compounds obtained by the preparation method. Background Art

[0003] In recent years, nucleic acid drugs have attracted attention as molecular entities for drug development of new drugs. Since natural nucleic acids are prone to hydrolysis by enzymes in the body, various studies have been conducted on modified nucleic acids. For example, it has been reported that scpBNA has a high binding affinity for single-stranded RNA and excellent stability in the body (Patent Document 1 and Non-Patent Documents 1~2).

[0004] Prior art literature

[0005] Patent Literature

[0006] Patent document 1: WO2015 / 125783

[0007] Non-patent literature

[0008] Non-patent literature 1: Chem. Commun., 2015, Vol.51, p.9737-9740

[0009] Non-patent literature 2: J. Org. Chem., 2016, Vol.81, p.11000-11008 Summary of the invention

[0010] 1. Technical issues to be resolved

[0011] However, it has been found that the production of scpBNA according to the prior art requires a multi-step process, and there is room for improvement in terms of the production method for the purpose of large-scale synthesis.

[0012] The object of the present invention is to provide a novel preparation method of spirocyclopropene bridged nucleic acid (scpBNA) and its precursor.

[0013] In addition, the present invention aims to provide a method for efficiently preparing spirocyclopropene-bridged nucleic acid (scpBNA) and its precursor.

[0014] Furthermore, the present invention aims to provide a compound that can be used in the preparation method and the like and a preparation method thereof.

[0015] (II) Technical solution

[0016] Therefore, the inventors of the present application conducted intensive studies to solve the above-mentioned technical problems and found that scpBNA and the like can be efficiently synthesized via an intermediate compound represented by formula (I) described later, thereby completing the present invention.

[0017] That is, the present invention relates to the following [1] to

[37] .

[0018] [1] A method for producing a compound represented by formula (II), comprising at least the step of intramolecular cyclization of a compound represented by formula (I).

[0019] [Chemical formula 1]

[0020]

[0021] Where:

[0022] X represents a nucleic acid base portion which may have one or more substituents selected from the group α, wherein the group α consists of a hydroxyl group, a hydroxyl group protected by a protective group for nucleic acid synthesis, an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, a thiol group, a thiol group protected by a protective group for nucleic acid synthesis, an alkylthio group having 1 to 5 carbon atoms, an amino group, an amino group protected by a protective group for nucleic acid synthesis, an amino group substituted by an alkyl group having 1 to 5 carbon atoms, and a halogen atom,

[0023] R 1 and R 2 Each independently represents 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 branch or a ring, an alkenyl group having 2 to 7 carbon atoms which may form a branch or a ring, an aryl group having 3 to 10 carbon atoms which may have one or more substituents selected from the α group and may contain a heteroatom, an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may have one or more substituents selected from the α group and may contain a heteroatom, an acyl group which may have one or more substituents selected from the α group, a silyl group which may have one or more substituents selected from the α group, a phosphoryl group which may have one or more substituents selected from the α group, a phosphoryl group protected by a protecting group in nucleic acid synthesis, -P(R 3 )R 4 , in which R 3 and R 4each independently represents a hydroxyl group, a hydroxyl group protected by a protecting group for nucleic acid synthesis, a thiol group, a thiol group protected by 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 by an alkyl group having 1 to 6 carbon atoms,

[0024] 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 may form a branch or a ring; an aralkyl group having an aryl group having 3 to 12 carbon atoms which may contain a heteroatom; or a silyl group.

[0025] [Chemical formula 2]

[0026]

[0027] In the formula, X, R 1 , R 2 and R 5 With the X, R 1 , R 2 and R 5 same.

[0028] [2] The production method according to [1], wherein the intramolecular cyclization is carried out in the presence of a base.

[0029] [3] The preparation method according to [2], wherein the base is an alkoxide.

[0030] [4] The preparation method according to any one of [1] to [3], further comprising: 6 A step of preparing a compound represented by formula (I) by deprotection.

[0031] [Chemical formula 3]

[0032]

[0033] Where:

[0034] X represents a nucleic acid base portion which may have one or more substituents selected from the group α, wherein the group α consists of a hydroxyl group, a hydroxyl group protected by a protective group for nucleic acid synthesis, an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, a thiol group, a thiol group protected by a protective group for nucleic acid synthesis, an alkylthio group having 1 to 5 carbon atoms, an amino group, an amino group protected by a protective group for nucleic acid synthesis, an amino group substituted by an alkyl group having 1 to 5 carbon atoms, and a halogen atom,

[0035] R 1 and R 2Each independently represents 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 branch or a ring, an alkenyl group having 2 to 7 carbon atoms which may form a branch or a ring, an aryl group having 3 to 10 carbon atoms which may have one or more substituents selected from the α group and may contain a heteroatom, an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may have one or more substituents selected from the α group and may contain a heteroatom, an acyl group which may have one or more substituents selected from the α group, a silyl group which may have one or more substituents selected from the α group, a phosphoryl group which may have one or more substituents selected from the α group, a phosphoryl group protected by a protecting group in nucleic acid synthesis, -P(R 3 )R 4 , in which R 3 and R 4 each independently represents a hydroxyl group, a hydroxyl group protected by a protecting group for nucleic acid synthesis, a thiol group, a thiol group protected by 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 by an alkyl group having 1 to 6 carbon atoms,

[0036] R 5 represents a hydrogen atom; a halogen atom; an alkyl group having 1 to 7 carbon atoms which may be substituted by an aryl group having 3 to 12 carbon atoms which may contain a heteroatom and may form a branch or a ring; an aralkyl group having an aryl group having 3 to 12 carbon atoms which may contain a heteroatom; or a silyl group,

[0037] R 6 Represents a protecting group for hydroxyl groups in nucleic acid synthesis.

[0038] [5] The preparation method according to [4], wherein R 6 It is acetyl.

[0039] [6] The production method according to any one of [1] to [5], further comprising the step of preparing the compound represented by formula (I) using the compound represented by formula (V) as a raw material.

[0040] [Chemical formula 4]

[0041]

[0042] Where:

[0043] R 1 and R 2Each independently represents 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 branch or a ring, an alkenyl group having 2 to 7 carbon atoms which may form a branch or a ring, an aryl group having 3 to 10 carbon atoms which may have one or more substituents selected from the α group and may contain a heteroatom, an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may have one or more substituents selected from the α group and may contain a heteroatom, an acyl group which may have one or more substituents selected from the α group, a silyl group which may have one or more substituents selected from the α group, a phosphoryl group which may have one or more substituents selected from the α group, a phosphoryl group protected by a protecting group in nucleic acid synthesis, -P(R 3 )R 4 , in which R 3 and R 4 each independently represents a hydroxyl group, a hydroxyl group protected by a protecting group for nucleic acid synthesis, a thiol group, a thiol group protected by 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 by an alkyl group having 1 to 6 carbon atoms,

[0044] The α group is composed of hydroxyl, hydroxyl protected by a protecting group for nucleic acid synthesis, alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, thiol, thiol protected by a protecting group for nucleic acid synthesis, alkylthio having 1 to 5 carbon atoms, amino, amino protected by a protecting group for nucleic acid synthesis, amino substituted by an alkyl having 1 to 5 carbon atoms, and halogen atoms.

[0045] R 6 and R 7 each independently a protecting group for a hydroxyl group for nucleic acid synthesis, an alkyl group having 1 to 7 carbon atoms which may form a branch or a ring, an alkenyl group having 2 to 7 carbon atoms which may form a branch or a ring, an aryl group having 3 to 10 carbon atoms which may have one or more substituents selected from the α group and may contain a heteroatom, an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may have one or more substituents selected from the α group and may contain a heteroatom, an acyl group which may have one or more substituents selected from the α group, a silyl group which may have one or more substituents selected from the α group, a phosphoryl group which may have one or more substituents selected from the α group, or a phosphoryl group protected by a protecting group for nucleic acid synthesis, or

[0046] R 6 and R 7 Common representation -C(R 8 )(R 9 )-, in which R 8 and R 9Each 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 may form a branch or a ring, or an aralkyl group having an aryl group having 3 to 12 carbon atoms which may contain a heteroatom.

[0047] [7] The preparation method according to [6], wherein R 1 and R 2 It is benzyl.

[0048] [8] A method for preparing a compound represented by formula (III), the method comprising the step of cyclopropanating the compound represented by formula (II), wherein the cyclopropanation step comprises the step of post-treating the reaction solution with ammonia.

[0049] [Chemical formula 5]

[0050]

[0051] In the formula, X, R 1 , R 2 and R 5 With the X, R 1 , R 2 and R 5 Same, R 5’ Independent of R 5 , and with R 5 The definition is the same.

[0052] [9] The preparation method according to [8], wherein X is a group having a pyrimidine skeleton.

[0053]

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

[0054]

[11] The preparation method according to

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

[0055]

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

[0056]

[13] The preparation method according to

[12] , comprising the step of preparing the compound represented by formula (I) using the preparation method described in any one of [4] to [7].

[0057]

[14] The preparation method according to

[12] or

[13] , wherein the intramolecular cyclization step is carried out using the preparation method described in any one of [1] to [7].

[0058]

[15] The production method according to any one of

[12] to

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

[11] .

[0059]

[16] The compound represented by the formula (IV), wherein X is 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl, R 1 and R 2 is benzyl, R 6 is the case of acetyl, and

[0060] X is 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl, R 1 , R 2 and R 6 For the case of acetyl group.

[0061]

[17] The compound according to

[16] , wherein R 6 It is acetyl.

[0062]

[18] The compound according to

[16] or

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

[0063]

[19] The compound according to

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

[0064]

[20] The compound according to any one of

[16] to

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

[0065] [Chemical formula 6]

[0066]

[0067]

[21] The compound according to

[16] or

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

[0068]

[22] The compound according to

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

[0069]

[23] The compound according to any one of

[16] ,

[17] ,

[21] , and

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

[0070] [Chemical formula 7]

[0071]

[0072]

[24] The compound represented by the formula (I), wherein X is 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl, R 1 and R 2 is the case of benzyl, and

[0073] X is 2-oxo-4-amino-1,2-dihydropyrimidin-1-yl, R 1 and R 2 For the case of hydrogen atoms.

[0074]

[25] The compound according to

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

[0075]

[26] The compound according to

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

[0076]

[27] The compound according to any one of

[24] to

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

[0077] [Chemical formula 8]

[0078]

[0079]

[28] The compound according to

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

[0080]

[29] The compound according to

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

[0081]

[30] The compound according to any one of

[24] ,

[28] and

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

[0082] [Chemical formula 9]

[0083]

[0084]

[31] The compound represented by the formula (II), wherein X is 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl, R 1 is naphthyl, R 2 is the case of benzyl, and

[0085] X is 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl, R 1 is naphthyl, R 2 For the case of hydrogen atoms.

[0086]

[32] The compound according to

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

[0087]

[33] The compound according to

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

[0088]

[34] The compound according to any one of

[31] to

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

[0089] [Chemical formula 10]

[0090]

[0091]

[35] The compound according to

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

[0092]

[36] The compound according to

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

[0093]

[37] The compound according to any one of

[31] ,

[35] and

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

[0094] [Chemical formula 11]

[0095]

[0096] (III) Beneficial effects

[0097] According to the present invention, scpBNA can be produced efficiently. DETAILED DESCRIPTION

[0098] The present invention is characterized by using an intermediate compound represented by formula (I) described later.

[0099] In the present invention, it is speculated that the use of the compound eliminates the need for the stereoinversion step of the 2'-hydroxyl group of the nucleoside ribose moiety, which increases the number of steps in the prior art, and thus reduces the number of steps, and scpBNA can be efficiently prepared. However, the above speculation does not limit the present invention.

[0100] First, the terms used in this specification are defined.

[0101] The so-called "nucleic acid base part" refers to all heterocyclic groups of 5 to 20 rings with a structure in which the carbon atom of the ring atom of the hydrocarbon ring is replaced with one or more heteroatoms such as nitrogen atoms, sulfur atoms or oxygen atoms, and aromaticity, including monocyclic and condensed rings. Specifically, as a hydrocarbon ring, for example, benzene, naphthalene, anthracene, phenanthrene, indane, indene, tetralin, biphenyl, etc. can be listed. As a heterocycle, for example, purine nucleic acid bases or pyrimidine nucleic acid bases can be listed. Any ring can have one or more substituents selected from the following α groups. Among them, purine nucleic acid bases or pyrimidine nucleic acid bases include known bases (for example, guanine, adenine, cytosine, thymine, uracil) that are usually used as constituents of nucleic acids and other bases similar to these bases that can act or substitute as bases of nucleic acid components All chemical structures and their tautomers (for example, ketoenol tautomers, imine enamine tautomers). In addition, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiol, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridazine, indolizine, indole, isoindole, isoquinoline, quinoline, naphthyridine, quinoxaline, quinazoline, pteridine, carbazole, phenanthridine, acridine, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, etc. are also included. Preferably, it is a purine nucleic acid base or a pyrimidine nucleic acid base, or a purine nucleic acid base or a pyrimidine nucleic acid base which may have one or more substituents selected from the following α group, specifically, preferably, purin-9-yl, 2-oxo-pyrimidin-1-yl, or purin-9-yl or 2-oxo-pyrimidin-1-yl having a substituent selected from the following α group.

[0102] α Group: hydroxyl, hydroxyl protected by a protecting group for nucleic acid synthesis, alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, thiol, thiol protected by a protecting group for nucleic acid synthesis, alkylthio having 1 to 5 carbon atoms, amino, amino protected by a protecting group for nucleic acid synthesis, amino substituted by an alkyl having 1 to 5 carbon atoms, and halogen atoms.

[0103] Preferred groups of the “purine nucleic acid base which may have a substituent” are 6-aminopurine-9-yl (i.e., adenine), 6-aminopurine-9-yl whose amino group is protected by a protecting group for nucleic acid synthesis, 2,6-diaminopurine-9-yl, 2-amino-6-chloropurine-9-yl, 2-amino-6-chloropurine-9-yl whose amino group is protected by a protecting group for nucleic acid synthesis, 2-amino-6-fluoropurine-9-yl, 2-amino-6-fluoropurine-9-yl whose amino group is protected by a protecting group for nucleic acid synthesis, 2-amino-6-bromopurine-9-yl. -yl, 2-amino-6-bromopurin-9-yl, 2-amino-6-hydroxypurin-9-yl (i.e., guanyl) in which the amino group is protected by a protecting group for nucleic acid synthesis, 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-dichloroproline-2-yl or 6-mercaptopurin-9-yl in which one or both of the amino group and the hydroxy group are protected by a protecting group for nucleic acid synthesis.

[0104] Preferred groups of the “pyrimidine nucleic acid base which may have a substituent” include 2-oxo-4-amino-1,2-dihydropyrimidin-1-yl (i.e., cytosine), 2-oxo-4-amino-1,2-dihydropyrimidin-1-yl wherein one or both of the amino group and the hydroxyl group are protected by a protective 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 wherein the amino group is protected by a protective group for nucleic acid synthesis, 4-amino-2-oxo-5-chloro-1,2-dihydropyrimidin-1-yl, 2-oxo-4-amino-5-fluoro-1,2-dihydropyrimidin-1-yl, 2-oxo-4-methoxy-1,2-dihydropyrimidin-1-yl, 2-oxo-4-thiol-1,2-dihydropyrimidin-1-yl, 2-oxo-4-hydroxy-1,2-dihydropyrimidin-1-yl (i.e., uracilyl), 2-oxo-4-hydroxy-5-methyl-1,2-dihydropyrimidin-1-yl (i.e., thymidyl), 4-amino-5-methyl-2-oxo-1,2-dihydropyrimidin-1-yl (i.e., 5-methylcytosyl), or 2-oxo-4-amino-5-methyl-1,2-dihydropyrimidin-1-yl whose amino group is protected by a protecting group for nucleic acid synthesis.

[0105] Among the “purine nucleic acid base or pyrimidine nucleic acid base which may have a substituent”, further preferred are 6-aminopurin-9-yl (i.e., adenine), 6-aminopurin-9-yl in which the amino group is protected by 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., guanine), 2-amino-6-hydroxypurin-9-yl in which one or both of the amino group and the hydroxy group are protected by 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., cytosine The amino group of the present invention is 2-oxo-4-amino-1,2-dihydropyrimidin-1-yl (for example, 2-oxo-4-benzoylamino-1,2-dihydropyrimidin-1-yl), 2-oxo-4-hydroxy-1,2-dihydropyrimidin-1-yl (i.e., uracilyl), 2-oxo-4-hydroxy-5-methyl-1,2-dihydropyrimidin-1-yl (i.e., thymidyl), 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 (for example, 2-oxo-4-benzoylamino-5-methyl-1,2-dihydropyrimidin-1-yl) whose amino group is protected by a protecting group for nucleic acid synthesis.

[0106] The term "protecting group for amino group in nucleic acid synthesis", "protecting group for hydroxyl group in nucleic acid synthesis", "amino group protected by protecting group in nucleic acid synthesis" or "hydroxyl group protected by protecting group in nucleic acid synthesis" is not particularly limited as long as it can stably protect amino group or 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, t-valer ... Alkylcarbonyl groups such as isovaleryl, octanoyl, nonanoyl, decanoyl, 3-methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl, 3,7-dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, 1-methylpentadecanoyl, 14-methylpentadecanoyl, 13,13-dimethyltetradecanoyl, heptadecanoyl, 15-methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl, nonadecanoyl, 4-oxopentanoyl (levulinoyl), eicosanoyl and heneicosanoyl group); carboxylated alkylcarbonyl such as succinyl, glutaryl and adipoyl; halogenated lower alkylcarbonyl such as chloroacetyl, dichloroacetyl, trichloroacetyl and trifluoroacetyl; alkoxy lower alkylcarbonyl such as methoxyacetyl, phenoxyacetyl and 2-(4-tert-butyl)phenoxyacetyl; "aliphatic acyl" of unsaturated alkylcarbonyl such as (E)-2-methyl-2-butenoyl, such as arylcarbonyl such as benzoyl, α-naphthoyl and β-naphthoyl; 2-bromobenzoyl halogenated arylcarbonyl such as 2,4,6-trimethylbenzoyl and 4-toluoyl; lower alkylated arylcarbonyl such as 4-anisyl (4-anisoyl); carboxylated arylcarbonyl such as 2-carboxybenzoyl, 3-carboxybenzoyl and 4-carboxybenzoyl; lower alkoxycarbonylated arylcarbonyl such as 2-(methoxycarbonyl)benzoyl; nitroated arylcarbonyl such as 4-nitrobenzoyl and 2-nitrobenzoyl;"Aromatic acyl" such as arylcarbonyl such as 4-phenylbenzoyl, "lower alkyl" such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-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, and "vinyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 1-methyl 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-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 "Lower alkenyl" such as 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, and 5-hexenyl; "halogenated lower alkyl" such as 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, 2,2,2-trifluoroethyl, and 2,2,2-trichloro-1, 1-dimethylethyl; methyl 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, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 4,4'-dimethoxy alkyl groups such as triphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl and 4-cyanobenzyl, “aryl groups substituted with 1 to 3 aryl groups” such as methyl triphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl and 4-cyanobenzyl, “aryl groups substituted with halogen atoms, lower alkoxy groups or nitro groups” such as 4-chlorophenyl, 2-chlorophenyl, 4-methoxyphenyl, 4-nitrophenyl and 2,4-dinitrophenyl, and tri-lower alkylsilyl groups such as trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, tert-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-tert-butylsilyl and triisopropylsilyl;"Silyl" such as lower alkylsilyl substituted with 1 to 2 aryl groups such as diphenylmethylsilyl, tert-butyldiphenylsilyl, diphenylisopropylsilyl and phenyldiisopropylsilyl, "tetrahydropyranyl or tetrahydrothiopyranyl" such as tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-4-yl and 4-methoxytetrahydrothiopyran-4-yl, "tetrahydrofuranyl or tetrahydrothiophenyl" such as tetrahydrofuran-2-yl and tetrahydrothiophen-2-yl, "lower alkoxymethyl" such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl and tert-butoxymethyl, "lower alkoxyalkyl" such as lower alkoxyethyl such as 1-ethoxyethyl and 1-(isopropoxy)ethyl, "lower alkoxylated lower alkyl" such as 2-methoxyethoxymethyl "halogenated lower alkoxymethyl" such as 2,2,2-trichloroethoxymethyl and bis(2-chloroethoxy)methyl; "aralkyloxymethyl whose aryl ring may be substituted with 1 to 2 lower alkoxy groups or nitro" such as benzyloxymethyl, 4-methoxybenzyloxymethyl and 2-naphthylmethoxymethyl, such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl and isobutoxycarbonyl; lower alkoxycarbonyl substituted with halogen or tri-lower alkylsilyl such as 2,2,2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl; alkenyloxycarbonyl such as vinyloxycarbonyl and aryloxycarbonyl; aralkyloxycarbonyl whose aryl ring may be substituted with 1 to 2 lower alkoxy groups or nitro such as benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitrobenzyloxycarbonyl;The "oxycarbonyl" of 9-fluorenylmethyloxycarbonyl, "carbamoyl group whose nitrogen atom may be substituted 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 morpholinecarbamoyl, for example, as the "protecting group for the hydroxyl group in nucleic acid synthesis", preferably "aliphatic acyl group", "aromatic acyl group", "methyl group substituted with 1 to 3 aryl groups", "methyl group substituted with 1 to 3 aryl groups whose aryl ring is substituted with a lower alkyl group, a lower alkoxy group, a halogen group or a cyano group" or "silyl group" is further preferred, and The protective group of "hydroxyl protected by a protective group for nucleic acid synthesis" is preferably "aliphatic acyl", "aromatic acyl", "methyl substituted by 1 to 3 aryl groups", "aryl substituted by a halogen atom, a lower alkoxy group or a nitro group", "lower alkyl" or "lower alkenyl", and more preferably benzoyl, benzyl, 2-chlorophenyl, 4-chlorophenyl or 2-propenyl. ;

[0107] The protecting group of the "thiol group protected by a protecting group for nucleic acid synthesis" is not particularly limited as long as the thiol group can be stably protected during nucleic acid synthesis. Specifically, it refers to a protecting group that is stable under acidic or neutral conditions and can be cleaved by chemical methods such as hydrogenolysis, hydrolysis, electrolysis and photolysis. For example, in addition to the groups listed above as the protecting groups for the hydroxyl group, "disulfide-forming groups" such as alkylthio groups such as methylthio, ethylthio and tert-butylthio; and arylthio groups such as benzylthio can be listed. Preferably, it is an "aliphatic acyl group" or an "aromatic acyl group", and more preferably, it is a benzoyl group.

[0108] The "protecting group" of the "phosphoryl group protected by a protecting group for nucleic acid synthesis" is not particularly limited as long as it can stably protect the phosphoryl 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 methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-methylbutyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-methylbutyl, 2-methylpentyl ... "Lower alkyl" such as pentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl and 2-ethylbutyl; "Cyanated lower alkyl" such as 2-cyanoethyl and 2-cyano-1,1-dimethylethyl; "Silyl-substituted ethyl" such as 2-methyldiphenylsilylethyl, 2-trimethylsilylethyl and 2-triphenylsilylethyl; "Trichloroethyl" such as 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloro-1,The “halogenated lower alkyl” such as 1-dimethylethyl, vinyl, 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, 3-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 "Lower alkenyl" such as -4-pentenyl, 2-methyl-4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl, "cycloalkyl" such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl and adamantyl, "cyanated lower alkenyl" 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-phenylethyl "Aralkyl" such as phenylbutyl, 1-naphthylbutyl, 2-naphthylbutyl, 3-naphthylbutyl, 4-naphthylbutyl, 1-phenylpentyl, 2-phenylpentyl, 3-phenylpentyl, 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, 6-naphthylpentyl, 4-chlorobenzyl, 2-(4-nitrophenyl)ethyl, o-nitrobenzyl, 4-nitrobenzyl, 2,4-dinitrobenzyl, 4-chloro-2-nitrobenzyl The "aryl alkyl group whose aryl ring is substituted with a nitro group or a halogen atom" such as phenyl, indenyl, naphthyl, phenanthrenyl, anthracenyl, and "aryl group substituted with a lower alkyl group, a halogen atom, or a nitro group" such as 2-methylphenyl, 2,6-dimethylphenyl, 2-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2-bromophenyl, 4-nitrophenyl, and 4-chloro-2-nitrophenyl are preferably "lower alkyl groups", "lower alkyl groups substituted with a cyano group", "arylalkyl groups", "arylalkyl groups whose 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 2-cyanoethyl, 2,2,2-trichloroethyl, benzyl, 2-chlorophenyl, or 4-chlorophenyl.

[0109] The term "alkyl" generally refers to a straight or branched alkyl group having 1 to 20 carbon atoms, and includes, for example, a straight or branched alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-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 (these groups are also referred to as lower alkyl groups in this specification), and a straight or branched alkyl group having 7 to 20 carbon atoms such as heptyl, octyl, nonyl, and decyl. In addition, a part of these groups may form a ring.

[0110] The so-called "alkoxy" generally refers to an alkoxy group having the above-mentioned alkyl group, for example, including methyloxy (methoxy), ethyloxy (ethoxy), n-propyloxy (n-propoxy), isopropoxy, n-butyloxy (n-butoxy), isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy (n-pentoxy), etc.

[0111] The so-called "cyanoalkoxy" generally refers to a group formed by substituting any number of cyano groups in the above 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.

[0112] The so-called "alkylthio" generally refers to an alkylthio group having the above alkyl group, and includes, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, n-pentylthio and the like.

[0113] The so-called "alkylamino" generally refers to an alkylamino group having one or two of the alkyl groups, and includes, for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, di(sec-butyl)amino, di(tert-butyl)amino, pentylamino and the like.

[0114] The so-called "alkenyl" generally refers to a straight chain or branched alkenyl group having 2 to 20 carbon atoms, and includes, for example, 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, The invention also includes a straight chain or branched chain alkenyl group having 2 to 6 carbon atoms such as 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 (in this specification, these groups are also referred to as lower alkenyl groups.), and heptenyl, geranyl, and farnesyl. In addition, a part of these groups may form a ring.

[0115] The so-called "aryl" generally refers to a monovalent substituent with 6 to 14 carbon atoms from an aromatic hydrocarbon group by removing one hydrogen atom, and examples thereof include phenyl, indenyl, naphthyl, phenanthrenyl, anthracenyl, etc. In addition, the aryl ring may be substituted by one or more groups such as halogen atoms, lower alkyl groups, hydroxyl groups, alkoxy groups, aryloxy groups, amino groups, nitro groups, trifluoromethyl groups, phenyl groups, etc., and examples of such 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, biphenyl, etc. In addition, the aryl group may contain heteroatoms, such as heteroaryl groups in which at least one carbon atom constituting the ring structure of the aryl group is substituted by a heteroatom (e.g., nitrogen atom, oxygen atom, sulfur atom, etc.). Examples of the heteroaryl group include a pyridyl group, a pyrrolyl group, a quinolyl group, an indolyl group, an imidazolyl group, a furyl group, and a thienyl group.

[0116] The so-called "aralkyl" generally refers to an alkyl group having 1 to 6 carbon atoms substituted by an aryl group, for example, "a methyl group substituted by 1 to 3 aryl groups" such as benzyl, α-naphthylmethyl, β-naphthylmethyl, indenylmethyl, phenanthrylmethyl, anthracenylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl, or "a methyl group substituted by 1 to 3 aryl groups in which the aryl ring is substituted by a lower alkyl group, a lower alkoxy group, a halogen group, or a cyano group" such as 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 4,4'-dimethoxytriphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, or "a methyl group substituted by 1 to 3 aryl groups in which the aryl ring is substituted by a lower alkyl group, a lower alkoxy group, a halogen group, or a cyano group" such as 1-phenethyl, 2-phenethyl, 1-naphthylethyl, 2-naphthyl ethyl, 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, 3-phenylpentyl, 4-phenylpentyl, 5-phenylpentyl, 1- “Alkyl groups having 2 to 6 carbon atoms substituted with an aryl group” such as 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.

[0117] Examples of the “acyl group” include alkylcarbonyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, t-valeryl, n-valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, 3-methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl, 3,7-dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, 1-methylpentadecanoyl, 14-methylpentadecanoyl, 13,13-dimethyltetradecanoyl, heptadecanoyl, 15-methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl, nonadecanoyl, eicosanoyl, and heneicosanoyl; carboxylated alkylcarbonyl groups such as succinyl, glutaryl, and adipoyl; and chloroacetyl, dichloroacetyl, trichloroacetyl, and trifluoroacetyl. Halogenated lower alkylcarbonyl; lower alkoxy lower alkylcarbonyl such as methoxyacetyl; unsaturated alkylcarbonyl such as (E)-2-methyl-2-butenoyl; arylcarbonyl such as benzoyl, α-naphthoyl, β-naphthoyl; halogenated arylcarbonyl such as 2-bromobenzoyl, 4-chlorobenzoyl; lower alkylcarbonyl such as 2,4,6-trimethylbenzoyl, 4-toluoyl The “aromatic acyl” includes an arylcarbonyl group; a lower alkoxylated arylcarbonyl group such as 4-anisyl; a carboxylated arylcarbonyl group such as 2-carboxybenzoyl, 3-carboxybenzoyl and 4-carboxybenzoyl; a nitroated arylcarbonyl group such as 4-nitrobenzoyl and 2-nitrobenzoyl; a lower alkoxycarbonylated arylcarbonyl group such as 2-(methoxycarbonyl)benzoyl; and an arylated arylcarbonyl group such as 4-phenylbenzoyl.

[0118] Examples of the “silyl group” include “tri-lower alkylsilyl groups” such as trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, tert-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-tert-butylsilyl and triisopropylsilyl; and “lower alkylsilyl groups substituted with 1 to 2 aryl groups” such as diphenylmethylsilyl, butyldiphenylbutylsilyl, diphenylisopropylsilyl and phenyldiisopropylsilyl.

[0119] Examples of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

[0120] Next, the present invention will be described in detail.

[0121] The method for producing the compound represented by formula (III) of the present invention may be any method using the compound represented by formula (I) as a raw material, and may include at least a step of using the compound represented by formula (I).

[0122] [Chemical formula 12]

[0123]

[0124] Where:

[0125] X represents a nucleic acid base portion which may have one or more substituents selected from Group α,

[0126] R 1 and R 2 Each independently represents a hydrogen atom, a protecting group for a hydroxyl group for nucleic acid synthesis, an alkyl group having 1 to 7 carbon atoms which may form a branch or a ring, an alkenyl group having 2 to 7 carbon atoms which may form a branch or a ring, an aryl group having 3 to 10 carbon atoms which may have one or more substituents selected from the aforementioned α group and may contain a heteroatom, an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may have one or more substituents selected from the aforementioned α group and may contain a heteroatom, an acyl group which may have one or more substituents selected from the aforementioned α group, a silyl group which may have one or more substituents selected from the aforementioned α group, a phosphoryl group which may have one or more substituents selected from the aforementioned α group, a phosphoryl group protected by a protecting group for nucleic acid synthesis, -P(R 3 )R 4 , in which R 3 and R 4 each independently represents a hydroxyl group, a hydroxyl group protected by a protecting group for nucleic acid synthesis, a thiol group, a thiol group protected by 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 by an alkyl group having 1 to 6 carbon atoms,

[0127] 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 may form a branch or a ring; an aralkyl group having an aryl group having 3 to 12 carbon atoms which may contain a heteroatom; or a silyl group.

[0128] As X in formula (I), the nucleic acid base part can be listed.Wherein, from the perspective of introduction into nucleic acid drugs, preferably purine nucleic acid base or pyrimidine nucleic acid base with substituent, for example, preferably represented by the following structural formula, 2-oxo-4-hydroxyl-5-methyl-1,2-dihydropyrimidine-1-base (thymine base), 2-oxo-4-amino-1,2-dihydropyrimidine-1-base (cytosine base), 6-aminopurine-9-base (adenine base), 2-amino-6-hydroxypurine-9-base (guanine base), 4-amino-5-methyl-2-oxo-1,2-dihydropyrimidine-1-base and 2-oxo-4-hydroxyl-1,2-dihydropyrimidine-1-base (uracil base) and amino in these groups, one or more protected groups in carbonyl and tautomers of these groups.

[0129] [Chemical formula 13]

[0130]

[0131] R in formula (I) 1 ~R 5 The above substituents can be appropriately set by referring to each of them independently. 3 )R 4 The group represented by is preferably a group represented by the chemical formula -P(OC2H4CN)(N(iPr)2) or a group represented by the chemical formula -P(OCH3)(N(iPr)2). wherein iPr represents an isopropyl group.

[0132] As a preparation method using a compound represented by formula (I) as a raw material, for example, a method using a compound represented by formula (II) obtained by intramolecular cyclization of the compound represented by formula (I) can be cited. Therefore, as one embodiment of the present invention, a method including at least a step of intramolecular cyclization of the compound represented by formula (I) can be cited. Hereinafter, this step is sometimes also recorded as step A.

[0133] As a method for intramolecular cyclization, a known method in the art can be used, for example, an addition reaction of an alcohol to an alkyne can be used. In the addition reaction, it is generally preferred to add a base to the substrate and react in a solvent or without a solvent while cooling or heating as needed.

[0134] Examples of the base include alkoxides such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, lithium methoxide, lithium ethoxide, lithium tert-butoxide, potassium methoxide, potassium ethoxide, and potassium tert-butoxide; carbonates such as sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate; organometallic reagents such as methyl lithium, ethyl lithium, n-butyl lithium, and methyl magnesium chloride; metal hydrides such as sodium hydride; metal amides such as lithium diisopropylamide, potassium hexamethyldisilazane, sodium hexamethyldisilazane, and lithium dicyclohexylamide; and organic bases such as triethylamine, diisopropylethylamine, tributylamine, tert-butylamine, N,N-dimethylaniline, N,N-diethylaniline, pyridine, 4-dimethylaminopyridine, pyrrolidine, piperidine, collidine, lutidine, morpholine, piperazine, diazabicycloundecene, diazabicyclononene, and 1,4-diazabicyclo[2.2.2]octane. These bases may be used alone or in combination, and may be selected in consideration of the type, reactivity, or selectivity of the substrate.

[0135] The amount of substrate, base, etc., reaction temperature, reaction time, etc. in the reaction 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 is 1.0 equivalent to 30 equivalents. In addition, there is no particular restriction on the purification after the reaction.

[0136] The compound represented by formula (I) has the above R 1 ~R 5 and X, commercially available products can be used, and compounds prepared by known methods can also be used. For example, compounds in which X is a group having a uracil skeleton that may have a substituent (preferably a hydroxyl group, an amino group, a hydroxyl group and an amino group protected by a protective group), or a group having a cytosine skeleton that may have a substituent (preferably a hydroxyl group, an amino group, a hydroxyl group and an amino group protected by a protective group), and their tautomers can be listed. The specific structure is as follows.

[0137] [Chemical formula 14]

[0138]

[0139] Similarly, examples of the compound represented by formula (I) include compounds wherein X is a group having a purine skeleton which may have a substituent (preferably a hydroxyl group, an amino group, a hydroxyl group and an amino group protected by a protecting group) and tautomers thereof.

[0140] [Chemical formula 15]

[0141]

[0142] In the present invention, as the compound represented by formula (I), X can be used as 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl, R 1 and R 2is benzyl, R 5 is a hydrogen atom, and X is 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl, R 1 , R 2 and R 5 A compound containing hydrogen atoms.

[0143] In addition, the compound represented by formula (I) can be prepared by deprotecting the compound represented by the following formula (IV). Therefore, as one embodiment of the present invention, a preparation method further comprising the step of deprotecting the compound represented by the following formula (IV) to prepare the compound represented by formula (I) can be listed.

[0144] [Chemical formula 16]

[0145]

[0146] Where:

[0147] X represents a nucleic acid base portion which may have one or more substituents selected from Group α,

[0148] R 1 and R 2 Each independently represents a hydrogen atom, a protecting group for a hydroxyl group for nucleic acid synthesis, an alkyl group having 1 to 7 carbon atoms which may form a branch or a ring, an alkenyl group having 2 to 7 carbon atoms which may form a branch or a ring, an aryl group having 3 to 10 carbon atoms which may have one or more substituents selected from the aforementioned α group and may contain a heteroatom, an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may have one or more substituents selected from the aforementioned α group and may contain a heteroatom, an acyl group which may have one or more substituents selected from the aforementioned α group, a silyl group which may have one or more substituents selected from the aforementioned α group, a phosphoryl group which may have one or more substituents selected from the aforementioned α group, a phosphoryl group protected by a protecting group for nucleic acid synthesis, -P(R 3 )R 4 , in which R 3 and R 4 each independently represents a hydroxyl group, a hydroxyl group protected by a protecting group for nucleic acid synthesis, a thiol group, a thiol group protected by 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 by an alkyl group having 1 to 6 carbon atoms,

[0149] R 5represents a hydrogen atom; a halogen atom; an alkyl group having 1 to 7 carbon atoms which may be substituted by an aryl group having 3 to 12 carbon atoms which may contain a heteroatom and may form a branch or a ring; an aralkyl group having an aryl group having 3 to 12 carbon atoms which may contain a heteroatom; or a silyl group,

[0150] R 6 Represents a protecting group for hydroxyl groups in nucleic acid synthesis.

[0151] As a preferred embodiment of the present invention, the following embodiment can be cited, that is, the compound represented by formula (I) is prepared by deprotecting the compound represented by formula (IV), wherein the group R in formula (IV) is 6 Indicates a group that can be removed.

[0152] R in formula (IV) 1 ~R 6 and X can be appropriately set independently with reference to the above-mentioned substituents, and can be selected according to the desired structure of the compound represented by formula (I).

[0153] The deprotection method can be appropriately selected according to the type of protecting group according to the known method in the art. 6 When it is an acetyl group, it is preferably dissolved in an organic solvent and a base is added, and the reaction is carried out by cooling or heating as required. For example, the reaction temperature is -80 to 200°C, the reaction time is 0.1 to 24 hours, and the amount of the base used is 1.0 equivalent to 30 equivalents.

[0154] The compound represented by formula (IV) has the above R 1 ~R 6 and X, commercially available products may be used, or compounds prepared by known methods may be used. For example, R 6 A compound in which X is an acetyl group or a group having a uracil skeleton which may have a substituent (preferably a hydroxyl group, an amino group, a hydroxyl group and an amino group protected by a protective group), or a compound having a cytosine skeleton which may have a substituent (preferably a hydroxyl group, an amino group, a hydroxyl group and an amino group protected by a protective group), and their tautomers. The specific structure is as follows.

[0155] [Chemical formula 17]

[0156]

[0157] Similarly, examples of the compound represented by formula (IV) include compounds wherein X is a group having a purine skeleton which may have a substituent (preferably a hydroxyl group, an amino group, a hydroxyl group and an amino group protected by a protecting group) and tautomers thereof.

[0158] [Chemical formula 18]

[0159]

[0160] In the present invention, as the compound represented by formula (IV), a compound in which X is 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl, R 1 and R 2 is benzyl, R 6 is an acetyl group, and X is a 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl group, R 1 , R 2 and R 6 A compound containing acetyl.

[0161] In addition, the compound represented by formula (I) can be prepared, for example, by using the compound represented by the following formula (V) as a raw material. Therefore, as one embodiment of the present invention, a preparation method comprising the step of using the compound represented by the following formula (V) as a raw material to prepare the compound represented by formula (I) can be listed.

[0162] [Chemical formula 19]

[0163]

[0164] Where:

[0165] R 1 and R 2 Each independently represents 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 branch or a ring, an alkenyl group having 2 to 7 carbon atoms which may form a branch or a ring, an aryl group having 3 to 10 carbon atoms which may have one or more substituents selected from the α group and may contain a heteroatom, an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may have one or more substituents selected from the α group and may contain a heteroatom, an acyl group which may have one or more substituents selected from the α group, a silyl group which may have one or more substituents selected from the α group, a phosphoryl group which may have one or more substituents selected from the α group, a phosphoryl group protected by a protecting group in nucleic acid synthesis, -P(R 3 )R 4 , in which R 3 and R 4 each independently represents a hydroxyl group, a hydroxyl group protected by a protecting group for nucleic acid synthesis, a thiol group, a thiol group protected by 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 by an alkyl group having 1 to 6 carbon atoms,

[0166] The α group is composed of hydroxyl, hydroxyl protected by a protecting group for nucleic acid synthesis, alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, thiol, thiol protected by a protecting group for nucleic acid synthesis, alkylthio having 1 to 5 carbon atoms, amino, amino protected by a protecting group for nucleic acid synthesis, amino substituted by an alkyl having 1 to 5 carbon atoms, and halogen atoms.

[0167] R 6 and R 7 each independently a protecting group for a hydroxyl group for nucleic acid synthesis, an alkyl group having 1 to 7 carbon atoms which may form a branch or a ring, an alkenyl group having 2 to 7 carbon atoms which may form a branch or a ring, an aryl group having 3 to 10 carbon atoms which may have one or more substituents selected from the α group and may contain a heteroatom, an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may have one or more substituents selected from the α group and may contain a heteroatom, an acyl group which may have one or more substituents selected from the α group, a silyl group which may have one or more substituents selected from the α group, a phosphoryl group which may have one or more substituents selected from the α group, or a phosphoryl group protected by a protecting group for nucleic acid synthesis, or

[0168] R 6 and R 7 Common representation -C(R 8 )(R 9 )-, in which 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 may form a branch or a ring, or an aralkyl group having an aryl group having 3 to 12 carbon atoms which may contain a heteroatom.

[0169] R in formula (V) 1 ~R 4 and R 6 ~R 7 The substituents can be appropriately set with reference to each of the above substituents independently, and can be selected according to the structure of the compound represented by the desired formula (I).

[0170] The method for producing the compound of formula (I) from the compound of formula (V) can be carried out by referring to the known methods in the relevant technical field. However, from the viewpoint of simplifying the production process, the method can be carried out as follows.

[0171] Specifically, for example, the compound of formula (V) is first reacted in the presence of a reaction reagent to prepare a 4-formyl compound represented by formula (VI). The reaction temperature is preferably -80 to 200°C and the reaction time is 0.1 to 24 hours.

[0172] [Chemical formula 20]

[0173]

[0174] Where:

[0175] R 1 and R 2 Each independently represents 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 branch or a ring, an alkenyl group having 2 to 7 carbon atoms which may form a branch or a ring, an aryl group having 3 to 10 carbon atoms which may have one or more substituents selected from the α group and may contain a heteroatom, an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may have one or more substituents selected from the α group and may contain a heteroatom, an acyl group which may have one or more substituents selected from the α group, a silyl group which may have one or more substituents selected from the α group, a phosphoryl group which may have one or more substituents selected from the α group, a phosphoryl group protected by a protecting group in nucleic acid synthesis, -P(R 3 )R 4 , in which R 3 and R 4 each independently represents a hydroxyl group, a hydroxyl group protected by a protecting group for nucleic acid synthesis, a thiol group, a thiol group protected by 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 by an alkyl group having 1 to 6 carbon atoms,

[0176] The α group is composed of hydroxyl, hydroxyl protected by a protecting group for nucleic acid synthesis, alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, thiol, thiol protected by a protecting group for nucleic acid synthesis, alkylthio having 1 to 5 carbon atoms, amino, amino protected by a protecting group for nucleic acid synthesis, amino substituted by an alkyl having 1 to 5 carbon atoms, and halogen atoms.

[0177] R 6 and R 7 each independently a protecting group for a hydroxyl group for nucleic acid synthesis, an alkyl group having 1 to 7 carbon atoms which may form a branch or a ring, an alkenyl group having 2 to 7 carbon atoms which may form a branch or a ring, an aryl group having 3 to 10 carbon atoms which may have one or more substituents selected from the α group and may contain a heteroatom, an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may have one or more substituents selected from the α group and may contain a heteroatom, an acyl group which may have one or more substituents selected from the α group, a silyl group which may have one or more substituents selected from the α group, a phosphoryl group which may have one or more substituents selected from the α group, or a phosphoryl group protected by a protecting group for nucleic acid synthesis, or

[0178] R 6 and R 7 Common representation -C(R 8 )(R 9 )-, in which 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 may form a branch or a ring, or an aralkyl group having an aryl group having 3 to 12 carbon atoms which may contain a heteroatom.

[0179] As a reaction reagent, the reaction reagent used in a known oxidation reaction can be used. For example, it can be a known oxidant, and examples thereof 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, sulfur trioxide-pyridine complex / dimethyl sulfoxide, etc. Among them, sulfur trioxide-pyridine complex / dimethyl sulfoxide with mild reaction conditions is preferred. The amount of the reaction reagent is preferably 1.0 equivalent to 20 equivalents.

[0180] R in formula (VI) 1 ~R 4 and R 6 ~R 7 The substituents can be appropriately set with reference to each of the above substituents independently, and can be selected according to the structure of the compound represented by the desired formula (I).

[0181] Next, the obtained 4-formyl compound is reacted according to a known method to prepare a 4-dibromovinyl compound.

[0182] Next, R is introduced into the 4-dibromovinyl compound. 5 , thereby preparing 5 Alternatively, a 4-ethynyl compound is prepared from a 4-dibromovinyl compound, and then R 5 , thereby preparing 5 4-ethynyl compounds.

[0183] Then, concentrated sulfuric acid is added to the acetic acid-acetic anhydride solution of the obtained 4-ethynyl compound to synthesize a compound represented by the following formula (VII), and a nucleic acid base moiety is introduced at position 1 of the compound, thereby preparing a 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 is preferably 0.01 equivalent to 1.0 equivalent. By adopting this reaction condition, a two-stage reaction can be performed in one stage, which can improve the efficiency of the synthesis.

[0184] [Chemical formula 21]

[0185]

[0186] Where:

[0187] R 1 and R 2 Each independently represents 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 branch or a ring, an alkenyl group having 2 to 7 carbon atoms which may form a branch or a ring, an aryl group having 3 to 10 carbon atoms which may have one or more substituents selected from the α group and may contain a heteroatom, an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may have one or more substituents selected from the α group and may contain a heteroatom, an acyl group which may have one or more substituents selected from the α group, a silyl group which may have one or more substituents selected from the α group, a phosphoryl group which may have one or more substituents selected from the α group, a phosphoryl group protected by a protecting group in nucleic acid synthesis, -P(R 3 )R 4 , in which R 3 and R 4 each independently represents a hydroxyl group, a hydroxyl group protected by a protecting group for nucleic acid synthesis, a thiol group, a thiol group protected by 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 by an alkyl group having 1 to 6 carbon atoms,

[0188] The α group is composed of hydroxyl, hydroxyl protected by a protecting group for nucleic acid synthesis, alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, thiol, thiol protected by a protecting group for nucleic acid synthesis, alkylthio having 1 to 5 carbon atoms, amino, amino protected by a protecting group for nucleic acid synthesis, amino substituted by an alkyl having 1 to 5 carbon atoms, and halogen atoms.

[0189] R 5represents a hydrogen atom; a halogen atom; an alkyl group having 1 to 7 carbon atoms which may be substituted by an aryl group having 3 to 12 carbon atoms which may contain a heteroatom and may form a branch or a ring; an aralkyl group having an aryl group having 3 to 12 carbon atoms which may contain a heteroatom; or a silyl group,

[0190] R 6 and R 7 Each independently represents a protecting group for a hydroxyl group for nucleic acid synthesis, an alkyl group having 1 to 7 carbon atoms which may form a branch or a ring, an alkenyl group having 2 to 7 carbon atoms which may form a branch or a ring, an aryl group having 3 to 10 carbon atoms which may have one or more arbitrary substituents selected from the α group and may contain a heteroatom, an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may have one or more arbitrary substituents selected from the α group and may contain a heteroatom, an acyl group which may have one or more arbitrary substituents selected from the α group, a silyl group which may have one or more arbitrary substituents selected from the α group, a phosphoryl group which may have one or more arbitrary substituents selected from the α group, or a phosphoryl group protected by a protecting group for nucleic acid synthesis.

[0191] R in formula (VII) 1 ~R 7 The substituents can be appropriately set with reference to each of the above substituents independently, and can be selected according to the structure of the compound represented by the desired formula (I).

[0192] The compound represented by formula (V) has the above R 1 ~R 4 and R 6 ~R 7 , a commercially available product may be used, or a compound prepared by a known method may be used.

[0193] The obtained compound represented by formula (I) can be purified as appropriate according to a known technique.

[0194] In this way, through step A, a compound represented by the following formula (II) can be produced from a compound represented by formula (I).

[0195] [Chemical formula 22]

[0196]

[0197] Where:

[0198] X represents a nucleic acid base portion which may have one or more substituents selected from the group α,

[0199] R 1 and R 2Each independently represents a hydrogen atom, a protecting group for a hydroxyl group for nucleic acid synthesis, an alkyl group having 1 to 7 carbon atoms which may form a branch or a ring, an alkenyl group having 2 to 7 carbon atoms which may form a branch or a ring, an aryl group having 3 to 10 carbon atoms which may have one or more substituents selected from the aforementioned α group and may contain a heteroatom, an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may have one or more substituents selected from the aforementioned α group and may contain a heteroatom, an acyl group which may have one or more substituents selected from the aforementioned α group, a silyl group which may have one or more substituents selected from the aforementioned α group, a phosphoryl group which may have one or more substituents selected from the aforementioned α group, a phosphoryl group protected by a protecting group for nucleic acid synthesis, -P(R 3 )R 4 , in which R 3 and R 4 each independently represents a hydroxyl group, a hydroxyl group protected by a protecting group for nucleic acid synthesis, a thiol group, a thiol group protected by 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 by an alkyl group having 1 to 6 carbon atoms,

[0200] 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 may form a branch or a ring; an aralkyl group having an aryl group having 3 to 12 carbon atoms which may contain a heteroatom; or a silyl group.

[0201] In addition, the substituent in the formula (II) can be appropriately set according to the compound represented by the formula (I) used.

[0202] Next, the method for preparing the compound represented by the following formula (III) from the compound represented by the formula (II) is described. Specifically, the compound represented by the formula (III) can be prepared by cyclopropanating the compound represented by the formula (II). Therefore, as one embodiment of the present invention, a method including a step of cyclopropanating the compound represented by the formula (II) can be listed. Later, this step is sometimes recorded as step B.

[0203] [Chemical formula 23]

[0204]

[0205] Where:

[0206] X represents a nucleic acid base portion which may have one or more substituents selected from the group α,

[0207] R 1 and R 2Each independently represents a hydrogen atom, a protecting group for a hydroxyl group for nucleic acid synthesis, an alkyl group having 1 to 7 carbon atoms which may form a branch or a ring, an alkenyl group having 2 to 7 carbon atoms which may form a branch or a ring, an aryl group having 3 to 10 carbon atoms which may have one or more substituents selected from the aforementioned α group and may contain a heteroatom, an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may have one or more substituents selected from the aforementioned α group and may contain a heteroatom, an acyl group which may have one or more substituents selected from the aforementioned α group, a silyl group which may have one or more substituents selected from the aforementioned α group, a phosphoryl group which may have one or more substituents selected from the aforementioned α group, a phosphoryl group protected by a protecting group for nucleic acid synthesis, -P(R 3 )R 4 , in which R 3 and R 4 each independently represents a hydroxyl group, a hydroxyl group protected by a protecting group for nucleic acid synthesis, a thiol group, a thiol group protected by 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 by an alkyl group having 1 to 6 carbon atoms,

[0208] R 5 and R 5’ represents a hydrogen atom; an alkyl group having 1 to 7 carbon atoms which may be substituted by an aryl group having 3 to 12 carbon atoms which may contain a heteroatom and may form a branch or a ring; or an aralkyl group having an aryl group having 3 to 12 carbon atoms which may contain a heteroatom.

[0209] As a method for cyclopropanation, for example, the Simmons-Smith reaction can be used. The reaction can be carried out in the presence of a zinc carbene, and there are also methods of using diethyl zinc instead of zinc, and methods of using CH2N2-ZnI2-based reagents. For example, the amount of the zinc carbene that makes the reaction proceed is preferably 1.0 equivalent to 20 equivalents.

[0210] The cyclopropanation reaction of step B can be carried out in the presence of an organic acid because the reaction progress varies depending on the type of zinc carbene. The presence of an organic acid can suppress the generation of precipitation or suppress side reactions. As the organic acid, there is no restriction as long as it is a known organic acid, and formic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, diphenylphosphoric acid, p-toluenesulfonic acid, phenol, etc. can be preferably used. The amount of the organic acid is preferably 0.5 equivalents to 2.0 equivalents relative to the zinc carbene used.

[0211] The reaction in the presence of an organic acid can be applied to any compound represented by formula (II) without particular limitation, but preferably the compound wherein X in formula (II) has a purine skeleton and its tautomer.

[0212] The compound represented by formula (II) used in the reaction may be a commercially available product or a compound prepared by a known method. Alternatively, a compound prepared by the above-mentioned step A may be used.

[0213] As the compound represented by formula (II), for example, X is a group having a uracil skeleton which may have a substituent (preferably a hydroxyl group, an amino group, a hydroxyl group and an amino group protected by a protective group), or a group having a cytosine skeleton which may have a substituent (preferably a hydroxyl group, an amino group, a hydroxyl group and an amino group protected by a protective group), and their tautomers. The specific structure is as follows.

[0214] [Chemical formula 24]

[0215]

[0216] Similarly, examples of the compound represented by formula (II) include compounds wherein X is a group having a purine skeleton having a substituent (preferably a hydroxyl group, an amino group, a hydroxyl group and an amino group protected by a protecting group) and tautomers thereof.

[0217] [Chemical formula 25]

[0218]

[0219] In the present invention, as the compound represented by formula (II), a compound in which X is 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl, R 1 is naphthyl, R 2 is benzyl, R 5 is a hydrogen atom, and X is 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl, R 1 is naphthyl, R 2 and R 5 A compound containing hydrogen atoms.

[0220] In addition, from the perspective of improving the yield, the compound represented by formula (II) provided for cyclopropanation may be a compound formed by protecting part or all of it with a known protecting group when there is an active reactive group in, for example, the group X. For example, when X has a compound having a purine skeleton into which a protecting group is introduced, side reactions with X as a reaction point can be suppressed, thereby improving the yield.

[0221] The purification of the compound obtained in step B can be appropriately carried out according to known techniques. For example, from the perspective of facilitating post-treatment of the reaction, a step of post-treating the reaction solution with ammonia may be included. By treating with ammonia, it becomes easy to remove the residue of the reagent, and it can be used appropriately.

[0222] The above post-treatment method can be applied to all compounds represented by formula (III), but compounds wherein X in formula (III) has a pyrimidine skeleton are preferred. In this case, the interface between the organic layer and the aqueous layer becomes clear, and separation can be performed efficiently.

[0223] In this way, the compound represented by formula (III) can be produced from the compound represented by formula (II).

[0224] As one embodiment of the present invention, if the compound represented by formula (II) is prepared according to step A, then as a method for preparing the compound represented by formula (III) of the present invention, a method including at least step A and step B can be listed. In addition, a method further including the following step is included, that is, the step of preparing the compound represented by formula (I) in step A by the method. The compound represented by formula (III) can be a compound having a group protected by a protective group for nucleic acid synthesis (hydroxyl, thiol, amino, etc.) as X, and can be a compound having a group formed by deprotecting a part or all of the groups protected by the protective group for nucleic acid synthesis as X. As a method for deprotecting the group protected by the protective group for nucleic acid synthesis (hydroxyl, thiol, amino, etc.), deprotection can be carried out by a known method [for example, treatment with a weak acid (such as carboxylic acid, silica gel, etc.)].

[0225] In addition, in the present invention, when preparing various compounds represented by formula (III), for example, the compounds represented by formula (VII) can be prepared in the same manner and the desired nucleic acid base moieties can be introduced into each of them, thereby enabling efficient preparation.

[0226] The compound represented by formula (III) obtained by the present invention can be phosphoramidated by a known method. The obtained phosphoramidite derivative is expected to be used as a raw material for synthesizing nucleic acid drugs (antisense nucleic acid drugs) for treating diseases by inhibiting the action of specific genes.

[0227] Example

[0228] Hereinafter, the present invention will be described in detail using examples, but the present invention is not limited thereto. In the following examples, room temperature refers to 15 to 35°C.

[0229] Example 1: Synthesis of common intermediate compounds

[0230] [Chemical formula 26]

[0231]

[0232] (1) Synthesis of Compound 2

[0233] [Chemical formula 27]

[0234]

[0235] 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, and after cooling to an internal temperature of 7°C, sulfur trioxide-pyridine complex (15.9 g, 0.100 mol, 2.0 eq) was added in small amounts, and stirred at room temperature for 21.5 hours. To the reaction solution, commercial water (300 mL) was added, and extraction and separation were performed with a mixed solvent of ethyl acetate (200 mL) and hexane (100 mL) to obtain an organic layer I and an aqueous layer I. The organic layer I was washed with a mixed solution of commercial water (200 mL) and a saturated aqueous ammonium chloride solution (100 mL) to obtain an organic layer II and an aqueous layer II. The organic layer II is further washed with a mixed solution of city water (100mL) and saturated ammonium chloride aqueous solution (100mL) to obtain an organic layer III and an aqueous layer III. The aqueous layers II and III are combined, extracted with ethyl acetate (100mL), and washed with city water (100mL) to obtain an organic layer IV. The organic layers III and IV are combined, washed with saturated brine (100mL), and dried with anhydrous sodium sulfate, and the solvent is removed by reduced pressure distillation to obtain a crude product of compound 2 (20.24g) as a light orange oily liquid. The obtained compound 2 is not purified, the yield is quantitative, and enters the next step.

[0236] 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=12.0Hz, 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)

[0237] (2) Synthesis of Compound 3

[0238] [Chemical formula 28]

[0239]

[0240] The crude product of compound 2 (20.24 g) obtained in the previous step was azeotroped with toluene and then dissolved in anhydrous dichloromethane (250 mL), and carbon tetrabromide (33.1 g, 100 mmol, 2.0 eq) was added. Then, triphenylphosphine (52.4 g, 200 mmol, 4.0 eq) was added at an internal temperature of 20°C or less, and stirred at room temperature for 1.5 hours. Then, triethylamine (41.5 mL, 300 mmol, 6.0 eq) was added at an internal temperature of 25°C or less, and stirred for further 2 hours. Hexane (200 mL) was added to the reaction solution and ice-bathed, and the insoluble matter was filtered out and washed with ethyl acetate and dichloromethane (50 mL). The washing liquid and the filtrate were combined and removed by vacuum distillation. The residue obtained was introduced into a silica gel column (pad of silica gel) (silica gel: 100g) using a mixed solution (300mL) of dichloromethane / hexane = 1 / 1 (v / v), and eluted with hexane / ethyl acetate = 1 / 2 (v / v) (300mL), followed by ethyl acetate (400mL). The eluent was concentrated under reduced pressure, and the residue obtained was suspended and washed with hexane / ethyl acetate = 1 / 1 (v / v) (200mL), and the insoluble matter was filtered out. The mother liquor was concentrated under reduced pressure, and the residue obtained was suspended and washed with hexane / ethyl acetate = 2 / 1 (v / v) (100mL), and the insoluble matter was filtered out. The mother liquor was concentrated under reduced pressure to obtain a mixture (28.1g) of compound 3 and triphenylphosphine oxide as a brown viscous liquid. The obtained compound 3 was not further purified, the yield was quantitative, and it entered the next step.

[0241] 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=12.0Hz, 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)

[0242] (3) Synthesis of Compound 4

[0243] [Chemical formula 29]

[0244]

[0245] Under nitrogen atmosphere, the mixture of compound 3 obtained in the previous step and triphenylphosphine oxide (28.1 g) was azeotroped with anhydrous tetrahydrofuran and then dissolved in anhydrous tetrahydrofuran. At an internal temperature below -50°C, n-butyl lithium (1.6 M hexane solution, 71 mL, 110 mmol, 2.2 eq) was added dropwise over 30 minutes, and stirred at -70°C for 1 hour. Water (100 mL) was added at the same temperature, and ethyl acetate (400 mL), city water (100 mL), and saturated brine (100 mL) were added to extract to obtain an organic layer I and an aqueous layer I. The obtained aqueous layer I was extracted with ethyl acetate (100 mL) to obtain an organic layer II. The organic layers I and II were combined, washed with a saturated aqueous ammonium chloride solution (200 mL) and a saturated brine (100 mL) in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product of compound 4 (21.2 g) as a brown liquid. The obtained compound 4 was not purified, the yield was quantitative, and it entered the next step.

[0246] 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)

[0247] (4) Synthesis of Compound 5

[0248] [Chemical formula 30]

[0249]

[0250] To the acetic anhydride (94.5 mL, 1.00 mol) solution of the crude product (21.0 g) of compound 4 obtained in the previous step, a solution of concentrated sulfuric acid (255 mg, 2.60 mmol, 0.05 eq) in acetic acid (60 mL, 1.0 mol) was added, and stirred at room temperature for 7 hours. Acetic acid (57.2 mL, 1.00 mol) was added to the reaction solution, and further stirred for 15 hours. Under an ice bath, the reaction solution was injected into a mixed solution of ethyl acetate (200 mL) and saturated sodium bicarbonate water (300 mL), and the aqueous layer was extracted twice with ethyl acetate (100 mL), and the combined organic layer was washed with saturated sodium bicarbonate water (100 mL), city water (100 mL), and saturated brine (100 mL) in sequence. 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.

[0251] 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)

[0252] Example 2: Synthesis of T-dibenzyl

[0253] [Chemical formula 31]

[0254]

[0255] (1) Synthesis of Compound 6

[0256] [Chemical formula 32]

[0257]

[0258] Under 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), trimethylsilyl trifluoromethanesulfonate (2.71 mL, 15.0 mmol, 1.5 eq) were added to anhydrous acetonitrile solution (50 mL) of compound 5 (4.38 g, 10.0 mmol) in sequence, and heated under reflux for 5 hours. The reaction solution cooled to room temperature was added to saturated sodium bicarbonate water (300 mL), and extracted twice with ethyl acetate (300 mL, 200 mL). After drying with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (silica gel: 80 g, hexane / ethyl acetate = 2 / 1~1 / 2 (v / v)) to obtain compound 6 (4.02 g, 7.97 mmol, 79.7%) as a light yellow amorphous solid.

[0259] 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)

[0260] (2) Synthesis of Compound 7

[0261] [Chemical formula 33]

[0262]

[0263] Potassium carbonate (821 mg, 5.94 mmol, 3.0 eq) was added to a methanol solution (10 mL) of compound 6 (1.0 g, 2.0 mmol), and stirred at room temperature for 20 minutes. City water (10 mL), ethyl acetate (10 mL) were added, and ethyl acetate (60 mL) was further added for extraction. The obtained organic layer was washed with a mixture of city water (30 mL) and saturated brine (a small amount), followed by saturated brine (10 mL), and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain compound 7 (0.83 g, 1.8 mmol, 91%) as a white solid.

[0264] 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=5.9Hz, 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)

[0265] (3) Synthesis of Compound 8

[0266] [Chemical formula 34]

[0267]

[0268] Under nitrogen atmosphere, potassium tert-butoxide (303mg, 2.70mmol, 2.5eq) was added to anhydrous dimethyl sulfoxide solution (10mL) of compound 7 (500mg, 1.08mmol), and stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride solution (100mL) was added, and extracted with ethyl acetate (100mL). The obtained organic layer was washed twice with city water (50mL), then washed once with saturated brine (50mL), and dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product (435mg) of compound 8 as a light yellow amorphous solid. The crude product of compound 8 obtained is not purified and enters the next step.

[0269] 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)

[0270] (4) Synthesis of Compound 9

[0271] [Chemical formula 35]

[0272]

[0273] Under nitrogen atmosphere, in an ice bath, to a solution of compound 8 (2.67 g, 5.77 mmol) in anhydrous dichloromethane (50 mL), a solution of diiodomethane (7.73 g, 28.9 mmol, 5.0 eq) in anhydrous dichloromethane (15 mL) was added dropwise, and washed with anhydrous dichloromethane (5 mL), and then diethylzinc (1.0 M hexane solution, 28.9 mL, 28.9 mmol, 5.0 eq) was added dropwise over 15 minutes, and stirred at the same temperature for 2 hours, and then stirred at room temperature for 20 hours. 25 w / w% ammonia water (20 mL) and water (50 mL) were added dropwise over 5 minutes at 10°C or less, and extracted twice with ethyl acetate (150 mL). The obtained organic layer was washed with city water and then with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained 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.

[0274] 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, , 1.03-0.96 (m, 1H), 0.96-0.89(m, 1H), 0.75-0.65 (m, 2H)

[0275] Compound 9 can be synthesized by using the method described in WO2015 / 125783 as a conventional synthesis method through 11 steps of transformation from compound 1. However, by using the methods of Examples 1 and 2, the transformation from compound 1 to compound 9 can be performed through 8 steps, which can reduce the number of steps.

[0276] Example 3: Synthesis of G-dibenzyl (Part 1)

[0277] [Chemical formula 36]

[0278]

[0279] (1) Synthesis of Compound 10

[0280] [Chemical formula 37]

[0281]

[0282] Under nitrogen atmosphere, in an ice bath, N,O-bis(trimethylsilyl)acetamide (1.5 mL, 8.3 mmol, 2.0 eq) and trimethylsilyl trifluoromethanesulfonate (1.8 mL, 13 mmol, 3.0 eq) were added to a 1,2-dichloroethane (20 mL) solution of compound 5 (1.86 g, 4.24 mmol) and ON,N-diphenylcarbamoyl-N-isobutyrylguanine (1.94 g, 4.66 mmol, 1.1 eq) in sequence, and heated to reflux for 2.5 hours. The reaction solution cooled to room temperature was placed in an ice bath, saturated sodium bicarbonate water (50 mL) was added, and chloroform was extracted twice (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 obtained 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 light yellow amorphous solid.

[0283] 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=5.9Hz, 1H), 4.78 (d, J=11.7 Hz, 1H), 4.67 (d, J=11.7 Hz, 1H), 4.52 (d, J=12.1Hz, 1H), 4.47 (d, J=12.1 Hz, 1H), 3.81 (d, J=10.9 Hz, 1H), 3.68 (d, J=10.9Hz, 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)

[0284] (2) Synthesis of Compound 12

[0285] [Chemical formula 38]

[0286]

[0287] Under 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 minutes. Methanol (8.0 μL, 0.20 mmol, 1.6 eq) was added, and further stirred for 3 hours. 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 further stirred for 16 hours. Ethyl acetate (10 mL) and city water (10 mL) were added, and extracted twice with ethyl acetate. The combined organic layers were washed twice with 1M aqueous hydrochloric acid solution (20 mL), then washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a mixture of compound 12 and diphenylamine as a light brown amorphous solid (76.2 mg, purity 72% according to the integral ratio of 1H-NMR, yield 78%).

[0288] 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=11.4Hz, 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)

[0289] (3) Synthesis of Compound 13

[0290] [Chemical formula 39]

[0291]

[0292] Under nitrogen atmosphere, N, N-diisopropylethylamine (0.10mL, 0.59mmol, 3.0eq) and N, N-diphenylcarbamoyl chloride (56mg, 0.24mmol, 1.2eq) were added to a solution of anhydrous pyridine (0.8mL) of compound 12 (110mg, 0.197mmol) in sequence, and stirred at room temperature for 6 hours. City water (0.1mL) was added, and the solvent was removed by distillation under reduced pressure, and then azeotroped with toluene twice. The residue was dissolved in ethyl acetate, and washed with 1M aqueous hydrochloric acid solution, saturated sodium bicarbonate water, and saturated brine in sequence, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was azeotroped with toluene twice to obtain a crude product (178mg) of compound 13 as a red amorphous solid. The obtained compound 13 was not purified and entered the next step.

[0293] 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)

[0294] (4) Synthesis of Compound 14

[0295] [Chemical formula 40]

[0296]

[0297] Under nitrogen atmosphere, diethylzinc (1M hexane solution, 2.0 mL, 2.0 mmol, 10 eq) was added to anhydrous dichloromethane (3 mL) after ice bath, and then a solution of trifluoroacetic acid (230 mg, 2.02 mmol, 10 eq) in anhydrous dichloromethane (1 mL) was added dropwise over 5 minutes, and stirred at the same temperature for 30 minutes. Then, a solution of diiodomethane (542 mg, 2.02 mmol, 10 eq) in anhydrous dichloromethane (1 mL) was added dropwise over 5 minutes, and further stirred at the same temperature for 30 minutes. A solution of the crude product of compound 13 (178 mg) in anhydrous dichloromethane (0.5 mL, further washed with 0.5 mL) was added dropwise to the solution, and stirred at the same temperature for 3 hours. A 0.5 M aqueous hydrochloric acid solution (10 mL) and chloroform (15 mL) were added, and stirred vigorously at room temperature for 1 hour. The obtained solution was separated into an aqueous layer and an organic layer, and the aqueous layer was further extracted with chloroform, combined with the previous organic layer and washed with saturated brine, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (silica gel: 14 g, hexane / ethyl acetate / methanol = 90 / 5 / 5~75 / 20 / 5 (v / v / v)) to obtain compound 14 (86.4 mg, 0.113 mmol, 57.2%) as a reddish brown viscous liquid.

[0298] 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)

[0299] (5) Synthesis of the compound represented by formula (a)

[0300] [Chemical formula 41]

[0301]

[0302] It was confirmed that compound 14 can be easily converted into the compound represented by formula (a) by treating it with a weak acid (carboxylic acid or the like).

[0303] As with compound 14, the compound represented by the following formula (a) which can be used as a precursor of scpBNA can be synthesized by transforming compound 1 through 12 steps using the method described in WO2015 / 125783 as a conventional synthesis method. However, by using the methods of Examples 1 and 3, the transformation of compound 1 to the compound represented by formula (a) can be performed through 9 steps, which can reduce the number of steps.

[0304] [Chemical formula 42]

[0305]

[0306] Example 4: Synthesis of G-dibenzyl (Part 2)

[0307] [Chemical formula 43]

[0308]

[0309] (1) Synthesis of Compound 15

[0310] [Chemical formula 44]

[0311]

[0312] Under nitrogen atmosphere, in an ice bath, to a solution of compound 5 (4.0 g, purity 80%, 7.3 mmol) in 1,2-dichloroethane (100 mL), 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), trimethylsilyl trifluoromethanesulfonate (2.64 mL, 14.6 mmol, 2.0 eq) were added in sequence, and 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 stirred at the same temperature for further 1 hour, heated to reflux for 2 hours, cooled to room temperature and stirred for further 3 hours. Saturated sodium bicarbonate water (50 mL) was added in an ice bath, and extracted 3 times with chloroform. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained 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 as a light brown amorphous solid (3.00 g, according to 1H-NMR, compound 15: compound 16 = 85:15, 4.25 mmol, yield 58%).

[0313] 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 = 5.0Hz, 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, 6.9Hz, 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)

[0314] (2) Synthesis of Compound 17

[0315] [Chemical Formula 45]

[0316]

[0317] Under an ice bath, potassium carbonate (2.07g, 15.0mmol, 3.0eq) was added to a methanol (30mL) solution of a mixture of compound 15 and compound 16 (3.0g, 5.0mmol, compound 15: compound 16 = 85: 15), and stirred at the same temperature for 30 minutes. Potassium carbonate (0.50g, 3.6mmol, 0.72eq) was added and further stirred for 15 minutes. After adding a saturated aqueous ammonium chloride solution, it was extracted with ethyl acetate, and the organic layer was washed with city water and saturated brine in sequence, and dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the obtained residue was purified by silica gel column chromatography (silica gel: 30g, chloroform / ethyl acetate = 1 / 0~4 / 1 (v / v)) to obtain a mixture of compound 17 and compound 17' as a white amorphous solid (2.41g, compound 17: compound 17' = 85: 15, 4.32mmol, yield 86%).

[0318] 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)

[0319] (3) Synthesis of Compound 18

[0320] [Chemical Formula 46]

[0321]

[0322] Under 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, and then potassium tert-butoxide (273 mg, 2.43 mmol, 1.4 eq) was added and stirred for further 3 hours. Ethyl acetate (150 mL) and city water (50 mL) were added under ice bath, and extracted twice with ethyl acetate. The combined organic layer was washed twice with commercial water and then with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product of a mixture of Compound 18 and Compound 18' as a pale brown amorphous solid (904 mg, Compound 18:Compound 18'=85:15).

[0323] 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=6.9Hz, 0.45H), 1.27 (d, J=6.9 Hz, 2.55H), 1.25 (d, J = 6.9 Hz, 0.45H)

[0324] (4) Synthesis of Compound 19

[0325] The same conditions as in step (3) of Example 3 were used for the reaction.

[0326] (5) Synthesis of Compound 20

[0327] The same conditions as step (4) of Example 3 were used for the reaction.

[0328] It was found that, similarly to Example 3, regardless of the presence or absence of a protecting group, scpBNA into which a compound having a guanine skeleton was introduced could be obtained.

[0329] Example 5: Synthesis of A-dibenzyl (Part 1)

[0330] [Chemical formula 47]

[0331]

[0332] (1) Synthesis of Compound 21

[0333] [Chemical formula 48]

[0334]

[0335] Under nitrogen atmosphere, N6-benzoyl adenine (1.60 g, 6.69 mmol, 1.1 eq) was added to an acetonitrile solution (80 mL) of compound 5 (3.32 g, purity 80%, 6.08 mmol), and then N,O-bis(trimethylsilyl)acetamide (2.61 mL, 18.2 mmol, 3.0 eq) and trimethylsilyl trifluoromethanesulfonate (1.65 mL, 9.12 mmol, 1.5 eq) were added in sequence under ice bath, and stirred at room temperature for 18 hours. After heating under reflux for 5.5 hours, the mixture was cooled, stirred at room temperature for 18 hours, heated under reflux for 6 hours, cooled to room temperature again, and stirred at room temperature for 20 hours. Under ice bath, saturated sodium bicarbonate water was added, and the mixture was extracted with ethyl acetate, and then the organic layer was washed with city water and saturated brine in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained 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 light brown amorphous solid.

[0336] 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)

[0337] (2) Synthesis of Compound 22

[0338] [Chemical formula 49]

[0339]

[0340] Under ice bath, 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), and stirred at the same temperature for 30 minutes. After adding saturated aqueous ammonium chloride solution and extracting with ethyl acetate twice, the combined organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain a crude product (1.50 g) of compound 22 as a light orange amorphous solid. The obtained compound 22 was not purified and directly entered the next reaction.

[0341] 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)

[0342] (3) Synthesis of Compound 23

[0343] [Chemical formula 50]

[0344]

[0345] Under nitrogen atmosphere, potassium tert-butoxide (545mg, 4.85mmol, 2.0eq) was added to the crude product (1.50g) of compound 22 obtained in the previous process in anhydrous dimethyl sulfoxide solution (30mL), and stirred at room temperature for 2.5 hours. Saturated aqueous ammonium chloride solution and ethyl acetate were added, and after extraction with ethyl acetate twice, the combined organic layer was washed successively with city water and saturated brine, dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The obtained residue was purified with silica gel column (NH2 silica gel, hexane / ethyl acetate / methanol=8 / 8 / 1), and compound 23 (1.18g, 2.05mmol, 2 process yield 84.4%) as a brown viscous liquid was obtained.

[0346] 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)

[0347] (4) Synthesis of Compound 24

[0348] [Chemical formula 51]

[0349]

[0350] Under nitrogen atmosphere, diethylzinc (1M hexane solution, 2.4 mL, 2.4 mmol, 10 eq) was added to anhydrous dichloromethane (2.8 mL) after ice bath, and then a solution of trifluoroacetic acid (274 mg, 2.40 mmol, 10 eq) in anhydrous dichloromethane (1 mL) was added dropwise over 5 minutes, and stirred at the same temperature for 30 minutes, and then a solution of diiodomethane (643 mg, 2.40 mmol, 10 eq) in anhydrous dichloromethane (1 mL) was added dropwise over 5 minutes, and further stirred at the same temperature for 30 minutes to prepare a zinc carbene solution. Under nitrogen atmosphere, a zinc carbene solution (720 μL) was added dropwise to a solution of compound 23 (138 mg, 0.240 mmol) in anhydrous dichloromethane (2.0 mL) after ice bath. After stirring at the same temperature for 1.5 hours, zinc carbene solution (720 μL) was added dropwise, and zinc carbene solution (720 μL) was added dropwise after stirring for 1 hour. Zinc carbene solution (1.5 mL each) was further added dropwise after 30 minutes and 75 minutes, and stirred for 1.5 hours. Saturated aqueous ammonium chloride solution and chloroform were added, and after vigorous stirring at room temperature for 30 minutes, the obtained solution was separated into an aqueous layer and an organic layer, and the aqueous layer was further extracted with chloroform. The combined organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain a residue. The ratio of the obtained residue, compound 24 and compound 25 was 3:1 (calculated by LC / MS and 1H-NMR).

[0351] Example 6: Synthesis of A-dibenzyl (Part 2)

[0352] [Chemical formula 52]

[0353]

[0354] (1) Synthesis of Compound 26

[0355] [Chemical formula 53]

[0356]

[0357] Under nitrogen atmosphere, trimethylsilyl chloride (11 mL, 87.1 mmol, 29 eq) was added to a solution of adenine (1.01 g, 7.47 mmol, 2.5 eq) in bis(trimethylsilyl)amine (25 mL), and the mixture was heated to reflux for 5 hours. The mixture was cooled and concentrated under reduced pressure, and the obtained residue was dissolved in 1,2-dichloroethane (5 mL) under nitrogen atmosphere, and a solution of compound 5 (1.32 g, 3.00 mmol) in dichloroethane (10 mL) was added, followed by trimethylsilyl trifluoromethanesulfonate (2.70 mL, 14.9 mmol, 5.0 eq), and the mixture was stirred at room temperature for 17.5 hours. Saturated sodium bicarbonate water (200 mL) was added, and the mixture was extracted twice with ethyl acetate (200 mL), and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained 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.

[0358] 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)

[0359] (2) Synthesis of Compound 27

[0360] [Chemical formula 54]

[0361]

[0362] Potassium tert-butoxide (432mg, 3.85mmol, 5.0eq) was added to a tert-butyl alcohol solution (4mL) of compound 26 (395mg, 0.769mmol), and stirred at room temperature for 1.5 hours. After adding potassium tert-butoxide (480mg, 4.28mmol, 5.6eq) and stirring for 1 hour, potassium tert-butoxide (300mg, 2.67mmol, 3.5eq) was added and further stirred for 1 hour. City water (6mL) and saturated brine (12mL) were added, and after being extracted with ethyl acetate twice, the combined organic layer was washed with saturated brine, dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain a crude product (315mg) of compound 27 as an orange amorphous solid. The crude product of compound 27 obtained was not purified and entered the next step.

[0363] 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)

[0364] (3) Synthesis of Compound 28

[0365] [Chemical formula 55]

[0366]

[0367] Under nitrogen atmosphere, to the N, N- dimethylformamide solution (2mL) of compound 27 (100mg, 0.212mmol), sodium iodide (318mg, 2.12mmol, 10eq) was added, and then benzyl chloromethyl ether (300μL, 2.16mmol, 10eq) was added under ice bath, and stirred at room temperature for 3 hours. Saturated sodium bicarbonate water (6mL) and city water (12mL) were added, and after being extracted twice with ethyl acetate, the combined organic layer was washed with 15w / w% sodium thiosulfate aqueous solution and saturated brine in sequence, and dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain a crude product (390mg) of compound 28 as an orange oily liquid. The crude product of compound 28 obtained was not purified and entered the next step.

[0368] (4) Synthesis of Compound 29

[0369] [Chemical formula 56]

[0370]

[0371] Under nitrogen atmosphere, benzoyl chloride (120 μL, 1.03mmol, 4.9eq) was added to the pyridine solution (3mL) of the crude product (390mg) of compound 28 obtained in the previous process, and stirred at room temperature for 5 hours. City water (20mL) was added, and after being extracted twice with ethyl acetate, the combined organic layer was washed with 1M aqueous hydrochloric acid solution, city water, and saturated brine in sequence, dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH2 silica gel: 20g, hexane / ethyl acetate / methanol = 85 / 10 / 5 ~ 70 / 25 / 5 (v / v / v)) to obtain compound 29 (60.5mg, 0.0870mol, yield 41.0%) as a light yellow oily liquid.

[0372] 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)

[0373] (5) Synthesis of Compound 29

[0374] [Chemical formula 57]

[0375]

[0376] Under 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), and then benzyl chloromethyl ether (250 μL, 1.80 mmol, 2.5 eq) was added under ice bath, 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 further 1.5 hours. Triethylamine (2.0 mL, 14.4 mmol, 20 eq) and benzoyl chloride (400 μL, 3.44 mmol, 4.7 eq) were added at the same temperature, and stirred for 2 hours. After adding ethyl acetate (30mL) and city water (10mL) and stirring, the organic layer was separated from the aqueous layer, and the organic layer was washed with 15w / w% sodium thiosulfate aqueous solution, city water, and saturated brine in sequence, dried with anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH2 silica gel: 30g, hexane / ethyl acetate / methanol=90 / 5 / 5~85 / 10 / 5 (v / v / v)) to obtain compound 29 (462.6mg, purity 70%, 0.465mmol, yield 63.6%) as a light yellow oily liquid.

[0377] (6) Synthesis of Compound 30

[0378] [Chemical formula 58]

[0379]

[0380] Under nitrogen atmosphere, diethylzinc (1M hexane solution, 0.25 mL, 0.25 mmol, 7.0 eq) was added to anhydrous dichloromethane (0.25 mL) after ice bath, and then 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 minute, and the mixture was stirred at the same temperature for 30 minutes. Then, a solution of diiodomethane (67.4 mg, 0.259 mmol, 7.0 eq) in anhydrous dichloromethane (0.25 mL) was added dropwise over 1 minute, and the mixture was further stirred at the same temperature for 30 minutes to prepare a zinc carbene solution. A solution of compound 29 (25.0 mg, 0.0359 mmol) in anhydrous dichloromethane (0.5 mL, further washed with 0.5 mL) was added dropwise to the solution, and the mixture was stirred at the same temperature for 4.5 hours. Saturated aqueous ammonium chloride solution (20 mL) and chloroform (20 mL) were added, and after vigorous stirring at room temperature for 30 minutes, the obtained solution was separated into an aqueous layer and an organic layer, and the aqueous layer was further extracted with chloroform. The combined organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The obtained 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, yield 78.5%) as a light yellow oily liquid.

[0381] 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)

[0382] (7) Synthesis of the compound represented by formula (b)

[0383] [Chemical formula 59]

[0384]

[0385] It was confirmed that compound 30 can be easily converted into the compound represented by formula (b) by treating it with a weak acid (carboxylic acid, silica gel, etc.).

[0386] As with compound 30, the compound represented by the following formula (b) which can be used as a precursor of scpBNA can be synthesized by transforming compound 1 through 12 steps using the method described in WO2015 / 125783 as a conventional synthesis method. However, by using the methods of Examples 1 and 6, the transformation of compound 1 to the compound represented by formula (b) can be performed through 9 steps, which can reduce the number of steps.

[0387] [Chemical formula 60]

[0388]

[0389] Industrial Applicability

[0390] According to the present invention, nucleosides of spirocyclopropene-bridged nucleic acids (scpBNA) can be efficiently prepared, and thus can be suitably used in the field of nucleic acid drugs, for example.

Claims

1. A method for preparing a compound represented by formula (III), the method comprising the step of cyclopropanating the compound represented by formula (II), wherein the cyclopropanation step comprises the step of post-treating the reaction solution with ammonia, In formula (II), X represents a nucleic acid base portion optionally having one or more substituents selected from Group α, wherein The α group is composed of hydroxyl, hydroxyl protected by a protecting group for nucleic acid synthesis, alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, thiol, thiol protected by a protecting group for nucleic acid synthesis, alkylthio having 1 to 5 carbon atoms, amino, amino protected by a protecting group for nucleic acid synthesis, amino substituted by an alkyl having 1 to 5 carbon atoms, and halogen atoms. R 1 and R 2 Each independently represents a hydrogen atom, a protecting group for a hydroxyl group for nucleic acid synthesis, an alkyl group having 1 to 7 carbon atoms which may form a branch or a ring, an alkenyl group having 2 to 7 carbon atoms which may form a branch or a ring, an aryl group having 3 to 10 carbon atoms which may have one or more substituents selected from the α group and may contain a heteroatom, an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may have one or more substituents selected from the α group and may contain a heteroatom, an acyl group which may have one or more substituents selected from the α group, a silyl group which may have one or more substituents selected from the α group, a phosphoryl group which may have one or more substituents selected from the α group, a phosphoryl group protected by a protecting group for nucleic acid synthesis, -P(R 3 )R 4 , in which R 3 and R 4 each independently represents a hydroxyl group, a hydroxyl group protected by a protecting group for nucleic acid synthesis, a thiol group, a thiol group protected by 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 by 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 is optionally substituted by an aryl group having 3 to 12 carbon atoms which may contain a heteroatom and which may form a branch or a ring; an aralkyl group having an aryl group having 3 to 12 carbon atoms which may contain a heteroatom; or a silyl group, In formula (III), X, R 1 , R 2 and R 5 and X, R in the formula (II) 1 , R 2 and R 5 Same, R 5’ Independent of R 5 , and with R 5 The definition is the same.

2. The preparation method according to claim 1, wherein X is a group having a pyrimidine skeleton.

3. The preparation method according to claim 1 or 2, wherein X is a group having a uracil skeleton which may have a substituent, a group having a cytosine skeleton which may have a substituent, or a group having a thymine skeleton which may have a substituent.

4. The preparation method according to claim 1 or 2, wherein: X is a group having a uracil skeleton which may have a substituent or a group having a cytosine skeleton which may have a substituent.

5. The preparation method according to claim 1 or 2, wherein: Cyclopropanation was carried out using the Simmons-Smith reaction.

6. The preparation method according to claim 1 or 2, wherein: The compound represented by formula (II) is a compound selected from the following, 。 7. A method for preparing a compound represented by formula (III), which comprises at least the step of cyclopropanating a compound represented by formula (II) in the presence of an organic acid. In formula (II), X represents a nucleic acid base portion optionally having one or more substituents selected from Group α, wherein The α group is composed of hydroxyl, hydroxyl protected by a protecting group for nucleic acid synthesis, alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, thiol, thiol protected by a protecting group for nucleic acid synthesis, alkylthio having 1 to 5 carbon atoms, amino, amino protected by a protecting group for nucleic acid synthesis, amino substituted by an alkyl having 1 to 5 carbon atoms, and halogen atoms. R 1 and R 2 Each independently represents a hydrogen atom, a protecting group for a hydroxyl group for nucleic acid synthesis, an alkyl group having 1 to 7 carbon atoms which may form a branch or a ring, an alkenyl group having 2 to 7 carbon atoms which may form a branch or a ring, an aryl group having 3 to 10 carbon atoms which may have one or more substituents selected from the α group and may contain a heteroatom, an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may have one or more substituents selected from the α group and may contain a heteroatom, an acyl group which may have one or more substituents selected from the α group, a silyl group which may have one or more substituents selected from the α group, a phosphoryl group which may have one or more substituents selected from the α group, a phosphoryl group protected by a protecting group for nucleic acid synthesis, -P(R 3 )R 4 , in which R 3 and R 4 each independently represents a hydroxyl group, a hydroxyl group protected by a protecting group for nucleic acid synthesis, a thiol group, a thiol group protected by 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 by 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 is optionally substituted by an aryl group having 3 to 12 carbon atoms which may contain a heteroatom and which may form a branch or a ring; an aralkyl group having an aryl group having 3 to 12 carbon atoms which may contain a heteroatom; or a silyl group, In formula (III), X, R 1 , R 2 and R 5 and X, R in the formula (II) 1 , R 2 and R 5 Same, R 5’ Independent of R 5 , and with R 5 The definition is the same.

8. The preparation method according to claim 7, wherein: X is a group having a purine skeleton.

9. The preparation method according to claim 7, wherein: X is a group having a uracil skeleton which may have a substituent, a group having a cytosine skeleton which may have a substituent, or a group having a thymine skeleton which may have a substituent.

10. The preparation method according to claim 7, wherein: X is a group having a uracil skeleton which may have a substituent or a group having a cytosine skeleton which may have a substituent.

11. The preparation method according to claim 7 or 8, wherein: Cyclopropanation was carried out using the Simmons-Smith reaction.

12. The preparation method according to claim 7 or 8, wherein: The compound represented by formula (II) is a compound selected from the following, 。 13. A compound represented by formula (IV), In formula (IV), X represents a nucleic acid base portion optionally having one or more substituents selected from Group α, wherein The α group is composed of hydroxyl, hydroxyl protected by a protecting group for nucleic acid synthesis, alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, thiol, thiol protected by a protecting group for nucleic acid synthesis, alkylthio having 1 to 5 carbon atoms, amino, amino protected by a protecting group for nucleic acid synthesis, amino substituted by an alkyl having 1 to 5 carbon atoms, and halogen atoms. R 1 and R 2 Each independently represents a hydrogen atom, a protecting group for a hydroxyl group for nucleic acid synthesis, an alkyl group having 1 to 7 carbon atoms which may form a branch or a ring, an alkenyl group having 2 to 7 carbon atoms which may form a branch or a ring, an aryl group having 3 to 10 carbon atoms which may have one or more substituents selected from the α group and may contain a heteroatom, an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may have one or more substituents selected from the α group and may contain a heteroatom, an acyl group which may have one or more substituents selected from the α group, a silyl group which may have one or more substituents selected from the α group, a phosphoryl group which may have one or more substituents selected from the α group, a phosphoryl group protected by a protecting group for nucleic acid synthesis, -P(R 3 )R 4 , in which R 3 and R 4 each independently represents a hydroxyl group, a hydroxyl group protected by a protecting group for nucleic acid synthesis, a thiol group, a thiol group protected by 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 by 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 is optionally substituted by an aryl group having 3 to 12 carbon atoms which may contain a heteroatom and which may form a branch or a ring; an aralkyl group having an aryl group 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, Among them, X is not included in 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl, R 1 and R 2 is benzyl, R 6 is the case of acetyl, and X is 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl, R 1 , R 2 and R 6 For the case of acetyl group.

14. The compound according to claim 13, wherein R 6 It is acetyl.

15. The compound according to claim 13 or 14, wherein X is a group having a uracil skeleton having a substituent or a group having a cytosine skeleton having a substituent.

16. The compound according to claim 15, wherein The substituent is selected from the group consisting of a hydroxyl group and an alkyl group having 1 to 6 carbon atoms.

17. The compound according to any one of claims 13 to 16, wherein The compound represented by formula (IV) is a compound selected from the following, 。 18. The compound according to claim 13 or 14, wherein X is a group having a purine skeleton having a substituent.

19. The compound according to claim 18, wherein The substituent is selected from the group consisting of a hydroxyl group, an amino group, and an amino group protected by a protecting group.

20. The compound according to any one of claims 13, 14, 18, and 19, wherein The compound represented by formula (IV) is a compound selected from the following, 。 21. A compound represented by formula (I), In formula (I), X represents a nucleic acid base portion optionally having one or more substituents selected from Group α, wherein The α group is composed of hydroxyl, hydroxyl protected by a protecting group for nucleic acid synthesis, alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, thiol, thiol protected by a protecting group for nucleic acid synthesis, alkylthio having 1 to 5 carbon atoms, amino, amino protected by a protecting group for nucleic acid synthesis, amino substituted by an alkyl having 1 to 5 carbon atoms, and halogen atoms. R 1 and R 2 Each independently represents a hydrogen atom, a protecting group for a hydroxyl group for nucleic acid synthesis, an alkyl group having 1 to 7 carbon atoms which may form a branch or a ring, an alkenyl group having 2 to 7 carbon atoms which may form a branch or a ring, an aryl group having 3 to 10 carbon atoms which may have one or more substituents selected from the α group and may contain a heteroatom, an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may have one or more substituents selected from the α group and may contain a heteroatom, an acyl group which may have one or more substituents selected from the α group, a silyl group which may have one or more substituents selected from the α group, a phosphoryl group which may have one or more substituents selected from the α group, a phosphoryl group protected by a protecting group for nucleic acid synthesis, -P(R 3 )R 4 , in which R 3 and R 4 each independently represents a hydroxyl group, a hydroxyl group protected by a protecting group for nucleic acid synthesis, a thiol group, a thiol group protected by 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 by 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 is optionally substituted by an aryl group having 3 to 12 carbon atoms which may contain a heteroatom and which may form a branch or a ring; an aralkyl group having an aryl group having 3 to 12 carbon atoms which may contain a heteroatom; or a silyl group, Among them, X is not included in 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl, R 1 and R 2 is the case of benzyl, and X is 2-oxo-4-amino-1,2-dihydropyrimidin-1-yl, R 1 and R 2 For the case of hydrogen atoms.

22. The compound according to claim 21, wherein X is a group having a uracil skeleton having a substituent or a group having a cytosine skeleton having a substituent.

23. The compound according to claim 22, wherein The substituent is selected from the group consisting of a hydroxyl group and an alkyl group having 1 to 6 carbon atoms.

24. The compound according to any one of claims 21 to 23, wherein The compound represented by formula (I) is a compound selected from the following: 。 25. The compound according to claim 21, wherein X is a group having a purine skeleton having a substituent.

26. The compound according to claim 25, wherein The substituent is selected from the group consisting of a hydroxyl group, an amino group, and an amino group protected by a protecting group.

27. The compound according to any one of claims 21, 25, and 26, wherein The compound represented by formula (I) is a compound selected from the following: 。 28. A compound represented by formula (II), In formula (II), X represents a nucleic acid base portion optionally having one or more substituents selected from Group α, wherein The α group is composed of hydroxyl, hydroxyl protected by a protecting group for nucleic acid synthesis, alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, thiol, thiol protected by a protecting group for nucleic acid synthesis, alkylthio having 1 to 5 carbon atoms, amino, amino protected by a protecting group for nucleic acid synthesis, amino substituted by an alkyl having 1 to 5 carbon atoms, and halogen atoms. R 1 and R 2 Each independently represents a hydrogen atom, a protecting group for a hydroxyl group for nucleic acid synthesis, an alkyl group having 1 to 7 carbon atoms which may form a branch or a ring, an alkenyl group having 2 to 7 carbon atoms which may form a branch or a ring, an aryl group having 3 to 10 carbon atoms which may have one or more substituents selected from the α group and may contain a heteroatom, an aralkyl group having an aryl moiety having 3 to 12 carbon atoms which may have one or more substituents selected from the α group and may contain a heteroatom, an acyl group which may have one or more substituents selected from the α group, a silyl group which may have one or more substituents selected from the α group, a phosphoryl group which may have one or more substituents selected from the α group, a phosphoryl group protected by a protecting group for nucleic acid synthesis, -P(R 3 )R 4 , in which R 3 and R 4 each independently represents a hydroxyl group, a hydroxyl group protected by a protecting group for nucleic acid synthesis, a thiol group, a thiol group protected by 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 by 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 is optionally substituted by an aryl group having 3 to 12 carbon atoms which may contain a heteroatom and which may form a branch or a ring; an aralkyl group having an aryl group having 3 to 12 carbon atoms which may contain a heteroatom; or a silyl group, Among them, X is not included in 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl, R 1 is naphthyl, R 2 is the case of benzyl, and X is 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl, R 1 is naphthyl, R 2 For the case of hydrogen atoms.

29. The compound according to claim 28, wherein X is a group having a uracil skeleton having a substituent or a group having a cytosine skeleton having a substituent.

30. The compound according to claim 29, wherein The substituent is selected from the group consisting of a hydroxyl group and an alkyl group having 1 to 6 carbon atoms.

31. The compound according to any one of claims 28 to 30, wherein The compound represented by formula (II) is a compound selected from the following, 。 32. The compound according to claim 28, wherein X is a group having a purine skeleton having a substituent.

33. The compound according to claim 32, wherein The substituent is selected from the group consisting of a hydroxyl group, an amino group, and an amino group protected by a protecting group.

34. A compound according to any one of claims 28, 32, and 33, wherein The compound represented by formula (II) is a compound selected from the following, 。 35. The preparation method or compound according to any one of claims 1, 7, 13-14, 21 and 28, wherein X is a purine nucleic acid base which may have a substituent or a pyrimidine nucleic acid base which may have a substituent.

36. The method or compound according to claim 35, wherein: X is selected from the group consisting of 2-oxo-4-hydroxy-5-methyl-1,2-dihydropyrimidin-1-yl (thymidyl), 2-oxo-4-amino-1,2-dihydropyrimidin-1-yl (cytosinyl), 6-aminopurin-9-yl (adenyl), 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), and groups in which one or more of the amino group and the carbonyl group in these groups are protected by a protecting group, and tautomers of these groups, 。 37. The method or compound according to claim 35, wherein: X is a group having a uracil skeleton which may have a substituent, a group having a cytosine skeleton which may have a substituent, a group having a purine skeleton which may have a substituent, or a tautomer of these groups.

38. The method or compound according to claim 35 or 37, wherein: The substituent possessed by X is one or more selected from the group consisting of a hydroxyl group, an amino group, and a hydroxyl group and an amino group protected by a protecting group.

39. The method or compound according to claim 35, wherein: X is 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl.

40. The preparation method or compound according to any one of claims 1 to 39, wherein R 1 and / or R 2 -P(R 3 )R 4 , -P(R 3 )R 4 It is a group represented by the chemical formula -P(OC2H4CN)(N(iPr)2) or a group represented by the chemical formula -P(OCH3)(N(iPr)2), wherein iPr represents an isopropyl group.

41. The preparation method or compound according to any one of claims 1, 13, 21, 28 and 35 to 40, wherein X is 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl, R 1 and R 2 is benzyl, R 5 is a hydrogen atom; or, X is 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl, R 1 , R 2 and R 5 A hydrogen atom.

42. The preparation method according to any one of claims 1 to 12 and 35 to 41, wherein The cyclopropanation is carried out by reaction in the presence of a zinc carbene.

43. The preparation method according to claim 42, wherein The cyclopropanation is carried out in the presence of an organic acid.

44. The preparation method according to claim 43, wherein The organic acid is at least one selected from the group consisting of formic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, diphenylphosphoric acid, p-toluenesulfonic acid and phenol.

45. The preparation method according to claim 43 or 44, wherein: The amount of the organic acid used is 0.5 equivalent to 2.0 equivalents relative to the zinc carbene.

46. ​​The preparation method according to any one of claims 1 to 12 and 35 to 45, wherein The compound represented by formula (II) is a compound selected from the following, 。 47. The preparation method according to any one of claims 1 to 12 and 35 to 45, wherein The compound represented by formula (II) is: X is 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl, R 1 is naphthyl, R 2 is benzyl, R 5 is a hydrogen atom; or X is 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl, R 1 is naphthyl, R 2 and R 5 A compound containing hydrogen atoms.

48. The preparation method according to any one of claims 1 to 12 and 35 to 45, wherein In the compound represented by formula (II), X is a group having a purine skeleton into which a protecting group is introduced.

49. The preparation method according to any one of claims 1 to 12 and 35 to 48, wherein In the compound represented by formula (III), X is a group having a pyrimidine skeleton.

50. The preparation method according to any one of claims 1 to 12 and 35 to 49, wherein The compound represented by formula (III) is a compound having as X a group protected by a protecting group for nucleic acid synthesis, or a compound having as X a group formed by deprotecting part or all of the group protected by a protecting group for nucleic acid synthesis.

51. The preparation method according to claim 50, wherein: The groups protected by the protecting groups for nucleic acid synthesis are hydroxyl, sulfhydryl or amino.

52. A method for preparing a phosphoramidite derivative, comprising: A step of phosphoramiditizing the compound represented by the formula (III) obtained by the production method according to any one of claims 1 to 12 and 31 to 51 to obtain a phosphoramidite derivative.

53. A method for producing a nucleic acid drug, characterized in that: The phosphoramidite derivative obtained in claim 52 is used.

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