Compound or salt thereof, and method for producing the same

Abstract

The present invention relates to providing a novel method for producing a compound that has MsPA linkage, is not explosive, and does not produce a toxic gas, as well as providing a compound or a salt thereof that can be used in the production of, or as a precursor for, e.g. an oligonucleotide having a MsPA structure or an Amidite Block having a MsPA structure.　A method for producing a compound represented by general formula (2) or a salt thereof includes a step (1) for reacting a compound represented by general formula (1) or a salt thereof with RaSO2NH2 or a derivative thereof and an azodicarboxylic acid or a derivative thereof. (In the formula, Base represents a nucleobase that may be modified. When there are two or more Bases present, the plurality of Bases that are present are the same or different.　Each B1 independently represents a hydrogen atom or the like. When there are two or more B1s present, the plurality of B1s that are present are the same or different.)

Description

Compound or salt thereof, and method for producing same

[0001] The present invention relates to a compound or a salt thereof that can be used to produce, for example, an oligonucleotide having an MsPA structure or an amidite block having an MsPA structure, or as a precursor thereof, and a method for producing the same.

[0002] Mesyl phosphoramidate (MsPA) conjugates have recently attracted attention as an alternative to PS for RNase H1-mediated knockdown of microRNA targets and modulation of mRNA splicing, and as a next-generation chemical platform for antisense oligonucleotide (ASO) drugs (see, for example, Non-Patent Documents 1-3).

[0003] To date, the synthesis of MsPA conjugates has been performed using methanesulfonyl azide (MsN ３ ) has been reported (see, for example, Non-Patent Documents 4 and 5). ３ MsN has the property of exploding when exposed to heat or impact. It also decomposes easily in water, producing hydrogen azide, a toxic and explosive gas. ３ Therefore, it is desirable to develop a novel method for synthesizing MsPA conjugates without using .

[0004] Proc. Natl. Acad. Sci. U. S. A. , 117, 32370-32379. Proc. Natl. Acad. Sci. U. S. A. , 116, 1229-1234. Nucleic Acid Ther. , 31, 190-200. Nucleic Acids Research, 2021, 49, 9026-9041. Nucleic Acids Research, 2022, 50, 7235-7246.

[0005] In view of the above circumstances, an object of the present invention is to provide a novel method for producing a compound having an MsPA bond, which is non-explosive and does not generate toxic gases.

[0006] Another object of the present invention is to provide a compound or a salt thereof that can be used to produce, for example, an oligonucleotide having an MsPA structure or an amidite block (a phosphoramidite oligomer having a length of several bases) having an MsPA structure, or as a precursor thereof.

[0007] As a result of extensive research to solve the above problems, the present inventors have discovered methanesulfonamide (MsNH), which is non-explosive and does not generate toxic gases. ２ The present invention has been completed by successfully developing a synthetic method using a ) derivative.

[0008] That is, the present invention provides the following methods for producing the compounds or salts thereof.

[0009] [1] A compound represented by general formula (1) or a salt thereof, and R ａ SO ２ NH ２ or a derivative thereof, and azodicarboxylic acid or a derivative thereof. (Wherein, Base represents a nucleic acid base which may be modified. When two or more Bases are present, the multiple Bases present may be the same or different. B １ each independently represents a hydrogen atom, an optionally protected hydroxyl group, a halogen atom, an alkoxyl group having 1 to 4 carbon atoms, or a methoxyethoxy (MOE) group. １ If there are two or more B １ are the same or different. B ２ are each independently a hydrogen atom, a halogen atom, an alkoxyl group having 1 to 4 carbon atoms, or a methoxyethoxy (MOE) group, or B １ and form an LNA (Locked nucleic acid) ring. The LNA ring may be substituted with an alkyl group having 1 to 4 carbon atoms, a hydroxyl group, or an alkoxyl group having 1 to 4 carbon atoms. ２ are the same or different. W represents a hydrogen atom or a protecting group. Each Z is independently O, S, a lone electron pair, or R ａ SO ２N. Multiple Z's are the same or different. Each Q independently represents an alkoxy group having 1 to 6 carbon atoms, a dialkylamino group having 1 to 6 carbon atoms, an allyloxy group, a 2-cyanoethoxy group, a 2-nitroethoxy group, or a piperazino group in which the nitrogen atom at position 4 is protected with a protecting group and which may be further substituted. When there are two or more Q's, the multiple Q's are the same or different. n represents any integer of 0 or more. R ａ represents an optionally substituted organic group having 1 to 10 carbon atoms; and T represents a hydrogen atom, a pseudo-solid-phase protecting group, a solid-phase protecting group, a silyl-based protecting group, or an acyl-based protecting group.

[0010] [2] A compound represented by general formula (1) or a salt thereof, and R ａ SO ２ A method for producing a compound represented by general formula (2) or a salt thereof, comprising: a step (2) of reacting with NVY. (Wherein, Base represents a nucleic acid base which may be modified. When two or more Bases are present, the multiple Bases present may be the same or different. B １ each independently represents a hydrogen atom, an optionally protected hydroxyl group, a halogen atom, an alkoxyl group having 1 to 4 carbon atoms, or a methoxyethoxy (MOE) group. １ If there are two or more B １ are the same or different. B ２ are each independently a hydrogen atom, a halogen atom, an alkoxyl group having 1 to 4 carbon atoms, or a methoxyethoxy (MOE) group, or B １ and form an LNA (Locked nucleic acid) ring. The LNA ring may be substituted with an alkyl group having 1 to 4 carbon atoms, a hydroxyl group, or an alkoxyl group having 1 to 4 carbon atoms. ２ are the same or different. W represents a hydrogen atom or a protecting group. Each Z is independently O, S, a lone electron pair, or R ａ SO ２N. Multiple Z's are the same or different. Each Q independently represents an alkoxy group having 1 to 6 carbon atoms, a dialkylamino group having 1 to 6 carbon atoms, an allyloxy group, a 2-cyanoethoxy group, a 2-nitroethoxy group, or a piperazino group in which the nitrogen atom at position 4 is protected with a protecting group and which may be further substituted. When there are two or more Q's, the multiple Q's are the same or different. n represents any integer of 0 or more. R ａ represents an optionally substituted organic group having 1 to 10 carbon atoms; V represents a halogen atom; Y represents a hydrogen atom, an alkali metal atom, an alkaline earth metal atom, an amine salt, or a quaternary ammonium salt; and T represents a pseudo-solid-phase protecting group, a solid-phase protecting group, a silyl-based protecting group, or an acyl-based protecting group.

[0011] [3] A compound represented by general formula (1) or a salt thereof, and R ａ SO ２ NYOCOR ｂ and M １ -X １ A method for producing a compound represented by general formula (2) or a salt thereof, comprising step (3) of reacting (Wherein, Base represents a nucleic acid base which may be modified. When two or more Bases are present, the multiple Bases present may be the same or different. B １ each independently represents a hydrogen atom, an optionally protected hydroxyl group, a halogen atom, an alkoxyl group having 1 to 4 carbon atoms, or a methoxyethoxy (MOE) group. １ If there are two or more B １ are the same or different. B ２ are each independently a hydrogen atom, a halogen atom, an alkoxyl group having 1 to 4 carbon atoms, or a methoxyethoxy (MOE) group, or B １ and form an LNA (Locked nucleic acid) ring. The LNA ring may be substituted with an alkyl group having 1 to 4 carbon atoms, a hydroxyl group, or an alkoxyl group having 1 to 4 carbon atoms. ２are the same or different. W represents a hydrogen atom or a protecting group. Each Z is independently O, S, a lone electron pair, or R ａ SO ２ N. Multiple Z's are the same or different. Each Q independently represents an alkoxy group having 1 to 6 carbon atoms, a dialkylamino group having 1 to 6 carbon atoms, an allyloxy group, a 2-cyanoethoxy group, a 2-nitroethoxy group, or a piperazino group in which the nitrogen atom at position 4 is protected with a protecting group and which may be further substituted. When there are two or more Q's, the multiple Q's are the same or different. n represents any integer of 0 or more. R ａ represents an organic group having 1 to 10 carbon atoms which may be substituted. ｂ represents an optionally substituted alkyl group having 1 to 10 carbon atoms, or an optionally substituted aryl group having 3 to 10 carbon atoms. Y represents a hydrogen atom, an alkali metal atom, an alkaline earth metal atom, an amine salt, or a quaternary ammonium salt. T represents a pseudo-solid-phase protecting group, a solid-phase protecting group, a silyl-based protecting group, or an acyl-based protecting group. M １ is selected from Fe, Mn, Zn, Ni, or Cu. １ are Cl, Br, SO ４ , P.O. ４ , CO ３ , R ｘ COO, R ｘ SO ３、 BF ４ , and PF ６ The number of atoms or atomic groups is selected from M １ Depends on the valence of R ｘ represents an organic group having 1 to 10 carbon atoms which may be substituted.

[0012] [4] The R ａ SO ２ NH ２ or a derivative thereof, methanesulfonamide, ethanesulfonamide, propanesulfonamide, benzenesulfonamide, or methylphenylsulfonamide.

[0013] [5] The azodicarboxylic acid or a derivative thereof is R １０OCON=NCOOR １０ (In the formula, R １０ represents an organic group having 1 to 10 carbon atoms which may be substituted. １０ are the same or different. ) or (R １１ ) ２ NCON=NCON(R １１ ) ２ R １１ represents a hydrogen atom or an organic group having 1 to 10 carbon atoms which may be substituted. １１ are the same or different.) The manufacturing method according to [1] or [4].

[0014] [6] The production method according to [1] or [4], wherein the azodicarboxylic acid or a derivative thereof is dimethyl azodicarboxylate, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), di-tert-butyl azodicarboxylate, bis(methoxyethyl) azodicarboxylate, bis(2,2,2-trichloroethyl) azodicarboxylate, dibenzyl azodicarboxylate, azobis(N,N-dimethylformamide), 1,1-(azodicarbonyl)dipiperidine, or a combination thereof.

[0015] [7] The R ａ SO ２ NVY is CH ３ SO ２ NCl-Li, CH ３ SO ２ NCl-Na, CH ３ SO ２ NCl-K, CH ３ SO ２ NCl-Cs, CH ３ SO ２ NCl - Trimethylammonium, CH ３ SO ２ NCl - Triethylammonium, CH ３ SO ２ NCl - Diisopropylethylammonium, CH ３ SO ２ NCl - tetramethylammonium, CH ３ SO ２ NCl - tetraethylammonium, CH３ SO ２ NCl - tetrapropylammonium, CH ３ SO ２ NCl - tetrabutylammonium, C ２ H ５ SO ２ NCl-Li, C ２ H ５ SO ２ NCl-Na, C ２ H ５ SO ２ NCl-K, C ２ H ５ SO ２ NCl-Cs, C ２ H ５ SO ２ NCl - trimethylammonium, C ２ H ５ SO ２ NCl - triethylammonium, C ２ H ５ SO ２ NCl - diisopropylethylammonium, C ２ H ５ SO ２ NCl - tetramethylammonium, C ２ H ５ SO ２ NCl - tetraethylammonium, C ２ H ５ SO ２ NCl - tetrapropylammonium, C ２ H ５ SO ２ NCl - tetrabutylammonium, C ３ H ７ SO ２ NCl-Li, C ３ H ７ SO ２ NCl-Na, C ３ H ７ SO ２ NCl-K, C ３ H ７ SO ２ NCl-Cs, C ３ H ７ SO ２ NCl - trimethylammonium, C ３ H ７ SO２ NCl - triethylammonium, C ３ H ７ SO ２ NCl - diisopropylethylammonium, C ３ H ７ SO ２ NCl - tetramethylammonium, C ３ H ７ SO ２ NCl - tetraethylammonium, C ３ H ７ SO ２ NCl - tetrapropylammonium, C ３ H ７ SO ２ NCl - tetrabutylammonium, C ６ H ５ SO ２ NCl-Li, C ６ H ５ SO ２ NCl-Na, C ６ H ５ SO ２ NCl-K, C ６ H ５ SO ２ NCl-Cs, C ６ H ５ SO ２ NCl - trimethylammonium, C ６ H ５ SO ２ NCl - triethylammonium, C ６ H ５ SO ２ NCl - diisopropylethylammonium, C ６ H ５ SO ２ NCl - tetramethylammonium, C ６ H ５ SO ２ NCl - tetraethylammonium, C ６ H ５ SO ２ NCl - tetrapropylammonium, C ６ H ５ SO ２ NCl - tetrabutylammonium, CH ３ C ６ H ４ SO２ NCl-Li, CH ３ C ６ H ４ SO ２ NCl-Na, CH ３ C ６ H ４ SO ２ NCl-K, CH ３ C ６ H ４ SO ２ NCl-Cs, CH ３ C ６ H ４ SO ２ NCl - Trimethylammonium, CH ３ C ６ H ４ SO ２ NCl - Triethylammonium, CH ３ C ６ H ４ SO ２ NCl - Diisopropylethylammonium, CH ３ C ６ H ４ SO ２ NCl - tetramethylammonium, CH ３ C ６ H ４ SO ２ NCl - tetraethylammonium, CH ３ C ６ H ４ SO ２ NCl - tetrapropylammonium, CH ３ C ６ H ４ SO ２ NCl-tetrabutylammonium chloride, or a combination thereof.

[0016] [8] The R ａ SO ２ NYOCOR ｂ is CH ３ SO ２ NHOCOC ６ H ５ , C.H. ３ SO ２ NHOCOC ６ H ４ CH ３ , C.H.３ SO ２ NHOCOC ６ H ４ NO ２ 、CH ３ SO ２ NHOCOCH ３ 、CH ３ SO ２ NHOCOC ２ H ５ 、CH ３ SO ２ NHOCOC ３ H ７ 、C ２ H ５ SO ２ NHOCOC ６ H ５ 、C ２ H ５ SO ２ NHOCOC ６ H ４ NO ２ 、C ２ H ５ SO ２ NHOCOC ６ H ４ CH ３ 、C ２ H ５ SO ２ NHOCOCH ３ 、C ２ H ５ SO ２ NHOCOC ２ H ５ 、C ２ H ５ SO ２ NHOCOC ３ H ７ 、C ３ H ７ SO ２ NHOCOC ６ H ５ 、C ３ H ７ SO ２ NHOCOC ６ H ４ NO ２ 、C ３ H ７ SO ２ NHOCOC ６ H ４ CH ３ 、C３ H ７ SO ２ NHOCOCH ３ 、C ３ H ７ SO ２ NHOCOC ２ H ５ 、C ３ H ７ SO ２ NHOCOC ３ H ７ 、C ６ H ５ SO ２ NHOCOC ６ H ５ 、C ６ H ５ SO ２ NHOCOC ６ H ４ CH ３ 、C ６ H ５ SO ２ NHOCOC ６ H ４ NO ２ 、C ６ H ５ SO ２ NHOCOCH ３ 、C ６ H ５ SO ２ NHOCOC ２ H ５ 、C ６ H ５ SO ２ NHOCOC ３ H ７ 、CH ３ C ６ H ４ SO ２ NHOCOC ６ H ５ 、CH ３ C ６ H ４ SO ２ NHOCOC ６ H ４ CH ３ 、CH ３ C ６ H ４ SO ２ NHOCOC ６ H ４ NO ２, C.H. ３ C ６ H ４ SO ２ NHOCOCH ３ , C.H. ３ C ６ H ４ SO ２ NHOCOC ２ H ５ , C.H. ３ C ６ H ４ SO ２ NHOCOC ３ H ７ [3] The manufacturing method according to [3],

[0017] [9] The method according to any one of [1] to [8], wherein T is a pseudo-solid-phase protecting group having a phenyl group substituted with an alkyloxy group having from 10 to 300 carbon atoms and / or an alkenyloxy group having from 10 to 300 carbon atoms.

[0018]

[10] The method according to any one of [1] to [9], wherein T is a group represented by general formula (3): (wherein, R each independently represents an alkyl group having 10 to 40 carbon atoms which may be substituted; m1 represents an integer of 1 to 5; when m1 is 2 or more, a plurality of RO's may be the same or different; X represents O, S, NH, or NR Ｎ n1 represents an integer of 1 to 4. Ｎ represents an optionally substituted alkyl group having 1 to 6 carbon atoms. * represents the bond to the general formulae (1) and (2).

[0019]

[11] The method according to any one of [1] to

[10] , wherein Q is a 2-cyanoethoxy group.

[0020]

[12] The production method according to any one of [1] to

[11] , wherein a step (4) of reacting a compound represented by general formula (4) or a salt thereof with a compound represented by general formula (5) or a salt thereof is carried out before the step (1), (2), or (3).

[0021]

[13] The method according to

[12] , wherein the step (4) and the step (1), (2), or (3) are carried out continuously.

[0022]

[14] A method for producing a compound represented by general formula (6) or a salt thereof, comprising: a step (5) of deprotecting T of a compound represented by general formula (2) or a salt thereof obtained by the production method according to any one of [1] to

[13] ; and a step (6) of phosphoramiditizing the compound to obtain a compound represented by general formula (6) or a salt thereof. (Wherein, Base represents a nucleic acid base which may be modified. When two or more Bases are present, the multiple Bases present may be the same or different. B １ each independently represents a hydrogen atom, an optionally protected hydroxyl group, a halogen atom, an alkoxyl group having 1 to 4 carbon atoms, or a methoxyethoxy (MOE) group. １ If there are two or more B １ are the same or different. B ２ are each independently a hydrogen atom, a halogen atom, an alkoxyl group having 1 to 4 carbon atoms, or a methoxyethoxy (MOE) group, or B １ and form an LNA (Locked nucleic acid) ring. The LNA ring may be substituted with an alkyl group having 1 to 4 carbon atoms, a hydroxyl group, or an alkoxyl group having 1 to 4 carbon atoms. ２ are the same or different. W represents a hydrogen atom or a protecting group. Each Z is independently O, S, a lone electron pair, or R ａ SO ２ N. Multiple Z's are the same or different. Each Q independently represents an alkoxy group having 1 to 6 carbon atoms, a dialkylamino group having 1 to 6 carbon atoms, an allyloxy group, a 2-cyanoethoxy group, a 2-nitroethoxy group, or a piperazino group in which the nitrogen atom at position 4 is protected with a protecting group and which may be further substituted. When there are two or more Q's, the multiple Q's are the same or different. n represents any integer of 0 or more. R ａ represents an organic group having 1 to 10 carbon atoms which may be substituted.

[0023]

[15] A method for producing a compound represented by general formula (7) or a salt thereof, comprising a step (7) of deprotecting a protecting group of a compound represented by general formula (2) or a salt thereof obtained by the production method according to any one of [1] to

[13] to obtain a compound represented by general formula (7) or a salt thereof. (Wherein, Base represents a nucleic acid base which may be modified. When two or more Bases are present, the multiple Bases present may be the same or different. B １ each independently represents a hydrogen atom, a hydroxyl group, a halogen atom, an alkoxyl group having 1 to 4 carbon atoms, or a methoxyethoxy (MOE) group. １ If there are two or more B １ are the same or different. B ２ are each independently a hydrogen atom, a halogen atom, an alkoxyl group having 1 to 4 carbon atoms, or a methoxyethoxy (MOE) group, or B １ and form an LNA (Locked nucleic acid) ring. The LNA ring may be substituted with an alkyl group having 1 to 4 carbon atoms, a hydroxyl group, or an alkoxyl group having 1 to 4 carbon atoms. ２ are the same or different. Each Z is independently O, S, a lone electron pair, or R ａ SO ２ N. Multiple Z's may be the same or different. n represents an integer of 0 or more. R ａ represents an organic group having 1 to 10 carbon atoms which may be substituted.

[0024] The present invention also provides the following compound or a salt thereof:

[0025]

[16] A compound represented by general formula (8) or a salt thereof: (Wherein, Base represents a nucleic acid base which may be modified. When two or more Bases are present, the multiple Bases present may be the same or different. B １ each independently represents a hydrogen atom, an optionally protected hydroxyl group, a halogen atom, an alkoxyl group having 1 to 4 carbon atoms, or a methoxyethoxy (MOE) group. １If there are two or more B １ are the same or different. B ２ are each independently a hydrogen atom, a halogen atom, an alkoxyl group having 1 to 4 carbon atoms, or a methoxyethoxy (MOE) group, or B １ and form an LNA (Locked nucleic acid) ring. The LNA ring may be substituted with an alkyl group having 1 to 4 carbon atoms, a hydroxyl group, or an alkoxyl group having 1 to 4 carbon atoms. ２ are the same or different. W represents a hydrogen atom or a protecting group. Each Z is independently O, S, a lone electron pair, or R ａ SO ２ When two or more Z's are present, the plural Z's may be the same or different, but at least one Z's is R ａ SO ２ N. Each Q independently represents an alkoxy group having 1 to 6 carbon atoms, a dialkylamino group having 1 to 6 carbon atoms, an allyloxy group, a 2-cyanoethoxy group, a 2-nitroethoxy group, or a piperazino group in which the nitrogen atom at the 4-position is protected with a protecting group and which may be further substituted. When there are two or more Qs, the multiple Qs may be the same or different. R ａ represents an organic group having 1 to 10 carbon atoms which may be substituted. n represents any integer of 0 or more. R each independently represents an alkyl group having 10 to 40 carbon atoms which may be substituted. m represents an integer of 1 to 5. When m is 2 or more, multiple ROs may be the same or different. X represents O, S, NH, or NR Ｎ n1 represents an integer of 1 to 4. Ｎ represents an optionally substituted alkyl group having 1 to 6 carbon atoms.

[0026]

[17] A compound represented by general formula (9) or a salt thereof: (Wherein, Base represents a nucleic acid base which may be modified. When two or more Bases are present, the multiple Bases present may be the same or different. B １each independently represents a hydrogen atom, an optionally protected hydroxyl group, a halogen atom, an alkoxyl group having 1 to 4 carbon atoms, or a methoxyethoxy (MOE) group. １ If there are two or more B １ are the same or different. B ２ are each independently a hydrogen atom, a halogen atom, an alkoxyl group having 1 to 4 carbon atoms, or a methoxyethoxy (MOE) group, or B １ and form an LNA (Locked nucleic acid) ring. The LNA ring may be substituted with an alkyl group having 1 to 4 carbon atoms, a hydroxyl group, or an alkoxyl group having 1 to 4 carbon atoms. ２ are the same or different. W represents a hydrogen atom or a protecting group. Each Z is independently O, S, a lone electron pair, or R ａ SO ２ When two or more Z's are present, the plural Z's may be the same or different, but at least one Z's is R ａ SO ２ N. Each Q independently represents an alkoxy group having 1 to 6 carbon atoms, a dialkylamino group having 1 to 6 carbon atoms, an allyloxy group, a 2-cyanoethoxy group, a 2-nitroethoxy group, or a piperazino group in which the nitrogen atom at the 4-position is protected with a protecting group and which may be further substituted. When there are two or more Qs, the multiple Qs may be the same or different. R ａ represents an organic group having 1 to 10 carbon atoms which may be substituted, and n represents an integer of 0 or more. １ , R ２ , and R ３ each independently represents an optionally substituted alkyl group having 10 to 40 carbon atoms; X represents O, S, NH, or NR Ｎ n1 represents an integer of 1 to 4. Ｎ represents an optionally substituted alkyl group having 1 to 6 carbon atoms.

[0027] The method for producing the compound or a salt thereof of the present invention includes the novel steps described above, and therefore the compound or a salt thereof can be obtained safely without being explosive or generating toxic gases.

[0028] Furthermore, the compound of the present invention or a salt thereof is a novel compound and can be used, for example, to produce an oligonucleotide having an MsPA structure or an amidite block having an MsPA structure, or as a precursor thereof.

[0029] Hereinafter, embodiments of the present invention will be described in detail.

[0030] [Compound and Salt Thereof] The compound or salt thereof of the present invention is a compound represented by general formula (8) or a salt thereof. (Wherein, Base represents a nucleic acid base which may be modified. When two or more Bases are present, the multiple Bases present may be the same or different. B １ each independently represents a hydrogen atom, an optionally protected hydroxyl group, a halogen atom, an alkoxyl group having 1 to 4 carbon atoms, or a methoxyethoxy (MOE) group. １ If there are two or more B １ are the same or different. B ２ are each independently a hydrogen atom, a halogen atom, an alkoxyl group having 1 to 4 carbon atoms, or a methoxyethoxy (MOE) group, or B １ and form an LNA (Locked nucleic acid) ring. The LNA ring may be substituted with an alkyl group having 1 to 4 carbon atoms, a hydroxyl group, or an alkoxyl group having 1 to 4 carbon atoms. ２ are the same or different. W represents a hydrogen atom or a protecting group. Each Z is independently O, S, a lone electron pair, or R ａ SO ２ When two or more Z's are present, the plural Z's may be the same or different, but at least one Z's is R ａ SO ２N. Each Q independently represents an alkoxy group having 1 to 6 carbon atoms, a dialkylamino group having 1 to 6 carbon atoms, an allyloxy group, a 2-cyanoethoxy group, a 2-nitroethoxy group, or a piperazino group in which the nitrogen atom at the 4-position is protected with a protecting group and which may be further substituted. When there are two or more Qs, the multiple Qs may be the same or different. R ａ represents an organic group having 1 to 10 carbon atoms which may be substituted. n represents any integer of 0 or more. R each independently represents an alkyl group having 10 to 40 carbon atoms which may be substituted. m represents an integer of 1 to 5. When m is 2 or more, multiple ROs may be the same or different. X represents O, S, NH, or NR Ｎ n1 represents an integer of 1 to 4. Ｎ represents an optionally substituted alkyl group having 1 to 6 carbon atoms.

[0031] In the general formula (8), Base represents an optionally modified nucleic acid base. When two or more Bases are present, the multiple Bases present may be the same or different.

[0032] The nucleic acid base as the Base is not particularly limited, and may be a naturally occurring nucleic acid base or an artificially synthesized nucleic acid base.

[0033] Examples of the Base include an adenyl group, a guanyl group, a cytosyl group, a thyminyl group, or a uracil group, and derivatives thereof, as well as modified forms thereof. Examples of the modified forms include an 8-bromoadenylate group, an 8-bromoguanyl group, a 5-bromocytosyl group, a 5-iodocytosyl group, a 5-uracil group (pseudouracil group), a 5-bromouracil group, a 5-iodouracil group, a 5-fluorouracil group, a 5-methylcytosyl group, an 8-oxoguanyl group, and a hypoxanthinyl group. The polar group of the Base may be protected with a known protecting group or the like.

[0034] Examples of the protecting group include an acetyl group, an isobutyryl group, a trifluoroacetyl group, a pivaloyl group, a pivaloyloxymethyl group, a benzoyl group, a dimethylformamidino (dmf) group, a phenoxyacetyl group, a 4-isopropylphenoxyacetyl group, a 4-t-butylphenoxyacetyl group, and a 9-fluorenylmethyloxycarbonyl group.

[0035] Examples of the modified form include nucleic acid bases in which the amino group is modified with an acyl group.

[0036] In the above general formula (8), B １ each independently represents a hydrogen atom, an optionally protected hydroxyl group, a halogen atom, an alkoxyl group having 1 to 4 carbon atoms, or a methoxyethoxy (MOE) group. １ If there are two or more B １ are the same or different.

[0037] B １ Examples of the halogen atom as include an F atom, a Cl atom, a Br atom, and an iodine atom.

[0038] B １ Examples of the alkoxyl group having 1 to 4 carbon atoms as the alkyl group include a methoxy group, an ethoxy group, an n-propyloxy group, an isopropyloxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, and a t-butoxy group.

[0039] In the above general formula (8), B ２ are each independently a hydrogen atom, a halogen atom, an alkoxyl group having 1 to 4 carbon atoms, or a methoxyethoxy (MOE) group, or B １ and form an LNA (Locked nucleic acid) ring. The LNA ring may be substituted with an alkyl group having 1 to 4 carbon atoms, a hydroxyl group, or an alkoxyl group having 1 to 4 carbon atoms. ２ are the same or different.

[0040] B ２Examples of the halogen atom as include an F atom, a Cl atom, a Br atom, and an iodine atom.

[0041] B ２ Examples of the alkoxyl group having 1 to 4 carbon atoms as the alkyl group include a methoxy group, an ethoxy group, an n-propyloxy group, an isopropyloxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, and a t-butoxy group.

[0042] B ２ Examples of the alkyl group having 1 to 4 carbon atoms as a substituent in the LNA ring include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, and a t-butyl group.

[0043] B ２ Examples of the alkoxyl group having 1 to 4 carbon atoms as a substituent in the LNA ring include a methoxy group, an ethoxy group, an n-propyloxy group, an isopropyloxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, and a t-butoxy group.

[0044] In the above general formula (8), W represents a hydrogen atom or a protecting group.

[0045] The protecting group for W is not particularly limited, and for example, a protecting group for the 5'-hydroxyl group of the ribose ring used in known nucleic acid modification or nucleic acid synthesis can be used as appropriate. Examples of the protecting group include a trityl-based protecting group, a silyl-based protecting group, and levulinic acid, which are cleaved by an acid.

[0046] The trityl-based protecting group includes a trityl group or a derivative thereof. Examples of the trityl-based protecting group include an alkoxy group having 1 to 5 carbon atoms, an alkyl group having 1 to 5 carbon atoms, a halogen atom, or a trityl group optionally substituted with two or more of these. More specific examples include a trityl group, a 4-methoxytrityl group, and a 4,4'-dimethoxytrityl group.

[0047] In the case of the above substitution, examples of the substituent include a hydroxyl group, an amino group, an ammonium group, and a halogen atom.

[0048] The silyl-based protecting group includes a silyl group or a derivative thereof. Examples of the silyl-based protecting group include an alkoxy group having 1 to 5 carbon atoms, an alkyl group having 1 to 5 carbon atoms, an aryl group such as a phenyl group, and a silyl group which may be substituted with two or more of these. More specific examples include a trimethylsilyl group, a triethylsilyl group, an isopropyldimethylsilyl group, a tert-butyldimethylsilyl group, a dimethylmethoxysilyl group, a methyldimethoxysilyl group, and a tert-butyldiphenylsilyl group.

[0049] In the case of the above substitution, examples of the substituent include a hydroxyl group, an amino group, an ammonium group, and a halogen atom.

[0050] In the general formula (8), each Z is independently O, S, a lone electron pair, or R ａ SO ２ When two or more Z's are present, the plural Z's may be the same or different, but at least one Z's is R ａ SO ２ When Z is a lone pair of electrons, there is no atom of Z, and for example, one lone pair of electrons exists on a P atom.

[0051] In the above general formula (8), R ａ represents an organic group having 1 to 10 carbon atoms which may be substituted.

[0052] R ａ Examples of the organic group as the above include groups in which one hydrogen atom has been removed from a monovalent organic group having 1 to 10 carbon atoms. The monovalent organic group having 1 to 10 carbon atoms may be a group having any of a chain structure, a cyclic structure, or a combination thereof. Examples of the chain structure include chain hydrocarbon groups, whether saturated or unsaturated, straight or branched. Examples of the cyclic structure include cyclic hydrocarbon groups, whether alicyclic, aromatic, or heterocyclic. Among these, preferred monovalent organic groups are monovalent chain hydrocarbon groups having 1 to 10 carbon atoms, monovalent alicyclic hydrocarbon groups having 3 to 10 carbon atoms, and monovalent aromatic hydrocarbon groups having 6 to 10 carbon atoms.

[0053] Examples of the substituent on the organic group having 1 to 10 carbon atoms include a hydroxyl group, an amino group, an ammonium group, and a halogen atom.

[0054] R ａ More specific examples of the organic group as include a methyl group, an ethyl group, a propyl group, a butyl group, a phenyl group, a 2-methylphenyl group, a 3-methylphenyl group, and a 4-methylphenyl group.

[0055] In the general formula (8), each Q independently represents an alkoxy group having 1 to 6 carbon atoms, a dialkylamino group having 1 to 6 carbon atoms, an allyloxy group, a 2-cyanoethoxy group, a 2-nitroethoxy group, or a piperazino group in which the nitrogen atom at position 4 is protected with a protecting group and which may be further substituted. When two or more Qs are present, the multiple Qs may be the same or different.

[0056] Examples of the substituent include a hydroxyl group, an amino group, an ammonium group, and a halogen atom.

[0057] In the above general formula (8), Q is preferably, for example, a 2-cyanoethoxy group.

[0058] In the above general formula (8), n represents any integer equal to or greater than 0. n may be, for example, 0 to 500, 0 to 200, 0 to 100, 0 to 80, 0 to 50, 0 to 40, 0 to 30, 0 to 20, 0 to 10, 0 to 5, etc., depending on the intended use and application.

[0059] In the general formula (8), each R independently represents an optionally substituted alkyl group having 10 to 40 carbon atoms. The R may be an alkyl group having 13 to 30 carbon atoms or an alkyl group having 15 to 20 carbon atoms, with an alkyl group having 18 carbon atoms being preferred. When there are multiple Rs, each may independently represent a linear or branched alkyl group, but a linear alkyl group is preferred. Furthermore, when the R is an alkyl group having 10 to 40 carbon atoms, synthesis of oligonucleotides, particularly by liquid phase synthesis, is facilitated, and improved solubility and resolution can also be achieved.

[0060] Examples of the substituent on the alkyl group having 10 to 40 carbon atoms include a hydroxyl group, an amino group, an ammonium group, and a halogen atom.

[0061] In the general formula (8), m represents an integer of 1 to 5. When m is 2 or more, the multiple RO groups may be the same or different. When m is 2 or more, the multiple RO groups may be the same or different. m is preferably an integer of 2 to 4, and more preferably 3. Furthermore, when the carbonyl group (C═O group) directly bonded to the phenyl group is considered to be at position 1, the RO group is preferably bonded to position 3, 4, or 5, and when m=3, it is preferably bonded to position 3, 4, or 5. Furthermore, by adjusting the value of m within the above range, the solubility in nonpolar solvents can be adjusted.

[0062] In the general formula (8), X is O, S, NH, or NR Ｎ Represents.

[0063] In the above general formula (8), R Ｎ represents an alkyl group having 1 to 6 carbon atoms, which may be substituted. Ｎ Examples of such alkyl groups include a methyl group, an ethyl group, a 1-propyl group, a 1-methyl-1-ethyl group, a 1-butyl group, a 1-methyl-1-propyl group, a 1,1-dimethyl-1-ethyl group, a 2-methyl-1-propyl group, a 1-pentyl group, and a 2-pentyl group.

[0064] In the above general formula (8), n1 represents an integer of 1 to 4. In particular, n is preferably 1 or 2.

[0065] The compound or salt is preferably a compound or salt represented by general formula (9). (Wherein, Base represents a nucleic acid base which may be modified. When two or more Bases are present, the multiple Bases present may be the same or different. B １each independently represents a hydrogen atom, an optionally protected hydroxyl group, a halogen atom, an alkoxyl group having 1 to 4 carbon atoms, or a methoxyethoxy (MOE) group. １ If there are two or more B １ are the same or different. B ２ are each independently a hydrogen atom, a halogen atom, an alkoxyl group having 1 to 4 carbon atoms, or a methoxyethoxy (MOE) group, or B １ and form an LNA (Locked nucleic acid) ring. The LNA ring may be substituted with an alkyl group having 1 to 4 carbon atoms, a hydroxyl group, or an alkoxyl group having 1 to 4 carbon atoms. ２ are the same or different. W represents a hydrogen atom or a protecting group. Each Z is independently O, S, a lone electron pair, or R ａ SO ２ When two or more Z's are present, the plural Z's may be the same or different, but at least one Z's is R ａ SO ２ N. Each Q independently represents an alkoxy group having 1 to 6 carbon atoms, a dialkylamino group having 1 to 6 carbon atoms, an allyloxy group, a 2-cyanoethoxy group, a 2-nitroethoxy group, or a piperazino group in which the nitrogen atom at the 4-position is protected with a protecting group and which may be further substituted. When there are two or more Qs, the multiple Qs may be the same or different. R ａ represents an organic group having 1 to 10 carbon atoms which may be substituted, and n represents an integer of 0 or more. １ , R ２ , and R ３ each independently represents an optionally substituted alkyl group having 10 to 40 carbon atoms; X represents O, S, NH, or NR Ｎ n1 represents an integer of 1 to 4. Ｎ represents an optionally substituted alkyl group having 1 to 6 carbon atoms.

[0066] In the above general formula (9), Base, B １ , B ２, W, Z, Q, n, X, and n1 are the same as in the general formula (8) above, for example, as referred to throughout this specification.

[0067] In the above general formula (9), R １ , R ２ , and R ３ Each of the R independently represents an alkyl group having 10 to 40 carbon atoms, which may be substituted. １ , R ２ , and R ３ may be an alkyl group having 13 to 30 carbon atoms, or an alkyl group having 15 to 20 carbon atoms, and among these, an alkyl group having 18 carbon atoms is preferred. １ , R ２ , and R ３ may each independently be a linear alkyl group or a branched alkyl group, but it is preferable that all of them are linear alkyl groups.

[0068] Examples of the substituent on the alkyl group having 10 to 40 carbon atoms include a hydroxyl group, an amino group, an ammonium group, and a halogen atom.

[0069] [Method for producing the compound and its salt] The method for producing the compound of the present invention or its salt comprises reacting a compound represented by general formula (1) or its salt with R ａ SO ２ NH ２ or a derivative thereof, and azodicarboxylic acid or a derivative thereof. (Wherein, Base represents a nucleic acid base which may be modified. When two or more Bases are present, the multiple Bases present may be the same or different. B １ each independently represents a hydrogen atom, an optionally protected hydroxyl group, a halogen atom, an alkoxyl group having 1 to 4 carbon atoms, or a methoxyethoxy (MOE) group. １ If there are two or more B １ are the same or different. B ２are each independently a hydrogen atom, a halogen atom, an alkoxyl group having 1 to 4 carbon atoms, or a methoxyethoxy (MOE) group, or B １ and form an LNA (Locked nucleic acid) ring. The LNA ring may be substituted with an alkyl group having 1 to 4 carbon atoms, a hydroxyl group, or an alkoxyl group having 1 to 4 carbon atoms. ２ are the same or different. W represents a hydrogen atom or a protecting group. Each Z is independently O, S, a lone electron pair, or R ａ SO ２ represents N. Multiple Z's are the same or different. Each Q independently represents an alkoxy group having 1 to 6 carbon atoms, a dialkylamino group having 1 to 6 carbon atoms, an allyloxy group, a 2-cyanoethoxy group, a 2-nitroethoxy group, or a piperazino group in which the nitrogen atom at position 4 is protected with a protecting group and which may be further substituted. When there are two or more Y's, the multiple Y's are the same or different. n represents any integer of 0 or more. R ａ represents an optionally substituted organic group having 1 to 10 carbon atoms; and T represents a hydrogen atom, a pseudo-solid-phase protecting group, a solid-phase protecting group, a silyl-based protecting group, or an acyl-based protecting group.

[0070] The method for producing a compound or a salt thereof comprising the above step (1) has the novel step, and therefore the compound or a salt thereof can be safely obtained without being explosive and without generating toxic gases.

[0071] In the general formula (1) and the general formula (2) in the above step (1), Base, B １ , B ２ , W, Z, Q, and n are the same as those in the general formula (8) above, for example, as referred to throughout this specification.

[0072] In the above step (1), a compound represented by general formula (1) or a salt thereof and R ａ SO ２ NH ２ The method for reacting the compound or a derivative thereof with azodicarboxylic acid or a derivative thereof is not particularly limited.

[0073] In the above general formulas (1) and (2), T represents a hydrogen atom, a pseudo solid-phase protecting group, a solid-phase protecting group, a silyl-based protecting group, or an acyl-based protecting group.

[0074] In the above general formula (1) and general formula (2), T is preferably a pseudo-solid-phase protecting group having a phenyl group substituted with, for example, an alkyloxy group having from 10 to 300 carbon atoms and / or an alkenyloxy group having from 10 to 300 carbon atoms.

[0075] Examples of the alkyloxy group having 10 to 300 carbon atoms as T include an alkyloxy group having 13 to 200 carbon atoms, an alkyloxy group having 15 to 100 carbon atoms, and an alkyloxy group having 20 to 50 carbon atoms.

[0076] Examples of the alkenyloxy group having 10 to 300 carbon atoms as T include an alkyloxy group having 13 to 200 carbon atoms, an alkenyloxy group having 15 to 100 carbon atoms, and an alkenyloxy group having 20 to 50 carbon atoms.

[0077] In the above general formulas (1) and (2), examples of the pseudo-solid-phase protecting group include alkoxyphenyl derivatives described in Japanese Patent Publication No. 2020-011932.

[0078] In the above general formulas (1) and (2), T is preferably, for example, a group represented by general formula (3). (wherein, R each independently represents an alkyl group having 10 to 40 carbon atoms which may be substituted; m1 represents an integer of 1 to 5; when m1 is 2 or more, a plurality of RO's may be the same or different; X represents O, S, NH, or NR Ｎ n1 represents an integer of 1 to 4. Ｎ represents an optionally substituted alkyl group having 1 to 6 carbon atoms. * represents the bond to the general formulae (1) and (2).

[0079] In the general formula (3), each R independently represents an optionally substituted alkyl group having 10 to 40 carbon atoms. The R may be an alkyl group having 13 to 30 carbon atoms or an alkyl group having 15 to 20 carbon atoms, with an alkyl group having 18 carbon atoms being preferred. When there are multiple Rs, each may independently represent a linear or branched alkyl group, but a linear alkyl group is preferred. Furthermore, when the R is an alkyl group having 10 to 40 carbon atoms, synthesis of oligonucleotides by the liquid phase synthesis method of the present invention is facilitated, and improved solubility and resolution can also be obtained.

[0080] Examples of the substituent on the alkyl group having 13 to 30 carbon atoms include a hydroxyl group, an amino group, an ammonium group, and a halogen atom.

[0081] In the general formula (3), m1 represents an integer of 1 to 5. When m1 is 2 or greater, the multiple ROs may be the same or different. m1 is preferably an integer of 2 to 4, and more preferably m1 is 3. Furthermore, when the carbonyl group (C═O group) directly bonded to the phenyl group is considered to be at position 1, the RO group is preferably bonded to position 3, 4, or 5; when m1=3, it is preferably bonded to position 3, 4, or 5. Furthermore, by adjusting the value of m1 within the above range, the solubility in nonpolar solvents during the synthesis of the oligonucleotide of the present invention can be adjusted.

[0082] In the general formula (3), X is O, S, NH, or NR Ｎ In particular, X is preferably O.

[0083] In the above general formula (3), n1 represents an integer of 1 to 4. In particular, n1 is preferably 1 or 2.

[0084] In the above general formula (3), R Ｎ represents an alkyl group having 1 to 6 carbon atoms, which may be substituted. ＮExamples of such alkyl groups include a methyl group, an ethyl group, a 1-propyl group, a 1-methyl-1-ethyl group, a 1-butyl group, a 1-methyl-1-propyl group, a 1,1-dimethyl-1-ethyl group, a 2-methyl-1-propyl group, a 1-pentyl group, and a 2-pentyl group.

[0085] The group represented by the general formula (3) above as T is preferably a group represented by the following general formula (10). (wherein R １０ , R ２０ , and R ３０ each independently represents an optionally substituted alkyl group having 10 to 40 carbon atoms; X represents O, S, NH, or NR Ｎ n1 represents an integer of 1 to 4. Ｎ represents an alkyl group having 1 to 6 carbon atoms, which may be substituted. * represents a bonding site in the above general formulas (1), (2), etc.)

[0086] In the above general formula (10), R １０ , R ２０ , and R ３０ Each of the R independently represents an alkyl group having 10 to 40 carbon atoms, which may be substituted. １０ , R ２０ , and R ３０ may be an alkyl group having 13 to 30 carbon atoms, or an alkyl group having 15 to 20 carbon atoms, and among these, an alkyl group having 18 carbon atoms is preferred. １０ , R ２０ , and R ３０ may each independently be a linear alkyl group or a branched alkyl group, but it is preferable that all of them are linear alkyl groups.

[0087] In the general formula (10), X and n1 are the same as in the general formula (8), for example, as referred to throughout this specification.

[0088] In the above general formula (1) and general formula (2), new or known solid-phase protecting groups can be appropriately used, such as porous glass (CPG) supports, cross-linked polystyrene bead supports, Nittophase (registered trademark), etc.

[0089] In the above general formulas (1) and (2), new or known silyl protecting groups can be used as appropriate, such as trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, and tert-butyldiphenylsilyl.

[0090] In the above general formula (1) and general formula (2), new or known acyl protecting groups can be used as appropriate. Examples of the acyl protecting group include a formyl group, an acetyl group, a chloroacetyl group, a dichloroacetyl group, a trichloroacetyl group, a trifluoroacetyl group, a methoxyacetyl group, a phenoxyacetyl group, a phenylacetyl group, a diphenylacetyl group, a propionyl group, a pivaloyl group, a 1-adamantanecarbonyl group, a benzoyl group, a 2-(trimethylsilyl)benzoyl group, a 4-nitrobenzoyl group, a pyridylcarbonyl group, a methoxycarbonyl group, a methoxymethylcarbonyl group, a 9-fluorenylmethylcarbonyl group, an ethoxycarbonyl group, a trichloroethylcarbonyl group, a levulinoyl group, a tert-butyloxycarbonyl group, a vinyloxycarbonyl group, an allyloxycarbonyl group, a p-nitrophenoxycarbonyl group, a benzyloxycarbonyl group, a nitrobenzyloxycarbonyl group, a dimethoxybenzyloxycarbonyl group, and a phenacyloxycarbonyl group.

[0091] In the above general formulas (1) and (2), Q is preferably, for example, a 2-cyanoethoxy group.

[0092] In the above step (1), R ａ SO ２ NH ２ As the derivatives thereof, novel or known compounds can be appropriately used.

[0093] In the above step (1), R ａ represents an organic group having 1 to 10 carbon atoms which may be substituted.

[0094] R ａ Examples of the organic group as the above include groups in which one hydrogen atom has been removed from a monovalent organic group having 1 to 10 carbon atoms. The monovalent organic group having 1 to 10 carbon atoms may be a group having any of a chain structure, a cyclic structure, or a combination thereof. Examples of the chain structure include chain hydrocarbon groups, whether saturated or unsaturated, straight or branched. Examples of the cyclic structure include cyclic hydrocarbon groups, whether alicyclic, aromatic, or heterocyclic. Among these, preferred monovalent organic groups are monovalent chain hydrocarbon groups having 1 to 10 carbon atoms, monovalent alicyclic hydrocarbon groups having 3 to 10 carbon atoms, monovalent aromatic hydrocarbon groups having 6 to 10 carbon atoms, or combinations thereof.

[0095] R ａ More specific examples of the organic group as include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a heptyl group, a phenyl group, a 2-methylphenyl group, a 3-methylphenyl group, and a 4-methylphenyl group.

[0096] Examples of the substituent on the organic group having 1 to 10 carbon atoms include a hydroxyl group, an amino group, an ammonium group, and a halogen atom.

[0097] The above R ａ SO ２ NH ２ The derivatives of the above R ａ SO ２ NH ２ The modification may be carried out by a novel or known method.

[0098] Examples of the derivatives include R ａ Examples of the organic group include those in which a hydrogen atom is substituted with a halogen atom, a hydroxyl group, an amino group, a carbonyl group, or the like.

[0099] The above R ａ SO ２ NH ２Examples of the sulfonamide include methanesulfonamide, ethanesulfonamide, propanesulfonamide, phenylsulfonamide, (2-methylphenyl)sulfonamide, (3-methylphenyl)sulfonamide, (4-methylphenyl)sulfonamide, etc. These compounds may be used alone or in combination of two or more.

[0100] In the above step (1), the azodicarboxylic acid or a derivative thereof is １０ OCON=NCOOR １０ (hereinafter also referred to as "general formula (11)") (wherein, R １０ represents an organic group having 1 to 10 carbon atoms which may be substituted. １０ are the same or different. ) or (R １１ ) ２ NCON=NCON(R １１ ) ２ (hereinafter also referred to as "general formula (12)") (wherein, R １１ represents an organic group having 1 to 10 carbon atoms which may be substituted. １１ are the same or different.)

[0101] In the above step (1), the azodicarboxylic acid or a derivative thereof may be a novel or known compound.

[0102] In the above general formula (11), R １０ and R １１ R each independently represents an organic group having 1 to 10 carbon atoms which may be substituted. １０ and R １１ are the same or different.

[0103] R １０ and R １１Examples of the organic group as the above include groups in which one hydrogen atom has been removed from a monovalent organic group having 1 to 10 carbon atoms. The monovalent organic group having 1 to 10 carbon atoms may be a group having any of a chain structure, a cyclic structure, or a combination thereof. The chain structure includes a chain hydrocarbon group, whether saturated or unsaturated, straight or branched. The cyclic structure includes a cyclic hydrocarbon group, whether alicyclic, aromatic, or heterocyclic. Of these, the monovalent organic group is preferably a monovalent chain hydrocarbon group having 1 to 10 carbon atoms, a monovalent alicyclic hydrocarbon group having 3 to 10 carbon atoms, a monovalent aromatic hydrocarbon group having 6 to 10 carbon atoms, or a combination thereof.

[0104] Examples of the substituent include a hydroxyl group, an amino group, an ammonium group, and a halogen atom.

[0105] R １０ and R １１ More specifically, examples of the organic group include a methyl group, an ethyl group, a propyl group, a butyl group, a chloroethyl group, a benzyl group, a phenyl group, and a methylphenyl group.

[0106] The derivative of azodicarboxylic acid represented by the general formula (11) refers to a compound in which a part of the azodicarboxylic acid is chemically modified. The modification can be carried out by a new or known method.

[0107] Examples of the derivatives include R １０ , R １１ 、 Alternatively, hydrogen atoms on both organic groups may be substituted with halogen atoms, hydroxyl groups, amino groups, carbonyl groups, or the like.

[0108] Examples of the azodicarboxylic acids represented by the general formula (11) and the general formula (12) include dimethyl azodicarboxylate, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), di-tert-butyl azodicarboxylate, bis(methoxyethyl) azodicarboxylate, bis(2,2,2-trichloroethyl) azodicarboxylate, dibenzyl azodicarboxylate, azobis(N,N-dimethylformamide), 1,1-(azodicarbonyl)dipiperidine, and combinations thereof. These compounds may be used alone or in combination of two or more.

[0109] As the azodicarboxylic acid represented by the general formula (11) and the general formula (12), for example, a Mitsunobu reagent may be used.

[0110] In the above step (1), R ａ SO ２ NH ２ The compound represented by general formula (1) or a derivative thereof may be present in an amount of, for example, 10 to 2000 mol %, or may be 100 to 1000 mol %, 300 to 800 mol %, or 500 to 600 mol %, based on the total amount of the compound represented by general formula (1) or a salt thereof.

[0111] In the above step (1), the azodicarboxylic acid or a derivative thereof can be present in an amount of, for example, 10 to 1000 mol %, or can be 100 to 500 mol %, 150 to 400 mol %, or 200 to 300 mol %, based on the total amount of azodicarboxylic acid or a derivative thereof.

[0112] In the above step (1), a compound represented by general formula (1) or a salt thereof, R ａ SO ２ NH ２ The azodicarboxylic acid or a derivative thereof and the azodicarboxylic acid or a derivative thereof can be reacted by adding a part or all of them simultaneously or sequentially to the reaction system as appropriate.

[0113] In the above step (1), known methods may be appropriately applied for the reaction temperature, reaction time, separation and purification treatment, etc.

[0114] In the above step (1), a base may be present in the reaction system. The base may be either an organic base or an inorganic base.

[0115] More specific examples of the organic base include methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, ethylenediamine, diisopropylethylamine, tetramethylethylenediamine, hexamethylenediamine, spermidine, spermine, amantadine, benzylamine, pyridine, aniline, dimethylaniline, toluidine, pyrrolidine, piperidine, piperazine, morpholine, diazabicycloundecene (DBU), 1-methylimidazole, tetramethylammonium hydroxide, tetraethylammonium hydroxide, tetrabutylammonium hydroxide, benzyltrimethylammonium hydroxide, benzyltriethylammonium hydroxide, hexadecyltrimethylammonium hydroxide, and combinations thereof. These compounds may be used alone or in combination of two or more.

[0116] More specifically, examples of the inorganic base include lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, and combinations thereof. These compounds may be used alone or in combination of two or more.

[0117] Another embodiment of the method for producing a compound represented by general formula (2) or a salt thereof of the present invention comprises reacting a compound represented by general formula (1) or a salt thereof with R ａ SO ２ The method for producing a compound represented by general formula (2) or a salt thereof includes a step (2) of reacting with NVY. (Wherein, Base represents a nucleic acid base which may be modified. When two or more Bases are present, the multiple Bases present may be the same or different. B １each independently represents a hydrogen atom, an optionally protected hydroxyl group, a halogen atom, an alkoxyl group having 1 to 4 carbon atoms, or a methoxyethoxy (MOE) group. １ If there are two or more B １ are the same or different. B ２ are each independently a hydrogen atom, a halogen atom, an alkoxyl group having 1 to 4 carbon atoms, or a methoxyethoxy (MOE) group, or B １ and form an LNA (Locked nucleic acid) ring. The LNA ring may be substituted with an alkyl group having 1 to 4 carbon atoms, a hydroxyl group, or an alkoxyl group having 1 to 4 carbon atoms. ２ are the same or different. W represents a hydrogen atom or a protecting group. Each Z is independently O, S, a lone electron pair, or R ａ SO ２ N. Multiple Z's are the same or different. Each Q independently represents an alkoxy group having 1 to 6 carbon atoms, a dialkylamino group having 1 to 6 carbon atoms, an allyloxy group, a 2-cyanoethoxy group, a 2-nitroethoxy group, or a piperazino group in which the nitrogen atom at position 4 is protected with a protecting group and which may be further substituted. When there are two or more Q's, the multiple Q's are the same or different. n represents any integer of 0 or more. R ａ represents an optionally substituted organic group having 1 to 10 carbon atoms; V represents a halogen atom; Y represents a hydrogen atom, an alkali metal atom, an alkaline earth metal atom, an amine salt, or a quaternary ammonium salt; and T represents a pseudo-solid-phase protecting group, a solid-phase protecting group, a silyl-based protecting group, or an acyl-based protecting group.

[0118] The method for producing a compound or a salt thereof comprising the above step (2) has the novel step, and therefore can safely produce the compound or a salt thereof without generating any explosive or toxic gases.

[0119] In the general formula (1) and general formula (2) in the above step (2), Base, B １ , B ２, W, Z, Q, n, and T are the same as those in the general formula (1) of the above step (1), for example, as referred to throughout the present specification.

[0120] In the above step (2), a compound represented by general formula (1) or a salt thereof and R ａ SO ２ The method for reacting with NVY or a derivative thereof is not particularly limited.

[0121] In the above general formulas (1) and (2), Q is preferably, for example, a 2-cyanoethoxy group.

[0122] In the above step (2), R ａ SO ２ NVY (hereinafter also referred to as "general formula (13)") or a derivative thereof may be a novel or known compound, as appropriate.

[0123] In the above general formula (13), R ａ represents an organic group having 1 to 10 carbon atoms which may be substituted.

[0124] R ａ Examples of the organic group as the above include groups in which one hydrogen atom has been removed from a monovalent organic group having 1 to 10 carbon atoms. The monovalent organic group having 1 to 10 carbon atoms may be a group having any of a chain structure, a cyclic structure, or a combination thereof. Examples of the chain structure include chain hydrocarbon groups, whether saturated or unsaturated, straight or branched. Examples of the cyclic structure include cyclic hydrocarbon groups, whether alicyclic, aromatic, or heterocyclic. Among these, preferred monovalent organic groups are monovalent chain hydrocarbon groups having 1 to 10 carbon atoms, monovalent alicyclic hydrocarbon groups having 3 to 10 carbon atoms, monovalent aromatic hydrocarbon groups having 6 to 10 carbon atoms, or combinations thereof.

[0125] Examples of the substituent on the organic group having 1 to 10 carbon atoms include a hydroxyl group, an amino group, an ammonium group, and a halogen atom.

[0126] R ａMore specifically, examples of the organic group include a methyl group, an ethyl group, a propyl group, a butyl group, a chloroethyl group, a benzyl group, a phenyl group, and a methylphenyl group.

[0127] The above R ａ SO ２ The derivatives of NVY are the above-mentioned R ａ SO ２ The term "NVY" refers to a compound in which a portion of NVY has been chemically modified. The modification can be carried out by a novel or known method.

[0128] Examples of the derivatives include R ａ Examples of the organic group include those in which a hydrogen atom is substituted with a halogen atom, a hydroxyl group, an amino group, a carbonyl group, or the like.

[0129] In the above general formula (13), V represents a halogen atom.

[0130] Examples of the halogen atom represented by V include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

[0131] In the above general formula (13), Y represents a hydrogen atom, an alkali metal atom, an alkaline earth metal atom, an amine salt, or a quaternary ammonium salt.

[0132] As the alkali metal atom represented by Y, any known atom can be used as appropriate, and examples thereof include a lithium atom, a sodium atom, a potassium atom, and a cesium atom.

[0133] As the alkaline earth metal atom represented by Y, known ones can be appropriately used, and examples thereof include a magnesium atom, a calcium atom, a strontium atom, and a barium atom. When Y is an alkaline earth metal atom, (R ａ SO ２ N.V.) ２ It may also be in the form of Y.

[0134] As the amine salt for Y, known amine salts can be appropriately used, and examples thereof include methylamine salt, dimethylamine salt, trimethylamine salt, ethylamine salt, diethylamine salt, triethylamine salt, ethylenediamine salt, diisopropylethylamine salt, tetramethylethylenediamine salt, hexamethylenediamine salt, spermidine salt, spermine salt, amantadine salt, pyridine salt, aniline salt, toluidine salt, pyrrolidine salt, piperidine salt, piperazine salt, morpholine salt, diazabicycloundecene (DBU) salt, and 1-methylimidazole salt.

[0135] As the quaternary ammonium salt for Y, any known salt can be used appropriately, and examples thereof include tetramethylammonium salt, tetraethylammonium salt, tetrabutylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, and hexadecyltrimethylammonium salt.

[0136] In the step (2), the R ａ SO ２ There is no particular limitation on the method for making NVY or a derivative thereof present in the reaction system. For example, ａ SO ２ NVY or its derivatives are added to the reaction system, or ａ SO ２ The above R is obtained by using a component such as NVY or a precursor of a derivative thereof. ａ SO ２ A method of producing NVY or a derivative thereof in a reaction system (in situ) may also be used.

[0137] The above R ａ SO ２ As a method for producing NVY or a derivative thereof in a reaction system, for example, a method for producing NVY or a derivative thereof in a reaction system using the above-mentioned R ａ SO ２ NH ２ or its derivatives and t-butyl hypochlorite ((CH ３ ) ３ COCl) in the situ.

[0138] The above R ａ SO２ As NVY or a derivative thereof, for example, a known chloramine compound can be used.

[0139] The above R ａ SO ２ NVY is, for example, CH ３ SO ２ NCl-Li, CH ３ SO ２ NCl-Na, CH ３ SO ２ NCl-K, CH ３ SO ２ NCl-Cs, CH ３ SO ２ NCl - Trimethylammonium, CH ３ SO ２ NCl - Triethylammonium, CH ３ SO ２ NCl - Diisopropylethylammonium, CH ３ SO ２ NCl - tetramethylammonium, CH ３ SO ２ NCl - tetraethylammonium, CH ３ SO ２ NCl - tetrapropylammonium, CH ３ SO ２ NCl - tetrabutylammonium, C ２ H ５ SO ２ NCl-Li, C ２ H ５ SO ２ NCl-Na, C ２ H ５ SO ２ NCl-K, C ２ H ５ SO ２ NCl-Cs, C ２ H ５ SO ２ NCl - trimethylammonium, C ２ H ５ SO ２ NCl - triethylammonium, C ２ H ５ SO ２ NCl - diisopropylethylammonium, C ２ H５ SO ２ NCl - tetramethylammonium, C ２ H ５ SO ２ NCl - tetraethylammonium, C ２ H ５ SO ２ NCl - tetrapropylammonium, C ２ H ５ SO ２ NCl - tetrabutylammonium, C ３ H ７ SO ２ NCl-Li, C ３ H ７ SO ２ NCl-Na, C ３ H ７ SO ２ NCl-K, C ３ H ７ SO ２ NCl-Cs, C ３ H ７ SO ２ NCl - trimethylammonium, C ３ H ７ SO ２ NCl - triethylammonium, C ３ H ７ SO ２ NCl - diisopropylethylammonium, C ３ H ７ SO ２ NCl - tetramethylammonium, C ３ H ７ SO ２ NCl - tetraethylammonium, C ３ H ７ SO ２ NCl - tetrapropylammonium, C ３ H ７ SO ２ NCl - tetrabutylammonium, C ６ H ５ SO ２ NCl-Li, C ６ H ５ SO ２ NCl-Na, C ６ H ５ SO ２ NCl-K, C６ H ５ SO ２ NCl-Cs, C ６ H ５ SO ２ NCl - trimethylammonium, C ６ H ５ SO ２ NCl - triethylammonium, C ６ H ５ SO ２ NCl - diisopropylethylammonium, C ６ H ５ SO ２ NCl - tetramethylammonium, C ６ H ５ SO ２ NCl - tetraethylammonium, C ６ H ５ SO ２ NCl - tetrapropylammonium, C ６ H ５ SO ２ NCl - tetrabutylammonium, CH ３ C ６ H ４ SO ２ NCl-Li, CH ３ C ６ H ４ SO ２ NCl-Na, CH ３ C ６ H ４ SO ２ NCl-K, CH ３ C ６ H ４ SO ２ NCl-Cs, CH ３ C ６ H ４ SO ２ NCl - Trimethylammonium, CH ３ C ６ H ４ SO ２ NCl - Triethylammonium, CH ３ C ６ H ４ SO ２ NCl - Diisopropylethylammonium, CH ３ C ６ H ４ SO２ NCl - tetramethylammonium, CH ３ C ６ H ４ SO ２ NCl - tetraethylammonium, CH ３ C ６ H ４ SO ２ NCl - tetrapropylammonium, CH ３ C ６ H ４ SO ２ NCl-tetrabutylammonium, or a combination thereof. These compounds may be used alone or in combination of two or more.

[0140] In the step (2), the R ａ SO ２ NVY or a derivative thereof can be present in an amount of, for example, 10 to 500 mol %, or alternatively, 50 to 400 mol %, 75 to 300 mol %, or 100 to 200 mol %, based on the total amount of the compound represented by general formula (1) or a salt thereof.

[0141] In the above step (2), a compound represented by general formula (1) or a salt thereof and R ａ SO ２ NVY or a derivative thereof can be reacted by adding a part or all of it simultaneously or sequentially to the reaction system as appropriate.

[0142] In the above step (2), known methods may be appropriately applied for the reaction temperature, reaction time, separation and purification treatment, etc.

[0143] In the above step (2), R ａ SO ２ A sulfonamide corresponding to NVY or a derivative thereof may be present in the reaction system in an amount of, for example, 0 to 2000 mol % based on the total amount of the compound represented by formula (1) or a salt thereof.

[0144] Another embodiment of the method for producing the compound represented by formula (2) or a salt thereof of the present invention is to ａ SO ２ NYOCOR ｂ and M１ -X １ and (3) reacting the compound represented by formula (2) or a salt thereof. (Wherein, Base represents a nucleic acid base which may be modified. When two or more Bases are present, the multiple Bases present may be the same or different. B １ each independently represents a hydrogen atom, an optionally protected hydroxyl group, a halogen atom, an alkoxyl group having 1 to 4 carbon atoms, or a methoxyethoxy (MOE) group. １ If there are two or more B １ are the same or different. B ２ are each independently a hydrogen atom, a halogen atom, an alkoxyl group having 1 to 4 carbon atoms, or a methoxyethoxy (MOE) group, or B １ and form an LNA (Locked nucleic acid) ring. The LNA ring may be substituted with an alkyl group having 1 to 4 carbon atoms, a hydroxyl group, or an alkoxyl group having 1 to 4 carbon atoms. ２ are the same or different. W represents a hydrogen atom or a protecting group. Each Z is independently O, S, a lone electron pair, or R ａ SO ２ N. Multiple Z's are the same or different. Each Q independently represents an alkoxy group having 1 to 6 carbon atoms, a dialkylamino group having 1 to 6 carbon atoms, an allyloxy group, a 2-cyanoethoxy group, a 2-nitroethoxy group, or a piperazino group in which the nitrogen atom at position 4 is protected with a protecting group and which may be further substituted. When there are two or more Q's, the multiple Q's are the same or different. n represents any integer of 0 or more. R ａ represents an organic group having 1 to 10 carbon atoms which may be substituted. ｂ represents an optionally substituted alkyl group having 1 to 10 carbon atoms, or an optionally substituted aryl group having 3 to 10 carbon atoms. Y represents a hydrogen atom, an alkali metal atom, an alkaline earth metal atom, an amine salt, or a quaternary ammonium salt. T represents a pseudo-solid-phase protecting group, a solid-phase protecting group, a silyl-based protecting group, or an acyl-based protecting group. M１ is selected from Fe, Mn, Zn, Ni, or Cu. １ are Cl, Br, SO ４ , P.O. ４ , CO ３ , R ｘ COO, R ｘ SO ３、 BF ４ , and PF ６ The number of atoms or atomic groups is selected from M １ Depends on the valence of R ｘ represents an organic group having 1 to 10 carbon atoms which may be substituted.

[0145] The method for producing a compound or a salt thereof comprising the above step (3) has the novel step, and therefore can safely produce the compound or a salt thereof without generating any explosive or toxic gases.

[0146] In the general formula (1) and general formula (2) in the above step (3), Base, B １ , B ２ , W, Z, Q, n, T, and R ａ are the same as those in the general formula (1) in the above step (1), for example, and are incorporated herein by reference in their entirety.

[0147] In the above step (3), R ａ SO ２ NYOCOR ｂ and M １ -X １ The method for reacting is not particularly limited.

[0148] In the above general formulas (1) and (2), Q is preferably, for example, a 2-cyanoethoxy group.

[0149] In the above step (3), R ａ SO ２ NYOCOR ｂ (hereinafter also referred to as "general formula (14)") or a derivative thereof, a novel or known compound can be appropriately used.

[0150] In the above general formula (14), R ａ represents an organic group having 1 to 10 carbon atoms which may be substituted.

[0151] R ａ Examples of the organic group as the above include groups in which one hydrogen atom has been removed from a monovalent organic group having 1 to 10 carbon atoms. The monovalent organic group having 1 to 10 carbon atoms may be a group having any of a chain structure, a cyclic structure, or a combination thereof. Examples of the chain structure include chain hydrocarbon groups, whether saturated or unsaturated, straight or branched. Examples of the cyclic structure include cyclic hydrocarbon groups, whether alicyclic, aromatic, or heterocyclic. Among these, preferred monovalent organic groups are monovalent chain hydrocarbon groups having 1 to 10 carbon atoms, monovalent alicyclic hydrocarbon groups having 3 to 10 carbon atoms, monovalent aromatic hydrocarbon groups having 6 to 10 carbon atoms, or combinations thereof.

[0152] Examples of the substituent on the organic group having 1 to 10 carbon atoms include a hydroxyl group, an amino group, an ammonium group, and a halogen atom.

[0153] R ａ More specifically, examples of the organic group include a methyl group, an ethyl group, a propyl group, a butyl group, a chloroethyl group, a benzyl group, a phenyl group, and a methylphenyl group.

[0154] In the above general formula (14), R ｂ represents an optionally substituted alkyl group having 1 to 10 carbon atoms, or an optionally substituted aryl group having 3 to 10 carbon atoms.

[0155] R ｂ Examples of the alkyl group having 1 to 10 carbon atoms as the alkyl group include a methyl group, an ethyl group, a 1-propyl group, a 1-methyl-1-ethyl group, a 1-butyl group, a 1-methyl-1-propyl group, a 1,1-dimethyl-1-ethyl group, a 2-methyl-1-propyl group, a 1-pentyl group, a 2-pentyl group, and a benzyl group.

[0156] R ｂ Examples of the aryl group having 3 to 10 carbon atoms as the aryl group include a phenyl group, a naphthyl group, a methylphenyl group, a nitrophenyl group, a fluorophenyl group, a chlorophenyl group, a bromophenyl group, and an iodophenyl group.

[0157] Examples of the substituent include a hydroxyl group, an amino group, an ammonium group, and a halogen atom.

[0158] In the above general formula (14), Y represents a hydrogen atom, an alkali metal atom, an alkaline earth metal atom, an amine salt, or a quaternary ammonium salt.

[0159] As the alkali metal atom represented by Y, any known atom can be used as appropriate, and examples thereof include a lithium atom, a sodium atom, a potassium atom, and a cesium atom.

[0160] As the alkaline earth metal atom represented by Y, known ones can be appropriately used, and examples thereof include a magnesium atom, a calcium atom, a strontium atom, and a barium atom. When Y is an alkaline earth metal atom, (R ａ SO ２ NOCOR ｂ ) ２ It may also be in the form of Y.

[0161] As the amine salt for Y, known amine salts can be appropriately used, and examples thereof include methylamine salt, dimethylamine salt, trimethylamine salt, ethylamine salt, diethylamine salt, triethylamine salt, ethylenediamine salt, diisopropylethylamine salt, tetramethylethylenediamine salt, hexamethylenediamine salt, spermidine salt, spermine salt, amantadine salt, benzylamine salt, pyridine salt, aniline salt, dimethylaniline salt, toluidine salt, pyrrolidine salt, piperidine salt, piperazine salt, morpholine salt, diazabicycloundecene (DBU) salt, 1-methylimidazole salt, and the like.

[0162] As the quaternary ammonium salt for Y, any known salt can be used appropriately, and examples thereof include tetramethylammonium salt, tetraethylammonium salt, tetrabutylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, and hexadecyltrimethylammonium salt.

[0163] The above R ａ SO ２ NYOCOR ｂThe derivatives of the above R ａ SO ２ NYOCOR ｂ The modification may be carried out by a novel or known method.

[0164] Examples of the derivatives include R ａ On the organic group of R ｂ or both of the groups, hydrogen atoms of which have been substituted with halogen atoms, hydroxyl groups, amino groups, carbonyl groups, etc.

[0165] The above R ａ SO ２ NYOCOR ｂ For example, CH ３ SO ２ NHOCOC ６ H ５ , C.H. ３ SO ２ NHOCOC ６ H ４ CH ３ , C.H. ３ SO ２ NHOCOC ６ H ４ NO ２ , C.H. ３ SO ２ NHOCOCH ３ , C.H. ３ SO ２ NHOCOC ２ H ５ , C.H. ３ SO ２ NHOCOC ３ H ７ , C ２ H ５ SO ２ NHOCOC ６ H ５ , C ２ H ５ SO ２ NHOCOC ６ H ４ NO ２ , C ２ H ５ SO ２ NHOCOC ６ H ４ CH ３ , C ２ H５ SO ２ NHOCOCH ３ 、C ２ H ５ SO ２ NHOCOC ２ H ５ 、C ２ H ５ SO ２ NHOCOC ３ H ７ 、C ３ H ７ SO ２ NHOCOC ６ H ５ 、C ３ H ７ SO ２ NHOCOC ６ H ４ NO ２ 、C ３ H ７ SO ２ NHOCOC ６ H ４ CH ３ 、C ３ H ７ SO ２ NHOCOCH ３ 、C ３ H ７ SO ２ NHOCOC ２ H ５ 、C ３ H ７ SO ２ NHOCOC ３ H ７ 、C ６ H ５ SO ２ NHOCOC ６ H ５ 、C ６ H ５ SO ２ NHOCOC ６ H ４ CH ３ 、C ６ H ５ SO ２ NHOCOC ６ H ４ NO ２ 、C ６ H ５ SO ２ NHOCOCH３ , C ６ H ５ SO ２ NHOCOC ２ H ５ , C ６ H ５ SO ２ NHOCOC ３ H ７ , C.H. ３ C ６ H ４ SO ２ NHOCOC ６ H ５ , C.H. ３ C ６ H ４ SO ２ NHOCOC ６ H ４ CH ３ , C.H. ３ C ６ H ４ SO ２ NHOCOC ６ H ４ NO ２ , C.H. ３ C ６ H ４ SO ２ NHOCOCH ３ , C.H. ３ C ６ H ４ SO ２ NHOCOC ２ H ５ , C.H. ３ C ６ H ４ SO ２ NHOCOC ３ H ７ These compounds may be used alone or in combination of two or more.

[0166] In the above step (3), the M １ -X １ (hereinafter also referred to as "general formula (15)") or a derivative thereof, a novel or known compound can be appropriately used.

[0167] In the above general formula (15), M １ is selected from Fe, Mn, Zn, Ni, or Cu.

[0168] In the general formula (15), X １ are Cl, Br, SO ４ , P.O. ４ , CO ３ , R ｘ COO, R ｘ SO ３、 BF ４ , and PF ６ The number of atoms or atomic groups is selected from M １ Depending on the valence of

[0169] R ｘ R in COO ｘ represents an organic group having 1 to 10 carbon atoms which may be substituted.

[0170] R ｘ Examples of the organic group as the above include groups in which one hydrogen atom has been removed from a monovalent organic group having 1 to 10 carbon atoms. The monovalent organic group having 1 to 10 carbon atoms may be a group having any of a chain structure, a cyclic structure, or a combination thereof. Examples of the chain structure include chain hydrocarbon groups, whether saturated or unsaturated, straight or branched. Examples of the cyclic structure include cyclic hydrocarbon groups, whether alicyclic, aromatic, or heterocyclic. Among these, preferred monovalent organic groups are monovalent chain hydrocarbon groups having 1 to 10 carbon atoms, monovalent alicyclic hydrocarbon groups having 3 to 10 carbon atoms, monovalent aromatic hydrocarbon groups having 6 to 10 carbon atoms, or combinations thereof.

[0171] Examples of the substituent on the organic group having 1 to 10 carbon atoms include a hydroxyl group, an amino group, an ammonium group, and a halogen atom.

[0172] R ｘ More specifically, examples of the organic group as include a methyl group, an ethyl group, a propyl group, a butyl group, a benzyl group, a phenyl group, a methylphenyl group, a methylphenyl group, and a nitrophenyl group.

[0173] R ｘ R in COO ｘ represents an organic group having 1 to 10 carbon atoms which may be substituted, R ｘ R in COO ｘThis is the same as in the case of

[0174] M represented by the above general formula (15) １ -X １ For example, FeCl ２ , FeBr ２ , FeI ２ , FeSO ４ , Fe ３ (P.O. ４ ) ２ , FeCO ３ , Fe(OCOCH ３ ) ２ , Fe(OCOCF ３ ) ２ , Fe(OCOC ６ H ５ ), MnCl ２ , MnBr ２ , MnI ２ , MnSO ４ , Mn ３ (P.O. ４ ) ２ , MnCO ３ , Mn(OCOCH ３ ) ２ , Mn(OCOCF ３ ) ２ , Mn(OCOC ６ H ５ ), ZnCl ２ , ZnBr ２ , ZnI ２ , ZnSO ４ , Zn ３ (P.O. ４ ) ２ , ZnCO ３ , Zn(OCOCH ３ ) ２ , Zn(OCOCF ３ ) ２ , Zn(OCOC ６ H ５ ), NiCl ２ , NiBr ２ , NiI ２ , NiSO ４ , Ni ３ (P.O. ４ ) ２ , Nico ３ , Ni(OCOCH ３ ) ２ , Ni(OCOCF３ ) ２ , Ni(OCOC ６ H ５ ), CuCl ２ , CuBr ２ , CuI ２ , CuSO ４ , Cu ３ (P.O. ４ ) ２ , CuCO ３ , Cu(OCOCH ３ ) ２ , Cu(OCOCF ３ ) ２ , Cu(OCOC ６ H ５ These compounds may be used alone or in combination of two or more.

[0175] In the above step (3), the R ａ SO ２ NYOCOR ｂ The compound represented by general formula (1) or a derivative thereof may be present in an amount of, for example, 10 to 400 mol %, 50 to 350 mol %, 100 to 300 mol %, or 150 to 250 mol %, based on the total amount of the compound represented by general formula (1) or a salt thereof.

[0176] In the above step (3), the M １ -X １ can be present in an amount of, for example, 1 to 300 mol %, or may be 10 to 200 mol %, 50 to 150 mol %, or 90 to 110 mol %, based on the total amount of the compound represented by general formula (1) or a salt thereof.

[0177] In the above step (3), a compound represented by general formula (1) or a salt thereof, R ａ SO ２ NYOCOR ｂ or a derivative thereof, and the M １ -X １ can be added to the reaction system in part or in whole, simultaneously or sequentially, as appropriate, to carry out the reaction.

[0178] In the above step (3), known methods may be appropriately applied for the reaction temperature, reaction time, separation and purification treatment, etc.

[0179] In the above step (3), a base may be present in the reaction system. The base may be either an organic base or an inorganic base.

[0180] More specific examples of the organic base include methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, ethylenediamine, diisopropylethylamine, tetramethylethylenediamine, hexamethylenediamine, spermidine, spermine, amantadine, benzylamine, pyridine, aniline, dimethylaniline, toluidine, pyrrolidine, piperidine, piperazine, morpholine, diazabicycloundecene (DBU), 1-methylimidazole, tetramethylammonium hydroxide, tetraethylammonium hydroxide, tetrabutylammonium hydroxide, benzyltrimethylammonium hydroxide, benzyltriethylammonium hydroxide, hexadecyltrimethylammonium hydroxide, and combinations thereof. These compounds may be used alone or in combination of two or more.

[0181] More specifically, examples of inorganic salts include lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, and combinations thereof. These compounds may be used alone or in combination of two or more.

[0182] In the method for producing a compound represented by general formula (2) or a salt thereof of the present invention, step (4) of reacting a compound represented by general formula (4) or a salt thereof with a compound represented by general formula (5) or a salt thereof can be carried out before the above step (1), (2), or (3).

[0183] The method for producing a compound or a salt thereof comprising the above step (4) can more simply, efficiently, safely obtain a compound represented by the general formula (2) or a salt thereof without generating explosive or toxic gases by carrying out the above step (1), (2), or (3) after the above step (4).

[0184] In the general formula (4) and the general formula (5) in the above step (4), Base, B １ , B ２ , W, Z, Q, n, and T are the same as those in the general formula (1) of the above step (1), for example, as referred to throughout the present specification.

[0185] In the step (4), the method for reacting the compound of the general formula (4) with the compound of the general formula (5) is not particularly limited.

[0186] In the above production method, it is preferable that the step (4) and the step (1), (2), or (3) are carried out continuously.

[0187] Furthermore, the method for producing a compound represented by general formula (6) or a salt thereof of the present invention includes a step (5) of deprotecting T of a compound represented by general formula (2) or a salt thereof obtained by any of the production methods described above, and then a step (6) of converting the compound to a phosphoramidite to obtain a compound represented by general formula (6) or a salt thereof.

[0188] The method for producing a compound or a salt thereof comprising the above steps (5) and (6) can more simply, efficiently, safely obtain a compound represented by the general formula (6) or a salt thereof without generating explosive or toxic gases by carrying out the above steps (5) and (6).

[0189] In the general formula (6) of the above step (5), Base, B １ , B ２ ,W, Z, Q, n, and ,R ａ are the same as those in the general formula (1) in the above step (1), for example, and are incorporated herein by reference in their entirety.

[0190] In the above step (5), the method for deprotecting T of the compound represented by the above general formula (2) or a salt thereof is not particularly limited.

[0191] In the above step (6), the method for converting the compound or salt obtained by deprotection in the above step (5) into a phosphoramidite is not particularly limited.

[0192] Furthermore, the method for producing a compound represented by general formula (7) or a salt thereof of the present invention includes a step (7) of deprotecting the protecting group of the compound represented by general formula (2) or a salt thereof obtained by any of the production methods described above to obtain a compound represented by general formula (7) or a salt thereof.

[0193] The method for producing a compound or a salt thereof comprising the above step (7) can more simply, efficiently, safely obtain a compound represented by the above general formula (7) or a salt thereof without generating explosive or toxic gases by carrying out the above step (7).

[0194] In the general formula (7) of the above step (7), Base, B １ , B ２ , Z, n, and , R ａ are the same as those in the general formula (1) in the above step (1), for example, and are incorporated herein by reference in their entirety.

[0195] In the above step (7), the method for deprotecting the protecting group of the compound represented by the above general formula (2) or a salt thereof is not particularly limited.

[0196] Examples that specifically demonstrate the configuration and effects of the present invention will be described below. Concentration operations in the examples were carried out under reduced pressure unless otherwise specified. Unless otherwise specified, blend amounts are based on parts by mass.

[0197] The evaluation items in the examples were measured as follows.

[0198] <NMR Spectrum Measurement> １ H-NMR, ３１ The P-NMR spectrum was measured using a nuclear magnetic resonance spectrometer (manufactured by JEOL Ltd., product name JNM-ECZL400S).

[0199] <Measurement of MS spectrum> Measurement of MS spectrum was performed using a time-of-flight mass spectrometer (manufactured by Waters, product name BioAccord LC-MS system). [Example 1] Synthesis of DMTr-dT-p(III)-dT-Fujimat (registered trademark) (4) It was synthesized according to the method described in WO2020-017085.

[0200] (Step 1) To a suspension of Fujimat (registered trademark) (1) (4.95 g, 5.02 mmol), 5'-O-(4,4'-dimethoxytrityl)thymidine (3.28 g, 6.03 mmol), and 1-methylimidazole (2.27 g, 27.62 mmol) in THF (50 mL) was added (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU) (4.73 g, 11.05 mmol), followed by stirring at room temperature for 3.5 hours. Acetonitrile (248 mL) was added dropwise to the reaction solution, and the precipitated solid was filtered. The solid was washed with an acetonitrile-THF mixed solvent and then dried under reduced pressure at 50°C to obtain DMTr-dT-Fujimat (registered trademark) (2) (7.16 g, 95%). ＋ ) Calcd For C ９４ H １４６ N ２ O １３ Na:1534.0723, Found:1534.0759.

[0201] (Step-2) Pyrrole (0.64 g, 9.60 mmol) and trifluoroacetic acid (0.27 g, 2.40 mmol) were added to a dichloromethane-toluene (1:1) solution (20 mL) of DMTr-dT-Fujimat (registered trademark) (2) (2.00 g, 1.32 mmol), and the mixture was stirred at room temperature for 2 hours. Pyridine (0.19 g) was added to the reaction solution, and then acetonitrile (140 mL) was added dropwise to precipitate a solid, which was then filtered. The solid was washed with an acetonitrile-toluene-dichloromethane mixed solvent and a toluene-acetonitrile mixed solvent, and then dried under reduced pressure at 50°C to obtain HO-dT-Fujimat (registered trademark) (3) (1.66 g, 103%). MS (ESI, MNa ＋ ) calcd C ７３ H １２８ N ２ O １１ Na:1231.9416, Found:1231.9432.

[0202] (Step 3) 5-(benzylthio)-1H-tetrazole (0.51 g, 2.66 mmol) was added to a solution (16.5 mL) of HO-dT-Fujimat® (3) (1.65 g, 1.36 mmol) and DMTr-dT-phosphoramidite (2.03 g, 2.73 mmol) in dichloromethane-toluene-1-methyl-2-pyrrolidone (9:9:2), and the mixture was stirred at room temperature for 2 hours. Acetonitrile (116 mL) was added dropwise to the reaction solution, and the precipitated solid was filtered. The solid was washed with an acetonitrile-toluene-dichloromethane mixed solvent and then dried under reduced pressure at room temperature to obtain the title compound (4) (2.54 g, 100%). MS (ESI) [M+Et ３ N.H.] ＋ calcd C １０７ H １６２ N ５ O １９ PC ６ H １５ NH ＋ :1954.2879, Found:1954.3607. ３１ P-NMR (100MHz, CDCl ３ ): δ139.9, 134.0.

[0203] [Example 1] The method was used and the following compounds were synthesized. DMTr-A ＭＯＥ -p(III)-G ＭＯＥ - Fujimat (registered trademark) (5) MS(ESI)[M+H] ＋ calcd C １２４ H １８２ N １１ O ２２ PH ＋ :2209.3271. Found: 2209.3523 ３１ P-NMR (100MHz, CDCl ３ ): δ139.4, 140.8.

[0204] DMTr-A Ｍｅ -p(III)-U Ｍｅ - Fujimat (registered trademark) (6) MS(ESI)[M+H] ＋ calcd C １１５ H １６7 N ８ O ２０ PH ＋ :2012.2107, Found:2012.2348. ３１ P-NMR (100MHz, CDCl ３ ): δ140.5, 141.3.

[0205] DMTr-dC-p(III)-dU Ｆ - Fujimat (registered trademark) (7) MS(ESI)[M+Na] ＋ calcd C １１２ H １６２ FN ６ O １９ PNa ＋ : 1968.1509. Found: 1968.1676. ３１ P-NMR (100MHz, CDCl ３ ): δ139.4, 140.0.

[0206] DMTr-dC-p(III)-U ＴＢＳ - Fujimat (registered trademark) (8) MS(ESI)[M+Na] ＋ calcd C １１８ H１７７ N ６ O ２０ PSiNa ＋ :2080.2417. Found:2080.2459. ３１ P-NMR (100MHz, CDCl ３ ): δ139.5, 140.5.

[0207] Example 2: Synthesis of DMTr-dT-p(III)-dT(9)

[0208] DMTr-dT-p(III)-dT-Fujimat® (4) (2.50 g, 1.35 mmol) in THF (25 mL) was diluted with 2M NH ３ After adding a 2M NH3 / methanol solution (6.7 mL), the mixture was stirred at room temperature for 20 hours. ３ After adding a methanol solution (1.69 mL) and stirring for 3 hours, THF (5 mL) was added and stirring was continued for 3.5 hours.

[0209] Acetonitrile (90 mL) was added dropwise to the reaction solution, and then Celite (2.50 g) was added to filter the insoluble matter. The insoluble matter was washed with an acetonitrile-dichloromethane mixed solvent, and the filtrate was concentrated to dryness under reduced pressure. Dichloromethane (25 mL) was added to the dried matter to dissolve the solution, and the solution was added dropwise to diisopropyl ether (75 mL), and the precipitate was collected by filtration. The solid was washed with diisopropyl ether and then dried at room temperature under reduced pressure to obtain the title compound (9) (0.94 g, 79%). MS (ESI) [M+Na] ＋ calcd C ４４ H ４８ N ５ O １３ PNa ＋ :908.2884, Found:908.3431. ３１ P-NMR (100MHz, CDCl ３ ): δ139.7, 140.7.

[0210] Example 3: Synthesis of DMTr-dT-p(III)-dT-TBDPS (10)

[0211] Imidazole (0.42 g, 6.10 mol) and tert-butyl(chloro)diphenylsilane (0.84 g, 3.05 mmol) were added to a dichloromethane solution (9 mL) of DMTr-dT-p(III)-dT (9) (0.90 g, 1.02 mmol), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was purified by column chromatography (spherical neutral silica gel, developing solvent: dichloromethane-2-propanol) to give the title compound (10) (1.06 g, 93%). MS (ESI) [M+Na] ＋ calcd C ６０ H ６６ N ５ O １３ PSiNa ＋ :1146.4062, Found:1146.4390. ３１ P-NMR (100MHz, CDCl ３ ): δ139.5, 139.7.

[0212] [Example 4] DMTr-dT-p(III)-dT-po-dA-ps-dT-Fujimat (registered trademark) (11)

[0213] The following compounds were synthesized according to the method described in WO2020-017085 and the method of Example 1. MS (ESI) [M+H] ＋ calcd C １４０ H １９９ N １４ O ３1 P ３ SH ＋ :2698.3438, Found: 2698.3482 ３１ P-NMR (100MHz, CDCl ３ ): δ-2.2, -2.2, -2.1, 67.4, 139.5-140.5 (m).

[0214] Example 5: Synthesis of methanesulfonyl azanyl benzoate (12)

[0215] Triethylamine (0.81 mL, 5.8 mmol) was added to a solution of N-hydroxymethanesulfonamide (0.5 g, 4.5 mmol) in THF (45 mL) at an internal temperature of -4°C, and the mixture was stirred at the same temperature for approximately 20 minutes. Next, a solution of benzoyl chloride (0.82 g, 5.8 mmol) in THF (0.5 mL) was added dropwise at -5°C over 30 minutes. After stirring at -5°C for 3 hours, dilute hydrochloric acid and brine were added and the mixture was separated. Dilute hydrochloric acid and brine were added to the organic layer (upper layer), and the mixture was mixed and then separated. Water was added to the organic layer (upper layer), and the mixture was mixed and then separated. The organic layer was dried over anhydrous magnesium sulfate. After removing the magnesium sulfate by filtration, the filtrate was concentrated to dryness under reduced pressure to obtain a crude product (1.06 g). The crude product was purified by column chromatography (spherical neutral silica gel, developing solvent: hexane-AcOEt) to obtain the title compound (0.37 g, 38%). １ H-NMR (400MHz, CDCl ３ ): δ3.16 (s, 3H), 7.51-7.55 (t, 2H), 7.67-7.71 (t, 1H), 8.09-8.11 (d, 2H), 8.95 (s, 1H).

[0216] Example 6: Synthesis of DMTr-dT-mspa-dT-Fujimat (registered trademark) (13)

[0217] Method using Mitsunobu Reagent [Reaction Condition 1-1] Under nitrogen purging, diisopropyl azodicarboxylate (40% toluene solution) (59 μL, 0.12 mmol) was added to a suspension of DMTr-dT-p(III)-dT-Fujimat® (4) (100 mg, 0.05 mmol), methanesulfonamide (26 mg, 0.27 mmol), and molecular sieves 3A in dichloromethane (2 mL), and the mixture was stirred at room temperature overnight. After confirming the completion of the reaction, the reaction solution was filtered through a syringe filter. Acetonitrile (10 mL) was added dropwise to the filtrate, and the resulting precipitate was collected by filtration. The filtered product was washed with an acetonitrile-dichloromethane mixed solvent. The wet product was dried under reduced pressure to obtain a solid (90 mg, 86% yield) composed primarily of the title compound (13). As a result of measurement under HPLC condition 1, the HPLC area percentage of the title compound (13) was 80% (retention time: 49.2, 49.8 minutes).

[0218] <HPLC conditions 1> Column: Cadenza CD-C18 (250mm x 4.6mm, 3μm) Mobile phase A: 10mM HCOOH / TEA in MeOH Mobile phase B: 10mM HCOOH / TEA in IPA Flow rate: 0.3mL / min Injection volume: 1.5 μL Column temperature: 35°C Detection wavelength: 260 nm Gradient conditions: Ratio of mobile phase B 0 min: 30%, 16.5 min: 60%, 41.25 min: 69%, 70 min: 100%, 85 min 100%, 85.1 min: 30%, 103 min: 30%.

[0219] [Reaction Condition 1-2] Under nitrogen purging, diisopropyl azodicarboxylate (40% toluene solution) (59 μL, 0.12 mmol) was added to a suspension of DMTr-dT-p(III)-dT-Fujimat® (4) (100 mg, 0.05 mmol), methanesulfonamide (26 mg, 0.27 mmol), triethylamine (0.75 μL, 0.005 mmol), and molecular sieves 3A in dichloromethane (2 mL), and the mixture was stirred overnight at room temperature. After confirming the completion of the reaction, the reaction solution was filtered through a syringe filter. Acetonitrile (10 mL) was added dropwise to the filtrate, and the resulting precipitate was collected by filtration. The filtered product was washed with an acetonitrile-dichloromethane mixed solvent. The wet product was dried under reduced pressure to obtain a solid (96 mg, yield 91%) composed primarily of the title compound (13). As a result of measurement under HPLC condition 1, the HPLC area percentage of the title compound (13) was 72% (retention time: 50.5, 51.1 minutes).

[0220] Method using chloramine [Reaction condition 2-1] Under nitrogen purging, a solution of N-chloromethanesulfonamide sodium salt (12 mg, 0.08 mmol) in DMF (0.1 mL) and dichloromethane (0.3 mL) was added dropwise to a suspension of DMTr-dT-p(III)-dT-Fujimat® (4) (100 mg, 0.05 mmol) and molecular sieves 3A in dichloromethane (0.8 mL), and the mixture was stirred at room temperature for 30 minutes. After confirming the completion of the reaction, the reaction solution was passed through silica gel and filtered. Acetonitrile (8 mL) was added dropwise to the filtrate, and the resulting precipitate was collected by filtration. The filtered product was washed with an acetonitrile-dichloromethane mixed solvent. The wet product was dried under reduced pressure to obtain a solid (75 mg, yield 71%) consisting primarily of the title compound (13). As a result of measurement under HPLC condition 1, the HPLC area percentage of the title compound (13) was 34% (retention time: 52.5, 53.0 minutes). [Reaction condition 2-2] Under nitrogen purging, a solution of N-chloromethanesulfonamide sodium salt (25 mg, 0.16 mmol) and methanesulfonamide (77 mg, 0.81 mmol) in DMF (0.2 mL) and dichloromethane (0.6 mL) was added dropwise to a suspension of DMTr-dT-p(III)-dT-Fujimat® (4) (200 mg, 0.11 mmol) and molecular sieves 3A in dichloromethane (1.6 mL), and the mixture was stirred at room temperature for 30 minutes. After confirming the completion of the reaction, the reaction solution was passed through silica gel and filtered. Acetonitrile (12 mL) was added dropwise to the filtrate, and the resulting precipitate was collected by filtration. The filtered product was washed with an acetonitrile-dichloromethane mixed solvent. The wet product was dried under reduced pressure to obtain a solid (149 mg, yield 71%) composed mainly of the title compound (13). Measurement under HPLC condition 1 showed that the HPLC area percentage of the title compound (13) was 87% (retention time: 49.2, 49.8 minutes).

[0221] FeCl ２ [Reaction Condition 3-1] Under nitrogen purging, methanesulfonylazanyl benzoate (12) (28 mg, 0.13 mmol), FeCl ２ ・4H ２This was added to a suspension of 1.5 mL of dichloromethane (4.3 mg, 0.02 mmol) and stirred at room temperature for at least 10 minutes. DMTr-dT-p(III)-dT-Fujimat (registered trademark) (4) (200 mg, 0.11 mmol) was added, and the mixture was washed with 0.5 mL of dichloromethane and then stirred at room temperature. After confirming the completion of the reaction (approximately 3 hours), 16 mL of ethanol was added dropwise over 1 hour, and the resulting precipitate was collected by filtration. The filtered product was washed with an ethanol-dichloromethane mixed solvent and ethanol. The wet product was dried under reduced pressure to obtain a solid (153 mg, 73% yield) composed primarily of the title compound (13). The HPLC area percentage of the title compound (13) was 22% (retention time: 48.8, 49.3 minutes), and the HPLC area percentage of the DMTr-depleted compound (13) was 46% (retention time: 44.4, 45.0 minutes).

[0222] [Reaction Condition 3-2] Methanesulfonylazanyl benzoate (12) (46 mg, 0.22 mmol), FeCl ２ ・4H ２ N,N-diisopropylethylamine (15 μL, 0.11 mmol) was added to a suspension of 1.5 mL of dichloromethane (21.5 mg, 0.11 mmol) and the mixture was stirred at room temperature for at least 10 minutes. DMTr-dT-p(III)-dT-Fujimat® (4) (200 mg, 0.11 mmol) was added, and the mixture was washed with 0.5 mL of dichloromethane and then stirred at room temperature. After confirming the completion of the reaction (approximately 1 hour), N,N-diisopropylethylamine (15 μL, 0.11 mmol) was added. Ethanol (16 mL) was added dropwise over 1 hour, and the resulting precipitate was collected by filtration. The filtered product was washed with an ethanol-dichloromethane mixed solvent and ethanol. The wet product was dried under reduced pressure to obtain a solid (192 mg, 91% yield) composed primarily of the title compound (13). The HPLC area percentage of the title compound (13) was 85% (retention time: 49.3, 49.8 minutes). Compound (13) MS (ESI) [M+Na] ＋ calcd C １０８ H １６５ N ６ O ２１ PSNa ＋:1968.1378, Found:1968.1765. ３１ P-NMR (100MHz, CDCl ３ ): δ -3.1, -3.0. Compound (13) de-DMTr form MS (ESI) [M+Na] ＋ calcd C ８７ H １４７ N ６ O １９ PSNa ＋ :1666.0072, Found:1666.0056.

[0223] Example 7 DMTr-A ＭＯＥ -mspa-G ＭＯＥ -Synthesis of Fujimat® (14)

[0224] Method using Mitsunobu reagent: According to the method of [Reaction condition 1-1], DMTr-A ＭＯＥ -p(III)-G ＭＯＥ A solid (183 mg, 88%) containing the title compound (14) as the main component was obtained from Fujimat (registered trademark) (5) (200 mg, 0.09 mmol). HPLC area percentage: 64% (retention time: 48.3 minutes, HPLC condition 1).

[0225] Method using chloramine: According to the method of [Reaction Condition 2-2], DMTr-A ＭＯＥ -p(III)-G ＭＯＥ A solid (150 mg, 72%) containing the title compound (14) as the main component was obtained from Fujimat (registered trademark) (5) (200 mg, 0.09 mmol). HPLC area percentage: 77% (retention time: 48.3 minutes, HPLC condition 1).

[0226] FeCl ２ According to the method of [Reaction Condition 3-2], DMTr-A ＭＯＥ -p(III)-G ＭＯＥ A solid (181 mg, 87%) containing the title compound (14) as the main component was obtained from Fujimat (registered trademark) (5) (200 mg, 0.09 mmol). HPLC area percentage: 67% (retention time: 48.4 minutes, HPLC condition 1). MS (ESI) [M+H] ＋calcd C １２５ H １８６ N １２ O ２４ P.S. ＋ :2302.3161. Found:2302.3202. ３１ P-NMR (100MHz, CDCl ３ ): δ-2.8ppm.

[0227] Example 8 DMTr-A Ｍｅ -mspa-U Ｍｅ -Synthesis of Fujimat® (15)

[0228] Method using Mitsunobu reagent: According to the method of [Reaction condition 1-1], DMTr-A Ｍｅ -p(III)-U Ｍｅ A solid (175 mg, 84%) containing the title compound (15) as the main component was obtained from Fujimat (registered trademark) (6) (200 mg, 0.10 mmol). HPLC area percentage: 66% (retention time: 49.2 minutes, HPLC condition 1).

[0229] Method using chloramine: According to the method of [Reaction Condition 2-2], DMTr-A Ｍｅ -p(III)-U Ｍｅ A solid (161 mg, 77%) containing the title compound (15) as the main component was obtained from Fujimat (registered trademark) (6) (200 mg, 0.10 mmol). HPLC area percentage: 80% (retention time: 49.0 minutes, HPLC condition 1).

[0230] FeCl ２ According to the method of [Reaction Condition 3-2], DMTr-A Ｍｅ -p(III)-U Ｍｅ A solid (188 mg, 90%) containing the title compound (15) as the main component was obtained from Fujimat (registered trademark) (6) (200 mg, 0.10 mmol). HPLC area percentage: 53% (retention time: 49.2 minutes, HPLC condition 1). MS (ESI) [M+H] ＋ calcd C １１６ H １７１ N ９ O ２２ P.S. ＋:2105.1992, Found:2105.2287. ３１ P-NMR (100MHz, CDCl ３ ): δ-3.1, -2.8.

[0231] Example 9 DMTr-dC-mspa-dU Ｆ -Synthesis of Fujimat® (16)

[0232] Method using Mitsunobu reagent: According to the method in [Reaction condition 1-1], DMTr-dC-p(III)-dU Ｆ A solid (166 mg, 79%) containing the title compound (16) as the main component was obtained from Fujimat (registered trademark) (7) (200 mg, 0.10 mmol). HPLC area percentage: 68% (retention time: 52.9, 53.4 min, HPLC condition 1).

[0233] Method using chloramine: According to the method in [Reaction condition 2-2], DMTr-dC-p(III)-dU Ｆ A solid (148 mg, 71%) containing the title compound (16) as the main component was obtained from Fujimat (registered trademark) (7) (200 mg, 0.10 mmol). HPLC area percentage: 77% (retention time: 53.0, 53.5 min, HPLC condition 1).

[0234] FeCl ２ According to the method of [Reaction Condition 3-2], DMTr-dC-p(III)-dU Ｆ A solid (181 mg, 90%) containing the title compound (15) as the main component was obtained from Fujimat (registered trademark) (7) (200 mg, 0.10 mmol). HPLC area percentage: 74% (retention time: 53.0, 53.5 min, HPLC condition 1). MS (ESI) [M+Na] ＋ calcd C １１３ H １６５ FN ７ NaO ２１ P.S. ＋ :2061.1392, Found:2061.1590. ３１ P-NMR (100MHz, CDCl ３ ): δ-3.9, -2.8.

[0235] Example 10: DMTr-dC-mspa-U ＴＢＳ -Synthesis of Fujimat® (17)

[0236] Method using Mitsunobu reagent: According to the method in [Reaction condition 1-1], DMTr-dC-p(III)-U ＴＢＳ A solid (183 mg, 88%) containing the title compound (17) as the main component was obtained from Fujimat (registered trademark) (8) (200 mg, 0.10 mmol). HPLC area percentage: 64% (retention time: 57.9 minutes, HPLC condition 1).

[0237] Method using chloramine: According to the method of [Reaction Condition 2-2], DMTr-dC-p(III)-U ＴＢＳ A solid (144 mg, 69%) containing the title compound (17) as the main component was obtained from Fujimat (registered trademark) (8) (200 mg, 0.10 mmol). HPLC area percentage: 80% (retention time: 57.9 minutes, HPLC condition 1).

[0238] FeCl ２ According to the method of [Reaction Condition 3-2], DMTr-dC-p(III)-U ＴＢＳ A solid (167 mg, 80%) containing the title compound (15) as the main component was obtained from Fujimat (registered trademark) (8) (200 mg, 0.10 mmol). HPLC area percentage: 67% (retention time: 58.0 minutes, HPLC condition 1). MS (ESI) [M+Na] ＋ calcd C １１９ H １８０ N ７ O ２２ PSSiNa ＋ :2173.2301, Found:2173.2589. ３１ P-NMR (100MHz, CDCl ３ ): δ-3.3, -3.1.

[0239] Example 11: Synthesis of DMTr-dT-mspa-dT (18)

[0240] According to the method of [Reaction Condition 1-1] using Mitsunobu Reagent, a filtrate containing the title compound (18) as the main component was obtained from DMTr-dT-p(III)-dT (9) (200 mg, 0.23 mmol). Diisopropyl ether (40 mL) was added dropwise to the filtrate, and the resulting precipitate was collected by filtration. The filtered product was washed with a diisopropyl ether-dichloromethane mixed solvent and dried under reduced pressure at room temperature to obtain a solid (152 mg, 69%) containing the title compound (18) as the main component. Measurement under HPLC Condition 2 showed that the HPLC area percentage of the title compound (15) was 42% (retention time: 47.1, 47.5 minutes).

[0241] <HPLC conditions 2> Column: Inertsil ODS-3.5um (150MM x 4.6MM, 3.5μM) Mobile phase A: 5mM HCOOH / TEA in Water Mobile phase B: 5mM HCOOH / TEA in MeCN Flow rate: 0.4mL / min Injection volume: 1.5 μL Column temperature: 35°C Detection wavelength: 260 nm Gradient conditions: Ratio of mobile phase B 0 min: 20%, 50 min: 55%, 80 min: 100%, 94 min: 100%, 94.1 min: 20%, 110 min: 20%.

[0242] Method using chloramine: According to the method in [Reaction condition 2-2], a reaction solution containing the title compound (18) as the main component was obtained from DMTr-dT-p(III)-dT (9) (200 mg, 0.23 mmol). The reaction solution was filtered, and phosphate buffer (3 mL) was added to the filtrate for phase separation. The organic layer was washed with water and saturated saline. The organic layer was added dropwise to diisopropyl ether (16 mL), and the resulting precipitate was collected by filtration. The filtered product was washed with a diisopropyl ether-dichloromethane mixed solvent and dried under reduced pressure at room temperature to obtain a solid (151 mg, 68%) containing the title compound (15) as the main component. Measurement under HPLC condition 2 revealed that the HPLC area percentage of the title compound (18) was 80% (retention time: 47.1, 47.5 minutes).

[0243] FeCl ２According to the method of [Reaction Condition 3-2], a reaction solution containing the title compound (15) as the main component was obtained from DMTr-dT-p(III)-dT (9) (200 mg, 0.10 mmol). After confirming the completion of the reaction (approximately 1 hour), N,N-diisopropylethylamine (15 μL, 0.11 mmol) was added. After filtering through Celite, the filtrate was concentrated to dryness at room temperature and purified by column chromatography (spherical neutral silica gel, developing solvent: dichloromethane-2-propanol) to obtain a solid (160 mg, 72%) containing the title compound (15) as the main component. Measurement under HPLC Condition 2 revealed that the HPLC area percentage of the title compound (15) was 91% (retention time: 47.3, 47.7 min). MS (ESI) [M+Et ３ N.H.] ＋ calcd C ４５ H ５１ N ６ O １５ PSC ６ H １５ NH ＋ :1080.4148, Found:1080.4084 ３１ P-NMR (100MHz, CDCl ３ ): δ-3.1, -3.1.

[0244] Example 12: Synthesis of DMTr-dT-mspa-dT-TBDPS (19)

[0245] According to the method described in [Reaction Condition 1-1] using Mitsunobu Reagent, a filtrate containing the title compound (19) as the main component was obtained from DMTr-dT-p(III)-dT-TBDPS (10) (200 mg, 0.18 mmol). Diisopropyl ether (50 mL) was added dropwise to the filtrate, and the resulting precipitate was collected by filtration. The filtered product was washed with a diisopropyl ether-dichloromethane mixed solvent and dried under reduced pressure at room temperature to obtain a solid (145 mg, 67%) containing the title compound (19) as the main component. Measurement under HPLC Condition 3 revealed that the HPLC area percentage of the title compound (19) was 93% (retention time: 73.3, 74.9 minutes).

[0246] <HPLC conditions 3> Column: Inertsil ODS-3.5um (150MM x 4.6MM, 3.5μM) Mobile phase A: 5mM HCOOH / TEA in Water Mobile phase B: 5mM HCOOH / TEA in MeCN Flow rate: 0.4mL / min Injection volume: 1.5 μL Column temperature: 35°C Detection wavelength: 260 nm Gradient conditions: Ratio of mobile phase B 0 min: 40%, 25 min: 55%, 60 min: 68.5%, 100 min: 100%, 114 min: 100%, 114.1 min: 40%, 130 min: 40%.

[0247] According to the method described in [Reaction Condition 2-2] using chloramine, a filtrate containing the title compound (19) as the main component was obtained from DMTr-dT-p(III)-dT-TBDPS (10) (200 mg, 0.18 mmol). The filtrate was added dropwise to diisopropyl ether (16 mL), and the resulting precipitate was collected by filtration. The precipitate was washed with a diisopropyl ether-dichloromethane mixed solvent and dried under reduced pressure at room temperature to obtain a solid (127 mg, 59%) containing the title compound (19) as the main component. Measurement under HPLC Condition 3 revealed that the HPLC area percentage of the title compound (19) was 93% (retention time: 73.6, 75.1 minutes).

[0248] FeCl ２ According to the method of [Reaction Condition 3-2], a reaction solution containing the title compound (19) as the main component was obtained from DMTr-dT-p(III)-dT-TBDPS (10) (200 mg, 0.18 mmol). After confirming the completion of the reaction (approximately 1 hour), N,N-diisopropylethylamine (15 μL, 0.11 mmol) was added. After filtering through Celite, the filtrate was concentrated to dryness at room temperature and purified by column chromatography (spherical neutral silica gel, developing solvent: dichloromethane-2-propanol) to obtain a solid (111 mg, 51%) containing the title compound (19) as the main component. Measurement under HPLC Condition 3 revealed that the HPLC area percentage of the title compound (19) was 88% (retention time: 73.4, 75.0 min). MS (ESI) [M+Et ３ NH] ＋ calcd C ６ H ６９N ６ O １５ PSSi+C ６ H １5 NH ＋ :1318.5326. Found:1318.5477 ３１ P-NMR (100MHz, CDCl ３ ): δ-3.2, -3.1.

[0249] Example 13 Synthesis of DMTr-dT-mspa-dT-po-dA-ps-dT-Fujimat® (20) and DMTr-dT-mspa-dT-po-dA-ps-dT (21)

[0250] (Step 1) Method using Mitsunobu reagent: Under nitrogen purging, diisopropyl azodicarboxylate (40% toluene solution) (163 μL, 0.33 mmol) was added to a suspension of DMTr-dT-p(III)-dT-po-dA-ps-dT-Fujimat® (11) (200 mg, 0.07 mmol), methanesulfonamide (71 mg, 0.74 mmol), and molecular sieves 3A in dichloromethane (4 mL), and the mixture was stirred at room temperature overnight. After confirming the completion of the reaction, the reaction solution was filtered through a syringe filter. Acetonitrile (50 mL) was added dropwise to the filtrate, and the resulting precipitate was collected by filtration. The filtered product was washed with an acetonitrile-dichloromethane mixed solvent. The wet product was dried under reduced pressure to obtain a solid (168 mg, 81%) consisting primarily of the title compound (20).

[0251] According to the method of [Reaction Condition 2-2] using chloramine, a solid (145 mg, 70%) consisting mainly of the title compound (20) was obtained from dT-p(III)-dT-po-dA-ps-dT (11) (200 mg, 0.07 mmol).

[0252] FeCl ２ According to the method described in [Reaction Condition 3-2], a solid (189 mg, 91%) containing the title compound (20) as the main component was obtained from dT-p(III)-dT-po-dA-ps-dT (11) (200 mg, 0.10 mmol). MS (ESI) [M+H] ＋calcd C １４１ H ２０１ N １５ O ３３ P ３ S ２ ＋ :2789.3160. Found:2789.4839 ３１ P-NMR (100MHz, CDCl ３ ): δ-3.5, -3.4, -2.1, 67.3.

[0253] (Step-2) 2 mL of a 40% aqueous methylamine solution was added to 10 mg of a solid containing compound (20) as the main component obtained according to each reaction condition, and the mixture was heated and stirred at 65°C for approximately 30 minutes. After cooling, the mixture was concentrated to dryness, dissolved in pure water, and the insoluble matter was filtered. The filtrate was measured under HPLC condition 4. As a result, the HPLC area percentage of the title compound (21) was 61% (retention time: 13.8 minutes) in [reaction condition 1-1], 65% (retention time: 13.6 minutes) in [reaction condition 2-2], and 66% (retention time: 13.8 minutes) in [reaction condition 3-2].

[0254] <HPLC conditions 4> Column: Inertsil ODS-3.5um (150MM x 4.6MM, 3.5μM) Mobile phase A: 5mM HCOOH / TEA in Water Mobile phase B: 5mM HCOOH / TEA in MeCN Flow rate: 0.8mL / min Injection volume: 1.5 μL Column temperature: 35°C Detection wavelength: 260 nm Gradient conditions: Ratio of mobile phase B 0 min: 20%, 25 min: 55%, 40 min: 100%, 47 min: 100%, 47.1 min: 20%, 55 min: 20%. HRMS (ESI) [M+Et ３ N.H.] ＋ calcd C ６２ H ７３ N １２ O ２６ P ３ S ２ C ６ H １５ NH ＋ :1660.4691. Found:1660.5090.

[0255] Example 14 dMTr-A Ｍｅ -mspa-U ＭｅSynthesis of (25)

[0256] Method using Mitsunobu reagent (Step 1) Under nitrogen substitution, DMT-U Ｍｅ To a suspension of Nittophase (22) (250 mg, 0.05 mmol) in dichloromethane (2.5 mL), trifluoroacetic acid (23 μL, 0.30 mmol) and pyrrole (83 μL, 1.20 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Nittophase was collected from the reaction mixture by filtration, and a suspension of the collected Nittophase in acetonitrile (2.5 mL) was added with 5-(benzylthio)-1H-tetrazole (46 mg, 0.24 mmol) and DMTr-A Ｍｅ DMTr-A was filtered from the reaction mixture. Ｍｅ -p(III)-U Ｍｅ -Nittophase (23) was obtained.

[0257] (Step-2) DMTr-A under nitrogen substitution Ｍｅ -p(III)-U Ｍｅ To a suspension of Nittophase (23) and molecular sieves 3A in dichloromethane (5 mL), methanesulfonamide (44 mg, 0.46 mmol) and diisopropyl azodicarboxylate (40% toluene solution) (93 μL, 0.19 mmol) were added, and the mixture was stirred at room temperature overnight. DMTr-A was isolated by filtration from the reaction mixture. Ｍｅ -mspa-U Ｍｅ -Nittophase (24) was obtained.

[0258] (Step-3) DMTr-A at room temperature Ｍｅ -mspa-U ＭｅAcetonitrile (1 mL) and 28% aqueous ammonia (16.5 mL) were added to Nittophase (24), and the mixture was stirred at 60°C for 6 hours. After cooling, Nittophase was removed by filtration, and the resulting filtrate was concentrated to obtain a dry product (29 mg, 60%) consisting mainly of the title compound (25). Measurement under HPLC condition 4 revealed that the HPLC area percentage of the title compound (25) was 51% (retention time: 19.1 minutes), and the DMTr-free form of compound (25) was 25% (retention time: 2.7 minutes).

[0259] FeCl ２ (Step-1) Using DMT-U under nitrogen substitution Ｍｅ To a suspension of Nittophase (22) (200 mg, 0.04 mmol) in dichloromethane (3 mL), trifluoroacetic acid (28 μL, 0.36 mmol) and pyrrole (100 μL, 1.5 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Nittophase was collected from the reaction mixture by filtration, and a suspension of the collected Nittophase in acetonitrile (2 mL) was added with 5-(benzylthio)-1H-tetrazole (30 mg, 0.15 mmol) and DMTr-A Ｍｅ DMTr-A was filtered from the reaction mixture. Ｍｅ -p(III)-U Ｍｅ -Nittophase (23) was obtained.

[0260] (Step-2) DMTr-A Ｍｅ -p(III)-U Ｍｅ Nittophase (23) was mixed with methanesulfonylazanyl benzoate (12) (17 mg, 0.08 mmol), and a suspension of N,N-diisopropylethylamine (6 μL, 0.04 mmol) in dichloromethane (2 mL) was added. ２ ・4H ２ 0 (7.8 mg, 0.04 mmol) was added and stirred for 1 hour. DMTr-A was filtered from the reaction mixture. Ｍｅ -mspa-U Ｍｅ -Nittophase (24) was obtained.

[0261] (Step-3) DMTr-A at room temperature Ｍｅ -mspa-U Ｍｅ To Nittophase (24), 28% aqueous ammonia (1.5 mL) and ethanol (0.5 mL) were added, followed by stirring at 60°C for 7 hours. After cooling, Nittophase was removed by filtration, and the resulting filtrate was concentrated to dryness to obtain a solid (15 mg). As a result of measurement under HPLC condition 4, the HPLC area percentage of the title compound (25) was 0%, and the DMTr-free form of compound (25) was 31% (retention time: 2.7 minutes). The yield calculated as the DMT-free form was 58%. Compound (25) MS (ESI) [M-H] － calcd C ４３ H ４８ N ８ O １５ P.S. － :979.2697, Found:979.2578. ３１ P-NMR (100MHz, CDCl ３ ): δ-2.4, -1.8. DMT-free MS (ESI) [MH] of compound (25) － calcd C ２２ H ３０ N ８ O １３ P.S. － :677.1396, Found:677.1433.

[0262] Example 15: Method without isolation of DMTr-p(III)-dT-Fujimat®

[0263] Method using Mitsunobu reagent: Under nitrogen purging, 5-(benzylthio)-1H-tetrazole (62 mg, 0.32 mmol) was added to a solution (2 mL) of HO-dT-Fujimat® (3) (200 mg, 0.17 mmol) and DMTr-dT-phosphoramidite (246 mg, 0.33 mmol) in dichloromethane-toluene-1-methyl-2-pyrrolidone (9:9:2), followed by stirring at room temperature for 2 hours. After confirming the completion of the reaction, methanesulfonamide (157 mg, 1.65 mmol), 3Å molecular sieves, and dichloromethane (3 mL) were added to the reaction solution. Next, diisopropyl azodicarboxylate (40% toluene solution) (331 μL, 0.66 mmol) was added, followed by stirring at room temperature overnight. After confirming the completion of the reaction, the reaction solution was filtered through a syringe filter. Acetonitrile (25 mL) was added dropwise to the filtrate, and the resulting precipitate was collected by filtration. The filtered product was washed with an acetonitrile-dichloromethane mixed solvent. The wet product was dried under reduced pressure to obtain a solid containing the title compound (13) (289 mg, yield 90%). Measurement under HPLC condition 1 showed that the HPLC area percentage of the title compound (13) was 6% (retention time: 50.9, 51.5 minutes).

[0264] Method using chloramine: 5-(benzylthio)-1H-tetrazole (62 mg, 0.32 mmol) was added to a solution (2 mL) of DMTr-dT-phosphoramidite (246 mg, 0.33 mmol) in dichloromethane-toluene-1-methyl-2-pyrrolidone (9:9:2), and the mixture was stirred at room temperature for 2 hours. After confirming the completion of the reaction, a solution of N-chloromethanesulfonamide sodium salt (25 mg, 0.16 mmol) and methanesulfonamide (75 mg, 0.50 mmol) in DMF (0.3 mL) and dichloromethane (0.3 mL) was added dropwise to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. After confirming the completion of the reaction, the reaction solution was passed through silica gel and filtered. Acetonitrile (14 mL) was added dropwise to the filtrate, and the resulting precipitate was collected by filtration. The filtered product was washed with an acetonitrile-dichloromethane mixed solvent. The wet product was dried under reduced pressure to obtain a solid (320 mg, yield 99%) containing the title compound (13) as the main component. As a result of measurement under HPLC condition 1, the HPLC area percentage of the title compound (13) was 40% (retention time: 49.0, 49.5 minutes).

[0265] FeCl ２ Under nitrogen purging, 5-(benzylthio)-1H-tetrazole (62 mg, 0.32 mmol) was added to a dichloromethane solution (2 mL) of HO-dT-Fujimat® (3) (200 mg, 0.17 mmol) and DMTr-dT-phosphoramidite (246 mg, 0.33 mmol), and the mixture was stirred at room temperature for 2 hours. After confirming the completion of the reaction, the reaction mixture was diluted with methanesulfonylazanyl benzoate (12) (78 mg, 0.37 mmol), FeCl ２ ・4H ２0 (66 mg, 0.34 mmol) was added and the mixture was stirred for about 1 hour. After confirming the completion of the reaction, ethanol (16 mL) was added dropwise over 1 hour, and the resulting precipitate was collected by filtration. The filtered product was washed with an ethanol-dichloromethane mixed solvent and ethanol. The wet product was dried under reduced pressure to obtain a solid (301 mg, yield 93%) composed mainly of the title compound (13). The HPLC area percentage value of the title compound (13) was 45% (retention time: 48.7, 49.2 minutes), and the HPLC area percentage value of the DMTr-depleted title compound (13) was 39% (retention time: 44.5, 45.0 minutes).

[0266] Example 16: Synthesis of methanesulfonyl azanyl pivalate (26)

[0267] Triethylamine (0.97 mL, 6.9 mmol) was added to a solution of N-hydroxymethanesulfonamide (0.7 g, 6.3 mmol) in THF (63 mL) at an internal temperature of 0°C, and the mixture was stirred at the same temperature for approximately 10 minutes. Next, a solution of pivaloyl chloride (0.91 g, 7.5 mmol) in THF (0.7 mL) was added dropwise at 1.5°C over 34 minutes. After stirring at 3°C ​​for 3 hours, dilute hydrochloric acid and brine were added and the mixture was separated. Dilute hydrochloric acid and brine were added to the organic layer (upper layer), and the mixture was mixed and then separated. Brine was added to the organic layer (upper layer), and the mixture was mixed and then separated. The organic layer was dried over anhydrous magnesium sulfate. After removing the magnesium sulfate by filtration, the filtrate was concentrated to dryness under reduced pressure to obtain a crude product (1.09 g). The crude product was purified by column chromatography (spherical neutral silica gel, developing solvent: hexane-AcOEt) to obtain the title compound (1.01 g, 82%). １ H-NMR (400MHz, CDCl ３ ): δ1.34 (s, 9H), 3.09 (s, 3H), 8.70 (s, 1H).

[0268] Example 17: Synthesis of benzenesulfonyl azanyl benzoate (27)

[0269] Triethylamine (0.89 mL, 6.3 mmol) was added to a solution of N-hydroxybenzenesulfonamide (1.0 g, 5.8 mmol) in dichloromethane (30.0 mL) at an internal temperature of 0°C, and the mixture was stirred at the same temperature for approximately 15 minutes. Next, a solution of benzoyl chloride (0.89 g, 6.3 mmol) in dichloromethane (1.0 mL) was added dropwise at 0°C over 28 minutes. After stirring at 2°C for approximately 1.5 hours, the temperature was raised to room temperature and the mixture was stirred for an additional approximately 1 hour. An aqueous ammonium chloride solution was added, and the mixture was separated. The aqueous layer (upper layer) was extracted three times with dichloromethane. The organic layers were combined and dried over anhydrous magnesium sulfate. After removing the magnesium sulfate by filtration, the filtrate was concentrated to dryness under reduced pressure to obtain a crude product (1.77 g). The crude product was purified by column chromatography (spherical neutral silica gel, developing solvent: hexane-AcOEt) to obtain the title compound (0.87 g, 54%). １ H-NMR (400MHz, CDCl ３ ): δ7.42-7.51 (m, 4H), 7.59-7.64 (m, 2H), 7.89-7.96 (m, 4H), 9.24 (s, 1H).

[0270] Example 18 Synthesis of N-chloromethanesulfonamide tetrabutylammonium salt (28) Tetrabutylammonium bromide (355 mg, 1.3 mmol) was added to a solution of N-chloromethanesulfonamide sodium salt (250 mg, 2.0 mmol) in water (5 mL), and the mixture was stirred overnight. Dichloromethane was added to the reaction mixture, and the aqueous and organic layers were separated. The aqueous layer was extracted with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (0.33 g, 68%). １ H-NMR (400MHz, CDCl ３ ): δ1.02 (t, 12H), 1.44-1.52 (m, 8H), 1.68 (m, 8H), 2.95 (s, 3H), 3.37 (t, 8H)

[0271] Example 19: Synthesis of DMTr-dT-mspa-dT-Fujimat (registered trademark) (13)

[0272] Method using Mitsunobu reagent: Under nitrogen purging, diethyl azodicarboxylate (40% toluene solution) (50 μL, 0.12 mmol) was added to a suspension of DMTr-dT-p(III)-dT-Fujimat® (4) (100 mg, 0.05 mmol), methanesulfonamide (26 mg, 0.27 mmol), and molecular sieves 3A in dichloromethane (2 mL), and the mixture was stirred overnight at room temperature. After confirming the completion of the reaction, the reaction solution was filtered through a syringe filter and washed with 2 mL of dichloromethane. Acetonitrile (20 mL) was added dropwise to the filtrate, and the resulting precipitate was collected by filtration. The filtered product was then washed with acetonitrile. The wet product was dried under reduced pressure to obtain a solid (98 mg, yield 93%) consisting primarily of the title compound (13). As a result of measurement under HPLC condition 1, the HPLC area percentage of the title compound (13) was 70% (retention time: 49.4, 50.0 minutes).

[0273] Under nitrogen purging, di-tert-butyl azodicarboxylate (20% toluene solution) (143 μL, 0.12 mmol) was added to a suspension of DMTr-dT-p(III)-dT-Fujimat® (4) (100 mg, 0.05 mmol), methanesulfonamide (26 mg, 0.27 mmol), and molecular sieves 3A in dichloromethane (2 mL), and the mixture was stirred at room temperature overnight. After confirming the completion of the reaction, the reaction solution was filtered through a syringe filter and washed with 2 mL of dichloromethane. Acetonitrile (20 mL) was added dropwise to the filtrate, and the resulting precipitate was collected by filtration. The filtered product was washed with acetonitrile. The wet product was dried under reduced pressure to obtain a solid (98 mg, yield 93%) composed primarily of the title compound (13). As a result of measurement under HPLC condition 1, the HPLC area percentage of the title compound (13) was 61% (retention time: 49.4, 49.9 minutes).

[0274] Under nitrogen purging, dibenzyl azodicarboxylate (40% dichloromethane solution) (63 μL, 0.12 mmol) was added to a suspension of DMTr-dT-p(III)-dT-Fujimat® (4) (100 mg, 0.05 mmol), methanesulfonamide (26 mg, 0.27 mmol), and molecular sieves 3A in dichloromethane (2 mL), and the mixture was stirred at room temperature overnight. After confirming the completion of the reaction, the reaction solution was filtered through a syringe filter and washed with 2 mL of dichloromethane. Acetonitrile (20 mL) was added dropwise to the filtrate, and the resulting precipitate was collected by filtration. The filtered product was washed with acetonitrile. The wet product was dried under reduced pressure to obtain a solid (91 mg, 87% yield) composed primarily of the title compound (13). As a result of measurement under HPLC condition 1, the HPLC area percentage of the title compound (13) was 61% (retention time: 49.3, 49.9 minutes).

[0275] Method using chloramine: Under nitrogen purging, a solution of N-chloromethanesulfonamide tetrabutylammonium salt (28) (60 mg, 0.16 mmol) and methanesulfonamide (77 mg, 0.81 mmol) in DMF (0.2 mL) and dichloromethane (0.6 mL) was added dropwise to a suspension of DMTr-dT-p(III)-dT-Fujimat® (4) (200 mg, 0.11 mmol) and molecular sieves 3A in dichloromethane (1.6 mL), and the mixture was stirred at room temperature for 30 minutes. After confirming the completion of the reaction, the reaction solution was passed through silica gel and filtered. Acetonitrile (12 mL) was added dropwise to the filtrate, and the resulting precipitate was collected by filtration. The filtered product was washed with an acetonitrile-dichloromethane mixed solvent. The wet product was dried under reduced pressure to obtain a solid (155 mg, yield 69%) consisting primarily of the title compound (13). As a result of measurement under HPLC condition 1, the HPLC area percentage of the title compound (13) was 42% (retention time: 49.4, 49.9 minutes).

[0276] Method using methanesulfonylazanil: Under nitrogen purging, methanesulfonylazanil benzoate (12) (46 mg, 0.22 mmol), CuCl ２N,N-Diisopropylamine (15 μL, 0.11 mmol) was added to a suspension of 14.5 mg (14.5 mg, 0.11 mmol) in dichloromethane (2.0 mL), and the mixture was stirred at room temperature for 1 minute. DMTr-dT-p(III)-dT-Fujimat® (4) (200 mg, 0.11 mmol) was added, and the mixture was stirred at room temperature for 4 hours. After confirming the completion of the reaction, ethanol (16 mL) was added dropwise over 35 minutes, and the resulting precipitate was collected by filtration. The filtered product was washed with an ethanol-dichloromethane mixed solvent. The wet product was dried under reduced pressure to obtain a solid (161 mg, 77% yield) composed mainly of the title compound (13). The HPLC area percentage of the title compound (13) was 29% (retention time: 49.4, 49.9 minutes).

[0277] Under nitrogen purging, methanesulfonylazanyl benzoate (12) (46 mg, 0.22 mmol), FeBr ２ N,N-Diisopropylamine (15 μL, 0.11 mmol) was added to a suspension of 13 (23.3 mg, 0.11 mmol) in dichloromethane (2.0 mL), and the mixture was stirred for 4 minutes at room temperature. DMTr-dT-p(III)-dT-Fujimat® (4) (200 mg, 0.11 mmol) was added, and the mixture was stirred for 1 hour at room temperature. After confirming the completion of the reaction, ethanol (16 mL) was added dropwise over 40 minutes, and the resulting precipitate was collected by filtration. The filtered product was washed with an ethanol-dichloromethane mixed solvent. The wet product was dried under reduced pressure to obtain a solid (180 mg, 86% yield) composed mainly of the title compound (13). The HPLC area percentage of the title compound (13) was 31% (retention time: 49.4, 50.0 minutes).

[0278] Under nitrogen, methanesulfonylazanyl benzoate (12) (46 mg, 0.22 mmol), Fe(OAc) ２N,N-Diisopropylamine (15 μL, 0.11 mmol) was added to a suspension of (18.8 mg, 0.11 mmol) in dichloromethane (2.0 mL) and stirred for 1 minute at room temperature. DMTr-dT-p(III)-dT-Fujimat® (4) (200 mg, 0.11 mmol) was added, and the mixture was stirred for 2 hours at room temperature. Methanesulfonylazanyl benzoate (12) (23 mg, 0.11 mmol) was added, and the mixture was stirred overnight. Ethanol (16 mL) was added dropwise over 30 minutes, and the resulting precipitate was collected by filtration. The filtered product was washed with an ethanol-dichloromethane mixed solvent. The wet product was dried under reduced pressure to obtain a solid (166 mg, yield 79%) consisting primarily of the title compound (13). The HPLC area percentage of the title compound (13) was 36% (retention time: 49.4, 50.0 min).

[0279] Under nitrogen, methanesulfonylazanyl pivalate (26) (42 mg, 0.22 mmol), FeCl ２ ・4H ２ N,N-Diisopropylamine (15 μL, 0.11 mmol) was added to a suspension of 1H (21.5 mg, 0.11 mmol) in dichloromethane (2.0 mL), and the mixture was stirred at room temperature for 1 minute. DMTr-dT-p(III)-dT-Fujimat® (4) (200 mg, 0.11 mmol) was added, and the mixture was stirred at room temperature for 35 minutes. Ethanol (16 mL) was added dropwise over 30 minutes, and the resulting precipitate was collected by filtration. The filtered product was washed with an ethanol-dichloromethane mixed solvent. The wet product was dried under reduced pressure to obtain a solid (178 mg, 85% yield) composed mainly of the title compound (13). The HPLC area percentage of the title compound (13) was 73% (retention time: 49.4, 50.0 minutes).

[0280] Example 20: Synthesis of DMTr-dT-bspa-dT-Fujimat (registered trademark) (29)

[0281] Method using Mitsunobu reagent: Under nitrogen purging, diisopropyl azodicarboxylate (40% toluene solution) (59 μL, 0.12 mmol) was added to a suspension of DMTr-dT-p(III)-dT-Fujimat® (4) (100 mg, 0.05 mmol), benzenesulfonamide (42 mg, 0.27 mmol), and molecular sieves 3A in dichloromethane (2 mL), and the mixture was stirred overnight at room temperature. After confirming the completion of the reaction, the reaction solution was filtered through a syringe filter and washed with 2 mL of dichloromethane. Acetonitrile (20 mL) was added dropwise to the filtrate, and the resulting precipitate was collected by filtration. The filtered product was then washed with acetonitrile. The wet product was dried under reduced pressure to obtain a solid (94 mg, 87% yield) consisting primarily of the title compound (13). As a result of measurement under HPLC condition 1, the HPLC area percentage of the title compound (29) was 77% (retention time: 49.9, 50.3 minutes).

[0282] Method using chloramine: Under nitrogen purging, a solution of N-chlorobenzenesulfonamide sodium salt (35 mg, 0.16 mmol) and benzenesulfonamide (127 mg, 0.81 mmol) in DMF (0.2 mL) and dichloromethane (0.6 mL) was added dropwise to a suspension of DMTr-dT-p(III)-dT-Fujimat® (4) (200 mg, 0.11 mmol) and molecular sieves 3A in dichloromethane (1.6 mL), and the mixture was stirred at room temperature for 30 minutes. After confirming the completion of the reaction, the reaction solution was passed through silica gel and filtered. Acetonitrile (12 mL) was added dropwise to the filtrate, and the resulting precipitate was collected by filtration. The filtered product was washed with an acetonitrile-dichloromethane mixed solvent. The wet product was dried under reduced pressure to obtain a solid (154 mg, yield 68%) consisting primarily of the title compound. As a result of measurement under HPLC condition 1, the HPLC area percentage of the title compound (29) was 75% (retention time: 49.8, 50.2 minutes).

[0283] Method using benzenesulfonylazanyl benzoate: Benzenesulfonylazanyl benzoate (27) (60 mg, 0.22 mmol), FeCl ２ ・4H ２N,N-Diisopropylamine (15 μL, 0.11 mmol) was added to a suspension of 21.5 mg (0.11 mmol) of 2H2O (21.5 mg, 0.11 mmol) in dichloromethane (2.0 mL), and the mixture was stirred at room temperature for 2 minutes. DMTr-dT-p(III)-dT-Fujimat® (4) (200 mg, 0.11 mmol) was added, and the mixture was stirred at room temperature for approximately 3 hours. Ethanol (16 mL) was added dropwise over 38 minutes, and the resulting precipitate was collected by filtration. The filtered product was washed with an ethanol-dichloromethane mixed solvent. The wet product was dried under reduced pressure to obtain a solid (178 mg, 82% yield) composed mainly of the title compound (29). The HPLC area percentage of the title compound (29) was 70% (retention time: 49.8, 50.2 minutes). Compound (29) MS (ESI) [M+Na] ＋ calcd C １１３ H １６７ N ６ O ２１ PSNa ＋ :2030.1535, Found:2030.1500. ３１ P-NMR (100MHz, CDCl ３ ): δ-4.0, -3.9.

[0284] The production method of the present invention can be used for producing oligonucleotides having an MsPA structure or amidite blocks having an MsPA structure. Furthermore, the production method of the present invention can safely obtain MsPA. These methods are extremely useful for synthesizing various nucleic acid drugs and, ultimately, are extremely useful for the development of nucleic acid drugs.

Claims

1. A compound represented by general formula (1) or a salt thereof, and R ａ SO ２ N.H. ２ or a derivative thereof, and azodicarboxylic acid or a derivative thereof. (In the formula, Base represents a nucleic acid base which may be modified. When two or more Bases are present, the multiple Bases present may be the same or different. １ each independently represents a hydrogen atom, an optionally protected hydroxyl group, a halogen atom, an alkoxyl group having 1 to 4 carbon atoms, or a methoxyethoxy (MOE) group. １ If there are two or more, １ are the same or different. B ２ are each independently a hydrogen atom, a halogen atom, an alkoxyl group having 1 to 4 carbon atoms, or a methoxyethoxy (MOE) group, or B １ and form an LNA (Locked Nucleic Acid) ring. The LNA ring may be substituted with an alkyl group having 1 to 4 carbon atoms, a hydroxyl group, or an alkoxyl group having 1 to 4 carbon atoms. ２ are the same or different; W represents a hydrogen atom or a protecting group; Z each independently represents O, S, a lone electron pair, or R ａ SO ２ N. Multiple Z's are the same or different. Each Q independently represents an alkoxy group having 1 to 6 carbon atoms, a dialkylamino group having 1 to 6 carbon atoms, an allyloxy group, a 2-cyanoethoxy group, a 2-nitroethoxy group, or a piperazino group in which the nitrogen atom at the 4-position is protected with a protecting group and which may be further substituted. When there are two or more Q's, the multiple Q's are the same or different. n represents any integer of 0 or more. R ａ represents an organic group having 1 to 10 carbon atoms which may be substituted; T represents a hydrogen atom, a pseudo solid-phase protecting group, a solid-phase protecting group, a silyl-based protecting group, or an acyl-based protecting group.

2. A compound represented by general formula (1) or a salt thereof, and R ａ SO ２ A method for producing a compound represented by general formula (2) or a salt thereof, comprising: a step (2) of reacting with NVY. (In the formula, Base represents a nucleic acid base which may be modified. When two or more Bases are present, the multiple Bases present may be the same or different. １ each independently represents a hydrogen atom, an optionally protected hydroxyl group, a halogen atom, an alkoxyl group having 1 to 4 carbon atoms, or a methoxyethoxy (MOE) group. １ If there are two or more, １ are the same or different. B ２ are each independently a hydrogen atom, a halogen atom, an alkoxyl group having 1 to 4 carbon atoms, or a methoxyethoxy (MOE) group, or B １ and form an LNA (Locked Nucleic Acid) ring. The LNA ring may be substituted with an alkyl group having 1 to 4 carbon atoms, a hydroxyl group, or an alkoxyl group having 1 to 4 carbon atoms. ２ are the same or different; W represents a hydrogen atom or a protecting group; Z each independently represents O, S, a lone electron pair, or R ａ SO ２ N. Multiple Z's are the same or different. Each Q independently represents an alkoxy group having 1 to 6 carbon atoms, a dialkylamino group having 1 to 6 carbon atoms, an allyloxy group, a 2-cyanoethoxy group, a 2-nitroethoxy group, or a piperazino group in which the nitrogen atom at the 4-position is protected with a protecting group and which may be further substituted. When there are two or more Q's, the multiple Q's are the same or different. n represents any integer of 0 or more. R ａ represents an organic group having 1 to 10 carbon atoms which may be substituted; V represents a halogen atom; Y represents a hydrogen atom, an alkali metal atom, an alkaline earth metal atom, an amine salt, or a quaternary ammonium salt; T represents a pseudo solid-phase protecting group, a solid-phase protecting group, a silyl-based protecting group, or an acyl-based protecting group.

3. A compound represented by general formula (1) or a salt thereof, and R ａ SO ２ NYOCOR ｂ and M. １ -X １ A method for producing a compound represented by general formula (2) or a salt thereof, comprising the step (3) of reacting (In the formula, Base represents a nucleic acid base which may be modified. When two or more Bases are present, the multiple Bases present may be the same or different. １ each independently represents a hydrogen atom, an optionally protected hydroxyl group, a halogen atom, an alkoxyl group having 1 to 4 carbon atoms, or a methoxyethoxy (MOE) group. １ If there are two or more, １ are the same or different. B ２ are each independently a hydrogen atom, a halogen atom, an alkoxyl group having 1 to 4 carbon atoms, or a methoxyethoxy (MOE) group, or B １ and form an LNA (Locked Nucleic Acid) ring. The LNA ring may be substituted with an alkyl group having 1 to 4 carbon atoms, a hydroxyl group, or an alkoxyl group having 1 to 4 carbon atoms. ２ are the same or different; W represents a hydrogen atom or a protecting group; Z each independently represents O, S, a lone electron pair, or R ａ SO ２ N. Multiple Z's are the same or different. Each Q independently represents an alkoxy group having 1 to 6 carbon atoms, a dialkylamino group having 1 to 6 carbon atoms, an allyloxy group, a 2-cyanoethoxy group, a 2-nitroethoxy group, or a piperazino group in which the nitrogen atom at the 4-position is protected with a protecting group and which may be further substituted. When there are two or more Q's, the multiple Q's are the same or different. n represents any integer of 0 or more. R ａ R represents an organic group having 1 to 10 carbon atoms which may be substituted. ｂ represents an optionally substituted alkyl group having 1 to 10 carbon atoms, or an optionally substituted aryl group having 3 to 10 carbon atoms. Y represents a hydrogen atom, an alkali metal atom, an alkaline earth metal atom, an amine salt, or a quaternary ammonium salt. T represents a pseudo solid-phase protecting group, a solid-phase protecting group, a silyl-based protecting group, or an acyl-based protecting group. M １ is selected from Fe, Mn, Zn, Ni, or Cu. １ is Cl, Br, SO ４ , P.O. ４ , CO ３ , R ｘ COO, R ｘ SO ３、 BF ４ , and P.F. ６ The number of the atoms or atomic groups is selected from the group consisting of M １ Depends on the valence of R ｘ represents an organic group having 1 to 10 carbon atoms which may be substituted.

4. The azodicarboxylic acid or its derivative is R １０ OCON=NCOOR １１ (In the formula, R １０ R represents an organic group having 1 to 10 carbon atoms which may be substituted. １１ represents an optionally substituted organic group having 1 to 10 carbon atoms.

5. The method according to claim 1, wherein the azodicarboxylic acid or a derivative thereof is dimethyl azodicarboxylate, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), di-tert-butyl azodicarboxylate, bis(methoxyethyl) azodicarboxylate, bis(2,2,2-trichloroethyl) azodicarboxylate, dibenzyl azodicarboxylate, azobis(N,N-dimethylformamide), 1,1-(azodicarbonyl)dipiperidine, or a combination thereof.

6. The above R ａ SO ２ NVY is CH ３ SO ２ NCl-Li, CH ３ SO ２ NCl-Na, CH ３ SO ２ NCl-K, CH ３ SO ２ NCl-Cs, CH ３ SO ２ NCl-Trimethylammonium, CH ３ SO ２ NCl-Triethylammonium, CH ３ SO ２ NCl-Diisopropylethylammonium, CH ３ SO ２ NCl-Tetramethylammonium, CH ３ SO ２ NCl-Tetraethylammonium, CH ３ SO ２ NCl-Tetrapropylammonium, CH ３ SO ２ NCl-Tetrabutylammonium, C ２ H ５ SO ２ NCl-Li, C ２ H ５ SO ２ NCl-Na, C ２ H ５ SO ２ NCl-K, C ２ H ５ SO ２ NCl-Cs, C ２ H ５ SO ２ NCl-trimethylammonium, C ２ H ５ SO ２ NCl-triethylammonium, C ２ H ５ SO ２ NCl-Diisopropylethylammonium, C ２ H ５ SO ２ NCl-Tetramethylammonium, C ２ H ５ SO ２ NCl-Tetraethylammonium, C ２ H ５ SO ２ NCl-Tetrapropylammonium, C ２ H ５ SO ２ NCl-Tetrabutylammonium, C ３ H ７ SO ２ NCl-Li, C ３ H ７ SO ２ NCl-Na, C ３ H ７ SO ２ NCl-K, C ３ H ７ SO ２ NCl-Cs, C ３ H ７ SO ２ NCl-trimethylammonium, C ３ H ７ SO ２ NCl-triethylammonium, C ３ H ７ SO ２ NCl-Diisopropylethylammonium, C ３ H ７ SO ２ NCl-Tetramethylammonium, C ３ H ７ SO ２ NCl-Tetraethylammonium, C ３ H ７ SO ２ NCl-Tetrapropylammonium, C ３ H ７ SO ２ NCl-Tetrabutylammonium, C ６ H ５ SO ２ NCl-Li, C ６ H ５ SO ２ NCl-Na, C ６ H ５ SO ２ NCl-K, C ６ H ５ SO ２ NCl-Cs, C ６ H ５ SO ２ NCl-trimethylammonium, C ６ H ５ SO ２ NCl-triethylammonium, C ６ H ５ SO ２ NCl-Diisopropylethylammonium, C ６ H ５ SO ２ NCl-Tetramethylammonium, C ６ H ５ SO ２ NCl-Tetraethylammonium, C ６ H ５ SO ２ NCl-Tetrapropylammonium, C ６ H ５ SO ２ NCl-Tetrabutylammonium, CH ３ C ６ H ４ SO ２ NCl-Li, CH ３ C ６ H ４ SO ２ NCl-Na, CH ３ C ６ H ４ SO ２ NCl-K, CH ３ C ６ H ４ SO ２ NCl-Cs, CH ３ C ６ H ４ SO ２ NCl-Trimethylammonium, CH ３ C ６ H ４ SO ２ NCl-Triethylammonium, CH ３ C ６ H ４ SO ２ NCl-Diisopropylethylammonium, CH ３ C ６ H ４ SO ２ NCl-Tetramethylammonium, CH ３ C ６ H ４ SO ２ NCl-Tetraethylammonium, CH ３ C ６ H ４ SO ２ NCl-Tetrapropylammonium, CH ３ C ６ H ４ SO ２ 3. The method of claim 2, wherein the ammonium nitrate is tetrabutylammonium chloride, ...

7. The method according to any one of claims 1 to 6, wherein T is a pseudo solid-phase protecting group having a phenyl group substituted with an alkyloxy group having from 10 to 300 carbon atoms and / or an alkenyloxy group having from 10 to 300 carbon atoms.

8. The method according to any one of claims 1 to 6, wherein T is a group represented by general formula (3). (In the formula, each R independently represents an optionally substituted alkyl group having 10 to 40 carbon atoms; m1 represents an integer of 1 to 5. When m1 is 2 or more, a plurality of RO's may be the same or different; X represents O, S, NH, or NR Ｎ n1 represents an integer of 1 to 4. Ｎ represents an optionally substituted alkyl group having 1 to 6 carbon atoms. * represents a bond to the general formulae (1) and (2).

9. The method according to any one of claims 1 to 6, wherein Q is a 2-cyanoethoxy group.

10. The method according to any one of claims 1 to 6, further comprising, prior to the steps (1), (2), or (3), carrying out a step (4) of reacting a compound represented by general formula (4) or a salt thereof with a compound represented by general formula (5) or a salt thereof.

11. The method of claim 10, wherein step (4) and step (1), (2), or (3) are carried out in a continuous process.

12. A method for producing a compound represented by general formula (6) or a salt thereof, comprising the step (5) of deprotecting T of a compound represented by general formula (2) or a salt thereof obtained by the method according to any one of claims 1 to 6, and then the step (6) of phosphoramidite formation to obtain a compound represented by general formula (6) or a salt thereof.

13. A method for producing a compound represented by general formula (7) or a salt thereof, comprising a step (7) of deprotecting a protecting group of a compound represented by general formula (2) or a salt thereof obtained by the method according to any one of claims 1 to 6 to obtain a compound represented by general formula (7) or a salt thereof.

14. A compound represented by general formula (8) or a salt thereof. (In the formula, Base represents a nucleic acid base which may be modified. When two or more Bases are present, the multiple Bases present may be the same or different. １ each independently represents a hydrogen atom, an optionally protected hydroxyl group, a halogen atom, an alkoxyl group having 1 to 4 carbon atoms, or a methoxyethoxy (MOE) group. １ If there are two or more, １ are the same or different. B ２ are each independently a hydrogen atom, a halogen atom, an alkoxyl group having 1 to 4 carbon atoms, or a methoxyethoxy (MOE) group, or B １ and form an LNA (Locked Nucleic Acid) ring. The LNA ring may be substituted with an alkyl group having 1 to 4 carbon atoms, a hydroxyl group, or an alkoxyl group having 1 to 4 carbon atoms. ２ are the same or different; W represents a hydrogen atom or a protecting group; Z each independently represents O, S, a lone electron pair, or R ａ SO ２ When two or more Z's are present, the multiple Z's may be the same or different, but at least one Z' is R ａ SO ２ N. Each Q independently represents an alkoxy group having 1 to 6 carbon atoms, a dialkylamino group having 1 to 6 carbon atoms, an allyloxy group, a 2-cyanoethoxy group, a 2-nitroethoxy group, or a piperazino group in which the nitrogen atom at the 4-position is protected with a protecting group and which may be further substituted. When there are two or more Qs, the multiple Qs may be the same or different. R ａ represents an organic group having 1 to 10 carbon atoms which may be substituted. n represents any integer of 0 or more. R each independently represents an alkyl group having 10 to 40 carbon atoms which may be substituted. m represents an integer of 1 to 5. When m is 2 or more, the multiple RO's present are the same or different. X represents O, S, NH, or NR Ｎ n1 represents an integer of 1 to 4. Ｎ represents an optionally substituted alkyl group having 1 to 6 carbon atoms.

15. A compound represented by general formula (9) or a salt thereof. (In the formula, Base represents a nucleic acid base which may be modified. When two or more Bases are present, the multiple Bases present may be the same or different. １ each independently represents a hydrogen atom, an optionally protected hydroxyl group, a halogen atom, an alkoxyl group having 1 to 4 carbon atoms, or a methoxyethoxy (MOE) group. １ If there are two or more, １ are the same or different. B ２ are each independently a hydrogen atom, a halogen atom, an alkoxyl group having 1 to 4 carbon atoms, or a methoxyethoxy (MOE) group, or １ and form an LNA (Locked Nucleic Acid) ring. The LNA ring may be substituted with an alkyl group having 1 to 4 carbon atoms, a hydroxyl group, or an alkoxyl group having 1 to 4 carbon atoms. ２ are the same or different; W represents a hydrogen atom or a protecting group; Z each independently represents O, S, a lone electron pair, or R ａ SO ２ When two or more Z's are present, the multiple Z's may be the same or different, but at least one Z' is R ａ SO ２ N. Each Q independently represents an alkoxy group having 1 to 6 carbon atoms, a dialkylamino group having 1 to 6 carbon atoms, an allyloxy group, a 2-cyanoethoxy group, a 2-nitroethoxy group, or a piperazino group in which the nitrogen atom at the 4-position is protected with a protecting group and which may be further substituted. When there are two or more Qs, the multiple Qs may be the same or different. R ａ represents an organic group having 1 to 10 carbon atoms which may be substituted. n represents an integer of 0 or more. １ , R ２ , and R ３ Each of X is independently an optionally substituted alkyl group having 10 to 40 carbon atoms. Ｎ n1 represents an integer of 1 to 4. Ｎ represents an optionally substituted alkyl group having 1 to 6 carbon atoms.

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