Method for producing peptide compound, reagent for protective group formation use, and dinaphthylmethyl compound

Abstract

The present invention addresses the problem of providing: a method for producing a peptide compound excellent with respect to yield and crystallization properties; a reagent for protective group formation use, the reagent being excellent with respect to yield and crystallization properties; and a novel dinaphthylmethyl compound. The present invention provides a method for producing a peptide compound, the method including a step in which a dinaphthylmethyl compound represented by formula (1) is used. In formula (1), YA represents -OH, -NHR, or the like; R represents a hydrogen atom, an alkyl group, or the like; ZA represents a hydrogen atom, or the like; RA and RB each independently represent an aliphatic hydrocarbon group, or an organic group having an aliphatic hydrocarbon group; at least one of the aliphatic hydrocarbon groups has 12 or more carbon atoms; m and n each independently represent an integer of 0-7; m + n is 1 or more; and when m or n is 2 or more, RA's or RB's may be the same as or different from each other.

Description

Method for producing peptide compounds, reagent for forming protecting groups, and dinaphthylmethyl compounds

[0001] The present invention relates to a method for producing a peptide compound, a reagent for forming a protecting group, and a dinaphthylmethyl compound.

[0002] Methods for producing peptides include 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 requires the use of excess reaction reagents to compensate for low reactivity. This poses problems in tracking the reaction and analyzing the reaction product while it is supported on the carrier. On the other hand, the liquid-phase method has good reactivity, and the intermediate peptide can be purified by extraction, washing, isolation, etc. after the condensation reaction. However, the liquid-phase method still has issues in the coupling reaction and deprotection steps.

[0003] Known conventional protecting group-forming reagents include a compound having a fluorene structure described in Patent Document 1 and a compound having a diphenylmethane structure described in Patent Document 2. Furthermore, Patent Document 3 describes the use of a condensed polycyclic aromatic hydrocarbon compound as a protecting group-forming reagent.

[0004] International Publication No. WO2010 / 104169 International Publication No. WO2010 / 113939 International Publication No. WO2020 / 262258

[0005] The problem to be solved by one embodiment of the present invention is to provide a method for producing a peptide compound which is excellent in yield and crystallization property. The problem to be solved by another embodiment of the present invention is to provide a reagent for protecting group formation which is excellent in yield and crystallization property. The problem to be solved by yet another embodiment of the present invention is to provide a novel dinaphthylmethyl compound.

[0006] As a result of intensive investigations aimed at solving the above-mentioned problems, the present inventors have found that peptide compounds can be produced in high yields by using a dinaphthylmethyl compound represented by the following formula (1) as a protecting group-forming reagent. The present invention was completed based on the above-mentioned findings.

[0007] According to the present invention, the following inventions are provided: <1> A method for producing a peptide compound, which comprises a step of using a dinaphthylmethyl compound represented by the following formula (1): In formula (1), 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; Z Ａ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; R Ａ and R Ｂ each independently represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, at least one of the aliphatic hydrocarbon groups having 12 or more carbon atoms, m and n each independently represent an integer of 0 to 7, m+n is 1 or more, and when m or n is 2 or more, each R Ａ and R Ｂand may be the same or different. <2> The method for producing a peptide compound according to <1>, wherein the step of using the dinaphthylmethyl 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 dinaphthylmethyl compound represented by formula (1). <3> The method for producing a peptide compound according to <2>, wherein the amino acid compound or peptide compound in the C-terminal protection step is an N-terminally protected amino acid compound or an N-terminally protected peptide compound, and further comprising: an N-terminal deprotection step of deprotecting the N-terminus of the N-terminally protected and C-terminally protected amino acid compound or the N-terminally protected and C-terminally protected peptide compound obtained in the C-terminal protection step; a peptide chain elongation step of condensing the N-terminal protected amino acid compound or the N-terminally protected peptide compound to the N-terminus of the C-terminally protected amino acid compound or the C-terminally protected peptide compound obtained in the N-terminal deprotection step; and a precipitation step of precipitating the N-terminally protected and C-terminally protected peptide compound obtained in the peptide chain elongation step. <4> A method for producing a peptide compound according to <3>, further comprising, after the precipitation step, one or more of the following steps in this order: deprotecting the N-terminus of the obtained N-terminally protected and C-terminally protected peptide compound; 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 precipitating the obtained N-terminally protected and C-terminally protected peptide compound. <5> A method for producing a peptide compound according to any one of <1> to <4>, further comprising a C-terminal deprotection step of deprotecting a C-terminal protecting group. <6> A method for producing a peptide compound according to any one of <1> to <5>, wherein the total number of carbon atoms in the aliphatic hydrocarbon groups is 36 to 80. <7> R Ａ and R Ｂ are each independently a group represented by the following formula (f1) or formula (a1): In formula (f1), the wavy line represents the bonding position to other structures, m9 represents an integer of 1 to 3, and X ９ each independently represents a single bond, —O—, —S—, —COO—, —OCO—, —OCONH—, —NHCONH—, —NHCO—, or —CONH—; R ９each 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, 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. In formula (a1), the wavy line represents the bonding position to other structures, m20 represents an integer of 1 to 10, and X ２０ each independently represents a single bond, —O—, —S—, —COO—, —OCO—, —OCONH—, —NHCONH—, —NHCO—, or —CONH—; R ２０ each independently represents a divalent aliphatic hydrocarbon group, R ２０ At least one of the above is a divalent aliphatic hydrocarbon group having 5 or more carbon atoms. <8> A reagent for forming a protecting group, comprising a dinaphthylmethyl compound represented by the following formula (1): In formula (1), 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; Z Ａ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; R Ａ and R Ｂ each independently represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, at least one of the aliphatic hydrocarbon groups having 12 or more carbon atoms, m and n each independently represent an integer of 0 to 7, m+n is 1 or more, and when m or n is 2 or more, each R Ａ and R Ｂmay be the same or different. <9> The reagent for forming a protecting group according to <8>, which is a reagent for forming a protecting group of a carboxy group or an amide group. <10> The reagent for forming a protecting group according to <8> or <9>, which is a reagent for forming a C-terminal protecting group of an amino acid compound or a peptide compound. <11> A dinaphthylmethyl compound represented by the following formula (1): In formula (1), 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; Z Ａ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; R Ａ and R Ｂ each independently represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, at least one of the aliphatic hydrocarbon groups having 12 or more carbon atoms, m and n each independently represent an integer of 0 to 7, m+n is 1 or more, and when m or n is 2 or more, each R Ａ and R Ｂ may be the same or different. Ａ and R Ｂ are each independently a group represented by the following formula (f1) or (a1): In formula (f1), the wavy line represents the bonding position to other structures, m9 represents an integer of 1 to 3, and X ９ each independently represents a single bond, —O—, —S—, —COO—, —OCO—, —OCONH—, —NHCONH—, —NHCO—, or —CONH—; R ９ each independently represents a divalent aliphatic hydrocarbon group, Ar １ represents an (m10+1)-valent aromatic group or an (m10+1)-valent heteroaromatic group, m10 represents an integer of 1 to 3, X １０ each independently represents a single bond, —O—, —S—, —COO—, —OCO—, —OCONH—, —NHCONH—, —NHCO—, or —CONH—; R１０ 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. In formula (a1), the wavy line represents the bonding position to other structures, m20 represents an integer of 1 to 10, and X ２０ each independently represents a single bond, —O—, —S—, —COO—, —OCO—, —OCONH—, —NHCONH—, —NHCO—, or —CONH—; R ２０ each independently represents a divalent aliphatic hydrocarbon group, R ２０ At least one of the groups is a divalent aliphatic hydrocarbon group having 5 or more carbon atoms.

[0008] According to the present invention, a peptide compound can be produced in high yield and with excellent crystallization properties.

[0009] The contents of the present disclosure will be described in detail below. The following description of the constituent elements may be based on representative embodiments of the present disclosure, but the present disclosure is not limited to such embodiments. In this specification, unless otherwise specified, each term has the following meaning. A numerical range expressed using "to" means a range that includes the numerical values ​​before and after "to" as the upper and lower limits. In numerical ranges described in stages in this specification, the upper or lower limit described in one numerical range may be replaced with the upper or lower limit of another numerical range described in stages. Furthermore, in numerical ranges described in this specification, the upper or lower limit of that numerical range may be replaced with a value shown in the examples. The term "step" includes not only independent steps, but also steps that cannot be clearly distinguished from other steps, as long as the intended purpose of the step is achieved. In the description of groups (atomic groups) in this specification, a notation that does not specify whether they are substituted or unsubstituted 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). The chemical structural formula may be expressed as a simplified structural formula in which hydrogen atoms are omitted. A combination of two or more preferred embodiments is a more preferred embodiment.

[0010] The alkyl group may be linear or branched, and may be substituted with a halogen atom or the like. Examples of alkyl groups having 1 to 6 carbon atoms (also referred to as "number of carbon atoms") include methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl. Examples of alkenyl groups having 2 to 6 carbon atoms include 1-propenyl. Examples of aryl groups are preferably aryl groups having 6 to 14 carbon atoms, such as phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, and 2-anthryl. Among these, aryl groups having 6 to 10 carbon atoms are more preferred, and phenyl is particularly preferred. Examples of silyl groups include trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, and tert-butyldiethylsilyl. Examples of halogen atoms include fluorine, chlorine, bromine, and iodine. Examples of alkoxy groups having 1 to 6 carbon atoms include methoxy, ethoxy, and propoxy. An example of an aralkyl group having 7 to 10 carbon atoms is benzyl. An example of an acyl group having 1 to 6 carbon atoms is acetyl or propionyl. An example of an aralkyl-carbonyl group having 7 to 10 carbon atoms is benzylcarbonyl. An example of an alkoxycarbonyl group having 1 to 6 carbon atoms is methoxycarbonyl, ethoxycarbonyl, or a Boc group. The Boc group refers to a tert-butoxycarbonyl group. An example of an aralkyloxycarbonyl group having 7 to 14 carbon atoms is benzyloxycarbonyl or an Fmoc group. The Fmoc group refers to a 9-fluorenylmethoxycarbonyl group.

[0011] (Method for Producing Peptide Compound) The method for producing a peptide compound according to the present disclosure includes a step of using a dinaphthylmethyl compound represented by the following formula (1). In formula (1), 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; Z Ａrepresents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; R Ａ and R Ｂ each independently represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, at least one of the aliphatic hydrocarbon groups having 12 or more carbon atoms, m and n each independently represent an integer of 0 to 7, m+n is 1 or more, and when m or n is 2 or more, each R Ａ and R Ｂ may be the same or different.

[0012] The compound represented by formula (1) according to the present disclosure has at least one aliphatic hydrocarbon group having 12 or more carbon atoms, and therefore the protected compound has excellent solubility in hydrophobic solvents. Ａ , and R Ｂ The aliphatic hydrocarbon groups in the compound aggregate with each other, and the presence of a naphthalene ring causes π-π interactions (π-π stacking) between the naphthalene rings in the resulting peptide compound, resulting in excellent crystallization properties as well as excellent purification and separability. In other words, when the protected compound is subjected to a reaction, the reaction proceeds quickly due to its excellent solubility in a hydrophobic reaction solvent, and the target product can be efficiently crystallized and purified by adding a polar solvent, which is a poor solvent, during purification, which is presumably why the yield of the resulting compound (peptide compound, etc.) is excellent.

[0013] Furthermore, in formula (1), Z Ａ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. The compound represented by formula (1) according to the present disclosure has low steric hindrance and is therefore excellent in loading yield (protection of amino acids).

[0014] Also, Y bonded to the naphthalene ring via a di- or tri-substituted methylene group Ａ This is believed to be because the naphthalene ring contributes to electron donating properties or cation stabilization.

[0015] Furthermore, the compound represented by formula (1) according to the present disclosure, due to its structure, can suppress side reactions, synthesize peptides with high purity, is stable during the peptide synthesis reaction, and is easy to deprotect (remove).

[0016] 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 dinaphthylmethyl 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. In particular, the dinaphthylmethyl compound represented by formula (1) is preferably used for forming a protecting group, and more preferably used for forming a C-terminal protecting group in an amino acid compound or a peptide compound.

[0017] <Dinaphthylmethyl Compound Represented by Formula (1)> The dinaphthylmethyl compound represented by formula (1) according to the present disclosure (hereinafter also simply referred to as "compound represented by formula (1)") is shown below.

[0018] In formula (1), 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; Z Ａ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; R Ａ and R Ｂ each independently represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, at least one of the aliphatic hydrocarbon groups having 12 or more carbon atoms, m and n each independently represent an integer of 0 to 7, m+n is 1 or more, and when m or n is 2 or more, each R Ａ and R Ｂ may be the same or different.

[0019] Y in formula (1) Ａis preferably -OH, -NHR, or -SH, and more preferably -OH or -NHR, from the viewpoints of deprotection rate, solvent solubility, and yield. Examples of the alkyl group for R include alkyl groups having 1 to 30 carbon atoms (also referred to as "number of carbon atoms"), preferably alkyl groups having 1 to 10 carbon atoms, and more preferably alkyl groups having 1 to 6 carbon atoms. Among these, methyl and ethyl groups are more preferred.

[0020] 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 (aryl 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, with a benzyl group being more preferred.

[0021] 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 (heteroaryl 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.

[0022] 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. Ａ Ga-NH２ Therefore, when R is an Fmoc group and when R is a hydrogen atom, they can be considered equivalent.

[0023] Z in formula (1) Ａ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, preferably a hydrogen atom or a methyl group, and more preferably a hydrogen atom.

[0024] In formula (1), R Ａ In terms of deprotection rate, solvent solubility, and yield, m, which is the number of substitutions in R, is preferably an integer of 1 to 4, more preferably an integer of 1 to 3, and particularly preferably 1 or 2. Ｂ From the viewpoints of deprotection rate, solvent solubility, and yield, n, which is the number of substitutions, is preferably an integer of 1 to 4, more preferably an integer of 1 to 3, and particularly preferably 1 or 2.

[0025] In formula (1), m+n is 1 or more, and from the viewpoints of deprotection rate, solvent solubility, and yield, is preferably an integer of 1 to 6, more preferably an integer of 1 to 4, and even more preferably 1 to 3.

[0026] In formula (1), R Ａ and R Ｂ each independently represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and at least one of the aliphatic hydrocarbon groups has 12 or more carbon atoms.

[0027] In this specification, the term "organic group having an aliphatic hydrocarbon group" refers to a monovalent (one bond) organic group having an aliphatic hydrocarbon group in its molecular structure. The term "aliphatic hydrocarbon group" refers to a linear, branched, or cyclic, saturated or unsaturated aliphatic hydrocarbon group having 5 or more carbon atoms. From the viewpoints of solvent solubility, crystallization ability, and yield, an aliphatic hydrocarbon group having 5 to 60 carbon atoms is preferred, an aliphatic hydrocarbon group having 5 to 30 carbon atoms is more preferred, and an aliphatic hydrocarbon group having 10 to 30 carbon atoms is particularly preferred. From the viewpoints of solvent solubility, crystallization ability, 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 a terminal (monovalent group) or at another location (for example, a divalent group).

[0028] Examples of the "aliphatic hydrocarbon group" include alkyl groups, cycloalkyl groups, alkenyl groups, and alkynyl groups. Specific examples include monovalent groups such as pentyl, hexyl, octyl, decyl, hexadecyl, octadecyl, icosyl, docosyl, tetracosyl, lauryl, tridecyl, myristyl, oleyl, and isostearyl groups, as well as divalent groups derived therefrom (divalent groups obtained by removing one hydrogen atom from the above monovalent groups), and groups obtained by removing hydroxyl groups and the like from various steroid groups.

[0029] Furthermore, as the "alkyl group", for example, an alkyl group having 5 to 30 carbon atoms is preferred, and examples thereof include 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, an isostearyl group, etc., with an octadecyl group, an icosyl group, a docosyl group, or a tetracosyl group being preferred, and an icosyl group, a docosyl group, or a tetracosyl group being more preferred. As the "cycloalkyl group", for example, a cycloalkyl group having 5 to 30 carbon atoms is preferred, and examples thereof include a cyclopentyl group, a cyclohexyl group, an isobornyl group, a tricyclodecanyl group, etc. Furthermore, these may be linked repeatedly, or may have a condensed ring structure of two or more rings.

[0030] The "alkenyl group" is preferably an alkenyl group having 5 to 30 carbon atoms, for example, a pentenyl group, a hexenyl group, an oleyl group, etc. The "alkynyl group" is preferably an alkynyl group having 5 to 30 carbon atoms, for example, a 4-pentynyl group, a 5-hexenyl group, etc. The "steroid group" is preferably a group having a cholesterol structure or an estradiol structure, for example. The above 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.

[0031] The silyl group is preferably a trialkylsilyl group, and more preferably a silyl group having three alkyl groups of 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 of 1 to 3 carbon atoms. The hydrocarbon group having a silyloxy structure preferably has 1 to 3 silyloxy structures. Furthermore, the hydrocarbon group having a silyloxy structure preferably has 10 or more carbon atoms, more preferably 10 to 100 carbon atoms, and particularly preferably 16 to 50 carbon atoms.

[0032] Preferred examples of the hydrocarbon group having a silyloxy structure include groups represented by the following formula (Si):

[0033]

[0034] In formula (Si), R ｓｉ１ represents a single bond or an alkylene group having 1 to 3 carbon atoms, R ｓｉ２ represents an alkylene group having 1 to 3 carbon atoms, and R ｓｉ３ and R ｓｉ４ are each independently 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.

[0035] 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.

[0036] 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. 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 number of carbon atoms in the organic group having a perfluoroalkyl structure is preferably 5 or more, more preferably 10 or more, even more preferably 10 to 100, and particularly preferably 16 to 50. Preferred examples of the organic group having a perfluoroalkyl structure include the groups shown below.

[0037]

[0038] The moiety other than the aliphatic hydrocarbon group in the organic group having an aliphatic hydrocarbon group can be set as desired. For example, the organic group may have a moiety such as -O-, -S-, -COO-, -OCONH-, -CONH-, or a hydrocarbon group (monovalent or divalent group) other than an "aliphatic hydrocarbon group." Examples of hydrocarbon groups other than aliphatic hydrocarbon groups include aliphatic hydrocarbon groups having 1 to 4 carbon atoms and aromatic hydrocarbon groups. Specific examples include monovalent groups such as alkyl groups and aryl groups having 1 to 4 carbon atoms, as well as divalent groups derived therefrom. Examples of "aryl groups" include preferably aryl groups having 6 to 14 carbon atoms, such as phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, and 2-anthryl. Among these, aryl groups having 6 to 10 carbon atoms are more preferred, and phenyl is particularly preferred. The aliphatic hydrocarbon groups and hydrocarbon groups other than the aliphatic hydrocarbon groups may be substituted with a substituent selected from halogen atoms, oxo groups, and the like.

[0039] The above R ＡIn the formula, the bond (substitution) of the organic group having an aliphatic hydrocarbon group to the naphthalene ring is Ａ Even if the aliphatic hydrocarbon group present in the R Ａ In view of ease of synthesis of the compound, it is preferable that the bond is formed via —O—, —S—, —COO—, —OCONH—, —CONH—, or the like moiety present in the alkyl group. Preferably, the bond is formed via —O—, —S—, —COO—, or —CONH—, and particularly preferably via —O—.

[0040] In the compound represented by formula (1) according to the present disclosure, R Ａ , and R Ｂ From the viewpoints of solvent solubility, crystallization property, and yield, the total number of carbon atoms in all of 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.

[0041] In addition, the compound represented by formula (1) according to the present disclosure is R Ａ and R Ｂ At least one aliphatic hydrocarbon group has 12 or more carbon atoms. Ａ and R Ｂ At least one of the groups is more preferably an aliphatic hydrocarbon group having 12 to 100 carbon atoms, even more preferably an aliphatic hydrocarbon group having 14 to 40 carbon atoms, and particularly preferably an aliphatic hydrocarbon group having 16 to 36 carbon atoms.

[0042] The compound represented by formula (1) according to the present disclosure is R Ａ and R ＢWhen the carbon number of at least one of the aliphatic hydrocarbon groups is preferably 14 or more, more preferably 16 or more, even more preferably 18 or more, and particularly preferably 20 or more, a more excellent effect is exhibited. The reason for this is thought to be that as the carbon number increases, the contribution rate of hydrophobicity to the entire molecule increases, making it easier to dissolve in hydrophobic solvents, and also, in hydrophilic solvents, as the carbon number increases, the cohesive force increases, making it easier to crystallize. Furthermore, from the viewpoint of crystallization property and yield, the aliphatic hydrocarbon group is preferably an alkyl group, more preferably a linear alkyl group. In addition, when one R Ａ , and R Ｂ are each independently, from the viewpoints of solvent solubility, crystallization property, and yield, preferably have 12 to 200 carbon atoms, more preferably have 18 to 150 carbon atoms, further preferably have 18 to 100 carbon atoms, and particularly preferably have 20 to 80 carbon atoms.

[0043] From the viewpoints of solvent solubility, crystallization property, and yield, in formula (1), R Ａ and R Ｂ are each independently preferably a group represented by any one of the following formula (f1), formula (a1), formula (b1) and formula (e1), more preferably a group represented by the following formula (f1) or formula (a1), and particularly preferably a group represented by the following formula (f1):

[0044] In formula (f1), the wavy line represents the bonding position to other structures, m9 represents an integer of 1 to 3, and X ９ each independently represents a single bond, —O—, —S—, —COO—, —OCO—, —OCONH—, —NHCONH—, —NHCO—, or —CONH—; R ９ each independently represents a divalent aliphatic hydrocarbon group, Ar １ represents an (m10+1)-valent aromatic group or an (m10+1)-valent heteroaromatic group, m10 represents an integer of 1 to 3, X １０ each independently represents a single bond, —O—, —S—, —COO—, —OCO—, —OCONH—, —NHCONH—, —NHCO—, or —CONH—; R １０each 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.

[0045] In formula (a1), the wavy line represents the bonding position to other structures, m20 represents an integer of 1 to 10, and X ２０ each independently represents a single bond, —O—, —S—, —COO—, —OCO—, —OCONH—, —NHCONH—, —NHCO—, or —CONH—; R ２０ each independently represents a divalent aliphatic hydrocarbon group, R ２０ At least one of the groups is a divalent aliphatic hydrocarbon group having 5 or more carbon atoms.

[0046]

[0047] In formula (b1), the wavy line represents the bonding position to other structures, 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.

[0048]

[0049] In formula (e1), the wavy line represents the bonding position with other structures, 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.

[0050] In formula (f1), m9 is preferably 1 or 2, and more preferably 1. X in formula (f1) ９ and X １０ are each independently preferably —O—, —S—, —COO—, —OCONH—, or —CONH—, and more preferably —O—. ９ are each independently preferably an alkylene group having 1 to 10 carbon atoms, more preferably an alkylene group having 1 to 4 carbon atoms, and particularly preferably a methylene group. 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. m10 in formula (f1) is preferably 2 or 3, more preferably 2. Ar in formula (f1) １ is preferably an (m10+1)-valent aromatic group, more preferably a group in which (m10+1) hydrogen atoms have been removed from benzene or a group in which (m10+1) hydrogen atoms have been removed from naphthalene, and particularly preferably a group in which (m10+1) hydrogen atoms have been removed from benzene.

[0051] Furthermore, 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.

[0052]

[0053] In formula (f2), the wavy line portion represents a bonding position with another structure, m10 represents an integer of 1 to 3, m11 represents an integer of 1 to 3, and X １０ each independently represents a single bond, —O—, —S—, —COO—, —OCO—, —OCONH—, —NHCONH—, —NHCO—, or —CONH—; R １０each independently represents a monovalent aliphatic hydrocarbon group having 5 or more carbon atoms.

[0054] m10 and X in formula (f2) １０ and R １０ are m10 and X in formula (f1), respectively. １０ and R １０ In formula (f2), m11 is preferably 1 or 2, and more preferably 1.

[0055] In formula (a1), m20 is preferably 1 or 2. X in formula (a1) ２０ are each independently preferably —O—, —S—, —COO—, —OCONH—, or —CONH—, and more preferably —O—. 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.

[0056] In formula (b1), mb is preferably 1. In formula (b1), b1 to b4 are each independently preferably 1 or 2, more preferably 1. X in formula (b1) ｂ１ ~X ｂ４ are each independently preferably —O—, —S—, —COO—, —OCONH—, or —CONH—, and more preferably —O—. 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. 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.

[0057] In terms of solvent solubility, the compound represented by formula (1) according to the present disclosure may have the aliphatic hydrocarbon group be a branched aliphatic hydrocarbon group or the group shown below. The wavy line portion represents the bonding position with 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 group shown below is 14 to 300.

[0058]

[0059] 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.

[0060] Specific examples of the dinaphthylmethyl compound represented by formula (1) include the compounds shown below, but needless to say, the compound is not limited to these. ｇ represents an aliphatic hydrocarbon group.

[0061]

[0062] <Method for Producing Dinaphthylmethyl Compound Represented by Formula (1)> The method for producing the fused polycyclic aromatic hydrocarbon compound represented by formula (1) is not particularly limited, and the compound can be produced by reference to known methods. Unless otherwise specified, the raw material compounds used in the production of the dinaphthylmethyl compound represented by formula (1) may be commercially available compounds, or the compound can be produced by known methods or methods similar thereto. If necessary, the produced dinaphthylmethyl compound represented by formula (1) may be purified by known purification methods. For example, methods for isolation and purification by recrystallization, column chromatography, etc., and methods for purification by reprecipitation by changing the solution temperature or solution composition, etc., can be used.

[0063] The synthesis method of the dinaphthylmethyl compound represented by formula (1) is not particularly limited, but for example, the compound can be synthesized according to the following scheme: Alternatively, the compound can be synthesized by referring to the synthesis method described in WO 2010 / 113939.

[0064]

[0065] A represents a naphthalene ring. Ａ and R Ｂ each independently represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, and at least one of the aliphatic hydrocarbon groups has 12 or more carbon atoms. a and b each independently represent an integer of 0 to 7, a+b is 1 or more, and when a or b is 2 or more, each R Ａ and R Ｂ may be the same or different. X represents a halogen or OR, and R represents an alkyl group or an aromatic group which may have a substituent. X １００ represents Cl, Br or I. １０２ represents a hydrogen atom, an alkyl group, or an Fmoc group. Ｘ represents an alkyl group.

[0066] (Method for producing peptide compound) In the method for producing a peptide compound according to the present disclosure, the step of using the dinaphthylmethyl 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 dinaphthylmethyl compound represented by formula (1) above.

[0067] Furthermore, in the method for producing a peptide compound according to the present disclosure, preferably, the amino acid compound or peptide compound in the C-terminal protection step is an N-terminally protected amino acid compound or an N-terminally protected peptide compound, and from the viewpoint of ease of synthesis of the peptide compound and yield, it is more preferable that the method further comprises 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, a peptide chain elongation step of condensing the N-terminal of the C-terminally protected amino acid compound or C-terminally protected peptide compound obtained in the N-terminal deprotection step with an N-terminally protected amino acid compound or an N-terminally protected peptide compound, and a precipitation step of precipitating the N-terminally protected C-peptide compound obtained in the peptide chain elongation step. It is particularly preferred that the method for producing a peptide compound according to the present disclosure further comprises, after the precipitation step, one or more of the following steps in this order: deprotecting the N-terminus of the obtained N-terminally protected and C-terminally protected peptide compound; 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 precipitating the obtained N-terminally protected and C-terminally protected peptide compound. Furthermore, it is preferred that the method for producing a peptide compound according to the present disclosure further comprises a C-terminal deprotection step of deprotecting the C-terminal protecting group.

[0068] 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 dinaphthylmethyl compound represented by formula (1) in a solvent. Each of the above steps will be described in detail below.

[0069] <Dissolving Step> The method for producing a peptide compound according to the present disclosure preferably includes a dissolving step of dissolving the dinaphthylmethyl compound represented by formula (1) in a solvent prior to the C-terminal protection step. While common organic solvents can be used for the reaction, it is preferable to select a solvent that has high solubility for the dinaphthylmethyl compound represented by formula (1). Higher solubility in the solvent is expected to result in better reactivity, so it is preferable to select a solvent that has high solubility for the dinaphthylmethyl compound represented by formula (1). Specific examples include halogenated hydrocarbons such as chloroform and dichloromethane; and nonpolar organic solvents such as 1,4-dioxane, tetrahydrofuran, and cyclopentyl methyl ether. Two or more of these solvents may be mixed in an appropriate ratio. Furthermore, the halogenated hydrocarbons or nonpolar organic solvents may be mixed in an appropriate ratio with 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; or sulfoxides such as dimethyl sulfoxide, as long as the dinaphthylmethyl compound represented by formula (1) can be dissolved. In addition, solvents described in Organic Process Research & Development, 2017, 21, 3, 365-369 may be used.

[0070] <C-Terminal Protection Step> The method for producing a peptide compound according to the present disclosure preferably 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 a dinaphthylmethyl compound represented by formula (1). The amino acid compound or peptide compound used in the C-terminal protection step is not particularly limited and any known compound can be used, but an N-terminal protected amino acid compound or an N-terminal protected peptide compound is preferred, and an Fmoc-protected amino acid compound or an Fmoc-protected peptide compound is more preferred. Furthermore, in the amino acid compound or peptide compound used in the C-terminal protection step, groups other than the C-terminal portion, such as hydroxy groups, amino groups, carbonyl groups, amide groups, imidazole groups, indole groups, guanidyl groups, and mercapto groups, are preferably 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 fused polycyclic aromatic hydrocarbon compound represented by the above formula (1).

[0071] Y in formula (1) Ａ When using a dinaphthylmethyl compound represented by the above formula (1) in which Y is —OH or —SH, the reaction is preferably carried out in a solvent that does not affect the reaction, in the presence of a condensation additive (condensation activator), with the addition of a condensation agent, or in the presence of an acid catalyst. Ａ When using a dinaphthylmethyl compound represented by formula (1) in which is -NHR, 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 dinaphthylmethyl compound represented by formula (1).

[0072] 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, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorphonium chloride (DMT-MM), 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-(benzotriazole ... Examples of suitable benzotriazol-1-yloxytrimethyluronium tetrafluoroborate include (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (COMU), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), its hydrochloride salt (EDC·HCl), and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBop). Among these, DIC, EDC, EDC·HCl, DMT-MM, HBTU, HATU, and COMU are preferred. The amount of the condensing agent used is preferably 1 to 10 molar equivalents, more preferably 1 to 5 molar equivalents, relative to 1 molar equivalent of the dinaphthylmethyl compound represented by the above formula (1).

[0073] The acid catalyst used in the condensation reaction can be any acid catalyst commonly used in peptide synthesis, without limitation, and examples thereof include methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, etc. Among these, methanesulfonic acid and p-toluenesulfonic acid are preferred. The amount of the acid catalyst used is preferably more than 0 molar equivalents and not more than 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 dinaphthylmethyl compound represented by formula (1) above.

[0074] 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, in the presence of a condensation agent, converts an amino acid into a corresponding activated ester, symmetrical acid anhydride, or the like, 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. 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, and ethyl(hydroxyimino)cyanoacetate (Oxyma). 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 not more than 4.0 molar equivalents, and more preferably 0.1 to 1.5 molar equivalents, relative to the amino acid compound or peptide compound.

[0075] The base can be any base commonly used in peptide synthesis, and examples thereof include tertiary amines such as diisopropylethylamine. The solvent can be any of the solvents described above in the dissolution step. The reaction temperature is not particularly limited, but is preferably −10° C. to 80° C., and more preferably 0° C. to 40° C. The reaction time is not particularly limited, but is preferably 1 hour to 30 hours. The progress of the reaction can be monitored by methods similar to those used in general liquid-phase organic synthesis reactions. That is, the reaction can be monitored using thin-layer silica gel chromatography, high-performance liquid chromatography, NMR, or the like.

[0076] The N-terminally protected, C-terminally protected amino acid compound or N-terminally protected, C-terminally protected peptide compound obtained by the above-mentioned C-terminal protection step may be purified. For example, the obtained N-terminally protected, C-terminally protected amino acid compound or N-terminally protected, C-terminally protected peptide compound is dissolved in a solvent, and then the desired organic synthesis reaction is carried out. To isolate the resulting product, a preferred method is to change the solvent in which the N-terminally protected, C-terminally protected amino acid compound or N-terminally protected, C-terminally protected peptide compound is dissolved (e.g., by changing the solvent composition or type of solvent) and then reprecipitation. Specifically, for example, the reaction is carried out under conditions that allow the N-terminally protected, C-terminally protected amino acid compound or N-terminally protected, C-terminally protected peptide compound to dissolve. After the reaction, the solvent is distilled off and then solvent replacement is performed. Alternatively, after the reaction, a polar solvent is added to the reaction system without distilling off the solvent, thereby precipitating the aggregates and removing impurities. As the replacement solvent, polar organic solvents such as methanol, acetonitrile, water, etc. are used alone or in combination. That is, the reaction is carried out under conditions in which the N-terminal-protected and C-terminal-protected amino acid compound or the N-terminal-protected and C-terminal-protected peptide compound dissolves, and after the reaction, solvent substitution is carried out using, for example, a halogenated solvent, THF, or the like for dissolution, and a polar organic solvent such as methanol, acetonitrile, or water for precipitation.

[0077] <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-terminally protected amino acid compound or N-terminally protected C-terminally protected peptide compound obtained in the above-mentioned C-terminal protection step. As the N-terminal protecting group, any of the amino group protecting groups described below that are commonly used in technical fields such as peptide chemistry can be used, but in the present disclosure, a Boc group, a benzyloxycarbonyl group (hereinafter also referred to as a Cbz group or a Z group), or an Fmoc group is preferably used.

[0078] 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 dinaphthylmethyl compound represented by formula (1) is preferred. For example, in the case of an Fmoc group, deprotection is carried out by treatment with a base, and in the case of a Boc group, deprotection is carried out by treatment with an acid. The reaction is carried out in a solvent that does not affect the reaction.

[0079] Examples of the base 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 described above in the dissolution step can be suitably used.

[0080] <Peptide Chain Elongation Step> The method for producing a peptide compound according to the present disclosure preferably includes a peptide chain elongation step in which an N-terminal protected amino acid compound or an N-terminal protected peptide compound is condensed with 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 N-terminal protected peptide compound is not particularly limited and any desired compound can be used, although an Fmoc-protected amino acid compound or an Fmoc-protected peptide compound is preferably used. Furthermore, it is preferable that groups other than the C-terminal portion of the N-terminal protected amino acid compound or N-terminal protected peptide compound, such as hydroxy 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.

[0081] <Precipitation Step> The method for producing a peptide compound according to the present disclosure preferably further comprises a precipitation step of precipitating the N-terminal-protected and C-terminal-protected peptide compound obtained in the peptide chain elongation step. The precipitation step can be carried out in the same manner as the precipitation method for purification that may be carried out after the C-terminal protection step described above.

[0082] <Chain elongation> The method for producing a peptide compound according to the present disclosure preferably further comprises, after the precipitation step, one or more of the following steps: deprotecting the N-terminus of the obtained N-terminally protected and C-terminally protected peptide compound; 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 precipitating the obtained N-terminally protected and C-terminally protected peptide compound. By repeating the above three steps, chain elongation 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 step described above.

[0083] <C-Terminal Deprotection Step> The method for producing a peptide compound according to the present disclosure preferably further comprises a C-terminal deprotection step of deprotecting a C-terminal protecting group. In the C-terminal deprotection step, the C-terminal protecting group formed by the dinaphthylmethyl compound represented by formula (1) in a C-terminally protected peptide compound having a desired number of amino acid residues is removed to obtain the final target peptide compound. Preferred methods for removing the C-terminal protecting group include deprotection methods 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) and hydrochloric acid. The acid concentration can be appropriately selected depending on the side chain protecting group of the amino acid to be elongated and the deprotection conditions, and is typically 1% by mass to 100% by mass relative to the total mass of the solvent used. The TFA concentration is preferably 70% by mass or less, more preferably 50% by mass or less, even more preferably 30% by mass or less, and particularly preferably 10% by mass or less. The deprotection time is preferably 5 hours or less, more preferably 3 hours or less, and even more preferably 1 hour or less.

[0084] The final target peptide compound obtained by the peptide compound production method according to the present disclosure can be isolated and purified according to methods commonly used in peptide chemistry. For example, the final target peptide compound can be isolated and purified by subjecting the reaction mixture to extraction and washing, crystallization, chromatography, etc. The type of peptide produced by the peptide compound production method according to the present disclosure is not particularly limited, but it is preferable that the number of amino acid residues of the peptide compound is, for example, several tens or less. The peptides obtained by the peptide compound production method according to the present disclosure, like existing or unknown synthetic peptides and natural peptides, can be used in various fields, including, but not limited to, pharmaceuticals, food, cosmetics, electronic materials, biosensors, etc. In the peptide compound production method 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.

[0085] 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.

[0086] Examples of the protecting group for a hydroxy group include an alkyl group having 1 to 6 carbon atoms, an aryl group, a trityl group, an aralkyl group having 7 to 10 carbon atoms, a formyl group, an acyl group having 1 to 6 carbon atoms, a benzoyl group, an aralkyl-carbonyl group having 7 to 10 carbon atoms, a 2-tetrahydropyranyl group, a 2-tetrahydrofuranyl group, a silyl group, an alkenyl group having 2 to 6 carbon atoms, etc. These groups may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, an alkoxy group having 1 to 6 carbon atoms (e.g., methoxy, ethoxy, propoxy), and a nitro group.

[0087] Examples of protecting groups for amino groups include formyl, acyl groups having 1 to 6 carbon atoms, alkoxycarbonyl groups having 1 to 6 carbon atoms, benzoyl groups, aralkyl-carbonyl groups having 7 to 10 carbon atoms, aralkyloxycarbonyl groups having 7 to 14 carbon atoms, trityl groups, monomethoxytrityl groups, 1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl groups, phthaloyl groups, N,N-dimethylaminomethylene groups, silyl groups, alkenyl groups having 2 to 6 carbon atoms, etc. These groups may be substituted with 1 to 3 substituents selected from the group consisting of halogen atoms, alkoxy groups having 1 to 6 carbon atoms, and nitro groups.

[0088] Examples of the protecting group for the carboxy group include the above-mentioned protecting groups for the hydroxy group, a trityl group, and the like.

[0089] Examples of protecting groups for carbonyl groups include cyclic acetals (e.g., 1,3-dioxane) and acyclic acetals (e.g., di(alkyl having 1 to 6 carbon atoms)acetals). Examples of protecting groups for guanidyl groups include 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl group, 2,3,4,5,6-pentamethylbenzenesulfonyl group, tosyl group, and nitro group. Examples of protecting groups for mercapto groups (sulfhydryl groups) include trityl group, 4-methylbenzyl group, acetylaminomethyl group, t-butyl group, and t-butylthio group. These protecting groups can be removed by known methods, for example, in accordance with the method described in Protective Groups in Organic Synthesis, John Wiley and Sons (1980). For example, methods using acids, bases, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halides, etc., reduction methods, etc. can be used.

[0090] (Protecting Group Forming Reagent) The protecting group forming reagent according to the present disclosure contains a dinaphthylmethyl compound represented by the following formula (1). In formula (1), 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; Z Ａ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; R Ａ and R Ｂ each independently represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, at least one of the aliphatic hydrocarbon groups having 12 or more carbon atoms, m and n each independently represent an integer of 0 to 7, m+n is 1 or more, and when m or n is 2 or more, each R Ａ and R Ｂ may be the same or different.

[0091] 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.

[0092] A preferred embodiment of the dinaphthylmethyl 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 dinaphthylmethyl compound represented by formula (1) according to the present disclosure described above. The protecting group forming reagent according to the present disclosure may be a solid reagent or a liquid reagent. The content of the dinaphthylmethyl 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.

[0093] The protecting group-forming reagent according to the present disclosure may contain components other than the dinaphthylmethyl compound represented by formula (1). The other components may include known components. For example, water, an organic solvent, an antioxidant, a pH adjuster, etc.

[0094] (Dinaphthylmethyl Compound Represented by Formula (1)) The compound according to the present disclosure is a dinaphthylmethyl compound represented by the following formula (1). In formula (1), 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; Z Ａ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; R Ａ and R Ｂ each independently represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, at least one of the aliphatic hydrocarbon groups having 12 or more carbon atoms, m and n each independently represent an integer of 0 to 7, m+n is 1 or more, and when m or n is 2 or more, each R Ａand R Ｂ may be the same or different.

[0095] In formula (1), preferably, R Ａ and R Ｂ are each independently a group represented by the following formula (f1) or formula (a1): In formula (f1), the wavy line represents the bonding position to other structures, m9 represents an integer of 1 to 3, and X ９ each independently represents a single bond, —O—, —S—, —COO—, —OCO—, —OCONH—, —NHCONH—, —NHCO—, or —CONH—; R ９ each independently represents a divalent aliphatic hydrocarbon group, Ar １ represents an (m10+1)-valent aromatic group or an (m10+1)-valent heteroaromatic group, m10 represents an integer of 1 to 3, 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. In formula (a1), the wavy line represents the bonding position to other structures, m20 represents an integer of 1 to 10, and X ２０ each independently represents a single bond, —O—, —S—, —COO—, —OCO—, —OCONH—, —NHCONH—, —NHCO—, or —CONH—; R ２０ each independently represents a divalent aliphatic hydrocarbon group, R ２０ At least one of the groups is a divalent aliphatic hydrocarbon group having 5 or more carbon atoms.

[0096] The preferred embodiments of the dinaphthylmethyl compound represented by formula (1) are the same as the preferred embodiments of the dinaphthylmethyl compound represented by formula (1) described above.

[0097] The dinaphthylmethyl compound represented by formula (1), which is a compound according to the present disclosure, is a novel compound and can be suitably used in the production of peptide compounds. In particular, it can be suitably used as a reagent for forming a protecting group, more suitably used as a reagent for forming a protecting group of a carboxy group or an amide group, and particularly suitably used as a reagent for forming a C-terminal protecting group of an amino acid compound or a peptide compound.

[0098] The present invention will be explained in more detail with reference to the following examples, but the present invention is not limited to these examples.

[0099] 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, percentages are based on mass.

[0100] 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 (Biotage) or Hi-Flash Column W001, W002, W003, W004, or W005 (Yamazen Corporation). The mixture ratio of the eluent used in column chromatography is a volume ratio. For example, "gradient elution of hexane:ethyl acetate = 50:50 to 0:100" means that the eluent of 50% hexane / 50% ethyl acetate was finally changed to an eluent of 0% hexane / 100% ethyl acetate. 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 of 50% hexane / 50% ethyl acetate was changed to an eluent of 0% hexane / 100% ethyl acetate, and then finally changed to an eluent of 20% methanol / 80% ethyl acetate.

[0101] MS spectra were measured using an ACQUITY SQD LC / MS System (manufactured by Waters Corporation; ionization method: ESI (ElectroSpray Ionization)). NMR spectra were measured using tetramethylsilane as an internal standard on a Bruker AV300 (manufactured by Bruker Corporation, 300 MHz) or a Bruker AV400 (manufactured by Bruker Corporation, 400 MHz), and all δ values ​​are shown in ppm.

[0102] <Synthesis of Protecting Group Forming Reagent (Compound (1-1), Compound (1-N-1))> In the following formula, C １８ H ３７ indicates a straight chain group.

[0103] 6-Methoxy-2-naphthoic acid (15.0 g, 74.2 mmol) and toluene (150 mL) were mixed, and under a nitrogen atmosphere and ice-cooling, oxalyl chloride (12.7 mL, 148 mmol) and N,N-dimethylformamide (1 drop) were added. The reaction mixture was stirred at 60°C for 30 minutes, then cooled to 40°C, and 2-methoxynaphthalene (14.1 g, 89.1 mmol) and methanesulfone (9.64 mL, 148 mmol) were added. The mixture was stirred under reflux for 7 hours, then returned to room temperature, and 10% aqueous potassium carbonate solution (5 mL) was added and stirred for 30 minutes. The precipitated solid was filtered, washed with water, and dried under reduced pressure to obtain intermediate (1-1) (2.40 g, 9.4%). １ H-NMR (CDCl ３ , 400MHz) δ=3.98 (6H, s), 7.10-7.25 (4H, m), 7.80-7.88 (4H, m), 7.97 (2H, dd), 8.26 (2H, d).

[0104] Under a nitrogen atmosphere, intermediate (1-1) (2.36 g, 6.89 mmol) and dichloromethane (12 mL) were mixed, and under ice-cooling, a 1 mol / L solution of boron tribromide in dichloromethane (27.6 mL, 27.6 mmol) was added and stirred for 30 minutes. An additional 1 mol / L solution of boron tribromide in dichloromethane (27.6 mL, 27.6 mmol) was added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was stirred for 30 minutes, then allowed to stand and the supernatant liquid was removed. The residue was washed with water and dried under reduced pressure to obtain intermediate (1-2) (2.30 g). １ H-NMR (DMSO, 400MHz) δ = 7.18 (2H, dd), 7.25 (2H, d), 7.81 (2H, dd), 7.86 (2H, d), 7.97 (2H, d), 8.27 (2H, s), 10.2 (2H, s).

[0105] Under a nitrogen atmosphere, intermediate (1-2) (2.30 g, 7.32 mmol), 1-bromooctadecane (5.12 g, 15.4 mmol), potassium carbonate (3.03 g, 22.0 mmol), and N,N-dimethylacetamide (23 mL) were mixed and stirred at 110°C for 3 hours. The reaction mixture was cooled to 80°C, and acetic acid (1.76 mL, 30.7 mmol) and water (46 mL) were added dropwise, taking care to avoid foaming. The reaction mixture was cooled to 30°C, and the precipitated solid was filtered, washed (with water, methanol, and acetone, in that order), and dried under reduced pressure to obtain intermediate (1-3) (5.36 g, 30.7 mmol). １ H-NMR (CDCl ３ , 400MHz) δ = 0.89 (6H, t), 1.15-1.60 (60H, m), 1.80-1.94 (4H, m), 4.12 (4 H, t), 7.15-7.24 (4H, m), 7.76-7.86 (4H, m), 7.96 (2H, dd), 8.25 (2H, s).

[0106] Under a nitrogen atmosphere, intermediate (1-3) (5.00 g, 6.47 mmol), tetrahydrofuran (53 mL), and methanol (5.3 mL) were mixed, and sodium borohydride (0.245 g, 6.47 mmol) was added at 40°C, followed by stirring for 2 hours. After completion of the reaction, acetone (2.4 mL) was added and stirred for 30 minutes, followed by stirring for 20 minutes. Methanol (130 mL) was added dropwise to the reaction mixture, followed by stirring for 30 minutes. The temperature of the reaction mixture was lowered to 80°C, and acetic acid (1.76 mL, 30.7 mmol) was added dropwise. The precipitated solid was filtered, washed (with methanol, then with acetone), and dried under reduced pressure to obtain compound (1-1) (4.80 g, 90%). １ H-NMR (CDCl ３ , 400MHz) δ = 0.88 (6H, t), 1.12-1.65 (60H, m), 1.79-1.93 (4H, m), 2.37 (1H, d), 4.05 (4H, t), 6.0 0-6.18 (1H, s) 7.12 (2H, d), 7.14 (2H, dd) 7.40 (2H, dd), 7.68 (2H, d), 7.71 (2H, d), 7.86 (2H, s).

[0107] Under a nitrogen atmosphere, intermediate (1-4) (0.77 g, 0.938 mmol), (9H-fluoren-9-ylmethoxy)carboxamide (0.269 g, 1.13 mmol), and toluene (19 mL) were mixed, and methanesulfonic acid (9.1 μL, 0.141 mmol) was added at 40° C., followed by stirring for 2 hours. After completion of the reaction, diisopropylamine (0.026 mL, 0.19 mmol) was added and the mixture was stirred for 30 minutes. Water (4 mL) was added to the reaction mixture, followed by separation. Methanol (19 mL) was added dropwise to the organic layer, and the mixture was stirred for 30 minutes. The precipitated solid was filtered, washed (with methanol, then acetonitrile), and dried under reduced pressure to obtain compound (1-N-1) (0.92 g, 94%). １ H-NMR (CDCl ３, 400MHz) δ = 0.88 (6H, t), 1.18-1.64 (60H, m), 1.76-1.91 (4H, m), 4.05 (4H, t), 4.16-4.3 0 (1H, m), 4.38-4.56 (2H, m), 5.41-5.60 (1H, m), 6.18-6.30 (1H, m), 7.03-7.85 (20H, m).

[0108] <Synthesis of Protecting Group Forming Reagent (Compound (1-2), Compound (1-N-2)>> The following compound (1-2) was obtained by synthesis in the same manner as the compound (1-1). ２２ H ４５ indicates a straight chain group.

[0109] １ H-NMR (CDCl ３ , 400MHz) δ = 0.88 (6H, t), 1.13-1.66 (76H, m), 1.78-1.91 (4H, m), 2.33 (1H, d) 4.06 (4H, t), 6.0 1-6.16 (1H, s) 7.10 (2H, d), 7.14 (2H, dd) 7.41 (2H, dd), 7.66 (2H, d), 7.72 (2H, d), 7.84 (2H, s).

[0110] The following compound (1-N-2) was obtained in the same manner as in the case of the above compound (1-N-1). ２２ H ４５ indicates a straight chain group.

[0111] １ H-NMR (CDCl ３ , 400MHz) δ = 0.87 (6H, t), 1.19-1.63 (76H, m), 1.76-1.92 (4H, m), 4.06 (4H, t), 4.17-4.3 3 (1H, m), 4.37-4.57 (2H, m), 5.42-5.59 (1H, m), 6.18-6.31 (1H, m), 7.04-7.85 (20H, m).

[0112] <Synthesis of protected peptide (four-residue peptide: Fmoc-Lys(Boc)-Gly-His(Trt)-Lys(Boc)-NH-protecting group)> Details of each abbreviation other than those mentioned above are as follows: Lys(Boc): Boc-protected lysine residue Gly: glycine residue His(Trt): Trt-protected arginine residue Trt: triphenylmethyl group

[0113] Example 1: Synthesis of Fmoc-Lys(Boc)-N-DiNaphTAG (1) The above compound (1-N-2) (also referred to as "DiNaphTAG (1)") (5.00 g, 4.33 mmol) was dissolved in tetrahydrofuran (87 mL), and diazabicycloundecene (DBU, 1.2 molar equivalents) was added at 48°C and stirred. After completion of the deprotection reaction, N-methylmorpholine (2.0 molar equivalents) and methanesulfonic acid (1.3 molar equivalents) were added sequentially, followed by the addition of Fmoc-Lys(Boc)-OH (1.2 molar equivalents) and (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (COMU, 1.2 molar equivalents) and stirring. After the condensation reaction was completed, methanol (430 mL) was added and stirred at room temperature, and the precipitate was filtered, washed with methanol and acetonitrile, and dried under reduced pressure to obtain Fmoc-Lys(Boc)-NH-DiNaphTAG (1) (5.91 g, yield 98.7%).

[0114] Example 2: Synthesis of Fmoc-His(Trt)-Lys(Boc)-NH-DiNaphTAG (1) Fmoc-Lys(Boc)-NH-DiNaphTAG (1) (5.60 g, 4.05 mmol) was dissolved in tetrahydrofuran (81 mL), and diazabicycloundecene (DBU, 1.2 molar equivalents) was added and stirred. After completion of the deprotection reaction, N-methylmorpholine (2.0 molar equivalents) and methanesulfonic acid (1.3 molar equivalents) were added sequentially, followed by Fmoc-His(Trt)-OH (1.2 molar equivalents) and (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (COMU, 1.2 molar equivalents) and stirring. After the condensation reaction was completed, methanol (400 mL) was added under ice cooling and stirred, and the precipitate was filtered, washed with methanol and acetonitrile, and dried under reduced pressure to obtain Fmoc-His(Trt)-Lys(Boc)-NH-DiNaphTAG (1) (6.93 g, yield 97.1%).

[0115] Example 3 Synthesis of Fmoc-Gly-His(Trt)-Lys(Boc)-NH-DiNaphTAG (1) Fmoc-His(Trt)-Lys(Boc)-NH-DiNaphTAG (1) (6.60 g, 3.74 mmol) was dissolved in tetrahydrofuran (75 mL), and diazabicycloundecene (DBU, 1.2 molar equivalents) was added and stirred. After completion of the deprotection reaction, N-methylmorpholine (2.0 molar equivalents) and methanesulfonic acid (1.3 molar equivalents) were added sequentially, followed by the addition of Fmoc-His(Trt)-OH (1.2 molar equivalents) and (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (COMU, 1.2 molar equivalents) and stirring. After completion of the condensation reaction, methanol (370 mL) was added under ice cooling and stirred, and the precipitate was filtered. The precipitate was washed with methanol and acetonitrile and dried under reduced pressure to obtain Fmoc-His(Trt)-Lys(Boc)-NH-DiNaphTAG (1) (6.72 g, yield 98.6%).

[0116] Example 4 Synthesis of Fmoc-Lys(Boc)-Gly-His(Trt)-Lys(Boc)-NH-DiNaphTAG (1) Fmoc-Gly-His(Trt)-Lys(Boc)-NH-DiNaphTAG (1) (6.40 g, 3.52 mmol) was dissolved in tetrahydrofuran (70 mL), and diazabicycloundecene (DBU, 1.2 molar equivalents) was added and stirred. After completion of the deprotection reaction, N-methylmorpholine (2.0 molar equivalents) and methanesulfonic acid (1.3 molar equivalents) were added sequentially, followed by the addition of Fmoc-His(Trt)-OH (1.2 molar equivalents) and (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (COMU, 1.2 molar equivalents) and stirring. After completion of the condensation reaction, methanol (350 mL) was added under ice cooling and the mixture was stirred. The precipitate was filtered. The precipitate was washed with methanol and acetonitrile and dried under reduced pressure to obtain Fmoc-Lys(Boc)-His(Trt)-Lys(Boc)-NH-DiNaphTAG (1) (6.88 g, yield 95.5%).

[0117] Deprotected peptide (four-residue peptide: Lys-Gly-His-Lys-NH ２ Synthesis of Lys-Gly-His-Lys-NH ２ Synthesis of Fmoc-Lys(Boc)-His(Trt)-Lys(Boc)-NH-DiNaphTAG (1) (0.100 g) was added with a mixed solution of trifluoroacetic acid (TFA, 1.98 mL), triisopropylsilane (TIPS, 0.535 mL), 3,6-dioxa-1,8-octanedithiol (DODT, 0.535 mL), and water (0.535 mL), and the mixture was stirred at 50°C for 2 hours. After the deprotection reaction was completed, the mixture was returned to room temperature, cyclopentyl methyl ether (CPME, 10 mL) was added, and the mixture was stirred. The supernatant was removed by centrifugation. The addition of CPME, centrifugation, and removal of the supernatant were repeated twice to obtain Lys-Gly-His-Lys-NH ２ (HPLC purity 96.2%, wavelength 220 nm). Electron spray ionization mass spectrometry (ESI-MS) (+)=510.

Claims

1. A method for producing a peptide compound, comprising a step of using a dinaphthylmethyl compound represented by the following formula (1): In formula (1), 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; Z Ａ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; R Ａ and R Ｂ each independently represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, at least one of the aliphatic hydrocarbon groups having 12 or more carbon atoms, m and n each independently represent an integer of 0 to 7, m+n is 1 or more, and when m or n is 2 or more, each R Ａ and R Ｂ may be the same or different.

2. The method for producing a peptide compound according to claim 1, wherein the step of using the dinaphthylmethyl 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 dinaphthylmethyl compound represented by formula (1).

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

4. The method for producing a peptide compound according to claim 3, further comprising, after the precipitation step, one or more of the following steps in this order: deprotecting the N-terminus of the obtained N-terminus-protected, C-terminus-protected peptide compound; condensing an N-terminus-protected amino acid compound or an N-terminus-protected peptide compound to the N-terminus of the obtained C-terminus-protected peptide compound; and precipitating the obtained N-terminus-protected, C-terminus-protected peptide compound.

5. A method for producing a peptide compound according to any one of claims 1 to 4, further comprising a C-terminal deprotection step of deprotecting a C-terminal protecting group.

6. The method for producing a peptide compound according to any one of claims 1 to 4, wherein the total number of carbon atoms in the aliphatic hydrocarbon groups is 36 to 80.

7. R Ａ and R Ｂ each independently represents a group represented by the following formula (f1) or formula (a1): In formula (f1), the wavy line portion represents a bonding position with other structures, m9 represents an integer of 1 to 3, and X ９ each independently represents a single bond, —O—, —S—, —COO—, —OCO—, —OCONH—, —NHCONH—, —NHCO—, or —CONH—; R ９ each independently represents a divalent aliphatic hydrocarbon group; Ar １ represents a (m10+1)-valent aromatic group or a (m10+1)-valent heteroaromatic group, m10 represents an integer of 1 to 3, 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. In formula (a1), the wavy line portion represents a bonding position with other structures, m20 represents an integer of 1 to 10, and X ２０ each independently represents a single bond, —O—, —S—, —COO—, —OCO—, —OCONH—, —NHCONH—, —NHCO—, or —CONH—; R ２０ each independently represents a divalent aliphatic hydrocarbon group; R ２０ At least one of the groups is a divalent aliphatic hydrocarbon group having 5 or more carbon atoms.

8. A protecting group forming reagent comprising a dinaphthylmethyl compound represented by the following formula (1): In formula (1), 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; Z Ａ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; R Ａ and R Ｂ each independently represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, at least one of the aliphatic hydrocarbon groups having 12 or more carbon atoms, m and n each independently represent an integer of 0 to 7, m+n is 1 or more, and when m or n is 2 or more, each R Ａ and R Ｂ may be the same or different.

9. The protecting group forming reagent according to claim 8, wherein the protecting group forming reagent is a protecting group forming reagent for a carboxy group or an amide group.

10. The reagent for forming a protecting group according to claim 8 or 9, which is a reagent for forming a protecting group at the C-terminus of an amino acid compound or a peptide compound.

11. A dinaphthylmethyl compound represented by the following formula (1): In formula (1), 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; Z Ａ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; R Ａ and R Ｂ each independently represents an aliphatic hydrocarbon group or an organic group having an aliphatic hydrocarbon group, at least one of the aliphatic hydrocarbon groups having 12 or more carbon atoms, m and n each independently represent an integer of 0 to 7, m+n is 1 or more, and when m or n is 2 or more, each R Ａ and R Ｂ may be the same or different.

12. R Ａ and R Ｂ The dinaphthylmethyl compound according to claim 11, wherein each of the following independently represents a group represented by formula (f1) or formula (a1): In formula (f1), the wavy line portion represents a bonding position with other structures, m9 represents an integer of 1 to 3, and X ９ each independently represents a single bond, —O—, —S—, —COO—, —OCO—, —OCONH—, —NHCONH—, —NHCO—, or —CONH—; R ９ each independently represents a divalent aliphatic hydrocarbon group; Ar １ represents a (m10+1)-valent aromatic group or a (m10+1)-valent heteroaromatic group, m10 represents an integer of 1 to 3, 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. In formula (a1), the wavy line portion represents a bonding position with other structures, m20 represents an integer of 1 to 10, and X ２０ each independently represents a single bond, —O—, —S—, —COO—, —OCO—, —OCONH—, —NHCONH—, —NHCO—, or —CONH—; R ２０ each independently represents a divalent aliphatic hydrocarbon group; R ２０ At least one of the groups is a divalent aliphatic hydrocarbon group having 5 or more carbon atoms.

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