Method for producing compound, compound, and nucleotide prodrug precursor

Abstract

Provided are: a method for producing a compound useful as a nucleotide prodrug; a compound useful as a starting material or an intermediate of the production method; and a nucleotide prodrug precursor.　A method for producing a compound according to the present invention comprises: an aryloxylation step for reacting a compound (1) with a phenol compound ArOH to obtain a compound (2); an oxidative halogenation step for oxidatively halogenating the compound (2) with a halogenating agent to obtain a compound (3); and an amination step for reacting the compound (3) with a compound (5) to obtain a compound (4). In the formula, R11-R15 are a hydrogen atom, etc., R1 is an optionally substituted aryl group, R2-R4 are a hydrogen atom, etc., R5 is an optionally substituted alkyl group, R6 is an amino acid side chain, etc., Ar is an optionally substituted aryl group, X is a halogenyl group, A- is a counter anion, and Bs represents a nucleic acid base optionally having a protecting group.

Description

Methods for producing compounds, compounds, and nucleotide prodrug precursors

[0001] The present invention relates to a method for producing a compound, a compound, and a nucleotide prodrug precursor. More specifically, the present invention relates to a method for producing a compound useful as a nucleotide prodrug, a compound useful as a starting material or intermediate in the production method, and a nucleotide prodrug precursor.

[0002] Nucleotide analogs have a structure similar to that of nucleotides and can be mistakenly incorporated into cancer cells or viruses during DNA or RNA synthesis, thereby inhibiting said synthesis. Nucleotide prodrugs are prodrug-modified nucleotide analogs designed to act effectively at target sites in the body. Among these, nucleotide prodrugs in which an aryloxy group and an amino acid ester residue are bound to the phosphorus atom are collectively called protides and have begun to be put into practical use. For example, remdesivir, a type of protide, is disclosed in Patent Document 1.

[0003] Special Publication No. 2013-535453

[0004] An objective of the present invention is to provide a method for producing a compound useful as a nucleotide prodrug, a compound useful as a starting material or intermediate for the production method, and a nucleotide prodrug precursor.

[0005] Specific means for solving the above problems include the following embodiments: <1> A method for producing a compound, comprising: an aryloxylation step of reacting a compound represented by the following general formula (1) with a phenolic compound represented by the formula ArOH (wherein Ar is as described below) to obtain a compound represented by the following general formula (2), an oxidative halogenation step of oxidatively halogenating the compound represented by the following general formula (2) with a halogenating agent to obtain a compound represented by the following general formula (3), and an amination step of reacting the compound represented by the following general formula (3) with an amino acid ester represented by the following general formula (5) to obtain a compound represented by the following general formula (4). (In general formula (1), 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 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 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 5-membered or greater heterocycle which may or may not have a substituent, and Bs represents a nucleobase, which may or may not have a protecting group for the nucleobase. (In general formula (2), R １１ ~R １５ , R １ ~R ４ and Bs are as defined above, Ar represents an aryl group having or having no substituent, A － represents a counter anion.) (In general formula (3), R １１ ~R １５ , Ar, and Bs are as defined above, and X represents a halogenyl group. (In general formula (4), R １１ ~R １５ , Ar, and Bs are as described above, and R ５ represents an alkyl group having or without a substituent, R ６ represents a hydrogen atom, an alkyl group with or without a substituent, or the side chain of an amino acid. (In general formula (5), R ５ and R ６ is as mentioned above.)

[0006] <2> R １ is a 4-methoxyphenyl group.

[0007] <3> A method for producing a compound, comprising: an oxidative halogenation step of oxidatively halogenating a compound represented by the following general formula (2) with a halogenating agent to obtain a compound represented by the following general formula (3); and an amination step of reacting the compound represented by the following general formula (3) with an amino acid ester represented by the following general formula (5) to obtain a compound represented by the following general formula (4). (In general formula (2), 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 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 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, Ar represents an aryl group which may or may not have a substituent, Bs represents a nucleic acid base which may or may not have a protecting group for the nucleic acid base, A － represents a counter anion.) (In general formula (3), R １１ ~R １５ , Ar, and Bs are as defined above, and X represents a halogenyl group. (In general formula (4), R １１ ~R １５ , Ar, and Bs are as described above, and R ５ represents an alkyl group having or without a substituent, R ６ represents a hydrogen atom, an alkyl group with or without a substituent, or the side chain of an amino acid. (In general formula (5), R ５ and R ６ is as mentioned above.)

[0008] <4> R １ is a 4-methoxyphenyl group.

[0009] <5> A method for producing a compound, comprising an amination step of reacting a compound represented by the following general formula (3) with an amino acid ester represented by the following general formula (5) to obtain a compound represented by the following general formula (4): (In general formula (3a), 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 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, Ar represents an aryl group which may or may not have a substituent, X represents a halogenyl 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 １１ ~R １５ , Ar, and Bs are as described above, and R ５ represents an alkyl group having or without a substituent, R ６ represents a hydrogen atom, an alkyl group with or without a substituent, or the side chain of an amino acid. (In general formula (5), R ５ and R ６ is as mentioned above.)

[0010] <6> A method for producing the compound according to any one of <1> to <5>, wherein the stereochemistry of the phosphorus atom is controlled.

[0011] <7> A compound represented by the following general formula (1a): (In general formula (1a), R １１ａ ~R １５ａindependently 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 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 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 5-membered or greater heterocycle which may or may not have a substituent, and Bs represents a nucleobase, which may or may not have a protecting group for the nucleobase.

[0012] <8> R １ is a 4-methoxyphenyl group.

[0013] <9> A compound represented by the following general formula (2a): (In general formula (2a), 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 １３ and R １４ 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 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 ４are bonded to each other to form a heterocycle of 5 or more members which may or may not have a substituent, Ar represents an aryl group which may or may not have a substituent, Bs represents a nucleic acid base which may or may not have a protecting group for the nucleic acid base, A － represents a counter anion.)

[0014] <10> R １ is a 4-methoxyphenyl group.

[0015] <11> A compound represented by the following general formula (3a): (In general formula (3a), 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 １３ and R １４ 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, Ar represents an aryl group which may or may not have a substituent, X represents a halogenyl group, and Bs represents a nucleic acid base which may or may not have a protecting group for the nucleic acid base.

[0016] <12> The compound according to any one of <7> to <11>, wherein the stereochemistry of the phosphorus atom is controlled.

[0017] <13> A nucleotide prodrug precursor comprising the compound according to any one of <7> to <11>.

[0018] <14> A nucleotide prodrug precursor comprising the compound according to <12>.

[0019] According to the present invention, there can be provided a method for producing a compound useful as a nucleotide prodrug, a compound useful as a starting material or intermediate for the production method, and a nucleotide prodrug precursor.

[0020] 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.

[0021] <Method for producing compounds> The method for producing a compound according to the first embodiment includes the above-mentioned aryloxylation step, the above-mentioned oxidative halogenation step, and the above-mentioned amination step. The method for producing a compound according to the second embodiment includes the above-mentioned oxidative halogenation step and the above-mentioned amination step. The method for producing a compound according to the third embodiment includes the above-mentioned amination step. Any of these production methods can produce a compound useful as a nucleotide prodrug.

[0022] [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) to obtain the compound represented by the general formula (2).

[0023] (Compound represented by general formula (1)) In the compound represented by general formula (1), 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 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 １ represents an aryl group having or without a substituent, R ２ ~R ４each 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 5-membered or greater heterocycle which may or may not have a substituent, and Bs represents a nucleic acid base which may or may not have a protecting group for the nucleic acid base. The compound represented by general formula (1) may be used alone or in combination of two or more.

[0024] R １ Examples 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.

[0025] 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.

[0026] R ３ and R ４may 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.

[0027] 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 １５Examples 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.

[0028] R １３ and R １４ 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.

[0029] 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:

[0030] 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, a 4,4',4''-trimethoxytrityl group, and a diphenylcarbamoyl group.

[0031] Examples of nucleic acid bases having a protecting group include nucleic acid bases represented by the following formula:

[0032] The compound represented by formula (1) can be produced, for example, by the method described in the Examples.

[0033] (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.

[0034] Specific examples of Ar include a phenyl group, a 3-methyl-4-nitrophenyl group, a 2-nitrophenyl group, a 4-nitrophenyl group, a 2,4,6-trifluorophenyl group, and a 2,4,5-trichlorophenyl group, and among these, a phenyl group is particularly preferred.

[0035] The amount of the phenol compound used in this step is, for example, in a molar ratio within a range of 1 to 100 times, and preferably within a range of 1.5 to 3 times, per mole of the compound represented by the general formula (1).

[0036] (Compound represented by general formula (2)) In the compound represented by general formula (2), R １１ ~R １５ , R １ ~R ４ , Ar, and Bs are as described above, and A － represents a counter anion. The compound represented by formula (2) may be used alone or in combination of two or more.

[0037] A － Examples of the counter anion represented by the formula (I) include halide ions such as fluoride ion, chloride ion, and bromide ion; hydroxide ion; inorganic acid ions such as sulfate ion, nitrate ion, carbonate ion, tetrafluoroborate ion, and hexafluorophosphate ion; and organic acid ions such as formate ion, trifluoromethanesulfonate ion, bistrifluoromethanesulfonylimide ion, and acetate ion, with trifluoromethanesulfonate ion being particularly preferred.

[0038] (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.

[0039] The amount of the activator used in this step is, for example, in a molar ratio within a range of 1 to 100 times, and preferably within a range of 2 to 5 times, per mole of the compound represented by the general formula (1).

[0040] 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.

[0041] The reaction time in this step is, for example, within the range of 0.05 to 10 hours, and preferably within the range of 0.1 to 3 hours.

[0042] The reaction temperature in this step is, for example, within the range of -78 to 30°C, and preferably within the range of -40 to 0°C.

[0043] [Oxidative Halogenation Step] In the oxidative halogenation step, the compound represented by the general formula (2) is oxidatively halogenated with a halogenating agent to obtain the compound represented by the general formula (3).

[0044] (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.

[0045] 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 (2) to 1 mole of the compound.

[0046] (Compound represented by general formula (3)) In the compound represented by general formula (3), R １１ ~R １５ , Ar, and Bs are as defined above, and X represents a halogenyl group. The compound represented by formula (3) may be used alone or in combination of two or more.

[0047] Examples of the halogen group represented by X include a fluoro group, a chloro group, and a bromo group.

[0048] 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.

[0049] The reaction time in this step is, for example, within the range of 0.05 to 10 hours, and preferably within the range of 0.05 to 1 hour.

[0050] The reaction temperature in this step is, for example, within the range of -78 to 30°C, and preferably within the range of -40 to 0°C.

[0051] In the amination step, the compound represented by the general formula (3) is reacted with the amino acid ester represented by the general formula (5) to obtain the compound represented by the general formula (4). The amino acid ester acts as an aminating agent.

[0052] (Amino acid ester represented by general formula (5)) R ５ represents an alkyl group having or without a substituent, R ６ represents a hydrogen atom, an alkyl group with or without a substituent, or the side chain of an amino acid. ５ and R ６ Examples of the substituted or unsubstituted alkyl group represented by the formula (I) include C1 to C6 alkyl groups, which may be substituted or unsubstituted, and specific examples thereof include methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, tert-butyl, and n-pentyl groups. Examples of the substituent include alkyl groups, which may be substituted or unsubstituted, hydroxyl groups, amino groups, alkoxy groups, imino groups, and halogenyl groups. Examples of the alkyl group include C1 to C6 alkyl groups, which may be substituted or unsubstituted, and specific examples thereof include methyl and ethyl groups. When the alkyl group has a substituent, examples of the substituent include hydroxyl groups, amino groups, alkoxy groups, imino groups, and halogenyl groups. Examples of the alkoxy group include C1 to C6 alkoxy groups, which may be substituted or unsubstituted, and specific examples thereof include methoxy and ethoxy groups. Examples of the halogenyl group include fluoro, chloro, and bromo groups.

[0053] R ６ Examples of the amino acid side chain represented by include the side chain of an α-amino acid, and specifically include at least one side chain selected from the group consisting of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, glutamine, arginine, serine, threonine, valine, tryptophan, and tyrosine, with the side chain of alanine being particularly preferred.

[0054] The amount of the amino acid ester represented by general formula (5) used in this step is, for example, in a molar ratio within a range of 1 to 100 times, and preferably within a range of 3 to 10 times, per mole of the compound represented by general formula (3).

[0055] (Compound represented by general formula (4)) In the compound represented by general formula (4), R １１ ~R １５ , R ５ , R ６ , Ar, and Bs are as defined above. The compound represented by formula (4) may be used alone or in combination of two or more.

[0056] 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.

[0057] The reaction time in this step is, for example, within the range of 0.05 to 10 hours, and preferably within the range of 0.05 to 0.5 hours.

[0058] The reaction temperature in this step is, for example, within the range of -78 to 30°C, and preferably within the range of -40 to 0°C.

[0059] In the compounds represented by the general formulas (1) to (4), Specific examples of the monovalent group represented by the formula include monovalent groups represented by the following formula: In the following formula, R and Bs are as defined above.

[0060] <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 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 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 １ ~R ４ and Bs are as described above. 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.

[0061] 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 １５ａExamples 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.

[0062] R １３ａ and R １４ａ 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.

[0063] The compound according to the second embodiment is represented by the general formula (2a). In the compound represented by the general formula (2a), R １１ａ ~R １５ａ , R １ ~R ４ , Ar, A ー and Bs are as described above. The compound according to the second embodiment is useful as an intermediate in the method for producing the compound according to the first embodiment and as a starting material in the method for producing the compound according to the second embodiment.

[0064] The compound according to the third embodiment is represented by the general formula (3a). In the compound represented by the general formula (3a), R １１ａ ~R １５ａ , Ar, X, and Bs 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.

[0065] In the compounds represented by the general formulas (1a) to (3a), Specific examples of the monovalent group represented by the formula include monovalent groups represented by the following formula: In the following formula, R' and Bs are as defined above.

[0066] In terms of ease of control of the stereochemistry of the phosphorus atom in the nucleotide prodrug to be produced, etc., it is preferable that the stereochemistry of the phosphorus atom is controlled in the methods for producing the compounds according to the first to third embodiments and in the compounds according to the first to third embodiments. Examples of compounds represented by the general formula (1) above 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 compounds represented by the general formula (2) above 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 compounds represented by the general formula (3) above 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 compounds represented by the general formula (4) above in which the stereochemistry of the phosphorus atom is controlled include compounds represented by the following general formula (401) and general formula (402).

[0067]

[0068] In the above formula, R １１ ~R １５ , R １ ~R ６ , Ar, A ー , X, and Bs are as described above.

[0069] 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.

[0070] <Nucleotide Prodrug Precursor> The nucleotide prodrug precursor according to this embodiment comprises a compound according to the first embodiment, a compound according to the second embodiment, or a compound according to the third embodiment. A nucleotide prodrug can be obtained from a nucleotide prodrug precursor comprising a compound according to the first embodiment by the method for producing a compound according to the first embodiment. A nucleotide prodrug can be obtained from a nucleotide prodrug precursor comprising a compound according to the second embodiment by the method for producing a compound according to the second embodiment. A nucleotide prodrug can be obtained from a nucleotide prodrug precursor comprising a compound according to the third embodiment by the method for producing a compound according to the third embodiment.

[0071] 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 85% 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, and Yamazen Universal Premium Amino 30 μm 60 Å was used as the amino 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 All reactions were carried out under an Ar atmosphere.

[0072] [Example 1: Production of Remdesivir] (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile [2]

[0073] Compound 1 (GS-441524, 5.82 g, 19.9 mmol) was dissolved in acetone (800 mL), and p-toluenesulfonic acid monohydrate (16.8 g, 88.1 mmol) and triethyl orthoformate (20.8 mL, 126 mmol) were added, followed by stirring at room temperature for 3 hours. ３ An aqueous solution (150 mL) was added until the pH reached 7, and then acetone was removed by distillation under reduced pressure. ３ (150 mL) was added, the organic layer was separated, and saturated NaHCO ３aqueous solution (3 x 150 mL), and the combined aqueous layers were washed with CHCl ３ The combined organic layer was extracted with anhydrous Na ２ SO ４ The extract was dried with ethyl acetate, filtered, and the solvent was evaporated under reduced pressure to give Compound 2 as a colorless foam (6.34 g, 19.1 mmol, 96%).

[0074] １ H-NMR (500MHz, DMSO-d ６ ) δ7.99-7.92 (m, 3H), 6.92 (q, J = 5.0Hz, 2H), 5.38 (d, J = 6.8Hz, 1H), 5.03 (t, J = 5.6Hz, 1H), 4.90 (d d, J = 6.8, 3.2Hz, 1H), 4.33 (td, J = 5.2, 3.1Hz, 1H), 3.59-3.49 (m, 2H), 1.64 (s, 3H), 1.37 (s, 3H); HRMS (ESI / QTOF) m / z: [M+H] ＋ Calcd for C １５ H １８ N ５ O ４ 332.1353; Found 332.1355.

[0075] ・(3aR,4R,6R,6aR)-4-(4-((bis(4-methoxyphenyl)(phenyl)methyl)amino)pyrrolo[2,1-f][1,2,4]tri azin-7-yl)-6-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile [2]

[0076] Compound 2 (6.32 g, 19.1 mmol) was azeotropically dried three times with dry pyridine and dissolved in dry pyridine (76.5 mL). TMSCl (5.5 mL, 43.4 mmol) was added and the mixture was stirred at 30°C for 6 hours. DMTrCl (10.9 g, 32.2 mmol) was then added and the mixture was stirred at 30°C for an additional 18 hours. The reaction solution was cooled to 0°C and pyridine-5% NaHCO ３ The reaction was quenched by adding an aqueous solution (1:1, v / v) (100 mL).３ (200 mL) was added, the organic layer was separated, and saturated NaHCO ３ aqueous solution (3 x 100 mL), and the combined aqueous layers were washed with CHCl ３ The combined organic layer was extracted with anhydrous Na ２ SO ４ The residue was purified by medium pressure preparative chromatography [neutral silica gel, hexane-EtOAc (9:1-4:6, v / v), Et ３ The resulting mixture was isolated and purified using a 1% NaCl solution to give Compound 3 as a colorless foam (10.8 g, 10.9 mmol, 90%).

[0077] １ H-NMR (500MHz, DMSO-d ６ ) δ8.87 (s, 1H), 7.70 (s, 1H), 7.36-7.24 (m, 9H), 7.19-7.16 (m, 1H), 6. 92 (d, J = 4.6 Hz, 1H), 6.84 (dt, J = 9.9, 2.5 Hz, 4H), 5.33 (d, J = 6.8 Hz, 1 H), 5.00 (t, J = 5.6 Hz, 1H), 4.85 (dd, J = 3.2 Hz, 1H), 4.29 (td, J = 5.2, 3 .2Hz, 1H), 3.71 (s, 6H), 3.57-3.45 (m, 2H), 1.61 (s, 3H), 1.34 (s, 3H); HRMS (ESI / QTOF) m / z: [M+H] ＋ Calcd for C ３６ H ３６ N ５ O ６ 634.2660; Found 634.2670.

[0078] ・2-chloro-1,3,2-oxazaphosphoridine (MeO-Ph type) [5]

[0079] (S)-(4-methoxyphenyl)((R)-pyrrolidine-2-yl)methanol 4 (1.55 g, 7.5 mmol) was azeotropically dried three times with dry toluene, and then dry toluene (7.5 mL) and N-methylmorpholine (1.65 mL, 15 mmol) were added to form a mixed solution. A dry toluene solution (5 mL) of phosphorus trichloride (0.65 mL, 7.5 mmol) was cooled to 0°C, and the mixed solution was added dropwise thereto. The mixture was then returned to room temperature and stirred for 2 hours. The reaction solution was cooled to -78°C, and the resulting salt was filtered off under an argon atmosphere. The solvent was then evaporated under reduced pressure to give compound 5 (2.01 g, 7.39 mmol, 99%) as a pale yellow oil. This product was used in the next reaction without further purification.

[0080] ・(3aR,4R,6R,6aR)-4-(4-((bis(4-methoxyphenyl)(phenyl)methyl)amino)p yrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(((1R,3S,3aR)-3-(4-methoxyphe nyl)tetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaphosphol-1-yl)oxy)m ethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile [6]

[0081] Compound 3 (1.90 g, 3.0 mmol) was azeotropically dried three times with dry pyridine, twice with dry toluene, and twice with dry THF, and then diluted with THF (15 mL), Et ３ N (2.9 mL, 21 mmol) was added to form a mixed solution. The mixed solution was cooled to -78°C, and a 1.23 M THF solution of 2-chloro-1,3,2-oxazaphosphoridine (5) (6 mL, 1.23 mmol) was added dropwise using a syringe. The reaction solution was returned to room temperature and stirred for 1 hour, then cooled to 0°C and dissolved in CHCl ３ (150 mL), saturated NaHCO ３ Aqueous solution (50 mL) was added. The organic layer was separated and washed with saturated NaHCO ３aqueous solution (2 x 50 mL), and the combined aqueous layers were washed with CHCl ３ The combined organic layer was extracted with anhydrous Na ２ SO ４ The residue was purified by silica gel column chromatography [NH-silica gel, toluene-EtOAc (8:2, v / v), Et ３ The fractions containing compound 6 were collected, and the solvent was removed under reduced pressure to give (Rp)-compound 6 (1.34 g, 1.5 mmol, 50%) as a colorless foam with a dr ratio of >99:1.

[0082] １ H-NMR (500MHz, CDCl ３ ) δ7.74 (s, 1H), 7.30-7.27 (m, 7H), 7.22-717 (m, 6H), 6.94 (d, J=4.4Hz, 1H), 6.83-6.81 (m, 6H), 6.5 1 (d, J = 4.4Hz, 1H), 6.38 (s, 1H), 5.71 (d, J = 6.4Hz, 1H), 5.41 (d, J = 6.8Hz, 1H), 4.95-4.93 (m, 1H), 4 .. 56 (q, J = 4.7Hz, 1H), 4.08-3.97 (m, 2H), 3.85-3.81 (m, 1H), 3.79 (s, 9H), 3.58-3.47 (m, 1H), 3.17- 3.10 (m, 1H), 1.73 (s, 3H), 1.63-1.57 (m, 2H), 1.31 (s, 3H), 1.22-1.16 (m, 1H), 1.02-0.94 (m, 1H); ３１ P-NMR (202MHz, CDCl ３ ) δ153.7; HRMS (ESI / QTOF) m / z: [M+H] ＋ Calcd for C ４８ H ５０ N ６ O ８ P 869.3428; Found 869.3443.

[0083] ・2-Ethylbutyl L-alaninate [8]

[0084] 2-Ethylbutyl L-alaninate hydrochloride 7 (103.5mg, 0.49mmol) in dry CH ３ Dissolve KHCO in CN (0.5 mL) ３ (73.5 mg, 0.73 mmol) was added and stirred at room temperature for 6 hours. The resulting salt was filtered off, and the filtrate was collected to obtain compound 8. The filtrate was dried over activated MS3A and stored in a refrigerator for 19 hours. This was used in the next reaction without further purification.

[0085] ・2-Ethylbutyl((S)-(((3aR,4R,6R,6aR)-6-(4-((bis(4-methoxyphenyl)(phenyl)methyl)amino)pyrrolo[2,1-f][1,2,4]tri azin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate [(Sp)-9]

[0086] (Rp)-6 (89.1 mg, 0.10 mmol) was dissolved in dry toluene (0.5 mL), activated MS4A was added, and the mixture was cooled to -40°C. ３ 0.3 mL of CN solution (0.5 mL) was added dropwise, and the mixture was stirred at -40°C for 1.5 hours. ３ A solution of NBS (26.7 mg, 0.15 mmol) dissolved in CN (0.3 mL) was added dropwise in an amount of 0.2 mL, and the mixture was stirred at 40° C. for 5 minutes. ３ CN solution (0.5 mL, 0.5 mmol) was added dropwise, and the mixture was allowed to return to room temperature and stirred for 5 minutes. ２ Cl ２ (20 mL). The organic layer was diluted with 1.0 M NaH ２ P.O. ４　 Aqueous solution (3 x 20 mL), saturated NaHCO ３ The combined organic layers were washed with anhydrous Na２ SO ４ The residue was purified by silica gel column chromatography [fine-silica gel (40-50 μm), toluene-hexane-EtOAc (1:1:2, v / v / v), pyridine 1%] to give (Sp)-9 as a colorless foam with a dr > 99:1 (37.7 mg, 0.04 mmol, 40%).

[0087] １ H-NMR (500MHz, CDCl ３ ) δ7.65 (s, 1H), 7.24-7.20 (m, 7H), 7.13-7.10 (m, 7H), 6.89 (d, J = 4.4Hz, 1H), 6.75 (dt, J = 9.6, 2 .6Hz, 4H), 6.49 (d, J=3.8Hz, 1H), 6.35 (s, 1H), 5.35 (d, J=6.4Hz, 1H), 4.82 (dd, J=6.8, 4.2Hz, 1 H), 4.49 (q, J = 4.8Hz, 1H), 4.27-4.18 (m, 2H), 3.98-3.88 (m, 3H), 3.72 (s, 6H), 3.49 (t, J = 10.0H z, 1H), 1.67 (s, 3H), 1.46-1.38 (m, 1H), 1.30 (s, 3H), 1.27-1.21 (m, 7H), 0.79 (t, J = 7.4Hz, 6H); ３１ P-NMR (202MHz, CDCl ３ ) δ3.03; HRMS (ESI / QTOF) m / z: [M+H] ＋ Calcd for C ５１ H ５８ N ６ O １０ P 945.3952; Found 945.3947.

[0088] ・Remdesivir

[10]

[0089] Compound 9 (0.273 g, 0.29 mmol) was dissolved in dry THF (3.9 mL) and cooled to 0° C. 37% hydrochloric acid (0.34 mL) was added dropwise, and the mixture was allowed to return to room temperature and stirred for 23 hours. ３ The aqueous solution was added until pH = 7 and extracted with EtOAc (3 x 50 mL).２ SO ４ The residue was purified by medium-pressure preparative column chromatography [neutral-silica gel, CHCl ３ -MeOH (100:0-9:1 v / v)] to give (Sp)-remdesivir 10 as a colorless foam with a dr > 99:1 (14 mg, 0.024 mmol, 8%).

[0090] １ H-NMR (400MHz, DMSO-d ６ ) δ7.86 (d, J=19.2Hz, 3H), 7.32-7.29 (m, 2H), 7.14 (dd, J=8.3, 2.6Hz, 3H), 6.85 (d, J=4.6Hz , 1H), 6.79 (d, J = 4.1Hz, 1H), 6.30-6.26 (m, 1H), 6.00 (dd, J = 13.3, 10.1Hz, 1H), 5.33 (d, J = 5.9Hz, 1H), 4.60 (t, J = 5.7Hz, 1H), 4.24-4.16 (m, 3H), 4.07-4.01 (m, 1H), 3.96-3.88 (m, 2H) ), 3.84-3.76 (m, 2H), 1.37 (tt, J=18.4, 5.9Hz, 1H), 1.24-1.13 (m, 7H), 0.78-0.73 (t, 6H); ３１ P-NMR (162MHz, DMSO-d ６ ) δ4.3; HRMS (ESI / QTOF) m / z: [M+H] ＋ Calcd for C ２７ H ３６ N ６ O ８ P 603.2326; found, 603.2334.

[0091] [Example 2: Production of Sofosbuvir]・1-((2R,3R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-3-fluoro-5-((((1R,3S,3aR)-3-(4-methoxyphenyl)tetrahydro-1H, 3H-pyrrolo[1,2-c][1,3,2]oxazaphosphol-1-yl)oxy)methyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione [(Rp)-12]

[0092] 1-((2R,3R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-3-fluoro-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (11, 0.637 g, 1.7 mmol) was azeotropically dried three times with dry pyridine, twice with dry toluene, and twice with dry THF, and then extracted with dry THF (8.5 mL), Et ３ N (1.65 mL, 11.9 mmol) was added. The mixed solution was cooled to -78°C, and a 1.25 M THF solution of 2-chloro-1,3,2-oxazaphosphoridine (5) (3.4 mL, 4.25 mmol) was added dropwise using a syringe. The reaction solution was stirred at room temperature for 1 hour, cooled to 0°C, and then dissolved in CHCl ３ (200 mL), saturated NaHCO ３ Aqueous solution (50 mL) was added. The organic layer was separated and washed with saturated NaHCO ３ aqueous solution (2 x 50 mL), and the combined aqueous layers were washed with CHCl ３ (2 x 50 mL). The combined organic layers were extracted with anhydrous Na ２ SO ４ The residue was purified by silica gel column chromatography [NH-silica gel, toluene-EtOAc (1:9, v / v), Et ３The fractions containing compound 12 were collected, and the solvent was removed under reduced pressure to give (Rp)-12 (0.42 g, 0.70 mmol, 46%) as a colorless foam with a dr > 99:1.

[0093] １ H-NMR (500MHz, CDCl ３ ) δ8.12 (d, J=8.4Hz, 1H), 7.20 (dt, J=9.0, 2.2Hz, 2H), 6.90 (dt, J=9.4, 2.4Hz, 2H), 6.20 (d, J= 17.3Hz, 1H), 5.71-5.68 (m, 2H), 4.26 (qd, J=5.9, 1.6Hz, 1H), 4.09 (dd, J=9.0, 1.4Hz, 1H), 4. 01-3.85 (m, 3H), 3.82 (s, 3H), 3.64-3.56 (m, 1H), 3.21-3.14 (m, 1H), 1.72-1.58 (m, 2H), 1.35 (q, J=10.8Hz, 3H), 1.26 (m, 1H), 1.07-1.00 (m, 1H), 0.93 (t, J=3.0Hz, 9H), 0.19-0.14 (m, 6H); ３１ P-NMR (202MHz, CDCl ３ ) δ154.4; HRMS (ESI / QTOF) m / z: [M+H] ＋ Calcd for C ２８ H ４２ FN ３ O ７ PSi 610.2514; Found 610.2508.

[0094] ・Isopropyl L-alaninate

[14]

[0095] Isopropyl L-alaninate Hydrochloride 13 (84.6 mg, 0.5 mmol) in dry CH ３ Dissolve KHCO in CN (0.5 mL) ３ (75.2 mg, 0.75 mmol) was added and stirred at room temperature for 5 hours. The resulting salt was filtered off, and the filtrate was collected to obtain compound 14. The filtrate was dried over activated MS3A and stored in a refrigerator for 20 hours. This was used in the next reaction without further purification.

[0096] ・Isopropyl((S)-(((2R,3R,4R,5R)-3-((tert-butyldimethylsilyl)oxy)-5-(2,4-dioxo-3,4-dihydropyrim idin-1(2H)-yl)-4-fluoro-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate [(Sp)-15]

[0097] (Rp)-12 (61.1 mg, 0.10 mmol) was dissolved in dry toluene (0.5 mL), dried with activated MS4A for 24 hours, and cooled to -40°C. ３ 0.3 mL of CN solution (0.5 mL) was added dropwise, and the mixture was stirred at -40°C for 2 hours. ３ 0.2 mL of NBS (29.5 mg, 0.16 mmol) dissolved in CN (0.3 mL) was added dropwise, and the mixture was stirred at −40° C. for 5 minutes to obtain a 1.0 M solution of Compound 14 in CH ３ After adding CN solution (0.5 mL, 0.5 mmol), the mixture was allowed to warm to room temperature and stirred for 5 minutes. The mixture was diluted with EtOAc (15 mL), and diluted with citrate buffer (pH 7) (2 × 15 mL), saturated NaHCO ３ aqueous solution (1 x 15 mL), and the combined organic layers were washed with anhydrous MgSO ４ The residue was purified by silica gel column chromatography [fine-silica gel (40-50 μm), toluene-EtOAc (2:8, v / v), Et ３ N 1%] to give (Sp)-15 as a colorless foam with a dr>99:1 (43.1 mg, 0.067 mmol, 67%). １ H-NMR (500MHz, CDCl ３) δ7.58 (d, J=8.0Hz, 1H), 7.35 (t, J=7.8Hz, 2H), 7.25-7.17 (m, 3H), 6.17 (d, J=18.5Hz , 1H), 5.67 (d, J = 8.0Hz, 1H), 5.04-4.99 (m, 1H), 4.62 (qd, J = 6.2, 2.0Hz, 1H), 4.27 (d q, J = 12.0, 2.7Hz, 1H), 4.14 (d, J = 8.8Hz, 1H), 4.03-3.95 (m, 2H), 3.90-3.80 (m, 1H), 1.39-1.33 (m, 6H), 1.24 (dd, J = 6.2, 1.0Hz, 6H), 0.94 (t, J = 2.7Hz, 9H), 0.17 (d, 6H); ３１ P-NMR (202MHz, CDCl ３ ) δ3.06; HRMS (ESI / QTOF) m / z: [M+H] ＋ Calcd for C ２８ H ４３ FN ３ O ９ PSi 644.2563; Found 644.2567.

[0098] ・Sofosbuvir

[16]

[0099] (Sp)-15 (84.4 mg, 0.13 mmol) ２ 0 (0.2 mL) was added, cooled to 0°C, and TFA-H ２ 0 (18:1 v / v) (3.8 mL) was added dropwise, and the mixture was allowed to warm to room temperature and stirred for 25 hours. TFA was evaporated under reduced pressure, and the resulting residue was cooled to 0°C and diluted with saturated NaHCO ３ Aqueous solution (20 mL) was added to neutralize the mixture until the pH reached 7. The mixture was extracted with EtOAc (3×20 mL), and the combined organic layers were washed with anhydrous Na ２ SO ４ The residue was purified by silica gel column chromatography [fine-silica gel (40-50 μm), CH ２ Cl ２ -MeOH (98:2-90:10, v / v)] to give (Sp)-sofosbuvir 16 as a colorless foam with a dr > 99:1 (46.1 mg, 0.087 mmol, 67%).

[0100] １ H-NMR (500MHz, CD ３ O.D.) δ7.64 (d, J=8.4Hz, 1H), 7.40 (t, J=7.8Hz, 2H), 7.28 (m, 2H), 7.22 (m, 1H), 6. 14 (d, J = 17.7Hz, 1H), 5.64 (d, J = 8.0Hz, 1H), 5.01-4.96 (m, 1H), 4.56-4.53 (m , 1H), 4.40 (qd, J = 6.0, 3.7Hz, 1H), 4.13 (dd, J = 9.6, 1.6Hz, 1H), 3.97-3.90 (m , 1H), 3.23 (q, J = 7.2Hz, 1H), 1.40-1.35 (m, 6H), 1.24 (dd, J = 6.4, 1.2Hz, 6H); ３１ P-NMR (202MHz, CD ３ OD) δ4.38; HRMS (ESI / QTOF) m / z: [M+H] ＋ Calcd for C ２２ H ３０ FN ３ O ９ P, 530.1704; found, 530.1713.

[0101] [Example 3: Production of NUC-1031]・4-((Bis(4-methoxyphenyl)(phenyl)methyl)amino)-1-((2R,4R,5R)-4-((tert-butyldimethylsilyl)oxy) -5-(((tert-butyldimethylsilyl)oxy)methyl)-3,3-difluorotetrahydrofuran-2-yl)pyrimidin-2(1H)-one

[18]

[0102] Gemcitabine 17 (0.79 g, 2.99 mmol) was azeotroped three times with dry pyridine and once with dry DMF, then dissolved in dry DMF (12 mL). TBSCl (2.27 g, 15 mmol) was added and the mixture was stirred at room temperature for 21 hours. MeOH (10 mL) was added to quench the reaction, and the resulting mixture was diluted with hexane-EtOAc (5:1, v / v) (50 mL), saturated NaHCO ３An aqueous solution (50 mL) was added, and the organic layer was separated and washed with saturated aqueous sodium bicarbonate (2 x 50 mL). The combined aqueous layers were extracted with hexane-EtOAc (5:1, v / v) (50 mL), and the combined organic layers were washed with anhydrous MgSO. ４ The resulting residue was dissolved in dry pyridine (2 mL), DMTrCl (1.53 g, 4.51 mmol) was added, and the mixture was stirred at room temperature for 15 hours. MeOH (5 mL) was added to the reaction mixture to quench the reaction, and the mixture was diluted with EtOAc (80 mL), saturated NaHCO ３ Aqueous solution (40 mL) was added, and the organic layer was separated and washed with saturated aqueous sodium bicarbonate (2 x 40 mL). The combined aqueous layers were extracted with EtOAc (2 x 40 mL), and the combined organic layers were washed with anhydrous MgSO ４ The residue was purified and isolated by medium-pressure preparative column chromatography [neutral-silica gel, hexane-EtOAc (72:28-45:55, v / v)] to give compound 18 (1.83 g, 2.3 mmol, 77%) as a colorless foam.

[0103] １ H-NMR (500MHz, CD ３ O.D.) δ7.60 (d, J=7.6Hz, 1H), 7.35-7.37 (m, 3H), 7.23 (d, J=7.6Hz, 3H), 7.15 (d, J=8.4Hz, 4H) , 6.88 (d, J = 8.8 Hz, 4H), 6.79 (d, J = 8.8 Hz, 1H), 6.18 (t, J = 6.8 Hz, 1H), 5.21 (d, J = 7.6 Hz, 1H), 4.28 (q, J = 20.7, 12.2Hz, 1H), 3.99 (d, J = 12.0Hz, 1H), 3.90 (d, J = 8.4Hz, 1H), 3.78 ( s, 6H), 0.92 (s, 9H), 0.78 (s, 9H), 0.13 (s, 3H), 0.11 (s, 3H), 0.02 (s, 3H), -0.03 (s, 3H); HRMS (ESI / QTOF) m / z: [M+H] ＋ Calcd for C ４２ H ５８ F ２ N ３ O ６ PSi ２ 794.3832; Found 794.3834.

[0104] ・4-((Bis(4-methoxyphenyl)(phenyl)methyl)amino)-1-((2R,4R,5R)-4-((tert-butyldimethy lsilyl)oxy)-3,3-difluoro-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one

[19]

[0105] Compound 18 (0.20 g, 0.26 mmol) was added with 0.1 M KOH ethanol solution (20 mL) and stirred at room temperature for 22 hours. 0.05% AcOH ethanol solution was added until the reaction solution reached pH 7, and the solvent was evaporated under reduced pressure. The residue was purified by medium pressure preparative chromatography [neutral-silica gel, CH ２ Cl ２ -MeOH (100:-99:1, v / v)] to obtain Compound 19 as a colorless foam (0.149 g, 0.22 mmol, 85%).

[0106] １ H-NMR (500MHz, CD ３ O.D.) δ7.74 (d, J=7.6Hz, 1H), 7.34-7.26 (m, 3H), 7.21 (d, J=8.8Hz, 3H), 7.14 (d, J=8. 8Hz, 4H), 6.88 (d, J = 8.8Hz, 4H), 6.79 (d, J = 8.8Hz, 1H), 6.15 (d, J = 12.8Hz, 1H), 5 .. 20 (d, J = 7.6 Hz, 1H), 4.18-4.12 (m, 1H), 4.01-3.97 (m, 1H), 3.98 (d, J = 12.0Hz, 1 H), 3.89 (d, J=8.8Hz, 1H), 3.78 (s, 6H), 0.77 (s, 9H), 0.02 (s, 3H), -0.03 (s, 3H); HRMS (ESI / QTOF) m / z: [M+H] ＋ Calcd for C ３６ H ４４ F ２ N ３ O ６ Si 680.2967; Found 680.2963.

[0107] ・4-((Bis(4-methoxyphenyl)(phenyl)methyl)amino)-1-((2R,4R,5R)-4 -((tert-butyldimethylsilyl)oxy)-3,3-difluoro-5-(((1R,3S,3aR)-3 -(4-methoxyphenyl)tetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaph osphor-1-yl)oxy)methyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one [(Rp)-20]

[0108] Compound 19 (1.15 g, 2.0 mmol) was azeotropically dried three times with dry pyridine, twice with dry toluene, and twice with dry THF, and then washed with dry THF (10 mL), Et ３ N (1.95 mL, 14 mmol) was added. The mixed solution was cooled to -78°C, and a 1.25 M THF solution of 2-chloro-1,3,2-oxazaphosphoridine (5) (4 mL, 5.0 mmol) was added dropwise using a syringe. The reaction solution was stirred at room temperature for 1 hour, cooled to 0°C, and then dissolved in CHCl ３（ 200 mL), saturated NaHCO ３ Aqueous solution (50 mL) was added. The organic layer was separated and washed with saturated NaHCO ３ aqueous solution (2 x 50 mL), and the combined aqueous layers were washed with CHCl ３ (2 x 50 mL). The combined organic layers were extracted with anhydrous Na ２ SO ４ The residue was purified by silica gel column chromatography [NH-silica gel, toluene-EtOAc (8:2, v / v), Et ３ The fractions containing compound 20 were collected, and the solvent was removed under reduced pressure to give (Rp)-compound 20 as a colorless foam with a dr > 99:1 (1.20 g, 1.34 mmol, 67%).

[0109] １ H-NMR (500MHz, CDCl ３) δ7.50 (d, J=7.4Hz, 1H), 7.32 (t, J=7.2Hz, 2H), 7.23-7.18 (m, 4H), 7.14 (q, J=8.6Hz, 4H), 6.91-6.84 (m, 7H) , 6.36 (d, J = 13.3 Hz, 1H), 5.84 (d, J = 6.4 Hz, 1H), 5.03 (d, J = 7.8 Hz, 1H), 4.61-4.52 (m, 1H), 4.04 (d, J = 8.4 Hz) , 1H), 3.97-3.90 (m, 2H), 3.86-3.83 (m, 1H), 3.82 (t, J = 3.8Hz, 9H), 3.68-3.56 (m, 1H), 3.30-3.23 (m, 1H), 1 .73-1.67 (m, 2H), 1.27-1.22 (m, 1H), 1.07-0.99 (m, 1H), 0.80 (d, J=6.0Hz, 9H), 0.04 (s, 3H), -0.02 (s, 3H); ３１ P-NMR (202MHz, CDCl ３ ) δ157.6; HRMS (ESI / QTOF) m / z: [M+H] ＋ Calcd for C ４８ H ５８ F ２ N ４ O ８ PSi 915.3724; Found 915.3726.

[0110] ・Benzyl L-alaninate

[22]

[0111] Benzyl L-alaninate hydrochloride 21 (0.22g, 1.0mmol) and KHCO ３ (0.15 g, 1.5 mmol) in dry CH ３ The resulting mixture was dissolved in CN (0.5 mL) and stirred at room temperature for 5 hours. The resulting salt was filtered off, and the filtrate was collected to give compound 22. The filtrate was dried over activated MS3A and stored in a refrigerator for 19 hours. This was used in the next reaction without further purification.

[0112] ・Benzyl((S)-(((2R,3R,5R)-5-(4-((bis(4-methoxyphenyl)(phenyl)methyl)amino)-2-oxopyrimidin-1(2H)-yl)-3-( (tert-butyldimethylsilyl)oxy)-4,4-difluorotetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate [(Sp)-23]

[0113] (Rp)-20 (0.18 g, 0.20 mmol) was dissolved in dry toluene (0.5 mL), dried with activated MS4A for 24 hours, and cooled to -40°C. ３ 0.5 mL of CN (0.7 mL) solution was added dropwise and stirred at -40°C for 3 hours. ３ 0.4 mL of NBS (53.1 mg, 0.30 mmol) dissolved in CN (0.5 mL) was added dropwise, and the mixture was stirred at −40° C. for 5 minutes. ３ A CN solution (0.5 mL, 0.5 mmol) was added dropwise, and the mixture was allowed to warm to room temperature and stirred for 5 minutes. ２ S ２ O ３ aqueous solution (30 mL), citrate buffer (pH = 7) (2 × 15 mL), saturated NaHCO ３ aqueous solution (1 x 15 mL), and the combined organic layers were washed with anhydrous MgSO ４ The residue was purified by silica gel column chromatography [fine-silica gel 40-50 μm, toluene-EtOAc (2:8, v / v), Et ３ N 1%] to obtain (Sp)-23 as a colorless foam with a dr of >99:1 (0.15 g, 0.16 mmol, 78%).

[0114] １ H-NMR (500MHz, CD ３O.D.) δ7.60 (d, J=8.0Hz, 1H), 7.36-7.25 (m, 11H), 7.23-7.16 (m, 6H), 7.14 (dd, J = 8.6, 3.0Hz, 3H), 6.88 (d, J = 8.8Hz, 3H), 6.25-6.19 (m, 1H), 5.20 (d, J = 8 0Hz, 1H), 5.13 (s, 2H), 4.95 (td, J=19.5, 9.4Hz, 1H), 4.00-3.88 (m, 4H), 3.77 (s, 6H), 1.34 (d, J = 7.2Hz, 3H), 0.75 (s, 9H), -0.02 (d, J = 10.0Hz, 6H); ３１ P-NMR (202MHz, CD ３ OD) δ3.85; HRMS (ESI / QTOF) m / z: [M+Na] ＋ Calcd for C ５２ H ６０ F ２ N ４ O １０ PSi 997.3778; Found 997.3787.

[0115] ・NUC-1031 [(Sp)-24]

[0116] Compound 23 (0.15 mg, 0.15 mmol) was treated with H ２ 0 (0.2 mL) was added, cooled to 0°C, and TFA-H ２ 0 (18:1 v / v) (3.8 mL) was added dropwise, and the mixture was allowed to warm to room temperature and stirred for 24 hours. TFA was removed by distillation under reduced pressure, and the resulting residue was cooled to 0°C and diluted with saturated NaHCO ３ Aqueous solution (20 mL) was added until pH = 7. The organic layer was extracted with EtOAc (20 mL) and saturated NaHCO ３ The combined organic layers were washed with anhydrous Na ２ SO ４ The residue was purified by silica gel column chromatography [fine-silica gel (40-50 μm), CH ２ C ２ 1-MeOH (98:2-85:15, v / v)] to give (Sp)-24 as a colorless foam with a dr of >99:1 (0.038 g, 0.066 mmol, 44%).

[0117] １ H-NMR(500MHz,CD ３ OD) δ7.83(d,J=7.6Hz,1H),7.38-7.29(m,7H),7.23-7.16(m,3H),6.26-6.18(m,1H),5.94(d,J=7.6Hz,1H),5.14(t,J=12.2Hz,2H),5.10-5.02(m,1H),4.07-4.02(m,1H),4.00(td,J=5.3,2.5Hz,1H),3.94(dd,J=12.8,2.0Hz,1H),3.88-3.83(m,1H),1.40-1.37(m,3H); ３１ P-NMR(202MHz,CD ３ OD) δ3.39; HRMS(ESI / QTOF) m / z:[M+H] ＋ Calcd for C ２５ H ２８ F ２ N ４ O ８ P 581.1613; Found,581.1593.

Claims

1. A method for producing a compound, comprising: an aryloxylation step of reacting a compound represented by the following general formula (1) with a phenolic compound represented by the formula ArOH (wherein Ar is as described below) to obtain a compound represented by the following general formula (2); an oxidative halogenation step of oxidatively halogenating the compound represented by the following general formula (2) with a halogenating agent to obtain a compound represented by the following general formula (3); and an amination step of reacting the compound represented by the following general formula (3) with an amino acid ester represented by the following general formula (5) to obtain a compound represented by the following general formula (4). (In general formula (1), 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 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 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 5-membered or greater heterocycle which may or may not have a substituent, and Bs represents a nucleobase, which may or may not have a protecting group for the nucleobase. (In general formula (2), R １１ ~R １５ , R １ ~R ４ and Bs are as defined above, Ar represents an aryl group having or having no substituent, A － represents a counter anion.) (In general formula (3), R １１ ~R １５ , Ar, and Bs are as defined above, and X represents a halogenyl group. (In general formula (4), R １１ ~R １５ , Ar, and Bs are as described above, and R ５ represents an alkyl group having or without a substituent, R ６ represents a hydrogen atom, an alkyl group with or without a substituent, or the side chain of an amino acid. (In general formula (5), R ５ and R ６ is as mentioned above.) 2. R １ The method for producing the compound according to claim 1, wherein is a 4-methoxyphenyl group.

3. A method for producing a compound, comprising: an oxidative halogenation step of oxidatively halogenating a compound represented by the following general formula (2) with a halogenating agent to obtain a compound represented by the following general formula (3); and an amination step of reacting the compound represented by the following general formula (3) with an amino acid ester represented by the following general formula (5) to obtain a compound represented by the following general formula (4). (In general formula (2), 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 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 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, Ar represents an aryl group which may or may not have a substituent, Bs represents a nucleic acid base which may or may not have a protecting group for the nucleic acid base, A － represents a counter anion.) (In general formula (3), R １１ ~R １５ , Ar, and Bs are as defined above, and X represents a halogenyl group. (In general formula (4), R １１ ~R １５ , Ar, and Bs are as described above, and R ５ represents an alkyl group having or without a substituent, R ６ represents a hydrogen atom, an alkyl group with or without a substituent, or the side chain of an amino acid. (In general formula (5), R ５ and R ６ is as mentioned above.) 4. R １ The method for producing the compound according to claim 3, wherein is a 4-methoxyphenyl group.

5. A method for producing a compound, comprising an amination step of reacting a compound represented by the following general formula (3) with an amino acid ester represented by the following general formula (5) to obtain a compound represented by the following general formula (4): (In general formula (3a), 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 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, Ar represents an aryl group which may or may not have a substituent, X represents a halogenyl 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 １１ ~R １５ , Ar, and Bs are as described above, and R ５ represents an alkyl group having or without a substituent, R ６ represents a hydrogen atom, an alkyl group with or without a substituent, or the side chain of an amino acid. (In general formula (5), R ５ and R ６ is as mentioned above.) 6. A method for producing the compound of any one of claims 1 to 5, wherein the stereochemistry of the phosphorus atom is controlled.

7. A compound represented by the following general formula (1a): (In general formula (1a), 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 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 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 5-membered or greater heterocycle which may or may not have a substituent, and Bs represents a nucleobase, which may or may not have a protecting group for the nucleobase.

8. R １ The compound according to claim 7, wherein is a 4-methoxyphenyl group.

9. A compound represented by the following general formula (2a): (In general formula (2a), 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 １３ and R １４ 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 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, Ar represents an aryl group which may or may not have a substituent, Bs represents a nucleic acid base which may or may not have a protecting group for the nucleic acid base, A － represents a counter anion.) 10. R １ The compound according to claim 9, wherein is a 4-methoxyphenyl group.

11. A compound represented by the following general formula (3a): (In general formula (3a), 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 １３ and R １４ 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, Ar represents an aryl group which may or may not have a substituent, X represents a halogenyl group, and Bs represents a nucleic acid base which may or may not have a protecting group for the nucleic acid base.

12. The compound of any one of claims 7 to 11, wherein the stereochemistry at the phosphorus atom is controlled.

13. A nucleotide prodrug precursor comprising the compound according to any one of claims 7 to 11.

14. A nucleotide prodrug precursor comprising the compound of claim 12.

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