Method for producing peptide compound, reagent for forming protecting group, and aromatic heterocyclic compound

Abstract

A method for producing a peptide compound, comprising a step of using an aromatic heterocyclic compound represented by formula (1), a reagent for forming a protecting group comprising the compound, and the compound. In formula (1), ring A represents an aromatic heterocyclic ring, and Y A are each independently -OH, -NHR, -SH, or -X 0 represents X 0 represents Cl, Br or I, R A and R C each independently represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and R B each independently represents a monovalent aliphatic hydrocarbon group, a (1+c)-valent aromatic group, or a (1+c)-valent heteroaromatic group; when a and c are both 0, R B is a monovalent aliphatic hydrocarbon group, and R A , R B and R C At least one aliphatic hydrocarbon group has 12 or more carbon atoms.

Description

[Technical Field]

[0001] The present disclosure relates to a method for producing a peptide compound, a reagent for forming a protecting group, and an aromatic heterocyclic compound. [Background technology]

[0002] Methods for producing peptides have generally been divided into solid-phase and liquid-phase methods. The solid-phase method has the advantage that isolation and purification after the reaction can be performed simply by washing the resin. However, the solid-phase method is essentially a heterogeneous reaction, and it is necessary to use an excess amount of reactant or reagent to compensate for the low reactivity. In addition, there are problems such as difficulty in tracking the reaction and analyzing the reaction product while it is supported on the support. On the other hand, the liquid phase method has the advantage that it has good reactivity and allows the intermediate peptide to be purified after the condensation reaction by extraction, washing, isolation, etc. However, the liquid phase method has the problem of complicating the production process, since it requires extraction and washing steps using a non-polar organic solvent and an acidic or basic aqueous solution, or an isolation and purification step such as crystallization, to remove residual reagents and by-products in each step of the coupling reaction and deprotection.

[0003] Furthermore, di- or trialkoxybenzyl alcohol compounds described in Patent Document 1 or Patent Document 2 are known as conventional reagents for forming a protecting group.

[0004] Patent Document 1: Japanese Patent Application Laid-Open No. 2000-44493 Patent Document 2: Japanese Patent Application Laid-Open No. 2009-185063 Summary of the Invention [Problem to be solved by the invention]

[0005] An object of one embodiment of the present invention is to provide a method for producing a peptide compound that is excellent in deprotection rate. Another problem to be solved by another embodiment of the present invention is to provide a reagent for forming a protecting group that is excellent in deprotection rate. A problem to be solved by yet another embodiment of the present invention is to provide a novel aromatic heterocyclic compound. [Means for solving the problem]

[0006] The means for solving the above problems include the following aspects. <1> The method includes a step of using an aromatic heterocyclic compound represented by the following formula (1): Method for producing peptide compounds.

[0007] [ka]

[0008] In formula (1), Ring A represents an aromatic heterocycle; Y A is -OH, -NHR, SH, or -X 0 R represents a hydrogen atom, an alkyl group, an aromatic group-substituted alkyl group, a heteroaromatic group-substituted alkyl group, or a 9-fluorenylmethoxycarbonyl group; and X 0 represents Cl, Br or I, R A each independently represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and ring A is R A may further have a substituent in addition to R B each independently represents a monovalent aliphatic hydrocarbon, a (1+c)-valent aromatic group, or a (1+c)-valent heteroaromatic group; R C each independently represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, m represents an integer of 0 to 2, a represents an integer of 0 to 5, and c represents an integer of 0 to 5; If a and c are both 0, R B is a monovalent aliphatic hydrocarbon group, R A , R B and R CAt least one aliphatic hydrocarbon group has 12 or more carbon atoms.

[0009] <2> the step of using the aromatic heterocyclic compound represented by formula (1) is a C-terminal protection step of protecting a carboxy group or an amide group of an amino acid compound or a peptide compound with the aromatic heterocyclic compound represented by formula (1); <1> A method for producing the peptide compound described in <3> The amino acid compound or peptide compound in the C-terminal protection step is an N-terminal protected amino acid compound or an N-terminal protected peptide compound. <2> A method for producing the peptide compound described in <4> an N-terminal deprotection step of deprotecting the N-terminus of the N-terminal protected amino acid compound or the N-terminal protected peptide compound obtained in the C-terminal protection step; and a peptide chain elongation step in which an N-terminal protected amino acid compound or an N-terminal protected peptide compound is condensed to the N-terminus of the C-terminal protected amino acid compound or C-terminal protected peptide compound obtained in the N-terminal deprotection step; Further comprising: <3> A method for producing the peptide compound described in <5> The method further comprises a precipitation step of precipitating the N-terminal protected and C-terminal protected peptide compound obtained in the peptide chain elongation step. <4> A method for producing the peptide compound described in <6> After the precipitation step, deprotecting the N-terminus of the obtained N-terminally protected and C-terminally protected peptide compound; a step of condensing an N-terminal protected amino acid compound or an N-terminal protected peptide compound to the N-terminus of the obtained C-terminal protected peptide compound; and a step of precipitating the obtained N-terminally protected C-terminally protected peptide compound. and also contains, in that order, one or more times, <5> A method for producing the peptide compound described in <7> Further comprising a C-terminal deprotection step of deprotecting the C-terminal protecting group. <1> ~ <6> 1. A method for producing a peptide compound according to any one of the preceding claims. <8> the ring A is a pyrrole ring, an indole ring, a carbazole ring, a pyrazole ring, an indazole ring, a furan ring, a thiophene ring, a benzofuran ring, or a benzothiophene ring; <1> ~ <7> 1. A method for producing a peptide compound according to any one of the preceding claims. <9> The ring A is represented by any one of the following formulas (10), (20), and (30): <1> ~ <8> 1. A method for producing a peptide compound according to any one of the preceding claims.

[0010] [ka]

[0011] In formula (10), R r10 ~R r14 Either of the Y in formula (1) A R r10 is a substituent, or R A represents R r11 ~R r14 are each independently a hydrogen atom, a substituent, or R A where R r10 ~R r14 At least one of A 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 r11 and R r12 , or R r13 and R r14 may each independently be linked to each other to form a ring. In formula (20), R r20 ~R r23 Either of the Y in formula (1) A R r20 is a substituent, or R A represents R r21 ~R r23 are each independently a hydrogen atom, a substituent, or R A where Rr20 ~R r23 At least one of A 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 r22 and R r23 may be linked to each other to form a ring. In formula (30), R r31 ~R r34 Either of the Y in formula (1) A and X is linked to a group containing a carbon atom having the formula 30 represents an oxygen atom or a sulfur atom, and R r31 ~R r34 are each independently a hydrogen atom, a substituent, or R A where R r31 ~R r34 At least one of A 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 r31 and R r32 , or R r33 and R r34 may each independently be linked to each other to form a ring.

[0012] <10> At least one of the above R A At least one aliphatic hydrocarbon group has 14 or more carbon atoms, <1> ~ <9> 1. A method for producing a peptide compound according to any one of the preceding claims. <11> The ring A represented by the formula (10) is represented by the formula (11), the compound represented by the formula (20) is represented by the formula (21), and the compound represented by the formula (30) is represented by the formula (31). <9> A method for producing the peptide compound described in

[0013] [ka] In formula (11), R r15 ~R r18 Either of the Y in formula (1) A R r15 ~R r18 each independently represents a hydrogen atom or a substituent, R A is 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 14 or more carbon atoms, and R r15 and R r16 , or R r17 and R r18 may each independently be linked to each other to form a ring. In formula (21), R r24 ~R r26 Either of the Y in formula (1) A R r24 ~R r26 each independently represents a hydrogen atom or a substituent, R A is 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 14 or more carbon atoms, and R r25 and R r26 may be linked to each other to form a ring. In equation (31), the wavy line represents Y in equation (1). A represents the position at which the carbon atom having the formula r31 represents an oxygen atom or a sulfur atom, and R r35 ~R r37 are each independently a hydrogen atom, a substituent, or R A represents 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 14 or more carbon atoms, provided that R r35 ~R r37 At least one of A and R r36and R r37 may be linked to each other to form a ring.

[0014] <12> All R A the total number of carbon atoms in all aliphatic hydrocarbon groups is 40 or more; <1> ~ <11> 1. A method for producing a peptide compound according to any one of the preceding claims. <13> Above R A is a group represented by the following formula (f1) or a group represented by the following formula (a1): <1> ~ <12> 1. A method for producing a peptide compound according to any one of the preceding claims.

[0015] [ka]

[0016] In formula (f1), the wavy line represents the bonding position to the aromatic heterocycle, 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, R 10 At least one of the groups is a monovalent aliphatic hydrocarbon group having 5 or more carbon atoms.

[0017] [ka]

[0018] In formula (a1), the wavy line represents the bonding position to the aromatic heterocycle, m20 represents an integer of 1 to 10, and X 20each independently represents a single bond, -O-, -S-, -COO-, -OCO-, -OCONH-, -NHCONH-, -NHCO-, or -CONH-; R 20 At least one of the groups is a divalent aliphatic hydrocarbon group having 5 or more carbon atoms.

[0019] <14> The group represented by the formula (f1) is a group represented by the following formula (f2): <13> A method for producing the peptide compound described in

[0020] [ka]

[0021] In formula (f2), the wavy line represents the bonding position to the aromatic heterocycle, 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.

[0022] <15> An aromatic heterocyclic compound represented by the following formula (1): Reagent for forming protecting groups.

[0023] [ka]

[0024] In formula (1), Ring A represents an aromatic heterocycle; Y A is -OH, -NHR, SH, or -X 0 R represents a hydrogen atom, an alkyl group, an aromatic group-substituted alkyl group, a heteroaromatic group-substituted alkyl group, or a 9-fluorenylmethoxycarbonyl group; and X 0 represents Cl, Br or I, R Aeach independently represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and ring A is R A may further have a substituent in addition to R B each independently represents a monovalent aliphatic hydrocarbon, a (1+c)-valent aromatic group, or a (1+c)-valent heteroaromatic group; R C each independently represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, m represents an integer of 0 to 2, a represents an integer of 0 to 5, and c represents an integer of 0 to 5; If a and c are both 0, R B is a monovalent aliphatic hydrocarbon group, R A , R B and R C At least one aliphatic hydrocarbon group has 12 or more carbon atoms.

[0025] <16> the protecting group-forming reagent is a protecting group-forming reagent for a carboxy group or an amide group; <15> The protecting group forming reagent according to claim 1. <17> the reagent for forming a protecting group is a reagent for forming a C-terminal protecting group of an amino acid compound or a peptide compound; <15> or <16> The protecting group forming reagent according to claim 1. <18> An aromatic heterocyclic compound represented by the following formula (1a):

[0026] [ka]

[0027] In formula (1a), Ring A represents an aromatic heterocycle; Y A is -OH, -NHR, SH, or -X 0 R represents a hydrogen atom, an alkyl group, an aromatic group-substituted alkyl group, a heteroaromatic group-substituted alkyl group, or a 9-fluorenylmethoxycarbonyl group; and X 0 represents Cl, Br or I, R Aeach independently represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and ring A is R A may further have a substituent in addition to R B each independently represents a monovalent aliphatic hydrocarbon, a (1+c)-valent aromatic group, or a (1+c)-valent heteroaromatic group; R C each independently represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, m represents an integer of 0 to 2, a represents an integer of 0 to 5, and c represents an integer of 0 to 5; If a and c are both 0, R B is a monovalent aliphatic hydrocarbon group, R A , R B and R C at least one aliphatic hydrocarbon group in at least one of the above has 12 or more carbon atoms; All R A , R B and R C The total number of carbon atoms in all the aliphatic hydrocarbon groups contained in the alkyl group is 40 or more.

[0028] <19> Ring A is represented by any one of the following formulas (10a), (20a), and (30a): <18> 1. The aromatic heterocyclic compound according to claim 1.

[0029] [ka]

[0030] In formula (10a), R r10 ~R r14 Either of the Y in formula (1a) A R r10 is a substituent, or R A represents R r10 ~R r14 are each independently a hydrogen atom, a substituent, or R A where R r11 ~R r14 At least one of Aand 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 14 or more carbon atoms, and R r11 and R r12 , or R r13 and R r14 may each independently be linked to each other to form a ring. In formula (20a), R r20 ~R r23 Either of the Y in formula (1a) A R r20 is a substituent, or R A represents R r21 ~R r23 are each independently a hydrogen atom, a substituent, or R A where R r20 ~R r23 At least one of A and R A are each independently an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and all R A Each aliphatic hydrocarbon group in R has 14 or more carbon atoms, r22 and R r23 may be linked to each other to form a ring. In formula (30a), R r31 ~R r34 Either of the Y in formula (1a) A and X is linked to a group containing a carbon atom having the formula r30 represents an oxygen atom or a sulfur atom, and R r31 ~R r34 are each independently a hydrogen atom, a substituent, or R A where R r31 ~R r34 At least one of A 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 14 or more carbon atoms, and R r31and R r32 , or R r33 and R r34 may each independently be linked to each other to form a ring.

[0031] <20> The above formula (10a) is represented by formula (11a), the above formula (20) is represented by formula (21a), and the above formula (30a) is represented by formula (31a). <18> or <19> 1. The aromatic heterocyclic compound according to claim 1.

[0032] [ka]

[0033] In formula (11a), R r15 ~R r18 Either of the Y in formula (1a) A R r15 ~R r18 each independently represents a hydrogen atom or a substituent, R A is 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 14 or more carbon atoms, and R r15 and R r16 , or R r17 and R r18 may each independently be linked to each other to form a ring. In formula (21a), R r24 ~R r26 Either of the Y in formula (1a) A R r24 ~R r26 each independently represents a hydrogen atom or a substituent, R A is 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 14 or more carbon atoms, and R r25 and R r26 may be linked to each other to form a ring. In formula (31a), the wavy line represents Y in formula (1).A represents the position at which the carbon atom having the formula r31 represents an oxygen atom or a sulfur atom, and R r35 ~R r37 are each independently a hydrogen atom, a substituent, or R A represents 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 14 or more carbon atoms, provided that R r35 ~R r37 At least one of A and R r36 may be linked to each other to form a ring.

[0034] <21> All R A , R B and R C the total number of carbon atoms in all aliphatic hydrocarbon groups is 40 to 80, <18> ~ <20> 1. The aromatic heterocyclic compound according to any one of the above items. <22> Above R A is a group represented by the following formula (f1) or a group represented by the following formula (a1): <18> ~ <21> 1. The aromatic heterocyclic compound according to any one of the above items.

[0035] [ka]

[0036] In formula (f1), the wavy line represents the bonding position to the aromatic heterocycle, 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 10each independently represents a single bond, -O-, -S-, -COO-, -OCO-, -OCONH-, -NHCONH-, -NHCO-, or -CONH-; R 10 each independently represents a monovalent aliphatic hydrocarbon group, R 10 At least one of the groups is a monovalent aliphatic hydrocarbon group having 5 or more carbon atoms.

[0037] [ka]

[0038] In formula (a1), the wavy line represents the bonding position to the aromatic heterocycle, 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 At least one of the groups is a divalent aliphatic hydrocarbon group having 5 or more carbon atoms.

[0039] <23> The group represented by the formula (f1) is a group represented by the following formula (f2): <22> 1. The aromatic heterocyclic compound according to claim 1.

[0040] [ka]

[0041] In formula (f2), the wavy line represents the bonding position to the aromatic heterocycle, 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. [Effects of the Invention]

[0042] According to one embodiment of the present invention, a method for producing a peptide compound that is excellent in deprotection rate can be provided. According to another embodiment of the present invention, a protecting group forming reagent having an excellent deprotection rate can be provided. According to yet another embodiment of the present invention, a novel aromatic heterocyclic compound can be provided. DETAILED DESCRIPTION OF THE INVENTION

[0043] 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, when a notation does not specify whether the group is substituted or unsubstituted, it encompasses both unsubstituted and substituted groups. For example, the term "alkyl group" encompasses not only alkyl groups without a substituent (unsubstituted alkyl groups) but also alkyl groups with a substituent (substituted alkyl groups). 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. In this specification, the terms "aromatic group" and "aryl group" have the same meaning, and the terms "heteroaromatic group" and "heteroaryl group" have the same meaning, i.e., the terms "aromatic group-substituted alkyl group" and "aryl group-substituted alkyl group" have the same meaning, and the terms "heteroaromatic group-substituted alkyl group" and "heteroaryl group-substituted alkyl group" have the same meaning.

[0044] (Method for producing peptide compounds) The method for producing a peptide compound according to the present disclosure includes a step of using an aromatic heterocyclic compound represented by the following formula (1) (hereinafter also referred to as a compound represented by formula (1)).

[0045] [ka]

[0046] In formula (1), Ring A represents an aromatic heterocycle; Y A is -OH, -NHR, SH, or -X 0 R represents a hydrogen atom, an alkyl group, an aromatic group-substituted alkyl group, a heteroaromatic group-substituted alkyl group, or a 9-fluorenylmethoxycarbonyl group (hereinafter also referred to as an Fmoc group); X 0 represents Cl, Br or I, R A each independently represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and ring A is R A may further have a substituent in addition to R B each independently represents a monovalent aliphatic hydrocarbon, a (1+c)-valent aromatic group, or a (1+c)-valent heteroaromatic group; R C each independently represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, m represents an integer of 0 to 2, a represents an integer of 0 to 5, and c represents an integer of 0 to 5; If a and c are both 0, R B is a monovalent aliphatic hydrocarbon group, R A , R B and RC At least one aliphatic hydrocarbon group has 12 or more carbon atoms.

[0047] The detailed mechanism by which the method for producing a peptide compound according to the present disclosure, which includes a step using the compound represented by formula (1), can provide a peptide compound in excellent yield is not clear, but is presumed to be as follows. The compound represented by formula (1) according to the present disclosure has a faster deprotection rate than conventional benzyl alcohol-type protecting group-forming reagents, and is therefore presumed to have a superior yield of the resulting peptide compound, etc. The reason for the superior deprotection rate is believed to be that the aromatic heterocycle has better electron donating properties than benzyl alcohol. In this specification, a faster deprotection rate is referred to as an excellent deprotection rate. Furthermore, when the compound represented by formula (1) is used as a C-terminal protecting group of a peptide, the deprotection rate is superior to that when conventional benzyl alcohol-type protecting group-forming reagents are used. For example, it is possible to selectively deprotect only the C-terminal protecting group while leaving the amino acid side chain protecting groups intact, i.e., to separate the side chain protecting groups of each amino acid. The deprotected C-terminus can also be used in subsequent reactions, such as condensation reactions with long-chain peptide fragments. Furthermore, in the case of peptides that are unstable in strong acids, decomposition of the peptide chain can be suppressed, leading to improved yields. Furthermore, the excellent deprotection rate in acid makes it suitable for the synthesis of acid-labile peptides. The compound represented by formula (1) is R A , R B and R C Since the number of carbon atoms in at least one aliphatic hydrocarbon group in at least one of R is 12 or more, the compound protected by the compound represented by formula (1) has excellent solubility in hydrophobic solvents. A , R B and R CThe aliphatic hydrocarbon groups in the compound represented by formula (1) aggregate intramolecularly and intermolecularly, and the compound represented by formula (1) contains 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 with the compound represented by formula (1) has excellent solubility in hydrophobic solvents, which are reaction solvents, and therefore the reaction proceeds rapidly. Furthermore, 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 compound (e.g., peptide compound). The above effects are A , R B and R C The carbon number of at least one aliphatic hydrocarbon group in the formula (1) is preferably 14 or more, and thus a more excellent effect is exhibited. A , R B and R C It is estimated that an increase in the number of carbon atoms in either of the above groups increases the contribution of hydrophobicity to the entire molecule represented by formula (1), making it easier to dissolve in hydrophobic solvents, and that an increase in the number of carbon atoms in hydrophilic solvents increases the cohesive force, making it easier to crystallize. Furthermore, the aromatic heterocyclic compound represented by formula (1) according to the present disclosure has the above structure, and therefore is stable during the peptide synthesis reaction but is easy to deprotect (remove). Furthermore, by using the aromatic heterocyclic compound represented by formula (1) according to the present disclosure, even difficult-to-synthesize peptides, such as unnatural peptides containing unnatural amino acids that are prone to side reactions, can be synthesized with high purity while suppressing side reactions. In the present disclosure, the C-terminal protecting group can be deprotected even under weak acid conditions, and side reactions of the resulting peptide can be suppressed. Examples of peptides suitable for deprotection of the C-terminal protecting group under weak acid conditions (ie, acid-labile peptides) include peptides having an N-alkylamide structure. From the viewpoint of suppressing side reactions of the resulting peptide and of stability over time, the method for producing a peptide compound according to the present disclosure is preferably a method for producing an acid-labile peptide compound, and more preferably a method for producing a peptide compound having an N-alkylamide structure.

[0048] The aromatic heterocyclic compound represented by the above formula (1) used in the method for producing a peptide compound according to the present disclosure will be described in detail below. In the method for producing a peptide compound according to the present disclosure, the aromatic heterocyclic compound represented by formula (1) can be used not only for forming a protecting group but also for modifying the peptide compound, adjusting the solubility in water or an organic solvent, improving crystallization, polymerizing, etc. Among these, the aromatic heterocyclic compound represented by formula (1) is preferably used to form a protecting group, and more preferably used to form a C-terminal protecting group in an amino acid compound or a peptide compound.

[0049] <Aromatic heterocyclic compound represented by formula (1)> The aromatic heterocyclic compound represented by formula (1) according to the present disclosure is shown below.

[0050] [ka]

[0051] In formula (1), rings A and Y A , R A , R B , R C , m, a and c have the same meanings as above.

[0052] In formula (1), ring A represents an aromatic heterocycle, and ring A is preferably Y A and R B a methylene group linked to R A In addition, the group may further have a substituent. Aromatic heterocyclic compounds are suitable for Y from the viewpoints of deprotection speed, crystallization property, and yield. AIn addition, it is preferably an aromatic heterocyclic compound having no SH group, amino group, OH group, or COOH group. Ring A may be either a monocyclic or polycyclic heterocycle. When ring A is a polycycle, it is preferably a fused polycyclic aromatic heterocycle having two or more rings formed by condensing aromatic heterocycles, 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.

[0053] Furthermore, ring A 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, more preferably having at least one heteroatom selected from a nitrogen atom and a sulfur atom, further preferably containing a nitrogen atom or a sulfur atom, and particularly preferably containing a nitrogen atom.

[0054] In terms of deprotection rate, crystallization property, and yield, when the heteroatom of ring A is a nitrogen atom, the nitrogen atom preferably further has a substituent. A The same applies to the preferred embodiments.

[0055] The number of ring members in ring A is not particularly limited, but is preferably a 5- to 8-membered ring, and more preferably a 5- or 6-membered ring.

[0056] From the viewpoints of deprotection rate, crystallization property, and yield, ring A 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.

[0057] Among these, from the viewpoints of deprotection rate, crystallization property, and yield, ring A is preferably a benzothiophene ring, a furan ring, a benzofuran ring, a pyrrole ring, an indole ring, a carbazole ring, a pyrazole ring, an indazole ring, or a thiophene ring, more preferably a benzothiophene ring, a furan ring, a benzofuran ring, an indole ring, a carbazole ring, an indazole ring, or a thiophene ring, still more preferably a benzofuran ring, an indole ring, a carbazole ring, or a thiophene ring, and particularly preferably a benzofuran ring, an indole ring, or a carbazole ring. When the C-terminus of the peptide to be protected is an amide, an indole ring is preferred, and when the C-terminus of the peptide to be protected is a carboxylic acid, a benzofuran ring is preferred.

[0058] From the viewpoints of deprotection rate, crystallization property, and yield, it is preferable that the nitrogen atom at the 1-position 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. 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, 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.

[0059] [Y A 〕 Y in Equation (1) A is preferably —OH, —NHR, or —SH, more preferably —OH or —NHR, from the viewpoints of deprotection rate, solvent solubility, and yield. The alkyl group for R includes an alkyl group having 1 to 30 carbon atoms (also referred to as "number of 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, and a hexyl group, and more preferably a methyl group and an ethyl group. Examples of the aromatic group-substituted alkyl group for R include aromatic group-substituted alkyl groups having 7 to 30 carbon atoms, preferably aromatic group-substituted alkyl groups having 7 to 20 carbon atoms, and more preferably aralkyl 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). 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 more preferably a benzyl group. Examples of the heteroaromatic group-substituted alkyl group for R include heteroaromatic group-substituted alkyl groups having 5 to 30 carbon atoms, preferably heteroaromatic group-substituted alkyl groups having 5 to 20 carbon atoms, and more preferably heteroaromatic group-substituted alkyl groups having 5 to 16 carbon atoms (for example, a group in which an alkylene group having 1 to 6 carbon atoms is bonded to a heteroaromatic group having 4 to 10 carbon atoms). Preferred specific examples include an indolylmethyl group, a furfuryl group, a benzofuranylmethyl group, a thiophenylmethyl group, and a benzothiophenylmethyl group. Among these, R is preferably a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aromatic group-substituted alkyl group having 7 to 16 carbon atoms, or an Fmoc group, more preferably a hydrogen atom, a methyl group, an ethyl group, a benzyl group, or an Fmoc group, and even more preferably a hydrogen atom or an Fmoc group. When R is an Fmoc group, the Fmoc group can be deprotected with a base such as 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) described below to obtain Y. Abecomes -NH2, it can be considered that when R is an Fmoc group, it is equivalent to when R is a hydrogen atom.

[0060] In addition, the compound represented by formula (1) may have the above substituents on ring A, R B The substituents or R A As, Y A and R B a group having a ring A having a methylene group linked to Y A and R B Rings A and Y having methylene groups linked thereto A

[0039] In other words, 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.

[0061] R on ring A in formula (1) A From the viewpoints of deprotection rate, solvent solubility, and yield, a is preferably an integer of 1 to 4, more preferably an integer of 1 to 3, and particularly preferably 1 or 2.

[0062] Furthermore, R in formula (1) B R above C From the viewpoints of deprotection rate, solvent solubility, and yield, c, which is the number of substitutions, is preferably an integer of 0 to 4, more preferably an integer of 0 to 2, further preferably 0 or 1, and particularly preferably 0. Furthermore, the value of a+c in formula (1) is preferably 0 or more, and from the viewpoints of deprotection rate, solvent solubility, and yield, is more preferably an integer of 1 to 6, still more preferably an integer of 1 to 4, particularly preferably 1 to 3, and most preferably 1.

[0063] [R A and R C 〕 R Aeach independently represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group. Also, R C each independently represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group. The "aliphatic hydrocarbon group" refers to a linear, branched, or cyclic saturated or unsaturated aliphatic hydrocarbon group, preferably an aliphatic hydrocarbon group having 5 or more carbon atoms, more preferably an aliphatic hydrocarbon group having 5 to 60 carbon atoms, still more preferably an aliphatic hydrocarbon group having 5 to 30 carbon atoms, and particularly preferably an aliphatic hydrocarbon group having 10 to 30 carbon atoms. 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 location of the "aliphatic hydrocarbon group" in the "organic group having an aliphatic hydrocarbon group" is not particularly limited, and may be present at the terminal (monovalent group) or at another location (for example, divalent group). In this specification, the term "organic group having an aliphatic hydrocarbon group" refers to a monovalent organic group (having one bond to ring A) that has an aliphatic hydrocarbon group in its molecular structure. The location of the "aliphatic hydrocarbon group" in the "organic group having an aliphatic hydrocarbon group" is not particularly limited, and may be present at the terminal (monovalent group) or at another location (for example, divalent group). Examples of the "aliphatic hydrocarbon group" include an alkyl group, a cycloalkyl group, an alkenyl group, and an alkynyl group. 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. The "alkyl group" is preferably an alkyl group having 5 to 30 carbon atoms, and examples thereof include pentyl, hexyl, octyl, 2-ethylhexyl, decyl, hexadecyl, octadecyl, icosyl, docosyl, tetracosyl, lauryl, tridecyl, myristyl, and isostearyl groups. Of these, octadecyl, icosyl, docosyl, and tetracosyl groups are preferred, and icosyl, docosyl, and tetracosyl groups are more preferred. The "cycloalkyl group" is preferably a cycloalkyl group having 5 to 30 carbon atoms, and examples thereof include 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 an alkenyl group having 5 to 30 carbon atoms, and examples thereof include a pentenyl group, a hexenyl group, and an oleyl group. The "alkynyl group" is preferably an alkynyl group having 5 to 30 carbon atoms, and examples thereof include a 4-pentynyl group and a 5-hexenyl group. As the "steroid group", for example, a group having a cholesterol structure or a group having an estradiol structure is 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.

[0064] 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.

[0065] Preferred examples of the hydrocarbon group having a silyloxy structure include groups represented by the following formula (Si):

[0066] [ka]

[0067] 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.

[0068] 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.

[0069] 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.

[0070] [ka]

[0071] 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. The "aryl group" is preferably an aryl group having 6 to 14 carbon atoms, such as a phenyl group, a 1-naphthyl group, a 2-naphthyl group, a biphenylyl group, a 2-anthryl group, etc. Among these, an aryl group having 6 to 10 carbon atoms is more preferred, and a phenyl group is particularly preferred. Furthermore, the aliphatic hydrocarbon groups and hydrocarbon groups other than the aliphatic hydrocarbon groups may be substituted with a substituent selected from a halogen atom (a chlorine atom, a bromine atom, a fluorine atom, an iodine atom), an oxo group, and the like.

[0072] Above R A In the formula, the bond (substitution) of the organic group having an aliphatic hydrocarbon group to ring A is A The bond may be via an aliphatic hydrocarbon group present in the above-mentioned R AThe bond may be formed via a moiety such as -O-, -S-, -COO-, -OCONH-, or -CONH- present in the alkyl group. From the viewpoint of ease of compound synthesis, the bond is preferably a carbon-carbon bond, a carbon-nitrogen bond, or a bond via -O-, -S-, -COO-, or -CONH-, and more preferably a carbon-carbon bond, a carbon-nitrogen bond, or a bond via -O-. When ring A is a ring containing an oxygen atom or a sulfur atom, the organic group containing an aliphatic hydrocarbon group is preferably bonded (substituted) to ring A via —O—. When ring A is a ring having a nitrogen atom, the bond (substitution) of the organic group having an aliphatic hydrocarbon group to ring A is preferably a direct carbon-nitrogen bond.

[0073] In the compound represented by formula (1) according to the present disclosure, all R A , R B and R C 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, particularly preferably 34 to 80, and most preferably 36 to 80. In addition, in the compound represented by formula (1) according to the present disclosure, 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, particularly preferably 34 to 80, and most preferably 36 to 80. In addition, the compound represented by formula (1) according to the present disclosure is R A , R B and R C In view of solvent solubility, crystallization property, and yield, at least one R A or R Cand a compound having at least one aliphatic hydrocarbon group having 12 or more carbon atoms, A In the above, it is more preferable that the compound has at least one aliphatic hydrocarbon group having 12 to 100 carbon atoms, even more preferable that the compound has at least one aliphatic hydrocarbon group having 18 to 40 carbon atoms, and particularly preferable that the compound has at least one aliphatic hydrocarbon group having 20 to 36 carbon atoms. The compound represented by formula (1) according to the present disclosure is R A , R B and R C A more excellent effect is exhibited when the number of carbon atoms in at least one aliphatic hydrocarbon group is preferably 14 or more, more preferably 16 or more, even more preferably 18 or more, and particularly preferably 20 or more. 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 increases in hydrophilic solvents, 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. Also, one R A , R B , or R C are each independently preferably 12 to 200, more preferably 18 to 150, further preferably 18 to 100, and particularly preferably 20 to 80, from the viewpoints of solvent solubility, crystallization property, and yield.

[0074] In the compound represented by formula (1) according to the present disclosure, R A , R B , or R C 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 32 to 200, even more preferably 38 to 100, and particularly preferably 40 to 80.

[0075] Furthermore, the aliphatic hydrocarbon group having 12 or more carbon atoms contained in the compound represented by formula (1) according to the present disclosure is R A , R B and R C In terms of solvent solubility, crystallization property, and yield, A and R C and R A It is more preferable that it is included in at least one of the above.

[0076] In formula (1), m represents an integer of 0 to 2. From the viewpoints of yield and compound stability of the peptide condensate, m is preferably 0 or 1. Furthermore, from the viewpoint of deprotection rate, m in formula (1) is preferably 1 or 2. Also, Y in formula (1) A When R is —NHR and R is a hydrogen atom, m in formula (1) is preferably 1 or 2, and more preferably 1, from the viewpoint of the deprotection rate. Also, Y in formula (1) A When m is —NHR and R is a substituent other than a hydrogen atom, m in formula (1) is preferably 0 or 1, and more preferably 0, from the viewpoint of the deprotection rate. Also, Y in formula (1) A When is —OH, m in formula (1) is preferably 0 or 1, more preferably 0, from the viewpoint of the deprotection rate.

[0077] [R B 〕 R in Equation (1) B are each independently, from the viewpoints of solvent solubility, crystallization property, and yield, preferably a monovalent aliphatic hydrocarbon group or a (1+c)-valent aromatic group, more preferably a monovalent alkyl group having 1 to 30 carbon atoms or a (1+c)-valent aromatic group having 6 to 30 carbon atoms, even more preferably a monovalent alkyl group having 1 to 26 carbon atoms or a (1+c)-valent aromatic group having 6 to 20 carbon atoms, and particularly preferably a monovalent alkyl group having 1 to 22 carbon atoms or a (1+c)-valent aromatic group having 6 to 10 carbon atoms. R B The monovalent alkyl group, (1+c)-valent aromatic group, and (1+c)-valent heteroaromatic group in the above formula may have a substituent. The substituent is not particularly limited, but may be 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.

[0078] R B Examples of the monovalent aliphatic hydrocarbon group in the formula (I) include a methyl group, a trifluoromethyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, a hexyl group, an octyl group, a 2-ethylhexyl group, a decyl group, a hexadecyl group, an octadecyl group, an icosyl group, a docosyl group, a tetracosyl group, a lauryl group, a tridecyl group, a myristyl group, and an isostearyl group. R B Examples of the (1+c)-valent aromatic group in the formula (I) include a phenyl group, a fluorophenyl group, a difluorophenyl group, a chlorophenyl group, a dichlorophenyl group, a trichlorophenyl group, a methylphenyl group (tolyl group), a dimethylphenyl group (xylyl group), a methoxyphenyl group, a dimethoxyphenyl group, a trimethoxyphenyl group, a phenylene group, a benzenetriyl group, a 1-naphthyl group, a 2-naphthyl group, a naphthylene group, and a naphthalenetriyl group. Among them, m=1 or 2 and Y AWhen is -OH, from the viewpoint of compound stability of the peptide condensate, it is preferably a phenyl group, a fluorophenyl group, a difluorophenyl group, a chlorophenyl group, a dichlorophenyl group, or a trichlorophenyl group, and more preferably a fluorophenyl group, a difluorophenyl group, a chlorophenyl group, a dichlorophenyl group, or a trichlorophenyl group. m=1 and Y A When is -NHR, from the viewpoint of the deprotection rate, a phenyl group, a methylphenyl group (tolyl group), a dimethylphenyl group (xylyl group), a methoxyphenyl group, a dimethoxyphenyl group, or a trimethoxyphenyl group is preferred, and a methylphenyl group (tolyl group), a dimethylphenyl group (xylyl group), a methoxyphenyl group, a dimethoxyphenyl group, or a trimethoxyphenyl group is more preferred. m=2 and Y A When is -NHR, from the viewpoint of compound stability of the peptide condensate, it is preferably a phenyl group, a fluorophenyl group, a difluorophenyl group, a chlorophenyl group, a dichlorophenyl group, or a trichlorophenyl group, and more preferably a fluorophenyl group, a difluorophenyl group, a chlorophenyl group, a dichlorophenyl group, or a trichlorophenyl group. R B Examples of the (1+c)-valent heteroaromatic group in the formula (1) include a (1+c)-valent monocyclic nitrogen-containing heteroaromatic group, a monocyclic oxygen-containing heteroaromatic group, a monocyclic sulfur-containing heteroaromatic group, a monocyclic nitrogen-containing oxygen-containing heteroaromatic group, a monocyclic nitrogen-containing sulfur-containing heteroaromatic group, a bicyclic nitrogen-containing heteroaromatic group, a bicyclic oxygen-containing heteroaromatic group, a bicyclic sulfur-containing heteroaromatic group, a bicyclic nitrogen-containing oxygen-containing heteroaromatic group, or a bicyclic nitrogen-containing sulfur-containing heteroaromatic group. Specific examples include a pyridyl group, a furanyl group, a thienyl group, a pyrrolyl group, an oxazolyl group, an imidazolyl group, a pyrazolyl group, a triazolyl group, a tetrazolyl group, a pyridinediyl group, a pyridinetriyl group, a furandiyl group, a thiophenediyl group, a pyrrolediyl group, a benzofurandiyl group, a benzothiophenediyl group, and an indolediyl group.

[0079] In formula (1), at least one R Aor R C is preferably a group represented by any one of the following formulas (f1), (a1), (b1) and (e1), more preferably a group represented by any one of the following formulas (f1) and (a1), and particularly preferably a group represented by the following formula (f1):

[0080] [ka]

[0081] 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, R 10 At least one of the groups is a monovalent aliphatic hydrocarbon group having 5 or more carbon atoms.

[0082] [ka]

[0083] 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 At least one of the groups is a divalent aliphatic hydrocarbon group having 5 or more carbon atoms.

[0084] [ka]

[0085] 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.

[0086] [ka]

[0087] 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.

[0088] 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) 9are 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.

[0089] 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.

[0090] [ka]

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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) b3is 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. b3 is preferably a straight chain alkyl group.

[0095] Furthermore, from the viewpoint of solvent solubility, the compound represented by formula (1) according to the present disclosure is 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.

[0096] [ka]

[0097] The substituent that the compound 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 the compound represented by formula (1) is a polymer, preferred examples of the substituent that may be present on ring A include a group represented by the following formula (M).

[0098] [ka]

[0099] In formula (M), rings A, Y A , X 0 , R A , R B , R C , m, a, and c represent rings A and Y in formula (1). A , X 0 , R A , R B , R C , m, a, and c have the same meanings, and the preferred embodiments are also the same. Furthermore, when the compound represented by formula (1) has a group represented by formula (M) as a substituent, it is preferable that the compound represented by formula (1) is a compound represented by formula (20) described below.

[0100] From the viewpoints of deprotection rate, crystallization property, solvent solubility, and yield, ring A in the above formula (1) is preferably a structure represented by any one of the following formulas (10), (20), and (30), more preferably a structure represented by formula (10) or formula (20), and further preferably a structure represented by formula (10).

[0101] [ka]

[0102] In formula (10), R r10 ~R r14 Either of the Y in formula (1) A A group containing a carbon atom having the formula (preferably Y A (carbon atom connected to R) r10 is a substituent, or R A represents R r11 ~R r14 are each independently a hydrogen atom, a substituent, or R A where R r10 ~R r14 At least one of A and R A are each independently an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and at least one R AAt least one aliphatic hydrocarbon group has 12 or more carbon atoms, and R r11 and R r12 , or R r13 and R r14 may each independently be linked to each other to form a ring, or may be linked to each other via a substituent to form a ring.

[0103] In formula (20), R r20 ~R r23 Either of the Y in formula (1) A A group containing a carbon atom having the formula (preferably Y A (carbon atom connected to R) r20 is a substituent, or R A represents R r21 ~R r23 are each independently a hydrogen atom, a substituent, or R A where R r20 ~R r23 At least one of A 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 r22 and R r23 may be linked to each other to form a ring, or may be linked to each other via a substituent to form a ring.

[0104] In formula (30), R r31 ~R r34 Either of the Y in formula (1) A A group containing a carbon atom having the formula (preferably Y A (carbon atom connected to X) 30 represents an oxygen atom or a sulfur atom, and R r31 ~R r34 are each independently a hydrogen atom, a substituent, or R A where R r31 ~R r34 At least one of A and R Aare 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 r31 and R r32 , or R r33 and R r34 may each independently be linked to each other to form a ring, or may be linked to each other via a substituent to form a ring.

[0105] The above formula (10) is preferably a structure represented by formula (11). The formula (20) is preferably a structure represented by formula (21). The formula (30) is preferably a structure represented by formula (31).

[0106] [ka]

[0107] In formula (11), R r15 ~R r18 Either of the Y in formula (1) A A group containing a carbon atom having the formula (preferably Y A (carbon atom connected to R) r15 ~R r18 each independently represents a hydrogen atom or a substituent, R A is 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 14 or more carbon atoms, and R r15 and R r16 , or R r17 and R r18 may each independently be linked to each other to form a ring, or may be linked to each other via a substituent to form a ring.

[0108] From the viewpoint of crystallization property and yield, R r15 and R r16 , or R r17 and R r18are preferably each independently linked to each other to form a ring. r15 and R r16 , or R r17 and R r18 are linked together to form a ring, formula (11) has an indole ring, and R r15 and R r16 , and R r17 and R r18 When these are linked to each other to form a ring, formula (11) has a carbazole ring.

[0109] In formula (21), R r24 ~R r26 Either of the Y in formula (1) A A group containing a carbon atom having the formula (preferably Y A (carbon atom connected to R) r24 ~R r26 each independently represents a hydrogen atom or a substituent, R A is 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 14 or more carbon atoms (preferably 16 or more carbon atoms), and R r25 and R r26 may be linked to each other to form a ring, or may be linked to each other via a substituent to form a ring. In formula (21), R r25 and R r26 are linked to each other to form a ring, the formula (21) has an indazole ring.

[0110] In equation (31), the wavy line represents Y in equation (1). A A group containing a carbon atom having the formula (preferably Y A represents the position of the bond to the carbon atom bonded to X r31 represents an oxygen atom or a sulfur atom, and R r35 ~R r37 are each independently a hydrogen atom, a substituent, or R A represents R A are each independently an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and at least one RA At least one aliphatic hydrocarbon group has 14 or more carbon atoms (preferably 16 or more carbon atoms), provided that R r35 ~R r37 At least one of A and R r36 and R r37 may be linked to each other to form a ring, or may be linked to each other via a substituent to form a ring. In formula (31), R r36 and R r37 are linked together to form a ring, and X r31 is a sulfur atom, formula (31) has a benzothiophene ring, In formula (31), R r36 and R r37 are linked together to form a ring, and X r31 When is an oxygen atom, formula (31) has a benzofuran ring. From the viewpoint of yield, in formula (31), R r36 and R r37 are preferably not linked to each other via a substituent to form a ring.

[0111] R in formula (10), formula (20), formula (30), formula (11), formula (21), or formula (31) A are R in Eq. (1), respectively. A The same applies to the preferred embodiments.

[0112] The substituents in formula (10), formula (20), formula (30), formula (11), formula (21), or formula (31) each independently represent a bond, 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 is 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 a bond, an alkoxy group, or an alkyl group.

[0113] R in formula (10), formula (20), formula (30), formula (11), formula (21), or formula (31) A is preferably a group represented by any one of the above formula (f1), formula (a1), formula (b1) or formula (e1), more preferably a group represented by any one of the above formula (f1) or formula (a1), further preferably a group represented by the above formula (f1), and particularly preferably a group represented by the above formula (f2).

[0114] From the viewpoints of solvent solubility, crystallization property, and yield, ring A in formula (1) is preferably a structure represented by formula (11) or formula (31), and more preferably a structure represented by formula (11). From the viewpoints of solvent solubility, crystallization property, and yield, the structure represented by formula (11) is preferably a carbazole ring or an indole ring, and the compound represented by formula (10) is more preferably a compound represented by any one of the following formulae (111) to (114).

[0115] [ka]

[0116] In formulas (111) to (114), R A represents an aliphatic hydrocarbon group having 12 or more carbon atoms or an organic group having an aliphatic hydrocarbon group having 12 or more carbon atoms, Y B is -OH, -NHR, -SH, or -X 0 R represents a hydrogen atom, an alkyl group, an aromatic group-substituted alkyl group, a heteroaromatic group-substituted alkyl group, or an Fmoc group; and X0 represents Cl, Br or I, R D represents a hydrogen atom, an alkyl group, an aryl group, or a heteroaryl group; R E represents a hydrogen atom, an alkyl group, an aryl group, or a heteroaryl group. Y in formulas (111) to (114) B , R A , R and X 0 is Y in Eq. (1) A , R A , R and X 0 The same applies to the preferred embodiments.

[0117] R in Equations (111) to (114) D From the viewpoints of deprotection rate, crystallization property, solvent solubility, and yield, is preferably a hydrogen atom, an aryl group, or a heteroaryl group, and more preferably a hydrogen atom or an aryl group. Especially R E is a hydrogen atom and Y B If -OH, R D is preferably a hydrogen atom, a phenyl group, or a phenyl group substituted with a halogen atom, and more preferably a hydrogen atom. E is a hydrogen atom and Y B If -NHR, then R D is preferably a hydrogen atom, a phenyl group, an alkoxyphenyl group, a dialkoxyphenyl group, or a trialkoxyphenyl group, and more preferably a hydrogen atom, a phenyl group, or a dialkoxyphenyl group. Also, R D The number of carbon atoms is preferably 1 to 30, more preferably 5 to 30, and particularly preferably 6 to 24.

[0118] The molecular weight of the compound represented by formula (1) is not particularly limited, but from the viewpoints of deprotection rate, 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.

[0119] Specific examples of the compound represented by formula (1) include, but are not limited to, the compounds shown below. In addition, R g represents 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.

[0120] [ka]

[0121] [ka]

[0122] [ka]

[0123] [ka]

[0124] [ka]

[0125] [ka]

[0126] <<Method for producing an aromatic heterocyclic compound represented by formula (1)>> The method for producing the aromatic heterocyclic compound 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 of the aromatic heterocyclic compound represented by formula (1) may be commercially available compounds or may be produced by known methods or methods equivalent thereto. If necessary, the produced aromatic heterocyclic compound 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.

[0127] The method for synthesizing the aromatic heterocyclic compound represented by formula (1) according to the present disclosure is not particularly limited, and the compound can be synthesized, for example, according to the following scheme 1 or scheme 2. The compound can also be synthesized by referring to the synthesis method described in WO 2010 / 113939.

[0128] [ka]

[0129] [ka]

[0130] R 100 is a hydrogen atom or OR 101 represents R 101 represents an alkyl group. X 100 represents Cl, Br, or I. R 102represents a hydrogen atom, an alkyl group, or an Fmoc group. 103 represents an alkyl group, an aromatic hydrocarbon group which may have a substituent, or an aromatic heterocyclic group which may have a substituent, n represents 1 or 2, k represents an integer of 1 to 5, and m represents 1 or 2.

[0131] <<Method for producing peptide compounds>> In the method for producing a peptide compound according to the present disclosure, the step of using the aromatic heterocyclic compound represented by formula (1) above is preferably a C-terminal protection step of protecting the carboxy group or amide group of an amino acid compound or a peptide compound with the aromatic heterocyclic compound represented by formula (1) above. Furthermore, from the viewpoints of ease of synthesis of the peptide compound and yield, the method for producing a peptide compound according to the present disclosure more preferably includes, in addition to a C-terminal protection step of protecting the carboxy group or amide group of an amino acid compound or peptide compound with an aromatic heterocyclic compound represented by formula (1) above, an N-terminal deprotection step of deprotecting the N-terminus of the N-terminally protected C-amino acid compound or N-terminally protected C-peptide compound obtained in the C-terminal protection step, and a peptide chain elongation step of condensing an N-terminally protected amino acid compound or an N-terminally protected peptide compound to the N-terminus of the C-terminally protected amino acid compound or C-terminally protected peptide compound obtained in the N-terminal deprotection step. It is even more preferable that the method further includes a precipitation step of precipitating the N-terminally protected C-peptide compound obtained in the peptide chain elongation step. It is particularly preferable that, after the precipitation step, the method further includes, once or more times, a step of deprotecting the N-terminus of the obtained N-terminally protected C-peptide compound, a step of condensing an N-terminally protected amino acid compound or an N-terminally protected peptide compound to the N-terminus of the obtained C-terminally protected peptide compound, and a step of precipitating the obtained N-terminally protected C-peptide compound, in this order. Furthermore, the method for producing a peptide compound according to the present disclosure preferably further comprises a C-terminal deprotection step of deprotecting the C-terminal protecting group. Furthermore, the method for producing a peptide compound according to the present disclosure preferably further comprises, before the C-terminal protection step, a dissolving step of dissolving the aromatic heterocyclic compound represented by formula (1) in a solvent. The following will explain each step in detail.

[0132] <<Dissolution Step>> The method for producing the peptide compound according to the present disclosure preferably includes a dissolution step of dissolving the aromatic heterocyclic compound represented by the above formula (1) in a solvent before the above C-terminal protection step. As the solvent, general organic solvents can be used in the reaction. However, since better reactivity can be expected as the solubility in the above solvent is higher, it is preferable to select a solvent with high solubility of the aromatic heterocyclic compound represented by the formula (1). Specifically, halogenated hydrocarbons such as chloroform and dichloromethane; nonpolar organic solvents such as 1,4-dioxane, tetrahydrofuran, and cyclopentyl methyl ether, etc. can be mentioned. These solvents may be used by mixing two or more of them in an appropriate ratio. Also, aromatic hydrocarbons such as benzene, toluene, and xylene; nitriles such as acetonitrile and propionitrile; ketones such as acetone and 2-butanone; amides such as N,N-dimethylformamide and N-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide can be mixed with the above halogenated hydrocarbons and nonpolar organic solvents in an appropriate ratio as long as the aromatic heterocyclic compound represented by the formula (1) can be dissolved. Also, the solvents described in Organic Process Research & Development, 2017, 21, 3, 365 - 369 may be used.

[0133] <C-terminal Protection Step> The method for producing the peptide compound according to the present disclosure includes a C-terminal protection step of protecting the carboxy group or amide group of an amino acid compound or a peptide compound with the aromatic heterocyclic compound represented by the above formula (1). The amino acid compound or peptide compound used in the above C-terminal protection step is not particularly limited, and known ones can be used. However, it is preferably an N-terminal protected amino acid compound or an N-terminal protected peptide compound, and more preferably an Fmoc protected amino acid compound or an Fmoc protected peptide compound. In addition, it is preferable that groups other than the C-terminal portion of the amino acid compound or peptide compound used in the above-mentioned C-terminal protection step, such as hydroxyl groups, amino groups, carbonyl groups, amide groups, imidazole groups, indole groups, guanidyl groups, and mercapto groups, are protected with known protecting groups such as those described below. The amount of the amino acid compound or peptide compound used as the reaction substrate is preferably 1 to 10 molar equivalents, more preferably 1 to 5 molar equivalents, even more preferably 1 to 2 molar equivalents, and particularly preferably 1 to 1.5 molar equivalents, relative to 1 molar equivalent of the aromatic heterocyclic compound represented by the above formula (1).

[0134] Y in Equation (1) A When an aromatic heterocyclic compound represented by the above formula (1) in which is —OH or —SH is used, the reaction is preferably carried out in a solvent that does not affect the reaction, in the presence of a condensation additive (condensation activator), by adding a condensation agent, or in the presence of an acid catalyst. Y in Equation (1) A When an aromatic heterocyclic compound represented by the above formula (1) in which is —NHR is used, it is preferable to add a condensing agent in the presence of a condensation additive (condensation activator) or to react the condensing agent with a base. The amount of the condensation additive used is preferably 0.05 to 1.5 molar equivalents relative to 1 molar equivalent of the aromatic heterocyclic compound represented by the above formula (1).

[0135] Condensing agents that are commonly used in peptide synthesis can be used without limitation in the present disclosure, and include, but are not limited to, for example, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorphonium chloride (DMTMM), O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), O-(6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU(6-Cl)), O-(benzotriazol-1 Examples of suitable fluorocarbons include (benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), O-(6-chlorobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TCTU), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (COMU), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), its hydrochloride (EDC·HCl), and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBop). Among these, DIC, EDC, EDC·HCl, DMT-MM, HBTU, HATU, or COMU is preferred. The amount of the condensing agent used is preferably 1 to 10 molar equivalents, and more preferably 1 to 5 molar equivalents, relative to 1 molar equivalent of the aromatic heterocyclic compound represented by the above formula (1).

[0136] As the acid catalyst used in the condensation reaction, any acid catalyst generally used in peptide synthesis can be used without limitation, and examples thereof include methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, and the like. Of these, methanesulfonic acid and p-toluenesulfonic acid are preferred. The amount of the acid catalyst used is preferably more than 0 molar equivalents and 4.0 molar equivalents, more preferably 0.05 to 1.5 molar equivalents, and even more preferably 0.1 to 0.3 molar equivalents, relative to 1 molar equivalent of the aromatic heterocyclic compound represented by the above formula (1).

[0137] In the above C-terminal protection step, it is preferable to add a condensation activator to promote the reaction or suppress side reactions such as racemization. The condensation activator in the present disclosure is a reagent that converts an amino acid into a corresponding activated ester, symmetrical acid anhydride, or the like in the presence of a condensation agent, thereby facilitating the formation of a peptide bond (amide bond). The condensation activator may be any condensation activator commonly used in peptide synthesis, without limitation, and examples thereof include 4-dimethylaminopyridine, N-methylimidazole, boronic acid derivatives, 1-hydroxybenzotriazole (HOBt), ethyl 1-hydroxytriazole-4-carboxylate (HOCt), 1-hydroxy-7-azabenzotriazole (HOAt), 3-hydroxy-1,2,3-benzotriazodin-4(3H)-one (HOOBt), N-hydroxysuccinimide (HOSu), N-hydroxyphthalimide (HOPht), N-hydroxy-5-norbornene-2,3-dicarboximide (HONb), pentafluorophenol, ethyl (hydroxyimino)cyanoacetate (Oxyma), etc. Among these, 4-dimethylaminopyridine, HOBt, HOCt, HOAt, HOOBt, HOSu, HONb, or Oxyma is preferred. The amount of the activator used is preferably more than 0 molar equivalents and 4.0 molar equivalents, and more preferably 0.1 to 1.5 molar equivalents, relative to the amino acid compound or peptide compound.

[0138] As the base, any base commonly used in peptide synthesis can be used without limitation, and examples thereof include tertiary amines such as diisopropylethylamine. As the solvent, the solvents mentioned in the above dissolution step can be preferably used. The reaction temperature is not particularly limited, but is preferably -10°C to 80°C, more preferably 0°C to 40°C. The reaction time is not particularly limited, but is preferably 1 hour to 30 hours. For the confirmation of the progress of the reaction, the same methods as those for general liquid-phase organic synthesis reactions can be applied. That is, the reaction can be traced using thin-layer silica gel chromatography, high-performance liquid chromatography, NMR, etc.

[0139] In addition, the N-terminal protected C-terminal protected amino acid compound or N-terminal protected C-terminal protected peptide compound obtained by the above C-terminal protection step may be purified. For example, in order to isolate the product obtained after dissolving the obtained N-terminal protected C-terminal protected amino acid compound or N-terminal protected C-terminal protected peptide compound in a solvent and performing a desired organic synthesis reaction, the solvent in which the N-terminal protected C-terminal protected amino acid compound or N-terminal protected C-terminal protected peptide compound is dissolved is changed (e.g., change in solvent composition, change in solvent type), and a method of reprecipitation is preferably mentioned. Specifically, for example, the reaction is carried out under conditions such that the N-terminal protected C-terminal protected amino acid compound or N-terminal protected C-terminal protected peptide compound dissolves. After the reaction, the solvent is distilled off and then the solvent is replaced, or after the reaction, without distilling off the solvent, a polar solvent is added to the reaction system to precipitate aggregates and eliminate impurities. As the replacement solvent, polar organic solvents such as methanol, acetonitrile, and water are used alone or in combination. That is, the reaction is carried out under conditions such that the N-terminal protected C-terminal protected amino acid compound or N-terminal protected C-terminal protected peptide compound dissolves. After the reaction, for solvent replacement, for example, halogenated solvents, THF, etc. are used for dissolution, and polar organic solvents such as methanol, acetonitrile, and water are used for precipitation.

[0140] <N-terminal deprotection step> The method for producing a peptide compound according to the present disclosure preferably includes an N-terminal deprotection step of deprotecting the N-terminus of the N-terminal protected amino acid compound or N-terminal protected peptide compound obtained in the above-mentioned C-terminal protection step. As the N-terminal protecting group, any of the below-described amino protecting groups commonly used in technical fields such as peptide chemistry can be used, but in the present disclosure, a tert-butoxycarbonyl group (hereinafter also referred to as a Boc group), a benzyloxycarbonyl group (hereinafter also referred to as a Cbz group or a Z group), or a 9-fluorenylmethoxycarbonyl group (hereinafter also referred to as an Fmoc group) is preferably used.

[0141] The deprotection conditions are appropriately selected depending on the type of the temporary protecting group, but a group that can be deprotected under conditions different from those for removing the protecting group derived from the aromatic heterocyclic compound represented by formula (1) is preferred. For example, in the case of an Fmoc group, the deprotection is carried out by treatment with a base, and in the case of a Boc group, the deprotection is carried out by treatment with an acid. The reaction is carried out in a solvent that does not affect the reaction.

[0142] Examples of bases include secondary amines such as dimethylamine and diethylamine, and non-nucleophilic organic bases such as 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), and 1,5-diazabicyclo[4.3.0]-5-nonene (DBN). As the solvent, the solvents exemplified in the dissolving step can be suitably used.

[0143] <Peptide chain elongation step> The method for producing a peptide compound according to the present disclosure preferably includes a peptide chain elongation step of condensing an N-terminal protected amino acid compound or an N-terminal protected peptide compound to the N-terminus of the C-terminal protected amino acid compound or C-terminal protected peptide compound obtained in the N-terminal deprotection step. The peptide chain elongation step is preferably carried out using the above-mentioned condensing agent, condensation additive, etc. under peptide synthesis conditions generally used in the field of peptide chemistry. The N-terminal protected amino acid compound or the N-terminal protected peptide compound is not particularly limited, and any desired compound can be used, but an Fmoc-protected amino acid compound or an Fmoc-protected peptide compound can be preferably used. In addition, hydroxy groups, amino groups, carbonyl groups, amide groups, imidazole groups, indole groups, guanidyl groups, mercapto groups, etc. other than the C-terminal portion in the N-terminal protected amino acid compound or the N-terminal protected peptide compound are preferably protected by known protecting groups such as the protecting groups described later.

[0144] <<Precipitation step>> The method for producing a peptide compound according to the present disclosure preferably further includes a precipitation step of precipitating the N-terminal protected C-terminal protected peptide compound obtained in the above peptide chain extension step. The above precipitation step can be carried out in the same manner as the precipitation method in purification, which may be carried out after the above C-terminal protection step described above.

[0145] <<Chain extension>> The method for producing a peptide compound according to the present disclosure preferably further includes, after the above precipitation step, a step of deprotecting the N-terminal of the obtained N-terminal protected C-terminal protected peptide compound, a step of condensing an N-terminal protected amino acid compound or an N-terminal protected peptide compound to the N-terminal of the obtained C-terminal protected peptide compound, and a step of precipitating the obtained N-terminal protected C-terminal protected peptide compound in this order one or more times. By repeating the above three steps, the chain extension of the obtained peptide compound can be easily carried out. Each step in the above three steps can be carried out in the same manner as the corresponding steps described above.

[0146] <C-terminal deprotection step> The method for producing a peptide compound according to the present disclosure preferably further includes a C-terminal deprotection step of deprotecting the C-terminal protecting group. In the C-terminal deprotection step, the C-terminal protecting group formed by the aromatic heterocyclic compound represented by formula (1) in the C-terminal protected peptide compound having the desired number of amino acid residues is removed, thereby obtaining the final target peptide compound. A preferred method for removing the C-terminal protecting group is a deprotection method using an acidic compound. Examples include a method using an acid catalyst and a method of hydrogenation using a metal catalyst. Examples of acid catalysts include trifluoroacetic acid (TFA), hydrochloric acid, trifluoroethanol (TFE), hexafluoroisopropanol (HFIP), and acetic acid. For peptides that are not decomposed by strong acids, TFA is preferred, and for peptides that are decomposed by strong acids, TFE, HFIP, or acetic acid are preferred. The concentration of the acid can be appropriately selected depending on the protecting group and deprotection conditions, and is preferably 0.01% by mass to 100% by mass, and more preferably 1% by mass to 100% by mass, based on the total mass of the solvent used. The concentration of TFA is preferably 70% by mass or less, more preferably 50% by mass or less, even more preferably 30% by mass or less, even more preferably 10% by mass or less, and particularly preferably 1% by mass or less. In the present disclosure, the C-terminal protecting group can be deprotected even under weak acid conditions, and side reactions of the resulting peptide can be suppressed. The deprotection time is preferably 5 hours or less, more preferably 3 hours or less, and even more preferably 1 hour or less.

[0147] The final target peptide compound obtained by the method for producing a peptide compound according to the present disclosure can be isolated and purified according to methods commonly used in peptide chemistry, for example, by subjecting the reaction mixture to extraction and washing, crystallization, chromatography, etc.

[0148] Although the type of peptide produced by the method for producing a peptide compound according to the present disclosure is not particularly limited, it is preferable that the number of amino acid residues of the peptide compound is, for example, not more than several tens. The peptides obtained by the method for producing a peptide compound according to the present disclosure can be used in various fields, such as medicine, food, cosmetics, electronic materials, and biosensors, just like existing or unknown synthetic peptides and natural peptides.

[0149] In the method for producing a peptide compound according to the present disclosure, the precipitation step can be omitted as appropriate to the extent that it does not affect the reaction in the subsequent step.

[0150] When the amino acid compound and peptide compound used in the method for producing a peptide compound according to the present disclosure have a hydroxy group, an amino group, a carboxy group, a carbonyl group, a guanidine group, a mercapto group, or the like, a protecting group that is generally used in peptide chemistry or the like may be introduced into these groups, and the target compound can be obtained by removing the protecting group as necessary after the reaction.

[0151] Examples of the protecting group for a hydroxy group include alkyl groups having 1 to 6 carbon atoms (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), phenyl group, trityl group, aralkyl groups having 7 to 10 carbon atoms (e.g., benzyl), formyl group, acyl groups having 1 to 6 carbon atoms (e.g., acetyl, propionyl), benzoyl group, aralkyl-carbonyl groups having 7 to 10 carbon atoms (e.g., benzylcarbonyl), 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, silyl groups (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), alkenyl groups having 2 to 6 carbon atoms (e.g., 1-propenyl), and the like. These groups may be substituted with 1 to 3 substituents selected from the group consisting of halogen atoms (e.g., fluorine atoms, chlorine atoms, bromine atoms, iodine atoms), alkyl groups having 1 to 6 carbon atoms (e.g., methyl, ethyl, propyl), alkoxy groups having 1 to 6 carbon atoms (e.g., methoxy, ethoxy, propoxy), and nitro groups.

[0152] Examples of the protecting group for an amino group include a formyl group, an acyl group having 1 to 6 carbon atoms (e.g., acetyl, propionyl), an alkoxycarbonyl group having 1 to 6 carbon atoms (e.g., methoxycarbonyl, ethoxycarbonyl, Boc group), a benzoyl group, an aralkyl-carbonyl group having 7 to 10 carbon atoms (e.g., benzylcarbonyl), an aralkyloxycarbonyl group having 7 to 14 carbon atoms (e.g., benzyloxycarbonyl, Fmoc group), a trityl group, a monomethoxytrityl group, a 1-(4,4-Dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl group, a phthaloyl group, an N,N-dimethylaminomethylene group, a silyl group (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), an alkenyl group having 2 to 6 carbon atoms (e.g., 1-propenyl), and the like. These groups may be substituted with 1 to 3 substituents selected from the group consisting of halogen atoms (e.g., fluorine atoms, chlorine atoms, bromine atoms, iodine atoms), alkoxy groups having 1 to 6 carbon atoms (e.g., methoxy, ethoxy, propoxy), and nitro groups.

[0153] Examples of the protecting group for a carboxy group include alkyl groups having 1 to 6 carbon atoms (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), aralkyl groups having 7 to 10 carbon atoms (e.g., benzyl), phenyl groups, trityl groups, silyl groups (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl, tert-butyldiphenylsilyl), alkenyl groups having 2 to 6 carbon atoms (e.g., 1-allyl), etc. These groups may be substituted with 1 to 3 substituents selected from the group consisting of halogen atoms (e.g., fluorine atoms, chlorine atoms, bromine atoms, iodine atoms), alkoxy groups having 1 to 6 carbon atoms (e.g., methoxy, ethoxy, propoxy), and nitro groups.

[0154] Examples of the protecting group for the carbonyl group include cyclic acetals (eg, 1,3-dioxane) and acyclic acetals (eg, di(alkyl having 1 to 6 carbon atoms)acetals).

[0155] Examples of the protecting group for the guanidyl group include a 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl group, a 2,3,4,5,6-pentamethylbenzenesulfonyl group, a tosyl group, and a nitro group.

[0156] Examples of the protecting group for the mercapto group (sulfhydryl group) include a trityl group, a 4-methylbenzyl group, an acetylaminomethyl group, a t-butyl group, and a t-butylthio group.

[0157] These protecting groups may be removed by known methods, such as those described in Protective Groups in Organic Synthesis, John Wiley and Sons (1980), etc. For example, methods using acids, bases, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halides (e.g., trimethylsilyl iodide, trimethylsilyl bromide, etc.), reduction methods, etc. may be used.

[0158] In the method for producing a peptide compound according to the present disclosure, the aromatic heterocyclic compound represented by formula (1) can be used not only for forming a protecting group but also for modifying the peptide compound, adjusting the solubility in water or an organic solvent, improving crystallization, polymerizing, etc. Among these, the aromatic heterocyclic compound represented by formula (1) is preferably used to form a protecting group, and more preferably used to form a C-terminal protecting group in an amino acid compound or a peptide compound.

[0159] (Protecting group forming reagents) The protecting group-forming reagent according to the present disclosure contains an aromatic heterocyclic compound represented by the above formula (1).

[0160] The protecting group forming reagent according to the present disclosure is preferably a reagent for forming a protecting group of a carboxy group or an amide group, and more preferably a reagent for forming a protecting group at the C-terminus of an amino acid compound or a peptide compound.

[0161] A preferred embodiment of the aromatic heterocyclic compound represented by formula (1) in the protecting group forming reagent according to the present disclosure is the same as the preferred embodiment of the aromatic heterocyclic compound represented by formula (1) used in the above-mentioned method for producing a peptide compound. The protecting group-forming reagent according to the present disclosure may be a solid reagent or a liquid reagent.

[0162] The content of the aromatic heterocyclic compound represented by formula (1) in the protecting group forming reagent according to the present disclosure is not particularly limited, but is preferably 0.1% by mass to 100% by mass, more preferably 1% by mass to 100% by mass, and even more preferably 3% by mass to 100% by mass, relative to the total mass of the protecting group forming reagent.

[0163] The protecting group-forming reagent according to the present disclosure may contain components other than the aromatic heterocyclic compound represented by formula (1). Other components may include known components, such as water, organic solvents, antioxidants, and pH adjusters.

[0164] (Aromatic heterocyclic compound represented by formula (1a)) The compound according to the present disclosure is an aromatic heterocyclic compound represented by the following formula (1a).

[0165] [ka]

[0166] In formula (1a), Ring A represents an aromatic heterocycle; Y A is -OH, -NHR, SH, or -X 0R represents a hydrogen atom, an alkyl group, an aromatic group-substituted alkyl group, a heteroaromatic group-substituted alkyl group, or an Fmoc group; and X 0 represents Cl, Br or I, R A each independently represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and R A , R B and R C at least one aliphatic hydrocarbon group in at least one of the rings has 12 or more carbon atoms, and ring A is R A may further have a substituent in addition to R B each independently represents a monovalent aliphatic hydrocarbon, a (1+c)-valent aromatic group, or a (1+c)-valent heteroaromatic group; R C each independently represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, m represents an integer of 0 to 2, a represents an integer of 0 to 5, and c represents an integer of 0 to 5; If a and c are both 0, R B is a monovalent aliphatic hydrocarbon group, R A , R B and R C The total number of carbon atoms in all the aliphatic hydrocarbon groups contained in the alkyl group is 40 or more.

[0167] The aromatic heterocyclic compound represented by formula (1a) according to the present disclosure and the aromatic heterocyclic compound represented by any one of formulas (10a) to (30a) according to the present disclosure described below are novel compounds and can be suitably used in the production of peptide compounds. In particular, the aromatic heterocyclic compound represented by formula (1a) according to the present disclosure and the aromatic heterocyclic compound represented by any one of formulas (10a) to (30a) described below can be suitably used as a reagent for forming a protecting group, more suitably used as a reagent for forming a protecting group for a carboxy group or an amide group, and particularly suitably used as a reagent for forming a protecting group for the C-terminus of an amino acid compound or a peptide compound.

[0168] The aromatic heterocyclic compound represented by formula (1a) in the compound according to the present disclosure is R A , R B and R C is the same as the aromatic heterocyclic compound represented by formula (1) in the above-described method for producing a peptide compound according to the present disclosure, except that the total number of carbon atoms in all of the aliphatic hydrocarbon groups contained therein is 40 or more, and preferred embodiments other than the preferred embodiment described below are also the same. The aromatic heterocyclic compound represented by the above formula (1a) can be synthesized in the same manner as the aromatic heterocyclic compound represented by the above formula (1).

[0169] The compound according to the present disclosure is an aromatic heterocyclic compound represented by any one of the following formulas (10a) to (30a).

[0170] [ka]

[0171] In formula (10a), R r10 ~R r14 Either of the Y in formula (1a) A R r10 is a substituent, or R A represents R r11 ~R r14 are each independently a hydrogen atom, a substituent, or R A where R r10 ~R r14 At least one of A 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 14 or more carbon atoms, and R r11 and R r12 , or R r13 and R r14 may each independently be linked to each other to form a ring, or may be linked to each other via a substituent to form a ring.

[0172] In formula (20a), R r20 ~R r23 Either of the Y in formula (1a) A R r20 is a substituent, or R A represents R r21 ~R r23 are each independently a hydrogen atom, a substituent, or R A where R r20 ~R r23 At least one of A and R A are each independently an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and all R A Each aliphatic hydrocarbon group in R has 14 or more carbon atoms, r22 and R r23 may be linked to each other to form a ring, or may be linked to each other via a substituent to form a ring.

[0173] In formula (30a), R r31 ~R r34 Either of the Y in formula (1a) A and X is linked to a group containing a carbon atom having the formula r30 represents an oxygen atom or a sulfur atom, and R r31 ~R r34 are each independently a hydrogen atom, a substituent, or R A where R r31 ~R r34 At least one of A 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 14 or more carbon atoms, and R r31 and R r32 , or R r33 and R r34 may each independently be linked to each other to form a ring, or may be linked to each other via a substituent to form a ring.

[0174] The aromatic heterocyclic compound represented by any one of formulas (10a) to (30a) according to the present disclosure has at least one R A The aromatic heterocyclic compound is the same as the aromatic heterocyclic compound represented by the formula (1) above, except that at least one aliphatic hydrocarbon group has 14 or more carbon atoms, and preferred embodiments other than those described below are also the same. A , R B and R C The total number of carbon atoms in all the aliphatic hydrocarbon groups contained in the alkyl group is preferably 40 or more.

[0175] R in the compound represented by any one of the above formulas (10a) to (30a) A is R in the aromatic heterocyclic compound represented by the above formula (1a). A The same applies to the preferred embodiments.

[0176] From the viewpoints of deprotection rate, crystallization property, solvent solubility, and yield, the aromatic heterocyclic compound represented by the above formula (1a) is preferably a compound represented by any one of the above formulas (10a) to (30a), more preferably a compound represented by the above formula (10a) or formula (20a), and particularly preferably a compound represented by the above formula (10a).

[0177] From the viewpoints of deprotection rate, crystallization property, solvent solubility, and yield, the compound represented by the formula (10a) is preferably a compound represented by the formula (11a), the compound represented by the formula (20) is preferably a compound represented by the formula (21a), and the compound represented by the formula (30a) is preferably a compound represented by the formula (31a).

[0178] [ka]

[0179] In formula (11a), R r15 ~R r18 Either of the Y in formula (1a) A R r15~R r18 each independently represents a hydrogen atom or a substituent, R A is 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 14 or more carbon atoms, and R r15 and R r16 , or R r17 and R r18 may each independently be linked to each other via a substituent to form a ring.

[0180] In formula (21a), R r24 ~R r26 Either of the Y in formula (1a) A R r24 ~R r26 each independently represents a hydrogen atom or a substituent, R A is 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 14 or more carbon atoms, and R r25 and R r26 may be linked to each other via a substituent to form a ring.

[0181] In formula (31a), the wavy line represents Y in formula (1). A represents the position at which the carbon atom having the formula r31 represents an oxygen atom or a sulfur atom, and R r35 ~R r37 are each independently a hydrogen atom, a substituent, or R A represents 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 14 or more carbon atoms, provided that R r35 ~R r37 At least one of A and R r36 may be linked to each other via a substituent to form a ring.

[0182] The compound represented by any one of the above formulas (11a) to (31a) contains at least one R A The present invention is similar to the compound represented by any one of formulas (10) to (30) in the method for producing a peptide compound according to the present disclosure, except that at least one aliphatic hydrocarbon group has 14 or more carbon atoms, and preferred embodiments other than those described below also apply.

[0183] From the viewpoints of deprotection rate, crystallization property, solvent solubility, and yield, the aromatic heterocyclic compound represented by the above formula (1a) is preferably a compound represented by the above formula (11a) or formula (31a), and more preferably a compound represented by the above formula (11a).

[0184] In the above formula (1a), the above formulas (10a) to (30a), and the above formulas (11a) to (31a), from the viewpoints of deprotection rate, crystallization property, solvent solubility, and yield, R A , R B and R C The total number of carbon atoms in all the aliphatic hydrocarbon groups contained in the alkyl group is preferably 40 to 200, more preferably 40 to 100, and even more preferably 40 to 80.

[0185] R in the compound represented by any one of the above formulas (11a) to (31a) A is R in the aromatic heterocyclic compound represented by the above formula (1a). A The same applies to the preferred embodiments. [Example]

[0186] 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.

[0187] 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.

[0188] MS spectra were measured using an ACQUITY SQD LC / MS System (Waters, ionization method: ESI (ElectroSpray Ionization)).

[0189] 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.

[0190] <Protecting Group Formation Reagent: Synthesis of Compound (1-1)>

[0191] [ka]

[0192] The intermediate (1-1) was synthesized by the method described in European Patent No. 2518041. Intermediate (1-1) (8.00 g, 10.3 mmol), indole-5-carboxaldehyde (2.99 g, 20.6 mmol), potassium tert-butoxide (2.20 g, 19.6 mmol), and tetrahydrofuran (THF, 100 mL) were mixed and stirred at 40°C under a nitrogen atmosphere for 3 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 resulting crude product was dissolved in dichloromethane, and methanol was added to precipitate a solid. The solid was filtered and dried to obtain intermediate (1-2) (8.70 g) (yield: 95%). Under a nitrogen atmosphere, intermediate (1-2) (5.00 g, 5.65 mmol), sodium borohydride (0.43 g, 11.3 mmol), and tetrahydrofuran / methanol (20 / 1 (vol% / vol%), 63 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 terminate (quench) the reaction. The mixture was extracted with dichloromethane, and the resulting organic layer was washed with water and saturated brine, followed by concentration 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 (1-1) (4.62 g) (yield: 92%). In the above, rt means room temperature, t-BuOK means potassium tert-butoxide, THF means tetrahydrofuran, and MeOH means methanol.

[0193] 1 H NMR(CDCl3:400MHz) δ:0.82-1.76(86H,m),3.83(4H,t),4.76(2H,d),5.22(2H,s),6.24(2H,d),6 .33(1H,t),6.53(1H,t),7.14(1H,d),7.20(1H,dd),7.29(1H,d),7.63(1H,d)

[0194] <Synthesis of Protecting Group Formation Reagents (Compounds (1-2) to (1-6))> The following compounds (1-2) to (1-6) were obtained by synthesis in the same manner as for the above compound (1-1).

[0195] [ka]

[0196] Compound (1-2) 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)

[0197] Compound (1-3) 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)

[0198] Compound (1-4) 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)

[0199] Compound (1-5) 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)

[0200] Compound (1-6) 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)

[0201] <Reagent for forming a protecting group (synthesis of compound (1-N-1)> Compound (1-N-1) was synthesized according to the following scheme.

[0202] [ka]

[0203] The intermediate (1-2) (2.00 g, 2.26 mmol), sodium triacetoxyborohydride (0.96 g, 4.52 mmol), 2M ethylamine tetrahydrofuran solution (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 (1-N-1) (1.90 g, yield: 94%). Note that NaBH(OAc)3 represents sodium triacetoxyborohydride, and EtNH2 represents ethylamine.

[0204] 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)

[0205] <Synthesis of Protecting Group Formation Reagents (Compounds (1-N-2) to (1-N-4))> The following compounds (1-N-2) to (1-N-4) were obtained by synthesis in the same manner as the above compound (1-1).

[0206] [ka]

[0207] Compound (1-N-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)

[0208] For compound (1-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), .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)

[0209] [[ID=第十三条]]For compound (1-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)

[0210] <Reagent for protecting group formation (Synthesis of compound (1-N-5)) Compound (1-N-5) was synthesized according to the following scheme.

[0211] [ka]

[0212] To a mixture of intermediate (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 (1-3) (11.1 g, yield: 96.9%). A mixture of intermediate (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 (1-4) (19.6 g, yield: 96.6%). Intermediate (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 (1-N-2) (1.01 g, yield 51.3%).

[0213] 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)

[0214] <Reagent for forming a protecting group (synthesis of compound (1-N-2-1)> Compound (1-N-2-1) was synthesized according to the following scheme.

[0215] [ka]

[0216] Under a nitrogen atmosphere, intermediate (1-3) (1.00 g, 1.13 mmol) was dissolved in tetrahydrofuran (5.7 mL), and phenylmagnesium bromide (1.0 mM tetrahydrofuran solution, 1.70 mL, 1.70 mmol) was added, followed by stirring at room temperature for 30 minutes. 2-Me-THF (8 mL) and saturated aqueous ammonium chloride solution (8 mL) were added to the reaction solution, and the organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Methanol was added to the resulting crude product, and the precipitated solid was filtered and dried to obtain intermediate (1-4) (1.04 g, yield: 96%). Intermediate (1-4) (200 mg, 0.21 mmol) and 9-fluorenylmethyl carbamate (199 mg, 0.83 mmol) were dissolved in tetrahydrofuran (2.0 mL), pyridinium p-toluenesulfonate (5.2 mg, 21 μmol) was added, and the mixture was stirred at 30° C. for 5 hours. Methanol was added to the reaction solution, and the precipitated solid was washed with methanol and hexane, filtered, and dried to obtain intermediate (1-5) (286 mg, containing 9-fluorenylmethyl carbamate). Intermediate (1-5) (286 mg, containing 9-fluorenylmethyl carbamate) was dissolved in tetrahydrofuran (2.9 mL), DBU (0.14 mL, 0.96 mmol) was added, and the mixture was stirred at room temperature for 20 minutes. Methanol was added to the reaction mixture, and the precipitated solid was washed with methanol and hexane, filtered, and dried to obtain compound (1-N-2-1) (105 mg, 53% yield for two steps).

[0217] Compound (1-N-2-1) 1 The H NMR results are shown below. 1 H NMR(CDCl3,400MHz) δ:0.88(6H,t),1.20-1.46(76H,m),1.66-1.75(4H,m),1.86(2H,br),3.83(4H,t),5.17(2H,s),5.49(1H,b r),6.24(2H,d),6.32(1H,t),7.01(1H,t),7.04(1H,s),7.13(1H,t),7.20-7.34(4H,m),7.44-7.48(3H,m)

[0218] <Synthesis of Protecting Group Forming Reagents (Compounds (1-N-2-2) and (1-N-2-3)> The following compounds (1-N-2-2) and (1-N-2-3) were obtained by synthesis in the same manner as the above compound (1-N-2-1).

[0219] [ka]

[0220] Compound (1-N-2-2) 1 The H NMR results are shown below. 1H NMR(CDCl3,400MHz) δ:0.88(6H,t),1.22-1.45(76H,m),1.66-1.75(4H,m),3.79(3H,s),3.83(4H,t),5.17(2H,s),5.45(1H,s),6.25(2H,d), 6.33(1H,t),6.83-6.86(2H,m),7.00(1H,t),7.04(1H,s),7.13(1H,t),7.22-7.28(1H,m),7.35-7.39(2H,m),7.43(1H,d)

[0221] Compound (1-N-2-3) 1 The H NMR results are shown below. 1 H NMR(CDCl3,400MHz) δ:0.88(6H,t),1.23-1.45(76H,m),1.66-1.75(4H,m),3.77(3H,s),3.83(4H,t),3.85(3H,s),5.19(2H,s),5.74(1H,br ),6.26(2H,d),6.32(1H,t),6.34(1H,dd),6.48(1H,d),6.99(1H,t),7.06-7.15(3H,m),7.23-7.27(1H,m),7.41(1H,d)

[0222] <Synthesis of protecting group forming reagent (compound (2-1))> Compound (2-1) was synthesized according to the following scheme.

[0223] [ka]

[0224] Intermediate (2-1) was synthesized by the method described in Tetrahedron Lett., 2018, 59, 2145-2149. Intermediate (1-1) (473 mg, 0.61 mmol), intermediate (2-1) (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 (2-2) (503 mg) (yield: 88%). Under a nitrogen atmosphere, intermediate (2-2) (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. The precipitated solid was filtered and dried to give compound (2-1) (115 mg) (yield: 77%). DMF stands for N,N-dimethylformamide.

[0225] 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)

[0226] <Synthesis of protecting group forming reagent (compound (3-1))> Compound (3-1) was synthesized according to the following scheme.

[0227] [ka]

[0228] 5-Bromoresorcinol (1.89 g, 10.0 mmol), 1-bromodocosane (7.78 g, 20.0 mmol), potassium carbonate (8.98 g, 65.0 mmol), and N,N-dimethylformamide (300 mL) were mixed and stirred at 80°C for 5 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, extracted with chloroform and water, and the organic layer was concentrated under reduced pressure. The resulting crude product was dissolved in chloroform, and methanol was added to precipitate a solid. The solid was filtered and dried to obtain intermediate (3-1) (5.20 g, yield: 65%). Intermediate (3-1) (1.61 g, 2.00 mmol), 5-formyl-2-thiopheneboronic acid (0.94 g, 6.00 mmol), sodium carbonate (0.76 g, 7.2 mmol), and tetrahydrofuran / water (15 / 1 (vol% / vol%), 64 mL) were mixed under a nitrogen atmosphere and degassed under reduced pressure at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.23 g, 0.20 mmol) was added and the mixture was heated to reflux for 14 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography (eluent: hexane / ethyl acetate = 95:5 to hexane / ethyl acetate = 50:50). The resulting solid was recrystallized from methanol, filtered, and dried to give intermediate (3-2) (0.93 g, yield: 55%). Under a nitrogen atmosphere, intermediate (3-2) (586 mg, 0.70 mmol), sodium borohydride (53.0 mg, 1.40 mmol), and tetrahydrofuran / methanol (20 / 1 (vol% / vol%), 7.4 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 (3-1) (528 mg, yield: 90%).

[0229] 1H NMR(CDCl3:400MHz) δ:0.82-1.84(86H,m),3.96(4H,t),4.82(2H,s),6.39(1H,t),6.71(2H,d),6.96(1H,d),7.14(1H,d)

[0230] <Synthesis of protecting group forming reagent (compound (4-1))> Compound (4-1) was synthesized according to the following scheme.

[0231] [ka]

[0232] 2,4-Dihydroxyacetophenone (3.92 g, 25.8 mmol), sodium bicarbonate (3.92 g, 25.8 mmol), intermediate (1-1) (3.92 g, 12.9 mmol), and dimethylformamide (100 mL) were mixed and stirred at 100 °C for 6 hours. The reaction mixture was then heated to room temperature, and 2-methyltetrahydrofuran, tetrahydrofuran, and 100 mL of distilled water were added. After separation, the upper layer was added to methanol. The resulting solid was filtered and dried to obtain intermediate (4-1) (11.0 g) (yield: 95%). Intermediate (4-1) (8.75 g, 9.25 mmol), potassium carbonate (2.28 g, 16.5 mmol), methyl bromoacetate (1.56 mL, 16.5 mmol), and dimethylformamide (100 mL) were mixed and stirred at an external temperature of 100 °C for 30 minutes. Diazabicycloundecene (4.96 mL, 33.0 mmol) was added to the resulting reaction solution, and the mixture was further stirred at an external temperature of 100 °C for 4 hours. After cooling the reaction solution, tetrahydrofuran (200 mL) and saturated aqueous ammonium chloride (100 mL) were added and the mixture was separated. The organic layer was then added to methanol (300 mL), and the resulting solid was filtered and dried to obtain a mixture (8.75 g) composed mainly of intermediate (4-2). This intermediate (4-2) (8.00 g, 8.46 mmol) was dissolved in tetrahydrofuran (80 mL) and stirred at 45 °C under a nitrogen atmosphere. A 3.6 M (=3.6 mol / L) toluene solution of sodium bis(2-methoxyethoxy)aluminum hydride (5.9 mL, 21.2 mmol) was added dropwise. The reaction solution was stirred at 45 °C for 30 min, and then acetone (8 mL) was added dropwise. A saturated aqueous solution of potassium sodium tartrate (80 mL) was then slowly added dropwise. The resulting solution was separated, and methanol was added to the organic layer. The precipitated solid was filtered and dried to obtain crude compound (4-1). This crude product was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 89:11 to hexane / ethyl acetate = 69:31) to obtain compound (4-1) (2.43 g, 31% yield).

[0233] 1 H NMR(CDCl3,400MHz) δ:0.88(6H,t),1.19-1.82(80H,m),2.12(3H,s),3.94(4H,t),4.69(2H,d),5 .12(2H,s),6.38(1H,t),6.57(2H,d),6.92(1H,dd),7.00(1H,s),7.33(1H,d)

[0234] <Synthesis of Protected Amino Acid Compound (N-Terminal Protected, C-Terminal Protected Amino Acid (1-1))> According to the following scheme, an N-terminal protected and C-terminal protected amino acid (1-1) was synthesized.

[0235] [ka]

[0236] Compound (1-1) (886 mg, 1.00 mmol), N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-leucine (530 mg, 1.50 mmol), and tetrahydrofuran (10 mL) were mixed at room temperature, and 4-dimethylaminopyridine (24.4 mg, 0.20 mmol) and diisopropylcarbodiimide (232 μL, 1.50 mmol) were added. After stirring at room temperature for 1 hour under a nitrogen atmosphere, methanol (50 mL) was added. The precipitated solid was filtered and dried under reduced pressure to give N-protected C-protected amino acid (1-1) (1160 mg, 97% yield).

[0237] In addition, Fmoc represents a 9-fluorenylmethoxycarbonyl group, and Leu represents a leucine residue.

[0238] <Synthesis of Protected Amino Acid Compounds (N-Terminally Protected and C-Terminally Protected Amino Acids (1-2) to (1-6), (2-1), (3-1), and (4-1), and N-Terminally Protected and C-Terminally Protected Amino Acid Comparative Compounds (1) and (2))> The N-protected and C-protected amino acids (1-2) to (1-6), (2-1), (3-1), and (4-1), as well as the N-terminally and C-terminally protected amino acid comparative examples (1) and (2) were synthesized by condensation with N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-leucine in the same manner as in the synthesis of the N-protected and C-protected amino acid (1-1), except that compound (1-2), compound (1-3), compound (1-4), compound (1-5), compound (1-6), compound (2-1), compound (3-1), compound (4-1), or comparative example compound (1) or (2) described below was used instead of compound (1-1).

[0239] <Synthesis of Protected Amino Acid Compound (N-Terminal Protected, C-Terminal Protected Amino Acid (1-N-1))> According to the following scheme, an N-terminal protected and C-terminal protected amino acid (1-N-1) was synthesized.

[0240] [ka]

[0241] Compound (1-N-1) (94.4 mg, 0.10 mmol), N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-leucine (53.0 mg, 0.15 mmol), and dichloromethane (1 mL) were mixed, and diisopropylethylamine (DIPEA, 2.2 molar equivalents) and (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (COMU, 1.5 molar equivalents) were added. After stirring at room temperature under a nitrogen atmosphere for 1 hour, methanol (5 mL) was added. The precipitated solid was filtered and dried to give the N-terminally and C-terminally protected amino acid (1-N-1) (116 mg, 93% yield).

[0242] <Synthesis of Protected Amino Acid Compounds (N-Terminally Protected, C-Terminally Protected Amino Acids (1-N-2), (1-N-3), (1-N-5), (1-N-2-1), (1-N-2-2), and (1-N-2-3), and N-Terminally Protected, C-Terminally Protected Amino Acid Comparative Compounds (3) and (4))> The N-protected, C-protected amino acids (1-N-2), (1-N-3), (1-N-5), (1-N-2-1), (1-N-2-2), and (1-N-2-3) as well as the N-terminally protected and C-terminally protected amino acid comparative compounds (3) and (4) were synthesized by condensation with N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-leucine in the same manner as in the synthesis of the N-protected, C-protected amino acid (1-N-1), except that compound (1-N-2), compound (1-N-3), compound (1-N-5), compound (1-N-2-1), compound (1-N-2-2), compound (1-N-2-3), or comparative compound (3) or (4) described below was used instead of compound (1-N-1).

[0243] (Examples 1 to 9 and Comparative Examples 1 and 2) (Rating 1) <Deprotection rate> For the compounds of the Examples and Comparative Examples synthesized above and shown in Table 1, the deprotection rate of the protected carboxylic acid moiety (C-terminal deprotection rate) was determined as follows. 100 mg of Fmoc-Leu-OTag (N-terminally protected and C-terminally protected amino acids (1-1) to (1-5), (2-1), and (3-1), and N-terminally protected and C-terminally protected amino acids using comparative compounds (1) and (2)) was mixed with Fmoc-Leu-OTag and an equimolar amount of Fmoc-Gly-OH (internal standard). Dichloromethane / trifluoroethanol / trifluoroacetic acid (100 / 10 / 1: vol%) was added to a substrate concentration of 0.026 M based on Fmoc-Leu-OTag, and the mixture was stirred at 30°C for 60 minutes. 20 μL of the reaction mixture was dissolved in 400 μL of MeOH (methanol), and the ratio of Fmoc-Leu-OH and Fmoc-Gly-OH produced by deprotecting Fmoc-Leu-OTag was quantified using Ultra Performance LC (Waters, model number: ACQUITY) to determine the deprotection rate (%), which was evaluated based on the following criteria. The column and measurement conditions used for ultra-performance liquid chromatography are shown below. Column: Waters, model number: BEH C18 1.7 μm, 2.1 mm x 30 mm Flow rate: 0.5mL / min Solvent: Solution A: 0.1% formic acid in water, Solution B: 0.1% formic acid in acetonitrile Gradient cycle: 0.00 min (solution A / solution B = 95 / 5), 2.00 min (solution A / solution B = 5 / 95), 3.00 min (solution A / solution B = 95 / 5) Detection wavelength: 254 nm

[0244] The deprotection rate was evaluated as "B" or higher and was deemed to be acceptable. The results are shown in Table 1. It can be said that the higher the deprotection rate, the faster the deprotection rate and the better the deprotection rate.

[0245] -Evaluation criteria- "A": The deprotection rate is 80% or more. "B": The deprotection rate is 50% or more and less than 80%. "C": The deprotection rate is 20% or more and less than 50%. "D": Deprotection rate is less than 20%.

[0246] [Table 1]

[0247] Details of the compounds in Table 1 are as follows: Comparative compound (1): 3,4,5-tris-(n-octadecyloxy)benzyl alcohol, synthesized by the method described in paragraphs 0015 to 0016 of JP-A No. 2000-44493. Comparative Example Compound (2): 3,5-bis(docosyloxy)benzyl alcohol, synthesized by the method described in paragraph 0104 of JP-A-2009-185063.

[0248] As shown in Table 1, the aromatic heterocyclic compounds represented by formula (1) used in Examples 1 to 9 have a superior deprotection rate compared to the compounds used in Comparative Examples 1 and 2, and therefore provide a superior yield of peptide compounds.

[0249] (Examples 10 to 15 and Comparative Examples 3 and 4) (Rating 2) <Deprotection rate> For the N-terminally protected and C-terminally protected amino acid compounds synthesized above and shown in Table 2, the deprotection rate of the protected carboxamide moiety (C-terminal deprotection rate) was determined as follows. 100 mg of Fmoc-Leu-NR-Tag (N-terminally protected and C-terminally protected amino acid using the compound of the Example, and N-terminally protected and C-terminally protected amino acid using the compound of the Comparative Example) was mixed with an equimolar amount of Fmoc-Gly-OH (internal standard) to the Fmoc-Leu-NR-Tag. Chloroform / triisopropylsilane / 3,6-dioxa-1,8-octanedithiol / water / trifluoroacetic acid (42.5 / 2.5 / 2.5 / 2.5 / 50:vol%) was added to the mixture so that the substrate concentration based on Fmoc-Leu-NR-Tag was 0.025 M, and the mixture was stirred at 30°C for 60 minutes. 5 μL of the reaction mixture was dissolved in 400 μL of MeOH (methanol), and the ratio of Fmoc-Leu-NH2 and Fmoc-Gly-OH produced by deprotecting Fmoc-Leu-NR-Tag was quantified using Ultra Performance LC (Waters, model number: ACQUITY) to determine the deprotection rate (%), which was evaluated based on the following criteria. The column and measurement conditions used for ultra-performance liquid chromatography are shown below. Column: Waters, model number: BEH C18 1.7 μm, 2.1 mm x 30 mm Flow rate: 0.5mL / min Solvent: Solution A: 0.1% formic acid in water, Solution B: 0.1% formic acid in acetonitrile Gradient cycle: 0.00 min (solution A / solution B = 95 / 5), 2.00 min (solution A / solution B = 5 / 95), 3.00 min (solution A / solution B = 95 / 5) Detection wavelength: 254 nm

[0250] The deprotection rate was evaluated as "B" or higher and was considered to be acceptable. The results are shown in Table 2. It can be said that the higher the deprotection rate, the faster the deprotection rate and the better the deprotection rate.

[0251] -Evaluation criteria- "A": Deprotection rate is 90% or more. "B": The deprotection rate is 80% or more and less than 90%. "C": The deprotection rate is 50% or more and less than 70%. "D": Deprotection rate is less than 50%.

[0252] [Table 2]

[0253] Details of the compounds in Table 2 are as follows:

[0254] Comparative compound (3) was synthesized according to the method described in paragraphs 0094 to 0097 of JP-A-2009-185063.

[0255] [ka]

[0256] Comparative compound (4) was synthesized according to the method described in paragraphs 0147 to 0155 of International Publication No. 2010 / 113939.

[0257] [ka]

[0258] As shown in Table 2, the aromatic heterocyclic compounds represented by formula (1) used in Examples 10 to 15 have a superior deprotection rate compared to the compounds used in Comparative Examples 3 and 4, and therefore provide a superior yield of peptide compound.

[0259] (Rating 3) An N-terminally protected and C-terminally protected peptide compound (7-residue peptide compound) was synthesized using the compound represented by formula (1) according to the present disclosure according to the method described below, and then the C-terminal protecting group was deprotected, and the deprotection rate was evaluated. Details of each abbreviation other than those mentioned above are shown below. Gly: glycine residue Asn(Trt):Trt (triphenylmethyl)-protected asparagine residue Trt: Trityl group Asp(tBu): tBu-protected aspartic acid residue tBu: t-butyl group Phe: phenylalanine residue Glu(tBu): tBu-protected glutamic acid residue

[0260] <Synthesis of N-terminally protected C-terminally protected peptide (7-residue peptide: Fmoc-Gly-Gly-Asn(Trt)-Gly-Asp(tBu)-Phe-Glu(tBu)-O-protecting group)> 〔Synthesis Example 1: Synthesis of Fmoc-Glu(tBu)-O-5-IndoTAG(1)〕 1-(3,5-Bis(docosyloxy)benzyloxy)-1H-indol-5-ylmethanol (corresponding to Compound (1-1). Hereinafter, also referred to as "5-IndoTAG(1)") (1.00 g, 1.13 mmol) and Fmoc-Glu(tBu)-OH (1.5 molar equivalents) were dissolved in dichloromethane (23 mL), and 4-dimethylaminopyridine (0.2 molar equivalents) and diisopropylcarbodiimide (1.5 molar equivalents) were added and stirred. After completion of the condensation reaction, acetonitrile (MeCN, 100 mL) was added and stirred, the precipitate was filtered, washed with acetonitrile, and dried under reduced pressure to obtain Fmoc-Glu(tBu)-O-5-IndoTAG(1) (1.46 g, yield 100%). Fmoc-Glu(tBu)-O-5-IndoTAG(1) is a peptide compound in which the N-terminus is protected by an Fmoc group and the C-terminus is protected by an aromatic heterocyclic compound represented by Formula (1) according to the present disclosure.

[0261] 〔Synthesis Example 2: Synthesis of Fmoc-Phe-Glu(tBu)-O-5-IndoTAG(1)〕 Fmoc-Glu(tBu)-O-5-IndoTAG (1) (1.34 g, 1.04 mmol) was dissolved in chloroform (2.6 mL), and diazabicycloundecene (DBU, 2.0 molar equivalents) was added and stirred. After completion of the deprotection reaction, a chloroform solution containing methanesulfonic acid (2.1 molar equivalents) and N-methylmorpholine (2.1 molar equivalents) was added, followed by Fmoc-Phe-OH (1.2 molar equivalents), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (COMU, 1.2 molar equivalents), and stirring. After the condensation reaction was completed, MeCN (50 mL) was added and stirred. The precipitate was filtered, washed with acetonitrile, and dried under reduced pressure to obtain Fmoc-Phe-Glu(tBu)-O-5-IndoTAG (1) (1.49 g, 100% yield).

[0262] Synthesis Example 3: Synthesis of Fmoc-Asp(tBu)-Phe-Glu(tBu)-O-5-IndoTAG (1) Fmoc-Phe-Glu(tBu)-O-5-IndoTAG (1) (1.49 g, 1.03 mmol) was dissolved in chloroform (5.0 mL), DBU (2.0 molar equivalents) was added, and the mixture was stirred. After the deprotection reaction was complete, a chloroform solution containing methanesulfonic acid (2.1 molar equivalents) and N-methylmorpholine (2.1 molar equivalents) was added, followed by Fmoc-Asp(tBu)-OH (1.2 molar equivalents) and COMU (1.2 molar equivalents) and stirring. After the condensation reaction was complete, MeCN (50 mL) was added and the mixture was stirred. The precipitate was filtered, washed with acetonitrile, and dried under reduced pressure to give Fmoc-Asp(tBu)-Phe-Glu(tBu)-O-5-IndoTAG (1) (1.46 g, 87.6% yield).

[0263] Synthesis Example 4: Synthesis of Fmoc-Gly-Asp(tBu)-Phe-Glu(tBu)-O-5-IndoTAG (1) Fmoc-Asp(tBu)-Phe-Glu(tBu)-O-5-IndoTAG (1) (1.31 g, 0.812 mmol) was dissolved in chloroform (4.0 mL), DBU (2.0 molar equivalents) was added, and the mixture was stirred. After the deprotection reaction was complete, a chloroform solution containing methanesulfonic acid (2.1 molar equivalents) and N-methylmorpholine (2.1 molar equivalents) was added, followed by Fmoc-Gly-OH (1.2 molar equivalents) and COMU (1.2 molar equivalents) and stirring. After the condensation reaction was complete, MeOH (50 mL) was added and the mixture was stirred. The precipitate was filtered, washed with acetonitrile, and dried under reduced pressure to give Fmoc-Gly-Asp(tBu)-Phe-Glu(tBu)-O-5-IndoTAG (1) (1.36 g, 100% yield).

[0264] Synthesis Example 5: Synthesis of Fmoc-Asn(Trt)-Gly-Asp(tBu)-Phe-Glu(tBu)-O-5-IndoTAG (1) Fmoc-Gly-Asp(tBu)-Phe-Glu(tBu)-O-5-IndoTAG (1) (1.36 g, 0.815 mmol) was dissolved in chloroform (3.8 mL), DBU (2.0 molar equivalents) was added, and the mixture was stirred. After the deprotection reaction was complete, a chloroform solution containing methanesulfonic acid (2.1 molar equivalents) and N-methylmorpholine (2.1 molar equivalents) was added, followed by Fmoc-Asn(Trt)-OH (1.2 molar equivalents) and COMU (1.2 molar equivalents) and stirring. After the condensation reaction was complete, MeCN (50 mL) was added and the mixture was stirred. The precipitate was filtered, washed with acetonitrile, and dried under reduced pressure to give Fmoc-Asn(Trt)-Gly-Asp(tBu)-Phe-Glu(tBu)-O-5-IndoTAG (1) (1.35 g, 81.8% yield).

[0265] Synthesis Example 6: Synthesis of Fmoc-Gly-Gly-Asn(Trt)-Gly-Asp(tBu)-Phe-Glu(tBu)-O-5-IndoTAG (1) Fmoc-Asn(Trt)-Gly-Asp(tBu)-Phe-Glu(tBu)-O-5-IndoTAG(1) (1.00 g, 0.494 mmol) was dissolved in chloroform (6.0 mL), and DBU (2.0 molar equivalents) was added and stirred. After completion of the deprotection reaction, a chloroform solution containing methanesulfonic acid (2.1 molar equivalents) and N-methylmorpholine (2.1 molar equivalents) was added, and then Fmoc-Gly-Gly-OH (1.2 molar equivalents) and COMU (1.2 molar equivalents) were added and stirred. After completion of the condensation reaction, MeCN (50 mL) was added and stirred, and the precipitate was filtered, washed with acetonitrile, and dried under reduced pressure to obtain Fmoc-Gly-Gly-Asn(Trt)-Gly-Asp(tBu)-Phe-Glu(tBu)-O-5-IndoTAG(1) (1.02 g, yield 96.6%).

[0266] <Deprotection of C-terminal protecting group> [Synthesis Example 7: Synthesis of Fmoc-Gly-Gly-Asn(Trt)-Gly-Asp(tBu)-Phe-Glu(tBu)-OH] To Fmoc-Gly-Gly-Asn(Trt)-Gly-Asp(tBu)-Phe-Glu(tBu)-O-5-IndoTAG(.) (500 mg, 0.234 mmol), a mixed solvent of cooled dichloromethane, 2,2,2-trifluoroethanol, and trifluoroacetic acid (9.0 mL, volume ratio 100:10:2) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was filtered, and diisopropyl ether (80 mL) was added to the filtrate. The precipitate formed was centrifuged and recovered. Thereafter, the recovered precipitate was suspended again in diisopropyl ether (80 mL) and centrifuged, and this operation was repeated twice. Then, by drying under reduced pressure, Fmoc-Gly-Gly-Asn(Trt)-Gly-Asp(tBu)-Phe-Glu(tBu)-OH(X) (297 mg, yield 100%) in which only the C-terminal protecting group (5-IndoTAG(1)) was deprotected was obtained. Electrospray ionization mass spectrometry (ESI-MS) (+) = 1,271.5

[0267] Synthesis Example 8: Synthesis of Fmoc-Gly-Gly-Asn(Trt)-Gly-Asp(tBu)-Phe-Glu(tBu)-OH Fmoc-Gly-Gly-Asn(Trt)-Gly-Asp(tBu)-Phe-Glu(tBu)-O-BfTAG(2) was synthesized (total yield 81%) in the same manner as in Synthesis Example 1-6, except that compound (4-1) (hereinafter also referred to as "BfTAG(2)") was used instead of compound (1-1) in Synthesis Example 1. Similarly to Synthesis Example 7, only the C-terminal protecting group (BfTAG(2)) was selectively deprotected to obtain Fmoc-Gly-Gly-Asn(Trt)-Gly-Asp(tBu)-Phe-Glu(tBu)-OH.

[0268] In the seven-residue peptide from which the C-terminal protecting group was deprotected, the Trt group protecting Asn, the tBu group protecting Asp, and the tBu group protecting Glu remained, and only the C-terminal protecting group was deprotected. As shown above, the method for producing a peptide compound according to the present disclosure can selectively deprotect only the C-terminal protecting group while leaving the protecting groups of the amino acid side chains intact, so the method for producing a peptide compound according to the present disclosure is excellent in deprotection speed. Furthermore, the yield of the resulting peptide compound is also excellent.

[0269] <Synthesis of 9-residue peptide: Pyr-His-Trp-Ser-Tyr-dLeu-Leu-Arg-Pro-NHEt> Details of each abbreviation other than those mentioned above are shown below. Pyr(Boc): Boc-protected pyroglutamic acid residue His(Boc): Boc-protected histamine residue Trp(Boc): Boc-protected tryptophan residue Boc: t-butoxycarbonyl group Ser(tBu): tBu-protected serine residue tBu: t-butyl group Tyr(tBu): tBu-protected tyrosine residue dLeu: D-leucine residue Arg(pbf): pbf-protected arginine residue pbf: 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl group Pro: proline residue Et: ethyl group

[0270] (Synthesis Example 9: Synthesis of Fmoc-Pro-NEtTAG (3)) N-(1-(3,5-bis(docosanoyloxybenzyloxy))-1H-indol-3-ylmethyl)ethanamine (corresponding to the above compound (1-N-2), also referred to as "NEtTAG (3)") (2.00 g, 2.19 mmol) and Fmoc-Pro-OH (1.5 molar equivalents) were dissolved in tetrahydrofuran (11 mL), and diisopropylethylamine (2.2 molar equivalents) and (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (COMU, 1.5 molar equivalents) were added and stirred. After completion of the condensation reaction, acetonitrile (60 mL) was added and stirred. The precipitate was filtered, washed with acetonitrile, and dried under reduced pressure to give Fmoc-Pro-NEtTAG (3) (2.62 g, 96.9% yield).

[0271] (Synthesis Example 10: Synthesis of Fmoc-Arg(pbf)-Pro-NEtTAG (3)) Fmoc-Pro-NEtTAG (3) (2.60 g, 2.11 mmol) was dissolved in tetrahydrofuran (11 mL), and diazabicycloundecene (DBU, 2.0 molar equivalents) was added and stirred. After completion of the deprotection reaction, N-methylmorpholine (2.05 molar equivalents) and methanesulfonic acid (2.0 molar equivalents) were added, followed by Fmoc-Arg(pbf)-OH (1.25 molar equivalents), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (COMU, 1.25 molar equivalents), and stirring. After the condensation reaction was completed, acetonitrile (55 mL) was added and stirred. The precipitate was filtered, washed with acetonitrile, and dried under reduced pressure to obtain Fmoc-Arg(pbf)-Pro-O-NEtTAG (3) (3.43 g, yield 99.1%).

[0272] (Synthesis Example 11: Synthesis of Fmoc-Leu-Arg(pbf)-Pro-O-NEtTAG (3)) Fmoc-Arg(pbf)-Pro-NEtTAG (3) (3.41 g, 2.08 mmol) was dissolved in tetrahydrofuran (10 mL), and diazabicycloundecene (DBU, 2.0 molar equivalents) was added and stirred. After the deprotection reaction was completed, N-methylmorpholine (2.05 molar equivalents) and methanesulfonic acid (2.0 molar equivalents) were added, followed by Fmoc-Leu-OH (1.25 molar equivalents) and (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (COMU, 1.25 molar equivalents). After the condensation reaction was completed, acetonitrile (55 mL) was added and stirred. The precipitate was filtered, washed with acetonitrile, and dried under reduced pressure to obtain Fmoc-Leu-Arg(pbf)-Pro-NEtTAG (3) (3.45 g, yield 94.6%).

[0273] (Synthesis Example 12: Synthesis of Fmoc-dLeu-Leu-Arg(pbf)-Pro-O-NEtTAG (3)) Fmoc-Leu-Arg(pbf)-Pro-O-NEtTAG (3) (3.42 g, 1.95 mmol) was dissolved in tetrahydrofuran (9.7 mL), DBU (2.0 mol equivalents) was added, and the mixture was stirred. After the deprotection reaction was completed, N-methylmorpholine (2.05 mol equivalents) and methanesulfonic acid (2.0 mol equivalents) were added, followed by Fmoc-dLeu-OH (1.25 mol equivalents), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (COMU, 1.25 mol equivalents), and the mixture was stirred. After the condensation reaction was completed, acetonitrile (50 mL) was added and stirred. The precipitate was filtered, washed with acetonitrile, and dried under reduced pressure to obtain Fmoc-dLeu-Leu-Arg(pbf)-Pro-NEtTAG (3) (3.45 g, yield 94.8%).

[0274] (Synthesis Example 13: Synthesis of Fmoc-Tyr(tBu)-dLeu-Leu-Arg(pbf)-Pro-O-NEtTAG (3)) Fmoc-dLeu-Leu-Arg(pbf)-Pro-O-NEtTAG (3) (3.48 g, 1.86 mmol) was dissolved in tetrahydrofuran (9.3 mL), DBU (2.0 mol equivalents) was added, and the mixture was stirred. After the deprotection reaction was complete, N-methylmorpholine (2.05 mol equivalents) and methanesulfonic acid (2.0 mol equivalents) were added, followed by Fmoc-Tyr(tBu)-OH (1.25 mol equivalents), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (COMU, 1.25 mol equivalents), and the mixture was stirred. After the condensation reaction was completed, acetonitrile (95 mL) was added and stirred. The precipitate was filtered, washed with acetonitrile, and dried under reduced pressure to obtain Fmoc-Tyr(tBu)-dLeu-Leu-Arg(pbf)-Pro-NEtTAG (3) (3.74 g, yield 96.2%).

[0275] (Synthesis Example 14: Synthesis of Fmoc-Ser(tBu)-Tyr(tBu)-dLeu-Leu-Arg(pbf)-Pro-O-NEtTAG (3)) Fmoc-Tyr(tBu)-dLeu-Leu-Arg(pbf)-Pro-O-NEtTAG (3) (3.67 g, 1.76 mmol) was dissolved in tetrahydrofuran (8.8 mL), DBU (2.0 mol equivalents) was added, and the mixture was stirred. After the deprotection reaction was complete, N-methylmorpholine (2.05 mol equivalents) and methanesulfonic acid (2.0 mol equivalents) were added, followed by Fmoc-Ser(tBu)-OH (1.25 mol equivalents), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (COMU, 1.25 mol equivalents), and the mixture was stirred. After the condensation reaction was completed, acetonitrile (90 mL) was added and stirred. The precipitate was filtered, washed with acetonitrile, and dried under reduced pressure to obtain Fmoc-Ser(tBu)-Tyr(tBu)-dLeu-Leu-Arg(pbf)-Pro-O-NEtTAG (3) (3.72 g, 94.9% yield).

[0276] (Synthesis Example 15: Synthesis of Fmoc-Trp(Boc)-Ser(tBu)-Tyr(tBu)-dLeu-Leu-Arg(pbf)-Pro-O-NEtTAG (3)) Fmoc-Ser(tBu)-Tyr(tBu)-dLeu-Leu-Arg(pbf)-Pro-O-NEtTAG (3) (3.67 g, 1.65 mmol) was dissolved in tetrahydrofuran (8.2 mL), DBU (2.0 mol equivalents) was added, and the mixture was stirred. After the deprotection reaction was complete, N-methylmorpholine (2.05 mol equivalents) and methanesulfonic acid (2.0 mol equivalents) were added, followed by Fmoc-Trp(Boc)-OH (1.25 mol equivalents), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (COMU, 1.25 mol equivalents), and the mixture was stirred. After the condensation reaction was completed, acetonitrile (80 mL) was added and stirred. The precipitate was filtered, washed with acetonitrile, and dried under reduced pressure to give Fmoc-Trp(Boc)-Ser(tBu)-Tyr(tBu)-dLeu-Leu-Arg(pbf)-Pro-NEtTAG (3) (3.79 g, 91.5% yield).

[0277] (Synthesis Example 16: Synthesis of Fmoc-His(Boc)-Trp(Boc)-Ser(tBu)-Tyr(tBu)-dLeu-Leu-Arg(pbf)-Pro-O-NEtTAG (3)) Fmoc-Trp(Boc)-Ser(tBu)-Tyr(tBu)-dLeu-Leu-Arg(pbf)-Pro-O-NEtTAG (3) (3.78 g, 1.50 mmol) was dissolved in tetrahydrofuran (7.5 mL), DBU (2.0 mol equivalents) was added, and the mixture was stirred. After the deprotection reaction was complete, N-methylmorpholine (2.05 mol equivalents) and methanesulfonic acid (2.0 mol equivalents) were added, followed by Fmoc-His(Boc)-OH (1.25 mol equivalents), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (COMU, 1.25 mol equivalents), and the mixture was stirred. After the condensation reaction was completed, acetonitrile (75 mL) was added and stirred. The precipitate was filtered, washed with acetonitrile, and dried under reduced pressure to give Fmoc-His(Boc)-Trp(Boc)-Ser(tBu)-Tyr(tBu)-dLeu-Leu-Arg(pbf)-Pro-NEtTAG (3) (3.45 g, 83.4% yield).

[0278] (Synthesis Example 17: Synthesis of Pyr(Boc)-His(Boc)-Trp(Boc)-Ser(tBu)-Tyr(tBu)-dLeu-Leu-Arg(pbf)-Pro-O-NEtTAG (3)) Fmoc-His(Boc)-Trp(Boc)-Ser(tBu)-Tyr(tBu)-dLeu-Leu-Arg(pbf)-Pro-O-NEtTAG (3) (1.96 g, 0.71 mmol) was dissolved in tetrahydrofuran (4.7 mL), DBU (2.0 mol equivalents) was added, and the mixture was stirred. After the deprotection reaction was complete, N-methylmorpholine (2.05 mol equivalents) and methanesulfonic acid (2.0 mol equivalents) were added, followed by Fmoc-Pyr(Boc)-OH (1.25 mol equivalents), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (COMU, 1.25 mol equivalents), and the mixture was stirred. After the condensation reaction was completed, 2-Me-THF (10 mL) and saturated aqueous sodium bicarbonate (10 mL) were added and the layers were separated. The organic layer was then washed with saturated aqueous sodium bicarbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the resulting solid was washed with hexane to give Pyr(Boc)-His(Boc)-Trp(Boc)-Ser(tBu)-Tyr(tBu)-dLeu-Leu-Arg(pbf)-Pro-NEtTAG (3) (1.94 g, 99.4% yield).

[0279] (Synthesis Example 18: Synthesis of Pyr-His-Trp-Ser-Tyr-dLeu-Leu-Arg-Pro-NHEt) Pyr(Boc)-His(Boc)-Trp(Boc)-Ser(tBu)-Tyr(tBu)-dLeu-Leu-Arg(pbf)-Pro-O-NEtTAG (3) (1.90 g, 0.87 mmol) was added to a mixture of trifluoroacetic acid (TFA, 26.6 mL), triisopropylsilane (TIPS, 0.72 mL), 3,6-dioxa-1,8-octanedithiol (DODT, 0.72 mL), and water (0.72 mL) and stirred for 90 min. After completion of the deprotection reaction, methyl tert-butyl ether (MTBE, 60 mL) was added and stirred. The supernatant was removed by centrifugation. The addition of MTBE, centrifugation, and removal of the supernatant were repeated three times to obtain Pyr-His-Trp-Ser-Tyr-dLeu-Leu-Arg-Pro-NHEt (0.812 g, yield 93.4%). Electron spray ionization mass spectrometry (ESI-MS) (+) = 1,209.8

[0280] <Synthesis of Five-Residue Peptide: Fmoc-MeNle-MeNle-Arg(Pbf)-Cys(Trt)-Gly-NH2> Details of each abbreviation other than those mentioned above are shown below. MeNle: N-methylnorleucine residue Cys(Trt):Trt-protected cysteine ​​residue Gly: glycine residue

[0281] [Synthesis Example 19: Synthesis of Fmoc-Gly-NH-DMPIndoTAG (4)] Fmoc-Gly-NH-DMPIndoTAG(4) was synthesized in the same manner as in Synthesis Example 9, except that compound (1-N-2-3) (hereinafter also referred to as "DMPIndoTAG(4)") was used instead of compound (1-N-2) in Synthesis Example 9, and Fmoc-Gly-OH was used instead of Fmoc-Pro-OH.

[0282] [Synthesis Example 20: Synthesis of Fmoc-MeNle-MeNle-Arg(Pbf)-Cys(Trt)-Gly-NH-DMPIndoTAG (4)] Using the Fmoc-Gly-NH-DMPIndoTAG (4) obtained in Synthesis Example 19, the removal of the Fmoc group and the condensation reaction of amino acids were repeated in the same manner as in Synthesis Example 10 to synthesize Fmoc-MeNle-MeNle-Arg(Pbf)-Cys(Trt)-Gly-NH-DMPIndoTAG (4) (total yield 75%).

[0283] The C-terminal protecting group DMPIndoTAG(4) of Fmoc-MeNle-MeNle-Arg(Pbf)-Cys(Trt)-Gly-NH2-DMPIndoTAG(4) obtained in Synthesis Example 20 above can be deprotected with low concentrations of TFA, and therefore is suitable for the synthesis of acid-labile peptides.

[0284] The aromatic heterocyclic compounds represented by formula (1) used in Synthesis Examples 19 and 20 are excellent in deprotection rate and yield of the resulting peptide compounds.

[0285] The disclosures of Japanese Patent Application No. 2019-035775, filed on February 28, 2019, and Japanese Patent Application No. 2019-122489, filed on June 28, 2019, are incorporated herein by reference in their 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. The process includes a C-terminal protection step of protecting a carboxy group or an amide group of an amino acid compound or a peptide compound with an aromatic heterocyclic compound represented by the following formula (1): A method for producing a peptide compound. 【Chemistry 1】 In formula (1), Ring A represents an aromatic heterocycle; Y Ａ is -OH, -NHR, SH, or -X ０ R represents a hydrogen atom, an alkyl group, an aromatic group-substituted alkyl group, a heteroaromatic group-substituted alkyl group, or a 9-fluorenylmethoxycarbonyl group; X ０ represents Cl, Br or I; R A is a group represented by the following formula (f2): R Ｂ each independently represents a monovalent aliphatic hydrocarbon, a (1+c)-valent aromatic group, or a (1+c)-valent heteroaromatic group; R Ｃ each independently represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, m represents an integer of 0 to 2; a represents an integer of 1 to 5; and c represents an integer of 0 to 5. 【Chemistry 2】 In formula (f2), the wavy line portion represents the bonding position to the aromatic heterocycle, m10 represents an integer of 2 to 3, m11 represents an integer of 0 to 3, each X 10 independently represents a single bond, -O-, -S-, -COO-, -OCO-, -OCONH-, -NHCONH-, -NHCO-, or -CONH-, and each R 10 independently represents a monovalent aliphatic hydrocarbon group having 12 or more carbon atoms.

2. The method for producing a peptide compound according to claim 1 , wherein the amino acid compound or peptide compound in the C-terminal protection step is an N-terminal protected amino acid compound or an N-terminal protected peptide compound.

3. an N-terminal deprotection step of deprotecting the N-terminus of the N-terminal protected amino acid compound or the N-terminal protected peptide compound obtained in the C-terminal protection step; and a peptide chain elongation step of condensing an N-terminal protected amino acid compound or an N-terminal protected peptide compound to the N-terminus of the C-terminal protected amino acid compound or C-terminal protected peptide compound obtained in the N-terminal deprotection step; The method for producing the peptide compound according to claim 2, further comprising:

4. The method for producing a peptide compound according to claim 3, further comprising a precipitation step of precipitating the N-terminal-protected and C-terminal-protected peptide compound obtained in the peptide chain elongation step.

5. After the precipitation step, a step of deprotecting the N-terminus of the obtained N-terminus-protected and C-terminus-protected peptide compound; a step of condensing an N-terminal protected amino acid compound or an N-terminal protected peptide compound to the N-terminus of the obtained C-terminal protected peptide compound; and Precipitating the resulting N-terminally protected C-terminally protected peptide compound. The method for producing a peptide compound according to claim 4, further comprising the steps of:

6. The method for producing the peptide compound according to any one of claims 1 to 5, further comprising a C-terminal deprotection step of deprotecting a C-terminal protecting group.

7. The method for producing a peptide compound according to any one of claims 1 to 6, wherein the ring A is a pyrrole ring, an indole ring, a carbazole ring, a pyrazole ring, an indazole ring, a furan ring, a thiophene ring, a benzofuran ring, or a benzothiophene ring.

8. The method for producing a peptide compound according to any one of claims 1 to 7, wherein the ring A is represented by any one of the following formulas (10), (20), and (30): 【Chemistry 3】 In formula (10), R ｒ１０ ~R ｒ１４ is Y in formula (1). Ａ and R ｒ１０ is a substituent, or R Ａ represents R ｒ１１ ~R ｒ１４ are each independently a hydrogen atom, a substituent, or R Ａ where R ｒ１０ ~R ｒ１４ At least one of Ａ 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 ｒ１１ and R ｒ１２ , or R ｒ１３ and R ｒ１４ may each independently be linked to each other to form a ring. In formula (20), R ｒ２０ ~R ｒ２３ is Y in formula (1). Ａ and R ｒ２０ is a substituent, or R Ａ represents R ｒ２１ ~R ｒ２３ are each independently a hydrogen atom, a substituent, or R Ａ where R ｒ２０ ~R ｒ２３ At least one of is R Ａ 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 ｒ２２ and R ｒ２３ may be linked to each other to form a ring. In formula (30), R ｒ３１ ~R ｒ３４ is Y in formula (1). Ａ and X is linked to a group containing a carbon atom having the formula ３０ represents an oxygen atom or a sulfur atom, R ｒ３１ ~R ｒ３４ are each independently a hydrogen atom, a substituent, or R Ａ where R ｒ３１ ~R ｒ３４ At least one of is R Ａ 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 ｒ３１ and R ｒ３２ , or R ｒ３３ and R ｒ３４ may each independently be linked to each other to form a ring.

9. The at least one R Ａ The method for producing a peptide compound according to any one of claims 1 to 8, wherein at least one aliphatic hydrocarbon group has 14 or more carbon atoms.

10. The method for producing a peptide compound according to claim 8, wherein the ring A represented by formula (10) is represented by formula (11), the compound represented by formula (20) is represented by formula (21), and the compound represented by formula (30) is represented by formula (31). 【Chemistry 4】 In formula (11), R ｒ１５ ~R ｒ１８ is Y in formula (1). Ａ and R ｒ１５ ~R ｒ１８ each independently represents a hydrogen atom or a substituent; R Ａ is 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 14 or more carbon atoms, and R ｒ１５ and R ｒ１６ , or R ｒ１７ and R ｒ１８ may each independently be linked to each other to form a ring. In formula (21), R ｒ２４ ~R ｒ２６ is Y in formula (1). Ａ and R ｒ２４ ~R ｒ２６ each independently represents a hydrogen atom or a substituent; R Ａ is 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 14 or more carbon atoms, and R ｒ２５ and R ｒ２６ may be linked to each other to form a ring. In formula (31), the wavy line part represents Y in formula (1). Ａ represents the position at which the carbon atom having the formula ｒ３１ represents an oxygen atom or a sulfur atom, R ｒ３５ ~R ｒ３７ Each independently represents a hydrogen atom, a substituent, or R Ａ represents 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 14 or more carbon atoms, provided that R ｒ３５ ~R ｒ３７ At least one of Ａ and R ｒ３６ and R ｒ３７ may be linked to each other to form a ring.

11. All R Ａ The method for producing a peptide compound according to any one of claims 1 to 10, wherein the total number of carbon atoms in all of the aliphatic hydrocarbon groups contained in is 40 or more.

12. The present invention includes an aromatic heterocyclic compound represented by the following formula (1): Reagent for forming protecting groups. 【Chemistry 5】 In formula (1), Ring A represents an aromatic heterocycle; Y Ａ is -OH, -NHR, SH, or -X ０ R represents a hydrogen atom, an alkyl group, an aromatic group-substituted alkyl group, a heteroaromatic group-substituted alkyl group, or a 9-fluorenylmethoxycarbonyl group; X ０ represents Cl, Br or I; R A is a group represented by the following formula (f2): R Ｂ each independently represents a monovalent aliphatic hydrocarbon, a (1+c)-valent aromatic group, or a (1+c)-valent heteroaromatic group; R Ｃ each independently represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, m represents an integer of 0 to 2; a represents an integer of 1 to 5; and c represents an integer of 0 to 5. 【Chemistry 6】 In formula (f2), the wavy line portion represents the bonding position to the aromatic heterocycle, m10 represents an integer of 2 to 3, m11 represents an integer of 0 to 3, each X 10 independently represents a single bond, -O-, -S-, -COO-, -OCO-, -OCONH-, -NHCONH-, -NHCO-, or -CONH-, and each R 10 independently represents a monovalent aliphatic hydrocarbon group having 12 or more carbon atoms.

13. The protecting group forming reagent according to claim 12 , wherein the protecting group forming reagent is a protecting group forming reagent for a carboxy group or an amide group.

14. The protecting group forming reagent according to claim 12 or 13, wherein the protecting group forming reagent is a protecting group forming reagent for a C-terminus of an amino acid compound or a peptide compound.

15. An aromatic heterocyclic compound represented by the following formula (1a): 【Chemistry 7】 In formula (1a), Ring A represents an aromatic heterocycle; Y Ａ is -OH, -NHR, SH, or -X ０ R represents a hydrogen atom, an alkyl group, an aromatic group-substituted alkyl group, a heteroaromatic group-substituted alkyl group, or a 9-fluorenylmethoxycarbonyl group; X ０ represents Cl, Br or I; R A is a group represented by the following formula (f2): R Ｂ each independently represents a monovalent aliphatic hydrocarbon, a (1+c)-valent aromatic group, or a (1+c)-valent heteroaromatic group; R Ｃ each independently represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, m represents an integer of 0 to 2; a represents an integer of 1 to 5; c represents an integer of 0 to 5; All R Ａ , R Ｂ and R Ｃ The total number of carbon atoms in all of the aliphatic hydrocarbon groups contained in the alkyl group is 40 or more. 【Chemistry 8】 In formula (f2), the wavy line portion represents the bonding position to the aromatic heterocycle, m10 represents an integer of 2 to 3, m11 represents an integer of 0 to 3, each X 10 independently represents a single bond, -O-, -S-, -COO-, -OCO-, -OCONH-, -NHCONH-, -NHCO-, or -CONH-, and each R 10 independently represents a monovalent aliphatic hydrocarbon group having 12 or more carbon atoms.

16. The aromatic heterocyclic compound according to claim 15, wherein ring A is represented by any one of the following formulas (10a), (20a), and (30a): 【Chemistry 9】 In formula (10a), R ｒ１０ ~R ｒ１４ is Y in formula (1a). Ａ and R ｒ１０ is a substituent, or R Ａ represents R ｒ１０ ~R ｒ１４ are each independently a hydrogen atom, a substituent, or R Ａ where R ｒ１１ ~R ｒ１４ At least one of is R Ａ 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 14 or more carbon atoms, and R ｒ１１ and R ｒ１２ , or R ｒ１３ and R ｒ１４ may each independently be linked to each other to form a ring. In formula (20a), R ｒ２０ ~R ｒ２３ is Y in formula (1a). Ａ and R ｒ２０ is a substituent, or R Ａ represents R ｒ２１ ~R ｒ２３ are each independently a hydrogen atom, a substituent, or R Ａ where R ｒ２０ ~R ｒ２３ At least one of Ａ and R Ａ are each independently an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and all R Ａ Each aliphatic hydrocarbon group in R has 14 or more carbon atoms, ｒ２２ and R ｒ２３ may be linked to each other to form a ring. In formula (30a), R ｒ３１ ~R ｒ３４ is Y in formula (1a). Ａ and X is linked to a group containing a carbon atom having the formula ｒ３０ represents an oxygen atom or a sulfur atom, R ｒ３１ ~R ｒ３４ are each independently a hydrogen atom, a substituent, or R Ａ where R ｒ３１ ~R ｒ３４ At least one of is R Ａ 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 14 or more carbon atoms, and R ｒ３１ and R ｒ３２ , or R ｒ３３ and R ｒ３４ may each independently be linked to each other to form a ring.

17. The aromatic heterocyclic compound according to claim 15 or 16, wherein the formula (10a) is represented by formula (11a), the formula (20) is represented by formula (21a), and the formula (30a) is represented by formula (31a). 【Chemistry 10】 In formula (11a), R ｒ１５ ~R ｒ１８ is Y in formula (1a). Ａ and R ｒ１５ ~R ｒ１８ each independently represents a hydrogen atom or a substituent; R Ａ is 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 14 or more carbon atoms, and R ｒ１５ and R ｒ１６ , or R ｒ１７ and R ｒ１８ may each independently be linked to each other to form a ring. In formula (21a), R ｒ２４ ~R ｒ２６ is Y in formula (1a). Ａ and R ｒ２４ ~R ｒ２６ each independently represents a hydrogen atom or a substituent; R Ａ is 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 14 or more carbon atoms, and R ｒ２５ and R ｒ２６ may be linked to each other to form a ring. In formula (31a), the wavy line portion represents Y in formula (1). Ａ represents the position at which the carbon atom having the formula ｒ３１ represents an oxygen atom or a sulfur atom, R ｒ３５ ~R ｒ３７ Each independently represents a hydrogen atom, a substituent, or R Ａ represents 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 14 or more carbon atoms, provided that R ｒ３５ ~R ｒ３７ At least one of is R Ａ and R ｒ３６ may be linked to each other to form a ring.

18. All R Ａ , R Ｂ and R Ｃ The aromatic heterocyclic compound according to any one of claims 15 to 17, wherein the total number of carbon atoms in all aliphatic hydrocarbon groups is 40 to 80.

Images