Process for production of cyclopeptide compounds

Abstract

Provided is a cyclization method by means of a cyclization position as a cyclization method in the production of a cyclopeptide compound having a double bond cross-linked between amino acids, which can reduce the amount of cyclic dimer generation as a by-product. Also provided is an efficient production method as a method for producing a cyclized precursor peptide compound in which three fragment peptides are each synthesized and liquid phase fragment coupling is performed for synthesis. Further, a crystal of a cyclopeptide compound and a method for producing the crystal by crystallization are provided.

Description

Technical Field

[0001] This invention relates to a method for producing cyclic peptide compounds, and more particularly to a method for producing cyclic peptide compounds that selectively inhibit KRAS relative to HRAS and NRAS. Background Technology

[0002] RAS are proteins belonging to the small GTPase family, of which KRAS, NRAS, and HRAS are known. RAS are defined as being in an activated or inactivated state based on their binding to GDP or GTP. They are activated by the exchange reaction from GDP to GTP via GEF (guanine nucleotide exchange factor) and inactivated by the hydrolysis of GTP via GAP (GTPase activator protein) (Non-Patent Literature 1). Activated RAS induces cell proliferation, survival, and differentiation by activating various downstream signals in the MAPK, PI3K / Akt, and RAL pathways, and constitutive activation of RAS plays a crucial role in cancer development and progression. In cancer, the RAS-RAF-MEK-ERK pathway is known to be activated by upstream RAS signaling, constitutive RAS activation, and / or activating mutations in RAS (Non-Patent Literature 2). These activating mutations in RAS have been found in various cancer types. G12, G13, and Q61 are considered hotspots for RAS mutations, with G12 frequently found in KRAS and Q61 frequently found in NRAS. These mutations are also known to be associated with patient prognosis (Non-Patent Literature 3).

[0003] In this regard, cyclic peptide compounds represented by the following formula (1) (hereinafter also referred to as cyclic peptide compound (1)) have been reported, which are selective for RAS, specifically, selectively inhibit KRAS relative to HRAS and NRAS (Patent Document 1).

[0004] [Formula 1]

[0005]

[0006] [List of Citations]

[0007] [Patent Literature]

[0008] [Patent Document 1]

[0009] International Publication Number WO 2022 / 234853

[0010] [Non-patent literature]

[0011] [Non-patent literature 1]

[0012] Nat. Rev. Drug Discov. November 2014; 13(11): 828-851.

[0013] [Non-patent literature 2]

[0014] Nat. Rev. Drug Discov. Dec 2014; 13(12): 928-942.

[0015] [Non-patent literature 3]

[0016] Nat. Rev. Drug Discov. November 2016; 15(11): 771-785. Summary of the Invention

[0017] [Technical Issues]

[0018] To the best of the inventors' knowledge, there are no reported examples regarding the preferred position of the cyclized precursor peptide compound (1) in the production of cyclic peptide compounds (1) having double bonds crosslinked between amino acids. Patent Document 1 describes a method for producing cyclic peptide compound (1) by a cyclization reaction at cyclization position A. However, as described in Examples 1 to 26 below, in the production method described in Patent Document 1, cyclic dimers are found as byproducts in addition to the target cyclic peptide compound (1), and the ratio of cyclic peptide compound (1) to cyclic dimers is 75:25, resulting in low selectivity.

[0019] [Equation 2]

[0020]

[0021] Furthermore, the cyclized precursor peptide compound described in Patent Document 1 is produced by sequentially linking amino acids or some tripeptides using the Fmoc method and synthesizing them on a solid phase. Since solid-phase synthesis requires excess amino acids and reagents in each step, as well as a large amount of organic solvent for washing, it is desirable to avoid solid-phase synthesis as much as possible for large-scale production. Moreover, to the best of the inventors' knowledge, there are no reported examples of crystals of the cyclic peptide compound (1).

[0022] The present invention was made in response to this situation, and its object is to provide an efficient method for producing cyclic peptide compounds (1) having double bonds crosslinked between amino acids.

[0023] Another object of the present invention is to provide a crystal of a cyclic peptide compound (1) with excellent stability.

[0024] [Solution to the problem]

[0025] In view of the above, the inventors have conducted in-depth research and finally completed this invention. That is, in one aspect, the invention provides a cyclization method by means of cyclization positions as a cyclization method in the production of a cyclic peptide compound (1) having double bonds crosslinked between amino acids, which can reduce the amount of cyclic dimers as byproducts. In another aspect, the invention also provides an efficient production method as a method for producing a cyclized precursor peptide compound, wherein three fragment peptides are each synthesized and subjected to liquid-phase fragment coupling for synthesis. In another aspect, the invention further provides a crystal of the cyclic peptide compound (1) and a method for producing the crystal by crystallization.

[0026] In one specific non-limiting aspect, the invention covers the following.

[0027] [A1] A method for producing a cyclic peptide compound represented by formula (1) or a salt thereof or a solvate thereof, the method comprising the step of reacting an N-terminal amino acid residue of a peptide compound represented by formula (2) or (3) with a C-terminal amino acid residue of the peptide compound in a solvent to perform cyclization (cyclization step):

[0028] [Formula 3]

[0029]

[0030]

[0031] Where R1 is a C1-C6 alkyl group;

[0032] P1 is a C1-C6 alkyl group;

[0033] R2 is a C1-C6 alkyl group;

[0034] R3 is hydrogen, or R3 together with P3, the carbon atom bonded to R3 and the nitrogen atom bonded to P3 form a 4- to 7-membered saturated heterocycle;

[0035] P3 is a C1-C6 alkyl or C3-C8 cycloalkyl, or P3 together with R3, the carbon atom bonded to R3 and the nitrogen atom bonded to P3 to form a 4- to 7-membered saturated heterocycle;

[0036] P4 is a C1-C6 alkyl group;

[0037] R5 is a benzyl group optionally substituted with one or more groups selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, and C3-C8 cycloalkyl;

[0038] P6 is a C1-C6 alkyl group;

[0039] R7 is a phenethyl group optionally substituted with one or more groups selected from the group consisting of: halogen, C1-C6 haloalkyl and C1-C6 alkoxy;

[0040] R8, together with P8, the carbon atom bonded to R8, and the nitrogen atom bonded to P8, forms a 4- to 7-membered saturated heterocycle, wherein the 4- to 7-membered saturated heterocycle is optionally substituted with a C1-C6 alkoxy group.

[0041] R9, together with Q9 and the carbon atoms bonded to R9 and Q9, forms a 3- to 8-membered alicyclic ring, wherein the 3- to 8-membered alicyclic ring is optionally substituted with one or more C1-C6 alkyl groups;

[0042] P9 is hydrogen or a C1-C6 alkyl group;

[0043] R 10 It is a C1-C6 alkyl or C3-C8 cycloalkyl;

[0044] P 10 It is a C1-C6 alkyl group;

[0045] R 11 It is a di-C1-C6 alkylaminocarbonyl or a 4- to 8-membered cyclic aminocarbonyl;

[0046] P 11 It is a C1-C6 alkyl group;

[0047] X1 and X5 are each independently hydrogen or protecting groups for amino groups; and

[0048] X2 and X4 are each independently a halogen, a hydroxyl group, an optionally substituted alkoxy group, an optionally substituted aryloxy group, an optionally substituted arylalkoxy group, an optionally substituted cyclic aminooxy group, or a group consisting of -OSiR. x R y R z The group represented, where R x R y and R z Each can be an alkyl or aryl group independently.

[0049] [A2] A method for producing a cyclic peptide compound represented by formula (1) or a salt thereof or a solvate thereof, said method comprising:

[0050] (a) The step of providing a peptide compound or a salt thereof represented by formulas (4) to (6) or a solvation of said peptide compound or salt;

[0051] (b) The step of reacting the N-terminal amino acid residues of the peptide compound represented by formulas (4) to (6) with the C-terminal amino acid residues of the peptide compound in a solvent to perform a linking step; and

[0052] (c) The step of reacting the N-terminal amino acid residues of the peptide compound obtained in step (b) with the C-terminal amino acid residues of the peptide compound in a solvent to perform cyclization (cyclization step):

[0053] [Formula 4]

[0054]

[0055]

[0056] Where R1 is a C1-C6 alkyl group;

[0057] P1 is a C1-C6 alkyl group;

[0058] R2 is a C1-C6 alkyl group;

[0059] R3 is hydrogen, or R3 together with P3, the carbon atom bonded to R3 and the nitrogen atom bonded to P3 form a 4- to 7-membered saturated heterocycle;

[0060] P3 is a C1-C6 alkyl or C3-C8 cycloalkyl, or P3 together with R3, the carbon atom bonded to R3 and the nitrogen atom bonded to P3 to form a 4- to 7-membered saturated heterocycle;

[0061] P4 is a C1-C6 alkyl group;

[0062] R5 is a benzyl group optionally substituted with one or more groups selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, and C3-C8 cycloalkyl;

[0063] P6 is a C1-C6 alkyl group;

[0064] R7 is a phenethyl group optionally substituted with one or more groups selected from the group consisting of: halogen, C1-C6 haloalkyl and C1-C6 alkoxy;

[0065] R8, together with P8, the carbon atom bonded to R8, and the nitrogen atom bonded to P8, forms a 4- to 7-membered saturated heterocycle, wherein the 4- to 7-membered saturated heterocycle is optionally substituted with a C1-C6 alkoxy group.

[0066] R9, together with Q9 and the carbon atoms bonded to R9 and Q9, forms a 3- to 8-membered alicyclic ring, wherein the 3- to 8-membered alicyclic ring is optionally substituted with one or more C1-C6 alkyl groups;

[0067] P9 is hydrogen or a C1-C6 alkyl group;

[0068] R 10 It is a C1-C6 alkyl or C3-C8 cycloalkyl;

[0069] P 10 It is a C1-C6 alkyl group;

[0070] R 11 It is a di-C1-C6 alkylaminocarbonyl or a 4- to 8-membered cyclic aminocarbonyl;

[0071] P 11 It is a C1-C6 alkyl group;

[0072] X1, X3, and X5 are each independently hydrogen or protecting groups for amino groups; and

[0073] X2, X4, and X6 are each independently a halogen, a hydroxyl group, an optionally substituted alkoxy group, an optionally substituted aryloxy group, an optionally substituted arylalkoxy group, an optionally substituted cyclic aminooxy group, or a group consisting of -OSiR. x R y R z The group represented, where R x R y and R z Each can be an alkyl or aryl group independently.

[0074] [A3] According to the method described in [A2], the method includes, in step (b),

[0075] (b-1) The step of reacting the N-terminal amino acid residues of the peptide compound represented by formula (5) with the C-terminal amino acid residues of the peptide compound represented by formula (6) in a solvent to link them, thereby converting them into the peptide compound represented by formula (7) (linking step):

[0076] [Formula 5]

[0077]

[0078] Among them, R1, R2, R3, R7, R8, R9, R 10 R 11 P1, P3, P8, P9, P 10 P 11 Q9, X4, and X5 are the same as in [A2].

[0079] [A4] According to the method described in [A3], the method further includes, in step (b),

[0080] (b-2) The step of reacting the N-terminal amino acid residues of the peptide compound represented by formula (4) with the C-terminal amino acid residues of the peptide compound represented by formula (7) in a solvent to link them, thereby converting them into the peptide compound represented by formula (2) (linking step), and

[0081] The method further includes, in step (c),

[0082] (c-1) The step of reacting the N-terminal amino acid residue of the peptide compound represented by formula (2) with the C-terminal amino acid residue of the peptide compound in a solvent to perform cyclization (cyclization step).

[0083] [A5] According to the method described in [A3], the method further includes, in step (b),

[0084] (b-3) The step of reacting the N-terminal amino acid residues of the peptide compound represented by formula (7) with the C-terminal amino acid residues of the peptide compound represented by formula (4) in a solvent to link them, thereby converting them into the compound represented by formula (3) (linking step), and

[0085] The method further includes, in step (c),

[0086] (c-2) The step of reacting the N-terminal amino acid residue of the peptide compound represented by formula (3) with the C-terminal amino acid residue of the peptide compound in a solvent to perform cyclization (cyclization step).

[0087] [A6] The method according to any one of [A1] to [A5], wherein the connection between the N-terminal amino acid residue of the peptide compound and the C-terminal amino acid residue of the peptide compound is the connection between the amino group of the N-terminal amino acid residue and the carboxyl group of the C-terminal amino acid residue.

[0088] [A7] The method according to any one of [A1] to [A6], wherein the connection between the N-terminal amino acid residue of the peptide compound and the C-terminal amino acid residue of the peptide compound is achieved by means of an amide bond between the amino group of the N-terminal amino acid residue and the carboxyl group of the C-terminal amino acid residue.

[0089] [A8] According to any one of [A1] to [A7], the solvent in the cyclization step comprises one or more of the group consisting of: nitrile solvents, halogen solvents, ether solvents, amide solvents, ester solvents and carbonate solvents.

[0090] [A9] According to the method described in [A8],

[0091] The nitrile solvents mentioned herein are one or more selected from the group consisting of acetonitrile and propionitrile.

[0092] The halogen solvents mentioned therein are one or more selected from the group consisting of: dichloromethane, chloroform, and 1,2-dichloroethane.

[0093] The ether solvents mentioned herein are one or more selected from the group consisting of: diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentylmethyl ether, 4-methyltetrahydropyran, 1,3-dioxane, 1,4-dioxane, 1,2-dimethoxyethane, diisopropyl ether, tert-butylmethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, anisole, and tetraethylene glycol dimethyl ether.

[0094] The amide solvents mentioned therein are one or more selected from the group consisting of: DMF, NMP, DMA, NEP, NBP, and formamide.

[0095] The ester solvents mentioned herein are one or more selected from the group consisting of: methyl acetate, ethyl acetate, methyl propionate, butyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, amyl acetate, and γ-valerate.

[0096] The carbonate solvents mentioned therein are one or more of the following: dimethyl carbonate, diethyl carbonate, and dibutyl carbonate.

[0097] [A10] According to the method of [A8], the solvent in the cyclization step is one or more of the group consisting of: acetonitrile, dimethyl carbonate, 2-methyltetrahydropyran, 4-methyltetrahydropyran, tetrahydrofuran, ethyl acetate, isopropyl acetate, dichloromethane, DMF and anisole.

[0098] [A11] According to the method of [A8], the solvent in the cyclization step is one or more of the group consisting of acetonitrile, 2-methyltetrahydrofuran, ethyl acetate and dichloromethane.

[0099] [A12] According to the method of [A8], the solvent in the cyclization step is acetonitrile, 2-methyltetrahydrofuran or ethyl acetate.

[0100] [A13] The method according to any one of [A1] to [A12], wherein the cyclization step is performed in the presence of a condensation agent.

[0101] [A14] According to the method of [A13], the condensing agent in the cyclization step is one or more selected from the group consisting of: HATU, COMU, DMT-MM, PyOxim, PyBOP, HCTU, T3P, EDCI, BEP and PyClop.

[0102] [A15] According to the method of [A13], the condensing agent in the cyclization step is selected from the group consisting of: HATU, COMU, PyOxim, PyBOP, HCTU and T3P.

[0103] [A16] According to the method of [A13], the condensing agent in the cyclization step is HATU.

[0104] [A17] According to the method of [A13], the condensing agent in the cyclization step is COMU.

[0105] [A18] According to the method of [A13], the condensing agent in the cyclization step is HATU and the solvent in the cyclization step is acetonitrile.

[0106] [A19] According to the method of [A13], the condensing agent in the cyclization step is HATU, and the solvent in the cyclization step is 2-methyltetrahydrofuran.

[0107] [A20] According to the method of [A13], the condensing agent in the cyclization step is COMU and the solvent in the cyclization step is acetonitrile.

[0108] [A21] According to the method of [A13], the condensing agent in the cyclization step is COMU, and the solvent in the cyclization step is 2-methyltetrahydrofuran.

[0109] [A22] The method according to any one of [A1] to [A21], wherein the cyclization step is carried out in the presence of a base.

[0110] [A23] According to the method of [A22], the base in the cyclization step is an organic base.

[0111] [A24] According to the method of [A22], the base in the cyclization step is an organic base containing a tertiary amine.

[0112] [A25] According to the method of [A22], the base in the cyclization step is one or more selected from the group consisting of: 2,2,6,6-tetramethylpiperidine, N-methylmorpholine, N,N-diisopropylethylamine (DIPEA), 2,4,6-trimethylpyridine, 2,6-dimethylpyridine, pyridine, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), 2,3,6,7-tetrahydro-1H,5H-9-azabenzo[ij]quinolidine, 1,4-diazabicyclo[2.2.2]octyl Alkane (DABCO), 1,5-diazabicyclo[4.3.0]-5-nonene (DBN), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, 1,1,3,3-tetramethylguanidine (TMG), 1,8-bis(tetramethylguanidine)naphthalene (TMGN), 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), triethylamine (TEA), trimethylamine, 1-methylpiperidine, N,N'-dimethylpiperazine, N-ethylpiperazine, and p-dimethylaminopyridine (DMAP).

[0113] [A26] According to the method of [A22], the base in the cyclization step is one or more selected from the group consisting of: 2,2,6,6-tetramethylpiperidine, N-methylmorpholine, N,N-diisopropylethylamine (DIPEA), 2,4,6-trimethylpyridine, 2,6-dimethylpyridine and pyridine.

[0114] [A27] According to the method of [A22], the condensing agent in the cyclization step is HATU, the solvent in the cyclization step is acetonitrile, and the base in the cyclization step is N,N-diisopropylethylamine (DIPEA).

[0115] [A28] According to the method of [A22], the condensing agent in the cyclization step is HATU, the solvent in the cyclization step is 2-MeTHF, and the base in the cyclization step is N,N-diisopropylethylamine (DIPEA).

[0116] [A29] According to the method of [A22], the condensing agent in the cyclization step is COMU, the solvent in the cyclization step is acetonitrile, and the base in the cyclization step is 2,6-dimethylpyridine.

[0117] [A30] According to the method of [A22], the condensing agent in the cyclization step is COMU, the solvent in the cyclization step is 2-methyltetrahydrofuran, and the base in the cyclization step is 2,6-dimethylpyridine.

[0118] [A31] The method according to any one of [A1] to [A30], wherein the cyclization step is performed by a liquid phase method.

[0119] [A32] The method according to any one of [A1] to [A31], wherein in the cyclization step, the peptide compound and the base are mixed in a mixed solution obtained by mixing the solvent and the condensation reagent in the cyclization step.

[0120] [A33] The method according to any one of [A1] to [A32], wherein the total content of byproducts generated in the cyclization step is less than 20%, less than 15%, less than 10%, less than 5%, or less than 3%, as determined by the UV area value at 220 nm obtained by HPLC analysis, based on the total amount of product.

[0121] [A34] The method according to any one of [A1] to [A33], wherein, based on the total amount of product, the content of each of the byproducts generated in the cyclization step is less than 15%, less than 10%, less than 5%, less than 3%, less than 1%, or is an undetectable amount, as determined by the UV area value at 220 nm obtained by HPLC analysis.

[0122] [A35] The method according to any one of [A1] to [A34], wherein, based on the total amount of product, the content of each of the byproducts generated in the cyclization step is less than 15%, less than 10%, less than 5%, less than 3%, less than 1%, or is an undetectable amount, as determined by the UV area value at 220 nm obtained by HPLC analysis, and the byproducts comprise epimers and / or cyclic dimers.

[0123] [A36] The method according to any one of [A1] to [A35], wherein the byproduct generated in the cyclization step comprises an epimer, and the content of the epimer is less than 10%, less than 7.5%, less than 5%, less than 2.5% or less than 1% based on the total amount of product, as determined by the UV area value at 220 nm obtained by HPLC analysis.

[0124] [A37] The method according to any one of [A1] to [A36], wherein the byproduct generated in the cyclization step comprises a cyclic dimer, and the content of the cyclic dimer is less than 15%, less than 10%, less than 5%, less than 2.5% or less than 1% based on the total amount of product, as determined by the UV area value at 220 nm obtained by HPLC analysis.

[0125] [A38] The method according to any one of [A1] to [A37], wherein the solvent in the connecting step comprises one or more of the group consisting of: nitrile solvents, halogen solvents, ether solvents, amide solvents, ester solvents and carbonate solvents.

[0126] [A39] According to the method described in [A38],

[0127] The nitrile solvents mentioned herein are one or more selected from the group consisting of acetonitrile and propionitrile.

[0128] The halogen solvents mentioned therein are one or more selected from the group consisting of: dichloromethane, chloroform, and 1,2-dichloroethane.

[0129] The ether solvents mentioned herein are one or more selected from the group consisting of: diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentylmethyl ether, 4-methyltetrahydropyran, 1,3-dioxane, 1,4-dioxane, 1,2-dimethoxyethane, diisopropyl ether, tert-butylmethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, anisole, and tetraethylene glycol dimethyl ether.

[0130] The amide solvents mentioned therein are one or more selected from the group consisting of: DMF, NMP, DMA, NEP, NBP, and formamide.

[0131] The ester solvents mentioned herein are one or more selected from the group consisting of: methyl acetate, ethyl acetate, methyl propionate, butyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, amyl acetate, and γ-valerate.

[0132] The carbonate solvents mentioned therein are one or more of the following: dimethyl carbonate, diethyl carbonate, and dibutyl carbonate.

[0133] [A40] According to the method of [A38], the solvent in the connecting step is one or more of the group consisting of: acetonitrile, dimethyl carbonate, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, THF, ethyl acetate, isopropyl acetate, DMF and anisole.

[0134] [A41] According to the method of [A38], the solvent in the connecting step is a mixture of one or more of the following groups with DMF: acetonitrile, dimethyl carbonate, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, THF, ethyl acetate, isopropyl acetate and anisole.

[0135] [A42] According to the method of [A38], the solvent in the connecting step is a mixed solvent of acetonitrile, 2-methyltetrahydrofuran and DMF.

[0136] [A43] According to the method of [A38], the solvent in the connecting step is a mixed solvent of 2-methyltetrahydrofuran and DMF.

[0137] [A44] The method according to any one of [A1] to [A43], wherein the joining step is performed in the presence of a condensing agent.

[0138] [A45] According to the method of [A44], the condensing agent in the ligation step is one or more selected from the group consisting of: HATU, COMU, DMT-MM, PyOxim, PyBOP, HCTU, T3P, EDCI, BEP and PyClop.

[0139] [A46] According to the method of [A44], the condensing agent in the ligation step is selected from the group consisting of: HATU, COMU, PyOxim, PyBOP, HCTU and T3P.

[0140] [A47] According to the method of [A44], the condensing agent in the ligation step is selected from the group consisting of HATU and COMU.

[0141] [A48] According to the method of [A44], the condensing agent in the ligation step is HATU.

[0142] [A49] According to the method of [A44], the condensing agent in the connection step is COMU.

[0143] [A50] According to the method of [A44], the condensing agent in the ligation step is HATU, and the solvent in the ligation step is acetonitrile or 2-MeTHF.

[0144] [A51] According to the method of [A44], the condensing agent in the linking step is HATU, and the solvent in the linking step is a mixed solvent of acetonitrile, 2-MeTHF and DMF.

[0145] [A52] According to the method of [A44], the condensing agent in the ligation step is COMU, and the solvent in the ligation step is acetonitrile or 2-MeTHF.

[0146] [A53] According to the method of [A44], the condensing agent in the linking step is COMU, and the solvent in the linking step is a mixed solvent of acetonitrile, 2-MeTHF and DMF.

[0147] [A54] The method according to any one of [A1] to [A53], wherein the connection step is performed in the presence of an alkali.

[0148] [A55] According to the method of [A54], the base in the connection step is an organic base.

[0149] [A56] According to the method of [A54], the base in the connecting step is an organic base containing a tertiary amine.

[0150] [A57] According to the method of [A54], the base in the connecting step is one or more selected from the group consisting of: 2,2,6,6-tetramethylpiperidine, N-methylmorpholine, N,N-diisopropylethylamine (DIPEA), 2,4,6-trimethylpyridine, 2,6-dimethylpyridine, pyridine, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), 2,3,6,7-tetrahydro-1H,5H-9-azabenzo[ij]quinolidine, 1,4-diazabicyclo[2.2.2]octyl Alkane (DABCO), 1,5-diazabicyclo[4.3.0]-5-nonene (DBN), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, 1,1,3,3-tetramethylguanidine (TMG), 1,8-bis(tetramethylguanidine)naphthalene (TMGN), 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), triethylamine (TEA), trimethylamine, 1-methylpiperidine, N,N'-dimethylpiperazine, N-ethylpiperazine, and p-dimethylaminopyridine (DMAP).

[0151] [A58] According to the method of [A54], the base in the connection step is one or more selected from the group consisting of: 2,2,6,6-tetramethylpiperidine, N-methylmorpholine, N,N-diisopropylethylamine (DIPEA), 2,4,6-trimethylpyridine, 2,6-dimethylpyridine and pyridine.

[0152] [A59] According to the method of [A54], the condensing agent in the linking step is HATU, the solvent in the linking step is acetonitrile or 2-MeTHF, and the base in the linking step is N,N-diisopropylethylamine (DIPEA).

[0153] [A60] According to the method of [A54], the condensing agent in the linking step is HATU, the solvent in the linking step is a mixed solvent of acetonitrile, 2-methyltetrahydrofuran and DMF, and the base in the linking step is N,N-diisopropylethylamine (DIPEA).

[0154] [A61] According to the method of [A54], the condensing agent in the linking step is COMU, the solvent in the linking step is acetonitrile or 2-methyltetrahydrofuran, and the base in the linking step is N-methylmorpholine or 2,6-dimethylpyridine.

[0155] [A62] According to the method of [A54], the condensing agent in the linking step is COMU, the solvent in the linking step is a mixed solvent of acetonitrile, 2-methyltetrahydrofuran and DMF, and the base in the linking step is N-methylmorpholine or 2,6-dimethylpyridine.

[0156] [A62-1] According to the method of [A54], the condensing agent in the linking step is HATU, the solvent in the linking step is a mixed solvent of acetonitrile and 2-methyltetrahydrofuran, and the base in the linking step is N-methylmorpholine.

[0157] [A62-2] According to the method of [A54], the condensing agent in the linking step is HATU, the solvent in the linking step is acetonitrile, and the base in the linking step is N-methylmorpholine.

[0158] [A63] The method according to any one of [A1] to [A62], wherein the connection step is performed by a liquid phase method.

[0159] [A64] The method according to any one of [A1] to [A63], wherein column chromatography is used to separate and / or purify the cyclic peptide compound or its salt or solvates thereof.

[0160] [A65] The method according to any one of [A1] to [A63], wherein column chromatography is not used to separate and / or purify the cyclic peptide compound or its salt or solvates thereof.

[0161] [A66] The method according to any one of [A1] to [A65] further comprises the step of separating and / or purifying the cyclic peptide compound or its salt or its solvates by crystallization to obtain crystals of the cyclic peptide compound or its salt or its solvates.

[0162] [A67] The method according to any one of [A1] to [A66], wherein R1 is a C3-C4 alkyl group.

[0163] [A67-1] The method according to any one of [A1] to [A66], wherein R1 is n-propyl.

[0164] [A67-2] The method according to any one of [A1] to [A66], wherein R1 is 2-methylpropyl.

[0165] [A68] The method according to any one of [A1] to [A67], wherein P1 is a C1-C4 alkyl group.

[0166] [A68-1] The method according to any one of [A1] to [A67], wherein P1 is methyl.

[0167] [A69] The method according to any one of [A1] to [A68], wherein R2 is a C3-C4 alkyl group.

[0168] [A69-1] The method according to any one of [A1] to [A68], wherein R2 is 1-methylpropyl.

[0169] [A70] The method according to any one of [A1] to [A69], wherein R3 is hydrogen, or R3 together with P3, the carbon atom bonded to R3 and the nitrogen atom bonded to P3 form a 5-membered saturated heterocycle.

[0170] [A70-1] The method according to any one of [A1] to [A69], wherein R3 is hydrogen.

[0171] [A70-2] The method according to any one of [A1] to [A69], wherein R3, together with P3, the carbon atom bonded to R3 and the nitrogen atom bonded to P3, forms a 5-membered saturated heterocycle.

[0172] [A71] The method according to any one of [A1] to [A70], wherein P3 is a C1-C4 alkyl group, or P3 together with R3, the carbon atom bonded to R3 and the nitrogen atom bonded to P3 to form a 5-membered saturated heterocycle.

[0173] [A71-1] The method according to any one of [A1] to [A70], wherein P3 is methyl.

[0174] [A71-2] The method according to any one of [A1] to [A70], wherein P3, together with R3, the carbon atom bonded to R3 and the nitrogen atom bonded to P3, forms a 5-membered saturated heterocycle.

[0175] [A72] The method according to any one of [A1] to [A71], wherein P4 is a C1-C4 alkyl group.

[0176] [A72-1] The method according to any one of [A1] to [A71], wherein P4 is methyl.

[0177] [A73] The method according to any one of [A1] to [A72], wherein R5 is a benzyl group optionally substituted with a C1-C4 haloalkyl group.

[0178] [A73-1] The method according to any one of [A1] to [A72], wherein R5 is 4-trifluoromethylbenzyl.

[0179] [A74] The method according to any one of [A1] to [A73], wherein P6 is a C1-C4 alkyl group.

[0180] [A74-1] The method according to any one of [A1] to [A73], wherein P6 is methyl.

[0181] [A75] The method according to any one of [A1] to [A74], wherein R7 is a phenethyl group optionally substituted with one or more groups selected from the group consisting of: halogen, trifluoromethyl and methoxy.

[0182] [A75-1] The method according to any one of [A1] to [A74], wherein R7 is 3-methoxy-4-trifluoromethylphenylethyl.

[0183] [A75-2] The method according to any one of [A1] to [A74], wherein R7 is 3,5-difluoro-4-trifluoromethylphenylethyl.

[0184] [A76] The method according to any one of [A1] to [A75], wherein R8, together with P8, the carbon atom bonded to R8 and the nitrogen atom bonded to P8, forms a 5-membered saturated heterocycle, said 5-membered saturated heterocycle being substituted with a C1-C4 alkyl group.

[0185] [A76-1] The method according to any one of [A1] to [A75], wherein R8, together with P8, the carbon atom bonded to R8 and the nitrogen atom bonded to P8, forms a 5-membered saturated heterocycle, said 5-membered saturated heterocycle being substituted with an ethoxy group.

[0186] [A77] The method according to any one of [A1] to [A76], wherein R9, together with Q9 and the carbon atoms bonded to R9 and Q9, forms a 4- to 6-membered alicyclic ring.

[0187] [A77-1] The method according to any one of [A1] to [A76], wherein R9, together with Q9 and the carbon atoms bonded to R9 and Q9, forms a 4-membered alicyclic ring.

[0188] [A77-2] The method according to any one of [A1] to [A76], wherein R9, together with Q9 and the carbon atoms bonded to R9 and Q9, forms a 5-membered alicyclic ring.

[0189] [A78] The method according to any one of [A1] to [A77], wherein P9 is hydrogen or C1-C4 alkyl.

[0190] [A78-1] The method according to any one of [A1] to [A77], wherein P9 is hydrogen.

[0191] [A78-2] The method according to any one of [A1] to [A77], wherein P9 is methyl.

[0192] [A79] The method according to any one of [A1] to [A78], wherein R 10 It is a C4-C6 cycloalkyl group.

[0193] [A79-1] The method according to any one of [A1] to [A78], wherein R 10 It is cyclopentyl.

[0194] [A80] The method according to any one of [A1] to [A79], wherein P 10 It is a C1-C4 alkyl group.

[0195] [A80-1] The method according to any one of [A1] to [A79], wherein P 10 It is a methyl group.

[0196] [A81] The method according to any one of [A1] to [A80], wherein R 11 It is a di-C1-C4 alkylaminocarbonyl or a 5- to 6-membered cyclic aminocarbonyl.

[0197] [A81-1] The method according to any one of [A1] to [A80], wherein R 11 It is a dimethylaminocarbonyl group.

[0198] [A82] The method according to any one of [A1] to [A81], wherein P 11It is a C1-C4 alkyl group.

[0199] [A82-1] The method according to any one of [A1] to [A81], wherein P 11 It is a methyl group.

[0200] [A83] The method according to any one of [A1] to [A82], wherein X1, X3 and X5 are each independently selected from the group consisting of: hydrogen, urethane-based protecting groups, acyl-based protecting groups, sulfonamide-based protecting groups and silyl-based protecting groups.

[0201] [A84] According to the method of [A83], the urethane-based protecting group is selected from the group consisting of: Fmoc group, Cbz group, Troc group, Alloc group, Teoc group, TSoc group, BIBSoc group, IPCSoc group, BBSoc group, CHBSoc group, CDBSoc group and Boc group.

[0202] [A85] According to the method of [A83], the acyl-based protecting group is selected from the group consisting of: trifluoroacetyl group, acetyl group and benzoyl group.

[0203] [A86] According to the method of [A83], the sulfonamide-based protecting group is selected from the group consisting of: 2-nitrobenzenesulfonyl group, 4-nitrobenzenesulfonyl group and 2,4-dinitrobenzenesulfonyl group.

[0204] [A87] According to the method of [A83], the silyl-based protecting group is selected from the group consisting of: TMS group, TBDMS group, TES group, TIPS group and TBDPS group.

[0205] [A88] The method according to any one of [A1] to [A87], wherein X1 is hydrogen or a urethane-based protecting group.

[0206] [A88-1] The method according to any one of [A1] to [A87], wherein X1 is hydrogen.

[0207] [A88-2] The method according to any one of [A1] to [A87], wherein X1 is an Fmoc group.

[0208] [A89] The method according to any one of [A1] to [A88], wherein X3 is hydrogen or a urethane-based protecting group.

[0209] [A89-1] The method according to any one of [A1] to [A88], wherein X3 is hydrogen.

[0210] [A89-2] The method according to any one of [A1] to [A88], wherein X3 is a Cbz group.

[0211] [A90] The method according to any one of [A1] to [A89], wherein X5 is hydrogen or a urethane-based protecting group.

[0212] [A90-1] The method according to any one of [A1] to [A89], wherein X5 is hydrogen.

[0213] [A90-2] The method according to any one of [A1] to [A89], wherein X5 is a Cbz group.

[0214] [A91] The method according to any one of [A1] to [A90], wherein X2, X4 and X6 are each independently a halogen, a hydroxyl group, an optionally substituted C1-C6 alkoxy group, or an optionally substituted C6-C6 alkoxy group. 10 aryloxy group, optionally substituted C7-C 14 Arylalkoxy, optionally substituted 4- to 8-membered cyclic aminooxy, or derived from -OSiR x R y R z The group represented, where R x R y and R z Each is independently a C1-C6 alkyl or C6-C 10 Aryl.

[0215] [A91-1] The method according to any one of [A1] to [A90], wherein the halogen is chlorine or bromine.

[0216] [A91-2] The method according to any one of [A1] to [A90], wherein the optionally substituted alkoxy group is tert-butoxy, methoxy, ethoxy or isopropoxy.

[0217] [A91-3] The method according to any one of [A1] to [A90], wherein the optionally substituted aryloxy group is a pentafluorophenyloxy or a nitrophenyloxy.

[0218] [A91-4] The method according to any one of [A1] to [A90], wherein the optionally substituted arylalkoxy group is an optionally substituted benzyloxy group.

[0219] [A91-5] The method according to any one of [A1] to [A90], wherein the optionally substituted cyclic amino group is an N-hydroxysuccinic acid imino group.

[0220] [A91-6] The method according to any one of [A1] to [A90], wherein the -OSiR x R y R z The indicated group is trimethylsilyloxy, triethylsilyloxy, triisopropylsilyloxy, triphenylsilyloxy, tri-tert-butylsilyloxy, di-tert-butylisobutylsilyloxy, or tri(triethylsilyl)silyloxy.

[0221] [A92] The method according to any one of [A1] to [A91], wherein X2 is a hydroxyl group, tert-butoxy or benzyloxy.

[0222] [A92-1] The method according to any one of [A1] to [A91], wherein X2 is a hydroxyl group.

[0223] [A92-2] The method according to any one of [A1] to [A91], wherein X2 is tert-butoxy.

[0224] [A93] The method according to any one of [A1] to [A92], wherein X4 is a hydroxyl group, tert-butoxy or benzyloxy.

[0225] [A93-1] The method according to any one of [A1] to [A92], wherein X4 is a hydroxyl group.

[0226] [A93-2] The method according to any one of [A1] to [A92], wherein X4 is tert-butoxy.

[0227] [A94] The method according to any one of [A1] to [A93], wherein X6 is a hydroxyl group, tert-butoxy or benzyloxy.

[0228] [A94-1] The method according to any one of [A1] to [A93], wherein X6 is a hydroxyl group.

[0229] [A94-2] The method according to any one of [A1] to [A93], wherein X6 is tert-butoxy.

[0230] [A95] The method according to any one of [A1] to [A94], wherein the cyclic peptide compound or its salt or solvates thereof are solvates of the cyclic peptide compound.

[0231] [A95-1] According to the method of [A95], the solvate of the cyclic peptide compound is a hydrate of the cyclic peptide compound.

[0232] [A96] The method according to any one of [A1] to [A95], wherein the cyclic peptide compound is represented by formula (1a):

[0233] [Formula 6]

[0234] .

[0235] [A97] The method according to any one of [A1] to [A95], wherein the cyclic peptide compound is a crystal of a cyclic peptide compound represented by formula (1a):

[0236] [Formula 7]

[0237] .

[0238] [A97-1] According to the method of [A97], the crystal of the cyclic peptide compound is a nonsolvent crystal or a solvate crystal.

[0239] [A97-2] According to the method of [A97], the crystal of the cyclic peptide compound is a solvate crystal.

[0240] [A97-3] According to the method of [A97-2], the solvate crystal of the cyclic peptide compound is a hydrate crystal.

[0241] [B1] A method for preparing a cyclic peptide compound represented by formula (1a) or a salt thereof or a solvate thereof, the method comprising the step of reacting an N-terminal amino acid residue of a peptide compound represented by formula (2a) or (3a) with a C-terminal amino acid residue of the peptide compound in a solvent to perform cyclization (cyclization step):

[0242] [Formula 8]

[0243]

[0244]

[0245]

[0246] X1 and X5 are each independently hydrogen or protecting groups for amino groups; and

[0247] X2 and X4 are each independently a hydroxyl group, optionally a substituted alkoxy group, optionally a substituted aryloxy group, optionally a substituted arylalkoxy group, optionally a substituted cyclic aminooxy group, or a group consisting of -OSiR. x R y R z The group represented, where R x R y and R z Each can be an alkyl or aryl group independently.

[0248] [B2] A method for producing a cyclic peptide compound represented by formula (1a) or a salt thereof or a solvate thereof, said method comprising:

[0249] (a) The step of providing a peptide compound or a salt thereof, or a solvate of said peptide compound or salt, represented by formulas (4a) to (6a);

[0250] (b) The step of reacting the N-terminal amino acid residues of the peptide compounds represented by formulas (4a) to (6a) with the C-terminal amino acid residues of the peptide compounds in a solvent to perform a linking step; and

[0251] (c) The step of reacting the N-terminal amino acid residues of the peptide compound obtained in step (b) with the C-terminal amino acid residues of the peptide compound in a solvent to perform cyclization (cyclization step):

[0252] [Formula 9]

[0253]

[0254]

[0255] X1, X3, and X5 are each independently hydrogen or protecting groups for amino groups; and

[0256] X2, X4, and X6 are each independently a hydroxyl group, optionally a substituted alkoxy group, optionally a substituted aryloxy group, optionally a substituted arylalkoxy group, optionally a substituted cyclic aminooxy group, or a group consisting of -OSiR. x R y R z The group represented, where R x R y and R z Each can be an alkyl or aryl group independently.

[0257] [B3] According to the method described in [B2], the method includes, in step (b),

[0258] (b-1) The step of reacting the N-terminal amino acid residues of the peptide compound represented by formula (5a) with the C-terminal amino acid residues of the peptide compound represented by formula (6a) in a solvent to link them, thereby converting them into the peptide compound represented by formula (7a) (linking step):

[0259] [Formula 10]

[0260]

[0261] X4 and X5 are the same as in [B2].

[0262] [B4] According to the method described in [B3], the method further includes, in step (b),

[0263] (b-2) The step of reacting the N-terminal amino acid residues of the peptide compound represented by formula (4a) with the C-terminal amino acid residues of the peptide compound represented by formula (7a) in a solvent to link them, thereby converting them into the peptide compound represented by formula (2a) (linking step), and

[0264] The method further includes, in step (c),

[0265] (c-1) The step of reacting the N-terminal amino acid residue of the peptide compound represented by formula (2a) with the C-terminal amino acid residue of the peptide compound in a solvent to perform cyclization (cyclization step).

[0266] [B5] According to the method described in [B3], the method further includes, in step (b),

[0267] (b-3) The step of reacting the N-terminal amino acid residues of the peptide compound represented by formula (7a) with the C-terminal amino acid residues of the peptide compound represented by formula (4a) in a solvent to link them, thereby converting them into the peptide compound represented by formula (3a) (the linking step), and

[0268] The method further includes, in step (c),

[0269] (c-2) The step of reacting the N-terminal amino acid residue of the peptide compound represented by formula (3a) with the C-terminal amino acid residue of the peptide compound in a solvent to perform cyclization (cyclization step).

[0270] [B6] The method according to any one of [B1] to [B5], wherein the solvent in the cyclization step is the solvent according to any one of [A8] to [A12].

[0271] [B7] The method according to any one of [B1] to [B6], wherein the cyclization step is performed in the presence of a condensation reagent.

[0272] [B8] According to the method of [B7], the condensing agent in the cyclization step is a condensing agent according to any one of [A14] to [A17].

[0273] [B9] According to the method of [B7], the solvent and the condensing agent in the cyclization step are the solvent and condensing agent according to any one of [A18] to [A21].

[0274] [B10] The method according to any one of [B1] to [B9], wherein the cyclization step is carried out in the presence of a base.

[0275] [B11] According to the method of [B10], the base in the cyclization step is the base according to any one of [A24] to [A26].

[0276] [B12] The method according to [B10], wherein the solvent, condensing agent and base in the cyclization step are any one of the solvent, condensing agent and base according to [A27] to [A30].

[0277] [B13] The method according to any one of [B1] to [B12], wherein the cyclization step is performed by a liquid phase method.

[0278] [B14] The method according to any one of [B1] to [B13], wherein in the cyclization step, the peptide compound and the base are mixed in a mixed solution obtained by mixing the solvent and the condensation reagent in the cyclization step.

[0279] [B15] The method according to any one of [B1] to [B14], wherein, based on the total amount of product, the content of the total byproduct generated in the cyclization step is less than 20%, less than 15%, less than 10%, less than 5%, or less than 3%, as determined by the UV area value at 220 nm obtained by HPLC analysis.

[0280] [B16] The method according to any one of [B1] to [B15], wherein, based on the total amount of product, the content of each of the byproducts generated in the cyclization step is less than 15%, less than 10%, less than 5%, less than 3%, less than 1%, or is an undetectable amount, as determined by the UV area value at 220 nm obtained by HPLC analysis.

[0281] [B17] The method according to any one of [B1] to [B16], wherein, based on the total amount of product, the content of each of the byproducts generated in the cyclization step is less than 15%, less than 10%, less than 5%, less than 3%, less than 1%, or is an undetectable amount, as determined by the UV area value at 220 nm obtained by HPLC analysis, and the byproducts comprise epimers and / or cyclic dimers.

[0282] [B18] The method according to any one of [B1] to [B17], wherein the byproduct generated in the cyclization step comprises an epimer, and the content of the epimer is less than 10%, less than 7.5%, less than 5%, less than 2.5%, or less than 1% based on the total amount of product, as determined by the UV area value at 220 nm obtained by HPLC analysis.

[0283] [B19] The method according to any one of [B1] to [B18], wherein the byproduct generated in the cyclization step comprises a cyclic dimer, and the content of the cyclic dimer is less than 15%, less than 10%, less than 5%, less than 2.5% or less than 1% based on the total amount of product, as determined by the UV area value at 220 nm obtained by HPLC analysis.

[0284] [B20] The method according to any one of [B1] to [B19], wherein the solvent in the connecting step is the solvent according to any one of [A38] to [A43].

[0285] [B21] The method according to any one of [B1] to [B20], wherein the joining step is performed in the presence of a condensing agent.

[0286] [B22] According to the method of [B21], the condensing agent in the connecting step is a condensing agent according to any one of [A45] to [A49].

[0287] [B23] According to the method of [B21], the solvent and the condensing agent in the connecting step are the solvent and condensing agent according to any one of [A50] to [A53].

[0288] [B24] The method according to any one of [B1] to [B23], wherein the connection step is performed in the presence of an alkali.

[0289] [B25] The method according to [B24], wherein the base in the connection step is the base according to any one of [A55] to [A59].

[0290] [B26] The method according to [B24], wherein the solvent, condensing agent and base in the connecting step are the solvent, condensing agent and base according to any one of [A60] to [A62].

[0291] [B27] The method according to any one of [B1] to [B26], wherein the connection step is performed by a liquid phase method.

[0292] [B28] The method according to any one of [B1] to [B27], wherein column chromatography is used to separate and / or purify the cyclic peptide compound or its salt or solvates thereof.

[0293] [B29] The method according to any one of [B1] to [B27], wherein column chromatography is not used to separate and / or purify the cyclic peptide compound or its salt or solvates thereof.

[0294] [B30] The method according to any one of [B1] to [B29] further comprises the step of obtaining crystals of the cyclic peptide compound or its salt or its solvates by crystallization and / or purification.

[0295] [C1] A compound or a salt thereof represented by formula (4a),

[0296] [Equation 11]

[0297]

[0298] Where X1 is hydrogen or a protecting group for an amino group; and

[0299] X2 is a hydroxyl group, optionally a substituted alkoxy group, optionally a substituted aryloxy group, optionally a substituted arylalkoxy group, optionally a substituted cyclic aminooxy group, or a group consisting of -OSiR. x R y R z The group represented, where R x R y and R z Each can be an alkyl or aryl group independently.

[0300] [C2] The compound or salt thereof according to [C1], wherein X1 is hydrogen.

[0301] [C3] The compound or salt thereof according to [C1], wherein X1 is an Fmoc group.

[0302] [C4] The compound or salt thereof according to any one of [C1] to [C3], wherein X2 is tert-butoxy.

[0303] [C5] 2-[methyl-[(2S)-2-[(4Z,7S)-7-(methylamino)-8-oxo-2,3,6,7-tetrahydroazacyclooctatetraen-1-yl]-3-[4-(trifluoromethyl)phenyl]propionyl]amino]tert-butyl acetate (compound 9).

[0304] [C6] A compound or a salt thereof represented by formula (5a),

[0305] [Equation 12]

[0306]

[0307] Where X3 is hydrogen or a protecting group for an amino group; and

[0308] X4 is a hydroxyl group, optionally a substituted alkoxy group, optionally a substituted aryloxy group, optionally a substituted arylalkoxy group, optionally a substituted cyclic aminooxy group, or a group consisting of -OSiR. x R y R zThe group represented, where R x R y and R z Each can be an alkyl or aryl group independently.

[0309] [C7] The compound or salt thereof according to [C6], wherein X3 is hydrogen.

[0310] [C8] The compound or salt thereof according to [C6], wherein X3 is an Fmoc group or a Cbz group.

[0311] [C9] The compound or salt thereof according to any one of [C6] to [C8], wherein X4 is tert-butoxy.

[0312] [C10] (2S)-1-[(2S,3S)-3-methyl-2-[[(2S)-2-(methylamino)pentanoyl]amino]pentanoyl]pyrrolidine-2-acetic acid tert-butyl ester (compound 13).

[0313] [C11] A compound or a salt thereof represented by formula (6a),

[0314] [Equation 13]

[0315]

[0316] Where X5 is hydrogen or a protecting group for an amino group; and

[0317] X6 is a hydroxyl group, optionally a substituted alkoxy group, optionally a substituted aryloxy group, optionally a substituted arylalkoxy group, optionally a substituted cyclic aminooxy group, or a group consisting of -OSiR. x R y R z The group represented, where R x R y and R z Each can be an alkyl or aryl group independently.

[0318] [C12] The compound or salt thereof according to [C11], wherein X5 is hydrogen.

[0319] [C13] The compound or salt thereof according to [C11], wherein X5 is a Cbz group.

[0320] [C14] The compound or salt thereof according to any one of [C11] to [C13], wherein X6 is a hydroxyl or tert-butoxy group.

[0321] [C15] (3S)-3-[[(2S)-2-[[1-[[(2S,4R)-1-[(2S)-2-(benzyloxycarbonylamino)-4-[3-methoxy-4-(trifluoromethyl)phenyl]butyryl]-4-ethoxy-pyrrolidine-2-carbonyl]-methyl-amino]cyclobutanecarbonyl]-methyl-amino]-2-cyclopentyl-acetyl]-methyl-amino]-4-(dimethylamino)-4-oxo-butyric acid (compound 20).

[0322] [C16] A compound or a salt thereof represented by formula (7a),

[0323] [Formula 14]

[0324]

[0325] Where X5 is hydrogen or a protecting group for an amino group; and

[0326] X4 is a hydroxyl group, optionally a substituted alkoxy group, optionally a substituted aryloxy group, optionally a substituted arylalkoxy group, optionally a substituted cyclic aminooxy group, or a group consisting of -OSiR. x R y R z The group represented, where R x R y and R z Each can be an alkyl or aryl group independently.

[0327] [C17] The compound or salt thereof according to [C16], wherein X5 is hydrogen.

[0328] [C18] The compound or salt thereof according to [C16], wherein X5 is a Cbz group.

[0329] [C19] The compound or salt thereof according to any one of [C16] to [C18], wherein X6 is a hydroxyl or tert-butoxy group.

[0330] [C20] (2S)-1-[(2S,3S)-2-[[(2S)-2-[[(3S)-3-[[(2S)-2-[[1-[[(2S,4R)-1-[(2S)-2-(benzyloxycarbonylamino)-4-[3-methoxy-4-(trifluoromethyl)phenyl]butyryl]-4-ethoxy-pyrrolidine-2-carbonyl]-methyl-amino]cyclobutanecarbonyl]-methyl-amino]-2-cyclopentylacetyl]-methyl-amino]-4-(dimethylamino)-4-oxo-butyryl]-methyl-amino]valeryl]amino]-3-methyl-valeryl]pyrrolidine-2-carboxylic acid (compound 22).

[0331] [C20-1] (2S)-1-[(2S,3S)-2-[[(2S)-2-[[(3S)-3-[[(2S)-2-[[1-[[(2S,4R)-1-[(2S)-2-amino-4-[3-methoxy-4-(trifluoromethyl)phenyl]butyryl]-4-ethoxy-pyrrolidine-2-carbonyl]-methyl-amino]cyclobutanecarbonyl]-methyl-amino]-2-cyclopentyl-acetyl]-methyl-amino]-4-(dimethylamino)-4-oxo-butyryl]-methyl-amino]valeryl]amino]-3-methyl-valeryl]pyrrolidine-2-carboxylic acid tert-butyl ester (compound 37).

[0332] [C21] A compound or a salt thereof represented by formula (2a),

[0333] [Formula 15]

[0334]

[0335] Where X5 is hydrogen or a protecting group for an amino group; and

[0336] X2 is a hydroxyl group, optionally a substituted alkoxy group, optionally a substituted aryloxy group, optionally a substituted arylalkoxy group, optionally a substituted cyclic aminooxy group, or a group consisting of -OSiR. x R y R z The group represented, where R x R y and R z Each can be an alkyl or aryl group independently.

[0337] [C22] The compound or salt thereof according to [C21], wherein X5 is hydrogen.

[0338] [C23] The compound or salt thereof according to [C21], wherein X5 is a Cbz group.

[0339] [C24] The compound or salt thereof according to any one of [C21] to [C23], wherein X2 is a hydroxyl or tert-butoxy group.

[0340] [C25] 2-[[(2S)-2-[(4Z,7S)-7-[[(2S)-1-[(2S,3S)-2-[[(2S)-2-[[(3S)-3-[[(2S)-2-[[1-[[(2S,4R)-1-[(2S)-2-amino-4-[3-methoxy-4-(trifluoromethyl)phenyl]butyryl]-4-ethoxy-pyrrolidine-2-carbonyl]-methyl-amino]cyclobutanecarbonyl [-Methyl-amino]-2-cyclopentyl-acetyl]-methyl-amino]-4-(dimethylamino)-4-oxo-butyryl]-methyl-amino]valeryl]amino]-3-methyl-valeryl]pyrrolidine-2-carbonyl]-methyl-amino]-8-oxo-2,3,6,7-tetrahydroazacyclooctatetraen-1-yl]-3-[4-(trifluoromethyl)phenyl]propionyl]-methyl-amino]acetic acid (compound 24).

[0341] [C26] A compound represented by formula (3a) or a salt thereof,

[0342] [Formula 16]

[0343]

[0344] Where X1 is hydrogen or a protecting group for an amino group; and

[0345] X4 is a hydroxyl group, optionally a substituted alkoxy group, optionally a substituted aryloxy group, optionally a substituted arylalkoxy group, optionally a substituted cyclic aminooxy group, or a group consisting of -OSiR. x R y R z The group represented, where R x R y and R z Each can be an alkyl or aryl group independently.

[0346] [C27] The compound or salt thereof according to [C26], wherein X1 is hydrogen.

[0347] [C28] The compound or salt thereof according to [C26], wherein X1 is an Fmoc group.

[0348] [C29] The compound or salt thereof according to any one of [C26] to [C28], wherein X4 is a hydroxyl or tert-butoxy group.

[0349] [C30] (S)-2-[(S)-3-[(S)-2-cyclopentyl-2-[1-[(2S,4R)-4-ethoxy-1-[(S)-4-[3-methoxy-4-(trifluoromethyl)phenyl]-2-[(2-[(S)-N-methyl-2-[(R,Z)-3-(methylamino)-2-oxo-3,4,7,8-tetrahydroazacyclooctatetraen-1(2H)-yl]-3-[4-(trifluoromethyl)phenyl]propamido]acetamido]butyryl]-N-methylpyrrolidine-2-carbamoyl]-N-methylcyclobutane-1-carbamoyl]-N-methylacetamido]-4-(dimethylamino)-N-methyl-4-oxobutamido]valoyl]-L-isoleucyl-L-proline (Compound 40).

[0350] [C31] A method for producing a compound according to any one of [C1] to [C30], wherein solid-phase synthesis is not used.

[0351] [C32] A method for producing a cyclic peptide compound represented by formula (1a), wherein solid-phase synthesis is not used.

[0352] [D1] A crystal of a cyclic peptide compound represented by formula (1a) or a salt thereof or a solvate thereof:

[0353] [Equation 17]

[0354]

[0355] [D2] The crystal according to [D1], wherein the crystal is selected from the group consisting of: nonsolvent crystals of cyclic peptide compounds, solvate crystals of cyclic peptide compounds, nonsolvent crystals of salts of cyclic peptide compounds, and solvate crystals of salts of cyclic peptide compounds.

[0356] [D3] The crystal according to [D2], wherein the crystal is a solvate crystal of a cyclic peptide compound.

[0357] [D4] The crystal according to [D3], wherein the solvate crystal is a hydrate crystal of a cyclic peptide compound.

[0358] [D5] The crystal according to [D4], wherein the hydrate crystal is a form A crystal, and the diffraction angle (2θ value) of the form A crystal obtained by powder X-ray diffraction includes at least 7 peaks selected from the group consisting of: 6.93°, 7.56°, 8.26°, 9.00°, 9.58°, 10.35°, 11.35°, 12.26°, 12.85°, 13.51°, 14.12°, 14.69°, 15.46°, 15.92°, 17.43° and 17.73° (±0.2°).

[0359] [D5-1] The crystal according to [D4], wherein the hydrate crystal is a form A crystal, and the diffraction angle (2θ value) of the form A crystal obtained by powder X-ray diffraction includes at least eight peaks selected from the group consisting of: 6.93°, 7.56°, 8.26°, 9.00°, 9.58°, 10.35°, 11.35°, 12.26°, 12.85°, 13.51°, 14.12°, 14.69°, 15.46°, 15.92°, 17.43° and 17.73° (±0.2°).

[0360] [D5-2] The crystal according to [D4], wherein the hydrate crystal is a form A crystal, and the diffraction angles (2θ values) of the form A crystal obtained by powder X-ray diffraction include peaks of 6.93°, 7.56°, 8.26°, 9.00°, 9.58°, 10.35°, 11.35°, 12.26°, 12.85°, 13.51°, 14.12°, 14.69°, 15.46°, 15.92°, 17.43° and 17.73° (±0.2°).

[0361] [D5-3] A crystal of form A according to any one of [D5] to [D5-2], wherein the diffraction angle (2θ value) is the diffraction angle (2θ value) of a hydrate crystal stored at 10% or higher relative humidity for 15 minutes or longer.

[0362] [D6] The crystal according to [D4], wherein the hydrate crystal is a form B crystal, and the diffraction angle (2θ value) of the form B crystal obtained by powder X-ray diffraction includes at least 7 peaks selected from the group consisting of: 4.99°, 8.65°, 9.85°, 10.84°, 11.32°, 12.35°, 13.20°, 14.44°, 15.20°, 16.03°, 16.69°, 17.21°, 18.82°, 19.49° and 20.03° (±0.2°).

[0363] [D6-1] The crystal according to [D4], wherein the hydrate crystal is a form B crystal, and the diffraction angle (2θ value) of the form B crystal obtained by powder X-ray diffraction includes at least eight peaks selected from the group consisting of: 4.99°, 8.65°, 9.85°, 10.84°, 11.32°, 12.35°, 13.20°, 14.44°, 15.20°, 16.03°, 16.69°, 17.21°, 18.82°, 19.49° and 20.03° (±0.2°).

[0364] [D6-2] The crystal according to [D4], wherein the hydrate crystal is a form B crystal, the diffraction angles (2θ values) of the form B crystal obtained by powder X-ray diffraction include peaks of 4.99°, 8.65°, 9.85°, 10.84°, 11.32°, 12.35°, 13.20°, 14.44°, 15.20°, 16.03°, 16.69°, 17.21°, 18.82°, 19.49° and 20.03° (±0.2°).

[0365] [D6-3] Form B crystal according to any one of [D6] to [D6-2], wherein the diffraction angle (2θ value) is the diffraction angle (2θ value) of a hydrate crystal stored at 30% or higher relative humidity for 15 minutes or longer.

[0366] [D7] The crystal according to [D3], wherein the solvate crystal is a form F crystal, the diffraction angle (2θ value) of the form F crystal obtained by powder X-ray diffraction includes at least 7 peaks selected from the group consisting of: 6.99°, 8.49°, 9.49°, 9.88°, 10.21°, 11.81°, 12.32°, 12.75°, 13.17°, 13.94°, 14.92°, 15.20°, 15.64°, 16.78°, 17.01° and 17.47° (±0.2°).

[0367] [D7-1] The crystal according to [D3], wherein the solvate crystal is a form F crystal, the diffraction angle (2θ value) of the form F crystal obtained by powder X-ray diffraction includes at least 8 peaks selected from the group consisting of: 6.99°, 8.49°, 9.49°, 9.88°, 10.21°, 11.81°, 12.32°, 12.75°, 13.17°, 13.94°, 14.92°, 15.20°, 15.64°, 16.78°, 17.01° and 17.47° (±0.2°).

[0368] [D7-2] The crystal according to [D3], wherein the solvate crystal is a form F crystal, and the diffraction angles (2θ values) of the form F crystal obtained by powder X-ray diffraction include peaks of 6.99°, 8.49°, 9.49°, 9.88°, 10.21°, 11.81°, 12.32°, 12.75°, 13.17°, 13.94°, 14.92°, 15.20°, 15.64°, 16.78°, 17.01° and 17.47° (±0.2°).

[0369] [D7-3] The crystal according to any one of [D7] to [D7-2], wherein the solvate crystal is an acetone / heptane / water solvate.

[0370] [D8] The crystal according to [D4], wherein the hydrate crystal is a form J crystal, and the diffraction angle (2θ value) of the form J crystal obtained by powder X-ray diffraction includes at least 7 peaks selected from the group consisting of: 6.95°, 7.33°, 7.93°, 8.84°, 9.45°, 9.97°, 10.44°, 11.19°, 12.43°, 12.93°, 13.46°, 14.36°, 14.74°, 15.21°, 15.87°, 16.76°, 20.87° and 22.97° (±0.2°).

[0371] [D8-1] The crystal according to [D4], wherein the hydrate crystal is a form J crystal, and the diffraction angle (2θ value) of the form J crystal obtained by powder X-ray diffraction includes at least eight peaks selected from the group consisting of: 6.95°, 7.33°, 7.93°, 8.84°, 9.45°, 9.97°, 10.44°, 11.19°, 12.43°, 12.93°, 13.46°, 14.36°, 14.74°, 15.21°, 15.87°, 16.76°, 20.87° and 22.97° (±0.2°).

[0372] [D8-2] The crystal according to [D4], wherein the hydrate crystal is a form J crystal, and the diffraction angles (2θ values) of the form J crystal obtained by powder X-ray diffraction include peaks of 6.95°, 7.33°, 7.93°, 8.84°, 9.45°, 9.97°, 10.44°, 11.19°, 12.43°, 12.93°, 13.46°, 14.36°, 14.74°, 15.21°, 15.87°, 16.76°, 20.87° and 22.97° (±0.2°).

[0373] [D8-3] A crystal of form J according to any one of [D8] to [D8-2], wherein the diffraction angle (2θ value) is the diffraction angle (2θ value) of a hydrate crystal stored at 10% or higher relative humidity for 15 minutes or longer.

[0374] [D9] The crystal according to [D4], wherein the hydrate crystal is a form Y crystal, the diffraction angle (2θ value) of the form Y crystal obtained by powder X-ray diffraction includes at least 7 peaks selected from the group consisting of: 5.13°, 8.33°, 8.82°, 9.80°, 10.32°, 11.39°, 12.58°, 13.28°, 14.80°, 15.40°, 15.88°, 17.12°, 17.67°, 19.18°, 19.54° and 21.24° (±0.2°).

[0375] [D9-1] The crystal according to [D4], wherein the hydrate crystal is a form Y crystal, and the diffraction angle (2θ value) of the form Y crystal obtained by powder X-ray diffraction includes at least eight peaks selected from the group consisting of: 5.13°, 8.33°, 8.82°, 9.80°, 10.32°, 11.39°, 12.58°, 13.28°, 14.80°, 15.40°, 15.88°, 17.12°, 17.67°, 19.18°, 19.54° and 21.24° (±0.2°).

[0376] [D9-2] The crystal according to [D4], wherein the hydrate crystal is a form Y crystal, and the diffraction angles (2θ values) of the form Y crystal obtained by powder X-ray diffraction include peaks of 5.13°, 8.33°, 8.82°, 9.80°, 10.32°, 11.39°, 12.58°, 13.28°, 14.80°, 15.40°, 15.88°, 17.12°, 17.67°, 19.18°, 19.54° and 21.24° (±0.2°).

[0377] [D9-3] A Y crystal according to any one of [D9] to [D9-2], wherein the diffraction angle (2θ value) is the diffraction angle (2θ value) of a hydrate crystal stored at 30% or higher relative humidity for 15 minutes or longer.

[0378] [D10] The crystal according to [D3], wherein the hydrate crystal is a form K crystal, and the diffraction angle (2θ value) of the form K crystal obtained by powder X-ray diffraction includes at least 7 peaks selected from the group consisting of: 7.49°, 7.91°, 8.14°, 9.11°, 9.33°, 11.04°, 11.71°, 12.52°, 13.21°, 13.70°, 14.82°, 15.13°, 15.52°, 15.68°, 17.22° and 17.51° (±0.2°).

[0379] [D10-1] The crystal according to [D3], wherein the hydrate crystal is a form K crystal, and the diffraction angle (2θ value) of the form K crystal obtained by powder X-ray diffraction includes at least eight peaks selected from the group consisting of: 7.49°, 7.91°, 8.14°, 9.11°, 9.33°, 11.04°, 11.71°, 12.52°, 13.21°, 13.70°, 14.82°, 15.13°, 15.52°, 15.68°, 17.22° and 17.51° (±0.2°).

[0380] [D10-2] According to the crystal described in [D3], wherein the solvate crystal is a form K crystal, and the diffraction angles (2θ values) of the form K crystal obtained by powder X-ray diffraction include peaks of 7.49°, 7.91°, 8.14°, 9.11°, 9.33°, 11.04°, 11.71°, 12.52°, 13.21°, 13.70°, 14.82°, 15.13°, 15.52°, 15.68°, 17.22° and 17.51° (±0.2°).

[0381] [D11] The crystal according to [D3], wherein the solvate crystal is a G dimethyl sulfoxide / heptane / water solvate crystal having the single-crystal X-ray analysis structure shown in FIG1.

[0382] [D11-1] The crystal according to [D3], wherein the solvate crystal is in the form of E 2-propanol / heptane / water solvate crystal, having the single-crystal X-ray analysis structure shown in FIG3.

[0383] [D11-2] The crystal according to [D3], wherein the solvate crystal is in the form of H ethanol / water solvate crystal, having the single-crystal X-ray analysis structure shown in FIG8.

[0384] [D11-3] The crystal according to [D3], wherein the solvate crystal is in the form of D1,4-dioxane / water solvate crystal, having the single-crystal X-ray analysis structure shown in FIG26.

[0385] [D11-4] The crystal according to [D3], wherein the solvate crystal is in the form of L dimethyl sulfoxide / water solvate crystal, having the single-crystal X-ray analysis structure shown in FIG28.

[0386] [D11-5] The crystal according to [D3], wherein the solvate crystal is a form M propylene glycol / water solvate crystal having the single-crystal X-ray analysis structure shown in FIG31.

[0387] [D11-6] The crystal according to [D3], wherein the solvate crystal is a form M propylene glycol / water solvate crystal having the diffraction angles obtained by powder X-ray diffraction as shown in FIG29.

[0388] [D11-7] The crystal according to [D3], wherein the solvate crystal is in the form of M propylene glycol / water solvate crystal, exhibiting the thermogravimetric-differential thermal analysis data shown in Figure 30(A).

[0389] [D11-8] The crystal according to [D3], wherein the solvate crystal is in the form of N-propylene glycol solvate crystal, having the diffraction angle obtained by powder X-ray diffraction as shown in FIG29.

[0390] [D11-9] The crystal according to [D3], wherein the solvate crystal is in the form of N-propylene glycol solvate crystal, exhibiting the thermogravimetric-differential thermal analysis data shown in Figure 30(B).

[0391] [D12] A method for producing crystals of a cyclic peptide compound according to any one of [D1] to [D10-2], the method comprising: dissolving the cyclic peptide compound in a polar organic solvent to obtain a solution, the amount of the polar organic solvent allowing the cyclic peptide compound to dissolve therein; and adding a hydrocarbon solvent or water to the solution to obtain crystals of the cyclic peptide compound.

[0392] [D12-1] The method according to [D12] wherein the purity of the original material cyclic peptide compound is 85% or higher.

[0393] [D13] A method for producing crystals of a cyclic peptide compound according to any one of [D1] to [D10-2], the method comprising the step of adding a mixed solution of a hydrocarbon solvent and a polar organic solvent or a mixed solution of water and a polar organic solvent to the amorphous cyclic peptide compound to obtain crystals of the cyclic peptide compound.

[0394] [D14] The method according to any one of [D12] to [D13-1], wherein the polar organic solvent is one or more selected from the group consisting of: DMSO, acetone, 2-butanone, methanol, ethanol, 1-propanol, 2-propanol, propylene glycol, 1,4-dioxane and ethyl acetate.

[0395] [D15] The method according to [D14], wherein the polar organic solvent is acetone.

[0396] [D15-1] The method according to [D14], wherein the polar organic solvent is ethanol.

[0397] [D16] The method according to any one of [D12] to [D13-1], wherein the hydrocarbon solvent is one or more selected from the group consisting of: heptane, hexane, pentane, toluene and xylene.

[0398] [D17] The method according to [D16], wherein the hydrocarbon solvent is heptane.

[0399] [D18] A method for producing crystals of a cyclic peptide compound according to any one of [D1] to [D10-2], the method comprising: dissolving the amorphous cyclic peptide compound in DMSO to obtain a solution; freeze-drying the solution to obtain a freeze-dried product of the cyclic peptide compound; and adding a mixed solution of water and a polar organic solvent to the freeze-dried product to obtain crystals of the cyclic peptide compound.

[0400] [D19] According to the method of [D18], the polar organic solvent is one or more selected from the group consisting of: DMSO, acetone, 2-butanone, methanol, ethanol, 1-propanol, 2-propanol, 1,4-dioxane and propylene glycol.

[0401] [D20] According to the method of [D19], the polar organic solvent is acetone.

[0402] [D21] The method according to any one of [D12] to [D20] further includes a step of filtering the crystals after the step of obtaining the crystals of the cyclic peptide compound.

[0403] [D22] The method according to any one of [D12] to [D21] further includes a step of drying the crystals after the step of obtaining the crystals of the cyclic peptide compound.

[0404] [D23] The method according to any one of [D12] to [D22], wherein the crystal of the cyclic peptide compound is a solvate crystal.

[0405] [D24] According to the method of [D23], the solvate crystal of the cyclic peptide compound is a hydrate crystal.

[0406] [D25] According to the method of [D21] or [D22], wherein the crystals of the cyclic peptide compound are formed in a solvent as solvate crystals and obtained as hydrate crystals after a filtration step and / or a drying step.

[0407] [D26] A composition comprising a cyclic peptide compound represented by formula (1a) or a salt thereof or a solvate thereof, wherein said compound contains a cyclic dimer of formula (1a) as an impurity in an amount of 1.5 w / w% or less:

[0408] [Formula 18]

[0409]

[0410] [D27] A composition comprising a cyclic peptide compound represented by formula (1a) or a salt thereof or a solvate thereof, wherein said compound contains a cyclic dimer of formula (1a) as an impurity in an amount of 0.001 w / w% or higher:

[0411] [Formula 19]

[0412]

[0413] [D28] A composition comprising a cyclic peptide compound represented by formula (1a) or a salt thereof or a solvate thereof, wherein said compound contains acetone in a proportion of 2.0 w / w% or less:

[0414] [Formula 20]

[0415]

[0416] [D29] A composition comprising a cyclic peptide compound represented by formula (1a) or a salt thereof or a solvate thereof, wherein said compound contains acetone in a proportion of 0.001 w / w% or higher:

[0417] [Equation 21]

[0418]

[0419] In the above numbering, unless otherwise stated, the number referenced in a dependent entry includes the branch number of that number. For example, [A67] referenced in a dependent entry means that it includes not only [A67] but also its branch number [A67-1]. The same applies to other numbering.

[0420] [Beneficial effects of the invention]

[0421] According to the present invention, cyclic peptide compounds or their salts or solvates can be efficiently produced while suppressing the formation of cyclic dimers as byproducts. The production method of the present invention enables the reduction of peptide compound production costs and also reduces environmental impact; therefore, the production method of the present invention is particularly useful for large-scale peptide synthesis. Attached Figure Description

[0422] [Figure 1] Figure 1 shows the crystal structure of the crystal (form G) obtained in Example 3-1. Compound 1 is drawn using a capping rod model, and the others are drawn using a ball-and-stick model.

[0423] [Figure 2] Figure 2 shows the powder X-ray diffraction measurements of the crystal (Form A) obtained in Example 3-2. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°).

[0424] [ Figure 3 Figure 3 shows the crystal structures of the crystals obtained in Examples 3-3. Compound 1 is drawn using a capping rod model, and the others are drawn using a ball-and-stick model.

[0425] [Figure 4] Figure 4 shows the powder X-ray diffraction measurements of the crystal (form E) obtained in Example 3-3. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°).

[0426] [Figure 5] Figure 5 shows the powder X-ray diffraction measurements of the crystals (Form B) obtained in Examples 3-4. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°).

[0427] [Figure 6] Figure 6 shows the powder X-ray diffraction measurements of the crystals (Form B) obtained in Examples 3-5. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°).

[0428] [Figure 7] Figure 7 shows the crystal structures of the crystals (form H) obtained in Examples 3-6. Compound 1 is drawn using a capping rod model, and the others are drawn using a ball-and-stick model.

[0429] [Figure 8] Figure 8 shows the powder X-ray diffraction measurements of the crystals (Form B) obtained in Examples 3-6. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°).

[0430] [Figure 9] Figure 9 shows the crystal structures of the crystals (form C) obtained in Examples 3-7. Compound 1 is drawn using a capping bar model, and the others are drawn using a ball-and-stick model.

[0431] [Figure 10] Figure 10 shows the powder X-ray diffraction measurements of the crystals (Form B) obtained in Examples 3-7. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°).

[0432] [Figure 11] Figure 11 shows the powder X-ray diffraction measurements of the crystals (Form A) obtained in Examples 3-8. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°).

[0433] [Figure 12] Figure 12 shows the thermogravimetric-differential thermal analysis results of the crystals (form A) obtained in Examples 3-8. The horizontal axis represents temperature (°C), and the right vertical axis represents the weight change (%) of the sample in the thermogravimetric analysis. The left vertical axis represents the heat flow observed in the differential thermal analysis.

[0434] [Figure 13] Figure 13 shows the crystals (form A) obtained in Examples 3-8. 1 H-NMR measurement results. The vertical axis represents signal intensity, and the horizontal axis represents chemical shift δ (ppm).

[0435] [Figure 14] Figure 14 shows the powder X-ray diffraction measurements of the crystals (Form A) obtained in Examples 3-9. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°).

[0436] [Figure 15] Figure 15 shows the thermogravimetric-differential thermal analysis results of the crystals (form A) obtained in Examples 3-9. The horizontal axis represents temperature (°C), and the right vertical axis represents the weight change (%) of the sample in the thermogravimetric analysis. The left vertical axis represents the heat flow observed in the differential thermal analysis.

[0437] [Figure 16] Figure 16 shows the crystals (form A) obtained in Examples 3-9. 1 H-NMR measurement results. The vertical axis represents signal intensity, and the horizontal axis represents chemical shift δ (ppm).

[0438] [Figure 17] Figure 17 shows the powder X-ray diffraction measurements of the crystal (form F) obtained in Examples 3-10. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°).

[0439] [Figure 18] Figure 18 shows the crystal structure of the crystal (form F) obtained in Examples 3-11. Compound 1 is drawn using a capping rod model, and the others are drawn using a ball-and-stick model.

[0440] [Figure 19] Figure 19 shows the powder X-ray diffraction measurements of the crystal (Form A) obtained in Examples 3-12. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°).

[0441] [Figure 20] Figure 20 shows the thermogravimetric-differential thermal analysis results of the crystal (form A) obtained in Example 3-12. The horizontal axis represents temperature (°C), and the right vertical axis represents the weight change (%) of the sample in the thermogravimetric analysis. The left vertical axis represents the heat flow observed in the differential thermal analysis.

[0442] [Figure 21] Figure 21 shows the powder X-ray diffraction measurements of the crystals obtained in Example 3-12 at relative humidity levels of (A) 0% (Form J), (B) 10% (Form A), (C) 20% (Form A), (D) 50% (Form A), and (E) 90% (Form A). The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). The peaks around 4.89° and 6.65° in the figure are peaks originating from the measuring equipment.

[0443] [Figure 22] Figure 22 shows the powder X-ray diffraction measurements of the crystal (Form B) obtained in Example 3-13. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°).

[0444] [Figure 23] Figure 23 shows the thermogravimetric-differential thermal analysis results of the crystal (form B) obtained in Example 3-13. The horizontal axis represents temperature (°C), and the right vertical axis represents the weight change (%) of the sample during thermogravimetric analysis. The left vertical axis represents the heat flow observed in differential thermal analysis.

[0445] [Figure 24] Figure 24 shows the powder X-ray diffraction measurements of the crystals obtained in Example 3-13 at relative humidity levels of (A) 0% (Form Y), (B) 30% (Form B), (C) 50% (Form B), and (D) 90% (Form B). The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). The peak around 6.63° in the figure is the peak originating from the measuring device.

[0446] [Figure 25] Figure 25 shows the crystal structure of the crystals (form B) obtained in Examples 3-14. Compound 1 is drawn using a capping rod model, and the others are drawn using a ball-and-stick model.

[0447] [Figure 26] Figure 26 shows the crystal structure of the crystal (form D) obtained in Examples 3-15. Compound 1 is drawn using a capping rod model, and the others are drawn using a ball-and-stick model.

[0448] [Figure 27] Figure 27 shows the crystal structure of the crystals (form L) obtained in Examples 3-16. Compound 1 is drawn using a capping rod model, and the others are drawn using a ball-and-stick model.

[0449] [Figure 28] Figure 28 shows the powder X-ray diffraction measurements of the crystal (form L) obtained in Examples 3-16 (A: wet powder, B: dry powder). The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°).

[0450] [Figure 29] Figure 29 shows the powder X-ray diffraction measurements of the crystals obtained in Examples 3-17 (A: Form M, B: Form N). The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°).

[0451] [Figure 30] Figure 30 shows the thermogravimetric-differential thermal analysis results of the crystal (form N) obtained in Example 3-17. The horizontal axis represents temperature (°C), and the right vertical axis represents the weight change (%) of the sample in the thermogravimetric analysis. The left vertical axis represents the heat flow observed in the differential thermal analysis.

[0452] [Figure 31] Figure 31 shows the crystal structure of the crystal (form M) obtained in Examples 3-18. Compound 1 is drawn using a capping rod model, and the others are drawn using a ball-and-stick model.

[0453] [Figure 32] Figure 32 shows the powder X-ray diffraction measurements of the crystal (form K) obtained in Example 3-19. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°).

[0454] [Figure 33] Figure 33 shows the thermogravimetric-differential thermal analysis results of the crystal (form K) obtained in Example 3-19. The horizontal axis represents temperature (°C), and the right vertical axis represents the weight change (%) of the sample in the thermogravimetric analysis. The left vertical axis represents the heat flow observed in the differential thermal analysis.

[0455] [Figure 34] Figure 34 shows the crystal (form K) obtained in Example 3-19. 1 H-NMR measurement results. The vertical axis represents signal intensity, and the horizontal axis represents chemical shift δ (ppm).

[0456] [Figure 35] Figure 35 shows the powder X-ray diffraction measurements of the crystals obtained in (A) Example 5-1, (B) Example 5-2, (C) Example 5-3, (D) Example 5-4, (E) Example 5-5, (F) Example 5-6, (G) Example 5-7, (H) Example 5-8, and (I) Example 5-9. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°).

[0457] [Figure 36] Figure 36 shows the powder X-ray diffraction measurements of the crystal (Form B) obtained in Example 3-22. The vertical axis represents the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). Detailed Implementation

[0458] abbreviation

[0459] The abbreviations used in this article are listed below.

[0460] 2-MeTHF: 2-Methyltetrahydrofuran

[0461] 20% Pip / DMF: N,N-dimethylformamide solution containing 20% ​​piperidine

[0462] EtOAc: Ethyl acetate

[0463] Alloc: allyloxycarbonyl

[0464] BEP: 2-Bromo-1-ethylpyridinium tetrafluoroborate

[0465] BHT: 2,6-Di-tert-butyl-4-methylphenol

[0466] Boc: tert-butoxycarbonyl

[0467] Cbz: Benzyloxycarbonyl

[0468] COMU: (1-Cyano-2-ethoxy-2-oxoethyleneaminooxy)dimethylamino-morpholino-carbomony hexafluorophosphate

[0469] CPME: Cyclopentylmethyl ether

[0470] CSA: 10-Camphorsulfonic acid

[0471] DCM: Dichloromethane

[0472] DEPBT: Diethyl 3,4-dihydro-4-oxo-1,2,3-benzotriazine-3-ester of phosphate

[0473] DIPEA: N,N-Diisopropylethylamine

[0474] DMA: N,N-dimethylacetamide

[0475] DMAP: 4-Dimethylaminopyridine

[0476] DMF: N,N-dimethylformamide

[0477] DMSO: Dimethyl sulfoxide

[0478] DMT-MM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride

[0479] EDCI: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0480] FDPP: Pentafluorophenyl diphenyl phosphonite

[0481] Fmoc or FMOC: 9-fluorenylmethyloxycarbonyl

[0482] HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate

[0483] HMDS: 1,1,1,3,3,3-Hexamethyldisilazane

[0484] HOAt: 1-Hydroxy-7-azabenzotriazole

[0485] HOBt: 1-Hydroxybenzotriazole

[0486] IPAc: Isopropyl acetate

[0487] MeCN: Acetonitrile

[0488] MTBE: Methyl tert-butyl ether

[0489] MTHP: 4-Methyltetrahydropyran

[0490] NMM: 4-Methylmorpholine

[0491] NMP: N-methylpyrrolidone

[0492] PyBOP: 1H-benzotriazol-1-yloxytripyrrolidinephosphonium hexafluorophosphate

[0493] PyClop: Chlorotripyrrolidine-based phosphonium hexafluorophosphate

[0494] PyOxim: (Ethylcyano(hydroxyimino)acetate-O2)-tris-(1-pyrrolidinyl)-phosphonium hexafluorophosphate

[0495] T3P: Propylphosphonic anhydride

[0496] TBAF: Tetrabutylammonium fluoride

[0497] Teoc: 2-(trimethylsilyl)ethoxycarbonyl

[0498] TFA: Trifluoroacetic acid

[0499] THF: Tetrahydrofuran

[0500] TMSOTf: Trimethylsilyl trifluoromethanesulfonate

[0501] Troc: 2,2,2-trichloroethoxycarbonyl

[0502] PDA: Photodiode Array

[0503] FA: Formic acid

[0504] qNMR: Quantitative nuclear magnetic resonance

[0505] UPLC: Ultra-high performance liquid chromatography (a trademark of Waters Corporation)

[0506] HPLC: High Performance Liquid Chromatography

[0507] Et: Ethyl

[0508] DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene

[0509] ESI: Electrospray Ionization

[0510] Bu: Butyl

[0511] Me: Methyl

[0512] oxyma: Ethyl cyano(oxime)

[0513] DIC: N,N'-Diisopropylcarbodiimide

[0514] TFE: 2,2,2-trifluoroethanol

[0515] IPA: 2-Propanol

[0516] NMI: 1-Methylimidazole

[0517] TCFH: Chloro-N,N,N',N'-Tetramethylformamidin hexafluorophosphate

[0518] NMR: Nuclear Magnetic Resonance

[0519] TMS: Tetramethylsilane

[0520] Definition of functional groups, etc. (All terms and phrases used in this article are as commonly understood in the art. Examples are given below, but are not limited thereto.)

[0521] As used herein, the term "halogen" refers to, for example, F, Cl, Br, or I.

[0522] As used herein, the term "alkyl" refers to a subset of monovalent groups derived from aliphatic hydrocarbons by removing any one hydrogen atom, and having a hydrocarbon group structure that is free of heteroatoms (atoms other than carbon and hydrogen atoms) or unsaturated carbon-carbon bonds and contains hydrogen and carbon atoms in the main chain. Alkyl groups include not only linear forms but also branched forms. Specifically, alkyl groups are those having 1 to 20 carbon atoms (C1 to C2). 20 The following text "C" p To C q "Refers to an alkyl group having a carbon number of p to q, preferably C1 to C2." 10 Alkyl groups, and more preferably C1 to C6 alkyl groups. Specific examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl (2-methylpropyl), n-pentyl, sec-pentyl (1-methylbutyl), tert-pentyl (1,1-dimethylpropyl), neopentyl (2,2-dimethylpropyl), isopentyl (3-methylbutyl), 3-pentyl (1-ethylpropyl), 1,2-dimethylpropyl, 2-methylbutyl, n-hexyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1,1,2,2-tetramethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, and 2-ethylbutyl.

[0523] In this document, "alkenyl" refers to a monovalent group having at least one double bond (two adjacent sp2 carbon atoms). Depending on the conformation of the double bond and substituents (if present), the geometry of the double bond can be engegen (E) or zusammen (Z) and in cis or trans conformations. Alkenyl groups include not only straight-chain forms but also branched forms. Preferred examples of alkenyl groups include C2-C... 10 Alkenyl groups, and more preferred examples include C2-C6 alkenyl groups. Specific examples of alkenyl groups include vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl (including cis and trans), 3-butenyl, pentenyl, 3-methyl-2-butenyl, and hexenyl.

[0524] As used herein, "alkynyl" is a monovalent group having at least one triple bond (two adjacent sp carbon atoms). Alynyl groups include both straight-chain and branched forms. Preferred examples of alkynyl groups include C2-C... 10 The alkynyl group, and more preferably a C2-C6 alkynyl group. Specific examples of alkynyl groups include ethynyl, 1-propynyl, propynyl, 3-butynyl, pentyynyl, and hexynyl.

[0525] As used herein, “cycloalkyl” means a saturated or partially saturated cyclic monovalent aliphatic hydrocarbon group and includes monocyclic, bicyclic, and spirocyclic groups. Cycloalkyl is preferably C3-C8 cycloalkyl, more preferably C3-C7 cycloalkyl, and still more preferably C3-C6 cycloalkyl. Specific examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclic [2.2.1]heptyl, and spiro[3.3]heptyl.

[0526] As used herein, the term "aryl" refers to a monovalent aromatic hydrocarbon ring, i.e., an aromatic hydrocarbon ring group. Preferred examples of aryl groups include C6-C... 10 Aryl. Specific examples of aryl groups include phenyl and naphthyl groups (such as 1-naphthyl and 2-naphthyl).

[0527] As used herein, the term "heteroaryl" refers to an aromatic cyclic monovalent group containing a carbon atom and 1 to 5 heteroatoms, i.e., an aromatic heterocyclic group. The ring can be a monocyclic ring, a fused ring with other rings, and can also be partially saturated. The number of atoms in the ring constituting the heteroaryl is preferably 5 to 10 (5-membered to 10-membered heteroaryl), and more preferably 5 to 7 (5-membered to 7-membered heteroaryl). Specific examples of heteroaryl groups include furanyl, thiopheneyl, pyrroloyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, benzothiopheneyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzoimidazolyl, benzotriazolyl, indoleyl, isoindoleyl, indazoleyl, azaindoleyl, quinolinyl, isoquinolinyl, cenolinyl, quinazolinyl, quinoxolinyl, benzodioxacyclopentenyl, inazinyl, and imidazopyridyl, pyrazolpyridyl, imidazopyridyl, triazolpyridyl, pyrrolopyrazinyl, and flopyridyl.

[0528] As used herein, the term "aralkyl (arylalkyl)" means a group in which one or more hydrogen atoms of an "alkyl" group as defined herein are replaced by an "aryl" group as defined herein. As an aralkyl group, C7-C 14 Aryl groups are preferred, and C7-C 10 Aryl groups are preferred. Specific examples of aryl groups include benzyl, phenethyl, and 3-phenylpropyl.

[0529] As used herein, the term "heteroarylalkyl" means a group in which one or more hydrogen atoms of an "alkyl" as defined herein are replaced by a "heteroaryl" as defined herein. As heteroarylalkyl groups, 5- to 10-membered heteroaryl-C1-C6 alkyl groups are preferred, and 5- to 10-membered heteroaryl-C1-C2 alkyl groups are more preferred. Specific examples of heteroarylalkyl groups include 3-thienylmethyl, 4-thiazolylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-(2-pyridyl)ethyl, 2-(3-pyridyl)ethyl, 2-(4-pyridyl)ethyl, 2-(6-quinolinyl)ethyl, 2-(7-quinolinyl)ethyl, 2-(6-indolyl)ethyl, 2-(5-indolyl)ethyl, and 2-(5-benzofuranyl)ethyl.

[0530] As used herein, the term "alkoxy" means an oxygen group bonded to an alkyl group as defined herein. C1-C6 alkoxy groups are preferred, and C1-C4 alkoxy groups are more preferred. Specific examples of alkoxy groups include methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, and 3-methylbutoxy.

[0531] As used herein, the term "alkoxyalkyl" means a group in which one or more hydrogen atoms of an alkyl group as defined herein are replaced by an alkoxy group as defined herein. C1-C6 alkoxy-C1-C6 alkyl groups are preferred, and C1-C6 alkoxy-C1-C2 alkyl groups are more preferred. Specific examples of alkoxyalkyl groups include methoxymethyl, ethoxymethyl, 1-propoxymethyl, 2-propoxymethyl, n-butoxymethyl, isobutoxymethyl, sec-butoxymethyl, tert-butoxymethyl, pentomethyl, 3-methylbutoxymethyl, 1-methoxyethyl, 2-methoxyethyl, and 2-ethoxyethyl.

[0532] As used herein, the term "aryloxy group" refers to an oxygen group bonded to an "aryl" group as defined herein. As an aryloxy group, C6-C... 10 Aryloxy groups are preferred. Specific examples of aryloxy groups include phenoxy, 1-naphthoxy, and 2-naphthoxy.

[0533] As used herein, the term "aranalkoxy" refers to an oxygen group bonded to an aralkyl group as defined herein. As an aranalkoxy group, C7-C 14 Arylalkoxy groups are preferred, and C7-C 10 Arylalkoxy groups are preferred. Specific examples of arylalkoxy groups include benzyloxy, phenylethoxy, and 3-phenylpropoxy.

[0534] As used herein, the term "amino" refers in a narrow sense to -NH2 and in a broad sense to -NRR'. In this document, R and R' are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups, or R and R' indicate that they form a ring together with the nitrogen atom to which they are bonded. Preferred examples of amino groups include -NH2, mono-C1-C6 alkylamino groups, di-C1-C6 alkylamino groups, and 4- to 8-membered cyclic amino groups.

[0535] As used herein, the term "monoalkylamino" means that R is hydrogen and R' is an amino group as defined herein, or an alkyl group as defined herein. Preferred examples of monoalkylamino groups include mono-C1-C6 alkylamino groups. Specific examples of monoalkylamino groups include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, sec-butylamino, and tert-butylamino.

[0536] As used herein, the term "dialkylamino" means that R and R' are independently groups of "amino" as defined herein, or "alkyl" as defined herein. Preferred examples of dialkylamino include di-C1-C6 alkylamino. Specific examples of dialkylamino include dimethylamino and diethylamino.

[0537] As used herein, the term "cyclic amino" means a group in which R and R', in the "amino" group as defined herein, form a ring together with the nitrogen atom to which they are bonded. Preferred examples of cyclic amino groups include 4- to 8-membered cyclic amino groups. Specific examples of cyclic amino groups include 1-azacyclobutane, 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-morpholinyl, 3-oxazolidinyl, 1,1-thiomorpholinyl-4-yl, and 3-oxa-8-azabicyclo[3.2.1]octane-8-yl.

[0538] As used herein, the term “cyclic aminooxy” means an oxygen group bonded to a “cyclic amino” as defined herein. Preferred examples of cyclic aminooxy groups include 4- to 8-membered cyclic aminooxy groups. Specific examples of cyclic aminooxy groups include 1-azacyclobutyloxy, 1-pyrrolidinyloxy, 1-piperidinyloxy, 1-piperazinyloxy, 4-morpholinyloxy, 3-oxazolidinyloxy, 1,1-thiomorpholinyl-4-yloxy, and 3-oxa-8-azabicyclo[3.2.1]octane-8-yloxy.

[0539] As used herein, the term "aminocarbonyl" means a carbonyl group bonded to an "amino" group as defined herein. Preferred examples of aminocarbonyl groups include -CONH2, mono-C1-C6 alkylaminocarbonyl, di-C3-C6 cycloalkylaminocarbonyl, di-C1-C6 alkylaminocarbonyl, and 4- to 8-membered cyclic aminocarbonyl groups. Specific examples of aminocarbonyl groups include -CONH2, dimethylaminocarbonyl, 1-azacyclobutylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, 1-piperazinylcarbonyl, 4-morpholinylcarbonyl, 3-oxazolylalkylcarbonyl, 1,1-thiodimorpholinyl-4-ylcarbonyl, and 3-oxa-8-azabicyclo[3.2.1]octane-8-ylcarbonyl.

[0540] As used herein, “haloalkyl” means a group in which one or more hydrogen atoms of an alkyl group as defined herein are replaced by a halogen. Halo-C1-C6 alkyl groups are preferred, and fluoro-C1-C6 alkyl groups are more preferred. Specific examples of haloalkyl groups include difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3-difluoropropyl, 4,4-difluorobutyl, and 5,5-difluoropentyl.

[0541] As used herein, the term "alicyclic ring" refers to a non-aromatic hydrocarbon ring. Alicyclic rings may have unsaturated bonds in the ring. The carbon atoms constituting the ring may also be oxidized to form carbonyl groups. Alicyclic rings may be monocyclic (referred to herein as monocyclic alicyclic rings) or may form fused rings with saturated alicyclic rings such as cyclopentane and cyclohexane rings or aromatic hydrocarbon rings such as benzene and naphthalene rings. As alicyclic rings, 3- to 10-membered alicyclic rings are preferred, and more preferably 3- to 8-membered alicyclic rings. Specific examples of alicyclic rings include cyclopropane rings, cyclobutane rings, cyclopentane rings, cyclohexane rings, cycloheptane rings, cyclooctane rings, and bicyclic [2.2.1]heptane rings.

[0542] As used herein, the term "saturated heterocycle" refers to a non-aromatic heterocycle that preferably contains 1 to 5, more preferably 1 to 3, heteroatoms in the atoms constituting the ring and does not have unsaturated bonds in the ring. A saturated heterocycle has no double or triple bonds in the ring. The saturated heterocycle can be a monocyclic ring, or it can form a fused or spirocyclic ring with saturated alicyclic rings such as cyclopentane and cyclohexane rings, or saturated heterocycles such as tetrahydropyran, dioxane, and pyrrolidine rings. As saturated heterocycles, 4- to 10-membered saturated heterocycles are preferred, more preferably 4- to 7-membered saturated heterocycles, and still more preferably 5-membered saturated heterocycles. Specific examples of saturated heterocycles include azo-butane rings, oxonizo-butane rings, oxonizo-butane rings, tetrahydropyran rings, tetrahydropyran rings, morpholine rings, thiomorpholine rings, pyrrolidine rings, 2-oxopyrrolidine rings, 4-oxopyrrolidine rings, piperidine rings, 4-oxopiperidine rings, piperazine rings, pyrazolidine rings, imidazoline rings, oxazolidine rings, isoxazolidine rings, thiazoline rings, isothiazolidine rings, thiadiazoline rings, oxazolidine ketone rings, dioxane rings, dioxane rings, thiohexacyclic butane rings, octahydroindole rings, dihydroindole rings, azo-heptane rings, dioxane-heptane rings, and 5,9-dioxanespiro[3.5]nonane rings.

[0543] As used herein, examples of "protecting groups for amino groups" include urethane-based protecting groups, acyl-based protecting groups, sulfonamide-based protecting groups, and silyl-based protecting groups. Specific examples of urethane-based protecting groups include 9-fluorenylmethyloxycarbonyl (Fmoc group), benzyloxycarbonyl (Cbz group), 2,2,2-trichloroethoxycarbonyl (Troc group), allyloxycarbonyl (Alloc group), 2-(trimethylsilyl)ethoxycarbonyl (Teoc group), triisopropylsilyloxycarbonyl (TSoc group), di-tert-butylisobutylsilyloxycarbonyl (BIBSoc group), di-isopropyl-tert-butylsilyloxycarbonyl (IPCSoc group), benzyl-di-tert-butylsilyloxycarbonyl (BBSoc group), di-tert-butylcyclohexylsilyloxycarbonyl (CHBSoc group), di-tert-butyloctadecylsilyloxycarbonyl (CDBSoc group), and tert-butoxycarbonyl (Boc group). Specific examples of acyl-based protecting groups include trifluoroacetyl groups, acetyl groups, and benzoyl groups. Specific examples of sulfonamide-based protecting groups include 2-nitrobenzenesulfonyl groups, 4-nitrobenzenesulfonyl groups, and 2,4-dinitrobenzenesulfonyl groups. Specific examples of silyl-based protecting groups include trimethylsilyl groups (TMS groups), tert-butyldimethylsilyl groups (TBDMS groups), triethylsilyl groups (TES groups), triisopropylsilyl groups (TIPS groups), and tert-butyldiphenylsilyl groups (TBDPS groups).

[0544] As used herein, the term "optionally substituted" means that the group may be substituted with any substituent.

[0545] As used herein, the term "optionally protected" means that the group can be protected by any protecting group.

[0546] As used herein, the term "one or more" refers to a quantity of one or two or more. When the term "one or more" is used in a context relating to substituents of a group, the term refers to a quantity from 1 to the maximum acceptable number of substituents for that group. Specific examples of the term "one or more" include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and / or greater quantities.

[0547] As used herein, the term "peptide compound" means a compound in which two or more amino acid residues are linked by an amide bond. Peptides having ester bonds in a portion of their main chain, such as phenyl peptides, are also included in the term "peptide compound" herein. There is no particular limitation on the number of amino acid residues contained in the peptides according to this disclosure, but preferably 5 to 30 residues, more preferably 8 to 15 residues, and still more preferably 9 to 13 residues. The peptide compounds according to this disclosure preferably contain at least 3, more preferably at least 5, and still more preferably at least 6 N-substituted amino acids. These N-substituted amino acids may be present in the peptide compound continuously or discontinuously. The peptide compounds according to this disclosure may be linear or cyclic, and are preferably cyclic peptide compounds.

[0548] As used herein, the term "cyclic peptide compound" is a peptide compound having a cyclic structure consisting of four or more amino acid residues. The cyclic structure of a cyclic peptide compound may contain bonds other than amide bonds, and may contain bonds selected from, for example, the group consisting of: COC, C(O)-O, and C(S)-O bonds via oxygen atoms; C(O)-S, C(S)-S, CSSC, CSC, CS(O)-C, and CS(O2)-C bonds via sulfur atoms; CNC, C=NC, NC(O)-N, NC(S)N, and C(S)-N bonds via nitrogen atoms; and CC bonds. In addition to a cyclic structure, a cyclic peptide compound may have amino acids or chain peptide structures not included in the cyclic structure. It may also have structures other than amino acid and chain peptide structures.

[0549] The term "cyclization" in peptide compounds refers to the formation of a cyclic structure containing four or more amino acid residues. The number of amino acids in the cyclic moiety of a cyclic peptide compound is not particularly limited herein, but examples include 4 to 20 residues, 5 to 15 residues, and 6 to 13 residues. Methods for converting linear peptide compounds into cyclic peptide compounds can be implemented via intramolecular bonding reactions as described in: *Comprehensive Organic Transformations, A Guide to Functional Group Preparations*, 3rd edition (by RC Larock), and *March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure*, 7th edition (by MB Smith and J. March), etc. Further functional group conversion reactions can also be performed after the bonding reaction. Examples of bonding reactions include C(O)-N bonds formed by carboxylic acids and amines; COC, C(O)-O, and C(S)-O bonds via oxygen atoms; C(O)-S, C(S)-S, CSSC, CSC, CS(O)-C, and CS(O2)-C bonds via sulfur atoms; and CNC, C=NC, NC(O)-N, NC(S)N, and C(S)-N bonds via nitrogen atoms. Further examples include C / C bonding reactions catalyzed by transition metals, such as the Suzuki, Heck, and Sonogashira reactions. Examples of functional group transformation reactions following bonding reactions include oxidation or reduction reactions. Specific examples include reactions in which sulfur atoms are oxidized and converted into sulfoxide or sulfone groups. Other examples include reduction reactions in which triple or double bonds in carbon-carbon bonds are reduced and converted into double or single bonds. Two amino acids can bond together at the main chain of the amino acid to form a closed ring structure via peptide bonds, or they can form a covalent bond between the two amino acids via, for example, bonds between the side chains of the two amino acids or between the side chains and the main chain.

[0550] As used herein, the term "amino acid" includes both natural and non-natural amino acids. As used herein, the term "amino acid" may refer to an amino acid residue. As used herein, the term "natural amino acid" refers to Gly, Ala, Ser, Thr, Val, Leu, Ile, Phe, Tyr, Trp, His, Glu, Asp, Gln, Asn, Cys, Met, Lys, Arg, and Pro. Examples of non-natural amino acids include, but are not particularly limited to, β-amino acids, D-type amino acids, N-substituted amino acids, α,α-disubstituted amino acids, amino acids having side chains different from those of natural amino acids, and hydroxycarboxylic acids. As used herein, amino acids can have any configuration. There are no particular restrictions on the choice of side chains for amino acids, and, in addition to hydrogen atoms, side chains are freely selected from, for example, alkyl groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups, aralkyl groups, heteroarylalkyl groups, cycloalkyl groups, and spiro-bonded cycloalkyl groups. Each side chain may have substituents. Substituents are not limited, and one or two or more substituents may be independently and freely selected from any substituents, including, for example, halogen atoms, oxygen atoms, nitrogen atoms, sulfur atoms, boron atoms, silicon atoms, or phosphorus atoms. That is, examples of side chains include alkyl groups, alkoxy groups, alkoxyalkyl groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups, aralkyl groups, and cycloalkyl groups that can be substituted or oxidized; amino carbonyl groups and halogen atoms. In a non-limiting embodiment, as used herein, an amino acid may be a compound having a carboxyl group and an amino group in the same molecule (even in this case, proline, hydroxyproline, azacyclobutane-2-carboxylic acid, etc., in which the nitrogen atom of the amino group forms a ring together with any atom of the side chain are also included in the amino acid).

[0551] As used in this article, the "amino acid residues" that make up peptide compounds are sometimes simply referred to as "amino acids".

[0552] As used herein, the term "N-terminal amino acid residue" refers to an amino acid residue located at the N-terminus of a peptide. As used herein, the term "C-terminal amino acid residue" refers to an amino acid residue located at the C-terminus of a peptide.

[0553] As used herein, the terms “number of amino acids (amino acid number)” or “number of amino acid residues (amino acid residue number)” refer to the number of amino acid residues (amino acid units) that make up a peptide compound, and are intended to refer to the number of amino acid units generated when cleaving amide bonds, ester bonds, and bonds that link the cyclized portions of amino acids.

[0554] As used herein, the term "amino acid" constituting a peptide compound includes all isotopes corresponding to each amino acid. An isotope of an "amino acid" is a form in which at least one atom is replaced by atoms having the same atomic number (number of protons) but different mass numbers (total number of protons and neutrons) in an abundance ratio different from the natural abundance ratio. Examples of isotopes included in the "amino acids" constituting the peptide compounds described herein include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine atoms, etc., and they each include... 2 H, 3 H; 13 C 14 C; 15 N; 17 O、 18 O; 31 P, 32 P; 35 S; 18 F; 36 Cl; etc. All compounds containing any proportion of radioactive or non-radioactive isotopes are included within the scope of this invention.

[0555] Examples of substituents containing halogen atoms in this article include alkyl groups, cycloalkyl groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups, and aralkyl groups having halogens as substituents, and more specifically including fluoroalkyl, difluoroalkyl, and trifluoroalkyl groups.

[0556] Examples of substituents containing an O atom include hydroxyl (-OH), oxy group (-OR), carbonyl group (-C(=O)-R), carboxyl group (-CO2H), oxycarbonyl group (-C(=O)-OR), carbonyloxy group (-OC(=O)-R), thiocarbonyl group (-C(=O)-SR), carbonylthio group (-SC(=O)-R), aminocarbonyl group (-C(=O)-NHR), carbonylamino group (-NH-C(=O)-R), oxycarbonylamino group (-NH-C(=O)-OR), sulfonylamino group (-NH-SO2-R), aminosulfonyl group (-SO2-NHR), aminosulfonylamino group (-NH-SO2-NHR), thiocarboxyl group (-C(=O)-SH), and carboxylcarbonyl group (-C(=O)-CO2H).

[0557] Examples of oxy groups (-OR) include alkoxy, cycloalkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, and aralkyloxy. Alkoxy groups are preferably C1-C4 or C1-C2 alkoxy groups, and particularly preferably methoxy or ethoxy groups.

[0558] Examples of carbonyl groups (-C=OR) include formyl (-C=OH), alkyl carbonyl, cycloalkyl carbonyl, alkenyl carbonyl, alkynyl carbonyl, aryl carbonyl, heteroaryl carbonyl, and aralkyl carbonyl.

[0559] Examples of oxycarbonyl groups (-C=O-OR) include alkyloxycarbonyl, cycloalkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, and aralkyloxycarbonyl.

[0560] Examples of carbonyloxy groups (-OC=OR) include alkyl carbonyloxy, cycloalkyl carbonyloxy, alkenyl carbonyloxy, alkynyl carbonyloxy, aryl carbonyloxy, heteroaryl carbonyloxy, and aralkyl carbonyloxy.

[0561] Examples of thiocarbonyl (-C=O-SR) include alkylthiocarbonyl, cycloalkylthiocarbonyl, alkenylthiocarbonyl, alkynylthiocarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl, and aralkylthiocarbonyl.

[0562] Examples of carbonyl thio groups (-SC=OR) include alkyl carbonyl thio, cycloalkyl carbonyl thio, alkenyl carbonyl thio, alkynyl carbonyl thio, aryl carbonyl thio, heteroaryl carbonyl thio, and aralkyl carbonyl thio.

[0563] Examples of aminocarbonyl groups (-C=O-NHR) include alkylaminocarbonyl groups (e.g., C1-C6 or C1-C4 alkylaminocarbonyl groups, and particularly ethylaminocarbonyl and methylaminocarbonyl groups), cycloalkylaminocarbonyl groups, alkenylaminocarbonyl groups, alkynylaminocarbonyl groups, arylaminocarbonyl groups, heteroarylaminocarbonyl groups, and aralkylaminocarbonyl groups. Further examples include groups in which the H atom bonded to the N atom in -C=O-NHR is further replaced by an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl group.

[0564] Examples of carbonylamino groups (-NH-C=OR) include alkylcarbonylamino, cycloalkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, and aralkylcarbonylamino. Further examples include groups in which the H atom bonded to the N atom in -NH-C=OR is further replaced by an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl group.

[0565] Examples of oxycarbonylamino groups (-NH-C=O-OR) include alkoxycarbonylamino, cycloalkoxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, aryloxycarbonylamino, heteroaryloxycarbonylamino, and aralkyloxycarbonylamino. Further examples include groups in which the H atom bonded to the N atom in -NH-C=O-OR is further replaced by an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl group.

[0566] Examples of sulfonylamino (-NH-SO2-R) include alkylsulfonylamino, cycloalkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, and aralkylsulfonylamino. Further examples include groups in which the H atom bonded to the N atom in -NH-SO2-R is further replaced by an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl group.

[0567] Examples of aminosulfonyl (-SO2-NHR) include alkylaminosulfonyl, cycloalkylaminosulfonyl, alkenylaminosulfonyl, alkynylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, and aralkylaminosulfonyl. Further examples include groups in which the H atom bonded to the N atom in -SO2-NHR is further replaced by an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl group.

[0568] Examples of aminosulfonylamino (-NH-SO2-NHR) include alkylaminosulfonylamino, cycloalkylaminosulfonylamino, alkenylaminosulfonylamino, alkynylaminosulfonylamino, arylaminosulfonylamino, heteroarylaminosulfonylamino, and aralkylaminosulfonylamino. Furthermore, the two H atoms bonded to the N atom in -NH-SO2-NHR can be substituted by substituents, each independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl groups, and these two substituents can form a ring.

[0569] Examples of substituents containing an S atom include groups such as thiols (-SH), thiols (-SR), sulfinyl groups (-S(=O)-R), sulfonyl groups (-SO2-R), and sulfonyl groups (-SO3H).

[0570] Examples of selectable thio groups (-SR) include alkyl thio, cycloalkyl thio, alkenyl thio, alkynyl thio, aryl thio, heteroaryl thio, and aralkyl thio.

[0571] Examples of sulfonyl groups (-SO2-R) include alkylsulfonyl, cycloalkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heteroarylsulfonyl, and aralkylsulfonyl.

[0572] Examples of substituents containing an N atom include groups such as azide (-N3; also known as "azide group"), cyano (-CN), primary amino (-NH2), secondary amino (-NH-R; also known as monosubstituted amino), tertiary amino (-NR(R'); also known as disubstituted amino), amido (-C(=NH)-NH2), substituted amido (-C(=NR)-NR'R''), guanidino (-NH-C(=NH)-NH2), substituted guanidino (-NR-C(=NR''')-NR'R''), aminocarbonylamino (-NR-CO-NR'R''), pyridyl, piperidinyl, morpholino, and azircyclic butyl.

[0573] Examples of secondary amino groups (-NH-R; monosubstituted amino groups) include alkylamino, cycloalkylamino, alkenylamino, alkynylamino, arylamino, heteroarylamino, and aralkylamino.

[0574] Examples of tertiary amino groups (-NR(R'): disubstituted amino) include amino groups having any two substituents, each independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, such as alkyl (aralkyl)amino. These two substituents can form a ring. Specific examples include dialkylamino groups, particularly C1-C6 dialkylamino, C1-C4 dialkylamino, dimethylamino, and diethylamino. As used herein, the term "C" refers to... p -C q "Dialkylamino group" refers to a group in which the amino group is bonded by two C atoms. p -C q Alkyl groups are substituted groups. C p -C q The alkyl groups can be the same or different.

[0575] Examples of substituted amidoyl groups (-C(=NR)-NR'R'') include those in which the three substituents R, R', and R'' on the N atom are each independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl groups, such as alkyl(aralkyl)(aryl)amidinyl.

[0576] Examples of substituted guanidino groups (-NR-C(=NR''')-NR'R'') include groups in which R, R', R'' and R''' are each independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and aralkyl groups, and groups in which these substituents form a ring.

[0577] Examples of aminocarbonylamino (-NR-CO-NR'R'') include groups in which R, R', and R'' are each independently selected from hydrogen atoms, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl groups, and groups in which these substituents form a ring.

[0578] The compounds according to the invention can be their salts, preferably chemically acceptable salts. Additionally, the compounds or their salts according to the invention can be their solvates, preferably chemically acceptable solvates. Examples of salts of the compounds according to the invention include: hydrochlorides; hydrobroms; hydroiodates; phosphates; phosphonates; sulfates; sulfonates, such as methanesulfonates and p-toluenesulfonates; carboxylates, such as acetates, citrates, malates, tartrates, succinates, and salicylates; alkali metal salts, such as sodium and potassium salts; alkali metal salts, such as magnesium and calcium salts; and ammonium salts, such as ammonium salts, alkylammonium salts, dialkylammonium salts, trialkylammonium salts, and tetraalkylammonium salts. These salts are produced, for example, by contacting the compound with an acid or base that can be used to produce a pharmaceutical product. In the invention, a solvate of the compound is a solvate in which the compound and the solvent together form a molecular aggregate, and there is no particular limitation as long as the solvate is formed by a solvent. When the solvent is water, the solvate is called a hydrate. The solvates of the compounds according to the invention are preferably hydrates, and specific examples of such hydrates include monohydrates to decahydrates, preferably monohydrates to pentahydrates, and still more preferably monohydrates to trihydrates. The solvates of the compounds according to the invention include not only solvates formed from a single solvent (such as water, alcohols (such as methanol, ethanol, 1-propanol and 2-propanol) or dimethylformamide), but also solvates formed from multiple solvents.

[0579] When a compound according to the invention is obtained in free form, it can conventionally be converted to its hydrate or solvate state. When a compound according to the invention is obtained in free form, it can conventionally be converted to a salt state that can be formed from the compound or its hydrate or solvate. Examples include hydrates and ethanolates of cyclic peptide compounds or their salts represented by formula (1a). Specific examples include, but are not limited to, hemihydrates, monohydrates, dihydrates, trihydrates, tetrahydrates, pentahydrates, hexahydrates, heptahydrates, octahydrates, nonahydrates, decahydrates or monoethanolates of cyclic peptide compounds represented by formula (1a); hemihydrates, monohydrates, dihydrates, trihydrates, tetrahydrates, pentahydrates, hexahydrates, heptahydrates, octahydrates, nonahydrates, decahydrates or monoethanolates of sodium salts of compounds represented by formula (1a); or hydrates or ethanolates of hydrochloride salts of cyclic peptide compounds represented by formula (1a). The hydrates or solvates can be produced in crystalline or amorphous forms. In the case of crystalline form, hydrates or solvates can have crystalline polymorphs. As for the method for producing hydrates or solvates, they can be obtained by conventional methods, such as by adding a solvent such as ethanol and / or water to a cyclic peptide compound represented by formula (1a) or a peptide compound described herein, followed by stirring, cooling, concentrating and / or drying.

[0580] [Equation 22]

[0581]

[0582] When the compound according to the invention is obtained in the form of its salt, hydrate or solvate, the compound can be conventionally converted to its free form.

[0583] As used herein, the term "solvent A / water solvate crystal" refers to a crystal in which solvent A molecules and water molecules are contained within the crystal lattice of the compound. As used herein, the term "solvent A / solvent B / water solvate crystal" refers to a crystal in which solvent A molecules, solvent B molecules, and water molecules are contained within the crystal lattice of the compound. Specifically, for example, the term "acetone / heptane / water solvate crystal" refers to a crystal in which acetone, heptane, and water are contained within the crystal lattice of the compound.

[0584] As used herein, the term "and / or" includes any combination of "and" and "or" in appropriate combinations. Specifically, for example, the terms "A, B, and / or C" include the following seven variations:

[0585] (i) A, (ii) B, (iii) C, (iv) A and B, (v) A and C, (vi) B and C, and (vii) A, B and C.

[0586] As used herein, the term "episomer" means a compound in which the configuration of the side chain bonded to the α-carbon of an amino acid residue constituting a cyclic peptide compound is spatially reversed. "Episomers" include cyclic peptide compounds in which the α-carbon of the C-terminal amino acid residue of the linear peptide compound is spatially reversed when the linear peptide compound is cyclized to produce the cyclic peptide compound. Epiomers in the total product comprising the cyclic peptide compound produced by the method of the present invention can be determined, for example, by UV area values ​​at 210 nm or 220 nm obtained by HPLC analysis.

[0587] As used herein, the term "cyclic dimer" refers to a compound in which peptide compounds, as the original materials of a cyclic peptide compound, are linearly bonded to each other and then further cyclized. Cyclic dimers in the total product including cyclic peptide compounds produced by the method of the present invention can be determined, for example, by UV area values ​​at 210 nm or 220 nm obtained by HPLC analysis.

[0588] Methods for producing cyclic peptide compounds

[0589] In one aspect, the present invention relates to a method for producing a cyclic peptide compound represented by formula (1) or a salt thereof or a solvate thereof. The method comprises a step of reacting an N-terminal amino acid residue of a peptide compound represented by formula (2) or (3) with a C-terminal amino acid residue of the peptide compound in a solvent to perform cyclization (cyclization step) (hereinafter also referred to as "Aspect 1").

[0590] [Equation 23]

[0591]

[0592]

[0593] In one aspect, the present invention relates to a method for producing a cyclic peptide compound represented by formula (1) or a salt thereof or a solvate thereof. The method comprises:

[0594] (a) The step of providing a peptide compound or a salt thereof, or a solvation of a peptide compound or a salt, represented by formulas (4) to (6).

[0595] (b) The step of reacting the N-terminal amino acid residues of the peptide compounds represented by formulas (4) to (6) with the C-terminal amino acid residues of the peptide compounds in a solvent to perform the linking step, and

[0596] (c) The step of reacting the N-terminal amino acid residues of the peptide compound obtained in step (b) with the C-terminal amino acid residues of the peptide compound in a solvent to carry out cyclization (cyclization step) (hereinafter also referred to as "aspect 2").

[0597] [Equation 24]

[0598]

[0599]

[0600] In aspect 2, step (b) may include (b-1) reacting the N-terminal amino acid residues of the peptide compound represented by formula (5) with the C-terminal amino acid residues of the peptide compound represented by formula (6) in a solvent to link them, thereby converting them into the peptide compound represented by formula (7) (linking step).

[0601] [Equation 25]

[0602]

[0603] In aspect 2, in addition to step (b-1), step (b) may also include,

[0604] (b-2) The step of reacting the N-terminal amino acid residues of the peptide compound represented by formula (4) with the C-terminal amino acid residues of the peptide compound represented by formula (7) in a solvent to link them, thereby converting them into the peptide compound represented by formula (2) (linking step), and

[0605] Step (c) may include

[0606] (c-1) The step of reacting the N-terminal amino acid residue of the peptide compound represented by formula (2) with the C-terminal amino acid residue of the peptide compound in a solvent to perform cyclization (cyclization step).

[0607] In aspect 2, in addition to step (b-1), step (b) may also include,

[0608] (b-3) The step of reacting the N-terminal amino acid residues of the peptide compound represented by formula (7) with the C-terminal amino acid residues of the peptide compound represented by formula (4) in a solvent to link them, thereby converting them into the compound represented by formula (3) (linking step), and

[0609] Step (c) may include

[0610] (c-2) The step of reacting the N-terminal amino acid residue of the peptide compound represented by formula (3) with the C-terminal amino acid residue of the peptide compound in a solvent to perform cyclization (cyclization step).

[0611] In aspects 1 and 2, the connection between the N-terminal amino acid residue of the peptide compound and the C-terminal amino acid residue of the peptide compound is preferably the connection between the amino group of the N-terminal amino acid residue and the carboxyl group of the C-terminal amino acid residue, and the connection between the N-terminal amino acid residue of the peptide compound and the C-terminal amino acid residue of the peptide compound is more preferably the connection by means of an amide bond between the amino group of the N-terminal amino acid residue and the carboxyl group of the C-terminal amino acid residue.

[0612] In one aspect, the solvent in the cyclization step preferably comprises one or more of the group consisting of nitrile solvents, halogen solvents, ether solvents, amide solvents, ester solvents, and carbonate solvents. Specific examples of nitrile solvents include acetonitrile and propionitrile. Specific examples of halogen solvents include dichloromethane, chloroform, and 1,2-dichloroethane. Specific examples of ether solvents include diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentylmethyl ether, 4-methyltetrahydropyran, 1,3-dioxane, 1,4-dioxane, 1,2-dimethoxyethane, diisopropyl ether, tert-butylmethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, anisole, and tetraethylene glycol dimethyl ether. Specific examples of amide solvents include DMF, NMP, DMA, NEP, NBP, and formamide. Specific examples of ester solvents include methyl acetate, ethyl acetate, methyl propionate, butyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, amyl acetate, and γ-valerol. Specific examples of carbonate solvents include dimethyl carbonate, diethyl carbonate, and dibutyl carbonate. The solvent in the cyclization step is preferably one or more of the group consisting of: acetonitrile, dimethyl carbonate, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, tetrahydrofuran, ethyl acetate, isopropyl acetate, dichloromethane, DMF, and anisole, more preferably one or more of the group consisting of: acetonitrile, 2-methyltetrahydrofuran, ethyl acetate, and dichloromethane, and still more preferably acetonitrile, 2-methyltetrahydrofuran, or ethyl acetate.

[0613] In one aspect, the cyclization step can be carried out by stirring the reaction mixture in a solvent for 10 minutes to 48 hours, with or without a condensing agent, with or without a base, at a temperature between -20°C and the solvent boiling point, preferably between -20°C and 100°C, and preferably between -5°C and 60°C.

[0614] The condensing agents and bases used in the cyclization step, and their amounts, are not particularly restricted, but commonly used condensing agents and bases in peptide synthesis, and their amounts, are preferred (see, for example, Peptide Coupling Reagents, More than a Letter Soup (Chem. Rev. 2011, 111, 6557-6602.)). When no condensing agent is used in the cyclization step, the carboxyl group can be converted to an active ester beforehand.

[0615] Specific examples of condensing agents in the cyclization step include N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI HCl), 1-hydroxy-1H-benzotriazole (HOBt), 1-hydroxy-7-azatriazole (HOAt), ethyl 2-cyano-2-(oxime)acetate (oxyma), and 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (HOOBt). Or HODhbt), N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), 2,3,4,5,6-pentafluorophenol (HOPfp), N-hydroxysuccinimide (HOSu), 6-chloro-1-hydroxy-1H-benzotriazole (Cl-HOBt), O-(1H-benzotriazole-1-yl)-N,N,N',N'-tetramethylureon hexafluorophosphate (HBTU), O-(7-aza-1H-benzotriazole-1-yl)-N,N,N',N'-tetramethylureon hexafluorophosphate (HATU), N-[1 -(cyano-2-ethoxy-2-oxoethyl iminooxy)dimethylamino(morpholino)]ureon hexafluorophosphate (COMU), O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N',N'-tetramethylureon hexafluorophosphate (HOTU), O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethylureon tetrafluoroborate (TBTU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylureon tetrafluoroborate (TATU), [ethylcyano(oxime)acetate-O 2Tri-1-pyrrolylphosphonium hexafluorophosphate (PyOxim), 2-bromo-1-ethylpyridinium tetrafluoroborate (BEP), 1H-benzotriazol-1-yloxy-tris(pyrrolidone)phosphonium hexafluorophosphate (PyBOP), 1H-benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), bromotris(pyrrolidone)phosphonium hexafluorophosphate (PyBroP), chlorotris(pyridinone)phosphonium hexafluorophosphate (PyCloP), (7-azabenzotriazol-1-oxy)tripyrrolidone)phosphonium hexafluorophosphate (PyAOP), bromotris(dimethylamino)phosphonium hexafluorophosphate (Brop), 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazine-4(3H)-one (DEPBT) N,N,N',N'-Tetramethyl-O-(N-succinimide)ureon tetrafluoroborate (TSTU), N,N,N',N'-Tetramethyl-O-(N-succinimide)ureon hexafluorophosphate (HSTU), O-(3,4-dihydro-4-oxo-1,2,3-benzotriazine-3-yl)-N,N,N',N'-tetramethylureon tetrafluoroborate (TDBTU), tetramethylthiourea-onium S-(1-oxide-2-pyridyl)-N,N,N',N'-tetrafluoroborate (TOTT), O-(2-oxo-1(2H)pyridyl)-N,N,N',N'-tetramethylurea-onium tetrafluoroborate (TPTU), N,N'-carbonyldiimidazole (CDI), 1,1'-carbonyl-di-(1,2,4-triazole) (CDT), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) and propylphosphonic anhydride (T3P). From the perspective of suppressing byproducts, the condensing agent in the cyclization step is preferably one or more selected from the group consisting of: HATU, COMU, DMT-MM, PyOxim, PyBOP, HCTU, T3P, EDCI, BEP, and PyClop, more preferably one selected from the group consisting of: HATU, COMU, PyOxim, PyBOP, HCTU, and T3P, and still more preferably HATU or COMU. Furthermore, the combination of solvent and condensing agent is preferably HATU and acetonitrile or 2-methyltetrahydrofuran; or COMU and acetonitrile or 2-methyltetrahydrofuran, because it can further suppress byproducts.

[0616] Organic bases are suitable as the base in the cyclization step, and organic bases containing tertiary amines are particularly preferred. Specific examples of such bases include 2,2,6,6-tetramethylpiperidine, N-methylmorpholine, N,N-diisopropylethylamine (DIPEA), 2,4,6-trimethylpyridine, 2,6-dimethylpyridine, pyridine, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), 2,3,6,7-tetrahydro-1H,5H-9-azabenzo[ij]quinolidine, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-di... Azabicyclo[4.3.0]-5-nonene (DBN), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, 1,1,3,3-tetramethylguanidine (TMG), 1,8-bis(tetramethylguanidine)naphthalene (TMGN), 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), triethylamine (TEA), trimethylamine, 1-methylpiperidine, N,N'-dimethylpiperazine, N-ethylpiperazine, and p-dimethylaminopyridine (DMAP). From the perspective of suppressing byproducts, the base in the cyclization step is preferably one or more selected from the group consisting of: 2,2,6,6-tetramethylpiperidine, N-methylmorpholine, N,N-diisopropylethylamine (DIPEA), 2,4,6-trimethylpyridine, 2,6-dimethylpyridine, and pyridine, and more preferably N,N-diisopropylethylamine (DIPEA) or 2,6-dimethylpyridine. Furthermore, the preferred combinations of solvent, condensing agent, and base are HATU, acetonitrile, and N,N-diisopropylethylamine (DIPEA); HATU, 2-methyltetrahydrofuran, and N,N-diisopropylethylamine (DIPEA); COMU, acetonitrile, and 2,6-dimethylpyridine; or COMU, 2-methyltetrahydrofuran, and 2,6-dimethylpyridine, as these combinations can further suppress byproducts.

[0617] In one respect, the cyclization step is carried out via a liquid-phase method.

[0618] In one aspect, the cyclization step is performed by mixing the peptide compound and optionally a base in a mixed solution obtained by mixing a solvent and a condensation agent. Such an operation may be referred to herein as “reverse dropwise addition.” Over long periods, such as hours to days, preferably 1 to 24 hours, and more preferably 1 to 10 hours, reverse dropwise addition of the peptide compound and base can suppress the formation of byproducts without the need for dilution with large amounts of solvent.

[0619] The cyclic peptide compounds produced by the method of the present invention have high purity and low content of byproducts (such as epimers and cyclic dimers), as described below.

[0620] In one respect, based on the total amount of product, the content of total byproducts generated in the cyclization step is less than 20%, less than 15%, less than 10%, less than 5%, or less than 3%, as determined by the UV area value at 220 nm obtained by HPLC analysis.

[0621] In one respect, based on the total amount of product, the content of each of the byproducts generated in the cyclization step is less than 15%, less than 10%, less than 5%, less than 3%, less than 1%, or is an undetectable amount, as determined by the UV area value at 220 nm obtained by HPLC analysis.

[0622] In one respect, based on the total amount of product, the content of each of the byproducts generated in the cyclization step is less than 15%, less than 10%, less than 5%, less than 3%, less than 1%, or is an undetectable amount, as determined by the UV area value at 220 nm obtained by HPLC analysis, and the byproducts contain epimers and / or cyclic dimers.

[0623] In one respect, the byproducts generated in the cyclization step include epimers, and based on the total amount of product, the content of epimers is less than 10%, less than 7.5%, less than 5%, less than 2.5%, or less than 1%, as determined by the UV area value at 220 nm obtained by HPLC analysis.

[0624] In one respect, the byproducts generated in the cyclization step contain cyclic dimers, and the content of cyclic dimers is less than 15%, less than 10%, less than 5%, less than 2.5%, or less than 1% based on the total product, as determined by the UV area value at 220 nm obtained by HPLC analysis.

[0625] In one aspect, the solvent in the cyclization step preferably comprises one or more of the group consisting of nitrile solvents, halogen solvents, ether solvents, amide solvents, ester solvents, and carbonate solvents. Examples of nitrile solvents, halogen solvents, ether solvents, amide solvents, ester solvents, and carbonate solvents include those exemplified as solvents in the above-described cyclization step. The solvent used in the connecting step is preferably one or more of the following: acetonitrile, dimethyl carbonate, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, tetrahydrofuran, ethyl acetate, isopropyl acetate, DMF, and anisole. More preferably, it is a mixed solvent of one or more of the following and DMF: acetonitrile, dimethyl carbonate, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, tetrahydrofuran, ethyl acetate, isopropyl acetate, and anisole. Even more preferably, it is a mixed solvent of acetonitrile, 2-methyltetrahydrofuran, and DMF, and particularly preferably, it is a mixed solvent of 2-methyltetrahydrofuran and DMF.

[0626] In one aspect, the linking step can be carried out by stirring the reaction mixture in a solvent for 10 minutes to 48 hours, with or without a condensing agent, with or without a base, at a temperature between -20°C and the solvent boiling point, preferably between -20°C and 100°C, and preferably between -5°C and 60°C.

[0627] The condensing agents and bases used in the ligation step and their amounts are not particularly restricted, but commonly used condensing agents and bases in peptide synthesis and their amounts are preferred (see, for example, Peptide Coupling Reagents, More than a Letter Soup (Chem. Rev. 2011, 111, 6557-6602.)). When no condensing agent is used in the ligation step, the carboxyl group can be converted to an active ester beforehand.

[0628] Examples of condensing agents in the linking step include those exemplified as condensing agents in the cyclization step described above. From the perspective of suppressing byproducts, the condensing agent in the linking step is preferably one or more selected from the group consisting of: HATU, COMU, DMT-MM, PyOxim, PyBOP, HCTU, T3P, EDCI, BEP, and PyClop, more preferably one selected from the group consisting of: HATU, COMU, PyOxim, PyBOP, HCTU, and T3P, and still more preferably HATU or COMU. Furthermore, the combination of solvent and condensing agent is preferably HATU and acetonitrile or 2-methyltetrahydrofuran; a mixed solvent of HATU and acetonitrile, 2-methyltetrahydrofuran, and DMF; COMU and acetonitrile or 2-methyltetrahydrofuran; or a mixed solvent of COMU and acetonitrile, 2-methyltetrahydrofuran, and DMF, because it can suppress byproducts even further.

[0629] Examples of bases in the linking step include those exemplified as bases in the above-described cyclization step. From the perspective of suppressing byproducts, the base in the linking step is preferably one or more selected from the group consisting of: 2,2,6,6-tetramethylpiperidine, N-methylmorpholine, N,N-diisopropylethylamine (DIPEA), 2,4,6-trimethylpyridine, 2,6-dimethylpyridine, pyridine, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), 2,3,6,7-tetrahydro-1H,5H-9-azabenzo[ij]quinolidine, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]-5-nonene (DBN), 7-methyl-1 ,5,7-triazabicyclo[4.4.0]dec-5-ene, 1,1,3,3-tetramethylguanidine (TMG), 1,8-bis(tetramethylguanidinyl)naphthalene (TMGN), 2-tert-butyl-1,1,3,3-tetramethylguanidine (BMTG), triethylamine (TEA), trimethylamine, 1-methylpiperidine, N,N'-dimethylpiperazine, N-ethylpiperazine and p-dimethylaminopyridine (DMAP), and preferably one or more of the group consisting of: 2,2,6,6-tetramethylpiperidine, N-methylmorpholine, N,N-diisopropylethylamine (DIPEA), 2,4,6-trimethylpyridine, 2,6-dimethylpyridine and pyridine. Furthermore, the preferred combination of solvent, condensing agent, and base is HATU, acetonitrile, or 2-methyltetrahydrofuran, and N,N-diisopropylethylamine (DIPEA); HATU, a mixed solvent of acetonitrile, 2-methyltetrahydrofuran, and DMF, and N,N-diisopropylethylamine (DIPEA); COMU, acetonitrile, or 2-methyltetrahydrofuran, and N-methylmorpholine or 2,6-dimethylpyridine; or COMU, a mixed solvent of acetonitrile, 2-methyltetrahydrofuran, and DMF, and N-methylmorpholine or 2,6-dimethylpyridine, because byproducts can be suppressed even further.

[0630] In one respect, the connection step is performed using a liquid-phase method.

[0631] In one aspect, the method of the present invention further includes the step of providing a peptide compound represented by formulas (4) to (6) or a salt thereof or a solvate thereof. The peptide compounds represented by formulas (4) to (6) can be produced, for example, by the following general production methods.

[0632] General production method of peptide compounds represented by formula (4) (peptide compound (4))

[0633] The general method for producing peptide compound (4) is shown below. In the following scheme, Pg4 and Pg5 represent protecting groups for the amino group, Xg6 represents the oxygen atom and the protecting group bonded to it, R5 represents the side chain of the amino acid, and P4 and P6 represent substituents for the nitrogen atom.

[0634] Peptide compound (4) can be produced using the following methods.

[0635] [Equation 26]

[0636]

[0637] According to the method of Freidinger et al. (J. Org. Chem., 1983, 48(1), 77-81), the oxazolidinone form with a cyclic protecting group can be obtained by reacting an aldehyde with a protected amino acid. Next, according to the method of Nguyen et al. (Synthesis, 2009, 12, 1991), an alkyl group with an alkene can be introduced onto the nitrogen atom by a ring-opening reaction using a silicon compound with an alkene. The amino acid can then be extended on the C-terminal side by condensing the C-terminus of the protected amino acid. For the condensation reaction, the condensing reagent and base used in the above linking step can be used. Various methods are possible, such as combinations of DIC and Oxyma, DIC and HOAt, HATU and DIPEA, or via mixed anhydrides or acid halides, as activators of the carboxyl group. Then, after deprotection of the protecting group used on the amino group, the protected amino acid with an alkene as a side chain can be extended. Next, through metathesis reactions, intramolecular olefins can be cyclized. In the metathesis reactions, the following olefins are listed: dichloro(2-isopropoxybenzyl)(tricyclohexylphosphine)ruthenium(II): CAS No. 203714-71-0, dichloro(3-phenyl-1H-inden-1-ylidene)bis(tricyclohexylphosphine)ruthenium(II): CAS No. 250220-36-1, dichloro(benzyl)bis(tricyclohexylphosphine)ruthenium(II): CAS No. 172222-30-9, [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidine]dichloro(3-phenyl-1H-inden-1-ylidene)(tricyclohexylphosphine)ruthenium(II): CAS No. CAS No. 536724-67-1, [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinedimethyl]dichloro(benzylene)(tricyclohexylphosphine)ruthenium(II): CAS No. 246047-72-3, [1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinedimethyl]dichloro(2-isopropoxybenzylene)ruthenium(II): CAS No. 301224-40-8, [1,3-bis-(2-tolyl)-2-imidazolidinedimethyl]dichloro(2-isopropoxybenzylene)ruthenium(II): CAS CAS No. 927429-61-6, [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinedimethyl]dichloro[(2-isopropoxy)(5-trifluoroacetamido)benzylidene]ruthenium(II): CAS No. 1025728-56-6, [1,3-bis(2,6-diisopropylphenyl)-2-imidazolidinedimethyl]dichloro[5-(isobutoxycarbonylamido)-2-isopropoxybenzylidene]ruthenium(II): CAS No. 1212009-05-6, etc., can be used as catalysts.Next, the C-terminal protecting group can be deprotected to produce an unprotected C-terminal peptide compound (4), or the N-terminal protecting group can be deprotected to produce an unprotected N-terminal peptide compound (4).

[0638] Peptide compound (4) can also be produced using the following methods.

[0639] [Equation 27]

[0640]

[0641] By acting an alkylating agent containing an alkene on an amino acid in the presence of a base, an alkyl group containing an alkene can be introduced into the nitrogen atom. Next, the amino acid can be extended at the C-terminus by condensing the C-terminus of the protected amino acid. For the condensation reaction, the condensing agent and base used in the linking step described above can be used. For example, combinations of DIC and Oxyma, DIC and HOAt, HATU and DIPEA, or via mixed anhydrides or acid halides are possible as activators of the carboxyl group. Subsequently, after deprotection of the protecting group used on the amino group, the protected amino acid containing an alkene as a side chain can be extended. Next, the intramolecular alkene can be cyclized by a metathesis reaction. The catalyst used in the metathesis reaction is the same as described above. Next, the C-terminal protecting group can be deprotected to produce an unprotected C-terminal peptide compound (4), or the N-terminal protecting group can be deprotected to produce an unprotected N-terminal peptide compound (4).

[0642] General production method of peptide compounds represented by formula (5) (peptide compound (5))

[0643] The general method for producing peptide compound (5) is shown below. In the following scheme, Pg1 and Pg2 represent protecting groups for the amino group, Xg3 represents the oxygen atom and the protecting group bonded to it, R1, R2 and R3 represent the side chains of the amino acid, and P1 and P3 represent substituents for the nitrogen atom.

[0644] Peptide compound (5) can be produced using the following methods.

[0645] [Equation 28]

[0646]

[0647] The amino acid can be extended at the N-terminus by condensing a protected amino acid with its C-terminus protected amino acid. For the condensation reaction, the condensation reagent and base used in the linking step described above can be used. Various methods are possible, such as combinations of DIC and Oxyma, DIC and HOAt, HATU and DIPEA, or via mixed anhydrides or acid halides, as activators of the carboxyl group. Then, after deprotection of the protecting group used on the amino group, the protected amino acid can be condensed to synthesize a fragment consisting of three amino acids. Next, the C-terminal protecting group can be deprotected to produce an unprotected C-terminal peptide compound (5), or the N-terminal protecting group can be deprotected to produce an unprotected N-terminal peptide compound (5).

[0648] Peptide compound (5) can also be produced by solid-phase synthesis. In this case, Xg3 in the above formula is an amino acid bonded to a solid-phase support via an oxygen atom and a linker bonded thereto. The protected amino acid can be condensed with it, thereby elongating the amino acid on the N-terminal side. For the condensation reaction, the condensation reagent and base used in the linking step described above can be used. For example, combinations of DIC and Oxyma, combinations of DIC and HOAt, combinations of HATU and DIPEA, or via mixed anhydrides or acid halides are possible as activators of the carboxyl group. Then, by sequentially deprotecting the protecting group used on the amino group and condensing the protected amino acid, a fragment consisting of 3 amino acids can be synthesized. Next, by cleaving from the solid phase, an unprotected C-terminal peptide compound (5) can be obtained.

[0649] General production method of peptide compounds represented by formula (6) (peptide compound (6))

[0650] The general production method of peptide compound (6) is shown below. In the following scheme, Pg7, Pg8, Pg9 and Pg 10 Xg represents the protecting group used for the amino group. 11 Represents an oxygen atom and its bonded protecting group, R7, R8, R9, Q9, R 10 and R 11 This represents the side chain of an amino acid, and P8, P9, P... 10 and P 11 Substituents representing nitrogen atoms.

[0651] Peptide compounds (6) can be produced using the following methods.

[0652] [Equation 29]

[0653]

[0654] The amino acid can be extended at the N-terminus by condensing a protected amino acid with an amino acid backbone having a carboxyl group protected. For the condensation reaction, the condensation reagent and base used in the linking step described above can be used. For example, combinations of DIC and Oxyma, DIC and HOAt, HATU and DIPEA, or via mixed anhydrides or acid halides are possible as activators of the carboxyl group. Then, by sequentially deprotecting the protecting group used on the amino group and condensing the protected amino acid, a fragment consisting of 5 amino acids can be synthesized. Next, the C-terminal protecting group can be deprotected to produce a C-terminal unprotected peptide compound (6), or the N-terminal protecting group can be deprotected to produce an N-terminal unprotected peptide compound (6).

[0655] Peptide compound (6) can also be produced by solid-phase synthesis. In this case, Xg in the above formula... 11 It is an amino acid having a β-amino acid backbone bonded to a solid support via an oxygen atom and a linker bonded thereto. The protected amino acid can be condensed with it, thereby elongating the amino acid on the N-terminal side. For the condensation reaction, the condensation reagent and base used in the above-described linking step can be used. For example, combinations of DIC and Oxyma, combinations of DIC and HOAt, combinations of HATU and DIPEA, or via mixed anhydrides or acid halides are possible as activators of the carboxyl group. Subsequently, by sequentially deprotecting the protecting group used on the amino group and condensing the protected amino acid, a fragment consisting of 5 amino acids can be synthesized. Next, by cleaving from the solid phase, an unprotected peptide compound at the C-terminus can be obtained (6).

[0656] In the methods for producing peptide compounds represented by equations (4) to (6) above, the chemical reaction may occur with functional groups other than the target functional group. In such cases, by introducing a protecting group into the non-target functional group, only the desired reaction can be allowed to proceed. For such protecting group desorption reactions, the method described, for example, in "Greene's, 'Protective Groups in Organic Synthesis' (5th edition, John Wiley & Sons 2014)" can be used. For reactions involving the transformation of compound functional groups, see Comprehensive Organic Transformations: A Guide to Functional Group Preparations (5th edition), Larock and March, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (8th edition), Smith.

[0657] In one aspect, column chromatography can be used to separate and / or purify cyclic peptide compounds or their salts or solvates produced by the methods of the present invention, or column chromatography can be omitted.

[0658] The cyclic peptide compounds or their salts or solvates produced by the method of the present invention can be separated and / or purified by crystallization. Specifically, for example, the reaction solution after the condensation reaction can be handled separately, with the organic layer concentrated and / or filtered as needed, and then a solvent suitable for crystallization added to the obtained residue, optionally with the addition of seed crystals, and stirred as needed to obtain crystals of the cyclic peptide compound or its salts or solvates. The solvent added during crystallization is not particularly limited, but preferably is a solvent capable of reducing the solubility of the cyclic peptide compound in the solution. For example, a solvent capable of such operations can be used when the cyclic peptide compound can be crystallized by reducing its solubility by adding a poor solvent or a cooling solution. Furthermore, when crystals of the cyclic peptide compound can be obtained by keeping the coarse crystals of the cyclic peptide compound in suspension for any period of time, a solvent capable of such operations can be used for crystallization. Specific examples of solvents added during crystallization include acetone, water, DMSO, acetonitrile, ethanol, and mixtures thereof.

[0659] The following are descriptions of each symbol used in the structural formulas of cyclic peptide compounds represented by formula (1) and peptide compounds represented by formulas (2) to (7).

[0660] R1 is a C1-C6 alkyl group. R1 is preferably a C3-C4 alkyl group, and more preferably n-propyl or 2-methylpropyl.

[0661] P1 is a C1 to C6 alkyl group. P1 is preferably a C1-C4 alkyl group, and more preferably a methyl group.

[0662] R2 is a C1-C6 alkyl group. R2 is preferably a C3-C4 alkyl group, and more preferably a 1-methylpropyl group.

[0663] R3 is a hydrogen atom, or R3 together with P3, the carbon atom bonded to R3, and the nitrogen atom bonded to P3 forms a 4- to 7-membered saturated heterocycle. Preferably, R3 is hydrogen, or R3 together with P3, the carbon atom bonded to R3, and the nitrogen atom bonded to P3 forms a 5-membered saturated heterocycle. In one aspect, R3 is preferably hydrogen. In another aspect, R3 preferably forms a 5-membered saturated heterocycle together with P3, the carbon atom bonded to R3, and the nitrogen atom bonded to P3.

[0664] P3 is a C1-C6 alkyl or a C3-C8 cycloalkyl, or P3, together with R3, the carbon atom bonded to R3, and the nitrogen atom bonded to P3, forms a 4- to 7-membered saturated heterocycle. Preferably, P3 is a C1-C4 alkyl, or P3, together with R3, the carbon atom bonded to R3, and the nitrogen atom bonded to P3, forms a 5-membered saturated heterocycle. In one aspect, P3 is preferably methyl. In another aspect, P3 preferably forms a 5-membered saturated heterocycle together with R3, the carbon atom bonded to R3, and the nitrogen atom bonded to P3.

[0665] P4 is a C1 to C6 alkyl group. P4 is preferably a C1-C4 alkyl group, and more preferably a methyl group.

[0666] R5 is a benzyl group optionally substituted with one or more groups selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, and C3-C8 cycloalkyl. R5 is preferably a benzyl group optionally substituted with a C1-C4 haloalkyl, and more preferably 4-trifluoromethylbenzyl.

[0667] P6 is a C1 to C6 alkyl group. P6 is preferably a C1-C4 alkyl group, and more preferably a methyl group.

[0668] R7 is a phenethyl group optionally substituted with one or more groups selected from the group consisting of: halogen, C1-C6 haloalkyl, and C1-C6 alkoxy. R7 is preferably a phenethyl group optionally substituted with one or more groups selected from the group consisting of: halogen, trifluoromethyl, and methoxy, and more preferably 3-methoxy-4-trifluoromethylphenethyl or 3,5-difluoro-4-trifluoromethylphenethyl.

[0669] R8, together with P8, the carbon atom bonded to R8, and the nitrogen atom bonded to P8, forms a 4- to 7-membered saturated heterocycle, which is optionally substituted with a C1-C6 alkoxy group. R8 preferably forms a 5-membered saturated heterocycle together with the carbon atom bonded to P8, the carbon atom bonded to R8, and the nitrogen atom bonded to P8, which is substituted with a C1-C4 alkyl group, and more preferably forms a 5-membered saturated heterocycle together with the carbon atom bonded to P8, the carbon atom bonded to R8, and the nitrogen atom bonded to P8, which is substituted with an ethoxy group.

[0670] R9, together with Q9 and the carbon atoms bonded to R9 and Q9, forms a 3- to 8-membered alicyclic ring, which is optionally substituted with one or more C1-C6 alkyl groups. R9 preferably forms a 4- to 6-membered alicyclic ring together with Q9 and the carbon atoms bonded to R9 and Q9. In one aspect, R9 preferably forms a 4-membered alicyclic ring together with Q9 and the carbon atoms bonded to R9 and Q9. In another aspect, R9 preferably forms a 5-membered alicyclic ring together with Q9 and the carbon atoms bonded to R9 and Q9.

[0671] P9 is hydrogen or a C1-C6 alkyl group. P9 is preferably hydrogen or a C1-C4 alkyl group. In one aspect, P9 is preferably hydrogen. In another aspect, P9 is preferably methyl.

[0672] R 10 It is a C1-C6 alkyl or C3-C8 cycloalkyl. R 10 Preferably, it is a C4-C6 cycloalkyl group, and more preferably a cyclopentyl group.

[0673] P 10 It is a C1 to C6 alkyl group. P 10 Preferably, it is a C1-C4 alkyl group, and more preferably a methyl group.

[0674] R 11 It is a di-C1-C6 alkylaminocarbonyl or a 4- to 8-membered cyclic aminocarbonyl. R 11Preferably, it is a di-C1-C4 alkylaminocarbonyl or a 5- to 6-membered cyclic aminocarbonyl, and more preferably a dimethylaminocarbonyl.

[0675] P 11 It is a C1 to C6 alkyl group. P 11 Preferably, it is a C1-C4 alkyl group, and more preferably a methyl group.

[0676] X1, X3, and X5 are each independently hydrogen or a protecting group for an amino group. X1, X3, and X5 are preferably each independently selected from the group consisting of: hydrogen, urethane-based protecting groups, acyl-based protecting groups, sulfonamide-based protecting groups, and silyl-based protecting groups. In one aspect, the urethane-based protecting group is selected from the group consisting of: Fmoc group, Cbz group, Troc group, Alloc group, Teoc group, TSoc group, BIBSoc group, IPCSoc group, BBSoc group, CHBSoc group, CDBSoc group, and Boc group. In another aspect, the acyl-based protecting group is selected from the group consisting of: trifluoroacetyl group, acetyl group, and benzoyl group. In one aspect, the protecting group based on sulfonamide is selected from the group consisting of: 2-nitrobenzenesulfonyl group, 4-nitrobenzenesulfonyl group, and 2,4-dinitrobenzenesulfonyl group. In another aspect, the protecting group based on silyl group is selected from the group consisting of: TMS group, TBDMS group, TES group, TIPS group, and TBDPS group.

[0677] In one aspect, X1 is hydrogen or a urethane-based protecting group. In another aspect, X1 is preferably hydrogen. In another aspect, X1 is preferably an Fmoc group.

[0678] In one aspect, X3 is hydrogen or a urethane-based protecting group. In another aspect, X3 is preferably hydrogen. In another aspect, X3 is preferably a Cbz group.

[0679] In one aspect, X5 is hydrogen or a urethane-based protecting group. In another aspect, X5 is preferably hydrogen. In another aspect, X5 is preferably a Cbz group.

[0680] X2, X4, and X6 are each independently a halogen, a hydroxyl group, an optionally substituted alkoxy group, an optionally substituted aryloxy group, an optionally substituted arylalkoxy group, an optionally substituted cyclic aminooxy group, or a group consisting of -OSiR. x R y Rz The group represented, where R x R y and R z Each is independently alkyl or aryl. X2, X4 and X6 are preferably independently halogenated, hydroxyl groups, optionally substituted C1-C6 alkoxy groups, optionally substituted C6-C6 alkoxy groups. 10 aryloxy group, optionally substituted C7-C 14 Arylalkoxy, optionally substituted 4- to 8-membered cyclic aminooxy, or derived from -OSiR x R y R z The group represented, where R x R y and R z Each is independently a C1-C6 alkyl or C6-C 10 Aryl. In one aspect, the halogen is chlorine or bromine. In one aspect, the optionally substituted alkoxy group is tert-butoxy, methoxy, ethoxy, or isopropoxy. In one aspect, the optionally substituted aryloxy group is pentafluorophenyloxy or nitrophenyloxy. In one aspect, the optionally substituted arylalkoxy group is optionally substituted benzyloxy. In one aspect, the optionally substituted cyclic aminooxy group is N-hydroxysuccinicotinamide. In one aspect, -OSiR x R y R z The indicated group is trimethylsilyloxy, triethylsilyloxy, triisopropylsilyloxy, triphenylsilyloxy, tri-tert-butylsilyloxy, di-tert-butylisobutylsilyloxy, or tri(triethylsilyl)silyloxy.

[0681] In one aspect, X2 is a hydroxyl group, a tert-butoxy group, or a benzyloxy group. In another aspect, X2 is preferably a hydroxyl group. In another aspect, X2 is preferably a tert-butoxy group.

[0682] In one aspect, X4 is a hydroxyl group, a tert-butoxy group, or a benzyloxy group. In another aspect, X4 is preferably a hydroxyl group. In another aspect, X4 is preferably a tert-butoxy group.

[0683] In one aspect, X6 is a hydroxyl group, a tert-butoxy group, or a benzyloxy group. In another aspect, X6 is preferably a hydroxyl group. In yet another aspect, X6 is preferably a tert-butoxy group.

[0684] In one aspect of the structural formulas of cyclic peptide compounds represented by formula (1) and peptide compounds represented by formulas (2) and (3),

[0685] R1 is a C1-C6 alkyl group;

[0686] P1 is a C1-C6 alkyl group;

[0687] R2 is a C1-C6 alkyl group;

[0688] R3 is hydrogen, or R3 together with P3, the carbon atom bonded to R3 and the nitrogen atom bonded to P3 form a 4- to 7-membered saturated heterocycle;

[0689] P3 is a C1-C6 alkyl or C3-C8 cycloalkyl, or P3 together with R3, the carbon atom bonded to R3 and the nitrogen atom bonded to P3 to form a 4- to 7-membered saturated heterocycle;

[0690] P4 is a C1-C6 alkyl group;

[0691] R5 is a benzyl group optionally substituted with one or more groups selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, and C3-C8 cycloalkyl;

[0692] P6 is a C1-C6 alkyl group;

[0693] R7 is a phenethyl group optionally substituted with one or more groups selected from the group consisting of: halogen, C1-C6 haloalkyl and C1-C6 alkoxy;

[0694] R8, together with P8, the carbon atom bonded to R8, and the nitrogen atom bonded to P8, forms a 4- to 7-membered saturated heterocycle, wherein the 4- to 7-membered saturated heterocycle is optionally substituted with a C1-C6 alkoxy group.

[0695] R9, together with Q9 and the carbon atoms bonded to R9 and Q9, forms a 3- to 8-membered alicyclic ring, wherein the 3- to 8-membered alicyclic ring is optionally substituted with one or more C1-C6 alkyl groups;

[0696] P9 is hydrogen or a C1-C6 alkyl group;

[0697] R 10 It is a C1-C6 alkyl or C3-C8 cycloalkyl;

[0698] P 10 It is a C1-C6 alkyl group;

[0699] R 11 It is a di-C1-C6 alkylaminocarbonyl or a 4- to 8-membered cyclic aminocarbonyl;

[0700] P11 It is a C1-C6 alkyl group;

[0701] X1 and X5 are each independently hydrogen or protecting groups for amino groups; and

[0702] X2 and X4 are each independently a halogen, a hydroxyl group, an optionally substituted alkoxy group, an optionally substituted aryloxy group, an optionally substituted arylalkoxy group, an optionally substituted cyclic aminooxy group, or a group consisting of -OSiR. x R y R z The group represented, where R x R y and R z Each can be an alkyl or aryl group independently.

[0703] In one aspect of the structural formulas of the cyclic peptide compounds represented by formula (1) and the peptide compounds represented by formulas (2) and (3), preferably,

[0704] R1 is a C3-C4 alkyl group;

[0705] P1 is a C1-C4 alkyl group;

[0706] R2 is a C3-C4 alkyl group;

[0707] R3 is a hydrogen atom, or R3 together with P3, the carbon atom attached to R3 and the nitrogen atom attached to P3 form a 5-membered saturated heterocycle;

[0708] P3 is a C1-C4 alkyl group, or P3 together with R3, the carbon atom bonded to R3 and the nitrogen atom bonded to P3 form a 5-membered saturated heterocycle;

[0709] P4 is a C1-C4 alkyl group;

[0710] R5 is a benzyl group optionally substituted with a C1-C4 haloalkyl group;

[0711] P6 is a C1-C4 alkyl group;

[0712] R7 is a phenethyl group optionally substituted with one or more groups selected from the group consisting of: halogen, trifluoromethyl, and methoxy;

[0713] R8, together with P8, the carbon atom bonded to R8, and the nitrogen atom bonded to P8, forms a 5-membered saturated heterocycle, which is substituted with C1-C4 alkyl groups.

[0714] R9, together with Q9 and the carbon atoms bonded to R9 and Q9, form 4- to 6-membered alicyclic rings;

[0715] P9 is hydrogen or a C1-C4 alkyl group;

[0716] R 10 It is a C4-C6 cycloalkyl group;

[0717] P 10 It is a C1-C4 alkyl group;

[0718] R 11 It is a di-C1-C4 alkylaminocarbonyl or a 5- to 6-membered cyclic aminocarbonyl;

[0719] P 11 It is a C1-C4 alkyl group;

[0720] X1 and X5 are each independently selected from the group consisting of: hydrogen, urethane-based protecting groups, acyl-based protecting groups, sulfonamide-based protecting groups, and silyl-based protecting groups; and

[0721] X2 and X4 are each independently a halogen, a hydroxyl group, an optionally substituted C1-C6 alkoxy group, or an optionally substituted C6-C6 alkoxy group. 10 aryloxy group, optionally substituted C7-C 14 Arylalkoxy, optionally substituted 4- to 8-membered cyclic aminooxy, or derived from -OSiR x R y R z The group represented, where R x R y and R z Each is independently a C1-C6 alkyl or C6-C 10 Aryl.

[0722] In one aspect of the structural formula of the cyclic peptide compound represented by formula (1) and the structural formula of the peptide compound represented by formulas (2) and (3), more preferably,

[0723] R1 is n-propyl or 2-methylpropyl;

[0724] P1 is a methyl group;

[0725] R2 is 1-methylpropyl;

[0726] R3 is a hydrogen atom, or R3 together with P3, the carbon atom attached to R3 and the nitrogen atom attached to P3 form a 5-membered saturated heterocycle;

[0727] P3 is a methyl group, or P3 together with R3, the carbon atom bonded to R3 and the nitrogen atom bonded to P3 form a 5-membered saturated heterocycle;

[0728] P4 is a methyl group;

[0729] R5 is 4-trifluoromethylbenzyl;

[0730] P6 is a methyl group;

[0731] R7 is 3-methoxy-4-trifluoromethylphenylethyl or 3,5-difluoro-4-trifluoromethylphenylethyl;

[0732] R8, together with P8, the carbon atom bonded to R8, and the nitrogen atom bonded to P8, forms a 5-membered saturated heterocycle, which is optionally substituted with an ethoxy group.

[0733] R9 and Q9, as well as the carbon atoms bonded to R9 and Q9, together form a 4-membered alicyclic ring or a 5-membered alicyclic ring;

[0734] P9 is either hydrogen or methyl;

[0735] R 10 It is cyclopentyl;

[0736] P 10 It is methyl;

[0737] R 11 It is dimethylaminocarbonyl;

[0738] P 11 It is methyl;

[0739] X1 is hydrogen or a urethane-based protecting group;

[0740] X5 is a hydrogen or urethane-based protecting group;

[0741] X2 is a hydroxyl group, a tert-butoxy group, or a benzyloxy group; and

[0742] X4 is a hydroxyl group, tert-butoxy group, or benzyloxy group.

[0743] In one aspect of the structural formulas of peptide compounds represented by equations (4) to (6),

[0744] R1 is a C1-C6 alkyl group;

[0745] P1 is a C1-C6 alkyl group;

[0746] R2 is a C1-C6 alkyl group;

[0747] R3 is hydrogen, or R3 together with P3, the carbon atom bonded to R3 and the nitrogen atom bonded to P3 form a 4- to 7-membered saturated heterocycle;

[0748] P3 is a C1-C6 alkyl or C3-C8 cycloalkyl, or P3 together with R3, the carbon atom bonded to R3 and the nitrogen atom bonded to P3 to form a 4- to 7-membered saturated heterocycle;

[0749] P4 is a C1-C6 alkyl group;

[0750] R5 is a benzyl group optionally substituted with one or more groups selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, and C3-C8 cycloalkyl;

[0751] P6 is a C1-C6 alkyl group;

[0752] R7 is a phenethyl group optionally substituted with one or more groups selected from the group consisting of: halogen, C1-C6 haloalkyl and C1-C6 alkoxy;

[0753] R8, together with P8, the carbon atom bonded to R8, and the nitrogen atom bonded to P8, forms a 4- to 7-membered saturated heterocycle, wherein the 4- to 7-membered saturated heterocycle is optionally substituted with a C1-C6 alkoxy group.

[0754] R9, together with Q9 and the carbon atoms bonded to R9 and Q9, forms a 3- to 8-membered alicyclic ring, wherein the 3- to 8-membered alicyclic ring is optionally substituted with one or more C1-C6 alkyl groups;

[0755] P9 is hydrogen or a C1-C6 alkyl group;

[0756] R 10 It is a C1-C6 alkyl or C3-C8 cycloalkyl;

[0757] P 10 It is a C1-C6 alkyl group;

[0758] R 11 It is a di-C1-C6 alkylaminocarbonyl or a 4- to 8-membered cyclic aminocarbonyl;

[0759] P 11 It is a C1-C6 alkyl group;

[0760] X1, X3, and X5 are each independently hydrogen or protecting groups for amino groups; and

[0761] X2, X4, and X6 are each independently a halogen, a hydroxyl group, an optionally substituted alkoxy group, an optionally substituted aryloxy group, an optionally substituted arylalkoxy group, an optionally substituted cyclic aminooxy group, or a group consisting of -OSiR. x R y R z The group represented, where R x R y and R z Each can be an alkyl or aryl group independently.

[0762] In one aspect of the structural formula of the peptide compound represented by formulas (4) to (6), preferably,

[0763] R1 is a C3-C4 alkyl group;

[0764] P1 is a C1-C4 alkyl group;

[0765] R2 is a C3-C4 alkyl group;

[0766] R3 is a hydrogen atom, or R3 together with P3, the carbon atom attached to R3 and the nitrogen atom attached to P3 form a 5-membered saturated heterocycle;

[0767] P3 is a C1-C4 alkyl group, or P3 together with R3, the carbon atom bonded to R3 and the nitrogen atom bonded to P3 form a 5-membered saturated heterocycle;

[0768] P4 is a C1-C4 alkyl group;

[0769] R5 is a benzyl group optionally substituted with a C1-C4 haloalkyl group;

[0770] P6 is a C1-C4 alkyl group;

[0771] R7 is a phenethyl group optionally substituted with one or more groups selected from the group consisting of: halogen, trifluoromethyl, and methoxy;

[0772] R8, together with P8, the carbon atom bonded to R8, and the nitrogen atom bonded to P8, forms a 5-membered saturated heterocycle, which is substituted with C1-C4 alkyl groups.

[0773] R9, together with Q9 and the carbon atoms bonded to R9 and Q9, form 4- to 6-membered alicyclic rings;

[0774] P9 is hydrogen or a C1-C4 alkyl group;

[0775] R 10 It is a C4-C6 cycloalkyl group;

[0776] P 10 It is a C1-C4 alkyl group;

[0777] R 11 It is a di-C1-C4 alkylaminocarbonyl or a 5- to 6-membered cyclic aminocarbonyl;

[0778] P 11 It is a C1-C4 alkyl group;

[0779] X1, X3, and X5 are each independently selected from the group consisting of: hydrogen, urethane-based protecting groups, acyl-based protecting groups, sulfonamide-based protecting groups, and silane-based protecting groups; and

[0780] X2, X4, and X6 are each independently a halogen, a hydroxyl group, an optionally substituted C1-C6 alkoxy group, or an optionally substituted C6-C6 alkoxy group. 10 aryloxy group, optionally substituted C7-C 14 Arylalkoxy, optionally substituted 4- to 8-membered cyclic aminooxy, or derived from -OSiR x R y R z The group represented, where R x R y and R z Each is independently a C1-C6 alkyl or C6-C 10 Aryl.

[0781] In one aspect of the structural formula of the peptide compound represented by formulas (4) to (6), more preferably,

[0782] R1 is n-propyl or 2-methylpropyl;

[0783] P1 is a methyl group;

[0784] R2 is 1-methylpropyl;

[0785] R3 is a hydrogen atom, or R3 together with P3, the carbon atom attached to R3 and the nitrogen atom attached to P3 form a 5-membered saturated heterocycle;

[0786] P3 is a methyl group, or P3 together with R3, the carbon atom bonded to R3 and the nitrogen atom bonded to P3 form a 5-membered saturated heterocycle;

[0787] P4 is a methyl group;

[0788] R5 is 4-trifluoromethylbenzyl;

[0789] P6 is a methyl group;

[0790] R7 is 3-methoxy-4-trifluoromethylphenylethyl or 3,5-difluoro-4-trifluoromethylphenylethyl;

[0791] R8, together with P8, the carbon atom bonded to R8, and the nitrogen atom bonded to P8, forms a 5-membered saturated heterocycle, which is optionally substituted with an ethoxy group.

[0792] R9 and Q9, as well as the carbon atoms bonded to R9 and Q9, together form a 4-membered alicyclic ring or a 5-membered alicyclic ring;

[0793] P9 is either hydrogen or methyl;

[0794] R 10 It is cyclopentyl;

[0795] P 10 It is methyl;

[0796] R 11 It is dimethylaminocarbonyl;

[0797] P 11 It is methyl;

[0798] X1 is hydrogen or a urethane-based protecting group;

[0799] X3 is a hydrogen or a urethane-based protecting group;

[0800] X5 is a hydrogen or urethane-based protecting group;

[0801] X2 is a hydroxyl group, tert-butoxy group, or benzyloxy group;

[0802] X4 is a hydroxyl group, a tert-butoxy group, or a benzyloxy group; and

[0803] X6 is a hydroxyl group, tert-butoxy group, or benzyloxy group.

[0804] In one aspect, the cyclic peptide compound or its salt or solvate thereof produced by the method of the present invention is preferably a solvate, and more preferably a hydrate.

[0805] In one aspect, the cyclic peptide compound produced by the method of the present invention is a cyclic peptide compound represented by the following formula (1a):

[0806] [Formula 30]

[0807]

[0808] Or their salts, or their solvates.

[0809] In one aspect, the present invention relates to a method for producing a cyclic peptide compound represented by formula (1a) or a salt thereof or a solvate thereof. The method comprises a step of reacting an N-terminal amino acid residue of a peptide compound represented by formula (2a) or (3a) with a C-terminal amino acid residue of the peptide compound in a solvent to perform a cyclization step (hereinafter also referred to as "Aspect 1'").

[0810] [Equation 31]

[0811]

[0812]

[0813]

[0814] In one aspect, the present invention relates to a method for producing a cyclic peptide compound represented by formula (1a) or a salt thereof or a solvate thereof. The method comprises:

[0815] (a) The step of providing a peptide compound or a salt thereof represented by formulas (4a) to (6a) or a solvate thereof;

[0816] (b) The step of reacting the N-terminal amino acid residues of the peptide compounds represented by formulas (4a) to (6a) with the C-terminal amino acid residues of the peptide compounds to perform a linking step; and

[0817] (c) The step of reacting the N-terminal amino acid residue of the peptide compound obtained in step (b) with the C-terminal amino acid residue of the peptide compound to perform cyclization (hereinafter also referred to as "aspect 2'").

[0818] [Equation 32]

[0819]

[0820]

[0821] In aspect 2', step (b) may include (b-1) linking the N-terminal amino acid residue of the peptide compound represented by formula (5a) to the C-terminal amino acid residue of the peptide compound represented by formula (6a), thereby converting them into the peptide compound represented by formula (7a).

[0822] [Equation 33]

[0823]

[0824] In aspect 2', in addition to step (b-1), step (b) may also include,

[0825] (b-2) The step of linking the N-terminal amino acid residues of the peptide compound represented by formula (4a) to the C-terminal amino acid residues of the peptide compound represented by formula (7a), thereby converting them into the peptide compound represented by formula (2a) (the linking step), and

[0826] Step (c) may include

[0827] (c-1) The step of reacting the N-terminal amino acid residue of the peptide compound represented by formula (2a) with the C-terminal amino acid residue of the peptide compound in a solvent to perform cyclization (cyclization step).

[0828] In aspect 2', in addition to step (b-1), step (b) may also include,

[0829] (b-3) The step of linking the N-terminal amino acid residue of the peptide compound represented by formula (7a) to the C-terminal amino acid residue of the peptide compound represented by formula (4a), thereby converting them into the peptide compound represented by formula (3a) (the linking step), and

[0830] Step (c) may include

[0831] (c-2) The step of reacting the N-terminal amino acid residue of the peptide compound represented by formula (3a) with the C-terminal amino acid residue of the peptide compound in a solvent to perform cyclization (cyclization step).

[0832] In aspects 1' and 2', the connection between the N-terminal amino acid residue of the peptide compound and the C-terminal amino acid residue of the peptide compound is preferably the connection between the amino group of the N-terminal amino acid residue and the carboxyl group of the C-terminal amino acid residue, and the connection between the N-terminal amino acid residue of the peptide compound and the C-terminal amino acid residue of the peptide compound is more preferably the connection by means of an amide bond between the amino group of the N-terminal amino acid residue and the carboxyl group of the C-terminal amino acid residue.

[0833] The solvent, condensing agent, base, byproduct generated in the cyclization step, solvent, condensing agent, base, etc. in aspects 1' and 2' are the same as those described in aspects 1 and 2 above.

[0834] The symbols used in the structural formulas of the cyclic peptide compounds represented by formula (1a) and the peptide compounds represented by formulas (2a) to (7a) in aspects 1' and 2' are the same as those described in aspects 1 and 2 above.

[0835] peptide compounds

[0836] In one aspect, the present invention relates to compounds represented by formula (4a).

[0837] [Formula 34]

[0838]

[0839] In formula (4a), X1 is hydrogen or a protecting group for the amino group. Here, the protecting group in X1 is the same as those described in aspects 1 and 2 above. In one aspect, X1 is preferably hydrogen. In another aspect, X1 is preferably an Fmoc group.

[0840] In formula (4a), X2 is a hydroxyl group, optionally substituted alkoxy group, optionally substituted aryloxy group, optionally substituted arylalkoxy group, optionally substituted cyclic aminooxy group, or a group consisting of -OSiR. x R y R z The group represented, where R x R y and R z Each is independently alkyl or aryl. Here, the optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted arylalkoxy, optionally substituted cyclic aminooxy, and -OSiR in X2 x R y R z Same as those described in aspects 1 and 2 above. In one aspect, X2 is preferably tert-butoxy.

[0841] In one aspect, the compound represented by formula (4a) is preferably 2-[methyl-[(2S)-2-[(4Z,7S)-7-(methylamino)-8-oxo-2,3,6,7-tetrahydroazacyclooctatetraen-1-yl]-3-[4-(trifluoromethyl)phenyl]propionyl]amino]tert-butyl acetate (compound 9).

[0842] In one respect, the compound represented by formula (4a) (peptide compound (4a)) can be produced by the following method.

[0843] [Formula 35]

[0844]

[0845] According to the method of Freidinger et al. (J. Org. Chem., 1983, 48(1), 77-81), an oxazolidinone form with a cyclic protecting group can be obtained (4a-2) by reacting an aldehyde with a protected amino acid (4a-1). Next, according to the method of Nguyen et al. (Synthesis, 2009, 12, 1991), a compound with an alkyl group (4a-3) having an alkene introduced on a nitrogen atom can be obtained by ring-opening a silicon compound having an alkene. The amino acid can then be extended at the C-terminus by condensing its C-terminus protected amino acid (4a-4). For the condensation reaction, the condensing reagent and base used in the above linking steps can be used. Various methods are possible, such as combinations of DIC and Oxyma, DIC and HOAt, HATU and DIPEA, or via mixed anhydrides or acid halides, as activators of the carboxyl group. Then, after deprotection of the protecting group used on the amino group, the protected amino acids (4a-6) with olefins as side chains can be extended. Next, the intramolecular olefins can be cyclized through a metathesis reaction.In metathesis reactions, dichloro(2-isopropoxybenzyl)(tricyclohexylphosphine)ruthenium(II): CAS No. 203714-71-0, dichloro(3-phenyl-1H-inden-1-ylidene)bis(tricyclohexylphosphine)ruthenium(II): CAS No. 250220-36-1, dichloro(benzyl)bis(tricyclohexylphosphine)ruthenium(II): CAS No. 172222-30-9, [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidine]dichloro(3-phenyl-1H-inden-1-ylidene)(tricyclohexylphosphine)ruthenium(II): CAS No. CAS No. 536724-67-1, [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinedimethyl]dichloro(benzylene)(tricyclohexylphosphine)ruthenium(II): CAS No. 246047-72-3, [1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinedimethyl]dichloro(2-isopropoxybenzylene)ruthenium(II): CAS No. 301224-40-8, [1,3-bis-(2-tolyl)-2-imidazolidinedimethyl]dichloro(2-isopropoxybenzylene)ruthenium(II): CAS References 927429-61-6, [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinedimethyl]dichloro[(2-isopropoxy)(5-trifluoroacetamido)benzylidene]ruthenium(II): CAS No. 1025728-56-6, and [1,3-bis(2,6-diisopropylphenyl)-2-imidazolidinedimethyl]dichloro[5-(isobutoxycarbonylamido)-2-isopropoxybenzylidene]ruthenium(II): CAS No. 1212009-05-6, can be used as catalysts. Next, the C-terminal protecting group can be deprotected to produce an unprotected C-terminal peptide compound (4a), or the N-terminal protecting group can be deprotected to produce an unprotected N-terminal peptide compound (4a).

[0846] Peptide compound (4a) can also be produced using the following methods.

[0847] [Formula 36]

[0848]

[0849] By acting an alkylating agent containing an alkene on amino acids (4a-9) in the presence of a base, amino acids (4a-10) with alkyl groups specifically introduced onto the N atom can be obtained. Then, the amino acid can be extended on the C-terminal side by condensing the C-terminus of the protected amino acid (4a-4). For the condensation reaction, the condensing agent and base used in the linking step described above can be used. Various methods are possible, such as combinations of DIC and Oxyma, DIC and HOAt, HATU and DIPEA, or via mixed anhydrides or acid halides, as activators of the carboxyl group. After deprotection using the protecting group applied to the amino group, the protected amino acid with an alkene as a side chain can then be extended. Next, the intramolecular alkene can be cyclized via a metathesis reaction. The catalyst used in the metathesis reaction is the same as described above. Next, the C-terminal protecting group can be deprotected to produce an unprotected C-terminal peptide compound (4a), or the N-terminal protecting group can be deprotected to produce an unprotected N-terminal peptide compound (4a).

[0850] In one aspect, the present invention relates to compounds represented by formula (5a).

[0851] [Formula 37]

[0852]

[0853] In formula (5a), X3 is hydrogen or a protecting group for the amino group. Here, the protecting group for the amino group in X3 is the same as those described in aspects 1 and 2 above. In one aspect, X3 is preferably hydrogen. In another aspect, X3 is preferably an Fmoc group or a Cbz group.

[0854] In formula (5a), X4 is a hydroxyl group, optionally substituted alkoxy group, optionally substituted aryloxy group, optionally substituted arylalkoxy group, optionally substituted cyclic aminooxy group, or a group consisting of -OSiR. x R y R z The group represented, where R x R y and R z Each is independently alkyl or aryl. Here, the optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted arylalkoxy, optionally substituted cyclic aminooxy, and -OSiR in X2 x R y R zSame as those described in aspects 1 and 2 above. In one aspect, X4 is preferably tert-butoxy.

[0855] In one aspect, the compound represented by formula (5a) is preferably (2S)-1-[(2S,3S)-3-methyl-2-[[(2S)-2-(methylamino)pentanoyl]amino]pentanoyl]pyrrolidine-2-acetic acid tert-butyl ester (compound 13).

[0856] In one respect, the compound represented by formula (5a) (peptide compound (5a)) can be produced by the following method.

[0857] [Formula 38]

[0858]

[0859] Compound (5a-3) can be obtained by condensing the protected amino acid (5a-2) with its C-terminal protected proline (5a-1). For the condensation reaction, the condensing reagent and base used in the linking step described above can be used, and various methods are possible, such as combinations of DIC and Oxyma, DIC and HOAt, HATU and DIPEA, or via mixed anhydrides or acid halides, as activators of the carboxyl group. Subsequently, after deprotection of the protecting group used on the nitrogen atom, the protected amino acid (5a-4) can be condensed to synthesize a fragment (5a-5) consisting of three amino acids. Next, the C-terminal protecting group can be deprotected to produce an unprotected C-terminal peptide compound (5a), or the N-terminal protecting group can be deprotected to produce an unprotected N-terminal peptide compound (5a).

[0860] In one aspect, the present invention relates to compounds represented by formula (6a).

[0861] [Formula 39]

[0862]

[0863] In formula (6a), X5 is hydrogen or a protecting group for the amino group. Here, the protecting group for the amino group in X5 is the same as those described in aspects 1 and 2 above. In one aspect, X5 is preferably hydrogen. In another aspect, X5 is preferably a Cbz group.

[0864] In formula (6a), X6 is a hydroxyl group, optionally substituted alkoxy group, optionally substituted aryloxy group, optionally substituted arylalkoxy group, optionally substituted cyclic aminooxy group, or a group consisting of -OSiR.x R y R z The group represented, where R x R y and R z Each is independently alkyl or aryl. Here, the optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted arylalkoxy, optionally substituted cyclic aminooxy, and -OSiR in X6 x R y R z Same as those described in aspects 1 and 2 above. In one aspect, X6 is preferably tert-butoxy.

[0865] In one aspect, the compound represented by formula (6a) is preferably (3S)-3-[[(2S)-2-[[1-[[(2S,4R)-1-[(2S)-2-(benzyloxycarbonylamino)-4-[3-methoxy-4-(trifluoromethyl)phenyl]butyryl]-4-ethoxy-pyrrolidine-2-carbonyl]-methyl-amino]cyclobutanecarbonyl]-methyl-amino]-2-cyclopentyl-acetyl]-methyl-amino]-4-(dimethylamino)-4-oxo-butyric acid (compound 20).

[0866] In one respect, the compound represented by formula (6a) (peptide compound (6a)) can be produced by the following method.

[0867] [Formula 40]

[0868]

[0869] Compound (6a-3) can be obtained by condensing a protected amino acid (6a-2) with an amino acid (6a-1) having a β-amino acid backbone with a carboxyl group protected. For the condensation reaction, the condensing reagent and base used in the linking step described above can be used, and various methods are possible, such as combinations of DIC and Oxyma, DIC and HOAt, HATU and DIPEA, or via mixed anhydrides or acid halides, as activators of the carboxyl group. Subsequently, by sequentially deprotecting the amino group and condensing the protected amino acid, a fragment consisting of 5 amino acids (6a-9) can be synthesized. Next, the C-terminal protecting group can be deprotected to produce an unprotected C-terminal peptide compound (6a), or the N-terminal protecting group can be deprotected to produce an unprotected N-terminal peptide compound (6a).

[0870] In one aspect, the present invention relates to compounds represented by formula (7a).

[0871] [Formula 41]

[0872]

[0873] In formula (7a), X5 is hydrogen or a protecting group for the amino group. Here, the protecting group for the amino group in X5 is the same as those described in aspects 1 and 2 above. In one aspect, X5 is preferably hydrogen. In another aspect, X5 is preferably a Cbz group.

[0874] In formula (7a), X4 is a hydroxyl group, optionally substituted alkoxy group, optionally substituted aryloxy group, optionally substituted arylalkoxy group, optionally substituted cyclic aminooxy group, or a group consisting of -OSiR. x R y R z The group represented, where R x R y and R z Each is independently alkyl or aryl. Here, the optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted arylalkoxy, optionally substituted cyclic aminooxy, and -OSiR in X4 x R y R z Same as those described in aspects 1 and 2 above. In one aspect, X4 is preferably a hydroxyl group or a tert-butoxy group.

[0875] In one aspect, the compound represented by formula (7a) is preferably (2S)-1-[(2S,3S)-2-[[(2S)-2-[[(3S)-3-[[(2S)-2-[[1-[[(2S,4R)-1-[(2S)-2-(benzyloxycarbonylamino)-4-[3-methoxy-4-(trifluoromethyl)phenyl]butyryl]-4-ethoxy-pyrrolidine-2-carbonyl]-methyl-amino]cyclobutanecarbonyl]-methyl-amino]-2-cyclopentylacetyl]-methyl-amino]-4-(dimethylamino)-4-oxo-butyryl]-methyl-amino]valanoyl]amino]-3-methyl-valanoyl]pyrrolidine-2-carboxylic acid (compound 22). Furthermore, in one aspect, the compound represented by formula (7a) is preferably (2S)-1-[(2S,3S)-2-[[(2S)-2-[[(3S)-3-[[(2S)-2-[[1-[[(2S,4R)-1-[(2S)-2-amino-4-[3-methoxy-4-(trifluoromethyl)phenyl]butyryl]-4-ethoxy-pyrrolidine-2-carbonyl]-methyl-amino]cyclobutanecarbonyl]-methyl-amino]-2-cyclopentyl-acetyl]-methyl-amino]-4-(dimethylamino)-4-oxo-butyryl]-methyl-amino]pentanoyl]amino]-3-methyl-pentanoyl]pyrrolidine-2-carboxylic acid tert-butyl ester (compound 37).

[0876] In one aspect, the compound represented by formula (7a) can be produced by reacting the N-terminal amino acid residue of the peptide compound represented by formula (5a) with the C-terminal amino acid residue of the peptide compound represented by formula (6a) in a solvent to perform a linking step (linking step). The solvent, condensing agent, base, etc., in the linking step are the same as those described in aspects 1 and 2 above.

[0877] In one aspect, the present invention relates to compounds represented by formula (2a).

[0878] [Equation 42]

[0879]

[0880] In formula (2a), X5 is hydrogen or a protecting group for the amino group. Here, the protecting group for the amino group in X5 is the same as those described in aspects 1 and 2 above. In one aspect, X5 is preferably hydrogen. In another aspect, X5 is preferably a Cbz group.

[0881] In formula (2a), X2 is a hydroxyl group, optionally substituted alkoxy group, optionally substituted aryloxy group, optionally substituted arylalkoxy group, optionally substituted cyclic aminooxy group, or a group consisting of -OSiR. x R y R z The group represented, where R x R y and R z Each is independently alkyl or aryl. Here, the optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted arylalkoxy, optionally substituted cyclic aminooxy, and -OSiR in X2 x R y R z Same as those described in aspects 1 and 2 above. In one aspect, X2 is preferably a hydroxyl group or a tert-butoxy group.

[0882] In one aspect, the compound represented by formula (2a) is preferably 2-[[(2S)-2-[(4Z,7S)-7-[[(2S)-1-[(2S,3S)-2-[[(2S)-2-[[(3S)-3-[[(2S)-2-[[1-[[(2S,4R)-1-[(2S)-2-amino-4-[3-methoxy-4-(trifluoromethyl)phenyl]butyryl]-4-ethoxy-pyrrolidine-2-carbonyl]-methyl-amino]cyclo [Butanecarbonyl]-methyl-amino]-2-cyclopentyl-acetyl]-methyl-amino]-4-(dimethylamino)-4-oxo-butyryl]-methyl-amino]valeryl]amino]-3-methyl-valeryl]pyrrolidine-2-carbonyl]-methyl-amino]-8-oxo-2,3,6,7-tetrahydroazacyclooctatetraen-1-yl]-3-[4-(trifluoromethyl)phenyl]propionyl]-methyl-amino]acetic acid (compound 24).

[0883] In one aspect, the compound represented by formula (2a) can be produced by reacting the N-terminal amino acid residue of the peptide compound represented by formula (4a) with the C-terminal amino acid residue of the peptide compound represented by formula (7a) in a solvent to perform a linking step (linking step). The solvent, condensing agent, base, etc., in the linking step are the same as those described in aspects 1 and 2 above.

[0884] In one aspect, the present invention relates to compounds represented by formula (3a).

[0885] [Formula 43]

[0886]

[0887] In formula (3a), X1 is hydrogen or a protecting group for the amino group. Here, the protecting group for the amino group in X1 is the same as those described in aspects 1 and 2 above. In one aspect, X1 is preferably hydrogen. In another aspect, X1 is preferably an Fmoc group.

[0888] In formula (3a), X4 is a hydroxyl group, optionally substituted alkoxy group, optionally substituted aryloxy group, optionally substituted arylalkoxy group, optionally substituted cyclic aminooxy group, or a group consisting of -OSiR. x R y R z The group represented, where R x R y and R z Each is independently alkyl or aryl. Here, the optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted arylalkoxy, optionally substituted cyclic aminooxy, and -OSiR in X4 x R y R z Same as those described in aspects 1 and 2 above. In one aspect, X4 is preferably a hydroxyl group or a tert-butoxy group.

[0889] In one aspect, the compound represented by formula (3a) is preferably (S)-2-[(S)-3-[(S)-2-cyclopentyl-2-[1-[(2S,4R)-4-ethoxy-1-[(S)-4-[3-methoxy-4-(trifluoromethyl)phenyl]-2-[(2-[(S)-N-methyl-2-[(R,Z)-3-(methylamino)-2-oxo-3,4,7,8-tetrahydroazacyclooctatetraen-1(2H)-yl]-3-[4-(trifluoromethyl)phenyl]propamido]acetamido]butyryl]-N-methylpyrrolidine-2-carbamoyl]-N-methylcyclobutane-1-carbamoyl]-N-methylacetamido]-4-(dimethylamino)-N-methyl-4-oxobutamido]valoyl]-L-isoleucyl-L-proline (compound 40).

[0890] In one aspect, the compound represented by formula (3a) can be produced by reacting the N-terminal amino acid residue of the peptide compound represented by formula (7a) with the C-terminal amino acid residue of the peptide compound represented by formula (4a) in a solvent to perform a linking step (linking step). The solvent, condensing agent, base, etc., in the linking step are the same as those described in aspects 1 and 2 above.

[0891] In the production methods of the compounds represented by formulas (2a) to (7a), solid-phase synthesis is preferably not used.

[0892] In the production method of the cyclic peptide compound represented by formula (1a), it is preferable not to use solid-phase synthesis.

[0893] Crystals of cyclic peptide compounds

[0894] In one aspect, the present invention relates to crystals of cyclic peptide compounds represented by formula (1a), or salts thereof, or solvates thereof. Specific examples of crystals of the compound include unsolvable or solvable crystals of the compound, or unsolvable or solvable crystals of salts of the compound. Preferably, solvable crystals of cyclic peptide compounds represented by formula (1a) are preferred. Preferred examples of solvable crystals include hydrate crystals.

[0895] The diffraction angle 2θ in powder X-ray diffraction is the diffraction peak measured using CuKα or CuKα1 radiation. Crystals further identified by the diffraction angle 2θ in powder X-ray diffraction from these solvate crystals can be referred to as “form A crystals” of the hydrates shown below, for example, or simply “form A”.

[0896] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal is a crystal of form A having a powder X-ray diffraction pattern comprising at least seven of the following peaks in the form of a diffraction angle 2θ in powder X-ray diffraction. Note that the diffraction angles (2θ values) described below are preferably those of hydrate crystals stored at 10% or higher relative humidity for 15 minutes or longer, and more preferably those of hydrate crystals stored at 10% relative humidity for 15 minutes.

[0897] 6.93°, 7.56°, 8.26°, 9.00°, 9.58°, 10.35°, 11.35°, 12.26°, 12.85°, 13.51°, 14.12°, 14.69°, 15.46°, 15.92°, 17.43°, and 17.73° (±0.2°)

[0898] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal is a crystal of form A having a powder X-ray diffraction pattern comprising at least eight peaks of the form of a diffraction angle 2θ in powder X-ray diffraction. Note that the diffraction angles (2θ values) described below are preferably those of hydrate crystals stored at 10% or higher relative humidity for 15 minutes or longer, and more preferably those of hydrate crystals stored at 10% relative humidity for 15 minutes.

[0899] 6.93°, 7.56°, 8.26°, 9.00°, 9.58°, 10.35°, 11.35°, 12.26°, 12.85°, 13.51°, 14.12°, 14.69°, 15.46°, 15.92°, 17.43°, and 17.73° (±0.2°)

[0900] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal is a crystal of form A having a powder X-ray diffraction pattern comprising the following peaks in the form of a diffraction angle 2θ in powder X-ray diffraction. Note that the diffraction angle (2θ value) described below is preferably the diffraction angle (2θ value) of a hydrate crystal stored at 30% or higher relative humidity for 15 minutes or longer, and more preferably the diffraction angle (2θ value) of a hydrate crystal stored at 30% relative humidity for 15 minutes.

[0901] 6.93°, 7.56°, 8.26°, 9.00°, 9.58°, 10.35°, 11.35°, 12.26°, 12.85°, 13.51°, 14.12°, 14.69°, 15.46°, 15.92°, 17.43°, and 17.73° (±0.2°)

[0902] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal is a form B crystal having a powder X-ray diffraction pattern comprising at least seven of the following peaks in the form of a diffraction angle 2θ in powder X-ray diffraction. Note that the diffraction angles (2θ values) described below are preferably those of hydrate crystals stored at a relative humidity of 30% or higher for 15 minutes or longer, and more preferably those of hydrate crystals stored at a relative humidity of 30% for 15 minutes.

[0903] 4.99°, 8.65°, 9.85°, 10.84°, 11.32°, 12.35°, 13.20°, 14.44°, 15.20°, 16.03°, 16.69°, 17.21°, 18.82°, 19.49°, and 20.03° (±0.2°)

[0904] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal is a form B crystal having a powder X-ray diffraction pattern comprising at least eight peaks of the form of a diffraction angle 2θ in powder X-ray diffraction. Note that the diffraction angles (2θ values) described below are preferably those of hydrate crystals stored at a relative humidity of 30% or higher for 15 minutes or longer, and more preferably those of hydrate crystals stored at a relative humidity of 30% for 15 minutes.

[0905] 4.99°, 8.65°, 9.85°, 10.84°, 11.32°, 12.35°, 13.20°, 14.44°, 15.20°, 16.03°, 16.69°, 17.21°, 18.82°, 19.49°, and 20.03° (±0.2°)

[0906] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal is a form B crystal having a powder X-ray diffraction pattern comprising the following peaks in the form of a diffraction angle 2θ in powder X-ray diffraction. Note that the diffraction angle (2θ value) described below is preferably the diffraction angle (2θ value) of a hydrate crystal stored at 30% or higher relative humidity for 15 minutes or longer, and more preferably the diffraction angle (2θ value) of a hydrate crystal stored at 30% relative humidity for 15 minutes.

[0907] 4.99°, 8.65°, 9.85°, 10.84°, 11.32°, 12.35°, 13.20°, 14.44°, 15.20°, 16.03°, 16.69°, 17.21°, 18.82°, 19.49°, and 20.03° (±0.2°)

[0908] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a solvate crystal, the crystal is a form F crystal having a powder X-ray diffraction pattern comprising at least 7 of the following peaks in the form of a diffraction angle 2θ in powder X-ray diffraction.

[0909] 6.99°, 8.49°, 9.49°, 9.88°, 10.21°, 11.81°, 12.32°, 12.75°, 13.17°, 13.94°, 14.92°, 15.20°, 15.64°, 16.78°, 17.01°, and 17.47° (±0.2°)

[0910] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a solvate crystal, the crystal is a form F crystal having a powder X-ray diffraction pattern comprising at least eight of the following peaks in the form of a diffraction angle 2θ in powder X-ray diffraction.

[0911] 6.99°, 8.49°, 9.49°, 9.88°, 10.21°, 11.81°, 12.32°, 12.75°, 13.17°, 13.94°, 14.92°, 15.20°, 15.64°, 16.78°, 17.01°, and 17.47° (±0.2°)

[0912] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a solvate crystal, the crystal is a form F crystal having a powder X-ray diffraction pattern including the following peaks in the form of a diffraction angle 2θ in powder X-ray diffraction.

[0913] 6.99°, 8.49°, 9.49°, 9.88°, 10.21°, 11.81°, 12.32°, 12.75°, 13.17°, 13.94°, 14.92°, 15.20°, 15.64°, 16.78°, 17.01°, and 17.47° (±0.2°)

[0914] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a solvate crystal, the crystal is a crystal in the form J having a powder X-ray diffraction pattern comprising at least seven of the following peaks in the form of a diffraction angle 2θ in powder X-ray diffraction. Note that the diffraction angles (2θ values) described below are preferably those of solvate crystals stored at a relative humidity of less than 10% for 15 minutes or longer, and more preferably those of solvate crystals stored at a relative humidity of less than 10% for 15 minutes.

[0915] 6.95°, 7.33°, 7.93°, 8.84°, 9.45°, 9.97°, 10.44°, 11.19°, 12.43°, 12.93°, 13.46°, 14.36°, 14.74°, 15.21°, 15.87°, 16.76°, 20.87°, and 22.97° (±0.2°)

[0916] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a solvate crystal, the crystal is a crystal in the form J having a powder X-ray diffraction pattern comprising at least eight peaks in the form of a diffraction angle 2θ in powder X-ray diffraction. Note that the diffraction angles (2θ values) described below are preferably those of solvate crystals stored at a relative humidity of less than 10% for 15 minutes or longer, and more preferably those of solvate crystals stored at a relative humidity of less than 10% for 15 minutes.

[0917] 6.95°, 7.33°, 7.93°, 8.84°, 9.45°, 9.97°, 10.44°, 11.19°, 12.43°, 12.93°, 13.46°, 14.36°, 14.74°, 15.21°, 15.87°, 16.76°, 20.87°, and 22.97° (±0.2°)

[0918] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a solvate crystal, the crystal is a crystal in the form of J having a powder X-ray diffraction pattern including the following peaks in the form of a diffraction angle 2θ in powder X-ray diffraction. Note that the diffraction angle (2θ value) described below is preferably the diffraction angle (2θ value) of a solvate crystal stored at a relative humidity of less than 10% for 15 minutes or longer, and more preferably the diffraction angle (2θ value) of a solvate crystal stored at a relative humidity of less than 10% for 15 minutes.

[0919] 6.95°, 7.33°, 7.93°, 8.84°, 9.45°, 9.97°, 10.44°, 11.19°, 12.43°, 12.93°, 13.46°, 14.36°, 14.74°, 15.21°, 15.87°, 16.76°, 20.87°, and 22.97° (±0.2°).

[0920] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal is a crystal in the form J having a powder X-ray diffraction pattern comprising at least seven of the following peaks in the form of a diffraction angle 2θ in powder X-ray diffraction. Note that the diffraction angle (2θ value) described below is preferably the diffraction angle (2θ value) of a hydrate crystal stored at a relative humidity of less than 10% for 15 minutes or longer, and more preferably the diffraction angle (2θ value) of a hydrate crystal stored at a relative humidity of less than 10% for 15 minutes.

[0921] 6.95°, 7.33°, 7.93°, 8.84°, 9.45°, 9.97°, 10.44°, 11.19°, 12.43°, 12.93°, 13.46°, 14.36°, 14.74°, 15.21°, 15.87°, 16.76°, 20.87°, and 22.97° (±0.2°)

[0922] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal is a crystal of form J having a powder X-ray diffraction pattern comprising at least eight peaks of the form of a diffraction angle 2θ in powder X-ray diffraction. Note that the diffraction angle (2θ value) described below is preferably the diffraction angle (2θ value) of a hydrate crystal stored at a relative humidity of less than 10% for 15 minutes or longer, and more preferably the diffraction angle (2θ value) of a hydrate crystal stored at a relative humidity of less than 10% for 15 minutes.

[0923] 6.95°, 7.33°, 7.93°, 8.84°, 9.45°, 9.97°, 10.44°, 11.19°, 12.43°, 12.93°, 13.46°, 14.36°, 14.74°, 15.21°, 15.87°, 16.76°, 20.87°, and 22.97° (±0.2°)

[0924] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal is a crystal in the form J having a powder X-ray diffraction pattern including the following peaks in the form of a diffraction angle 2θ in powder X-ray diffraction. Note that the diffraction angle (2θ value) described below is preferably the diffraction angle (2θ value) of a hydrate crystal stored at a relative humidity of less than 10% for 15 minutes or longer, and more preferably the diffraction angle (2θ value) of a hydrate crystal stored at a relative humidity of less than 10% for 15 minutes.

[0925] 6.95°, 7.33°, 7.93°, 8.84°, 9.45°, 9.97°, 10.44°, 11.19°, 12.43°, 12.93°, 13.46°, 14.36°, 14.74°, 15.21°, 15.87°, 16.76°, 20.87°, and 22.97° (±0.2°)

[0926] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal comprises a crystal of form J having a powder X-ray diffraction pattern at a relative humidity of less than 10%, the powder X-ray diffraction pattern comprising at least seven of the following peaks in the form of a diffraction angle 2θ in powder X-ray diffraction: 6.95°, 7.33°, 7.93°, 8.84°, 9.45°, 9.97°, 10.44°, 11.19°, 12.43°, 12.93°, 13.46°, 14.36°, 14.74°, 15.21°, 15.87°, 16.76°, 20.87°, and 22.97° (±0.2°), and comprises a crystal of form A having a powder X-ray diffraction pattern at a relative humidity of 10% or higher, the powder X-ray diffraction pattern comprising at least seven of the following peaks in the form of a hydrated ... The peaks are: 6.93°, 7.56°, 8.26°, 9.00°, 9.58°, 10.35°, 11.35°, 12.26°, 12.85°, 13.51°, 14.12°, 14.69°, 15.46°, 15.92°, 17.43°, and 17.73° (±0.2°).

[0927] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal comprises a crystal of form J having a powder X-ray diffraction pattern at a relative humidity of less than 10%, the powder X-ray diffraction pattern comprising at least eight of the following peaks in the form of diffraction angle 2 in powder X-ray diffraction: 6.95°, 7.33°, 7.93°, 8.84°, 9.45°, 9.97°, 10.44°, 11.19°, 12.43°, 12.93°, 13.46°, 14.36°, 14.74°, 15.21°, 15.87°, 16.76°, 20.87°, and 22.97° (±0.2°), and comprises a crystal of form A having a powder X-ray diffraction pattern at a relative humidity of 10% or higher, ... The peaks are: 6.93°, 7.56°, 8.26°, 9.00°, 9.58°, 10.35°, 11.35°, 12.26°, 12.85°, 13.51°, 14.12°, 14.69°, 15.46°, 15.92°, 17.43°, and 17.73° (±0.2°).

[0928] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal comprises a form J crystal having a powder X-ray diffraction pattern at a relative humidity of less than 10%, the powder X-ray diffraction pattern comprising peaks of 6.95°, 7.33°, 7.93°, 8.84°, 9.45°, 9.97°, 10.44°, 11.19°, 12.43°, 12.93°, 13.46°, 14.36°, 14.74°, 15.21°, 15.87°, 16.76°, 20.87°, and 22.97° (±0.2°) in the form of diffraction angles 2θ in powder X-ray diffraction, and comprises a form A crystal having a powder X-ray diffraction pattern at a relative humidity of 10% or higher, the powder X-ray diffraction pattern comprising a hydrate crystal having a relative humidity of 10% or higher, the powder X-ray diffraction pattern comprising a hydrate crystal having a relative humidity of less than 10%, ... The X-ray diffraction pattern includes peaks at 6.93°, 7.56°, 8.26°, 9.00°, 9.58°, 10.35°, 11.35°, 12.26°, 12.85°, 13.51°, 14.12°, 14.69°, 15.46°, 15.92°, 17.43°, and 17.73° (±0.2°).

[0929] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a solvate crystal, the crystal is a Y crystal having a powder X-ray diffraction pattern comprising at least seven of the following peaks in the form of a diffraction angle 2θ in powder X-ray diffraction. Note that the diffraction angles (2θ values) described below are preferably those of solvate crystals stored at a relative humidity of less than 30% for 15 minutes or longer, and more preferably those of solvate crystals stored at a relative humidity of less than 30% for 15 minutes.

[0930] 5.13°, 8.33°, 8.82°, 9.80°, 10.32°, 11.39°, 12.58°, 13.28°, 14.80°, 15.40°, 15.88°, 17.12°, 17.67°, 19.18°, 19.54°, and 21.24° (±0.2°)

[0931] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a solvate crystal, the crystal is a Y crystal having a powder X-ray diffraction pattern comprising at least eight of the following peaks in the form of a diffraction angle 2θ in powder X-ray diffraction. Note that the diffraction angles (2θ values) described below are preferably those of solvate crystals stored at a relative humidity of less than 30% for 15 minutes or longer, and more preferably those of solvate crystals stored at a relative humidity of less than 30% for 15 minutes.

[0932] 5.13°, 8.33°, 8.82°, 9.80°, 10.32°, 11.39°, 12.58°, 13.28°, 14.80°, 15.40°, 15.88°, 17.12°, 17.67°, 19.18°, 19.54°, and 21.24° (±0.2°)

[0933] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a solvate crystal, the crystal is a Y crystal having a powder X-ray diffraction pattern including the following peaks in the form of a diffraction angle 2θ in powder X-ray diffraction. Note that the diffraction angles (2θ values) described below are preferably those of solvate crystals stored at a relative humidity of less than 30% for 15 minutes or longer, and more preferably those of solvate crystals stored at a relative humidity of less than 30% for 15 minutes.

[0934] 5.13°, 8.33°, 8.82°, 9.80°, 10.32°, 11.39°, 12.58°, 13.28°, 14.80°, 15.40°, 15.88°, 17.12°, 17.67°, 19.18°, 19.54°, and 21.24° (±0.2°)

[0935] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal is a Y crystal having a powder X-ray diffraction pattern comprising at least seven of the following peaks in the form of a diffraction angle 2θ in powder X-ray diffraction. Note that the diffraction angles (2θ values) described below are preferably the diffraction angles (2θ values) of solvate crystals stored at a relative humidity of less than 30% for 15 minutes or longer, and more preferably the diffraction angles (2θ values) of hydrate crystals stored at a relative humidity of less than 30% for 15 minutes.

[0936] 5.13°, 8.33°, 8.82°, 9.80°, 10.32°, 11.39°, 12.58°, 13.28°, 14.80°, 15.40°, 15.88°, 17.12°, 17.67°, 19.18°, 19.54°, and 21.24° (±0.2°)

[0937] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal is a Y crystal having a powder X-ray diffraction pattern comprising at least eight peaks of the following in the form of a diffraction angle 2θ in powder X-ray diffraction. Note that the diffraction angles (2θ values) described below are preferably the diffraction angles (2θ values) of solvate crystals stored at a relative humidity of less than 30% for 15 minutes or longer, and more preferably the diffraction angles (2θ values) of hydrate crystals stored at a relative humidity of less than 30% for 15 minutes.

[0938] 5.13°, 8.33°, 8.82°, 9.80°, 10.32°, 11.39°, 12.58°, 13.28°, 14.80°, 15.40°, 15.88°, 17.12°, 17.67°, 19.18°, 19.54°, and 21.24° (±0.2°)

[0939] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal is a Y crystal having a powder X-ray diffraction pattern including the following peaks in the form of a diffraction angle 2θ in powder X-ray diffraction. Note that the diffraction angle (2θ value) described below is preferably the diffraction angle (2θ value) of a hydrate crystal stored at a relative humidity of less than 30% for 15 minutes or longer, and more preferably the diffraction angle (2θ value) of a hydrate crystal stored at a relative humidity of less than 30% for 15 minutes.

[0940] 5.13°, 8.33°, 8.82°, 9.80°, 10.32°, 11.39°, 12.58°, 13.28°, 14.80°, 15.40°, 15.88°, 17.12°, 17.67°, 19.18°, 19.54°, and 21.24° (±0.2°)

[0941] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal comprises a Y crystal having a powder X-ray diffraction pattern at a relative humidity of less than 30%, the powder X-ray diffraction pattern comprising at least seven of the following peaks in the form of a diffraction angle 2θ in powder X-ray diffraction: 5.13°, 8.33°, 8.82°, 9.80°, 10.32°, 11.39°, 12.58°, 13.28°, 14.80°, 15.40°, 15.88°, 17.12°, 17.67°, 19.18°, 19.54°, and 21.24° (±0.2°), and also comprises a B crystal having a powder X-ray diffraction pattern at a relative humidity of 30% or higher, the powder X-ray diffraction pattern comprising at least seven of the following peaks in the form of a hydrated ... The peaks are: 4.99°, 8.65°, 9.85°, 10.84°, 11.32°, 12.35°, 13.20°, 14.44°, 15.20°, 16.03°, 16.69°, 17.21°, 18.82°, 19.49°, and 20.03° (±0.2°).

[0942] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal comprises a Y crystal having a powder X-ray diffraction pattern at a relative humidity of less than 30%, the powder X-ray diffraction pattern comprising at least eight of the following peaks in the form of diffraction angle 2 in powder X-ray diffraction: 5.13°, 8.33°, 8.82°, 9.80°, 10.32°, 11.39°, 12.58°, 13.28°, 14.80°, 15.40°, 15.88°, 17.12°, 17.67°, 19.18°, 19.54°, and 21.24° (±0.2°), and also comprises a B crystal having a powder X-ray diffraction pattern at a relative humidity of 30% or higher, the powder X-ray diffraction pattern comprising at least eight of the following peaks in the form of diffraction angle 2 in powder X-ray diffraction: 5.13°, 8.33°, 8.82°, 9.80°, 10.32°, 11.39°, 12.58°, 13.28°, 14.80°, 15.40°, 15.88°, 17.12°, 17.67°, 19.18°, 19.54°, and 21.24° (±0.2°), and includes a B crystal having a powder X-ray diffraction pattern at a relative humidity of 30% or higher, the powder X-ray diffraction pattern comprising at least eight of the following peaks in the form of diffraction angle 2 in powder X-ray diffraction: 5.13°, 8.33°, 8.82 The peaks are: 4.99°, 8.65°, 9.85°, 10.84°, 11.32°, 12.35°, 13.20°, 14.44°, 15.20°, 16.03°, 16.69°, 17.21°, 18.82°, 19.49°, and 20.03° (±0.2°).

[0943] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal comprises a Y crystal having a powder X-ray diffraction pattern at a relative humidity of less than 30%, the powder X-ray diffraction pattern comprising peaks of 5.13°, 8.33°, 8.82°, 9.80°, 10.32°, 11.39°, 12.58°, 13.28°, 14.80°, 15.40°, 15.88°, 17.12°, 17.67°, 19.18°, 19.54°, and 21.24° (±0.2°) in the form of diffraction angle 2θ in powder X-ray diffraction, and comprises a B crystal having a powder X-ray diffraction pattern at a relative humidity of 30% or higher, the powder X-ray diffraction pattern comprising peaks of 5.13°, 8.33°, 8.82°, 9.80°, 10.32°, 11.39°, 12.58°, 13.28°, 14.80°, 15.40°, 15.88°, 17.12°, 17.67°, 19.18°, 19.54°, and 21.24° (±0.2°), and comprises a B crystal having a powder X-ray diffraction pattern at a relative humidity of 30% or higher, the powder X-ray diffraction pattern comprising peaks of 5.13°, 8.33°, 8.82°, 9.80°, 10.32°, 11.39°, 12.58°, 13.28°, 14.80°, 15.40°, The X-ray diffraction pattern includes peaks at 4.99°, 8.65°, 9.85°, 10.84°, 11.32°, 12.35°, 13.20°, 14.44°, 15.20°, 16.03°, 16.69°, 17.21°, 18.82°, 19.49°, and 20.03° (±0.2°).

[0944] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal is a K crystal having a powder X-ray diffraction pattern comprising at least 7 of the following peaks in the form of a diffraction angle 2θ in powder X-ray diffraction.

[0945] 7.49°, 7.91°, 8.14°, 9.11°, 9.33°, 11.04°, 11.71°, 12.52°, 13.21°, 13.70°, 14.82°, 15.13°, 15.52°, 15.68°, 17.22°, and 17.51° (±0.2°)

[0946] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal is a K crystal having a powder X-ray diffraction pattern comprising at least eight of the following peaks in the form of a diffraction angle 2θ in powder X-ray diffraction.

[0947] 7.49°, 7.91°, 8.14°, 9.11°, 9.33°, 11.04°, 11.71°, 12.52°, 13.21°, 13.70°, 14.82°, 15.13°, 15.52°, 15.68°, 17.22°, and 17.51° (±0.2°)

[0948] In one aspect, when the crystal of the cyclic peptide compound of formula (1a) is a hydrate crystal, the crystal is a K crystal having a powder X-ray diffraction pattern including the following peaks in the form of a diffraction angle 2θ in powder X-ray diffraction.

[0949] 7.49°, 7.91°, 8.14°, 9.11°, 9.33°, 11.04°, 11.71°, 12.52°, 13.21°, 13.70°, 14.82°, 15.13°, 15.52°, 15.68°, 17.22°, and 17.51° (±0.2°)

[0950] In one aspect, the present invention relates to a method for producing crystals of a cyclic peptide compound represented by formula (1a) or a salt thereof or a solvate thereof. The method comprises: dissolving the cyclic peptide compound in a polar organic solvent to obtain a solution, the amount of which allows the cyclic peptide compound to dissolve therein; and adding a hydrocarbon solvent or water to the solution to obtain crystals of the cyclic peptide compound (hereinafter also referred to as "Aspect 3"). In Aspect 3, the nature of the cyclic peptide compound to be dissolved is not limited, and for example, cyclic peptide compounds in a solid state, an amorphous state, or a crystalline state can be used.

[0951] In one aspect, the present invention relates to a method for producing crystals of a cyclic peptide compound represented by formula (1a) or a salt thereof or a solvate thereof. The method comprises the step of adding a mixed solution of a hydrocarbon solvent and a polar organic solvent or a mixed solution of water and a polar organic solvent to a cyclic peptide compound in an amorphous or crystalline state to obtain crystals of the cyclic peptide compound (hereinafter also referred to as "Aspect 4").

[0952] As polar organic solvents used in aspects 3 and 4, examples preferably include DMSO, acetone, 2-butanone, methanol, ethanol, 1-propanol, 2-propanol, ethyl acetate, propylene glycol, and mixtures thereof, with acetone being more preferred. As for the "amount in which the cyclic peptide compound is permitted to dissolve" in aspect 3, the polar organic solvent can be used in the range of 3 v / w to 10 v / w, preferably in the range of 3 v / w to 7 v / w, relative to the cyclic peptide compound of formula (1a).

[0953] Specifically, examples of hydrocarbon solvents used in aspects 3 and 4 include heptane, hexane, pentane, toluene, xylene, and mixtures thereof, with heptane being more preferred.

[0954] In aspect 4, as the mixing ratio of hydrocarbon solvent and polar organic solvent in the mixed solution of hydrocarbon solvent and polar organic solvent, 0.5 to 10 parts by weight of hydrocarbon solvent can be used relative to 1 part by weight of polar organic solvent, and preferably 1 to 7 parts by weight of hydrocarbon solvent, and even more preferably 1 to 5 parts by weight of hydrocarbon solvent. Furthermore, in aspect 4, as the mixing ratio of water and polar organic solvent in the mixed solution of water and polar organic solvent, 0.5 to 10 parts by weight of water can be used relative to 1 part by weight of polar organic solvent, and preferably 1 to 7 parts by weight of water, and even more preferably 1 to 5 parts by weight of water.

[0955] Furthermore, in one aspect of aspect 4, in the operation of adding a mixed solution of a hydrocarbon solvent and a polar organic solvent or a mixed solution of water and a polar organic solvent to a cyclic peptide compound in an amorphous or crystalline state, glass beads (e.g., 1 to 5 beads) can be added to the crystal and shaken.

[0956] In one aspect, the present invention relates to a method for producing crystals of a cyclic peptide compound represented by formula (1a) or a salt thereof or a solvate thereof. The method comprises: dissolving an amorphous cyclic peptide compound in DMSO to obtain a solution; freeze-drying the solution to obtain a freeze-dried product of the cyclic peptide compound; and adding a mixed solution of water and a polar organic solvent to the freeze-dried product to obtain crystals of the cyclic peptide compound (hereinafter also referred to as "Aspect 5").

[0957] As a polar organic solvent used in aspect 5, examples of preferred solvents include DMSO, acetone, 2-butanone, methanol, ethanol, 1-propanol, 2-propanol, propylene glycol, and mixtures thereof, with acetone being more preferred.

[0958] In aspect 5, as the mixing ratio of water and polar organic solvent in the mixed solution of water and polar organic solvent, 0.5 to 10 parts by weight of water can be used relative to 1 part by weight of polar organic solvent, and preferably 1 to 7 parts by weight of water, and even more preferably 1 to 5 parts by weight of water.

[0959] In one aspect, the present invention relates to a method for producing crystals of a cyclic peptide compound represented by formula (1a) or a salt thereof or a solvate thereof. The method includes the step of heating the crystals of the cyclic peptide compound to obtain another crystalline polymorph of the cyclic peptide compound (hereinafter also referred to as "Aspect 6"). The heating temperature is, for example, from 30°C to 350°C, preferably from 30°C to 120°C.

[0960] In aspects 3 to 6, the method may further include a step of filtering the crystals after the step of obtaining the crystals of the cyclic peptide compound.

[0961] In aspects 3 to 6, the method may further include a step of drying the crystals after the step of obtaining the crystals of the cyclic peptide compound.

[0962] In one aspect, the crystals of the cyclic peptide compounds produced by the method of the present invention are preferably solvate crystals, and more preferably hydrate crystals.

[0963] In one aspect, the crystals of the cyclic peptide compound produced by the method of the present invention are formed in a solvent as solvate crystals and obtained as hydrate crystals after a filtration step and / or a drying step. Furthermore, in another aspect, the crystals of the cyclic peptide compound produced by the method of the present invention are obtained as hydrate crystals by incorporating atmospheric moisture after a filtration step and / or a drying step.

[0964] Compositions containing cyclic peptide compounds

[0965] In one aspect, the present invention relates to compositions comprising a cyclic peptide compound represented by formula (1a) or a salt thereof or a solvate thereof. The compound contains a cyclic dimer of formula (1a) as an impurity in an amount of 1.5 w / w% or less.

[0966] In one aspect, the present invention relates to compositions comprising a cyclic peptide compound represented by formula (1a) or a salt thereof or a solvate thereof. The compound contains a cyclic dimer of formula (1a) as an impurity in an amount of 0.001 w / w% or higher.

[0967] In one aspect, the present invention relates to compositions comprising a cyclic peptide compound represented by formula (1a) or a salt thereof or a solvate thereof. The compound contains acetone in a proportion of 2.0 w / w% or less.

[0968] In one aspect, the present invention relates to compositions comprising a cyclic peptide compound represented by formula (1a) or a salt thereof or a solvate thereof. The compound contains acetone in a proportion of 0.001 w / w% or higher.

[0969] [Example]

[0970] The invention will be further described through the following examples, but the invention is not limited thereto. Except for those specifically described, the original starting materials, starting raw materials, solvents, and reagents were obtained from commercial suppliers or synthesized using known methods. Compound 25 used in Examples 1-26 described below was synthesized using the method described in International Publication No. WO 2022 / 234853.

[0971] The LCMS analysis conditions are shown below.

[0972] LCMS Analysis Conditions and Methods 1

[0973] Equipment: Shimadzu LCMS 2020

[0974] Column: CORTECS C18 column, 3.0 mm ID × 50 mm, 2.7 μm

[0975] Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[0976] Elution method: B) 5% (0 min) → 95% (2.0 min) → 95% (2.8 min) → 5% (2.81 min) → 5% (3 min)

[0977] Flow rate: 1.5 mL / min

[0978] Column temperature: 40°C

[0979] Detection wavelength: 190 nm to 800 nm (PDA)

[0980] LCMS Analysis Conditions and Methods 2

[0981] Equipment: Waters UPLC / SQD

[0982] Column: Ascentis Express RP 90A amide, 2.1 mm ID × 50 mm, 2.7 μm (PDA)m

[0983] Mobile phase: 0.1% FA / water (A), 0.1% FA / MeCN (B)

[0984] Elution method: B) 5% (0 min) → 100% (4.5 min) → 100% (5.0 min) → 5% (5.01 min) → 5% (7 min)

[0985] Flow rate: 0.5 mL / min

[0986] Column temperature: 40°C

[0987] Detection wavelength: 210 nm to 400 nm (PDA)

[0988] LCMS Analysis Conditions and Methods 3

[0989] Equipment: Waters UPLC / SQD

[0990] Column: Ascentis Express 90A C18, 2.1 mm ID × 50 mm, 2.7 μm

[0991] Mobile phase: 0.1% FA / water (A), 0.1% FA / MeCN (B)

[0992] Elution method: B) 5% (0 min) → 100% (5 min) → 5% (5.01 min) → 5% (7 min)

[0993] Flow rate: 0.5 mL / min

[0994] Column temperature: Off

[0995] Detection wavelength: 210 nm to 400 nm (PDA)

[0996] LCMS Analysis Conditions and Methods 4

[0997] Equipment: Waters UPLC / SQD

[0998] Column: ACQUITY UPLC BEH C18 column, 2.1 mm ID × 50 mm, 1.7 μm

[0999] Mobile phase: 0.1% FA / water (A), 0.1% FA / MeCN (B)

[1000] Elution method: B) 5% (0 min) → 98% (8 min) → 98% (10 min) → 5% (10.01 min) → 5% (12 min)

[1001] Flow rate: 0.5 mL / min

[1002] Column temperature: 60°C

[1003] Detection wavelength: 210 nm to 400 nm (PDA)

[1004] LCMS Analysis Conditions and Methods 5

[1005] Equipment: Waters UPLC / SQD

[1006] Column: Ascentis Express C18 2.1 × 50 mm, 5 μm

[1007] Mobile phase: 10 mM ammonium acetate (A) and MeOH (B) in water.

[1008] Elution method: B) 50% (0 min) → 100% (1 min) → 100% (1.99 min) → 50% (2.01 min) → 50% (2.5 min)

[1009] Flow rate: 1.0 mL / min

[1010] Column temperature: 35°C

[1011] Detection wavelength: 210 nm to 400 nm (PDA)

[1012] LCMS Analysis Conditions and Methods M

[1013] Equipment: Waters Acquity UPLC / QDa

[1014] Column: Ascentis Express 90A C18, 2.1 mm ID × 50 mm, 2.7 μm

[1015] Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[1016] Elution method: B) 5% (0 min) → 100% (5 min) → 5% (5.01 min) → 5% (7 min)

[1017] Flow rate: 0.5 mL / min

[1018] Column temperature: 35°C

[1019] Detection wavelength: 210 nm (PDA)

[1020] LCMS Analysis Conditions and Methods K-1

[1021] Equipment: Waters Acquity UPLC / QDa

[1022] Column: CAPCELL CORE ADME, 2.1 mm × 50 mm, 2.7 μm (Osaka Soda)

[1023] Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[1024] Elution method: B) 5% (0 min) → 100% (10 min) → 5% (10.1 min) → 5% (12 min)

[1025] Flow rate: 0.5 mL / min

[1026] Column temperature: 35°C

[1027] Detection wavelength: 210 nm (PDA)

[1028] LCMS Analysis Conditions and Methods K-2

[1029] Equipment: Waters Acquity UPLC / QDa

[1030] Column: CAPCELL CORE ADME, 2.1 mm × 50 mm, 2.7 μm (Osaka Soda)

[1031] Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[1032] Elution method: B) 5% (0 min) → 100% (5 min) → 5% (5.1 min) → 5% (7 min)

[1033] Flow rate: 0.5 mL / min

[1034] Column temperature: 35°C

[1035] Detection wavelength: 210 nm (PDA)

[1036] LCMS Analysis Conditions and Methods (P3-4)

[1037] Equipment: Waters Acquity UPLC / QDa

[1038] Column: Ascentis Express 90A C18, 2.1 mm ID × 50 mm, 2.7 μm

[1039] Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[1040] Elution method: B) 5% (0 min) → 100% (5 min) → 5% (5.01 min) → 5% (7 min)

[1041] Flow rate: 0.5 mL / min

[1042] Column temperature: 35°C

[1043] Detection wavelength: 210 nm (PDA)

[1044] LCMS Analysis Conditions and Methods FC 2

[1045] Equipment: Waters UPLC

[1046] Column: ACQUITY UPLC CSH C18, 2.1 mm ID × 100 mm, 1.7 μm

[1047] Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[1048] Elution method: B) 20% (0 min) → 100% (10 min) → 100% (13.5 min) → 20% (13.6 min) → 20% (15.5 min)

[1049] Flow rate: 0.3 mL / min

[1050] Column temperature: 50°C

[1051] Detection wavelength: 210 nm (PDA)

[1052] LC analysis conditions and methods cyc

[1053] Equipment: Waters UPLC

[1054] Column: ACQUITY UPLC CSH phenyl-hexyl, 2.1 mm ID × 150 mm, 1.7 μm

[1055] Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[1056] Elution method: B) 20% (0 min) → 100% (24 min) → 100% (29 min) → 20% (29.1 min) → 20% (34 min)

[1057] Flow rate: 0.3 mL / min

[1058] Column temperature: 50°C

[1059] Detection wavelength: 220 nm (PDA)

[1060] LC analysis conditions and methods H

[1061] Equipment: Waters UPLC

[1062] Column: Ascentis Express RP-amide, 3.0 mm ID × 50 mm ×, 2.7 μm

[1063] Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[1064] Elution method: B) 5% (0 min) → 95% (10.0 min) → 95% (12.0 min) → 5% (12.1 min) → 5% (15.0 min)

[1065] Flow rate: 0.7 mL / min

[1066] Column temperature: 30°C

[1067] Detection wavelength: 210 nm (PDA)

[1068] The HPLC analysis conditions are shown below.

[1069] HPLC Analytical Conditions and Methods 1

[1070] Equipment: Waters Class H

[1071] Column: ACQUITY UPLC BEH C18 column, 2.1 mm ID × 50 mm, 1.7 μm

[1072] Mobile phase: 0.1% FA / water (A), 0.1% FA / MeCN (B)

[1073] Elution method: B) 5% (0 min) → 98% (4.0 min) → 98% (6.0 min) → 5% (6.01 min) → 5% (8 min)

[1074] Flow rate: 0.5 mL / min

[1075] Column temperature: 60°C

[1076] Detection wavelength: 210 nm (PDA)

[1077] The qNMR measurement method involves dissolving the residue containing the target compound and an internal standard in CDCl3 or DMSO-d6 and placing them under the following analytical conditions. The yield is calculated using the concentration of the target compound in the residue, determined by qNMR or HPLC, according to the following expression.

[1078] [Expression 1]

[1079]

[1080] Measuring instrument: Bruker Avance III 400

[1081] Internal standard: 3,5-bis(trifluoromethyl)benzoic acid

[1082] Measurement conditions ( 19 F-NMR: CDCl3 or DMSO-d6, 24.8℃, pulse angle 90°, digital resolution 0.24Hz, relaxation time 15 seconds, no rotation, total number of cycles 64

[1083] Measuring instrument: JEOL JNM-ECZ500R / S1

[1084] Measurement conditions ( 1H-NMR: Methanol-d4, 25.3℃, pulse angle 45°, digital resolution 0.76 Hz, relaxation time 5 seconds, rotation present, total number of times 8

[1085] The measurements by LCMS, LC and HPLC are performed by preparing a mixed solution containing the target compound as a sample according to any of the following methods and placing it under the analytical conditions described above.

[1086] Sample preparation method 1: Dilute the mixed solution containing the target compound with acetonitrile.

[1087] Sample preparation method 2: Dilute the mixed solution containing the target compound with a mixed solution of acetonitrile and water at a ratio of 9:1.

[1088] Sample preparation method K: Dilute the mixed solution containing the target compound with a mixed solution of acetonitrile and n-propylamine at a ratio of 100:1.

[1089] The reaction conversion rate is calculated using any of the following expressions, employing the area values ​​of the original material and the target material calculated by HPLC analysis, or the area values ​​of the original material, the area values ​​of the original material and the target material, or the area values ​​of the original material before and after the reaction.

[1090] Expression 1: Reaction conversion rate (%) = Area of ​​target material / (Area of ​​original material + Area of ​​target material) × 100

[1091] Expression 2: Reaction conversion rate (%) = 100 - (Area value of the original material after reaction / Area value of the original material before reaction × 100)

[1092] The cyclization selectivity (compound 1 / cyclic dimer) is calculated using the area values ​​of the target material and the cyclic dimer calculated by HPLC analysis, as expressed by the following expression.

[1093] Expression 1: Compound 1 ratio (%) = Area of ​​Compound 1 / (Area of ​​Compound 1 + Area of ​​cyclic dimer) × 100

[1094] Expression 2: Cyclic dimer ratio (%) = Area of ​​cyclic dimer / (Area of ​​compound 1 + Area of ​​cyclic dimer) × 100

[1095] Example 1-1

[1096] Synthesis of Compound 2: (4S)-5-oxo-4-[[4-(trifluoromethyl)phenyl]methyl]oxazolidine-3-carboxylic acid 9H-fluorene-9-ylmethyl ester

[1097] [Formula 44]

[1098]

[1099] DCM (45 L) and (2S)-2-{[(9H-fluorene-9-ylmethoxy)carbonyl]amino}-3-[4-(trifluoromethyl)phenyl]propionic acid (3.05 kg) were added to a reaction vessel purged with nitrogen at room temperature, and the mixture was stirred. Paraformaldehyde (0.90 kg) and MgSO4 (2.02 kg) were then added, and the mixture was stirred at 20 °C for 10 min. The external temperature of the reaction vessel was cooled to 15 °C, and BF3OEt2 (0.95 kg) was slowly added dropwise at an internal temperature of 15 °C to 20 °C. The reaction mixture was stirred at 20 °C to 25 °C for 12 h, then filtered through a silica gel-lined filter (3.05 kg) and washed with DCM (15.3 L × 2). The filtrate was concentrated under reduced pressure at an external temperature of 30°C, and the crude product containing compound 2 was purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) and concentrated under reduced pressure to obtain compound 2 (2.76 kg).

[1100] Example 1-2

[1101] Synthesis of Compound 3: (2S)-2-[but-3-enyl(9H-fluorene-9-ylmethoxycarbonyl)amino]-3-[4-(tri-] [Fluoromethyl]phenyl]propionic acid

[1102] [Formula 45]

[1103]

[1104] Toluene (22.4 L) and compound 2 (2.80 kg) were added to a nitrogen-purged reaction vessel at room temperature, and the mixture was stirred. Allyltrimethylsilane (1.37 kg) and ZnBr2 (1.35 kg) were then added, and the mixture was stirred at 20 °C for 10 minutes. The internal temperature of the reaction vessel was raised to 40 °C to 45 °C, and the reaction mixture was stirred for 10 hours. The reaction mixture was added to ice water (28.0 L) at an internal temperature of 10 °C ± 5 °C and stirred. The aqueous layer was drained, and the organic layer was washed with 5% brine (28.0 L). The resulting organic layer was concentrated under reduced pressure at an external temperature of 45 °C to 50 °C to obtain compound 3 (2.44 kg).

[1105] Example 1-3

[1106] Synthesis of Compound 4: 2-[[(2S)-2-[but-3-enyl(9H-fluorene-9-ylmethoxycarbonyl)amino]-3- [4-(trifluoromethyl)phenyl]propionyl]-methyl-amino]tert-butyl acetate

[1107] [Formula 46]

[1108]

[1109] N-methyl-2-pyrrolidone (17.0 L) and compound 3 (2.44 kg) were added to a nitrogen-purged reaction vessel at room temperature, and the mixture was stirred. Subsequently, sarcosine tert-butyl hydrochloride (0.87 kg) and HATU (2.18 kg) were added at 20 °C, and the mixture was stirred for 30 min. DIPEA (1.85 kg) was added dropwise over 60 min at an internal temperature of 15 °C to 20 °C. The reaction mixture was stirred at 20 °C to 25 °C for 3 h and then diluted with methyl tert-butyl ether (48.8 L). The organic layer was washed with water (48.8 L × 2) and 5% brine (24.4 L), and then concentrated under reduced pressure to obtain a crude product containing compound 4. The resulting crude product was column purified (petroleum ether / ethyl acetate = 4 / 1) and concentrated under reduced pressure at 35 °C to obtain compound 4 (2.79 kg), a deep yellow oil.

[1110] Examples 1-4

[1111] Synthesis of Compound 5: 2-[[(2S)-2-(but-3-enylamino)-3-[4-(trifluoromethyl)phenyl]propionyl tert-butyl [-methyl-amino]acetate

[1112] [Formula 47]

[1113]

[1114] Toluene (28.0 L) and compound 4 (2.79 kg) were added to a nitrogen-purged reaction vessel at room temperature, and the mixture was stirred. DBU (0.67 kg) was then added at an internal temperature of 20 °C, and the mixture was stirred for 2 hours. The reaction mixture was added to ice water (27.9 L) at an internal temperature of 20 °C ± 5 °C and stirred. After stirring and the addition of ethyl acetate (14.0 L), the aqueous layer was drained. The organic layer was washed with 5% brine (28.0 L) and concentrated under reduced pressure at 45 ± 5 °C. The crude product containing compound 5 was subjected to column purification (petroleum ether / ethyl acetate = 4 / 1) and then concentrated under reduced pressure to obtain compound 5 (1.49 kg) as a pale yellow oil.

[1115] Examples 1-5

[1116] Synthesis of Compound 6: N-[(1S)-1-chlorocarbonylbut-3-enyl]-N-methylcarbamate 9H-fluorene-9-yl Methyl ester

[1117] [Formula 48]

[1118]

[1119] DCM (10 L), (2S)-2-[9H-fluorene-9-ylmethoxycarbonyl(methyl)amino]pent-4-enoic acid (1.7 kg), and DMF (0.02 kg) were added to a nitrogen-purged reaction vessel at an internal temperature of 20 °C, and the mixture was stirred. Oxaloyl chloride (1.84 kg) was added at an internal temperature of 10 °C for 2 hours, and the mixture was stirred for another 2 hours while maintaining the internal temperature at 10 °C. The resulting solution was concentrated under reduced pressure at 30 °C to 35 °C. The concentrated product was then added to DCM (3.4 L) and concentrated under reduced pressure twice to obtain compound 6 (1.65 kg), which was a yellow oil.

[1120] Examples 1-6

[1121] Synthesis of compound 7: 2-[[(2S)-2-[but-3-enyl-[(2S)-2-[9H-fluorene-9-ylmethoxycarbonyl] [(methyl)amino]pent-4-enoyl]amino]-3-[4-(trifluoromethyl)phenyl]propionyl]-methyl-amino]tert-butyl acetate

[1122] [Formula 49]

[1123]

[1124] DCM (15.0 L) and compound 5 (1.49 kg) were added to a reaction vessel purged with nitrogen at room temperature, and the mixture was stirred. Then, compound 6 (1.72 kg) dissolved in DCM (2.96 L) was added over 1 hour at an internal temperature of 0–10 °C. The mixture was stirred at an internal temperature of 10 °C for 30 minutes, followed by dropwise addition of DIPEA (0.926 kg) over 1 hour at an internal temperature of 0–10 °C. After stirring at 20 °C for 2 hours, the reaction solution was added to ice water (14.8 L) at an internal temperature of 20 °C and stirred. Organic layer 1 was obtained by liquid-liquid separation. The aqueous layer was extracted with DCM (7.4 L) and combined with the obtained organic layer 1. The combined organic layers were washed with 5% brine (14.9 L × 2) and concentrated under reduced pressure at 30 °C ± 5 °C. The concentrated product containing compound 7 was subjected to column purification (petroleum ether / ethyl acetate = 5 / 1) and concentrated under reduced pressure to obtain compound 7 as a colorless powder (1.97 kg).

[1125] Examples 1-7

[1126] Synthesis of Compound 8: 2-[[(2S)-2-[(4Z,7S)-7-[9H-fluorene-9-ylmethoxycarbonyl(methyl)amino] [1-8-oxo-2,3,6,7-tetrahydroazacyclooctatetraen-1-yl]-3-[4-(trifluoromethyl)phenyl]propionyl]-methyl-amino [Bacillus] tert-butyl acetate

[1127] [Formula 50]

[1128]

[1129] Toluene (59.0 L) and compound 7 (0.655 kg) were added to a nitrogen-purged reaction vessel at room temperature, and the mixture was stirred. Then, p-benzoquinone (28.4 g) was added, and the internal temperature was increased to 100 °C. After 20 minutes, a solution of first-generation HOVEYDA-GRUBBS catalyst (42.0 g) in toluene (100 mL) was added dropwise to the mixture, which had been heated to 100 °C. The above reaction was repeated in three batches. The resulting solutions from the three batches were mixed and concentrated under reduced pressure at 45 °C. The crude product containing compound 8 was column purified (petroleum ether / ethyl acetate = 4 / 1) and concentrated under reduced pressure to obtain compound 8 (1.05 kg) as a yellow oil.

[1130] Examples 1-8

[1131] Synthesis of Compound 9: 2-[methyl-[(2S)-2-[(4Z,7S)-7-(methylamino)-8-oxo-2,3,6,7-] Tetrahydroazacyclooctatetraen-1-yl]-3-[4-(trifluoromethyl)phenyl]propionyl]amino]tert-butyl acetate

[1132] [Formula 51]

[1133]

[1134] Toluene (11.0 L) and compound 8 (1.05 kg) were added to a nitrogen-purged reaction vessel at room temperature, and the mixture was stirred. DBU (223 g) was then added to the mixture at 10 °C, and the mixture was stirred at an internal temperature of 20 °C for 2 hours. The resulting solution was added to ice water (11.0 L) at 10 °C ± 5 °C and stirred. The mixture was extracted with ethyl acetate (5.25 L). The organic layer was washed with 5% brine (5.25 L) and concentrated to approximately 1.1 L under reduced pressure at 40 °C. Toluene (9.5 L) and a 1M potassium dihydrogen phosphate aqueous solution (6.3 L) were added to the concentrated solution, and the mixture was stirred at 20 °C for 3 hours. The resulting solution was filtered, and the filtrate was washed with a toluene / n-heptane mixture of 1 / 1 (11.0 L). Ethanol (31.5 L) was added to the resulting filtrate, and the mixture was heated to 40 °C to dissolve it. D(-)-tartaric acid (215 g) was added, and the mixture was stirred at 20 °C for 3 hours to obtain a precipitate. The resulting precipitate was filtered and washed with n-heptane (3.15 L × 2). The washed precipitate was transferred to a reaction vessel, to which 1 M tripotassium phosphate aqueous solution was added, and the pH was adjusted to 7 to 8. The mixture was extracted with DCM (10.5 L). The organic layer was washed with 5% brine (5.25 L), and the resulting solution was concentrated to about 0.5 L under reduced pressure at 40 °C. n-Heptane (10.5 L) was added to the concentrated solution to obtain a precipitate. The resulting precipitate was filtered and washed with n-heptane (3.15 L). The resulting residue was dried under reduced pressure to obtain compound 9 (449 g) as a colorless solid.

[1135] LCMS (ESI) of compound 9: Retention time: 1.24 min, m / z = 498 [M+H] + (LCMS Analysis Conditions and Methods 1)

[1136] Examples 1-9

[1137] Synthesis of Compound 10: (2S)-1-[(2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoyl] tert-butyl pyrrolidine-2-carboxylate

[1138] [Equation 52]

[1139]

[1140] (2S)-pyrrolidine-2-carboxylic acid tert-butyl ester (18.8 g), (2S,3S)-2-(benzyloxycarbonylamino)-3-methylvaleric acid (20.0 g), and DMF (140 mL) were added to the reaction vessel after purging with nitrogen at room temperature, and the mixture was stirred. The resulting solution was cooled to 0°C and DIPEA (52.7 mL) was added. A solution of 50 wt.% propylphosphonic anhydride in ethyl acetate (58.3 mL) was added to the mixture at 0°C for 20 minutes, and the mixture was stirred at 0°C for 1.5 hours. Water (100 mL) and ethyl acetate (200 mL) were added to the mixture in this order. The aqueous layer 1 and organic layer 1 were separated by liquid-liquid separation, and the aqueous layer 1 was separated. Organic layer 1 was washed with 5% potassium bisulfate aqueous solution (100 mL), 5% sodium carbonate aqueous solution (100 mL), and 10% brine (100 mL). Water (100 mL) and ethyl acetate (200 mL) were added to the separated aqueous layer 1, and organic layer 2 was obtained by liquid-liquid separation after stirring. Organic layers 1 and 2 were combined and concentrated under reduced pressure to obtain compound 10 (33.8 g).

[1141] LCMS (ESI) of compound 10: Retention time: 2.75 min, m / z = 419 [M+H] + (LCMS Analysis Conditions and Methods 2)

[1142] Example 1-10

[1143] Synthesis of Compound 11: (2S)-1-[(2S,3S)-2-amino-3-methyl-pentanoyl]pyrrolidine-2-carboxylic acid tert- Butyl acetate

[1144] [Formula 53]

[1145]

[1146] In a nitrogen-purged reaction vessel, a solution of compound 10 (31.6 g) obtained in Examples 1-9 in 2-MeTHF (221 mL) was cooled to 10 °C. 5% Pd / C (6.32 g, 50% water content) was added to the solution, followed by the addition of triethylsilane (60.3 mL) over 20 minutes. The resulting mixture was stirred at an internal temperature of 15 °C for 6 hours, and then further stirred at room temperature for 17 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 11. Compound 11 was used in Examples 1-11 without further purification.

[1147] LCMS (ESI) of compound 11: Retention time: 1.14 min, m / z = 285 [M+H] + (LCMS Analysis Conditions and Methods 2)

[1148] Example 1-11

[1149] Synthesis of Compound 12: (2S)-1-[(2S,3S)-2-[[(2S)-2-[9H-fluorene-9-ylmethoxycarbonyl(methyl)] [3-methyl-valeryl]pyrrolidine-2-carboxylic acid tert-butyl ester

[1150] [Formula 54]

[1151]

[1152] (2S)-2-[9H-fluorene-9-ylmethoxycarbonyl(methyl)amino]valeric acid (28.0 g) and DIPEA (39.6 mL) were added to a solution (221 mL) of compound 11 obtained in Examples 1-10 at 5 °C. HATU (34.5 g) was slowly added to the mixture at 2.5 °C, and the resulting solution was stirred at 2.5 °C for 1 hour, and then stirred at room temperature for 2.5 hours. 5% aqueous sodium carbonate solution (189 mL) and water (150 mL) were added to the mixture in this order. The resulting solution was extracted with toluene (80 mL) and 2-MeTHF (140 mL). The organic layer was washed with 5% potassium hydrogen sulfate solution (190 mL × 2) and 10% brine (190 mL × 2). The resulting organic layer was concentrated under reduced pressure to obtain compound 12. Compound 12 was used in Examples 1-12 without further purification.

[1153] LCMS (ESI) of compound 12: Retention time: 3.43 min, m / z = 620 [M+H] + (LCMS Analysis Conditions and Methods 2)

[1154] Example 1-12

[1155] Synthesis of compound 13: (2S)-1-[(2S,3S)-3-methyl-2-[[(2S)-2-(methylamino)pentanoyl] [Amino]valeryl]pyrrolidine-2-acetic acid tert-butyl ester

[1156] [Formula 55]

[1157]

[1158] Compound 12 (296 mg), synthesized by the same method as in Examples 1-11, and toluene (2.07 mL) were added to the nitrogen-purged reaction vessel, and the mixture was stirred. DBU (0.072 mL) was added to the mixture, and the mixture was stirred for 30 minutes. Acetonitrile (1.00 mL) was added to the mixture, and the mixture was stirred for 30 minutes. DBU (0.072 mL) was added, and the mixture was stirred for another 30 minutes. After adding 1N hydrochloric acid (2.00 mL) and n-heptane (1.00 mL), the aqueous layer 1 and organic layer 1 were separated. Organic layer 1 was extracted with 1N hydrochloric acid (1.00 mL) to obtain aqueous layer 2 containing compound 13. Aqueous layers 1 and 2 were combined, extracted with 5% potassium carbonate aqueous solution (2.00 mL) and toluene (4.00 mL), and the organic layer containing compound 13 was separated. The resulting organic layer was washed with 10% brine (2.00 mL) and then concentrated under reduced pressure to obtain compound 13 (166 mg).

[1159] LCMS (ESI) of compound 13: Retention time: 1.36 min, m / z = 398 [M+H] + (LCMS Analysis Conditions and Methods 2)

[1160] Example 1-13

[1161] Synthesis of Compound 14-Resin

[1162] Compound 14: (3S)-4-(dimethylamino)-3-[9H-fluorene-9-ylmethoxycarbonyl(methyl)amino]-4-oxo butyric acid

[1163] [Formula 56]

[1164]

[1165] 2-Chlorotriphenylmethyl chloride resin (1.12 mmol / g, 70 g, 78.4 mmol) and DCM (560 mL) were added to a reaction vessel equipped with a filter (1 L), and the mixture was allowed to stand at room temperature for 30 min. After filtering the DCM under reduced pressure, a solution of (3S)-4-(dimethylamino)-3-[9H-fluorene-9-ylmethoxycarbonyl(methyl)amino]-4-oxy-butyric acid (23.4 g, 56.0 mmol) in DCM (140 mL) was added, and the mixture was washed with another 140 mL of DCM. DIPEA (27.4 mL) was added to the reaction vessel, and after stirring for 45 min, DCM (140 mL) was added, and the mixture was stirred at room temperature for 105 min. The reaction solution was filtered under reduced pressure and subsequently washed with DCM (280 mL × 2). A solution of methanol (28.0 mL) and DIPEA (14.0 mL) in DMF (238 mL) was added to the reaction vessel, and the mixture was stirred at room temperature for 120 minutes. After filtering the reaction solution under reduced pressure, IPA (280 mL) was added, and the mixture was stirred. After 15 minutes, the reaction solution was filtered under reduced pressure, DMF (280 mL) was added, and the mixture was stirred for 15 minutes. After filtering the reaction solution under reduced pressure, Examples 1-14 were continued using the full amount of Compound 14-Resin (excluding the portion used to measure the loading).

[1166] The amount of amino acids loaded on the resin was calculated as follows. The resulting compound 14-resin (4.76 mg) was placed in a reaction vessel, 20% Pip / DMF solution (50 mL) was added, and the mixture was shaken at room temperature for 1 hour. The absorbance of the solution (301 nm) was measured using a Shimadzu UV-1600 PC (cell length: 1.0 cm), and the loading amount of compound 14-resin was calculated to be 0.632 mmol / g.

[1167] Example 1-14

[1168] Synthesis of Compound 15 - Resin

[1169] Compound 15: (3S)-3-[[(2S)-2-cyclopentyl-2-[9H-fluorene-9-ylmethoxycarbonyl(methyl)amino]ethyl [Acyl]-methyl-amino]-4-(dimethylamino)-4-oxo-butyric acid

[1170] [Formula 57]

[1171]

[1172] Compound 14-resin (0.632 mmol / g) was charged into a reaction vessel equipped with a filter (1 L), and 20% Pip / DMF solution (280 mL) was added. The mixture was stirred at room temperature for 10 min to carry out the de-Fmoc reaction. The reaction solution was filtered under reduced pressure, and 20% Pip / DMF solution (280 mL) was added again. The mixture was stirred at room temperature for 10 min to carry out the de-Fmoc reaction. The reaction mixture was filtered under reduced pressure, and the resin was washed 10 times with DMF (280 mL). The condensation reaction of Fmoc-MeGly(cPent)-OH (CAS No. 187475-29-2) was carried out on the resulting resin. The condensation reaction was carried out by adding a solution of Fmoc-MeGly(cPent)-OH (Cas No. 187475-29-2, 42.5 g), oxyma (7.96 g), and DIC (34.9 mL) in DMF (280 mL) to the resin, stirring the mixture for 5 minutes, and allowing it to stand at room temperature for 16 hours. The condensation reaction solution was filtered under reduced pressure, loaded into IPA (280 mL), and the mixture was stirred. After 10 minutes, the reaction solution was filtered under reduced pressure, DMF (280 mL) was added, and the mixture was stirred for 10 minutes. After filtering the reaction solution under reduced pressure, Examples 1-15 were continued using the full amount of Compound 15-resin (excluding the portion used to measure the loading).

[1173] The amount of amino acids loaded on the resin was calculated as follows. The resulting compound 15-resin (4.91 mg) was placed in a reaction vessel, 20% Pip / DMF solution (50 mL) was added, and the mixture was shaken at room temperature for 1 hour. The absorbance of the solution (301 nm) was measured using a Shimadzu UV-1600 PC (cell length: 1.0 cm), and the loading amount of compound 15-resin was calculated to be 0.635 mmol / g.

[1174] Using a small amount of compound 15 loaded on the resin, the compound was excised from the resin by TFE / DCM (1 / 1) and the structure was confirmed by LC / MS.

[1175] LCMS (ESI) of compound 15: Retention time: 2.53 min, m / z = 536 [M+H] + (LCMS Analysis Conditions and Methods 2)

[1176] Example 1-15

[1177] Synthesis of Compound 16-Resin

[1178] Compound 16: (3S)-3-[[(2S)-2-cyclopentyl-2-[[1-[9H-fluorene-9-ylmethoxycarbonyl(methyl)amino [Cyclobutanecarbonyl]-methyl-amino]acetyl]-methyl-amino]-4-(dimethylamino)-4-oxo-butyric acid

[1179] [Formula 58]

[1180]

[1181] Compound 15-resin (0.635 mmol / g) was loaded into a reaction vessel equipped with a filter (1 L), and 20% Pip / DMF solution (280 mL) was added. The mixture was stirred at room temperature for 5 minutes to carry out the de-Fmoc reaction. After filtering the reaction solution under reduced pressure, 20% Pip / DMF solution (280 mL) was added again, and the mixture was stirred at room temperature for 5 minutes to carry out the de-Fmoc reaction. The reaction solution was filtered under reduced pressure, and the resin was then washed 10 times with DMF (280 mL). The condensation reaction of Fmoc-MecVal-OH (CAS No. 1700368-07-5) was carried out on the resulting resin. The condensation reaction was carried out by adding a solution of Fmoc-MecVal-OH (CAS No. 1700368-07-5, 39.4 g) and oxyma (7.96 g) in DMF (280 mL), followed by the addition of DIC (34.9 mL), stirring the mixture for 5 minutes, and then allowing it to stand for 94 hours. After filtering the condensation reaction solution under reduced pressure, the resin was washed with each of DMF (280 mL), IPA (280 mL), and DMF (280 mL). After filtering the washing solution under reduced pressure, the entire amount of the resulting compound 16-resin (excluding the portion used to measure the loading) was used to continue in Examples 1-17.

[1182] The amount of amino acids loaded on the resin was calculated as follows. The resulting compound 16-resin (5.24 mg) was placed in a reaction vessel, 20% Pip / DMF solution (50 mL) was added, and the mixture was shaken at room temperature for 1 hour. The absorbance of the solution (301 nm) was measured (using a Shimadzu UV-1600 PC (cell length: 1.0 cm)), and the loading on the compound 16-resin was calculated to be 0.513 mmol / g.

[1183] Using a small amount of compound 16 loaded on the resin, the compound was excised from the resin by TFE / DCM (1 / 1) and the structure was confirmed by LC / MS.

[1184] LCMS (ESI) of compound 16: Retention time: 2.75 min, m / z = 647 [M+H] + (LCMS Analysis Conditions and Methods 2)

[1185] Example 1-16

[1186] Synthesis of Compound 17: (2S,4R)-2-chlorocarbonyl-4-ethoxy-pyrrolidine-1-carboxylic acid 9H-fluorene-9-ylmethyl ester

[1187] [Formula 59]

[1188]

[1189] In a reaction vessel purged with nitrogen at room temperature, (2S,4R)-4-ethoxy-1-(9H-fluorene-9-ylmethoxycarbonyl)pyrrolidine-2-carboxylic acid (Cas No. 1446478-31-4, 42.7 g), toluene (128 mL), and thionyl chloride (12.3 mL) were added sequentially. After stirring at an external temperature of 60 °C for 0.5 hours, the mixture was stirred at an external temperature of 55 °C for 3 hours. A portion of the reaction mixture was sampled and diluted in MeOH, and allowed to stand for 5 minutes to convert to the corresponding compound 18. The conversion to compound 17 was thus confirmed by HPLC analysis to be 99.9% (equation 1 for conversion calculation). The external temperature of the reaction vessel was set to 40 °C, and the reaction solution was concentrated under reduced pressure. After concentration under reduced pressure, the addition of DCM (214 mL) and concentration under reduced pressure were repeated twice. The resulting concentrated solution was dried overnight under reduced pressure to obtain a crude product containing compound 17 (45.5 g, 95% yield).

[1190] Compound 18: (2S,4R)-4-ethoxypyrrolidine-1,2-dicarboxylic acid O1-(9H-fluorene-9-ylmethyl ester)O2-methyl ester

[1191] [Formula 60]

[1192]

[1193] LCMS (ESI) of compound 18: Retention time: 2.68 min, m / z = 396 [M+H] + (LCMS Analysis Conditions and Methods 2)

[1194] Example 1-17

[1195] Synthesis of Compound 19-Resin

[1196] Compound 19: (3S)-3-[[(2S)-2-cyclopentyl-2-[[1-[[(2S,4R)-4-ethoxy-1-(9H-fluorene-9- [[methyl-amino]cyclobutane][[methyl-amino]acetyl][[methyl-amino]] ]-4-(dimethylamino)-4-oxo-butyric acid

[1197] [Formula 61]

[1198]

[1199] Compound 16-resin (0.513 mmol / g) was loaded into a reaction vessel equipped with a filter (1 L) and swollen with DMF (280 mL) for 15 minutes, the solution being drained twice. A 20% Pip / DMF solution (280 mL) was added to the swollen resin, and the mixture was stirred at room temperature for 15 minutes to carry out the de-Fmoc reaction. After filtering the reaction solution under reduced pressure, another 20% Pip / DMF solution (280 mL) was added, and the mixture was stirred at room temperature for 15 minutes to carry out the de-Fmoc reaction. The reaction solution was filtered under reduced pressure, and the resin was then washed 13 times with DCM (280 mL). The condensation reaction of compound 17 was carried out on the resulting resin. The condensation reaction was carried out by sequentially adding a DCM solution (280 mL) of compound 17 (46.0 g) obtained in Examples 1-16 and trimethylpyridine (74.0 mL), stirring the mixture for 5 minutes, and allowing it to stand at room temperature for 4 hours. After filtering the condensation reaction solution under reduced pressure, the resin was washed with DCM (280 mL), and the entire amount of the resulting compound 19-resin (excluding the portion used to measure the loading) was used to continue with Examples 1-18.

[1200] The amount of amino acids loaded on the resin was calculated as follows. The resulting compound 17-resin (7.27 mg) was placed in a reaction vessel, 20% Pip / DMF solution (50 mL) was added, and the mixture was shaken at room temperature for 1 hour. The absorbance of the solution was measured (301 nm) using a Shimadzu UV-1600 PC (cell length: 1.0 cm), and the loading of compound 19-resin was calculated to be 0.473 mmol / g.

[1201] Using a small amount of compound 19 loaded on the resin, the compound was excised from the resin by TFE / DCM (1 / 1) and the structure was confirmed by LC / MS.

[1202] LCMS (ESI) of compound 17: Retention time: 2.68 min, m / z = 788 [M+H] + (LCMS Analysis Conditions and Methods 2)

[1203] Example 1-18

[1204] Synthesis of Compound 20-Resin

[1205] Compound 20: (3S)-3-[[(2S)-2-[[1-[[(2S,4R)-1-[(2S)-2-(benzyloxycarbonylamino)- 4-[3-methoxy-4-(trifluoromethyl)phenyl]butyryl]-4-ethoxy-pyrrolidine-2-carbonyl]-methyl-amino]cyclobutane [carbonyl]-methyl-amino]-2-cyclopentyl-acetyl]-methyl-amino]-4-(dimethylamino)-4-oxo-butyric acid

[1206] [Formula 62]

[1207]

[1208] Compound 19-resin (0.473 mmol / g) was loaded into a reaction vessel equipped with a filter (1 L) and swollen with DMF (280 mL) for 15 minutes. The solution was drained twice. 20% Pip / DMF solution (280 mL) was added to the swollen resin, and the mixture was shaken at room temperature for 15 minutes to carry out the de-Fmoc reaction. After filtering the reaction solution under reduced pressure, 20% Pip / DMF solution (280 mL) was added again, and the mixture was shaken at room temperature for 15 minutes to carry out the de-Fmoc reaction. The reaction solution was filtered under reduced pressure, and the resin was then washed 13 times with DMF (280 mL). The condensation reaction of Cbz-Hph(4-CF3-3-OMe)-OH was carried out on the resulting resin. The condensation reaction was carried out by adding a solution of Cbz-Hph(4-CF3-3-OMe)-OH (46.1 g) and oxyma (7.96 g) in DMF (280 mL) and DIC (34.9 mL), stirring the mixture for 5 minutes, and then allowing it to stand for 3.5 hours. The condensation reaction solution was filtered under reduced pressure, and the resin was then washed twice with DMF (280 mL). IPA (280 mL) was added, and the mixture was stirred for 15 minutes. After draining the solution, DCM (280 mL) was added, and the mixture was stirred for 15 minutes. The washing with IPA (280 mL) and DCM (280 mL) and draining the solution were repeated again. After washing with IPA (280 mL × 3), the resin was dried under reduced pressure. After drying under reduced pressure, the resulting compound 20-resin weighed 122 g.

[1209] Using a small amount of compound 20 loaded on the resin, the compound was excised from the resin by TFE / DCM (1 / 1) and the structure was confirmed by LC / MS.

[1210] LCMS (ESI) of compound 20: Retention time: 2.91 min, m / z = 960 [M+H] + (LCMS Analysis Conditions and Methods 2)

[1211] Example 1-19

[1212] Synthesis of Compound 20

[1213] [Formula 63]

[1214]

[1215] Compound 20-resin (60.0 g), obtained by the same method as compound 20-resin (122 g) obtained in Examples 1-18, and 2-MeTHF (1.10 L) were added sequentially to a reaction vessel purged with nitrogen at room temperature. The external temperature of the reaction vessel was set to 0 °C, and hexamethyldisilazane (77.3 mL) was added. After stirring for 20 min, trimethylsilane trifluoromethanesulfonate (50.0 mL) was added to bring the internal temperature below 7 °C. Twenty min after the addition was complete, the reaction mixture was filtered under reduced pressure, and the residue was washed with 2-MeTHF (364 mL × 3). The filtrate was washed with 5% disodium hydrogen phosphate aqueous solution (1.10 L), 5% potassium hydrogen sulfate aqueous solution (1.10 L), and 5% sodium chloride aqueous solution (1.10 L). The resulting organic layer was concentrated under reduced pressure to obtain 77.6 g of crude product. A portion of the obtained crude product and 3,5-bis(trifluoromethyl)benzoic acid were dissolved in CDCl3 and analyzed by qNMR. After content correction, the content of compound 20 was calculated to be 69.0 g.

[1216] LCMS (ESI) of compound 20: Retention time: 3.90 min, m / z = 960 [M+H] + (LCMS Analysis Conditions and Methods 3)

[1217] Example 1-20

[1218] Synthesis of compound 21: (2S)-1-[(2S,3S)-2-[[(2S)-2-[[(3S)-3-[[(2S)-2-[[1- [[(2S,4R)-1-[(2S)-2-benzyloxycarbonylamino)-4-[3-methoxy-4-(trifluoromethyl)phenyl]butyryl]-4- [ethoxy-pyrrolidine-2-carbonyl]-methyl-amino]cyclobutanecarbonyl]-methyl-amino]-2-cyclopentyl-acetyl]-methyl- [amino]-4-(dimethylamino)-4-oxo-butyryl]-methyl-amino]valeryl]amino]-3-methyl-valeryl]pyrrole tert-butyl alkyl-2-carboxylate

[1219] [Formula 64]

[1220]

[1221] The crude product containing compound 20 (80.7 g) and compound 13 (45.8 g) were added to the reaction vessel. After purging with nitrogen, 2-MeTHF (484 mL), DIPEA (64.5 mL), and DMF (121 mL) were added at room temperature, and the mixture was stirred. HATU (48.0 g) was added to the resulting solution at room temperature. After 1 hour, the reaction mixture was sampled for sample preparation (sample preparation method 2), and the reaction conversion was confirmed by HPLC analysis to be 98% or higher (calculation expression 1 for reaction conversion). The external temperature of the reaction vessel was set to 5°C, and 2.5% ammonia solution (484 mL) was added to the reaction mixture. After the aqueous layer was removed by liquid separation, the organic layer was washed with 10% sodium bisulfate solution (484 mL), 5% sodium carbonate solution (484 mL), and 5% brine (484 mL). The resulting organic layer was concentrated under reduced pressure, with the external temperature set to 40°C. 2-MeTHF (161 mL × 2) was added to the resulting concentrated mixture, and the concentration was repeated under reduced pressure to obtain 134 g of crude product. The yield of the crude product was not calculated and was used in Examples 1-21.

[1222] LCMS (ESI) of compound 21: Retention time: 5.02 min, m / z = 1340 [M+H] + (LCMS Analysis Conditions and Methods 3)

[1223] Example 1-21

[1224] Synthesis of compound 22: (2S)-1-[(2S,3S)-2-[[(2S)-2-[[(3S)-3-[[(2S)-2-[[1- [[(2S,4R)-1-[(2S)-2-(benzyloxycarbonylamino)-4-[3-methoxy-4-(trifluoromethyl)phenyl]butyryl]- [4-ethoxy-pyrrolidine-2-carbonyl]-methyl-amino]cyclobutanecarbonyl]-methyl-amino]-2-cyclopentylacetyl]-methyl [-amino]-4-(dimethylamino)-4-oxo-butyryl]-methyl-amino]valeryl]amino]-3-methyl-valeryl] pyrrolidine-2-carboxylic acid

[1225] [Formula 65]

[1226]

[1227] In a nitrogen-purged reaction vessel, a solution of crude product containing compound 19 (111 g) in 2-MeTHF (666 mL) from Examples 1-20 was added in this order: hexamethyldisilazane (69.5 mL), followed by trimethyltrifluoromethanesulfonate (44.9 mL), ensuring the internal temperature did not exceed 15°C. After the addition was complete, the external temperature was raised to 10°C and the mixture was stirred for 1 hour and 20 minutes. The reaction mixture was sampled for sample preparation (sample preparation method 2), and the conversion of compound 22 to 99% was confirmed by HPLC analysis (conversion calculation expression 1). A mixed solution of 5% sodium carbonate aqueous solution (555 mL) and 5% brine (333 mL) was added at an external temperature of 0°C, ensuring the internal temperature did not exceed 25°C. After the addition was complete, the aqueous layer was removed by liquid separation. The resulting organic layer was washed with 555 mL of 10% sodium bisulfate aqueous solution, 555 mL of 5% sodium carbonate aqueous solution, and 555 mL of 5% brine. The resulting organic layer was concentrated under reduced pressure at an external temperature of 40 °C. 2-MeTHF (222 mL × 2) was added to the concentrated product, and the concentration under reduced pressure was repeated to obtain 128 g of crude product. The obtained crude product and 3,5-bis(trifluoromethyl)benzoic acid were dissolved in CDCl3 and analyzed by qNMR, and the content of compound 22 was thus calculated to be 96.1 g.

[1228] LCMS (ESI) of compound 22: Retention time: 4.24 min, m / z = 1283 [M+H] + (LCMS Analysis Conditions and Methods 3)

[1229] Example 1-22

[1230] Compound 23: 2-[[(2S)-2-[(4Z,7S)-7-[[(2S)-1-[(2S,3S)-2-[[(2S)-2-[[(3S)- 3-[[(2S)-2-[[1-[[(2S,4R)-1-[(2S)-2-(benzyloxycarbonylamino)-4-[3-methoxy-4-(trifluoromethyl) [[phenyl]butyryl]-4-ethoxy-pyrrolidine-2-carbonyl]-methyl-amino]cyclobutanecarbonyl]-methyl-amino]-2-cyclo [pentyl-acetyl]-methyl-amino]-4-(dimethylamino)-4-oxo-butyryl]-methyl-amino]pentanoyl]amino]- [3-Methyl-pentanoyl]pyrrolidine-2-carbonyl]-methyl-amino]-8-oxo-2,3,6,7-tetrahydroazacyclooctatetraene-1- 3-[4-(trifluoromethyl)phenyl]propionyl]-methyl-amino]tert-butyl acetate

[1231] [Formula 66]

[1232]

[1233] The crude product containing compound 22 (94.0 g) and compound 9 (40.1 g) from Examples 1-21 were added to the reaction vessel, and after nitrogen purging, 2-MeTHF (564 mL) and DMF (141 mL) were added and the mixture was stirred at room temperature. DIPEA (56.2 mL) was added, and the mixture was stirred at an external temperature of 43 °C for 1 hour. After cooling to an external temperature of 33 °C, HATU (41.8 g) was added to the resulting solution. After 1 hour, the mixture was cooled to room temperature and stirred for 6 hours. The reaction mixture was sampled for sample preparation (sample preparation method 2), and the reaction conversion was confirmed by HPLC analysis to be 98% or more (reaction conversion calculation expression 1). The solution was washed at room temperature with 2.8% ammonia solution (564 mL). The organic layer was washed with 10% sodium bisulfate solution (564 mL), 5% sodium carbonate solution (564 mL), and 5% brine (564 mL). The resulting solution was concentrated under reduced pressure at an external temperature of 40°C to obtain 157 g of crude product. The obtained crude product containing compound 23 and 3,5-bis(trifluoromethyl)benzoic acid were dissolved in CDCl3 and analyzed by qNMR, and the content of compound 23 was thus calculated to be 127.8 g (98.9% yield).

[1234] LCMS (ESI) of compound 23: retention time: 5.34 min, m / z = 1763 [M+H] + (LCMS Analysis Conditions and Methods 3)

[1235] Example 1-23

[1236] Synthesis of compound 24: 2-[[(2S)-2-[(4Z,7S)-7-[[(2S)-1-[(2S,3S)-2-[[(2S)-2- [[(3S)-3-[[(2S)-2-[[1-[[(2S,4R)-1-[(2S)-2-amino-4-[3-methoxy-4-(trifluoromethyl)phenyl]] [Butyryl]-4-ethoxy-pyrrolidine-2-carbonyl]-methyl-amino]cyclobutanecarbonyl]-methyl-amino]-2-cyclopentyl-ethyl [Acyl]-methyl-amino]-4-(dimethylamino)-4-oxo-butyryl]-methyl-amino]valeryl]amino]-3-methyl- [Valanoyl]pyrrolidine-2-carbonyl]-methyl-amino]-8-oxo-2,3,6,7-tetrahydroazacyclooctatetraen-1-yl]-3-[4- [(trifluoromethyl)phenyl]propionyl]-methyl-amino]acetic acid

[1237] [Formula 67]

[1238]

[1239] The crude product containing compound 23 (90.8 g), L-cysteine ​​(6.3 g), and 2-MeTHF (363 mL) were added sequentially to the reaction vessel. After purging the reaction vessel with nitrogen, the external temperature was set to 20°C. Hexamethyldisilazane (119 mL) was added while stirring. Subsequently, trimethylsilane trifluoromethanesulfonate (93.5 mL) was added over 20 minutes. After 25 minutes, the mixture was heated to an internal temperature of 50°C. After stirring at this temperature for 8 hours, the reaction mixture was cooled to room temperature and stored overnight. The mixture was reheated to an internal temperature of 50°C, and the reaction solution was stirred at 50°C for 4 hours. After cooling to an external temperature of 0°C, a 5% sodium carbonate aqueous solution (272 mL) was slowly added dropwise, ensuring the internal temperature did not exceed 40°C. Subsequently, the aqueous layer containing compound 24 was separated by liquid separation. 2-MeTHF (727 mL), MeCN (182 mL), and 10% sodium bisulfate (545 mL) were added to the aqueous layer, and liquid separation was performed. After the aqueous layer was drained, the organic layer was washed with 5% disodium hydrogen phosphate aqueous solution (545 mL × 2) and 10% sodium chloride aqueous solution (273 mL × 2). The obtained organic layer was concentrated under reduced pressure, with the external temperature set to 40 °C. 2-MeTHF (182 mL × 2) was added to the resulting concentrated product, and the concentration under reduced pressure was repeated to obtain 115 g of crude product. The crude product containing compound 24 and 3,5-bis(trifluoromethyl)benzoic acid were dissolved in DMSO-d6 and analyzed by qNMR, and the content of compound 24 was thus calculated to be 68.2 g (83.9% yield).

[1240] LCMS (ESI) of compound 24: Retention time: 4.37 min, m / z = 1572 [M+H] + (LCMS Analysis Conditions and Methods 4)

[1241] The deprotection reaction of the Cbz group is typically carried out under catalytic hydrogen reduction conditions in the presence of a metal catalyst (e.g., palladium / carbon). However, when the conditions of the conventional catalytic hydrogen reduction method are applied to the deprotection reaction of the Cbz group in compound 23, which contains an olefin in the molecule, there is a problem that the olefin in the molecule is reduced. To solve this problem, the inventors have discovered a method by which the deprotection of the Cbz group can be achieved under the conditions described in Examples 1-23, i.e., TMSOTf / HMDS conditions, without reducing the intramolecular olefin.

[1242] Example 1-24-1

[1243] Synthesis of Compound 1: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentane [2,N,2,14,18,21,24,36-octamethyl-2,8-ethoxy-3,2-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,24,36-octamethyl 10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecoxo-13-propyl-38- [[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetetracyclo] [37.5.1.0 4,8 .0 26,30 [42-ene-23,1'-cyclobutane]-17-carboxamide (cyclization position B)

[1244] [Formula 68]

[1245]

[1246] In a nitrogen-purged reaction vessel, a solution of COMU (65.0 g) in acetonitrile (1.9 L) was cooled to 0°C. Compound 24 (62.7 g) and a solution of dimethylpyridine (21.3 mL) in acetonitrile (0.941 L) were slowly added dropwise (4.4 mL / min) to the resulting solution. Immediately after addition, the reaction mixture was sampled for sample preparation (sample preparation method 2), and the reaction conversion was confirmed by HPLC to be 99% (calculation expression 1 for reaction conversion) and that the ratio of compound 1 to cyclic dimer was 98 / 2 (calculation expressions 1 and 2 for cyclization selectivity). The external temperature of the reaction vessel was heated to 40°C, and the reaction solution was concentrated. The external temperature of the reaction vessel was cooled to 25°C, and isopropyl acetate (627 mL) and a 2.5% ammonia solution (627 mL) were added to the resulting concentrated product, and the mixture was stirred. After the aqueous layer was drained, the resulting organic layer was washed with 10% sodium bisulfate aqueous solution (627 mL), 5% disodium hydrogen phosphate aqueous solution (627 mL × 2), and 5% sodium chloride aqueous solution (627 mL) by liquid-liquid separation. The resulting organic layer was then washed with 0.5% sodium chloride aqueous solution (627 mL × 2). The external temperature was set to 40°C, and the resulting organic layer was concentrated under reduced pressure to obtain 92.23 g of crude product containing compound 1. The obtained crude product containing compound 1 was used in Examples 1-25.

[1247] Cyclic dimers:

[1248] [Formula 69]

[1249]

[1250] LCMS (ESI) of compound 1: Retention time: 6.07 min, m / z = 1555 [M+H] + (LCMS Analysis Conditions and Methods 4)

[1251] LCMS (ESI) of the cyclic dimer: retention time: 7.63 min, m / z = 1555 [M+H] 2+ (LCMS Analysis Conditions and Methods 4)

[1252] HPLC of compound 1: Retention time: 4.09 min (HPLC analysis conditions, method 1)

[1253] HPLC of the cyclic dimer: Retention time: 4.91 min (HPLC analysis conditions, method 1)

[1254] Example 1-24-2

[1255] Synthesis of Compound 1: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentane [2,N,2,14,18,21,24,36-octamethyl-2,8-ethoxy-3,2-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,24,36-octamethyl 10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecoxo-13-propyl-38- [[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetetracyclo] [37.5.1.0 4,8 .0 26,30 [42-ene-23,1'-cyclobutane]-17-carboxamide (cyclization position B)

[1256] [Formula 70]

[1257]

[1258] HATU (72.6 mg) and acetonitrile (1.80 mL) were added to the reaction vessel. A solution of the crude product containing compound 24 (100 mg) and DIPEA (40 μL) from Examples 1-23 in acetonitrile (5.5 mL) was added dropwise over 5 hours and 42 minutes. Immediately after addition, the reaction mixture was sampled for sample preparation (sample preparation method 2), and the reaction conversion was confirmed by HPLC to be 99% (calculation expression 1 for reaction conversion), and compound 1 / cyclic dimer = 98 / 2 (calculation expressions 1 and 2 for cyclization selectivity).

[1259] HPLC of compound 1: Retention time: 3.99 minutes (HPLC analysis conditions, method 1)

[1260] HPLC of the cyclic dimer: Retention time: 4.80 min (HPLC analysis conditions, method 1)

[1261] Example 1-25

[1262] Crystallization of compound 1: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentane [2,N,2,14,18,21,24,36-octamethyl-2,8-ethoxy-3,2-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,24,36-octamethyl 10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecoxo-13-propyl-38- [[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetetracyclo] [37.5.1.0 4,8 .0 26,30 [42-ene-23,1'-cyclobutane]-17-carboxamide hydrate crystals (form A) synthesis

[1263] 24 g of the concentrated, dried product containing compound 1, obtained in Example 1-24-1, was loaded onto a Biotage Sfar C18 Duo 100 Å 30 μm 240 g container and developed with 0.1% formic acid-water / 0.1% formic acid-acetonitrile = 90 / 10 → 18 / 82, and purified. Acetone (29.0 mL) and heptane (29.0 mL) were added to the resulting compound 1 (9.70 g) at an external temperature of 35 °C. After confirming dissolution, acetone / heptane / water solvate crystals of compound 1 (form F) (approximately 1.00 mg) obtained by the same procedure as in Examples 3-8 were added to the reaction vessel, and the mixture was stirred at 35 °C for 23 h. The mixture was cooled to 25 °C and stirred further for 6 h. After 1 h, heptane (4.90 mL) was added, and the mixture was stirred at 25 °C for 14 h. Heptane (4.90 mL) was added over a further 1 hour, and the mixture was stirred for 3 hours. Finally, heptane (4.90 mL) was added over a further 2 hours, and the mixture was stirred for 3 hours. The reaction mixture was filtered under reduced pressure, and the resulting crystals were washed with a mixture of acetone (7.76 mL) and heptane (11.6 mL). The resulting crystals were dried for 16 hours at an external temperature of 40 °C. The dried powder was collected to obtain a white powder (6.8 g, form A).

[1264] Example 1-26

[1265] Synthesis of Compound 1: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentane [2,N,2,14,18,21,24,36-octamethyl-2,8-ethoxy-3,2-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,24,36-octamethyl 10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecoxo-13-propyl-38- [[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetetracyclo] [37.5.1.0 4,8 .0 26,30 [42-en-23,1'-cyclobutane]-17-carboxamide (cyclization position A)

[1266] [Formula 71]

[1267]

[1268] HATU (6.94 g) and acetonitrile (180 mL) were added to the nitrogen-purged reaction vessel. After confirming the dissolution of HATU, a solution of acetonitrile (540 mL) containing compound 25 (9.56 g) and DIPEA (3.82 mL) was added dropwise over 6 hours. Immediately after the addition was complete, a 10 μL sample of the reaction mixture was taken and diluted in 0.1 mL of acetonitrile containing 2 μL of ethanolamine. LCMS analysis confirmed that compound 1 / cyclic dimer = 75 / 25 (calculated expressions 1 and 2 for cyclization selectivity).

[1269] LCMS (ESI) of compound 1: Retention time: 0.78 min, m / z = 1553 [MH] - (LCMS Analysis Conditions and Methods 5)

[1270] LCMS (ESI) of the cyclic dimer: retention time: 0.94 min, m / z = 1553 [MH] 2- (LCMS Analysis Conditions and Methods 5)

[1271] Chemical name and structural formula of compound 25:

[1272] (3S)-3-[[(2S)-2-cyclopentyl-2[[1-[[(2S,4R)-4-ethoxy-1-[(2S)-4-[3-methoxy-4-(trifluoromethyl)phenyl]-2-[[2-[methyl-[(2S)-2-[(4Z,7S)-7-[methyl-[(2S)-1-[(2S,3S)-3-methyl-2-[[(2S)-2-(methylamino) [Valanoyl]amino]valanoyl]pyrrolidine-2-carbonyl]amino]-8-oxo-2,3,6,7-tetrahydroazacyclooctatetraen-1-yl]-3-[4-(trifluoromethyl)phenyl]propionyl]amino]acetyl]amino]butyryl]pyrrolidine-2-carbonyl]-methyl-amino]cyclobutanecarbonyl]-methyl-amino]acetyl]-methyl-amino]-4-(dimethylamino)-4-oxo-butyric acid

[1273] [Equation 72]

[1274]

[1275] Example 2-1

[1276] Compound 26: (S)-2-(but-3-en-1-ylamino)-3-(4-(trifluoromethyl)phenyl)propionic acid

[1277] [Formula 73]

[1278]

[1279] Acetonitrile (822 mL), 4-bromo-1-butene (235.07 g), and triethylamine (17.66 g) were added to a nitrogen-purged reaction vessel at an external temperature of 25 °C, and the mixture was stirred for 1 hour. Subsequently, (S)-2-amino-3-(4-(trifluoromethyl)phenyl)propionic acid (135.46 g), water (676 mL), and triethylamine (158.19 g) were added, the external temperature was raised to 70 °C, and the mixture was stirred for 3.5 hours. After cooling to 25 °C, the precipitated solid was filtered through a Kiriyama funnel and washed with a mixture of acetonitrile and water (1:1, 676 mL). The solid was then further washed with acetonitrile (676 mL). The resulting wet powder was dried, with the external temperature set to 40 °C. The dried powder was collected to obtain a white solid (124.73 g).

[1280] LCMS (ESI) of compound 26: Retention time: 2.34 min, m / z = 288 [M+H] + (LCMS Analysis Conditions and Methods, pp. 3-4)

[1281] Example 2-2

[1282] Compound 27: (S)-N-(2-(but-3-en-1-ylamino)-3-(4-(trifluoromethyl)phenyl)propionyl)-N- Methylglycine tert-butyl hydrochloride

[1283] [Formula 74]

[1284]

[1285] (S)-2-(but-3-en-1-ylamino)-3-(4-(trifluoromethyl)phenyl)propionic acid (107.26 g), sarcosine tert-butyl hydrochloride (102.00 g), acetonitrile (751 mL), and diazabicycloundecene (233.03 g) were added to a nitrogen-purged reaction vessel at an external temperature of 25°C, and the mixture was stirred for 10 minutes. After confirming that the solution was homogeneous, the external temperature was set to 2°C, and a 50% solution of propanephosphonic anhydride in 2-methyltetrahydrofuran (309.03 g) was added dropwise over 2 hours and 14 minutes. After confirming that the reaction was complete, toluene (751 mL) and 1N NaOH aqueous solution (536 mL) were added to the reaction mixture, and the mixture was stirred for 30 minutes. The aqueous layer was removed by liquid-liquid separation. The organic layer was stored at room temperature overnight. After storage, a 5% sodium carbonate aqueous solution (536 mL) was added to the organic layer, stirred for 10 minutes, and then the aqueous layer was removed by liquid-liquid separation. Subsequently, a 5% sodium dihydrogen phosphate aqueous solution (751 mL) was added to the organic layer, stirred for 10 minutes, and then the aqueous layer was removed by liquid-liquid separation. Again, a 5% sodium dihydrogen phosphate aqueous solution (751 mL) was added to the organic layer, the mixture was stirred for 10 minutes, and then the aqueous layer was removed by liquid-liquid separation. Subsequently, a 5% brine solution (751 mL) was added to the organic layer, stirred for 10 minutes, and then the aqueous layer was removed by liquid-liquid separation. The organic layer was stored overnight at an external temperature of 5°C. After storage, the organic layer was concentrated to approximately 215 mL under reduced pressure at 40°C. Toluene (215 mL) was added to the concentrated solution, and the mixture was concentrated to approximately 215 mL under reduced pressure at 40°C. This operation was repeated twice. The precipitated inorganic salts were filtered, the target material and toluene in the resulting filtrate were quantified, and toluene was added to bring the volume to 296 mL. In another reaction vessel, pyridine hydrochloride (43.28 g) and acetonitrile (148 mL) were added, and the prepared solution was added dropwise to the solution of the target material in toluene over 45 minutes at an external temperature of 25 °C. Precipitation of crystals was confirmed during the dropwise addition. The mixture was then washed with acetonitrile (74 mL) and stirred for 1 hour. Subsequently, toluene (1.7 L) was added, the mixture was stirred for 1 hour, and then the external temperature was lowered to 0 °C and the mixture was stirred further for 2 hours. The resulting crystals were filtered through a Kiriyama funnel and washed twice with toluene (296 mL), and cooled to 0 °C. The resulting wet powder was stored at an external temperature of 5 °C for one weekend. After storage, the wet powder was dried, with the external temperature set to 40 °C. The dried powder was collected to obtain a white solid (98.66 g).

[1286] LCMS (ESI) of compound 27: Retention time: 3.03 min, m / z = 415 [M+H] + (LCMS Analysis Conditions and Methods, pp. 3-4)

[1287] Example 2-3

[1288] Compound 28: 2-[[(2S)-2-[(4Z,7S)-7-[9H-fluorene-9-ylmethoxycarbonyl(methyl)amino]-8-oxo [-2,3,6,7-tetrahydroazacyclooctatetraen-1-yl]-3-[4-(trifluoromethyl)phenyl]propionyl]-methyl-amino]acetic acid

[1289] [Formula 75]

[1290]

[1291] 2-MeTHF (1.35 mL), compound 8 (145 mg), and HMDS (98 μL) were added to the reaction vessel at room temperature, and the mixture was stirred. TMSOTf (51 μL) was then added to the mixture at room temperature, and the mixture was stirred for 4 hours. After confirming a conversion of 99% or more by HPLC, the external temperature was cooled to 5°C, and 1.35 mL of a 5% potassium dihydrogen phosphate aqueous solution was slowly added at an internal temperature of 15°C or lower, while the mixture was stirred at room temperature. The aqueous layer was removed by liquid-liquid separation. The organic layer was washed with 1.35 mL × 2 of a 5% sodium dihydrogen phosphate aqueous solution and 1.35 mL of 5% brine, and the organic layer was concentrated under reduced pressure at an external temperature of 40°C to obtain compound 28 (133 mg).

[1292] LCMS (ESI) of compound 28: Retention time: 4.34 min, m / z = 664 [M+H] + (LCMS Analysis Conditions and Methods, pp. 3-4)

[1293] A solution of compound 8 (3.89 kg) in 2-MeTHF (20.5 kg) was added to the reaction vessel at room temperature, then cooled to an external temperature of 15°C. HMDS (2.19 kg) was added, and the mixture was stirred. TMSOTf (1.80 kg) was then slowly added to the mixed solvent at an internal temperature of 25°C or lower, and the mixture was stirred at an internal temperature of 25°C for 2 hours. 2-MeTHF (16.6 kg) and acetonitrile (4.60 kg) were added, and after cooling to an internal temperature of 15°C or lower, a 5% aqueous solution of sodium bicarbonate (27.3 kg) was slowly added at an internal temperature of 30°C. The mixture was stirred at room temperature, and the aqueous layer was removed by liquid-liquid separation. The organic layer was washed with a 5% aqueous solution of sodium bisulfate (27.2 kg) and 5% brine (27.2 kg × 3), and concentrated to 10 L at an external temperature of 40°C. Toluene (56.0 kg) was added to the concentrated solution, and the mixture was concentrated to 55 L at an external temperature of 40 °C. This process was repeated twice, adding toluene (15.6 kg) and concentrating to 54 L at an external temperature of 40 °C. After confirming crystal precipitation, cyclohexane (14.0 kg) was added, and the mixture was stirred overnight. The mixture was filtered, and the crystals were washed with a 3:1 toluene / cyclohexane solution (15.2 kg). The resulting wet crystals were dried under reduced pressure at an external temperature of 50 °C to obtain a white solid, 28-toluene monosolvent (3.21 kg).

[1294] Example 2-4

[1295] Synthesis of Compound 10: N-[(benzyloxy)carbonyl]-L-isoleucyl-L-proline tert-butyl ester

[1296] [Formula 76]

[1297]

[1298] Toluene (583 g) and 5% sodium bisulfate aqueous solution (2066 g) were added to (2S,3S)-2-{[(benzyloxy)carbonyl]amino}-3-methylpentanoic acid N-cyclohexylcyclohexammonium (135 g), and the organic layer was separated after stirring at room temperature for 10 min. The resulting organic layer was washed with 5% sodium bisulfate aqueous solution (2066 g), followed by washing with 5% brine (1397 g), and the solvent was distilled off under reduced pressure. Toluene (55 mL), 1,3-dimethyl-2-imidazolium ketone (270 mL), (2S)-2-(tert-butoxycarbonyl)pyrrolidine-1-onium chloride (75.3 g), 2-methyltetrahydrofuran (540 mL), and 4-methylmorpholine (133 mL) were added to the resulting residue, and the mixture was stirred at an external temperature of 15 °C. A 50% solution of propylphosphonic anhydride in 2-methyltetrahydrofuran (370 mL) was added dropwise to the mixture over approximately 1 hour, and the resulting reaction mixture was stirred at an external temperature of 20°C for 1 hour. A 5% aqueous solution of sodium bicarbonate (993 g) and 1-methylimidazole (24 mL) were added to the reaction mixture at an internal temperature of 20°C or lower, and the mixture was stirred at an external temperature of 20°C for approximately 30 minutes. The organic layer was then separated. The resulting organic layer was washed in this order with a 10% aqueous solution of sodium bisulfate (709 g), a 10% aqueous solution of sodium bisulfate (639 g), and a 10% aqueous solution of sodium bicarbonate (710 g), and the solvent was distilled off under reduced pressure to obtain a solution containing the title compound (137 g).

[1299] LCMS (ESI) of compound 10: Retention time: 4.21 min, m / z = 419 [M+H] + (LCMS Analysis Conditions and Methods M)

[1300] Example 2-5

[1301] Synthesis of Compound 11: L-Isoleucyl-L-proline tert-butyl ester

[1302] [Formula 77]

[1303]

[1304] Pd / C (50% wet, 36.7 g) and 2-methyltetrahydrofuran (253 mL) were stirred at an external temperature of 25 °C and an external temperature of 0.4 MPa for 2 hours. A solution containing compound 10 obtained in Examples 2-4 (137 g) and 2-methyltetrahydrofuran (495 mL) were added to the resulting mixture, and the mixture was stirred at an external temperature of 25 °C and an external temperature of 0.2 MPaG for 2 hours. The reaction mixture was filtered, the solid was washed three times with 2-methyltetrahydrofuran (127 mL), all filtrates were combined, and the solvent was distilled off under reduced pressure to obtain a solution containing the title compound (160 g).

[1305] LCMS (ESI) of compound 11: Retention time: 2.40 min, m / z = 285 [M+H] + (LCMS Analysis Conditions and Methods M)

[1306] Example 2-6

[1307] Synthesis of Compound 29: N-[(benzyloxy)carbonyl]-N-methyl-L-n-valine-L-isoleucyl-L-proline amino acid tert-butyl ester

[1308] [Formula 78]

[1309]

[1310] A mixture of a solution (120 g) containing compound 11 obtained in Examples 2-5, N-[(benzyloxy)carbonyl]-N-methyl-L-n-valine (72.12 g), 2-methyltetrahydrofuran (257 mL), and 4-methylmorpholine (100 mL) was stirred at an external temperature of 15°C. After approximately 40 minutes, a 50% solution of propylphosphonic anhydride in 2-methyltetrahydrofuran (277 mL) was added dropwise to the mixture, and the resulting reaction mixture was stirred at an external temperature of 20°C for 1 hour. At an internal temperature of 30°C or lower, a 5% aqueous solution of sodium bicarbonate (472 g) and 1-methylimidazole (18 mL) were added to the reaction mixture, and after stirring at an external temperature of 15°C for approximately 30 minutes, the organic layer was separated. The obtained organic layer was washed in this order with 10% sodium bisulfate aqueous solution (338 g), 10% sodium bisulfate aqueous solution (338 g), and 10% sodium bicarbonate aqueous solution (340 g) at an external temperature of 20°C, and the solvent was distilled off under reduced pressure to obtain a solution containing the title compound (219 g).

[1311] LCMS (ESI) of compound 29: Retention time: 4.58 min, m / z = 532 [M+H] + (LCMS Analysis Conditions and Methods M)

[1312] Example 2-7

[1313] Synthesis of Compound 13: N-methyl-L-n-valine-L-isoleucyl-L-proline tert-butyl ester

[1314] [Formula 79]

[1315]

[1316] Pd / C (50% wet, 22.9 g) and 2-methyltetrahydrofuran (400 mL) were stirred at an external temperature of 25 °C and an external temperature of 0.4 MPaG for 2 hours. A solution containing compound 29 obtained in Examples 2-6 (182 g) and 2-methyltetrahydrofuran (50 mL) were added to the resulting mixture, and the mixture was stirred at an external temperature of 25 °C and an external temperature of 0.4 MPaG for 2 hours. The reaction mixture was filtered, the solids were washed three times with 2-methyltetrahydrofuran (100 mL), and all filtrates were combined and concentrated under reduced pressure to obtain a solution containing the title compound (109 g). For 9.5346 g of this solution, the solvent was distilled off under reduced pressure, and heptane (100 mL) was added to the resulting residue. The mixture was dissolved at an external temperature of 50°C, and seed crystals (11.0 mg) obtained in Example 2-7-1 were added at an internal temperature of 40°C. After stirring the mixture at an external temperature of 42°C for 15 min, at an external temperature of 43°C for 13 min, and at an external temperature of 44°C for 17 min, the external temperature was cooled to 0°C at a rate of 12°C per hour, and the mixture was further stirred at an external temperature of 0°C for 1.5 h. The resulting solid was filtered, washed with cold heptane (25 mL), and dried under reduced pressure at an external temperature of 30°C to 40°C to obtain the title compound (4.8474 g).

[1317] LCMS (ESI) of compound 13: Retention time: 2.56 min, m / z = 398 [M+H] + (LCMS Analysis Conditions and Methods M)

[1318] Example 2-7-1

[1319] Synthesis of seed crystals of compound 13: N-methyl-L-n-valine-L-isoleucyl-L-proline tert-butyl ester

[1320] A portion of the solution containing the title compound obtained from the reactions of Examples 2-7 was concentrated under reduced pressure, and heptane (7622 μL) was added to the resulting residue (0.3811 g). After dissolving the resulting solid at an external temperature of 50 °C, it was cooled to room temperature with stirring, and heptane (3811 μL) was added to the resulting slurry while stirring continued. The solid was filtered, washed with heptane (1906 μL), and dried under reduced pressure at room temperature to obtain the title compound (0.2187 g).

[1321] LCMS (ESI) of seed crystals of compound 13: retention time: 2.60 min, m / z = 398 [M+H] + (LCMS Analysis Conditions and Methods M)

[1322] Example 2-8-1

[1323] Synthesis of compound A11: (tert-butyl(3S)-3-[benzyloxycarbonyl(methyl)amino]-4-(dimethylamino) (4-oxobutyrate)

[1324] [Formula 80]

[1325]

[1326] (2S)-2-(((benzyloxy)carbonyl)(methyl)amino)-4-tert-butoxy-4-oxobutyric acid dicyclohexylamine salt (Cas No. 42417-70-9, 25.00 g, 48.2 mmol) and 2-methyltetrahydrofuran (126 g) were added to the reaction vessel at 25 °C. The separation and washing with a 10% sodium bisulfate monohydrate solution (150 g) was repeated twice, followed by washing with a 5% sodium chloride solution (150 g). The obtained organic layer was concentrated under reduced pressure. The addition of 2-methyltetrahydrofuran (95 g) to the resulting residue and the concentration under reduced pressure were repeated twice. At 25 °C, 2-methyltetrahydrofuran (95 g), acetonitrile (75 g), DIPEA (35.46 g, 274 mmol), and dimethylamine hydrochloride (7.88 g, 96.6 mmol) were added to the resulting residue (47.91 g). A solution of propylphosphonic anhydride in 2-methyltetrahydrofuran (50.4 wt%, 61.33 g, 97.1 mmol) was added dropwise over 1 hour and 30 minutes. Samples were taken 1 hour after the addition was complete, and the reaction was confirmed by HPLC analysis. 2M sodium hydroxide aqueous solution (150 g) was added. The mixture was stirred for 10 minutes, then allowed to stand, and the aqueous layer was subsequently removed. The resulting organic layer was washed with 2M sodium hydroxide aqueous solution (150 g), 13% sulfuric acid aqueous solution (150 g), 10% sodium bisulfate monohydrate aqueous solution (150 g), and 5% sodium carbonate aqueous solution (150 g), and then concentrated under reduced pressure. The addition of 2-methyltetrahydrofuran (125 g) and concentration under reduced pressure was repeated twice to obtain a solution containing compound A11 (42.39 g).

[1327] LCMS (ESI) of compound A11: Retention time: 3.37 min, m / z = 387 [M+Na] + (LCMS Analysis Conditions and Methods K-2)

[1328] Example 2-8-2

[1329] Synthesis of compound A12: (tert-butyl(3S)-4-(dimethylamino)-3-(methylamino)-4-oxo-butanediol) (esters)

[1330] [Formula 81]

[1331]

[1332] 10% palladium on carbon (54.33% wet, 3.39 g, 1.45 mmol, 3 mol%, based on Pd metal) and 2-methyltetrahydrofuran (75 g) were added to the reaction vessel. Nitrogen purging was performed at 25 °C, followed by hydrogen purging, and the mixture was stirred for 2 hours under a hydrogen atmosphere (0.40 MPaG). A solution of compound A11 obtained in Example 2-8-1 (42.39 g) and 2-methyltetrahydrofuran (22 g) were added. After stirring for 1 hour and 30 minutes under a hydrogen atmosphere (0.20 MPaG), a sample was taken, and the reaction was confirmed by HPLC analysis. After filtration of the reaction mixture, the cake was washed twice with 2-methyltetrahydrofuran (75 g). A mixture of the filtrate and washings was concentrated under reduced pressure to obtain a solution containing compound A12 (30.76 g).

[1333] LCMS (ESI) of compound A12: Retention time: 1.44 min, m / z = 231 [M+H] + (LCMS Analysis Conditions and Methods K-2)

[1334] Example 2-8-3

[1335] Synthesis of compound A14: (tert-butyl(3S)-3-[[(2S)-2-[benzyloxycarbonyl(methyl)amino]-2-) [Cyclopentyl-acetyl]-methyl-amino]-4-(dimethylamino)-4-oxo-butyrate

[1336] [Equation 82]

[1337]

[1338] A solution (30.76 g) of compound A12 obtained in Example 2-8-2, (S)-2-(((benzyloxy)carbonyl)(methyl)amino)-2-cyclopentylacetic acid (Cas No. 2411591-78-9, 16.96 g, 58.2 mmol), 2-methyltetrahydrofuran (40 g), acetonitrile (17 g), and DIPEA (27.74 g, 215 mmol) were added to the reaction vessel at 25 °C. HATU (27.49 g, 72.3 mmol) was added over 10 minutes. Samples were taken 3 hours after the addition, and the reaction was confirmed by HPLC analysis. Toluene (30 g), 5% potassium carbonate aqueous solution (23 g), and 1-methylimidazole (3.97 g, 48.4 mmol) were added, and the mixture was stirred for 30 minutes. Add 2.5% ammonia solution (88 g) and 2-methyltetrahydrofuran (25 g). Stir the mixture for 10 minutes, then let it stand and remove the aqueous layer. Wash the resulting organic layer with 2.5% ammonia solution (113 g), 10% sodium bisulfate monohydrate solution (113 g, twice), and 5% potassium carbonate solution (113 g), and then concentrate under reduced pressure. Add 2-methyltetrahydrofuran (42 g), and concentrate the mixture under reduced pressure to obtain a solution containing compound A14 (52.78 g).

[1339] LCMS (ESI) of compound A14: Retention time: 4.10 min, m / z = 526 [M+Na] + (LCMS Analysis Conditions and Methods K-2)

[1340] Example 2-8-4

[1341] Synthesis of compound A15: (tert-butyl(3S)-3-[[(2S)-2-cyclopentyl-2-(methylamino)acetyl]- [Methyl-amino]-4-(dimethylamino)-4-oxo-butyrate

[1342] [Formula 83]

[1343]

[1344] 10% palladium on carbon (54.33% wet, 3.39 g, 1.45 mmol, 3 mol%, based on Pd metal) and 2-methyltetrahydrofuran (75 g) were added to the reaction vessel. Nitrogen purging was performed at 25 °C, followed by hydrogen purging, and the mixture was stirred for 2 hours under a hydrogen atmosphere (0.40 MPaG). A solution of compound A14 obtained in Example 2-8-3 (52.78 g) and 2-methyltetrahydrofuran (15 g) were added, and the temperature was then raised to 30 °C. After stirring for 2 hours under a hydrogen atmosphere (0.20 MPaG), a sample was taken, and the reaction was confirmed by HPLC analysis. After filtering the reaction mixture, the cake was washed twice with 2-methyltetrahydrofuran (75 g). After concentrating the mixture of filtrate and washing solution under reduced pressure, the addition of acetonitrile (75 g) and concentration under reduced pressure were repeated twice to obtain a solution (42.5 mL) containing compound A15.

[1345] LCMS (ESI) of compound A15: Retention time: 2.96 min, m / z = 370 [M+H] + (LCMS Analysis Conditions and Methods K-1)

[1346] Example 2-8-5

[1347] Synthesis of compound A16: ((3S)-3-[[(2S)-2-cyclopentyl-2-(methylamino)acetyl]-methyl-amino tert-butyl 4-(dimethylamino)-4-oxo-butyrate hydrochloride

[1348] [Formula 84]

[1349]

[1350] A solution (42.5 mL) of compound A15 obtained in Example 2-8-4 and acetonitrile (8.0 g) were added to the reaction vessel. After adding MTBE (65 g) at 40 °C, a solution of pyridine hydrochloride in acetonitrile (16.94 w / w%, 4.50 g) was added dropwise over 30 minutes. After stirring for 1 hour, a solution of pyridine hydrochloride in acetonitrile (16.94 w / w%, 31.34 g) was added dropwise over 3 hours and 30 minutes, followed by the addition of acetonitrile (14 g). After stirring for 1 hour, the mixture was cooled to 10 °C over 6 hours. Stirring was further performed at 10 °C for 11 hours, and then the slurry was filtered. The resulting solid was washed twice with MTBE (38 g) and dried under reduced pressure to obtain compound A16 (15.68 g).

[1351] LCMS (ESI) of compound A16: Retention time: 2.92 min, m / z = 370 [M+H] + (LCMS Analysis Conditions and Methods K-1)

[1352] Example 2-8-6

[1353] Synthesis of Compound 30: ((S)-3-((S)-2-(1-(((benzyloxy)carbonyl)(methyl)amino)-N-methyl (cyclobutane-1-formamido)-2-cyclopentyl-N-methylacetamido)-4-(dimethylamino)-3-oxo-butyrate tert-butyl ester)

[1354] [Formula 85]

[1355]

[1356] Acetonitrile (224 mL), DIPEA (150 g), compound A16 (74.56 g) obtained in Example 2-8-5, and 1-(benzyloxycarbonyl(methyl)amino)cyclobutyric acid (Cas No. 1408729-60-1, 131 g) were added to a nitrogen-purged reaction vessel (2 L), and the mixture was stirred at room temperature for 10 minutes. After confirming complete dissolution, a solution of 50 wt.% propylphosphonic anhydride in 2-methyltetrahydrofuran (339 g) was added to the mixture over 15 minutes. After the reaction was complete, the internal temperature was raised to 60 °C, and the mixture was stirred for 2 hours. The reaction mixture was sampled for sample preparation (sample preparation method K), and the reaction conversion was confirmed by HPLC analysis to be 99% or higher (calculation expression 1 for reaction conversion). Add 447 mL of 5% potassium carbonate aqueous solution and 90 g of N,N-dimethyl-4-aminopyridine, and stir the mixture further for 1 hour and 30 minutes. Cool the internal temperature to 25°C, add toluene (373 mL), and remove the aqueous layer by liquid separation. Wash the organic layer with 4% sulfuric acid aqueous solution (447 mL × 2) and 5% sodium carbonate aqueous solution (447 mL × 2). Concentrate the resulting organic layer to 226 mL under reduced pressure at an external temperature of 60°C. After concentration under reduced pressure, add 447 mL of THF and concentrate to 226 mL under reduced pressure twice to give a solution of compound 30 in THF (167.76 g). The yield of the resulting solution was not calculated and it was used in Examples 2-9.

[1357] LCMS (ESI) of compound 30: Retention time: 7.02 min, m / z = 637.43 [M+Na] + (LCMS Analysis Conditions and Methods K-1)

[1358] Example 2-9

[1359] Synthesis of Compound 31: ((S)-3...

Claims

1. A method for producing a cyclic peptide compound represented by formula (1) or a salt thereof or a solvate thereof, the method comprising the step of reacting an N-terminal amino acid residue of a peptide compound represented by formula (2) or (3) with a C-terminal amino acid residue of the peptide compound in a solvent to perform a cyclization step (cyclization step): [Formula 1] Where R1 is a C1-C6 alkyl group; P1 is a C1-C6 alkyl group; R2 is a C1-C6 alkyl group; R3 is hydrogen, or R3 together with P3, the carbon atom bonded to R3 and the nitrogen atom bonded to P3 form a 4- to 7-membered saturated heterocycle; P3 is a C1-C6 alkyl or C3-C8 cycloalkyl, or P3 together with R3, the carbon atom bonded to R3 and the nitrogen atom bonded to P3 to form a 4- to 7-membered saturated heterocycle; P4 is a C1-C6 alkyl group; R5 is a benzyl group optionally substituted with one or more groups selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, and C3-C8 cycloalkyl; P6 is a C1-C6 alkyl group; R7 is a phenethyl group optionally substituted with one or more groups selected from the group consisting of: halogen, C1-C6 haloalkyl and C1-C6 alkoxy; R8, together with P8, the carbon atom bonded to R8, and the nitrogen atom bonded to P8, forms a 4- to 7-membered saturated heterocycle, wherein the 4- to 7-membered saturated heterocycle is optionally substituted with a C1-C6 alkoxy group. R9, together with Q9 and the carbon atoms bonded to R9 and Q9, forms a 3- to 8-membered alicyclic ring, wherein the 3- to 8-membered alicyclic ring is optionally substituted with one or more C1-C6 alkyl groups; P9 is hydrogen or a C1-C6 alkyl group; R 10 It is a C1-C6 alkyl or C3-C8 cycloalkyl; P 10 It is a C1-C6 alkyl group; R 11 It is a di-C1-C6 alkylaminocarbonyl or a 4- to 8-membered cyclic aminocarbonyl; P 11 It is a C1-C6 alkyl group; X1 and X5 are each independently hydrogen or protecting groups for amino groups; and X2 and X4 are each independently a halogen, a hydroxyl group, an optionally substituted alkoxy group, an optionally substituted aryloxy group, an optionally substituted arylalkoxy group, an optionally substituted cyclic aminooxy group, or a group consisting of -OSiR. x R y R z The group represented, where R x R y and R z Each can be an alkyl or aryl group independently.

2. A method for producing a cyclic peptide compound represented by formula (1) or a salt thereof or a solvate thereof, said method comprising: (a) The step of providing a peptide compound or a salt thereof represented by formulas (4) to (6) or a solvation of said peptide compound or salt; (b) The step of reacting the N-terminal amino acid residues of the peptide compound represented by formulas (4) to (6) with the C-terminal amino acid residues of the peptide compound in a solvent to perform the linking step. as well as (c) The step of reacting the N-terminal amino acid residues of the peptide compound obtained in step (b) with the C-terminal amino acid residues of the peptide compound in a solvent to perform cyclization (cyclization step): [Equation 2] Where R1 is a C1-C6 alkyl group; P1 is a C1-C6 alkyl group; R2 is a C1-C6 alkyl group; R3 is hydrogen, or R3 together with P3, the carbon atom bonded to R3 and the nitrogen atom bonded to P3 form a 4- to 7-membered saturated heterocycle; P3 is a C1-C6 alkyl or C3-C8 cycloalkyl, or P3 together with R3, the carbon atom bonded to R3 and the nitrogen atom bonded to P3 to form a 4- to 7-membered saturated heterocycle; P4 is a C1-C6 alkyl group; R5 is a benzyl group optionally substituted with one or more groups selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, and C3-C8 cycloalkyl; P6 is a C1-C6 alkyl group; R7 is a phenethyl group optionally substituted with one or more groups selected from the group consisting of: halogen, C1-C6 haloalkyl and C1-C6 alkoxy; R8, together with P8, the carbon atom bonded to R8, and the nitrogen atom bonded to P8, forms a 4- to 7-membered saturated heterocycle, wherein the 4- to 7-membered saturated heterocycle is optionally substituted with a C1-C6 alkoxy group. R9, together with Q9 and the carbon atoms bonded to R9 and Q9, forms a 3- to 8-membered alicyclic ring, wherein the 3- to 8-membered alicyclic ring is optionally substituted with one or more C1-C6 alkyl groups; P9 is hydrogen or a C1-C6 alkyl group; R 10 It is a C1-C6 alkyl or C3-C8 cycloalkyl; P 10 It is a C1-C6 alkyl group; R 11 It is a di-C1-C6 alkylaminocarbonyl or a 4- to 8-membered cyclic aminocarbonyl; P 11 It is a C1-C6 alkyl group; X1, X3, and X5 are each independently hydrogen or protecting groups for amino groups; and X2, X4, and X6 are each independently a halogen, a hydroxyl group, an optionally substituted alkoxy group, an optionally substituted aryloxy group, an optionally substituted arylalkoxy group, an optionally substituted cyclic aminooxy group, or a group consisting of -OSiR. x R y R z The group represented, where R x R y and R z Each can be an alkyl or aryl group independently.

3. The method according to claim 2, wherein step (b) includes, (b-1) The step of reacting the N-terminal amino acid residues of the peptide compound represented by formula (5) with the C-terminal amino acid residues of the peptide compound represented by formula (6) in a solvent to link them, thereby converting them into the peptide compound represented by formula (7) (linking step): [Formula 3] Among them, R1, R2, R3, R7, R8, R9, R 10 R 11 P1, P3, P8, P9, P 10 P 11 Q9, X4, and X5 are the same as in claim 2.

4. The method according to claim 3, wherein step (b) further comprises, (b-2) The step of reacting the N-terminal amino acid residues of the peptide compound represented by formula (4) with the C-terminal amino acid residues of the peptide compound represented by formula (7) in a solvent to link them, thereby converting them into the peptide compound represented by formula (2) (the linking step), and The method includes step (c) as follows: (c-1) The step of reacting the N-terminal amino acid residue of the peptide compound represented by formula (2) with the C-terminal amino acid residue of the peptide compound in a solvent to perform cyclization (cyclization step).

5. The method according to claim 3, wherein step (b) further comprises, (b-3) The step of reacting the N-terminal amino acid residues of the peptide compound represented by formula (7) with the C-terminal amino acid residues of the peptide compound represented by formula (4) in a solvent to link them, thereby converting them into the compound represented by formula (3) (linking step), and The method includes step (c) as follows: (c-2) The step of reacting the N-terminal amino acid residue of the peptide compound represented by formula (3) with the C-terminal amino acid residue of the peptide compound in a solvent to perform cyclization (cyclization step).

6. The method according to any one of claims 1 to 5, wherein the linking of the N-terminal amino acid residue of the peptide compound to the C-terminal amino acid residue of the peptide compound is the linking of the amino group of the N-terminal amino acid residue to the carboxyl group of the C-terminal amino acid residue.

7. The method according to any one of claims 1 to 6, wherein the solvent in the cyclization step comprises one or more of the group consisting of nitrile solvents, halogen solvents, ether solvents, amide solvents, ester solvents and carbonate solvents.

8. The method according to any one of claims 1 to 7, wherein the cyclization step is performed in the presence of a condensation agent.

9. The method according to any one of claims 1 to 8, wherein the cyclization step is carried out in the presence of a base.

10. The method according to any one of claims 1 to 9, wherein the cyclization step is performed by a liquid-phase method.

11. The method according to any one of claims 1 to 10, wherein the solvent in the connecting step comprises one or more of the group consisting of nitrile solvents, halogen solvents, ether solvents, amide solvents, ester solvents and carbonate solvents.

12. A crystal of a cyclic peptide compound represented by formula (1a) or a salt thereof or a solvate thereof: [Formula 4] 。 13. The crystal of claim 12, wherein the crystal is a solvate crystal, wherein the solvate crystal is a hydrate crystal, wherein the hydrate crystal is a form A crystal, wherein the diffraction angle (2θ value) of the form A crystal obtained by powder X-ray diffraction comprises at least seven peaks selected from the group consisting of: 6.93°, 7.56°, 8.26°, 9.00°, 9.58°, 10.35°, 11.35°, 12.26°, 12.85°, 13.51°, 14.12°, 14.69°, 15.46°, 15.92°, 17.43° and 17.73° (±0.2°), and wherein the diffraction angle (2θ value) is the diffraction angle (2θ value) of the hydrate crystal stored at 10% or higher relative humidity for 15 minutes or longer.

14. The crystal of claim 12, wherein the crystal is a solvate crystal, wherein the solvate crystal is a hydrate crystal, wherein the hydrate crystal is a form B crystal, wherein the diffraction angle (2θ value) of the form B crystal obtained by powder X-ray diffraction comprises at least seven peaks selected from the group consisting of: 4.99°, 8.65°, 9.85°, 10.84°, 11.32°, 12.35°, 13.20°, 14.44°, 15.20°, 16.03°, 16.69°, 17.21°, 18.82°, 19.49° and 20.03° (±0.2°), and wherein the diffraction angle (2θ value) is the diffraction angle (2θ value) of the hydrate crystal stored at 30% or higher relative humidity for 15 minutes or longer.

15. A method for producing crystals of the cyclic peptide compound according to any one of claims 12 to 14, the method comprising: The step of dissolving the cyclic peptide compound in a polar organic solvent to obtain a solution, wherein the amount of polar organic solvent allows the cyclic peptide compound to dissolve therein; The steps include adding a hydrocarbon solvent or water to the solution to obtain crystals of the cyclic peptide compound.

16. The method of claim 15, further comprising a step of filtering the crystals after the step of obtaining the crystals of the cyclic peptide compound.

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