Method for producing nucleic acid compounds and nucleic acid compounds

Abstract

Provided are: a nucleic acid compound manufacturing method that uses a nucleic acid compound that is preserved by a structure in which either one of the third position or fifth position of a ribose structure is represented by formula (1); as well as said nucleic acid compound. In formula (1), ring A represents a condensed polycyclic aromatic hydrocarbon ring or an aromatic heterocycle, YA represents each of -OCR2-, -NRCR2-, or -SCR2- independently, R represents a hydrogen atom, an alkyl group, and an aromatic group or aromatic group-substituted alkyl group, k represents an integer from one to five, RA is an organic group having each of an aliphatic hydrocarbon group or an aliphatic hydrocarbon group independently. For the k-number of RA, at least one of the carbon numbers of the aliphatic hydrocarbon group is 12 or more, and the ring A may include a substituent in addition to YA and RA.

Description

[Technical Field]

[0001] The present disclosure relates to methods for producing nucleic acid compounds and nucleic acid compounds. [Background technology]

[0002] Methods for synthesizing oligonucleotides include the phosphate triester method, the H-phosphonate method, and the phosphoramidite method, and currently, solid-phase synthesis using the phosphoramidite method (solid-phase method) is the most widely used. The solid-phase method has been optimized and automated, giving it the advantage of speed, but there are limitations on scale-up due to equipment restrictions, and it requires excessive use of reagents and raw materials, making it difficult to check the progress of the reaction during the process and to analyze the structure of intermediates. The liquid phase method has the advantage of being highly reactive and allowing intermediates to be purified after the condensation reaction by extraction, washing, isolation, etc. However, the operation is complicated, requiring an extraction and washing step to remove residual reagents and by-products, or an isolation and purification step such as crystallization, and furthermore, the yield is low, making it difficult to rapidly synthesize large amounts of oligonucleotides with high polymerization degrees.

[0003] Furthermore, as conventional synthesis methods, the oligonucleotide synthesis methods described in Patent Document 1 and Patent Document 2 are known.

[0004] Patent Document 1: Japanese Patent Application Laid-Open No. 2016-179993 Patent Document 2: International Publication No. 2014 / 077292 Summary of the Invention [Problem to be solved by the invention]

[0005] According to one embodiment of the present invention, there is provided a method for producing a nucleic acid compound with excellent yield. Furthermore, according to yet another embodiment of the present invention, there is provided a novel nucleic acid compound. [Means for solving the problem]

[0006] The means for solving the above problems include the following aspects. <1> A method for producing a nucleic acid compound using a nucleic acid compound in which either the 3rd or 5th position of the ribose structure is protected with a structure represented by the following formula (1):

[0007] [ka]

[0008] In formula (1), ring A represents a fused polycyclic aromatic hydrocarbon ring or an aromatic heterocycle; Y A represents *-OCR2-**, *-NRCR2-**, or *-SCR2-**, and each R independently represents a hydrogen atom, an alkyl group, an aromatic group, or an aromatic group-substituted alkyl group; k represents an integer of 1 to 5; The wavy line and * represent bonding positions to other structures, and ** represents bonding positions to ring A. R A are each independently an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and k R A At least one aliphatic hydrocarbon group has 12 or more carbon atoms, Ring A is Y A and R A In addition, the group may further have a substituent.

[0009] <2> The nucleic acid compound protected by the structure represented by the above formula (1) is a compound represented by the following formula (2): <1> A method for producing the nucleic acid compound described in .

[0010] [ka]

[0011] In formula (2), m represents an integer of 0 or more, n represents 1 to 6, Each Base independently represents a nucleobase or a modified nucleobase; P 1 represents a hydrogen atom or a hydroxy protecting group, R 1 represents an oxygen atom, a sulfur atom, or a borano group, R 2 represents a hydrogen atom, a substituted or unsubstituted hydroxy group, a substituted or unsubstituted mercapto group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted amino group, X's each independently represent a hydrogen atom, a hydroxyl group, a halogen atom, or an organic group bridging with the carbon atom at the 4'-position of the ribose structure; Each L independently represents a single bond or a divalent linking group; Ring A represents a fused polycyclic aromatic hydrocarbon ring or an aromatic heterocycle; Y A each independently represents a single bond, *-OCR2-**, *-NRCR2-**, or *-SCR2-**, * indicates the bonding position with L, ** represents the bonding position to ring A, each R independently represents a hydrogen atom, an alkyl group, an aromatic group, or an aromatic group-substituted alkyl group, k represents an integer of 1 to 5; R A are each independently an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and k R A At least one aliphatic hydrocarbon group has 12 or more carbon atoms, Ring A is Y A and R A In addition, the group may further have a substituent.

[0012] <3> R in the above formula (2) 1 is an oxygen atom or a sulfur atom, and R 2 is a hydroxy group; <2> A method for producing the nucleic acid compound described in . <4> Above P 1 represents a hydroxy protecting group that can be deprotected with a weak acid, and Step A: a step of deprotecting the protecting group at the 5-terminal of the ribose structure in a nucleic acid compound having a structure represented by formula (1) bound to the 3-terminal of the ribose structure; Step B: reacting the nucleic acid compound obtained in Step A with a nucleic acid compound in which the 3-position of the ribose structure has been phosphoramidite-modified and the 5-position hydroxyl group has been protected with a protecting group that can be removed with a weak acid, thereby condensing them through a phosphite triester bond; Step C: reacting the nucleic acid compound obtained in step B with an oxidizing agent or a sulfurizing agent; nucleic acid converting a phosphite triester bond of the compound to a phosphate triester bond or a thiophosphate triester bond; Step D: Precipitating the nucleic acid compound obtained in step C; Using a liquid phase synthesis method including the following in this order, <1> ~ <3> 10. A method for producing a nucleic acid compound according to any one of the preceding claims. <5> Above P 1 represents a hydrogen atom, and Step B: A step of reacting a nucleic acid compound having a structure represented by the above formula (1) bound to the 3-terminal of a ribose structure with a nucleic acid compound having a phosphoramidite at the 3-position and a protecting group that can be removed with a weak acid at the 5-position of the hydroxyl group, to condense them through a phosphite triester bond; Step C: reacting the nucleic acid compound obtained in step B with an oxidizing agent or a sulfurizing agent; nucleic acid converting a phosphite triester bond of the compound to a phosphate triester bond or a thiophosphate triester bond; Step A: a step of deprotecting the protecting group at the 5-terminal of the nucleic acid compound obtained in Step C above; Step D: Precipitating the nucleic acid compound obtained in step A; Using a liquid phase synthesis method containing the following in this order: <1> ~ <3> 10. A method for producing a nucleic acid compound according to any one of the preceding claims. <6> L in the above formula (2) is a group represented by the following formula (1L): <2> or <3> A method for producing the nucleic acid compound described in .

[0013] [ka]

[0014] In formula (1L), * represents Y A represents the bonding position with the oxygen atom at position 3 of the ribose structure, and ** represents the bonding position with the oxygen atom at position 3 of the ribose structure. L 1 represents an alkylene group having 1 to 22 carbon atoms, L 2 is a single bond or #-C(=O)N(R 2L )-R 1L -N(R 3L )-##, # is L 1 represents the bonding position with ## represents the bond position with C=O, R 1L represents an alkylene group having 1 to 22 carbon atoms, R 2L and R 3L each independently represents a hydrogen atom or an alkyl group having 1 to 22 carbon atoms, R 2L and R 3L may be bonded to each other to form an alkylene group having 1 to 22 carbon atoms.

[0015] <7> Ring A in the structure represented by the above formula (1) is a naphthalene ring. <1> ~ <6> 10. A method for producing a nucleic acid compound according to any one of the preceding claims. <8> All R A the total number of carbon atoms in all aliphatic hydrocarbon groups is 36 to 80, <1> ~ <7> 10. A method for producing a nucleic acid compound according to any one of the preceding claims. <9> The structure represented by the formula (1) has a structure represented by any one of the following formulas (10) to (30): <1> ~ <8> 10. A method for producing a nucleic acid compound according to any one of the preceding claims.

[0016] [ka]

[0017] In formula (10), formula (20), or formula (30), Y A each independently represents *-OCR2-**, *-NRCR2-**, or *-SCR2-**, ** represents the bonding position to the condensed polycyclic aromatic hydrocarbon ring, * represents the bonding position to another structure, each R independently represents a hydrogen atom, an alkyl group, an aromatic group, or an aromatic group-substituted alkyl group, and R A are each independently an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and one or two R A At least one aliphatic hydrocarbon group in R has 12 or more carbon atoms, S each independently represents a substituent; n10 represents an integer of 0 to 6; n20, n21, and n30 each independently represent an integer of 0 to 5;

[0018] <10> R in the above formula (10), formula (20), or formula (30) A are each independently a group represented by the following formula (1f) or formula (a1): <9> A method for producing the nucleic acid compound described in .

[0019] [ka]

[0020] In formula (f1), the wavy line represents a bonding position with other structures, m9 represents an integer of 1 to 3, and X 9 each independently represents a single bond, -O-, -S-, -COO-, -OCO-, -OCONH-, -NHCONH-, -NHCO-, or -CONH-; R 9 each independently represents a divalent aliphatic hydrocarbon group, Ar 1 represents an (m10+1)-valent aromatic group or an (m10+1)-valent heteroaromatic group, m10 represents an integer of 1 to 3, and X 10 each independently represents a single bond, -O-, -S-, -COO-, -OCO-, -OCONH-, -NHCONH-, -NHCO-, or -CONH-; R 10 each independently represents a monovalent aliphatic hydrocarbon group having 5 or more carbon atoms.

[0021] [ka]

[0022] In formula (a1), the wavy line represents the bonding position to other structures, m20 represents an integer of 1 to 10, and X 20 each independently represents a single bond, -O-, -S-, -COO-, -OCO-, -OCONH-, -NHCONH-, -NHCO-, or -CONH-; R 20 each independently represents a divalent aliphatic hydrocarbon group, R 20 At least one of the groups is a divalent aliphatic hydrocarbon group having 5 or more carbon atoms.

[0023] <11> The group represented by the formula (f1) is a group represented by the following formula (f2): <10> A method for producing the nucleic acid compound described in .

[0024] [ka]

[0025] In formula (f2), the wavy line represents a bonding position with another structure, m10 represents an integer of 1 to 3, m11 represents an integer of 1 to 3, and X 10 each independently represents a single bond, -O-, -S-, -COO-, -OCO-, -OCONH-, -NHCONH-, -NHCO-, or -CONH-; R 10 each independently represents a monovalent aliphatic hydrocarbon group having 5 or more carbon atoms.

[0026] <12> Ring A in the structure represented by the above formula (1) has an indole ring or a carbazole ring. <1> ~ <6> 10. A method for producing a nucleic acid compound according to any one of the preceding claims. <13> Ring A in the structure represented by the above formula (1) is a structure represented by the following formula (40): <1> ~ <6> and <12> 10. A method for producing a nucleic acid compound according to any one of the preceding claims.

[0027] [ka]

[0028] In formula (40), R r10 is a substituent, or R A represents R r11 ~R r14 are each independently a hydrogen atom, a substituent, or Y A , or R A represents Y A each independently represents *-OCR2-**, *-NRCR2-**, or *-SCR2-**, ** represents the bonding position to ring A, * represents the bonding position to another structure, and each R independently represents a hydrogen atom, an alkyl group, an aromatic group, or an aromatic group-substituted alkyl group, provided that R r11 ~R r14 At least one of the is Y A and R A are each independently an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and one or more R A At least one aliphatic hydrocarbon group in R has 12 or more carbon atoms, r11 and R r12 , or R r13 and R r14 may each independently be linked to each other to form a ring.

[0029] <14> The structure represented by the above formula (1) is a structure represented by either the following formula (400) or formula (50): <1> ~ <6> , <12> and <13> 10. A method for producing a nucleic acid compound according to any one of the preceding claims.

[0030] [ka]

[0031] In formula (400) and formula (50), Y Aeach independently represents *-OCR2-**, *-NRCR2-**, or *-SCR2-**, ** represents the bonding position to the aromatic heterocycle, * represents the bonding position to another structure, each R independently represents a hydrogen atom, an alkyl group, an aromatic group, or an aromatic group-substituted alkyl group, and R A are each independently an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and one R A At least one aliphatic hydrocarbon group in R has 12 or more carbon atoms, S each independently represents a substituent; n40 represents an integer of 0 to 5; and n50 represents an integer of 0 to 7.

[0032] <15> One or more of the above R A At least one aliphatic hydrocarbon group has 14 or more carbon atoms. <1> ~ <6> and <12> ~ <14> 10. A method for producing a nucleic acid compound according to any one of the preceding claims. <16> All R A the total number of carbon atoms in all aliphatic hydrocarbon groups is 40 or more; <1> ~ <6> and <12> ~ <15> 10. A method for producing a nucleic acid compound according to any one of the preceding claims. <17> R in the above formula (400) or formula (50) A are each independently a group represented by the following formula (f1) or formula (a1): <14> A method for producing the nucleic acid compound described in .

[0033] [ka]

[0034] In formula (f1), the wavy line represents a bonding position with other structures, m9 represents an integer of 1 to 3, and X 9 each independently represents a single bond, -O-, -S-, -COO-, -OCO-, -OCONH-, -NHCONH-, -NHCO-, or -CONH-; R 9 each independently represents a divalent aliphatic hydrocarbon group, Ar 1 represents an (m10+1)-valent aromatic group or an (m10+1)-valent heteroaromatic group, m10 represents an integer of 1 to 3, and X10 each independently represents a single bond, -O-, -S-, -COO-, -OCO-, -OCONH-, -NHCONH-, -NHCO-, or -CONH-; R 10 each independently represents a monovalent aliphatic hydrocarbon group having 5 or more carbon atoms.

[0035] [ka]

[0036] In formula (a1), the wavy line represents the bonding position to other structures, m20 represents an integer of 1 to 10, and X 20 each independently represents a single bond, -O-, -S-, -COO-, -OCO-, -OCONH-, -NHCONH-, -NHCO-, or -CONH-; R 20 each independently represents a divalent aliphatic hydrocarbon group, R 20 At least one of the groups is a divalent aliphatic hydrocarbon group having 5 or more carbon atoms.

[0037] <18> The group represented by the formula (f1) is a group represented by the following formula (f2): <17> A method for producing the nucleic acid compound described in .

[0038] [ka]

[0039] In formula (f2), the wavy line represents a bonding position with another structure, m10 represents an integer of 1 to 3, m11 represents an integer of 1 to 3, and X 10 each independently represents a single bond, -O-, -S-, -COO-, -OCO-, -OCONH-, -NHCONH-, -NHCO-, or -CONH-; R 10 each independently represents a monovalent aliphatic hydrocarbon group having 5 or more carbon atoms.

[0040] <19> A nucleic acid compound in which either the 3- or 5-hydroxy group of the ribose structure is protected by a structure represented by the following formula (1a):

[0041] [ka]

[0042] In formula (1a), ring A represents a fused polycyclic aromatic hydrocarbon ring or an aromatic heterocycle; Y A represents *-OCR2-**, *-NRCR2-**, or *-SCR2-**, R each independently represents a hydrogen atom, an alkyl group, an aromatic group, or an aromatic group-substituted alkyl group; k represents an integer of 1 to 5; The wavy line and * represent the bonding position with the hydroxy group at position 3 or 5 of the ribose structure or the bonding position with another structure. ** represents the bonding position to ring A, R A are each independently an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and k R A At least one aliphatic hydrocarbon group has 12 or more carbon atoms, Ring A is Y A and R A In addition, the group may further have a substituent.

[0043] <20> The nucleic acid compound protected by the structure represented by the above formula (1) is a compound represented by the following formula (2): <19> The nucleic acid compound according to claim 1.

[0044] [ka]

[0045] In formula (2), m represents an integer of 0 or more, n represents 1 to 6, Each Base independently represents a nucleobase or a modified nucleobase; P 1 represents a hydrogen atom or a hydroxy protecting group, R 1 represents an oxygen atom, a sulfur atom, or a borano group, R 2 represents a hydrogen atom, a substituted or unsubstituted hydroxy group, a substituted or unsubstituted mercapto group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted amino group, X's each independently represent a hydrogen atom, a hydroxyl group, a halogen atom, or an organic group bridging with the carbon atom at the 4'-position of the ribose structure; Each L independently represents a single bond or a divalent linking group; Ring A represents a fused polycyclic aromatic hydrocarbon ring or an aromatic heterocycle; Y A each independently represents a single bond, *-OCR2-**, *-NRCR2-**, or *-SCR2-**, * indicates the bonding position with L, ** represents the bonding position to ring A, each R independently represents a hydrogen atom, an alkyl group, an aromatic group, or an aromatic group-substituted alkyl group, k represents an integer of 1 to 5; R A are each independently an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and k R A At least one aliphatic hydrocarbon group has 12 or more carbon atoms, Ring A is Y A and R A In addition, the group may further have a substituent.

[0046] <21> R in the above formula (2) 1 is an oxygen atom or a sulfur atom, and R 2 is a hydroxy group; <20> The nucleic acid compound according to claim 1. <22> L in the above formula (2) is a group represented by the following formula (1L): <20> or <21> The nucleic acid compound according to claim 1.

[0047] [ka]

[0048] In formula (1L), * represents Y A represents the bonding position with ** indicates the bond position with the oxygen atom at position 3 of the ribose structure, L 1 represents an alkylene group having 1 to 22 carbon atoms, L 2 is a single bond or #-C(=O)N(R 2L )-R 1L -N(R 3L )-##, # is L 1 represents the bonding position with ## represents the bond position with C=O, R 1L represents an alkylene group having 1 to 22 carbon atoms, R 2L and R 3L each independently represents a hydrogen atom or an alkyl group having 1 to 22 carbon atoms, R 2L and R 3L may be bonded to each other to form an alkylene group having 1 to 22 carbon atoms.

[0049] <23> Ring A in the structure represented by the above formula (1a) is a naphthalene ring. <19> ~ <22> 10. The nucleic acid compound according to any one of claims 1 to 9. <24> All R A the total number of carbon atoms in all aliphatic hydrocarbon groups is 36 to 80, <19> ~ <23> 10. The nucleic acid compound according to any one of claims 1 to 9. <25> The structure represented by the formula (1a) has a structure represented by any one of the following formulas (10) to (30): <19> ~ <24> 10. The nucleic acid compound according to any one of claims 1 to 9.

[0050] [ka]

[0051] In formula (10), formula (20), or formula (30), Y Aeach independently represents *-OCR2-**, *-NRCR2-**, or *-SCR2-**, ** represents the bonding position to the condensed polycyclic aromatic hydrocarbon ring, * represents the bonding position to another structure, each R independently represents a hydrogen atom, an alkyl group, an aromatic group, or an aromatic group-substituted alkyl group, and R A are each independently an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and one or two R A At least one aliphatic hydrocarbon group in R has 12 or more carbon atoms, S each independently represents a substituent; n10 represents an integer of 0 to 6; n20, n21, and n30 each independently represent an integer of 0 to 5;

[0052] <26> R in the above formula (10), formula (20), or formula (30) A are each independently a group represented by the following formula (f1) or formula (a1): <25> The nucleic acid compound according to claim 1.

[0053] [ka]

[0054] In formula (f1), the wavy line represents a bonding position with other structures, m9 represents an integer of 1 to 3, and X 9 each independently represents a single bond, -O-, -S-, -COO-, -OCO-, -OCONH-, -NHCONH-, -NHCO-, or -CONH-; R 9 each independently represents a divalent aliphatic hydrocarbon group, Ar 1 represents an (m10+1)-valent aromatic group or an (m10+1)-valent heteroaromatic group, m10 represents an integer of 1 to 3, and X 10 each independently represents a single bond, -O-, -S-, -COO-, -OCO-, -OCONH-, -NHCONH-, -NHCO-, or -CONH-; R 10 each independently represents a monovalent aliphatic hydrocarbon group having 5 or more carbon atoms.

[0055] [ka]

[0056] In formula (a1), the wavy line represents the bonding position to other structures, m20 represents an integer of 1 to 10, and X 20 each independently represents a single bond, -O-, -S-, -COO-, -OCO-, -OCONH-, -NHCONH-, -NHCO-, or -CONH-; R 20 each independently represents a divalent aliphatic hydrocarbon group, R 20 At least one of the groups is a divalent aliphatic hydrocarbon group having 5 or more carbon atoms.

[0057] <27> The group represented by the formula (f1) is a group represented by the following formula (f2): <26> The nucleic acid compound according to claim 1.

[0058] [ka]

[0059] In formula (f2), the wavy line represents a bonding position with another structure, m10 represents an integer of 1 to 3, m11 represents an integer of 1 to 3, and X 10 each independently represents a single bond, -O-, -S-, -COO-, -OCO-, -OCONH-, -NHCONH-, -NHCO-, or -CONH-; R 10 each independently represents a monovalent aliphatic hydrocarbon group having 5 or more carbon atoms.

[0060] <28> The ring A in the compound represented by the formula (1a) has an indole ring or a carbazole ring. <19> ~ <22> 10. The nucleic acid compound according to any one of claims 1 to 9. <29> The structure of ring A in the compound represented by formula (1a) is a structure represented by formula (40): <19> ~ <22> and <28> 10. The nucleic acid compound according to any one of claims 1 to 9.

[0061] [ka]

[0062] In formula (40), R r10 is a substituent, or R A represents R r11 ~R r14 are each independently a hydrogen atom, a substituent, or Y A , or R A represents Y A each independently represents *-OCR2-**, *-NRCR2-**, or *-SCR2-**, ** represents the bonding position to ring A, * represents the bonding position to another structure, and each R independently represents a hydrogen atom, an alkyl group, an aromatic group, or an aromatic group-substituted alkyl group, provided that R r11 ~R r14 At least one of the is Y A and R A are each independently an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and one or more R A At least one aliphatic hydrocarbon group in R has 12 or more carbon atoms, r11 and R r12 , or R r13 and R r14 may each independently be linked to each other to form a ring.

[0063] <30> The structure represented by the above formula (1a) has a structure represented by either the following formula (400) or formula (50): <19> ~ <22> , <28> or <29> 10. The nucleic acid compound according to any one of claims 1 to 9.

[0064] [ka]

[0065] In formula (400) and formula (50), Y A each independently represents *-OCR2-**, *-NRCR2-**, or *-SCR2-**, ** represents the bonding position to the aromatic heterocycle, * represents the bonding position to another structure, each R independently represents a hydrogen atom, an alkyl group, an aromatic group, or an aromatic group-substituted alkyl group, and R Aare each independently an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and one R A At least one aliphatic hydrocarbon group in R has 12 or more carbon atoms, S each independently represents a substituent; n40 represents an integer of 0 to 5; and n50 represents an integer of 0 to 7.

[0066] <31> One or more of the above R A At least one aliphatic hydrocarbon group has 14 or more carbon atoms. <19> ~ <22> and <28> ~ <30> 10. A method for producing a nucleic acid compound according to any one of the preceding claims. <32> All R A the total number of carbon atoms in all aliphatic hydrocarbon groups is 40 or more; <19> ~ <22> and <28> ~ <31> 10. A method for producing a nucleic acid compound according to any one of the preceding claims. <33> R in the above formula (400) or formula (50) A are each independently a group represented by the following formula (f1) or formula (a1): <30> The nucleic acid compound according to claim 1.

[0067] [ka]

[0068] In formula (f1), the wavy line represents a bonding position with other structures, m9 represents an integer of 1 to 3, and X 9 each independently represents a single bond, -O-, -S-, -COO-, -OCO-, -OCONH-, -NHCONH-, -NHCO-, or -CONH-; R 9 each independently represents a divalent aliphatic hydrocarbon group, Ar 1 represents an (m10+1)-valent aromatic group or an (m10+1)-valent heteroaromatic group, m10 represents an integer of 1 to 3, and X 10 each independently represents a single bond, -O-, -S-, -COO-, -OCO-, -OCONH-, -NHCONH-, -NHCO-, or -CONH-; R 10 each independently represents a monovalent aliphatic hydrocarbon group having 5 or more carbon atoms.

[0069] [ka] In formula (a1), the wavy line represents the bonding position to other structures, m20 represents an integer of 1 to 10, and X 20 each independently represents a single bond, -O-, -S-, -COO-, -OCO-, -OCONH-, -NHCONH-, -NHCO-, or -CONH-; R 20 each independently represents a divalent aliphatic hydrocarbon group, R 20 At least one of the groups is a divalent aliphatic hydrocarbon group having 5 or more carbon atoms.

[0070] <34> The group represented by the formula (f1) is a group represented by the following formula (f2): <33> The nucleic acid compound according to claim 1.

[0071] [ka]

[0072] In formula (f2), the wavy line represents a bonding position with another structure, m10 represents an integer of 1 to 3, m11 represents an integer of 1 to 3, and X 10 each independently represents a single bond, -O-, -S-, -COO-, -OCO-, -OCONH-, -NHCONH-, -NHCO-, or -CONH-; R 10 each independently represents a monovalent aliphatic hydrocarbon group having 5 or more carbon atoms. [Effects of the Invention]

[0073] According to one embodiment of the present invention, a method for producing a nucleic acid compound with excellent yield can be provided. Furthermore, according to yet another embodiment of the present invention, a novel nucleic acid compound can be provided. DETAILED DESCRIPTION OF THE INVENTION

[0074] The present disclosure will be described in detail below. The following description of the components may be based on representative embodiments of the present disclosure, but the present disclosure is not limited to such embodiments. Furthermore, in this specification, a numerical range expressed using "to" means a range that includes the numerical values ​​before and after "to" as the lower and upper limits. In the present specification, the upper or lower limit of one numerical range may be replaced with the upper or lower limit of another numerical range. In addition, in the present specification, the upper or lower limit of a numerical range may be replaced with a value shown in the examples. In this specification, the term "process" includes not only an independent process but also a process that cannot be clearly distinguished from other processes as long as the intended purpose of the process is achieved. In the description of groups (atomic groups) in this specification, any notation that does not indicate substituted or unsubstituted means that the group does not have a substituent. Only For example, "alkyl group" means an alkyl group that does not have a substituent (unsubstituted alkyl group). Only It is inclusive. In addition, chemical structural formulas in this specification may be written as simplified structural formulas in which hydrogen atoms are omitted. In the present disclosure, "% by mass" and "% by weight" are synonymous, and "parts by mass" and "parts by weight" are synonymous. Also, in the present disclosure, a combination of two or more preferred embodiments is a more preferred embodiment.

[0075] In this specification, unless otherwise specified, each term has the following meaning. "Nucleoside" refers to a compound in which a purine base, pyrimidine base, or artificial nucleic acid base is bound to a ribose sugar or a deoxyribose sugar, and "nucleotide" refers to a compound in which a phosphate is ester-linked to the 5th position of the ribose structure of a nucleoside. The term "nucleotide" is used interchangeably with "polynucleotide" and "oligonucleotide," and "polynucleotide" and "oligonucleotide" refer to a group of deoxyribonucleotides or oligonucleotides of any length joined by phosphodiester bonds between the fifth carbon atom of the ribose structure and the third carbon atom of the ribose structure. Bonu It refers to a polymer of nucleotides. The term "nucleic acid compound" includes "nucleosides," "nucleotides," "polynucleotides," and "oligonucleotides."

[0076] The "alkyl group" includes an alkyl group having a predetermined number of carbon atoms, for example, an alkyl group having 1 to 30 carbon atoms, preferably an alkyl group having 1 to 10 carbon atoms, and more preferably an alkyl group having 1 to 6 carbon atoms. Suitable specific examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, a hexyl group, etc. Hereinafter, the number of carbon atoms will be referred to as C 1-30 It is sometimes abbreviated as C, as in: Examples of the "aryl group" include aryl groups having 6 to 14 carbon atoms. Preferred specific examples include a phenyl group, a 1-naphthyl group, a 2-naphthyl group, a biphenylyl group, and a 2-anthryl group. The "aromatic group" for R is preferably an aryl group having 6 to 20 carbon atoms, and particularly preferably a phenyl group or a naphthyl group. Examples of "aromatic group-substituted alkyl groups" include aromatic group-substituted alkyl groups having 7 to 30 carbon atoms. Of these, aromatic group-substituted alkyl groups having 7 to 20 carbon atoms are preferred, and aromatic group-substituted alkyl groups having 7 to 16 carbon atoms (for example, a group in which an alkylene group having 1 to 6 carbon atoms is bonded to an aromatic group having 6 to 10 carbon atoms) are more preferred. Suitable specific examples include a benzyl group, a 1-phenylethyl group, a 2-phenylethyl group, a 1-phenylpropyl group, a naphthylmethyl group, a 1-naphthylethyl group, and a 1-naphthylpropyl group, and a benzyl group is more preferred. The "halogen atom" includes a chlorine atom, a bromine atom, a fluorine atom, an iodine atom, and the like.

[0077] The term "alkoxy group" refers to an alkoxy group having a specific number of carbon atoms, such as an alkoxy group having 1 to 6 carbon atoms. Specific examples of the alkoxy group having 1 to 6 carbon atoms include linear, cyclic, or branched alkyloxy groups having 1 to 6 carbon atoms, such as a methoxy group, ethoxy group, propoxy group, isopropoxy group, cyclopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, cyclobutoxy group, pentyloxy group, and hexyloxy group.

[0078] The "hydroxy-protecting group" includes all groups that can be used as a protecting group for a normal hydroxy group, and for example, those described in T.W. Greene et al., Protective Groups in Organic Synthesis, 4th Edition, pp. 16-299, 2007, John Wiley & Sons, Inc. can be used. Specifically, an alkenyl group having 2 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms and an aryl group, an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms and an aryl group can be used. base, Examples thereof include an alkyl group having 1 to 6 carbon atoms, an acyl group, an alkoxycarbonyl group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 1 to 6 carbon atoms and an aryl group, an alkylsulfonyl group having 1 to 6 carbon atoms, an arylsulfonyl group, a carbamoyl group, a silyl group, a tetrahydrofuranyl group, or a tetrahydropyranyl group. More specific examples include a methyl group, a benzyl group, a p-methoxybenzyl group, a tert-butyl group, a methoxymethyl group, a methoxyethyl group, a 2-tetrahydropyranyl group, an ethoxyethyl group, a cyanoethyl group, a cyanoethoxymethyl group, a nitroethyl group, a phenylcarbamoyl group, a 1,1-dioxothiomorpholine-4-thiocarbamoyl group, an acetyl group, a pivaloyl group, a benzoyl group, a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a tert-butyldimethylsilyl group, a [(triisopropylsilyl)oxy]methyl (Tom) group, a 1-(4-chlorophenyl)-4-ethoxypiperidin-4-yl (Cpep) group, a monomethoxytrityl group, and a dimethoxytrityl group.

[0079] The "nucleobase" is not particularly limited as long as it is used in the synthesis of nucleic acids, and examples thereof include pyrimidine bases such as cytosyl, uracil, and thyminyl groups, and purine bases such as adenyl and guanyl groups. Furthermore, the term "nucleobase" also encompasses, for example, a nucleobase having an amino group, such as an adenyl group, a guanyl group, or a cytosyl group, in which the amino group is protected with a protecting group. As the nucleobase in which the amino group is protected with a protecting group, a nucleobase in which the amino group of the nucleobase is protected with a protecting group that can withstand the deprotection conditions for the 5-position of the ribose structure is preferred.

[0080] In addition to the above groups, the "nucleobase" also encompasses modified nucleobases (e.g., 8-bromoadenyl group, 8-bromoguanyl group, 5-bromocytosyl group, 5-iodocytosyl group, 5-bromouracil group, 5-iodouracil group, 5-fluorouracil group, 5-methylcytosyl group, 8-oxoguanyl group, hypoxanthinyl group, etc.) in which the nucleobase is substituted with 1 to 3 optional substituents (e.g., halogen atoms, alkyl groups, aromatic group-substituted alkyl groups, alkoxy groups, acyl groups, alkoxyalkyl groups, hydroxy groups, amino groups, monoalkylamino groups, dialkylamino groups, carboxy groups, aryl groups, heteroaryl groups, cyano groups, nitro groups, etc.) at any positions.

[0081] Examples of the "protective group for an amino group" include the protecting groups described in T.W. Greene et al., Protective Groups in Organic Synthesis, 4th Edition, pp. 696-926, 2007, John Wiley & Sons, INC. Specific examples of the "amino-protecting group" include a pivaloyl group, a pivaloyloxymethyl group, a trifluoroacetyl group, a phenoxyacetyl group, a 4-isopropylphenoxyacetyl group, a 4-tert-butylphenoxyacetyl group, an acetyl group, a benzoyl group, an isobutyryl group, a dimethylformamidinyl group, and a 9-fluorenylmethyloxycarbonyl group (Fmoc group). Among these, a phenoxyacetyl group, a 4-isopropylphenoxyacetyl group, an acetyl group, a benzoyl group, an isobutyryl group, or a dimethylformamidinyl group is preferred.

[0082] In addition, the above-mentioned nucleic acid base may have its carbonyl group protected.As a method for protecting the carbonyl group of the nucleic acid base, for example, phenol, 2,5-dichlorophenol, 3-chlorophenol, 3,5-dichlorophenol, 2-formylphenol, 2-naphthol, 4-methoxyphenol, 4-chlorophenol, 2-nitrophenol, 4-nitrophenol, 4-acetylaminophenol, pentafluorophenol, 4-pivaloyloxybenzyl alcohol, 4-nitrophenethyl alcohol, 2-(methylsulfonyl)ethanol, 2-(phenylsulfonyl)ethanol, 2-cyanoethanol, 2-(trimethylsilyl)ethanol, dimethylcarbamic acid chloride, diethylcarbamic acid chloride, ethylphenylcarbamic acid chloride, 1-pyrrolidinecarboxylic acid chloride, 4-morpholinecarboxylic acid chloride, diphenylcarbamic acid chloride, etc. may be reacted.In addition, there are cases where it is not necessary to introduce a protective group for the carbonyl group.

[0083] (Method of producing nucleic acid compounds) The method for producing a nucleic acid compound according to the present disclosure uses a nucleic acid compound in which the hydroxy group at either the 3-position (hereinafter sometimes simply referred to as "3-position") or the 5-position (hereinafter sometimes simply referred to as "5-position") of the ribose structure is protected with a structure represented by the following formula (1): In the method for producing a nucleic acid compound according to the present disclosure, a nucleic acid compound in which the hydroxy groups at the 3- and 5-positions are protected with a structure represented by formula (1) can be used. However, from the viewpoint of reactivity, it is preferable to use a nucleic acid compound in which the hydroxy group at the 3-position is protected with a structure represented by formula (1).

[0084] [ka]

[0085] In formula (1), ring A represents a fused polycyclic aromatic hydrocarbon ring or an aromatic heterocycle; Y A represents *-OCR2-**, *-NRCR2-**, or *-SCR2-**, and each R independently represents a hydrogen atom, an alkyl group, an aromatic group, or an aromatic group-substituted alkyl group; k represents an integer of 1 to 5, the wavy line and * represent the bonding position to another structure, ** represents the bonding position to ring A, and R A are each independently an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and k R A wherein at least one aliphatic hydrocarbon group has 12 or more carbon atoms, and ring A is Y A and R A In addition, the group may further have a substituent.

[0086] The detailed mechanism by which the method for producing a nucleic acid compound according to the present disclosure uses a nucleic acid compound protected by the structure represented by formula (1) above to obtain a nucleic acid compound with excellent yield is not clear, but is presumed to be as follows. The structure represented by formula (1) is composed of k R ASince the number of carbon atoms in at least one aliphatic hydrocarbon group in the formula (1) is 12 or more, the compound protected by the structure represented by formula (1) has excellent solubility in hydrophobic solvents. A The aliphatic hydrocarbon groups in the structure (1) aggregate together, and the structure (1) has a polycyclic aromatic hydrocarbon ring or an aromatic heterocycle, which causes π-π interactions (π-π stacking) between the aromatic heterocycles, resulting in excellent crystallization properties, as well as excellent purification and separability. In other words, it is presumed that the compound protected by the structure (1) has excellent solubility in a hydrophobic solvent, which is the reaction solvent, so the reaction proceeds quickly, and the target product can be efficiently crystallized and purified by adding a polar solvent, which is a poor solvent, during purification, resulting in an excellent yield of the resulting nucleic acid compound. The above effect is k R A In formula (1), the carbon number of at least one aliphatic hydrocarbon group is preferably 14 or more, and a more excellent effect is exhibited. A As the number of carbon atoms increases, the contribution of hydrophobicity to the entire molecule represented by formula (1) increases, making it easier to dissolve in hydrophobic solvents. In addition, in hydrophilic solvents, the cohesive force increases as the number of carbon atoms increases, making it easier to crystallize. Furthermore, the structure represented by formula (1) according to the present disclosure is stable during the synthesis reaction of the nucleic acid compound and can be easily deprotected (removed) due to the structure described above. Furthermore, by using a nucleic acid compound protected by the structure represented by formula (1) according to the present disclosure, even difficult-to-synthesize nucleic acid compounds such as artificial nucleic acids containing non-natural structures that are prone to side reactions can be synthesized with high purity while suppressing side reactions.

[0087] The structure represented by the above formula (1) used in the method for producing a nucleic acid compound according to the present disclosure will be described in detail below.

[0088] <Structure represented by formula (1)> The structure represented by formula (1) used in the method for producing a nucleic acid compound according to the present disclosure is shown below.

[0089] [ka]

[0090] In formula (1), ring A represents a fused polycyclic aromatic hydrocarbon ring or an aromatic heterocycle; Y A represents *-OCR2-**, *-NRCR2-**, or *-SCR2-**, each R independently represents a hydrogen atom, an alkyl group, an aromatic group, or an aromatic group-substituted alkyl group, k represents an integer of 1 to 5, the wavy line portion and * represent the bonding position to another structure, ** represents the bonding position to ring A, and R A are each independently an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and k R A wherein at least one aliphatic hydrocarbon group has 12 or more carbon atoms, and ring A is Y A and R A In addition, the group may further have a substituent. From the viewpoint of stability, in formula (1), ring A is preferably a fused polycyclic aromatic hydrocarbon ring.

[0091] -Fused polycyclic aromatic hydrocarbon ring- When ring A in formula (1) is a fused polycyclic aromatic hydrocarbon ring, it represents a fused polycyclic aromatic hydrocarbon ring in which two or more aromatic hydrocarbon rings are fused together, and ring A is preferably Y A and R A In addition, the group may further have a substituent. When ring A is a fused polycyclic aromatic hydrocarbon ring, from the viewpoints of stability, crystallization property, and yield, ring A is preferably a fused polycyclic aromatic hydrocarbon ring having two to four rings, more preferably a fused polycyclic aromatic hydrocarbon ring having two or three rings, and particularly preferably a fused polycyclic aromatic hydrocarbon ring having two rings. Among these, from the viewpoints of stability, crystallization property, and yield, ring A is preferably a naphthalene ring, an anthracene ring, a phenanthrene ring, a tetracene ring, a triphenylene ring, a pyrene ring, or a chrysene ring, more preferably a naphthalene ring, an anthracene ring, or a phenanthrene ring, and particularly preferably a naphthalene ring. From the viewpoint of yield, ring A is preferably a ring having at least a naphthalene ring structure. Furthermore, ring A may have a substituent, and as described later, two or more substituents may be bonded to form a ring structure, or ring A may have a structure in which an aliphatic hydrocarbon ring, an aliphatic heterocycle, a heteroaromatic ring, or the like is further condensed with ring A.

[0092] -Aromatic heterocycle- When ring A in formula (1) is an aromatic heterocycle, the aromatic heterocycle may be a monocycle or a fused polycyclic aromatic hydrocarbon ring in which two or more aromatic hydrocarbon rings are fused together. A and R A In addition, the group may further have a substituent. Aromatic heterocycles are preferred over Y in terms of stability, crystallization, and yield. A In addition, it is preferably an aromatic heterocycle that does not have an SH group, an amino group, an OH group, or a COOH group. When ring A is an aromatic heterocycle and is polycyclic, it is preferably a fused polycyclic aromatic heterocycle having two or more rings to which the aromatic heterocycle is fused, more preferably a fused polycyclic aromatic heterocycle having two to four rings, and even more preferably a fused polycyclic aromatic heterocycle having two or three rings.

[0093] The aromatic heterocycle is preferably a heterocycle having at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom, and more preferably a heterocycle having at least one heteroatom selected from the group consisting of a nitrogen atom and a sulfur atom. group It is more preferable that the heterocyclic group contains at least one heteroatom selected from the above, further preferably contains a nitrogen atom or a sulfur atom, and particularly preferably contains a nitrogen atom.

[0094] From the viewpoints of stability, crystallization property, and yield, it is preferable that the heteroatom of the aromatic heterocycle further has a substituent. A The same applies to the preferred embodiments.

[0095] The aromatic heterocycle is not particularly limited, but is preferably a 5- to 8-membered ring, and more preferably a 5- or 6-membered ring. From the viewpoints of stability, crystallization property, and yield, the aromatic heterocycle is preferably a 5- to 8-membered aromatic heterocycle, more preferably a 5- or 6-membered aromatic heterocycle, still more preferably a 2- or 3-ring fused polycyclic aromatic heterocycle containing a 5- or 6-membered ring having at least one heteroatom selected from a nitrogen atom and a sulfur atom, and particularly preferably a 2- or 3-ring fused polycyclic aromatic heterocycle containing a 5- or 6-membered ring having a nitrogen atom or a sulfur atom.

[0096] Among these, when ring A is an aromatic heterocycle, examples of ring A include a benzothiophene ring, a furan ring, a benzofuran ring, a pyrrole ring, an indole ring, a carbazole ring, a pyrazole ring, an indazole ring, and a thiophene ring. From the viewpoints of stability, crystallization property, and yield, ring A is preferably an indole ring, a carbazole ring, or an indazole ring, and more preferably an indole ring or a carbazole ring. When ring A is an aromatic heterocycle, from the viewpoints of stability, crystallization property, and yield, it is preferable that the nitrogen atom at position 1 on the pyrrole ring, indole ring, carbazole ring, pyrazole ring, or indazole ring has a substituent on the nitrogen atom. A The same applies to the preferred embodiments. Furthermore, when ring A is an aromatic heterocycle, from the viewpoint of yield, ring A is preferably a bicyclic or tricyclic fused polycyclic aromatic heterocycle containing a five-membered ring having a nitrogen atom, and more preferably an indole ring or a carbazole ring. Furthermore, when ring A is an aromatic heterocycle, ring A may have a substituent, and as described later, two or more substituents may be bonded to form a ring structure, or ring A may have a structure in which an aliphatic hydrocarbon ring, a polycyclic aromatic hydrocarbon ring, an aliphatic heterocycle, or the like is further condensed with ring A.

[0097] Y on ring A in formula (1) A The substitution number n is preferably 1 from the viewpoints of stability, crystallization property, and yield.

[0098] Y in Equation (1) A are each independently *-OCR2-**, *-NRCR2-**, or *-SCR2-**, and from the viewpoints of stability, solvent solubility, and yield, *-OCR2-** or *-NRCR2-** is preferred, *-OCH2-** or *-NRCH2-** is more preferred, and *-NRCH2-** is particularly preferred. In addition, the compound forming the structure represented by formula (1) includes compounds represented by formula (1) to Okeru Y A The structure up to the terminal on the * side is preferably a compound having the following structure: Specifically, from the viewpoints of stability, solvent solubility, and yield, it is preferably **-CR2OH, **-CR2NHR, or **-CR2SH, more preferably **-CH2OH, **-CH2NHR, or **-CH2SH, even more preferably **-CH2OH or **-CH2NHR, and particularly preferably **-CH2NHR. In addition, in formula (1), Y A If you have two Y A are preferably the same group.

[0099] Each R in *-NRCR2-** independently represents a hydrogen atom, an alkyl group, an aromatic group, or an aromatic group-substituted alkyl group, and the alkyl group is preferably an alkyl group having 1 to 10 carbon atoms, and more preferably an alkyl group having 1 to 6 carbon atoms. Among these, it is preferable that each R in *-NRCR2-** is independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an aromatic group-substituted alkyl group having 7 to 16 carbon atoms, more preferably a hydrogen atom, a methyl group, an ethyl group, or a benzyl group, and even more preferably a hydrogen atom. The compound represented by formula (1) may have a substituent on ring A. That is, the compound represented by formula (1) may be a polymer such as a dimer. From the viewpoint of ease of synthesis, the polymer is preferably a dimer to a hexamer, more preferably a dimer to a tetramer, and particularly preferably a dimer.

[0100] R on ring A in formula (1) A The substitution number k is preferably an integer of 1 to 4, more preferably an integer of 1 to 3, and particularly preferably 1 or 2, from the viewpoints of crystallization property, solvent solubility, and yield.

[0101] R A each independently represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group. An "organic group having an aliphatic hydrocarbon group" is a monovalent (one bond) organic group that has an aliphatic hydrocarbon group in its molecular structure. The term "aliphatic hydrocarbon group" refers to a linear, branched, or cyclic saturated or unsaturated aliphatic hydrocarbon group having 5 or more carbon atoms. From the viewpoints of solvent solubility, crystallization property, and yield, an aliphatic hydrocarbon group having 5 to 60 carbon atoms is preferred, an aliphatic hydrocarbon group having 5 to 30 carbon atoms is more preferred, and an aliphatic hydrocarbon group having 10 to 30 carbon atoms is particularly preferred. Furthermore, from the viewpoints of solvent solubility, crystallization property, and yield, the "aliphatic hydrocarbon group" preferably has 12 or more carbon atoms, more preferably has 14 or more carbon atoms, even more preferably has 16 or more carbon atoms, and particularly preferably has 18 or more carbon atoms. The position of the aliphatic hydrocarbon group in the organic group having an aliphatic hydrocarbon group is not particularly limited, and may be present at a terminal (monovalent group) or at another position (for example, divalent group). Examples of "aliphatic hydrocarbon groups" include alkyl groups, cycloalkyl groups, alkenyl groups, and alkynyl groups. Specific examples include monovalent groups such as pentyl, hexyl, octyl, decyl, hexadecyl, octadecyl, icosyl, docosyl, tetracosyl, lauryl, tridecyl, myristyl, oleyl, and isostearyl groups, as well as divalent groups derived therefrom (divalent groups obtained by removing one hydrogen atom from the above monovalent groups), and groups obtained by removing hydroxyl groups and the like from various steroid groups. Furthermore, the "alkyl group" is preferably, for example, an alkyl group having 5 to 30 carbon atoms, such as a pentyl group, hexyl group, octyl group, 2-ethylhexyl group, decyl group, hexadecyl group, octadecyl group, icosyl group, docosyl group, tetracosyl group, lauryl group, tridecyl group, myristyl group, isostearyl group, etc., with an octadecyl group, icosyl group, docosyl group, or tetracosyl group being preferred, and an icosyl group, docosyl group, or tetracosyl group being more preferred. The "cycloalkyl group" is preferably, for example, a cycloalkyl group having 5 to 30 carbon atoms, such as a cyclopentyl group, a cyclohexyl group, an isobornyl group, a tricyclodecanyl group, etc. These may be repeatedly linked together, or may have a condensed ring structure of two or more rings. The "alkenyl group" is preferably, for example, an alkenyl group having 5 to 30 carbon atoms, such as a pentenyl group, a hexenyl group, or an oleyl group. The "alkynyl group" is preferably, for example, an alkynyl group having 5 to 30 carbon atoms, such as a 4-pentynyl group, a 5-hexenyl group, or the like. As the "steroid group", for example, a group having a cholesterol structure, a group having an estradiol structure, etc. are preferred. The organic group may be further substituted with a silyl group, a hydrocarbon group having a silyloxy structure, or an organic group having a perfluoroalkyl structure.

[0102] The silyl group is preferably a trialkylsilyl group, and more preferably a silyl group having three alkyl groups each having 1 to 3 carbon atoms. The silyloxy structure in the hydrocarbon group having a silyloxy structure is preferably a trialkylsilyloxy structure, and more preferably a silyloxy structure having three alkyl groups having 1 to 3 carbon atoms. The hydrocarbon group having a silyloxy structure preferably has 1 to 3 silyloxy structures. Furthermore, the hydrocarbon group having the silyloxy structure preferably has 10 or more carbon atoms, more preferably 10 to 100 carbon atoms, and particularly preferably 16 to 50 carbon atoms.

[0103] Preferred examples of the hydrocarbon group having a silyloxy structure include groups represented by the following formula (Si):

[0104] [ka]

[0105] In formula (Si), R si1 represents a single bond or an alkylene group having 1 to 3 carbon atoms, and R si2 represents an alkylene group having 1 to 3 carbon atoms, and R si3 and R si4 each independently represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or -OSiR si5 R si6 R si7 represents R si5 ~R si7 each independently represents an alkyl group having 1 to 6 carbon atoms or an aryl group.

[0106] R in formula (Si) si5 ~R si7 are each independently preferably an alkyl group having 1 to 6 carbon atoms or a phenyl group, more preferably an alkyl group having 1 to 6 carbon atoms, and particularly preferably a linear or branched alkyl group having 1 to 4 carbon atoms.

[0107] The perfluoroalkyl structure in the organic group having a perfluoroalkyl structure is preferably a perfluoroalkyl structure having 1 to 20 carbon atoms, more preferably a perfluoroalkyl structure having 5 to 20 carbon atoms, and particularly preferably a perfluoroalkyl structure having 7 to 16 carbon atoms. In addition, the perfluoroalkyl structure may be linear, branched, or have a cyclic structure. The organic group having a perfluoroalkyl structure is preferably a perfluoroalkyl group, an alkyl group having a perfluoroalkyl structure, or an alkyl group having a perfluoroalkyl structure and an amide bond in the alkyl chain. The organic group having a perfluoroalkyl structure preferably has 5 or more carbon atoms, more preferably 10 or more carbon atoms, further preferably 10 to 100 carbon atoms, and particularly preferably 16 to 50 carbon atoms. Preferred examples of the organic group having a perfluoroalkyl structure include the groups shown below.

[0108] [ka]

[0109] The moiety other than the "aliphatic hydrocarbon group" in the "organic group having an aliphatic hydrocarbon group" can be set arbitrarily. For example, it may have a moiety such as -O-, -S-, -COO-, -OCONH-, -CONH-, or a hydrocarbon group (monovalent group or divalent group) other than the "aliphatic hydrocarbon group." Examples of "hydrocarbon groups" other than "aliphatic hydrocarbon groups" include aromatic hydrocarbon groups, and specifically, for example, monovalent groups such as aryl groups and divalent groups derived therefrom are used. Among the "aryl groups", aryl groups having 6 to 10 carbon atoms are more preferred, and phenyl groups are particularly preferred. The aliphatic hydrocarbon groups and hydrocarbon groups other than the aliphatic hydrocarbon groups may be substituted with a substituent selected from a halogen atom, an oxo group, and the like.

[0110] The bond (substitution) to ring A of the "organic group having an aliphatic hydrocarbon group" is A The above R A It may be via a moiety such as -O-, -S-, -COO-, -OCONH-, -CONH-, etc. present in . transformation From the viewpoint of ease of synthesis of the compound, those bonded directly via a carbon-carbon bond, those bonded directly via a nitrogen-carbon bond derived from ring A, or those bonded via -O-, -S-, -COO-, or -CONH- are preferred, and those bonded directly via a nitrogen-carbon bond derived from ring A or those bonded directly via a carbon-carbon bond are particularly preferred.

[0111] R A In view of solvent solubility, crystallization property, and yield, the organic group having an aliphatic hydrocarbon group is preferably an aromatic hydrocarbon group having an aliphatic hydrocarbon group, more preferably a phenyl group having an aliphatic hydrocarbon group, and even more preferably a phenyl group having an alkoxy group.

[0112] In the structure represented by formula (1), all R A From the viewpoints of solvent solubility, crystallization property, and yield, the total number of carbon atoms in all the aliphatic hydrocarbon groups is preferably 24 or more, more preferably 24 to 200, even more preferably 32 to 100, still more preferably 34 to 80, particularly preferably 36 to 80, and most preferably 40 to 80. The compound represented by formula (1) according to the present disclosure has k R AThe number of carbon atoms in at least one aliphatic hydrocarbon group in the formula (I) is preferably 14 or more, more preferably 16 or more, even more preferably 18 or more, and particularly preferably 20 or more. Within the above range, a more excellent effect is exhibited. The reason for this is thought to be that as the number of carbon atoms increases, the contribution of hydrophobicity to the entire molecule increases, making it easier to dissolve in hydrophobic solvents, and also that as the number of carbon atoms increases, the cohesive force in hydrophilic solvents increases, making it easier to crystallize. Furthermore, from the viewpoints of crystallization properties and yield, the aliphatic hydrocarbon group is preferably an alkyl group, and more preferably a linear alkyl group.

[0113] In addition, the structure represented by formula (1) has k R A At least one R in A and from the viewpoints of solvent solubility, crystallization property, and yield, k R A In the formula (I), it is preferable that the compound (I) has at least one aliphatic hydrocarbon group having 12 to 100 carbon atoms, more preferable that the compound (I) has at least one aliphatic hydrocarbon group having 18 to 40 carbon atoms, and even more preferable that the compound (I) has at least one aliphatic hydrocarbon group having 20 to 36 carbon atoms. Also, one R A are each independently preferably 12 to 200, more preferably 14 to 150, further preferably 16 to 100, and particularly preferably 20 to 80, from the viewpoints of solvent solubility, crystallization property, and yield. Furthermore, the aliphatic hydrocarbon group having 12 or more carbon atoms contained in the structure represented by formula (1) is preferably R A It is preferable that the compound is included in at least one of the above.

[0114] In formula (1), at least one R Ais preferably a group represented by the following formula (f1), formula (a1), formula (b1) or formula (e1), more preferably a group represented by the following formula (f1) or formula (a1), and particularly preferably a group represented by the following formula (f1), from the viewpoints of solvent solubility, crystallization property and yield.

[0115] [ka]

[0116] In formula (f1), the wavy line represents the bonding position to ring A, m9 represents an integer of 0 to 3, and X 9 each independently represents a single bond, -O-, -S-, -COO-, -OCO-, -OCONH-, -NHCONH-, -NHCO-, or -CONH-; R 9 each independently represents a divalent aliphatic hydrocarbon group, Ar 1 represents an (m10+1)-valent aromatic group or an (m10+1)-valent heteroaromatic group, m10 represents an integer of 1 to 3, and X 10 each independently represents a single bond, -O-, -S-, -COO-, -OCO-, -OCONH-, -NHCONH-, -NHCO-, or -CONH-; R 10 each independently represents a monovalent aliphatic hydrocarbon group having 5 or more carbon atoms.

[0117] [ka]

[0118] In formula (a1), the wavy line represents the bonding position to ring A, m20 represents an integer of 1 to 10, and X 20 each independently represents a single bond, -O-, -S-, -COO-, -OCO-, -OCONH-, -NHCONH-, -NHCO-, or -CONH-; R 20 each independently represents a divalent aliphatic hydrocarbon group.

[0119] [ka]

[0120] In formula (b1), the wavy line represents the bonding position to ring A, mb represents 1 or 2, b1 to b4 each independently represent an integer of 0 to 2, and X b1 ~X b4 each independently represents a single bond, -O-, -S-, -COO-, -OCONH-, or -CONH-; R b2 and R b4 each independently represents a hydrogen atom, a methyl group, or an aliphatic hydrocarbon group having 5 or more carbon atoms; R b3 represents an aliphatic hydrocarbon group having 5 or more carbon atoms.

[0121] [ka]

[0122] In formula (e1), the wavy line represents the bonding position with ring A, and X e1 represents a single bond, -O-, -S-, -NHCO-, or -CONH-; me represents an integer of 0 to 15; e1 represents an integer of 0 to 11; e2 represents an integer of 0 to 5; X e2 each independently represents a single bond, -O-, -S-, -COO-, -OCONH-, -NHCO-, or -CONH-; R e2 each independently represents an organic group having a hydrogen atom, a methyl group, or an aliphatic hydrocarbon group having 5 or more carbon atoms.

[0123] In formula (f1), m9 is preferably 0 or 1, and more preferably 1. X in formula (f1) 9 and X 10 are each independently preferably a single bond, -O-, -S-, -COO-, -OCONH-, or -CONH-, and more preferably a single bond. R in formula (f1) 9 are each independently preferably an alkylene group having 1 to 10 carbon atoms, more preferably an alkylene group having 1 to 4 carbon atoms, and particularly preferably a methylene group. R in formula (f1)10 are each independently preferably a monovalent aliphatic hydrocarbon group having 5 to 60 carbon atoms, more preferably a monovalent aliphatic hydrocarbon group having 12 to 50 carbon atoms, still more preferably a monovalent aliphatic hydrocarbon group having 18 to 40 carbon atoms, and particularly preferably a monovalent aliphatic hydrocarbon group having 20 to 32 carbon atoms. 10 are each independently preferably a linear alkyl group or a branched alkyl group, more preferably a linear alkyl group. In formula (f1), m10 is preferably 2 or 3, and more preferably 2. Ar in formula (f1) 1 is preferably an (m10+1)-valent aromatic group, and more preferably a group in which (m10+1) hydrogen atoms have been removed from benzene.

[0124] Moreover, the group represented by the above formula (f1) is preferably a group represented by the following formula (f2) from the viewpoints of solvent solubility, crystallization property, and yield.

[0125] [ka]

[0126] In formula (f2), the wavy line represents the bonding position to ring A, m10 represents an integer of 1 to 3, m11 represents an integer of 0 to 3, and X 10 each independently represents a single bond, -O-, -S-, -COO-, -OCO-, -OCONH-, -NHCONH-, -NHCO-, or -CONH-; R 10 each independently represents a monovalent aliphatic hydrocarbon group having 5 or more carbon atoms.

[0127] m10 and X in formula (f2) 10 and R 10 are m10 and X in equation (f1), respectively. 10 and R 10 The same applies to the preferred embodiments. In formula (f2), m11 is preferably 0 or 1, and more preferably 1.

[0128] In formula (a1), m20 is preferably 1 or 2, and more preferably 1. X in formula (a1) 20 are each independently preferably -O-, -S-, -COO-, -OCONH- or -CONH-, more preferably -O-. R in formula (a1) 20 is preferably a divalent aliphatic hydrocarbon group having 5 or more carbon atoms, more preferably a divalent aliphatic hydrocarbon group having 5 to 60 carbon atoms, even more preferably a divalent aliphatic hydrocarbon group having 8 to 40 carbon atoms, and particularly preferably a divalent aliphatic hydrocarbon group having 12 to 32 carbon atoms. 20 is preferably a straight chain alkylene group.

[0129] In formula (b1), mb is preferably 1. In formula (b1), b1 to b4 each independently represent preferably 1 or 2, and more preferably 1. X in formula (b1) b1 ~X b4 are each independently preferably -O-, -S-, -COO-, -OCONH- or -CONH-, more preferably -O-. R in formula (b1) b2 and R b4 are each independently preferably a hydrogen atom, a methyl group, or an aliphatic hydrocarbon group having 5 to 60 carbon atoms, more preferably a hydrogen atom, a methyl group, or an alkyl group having 8 to 40 carbon atoms, and particularly preferably a hydrogen atom, a methyl group, or an alkyl group having 12 to 32 carbon atoms. R in formula (b1) b3 is preferably a monovalent aliphatic hydrocarbon group having 5 to 60 carbon atoms, more preferably a monovalent aliphatic hydrocarbon group having 5 to 60 carbon atoms, still more preferably a monovalent aliphatic hydrocarbon group having 8 to 40 carbon atoms, and particularly preferably a monovalent aliphatic hydrocarbon group having 12 to 32 carbon atoms. b3is preferably a straight chain alkyl group.

[0130] In addition, the structure represented by formula (1) is R A Preferred examples of the aliphatic hydrocarbon group in the formula (I) include branched aliphatic hydrocarbon groups, and more preferred examples include the groups shown below. Note that the wavy line portion represents the bonding position to other structures, nt2 represents an integer of 3 or more, and nt3 represents an integer set so that the total number of carbon atoms in the following group is 14 to 300.

[0131] [ka]

[0132] The substituent that the structure represented by formula (1) may have on ring A is not particularly limited, and examples thereof include an alkoxy group, an aryloxy group, a halogen atom, an alkyl group, a halogenated alkyl group, an aryl group, an acyl group, an acyloxy group, an alkoxycarbonyl group, an aryloxycarbonyl group, an alkylthio group, an arylthio group, R st -CO-NR st -, -CON(R st ) 2, dialkylamino groups, alkylarylamino groups, diarylamino groups, and groups combining two or more of these groups. st represents a hydrogen atom, an alkyl group, or an aryl group. When ring A in formula (1) is an aromatic heterocycle, the structure represented by formula (1) preferably does not have a substituent on the aromatic heterocycle, from the viewpoints of stability, crystallization property, solvent solubility, and yield. Furthermore, when ring A in formula (1) is a fused polycyclic aromatic hydrocarbon ring and has a polymeric structure, preferred examples of the substituent that may be present on ring A include a group represented by the following formula (M):

[0133] [ka]

[0134] In formula (M), the wavy line represents the bonding position with ring A in formula (1), ring B represents a fused polycyclic aromatic hydrocarbon ring, and Y B are each independently, -CR b 2OH, -CR b 2NHR b , -CHSH, or -CR b 2X 0 represents R b represents a hydrogen atom, an alkyl group, an aromatic group, or an aromatic group-substituted alkyl group; X 0 represents Cl, Br, or I; kb represents an integer of 1 to 5; nb represents 1 or 2; R B are each independently an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and at least one R B at least one aliphatic hydrocarbon group in the ring B has 12 or more carbon atoms; and B and R B In addition, the group may further have a substituent.

[0135] Rings B and Y in formula (M) B , R b , kb, nb, and , R B respectively represent rings A and Y in formula (1). A ,R,k,n,and ,R A The same applies to the preferred embodiments. Furthermore, when ring A in formula (1) is a fused polycyclic aromatic hydrocarbon ring and has a group represented by formula (M) as a substituent, the structure represented by formula (1) is preferably a structure represented by formula (20) described below.

[0136] From the viewpoints of stability, crystallization property, solvent solubility, and yield, the structure represented by the above formula (1) is preferably a structure represented by the following formula (10), formula (20), or formula (30), and more preferably a structure represented by the following formula (10).

[0137] [ka]

[0138] In formula (10), formula (20), or formula (30), Y A each independently represents *-OCR2-**, *-NRCR2-**, or *-SCR2-**, ** represents the bonding position to ring A, * represents the bonding position to another structure, each R independently represents a hydrogen atom, an alkyl group, an aromatic group, or an aromatic group-substituted alkyl group, and R A are each independently an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and at least one R A At least one aliphatic hydrocarbon group has 12 or more carbon atoms, and R S each independently represents a substituent; n10 represents an integer of 0 to 6; n20, n21, and n30 each independently represent an integer of 0 to 5;

[0139] Y in formula (10), formula (20) or formula (30) A , R A and R are the Y in formula (1), A , R A and R, and preferred embodiments are also the same. In formula (10), n10 is preferably an integer of 0 to 2, more preferably 0 or 1, and particularly preferably 0. In formula (20), n20 and n21 each independently represent preferably an integer of 0 to 2, more preferably 0 or 1, and particularly preferably 0. The two Y in equation (20) A are preferably the same group. In addition, the two R A are preferably the same group. In formula (30), n30 is preferably an integer of 0 to 2, more preferably 0 or 1, and particularly preferably 0. The two R in Eq. (30) A are preferably the same group. R in formula (10), formula (20) or formula (30) Seach independently represents an alkoxy group, an aryloxy group, a halogen atom, an alkyl group, a halogenated alkyl group, an aryl group, an acyl group, an acyloxy group, an alkoxycarbonyl group, an aryloxycarbonyl group, an alkylthio group, an arylthio group, R st -CO-NR st -, -CON(R st )2, preferably a dialkylamino group, an alkylarylamino group, a diarylamino group, or a group consisting of a combination of two or more of these, more preferably an alkoxy group, an aryloxy group, a halogen atom, an alkyl group, a halogenated alkyl group, or an aryl group, and even more preferably an alkoxy group or an alkyl group.

[0140] R in Equation (10) A is preferably a group represented by the above formula (f1), formula (a1), formula (b1) or formula (e1), more preferably a group represented by the above formula (f1) or formula (a1), still more preferably a group represented by the above formula (f1), and particularly preferably a group represented by the above formula (f2), from the viewpoints of solvent solubility, crystallization property and yield.

[0141] R in equation (20) A are each independently preferably a group represented by the above formula (f1), formula (a1), formula (b1) or formula (e1), and more preferably a group represented by the above formula (f1) or formula (a1), from the viewpoints of solvent solubility, crystallization property and yield.

[0142] R in Equation (30) A are each independently preferably a group represented by the above formula (f1), formula (a1), formula (b1) or formula (e1), and more preferably a group represented by the above formula (f1) or formula (a1), from the viewpoints of solvent solubility, crystallization property and yield.

[0143] From the viewpoints of stability, crystallization property, solvent solubility, and yield, when the compound represented by the above formula (1) is an aromatic heterocycle, it is preferable that ring A in the structure represented by formula (1) is a structure represented by the following formula (40).

[0144] [ka]

[0145] In formula (40), R r10 is a substituent, or R A represents R r11 ~R r14 are each independently a hydrogen atom, a substituent, or Y A , or R A represents Y A each independently represents *-OCR2-**, *-NRCR2-**, or *-SCR2-**, ** represents the bonding position to ring A, * represents the bonding position to another structure, and each R independently represents a hydrogen atom, an alkyl group, an aromatic group, or an aromatic group-substituted alkyl group, provided that R r11 ~R r14 At least one of the is Y A and R A are each independently an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and one or more R A At least one aliphatic hydrocarbon group in R has 12 or more carbon atoms, r11 and R r12 , or R r13 and R r14 may each independently be linked to each other to form a ring.

[0146] From the viewpoint of crystallization property and yield, R r11 and R r12 , or R r13 and R r14 are preferably each independently linked to each other to form a ring. r11 and R r12 , or R r13 and R r14 are linked to each other to form a ring, the structure represented by formula (40) is a compound having an indole ring, and R r11 and R r12 , and R r13 and R r14When these are linked to each other to form a ring, the structure represented by formula (40) is a compound having a carbazole ring.

[0147] From the viewpoints of stability, crystallization property, solvent solubility, and yield, when the structure represented by the above formula (1) is an aromatic heterocycle, the structure represented by the above formula (1) is preferably a structure represented by either the following formula (400) or formula (50):

[0148] [ka]

[0149] In formula (400) and formula (50), Y A each independently represents *-OCR2-**, *-NRCR2-**, or *-SCR2-**, ** represents the bonding position to the aromatic heterocycle, * represents the bonding position to another structure, each R independently represents a hydrogen atom, an alkyl group, an aromatic group, or an aromatic group-substituted alkyl group, and R A are each independently an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and one R A At least one aliphatic hydrocarbon group in R has 12 or more carbon atoms, S each independently represents a substituent; n40 represents an integer of 0 to 5; and n50 represents an integer of 0 to 7.

[0150] Y in formula (40), formula (400), or formula (50) A , R A and R are the Y in formula (1), A , R A and R, and preferred embodiments are also the same.

[0151] The substituents in the formula (40), the formula (400), or the formula (50) each independently represent an alkoxy group, an aryloxy group, a halogen atom, an alkyl group, a halogenated alkyl group, an aryl group, an acyl group, an acyloxy group, an alkoxycarbonyl group, an aryloxycarbonyl group, an alkylthio group, an arylthio group, R st-CO-NR st -, -CON(R st )2, preferably a dialkylamino group, an alkylarylamino group, a diarylamino group, or a group consisting of a combination of two or more of these, more preferably an alkoxy group, an aryloxy group, a halogen atom, an alkyl group, a halogenated alkyl group, or an aryl group, and even more preferably an alkoxy group or an alkyl group.

[0152] From the viewpoints of solvent solubility, crystallization property, and yield, n40 is preferably an integer of 0 or 1, and more preferably 0. From the viewpoints of solvent solubility, crystallization property, and yield, n50 is preferably an integer of 0 to 2, more preferably 0 or 1, and even more preferably 0.

[0153] In formula (40), formula (400), or formula (50), R A is preferably a group represented by the above formula (f1), formula (a1), formula (b1) or formula (e1), more preferably a group represented by the above formula (f1) or formula (a1), still more preferably a group represented by the above formula (f1), and particularly preferably a group represented by the above formula (f2), from the viewpoints of solvent solubility, crystallization property and yield.

[0154] The molecular weight of the compound having the structure represented by formula (1) is not particularly limited, but from the viewpoints of crystallization property, solvent solubility, and yield, it is preferably 340 to 3,000, more preferably 400 to 2,000, even more preferably 500 to 1,500, and particularly preferably 800 to 1,300. Furthermore, when the molecular weight is 3,000 or less, the proportion of formula (1) in the target product is appropriate, and the proportion of the compound obtained by deprotecting formula (1) is not reduced, resulting in excellent productivity.

[0155] Specific examples of the structure represented by formula (1) include, but are not limited to, the structures shown below. In addition, R grepresents an aliphatic hydrocarbon group having 12 or more carbon atoms, preferably an aliphatic hydrocarbon group having 12 to 100 carbon atoms, more preferably an aliphatic hydrocarbon group having 18 to 40 carbon atoms, and particularly preferably an aliphatic hydrocarbon group having 20 to 32 carbon atoms. Furthermore, the aliphatic hydrocarbon group is preferably a linear alkyl group, a branched alkyl group, or a cyclic alkyl group, and more preferably a linear alkyl group. In the compounds shown below, * indicates the position of connection to other structures, preferably the position of connection to L in formula (2).

[0156] [ka]

[0157] [ka]

[0158] [ka]

[0159] [ka]

[0160] [ka]

[0161] [ka]

[0162] In addition, the protecting group forming reagents described in PCT / JP2020 / 007477, PCT / JP2020 / 007478, PCT / JP2020 / 024231, or PCT / JP2020 / 024232 are also suitable examples of compounds that form a structure represented by formula (1) (protecting group forming reagents that form compounds protected by a structure represented by formula (1)).

[0163] <<Method for producing a compound that forms a structure represented by formula (1)>> The method for producing the compound forming the structure represented by formula (1) according to the present disclosure is not particularly limited, and the compound can be produced by referring to known methods. Unless otherwise specified, the starting compounds used in the production may be commercially available compounds or may be produced by known methods or methods equivalent thereto. If necessary, the produced compound forming the structure represented by formula (1) may be purified by a known purification method, such as a method of isolation and purification by recrystallization, column chromatography, or the like, or a method of purification by reprecipitation by changing the solution temperature or solution composition, or the like.

[0164] Compounds that form the structure represented by formula (1) Things For example, it can be synthesized according to the following scheme: Alternatively, it can be synthesized with reference to the synthesis method described in WO 2010 / 113939.

[0165] [ka]

[0166] R 100 is a hydrogen atom or OR 101 represents R 101 represents an alkyl group, and X 100 represents Cl, Br, or I, and R 102 represents a hydrogen atom or an alkyl group, and ring A represents a fused polycyclic aromatic hydrocarbon ring or an aromatic heterocycle.

[0167] <<Compound protected by the structure represented by formula (1)>> In the method for producing a nucleic acid compound according to the present disclosure, the compound protected by the structure represented by formula (1) is preferably a compound represented by the following formula (2):

[0168] [ka]

[0169] In formula (2), m represents an integer of 0 or more, n represents 1 to 6, Each Base independently represents a nucleobase or a modified nucleobase; P 1 represents a hydrogen atom or a hydroxy protecting group, R 1 represents an oxygen atom, a sulfur atom, or a borano group, R 2 represents a hydrogen atom, a substituted or unsubstituted hydroxy group, a substituted or unsubstituted mercapto group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted amino group, X's each independently represent a hydrogen atom, a hydroxyl group, a halogen atom, or an organic group bridging with the carbon atom at the 4'-position of the ribose structure; Each L is independently a single bond or a divalent linking group. of Represents, Ring A represents a fused polycyclic aromatic hydrocarbon ring or an aromatic heterocycle; Y A each independently represents a single bond, *-OCR2-**, *-NRCR2-**, or *-SCR2-**, * represents the bonding position to L, ** represents the bonding position to ring A, and each R independently represents a hydrogen atom, an alkyl group, an aromatic group, or an aromatic group-substituted alkyl group, k represents an integer of 1 to 5; R A are each independently an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and k R A At least one aliphatic hydrocarbon group has 12 or more carbon atoms, Ring A is Y A and R A In addition, the group may further have a substituent.

[0170] In formula (2), rings A, R A , Y A and k are ring A in formula (1), respectively. 、R A , Y A and k have the same meanings, and the preferred embodiments are also the same.

[0171] m represents any integer equal to or greater than 0. There is no particular upper limit to m, but it is preferably 49 or less, more preferably 29 or less, and even more preferably 19 or less. From the viewpoint of reactivity and yield, m is preferably 0. When m is 0, the compound represented by formula (2) used in the method for producing a nucleic acid compound according to the present disclosure represents a "nucleoside" and represents the starting compound at the 3-terminal end in the synthesis of a nucleic acid compound.

[0172] n represents 1 or 2. In view of reactivity and yield, n is preferably 1. P 1 represents a hydrogen atom or a hydroxy-protecting group (hereinafter, sometimes referred to as "optionally protected"). P 1 The hydroxy-protecting group in is preferably a hydroxy-protecting group that can be deprotected under acidic conditions. Specific examples include a trityl group, a 9-(9-phenyl)xanthenyl group, a 9-phenylthioxanthenyl group, a di(alkoxy having 1 to 6 carbon atoms)trityl group such as a 1,1-bis(4-methoxyphenyl)-1-phenylmethyl group (dimethoxytrityl group), and a mono(alkoxy having 1 to 18 carbon atoms)trityl group such as a 1-(4-methoxyphenyl)-1,1-diphenylmethyl group (monomethoxytrityl group). Among these, from the viewpoints of ease of deprotection and availability, a monomethoxytrityl group or a dimethoxytrityl group is preferred, and a dimethoxytrityl group is more preferred.

[0173] Each X independently represents a hydrogen atom, a hydroxyl group, a halogen atom, or an organic group bridging with the carbon atom at the 4'-position of the ribose structure. The hydroxy group in X may be protected. Preferred examples of the protecting group include an alkyl group, an aromatic group-substituted alkyl group, an electron-withdrawing group-substituted alkyl group, an alkoxy group, an acyl group, an alkoxyalkyl group, a carbamoyl group, and a silyl group. The halogen atom represented by X is preferably a fluorine atom or a chlorine atom, more preferably a fluorine atom.

[0174] The organic group bridging the 4' carbon atom of the ribose structure is not particularly limited as long as it bridges the 2' and 4' positions of the ribose structure, and examples thereof include alkylene groups having 2 to 7 carbon atoms. The alkylene group may have, for example, —O—, —NR , or the like in the carbon-carbon bond. LN -, -S-, -CO-, -COO-, -OCONR LN -,-CONR LN -(R LN represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms), and the like. More specifically, -ORi, -O-NR LN -Rj, -O-Rk-O-Rl, etc. Ri, Rj, Rk and Rl represent an alkylene group having 1 to 6 carbon atoms bridging at the 4'-position, and it is preferable that Ri, Rj, Rk and Rl are each independently a methylene group or an ethylene group. The organic groups that bridge with the 4' carbon atom of the ribose structure include *-O-CH2-**, *-O-CH2-CH2-**, and *-O-NR LN -CH2-**, *-O-CH2-O-CH2-**, *-SS-CH2-**, *-NR LN -CO-**, *-NR LN -CO-NR LN-CH2-** is preferred, and *-O-CH2-**, *-O-CH2-CH2-**, *-O-NH-CH2-**, *-ON(CH3)-CH2-**, or *-O-CH2-O-CH2-**, *-SS-CH2-**, *-N(Me)-CO-**, *-NH-CO-NH-CH2-** are more preferred. R LN represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, * represents the bond to the 2'-position of the ribose structure, and ** represents the bond to the 4'-position of the ribose structure. Rank and represents the binding site of

[0175] Examples of nucleosides bridged at the 2' and 4' positions include: As shown below Compounds include, but are not limited to: Me represents a methyl group, Base represents a nucleobase or a modified nucleobase, and the wavy line represents a binding site to another moiety.

[0176] [ka]

[0177] R 1 represents an oxygen atom, a sulfur atom, or a borano group (-BH3). From the viewpoints of reactivity and yield, it is preferably an oxygen atom.

[0178] R 2 represents a hydrogen atom, a substituted or unsubstituted hydroxy group, a substituted or unsubstituted mercapto group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted amino group. Examples of the substituent include a halogen atom, an alkyl group, an aromatic group-substituted alkyl group, an alkoxy group, an acyl group, an alkoxyalkyl group, a hydroxy group, an amino group, a monoalkylamino group, a dialkylamino group, a carboxy group, a cyano group, and a nitro group.

[0179] R 2The substituent of the hydroxy group is preferably a substituted or unsubstituted hydroxy group, and more preferably a substituted hydroxy group. 1 Among these, a 1-nitroethyl group or a 1-cyanoethyl group is preferred, and a 1-cyanoethyl group is more preferred. From the viewpoint of reactivity and yield, R 2 is more preferably a group represented by the following formula (2a):

[0180] [ka]

[0181] In formula (2a), n 2D represents an integer of 1 to 5, WG represents an electron-withdrawing group, and the wavy line represents the bond to the phosphorus atom in the above formula (2). Examples of the electron-withdrawing group include a cyano group and a nitro group. 2D is preferably 1 to 4, more preferably 1 to 3, further preferably 1 or 2, and particularly preferably 2. From the viewpoint of excellent yield, R in formula (2) 1 is an oxygen atom or a sulfur atom, and R 2 is preferably a substituted or unsubstituted hydroxy group, and R in formula (2) 1 is an oxygen atom, and R 2 is more preferably a group represented by the above formula (2a).

[0182] L in formula (2) is preferably a group represented by the following formula (1L).

[0183] [ka]

[0184] In formula (1L), * represents Y Arepresents the bonding position with the oxygen atom at position 3 of the ribose structure, and ** represents the bonding position with the oxygen atom at position 3 of the ribose structure. L 1 represents an alkylene group having 1 to 22 carbon atoms, L 2 is a single bond or #-C(=O)N(R 2L )-R 1L -N(R 3L )-##, where # is L 1 represents the bonding position with C=O, ## represents the bonding position with C=O, and R 1L represents an alkylene group having 1 to 22 carbon atoms, and R 2L and R 3L each independently represents a hydrogen atom or an alkyl group having 1 to 22 carbon atoms; R 2L and R 3L may be bonded to each other to form an alkylene group having 1 to 22 carbon atoms.

[0185] A preferred embodiment of L represented by the above formula (1L) is 1 represents an ethylene group or CH2-O-1,4-phenylene-O-CH2, and L 2 represents a single bond, or #-C(=O)N(R 2L )-R 1 -N(R 3L )-## 、 The above # is L 1 represents the bonding position with C=O, ## represents the bonding position with C=O, and R 1L represents an alkylene group having 1 to 6 carbon atoms, and R 2L and R 3L each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R 2L and R 3L may be bonded to each other to form an alkylene group having 1 to 6 carbon atoms.

[0186] Another preferred embodiment of L represented by the above formula (1L) is 1 represents an ethylene group, and L 2L is a group representing a single bond.

[0187] Another preferred embodiment of L represented by the above formula (1L) is 1 represents an ethylene group, and L 2 N(R 2L )-R 1 -N(R 3 ) portion is a group representing a piperazinylene group.

[0188] Another preferred embodiment of L represented by the above formula (1L) is 1 represents an ethylene group, and L 2 But #-C(=O)N(R 2L )-R 1L -N(R 3L )-##. The # is a group represented by L 1 represents the bonding position with C=O, ## represents the bonding position with C=O, and R 1L represents a pentylene group or a hexylene group, and R 2L and R 3L each independently represents a hydrogen atom or a methyl group.

[0189] The above L is particularly preferably a succinyl group (**-CO-CH2-CH2-CO-*) from the viewpoint of easy availability and low cost.

[0190] A preferred embodiment of the compound represented by formula (2) is a compound represented by formula (2), in which m is 0, n is 1 or 2, and ring A represents a fused polycyclic aromatic hydrocarbon ring or an aromatic heterocycle. Base is a cytosyl group, a uracil group, a thyminyl group, an adenyl group, or a guanyl group, each of which may be protected; P 1 is a di(C1-C6 alkoxy)trityl group or a mono(C1-C6 alkoxy)trityl group, X is a hydrogen atom, a hydroxy group, a halogen atom, or an organic group bridging with the carbon atom at the 4'-position of the ribose structure, L has a structural formula represented by formula (1L), and Y A , and R A are compounds having the same combinations of groups as those shown as preferred embodiments in formula (1).

[0191] Another preferred embodiment of the compound represented by the above formula (2) is a compound represented by the following formula (2): m is 0, n is 1 or 2, ring A represents a fused polycyclic aromatic hydrocarbon ring or an aromatic heterocycle, Base is a cytosyl group, a uracil group, a thyminyl group, an adenyl group, or a guanyl group, each of which may be protected, and P 1 is a dimethoxytrityl group or a monomethoxytrityl group, X is a hydrogen atom, a hydroxy group, a halogen atom, or an organic group bridging with the carbon atom at the 4' position of the ribose structure, L has a structural formula represented by formula (1L), and Y A , and R A are compounds having the same combinations of groups as those shown as preferred embodiments in formula (1).

[0192] Represented by the above formula (2) transformation In still another preferred embodiment of the compound, in formula (2), m is 0, n is 1 or 2, ring A represents a fused polycyclic aromatic hydrocarbon ring or an aromatic heterocycle, Base is a cytosyl group, a uracil group, a thyminyl group, an adenyl group, or a guanyl group, each of which may be protected; P 1 is a dimethoxytrityl group, and X is a hydrogen atom or a fluorine atom. 、 L has a structural formula represented by formula (1L), and Y A , and R A are compounds having the same combinations of groups as those shown as preferred embodiments in formula (1).

[0193] Specific examples of the compound represented by formula (2) are listed below, but needless to say, the compound is not limited to these. Note that DMTr represents a dimethoxytrityl group.

[0194] [ka]

[0195] The method for producing a nucleic acid compound according to the present disclosure comprises the steps of: 1 represents a hydroxy protecting group that can be deprotected with a weak acid, and Step A: a step of deprotecting the 5-terminal of the ribose structure in a nucleic acid compound having a structure represented by formula (1) bound to the 3-terminal of the ribose structure (hereinafter also referred to as a "deprotection step"); Step B: A step of reacting the nucleic acid compound obtained in Step A with a nucleic acid compound in which the 3-position of the ribose structure has been phosphoramidite-modified and the 5-position hydroxyl group has been protected with a protecting group that can be removed with a weak acid, to condense them through a phosphite triester bond (hereinafter also referred to as the "nucleic acid extension step"); Step C: reacting the nucleic acid compound obtained in step B with an oxidizing agent or a sulfurizing agent; nucleic acid a step of converting a phosphite triester bond of the compound into a phosphate triester bond or a thiophosphate triester bond (hereinafter also referred to as an "oxidation or sulfurization step"); It is preferable to use a liquid phase synthesis method (hereinafter also referred to as "liquid phase synthesis method A") that includes, in this order: step D; and a step of precipitating the nucleic acid compound obtained in step C (hereinafter also referred to as "precipitation step").

[0196] In another embodiment of the method for producing a nucleic acid compound according to the present disclosure, 1 represents a hydrogen atom, and Step B: A step of reacting a nucleic acid compound having a structure represented by the above formula (1) bound to the 3-terminal of a ribose structure with a nucleic acid compound having a phosphoramidite at the 3-position of the ribose structure and a hydroxyl group at the 5-position protected with a hydroxyl-protecting group that can be removed with a weak acid, thereby condensing them through a phosphite triester bond; Step C: reacting the nucleic acid compound obtained in step B with an oxidizing agent or a sulfurizing agent; nucleic acid converting a phosphite triester bond of the compound to a phosphate triester bond or a thiophosphate triester bond; Step A: a step of deprotecting the protecting group at the 5-terminal of the nucleic acid compound obtained in Step C above; Step D: Precipitating the nucleic acid compound obtained in step A; It is preferable to use a liquid phase synthesis method (hereinafter also referred to as "liquid phase synthesis method B") that includes the following in this order. The method for producing a nucleic acid compound according to the present disclosure has excellent yields by using a liquid phase synthesis method including a deprotection step, a nucleic acid extension step, and a precipitation step in a specific order. Each step of the liquid phase synthesis methods A and B will be described in detail below. The explanation of each step is common to both liquid phase synthesis methods A and B.

[0197] <<Step A; Deprotection step>> The deprotection step in the method for producing a nucleic acid compound according to the present disclosure is a step of deprotecting the protecting group at the 5-terminus of the nucleic acid compound. The nucleic acid compound from which the protecting group at the 5-terminus is to be deprotected may be a nucleic acid compound having a structure represented by the above formula (1) bound to the 3-terminus of the ribose structure, or may be a nucleic acid compound obtained by a nucleic acid elongation step and an oxidation or sulfurization step. The deprotection step in the method for producing a nucleic acid compound according to the present disclosure is preferably a step of deprotecting the protecting group at the 5-terminal by adding an acid. When a nucleic acid extension step is performed after the deprotection step, the deprotection step in the method for producing a nucleic acid compound according to the present disclosure more preferably includes a step of removing the hydroxy protecting group at the 5-terminal by adding an acid, followed by neutralization by adding an organic base.

[0198] The acid used to remove the hydroxy-protecting group at the 5-terminal of the ribose structure is not particularly limited as long as it can remove the hydroxy-protecting group, and examples thereof include trifluoroacetic acid, dichloroacetic acid, trifluoromethanesulfonic acid, trichloroacetic acid, methanesulfonic acid, hydrochloric acid, acetic acid, and p-toluenesulfonic acid. From the viewpoint of deprotection reactivity, the acid is preferably trifluoroacetic acid, dichloroacetic acid, trifluoromethanesulfonic acid, or trichloroacetic acid, more preferably trifluoroacetic acid, dichloroacetic acid, or trifluoromethanesulfonic acid, still more preferably trifluoroacetic acid or trifluoromethanesulfonic acid, and particularly preferably trifluoroacetic acid. These acids may be used after diluting with a non-polar solvent as described below. Alternatively, the acids may be used in combination with a specific base to appropriately adjust the acidity. The amount of acid used is preferably 1 mol to 100 mol, more preferably 1 mol to 40 mol, per mol of the nucleic acid compound to be deprotected.

[0199] The deprotection step is preferably carried out in a solvent that does not affect the reaction. The solvent used in the deprotection step is preferably a non-polar solvent that has high solubility for nucleic acid compounds, from the viewpoint of deprotection reactivity. Specific examples of the nonpolar solvent include halogenated solvents such as chloroform, dichloromethane, 1,2-dichloroethane, etc.; aromatic solvents such as benzene, toluene, xylene, mesitylene, etc.; ester solvents such as ethyl acetate, isopropyl acetate, etc.; aliphatic solvents such as hexane, pentane, heptane, octane, nonane, cyclohexane, etc.; and nonpolar ether solvents such as diethyl ether, cyclopentyl methyl ether, tert-butyl methyl ether, etc. Two or more of these solvents may be mixed in an appropriate ratio. Furthermore, the nonpolar solvent may be mixed with a polar solvent such as a nitrile solvent such as acetonitrile or propionitrile, or an amide solvent such as N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpiperidone in an appropriate ratio as long as the nucleic acid compound can be dissolved therein. Among these, the non-polar solvent is preferably dichloromethane, chloroform, 1,2-dichloroethane, benzene, toluene, xylene, mesitylene, hexane, pentane, heptane, nonane, cyclohexane, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, cyclopentyl methyl ether, or a combination thereof, and more preferably chloroform, dichloromethane, or toluene.

[0200] In the deprotection step, the content of the nucleic acid compound in the solvent is not particularly limited as long as it is dissolved, but is preferably 1% by mass to 30% by mass relative to the total mass of the solvent. In the deprotection step, from the viewpoint of continuously carrying out steps other than the deprotection step in a liquid phase, it is preferable to use a cation scavenger during or after the removal reaction of the hydroxy protecting group at the 5-terminal of the ribose structure.

[0201] The cation scavenger is not particularly limited as long as it does not cause reprotection (return of the raw material) by the removed protecting group.

[0202] In the deprotection step, the amount of the cation scavenger used is preferably 1 mol to 50 mol, more preferably 5 mol to 20 mol, per 1 mol of the nucleic acid compound. The cation scavenger may be used alone or in combination of two or more kinds.

[0203] The reaction temperature in the deprotection step is not particularly limited as long as the reaction proceeds, but is preferably from -10°C to 50°C, more preferably from 0°C to 40°C. The reaction time varies depending on the type of nucleic acid compound, the type of acid, the type of solvent, the reaction temperature, etc., but is preferably 5 minutes to 5 hours.

[0204] In the method for producing a nucleic acid compound according to the present disclosure, when a condensation step is performed after the deprotection step, from the viewpoint of suppressing deprotection of a nucleic acid compound in which the 3-position of the ribose structure is phosphoramidite-converted and the 5-position hydroxy group is protected with a protecting group that can be deprotected with a weak acid, it is preferable to remove or neutralize the acid used to remove the hydroxy protecting group, and it is more preferable to neutralize the acid used to remove the hydroxy protecting group with an organic base. Suitable examples of organic base compounds used for neutralization include those that can neutralize the above acids and whose resulting salts can function as condensing agents. From the viewpoint of ensuring that the reaction proceeds smoothly, the organic base is preferably pyridine, 2,4,6-trimethylpyridine, benzimidazole, 1,2,4-triazole, N-phenylimidazole, 2-amino-4,6-dimethylpyrimidine, 1,10-phenanthroline, imidazole, N-methylimidazole, 2-chlorobenzimidazole, 2-bromobenzimidazole, 2-methylimidazole, 2-phenylbenzimidazole, N-phenylbenzimidazole, or 5-nitrobenzimidazole, and more preferably pyridine, 2,4,6-trimethylpyridine, , benzimidazole, 1,2,4-triazole, N-phenylimidazole, N-methylimidazole, 2-amino-4,6-dimethylpyrimidine, or 1,10-phenanthroline are more preferred, pyridine, 2,4,6-trimethylpyridine, benzimidazole, 1,2,4-triazole, or N-phenylimidazole are even more preferred, pyridine, 2,4,6-trimethylpyridine, benzimidazole, or 1,2,4-triazole are particularly preferred, and pyridine, 2,4,6-trimethylpyridine, or benzimidazole are most preferred.

[0205] In the deprotection step, the amount of the organic base used is preferably 1 mol to 10 mol, more preferably 1 mol to 3 mol, per 1 mol of the acid. In the deprotection step, the combination of an acid and an organic base is preferably trifluoroacetic acid and pyridine, trifluoroacetic acid and 2,4,6-trimethylpyridine, or trifluoromethanesulfonic acid and benzimidazole.

[0206] <<Step B; Nucleic acid extension step>> The nucleic acid extension step in the method for producing a nucleic acid compound according to the present disclosure is a step of reacting a nucleic acid compound having a structure represented by formula (1) attached to the 3-terminus with a nucleic acid compound in which the 3-position of the ribose structure has been phosphoramidite-modified and the 5-position hydroxyl group has been protected with a protecting group that can be removed with a weak acid, thereby condensing them through a phosphite triester bond.

[0207] The nucleic acid compound used in the nucleic acid elongation step, in which the 3-position of the ribose structure is phosphoramidite-modified and the 5-position hydroxy group is protected with a protecting group that can be removed with a weak acid, is preferably a compound represented by the following formula M-1.

[0208] [ka]

[0209] In formula M-1, P 1 represents a hydroxy protecting group, WG represents an electron-withdrawing group, X each independently represents a hydrogen atom, a hydroxy group, a halogen atom, or an organic group bridging with the carbon atom at position 4 of the ribose structure, R 8 represents an oxygen atom or a sulfur atom, and R 9 and R 10 each independently represents an alkyl group or a 5- or 6-membered saturated cyclic amino group formed together with the adjacent nitrogen atom, and m1 represents an integer of 0 or greater. P 1 , X and m1 are P in formula (2) 1 , m1 and m2 have the same meanings as X and m1, and preferred embodiments are also the same. Examples of the electron-withdrawing group include a cyano group and a nitro group. R 9 and R 10 The saturated cyclic amino group in the formula (I) may have one oxygen atom or one sulfur atom as a ring-constituting atom in addition to the nitrogen atom. In the compound represented by formula M-1, when m1 is 1, that is, when the 5-position is P 1 and a phosphoramidite at the 3-position.

[0210] The nucleic acid compound used in the nucleic acid elongation step has the 3-position of the ribose structure phosphoramidite and the 5-position hydroxyl group protected with a protecting group that can be removed with a weak acid, and the 5-position of the ribose structure is P 1 and the hydroxy group at position 3 of the ribose structure is not protected. Nucleosides of was polymerized PolynucleosidesIt can be produced by reacting the above with a phosphoramidite reagent represented by the following general formula (c) or (d) according to a known method (M. H. Caruthers et al., Method in Enzymology 1987, 154, 287-313; S. L. Beaucage and M. H. Caruthers, Tetrahedron Letters 1981, 22, 1859-1862).

[0211] [ka]

[0212] In formulas (c) and (d), R 11 represents a halogen atom, and WG, R 9 and R 10 is the formula M-1 W.G., R 9 and R 10 is synonymous with.

[0213] The nucleic acid extension step is preferably carried out in a solvent that does not affect the reaction. protection The same non-polar solvents as in step (1) can be used. In addition, the non-polar solvent may be a nitrile solvent such as acetonitrile or propionitrile; a ketone solvent such as acetone or 2-butanone; an amide solvent such as N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone; a polar ether solvent such as 1,4-dioxane or tetrahydrofuran; or a sulfoxide solvent such as dimethyl sulfoxide, which is used to protect the hydroxyl group P at the 5-position of the ribose structure. 1 They may be mixed in an appropriate ratio as long as the nucleic acid compound from which the base has been removed can be dissolved. In this case, the polar solvent is preferably an amide solvent, a nitrile solvent, or a combination thereof, more preferably acetonitrile, N,N-dimethylformamide, N-methylpiperidone, or a combination thereof, and particularly preferably acetonitrile. The polar solvent may be added as a solution of a nucleic acid or compound in which the 3-position of the ribose structure has been phosphoramidite-modified and the 5-position of the ribose structure has been protected, a condensing agent, or the like.

[0214] The 3rd position of the ribose structure is phosphoramidite-modified, and the 5th position is P 1 The amount of the nucleic acid compound protected by P at the 5-position of the ribose structure obtained in the above deprotection step is 1 The amount of the amine is preferably 1 mole to 10 moles, more preferably 1 mole to 5 moles, per mole of the nucleic acid compound from which the amine has been removed.

[0215] The reaction temperature in the nucleic acid extension step is not particularly limited as long as the reaction proceeds, but is preferably 0°C to 100°C, more preferably 20°C to 50°C. The reaction time in the nucleic acid extension step can be appropriately set depending on the type of nucleic acid compound to be condensed, the reaction temperature, etc., and is preferably 5 minutes to 24 hours.

[0216] <<Step C: Oxidation or sulfurization step>> The oxidation or sulfurization step in the method for producing a nucleic acid compound according to the present disclosure comprises reacting an oxidizing agent or a sulfurizing agent with the nucleic acid compound obtained in the step preceding the oxidation or sulfurization step, nucleic acid This is a process for converting the phosphite triester bond of the compound into a phosphate triester bond or a thiophosphate triester bond.

[0217] The "oxidizing agent" used in the oxidation or sulfurization step is not particularly limited as long as it can oxidize a phosphite triester bond to a phosphate triester bond without oxidizing other sites. However, it is preferable to use iodine, (1S)-(+)-(10-camphanylsulfonyl)oxaziridine, tert-butyl hydroperoxide (TBHP), 2-butanone peroxide, 1,1-dihydroperoxycyclododecane, bis(trimethylsilyl)peroxide, or m-chloroperbenzoic acid. From the viewpoint of achieving a good oxidation reaction, iodine, (1S)-(+)-(10-camphanylsulfonyl)oxaziridine, tert-butyl hydroperoxide, 2-butanone peroxide, and 1,1-dihydroperoxycyclododecane are more preferred, iodine, (1S)-(+)-(10-camphanylsulfonyl)oxaziridine, tert-butyl hydroperoxide, and 2-butanone peroxide are even more preferred, iodine and tert-butyl hydroperoxide are even more preferred, and iodine is particularly preferred. The above oxidizing agent can be used after diluting it with an appropriate solvent to a concentration of 0.05 (mol / L) (hereinafter, sometimes referred to as "M") to 2M. The dilution solvent is not particularly limited as long as it is a solvent inert to the reaction, and examples thereof include pyridine, THF, dichloromethane, water, and any mixture thereof. Among these, for example, iodine / water / pyridine-THF, iodine / pyridine-acetic acid, peroxidizing agent (TBHP) / dichloromethane, or tert-butyl hydroperoxide / nonane are preferably used.

[0218] The "sulfurizing agent" used in the oxidation or sulfurization step is not particularly limited as long as it can convert a phosphite triester bond to a thiophosphate triester bond; however, it is preferable to use 3-((N,N-dimethylaminomethylidene)amino)-3H-1,2,4-dithiazole-5-thione (DDTT), 3H-1,2-benzodithiol-3-one-1,1-dioxide (Beaucage reagent), 3H-1,2-benzodithiol-3-one, phenylacetyl disulfide (PADS), tetraethylthiuram disulfide (TETD), 3-amino-1,2,4-dithiazole-5-thione (ADTT), or sulfur. From the viewpoint of enabling the reaction to proceed smoothly, 3-((N,N-dimethylaminomethylidene)amino)-3H-1,2,4-dithiazole-5-thione (DDTT), 3H-1,2-benzodithiol-3-one-1,1-dioxide (Beaucage reagent), 3H-1,2-benzodithiol-3-one, and phenylacetyl disulfide (PADS) are more preferred, 3-((N,N-dimethylaminomethylidene)amino)-3H-1,2,4-dithiazole-5-thione and 3H-1,2-benzodithiol-3-one-1,1-dioxide are even more preferred, and 3-((N,N-dimethylaminomethylidene)amino)-3H-1,2,4-dithiazole-5-thione is particularly preferred. The sulfurizing agent can be used after diluting it with an appropriate solvent to a concentration of 0.05M to 2M. The dilution solvent is not particularly limited as long as it is inert to the reaction, and examples thereof include dichloromethane, acetonitrile, pyridine, and any mixture thereof.

[0219] The amount of the oxidizing agent or sulfurizing agent used is preferably 1 mol to 50 mol, more preferably 1 mol to 5 mol, per mol of the nucleic acid compound obtained in the nucleic acid elongation step. The reaction temperature in the oxidation or sulfurization step is not particularly limited as long as the reaction proceeds, but is preferably 0°C to 100°C, more preferably 20°C to 50°C. The reaction time can be appropriately set depending on the type of nucleic acid compound obtained in the nucleic acid elongation step, the type of oxidizing agent or sulfurizing agent used, the reaction temperature, etc., and is preferably 1 minute to 3 hours.

[0220] <<Step D; Precipitation step>> The method for producing a nucleic acid compound according to the present disclosure includes a step of precipitating the nucleic acid compound obtained in a step prior to the precipitation step. Contains . As a method for precipitating the nucleic acid compound obtained in step C in the precipitation step, a method of precipitation using a polar solvent is preferred. Examples of the polar solvent include alcohol-based solvents such as methanol, ethanol, and isopropanol; nitrile-based solvents such as acetonitrile and propionitrile; ketone-based solvents such as acetone and 2-butanone; polar ether-based solvents such as 1,4-dioxane and tetrahydrofuran; amide-based solvents such as dimethylformamide, dimethylacetamide, and N-methylpiperidone; sulfoxide-based solvents such as dimethyl sulfoxide; water; and mixed solvents of two or more of these. Among the above polar solvents, alcohol-based solvents or nitrile-based solvents are preferred, and methanol or acetonitrile are more preferred. As the polar solvent in the precipitation step, methanol is particularly preferred from a practical viewpoint. The polar solvent may contain water to minimize loss of the target substance into the polar solvent. In particular, when acetonitrile is used as the polar solvent, the target substance tends to dissolve in the polar solvent, resulting in increased loss. However, using acetonitrile containing a small amount of water can minimize this loss. In this case, the water content in the polar solvent is preferably 1% by volume (v / v) to 10% by volume (v / v), and more preferably 3% by volume (v / v) to 8% by volume (v / v). When the water content in the polar solvent is 1% by volume or more, loss of the target substance into the polar solvent can be suppressed, and when the water content in the polar solvent is 10% by volume or less, it tends to be easier to remove unnecessary substances from the polar solvent.

[0221] When iodine is used as an oxidizing agent, a solution of methanol saturated with sodium thiosulfate (hypo) can be used as the precipitating solvent, which can eliminate the coloring caused by iodine and allow the isolation of nucleic acid compounds with protected 5-position of the ribose structure with high purity. When using a sulfurizing agent, a solution saturated with a trivalent phosphorus reagent (e.g., trimethyl phosphite, triethyl phosphite, tris(2-carboxyethyl)phosphine, etc.) or a reducing agent such as hypophosphate may be used as the precipitating solvent. This allows for the isolation of a nucleic acid compound with a protected 5-position of the ribose structure at a high purity.

[0222] Examples of the method for producing a nucleic acid compound including the above steps A to D include: the below described However, the scheme is not particularly limited. In the following scheme, R 1 , R 2 , X, m1, L, Y A , n, ring A and R A is R in equation (2). 1 , R 2 , X, m1, L, Y A , n, ring A and R A is synonymous with.

[0223] [ka]

[0224] In the method for producing a nucleic acid compound according to the present disclosure, the above steps A to D can be repeated a desired number of times to obtain a target nucleic acid compound with high purity and high yield.

[0225] <<Step E; Nucleic acid compound isolation step>> The method for producing a nucleic acid compound according to the present disclosure preferably includes, after steps A to D, a step of deprotecting each protecting group in the nucleic acid compound obtained in step D and isolating the nucleic acid compound. The method for deprotecting the protecting group of the nucleic acid base may be, for example, a step of removing the protecting group according to the deprotection method described in Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons (1999) or the like. Specifically, protecting groups of nucleic acid bases, such as phenoxyacetyl and acetyl groups, and cyanoethyl groups protecting the phosphate skeleton can be removed by treatment with ammonia water, an ammonia water / ethanol solution, or a mixture of ammonia water and an aqueous methylamine solution. The hydroxy-protecting group at the 5-position of the nucleotide can be removed by treatment with the acid used in Step A or an appropriately diluted solution thereof. No protecting group, i.e., P at position 5 of the ribose structure 1 Nucleotides and the like in which is a hydrogen atom are easily decomposed by enzymes, so it is preferable to isolate nucleic acid compounds under controlled air cleanliness.

[0226] The conditions for deprotecting the structure represented by formula (1) can be appropriately set depending on L in formula (2). Regarding the condition for the structure of the compound represented by formula (1), for example, when L in formula (1) is formula (1L), a deprotection method using a basic compound is preferred, and the protection group can be removed by treating with ammonia water, an ammonia water / ethanol solution, or a mixed solution of ammonia water and an aqueous methylamine solution.

[0227] The final target nucleic acid compound obtained by the method for producing a nucleic acid compound according to the present disclosure can be isolated and purified according to a method commonly used in the synthesis of nucleic acid compounds. For example, the final target nucleic acid compound can be isolated and purified by subjecting the reaction mixture to extraction and washing, crystallization, chromatography, etc.

[0228] The progress of the reaction in each of the above steps can be confirmed by the same method as in general liquid-phase organic synthesis reactions, i.e., thin-layer silica gel chromatography, high-performance liquid chromatography, etc.

[0229] The nucleic acid compound obtained in step (D) or step (E) can be further subjected to a synthetic reaction to be converted into a desired nucleic acid compound derivative. The nucleic acid compounds produced by the nucleic acid compound production method according to the present disclosure can be used for a variety of applications, such as various human or veterinary pharmaceuticals (RNA, DNA, oligonucleic acid drugs, etc.), functional foods, specified health foods, food, chemical products, and polymeric materials for biological or industrial use.

[0230] (nucleic acid compound) The nucleic acid compound according to the present disclosure is a nucleic acid compound in which either the 3- or 5-hydroxy group of the ribose structure is protected by a structure represented by the following formula (1a):

[0231] [ka]

[0232] In formula (1), ring A represents a fused polycyclic aromatic hydrocarbon ring or an aromatic heterocycle; Y A represents *-OCR2-**, *-NRCR2-**, or *-SCR2-**, and each R independently represents a hydrogen atom, an alkyl group, an aromatic group, or an aromatic group-substituted alkyl group; k represents an integer of 1 to 5; The wavy line and * represent the bonding position with the hydroxy group at position 3 or 5 of the ribose structure or the bonding position with another structure. ** represents the bonding position to ring A, R A are each independently an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and k R A At least one aliphatic hydrocarbon group has 12 or more carbon atoms, Ring A is Y A and R A In addition, the group may further have a substituent.

[0233] The nucleic acid compound according to the present disclosure, in which either the 3-position or the 5-position of the ribose structure is protected by the structure represented by the above formula (1a), is a novel compound and can be suitably used in the production of nucleic acid compounds. The structure represented by formula (1a) in the compound according to the present disclosure is the same as the structure represented by formula (1) described above in the method for producing a nucleic acid compound according to the present disclosure, and the same also applies to preferred embodiments other than those described below.

[0234] The structure represented by the above formula (1a) can be synthesized in the same manner as the structure represented by the above formula (1).

[0235] The nucleic acid compound protected by the structure represented by the above formula (1a) is preferably a compound represented by the following formula (2a):

[0236] [ka]

[0237] In formula (2a), m represents an integer of 0 or more, n represents 1 to 6, Each Base independently represents a nucleobase or a modified nucleobase; P 1 represents a hydrogen atom or a protecting group, R 1 represents an oxygen atom, a sulfur atom, or a borano group, R 2 represents a hydrogen atom, a substituted or unsubstituted hydroxy group, a substituted or unsubstituted mercapto group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted amino group, X's each independently represent a hydrogen atom or a hydroxyl group. , Ha represents an organic group bridging with the halogen atom or the carbon atom at the 4' position of the ribose structure, Each L independently represents a single bond or a divalent linking group. death, Ring A represents a fused polycyclic aromatic hydrocarbon ring or an aromatic heterocycle; Y A each independently represents a single bond, *-OCR2-**, *-NRCR2-**, or *-SCR2-**, * indicates the bonding position with L, ** represents the bonding position to ring A, R each independently represents a hydrogen atom, an alkyl group, an aromatic group, or an aromatic group-substituted alkyl group; k represents an integer of 1 to 5; R A are each independently an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and k R AAt least one aliphatic hydrocarbon group has 12 or more carbon atoms, Ring A is Y A and R A In addition, the group may further have a substituent.

[0238] In formula (2a), m, n, Base, P 1 , R 2 , X, R 1 , L, Ring A, Y A , and R A are m, n, Base, and P in the above formula (2). 1 , R 2 , X, R 1 , L, Ring A, Y A , and R A The same applies to the preferred embodiments.

[0239] The compound represented by the formula (2a) can be synthesized in the same manner as the compound represented by the formula (2). [Example]

[0240] The following examples further illustrate the embodiments of the present invention. The materials, amounts used, ratios, processing details, processing procedures, etc. shown in the following examples can be changed as appropriate without departing from the spirit of the embodiments of the present invention. Therefore, the scope of the embodiments of the present invention is not limited to the specific examples shown below. Unless otherwise specified, "parts" and "%" are based on mass.

[0241] Unless otherwise specified, purification by column chromatography was performed using an automatic purification system ISOLERA (Biotage) or a medium pressure liquid chromatograph YFLC-Wprep2XY.N (Yamazen Corporation). Unless otherwise specified, the carrier used in silica gel column chromatography was SNAPKP-Sil Cartridge (manufactured by Biotage), or Hi-Flash Column W001, W002, W003, W004, or W005 (manufactured by Yamazen Corporation). The mixing ratio of the eluent used in column chromatography is a volume ratio. For example, "hexane:ethyl acetate gradient elution = 50:50 to 0:100" means that the eluent of 50% hexane / 50% ethyl acetate was finally changed to 0% hexane / 100% ethyl acetate. Furthermore, for example, "gradient elution of hexane:ethyl acetate = 50:50 to 0:100, gradient elution of methanol:ethyl acetate = 0:100 to 20:80" means that the eluent was changed from 50% hexane / 50% ethyl acetate to 0% hexane / 100% ethyl acetate, then to 0% methanol / 100% ethyl acetate, and finally to 20% methanol / 80% ethyl acetate.

[0242] MS spectra were measured using an ACQUITY SQD LC / MS System (Waters, ionization method: ESI (ElectroSpray Ionization)). NMR spectra were measured using tetramethylsilane as an internal standard with a Bruker AV300 (manufactured by Bruker, 300 MHz) or a Bruker AV400 (manufactured by Bruker, 400 MHz), and all δ values ​​are shown in ppm. The abbreviations used in the examples are as follows: TFA: Trifluoroacetic acid NMP: N-methyl-2-pyrrolidone THF: Tetrahydrofuran HBTU: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate DMAP: N,N-dimethyl-4-aminopyridine DIPEA: N,N-diisopropylethylamine EDC: 1,2-dichloroethane DCM: dichloromethane

[0243] (Synthesis of Compound (1); Nucleoside) Compound (1) was synthesized according to the following scheme.

[0244] [ka]

[0245] Intermediate (1-1) was synthesized by the method described in paragraph 0216 of European Patent Application Publication No. 2518041. Intermediate (1-1) (12.00 g, 15.5 mmol), methyl 6-hydroxy-2-naphthoate (6.26 g, 30.9 mmol), potassium carbonate (8.55 g, 61.9 mmol), and N-methylpyrrolidone (155 mL) as a solvent were mixed to obtain a reaction solution. The resulting reaction solution was stirred at 100°C under nitrogen for 4 hours. After completion of the reaction, the reaction solution was cooled to room temperature (25°C), diluted with cyclopentyl methyl ether, and washed with water using a separatory funnel. Methanol was added to the resulting organic layer, and the precipitated solid was filtered and dried to obtain intermediate (1-2) (13.8 g, 95% yield). Intermediate (1-2) (4.00 g, 4.25 mmol) and tetrahydrofuran (66 mL) as a solvent were mixed and stirred at 30°C, and then a 3.6 M toluene solution of sodium bis(2-methoxyethoxy)aluminum hydride (3.5 mL, 12.8 mmol) was added dropwise using a dropping funnel. After the addition, the reaction solution was stirred at 30°C under nitrogen for 2 hours. After the reaction was completed, saturated aqueous potassium sodium tartrate solution (50 mL) was slowly added dropwise while stirring at 30°C. After the addition, the aqueous phase was removed, and methanol was added to the resulting organic layer. The precipitated solid was filtered and dried to obtain intermediate (1-3) (3.87 g, yield 99%). Intermediate (1-3) (190 mg, 0.21 mmol), the triethylamine salt of 5'-O-(4,4'-dimethoxytrityl)thymidine-3'-O-succinate (186 mg, 0.25 mmol), and dichloromethane (25 mL) were mixed and stirred at room temperature (25 °C). N,N-dimethylaminopyridine (40 mg, 0.33 mmol), diisopropylethylamine (57 μL, 0.33 mmol), and 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide hexafluorophosphate (123 mg, 0.33 mmol) were added. After the addition, the reaction solution was stirred overnight under nitrogen. After the reaction was completed, methanol was added, and the precipitated solid was filtered and dried to obtain compound (1) (379 mg, 98% yield). ESI-MS: [MH] - =1538

[0246] (Synthesis of Compound (2); Nucleoside) Compound (2) was synthesized according to the following scheme.

[0247] [ka]

[0248] Intermediate (1-1) (8.00 g, 10.3 mmol), indole-5-carboxaldehyde (5.98 g, 41.2 mmol), potassium tert-butoxide (t-BuOK) (4.62 g, 41.2 mmol), and tetrahydrofuran (100 mL) as a solvent were mixed to obtain a reaction solution. The resulting reaction solution was stirred at 40 °C under nitrogen for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature (25 °C), diluted with cyclopentyl methyl ether, washed with water using a separatory funnel, and concentrated under reduced pressure. The obtained crude product was dissolved in dichloromethane, and methanol was added to precipitate a solid. The precipitated solid was filtered and dried to obtain intermediate (2-1) (9.11 g, 95% yield). Intermediate (2-1) (5.0 g, 5.65 mmol) was mixed with methylene chloride (75 mL) as a solvent and dissolved at 30° C. After that, hydroxylamine hydrochloride (2.36 g, 34 mmol) and triethylamine (7.88 mL, 56.5 mmol) were added and stirred for 2 hours at 30° C. The reaction solution was cooled to room temperature, methanol was added, and the resulting precipitate was filtered and dried to obtain intermediate (2-2) (4.9 g, yield: 97%). Intermediate (2-2) (2.00 g, 2.22 mmol) was mixed with tetrahydrofuran (37 mL) and acetic acid (10 mL) at room temperature, followed by the addition of zinc dust (1.75 g, 26.7 mmol). After refluxing for 1 hour, the zinc dust was removed using Celite, and the resulting filtrate was concentrated under reduced pressure. Methanol (750 mL) was added to the resulting crude product, and the resulting precipitate was filtered and dried. The resulting solid was purified by column chromatography (NH silica gel, hexane:ethyl acetate = 4:1 to 1:9) to obtain intermediate (2-3) (1.01 g, 51.3% yield). Intermediate (2-3) (88.5 mg, 0.10 mmol), the triethylamine salt of 5'-O-(4,4'-dimethoxytrityl)thymidine-3'-O-succinate (111 mg, 0.15 mmol), and dichloromethane (1 mL) were mixed and stirred at room temperature (25 °C). 4-Dimethylaminopyridine (18.3 mg, 0.15 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (28.8 mg, 0.15 mmol) were added. The reaction solution was stirred at room temperature under nitrogen for 1 hour. After the reaction was complete, methanol was added, and the precipitated solid was filtered and dried to obtain compound (2) (138 mg, 91%). ESI-MS: [M-H] - =1512

[0249] (Synthesis of Compound (3); Nucleotide) Compound (3) was synthesized according to the following scheme.

[0250] [ka]

[0251] Compound (1) (100 mg, 0.065 mmol), pyrrole (45 μL, 0.65 mmol), and dichloromethane (1.4 mL) as a solvent were mixed and stirred at room temperature (25°C). Trifluoroacetic acid (49 μL, 0.65 mmol) was added, and the reaction solution was stirred at room temperature under nitrogen for 15 minutes to perform deprotection of the 5'-position. After deprotection, pyridine (52 μL, 0.65 mmol) was added, and the reaction solution was stirred at room temperature under nitrogen for 15 min to neutralize. Subsequently, a 0.25 M solution of 4,5-dicyanoimidazole (DCI) in acetonitrile (44 μL, 0.18 mmol) and 5'-O-(4,4'-dimethoxytrityl)thymidine-3'-[O-(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite (193.4 mg, 0.26 mmol) were added, and the reaction solution was stirred at room temperature under nitrogen for 15 min to form the phosphite triester by condensation. After condensation, iodine / pyridine / tetrahydrofuran / water solution (1.8 mL) was added, and the reaction solution was stirred at room temperature under nitrogen for 1 h to form the phosphate triester by oxidation. To the resulting reaction solution, a saturated methanol solution of sodium thiosulfate (14 mL) was added, and the precipitated solid was filtered and dried to obtain compound (3) (122 mg, 99% yield). ESI-MS: [M−H] - =1895

[0252] (Synthesis of Compound (4); Nucleotide) Compound (4) was synthesized according to the following scheme. Compound (4) was synthesized in the same manner as compound (3). Yield 96%, ESI-MS: [MH] - =1867.

[0253] [ka]

[0254] (Synthesis of comparative compounds) Comparative compound (1) was synthesized by the method described in paragraph 0205 of Japanese Patent No. 6281599 as Comparative compound (1-1). of It was synthesized in the same manner as compound (3). Yield 83%, ESI-MS: [MH] - =1739.

[0255] [ka]

[0256] 〔evaluation〕 [Table 1]

[0257] It can be seen that the methods for producing nucleic acid compounds according to the present disclosure in Examples 1 and 2 are superior to the production method in Comparative Example 1 in terms of the yield of the resulting nucleic acid compound.

[0258] Example 3 (Synthesis of Compound (5); Nucleotide) Compound (5) was synthesized according to the following scheme. Compound (5) was synthesized in the same manner as compound (3), except that 5'-O-(4,4'-dimethoxytrityl)thymidine-3'-[O-(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite used in the synthesis of compound (3) was replaced with 2'-O-methyl-5'-O-(4,4'-dimethoxytrityl)uridine-3'-[O-(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite. Yield 98%, ESI-MS: [MH] - =1911.

[0259] [ka]

[0260] Example 4 (Synthesis of Compound (6); Nucleotide) Compound (6) was synthesized according to the following scheme. Compound (6) was synthesized in the same manner as compound (3), except that 5'-O-(4,4'-dimethoxytrityl)thymidine-3'-[O-(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite used in the synthesis of compound (3) was replaced with LNA-T-CE-phosphoramidite. Yield 94%, ESI-MS: [MH] - =1923.

[0261] [ka]

[0262] Example 5 (Synthesis of Compound (7); Nucleotide) Compound (7) was synthesized according to the following scheme. Compound (7) was synthesized in the same manner as compound (4), except that 5'-O-(4,4'-dimethoxytrityl)thymidine-3'-[O-(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite used in the synthesis of compound (4) was replaced with 2'-O-methyl-5'-O-(4,4'-dimethoxytrityl)uridine-3'-[O-(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite. Yield 94%, ESI-MS: [MH] - =1883.

[0263] [ka]

[0264] Example 6 (Synthesis of Compound (8); Nucleotide) Compound (8) was synthesized according to the following scheme. Compound (8) was synthesized in the same manner as compound (4), except that 5'-O-(4,4'-dimethoxytrityl)thymidine-3'-[O-(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite used in the synthesis of compound (4) was replaced with LNA-T-CE-phosphoramidite. Yield 94%, ESI-MS: [MH] - =1895.

[0265] [ka]

[0266] Examples 7 and 8 (Synthesis of Compound (9) and Compound (10); Nucleotides) Compounds (9) and (10) were synthesized according to the following scheme. Compound (9) was synthesized in the same manner as compound (3), except that the raw material used in the synthesis of compound (3) was replaced with compound (3) (100 mg, 0.053 mmol) and N-benzoyl-5'-O-(4,4'-dimethoxytrityl)adenosine-3'-[O-(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite instead of 5'-O-(4,4'-dimethoxytrityl)thymidine-3'-[O-(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite. The yield of compound (9) was 96%. Next, compound (9) was mixed with a 28% aqueous ammonia / ethanol (v / v=3 / 1) solution and stirred at 60°C for 5 hours. After the reaction was completed, the solvent was removed using a centrifugal evaporator. 0.1M aqueous ammonium acetate solution was added to the obtained crude product, and after removing insoluble matter, the product was passed through a C18 cartridge column (GE). L After washing with 0.1 M ammonium acetate solution and water, the DMTr group at position 5 was removed with 2% trifluoroacetic acid solution, and then washed again with water. 8 months Elution from the cartridge column gave compound (10). ESI-MS: [MH] -=858.2、 Yield 84 %in there were.

[0267] [ka]

[0268] It can be seen that the nucleic acid compound production methods according to the present disclosure using the compounds of Examples 3 to 8 are superior in yield to the nucleic acid compound obtained by the production method using the comparative compound of Comparative Example 1.

[0269] <Synthesis of Protecting Group Formation Reagents (Compounds (A-2) to (A-6))> By synthesizing in the same manner as the above intermediate (1-1), the following compound Compounds (A-2) to (A-6) were obtained.

[0270] [ka]

[0271] Compound (A-2) 1 The H NMR results are shown below. 1 H NMR(CDCl3:400MHz) δ:0.88(6H,t),1.20-1.74(80H,m),3.81(4H,t),4.74(2H,d),5.39(2H,s),6.14(2H,d ),6.30(1H,t),6.53(1H,s),7.10(1H,t),7.16(1H,t),7.25-7.30(1H,d),7.61(1H,d)

[0272] Compound (A-3) 1 The H NMR results are shown below. 1 H NMR(CDCl3:400MHz) δ:0.88(6H,t),1.20-1.74(80H,m),3.84(4H,t),4.88(2H,d),5.18(2H,s),6.2 8(2H,d),6.35(1H,t),6.53(1H,s),7.13-7.28(3H,m),7.31(1H,d),7.75(1H,d)

[0273] Compound (A-4) 1 The H NMR results are shown below. 1 H NMR(CDCl3:400MHz) δ:0.88(6H,t),1.19-1.47(76H,m),1.66-1.76(4H,m),3.84(4H,t),4.83(2H,d),5.15(2 H,s),6.23(2H,d),6.35(1H,t),7.12-7.16(2H,m),7.17-7.21(1H,m),7.69-7.72(1H,m)

[0274] Compound (A-5) 1 The H NMR results are shown below. 1 H NMR(CDCl3,400MHz) δ:0.88(6H,t),1.18-1.47(76H,m),1.66-1.77(4H,m),3.86(4H,t),4.84(2H,d),5 .13(2H,s),6.24(2H,d),6.36(1H,t),7.08-7.13(2H,m),7.28(1H,d),7.64(1H,d)

[0275] Compound (A-6) 1 The H NMR results are shown below. 1 H NMR(CDCl3,400MHz) δ:0.88(6H,t),1.18-1.45(76H,m),1.48(1H, t),1.67-1.77(4H,m),3.86(4H,t),4.82(2H,d),5.12(2H,s),6.21(2H,d),6.36(1H,t),7.12(1H,s),7.37(1H,s),7.81(1H,s)

[0276] <Reagent for forming a protecting group (synthesis of compound (AN-1)> Compound (AN-1) was synthesized according to the following scheme.

[0277] [ka]

[0278] The compound (A-2) (2.00 g, 2.26 mmol) synthesized above, sodium triacetoxyborohydride (0.96 g, 4.52 mmol), ethylamine tetrahydrofuran solution (2 M) (3.39 mL, 6.78 mmol), acetic acid (0.34 mL, 6.78 mmol), and tetrahydrofuran (25 mL) were mixed and stirred at 90 °C for 7 hours under a nitrogen atmosphere. The reaction solution was cooled to 0 °C, and water (10 mL) was slowly added dropwise to quench the reaction. The mixture was extracted with dichloromethane, and the resulting organic layer was washed with saturated aqueous sodium bicarbonate and concentrated under reduced pressure. The resulting crude product was dissolved in dichloromethane, and methanol was added. The precipitated solid was filtered and dried to obtain compound (AN-1) (1.90 g, yield: 94%). Note that NaBH(OAc)3 represents sodium triacetoxyborohydride, and EtNH2 represents ethylamine.

[0279] 1 H NMR(CDCl3,400MHz) δ:0.88(6H,t),1.15(3H,t),1.20-1.76(80H,m),2.72(2H,q),3.83(4H,t),3.89(2H,s),5.19(2H ,s),6.24(2H,d),6.32(1H,t),6.49(1H,dd),7.11(1H,d),7.15(1H,dd),7.25(2H,d),7.57(1H,d)

[0280] <Synthesis of protecting group formation reagents (compounds (AN-2) to (AN-4))> The following compounds (AN-2) to (1-N-4) were obtained by synthesis in the same manner as for the above compound (AN-1).

[0281] [ka]

[0282] Compound (AN-2) 1 The H NMR results are shown below. 11H NMR (CDCl3: 400 MHz) δ: 0.88 (6H, t), 1.14 (3H, t), 1.18 - 1.44 (76H, m), 1.66 - 1.74 (4H, m), 2.75 (2H, q), 3.83 (4H, t), 3.99 (2H, s), 5.17 (2H, s), 6.26 (2H, d), 6.33 (1H, t), 7.07 (1H, s), 7.11 (1H, t), 7.17 (1H, t), 7.25 - 7.29 (1H, m), 7.65 (1H, d)

[0283] For compound (A-N-3) 1 The 1H NMR results are shown below. 1 1H NMR (CDCl3: 400 MHz) δ: 0.88 (6H, t), 1.22 - 1.43 (76H, m), 1.64 - 1.72 (4H, m), 3.74 (6H, s), 3.82 (4H, d), 3.82 (3H, s), 3.95 (4H, d), 5.16 (2H, s), 6.13 (2H, s), 6.26 (2H, d), 6.31 (1H, t), 7.07 (1H, td), 7.15 (1H, td), 7.15 (1H, s), 7.24 - 7.28 (1H, m), 7.50 (1H, d)

[0284] For compound (A-N-4) 1 The 1H NMR results are shown below. 1 1H NMR (CDCl3: 400 MHz) δ: 0.88 (6H, t), 1.21 - 1.44 (76H, m), 1.65 - 1.74 (4H, m), 2.28 (3H, s), 3.78 (2H, s), 3.83 (4H, t), 3.99 (2H, s), 5.17 (2H, s), 5.87 - 5.90 (1H, m), 6.05 (1H, d), 6.26 (2H, d), 6.33 (1H, t), 7.07 (1H, s), 7.10 (1H, td), 7.18 (1H, td), 7.24 - 7.29 (1H, m), 7.63 (1H, d)

[0285] <Reagent for protecting group formation (Synthesis of compound (A-N-5)) Compound (A-N-5) was synthesized according to the following scheme.

[0286] [ka]

[0287] To a mixture of intermediate (A-1-1) (10.0 g, 12.9 mmol), indole-3-carbaldehyde (7.48 g, 51.6 mmol), and tetrahydrofuran (129 mL), potassium tert-butoxide (5.79 g, 51.6 mmol) was added, and the mixture was stirred at 60° C. for 2.5 hours. Cyclopentyl methyl ether (250 mL) and water (250 mL) were added to the reaction solution, and after separation, methanol (1 L) was added to the organic layer. The resulting precipitate was collected by filtration and dried to obtain intermediate (A-1-3) (11.1 g, yield: 96.9%). A mixture of intermediate (A-1-3) (20.0 g, 22.6 mmol) and methylene chloride (302 mL) was dissolved at 30° C., and then hydroxylamine hydrochloride (9.43 g, 136 mmol) and triethylamine (31.5 mL, 226 mmol) were added and stirred for 2 hours at 30° C. The reaction solution was cooled to room temperature, and methanol (2 L) was added. The resulting precipitate was collected by filtration and dried to obtain intermediate (A-1-4) (19.6 g, yield: 96.6%). Intermediate (A-1-4) (2.00 g, 2.22 mmol), tetrahydrofuran (37 mL), and acetic acid (10 mL) were mixed at room temperature, and then zinc dust (1.75 g, 26.7 mmol) was added. After refluxing for 1 hour, the zinc dust was removed using Celite, and the resulting filtrate was concentrated. Methanol (750 mL) was added to the resulting crude product, and the resulting precipitate was collected by filtration and dried. The resulting solid was purified by column chromatography (NH silica gel, hexane:ethyl acetate = 4:1 to 1:9) to obtain compound (AN-5) (1.01 g, yield 51.3%).

[0288] 1H NMR(CDCl3,400MHz) δ:0.88(6H,t),1.20-1.44(76H,m),1.66-1.75(4H,m),3.84(4H,t),4.06(2H,d),5.17(2H,s) ,6.27(2H,d),6.33(1H,t),7.04(1H,s),7.12(1H,dt),7.19(1H,dt),7.29(1H,d),7.65(1H,d)

[0289] <Synthesis of protecting group forming reagent (compound (B-1))> Compound (B-1) was synthesized according to the following scheme.

[0290] [ka]

[0291] Intermediate (B-1) was synthesized by the method described in Tetrahedron Lett., 2018, 59, 2145-2149. Intermediate (1-1) (473 mg, 0.61 mmol), intermediate (B-1) (149 mg, 0.76 mmol), potassium tert-butoxide (86.5 mg, 0.77 mmol), and tetrahydrofuran / N,N-dimethylformamide (2 / 3 (vol% / vol%), 25 mL) were mixed and heated to reflux for 4 hours. The reaction solution was cooled to room temperature and extracted with cyclopentyl methyl ether and water, and the organic layer was concentrated under reduced pressure. The obtained crude product was dissolved in dichloromethane, and methanol was added to precipitate a solid. The solid was filtered and dried to obtain intermediate (B-2) (503 mg) (yield: 88%). Under a nitrogen atmosphere, intermediate (B-2) (149 mg, 0.16 mmol), sodium borohydride (12.1 mg, 0.32 mmol), and tetrahydrofuran / methanol (20 / 1 (vol% / vol%), 2 mL) were mixed and stirred at room temperature for 2 hours. The reaction solution was cooled to 0°C, and water (10 mL) was slowly added dropwise to quench the reaction. The mixture was extracted with dichloromethane, and the resulting organic layer was washed with water and saturated brine and concentrated under reduced pressure. The resulting crude product was dissolved in dichloromethane, and methanol was added to precipitate a solid. The solid was filtered and dried to obtain compound (B-1) (115 mg) (yield: 77%). DMF stands for N,N-dimethylformamide.

[0292] 1 H NMR(CDCl3:400MHz) δ:0.84-1.72(86H,m),3.80(4H,t),4.86(2H,d),5.42(2H,s),6.27(2H,d),6.31( 1H,t),7.22-7.29(2H,m),7.33-7.39(2H,m),7.41-7.47(2H,m),8.10-8.14(2H,m)

[0293] <Synthesis of protecting group forming reagent (compound (B-2))>

[0294] [ka]

[0295] Compound (B-2) was obtained by synthesis in the same manner as compound (B-1). 1 H-NMR(CDCl3,300MHz)δ=0.88(9H,t),1.19-1.85(96H,m),3.93-4.01(6H,m),4.83(2H,d), 5.06(2H,s),6.42(1H,t),6.67(2H,d),7.22-7.26(2H,m),7.46(1H,dd),7.72-7.77(3H,m).

[0296] <Synthesis of protecting group forming reagent (compound (B-3))>

[0297] [ka]

[0298] Compound (B-3) was obtained by synthesis in the same manner as compound (B-1). 1 H-NMR(CDCl3,400MHz)δ=0.88(6H,t),1.24-1.58(64H,m),2.04(4H,m),3.41(4H,t),3.58(4H,t),4.05(4H, t),4.83(2H,d),5.10(2H,s),6.44(1H,t),6.63(2H,d),7.20-7.26(2H,m),7.45(1H,dd),7.72-7.76(3H,m).

[0299] <Synthesis of protecting group forming reagent (compound (B-4))>

[0300] [ka]

[0301] Intermediate (1-1) (3.00 g, 3.87 mmol), 2-hydroxy-1-naphthaldehyde (1.00 g, 3.87 mmol), potassium carbonate (1.07 g, 7.73 mmol), and N,N-dimethylacetamide (DMAc, 30 mL) were mixed and stirred under a nitrogen atmosphere at 100°C for 3 hours. The reaction solution was cooled to room temperature, and methanol was added to precipitate a solid. The solid was filtered and dried under reduced pressure to obtain intermediate (B-3) (4.46 g). Under a nitrogen atmosphere, intermediate (B-3) (3.52 g, 3.86 mmol), tetrahydrofuran (154 mL), and methanol (7.7 mL) were mixed and stirred at room temperature, and then sodium borohydride (0.292 g, 7.72 mmol) was added. The reaction solution was stirred at 40°C for 30 minutes, and after confirming the disappearance of the raw materials, silica gel (50 g) was added to the reaction solution in small portions to quench the reaction. After filtering the silica gel and concentrating the filtrate under reduced pressure, the resulting residue was dissolved in THF (15 mL), and methanol (100 mL) was added. The precipitated solid was filtered and dried to obtain compound (B-4) (3.44 g, 98% yield). 1 H-NMR(CDCl3,400MHz)δ=0.88(6H,t),1.19-1.80(80H,m),3.92(4H,t),5.17(2H,s),5.22(2H,d ),6.40(1H,s),6.58(2H,d),7.29(1H,t),7.37(1H,t),7.53(1H,t),7.80(2H,dd),8.14(1H,d).

[0302] <Synthesis of protecting group forming reagent (compound (B-5))>

[0303] [ka]

[0304] Compound (1-5) was obtained by synthesis in the same manner as compound (1-4). 1 H-NMR(CDCl3,400MHz)δ=0.88(6H,t),1.19-1.85(80H,m),3.95(4H,t),5.06(2H,d),5.18(2H,s), 6.42(1H,t),6.63(2H,d),6.82(1H,d),7.38(1H,d),7.48-7.65(2H,m),8.12(1H,d),8.41(1H,d).

[0305] <Synthesis of protecting group forming reagent (compound (C-1))>

[0306] [ka]

[0307] Intermediate (C-1) was synthesized by the method described in J. Am. Chem. Soc., 2010, 132, 14625-14637. Intermediate (C-1) (346 mg, 1.00 mmol), 1-bromodocosane (1166 mg, 3.00 mmol), potassium carbonate (897 mg, 6.5 mmol), and N,N-dimethylformamide (DMF, 10 mL) were mixed and stirred at 80 °C for 2 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, extracted with dichloromethane and water, and the organic phase was concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 1 / 9 to 3 / 7 (volume ratio)), recrystallized from acetonitrile, filtered, and dried to obtain compound (C-1) (200 mg, 21% yield). 1 H-NMR(CDCl3,400MHz)δ=0.83-1.63(86H,m),3.86-3.92(4H,m),4.79(4H,d),7.12(2H,d),7.20(2H,dd),7.40(2H,d),7.82(2H,d),7.91(2H,d).

[0308] <Synthesis of protecting group forming reagent (compound (C-2))>

[0309] [ka]

[0310] Compound (C-2) was obtained by synthesizing in the same manner as compound (C-1), except that the length of the alkyl group in the bromide used was changed.

[0311] <Synthesis of protecting group forming reagent (compound (D-1))>

[0312] [ka]

[0313] Intermediate (D-1) was synthesized by the method described in Journal of Organic Chemistry, 2009, 74, 2, 520-529. Intermediate (D-1) (132 mg, 0.7 mmol), 1-bromodocosane (601 mg, 1.54 mmol), potassium carbonate (388 mg, 2.8 mmol), N,N-dimethylacetamide (DMAc, 3.5 mL), and tetrahydrofuran (3.5 mL) were mixed and stirred under a nitrogen atmosphere at 90°C for 5 hours. The reaction solution was cooled to room temperature, and methanol was added to precipitate a solid. The solid was filtered, washed with water and methanol, and then dried under reduced pressure to obtain intermediate (D-2) (480 mg, 85%). Under a nitrogen atmosphere, intermediate (D-2) (480 mg, 0.6 mmol), tetrahydrofuran (90 mL), and methanol (4.5 mL) were mixed, and sodium borohydride (68 mg, 1.8 mmol) was added. The reaction solution was heated to 40°C and stirred for 2 hours, after which the reaction was quenched by adding silica gel. The reaction solution was filtered, and the organic phase was concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography (eluent: hexane / dichloromethane = 7 / 3 to 1 / 1 (volume ratio)) to obtain compound (D-1) (427 mg, 89% yield). 1 H-NMR(CDCl3,400MHz)δ=0.88(6H,t),1.25-1.53(76H,m),1.80-1.87(4H,m),4.05(2H, t),4.11(2H,t),5.16(2H,d),7.10(1H,d),7.19-7.25(2H,m),7.68(1H,d),8.01(1H,d).

[0314] Example 101 Instead of the intermediate (2-3) in Example 1, any of the compounds (A-2) to (A-6), (AN-1) to (AN-5), (B-1) to (B-5), (C-1), (C-2) or (D-1) is used to prepare a compound corresponding to the above compound (1) and a compound corresponding to the above compound (3), in the same manner as in Example 1, and the yields are evaluated. Regardless of which compound is used, the yield of the resulting nucleic acid compound is excellent.

[0315] The disclosure of Japanese Patent Application No. 2019-157402, filed on August 29, 2019, is incorporated herein by reference in its entirety. All publications, patent applications, and technical standards mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent application, or technical standard was specifically and individually indicated to be incorporated by reference.

Claims

1. A method for producing a nucleic acid compound using a nucleic acid compound in which either the 3-position or the 5-position of a ribose structure is protected with a structure containing a group represented by the following formula (1): 【Chemistry 1】 [In formula (1), ring A represents a naphthalene ring, Y Ａ is *-OCR ２ -**, *-NRCR ２ -** or *-SCR ２ -**, each R independently represents a hydrogen atom, an alkyl group, an aromatic group, or an aromatic group-substituted alkyl group, k represents an integer of 1 or 2; The wavy line and * represent the bonding position to L in the following formula (2), and ** represents the bonding position to ring A: R Ａ are each independently an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and k R Ａ At least one aliphatic hydrocarbon group has 12 or more carbon atoms. The nucleic acid compound protected by a structure containing a group represented by formula (1) is a compound represented by the following formula (2): 【Chemistry 2】 [In formula (2), m represents an arbitrary integer of 0 or more, n represents 1; Each Base independently represents a nucleobase or a modified nucleobase; P １ represents a hydrogen atom or a hydroxy protecting group, R １ represents an oxygen atom, a sulfur atom, or a borano group, R ２ represents a hydrogen atom, a substituted or unsubstituted hydroxy group, a substituted or unsubstituted mercapto group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted amino group, X's each independently represent a hydrogen atom, a hydroxyl group, a halogen atom, or an alkylene group having 2 to 7 carbon atoms bridging with the carbon atom at the 4'-position of the ribose structure; Each L independently represents a divalent linking group. Ring A represents a naphthalene ring; Y Ａ are each independently, *-OCR ２ -**, *-NRCR ２ -** or *-SCR ２ - represents **, * represents the bonding position with L, ** represents the bonding position to ring A, each R independently represents a hydrogen atom, an alkyl group, an aromatic group, or an aromatic group-substituted alkyl group, k represents an integer of 1 or 2; R Ａ are each independently an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and k R Ａ At least one aliphatic hydrocarbon group has 12 or more carbon atoms. L in the formula (2) is a group represented by the following formula (1L): 【Transformation 3】 [In formula (1L), * represents Y Ａ ** represents the bonding position with the oxygen atom at position 3 of the ribose structure, L １ represents an alkylene group having 1 to 22 carbon atoms, L ２ is a single bond or #-C(=O)N(R ２Ｌ )-R １Ｌ -N(R ３Ｌ )-##, # is L １ represents the bonding position with ## represents the bond position to C═O, R １Ｌ represents an alkylene group having 1 to 22 carbon atoms, R ２Ｌ and R ３Ｌ each independently represents a hydrogen atom or an alkyl group having 1 to 22 carbon atoms, R ２Ｌ and R ３Ｌ may be bonded to each other to form an alkylene group having 1 to 22 carbon atoms.] The group represented by formula (1) is a group represented by formula (10) or (30): 【Chemistry 4】 [In formula (10) or formula (30), Y Ａ are each independently, *-OCR ２ -**, *-NRCR ２ -** or *-SCR ２ -**, ** represents the bonding position to the naphthalene ring, * represents the bonding position to L in formula (2), each R independently represents a hydrogen atom, an alkyl group, an aromatic group or an aromatic group-substituted alkyl group, and R Ａ are each independently an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and one or two R Ａ At least one aliphatic hydrocarbon group has 12 or more carbon atoms. R in the formula (10) or (30) Ａ are each independently a group represented by the following formula (f2) or formula (a1), 【Transformation 5】 [In formula (f2), the wavy line portion represents the bonding position to the naphthalene ring, m10 represents an integer of 1 to 3, m11 represents an integer of 1 to 3, and X １０ each independently represents a single bond, —O—, —S—, —COO—, —OCO—, —OCONH—, —NHCONH—, —NHCO—, or —CONH—; R １０ each independently represents a monovalent aliphatic hydrocarbon group having 5 or more carbon atoms. 【Transformation 6】 [In formula (a1), the wavy line represents the bonding position to the naphthalene ring, m20 represents an integer of 1 to 10, and X ２０ each independently represents a single bond, —O—, —S—, —COO—, —OCO—, —OCONH—, —NHCONH—, —NHCO—, or —CONH—; R ２０ each independently represents a divalent aliphatic hydrocarbon group, R ２０ At least one of the groups is a divalent aliphatic hydrocarbon group having 5 or more carbon atoms. The P １ represents a hydroxy protecting group that can be deprotected with a weak acid, and Step A: P in the compound represented by formula (2) １ and deprotecting the hydroxy protecting group deprotectable with a weak acid represented by the formula: Step B: reacting the nucleic acid compound obtained in Step A with a nucleoside in which the 3-position of the ribose structure has been phosphoramidite-modified and the 5-position hydroxyl group has been protected with a protecting group that can be removed with a weak acid, thereby condensing them through a phosphite triester bond; Step C: reacting the nucleic acid compound obtained in Step B with an oxidizing agent or a sulfurizing agent to convert the phosphite triester bond of the nucleic acid compound into a phosphate triester bond or a thiophosphate triester bond; Step D: Precipitating the nucleic acid compound obtained in step C; A method for producing a nucleic acid compound using a liquid phase synthesis method comprising the steps of:

2. R in the formula (2) １ is an oxygen atom or a sulfur atom, and R ２ The method for producing a nucleic acid compound according to claim 1, wherein is a hydroxy group.

3. All R Ａ The method for producing a nucleic acid compound according to claim 1 or 2, wherein the total number of carbon atoms in all of the aliphatic hydrocarbon groups contained in

4. k R Ａ The method for producing a nucleic acid compound according to any one of claims 1 to 3, wherein at least one aliphatic hydrocarbon group in the formula (I) has 14 or more carbon atoms.

5. All R Ａ The method for producing a nucleic acid compound according to any one of claims 1 to 4, wherein the total number of carbon atoms in all of the aliphatic hydrocarbon groups contained in

6. A nucleic acid compound in which either the 3- or 5-position hydroxy group of a ribose structure is protected by a structure containing a group represented by the following formula (1a): 【Transformation 7】 [In formula (1a), ring A represents a naphthalene ring, Y Ａ is *-OCR ２ -**, *-NRCR ２ -** or *-SCR ２ - represents **, R's each independently represent a hydrogen atom, an alkyl group, an aromatic group, or an aromatic group-substituted alkyl group; k represents an integer of 1 or 2; The wavy line and * represent the bonding position with L in the following formula (2): ** represents the bonding position to ring A, R Ａ are each independently an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and k R Ａ At least one aliphatic hydrocarbon group has 12 or more carbon atoms. The nucleic acid compound protected by a structure containing a group represented by formula (1a) is a compound represented by the following formula (2): 【Transformation 8】 [In formula (2), m represents an arbitrary integer of 0 or more, n represents 1; Each Base independently represents a nucleobase or a modified nucleobase; P １ represents a hydrogen atom or a hydroxy protecting group, R １ represents an oxygen atom, a sulfur atom, or a borano group, R ２ represents a hydrogen atom, a substituted or unsubstituted hydroxy group, a substituted or unsubstituted mercapto group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted amino group, X's each independently represent a hydrogen atom, a hydroxyl group, a halogen atom, or an alkylene group having 2 to 7 carbon atoms bridging with the carbon atom at the 4'-position of the ribose structure; Each L independently represents a divalent linking group. Ring A represents a naphthalene ring; Y Ａ are each independently, *-OCR ２ -**, *-NRCR ２ -** or *-SCR ２ - represents **, * represents the bonding position with L, ** represents the bonding position to ring A, each R independently represents a hydrogen atom, an alkyl group, an aromatic group, or an aromatic group-substituted alkyl group, k represents an integer of 1 or 2; R Ａ are each independently an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and k R Ａ At least one aliphatic hydrocarbon group has 12 or more carbon atoms. L in the formula (2) is a group represented by the following formula (1L): 【Chemistry 9】 [In formula (1L), * represents Y Ａ ** represents the bonding position with the oxygen atom at position 3 of the ribose structure, L １ represents an alkylene group having 1 to 22 carbon atoms, L ２ is a single bond or #-C(=O)N(R ２Ｌ )-R １Ｌ -N(R ３Ｌ )-##, # is L １ represents the bonding position with ## represents the bond position to C═O, R １Ｌ represents an alkylene group having 1 to 22 carbon atoms, R ２Ｌ and R ３Ｌ each independently represents a hydrogen atom or an alkyl group having 1 to 22 carbon atoms, R ２Ｌ and R ３Ｌ may be bonded to each other to form an alkylene group having 1 to 22 carbon atoms.] The group represented by formula (1a) is a group represented by formula (10) or (30): 【Chemistry 10】 [In formula (10) or formula (30), Y Ａ are each independently, *-OCR ２ -**, *-NRCR ２ -** or *-SCR ２ -**, ** represents the bonding position to the naphthalene ring, * represents the bonding position to L in formula (2), each R independently represents a hydrogen atom, an alkyl group, an aromatic group or an aromatic group-substituted alkyl group, and R Ａ are each independently an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and one or two R Ａ At least one aliphatic hydrocarbon group has 12 or more carbon atoms. R in the formula (10) or (30) Ａ are each independently a group represented by the following formula (f2) or formula (a1): 【Chemistry 11】 [In formula (f2), the wavy line portion represents the bonding position to the naphthalene ring, m10 represents an integer of 1 to 3, m11 represents an integer of 1 to 3, and X １０ each independently represents a single bond, —O—, —S—, —COO—, —OCO—, —OCONH—, —NHCONH—, —NHCO—, or —CONH—; R １０ each independently represents a monovalent aliphatic hydrocarbon group having 5 or more carbon atoms. 【Chemistry 12】 [In formula (a1), the wavy line represents the bonding position to the naphthalene ring, m20 represents an integer of 1 to 10, and X ２０ each independently represents a single bond, —O—, —S—, —COO—, —OCO—, —OCONH—, —NHCONH—, —NHCO—, or —CONH—; R ２０ each independently represents a divalent aliphatic hydrocarbon group, R ２０ At least one of the groups is a divalent aliphatic hydrocarbon group having 5 or more carbon atoms.

7. R in the formula (2) １ is an oxygen atom or a sulfur atom, and R ２ The nucleic acid compound of claim 6, wherein is a hydroxy group.

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