Method for producing a manufacturing intermediate, the manufacturing intermediate itself, and a method for producing a cross-linked artificial nucleic acid intermediate using the same.

Abstract

To provide a method for producing a manufacturing intermediate that is advantageous and safe for industrial manufacturing, the manufacturing intermediate itself, and a method for producing a cross-linked artificial nucleic acid intermediate using the same. [Solution] Formula (I): TIFF2026131783000110.tif26165 [In the formula, each symbol is defined as defined in the specification.] From the compound represented by, Formula (IV): TIFF2026131783000111.tif22165 [In the formula, each symbol is defined as defined in the specification.] This includes a method for producing the compound represented by [the given symbol].

Description

Technical Field

[0001] The present invention relates to a method for producing a production intermediate, the production intermediate, and a method for producing a crosslinked artificial nucleic acid intermediate using them.

Background Art

[0002] As methods for treating diseases with nucleic acid pharmaceuticals, there are the antisense method, the antigene method, the method using aptamers, the method using siRNA, and the like. Among these, the antisense method is a technique for adjusting the function of RNA involved in a disease and treating or preventing the disease by introducing an oligonucleotide (antisense strand) complementary to mRNA or non-translated RNA involved in the disease from the outside and forming a double strand.

[0003] As materials for such nucleic acid pharmaceuticals, various artificial nucleic acids have been developed, such as ALNA[Ms] (ALNA means 2'-amino LNA (Locked nucleic acid)), ALNA[mU], ALNA[ipU], A LNA[oxz], ALNA[Trz], guanidine-crosslinked artificial nucleic acid (GuNA), etc. have been found (Patent Document 1). These ALNA and GuNA are key intermediates of the following crosslinked artificial nucleic acids, respectively:

Chemical formula

[0004] Regarding the method for producing the crosslinked artificial nucleic acid intermediate, it is described in Patent Document 1 and Non-Patent Documents 1 and 2.

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

[0006] [Non-Patent Document 1] J. Org. Chem. 2012, 77, 23, 10718-10728 [Non-Patent Document 2] Org Biomol. Chem. 2003 Feb 21;1(4):655-63 [Overview of the Initiative]

[0007] The method for producing the cross-linked artificial nucleic acid intermediate described in Patent Documents 1, 2, and Non-Patent Document 1 involves introducing nitrogen atoms contained in the cross-linking structure between the 4' and 2' ribosyl ring atoms, and using metal arginine which poses a risk of explosion and / or the generation of toxic gases. A azide compound that uses a reagent and has explosive potential as a manufacturing intermediate. Because it goes through this process, there was room for improvement. Furthermore, although the method for producing the cross-linked artificial nucleic acid intermediate described in Non-Patent Literature 2 does not go through an azide compound, it has been reported that the yield of the step in introducing nitrogen atoms included in the cross-linking structure between the 4' and 2' ribosyl ring atoms is extremely low. Given this situation, ALNA[Ms], ALNA[m Cross-linked humans such as U], ALNA[ipU], ALNA[oxz], ALNA[Trz], GuNA, etc. There is a need for industrially superior manufacturing methods for synthetic nucleic acid intermediates.

[0008] Conventional methods for producing cross-linked artificial nucleic acid intermediates use metal azides, which have the aforementioned hazards, and involve an azide compound, also with the aforementioned hazards, as a manufacturing intermediate. Therefore, there was room for improvement in terms of worker safety during the manufacturing process. Furthermore, manufacturing methods that do not involve an azide compound have low yields and are unsuitable for large-scale production, posing challenges as industrial manufacturing methods.

[0009] Therefore, an object of the present invention is to provide a method for producing a production intermediate, the production intermediate, and a method for producing a crosslinked artificial nucleic acid intermediate using them, which solve the above problems and are advantageous and safe for industrial production.

[0010] As a result of various studies to safely and reproducibly carry out each production step with a good yield, the present inventors have found that by performing a reductive amination reaction, it is possible to produce a production intermediate useful for producing a crosslinked artificial nucleic acid intermediate safely and with a good yield without using the above-mentioned dangerous reagents and production intermediates. Also, by using a step of crystallizing one kind of production intermediate, an industrially advantageous production method capable of producing a target crosslinked artificial nucleic acid intermediate with a good yield and high quality has been found. In addition, several novel production intermediates useful in these production methods have been found. That is, the present invention includes the following several embodiments.

[0011] A first embodiment of the present invention is a method for producing a compound represented by the following formula (IV). [1] Formula (I): [Chemical formula] <​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​represents a protecting group for a hydroxyl group, R 2 represents a protecting group for a hydroxyl group, R 3 and R 4 are the same or different and each independently represents a protecting group for a hydroxyl group, or R 3 and R 4 together represent a cyclic protecting group for a diol formed, R 5 and R 6 One of them represents a hydrogen atom or a protecting group for an amino group, and the other represents a protecting group for an amino group.] A method for producing a compound represented by the following production method includes the following steps 1 to 3: Step 1: Formula (I):

Chemical formula

Chemical formula

Chemical formula

[0012] A second embodiment of the present invention is a method for producing a compound represented by the following formula (XIII). [4] Formula (IV): [ka] [In the formula, R 1 This indicates a protecting group for hydroxyl groups. R 2 This indicates a protecting group for hydroxyl groups. R 3 and R 4 These are either identical or different, each independently representing a hydroxyl group protecting group, or R 3 and R 4 It shows the cyclic protecting group of the diol that is formed together, R 5 and R 6 One side represents a protecting group for a hydrogen atom or an amino group, and the other side represents a protecting group for an amino group. From the compound represented by, Equation (XIII): [ka] [In the formula, R 1 This indicates a protecting group for hydroxyl groups. R 2 This indicates a protecting group for hydroxyl groups. R 5 and R 6 One of them represents a protecting group for a hydrogen atom or an amino group, and the other represents a protecting group for an amino group. B represents the base portion of a nucleic acid, which may be substituted with one or more substituents. A method for producing a compound represented by the following steps 9-11; Step 9: A compound represented by formula (IV), produced by the manufacturing method described in any one of the above items [1] to [3], is, if necessary, R 3 and R 4 The reaction is performed to convert the acyl group, Formula (XI): [ka] [In the formula, R 1 This indicates a protecting group for hydroxyl groups. R 2 This indicates a protecting group for hydroxyl groups. R 3a This indicates an acyl group, R 4a This indicates an acyl group, R 5 and R 6 One side represents a protecting group for a hydrogen atom or an amino group, and the other side represents a protecting group for an amino group. A process to obtain a compound represented by; Step 10: By subjecting the compound represented by formula (XI) to a glucosylation reaction, Equation (XII): [ka] [In the formula, R 1 This indicates a protecting group for hydroxyl groups. R 2 This indicates a protecting group for hydroxyl groups. R 4a This indicates an acyl group, R 5 and R 6 One of them represents a protecting group for a hydrogen atom or an amino group, and the other represents a protecting group for an amino group. B represents the base portion of a nucleic acid, which may be substituted with one or more substituents. A step of obtaining a compound represented by; and Step 11: The step of subjecting the compound represented by formula (XII) to a deprotection reaction of the acyl group. A manufacturing method that includes this. [5]B is equation (XXIV): [ka] [In the formula, R 12 This represents a hydrogen atom, an alkyl group, an alkoxy group, or an alkoxyalkyl group. X is an oxygen atom or NR 13 (R 13 (This indicates a protecting group for a hydrogen atom or an amino group.) A double line consisting of a solid and a dotted line indicates a single or double bond. The manufacturing method described in [4] above, represented by [ ].

[0013] A third embodiment of the present invention is a method for producing a compound represented by the following formula (XVII). [6] Equation (XIII'): [ka] [In the formula, R 1 This indicates a protecting group for hydroxyl groups. R 2 This indicates a protecting group for hydroxyl groups. R 5 and R 6 One of them represents a protecting group for a hydrogen atom or an amino group, and the other represents a protecting group for an amino group. R 12 This represents a hydrogen atom, an alkyl group, an alkoxy group, or an alkoxyalkyl group. X is an oxygen atom or NR 13 (R 13 (This indicates a protecting group for a hydrogen atom or an amino group.) A double line consisting of a solid and a dotted line indicates a single or double bond. From the compound represented by, Formula (XVII): [ka] [In the formula, R 1 This indicates a protecting group for a hydrogen atom or a hydroxyl group. R 12 This represents a hydrogen atom, an alkyl group, an alkoxy group, or an alkoxyalkyl group. X is an oxygen atom or NR 13 (R 13 (This indicates a protecting group for a hydrogen atom or an amino group.) The double line consisting of a solid line and a dotted line indicates a single bond or a double bond. A method for producing a compound represented by the following, the production method comprising the following steps 12 to 15; Step 12: Subjecting the compound represented by formula (XIII’) produced by the production method according to the above [4] or [5] to a sulfonylation reaction, Formula (XIV):

Chemical formula

Chemical formula

[0014] Some further embodiments of the present invention are the following compounds. [7] Formula (II): [ka] [In the formula, R 1 This indicates a protecting group for hydroxyl groups. R 2 This indicates a protecting group for hydroxyl groups. R 3 and R 4 These are either identical or different, each independently representing a hydroxyl group protecting group, or R 3 and R 4 It shows the cyclic protecting group of the diol that is formed together, R 7 [This represents a hydrogen atom or an alkyl group.] A compound represented by the formula. [8] Formula (III): [ka] [In the formula, R 1 This indicates a protecting group for hydroxyl groups. R 2 This indicates a protecting group for hydroxyl groups. R 3 and R 4 These are either identical or different, each independently representing a hydroxyl group protecting group, or R 3 and R 4 This shows the cyclic protecting group of the diol formed by the combination of these two components. A compound represented by the formula. [9] Formula (IV): [ka] [In the formula, R 1 This indicates a protecting group for hydroxyl groups. R 2 This represents a benzyl group, 4,4'-dimethoxytrityl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethylsilyl)ethoxymethyl group, 2-methoxyethoxymethyl group, cyanoethyl group, benzoyl group, or acetyl group. R 3 and R4 These are either identical or different, each independently representing a hydroxyl group protecting group, or R 3 and R 4 It shows the cyclic protecting group of the diol that is formed together, R 5 and R 6 One side represents a protecting group for a hydrogen atom or an amino group, and the other side represents a protecting group for an amino group. A compound represented by the formula.

[10] Formula (XI): [ka] [In the formula, R 1 This indicates a protecting group for hydroxyl groups. R 2 This indicates a protecting group for hydroxyl groups. R 3a and R 4a This indicates an acyl group, R 5 and R 6 One side represents a protecting group for a hydrogen atom or an amino group, and the other side represents a protecting group for an amino group. A compound represented by the formula.

[11] Formula (XI): [ka] [In the formula, R 1 This indicates a protecting group for hydroxyl groups. R 2 This represents a benzyl group, 4,4'-dimethoxytrityl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethylsilyl)ethoxymethyl group, 2-methoxyethoxymethyl group, cyanoethyl group, benzoyl group, or acetyl group. R 3a and R 4a This indicates an acyl group, R 5 and R 6 One side represents a protecting group for a hydrogen atom or an amino group, and the other side represents a protecting group for an amino group. The compound described above in

[10] , represented by

[10] .

[12] Equation (XII): [ka] [In the formula, R 1 This indicates a protecting group for hydroxyl groups. R 2 This indicates a protecting group for hydroxyl groups. R 4a This indicates an acyl group, R 5 and R 6 One of them represents a protecting group for a hydrogen atom or an amino group, and the other represents a protecting group for an amino group. B represents the base portion of a nucleic acid, which may be substituted with one or more substituents. A compound represented by the formula.

[13] Equation (XII): [ka] [In the formula, R 1 This indicates a protecting group for hydroxyl groups. R 2 These are benzyl group, 4,4'-dimethoxytrityl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethylsilyl)ethoxymethyl group, 2-methoxyethoxymethyl The group represents a cyanoethyl group, a benzoyl group, or an acetyl group. R 4a This indicates an acyl group, R 5 and R 6 One of them represents a protecting group for a hydrogen atom or an amino group, and the other represents a protecting group for an amino group. B represents the base portion of a nucleic acid, which may be substituted with one or more substituents. The compound described above

[12] , represented by

[12] .

[14] The compounds described in

[12] or

[13] above, wherein B is thyminyl.

[15] Equation (XIII): [ka] [In the formula, R 1 This indicates a protecting group for hydroxyl groups. R 2 This represents a benzyl group, 4,4'-dimethoxytrityl group, t-butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethylsilyl)ethoxymethyl group, 2-methoxyethoxymethyl group, cyanoethyl group, benzoyl group, or acetyl group. R 5 and R 6 One of them represents a protecting group for a hydrogen atom or an amino group, and the other represents a protecting group for an amino group. B represents the base portion of a nucleic acid, which may be substituted with one or more substituents. A compound represented by the formula.

[16] The compound described in

[15] above, wherein B is thyminyl.

[17] Formula (XIV): [ka] [In the formula, R 1 This indicates a protecting group for hydroxyl groups. R 2 This indicates a protecting group for hydroxyl groups. R 5 and R 6 One of them represents a protecting group for a hydrogen atom or an amino group, and the other represents a protecting group for an amino group. R 11 This indicates an alkyl group or aryl group. R 12 This represents a hydrogen atom, an alkyl group, an alkoxy group, or an alkoxyalkyl group. X is an oxygen atom or NR 13 (R 13 (This indicates a protecting group for a hydrogen atom or an amino group.) A double line consisting of a solid and a dotted line indicates a single or double bond. A compound represented by the formula.

[18] Formula (XIV): [ka] [In the formula, R 1 This indicates a protecting group for hydroxyl groups. R 2 This represents a benzyl group, 4,4'-dimethoxytrityl group, t-butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethylsilyl)ethoxymethyl group, 2-methoxyethoxymethyl group, cyanoethyl group, benzoyl group, or acetyl group. R 5 and R 6 One of them represents a protecting group for a hydrogen atom or an amino group, and the other represents a protecting group for an amino group. R 11 This indicates an alkyl group or aryl group. R 12 This represents a hydrogen atom, an alkyl group, an alkoxy group, or an alkoxyalkyl group. X is an oxygen atom or NR 13 (R 13 (This indicates a protecting group for a hydrogen atom or an amino group.) A double line consisting of a solid and a dotted line indicates a single or double bond. The compound described above

[17] , represented by

[17] .

[19] R 12 The compounds described in

[17] or

[18] above, wherein is a methyl group and X is an oxygen atom.

[20] Formula (XV): [ka] [In the formula, R 1 This indicates a protecting group for hydroxyl groups. R 2 This indicates a protecting group for hydroxyl groups. R 5 and R 6 One of them represents a protecting group for a hydrogen atom or an amino group, and the other represents a protecting group for an amino group. R 12This represents a hydrogen atom, an alkyl group, an alkoxy group, or an alkoxyalkyl group. X is an oxygen atom or NR 13 (R 13 (This indicates a protecting group for a hydrogen atom or an amino group.) A double line consisting of a solid and a dotted line indicates a single or double bond. A compound represented by the formula.

[21] Formula (XV): [ka] [In the formula, R 1 This indicates a protecting group for hydroxyl groups. R 2 This represents a benzyl group, 4,4'-dimethoxytrityl group, t-butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethylsilyl)ethoxymethyl group, 2-methoxyethoxymethyl group, cyanoethyl group, benzoyl group, or acetyl group. R 5 and R 6 One of them represents a protecting group for a hydrogen atom or an amino group, and the other represents a protecting group for an amino group. R 12 This represents a hydrogen atom, an alkyl group, an alkoxy group, or an alkoxyalkyl group. X is an oxygen atom or NR 13 (R 13 (This indicates a protecting group for a hydrogen atom or an amino group.) A double line consisting of a solid and a dotted line indicates a single or double bond. The compound described in

[20] , represented by

[20] .

[22] R 12 The compounds described in

[20] or

[21] above, wherein is a methyl group and X is an oxygen atom.

[23] R 12 is a methyl group, X is an oxygen atom, and R 1 is a benzyl group, R 2 is a benzyl group, R 5 is a benzyloxycarbonyl group, R 6The compound described in any one of the above

[20] to

[22] , wherein is a hydrogen atom, and the double line consisting of a solid line and a dotted line is a single bond or a double bond.

[24] Crystals of the compound described in

[23] above.

[25] In powder X-ray diffraction spectra measured using CuKα emission, the diffraction angles represented by 2θ were 7.4±0.2°, 19.2±0.2°, 20.1±0.2°, 21.3±0.2° and 24.7 A crystal of the compound described in

[24] above, having a peak at ±0.2°.

[26] Formula (XVI): [ka] [In the formula, R 1 This indicates a protecting group for hydroxyl groups. R 2 This indicates a protecting group for hydroxyl groups. R 12 This represents a hydrogen atom, an alkyl group, an alkoxy group, or an alkoxyalkyl group. R 14 The hydrogen atom, benzyloxycarbonyl group, isobutyryl group, benzoyl group, t-butoxycarbonyl group, trimethylsilylethoxycarbonyl (Teoc) group, allyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, acetyl group, formyl group, 4-methoxybenzyl group, allyl group, It shows a benzyl group or a 2-nitrobenzenesulfonyl group, X is an oxygen atom or NR 13 (R 13 (This indicates a protecting group for a hydrogen atom or an amino group.) A double line consisting of a solid and a dotted line indicates a single or double bond. A compound represented by the formula.

[27] Formula (XVI): [ka] [In the formula, R 1This indicates a protecting group for hydroxyl groups. R 2 This represents a benzyl group, 4,4'-dimethoxytrityl group, t-butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethylsilyl)ethoxymethyl group, 2-methoxyethoxymethyl group, cyanoethyl group, benzoyl group, or acetyl group. R 12 This represents a hydrogen atom, an alkyl group, an alkoxy group, or an alkoxyalkyl group. R 14 This represents a hydrogen atom, a benzyloxycarbonyl group, an isobutyryl group, a benzoyl group, a t-butoxycarbonyl group, a trimethylsilylethoxycarbonyl group, an allyloxycarbonyl group, a 9-fluorenylmethoxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, an acetyl group, a formyl group, a 4-methoxybenzyl group, an allyl group, a benzyl group, or a 2-nitrobenzenesulfonyl group. X is an oxygen atom or NR 13 (R 13 (This indicates a protecting group for a hydrogen atom or an amino group.) A double line consisting of a solid and a dotted line indicates a single or double bond. The compound described above

[26] , represented by

[26] .

[0015] A further embodiment of the present invention is a method for producing a compound of the following formula (XVII).

[28] Equation (I): [ka] [In the formula, R 1 This indicates a protecting group for hydroxyl groups. R 2 This indicates a protecting group for hydroxyl groups. R 3 and R 4 These are either identical or different, each independently representing a hydroxyl group protecting group, or R 3 and R 4 This shows the cyclic protecting group of the diol formed by the combination of these two components. From the compound represented by, Formula (XVII): [ka] [In the formula, R 1 This indicates a protecting group for a hydrogen atom or a hydroxyl group. R 12 This represents a hydrogen atom, an alkyl group, an alkoxy group, or an alkoxyalkyl group. X is an oxygen atom or NR 13 (R 13 (This indicates a protecting group for a hydrogen atom or an amino group.) A double line consisting of a solid and a dotted line indicates a single or double bond. A method for producing a compound represented by the following steps 1-3, 9-15; Step 1: Equation (I): [ka] [In the formula, each symbol has the same meaning as above.] The compound represented by, Formula (V): [ka] [In the formula, R 7 [This represents a hydrogen atom or an alkyl group.] By reacting a compound represented by or a salt thereof, Formula (II): [ka] [In the formula, R 1 This indicates a protecting group for hydroxyl groups. R 2 This indicates a protecting group for hydroxyl groups. R 3 and R 4 These are either identical or different, each independently representing a hydroxyl group protecting group, or R 3and R 4 It shows the cyclic protecting group of the diol that is formed together, R 7 [This represents a hydrogen atom or an alkyl group.] A process to obtain a compound represented by; Step 2: The compound represented by formula (II) is subjected to a reduction reaction with a reducing agent, Formula (III): [ka] [In the formula, R 1 This indicates a protecting group for hydroxyl groups. R 2 This indicates a protecting group for hydroxyl groups. R 3 and R 4 These are either identical or different, each independently representing a hydroxyl group protecting group, or R 3 and R 4 This shows the cyclic protecting group of the diol formed by the combination of these two components. A process to obtain a compound represented by; Step 3: The compound represented by formula (III) is subjected to an amino group protection reaction, resulting in formula (IV): [ka] [In the formula, R 1 This indicates a protecting group for hydroxyl groups. R 2 This indicates a protecting group for hydroxyl groups. R 3 and R 4 These are either identical or different, each independently representing a hydroxyl group protecting group, or R 3 and R 4 It shows the cyclic protecting group of the diol that is formed together, R 5 and R 6 One side represents a protecting group for a hydrogen atom or an amino group, and the other side represents a protecting group for an amino group. A process to obtain a compound represented by; Step 9: The compound represented by formula (IV) is, if necessary, R 3 and R 4 The reaction is performed to convert the acyl group, Formula (XI): [ka] [In the formula, R 1 This indicates a protecting group for hydroxyl groups. R 2 This indicates a protecting group for hydroxyl groups. R 3a This indicates an acyl group, R 4a This indicates an acyl group, R 5 and R 6 One side represents a protecting group for a hydrogen atom or an amino group, and the other side represents a protecting group for an amino group. A process to obtain a compound represented by; Step 10: By subjecting the compound represented by formula (XI) to a glucosylation reaction, Equation (XII'): [ka] [In the formula, R 1 This indicates a protecting group for hydroxyl groups. R 2 This indicates a protecting group for hydroxyl groups. R 4a This indicates an acyl group, R 5 and R 6 One of them represents a protecting group for a hydrogen atom or an amino group, and the other represents a protecting group for an amino group. B is given by equation (XXIV): [ka] [In the formula, R 12 This represents a hydrogen atom, an alkyl group, an alkoxy group, or an alkoxyalkyl group. X is an oxygen atom or NR 13 (R 13 (This indicates a protecting group for a hydrogen atom or an amino group.) A double line consisting of a solid and a dotted line indicates a single or double bond. This shows the compound represented by [the formula shown]. A process to obtain a compound represented by; Step 11: The compound represented by formula (XII') is subjected to a deprotection reaction of the acyl group, resulting in formula (XIII'): [ka] [In the formula, R 1 This indicates a protecting group for hydroxyl groups. R 2 This indicates a protecting group for hydroxyl groups. R 5 and R 6 One side represents a protecting group for a hydrogen atom or an amino group, and the other side represents a protecting group for an amino group. Show the basis, B is given by equation (XXIV): [ka] [In the formula, each symbol has the same meaning as above.] This shows the compound represented by [the formula shown]. A process to obtain a compound represented by; Step 12: The compound represented by formula (XIII') is subjected to a sulfonylation reaction, Formula (XIV): [ka] [In the formula, R 1 This indicates a protecting group for hydroxyl groups. R 2 This indicates a protecting group for hydroxyl groups. R 5 and R 6 One of them represents a protecting group for a hydrogen atom or an amino group, and the other represents a protecting group for an amino group. R 11 This indicates an alkyl group or aryl group. R 12 This represents a hydrogen atom, an alkyl group, an alkoxy group, or an alkoxyalkyl group. X is an oxygen atom or NR 13 (R 13 (This indicates a protecting group for a hydrogen atom or an amino group.) A double line consisting of a solid and a dotted line indicates a single or double bond. A process to obtain a compound represented by; Step 13: The compound represented by formula (XIV) is subjected to a cyclization reaction, Formula (XV): [ka] [In the formula, R 1 This indicates a protecting group for hydroxyl groups. R 2 This indicates a protecting group for hydroxyl groups. R 5 and R 6 One of them represents a protecting group for a hydrogen atom or an amino group, and the other represents a protecting group for an amino group. R 12 This represents a hydrogen atom, an alkyl group, an alkoxy group, or an alkoxyalkyl group. X is an oxygen atom or NR 13 (R 13 (This indicates a protecting group for a hydrogen atom or an amino group.) A double line consisting of a solid and a dotted line indicates a single or double bond. A process to obtain a compound represented by; Step 14: The compound represented by formula (XV) is subjected to a ring-closing reaction, Formula (XVI): [ka] [In the formula, R 1 This indicates a protecting group for hydroxyl groups. R 2This indicates a protecting group for hydroxyl groups. R 12 This represents a hydrogen atom, an alkyl group, an alkoxy group, or an alkoxyalkyl group. R 14 This indicates a protecting group for a hydrogen atom or an amino group. X is an oxygen atom or NR 13 (R 13 (This indicates a protecting group for a hydrogen atom or an amino group.) A double line consisting of a solid and a dotted line indicates a single or double bond. The process of obtaining a compound represented by; and Step 15: A process of subjecting a compound represented by formula (XVI) to a deprotection reaction, or a deprotection reaction followed by a hydroxyl group protection reaction. A manufacturing method that includes this.

[0016] Further embodiments of the present invention are methods for producing the following modified oligonucleotides or salts thereof.

[29] Formula (XVII´´): [ka] [In the formula, R 1a This indicates a protecting group for hydroxyl groups. R 12 This represents a hydrogen atom, an alkyl group, an alkoxy group, or an alkoxyalkyl group. X is an oxygen atom or NR 13 (R 13 (This indicates a protecting group for a hydrogen atom or an amino group.) A double line consisting of a solid and a dotted line indicates a single or double bond. From the compound represented by, Below formula: [ka] A method for producing a modified oligonucleotide or a salt thereof, wherein the production method is A step of producing a compound represented by formula (XVII'') by the manufacturing method described in [6] above, A step of producing ALNA[Ms]amidite from a compound represented by formula (XVII''), a step of subjecting ALNA[Ms]amidite and DNA synthesis amidite to a phosphoramidite process, and If necessary, the phosphodiester bond is subjected to a thiolation reaction. A manufacturing method that includes this.

[30] Formula (XVII´´): [ka] [In the formula, R 1a This indicates a protecting group for hydroxyl groups. R 12 This represents a hydrogen atom, an alkyl group, an alkoxy group, or an alkoxyalkyl group. X is an oxygen atom or NR 13 (R 13 (This indicates a protecting group for a hydrogen atom or an amino group.) A double line consisting of a solid and a dotted line indicates a single or double bond. From the compound represented by, Below formula: [ka] A method for producing a modified oligonucleotide or a salt thereof, wherein the production method is A step of producing a compound represented by formula (XVII'') by the manufacturing method described in [6] above, A step of producing ALNA[Ms]amidite from a compound represented by formula (XVII''), a step of subjecting ALNA[Ms]amidite and DNA synthesis amidite to a phosphoramidite process, and If necessary, the phosphodiester bond is subjected to a thiolation reaction. A manufacturing method that includes this.

[31] The following formula is manufactured by the manufacturing method described in

[29] above: [ka] Modified oligonucleotides or their salts, as indicated by [the symbol].

[32] The following formula is produced by the manufacturing method described in

[30] above: [ka] Modified oligonucleotides or their salts, as indicated by [the symbol].

[0017] According to the first embodiment of the present invention, a method for producing the compound of formula (IV), a manufacturing intermediate useful for producing cross-linked artificial nucleic acid intermediates useful as intermediates for nucleic acid drugs and the like can be produced in a manner suitable for industrial production. More specifically, from the compound of formula (I) to the compound of formula (II By utilizing a reductive amination reaction in the production of compound I), the compound of formula (III) and the subsequent compound of formula (IV) can be safely produced in good yield. According to the second embodiment of the present invention, which is a method for producing the compound of formula (XIII), another novel production intermediate, the compound of formula (XIII), can be produced in good yield from the compound of formula (IV) produced by the production method of the first embodiment described above. Furthermore, according to the third embodiment of the present invention, which is a method for producing the compound of formula (XVII), the compound of formula (XVII), which is one of the target cross-linked artificial nucleic acid intermediates, can be produced in a manner suitable for industrial production from the compound of formula (XIII') produced by the production method of the second embodiment described above. More specifically, it is possible to obtain the compound of formula (XV), which is one of the production intermediates, as a crystal. By going through this crystallization step, the compound of formula (XV) can be produced with high purity and good yield through simple purification. Moreover, by carrying out subsequent steps using this compound, the compound of formula (XVII), which is one of the target cross-linked artificial nucleic acid intermediates, can be obtained in high quality. Although the manufacturing methods of the first to third embodiments described above are each industrially advantageous independently, combining them allows for the safe, reproducible, high-yield, and high-quality production of the cross-linked target material. This method is highly industrially advantageous because it allows for the production of artificial nucleic acid intermediates. A combination of these manufacturing methods also constitutes one embodiment of the present invention. Some of the intermediate compounds produced in the manufacturing methods of the first to third embodiments described above are also industrially advantageous intermediate compounds, and each is an embodiment of one of the present inventions. Furthermore, a method for producing a modified oligonucleotide or a salt thereof, including the above-described manufacturing method, and a modified oligonucleotide or a salt thereof produced by the manufacturing method thereof, are embodiments of the present invention. [Brief explanation of the drawing]

[0018] [Figure 1] This is the powder X-ray diffraction pattern of the crystalline compound (compound 14) of formula (XV'). [Modes for carrying out the invention]

[0019] The definitions of each group used herein are as follows:

[0020] In this specification, the term "alkyl group" refers to a group having 1 to 6 carbon atoms (C 1~6 This refers to a linear or branched saturated hydrocarbon group having 1 to 4 carbon atoms. 1~4 A group of the following is preferred. Specifically, examples include a methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, 2-methyl-n-butyl group, i-amyl(3-methyl-n-butyl) group, 2-methyl-n-pentyl group, and so on, with the methyl group being preferred.

[0021] In this specification, "alkoxy group" means a group in which the alkyl group is bonded to an oxygen atom. A valence group refers to a group with 1 to 6 carbon atoms (C 1~6 Examples include linear or branched alkyl-O- groups having 1 to 4 carbon atoms (C 1~4 ) alkyl-O- groups are preferred. Specifically, methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, t-butoxy group, 2-methyl Examples include the n-propoxy group and the 3-methyl-n-butoxy group, with the methoxy group being preferred. It can be raised.

[0022] In this specification, "alkoxyalkyl group" refers to the alkyl group substituted with one or two alkoxy groups. Specifically, examples include methoxymethyl group, methoxyethyl group, methoxypropyl group, etc., with methoxymethyl group being preferred.

[0023] In this specification, the term "alkylene group" refers to a group having 1 to 6 carbon atoms (C 1~6 A divalent group obtained by removing two hydrogen atoms from a straight-chain or branched-chain saturated hydrocarbon, specifically including methylene, ethylene, n-propylene, isopropylidene, butylene, hexylene, cyclopentylene, and cyclohexylene groups.

[0024] In this specification, the term "alkynyl group" refers to a group having 2 to 6 carbon atoms (C 2-6 ), preferably with 2 to 4 carbon atoms (C 2-4 ), more preferably having 2 to 3 carbon atoms (C 2-3 Examples include linear or branched alkynyl groups. Specifically, these include ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 1-pentynyl group, 2-pentynyl group, 3-pentynyl group, 4-pentynyl group, 1-hexynyl group, 1-methyl-2-propynyl group, and 1-methyl-2-butynyl group.

[0025] In this specification, the term "aryl group" means a functional group or substituent derived from aromatic hydrocarbons (monocyclic, bicyclic, and tricyclic). Preferably, it refers to a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 11 carbon atoms in the ring structure, and more preferably, a five-membered or six-membered aromatic hydrocarbon group. Among these, phenyl is preferred. The aryl group may also be substituted, and such substituents on the aryl group may include a hydroxyl group, a halogen atom, a nitro group, a cyano group, or one or more substituents. 1-6 alkyl group , C which may be substituted with one or more substituents 2-6 The alkenyl group may be substituted with one or more substituents. 2-6 Alkynyl group, C 1-6 Alkoxy group, aryloxy group, amino group, one or more C 1-3 Examples include one or more (preferably 1 to 3) identical or different groups selected from the group consisting of amino groups and aryl groups, which may be substituted with alkyl groups, and preferably C, which may be substituted with one or more substituents. 1-6 Alkyl alkyl group, one or more C 1-3 Examples include amino groups which may be substituted with alkyl groups, and halogen atoms, more preferably trifluoromethyl groups, dimethylamino groups, and chloro atoms. Specific examples of aryl groups that may be substituted with one or more substituents include 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2,6-dimethylphenyl group, 2,4-dimethylphenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2,4-dichlorophenyl group, 2,5-dichlorophenyl group, 2,6-dichlorophenyl group, 2-bromophenyl group, 4-methoxyphenyl group, 4-chloro-2-nitrophenyl group, 4-nitrophenyl group, 2-nitrophenyl group, 2,4-dinitrophenyl group, 2-trifluoromethylphenyl group, 3-trifluoromethylphenyl group, 4-trifluoromethylphenyl group, 2-dimethylaminophenyl group, 3-dimethylaminophenyl group, 4-dimethylaminophenyl group, 2-biphenyl group, 3-biphenyl group, and 4-biphenyl group.

[0026] In this specification, the term "halogen atom" includes, for example, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0027] In this specification, the term "protecting group" as used within the sections on "hydroxyl group protecting group" and "amino group protecting group" is not particularly limited, as long as it can stably protect an amino group or a hydroxyl group during nucleic acid synthesis. Specifically, it refers to a protecting group that is stable under acidic or neutral conditions and can be cleaved by chemical methods such as hydrolysis, hydrolysis, electrolysis, and photolysis.

[0028] In this specification, "hydroxyl group protecting group" refers to a protecting group commonly used in organic synthesis (especially nucleic acid synthesis), and includes, for example, acyl groups; alkyl groups; methyl groups substituted with 1 to 3 aryl groups; methyl groups substituted with 1 to 3 aryl groups substituted with alkyl groups, alkoxy groups, halogen atoms and / or cyano groups; methyl groups substituted with alkoxy groups; silyl groups; silyloxymethyl groups; or carbonate groups. Specific examples include benzyl (sometimes referred to as Bn) groups, 4,4'-dimethoxytrityl ( (Sometimes referred to as DMTr) group, 4-methoxytrityl group, triphenylmethyl group, 2-naphthylmethyl group, cyanoethoxycarbonyl group, cyanoethyl group, methoxymethyl group, methylthiomethyl group, benzyloxymethyl group, 4-methoxybenzyloxymethyl group, t-butyloxymethyl group, trimethylsilyloxymethyl group, t-butyldimethylsilyloxymethyl group, t-butyldiphenylsilyloxymethyl group, triethylsilyloxymethyl group, triisopropylsilyloxymethyl group, 2-methoxyethoxymethyl group, 2,2,2-trichloroethoxymethyl group, 2-(tri Methylsilyl)ethoxymethyl group, 1-ethoxyethyl group, tetrahydropyranyl group, tri Methylsilyl (sometimes referred to as TMS) group, triethylsilyl group, triisopropylsilyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, triphenylsilyl group, 4-methoxybenzyl group, 3,4-dimethoxybenzyl group, 2,6-dimethoxybenzyl group, p-phenylbenzyl group, benzoyl (sometimes referred to as Bz) group, phenoxyacetyl group, benzyloxycarbonyl (sometimes referred to as Cbz) group, t- 9-Fluorenylmethyloxycarbonyl (sometimes referred to as Boc) group, 9-Fluorenylmethyloxycarbonyl Examples include bonyl (sometimes referred to as Fmoc) groups or acetyl (sometimes referred to as Ac) groups. For example, benzyl group, 4,4'-dimethoxytrityl group, t-butyldimethyl Silyl group, t-butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethylsilyl)ethoxymethyl group, 2-methoxyethoxy A methyl group, cyanoethyl group, benzoyl group, or acetyl group is preferred, and a benzyl group, 4,4'-dimethoxytrityl group, or acetyl group is more preferred.

[0029] In this specification, "cyclic protecting group of a diol" means a cyclic protecting group of a hydroxyl group (diol) formed when the oxygen atoms of the two hydroxyl groups of a diol are combined with an alkylene group. Specifically, this includes methoxymethylene acetal group, isopropylidene ketal group, methylene acetal group, ethylidene acetal group, t-butylmethylidene acetal group, 1-t-butylethylidene ketal group, 1-phenylethylidene ketal group, 1-(4-methoxyphenyl)ethylidene ketal group, 2,2,2-trichloroethylidene acetal group, and benzylidene Acetal group, 4-methoxybenzylidene acetal group, 2,4-methoxybenzylidene 3,4-methoxybenzylidene acetal group, cyclopentylidene Tar group, cyclohexyllidene ketal group, cycloheptyllidene ketal group, benzophenone ketal group, ethoxymethylene acetal group, 1-methoxyethylidene orthoester group, 1-ethoxyethylidene orthoester group, 1-benzyloxybenzylidene Examples of cyclic acetal protecting groups include rutoester groups, di-t-butylsilylene groups, diisopropylsilylene groups, methylcyclohexylsilylene groups, dicyclohexylsilylene groups, 1,3-(1,1,3,3-tetraisopropyl)disiloxanylidene groups, 1,1,3,3-tetra-t-butoxydisiloxanylidene groups, and cyclic carbonate groups. Isopropylidene ketal groups, methylene acetal groups, ethylidene acetal groups, benzylidene acetal groups, 4-methoxybenzylidene acetal groups, or 1-benzyloxybenzylidene orthoester groups are preferred, with isopropylidene ketal groups being more preferred. Note that the specific examples of the above cyclic protecting groups are names of groups including the oxygen atom that forms the cyclic structure, following the conventions of organic synthesis chemistry. For example, R 3 and R 4 The specific name of the cyclic protecting group of a diol formed by the combination of these is R 3 and R 4 These are the names of the groups that include the oxygen atoms to which they are bonded.

[0030] In this specification, "amino group protecting group" means a protecting group commonly used in organic synthesis (particularly nucleic acid synthesis), and includes, for example, aliphatic acyl groups; aromatic acyl groups; sulfonyl groups; alkyl groups; methyl groups substituted with 1 to 3 aryl groups; and methyl groups substituted with 1 to 3 aryl groups substituted with a halogen atom and / or a cyano group. Specific examples include acetyl (Ac) group, formyl group, phenoxyacetyl group, t-butylphenoxyacetyl group, p-isopropylphenoxyacetyl group, trifluoroacetyl group, propionyl group, isobutyryl group, benzoyl (Bz) group, methoxycarbonyl group, ethoxycarbonyl group, t-butoxycarbonyl group, trimethylsilylethoxycarbonyl group, cyanoethoxycarbonyl group, benzyloxycarbonyl (Cbz) group, allyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group, dimethylaminomethylyl group, 2,2,2-trichloroethoxycarbonyl group, t-amyloxycarbonyl group, 4-methoxybenzyl group, triphenylmethyl group, 2-nitrobenzenesulfonyl group, 4-nitrobenzenesulfonyl group, 2,4-dinitrobenzenesulfonyl group, 2-(trimethylsilyl)ethoxymethyl group, benzyl (Bn) group, or allyl group. For example, benzyloxycarbonyl group, isobutyryl group, benzoyl group, t-butoxycarbonyl group, trimethylsilylethoxycarbonyl group, allyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, acetyl group, formyl group, trifluoroacetyl group, 4-methoxybenzyl group, allyl group, benzyl group or 2-nitrobenzenesulfonyl group are preferred, and benzyloxycarbonyl group, acetyl group, 4-methoxybenzyl group or allyl group are more preferred.

[0031] In this specification, examples of the term "acyl group" include aliphatic acyl groups and aromatic acyl groups. Specifically, examples of aliphatic acyl groups include the formyl group and the acetyl group. , propionyl group, butyryl group, isobutyryl group, pentanoyl group, pivaloyl group, valeryl group, isovaleryl group, octanoyl group, nonanoyl group, decanoyl group, 3-methylnonanoyl group, 8-methylnonanoyl group, 3-ethyloctanoyl group, 3,7-dimethyloctanoyl group, undecanoyl group, dodecanoyl group, tridecanoyl group, tetradecanoyl group, pentadecanoyl group, hexadecanoyl group, 1-methylpentadecanoyl group, 14-methylpentadecanoyl group, 13,13-dimethyltetradecanoyl group, heptadecanoyl group, 15-methylhexadecanoyl group, octadecanoyl group, 1-methylheptadecanoyl Examples include alkylcarbonyl groups such as nonadecanoyl, aicosanoyl, and henaicosanoyl groups; aryloxyalkylcarbonyl groups such as phenoxyacetyl; carboxylated alkylcarbonyl groups such as succinoyl, glutaloyl, and adipoyl groups; carbonyl groups substituted with halogen atoms and C1-C6 alkyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl, and trifluoroacetyl groups; alkoxyalkylcarbonyl groups such as methoxyacetyl; and unsaturated alkylcarbonyl groups such as (E)-2-methyl-2-butenoyl. Examples of aromatic acyl groups include arylcarbonyl groups such as benzoyl, α-naphthoyl, and β-naphthoyl groups; halogenoarylcarbonyl groups such as 2-bromobenzoyl and 4-chlorobenzoyl groups; arylcarbonyl groups substituted with C1 to C6 alkyl groups such as 2,4,6-trimethylbenzoyl and 4-toluyl groups; arylcarbonyl groups substituted with C1 to C6 alkoxy groups such as 4-anissoyl groups; carboxylated arylcarbonyl groups such as 2-carboxybenzoyl, 3-carboxybenzoyl, and 4-carboxybenzoyl groups; nitrated arylcarbonyl groups such as 4-nitrobenzoyl and 2-nitrobenzoyl groups; carbonylated arylcarbonyl groups substituted with C1 to C6 alkoxy groups such as 2-(methoxycarbonyl)benzoyl group; and arylated arylcarbonyl groups such as 4-phenylbenzoyl group.

[0032] In this specification, examples of the term "silyl group" include silyl groups substituted with C1 to C6 alkyl groups such as trimethylsilyl group, triethylsilyl group, isopropyldimethylsilyl group, t-butyldimethylsilyl group, methyldiisopropylsilyl group, methyldi-t-butylsilyl group, and triisopropylsilyl group; silyl groups substituted with three C1 to C6 alkyl groups and substituted with one or two aryl groups such as t-butyldiphenylsilyl group, diphenylmethylsilyl group, butyldiphenylbutylsilyl group, diphenylisopropylsilyl group, and phenyldiisopropylsilyl group; and triphenylsilyl group.

[0033] In this specification, examples of the term "silyloxy group" include silyloxy groups substituted with alkyl groups such as trimethylsilyloxymethyl group, t-butyldimethylsilyloxymethyl group, texyldimethylsilyloxymethyl group, triethylsilyloxymethyl group, and triisopropylsilyloxymethyl group; and silyloxy groups substituted with aryl groups such as t-butyldiphenylsilyloxymethyl group.

[0034] In this specification, the term “nucleic acid base moiety which may be substituted with one or more substituents” includes the base moieties of natural and unnatural nucleic acids, and encompasses aromatic heterocyclic groups (e.g., monocyclic, dicyclic, tricyclic groups, etc.). Nucleic acid base moieties include not only known purine and pyrimidine heterocycles, but also their heterocyclic analogs and tautomers. Specific examples of nucleic acid base moieties include adeninyl, guaninyl, thyminyl, dihydrothyminyl, cytosinyl, uracinyl, dihydrouracil, purinyl, xanthinyl, diaminopurinyl, and 8-oxo-N. 6 -Methyladenyl, 7-Deazaxanthinyl, 7-Deazaguaninyl, 2-Thiothyminyl, N 4 , N 4 -Ethanosytosinyl, N 6 , N 6 -Ethano-2,6-diaminopurinyl,5-methylcytosinyl,5-(C3 ~C 6 )-Archini Lucitosinyl, 5-fluorocytosinyl, 5-bromouracinyl, pseudoisocytosinyl, 2-hydroxy-5-methyl-4-triazolopyridinyl, isocytosinyl, isoguani Nyl, inosinyl, 6-aminoprinyl, 2-aminoprinyl, 6-chloro-2-aminoprinyl, 6-chloroprinyl, N 6 -Allylprinyl, N 6 -Acylprinyl, N 6 - Benzylprinyl, N 6 -Haloprinil, N 6 -Vinyl plinyl, N 6 - Acetylene plinyl, N 6 -Asylprini, N 6 -Hydroxyalkylprinyl, N 6 - Thioalkylprinyl, N 2 -alkylprinyl, N 4 -alkylpyrimidinyl, N 4 -Acylpyrimidinyl, N 4 - Benzylprinyl, N 4 -halopyrimidinyl, N 4 -Vinylpyrimidinyl, N 4 - Acetylpyrimidini Ru, N 4 -Hydroxyalkylpyrimidinyl, N 6 - Thioalkylpyrimidinyl, 6-Azapi Limidinil, 6-Azacytosinil, 2-and / or 4-Mercaptopyrimidinil, Urasinil, C 5 -alkylpyrimidinyl, C 5 - Benzylpyrimidinyl, C 5 - Halopyrimidinyl, C 5 -Vinylpyrimidinyl, C 5 - Acetylene pyrimidinyl, C 5 -Acylpyrimidinyl , C 5 -Hydroxyalkylprinyl, C 5 -Amidopyrimidinyl, C 5 -Cyanopyrimidinyl, C 5- Nitropyrimidinyl, C 5 -aminopyrimidinyl, N 2 -alkylprinyl, N 2 -alkyl-6-thioprinyl, 5-cytidinyl, 5-azauracinyl, trazolopyridinyl, i Examples include midazolopyridinyl, pyrrolopyrimidinyl, or pyrazolopyrimidinyl. Preferred nucleic acid base moieties include adeninyl, guaninyl, 2,6-diaminopurinyl, thyminyl, dihydrothyminyl, 2-thiothyminyl, cytosinyl, 5-methylcytosinyl, uracinyl, dihydrouracil, 5-fluorocytosinyl, xanthinyl, 6-aminopurinyl, 2-aminopurinyl, 6-chloro-2-aminopurinyl, or 6-chloropurinyl. These nucleic acid base moieties may be substituted with one or more substituents, preferably one or two substituents. Such substituents include hydroxyl groups, alkoxy groups, mercapto groups, alkylthio groups, amino groups, alkyl-substituted amino groups, alkyl groups, alkynyl groups, oxo groups, thioxo groups, or halogen atoms. Functional oxygen, sulfur, and nitrogen groups on the base moiety may be protected and / or deprotected as needed. Suitable protecting groups are well known to those skilled in the art, and examples include the hydroxyl group protecting group and amino group protecting group mentioned above. Preferably, these include diphenylaminocarbonyl group, silyl group (e.g., trimethylsilyl group, dimethylhexylsilyl group, t-butyldimethylsilyl group, and t-butyldiphenylsilyl group), trityl group, alkyl group, acyl group (e.g., acetyl group, propionyl group, isobutyryl group, benzoyl group, phenoxyacetyl group), alkoxycarbonyl group (e.g., t-butoxycarbonyl group, benzyloxycarbonyl group, diphenylaminocarbonyl group (sometimes referred to as DPC), cyanoethoxycarbonyl group), sulfonyl group (e.g., methanesulfonyl group, and p-toluenesulfonyl group), and dimethylaminomethylenyl group.

[0035] <Manufacturing method and form of compound> Some embodiments of the present invention, including some manufacturing methods and some compounds, include one or more embodiments of the manufacturing method and one or more embodiments of the compounds, as described below.

[0036] In one embodiment of the above-described example, in steps 1 to 3 of this specification, in formulas (I) to (V), R 1 R is a protecting group for hydroxyl groups, 2 R is a protecting group for hydroxyl groups, 3 and R 4 is R 3 and R 4 It is a cyclic protecting group of a diol formed by the combination of R 5 and R 6 R is a protecting group for amino groups, 7 This includes a manufacturing method comprising one or more steps 1 to 3 using a compound that is an alkyl group or a hydrogen atom, and the compound used in this manufacturing method.

[0037] In one embodiment of the above-described example, in steps 1 to 3 of this specification, in formulas (I) to (V), R 1 R is a protecting group for hydroxyl groups, 2 R is a protecting group for hydroxyl groups, 3 and R 4 is R 3 and R 4 It is a cyclic protecting group of a diol formed by the combination of R 5 R is a protecting group for amino groups, 6 R is a hydrogen atom, 7 Step 1 to 3 using a compound that is a hydrogen atom The present invention includes a manufacturing method that includes the above steps, and the compound used in this manufacturing method.

[0038] In one embodiment of the above-described example, in steps 1 to 3 of this specification, in formulas (I) to (V), R 1 The group consists of a benzyl group, a 4,4'-dimethoxytrityl group, and a t-butyldimethylsilyl group. t-butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethylsilyl)ethoxymethyl group, 2-methoxyethoxymethyl group , a cyanoethyl group, a benzoyl group or an acetyl group, R 2 The benzyl group is 4,4' -Dimethoxytrityl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethylsilyl R is a lyl-ethoxymethyl group, a 2-methoxyethoxymethyl group, a cyanoethyl group, a benzoyl group, or an acetyl group. 3 and R 4 is R 3 and R 4 Together, they form an isopropylidene ketal group, a methylene acetal group, an ethylidene acetal group, and a benzylidene acetal group. 1-acetal group, 4-methoxybenzylidene acetal group or 1-benzyloxyb It is a dzylidene orthoester group, R 5 R is a benzyloxycarbonyl group, isobutyryl group, benzoyl group, t-butoxycarbonyl group, trimethylsilylethoxycarbonyl group, allyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, acetyl group, formyl group, trifluoroacetyl group, 4-methoxybenzyl group, allyl group, benzyl group, or 2-nitrobenzenesulfonyl group. 6 R is a hydrogen atom, 7 This includes a manufacturing method comprising one or more steps 1 to 3 using a compound that is a hydrogen atom, and the compound used in this manufacturing method.

[0039] In one embodiment of the above-described example, in steps 1 to 3 of this specification, in formulas (I) to (V), R 1 R is a benzyl group, a 4,4'-dimethoxytrityl group, or an acetyl group. 2 R is a benzyl group, a 4,4'-dimethoxytrityl group, or an acetyl group. 3 and R 4 is R 3 and R 4 The isopropylidene ketal group, R5 These are benzyloxycarbonyl groups, acetyl groups, 4-methoxybenzyl groups, or allyl groups. , R 6 R is a hydrogen atom, 7 This includes a manufacturing method comprising one or more steps 1 to 3 using a compound that is a hydrogen atom, and the compound used in this manufacturing method.

[0040] In one embodiment of the above-described specification, in steps 1 to 8, R in formulas (I) to (X) 1 R is a protecting group for hydroxyl groups, 2 R is a protecting group for hydroxyl groups, 3 and R 4 is R 3 and R 4 It is a cyclic protecting group of a diol formed by the combination of R 5 and R 6 R is a protecting group for amino groups, 7 This includes a manufacturing method comprising one or more steps 1 to 8 using a compound that is an alkyl group or a hydrogen atom, and the compound used in this manufacturing method.

[0041] In one embodiment of the above-described specification, in steps 1 to 8, R in formulas (I) to (X) 1 R is a protecting group for hydroxyl groups, 2 R is a protecting group for hydroxyl groups, 3 and R 4 is R 3 and R 4 It is a cyclic protecting group of a diol formed by the combination of R 5 R is a protecting group for amino groups, 6 R is a hydrogen atom, 7 This includes a manufacturing method comprising one or more steps 1 to 8 using a compound that is a hydrogen atom, and the compound used in this manufacturing method.

[0042] In one embodiment of the above-described specification, in steps 1 to 8, R in formulas (I) to (X) 1 The group consists of a benzyl group, a 4,4'-dimethoxytrityl group, and a t-butyldimethylsilyl group. t-butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethylsilyl)ethoxymethyl group, 2-methoxyethoxymethyl group , a cyanoethyl group, a benzoyl group or an acetyl group, R 2 The benzyl group is 4,4' -Dimethoxytrityl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethylsilyl R is a lyl-ethoxymethyl group, a 2-methoxyethoxymethyl group, a cyanoethyl group, a benzoyl group, or an acetyl group. 3 and R 4 is R 3 and R 4 When these come together, they form an iso Propyridene ketal group, methylene acetal group, ethylidene acetal group, benzyl Denacetal group, 4-methoxybenzylideneacetal group, or 1-benzyloxy It is a benzylidene orthoester group, R 5 R is a benzyloxycarbonyl group, isobutyryl group, benzoyl group, t-butoxycarbonyl group, trimethylsilylethoxycarbonyl group, allyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, acetyl group, formyl group, trifluoroacetyl group, 4-methoxybenzyl group, allyl group, benzyl group, or 2-nitrobenzenesulfonyl group. 6 R is a hydrogen atom, 7 This includes a manufacturing method comprising one or more steps 1 to 8 using a compound that is a hydrogen atom, and the compound used in this manufacturing method.

[0043] In one embodiment of the above-described specification, in steps 1 to 8, R in formulas (I) to (X) 1 R is a benzyl group, a 4,4'-dimethoxytrityl group, or an acetyl group. 2 R is a benzyl group, a 4,4'-dimethoxytrityl group, or an acetyl group. 3 and R 4 is R 3 and R 4 It is an isopropylidene ketal group formed by the combination of R 5 The group is a benzyloxycarbonyl group, an acetyl group, a 4-methoxybenzyl group, or an allyl group. And R 6 R is a hydrogen atom, 7 This includes a manufacturing method comprising one or more steps 1 to 8 using a compound that is a hydrogen atom, and the compound used in this manufacturing method.

[0044] In one embodiment of the above-described specification, in steps 1 to 11, R in formulas (I) to (XIII) 1 R is a protecting group for hydroxyl groups, 2 R is a protecting group for hydroxyl groups, 3 and R 4 is R 3 and R 4 It is a cyclic protecting group of a diol formed by the combination of R 3a and R 4a R is an acyl group, 5 and R 6 R is a protecting group for amino groups, 7 A manufacturing method comprising one or more steps 1 to 11 using a compound in which is an alkyl group or hydrogen atom and B is the base portion of a nucleic acid, and the compound used in this manufacturing method.

[0045] In one embodiment of the above-described specification, in steps 1 to 11, R in formulas (I) to (XIII) 1 R is a protecting group for hydroxyl groups, 2 R is a protecting group for hydroxyl groups, 3 and R 4 is R 3 and R 4 It is a cyclic protecting group of a diol formed by the combination of R 3a and R 4a is an acetyl group, R 5 R is a protecting group for amino groups,6 R is a hydrogen atom, 7 A manufacturing method comprising one or more steps 1 to 11 using a compound in which is a hydrogen atom and B is the base portion of a nucleic acid, and the compound used in this manufacturing method.

[0046] In one embodiment of the above-described specification, in steps 1 to 11, R in formulas (I) to (XIII) 1 These are benzyl group, 4,4'-dimethoxytrityl group, and t-butyldimethyl Silyl group, t-butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethylsilyl)ethoxymethyl group, 2-methoxyethoxy R is a methyl group, cyanoethyl group, benzoyl group, or acetyl group. 2 These are benzyl group, 4,4'-dimethoxytrityl group, t-butyldimethylsilyl group, and t-butyldiphenyl Silyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(tri The group is a methylsilyl)ethoxymethyl group, a 2-methoxyethoxymethyl group, a cyanoethyl group, a benzoyl group, or an acetyl group, and R 3 and R 4 is R 3 and R 4 Together they form an isopropylidene ketal group, a methylene acetal group, and an ethylidene acetal group. benzylidene acetal group, 4-methoxybenzylidene acetal group or 1-benzylidene acetal group It is a luoxybenzylidene orthoester group, R 3a and R 4a is an acetyl group, R 5 R is a benzyloxycarbonyl group, isobutyryl group, benzoyl group, t-butoxycarbonyl group, trimethylsilylethoxycarbonyl group, allyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, acetyl group, formyl group, trifluoroacetyl group, 4-methoxybenzyl group, allyl group, benzyl group, or 2-nitrobenzenesulfonyl group.6 R is a hydrogen atom, 7 Steps 1 to 11 include one or more steps using a compound in which is a hydrogen atom and B is the base portion of a nucleic acid. This includes a manufacturing method and the compound used in this manufacturing method.

[0047] In one embodiment of the above-described specification, in steps 1 to 11, R in formulas (I) to (XIII) 1 is a benzyl group, a 4,4'-dimethoxytrityl group, or an acetyl group. R 2 R is a benzyl group, a 4,4'-dimethoxytrityl group, or an acetyl group. 3 and R 4 is R 3 and R 4 It is an isopropylidene ketal group formed by the combination of R 3a and R 4a is an acetyl group, R 5 R is a benzyloxycarbonyl group, an acetyl group, a 4-methoxybenzyl group, or an allyl group. 6 R is a hydrogen atom, 7 A manufacturing method comprising one or more steps 1 to 11 using a compound in which is a hydrogen atom and B is the base portion of a nucleic acid, and the compound used in this manufacturing method.

[0048] In one embodiment of the above-described specification, in steps 1 to 11, R in formulas (I) to (XIII) 1 is a benzyl group, a 4,4'-dimethoxytrityl group, or an acetyl group. R 2 R is a benzyl group, a 4,4'-dimethoxytrityl group, or an acetyl group. 3 and R 4 is R 3 and R 4 It is an isopropylidene ketal group formed by the combination of R 3a and R 4a is an acetyl group, R 5R is a benzyloxycarbonyl group, an acetyl group, a 4-methoxybenzyl group, or an allyl group. 6 R is a hydrogen atom, 7 A manufacturing method comprising one or more steps 1 to 11 using a compound in which is a hydrogen atom and B is adeninyl, guaninyl, 2,6-diaminopurinyl, thyminyl, dihydrothyminyl, 2-thiothyminyl, cytosycinyl, 5-methylcytosycinyl, uracinyl, dihydrouracil, 5-fluorocytosycinyl, xanthinyl, 6-aminopurinyl, 2-aminopurinyl, 6-chloro-2-aminopurinyl, or 6-chloropurinyl, and the compound used in this manufacturing method.

[0049] In one embodiment of the above-described specification, in steps 1 to 11, R in formulas (I) to (XIII) 1 is a benzyl group, a 4,4'-dimethoxytrityl group, or an acetyl group. R 2 R is a benzyl group, a 4,4'-dimethoxytrityl group, or an acetyl group. 3 and R 4 is R 3 and R 4 It is an isopropylidene ketal group formed by the combination of R 3a and R 4a is an acetyl group, R 5 R is a benzyloxycarbonyl group, an acetyl group, a 4-methoxybenzyl group, or an allyl group. 6 R is a hydrogen atom, 7 A manufacturing method comprising one or more steps 1 to 11 using a compound in which is a hydrogen atom and B is thyminyl, and the compound used in this manufacturing method.

[0050] As one embodiment of the above-described specification, in steps 1 to 3 and steps 9 to 11, in formulas (I) to (XIII), R 1 R is a protecting group for hydroxyl groups, 2 R is a protecting group for hydroxyl groups, 3 and R 4 is R 3and R 4 It is a cyclic protecting group of a diol formed by the combination of R 3a and R 4a R is an acyl group, 5 and R 6 R is a protecting group for amino groups, 7 A manufacturing method comprising one or more steps 1-3 and 9-11 using a compound in which is an alkyl group or hydrogen atom and B is the base portion of a nucleic acid, and the compound used in this manufacturing method.

[0051] As one embodiment of the above-described specification, in steps 1 to 3 and steps 9 to 11, in formulas (I) to (XIII), R 1 R is a protecting group for hydroxyl groups, 2 R is a protecting group for hydroxyl groups, 3 and R 4 is R 3 and R 4 It is a cyclic protecting group of a diol formed by the combination of R 3a and R 4a is an acetyl group, R 5 R is a protecting group for amino groups, 6 R is a hydrogen atom, 7 A manufacturing method comprising one or more steps 1-3 and 9-11 using a compound in which is a hydrogen atom and B is the base portion of a nucleic acid, and the compound used in this manufacturing method.

[0052] In one embodiment of the above-described specification, in steps 1 to 3 and steps 9 to 11, In formulas (I) to (XIII), R 1 The group is a benzyl group, a 4,4'-dimethoxytrityl group, t -Butyldimethylsilyl group, t-butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethylsilyl)ethoxymethyl group, 2- R is a methoxyethoxymethyl group, a cyanoethyl group, a benzoyl group, or an acetyl group. 2 The group is benzyl group, 4,4'-dimethoxytrityl group, t-butyldimethylsilyl group, t- Butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethylsilyl)ethoxymethyl group, 2-methoxyethoxymethyl group, shea It is a noethyl group, a benzoyl group, or an acetyl group, R 3 and R 4 is R 3 and R 4 The group formed together is an isopropylidene ketal group, a methylene acetal group, an ethylidene acetal group, a benzylidene acetal group, a 4-methoxybenzylidene acetal group, or a 1-benzyloxybenzylidene orthoester group, and R 3a and R 4a is an acetyl group, R 5 R is a benzyloxycarbonyl group, isobutyryl group, benzoyl group, t-butoxycarbonyl group, trimethylsilylethoxycarbonyl group, allyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, acetyl group, formyl group, trifluoroacetyl group, 4-methoxybenzyl group, allyl group, benzyl group, or 2-nitrobenzenesulfonyl group. 6 R is a hydrogen atom, 7 A manufacturing method comprising one or more steps 1-3 and 9-11 using a compound in which is a hydrogen atom and B is the base portion of a nucleic acid, and the compound used in this manufacturing method.

[0053] As one embodiment of the above-described specification, in steps 1 to 3 and steps 9 to 11, in formulas (I) to (XIII), R 1 The benzyl group, the 4,4'-dimethoxytrityl group, and is an acetyl group, R 2 These are benzyl groups, 4,4'-dimethoxytrityl groups, or acetone groups. It is a chill group, R 3 and R 4 is R 3 and R 4 It is an isopropylidene ketal group formed by the combination of R 3a and R 4a is an acetyl group, R5 R is a benzyloxycarbonyl group, an acetyl group, a 4-methoxybenzyl group, or an allyl group. 6 is hydrogen It is an atom, R 7 A manufacturing method comprising one or more steps 1-3 and 9-11 using a compound in which is a hydrogen atom and B is the base portion of a nucleic acid, and the compound used in this manufacturing method.

[0054] As one embodiment of the above-described specification, in steps 1 to 3 and steps 9 to 11, in formulas (I) to (XIII), R 1 The benzyl group, the 4,4'-dimethoxytrityl group, and is an acetyl group, R 2 These are benzyl groups, 4,4'-dimethoxytrityl groups, or acetone groups. It is a chill group, R 3 and R 4 is R 3 and R 4 It is an isopropylidene ketal group formed by the combination of R 3a and R 4a is an acetyl group, R 5 R is a benzyloxycarbonyl group, an acetyl group, a 4-methoxybenzyl group, or an allyl group. 6 is hydrogen It is an atom, R 7 A manufacturing method comprising one or more steps of steps 1 to 3 and 9 to 11 using a compound in which is a hydrogen atom and B is adeninyl, guaninyl, 2,6-diaminopurinyl, thyminyl, dihydrothyminyl, 2-thiothyminyl, cytosycinyl, 5-methylcytosycinyl, uracinyl, dihydrouracil, 5-fluorocytosycinyl, xanthinyl, 6-aminopurinyl, 2-aminopurinyl, 6-chloro-2-aminopurinyl, or 6-chloropurinyl, and the compound used in this manufacturing method.

[0055] As one embodiment of the above-described specification, in steps 1 to 3 and steps 9 to 11, in formulas (I) to (XIII), R 1 The benzyl group, the 4,4'-dimethoxytrityl group, and is an acetyl group, R 2 These are benzyl groups, 4,4'-dimethoxytrityl groups, or acetone groups. It is a chill group, R 3 and R 4 is R 3 and R 4 It is an isopropylidene ketal group formed by the combination of R 3a and R 4a is an acetyl group, R 5 R is a benzyloxycarbonyl group, an acetyl group, a 4-methoxybenzyl group, or an allyl group. 6 is hydrogen It is an atom, R 7 Steps 1-3 using a compound in which is a hydrogen atom and B is thyminyl A manufacturing method comprising one or more steps 9 to 11, and the compound used in this manufacturing method.

[0056] As one embodiment of the above-described model, in steps 1 to 14, 15-1 and 15-2 of this specification, in formulas (I) to (XI), formula (XII'), formula (XIII'), formula (XIV) to (XVII), formula (XVII'), and formula (XVII''), R 1 R is a protecting group for hydroxyl groups, 1a R is a protecting group for hydroxyl groups, 2 R is a protecting group for hydroxyl groups, 3 and R 4 is R 3 and R 4 It is a cyclic protecting group of a diol formed by the combination of R 3a and R 4a R is an acyl group, 5 and R 6 R is a protecting group for amino groups, 7 R is an alkyl group or a hydrogen atom, 11 R is an alkyl group, 12 R is a hydrogen atom, alkyl group, alkoxy group, or alkoxyalkyl group, 14 X is a protecting group for a hydrogen atom or an amino group, and X is an oxygen atom or NR 13 (R 13(where represents a protecting group for a hydrogen atom or an amino group), and the double line consisting of a solid line and a dotted line represents a manufacturing method comprising one or more steps of steps 1 to 14, 15-1 and 15-2 using a compound that has a single bond or a double bond, and the compound used in this manufacturing method.

[0057] As one embodiment of the above-described model, in steps 1 to 14, 15-1 and 15-2 of this specification, in formulas (I) to (XI), formula (XII'), formula (XIII'), formula (XIV) to (XVII), formula (XVII'), and formula (XVII''), R 1 R is a protecting group for hydroxyl groups, 1a R is a protecting group for hydroxyl groups, 2 R is a protecting group for hydroxyl groups, 3 and R 4 is R 3 and R 4 It is a cyclic protecting group of a diol formed by the combination of R 3a and R 4a is an acetyl group, R 5 R is a protecting group for amino groups, 6 R is a hydrogen atom, 7 R is a hydrogen atom, 11 R is an alkyl group, 12 R is a hydrogen atom or a methyl group, 14 A manufacturing method comprising one or more steps, steps 1 to 14, 15-1 and 15-2, using a compound in which is a protecting group for a hydrogen atom or an amino group, X is an oxygen atom, and the double line consisting of a solid and a dotted line represents a double bond, and the compound used in this manufacturing method.

[0058] As one embodiment of the above-described model, in steps 1 to 14, 15-1 and 15-2 of this specification, in formulas (I) to (XI), formula (XII'), formula (XIII'), formula (XIV) to (XVII), formula (XVII'), and formula (XVII''), R 1 The group consists of a benzyl group, a 4,4'-dimethoxytrityl group, a t-butyldimethylsilyl group, and a t-butyldiphenylsilyl group. methyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethyl The group is a lucilyl)ethoxymethyl group, a 2-methoxyethoxymethyl group, a cyanoethyl group, a benzoyl group, or an acetyl group, R 1a The benzyl group, the 4,4'-dimethoxytrityl group, The group is t-butyldimethylsilyl, t-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl, or acetyl. R 2 The group is benzyl, 4,4'-dimethoxytrityl, t-butyldimethylsilyl, t -Butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethylsilyl)ethoxymethyl group, 2-methoxyethoxymethyl group, sil R is an anoethyl group, a benzoyl group, or an acetyl group. 3 and R 4 is R 3 and R 4 The group formed together is an isopropylidene ketal group, a methylene acetal group, an ethylidene acetal group, a benzylidene acetal group, a 4-methoxybenzylidene acetal group, or a 1-benzyloxybenzylidene orthoester group, and R 3a and R 4a is an acetyl group, R 5 R is a benzyloxycarbonyl group, isobutyryl group, benzoyl group, t-butoxycarbonyl group, trimethylsilylethoxycarbonyl group, allyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, acetyl group, formyl group, trifluoroacetyl group, 4-methoxybenzyl group, allyl group, benzyl group, or 2-nitrobenzenesulfonyl group. 6 R is a hydrogen atom, 7 R is a hydrogen atom, 11 R is a methyl group, 12 is a hydrogen atom or methyl It is a base, R 14A manufacturing method comprising one or more steps, steps 1 to 14, steps 15-1 and 15-2, using a compound in which is a benzyloxycarbonyl group, isobutyryl group, benzoyl group, t-butoxycarbonyl group, trimethylsilylethoxycarbonyl group, allyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, acetyl group, formyl group, trifluoroacetyl group, 4-methoxybenzyl group, allyl group, benzyl group or 2-nitrobenzenesulfonyl group, where X is an oxygen atom, and the double line consisting of a solid line and a dotted line represents a double bond, and the compound used in this manufacturing method.

[0059] As one embodiment of the above-described model, in steps 1 to 14, 15-1 and 15-2 of this specification, in formulas (I) to (XI), formula (XII'), formula (XIII'), formula (XIV) to (XVII), formula (XVII'), and formula (XVII''), R 1 R is a benzyl group, a 4,4'-dimethoxytrityl group, or an acetyl group. 1a R is a benzyl group, a 4,4'-dimethoxytrityl group, or an acetyl group. 2 The benzyl group is 4,4'-dimethoxy. It is a trityl group or an acetyl group, R 3 and R 4 is R 3 and R 4 It is an isopropylidene ketal group formed by the combination of R 3a and R 4a is an acetyl group, R 5 These are benzyloxycarbonyl groups, acetyl groups, 4-methoxybenzyl groups, or allyl groups. It is a base, R 6 R is a hydrogen atom, 7 R is a hydrogen atom, 11 R is a methyl group, 12 R is a hydrogen atom or a methyl group, 14 is a benzyloxycarbonyl group, an acetyl group, a 4-methoxybenzyl group, or an allyl group, and X is an oxygen atom, with solid lines and dots. The double line representing the line is a manufacturing method comprising one or more steps, steps 1-14, 15-1, and 15-2, using a compound that has a double bond, and the compound used in this manufacturing method.

[0060] As one embodiment of the above-described model, in steps 1 to 14, 15-1 and 15-2 of this specification, in formulas (I) to (XI), formula (XII'), formula (XIII'), formula (XIV) to (XVII), formula (XVII'), and formula (XVII''), R 1 R is a benzyl group, a 4,4'-dimethoxytrityl group, or an acetyl group. 1a R is a benzyl group, a 4,4'-dimethoxytrityl group, or an acetyl group. 2 The benzyl group is 4,4'-dimethoxy. It is a trityl group or an acetyl group, R 3 and R 4 is R 3 and R 4 It is an isopropylidene ketal group formed by the combination of R 3a and R 4a is an acetyl group, R 5 These are benzyloxycarbonyl groups, acetyl groups, 4-methoxybenzyl groups, or allyl groups. It is a base, R 6 R is a hydrogen atom, 7 R is a hydrogen atom, 11 R is a methyl group, 12 R is a methyl group, 14 It consists of a benzyloxycarbonyl group, an acetyl group, and a 4-methoxyb A manufacturing method comprising one or more steps, steps 1 to 14, 15-1, and 15-2, using a compound that is an oxyl group or an allyl group, where X is an oxygen atom, and the double line consisting of a solid line and a dotted line represents a double bond, and the compound used in this manufacturing method.

[0061] As one embodiment of the above embodiment, in steps 1 to 3, 9 to 14, 15-1 and 15-2 of this specification, in formulas (I) to (XI), formula (XII'), formula (XIII'), formula (XIV) to (XVII), formula (XVII'), and formula (XVII''), R1 R is a protecting group for hydroxyl groups, 1a R is a protecting group for hydroxyl groups, 2 R is a protecting group for hydroxyl groups, 3 and R 4 is R 3 and R 4 It is a cyclic protecting group of a diol formed by the combination of R 3a and R 4a R is an acyl group, 5 and R 6 R is a protecting group for amino groups, 7 R is an alkyl group or a hydrogen atom, 11 R is an alkyl group, 12 R is a hydrogen atom, alkyl group, alkoxy group, or alkoxyalkyl group, 14 X is a protecting group for a hydrogen atom or an amino group, and X is an oxygen atom or NR 13 (R 13 (where represents a protecting group for a hydrogen atom or an amino group), and the double line consisting of a solid line and a dotted line represents a manufacturing method comprising one or more steps of steps 1-3, 9-14, 15-1 and 15-2 using a compound that has a single bond or a double bond, and the compound used in this manufacturing method.

[0062] As one embodiment of the above embodiment, in steps 1 to 3, 9 to 14, 15-1 and 15-2 of this specification, in formulas (I) to (XI), formula (XII'), formula (XIII'), formula (XIV) to (XVII), formula (XVII'), and formula (XVII''), R 1 R is a protecting group for hydroxyl groups, 1a R is a protecting group for hydroxyl groups, 2 R is a protecting group for hydroxyl groups, 3 and R 4 is R 3 and R 4 It is a cyclic protecting group of a diol formed by the combination of R 3a and R 4a is an acetyl group, R 5 R is a protecting group for amino groups, 6 R is a hydrogen atom, 7 R is a hydrogen atom, 11 R is an alkyl group,12 R is a hydrogen atom or a methyl group, 14 A manufacturing method comprising one or more steps, steps 1-3, 9-14, 15-1, and 15-2, using a compound in which is a protecting group for a hydrogen atom or an amino group, X is an oxygen atom, and the double line consisting of a solid and a dotted line represents a double bond, and the compound used in this manufacturing method.

[0063] As one embodiment of the above embodiment, in steps 1 to 3, 9 to 14, 15-1 and 15-2 of this specification, in formulas (I) to (XI), formula (XII'), formula (XIII'), formula (XIV) to (XVII), formula (XVII'), and formula (XVII''), R 1 The group consists of a benzyl group, a 4,4'-dimethoxytrityl group, a t-butyldimethylsilyl group, and a t-butyldiphosphate group. Nylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-( The group is trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl, or acetyl. 1a The benzyl group, 4,4'-dimethoxytri Tyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethylsilyl)ethoxymethyl group, 2-methoxyethoxymethyl group, cyanoethyl group, benzoyl group or acetyl group And R 2 It consists of a benzyl group, a 4,4'-dimethoxytrityl group, and a t-butyldimethylsilicone group. t-butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethylsilyl)ethoxymethyl group, 2-methoxyethoxymethyl R is a cyanoethyl group, a benzoyl group, or an acetyl group. 3 and R 4 is R 3 and R 4The group formed together is an isopropylidene ketal group, a methylene acetal group, an ethylidene acetal group, a benzylidene acetal group, a 4-methoxybenzylidene acetal group, or a 1-benzyloxybenzylidene orthoester group, and R 3a and R 4a is an acetyl group, R 5 R is a benzyloxycarbonyl group, isobutyryl group, benzoyl group, t-butoxycarbonyl group, trimethylsilylethoxycarbonyl group, allyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, acetyl group, formyl group, trifluoroacetyl group, 4-methoxybenzyl group, allyl group, benzyl group, or 2-nitrobenzenesulfonyl group. 6 R is a hydrogen atom, 7 R is a hydrogen atom, 11 R is a methyl group, 12 R is a hydrogen atom or a methyl group, 14 A manufacturing method comprising one or more steps 1-3, 9-14, 15-1, and 15-2 using a compound in which is a benzyloxycarbonyl group, isobutyryl group, benzoyl group, t-butoxycarbonyl group, trimethylsilylethoxycarbonyl group, allyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, acetyl group, formyl group, trifluoroacetyl group, 4-methoxybenzyl group, allyl group, benzyl group, or 2-nitrobenzenesulfonyl group, where X is an oxygen atom, and the double line consisting of a solid line and a dotted line represents a double bond, and the compound used in this manufacturing method.

[0064] As one embodiment of the above embodiment, in steps 1 to 3, 9 to 14, 15-1 and 15-2 of this specification, in formulas (I) to (XI), formula (XII'), formula (XIII'), formula (XIV) to (XVII), formula (XVII'), and formula (XVII''), R 1 R is a benzyl group, a 4,4'-dimethoxytrityl group, or an acetyl group. 1a is a benzyl group, 4 ,4'-dimethoxytrityl group or acetyl group, R 2 The benzyl group is 4,4'-di It is a methoxytrityl group or an acetyl group, R 3 and R 4 is R 3 and R 4 It is an isopropylidene ketal group formed by the combination of R 3a and R 4a is an acetyl group, R 5 The benzyloxycarbonyl group, acetyl group, 4-methoxybenzyl group and It is an allyl group, R 6 R is a hydrogen atom, 7 R is a hydrogen atom, 11 R is a methyl group, 12 R is a hydrogen atom or a methyl group, 14 is a benzyloxycarbonyl group, an acetyl group, a 4-methoxybenzyl group, or an allyl group, and X is an oxygen atom. The double line, consisting of a line and a dotted line, represents a manufacturing method comprising one or more steps, such as steps 1-3, 9-14, 15-1, and 15-2, using a compound that has a double bond, and also includes the compound used in this manufacturing method.

[0065] As one embodiment of the above embodiment, in steps 1 to 3, 9 to 14, 15-1 and 15-2 of this specification, in formulas (I) to (XI), formula (XII'), formula (XIII'), formula (XIV) to (XVII), formula (XVII'), and formula (XVII''), R 1 R is a benzyl group, a 4,4'-dimethoxytrityl group, or an acetyl group. 1a is a benzyl group, 4 ,4'-dimethoxytrityl group or acetyl group, R 2 R is a benzyl group, a 4,4'-dimethoxytrityl group, or an acetyl group. 3 and R 4 is R 3 and R 4 It is an isopropylidene ketal group formed by the combination of R 3a and R 4ais an acetyl group, R 5 The benzyloxycarbonyl group, acetyl group, 4-methoxybenzyl group and It is an allyl group, R 6 R is a hydrogen atom, 7 R is a hydrogen atom, 11 R is a methyl group, 12 R is a methyl group, 14 It is a benzyloxycarbonyl group, an acetyl group, A manufacturing method comprising one or more steps, steps 1-3, 9-14, 15-1, and 15-2, using a compound that is a 4-methoxybenzyl group or an allyl group, where X is an oxygen atom, and the double line consisting of a solid line and a dotted line represents a double bond, and the compound used in this manufacturing method.

[0066] In one embodiment of the above-described specification, in steps 16 to 18, in formulas (I), (IV'), (XVIII) to (XX), R 1 R is a protecting group for hydroxyl groups, 2 R is a protecting group for hydroxyl groups, 3 and R 4 is R 3 and R 4 It is a cyclic protecting group of a diol formed by the combination of R 5 R is a protecting group for amino groups, 8 This includes a manufacturing method comprising one or more steps 16 to 18 using a compound that is an alkoxy group, and the compound used in this manufacturing method.

[0067] In one embodiment of the above-described specification, in steps 16 to 18, in formulas (I), (IV'), (XVIII) to (XX), R 1 R is a protecting group for hydroxyl groups, 2 R is a protecting group for hydroxyl groups, 3 and R 4 is R 3 and R 4 It is a cyclic protecting group of a diol formed by the combination of R 5 R is a protecting group for amino groups, 8This includes a manufacturing method comprising one or more steps 16 to 18 using a compound having a methoxy group in the para position, and the compound used in this manufacturing method.

[0068] In one embodiment of the above-described specification, in steps 16 to 18, in formulas (I), (IV'), (XVIII) to (XX), R 1 The benzyl group is 4,4'-dimethoxy. Trityl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethylsilyl)ethoxymethyl group, 2-methoxyethoxymethyl group, cyanoethyl group, benzoyl group or acetyl It is a group, R 2 These are benzyl group, 4,4'-dimethoxytrityl group, and t-butyldimethyl Silyl group, t-butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethylsilyl)ethoxymethyl group, 2-methoxyethoxy R is a methyl group, cyanoethyl group, benzoyl group, or acetyl group. 3 and R 4 is R 3 and R 4 Together, these are formed an isopropylidene ketal group, a methylene acetal group, an ethylidene acetal group, a benzylidene acetal group, and 4-methoxybenzylidene It is an acetal group or a 1-benzyloxybenzylidene orthoester group, R 5 R is a benzyloxycarbonyl group, isobutyryl group, benzoyl group, t-butoxycarbonyl group, trimethylsilylethoxycarbonyl group, allyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, acetyl group, formyl group, trifluoroacetyl group, 4-methoxybenzyl group, allyl group, benzyl group, or 2-nitrobenzenesulfonyl group. 8 This includes a manufacturing method comprising one or more steps 16 to 18 using a compound having a methoxy group in the para position, and the compound used in this manufacturing method.

[0069] As one embodiment of the above-described specification, in steps 16 to 18, in formulas (I), (IV'), and (XVIII) to (XX), R 1 The benzyl group, 4,4'-dimethyl It is a xytrityl group or an acetyl group, R 2 The benzyl group, 4,4'-dimethoxytri It is a til group or an acetyl group, R 3 and R 4 is R 3 and R 4 It is an isopropylidene ketal group formed by the combination of R 5 R is a benzyloxycarbonyl group, an acetyl group, a 4-methoxybenzyl group, or an allyl group. 8 This includes a manufacturing method comprising one or more steps 16 to 18 using a compound having a methoxy group in the para position, and the compound used in this manufacturing method.

[0070] As one embodiment of the above-described specification, in steps 19 to 21, in formulas (I), (IV), and (XXI) to (XXIII), R 1 R is a protecting group for hydroxyl groups, 2 R is a protecting group for hydroxyl groups, 3 and R 4 is R 3 and R 4 It is a cyclic protecting group of a diol formed by the combination of R 5 and R 6 R is a protecting group for amino groups, 9 R is an alkyl group or a hydrogen atom, 10 This includes a manufacturing method comprising one or more steps 19 to 21 using a compound that is an alkyl group or a hydrogen atom, and the compound used in this manufacturing method.

[0071] As one embodiment of the above-described specification, in steps 19 to 21, in formulas (I), (IV), and (XXI) to (XXIII), R 1 R is a protecting group for hydroxyl groups, 2 R is a protecting group for hydroxyl groups,3 and R 4 is R 3 and R 4 It is a cyclic protecting group of a diol formed by the combination of R 5 R is a protecting group for amino groups, 6 R is a hydrogen atom, 9 R is a hydrogen atom, 10 This includes a manufacturing method comprising one or more steps 19 to 21 using a compound that is a hydrogen atom, and the compound used in this manufacturing method.

[0072] As one embodiment of the above-described specification, in steps 19 to 21, in formulas (I), (IV), and (XXI) to (XXIII), R 1 The benzyl group, 4,4'-dimethyl Xytrityl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethylsilyl)ethoxymethyl group, 2-methoxyethoxymethyl group, cyanoethyl group, benzoyl group or It is a cetyl group, R 2 The group consists of a benzyl group, a 4,4'-dimethoxytrityl group, and a t-butyl dimethyl group. t-butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethylsilyl)ethoxymethyl group, 2-methoxyeth R is a ximethyl group, a cyanoethyl group, a benzoyl group, or an acetyl group. 3 and R 4 is R 3 and R 4 The group formed together is an isopropylidene ketal group, a methylene acetal group, an ethylidene acetal group, a benzylidene acetal group, a 4-methoxybenzylidene acetal group, or a 1-benzyloxybenzylidene orthoester group, and R 5R is a benzyloxycarbonyl group, isobutyryl group, benzoyl group, t-butoxycarbonyl group, trimethylsilylethoxycarbonyl group, allyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, acetyl group, formyl group, trifluoroacetyl group, 4-methoxybenzyl group, allyl group, benzyl group, or 2-nitrobenzenesulfonyl group. 6 R is a hydrogen atom, 9 R is a hydrogen atom, 10 This is a manufacturing process that includes one or more steps from steps 19 to 21 using a compound that is a hydrogen atom. The method and the compound used in this manufacturing method are included.

[0073] As one embodiment of the above-described specification, in steps 19 to 21, in formulas (I), (IV), and (XXI) to (XXIII), R 1 The benzyl group, 4,4'-dimethyl It is a xytrityl group or an acetyl group, R 2 The benzyl group, 4,4'-dimethoxytri It is a til group or an acetyl group, R 3 and R 4 is R 3 and R 4 It is an isopropylidene ketal group formed by the combination of R 5 R is a benzyloxycarbonyl group, an acetyl group, a 4-methoxybenzyl group, or an allyl group. 6 R is a hydrogen atom, 9 is hydrogen It is an atom, R 10 This includes a manufacturing method comprising one or more steps 19 to 21 using a compound that is a hydrogen atom, and the compound used in this manufacturing method.

[0074] <Another embodiment of the compound> Another embodiment of the above embodiment compound is, in formula (IV), R 1 R is a protecting group for hydroxyl groups, 2 The group is benzyl, 4,4'-dimethoxytrityl, t-butyldimethylsilyl, t -Butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethylsilyl)ethoxymethyl group, 2-methoxyethoxymethyl group, sil R is an anoethyl group, a benzoyl group, or an acetyl group. 3 and R 4 is R 3 and R 4 It is a cyclic protecting group of a diol formed by the combination of R 5 and R 6 It contains compounds that are protecting groups for amino groups.

[0075] Another embodiment of the above embodiment compound is, in formula (IV), R 1 R is a protecting group for hydroxyl groups, 2 The group is benzyl, 4,4'-dimethoxytrityl, t-butyldimethylsilyl, t -Butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethylsilyl)ethoxymethyl group, 2-methoxyethoxymethyl group, sil R is an anoethyl group, a benzoyl group, or an acetyl group. 3 and R 4 is R 3 and R 4 It is a cyclic protecting group of a diol formed by the combination of R 5 R is a protecting group for amino groups, 6 It contains a compound that is a hydrogen atom.

[0076] Another embodiment of the above embodiment compound is, in formula (IV), R 1 The benzyl group, 4,4'- Dimethoxytrityl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethylsilyl R) is an ethoxymethyl group, a 2-methoxyethoxymethyl group, a cyanoethyl group, a benzoyl group, or an acetyl group. 2 The group consists of a benzyl group, a 4,4'-dimethoxytrityl group, and a t-butyl group. Dimethylsilyl group, t-butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethylsilyl)ethoxymethyl group, 2-methoxy The group is a thyethoxymethyl group, a cyanoethyl group, a benzoyl group, or an acetyl group, R 3 and R 4 is R 3 and R 4 The group formed together is an isopropylidene ketal group, a methylene acetal group, an ethylidene acetal group, a benzylidene acetal group, a 4-methoxybenzylidene acetal group, or a 1-benzyloxybenzylidene orthoester group, and R 5 R is a benzyloxycarbonyl group, isobutyryl group, benzoyl group, t-butoxycarbonyl group, trimethylsilylethoxycarbonyl group, allyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, acetyl group, formyl group, trifluoroacetyl group, 4-methoxybenzyl group, allyl group, benzyl group, or 2-nitrobenzenesulfonyl group. 6 It contains a compound that is a hydrogen atom.

[0077] Another embodiment of the above embodiment compound is, in formula (IV), R 1 The benzyl group, 4,4'- It is a dimethoxytrityl group or an acetyl group, R 2 The benzyl group, 4,4'-dimethyl It is a xytrityl group or an acetyl group, R 3 and R 4 is R 3 and R 4 It is an isopropylidene ketal group formed by the combination of R 5 is a benzyloxycarbonyl group, a The group is a cetyl group, a 4-methoxybenzyl group, or an allyl group, R 6 is a compound of hydrogen atoms Includes objects.

[0078] Another embodiment of the above embodiment compound is, in formula (XIII), R1 The group is benzyl, 4,4'-dimethoxytrityl, t-butyldimethylsilyl, t-butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethyl The group is a silyl)ethoxymethyl group, a 2-methoxyethoxymethyl group, a cyanoethyl group, a benzoyl group, or an acetyl group, and R 2 R is a protecting group for hydroxyl groups, 5 and R 6 B is a protecting group for amino groups, and B contains compounds that are the base portion of nucleic acids.

[0079] Another embodiment of the above embodiment compound is, in formula (XIII), R 1 The group is benzyl, 4,4'-dimethoxytrityl, t-butyldimethylsilyl, t-butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethyl The group is a silyl)ethoxymethyl group, a 2-methoxyethoxymethyl group, a cyanoethyl group, a benzoyl group, or an acetyl group, and R 2 R is a protecting group for hydroxyl groups, 5 R is a protecting group for amino groups, 6 is a hydrogen atom, and B contains compounds that are the base portion of nucleic acids.

[0080] Another embodiment of the above embodiment compound is, in formula (XIII), R 1 The group is benzyl, 4,4'-dimethoxytrityl, t-butyldimethylsilyl, t-butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethyl The group is a silyl)ethoxymethyl group, a 2-methoxyethoxymethyl group, a cyanoethyl group, a benzoyl group, or an acetyl group, and R 2 The benzyl group, 4,4'-dimethoxytrityl group, t- Butyldimethylsilyl group, t-butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethylsilyl)ethoxymethyl group, 2-methyl R is a toxicethoxymethyl group, a cyanoethyl group, a benzoyl group, or an acetyl group. 5 R is a benzyloxycarbonyl group, isobutyryl group, benzoyl group, t-butoxycarbonyl group, trimethylsilylethoxycarbonyl group, allyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, acetyl group, formyl group, trifluoroacetyl group, 4-methoxybenzyl group, allyl group, benzyl group, or 2-nitrobenzenesulfonyl group. 6 is a hydrogen atom, and B contains compounds that are the base portion of nucleic acids.

[0081] Another embodiment of the above embodiment compound is, in formula (XIII), R 1 R is a benzyl group, a 4,4'-dimethoxytrityl group, or an acetyl group. 2 R is a benzyl group, a 4,4'-dimethoxytrityl group, or an acetyl group. 5 R is a benzyloxycarbonyl group, an acetyl group, a 4-methoxybenzyl group, or an allyl group. 6 is a hydrogen atom, and B is the nucleus It contains compounds that are the base portion of an acid.

[0082] Another embodiment of the above embodiment compound is, in formula (XIII), R 1 R is a benzyl group, a 4,4'-dimethoxytrityl group, or an acetyl group. 2 R is a benzyl group, a 4,4'-dimethoxytrityl group, or an acetyl group. 5 R is a benzyloxycarbonyl group, an acetyl group, a 4-methoxybenzyl group, or an allyl group. 6The compounds include those in which B is a hydrogen atom, and B is adeninyl, guaninyl, 2,6-diaminopurinyl, thyminyl, dihydrothyminyl, 2-thiothyminyl, cytosycinyl, 5-methylcytosycinyl, uracinyl, dihydrouracil, 5-fluorocytosycinyl, xanthinyl, 6-aminopurinyl, 2-aminopurinyl, 6-chloro-2-aminopurinyl, or 6-chloropurinyl.

[0083] Another embodiment of the above embodiment compound is, in formula (XIII), R 1 R is a benzyl group, a 4,4'-dimethoxytrityl group, or an acetyl group. 2 is a benzyl group, a 4,4'-dimethoxytrityl group or an acetyl group, R 5 It consists of a benzyloxycarbonyl group, an acetyl group, and a 4- Methoxybenzyl group or allyl group, R 6 The compound contains a hydrogen atom and B is thyminyl.

[0084] Another embodiment of the above embodiment compound is, in formula (XVI), R 1 R is a protecting group for hydroxyl groups, 2 R is a protecting group for hydroxyl groups, 12 R is a hydrogen atom, alkyl group, alkoxy group, or alkoxyalkyl group, 14 X is a hydrogen atom, benzyloxycarbonyl group, isobutyryl group, benzoyl group, t-butoxycarbonyl group, trimethylsilylethoxycarbonyl group, allyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, acetyl group, formyl group, trifluoroacetyl group, 4-methoxybenzyl group, allyl group, benzyl group, or 2-nitrobenzenesulfonyl group, and X is an oxygen atom or NR 13 (R 13 (where represents a protecting group for a hydrogen atom or an amino group), and double lines consisting of solid and dotted lines include compounds with single or double bonds.

[0085] Another embodiment of the above embodiment compound is, in formula (XVI), R 1 R is a protecting group for hydroxyl groups, 2R is a protecting group for hydroxyl groups, 12 R is a hydrogen atom or a methyl group, 14 X is a hydrogen atom, benzyloxycarbonyl group, isobutyryl group, benzoyl group, t-butoxycarbonyl group, trimethylsilylethoxycarbonyl group, allyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, acetyl group, formyl group, trifluoroacetyl group, 4-methoxybenzyl group, allyl group, benzyl group, or 2-nitrobenzenesulfonyl group, X is an oxygen atom, and the double line consisting of a solid line and a dotted line contains compounds with a double bond.

[0086] Another embodiment of the above embodiment compound is, in formula (XVI), R 1 The benzyl group is 4,4' -Dimethoxytrityl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethylsilyl R is a lyl-ethoxymethyl group, a 2-methoxyethoxymethyl group, a cyanoethyl group, a benzoyl group, or an acetyl group. 2 The group is benzyl, 4,4'-dimethoxytrityl, t- t-butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethylsilyl)ethoxymethyl group, 2-meth R is a xyethoxymethyl group, a cyanoethyl group, a benzoyl group, or an acetyl group. 12 R is a hydrogen atom or a methyl group, 14 The group is a benzyloxycarbonyl group, isobutyryl group, benzoyl group, t-butoxycarbonyl group, trimethylsilylethoxycarbonyl group, allyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, acetyl group, formyl group, trifluoroacetyl group, 4-methoxybenzyl group, allyl group, benzyl group, or 2-nitrobenzenesulfonyl group, where X is an oxygen atom, and the double line consisting of a solid and a dotted line contains compounds with a double bond.

[0087] Another embodiment of the above embodiment compound is, in formula (XVI), R 1 The benzyl group is 4,4' - Dimethoxytrityl group or acetyl group, R 2 The benzyl group, 4,4'-dimethyl It is a xytrityl group or an acetyl group, R 12 R is a hydrogen atom or a methyl group, 14 These are benzyloxycarbonyl groups, acetyl groups, 4-methoxybenzyl groups, or allyl groups. The diagram includes compounds where X is an oxygen atom, and the double lines, consisting of solid and dotted lines, represent double bonds.

[0088] Another embodiment of the above embodiment compound is, in formula (XVI), R 1 The benzyl group is 4,4' - Dimethoxytrityl group or acetyl group, R 2 The benzyl group, 4,4'-dimethyl It is a xytrityl group or an acetyl group, R 12 R is a methyl group, 14 is a benzyloxycarbonyl group, an acetyl group, a 4-methoxybenzyl group, or an allyl group, and X is The double line, consisting of a solid and a dotted line, represents an oxygen atom and includes compounds with a double bond.

[0089] <Manufacturing method> The above manufacturing method will be described in detail below. In this specification, compounds represented by formula (I), compounds represented by formula (II), etc., are also referred to as compounds of formula (I), compounds of formula (II), etc., or compounds of a certain formula.

[0090] (1) Method for producing the compound represented by formula (IV) The compound represented by formula (IV) can be prepared as follows. [ka] (In the formula, each symbol has the same meaning as above.)

[0091] <Process 1> This step involves subjecting the compound of formula (I) and the compound of formula (V) or a salt thereof (such as hydrochloride, sulfate, or phosphate, preferably hydrochloride) to an oximation reaction in a suitable solvent to obtain the compound of formula (II). Any solvent that does not affect this reaction can be used, such as aromatic hydrocarbons (benzene, toluene, xylene, etc.), aprotic polar solvents (N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, etc.), nitriles (acetonitrile, etc.), ketones (acetone, methyl ethyl ketone, etc.), esters (ethyl acetate, isopropyl acetate, etc.), ethers (diethyl ether, tetrahydrofuran, dimethoxyethane, etc.), halogenated solvents (dichloromethane, chloroform, etc.), alcohols (methanol, ethanol, isopropanol, etc.), etc., and these can also be used in appropriate combinations. When using a salt of the compound of formula (V), the reaction can be carried out in the presence of a base. Examples of bases include pyridine, sodium acetate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, and potassium bicarbonate, with pyridine being preferred. The solvent is the same as described above. Furthermore, when using a salt of the compound of formula (V), if a combination of alcohols, tetrahydrofuran, and water, or N,N-dimethylformamide or dioxane is used as the solvent, it is not necessary to add a base. The amount of compound (V) or its salt used is preferably 1 to 3 times the molar equivalent of 1 mole of compound (I). The amount of base used is preferably 1 to 10 times the molar equivalent of 1 mole of compound (I). The reaction temperature is preferably 40°C to 80°C, and particularly preferably 50°C to 70°C.

[0092] <Process 2> This step involves subjecting the compound of formula (II) to a reduction reaction with a reducing agent in a suitable solvent to obtain the compound of formula (III). Any solvent that does not affect this reaction can be used, such as aromatic hydrocarbons (benzene, toluene, xylene, etc.), ethers (diethyl ether, tetrahydrofuran, dimethoxyethane, etc.), halogenated solvents (dichloromethane, chloroform, etc.), etc., and these can also be used in appropriate combinations. Of these, ethers are preferred, and tetrahydrofuran is more preferred. As a reducing agent, sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al ) or lithium aluminum hydride is preferred. Using sodium bis(2-methoxyethoxy)aluminum hydride is more preferable because the reaction proceeds without by-products. The amount of reducing agent used is preferably 2 to 3 times the molar equivalent of 1 mole of the compound of formula (II). The reaction temperature is preferably 20°C to 60°C, and particularly preferably 30°C to 50°C.

[0093] <Process 3> This step involves subjecting the compound of formula (III) to an amino group protection reaction in a suitable solvent to obtain the compound of formula (IV). The protection of amino groups can be carried out under reaction conditions commonly known in organic synthesis (e.g., nucleic acid synthesis), for example, Theodra W. Greene, Peter GM Wuts, “Protective Groups in Organic Synthesis” 4 th This can be carried out in accordance with the method described in . Ed. / John Wiley & Sons, Inc., 2007. For example, it can be carried out by using N-carbobenzooxysuccinimide in a solvent in the presence of a base. Any solvent that does not affect this reaction can be used, such as aromatic hydrocarbons (benzene, toluene, xylene, etc.), aprotic polar solvents (N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, etc.), nitriles (acetonitrile, etc.), ketones (acetone, methyl ethyl ketone, etc.), esters (ethyl acetate, isopropyl acetate, etc.), ethers (diethyl ether, tetrahydrofuran, dimethoxyethane, etc.), halogenated solvents (dichloromethane, chloroform, etc.), etc., and these can also be used in appropriate combinations. Of these, when sodium hydroxide is used as the base, esters, especially ethyl acetate, are preferred. When potassium carbonate is used as the base, ethers, especially tetrahydrofuran, are preferred. Examples of bases include basic inorganic salts such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, and potassium bicarbonate, with sodium hydroxide or potassium carbonate being preferred. The amount of base used should be such that the pH of the reaction solution becomes weakly basic. The amount of carbobenzooxyoxysuccinimide used is preferably 1 to 1.5 times the molar equivalent of 1 mole of the compound of formula (III). The reaction temperature is preferably between 0°C and 40°C, and particularly between 10°C and 30°C.

[0094] (2) Method for producing the compound of formula (I) The compound of formula (I) can be prepared as follows: [ka] (In the formula, each symbol has the same meaning as above.)

[0095] The compound of formula (VI) is commercially available, and steps 4-8 are carried out by known methods, for example, according to the method described in Kei Fukuyama et al., Org. Lett. 2015, 17, 828-831. It is possible.

[0096] (3) Method for producing a compound represented by formula (XIII) from a compound represented by formula (IV) The compound represented by formula (XIII) can be prepared from the compound represented by formula (IV) or formula (IV') as follows: [ka] (In the formula, each symbol has the same meaning as above.) The compound represented by formula (IV') is the R of the compound represented by formula (IV). 6 is a hydrogen atom It is a compound.

[0097] <Process 9> A compound of formula (IV) or formula (IV') is dissolved in a suitable solvent, R 3 and R 4 By subjecting it to a conversion reaction to an acyl group, R 3 and R 4 This is a step in which the compound is converted to an acyl group to obtain the compound of formula (XI). R 3 and R 4 The conversion reaction to the acyl group is described in J. Org. Chem. 2011, 76, 9891-9899 and W This can be done in accordance with the methods described in O2017 / 047816, etc. For example, the compound of formula (IV) can be prepared by reacting it with an acid catalyst in a suitable solvent in the presence of an acid anhydride. An acid may be added as needed. Any solvent that does not affect this reaction can be used, such as aromatic hydrocarbons (benzene, toluene, xylene, etc.), aprotic polar solvents (N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, etc.), nitriles (acetonitrile, etc.), ketones (acetone, methyl ethyl ketone, etc.), esters (ethyl acetate, isopropyl acetate, etc.), ethers (diethyl ether, tetrahydrofuran, dimethoxyethane, etc.), halogenated solvents (dichloromethane, chloroform, etc.), etc., and these can also be used in appropriate combinations. Of these, ethyl acetate is preferably used. As an acid anhydride, acetic anhydride is preferred, and the amount is preferably 1 to 10 times the molar equivalent of 1 mole of the compound of formula (IV). As an acid, acetic acid is preferred, and the amount is 1 to 1 mole of the compound of formula (IV). A 20-fold molar equivalent is preferable. As an acid catalyst, sulfuric acid is preferred, and the amount is preferably 0.01 to 0.20 times the molar equivalent of 1 mole of the compound of formula (IV). The reaction temperature is preferably between 10 and 40°C.

[0098] <Step 10> This process involves introducing the base portion of a nucleic acid into the compound of formula (XI) by subjecting it to a glycosylation reaction in a suitable solvent to obtain the compound of formula (XII). The introduction of the base portion of nucleic acids into the compound of formula (XI) by glycosylation reaction can be carried out in accordance with the methods described in J. Org. Chem. 2011, 76, 9891-9899 and WO2017 / 047816, etc. It is possible. For example, the compound of formula (XII) can be produced by reacting the compound of formula (XI) with N,O-bis(trimethylsilyl)acetamide and a nucleic acid base in a suitable solvent in the presence of trimethylsilyl trifluoromethanesulfonate. Nucleic acid bases include, for example, thymine (T). While thymine (T) is reacted as a nucleic acid base, by reacting it with another nucleic acid base instead of thymine (T), other nucleic acid bases can be used. Various nucleic acid bases can be introduced. Any solvent that does not affect this reaction can be used, such as aromatic hydrocarbons (benzene, toluene, xylene, etc.), aprotic polar solvents (N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, etc.), nitriles (acetonitrile, etc.), ketones (acetone, methyl ethyl ketone, etc.), esters (ethyl acetate, isopropyl acetate, etc.), ethers (diethyl ether, tetrahydrofuran, dimethoxyethane, etc.), halogenated solvents (dichloromethane, chloroform, etc.), etc., and these can also be used in appropriate combinations. Of these, acetonitrile is preferably used. The reaction temperature is preferably 60 to 100°C.

[0099] <Step 11> This step involves subjecting the compound of formula (XII) to a deprotection reaction of the acyl group in a suitable solvent to obtain the compound of formula (XIII). Deprotection reactions are described in J. Org. Chem. 2011, 76, 9891-9899 and WO2017 / 047816, etc. This can be done in accordance with the method described in [reference]. For example, deprotection reactions can be carried out in a suitable solvent in the presence of a base. Any solvent that does not affect this reaction can be used, such as aromatic hydrocarbons (benzene, toluene, xylene, etc.), aprotic polar solvents (N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, etc.), nitriles (acetonitrile, etc.), ketones (acetone, methyl ethyl ketone, etc.), esters (ethyl acetate, isopropyl acetate, etc.), ethers (diethyl ether, tetrahydrofuran, dimethoxyethane, etc.), halogenated solvents (dichloromethane, chloroform, etc.), alcohols (methanol, ethanol, isopropanol, etc.), etc., and these can also be used in appropriate combinations. Of these, alcohols (methanol, ethanol, etc.) are preferred. Methylamine is a suitable base. The amount of base used is preferably 3 to 30 times the molar equivalent of 1 mole of the compound of formula (XII). The reaction temperature is preferably between 0°C and 50°C, and particularly between 15°C and 30°C. Furthermore, this deprotection reaction can also be carried out by hydrolysis.

[0100] (4) Method for producing a compound represented by formula (XVII') or a compound represented by formula (XVII'') from a compound represented by formula (XIII'). The compound represented by formula (XVII') or the compound represented by formula (XVII'') can be prepared from the compound represented by formula (XIII') as follows. [ka] (In the formula, each symbol has the same meaning as above.) The compound represented by formula (XIII') is a compound in which B of the compound represented by formula (XIII) is Formula (XXIV): [ka] [In the formula, R 12 This represents a hydrogen atom, an alkyl group, an alkoxy group, or an alkoxyalkyl group. X is an oxygen atom or NR 13 (R 13 (This indicates a protecting group for a hydrogen atom or an amino group.) A double line consisting of a solid and a dotted line indicates a single or double bond. It is a compound represented by [formula]. The compound represented by formula (XVII') is the R of the compound represented by formula (XVII). 1 It is a compound in which the atom is a hydrogen atom. The compound represented by formula (XVII'') is the R of the compound represented by formula (XVII). 1 R 1a It is a compound that is [this compound].

[0101] <Step 12> This is a step to obtain the compound of formula (XIV) by subjecting the compound of formula (XIII') to a sulfonylation reaction in a suitable solvent. The sulfonylation reaction can be carried out according to the method described in WO2017 / 047816, etc. For example, the compound of formula (XIV) can be produced by reacting the compound of formula (XIII') in a suitable solvent in the presence of a hydroxyl group activator and a base. Any solvent that does not affect this reaction can be used, such as aromatic hydrocarbons (benzene, toluene, xylene, etc.), aprotic polar solvents (N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, etc.), nitriles (acetonitrile, etc.), ketones (acetone, methyl ethyl ketone, etc.), esters (ethyl acetate, isopropyl acetate, etc.), ethers (diethyl ether, tetrahydrofuran, dimethoxyethane, etc.), halogenated solvents (dichloromethane, chloroform, etc.), etc. These can also be used in appropriate combinations. Of these, ethers are preferred, and tetrahydrofuran is more preferred. Examples of hydroxyl group activators include methanesulfonyl chloride, trifluoromethanesulfonyl chloride, p-toluenesulfonyl chloride, 2-nitrobenzenesulfonyl chloride, methanesulfonic anhydride, or trifluoromethanesulfonic anhydride, with methanesulfonyl chloride being preferred. Examples of bases include triethylamine, pyridine, diisopropylethylamine, 2,6-lutidine, and 4-dimethylaminopyridine, with triethylamine or pyridine being preferred. The amount of hydroxyl group activator used is preferably 1 to 2 times the molar equivalent per mole of compound (XIII'). The amount of base used is preferably 1 to 4 times the molar equivalent per mole of compound (XIII'). The reaction temperature is preferably between 5°C and 45°C, and particularly between 15°C and 35°C.

[0102] <Step 13> This is a step to obtain the compound of formula (XV) by subjecting the compound of formula (XIV) to a cyclization reaction in a suitable solvent. Cyclization reactions can be carried out in a suitable solvent in the presence of a base. Any solvent that does not affect this reaction can be used. Examples include aromatic hydrocarbons (benzene, toluene, xylene, etc.), aprotic polar solvents (N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, etc.), nitriles (acetonitrile, etc.), ketones (acetone, methyl ethyl ketone, etc.), esters (ethyl acetate, isopropyl acetate, etc.), ethers (diethyl ether, tetrahydrofuran, dimethoxyethane, etc.), halogenated solvents (dichloromethane, chloroform, etc.), etc., and these can also be used in appropriate combinations. Pyridine can also be used as a solvent. Examples of bases include diazabicycloundecene and sodium hydride, with diazabicycloundecene being preferred. The amount of base used is preferably 1 to 4 times the molar equivalent of diazabicycloundecene and 1 time the molar equivalent of sodium hydride per mole of compound (XIV). The reaction temperature is preferably between 5°C and 45°C, and particularly between 15°C and 35°C. The compound of formula (XV) obtained by this process can be isolated as a crystal, and among these, R 1 The benzyl group is R 2 The benzyl group is R 5 is a benzyloxycarbonyl group, and R 6 X is a hydrogen atom, X is an oxygen atom, and R 12 Since the compound of formula (XV'), in which is a methyl group and the double line consisting of a solid and a dotted line is a double bond (compound 14 in Example 1(11) described later), can preferably be isolated as a crystal, in this step, the corresponding compound of formula (XIV')(R 11 It is preferable to use a compound containing a methyl group (such as a methyl group) to produce the compound of formula (XV'). Among the compounds of formula (XV), the crystallization method for formula (XV') includes adding a poor solvent to induce crystallization, crystallizing from a mixture of a good solvent and a poor solvent, reducing the solubility of the compound by cooling to induce crystallization, or a combination of these methods. Crystallization in this step can be efficiently carried out by adding water dropwise as the poor solvent and cooling to approximately 10°C. The powder X-ray diffraction patterns measured by CuKα emission from the crystals of the compound of formula (XV') are shown in Table 1 and Figure 1. However, it should be noted that, as is well known in this field, the diffraction peak intensities in the experimental patterns may differ and vary due to the preferred orientation in the prepared sample.

[0103] <Step 14> The compound of formula (XV) is subjected to a ring-closing reaction in a suitable solvent to obtain the compound of formula (XVI). It is about that much. Ring-closing reactions can be carried out in a suitable solvent in the presence of a base. Any solvent that does not affect this reaction can be used, such as aromatic hydrocarbons (benzene, toluene, xylene, etc.), aprotic polar solvents (N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, etc.), nitriles (acetonitrile, etc.), ketones (acetone, methyl ethyl ketone, etc.), esters (ethyl acetate, isopropyl acetate, etc.), ethers (diethyl ether, tetrahydrofuran, dimethoxyethane, etc.), halogenated solvents (dichloromethane, chloroform, etc.), etc., and these can also be used in appropriate combinations. Of these, aprotic polar solvents are preferred, and N,N-dimethylformamide is more preferred. Sodium hydride is an example of a base. The amount of base used is preferably 1 to 3 times the molar equivalent of 1 mole of the compound of formula (XV). The reaction temperature is preferably between -10°C and 30°C, and particularly between 0°C and 10°C.

[0104] <Process 15-1> This step involves subjecting the compound of formula (XVI) to a deprotection reaction in a suitable solvent to obtain the compound of formula (XVII'). Deprotection reactions can be carried out under reaction conditions commonly known in organic synthesis (e.g., nucleic acid synthesis), for example, Theodra W. Greene, Peter GM Wuts, “Protective Groups in Organic Synthesis” 4 th This can be carried out in accordance with the method described in . Ed. / John Wiley & Sons, Inc., 2007. For example, it can be carried out in a suitable solvent, in the presence of palladium-carbon hydroxide, and under a hydrogen atmosphere. Any solvent that does not affect this reaction can be used, such as aprotic polar solvents (N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, etc.), nitriles (acetonitrile, etc.), ketones (acetone, methyl ethyl ketone, etc.), esters (ethyl acetate, isopropyl acetate, etc.), ethers (diethyl ether, tetrahydrofuran, dimethoxyethane, etc.), halogenated solvents (dichloromethane, chloroform, etc.), or alcohols (methanol, ethanol, isopropanol, etc.). These can also be used in appropriate combinations. Of these, alcohols are preferred, and methanol is more preferred. The amount of palladium-carbon hydroxide used is preferably 1 to 30% by weight relative to the compound of formula (XVI). The reaction temperature is preferably between 0°C and 30°C.

[0105] <Process 15-2> This step involves subjecting the compound of formula (XVII') to a hydroxyl group protection reaction in a suitable solvent. The hydroxyl group protection reaction can be carried out under reaction conditions commonly known in organic synthesis chemistry (e.g., nucleic acid synthesis), for example, according to the method described in WO2017 / 047816. This reaction can be carried out, for example, by using 4,4'-dimethoxytrityl chloride in a solvent in the presence of a base. Any solvent that does not affect this reaction can be used, such as aromatic hydrocarbons (benzene, toluene, xylene, etc.), aprotic polar solvents (N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, etc.), nitriles (acetonitrile, etc.), ketones (acetone, methyl ethyl ketone, etc.), esters (ethyl acetate, isopropyl acetate, etc.), ethers (diethyl ether, tetrahydrofuran, dimethoxyethane, etc.), halogenated solvents (dichloromethane, chloroform, etc.), etc., and these can also be used in appropriate combinations. Pyridine can also be used as a solvent. Examples of bases include pyridine, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, and potassium bicarbonate, with pyridine being preferred. It seems so. The reaction temperature is preferably between 0°C and 50°C, and particularly between 15°C and 30°C.

[0106] (5) Method for producing a compound represented by formula (IV) from a compound represented by formula (I) (alternative method) The compound represented by formula (IV) or formula (IV') can also be produced from the compound represented by formula (I) by a method other than the method described in (3), for example, by scheme 1 or scheme 2 below. <Alternative Method 1> [ka] (In the formula, each symbol has the same meaning as above.) <Alternative Method 2> [ka] (In the formula, each symbol has the same meaning as above.)

[0107] <Step 16> This process involves reacting the compound of formula (I) with the compound of formula (XX) in a suitable solvent, and then treating it with a reducing agent to obtain the compound of formula (XVIII). Any solvent that does not affect this reaction can be used, such as aromatic hydrocarbons (benzene, toluene, xylene, etc.), aprotic polar solvents (N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, etc.), nitriles (acetonitrile, etc.), esters (ethyl acetate, isopropyl acetate, etc.), ethers (diethyl ether, tetrahydrofuran, dimethoxyethane, etc.), halogenated solvents (dichloromethane, chloroform, etc.), alcohols (methanol, ethanol, isopropanol, etc.), etc., and these can also be used in appropriate combinations. Preferred reducing agents include sodium cyanoborohydride, sodium triacetoxyborohydride, and sodium borohydride, with sodium triacetoxyborohydride being more preferred. The amount of compound (XX) used is preferably 1 to 2 times the molar equivalent of compound (I) per mole. The amount of reducing agent used is preferably 1 to 3 times the molar equivalent of compound (I) per mole. The reaction temperature is preferably between 0°C and 50°C, and particularly between 15°C and 30°C.

[0108] <Step 17> This step involves subjecting the compound of formula (XVIII) to an amino group protection reaction in a suitable solvent to obtain the compound of formula (XIX). The protection reaction is described in Theodra W. Greene, Peter GM Wuts, “Protective Groups in Organic Synthesis” 4 th This can be carried out in accordance with the methods described in . Ed. / John Wiley & Sons, Inc., 2007, et al. For example, it can be carried out using benzyl chloroformate or N-carbobenzooxyoxysuccinimide in a solvent. Any solvent that does not affect this reaction can be used, such as aromatic hydrocarbons (benzene, toluene, and xylene, etc.), aprotic polar solvents (N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, etc.), nitriles (acetonitrile, etc.), ketones (acetone, methyl ethyl ketone, etc.), esters (ethyl acetate, isopropyl acetate, etc.), ethers (diethyl ether, tetrahydrofuran, dimethoxyethane, etc.), halogenated solvents (dichloromethane, chloroform, etc.), etc., and these can also be used in appropriate combinations. The amount of benzyl chloroformate or N-carbobenzooxyoxysuccinimide used is preferably 1 to 2 times the molar equivalent of 1 mole of the compound of formula (XVIII). The reaction temperature is preferably between 0°C and 50°C, and particularly between 15°C and 30°C.

[0109] <Step 18> This step involves subjecting the compound of formula (XIX) to a deprotection reaction in a suitable solvent to obtain the compound of formula (IV'). The deprotection reaction is described in Theodra W. Greene, Peter GM Wuts, “Protective Groups in Organic Synthesis” 4 th This can be carried out in accordance with the method described in . Ed. / John Wiley & Sons, Inc., 2007, et al. For example, it can be carried out by using ammonium hexanitratocerium(IV)ate in a solvent. Any solvent that does not affect this reaction can be used, such as aromatic hydrocarbons (benzene, toluene, and xylene, etc.), aprotic polar solvents (N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, etc.), nitriles (acetonitrile, etc.), ketones (acetone, methyl ethyl ketone, etc.), esters (ethyl acetate, isopropyl acetate, etc.), ethers (diethyl ether, tetrahydrofuran, dimethoxyethane, etc.), halogenated solvents (dichloromethane, chloroform, etc.), alcohols (methanol, ethanol, isopropanol, etc.), etc., and these can also be used in appropriate combinations. The amount of ammonium hexanitratocerium(IV)ate is preferably 1 to 3 times the molar equivalent of the compound of formula (XIX). The reaction proceeds most favorably at temperatures between 0°C and 50°C, particularly between 0°C and 10°C.

[0110] <Step 19> This process involves reacting the compound of formula (I) with the compound of formula (XXIII) in a suitable solvent, and then treating it with a reducing agent to obtain the compound of formula (XXI). Any solvent that does not affect this reaction can be used, such as aromatic hydrocarbons (benzene, toluene, xylene, etc.), aprotic polar solvents (N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, etc.), nitriles (acetonitrile, etc.), esters (ethyl acetate, isopropyl acetate, etc.), ethers (diethyl ether, tetrahydrofuran, dimethoxyethane, etc.), halogenated solvents (dichloromethane, chloroform, etc.), alcohols (methanol, ethanol, isopropanol, etc.), etc., and these can also be used in appropriate combinations. Preferred reducing agents include sodium cyanoborohydride, sodium triacetoxyborohydride, and sodium borohydride, with sodium triacetoxyborohydride being more preferred. The amount of compound (XXIII) or its salt used is preferably 1 to 2 times the molar equivalent of the compound (I). The amount of reducing agent used is 1 to 3 per mole of compound (I). A molar equivalent of twice the amount is preferable. The reaction temperature is preferably between -25°C and 50°C, and particularly between 15°C and 30°C.

[0111] <Process 20> This step involves subjecting the compound of formula (XXI) to a deprotection reaction to obtain the compound of formula (XXII). The deprotection reaction is described in Theodra W. Greene, Peter GM Wuts, “Protective Groups in Organic Synthesis” 4 th This can be done in accordance with the method described in . Ed. / John Wiley & Sons, Inc., 2007, etc. For example, the compound of formula (XXI) can be dissolved in a suitable solvent with 1,3-dimethylbarbital. In the presence of tulic acid or a combination of polymethylhydrosiloxane and zinc(II) chloride, a deprotection reaction is carried out using a catalyst (tetrakis(triphenylphosphine)palladium(0)). It can be carried out in the presence of 2-mercaptobenzoic acid using a catalyst (1,4-bis(diphenylphosphin)butane-palladium(II) chloride or bis(dibenzylideneacetone)palladium(O)). Alternatively, a catalyst (tris(triphenylphosphine)rhodium(I) chloride or ve Deprotection can be carried out using dzylidene-bis(tricyclohexylphosphine)dichlororuthenium(II)). Any solvent that does not affect this reaction can be used, such as aromatic hydrocarbons (benzene, toluene, xylene, etc.), aprotic polar solvents (N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, etc.), nitriles (acetonitrile, etc.), ketones (acetone, methyl ethyl ketone, etc.), esters (ethyl acetate, isopropyl acetate, etc.), ethers (diethyl ether, tetrahydrofuran, dimethoxyethane, etc.), halogenated solvents (dichloromethane, chloroform, etc.), alcohols (methanol, ethanol, isopropanol, etc.), etc., and these can also be used in appropriate combinations. The 1,3-dimethylbarbituric acid, polymethylhydrosiloxane, and zinc(II) chloride used are Alternatively, the amount of 2-mercaptobenzoic acid is preferably 1 to 3 times the molar equivalent of the compound of formula (XXI). The amount of catalyst used is 0.05 to 0.1 times the molar equivalent of the compound of formula (XXI). This is preferable. The reaction temperature is preferably 0°C to 50°C, particularly 30°C to 50°C. The catalyst is tris(triphenylphosphine)rhodium(I) chloride or benzylidene-bis(tri In reactions using cyclohexylphosphine (dichlororuthenium(II))), the reaction temperature is preferably 80°C to 120°C.

[0112] <Step 21> This step involves subjecting the compound of formula (XXII) to an amino group protection reaction to obtain the compound of formula (IV). The protection reaction is described in Theodra W. Greene, Peter GM Wuts, “Protective Groups in Organic Synthesis” 4 th This can be carried out in accordance with the methods described in . Ed. / John Wiley & Sons, Inc., 2007, et al. For example, the compound of formula (IV) can be produced by reacting the compound of formula (XXII) with benzyl chloroformate or N-carbobenzooxyoxysuccinimide in a suitable solvent. Any solvent that does not affect this reaction can be used, such as aromatic hydrocarbons (benzene, toluene, xylene, etc.), aprotic polar solvents (N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, etc.), nitriles (acetonitrile, etc.), ketones (acetone, methyl ethyl ketone, etc.), esters (ethyl acetate, isopropyl acetate, etc.), ethers (diethyl ether, tetrahydrofuran, dimethoxyethane, etc.), halogenated solvents (dichloromethane, chloroform, etc.), etc., and these can also be used in appropriate combinations. The amount of benzyl chloroformate or N-carbobenzooxyoxysuccinimide used is preferably 1 to 2 times the molar equivalent of the compound of formula (XVIII). The reaction temperature is preferably between 0°C and 50°C, and particularly between 15°C and 30°C.

[0113] (6) Method for producing a compound represented by formula (XVII') or a compound represented by formula (XVII'') from a compound represented by formula (VI). The compound represented by formula (XVII') or the compound represented by formula (XVII'') can be prepared from the compound represented by formula (VI) as follows. [ka] (In the formula, each symbol has the same meaning as above.) Steps 1 to 15-2 are as described in (1) to (4) above.

[0114] In the above manufacturing method, each step from 1 to 13 allows for the isolation of the target compound at each step. Furthermore, in each step from 1 to 13, the reaction solution containing the crude reaction product can be used in the next step without isolating the reaction product, or a concentrated reaction solution can be used in the next step. The compound of formula (XV) obtained in this way can be isolated and purified as crystals. Also, each step from 14 to 15-2 allows for the isolation of the target compound at each step. Furthermore, in each step from 14 to 15-2, the reaction solution containing the crude reaction product can be used in the next step without isolating the reaction product, or a concentrated reaction solution can be used in the next step.

[0115] In this specification, the above-mentioned compounds, intermediate compounds, starting compounds, etc., are defined as having a functional group (for example, If it has a hydroxyl group, amino group, carboxyl group, etc., then see Theodora W. Greene, Peter G. The target compound can be obtained by protecting the compound with a protecting group commonly used in organic synthesis, in accordance with the methods described in M. Wuts, "Protective Groups in Organic Synthesis," 4th ed., John Wi Ley & Sons, Inc., 1999, and then removing the protecting group after the reaction.

[0116] (7) Compounds obtained in the manufacturing methods of (1) to (6) In the manufacturing methods described in (1) to (6) above, the compounds represented by formulas (II), (III), (IV), (XI), (XII), (XII'), (XIII), (XIII'), (XIV), (XIV'), (XV), (XV'), and (XVI) are all novel compounds.

[0117] When isolating the compounds obtained in each step of the above manufacturing method, all compounds can also be obtained as salts. The salts can be any salt that is commonly used industrially, such as inorganic salts like hydrochloride, sulfate, phosphate, and hydrobromide, as well as acetates and fumarates. Examples include organic salts such as oxalates, citrates, methanesulfons, benzenesulfons, tosyl salts, and maleates, as well as alkali metal salts such as sodium salts and potassium salts. Conversion to such salts can be carried out according to conventional methods.

[0118] (8) Method for producing modified oligonucleotides or salts thereof from compounds represented by formula (XVII'') ALNA[Ms]amidite can be produced from the compound represented by formula (XVII'') by known methods (for example, as described in International Publication No. 2017 / 047816, International Publication No. 2020 / 100826, etc.). The obtained ALNA[Ms] amidite and commercially available amidites for DNA synthesis (e.g., N6-Benzoyl-DMT-2'-deoxyadenosine-3'-CE Phosphoramidite, N2-Isobutyryl-5'-O-(4,4'-dimethoxytrityl)-2'-deoxyguanosine-3'-cyanoethyl Phosphoramidite, N2-Dimethylformamidine-5'-O-(4,4'-dimethoxytrityl)-2'-deoxyguanosine-3'-cyanoethyl Phosphoramidite, N4-Benzoyl-5'-O-(4,4'-dimethoxytrityl)-2'-deoxycytidine-3'-cyanoethyl Phosphoramidite, 5'-O-(4,4'-Dimethoxytrityl)-thymidine-3'-cyanoethyl Phosphoramidite) is made public in a way that is not known (e.g., by the government) In accordance with International Publication No. 2020 / 100826, International Publication No. 2020 / 203880, etc., the material is subjected to the phosphoramidite method, and if necessary, subjected to a thiolation reaction of the phosphodiester bond in accordance with known methods, thereby producing the following formula: formula: [ka] or formula: [ka] Modified oligonucleotides represented by or salts thereof can be produced. Specifically, examples of salts include sodium salts and potassium salts, with sodium salts being preferred.

[0119] The process for producing ALNA[Ms]amidite from a compound represented by formula (XVII'') includes, for example, the steps of (a) introducing a hydroxyl group protecting group and undergoing an optional nucleic acid base exchange reaction (transglycosyl reaction), (b) sulfonamidation of the imino nitrogen atom, (c) deprotection of the hydroxyl group protecting group, and (d) phosphoramidation to produce the desired ALNA[Ms]amidite. ALNA[Ms] has the following structural formula: [ka] It is represented as follows.

[0120] <(a) Introduction of hydroxyl group protecting groups, and any nucleic acid base exchange reaction (transglycosyl reaction)> The introduction of hydroxyl group protecting groups can be carried out under reaction conditions well known in organic synthesis (e.g., nucleic acid synthesis), depending on the type of protecting group. For example, if the hydroxyl group protecting group is a silyl type protecting group (e.g., TMS), a silylation agent (e.g., BSA, hexamethyldisilazane, TMS chloride) can be used. In this case, a Lewis acid (e.g., TMSOTf, TBSOTf, tin chloride) may be added. The silylation agent can be used in amounts of approximately 1 to 20 molar equivalents relative to the reaction substrate, and the Lewis acid can be used in catalytic amounts (approximately 0.05 molar equivalents) to 2 molar equivalents. Any solvent that does not affect the reaction can be used, and the reaction can be carried out in a suitable solvent (for example, ethers such as THF, halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform, hydrogen carbides such as benzene and toluene, acetonitrile, water, or a mixture thereof). The reaction proceeds preferably at temperatures from 0°C to high temperatures, particularly from room temperature to about 60°C. Furthermore, by a nucleic acid base exchange reaction (transglycosyl reaction), the nucleic acid base portion (thymine (T)) of the compound represented by formula (XVII'') can be replaced with another optionally protected nucleic acid base portion (e.g., adenine (A), guanine (G), uracil (U), cytosine (C), or 5-methylcytosine (MeC)). This base exchange reaction is carried out by Louis The reaction can be carried out in the presence of sic acid (e.g., TMSOTf, TBSOTf), and the reaction can be accelerated by reacting with a silylating agent.

[0121] <(b) Sulfonamidation on the imino nitrogen atom> Examples of sulfonamidation reagents used in the sulfonamidation reaction include alkyl sulfonyl halide reagents (e.g., methanesulfonyl chloride (MsCl)), alkyl sulfonic anhydrides (e.g., methanesulfonic anhydride), aromatic sulfonyl halide reagents (e.g., benzenesulfonyl chloride), or aromatic sulfonic anhydrides (e.g., benzenesulfonic anhydride), and can be used in the presence of a base (e.g., triethylamine, DIPEA). The sulfonamidation reagent can be used in approximately equivalent moles to some excess equivalent moles (e.g., about 1.0 molar equivalent) relative to the reaction substrate. Any solvent that does not affect the reaction can be used, and the reaction can be carried out in a suitable solvent (such as ethers like THF, halogenated hydrocarbons like dichloromethane, dichloroethane, and chloroform, hydrogen carbides like benzene and toluene, acetonitrile, water, or a mixture thereof). The reaction preferably proceeds at a temperature of -25°C to room temperature, particularly 0°C to room temperature.

[0122] (c) Deprotection of the protecting group of the hydroxyl group. The deprotection reaction of hydroxyl groups can be carried out under appropriate reaction conditions (e.g., reagents) depending on the type of protecting group. For example, when the protecting group of the hydroxyl group is a silyl protecting group (e.g., TMS), it can be carried out by hydrolysis under acidic conditions (e.g., acetic acid-THF-water) or by treatment with a fluoride ion donating reagent (e.g., TBAF). Any solvent that does not affect the reaction can be used, and the reaction can be carried out in a suitable solvent (for example, ethers such as THF, halogenated hydrocarbons such as dichloromethane, water, or a mixture thereof). The reaction preferably proceeds at a temperature of -25°C to 100°C, particularly 0°C to 50°C.

[0123] <(d) Phosphoamidite formation> Phosphoamidite formation is a reaction condition that is generally known in organic synthesis (especially nucleic acid synthesis). For example, it can be done under reagent conditions. Examples of phosphoramidite reagents include the following formula: [ka] Examples include, but are not limited to, the phosphoramidite reaction. The phosphoramidite reaction may be carried out in the presence of a base (e.g., DIPEA) or an acid (e.g., diisopropylammonium tetrazolide, 4,5-dicyanoimidazole) as appropriate. The phosphoramidite reagent can be used in amounts of 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents (for example, 3 molar equivalents), relative to the reaction substrate. Any solvent that does not affect the reaction can be used, and the reaction can be carried out in a suitable solvent (such as ethers like THF, halogenated hydrocarbons like dichloromethane, dichloroethane, chloroform, acetonitrile, or a mixture thereof). The reaction preferably proceeds at temperatures from -25°C to 60°C, particularly from 0°C to room temperature. In the phosphoramidite process using ALNA[Ms] amidite and DNA synthesis amidite, an oligomerization reaction occurs. After the oligomerization reaction, modified oligonucleotides or salts thereof can be produced by deprotecting the amino protecting group and hydroxyl protecting group as needed. In the synthesis of oligonucleotides by the phosphoramidite method, an oxidizing agent is used to convert the phosphite group to a phosphate group. If DDTT (((dimethylamino-methylidene)amino)-3H-1,2,4-dithiazaolin-3-thione) or Beaucage reagent (3H-1,2-benzodithiol-3-one-1,1-dioxide) is used instead of the oxidizing agent used at this time, a phosphorothioate oligomer with a protecting group is obtained in which the oxygen atom at P=O of the phosphate group is replaced with sulfur, such as P=S, to form a thiophosphate group. If necessary, known thiolation reagents can be used in the step of subjecting the phosphodiester bond to a thiolation reaction. Examples of commercially available thiolation reagents include, but are not limited to, Sulfurizing Reagent II (Gren Research Corporation).

[0124] All documents, patent applications, and technical standards described herein are incorporated by reference to the same extent as if each individual document, patent application, and technical standard were specifically and individually noted to be incorporated by reference. [Examples]

[0125] The present invention will be specifically described below with reference to examples, but the present invention is not limited in any way by these examples.

[0126] The abbreviations used represent the following meanings: Bn: Benzyl Cbz: Benzyloxycarbonyl Ac: Acetyl DMTr:4,4'-Dimethoxytrityl

[0127] Compound identification is performed using methods such as LC-MS, NMR spectroscopy, and high-performance liquid chromatography (HPLC). I did it. Hydrogen nuclear magnetic resonance in NMR ( 1 In Η-NMR, the resonance frequency is 400 MHz. The symbols used in NMR are: s for single line, d for double line, and dd for double line. The double line and J represent coupling constants.

[0128] Example 1: Method for producing compounds 2-17 and these compounds [ka]

[0129] (1) Synthesis of compound 2 (1)-1: Under a nitrogen atmosphere, dissolve compound 1 (44.2 g, 170 mmol) and nor-AZADO (1.2 mg, 0.0086 mmol) in dichloromethane (22.8 mL), then add saturated sodium bicarbonate solution (114 mL) and potassium bromide. (2.00 g, 16.9 mmol) was added. Compound 1 was obtained commercially. Cooled to 0 °C, 12% A mixture of (w / w) sodium hypochlorite aqueous solution (178 mL) and saturated sodium bicarbonate solution (91 mL) was added dropwise over 20 minutes and stirred at 0°C for 40 minutes. nor-AZADO (1.2 mg, 0.0086 mmol), dichloromethane (22.8 mL), and 12% (w / w) sodium hypochlorite aqueous solution (33 mL) and saturated sodium bicarbonate solution (17 The mixture was added dropwise (mL) and stirred for another 30 minutes at the same temperature. 30% (w / w) sodium thiosulfate at 0°C Aqueous solution (50 mL) and dichloromethane (400 mL) were added, and the organic layer was separated. The aqueous layer was extracted with dichloromethane (6 × 200 mL), the organic layer was collected, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain the crude compound 2 (43.1 g) as a pale yellow viscous substance. This was obtained. The obtained crude material was used as is in the next step (2)-1. MS(ESI): m / z = 259 (M+H) + (1)-2 (non-isolated method): Under a nitrogen atmosphere, compound 1 (14.8 g, 56.9 mmol), n Bu4HSO4 (978 mg, 2.88 mmol) and nor-AZADO (9.5 mg, 0.069 mmol) in dichloromethane (30 mL) It was dissolved in water. Cooled to 0°C, sodium hypochlorite pentahydrate (15.1 g, 91.8 mmol) and water. A sodium hypochlorite aqueous solution prepared from tap water (7.8 mL) was added dropwise over 30 minutes, and the mixture was stirred at 0 °C for 1 hour. A 30% (w / w) sodium thiosulfate aqueous solution (30 mL) was added, and the organic layer was separated. Tap water (30 mL) was added, and the aqueous layer was extracted with dichloromethane (3 × 30 mL), and the organic layer was separated. In summary, by substituting and concentrating the solution of compound 2 in tetrohydrofuran solvent under reduced pressure, the solution turned yellow. It was obtained as a liquid. The obtained solution was used directly in the next step (2)-2.

[0130] (2) Synthesis of compound 4 (2)-1: Under a nitrogen atmosphere, the crude compound 2 obtained in (1)-1 (43.1 g) was tetrapod. It was dissolved in hydrofuran (340 mL). Paraformaldehyde (10.2 g, 340 mmol) and potassium carbonate (47.0 g, 340 mmol) were added, and the mixture was stirred at room temperature for 3.5 hours, followed by a further 3 hours at 30 °C. The mixture was stirred. After cooling to room temperature, insoluble matter was removed by filtration, and the solid on the filter paper was washed with tetrahydrofuran (50 mL). The filtrates were combined, tap water (69 mL) was added, and the mixture was cooled to 0 °C. Sodium borohydride (12.9 g, 340 mmol) was added over 15 minutes. After stirring at 0 °C for 30 minutes, the reaction mixture was allowed to stand, and the organic layer was separated. The aqueous layer was extracted with tetrahydrofuran (3 × 80 mL), the organic layer was collected, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (200 mL). The solution was passed through a column packed with silica gel 60 N (neutral, 90 g), followed by ethyl acetate (600 mL). The eluates were combined and concentrated under reduced pressure to obtain the crude compound 4 (44.0 g) as a white solid. The resulting crude compound was suspended in a mixture of n-hexane (85 mL) and diethyl ether (15 mL), stirred at room temperature for 2 hours, and then the solid was filtered off. The solid was washed with n-hexane-diethyl ether (9:1, v / v) (2 × 50 mL), and the solid was dried under reduced pressure to obtain compound 4 (41.3 g, 142 mmol, 2-step process from compound 1 ((1)-1 and (2)-1)) with a yield of 83%) as a white solid. Ta. MS(ESI): m / z = 291 (M+H) + 1H NMR (400 MHz, CDCl3) δ 5.92 (d, J = 4.0 Hz, 1H), 4.73 (dd, J = 6.4, 4.0 Hz, 1H), 4.58 (dd, J= 7.4, 6.8 Hz, 1H), 4.32 (d, J = 6.8 Hz, 1H), 4.16 (dd, J = 9.4, 7.4 Hz, 1H), 3.92 (dd, J = 9.2, 6.4 Hz, 1H), 3.79 (dd, J = 11.6, 4.4 Hz, 1H), 3.61 (dd, J = 11.8, 7.8 Hz, 1H), 2.74 (d, J = 6.8 Hz, 1H), 1.98 (dd, J = 7.8, 4.6 Hz, 1H), 1.63 (s, 3H), 1.47 (s, 3H), 1.41 (s, 3H), 1.35 (s, 3H). (2)-2 (non-isolated method): Under a nitrogen atmosphere, a tether containing compound 2 obtained in (1)-2 73.5 mL of tetrahydrofuran was added to the tetrahydrofuran solution. Paraformaldehyde Add 3.6 g, 102 mmol of chlorine dioxide and 15.7 g, 114 mmol of potassium carbonate, and stir at 30 °C for 21 hours. Then add 1.8 g, 51 mmol of paraformaldehyde and 7.9 g, 57 mmol of potassium carbonate, and stir at 30 °C for 21 hours, then cool to 20 °C. Remove insoluble matter by filtration, and wash the solid on the filter paper with tetrahydrofuran (7 × 30 mL). Combine the filtrates, concentrate under reduced pressure, add tetrahydrofuran (30 mL) and tap water (22 mL), then cool to 0 °C. Sodium borohydride (4.3 g, 114 mmol) was added over 16 minutes. The temperature was raised to 20 °C, and after stirring for 1 hour, the reaction mixture was allowed to stand and the organic layer was separated. The aqueous layer was separated into tetrahydrofuran (2 × 30 Extraction was performed using acetic acid (mL), the organic layer was collected, concentrated under reduced pressure, the residue was dissolved in ethyl acetate (84 mL), and the solution was passed through silica gel (40 μm, 13.96 g) packed into a short column. After passing ethyl (168 mL) through the solution, the eluate was concentrated under reduced pressure to obtain the crude compound 4 (10.3 g). It was obtained as a yellowish-green solid.

[0131] (3) Synthesis of compound 5 (3)-1: Under a nitrogen atmosphere, tetrahydrofuran (140 mL) and 60% (w / w) sodium hydride (dispersion in paraffin liquid) (14.3 g, 357 mmol) were mixed at 0 °C. Compound 4 (41.3 g, 142 mmol) dissolved in tetrahydrofuran (140 mL) was added dropwise at 0 °C, and The mixture was washed with trahydrofuran (35 mL). After stirring at 0 °C for 10 minutes, benzyl bromide (37.5 mL, 315 mmol) was added, and the mixture was stirred for a further 4 hours at 50 °C. The reaction mixture was cooled to 0 °C, and then cooled to 0 °C. The reaction solution was added dropwise to 700 mL of tap water. Ethyl acetate (700 mL) was added, and the organic layer was separated. After extracting the aqueous layer with ethyl acetate (2 × 350 mL), the organic layer was combined and saturated brine (150 mL) The organic layer was washed with (mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. It shrunk. Dissolve the residue in n-hexane (400 mL), and freeze the solution in silica gel 60 N (neutral, 201 g). The solution was passed through a column packed with [a certain substance]. After passing n-hexane (800 mL) through, ethyl acetate (1.60 L) was added. By passing the solution through and concentrating only the ethyl acetate eluate under reduced pressure, compound 5 (65.0 g, 138 mmol, 97% yield) was obtained as a pale yellow solid. MS(ESI): m / z = 471 (M+H) + 1H NMR (400 MHz, CDCl3) δ 7.36-7.24 (m, 10H), 5.84 (d, J = 4.0 Hz, 1H), 4.81-4.74 (m, 2H), 4.67 (dd, J = 5.2, 4.0 Hz, 1H), 4.54 (d, J = 11.6 Hz, 1H), 4.48-4.38 (m, 2H), 4.26 (d, J = 5.2 Hz, 1H), 4.05 (dd, J = 9.2, 7.7 Hz, 1H), 3.77 (dd, J = 9.2, 6.4 Hz, 1H), 3.68 (d, J = 10.4 Hz, 1H), 3.58 (d, J= 10.4 Hz, 1H), 1.61 (s, 3H), 1.40 (s, 3H), 1.38 (s, 3H), 1.30 (s, 3H). (3)-2 (Non-isolated method): Under a nitrogen atmosphere, the crude compound 4 obtained in (2)-2 (8.56 g) was dissolved in tetrahydrofuran (26 mL), and sodium hydroxide (3.0 g, 75 mmol) was added. The mixture was stirred at 20°C for 30 minutes, then cooled to 0°C. Benzyl bromide (11.2 g, 65 mmol) was added, and the mixture was stirred at 50°C for a further 2 hours and 30 minutes. The reaction mixture was cooled to 20°C, tap water (17 mL) and ethyl acetate (17 mL) were added, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (17 mL), the organic layer was collected, and washed with saturated sodium bicarbonate solution (26 mL). The organic layer was concentrated under reduced pressure. By drying, a crude form of compound 5 (14.3 g) was obtained as a yellow viscous substance.

[0132] (4) Synthesis of compound 6 (4)-1: Under a nitrogen atmosphere, compound 5 (10.0 g, 21.2 mmol) is dissolved in acetonitrile (64 mL). Dissolve in [a solution], and add iodine (1.62 g, 6.38 mmol), sodium periodate (9.10 g, 42.5 mmol), and tap water (21 mL) at room temperature. Stir at 70 °C for 4.5 hours, then add sodium periodate. (1.00 g, 4.67 mmol) was added and the mixture was stirred for a further 1.5 hours. The reaction mixture was cooled to room temperature, ethyl acetate (175 mL) was added, and insoluble matter was removed by filtration. The filtered product was washed with ethyl acetate (175 mL). The mixture was then combined. After adding 30% (w / w) sodium thiosulfate aqueous solution to the filtrate, The organic layer was separated. The aqueous layer was extracted with ethyl acetate (2 × 100 mL), and the organic layer was combined and saturated. Washed with saline solution (60 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and then filtered. The solution was concentrated under reduced pressure. The residue was dissolved in n-hexane-ethyl acetate (4:1, v / v) and passed through a column. The compound was supported on packed silica gel 60 N (neutral, 26 g). 200 mL of n-hexane-ethyl acetate (4:1, v / v) was passed through, and the eluate was concentrated under reduced pressure to obtain compound 6 (7.00 g, 17.5 mmol, yield 82%) as a pale yellow viscous substance. MS(ESI): m / z = 421 (M+Na) + 1 H NMR (400 MHz, CDCl3) δ 9.91 (s, 1H), 7.35-7.22 (m, 10H), 5.84 (d, J = 3.2 Hz, 1H), 4.71 (d, J = 12.4 Hz, 1H), 4.61-4.57 (m, 2H), 4.51-4.47 (m, 2H), 4.37 (d, J = 4.4 Hz, 1H), 3.68 (d, J = 10.8 Hz, 1H), 3.61 (d, J= 10.8 Hz, 1H), 1.60 (s, 3H), 1.35 (s, 3H). (4)-2 (Non-isolated method): Under a nitrogen atmosphere, the crude compound 5 obtained in (3)-2 (14.3 g) was dissolved in acetonitrile (42 mL), and iodine (2.29 g, 9.02 mmol), sodium periodate (12.7 g, 59.4 mmol), and tap water (29 mL) were added at room temperature. At 70 °C for 5 hours After stirring, acetonitrile (42 mL), iodine (4.58 g, 18.0 mmol), and sodium periodate (8.85 g, 41.4 mmol) were added, and the mixture was stirred for a further 16 hours and 30 minutes. The reaction mixture was cooled to 20 °C, ethyl acetate (28 mL) was added, and insoluble matter was removed by filtration. The solid on the filter paper was then removed. The mixture was washed with ethyl acetate (2 × 28 mL). After adding 36 g of 30% (w / w) sodium thiosulfate aqueous solution to the filtrate, the organic layer was separated. The aqueous layer was extracted with ethyl acetate (2 × 28 mL), the organic layers were combined, concentrated under reduced pressure, and dried under reduced pressure to obtain crude compound 6 (11.3 g) as a brown liquid. I got it.

[0133] (5) Synthesis of compound 7 (5)-1: Under a nitrogen atmosphere, dissolve compound 6 (5.50 g, 13.8 mmol) in tetrohydrofuran (55 mL), and add pyridine (5.5 mL) and hydroxylamine hydrochloride (1.15 g, 16.5 mmol). The mixture was stirred at 40°C for 1.5 hours, then stirred again at 60°C for another 1.5 hours. The reaction mixture was concentrated under reduced pressure, and tap water (40 mL) and ethyl acetate (40 mL) were added to the concentrated residue and separated. The aqueous layer was acetic acid. Extraction was performed with ethyl acetate (40 mL x 3), and the collected organic layer was washed with saturated saline solution (20 mL). The chamber was dried with anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified in normal phase (Biotage isolera, stationary phase: SNAP ultra 50 g, mobile phase: hexane / ethyl acetate = 90 / 10 to 60 / 40), and the eluate containing the target compound was concentrated under reduced pressure. Compound 7 (4.79 g, 11.6 mmol, yield 84%) was obtained as a pale yellow viscous substance by adding toluene (20 mL) to the concentrated residue and concentrating under reduced pressure twice. MS(ESI): m / z = 414 (M+H) + (5)-2 (Non-isolated method): Using the crude compound 6 obtained in (4)-2 (11.3 g) The same reaction and post-treatment as described in (5)-1 above was carried out, and the crude compound 7 (10.5 g) was converted into a yellow viscous substance. The obtained crude material was used directly in the next step (6)-2.

[0134] (6) Synthesis of compound 8 (6)-1: Under a nitrogen atmosphere, crude compound 7 (7.67 g) was dissolved in tetrahydrofuran (34 mL). After raising the temperature of the solution to 40 °C, 60% (w / w) bis(2-methoxyethoxy)hydride was added. A solution of sodium toluene (14.4 g, 42.6 mmol) was added dropwise over 32 minutes, and the mixture was stirred at 40 °C for 80 minutes. After the reaction mixture cooled to room temperature, 28 mL of 2 M sodium hydroxide aqueous solution was added. The solution was added dropwise over several minutes and stirred at room temperature for 15 minutes. Ethyl acetate (34 mL) was added, and the organic layer was separated. The organic layer was washed with 10% (w / w) saline solution (2 × 17 mL), and then concentrated under reduced pressure. The residue was then concentrated under reduced pressure with the addition of toluene (50 mL), and this process was repeated twice. The compound 8 was dissolved in (20 mL), and 10% (w / w) citric acid aqueous solution (68 mL) and tap water (21 mL) were added to separate the aqueous layer containing compound 8. The obtained aqueous layer was used as is in the next step (7)-1. (6)-2 (Non-isolated method): Using the crude compound 7 obtained in (5)-2 (10.5 g) The same reaction and post-treatment as described above were carried out to obtain an aqueous layer containing compound 8. The obtained aqueous layer was then used as is. It was used in the next step (7)-2. MS(ESI): m / z = 400 (M+H) +

[0135] (7) Synthesis of compound 9 (7)-1: Under a nitrogen atmosphere, 20 mL of 5 M sodium hydroxide aqueous solution was added to the aqueous layer containing compound 8 obtained in (6)-1 at 25 °C. 15 mL of ethyl acetate was added at room temperature, and a solution of N-carbobenzooxyoxysuccinimide (4.28 g, 17.0 mmol) in ethyl acetate (25 mL) was added dropwise over 6 minutes, and the mixture was stirred at room temperature for 40 minutes. The organic layer was separated, and N-methylpiperazolite was added. Add (0.94 mL, 8.5 mmol) and stir at room temperature for 30 minutes. The reaction mixture was sequentially washed with 10% (w / w) saline (14 mL), 10% (w / w) citric acid aqueous solution (14 mL), 10% (w / w) saline (14 mL), 5% (w / w) sodium bicarbonate solution (14 mL), and 10% (w / w) saline (14 mL). The organic layer was treated with anhydrous magnesium sulfate. After drying and filtering, the filtrate was concentrated under reduced pressure to obtain the crude compound 9 (9.93 g) as a pale yellow substance. It was obtained as a colored viscous material. The obtained crude material was used as is in the next step (the same step as in (8)-2). 1 H NMR (400 MHz, CDCl3) δ 7.38-7.21 (m, 15H), 5.75 (d, J = 4.0 Hz, 1H), 5.30-5.29 (m, 1H), 5.08 (s, 2H), 4.75 (d, J = 12 Hz, 1H), 4.62 (dd, J = 4.8 Hz, 4.4 Hz, 1H), 4.52-4.47 (m, 2H), 4.37 (d, J = 12 Hz, 1H), 4.22 (d, J = 5.2 Hz, 1H), 3.71 (dd, J = 14 Hz, 4 Hz, 1H), 3.60 (dd, J = 14.4 Hz, 8.4 Hz, 1H), 3.49 (d, J = 10.8 Hz, 1H), 3.40 (d, J = 10.8 Hz, 1H), 1.57 (s, 3H), 1.32 (s, 3H). (7)-2 (Non-isolated method): Add the above aqueous layer containing compound 8 obtained in (6)-2 By performing the same reaction and workup as described in (7)-1, crude compound 9 (7.26 g) was obtained. The resulting crude material was used directly in the next step (8)-2.

[0136] (8) Synthesis of compound 10 (8)-1: Under a nitrogen atmosphere, dissolve compound 9 (2.56 g, 4.79 mmol) in acetic acid (5.12 mL). The mixture was then mixed with acetic anhydride (2.56 mL) and sulfuric acid (13 μL) at room temperature and stirred for 1 hour at the same temperature. Under ice cooling, saturated sodium bicarbonate solution (75 mL) was added dropwise to the reaction mixture, followed by the addition of ethyl acetate (75 mL) and subsequent liquid-liquid separation. The aqueous layer was extracted with ethyl acetate (75 mL × 3), and the combined organic layer was then treated with saturated sodium bicarbonate solution (50 mL) The layers were then sequentially washed with saturated sodium bicarbonate solution (50 mL). The organic layer was dried with anhydrous magnesium sulfate and filtered. The filtrate was separated and concentrated under reduced pressure to obtain the crude compound 10 (2.82 g). It was then used in the next step (9)-1. MS(ESI): m / z = 579 (M+H) + (8)-2 (Non-isolated method): Using the crude compound 9 obtained in (7)-2 (7.26 g) The reaction and post-treatment were carried out in the same manner as in (8)-1 above, and crude compound 10 (7.69 g) was obtained as a brown viscous substance. The obtained crude substance was used as is in the next step (9)-2.

[0137] (9) Synthesis of compound 11 (9)-1: Under a nitrogen atmosphere, the crude compound 10 obtained in (8)-1 (3.15 g) was acetate. Dissolve in tonitrile (13.5 mL) and combine with thymine (875 mg, 6.94 mmol) and N,O-bis(trimethicone). Lucilyl acetamide (8.63 mL, 34.6 mmol) was added, and the mixture was refluxed at 90°C for 1 hour and stirred. The reaction mixture was cooled to 0°C, and TMSOTf (1.15 mL, 6.36 mmol) was added dropwise over 2 minutes. The mixture was then refluxed at 90°C for 1 hour and stirred. The reaction mixture was cooled to 0°C, saturated sodium bicarbonate solution (20 mL) was added dropwise, followed by ethyl acetate (40 mL). Insoluble matter was filtered off, and the filtered product was washed with ethyl acetate (40 mL × 3). The combined filtrate was concentrated under reduced pressure, and the concentrate was extracted with ethyl acetate (40 mL × 2). The combined organic layer was washed with saturated brine (20 mL). The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to obtain the crude compound 11 (3.78 g) as a pale yellow solid. The obtained crude compound was used directly in the next step (10)-1. MS(ESI): m / z = 645 (M+H) + (9)-2 (Non-isolated method): Using the crude compound 10 (7.69 g) obtained in (8)-2, the same reaction and workup as in (9)-1 above was carried out to obtain the crude compound 11 (8.17 g). The obtained crude compound was used as is in the next step (10)-2.

[0138] (10) Synthesis of compound 12 (10)-1: Under a nitrogen atmosphere, the crude compound 11 obtained in (9)-1 (3.78 g) was treated with a t After dissolving in trahydrofuran (11.6 mL), add 40% methylamine aqueous solution (7.56 mL) at room temperature. The mixture was added and stirred at the same temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and tap water (20 mL) and saturated ammonium chloride aqueous solution (20 mL) were added to the concentrate and extracted with ethyl acetate (50 mL × 3). The organic layer was washed with saturated brine (25 mL). The organic layer was dried with anhydrous magnesium sulfate, the drying agent was filtered off, and the filtrate was concentrated under reduced pressure to obtain the crude material (3.14 g). The crude material was then processed in the normal phase. Purification (Stationary phase: 41 g of 60N silica gel manufactured by Kanto Chemical, Mobile phase: Hexane / ethyl acetate = 50 / 50) The eluate containing the target substance is concentrated under reduced pressure to extract compound 12 (2.28 g, 3.78 mmol, The three steps from compound 9 ((8)-1, (9)-1 and (10)-1) yielded 70% were solidified into a colorless solution. I acquired it physically. MS(ESI): m / z = 603 (M+H) + (10)-2 (Non-isolated method): Use the crude compound 11 obtained in (9)-2 (8.17 g). The reaction and post-treatment were carried out in the same manner as in (10)-1 above, and crude compound 12 (6.79 g) was obtained as a brown viscous substance. The obtained crude substance was used as is in the next step (11)-2.

[0139] (11) Synthesis of compound 14 (11)-1: Under a nitrogen atmosphere, crude compound 12 (16.9 g) was dissolved in pyridine (30 mL), and methanesulfonyl chloride (2.33 g, 20.5 mmol) was added dropwise over 2 minutes at 0 °C. After stirring at room temperature for 2 hours and 10 minutes, 1,8-diazabicyclo[5.4.0]undeca-7-ene (7.82 g, 51.2 mmol) was added dropwise over 8 minutes. After stirring at room temperature for 3 hours, ethyl acetate (100 mL) and tap water (30 mL) were added. (mL) was added. After separating the organic layer, it was washed with tap water (2 × 30 mL), and the organic layer was distilled under reduced pressure. The residue was removed. The residue was suspended in ethyl acetate (30 mL), then toluene (60 mL) was added, and after stirring at room temperature, the solid was filtered off. The solid was washed with ethyl acetate-toluene (1:2, v / v) (2 × 10 mL), and the solid was dried under reduced pressure to obtain compound 14 (6.22 g, 10.7 mmol, from compound 6 in 7 steps). (5)-1, (6)-1, (7)-1, (8)-1, (9)-1, (10)-1 and (11)-1 (same process) yielded a pale yellow solid (62%). 1H NMR (400 MHz, CDCl3) δ 7.39-7.26 (m, 13H), 7.17-7.10 (m, 3H), 5.98 (d, J = 6.4 Hz, 1H), 5.19 (dd, J = 6.4, 1.6 Hz, 1H), 5.12-5.04 (m, 3H), 4.74 (d, J = 12 Hz, 1H), 4.55 (d, J = 12 Hz, 1H), 4.36-4.28 (m, 3H), 3.57-3.51 (m, 1H), 3.40-3.34 (m, 1H), 3.23 (s, 2H), 1.95 (s, 3H). (11)-2 (Non-isolated method): The crude compound 12 obtained in (10)-2 (6.79 g) Dissolve in tetrahydrofuran (34 mL), add triethylamine (3.33 g, 32.9 mmol) and methanesulfonyl chloride (1.86 g, 16.2 mmol) at 10 °C, and stir at 25 °C for 2 hours and 30 minutes. Add 1,8-diazabicyclo[5.4.0]undeca-7-ene (4.92 g, 32.3 mmol) to the reaction mixture at 25 °C. Add the following ingredients and stir at the same temperature for 3 hours and 30 minutes, then add tap water (65 mL) dropwise over 5 minutes. After cooling to 10 °C, stir for 1 hour, filter out the solid, and dry under reduced pressure. Add the dried solid to ethyl acetate (7 mL). After suspension, toluene (14 mL) was added, and the mixture was stirred at 20 °C before filtering out the solid. The solid was washed with ethyl acetate-toluene (1:2, v / v) (9 mL), and the solid was dried under reduced pressure to obtain compound 14 (2.80 g, 4.8 mmol, 11 steps from compound 1 ((1)-2, (2)-2, (3)-2, (4)-2, (5)-2, (6)-2, (7)-2, (8)-2, (9)-2, (10)-2, and (11)-2)) as a white solid (yield 8%). (11)-3 (Method including isolation of compound 13): Under a nitrogen atmosphere, compound 12 (113 mg, 0.187 mmol) was dissolved in tetrahydrofuran (2.26 mL), pyridine (60 μL, 0.748 mmol) was added, and then methanesulfonyl chloride (17.5 μL, 0.224 mmol) and 4-dimethylaminopyridine (30 mg, 0.245 mmol) were added at room temperature, and the mixture was stirred for 17 hours at room temperature. The solution was concentrated under reduced pressure, and ethyl acetate (5 mL) and tap water (5 mL) were added to the concentration residue for liquid-liquid separation. The aqueous layer was extracted with ethyl acetate (5 mL × 3), and the combined organic layer was washed with saturated brine. Organic The layer was dried with anhydrous magnesium sulfate, the drying agent was filtered off, and the filtrate was concentrated under reduced pressure to obtain the crude product (0.14 g) as a pale yellow solid. The crude product was purified in normal phase (Biotage isolera, stationary phase: sfar HD 10 g, mobile phase: hexane / ethyl acetate = 90 / 10 ~ 40 / 60), and the solution containing the target substance was obtained. The extract was concentrated under reduced pressure. The concentration residue was then concentrated under reduced pressure again by adding toluene (5 mL). By repeating the procedure, a crude form of compound 13 (0.14 g) was obtained as a colorless solid. MS(ESI): m / z = 681 (M+H) + Under a nitrogen atmosphere, crude compound 13 (0.14 g) was dissolved in DMF (2.54 mL), and then incubated at 0 °C until 60% dissolved. (w / w) sodium hydride (dispersion in paraffin liquid) (7.4 mg, 0.185 mmol) was added and the mixture was stirred at the same temperature for 16 hours. Tap water (5 mL) and ethyl acetate (5 mL) were added to the reaction mixture at 0 °C and separated. The aqueous layer was extracted with ethyl acetate (5 mL × 2), and the combined organic layer was washed with saturated brine (3 mL). The organic layer was dried over anhydrous magnesium sulfate, the drying agent was filtered off, and the filtrate was obtained. The compounds were concentrated under reduced pressure. The concentrated residue was purified in normal phase (Biotage isolera, stationary phase: sfar HD 10 g, mobile phase: hexane / ethyl acetate / methanol = 90 / 10 / 0 ~ 0 / 100 / 0 ~ 0 / 90 / 10), and the eluates containing compound 14 and compound 15 were concentrated under reduced pressure to obtain compound 14 (0.10 g, 0.171 mmol) and compound 15 (0.01 g, 0.017 mmol), respectively, as colorless solids. I obtained it.

[0140] <Powder X-ray diffraction measurement of the crystals of compound 14> Powder X-ray diffraction (XRD) measurements are performed using a powder X-ray diffractometer: MiniFlex600 (Rigaku Corporation). The following procedure was performed using CuKα emission. X-ray generator: X-ray tube (copper, tube voltage: 40kV, tube current: 15mA) Detector: D / teX Ultra 2 (standard mode) Measurement range: 3.0~40.0° Scan speed: 10.0° / min Sampling width: 0.020° The results of the powder X-ray diffraction (XRD) patterns of compound 14 are shown in Figure 1 and Table 1. It can be seen that 14 was isolated as a crystal.

[0141] [Table 1] TIFF2026131783000071.tif129161

[0142] The characteristic peak in the powder X-ray diffraction pattern of compound 14 crystals is represented by 2θ. Diffraction angles of 7.4±0.2°, 19.2±0.2°, 20.1±0.2°, 21.3±0.2°, and 24.7±0.2° were observed.

[0143] (12) Synthesis of compound 15 (12)-1: Under a nitrogen atmosphere, compound 14 (0.10 g, 0.17 mmol) was mixed with compound 15 (0.01 g, 0.017 mmol), and dissolved in N,N-dimethylformamide (2.5 mL) under a nitrogen atmosphere. At ℃, 60% (w / w) sodium hydride (dispersion in paraffin liquid) (7.4 mg, 0.19 mmol) was added and stirred at the same temperature for 16 hours. Tap water (5 mL) and ethyl acetate (5 mL) were added at 0 ℃ and the aqueous layer was separated. The aqueous layer was extracted with ethyl acetate (5 mL × 3) and the organic layers were combined and saturated. Washed with saline solution (3 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue was purified using normal phase (Biotage isolera, stationary phase: sfar HD 10 g, transfer). Dynamic phase: Hexane / Ethyl acetate / Methanol = 90 / 10 / 0 ~ 0 / 100 / 0 ~ 0 / 80 / 20) A crude form of compound 15 (0.10 g) was obtained as a colorless solid. The obtained crude form was then used as follows. It was used in step (13). MS(ESI): m / z = 585 (M+H) + (12)-2 (Method without adding compound 15 as a starting material): Under a nitrogen atmosphere, compound 14 (2.46 g, 4.28 mmol) was dissolved in N,N-dimethylformamide (13 mL). After cooling to 0 °C, 60% (w / w) sodium hydride (dispersion in Paraffin Liquid) (254 mg, 6.4 mmol) was added and the mixture was stirred at the same temperature for 3 hours and 50 minutes. 60% (w / w) sodium hydride (dispersion in Paraffin Liquid) (38 mg, 0.95 mmol) was added and the mixture was stirred at 0 °C for 1 hour and 40 minutes. Further 60% (w / w) sodium hydride (dispersion in Paraffin Liquid) (55 mg, 1.4 mmol) was added. The mixture was stirred at 0°C for 17 hours and 50 minutes. After raising the temperature to 10°C, tap water (13 mL) and ethyl acetate (12 mL) were added. After raising the temperature to 20°C, the mixture was stirred for 10 minutes. After separating the aqueous layer, ethyl acetate (3 × 12 mL) was added. The compound was extracted using [method]. The organic layers were combined and concentrated under reduced pressure to obtain the crude compound 15 (2.21 g) as a yellow viscous substance.

[0144] (13) Synthesis of compound 16 (13): Under a nitrogen atmosphere, crude compound 15 obtained in (12)-1 (0.10 g) was dissolved in methanol (2.0 mL). At room temperature, Pd(OH)2 / C (20% (w / w) Pd, 50% (w / w) wet) (12 mg) was added and the mixture was stirred under a hydrogen atmosphere for 7 hours. Acetic acid (1.0 mL) was added to the reaction mixture and stirred under a hydrogen atmosphere. After stirring under gas for a further 16 hours, insoluble matter was removed by filtration. The solid on the filter paper was washed with acetic acid (3 × 1 mL), and the combined filtrates were concentrated under reduced pressure. The residue was then concentrated under reduced pressure twice by adding toluene (5 mL) to the residue, thereby obtaining the crude compound 16 (0.060 g). It was obtained as a pale yellow viscous substance. The obtained crude material was used directly in the next step (14). MS(ESI): m / z = 270 (M+H) +

[0145] (14) Synthesis of compound 17 (14): Under a nitrogen atmosphere, the crude compound 16 obtained in (13) (0.060 g) was dissolved in pyridine (0.5 mL) and 4,4'-dimethoxytrityl chloride (58 mg, 0.17 mmol) was prepared at room temperature. The mixture was added and stirred at the same temperature for 21 hours. 4,4'-Dimethoxytrityl chloride (12 mg, 0.035 mmol) was added and the mixture was stirred at room temperature for 20 hours. A further 4,4'-Dimethoxytrityl chloride (23 mg, 0.067 mmol) was added and the mixture was stirred at room temperature for 24 hours. Methanol was added to the reaction mixture, and the solvent was removed under reduced pressure. Dichloromethane (10 mL) and saturated sodium bicarbonate solution (5 mL) were added to the residue, and the aqueous layer was separated. The aqueous layer was extracted with dichloromethane (2 × 10 mL), and the combined organic layers were washed with saturated brine (5 mL). The organic layers were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude compound 17 obtained was purified by column chromatography (neutral silica gel, dichloromethane-methanol (9:1, v / v)) to obtain compound 17 (42.4 mg, 0.074 mmol, 40% yield from three steps ((12)-1, (13) and (14)) from compounds 14 and 15) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.50-11.20 (br, 1H), 7.62 (d, J = 1.2 Hz, 1H), 7.46-7.43 (m, 2H), 7.35-7.22 (m, 7H), 6.93-6.89 (m, 4H), 5.50-5.35 (br, 1H), 5.35 (s, 1H), 4.06 (s, 1H), 3.74 (s, 6H), 3.36-3.26 (m, 3H), 2.84 (d, J = 10 Hz, 1H), 2.63 (d, J = 9.6 Hz, 1H), 1.50 (s, 3H). MS(ESI): m / z = 573 (M+H) +

[0146] Example 2: Method for producing compound 9 (Alternative method 1) Compound 9 was produced from compound 6 via compounds 18 and 19 using the following method. [ka]

[0147] (1) Synthesis of compound 19 Under a nitrogen atmosphere, compound 6 (479 mg, 1.20 mmol) was dissolved in dichloromethane (9.6 mL), and after adding 4-methoxybenzylamine (188 μL, 1.45 mmol), the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (356 mg, 1.67 mmol) was added to the reaction mixture, and the mixture was heated in a room atmosphere. The mixture was stirred at warm temperature for 14 hours. Saturated sodium bicarbonate solution (4.8 mL) and benzyl chloroformate (250 μL, 1.77 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for a further 3 hours. Saturated sodium bicarbonate solution (4.8 mL) was added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted with dichloromethane (3 × 10 mL), and the combined organic layers were washed with saturated brine (4 mL). The organic layers were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 19 (931 mg) as a pale yellow viscous substance. The obtained crude substance was used directly in the next step (2). Compound 18 MS(ESI): m / z = 521 (M+H) + Compound 19 MS(ESI): m / z = 654 (M+H) +

[0148] (2) Synthesis of compound 9 Under a nitrogen atmosphere, the crude compound 19 (931 mg) obtained in step (1) was dissolved in acetonitrile (14 mL), and tap water (2.8 mL) was added. (NH4)2Ce(NO3)6 (2.37 g, 4.32 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Under ice cooling, saturated sodium bicarbonate solution (40 mL) and ethyl acetate (40 mL) were added to the reaction mixture, and insoluble matter was removed by filtration. The solid on the filter paper was sequentially washed with ethyl acetate (2 × 20 mL), tap water (20 mL), and saturated sodium bicarbonate solution (2 × 20 mL) to separate the organic layer of the filtrate. The aqueous layer was extracted with ethyl acetate (3 × 80 mL), and the combined organic layer was washed with saturated saline solution (60 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was then processed under reduced pressure. The compound 9 obtained was concentrated. The crude compound 9 was subjected to column chromatography (neutral silica gel, hexacrystalline silica gel). By purification with ethyl acetate (9:1-3:1, v / v), compound 9 (379 mg, 0.710 mmol, A two-step process ((1) and (2)) from compound 6 yielded a pale yellow viscous substance with a yield of 59%. 1 H NMR (400 MHz, CDCl3) δ 7.39-7.20 (m, 15H), 5.75 (d, J = 4.0 Hz, 1H), 5.32-5.27 (m, 1H), 5.08 (s, 2H), 4.77-4.72 (m, 1H), 4.63-4.59 (m, 1H), 4.52-4.47 (m, 2H), 4.40-4.35 (m, 1H), 4.25-4.19 (m, 1H), 3.75-3.69 (m, 1H), 3.63-3.57 (m, 1H), 3.52-3.48 (m, 1H), 3.43-3.38 (m, 1H), 1.57 (s, 3H), 1.32 (s, 3H). MS(ESI): m / z = 534 (M+H) +

[0149] Example 3: Method for producing compound 9 (Alternative method 2) Compound 9 was prepared from compound 6 via compound 20 and compound 21 using the following method. [ka]

[0150] (1) Synthesis of compound 20 Under a nitrogen atmosphere, dissolve compound 6 (1.49 g, 3.74 mmol) in dichloromethane (15 mL). At room temperature, allylamine (256 mg, 4.49 mmol) and sodium triacetoxyboronhydride were used. Add (1.11 g, 5.24 mmol) and stir overnight at the same temperature. Quench with 2 M sodium hydroxide solution and separate the organic layer. Wash the organic layer twice with saturated saline solution and combine with the aqueous layer. The material was extracted once with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain the crude compound 20 (1.61 g). The obtained crude compound was used directly in the next step (2). 1 H NMR (400 MHz, CDCl3) δ 7.35-7.23 (m, 10H), 5.92-5.82 (m, 1H), 5.77 (d, J = 4.0 Hz, 1H), 5.18-5.04 (m, 2H), 4.75 (d, J = 12 Hz, 1H), 4.61 (dd, J = 5.2 Hz, 4 Hz, 1H), 4.53 (d, J = 12 Hz, 2H), 4.41 (d, J = 12 Hz, 1H), 4.24 (d, J = 5.2 Hz, 1H), 3.77 (d, J = 10.4 Hz, 1H), 3.52 (d, J = 10.8 Hz, 1H), 3.28-3.16 (m, 3H), 2.77 (d, J = 12 Hz, 1H), 2.05 (s, 1H),1.61 (s, 3H), 1.33 (s, 3H).

[0151] (2) Synthesis of compound 21 Under a nitrogen atmosphere, crude compound 20 (1.25 g) was dissolved in dichloromethane (13 mL). At 40 °C, N,N-dimethylbarbitulic acid (680 mg, 4.36 mmol) and tetrakis(triphenylphosphorus) were dissolved. Fin)Palladium(0) (168 mg, 0.145 mmol) was added and stirred at the same temperature for 75 minutes. Isopropyl acetate was added and the mixture was washed successively with an aqueous sodium hydroxide solution and brine. After concentrating the organic layer under reduced pressure, the residue was dissolved in toluene and extracted with an aqueous citric acid solution (13 mL). The aqueous layer containing the crude form of Compound 21 was used as it was in the next step (3).

[0152] (3) Synthesis of Compound 9 Under a nitrogen atmosphere, 5 M aqueous sodium hydroxide solution (4 mL) was added to the entire amount of the aqueous layer obtained in step (2). , ethyl acetate (3 mL) was added. Next, N-(benzylo xycarbonyl oxy)succinimide (724 mg, 2.90 mmol) dissolved in ethyl acetate (5 mL) was added dropwise at room temperature and the reaction solution was stirred. After adding N-methylpiperazine (100.17 g, 2.90 mmol) for quenching, the organic layer was separated and washed successively with 10% (w / w) aqueous citric acid solution, 10% (w / w) brine, 5% (w / w) aqueous sodium bicarbonate solution, 10% (w / w) brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude form of Compound 9 (1.01 g, HPLC purity of 73.0% (220 nm) for three steps ((1), (2) and (3)) from Compound 6). 1H NMR (400 MHz, CDCl3) δ 7.40-7.21 (m, 15H), 5.75 (d, J = 4.0 Hz, 1H), 5.32-5.27 (m,, 1H), 5.08 (s, 2H), 4.75 (d, J = 12 Hz, 1H), 4.61 (dd, J = 4.4 Hz, 4.4 Hz, 1H), 4.52-4.47 (m, 2H), 4.37 (d, J = 12 Hz, 1H), 4.22 (d, J = 5.2 Hz, 1H), 3.71 (dd, J = 14.4 Hz, 4 Hz, 1H), 3.60 (dd, J = 14.4 Hz, 8 Hz, 1H), 3.49 (d, J = 10.4 Hz, 1H), 3.40 (d, J = 10.8 Hz, 1H), 1.56 (s, 3H), 1.32 (s, 3H).

[0153] The disclosure of Japanese Patent Application No. 2022-204199 (filing date: December 21, 2022) is incorporated herein by reference in its entirety. All documents, patent applications, and technical standards described herein are incorporated by reference to the same extent as if each individual document, patent application, and technical standard were specifically and individually noted to be incorporated by reference.

Claims

1. Equation (I): 【Chemistry 1】 [In the formula, R １ This indicates a protecting group for hydroxyl groups. R ２ This indicates a protecting group for hydroxyl groups. R ３ and R ４ These are either identical or different, each independently representing a hydroxyl group protecting group, or R ３ and R ４ This shows the cyclic protecting group of the diol formed by the combination of these two components. From the compound represented by, Formula (IV): 【Chemistry 2】 [In the formula, R １ This indicates a protecting group for hydroxyl groups. R ２ This indicates a protecting group for hydroxyl groups. R ３ and R ４ are the same or different and each independently represents a protecting group for a hydroxyl group, or R ３ and R ４ together represent a cyclic protecting group for a diol formed, R ５ and R ６ One side represents a protecting group for a hydrogen atom or an amino group, and the other side represents a protecting group for an amino group. A method for producing a compound represented by the following steps 1 to 3: Process 1: Equation (I): 【Transformation 3】 [In the formula, each symbol has the same meaning as above.] The compound represented by, Formula (V): 【Chemistry 4】 [In the formula, R ７ [This represents a hydrogen atom or an alkyl group.] By reacting a compound represented by or a salt thereof, Formula (II): 【Transformation 5】 [In the formula, R １ This indicates a protecting group for hydroxyl groups. R ２ This indicates a protecting group for hydroxyl groups. R ３ and R ４ These are either identical or different, each independently representing a hydroxyl group protecting group, or R ３ and R ４ It shows the cyclic protecting group of the diol that is formed together, R ７ [This represents a hydrogen atom or an alkyl group.] A step to obtain a compound represented by; Process 2: The compound represented by formula (II) is subjected to a reduction reaction with a reducing agent, Formula (III): 【Transformation 6】 [In the formula, R １ This indicates a protecting group for hydroxyl groups. R ２ This indicates a protecting group for hydroxyl groups. R ３ and R ４ These are either identical or different, each independently representing a hydroxyl group protecting group, or R ３ and R ４ This shows the cyclic protecting group of the diol formed by the combination of these two components. A step of obtaining a compound represented by; and Step 3: A step of subjecting the compound represented by formula (III) to an amino group protection reaction. A manufacturing method that includes this.

2. The reducing agent used in step 2 is sodium bis(2-methoxyethoxy)aluminum hydride. The manufacturing method according to claim 1, wherein the material is (Red-Al).

3. Equation (I): 【Transformation 7】 [In the formula, R １ This indicates a protecting group for hydroxyl groups. R ２ This indicates a protecting group for hydroxyl groups. R ３ and R ４ These are either identical or different, each independently representing a hydroxyl group protecting group, or there are Iha, R ３ and R ４ This shows the cyclic protecting group of the diol formed by the combination of these two components. The compound represented by the following steps 4-8; Step 4: Equation (VI): 【Transformation 8】 [In the formula, R ３ and R ４ These are either identical or different, each independently representing a hydroxyl group protecting group, or R ３ and R ４ This shows the cyclic protecting group of the diol formed by the combination of these two components. The compound represented by is subjected to an oxidation reaction, Formula (VII): 【Chemistry 9】 [In the formula, R ３ and R ４ These are either identical or different, each independently representing a hydroxyl group protecting group, or R ３ and R ４ This shows the cyclic protecting group of the diol formed by the combination of these two components. A step to obtain a compound represented by; Steps 5-7: The compound represented by formula (VII) is subjected sequentially to an aldol reaction (step 5), a reduction reaction (step 6), and a hydroxyl group protection reaction (step 7). Formula (X): 【Chemistry 10】 [In the formula, R １ R indicates a protecting group for hydroxyl groups. ２ R indicates a protecting group for hydroxyl groups. ３ and R ４ These are either identical or different, each independently representing a hydroxyl group protecting group, or R ３ and R ４ This shows the cyclic protecting group of the diol formed by the combination of these two components. A step of obtaining a compound represented by; and Step 8: A step of subjecting the compound represented by formula (X) to an oxidative cleavage reaction. The manufacturing method according to claim 1, which is produced by a process including the following.

4. Formula (IV): 【Chemistry 11】 [In the formula, R １ This indicates a protecting group for hydroxyl groups. R ２ This indicates a protecting group for hydroxyl groups. R ３ and R ４ These are either identical or different, each independently representing a hydroxyl group protecting group, or R ３ and R ４ It shows the cyclic protecting group of the diol that is formed together, R ５ and R ６ One side represents a protecting group for a hydrogen atom or an amino group, and the other side represents a protecting group for an amino group. From the compound represented by, Equation (XIII): 【Chemistry 12】 [In the formula, R １ This indicates a protecting group for hydroxyl groups. R ２ This indicates a protecting group for hydroxyl groups. R ５ and R ６ One of them represents a protecting group for a hydrogen atom or an amino group, and the other represents a protecting group for an amino group. B represents the base portion of a nucleic acid, which may be substituted with one or more substituents. A method for producing a compound represented by the following steps 9 to 11; Step 9: A compound represented by formula (IV), produced by the manufacturing method described in any one of claims 1 to 3, is optionally R ３ and R ４ The reaction is performed to convert the acyl group, Formula (XI): 【Chemistry 13】 [In the formula, R １ This indicates a protecting group for hydroxyl groups. R ２ This indicates a protecting group for hydroxyl groups. R ３ａ This indicates an acyl group, R ４ａ This indicates an acyl group, R ５ and R ６ One side represents a protecting group for a hydrogen atom or an amino group, and the other side represents a protecting group for an amino group. A step to obtain a compound represented by; Step 10: By subjecting the compound represented by formula (XI) to a glucosylation reaction, Equation (XII): 【Chemistry 14】 [In the formula, R １ This indicates a protecting group for hydroxyl groups. R ２ This indicates a protecting group for hydroxyl groups. R ４ａ This indicates an acyl group, R ５ and R ６ One of them represents a protecting group for a hydrogen atom or an amino group, and the other represents a protecting group for an amino group. B represents the base portion of a nucleic acid, which may be substituted with one or more substituents. A step of obtaining a compound represented by; and Step 11: The step of subjecting the compound represented by formula (XII) to a deprotection reaction of the acyl group. A manufacturing method that includes this.

5. B is equation (XXIV): 【Chemistry 15】 [In the formula, R １２ This represents a hydrogen atom, an alkyl group, an alkoxy group, or an alkoxyalkyl group. X is an oxygen atom or NR １３ (R １３ (This indicates a protecting group for a hydrogen atom or an amino group.) A double line consisting of a solid and a dotted line indicates a single or double bond. The manufacturing method according to claim 4, as represented by [the method described in claim 4].

6. Equation (XIII'): 【Chemistry 16】 [In the formula, R １ This indicates a protecting group for hydroxyl groups. R ２ This indicates a protecting group for hydroxyl groups. R ５ and R ６ One of them represents a protecting group for a hydrogen atom or an amino group, and the other represents a protecting group for an amino group. R １２ This represents a hydrogen atom, an alkyl group, an alkoxy group, or an alkoxyalkyl group. X is an oxygen atom or NR １３ (R １３ (This indicates a protecting group for a hydrogen atom or an amino group.) A double line consisting of a solid and a dotted line indicates a single or double bond. From the compound represented by, Formula (XVII): 【Chemistry 17】 [In the formula, R １ This indicates a protecting group for a hydrogen atom or a hydroxyl group. R １２ This represents a hydrogen atom, an alkyl group, an alkoxy group, or an alkoxyalkyl group. X is an oxygen atom or NR １３ (R １３ (This indicates a protecting group for a hydrogen atom or an amino group.) A double line consisting of a solid and a dotted line indicates a single or double bond. A method for producing a compound represented by the following steps 12 to 15; Step 12: A compound represented by formula (XIII'), produced by the manufacturing method described in claim 4, is subjected to a sulfonylation reaction. Formula (XIV): [Chemistry 18] [In the formula, R １ This indicates a protecting group for hydroxyl groups. R ２ This indicates a protecting group for hydroxyl groups. R ５ and R ６ one of which represents a hydrogen atom or a protecting group for an amino group, and the other represents a protecting group for an amino group, R １１ This indicates an alkyl group or aryl group. R １２ This represents a hydrogen atom, an alkyl group, an alkoxy group, or an alkoxyalkyl group. X is an oxygen atom or NR １３ (R １３ (This indicates a protecting group for a hydrogen atom or an amino group.) A double line consisting of a solid and a dotted line indicates a single or double bond. A step to obtain a compound represented by; Step 13: The compound represented by formula (XIV) is subjected to a cyclization reaction, Formula (XV): 【Chemistry 19】 [In the formula, R １ This indicates a protecting group for hydroxyl groups. R ２ represents a protecting group for a hydroxyl group, R ５ and R ６ One of them represents a protecting group for a hydrogen atom or an amino group, and the other represents a protecting group for an amino group. R １２ This represents a hydrogen atom, an alkyl group, an alkoxy group, or an alkoxyalkyl group. X is an oxygen atom or NR １３ (R １３ (This indicates a protecting group for a hydrogen atom or an amino group.) A double line consisting of a solid and a dotted line indicates a single or double bond. A step to obtain a compound represented by; Step 14: The compound represented by formula (XV) is subjected to a ring-closing reaction, Formula (XVI): 【Chemistry 20】 [In the formula, R １ This indicates a protecting group for hydroxyl groups. R ２ This indicates a protecting group for hydroxyl groups. R １２ This represents a hydrogen atom, an alkyl group, an alkoxy group, or an alkoxyalkyl group. R １４ This indicates a protecting group for a hydrogen atom or an amino group. X is an oxygen atom or NR １３ (R １３ (This indicates a protecting group for a hydrogen atom or an amino group.) A double line consisting of a solid and a dotted line indicates a single or double bond. The process of obtaining a compound represented by; and Step 15: A step of subjecting a compound represented by formula (XVI) to a deprotection reaction, or a deprotection reaction followed by a hydroxyl group protection reaction. A manufacturing method that includes this.

7. Formula (II): 【Chemistry 21】 [In the formula, R １ This indicates a protecting group for hydroxyl groups. R ２ This indicates a protecting group for hydroxyl groups. R ３ and R ４ These are either identical or different, each independently representing a hydroxyl group protecting group, or R ３ and R ４ It shows the cyclic protecting group of the diol that is formed together, R ７ This represents a hydrogen atom or an alkyl group. A compound represented by the formula.

8. Formula (III): 【Chemistry 22】 [In the formula, R １ This indicates a protecting group for hydroxyl groups. R ２ This indicates a protecting group for hydroxyl groups. R ３ and R ４ These are either identical or different, each independently representing a hydroxyl group protecting group, or R ３ and R ４ This shows the cyclic protecting group of the diol formed by the combination of these two components. A compound represented by the formula.

9. Formula (IV): 【Chemistry 23】 [In the formula, R １ This indicates a protecting group for hydroxyl groups. R ２ This represents a benzyl group, 4,4'-dimethoxytrityl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethylsilyl)ethoxymethyl group, 2-methoxyethoxymethyl group, cyanoethyl group, benzoyl group, or acetyl group. R ３ and R ４ These are either identical or different, each independently representing a hydroxyl group protecting group, or R ３ and R ４ It shows the cyclic protecting group of the diol that is formed together, R ５ and R ６ One side represents a protecting group for a hydrogen atom or an amino group, and the other side represents a protecting group for an amino group. A compound represented by the formula.

10. Formula (XI): 【Chemistry 24】 [In the formula, R １ This indicates a protecting group for hydroxyl groups. R ２ This indicates a protecting group for hydroxyl groups. R ３ａ and R ４ａ This indicates an acyl group, R ５ and R ６ One side represents a protecting group for a hydrogen atom or an amino group, and the other side represents a protecting group for an amino group. A compound represented by the formula.

11. Formula (XI): 【Chemistry 25】 [In the formula, R １ This indicates a protecting group for hydroxyl groups. R ２ This represents a benzyl group, 4,4'-dimethoxytrityl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethylsilyl)ethoxymethyl group, 2-methoxyethoxymethyl group, cyanoethyl group, benzoyl group, or acetyl group. R ３ａ and R ４ａ This indicates an acyl group, R ５ and R ６ One side represents a protecting group for a hydrogen atom or an amino group, and the other side represents a protecting group for an amino group. The compound according to claim 10, represented by the following:

12. Equation (XII): 【Chemistry 26】 [In the formula, R １ This indicates a protecting group for hydroxyl groups. R ２ This indicates a protecting group for hydroxyl groups. R ４ａ This indicates an acyl group, R ５ and R ６ One of them represents a protecting group for a hydrogen atom or an amino group, and the other represents a protecting group for an amino group. B represents the base portion of a nucleic acid, which may be substituted with one or more substituents. A compound represented by the formula.

13. Equation (XII): 【Chemistry 27】 [In the formula, R １ This indicates a protecting group for hydroxyl groups. R ２ This represents a benzyl group, 4,4'-dimethoxytrityl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethylsilyl)ethoxymethyl group, 2-methoxyethoxymethyl group, cyanoethyl group, benzoyl group, or acetyl group. R ４ａ This indicates an acyl group, R ５ and R ６ One of them represents a protecting group for a hydrogen atom or an amino group, and the other represents a protecting group for an amino group. B represents the base portion of a nucleic acid, which may be substituted with one or more substituents. The compound according to claim 12, represented by the following:

14. The compound according to claim 12 or 13, wherein B is thyminyl.

15. Equation (XIII): 【Chemistry 28】 [In the formula, R １ This indicates a protecting group for hydroxyl groups. R ２ This represents a benzyl group, 4,4'-dimethoxytrityl group, t-butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethylsilyl)ethoxymethyl group, 2-methoxyethoxymethyl group, cyanoethyl group, benzoyl group, or acetyl group. R ５ and R ６ One of them represents a protecting group for a hydrogen atom or an amino group, and the other represents a protecting group for an amino group. B represents the base portion of a nucleic acid, which may be substituted with one or more substituents. A compound represented by the formula.

16. The compound according to claim 15, wherein B is thyminyl.

17. Formula (XIV): 【Chemistry 29】 [In the formula, R １ This indicates a protecting group for hydroxyl groups. R ２ This indicates a protecting group for hydroxyl groups. R ５ and R ６ One of them represents a protecting group for a hydrogen atom or an amino group, and the other represents a protecting group for an amino group. R １１ This indicates an alkyl group or aryl group. R １２ This represents a hydrogen atom, an alkyl group, an alkoxy group, or an alkoxyalkyl group. X is an oxygen atom or NR １３ (R １３ (This indicates a protecting group for a hydrogen atom or an amino group.) A double line consisting of a solid and a dotted line indicates a single or double bond. A compound represented by the formula.

18. Formula (XIV): 【Transformation 30】 [In the formula, R １ This indicates a protecting group for hydroxyl groups. R ２ This represents a benzyl group, 4,4'-dimethoxytrityl group, t-butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethylsilyl)ethoxymethyl group, 2-methoxyethoxymethyl group, cyanoethyl group, benzoyl group, or acetyl group. R ５ and R ６ One of them represents a protecting group for a hydrogen atom or an amino group, and the other represents a protecting group for an amino group. R １１ This indicates an alkyl group or aryl group. R １２ This represents a hydrogen atom, an alkyl group, an alkoxy group, or an alkoxyalkyl group. X is an oxygen atom or NR １３ (R １３ (This indicates a protecting group for a hydrogen atom or an amino group.) A double line consisting of a solid and a dotted line indicates a single or double bond. The compound according to claim 17, represented by the formula.

19. R １２ The compound according to claim 17 or 18, wherein is a methyl group and X is an oxygen atom.

20. Formula (XV): 【Chemistry 31】 [In the formula, R １ This indicates a protecting group for hydroxyl groups. R ２ This indicates a protecting group for hydroxyl groups. R ５ and R ６ One of them represents a protecting group for a hydrogen atom or an amino group, and the other represents a protecting group for an amino group. R １２ This represents a hydrogen atom, an alkyl group, an alkoxy group, or an alkoxyalkyl group. X is an oxygen atom or NR １３ (R １３ (This indicates a protecting group for a hydrogen atom or an amino group.) A double line consisting of a solid and a dotted line indicates a single or double bond. A compound represented by the formula.

21. Formula (XV): 【Chemistry 32】 [In the formula, R １ This indicates a protecting group for hydroxyl groups. R ２ This represents a benzyl group, 4,4'-dimethoxytrityl group, t-butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethylsilyl)ethoxymethyl group, 2-methoxyethoxymethyl group, cyanoethyl group, benzoyl group, or acetyl group. R ５ and R ６ One of them represents a protecting group for a hydrogen atom or an amino group, and the other represents a protecting group for an amino group. R １２ This represents a hydrogen atom, an alkyl group, an alkoxy group, or an alkoxyalkyl group. X is an oxygen atom or NR １３ (R １３ (This indicates a protecting group for a hydrogen atom or an amino group.) A double line consisting of a solid and a dotted line indicates a single or double bond. The compound according to claim 20, as represented by the compound.

22. R １２ The compound according to claim 20 or 21, wherein is a methyl group and X is an oxygen atom.

23. R １２ is a methyl group, X is an oxygen atom, and R １ is a benzyl group, R ２ is a benzyl group, R ５ is a benzyloxycarbonyl group, R ６ The compound according to claim 20 or 21, wherein is a hydrogen atom, and the double line consisting of a solid line and a dotted line is a single bond or a double bond.

24. A crystal of the compound according to claim 23.

25. A crystal of the compound according to claim 24, wherein the powder X-ray diffraction spectrum measured using CuKα emission has peaks at diffraction angles represented by 2θ, namely 7.4±0.2°, 19.2±0.2°, 20.1±0.2°, 21.3±0.2°, and 24.7±0.2°.

26. Formula (XVI): 【Transformation 33】 [In the formula, R １ This indicates a protecting group for hydroxyl groups. R ２ This indicates a protecting group for hydroxyl groups. R １２ This represents a hydrogen atom, an alkyl group, an alkyloxy group, or an alkoxyalkyl group. R １４ This represents a hydrogen atom, a benzyloxycarbonyl group, an isobutyryl group, a benzoyl group, a t-butoxycarbonyl group, a trimethylsilylethoxycarbonyl group, an allyloxycarbonyl group, a 9-fluorenylmethoxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, an acetyl group, a formyl group, a 4-methoxybenzyl group, an allyl group, a benzyl group, or a 2-nitrobenzenesulfonyl group. X is an oxygen atom or NR １３ (R １３ (This indicates a protecting group for a hydrogen atom or an amino group.) A double line consisting of a solid and a dotted line indicates a single or double bond. A compound represented by the formula.

27. Formula (XVI): 【Transformation 34】 [In the formula, R １ This indicates a protecting group for hydroxyl groups. R ２ This represents a benzyl group, 4,4'-dimethoxytrityl group, t-butyldiphenylsilyl group, trimethylsilyl group, methoxymethyl group, benzyloxymethyl group, 2-(trimethylsilyl)ethoxymethyl group, 2-methoxyethoxymethyl group, cyanoethyl group, benzoyl group, or acetyl group. R １２ This represents a hydrogen atom, an alkyl group, an alkoxy group, or an alkoxyalkyl group. R １４ This represents a hydrogen atom, a benzyloxycarbonyl group, an isobutyryl group, a benzoyl group, a t-butoxycarbonyl group, a trimethylsilylethoxycarbonyl group, an allyloxycarbonyl group, a 9-fluorenylmethoxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, an acetyl group, a formyl group, a 4-methoxybenzyl group, an allyl group, a benzyl group, or a 2-nitrobenzenesulfonyl group. X is an oxygen atom or NR １３ (R １３ (This indicates a protecting group for a hydrogen atom or an amino group.) A double line consisting of a solid and a dotted line indicates a single or double bond. The compound according to claim 26, represented by the following:

28. Formula (XVII''): 【Chemistry 35】 [In the formula, R １a This indicates a protecting group for hydroxyl groups. R １２ This represents a hydrogen atom, an alkyl group, an alkoxy group, or an alkoxyalkyl group. X is an oxygen atom or NR １３ (R １３ (This indicates a protecting group for a hydrogen atom or an amino group.) A double line consisting of a solid and a dotted line indicates a single or double bond. From the compound represented by, Below formula: 【Transformation 36】 A method for producing a modified oligonucleotide or a salt thereof, wherein the production method is A step of producing a compound represented by formula (XVII'') by the manufacturing method described in claim 6, a step of producing ALNA[Ms]amidite from a compound represented by formula (XVII''), a step of subjecting the ALNA[Ms]amidite and DNA synthesis amidite to a phosphoramidite method, and If necessary, the phosphodiester bond is subjected to a thiolation reaction. A manufacturing method that includes this.

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