Method for producing compound, and compound

Abstract

Provided are: a method for producing a compound useful as a nucleic acid monomer; and a compound useful as a starting material or an intermediate in the production method.　The method for producing a compound according to the present invention involves: an aryl oxidation step for reacting a compound (1) with a phenol compound ArOH in the presence of an amino group-protecting agent to obtain a compound (2); an amination step for reacting the compound (2) with an amine compound HNR6R7 to obtain a compound (3); and an oxidative halogenation step for oxidatively halogenating the compound (3) with a halogenating agent to obtain a compound (4). In the formula, R1 is an aryl group having or not having a substituent, R2 to R4 are each a hydrogen atom or the like, R5 is a protecting group for an amino group, R6 and R7 are each a hydrogen atom or the like, Ar is an aryl group having or not having a substituent, X is a halogenyl group, Nu is a monovalent group (5) or (6), R11 to R15 are each a hydrogen atom or the like, R21 is a protecting group for an amino group, and Bs is a nucleic acid base which may have a protecting group.

Description

Compound manufacturing method and compound

[0001] The present invention relates to a method for producing a compound and the compound. More specifically, the present invention relates to a method for producing a compound useful as a nucleic acid monomer, and a compound useful as a starting material or intermediate for the production method.

[0002] Antisense molecules, which have a base sequence complementary to that of a target nucleic acid, form a complementary duplex with the target nucleic acid and can inhibit protein production from the target nucleic acid. When a disease-related gene is selected as the target nucleic acid, antisense molecules act directly on the disease-related gene, and are therefore attracting attention as effective medicines for gene therapy.

[0003] In order to efficiently inhibit the production of a target protein, antisense molecules (nucleic acid oligomers) are primarily required to have cell membrane permeability, nuclease resistance, chemical stability in the body (e.g., in an environment of pH 7.4), and the ability to form stable duplexes only with specific base sequences. Known examples of antisense molecules include morpholino nucleic acids.

[0004] Antisense molecules can be chemically synthesized, for example, by polymerizing nucleic acid monomers. For example, morpholino nucleic acids can be chemically synthesized by polymerizing morpholino nucleic acid monomers. Examples of methods for producing nucleic acid monomers include the method for producing morpholino nucleic acid monomers disclosed in Patent Document 1.

[0005] International Publication No. 2024 / 010870

[0006] An object of the present invention is to provide a method for producing a compound useful as a nucleic acid monomer, and a compound useful as a starting material or intermediate for the production method.

[0007] Specific means for solving the above problems include the following embodiments: <1> An aryloxylation step of reacting a compound represented by the following general formula (1) with a phenol compound represented by the formula ArOH (wherein Ar is as described below) in the presence of an amino group-protecting agent to obtain a compound represented by the following general formula (2); ６ R ７ (In the formula, R ６ and R ７ is as described below.) to obtain a compound represented by the following general formula (3), and an oxidative halogenation step to oxidatively halogenate the compound represented by the following general formula (3) with a halogenating agent to obtain a compound represented by the following general formula (4). (In general formula (1), R １ represents an aryl group having or without a substituent, R ２ ~R ４ each independently represents a hydrogen atom, a halogen group, or an alkyl group having or without a substituent, or R ３ and R ４ are bonded to each other to form a heterocycle of 5 or more members which may or may not have a substituent, and Nu is represented by the following general formula (5) or (6): (In general formula (5) or (6), R １１ ~R １５ each independently represents a hydrogen atom, a halogenyl group, a substituted or unsubstituted alkyl group, a group represented by the formula OR (wherein R represents a hydroxyl-protecting group or a substituted or unsubstituted alkyl group), an amino group, an azide group, or a cyano group, or R １３ and R １４ , or R １３ and R １５ are bonded to each other to form a ring of 5 or more members, which may or may not have a substituent and which may or may not have a hetero atom; R ２１ represents a protecting group for an amino group, and Bs represents a nucleic acid base, which may or may not have a protecting group for the nucleic acid base. (In general formula (2), R １ ~R４ and Nu are as described above, and R ５ represents a protecting group for an amino group, and Ar represents an aryl group which may or may not have a substituent. (In general formula (3), R １ ~R ５ and Nu are as described above, and R ６ and R ７ each independently represents a hydrogen atom, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted aryl group, or R ６ and R ７ are bonded to each other to form a heterocyclic ring which may or may not have a substituent. (In general formula (4), R ６ , R ７ , and Nu are as defined above, and X represents a halogenyl group.

[0008] <2> The compound represented by the following general formula (2) is ６ R ７ (In the formula, R ６ and R ７ is as described below.) to obtain a compound represented by the following general formula (3), and an oxidative halogenation step to oxidatively halogenate the compound represented by the following general formula (3) with a halogenating agent to obtain a compound represented by the following general formula (4). (In general formula (2), R １ represents an aryl group having or without a substituent, R ２ ~R ４ each independently represents a hydrogen atom, a halogen group, or an alkyl group having or without a substituent, or R ３ and R ４ are bonded to each other to form a heterocyclic ring of 5 or more members which may or may not have a substituent, R ５ represents a protecting group for an amino group, Ar represents an aryl group having or having no substituent, and Nu represents a group represented by the following general formula (5) or (6): (In general formula (5) or (6), R １１ ~R １５each independently represents a hydrogen atom, a halogenyl group, a substituted or unsubstituted alkyl group, a group represented by the formula OR (wherein R represents a hydroxyl-protecting group or a substituted or unsubstituted alkyl group), an amino group, an azide group, or a cyano group, or R １３ and R １４ , or R １３ and R １５ are bonded to each other to form a ring of 5 or more members, which may or may not have a substituent and which may or may not have a hetero atom; R ２１ represents a protecting group for an amino group, and Bs represents a nucleic acid base, which may or may not have a protecting group for the nucleic acid base. (In general formula (3), R １ ~R ５ and Nu are as described above, and R ６ and R ７ each independently represents a hydrogen atom, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted aryl group, or R ６ and R ７ are bonded to each other to form a heterocyclic ring which may or may not have a substituent. (In general formula (4), R ６ , R ７ , and Nu are as defined above, and X represents a halogenyl group.

[0009] <3> A method for producing a compound, comprising an oxidative halogenation step of oxidatively halogenating a compound represented by the following general formula (3) with a halogenating agent to obtain a compound represented by the following general formula (4): (In general formula (3), R １ represents an aryl group having or without a substituent, R ２ ~R ４ each independently represents a hydrogen atom, a halogen group, or an alkyl group having or without a substituent, or R ３ and R ４ are bonded to each other to form a heterocyclic ring of 5 or more members which may or may not have a substituent, R ５ represents a protecting group for an amino group, R ６ and R ７each independently represents a hydrogen atom, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted aryl group, or R ６ and R ７ are bonded to each other to form a heterocycle having or not having a substituent, and Nu is represented by the following general formula (5) or (6): (In general formula (5) or (6), R １１ ~R １５ each independently represents a hydrogen atom, a halogenyl group, a substituted or unsubstituted alkyl group, a group represented by the formula OR (wherein R represents a hydroxyl-protecting group or a substituted or unsubstituted alkyl group), an amino group, an azide group, or a cyano group, or R １３ and R １４ , or R １３ and R １５ are bonded to each other to form a ring of 5 or more members, which may or may not have a substituent and which may or may not have a hetero atom; R ２１ represents a protecting group for an amino group, and Bs represents a nucleic acid base, which may or may not have a protecting group for the nucleic acid base. (In general formula (4), R ６ , R ７ , and Nu are as defined above, and X represents a halogenyl group.

[0010] <4> The method for producing the compound according to <1> or <2>, wherein Ar is an aryl group having or without a substituent such that the pKa of the phenol compound represented by the formula ArOH is 6.4 to 7.7.

[0011] <5> R １ <1> - <3> The method for producing the compound according to any one of <1> to <3>, wherein is a 4-methoxyphenyl group.

[0012] <6> R １ is a 4-methoxyphenyl group.

[0013] <7> A method for producing the compound according to any one of <1> to <3>, wherein the stereochemistry of the phosphorus atom is controlled.

[0014] <8> R １is a 4-methoxyphenyl group.

[0015] <9> The method for producing a compound according to <1>, wherein the compound represented by general formula (1) is a morpholino nucleic acid monomer derivative represented by general formula (11): (In general formula (11), R １ ~R ４ , R ２１ , and Bs are as described above.) (In general formula (12), R １ ~R ５ , R ２１ , Ar, and Bs are as defined above.) (In general formula (13), R １ ~R ７ , R ２１ , and Bs are as described above.) (In general formula (14), R ６ , R ７ , R ２１ , X, and Bs are as described above.)

[0016] <10> The method for producing a compound according to <2>, wherein the compound represented by general formula (2) is a morpholino nucleic acid monomer derivative represented by the following general formula (12): The compound represented by general formula (3) is a morpholino nucleic acid monomer derivative represented by the following general formula (13): The compound represented by general formula (4) is a morpholino nucleic acid monomer represented by the following general formula (14): The method for producing the compound is a method for producing a morpholino nucleic acid monomer: (In general formula (12), R １ ~R ５ , R ２１ , Ar, and Bs are as defined above.) (In general formula (13), R １ ~R ７ , R ２１ , and Bs are as described above.) (In general formula (14), R ６ , R ７ , R ２１ , X, and Bs are as described above.)

[0017] <11> The method for producing a compound according to <3>, wherein the compound represented by general formula (3) is a morpholino nucleic acid monomer derivative represented by the following general formula (13): (In general formula (13), R １ ~R ７ , R ２１ , and Bs are as described above.) (In general formula (14), R ６ , R ７ , R ２１ , X, and Bs are as described above.)

[0018] <12> The method for producing a compound according to <9> or <10>, wherein Ar is an aryl group having or without a substituent such that the pKa of the phenol compound represented by the formula ArOH is 6.4 to 7.7.

[0019] <13> R １ <12> The method for producing the compound according to any one of <9> to <11>, wherein is a 4-methoxyphenyl group.

[0020] <14> R １ is a 4-methoxyphenyl group.

[0021] <15> A method for producing the compound according to any one of <9> to <11>, in which the stereochemistry of the phosphorus atom is controlled.

[0022] <16> R １ is a 4-methoxyphenyl group.

[0023] <17> A compound represented by the following general formula (1a): (In general formula (1a), R １ represents an aryl group having or without a substituent, R ２ ~R ４ each independently represents a hydrogen atom, a halogen group, or an alkyl group having or without a substituent, or R ３ and R ４ are bonded to each other to form a heterocycle of 5 or more members which may or may not have a substituent, and Nu′ is a group represented by the following general formula (5a) or (6a): (In general formula (5a) or (6a), R １１ａ , R １２ａ , and R １４ａ each independently represents a hydrogen atom, a halogenyl group, a substituted or unsubstituted alkyl group, a group represented by the formula OR′ (wherein R′ represents a hydrogen atom, a hydroxyl-protecting group, or a substituted or unsubstituted alkyl group), an amino group, an azide group, or a cyano group; R １３ｂ and R １５ｂ are bonded to each other to form a ring of 5 or more members, which may or may not have a substituent and which may or may not have a hetero atom; R ２１ａ represents a hydrogen atom or a protecting group for an amino group, and Bs represents a nucleic acid base, which may or may not have a protecting group for the nucleic acid base.

[0024] <18> A compound represented by the following general formula (2a): (In general formula (2a), R １ represents an aryl group having or without a substituent, R ２ ~R ４ each independently represents a hydrogen atom, a halogen group, or an alkyl group having or without a substituent, or R ３ and R ４ are bonded to each other to form a heterocyclic ring of 5 or more members which may or may not have a substituent, R ５ａ represents a hydrogen atom or a protecting group for an amino group, Ar represents an aryl group having or having no substituent, and Nu″ represents a group represented by the following general formula (5b) or (6a): (In general formula (5b) or (6a), R １１ａ ~R１５ａ independently represent a hydrogen atom, a halogenyl group, a substituted or unsubstituted alkyl group, a group represented by the formula OR' (wherein R' represents a hydrogen atom, a hydroxyl-protecting group, or a substituted or unsubstituted alkyl group), an amino group, an azide group, or a cyano group, or R １３ａ and R １４ａ , or R １３ａ and R １５ａ are bonded to each other to form a ring of 5 or more members, which may or may not have a substituent and which may or may not have a hetero atom; R ２１ａ represents a hydrogen atom or a protecting group for an amino group, and Bs represents a nucleic acid base, which may or may not have a protecting group for the nucleic acid base.

[0025] <19> A compound represented by the following general formula (3a): (In general formula (3a), R １ represents an aryl group having or without a substituent, R ２ ~R ４ each independently represents a hydrogen atom, a halogen group, or an alkyl group having or without a substituent, or R ３ and R ４ are bonded to each other to form a heterocyclic ring of 5 or more members which may or may not have a substituent, R ５ａ represents a hydrogen atom or a protecting group for an amino group, R ６ and R ７ each independently represents a hydrogen atom, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted aryl group, or R ６ and R ７ are bonded to each other to form a heterocycle having or not having a substituent, and Nu″ is a group represented by the following general formula (5b) or (6a): (In general formula (5b) or (6a), R １１ａ ~R １５ａ independently represent a hydrogen atom, a halogenyl group, a substituted or unsubstituted alkyl group, a group represented by the formula OR' (wherein R' represents a hydrogen atom, a hydroxyl-protecting group, or a substituted or unsubstituted alkyl group), an amino group, an azide group, or a cyano group, or R １３ａ and R１４ａ , or R １３ａ and R １５ａ are bonded to each other to form a ring of 5 or more members, which may or may not have a substituent and which may or may not have a hetero atom; R ２１ａ represents a hydrogen atom or a protecting group for an amino group, and Bs represents a nucleic acid base, which may or may not have a protecting group for the nucleic acid base.

[0026] <20> The compound according to <18>, wherein Ar represents an aryl group having or without a substituent such that the pKa of the phenol compound represented by the formula ArOH is 6.4 to 7.7.

[0027] <21> R １ is a 4-methoxyphenyl group.

[0028] <22> R １ is a 4-methoxyphenyl group.

[0029] <23> The compound according to any one of <17> to <19>, wherein the stereochemistry of the phosphorus atom is controlled.

[0030] <24> R １ is a 4-methoxyphenyl group.

[0031] <25> The compound according to <17>, wherein the compound represented by the general formula (1a) is a morpholino nucleic acid monomer derivative represented by the following general formula (11a): (In general formula (11), R １ ~R ４ , R ２１ａ , and Bs are as described above.)

[0032] <26> The compound according to <18>, wherein the compound represented by the general formula (2a) is a morpholino nucleic acid monomer derivative represented by the following general formula (12a): (In general formula (12a), R １ ~R ４ , R ５ａ , R ２１ａ , Ar, and Bs are as defined above.)

[0033] <27> The compound according to <19>, wherein the compound represented by the general formula (3a) is a morpholino nucleic acid monomer derivative represented by the following general formula (13a): (In general formula (13), R １ ~R ４ , R ５ａ , R ６ , R ７ , R ２１ａ , and Bs are as described above.)

[0034] <28> The compound according to <26>, wherein Ar represents an aryl group having or without a substituent such that the pKa of the phenol compound represented by the formula ArOH is 6.4 to 7.7.

[0035] <29> R １ <26> The compound according to any one of <25> to <27>, wherein

[0036] <30> R １ is a 4-methoxyphenyl group.

[0037] <31> The compound according to any one of <25> to <27>, wherein the stereochemistry of the phosphorus atom is controlled.

[0038] <32> R １ is a 4-methoxyphenyl group.

[0039] According to the present invention, it is possible to provide a method for producing a compound useful as a nucleic acid monomer, and a compound useful as a starting material or intermediate for the production method.

[0040] Hereinafter, embodiments of the present invention will be described. However, the present invention is not limited to the following embodiments. In this specification, the term "process" includes not only an independent process but also a process that cannot be clearly distinguished from other processes as long as the intended purpose of the process is achieved. In addition, in this specification, "to" indicates a range that includes the numerical values ​​before and after it as the minimum and maximum values, respectively. Furthermore, in this specification, when multiple substances corresponding to each component are present in the composition, the amount of each component in the composition means the total amount of the multiple substances present in the composition, unless otherwise specified.

[0041] <Method for Producing Compounds> The method for producing a compound according to the first embodiment includes the aryloxylation step, the amination step, and the oxidative halogenation step. The method for producing a compound according to the second embodiment includes the amination step and the oxidative halogenation step. The method for producing a compound according to the third embodiment includes the oxidative halogenation step. Any of these production methods can produce a compound useful as a nucleic acid monomer.

[0042] [Aryloxylation Step] In the aryloxylation step, the compound represented by the general formula (1) is reacted with a phenol compound represented by the formula ArOH (wherein Ar is as described below) in the presence of an amino group-protecting agent to obtain a compound represented by the general formula (2).

[0043] (Compound represented by general formula (1)) In the compound represented by general formula (1), R １ represents an aryl group having or without a substituent, R ２ ~R ４ each independently represents a hydrogen atom, a halogen group, or an alkyl group having or without a substituent, or R ３ and R ４ are bonded to each other to form a heterocyclic ring of 5 or more members, which may or may not have a substituent, and Nu represents a monovalent group represented by the following general formula (5) or (6): The compound represented by general formula (1) may be used alone or in combination of two or more.

[0044] R １Examples of the R include a phenyl group with or without a substituent, and a naphthyl group with or without a substituent. Examples of the substituent include a hydroxyl group, an amino group, an alkoxy group, an imino group, and a halogenyl group. Examples of the alkoxy group include a C1 to C6 alkoxy group, specifically, for example, a methoxy group, an ethoxy group, and the like. Examples of the halogenyl group include a fluoro group, a chloro group, and a bromo group. R １ is preferably a 4-methoxyphenyl group in terms of ease of synthesis, reactivity, etc.

[0045] R ２ ~R ４ Examples of the halogen group represented by R include a fluoro group, a chloro group, and a bromo group. ２ ~R ４ Examples of the substituted or unsubstituted alkyl group represented by the formula (I) include C1 to C6 alkyl groups having or without substituents, and specific examples thereof include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, etc.

[0046] R ３ and R ４ may be bonded to each other to form a 5- or more-membered heterocyclic ring, which may or may not have a substituent. The number of members in the ring is preferably 5 to 10, more preferably 5 to 8, and even more preferably 5 to 7. Examples of the substituent include an alkyl group, a hydroxyl group, an amino group, an alkoxy group, an imino group, a halogen group, and the like, which may or may not have a substituent. Examples of the alkyl group include a C1 to C6 alkyl group, and specific examples thereof include a methyl group and an ethyl group. When the alkyl group has a substituent, examples of the substituent include a hydroxyl group, an amino group, an alkoxy group, an imino group, a halogen group, and the like. Examples of the alkoxy group include a C1 to C6 alkoxy group, and specific examples thereof include a methoxy group and an ethoxy group. Examples of the halogen group include a fluoro group, a chloro group, a bromo group, and the like.

[0047] In the general formula (5) or (6), R １１ ~R １５ each independently represents a hydrogen atom, a halogenyl group, a substituted or unsubstituted alkyl group, a group represented by the formula OR (wherein R represents a hydroxyl-protecting group or a substituted or unsubstituted alkyl group), an amino group, an azide group, or a cyano group, or R １３ and R １４ , or R １３ and R １５ are bonded to each other to form a ring of 5 or more members, which may or may not have a substituent and which may or may not have a hetero atom; R ２１ represents a protecting group for an amino group, and Bs represents a nucleic acid base, with or without a protecting group for the nucleic acid base.

[0048] R １１ ~R １５ Examples of the halogen group represented by R include a fluoro group, a chloro group, and a bromo group. １１ ~R １５ Examples of the substituted or unsubstituted alkyl group represented by the formula (I) include C1 to C6 alkyl groups having or without substituents, and specific examples thereof include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, etc. Examples of the hydroxyl-protecting group represented by R include an acetyl group, a phenylacetyl group, a phenoxyacetyl (Pac) group, a chloroacetyl group, a pivaloyl group, a benzyl group, a 4-methoxybenzyl group, a benzoyl group, a 4-methoxybenzoyl group, a triphenylmethyl (Tr) group, a 4,4'-dimethoxytrityl (DMTr) group, a 4-methoxytrityl (MMTr) group, a 9-phenylxanthenyl group, a t-butoxycarbonyl group, a trimethylsilyl group, a t-butyldimethylsilyl group, a t-butyldiphenylsilyl group, a triisopropylsilyl group, a cyanomethoxymethyl group, a 2-(cyanoethoxy)ethyl group, a cyanoethoxymethyl group, etc. Examples of the alkyl group represented by R, which may or may not have a substituent, include a C1 to C6 alkyl group, which may or may not have a substituent, and specific examples thereof include a methyl group, a methoxyethyl group, etc.

[0049] R １３ and R １４ , or R １３ and R １５ may be bonded to each other to form a 5-membered or greater ring, which may or may not have a substituent and which may or may not have a heteroatom. Examples of the substituent include substituents bonded to atoms forming the ring, specifically alkyl groups, oxo groups (=O), and the like, which may or may not have a substituent. Examples of the alkyl group include C1-C6 alkyl groups, specifically, methyl groups, ethyl groups, and the like. When the alkyl group has a substituent, examples of the substituent include halogenyl groups such as fluoro groups, chloro groups, and bromo groups, amino groups, and imino groups. Examples of heteroatoms include oxygen atoms, nitrogen atoms, and sulfur atoms. The ring is preferably 5 to 10-membered, more preferably 5 to 8-membered, and even more preferably 5 to 7-membered.

[0050] R １３ and R １５ are bonded to each other to form a 5 or more membered ring which may or may not have a substituent and which may or may not have a heteroatom, examples of the monovalent group represented by general formula (5) include monovalent groups represented by the following general formula (5c):

[0051]

[0052] In the above general formula, d represents 0 or 1, and R １６ and R １７ each independently represents a hydrogen atom or an alkyl group, or R １６ and R １７ together with the adjacent carbon atom to form a carbonyl group, and J is an oxygen atom or N—R １８ (In the formula, R １８ represents an alkyl group; １１ , R １４ , and Bs are as described above. １６ ~R １８Examples of the alkyl group represented by include C1 to C6 alkyl groups, and specific examples include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, a sec-butyl group, a tert-butyl group, and an n-pentyl group.

[0053] Specific examples of the monovalent group represented by general formula (5) include monovalent groups represented by the following formula: In the following formula, R and Bs are as defined above.

[0054] R ２１ Examples of the amino-protecting group represented by the formula (I) include an acetyl group, a phenylacetyl group, a phenoxyacetyl (Pac) group, a 4-tert-butylphenoxyacetyl group, a 4-isopropylphenoxyacetyl group, a chloroacetyl group, a trifluoroacetyl group, a propionyl group, a butyryl group, an isobutyryl group, a pivaloyl group, a benzyl group, a 4-methoxybenzyl group, a benzoyl group, a 4-methoxybenzoyl group, a triphenylmethyl (Tr) group, a 4,4'-dimethoxytrityl (DMTr) group, a 4-methoxytrityl (MMTr) group, a 9-phenylxanthenyl group, a 9-fluorenylmethyloxycarbonyl group, a t-butoxycarbonyl group, a trimethylsilyl group, a t-butyldimethylsilyl group, a t-butyldiphenylsilyl group, a cyanomethoxymethyl group, a 2-(cyanoethoxy)ethyl group, a cyanoethoxymethyl group, a (dimethylamino)methyl group, and the like. Among these, a trityl group is preferred in terms of ease of synthesis, reactivity, and the like.

[0055] Examples of the nucleobase represented by Bs include adenine, guanine, cytosine, 5-methylcytosine, thymine, uracil, 2-fluoroadenine, 2-chloroadenine, 5-fluorouracil, 5-fluorocytosine, and nucleobases selected from the group consisting of nucleobases represented by the following formula:

[0056] When the nucleic acid base has a protecting group, the type of the protecting group is not particularly limited. Examples of the protecting group include a benzyl group, a benzoyl group, a 4-methoxybenzoyl group, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a phenylacetyl group, a phenoxyacetyl (Pac) group, a chloroacetyl group, a 4-tert-butylphenoxyacetyl group, a 4-isopropylphenoxyacetyl group, a (dimethylamino)methylene group, an amidyl-type protecting group (e.g., a dimethylformamidyl group, a diphenylformamidyl group, etc.), a cyanoethyl group, a trityl group, a 4-methoxytrityl group, a 4,4'-dimethoxytrityl (DMTr) group, and a 4,4',4''-trimethoxytrityl group.

[0057] Examples of nucleic acid bases having a protecting group include nucleic acid bases represented by the following formula:

[0058] The compound represented by formula (1) can be produced, for example, by the method described in the Examples.

[0059] (Amino Group Protecting Agent) Examples of the amino group protecting agent include phenyl isocyanate, which may or may not have a substituent. Examples of the substituent include a hydroxyl group, an amino group, an alkoxy group, an imino group, a halogen group, and a nitro group. Examples of the alkoxy group include a C1 to C6 alkoxy group, and specific examples include a methoxy group and an ethoxy group. Examples of the halogen group include a fluoro group, a chloro group, and a bromo group. As the amino group protecting agent, 3,4-dichlorophenyl isocyanate is particularly preferred, as it facilitates the reaction to proceed completely and makes it easy to isolate the target product. The amino group protecting agents may be used alone or in combination of two or more.

[0060] The amount of the amino group protecting agent used in this step is, for example, within a range of 1 to 100 times, and preferably within a range of 1 to 5 times, the molar ratio of the amount of the compound represented by the general formula (1).

[0061] (Phenol Compound Represented by the Formula ArOH) Ar represents an aryl group which may or may not have a substituent. Examples of Ar include a phenyl group which may or may not have a substituent, and a naphthyl group which may or may not have a substituent. Examples of the substituent include a hydroxyl group, an amino group, an alkoxy group, an imino group, a halogenyl group, a nitro group, etc. Examples of the alkoxy group include a C1 to C6 alkoxy group, and specific examples include a methoxy group and an ethoxy group. Examples of the halogenyl group include a fluoro group, a chloro group, a bromo group, etc.

[0062] Ar is preferably an aryl group with or without a substituent such that the pKa of the phenol compound represented by the formula ArOH is 6.4 to 7.7. From the viewpoints of ease of synthesis, reactivity, etc., the pKa is preferably 6.6 to 7.5, and more preferably 6.8 to 7.4. Examples of phenol compounds represented by the formula ArOH include 3-methyl-4-nitrophenol (7.33), 2-nitrophenol (7.23), 4-nitrophenol (7.15), 2,4,6-trifluorophenol (7.12), and 2,4,5-trichlorophenol (6.8) (the number in parentheses indicates the pKa of the parenthesized compound). From the viewpoints of ease of synthesis, reactivity, etc., 4-nitrophenol is preferred.

[0063] The amount of the phenol compound represented by the formula ArOH used in this step is, for example, in a molar ratio within a range of 0.9 to 100 times, and preferably within a range of 0.9 to 1.1 times, per mole of the compound represented by the general formula (1).

[0064] (Compound represented by general formula (2)) In the compound represented by general formula (2), R １ ~R ４ and Nu are as described above, and R ５ represents a protecting group for an amino group, and Ar is as defined above. The compound represented by formula (2) may be used alone or in combination of two or more.

[0065] R ５Examples of the amino-protecting group represented by the formula (I) include a phenyl group, an acetyl group, a phenylacetyl group, a phenylcarbamoyl group, a chlorophenylcarbamoyl group, a dichlorophenylcarbamoyl group, a nitrophenylcarbamoyl group, a phenoxyacetyl (Pac) group, a 4-tert-butylphenoxyacetyl group, a 4-isopropylphenoxyacetyl group, a chloroacetyl group, a trifluoroacetyl group, a propionyl group, a butyryl group, an isobutyryl group, a pivaloyl group, a benzyl group, and a 4-methoxybenzyl group. , benzoyl group, 4-methoxybenzoyl group, triphenylmethyl (Tr) group, 4,4'-dimethoxytrityl (DMTr) group, 4-methoxytrityl (MMTr) group, 9-phenylxanthenyl group, 9-fluorenylmethyloxycarbonyl group, t-butoxycarbonyl group, trimethylsilyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, cyanomethoxymethyl group, 2-(cyanoethoxy)ethyl group, cyanoethoxymethyl group, (dimethylamino)methyl group, etc. Among these, in terms of ease of synthesis, reactivity, etc., phenylcarbamoyl group and dichlorophenylcarbamoyl group are preferred, and 3,4-dichlorophenylcarbamoyl group is particularly preferred.

[0066] (Activator) In the aryloxylation step, an activator may be used. Examples of the activator include N-(cyanomethyl)pyrrolidinium triflate (hereinafter referred to as "CMPT") and N-(cyanomethyl)dimethylammonium triflate. The activator may be used alone or in combination of two or more.

[0067] The amount of the activator used in this step is, for example, within a range of 1 to 100 times, and preferably 2 to 3 times, the molar ratio of the activator to 1 mole of the compound represented by the general formula (1).

[0068] The solvent that can be used in this step is not particularly limited as long as it is not involved in the reaction, and examples thereof include nitrile solvents such as acetonitrile, propionitrile, and isobutyronitrile; dichloromethane; toluene; and mixed solvents of two or more of the above solvents.

[0069] The reaction time in this step is, for example, within the range of 0.1 to 10 hours, and preferably within the range of 0.1 to 0.5 hours.

[0070] The reaction temperature in this step is, for example, within the range of -78 to 30°C, and preferably within the range of -20 to 0°C.

[0071] [Amination Step] In the amination step, the compound represented by the general formula (2) is reacted with a compound represented by the formula HNR ６ R ７ (In the formula, R ６ and R ７ is as described below.) to obtain a compound represented by the above general formula (3). The above amine compound acts as an aminating agent.

[0072] (Formula HNR ６ R ７ an amine compound represented by the formula: R ６ and R ７ each independently represents a hydrogen atom, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted aryl group, or R ６ and R ７ are bonded to each other to form a heterocyclic ring having or without a substituent. ６ and R ７ Examples of the alkyl group represented by R, which may or may not have a substituent, include C1 to C6 alkyl groups, which may or may not have a substituent, and specific examples include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, etc. ６ and R ７ Examples of the aryl group represented by R may include a phenyl group having or having no substituent, and a naphthyl group having or having no substituent. ６ and R ７may be bonded to each other to form a heterocyclic ring with or without a substituent. The ring may have, for example, 5 or more members, preferably 5 to 10 members, more preferably 5 to 8 members, and even more preferably 5 to 7 members. Examples of the substituent include an alkyl group, a hydroxyl group, an amino group, an alkoxy group, an imino group, a halogen group, and the like, which may or may not have a substituent. Examples of the alkyl group include a C1 to C6 alkyl group, and specific examples thereof include a methyl group and an ethyl group. When the alkyl group has a substituent, examples of the substituent include a hydroxyl group, an amino group, an alkoxy group, an imino group, a halogen group, and the like. Examples of the alkoxy group include a C1 to C6 alkoxy group, and specific examples thereof include a methoxy group and an ethoxy group. Examples of the halogen group include a fluoro group, a chloro group, a bromo group, and the like. R ６ and R ７ In terms of ease of synthesis, reactivity, etc., a methyl group is preferred.

[0073] In this step, the formula HNR ６ R ７ The amount of the amine compound represented by the formula (2) used is, for example, in a molar ratio range of 1 to 100 times, and preferably in a range of 5 to 20 times, per 1 mole of the compound represented by the formula (2).

[0074] (Compound represented by general formula (3)) In the compound represented by general formula (3), R １ ~R ７ and Nu are as defined above. The compound represented by formula (3) may be used alone or in combination of two or more.

[0075] The solvent that can be used in this step is not particularly limited as long as it is not involved in the reaction, and examples thereof include toluene, dichloromethane, acetonitrile, tetrahydrofuran, and mixed solvents of two or more of the above solvents.

[0076] The reaction time in this step is, for example, within the range of 0.1 to 10 hours, and preferably within the range of 0.5 to 1 hour.

[0077] The reaction temperature in this step is, for example, within the range of -78 to 30°C, and preferably within the range of -20 to 0°C.

[0078] [Oxidative Halogenation Step] In the oxidative halogenation step, the compound represented by the general formula (3) is oxidatively halogenated with a halogenating agent to obtain the compound represented by the general formula (4).

[0079] (Halogenating Agent) Examples of the halogenating agent include carbon tetrachloride, carbon tetrabromide, iodine, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, etc. The halogenating agents may be used alone or in combination of two or more.

[0080] The amount of the halogenating agent used in this step is, for example, within a range of 1 to 100 times, and preferably within a range of 1 to 3 times, the molar ratio of the amount of the compound represented by the general formula (3).

[0081] (Compound represented by general formula (4)) In the compound represented by general formula (4), R ６ , R ７ and Nu are as defined above, and X represents a halogenyl group. The compound represented by formula (4) may be used alone or in combination of two or more.

[0082] Examples of the halogen group represented by X include a fluoro group, a chloro group, and a bromo group.

[0083] The solvent that can be used in this step is not particularly limited as long as it is not involved in the reaction, and examples thereof include toluene, dichloromethane, acetonitrile, tetrahydrofuran, and mixed solvents of two or more of the above solvents.

[0084] The reaction time in this step is, for example, within the range of 0.1 to 10 hours, and preferably within the range of 0.1 to 0.5 hours.

[0085] The reaction temperature in this step is, for example, within the range of -78 to 30°C, and preferably within the range of -20 to 0°C.

[0086] In a more specific aspect of the method for producing a compound according to the first embodiment, the compound represented by general formula (1) is a morpholino nucleic acid monomer derivative represented by general formula (11), the compound represented by general formula (2) is a morpholino nucleic acid monomer derivative represented by general formula (12), the compound represented by general formula (3) is a morpholino nucleic acid monomer derivative represented by general formula (13), the compound represented by general formula (4) is a morpholino nucleic acid monomer represented by general formula (14), and the method for producing the compound is a method for producing a morpholino nucleic acid monomer.

[0087] In a more specific aspect of the method for producing a compound according to the second embodiment, the compound represented by general formula (2) above is a morpholino nucleic acid monomer derivative represented by general formula (12) above, the compound represented by general formula (3) above is a morpholino nucleic acid monomer derivative represented by general formula (13) above, the compound represented by general formula (4) above is a morpholino nucleic acid monomer represented by general formula (14) above, and the method for producing the compound is a method for producing a morpholino nucleic acid monomer.

[0088] In a more specific aspect of the method for producing a compound according to the third embodiment, the compound represented by general formula (3) is a morpholino nucleic acid monomer derivative represented by general formula (13), the compound represented by general formula (4) is a morpholino nucleic acid monomer represented by general formula (14), and the method for producing the compound is a method for producing a morpholino nucleic acid monomer.

[0089] <Compound> The compound according to the first embodiment is represented by the above general formula (1a). In the compound represented by the general formula (1a), R １ ~R ４ is as described above, and Nu' represents a monovalent group represented by general formula (5a) or (6a). The compound according to the first embodiment is useful as a starting material in a method for producing the compound according to the first embodiment.

[0090] In general formula (5a) or (6a), R １１ａ , R １２ａ , and R１４ａ each independently represents a hydrogen atom, a halogenyl group, a substituted or unsubstituted alkyl group, a group represented by the formula OR′ (wherein R′ represents a hydrogen atom, a hydroxyl-protecting group, or a substituted or unsubstituted alkyl group), an amino group, an azide group, or a cyano group; R １３ｂ and R １５ｂ are bonded to each other to form a ring of 5 or more members, which may or may not have a substituent and which may or may not have a hetero atom; R ２１ａ represents a hydrogen atom or a protecting group for an amino group, and Bs is as defined above.

[0091] R １１ａ , R １２ａ , and R １４ａ Examples of the halogen group represented by R include a fluoro group, a chloro group, and a bromo group. １１ａ , R １２ａ , and R １４ａ Examples of the alkyl group represented by the formula (I) which may or may not have a substituent include alkyl groups of C1 to C6 which may or may not have a substituent, and specific examples thereof include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, etc. Examples of the hydroxyl-protecting group represented by R' include an acetyl group, a phenylacetyl group, a phenoxyacetyl (Pac) group, a chloroacetyl group, a pivaloyl group, a benzyl group, a 4-methoxybenzyl group, a benzoyl group, a 4-methoxybenzoyl group, a triphenylmethyl (Tr) group, a 4,4'-dimethoxytrityl (DMTr) group, a 4-methoxytrityl (MMTr) group, a 9-phenylxanthenyl group, a t-butoxycarbonyl group, a trimethylsilyl group, a t-butyldimethylsilyl group, a t-butyldiphenylsilyl group, a triisopropylsilyl group, a cyanomethoxymethyl group, a 2-(cyanoethoxy)ethyl group, a cyanoethoxymethyl group, etc. Examples of the alkyl group represented by R', which may or may not have a substituent, include a C1 to C6 alkyl group, which may or may not have a substituent, and specific examples thereof include a methyl group, a methoxyethyl group, etc.

[0092] R １３ｂand R １５ｂ are bonded to each other to form a 5-membered or greater ring, which may or may not have a substituent and which may or may not have a heteroatom. Examples of the substituent include substituents bonded to atoms forming the ring, specifically alkyl groups, oxo groups (=O), and the like, which may or may not have a substituent. Examples of the alkyl group include C1-C6 alkyl groups, specifically, methyl groups, ethyl groups, and the like. When the alkyl group has a substituent, examples of the substituent include halogenyl groups such as fluoro groups, chloro groups, and bromo groups, amino groups, and imino groups. Examples of heteroatoms include oxygen atoms, nitrogen atoms, and sulfur atoms. The ring is preferably 5 to 10-membered, more preferably 5 to 8-membered, and even more preferably 5 to 7-membered.

[0093] Examples of the monovalent group represented by general formula (5a) include the monovalent group represented by general formula (5c) above. Specific examples of the monovalent group represented by general formula (5a) include the monovalent groups represented by the following formulas: In the following formulas, R' and Bs are as defined above.

[0094] R ２１ａ The protecting group for the amino group represented by R ２１ The amino-protecting group represented by is as described above.

[0095] The compound according to the second embodiment is represented by the general formula (2a). In the compound represented by the general formula (2a), R １ ~R ４ is as described above, and R ５ａ represents a hydrogen atom or a protecting group for an amino group, Ar is as defined above, and Nu" represents a monovalent group represented by the following general formula (5b) or (6a). The compound according to the second embodiment is useful as an intermediate in the production method of the compound according to the first embodiment and as a starting material in the production method of the compound according to the second embodiment.

[0096] R ５ａ The protecting group for the amino group represented by R ５ The amino-protecting group represented by is as described above.

[0097] In general formula (5b) or (6a), R １１ａ ~R １５ａ each independently represents a hydrogen atom, a halogenyl group, a substituted or unsubstituted alkyl group, a group represented by the formula OR′ (wherein R′ is as defined above), an amino group, an azide group, or a cyano group, or R １３ａ and R １４ａ , or R １３ａ and R １５ａ are bonded to each other to form a ring of 5 or more members, which may or may not have a substituent and which may or may not have a hetero atom; R ２１ａ and Bs are as described above.

[0098] R １１ａ ~R １５ａ Examples of the halogen group represented by R include a fluoro group, a chloro group, and a bromo group. １１ａ ~R １５ａ Examples of the alkyl group represented by the formula (I) may include a C1 to C6 alkyl group having or without a substituent, and specific examples thereof include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, and the like. Examples of the hydroxyl-protecting group represented by R' include an acetyl group, a phenylacetyl group, a phenoxyacetyl (Pac) group, a chloroacetyl group, a pivaloyl group, a benzyl group, a 4-methoxybenzyl group, a benzoyl group, a 4-methoxybenzoyl group, a triphenylmethyl (Tr) group, a 4,4'-dimethoxytrityl (DMTr) group, a 4-methoxytrityl (MMTr) group, a 9-phenylxanthenyl group, a t-butoxycarbonyl group, a trimethylsilyl group, a t-butyldimethylsilyl group, a t-butyldiphenylsilyl group, a cyanomethoxymethyl group, a 2-(cyanoethoxy)ethyl group, a cyanoethoxymethyl group, etc. Examples of the substituted or unsubstituted alkyl group represented by R' include a substituted or unsubstituted C1 to C6 alkyl group, and specific examples thereof include a methyl group, a methoxyethyl group, etc.

[0099] R １３ａ and R １４ａ, or R １３ａ and R １５ａ may be bonded to each other to form a 5-membered or greater ring, which may or may not have a substituent and which may or may not have a heteroatom. Examples of the substituent include substituents bonded to atoms forming the ring, specifically alkyl groups, oxo groups (=O), and the like, which may or may not have a substituent. Examples of the alkyl group include C1-C6 alkyl groups, specifically, methyl groups, ethyl groups, and the like. When the alkyl group has a substituent, examples of the substituent include halogenyl groups such as fluoro groups, chloro groups, and bromo groups, amino groups, and imino groups. Examples of heteroatoms include oxygen atoms, nitrogen atoms, and sulfur atoms. The ring is preferably 5 to 10-membered, more preferably 5 to 8-membered, and even more preferably 5 to 7-membered.

[0100] R １３ａ and R １５ａ When these bond to each other to form a 5-membered or greater ring which may or may not have a substituent and which may or may not have a heteroatom, examples of the monovalent group represented by general formula (5b) include the monovalent group represented by general formula (5c) above. Specific examples of the monovalent group represented by general formula (5b) include the monovalent groups listed as specific examples of the monovalent group represented by general formula (5a) as well as monovalent groups represented by the following formulas: In the following formulas, R' and Bs are as defined above.

[0101] The compound according to the third embodiment is represented by the general formula (3a). In the compound represented by the general formula (3a), R １ ~R ４ , R ５ａ , R ６ , R ７ , and Nu″ are as described above. The compound according to the third embodiment is useful as an intermediate in the method for producing the compound according to the first embodiment, an intermediate in the method for producing the compound according to the second embodiment, and a starting material in the method for producing the compound according to the third embodiment.

[0102] In a more specific aspect of the compound according to the first embodiment, the compound represented by the general formula (1a) is a morpholino nucleic acid monomer derivative represented by the general formula (11a).

[0103] In a more specific aspect of the compound according to the second embodiment, the compound represented by the general formula (2a) is a morpholino nucleic acid monomer derivative represented by the general formula (12a).

[0104] In a more specific aspect of the compound according to the third embodiment, the compound represented by the general formula (3a) is a morpholino nucleic acid monomer derivative represented by the general formula (13a).

[0105] In terms of ease of control of the stereochemistry of the phosphorus atom in the nucleotide unit in the nucleic acid oligomer obtained from the produced nucleic acid monomer, the stereochemistry of the phosphorus atom is preferably controlled in the methods for producing the compounds according to the first to third embodiments and the compounds according to the first to third embodiments. Examples of the compound represented by the general formula (1) in which the stereochemistry of the phosphorus atom is controlled include compounds represented by the following general formula (101) and general formula (102). Examples of the compound represented by the general formula (2) in which the stereochemistry of the phosphorus atom is controlled include compounds represented by the following general formula (201) and general formula (202). Examples of the compound represented by the general formula (3) in which the stereochemistry of the phosphorus atom is controlled include compounds represented by the following general formula (301) and general formula (302). Examples of the compound represented by the general formula (4) in which the stereochemistry of the phosphorus atom is controlled include compounds represented by the following general formula (401) and general formula (402).

[0106]

[0107] In the above formula, R １ ~R ７ , Ar, and X are as defined above, and Nu''' represents a monovalent group represented by the following general formula (500) or (600).

[0108]

[0109] In the above formula, R １１ ~R １５ , R ２１ , and Bs are as described above.

[0110] In the methods for producing the compounds according to the first to third embodiments and the compounds according to the first to third embodiments, the stereochemical purity of the phosphorus atom is preferably 90:10 or more, more preferably 95:5 or more. The stereochemical purity of the phosphorus atom can be evaluated, for example, by １ H NMR, ３１ P NMR, HPLC, etc.

[0111] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples. The solvent used in the reaction was distilled and then dried over molecular sieves. １ H NMR was measured at 400 and 500 MHz and CDCl ３ Tetramethylsilane (δ 0.0) was used as the internal standard. ３１ P NMR was measured at 161.7 and 202.6 MHz, and H ３ P.O. ４was used as an external standard (δ 0.0). For silica gel column chromatography, manual columns were used, including Kanto Silica Gel 60N (spherical, neutral, 63-210 μm) as neutral silica gel, Fuji Silysia Chemical Ltd. CHROMATOREX (NH-DM1020) as amino silica gel, and Fuji Silysia Chemical Ltd. diamino silica gel. CHROMATOREX (DNH MB 100-75 / 200) was used, and for the automated column, Yamazen Universal Premium Silica Gel 30 μm 60 Å was used as the neutral silica gel, Yamazen Universal Premium Amino 30 μm 60 Å was used as the amino silica gel, and Yamazen Universal Column Diol 40 μm 60 Å was used as the diol silica gel. For thin-layer chromatography (TLC), TLC plates Silica gel 60 F was used as the neutral silica gel. ２５４ (Merck, No. 5715), and NH as amino silica gel. ２ Silica gel 60F ２５４ Plate-Wako was used. All reactions were carried out under an Ar atmosphere. It is preferable to use diol silica gel for final purification, as this makes it easier to prevent the target product from decomposing during purification.

[0112] [Synthesis Example 1] 2-Chloro-1,3,2-oxazaphospholidine (MeO-Ph type) [D-1]

[0113] (S)-(4-Methoxyphenyl)((R)-pyrrolidin-2-yl)methanol (2.59 g, 12.5 mmol) was azeotropically dried three times with dry toluene, and then dry toluene (12.5 mL) and N-methylmorpholine (2.89 mL, 26.3 mmol) were added. The mixed solution was added dropwise to a solution of phosphorus trichloride (1.15 mL, 13.1 mmol) in dry toluene (12.5 mL) at 0°C. The reaction mixture was stirred at room temperature for 2 hours, and the resulting salt was filtered off at -78°C under an Ar atmosphere. The solvent was then evaporated under reduced pressure to obtain D-1 (yellow oil). This product was used in the next reaction without further purification.

[0114] [Synthesis Example 2] ・2-Chloro-1,3,2-oxazaphospholidine (MeO-Ph type) [L-1]

[0115] (R)-(4-Methoxyphenyl)((S)-pyrrolidin-2-yl)methanol (1.04 g, 5.0 mmol) was azeotropically dried three times with dry toluene, and then dry toluene (5.0 mL) and N-methylmorpholine (1.10 mL, 10.5 mmol) were added. The mixed solution was added dropwise to a solution of phosphorus trichloride (0.46 mL, 5.25 mmol) in dry toluene (5.0 mL) at 0°C. The reaction mixture was stirred at room temperature for 2 hours, and the resulting salt was filtered off at -78°C under an Ar atmosphere. The solvent was then evaporated under reduced pressure to obtain L-1 (yellow oil). This product was used in the next reaction without further purification.

[0116] [Example 1-1] Morpholino thymidine (Rp)-oxazaphospholidine monomer [(Rp)-2t]

[0117] 5'-OH-N-trityl-morpholino thymidine (2.42 g, 5.0 mmol) was azeotropically dried three times with dry pyridine, twice with dry toluene, and twice with dry tetrahydrofuran (hereinafter referred to as "THF"), and then dry THF (10 mL) and triethylamine (hereinafter referred to as "TEA") (4.86 mL, 35 mmol) were added. The mixed solvent was cooled to -78°C, and a 1.25 M THF solution (10 mL, 12.5 mmol) of D-1 was added dropwise. The reaction solution was stirred at room temperature for 90 minutes, and CHCl ３ (300 mL) was added to quench the reaction. ３ aqueous solution (3 x 50 mL), and the aqueous layer was washed with CHCl ３ (50 mL). The combined organic layer was back-extracted with anhydrous Na ２ SO ４ The residue was purified by silica gel column chromatography [NH-silica gel, CHCl ３ , TEA 1v / v%] to obtain (Rp)-2t. (Rp)-2t: 1.96 g, 2.7 mmol, 56%, dr>99:1, colorless foam

[0118] (Rp)-2t １ H NMR (500MHz, CDCl ３ ) δ8.20 (br, 1H), 7.41 (m, 5H), 7.27-7.21 (m, 10H), 7.18-7.11 (m, 7H), 7.05 (d, J = 8.4Hz, 2H), 6.86 (d, J = 6.4Hz) , 2H), 6.11 (dd, J = 9.4, 2.2Hz, 1H), 5.37 (d, J = 6.0Hz, 1H), 4.28-4.25 (m, 1H), 3.89-3.85 (m, 2H), 3.82 (s, 3H), 3.80-3.77 (m, 2H), 3.55-3.52 (m, 1H), 3.31 (d, J = 11.2Hz, 1H), 3.18-3.12 (m, 2H), 1.79 (d, J = 1.0Hz, 3H), 1.6 7-1.60 (m, 2H), 1.52 (dd, J = 11.8, 10.6Hz, 1H), 1.39 (dd, J = 11.2, 9.6Hz, 1H), 1.20-1.16 (m, 1H), 0.94 (m, 1H); ３１ P{ １H}NMR (202MHz, CDCl ３ ) δ158.3; ESI-MS m / z calcd for C ４１ H ４４ N ４ O ６ P[M+H] ＋ , 719.2993; found 719.2995.

[0119] [Example 1-2] Morpholino thymidine (Sp)-oxazaphospholidine monomer [(Sp)-2t]

[0120] 5'-OH-N-trityl-morpholino thymidine (0.97 g, 2.0 mmol) was azeotropically dried three times with dry pyridine, twice with dry toluene, and twice with THF, and then dry THF (4.0 mL) and TEA (1.94 mL, 14 mmol) were added. The mixed solvent was cooled to -78°C, and a 1.25 M L-1 THF solution (4.0 mL, 5.0 mmol) was added dropwise. The reaction solution was stirred at room temperature for 90 minutes, and CHCl ３ (300 mL) was added to quench the reaction. ３ aqueous solution (3 x 50 mL), and the aqueous layer was washed with CHCl ３ (50 mL). The combined organic layer was back-extracted with anhydrous Na ２ SO ４ The residue was purified by silica gel column chromatography [NH-silica gel, CHCl ３ , TEA 1v / v%] to obtain (Sp)-2t. (Sp)-2t: 1.20g, 0.17mmol, 83%, dr>99:1, colorless foam

[0121] (Sp)-2t １ H NMR (400MHz, CDCl ３) δ7.52 (m, 6H), 7.27-7.07 (m, 17H), 6.99-6.82 (m, 4H), 6.10 (d, J = 9.1Hz, 1 H), 5.67 (d, J=6.4Hz, 1H), 4.41-4.26 (m, 1H), 4.10-3.85 (m, 1H), 3.82-3.73 (m, 6H), 3.67 (m, 1H), 3.60-3.51 (m, 1H), 3.33-3.00 (m, 4H), 1.74 (s, 3H), 1 .66-1.59 (m, 2H), 1.50-1.33 (m, 2H), 1.30-1.07 (m, 2H), 1.00-0.88 (m, 1H); ３１ P{ １ H}NMR (162MHz, CDCl ３ ) δ156.5; ESI-MS m / z calcd for C ４１ H ４４ N ４ O ６ P[M+H] ＋ , 719.2993; found 719.2994.

[0122] [Example 2-1] Morpholino adenosine (Rp)-oxazaphospholidine monomer [(Rp)-2a]

[0123] N ６ Benzoyl-5'-OH-N-trityl-morpholino adenosine (2.98 g, 5.0 mmol) was azeotropically dried three times with dry pyridine, twice with dry toluene, and twice with dry THF, and then dry THF (10 mL) and TEA (4.86 mL, 35 mmol) were added. The mixed solvent was cooled to -78°C, and a 1.25 M L-1 THF solution (10 mL, 12.5 mmol) was added dropwise. The reaction solution was stirred at room temperature for 3 hours, and CHCl ３ (300 mL) was added to quench the reaction. ３ aqueous solution (2 x 50 mL), and the aqueous layer was washed with CHCl ３ (50 mL). The combined organic layer was extracted with anhydrous Na ２ SO ４The mixture was dried with hexane, filtered, and the solvent was evaporated under reduced pressure. The residue was isolated and purified by silica gel column chromatography [NH-silica gel, toluene-ethyl acetate (hereinafter referred to as "AcOEt") (1:1, v / v), TEA 1 vol%] to obtain (Rp)-2a. ((Rp)-2a: 2.12 g, 2.50 mmol, 50%, dr>99:1, colorless foam

[0124] (Rp)-2a １ H NMR (500MHz, CDCl ３ ) δ8.90 (s, 1H), 8.80 (s, 1H), 8.16 (s, 1H), 8.05-7.92 (m, 2H), 7.62-7.51 (m, 4H), 7.47-7.29 (m, 7H), 7.27-7.23 (m, 13H), 7.16-7.05 (m, 6H), 6.93-6.82 (m, 3H), 6.42 (dd, J=9.8, 2.2Hz, 1H), 5.42 (d, J=6.0Hz, 1H), 4.40-4.3 8 (m, 1H), 3.89 (dd, J = 10.5, 4.5Hz, 2H), 3.82-3.72 (m, 7H), 3.56-3.49 (m, 1H), 3.46 (d, J = 11.2Hz, 1H), 3.25 (d , J=12Hz, 1H), 3.20-3.01 (m, 2H), 1.79-1.70 (m, 1H), 1.67-1.55 (m, 2H), 1.16-1.07 (m, 1H), 0.96-0.88 (m, 1H); ３１ P{ １ H}NMR (202MHz, CDCl ３ ) δ158.9; ESI-MS m / z calcd for C ４８ H ４７ N ７ O ５ P[M+H] ＋ , 832.3371; found 832.3371.

[0125] [Example 2-2] Morpholino adenosine (Sp)-oxazaphospholidine monomer [(Sp)-2a]

[0126] N ６Benzoyl-5'-OH-N-trityl-morpholino adenosine (2.98 g, 5.0 mmol) was azeotropically dried three times with dry pyridine, twice with dry toluene, and twice with dry THF, and then dry THF (10 mL) and TEA (4.86 mL, 35 mmol) were added. The mixed solvent was cooled to -78°C, and a 1.25 M L-1 THF solution (10 mL, 12.5 mmol) was added dropwise. The reaction solution was stirred at room temperature for 3 hours, and CHCl ３ (300 mL) was added to quench the reaction. ３ aqueous solution (2 x 50 mL), and the aqueous layer was washed with CHCl ３ (50 mL). The combined organic layer was extracted with anhydrous Na ２ SO ４ The mixture was dried with hexane, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [NH-silica gel, toluene-AcOEt (1:1, v / v), TEA 1 vol%] to obtain (Sp)-2a. (Sp)-2a: 1.29 g, 1.52 mmol, 30%, dr>99:1, yellow foam

[0127] (Sp)-2a １ H NMR (500MHz, CDCl ３ ) δ8.84 (s, 1H), 8.80 (s, 1H), 8.01-7.99 (m, 2H), 7.97 (s, 1H), 7.60 (t, J=7.4Hz, 1H), 7.53-7.41 (m, 8H), 7.32-7.2 5 (m, 12H), 7.18-7.13 (m, 6H), 6.93-6.82 (m, 3H), 6.39 (dd, J = 10.0, 2.4Hz, 1H), 5.65 (d, J = 6.4Hz, 1H), 4.38 (m, 1 H), 3.97-3.91 (m, 1H), 3.83-3.75 (m, 6H), 3.73-3.67 (m, 1H), 3.54 (m, 1H), 3.48 (d, J = 11.2Hz, 1H), 3.35 (d, J = 12 0Hz, 1H), 3.21-3.10 (m, 1H), 1.81 (t, J=10.4Hz, 1H), 1.64-1.54 (m, 5H), 1.18-1.07 (m, 1H), 0.96-0.90 (m, 1H); ３１ P{ １ H}NMR (202MHz, CDCl ３) δ156.9; ESI-MS m / z calcd for C ４８ H ４７ N ７ O ５ P[M+H] ＋ , 832.3371; found 832.3374.

[0128] [Example 3-1] Morpholino guanosine (Rp)-oxazaphospholidine monomer [(Rp)-2g]

[0129] N ２ -Isobutyryl-O ６ -cyanoethyl-5'-OH-N-trityl-morpholino guanosine (0.98 g, 1.55 mmol) was azeotropically dried three times with dry pyridine, twice with dry toluene, and twice with dry THF, and then dry THF (3.1 mL) and TEA (1.51 mL, 10.9 mmol) were added. The mixed solvent was cooled to -78°C, and a 1.25 M THF solution (3.1 mL, 3.88 mmol) of D-1 was added dropwise. The reaction solution was stirred at 0°C for 75 minutes, and CHCl ３ The reaction was quenched by adding saturated NaHCO (100 mL). ３ aqueous solution (2 x 40 mL), and the aqueous layer was washed with CHCl ３ (50 mL). The combined organic layer was back-extracted with anhydrous Na ２ SO ４ The residue was purified by silica gel column chromatography [NH-silica gel, hexane-AcOEt (1:3, v / v)] to obtain (Rp)-2g. (Rp)-2g: 0.47 g, 0.55 mmol, 35%, dr>99:1, colorless foam

[0130] (Rp)-2g １ H NMR (500MHz, CDCl ３δ 7.99 (s, 1H), 7.77 (s, 1H), 7.43 - 7.31 (m, 5H), 7.27 - 7.22 (m, 13H), 7.14 (t, J = 7.2 Hz, 3H), 7.08 - 7.05 (m, 2H), 6.88 - 6.80 (m, 2H), 6.22 (dd, J = 10.0, 2.4 Hz, 1H), 5.40 (d, J = 6.4 Hz, 1H), 4.82 - 4.72 (m, 2H), 4.36 - 4.34 (m, 1H), 3.87 (dd, J = 11.0, 4.5 Hz, 2H), 3.82 - 3.73 (m, 5H), 3.56 - 3.48 (m, 1H), 3.40 (d, J = 11.2 Hz, 1H), 3.21 (d, J = 12.0 Hz, 1H), 3.17 - 3.03 (m, 2H), 3.02 - 2.97 (dt, J = 13.0, 1.0 Hz, 2H), 1.73 - 1.68 (dd, J = 11.0, 10.0 Hz, 1H), 1.65 - 1.58 (m, 3H), 1.56 (s, 2H), 1.35 (dd, J = 10.4, 6.8 Hz, 6H), 1.12 (m, 1H), 0.96 - 0.88 (m, 1H); ３１ P{ １ H} NMR (202 MHz, CDCl ３ 3) δ 158.9; ESI - MS m / z calcd for C ４８ 46 ５２ H ８ 4 ６ N ＋ 2 O P [M + H] ２ ６

[0131] [Example 3 - 2] - Morpholino guanosine (Sp) - oxazaphospholidine monomer [(Sp) - 2g]

[0132] N ３ - Isobutyryl - O ３ It should be noted that there may be some inaccuracies in the original text regarding the chemical shift values and other details which might require further verification and correction in a proper chemical context. Also, the formatting and line breaks in the original text seem a bit irregular and might need to be adjusted for better readability in a chemical document. The translation is done as per the given rules while trying to make sense of the chemical information presented.-cyanoethyl-5'-OH-N-trityl-morpholino guanosine (0.98 g, 1.55 mmol or 1.26 g, 2.0 mmol) was azeotropically dried three times with dry pyridine, twice with dry toluene, and twice with dry THF, and then dry THF (10 mL) and TEA (4.86 mL, 35 mmol) were added. The mixed solvent was cooled to -78°C, and a 1.25 M L-1 THF solution (10 mL, 12.5 mmol) was added dropwise. The reaction solution was stirred at room temperature for 1 hour, and CHCl ３ (300 mL) was added to quench the reaction. ３ aqueous solution (2 x 50 mL), and the aqueous layer was washed with CHCl ３ (50 mL). The combined organic layer was back-extracted with anhydrous Na ２ SO ４ The mixture was dried with hexane, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [NH-silica gel, hexane-AcOEt (1:3, v / v)] to obtain (Sp)-2g. (Sp)-2g: 0.98 g, 1.13 mmol, 48%, dr>99:1, colorless foam

[0133] (Sp)-2g １ H NMR (500MHz, CDCl ３) δ7.80 (s, 1H), 7.77 (s, 1H), 7.47 (s, 5H), 7.32-7.24 (m, 13H), 7.18-7.05 (m, 10H), 6.93-6.82 (m, 3H), 6.19 (dd, J = 9.8, 2.2Hz, 1H) , 5.66 (d, J = 6.4Hz, 1H), 4.82-4.72 (m, 2H), 4.33 (m, 1H), 3.96-3.90 (m, 1H), 3.82-3.80 (m, 3H), 3.78-3.72 (m, 1H), 3.67 (td, J = 10 .. 9, 6.6Hz, 1H), 3.58-3.51 (m, 1H), 3.44 (d, J = 11.2Hz, 1H), 3.34 (d, J = 12.0Hz, 1H), 3.22-3.03 (m, 2H), 3.02-2.97 (m, 2H), 1.79-1. 71 (m, 1H), 1.62 (dt, J = 15.4, 6.4Hz, 2H), 1.56-1.52 (m, 1H), 1.36-1.31 (m, 6H), 1.16 (td, J = 12.1, 6.0Hz, 1H), 0.97-0.90 (m, 1H); ３１ P{ １ H}NMR (202MHz, CDCl ３ ) δ156.5; ESI-MS m / z calcd for C ４８ H ５２ N ８ O ６ P [M+H] ＋ , 867.3742; found 867.3765.

[0134] [Example 4-1] Morpholinocytidine (Rp)-oxazaphospholidine monomer [(Rp)-2c]

[0135] N ４ Benzoyl-5'-OH-N-trityl-morpholino cytidine (2.50 g, 4.37 mmol) was azeotropically dried three times with dry pyridine, twice with dry toluene, and twice with dry THF, and then dry THF (20 mL) and TEA (4.50 mL, 32 mmol) were added. The mixed solvent was cooled to -78°C, and a 1.25 M THF solution (20 mL, 8.64 mmol) of D-1 was added dropwise. The reaction solution was stirred at room temperature for 90 minutes, and CHCl ３(300 mL) was added to quench the reaction. ３ The aqueous layer was washed with CHCl ３ (50 mL). The combined organic layer was back-extracted with anhydrous Na ２ SO ４ The mixture was dried with hexane, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [DNH-silica gel, hexane-AcOEt (1:3 → 1:5, v / v), 1 v / v% TEA] to obtain (Rp)-2c. (Rp)-2c: 1.37 g, 1.70 mmol, 39%, dr>99:1, colorless foam.

[0136] (Rp)-2c １ H NMR (500MHz, CDCl ３ ) δ7.95 (d, J=7.2Hz, 1H), 7.86 (d, J=7.2Hz, 2H), 7.60 (t, J=7.4Hz, 1H), 7.54-7.49 (m, 3H), 7.45 (d, J=20.9Hz, 5H), 7.24 (d, J=8. 0Hz, 4H), 7.19-7.13 (m, 2H), 7.07-7.04 (m, 2H), 6.93-6.89 (m, 2H), 6.26 (dd, J=9.0, 2.2Hz, 1H), 5.31 (d, J=5.2Hz, 1H), 4.27-4. 24 (m, 1H), 4.14-4.09 (m, 1H), 4.03-3.96 (m, 1H), 3.91-3.85 (m, 1H), 3.82 (t, J = 3.4Hz, 3H), 3.81-3.72 (m, 1H), 3.59-3.51 (m, 1H) ), 3.47 (d, J = 11.2 Hz, 1H), 3.22-3.15 (m, 1H), 3.12 (d, J = 12.0Hz, 1H), 1.67-1.60 (m, 1H), 1.21-1.09 (m, 2H), 1.01-0.88 (m, 2H); ３１ P{ １ H}NMR (202MHz, CDCl ３ ) δ159.6; ESI-MS m / z calcd for C ４７ H ４７ N ５ O ６ P [M+H] ＋ , 808.3259; found 808.3256.

[0137] [Example 4-2] Morpholinocytidine (Sp)-oxazaphospholidine monomer [(Sp)-2c]

[0138] N ４ Benzoyl-5'-OH-N-trityl-morpholino cytidine (2.50 g, 4.37 mmol) was azeotropically dried three times with dry pyridine, twice with dry toluene, and twice with dry THF, and then dry THF (20 mL) and TEA (4.50 mL, 32 mmol) were added. The mixed solvent was cooled to -78°C, and a 1.25 M L-1 THF solution (20 mL, 8.64 mmol) was added dropwise. The reaction solution was stirred at room temperature for 90 minutes, and CHCl ３ (300 mL) was added to quench the reaction. ３ The aqueous layer was washed with CHCl ３ (50 mL). The combined organic layer was back-extracted with anhydrous Na ２ SO ４ The mixture was dried at 77°C, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [DNH-silica gel, hexane-AcOEt (1:3 → 1:5, v / v), 1 v / v% TEA] to obtain (Sp)-2c. (Sp)-2c: 1.67 g, 2.07 mmol, 48%, dr>99:1, colorless foam)

[0139] (Sp)-2c １ H NMR (500MHz, CDCl ３) δ7.87 (d, J=7.2Hz, 2H), 7.65 (d, J=7.2Hz, 1H), 7.60 (t, J=7.4Hz, 1H), 7.52-7.46 (m, 9H), 7.18-7.13 (m, 10H), 6.88-6.82 (m, 3H), 6.24 (dd, J=9.0, 2.2Hz, 1H), 5.67 (d, J=6.4Hz, 1H), 4.35-4.31 (m, 1H), 3 .. 92-3.85 (m, 1H), 3.83-3.73 (m, 3H), 3.60-3.52 (m, 2H), 3.23-3.19 (m, 1H), 3.18-3.12 (m, 1H), 1.72- 1.52 (m, 1H), 1.50-1.42 (m, 1H), 1.30-1.22 (m, 1H), 1.15 (td, J = 11.8, 6.0Hz, 1H), 0.99-0.88 (m, 1H); ３１ P{ １ H}NMR (202MHz, CDCl ３ ) δ156.0; ESI-MS m / z calcd for C ４７ H ４７ N ５ O ６ P [M+H] ＋ , 808.3259; found 808.3260.

[0140] [Example 5-1] Morpholino thymidine (Rp)-dimethylaminophosphorochloridate monomer ((Rp)-3t)

[0141] (Rp)-2t (0.11 g, 0.15 mmol) was added to CH ３ CN (1.5 mL) was added and the mixture was dried over activated molecular sieves 3A (hereinafter referred to as "MS3A"). This mixture was added to a recovery flask, cooled to 0°C, and phenyl isocyanate (0.082 mL, 0.75 mmol) was added and stirred. 4-nitrophenol (21 mg, 0.15 mmol), CMPT (0.078 g, 0.30 mmol), CH ３ CN (1.5 mL) was added and dried with MS3A. This mixed solution was added dropwise to a recovery flask and stirred at 0°C for 40 minutes. The reaction solution was cooled to -20°C, and N-(trimethylsilyl)dimethylamine (hereinafter referred to as "TMSNMe") was added.２ ") (0.10 mL, 0.63 mmol), 2M dimethylamine (hereinafter referred to as "NHMe ２ ") in THF (0.63 mL, 1.26 mmol) was added in this order, and the mixture was stirred at -20°C for 1 hour. After the reaction, the solvent and volatile substances were evaporated under reduced pressure, and the residue was ２ Cl ２ The reaction solution was cooled to 0°C, and N-chlorosuccinimide (hereinafter referred to as "NCS") (84 mg, 0.63 mmol) was added, followed by stirring at 0°C for 10 minutes. EtOAc (20 mL) was added, followed by the addition of saturated NaHCO ３ aqueous solution (10 mL) and saturated Na ２ S ２ O ３ The reaction was quenched by adding saturated aqueous NaHCO (10 mL). ３ The organic layer was washed with aqueous solution (2×20 mL) and saturated brine (20 mL). ２ SO ４ The residue was purified by PTLC (neutral-silica gel, CHCl ３ -acetone (9:1, v / v), neutral silica gel, hexane-EtOAc (1:5, v / v)] to obtain (Rp)-3t. (Rp)-3t: 8.8 mg, 14.5 μmol, 16%, dr=97:3

[0142] (Rp)-3t (synthesized from (Rp)-2t) １ H NMR (500MHz, CDCl ３ ) δ8.28 (s, 1H), 7.46 (m, 6H), 7.31 (t, J = 7.8Hz, 6H), 7.24-7.14 (m, 3H), 7.05 (s, 1H), 6.13 (dd, J = 9.6, 1.8Hz, 1H), 4.40 (m, 1 H), 4.16-4.05 (m, 2H), 3.38 (d, J = 11.4Hz, 1H), 3.16 (d, J = 11.9Hz, 1H), 2.65 (d, J = 13.7Hz, 6H), 1.84 (s, 3H), 1.46 (m, 2H); ３１ P{ １ H}NMR (202MHz, CDCl ３ ) δ19.0, 18.7.

[0143] [Example 5-2] Morpholino thymidine (Sp)-dimethylaminophosphorochloridate monomer ((Sp)-3t)

[0144] (Sp)-2t (0.72 g, 1.0 mmol) was added to CH ３ CN (10.0 mL) was added and dried with activated MS3A. This mixed solution was added to a recovery flask, cooled to 0°C, and phenyl isocyanate (0.54 mL, 5.0 mmol) was added and stirred. 4-nitrophenol (139 mg, 1.0 mmol), CMPT (0.52 g, 2.0 mmol), CH ３ CN (10.0 mL) was added and dried with MS3A. This mixed solution was added dropwise to a recovery flask and stirred at 0°C for 40 minutes. The reaction solution was cooled to -20°C, and TMSNMe ２ (0.80 mL, 5.0 mmol), 2M NHMe ２ A THF solution (5.0 mL, 10.0 mmol) of the above was added in turn, and the mixture was stirred at −20° C. for 1 hour. After the reaction, the solvent and volatile substances were evaporated under reduced pressure, and the residue was ２ Cl ２ (20 mL) was added. The reaction solution was cooled to 0° C., and NCS (391 mg, 2.93 mmol) was added, followed by stirring at 0° C. for 10 minutes. EtOAc (20 mL) was added, followed by saturated NaHCO ３ aqueous solution (10 mL) and saturated Na ２ S ２ O ３ The reaction was quenched by adding saturated aqueous NaHCO (10 mL). ３ The organic layer was washed with aqueous solution (2×20 mL) and saturated brine (20 mL). ２ SO ４ The residue was purified by PTLC (neutral-silica gel, CHCl ３ -acetone (9:1, v / v), neutral-silica gel, hexane-EtOAc (1:5, v / v)] to obtain (Sp)-3t. (Sp)-3t: colorless solid, 0.264 g, 43.2 μmol, 45%, dr=97:3

[0145] (Sp)-3t (synthesized from (Sp)-2t) １ H NMR (400MHz, CDCl ３ ) δ8.07 (s, 1H), 7.49 (dr, 5H), 7.31 (t, J = 7.5Hz, 5H), 7.20 (t, J = 7.1Hz, 2 H), 7.04 (d, J = 0.9Hz, 1H), 6.17-6.12 (dd, J = 9.6, 2.4Hz, 1H), 4.40 (dd, J = 5.4, 3.8Hz, 1H), 4.18-4.04 (m, 2H), 3.38 (d, J = 11.4Hz, 1H), 3.16 (d, J = 11.9Hz, 1H), 2.65 (d, J = 13.7Hz, 6H), 1.84 (s, 3H), 1.53-1.38 (m, 2H); ３１ P{ １ H}NMR (162MHz, CDCl ３ ) δ19.0, 18.7.

[0146] [Example 6-1] Morpholino adenosine (Rp)-dimethylaminophosphorochloridate monomer ((Rp)-3a)

[0147] (Rp)-2a (0.17g, 0.20mmol) with CH ２ Cl ２ (2.0 mL) was added and dried over activated molecular sieves 4A (hereinafter referred to as "MS4A"). This mixed solution was added to a recovery flask, cooled to 0°C, and PhNCO (0.11 mL, 1.0 mmol) was added and stirred. 4-Nitrophenol (0.028 g, 0.20 mmol), CMPT (0.10 g, 0.40 mmol), CH ３ CN (2.0 mL) was added and dried with MS3A. This mixed solution was added dropwise to a recovery flask and stirred at 0°C for 40 minutes. The reaction solution was cooled to -20°C, and TMSNMe ２ (0.14 mL, 0.88 mmol), 2M NHMe ２ A THF solution (0.88 mL, 1.76 mmol) of the above was added in turn, and the mixture was stirred at −20° C. for 1 hour. After the reaction, the solvent and volatile substances were evaporated under reduced pressure, and the residue was ２ Cl ２The reaction solution was cooled to 0°C, NCS (0.060 g, 0.45 mmol) was added, and the mixture was stirred at 0°C for 10 minutes. ２ Cl ２ (50 mL) was added, followed by saturated NaHCO ３ aqueous solution (25 mL) and saturated Na ２ S ２ O ３ The reaction was quenched by adding saturated aqueous NaHCO (25 mL). ３ The organic layer was washed with aqueous solution (3×50 mL) and saturated brine (50 mL). ２ SO ４ The residue was purified by PTLC (neutral-silica gel, CHCl ３ -acetone (9:1, v / v), neutral-silica gel, hexane-AcOEt (1:5, v / v)] to obtain (Rp)-3a. (Rp)-3a: 14.7 mg, 21 μmol, 16%, dr=97:3, colorless solid,

[0148] (Rp)-3a (synthesized from (Rp)-2a) １ H NMR (500MHz, CDCl ３ ) δ8.91 (s, 1H), 8.81 (s, 1H), 8.01-7.99 (m, 3H), 7.54-7.47 (m, 8H), 7.37-7.30 (m , 6H), 7.22-7.14 (m, 4H), 6.42 (dd, J=9.6, 2.4Hz, 1H), 4.53 (m, 1H), 4.29-4.10 (m , 3H), 3.55 (dt, J = 11.5, 2.5Hz, 1H), 3.25 (d, J = 11.6Hz, 1H), 2.62 (dd, J = 14.1, 9 .6Hz, 6H), 1.83 (dd, J=11.2, 10.0Hz, 1H), 1.71-1.65 (m, 1H), 1.47-1.25 (m, 2H); ３１ P{ １ H}NMR (202MHz, CDCl ３ ) δ19.1, 18.7.

[0149] [Example 6-2] Morpholino adenosine (Sp)-dimethylaminophosphorochloridate monomer ((Sp)-3a)

[0150] (Sp)-2a (0.17g, 0.20mmol) with CH ２ Cl ２ (2.0 mL) was added and dried over activated MS4A. This mixed solution was added to a recovery flask, cooled to 0°C, and PhNCO (0.11 mL, 1.0 mmol) was added and stirred. A vial was charged with 4-nitrophenol (0.028 g, 0.20 mmol), CMPT (0.10 g, 0.40 mmol), CH ３ CN (2.0 mL) was added and dried with MS3A. This mixed solution was added dropwise to a recovery flask and stirred at 0°C for 40 minutes. The reaction solution was cooled to -20°C, and TMSNMe ２ (0.14 mL, 0.88 mmol), 2M NHMe ２ A THF solution (0.88 mL, 1.76 mmol) of the above was added in turn, and the mixture was stirred at −20° C. for 1 hour. After the reaction, the solvent and volatile substances were evaporated under reduced pressure, and the residue was ２ Cl ２ The reaction solution was cooled to 0°C, NCS (0.060 g, 0.45 mmol) was added, and the mixture was stirred at 0°C for 10 minutes. ２ Cl ２ (50 mL) was added, followed by saturated NaHCO ３ aqueous solution (25 mL) and saturated Na ２ S ２ O ３ The reaction was quenched by adding saturated aqueous NaHCO (25 mL). ３ The organic layer was washed with aqueous solution (3×50 mL) and saturated brine (50 mL). ２ SO ４ The residue was purified by PTLC (neutral-silica gel, CHCl ３-acetone (9:1, v / v), neutral-silica gel, hexane-AcOEt (1:5, v / v)] to obtain (Sp)-3a. (Sp)-3a: 28.5 mg, 39.5 μmol, 32%, dr=98:2, colorless solid

[0151] (Sp)-3a (synthesized from (Sp)-2a) １ H NMR (400MHz, CDCl ３ ) δ8.91 (s, 1H), 8.80 (s, 1H), 8.14-7.94 (m, 3H), 7.73-7.58 (m, 2H), 7.51 (t, J=7. 5Hz, 9H), 7.32 (t, J = 7.8Hz, 7H), 7.23-7.12 (m, 3H), 6.43 (dd, J = 9.6, 2.3Hz, 1H) , 4.54-4.51 (m, 1H), 4.19-4.08 (m, 2H), 3.55 (d, J = 11.4Hz, 1H), 3.26 (d, J = 11.9 Hz, 1H), 2.61 (d, J = 14.2Hz, 6H), 1.82 (t, J = 10.7Hz, 1H), 1.63 (t, J = 11.2Hz, 1H); ３１ P{ １ H}NMR (162MHz, CDCl ３ ) δ19.1, 18.7.

[0152] [Example 7-1] Morpholino guanosine (Rp)-dimethylaminophosphorochloridate monomer ((Rp)-3g)

[0153] (Rp)-2g (87 mg, 0.10 mmol) with CH ２ Cl ２ (1.0 mL) was added and dried over activated MS4A. This mixed solution was added to a recovery flask, cooled to 0°C, and PhNCO (54 μL, 0.50 mmol) was added and stirred. A vial was charged with 4-nitrophenol (14.0 mg, 0.10 mmol), CMPT (52 mg, 0.20 mmol), and CH ３ CN (1.0 mL) was added and dried over MS3A. This mixed solution was added dropwise to a recovery flask and stirred at 0°C for 40 minutes. The reaction solution was cooled to -20°C, and TMSNMe ２(80 μL, 0.50 mmol), 2M NHMe ２ A THF solution (0.50 mL, 1.0 mmol) of the above was added in turn, and the mixture was stirred at −20° C. for 1 hour. After the reaction, the solvent and volatile substances were evaporated under reduced pressure, and ２ Cl ２ The reaction solution was cooled to 0°C, NCS (30.0 mg, 0.23 mmol) was added, and the mixture was stirred at 0°C for 10 minutes. ２ Cl ２ (50 mL) was added, followed by saturated NaH ２ P.O. ３ The reaction was stopped by adding aqueous solution (50 mL). The organic layer was washed with saturated saline (50 mL). ２ SO ４ The residue was purified by PTLC [neutral-silica gel, hexane-AcOEt (1:3, v / v), neutral-silica gel, CHCl ３ -acetone (8:2, v / v)] to obtain (Rp)-3g (including by-products). (Rp)-3g:trace, dr = 96:4,

[0154] (Rp)-3g (synthesized from (Rp)-2g) １ H NMR (500MHz, CDCl ３ ) δ7.80 (d, J=11.0Hz, 2H), 7.52 (m, 6H), 7.31 (t, J=7.6Hz, 7H), 7.20-7.07 (m, 4H), 6 .25 (dd, J=9.6, 2.4Hz, 1H), 4.82-4.73 (m, 2H), 4.50-4.48 (m, 1H), 4.14-4.10 (m, 2) H), 3.50 (d, J = 11.2 Hz, 1H), 3.23 (d, J = 12.0 Hz, 1H), 3.04-2.99 (m, 3H), 2.63 (d, J = 5.5Hz, 6H), 1.77 (t, J = 10.6Hz, 1H), 1.61 (t, J = 11.2Hz, 4H), 1.36 (t, J = 6.6Hz, 6H); ３１ P{ １ H}NMR (202MHz, CDCl ３ ) δ19,1,18.8.

[0155] [Example 7-2] Morpholino guanosine (Sp)-dimethylaminophosphorochloridate monomer ((Sp)-3g)

[0156] (Sp)-2g (83 mg, 0.095 mmol) with CH ２ Cl ２ (1.0 mL) was added and dried over activated MS4A. This mixed solution was added to a recovery flask, cooled to 0°C, and PhNCO (54 μL, 0.50 mmol) was added and stirred. 4-Nitrophenol (13.6 mg, 0.098 mmol), CMPT (51.6 mg, 0.198 mmol), CH ３ CN (1.0 mL) was added and dried over MS3A. This mixed solution was added dropwise to a recovery flask and stirred at 0°C for 40 minutes. The reaction solution was cooled to -20°C, and TMSNMe ２ (80 μL, 0.50 mmol), 2M NHMe ２ A THF solution (0.50 mL, 1.0 mmol) of the above was added in turn, and the mixture was stirred at −20° C. for 1 hour. After the reaction, the solvent and volatile substances were evaporated under reduced pressure, and ２ Cl ２ The reaction solution was cooled to 0°C, NCS (33.6 mg, 0.25 mmol) was added, and the mixture was stirred at 0°C for 10 minutes. ２ Cl ２ (50 mL) was added, followed by saturated NaH ２ P.O. ３ The reaction was stopped by adding aqueous solution (50 mL). The organic layer was washed with saturated saline (50 mL). ２ SO ４ The residue was purified by PTLC [neutral-silica gel, hexane-AcOEt (1:3, v / v), neutral-silica gel, CHCl ３ -acetone (8:2, v / v)] to obtain (Sp)-3g (including by-products). (Sp)-3g: 1.5 mg, 2.0 μmol, 2.2%, dr=95:5

[0157] (Sp)-3g (synthesized from (Sp)-2g) １H NMR (500MHz, CDCl ３ ) δ8.00 (br, 2H), 7.84 (s, 1H), 7.82 (d, J=5.6Hz, 1H), 7.55-7.47 (m, 6H), 7.33-7.28 (m, 7H), 7.24- 7.14 (m, 6H), 6.25 (dd, J=10.0, 2.4Hz, 1H), 4.82-4.73 (m, 2H), 4.50-4.48 (m, 1H), 4.17-4.12 (m, 1 H), 4.11-4.05 (m, 1H), 3.54-3.48 (m, 1H), 3.24 (d, J = 11.6Hz, 1H), 3.01-2.96 (m, 3H), 2.70-2.67 (m, 2H), 2.65-2.58 (m, 6H), 1.89-1.83 (m, 2H), 1.76 (dd, J=11.2, 10.0Hz, 2H), 1.39-1.34 (m, 6H); ３１ P{ １ H}NMR (202MHz, CDCl ３ ) δ19.1, 18.8.

[0158] [Example 8-1] Morpholino cytidine (Rp)-dimethylaminophosphorochloridate monomer ((Rp)-3c)

[0159] (Rp)-2c (0.121 g, 0.15 mmol) was added to CH ２ Cl ２ (1.5 mL) was added and dried over activated MS4A. This mixed solution was added to a recovery flask, cooled to 0°C, and PhNCO (80.0 μL, 0.73 mmol) was added and stirred. A vial was charged with 4-nitrophenol (21 mg, 0.15 mmol), CMPT (77 mg, 0.30 mmol), and CH ３ CN (1.5 mL) was added, and the mixed solvent was dried with MS3A. This mixed solution was added dropwise, and the mixture was stirred at 0°C for 40 minutes. The reaction solution was cooled to -20°C, and methyl trimethylsilyl dimethyl ketene acetal (hereinafter referred to as "MTDA") (90 μL, 0.44 mmol), 2M NHMe ２ A THF solution (1.5 mL, 3.0 mmol) of the above was added in turn, and the mixture was stirred at −20° C. for 1 hour. After the reaction, the solvent and volatile substances were evaporated under reduced pressure, and ２ Cl２ The reaction solution was cooled to 0°C, NCS (56.4 mg, 0.42 mmol) was added, and the mixture was stirred at 0°C for 10 minutes. ２ Cl ２ (20 mL) was added, followed by saturated NaHCO ３ aqueous solution (10 mL) and saturated Na ２ SO ３ The reaction was quenched by adding saturated aqueous NaHCO (10 mL). ３ The organic layer was washed with aqueous solution (2×20 mL) and saturated brine (20 mL). ２ SO ４ The extract was dried with HCl, filtered, and the solvent was evaporated under reduced pressure. ２ Cl ２ -acetone (95:5-70:30, v / v)], and PTLC [neutral-silica gel, hexane-AcOEt (1:2, v / v)] to obtain (Rp)-3c. (Rp)-3c: 8.7 mg, 12.3 μmol, 8.7%, dr=98:2, colorless solid

[0160] (Rp)-3c (synthesized from (Rp)-2c) １ H NMR (500MHz, CDCl ３ ) δ8.69 (br, 1H), 7.87 (d, J = 7.2Hz, 2H), 7.73 (d, J = 7.2Hz, 1H), 7.61 (t, J = 7.4Hz, 1H) , 7.52-7.47 (m, 8H), 7.30 (t, J=7.6Hz, 6H), 7.19 (t, J=7.2Hz, 3H), 6.28 (dd, J=9.2, 2.4Hz, 1H), 4.43 (m, 1H), 4.20-4.10 (m, 2H), 3.65-3.59 (m, 1H), 3.16 (dd, J=9.6, 2. 4Hz, 1H), 2.80-2.49 (d, J = 14.0Hz, 6H), 1.54 (t, J = 11.2Hz, 1H), 1.31-1.16 (m, 1H); ３１ P{ １ H}NMR (202MHz, CDCl ３ ) δ19.0, 18.6.

[0161] [Example 8-2] Morpholino cytidine (Sp)-dimethylaminophosphorochloridate monomer ((Sp)-3c)

[0162] (Sp)-2c (0.122 g, 0.15 mmol) was added to CH ２ Cl ２ (1.5 mL) was added and dried over activated MS4A. This mixed solution was added to a recovery flask, cooled to 0°C, and PhNCO (80.0 μL, 0.73 mmol) was added and stirred. A vial was charged with 4-nitrophenol (21 mg, 0.15 mmol), CMPT (77 mg, 0.30 mmol), and CH ３ CN (1.5 mL) was added, and the mixed solvent was dried with MS3A. The mixed solution was added dropwise, and the mixture was stirred at 0°C for 40 minutes. The reaction solution was cooled to -20°C, and MTDA (90 μL, 0.44 mmol), 2M NHMe ２ A THF solution (1.5 mL, 3.0 mmol) of the above was added in turn, and the mixture was stirred at −20° C. for 1 hour. After the reaction, the solvent and volatile substances were evaporated under reduced pressure, and ２ Cl ２ The reaction solution was cooled to 0°C, NCS (56.4 mg, 0.42 mmol) was added, and the mixture was stirred at 0°C for 10 minutes. ２ Cl ２ (20 mL) was added, followed by saturated NaHCO ３ aqueous solution (10 mL) and saturated Na ２ SO ３ The reaction was quenched by adding saturated aqueous NaHCO (10 mL). ３ The organic layer was washed with aqueous solution (2×20 mL) and saturated brine (20 mL). ２ SO ４ The extract was dried with HCl, filtered, and the solvent was evaporated under reduced pressure. ２ Cl ２-acetone (95:5-70:30, v / v)], and PTLC [neutral-silica gel, hexane-AcOEt (1:2, v / v)] to obtain (Sp)-3c. (Sp)-3c: 12.6 mg, 18.0 μmol, 13%, dr=97:3, colorless solid

[0163] (Sp)-3c (synthesized from (Sp)-2c) １ H NMR (500MHz, CDCl ３ ) δ8.66 (s, 1H) 7.88-7.81 (m, 2H), 7.71 (d, J=7.2Hz, 1H), 7.60 (t, J=7.4Hz, 1H), 7.55-7.4 4 (m, 9H), 7.30 (t, J = 7.6Hz, 6H), 7.19 (t, J = 7.2Hz, 3H), 6.28 (dd, J = 9.2, 2.0 Hz, 1H), 4.46-4.41 (m, 1H), 4.18-4.08 (m, 2H), 3.67-3.55 (m, 1H), 3.17 (dd, J = 9.6, 2.4Hz, 1H), 2.65 (d, J = 14.1Hz, 6H), 1.53 (m, 1H), 1.30-1.20 (m, 1H); ３１ P{ １ H}NMR (202MHz, CDCl ３ ) δ19.0, 18.6.

[0164] Example 9 ((2S,6R)-6-(6-(2-cyanoethoxy)-2-(2-phenoxyacetylamido)-9H-purin-9-yl)-4-tritylmorpholin-2-yl)methyl (R)-dimethylphosphoramidochloridate ((Rp)-3g-PAC)

[0165] Step 1: Preparation of N-(6-(2-cyanoethoxy)-9-((2R,6S)-6-((((1R,3S,3aR)-3-(4-methoxyphenyl)tetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxaphosphol 1-yl)oxy)methyl)-4-tritylmorpholin-2-yl)-9H-purin-2-yl)-2-phenoxyacetamide ((Rp)-2g-PAC)

[0166] 0.30 g (1.45 mmol) of (S)-(4-methoxyphenyl)((R)-pyrrolidin-2-yl)methanol, which had been azeotropically distilled with toluene, was suspended in 2.0 mL of dehydrated toluene, and then 0.84 mL of N-methylmorpholine was added. 0.33 mL of phosphorus trichloride was added to a separately prepared reaction vessel, and then 1.0 mL of dehydrated toluene was added to dissolve the mixture, followed by cooling to 0°C. The toluene suspension of (S)-(4-methoxyphenyl)((R)-pyrrolidin-2-yl)methanol was cooled to 0°C and then added dropwise to a toluene solution of phosphorus trichloride, and the mixture was warmed to room temperature. After stirring at room temperature for 1 hour, the resulting salt was filtered under reduced pressure. The collected filtrate was concentrated, and then 10 mL of dehydrated THF was added to the resulting residue to prepare a phosphitylation reagent solution, which was then cooled to -78°C. N-(6-(2-cyanoethoxy)-9-((2R,6S)-6-(hydroxymethyl)-4-tritylmorpholin-2-yl)-9H-purin-2-yl)-2-phenoxyacetamide (0.33 g, 0.48 mmol), which had been azeotropically distilled with pyridine and toluene, was suspended in 10 mL of dehydrated THF, and 1.41 mL of triethylamine was added, followed by cooling to −78°C. The prepared phosphitylation reagent solution was added dropwise at −78°C, and the temperature was then raised to room temperature. After stirring for 1.5 hours, the reaction solution was diluted with dichloromethane, and the reaction was quenched by adding ice-cold saturated aqueous sodium bicarbonate. The mixture was extracted with chloroform, dried over sodium sulfate, and the solvent was evaporated to obtain a crude product. The resulting residue was purified by silica gel chromatography (amino silica gel, hexane:ethyl acetate=5:1 v / v) to obtain (Rp)-2g-PAC (0.065 g, 0.070 mmol, 5%) as a single stereoisomer.

[0167] １ H-NMR (400MHz, CDCl ３): δ8.77 (br, 1H), 8.04 (s, 1H), 7.55-7.03 (m, 22H), 6.86-6.81 (m, 2H), 6.26 (dd, J=9. 6, 2.3Hz, 1H), 5.38 (d, J=6.4Hz, 1H) 4.85-4.74 (m, 4H), 4.41-4.34 (m, 1H), 3.90-3.86 ( m, 2H), 3.79-3.71 (m, 4H), 3.56-3.46 (m, 1H), 3.39 (d, J = 11.0Hz, 1H), 3.21-3.08 (m, 2 H), 3.03 (t, J=6.6Hz, 2H), 1.73-1.55 (m, 4H), 1.15-1.06 (m, 1H), 0.952-0.853 (m, 1H); ３１ P-NMR (162MHz, CDCl ３ ): δ159.2; ESI-MS m / z Cald for C ５２ H ５２ N ８ O ７ P[M+H] ＋ :931.3691,found:931.3658.

[0168] Step 2: Preparation of ((2S,6R)-6-(6-(2-cyanoethoxy)-2-(2-phenoxyacetylamido)-9H-purin-9-yl)-4-tritylmorpholin-2-yl)methyl (R)-dimethylphosphoramidochloridate ((Rp)-3g-PAC)

[0169] (Rp)-2g-PAC (111 mg, 0.12 mmol) was dissolved in 1.5 mL of dehydrated dichloromethane, and then dehydrated overnight using MS4A. To this solution, a solution of CMPT (62 mg) and 4-nitrophenol (16 mg) dissolved in 1.0 mL of acetonitrile and dehydrated overnight using MS3A was added dropwise under ice cooling and argon substitution. After the dropwise addition, phenyl isocyanate (65 μL) was added and the mixture was stirred for 20 minutes. Next, while maintaining the temperature at 0°C, TMS-NMe ２ (95 μL) and 2.0 M NHMe ２A THF solution (1.2 mL) of the above was added dropwise and stirred for 1 hour. After distilling off the solvent, the residue was dissolved in 1.0 mL of dichloromethane, and N-chlorosuccinimide (44.5 mg) was added under ice-cooling and stirred for 15 minutes. After dilution with ice-cooled dichloromethane, saturated aqueous sodium bicarbonate and saturated aqueous sodium thiosulfate were added to quench the reaction. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off. The resulting residue was purified by preparative thin-layer chromatography (dichloromethane:acetone=10:1, v / v) to give (Rp)-3g-PAC (5.0 mg, 0.0061 mmol, 5%, dr=98:2).

[0170] １ H-NMR (400MHz, CDCl ３ ): δ8.82 (br, 1H), 7.86 (s, 1H), 7.51-7.08 (m, 20H), 6.28 (dd, J = 10.1, 2.3Hz, 1H), 4.86-4.74 (m, 4H), 4.50-4.48 (m, 1H), 4.14-4.10 (m, 2) H), 3.49 (d, J = 11.4Hz, 1H), 3.21 (d, J = 11.4Hz, 1H), 3.03 (t, J = 6.9Hz , 2H), 2.62 (d, J = 13.7Hz, 6H), 1.74-1.69 (m, 1H), 1.62-1.56 (m, 1H); ３１ P-NMR (162MHz, CDCl ３ ): δ19.1, 18.7; ESI-MS m / z Cald for C ４２ H ４３ ClN ８ O ６ P[M+H] ＋ :821.2726,found::821.2685.

[0171] Example 10 (2S,6R)-6-(6-(2-cyanoethoxy)-2-(2-phenoxyacetylamido)-9H-purin-9-yl)-4-tritylmorpholin-2-yl)methyl (S)-dimethylphosphoramidochloridate ((Sp)-3g-PAC)

[0172] Step 1: Preparation of N-(6-(2-cyanoethoxy)-9-((2R,6S)-6-((((1S,3R,3aS)-3-(4-methoxyphenyl)tetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxaphosphol 1-yl)oxy)methyl)-4-tritylmorpholin-2-yl)-9H-purin-2-yl)-2-phenoxyacetamide ((Sp)-2g-PAC)

[0173] 1.04 g (5.00 mmol) of (R)-(4-methoxyphenyl)((S)-pyrrolidin-2-yl)methanol, which had been azeotropically distilled with toluene, was suspended in 2.0 mL of dehydrated toluene, and then 2.90 mL of N-methylmorpholine was added. 1.13 mL of phosphorus trichloride was added to a separately prepared reaction vessel, and then 5.0 mL of dehydrated toluene was added to dissolve the mixture, followed by cooling to 0°C. The toluene suspension of (R)-(4-methoxyphenyl)((S)-pyrrolidin-2-yl)methanol was cooled to 0°C and then added dropwise to a toluene solution of phosphorus trichloride, and the mixture was warmed to room temperature. After stirring at room temperature for 3 hours, the resulting salt was filtered under reduced pressure. The collected filtrate was concentrated, and then 10 mL of dehydrated THF was added to the resulting residue to prepare a phosphitylation reagent solution, which was then cooled to -78°C. N-(6-(2-cyanoethoxy)-9-((2R,6S)-6-(hydroxymethyl)-4-tritylmorpholin-2-yl)-9H-purin-2-yl)-2-phenoxyacetamide (1.74 g, 2.50 mmol), which had been azeotropically distilled with pyridine and toluene, was suspended in 10 mL of dehydrated THF, and 2.44 mL of triethylamine was added, followed by cooling to −78°C. The prepared phosphitylation reagent solution was added dropwise at −78°C, and the temperature was then raised to room temperature. After stirring for 1.5 hours, the reaction solution was diluted with dichloromethane, and the reaction was quenched by adding ice-cold saturated aqueous sodium bicarbonate. The mixture was extracted with dichloromethane, dried over sodium sulfate, and the solvent was evaporated to obtain a crude product. The resulting residue was purified by silica gel chromatography (amino silica gel, hexane:ethyl acetate=1:1 to 1:4, v / v+1 vol% triethylamine) to obtain (Sp)-2g-PAC (0.72 g, 0.77 mmol, 31%) as a single stereoisomer.

[0174] １ H-NMR (400MHz, CDCl ３ ): δ8.77 (br, 1H), 7.84 (s, 1H), 7.58-7.06 (m, 22H), 6.88-6.85 (m, 2H), 6.23 (dd, J=9.8, 2.1Hz , 1H), 5.64 (d, J=6.4Hz, 1H), 4.85-4.73 (m, 4H), 4.35-4.32 (m, 1H), 3.94-3.89 (m, 1H), 3.80-3 .. 65 (m, 5H), 3.58-3.48 (m, 1H), 3.43 (d, J = 11.4Hz, 1H), 3.32 (d, J = 11.9Hz, 1H), 3.17-3.07 (m, 1H), 3.03 (td, J=6.6, 1.4Hz, 2H), 1.73-1,49 (m, 4H), 1.20-1.11 (m, 1H), 0.963-0.866 (m, 1H); ３１ P-NMR (162MHz, CDCl ３ ): δ157.3; ESI-MS m / z Cald for C ５２ H ５２ N ８ O ７ P[M+H] ＋ :931.3691,found:931.3658.

[0175] Step 2: Preparation of ((2S,6R)-6-(6-(2-cyanoethoxy)-2-(2-phenoxyacetylamido)-9H-purin-9-yl)-4-tritylmorpholin-2-yl)methyl (S)-dimethylphosphoramidochloridate ((Sp)-3g-PAC)

[0176] (Sp)-2g-PAC (100 mg, 0.11 mmol) was dissolved in 1.0 mL of dehydrated dichloromethane, and then dehydrated overnight using MS4A. To this solution, a solution of CMPT (55.8 mg) and 4-nitrophenol (14.9 mg) dissolved in 1.0 mL of acetonitrile and dehydrated overnight using MS3A was added dropwise under ice cooling and argon substitution. After the dropwise addition, phenyl isocyanate (70 μL) was added and the mixture was stirred for 20 minutes. Next, while maintaining the temperature at 0°C, TMSNMe ２ (100 μL) and 2.0 M NHMe ２A THF solution (1.27 mL) of the above was added dropwise and stirred for 1 hour. After distilling off the solvent, the residue was dissolved in 1.0 mL of dichloromethane, and N-chlorosuccinimide (50.7 mg) was added under ice-cooling and stirred for 15 minutes. After dilution with ice-cooled dichloromethane, the reaction was quenched with 1 M aqueous sodium dihydrogen phosphate. After extraction with dichloromethane, the organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated. The resulting residue was purified by silica gel chromatography (dichloromethane:acetone = 97:3 to 85:15, v / v) and preparative thin-layer chromatography (hexane:ethyl acetate = 1:4, v / v) to give (Sp)-3g-PAC (6.0 mg, 0.0073 mmol, 6.0%, dr = 95:5).

[0177] １ H-NMR (400MHz, CDCl ３ ): δ8.81 (br, 1H), 7.84 (s, 1H), 7.51-7.08 (m, 20H), 6.29 (dd, J=10.1, 2.3Hz, 1H), 4.81-4.76 (m, 4H), 4.50-4.48 (m, 1H), 4.17-4.05 (m, 2H), 3 .49 (d, J=11.4Hz, 1H), 3.22 (d, J=11.9Hz, 1H), 3.03 (t, J=6.6Hz, 2H), 2 .61 (d, J=14.0Hz, 6H), 1.71 (t, J=10.8Hz, 1H), 1.58 (t, J=11.9Hz, 1H); ３１ P-NMR (162MHz, CDCl ３ ): δ19.1, 18.7; ESI-MS m / z Cald for C ４２ H ４３ ClN ８ O ６ P[M+H] ＋ :821.2726,found:821.2841.

[0178] [Example 11-1] Morpholino thymidine (Rp)-dimethylaminophosphorochloridate monomer ((Rp)-3t)

[0179] (Rp)-2t (0.25 g, 0.35 mmol) was added to CH ２ Cl２ (3.5 mL) was added and dried with activated MS4A. 3 mL of this mixed solution was added to a recovery flask, cooled to 0°C, and 3,4-dichlorophenyl isocyanate (0.14 g, 0.75 mmol) was added and stirred. 4-Nitrophenol (56 mg, 0.40 mmol), CMPT (0.21 g, 0.80 mmol), CH ３ CN (4.0 mL) was added and dried with MS3A. 3 mL of this mixed solution was added dropwise to a recovery flask and stirred at 0°C for 1 hour. The reaction solution was cooled to -20°C, and TMSNMe ２ (0.24 mL, 1.5 mmol), 2M NHMe ２ A THF solution (1.5 mL, 3.0 mmol) of the above was added in turn, and the mixture was stirred at −20° C. for 1 hour. After the reaction, the solvent and volatile substances were evaporated under reduced pressure, and ２ Cl ２ The reaction solution was cooled to 0°C, NCS (0.12 g, 0.89 mmol) was added, and the mixture was stirred at 0°C for 10 minutes. ２ Cl ２ (100 mL) was added, followed by saturated NaH ２ P.O. ４ The reaction was stopped by adding aqueous solution (100 mL). The organic layer was washed with saturated saline (100 mL). ２ SO ４ The residue was dried over CH 4 , filtered, and the solvent was evaporated under reduced pressure. ２ Cl ２ (5 mL) was added, and the mixture was subjected to suction filtration to remove insoluble matter, and the solvent was evaporated under reduced pressure. The residue was isolated and purified by silica gel column chromatography [diol-silica gel, hexane-AcOEt (9:1-5:5, v / v)] to obtain (Rp)-3t. (Rp)-3t: colorless solid, 66.7 mg, 0.11 mmol, 37%, dr=97:3

[0180] [Example 11-2] Morpholino thymidine (Sp)-dimethylaminophosphorochloridate monomer ((Sp)-3t)

[0181] (Sp)-2t (0.25 g, 0.35 mmol) was added to CH ２ Cl ２ (3.5 mL) was added and dried with activated MS4A. 3 mL of this mixed solution was added to a recovery flask, cooled to 0°C, and 3,4-dichlorophenyl isocyanate (0.28 g, 1.49 mmol) was added and stirred. 4-Nitrophenol (112 mg, 0.80 mmol), CMPT (0.42 g, 1.60 mmol), CH ３ CN (8.0 mL) was added and dried with MS3A. 3 mL of this mixed solution was added dropwise to a recovery flask and stirred at 0°C for 1 hour. The reaction solution was cooled to -20°C, and TMSNMe ２ (0.24 mL, 1.5 mmol), 2M NHMe ２ A THF solution (1.5 mL, 3.0 mmol) of the above was added in turn, and the mixture was stirred at −20° C. for 1 hour. After the reaction, the solvent and volatile substances were evaporated under reduced pressure, and ２ Cl ２ The reaction solution was cooled to 0°C, NCS (0.12 g, 0.89 mmol) was added, and the mixture was stirred at 0°C for 10 minutes. ２ Cl ２ (100 mL) was added, followed by saturated NaH ２ P.O. ４ The reaction was stopped by adding aqueous solution (100 mL). The organic layer was washed with saturated saline (100 mL). ２ SO ４ The residue was dried over CH 4 , filtered, and the solvent was evaporated under reduced pressure. ２ Cl ２ (5 mL) was added, and the mixture was subjected to suction filtration to remove insoluble matter, and the solvent was evaporated under reduced pressure. The residue was isolated and purified by silica gel column chromatography [diol-silica gel, hexane-AcOEt (9:1-5:5, v / v)] to obtain (Sp)-3t. (Sp)-3t: colorless solid, 93.1 mg, 0.15 mmol, 51%, dr=96:4

[0182] [Example 12-1] Morpholino adenosine (Rp)-dimethylaminophosphorochloridate monomer ((Rp)-3a)

[0183] (Rp)-2a (0.18 g, 0.22 mmol) was added to CH ２ Cl ２ (2.0 mL) was added and dried with activated MS4A. This mixed solution was added to a recovery flask, cooled to 0°C, and 3,4-dichlorophenyl isocyanate (0.18 mL, 0.97 mmol) was added and stirred. 4-nitrophenol (0.042 g, 0.30 mmol), CMPT (0.16 g, 0.60 mmol), CH ３ CN (3.0 mL) was added and dried with MS3A. 2 mL of this mixed solution was added dropwise to a recovery flask and stirred at 0°C for 1 hour. The reaction solution was cooled to -20°C, and TMSNMe ２ (0.16 mL, 1.0 mmol), 2M NHMe ２ A THF solution (1.0 mL, 2.0 mmol) of the above was added in turn, and the mixture was stirred at −20° C. for 1 hour. After the reaction, the solvent and volatile substances were evaporated under reduced pressure, and ２ Cl ２ The reaction solution was cooled to 0°C, NCS (0.084 g, 0.62 mmol) was added, and the mixture was stirred at 0°C for 10 minutes. ２ Cl ２ (50 mL) was added, followed by saturated NaH ２ P.O. ４ The reaction was stopped by adding aqueous solution (50 mL). The organic layer was washed with saturated saline (50 mL). ２ SO ４ The residue was dried over 1000 kJ, filtered, and the solvent was evaporated under reduced pressure. ２ Cl ２ (6 mL) was added, and the mixture was subjected to suction filtration to remove insoluble matter, and the solvent was evaporated under reduced pressure. The residue was isolated and purified by silica gel column chromatography [diol-silica gel, hexane-AcOEt (9:1-5:5, v / v)] to obtain (Rp)-3a. (Rp)-3a: 68 mg, 0.094 mmol, 47%, dr=97:3, colorless solid.

[0184] [Example 12-2] Morpholino adenosine (Sp)-dimethylaminophosphorochloridate monomer ((Sp)-3a)

[0185] (Sp)-2a (0.17g, 0.20mmol) with CH ２ Cl ２ (2.0 mL) was added and dried over activated MS4A. This mixed solution was added to a recovery flask, cooled to 0°C, and PhNCO (0.11 mL, 1.0 mmol) was added and stirred. A vial was charged with 4-nitrophenol (0.028 g, 0.20 mmol), CMPT (0.10 g, 0.40 mmol), CH ３ CN (2.0 mL) was added and dried with MS3A. 2 mL of this mixed solution was added dropwise to a recovery flask and stirred at 0°C for 1 hour. 88% of the reaction solution was cooled to -20°C and TMSNMe ２ (0.14 mL, 0.88 mmol), 2M NHMe ２ A THF solution (0.88 mL, 1.76 mmol) of the above was added in turn, and the mixture was stirred at −20° C. for 1 hour. After the reaction, the solvent and volatile substances were evaporated under reduced pressure, and the residue was ２ Cl ２ 86% of the reaction solution was cooled to 0°C, and NCS (0.060 g, 0.45 mmol) was added, followed by stirring at 0°C for 10 minutes. ２ Cl ２ (50 mL) was added, followed by saturated NaHCO ３ aqueous solution (25 mL) and saturated Na ２ S ２ O ３ The reaction was quenched by adding a mixture of saturated aqueous NaHCO ３ The organic layer was washed with aqueous solution (3×50 mL) and saturated brine (50 mL). ２ SO ４ The residue was dried over 1000 kJ / min, filtered, and the solvent was removed by distillation under reduced pressure. 83% of the residue was purified by PTLC [neutral-silica gel, CHCl ３-acetone (9:1, v / v), neutral-silica gel, hexane-AcOEt (1:5, v / v)] to obtain (Sp)-3a. (Sp)-3a: 28.5 mg, 39.5 μmol, 32%, dr=98:2, colorless solid

[0186] [Example 13-1] Morpholino guanosine (Rp)-dimethylaminophosphorochloridate monomer ((Rp)-3g)

[0187] (Rp)-2g (0.18g, 0.20mmol) ２ Cl ２ (2.0 mL) was added and dried over activated MS4A. This mixed solution (2.0 mL) was added to a recovery flask and cooled to 0°C. 3,4-dichlorophenyl isocyanate (0.19 g, 1.0 mmol) was added and stirred. 4-Nitrophenol (0.041 g, 0.30 mmol), CMPT (0.16 g, 0.60 mmol), CH ３ CN (3.0 mL) was added and dried over MS3A. 2.0 mL of this mixed solution was added dropwise to a recovery flask and stirred at 0°C for 1 hour. The reaction solution was cooled to -20°C, and TMSNMe ２ (0.16 mL, 1.0 mmol), 2M NHMe ２ A THF solution (1.0 mL, 2.0 mmol) of the above was added in turn, and the mixture was stirred at −20° C. for 1 hour. After the reaction, the solvent and volatile substances were evaporated under reduced pressure, and ２ Cl ２ The reaction solution was cooled to 0°C, NCS (0.075 g, 0.56 mmol) was added, and the mixture was stirred at 0°C for 10 minutes. ２ Cl ２ (50 mL) was added, followed by saturated NaH ２ P.O. ３ The reaction was stopped by adding aqueous solution (50 mL). The organic layer was washed with saturated saline (50 mL). ２ SO ４ The residue was dried over CH 4 , filtered, and the solvent was evaporated under reduced pressure. ２ Cl ２(6 mL) was added, and the mixture was subjected to suction filtration to remove insoluble matter, and the solvent was evaporated under reduced pressure. The residue was isolated and purified by silica gel column chromatography [diol-silica gel, hexane-AcOEt (9:1-3:7, v / v)] to obtain (Rp)-3g. (Rp)-3g: 58.0 mg, 0.076 mmol, 38%, dr=95:5

[0188] [Example 13-2] Morpholino guanosine (Sp)-dimethylaminophosphorochloridate monomer ((Sp)-3g)

[0189] (Sp)-2g (0.30g, 0.35mmol) ２ Cl ２ (2.0 mL) was added and dried with activated MS4A. This mixed solution (3.0 mL) was added to a recovery flask and cooled to 0°C. 3,4-dichlorophenyl isocyanate (0.15 g, 0.79 mmol) was added and stirred. 4-Nitrophenol (0.056 g, 0.40 mmol), CMPT (0.21 g, 0.81 mmol), CH ３ CN (4.0 mL) was added and dried with MS3A. 3.0 mL of this mixed solution was added dropwise to a recovery flask and stirred at 0°C for 1 hour. The reaction solution was cooled to -20°C, and TMSNMe ２ (0.24 mL, 1.5 mmol), 2M NHMe ２ A THF solution (1.5 mL, 3.0 mmol) of the above was added in turn, and the mixture was stirred at −20° C. for 1 hour. After the reaction, the solvent and volatile substances were evaporated under reduced pressure, and ２ Cl ２ The reaction solution was cooled to 0°C, NCS (0.13 g, 0.96 mmol) was added, and the mixture was stirred at 0°C for 10 minutes. ２ Cl ２ (50 mL) was added, followed by saturated NaH ２ P.O. ３ The reaction was stopped by adding aqueous solution (50 mL). The organic layer was washed with saturated saline (50 mL). ２ SO ４ The residue was dried over CH 4 , filtered, and the solvent was evaporated under reduced pressure. ２ Cl２ (6 mL) was added, and the mixture was subjected to suction filtration to remove insoluble matter, and the solvent was evaporated under reduced pressure. The residue was isolated and purified by silica gel column chromatography [diol-silica gel, hexane-AcOEt (9:1-3:7, v / v)] to obtain (Sp)-3g. (Sp)-3g: 85.1 mg, 0.11 mmol, 37%, dr=93:7

[0190] [Example 14-1] Morpholino cytidine (Rp)-dimethylaminophosphorochloridate monomer ((Rp)-3c)

[0191] (Rp)-2c (0.18 g, 0.22 mmol) was added to CH ２ Cl ２ (2.0 mL) was added and dried over activated MS4A. This mixed solution (2.0 mL) was added to a recovery flask and cooled to 0°C. 3,4-dichlorophenyl isocyanate (0.19 mL, 1.0 mmol) was added and stirred. 4-Nitrophenol (42 mg, 0.30 mmol), CMPT (0.159 g, 0.61 mmol), CH ３ CN (3.0 mL) was added, and the mixed solvent was dried over MS3A. This mixed solution (2.0 mL) was added dropwise, and the mixture was stirred at 0°C for 1 hour. The reaction solution was cooled to -20°C, and MTDA (0.12 mL, 0.59 mmol), 2M NHMe ２ A THF solution (2.0 mL, 4.0 mmol) of the above was added in this order, and the mixture was stirred at −20° C. for 1 hour. After the reaction, the solvent and volatile substances were evaporated under reduced pressure, and ２ Cl ２ The reaction solution was cooled to 0°C, NCS (0.084 g, 0.63 mmol) was added, and the mixture was stirred at 0°C for 10 minutes. ２ Cl ２ (50 mL) was added, followed by saturated NaH ２ P.O. ３ The reaction was stopped by adding aqueous solution (50 mL). The organic layer was washed with saturated saline (50 mL). ２ SO ４ The residue was dried over CH 4 , filtered, and the solvent was evaporated under reduced pressure. ２ Cl ２(6 mL) was added, and the mixture was subjected to suction filtration to remove insoluble matter, and the solvent was evaporated under reduced pressure. The residue was isolated and purified by silica gel column chromatography [diol-silica gel, hexane-AcOEt (7:3-2:8, v / v)] to obtain (Rp)-3c. (Rp)-3c: 66 mg, 0.95 mmol, 47%, dr=96:4, colorless solid

[0192] [Example 14-2] Morpholino cytidine (Sp)-dimethylaminophosphorochloridate monomer ((Sp)-3c)

[0193] (Sp)-2c (287.2 mg, 0.36 mmol) was added to CH ２ Cl ２ (3.5 mL) was added and dried over activated MS4A. This mixed solution (3.0 mL) was added to a recovery flask and cooled to 0°C. PhNCO (0.16 mL, 1.5 mmol) was added and stirred. A vial was charged with 4-nitrophenol (112 mg, 0.80 mmol), CMPT (416 mg, 1.6 mmol), CH ３ CN (8.0 mL) was added, and the mixed solvent was dried over MS3A. This mixed solution (3.0 mL) was added dropwise, and the mixture was stirred at 0°C for 1 hour. The reaction solution was cooled to -20°C, and MTDA (0.18 mL, 0.90 mmol), 2M NHMe ２ A THF solution (0.18 mL, 0.90 mmol) of the above was added in turn, and the mixture was stirred at −20° C. for 1 hour. After the reaction, the solvent and volatile substances were evaporated under reduced pressure, and the resulting mixture was ２ Cl ２ The reaction solution was cooled to 0°C, NCS (122.4 mg, 0.91 mmol) was added, and the mixture was stirred at 0°C for 10 minutes. ２ Cl ２ (50 mL) was added, followed by saturated NaH ２ P.O. ３ The reaction was stopped by adding aqueous solution (50 mL). The organic layer was washed with saturated saline (50 mL). ２ SO ４The extract was dried with HCl, filtered, and the solvent was removed by distillation under reduced pressure. ３ hexane:AcOEt (100:0-95:5), diol-silica gel, hexane:AcOEt (100:0-40:60), diol-silica gel, toluene:AcOEt (100:0), diol-silica gel, toluene:AcOEt (100:0-70:30)] to obtain (Sp)-3c. (Sp)-3c: 77 mg, 0.11 mmol, 37%, dr = 96:4, colorless solid

Claims

an aryloxylation step of reacting a compound represented by the following general formula (1) with a phenol compound represented by the formula ArOH (wherein Ar is as described below) in the presence of an amino group-protecting agent to obtain a compound represented by the following general formula (2); The compound represented by the following general formula (2) is represented by the formula HNR ６ R ７ (In the formula, R ６ and R ７ is as described below.) to obtain a compound represented by the following general formula (3); an oxidative halogenation step of oxidatively halogenating a compound represented by the following general formula (3) with a halogenating agent to obtain a compound represented by the following general formula (4); A method for producing a compound comprising: (In general formula (1), R １ represents an aryl group having or without a substituent, R ２ ~R ４ each independently represents a hydrogen atom, a halogen group, or an alkyl group having or without a substituent, or R ３ and R ４ are bonded to each other to form a heterocyclic ring of 5 or more members, which may or may not have a substituent, and Nu is represented by the following general formula (5) or (6): (In general formula (5) or (6), R １１ ~R １５ each independently represents a hydrogen atom, a halogenyl group, a substituted or unsubstituted alkyl group, a group represented by the formula OR (wherein R represents a hydroxyl-protecting group or a substituted or unsubstituted alkyl group), an amino group, an azide group, or a cyano group, or R １３ and R １４ , or R １３ and R １５ are bonded to each other to form a ring of 5 or more members, which may or may not have a substituent and which may or may not have a hetero atom; R ２１ represents a protecting group for an amino group, and Bs represents a nucleic acid base, which may or may not have a protecting group for the nucleic acid base. represents a monovalent group represented by the formula: (In general formula (2), R １ ~R ４ and Nu are as described above, and R ５ represents a protecting group for an amino group, and Ar represents an aryl group which may or may not have a substituent. (In general formula (3), R １ ~R ５ and Nu are as described above, and R ６ and R ７ each independently represents a hydrogen atom, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted aryl group, or R ６ and R ７ are bonded to each other to form a heterocyclic ring which may or may not have a substituent. (In general formula (4), R ６ , R ７ , and Nu are as defined above, and X represents a halogenyl group. 　 The compound represented by the following general formula (2) is represented by the formula HNR ６ R ７ (In the formula, R ６ and R ７ is as described below.) to obtain a compound represented by the following general formula (3); an oxidative halogenation step of oxidatively halogenating a compound represented by the following general formula (3) with a halogenating agent to obtain a compound represented by the following general formula (4); A method for producing a compound comprising: (In general formula (2), R １ represents an aryl group having or without a substituent, R ２ ~R ４ each independently represents a hydrogen atom, a halogen group, or an alkyl group having or without a substituent, or R ３ and R ４ are bonded to each other to form a heterocyclic ring of 5 or more members which may or may not have a substituent, R ５ represents a protecting group for an amino group, Ar represents an aryl group having or having no substituent, and Nu represents a group represented by the following general formula (5) or (6): (In general formula (5) or (6), R １１ ~R １５ each independently represents a hydrogen atom, a halogenyl group, a substituted or unsubstituted alkyl group, a group represented by the formula OR (wherein R represents a hydroxyl-protecting group or a substituted or unsubstituted alkyl group), an amino group, an azide group, or a cyano group, or R １３ and R １４ , or R １３ and R １５ are bonded to each other to form a ring of 5 or more members, which may or may not have a substituent and which may or may not have a hetero atom; R ２１ represents a protecting group for an amino group, and Bs represents a nucleic acid base, which may or may not have a protecting group for the nucleic acid base. represents a monovalent group represented by the formula: (In general formula (3), R １ ~R ５ and Nu are as described above, and R ６ and R ７ each independently represents a hydrogen atom, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted aryl group, or R ６ and R ７ are bonded to each other to form a heterocyclic ring which may or may not have a substituent. (In general formula (4), R ６ , R ７ , and Nu are as defined above, and X represents a halogenyl group. 　 A method for producing a compound, comprising an oxidative halogenation step of oxidatively halogenating a compound represented by the following general formula (3) with a halogenating agent to obtain a compound represented by the following general formula (4): (In general formula (3), R １ represents an aryl group having or without a substituent, R ２ ~R ４ each independently represents a hydrogen atom, a halogen group, or an alkyl group having or without a substituent, or R ３ and R ４ are bonded to each other to form a heterocyclic ring of 5 or more members which may or may not have a substituent, R ５ represents a protecting group for an amino group, R ６ and R ７ each independently represents a hydrogen atom, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted aryl group, or R ６ and R ７ are bonded to each other to form a heterocycle having or not having a substituent, and Nu is represented by the following general formula (5) or (6): (In general formula (5) or (6), R １１ ~R １５ each independently represents a hydrogen atom, a halogenyl group, a substituted or unsubstituted alkyl group, a group represented by the formula OR (wherein R represents a hydroxyl-protecting group or a substituted or unsubstituted alkyl group), an amino group, an azide group, or a cyano group, or R １３ and R １４ , or R １３ and R １５ are bonded to each other to form a ring of 5 or more members, which may or may not have a substituent and which may or may not have a hetero atom; R ２１ represents a protecting group for an amino group, and Bs represents a nucleic acid base, which may or may not have a protecting group for the nucleic acid base. represents a monovalent group represented by the formula: (In general formula (4), R ６ , R ７ , and Nu are as defined above, and X represents a halogenyl group.

3. The method for producing a compound according to claim 1, wherein Ar is an aryl group having or without a substituent such that the pKa of the phenol compound represented by the formula ArOH is 6.4 to 7.

7. R １ The method for producing the compound according to any one of claims 1 to 3, wherein is a 4-methoxyphenyl group. R １ is a 4-methoxyphenyl group. 　 A method for producing the compound according to any one of claims 1 to 3, wherein the stereochemistry of the phosphorus atom is controlled. R １ is a 4-methoxyphenyl group. 　 The compound represented by the general formula (1) is a morpholino nucleic acid monomer derivative represented by the following general formula (11): The compound represented by the general formula (2) is a morpholino nucleic acid monomer derivative represented by the following general formula (12): The compound represented by the general formula (3) is a morpholino nucleic acid monomer derivative represented by the following general formula (13): The compound represented by the general formula (4) is a morpholino nucleic acid monomer represented by the following general formula (14): The method for producing the compound is a method for producing a morpholino nucleic acid monomer. A method for producing the compound of claim 1. (In general formula (11), R １ ~R ４ , R ２１ , and Bs are as described above.) (In general formula (12), R １ ~R ５ , R ２１ , Ar, and Bs are as defined above.) (In general formula (13), R １ ~R ７ , R ２１ , and Bs are as described above.) (In general formula (14), R ６ , R ７ , R ２１ , X, and Bs are as described above.) The compound represented by the general formula (2) is a morpholino nucleic acid monomer derivative represented by the following general formula (12): The compound represented by the general formula (3) is a morpholino nucleic acid monomer derivative represented by the following general formula (13): The compound represented by the general formula (4) is a morpholino nucleic acid monomer represented by the following general formula (14): The method for producing the compound is a method for producing a morpholino nucleic acid monomer. A method for producing the compound of claim 2. (In general formula (12), R １ ~R ５ , R ２１ , Ar, and Bs are as defined above.) (In general formula (13), R １ ~R ７ , R ２１ , and Bs are as described above.) (In general formula (14), R ６ , R ７ , R ２１ , X, and Bs are as described above.) 　 The compound represented by the general formula (3) is a morpholino nucleic acid monomer derivative represented by the following general formula (13): The compound represented by the general formula (4) is a morpholino nucleic acid monomer represented by the following general formula (14): The method for producing the compound is a method for producing a morpholino nucleic acid monomer. A method for producing the compound of claim 3. (In general formula (13), R １ ~R ７ , R ２１ , and Bs are as described above.) (In general formula (14), R ６ , R ７ , R ２１ , X, and Bs are as described above.) 　 The method for producing a compound according to claim 9 or 10, wherein Ar is an aryl group having or without a substituent such that the pKa of the phenol compound represented by the formula ArOH is 6.4 to 7.

7. R １ The method for producing the compound according to any one of claims 9 to 11, wherein is a 4-methoxyphenyl group. R １ is a 4-methoxyphenyl group. 　 A method for producing the compound according to any one of claims 9 to 11, wherein the stereochemistry of the phosphorus atom is controlled. R １ is a 4-methoxyphenyl group. 　 A compound represented by the following general formula (1a): (In general formula (1a), R １ represents an aryl group having or without a substituent, R ２ ~R ４ each independently represents a hydrogen atom, a halogen group, or an alkyl group having or without a substituent, or R ３ and R ４ are bonded to each other to form a heterocycle of 5 or more members which may or may not have a substituent, and Nu′ is a group represented by the following general formula (5a) or (6a): (In general formula (5a) or (6a), R １１ａ , R １２ａ , and R １４ａ each independently represents a hydrogen atom, a halogenyl group, a substituted or unsubstituted alkyl group, a group represented by the formula OR′ (wherein R′ represents a hydrogen atom, a hydroxyl-protecting group, or a substituted or unsubstituted alkyl group), an amino group, an azide group, or a cyano group; R １３ｂ and R １５ｂ are bonded to each other to form a ring of 5 or more members, which may or may not have a substituent and which may or may not have a hetero atom; R ２１ａ represents a protecting group for a hydrogen atom or an amino group, and Bs represents a nucleic acid base, which may or may not have a protecting group for the nucleic acid base. represents a monovalent group represented by the following formula: 　 A compound represented by the following general formula (2a): (In general formula (2a), R １ represents an aryl group having or without a substituent, R ２ ~R ４ each independently represents a hydrogen atom, a halogen group, or an alkyl group having or without a substituent, or R ３ and R ４ are bonded to each other to form a heterocyclic ring of 5 or more members which may or may not have a substituent, R ５ａ represents a hydrogen atom or a protecting group for an amino group, Ar represents an aryl group having or having no substituent, and Nu″ represents a group represented by the following general formula (5b) or (6a): (In general formula (5b) or (6a), R １１ａ ~R １５ａ independently represent a hydrogen atom, a halogenyl group, a substituted or unsubstituted alkyl group, a group represented by the formula OR′ (wherein R′ represents a hydrogen atom, a hydroxyl-protecting group, or a substituted or unsubstituted alkyl group), an amino group, an azide group, or a cyano group, or R １３ａ and R １４ａ , or R １３ａ and R １５ａ are bonded to each other to form a ring of 5 or more members, which may or may not have a substituent and which may or may not have a hetero atom; R ２１ａ represents a protecting group for a hydrogen atom or an amino group, and Bs represents a nucleic acid base, which may or may not have a protecting group for the nucleic acid base. represents a monovalent group represented by the following formula: 　 A compound represented by the following general formula (3a): (In general formula (3a), R １ represents an aryl group having or without a substituent, R ２ ~R ４ each independently represents a hydrogen atom, a halogen group, or an alkyl group having or without a substituent, or R ３ and R ４ are bonded to each other to form a heterocyclic ring of 5 or more members which may or may not have a substituent, R ５ａ represents a hydrogen atom or a protecting group for an amino group, R ６ and R ７ each independently represents a hydrogen atom, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted aryl group, or R ６ and R ７ are bonded to each other to form a heterocycle having or not having a substituent, and Nu″ is a group represented by the following general formula (5b) or (6a): (In general formula (5b) or (6a), R １１ａ ~R １５ａ independently represent a hydrogen atom, a halogenyl group, a substituted or unsubstituted alkyl group, a group represented by the formula OR' (wherein R' represents a hydrogen atom, a hydroxyl-protecting group, or a substituted or unsubstituted alkyl group), an amino group, an azide group, or a cyano group, or R １３ａ and R １４ａ , or R １３ａ and R １５ａ are bonded to each other to form a ring of 5 or more members, which may or may not have a substituent and which may or may not have a hetero atom; R ２１ａ represents a protecting group for a hydrogen atom or an amino group, and Bs represents a nucleic acid base, which may or may not have a protecting group for the nucleic acid base. represents a monovalent group represented by the following formula:

19. The compound according to claim 18, wherein Ar represents an aryl group with or without a substituent such that the pKa of the phenolic compound represented by the formula ArOH is 6.4 to 7.

7. R １ The compound according to any one of claims 17 to 19, wherein is a 4-methoxyphenyl group. R １ is a 4-methoxyphenyl group.

20. The compound of any one of claims 17 to 19, wherein the stereochemistry at the phosphorus atom is controlled. R １ is a 4-methoxyphenyl group. 　 The compound according to claim 17, wherein the compound represented by the general formula (1a) is a morpholino nucleic acid monomer derivative represented by the following general formula (11a): (In general formula (11), R １ ~R ４ , R ２１ａ , and Bs are as described above.) The compound according to claim 18, wherein the compound represented by the general formula (2a) is a morpholino nucleic acid monomer derivative represented by the following general formula (12a): (In general formula (12a), R １ ~R ４ , R ５ａ , R ２１ａ , Ar, and Bs are as defined above.) 　 The compound according to claim 19, wherein the compound represented by the general formula (3a) is a morpholino nucleic acid monomer derivative represented by the following general formula (13a): (In general formula (13), R １ ~R ４ , R ５ａ , R ６ , R ７ , R ２１ａ , and Bs are as described above.) 　 27. The compound according to claim 26, wherein Ar represents an aryl group with or without a substituent such that the pKa of the phenolic compound represented by the formula ArOH is 6.4 to 7.

7. R １ The compound according to any one of claims 25 to 27, wherein is a 4-methoxyphenyl group. R １ is a 4-methoxyphenyl group.

28. The compound of any one of claims 25 to 27, wherein the stereochemistry at the phosphorus atom is controlled. R １ is a 4-methoxyphenyl group.

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