Alkane halide, alkylating agent using same, and method for producing nucleoside derivative

Abstract

The purpose of the present invention is to provide an alkylating agent capable of alkylating a hydroxyl group at the 2 '-position of a synthetic intermediate of an AMIDITE compound in the presence of a base. The present invention provides an alkyl halide represented by general formula (I) capable of alkylation in the presence of a base. In the formula, X represents a halogen atom; n represents an integer of 1-5; r1 and R2 are the same or different and represent a methyl group, an ethyl group or a hydrogen atom; eWG represents a cyano group or a SO2R3 group, and R3 represents a phenyl group optionally substituted by a halogen atom, a methyl group, a nitro group, a methoxy group or a trifluoromethyl group, an alkyl group having 1-10 carbon atoms, or a benzyl group. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a novel alkyl halide, an alkylating agent using the same, and a method for producing a nucleoside derivative. Background Art

[0002] Examples of methods for synthesizing oligonucleic acids include the phosphotriester method, the H-phosphonate method, and the phosphoramidite method. As a general method, the phosphoramidite method is the most commonly used (Non-Patent Document 1).

[0003] As a raw material for nucleic acid synthesis based on the phosphoramidite method, a phosphoramidite of a nucleoside (hereinafter referred to as AMIDITE) is used. As a protecting group for the 2'-hydroxyl group of AMIDITE, for example, TBDMS (tert-butyldimethylsilyl), TOM (triisopropylsilyloxymethyl), ACE (bis(2-acetoxyethoxy)methyl), CEM (cyanoethoxymethyl) (Non-patent Document 2) and the like are known, and the RNA synthesis method using AMIDITE having these protecting groups cannot meet the requirements in terms of the yield and purity of the obtained RNA.

[0004] On the other hand, Patent Documents 1 to 3 describe AMIDITE (hereinafter referred to as AMIDITE compound) which enables synthesis of high-purity RNA by using the following groups as protecting groups for the 2'-hydroxyl group of AMIDITE.

[0005] [Chemistry 1]

[0006]

[0007] In the formula, n represents an integer of 1 to 5; R 1 and R 2 Identical or different, it represents a methyl group, an ethyl group or a hydrogen atom; EWG represents a cyano group or SO 2 R 3 Ji, R 3 It represents a phenyl group which may be substituted with a halogen atom, a methyl group, a nitro group, a methoxy group or a trifluoromethyl group, an alkyl group having 1 to 10 carbon atoms or a benzyl group.

[0008] The AMIDITE compound described in Patent Document 1 is synthesized by a complex synthesis method involving three steps, wherein a compound represented by the following formula (VI) is alkylated with an alkylating agent represented by the following formula (V).

[0009] [Chemistry 2]

[0010]

[0011] On the other hand, the method for producing CEM AMIDITE described in Non-Patent Document 2 describes a method for synthesizing in a short step by alkylating a compound represented by the following formula (VIII) using an alkylating agent represented by the following formula (VII), and it is expected that the AMIDITE compound can also be synthesized in a short step like CEM AMIDITE.

[0012] [Chemistry 3]

[0013]

[0014] Prior art literature

[0015] Patent Literature

[0016] Patent Document 1: International Publication No. 2013 / 027843

[0017] Patent Document 2: International Publication No. 2019 / 208571

[0018] Patent Document 3: International Publication No. 2021 / 079617

[0019] Non-patent literature

[0020] Non-patent document 1: Nielsen et al., Nucleic Acids Research, 1986, Vol. 14, p. 7391-7403.

[0021] Non-patent document 2: Ohgi et al., Organic Letters, 2005, Vol. 16, pp. 3477-3480. Summary of the invention

[0022] Problems to be solved by the invention

[0023] However, the alkylation of the 2'-hydroxyl group of the synthetic intermediate of the AMIDITE compound represented by formula (VI) by the alkylating agent represented by formula (V) requires the presence of an acid. Therefore, the alkylating agent represented by formula (V) is not applicable to the alkylation of the compound represented by formula (VIII) having a 4,4'-dimethoxytrityl (hereinafter referred to as DMTr) group which is easily decomposed in the presence of an acid.

[0024] Therefore, in order to synthesize an AMIDITE compound in a short number of steps, the present invention aims to provide an alkylating agent capable of alkylating the 2'-hydroxyl group of a synthetic intermediate of an AMIDITE compound in the presence of a base.

[0025] Means for solving problems

[0026] The present inventors have conducted intensive studies to solve the above-mentioned problems and have found the following inventions (1) to (7).

[0027] (1) an alkyl halide represented by the following general formula (I),

[0028] [Chemistry 4]

[0029]

[0030] In the formula, X represents a halogen atom; n represents an integer of 1 to 5; R 1 and R 2 Identical or different, it represents a methyl group, an ethyl group or a hydrogen atom; EWG represents a cyano group or SO 2 R 3 Ji, R 3 It represents a phenyl group which may be substituted with a halogen atom, a methyl group, a nitro group, a methoxy group or a trifluoromethyl group, an alkyl group having 1 to 10 carbon atoms or a benzyl group.

[0031] (2) The alkyl halide according to (1), wherein X is chlorine.

[0032] (3) The alkyl halide according to (1) or (2), wherein EWG is a cyano group.

[0033] (4) The alkyl halide according to any one of (1) to (3), wherein n is 1.

[0034] (5) The alkyl halide according to any one of (1) to (4), which is an alkylating agent.

[0035] (6) A method for producing a nucleoside derivative represented by the following general formula (III), comprising an alkylation step of reacting a halide represented by the following general formula (I) with a nucleoside derivative represented by the following general formula (II) in the presence of a base,

[0036] [Chemistry 5]

[0037]

[0038] In the formula, X represents a halogen atom; n represents an integer of 1 to 5; R 1 and R 2 Identical or different, it represents a methyl group, an ethyl group or a hydrogen atom; EWG represents a cyano group or SO 2 R 3 Ji, R 3 represents a phenyl group which may be substituted with a halogen atom, a methyl group, a nitro group, a methoxy group or a trifluoromethyl group, an alkyl group having 1 to 10 carbon atoms or a benzyl group;

[0039] [Chemistry 6]

[0040]

[0041] In the formula, G represents a protecting group of a hydroxyl group, and B represents a nucleic acid base that can be protected and / or substituted;

[0042] [Chemistry 7]

[0043]

[0044] In the formula, G represents a protective group of a hydroxyl group; B represents a nucleic acid base that may be protected and / or substituted; n represents an integer of 1 to 5; R 1 and R 2 Identical or different, it represents a methyl group, an ethyl group or a hydrogen atom; EWG represents a cyano group or SO 2 R 3 Ji, R 3 It represents a phenyl group which may be substituted with a halogen atom, a methyl group, a nitro group, a methoxy group or a trifluoromethyl group, an alkyl group having 1 to 10 carbon atoms or a benzyl group.

[0045] (7) The production method according to (6), wherein G is a trityl group, a 4-methoxytrityl group or a DMTr group.

[0046] Effects of the Invention

[0047] According to the present invention, by using an alkyl halide represented by the following general formula (I) as an alkylating agent, a nucleoside derivative represented by the following general formula (II) can be alkylated in the presence of a base to obtain a nucleoside derivative represented by the following general formula (III):

[0048] [Chemistry 8]

[0049]

[0050] In the formula, X represents a halogen atom; n represents an integer of 1 to 5; R 1 and R 2 Identical or different, it represents a methyl group, an ethyl group or a hydrogen atom; EWG represents a cyano group or SO 2 R 3 Ji, R 3 represents a phenyl group which may be substituted with a halogen atom, a methyl group, a nitro group, a methoxy group or a trifluoromethyl group, an alkyl group having 1 to 10 carbon atoms or a benzyl group;

[0051] [Chemistry 9]

[0052]

[0053] In the formula, G represents a protecting group of a hydroxyl group, and B represents a nucleic acid base that can be protected and / or substituted;

[0054] [Chemistry 10]

[0055]

[0056] In the formula, G represents a protective group of a hydroxyl group; B represents a nucleic acid base that may be protected and / or substituted; n represents an integer of 1 to 5; R 1 and R 2 Identical or different, it represents a methyl group, an ethyl group or a hydrogen atom; EWG represents a cyano group or SO 2 R 3 Ji, R 3 It represents a phenyl group which may be substituted with a halogen atom, a methyl group, a nitro group, a methoxy group or a trifluoromethyl group, an alkyl group having 1 to 10 carbon atoms or a benzyl group. DETAILED DESCRIPTION

[0057] Hereinafter, the present invention will be described in detail.

[0058] The alkyl halide of the present invention is characterized by being represented by the following general formula (I).

[0059] [Chemistry 11]

[0060]

[0061] In the formula, X represents a halogen atom; n represents an integer of 1 to 5; R 1 and R 2 Identical or different, it represents a methyl group, an ethyl group or a hydrogen atom; EWG represents a cyano group or SO 2 R 3 Ji, R 3 It represents a phenyl group which may be substituted with a halogen atom, a methyl group, a nitro group, a methoxy group or a trifluoromethyl group, an alkyl group having 1 to 10 carbon atoms or a benzyl group.

[0062] The alkyl halide represented by the above general formula (I) may be not only a single stereoisomer but also a mixture of stereoisomers such as a racemate (for example, a mixture of enantiomers).

[0063] Stereoisomers refer to compounds that have the same chemical structure but different configurations in three-dimensional space, and examples thereof include conformers, rotational isomers, tautomers, enantiomers, and diastereomers.

[0064] Examples of the halogen atom include fluorine, chlorine, bromine and iodine.

[0065] The alkyl group may be either linear or branched, and is preferably an alkyl group having 1 to 10 carbon atoms, and more preferably an alkyl group having 1 to 6 carbon atoms. Examples of the alkyl group include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, and hexyl.

[0066] In the above general formula (I), X is preferably chlorine, bromine or iodine, more preferably chlorine, and may also be an alkyl chloride represented by the following general formula (I').

[0067] [Chemistry 12]

[0068]

[0069] In the formula, n represents an integer of 1 to 5; R 1 and R 2 Identical or different, it represents a methyl group, an ethyl group or a hydrogen atom; EWG represents a cyano group or SO 2 R 3 Ji, R 3 It represents a phenyl group which may be substituted with a halogen atom, a methyl group, a nitro group, a methoxy group or a trifluoromethyl group, an alkyl group having 1 to 10 carbon atoms or a benzyl group.

[0070] In the above general formula (I), n is preferably an integer of 1 to 4, and more preferably 1.

[0071] In the above general formula (I), R 1 and R 2 Preferably, each is independently a methyl group or a hydrogen atom.

[0072] In the above general formula (I), X, n, R 1 , R 2 The preferred combination of EWG, preferably X is chlorine, n is 1, R 1 and R 2 are all hydrogen atoms, EWG is a cyano group, or X is chlorine, n is 1, R 1 Methyl, R 2 A combination of a hydrogen atom and a cyano group in EWG.

[0073] (Method for producing alkyl halide represented by general formula (I))

[0074] As an example of a method for producing an alkyl halide represented by the general formula (I), a method for producing an alkyl chloride represented by the general formula (I') is shown below.

[0075] Although not limited to the following, the alkyl chloride represented by the general formula (I') can be produced, for example, by reacting a compound represented by the following general formula (IV) with sulfonyl chloride in a solvent as shown in the following scheme 1.

[0076] Solution 1

[0077] [Chemistry 13]

[0078]

[0079] In the formula, n represents an integer of 1 to 5; R 1 and R 2 Identical or different, it represents a methyl group, an ethyl group or a hydrogen atom; EWG represents a cyano group or SO 2 R3 Ji, R 3 It represents a phenyl group which may be substituted with a halogen atom, a methyl group, a nitro group, a methoxy group or a trifluoromethyl group, an alkyl group having 1 to 10 carbon atoms or a benzyl group.

[0080] The molar equivalent of the sulfonyl chloride is preferably 0.5 to 10 molar equivalents, more preferably 0.5 to 2 molar equivalents, relative to the compound represented by the above general formula (IV).

[0081] Examples of the solvent used in the production of the alkyl chloride represented by the general formula (I') include, but are not limited to, chloroform, dichloromethane, and dichloroethane.

[0082] The amount of the solvent used in the production of the alkyl chloride represented by the general formula (I') is preferably 1 to 100 times by weight relative to the compound represented by the general formula (IV).

[0083] The reaction time for producing the alkyl chloride represented by the general formula (I') can be appropriately set, and is typically 1 hour or longer, for example, 1 to 2 hours.

[0084] The reaction temperature for producing the alkyl chloride represented by the general formula (I') can be appropriately set, and may be, for example, in the range of 10°C to 100°C, and is usually preferably room temperature (about 10°C to about 35°C).

[0085] The alkyl halide represented by the above general formula (I) can be used as an alkylating agent.

[0086] As a preferred embodiment, the alkyl chloride represented by the general formula (I') may be an alkyl chloride represented by the following formula (I'-1) or the following formula (I'-2).

[0087] [Chemistry 14]

[0088]

[0089] [Chemistry 15]

[0090]

[0091] In addition, the present invention also provides a method for producing a nucleoside derivative represented by the following general formula (III), which comprises an alkylation step of reacting the alkyl halide represented by the above general formula (I) with the nucleoside derivative represented by the following general formula (II) in the presence of a base. The steps of the production method are shown below.

[0092] [Chemistry 16]

[0093]

[0094] In the formula, G represents a protecting group of a hydroxyl group, and B represents a nucleic acid base that can be protected and / or substituted;

[0095] [Chemistry 17]

[0096]

[0097] In the formula, G represents a protective group of a hydroxyl group; B represents a nucleic acid base that may be protected and / or substituted; n represents an integer of 1 to 5; R 1 and R 2 Identical or different, it represents a methyl group, an ethyl group or a hydrogen atom; EWG represents a cyano group or SO 2 R 3 Ji, R 3 It represents a phenyl group which may be substituted with a halogen atom, a methyl group, a nitro group, a methoxy group or a trifluoromethyl group, an alkyl group having 1 to 10 carbon atoms or a benzyl group.

[0098] The nucleoside derivative represented by the general formula (III) is obtained by an alkylation step (Scheme 2 below) of reacting the alkyl halide represented by the general formula (I) with the nucleoside derivative represented by the general formula (II) in the presence of a base.

[0099] Solution 2

[0100] [Chemistry 18]

[0101]

[0102] In the formula, G represents a protective group of a hydroxyl group; B represents a nucleic acid base that may be protected and / or substituted; X represents a halogen atom; n represents an integer of 1 to 5; R 1 and R 2 Identical or different, it represents a methyl group, an ethyl group or a hydrogen atom; EWG represents a cyano group or SO 2 R 3 Ji, R 3 It represents a phenyl group which may be substituted with a halogen atom, a methyl group, a nitro group, a methoxy group or a trifluoromethyl group, an alkyl group having 1 to 10 carbon atoms or a benzyl group.

[0103] The nucleoside derivatives represented by the above general formulae (II) and (III) may be not only a single stereoisomer but also a mixture of stereoisomers such as a racemate (for example, a mixture of enantiomers).

[0104] The nucleoside derivative represented by the general formula (II) may be a commercially available product or may be synthesized by a known method or a method based thereon.

[0105] In the above general formula (II) and (III), G represents a protecting group, for example, a functional group that converts a hydroxyl group into an inert group, or a known protecting group for a hydroxyl group. For the protecting group for a hydroxyl group, for example, the records in the literature (Protective Groups in Organic Synthesis 4th edition, Greene et al., 2007, John Wiley & Sons, Inc.) can be cited. G is not limited to the following, and for example, tert-butyldimethylsilyl, bis(2-acetoxyethyloxy)methyl, triisopropylsilyloxymethyl, 1-(2-cyanoethoxy)ethyl, 2-cyanoethoxymethyl, 2-cyanoethyl, tosylethoxymethyl, trityl, 4-methoxytrityl or DMTr group can be cited, preferably trityl, 4-methoxytrityl or DMTr group.

[0106] In the above-mentioned general formula (II) and (III), B represents a nucleic acid base that can be protected and / or substituted. As a nucleic acid base, although it is not limited to the following, for example, adenine, cytosine, guanine, uracil, thymine, 5-methylcytosine, pseudouracil, 1-methylpseudouracil can be enumerated. In addition, as a substituent of a nucleic acid base, although it is not limited to the following, for example, a halogen atom, an acyl group, an alkyl group, an arylalkyl group, an alkoxy group, an alkoxyalkyl group, a cyanoalkyl group, a hydroxyl group, a hydroxymethyl group, an acyloxymethyl group, an amino group, a monoalkylamino group, a dialkylamino group, a carboxyl group, a cyano group and a nitro group and a combination of two or more substituents thereof can be enumerated.

[0107] When the nucleic acid base has an amino group outside the ring, as a protecting group for the amino group, a known protecting group used in the field of nucleic acid chemistry can be used, and although not limited to the following, for example, a methyl group, a benzoyl group, a 4-methoxybenzoyl group, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a phenylacetyl group, a phenoxyacetyl group, a 4-tert-butylphenoxyacetyl group, a 4-isopropylphenoxyacetyl group and a dimethylaminomethylene group and a combination of two or more of these protecting groups can be mentioned.

[0108] Examples of the base used in the alkylation step include, but are not limited to, tertiary amines, pyridine derivatives, aniline derivatives, and inorganic bases.

[0109] Examples of the tertiary amine include, but are not limited to, triethylamine, tri-n-butylamine, diisopropylethylamine, dicyclohexylmethylamine, 1,2,2,6,6-pentamethylpiperidine, and 1,2,2,6,6-pentamethyl-4-piperidinyl methacrylate.

[0110] Examples of the pyridine derivative include, but are not limited to, 2,6-lutidine, 2,6-di-tert-butylpyridine, 2,6-dimethoxypyridine, 2,6-dichloropyridine, and 2,6-dibromopyridine.

[0111] Examples of the aniline derivative include, but are not limited to, 2,6-dimethylaniline, 2,6-diisopropylaniline, N,N-dimethylaniline, N,N-diethylaniline, and N,N,2-trimethylaniline.

[0112] The molar equivalent of the base used in the alkylation step is preferably 1 to 10 molar equivalents, more preferably 2 to 4 molar equivalents, relative to the nucleoside derivative represented by the general formula (II).

[0113] An additive may be used in the alkylation step. Examples of the additive include, but are not limited to, tin compounds, boron compounds, and antimony compounds.

[0114] Examples of the tin compound include, but are not limited to, n-butyltin trichloride, dimethyltin dichloride, di-n-butyltin dichloride, di-tert-butyltin dichloride, diphenyltin dichloride, tri-n-butyltin chloride, and di-n-butyltin oxide.

[0115] The boron compound may be, but is not limited to, phenylboronic acid, 4-trifluoromethylphenylboric acid, 4-chlorophenylboric acid, 4-methoxyphenylboric acid, 2-trifluoromethylphenylboric acid, 2-chlorophenylboric acid, 2-biphenylboric acid, 2,6-dichlorophenylboric acid, 2-furylboric acid, 3-pyridylboric acid, 4-pyridylboric acid, diphenylboric acid, 2-aminoethyl diphenylboric acid, mesitylboric acid or triphenylborane.

[0116] The antimony compound is not limited to the following, but examples thereof include triphenylantimony dichloride, triphenylantimony oxide, and tetraphenylantimony bromide.

[0117] The molar equivalent of the additive used in the alkylation step is preferably 0.1 to 10 molar equivalents, more preferably 0.1 to 2 molar equivalents, relative to the nucleoside derivative represented by the general formula (II).

[0118] A solvent may be used in the alkylation step. Examples of the solvent include, but are not limited to, toluene, xylene, dichloromethane, chloroform, dichloroethane, methyl tert-butyl ether, cyclopentyl methyl ether, diethyl ether, dimethoxyethane, tetrahydrofuran, 1,4-dioxane, methyl ethyl ketone, methyl isobutyl ketone, acetone, methyl acetate, ethyl acetate, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, N,N'-dimethylpropylene urea, acetonitrile, propionitrile, dimethyl sulfoxide, and sulfolane.

[0119] The amount of the solvent used in the alkylation step is preferably 1 to 100 times by weight relative to the nucleoside derivative represented by the general formula (II).

[0120] The reaction time of the alkylation step can be appropriately set, and typically can be 2 hours or longer, for example, 2 hours to 24 hours.

[0121] The reaction temperature in the alkylation step can be appropriately set, and can be, for example, in the range of 10°C to 100°C, and is usually preferably room temperature (about 10°C to about 35°C).

[0122] Example

[0123] The present invention will be further described below using examples, but the technical scope of the present invention is not limited to these examples.

[0124] (Example 1)

[0125] Synthesis of 2-cyanoethoxymethoxymethyl (hereinafter referred to as "EMM") chloride (Scheme 3 below):

[0126] Solution 3

[0127] [Chemistry 19]

[0128]

[0129] EMM thiomethyl (10.0 g, 62.0 mmol) was dissolved in dichloromethane (100 mL), and then sulfonyl chloride (10.5 g, 78.0 mmol) was added. The reaction solution was stirred at room temperature for 1 hour, and the solvent was distilled off under reduced pressure. The resulting residue was purified by reduced pressure distillation (1 mmHg, 94° C.) to obtain EMM chloride (7.01 g, yield 76%) represented by the following formula (I'-1) as a yellow liquid.

[0130] [Chemistry 20]

[0131]

[0132] 1 H-NMR (400MHz, CDCl3 ): δ5.54 (s, 2H), 4.92 (s, 2H), 3.82 (t, J = 6.2Hz, 2H), 2.66 (t, J = 6.2Hz, 2H).

[0133] (Example 2)

[0134] Synthesis of 1-cyanopropan-2-yloxymethoxymethyl (hereinafter referred to as "PMM") chloride (Scheme 4 below):

[0135] Solution 4

[0136] [Chemistry 21]

[0137]

[0138] PMM thiomethyl (336 mg, 1.92 mmol) was dissolved in dichloromethane (1.70 mL), and then sulfonyl chloride (311 mg, 2.30 mmol) was added. The reaction solution was stirred at room temperature for 1 hour, and the solvent was distilled off under reduced pressure. The resulting residue was purified by reduced pressure distillation (4 mmHg, 110° C.) to obtain PMM chloride (189 mg, yield 60%) represented by the following formula (I'-2) as a yellow liquid.

[0139] [Chemistry 22]

[0140]

[0141] 1 H-NMR (400MHz, CDCl 3 ): δ5.60 (d, J=5.9Hz, 1H), 5.54 (d, J=5.9Hz, 1H), 4.97 (d, J=7.3Hz, 1H), 4.90 (d, J=7.3Hz, 1H), 4.0 7-4.00 (m, 1H), 2.61 (dd, J=16.7, 5.3Hz, 1H), 2.55 (dd, J=16.7, 6.2Hz, 2H), 1.35 (d, J=5.9Hz, 3H).

[0142] (Example 3)

[0143] Synthesis of DMTr-EMM-uridine (Scheme 5 below):

[0144] Solution 5

[0145] [Chemistry 23]

[0146]

[0147] DMTr-uridine (50.0 mg, 0.0915 mmol) was dissolved in tetrahydrofuran (0.500 mL), and then diisopropylethylamine (47.3 mg, 0.366 mmol) and di-n-butyltin dichloride (30.6 mg, 0.101 mmol) were added. After the reaction solution was stirred at room temperature for 30 minutes, EMM chloride (16.4 mg, 0.110 mmol) was added. The reaction solution was further stirred at room temperature for 4 hours, and then purified by column chromatography using amino silica gel as a filler (developing solvent: chloroform / methanol = 100 / 0 to 90 / 10) to obtain DMTr-EMM-uridine (39.1 mg, yield 65%).

[0148] Industrial Applicability

[0149] By using the alkyl halide of the present invention as an alkylating agent, the 2'-hydroxyl group of the synthetic intermediate of the AMIDITE compound can be alkylated in the presence of a base.

Claims

1. A haloalkane represented by the following general formula (I), [Chemistry 1] In the formula, X represents a halogen atom, n represents an integer of 1 to 5, and R 1 and R 2 Identical or different, it represents a methyl group, an ethyl group or a hydrogen atom; EWG represents a cyano group or SO2R 3 Ji, R 3 It represents a phenyl group which may be substituted with a halogen atom, a methyl group, a nitro group, a methoxy group or a trifluoromethyl group, an alkyl group having 1 to 10 carbon atoms or a benzyl group.

2. The alkyl halide according to claim 1, wherein X is chlorine.

3. The alkyl halide according to claim 1 or 2, wherein EWG is cyano.

4. The alkyl halide according to any one of claims 1 to 3, wherein n is 1. The alkyl halide according to any one of claims 1 to 4, which is an alkylating agent.

6. A method for producing a nucleoside derivative represented by the following general formula (III), comprising an alkylation step of reacting a haloalkyl represented by the following general formula (I) with a nucleoside derivative represented by the following general formula (II) in the presence of a base, [Chemistry 2] In the formula, X represents a halogen atom, n represents an integer of 1 to 5, and R 1 and R 2 Identical or different, it represents a methyl group, an ethyl group or a hydrogen atom; EWG represents a cyano group or SO2R 3 Ji, R 3 represents a phenyl group which may be substituted with a halogen atom, a methyl group, a nitro group, a methoxy group or a trifluoromethyl group, an alkyl group having 1 to 10 carbon atoms or a benzyl group; [Chemistry 3] In the formula, G represents a protecting group of a hydroxyl group, and B represents a nucleic acid base that can be protected and / or substituted; [Chemistry 4] In the formula, G represents a protective group of a hydroxyl group, B represents a nucleic acid base that can be protected and / or substituted, n represents an integer of 1 to 5, and R 1 and R 2 Identical or different, it represents a methyl group, an ethyl group or a hydrogen atom; EWG represents a cyano group or SO2R 3 Ji, R 3 It represents a phenyl group which may be substituted with a halogen atom, a methyl group, a nitro group, a methoxy group or a trifluoromethyl group, an alkyl group having 1 to 10 carbon atoms or a benzyl group.

7. The manufacturing method according to claim 6, wherein: G is trityl, 4-methoxytrityl or 4,4'-dimethoxytrityl.

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