Process for production of cyclopeptide compounds containing N-substituted amino acid residues

Abstract

The present inventors have discovered that by linking the N-terminal amino acid residue and the C-terminal amino acid residue of a peptide compound in a solvent containing one or more selected from the group consisting of acetonitrile, dimethyl carbonate, 2-MeTHF and anisole, a target cyclic peptide compound can be efficiently produced while preventing epimerization and reducing multimer formation, and the yield of the cyclic peptide compound can be improved. Wherein at least one of the N-terminal amino acid residue and the C-terminal amino acid residue is a cyclic amino acid residue.

Description

Technical Field

[0001] The present invention relates to a method for producing a cyclic peptide compound, the method comprising a cyclization step of a peptide compound comprising a C-terminal amino acid residue having a side chain on the α-carbon and an N-substituted amino acid residue on one or both of the N-terminal amino acid residue and the C-terminal amino acid residue. Background Art

[0002] A peptide is a molecule in which a large number of amino acids are linked. Peptides play an indispensable role in the life activities of organisms. These peptides can be extended to a desired peptide sequence by reacting an amino acid or a peptide with an activated carboxyl group at the C-terminus with an amino group of an amino acid or a peptide to form an amide bond. However, the problem in the production of peptides containing non-natural amino acids, particularly peptides containing N-methyl amino acids, is that the yield of the target material is reduced due to the low reactivity of the condensation reaction caused by the steric hindrance of the N-methyl group, the epimerization of the amino acid residue at the α-position, etc. (Non-Patent Document 1).

[0003] Removing by-products generated by side reactions such as epimerization usually requires a purification step. However, in industrial-scale peptide synthesis, the peptide purification step causes problems of longer production time and higher production cost. Therefore, a method is needed that can synthesize the peptide of interest without purification by column chromatography or cumbersome purification steps while minimizing by-products.

[0004] Epimerization problems also occur when synthesizing a cyclic peptide by linking the N-terminal amino acid residue of a linear peptide to the C-terminal amino acid residue of the linear peptide. Therefore, like in the extension reaction of an amino acid or a peptide, the cyclization reaction of a linear peptide also needs to avoid epimerization of the C-terminal amino acid residue at the α-position.

[0005] To prevent such epimerization of the C-terminal amino acid residue of a peptide at the α-position, a method can be adopted in which the carboxyl group at the C-terminus is activated to bind to another amino acid or peptide in which the C-terminal amino acid residue does not have a side chain or has a disubstituted group (α,α-disubstituted) on the α-carbon (Non-Patent Document 2).

[0006] At the same time, it is known that in the reaction of activating and cyclizing the carboxyl group of a linear peptide having a side chain on the α-carbon of the C-terminal amino acid residue, when at least one of the amino acid residues at the reaction point is an N-substituted amino acid residue, epimerization actually occurs when synthesizing a cyclic peptide by a cyclization reaction (Non-Patent Document 3). However, reaction conditions that allow the use of easily available and inexpensive reagents and reactive amino acid residues to suppress epimerization have not been clarified.

[0007] In addition, during this cyclization reaction, intermolecular reactions may also proceed competitively, leading to the formation of oligomers of the peptide (such as dimers and trimers) (Non-Patent Document 4). For the formation of such oligomers, reaction conditions that allow the use of readily available and inexpensive reagents and solvents and reactive amino acid residues to inhibit the formation of oligomers have not been clarified. In addition, these epimeric peptides and oligomers of the peptide need to be separated and removed from the cyclic peptide of interest because they are by-products. When producing such by-products in large quantities, cumbersome purification steps using a large amount of solvent (such as column chromatography) must be incorporated into the production process, resulting in a complex production process and increased costs. Therefore, a method for suppressing the formation of by-products is needed.

[0008] In order to improve the synthesis efficiency of cyclic peptides, it is therefore considered that the cyclization reaction is ideally carried out using a solvent that is favorable for liquid separation in the post-treatment step after the cyclization reaction. However, since the reaction solvents frequently used in the cyclization reaction are halogenated hydrocarbon solvents (such as dichloromethane) and amide solvents (such as DMF) with a large environmental load, it is also necessary to find alternative solvents from this point of view (Non-Patent Document 5).

[0009] Therefore, from the perspectives of the cost, environmental load, ease of production, and industrial applicability of the production method, it is important to find a combination of a reaction solvent, a reagent, and an amino acid residue that serves as a reaction point for suppressing the formation of by-products (such as epimers and oligomers) when activating the carboxyl group of a peptide having a side chain on the α-carbon of the C-terminal amino acid residue for the cyclization reaction, and a solvent that is favorable for liquid separation after the reaction.

[0010] [Citation List]

[0011] [Non-Patent Document]

[0012] [Non-Patent Document 1]

[0013] J. Peptide Res., 2005, 65, 153 - 166.

[0014] [Non-Patent Document 2]

[0015] Org. Lett. 2013, 15, 1155 - 1157.

[0016] [Non-Patent Document 3]

[0017] Org. Lett. 2012, 14, 612 - 615.

[0018] [Non-Patent Document 4]

[0019] Chem. Rev. 1997, 6, 2243 - 2266.

[0020] [Non-Patent Document 5]

[0021] Green Chem.Lett.Rev., 2021, 14, 153 - 164. Summary of the Invention

[0022] [Technical Problem]

[0023] The present invention has been accomplished in view of such circumstances, and an object of the present invention is to provide a method for efficiently producing a cyclic peptide compound of interest by suppressing epimerization and reducing oligomer formation in the synthesis of a cyclic peptide compound from a peptide compound containing a C-terminal amino acid residue having a side chain on the α-carbon and having an N-substituted amino acid residue on one or both of the N-terminal amino acid residue and the C-terminal amino acid residue, from the viewpoints of cost, environmental load, and ease of preparation. Specifically, an object of the present invention is to provide a method for cyclizing a peptide compound having a predetermined N-terminal amino acid residue and C-terminal amino acid residue, which can suppress epimerization and reduce the formation of oligomers.

[0024] [Solution to the Problem]

[0025] The inventors of the present invention have conducted in-depth research to solve the above problems, and as a result, it has been found that in the synthesis of a cyclic peptide compound from a peptide compound containing a C-terminal amino acid residue having a side chain on the α-carbon and having an N-substituted amino acid residue on at least one or both of the N-terminal amino acid residue and the C-terminal amino acid residue, epimerization can be suppressed and oligomer formation can be reduced, so that a cyclic peptide compound of interest can be efficiently produced.

[0026] In a specific non-limiting aspect, the present invention encompasses the following.

[0027] [1] A method for producing a cyclic peptide compound, or a salt thereof, or a solvate thereof, the method comprising:

[0028] a step of linking the N-terminal amino acid residue of a peptide compound with the C-terminal amino acid residue of the peptide compound in a solvent, wherein

[0029] at least one of the N-terminal amino acid residue and the C-terminal amino acid residue is a cyclic amino acid residue, and

[0030] the solvent includes one or more selected from the group consisting of acetonitrile, dimethyl carbonate, 2-MeTHF, and anisole.

[0031] [2] A method for producing a cyclic peptide compound, or a salt thereof, or a solvate thereof, the method comprising:

[0032] A step of linking the N-terminal amino acid residue of a peptide compound to the C-terminal amino acid residue of the peptide compound in a solvent, wherein

[0033] the N-terminal amino acid residue and the C-terminal amino acid residue of the peptide compound are each independently selected from one of the following a) to e):

[0034] a) the N-terminal amino acid residue is an N-substituted phenylalanine residue or an N-substituted phenylalanine derivative residue, and the C-terminal amino acid residue is a cyclic amino acid residue;

[0035] b) the N-terminal amino acid residue is an α,α-disubstituted amino acid residue, and the C-terminal amino acid residue is a cyclic amino acid residue;

[0036] c) the N-terminal amino acid residue is a cyclic amino acid residue, and the C-terminal amino acid residue is a homophenylalanine residue or a homophenylalanine derivative residue;

[0037] d) the N-terminal amino acid residue is a cyclic amino acid residue, and the C-terminal amino acid residue is an N-substituted Ala residue; and

[0038] e) the N-terminal amino acid residue is an N-substituted Gly residue, and the C-terminal amino acid residue is an N-substituted phenylalanine residue or an N-substituted phenylalanine derivative residue.

[0039] [3] The method according to [2], wherein the solvent comprises one or more selected from the group consisting of acetonitrile, dimethyl carbonate, 2-MeTHF, and anisole.

[0040] [4] The method according to [1] or [2], wherein the solvent is one selected from the group consisting of acetonitrile, dimethyl carbonate, 2-MeTHF, and anisole.

[0041] [5] The method according to [1] or [2], wherein the solvent is one selected from the group consisting of acetonitrile and dimethyl carbonate.

[0042] [6] The method according to [1] or [2], wherein the solvent is acetonitrile.

[0043] [7] The method according to [1] or [2], wherein the solvent is dimethyl carbonate.

[0044] [8] The method according to any one of [1] to [7], wherein linking the N-terminal amino acid residue of the peptide compound to the C-terminal amino acid residue of the peptide compound is to link the amino group of the N-terminal amino acid residue to the carboxyl group of the C-terminal amino acid residue.

[0045] [9]The method according to any one of [1] to [7], wherein connecting the N-terminal amino acid residue of the peptide compound to the C-terminal amino acid residue of the peptide compound is by connecting the amino group of the N-terminal amino acid residue to the carboxyl group of the C-terminal amino acid residue through an amide bond.

[0046]

[10] The method according to any one of [1] to [9], wherein the connecting step is carried out in the presence of a condensing reagent.

[0047]

[11] The method according to

[10] , wherein the condensing reagent is one selected from the group consisting of HATU, COMU, DMT-MM, PyOxim, PyBOP, and PyClop.

[0048]

[12] The method according to

[10] , wherein the condensing reagent is one selected from the group consisting of HATU and COMU.

[0049]

[13] The method according to

[10] , wherein the condensing reagent is HATU.

[0050]

[14] The method according to

[10] , wherein the condensing reagent is COMU.

[0051]

[15] The method according to

[10] , wherein the condensing reagent is HATU and the solvent is dimethyl carbonate.

[0052]

[16] The method according to

[10] , wherein the condensing reagent is HATU and the solvent is acetonitrile.

[0053]

[17] The method according to

[10] , wherein the condensing reagent is COMU and the solvent is dimethyl carbonate.

[0054]

[18] The method according to

[10] , wherein the condensing reagent is COMU and the solvent is acetonitrile.

[0055]

[19] The method according to any one of [1] to

[18] , wherein the connecting step is carried out in the presence of a base.

[0056]

[20] The method according to

[19] , wherein the base is an organic base.

[0057]

[21] The method according to

[19] , wherein the base is an organic base containing a tertiary amine.

[0058]

[22] The method according to

[19] , wherein the base is one selected from the group consisting of: N,N-diisopropylethylamine (DIPEA), 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), 2,3,6,7-tetrahydro-1H,5H-9-azabenz[ij]quinolizine, 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(tetramethylguanidino)naphthalene (TMGN), 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), triethylamine (TEA), trimethylamine, 1-methylpiperidine, N,N′-dimethylpiperazine, N-methylmorpholine, N-ethylmorpholine, and p-dimethylaminopyridine (DMAP).

[0059]

[23] The method according to

[19] , wherein the base is N,N-diisopropylethylamine (DIPEA).

[0060]

[24] The method according to

[19] , wherein the condensation reagent is HATU, the solvent is dimethyl carbonate, and the base is N,N-diisopropylethylamine (DIPEA).

[0061]

[25] The method according to

[19] , wherein the condensation reagent is HATU, the solvent is acetonitrile, and the base is N,N-diisopropylethylamine (DIPEA).

[0062]

[26] The method according to

[19] , wherein the condensation reagent is COMU, the solvent is dimethyl carbonate, and the base is N,N-diisopropylethylamine (DIPEA).

[0063]

[27] The method according to

[19] , wherein the condensation reagent is COMU, the solvent is acetonitrile, and the base is N,N-diisopropylethylamine (DIPEA).

[0064]

[28] The method according to any one of [1] to

[27] , wherein the C-terminal amino acid residue contained in the peptide compound is an amino acid residue having a side chain on the α-carbon of the carboxyl group.

[0065]

[29] The method according to any one of [1] to

[27] , wherein the peptide compound contains an amino acid residue of formula (1) at any one of the amino acid residues other than the N-terminal amino acid residue and the C-terminal amino acid residue:

[0066] [Formula 1]

[0067]

[0068] wherein

[0069] R 1 is hydrogen or C 1 -C 6 alkyl, and

[0070] R 2 and R 3 are each independently hydrogen or C 1 -C 6 alkyl; or R 2 and R 3 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle.

[0071]

[30] The method according to

[29] , wherein R 1 is C 1 -C 6 alkyl.

[0072]

[31] The method according to

[29] , wherein R 1 is methyl.

[0073]

[32] The method according to any one of

[29] to

[31] , wherein R 2 and R 3 are each independently C 1 -C 6 alkyl.

[0074]

[33] The method according to any one of

[29] to

[31] , wherein R 2 and R 3 are both methyl.

[0075]

[34] The method according to

[29] , wherein R 1 is C 1 -C 6 alkyl, and R 2 and R 3 are each independently C 1 -C 6 alkyl, or R2 and R 3 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle.

[0076]

[35] The method according to

[29] , wherein R 1 is methyl; and R 2 and R 3 are both methyl.

[0077]

[36] The method according to any one of [1] to

[35] , wherein the N-terminal amino acid residue of the peptide compound is a cyclic amino acid residue, or the C-terminal amino acid residue of the peptide compound is a cyclic amino acid residue.

[0078]

[37] The method according to any one of [1] to

[35] , wherein the N-terminal amino acid residue of the peptide compound is a cyclic amino acid residue and the C-terminal amino acid residue is a non-natural amino acid residue, or the N-terminal amino acid residue of the peptide compound is a non-natural amino acid residue and the C-terminal amino acid residue is a cyclic amino acid residue.

[0079]

[38] The method according to any one of [1] to

[35] , wherein the N-terminal amino acid residue of the peptide compound is a cyclic amino acid residue and the C-terminal amino acid residue is a homophenylalanine residue, a homophenylalanine derivative residue or an N-substituted Ala residue, or the N-terminal amino acid residue of the peptide compound is an N-substituted phenylalanine residue, an N-substituted phenylalanine derivative residue or an α,α-disubstituted amino acid residue and the C-terminal amino acid residue is a cyclic amino acid residue.

[0080] [38-1]The method according to any one of [1] to

[35] , wherein the N-terminal amino acid residue of the peptide compound is a cyclic amino acid residue and the C-terminal amino acid residue is a homophenylalanine derivative residue or an N-substituted Ala residue, or the N-terminal amino acid residue of the peptide compound is an N-substituted phenylalanine derivative residue or an α,α-disubstituted amino acid residue and the C-terminal amino acid residue is a cyclic amino acid residue.

[0081]

[39] The method according to any one of [1] to

[35] , wherein the N-terminal amino acid residue of the peptide compound is an N-substituted phenylalanine residue or an N-substituted phenylalanine derivative residue, and the C-terminal amino acid residue is a cyclic amino acid residue.

[0082] [39-1]The method according to any one of [1] to

[35] , wherein the N-terminal amino acid residue of the peptide compound is an N-substituted phenylalanine derivative residue, and the C-terminal amino acid residue is a cyclic amino acid residue.

[0083]

[40] The method according to any one of [1] to

[35] , wherein the N-terminal amino acid residue of the peptide compound is an α,α-disubstituted amino acid residue, and the C-terminal amino acid residue is a cyclic amino acid residue.

[0084]

[41] The method according to any one of [1] to

[35] , wherein the N-terminal amino acid residue of the peptide compound is a cyclic amino acid residue, and the C-terminal amino acid residue is a homophenylalanine residue or a homophenylalanine derivative residue.

[0085] [41-1] The method according to any one of [1] to

[35] , wherein the N-terminal amino acid residue of the peptide compound is a cyclic amino acid residue, and the C-terminal amino acid residue is a homophenylalanine derivative residue.

[0086]

[42] The method according to any one of [1] to

[35] , wherein the N-terminal amino acid residue of the peptide compound is a cyclic amino acid residue, and the C-terminal amino acid residue is an N-substituted Ala residue.

[0087]

[43] The method according to any one of [2] to

[35] , wherein the N-terminal amino acid residue of the peptide compound is an N-substituted Gly residue, and the C-terminal amino acid residue is an N-substituted phenylalanine residue or an N-substituted phenylalanine derivative residue.

[0088] [43-1] The method according to any one of [2] to

[35] , wherein the N-terminal amino acid residue of the peptide compound is an N-substituted Gly residue, and the C-terminal amino acid residue is an N-substituted phenylalanine derivative residue.

[0089]

[44] The method according to any one of [1] to

[42] , wherein the cyclic amino acid residue is one selected from a Pro residue, a proline derivative residue, and an Aze(2) residue.

[0090]

[45] The method according to any one of [1] to

[42] , wherein the cyclic amino acid residue is one selected from a Pro residue and an Aze(2) residue.

[0091]

[46] The method according to any one of [1] to

[42] , wherein the cyclic amino acid residue is a Pro residue.

[0092]

[47] The method according to any one of [1] to

[42] , wherein the cyclic amino acid residue is an Aze(2) residue.

[0093]

[48] The method according to any one of [2] to

[39] and

[43] , wherein the N-substituted phenylalanine derivative residue is an N-alkylphenylalanine derivative residue.

[0094]

[49] The method according to

[48] , wherein the N-alkylphenylalanine derivative residue is an EtPhe derivative residue.

[0095]

[50] The method according to

[49] , wherein the EtPhe derivative residue is an EtPhe(4-Me) residue.

[0096]

[51] The method according to any one of [2] to

[38] and

[41] , wherein the homophenylalanine derivative residue is an Hph(3,5-diF-4-CF 3 ) residue.

[0097]

[52] The method according to any one of [2] to

[38] and

[40] , wherein the α,α-disubstituted amino acid residue is a cLeu residue.

[0098]

[53] The method according to any one of [2] to

[38] and

[42] , wherein the N-substituted Ala residue is an N-alkyl Ala residue.

[0099]

[54] The method according to

[53] , wherein the N-alkyl Ala residue is a MeAla residue.

[0100]

[55] The method according to any one of [2] to

[37] and

[43] , wherein the N-substituted Gly residue is an N-alkyl Gly residue.

[0101]

[56] The method according to

[55] , wherein the N-alkyl Gly residue is a MeGly residue.

[0102]

[57] The method according to any one of [2] to

[37] , wherein the N-terminal amino acid residue and the C-terminal amino acid residue contained in the peptide compound are one selected from the following a′) to e′):

[0103] a′) The N-terminal amino acid residue is an EtPhe(4-Me) residue, and the C-terminal amino acid residue is an Aze(2) residue;

[0104] b′) The N-terminal amino acid residue is a cLeu residue, and the C-terminal amino acid residue is a Pro residue;

[0105] c′) The N-terminal amino acid residue is a Pro residue, and the C-terminal amino acid residue is an Uph(3,5-diF-4-CF 3 ) residue;

[0106] d′) The N-terminal amino acid residue is a MeGly residue, and the C-terminal amino acid residue is an EtPhe(4-Me) residue; and

[0107] e') The N-terminal amino acid residue is an Aze(2) residue, and the C-terminal amino acid residue is a MeAla residue.

[0108]

[58] The method according to any one of [1] to

[57] , wherein the number of amino acid residues of the cyclic peptide compound is from 9 to 15.

[0109]

[59] The method according to any one of [1] to

[57] , wherein the number of amino acid residues of the cyclic peptide compound is 11.

[0110]

[60] The method according to any one of [1] to

[59] , wherein the peptide compound is a linear peptide compound.

[0111]

[61] The method according to

[60] , wherein the number of amino acid residues of the linear peptide compound is from 9 to 15.

[0112]

[62] The method according to

[60] , wherein the number of amino acid residues of the linear peptide compound is 11.

[0113]

[63] The method according to any one of [1] to

[57] , wherein the peptide compound is a linear peptide compound selected from the group consisting of:

[0114] [Formula 2]

[0115]

[0116] [Formula 3]

[0117]

[0118] [Formula 4]

[0119]

[0120] [Formula 5]

[0121] and

[0122] [Formula 6]

[0123] or a salt thereof, or a solvate thereof.

[0124]

[64] The method according to any one of [1] to

[63] , wherein the cyclic peptide compound, or a salt thereof, or a solvate thereof is a solvate of the cyclic peptide compound.

[0125]

[65] The method according to

[64] , wherein the solvate of the cyclic peptide compound is a hydrate of the cyclic peptide compound.

[0126]

[66] According to the method described in any one of [1] to

[65] , wherein the cyclic peptide compound is represented by the following formula (2):

[0127] [Formula 7]

[0128]

[0129] [66-1] According to the method described in any one of [1] to

[66] , wherein column chromatography is not used to separate and / or purify the cyclic peptide compound.

[0130] [66-2] According to the method described in any one of [1] to [66-1], the method further includes the step of separating and / or purifying the cyclic peptide compound by crystallization to obtain crystals of the cyclic peptide compound.

[0131] [66-3] According to the method described in [66-2], wherein the crystals of the cyclic peptide compound are non-solvate crystals or solvate crystals of the cyclic peptide compound represented by the following formula (2):

[0132] [Formula 8]

[0133]

[0134] [66-4] According to the method described in [66-3], wherein the crystals of the cyclic peptide compound are solvate crystals.

[0135] [66-5] According to the method described in [66-4], wherein the solvate crystals of the cyclic peptide compound are hydrate crystals.

[0136]

[67] According to the method described in any one of [1] to

[66] , the method further includes the step of providing the peptide compound.

[0137]

[68] According to the method described in any one of [1] to

[67] , wherein the coupling step is carried out by a liquid phase method.

[0138]

[69] According to the method described in any one of [1] to

[68] , wherein in the coupling step, the peptide compound and the base are mixed in a mixed solution obtained by mixing the solvent and the condensing reagent.

[0139]

[70] According to the method described in any one of [1] to

[69] , wherein based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the total by-products formed in the coupling step is less than 20%, less than 15%, less than 10%, less than 5%, or less than 3%.

[0140]

[71] The method according to any one of [1] to

[69] , wherein based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of each by-product in the by-products formed in the linking step is less than 15%, less than 10%, less than 5%, less than 3%, less than 1%, or an undetectable amount.

[0141]

[72] The method according to any one of [1] to

[69] , wherein based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of each by-product in the by-products formed in the linking step is less than 15%, less than 10%, less than 5%, less than 3%, less than 1%, or an undetectable amount, and the by-products are epimers, dimers, and trimers.

[0142]

[73] The method according to any one of [1] to

[69] , wherein the by-products formed in the linking step contain epimers of the cyclic peptide compound, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the epimers is less than 10%, less than 7.5%, less than 5%, less than 2.5%, or less than 1%.

[0143]

[74] The method according to any one of [1] to

[69] , wherein the by-products formed in the linking step contain dimers, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the dimers is less than 15%, less than 10%, less than 5%, less than 2.5%, or less than 1%.

[0144]

[75] The method according to any one of [1] to

[69] , wherein the by-products formed in the linking step contain trimers, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the trimers is less than 5%, less than 2.5%, less than 1%, or an undetectable amount.

[0145]

[76] The method according to any one of [1] to

[69] , wherein the by-products formed in the linking step contain dimers and trimers, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the total content of the dimers and the trimers is less than 15%, less than 10%, less than 5%, less than 2.5%, or less than 1%.

[0146]

[77] A method for producing a cyclic peptide compound represented by the following formula (2):

[0147] [Formula 10]

[0148]

[0149] A method for preparing a cyclic peptide compound, or a salt or solvate thereof, the method comprising the following steps:

[0150] (1) Providing a linear peptide compound represented by the following formula:

[0151] [Formula 9]

[0152]

[0153] or a salt or solvate thereof; and

[0154] (2) Connecting the N-terminal amino acid residue of the linear peptide compound, or a salt or solvate thereof, to the C-terminal amino acid residue of the linear peptide compound, or a salt or solvate thereof.

[0155] [77-1] The method according to

[77] , wherein column chromatography is not used to separate and / or purify the cyclic peptide compound.

[0156] [77-2] The method according to any one of

[77] to [77-1], the method further comprising the step of separating and / or purifying the cyclic peptide compound by crystallization to obtain crystals of the cyclic peptide compound.

[0157] [77-3] The method according to [77-2], wherein the crystals of the cyclic peptide compound are non-solvate crystals or solvate crystals of the cyclic peptide compound represented by the following formula (2):

[0158] [Formula 11]

[0159]

[0160] [77-4] The method according to [77-3], wherein the crystals of the cyclic peptide compound are solvate crystals.

[0161] [77-5] The method according to [77-4], wherein the solvate crystals of the cyclic peptide compound are hydrate crystals.

[0162] [77-6] The method according to

[77] , wherein the connection step is carried out by a liquid phase method.

[0163]

[78] The method according to

[77] , wherein step (2) is carried out in the presence of a solvent.

[0164]

[79] The method according to

[78] , wherein the solvent comprises one or more selected from the group consisting of acetonitrile, dimethyl carbonate and 2-MeTHF.

[0165]

[80] According to the method of

[78] , wherein the solvent is one selected from the group consisting of acetonitrile, dimethyl carbonate, and 2-MeTHF.

[0166]

[81] According to the method of

[78] , wherein the solvent is one selected from the group consisting of acetonitrile and dimethyl carbonate.

[0167]

[82] According to the method of any one of

[77] to

[81] , wherein step (2) is carried out in the presence of a condensing agent.

[0168]

[83] According to the method of

[82] , wherein the condensing agent is one selected from the group consisting of COMU, HATU, PyBOP, PyOxim, PyClop, DMT-MM, DEPBT, FDPP, T3P, and BEP-BF4.

[0169]

[84] According to the method of

[82] , wherein the condensing agent is one selected from the group consisting of COMU and HATU.

[0170]

[85] According to the method of

[82] , wherein the condensing agent is one selected from the group consisting of COMU and HATU, and the solvent comprises one or more selected from the group consisting of acetonitrile, dimethyl carbonate, and 2-MeTHF.

[0171]

[86] According to the method of

[82] , wherein the condensing agent is one selected from the group consisting of COMU and HATU, and the solvent is one selected from the group consisting of acetonitrile and dimethyl carbonate.

[0172]

[87] According to the method of any one of

[77] to

[86] , wherein the linking step is carried out in the presence of a base.

[0173]

[88] According to the method of

[87] , wherein the base is an organic base.

[0174]

[89] According to the method of

[87] , wherein the base is an organic base containing a tertiary amine.

[0175]

[90] The method according to

[87] , wherein the base is one selected from the group consisting of N,N-diisopropylethylamine (DIPEA), 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), 2,3,6,7-tetrahydro-1H,5H-9-azabenz[ij]quinolizine, 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(tetramethylguanidino)naphthalene (TMGN), 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), triethylamine (TEA), trimethylamine, 1-methylpiperidine, N,N′-dimethylpiperazine, N-methylmorpholine, N-ethylmorpholine, and p-dimethylaminopyridine (DMAP).

[0176]

[91] The method according to

[87] , wherein the base is N,N-diisopropylethylamine (DIPEA).

[0177]

[92] The method according to

[87] , wherein the coupling reagent is one selected from the group consisting of COMU, HATU, PyBOP, PyOxim, PyClop, DMT-MM, DEPBT, FDPP, T3P, and BEP-BF4, the solvent comprises one or more selected from the group consisting of acetonitrile, dimethyl carbonate, and 2-MeTHF, and the base is N,N-diisopropylethylamine (DIPEA).

[0178]

[93] The method according to

[87] , wherein the coupling reagent is one selected from the group consisting of COMU and HATU, the solvent comprises one or more selected from the group consisting of acetonitrile, dimethyl carbonate, and 2-MeTHF, and the base is N,N-diisopropylethylamine (DIPEA).

[0179]

[94] The method according to

[87] , wherein the coupling reagent is one selected from the group consisting of COMU and HATU, the solvent is one selected from the group consisting of acetonitrile and dimethyl carbonate, and the base is N,N-diisopropylethylamine (DIPEA).

[0180]

[95] The method according to any one of

[77] to

[94] , wherein in step (2), the linear peptide compound, or a salt thereof, or a solvate thereof is mixed with the base in a mixed solution obtained by mixing the solvent and the coupling reagent.

[0181]

[96] The method according to any one of

[77] to

[95] , wherein based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the total by-products formed in the step is less than 10%, less than 7.5%, less than 5%, less than 3%, or less than 1%.

[0182]

[97] The method according to any one of

[77] to

[95] , wherein based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of each by-product among the by-products formed in the step is less than 10%, less than 7.5%, less than 5%, less than 3%, less than 1%, or an undetectable amount.

[0183]

[98] The method according to any one of

[77] to

[95] , wherein based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of each by-product among the by-products formed in the step is less than 10%, less than 7.5%, less than 5%, less than 3%, less than 1%, or an undetectable amount, and the by-products are epimers, dimers, and trimers.

[0184]

[99] The method according to any one of

[77] to

[95] , wherein the by-products formed in the step include epimers of the cyclic peptide compound, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the epimers is less than 3%, less than 1%, or an undetectable value.

[0185]

[100] The method according to any one of

[77] to

[95] , wherein the by-products formed in the step include dimers, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the dimers is less than 5%, less than 3%, or less than 1%.

[0186]

[101] The method according to any one of

[77] to

[95] , wherein the by-products formed in the step include trimers, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the trimers is less than 3%, less than 1%, or an undetectable amount.

[0187]

[102] The method according to any one of

[77] to

[95] , wherein the by-products formed in the step contain dimers and trimers, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the total content of the dimer and the trimer is less than 5%, less than 3%, or less than 1%.

[0188]

[103] A method for producing a cyclic peptide compound represented by the following formula (2):

[0189] [Formula 13]

[0190]

[0191] or a salt thereof, or a solvate thereof, the method comprising the following steps:

[0192] (1) Providing a linear peptide compound represented by the following formula:

[0193] [Formula 12]

[0194]

[0195] or a salt thereof, or a solvate thereof; and

[0196] (2) Connecting the N-terminal amino acid residue of the linear peptide compound, or a salt thereof, or a solvate thereof to the C-terminal amino acid residue of the linear peptide compound, or a salt thereof, or a solvate thereof.

[0197] [103-1] The method according to

[103] , wherein column chromatography is not used to separate and / or purify the cyclic peptide compound.

[0198] [103-2] The method according to any one of

[103] to [103-1], the method further comprising the step of separating and / or purifying the cyclic peptide compound by crystallization to obtain crystals of the cyclic peptide compound.

[0199] [103-3] The method according to [103-2], wherein the crystals of the cyclic peptide compound are non-solvate crystals or solvate crystals of the cyclic peptide compound represented by the following formula (2):

[0200] [Formula 14]

[0201]

[0202] [103-4] The method according to [103-3], wherein the crystals of the cyclic peptide compound are solvate crystals.

[0203] [103-5]The method according to [103-4], wherein the solvate crystal of the cyclic peptide compound is a hydrate crystal.

[0204] [103-6]The method according to

[103] , wherein the coupling step is carried out by a liquid phase method.

[0205]

[104] The method according to

[103] , wherein step (2) is carried out in the presence of a solvent.

[0206]

[105] The method according to

[104] , wherein the solvent comprises one or more selected from the group consisting of acetonitrile, dimethyl carbonate, 2-MeTHF, and anisole.

[0207]

[106] The method according to

[104] , wherein the solvent is one selected from the group consisting of acetonitrile, dimethyl carbonate, 2-MeTHF, and anisole.

[0208]

[107] The method according to

[104] , wherein the solvent is dimethyl carbonate.

[0209]

[108] The method according to any one of

[103] to

[107] , wherein step (2) is carried out in the presence of a condensing agent.

[0210]

[109] The method according to

[108] , wherein the condensing agent is one selected from the group consisting of COMU, HATU, PyBOP, PyOxim, PyClop, and DMT-MM.

[0211]

[110] The method according to

[108] , wherein the condensing agent is one selected from the group consisting of COMU and HATU.

[0212]

[111] The method according to

[108] , wherein the condensing agent is COMU.

[0213]

[112] The method according to

[108] , wherein the condensing agent is one selected from the group consisting of COMU, HATU, PyBOP, PyOxim, PyClop, and DMT-MM, and the solvent comprises one or more selected from the group consisting of acetonitrile, dimethyl carbonate, 2-MeTHF, and anisole.

[0214]

[113] The method according to

[108] , wherein the condensing agent is COMU, and the solvent is one selected from the group consisting of acetonitrile and dimethyl carbonate.

[0215]

[114] The method according to

[108] , wherein the condensing agent is COMU, and the solvent is dimethyl carbonate.

[0216]

[115] The method according to any one of

[103] to

[114] , wherein the linking step is carried out in the presence of a base.

[0217]

[116] The method according to

[115] , wherein the base is an organic base.

[0218]

[117] The method according to

[115] , wherein the base is an organic base comprising a tertiary amine.

[0219]

[118] The method according to

[115] , wherein the base is one selected from the group consisting of: N,N-diisopropylethylamine (DIPEA), 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), 2,3,6,7-tetrahydro-1H,5H-9-azabenz[ij]quinolizine, 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(tetramethylguanidino)naphthalene (TMGN), 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), triethylamine (TEA), trimethylamine, 1-methylpiperidine, N,N'-dimethylpiperazine, N-methylmorpholine, N-ethylmorpholine, and p-dimethylaminopyridine (DMAP).

[0220]

[119] The method according to

[115] , wherein the base is N,N-diisopropylethylamine (DIPEA).

[0221]

[120] The method according to

[115] , wherein the condensation reagent is COMU, the solvent is one selected from the group consisting of acetonitrile and dimethyl carbonate, and the base is N,N-diisopropylethylamine (DIPEA).

[0222]

[121] The method according to

[115] , wherein the condensation reagent is COMU, the solvent is dimethyl carbonate, and the base is N,N-diisopropylethylamine (DIPEA).

[0223]

[122] The method according to any one of

[103] to

[121] , wherein in step (2), the linear peptide compound, or a salt thereof, or a solvate thereof is mixed with the base in a mixed solution obtained by mixing the solvent and the condensation reagent.

[0224]

[123] The method according to any one of

[103] to

[122] , wherein based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the total by-products formed in the step is less than 20%, less than 15%, less than 10%, less than 5%, or less than 3%.

[0225]

[124] The method according to any one of

[103] to

[122] , wherein based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of each by-product among the by-products formed in the step is less than 15%, less than 10%, less than 7.5%, less than 5%, less than 2.5%, or less than 1%.

[0226]

[125] The method according to any one of

[103] to

[122] , wherein based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of each by-product among the by-products formed in the step is less than 15%, less than 10%, less than 7.5%, less than 5%, less than 2.5%, or less than 1%, and the by-products are epimers, dimers, and trimers.

[0227]

[126] The method according to any one of

[103] to

[122] , wherein the by-products formed in the step include epimers of the cyclic peptide compound, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the epimers is less than 3%, less than 1%, or an undetectable value.

[0228]

[127] The method according to any one of

[103] to

[122] , wherein the by-products formed in the step include dimers, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the dimers is less than 15%, less than 10%, or less than 5%.

[0229]

[128] The method according to any one of

[103] to

[122] , wherein the by-products formed in the step include trimers, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the trimers is less than 5%, less than 3%, or less than 1%.

[0230]

[129] The method according to any one of

[103] to

[122] , wherein the by-products formed in the step contain dimers and trimers, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the total content of the dimers and the trimers is less than 20%, less than 15%, less than 10%, less than 5% or less than 3%.

[0231]

[130] A method for producing a cyclic peptide compound represented by the following formula (2):

[0232] [Formula 16]

[0233]

[0234] or a salt thereof, or a solvate thereof, the method comprising the following steps:

[0235] (1) Providing a linear peptide compound represented by the following formula:

[0236] [Formula 15]

[0237]

[0238] or a salt thereof, or a solvate thereof; and

[0239] (2) Connecting the N-terminal amino acid residue of the linear peptide compound, or a salt thereof, or a solvate thereof to the C-terminal amino acid residue of the linear peptide compound, or a salt thereof, or a solvate thereof.

[0240] [130-1] The method according to

[130] , wherein column chromatography is not used to separate and / or purify the cyclic peptide compound.

[0241] [130-2] The method according to any one of

[130] to [130-1], the method further comprising the step of separating and / or purifying the cyclic peptide compound by crystallization to obtain crystals of the cyclic peptide compound.

[0242] [130-3] The method according to [130-2], wherein the crystals of the cyclic peptide compound are non-solvate crystals or solvate crystals of the cyclic peptide compound represented by the following formula (2):

[0243] [Formula 17]

[0244]

[0245] [130-4] The method according to [130-3], wherein the crystals of the cyclic peptide compound are solvate crystals.

[0246] [130-5]The method according to [130-4], wherein the solvate crystal of the cyclic peptide compound is a hydrate crystal.

[0247] [130-6]The method according to

[130] , wherein the coupling step is carried out by a liquid phase method.

[0248]

[131] The method according to

[130] , wherein step (2) is carried out in the presence of a solvent.

[0249]

[132] The method according to

[131] , wherein the solvent comprises one or more selected from the group consisting of acetonitrile, dimethyl carbonate, 2-MeTHF, and anisole.

[0250]

[133] The method according to

[131] , wherein the solvent is one selected from the group consisting of acetonitrile, dimethyl carbonate, 2-MeTHF, and anisole.

[0251]

[134] The method according to

[131] , wherein the solvent is dimethyl carbonate.

[0252]

[135] The method according to any one of

[130] to

[134] , wherein step (2) is carried out in the presence of a condensing agent.

[0253]

[136] The method according to

[135] , wherein the condensing agent is one selected from the group consisting of COMU, HATU, PyBOP, PyOxim, PyClop, and DMT-MM.

[0254]

[137] The method according to

[135] , wherein the condensing agent is one selected from the group consisting of COMU and HATU.

[0255]

[138] The method according to

[135] , wherein the condensing agent is COMU.

[0256]

[139] The method according to

[135] , wherein the condensing agent is one selected from the group consisting of COMU, HATU, PyBOP, PyOxim, PyClop, and DMT-MM, and the solvent comprises one or more selected from the group consisting of acetonitrile, dimethyl carbonate, 2-MeTHF, and anisole.

[0257]

[140] The method according to

[135] , wherein the condensing agent is one selected from the group consisting of COMU and HATU, and the solvent is one selected from the group consisting of acetonitrile and dimethyl carbonate.

[0258]

[141] The method according to

[135] , wherein the condensation reagent is COMU and the solvent is dimethyl carbonate.

[0259]

[142] The method according to any one of

[130] to

[141] , wherein the coupling step is carried out in the presence of a base.

[0260]

[143] The method according to

[142] , wherein the base is an organic base.

[0261]

[144] The method according to

[142] , wherein the base is an organic base containing a tertiary amine.

[0262]

[145] The method according to

[142] , wherein the base is one selected from the group consisting of N,N - diisopropylethylamine (DIPEA), 1,8 - diazabicyclo[5.4.0]-7 - undecene (DBU), 2,3,6,7 - tetrahydro - 1H,5H - 9 - azabenz[ij]quinolizine, 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(tetramethylguanidino)naphthalene (TMGN), 2 - tert - butyl - 1,1,3,3 - tetramethylguanidine (BTMG), triethylamine (TEA), trimethylamine, 1 - methylpiperidine, N,N′ - dimethylpiperazine, N - methylmorpholine, N - ethylmorpholine, and p - dimethylaminopyridine (DMAP).

[0263]

[146] The method according to

[142] , wherein the base is N,N - diisopropylethylamine (DIPEA).

[0264]

[147] The method according to

[142] , wherein the condensation reagent is one selected from the group consisting of COMU and HATU, the solvent is one selected from the group consisting of acetonitrile and dimethyl carbonate, and the base is N,N - diisopropylethylamine (DIPEA).

[0265]

[148] The method according to

[142] , wherein the condensation reagent is COMU, the solvent is dimethyl carbonate, and the base is N,N - diisopropylethylamine (DIPEA).

[0266]

[149] The method according to any one of

[130] to

[148] , wherein in step (2), the linear peptide compound, or a salt thereof, or a solvate thereof is mixed with the base in a mixed solution obtained by mixing the solvent and the condensation reagent.

[0267]

[150] The method according to any one of

[130] to

[149] , wherein based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the total by-products formed in the step is less than 10%, less than 7.5%, less than 5% or less than 2.5%.

[0268]

[151] The method according to any one of

[130] to

[149] , wherein based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of each by-product in the by-products formed in the step is less than 10%, less than 7.5%, less than 5%, less than 3%, less than 1%, or an undetectable amount.

[0269]

[152] The method according to any one of

[130] to

[149] , wherein based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of each by-product in the by-products formed in the step is less than 10%, less than 7.5%, less than 5%, less than 3%, less than 1%, or an undetectable amount, and the by-products are epimers, dimers and trimers.

[0270]

[153] The method according to any one of

[130] to

[149] , wherein the by-products formed in the step include epimers of the cyclic peptide compound, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the epimers is less than 7.5%, less than 5%, less than 3% or less than 1%.

[0271]

[154] The method according to any one of

[130] to

[149] , wherein the by-products formed in the step include dimers, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the dimers is less than 10%, less than 7.5%, less than 5%, less than 2.5% or less than 1%.

[0272]

[155] The method according to any one of

[130] to

[149] , wherein the by-products formed in the step include trimers, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the trimers is less than 3%, less than 1% or an undetectable amount.

[0273]

[156] The method according to any one of

[130] to

[149] , wherein the by-products formed in the step contain dimers and trimers, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the total content of the dimer and the trimer is less than 10%, less than 7.5%, less than 5%, less than 2.5%, or less than 1%.

[0274]

[157] A method for producing a cyclic peptide compound represented by the following formula (2):

[0275] [Formula 19]

[0276]

[0277] or a salt thereof, or a solvate thereof, the method comprising the following steps:

[0278] (1) Providing a linear peptide compound represented by the following formula:

[0279] [Formula 18]

[0280]

[0281] or a salt thereof, or a solvate thereof; and

[0282] (2) Connecting the N-terminal amino acid residue of the linear peptide compound, or a salt thereof, or a solvate thereof to the C-terminal amino acid residue of the linear peptide compound, or a salt thereof, or a solvate thereof.

[0283] [157-1]The method according to

[157] , wherein column chromatography is not used to separate and / or purify the cyclic peptide compound.

[0284] [157-2]The method according to any one of

[157] to [157-1], the method further comprising the step of separating and / or purifying the cyclic peptide compound by crystallization to obtain crystals of the cyclic peptide compound.

[0285] [157-3]The method according to [157-2], wherein the crystals of the cyclic peptide compound are non-solvate crystals or solvate crystals of the cyclic peptide compound represented by the following formula (2):

[0286] [Formula 20]

[0287]

[0288] [157-4]The method according to [157-3], wherein the crystals of the cyclic peptide compound are solvate crystals.

[0289] [157-5]The method according to [157-4], wherein the solvate crystal of the cyclic peptide compound is a hydrate crystal.

[0290] [157-6]The method according to

[157] , wherein the coupling step is carried out by a liquid phase method.

[0291]

[158] The method according to

[157] , wherein step (2) is carried out in the presence of a solvent.

[0292]

[159] The method according to

[158] , wherein the solvent comprises one or both selected from acetonitrile and dimethyl carbonate.

[0293]

[160] The method according to

[158] , wherein the solvent is dimethyl carbonate.

[0294]

[161] The method according to any one of

[157] to

[160] , wherein step (2) is carried out in the presence of a condensing agent.

[0295]

[162] The method according to

[161] , wherein the condensing agent is one selected from the group consisting of COMU, HATU, PyBOP, PyOxim, PyClop, DMT-MM and DEPBT.

[0296]

[163] The method according to

[161] , wherein the condensing agent is one selected from the group consisting of COMU and HATU.

[0297]

[164] The method according to

[161] , wherein the condensing agent is HATU.

[0298]

[165] The method according to

[161] , wherein the condensing agent is one selected from the group consisting of COMU, HATU, PyBOP, PyOxim, PyClop, DMT-MM and DEPBT, and the solvent comprises one or both selected from the group consisting of acetonitrile and dimethyl carbonate.

[0299] [165-1]The method according to

[161] , wherein the condensing agent is one selected from the group consisting of COMU and HATU, and the solvent is one selected from the group consisting of acetonitrile and dimethyl carbonate.

[0300]

[166] The method according to

[161] , wherein the condensing agent is one selected from the group consisting of COMU and HATU, and the solvent is dimethyl carbonate.

[0301]

[167] The method according to

[161] , wherein the condensation reagent is HATU and the solvent is dimethyl carbonate.

[0302]

[168] The method according to any one of

[157] to

[167] , wherein the linking step is carried out in the presence of a base.

[0303]

[169] The method according to

[168] , wherein the base is an organic base.

[0304]

[170] The method according to

[168] , wherein the base is an organic base containing a tertiary amine.

[0305]

[171] The method according to

[168] , wherein the base is one selected from the group consisting of N,N - diisopropylethylamine (DIPEA), 1,8 - diazabicyclo[5.4.0]undec - 7 - ene (DBU), 2,3,6,7 - tetrahydro - 1H,5H - 9 - azabenz[ij]quinolizine, 1,4 - diazabicyclo[2.2.2]octane (DABCO), 1,5 - diazabicyclo[4.3.0]non - 5 - ene (DBN), 7 - methyl - 1,5,7 - triazabicyclo[4.4.0]dec - 5 - ene, 1,1,3,3 - tetramethylguanidine (TMG), 1,8 - bis(tetramethylguanidino)naphthalene (TMGN), 2 - tert - butyl - 1,1,3,3 - tetramethylguanidine (BTMG), triethylamine (TEA), trimethylamine, 1 - methylpiperidine, N,N′ - dimethylpiperazine, N - methylmorpholine, N - ethylmorpholine, and p - dimethylaminopyridine (DMAP).

[0306]

[172] The method according to

[168] , wherein the base is N,N - diisopropylethylamine (DIPEA).

[0307] [172 - 1]The method according to

[168] , wherein the condensation reagent is one selected from the group consisting of COMU and HATU, the solvent is one selected from the group consisting of acetonitrile and dimethyl carbonate, and the base is N,N - diisopropylethylamine (DIPEA).

[0308]

[173] The method according to

[168] , wherein the condensation reagent is one selected from the group consisting of COMU and HATU, the solvent is dimethyl carbonate, and the base is N,N - diisopropylethylamine (DIPEA).

[0309]

[174] The method according to

[168] , wherein the condensation reagent is HATU, the solvent is dimethyl carbonate, and the base is N,N - diisopropylethylamine (DIPEA).

[0310]

[175] The method according to any one of

[157] to

[174] , wherein in step (2), the linear peptide compound, or a salt or solvate thereof, is mixed with the base in a mixed solution obtained by mixing the solvent and the condensing reagent.

[0311]

[176] The method according to any one of

[157] to

[175] , wherein based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the total by-products formed in the step is less than 10%, less than 7.5%, less than 5% or less than 2.5%.

[0312]

[177] The method according to any one of

[157] to

[175] , wherein based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of each by-product among the by-products formed in the step is less than 10%, less than 7.5%, less than 5%, less than 3%, less than 1%, or is an undetectable amount.

[0313]

[178] The method according to any one of

[157] to

[175] , wherein based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of each by-product among the by-products formed in the step is less than 10%, less than 7.5%, less than 5%, less than 3%, less than 1%, or is an undetectable amount, and the by-products are epimers, dimers and trimers.

[0314]

[179] The method according to any one of

[157] to

[175] , wherein the by-products formed in the step include epimers of the cyclic peptide compound, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the epimers is less than 7.5%, less than 5%, less than 3% or less than 1%.

[0315]

[180] The method according to any one of

[157] to

[175] , wherein the by-products formed in the step include dimers, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the dimers is less than 10%, less than 7.5%, less than 5%, less than 2.5% or less than 1%.

[0316]

[181] The method according to any one of

[157] to

[175] , wherein the by-product formed in the step contains a trimer, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the trimer is less than 3%, less than 1%, or an undetectable amount.

[0317]

[182] The method according to any one of

[157] to

[175] , wherein the by-product formed in the step contains a dimer and a trimer, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the total content of the dimer and the trimer is less than 10%, less than 7.5%, less than 5%, less than 2.5%, or less than 1%.

[0318]

[183] A method for producing a cyclic peptide compound represented by the following formula (2):

[0319] [Formula 22]

[0320]

[0321] or a salt thereof, or a solvate thereof, the method comprising the following steps:

[0322] (1) Providing a linear peptide compound represented by the following formula:

[0323] [Formula 21]

[0324]

[0325] or a salt thereof, or a solvate thereof; and

[0326] (2) Connecting the N-terminal amino acid residue of the linear peptide compound, or a salt thereof, or a solvate thereof to the C-terminal amino acid residue of the linear peptide compound, or a salt thereof, or a solvate thereof.

[0327] [183-1] The method according to

[182] , wherein column chromatography is not used to separate and / or purify the cyclic peptide compound.

[0328] [183-2] The method according to any one of

[183] to [183-1], the method further comprising the step of separating and / or purifying the cyclic peptide compound by crystallization to obtain crystals of the cyclic peptide compound.

[0329] [183-3] The method according to [183-2], wherein the crystals of the cyclic peptide compound are non-solvate crystals or solvate crystals of the cyclic peptide compound represented by the following formula (2):

[0330] [Formula 23]

[0331]

[0332] [183-4]The method according to [183-3], wherein the crystal of the cyclic peptide compound is a solvate crystal.

[0333] [183-5]The method according to [183-4], wherein the solvate crystal of the cyclic peptide compound is a hydrate crystal.

[0334] [183-6]The method according to

[183] , wherein the coupling step is carried out by a liquid phase method.

[0335]

[184] The method according to

[183] , wherein step (2) is carried out in the presence of a solvent.

[0336]

[185] The method according to

[184] , wherein the solvent comprises one or both selected from the group consisting of acetonitrile and dimethyl carbonate.

[0337]

[186] The method according to

[184] , wherein the solvent is acetonitrile.

[0338]

[187] The method according to any one of

[183] to

[186] , wherein step (2) is carried out in the presence of a condensing agent.

[0339]

[188] The method according to

[187] , wherein the condensing agent is one selected from the group consisting of COMU, HATU, PyBOP, PyOxim, PyClop and DMT-MM.

[0340]

[189] The method according to

[187] , wherein the condensing agent is one selected from the group consisting of COMU, HATU and PyOxim.

[0341]

[190] The method according to

[187] , wherein the condensing agent is COMU.

[0342]

[191] The method according to

[187] , wherein the condensing agent is one selected from the group consisting of COMU, HATU, PyBOP, PyOxim, PyClop and DMT-MM, and the solvent comprises one or both selected from the group consisting of acetonitrile and dimethyl carbonate.

[0343]

[192] The method according to

[187] , wherein the condensing agent is one selected from the group consisting of COMU, HATU and PyOxim, and the solvent is one selected from the group consisting of acetonitrile and dimethyl carbonate.

[0344]

[193] The method according to

[187] , wherein the condensation reagent is COMU and the solvent is one selected from the group consisting of acetonitrile and dimethyl carbonate.

[0345] [193-1]The method according to

[187] , wherein the condensation reagent is COMU and the solvent is acetonitrile.

[0346] [193-2]The method according to

[187] , wherein the condensation reagent is HATU and the solvent is dimethyl carbonate.

[0347]

[194] The method according to

[187] , wherein the condensation reagent is PyOxim and the solvent is dimethyl carbonate.

[0348]

[195] The method according to any one of

[183] to

[194] , wherein the linking step is carried out in the presence of a base.

[0349]

[196] The method according to

[195] , wherein the base is an organic base.

[0350]

[197] The method according to

[195] , wherein the base is an organic base containing a tertiary amine.

[0351]

[198] The method according to

[195] , wherein the base is one selected from the group consisting of: N,N-diisopropylethylamine (DIPEA), 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), 2,3,6,7-tetrahydro-1H,5H-9-azabenz[ij]quinolizine, 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(tetramethylguanidino)naphthalene (TMGN), 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), triethylamine (TEA), trimethylamine, 1-methylpiperidine, N,N′-dimethylpiperazine, N-methylmorpholine, N-ethylmorpholine, and p-dimethylaminopyridine (DMAP).

[0352]

[199] The method according to

[195] , wherein the base is N,N-diisopropylethylamine (DIPEA).

[0353]

[200] The method according to

[195] , wherein the condensing reagent is one selected from the group consisting of COMU, HATU, and PyOxim, the solvent is one selected from the group consisting of acetonitrile and dimethyl carbonate, and the base is N,N-diisopropylethylamine (DIPEA).

[0354]

[201] The method according to

[195] , wherein the condensing reagent is COMU, the solvent is one selected from the group consisting of acetonitrile and dimethyl carbonate, and the base is N,N-diisopropylethylamine (DIPEA).

[0355] [201-1]The method according to

[195] , wherein the condensing reagent is COMU, the solvent is acetonitrile, and the base is N,N-diisopropylethylamine (DIPEA).

[0356] [201-2]The method according to

[195] , wherein the condensing reagent is HATU, the solvent is dimethyl carbonate, and the base is N,N-diisopropylethylamine (DIPEA).

[0357]

[202] The method according to

[195] , wherein the condensing reagent is PyOxim, the solvent is dimethyl carbonate, and the base is N,N-diisopropylethylamine (DIPEA).

[0358]

[203] The method according to any one of

[183] to

[202] , wherein in step (2), the linear peptide compound, or a salt thereof, or a solvate thereof is mixed with the base in a mixed solution obtained by mixing the solvent and the condensing reagent.

[0359]

[204] The method according to any one of

[183] to

[203] , wherein based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the total by-products formed in the step is less than 15%, less than 10%, less than 7.5%, or less than 5%.

[0360]

[205] The method according to any one of

[183] to

[203] , wherein based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of each by-product in the by-products formed in the step is less than 10%, less than 7.5%, less than 5%, less than 3%, less than 1%, or is an undetectable amount.

[0361]

[206] A method according to any one of

[183] to

[203] , wherein based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of each by-product in the by-products formed in the step is less than 10%, less than 7.5%, less than 5%, less than 3%, less than 1%, or an undetectable amount, and the by-products are epimers, dimers, and trimers.

[0362]

[207] A method according to any one of

[183] to

[203] , wherein the by-products formed in the step include epimers of the cyclic peptide compound, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the epimers is less than 5%, less than 3%, or less than 1%.

[0363]

[208] A method according to any one of

[183] to

[203] , wherein the by-products formed in the step include dimers, and based on the total amount of the product, as determined by the UV area value at 220 nm through HPLC analysis, the content of the dimers is less than 10%, less than 7.5%, or less than 5%.

[0364]

[209] A method according to any one of

[183] to

[203] , wherein the by-products formed in the step include trimers, and based on the total amount of the product, as determined by the UV area value at 220 nm through HPLC analysis, the content of the trimers is less than 3%, less than 1%, or an undetectable amount.

[0365]

[210] A method according to any one of

[183] to

[203] , wherein the by-products formed in the step include dimers and trimers, and based on the total amount of the product, as determined by the UV area value at 220 nm through HPLC analysis, the total content of the dimers and the trimers is less than 10%, less than 7.5%, or less than 5%.

[0366]

[211] A method for inhibiting epimerization of a cyclic peptide compound in the production of a cyclic peptide compound, or a salt thereof, or a solvate thereof, the method comprising

[0367] the step of linking the N-terminal amino acid residue of a peptide compound with the C-terminal amino acid residue of the peptide compound in a solvent, wherein

[0368] at least one of the N-terminal amino acid residue and the C-terminal amino acid residue is a cyclic amino acid residue, and

[0369] The solvent includes one or more selected from the group consisting of acetonitrile, dimethyl carbonate, 2-MeTHF, and anisole.

[0370]

[212] A method for inhibiting the epimerization of a cyclic peptide compound, or a salt or solvate thereof, in the production of the cyclic peptide compound, the method comprising

[0371] the step of linking the N-terminal amino acid residue of the peptide compound to the C-terminal amino acid residue of the peptide compound in a solvent, wherein

[0372] the N-terminal amino acid residue and the C-terminal amino acid residue of the peptide compound are any one of the following a) to e):

[0373] a) The N-terminal amino acid residue is an N-substituted phenylalanine residue or an N-substituted phenylalanine derivative residue, and the C-terminal amino acid residue is a cyclic amino acid residue;

[0374] b) The N-terminal amino acid residue is an α,α-disubstituted amino acid residue, and the C-terminal amino acid residue is a cyclic amino acid residue;

[0375] c) The N-terminal amino acid residue is a cyclic amino acid residue, and the C-terminal amino acid residue is a homophenylalanine residue or a homophenylalanine derivative residue;

[0376] d) The N-terminal amino acid residue is a cyclic amino acid residue, and the C-terminal amino acid residue is an N-substituted Ala residue; and

[0377] e) The N-terminal amino acid residue is an N-substituted Gly residue, and the C-terminal amino acid residue is an N-substituted phenylalanine residue or an N-substituted phenylalanine derivative residue.

[0378]

[213] A method for inhibiting the epimerization of a cyclic peptide compound, or a salt or solvate thereof, in the production of the cyclic peptide compound, the method comprising the method according to any one of [1] to

[210] .

[0379]

[214] The method according to any one of

[211] to

[213] , wherein, based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the epimer formed in the step is less than 20%, less than 15%, less than 10%, less than 5%, or less than 3%.

[0380]

[215] According to the method according to any one of

[211] to

[213] , wherein based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the epimer formed in the step is less than 15%, less than 10%, less than 5%, less than 3%, less than 1%, or an undetectable amount.

[0381]

[216] A method for inhibiting the formation of oligomers in the production of a cyclic peptide compound, or a salt or solvate thereof, the method comprising

[0382] a step of linking the N-terminal amino acid residue of a peptide compound to the C-terminal amino acid residue of the peptide compound in a solvent, wherein

[0383] at least one of the N-terminal amino acid residue and the C-terminal amino acid residue is a cyclic amino acid residue, and

[0384] the solvent includes one or more selected from the group consisting of acetonitrile, dimethyl carbonate, 2-MeTHF, and anisole.

[0385]

[217] A method for inhibiting the formation of oligomers in the production of a cyclic peptide compound, or a salt or solvate thereof, the method comprising

[0386] a step of linking the N-terminal amino acid residue of a peptide compound to the C-terminal amino acid residue of the peptide compound in a solvent, wherein

[0387] the N-terminal amino acid residue and the C-terminal amino acid residue of the peptide compound are any one of the following a) to e):

[0388] a) The N-terminal amino acid residue is an N-substituted phenylalanine residue or an N-substituted phenylalanine derivative residue, and the C-terminal amino acid residue is a cyclic amino acid residue;

[0389] b) The N-terminal amino acid residue is an α,α-disubstituted amino acid residue, and the C-terminal amino acid residue is a cyclic amino acid residue;

[0390] c) The N-terminal amino acid residue is a cyclic amino acid residue, and the C-terminal amino acid residue is a homophenylalanine residue or a homophenylalanine derivative residue;

[0391] d) The N-terminal amino acid residue is a cyclic amino acid residue, and the C-terminal amino acid residue is an N-substituted Ala residue; and

[0392] e) The N-terminal amino acid residue is an N-substituted Gly residue, and the C-terminal amino acid residue is an N-substituted phenylalanine residue or an N-substituted phenylalanine derivative residue.

[0393]

[218] A method for inhibiting the formation of oligomers in the production of a cyclic peptide compound, or a salt thereof, or a solvate thereof, the method comprising the method according to any one of [1] to

[210] .

[0394]

[219] The method according to any one of

[216] to

[218] , wherein the by-product formed in the step contains a dimer, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the dimer is less than 15%, less than 10%, less than 5%, less than 2.5% or less than 1%.

[0395]

[220] The method according to any one of

[216] to

[218] , wherein the by-product formed in the step contains a trimer, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the trimer is less than 5%, less than 2.5%, less than 1% or an undetectable amount.

[0396]

[221] The method according to any one of

[216] to

[218] , wherein the by-product formed in the step contains a dimer and a trimer, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the total content of the dimer and the trimer is less than 15%, less than 10%, less than 5%, less than 2.5% or less than 1%.

[0397] In the above numbers, unless otherwise specified, the numbers cited in the dependent items include the branch numbers of the said numbers. For example,

[66] cited in the dependent items indicates not only

[66] , but also its branch numbers [66-1], etc. The same applies to other numbers.

[0398] [Advantages of the Invention]

[0399] According to the present invention, even when the cyclic peptide compound has an amino acid sequence containing a plurality of non-natural amino acid residues, the cyclic peptide compound, or a salt thereof, or a solvate thereof can be effectively produced, while suppressing the epimerization of amino acid residues and the formation of oligomers. The production method of the present invention enables the reduction of the production cost of peptide compounds, and also enables the reduction of the environmental load. Therefore, the production method of the present invention is particularly useful for large-scale peptide synthesis. Detailed Embodiments

[0400] Abbreviation

[0401] The abbreviations used herein are listed below.

[0402] 2-MeTHF: 2-Methyltetrahydrofuran

[0403] EtOAc: Ethyl acetate

[0404] Alloc: Allyloxycarbonyl

[0405] BEP: 2-Bromo-1-ethylpyridinium tetrafluoroborate

[0406] BHT: 2,6-Di-tert-butyl-4-methylphenol

[0407] Boc: tert-Butyloxycarbonyl

[0408] Cbz: Benzyloxycarbonyl

[0409] COMU: (1-Cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate

[0410] CPME: Cyclopentyl methyl ether

[0411] CSA: 10-Camphorsulfonic acid

[0412] DEPBT: Diethyl (3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl) phosphate

[0413] DIPEA: N,N-Diisopropylethylamine

[0414] DMA: Dimethylacetamide

[0415] DMAP: 4-Dimethylaminopyridine

[0416] DMF: N,N-Dimethylformamide

[0417] DMSO: Dimethyl sulfoxide

[0418] DMT-MM: 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholine hydrochloride

[0419] EDCI: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0420] FDPP: Pentafluorophenyl diphenylphosphinate

[0421] Fmoc: 9-Fluorenylmethyloxycarbonyl

[0422] HATU: O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate

[0423] HMDS: 1,1,1,3,3,3-Hexamethyldisilazane

[0424] HOAt: 1-Hydroxy-7-azabenzotriazole

[0425] HOBt: 1-Hydroxybenzotriazole

[0426] IPAc: Isopropyl acetate

[0427] MeCN: Acetonitrile

[0428] MTBE: Methyl tert-butyl ether

[0429] 2-MeTHF: 2-Methyltetrahydrofuran

[0430] MTHP: 4-Methyltetrahydropyran

[0431] NMM: 4-Methylmorpholine

[0432] NMP: N-Methylpyrrolidone

[0433] PyBOP: 1H-Benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate

[0434] PyClop: Chlorotris(pyrrolidino)phosphonium hexafluorophosphate

[0435] PyOxim: (Ethyl cyano(hydroxyimino)acetato-O2)-tris(1-pyrrolidino)-phosphonium hexafluorophosphate

[0436] T3P: Propylphosphonic anhydride

[0437] TBAF: Tetrabutylammonium fluoride

[0438] Teoc: 2-(Trimethylsilyl)ethoxycarbonyl

[0439] TFA: Trifluoroacetic acid

[0440] THF: Tetrahydrofuran

[0441] TMSOTf: Trimethylsilyl trifluoromethanesulfonate

[0442] Troc: 2,2,2-Trichloroethoxycarbonyl Definition of functional groups, etc. (All terms and phrases in this text are used in the manner commonly understood in the art. Examples are given below, but they are not limited to these.)

[0443] As used herein, examples of "halogen atom" include F, Cl, Br, and I.

[0444] As used herein, the term "alkyl" is a monovalent group derived by removing any one hydrogen atom from an aliphatic hydrocarbon and having a subset of hydrocarbon or hydrocarbyl group structures that contain no heteroatoms (which are atoms other than carbon and hydrogen atoms) or unsaturated carbon-carbon bonds and contain hydrogen and carbon atoms in the backbone. Alkyl includes not only straight-chain forms but also branched-chain forms. Specifically, the alkyl is an alkyl having 1 to 20 carbon atoms (C 1 -C 20 ), preferably a C 1 -C 10 alkyl, more preferably a C 1 -C 6 alkyl. Hereinafter, "C p -C q " means that it has p to q carbon atoms. Specific examples of alkyl 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.

[0445] As used herein, the term "alkenyl" is a monovalent group having at least one double bond (two adjacent SP 2 carbon atoms). Depending on the conformation of the double bond and substituents (if any), the geometric configuration of the double bond can exhibit entgegen (E) or zusammen (Z) as well as cis or trans conformations. Alkenyl includes not only straight-chain forms but also branched-chain forms. The alkenyl is preferably a C 2 -C 10 alkenyl, more preferably a C 2 -C 6 alkenyl. Specific examples thereof include vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl (which includes cis and trans), 3-butenyl, pentenyl, 3-methyl-2-butenyl, and hexenyl.

[0446] As used herein, the term "alkynyl" is a monovalent group having at least one triple bond (two adjacent SP carbon atoms). Alkynyl includes not only straight-chain forms but also branched-chain forms. The alkynyl is preferably a C 2 -C 10 alkynyl, more preferably a C 2 -C6 Alkynyl. Specific examples thereof include ethynyl, 1-propynyl, propargyl, 3-butynyl, pentynyl, hexynyl, 3-phenyl-2-propynyl, 3-(2'-fluorophenyl)-2-propynyl, 2-hydroxy-2-propynyl, 3-(3-fluorophenyl)-2-propynyl, and 3-methyl-(5-phenyl)-4-pentynyl.

[0447] As used herein, the term "cycloalkyl" means a saturated or partially saturated cyclic monovalent aliphatic hydrocarbon group and includes monocyclic, bicyclic, and spiro rings. Cycloalkyl is preferably C 3 -C 8 Cycloalkyl. Specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, and spiro[3.3]heptyl.

[0448] As used herein, the term "aryl" means a monovalent aromatic hydrocarbon ring, and preferably is C 6 -C 10 Aryl. Specific examples of aryl include phenyl and naphthyl (e.g., 1-naphthyl and 2-naphthyl).

[0449] As used herein, the term "heterocyclic group" means a non-aromatic cyclic monovalent group containing carbon atoms and 1 to 5 heteroatoms. The heterocyclic group may have double bonds and / or triple bonds in the ring. The carbon atoms in the ring can be oxidized to form carbonyl groups, and the ring can be monocyclic or fused rings. The number of atoms constituting the ring is preferably 4 to 10 (4-membered to 10-membered heterocyclic group), more preferably 4 to 7 (4-membered to 7-membered heterocyclic group). Specific examples of the heterocyclic group include azetidinyl, oxiranyl, oxetanyl, azetidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, tetrahydropyridyl, tetrahydropyrimidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolidinyl, imidolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,2-thiazinane, thiazolidinyl, azetidinyl, oxazolidinone, benzodioxolyl, benzoxazolyl, dioxolanyl, dioxanyl, tetrahydropyrrolo[1,2-c]imidazole, thiolanyl, 3,6-diazabicyclo[3.1.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 3-oxa-8-azabicyclo[3.2.1]octyl, sultam, and 2-oxaspiro[3.3]heptyl.

[0450] As used herein, the term "heteroaryl" means an aromatic cyclic monovalent group containing carbon atoms and 1 to 5 heteroatoms. The ring can be a monocyclic ring, or a fused ring with other rings, and can also be partially saturated. The number of atoms forming the ring is preferably 5 to 10 (5-membered to 10-membered heteroaryl), more preferably 5 to 7 (5-membered to 7-membered heteroaryl). Specific examples of heteroaryl include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, benzofuryl, benzothienyl, benzothiadiazole, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl, indolizinyl, and imidazopyridyl.

[0451] As used herein, the term "alkoxy" means an oxy group bonded to "alkyl" as defined above, and is preferably C 1 -C 6 alkoxy. Specific examples of alkoxy include methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and 3-methylbutoxy.

[0452] As used herein, the term "alkenyloxy" means an oxy group bonded to "alkenyl" as defined above, and is preferably C 2 -C 6 alkenyloxy. Specific examples of alkenyloxy include vinyloxy, allyloxy, 1-propenyloxy, 2-propenyloxy, 1-butenyloxy, 2-butenyloxy (including cis and trans), 3-butenyloxy, pentyloxy, and hexyloxy.

[0453] As used herein, the term "cycloalkoxy" means an oxy group bonded to "cycloalkyl" as defined above, and is preferably C 3 -C 8 cycloalkoxy. Specific examples of cycloalkoxy include cyclopropoxy, cyclobutoxy, and cyclopentyloxy.

[0454] As used herein, the term "aryloxy" means an oxy group bonded to "aryl" as defined above, and is preferably C 6 -C 10 aryloxy. Specific examples of aryloxy include phenoxy, 1-naphthyloxy, and 2-naphthyloxy.

[0455] As used herein, the term "amino" in the narrow sense means -NH 2, and in a broad sense means -NRR'. Herein, R and R' are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl, or R and R' together with the nitrogen atom to which they are attached form a ring. Preferred examples of the amino group include -NH 2 , mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino and 4- to 8-membered ring amino.

[0456] As used herein, the term "monoalkylamino" means the "amino" group defined above, where R is hydrogen and R' is the "alkyl" defined above, and preferably mono-C 1 -C 6 alkylamino. Specific examples of monoalkylamino include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, sec-butylamino and tert-butylamino.

[0457] As used herein, the term "dialkylamino" means the "amino" group defined above, where R and R' are each independently the "alkyl" defined above, and preferably di-C 1 -C 6 alkylamino. Specific examples of dialkylamino include dimethylamino and diethylamino.

[0458] As used herein, the term "ring amino" means the "amino" group defined above, where R and R' together with the nitrogen atom to which they are bonded form a ring, and preferably a 4- to 8-membered ring amino. Specific examples of ring amino include 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-morpholinyl, 3-oxazolidinyl, 1,1-dioxothiomorpholin-4-yl and 3-oxa-8-azabicyclo[3.2.1]octan-8-yl.

[0459] As used herein, "protected amino" means an amino group protected by an optional protecting group. Specific examples of protected amino include amino protected by a protecting group such as Boc, Fmoc, Cbz, Troc, A11oc, Teoc or Alloc.

[0460] As used herein, the term "aminocarbonyl" means a carbonyl group bonded to the "amino" defined above, and preferably -CONH 2 , mono-C 1 -C 6 alkylaminocarbonyl, di-C 1 -C 6 alkylaminocarbonyl, or 4- to 8-membered ring aminocarbonyl. Specific examples of aminocarbonyl include -CONH2 , dimethylaminocarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, 1-piperazinylcarbonyl, 4-morpholinylcarbonyl, 3-oxazolidinylcarbonyl, 1,1-dioxothiomorpholin-4-ylcarbonyl, and 3-oxa-8-azabicyclo[3.2.1]oct-8-ylcarbonyl.

[0461] As used herein, the term "alkenyloxycarbonyl" means a carbonyl group bonded to an "alkenyloxy" as defined above, and is preferably C 2 -C 6 alkenyloxycarbonyl. Specific examples of alkenyloxycarbonyl include vinyloxycarbonyl, allyloxycarbonyl, 1-propenyloxycarbonyl, 2-propenyloxycarbonyl, 1-butenyloxycarbonyl, 2-butenyloxycarbonyl (including cis and trans), 3-butenyloxycarbonyl, pentyenyloxycarbonyl, and hexyenyloxycarbonyl.

[0462] As used herein, the term "alkylsulfonyl" means a sulfonyl group bonded to an "alkyl" as defined above, and is preferably C 1 -C 6 alkylsulfonyl. Specific examples of alkylsulfonyl include methylsulfonyl.

[0463] As used herein, the term "hydroxyalkyl" means a group in which one or more hydrogens of the "alkyl" as defined above are replaced by a hydroxy group, and is preferably C 1 -C 6 hydroxyalkyl. Specific examples of hydroxyalkyl include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, and 5-hydroxypentyl.

[0464] As used herein, the term "haloalkyl" means a group in which one or more hydrogens of the "alkyl" as defined above are replaced by a halogen, and is preferably C 1 -C 6 haloalkyl, more preferably C 1 -C 6 fluoroalkyl. Specific examples of haloalkyl include difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3-difluoropropyl, 4,4-difluorobutyl, and 5,5-difluoropentyl.

[0465] As used herein, the term "cyanoalkyl" means a group in which one or more hydrogens of the "alkyl" as defined above are replaced by a cyano group, and is preferably C 1 -C 6 cyanoalkyl. Specific examples of cyanoalkyl include cyanomethyl and 2-cyanoethyl.

[0466] As used herein, the term "aminoalkyl" means a group in which one or more hydrogens of "alkyl" as defined above are replaced by "amino" as defined above, and is preferably C 1 -C 6 aminoalkyl. Specific examples of aminoalkyl include 1-pyridylmethyl, 2-(1-piperidyl)ethyl, 3-(1-piperidyl)propyl, and 4-aminobutyl.

[0467] As used herein, the term "cyanoalkyl" means a group in which one or more hydrogens of "alkyl" as defined above are replaced by cyano, and is preferably C 2 -C 6 cyanoalkyl. A specific example of carboxyalkyl is carboxymethyl.

[0468] As used herein, the term "alkenyloxycarbonylalkyl" means a group in which one or more hydrogens of "alkyl" as defined above are replaced by "alkenyloxycarbonyl" as defined above, and is preferably C 2 -C 6 alkenyloxycarbonyl-C 1 -C 6 alkyl, more preferably C 2 -C 6 alkenyloxycarbonyl-C 1 -C 2 alkyl. Specific examples of alkenyloxycarbonylalkyl include allyloxycarbonylmethyl and 2-(allyloxycarbonyl)ethyl.

[0469] As used herein, the term "alkoxyalkyl" means a group in which one or more hydrogens of "alkyl" as defined above are replaced by "alkoxy" as defined above, and is preferably C 1 -C 6 alkoxy-C 1 -C 6 alkyl, more preferably C 1 -C 6 alkoxy-C 1 -C 2 alkyl. Specific examples of alkoxyalkyl include methoxymethyl, ethoxymethyl, 1-propoxymethyl, 2-propoxymethyl, n-butoxymethyl, isobutoxymethyl, sec-butoxymethyl, tert-butoxymethyl, pentyloxymethyl, 3-methylbutoxymethyl, 1-methoxyethyl, 2-methoxyethyl, and 2-ethoxyethyl.

[0470] As used herein, the term "cycloalkylalkyl" means a group in which one or more hydrogens of "alkyl" as defined above are replaced by "cycloalkyl" as defined above, and is preferably C 3 -C 8 cycloalkyl-C 1 -C6 alkyl, more preferably C 3 -C 6 cycloalkyl-C 1 -C 2 alkyl. Specific examples of cycloalkylalkyl include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl.

[0471] As used herein, the term "cycloalkyloxyalkyl" means a group in which one or more hydrogens of the "alkyl" defined above are replaced by the "cycloalkyloxy" defined above, and is preferably C 3 -C 8 cycloalkyloxy-C 1 -C 6 alkyl, more preferably C 3 -C 6 cycloalkyloxy-C 1 -C 2 alkyl. Specific examples of cycloalkyloxyalkyl include cyclopropoxymethyl and cyclobutoxymethyl.

[0472] As used herein, the term "heterocyclylalkyl" means a group in which one or more hydrogens of the "alkyl" defined above are replaced by the "heterocyclyl" defined above, and is preferably 4- to 7-membered heterocyclyl-C 1 -C 6 alkyl, more preferably 4- to 7-membered heterocyclyl-C 1 -C 2 alkyl. Specific examples of heterocyclylalkyl include 2-(tetrahydro-2H-pyran-4-yl)ethyl and 2-(azetidin-3-yl)ethyl.

[0473] As used herein, the term "alkylsulfonylalkyl" means a group in which one or more hydrogens of the "alkyl" defined above are replaced by the "alkylsulfonyl" defined above, and is preferably C 1 -C 6 alkylsulfonyl-C 1 -C 6 alkyl, more preferably C 1 -C 6 alkylsulfonyl-C 1 -C 2 alkyl. Specific examples of alkylsulfonylalkyl include methylsulfonylmethyl and 2-(methylsulfonyl)ethyl.

[0474] As used herein, the term "aminocarbonylalkyl" means a group in which one or more hydrogens of the "alkyl" defined above are replaced by the "aminocarbonyl" defined above, and is preferably aminocarbonyl-C 1 -C 6 alkyl, more preferably aminocarbonyl-C 1-C 4 Alkyl. Specific examples of aminocarbonylalkyl include methylaminocarbonylmethyl, dimethylaminocarbonylmethyl, tert-butylaminocarbonylmethyl, 1-azetidinylcarbonylmethyl, 1-pyrrolidinylcarbonylmethyl, 1-piperidinylcarbonylmethyl, 4-morpholinylcarbonylmethyl, 2-(methylaminocarbonyl)ethyl, 2-(dimethylaminocarbonyl)ethyl, 2-(1-azetidinylcarbonyl)ethyl, 2-(1-pyrrolidinylcarbonyl)ethyl, 2-(4-morpholinylcarbonyl)ethyl, 3-(dimethylaminocarbonyl)propyl, and 4-(dimethylaminocarbonyl)butyl.

[0475] As used herein, the term "aryloxyalkyl" means a group in which one or more hydrogens of the "alkyl" defined above are replaced by the "aryloxy" defined above, and is preferably C 6 -C 10 aryloxy-C 1 -C 6 alkyl, more preferably C 6 -C 10 aryloxy-C 1 -C 2 alkyl. Specific examples of aryloxyalkyl include phenoxymethyl and 2-phenoxyethyl.

[0476] As used herein, the term "aralkyl (arylalkyl)" means a group in which at least one hydrogen atom of the "alkyl" defined above is replaced by the "aryl" defined above, and is preferably C 7 -C 14 aralkyl, more preferably C 7 -C 10 aralkyl. Specific examples of aralkyl include benzyl, phenethyl, and 3-phenylpropyl.

[0477] As used herein, the term "aralkyloxy" means an oxy group bonded to the "aralkyl" defined above, and is preferably C 7 -C 14 aralkyloxy, more preferably C 7 -C 10 aralkyloxy. Specific examples of aralkyloxy include benzyloxy, phenethyloxy, and 3-phenylpropoxy.

[0478] As used herein, the term "aralkyloxyalkyl" means a group in which one or more hydrogens of the "alkyl" defined above are replaced by the "aralkyloxy" defined above, and is preferably C 7 -C 14 aralkyloxy-C 1 -C 6 alkyl, more preferably C 7 -C 14 aralkyloxy-C1 -C 2 Alkyl. Specific examples of aralkyloxyalkyl include benzyloxymethyl and 1-(benzyloxy)ethyl.

[0479] As used herein, the term "heteroarylalkyl" means a group in which at least one hydrogen atom of the "alkyl" defined above is replaced by the "heteroaryl" defined above, and is preferably a 5- to 10-membered heteroaryl-C 1 -C 6 alkyl, more preferably a 5- to 10-membered heteroaryl-C 1 -C 2 alkyl. Specific examples of heteroarylalkyl 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-quinolyl)ethyl, 2-(7-quinolyl)ethyl, 2-(6-indolyl)ethyl, 2-(5-indolyl)ethyl, and 2-(5-benzofuranyl)ethyl.

[0480] As used herein, the term "heteroarylalkoxy" means an oxy group bonded to the "heteroarylalkyl" defined above, and is preferably a 5- to 10-membered heteroaryl-C 1 -C 6 alkoxy, more preferably a 5- to 10-membered heteroaryl-C 1 -C 2 alkoxy. Specific examples of heteroarylalkoxy include 3-thienylmethoxy and 3-pyridylmethoxy.

[0481] As used herein, the term "heteroarylalkoxyalkyl" means a group in which one or more hydrogens of the "alkyl" defined above are replaced by the "heteroarylalkoxy" defined above, and is preferably a 5- to 10-membered heteroaryl-C 1 -C 6 alkoxy-C 1 -C 6 alkyl, more preferably a 5- to 10-membered heteroaryl-C 1 -C 2 alkoxy-C 1 -C 2 alkyl. Specific examples of heteroarylalkoxyalkyl include 3-pyridylmethoxymethyl.

[0482] As used herein, the term "heterocycloalkylalkyl" means a group in which one or more hydrogens of the "alkyl" defined above are replaced by the "heterocycloalkyl" defined above, and is preferably a 4- to 7-membered heterocycloalkyl-C 1 -C 6 alkyl, more preferably a 4- to 7-membered heterocycloalkyl-C1 -C 2 Alkyl. Specific examples of heteroarylalkoxyalkyl include tetrahydro-4H-pyran-4-ylidene methyl and azetidin-3-ylidene methyl.

[0483] As used herein, the term "alkoxyalkenyl" means a group in which one or more hydrogens of the "alkenyl" defined above are replaced by the "alkoxy" defined above, and is preferably C 1 -C 6 Alkoxy C 2 -C 6 Alkenyl. Specific examples of alkoxyalkenyl include (E)-4-methoxybut-2-en-1-yl.

[0484] As used herein, the term "aminocarbonylalkenyl" means a group in which one or more hydrogens of the "alkenyl" defined above are replaced by the "aminocarbonyl" defined above, and is preferably aminocarbonyl-C 2 -C 6 Alkenyl. Specific examples of aminocarbonylalkenyl include (E)-3-(dimethylaminocarbonyl)prop-2-en-1-yl.

[0485] As used herein, the term "haloalkoxy" means a group in which one or more hydrogens of the "alkoxy" defined above are replaced by a halogen, and is preferably C 1 -C 6 Haloalkoxy. Specific examples of haloalkoxy include difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, and 2,2,2-trifluoroethoxy.

[0486] As used herein, the term "alkylene" means a divalent group derived from the above "alkyl" by further removing any one hydrogen atom, and is preferably C 4 -C 8 Alkylene. Specific examples of alkylene include -CH2-, -(CH2) 2 -, -(CH2) 3 -, -CH(CH 3 )CH2-, -C(CH 3 ) 2 -, -(CH2) 4 -, -CH(CH 3 )CH2CH2-, -C(CH 3 ) 2 CH2-, -CH2CH(CH 3 )CH2-, -CH 2 C(CH 3 ) 2 -, -CH 2 CH 2CH(CH 3 )-, -(CH 2 ) 5 -, -(CH 2 ) 6 -, -(CH 2 ) 7 -, and -(CH 2 ) 8 -.

[0487] As used herein, the term "alicyclic ring" means a non-aromatic hydrocarbon ring. The alicyclic ring may have unsaturated bonds in the ring and may be a polycyclic ring having two or more rings. The carbon atoms constituting the ring may be oxidized to form carbonyl groups. The alicyclic ring is preferably a 3- to 8-membered alicyclic ring. Specific examples thereof include a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a cyclooctane ring, and a bicyclo[2.2.1]heptane ring.

[0488] As used herein, the term "saturated heterocycle" means a non-aromatic heterocycle containing 1 to 5 heteroatoms in addition to carbon atoms and having no double bonds and / or triple bonds in the ring. The saturated heterocycle may be a monocyclic ring or may form a fused ring with another ring (e.g., an aromatic ring such as a benzene ring). The saturated heterocycle is preferably a 4- to 7-membered saturated heterocycle. Specific examples include an azetidine ring, an oxetane ring, a tetrahydrofuran ring, a tetrahydropyran ring, a morpholine ring, a thiomorpholine ring, a pyrrolidine ring, a 4-oxopyrrolidine ring, a piperidine ring, a 4-oxopiperidine ring, a piperazine ring, a pyrazolidine ring, an imidazolidine ring, an oxazolidine ring, an isoxazolidine ring, a thiazolidine ring, an isothiazolidine ring, a thiadiazolidine ring, an oxazolidinone ring, a dioxolane ring, a dioxane ring, a thietane ring, an octahydroindole ring, and a dihydroindole ring.

[0489] As used herein, the term "optionally substituted" means that the group may be substituted by any substituent.

[0490] As used herein, the term "optionally substituted" means that the group may be protected by any protecting group.

[0491] As used herein, the term "one or more" means a number of 1 or 2 or more. When the term "one or more" is used in the context of substituents of a group, the term means a number from 1 to the maximum number of substituents acceptable for the group. Specific examples of the term "one or more" include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and / or a greater number.

[0492] As used herein, the term "peptide compound (or "peptide")" means a compound in which two or more amino acids are linked by an amide bond. Peptide compounds having an ester bond in a portion of the backbone, such as peptoids, are also included in the term peptide compound (or peptide) herein. The number of amino acid residues in the peptide compound is not particularly limited, but is preferably from 5 to 30 residues, more preferably from 8 to 15 residues, and still more preferably from 9 to 13 residues. The peptide compounds synthesized in the present invention preferably contain at least three N-substituted amino acids in one peptide, more preferably at least five N-substituted amino acids. These N-substituted amino acids may be present continuously or discontinuously in the peptide compound. The peptide compounds according to the present invention may be linear or cyclic, and cyclic peptide compounds are preferred. The number of residues contained in the peptide compound is preferably from 5 to 30 residues, more preferably from 8 to 15 residues, and still more preferably from 9 to 13 residues. The peptide compound preferably contains at least three N-substituted amino acids in one peptide compound, more preferably at least five N-substituted amino acids. These N-substituted amino acids may be present continuously or discontinuously in the peptide compound. The peptide compounds according to the present invention may be linear or cyclic, and cyclic peptide compounds are preferred.

[0493] As used herein, a "linear peptide compound" means a peptide compound in which amino acids are linearly linked by an amide bond. Peptide compounds having an ester bond in a portion of the backbone and in which amino acids are linearly linked, such as peptoids, are also included in the linear peptide compounds herein. The linear peptide compound has an amino group that can be protected with a protecting group at the N-terminal amino acid residue and a carboxyl group that can be protected with a protecting group at the C-terminal amino acid residue.

[0494] As used herein, the term "cyclic peptide compound" refers to a peptide compound having a cyclic structure composed of 4 or more amino acid residues. The cyclic structure of the cyclic peptide compound may contain bonds other than the amide bond, such as an ester bond, an ether bond, a thioether bond or a carbon-carbon bond. In addition to the cyclic structure, the cyclic peptide compound may also have an amino acid or a chain peptide structure that is not included in the cyclic structure. It may also have a structure other than the amino acid and the chain peptide structure. Among these, covalent bonds such as an amide bond, a thioether bond or a carbon-carbon bond are preferred, and an amide bond is particularly preferred. The positions of the carboxyl group and the amino group of the cyclic peptide compound may be on the main chain or the side chain.

[0495] The "cyclization" of a peptide compound means forming a cyclic moiety containing 4 or more amino acid residues. The number of amino acids contained in the cyclic moiety of a cyclic peptide compound is not particularly limited herein, but examples thereof include 4 to 20 residues, 5 to 18 residues, 6 to 17 residues, 7 to 16 residues, 9 to 15 residues, 10 to 15 residues, and 11 to 14 residues. The conversion of a linear peptide compound to a cyclic peptide compound can be carried out by the methods described in Comprehensive Organic Transformations, A Guide to Functional Group Preparations, 3rd Edition (by R.C. Larock) or March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition (by M.B. Smith, J. March), etc., or by carrying out a bonding reaction in the molecule. A functional group transformation reaction can also be carried out after the bonding reaction. Examples of the bonding reaction include C(O)-N bonds formed from carboxylic acids and amines; C-O-C bonds, C(O)-O bonds, and C(S)-O bonds via an oxygen atom; C(O)-S bonds, C(S)-S bonds, C-S-S-C bonds, C-S-C bonds, C-S(O)-C bonds, and C-S(O2)-C bonds via a sulfur atom; and C-N-C bonds, C=N-C bonds, N-C(O)-N bonds, N-C(S)N bonds, and C(S)-N bonds via a nitrogen atom. Other examples thereof include C-C bond formation reactions catalyzed by transition metals, such as Suzuki reaction, Heck reaction, and Sonogashira reaction. Examples of the functional group transformation reaction further carried out after the bonding reaction include oxidation reaction or reduction reaction. Specific examples thereof include reactions in which a sulfur atom is oxidized and converted to a sulfoxide group or a sulfone group. Other examples thereof include reduction reactions in which, in a carbon-carbon bond, a triple bond or a double bond is reduced and converted to a double bond or a single bond. Two amino acids can be bonded through a peptide bond at the main chain of the amino acids to form a closed-loop structure, or a covalent bond can be formed between two amino acids via a bond, for example, between side chains or between a side chain and the main chain of the two amino acids.

[0496] As used herein, the term "amino acid" includes natural amino acids and unnatural amino acids. As used herein, the term "amino acid" may mean 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 unnatural amino acids include, but are not particularly limited to, β-amino acids, D-amino acids, N-substituted amino acids (excluding Pro), α,α-disubstituted amino acids, amino acids having side chains different from those of natural amino acids, and hydroxycarboxylic acids. The amino acids as used herein assume any conformation. The selection of the side chain of the amino acid is not particularly limited, and in addition to a hydrogen atom, the side chain may freely be selected from, for example, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an aralkyl group, a heteroaralkyl group, a cycloalkyl group, and a spiro-bonded cycloalkyl group. Each of the side chains may have a substituent. The substituent is also not limited, and may be, for example, one or both or more of any substituent independently and freely selected from substituents including a halogen atom, an O atom, an S atom, an N atom, a B atom, an Si atom, or a P atom. That is, examples of the side chain include an alkyl group, an alkoxy group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an aralkyl group, and a cycloalkyl group which may be substituted, or oxo, aminocarbonyl, and a halogen atom.

[0497] As used herein, the "amino acid residue" constituting a peptide compound is sometimes simply referred to as an "amino acid".

[0498] As used herein, the term "N-terminal amino acid residue" means an amino acid residue located at the N-terminus of a peptide. As used herein, the term "C-terminal amino acid residue" means an amino acid residue located at the C-terminus of a peptide.

[0499] As used herein, "non-natural amino acid residue" means an amino acid residue having a structure different from that of a natural amino acid residue. Examples of non-natural amino acids include β-amino acid residues, D-amino acid residues, N-substituted amino acid residues (excluding Pro), α,α-disubstituted amino acid residues, and amino acid residues having a side chain different from that of a natural amino acid. As used herein, "N-substituted non-natural amino acid residue" means an amino acid residue in which the hydrogen on the nitrogen of the amino group of the main chain of the non-natural amino acid residue is replaced by another atom or functional group. Amino acid residues in which the hydrogen on the nitrogen of the amino group in the main chain of a natural amino acid is replaced by another atom or functional group (excluding Pro), and amino acid residues that are different from a natural amino acid in structure in the side chain and in which the hydrogen on the nitrogen of the amino group of the main chain is replaced by another atom or functional group belong to N-substituted non-natural amino acid residues. Examples of N-substituted non-natural amino acid residues include N-methylglycine (MeGly) residues, N-methylalanine (MeAla) residues, and N-methylhomophenylalanine (MeHph) residues.

[0500] As used herein, the term "cyclic amino acid residue" means an amino acid residue having a cyclic structure, wherein the nitrogen atom of the amino group of the amino acid residue and any atom of the side chain together form a ring. Examples of cyclic amino acid residues include Pro residues (formula (i)), proline derivative residues (formula (ii)), and Aze(2) residues (formula (iii)):

[0501] [Formula 24]

[0502]

[0503] In formula (ii), each R independently represents an arbitrary substituent, and can be, for example, an alkyl group, a hydroxyl group, an alkoxy group, an amino group, an alkylamino group, etc.

[0504] As used herein, "N-substituted phenylalanine residue" means a phenylalanine residue in which the hydrogen on the nitrogen of the amino group of the phenylalanine residue is replaced by another atom or functional group. As used herein, "N-substituted phenylalanine derivative residue" means an amino acid residue in which the hydrogen on the nitrogen of the amino group of the phenylalanine residue is replaced by another atom or functional group and the hydrogen on the phenyl group of the phenylalanine residue is replaced by another atom or substituent. Examples of such substituents include alkyl, halogen, alkyl substituted with halogen, hydroxy, alkoxy, amino, and alkylamino. Examples of N-substituted phenylalanine residues include N-alkylphenylalanine residues, where the substituent on the nitrogen of the amino group of the N-substituted phenylalanine residue is alkyl. Examples of N-alkylphenylalanine residues include the EtPhe residue (Formula (v)). Examples of N-substituted phenylalanine derivative residues include such N-alkylphenylalanine derivative residues where the substituent on the nitrogen of the amino group of the N-substituted phenylalanine derivative residue is alkyl. Examples of N-alkylphenylalanine derivative residues include the EtPhe derivative residue, and examples of the EtPhe derivative residue include the EtPhe(4-Me) residue (Formula (vi)).

[0505] [Formula 25]

[0506]

[0507] As used herein, the term "α,α-disubstituted amino acid residue" means an amino acid residue in which both hydrogens on the α-carbon are replaced by other atoms and / or functional groups other than hydrogen. Examples of α,α-disubstituted amino acid residues include α,α-dialkyl amino acid residues (such as α,α-dimethyl amino acid residues) and the cLeu residue (Formula (vii)) in which the two groups present at the α-position are linked to form an alicyclic ring.

[0508] [Formula 26]

[0509]

[0510] As used herein, the term "homo-phenylalanine residue" means an amino acid residue in which the amino acid is homophenylalanine, and the term "homo-phenylalanine derivative residue" means an amino acid residue in which the hydrogen on the phenyl group of the homophenylalanine residue is replaced by another atom or substituent. Examples of such substituents include alkyl, halogen, alkyl substituted with halogen, hydroxy, alkoxy, amino, and alkylamino. Examples of homo-phenylalanine derivative residues include the Hph(3,5-diF-4-CF 3 ) residue (Formula (viii)).

[0511] [Formula 27]

[0512]

[0513] As used herein, "N-substituted Ala residue" means an alanine residue in which the hydrogen on the nitrogen of the amino group of the alanine residue is replaced by another atom or functional group. Examples of N-substituted Ala residues include N-alkyl Ala residues (Formula (ix)), where the substituent on the nitrogen of the amino group of the N-substituted alanine residue is an alkyl group. Examples of N-alkyl Ala residues preferably include C 1 -C 10 alkyl Ala residues, more preferably C 1 -C 6 alkyl Ala residues, such as MeAla residue (Formula (x)) or EtAla residue (Formula (xi)).

[0514] [Formula 28]

[0515]

[0516] As used herein, "N-substituted Gly residue" means a glycine residue in which the hydrogen on the nitrogen of the amino group of the glycine residue is replaced by another atom or functional group. Examples of N-substituted Gly residues include N-alkyl Gly residues (Formula (xii)), where the substituent on the nitrogen of the amino group of the N-substituted glycine residue is an alkyl group. Examples of N-alkyl Gly residues preferably include C 1 -C 10 alkyl Gly residues, more preferably C 1 -C 6 alkyl Gly residues, such as MeGly residue (Formula (xiii)) or EtGly residue (Formula (xiv)).

[0517] [Formula 29]

[0518]

[0519] As used herein, the "side chain of an amino acid", in the case of an α-amino acid, means the atomic group bonded to the carbon (α-carbon) to which the amino group and the carboxyl group are bonded. For example, the methyl group of Ala is the side chain of the amino acid. In the case of a β-amino acid, the atomic group attached to the α-carbon and / or β-carbon can be the side chain of the amino acid, and in the case of a γ-amino acid, the atomic group attached to the α-carbon, β-carbon, and / or γ-carbon can be the side chain of the amino acid. It should be noted that the α-carbon in α-amino acids, β-amino acids, and γ-amino acids refers to the first (in position α) carbon adjacent to the carboxyl group in the main chain of the amino acid. Additionally, the carbon adjacent to the α-carbon (the second (in position β) starting from the carboxyl group) is called the β-carbon, and the carbon adjacent to the β-carbon (the third (in position γ) starting from the carboxyl group) is called the γ-carbon.

[0520] As used herein, the term "main chain of an amino acid" means, in the case of an α-amino acid, the branched chain portion formed by an amino group, an α-carbon, and a carboxyl group; in the case of a β-amino acid, the branched chain portion formed by an amino group, a β-carbon, an α-carbon, and a carboxyl group; and in the case of a γ-amino acid, the branched chain portion formed by an amino group, a γ-carbon, a β-carbon, an α-carbon, and a carboxyl group.

[0521] The amino group in the main chain of an amino acid may be unsubstituted (-NH 2 ) or substituted (i.e., -NHR). R represents an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an aralkyl group, or a cycloalkyl group which may optionally have substituents, or the carbon chain bonded to the N atom and the carbon atom at the α-position may form a ring as in proline. Such amino acids in which the amino group on the main chain is substituted are sometimes referred to herein as "N-substituted amino acids" or "N-substituted amino acid residues". As used herein, examples of "N-substituted amino acids" or "N-substituted amino acid residues" preferably include, but are not limited to, N-alkyl amino acids, N-C 1 -C 6 alkyl amino acids, N-C 1 -C 4 alkyl amino acids, N-methyl amino acids, N-ethyl amino acids, N-C 7 -C 14 aralkyl amino acids, N-benzyl amino acids, N-phenethyl amino acids, proline, and Aze(2).

[0522] As used herein, the term "number of amino acids (amino acid number)" or "number of amino acid residues (amino acid residue number)" refers to the number of amino acid residues (amino acid units) constituting a peptide compound, and means the number of amino acid units generated when an amide bond, an ester bond, and a bond of a cyclized portion connecting amino acids are broken.

[0523] As used herein, the "amino acids" constituting a peptide compound include all isotopes corresponding to each amino acid. Isotopes of "amino acids" are forms in which at least one atom is replaced by an atom having the same atomic number (number of protons) and a different mass number (total number of protons and neutrons) in an abundance ratio different from the natural abundance ratio. Examples of isotopes contained in the "amino acids" forming a peptide compound include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, chlorine atoms, etc., and they respectively include 2 H, 3 H; 13 C, 14 C; 15 N; 17 O, 18 O; 31P, 32 P; 35 S; 18 F; 36 Cl, etc. For the compounds used herein, all compounds containing radioactive or non-radioactive isotope elements in any proportion are covered within the scope of the present invention.

[0524] Examples of substituents containing a halogen atom herein include alkyl groups, cycloalkyl groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups, and aralkyl groups having a halogen as a substituent, and more specifically include fluoroalkyl, difluoroalkyl, and trifluoroalkyl.

[0525] Examples of substituents containing an O atom include hydroxy (-OH), oxy (-OR), carbonyl (-C=O-R), carboxy (-CO 2 H), oxycarbonyl (-C=O-OR), carbonyloxy (-O-C=O-R), thiocarbonyl (-C=O-SR), carbonylthio (-S-C=O-R), aminocarbonyl (-C=O-NHR), carbonylamino (-NH-C=O-R), oxycarbonylamino (-NH-C=O-OR), sulfonylamino (-NH-SO 2 -R), aminosulfonyl (-SO 2 -NHR), amidosulfonylamino (-NH-SO 2 -NHR), thiocarboxy (-C(=O)-SH), and carboxycarbonyl (-C(=O)-CO 2 H) groups.

[0526] Examples of oxy (-OR) include alkoxy, cycloalkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, and aralkyloxy. The alkoxy is preferably C 1 -C 4 alkoxy, C 1 -C 2 alkoxy, and particularly preferably methoxy or ethoxy.

[0527] Examples of carbonyl (-C==O-R) include formyl (-C==O-H), alkylcarbonyl, cycloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, heteroarylcarbonyl, and aralkylcarbonyl.

[0528] Examples of oxycarbonyl (-C==O-OR) include alkoxycarbonyl, cycloalkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, and aralkyloxycarbonyl.

[0529] Examples of carbonyloxy (-O-C=O-R) include alkylcarbonyloxy, cycloalkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, and aralkylcarbonyloxy.

[0530] Examples of thiocarbonyl (-C==O-SR) include alkylthiocarbonyl, cycloalkylthiocarbonyl, alkenylthiocarbonyl, alkynylthiocarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl, and aralkylthiocarbonyl.

[0531] Examples of carbonylthio (-S-C==O-R) include alkylcarbonylthio, cycloalkylcarbonylthio, alkenylcarbonylthio, alkynylcarbonylthio, arylcarbonylthio, heteroarylcarbonylthio, and aralkylcarbonylthio.

[0532] Examples of aminocarbonyl (-C==O-NHR) include alkylaminocarbonyl (e.g., C 1 -C 6 or C 1 -C 4 alkylaminocarbonyl, especially ethylaminocarbonyl and methylaminocarbonyl), cycloalkylaminocarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, and aralkylaminocarbonyl. Additional examples thereof 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.

[0533] Examples of carbonylamino (-NH-C==O-R) include alkylcarbonylamino, cycloalkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, and aralkylcarbonylamino. Additional examples thereof include groups in which the H atom bonded to the N atom in -NH-C==O-R is further substituted by an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl group.

[0534] Examples of alkoxycarbonylamino (-NH--C==O-OR) include alkoxycarbonylamino, cycloalkoxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, aryloxycarbonylamino, heteroaryloxycarbonylamino, and aralkyloxycarbonylamino. Additional examples thereof include groups in which the H atom bonded to the N atom in -NH--C==O-OR is further substituted by an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl group.

[0535] Examples of sulfonylamino (-NH--SO 2 -R) include alkylsulfonylamino, cycloalkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, and aralkylsulfonylamino. Additional examples thereof include groups in which the H atom bonded to the N atom in -NH--SO 2 -R is further substituted by an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl group.

[0536] aminosulfonyl (-SO2 Examples of -NHR include alkylaminosulfonyl, cycloalkylaminosulfonyl, alkenylaminosulfonyl, alkynylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, and aralkylaminosulfonyl. Additional examples include groups in which the H atom bonded to the N atom in -SO 2 -NHR is further substituted with an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl group.

[0537] Sulfamoylamino (-NH-SO 2 -NHR) examples include alkylsulfamoylamino, cycloalkylsulfamoylamino, alkenylsulfamoylamino, alkynylsulfamoylamino, arylsulfamoylamino, heteroarylsulfamoylamino, and aralkylsulfamoylamino. With -NH-SO 2 The two H atoms bonded to the N atom in -NHR can each independently be substituted with a substituent selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, and the two substituents can form a ring.

[0538] Examples of substituents containing an S atom include groups such as mercapto (-SH), thio (-S-R), sulfinyl (-S=O-R), sulfonyl (-SO 2 -R), and sulfo (-SO 3 H).

[0539] Examples of thio (-S-R) that can be selected include alkylthio, cycloalkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, and aralkylthio, etc.

[0540] Sulfonyl (-SO 2 -R) examples include alkylsulfonyl, cycloalkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heteroarylsulfonyl, and aralkylsulfonyl.

[0541] Examples of substituents containing an N atom include, for example, azide (-N 3 ; also called the "azide group"), cyano (-CN), primary amino (-NH 2 ), secondary amino (-NH-R; also called monosubstituted amino), tertiary amino (-NR(R′); also called disubstituted amino), amidino (-C(=NH)-NH 2 ), substituted amidino (-C(=NR)-NR′R"), guanidino (-NH-C(=NH)-NH 2 ), substituted guanidino (-NR-C(=NR′″)-NR′R"), aminocarbonylamino (-NR-CO-NR′R"), pyridyl, piperidyl, morpholino, and azetidinyl.

[0542] Examples of secondary amino groups (-NH-R: mono-substituted amino groups) include alkylamino, cycloalkylamino, alkenylamino, alkynylamino, arylamino, heteroarylamino, and aralkylamino.

[0543] Examples of tertiary amino groups (-NR(R′): di-substituted amino groups) include amino groups having any two substituents each independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, for example, alkyl(aralkyl)amino. These any two substituents may form a ring. Specific examples thereof include dialkylamino, especially C 1 -C 6 dialkylamino, C 1 -C 4 dialkylamino, dimethylamino, and diethylamino. As used herein, the term "C p -C q dialkylamino group" means a group in which the amino group is substituted by two C p -C q alkyl groups. The C p -C q alkyl groups may be the same or different.

[0544] Examples of substituted amidino groups (-C(==NR)-NR′R″) include groups 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, for example, alkyl(aralkyl)(aryl)amidino.

[0545] 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, and groups in which these substituents form a ring.

[0546] Examples of aminocarbonylamino groups (-NR-CO-NR′R″) include groups in which R, R′, and R″ are each independently selected from a hydrogen atom, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, and groups in which these substituents form a ring.

[0547] The compounds according to the invention may be salts thereof, preferably their chemical or pharmaceutical salts. The compounds according to the invention or their salts may be solvates thereof, preferably their chemical or pharmaceutical solvates. Examples of salts of the compounds according to the invention include: hydrochloride; hydrobromide; hydroiodide; phosphate; phosphonate; sulfate; sulfonate such as mesylate and tosylate; carboxylate such as acetate, citrate, malate, tartrate, succinate and salicylate; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; and ammonium salts such as ammonium salt, alkylammonium salt, dialkylammonium salt, trialkylammonium salt and tetraalkylammonium salt. These salts are produced, for example, by contacting the compound with an acid or a base usable for the production of pharmaceuticals. In the present invention, a solvate of a compound means a molecular aggregate formed by the compound and a solvent, and there is no particular limitation as long as it is a solvate formed by a solvent that is allowed to be taken simultaneously with the administration of the drug. When the solvent is water, the solvate is called a hydrate. Examples of solvates of the compounds according to the invention are preferably hydrates, and specific examples of hydrates include mono-hydrate to deca-hydrate, preferably mono-hydrate to penta-hydrate, more preferably mono-hydrate to tri-hydrate. The solvates of the compounds according to the invention include not only solvates having a single solvent (such as water, alcohol (e.g., methanol, ethanol, 1-propanol or 2-propanol) or dimethylformamide), but also solvates having a plurality of solvents.

[0548] When the compound according to the invention is obtained in free form, the compound can be routinely converted into the state of its hydrate or its solvate. When the compound according to the invention is obtained in free form, the compound can be routinely converted into the state of a salt, its hydrate or its solvate that can be formed from the compound. Examples thereof include hydrates and ethanolates of the compound represented by formula (2) or its salt. Specific examples thereof include, but are not limited to, semi-hydrate, mono-hydrate, di-hydrate, tri-hydrate, tetra-hydrate, penta-hydrate, hexa-hydrate, hepta-hydrate, octa-hydrate, nona-hydrate, deca-hydrate or mono-ethanolate of the compound represented by formula (2); semi-hydrate, mono-hydrate, di-hydrate, tri-hydrate, tetra-hydrate, penta-hydrate, hexa-hydrate, hepta-hydrate, octa-hydrate, nona-hydrate, deca-hydrate or mono-ethanolate of the sodium salt of the compound represented by formula (2); or hydrates or ethanolates of the hydrochloride salt of the compound represented by formula (2). Hydrates or solvates can be produced in crystalline form or non-crystalline form. In the case of crystalline form, hydrates or solvates can have crystalline polymorphs. Regarding the method for producing hydrates or solvates, hydrates or solvates can be obtained by conventional methods, for example, by adding a solvent (such as ethanol and / or water) to the compound represented by formula (2) or the peptide compound described herein, followed by stirring, cooling, concentrating and / or drying.

[0549] [Formula 30]

[0550]

[0551] When the compounds according to the invention are obtained as salts, hydrates or solvates of the compounds, the compounds can be conventionally converted into their free forms.

[0552] As used herein, the meaning of the term "and / or" includes any combination in which "and" and "or" are appropriately combined. Specifically, for example, the term "A, B and / or C" includes the following seven variants:

[0553] (i) A, (ii) B, (iii) C, (iv) A and B, (v) A and C, (vi) B and C, and (vii) A, B and C.

[0554] As used herein, the term "epimer of a cyclic peptide compound" means a compound (epimer) in which the configuration of the side chain attached to the α-carbon of the amino acid residue constituting the cyclic peptide compound is spatially inverted. The "epimer of a cyclic peptide compound" includes a cyclic peptide compound in which when a linear peptide compound is cyclized to produce a cyclic peptide compound, the α-carbon of the C-terminal amino acid residue of the linear peptide compound is spatially inverted. The epimers of the cyclic peptide compounds in the total product containing cyclic peptide compounds produced by the method of the present invention can be determined, for example, by HPLC analysis by the UV area value at 210 nm or 220 nm.

[0555] As used herein, the term "epimerization" means inverting the spatial configuration on at least one of the multiple asymmetric carbons present in a molecule.

[0556] As used herein, the term "oligomer" means a compound in which two or more peptide compounds, which are starting materials for the cyclic peptide compound, are bound together. In particular, a compound formed by binding two peptide compounds is called a "dimer", and a compound formed by binding three peptide compounds is called a "trimer". A dimer can be a compound in which the peptide compounds are linearly bound to each other, or a cyclic dimer peptide compound (also called a "cyclic dimer") in which the peptide compounds are linearly bound and then further cyclized. A trimer can be a compound in which the peptide compounds are linearly bound to each other, or a cyclic trimer peptide compound (also called a "cyclic trimer") in which the peptide compounds are linearly bound and then further cyclized. An oligomer can be a compound in which the peptide compounds are linearly bound to each other, or a cyclic oligomer peptide compound in which the peptide compounds are linearly bound and then further cyclized. The oligomers (preferably dimers, trimers, more preferably cyclic dimers, cyclic trimers) in the total product containing the cyclic peptide compound produced by the method of the present invention can be determined, for example, by HPLC analysis by the UV area value at 210 nm or 220 nm.

[0557] Method for producing cyclic peptide compounds

[0558] In one aspect, the present invention relates to a method for producing a cyclic peptide compound, or a salt or solvate thereof, the method comprising the step of linking the N-terminal amino acid residue of a peptide compound to the C-terminal amino acid residue of the peptide compound in a solvent, wherein at least one of the N-terminal amino acid residue and the C-terminal amino acid residue is a cyclic amino acid residue, and the solvent comprises one or more selected from the group consisting of acetonitrile, dimethyl carbonate, 2-MeTHF, and anisole. Hereinafter, this aspect will also be referred to as "Aspect 1".

[0559] In Aspect 1, it is preferred that the N-terminal amino acid residue of the peptide compound is a cyclic amino acid residue, or the C-terminal amino acid residue of the peptide compound is a cyclic amino acid residue.

[0560] In Aspect 1, it is preferred that the N-terminal amino acid residue of the peptide compound is a cyclic amino acid residue and the C-terminal amino acid residue is a non-natural amino acid residue, or the N-terminal amino acid residue of the peptide compound is a non-natural amino acid residue and the C-terminal amino acid residue is a cyclic amino acid residue.

[0561] In aspect 1, it is preferred that the N-terminal amino acid residue of the peptide compound is a cyclic amino acid residue and the C-terminal amino acid residue is a homophenylalanine residue, a homophenylalanine derivative residue or an N-substituted Ala residue, or the N-terminal amino acid residue of the peptide compound is an N-substituted phenylalanine residue, an N-substituted phenylalanine derivative residue or an α,α-disubstituted amino acid residue and the C-terminal amino acid residue is a cyclic amino acid residue.

[0562] In aspect 1, it is more preferred that the N-terminal amino acid residue of the peptide compound is an N-substituted phenylalanine derivative residue and the C-terminal amino acid residue is a cyclic amino acid residue.

[0563] In aspect 1, it is more preferred that the N-terminal amino acid residue of the peptide compound is an α,α-disubstituted amino acid residue and the C-terminal amino acid residue is a cyclic amino acid residue.

[0564] In aspect 1, it is more preferred that the N-terminal amino acid residue of the peptide compound is a cyclic amino acid residue and the C-terminal amino acid residue is a homophenylalanine derivative residue.

[0565] In aspect 1, more preferably, the N-terminal amino acid residue of the peptide compound is a cyclic amino acid residue and the C-terminal amino acid residue is an N-substituted Ala residue.

[0566] In one aspect, the present invention relates to a method for producing a cyclic peptide compound, or a salt thereof, or a solvate thereof, the method comprising the step of linking the N-terminal amino acid residue of a peptide compound with the C-terminal amino acid residue of the peptide compound in a solvent, wherein the N-terminal amino acid residue and the C-terminal amino acid residue of the peptide compound are one selected from the following a) to e):

[0567] a) the N-terminal amino acid residue is an N-substituted phenylalanine residue or an N-substituted phenylalanine derivative residue and the C-terminal amino acid residue is a cyclic amino acid residue;

[0568] b) the N-terminal amino acid residue is an α,α-disubstituted amino acid residue and the C-terminal amino acid residue is a cyclic amino acid residue;

[0569] c) the N-terminal amino acid residue is a cyclic amino acid residue and the C-terminal amino acid residue is a homophenylalanine residue or a homophenylalanine derivative residue;

[0570] d) the N-terminal amino acid residue is a cyclic amino acid residue and the C-terminal amino acid residue is an N-substituted Ala residue; and

[0571] e) The N-terminal amino acid residue is an N-substituted Gly residue, and the C-terminal amino acid residue is an N-substituted phenylalanine residue or an N-substituted phenylalanine derivative residue. Hereinafter, this aspect will also be referred to as "Aspect 2".

[0572] In one aspect, the cyclic amino acid residue is one selected from a Pro residue, a proline derivative residue, and an Aze(2) residue, preferably one selected from a Pro residue and an Aze(2) residue, and more preferably a Pro residue or an Aze(2) residue.

[0573] In one aspect, the N-substituted phenylalanine derivative residue is an N-alkylphenylalanine derivative residue, preferably an EtPhe derivative residue, and more preferably an EtPhe(4-Me) residue.

[0574] In one aspect, the highly phenylalanine derivative residue is an Hph(3,5-diF-4-CF 3 ) residue.

[0575] In one aspect, the α,α-disubstituted amino acid residue is a cLeu residue.

[0576] In one aspect, the N-substituted Ala residue is an N-alkyl Ala residue, preferably a MeAla residue.

[0577] In one aspect, the N-substituted Gly residue is an N-alkyl Gly residue, preferably a MeGly residue.

[0578] In Aspect 2, the N-terminal amino acid residue and the C-terminal amino acid residue preferably included in the peptide compound are selected from one of the following a') to e'):

[0579] a') The N-terminal amino acid residue is an EtPhe(4-Me) residue, and the C-terminal amino acid residue is an Aze(2) residue;

[0580] b') The N-terminal amino acid residue is a cLeu residue, and the C-terminal amino acid residue is a Pro residue;

[0581] c') The N-terminal amino acid residue is a Pro residue, and the C-terminal amino acid residue is an Hph(3,5-diF-4-CF 3 ) residue;

[0582] d') The N-terminal amino acid residue is a MeGly residue, and the C-terminal amino acid residue is an EtPhe(4-Mel) residue; and

[0583] e') The N-terminal amino acid residue is an Aze(2) residue and the C-terminal amino acid residue is a MeAla residue.

[0584] In aspect 2, the solvent preferably comprises one or more selected from the group consisting of acetonitrile, dimethyl carbonate, 2-MeTHF, and anisole.

[0585] In one aspect, the solvent is one selected from the group consisting of acetonitrile, dimethyl carbonate, 2-MeTHF, and anisole, preferably one selected from the group consisting of acetonitrile and dimethyl carbonate, and more preferably acetonitrile or dimethyl carbonate.

[0586] In one aspect, the peptide compound of the present invention may be a linear peptide compound. In another aspect, the peptide compound of the present invention may be a cyclic peptide compound. In one aspect, the linear or cyclic peptide compound may contain a cyclic structure as part of its structure. Specific examples of the cyclic structure include those cyclic structures in which the side chain of one amino acid residue is connected to the side chain of another amino acid residue, those cyclic structures in which the N-substituent of one amino acid residue is connected to the side chain of another amino acid residue, and those cyclic structures in which the N-substituent of one amino acid residue is connected to the N-substituent of another amino acid residue. The two amino acid residues participating in the connection of the cyclic structure may be adjacent, or any number of amino acid residues may be present therebetween, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 amino acid residues. Examples of the size of the ring formed by the cyclic structure include, but are not particularly limited to, 4-membered rings, 5-membered rings, 6-membered rings, 7-membered rings, 8-membered rings, 9-membered rings, 10-membered rings, 11-membered rings, 12-membered rings, 13-membered rings, 14-membered rings, 15-membered rings, 16-membered rings, 17-membered rings, 18-membered rings, 19-membered rings, 20-membered rings, 21-membered rings, 22-membered rings, 23-membered rings, 24-membered rings, 25-membered rings, 26-membered rings, 27-membered rings, 28-membered rings, 29-membered rings, 30-membered rings, 31-membered rings, 32-membered rings, 33-membered rings, 34-membered rings, and 35-membered rings. When a cyclic structure is present in the peptide compound, the number of cyclic structures is not limited, but preferably one, two, three, four, or five cyclic structures are present.

[0587] In one aspect, the connection of the N-terminal amino acid residue of the peptide compound to the C-terminal amino acid residue is to connect the amino group of the N-terminal amino acid residue to the carboxyl group of the C-terminal amino acid residue. In one aspect, the amino group of the N-terminal amino acid residue and the carboxyl group of the C-terminal amino acid residue of the peptide compound are connected by an amide bond.

[0588] When the N-terminal amino acid residue and the C-terminal amino acid residue of a peptide compound are linked by an amide bond, a cyclic peptide compound, or a salt or solvate thereof, can be produced by condensing the amino group of the N-terminal amino acid residue with the carboxyl group of the C-terminal amino acid residue. The amide bond can be formed between the amino group in the main chain of the N-terminal amino acid residue and the carboxyl group in the main chain of the C-terminal amino acid residue, can be formed between the amino group in the main chain of the N-terminal amino acid residue and the carboxyl group in the side chain of the C-terminal amino acid residue, can be formed between the amino group in the side chain of the N-terminal amino acid residue and the carboxyl group in the main chain of the C-terminal amino acid residue, and can be formed between the amino group in the side chain of the N-terminal amino acid residue and the carboxyl group in the side chain of the C-terminal amino acid residue. In the condensation, a condensing reagent can be used to activate the carboxyl group in the system, or the carboxyl group can be previously converted into an active ester. As used herein, the term "condensation of an amino group and a carboxyl group" refers to a condensation in which the amino group and the carboxyl group are linked by an amide bond.

[0589] In one aspect, the linking step can be carried out by stirring the reaction mixture in a solvent at a temperature between -20 °C and close to the boiling point of the solvent, preferably between -20 °C and 100 °C, preferably between -5 °C and 60 °C, for 10 minutes to 48 hours in the presence or absence of a condensing reagent and in the presence or absence of a base. When a condensing reagent is used in the linking step, the condensing reagent or a solution containing the condensing reagent can be added to a solution containing the peptide compound and a base, or a solution containing the starting materials and optionally a base can be added to a solution containing the condensing reagent. When no condensing reagent is used in the linking step, the carboxyl group can be previously converted into an active ester.

[0590] There are no particular limitations on the condensing reagent, base, and their amounts used when condensing an amino group and a carboxyl group by an amide bond, as long as they can form an amide bond, but preferably the condensing reagents, bases, and their amounts used commonly in peptide synthesis are used (see, for example, Peptide Coupling Reagents, More than a Letter Soup (Chem. Rev. 2011, 111, 6557-6602.)).

[0591] Specific examples of the condensing reagent 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-azabenzotriazole (HOAt), 2-cyano-2-(hydroxyimino)ethyl acetate (oxyma), 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-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), N-[1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino(morpholino)]uronium hexafluorophosphate (COMU), O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HOTU), O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TATU), [ethyl cyano(hydroxyimino)acetato-O 2 tri-1-pyrrolidinylphosphonium hexafluorophosphate (PyOxim), 2-bromo-1-ethylpyridinium tetrafluoroborate (BEP), 1H-benzotriazol-1-yloxy-tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP), 1H-benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), bromotris(pyrrolidinyl)phosphonium hexafluorophosphate (PyBr αP), chlorotris(pyrrolidino)phosphonium hexafluorophosphate (PyCloP), (7-azabenzotriazol-1-yloxy)tris(pyrrolidino)phosphonium hexafluorophosphate (PyAOP), bromotris(dimethylamino)phosphonium hexafluorophosphate (Brop), 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT), N,N,N′,N′-tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate (TSTU), N,N,N′,N′-tetramethyl-O-(N-succinimidyl)uronium hexafluorophosphate (HSTU), O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TDBTU), tetramethylthiourea S-(1-oxide-2-pyridyl)-N,N,N′,N′-tetrafluoroborate (TOTT), O-(2-oxo-1(2H)-pyridyl)-N,N,N′,N′-tetramethyluronium 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). Among these, from the viewpoint of improving the conversion of the cyclization reaction and suppressing by-products, the condensation reagent of the present invention is preferably HATU, COMU, DMT-MM, PyOxim, PyBOP, or PyClop, more preferably HATU or COMU. Further, the combination of the solvent and the condensation reagent is preferably HATU and dimethyl carbonate or acetonitrile, or COMU and dimethyl carbonate or acetonitrile, because it allows further suppression of the formation of epimerization and dimer and trimer by-products.

[0592] As the base, an organic base is suitably used, and in particular, an organic base containing a tertiary amine is preferred. Specific examples of the base include N,N-diisopropylethylamine (DIPEA), 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), 2,3,6,7-tetrahydro-1H,5H-9-azabenz[ij]quinolizine, 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(tetramethylguanidino)naphthalene (TMGN), 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), triethylamine (TEA), trimethylamine, 1-methylpiperidine, N,N'-dimethylpiperazine, N-methylmorpholine, N-ethylmorpholine, and p-dimethylaminopyridine (DMAP). Among them, N,N-diisopropylethylamine (DIPEA) is preferred as the base of the present invention from the viewpoints of improving the conversion rate of the cyclization reaction and suppressing by-products. In addition, the combination of the solvent, the condensing agent, and the base is preferably HATU, dimethyl carbonate, and N,N-diisopropylethylamine (DIPEA); HATU, acetonitrile, and N,N-diisopropylethylamine (DIPEA); COMU, dimethyl carbonate, and N,N-diisopropylethylamine (DIPEA); or COMU, acetonitrile, and N,N-diisopropylethylamine (DIPEA) because epimerization and the formation of dimer and trimer by-products can be further suppressed.

[0593] In one aspect, the cyclic peptide compound produced by the method of the present invention may contain 8 to 20, preferably 9 to 15 amino acid residues, and at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, or at least 19 of the amino acid residues may be unnatural amino acid residues. In one aspect, the proportion of the unnatural amino acids contained in the cyclic peptide compound produced by the method of the present invention is, relative to the total number of amino acids contained in the peptide compound, for example, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, or 80% or more.

[0594] The unnatural amino acid residues contained in the cyclic peptide compound may be N-substituted unnatural amino acid residues or N-unsubstituted unnatural amino acid residues. Among them, amino acid residues in which the amino group in the main chain of natural amino acids is substituted by an atom or functional group other than hydrogen, or amino acid residues having a structure different from that of natural amino acids in the side chain and in which the amino group in the main chain is substituted by an atom or functional group other than hydrogen belong to N-substituted unnatural amino acid residues. Among them, amino acid residues in which the amino group in the main chain is not substituted but have a structure different from that of natural amino acids in the side chain belong to N-unsubstituted unnatural amino acid residues.

[0595] In one aspect, the cyclic peptide compound produced by the method of the present invention may contain at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18 or at least 19 N-substituted amino acid residues. In one aspect, the proportion of N-substituted amino acid residues contained in the cyclic peptide compound produced by the method of the present invention is, relative to the total number of amino acids contained in the peptide compound, for example, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more or 80% or more. The N-substituted amino acid residues may be N-substituted unnatural amino acid residues.

[0596] In one aspect, the cyclic peptide compound produced by the method of the present invention may contain at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18 or at least 19 N-unsubstituted unnatural amino acid residues. In one aspect, the proportion of N-unsubstituted unnatural amino acid residues contained in the cyclic peptide compound produced by the method of the present invention is, relative to the total number of amino acids contained in the peptide compound, for example, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more or 80% or more.

[0597] In one aspect, the cyclic peptide compounds produced by the method of the present invention may contain at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18 or at least 19 α,α-disubstituted amino acid residues. In one aspect, the proportion of α,α-disubstituted amino acid residues contained in the cyclic peptide compounds produced by the method of the present invention is, relative to the total number of amino acids contained in the peptide compound, for example 5% or more, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more or 80% or more.

[0598] The cyclic peptide compounds produced by the method of the present invention preferably contain 9 to 15 amino acid residues, and more preferably contain 11 amino acid residues. In the cyclic peptide compound, one or more, two or more, three or more, four or more, five or more or six or more of the amino acid residues may be N-substituted amino acid residues, and one or more or two or more of the amino acid residues may be N-unsubstituted unnatural amino acid residues. The method of the present invention is particularly useful for the large-scale production of cyclic peptide compounds containing a large number of such unnatural amino acid residues.

[0599] In one aspect, the C-terminal amino acid residue contained in the peptide compound is an amino acid residue having a side chain on the α-carbon of the carboxyl group.

[0600] In one aspect, the peptide compound contains an amino acid residue of formula (1) at any one of the amino acid residues other than the N-terminal amino acid residue and the C-terminal amino acid residue of the peptide compound:

[0601] [Formula 31]

[0602]

[0603] In the formula, R 1 is hydrogen or C 1 -C 6 alkyl; and R 2 and R 3 are each independently hydrogen or C 1 -C 6 alkyl, or R 2 and R 3 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle.

[0604] In the amino acid residue of formula (1), R 1Preferably C 1 -C 6 alkyl, more preferably methyl.

[0605] In the amino acid residue of formula (1), R 2 and R 3 are each independently preferably C 1 -C 6 alkyl, more preferably methyl.

[0606] In another aspect of the amino acid residue of formula (1), R 1 is C 1 -C 6 alkyl; and R 2 and R 3 are each independently C 1 -C 6 alkyl, or R 2 and R 3 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle.

[0607] In another aspect of the amino acid residue of formula (1), R 1 is preferably methyl; and R 2 and R 3 are both methyl.

[0608] In one aspect, the peptide compound is a linear peptide compound. The linear peptide compound preferably contains 9 to 15, more preferably 11 amino acid residues.

[0609] In one aspect, the peptide compound is a linear peptide compound selected from the group consisting of:

[0610] [Formula 32]

[0611]

[0612] [Formula 33]

[0613]

[0614] [Formula 34]

[0615]

[0616] [Formula 35]

[0617] and

[0618] [Formula 36]

[0619]

[0620] or a salt thereof, or a solvate thereof.

[0621] In one aspect, the cyclic peptide compound produced by the method of the present invention is preferably a solvate, more preferably a hydrate, DMSO-hydrate, acetone-hydrate or DMSO-solvate, and even more preferably a hydrate.

[0622] 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 (2):

[0623] [Formula 37]

[0624]

[0625] or a salt thereof, or a solvate thereof. As described in International Publication No. WO2021 / 090855, the cyclic peptide compound represented by the above formula can be used as a KRAS inhibitor and can be used for various KRAS-related diseases, such as KRAS-related cancers.

[0626] In one aspect, it is preferred not to use column chromatography in the separation and / or purification of the cyclic peptide compound produced by the method of the present invention, or a salt thereof, or a solvate thereof.

[0627] The cyclic peptide compound produced by the method of the present invention, or a salt thereof, or a solvate thereof can be separated and / or purified by crystallization instead of using column chromatography.

[0628] Specifically, for example, the reaction solution after the condensation reaction can be separately operated, the organic layer can be concentrated and / or filtered as needed, and then a solvent suitable for crystallization is added to the obtained residue, optionally a seed crystal is added, and stirring is performed as needed to obtain crystals of the cyclic peptide compound, or a salt thereof, or a solvate thereof. The solvent added during crystallization is not particularly limited as long as it is a solvent that can crystallize the cyclic peptide compound, but preferably a solvent that can perform an operation to reduce the solubility of the solution in which the cyclic peptide compound is dissolved. For example, when the solubility of the cyclic peptide compound can be reduced by adding a poor solvent or cooling the solution to crystallize the peptide compound, a solvent capable of performing such an operation can be used. In addition, when the crystals of the cyclic peptide compound can be obtained by maintaining the crude crystals of the cyclic peptide compound in a suspended state for an arbitrary period of time, a solvent capable of performing such an operation can be used for crystallization. Specific examples of the solvent added during crystallization include acetone, water, DMSO, acetonitrile, ethanol, and their mixed solvents.

[0629] In one aspect, the crystal of the cyclic peptide compound, or a salt or solvate thereof, produced by the method of the present invention can be a non-solvate crystal, a solvate crystal, a salt crystal or a salt solvate of the above formula (2) compound, as described below. In one aspect, a non-solvate crystal (an unsolvated crystal) can refer to a crystal other than a solvate crystal or a hydrate crystal. The crystal of the cyclic peptide compound, or a salt or solvate thereof, represented by formula (2) is preferably a solvate crystal, and more preferably a hydrate crystal.

[0630] In one aspect, the method of the present invention further includes the step of providing a peptide compound. The peptide compound can be produced, for example, by repeating the following step 1 and step 2, and optionally repeating step 1 and step 2 multiple times (preferably 2 to 20 times), and / or repeating the following step 1 and step 3, and optionally repeating step 1 and step 3 multiple times (preferably 2 to 20 times), and finally step 1 and step 4:

[0631] (Step 1) Link / condense a C-protected amino acid or a C-protected peptide with an N-protected amino acid or an N-protected peptide;

[0632] (Step 2) Remove / deprotect the N-protecting group after step 1;

[0633] (Step 3) Remove / deprotect the C-protecting group after step 1;

[0634] (Step 4) Remove / deprotect the C-protecting group after step 1, and then remove / deprotect the N-protecting group.

[0635] As used herein, the term "C-protected amino acid" means a natural or unnatural amino acid in which the carboxyl group is protected, and the term "C-protected peptide" means a peptide in which the carboxyl group of the C-terminal amino acid residue is protected. The peptide can consist of only natural amino acid residues, only unnatural amino acid residues, or any combination of natural amino acid residues and unnatural amino acid residues.

[0636] Any protecting group known in the art can be used as the protecting group for the carboxyl group of the "C-protected amino acid" and the "C-protected peptide". The solubility of the C-protected amino acid and the C-protected peptide in the solvent used in the reaction is at least 1% (w / v) or greater, and further preferably 5% (w / v) or greater. Specific examples of such protecting groups for the carboxyl group include a methyl group, an ethyl group, a t-Bu group, a trityl group, and a cumyl group, and among these groups, the t-Bu group is preferred.

[0637] As used herein, the term "N-protected amino acid" means a natural or unnatural amino acid in which the amino group is protected, and the term "N-protected peptide" means a peptide in which the amino group of the amino acid residue at the N-terminus is protected. A peptide can consist of only natural amino acid residues, only unnatural amino acid residues, or any combination of natural amino acid residues and unnatural amino acid residues.

[0638] Any protecting group known in the art can be used as the protecting group for the amino group of "N-protected amino acid" and "N-protected peptide". Specific examples of such protecting groups for the amino group include Cbz, p-nitrobenzyloxycarbonyl, 2-naphthylmethoxycarbonyl, diphenylmethoxycarbonyl, 9-anthrylmethoxycarbonyl, Teoc, Boc, trifluoroacetyl or Alloc, and among these, Cbz, Teoc or trifluoroacetyl is preferred.

[0639] As is known in the art, the protecting group for each of N-protected amino acid and C-protected amino acid and / or N-protected peptide and C-protected peptide is generally selected according to the chemical reaction conditions and can be determined by conventional methods known in the art. For example, when using a water-immiscible solvent (e.g., a lipophilic solvent), a hydrophilic protecting group may reduce the solubility of the protected compound in the organic solvent, and thus such a hydrophilic protecting group may not be a suitable protecting group. Therefore, when using a water-immiscible solvent as described herein, a lipophilic protecting group can be a preferred protecting group because, for example, it can maintain the solubility of the peptide compound in the water-immiscible solvent.

[0640] The selection of such protecting groups can be carried out by methods known in the art or described herein, such as the methods described in "Greene's Protective Groups in Organic Synthesis, 5th Edition, 2014". As a non-limiting example, an example of an N-protecting group that can be used in the method of the present invention is the Cbz group. When the amino acid has a steric interfering functional group such as a spiroalkyl group at the α-position of the amino acid residue, preferred examples include trifluoroacetyl.

[0641] In one aspect, the coupling step in the production method of the present invention is carried out by a liquid phase method.

[0642] In one aspect, the coupling step in the production method of the present invention is carried out by mixing a peptide compound and an optional base in a mixed solution obtained by mixing a mixed solvent and a condensing agent. This operation can be referred to herein as "reverse addition dropwise". Reverse addition dropwise of the peptide compound and the base over a long period of time, such as several hours to several days, preferably 1 to 24 hours, more preferably 1 to 10 hours, can suppress the formation of dimer and trimer by-products without the need to use a large amount of solvent for dilution.

[0643] The cyclic peptide compound produced by the method of the present invention has high purity and low content of by-products (e.g., epimers, dimers, and trimers), as described below.

[0644] In one aspect, based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the total by-products formed in the coupling step in the production method of the present invention is less than 20%, less than 15%, less than 10%, less than 5%, or less than 3%.

[0645] In one aspect, based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of each by-product in the by-products formed in the coupling step in the production method of the present invention is less than 15%, less than 10%, less than 5%, less than 3%, less than 1%, or an undetectable amount, and the by-products are epimers, dimers, and trimers.

[0646] In one aspect, the by-products formed in the coupling step in the production method of the present invention include epimers of the cyclic peptide compound, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the epimers is less than 10%, less than 7.5%, less than 5%, less than 2.5%, or less than 1%.

[0647] In one aspect, the by-products formed in the coupling step in the production method of the present invention include dimers, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the dimers is less than 15%, less than 10%, less than 5%, less than 2.5%, or less than 1%.

[0648] In one aspect, the by-products formed in the coupling step in the production method of the present invention include trimers, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the trimers is less than 5%, less than 2.5%, less than 1%, or an undetectable amount.

[0649] In one aspect, the by-products formed in the coupling step in the production method of the present invention include dimers and trimers, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the total content of dimers and trimers is less than 15%, less than 10%, less than 5%, less than 2.5%, or less than 1%.

[0650] In one aspect, the present invention relates to a method for producing a cyclic peptide compound represented by the following formula (2)

[0651] [Formula 39]

[0652]

[0653] or a salt thereof, or a solvate thereof, the method comprising the following steps:

[0654] (1) Providing a linear peptide compound represented by the following formula:

[0655] [Formula 38]

[0656]

[0657] or a salt thereof, or a solvate thereof (Compound B13); and

[0658] (2) Coupling the N-terminal amino acid residue of the linear peptide compound, or a salt thereof, or a solvate thereof with the C-terminal amino acid residue of the linear peptide compound, or a salt thereof, or a solvate thereof. Hereinafter, this aspect will also be referred to as "Aspect 3".

[0659] In Aspect 3, step (1) can provide the linear peptide compound, or a salt thereof, or a solvate thereof (Compound B13) according to the methods described in, for example, Examples B-1 to B-13 below.

[0660] In Aspect 3, step (2) is preferably carried out in the presence of a solvent. The solvent used in step (2) preferably includes one or more selected from the group consisting of acetonitrile, dimethyl carbonate, and 2-MeTHF, and more preferably is one selected from the group consisting of acetonitrile, dimethyl carbonate, and 2-MeTHF, and still more preferably is one selected from the group consisting of acetonitrile and dimethyl carbonate.

[0661] In Aspect 3, step (2) is preferably carried out in the presence of a condensation reagent. The condensation reagent used in step (2) is preferably one selected from the group consisting of COMU, HATU, PyBOP, PyOxim, PyClop, DMT-MM, DEPBT, FDPP, T3P, and BEP-BF4, and more preferably is one selected from the group consisting of COMU and HATU.

[0662] In aspect 3, the combination of the condensation reagent and the solvent is preferably a combination of one selected from the group consisting of COMU and HATU and one or more selected from the group consisting of acetonitrile, dimethyl carbonate, and 2-MeTHF, and more preferably a combination of one selected from the group consisting of COMU and HATU and one selected from the group consisting of acetonitrile and dimethyl carbonate.

[0663] In aspect 3, step (2) is preferably carried out in the presence of a base. The base used in step (2) is preferably an organic base, more preferably an organic base containing a tertiary amine, and further preferably one selected from the group consisting of: N,N-diisopropylethylamine (DIPEA), 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), 2,3,6,7-tetrahydro-1H,5H-9-azabenz[ij]quinolizine, 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(tetramethylguanidino)naphthalene (TMGN), 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), triethylamine (TEA), trimethylamine, 1-methylpiperidine, N,N′-dimethylpiperazine, N-methylmorpholine, N-ethylmorpholine, and p-dimethylaminopyridine (DMAP), and particularly preferably N,N-diisopropylethylamine (DIPEA).

[0664] In aspect 3, the combination of the condensation reagent, the solvent, and the base is preferably the following combination: one selected from the group consisting of COMU, HATU, PyBOP, PyOxim, PyClop, DMT-MM, DEPBT, FDPP, T3P, and BEP-BF4; one or more selected from the group consisting of acetonitrile, dimethyl carbonate, and 2-MeTHF; and N,N-diisopropylethylamine (DIPEA), and more preferably the following combination: one selected from the group consisting of COMU and HATU; one or more selected from the group consisting of acetonitrile, dimethyl carbonate, and 2-MeTHF; and N,N-diisopropylethylamine (DIPEA), and further preferably the following combination: one selected from the group consisting of COMU and HATU; one selected from the group consisting of acetonitrile and dimethyl carbonate; and N,N-diisopropylethylamine (DIPEA).

[0665] In aspect 3, step (2) is preferably carried out by mixing the peptide compound and the base in a mixed solution obtained by mixing the solvent and the condensation reagent. This can inhibit the formation of dimer and trimer by-products without using a large amount of solvent for dilution.

[0666] In aspect 3, based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the total by-products formed is preferably less than 10%, less than 7.5%, less than 5%, less than 3%, or less than 1%.

[0667] In aspect 3, based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of each by-product among the by-products formed is preferably less than 10%, less than 7.5%, less than 5%, less than 3%, less than 1%, or an undetectable amount.

[0668] In aspect 3, based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of each by-product among the by-products formed is preferably less than 10%, less than 7.5%, less than 5%, less than 3%, less than 1%, or an undetectable amount, and the by-products are epimers, dimers, and trimers.

[0669] In aspect 3, the by-products formed preferably contain epimers of the cyclic peptide compound, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the epimers is less than 3%, less than 1%, or an undetectable value.

[0670] In aspect 3, the by-products formed preferably contain dimers, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the dimers is less than 5%, less than 3%, or less than 1%.

[0671] In aspect 3, the by-products formed preferably contain trimers, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the trimers is less than 3%, less than 1%, or an undetectable amount.

[0672] In aspect 3, the by-products formed preferably contain dimers and trimers, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the total content of the dimers and trimers is less than 5%, less than 3%, or less than 1%.

[0673] In one aspect, the present invention relates to a method for producing a cyclic peptide compound represented by the following formula (2)

[0674] [Formula 41]

[0675]

[0676] A method for or its salt or its solvate, the method comprising the following steps:

[0677] (1) Providing a linear peptide compound represented by the following formula:

[0678] [Formula 40]

[0679]

[0680] or its salt or its solvate (Compound D21); and

[0681] (2) Connecting the N-terminal amino acid residue of the linear peptide compound, or its salt or its solvate, to the C-terminal amino acid residue of the linear peptide compound, or its salt or its solvate. Hereinafter, this aspect will also be referred to as "Aspect 4".

[0682] In Aspect 4, step (1) can provide the linear peptide compound, or its salt or its solvate (Compound D21) according to the methods described in the following Examples D-1 to D-21, for example.

[0683] In Aspect 4, step (2) is preferably carried out in the presence of a solvent. The solvent used in step (2) preferably contains one or more selected from the group consisting of acetonitrile, dimethyl carbonate, 2-MeTHF, and anisole, and more preferably is one selected from the group consisting of acetonitrile, dimethyl carbonate, 2-MeTHF, and anisole, and further preferably is dimethyl carbonate.

[0684] In Aspect 4, step (2) is preferably carried out in the presence of a condensation reagent. The condensation reagent used in step (2) is preferably one selected from the group consisting of COMU, HATU, PyBOP, PyOxim, PyClop, and DMT-MM, more preferably is one selected from the group consisting of COMU and HATU, and further preferably is COMU.

[0685] In Aspect 4, the combination of the condensation reagent and the solvent is preferably a combination of one selected from the group consisting of COMU, HATU, PyBOP, PyOxim, PyClop, and DMT-MM and one or more selected from the group consisting of acetonitrile, dimethyl carbonate, 2-MeTHF, and anisole, more preferably is a combination of COMU and one selected from the group consisting of acetonitrile and dimethyl carbonate, and further preferably is a combination of COMU and dimethyl carbonate.

[0686] In aspect 4, step (2) is preferably carried out in the presence of a base. The base used in step (2) is preferably an organic base, more preferably an organic base containing a tertiary amine, and further preferably one selected from the group consisting of N,N - diisopropylethylamine (DIPEA), 1,8 - diazabicyclo[5.4.0]-7 - undecene (DBU), 2,3,6,7 - tetrahydro - 1H,5H - 9 - azabenz[ij]quinolizine, 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(tetramethylguanidino)naphthalene (TMGN), 2 - tert - butyl - 1,1,3,3 - tetramethylguanidine (BTMG), triethylamine (TEA), trimethylamine, 1 - methylpiperidine, N,N′ - dimethylpiperazine, N - methylmorpholine, N - ethylmorpholine, and p - dimethylaminopyridine (DMAP), and particularly preferably N,N - diisopropylethylamine (DIPEA).

[0687] In aspect 4, the combination of the condensing agent with the solvent and the base is preferably a combination of COMU, one selected from the group consisting of acetonitrile and dimethyl carbonate, and N,N - diisopropylethylamine (DIPEA), and more preferably a combination of COMU, dimethyl carbonate, and N,N - diisopropylethylamine (DIPEA).

[0688] In aspect 4, step (2) is preferably carried out by mixing the peptide compound and the base in a mixed solution obtained by mixing the solvent and the condensing agent. This can inhibit the formation of dimer and trimer by - products without using a large amount of solvent for dilution.

[0689] In aspect 4, based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the total by - products formed is preferably less than 20%, less than 15%, less than 10%, less than 5%, or less than 3%.

[0690] In aspect 4, based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of each by - product among the by - products formed is preferably less than 15%, less than 10%, less than 7.5%, less than 5%, less than 2.5%, or less than 1%.

[0691] In aspect 4, based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of each by-product in the formed by-products is preferably less than 15%, less than 10%, less than 7.5%, less than 5%, less than 2.5% or less than 1%, and the by-products are epimers, dimers and trimers.

[0692] In aspect 4, the formed by-products preferably contain epimers of the cyclic peptide compound, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the epimers is less than 3%, less than 1% or an undetectable value.

[0693] In aspect 4, the formed by-products preferably contain dimers, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the dimers is less than 15%, less than 10% or less than 5%.

[0694] In aspect 4, the formed by-products preferably contain trimers, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the trimers is less than 5%, less than 3% or less than 1%.

[0695] In aspect 4, the formed by-products preferably contain dimers and trimers, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the total content of the dimers and trimers is less than 20%, less than 15%, less than 10%, less than 5% or less than 3%.

[0696] In one aspect, the present invention relates to a method for producing a cyclic peptide compound represented by the following formula (2)

[0697] [Formula 43]

[0698]

[0699] or a salt thereof, or a solvate thereof, the method comprising the following steps:

[0700] (1) Providing a linear peptide compound represented by the following formula:

[0701] [Formula 42]

[0702]

[0703] or a salt thereof, or a solvate thereof (Compound E9); and

[0704] (2) Connect the N-terminal amino acid residue of the linear peptide compound, or a salt or solvate thereof, to the C-terminal amino acid residue of the linear peptide compound, or a salt or solvate thereof. Hereinafter, this aspect will also be referred to as "Aspect 5".

[0705] In Aspect 5, step (1) can provide the linear peptide compound, or a salt or solvate thereof (Compound E9), for example, according to the methods described in Examples E-1 to E-9 below.

[0706] In Aspect 5, step (2) is preferably carried out in the presence of a solvent. The solvent used in step (2) preferably comprises one or more selected from the group consisting of acetonitrile, dimethyl carbonate, 2-MeTHF, and anisole, and more preferably is one selected from the group consisting of acetonitrile, dimethyl carbonate, 2-MeTHF, and anisole, and further preferably is dimethyl carbonate.

[0707] In Aspect 5, step (2) is preferably carried out in the presence of a condensing agent. The condensing agent used in step (2) is preferably one selected from the group consisting of COMU, HATU, PyBOP, PyOxim, PyClop, and DMT-MM, more preferably is one selected from the group consisting of COMU and HATU, and further preferably is COMU.

[0708] In Aspect 5, the combination of the condensing agent and the solvent is preferably a combination of one selected from the group consisting of COMU, HATU, PyBOP, PyOxim, PyClop, and DMT-MM and one or more selected from the group consisting of acetonitrile, dimethyl carbonate, 2-MeTHF, and anisole, more preferably is a combination of one selected from the group consisting of COMU and HATU and one selected from the group consisting of acetonitrile and dimethyl carbonate, and further preferably is a combination of COMU and dimethyl carbonate.

[0709] In aspect 5, step (2) is preferably carried out in the presence of a base. The base used in step (2) is preferably an organic base, more preferably an organic base containing a tertiary amine, and further preferably one selected from the group consisting of: N,N-diisopropylethylamine (DIPEA), 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), 2,3,6,7-tetrahydro-1H,5H-9-azabenzo[ij]quinolizine, 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(tetramethylguanidino)naphthalene (TMGN), 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), triethylamine (TEA), trimethylamine, 1-methylpiperidine, N,N'-dimethylpiperazine, N-methylmorpholine, N-ethylmorpholine, and p-dimethylaminopyridine (DMAP), and particularly preferably N,N-diisopropylethylamine (DIPEA).

[0710] In aspect 5, the combination of the condensing agent with the solvent and the base is preferably one of the following combinations: one selected from the group consisting of COMU and HATU; one selected from the group consisting of acetonitrile and dimethyl carbonate; and N,N-diisopropylethylamine (DIPEA), and more preferably the combination of COMU, dimethyl carbonate, and N,N-diisopropylethylamine (DIPEA).

[0711] In aspect 5, step (2) is preferably carried out by mixing the peptide compound and the base in a mixed solution obtained by mixing the solvent and the condensing agent. This can inhibit the formation of dimer and trimer by-products without the need to use a large amount of solvent for dilution.

[0712] In aspect 5, based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the total by-products formed is preferably less than 10%, less than 7.5%, less than 5%, or less than 2.5%.

[0713] In aspect 5, based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of each by-product in the by-products formed is preferably less than 10%, less than 7.5%, less than 5%, less than 3%, less than 1%, or an undetectable amount.

[0714] In aspect 5, based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of each by-product in the formed by-products is preferably less than 10%, less than 7.5%, less than 5%, less than 3%, less than 1%, or an undetectable amount, and the by-products are epimers, dimers, and trimers.

[0715] In aspect 5, the formed by-products preferably include epimers of the cyclic peptide compound, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the epimers is less than 7.5%, less than 5%, less than 3%, or less than 1%.

[0716] In aspect 5, the formed by-products preferably include dimers, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the dimers is less than 10%, less than 7.5%, less than 5%, less than 2.5%, or less than 1%.

[0717] In aspect 5, the formed by-products preferably include trimers, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the trimers is less than 3%, less than 1%, or an undetectable amount.

[0718] In aspect 5, the formed by-products preferably include dimers and trimers, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the total content of the dimers and trimers is less than 10%, less than 7.5%, less than 5%, less than 2.5%, or less than 1%.

[0719] In one aspect, the present invention relates to a method for producing a cyclic peptide compound represented by the following formula (2)

[0720] [Formula 45]

[0721]

[0722] or a salt thereof, or a solvate thereof, the method comprising the following steps:

[0723] (1) Providing a linear peptide compound represented by the following formula:

[0724] [Formula 44]

[0725]

[0726] or a salt thereof, or a solvate thereof (Compound C15); and

[0727] (2) Connect the N-terminal amino acid residue of the linear peptide compound, or a salt or solvate thereof, to the C-terminal amino acid residue of the linear peptide compound, or a salt or solvate thereof. Hereinafter, this aspect will also be referred to as "Aspect 6".

[0728] In Aspect 6, step (1) can provide the linear peptide compound, or a salt or solvate thereof (Compound C15), for example, according to the methods described in Examples C-1 to C-14 below.

[0729] In Aspect 6, step (2) is preferably carried out in the presence of a solvent. The solvent used in step (2) preferably includes one or both selected from acetonitrile and dimethyl carbonate, and more preferably dimethyl carbonate.

[0730] In Aspect 6, step (2) is preferably carried out in the presence of a condensing agent. The condensing agent used in step (2) is preferably one selected from the group consisting of COMU, HATU, PyBOP, PyOxim, PyClop, DMT-MM, and DEPBT, more preferably one selected from the group consisting of COMU and HATU, and still more preferably HATU.

[0731] In Aspect 6, the combination of the condensing agent and the solvent is preferably a combination of one selected from the group consisting of COMU, HATU, PyBOP, PyOxim, PyClop, DMT-MM, and DEPBT and one or both selected from the group consisting of acetonitrile and dimethyl carbonate, more preferably a combination of one selected from the group consisting of COMU and HATU and one selected from the group consisting of acetonitrile and dimethyl carbonate, still more preferably a combination of one selected from the group consisting of COMU and HATU and dimethyl carbonate, and particularly preferably a combination of HATU and dimethyl carbonate.

[0732] In aspect 6, step (2) is preferably carried out in the presence of a base. The base used in step (2) is preferably an organic base, more preferably an organic base containing a tertiary amine, and further preferably one selected from the group consisting of: N,N-diisopropylethylamine (DIPEA), 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), 2,3,6,7-tetrahydro-1H,5H-9-azabenz[ij]quinolizine, 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(tetramethylguanidino)naphthalene (TMGN), 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), triethylamine (TEA), trimethylamine, 1-methylpiperidine, N,N'-dimethylpiperazine, N-methylmorpholine, N-ethylmorpholine, and p-dimethylaminopyridine (DMAP), and particularly preferably N,N-diisopropylethylamine (DIPEA).

[0733] In aspect 6, the combination of the condensing reagent with the solvent and the base is preferably one selected from the group consisting of COMU and HATU, one selected from the group consisting of acetonitrile and dimethyl carbonate, and the combination with N,N-diisopropylethylamine (DIPEA), more preferably one selected from the group consisting of COMU and HATU, the combination of dimethyl carbonate and N,N-diisopropylethylamine (DIPEA), and further preferably the combination of HATU, dimethyl carbonate, and N,N-diisopropylethylamine (DIPEA).

[0734] In aspect 6, step (2) is preferably carried out by mixing the peptide compound and the base in a mixed solution obtained by mixing the solvent and the condensing reagent. This can inhibit the formation of dimer and trimer by-products without the need to use a large amount of solvent for dilution.

[0735] In aspect 6, as determined by UV area value at 220 nm using HPLC analysis, the content of the total by-products formed is preferably less than 10%, less than 7.5%, less than 5%, or less than 2.5%.

[0736] In aspect 6, based on the total amount of the product, as determined by UV area value at 220 nm using HPLC analysis, the content of each by-product in the by-products formed is preferably less than 10%, less than 7.5%, less than 5%, less than 3%, less than 1%, or an undetectable amount.

[0737] In aspect 6, based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of each by-product among the formed by-products is preferably less than 10%, less than 7.5%, less than 5%, less than 3%, less than 1%, or an undetectable amount, and the by-products are epimers, dimers, and trimers.

[0738] In aspect 6, the formed by-products preferably include epimers of the cyclic peptide compound, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the epimers is less than 7.5%, less than 5%, less than 3%, or less than 1%.

[0739] In aspect 6, the formed by-products preferably include dimers, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the dimers is less than 10%, less than 7.5%, less than 5%, less than 2.5%, or less than 1%.

[0740] In aspect 6, the formed by-products preferably include trimers, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the trimers is less than 3%, less than 1%, or an undetectable amount.

[0741] In aspect 6, the formed by-products preferably include dimers and trimers, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the total content of the dimers and trimers is less than 10%, less than 7.5%, less than 5%, less than 2.5%, or less than 1%.

[0742] In one aspect, the present invention relates to a method for producing a cyclic peptide compound represented by the following formula (2)

[0743] [Formula 47]

[0744]

[0745] or a salt thereof, or a solvate thereof, the method comprising the following steps:

[0746] (1) Providing a linear peptide compound represented by the following formula:

[0747] [Formula 46]

[0748]

[0749] or a salt thereof, or a solvate thereof (Compound A36); and

[0750] (2) Connect the N-terminal amino acid residue of the linear peptide compound, or a salt or solvate thereof, to the C-terminal amino acid residue of the linear peptide compound, or a salt or solvate thereof. Hereinafter, this aspect will also be referred to as "Aspect 7".

[0751] In Aspect 7, step (1) can provide the linear peptide compound, or a salt or solvate thereof (Compound A36), for example, according to the methods described in Examples A-1 to A-25 below.

[0752] In Aspect 7, step (2) is preferably carried out in the presence of a solvent. The solvent used in step (2) is preferably one or both selected from the group consisting of acetonitrile and dimethyl carbonate, and more preferably acetonitrile.

[0753] In Aspect 7, step (2) is preferably carried out in the presence of a condensing agent. The condensing agent used in step (2) is preferably one selected from the group consisting of COMU, HATU, PyBOP, PyOxim, PyClop, and DMT-MM, more preferably one selected from the group consisting of COMU, HATU, and PyOxim, and still further preferably COMU.

[0754] In Aspect 7, the combination of the condensing agent and the solvent is preferably a combination of one selected from the group consisting of COMU, HATU, PyBOP, PyOxim, PyClop, and DMT-MM and one or both selected from the group consisting of acetonitrile and dimethyl carbonate, more preferably a combination of one selected from the group consisting of COMU, HATU, and PyOxim and one selected from the group consisting of acetonitrile and dimethyl carbonate, still further preferably a combination of COMU and one selected from the group consisting of acetonitrile and dimethyl carbonate, and particularly preferably a combination of COMU and acetonitrile. In another embodiment of Aspect 7, the combination of the condensing agent and the solvent is preferably a combination of HATU and dimethyl carbonate, and a combination of PyOxim and dimethyl carbonate.

[0755] In aspect 7, step (2) is preferably carried out in the presence of a base. The base used in step (2) is preferably an organic base, more preferably an organic base containing a tertiary amine, and further preferably one selected from the group consisting of: N,N-diisopropylethylamine (DIPEA), 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), 2,3,6,7-tetrahydro-1H,5H-9-azabenz[ij]quinolizine, 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(tetramethylguanidino)naphthalene (TMGN), 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), triethylamine (TEA), trimethylamine, 1-methylpiperidine, N,N′-dimethylpiperazine, N-methylmorpholine, N-ethylmorpholine, and p-dimethylaminopyridine (DMAP), and particularly preferably N,N-diisopropylethylamine (DIPEA).

[0756] In aspect 7, the combination of the condensing agent with the solvent and the base is preferably one selected from the group consisting of COMU, HATU, and PyOxim, one selected from the group consisting of acetonitrile and dimethyl carbonate, and the combination with N,N-diisopropylethylamine (DIPEA), more preferably the combination of COMU, one selected from the group consisting of acetonitrile and dimethyl carbonate, and N,N-diisopropylethylamine (DIPEA), and further preferably the combination of COMU, acetonitrile, and N,N-diisopropylethylamine (DIPEA). In another embodiment of aspect 7, the combination of the condensing agent with the solvent and the base is preferably the combination of HATU, dimethyl carbonate, and N,N-diisopropylethylamine (DIPEA), and the combination of PyOxim, dimethyl carbonate, and N,N-diisopropylethylamine (DIPEA).

[0757] In aspect 7, step (2) is preferably carried out by mixing the peptide compound and the base in a mixed solution obtained by mixing the solvent and the condensing agent. This can inhibit the formation of dimer and trimer by-products without using a large amount of solvent for dilution.

[0758] In aspect 7, the content of the total by-products formed, as determined by UV area value at 220 nm using HPLC analysis, is preferably less than 15%, less than 10%, less than 7.5%, or less than 5%.

[0759] In aspect 7, based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of each by-product in the by-products formed is preferably less than 10%, less than 7.5%, less than 5%, less than 3%, less than 1%, or an undetectable amount.

[0760] In aspect 7, based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of each by-product in the by-products formed is preferably less than 10%, less than 7.5%, less than 5%, less than 3%, less than 1%, or an undetectable amount, and the by-products are epimers, dimers, and trimers.

[0761] In aspect 7, the by-products formed preferably include epimers of the cyclic peptide compound, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the epimers is less than 5%, less than 3%, or less than 1%.

[0762] In aspect 7, the by-products formed preferably include dimers, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the dimers is less than 10%, less than 7.5%, or less than 5%.

[0763] In aspect 7, the by-products formed preferably include trimers, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the trimers is less than 3%, less than 1%, or an undetectable amount.

[0764] In aspect 7, the by-products formed preferably include dimers and trimers, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the total content of the dimers and trimers is less than 10%, less than 7.5%, or less than 5%.

[0765] Method for suppressing epimerization of cyclic peptide compounds

[0766] In one aspect, the present invention relates to a method for inhibiting epimerization of a cyclic peptide compound in the production of the cyclic peptide compound, or a salt thereof, or a solvate thereof, the method comprising the step of linking the N-terminal amino acid residue of a peptide compound with the C-terminal amino acid residue of the peptide compound in a solvent, wherein at least one of the N-terminal amino acid residue and the C-terminal amino acid residue is a cyclic amino acid residue, and the solvent comprises one or more selected from the group consisting of acetonitrile, dimethyl carbonate, 2-MeTHF, and anisole. Hereinafter, this aspect will also be referred to as "aspect 8".

[0767] In one aspect, the present invention relates to a method for suppressing the epimerization of a cyclic peptide compound, or a salt or solvate thereof, in the production of the cyclic peptide compound, the method comprising the step of linking the N-terminal amino acid residue of a peptide compound with the C-terminal amino acid residue of the peptide compound in a solvent, wherein the N-terminal amino acid residue and the C-terminal amino acid residue of the peptide compound are each one selected from the following a) to e):

[0768] a) The N-terminal amino acid residue is an N-substituted phenylalanine residue or an N-substituted phenylalanine derivative residue, and the C-terminal amino acid residue is a cyclic amino acid residue;

[0769] b) The N-terminal amino acid residue is an α,α-disubstituted amino acid residue, and the C-terminal amino acid residue is a cyclic amino acid residue;

[0770] c) The N-terminal amino acid residue is a cyclic amino acid residue, and the C-terminal amino acid residue is a homophenylalanine residue or a homophenylalanine derivative residue;

[0771] d) The N-terminal amino acid residue is a cyclic amino acid residue, and the C-terminal amino acid residue is an N-substituted Ala residue; and

[0772] e) The N-terminal amino acid residue is an N-substituted Gly residue, and the C-terminal amino acid residue is an N-substituted phenylalanine residue or an N-substituted phenylalanine derivative residue. Hereinafter, this aspect will also be referred to as "Aspect 9".

[0773] In Aspects 8 and 9, the step of linking the N-terminal amino acid residue of the peptide compound with the C-terminal amino acid residue of the peptide compound is as described above in " Method for producing cyclic peptide compounds ".

[0774] In Aspects 8 and 9, based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the epimer formed is preferably less than 20%, less than 15%, less than 10%, less than 5% or less than 3%.

[0775] In Aspects 8 and 9, based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of the epimer formed is preferably less than 15%, less than 10%, less than 5%, less than 3%, less than 1%, or an undetectable amount.

[0776] Method for suppressing oligomer formation of cyclic peptide compounds

[0777] In one aspect, the present invention relates to a method for inhibiting the formation of oligomers of a cyclic peptide compound, or a salt or solvate thereof, the method comprising the step of linking the N-terminal amino acid residue of a peptide compound with the C-terminal amino acid residue of the peptide compound in a solvent, wherein at least one of the N-terminal amino acid residue and the C-terminal amino acid residue is a cyclic amino acid residue, and the solvent comprises one or more selected from the group consisting of acetonitrile, dimethyl carbonate, 2-MeTHF and anisole. Hereinafter, this aspect will also be referred to as "Aspect 10".

[0778] In one aspect, the present invention relates to a method for inhibiting the formation of oligomers of a cyclic peptide compound, or a salt or solvate thereof, the method comprising the step of linking the N-terminal amino acid residue of a peptide compound with the C-terminal amino acid residue of the peptide compound in a solvent, wherein the N-terminal amino acid residue and the C-terminal amino acid residue of the peptide compound are one selected from the following a) to e):

[0779] a) The N-terminal amino acid residue is an N-substituted phenylalanine residue or an N-substituted phenylalanine derivative residue, and the C-terminal amino acid residue is a cyclic amino acid residue;

[0780] b) The N-terminal amino acid residue is an α,α-disubstituted amino acid residue, and the C-terminal amino acid residue is a cyclic amino acid residue;

[0781] c) The N-terminal amino acid residue is a cyclic amino acid residue, and the C-terminal amino acid residue is a homophenylalanine residue or a homophenylalanine derivative residue;

[0782] d) The N-terminal amino acid residue is a cyclic amino acid residue, and the C-terminal amino acid residue is an N-substituted Ala residue; and

[0783] e) The N-terminal amino acid residue is an N-substituted Gly residue, and the C-terminal amino acid residue is an N-substituted phenylalanine residue or an N-substituted phenylalanine derivative residue. Hereinafter, this aspect will also be referred to as "Aspect 11".

[0784] In Aspects 10 and 11, the step of linking the N-terminal amino acid residue of the peptide compound with the C-terminal amino acid residue of the peptide compound is as described above in " Method for producing cyclic peptide compounds ".

[0785] In Aspects 10 and 11, the by-products formed preferably contain dimers, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of dimers is less than 15%, less than 10%, less than 5%, less than 2.5% or less than 1%.

[0786] In aspects 10 and 11, the by-products formed preferably contain trimers, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the content of trimers is less than 5%, less than 2.5%, less than 1%, or an undetectable amount.

[0787] In aspects 10 and 11, the by-products formed preferably contain dimers and trimers, and based on the total amount of the product, as determined by the UV area value at 220 nm using HPLC analysis, the total content of dimers and trimers is less than 15%, less than 10%, less than 5%, less than 2.5%, or less than 1%.

[0788] [Examples]

[0789] The content of the present invention will be further illustrated by the following examples, but the present invention is not limited to the content of the following examples. Unless otherwise specified, starting materials, starting raw materials, solvents, and reagents are obtained from commercial suppliers or synthesized using known methods.

[0790] The analysis conditions for HPLC are shown below.

[0791] HPLC analysis condition method 1

[0792] Apparatus: Waters ACQUITY UPLC H-Class Column: CAPCELL CORE ADME (OSAKA SODA), 2.1 mm ID × 50 mm, 2.7 μm Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[0793] Elution method: B): 5% (0 min) → 100% (5 min) → 5% (5.1 min) → 5% (7 min) Flow rate: 0.5 mL / min

[0794] Column temperature: 35 °C

[0795] Detection wavelength: 210 nm (PDA)

[0796] HPLC analysis condition method 2

[0797] Apparatus: Waters ACQUITY UPLC H-Class

[0798] Column: CAPCELL CORE ADME (OSAKA SODA), 2.1 mm ID × 50 mm, 2.7 μm Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[0799] Elution method: B): 5% (0 min) → 100% (7 min) → 5% (7.1 min) → 5% (9 min) Flow rate: 0.5 mL / min

[0800] Column temperature: 35 °C

[0801] Detection wavelength: 210 nm (PDA)

[0802] HPLC analysis condition method 3

[0803] Equipment: Waters ACQUITY UPLC H-Class

[0804] Column: ACQUITY UPLC CSH C18 (Waters), 2.1 mm ID × 150 mm, 1.7 μm Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[0805] Elution method: B) 20% (0 min) → 100% (24 min) → 100% (29 min) → 20% (29.1 min) → 20% (34 min)

[0806] Flow rate: 0.3 mL / min

[0807] Column temperature: 50 °C

[0808] Detection wavelength: 220 nm (PDA)

[0809] HPLC analysis condition method 4

[0810] Equipment: Waters ACQUITY UPLC H-Class

[0811] Column: Ascentis Express 90A C18 (Sigma-Aldrich), 2.1 mm ID × 50 mm, 2.7 μm Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[0812] Elution method: B): 5% (0 min) → 100% (5 min) → 5% (5.1 min) → 5% (7 min) Flow rate: 0.5 mL / min

[0813] Column temperature: 35 °C

[0814] Detection wavelength: 210 nm (PDA)

[0815] HPLC analysis condition method 5

[0816] Equipment: Waters ACQUITY UPLC H-Class

[0817] Column: CAPCELL CORE ADME (OSAKA SODA), 2.1 mm ID × 50 mm, 2.7 μm Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[0818] Elution method: B): 5% (0 min) → 100% (10 min) → 5% (10.1 min) → 5% (12 min) Flow rate: 0.5 mL / min

[0819] Column temperature: 35 °C

[0820] Detection wavelength: 210 nm (PDA)

[0821] HPLC analysis condition method 6

[0822] Equipment: Waters ACQUITY UPLC H-Class

[0823] Column: ACQUITY UPLC CSH C18 (Waters), 2.1 mm ID × 100 mm, 1.7 μm Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[0824] Elution method: B) 20% (0 min) → 100% (10 min) → 100% (13.5 min) → 20% (13.6 min) -→ 20% (18.0 min)

[0825] Flow rate: 0.3 mL / min

[0826] Column temperature: 50 °C

[0827] Detection wavelength: 210 nm (PDA)

[0828] HPLC analysis condition method 7

[0829] Equipment: Waters ACQUITY UPLC H-Class

[0830] Column: Ascentis Express 90A C18 (Sigma-Aldrich), 2.1 mm ID × 50 mm, 2.7 μm Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[0831] Elution method: B): 5% (0 min) → 100% (6 min) → 5% (6.1 min) → 5% (8 min) Flow rate: 0.5 mL / min

[0832] Column temperature: 35 °C

[0833] Detection wavelength: 210 nm (PDA)

[0834] HPLC analysis condition method 8

[0835] Equipment: Waters ACQUITY UPLC H-Class

[0836] Column: ACQUITY UPLC CSH C18 (Waters), 2.1 mm ID × 150 mm, 1.7 μm Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[0837] Elution method: B) 20% (0 min) → 100% (84 min) → 100% (89 min) → 20% (89.1 min) -→ 20% (94 min)

[0838] Flow rate: 0.3 mL / min

[0839] Column temperature: 50 °C

[0840] Detection wavelength: 210 nm (PDA)

[0841] HPLC analysis condition method 9

[0842] Equipment: Waters ACQUITY UPLC H-Class

[0843] Column: CHIRALPAK IC-3 (DAICEL) 4.6 mm ID × 150 mm, 3 μm

[0844] Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[0845] Elution method: B): 5% (0 min) → 100% (20 min) → 5% (20.1 min) → 5% (25 min)

[0846] Flow rate: 1.0 mL / min

[0847] Column temperature: 30 °C

[0848] Detection wavelength: 210 nm (PDA)

[0849] [Table 1]

[0850]

[0851]

[0852]

[0853] The analysis conditions of LCMS are shown below.

[0854] LCMS analysis condition method 1

[0855] Equipment: Waters ACQUITY UPLC H-Class + ACQUITY QDA

[0856] Column: CAPCELL CORE ADME (OSAKA SODA), 2.1 mm ID × 50 mm, 2.7 μm Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[0857] Elution method: B): 5% (0 min) → 100% (5 min) → 5% (5.1 min) → 5% (7 min) Flow rate: 0.5 mL / min

[0858] Column temperature: 35 °C

[0859] Detection wavelength: 210 nm (PDA)

[0860] LCMS analysis condition method 2

[0861] Equipment: Waters ACQUITY UPLC H-Class + ACQUITY QDA

[0862] Column: Ascentis Express 90A C18 (Sigma-Aldrich), 2.1 mm ID × 50 mm, 2.7 μm

[0863] Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[0864] Elution method: B) 5% (0 min) → 100% (6 min) → 5% (6.1 min) → 5% (8 min)

[0865] Flow rate: 0.5 mL / min

[0866] Column temperature: 35 °C

[0867] Detection wavelength: 210 nm (PDA)

[0868] LCMS analysis condition method 3

[0869] Equipment: Waters SQD2

[0870] Column: ACQUITY UPLC CSH C18 (Waters), 2.1 mm ID × 150 mm, 1.7 μm Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[0871] Elution method: B) 20% (0 min) → 100% (24 min) → 100% (29 min) → 20% (29.1 min) -→ 20% (34 min)

[0872] Flow rate: 0.3 mL / min

[0873] Column temperature: 50 °C

[0874] Detection wavelength: 220 nm (PDA)

[0875] LCMS analysis condition method 4

[0876] Equipment: Waters ACQUITY UPLC H-Class + ACQUITY QDA

[0877] Column: Ascentis Express 90A C18 (Sigma-Aldrich), 2.1 mm ID × 50 mm, 2.7 μm

[0878] Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[0879] Elution method: B): 5% (0 min) → 100% (5 min) → 5% (5.1 min) → 5% (7 min)

[0880] Flow rate: 0.5 mL / min

[0881] Column temperature: 35 °C

[0882] Detection wavelength: 210 nm (PDA)

[0883] LCMS analysis condition method 5

[0884] Equipment: Waters ACQUITY UPLC H-Class + ACQUITY QDA

[0885] Column: CAPCELL CORE ADME (OSAKA SODA), 2.1 mm ID × 50 mm, 2.7 μm

[0886] Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[0887] Elution method: B) 5% (0 min) → 100% (10 min) → 5% (10.1 min) → 5% (12 min)

[0888] Flow rate: 0.5 mL / min

[0889] Column temperature: 35 °C

[0890] Detection wavelength: 210 nm (PDA)

[0891] LCMS analysis condition method 6

[0892] Equipment: Waters ACQUITY UPLC H-class + SQ detector 2

[0893] Column: ACQUITY UPLC CSH C18 (Waters), 2.1 mm ID × 100 mm, 1.7 μm

[0894] Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[0895] Elution method: B) 20% (0 min) → 100% (10 min) → 100% (13.5 min) → 20% (13.6 min) → 20% (18.0 min)

[0896] Flow rate: 0.3 mL / min

[0897] Column temperature: 50 °C

[0898] Detection wavelength: 210 nm (PDA)

[0899] [Table 2]

[0900]

[0901]

[0902]

[0903]

[0904] 1 The 1H-NMR spectrum was measured using a nuclear magnetic resonance apparatus ECX500II (manufactured by JEOL Ltd.), and the chemical shift of Me 4 Si used as an internal standard substance was set to 0 ppm, and the deuterium lock signal from the sample solvent was referenced. As the sample solvent, a commercially available deuterated solvent was used according to the measurement purpose. The integral value of the signal was calculated based on the ratio of the signal area intensities of each signal.

[0905] By dissolving the residue containing the target compound and the internal standard substance in DMSO-d 6 and subjecting them to the following analysis conditions, the measurement method by qNMR is performed. Using the value of the content of the target material in the residue calculated by qNMR and the value of the purity of the target material in the residue calculated by HPLC, the yield is calculated by the following expression.

[0906] [Expression 1]

[0907]

[0908] Measurement equipment: JNM-ECZ500R

[0909] Internal standard substance: 1,3,5-trimethoxybenzene or 3,5-bis(trifluoromethyl)benzoic acid

[0910] Measurement conditions( 1 H-NMR): DMSO-d 6 , 24.3 °C, pulse angle 90 °C, digital resolution 0.25 Hz, relaxation time 60 seconds, no spin, number of accumulations 8 times

[0911] Measurement conditions( 19 F-NMR): DMSO-d 6 , 24.3 °C, pulse angle 90 °C, digital resolution 0.22 Hz, relaxation time 60 seconds, no spin, number of accumulations 8 times

[0912] The measurement methods by HPLC and LCMS are performed by preparing a mixed solution containing the target compound as a sample according to any of the following methods and subjecting it to the above analysis conditions.

[0913] Sample preparation method 1: Dilute the mixed solution containing the target compound with acetonitrile.

[0914] Sample preparation method 2: Dilute the mixed solution containing the target compound with a mixed solution of acetonitrile and propylamine at a ratio of 9:1.

[0915] Sample preparation method 3: Dilute the mixed solution containing the target compound with methanol.

[0916] Sample preparation method 4: Dilute the mixed solution containing the target compound with a mixed solution of methanol and water at a ratio of 4:1.

[0917] Sample preparation method 5: Dilute the mixed solution containing the target compound with a mixed solution of acetonitrile and propylamine at a ratio of 10:1.

[0918] Using the area value of the starting material and the area value of the target material, or the area value of the starting material, the area value of the propionamide derivative of the starting material, and the area value of the target, or the area value of the starting material before the reaction and the area value of the starting material after the reaction calculated by HPLC analysis, calculate the reaction conversion rate using any of the following formulas.

[0919] Calculation Expression 1: Reaction conversion rate (%) = Area value of the target material / (Area value of the starting material + Area value of the target material) × 100

[0920] Calculation Expression 2: Reaction conversion rate (%) = 100 - (Area value of the starting material after the reaction / Area value of the starting material before the reaction × 100)

[0921] Calculation Expression 3: Reaction conversion rate (%) = Area value of the target material / (Area value of the starting material + Area value of the propionamide derivative of the starting material + Area value of the target material) × 100

[0922] Example A-1

[0923] Synthesis of compound A2: tert-butyl (2S)-2-[benzyloxycarbonyl(methyl)amino]propionate

[0924] [Equation 48]

[0925]

[0926] Add compound A1 (5.00 g) to the reaction vessel. Next, add dichloromethane (10 mL) and cyclohexane (40 mL) to the reaction vessel at room temperature. Replace the inside of the reaction vessel with hydrogen and add tert-butyl 2,2,2-trichloroacetimidate (7.55 mL) and boron trifluoride diethyl ether complex (267 μL), and then stir the mixture at room temperature for 1 hour. Take a sample of the reaction mixture and prepare it as a sample (Sample Preparation Method 1), and confirm by HPLC analysis that the reaction conversion rate is 91.7% (Calculation Expression 1 of the reaction conversion rate). Filter the resulting slurry and wash the solid residue with cyclohexane. Wash the resulting filtrate with 10% aqueous citric acid solution (40 mL × 9), 5% aqueous sodium carbonate solution (40 mL × 3), and saturated aqueous NaCl solution (40 mL). Dehydrate the resulting organic layer with sodium sulfate and filter to remove sodium sulfate. Concentrate the resulting filtrate under reduced pressure at an external temperature of 40 °C to obtain a residue (5.05 g) containing compound A2.

[0927] LC retention time of compound A2: 3.769 minutes (HPLC analysis conditions: Method 1)

[0928] LCMS (ESI) retention time of compound A2: 3.845 minutes, m / z = 316.08 [M+Na]+ (LCMS analysis conditions: Method 1)

[0929] Example A-2

[0930] Synthesis of compound A3: tert-butyl (2S)-2-(methylamino)propionate

[0931] [Formula 49]

[0932]

[0933] The residue (4.03 g) containing compound A2 obtained in Example A-1 was added to a reaction vessel. Next, 2-MeTHF (42 mL) and 5% Pd / C (2.92 g, 50% water content) were added successively at room temperature. The inside of the reaction vessel was purged with hydrogen, and the mixture was stirred at room temperature for 2 hours. The inside of the reaction vessel was purged with hydrogen again, and then the mixture was stirred at room temperature for another 1 hour. The reaction mixture was sampled and prepared as a sample (Sample preparation method 1), and the reaction conversion rate was confirmed to be 99.9% or higher by HPLC analysis (Calculation formula 2 of the reaction conversion rate). The inside of the reaction vessel was purged with nitrogen, and then the reaction mixture was filtered under reduced pressure using filter paper and a filter. The reaction vessel and the filter paper and filter were washed with 2-MeTHF (21 mL × 2). The resulting filtrate and washing solution were mixed and concentrated under reduced pressure at an external temperature of 40 °C to obtain a residue (1.66 g) containing compound A3.

[0934] Example A-3

[0935] Synthesis of compound A5: tert-butyl (2S)-2-[[(2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoyl]-methyl-amino]propionate Example A-4

[0936] [Formula 50]

[0937]

[0938] The residue of compound A3 (1.66 g) obtained in Example A-2 and compound A4 (3.29 g) were added to a reaction vessel, and the reaction vessel was purged with nitrogen. Next, 2-MeTHF (16 mL), toluene (17 mL), MeCN (2.7 mL), and DIPEA (11.0 mL) were sequentially added at room temperature. HATU (5.96 g) was added with stirring, and then the mixture was stirred at room temperature for 2 hours. Samples of the reaction mixture were taken at 1 hour and 2 hours after the reaction and prepared as samples (Sample Preparation Method 1), and it was confirmed by HPLC analysis that there was no difference in the impurity profile. N-Methylimidazole (0.9 mL) was added to the reaction vessel, and 5% aqueous sodium carbonate solution (40 mL) was further added with stirring, and then the mixture was stirred for 1 hour. Next, 2.5% aqueous ammonia solution (40 mL) was added, and the mixture was stirred for 15 minutes. After discharging the aqueous layer, the resulting organic layer was washed with 2.5% aqueous ammonia solution (60 mL), 5% aqueous sodium bisulfate monohydrate solution (60 mL × 2), and 3% aqueous dipotassium hydrogen phosphate solution (60 mL). The resulting organic layer was dehydrated with sodium sulfate and filtered to remove sodium sulfate. The resulting filtrate was concentrated under reduced pressure at an external temperature of 40 °C to obtain a residue (3.88 g) containing compound A5.

[0939] LC retention time of compound A5: 4.161 minutes (HPLC analysis conditions: Method 1)

[0940] LCMS (ESI) retention time of compound A5: 3.708 minutes, m / z = 407.31 [M+H] + (LCMS analysis conditions: Method 2, the column of Method 4 was used as the LC column)

[0941] Synthesis of compound A7: (2S)-4-methyl-2-[methyl(2-trimethylsilylethoxycarbonyl)amino]pentanoic acid (2,3,4,5,6-pentafluorophenyl) ester

[0942] Example A-5 Synthesis of compound A8: (2S)-2-[methyl-[(2S,3S)-3-methyl-2-[[(2S)-4-methyl-2-[methyl

[0943] [Formula 51]

[0944]

[0945] At room temperature, compound A6 (15.8 g) and 2,3,4,5,6-pentafluorophenol (12.6 g) were added to a reaction vessel, and the reaction vessel was purged with nitrogen. Next, isopropyl acetate (100 mL) and DMF (100 mL) were added. The external temperature of the reaction vessel was set to 0 °C, and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (13.1 g) was added with stirring, and then the mixture was stirred at room temperature for 2 hours. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 1), and it was confirmed by HPLC analysis that the reaction conversion rate was 99.9% or higher (Calculation Expression 1 for Reaction Conversion Rate). The external temperature of the reaction vessel was set to 0 °C, and 0.5 N hydrochloric acid aqueous solution (100 mL) was added with stirring, and then the mixture was stirred at room temperature for 30 minutes. After discharging the aqueous layer, the obtained organic layer was washed with 0.5 N hydrochloric acid aqueous solution (100 mL), and then DMF (10 mL) and 5% potassium carbonate aqueous solution (100 mL) were added for washing. Next, the organic layer was washed with 5% potassium carbonate aqueous solution (100 mL) and saturated NaCl aqueous solution (100 mL). The obtained organic layer was dehydrated with sodium sulfate and filtered to remove sodium sulfate. The obtained filtrate was concentrated under reduced pressure at an external temperature of 40 °C to obtain a residue (23.9 g) containing compound A7.

[0946] LC retention time of compound A7: 5.195 minutes (HPLC analysis conditions: Method 1)

[0947] (2-trimethylsilylethoxycarbonyl)amino]pentanoyl]amino]pentanoyl]amino]propionate

[0948] Example A-6 Synthesis of compound A9: (2S)-2-[methyl-[(2S,3S)-3-methyl-2-[[(2S)-4-methyl-2-(methylamino)pentanoyl]amino]pentanoyl]amino]propionate

[0949] [Formula 52]

[0950]

[0951] The residue of compound A5 obtained in Example A-3 (2.88 g) and isopropyl acetate (8.3 mL) were added to a reaction vessel. Next, the residue of compound A7 obtained in Example A-4 (3.88 g), toluene (2.3 mL), acetone (23 mL), NMM (4.67 mL), and 5% Pd / C (1.51 g, 50% water content) were sequentially added at room temperature. The inside of the reaction vessel was purged with hydrogen, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 1), and it was confirmed by HPLC analysis that the reaction conversion rate was 99.9% or greater (Calculation Expression 1 for Reaction Conversion Rate). The inside of the reaction vessel was purged with nitrogen, and then the Pd / C was filtered under reduced pressure using filter paper and a filter. The reaction vessel and the filter paper and filter were washed with 2-MeTHF (50 mL). The resulting solution was concentrated under reduced pressure at an external temperature of 40 °C. The resulting residue was dissolved in 2-MeTHF (40 mL), and 5% potassium carbonate (40 mL) and DMAP (873 mg) were added with stirring, and then the mixture was stirred for 2.5 hours. Next, a 5% aqueous solution of potassium bisulfate (40 mL) was added, and the mixture was stirred for 30 minutes. After discharging the aqueous layer, the resulting organic layer was washed with a 5% aqueous solution of potassium bisulfate (40 mL) and a 5% aqueous solution of potassium carbonate (40 mL × 2). The resulting organic layer was dehydrated with sodium sulfate and filtered to remove the sodium sulfate. The resulting filtrate was concentrated under reduced pressure at an external temperature of 40 °C to obtain a residue (3.58 g) containing compound A8.

[0952] LC retention time of compound A8: 5.180 minutes (HPLC analysis conditions: Method 1)

[0953] LCMS (ESI) retention time of compound A8: 4.936 minutes, m / z = 544.31 [M+H] + (LCMS analysis conditions: Method 1)

[0954] Example A-7

[0955] Synthesis of compound A11: ((3S)-3-[benzyloxycarbonyl(methyl)amino]-4-(dimethylamino)-4-oxo-butyric acid tert-butyl ester) Example A-8

[0956] [Formula 53]

[0957]

[0958] At room temperature, the residue (2.56 g) of compound A8 obtained in Example A-5 and 2-MeTHF (5.0 mL) were added to a reaction vessel, and the reaction vessel was purged with nitrogen. Next, the external temperature of the reaction vessel was set to 50 °C, and 1 M TBAF (11.8 mL) was added with stirring, and then the mixture was stirred at an external temperature of 50 °C for 2 hours. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 1), and it was confirmed by HPLC analysis that the reaction conversion rate was 99.9% or higher (Calculation Expression 1 of Reaction Conversion Rate). The external temperature was set to 0 °C, and IPAc (10 mL) and 5% potassium carbonate (10 mL) were added with stirring, and then the mixture was stirred at room temperature for 15 minutes. After discarding the aqueous layer, the resulting organic layer was washed with 5% potassium carbonate (10 mL × 2). The resulting organic layer was dehydrated with sodium sulfate and filtered to remove the sodium sulfate. The resulting filtrate was concentrated under reduced pressure at an external temperature of 40 °C to obtain a residue (1.54 g) containing compound A9.

[0959] LC retention time of compound A9: 2.915 minutes (HPLC analysis conditions: Method 1)

[0960] LCMS (ESI) retention time of compound A9: 2.637 minutes, m / z = 400.34 [M+H] + (LCMS analysis conditions: Method 1)

[0961] Synthesis of compound A12: ((3S)-4-(dimethylamino)-3-(methylamino)-4-oxo-butyric acid tert-butyl ester)

[0962] Example A-9 Synthesis of compound A14: ((3S)-3-[[(2S)-2-[benzyloxycarbonyl(methyl)amino]-2-cyclopentyl-acetyl

[0963] [Formula 54]

[0964]

[0965] At room temperature, compound A10 (415 g) and 2-MeTHF (2.4 L) were successively added to a reaction vessel purged with nitrogen. The external temperature of the reaction vessel was set to 10 °C, and while stirring the reaction mixture, DIPEA (281 g) and a dimethylamine-THF solution (2 M, THF solution, 560 mL) were successively added, and the mixture was stirred for 30 minutes. After adding T3P (50 w / w%, 2-MeTHF solution, 750 mL), the external temperature of the reaction vessel was set to 25 °C, and the mixture was stirred for 1 hour. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 3), and it was confirmed by HPLC analysis that the reaction conversion rate was 100% or higher (starting material not detected) (Calculation Expression 1 of Reaction Conversion Rate). The external temperature of the reaction vessel was set to 10 °C, and a 10% aqueous solution of citric acid monohydrate (2.5 L) was added to the reaction mixture. The external temperature of the reaction vessel was set to 25 °C, and the mixture was stirred for 10 minutes. Then, stirring was stopped, and the aqueous layer was drained from the reaction vessel. The resulting organic layer was washed with a 10% aqueous solution of citric acid monohydrate (2.5 L) and a 5% aqueous solution of sodium carbonate (2.5 L × 2). The resulting product was concentrated under reduced pressure at an external temperature of 40 °C until the liquid volume reached approximately 500 mL to obtain a solution (500 g) containing compound A11.

[0966] LC retention time of compound A11: 3.510 minutes (HPLC analysis conditions: Method 3)

[0967] yl]-methyl-amino]-4-(dimethylamino)-4-oxo-butyric acid tert-butyl ester)

[0968] Example A-10

[0969] [Formula 55]

[0970]

[0971] At room temperature, 5% Pd / C (116 g, 50% water content), a solution containing compound A11 obtained in Example A-7 (485 g), and 2-MeTHF (2.1 L) were successively added to a reaction vessel purged with nitrogen. The external temperature of the reaction vessel was set to 25 °C, and the reaction vessel was pressurized with hydrogen until the internal pressure of the reaction vessel reached 0.18 MPaG. After stirring for 1 hour and 30 minutes, the reaction mixture was sampled and prepared as a sample (Sample Preparation Method 1), and it was confirmed by HPLC analysis that the reaction conversion rate was 100% or more (starting material not detected) (Calculation Expression 1 for Reaction Conversion Rate). After purging the inside of the reaction vessel with nitrogen, the reaction mixture was filtered under pressure. The inside of the reaction vessel and the filtration device were washed with 2-MeTHF (1.2 L × 2), and the filtrate and the washing solution were collected in a storage container as a storage solution. The obtained product was concentrated under reduced pressure at an external temperature of 40 °C until the liquid volume reached approximately 300 mL to obtain a solution (291 g) containing compound A12.

[0972] LC retention time of compound A12: 1.56 minutes (HPLC analysis conditions: Method 3)

[0973] Synthesis of compound A15: ((3S)-3-[[(2S)-2-cyclopentyl-2-(methylamino)acetyl]-methyl-amino]-4-(dimethylamino)-4-oxo-butyric acid tert-butyl ester)

[0974] Example A-11 Synthesis of compound A17: ((3S)-3-[[(2S)-2-cyclopentyl-2-[methyl-[1-[(2,2,2-trifluoroacetyl

[0975] [Formula 56]

[0976]

[0977] At room temperature, a solution containing A12 obtained in Example A-8 (291 g), compound A13 (49 w / w% 2-MeTHF solution, 548 g), 2-MeTHF (445 mL), and acetonitrile (310 mL) was added to a reaction vessel. The external temperature was cooled to 10 °C, and DIPEA (439 g) and HATU (434 g) were added sequentially, and then the external temperature was raised to 25 °C. After the reaction mixture was stirred at 25 °C for 5 hours, a sample of the reaction mixture was taken and prepared as a sample (Sample Preparation Method 1), and the reaction conversion rate was confirmed to be 98.6% by HPLC analysis (Calculation Expression 1 of Reaction Conversion Rate). CPME (402 mL), 5% aqueous potassium carbonate solution (309 mL), and N-methylimidazole (62.6 g) were added sequentially to the reaction vessel, and the mixture was stirred for 30 minutes. Then, 2.5% aqueous ammonia solution (1.2 L) was added, and the mixture was stirred for 10 minutes, and then the aqueous layer was drained. The resulting organic layer was washed with 2.5% aqueous ammonia solution (1.5 L), 10% aqueous sodium bisulfate monohydrate solution (1.5 L × 2), and 5% aqueous potassium carbonate solution (1.5 L). The resulting organic layer was concentrated under reduced pressure with stirring at an external temperature of 40 °C until the liquid volume reached approximately 700 mL to obtain a solution (649 g) containing compound A14.

[0978] The LC retention time of compound A14: 4.356 minutes (HPLC analysis conditions: Method 3)

[0979] yl)amino]cyclopentanecarbonyl]amino]acetyl]-methyl-amino]-4-(dimethylamino)-4-oxo-butyric acid tert-butyl ester)

[0980] ​ ​

[0981] [Formula 57]

[0982]

[0983] At room temperature, 5% Pd / C (112 g, 50% water content), a solution containing compound A14 obtained in Example A-9 (642 g), and 2-MeTHF (2.0 L) were sequentially added to a reaction vessel purged with nitrogen. The external temperature of the reaction vessel was set to 25 °C, and the reaction vessel was pressurized with hydrogen until the internal pressure of the reaction vessel reached 0.18 MPaG. The mixture was stirred for 2 hours, and it was confirmed that the internal pressure did not fluctuate. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 1), and it was confirmed by HPLC analysis that the reaction conversion rate was 100% or higher (starting material not detected) (Calculation Expression 1 of Reaction Conversion Rate). After purging the inside of the reaction vessel with nitrogen, the reaction mixture was filtered under pressure. The inside of the reaction vessel and the filtration device were washed with 2-MeTHF (1.1 L × 2), and the filtrate and the washing solution were collected as a storage solution. The obtained filtrate and washing solution were concentrated under reduced pressure with stirring at an external temperature of 40 °C until the liquid volume of the reaction mixture reached approximately 550 mL to obtain a solution (597 g) containing compound A15.

[0984] LC retention time of compound A15: 2.297 minutes (HPLC analysis conditions: Method 3)

[0985] ​

[0986] ​ ​

[0987] [Formula 58]

[0988]

[0989] At room temperature, compound A16 (333 g) and 2-MeTHF (1.8 L) were added to a reaction vessel purged with nitrogen. The external temperature of the reaction vessel was set to 10 °C, and DIPEA (477 g), a solution containing compound A15 obtained in Example A-10 (585 g), T3P (50 w / w%, 2-MeTHF solution, 1.2 L), and DMAP (180 g) were added sequentially. The external temperature of the reaction vessel was set to 50 °C, and the mixture was stirred for 5 hours. A sample of the reaction mixture was taken and prepared as a sample (Sample Preparation Method 1), and the reaction conversion rate was confirmed to be 99.4% by HPLC analysis (Calculation Expression 1 for Reaction Conversion Rate). The external temperature of the reaction vessel was set to 10 °C, and 5% aqueous sodium carbonate solution (2.2 L) was added. The external temperature of the reaction vessel was set to 25 °C, and the mixture was stirred for 30 minutes, then stirring was stopped, and the aqueous layer was drained from the reaction vessel. Then, 5% aqueous sodium bisulfate monohydrate solution (2.2 L) was added. After stirring the mixture for 10 minutes, stirring was stopped, and the aqueous layer was drained from the reaction vessel. The resulting organic layer was washed with 5% aqueous sodium bisulfate monohydrate solution (2.2 L) and 5% aqueous sodium carbonate solution (2.2 L). The resulting product was concentrated under reduced pressure at an external temperature of 40 °C until the liquid volume reached approximately 850 mL. After adding 2-MeTHF (650 mL), the mixture was concentrated under reduced pressure again at an external temperature of 40 °C until the liquid volume reached approximately 850 mL to obtain a solution (721 g) containing compound A17.

[0990] LC retention time of compound A17: 6.166 minutes (HPLC analysis conditions: Method 3)

[0991] Example A-12

[0992] Synthesis of Compound A18: ((3S)-3-[[(2S)-2-[(1-Aminocyclopentanecarbonyl)-methyl-amino]-2-cyclo pentyl-acetyl]-methyl-amino]-4-(dimethylamino)-4-oxo-butanoic acid tert-butyl ester)

[0993] [Formula 59]

[0994]

[0995] At room temperature, a solution containing compound A17 (3.42 kg), 2-MeTHF (3.4 L), and methanol (450 mL) were added sequentially to a reaction vessel purged with nitrogen. The external temperature of the reaction vessel was set to -20 °C, and while stirring, LiBH 4(4M, THF solution, 1.39 L), and then the mixture was stirred for 1 hour. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 4), and the reaction conversion rate was confirmed to be 100% or more (starting material not detected) by HPLC analysis (Calculation Expression 1 of Reaction Conversion Rate). The external temperature of the reaction vessel was set to -10 °C, and a 20% aqueous ammonium chloride solution (4.0 L) was added dropwise over 3 hours. The mixture was stirred at an external temperature of 25 °C for 1 hour, then stirring was stopped, and the aqueous layer was drained from the reaction vessel. The external temperature of the reaction vessel was set to 10 °C, and trifluoroacetic acid (158 g) was added. The external temperature of the reaction vessel was set to 25 °C, and the mixture was stirred for 1 hour. The resulting reaction mixture and the washing solution obtained by washing the reaction vessel with 2-MeTHF (100 mL × 2) were combined and collected in a storage container. A 2M aqueous sodium hydroxide solution (4.0 L) was added to another reaction vessel purged with nitrogen at room temperature, and the external temperature of the reaction vessel was set to 10 °C. The reaction mixture collected in the storage container was added dropwise thereto over 50 minutes, and then the external temperature of this reaction vessel was set to 25 °C. After the mixture was stirred for 10 minutes, stirring was stopped, and the aqueous layer was drained from the reaction vessel. The resulting organic layer was washed with a 2M aqueous sodium hydroxide solution (4.0 L) and a 10% aqueous dipotassium hydrogen phosphate solution (4.0 L). The resulting organic layer was concentrated under reduced pressure at an external temperature of 40 °C until the liquid volume reached approximately 1.3 L. After adding 2-MeTHF (1.6 L), the mixture was again concentrated under reduced pressure at an external temperature of 40 °C until the liquid volume reached approximately 1.3 L. This concentration operation was repeated three times to obtain a solution (1.19 kg) containing Compound A18.

[0996] LC retention time of Compound A18: 2.725 minutes (HPLC analysis conditions: Method 3)

[0997] Example A13

[0998] Synthesis of Compound A20: ((2S)-2-[[1-[[(1S)-2-[[(1S)-3-tert-Butoxy-1-(dimethylamino formyl)-3-oxo-propyl]-methyl-amino]-1-cyclopentyl-2-oxo-ethyl]-methyl-carbamoyl]cyclopentyl] carbamoyl]pyrrolidine-1-carboxylic acid benzyl ester)

[0999] [Formula 60]

[1000]

[1001] At room temperature, a solution containing Compound 18 obtained in Example A-12 (585 g, 2-MeTHF solution) and acetonitrile (1.6 L) were successively added to a reaction vessel purged with nitrogen. The external temperature of the reaction vessel was set to 10 °C, and Compound A19 (220 g), DIPEA (264 g), and 2-bromo-1-ethylpyridinium tetrafluoroborate (279 g) were successively added. The external temperature of the reaction vessel was set to 25 °C, and the mixture was stirred for 1 hour. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 1), and the reaction conversion rate was confirmed to be 99.6% by HPLC analysis (Calculation Expression 1 of Reaction Conversion Rate). The external temperature of the reaction vessel was set to 10 °C, and CPME (3.3 L), 5% aqueous potassium carbonate solution (2.0 L), and N-methylimidazole (55.8 g) were successively added. The external temperature of the reaction vessel was set to 25 °C, and the mixture was stirred for 30 minutes, and then the aqueous layer was drained from the reaction vessel. The resulting organic layer was washed with 5% aqueous sodium bisulfate monohydrate solution (2.5 L × 2) and 5% aqueous sodium carbonate solution (2.0 L × 2). The resulting organic layer was concentrated under reduced pressure at an external temperature of 40 °C until the liquid volume reached approximately 1 L. THF (1.6 L) was added to the resulting residue to obtain a solution containing Compound A20 (2.09 kg).

[1002] The LC retention time of Compound A20: 4.189 minutes (HPLC analysis conditions: Method 3)

[1003] Example A-14

[1004] Synthesis of Compound A21: ((3S)-3-[[(2S)-2-Cyclopentyl-2-[methyl-[1-[[(2S)-Pyrrolidine-2-carb onyl]amino]cyclopentanecarbonyl]amino]acetyl]-methyl-amino]-4-(dimethylamino)-4-oxo-butanoic acid tert-butyl ester)

[1005] [Formula 61]

[1006]

[1007] At room temperature, 5% Pd / C (100 g, 50% water content), a solution containing the compound A20 obtained in Example A-13 (2.09 kg), and THF (0.5 L) were successively added to a reaction vessel purged with nitrogen. The external temperature of the reaction vessel was set to 25 °C, and the reaction vessel was pressurized with hydrogen until the internal pressure of the reaction vessel reached 0.18 MPaG. After 2 hours and 30 minutes, it was confirmed that the internal pressure did not fluctuate. Then, the reaction vessel was purged with nitrogen, and then pressurized with hydrogen to 0.18 MPaG, and the reaction mixture was stirred for an additional 2 hours. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 1), and it was confirmed by HPLC analysis that the reaction conversion rate was 99.5% (Calculation Expression 1 for Reaction Conversion Rate). After purging the inside of the reaction vessel with nitrogen, the reaction mixture was filtered under pressure. The reaction vessel and the filtration device were washed with 2-MeTHF (1.0 L × 2). The resulting filtrate and washing solution were concentrated under reduced pressure at an external temperature of 40 °C until the liquid volume reached approximately 0.8 L to obtain a solution (530 g) containing the compound A21.

[1008] LC retention time of compound A21: 2.846 minutes (HPLC analysis conditions: Method 3)

[1009] Example A-15

[1010] Synthesis of Compound A23: ((3S)-3-[[(2S)-2-[[1-[[(2S)-1-[(2S)-2-(Benzyloxycarbonylamino )-4-[3,5-difluoro-4-(trifluoromethyl)phenyl]butanoyl]pyrrolidine-2-carbonyl]amino]cyclopentanecarbonyl]-methyl- amino]-2-cyclopentyl-acetyl]-methyl-amino]-4-(dimethylamino)-4-oxo-butanoic acid tert-butyl ester)

[1011] [Formula 62]

[1012]

[1013] At room temperature, a solution containing compound A21 obtained in Example A-14 (1.10 kg), 2-MeTHF (1.4 L), and compound A22 (545 g) were successively added to a reaction vessel purged with nitrogen. The external temperature of the reaction vessel was set to 10 °C, and DIPEA (432 g) and T3P (50 w / w% 2-MeTHF solution, 1.16 kg) were successively added with stirring. The external temperature of the reaction vessel was set to 25 °C, and the mixture was stirred for 1 hour. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 1), and the reaction conversion rate was confirmed to be 99.8% by HPLC analysis (Calculation Expression 1 of Reaction Conversion Rate). The external temperature of the reaction vessel was set to 15 °C, and 5% aqueous potassium carbonate solution (2.6 L) and N-methylimidazole (62.3 g) were added with stirring. The external temperature of the reaction vessel was set to 25 °C, and the mixture was stirred for 30 minutes, and then the aqueous layer was drained from the reaction vessel. The resulting organic layer was washed with 10% aqueous sodium bisulfate monohydrate solution (2.6 L × 2), and acetonitrile (10 L), MTBE (1.1 L), heptane (1.6 L), and 2.5% aqueous potassium carbonate solution (25 L) were successively added at an external temperature of 25 °C. After the mixture was stirred for 10 minutes, stirring was stopped, and then the aqueous layer was drained from the reaction vessel. Acetonitrile (1.5 L), 2-MeTHF (0.44 L), and 2.5% aqueous potassium carbonate solution (3.8 L) were added to the resulting organic layer, and the mixture was stirred for 10 minutes. After stirring was stopped, the aqueous layer was drained from the reaction vessel. Acetonitrile (1.5 L) and 2.5% aqueous potassium carbonate solution (3.8 L) were added to the resulting organic layer, and the mixture was stirred for 10 minutes. After stirring was stopped, the aqueous layer was drained from the reaction vessel. The resulting organic layer was concentrated under reduced pressure at an external temperature of 40 °C until the liquid volume reached approximately 1.5 L. IPAc (1.5 L) was added to the resulting residue, and the concentration under reduced pressure was repeated twice until the liquid volume of the reaction mixture reached approximately 1.5 L to obtain a solution (1.55 kg) containing compound A23.

[1014] The LC retention time of compound A23: 4.978 minutes (HPLC analysis conditions: Method 3)

[1015] Example A-16

[1016] Synthesis of Compound A24: ((3S)-3-[[(2S)-2-[[1-[[(2S)-1-[(2S)-2-(Benzyloxycarbonylamino )-4-[3,5-difluoro-4-(trifluoromethyl)phenyl]butanoyl]pyrrolidine-2-carbonyl]amino]cyclopentanecarbonyl]-methyl- amino]-2-cyclopentyl-acetyl]-methyl-amino]-4-(dimethylamino)-4-oxo-butanoic acid)

[1017] [Formula 63]

[1018]

[1019] At room temperature, a solution containing compound A23 obtained in Example A-15 (1.31 kg), isopropyl acetate (2.5 L), and hexamethyldisilazane (336 mL) were successively added to a reaction vessel purged with nitrogen. The external temperature of the reaction vessel was set to 0 °C, and trimethylsilyl trifluoromethanesulfonate (232 mL) was added with stirring. The external temperature was set to 25 °C, and the reaction mixture was stirred for 1 hour. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 1), and the reaction conversion rate was confirmed to be 99.9% by HPLC analysis (Calculation Expression 1 for Reaction Conversion Rate). The external temperature of the reaction vessel was set to 0 °C, and 2-MeTHF (3.2 L) and 5% aqueous sodium hydrogen phosphate solution (6.4 L) were successively added to the reaction vessel. The external temperature of the reaction vessel was set to 25 °C, and the reaction mixture was stirred for 10 minutes. Then, stirring was stopped, and the aqueous layer was drained from the reaction vessel. Then, the organic layer was washed with 5% aqueous sodium dihydrogen phosphate solution (6.4 L) and 15% sodium chloride (6.4 L). DIPEA (366 g) was added to the obtained organic layer with stirring, and then the mixture was concentrated under reduced pressure at an external temperature of 40 °C until the liquid volume reached approximately 1.2 L to obtain a solution containing compound A24 (1.27 kg).

[1020] LC retention time of compound A24: 4.220 minutes (HPLC analysis conditions: Method 3)

[1021] Example A-17

[1022] Synthesis of Compound A25: (2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(3S)-3-[[(2S)-2-[[1- [[(2S)-1-[(2S)-2-(Benzyloxycarbonylamino)-4-[3,5-difluoro-4-(trifluoromethyl)phenyl]butanoyl]pyrrolidine- 2-carbonyl]amino]cyclopentanecarbonyl]-methyl-amino]-2-cyclopentyl-acetyl]-methyl-amino]-4-(dimethylamm ino)-4-oxo-butyryl]-methyl-amino]-4-methyl-pentanoyl]amino]-3-methyl-pentanoyl]-methyl-amino]prop anoic acid tert-butyl ester

[1023] [Formula 64]

[1024]

[1025] A solution (4.02 g) containing compound A24 obtained in Example A-16 was added to a reaction vessel. At room temperature, the residue of compound A9 obtained in Example A-6 (0.797 g), 2-MeTHF (36 mL), DMF (9.2 mL), and DIPEA (1.77 mL) were added in sequence, and the reaction vessel was purged with nitrogen. Next, HATU (1.59 g) was added with stirring, and then the mixture was stirred at room temperature for 20 hours. Subsequently, the residue of compound A9 obtained in Example A-6 (0.04 g) and HATU (0.37 g) were added, and the mixture was stirred for 1 hour. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 1), and the reaction conversion rate was confirmed to be 99.9% by HPLC analysis (Calculation Expression 1 of Reaction Conversion Rate). 2.5% aqueous ammonia solution (32 mL) was added to the reaction vessel, and the mixture was stirred for 30 minutes. After draining the aqueous layer, the resulting organic layer was washed with 10% aqueous sodium bisulfate monohydrate solution (28 mL × 3) and 5% aqueous potassium carbonate solution (28 mL × 2). The resulting organic layer was dehydrated with sodium sulfate and filtered to remove sodium sulfate. The resulting product was concentrated under reduced pressure at an external temperature of 40 °C, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / heptane 70:30 to 100:0). The eluate containing the target material was concentrated under reduced pressure at an external temperature of 40 °C to obtain a residue (2.08 g) containing compound A25.

[1026] The LC retention time of compound A25: 21.235 minutes (HPLC analysis conditions: Method 3)

[1027] The LCMS (ESI) of compound A25: retention time: 21.82 minutes, m / z = 1325.478 [M+Na] + (LCMS analysis conditions: Method 3)

[1028] Example A-18

[1029] Synthesis of Compound A28: (2-[[(2S)-2-[Benzyloxycarbonyl(ethyl)amino]-3-(p-tolyl)propionyl -methyl-amino]acetic acid tert-butyl ester)

[1030] [Formula 65]

[1031]

[1032] At room temperature, compound A27 (350 g) and compound A26 (146 g) were added to a reaction vessel purged with nitrogen, and then 2-MeTHF (2.0 L) was added, and the mixture was stirred. The external temperature of the reaction vessel was set to 10 °C and DIPEA (630 mL) was added, and then T3P (50 w / w% 2-MeTHF solution, 1.02 kg) was added dropwise. The external temperature of the reaction vessel was set to 25 °C, and the mixture was stirred for 1 hour and 40 minutes. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 2), and the reaction conversion rate was confirmed to be 99.7% by HPLC analysis (Calculation Expression 3 for Reaction Conversion Rate). 5% aqueous sodium carbonate solution (2.0 L) was added dropwise, and then water (0.50 L) was added. After the mixture was stirred for 15 minutes, the aqueous layer was drained from the reaction vessel. The resulting organic layer was also washed with 5% aqueous sodium bisulfate monohydrate solution (2.0 L × 2) and 5% aqueous sodium carbonate solution (2.0 L) at an external temperature of 25 °C. The resulting organic layer was concentrated under reduced pressure at an external temperature of 40 °C until the liquid volume reached approximately 600 mL to obtain a solution (595 g) containing compound A28.

[1033] LC retention time of compound A28: 4.500 minutes (HPLC analysis conditions: Method 1)

[1034] Example A-19

[1035] Synthesis of Compound A29: (2-[[(2S)-2-(Ethylamino)-3-(p-tolyl)propionyl]-methyl-amino] acetic acid tert-butyl ester)

[1036] [Formula 66]

[1037]

[1038] A solution (589 g) containing compound A28 obtained in Example A-18 and 2-MeTHF (1.7 L) were added to the reaction vessel after purging with nitrogen, and then 5% Pd / C (142 g, 50% water content) was added. The external temperature of the reaction vessel was set to 25 °C, and the reaction vessel was pressurized with hydrogen until the internal pressure of the reaction vessel reached 0.18 MPaG. After 1 hour, it was confirmed that the internal pressure did not fluctuate. Then the reaction vessel was purged with nitrogen, and then further pressurized with hydrogen to 0.15 MPaG, and the reaction mixture was stirred for 5 hours. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 1), and the reaction conversion rate was confirmed to be 99.8% by HPLC analysis (Calculation Expression 1 of Reaction Conversion Rate). After purging the inside of the reaction vessel with nitrogen, the reaction mixture was filtered under pressure. The reaction vessel and the filtration device were washed with 2-MeTHF (1.0 L), and the filtrate and the washing solution were collected in a storage container as a storage solution. The obtained filtrate and washing solution were concentrated under reduced pressure at an external temperature of 40 °C until the liquid volume reached approximately 500 mL to obtain a solution (527 g) containing compound A29.

[1039] LC retention time of compound A29: 2.389 minutes (HPLC analysis conditions: Method 1)

[1040] Example A-20

[1041] Synthesis of Compound A31: ((2S)-2-[[(1S)-2-[(2-tert-butoxy-2-oxo-ethyl)-methyl-amino -2-oxo-1-(p-tolylmethyl)ethyl]-ethyl-carbamoyl]azetidine-1-carboxylic acid benzyl ester)

[1042] [Formula 67]

[1043]

[1044] At room temperature, a solution (522 g) containing compound A29 obtained in Example A-19, 2-MeTHF (1.4 L), and compound A30 (234 g) were successively added to a reaction vessel purged with nitrogen. The external temperature of the reaction vessel was set to 10 °C, and DIPEA (570 mL) was added with stirring, and then T3P (50 w / w% 2-MeTHF solution, 1.2 L) was added dropwise. The external temperature of the reaction vessel was set to 25 °C, and the reaction mixture was stirred for 2 hours and 30 minutes. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 1), and it was confirmed by HPLC analysis that the reaction conversion rate was 100% or higher (starting material not detected) (Calculation Expression 1 for Reaction Conversion Rate). The external temperature of the reaction vessel was set to 10 °C, and a 5% aqueous sodium carbonate solution (1.4 L) was added to the reaction mixture with stirring. The external temperature of the reaction vessel was set to 25 °C, and the mixture was stirred for 10 minutes, then stirring was stopped, and the aqueous layer was drained from the reaction vessel. The resulting organic layer was washed with a 5% aqueous sodium bisulfate monohydrate solution (1.4 L × 2) and a 5% aqueous sodium carbonate solution (1.4 L). The resulting organic layer was concentrated under reduced pressure until the liquid volume reached approximately 650 mL to obtain a solution (655 g) containing compound A31. A portion of the solution containing the obtained compound A31 (5.03 g) was purified by silica gel column chromatography (eluent: heptane / ethyl acetate 90:10 to 50:50). The eluate containing the target material was concentrated under reduced pressure at an external temperature of 40 °C to obtain a residue (2.88 g) containing compound A31.

[1045] The LC retention time of compound A31: 4.065 minutes (HPLC analysis conditions: Method 1)

[1046] Example A-21

[1047] Synthesis of Compound A32: 2-[[(2S)-2-[[(2S)-2-[benzyloxycarbonyl(methyl)amino]butanoyl]-ethyl -amino]-3-(p-tolyl)propanoyl]-methyl-amino]acetic acid

[1048] [Formula 68]

[1049]

[1050] The residue (2.57 g) of compound A31 obtained in Example A-20 was added to a reaction vessel. 2-MeTHF (24 mL) and HMDS (6.85 mL) were sequentially added at room temperature, and the reaction vessel was purged with nitrogen. Next, the external temperature of the reaction vessel was set to 0 °C, and TMSOTf (5.06 mL) was added with stirring, and then the mixture was stirred at room temperature for 2 hours. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 1), and the reaction conversion rate was confirmed to be 99.9% or higher by HPLC analysis (Calculation Expression 1 of Reaction Conversion Rate). The external temperature was set to 0 °C, and an aqueous solution of 5% sodium bisulfate monohydrate (20 mL) was added to the reaction vessel, and the mixture was stirred at room temperature for 20 minutes. After discarding the aqueous layer, the resulting organic layer was washed with an aqueous solution of 5% sodium bisulfate monohydrate (20 mL × 3). Next, an aqueous solution of 5% dipotassium hydrogen phosphate (20 mL × 2) was added to the resulting organic layer to transfer the product to the aqueous layer. After discharging the organic layer, isopropyl acetate (50 mL) and an aqueous solution of 5% sodium bisulfate monohydrate were added to the resulting aqueous layer until the pH reached 1 - 3 to transfer the product to the organic layer. The extraction with isopropyl acetate (50 mL) was repeated twice, and all the resulting organic layers were dehydrated with sodium sulfate and filtered to remove sodium sulfate. Then, the resulting filtrate was concentrated under reduced pressure at an external temperature of 40 °C. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol 100:0 to 80:20). The eluate containing the target material was concentrated under reduced pressure at an external temperature of 40 °C to obtain a residue (1.18 g) containing compound A32.

[1051] LCMS (ESI) retention time of compound A32: 3.045 minutes, m / z = 496.27 [M + H] + (LCMS analysis conditions: Method 2, the column of Method 4 was used as the LC column)

[1052] Example A-22

[1053] Synthesis of Compound A33: (2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(3S)-3-[[(2S)-2-[[1- [[(2S)-1-[(2S)-2-amino-4-[3,5-difluoro-4-(trifluoromethyl)phenyl]butanoyl]pyrrolidine-2-carbonyl]amino] cyclopentanecarbonyl]-methyl-amino]-2-cyclopentyl-acetyl]-methyl-amino]-4-(dimethylamino)-4-oxo-butanoyl -methyl-amino]-4-methyl-pentanoyl]amino]-3-methyl-pentanoyl]-methyl-amino]propionic acid tert-butyl ester

[1054] [Formula 69]

[1055]

[1056] Compound A25 (1.87 g) obtained in Example A-17 was added to a reaction vessel. Next, THF (18 mL) and 5% Pd / C (296 mg, 50% water content) were added in sequence at room temperature. The inside of the reaction vessel was purged with hydrogen, and the mixture was stirred at room temperature. The inside of the reaction vessel was purged with hydrogen again after 2 hours and 4 hours, 5% Pd / C (296 mg, 50% water content) was added after 5 hours, and the mixture was stirred for an additional 3 hours. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 1), and it was confirmed by HPLC analysis that the reaction conversion rate was 99.9% or greater (Calculation Expression 1 for Reaction Conversion Rate). The inside of the reaction vessel was purged with nitrogen, and then the reaction mixture was filtered under reduced pressure using filter paper and a filter. The reaction vessel and the filter paper and filter were washed with THF (9.0 mL × 2). The filtrate and the washing solution were combined and concentrated under reduced pressure at an external temperature of 40 °C to obtain a residue (1.68 g) containing Compound A33.

[1057] LC retention time of Compound A33: 4.256 minutes (HPLC analysis conditions: Method 2)

[1058] Example A-23

[1059] Synthesis of Compound A34: (2S)-2-[[(1S)-2-[[2-[[(1S)-1-[(2S)-2-[[1-[[(1S)-2- [[(1S)-3-[[(1S)-1-[[(1S,2S)-1-[[(1S)-2-tert-butoxy-1-methyl-2-oxo-ethyl]-methyl-amino formyl]-2-methyl-butyl]carbamoyl]-3-methyl-butyl]-methyl-amino]-1-(dimethylaminocarbonyl)- 3-oxo-propyl]-methyl-amino]-1-cyclopentyl-2-oxo-ethyl]-methyl-carbamoyl]cyclopentyl]carbamoyl -yl]pyrrolidine-1-carbonyl]-3-[3,5-difluoro-4-(trifluoromethyl)phenyl]propyl]amino-2-oxo-ethyl]-methyl-am ino]-2-oxo-1-(p-tolylmethyl)ethyl]-ethyl-carbamoyl]azetidine-1-carboxylic acid benzyl ester

[1060] [Formula 70]

[1061]

[1062] The residue (1.68 g) of compound A33 obtained in Example A-22 and the residue (0.856 g) of compound A32 obtained in Example A-21 were added to a reaction vessel. 2-MeTHF (13 mL), DMF (4.2 mL), and DIPEA (1.41 mL) were sequentially added at room temperature, and the reaction vessel was purged with nitrogen. Next, HATU (1.26 g) was added with stirring, and then the mixture was stirred at room temperature for 3 hours. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 1), and the reaction conversion rate was confirmed to be 99.8% by HPLC analysis (Calculation Expression 1 of Reaction Conversion Rate). 2.5% aqueous ammonia solution (10 mL) was added to the reaction vessel, and the mixture was stirred for 15 minutes. After discharging the aqueous layer, the resulting organic layer was washed with 10% aqueous sodium bisulfate monohydrate solution (10 mL × 3) and 5% aqueous potassium carbonate solution (10 mL × 2). The resulting organic layer was dehydrated with sodium sulfate and filtered to remove sodium sulfate. The resulting filtrate was concentrated under reduced pressure at an external temperature of 40 °C, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol 100:0 to 90:10). The eluate containing the target material was concentrated under reduced pressure at an external temperature of 40 °C to obtain a residue (1.96 g) containing compound 34.

[1063] The LC retention time of compound A34: 21.670 minutes (HPLC analysis conditions: Method 3)

[1064] The LCMS (ESI) retention time of compound A34: 22.30 minutes, m / z = 1668.168 [M+Na] + (LCMS analysis conditions: Method 3)

[1065] Example A-24

[1066] Synthesis of Compound A35: (2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(3S)-3-[[(2S)-2-[[1- [[(2S)-1-[(2S)-2-[[2-[[(2S)-2-[[(2S)-1-benzyloxycarbonylazetidine-2-carbonyl]-ethyl-am ino]-3-(p-tolyl)propanoyl]-methyl-amino]acetyl]amino]-4-[3,5-difluoro-4-(trifluoromethyl)phenyl] butanoyl]pyrrolidine-2-carbonyl]amino]cyclopentanecarbonyl]-methyl-amino]-2-cyclopentyl-acetyl]-methyl-amino]- 4-(dimethylamino)-4-oxo-butanoyl]-methyl-amino]-4-methyl-pentanoyl]amino]-3-methyl-pentanoyl]- methyl-amino]propanoic acid

[1067] [Formula 71]

[1068]

[1069] The residue (1.62 g) of Compound A34 obtained in Example A-23 was added to a reaction vessel. 2-MeTHF (16 mL) and HMDS (1.03 mL) were sequentially added at room temperature, and the reaction vessel was purged with nitrogen. Next, the external temperature of the reaction vessel was set to 0 °C, and TMSOTf (0.709 mL) was added with stirring, and then the mixture was stirred at room temperature for 3 hours. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 1), and the reaction conversion rate was confirmed to be 99.9% or greater by HPLC analysis (Calculation Expression 1 of Reaction Conversion Rate). The external temperature was set to 0 °C, and a 5% aqueous sodium bicarbonate solution (15 mL) was added to the reaction vessel, and the mixture was stirred at room temperature for 30 minutes. The aqueous layer was discarded, and then the resulting organic layer was washed with a 5% aqueous sodium dihydrogen phosphate solution (15 mL) and a 10% aqueous NaCl solution (15 mL). The resulting organic layer was dehydrated with sodium sulfate and filtered to remove the sodium sulfate. The resulting filtrate was concentrated under reduced pressure at an external temperature of 40 °C to obtain a residue (1.66 g) containing Compound A35.

[1070] LC retention time of Compound A35: 19.027 minutes (HPLC analysis conditions: Method 3)

[1071] Example A-25

[1072] Synthesis of Compound A36: (2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(3S)-3-[[(2S)-2-[[1- [[(2S)-1-[(2S)-2-[[2-[[(2S)-2-[[(2S)-azetidine-2-carbonyl]-ethyl-amino]-3-(p-tolyl yl)propanoyl]-methyl-amino]acetyl]amino]-4-[3,5-difluoro-4-(trifluoromethyl)phenyl]butanoyl]pyrrolidine- 2-carbonyl]amino]cyclopentanecarbonyl]-methyl-amino]-2-cyclopentyl-acetyl]-methyl-amino]-4-(dimethylam ino)-4-oxo-butanoyl]-methyl-amino]-4-methyl-pentanoyl]amino]-3-methyl-pentanoyl]-methyl-amino]prop anoic acid

[1073] [Formula 72]

[1074]

[1075] The residue of compound A35 (1.66 g) obtained in Example A-24 was added to a reaction vessel. Next, THF (11 mL) and 5% Pd / C (444 mg, 50% water content) were added sequentially at room temperature. The inside of the reaction vessel was purged with hydrogen, and the mixture was stirred at room temperature. After 2 hours, the inside of the reaction vessel was purged with hydrogen again, and the mixture was stirred for 4 hours. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 1), and the reaction conversion rate was confirmed to be 99.8% by HPLC analysis (Calculation Expression 1 of Reaction Conversion Rate). The inside of the reaction vessel was purged with nitrogen, and then the reaction mixture was filtered under reduced pressure using filter paper and a filter. The reaction vessel and the filter paper and filter were washed with THF (6.0 mL × 2). The resulting filtrate and washing solution were combined and concentrated under reduced pressure at an external temperature of 40°C. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol 100:0 to 80:20). The eluate containing the target material was concentrated under reduced pressure at an external temperature of 40°C to obtain a residue (1.02 g) containing compound A36.

[1076] The LC retention time of compound A36: 13.323 minutes (HPLC analysis conditions: Method 3)

[1077] The LCMS (ESI) retention time of compound A36: 13.76 minutes, m / z = 1456.124 [M+H] + (LCMS analysis conditions: Method 3)

[1078] Example B-1

[1079] Synthesis of Compound B1: O1-benzyl (2S)-azetidine-1,2-dicarboxylic acid O2-tert-butyl ester

[1080] [Formula 73]

[1081]

[1082] At room temperature, compound A30 (5.95 g), dichloromethane (12 mL), and cyclohexane (48 mL) were successively added to a reaction vessel purged with nitrogen. After adding 2,2,2-trichloroacetimidate tert-butyl ester (9.06 mL) and boron trifluoride diethyl ether complex (320 μL), the mixture was then stirred at room temperature for 1 hour. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 1), and the reaction conversion rate was confirmed to be 95.6% by HPLC analysis (Calculation Expression 1 for Reaction Conversion Rate). The resulting slurry was filtered, and the solid residue was washed with cyclohexane. The resulting filtrate was washed with 10% aqueous citric acid solution (40 mL × 9), 5% aqueous sodium carbonate solution (40 mL × 3), and 10% aqueous NaCl solution (40 mL). The resulting organic layer was dehydrated with sodium sulfate, and the resulting filtrate was filtered to remove sodium sulfate. The resulting product was concentrated under reduced pressure at an external temperature of 40 °C to obtain a residue (6.96 g) containing compound B1.

[1083] LC retention time of compound B1: 3.519 minutes (HPLC analysis conditions: Method 1)

[1084] LCMS (ESI) retention time of compound B1: 3.620 minutes, m / z = 314.10 [M+Na] + (LCMS analysis conditions: Method 1)

[1085] Example B-2

[1086] Synthesis of Compound B2: (2S)-azetidine-2-carboxylic acid tert-butyl ester

[1087] [Formula 74]

[1088]

[1089] The residue (6.00 g) containing compound B1 obtained in Example B-1 was added to a reaction vessel. Next, 2-MeTHF (62 mL) and 5% Pd / C (4.39 g, 50% water content) were successively added at room temperature. The inside of the reaction vessel was purged with hydrogen, and the mixture was stirred at room temperature for 2 hours. The inside of the reaction vessel was purged with hydrogen again, and the mixture was stirred at room temperature for an additional 2 hours. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 1), and the reaction conversion rate was confirmed to be 99.9% or greater by HPLC analysis (Calculation Expression 2 for Reaction Conversion Rate). The inside of the reaction vessel was purged with nitrogen, and then the reaction mixture was filtered under reduced pressure using filter paper and a filter. The reaction vessel and the filter paper and filter were washed with 2-MeTHF (30 mL × 2). The resulting solution was concentrated under reduced pressure at an external temperature of 40 °C to obtain a residue (2.23 g) containing compound B2.

[1090] Example B-3

[1091] Synthesis of Compound B3: (2S)-2-[methyl-[(2S)-2-[methyl-[(Z)-2-methylenepenta-3-enyloxy]carb onyl-amino]propanoyl]amino]butanoic acid tert-butyl ester

[1092] [Formula 75]

[1093]

[1094] At room temperature, the residue (2.33 g) of compound B2 obtained in Example B-2 and compound A1 (4.21 g) were added to a reaction vessel, and the reaction vessel was purged with nitrogen. Next, 2-MeTHF (43 mL), DIPEA (11.2 mL), and T3P (50 w / w% 2-MeTHF solution, 22.2 mL) were added in sequence, and then the mixture was stirred at room temperature for 2 hours. Samples of the reaction mixture were taken at 1 hour and 2 hours after the reaction and prepared as samples (Sample Preparation Method 1), and it was confirmed by HPLC analysis that the LC spectra showed little difference. 5% aqueous sodium carbonate solution (50 mL) was added, and the mixture was stirred for 10 minutes. After draining the aqueous layer, the resulting organic layer was washed with 5% aqueous sodium carbonate solution (50 mL × 3), 5% aqueous sodium bisulfate monohydrate solution (50 mL × 2), and again with 5% aqueous sodium carbonate solution (50 mL × 5). The resulting organic layer was dehydrated with sodium sulfate and filtered to remove the sodium sulfate. The resulting filtrate was concentrated under reduced pressure at an external temperature of 40 °C to obtain a residue (4.47 g) containing compound B3.

[1095] LC retention time of compound B3: 3.543 minutes (HPLC analysis conditions: Method 1)

[1096] LCMS (ESI) of compound B3: Retention time: 3.519 minutes, m / z = 377.23 [M+H] + (LCMS analysis conditions: Method 1)

[1097] Example B-4

[1098] Synthesis of Compound B4: (2S)-2-[methyl-[(2S)-2-(methylamino)propanoyl]amino]butanoic acid tert-butyl ester

[1099] [Formula 76]

[1100]

[1101] The residue (3.98 g) of Compound B3 obtained in Example B-3 was added to a reaction vessel. Next, 2-MeTHF (32 mL) and 5% Pd / C (2.27 g, 50% water content) were sequentially added at room temperature. The inside of the reaction vessel was purged with hydrogen, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 1), and the reaction conversion rate was confirmed to be 99.9% or greater by HPLC analysis (Calculation Expression 1 for Reaction Conversion Rate). The inside of the reaction vessel was purged with nitrogen, and then the reaction mixture was filtered under reduced pressure using filter paper and a filter. The reaction vessel and the filter paper and filter were washed with 2-MeTHF (15 mL × 2). The resulting filtrate and washing solution were combined and concentrated under reduced pressure at an external temperature of 40 °C to obtain a residue (2.71 g) containing Compound B4.

[1102] LC retention time of Compound B4: 1.670 minutes (HPLC analysis conditions: Method 1)

[1103] Example B-5

[1104] Synthesis of Compound B5: (2S)-1-[(2S)-2-[[(2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pent anoyl]-methyl-amino]propanoyl]azetidine-2-carboxylic acid tert-butyl ester

[1105] [Formula 77]

[1106]

[1107] The residue of compound B4 (2.71 g) obtained in Example B-4 and compound A4 (3.54 g) were added to a reaction vessel, and the reaction vessel was purged with nitrogen. Next, 2-MeTHF (17 mL), toluene (18 mL), MeCN (2.9 mL), and DIPEA (11.7 mL) were sequentially added at room temperature. HATU (6.35 g) was added under stirring, and then the mixture was stirred at room temperature for 2 hours. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 1), and it was confirmed by HPLC analysis that the reaction conversion rate was 99.9% or greater (Calculation Expression 1 of Reaction Conversion Rate). N-Methylimidazole (1.0 mL) was added to the reaction vessel, and 5% aqueous sodium carbonate solution (40 mL) was further added under stirring, and then the mixture was stirred for 1 hour. Next, 2.5% aqueous ammonia solution (40 mL) was added, and the mixture was stirred for 15 minutes. After draining the aqueous layer, the resulting organic layer was washed with 2.5% aqueous ammonia solution (60 mL), 5% aqueous sodium bisulfate monohydrate solution (60 mL × 2), and 3% aqueous dipotassium hydrogen phosphate solution (60 mL). The resulting organic layer was dehydrated with sodium sulfate and filtered to remove sodium sulfate. The obtained filtrate was concentrated under reduced pressure at an external temperature of 40 °C to obtain a residue (5.62 g) containing compound B5.

[1108] LC retention time of compound B5: 3.893 minutes (HPLC analysis conditions: Method 1)

[1109] LCMS (ESI) retention time of compound B5: 3.477 minutes, m / z = 490.31 [M+H] + (LCMS analysis conditions: Method 2, the column of Method 4 was used as the LC column)

[1110] Example B-6

[1111] Synthesis of Compound B6: (2S)-1-[(2S)-2-[methyl-[(2S,3S)-3-methyl-2-[[(2S)-4-methyl- 2-[methyl(2-trimethylsilylethoxycarbonyl)amino]pentanoyl]amino]pentanoyl]amino]propanoyl]azetidine -2-carboxylic acid tert-butyl ester

[1112] [Formula 78]

[1113]

[1114] The residue of compound B5 obtained in Example B-5 (4.60 g) and isopropyl acetate (11 mL) were added to a reaction vessel. Next, the residue of compound A7 obtained in Example A-4 (5.13 g), toluene (3.0 mL), acetone (31 mL), NMM (6.20 mL), and 5% Pd / C (2.00 g, 50% water content) were sequentially added at room temperature. The inside of the reaction vessel was purged with hydrogen, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 1), and the reaction conversion rate was confirmed to be 99.9% or more by HPLC analysis (Calculation Expression 1 of Reaction Conversion Rate). The inside of the reaction vessel was purged with nitrogen, and then the Pd / C was filtered under reduced pressure using filter paper and a filter. The reaction vessel and the filter paper and filter were washed with 2-MeTHF (50 mL). The resulting solution was concentrated under reduced pressure at an external temperature of 40 °C. The resulting residue was dissolved in MeTHF (40 mL), and 5% potassium carbonate (40 mL) and DMAP (1.15 g) were added with stirring, and then the mixture was stirred for 2.5 hours. Next, a 5% aqueous solution of potassium bisulfate (40 mL) was added, and the mixture was stirred for 30 minutes. After draining the aqueous layer, the resulting organic layer was washed with a 5% aqueous solution of potassium bisulfate (40 mL) and a 5% aqueous solution of potassium carbonate (40 mL × 2). The resulting organic layer was dehydrated with sodium sulfate and filtered to remove the sodium sulfate. The resulting filtrate was concentrated under reduced pressure at an external temperature of 40 °C to obtain a residue (5.05 g) containing compound B6.

[1115] LC retention time of compound B6: 4.937 minutes (HPLC analysis conditions: Method 1)

[1116] LCMS (ESI) retention time of compound B6: 4.739 minutes, m / z = 627.37 [M+H] + (LCMS analysis conditions: Method 1)

[1117] Example B-7

[1118] Synthesis of Compound B7: (2S)-1-[(2S)-2-[methyl-[(2S,3S)-3-methyl-2-[[(2S)-4-methyl- 2-(methylamino)pentanoyl]amino]pentanoyl]amino]propanoyl]azetidine-2-carboxylic acid tert-butyl ester

[1119] [Formula 79]

[1120]

[1121] At room temperature, the residue (4.05 g) of the compound B6 obtained in Example B-6 and 2-MeTHF (8.0 mL) were added to a reaction vessel, and the reaction vessel was purged with nitrogen. Next, the external temperature of the reaction vessel was set to 50 °C, and 1 M TBAF (16.1 mL) was added with stirring, and then the mixture was stirred at an external temperature of 50 °C for 2 hours. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 1), and it was confirmed by HPLC analysis that the reaction conversion rate was 99.9% or greater (Calculation Expression 1 of the reaction conversion rate). The external temperature was set to 0 °C, and IPAc (20 mL) and 5% potassium carbonate (20 mL) were added with stirring, and then the mixture was stirred at room temperature for 15 minutes. After discarding the aqueous layer, the obtained organic layer was washed with 5% potassium carbonate (20 mL × 2). The obtained organic layer was dehydrated with sodium sulfate and filtered to remove the sodium sulfate. The obtained filtrate was concentrated under reduced pressure at an external temperature of 40 °C to obtain a residue (2.70 g) containing the compound B7.

[1122] LC retention time of compound B7: 2.747 minutes (HPLC analysis conditions: Method 1)

[1123] LCMS (ESI) retention time of compound B7: 2.488 minutes, m / z = 483.35 [M+H] + (LCMS analysis conditions: Method 1)

[1124] Example B-8

[1125] Synthesis of Compound B8: (2S)-1-[(2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(3S)-3-[[(2S)-2- [[1-[[(2S)-1-[(2S)-2-(benzyloxycarbonylamino)-4-[3,5-difluoro-4-(trifluoromethyl)phenyl]butanoyl]pyr rolidine-2-carbonyl]amino]cyclopentanecarbonyl]-methyl-amino]-2-cyclopentyl-acetyl]-methyl-amino]-4-(dimethyl amino)-4-oxo-butanoyl]-methyl-amino]-4-methyl-pentanoyl]amino]-3-methyl-pentanoyl]-methyl-amino] tert-Butyl [propionyl]azetidine-2-carboxylate

[1126] [Formula 80]

[1127]

[1128] A solution (4.00 g) containing compound A24 obtained in Example A-16 was added to a reaction vessel. At room temperature, the residue of compound B7 obtained in Example B-7 (0.962 g), 2-MeTHF (36 mL), DMF (9.2 mL), and DIPEA (1.77 mL) were sequentially added, and the reaction vessel was purged with nitrogen. Next, HATU (1.59 g) was added with stirring, and then the mixture was stirred at room temperature for 20 hours. Subsequently, the residue of compound B7 obtained in Example B-7 (0.154 g) and HATU (1.20 g) were added, and the mixture was stirred for 3 hours. The reaction mixture was sampled and prepared into a sample (Sample Preparation Method 1), and the reaction conversion rate was confirmed to be 99.7% by HPLC analysis (Calculation Expression 1 of Reaction Conversion Rate). 2.5% aqueous ammonia solution (32 mL) was added to the reaction vessel, and the mixture was stirred for 30 minutes. After discharging the aqueous layer, the resulting organic layer was washed with 10% aqueous sodium bisulfate monohydrate solution (28 mL × 3) and 5% aqueous potassium carbonate solution (28 mL × 2). The resulting organic layer was dehydrated with sodium sulfate and filtered to remove sodium sulfate. The resulting filtrate was concentrated under reduced pressure at an external temperature of 40 °C, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / heptane 80:20 to 100:0). The eluate containing the target material was concentrated under reduced pressure at an external temperature of 40 °C to obtain a residue (1.75 g) containing compound B8.

[1129] LC retention time of compound B8: 20.037 minutes (HPLC analysis conditions: Method 3)

[1130] LCMS (ESI) retention time of compound B8: 20.69 minutes, m / z = 1408.072 [M+Na] + (LCMS analysis conditions: Method 3)

[1131] Example B-9

[1132] Synthesis of Compound B9: 2-[[(2S)-2-[(Benzyloxycarbonyl(ethyl)amino]-3-(p-tolyl)propionyl]- methyl-amino]acetic acid

[1133] [Formula 81]

[1134]

[1135] A solution (5.01 g) containing compound A28 obtained in Example A-18 was purified by silica gel column chromatography (eluent: heptane / ethyl acetate 100:0 to 80:20). The resulting product was concentrated under reduced pressure at an external temperature of 40 °C, and the eluate was removed to obtain a residue (2.71 g) containing compound A28. A residue (2.51 g) containing compound A28 was added to a reaction vessel. 2-MeTHF (28 mL) and HMDS (7.87 mL) were added sequentially at room temperature, and the reaction vessel was purged with nitrogen. Next, the external temperature of the reaction vessel was set to 0 °C, and TMSOTf (5.82 mL) was added with stirring, and then the mixture was stirred at room temperature for 2 hours. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 1), and it was confirmed by HPLC analysis that the reaction conversion rate was 99.9% or higher (Calculation Expression 1 for Reaction Conversion Rate). The external temperature was set to 0 °C, and an aqueous solution of 5% sodium bisulfate monohydrate (20 mL) was added to the reaction vessel, and the mixture was stirred at room temperature for 20 minutes. After discarding the aqueous layer, the resulting organic layer was washed with an aqueous solution of 5% sodium bisulfate monohydrate (20 mL × 3). Next, an aqueous solution of 5% dipotassium hydrogen phosphate (20 mL × 2) was added to the resulting organic layer to transfer the product to the aqueous layer. After discharging the organic layer, isopropyl acetate (50 mL) and an aqueous solution of 5% sodium bisulfate monohydrate were added to the resulting aqueous layer until the pH reached 1 - 3 to transfer the product to the organic layer. Extraction with isopropyl acetate (50 mL) was repeated twice, and all the resulting organic layers were dehydrated with sodium sulfate and filtered to remove the sodium sulfate. The resulting filtrate was concentrated under reduced pressure at an external temperature of 40 °C to obtain a residue (1.70 g) containing compound B9.

[1136] The LCMS (ESI) retention time of compound B9: 3.347 minutes, m / z = 413.29 [M+H] + (LCMS analysis conditions: Method 2, the column of Method 4 was used as the LC column)

[1137] Example B-10

[1138] Synthesis of Compound B10: (2S)-1-[(2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(3S)-3-[[(2S)- 2-[[1-[[(2S)-1-[(2S)-2-amino-4-[3,5-difluoro-4-(trifluoromethyl)phenyl]butanoyl]pyrrolidine-2-carbo nyl]amino]cyclopentanecarbonyl]-methyl-amino]-2-cyclopentyl-acetyl]-methyl-amino]-4-(dimethylamino)-4- oxo-butanoyl]-methyl-amino]-4-methyl-pentanoyl]amino]-3-methyl-pentanoyl]-methyl-amino]propionyl] tert-Butyl azetidine-2-carboxylate

[1139] [Formula 82]

[1140]

[1141] The residue (1.46 g) of Compound B8 obtained in Example B-8 was added to a reaction vessel. Next, THF (15 mL) and 5% Pd / C (235 mg, 50% water content) were added in sequence at room temperature. The inside of the reaction vessel was purged with hydrogen, and the mixture was stirred at room temperature. The inside of the reaction vessel was purged with hydrogen again after 2 hours and 4 hours, 5% Pd / C (223 mg, 50% water content) was added after 5 hours, and the mixture was stirred for an additional 6 hours. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 1), and it was confirmed by HPLC analysis that the reaction conversion rate was 99.9% or greater (Calculation Expression 1 of Reaction Conversion Rate). The inside of the reaction vessel was purged with nitrogen, and then the reaction mixture was filtered under reduced pressure using filter paper and a filter. The reaction vessel and the filter paper and filter were washed with THF (7.0 mL × 2). The resulting solution was concentrated under reduced pressure at an external temperature of 40 °C to obtain a residue (1.38 g) containing Compound B10.

[1142] LC retention time of Compound B10: 4.054 minutes (HPLC analysis conditions: Method 2)

[1143] Example B-11

[1144] Synthesis of Compound B11: (2S)-1-[(2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(3S)-3-[[(2S)- 2-[[1-[[(2S)-1-[(2S)-2-[[2-[[(2S)-2-[benzyloxycarbonyl(ethyl)amino]-3-(p-tolyl)propionyl yl]-methyl-amino]acetyl]amino]-4-[3,5-difluoro-4-(trifluoromethyl)phenyl]butanoyl]pyrrolidine-2-carbonyl] amino]cyclopentanecarbonyl]-methyl-amino]-2-cyclopentyl-acetyl]-methyl-amino]-4-(dimethylamino)-4-oxo -butanoyl]-methyl-amino]-4-methyl-pentanoyl]amino]-3-methyl-pentanoyl]-methyl-amino]propionyl]azet idine-2-carboxylate

[1145] [Formula 83]

[1146]

[1147] The residue (1.38 g) containing compound B10 obtained in Example B-10 and the residue (0.581 g) containing compound B9 obtained in Example B-9 were added to a reaction vessel. 2-MeTHF (9.6 mL), DMF (3.2 mL), and DIPEA (1.08 mL) were sequentially added at room temperature, and the reaction vessel was purged with nitrogen. Next, HATU (0.971 g) was added with stirring, and then the mixture was stirred at room temperature for 3 hours. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 1), and the reaction conversion rate was confirmed to be 99.3% by HPLC analysis (Calculation Expression 1 of Reaction Conversion Rate). 2.5% aqueous ammonia solution (10 mL) was added to the reaction vessel, and the mixture was stirred for 15 minutes. After discharging the aqueous layer, the resulting organic layer was washed with 10% aqueous sodium bisulfate monohydrate solution (10 mL × 3) and 5% aqueous potassium carbonate solution (10 mL × 2). The resulting organic layer was dehydrated with sodium sulfate and filtered to remove sodium sulfate. The resulting filtrate was concentrated under reduced pressure at an external temperature of 40 °C, and the resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / methanol 100:0 to 90:10). The eluate containing the target material was concentrated under reduced pressure at an external temperature of 40 °C to obtain a residue (1.32 g) containing compound B11.

[1148] LC retention time of compound B11: 21.617 minutes (HPLC analysis conditions: Method 3)

[1149] LCMS (ESI) retention time of compound B11: 22.21 minutes, m / z = 1668.111 [M+Na] + (LCMS analysis conditions: Method 3)

[1150] Example B-12

[1151] Synthesis of Compound B12: (2S)-1-[(2S)-2-[[(2S.3S)-2-[[(2S)-2-[[(3S)-3-[[(2S)- 2-[[1-[[(2S)-1-[(2S)-2-[[2-[[(2S)-2-[benzyloxycarbonyl(ethyl)amino]-3-(p-tolyl)propionyl yl]-methyl-amino]acetyl]amino]-4-[3.5-difluoro-4-(trifluoromethyl)phenyl]butanoyl]pyrrolidine-2-carbonyl] amino]cyclopentanecarbonyl]-methyl-amino]-2-cyclopentyl-acetyl]-methyl-amino]-4-(dimethylamino)-4-oxo -butanoyl]-methyl-amino]-4-methyl-pentanoyl]amino]-3-methyl-pentanoyl]-methyl-amino]propionyl]azet idine-2-carboxylic acid

[1152] [Formula 84]

[1153]

[1154] The residue (1.08 g) of compound B11 obtained in Example B-11 was added to a reaction vessel. 2-MeTHF (11 mL) and HMDS (0.688 mL) were sequentially added at room temperature, and the reaction vessel was purged with nitrogen. Next, the external temperature of the reaction vessel was set to 0 °C, and TMSOTf (0.475 mL) was added with stirring, and then the mixture was stirred at room temperature for 3 hours. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 1), and the reaction conversion rate was confirmed to be 99.9% or greater by HPLC analysis (Calculation Expression 1 of Reaction Conversion Rate). The external temperature was set to 0 °C, and 5% aqueous sodium bicarbonate solution (15 mL) was added to the reaction vessel, and the mixture was stirred at room temperature for 30 minutes. The aqueous layer was discarded, and then the obtained organic layer was washed with 5% aqueous sodium dihydrogen phosphate solution (15 mL) and 10% aqueous NaCl solution (15 mL). The obtained organic layer was dehydrated with sodium sulfate and filtered to remove sodium sulfate. The obtained filtrate was concentrated under reduced pressure at an external temperature of 40 °C, and the obtained residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol 100:0 to 80:20). The eluate containing the target material was concentrated under reduced pressure at an external temperature of 40 °C to obtain a residue (0.831 g) containing compound B12.

[1155] LC retention time of compound B12: 19.638 minutes (HPLC analysis conditions: Method 3)

[1156] Example B-13

[1157] Synthesis of Compound B13: (2S)-1-[(2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(3S)-3-[[(2S)- 2-Cyclopentyl-2-[[1-[[(2S)-1-[(2S)-4-[3,5-Difluoro-4-(trifluoromethyl)phenyl]-2-[[2-[(2S)-2-(ethyl amino)-3-(p-tolyl)propanoyl]-methyl-amino]acetyl]amino]butanoyl]pyrrolidine-2-carbonyl]amino] cyclopentanecarbonyl]-methyl-amino]acetyl]-methyl-amino]-4-(dimethylamino)-4-oxo-butanoyl]-methyl- amino]-4-methyl-valeryl]amino]-3-methyl-valeryl]methyl-amino]propanoyl]azetidine-2-carboxylic acid

[1158] [Formula 85]

[1159]

[1160] The residue of compound B12 (0.831 g) obtained in Example B-12 was added to a reaction vessel. Next, THF (5.7 mL) and 5% Pd / C (223 mg, 50% water content) were sequentially added at room temperature. The inside of the reaction vessel was purged with hydrogen, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 1), and the reaction conversion rate was confirmed to be 99.9% or greater by HPLC analysis (Calculation Expression 1 for Reaction Conversion Rate). The inside of the reaction vessel was purged with nitrogen, and then the reaction mixture was filtered under reduced pressure using filter paper and a filter. The reaction vessel and the filter paper and filter were washed with THF (3.0 mL × 2). The obtained filtrate and washing solution were combined and concentrated under reduced pressure at an external temperature of 40 °C to obtain a residue (0.726 g) containing compound B13.

[1161] LC retention time of compound B13: 12.613 minutes (HPLC analysis conditions: Method 3)

[1162] LCMS (ESI) retention time of compound B13: 13.10 minutes, m / z = 1456.124 [M+H] + (LCMS analysis conditions: Method 3)

[1163] Example B-14

[1164] Synthesis of Compound B1: (O2-tert-Butyl (2S)-azetidine-1,2-dicarboxylic acid O1-benzyl ester)

[1165] [Formula 86]

[1166]

[1167] Compound A30 (6.02 g) and cyclohexane (48.0 mL) were added to a reaction vessel at room temperature, and then dichloromethane (12.0 mL) was added, and the mixture was stirred. After adding tert-butyl 2,2,2-trichloroacetimidate (9.14 mL) and boron trifluoride diethyl ether complex (0.32 mL) under stirring, the mixture was stirred at room temperature for 1 hour. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 1), and the reaction conversion rate was confirmed to be 99.0% or greater by HPLC analysis (Calculation Expression 1 for Reaction Conversion Rate). The reaction mixture was filtered using filter paper and a membrane filter. The obtained filtrate was washed with 10% aqueous citric acid solution (48.0 mL × 10) and 5% aqueous sodium carbonate solution (48.0 mL × 2). The obtained organic layer was concentrated under reduced pressure to obtain a residue (7.42 g) containing compound B1. The obtained residue was diluted with acetonitrile and subjected to LCMS analysis (Method 1: Retention time of compound B1; 3.567 minutes, m / z = 313.94 [M+Na] +)。The resulting residue and 3,5-bis(trifluoromethyl)benzoic acid were dissolved in DMSO-d 6 and subjected to qNMR analysis (yield: 96.3%).

[1168] Example B-15

[1169] Synthesis of Compound B2: ((2S)-tert-Butyl azetidine-2-carboxylate)

[1170] [Formula 87]

[1171]

[1172] At room temperature, a residue containing the compound B1 obtained in Example B-14 (7.27 g, content: 96.2%) and 2-MeTHF (72.5 mL) were added to a reaction vessel. Subsequently, 5% Pd / C (5.00 g, 50% water content) was added, and the mixture was stirred. Nitrogen degassing was performed under stirring, followed by hydrogen degassing, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 1), and the reaction conversion rate was confirmed to be 99.9% or greater by HPLC analysis (Calculation Expression 2 for Reaction Conversion Rate). The reaction mixture was suction filtered using filter paper and a membrane filter, and the residue was washed with 2-MeTHF (36.2 mL × 2). The resulting filtrate was concentrated under reduced pressure to obtain a residue containing compound B2 (3.63 g). The obtained residue and 1,3,5-trimethoxybenzene were dissolved in DMSO-d 6 and subjected to qNMR analysis (yield: 81.2%).

[1173] Example B-16

[1174] Synthesis of Compound B3: ((2S)-1-[(2S)-2-[Benzyloxycarbonyl(methyl)amino]propanoyl]azetidine -2-carboxylic acid tert-butyl ester)

[1175] [Formula 88]

[1176]

[1177] At room temperature, the residue of compound B2 obtained in Example B-15 (3.39 g, content: 84.2%) and compound A1 (3.91 g) were added to a reaction vessel. Thereafter, 2-MeTHF (49.9 mL) was added, and the mixture was stirred. After adding NMM (4.89 mL) under stirring, T3P (1.6 M 2-MeTHF solution, 24.7 mL) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 2), and it was confirmed by HPLC analysis that the reaction conversion rate was 99.9% or more (Calculation Expression 3 of the reaction conversion rate). 5% aqueous sodium carbonate solution (43.0 mL) was added to the reaction mixture under stirring. The mixture was stirred at room temperature for 10 minutes, and then the aqueous layer was discharged. The organic layer was washed with 5% aqueous sodium bisulfate monohydrate solution (43.0 mL × 2) and 5% aqueous sodium carbonate solution (43.0 mL × 1). The obtained organic layer was concentrated under reduced pressure to obtain a residue containing compound B3 (6.40 g). The obtained residue was diluted with acetonitrile and subjected to LCMS analysis (Method 1: retention time of compound B3; 3.467 minutes, m / z = 377.11 [M+H] + ). The obtained residue and 3,5-bis(trifluoromethyl)benzoic acid were dissolved in DMSO-d 6 and subjected to qNMR analysis (yield: 96.5%). 2-MeTHF (12.0 mL) was added to the obtained residue to obtain a solution containing compound B3 (15.9 g, content: 37.0%).

[1178] Example B-17

[1179] Synthesis of Compound B4: ((2S)-1-[(2S)-2-(Methylamino)propanoyl]azetidine-2-carboxylic acid tert-but yl ester)

[1180] [Formula 89]

[1181]

[1182] At room temperature, the residue containing compound B3 obtained in Example B-16 (7.63 g, content: 37.0%) and 2-MeTHF (17.1 mL) were added to a reaction vessel. Then, 5% Pd / C (1.60 g, 50% water content) was added, and the mixture was stirred. Nitrogen degassing was performed under stirring, followed by hydrogen degassing, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 1), and the reaction conversion rate was confirmed to be 99.9% or higher by HPLC analysis (Calculation Expression 1 of Reaction Conversion Rate). The reaction mixture was suction filtered using filter paper and a membrane filter, and the residue was washed with 2-MeTHF (11.3 mL × 2). The resulting filtrate was concentrated under reduced pressure to obtain a residue containing compound B4 (1.97 g). The obtained residue was diluted with acetonitrile and subjected to LCMS analysis (Method 1: retention time of compound B4; 1.573 minutes, m / z = 243.09 [M+H] + ). The resulting residue and 1,3,5-trimethoxybenzene were dissolved in DMSO-d 6 6, and qNMR analysis was performed (yield: 99.4%).

[1183] Example B-18

[1184] Synthesis of Compound B5: ((2S)-1-[(2S)-2-[[(2S,3S)-2-(Benzyloxycarbonylamino)-3-methyl-pent anoyl]-methyl-amino]propanoyl]azetidine-2-carboxylic acid tert-butyl ester)

[1185] [Formula 90]

[1186]

[1187] At room temperature, the residue of compound B4 obtained in Example B-17 (1.86 g, content: 91.7%) and compound A4 (2.25 g) were added to a reaction vessel. Subsequently, DIPEA (7.38 mL), 2-MeTHF (5.13 mL), toluene (5.13 mL), and acetonitrile (1.71 mL) were added, and the mixture was stirred. Under stirring, HATU (4.03 g) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 2), and it was confirmed by HPLC analysis that the reaction conversion rate was 99.9% or higher (Calculation Expression 3 for Reaction Conversion Rate). N-Methylimidazole (0.56 mL) was added to the reaction mixture, then 5% aqueous sodium carbonate solution (10.3 mL) was added, and the mixture was stirred for 3 hours, and then the aqueous layer was drained. The organic layer was washed with 2.5% aqueous ammonia solution (13.7 mL × 2), 10% aqueous sodium bisulfate monohydrate solution (13.7 mL × 2), and 3% aqueous dipotassium hydrogen phosphate solution (13.7 mL × 1). The obtained organic layer was concentrated under reduced pressure to obtain a residue (4.94 g) containing compound B5. The obtained residue was dissolved in 2-MeTHF (6.0 mL), toluene (6.0 mL), and acetonitrile (2.0 mL), and washed with 5% aqueous sodium chloride solution (12.0 mL). The obtained organic layer was concentrated under reduced pressure to obtain a residue (4.43 g) containing compound B5. The obtained residue was diluted with acetonitrile and subjected to LCMS analysis (Method 4: Retention time of compound B5; 3.636 minutes, m / z = 490.36 [M+H] + ). The obtained residue and 3,5-bis(trifluoromethyl)benzoic acid were dissolved in DMSO-d 6 and subjected to qNMR analysis (Yield: 86.5%).

[1188] Example B-19

[1189] Synthesis of Compound A7: ((2S)-4-Methyl-2-[methyl(2-trimethylsilylethoxycarbonyl)amino] pentanoic acid (2,3,4,5,6-pentafluorophenyl) ester)

[1190] [Formula 91]

[1191]

[1192] At room temperature, compound A6 (10.0 g), isopropyl acetate (51.8 mL), and DMF (64.8 mL) were added to a reaction vessel. A solution of pentafluorophenol (7.95 g) in isopropyl acetate (13.0 mL) was added. The reaction vessel was cooled in an ice bath and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.28 g) was added, and the mixture was stirred for 30 minutes. Then, the reaction vessel was removed from the ice bath and the mixture was stirred at room temperature for 2 hours. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 1), and the reaction conversion rate was confirmed to be 99.9% or greater by HPLC analysis (Calculation Expression 2 of Reaction Conversion Rate). The reaction vessel was cooled in an ice bath and 0.5 M aqueous hydrochloric acid solution (64.8 mL) was added to the reaction mixture. The mixture was stirred for 10 minutes, and the aqueous layer was drained. The organic layer was washed with 0.5 M aqueous hydrochloric acid solution (64.8 mL × 1), 5% aqueous potassium carbonate solution (64.8 mL × 2), and 10% aqueous sodium chloride solution (64.8 mL × 1). The obtained organic layer was concentrated under reduced pressure to obtain a residue (15.2 g) containing compound A7. The obtained residue was diluted with acetonitrile and subjected to LCMS analysis (Method 4: Retention time of compound A7; 5.365 minutes, m / z = 428.27[M-C 2 H 4 +H] + ). The obtained residue and 3,5-bis(trifluoromethyl)benzoic acid were dissolved in DMSO-d 6 and subjected to qNMR analysis (Yield: 89.3%).

[1193] Example B-20

[1194] Synthesis of Compound B6: ((2S)-1-[(2S)-2-[Methyl-[(2S,3S)-3-methyl-2-[[(2S)-4-methyl- 2-[methyl(2-trimethylsilylethoxycarbonyl)amino]pentanoyl]amino]pentanoyl]amino]propanoyl]azetidine -2-carboxylic acid tert-butyl ester)

[1195] [Formula 92]

[1196]

[1197] At room temperature, the residue containing compound B5 obtained in Example B-18 (4.17 g, content: 67.5%) and the residue containing compound A7 obtained in Example B-19 (5.68 g, content: 92.5%) were added to a reaction vessel. Thereafter, acetone (19.3 mL) and isopropyl acetate (6.76 mL) were added, and the mixture was stirred. While stirring, NMM (3.82 mL) and 5% Pd / C (1.24 g, 50% water content) were added to the reaction mixture. Nitrogen degassing was carried out while stirring, then hydrogen degassing was carried out, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 1), and it was confirmed by HPLC analysis that the reaction conversion rate was 99.9% or more (Calculation Expression 1 of Reaction Conversion Rate). The reaction mixture was suction filtered using filter paper and a membrane filter, and the residue was washed with acetone (9.64 mL × 2). The obtained filtrate was concentrated under reduced pressure, and the residue was dissolved in toluene (18.3 mL). 4-Dimethylaminopyridine (0.708 g) and 5% aqueous potassium carbonate solution (18.3 mL) were added, and the mixture was stirred at room temperature for 2 hours. 4-Dimethylaminopyridine (0.351 g) was added to the reaction mixture, and the mixture was stirred for 2 hours. After standing overnight, the reaction mixture was stirred at room temperature for 3 hours and the aqueous layer was discharged. The organic layer was washed with 5% aqueous potassium bisulfate solution (18.3 mL × 2) and 5% aqueous potassium carbonate solution (18.3 mL × 2). The obtained organic layer was concentrated under reduced pressure to obtain a residue (4.17 g) containing compound B6. The obtained residue was diluted with acetonitrile and subjected to LCMS analysis (Method 1: retention time of compound B6; 4.793 minutes, m / z = 627.34 [M+H] + ). The obtained residue and 3,5-bis(trifluoromethyl)benzoic acid were dissolved in DMSO-d 6 6, and qNMR analysis was carried out (yield: 88.1%).

[1198] Example B-21

[1199] Synthesis of Compound B7: ((2S)-1-[(2S)-2-[Methyl-[(2S,3S)-3-methyl-2-[[(2S)-4-methyl- 2-(methylamino)pentanoyl]amino]pentanoyl]amino]propanoyl]azetidine-2-carboxylic acid tert-butyl ester)

[1200] [Formula 93]

[1201]

[1202] At room temperature, the residue containing compound B6 (3.98 g, content: 76.5%) and 2-MeTHF (9.06 mL) were added to a reaction vessel. The reaction vessel was heated in an oil bath set at 47 °C, and tetrabutylammonium fluoride (1 M THF solution, 12.1 mL) was added within 1 hour, and then the mixture was stirred for 2 hours. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 1), and it was confirmed by HPLC analysis that the reaction conversion rate was 99.9% or greater (Calculation Expression 1 for Reaction Conversion Rate). The reaction vessel was removed from the oil bath, and isopropyl acetate (9.06 mL) and 5% aqueous potassium carbonate solution (9.06 mL) were added to the reaction mixture. The mixture was stirred at room temperature for 10 minutes, and the aqueous layer was drained. The organic layer was washed with 5% aqueous potassium carbonate solution (9.06 mL × 2). The obtained organic layer was concentrated under reduced pressure to obtain a residue containing compound B7 (3.08 g). 2-MeTHF (9.1 mL) was added to the obtained residue to obtain a solution containing compound B7 (6.45 g, content: 31.2%). The obtained solution was diluted with acetonitrile and subjected to LCMS analysis (Method 1: retention time of compound B7; 2.552 minutes, m / z = 483.36 [M+H] + ). The obtained solution and 1,3,5-trimethoxybenzene were dissolved in DMSO-d 6 and subjected to qNMR analysis (yield: 85.4%).

[1203] Example B-22

[1204] Synthesis of Compound B16: ((2S,3S)-2-[[(2S)-2-[Benzyloxycarbonyl(methyl)amino]-4-methyl-pent anoyl]amino]-3-methyl-pentanoic acid tert-butyl ester)

[1205] [Formula 94]

[1206]

[1207] At room temperature, compound N-((benzyloxy)carbonyl)-N-methyl-L-leucine B15 (4.51 g) and compound L-isoleucine tert-butyl hydrochloride B14 (4.34 g) were added to a reaction vessel, and then 2-MeTHF (48.7 mL) was added, and the mixture was stirred. After adding DIPEA (15.2 mL) under stirring, T3P (1.6 M 2-MeTHF solution, 24.2 mL) was added dropwise while maintaining the internal temperature at 25 °C or lower, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 2), and it was confirmed by HPLC analysis that the reaction conversion rate was 99.7% or higher (Calculation Expression 3 for Reaction Conversion Rate). 5% Aqueous sodium carbonate solution (45.0 mL) was added to the reaction mixture under stirring while maintaining the internal temperature at 25 °C or lower. The mixture was stirred at room temperature for 10 minutes, and then the aqueous layer was drained. The organic layer was washed with 5% aqueous sodium bisulfate monohydrate solution (45.0 mL × 2) and 5% aqueous sodium carbonate solution (45.0 mL × 1). The obtained organic layer was concentrated under reduced pressure to obtain a residue (7.74 g) containing compound B16. The obtained residue was diluted with acetonitrile and subjected to LCMS analysis (Method 1: Retention time of compound B16; 4.642 minutes, m / z = 449.24 [M+H] + ). The obtained residue and 3,5-bis(trifluoromethyl)benzoic acid were dissolved in DMSO-d 6 and subjected to qNMR analysis (Yield: 99.9%).

[1208] Example B-23

[1209] Synthesis of Compound B17: ((2S,3S)-2-[[(2S)-2-[Benzyloxycarbonyl(methyl)amino]-4-methyl-pent anoyl]amino]-3-methyl-pentanoic acid)

[1210] [Formula 95]

[1211]

[1212] To the residue containing compound B16 obtained in Example B-22 (7.59 g, content: 93.3%) was added isopropyl acetate (12.5 mL) to prepare a solution containing compound B16. To the reaction vessel at room temperature was added the solution containing compound B16 prepared above (9.05 g) and isopropyl acetate (28.6 mL), and then hexamethyldisilazane (4.14 mL) was added. The reaction vessel was cooled in an ice bath, and trimethylsilyl trifluoromethanesulfonate (2.82 mL) was added with stirring. The reaction vessel was removed from the ice bath, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 1), and it was confirmed by HPLC analysis that the reaction conversion rate was 99.4% or greater (Calculation Expression 1 of Reaction Conversion Rate). The reaction vessel was cooled in an ice bath, and isopropyl acetate (9.5 mL) and 5% aqueous potassium hydrogen phosphate solution (24.5 mL) were added, and the resulting mixture was mixed in a separatory funnel. 0.5 M aqueous hydrochloric acid solution (20.0 mL) was added to the separatory funnel to wash the organic layer, and the aqueous layer was drained. The organic layer was washed with 5% sodium chloride solution (35.0 mL). The resulting organic layer was concentrated under reduced pressure to obtain a residue containing compound B17 (3.89 g). The obtained residue was diluted with acetonitrile and subjected to LCMS analysis (Method 1: retention time of compound B17; 3.635 minutes, m / z = 393.15 [M+H] + ). The resulting residue and 3,5-bis(trifluoromethyl)benzoic acid were dissolved in DMSO-d 6 and subjected to qNMR analysis (yield: 92.8%). 2-MeTHF (5.0 mL) was added to the resulting residue to obtain a solution containing compound B17 (8.06 g, content: 34.2%).

[1213] Example B-24

[1214] Synthesis of Compound B4: ((2S)-1-[(2S)-2-(Methylamino)propanoyl]azetidine-2-carboxylic acid tert-but yl ester)

[1215] [Formula 96]

[1216]

[1217] At room temperature, a solution containing compound B3 obtained in Example B-16 (8.12 g) and 2-MeTHF (18.1 mL) was added to a reaction vessel, and then 5% Pd / C (1.70 g, 50% water content) was added. Nitrogen degassing was carried out under stirring, then hydrogen degassing was carried out, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 1), and it was confirmed by HPLC analysis that the reaction conversion rate was 99.9% or more (Calculation Expression 1 of the reaction conversion rate). The reaction mixture was suction filtered using filter paper and a membrane filter, and the residue was washed with 2-MeTHF (12.1 mL × 2). The obtained filtrate was concentrated under reduced pressure to obtain a residue (2.13 g) containing compound B4. The obtained residue was diluted with acetonitrile and subjected to LCMS analysis (Method 2: retention time of compound B4; 1.573 minutes, m / z = 243.09 [M+H] + ). The obtained residue and 1,3,5-trimethoxybenzene were dissolved in DMSO-d 6 6, and qNMR analysis was carried out (yield: 98.3%). 2-MeTHF (3.5 mL) was added to the obtained residue to obtain a solution (4.340 g, content: 40.8%) containing compound B4.

[1218] Example B-25

[1219] Synthesis of Compound B18: (2-[[(2S)-2-[[(2S,3S)-2-[[(2S)-2-[Benzyloxycarbonyl(methyl)amino -4-methyl-valeryl]amino]-3-methyl-valeryl]-methyl-amino]propionyl]amino]acetic acid tert-butyl ester)

[1220] [Formula 97]

[1221]

[1222] A solution containing compound B17 (235 mg, content: 34.2%), a solution containing compound B4 (111 mg, content: 40.8%), DIPEA (67.9 μL), and acetonitrile (45 μL) were added to a reaction vessel. HATU (78.6 mg) was added to the reaction vessel, and the mixture was stirred at room temperature for 7 hours. The reaction mixture was sampled and prepared as a sample (Sample Preparation Method 2), and it was confirmed by HPLC analysis that the reaction conversion rate was 97.3% or more (Calculation Expression 4 of the reaction conversion rate) (Method 1: retention time of compound B18: 4.374 minutes, m / z = 639.37 [M+Na] + ). The ratio of compound B18 to BP1 was 40.2:59.8.

[1223] Calculation formula 4 for reaction conversion rate: Reaction conversion rate (%) = (area value of compound B18 + area value of compound BP1) / (area value of compound B4 + area value of compound B18 + area value of compound B18) × 100

[1224] Example B-26

[1225] Synthesis of Compound B20: (2S)-1-[(2S tert-butyl ((S2SS)-2-(Benzyloxycarbonylamino-(((benzyloxy) carbonyl)amino)-4-[-(-[-(3,5-difluoro-4-(trifluoromethyl)phenyl...

Claims

1. A method for producing a cyclic peptide compound, or a salt thereof, or a solvate thereof, the method comprises: a linking step of linking the N-terminal amino acid residue of a peptide compound with the C-terminal amino acid residue of the peptide compound in a solvent, wherein at least one of the N-terminal amino acid residue and the C-terminal amino acid residue is a cyclic amino acid residue, and the solvent comprises one or more selected from the group consisting of acetonitrile, dimethyl carbonate, 2-MeTHF, and anisole.

2. A method for producing a cyclic peptide compound, or a salt thereof, or a solvate thereof, the method comprises: a step of linking the N-terminal amino acid residue of a peptide compound with the C-terminal amino acid residue of the peptide compound in a solvent, wherein the N-terminal amino acid residue and the C-terminal amino acid residue of the peptide compound are any one of the following a) to e): a) The N-terminal amino acid residue is an N-substituted phenylalanine residue or an N-substituted phenylalanine derivative residue, and the C-terminal amino acid residue is a cyclic amino acid residue; b) The N-terminal amino acid residue is an α,α-disubstituted amino acid residue, and the C-terminal amino acid residue is a cyclic amino acid residue; c) The N-terminal amino acid residue is a cyclic amino acid residue, and the C-terminal amino acid residue is a homophenylalanine residue or a homophenylalanine derivative residue; d) The N-terminal amino acid residue is a cyclic amino acid residue, and the C-terminal amino acid residue is an N-substituted Ala residue; and e) The N-terminal amino acid residue is an N-substituted Gly residue, and the C-terminal amino acid residue is an N-substituted phenylalanine residue or an N-substituted phenylalanine derivative residue.

3. The method according to claim 2, wherein the solvent comprises one or more selected from the group consisting of acetonitrile, dimethyl carbonate, 2-MeTHF, and anisole.

4. The method according to any one of claims 1 to 3, wherein linking the N-terminal amino acid residue of the peptide compound with the C-terminal amino acid residue of the peptide compound is linking the amino group of the N-terminal amino acid residue with the carboxyl group of the C-terminal amino acid residue.

5. The method according to any one of claims 1 to 4, wherein the linking step is carried out in the presence of a condensation reagent.

6. The method according to claim 5, wherein the condensation reagent is one selected from the group consisting of HATU, COMU, DMT-MM, PyOxim, PyBOP, and PyClop.

7. The method according to any one of claims 1 to 6, wherein the linking step is carried out by a liquid phase method.

8. The method according to any one of claims 1, 3 to 7, wherein the N-terminal amino acid residue of the peptide compound is a cyclic amino acid residue and the C-terminal amino acid residue is a non-natural amino acid residue, or the N-terminal amino acid residue of the peptide compound is a non-natural amino acid residue and the C-terminal amino acid residue is a cyclic amino acid residue.

9. The method according to any one of claims 2 to 7, wherein the N-terminal amino acid residue and the C-terminal amino acid residue contained in the peptide compound are one selected from the following a') to e'): a′) The N-terminal amino acid residue is an EtPhe(4-Me) residue, and the C-terminal amino acid residue is an Aze(2) residue; b′) The N-terminal amino acid residue is a cLeu residue, and the C-terminal amino acid residue is a Pro residue; c′) The N-terminal amino acid residue is a Pro residue, and the C-terminal amino acid residue is an Hph (3,5-diF-4-CF 3 ) residue; d′) The N-terminal amino acid residue is a MeGly residue, and the C-terminal amino acid residue is an EtPhe(4-Me) residue; and e′) The N-terminal amino acid residue is an Aze(2) residue, and the C-terminal amino acid residue is a MeAla residue.

10. The method according to any one of claims 1 to 9, wherein the number of amino acid residues of the cyclic peptide compound is from 9 to 15.

11. The method according to any one of claims 1 to 10, wherein the peptide compound is a linear peptide compound selected from the group consisting of: [Formula 1] [Formula 2] [Formula 3] [Formula 4] and [Formula 5] or a salt thereof, or a solvate thereof.

12. The method according to any one of claims 1 to 11, wherein the cyclic peptide compound, or a salt thereof, or a solvate thereof is a solvate of the cyclic peptide compound.

13. The method according to claim 12, wherein the solvate of the cyclic peptide compound is a hydrate of the cyclic peptide compound.

14. The method according to any one of claims 1 to 13, wherein the cyclic peptide compound is represented by the following formula (2): [Formula 6] 15. The method according to any one of claims 1 to 14, further comprising the step of separating and / or purifying the cyclic peptide compound by crystallization to obtain crystals of the cyclic peptide compound.

16. The method according to claim 15, wherein the crystals of the cyclic peptide compound are non-solvate crystals or solvate crystals of the cyclic peptide compound represented by the following formula (2): [Formula 7] 17. The method according to claim 16, wherein the crystals of the cyclic peptide compound are solvate crystals.

18. The method according to claim 17, wherein the solvate crystals of the cyclic peptide compound are hydrate crystals.

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