Method for producing intermediate, intermediate for production, and method for producing bridged artificial nucleic acid intermediate using same

Abstract

The present invention addresses the problem of providing: a method for producing an intermediate, which is advantageous and safe for industrial production; the intermediate; and a method for producing a bridged artificial nucleic acid intermediate using the intermediate. Comprising a compound represented by formula (I) [in the formula, each symbol is as defined in the specification. ] [In the formula, each symbol is as defined in the description. ] A method for producing a compound represented by formula (1). # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a method for manufacturing an intermediate, the intermediate, and a method for manufacturing a bridged artificial nucleic acid intermediate using the same. Background Art

[0002] As a method for treating diseases based on nucleic acid drugs, there are an antisense method, an antigene method, a method using aptamers, a method using siRNA, and the like. Among them, the antisense method is a method in which an oligonucleotide (antisense strand) complementary to mRNA or non-translated RNA related to a disease is introduced from the outside to form a double strand, thereby regulating the function of RNA related to the disease and treating and preventing the disease.

[0003] As raw materials for such nucleic acid drugs, various artificial nucleic acids have been developed, and ALNA[Ms] (ALNA refers to 2'-amino LNA (Locked nucleic acid)), ALNA[mU], ALNA[ipU], ALNA[oxz], ALNA[Trz], guanidine-bridged artificial nucleic acid (GuNA), etc. having excellent in vitro and / or in vivo pharmacological activities have been discovered (Patent Document 1). It has been reported that these ALNAs and GuNAs are respectively manufactured from the key intermediates of the bridged artificial nucleic acids shown below (for example, see Patent Document 1 and Patent Document 2).

[0004] [Chemical Formula 1]

[0005]

[0006] Regarding the method for manufacturing the bridged artificial nucleic acid intermediate, it is described in Patent Document 1, Non-Patent Documents 1 and 2.

[0007] Prior Art Documents

[0008] Patent Documents

[0009] Patent Document 1: International Publication No. 2020 / 100826

[0010] Patent Document 2: International Publication No. 2017 / 047816

[0011] Non-Patent Documents

[0012] Non-Patent Document 1: J. Org. Chem. 2012, 77, 23, 10718–10728

[0013] Non-Patent Document 2: Org Biomol Chem. 2003 Feb 21; 1(4):655-63 Summary of the Invention

[0014] Regarding the manufacturing methods of this bridged artificial nucleic acid intermediate described in Patent Document 1, Patent Document 2, and Non-Patent Document 1, in the step of introducing the nitrogen atom contained in the bridging structure between the 4' and 2' ribosyl ring atoms, a metal azide with risks such as generation of explosive and / or toxic gases is used as a reagent, and moreover, as an intermediate for manufacturing, it passes through an azide compound with explosive risks. Therefore, there is room for improvement. In addition, regarding the manufacturing method of this bridged artificial nucleic acid intermediate described in Non-Patent Document 2, although it is a manufacturing method that does not pass through an azide compound, it has been reported that the yield of the step of introducing the nitrogen atom contained in the bridging structure between the 4' and 2' ribosyl ring atoms is very low. Due to such a situation, an industrially excellent manufacturing method for bridged artificial nucleic acid intermediates such as ALNA[Ms], ALNA[mU], ALNA[ipU], ALNA[oxz], ALNA[Trz], and GuNA is desired.

[0015] The conventional manufacturing methods of bridged artificial nucleic acid intermediates use the aforementioned hazardous metal azides, and moreover, as an intermediate for manufacturing, it passes through the aforementioned hazardous azide compound. Therefore, from the perspective of manufacturing, there is room for improvement in the safety of operators. In addition, the manufacturing method that does not pass through an azide compound has a low yield, which is not conducive to large-scale manufacturing, and there are problems as an industrial manufacturing method.

[0016] Therefore, an object of the present invention is to provide a manufacturing method of an intermediate for manufacturing, a manufacturing method of a bridged artificial nucleic acid intermediate using the intermediate, etc., which are advantageous and safe for industrial manufacturing, and these inventions solve the above problems.

[0017] The inventors of the present application have conducted various studies in order to safely and reproducibly carry out each manufacturing step with a high yield. As a result, they have found the following industrially advantageous manufacturing method. By performing a reductive amination reaction, this manufacturing method can safely manufacture an intermediate useful for manufacturing a bridged artificial nucleic acid intermediate with a high yield without using the aforementioned hazardous reagents and intermediates. In addition, they have found the following industrially advantageous manufacturing method. By adopting a step of crystallizing one of the manufacturing intermediates, a bridged artificial nucleic acid intermediate as the target can be manufactured with a high yield and high quality. In addition, some novel manufacturing intermediates useful in these manufacturing methods have been found.

[0018] That is, the present invention includes the following embodiments.

[0019] The first embodiment of the present invention is a manufacturing method of a compound represented by the following formula (IV).

[0020] [1] Manufacturing method, which is a method for manufacturing a compound represented by formula (IV) from a compound represented by formula (I),

[0021] [Chemical formula 2]

[0022]

[0023] [In the formula,

[0024] R 1 represents a protecting group for a hydroxyl group,

[0025] R 2 represents a protecting group for a hydroxyl group,

[0026] R 3 and R 4 are the same or different and each independently represents a protecting group for a hydroxyl group, or represents a cyclic protecting group of a diol formed by R 3 and R 4 together.]

[0027] [Chemical formula 3]

[0028]

[0029] [In the formula,

[0030] R 1 represents a protecting group for a hydroxyl group,

[0031] R 2 represents a protecting group for a hydroxyl group,

[0032] R 3 and R 4 are the same or different and each independently represents a protecting group for a hydroxyl group, or represents a cyclic protecting group of a diol formed by R 3 and R 4 together,

[0033] 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.]

[0034] The aforementioned manufacturing method includes the following steps 1 to 3,

[0035] Step 1:

[0036] A step of reacting a compound represented by formula (I) with a compound represented by formula (V) or a salt thereof to obtain a compound represented by formula (II),

[0037] [Chemical formula 4]

[0038]

[0039] [In the formula, the meanings of the symbols are the same as those described above.]

[0040] [Chemical Formula 5]

[0041] R 7 O-NH2 (V)

[0042] [In the formula, R 7 represents a hydrogen atom or an alkyl group.]

[0043] [Chemical Formula 6]

[0044]

[0045] [In the formula,

[0046] R 1 represents a protecting group for a hydroxyl group,

[0047] R 2 represents a protecting group for a hydroxyl group,

[0048] R 3 and R 4 are the same or different and each independently represents a protecting group for a hydroxyl group, or represents a cyclic protecting group for a diol formed by R 3 and R 4 together.]

[0049] R 7 represents a hydrogen atom or an alkyl group.]

[0050] Step 2:

[0051] A step of subjecting the compound represented by formula (II) to a reduction reaction using a reducing agent to obtain the compound represented by formula (III).

[0052] [Chemical Formula 7]

[0053]

[0054] [In the formula,

[0055] R 1 represents a protecting group for a hydroxyl group,

[0056] R 2 represents a protecting group for a hydroxyl group,

[0057] R 3 and R 4 are the same or different and each independently represents a protecting group for a hydroxyl group, or represents a cyclic protecting group for a diol formed by R 3 and R 4 together.]

[0058] And, Step 3:

[0059] A step of subjecting the compound represented by formula (III) to a reaction for protecting an amino group.

[0060] [2] The production method according to [1] above, wherein the reducing agent used in step 2 is sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al).

[0061] [3] The production method according to [1] or [2] above, wherein the compound represented by formula (I) is produced through steps 4 to 8 including the following:

[0062] [Chemical formula 8]

[0063]

[0064] [In the formula,

[0065] R 1 represents a protecting group for a hydroxyl group,

[0066] R 2 represents a protecting group for a hydroxyl group,

[0067] R 3 and R 4 are the same or different and each independently represents a protecting group for a hydroxyl group, or represents a cyclic protecting group of a diol formed by R 3 and R 4 together.]

[0068] Step 4:

[0069] A step of subjecting the compound represented by formula (VI) to an oxidation reaction to obtain the compound represented by formula (VII),

[0070] [Chemical formula 9]

[0071]

[0072] [In the formula, R 3 and R 4 are the same or different and each independently represents a protecting group for a hydroxyl group, or represents a cyclic protecting group of a diol formed by R 3 and R 4 together.]

[0073] [Chemical formula 10]

[0074]

[0075] [In the formula, R 3 and R 4 are the same or different and each independently represents a protecting group for a hydroxyl group, or represents a cyclic protecting group of a diol formed by R 3 and R 4Cyclic protecting groups of the diols formed together.

[0076] Steps 5 to 7:

[0077] A step of subjecting the compound represented by formula (VII) to an aldol condensation reaction (step 5), a reduction reaction (step 6), and a protecting reaction of a hydroxyl group (step 7) in sequence to obtain the compound represented by formula (X).

[0078] [Chemical formula 11]

[0079]

[0080] [In the formula, R 3 and R 4 are the same or different and each independently represents a protecting group for a hydroxyl group, or represents a cyclic protecting group of a diol formed by R 3 and R 4 together.

[0081] And, step 8:

[0082] A step of subjecting the compound represented by formula (X) to an oxidative cleavage reaction.

[0083] The second embodiment of the present invention is a method for producing a compound represented by the following formula (XIII).

[0084] [4] A production method, which is a method for producing a compound represented by formula (XIII) from a compound represented by formula (IV).

[0085] [Chemical formula 12]

[0086]

[0087] [In the formula,

[0088] R 1 represents a protecting group for a hydroxyl group,

[0089] R 2 represents a protecting group for a hydroxyl group,

[0090] R 3 and R 4 are the same or different and each independently represents a protecting group for a hydroxyl group, or represents a cyclic protecting group of a diol formed by R 3 and R 4 together,

[0091] 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.

[0092] [Chemical formula 13]

[0093]

[0094] [wherein,

[0095] R 1 represents a protecting group for a hydroxyl group,

[0096] R 2 represents a protecting group for a hydroxyl group,

[0097] 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,

[0098] B represents a base moiety of a nucleic acid which may be substituted with one or more substituents.]

[0099] The aforementioned production method includes the following steps 9 to 11,

[0100] Step 9:

[0101] Subjecting the compound represented by formula (IV) produced by the production method described in any one of the above [1] to [3] to a conversion reaction of R 3 and R 4 to an acyl group as needed, thereby obtaining a compound represented by formula (XI)

[0102] [Chemical formula 14]

[0103]

[0104] [wherein,

[0105] R 1 represents a protecting group for a hydroxyl group,

[0106] R 2 represents a protecting group for a hydroxyl group,

[0107] R 3a represents an acyl group,

[0108] R 4a represents an acyl group,

[0109] 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.]

[0110] Step 10:

[0111] Subjecting the compound represented by formula (XI) to a glycosylation reaction, thereby obtaining a compound represented by formula (XII)

[0112] [Chemical Formula 15]

[0113]

[0114] [wherein,

[0115] R 1 represents a protecting group for a hydroxyl group,

[0116] R 2 represents a protecting group for a hydroxyl group,

[0117] R 4a represents an acyl group,

[0118] R 5 and one of R 6 represents a hydrogen atom or a protecting group for an amino group, and the other represents a protecting group for an amino group,

[0119] B represents a base moiety of a nucleic acid which may be substituted with one or more substituents.]

[0120] And, Step 11:

[0121] a step of subjecting the compound represented by formula (XII) to a deprotection reaction of an acyl group.

[0122] [5] The production method according to [4] above, wherein B is represented by formula (XXIV).

[0123] [Chemical Formula 16]

[0124]

[0125] [wherein,

[0126] R 12 represents a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkyl group,

[0127] X represents an oxygen atom or NR 13 (R 13 represents a hydrogen atom or a protecting group for an amino group),

[0128] the double line composed of a solid line and a dotted line represents a single bond or a double bond.]

[0129] The third embodiment of the present invention is a method for producing a compound represented by the following formula (XVII).

[0130] [6] A production method, which is a method for producing a compound represented by formula (XVII) from a compound represented by formula (XIII’),

[0131] [Chemical Formula 17]

[0132]

[0133] [In the formula,

[0134] R 1 represents a protecting group for a hydroxyl group,

[0135] R 2 represents a protecting group for a hydroxyl group,

[0136] R 5 and one of R 6 represents a hydrogen atom or a protecting group for an amino group, and the other represents a protecting group for an amino group,

[0137] R 12 represents a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkyl group,

[0138] X represents an oxygen atom or NR 13 (R 13 represents a hydrogen atom or a protecting group for an amino group),

[0139] The double line composed of a solid line and a dotted line represents a single bond or a double bond.]

[0140] [Chemical formula 18]

[0141]

[0142] [In the formula,

[0143] R 1 represents a hydrogen atom or a protecting group for a hydroxyl group,

[0144] R 12 represents a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkyl group,

[0145] X represents an oxygen atom or NR 13 (R 13 represents a hydrogen atom or a protecting group for an amino group),

[0146] The double line composed of a solid line and a dotted line represents a single bond or a double bond.]

[0147] The aforementioned manufacturing method includes the following steps 12 to 15,

[0148] Step 12:

[0149] A step of subjecting the compound represented by formula (XIII') produced by the manufacturing method described in the above [4] or [5] to a sulfonylation reaction to obtain the compound represented by formula (XIV),

[0150] [Chemical formula 19]

[0151]

[0152] [In the formula,

[0153] R 1 represents a protecting group for a hydroxyl group,

[0154] R 2 represents a protecting group for a hydroxyl group,

[0155] R 5 and one of R 6 represents a protecting group for a hydrogen atom or an amino group, and the other represents a protecting group for an amino group,

[0156] R 11 represents an alkyl group or an aryl group,

[0157] R 12 represents a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkyl group,

[0158] X represents an oxygen atom or NR 13 (R 13 represents a protecting group for a hydrogen atom or an amino group),

[0159] The double line composed of a solid line and a dotted line represents a single bond or a double bond.]

[0160] Step 13:

[0161] The step of subjecting the compound represented by formula (XIV) to a cyclization reaction to obtain the compound represented by formula (XV),

[0162] [Chemical formula 20]

[0163]

[0164] [In the formula,

[0165] R 1 represents a protecting group for a hydroxyl group,

[0166] R 2 represents a protecting group for a hydroxyl group,

[0167] R 5 and one of R 6 represents a protecting group for a hydrogen atom or an amino group, and the other represents a protecting group for an amino group,

[0168] R 12 represents a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkyl group,

[0169] X represents an oxygen atom or NR 13 (R 13 represents a protecting group for a hydrogen atom or an amino group),

[0170] The double line composed of a solid line and a dotted line represents a single bond or a double bond.]

[0171] Step 14:

[0172] A step of subjecting the compound represented by formula (XV) to a ring-closure reaction to obtain the compound represented by formula (XVI),

[0173] [Chemical formula 21]

[0174]

[0175] [In the formula,

[0176] R 1 represents a protecting group for a hydroxyl group,

[0177] R 2 represents a protecting group for a hydroxyl group,

[0178] R 12 represents a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkyl group,

[0179] R 14 represents a hydrogen atom or a protecting group for an amino group,

[0180] X represents an oxygen atom or NR 13 (R 13 represents a hydrogen atom or a protecting group for an amino group),

[0181] The double line composed of a solid line and a dotted line represents a single bond or a double bond.)

[0182] And, step 15:

[0183] A step of subjecting the compound represented by formula (XVI) to a deprotection reaction, or further subjecting to a protection reaction for a hydroxyl group after the deprotection reaction.

[0184] Some other embodiments of the present invention are the following compounds.

[0185] [7] The compound represented by formula (II).

[0186] [Chemical formula 22]

[0187]

[0188] [In the formula,

[0189] R 1 represents a protecting group for a hydroxyl group,

[0190] R 2 represents a protecting group for a hydroxyl group,

[0191] R 3 and R 4 are the same or different and each independently represents a protecting group for a hydroxyl group, or represents R 3 and R 4A cyclic protecting group of the diol formed together

[0192] R 7 represents a hydrogen atom or an alkyl group.]

[0193] [8] The compound represented by formula (III).

[0194] [Chemical formula 23]

[0195]

[0196] [In the formula,

[0197] R 1 represents a protecting group for a hydroxyl group,

[0198] R 2 represents a protecting group for a hydroxyl group,

[0199] R 3 and R 4 are the same or different and each independently represents a protecting group for a hydroxyl group, or represents a cyclic protecting group of a diol formed by R 3 and R 4 together.]

[0200] [9] The compound represented by formula (IV).

[0201] [Chemical formula 24]

[0202]

[0203] [In the formula,

[0204] R 1 represents a protecting group for a hydroxyl group,

[0205] R 2 represents benzyl, 4,4'-dimethoxytrityl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl or acetyl,

[0206] R 3 and R 4 are the same or different and each independently represents a protecting group for a hydroxyl group, or represents a cyclic protecting group of a diol formed by R 3 and R 4 together,

[0207] 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.]

[0208] The compound represented by formula (XI).

[0209] [Chemical formula 25]

[0210]

[0211] [In the formula,

[0212] R 1 represents a protecting group for a hydroxyl group,

[0213] R 2 represents a protecting group for a hydroxyl group,

[0214] R 3a and R 4a represent an acyl group,

[0215] 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.]

[0216]

[11] The compound as described in the above

[10] , which is represented by formula (XI).

[0217] [Chemical formula 26]

[0218]

[0219] [In the formula,

[0220] R 1 represents a protecting group for a hydroxyl group,

[0221] R 2 represents benzyl, 4,4'-dimethoxytrityl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl or acetyl,

[0222] R 3a and R 4a represent an acyl group,

[0223] 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.]

[0224]

[12] The compound represented by formula (XII).

[0225] [Chemical formula 27]

[0226]

[0227] [In the formula,

[0228] R 1 represents a protecting group for a hydroxyl group,

[0229] R 2 represents a protecting group for a hydroxyl group,

[0230] R 4a represents an acyl group,

[0231] R 5 and R 6 in 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,

[0232] B represents a base moiety of a nucleic acid which may be substituted with one or more substituents.]

[0233]

[13] The compound as described in the above

[12] is represented by the formula (XII).

[0234] [Chemical formula 28]

[0235]

[0236] [In the formula,

[0237] R 1 represents a protecting group for a hydroxyl group,

[0238] R 2 represents benzyl, 4,4'-dimethoxytrityl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl or acetyl,

[0239] R 4a represents an acyl group,

[0240] R 5 and R 6 in 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,

[0241] B represents a base moiety of a nucleic acid which may be substituted with one or more substituents.]

[0242]

[14] The compound as described in the above

[12] or

[13] , wherein B is a thymine group.

[0243]

[15] The compound represented by the formula (XIII).

[0244] [Chemical formula 29]

[0245]

[0246] [In the formula,

[0247] R 1 represents a protecting group for a hydroxyl group,

[0248] R 2 represents benzyl, 4,4'-dimethoxytrityl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl or acetyl,

[0249] 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,

[0250] B represents a base moiety of a nucleic acid which may be substituted with one or more substituents.]

[0251]

[16] The compound as described in the above

[15] , wherein B is a thymine group.

[0252]

[17] The compound represented by formula (XIV).

[0253] [Chemical formula 30]

[0254]

[0255] [In the formula,

[0256] R 1 represents a protecting group for a hydroxyl group,

[0257] R 2 represents a protecting group for a hydroxyl group,

[0258] 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,

[0259] R 11 represents an alkyl or aryl group,

[0260] R 12 represents a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkyl group,

[0261] X represents an oxygen atom or NR 13 (R 13 represents a protecting group for a hydrogen atom or an amino group),

[0262] The double line composed of a solid line and a dotted line represents a single bond or a double bond.]

[0263]

[18] The compound as described in the above

[17] , which is represented by formula (XIV).

[0264] [Chemical Formula 31]

[0265]

[0266] [wherein,

[0267] R 1 represents a protecting group for a hydroxyl group,

[0268] R 2 represents benzyl, 4,4'-dimethoxytrityl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl or acetyl,

[0269] 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,

[0270] R 11 represents an alkyl group or an aryl group,

[0271] R 12 represents a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkyl group,

[0272] X represents an oxygen atom or NR 13 (R 13 represents a protecting group for a hydrogen atom or an amino group),

[0273] The double line composed of a solid line and a dotted line represents a single bond or a double bond.)

[0274]

[19] The compound as described in

[17] or

[18] above, wherein R 12 is methyl and X is an oxygen atom.

[0275]

[20] The compound represented by formula (XV).

[0276] [Chemical Formula 32]

[0277]

[0278] [wherein,

[0279] R 1 represents a protecting group for a hydroxyl group,

[0280] R 2 represents a protecting group for a hydroxyl group,

[0281] 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,

[0282] R 12 represents a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkyl group,

[0283] X represents an oxygen atom or NR 13 (R 13 represents a protecting group for a hydrogen atom or an amino group),

[0284] The double line composed of a solid line and a dotted line represents a single bond or a double bond.]

[0285]

[21] The compound as described in

[20] is represented by formula (XV).

[0286] [Chemical formula 33]

[0287]

[0288] [In the formula,

[0289] R 1 represents a protecting group for a hydroxyl group,

[0290] R 2 represents benzyl, 4,4'-dimethoxytrityl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl or acetyl,

[0291] 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,

[0292] R 12 represents a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkyl group,

[0293] X represents an oxygen atom or NR 13 (R 13 represents a hydrogen atom or a protecting group for an amino group),

[0294] The double line composed of a solid line and a dotted line represents a single bond or a double bond.]

[0295]

[22] For the compound as described in

[20] or

[21] above, wherein R 12 is methyl and X is an oxygen atom.

[0296]

[23] For the compound as described in any one of

[20] to

[22] above, wherein R 12 is methyl, X is an oxygen atom, R 1 is benzyl, R 2 is benzyl, R 5 is benzyloxycarbonyl,6 is a hydrogen atom, and the double line composed of solid and dotted lines is a single bond or a double bond.

[0297]

[24] The crystal of the compound described in

[23] above.

[0298]

[25] The crystal of the compound described in

[24] above, wherein, in the powder X-ray diffraction spectrum measured using CuKα radiation, peaks are present at 7.4 ± 0.2°, 19.2 ± 0.2°, 20.1 ± 0.2°, 21.3 ± 0.2° and 24.7 ± 0.2° as the diffraction angles represented by 2θ.

[0299]

[26] The compound represented by formula (XVI).

[0300] [Chemical formula 34]

[0301]

[0302] [In the formula,

[0303] R 1 represents a protecting group for the hydroxyl group,

[0304] R 2 represents a protecting group for the hydroxyl group,

[0305] R 12 represents a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkyl group,

[0306] R 14 represents a hydrogen atom, benzyloxycarbonyl, isobutyryl, benzoyl, tert-butoxycarbonyl, trimethylsilylethoxycarbonyl (Teoc) group, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, acetyl, formyl, 4-methoxybenzyl, allyl, benzyl or 2-nitrobenzenesulfonyl,

[0307] X represents an oxygen atom or NR 13 (R 13 represents a hydrogen atom or a protecting group for the amino group),

[0308] The double line composed of solid and dotted lines represents a single bond or a double bond.)

[0309]

[27] The compound described in

[26] above, which is represented by formula (XVI).

[0310] [Chemical formula 35]

[0311]

[0312] [In the formula,

[0313] R 1Represents a protecting group for a hydroxyl group,

[0314] R 2 represents benzyl, 4,4'-dimethoxytrityl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl or acetyl, R 12 represents a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkyl group,

[0315] R 14 represents a hydrogen atom, benzyloxycarbonyl, isobutyryl, benzoyl, tert-butoxycarbonyl, trimethylsilylethoxycarbonyl, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, acetyl, formyl, 4-methoxybenzyl, allyl, benzyl or 2-nitrobenzenesulfonyl,

[0316] X represents an oxygen atom or NR 13 (R 13 represents a protecting group for a hydrogen atom or an amino group),

[0317] The double line composed of a solid line and a dotted line represents a single bond or a double bond.]

[0318] A further embodiment of the present invention is a method for manufacturing a compound of the following formula (XVII).

[0319]

[28] A manufacturing method, which is a method for manufacturing a compound represented by formula (XVII) from a compound represented by formula (I),

[0320] [Chemical formula 36]

[0321]

[0322] [In the formula,

[0323] R 1 represents a protecting group for a hydroxyl group,

[0324] R 2 represents a protecting group for a hydroxyl group,

[0325] R 3 and R 4 are the same or different and each independently represents a protecting group for a hydroxyl group, or represents a cyclic protecting group for a diol formed by R 3 and R 4 together.]

[0326] [Chemical formula 37]

[0327]

[0328] [In the formula,

[0329] R 1 represents a protecting group for a hydrogen atom or a hydroxyl group,

[0330] R 12 represents a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkyl group,

[0331] X represents an oxygen atom or NR 13 (R 13 (represents a protecting group for a hydrogen atom or an amino group)),

[0332] The double line composed of a solid line and a dotted line represents a single bond or a double bond.)

[0333] The aforementioned production method includes the following steps 1 to 3, 9 to 15,

[0334] Step 1:

[0335] The step of reacting the compound represented by formula (I) with the compound represented by formula (V) or a salt thereof to obtain the compound represented by formula (II),

[0336] [Chemical formula 38]

[0337]

[0338] [In the formula, the meanings of the respective symbols are the same as above]

[0339] [Chemical formula 39]

[0340] R 7 O-NH2 (V)

[0341] [In the formula, R 7 represents a hydrogen atom or an alkyl group.)

[0342] [Chemical formula 40]

[0343]

[0344] [In the formula,

[0345] R 1 represents a protecting group for a hydroxyl group,

[0346] R 2 represents a protecting group for a hydroxyl group,

[0347] R 3 and R 4 are the same or different and each independently represents a protecting group for a hydroxyl group, or represents a cyclic protecting group of a diol formed by R 3 and R 4 together,

[0348] R 7represents a hydrogen atom or an alkyl group.

[0349] Step 2:

[0350] A step of subjecting the compound represented by formula (II) to a reduction reaction using a reducing agent to obtain the compound represented by formula (III),

[0351] [Chemical formula 41]

[0352]

[0353] [In the formula,

[0354] R 1 represents a protecting group for a hydroxyl group,

[0355] R 2 represents a protecting group for a hydroxyl group,

[0356] R 3 and R 4 are the same or different and each independently represents a protecting group for a hydroxyl group, or represents a cyclic protecting group of a diol formed by R 3 and R 4 together.

[0357] Step 3:

[0358] A step of subjecting the compound represented by formula (III) to a protecting reaction of an amino group to obtain the compound represented by formula (IV),

[0359] [Chemical formula 42]

[0360]

[0361] [In the formula,

[0362] R 1 represents a protecting group for a hydroxyl group,

[0363] R 2 represents a protecting group for a hydroxyl group,

[0364] R 3 and R 4 are the same or different and each independently represents a protecting group for a hydroxyl group, or represents a cyclic protecting group of a diol formed by R 3 and R 4 together,

[0365] 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.

[0366] Step 9:

[0367] The step of subjecting the compound represented by formula (IV) to a conversion reaction of R 3 and R 4 to an acyl group to obtain the compound represented by formula (XI),

[0368] [Chemical formula 43]

[0369]

[0370] [In the formula,

[0371] R 1 represents a protecting group for a hydroxyl group,

[0372] R 2 represents a protecting group for a hydroxyl group,

[0373] R 3a represents an acyl group,

[0374] R 4a represents an acyl group,

[0375] 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.]

[0376] Step 10:

[0377] The step of subjecting the compound represented by formula (XI) to a glycosylation reaction to obtain the compound represented by formula (XII’),

[0378] [Chemical formula 44]

[0379]

[0380] [In the formula,

[0381] R 1 represents a protecting group for a hydroxyl group,

[0382] R 2 represents a protecting group for a hydroxyl group,

[0383] R 4a represents an acyl group,

[0384] 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,

[0385] B represents the compound represented by formula (XXIV).

[0386] [Chemical formula 45]

[0387]

[0388] [In the formula,

[0389] R 12 represents a hydrogen atom, an alkyl group, an alkoxy group, or an alkoxyalkyl group,

[0390] X represents an oxygen atom or NR 13 (R 13 represents a protecting group for a hydrogen atom or an amino group),

[0391] The double line composed of a solid line and a dotted line represents a single bond or a double bond.]]

[0392] Step 11:

[0393] A step of subjecting the compound represented by formula (XII’) to a deprotection reaction of an acyl group to obtain a compound represented by formula (XIII’),

[0394] [Chemical formula 46]

[0395]

[0396] [In the formula,

[0397] R 1 represents a protecting group for a hydroxyl group,

[0398] R 2 represents a protecting group for a hydroxyl group,

[0399] 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,

[0400] B represents the compound represented by formula (XXIV).

[0401] [Chemical formula 47]

[0402]

[0403] [In the formula, the meanings of the symbols are the same as above.]]

[0404] Step 12:

[0405] A step of subjecting the compound represented by formula (XIII’) to a sulfonylation reaction to obtain a compound represented by formula (XIV),

[0406] [Chemical formula 48]

[0407]

[0408] [In the formula,

[0409] R 1Represents a protecting group for a hydroxyl group,

[0410] R 2 Represents a protecting group for a hydroxyl group,

[0411] 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,

[0412] R 11 Represents an alkyl group or an aryl group,

[0413] R 12 Represents a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkyl group,

[0414] X represents an oxygen atom or NR 13 (R 13 Represents a protecting group for a hydrogen atom or an amino group), and the double line composed of a solid line and a dotted line represents a single bond or a double bond.)

[0415] Step 13:

[0416] A step of subjecting the compound represented by formula (XIV) to a cyclization reaction to obtain a compound represented by formula (XV),

[0417] [Chemical formula 49]

[0418]

[0419] [In the formula,

[0420] R 1 Represents a protecting group for a hydroxyl group,

[0421] R 2 Represents a protecting group for a hydroxyl group,

[0422] 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,

[0423] R 12 Represents a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkyl group,

[0424] X represents an oxygen atom or NR 13 (R 13 Represents a protecting group for a hydrogen atom or an amino group), and the double line composed of a solid line and a dotted line represents a single bond or a double bond.)

[0425] Step 14:

[0426] A step of subjecting the compound represented by formula (XV) to a ring-closing reaction to obtain a compound represented by formula (XVI),

[0427] [Chemical Formula 50]

[0428]

[0429] [wherein,

[0430] R 1 represents a protecting group for a hydroxyl group,

[0431] R 2 represents a protecting group for a hydroxyl group,

[0432] R 12 represents a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkyl group,

[0433] R 14 represents a hydrogen atom or a protecting group for an amino group,

[0434] X represents an oxygen atom or NR 13 (R 13 represents a hydrogen atom or a protecting group for an amino group),

[0435] The double line composed of a solid line and a dotted line represents a single bond or a double bond.)

[0436] And, Step 15:

[0437] A step of subjecting the compound represented by formula (XVI) to a deprotection reaction, or further subjecting to a protection reaction of a hydroxyl group after the deprotection reaction.

[0438] A further embodiment of the present invention is a method for producing the following modified oligonucleotide or a salt thereof.

[0439]

[29] A production method, which is a method for producing the following modified oligonucleotide or a salt thereof from the compound represented by formula (XVII″),

[0440] [Chemical Formula 51]

[0441]

[0442] [wherein,

[0443] R 1a represents a protecting group for a hydroxyl group,

[0444] R 12 represents a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkyl group,

[0445] X represents an oxygen atom or NR 13 (R 13 represents a hydrogen atom or a protecting group for an amino group),

[0446] The double line composed of a solid line and a dotted line represents a single bond or a double bond.)

[0447] [Chemical Formula 52]

[0448]

[0449] The aforementioned production method includes the following steps:

[0450] A step of producing a compound represented by formula (XVII″) using the production method described in the above [6];

[0451] A step of producing an ALNA[Ms] amidite from the compound represented by formula (XVII″);

[0452] A step of carrying out the phosphoramidite method using the ALNA[Ms] amidite and an amidite for DNA synthesis; and

[0453] A step of subjecting the phosphodiester bond to a sulfurization reaction as needed.

[0454]

[30] A production method, which is a method for producing a modified oligonucleotide represented by the following Chemical Formula 54 or a salt thereof from a compound represented by formula (XVII″),

[0455] [Chemical Formula 53]

[0456]

[0457] [In the formula,

[0458] R 1a represents a protecting group for a hydroxyl group,

[0459] R 12 represents a hydrogen atom, an alkyl group, an alkoxy group, or an alkoxyalkyl group,

[0460] X represents an oxygen atom or NR 13 (R 13 represents a hydrogen atom or a protecting group for an amino group),

[0461] The double line composed of a solid line and a dotted line represents a single bond or a double bond.]

[0462] [Chemical Formula 54]

[0463]

[0464] The aforementioned production method includes the following steps:

[0465] A step of producing a compound represented by formula (XVII″) using the production method described in the above [6];

[0466] A step of producing an ALNA[Ms] amidite from the compound represented by formula (XVII″);

[0467] A process for carrying out the phosphoramidite method using an ALNA[Ms] amide and an amide for DNA synthesis; and

[0468] A process for subjecting a phosphodiester bond to a sulfurization reaction as needed.

[0469]

[31] A modified oligonucleotide represented by the following formula or a salt thereof, produced by the production method described in

[29] above.

[0470] [Chemical Formula 55]

[0471]

[0472]

[32] A modified oligonucleotide represented by the following formula or a salt thereof, produced by the production method described in

[30] above.

[0473] [Chemical Formula 56]

[0474]

[0475] According to the production method of the compound of formula (IV) which is the first embodiment of the present invention, a production intermediate useful for producing a bridged artificial nucleic acid intermediate useful as an intermediate for nucleic acid drugs, etc. can be produced by a method suitable for industrial production. More specifically, by using a reductive amination reaction when producing the compound of formula (III) from the compound of formula (I), the compound of formula (III) and the subsequent compound of formula (IV) can be safely produced in high yield.

[0476] According to the production method of the compound of formula (XIII) which is the second embodiment of the present invention, another novel production intermediate, the compound of formula (XIII), can be produced in high yield from the compound of formula (IV) produced by the production method of the first embodiment above.

[0477] Furthermore, according to the production method of the compound of formula (XVII) which is the third embodiment of the present invention, one of the target bridged artificial nucleic acid intermediates, the compound of formula (XVII), can be produced from the compound of formula (XIII’) produced by the production method of the second embodiment above by a method suitable for industrial production. More specifically, the compound of formula (XV), which is one of the production intermediates, can be obtained in crystalline form. By passing through this crystallization step, the compound of formula (XV) can be produced in high purity and high yield by simple purification. Moreover, by using this compound to carry out the subsequent steps, one of the target bridged artificial nucleic acid intermediates, the compound of formula (XVII), can be obtained with high quality.

[0478] The production methods of the first to third embodiments described above are each independently industrially advantageous. However, by combining them, it is possible to safely and reproducibly produce the bridged artificial nucleic acid intermediate as the target substance with a high yield and high quality, which is therefore very advantageous industrially. In addition, the combination of these production methods is also an embodiment of the present invention.

[0479] In addition, some of the production intermediate compounds in the production methods of the first to third embodiments described above are also intermediate compounds that are industrially advantageous, and are each an embodiment of the present invention.

[0480] Furthermore, a method for producing a modified oligonucleotide or a salt thereof including the above production method, and a modified oligonucleotide or a salt thereof produced by using the production method are an embodiment of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0481] Figure 1 is the powder X-ray diffraction pattern of the crystal of the compound of formula (XV') (Compound 14). DETAILED DESCRIPTION OF THE INVENTION

[0482] The definitions of the respective groups in this specification are as described below.

[0483] In this specification, the term "alkyl" means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms (C 1～6 ). Particularly preferred is a group having 1 to 4 carbon atoms (C 1～4 ). Specifically, examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-methyl-n-butyl, isopentyl (3-methyl-n-butyl) group, 2-methyl-n-pentyl, etc., and preferably methyl can be mentioned.

[0484] In this specification, "alkoxy" means a monovalent group formed by bonding the aforementioned alkyl to an oxygen atom, and examples include a linear or branched alkyl-O- group having 1 to 6 carbon atoms (C 1～6 ), and preferably an alkyl-O- group having 1 to 4 carbon atoms (C 1～4 ). Specifically, examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, 2-methyl-n-propoxy, 3-methyl-n-butoxy, etc., and preferably methoxy can be mentioned.

[0485] In this specification, "alkoxyalkyl" means the aforementioned alkyl substituted with 1 to 2 alkoxy groups. Specifically, examples include methoxymethyl, methoxyethyl, methoxypropyl, etc., and preferably methoxymethyl can be mentioned.

[0486] In this specification, the term "alkylene" is from 1 to 6 carbon atoms (C 1～6 ​A divalent group obtained by removing two hydrogen atoms from a straight-chain or branched saturated hydrocarbon. Specifically, examples include methylene, ethylene, n-propylene, isopropylidene, butylene, hexylene, cyclopentylene, cyclohexylene, etc.

[0487] In this specification, the term "alkynyl" refers to a straight-chain or branched alkynyl group having 2 to 6 carbon atoms (C 2-6 ), preferably 2 to 4 carbon atoms (C 2-4 ), more preferably 2 to 3 carbon atoms (C 2-3 ). Specifically, examples include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 1-methyl-2-propynyl, 1-methyl-2-butynyl, etc.

[0488] In this specification, the term "aryl" refers to a functional group or substituent derived from an aromatic hydrocarbon (monocyclic, bicyclic, and tricyclic). It preferably represents a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 11 ring-forming carbon atoms, and more preferably represents an aromatic hydrocarbon group of a 5-membered ring or 6-membered ring. Among them, phenyl is preferred. In addition, the aryl may be substituted, and examples of such substituents of the aryl include the same or different one or more (or preferably 1 to 3) groups selected from the group consisting of a hydroxyl group, a halogen atom, a nitro group, a cyano group, a C 1-6 alkyl group that can be substituted by one or more substituents, a C 2-6 alkenyl group that can be substituted by one or more substituents, a C 2-6 alkynyl group that can be substituted by one or more substituents, a C 1-6 alkoxy group, an aryloxy group, an amino group, an amino group that can be substituted by one or more C 1-3 alkyl groups, and an aryl group. Preferably, examples include a C 1-6 alkyl group that can be substituted by one or more substituents, an amino group that can be substituted by one or more C 1-3 alkyl groups, and a halogen atom. More preferably, examples include trifluoromethyl, dimethylamino, and chlorine atom, etc.

[0489] Specific examples of the aryl group that can be substituted by one or more substituents include 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,6-dimethylphenyl, 2,4-dimethylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 2-bromophenyl, 4-methoxyphenyl, 4-chloro-2-nitrophenyl, 4-nitrophenyl, 2-nitrophenyl, 2,4-dinitrophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-dimethylaminophenyl, 3-dimethylaminophenyl, 4-dimethylaminophenyl, 2-biphenyl, 3-biphenyl, 4-biphenyl, etc.

[0490] In this specification, as the term "halogen atom", for example, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom can be cited.

[0491] In this specification, the term "protecting group" described in "protecting group for hydroxyl group" and "protecting group for amino 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 hydrogenolysis, hydrolysis, electrolysis, and photolysis.

[0492] In this specification, the "protecting group for hydroxyl group" refers to a protecting group commonly used in organic synthetic chemistry (especially nucleic acid synthesis). For example, an acyl group; an alkyl group; a methyl group substituted with 1 to 3 aryl groups; a methyl group substituted with 1 to 3 aryl groups substituted with an alkyl group, an alkoxy group, a halogen atom, and / or a cyano group; a methyl group substituted with an alkoxy group; a silyl group; a silyloxymethyl group; or a carbonate group can be cited. As specific examples, a benzyl (sometimes referred to as Bn) group, a 4,4'-dimethoxytrityl (sometimes referred to as DMTr) group, a 4-methoxytrityl group, a triphenylmethyl group, a 2-naphthylmethyl group, a cyanoethoxycarbonyl group, a cyanoethyl group, a methoxymethyl group, a methylthiomethyl group, a benzyloxymethyl group, a 4-methoxybenzyloxymethyl group, a tert-butoxymethyl group, a trimethylsilyloxymethyl group, a tert-butyldimethylsilyloxymethyl group, a tert-hexyldimethylsilyloxymethyl group, a tert-butyldiphenylsilyloxymethyl group, a triethylsilyloxymethyl group, a triisopropylsilyloxymethyl group, a 2-methoxyethoxymethyl group, a 2,2,2-trichloroethoxymethyl group, a 2-(trimethylsilyl)ethoxymethyl group, a 1-ethoxyethyl group, a tetrahydropyranyl group, a trimethylsilyl (sometimes referred to as TMS) group, a triethylsilyl group, a triisopropylsilyl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, a triphenylsilyl group, a 4-methoxybenzyl group, a 3,4-dimethoxybenzyl group, a 2,6-dimethoxybenzyl group, a p-phenylbenzyl group, a benzoyl (sometimes referred to as Bz) group, a phenoxyacetyl group, a benzyloxycarbonyl (sometimes referred to as Cbz) group, a tert-butoxycarbonyl (sometimes referred to as Boc) group, a 9-fluorenylmethyloxycarbonyl (sometimes referred to as Fmoc) group, or an acetyl (sometimes referred to as Ac) group can be cited. For example, benzyl, 4,4'-dimethoxytrityl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl, or acetyl is preferred, and benzyl, 4,4'-dimethoxytrityl, or acetyl is more preferred.

[0493] In this specification, the so-called "cyclic protecting group of diol" refers to a cyclic protecting group of a hydroxyl group (diol) formed by the oxygen atoms of two hydroxyl groups of the diol together with an alkylene group. Specifically, examples thereof include cyclic acetal-type protecting groups such as methoxymethylene acetal group, isopropylidene ketal group, methylene acetal group, ethylidene acetal group, tert-butylmethylene acetal group, 1-tert-butylethylidene ketal group, 1-phenylethylidene ketal group, 1-(4-methoxyphenyl)ethylidene ketal group, 2,2,2-trichloroethylidene acetal group, benzylidene acetal group, 4-methoxybenzylidene acetal group, 2,4-methoxybenzylidene acetal group, 3,4-methoxybenzylidene acetal group, cyclopentylidene ketal group, cyclohexylidene ketal group, cycloheptylidene ketal group, benzophenone ketal group, ethoxymethylene acetal group, 1-methoxyethylidene orthoester group, 1-ethoxyethylidene orthoester group, 1-benzyloxybenzylidene orthoester group, di-tert-butylsilylene, diisopropylsilylene, methylcyclohexylsilylene, dicyclohexylsilylene, 1,3-(1,1,3,3-tetraisopropyl)disiloxane-1,3-diyl, 1,1,3,3-tetra-tert-butoxydisiloxane-1,3-diyl, and cyclic carbonate group. Preferred are isopropylidene ketal group, methylene acetal group, ethylidene acetal group, benzylidene acetal group, 4-methoxybenzylidene acetal group or 1-benzyloxybenzylidene orthoester group, and more preferred is isopropylidene ketal group. It should be noted that the specific examples of the above cyclic protecting groups are named according to the common names in organic synthetic chemistry, including the groups containing the oxygen atoms forming the cyclic structure. For example, R 3 and R 4 together form a specific example of the cyclic protecting group of diol, and the name is the name of the group including the oxygen atoms bonded to each of R 3 and R 4 respectively.

[0494] In the present specification, the so-called "protecting group for an amino group" refers to a protecting group commonly used in organic synthetic chemistry (especially nucleic acid synthesis). For example, aliphatic acyl groups; aromatic acyl groups; sulfonyl groups; alkyl groups; methyl groups substituted with 1 to 3 aryl groups; methyl groups substituted with 1 to 3 aryl groups substituted with a halogen atom and / or a cyano group can be cited. As specific examples, an acetyl (Ac) group, a formyl group, a phenoxyacetyl group, a tert-butylphenoxyacetyl group, a p-isopropylphenoxyacetyl group, a trifluoroacetyl group, a propionyl group, an isobutyryl group, a benzoyl (Bz) group, a methoxycarbonyl group, an ethoxycarbonyl group, a tert-butoxycarbonyl group, a trimethylsilylethoxycarbonyl group, a cyanoethoxycarbonyl group, a benzyloxycarbonyl (Cbz) group, an allyloxycarbonyl group, a 9-fluorenylmethoxycarbonyl group, a dimethylaminomethylene group, a 2,2,2-trichloroethoxycarbonyl group, a tert-pentyloxycarbonyl group, a 4-methoxybenzyl group, a triphenylmethyl group, a 2-nitrobenzenesulfonyl group, a 4-nitrobenzenesulfonyl group, a 2,4-dinitrobenzenesulfonyl group, a 2-(trimethylsilyl)ethoxymethyl group, a benzyl (Bn) group or an allyl group can be cited. For example, benzyloxycarbonyl, isobutyryl, benzoyl, tert-butoxycarbonyl, trimethylsilylethoxycarbonyl, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, acetyl, formyl, trifluoroacetyl, 4-methoxybenzyl, allyl, benzyl or 2-nitrobenzenesulfonyl is preferred, and benzyloxycarbonyl, acetyl, 4-methoxybenzyl or allyl is more preferred.

[0495] In this specification, examples of the term "acyl group" include aliphatic acyl groups and aromatic acyl groups. Specifically, examples of aliphatic acyl groups include alkyl carbonyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, 3-methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl, 3,7-dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, 1-methylpentadecanoyl, 14-methylpentadecanoyl, 13,13-dimethyltetradecanoyl, heptadecanoyl, 15-methylhexadecanoyl, octadecanoyl, 1-methyloctadecanoyl, nonadecanoyl, icosanoyl, and henicosanoyl; aryl-oxy-alkyl carbonyl groups such as phenoxyacetyl; carboxylated alkyl carbonyl groups such as succinyl, glutaryl, and adipoyl; carbonyl groups substituted with a halogen atom-substituted alkyl having 1 to 6 carbon atoms such as chloroacetyl, dichloroacetyl, trichloroacetyl, and trifluoroacetyl; alkoxy-alkyl carbonyl groups having 1 to 6 carbon atoms such as methoxyacetyl; and unsaturated alkyl carbonyl groups such as (E)-2-methyl-2-butenoyl. In addition, examples of aromatic acyl groups include aryl carbonyl groups such as benzoyl, α-naphthoyl, and β-naphthoyl; halogenated aryl carbonyl groups such as 2-bromobenzoyl and 4-chlorobenzoyl; aryl carbonyl groups substituted with an alkyl having 1 to 6 carbon atoms such as 2,4,6-trimethylbenzoyl and 4-toluoyl; aryl carbonyl groups substituted with an alkoxy having 1 to 6 carbon atoms such as 4-anisoyl; carboxylated aryl carbonyl groups such as 2-carboxybenzoyl, 3-carboxybenzoyl, and 4-carboxybenzoyl; nitrated aryl carbonyl groups such as 4-nitrobenzoyl and 2-nitrobenzoyl; carbonylated aryl carbonyl groups substituted with an alkoxy having 1 to 6 carbon atoms such as 2-(methoxycarbonyl)benzoyl; and arylated aryl carbonyl groups such as 4-phenylbenzoyl, etc.

[0496] In this specification, examples of the term "silyl group" include silyl groups substituted with an alkyl having 1 to 6 carbon atoms such as trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, tert-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-tert-butylsilyl, and triisopropylsilyl; silyl groups substituted with three alkyls having 1 to 6 carbon atoms substituted with 1 to 2 aryl groups such as tert-butyldiphenylsilyl, diphenylmethylsilyl, butyldiphenylbutylsilyl, diphenylisopropylsilyl, and phenyldiisopropylsilyl; and triphenylsilyl.

[0497] In this specification, examples of the term "silyloxy" include alkyl-substituted silyloxies such as trimethylsilyloxymethyl, tert-butyldimethylsilyloxymethyl, tert-hexyldimethylsilyloxymethyl, triethylsilyloxymethyl, and triisopropylsilyloxymethyl; and aryl-substituted silyloxies such as tert-butyldiphenylsilyloxymethyl.

[0498] In this specification, the "base moiety of a nucleic acid" in the term "base moiety of a nucleic acid which may be substituted with one or more substituents" includes the base moiety of a wild-type nucleic acid and the base moiety of a non-wild-type nucleic acid, and includes an aromatic heterocyclic group (e.g., a monocyclic group, a bicyclic group, a tricyclic group, etc.). The base moiety of a nucleic acid includes not only the heterocycles of known purines and pyrimidines, but also heterocyclic analogs and tautomers thereof. Specific examples of the base moiety of a nucleic acid include an adenine group, a guanine group, a thymine group, a dihydrothymine group, a cytosine group, a uracil group, dihydrouracil, a purine group, a xanthine group, a diaminopurine group, 8-oxo-N 6 -methyladenine group, 7-deazaxanthine group, 7-deazaguanine group, 2-thiothymine group, N 4 ,N 4 -bridged ethylene cytosine group, N 6 ,N 6 -bridged ethylene-2,6-diaminopurine group, 5-methylcytosine group, 5-(C 3 ~C 6 )-alkynyl cytosine group, 5-fluorocytosine group, 5-bromouracil group, pseudoisocytosine group, 2-hydroxy-5-methyl-4-triazolo pyridine group, isocytosine group, isoguanine group, inosine group, 6-aminopurine group, 2-aminopurine group, 6-chloro-2-aminopurine group, 6-chloropurine group, N 6 -allyl purine group, N 6 -acyl purine group, N 6 -benzyl purine group, N 6 -halogenated purine group, N 6 -vinyl purine group, N 6 -ethynyl purine group, N 6 -acyl purine group, N 6 -hydroxyalkyl purine group, N 6 -thioalkyl purine group, N 2 -alkyl purine group, N 4 -alkyl pyrimidine group, N 4 -acyl pyrimidine group, N 4 -benzyl purine group, N 4 -halogenated pyrimidine group, N 4 -vinyl pyrimidine group, N 4 -acetyl pyrimidine group, N4 -hydroxyalkylpyrimidinyl, N 6 -thioalkylpyrimidinyl, 6-azapyrimidinyl, 6-azacytosinyl, 2- and / or 4-mercaptopyrimidinyl, uracilyl, C 5 -alkylpyrimidinyl, C 5 -benzylpyrimidinyl, C 5 -halopyrimidinyl, C 5 -vinylpyrimidinyl, C 5 -ethynylpyrimidinyl, C 5 -acylpyrimidinyl, C 5 -hydroxyalkylpurinyl, C 5 -amidopyrimidinyl, C 5 -cyanopyrimidinyl, C 5 -nitropyrimidinyl, C 5 -aminopyrimidinyl, N 2 -alkylpurinyl, N 2 -alkyl-6-thiopurinyl, 5-cytidinyl, 5-azauracilyl, triazolopyridinyl, imidazopyridinyl, pyrrolopyrimidinyl, or pyrazolopyrimidinyl, etc. As a preferred base moiety of a nucleic acid, an adeninyl group, a guaninyl group, a 2,6-diaminopurinyl group, a thyminyl group, a dihydrothyminyl group, a 2-mercaptothyminyl group, a cytosinyl group, a 5-methylcytosinyl group, a uracilyl group, dihydrouracil, a 5-fluorocytosinyl group, a xanthinyl group, a 6-aminopurinyl group, a 2-aminopurinyl group, a 6-chloro-2-aminopurinyl group, or a 6-chloropurinyl group can be mentioned. These base moieties of nucleic acids can be substituted with one or more substituents, preferably with one or two substituents. As the substituent, a hydroxyl group, an alkoxy group, a mercapto group, an alkylthio group, an amino group, an amino group substituted with an alkyl group, an alkyl group, an alkynyl group, an oxo group, a thio group, or a halogen atom can be mentioned. The functional oxygen, sulfur, and nitrogen groups on the base moiety can be protected and / or deprotected as needed. Suitable protecting groups are well known to those skilled in the art. For example, the protecting groups for the aforementioned hydroxyl group, amino group, etc. can be mentioned. Preferably, diphenylaminocarbonyl, silyl (e.g., trimethylsilyl, dimethylhexylsilyl, tert-butyldimethylsilyl, and tert-butyldiphenylsilyl), triphenylmethyl, alkyl, acyl (e.g., acetyl, propionyl, isobutyryl, benzoyl, phenoxyacetyl), alkoxycarbonyl (e.g., tert-butoxycarbonyl, benzyloxycarbonyl, diphenylaminocarbonyl (sometimes referred to as DPC), cyanoethoxycarbonyl), sulfonyl (e.g., mesyl, and tosyl), dimethylaminomethylene, etc. can be mentioned.

[0499] <Method of manufacture and manner of the compound>

[0500] Some manufacturing methods and some compounds as embodiments of the present invention are described below, including embodiments containing more than one manufacturing method and embodiments containing more than one compound.

[0501] As one embodiment of the above, it includes a manufacturing method of one or more processes among Processes 1 to 3 in the present specification using R in Formulas (I) to (V) 1 being a protecting group for a hydroxyl group, R 2 being a protecting group for a hydroxyl group, R 3 and R 4 being R 3 and R 4 together forming a cyclic protecting group for a diol, R 5 and R 6 being a protecting group for an amino group, R 7 being an alkyl group or a hydrogen atom, and the compound used in this manufacturing method in one or more processes among Processes 1 to 3.

[0502] As one embodiment of the above, it includes a manufacturing method of one or more processes among Processes 1 to 3 in the present specification using R in Formulas (I) to (V) 1 being a protecting group for a hydroxyl group, R 2 being a protecting group for a hydroxyl group, R 3 and R 4 being R 3 and R 4 together forming a cyclic protecting group for a diol, R 5 being a protecting group for an amino group, R 6 being a hydrogen atom, R 7 being a hydrogen atom, and the compound used in this manufacturing method in one or more processes among Processes 1 to 3.

[0503] As one embodiment of the above, it includes a manufacturing method of one or more processes among Processes 1 to 3 in the present specification using R in Formulas (I) to (V) 1 being benzyl, 4,4'-dimethoxytrityl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl or acetyl, R 2 being benzyl, 4,4'-dimethoxytrityl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl or acetyl, R 3 and R 4 being R 3 and R 4An isopropylidene ketal group, a methylene acetal group, an ethylidene acetal group, a benzylidene acetal group, a 4-methoxybenzylidene acetal group, or a 1-benzyloxybenzyl orthoester group formed together, R 5 is benzyloxycarbonyl, isobutyryl, benzoyl, tert-butoxycarbonyl, trimethylsilylethoxycarbonyl, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, acetyl, formyl, trifluoroacetyl, 4-methoxybenzyl, allyl, benzyl, or 2-nitrobenzenesulfonyl, R 6 is a hydrogen atom, R 7 A manufacturing method of one or more processes among Processes 1 to 3 of a compound in which R is a hydrogen atom, and the compound used in this manufacturing method.

[0504] As one aspect of the above embodiment, it includes using R in Formulas (I) to (V) in Processes 1 to 3 included in this specification 1 is benzyl, 4,4'-dimethoxytriphenylmethyl, or acetyl, R 2 is benzyl, 4,4'-dimethoxytriphenylmethyl, or acetyl, R 3 and R 4 is R 3 and R 4 An isopropylidene ketal group formed together with R 5 is benzyloxycarbonyl, acetyl, 4-methoxybenzyl, or allyl, R 6 is a hydrogen atom, R 7 A manufacturing method of one or more processes among Processes 1 to 3 of a compound in which R is a hydrogen atom, and the compound used in this manufacturing method.

[0505] As one aspect of the above embodiment, it includes using R in Formulas (I) to (X) in Processes 1 to 8 included in this specification 1 is a protecting group for a hydroxyl group, R 2 is a protecting group for a hydroxyl group, R 3 and R 4 is R 3 and R 4 A cyclic protecting group of a diol formed together with R 5 and R 6 is a protecting group for an amino group, R 7 A manufacturing method of one or more processes among Processes 1 to 8 of a compound in which R is an alkyl group or a hydrogen atom, and the compound used in this manufacturing method.

[0506] As one aspect of the above embodiment, it includes using R in Formulas (I) to (X) in Processes 1 to 8 included in this specification 1 is a protecting group for a hydroxyl group, R 2 is a protecting group for a hydroxyl group, R 3and R 4 is R 3 with R 4 a cyclic protecting group of a diol formed together with R 5 a protecting group for an amino group, R 6 is a hydrogen atom, R 7 a method for producing one or more of the processes 1 to 8 of a compound in which R is a hydrogen atom, and the compound used in this production method.

[0507] As one aspect of the above embodiment, it includes using R in formulas (I) to (X) in processes 1 to 8 included in this specification 1 is benzyl, 4,4'-dimethoxytrityl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl or acetyl, R 2 is benzyl, 4,4'-dimethoxytrityl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl or acetyl, R 3 and R 4 is R 3 with R 4 a cyclic isopropylidene ketal group, methylene acetal group, ethylidene acetal group, benzylidene acetal group, 4-methoxybenzylidene acetal group or 1-benzyloxybenzyl orthoformate group formed together with R 5 is benzyloxycarbonyl, isobutyryl, benzoyl, tert-butoxycarbonyl, trimethylsilylethoxycarbonyl, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, acetyl, formyl, trifluoroacetyl, 4-methoxybenzyl, allyl, benzyl or 2-nitrobenzenesulfonyl, R 6 is a hydrogen atom, R 7 is a hydrogen atom, a method for producing one or more of the processes 1 to 8 of a compound, and the compound used in this production method.

[0508] As one aspect of the above embodiment, it includes using R in formulas (I) to (X) in processes 1 to 8 included in this specification 1 is benzyl, 4,4'-dimethoxytrityl or acetyl, R 2 is benzyl, 4,4'-dimethoxytrityl or acetyl, R 3 and R 4 is R 3 with R 4 a cyclic isopropylidene ketal group formed together with R5 is benzyloxycarbonyl, acetyl, 4-methoxybenzyl or allyl, R 6 is a hydrogen atom, R 7 A manufacturing method of one or more steps among steps 1 to 8 of a compound where R is a hydrogen atom, and the compound used in this manufacturing method.

[0509] As one mode of the above-described embodiment, it includes using R in formulas (I) to (XIII) in steps 1 to 11 included in this specification 1 is a protecting group for a hydroxyl group, R 2 is a protecting group for a hydroxyl group, R 3 and R 4 is R 3 and R 4 together form a cyclic protecting group for a diol, R 3a and R 4a is an acyl group, R 5 and R 6 is a protecting group for an amino group, R 7 is an alkyl group or a hydrogen atom, B is a base moiety of a nucleic acid, a manufacturing method of one or more steps among steps 1 to 11 of the compound, and the compound used in this manufacturing method.

[0510] As one mode of the above-described embodiment, it includes using R in formulas (I) to (XIII) in steps 1 to 11 included in this specification 1 is a protecting group for a hydroxyl group, R 2 is a protecting group for a hydroxyl group, R 3 and R 4 is R 3 and R 4 together form a cyclic protecting group for a diol, R 3a and R 4a is acetyl, R 5 is a protecting group for an amino group, R 6 is a hydrogen atom, R 7 is a hydrogen atom, B is a base moiety of a nucleic acid, a manufacturing method of one or more steps among steps 1 to 11 of the compound, and the compound used in this manufacturing method.

[0511] As one mode of the above-described embodiment, it includes using R in formulas (I) to (XIII) in steps 1 to 11 included in this specification 1 is benzyl, 4,4'-dimethoxytrityl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl or acetyl, R 2is benzyl, 4,4'-dimethoxytrityl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl or acetyl, R 3 and R 4 is R 3 and R 4 together form an isopropylidene ketal group, a methylene acetal group, an ethylidene acetal group, a benzylidene acetal group, a 4-methoxybenzylidene acetal group or a 1-benzyloxybenzyl orthoester group, R 3a and R 4a is acetyl, R 5 is benzyloxycarbonyl, isobutyryl, benzoyl, tert-butoxycarbonyl, trimethylsilylethoxycarbonyl, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, acetyl, formyl, trifluoroacetyl, 4-methoxybenzyl, allyl, benzyl or 2-nitrobenzenesulfonyl, R 6 is a hydrogen atom, R 7 is a hydrogen atom, and a method for producing one or more of steps 1 to 11 of a compound in which B is a base moiety of a nucleic acid, and the compound used in this production method.

[0512] As one mode of the above embodiment, it includes using R in formulas (I) to (XIII) in steps 1 to 11 included in this specification 1 is benzyl, 4,4'-dimethoxytrityl or acetyl, R 2 is benzyl, 4,4'-dimethoxytrityl or acetyl, R 3 and R 4 is R 3 and R 4 together form an isopropylidene ketal group, R 3a and R 4a is acetyl, R 5 is benzyloxycarbonyl, acetyl, 4-methoxybenzyl or allyl, R 6 is a hydrogen atom, R 7 is a hydrogen atom, and a method for producing one or more of steps 1 to 11 of a compound in which B is a base moiety of a nucleic acid, and the compound used in this production method.

[0513] As one mode of the above embodiment, it includes using R in formulas (I) to (XIII) in steps 1 to 11 included in this specification 1 is benzyl, 4,4'-dimethoxytrityl or acetyl, R 2 is benzyl, 4,4'-dimethoxytrityl or acetyl, R 3and R 4 is R 3 and R 4 together form an isopropylidene ketal group, R 3a and R 4a is an acetyl group, R 5 is a benzyloxycarbonyl group, acetyl group, 4-methoxybenzyl group or allyl group, R 6 is a hydrogen atom, R 7 is a hydrogen atom, B is an adenine group, guanine group, 2,6-diaminopurine group, thymine group, dihydrothymine group, 2-thiothymine group, cytosine group, 5-methylcytosine group, uracil group, dihydrouracil, 5-fluorocytosine group, xanthine group, 6-aminopurine group, 2-aminopurine group, 6-chloro-2-aminopurine group, or 6-chloropurine group, a manufacturing method of one or more processes among processes 1 to 11 of the compound, and the compound used in this manufacturing method.

[0514] As one mode of the above embodiment, it includes using R in formulas (I) to (XIII) in processes 1 to 11 included in this specification 1 is a benzyl group, 4,4'-dimethoxytrityl group or acetyl group, R 2 is a benzyl group, 4,4'-dimethoxytrityl group or acetyl group, R 3 and R 4 is R 3 and R 4 together form an isopropylidene ketal group, R 3a and R 4a is an acetyl group, R 5 is a benzyloxycarbonyl group, acetyl group, 4-methoxybenzyl group or allyl group, R 6 is a hydrogen atom, R 7 is a hydrogen atom, B is a thymine group, a manufacturing method of one or more processes among processes 1 to 11 of the compound, and the compound used in this manufacturing method.

[0515] As one mode of the above embodiment, it includes using R in formulas (I) to (XIII) in processes 1 to 3 and processes 9 to 11 included in this specification 1 is a protecting group for a hydroxyl group, R 2 is a protecting group for a hydroxyl group, R 3 and R 4 is R 3 and R 4 together form a cyclic protecting group for a diol, R 3a and R 4a is an acyl group, R 5 and R 6 is a protecting group for an amino group, R 7A method for manufacturing one or more of steps 1 to 3 and steps 9 to 11 of a compound in which A is an alkyl group or a hydrogen atom and B is a base moiety of a nucleic acid, and the compound used in this manufacturing method.

[0516] As one mode of the above-described embodiment, it includes using R in Formulas (I) to (XIII) in steps 1 to 3 and steps 9 to 11 included in this specification 1 is a protecting group for a hydroxyl group, R 2 is a protecting group for a hydroxyl group, R 3 and R 4 is R 3 and R 4 together form a cyclic protecting group for a diol, R 3a and R 4a is acetyl, R 5 is a protecting group for an amino group, R 6 is a hydrogen atom, R 7 is a hydrogen atom, and a method for manufacturing one or more of steps 1 to 3 and steps 9 to 11 of a compound in which B is a base moiety of a nucleic acid, and the compound used in this manufacturing method.

[0517] As one mode of the above-described embodiment, it includes using R in Formulas (I) to (XIII) in steps 1 to 3 and steps 9 to 11 included in this specification 1 is benzyl, 4,4'-dimethoxytrityl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl or acetyl, R 2 is benzyl, 4,4'-dimethoxytrityl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl or acetyl, R 3 and R 4 is R 3 and R 4 together form an isopropylidene ketal group, a methylene acetal group, an ethylidene acetal group, a benzylidene acetal group, a 4-methoxybenzylidene acetal group or a 1-benzyloxybenzyl orthoester group, R 3a and R 4a is acetyl, R 5 is benzyloxycarbonyl, isobutyryl, benzoyl, tert-butoxycarbonyl, trimethylsilylethoxycarbonyl, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, acetyl, formyl, trifluoroacetyl, 4-methoxybenzyl, allyl, benzyl or 2-nitrobenzenesulfonyl6 is a hydrogen atom, R 7 A manufacturing method of one or more processes among processes 1 to 3 and processes 9 to 11 of a compound in which R is a hydrogen atom, B is a base moiety of a nucleic acid, and the compound used in this manufacturing method.

[0518] As one mode of the above-described embodiment, it includes using R in formulas (I) to (XIII) in processes 1 to 3 and processes 9 to 11 included in this specification 1 is benzyl, 4,4'-dimethoxytrityl or acetyl, R 2 is benzyl, 4,4'-dimethoxytrityl or acetyl, R 3 and R 4 is R 3 and R 4 together form an isopropylidene ketal group, R 3a and R 4a is acetyl, R 5 is benzyloxycarbonyl, acetyl, 4-methoxybenzyl or allyl, R 6 is a hydrogen atom, R 7 is a hydrogen atom, B is a base moiety of a nucleic acid, A manufacturing method of one or more processes among processes 1 to 3 and processes 9 to 11 of a compound, and the compound used in this manufacturing method.

[0519] As one mode of the above-described embodiment, it includes using R in formulas (I) to (XIII) in processes 1 to 3 and processes 9 to 11 included in this specification 1 is benzyl, 4,4'-dimethoxytrityl or acetyl, R 2 is benzyl, 4,4'-dimethoxytrityl or acetyl, R 3 and R 4 is R 3 and R 4 together form an isopropylidene ketal group, R 3a and R 4a is acetyl, R 5 is benzyloxycarbonyl, acetyl, 4-methoxybenzyl or allyl, R 6 is a hydrogen atom, R 7 is a hydrogen atom, B is adenine, guanine, 2,6-diaminopurine, thymine, dihydrothymine, 2-thiothymine, cytosine, 5-methylcytosine, uracil, dihydrouracil, 5-fluorocytosine, xanthine, 6-aminopurine, 2-aminopurine, 6-chloro-2-aminopurine, or 6-chloropurine, A manufacturing method of one or more processes among processes 1 to 3 and processes 9 to 11 of a compound, and the compound used in this manufacturing method.

[0520] As one mode of the above-described embodiment, including the use of R in Formulas (I) to (XIII) in Steps 1 to 3 and Steps 9 to 11 included in this specification 1 is benzyl, 4,4'-dimethoxytrityl or acetyl, R 2 is benzyl, 4,4'-dimethoxytrityl or acetyl, R 3 and R 4 is R 3 and R 4 together form an isopropylidene ketal group, R 3a and R 4a is acetyl, R 5 is benzyloxycarbonyl, acetyl, 4-methoxybenzyl or allyl, R 6 is a hydrogen atom, R 7 is a hydrogen atom, a method for manufacturing one or more of Steps 1 to 3 and Steps 9 to 11 of a compound where B is thymine, and the compound used in this manufacturing method.

[0521] As one mode of the above-described embodiment, including the use of R in Formulas (I) to (XI), Formula (XII'), Formula (XIII'), Formulas (XIV) to (XVII), Formula (XVII'), and Formula (XVII'') in Steps 1 to 14, 15-1, and 15-2 included in this specification 1 is a protecting group for a hydroxyl group, R 1a is a protecting group for a hydroxyl group, R 2 is a protecting group for a hydroxyl group, R 3 and R 4 is R 3 and R 4 together form a cyclic protecting group for a diol, R 3a and R 4a is an acyl group, R 5 and R 6 is a protecting group for an amino group, R 7 is an alkyl group or a hydrogen atom, R 11 is an alkyl group, R 12 is a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkyl group, R 14 is a hydrogen atom or a protecting group for an amino group, X is an oxygen atom or NR 13 (R 13 represents a hydrogen atom or a protecting group for an amino group), a method for manufacturing one or more of Steps 1 to 14, Step 15-1, and Step 15-2 of a compound where the double line composed of a solid line and a dotted line is a single bond or a double bond, and the compound used in this manufacturing method.

[0522] As one mode of the above-described embodiment, it includes R in Formulas (I) to (XI), Formula (XII'), Formula (XIII'), Formulas (XIV) to (XVII), Formula (XVII'), and Formula (XVII'') used in Steps 1 to 14, 15-1, and 15-2 included in this specification 1 is a protecting group for a hydroxyl group, R 1a is a protecting group for a hydroxyl group, R 2 is a protecting group for a hydroxyl group, R 3 and R 4 is R 3 and R 4 together form a cyclic protecting group for a diol, R 3a and R 4a is an acetyl group, R 5 is a protecting group for an amino group, R 6 is a hydrogen atom, R 7 is a hydrogen atom, R 11 is an alkyl group, R 12 is a hydrogen atom or a methyl group, R 14 is a hydrogen atom or a protecting group for an amino group, X is an oxygen atom, a manufacturing method of one or more steps among Steps 1 to 14, Step 15-1, and Step 15-2 of a compound in which a double line composed of a solid line and a dotted line is a double bond, and the compound used in this manufacturing method.

[0523] As one mode of the above-described embodiment, it includes R in Formulas (I) to (XI), Formula (XII'), Formula (XIII'), Formulas (XIV) to (XVII), Formula (XVII'), and Formula (XVII'') used in Steps 1 to 14, 15-1, and 15-2 included in this specification 1 is benzyl, 4,4'-dimethoxytriphenylmethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl, or acetyl, R 1a is benzyl, 4,4'-dimethoxytriphenylmethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl, or acetyl, R 2 is benzyl, 4,4'-dimethoxytriphenylmethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl, or acetyl, R 3 and R 4 is R3 formed together with R 4 an isopropylidene ketal group, a methylene acetal group, an ethylidene acetal group, a benzylidene acetal group, a 4-methoxybenzylidene acetal group or a 1-benzyloxybenzyl orthoester group, R 3a and R 4a is acetyl, R 5 is benzyloxycarbonyl, isobutyryl, benzoyl, tert-butoxycarbonyl, trimethylsilylethoxycarbonyl, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, acetyl, formyl, trifluoroacetyl, 4-methoxybenzyl, allyl, benzyl or 2-nitrobenzenesulfonyl, R 6 is a hydrogen atom, R 7 is a hydrogen atom, R 11 is methyl, R 12 is a hydrogen atom or methyl, R 14 is benzyloxycarbonyl, isobutyryl, benzoyl, tert-butoxycarbonyl, trimethylsilylethoxycarbonyl, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, acetyl, formyl, trifluoroacetyl, 4-methoxybenzyl, allyl, benzyl or 2-nitrobenzenesulfonyl, X is an oxygen atom, a process for producing one or more processes among processes 1 to 14, process 15-1 and process 15-2 of a compound in which a double line composed of a solid line and a dotted line is a double bond, and the compound used in this production method.

[0524] As one mode of the above embodiment, it includes using R in formulas (I) to (XI), formula (XII'), formula (XIII'), formulas (XIV) to (XVII), formula (XVII') and formula (XVII'') in processes 1 to 14, 15-1 and 15-2 included in this specification 1 is benzyl, 4,4'-dimethoxytriphenylmethyl or acetyl, R 1a is benzyl, 4,4'-dimethoxytriphenylmethyl or acetyl, R 2 is benzyl, 4,4'-dimethoxytriphenylmethyl or acetyl, R 3 and R 4 is R 3 formed together with R 4 an isopropylidene ketal group, R 3a and R 4a is acetyl, R 5 is benzyloxycarbonyl, acetyl, 4-methoxybenzyl or allyl, R 6 is a hydrogen atom, R 7 is a hydrogen atom, R 11 is methyl, R 12 is a hydrogen atom or methyl, R 14A process for manufacturing one or more processes among processes 1 to 14, process 15-1, and process 15-2 of a compound where R is benzyloxycarbonyl, acetyl, 4-methoxybenzyl, or allyl, X is an oxygen atom, and the double bond formed by a solid line and a dotted line is a double bond, and the compound used in this manufacturing process.

[0525] As one mode of the above embodiment, it includes using R in formulas (I) to (XI), formula (XII′), formula (XIII′), formulas (XIV) to (XVII), formula (XVII′), and formula (XVII″) in processes 1 to 14, 15-1, and 15-2 included in this specification 1 is benzyl, 4,4'-dimethoxytrityl, or acetyl, R 1a is benzyl, 4,4'-dimethoxytrityl, or acetyl, R 2 is benzyl, 4,4'-dimethoxytrityl, or acetyl, R 3 and R 4 is R 3 and R 4 together form an isopropylidene ketal group, R 3a and R 4a is acetyl, R 5 is benzyloxycarbonyl, acetyl, 4-methoxybenzyl, or allyl, R 6 is a hydrogen atom, R 7 is a hydrogen atom, R 11 is methyl, R 12 is methyl, R 14 A process for manufacturing one or more processes among processes 1 to 14, process 15-1, and process 15-2 of a compound where R is benzyloxycarbonyl, acetyl, 4-methoxybenzyl, or allyl, X is an oxygen atom, and the double bond formed by a solid line and a dotted line is a double bond, and the compound used in this manufacturing process.

[0526] As one mode of the above embodiment, it includes using R in formulas (I) to (XI), formula (XII′), formula (XIII′), formulas (XIV) to (XVII), formula (XVII′), and formula (XVII″) in processes 1 to 3, 9 to 14, 15-1, and 15-2 included in this specification 1 is a protecting group for a hydroxyl group, R 1a is a protecting group for a hydroxyl group, R 2 is a protecting group for a hydroxyl group, R 3 and R 4 is R 3 and R 4 together form a cyclic protecting group for a diol, R 3a and R 4a is an acyl group, R 5 and R6 is a protecting group for an amino group, R 7 is an alkyl group or a hydrogen atom, R 11 is an alkyl group, R 12 is a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkyl group, R 14 is a hydrogen atom or a protecting group for an amino group, X is an oxygen atom or NR 13 (R 13 represents a hydrogen atom or a protecting group for an amino group), a process for producing a compound in which a double bond formed of a solid line and a dotted line is a single bond or a double bond, and one or more of processes 1 to 3, 9 to 14, process 15-1 and process 15-2, and the compound used in this production method.

[0527] As one mode of the above-described embodiment, it includes using R in formulas (I) to (XI), formula (XII'), formula (XIII'), formulas (XIV) to (XVII), formula (XVII') and formula (XVII'') in processes 1 to 3, 9 to 14, 15-1 and 15-2 included in this specification. 1 is a protecting group for a hydroxyl group, R 1a is a protecting group for a hydroxyl group, R 2 is a protecting group for a hydroxyl group, R 3 and R 4 is R 3 and R 4 together form a cyclic protecting group for a diol, R 3a and R 4a are acetyl groups, R 5 is a protecting group for an amino group, R 6 is a hydrogen atom, R 7 is a hydrogen atom, R 11 is an alkyl group, R 12 is a hydrogen atom or a methyl group, R 14 is a hydrogen atom or a protecting group for an amino group, X is an oxygen atom, a process for producing a compound in which a double bond formed of a solid line and a dotted line is a double bond, and one or more of processes 1 to 3, 9 to 14, process 15-1 and process 15-2, and the compound used in this production method.

[0528] As one mode of the above-described embodiment, it includes using R in formulas (I) to (XI), formula (XII'), formula (XIII'), formulas (XIV) to (XVII), formula (XVII') and formula (XVII'') in processes 1 to 3, 9 to 14, 15-1 and 15-2 included in this specification. 1is benzyl, 4,4'-dimethoxytrityl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl or acetyl, R 1a is benzyl, 4,4'-dimethoxytrityl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl or acetyl, R 2 is benzyl, 4,4'-dimethoxytrityl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl or acetyl, R 3 and R 4 is R 3 and R 4 together form an isopropylidene ketal group, a methylene acetal group, an ethylidene acetal group, a benzylidene acetal group, a 4-methoxybenzylidene acetal group or a 1-benzyloxybenzyl orthoester group, R 3a and R 4a is acetyl, R 5 is benzyloxycarbonyl, isobutyryl, benzoyl, tert-butoxycarbonyl, trimethylsilylethoxycarbonyl, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, acetyl, formyl, trifluoroacetyl, 4-methoxybenzyl, allyl, benzyl or 2-nitrobenzenesulfonyl, R 6 is a hydrogen atom, R 7 is a hydrogen atom, R 11 is methyl, R 12 is a hydrogen atom or methyl, R 14 is benzyloxycarbonyl, isobutyryl, benzoyl, tert-butoxycarbonyl, trimethylsilylethoxycarbonyl, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, acetyl, formyl, trifluoroacetyl, 4-methoxybenzyl, allyl, benzyl or 2-nitrobenzenesulfonyl, X is an oxygen atom, a process for one or more of processes 1 to 3, 9 to 14, process 15-1 and process 15-2 of a compound in which a double line composed of a solid line and a dotted line is a double bond, and the compound used in this manufacturing method.

[0529] As one mode of the above-described embodiment, it includes R in Formulas (I) to (XI), Formula (XII'), Formula (XIII'), Formulas (XIV) to (XVII), Formula (XVII'), and Formula (XVII'') used in Steps 1 to 3, 9 to 14, 15-1, and 15-2 included in this specification 1 is benzyl, 4,4'-dimethoxytriphenylmethyl, or acetyl, R 1a is benzyl, 4,4'-dimethoxytriphenylmethyl, or acetyl, R 2 is benzyl, 4,4'-dimethoxytriphenylmethyl, or acetyl, R 3 and R 4 is R 3 and R 4 together form an isopropylidene ketal group, R 3a and R 4a is acetyl, R 5 is benzyloxycarbonyl, acetyl, 4-methoxybenzyl, or allyl, R 6 is a hydrogen atom, R 7 is a hydrogen atom, R 11 is methyl, R 12 is a hydrogen atom or methyl, R 14 is benzyloxycarbonyl, acetyl, 4-methoxybenzyl, or allyl, X is an oxygen atom, a double bond composed of a solid line and a dotted line is a double bond, a manufacturing method for one or more steps in Steps 1 to 3, 9 to 14, Step 15-1, and Step 15-2, and the compound used in this manufacturing method.

[0530] As one mode of the above-described embodiment, it includes R in Formulas (I) to (XI), Formula (XII'), Formula (XIII'), Formulas (XIV) to (XVII), Formula (XVII'), and Formula (XVII'') used in Steps 1 to 3, 9 to 14, 15-1, and 15-2 included in this specification 1 is benzyl, 4,4'-dimethoxytriphenylmethyl, or acetyl, R 1a is benzyl, 4,4'-dimethoxytriphenylmethyl, or acetyl, R 2 is benzyl, 4,4'-dimethoxytriphenylmethyl, or acetyl, R 3 and R 4 is R 3 and R 4 together form an isopropylidene ketal group, R 3a and R 4a is acetyl, R 5 is benzyloxycarbonyl, acetyl, 4-methoxybenzyl, or allyl, R 6 is a hydrogen atom, R 7 is a hydrogen atom, R 11 is methyl, R12 is methyl, R 14 is benzyloxycarbonyl, acetyl, 4-methoxybenzyl or allyl, X is an oxygen atom, a double bond composed of a solid line and a dotted line is a double bond, a manufacturing method of one or more processes among processes 1 to 3, 9 to 14, process 15-1 and process 15-2, and the compound used in this manufacturing method.

[0531] As one mode of the above embodiment, it includes using R in formula (I), formula (IV′), formula (XVIII) to formula (XX) in processes 16 to 18 included in this specification 1 is a protecting group for a hydroxyl group, R 2 is a protecting group for a hydroxyl group, R 3 and R 4 is R 3 and R 4 together form a cyclic protecting group for a diol, R 5 is a protecting group for an amino group, R 8 is a manufacturing method of one or more processes among processes 16 to 18 of a compound having an alkoxy group, and the compound used in this manufacturing method.

[0532] As one mode of the above embodiment, it includes using R in formula (I), formula (IV′), formula (XVIII) to formula (XX) in processes 16 to 18 included in this specification 1 is a protecting group for a hydroxyl group, R 2 is a protecting group for a hydroxyl group, R 3 and R 4 is R 3 and R 4 together form a cyclic protecting group for a diol, R 5 is a protecting group for an amino group, R 8 is a manufacturing method of one or more processes among processes 16 to 18 of a compound having a para-methoxy group, and the compound used in this manufacturing method.

[0533] As one mode of the above embodiment, it includes using R in formula (I), formula (IV′), formula (XVIII) to formula (XX) in processes 16 to 18 included in this specification 1 is benzyl, 4,4′-dimethoxytrityl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl or acetyl, R 2is benzyl, 4,4'-dimethoxytrityl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl or acetyl, R 3 and R 4 is R 3 and R 4 together form an isopropylidene ketal group, a methylene acetal group, an ethylidene acetal group, a benzylidene acetal group, a 4-methoxybenzylidene acetal group or a 1-benzyloxybenzyl orthoester group, R 5 is benzyloxycarbonyl, isobutyryl, benzoyl, tert-butoxycarbonyl, trimethylsilylethoxycarbonyl, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, acetyl, formyl, trifluoroacetyl, 4-methoxybenzyl, allyl, benzyl or 2-nitrobenzenesulfonyl, R 8 A method for manufacturing one or more of the steps in steps 16 to 18 of a compound having a para-methoxy group, and the compound used in this manufacturing method.

[0534] As one mode of the above embodiment, it includes using R in formula (I), formula (IV') and formula (XVIII) to formula (XX) in steps 16 to 18 included in this specification 1 is benzyl, 4,4'-dimethoxytrityl or acetyl, R 2 is benzyl, 4,4'-dimethoxytrityl or acetyl, R 3 and R 4 is R 3 and R 4 together form an isopropylidene ketal group, R 5 is benzyloxycarbonyl, acetyl, 4-methoxybenzyl or allyl, R 8 A method for manufacturing one or more of the steps in steps 16 to 18 of a compound having a para-methoxy group, and the compound used in this manufacturing method.

[0535] As one mode of the above embodiment, it includes using R in formula (I), formula (IV) and formula (XXI) to formula (XXIII) in steps 19 to 21 included in this specification 1 is a protecting group for a hydroxyl group, R 2 is a protecting group for a hydroxyl group, R 3 and R 4 is R 3 and R 4 together form a cyclic protecting group for a diol, R 5 and R 6 is a protecting group for an amino group, R 9is an alkyl group or a hydrogen atom, R 10 A manufacturing method of one or more processes among processes 19 to 21 of a compound in which is an alkyl group or a hydrogen atom, and the compound used in this manufacturing method.

[0536] As one mode of the above embodiment, it includes using R in formula (I), formula (IV), and formula (XXI) to formula (XXIII) in processes 19 to 21 included in this specification 1 is a protecting group for a hydroxyl group, R 2 is a protecting group for a hydroxyl group, R 3 and R 4 is R 3 and R 4 together form a cyclic protecting group for a diol, R 5 is a protecting group for an amino group, R 6 is a hydrogen atom, R 9 is a hydrogen atom, R 10 is a hydrogen atom, A manufacturing method of one or more processes among processes 19 to 21 of a compound, and the compound used in this manufacturing method.

[0537] As one mode of the above embodiment, it includes using R in formula (I), formula (IV), and formula (XXI) to formula (XXIII) in processes 19 to 21 included in this specification 1 is benzyl, 4,4'-dimethoxytrityl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl or acetyl, R 2 is benzyl, 4,4'-dimethoxytrityl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl or acetyl, R 3 and R 4 is R 3 and R 4 together form an isopropylidene ketal group, a methylene acetal group, an ethylidene acetal group, a benzylidene acetal group, a 4-methoxybenzylidene acetal group or a 1-benzyloxybenzyl orthoester group, R 5 is benzyloxycarbonyl, isobutyryl, benzoyl, tert-butoxycarbonyl, trimethylsilylethoxycarbonyl, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, acetyl, formyl, trifluoroacetyl, 4-methoxybenzyl, allyl, benzyl or 2-nitrobenzenesulfonyl, R 6 is a hydrogen atom, R 9 is a hydrogen atom, R10 A manufacturing method for one or more of the processes in Processes 19 to 21 of a compound that is a hydrogen atom, and the compound used in this manufacturing method.

[0538] As one mode of the above-described embodiment, it includes R in Formula (I), Formula (IV), and Formula (XXI) to Formula (XXIII) used in Processes 19 to 21 included in this specification 1 being benzyl, 4,4'-dimethoxytrityl, or acetyl, R 2 being benzyl, 4,4'-dimethoxytrityl, or acetyl, R 3 and R 4 being R 3 and R 4 together forming an isopropylidene ketal group, R 5 being benzyloxycarbonyl, acetyl, 4-methoxybenzyl, or allyl, R 6 being a hydrogen atom, R 9 being a hydrogen atom, R 10 A manufacturing method for one or more of the processes in Processes 19 to 21 of a compound that is a hydrogen atom, and the compound used in this manufacturing method.

[0539] <Other modes of the compound>

[0540] As other modes of the compound of the above-described embodiment, it includes R in Formula (IV) 1 being a protecting group for a hydroxyl group, R 2 being benzyl, 4,4'-dimethoxytrityl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl, or acetyl, R 3 and R 4 being R 3 and R 4 together forming a cyclic protecting group for a diol, R 5 and R 6 being a compound that is a protecting group for an amino group.

[0541] As other modes of the compound of the above-described embodiment, it includes R in Formula (IV) 1 being a protecting group for a hydroxyl group, R 2 being benzyl, 4,4'-dimethoxytrityl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl, or acetyl, R 3 and R 4 being R 3With R 4 A cyclic protecting group of the diol formed together with R 5 Is a protecting group for the amino group, R 6 A compound that is a hydrogen atom.

[0542] As another form of the compound of the above embodiment, it contains R in formula (IV) 1 Is benzyl, 4,4'-dimethoxytrityl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl or acetyl, R 2 Is benzyl, 4,4'-dimethoxytrityl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl or acetyl, R 3 And R 4 Is R 3 With R 4 Together form an isopropylidene ketal group, a methylene acetal group, an ethylidene acetal group, a benzylidene acetal group, a 4-methoxybenzylidene acetal group or a 1-benzyloxybenzyl orthoester group, R 5 Is benzyloxycarbonyl, isobutyryl, benzoyl, tert-butoxycarbonyl, trimethylsilylethoxycarbonyl, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, acetyl, formyl, trifluoroacetyl, 4-methoxybenzyl, allyl, benzyl or 2-nitrobenzenesulfonyl, R 6 A compound that is a hydrogen atom.

[0543] As another form of the compound of the above embodiment, it contains R in formula (IV) 1 Is benzyl, 4,4'-dimethoxytrityl or acetyl, R 2 Is benzyl, 4,4'-dimethoxytrityl or acetyl, R 3 And R 4 Is R 3 With R 4 Together form an isopropylidene ketal group, R 5 Is benzyloxycarbonyl, acetyl, 4-methoxybenzyl or allyl, R 6 A compound that is a hydrogen atom.

[0544] As another form of the compound of the above embodiment, it contains R in formula (XIII) 1is benzyl, 4,4'-dimethoxytrityl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl or acetyl, R 2 is a protecting group for a hydroxyl group, R 5 and R 6 is a protecting group for an amino group, and B is a base moiety of a nucleic acid.

[0545] As another form of the compound of the above embodiment, it includes R in formula (XIII) 1 is benzyl, 4,4'-dimethoxytrityl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl or acetyl, R 2 is a protecting group for a hydroxyl group, R 5 is a protecting group for an amino group, R 6 is a hydrogen atom, and B is a base moiety of a nucleic acid.

[0546] As another form of the compound of the above embodiment, it includes R in formula (XIII) 1 is benzyl, 4,4'-dimethoxytrityl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl or acetyl, R 2 is benzyl, 4,4'-dimethoxytrityl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl or acetyl, R 5 is benzyloxycarbonyl, isobutyryl, benzoyl, tert-butoxycarbonyl, trimethylsilylethoxycarbonyl, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, acetyl, formyl, trifluoroacetyl, 4-methoxybenzyl, allyl, benzyl or 2-nitrobenzenesulfonyl, R 6 is a hydrogen atom, and B is a base moiety of a nucleic acid.

[0547] As another form of the compound of the above embodiment, it includes R in formula (XIII) 1 is benzyl, 4,4'-dimethoxytrityl or acetyl, R 2 is benzyl, 4,4'-dimethoxytrityl or acetyl, R 5is benzyloxycarbonyl, acetyl, 4-methoxybenzyl or allyl, and R 6 is a hydrogen atom, and B is a base moiety of a nucleic acid.

[0548] As another form of the compound of the above embodiment, R in formula (XIII) is included 1 is benzyl, 4,4'-dimethoxytrityl or acetyl, and R 2 is benzyl, 4,4'-dimethoxytrityl or acetyl, and R 5 is benzyloxycarbonyl, acetyl, 4-methoxybenzyl or allyl, and R 6 is a hydrogen atom, and B is adeninyl, guanyl, 2,6-diaminopurinyl, thyminyl, dihydrothyminyl, 2-thiothyminyl, cytosinyl, 5-methylcytosinyl, uracilyl, dihydrouracil, 5-fluorocytosinyl, xanthinyl, 6-aminopurinyl, 2-aminopurinyl, 6-chloro-2-aminopurinyl, or 6-chloropurinyl.

[0549] As another form of the compound of the above embodiment, R in formula (XIII) is included 1 is benzyl, 4,4'-dimethoxytrityl or acetyl, and R 2 is benzyl, 4,4'-dimethoxytrityl or acetyl, and R 5 is benzyloxycarbonyl, acetyl, 4-methoxybenzyl or allyl, and R 6 is a hydrogen atom, and B is thyminyl.

[0550] As another form of the compound of the above embodiment, R in formula (XVI) is included 1 is a protecting group for a hydroxyl group, and R 2 is a protecting group for a hydroxyl group, and R 12 is a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkyl group, and R 14 is a hydrogen atom, benzyloxycarbonyl, isobutyryl, benzoyl, tert-butoxycarbonyl, trimethylsilylethoxycarbonyl, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, acetyl, formyl, trifluoroacetyl, 4-methoxybenzyl, allyl, benzyl or 2-nitrobenzenesulfonyl, X is an oxygen atom or NR 13 (R 13 represents a hydrogen atom or a protecting group for an amino group), and the double line composed of a solid line and a dotted line is a single bond or a double bond.

[0551] As another form of the compound of the above embodiment, R in formula (XVI) is included 1 is a protecting group for a hydroxyl group, and R 2 is a protecting group for a hydroxyl group, and R 12is a hydrogen atom or a methyl group, R 14 is a hydrogen atom, benzyloxycarbonyl, isobutyryl, benzoyl, tert-butoxycarbonyl, trimethylsilylethoxycarbonyl, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, acetyl, formyl, trifluoroacetyl, 4-methoxybenzyl, allyl, benzyl or 2-nitrobenzenesulfonyl, X is an oxygen atom, and the double line composed of a solid line and a dotted line is a double bond compound.

[0552] As another form of the compound of the above embodiment, it contains R in formula (XVI) 1 is benzyl, 4,4'-dimethoxytrityl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl or acetyl, R 2 is benzyl, 4,4'-dimethoxytrityl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl or acetyl, R 12 is a hydrogen atom or a methyl group, R 14 is benzyl, 4,4'-dimethoxytrityl or acetyl, R

[0553] As another form of the compound of the above embodiment, it contains R in formula (XVI) 1 is benzyl, 4,4'-dimethoxytrityl or acetyl, R 2 is benzyl, 4,4'-dimethoxytrityl or acetyl, R 12 is a hydrogen atom or a methyl group, R 14 is benzyloxycarbonyl, acetyl, 4-methoxybenzyl or allyl, X is an oxygen atom, and the double line composed of a solid line and a dotted line is a double bond compound.

[0554] As another form of the compound of the above embodiment, it contains R in formula (XVI) 1 is benzyl, 4,4'-dimethoxytrityl or acetyl, R 2 is benzyl, 4,4'-dimethoxytrityl or acetyl, R 12 is a methyl group, R 14A compound where R is benzyloxycarbonyl, acetyl, 4-methoxybenzyl or allyl, X is an oxygen atom, and the double bond composed of a solid line and a dotted line is a double bond.

[0555] <Manufacturing Method>

[0556] Hereinafter, the above manufacturing method will be specifically described. It should be noted that in this specification, a compound represented by a certain formula such as the compound represented by formula (I) and the compound represented by formula (II) is also referred to as the compound of formula (I), the compound of formula (II), etc.

[0557] (1) Manufacturing method of the compound represented by formula (IV)

[0558] The compound represented by formula (IV) can be manufactured as described below.

[0559] [Chemical formula 57]

[0560]

[0561] (In the formula, the meanings of the respective symbols are the same as above.)

[0562] <Step 1>

[0563] The following steps: reacting the compound of formula (I) with the compound of formula (V) or its salt (hydrochloride, sulfate, phosphate, etc., preferably hydrochloride) in a suitable solvent to obtain the compound of formula (II).

[0564] As the solvent, any solvent that does not affect this reaction can be used. For example, 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. can be used, and they can also be used in appropriate combinations.

[0565] When using the salt of the compound of formula (V), the reaction can be carried out in the presence of a base. As the base, for example, pyridine, sodium acetate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, etc. can be cited, and pyridine is preferred. The solvent is the same as above.

[0566] In addition, when using the salt of the compound of formula (V), when using a solvent composed of a combination of an alcohol, tetrahydrofuran and water, N,N-dimethylformamide or dioxane as the solvent, the base can also not be added.

[0567] The amount of the compound of formula (V) or its salt is preferably 1 to 3 molar equivalents relative to 1 mole of the compound of formula (I). The amount of the base used is preferably 1 to 10 molar equivalents relative to 1 mole of the compound of formula (I).

[0568] The reaction temperature is preferably 40 °C to 80 °C, particularly preferably 50 °C to 70 °C.

[0569] <Step 2>

[0570] It is the following step: The compound of formula (II) is subjected to a reduction reaction in a suitable solvent using a reducing agent to obtain the compound of formula (III).

[0571] As the solvent, any solvent that does not affect this reaction can be used. For example, aromatic hydrocarbons (benzene, toluene, xylene, etc.), ethers (diethyl ether, tetrahydrofuran, dimethoxyethane, etc.), halogen solvents (dichloromethane, chloroform, etc.) can be cited, and they can also be used by appropriately combining them. Among them, ethers are preferred, and tetrahydrofuran is more preferred.

[0572] As the reducing agent, sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al) or lithium aluminum hydride is preferred. If sodium bis(2-methoxyethoxy)aluminum hydride is used, the reaction proceeds without by-products, so it is more preferred.

[0573] The amount of the reducing agent used is preferably 2 to 3 molar equivalents relative to 1 mole of the compound of formula (II).

[0574] The reaction temperature is preferably 20 °C to 60 °C, particularly preferably 30 °C to 50 °C.

[0575] <Step 3>

[0576] It is the following step: The compound of formula (III) is subjected to a protection reaction of the amino group in a suitable solvent to obtain the compound of formula (IV).

[0577] The protection reaction of the amino group can be carried out under reaction conditions generally known in organic synthetic chemistry (for example, nucleic acid synthesis). For example, it can be carried out according to the method described in Theodra W. Greene, Peter G. M. Wuts, “Protective Groups in Organic Synthesis” 4 th . Ed. / John Wiley & Sons, Inc., 2007. For example, it can be carried out using N-benzyloxycarbonyloxysuccinimide in a solvent in the presence of a base.

[0578] As the solvent, any solvent that does not affect this reaction can be used. For example, 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.) can be cited, and they can also be used by appropriately combining them. Among them, when sodium hydroxide is used as the base, esters are preferred, and ethyl acetate is particularly preferred. In addition, when potassium carbonate is used as the base, ethers are preferred, and tetrahydrofuran is particularly preferred.

[0579] As the base, basic inorganic salts can be cited. For example, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, etc. can be cited, and sodium hydroxide or potassium carbonate is preferred. The amount of the base used is such that the pH of the reaction solution becomes weakly basic.

[0580] The amount of benzyloxycarbonyloxysuccinimide used is preferably 1 to 1.5 times the molar equivalent relative to 1 mole of the compound of formula (III).

[0581] The reaction temperature is preferably 0°C to 40°C, and particularly preferably 10°C to 30°C.

[0582] (2) Method for producing the compound of formula (I)

[0583] The compound of formula (I) can be produced as described below.

[0584] [Chemical formula 58]

[0585]

[0586] (In the formula, the meanings of the respective symbols are the same as above.)

[0587] The compound of formula (VI) can be obtained commercially, and for steps 4 to 8, it can be produced according to known methods, for example, the method described in Kei Fukuyama et al., Org. Lett. 2015, 17, 828 - 831.

[0588] (3) Method for producing the compound represented by formula (XIII) from the compound represented by formula (IV)

[0589] The compound represented by formula (XIII) can be produced from the compound represented by formula (IV) or formula (IV′) as described below.

[0590] [Chemical formula 59]

[0591]

[0592] (In the formula, the meanings of the symbols are the same as those described above.)

[0593] The compound represented by formula (IV′) is the compound of formula (IV) where R 6 is a hydrogen atom.

[0594] <Step 9>

[0595] is the following step: reacting the compound of formula (IV) or formula (IV′) in a suitable solvent to effect the conversion of R 3 and R 4 to an acyl group, thereby converting R 3 and R 4 to an acyl group and obtaining the compound of formula (XI).

[0596] R 3 and R 4 The conversion reaction to an acyl group can be carried out according to the methods described in J. Org. Chem. 2011, 76, 9891 - 9899, WO2017 / 047816, etc.

[0597] For example, the compound of formula (IV) can be reacted in a suitable solvent in the presence of an acid anhydride with an acid catalyst to produce the compound of formula (XI). Acid can be added as needed.

[0598] As the solvent, any solvent that does not affect this reaction can be used. For example, 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.), halogen - based solvents (dichloromethane, chloroform, etc.) can be mentioned, and they can also be used by appropriately combining them. Among them, ethyl acetate is preferably used.

[0599] As the acid anhydride, acetic anhydride is preferably selected, and the amount is preferably 1 - 10 times the molar equivalent relative to 1 mole of the compound of formula (IV).

[0600] As the acid, acetic acid is preferably selected, and the amount is preferably 1 - 20 times the molar equivalent relative to 1 mole of the compound of formula (IV).

[0601] As the acid catalyst, sulfuric acid is preferably selected, and the amount is preferably 0.01 - 0.20 times the molar equivalent relative to 1 mole of the compound of formula (IV).

[0602] The reaction temperature is preferably 10 - 40 °C.

[0603] <Step 10>

[0604] The following step: subject the compound of formula (XI) to a glycosylation reaction in a suitable solvent to introduce the base moiety of a nucleic acid, thereby obtaining the compound of formula (XII).

[0605] The introduction of the base moiety of a nucleic acid based on the glycosylation reaction of the compound of formula (XI) can be carried out according to the methods described in J. Org. Chem. 2011, 76, 9891 - 9899, WO2017 / 047816, etc.

[0606] For example, for the compound of formula (XI), in a suitable solvent, N,O-bis(trimethylsilyl)acetamide and a nucleic acid base are reacted in the presence of trimethylsilyl trifluoromethanesulfonate to produce the compound of formula (XII).

[0607] The nucleic acid base is, for example, thymine (T). Reacting with thymine (T) as the nucleic acid base, in contrast, it can be reacted with other nucleic acid bases instead of thymine (T) to introduce various nucleic acid bases other than thymine. As the solvent, any solvent that does not affect this reaction can be used. For example, 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. can be used, and they can also be used in appropriate combinations. Among them, acetonitrile is preferably used.

[0608] The reaction temperature is preferably 60 - 100 °C.

[0609] <Step 11>

[0610] The following step: subject the compound of formula (XII) to a deprotection reaction of an acyl group in a suitable solvent to obtain the compound of formula (XIII).

[0611] The deprotection reaction can be carried out according to the methods described in J. Org. Chem. 2011, 76, 9891 - 9899, WO2017 / 047816, etc.

[0612] For example, the deprotection reaction can be carried out in a suitable solvent in the presence of a base.

[0613] As the solvent, any solvent that does not affect this reaction can be used. For example, 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, isopropyl alcohol, etc.) can be cited, and they can also be used by appropriately combining them. Among them, alcohols (methanol, ethanol, etc.) are preferred.

[0614] As the base, methylamine is preferred. The amount of the base used is preferably 3 to 30 times the molar equivalent relative to 1 mole of the compound of formula (XII).

[0615] The reaction temperature is preferably 0°C to 50°C, and particularly preferably 15°C to 30°C.

[0616] In addition, this deprotection reaction can also be carried out by hydrolysis.

[0617] (4) Method for producing the compound represented by formula (XVII′) or the compound represented by formula (XVII″) from the compound represented by formula (XIII′)

[0618] The compound represented by formula (XVII′) or the compound represented by formula (XVII″) can be produced from the compound represented by formula (XIII′) as described below.

[0619] [Chemical formula 60]

[0620]

[0621] (In the formula, the meanings of each symbol are the same as above.)

[0622] The compound represented by formula (XIII′) is the compound of formula (XIII) where B is the compound represented by formula (XXIV).

[0623] [Chemical formula 61]

[0624]

[0625] [In the formula,

[0626] R 12 represents a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkyl group,

[0627] X represents an oxygen atom or NR 13 (R 13 represents a hydrogen atom or a protecting group for an amino group),

[0628] A double line composed of a solid line and a dotted line represents a single bond or a double bond.

[0629] The compound represented by formula (XVII′) is the compound represented by formula (XVII) where R 1 is a hydrogen atom.

[0630] The compound represented by formula (XVII″) is the compound represented by formula (XVII) where R 1 is R 1a compound.

[0631] <Step 12>

[0632] The following step: subject the compound of formula (XIII’) to a sulfonylation reaction in a suitable solvent to obtain the compound of formula (XIV).

[0633] The sulfonylation reaction can be carried out according to the methods described in WO2017 / 047816 etc. For example, the compound of formula (XIII’) can be reacted in a suitable solvent in the presence of an activator for the hydroxyl group and a base to produce the compound of formula (XIV).

[0634] As the solvent, any solvent that does not affect this reaction can be used. For example, 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. can be mentioned, and they can also be used by appropriately combining them. Among them, ethers are preferred, and tetrahydrofuran is more preferred.

[0635] As the activator for the hydroxyl group, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, p-toluenesulfonyl chloride, 2-nitrobenzenesulfonyl chloride, methanesulfonic anhydride or trifluoromethanesulfonic anhydride can be mentioned, and methanesulfonyl chloride is preferred.

[0636] As the base, triethylamine, pyridine, diisopropylethylamine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, etc. can be mentioned, and triethylamine or pyridine is preferred.

[0637] The amount of the activator for the hydroxyl group used is preferably 1 to 2 molar equivalents relative to 1 mole of the compound of formula (XIII’). The amount of the base used is preferably 1 to 4 molar equivalents relative to 1 mole of the compound of formula (XIII’).

[0638] The reaction temperature is preferably 5°C to 45°C, particularly preferably 15°C to 35°C.

[0639] <Step 13>

[0640] The following process: subjecting the compound of formula (XIV) to a cyclization reaction in a suitable solvent to obtain the compound of formula (XV).

[0641] The cyclization reaction can be carried out in a suitable solvent in the presence of a base.

[0642] As the solvent, any solvent that does not affect this reaction can be used. For example, 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.) can be cited, and they can also be used by appropriately combining them. In addition, pyridine can also be used as the solvent.

[0643] Examples of the base include diazabicycloundecene, sodium hydride, etc., and diazabicycloundecene is preferred.

[0644] Regarding the amount of the base used, relative to 1 mole of the compound of formula (XIV), diazabicycloundecene is preferably 1 to 4 times the molar equivalent, and sodium hydride is preferably 1 times the molar equivalent.

[0645] The reaction temperature is preferably 5°C to 45°C, and particularly preferably 15°C to 35°C.

[0646] The compound of formula (XV) obtained by this process can be separated in the form of crystals. Among them, in particular, when R 1 is benzyl, R 2 is benzyl, R 5 is benzyloxycarbonyl, R 6 is a hydrogen atom, X is an oxygen atom, R 12 is methyl, and the double bond composed of a solid line and a dotted line is a double bond, the compound of formula (XV') (compound 14 in Example 1(11) described later) can be ideally separated in the form of crystals. Therefore, in this process, it is preferred to use the corresponding compound of formula (XIV') (R 11 is methyl, etc.) to produce the compound of formula (XV').

[0647] As the crystallization method of the compound of formula (XV') in formula (XV), methods such as adding a poor solvent for crystallization or crystallizing from a mixture of a good solvent and a poor solvent, methods of reducing the solubility of the compound by cooling for crystallization, or methods combining them can be cited. The crystallization in this process can be efficiently carried out by dropping water as a poor solvent and cooling to about 10°C.

[0648] The powder X-ray diffraction pattern of the crystal of the compound of formula (XV’) measured by CuKα radiation is shown in Table 1 and Figure 1 as shown. However, regarding the powder X-ray diffraction pattern, it should be noted that, as is known in the art, the intensities of the diffraction peaks in the experimental pattern may vary and fluctuate due to the preferred orientation in the prepared sample.

[0649] <Step 14>

[0650] is the following step: subjecting the compound of formula (XV) to a ring-closing reaction in a suitable solvent to obtain the compound of formula (XVI).

[0651] The ring-closing reaction can be carried out in a suitable solvent in the presence of a base.

[0652] As the solvent, any solvent that does not affect this reaction can be used. For example, aromatic hydrocarbons (such as benzene, toluene, xylene, etc.), aprotic polar solvents (such as N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, etc.), nitriles (such as acetonitrile, etc.), ketones (such as acetone, methyl ethyl ketone, etc.), esters (such as ethyl acetate, isopropyl acetate, etc.), ethers (such as diethyl ether, tetrahydrofuran, dimethoxyethane, etc.), halogenated solvents (such as dichloromethane, chloroform, etc.) can be mentioned, and they can also be used by appropriately combining them. Among them, aprotic polar solvents are preferred, and N,N-dimethylformamide is more preferred.

[0653] As the base, sodium hydride can be mentioned.

[0654] The usage amount of the base is preferably 1 to 3 molar equivalents relative to 1 mole of the compound of formula (XV).

[0655] The reaction temperature is preferably -10°C to 30°C, and particularly preferably 0°C to 10°C.

[0656] <Step 15-1>

[0657] is the following step: subjecting the compound of formula (XVI) to a deprotection reaction in a suitable solvent to obtain the compound of formula (XVII’).

[0658] The deprotection reaction can be carried out under reaction conditions generally known in organic synthetic chemistry (such as nucleic acid synthesis). For example, it can be carried out according to the method described in Theodra W. Greene, Peter G. M. Wuts, “Protective Groups in Organic Synthesis” 4 th . Ed. / John Wiley & Sons, Inc., 2007. For example, it can be carried out in a suitable solvent in the presence of palladium hydroxide on carbon and under a hydrogen atmosphere.

[0659] As the solvent, any solvent that does not affect this reaction can be used. For example, 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, isopropyl alcohol, etc.) can be cited, and they can also be used in appropriate combinations. Among them, alcohols are preferred, and methanol is more preferred.

[0660] The usage amount of palladium hydroxide on carbon is preferably 1 to 30% by weight based on the compound of formula (XVI).

[0661] The reaction temperature is preferably 0°C to 30°C.

[0662] <Process 15-2>

[0663] The following process: subjecting the compound of formula (XVII′) to a hydroxyl protection reaction in a suitable solvent.

[0664] [[ID=·16]]The hydroxyl protection reaction can be carried out under reaction conditions commonly known in organic synthetic chemistry (for example, nucleic acid synthesis). For example, it can be carried out according to the method described in WO2017 / 047816. This reaction can be carried out, for example, using 4,4′-dimethoxytriphenylmethyl chloride in a solvent in the presence of a base.

[0665] [[ID=·19]]As the solvent, any solvent that does not affect this reaction can be used. For example, 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.) can be cited, and they can also be used in appropriate combinations. In addition, pyridine can also be used as the solvent.

[0666] As the base, for example, pyridine, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, etc. can be cited, and pyridine is preferred.

[0667] The reaction temperature is preferably 0°C to 50°C, and particularly preferably 15 to 30°C.

[0668] (5) Method for producing the compound represented by formula (IV) from the compound represented by formula (I) (other methods)

[0669] Regarding the production of the compound represented by formula (IV) or formula (IV′) from the compound represented by formula (I), it can also be produced by, for example, the following synthesis route 1 or synthesis route 2, which is a method different from the method described in (3).

[0670] <Other method 1>

[0671] [Chemical formula 62]

[0672]

[0673] (In the formula, the meanings of the respective symbols are the same as above.)

[0674] <Other method 2>

[0675] [Chemical formula 63]

[0676]

[0677] (In the formula, the meanings of the respective symbols are the same as above.)

[0678] <Step 16>

[0679] It is the following step: After reacting the compound of formula (I) with the compound of formula (XX) in a suitable solvent, it is treated with a reducing agent to obtain the compound of formula (XVIII).

[0680] As the solvent, any solvent that does not affect this reaction can be used. For example, 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. can be used, and they can also be used by appropriately combining them.

[0681] As the reducing agent, sodium cyanoborohydride, sodium triacetoxyborohydride, and sodium borohydride are preferred, and sodium triacetoxyborohydride is more preferred.

[0682] The usage amount of the compound of formula (XX) is preferably 1 to 2 molar equivalents relative to 1 mole of the compound of formula (I). The amount of the reducing agent used is preferably 1 to 3 molar equivalents relative to 1 mole of the compound of formula (I).

[0683] The reaction temperature is preferably 0°C to 50°C, and particularly preferably 15°C to 30°C.

[0684] <Step 17>

[0685] It is a process of subjecting the compound of formula (XVIII) to a protection reaction of the amino group in a suitable solvent to obtain the compound of formula (XIX). The protection reaction can be carried out according to the methods described in Theodra W. Greene, Peter G. M. Wuts, “Protective Groups in Organic Synthesis” 4 th . Ed. / John Wiley & Sons, Inc., 2007, etc. For example, it can be carried out in a solvent using benzyl chloroformate or N-benzyloxycarbonyloxysuccinimide.

[0686] As the solvent, any solvent that does not affect this reaction can be used. For example, aromatic hydrocarbons (such as benzene, toluene, and xylene), aprotic polar solvents (such as N,N-dimethylformamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone), nitriles (such as acetonitrile), ketones (such as acetone and methyl ethyl ketone), esters (such as ethyl acetate and isopropyl acetate), ethers (such as diethyl ether, tetrahydrofuran, and dimethoxyethane), halogenated solvents (such as dichloromethane and chloroform), etc. can be used, and they can also be used in appropriate combinations.

[0687] The amount of benzyl chloroformate or N-benzyloxycarbonyloxysuccinimide used is preferably 1 to 2 molar equivalents relative to 1 mole of the compound of formula (XVIII).

[0688] The reaction temperature is preferably 0 °C to 50 °C, and particularly preferably 15 °C to 30 °C.

[0689] <Process 18>

[0690] It is a process of subjecting the compound of formula (XIX) to a deprotection reaction in a suitable solvent to obtain the compound of formula (IV’). The deprotection reaction can be carried out according to the methods described in Theodra W. Greene, Peter G. M. Wuts, “Protective Groups in Organic Synthesis” 4 th . Ed. / John Wiley & Sons, Inc., 2007, etc. For example, it can be carried out using ammonium cerium(IV) nitrate in a solvent.

[0691] As the solvent, any solvent that does not affect this reaction can be used. For example, aromatic hydrocarbons (such as benzene, toluene, and xylene), aprotic polar solvents (such as N,N-dimethylformamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone), nitriles (such as acetonitrile), ketones (such as acetone and methyl ethyl ketone), esters (such as ethyl acetate and isopropyl acetate), ethers (such as diethyl ether, tetrahydrofuran, and dimethoxyethane), halogenated solvents (such as dichloromethane and chloroform), alcohols (such as methanol, ethanol, and isopropyl alcohol), etc. can be cited, and they can also be used by appropriately combining them.

[0692] The amount of ammonium cerium(IV) nitrate is preferably 1 to 3 molar equivalents relative to the compound of formula (XIX).

[0693] Regarding the reaction temperature, it is preferably carried out at 0°C to 50°C, particularly preferably at 0°C to 10°C.

[0694] <Process 19>

[0695] It is the following process: After reacting the compound of formula (I) with the compound of formula (XXIII) in a suitable solvent, it is treated with a reducing agent to obtain the compound of formula (XXI).

[0696] As the solvent, any solvent that does not affect this reaction can be used. For example, aromatic hydrocarbons (such as benzene, toluene, and xylene), aprotic polar solvents (such as N,N-dimethylformamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone), nitriles (such as acetonitrile), esters (such as ethyl acetate and isopropyl acetate), ethers (such as diethyl ether, tetrahydrofuran, and dimethoxyethane), halogenated solvents (such as dichloromethane and chloroform), alcohols (such as methanol, ethanol, and isopropyl alcohol), etc. can be cited, and they can also be used by appropriately combining them.

[0697] As the reducing agent, sodium cyanoborohydride, sodium triacetoxyborohydride, and sodium borohydride are preferred, and sodium triacetoxyborohydride is more preferred.

[0698] The usage amount of the compound of formula (XXIII) or its salt is preferably 1 to 2 molar equivalents relative to the compound of formula (I). The amount of the reducing agent used is preferably 1 to 3 molar equivalents relative to 1 mole of the compound of formula (I).

[0699] The reaction temperature is preferably -25°C to 50°C, particularly preferably 15°C to 30°C.

[0700] <Process 20>

[0701] It is a process of subjecting the compound of formula (XXI) to a deprotection reaction to obtain the compound of formula (XXII). The deprotection reaction can be carried out according to the methods described in Theodra W. Greene, Peter G. M. Wuts, “Protective Groups in Organic Synthesis” 4 th . Ed. / John Wiley & Sons, Inc., 2007, etc. For example, in a suitable solvent, in the presence of a combination of 1,3-dimethylbarbituric acid, or polymethylhydrosiloxane and zinc(II) chloride, using a catalyst (tetrakis(triphenylphosphine)palladium(0)), the compound of formula (XXI) can be subjected to a deprotection reaction. Alternatively, it can also be carried out in the presence of 2-mercaptobenzoic acid using a catalyst (1,4-bis(diphenylphosphino)butane-palladium(II) chloride or bis(dibenzylideneacetone)palladium(0)).

[0702] Or, a deprotection reaction can be carried out using a catalyst (rhodium(I) chloride tris(triphenylphosphine) or ruthenium(II) benzylidene bis(tricyclohexylphosphine) dichloride).

[0703] As the solvent, any solvent that does not affect this reaction can be used. For example, 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. can be used, and they can also be used in appropriate combinations.

[0704] The amount of 1,3-dimethylbarbituric acid, polymethylhydrosiloxane, zinc(II) chloride or 2-mercaptobenzoic acid used is preferably 1 to 3 times the molar equivalent relative to the compound of formula (XXI). The amount of the catalyst used is preferably 0.05 to 0.1 times the molar equivalent relative to the compound of formula (XXI).

[0705] The reaction temperature is preferably 0°C to 50°C, particularly preferably 30°C to 50°C. It should be noted that the reaction temperature in the reaction using a catalyst (rhodium(I) chloride tris(triphenylphosphine) or ruthenium(II) benzylidene bis(tricyclohexylphosphine) dichloride) is preferably 80°C to 120°C.

[0706] <Process 21>

[0707] This is a process of subjecting the compound of formula (XXII) to a protection reaction of the amino group to obtain the compound of formula (IV). The protection reaction can be carried out according to the methods described in Theodra W. Greene, Peter G. M. Wuts, “Protective Groups in Organic Synthesis” 4 th . Ed. / John Wiley & Sons, Inc., 2007, etc. For example, the compound of formula (XXII) can be reacted with benzyl chloroformate or N-benzyloxycarbonyloxysuccinimide in a suitable solvent to produce the compound of formula (IV).

[0708] As the solvent, any solvent that does not affect this reaction can be used. For example, 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.) can be cited, and they can also be used by appropriately combining them.

[0709] The amount of benzyl chloroformate or N-benzyloxycarbonyloxysuccinimide used is preferably 1 to 2 molar equivalents relative to the compound of formula (XVIII).

[0710] The reaction temperature is preferably 0 °C to 50 °C, and particularly preferably 15 °C to 30 °C.

[0711] (6) Method for producing the compound represented by formula (XVII′) or the compound represented by formula (XVII″) from the compound represented by formula (VI)

[0712] The compound represented by formula (XVII′) or the compound represented by formula (XVII″) can be produced from the compound represented by formula (VI) as described below.

[0713] [Chemical formula 64]

[0714]

[0715] (In the formula, the meanings of the respective symbols are the same as described above.)

[0716] Steps 1 to 15-2 are as described in the aforementioned (1) to (4).

[0717] In the above manufacturing method, the compounds targeted can be separately isolated for each of the processes from Process 1 to Process 13. Additionally, in each of the processes from Process 1 to Process 13, the reaction product may not be separated, and the reaction solution containing the crude product of the reaction can be directly used for the next process or the concentrated reaction solution can be used for the next process. The compound of formula (XV) thus obtained can be isolated and purified in the form of crystals. Further, the compounds targeted can be separately isolated for each of the processes from Process 14 to Process 15-2. Additionally, in each of the processes from Process 14 to Process 15-2, the reaction product may not be separated, and the reaction solution containing the crude product of the reaction can be directly used for the next process or the concentrated reaction solution can be used for the next process.

[0718] In this specification, when the above-mentioned compounds, intermediate compounds, starting compounds, etc. have functional groups (such as hydroxyl group, amino group, carboxyl group, etc.), they can be protected using protecting groups commonly used in organic synthetic chemistry according to the methods described in Theodora W. Greene, Peter G. M. Wuts, "Protect ive Groups in Organic Synthe sis" 4th ed., John Wi Ley & Sons, Inc., 1999, etc. After the reaction, the protecting group is removed to obtain the targeted compound.

[0719] (7) The compounds obtained in the manufacturing methods of (1) to (6)

[0720] In the above manufacturing methods of (1) to (6), the compounds represented by formula (II), formula (III), formula (IV), formula (XI), formula (XII), formula (XII′), formula (XIII), formula (XIII′), formula (XIV), formula (XIV′), formula (XV), formula (XV′), and formula (XVI) are each novel compounds.

[0721] When separating the compounds obtained in each process of the above manufacturing method, all the compounds can also be obtained in the form of salts. As salts, any salts that can be commonly used industrially are acceptable. For example, inorganic acid salts such as hydrochloride, sulfate, phosphate, and hydrobromide, organic acid salts such as acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, toluenesulfonate, and maleate, and alkali metal salts such as sodium salt and potassium salt can be cited. The conversion to such salts can be carried out according to conventional methods.

[0722] (8) A method for manufacturing a modified oligonucleotide or a salt thereof from the compound represented by formula (XVII″)

[0723] The ALNA[Ms] amide compound can be produced from the compound represented by formula (XVII″) according to known methods (e.g., those described in International Publication No. 2017 / 047816, International Publication No. 2020 / 100826, etc.). For the obtained ALNA[Ms] amide compound and commercially available amide compounds for DNA synthesis (e.g., N6-benzoyl-DMT-2'-deoxyadenosine-3'-CE phosphoramidite, N2-isobutyryl-5'-O-(4,4'-dimethoxytriphenylmethyl)-2'-deoxyguanosine-3'-cyanoethyl phosphoramidite, N2-dimethylformamidine-5'-O-(4,4'-dimethoxytriphenylmethyl)-2'-deoxyguanosine-3'-cyanoethyl phosphoramidite, N4-benzoyl-5'-O-(4,4'-dimethoxytriphenylmethyl)-2'-deoxycytidine-3'-cyanoethyl phosphoramidite, 5'-O-(4,4'-dimethoxytriphenylmethyl)-thymidine-3'-cyanoethyl phosphoramidite), the phosphoramidite method can be carried out according to known methods (e.g., those described in International Publication No. 2020 / 100826, International Publication No. 2020 / 203880, etc.), and the sulfurization reaction of the phosphodiester bond can be carried out according to known methods as needed, thereby producing a modified oligonucleotide represented by the following formula or a salt thereof. As the salt, specifically, for example, sodium salt and potassium salt can be mentioned, and sodium salt is preferably mentioned.

[0724] Formula:

[0725] [Chemical formula 65]

[0726]

[0727] Or, formula:

[0728] [Chemical formula 66]

[0729]

[0730] As the process for producing the ALNA[Ms] amide compound from the compound represented by formula (XVII″), for example, it includes the steps of (a) introducing a protecting group for the hydroxyl group and an optional nucleic acid base exchange reaction (transglycosylation reaction), (b) sulfonamidation of the imino nitrogen atom, (c) deprotecting the protecting group of the aforementioned hydroxyl group, and (d) phosphoramidation to produce the desired ALNA[Ms] amide compound.

[0731] ALNA[Ms] is represented by the following structural formula.

[0732] [Chemical formula 67]

[0733]

[0734] <(a) Introduction of protecting group for hydroxyl group and optional nucleic acid base exchange reaction (transglycosylation reaction)>

[0735] The introduction of the protecting group for the hydroxyl group can be carried out under reaction conditions well-known in organic synthetic chemistry (e.g., nucleic acid synthesis) depending on the type of the protecting group. For example, when the protecting group for the hydroxyl group is a silyl-type protecting group (e.g., TMS), a silylating reagent (e.g., BSA, hexamethyldisilazane, TMS chloride) can be used. At this time, a Lewis acid (e.g., TMSOTf, TBSOTf, tin chloride) can be added.

[0736] The silylating reagent can be used in an amount of about 1 to about 20 molar equivalents relative to the reaction substrate, and the Lewis acid can be used in a catalytic amount (about 0.05 molar equivalent) to 2 molar equivalents.

[0737] As the solvent, any solvent that does not affect the reaction can be used, and the reaction can be carried out in a suitable solvent (e.g., ethers such as THF, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, hydrocarbons such as benzene, toluene, acetonitrile, water, or a mixed solvent thereof, etc.). Regarding the reaction temperature, it is preferably carried out at 0 °C to a high temperature, especially at room temperature to about 60 °C.

[0738] In addition, the nucleic acid base moiety (thymine (T)) of the compound represented by the formula (XVII″) can be replaced with other protectable nucleic acid base moieties (e.g., adenine (A), guanine (G), uracil (U), cytosine (C), or 5-methylcytosine (MeC)) by using a nucleic acid base exchange reaction (transglycosylation reaction). This base exchange reaction can be carried out in the presence of a Lewis acid (e.g., TMSOTf, TBSOTf), and the reaction can be promoted by reacting a silylating reagent.

[0739] <(b) Sulfonylation on imino nitrogen atom>

[0740] As the sulfonylation reagent used in the sulfonylation reaction, an alkylsulfonyl halide reagent (e.g., methanesulfonyl chloride (MsCl)), an alkylsulfonic anhydride (e.g., methanesulfonic anhydride), an aromatic sulfonyl halide reagent (e.g., benzenesulfonyl chloride), or an aromatic sulfonic anhydride (e.g., benzenesulfonic anhydride) can be mentioned, and it can be used in the presence of a base (e.g., triethylamine, DIPEA).

[0741] The sulfonylation reagent can be used in an amount of approximately equivalent molar amount to a slightly excessive equivalent molar amount (e.g., about 1.0 molar equivalent) relative to the reaction substrate.

[0742] As the solvent, 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, hydrocarbons like benzene, toluene, acetonitrile, water, or a mixed solvent thereof). Regarding the reaction temperature, it is preferably carried out at -25°C to room temperature, especially 0°C to room temperature.

[0743] <(c) Deprotection of the protecting group of the aforementioned hydroxyl group>

[0744] The deprotection reaction of the hydroxyl group can be carried out under appropriate reaction conditions (such as reagents, etc.) depending on the type of the protecting group. For example, when the protecting group of the hydroxyl group is a silyl-type protecting group (such as TMS), it can be carried out by hydrolysis under acidic conditions (such as acetic acid-THF-water) or by treatment with a reagent that provides fluoride ions (such as TBAF).

[0745] As the solvent, 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, water, or a mixed solvent thereof). Regarding the reaction temperature, it is preferably carried out at -25°C to 100°C, especially 0°C to 50°C.

[0746] <(d) Phosphoramidation>

[0747] Phosphoramidation can be carried out under reaction conditions (such as reagents) commonly known in organic synthesis (especially nucleic acid synthesis).

[0748] As the phosphoramidation reagent, for example, the following formula can be cited, but it is not limited thereto.

[0749] [Chemical formula 68]

[0750] and

[0751] This phosphoramidation reaction can be carried out in the presence of a suitable base (such as DIPEA) or a suitable acid (such as diisopropylammonium salt tetrazole, 4,5-dicyanoimidazole).

[0752] Relative to the reaction substrate, the phosphoramidation reagent can be used in an amount of 1 molar equivalent to 10 molar equivalents, preferably 1 molar equivalent to 5 molar equivalents (such as 3 molar equivalents).

[0753] As the solvent, 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 mixed solvent thereof). Regarding the reaction temperature, it is preferably carried out at -25°C to 60°C, especially 0°C to room temperature.

[0754] In the process of carrying out the phosphoramidite method using an ALNA[Ms] amide compound and an amide compound for DNA synthesis, an oligomerization reaction is carried out. After the oligomerization reaction is carried out, the amino protecting group and the hydroxy protecting group can be deprotected as needed, thereby producing a modified oligonucleotide or a salt thereof.

[0755] In the synthesis of an oligonucleotide based on the phosphoramidite method, an oxidizing agent can be used when converting a phosphite group into a phosphate group. If DDTT (((dimethylamino-methylene)amino)-3H-1,2,4-dithiazoline-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 can be obtained in which the oxygen atom in P=O of the phosphate group is replaced by sulfur in the form of P=S to form a phosphorothioate group.

[0756] In the process of subjecting a phosphodiester bond to a sulfurization reaction as needed, a known sulfurizing reagent can be used. As an example of a commercially available product of the sulfurizing reagent, Sulfurizing Reagent II (Gren Research Corporation) can be mentioned, but it is not limited thereto.

[0757] All documents, patent applications, and technical standards described in this specification are incorporated herein by reference to the same extent as if each individual document, patent application, and technical standard is specifically and separately described as being incorporated by reference.

[0758] Examples

[0759] Hereinafter, the present invention will be specifically described by way of examples, etc., but the present invention is not limited by any of them.

[0760] The abbreviations used respectively represent the following meanings.

[0761] Bn: benzyl

[0762] Cbz: benzyloxycarbonyl

[0763] Ac: acetyl

[0764] DMTr: 4,4'-dimethoxytrityl

[0765] The identification of the compound is carried out using LCMS, NMR spectroscopy, high performance liquid chromatography (HPLC), etc. In NMR, in proton nuclear magnetic resonance ( 1 Η-NMR), a mode with a resonance frequency of 400 MHz is used. As the symbols used in NMR, s represents a singlet, d represents a doublet, dd represents a doublet of doublets, and J represents the coupling constant.

[0766] Example 1: Manufacturing methods of Compounds 2 to 17 and these compounds

[0767] [Chemical formula 69]

[0768]

[0769] (1) Synthesis of Compound 2

[0770] (1)-1: Under a nitrogen atmosphere, Compound 1 (44.2 g, 170 mmol) and nor-AZADO (1.2 mg, 0.0086 mmol) were dissolved in dichloromethane (22.8 mL), and saturated aqueous sodium bicarbonate solution (114 mL) and potassium bromide (2.00 g, 16.9 mmol) were added. Compound 1 was obtained as a commercial product. The mixture was cooled to 0 °C, and a mixture of 12% (w / w) aqueous sodium hypochlorite solution (178 mL) and saturated aqueous sodium bicarbonate solution (91 mL) was added dropwise over 20 minutes, and the mixture was stirred at 0 °C for 40 minutes. nor-AZADO (1.2 mg, 0.0086 mmol), dichloromethane (22.8 mL), and a mixture of 12% (w / w) aqueous sodium hypochlorite solution (33 mL) and saturated aqueous sodium bicarbonate solution (17 mL) were added dropwise, and the mixture was further stirred at the same temperature for 30 minutes. At 0 °C, 30% (w / w) aqueous sodium thiosulfate 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 layers were collected, dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product of Compound 2 (43.1 g) in the form of a pale yellow viscous substance. The obtained crude product was directly used in the subsequent step (2)-1.

[0771] MS(ESI): m / z = 259 (M + H) +

[0772] (1)-2 (non-separation method): Under a nitrogen atmosphere, Compound 1 (14.8 g, 56.9 mmol), nBu4HSO4 (978 mg, 2.88 mmol) and nor-AZADO (9.5 mg, 0.069 mmol) were dissolved in dichloromethane (30 mL). The solution was cooled to 0 °C, and an aqueous sodium hypochlorite solution prepared from sodium hypochlorite pentahydrate (15.1 g, 91.8 mmol) and tap water (7.8 mL) was added dropwise over 30 minutes. The mixture was stirred at 0 °C for 1 hour. A 30% (w / w) aqueous sodium thiosulfate 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). The organic layers were collected, replaced with a tetrahydrofuran solvent under reduced pressure, and concentrated. Thus, a solution of Compound 2 was obtained in the form of a yellow solution. The obtained solution was directly used in the subsequent step (2)-2.

[0773] (2) Synthesis of Compound 4

[0774] (2)-1: Under a nitrogen atmosphere, the crude product of Compound 2 obtained in (1)-1 (43.1 g) was dissolved in tetrahydrofuran (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 and then further stirred at 30 °C for 3 hours. After cooling to room temperature, the 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 layers were 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 60N (neutral, 90 g), and then ethyl acetate (600 mL) was passed through. The eluates were combined and concentrated under reduced pressure. Thus, the crude product of Compound 4 (44.0 g) was obtained in the form of a white solid. The obtained crude product 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 dried under reduced pressure. Thus, Compound 4 (41.3 g, 142 mmol, 83% yield from two steps of Compound 1 ((1)-1 and (2)-1)) was obtained in the form of a white solid.

[0775] MS(ESI): m / z = 291 (M + H) +

[0776] 11H 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).

[0777] (2) - 2 (Non - separation method): Under a nitrogen atmosphere, tetrahydrofuran (73.5 mL) was added to a tetrahydrofuran solution containing the compound 2 obtained in (1) - 2. Paraformaldehyde (3.6 g, 102 mmol) and potassium carbonate (15.7 g, 114 mmol) were added and stirred at 30 °C for 21 hours. Further, paraformaldehyde (1.8 g, 51 mmol) and potassium carbonate (7.9 g, 57 mmol) were added and stirred at 30 °C for 21 hours, and then cooled to 20 °C. The insoluble matter was removed by filtration, and the solid on the filter paper was washed with tetrahydrofuran (7 × 30 mL). The filtrates were combined and concentrated under reduced pressure. After adding tetrahydrofuran (30 mL) and tap water (22 mL), it was cooled to 0 °C, and 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 solution was allowed to stand, and the organic layer was separated. The aqueous layer was extracted with tetrahydrofuran (2 × 30 mL), the organic layers were collected and concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (84 mL). The solution was passed through silica gel (40 μm, 13.96 g) packed in a short column. After passing through ethyl acetate (168 mL), the eluate was concentrated under reduced pressure, whereby a crude product of compound 4 (10.3 g) was obtained in the form of a yellow - green solid.

[0778] (3) Synthesis of compound 5

[0779] (3)-1: Under a nitrogen atmosphere, at 0 °C, tetrahydrofuran (140 mL) was mixed with 60% (w / w) sodium hydride (dispersed in liquid paraffin) (14.3 g, 357 mmol). At 0 °C, compound 4 (41.3 g, 142 mmol) dissolved in tetrahydrofuran (140 mL) was added dropwise, and rinsed with tetrahydrofuran (35 mL). After stirring at 0 °C for 10 minutes, benzyl bromide (37.5 mL, 315 mmol) was added, and the mixture was further stirred at 50 °C for 4 hours. The reaction solution was cooled to 0 °C, and the reaction solution was added dropwise to tap water (700 mL) cooled to 0 °C. 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 layers were collected, washed with saturated brine (150 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in n-hexane (400 mL), and the solution was passed through a column packed with silica gel 60N (neutral, 201 g). After passing n-hexane (800 mL), ethyl acetate (1.60 L) was passed through, and only the ethyl acetate eluate was concentrated under reduced pressure. Thus, compound 5 (65.0 g, 138 mmol, yield 97%) was obtained as a pale yellow solid.

[0780] MS(ESI): m / z = 471 (M + H) +

[0781] 1 H NMR(400MHz,CDCl3)δ7.36 - 7.24(m,10H),5.84(d,J = 4.0Hz,1H),4.81 - 4.74(m,2H),4.67(dd,J = 5.2,4.0Hz,1H),4.54(d,J = 11.6Hz,1H),4.48 - 4.38(m,2H),4.26(d,J = 5.2Hz,1H),4.05(dd,J = 9.2,7.7Hz,1H),3.77(dd,J = 9.2,6.4Hz,1H),3.68(d,J = 10.4Hz,1H),3.58(d,J = 10.4Hz,1H),1.61(s,3H),1.40(s,3H),1.38(s,3H),1.30(s,3H).

[0782] (3) - 2 (Non - separation method): Under a nitrogen atmosphere, the crude compound 4 (8.56 g) obtained in (2) - 2 was dissolved in tetrahydrofuran (26 mL), and sodium hydroxide (3.0 g, 75 mmol) was mixed. After stirring at 20 °C for 30 minutes, it was cooled to 0 °C, and benzyl bromide (11.2 g, 65 mmol) was added. It was further stirred at 50 °C for 2 hours and 30 minutes. The reaction solution was cooled to 20 °C, tap water (17 mL) and ethyl acetate (17 mL) were added, and the organic layer was separated. After extracting the aqueous layer with ethyl acetate (17 mL), the organic layers were collected and washed with a saturated aqueous sodium bicarbonate solution (26 mL). The organic layer was concentrated under reduced pressure and dried under reduced pressure, whereby the crude compound 5 (14.3 g) was obtained in the form of a yellow viscous substance.

[0783] (4) Synthesis of compound 6

[0784] (4) - 1: Under a nitrogen atmosphere, compound 5 (10.0 g, 21.2 mmol) was dissolved in acetonitrile (64 mL), and iodine (1.62 g, 6.38 mmol), sodium periodate (9.10 g, 42.5 mmol), and tap water (21 mL) were added at room temperature. After stirring at 70 °C for 4.5 hours, sodium periodate (1.00 g, 4.67 mmol) was added and stirring was continued for 1.5 hours. The reaction solution was cooled to room temperature, ethyl acetate (175 mL) was added, and the insoluble matter was removed by filtration. The residue on the sieve was washed with ethyl acetate (175 mL). The filtrate was collected. After adding a 30% (w / w) aqueous sodium thiosulfate solution to the filtrate, the organic layer was separated. The aqueous layer was extracted with ethyl acetate (2 × 100 mL), the organic layers were collected and washed with saturated brine (60 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in n - hexane - ethyl acetate (4:1, v / v), and it was loaded onto silica gel 60N (neutral, 26 g) packed in a column. n - Hexane - ethyl acetate (4:1, v / v) (200 mL) was passed through, and the eluate was concentrated under reduced pressure, whereby compound 6 (7.00 g, 17.5 mmol, yield 82%) was obtained in the form of a pale yellow viscous substance.

[0785] MS(ESI): m / z = 421 (M + Na) +

[0786] 11H 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).

[0787] (4) - 2 (Non - separation method): Under a nitrogen atmosphere, dissolve the crude product of compound 5 (14.3 g) obtained in (3) - 2 in acetonitrile (42 mL). At room temperature, add iodine (2.29 g, 9.02 mmol), sodium periodate (12.7 g, 59.4 mmol), and tap water (29 mL). After stirring at 70 °C for 5 hours, add acetonitrile (42 mL), iodine (4.58 g, 18.0 mmol), and sodium periodate (8.85 g, 41.4 mmol), and stir further for 16 hours and 30 minutes. Cool the reaction solution to 20 °C, add ethyl acetate (28 mL), remove the insoluble matter by filtration, and wash the solid on the filter paper with ethyl acetate (2 × 28 mL). After adding 30% (w / w) aqueous sodium thiosulfate solution (36 g) to the filtrate, separate the organic layer. Extract the aqueous layer with ethyl acetate (2 × 28 mL), collect the organic layer, concentrate it under reduced pressure, and dry it under reduced pressure to obtain the crude product of compound 6 (11.3 g) in the form of a brown liquid.

[0788] (5) Synthesis of compound 7

[0789] (5)-1: Under a nitrogen atmosphere, dissolve compound 6 (5.50 g, 13.8 mmol) in tetrahydrofuran (55 mL), add pyridine (5.5 mL) and hydroxylamine hydrochloride (1.15 g, 16.5 mmol). After stirring at 40 °C for 1.5 hours, further stir at 60 °C for 1.5 hours. Concentrate the reaction solution under reduced pressure, add tap water (40 mL) and ethyl acetate (40 mL) to the concentrated residue and perform liquid separation. The aqueous layer is extracted with ethyl acetate (40 mL × 3), and the collected organic layer is washed with saturated brine (20 mL). The organic layer is dried over anhydrous magnesium sulfate, filtered, and then the filtrate is concentrated under reduced pressure. The residue is purified by normal phase (Biotage isolera, stationary phase; SNAP ultra 50 g, mobile phase; hexane / ethyl acetate = 90 / 10 - 60 / 40), and the eluate containing the target compound is concentrated under reduced pressure. The operation of adding toluene (20 mL) to the concentrated residue and concentrating under reduced pressure is carried out twice. Thus, compound 7 (4.79 g, 11.6 mmol, yield 84%) is obtained in the form of a pale yellow viscous substance.

[0790] MS(ESI): m / z = 414 (M + H) +

[0791] (5)-2 (non-separation method): Use the crude product of compound 6 (11.3 g) obtained in (4)-2 to carry out the same reaction and post-treatment as in the above (5)-1, and obtain the crude product of compound 7 (10.5 g) in the form of a yellow viscous substance. The obtained crude product is directly used in the subsequent step (6)-2.

[0792] (6) Synthesis of compound 8

[0793] (6)-1: Under a nitrogen atmosphere, dissolve the crude product of compound 7 (7.67 g) in tetrahydrofuran (34 mL). After heating the solution to 40 °C, add a 60% (w / w) sodium bis(2-methoxyethoxy)aluminum hydride toluene solution (14.4 g, 42.6 mmol) dropwise over 32 minutes, and stir at 40 °C for 80 minutes. After cooling the reaction solution to room temperature, add 2 M aqueous sodium hydroxide solution (28 mL) dropwise over 10 minutes, and stir at room temperature for 15 minutes. Add ethyl acetate (34 mL), separate the organic layer, wash the organic layer with 10% (w / w) brine (2 × 17 mL), and then concentrate the organic layer under reduced pressure. The operation of adding toluene (50 mL) to the residue and concentrating under reduced pressure is repeated twice. Dissolve the residue in toluene (20 mL), add 10% (w / w) aqueous citric acid solution (68 mL) and tap water (21 mL), and separate the aqueous layer containing compound 8. The obtained aqueous layer is directly used in the subsequent step (7)-1.

[0794] (6) - 2 (Non - separation method): Using the crude product of compound 7 (10.5 g) obtained in (5) - 2, perform the same reaction and post - treatment as above to obtain an aqueous layer containing compound 8. The obtained aqueous layer is directly used in the subsequent step (7) - 2.

[0795] MS(ESI): m / z = 400 (M + H) +

[0796] (7) Synthesis of compound 9

[0797] (7) - 1: Under a nitrogen atmosphere, at 25 °C, add 5 M aqueous sodium hydroxide solution (20 mL) to the aforementioned aqueous layer containing compound 8 obtained in (6) - 1. Add ethyl acetate (15 mL) at room temperature, and dropwise add a solution of N - benzyloxycarbonyloxysuccinimide (4.28 g, 17.0 mmol) in ethyl acetate (25 mL) over 6 minutes, and stir at room temperature for 40 minutes. Separate the organic layer, add N - methylpiperazine (0.94 mL, 8.5 mmol), and stir at room temperature for 30 minutes. Wash the reaction solution successively with 10% (w / w) brine (14 mL), 10% (w / w) aqueous citric acid solution (14 mL), 10% (w / w) brine (14 mL), 5% (w / w) aqueous sodium bicarbonate solution (14 mL), and 10% (w / w) brine (14 mL). Dry the organic layer with anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product of compound 9 (9.93 g) in the form of a pale yellow viscous substance. The obtained crude product is directly used in the subsequent step (the same step as (8) - 2).

[0798] 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).

[0799] (7)-2 (Non-separation method): For the aforementioned aqueous layer containing Compound 8 obtained in (6)-2, the same reaction and post-treatment as in the above (7)-1 were carried out, whereby a crude form of Compound 9 (7.26 g) was obtained. The obtained crude form was directly used in the subsequent step (8)-2.

[0800] (8) Synthesis of Compound 10

[0801] (8)-1: Under a nitrogen atmosphere, 2.56 g (4.79 mmol) of Compound 9 was dissolved in acetic acid (5.12 mL). Acetic anhydride (2.56 mL) and sulfuric acid (13 μL) were added at room temperature, and the mixture was stirred at the same temperature for 1 hour. Under ice-cooling conditions, saturated aqueous sodium bicarbonate solution (75 mL) was added dropwise to the reaction solution, and then ethyl acetate (75 mL) was added and liquid separation was carried out. The aqueous layer was extracted with ethyl acetate (75 mL × 3), and the collected organic layer was washed successively with saturated aqueous sodium bicarbonate solution (50 mL) and saturated aqueous sodium bicarbonate solution (50 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure, whereby a crude form of Compound 10 (2.82 g) was obtained. The obtained crude form was directly used in the subsequent step (9)-1.

[0802] MS(ESI): m / z = 579 (M + H) +

[0803] (8)-2 (Non-separation method): Using the crude form of Compound 9 (7.26 g) obtained in (7)-2, the same reaction and post-treatment as in the above (8)-1 were carried out, and a crude form of Compound 10 (7.69 g) was obtained in the form of a brown viscous substance. The obtained crude form was directly used in the subsequent step (9)-2.

[0804] (9) Synthesis of Compound 11

[0805] (9)-1: Under a nitrogen atmosphere, the crude compound 10 (3.15 g) obtained in (8)-1 was dissolved in acetonitrile (13.5 mL), thymine (875 mg, 6.94 mmol) and N,O-bis(trimethylsilyl)acetamide (8.63 mL, 34.6 mmol) were added, and the mixture was refluxed and stirred at 90 °C for 1 hour. The reaction solution was cooled to 0 °C, TMSOTf (1.15 mL, 6.36 mmol) was added dropwise over 2 minutes, and then the mixture was refluxed and stirred at 90 °C for 1 hour. The reaction solution was cooled to 0 °C, saturated aqueous sodium hydrogen carbonate solution (20 mL) was added dropwise, ethyl acetate (40 mL) was added, the insoluble matter was separated by filtration, and the residue on the sieve was washed with ethyl acetate (40 mL × 3). The combined filtrates were concentrated under reduced pressure, the concentrate was extracted with ethyl acetate (40 mL × 2), and the collected organic layer was washed with saturated brine (20 mL). The organic layer was dried over anhydrous magnesium sulfate, the drying agent was separated by filtration, and the filtrate was concentrated under reduced pressure to obtain the crude compound 11 (3.78 g) in the form of a pale yellow solid. The obtained crude product was directly used in the subsequent step (10)-1.

[0806] MS(ESI): m / z = 645 (M + H) +

[0807] (9)-2 (non-separation method): Using the crude compound 10 (7.69 g) obtained in (8)-2, the same reaction and post-treatment as in the above (9)-1 were carried out to obtain the crude compound 11 (8.17 g). The obtained crude product was directly used in the subsequent step (10)-2.

[0808] Synthesis of compound 12

[0809] (10)-1: Under a nitrogen atmosphere, the crude compound 11 (3.78 g) obtained in (9)-1 was dissolved in tetrahydrofuran (11.6 mL), and then 40% aqueous methylamine solution (7.56 mL) was added at room temperature, followed by stirring at the same temperature for 1 hour. The reaction solution was concentrated under reduced pressure. Tap water (20 mL) and saturated ammonium chloride aqueous solution (20 mL) were added to the concentrated solution, and extraction was carried out with ethyl acetate (50 mL×3). The collected organic layer was washed with saturated brine (25 mL). The organic layer was dried over anhydrous magnesium sulfate, and then the dried material was filtered off. The filtrate was concentrated under reduced pressure to obtain the crude product (3.14 g). The crude product was purified by normal-phase chromatography (stationary phase: 41 g of silica gel 60N manufactured by Kanto Chemical, mobile phase: hexane / ethyl acetate = 50 / 50). The eluate containing the target compound was concentrated under reduced pressure to obtain compound 12 (2.28 g, 3.78 mmol) in the form of a colorless solid. The yield from the three steps ((8)-1, (9)-1, and (10)-1) of compound 9 was 70%).

[0810] MS(ESI): m / z = 603 (M + H) +

[0811] (10)-2 (non-separation method): Using the crude compound 11 (8.17 g) obtained in (9)-2, the same reaction and post-treatment as in the above (10)-1 were carried out to obtain the crude compound 12 (6.79 g) in the form of a brown viscous substance. The obtained crude product was directly used in the subsequent step (11)-2.

[0812] (11) Synthesis of compound 14

[0813] (11)-1: Under a nitrogen atmosphere, the crude form of compound 12 (16.9 g) was dissolved in pyridine (30 mL), and methanesulfonyl chloride (2.33 g, 20.5 mmol) was added dropwise at 0 °C over 2 minutes. After stirring at room temperature for 2 hours and 10 minutes, 1,8-diazabicyclo[5.4.0]undec-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. After separating the organic layer, it was washed with tap water (2 × 30 mL), and the organic layer was distilled off under reduced pressure. 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, whereby compound 14 (6.22 g, 10.7 mmol, yield 62% from 7 steps of compound 6 (the same steps as (5)-1, (6)-1, (7)-1, (8)-1, (9)-1, (10)-1, and (11)-1)) was obtained in the form of a pale yellow solid.

[0814] 1 H 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).

[0815] (11) - 2 (Non - separation method): Dissolve the crude form of compound 12 (6.79 g) obtained in (10) - 2 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]undec - 7 - ene (4.92 g, 32.3 mmol) to the reaction solution at 25 °C, stir at the same temperature for 3 hours and 30 minutes, and then add tap water (65 mL) dropwise over 5 minutes. After cooling to 10 °C, stir for 1 hour, filter the solid, and dry it under reduced pressure. Suspend the dried solid in ethyl acetate (7 mL), then add toluene (14 mL), stir at 20 °C, and filter the solid. Wash the solid with ethyl acetate–toluene (1:2, v / v) (9 mL), and dry the solid under reduced pressure. Thus, compound 14 (2.80 g, 4.8 mmol) is obtained in the form of a white solid (yield 8% from 11 steps ((1) - 2, (2) - 2, (3) - 2, (4) - 2, (5) - 2, (6) - 2, (7) - 2, (8) - 2, (9) - 2, (10) - 2, and (11) - 2) of compound 1).

[0816] (11) - 3 (Method including separation of compound 13): Under a nitrogen atmosphere, dissolve compound 12 (113 mg, 0.187 mmol) in tetrahydrofuran (2.26 mL), add pyridine (60 μL, 0.748 mmol) after that, then add methanesulfonyl chloride (17.5 μL, 0.224 mmol) and 4 - dimethylaminopyridine (30 mg, 0.245 mmol) at room temperature, and stir at room temperature for 17 hours. Concentrate the reaction solution under reduced pressure, add ethyl acetate (5 mL) and tap water (5 mL) to the concentrated residue and perform liquid - liquid separation. For the aqueous layer, extract it with ethyl acetate (5 mL × 3), and wash the collected organic layer with saturated brine. Dry the organic layer with anhydrous magnesium sulfate, filter and separate the dried material, and concentrate the filtrate under reduced pressure. Thus, a crude form (0.14 g) is obtained in the form of a pale yellow solid. Purify the crude form by normal - phase purification (Biotage isolera, stationary phase: HD 10 g, mobile phase: hexane / ethyl acetate = 90 / 10 - 40 / 60), and concentrate the eluate containing the target compound under reduced pressure. Perform the operation of adding toluene (5 mL) to the concentrated residue and concentrating it under reduced pressure twice. Thus, a crude form of compound 13 (0.14 g) is obtained in the form of a colorless solid.

[0817] MS(ESI): m / z = 681 (M + H) +

[0818] Under a nitrogen atmosphere, the crude of compound 13 (0.14 g) was dissolved in DMF (2.54 mL), and then 60% (w / w) sodium hydride (dispersed in liquid paraffin) (7.4 mg, 0.185 mmol) was added at 0 °C, 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 solution at 0 °C and liquid separation was carried out. The aqueous layer was extracted with ethyl acetate (5 mL×2), and the collected organic layer was washed with saturated brine (3 mL). The organic layer was dried over anhydrous magnesium sulfate, the dried material was separated by filtration, and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by normal phase (Biotage isolera, stationary phase: HD 10 g, mobile phase: hexane / ethyl acetate / methanol = 90 / 10 / 0 to 0 / 100 / 0 to 0 / 90 / 10), and the eluents containing compound 14 and compound 15 were concentrated under reduced pressure respectively. Thus, compound 14 (0.10 g, 0.171 mmol) and compound 15 (0.01 g, 0.017 mmol) were obtained in the form of colorless solids respectively.

[0819] <Powder X-ray diffraction measurement of crystals of compound 14>

[0820] For the powder X-ray diffraction (XRD) measurement, a powder X-ray diffractometer: MiniFlex600 (Rigaku Corporation) was used, and the measurement was carried out under the following conditions using CuKα radiation.

[0821] X-ray generating device: X-ray tube (copper, tube voltage: 40 kV, tube current: 15 mA)

[0822] Detector: D / teX Ultra 2 (standard mode)

[0823] Measurement range: 3.0 to 40.0°

[0824] Scanning speed: 10.0° / min

[0825] Sampling width: 0.020°

[0826] The results of the powder X-ray diffraction pattern (XRD) of compound 14 are shown in Figure 1 and Table 1. It can be seen that compound 14 was separated in the form of crystals.

[0827] [Table 1]

[0828] Table 1 XRD peaks of compound 14

[0829]

[0830]

[0831] Regarding the characteristic peaks in the powder X-ray diffraction pattern of the crystal of Compound 14, as the diffraction angle represented by 2θ, they were observed at 7.4 ± 0.2°, 19.2 ± 0.2°, 20.1 ± 0.2°, 21.3 ± 0.2°, and 24.7 ± 0.2°.

[0832] (12) Synthesis of Compound 15

[0833] (12) - 1: Under a nitrogen atmosphere, Compound 15 (0.01 g, 0.017 mmol) was added to Compound 14 (0.10 g, 0.17 mmol), and it was dissolved in N,N-dimethylformamide (2.5 mL) under a nitrogen atmosphere. 60% (w / w) sodium hydride (dispersed in liquid paraffin) (7.4 mg, 0.19 mmol) was added at 0 °C, and the mixture was stirred at the same temperature for 16 hours. Tap water (5 mL) and ethyl acetate (5 mL) were added at 0 °C, and the aqueous layer was separated. The aqueous layer was extracted with ethyl acetate (5 mL × 3), and the combined organic layer was washed with saturated brine (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 by normal phase (Biotage isolera, stationary phase: HD10g, mobile phase: hexane / ethyl acetate / methanol = 90 / 10 / 0 to 0 / 100 / 0 to 0 / 80 / 20), and the crude form of Compound 15 (0.10 g) was obtained as a colorless solid. The obtained crude form was directly used in the subsequent step (13).

[0834] MS(ESI): m / z = 585 (M + H) +

[0835] (12) - 2 (Method of not adding Compound 15 as a raw material): Under a nitrogen atmosphere, dissolve Compound 14 (2.46 g, 4.28 mmol) in N,N-dimethylformamide (13 mL). After cooling to 0 °C, add 60% (w / w) sodium hydride (dispersed in liquid paraffin) (254 mg, 6.4 mmol), and stir at the same temperature for 3 hours and 50 minutes. Add an additional 60% (w / w) sodium hydride (dispersed in liquid paraffin) (38 mg, 0.95 mmol), and stir at 0 °C for 1 hour and 40 minutes. Further add 60% (w / w) sodium hydride (dispersed in liquid paraffin) (55 mg, 1.4 mmol), and stir at 0 °C for 17 hours and 50 minutes. After heating to 10 °C, add tap water (13 mL) and ethyl acetate (12 mL). After heating to 20 °C, stir for 10 minutes. After separating the aqueous layer, extract with ethyl acetate (3 × 12 mL). Combine the organic layers and concentrate under reduced pressure. Thus, obtain the crude product of Compound 15 (2.21 g) in the form of a yellow viscous substance.

[0836] (13) Synthesis of Compound 16

[0837] (13): Under a nitrogen atmosphere, dissolve the crude product of Compound 15 (0.10 g) obtained in (12) - 1 in methanol (2.0 mL). Add Pd(OH)2 / C (20% (w / w) Pd, 50% (w / w) wet) (12 mg) at room temperature, and stir under a hydrogen atmosphere for 7 hours. Add acetic acid (1.0 mL) to the reaction solution, and after further stirring under a hydrogen atmosphere for 16 hours, remove the insoluble matter by filtration. Wash the solid on the filter paper with acetic acid (3 × 1 mL), and concentrate the combined filtrate under reduced pressure. Repeat the operation of adding toluene (5 mL) to the residue and concentrating under reduced pressure twice. Thus, obtain the crude product of Compound 16 (0.060 g) in the form of a pale yellow viscous substance. The obtained crude product is directly used in the subsequent step (14).

[0838] MS(ESI): m / z = 270 (M + H) +

[0839] (14) Synthesis of Compound 17

[0840] (14): Under a nitrogen atmosphere, the crude compound 16 (0.060 g) obtained in (13) was dissolved in pyridine (0.5 mL), and 4,4'-dimethoxytriphenylmethyl chloride (58 mg, 0.17 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 21 hours. 4,4'-Dimethoxytriphenylmethyl chloride (12 mg, 0.035 mmol) was added, and the mixture was stirred at room temperature for 20 hours. Further, 4,4'-dimethoxytriphenylmethyl 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 solution, and the solvent was distilled off under reduced pressure. Dichloromethane (10 mL) and saturated aqueous sodium hydrogen carbonate 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 layer was washed with saturated brine (5 mL). The organic layer was 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)), whereby compound 17 was obtained as a white solid (42.4 mg, 0.074 mmol, 40% yield from the three steps ((12) - 1, (13), and (14)) of compound 14 and compound 15).

[0841] 1 H NMR(400MHz,DMSO-d6)δ11.50-11.20(br,1H),7.62(d,J=1.2Hz,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=10Hz,1H),2.63(d,J=9.6Hz,1H),1.50(s,3H).

[0842] MS(ESI):m / z=573(M+H) +

[0843] Example 2: Method for producing compound 9 (Other method 1)

[0844] Compound 9 was produced from compound 6 via compound 18 and compound 19 using the following method.

[0845] [Chemical formula 70]

[0846]

[0847] (1) Synthesis of compound 19

[0848] Under a nitrogen atmosphere, compound 6 (479 mg, 1.20 mmol) was dissolved in dichloromethane (9.6 mL). 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 solution, and the mixture was stirred at room temperature for 14 hours. A saturated aqueous sodium bicarbonate solution (4.8 mL) and benzyl chloroformate (250 μL, 1.77 mmol) were added to the reaction solution, and the mixture was further stirred at room temperature for 3 hours. A saturated aqueous sodium bicarbonate solution (4.8 mL) was added to the reaction solution, 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 layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of compound 19 (931 mg) in the form of a pale yellow viscous substance. The obtained crude product was directly used in the subsequent step (2).

[0849] Compound 18 MS (ESI): m / z = 521 (M + H) +

[0850] Compound 19 MS (ESI): m / z = 654 (M + H) +

[0851] (2) Synthesis of compound 9

[0852] Under a nitrogen atmosphere, the crude product of 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 conditions, a saturated aqueous sodium bicarbonate solution (40 mL) and ethyl acetate (40 mL) were added to the reaction solution, and the insoluble matter was removed by filtration. The solid on the filter paper was washed successively with ethyl acetate (2 × 20 mL), tap water (20 mL), and a saturated aqueous sodium bicarbonate solution (2 × 20 mL), and the organic layer of the filtrate was separated. The aqueous layer was extracted with ethyl acetate (3 × 80 mL), and the combined organic layers were washed with saturated brine (60 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product of compound 9 obtained was purified by column chromatography (neutral silica gel, hexane–ethyl acetate (9:1–3:1, v / v)) to obtain compound 9 (379 mg, 0.710 mmol, 59% yield from two steps ((1) and (2)) of compound 6) in the form of a pale yellow viscous substance.

[0853] 11H 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).

[0854] MS (ESI): m / z = 534 (M + H) +

[0855] Example 3: Method for manufacturing Compound 9 (Another Method 2)

[0856] Compound 9 was manufactured from Compound 6 via Compound 20 and Compound 21 using the following method.

[0857] [Chemical Formula 71]

[0858]

[0859] (1) Synthesis of Compound 20

[0860] Under a nitrogen atmosphere, Compound 6 (1.49 g, 3.74 mmol) was dissolved in dichloromethane (15 mL). Allylamine (256 mg, 4.49 mmol) and sodium triacetoxyborohydride (1.11 g, 5.24 mmol) were added at room temperature, and the mixture was stirred overnight at the same temperature. The reaction was quenched by adding 2 M aqueous sodium hydroxide solution, and the organic layer was separated. The organic layer was washed twice with saturated brine, and the combined aqueous layers were extracted once with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product of Compound 20 (1.61 g). The obtained crude product was directly used in the subsequent step (2).

[0861] 11H 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).

[0862] (2) Synthesis of Compound 21

[0863] Under a nitrogen atmosphere, the crude of Compound 20 (1.25 g) was dissolved in dichloromethane (13 mL). At 40 °C, N,N - dimethylbarbituric acid (680 mg, 4.36 mmol) and tetrakis(triphenylphosphine)palladium(0) (168 mg, 0.145 mmol) were added, and the mixture was stirred at the same temperature for 75 minutes. Isopropyl acetate was added, and the mixture was washed successively with aqueous sodium hydroxide solution and brine. After concentrating the organic layer under reduced pressure, the residue was dissolved in toluene and extracted with aqueous citric acid solution (13 mL). The aqueous layer containing the crude of Compound 21 was directly used in the subsequent step (3).

[0864] (3) Synthesis of Compound 9

[0865] Under a nitrogen atmosphere, 5M aqueous sodium hydroxide solution (4 mL) and ethyl acetate (3 mL) were added to the entire amount of the aqueous layer obtained in step (2). Next, N - (benzyloxycarbonyloxy)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 quenching with N - methylpiperazine (100.17 g, 2.90 mmol), 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, and 10% (w / w) brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude of Compound 9 (1.01 g, HPLC purity from three steps ((1), (2) and (3)) of Compound 6 was 73.0% (220 nm)).

[0866] 11H 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).

[0867] The entire disclosure of Japanese Patent Application No. 2022 - 204199 (filing date: December 21, 2022) is incorporated herein by reference in its entirety.

[0868] All documents, patent applications, and technical standards described in this specification are incorporated herein by reference to the same extent as if each individual document, patent application, and technical standard is specifically and separately indicated as being incorporated by reference.

Claims

1. A manufacturing method, which is a method for manufacturing a compound represented by formula (IV) from a compound represented by formula (I), [Chemical formula 72] In formula (I), R 1 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 represents a cyclic protecting group for a diol formed together with R 3 together with R 4 forms a cyclic protecting group for a diol; [Chemical formula 73] In formula (IV), R 1 represents a protecting group for a hydroxyl group R 2 represents a protecting group for a hydroxyl group R 3 and R 4 which are the same or different and each independently represents a protecting group for a hydroxyl group, or represents a cyclic protecting group for a diol formed together with R 3 together with R 4 forms a cyclic protecting group for a diol 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; The manufacturing method includes the following steps 1 to 3, Step 1: A step of reacting the compound represented by formula (I) with a compound represented by formula (V) or a salt thereof to obtain a compound represented by formula (II), [Chemical formula 74] In formula (I), the meanings of the respective symbols are the same as above, [Chemical formula 75] R 7 O-NH2 (V) In formula (V), R 7 represents a hydrogen atom or an alkyl group, [Chemical formula 76] In formula (II), R 1 represents a protecting group for a hydroxyl group R 2 represents a protecting group for a hydroxyl group R 3 and R 4 which are the same or different and each independently represents a protecting group for a hydroxyl group, or represents a cyclic protecting group for a diol formed together with R 3 and R 4 together R 7 represents a hydrogen atom or an alkyl group; Step 2: A step of subjecting the compound represented by formula (II) to a reduction reaction using a reducing agent to obtain a compound represented by formula (III), [Chemical formula 77] In formula (III), R 1 represents a protecting group for a hydroxyl group R 2 represents a protecting group for a hydroxyl group R 3 and R 4 which are the same or different and each independently represents a protecting group for a hydroxyl group, or represents a cyclic protecting group for a diol formed together with R 3 together with R 4 forms; And, Step 3: A step of subjecting the compound represented by formula (III) to a protection reaction of the amino group.

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

3. The manufacturing method according to claim 1 or 2, wherein, The compound represented by formula (I) is manufactured through steps 4 to 8 including the following, [Chemical formula 78] In formula (I), R 1 represents a protecting group for a hydroxyl group R 2 represents a protecting group for a hydroxyl group R 3 and R 4 which are the same or different and each independently represents a protecting group for a hydroxyl group, or represents a cyclic protecting group for a diol formed together with R 3 and R 4 form together; Step 4: A step of subjecting the compound represented by formula (VI) to an oxidation reaction to obtain a compound represented by formula (VII), [Chemical formula 79] In formula (VI), R 3 and R 4 are the same or different and each independently represents a protecting group for a hydroxyl group, or represents a cyclic protecting group for a diol formed by 3 R 4 and R together. [Chemical formula 80] In formula (VII), R 3 and R 4 are the same or different and each independently represents a protecting group for a hydroxyl group, or represents a cyclic protecting group for a diol formed by 3 R 4 and Steps 5 to 7: A step of subjecting the compound represented by formula (VII) to an aldol condensation reaction (Step 5), a reduction reaction (Step 6), and a protection reaction of the hydroxyl group (Step 7) in sequence to obtain a compound represented by formula (X), [Chemical formula 81] In formula (X), R 3 and R 4 are the same or different and each independently represents a protecting group for a hydroxyl group, or represents a cyclic protecting group for a diol formed together by R 3 and R 4 ; And, Step 8: A step of subjecting the compound represented by formula (X) to an oxidative cleavage reaction.

4. A manufacturing method, which is a method for manufacturing a compound represented by formula (XIII) from a compound represented by formula (IV), [Chemical formula 82] In formula (IV), R 1 represents a protecting group for a hydroxyl group R 2 represents a protecting group for a hydroxyl group R 3 and R 4 which are the same or different and each independently represents a protecting group for a hydroxyl group, or represents a cyclic protecting group for a diol formed together with R 3 together with R 4 forms R 5 and R 6 one of which represents a protecting group for a hydrogen atom or an amino group, and the other represents a protecting group for an amino group, [Chemical formula 83] In formula (XIII), R 1 represents a protecting group for a hydroxyl group 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, B represents a base moiety of a nucleic acid which may be substituted by one or more substituents; The manufacturing method includes the following steps 9 to 11, Step 9: The step of subjecting the compound represented by the formula (IV) produced by the production method according to any one of claims 1 to 3 to the conversion reaction of R 3 and R 4 to an acyl group, thereby obtaining the compound represented by the formula (XI). [Chemical formula 84] In formula (XI), R 1 represents a protecting group for a hydroxyl group R 2 represents a protecting group for a hydroxyl group R 3a represents an acyl group R 4a represents 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; Step 10: A step of subjecting the compound represented by formula (XI) to a glycosylation reaction to obtain a compound represented by formula (XII), [Chemical formula 85] In formula (XII), R 1 represents a protecting group for a hydroxyl group R 2 represents a protecting group for a hydroxyl group R 4a represents an acyl group, R 5 and R 6 one of which 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 a base moiety of a nucleic acid which may be substituted by one or more substituents; And, Step 11: A step of subjecting the compound represented by formula (XII) to a deprotection reaction of the acyl group.

5. The manufacturing method according to claim 4, wherein B is represented by formula (XXIV), [Chemical formula 86] In formula (XXIV), R 12 represents a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkyl group, X represents an oxygen atom or NR 13 (R 13 represents a hydrogen atom or a protecting group for an amino group), The double line composed of a solid line and a dotted line represents a single bond or a double bond.

6. A manufacturing method, which is a method for manufacturing a compound represented by formula (XVII) from a compound represented by formula (XIII’), [Chemical formula 87] In formula (XIII’), R 1 represents a protecting group for a hydroxyl group 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 represents a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkyl group, X represents an oxygen atom or NR 13 (R 13 represents a hydrogen atom or a protecting group for an amino group), The double line composed of a solid line and a dotted line represents a single bond or a double bond, [Chemical formula 88] In formula (XVII), R 1 represents a protecting group for a hydrogen atom or a hydroxyl group R 12 represents a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkyl group, X represents an oxygen atom or NR 13 (R 13 represents a hydrogen atom or a protecting group for an amino group), The double line composed of a solid line and a dotted line represents a single bond or a double bond; The manufacturing method includes the following steps 12 to 15, Step 12: A step of subjecting the compound represented by formula (XIII’) prepared by the production method according to claim 4 or 5 to a sulfonylation reaction to obtain a compound represented by formula (XIV). [Chemical formula 89] In formula (XIV), R 1 represents a protecting group for a hydroxyl group R 2 represents a protecting group for a hydroxyl group R 5 and R 6 one of which 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 represents an alkyl or aryl group, R 12 represents a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkyl group, X represents an oxygen atom or NR 13 (R 13 represents a hydrogen atom or a protecting group for an amino group), The double line composed of a solid line and a dotted line represents a single bond or a double bond; Step 13: A step of subjecting the compound represented by formula (XIV) to a cyclization reaction to obtain a compound represented by formula (XV). [Chemical formula 90] In formula (XV), R 1 represents a protecting group for a hydroxyl group R 2 represents a protecting group for a hydroxyl group R 5 and R 6 one of which 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 represents a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkyl group, X represents an oxygen atom or NR 13 (R 13 represents a hydrogen atom or a protecting group for an amino group), The double line composed of a solid line and a dotted line represents a single bond or a double bond; Step 14: A step of subjecting the compound represented by formula (XV) to a ring closure reaction to obtain a compound represented by formula (XVI). [Chemical formula 91] In formula (XVI), R 1 represents a protecting group for a hydroxyl group R 2 represents a protecting group for a hydroxyl group R 12 represents a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkyl group, R 14 represents a protecting group for a hydrogen atom or an amino group X represents an oxygen atom or NR 13 (R 13 represents a hydrogen atom or a protecting group for an amino group), The double line composed of a solid line and a dotted line represents a single bond or a double bond; And, Step 15: A step of subjecting the compound represented by formula (XVI) to a deprotection reaction, or further subjecting to a protection reaction of a hydroxyl group after the deprotection reaction.

7. The compound represented by formula (II), [Chemical formula 92] In formula (II), R 1 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 represents a cyclic protecting group for a diol formed together with R 3 and R 4 together R 7 represents a hydrogen atom or an alkyl group.

8. The compound represented by formula (III), [Chemical formula 93] In formula (III), R 1 represents a protecting group for a hydroxyl group R 2 represents a protecting group for a hydroxyl group R 3 and R 4 which are the same or different and each independently represents a protecting group for a hydroxyl group, or represents a cyclic protecting group for a diol formed together with R 3 together with R 4 forms 9. The compound represented by formula (IV), [Chemical formula 94] In formula (IV), R 1 represents a protecting group for a hydroxyl group R 2 represents benzyl, 4,4'-dimethoxytrityl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl or acetyl, R 3 and R 4 which are the same or different and each independently represents a protecting group for a hydroxyl group, or represents a cyclic protecting group for a diol formed together with R 3 together with R 4 forms a cyclic protecting group for a diol R 5 and R 6 one of which represents a protecting group for a hydrogen atom or an amino group, and the other represents a protecting group for an amino group.

10. The compound represented by formula (XI), [Chemical formula 95] In formula (XI), R 1 represents a protecting group for a hydroxyl group R 2 represents a protecting group for a hydroxyl group R 3a and R 4a represent 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.

11. The compound according to claim 10, which is represented by formula (XI), [Chemical formula 96] In formula (XI), R 1 represents a protecting group for a hydroxyl group R 2 represents benzyl, 4,4'-dimethoxytrityl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl or acetyl, R 3a and R 4a represent 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.

12. The compound represented by formula (XII), [Chemical formula 97] In formula (XII), R 1 represents a protecting group for a hydroxyl group R 2 represents a protecting group for a hydroxyl group R 4a represents an acyl group R 5 and R 6 one of which 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 a base moiety of a nucleic acid which may be substituted with one or more substituents.

13. The compound according to claim 12, which is represented by formula (XII), [Chemical formula 98] In formula (XII), R 1 represents a protecting group for a hydroxyl group R 2 represents benzyl, 4,4'-dimethoxytrityl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl or acetyl, R 4a represents an acyl group R 5 and R 6 one of which 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 a base moiety of a nucleic acid which may be substituted with one or more substituents.

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

15. The compound represented by formula (XIII), [Chemical formula 99] In formula (XIII), R 1 represents a protecting group for a hydroxyl group R 2 represents benzyl, 4,4'-dimethoxytrityl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl or acetyl, 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 a base moiety of a nucleic acid which may be substituted with one or more substituents.

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

17. The compound represented by formula (XIV), [Chemical formula 100] In formula (XIV), R 1 represents a protecting group for a hydroxyl group R 2 represents a protecting group for a hydroxyl group R 5 and R 6 one of which 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 represents an alkyl or aryl group R 12 represents a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkyl group, X represents an oxygen atom or NR 13 (R 13 represents a hydrogen atom or a protecting group for an amino group), The double line composed of a solid line and a dotted line represents a single bond or a double bond.

18. The compound according to claim 17, which is represented by formula (XIV), [Chemical formula 101] In formula (XIV), R 1 represents a protecting group for a hydroxyl group R 2 represents benzyl, 4,4'-dimethoxytrityl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl or acetyl, 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 represents an alkyl or aryl group, R 12 represents a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkyl group, X represents an oxygen atom or NR 13 (R 13 represents a hydrogen atom or a protecting group for an amino group), The double line composed of a solid line and a dotted line represents a single bond or a double bond.

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

20. The compound represented by formula (XV), [Chemical formula 102] In formula (XV), R 1 represents a protecting group for a hydroxyl group 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 represents a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkyl group, X represents an oxygen atom or NR 13 (R 13 represents a hydrogen atom or a protecting group for an amino group), The double line composed of a solid line and a dotted line represents a single bond or a double bond.

21. The compound according to claim 20, which is represented by formula (XV), [Chemical formula 103] In formula (XV), R 1 represents a protecting group for a hydroxyl group R 2 represents benzyl, 4,4'-dimethoxytrityl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl or acetyl, R 5 and R 6 one of which 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 represents a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkyl group, X represents an oxygen atom or NR 13 (R 13 represents a hydrogen atom or a protecting group for an amino group), The double line composed of a solid line and a dotted line represents a single bond or a double bond.

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

23. The compound according to any one of claims 20 to 22, wherein, R 12 is methyl, X is an oxygen atom, R 1 is benzyl, R 2 is benzyl, R 5 is benzyloxycarbonyl, R 6 is a hydrogen atom, and the double line composed 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, In the powder X-ray diffraction spectrum measured using CuKα radiation, peaks are present at 7.4 ± 0.2°, 19.2 ± 0.2°, 20.1 ± 0.2°, 21.3 ± 0.2° and 24.7 ± 0.2° as the diffraction angle represented by 2θ.

26. The compound represented by formula (XVI), [Chemical formula 104] In formula (XVI), R 1 represents a protecting group for a hydroxyl group R 2 represents a protecting group for a hydroxyl group R 12 represents a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkyl group, R 14 represents a hydrogen atom, benzyloxycarbonyl, isobutyryl, benzoyl, tert-butoxycarbonyl, trimethylsilylethoxycarbonyl, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, acetyl, formyl, 4-methoxybenzyl, allyl, benzyl or 2-nitrobenzenesulfonyl, X represents an oxygen atom or NR 13 (R 13 represents a hydrogen atom or a protecting group for an amino group), The double line composed of solid and dotted lines represents a single bond or a double bond.

27. The compound according to claim 26, which is represented by formula (XVI), [Chemical formula 105] In formula (XVI), R 1 represents a protecting group for a hydroxyl group R 2 represents benzyl, 4,4'-dimethoxytrityl, tert-butyldiphenylsilyl, trimethylsilyl, methoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, 2-methoxyethoxymethyl, cyanoethyl, benzoyl or acetyl, R 12 represents a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkyl group, R 14 represents a hydrogen atom, benzyloxycarbonyl, isobutyryl, benzoyl, tert-butoxycarbonyl, trimethylsilylethoxycarbonyl, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, acetyl, formyl, 4-methoxybenzyl, allyl, benzyl or 2-nitrobenzenesulfonyl, X represents an oxygen atom or NR 13 (R 13 (represents a hydrogen atom or a protecting group for an amino group)), The double line composed of solid and dotted lines represents a single bond or a double bond.

28. A manufacturing method, which is a method for manufacturing a modified oligonucleotide represented by the following chemical formula 107 or a salt thereof from the compound represented by formula (XVII″), [Chemical formula 106] In formula (XVII″), R 1a represents a protecting group for a hydroxyl group R 12 represents a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkyl group, X represents an oxygen atom or NR 13 (R 13 represents a hydrogen atom or a protecting group for an amino group), The double line composed of solid and dotted lines represents a single bond or a double bond; [Chemical formula 107] The manufacturing method includes the following steps: A step of manufacturing the compound represented by formula (XVII″) using the manufacturing method according to claim 6; A step of manufacturing an ALNA[Ms] amide from the compound represented by formula (XVII″); A step of performing the phosphoramidite method using the ALNA[Ms] amide and an amide for DNA synthesis; and A step of subjecting the phosphodiester bond to a sulfurization reaction as needed.

29. A manufacturing method, which is a method for manufacturing a modified oligonucleotide represented by the following chemical formula 109 or a salt thereof from the compound represented by formula (XVII″), [Chemical formula 108] In formula (XVII″), R 1a represents a protecting group for a hydroxyl group R 12 represents a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkyl group, X represents an oxygen atom or NR 13 (R 13 represents a hydrogen atom or a protecting group for an amino group), The double line composed of solid and dotted lines represents a single bond or a double bond; [Chemical formula 109] The manufacturing method includes the following steps: A step of manufacturing the compound represented by formula (XVII″) using the manufacturing method according to claim 6; A step of manufacturing an ALNA[Ms] amide from the compound represented by formula (XVII″); A step of performing the phosphoramidite method using the ALNA[Ms] amide and an amide for DNA synthesis; and A step of subjecting the phosphodiester bond to a sulfurization reaction as needed.

30. The modified oligonucleotide represented by the following formula or a salt thereof manufactured by the manufacturing method according to claim 28, [Chemical formula 110] 31. The modified oligonucleotide represented by the following formula or a salt thereof manufactured by the manufacturing method according to claim 29, [Chemical formula 111]

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