Method for producing a peptide compound having a cyclic structure

Abstract

The invention provides a novel annulation metathesis reaction for constructing a peptide structure with a central ring. The invention provides a method for performing the annulation metathesis reaction, wherein the annulation metathesis reaction is performed under low dilution conditions (e.g., a concentration of 0.1 mol / L). The invention provides a method for performing an annulation metathesis reaction that is suitable for large scale production.

Description

Technical Field

[0001] This invention relates to a method for producing peptide compounds having a cyclic structure using a cyclization metathesis reaction. Background Technology

[0002] Recently, it has been found that certain cyclic peptide compounds containing non-natural amino acids improve the metabolic stability and membrane permeability of peptides (Non-Patent Literature 1 and 2). Some cyclic peptides have a dipeptide structure with a central ring (Patent Literature 1). Among the structures with a central ring, those with 5- to 7-membered rings are specifically called Friedinger lactams. Friedinger lactams are structures characterized by their ability to alter pharmacological activity and metabolic stability through conformational fixation, and are sometimes observed in drug design (Non-Patent Literature 3).

[0003] Mesocyclic rings are typically formed via cyclization metathesis using ruthenium-pyruvic complexes (represented by Hoveyda-Grubbs catalysts). When performing cyclization metathesis, substrates in which the N-terminal amino group is protected with Boc, Fmoc, etc., are commonly used (Non-Patent Literature 4 and 5). However, in these methods, unless high dilution conditions are employed (e.g., 0.01 mol / L), intermolecular reactions compete with the desired cyclization metathesis reaction (i.e., intramolecular reaction), and therefore the desired product cannot be obtained in high yield. On the other hand, when cyclization metathesis is carried out under high dilution conditions, the rate of the reaction may decrease due to the low substrate concentration, and the catalyst may deactivate, leading to an increase in catalyst quantity and the associated need for catalyst removal processes. Furthermore, since high dilution conditions require the use of large amounts of solvent, they are unsuitable for large-scale synthesis from a productivity perspective, such as in the production of active pharmaceutical ingredients (APIs).

[0004] [List of Citations]

[0005] [Patent Literature]

[0006] [Patent Document 1] International Publication No. WO 2022 / 234853

[0007] [Non-patent literature]

[0008] [Non-patent literature 1] Acc. Chem. Res. 2008, 41, 1331-1342.

[0009] [Non-patent literature 2] Angew. Chem. Int. Ed., 2013, 52, 254-269.

[0010] [Non-patent literature 3] Science, 1980, 210, 676-658.

[0011] [Non-Patent Literature 4] J. Org. Chem., 2003, 68, 62-69.

[0012] [Non-Patent Literature 5] J. Org.Chem., 2015, 80, 4904-4918. Summary of the Invention

[0013] [Technical Issues]

[0014] The present invention was made in view of these circumstances. In one aspect, the problem to be solved is to establish a novel cyclization metathesis reaction for constructing peptide structures with a central ring. In another aspect, the problem to be solved is to establish a method for carrying out a cyclization metathesis reaction under low dilution conditions (e.g., 0.1 mol / L). In another aspect, the problem to be solved is to establish a method for carrying out a cyclization metathesis reaction with high yield. In another aspect, the problem to be solved is to establish a method for carrying out a cyclization metathesis reaction with reduced byproduct formation. In yet another aspect, the problem to be solved is to establish a method for carrying out a cyclization metathesis reaction suitable for large-scale production.

[0015] [Solution to the problem]

[0016] The inventors have conducted in-depth research to address the aforementioned problems and have discovered that even at relatively high concentrations, in the presence of a catalyst (such as a metal-alkylene complex), cyclization metathesis reactions can be carried out by using substrates in which the N-terminal amino group is an unprotected amino acid, while maintaining intramolecular reaction selectivity.

[0017] In one specific non-limiting aspect, the invention covers the following.

[0018] [1] A method for producing a compound or a salt thereof represented by formula (1), the method comprising the step of contacting the compound or a salt thereof represented by formula (2) with a catalyst (metathesis step):

[0019] [Formula 1]

[0020]

[0021] in

[0022] R 1 It is hydrogen.

[0023] R2 It is hydrogen or C1-C6 alkyl;

[0024] R 3 Hydrogen, optionally substituted C1-C6 alkyl, optionally substituted halo-C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 14 Aryl, optionally substituted 5- to 14-membered heteroaryl, optionally substituted C7-C 14 Aryl groups, optionally substituted 3- to 14-membered heterocyclic groups, optionally substituted 5- to 10-membered heteroaryl-C1-C6 alkyl groups, optionally substituted C1-C6 alkoxy-C1-C6 alkyl groups, optionally substituted C1-C6 alkylthio-C1-C6 alkyl groups, optionally substituted C1-C6 alkylsulfinyl-C1-C6 alkyl groups, optionally substituted C1-C6 alkylsulfonyl-C1-C6 alkyl groups, optionally substituted carboxyl-C1-C6 alkyl groups, optionally substituted C7-C6 alkyl groups. 14 Ararylalkoxy-C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl-C1-C6 alkyl, optionally substituted C3-C8 cycloalkoxy-C1-C6 alkyl, optionally substituted 4- to 7-membered heterocyclic-C1-C3 alkyl, optionally substituted 5- to 10-membered heteroaryl-C1-C6 alkoxy-C1-C6 alkyl, or optionally substituted amino carbonyl (the relevant amino group is selected from the group consisting of: -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, N-C1-C6 alkyl-N-C2-C6 alkenylamino, N-C1-C6 alkyl-N-C1-C6 alkoxy-C1-C6 alkylamino, and 4- to 9-membered cycloamino).

[0025] R 4 OR 5 NHR 5 'Amino acid residues or peptide chains containing 1 to 20 amino acid residues, wherein the amino acid residues and peptide chains may have protecting groups,

[0026] R 5 As a protecting group against the carboxyl group,

[0027] R 5 ' is a protecting group targeting the amide group,

[0028] n is an integer from 1 to 4, and

[0029] X is optionally a substituted C1-C3 alkylene, -CH2OCH2-, or -CH2SCH2-.

[0030] [2] A method for producing a compound or a salt thereof represented by formula (3), the method comprising the step of hydrogenating a compound or a salt thereof represented by formula (1), the compound or a salt thereof being obtained by the method according to [1]:

[0031] [Equation 2]

[0032]

[0033] Where R 1 R 2 R 3 R 4 , n and X are respectively related to R in [1] 1 R 2 R 3 R 4 , n and X have the same meaning.

[0034] [3] A method for producing a compound or a salt thereof represented by formula (4), the method comprising the step of protecting an amino group of a compound or a salt thereof represented by formula (1) with a urethane protecting group, the compound or a salt thereof represented by formula (1) being obtained by the method according to [1]:

[0035] [Formula 3]

[0036]

[0037] Where R 2 R 3 R 4 , n and X are respectively related to R in [1] 2 R 3 R 4 , n and X have the same meaning, and X 1 It is a urethane protecting group.

[0038] [4] A method for producing a compound or a salt thereof represented by formula (5), the method comprising the step of protecting an amino group of a compound or a salt thereof represented by formula (3) with a urethane protecting group, the compound or a salt thereof represented by formula (3) being obtained by the method according to [2]:

[0039] [Formula 4]

[0040]

[0041] Where R 2 R 3 R 4 , n and X are respectively related to R in [1] 2 R 3 R 4 , n and X have the same meaning, and X 1 It is a urethane protecting group.

[0042] [5] The method according to any one of [1] to [4], wherein the catalyst is a metal-alkylene complex.

[0043] [6] The method according to any one of [1] to [5], wherein the catalyst is a ruthenium-alkylene complex, a molybdenum-alkylene complex or a tungsten-alkylene complex.

[0044] [7] The method according to any one of [1] to [6], wherein the catalyst is a ruthenium-trialkyl complex.

[0045] [8] The method according to any one of [1] to [7], wherein the catalyst is a ruthenium-pyruvate complex containing phosphine and / or N-heterocyclic carbene as ligands.

[0046] [9] The method according to any one of [1] to [8], wherein the catalyst is a first-generation Grubbs catalyst (dichloro(benzyl)bis(tricyclohexylphosphine)ruthenium(II)), a second-generation Grubbs catalyst (dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidine](benzyl)(tricyclohexylphosphine)ruthenium(II)), a third-generation Grubbs catalyst (dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidine](benzyl)bis(3-bromopyridine)ruthenium(II)), a Stewart-Grubbs catalyst (dichloro[1,3-bis(2-methylphenyl)-2-imidazolidine](2-isopropoxyphenylmethylene)ruthenium(II)), or a nitro-Grela catalyst. Catalysts (dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinedimethyl][(2-isopropoxy-5-nitrobenzyl)]ruthenium(II)), Zhan Catalyst-1B (dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinedimethyl][[5-[(dimethylamino)sulfonyl]-2-(1-methylethoxy-O)phenyl]methylene-C]ruthenium(II)), Zhan Catalyst-1C ({[2-(isopropoxy)-5-(N,N-dimethylaminosulfonyl)phenyl]methylene}(tricyclohexylphosphine)dichlororuthenium(II)), first-generation Hoveyda-Grubbs catalyst (dichloro(2-isopropoxyphenylmethylene)(tricyclohexylphosphine)ruthenium), second-generation Hoveyda-Grubbs catalyst Catalysts ((1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinedimethyl)dichloro(o-isopropoxyphenylmethylene)ruthenium), [1,3-bis-(2,6-isopropylphenyl)-2-imidazolidinedimethyl]dichloro(2-isopropoxybenzyl)ruthenium(II), bis[1-(2,6-diethylphenyl)-3,5,5-trimethyl-3-phenylpyrrolidine-2-yl](3-phenyl-1H-inden-1-yl)ruthenium chloride, [1-(2,6-diethylphenyl)-3,5,5-trimethyl-3-phenylpyrrolidine-2-yl](2-isopropoxy-5-nitrobenzyl)ruthenium(II) chloride Or [1-[2,4,6-trimethylphenyl]-3,5,5-trimethyl-3-phenyl-2-pyrrolinoside]dichloro(2-isopropoxybenzylidene)ruthenium(II).

[0047]

[10] The method according to any one of [1] to [9], wherein the catalyst is a first-generation Hoveyda-Grubbs catalyst (dichloro(2-isopropoxyphenylmethylene)(tricyclohexylphosphine)ruthenium), a second-generation Hoveyda-Grubbs catalyst ((1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinedimethyl)dichloro(o-isopropoxyphenylmethylene)ruthenium) or [1-[2,4,6-trimethylphenyl]-3,5,5-trimethyl-3-phenyl-2-pyrrolidinedimethyl]dichloro(2-isopropoxybenzylidene)ruthenium(II).

[0048]

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

[10] , wherein the compound represented by formula (2) or a salt thereof is a salt of the compound represented by formula (2).

[0049]

[12] According to the method of

[11] , the salt of the compound represented by formula (2) is a salt formed with a Bronsted acid having a pKa of 3 or less.

[0050]

[13] According to the method of

[12] , the salt of the compound represented by formula (2) is a hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, p-toluenesulfonate, trifluoromethanesulfonate or trifluoroacetate.

[0051]

[14] The method according to

[12] or

[13] , wherein the salt of the compound represented by formula (2) is a hydrochloride salt.

[0052]

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

[10] , wherein the compound represented by formula (2) or a salt thereof is a compound represented by formula (2), and an acid is used in the metathesis step.

[0053]

[16] According to the method of

[15] , the acid is a Bronsted acid having a pKa of 3 or less.

[0054] [16-1] According to the method of

[16] , the Bronsted acid is at least one Bronsted acid selected from the group consisting of: hydrogen chloride, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid and trifluoroacetic acid.

[0055]

[17] The method according to

[16] , wherein the Bronsted acid is hydrogen chloride.

[0056]

[18] The method according to

[15] , wherein the acid is a Lewis acid.

[0057] [18-1] According to the method of

[18] , the Lewis acid is at least one Lewis acid selected from the group consisting of boron trihalide, its solvated complex, titanium tetrahalide and titanium tetraalkoxy.

[0058]

[19] According to the method of

[18] , the acid is a boron trifluoride-tetrahydrofuran complex or a boron trifluoride-diethyl ether complex.

[0059]

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

[10] , wherein an alcohol and / or a Bronsted acid are further used as additives in the metathesis step, and the pKa of the additive is 4 to 17.

[0060] [20-1] The method according to

[12] ,

[16] or

[20] , wherein pKa is a measured value of pKa when water is used as a solvent at 25°C.

[0061]

[21] The method according to any one of

[20] , wherein the additive is at least one selected from the group consisting of: 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), 2-propanol, methanol, 2,2,2-trifluoroethanol (TFE) and acetic acid.

[0062]

[22] The method according to

[20] or

[21] , wherein the additive is 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) or acetic acid.

[0063]

[23] The method according to any one of

[20] to

[22] , wherein the additive is used in an amount of 0.1 mL to 100 mL per g of the compound represented by formula (2).

[0064] [23-1] The method according to any one of

[20] to

[22] , wherein the additive is used in an amount of 1 mL to 10 mL per g of the compound represented by formula (2).

[0065]

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

[23] , wherein the metathesis step is carried out by a liquid-phase synthesis method.

[0066]

[25] According to the method of

[24] , the solvent used in the liquid-phase synthesis method includes at least one selected from the group consisting of: ketone-based solvents, nitrile-based solvents, halogen-based solvents, ether-based solvents, amide-based solvents, ester-based solvents, aromatic hydrocarbon-based solvents, aliphatic hydrocarbon-based solvents and carbonate-based solvents.

[0067]

[26] According to the method of

[25] , wherein the ketone-based solvent is one or more selected from the group consisting of: acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, cyclopentanone, and diethyl ketone,

[0068] The solvent based on nitriles is one or more of the following: acetonitrile and propionitrile.

[0069] Halogen-based solvents are one or more of the following groups: dichloromethane, chloroform, and 1,2-dichloroethane.

[0070] The solvent based on the ether is one or more of the following groups: diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentylmethyl ether, 4-methyltetrahydropyran, 1,3-dioxolane, 1,4-dioxane, 1,2-dimethoxyethane, diisopropyl ether, methyl tert-butyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, anisole, and tetraethylene glycol dimethyl ether.

[0071] The amide-based solvent is one or more of the following groups: N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), N,N-dimethylacetamide (DMA), N-ethyl-2-pyrrolidone (NEP), N-butyl-2-pyrrolidone (NBP), 1,3-dimethyl-2-imidazolium ketone (DMI), and formamide.

[0072] The solvent based on the ester is one or more of the following: methyl acetate, ethyl acetate, methyl propionate, butyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, amyl acetate, and γ-valerate.

[0073] Solvents based on aromatic hydrocarbons are one or more of the following groups: toluene, o-xylene, m-xylene, p-xylene, mesitylene, chlorobenzene, fluorobenzene, and anisole.

[0074] The solvent based on aliphatic hydrocarbons is one or more of the following groups: pentane, hexane, heptane, octane, and cyclohexane, and

[0075] The carbonate-based solvent is one or more of the following groups: dimethyl carbonate, diethyl carbonate, and dibutyl carbonate.

[0076]

[27] The method according to any one of

[24] to

[26] , wherein the solvent used in the liquid-phase synthesis method is one or more of the group consisting of: acetone, methyl tert-butyl ether, dimethyl carbonate, 2-methyltetrahydropyran, 4-methyltetrahydropyran, tetrahydrofuran, ethyl acetate, isopropyl acetate, dichloromethane, 1,2-dichloroethane, toluene, chlorobenzene, heptane and cyclohexane.

[0077]

[28] The method according to any one of

[24] to

[27] , wherein the solvent used in the liquid-phase synthesis method is one or more of the group consisting of: acetone, methyl tert-butyl ether, dimethyl carbonate, ethyl acetate, toluene and dichloromethane.

[0078]

[29] The method according to any one of

[24] to

[28] , wherein the solvent used in the liquid-phase synthesis method is acetone or toluene.

[0079]

[30] The method according to any one of

[24] to

[29] , wherein the solvent used in the liquid-phase synthesis method is acetone.

[0080]

[31] According to any one of

[25] to

[30] , wherein the concentration of the compound represented by formula (2) or its salt is from 0.01 mol / L to 0.3 mol / L relative to the solvent used in the liquid-phase synthesis method.

[0081] [31-1] The method according to any one of

[25] to

[31] wherein the concentration of the compound represented by formula (2) or its salt is from 0.02 mol / L to 0.3 mol / L relative to the solvent used in the liquid-phase synthesis method.

[0082] [31-2] The method according to any one of

[25] to [31-1], wherein the concentration of the compound represented by formula (2) or its salt is from 0.033 mol / L to 0.3 mol / L relative to the solvent used in the liquid-phase synthesis method.

[0083] [31-3] The method according to any one of

[25] to [31-2], wherein the reaction mixture in the liquid-phase synthesis method is prepared by one of the following (a) to (d):

[0084] (a) A mixture of a compound represented by formula (2) or its salt, a catalyst, an acid, an additive and a solvent is prepared by adding a solvent mixture containing a compound represented by formula (2) or its salt to a solvent mixture containing a catalyst;

[0085] (b) A mixture of a compound represented by formula (2) or its salt, a catalyst, an acid, an additive and a solvent is prepared by adding a solvent mixture containing a compound represented by formula (2) or its salt to a solvent mixture containing a heated catalyst;

[0086] (c) A mixture of a compound represented by formula (2) or a salt thereof, a catalyst, an acid, an additive, and a solvent is prepared by adding a solvent mixture containing a catalyst to a solvent mixture containing a compound represented by formula (2) or a salt thereof; and

[0087] (d) A mixture is prepared by adding a solvent to a compound represented by formula (2) or a salt thereof, and then adding a catalyst, an acid and an additive.

[0088] [31-4] The method according to [31-3] (b) wherein heating is performed near the boiling point of the solvent.

[0089]

[32] The method according to any one of [1] to [31-4], wherein the compound represented by formula (2) or a salt thereof is obtained by condensing the compound represented by formula (6) and the compound represented by formula (7), and then deprotecting the urethane protecting group.

[0090] [Formula 5]

[0091]

[0092] Where R 2 R 3 R 4 , n and X are respectively related to R in [1] 2 R 3 R 4 , n and X have the same meaning, and X 2 It is a urethane protecting group.

[0093]

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

[32] , wherein R 2 It is hydrogen or a straight-chain C1-C3 alkyl group.

[0094]

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

[33] , wherein R 2 It can be hydrogen or methyl.

[0095]

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

[34] , wherein R 3Hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C7-C 14 Aryl group, optionally substituted 5- to 10-membered heteroaryl-C1-C6 alkyl group or optionally substituted 3- to 14-membered heterocyclic group.

[0096]

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

[35] , wherein R 3 It is hydrogen, C1-C6 alkyl, or optionally C7-C substituted with halogenated C1-C3 alkyl or C1-C6 alkyl. 14 Aryl alkyl group.

[0097]

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

[36] , wherein R 3 It is hydrogen, 2-methylpropyl, p-(trifluoromethyl)benzyl or p-methylbenzyl.

[0098]

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

[37] , wherein R 4 OR 5 NHR 5' , amino acid residues or peptide chains containing 2 to 13 amino acid residues,

[0099] R 5 The protecting group is an alkyl ester type protecting group, a benzyl ester type protecting group, a substituted alkyl ester type protecting group, or an alkenyl ester type protecting group, preferably a methyl group, an ethyl group, a tert-butyl group, a benzyl group, a triphenylmethyl group, a cumyl group, a methoxytriphenylmethyl group, a 2-(trimethylsilyl)ethyl group, a 2,2,2-trichloroethyl group, or an allyl group, and more preferably a tert-butyl or benzyl group.

[0100] R 5The protecting group is a phenylamide type protecting group, an alkylamide type protecting group, an alkenylamide type protecting group, a benzylamide type protecting group, or an alkoxyalkylamide type protecting group, preferably a phenyl group, a tert-butyl group, an allyl group, a benzyl group, a 4-methoxybenzyl group, a triphenylmethyl group, a cumyl group, a methoxymethyl group, or a benzyloxy-methyl group, and more preferably a phenyl group, and the 2 to 13 amino acid residues are selected from one or more of the following: glycine, alanine, isoleucine, leucine, valine, methionine, phenylalanine, tyrosine, proline, N-methylglycine, N-methylalanine, N-methylisoleucine, N-methylleucine, N-methylvaline, N-methylmethionine, N-methylphenylalanine, N-methyltyrosine, and N-methylproline.

[0101]

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

[38] , wherein n is an integer of 1 or 2.

[0102]

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

[39] , wherein n is 2.

[0103]

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

[40] , wherein X is an optionally substituted C1-C3 alkylene group.

[0104]

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

[41] , wherein X is a C1-C3 alkylene group.

[0105]

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

[42] , wherein X is methylene.

[0106] [43-1] The method according to any one of [1] to

[42] , wherein X is a methylene group and n is an integer of 1 or 2.

[0107] [43-2] The method according to any one of [1] to

[42] , wherein X is methylene and n is 2.

[0108]

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

[43] , wherein X 1 The group consisting of the following is selected: Fmoc group, Cbz group, Troc group, Alloc group, Teoc group, TSoc group, BIBSoc group, IPCSoc group, BBSoc group, CHBSoc group, CDBSoc group, and Boc group.

[0109]

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

[44] , wherein X 1 It is selected from one of the following groups: Fmoc group, Cbz group and Boc group.

[0110]

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

[45] , wherein X 1 It is an Fmoc group.

[0111]

[47] The method according to any one of

[32] to

[46] , wherein X 2 The group consisting of the following is selected: Fmoc group, Cbz group, Troc group, Alloc group, Teoc group, TSoc group, BIBSoc group, IPCSoc group, BBSoc group, CHBSoc group, CDBSoc group, and Boc group.

[0112]

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

[32] to

[47] , wherein X 2 It is selected from one of the following groups: Fmoc group, Cbz group and Boc group.

[0113]

[49] The method according to any one of

[32] to

[48] , wherein X 2 It is an Fmoc group.

[0114]

[50] A method for producing a cyclic peptide compound or a salt thereof, the method comprising the steps set forth in any one of [1] to

[49] , wherein the cyclic peptide compound or a salt thereof contains residues of a peptide produced in the steps set forth in any one of [1] to

[49] as part of the structure.

[0115]

[51] The method according to

[50] wherein the cyclic peptide compound or its salt contains 8 to 20 amino acid residues.

[0116]

[52] The method according to

[50] or

[51] , wherein the cyclic peptide compound or its salt contains 11 to 14 amino acid residues.

[0117]

[53] The method according to any one of

[50] to

[52] , wherein the cyclic peptide compound contains at least one non-natural amino acid residue.

[0118]

[54] The method according to any one of

[50] to

[53] , wherein the cyclic peptide compound contains at least four non-natural amino acid residues.

[0119]

[55] The method according to any one of

[50] to

[54] , wherein the cyclic peptide compound contains at least five non-natural amino acid residues.

[0120]

[56] The method according to any one of

[50] to

[55] , wherein the cyclic peptide compound is produced by amide cyclization of the N-terminal amino group and the C-terminal carboxyl group of the peptide compound.

[0121]

[57] The method according to any one of

[50] to

[55] , wherein the cyclic peptide compound is produced by thioether cyclization of the N-terminal chloroacetyl group and the C-terminal cysteine ​​side chain of the peptide compound.

[0122]

[58] The method according to any one of

[53] to

[57] , wherein the non-natural amino acid is an N-methyl amino acid residue.

[0123]

[59] According to

[50] to

[58] The method described in any one of the following embodiments, wherein the cyclic peptide compound produced is (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,24,36-octamethyl-10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecoxo-13-propyl-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0] 4,8 .0 26,30 [42-ene-23,1'-cyclobutane]-17-carboxamide.

[0124]

[60] (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,24,36-octamethyl-10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecoxo-13-propyl-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0] produced by the method according to any one of

[50] to

[58] . 4,8 .0 26,30 [42-ene-23,1'-cyclobutane]-17-carboxamide.

[0125]

[61] A compound or a salt thereof represented by formula (1a):

[0126] [Formula 6]

[0127]

[0128] Where Y is a hydroxyl group, optionally substituted C1-C 10 Alkyl groups, optionally substituted C6-C 16 aryloxy groups, optionally substituted C7-C 14 Alkoxy or optionally substituted 3- to 12-membered cyclic aminooxy groups.

[0129]

[62] The compound or salt thereof according to

[61] , wherein Y is tert-butoxy.

[0130]

[63] N-methyl-N-((S)-2-((S)-3-(methylamino)-2-oxo-2,3,4,7-tetrahydro-1H-aza-1-yl)-3-(4-(trifluoromethyl)phenyl)propionyl)glycine tert-butyl ester or its hydrochloride.

[0131]

[64] A compound or a salt thereof represented by formula (1b):

[0132] [Formula 7]

[0133]

[0134] Where R 6 It is methyl or trifluoromethyl, and

[0135] Z is a hydroxyl group, optionally substituted C1-C10 Alkyl groups, optionally substituted C6-C 16 aryloxy groups, optionally substituted C7-C 14 Alkoxy or optionally substituted 3- to 12-membered cyclic aminooxy groups.

[0136]

[65] The compound or salt thereof according to

[64] , wherein Z is tert-butoxy.

[0137]

[66] The compound or salt thereof according to

[64] or

[65] , wherein R 6 It is a methyl group.

[0138]

[67] The compound or salt thereof according to

[64] or

[65] , wherein R 6 It is trifluoromethyl.

[0139]

[68] N-methyl-N-((S)-2-((S,Z)-3-(methylamino)-2-oxo-3,4,7,8-tetrahydroazacyclooctatetraen-1(2H)-yl)-3-(p-tolyl)propionyl)glycine tert-butyl ester or its hydrochloride.

[0140]

[69] N-methyl-N-((S)-2-((S,Z)-3-(methylamino)-2-oxo-3,4,7,8-tetrahydroazacyclooctatetraen-1(2H)-yl)-3-(4-(trifluoromethyl)phenyl)propionyl)glycine tert-butyl ester or its hydrochloride.

[0141]

[70] N-methyl-N-((S)-2-((S,Z)-3-(methylamino)-2-oxo-2,3,4,5,8,9-hexahydro-1H-azacyclononaten-1-yl)-3-(p-tolyl)propionyl)glycine tert-butyl ester or its hydrochloride.

[0142]

[71] (S)-N,N-dimethyl-2-((S,Z)-3-(methylamino)-2-oxo-3,4,7,8-tetrahydroazacyclooctatetraen-1(2H)-yl)-3-(4-(trifluoromethyl)phenyl)propionamide or its hydrochloride.

[0143]

[72] The method for producing a compound or a salt thereof represented by formula (1) according to [1] includes the step of contacting a compound or a salt thereof represented by formula (2) with a catalyst (metathesis step), wherein R in formulas (1) and (2) 1 Compared to cases where the protective group is a urethane ester, the formation of impurities is suppressed.

[0144]

[73] The method for producing a compound or a salt thereof represented by formula (1) according to [1] includes the step of contacting a compound or a salt thereof represented by formula (2) with a catalyst (metathesis step), wherein R in formulas (1) and (2) 1 Compared to the case where the protecting group is a carbamate, dimer formation is suppressed.

[0145]

[74] A compound or a salt thereof represented by formula (1), wherein the purity of the compound or salt thereof represented by formula (1) is 90% or higher, preferably 95% or higher, more preferably 98% or higher, and most preferably 99% or higher, as determined by UVArea value at 210 nm from HPLC analysis.

[0146]

[75] A compound or a salt thereof represented by formula (1), wherein the content of impurities contained in the compound or salt thereof represented by formula (1) is less than 10%, preferably less than 5%, more preferably less than 1%, still more preferably less than 0.5%, and most preferably undetectable, as determined by UVArea value at 210 nm from HPLC analysis.

[0147] In the above numbering, unless otherwise stated, the number referenced in a dependent entry includes the branch number of that number. For example, the reference to

[31] in a dependent entry indicates that it includes not only

[31] , but also its branch numbers [31-1], [31-2], and [31-3]. The same applies to other numbering.

[0148] [Beneficial effects of the invention]

[0149] According to the present invention, peptide compounds having a peptide structure with a central ring can be produced efficiently. The production method of the present invention enables the reduction of production costs of peptide compounds and also reduces environmental impact; therefore, the production method of the present invention is particularly useful for large-scale peptide synthesis. Detailed Implementation

[0150] abbreviation

[0151] The abbreviations used in this article are listed below.

[0152] MTBE: Methyl tert-butyl ether

[0153] HFIP: 1,1,1,3,3,3-hexafluoro-2-propanol

[0154] MeTHF: 2-Methyltetrahydrofuran

[0155] DBU: 1,8-diazabicyclo[5.4.0]-7-undecene

[0156] TFE: 2,2,2-trifluoroethanol

[0157] TCFH: Chloro-N,N,N',N'-Tetramethylformamidin hexafluorophosphate

[0158] DIPEA: Diisopropylethylamine

[0159] Fmoc: 9-fluorenylmethyloxycarbonyl

[0160] Cbz: Benzyloxycarbonyl

[0161] Troc: 2,2,2-trichloroethoxycarbonyl

[0162] Alloc: allyloxycarbonyl

[0163] Teoc: 2-(trimethylsilyl)ethoxycarbonyl

[0164] TSoc: Triisopropylsilyloxycarbonyl

[0165] BIBSoc: di-tert-butylisobutylsilyloxycarbonyl

[0166] IPCSoc: Diisopropyltert-butylsilyloxycarbonyl

[0167] BBSoc: Benzyl di-tert-butylsilyloxycarbonyl

[0168] CHBSoc: di-tert-butylcyclohexylsilyloxycarbonyl

[0169] CDBSoc: tert-butyloctadecylsilyloxycarbonyl

[0170] Boc: tert-Butoxycarbonyl

[0171] Definition of functional groups, etc. (The terminology used in the following explanation is illustrative and not intended to be particularly limiting, and is terminology that will be commonly understood by those skilled in the art.)

[0172] As used herein, "halogen" includes fluorine, chlorine, bromine, and iodine. As used herein, F refers to fluorine, Cl refers to chlorine, Br refers to bromine, and I refers to iodine. Examples of halogens include fluorine, chlorine, and bromine, with fluorine and chlorine being preferred.

[0173] As used herein, "alkyl" refers to a straight-chain or branched monovalent saturated hydrocarbon group derived from saturated aliphatic hydrocarbons by removing any one of the hydrogen atoms. This group has a hydrocarbon group or subset of hydrocarbon group structures that do not contain heteroatoms (atoms other than carbon and hydrogen atoms) or unsaturated carbon-carbon bonds in their main chain, but contain hydrogen and carbon atoms. Alkyl groups include not only straight-chain alkyl groups but also branched alkyl groups. Specifically, alkyl groups are those having 1 to 20 carbon atoms (C1-C2). 20 Among them, "C" p -C q "Refers to alkyl groups with a carbon number of p to q, preferably C1-C 10 Alkyl, more preferably C1-C6 alkyl. 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. Specific examples of straight-chain C1-C6 alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl. Specific examples of straight-chain C1-C3 alkyl groups include methyl, ethyl, and n-propyl. Specific examples of branched C3-C6 alkyl groups include isopropyl, sec-butyl, tert-butyl, isobutyl (2-methylpropyl), 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, 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.

[0174] As used herein, “halogenated alkyl” is a group in which one or more hydrogen atoms of an alkyl group as defined herein are halogenated. Halogenated alkyl is preferably a group in which one or more and six or fewer hydrogen atoms of the alkyl group are halogenated. Halogenated alkyl is, for example, a halogenated C1-C… 20 Alkyl groups, preferably halogenated C1-C 10Alkyl groups, more preferably halogenated C1-C8 alkyl groups, still more preferably halogenated C1-C6 alkyl groups, and most preferably halogenated C1-C3 alkyl groups. Halogenated C1-C6 alkyl groups are, for example, groups in which one or more and six or fewer hydrogen atoms of the alkyl group are fluorinated, preferably groups in which one or more and five or fewer hydrogen atoms are fluorinated, more preferably groups in which one or more and four or fewer hydrogen atoms are fluorinated, and most preferably groups in which one or more and three or fewer hydrogen atoms are fluorinated. Specific examples of halogenated alkyl groups include difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3-difluoropropyl, 4,4-difluorobutyl, and 5,5-difluoropentyl.

[0175] As used herein, "alkenyl" is a straight-chain or branched monovalent unsaturated hydrocarbon group having one or more carbon-carbon double bonds (bonded by two adjacent sp2 carbon atoms). Depending on the conformation of the atom or group of atoms attached to the sp2 carbon atom, the geometry of the double bond can be entgegen (E) or zusammen (Z) and in cis or trans conformations. Alkenyl groups are, for example, C2-C 10 Alkenyl, preferably C2-C8 alkenyl, more preferably C2-C7 alkenyl, and most preferably C2-C6 alkenyl. Specific examples of alkenyl include ethenyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 1-butenyl, 2-butenyl (including cis and trans), 3-butenyl, pentenyl, and hexenyl.

[0176] As used herein, "alkynyl" is a straight-chain or branched monovalent unsaturated hydrocarbon group having one or more carbon-carbon triple bonds (composed of two adjacent sp carbon atoms). The alkynyl group is, for example, C2-C... 10 The alkynyl group, preferably C2-C8 alkynyl, more preferably C2-C7 alkynyl, and most preferably C2-C6 alkynyl. Specific examples of the alkynyl group include ethynyl, 1-propynyl, propynyl (2-propynyl), 1-butynyl, 2-butynyl, 3-butynyl, pentynyl, and hexynyl.

[0177] As used herein, “cycloalkyl” is a saturated or partially saturated cyclic monovalent non-aromatic hydrocarbon cyclic group (alicyclic cyclic group). The carbon atom constituting the ring can be oxidized to form a carbonyl group. Cycloalkyl can be selected from the group consisting of monocyclic, condensed, and spirocyclic. As used herein, a cycloalkyl containing a monocyclic ring is called a monocyclic cycloalkyl or monocyclic alicyclic cyclic group; a cycloalkyl containing a condensed ring is called a condensed cycloalkyl or condensed cycloalicyclic cyclic group; and a cycloalkyl containing a spirocyclic ring is called a spirocyclic cycloalkyl or spirocyclic alicyclic cyclic group. Cycloalkyl can form condensed rings with saturated alicyclic rings (such as cyclopentane or cyclohexane), unsaturated alicyclic rings (such as cycloheptene or cyclohexene), or aromatic hydrocarbon rings (such as benzene or naphthalene). Cycloalkyl can form spirocyclic rings with saturated alicyclic rings (such as cyclopropane, cyclobutane, cyclopentane, or cyclohexane). Cycloalkyl is, for example, C3-C 10 Cycloalkyl, preferably C3-C8 cycloalkyl, more preferably C3-C7 cycloalkyl, and most preferably C3-C6 cycloalkyl. Specific examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, spiro[3.3]heptyl, and cyclohexenyl.

[0178] As used herein, "aryl" is a monovalent aromatic hydrocarbon cyclic group consisting of a monovalent, monocyclic, or condensed ring that exhibits aromaticity. As used herein, aryl groups consisting of a monocyclic ring are called monocyclic aryl groups, and aryl groups consisting of a condensed ring are called condensed aryl groups. Aryl groups are, for example, C6-C... 14 Aryl, preferably C6 aryl, C 10 Aryl and C 14 Aryl, more preferably C6 aryl and C 10 Aryl, most preferably C6 aryl. Specific examples of aryl include phenyl, 1-naphthyl, 2-naphthyl, tolyl, and xylyl.

[0179] As used herein, "aralkyl (arylalkyl)" is a group in which one or more hydrogen atoms of an "alkyl" as defined herein are substituted with an "aryl" as defined herein. Aralkyl groups are, for example, C7-C 20 Aryl alkyl group, preferably C7-C 18 Aryl alkyl, more preferably C7-C 16 Aryl group, most preferably C7-C 14 Aryl group. C7-C 20 Aryl groups are, for example, C6-C 10 Aryl-C1-C 10 Alkyl, preferably C6-C 10 aryl-C1-C8 alkyl, more preferably C6 aryl-C1-C8 alkyl or C 10Aryl-C1-C8 alkyl, most preferably C6 aryl-C1-C8 alkyl. C7-C 18 Aryl groups are, for example, C6-C 10 aryl-C1-C8 alkyl, preferably C6-C 10 aryl-C1-C6 alkyl, more preferably C6 aryl-C1-C6 alkyl or C 10 Aryl-C1-C6 alkyl, most preferably C6 aryl-C1-C6 alkyl. C7-C 16 Aryl groups are, for example, C6-C 10 aryl-C1-C6 alkyl, preferably C6-C 10 aryl-C1-C4 alkyl, more preferably C6 aryl-C1-C4 alkyl or C 10 Aryl-C1-C4 alkyl, most preferably C6 aryl-C1-C4 alkyl. C7-C 14 Aryl groups are, for example, C6-C 10 aryl-C1-C4 alkyl, preferably C6-C 10 aryl-C1-C3 alkyl, more preferably C6 aryl-C1-C3 alkyl or C 10 Aryl-C1-C3 alkyl, most preferably C6 aryl-C1-C3 alkyl. Specific examples of aryl alkyl groups include benzyl, phenethyl, and 3-phenylpropyl.

[0180] As used herein, a "heterocyclic group" is a heterocyclic group that, as an atom other than a carbon atom constituting a ring, contains preferably one to five heteroatoms, more preferably one to three heteroatoms (these heteroatoms are selected from the group consisting of nitrogen, oxygen, and sulfur atoms), and may have double and / or triple bonds in the ring. The carbon atom of the ring of the heterocyclic group may be oxidized to form a carbonyl group. As used herein, a heterocyclic group containing a monocyclic ring is called a monocyclic heterocyclic group; a heterocyclic group containing a condensed ring is called a condensed ring heterocyclic group; and a heterocyclic group containing a spirocyclic ring is called a spirocyclic heterocyclic group. Heterocyclic groups may form condensed or spirocyclic rings with saturated alicyclic rings (such as cyclopentane or cyclohexane rings) or saturated heterocycles (such as tetrahydropyran, dioxane, or pyrrolidine rings). The number of atoms in the ring constituting the heterocyclic group is, for example, 3 to 14 (3-membered to 14-membered heterocyclic group), preferably 3 to 12 (3-membered to 12-membered heterocyclic group), more preferably 3 to 10 (3-membered to 10-membered heterocyclic group), and particularly preferably 4 to 7 (4-membered to 7-membered heterocyclic group). Specific examples of heterocyclic groups include azocyclobutane, ethylene oxide, oxocyclobutane, thiocyclobutane, tetrahydrofuranyl, pyrrolyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazoyl, isothiazolyl, thiadiazolyl, oxazolyl, dioxopentane, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 4-oxopyrrolyl, piperidinyl, 4-oxopyridinyl, piperazine, and dioxyl, and rings in which one or more single bonds in these saturated heterocycles are replaced by double or triple bonds.

[0181] As used herein, a "heteroaryl" is a monovalent aromatic heterocyclic group that contains at least one heteroatom in addition to a carbon atom and is composed of a monocyclic or fused ring exhibiting aromaticity. As used herein, a heteroaryl composed of a monocyclic ring is called a monocyclic heteroaryl, and a heteroaryl composed of a condensed ring is called a condensed-ring heteroaryl. The number of atoms in the ring constituting the heteroaryl is, for example, 5 to 14 (5-membered to 14-membered heteroaryl), preferably 5 to 13 (5-membered to 13-membered heteroaryl), more preferably 5 to 10 (5-membered to 10-membered heterocyclic group), and most preferably 5 to 7 (5-membered to 7-membered heteroaryl). Specific examples of heteroaryl groups include 5-membered heteroaryl groups, such as furanyl, thiopheneyl, pyrroleyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, or tetrazolyl; 6-membered heteroaryl groups, such as pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, or triazinyl; 9-membered heteroaryl groups, such as benzofuranyl, benzothiopheneyl, benzothiazolyl, benzoimidazolyl, benzotriazolyl, indolyl, inazolyl, or pyrazolopyridyl; and 10-membered heteroaryl groups, such as quinolinyl, isoquinolinyl, cyclolinyl, quinazolinyl, or quinoxalinyl.

[0182] As used herein, “alkoxy” is a group in which an alkyl group (-OR, where R is an alkyl group) is attached to an oxygen atom as defined herein. Alkoxy groups are, for example, C1-C 20 Alkoxy, preferably C1-C 10 Alkoxy, more preferably C1-C8 alkoxy, and most preferably C1-C6 alkoxy. Specific examples of alkoxy groups include methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, and 3-methylbutoxy.

[0183] As used herein, “alkylthio” is a group in which an alkyl group (-SR, where R is an alkyl group) is attached to a sulfur atom as defined herein. This is also called an alkylthio group. Alkylthio groups are, for example, C1-C... 20 Alkyl thio, preferably C1-C 10 Alkyl thio, more preferably C1-C8 alkyl thio, and most preferably C1-C6 alkyl thio. Specific examples of alkyl thio include methyl thio, ethyl thio, 1-propyl thio, 2-propyl thio, n-butyl thio, isobutyl thio, sec-butyl thio, tert-butyl thio, pentyl thio, and 3-methylbutyl thio.

[0184] As used herein, “alkyl sulfinyl” is a sulfinyl group (-S(=O)-R, where R is an alkyl group) attached to an alkyl group as defined herein. Alkyl sulfinyl groups are, for example, C1-C 20 alkyl sulfinyl, preferably C1-C 10 Alkyl sulfinyl, more preferably C1-C8 alkyl sulfinyl, and most preferably C1-C6 alkyl sulfinyl. Specific examples of alkyl sulfinyl include methyl sulfinyl, ethyl sulfinyl, 1-propyl sulfinyl, 2-propyl sulfinyl, n-butyl sulfinyl, isobutyl sulfinyl, sec-butyl sulfinyl, tert-butyl sulfinyl, pentyl sulfinyl, and 3-methylbutyl sulfinyl.

[0185] As used herein, “alkylsulfonyl” is a sulfonyl group (-S(=O)2-R, where R is an alkyl group) attached to an alkyl group as defined herein. Alkylsulfonyl groups are, for example, C1-C 20 Alkyl sulfonyl, preferably C1-C 10 Alkylsulfonyl, more preferably C1-C8 alkylsulfonyl, and most preferably C1-C6 alkylsulfonyl. Specific examples of alkylsulfinyl groups include methylsulfonyl, ethylsulfonyl, 1-propylsulfonyl, 2-propylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, and 3-methylbutylsulfonyl.

[0186] As used herein, “carboxyalkyl” is a group in which one or more hydrogen atoms of an alkyl group as defined herein are substituted with a “carboxyl” group. Carboxyalkyl is preferably a group in which one hydrogen atom of an alkyl group is substituted with a carboxyl group. Carboxyalkyl is, for example, a carboxyl C1-C… 20 Alkyl, preferably carboxyl C1-C 15 Alkyl, more preferably carboxyl C1-C 10 Alkyl, most preferably carboxyl C1-C6 alkyl. Specific examples of carboxyl alkyl include carboxymethyl and carboxyethyl.

[0187] As used herein, “aranalkoxy” is a group in which the alkyl portion of “aranyl” as defined herein is attached to an oxygen atom (-OR-Ar, where R is an alkylene group). Aranalkoxy groups are, for example, C7-C 20 Arylalkoxy, preferably C7-C 18 arylalkoxy, more preferably C7-C 16 Arylalkoxy, most preferably C7-C 14 Arylalkoxy group. C7-C 20 Aryl alkoxy groups are, for example, C6-C. 10 Aryl-C1-C 10 Alkoxy, preferably C6-C 10 aryl-C1-C8 alkoxy, more preferably C6 aryl-C1-C8 alkoxy or C 10 Aryl-C1-C8 alkoxy, most preferably C6 aryl-C1-C8 alkoxy. C7-C 18 Aryl alkoxy groups are, for example, C6-C. 10 aryl-C1-C8 alkoxy, preferably C6-C 10 aryl-C1-C6 alkoxy, more preferably C6 aryl-C1-C6 alkoxy or C 10 Aryl-C1-C6 alkoxy, most preferably C6 aryl-C1-C6 alkoxy. C7-C 16 Aryl alkoxy groups are, for example, C6-C. 10 aryl-C1-C6 alkoxy, preferably C6-C 10 aryl-C1-C4 alkoxy, more preferably C6 aryl-C1-C4 alkoxy or C 10 Aryl-C1-C4 alkoxy, most preferably C6 aryl-C1-C4 alkoxy. C7-C 14 Aryl alkoxy groups are, for example, C6-C. 10 aryl-C1-C4 alkoxy, preferably C6-C 10aryl-C1-C3 alkoxy, more preferably C6 aryl-C1-C3 alkoxy or C 10 Aryl-C1-C3 alkoxy, most preferably C6 aryl-C1-C3 alkoxy. Specific examples of arylalkoxy compounds include benzyloxy, phenylethoxy, and 3-phenylpropoxy.

[0188] As used herein, "aranyloxyalkyl" means a group in which one or more hydrogen atoms of an alkyl group as defined herein are substituted with an aranyloxy group as defined herein. Aranyloxyalkyl is preferably C7-C6. 14 Arylalkoxy-C1-C6 alkyl, more preferably C7-C 14 Ararylalkoxy-C1-C2 alkyl. Specific examples of ararylalkoxyalkyl groups include benzyloxymethyl and 1-(benzyloxy)ethyl.

[0189] As used herein, “cycloalkoxy” is a group in which a “cycloalkyl” as defined herein is attached to an oxygen atom (-OR, where R is a cycloalkyl group). Cycloalkoxy groups are, for example, C3-C… 10 Cycloalkoxy, preferably C3-C8 cycloalkoxy, more preferably C3-C7 cycloalkoxy, and most preferably C3-C6 cycloalkoxy. Specific examples of cycloalkoxy include cyclopropoxy, cyclobutoxy, and cyclopentoxy.

[0190] As used herein, "aryloxy group" is a group in which an aryl group (-OAr, where Ar is an aryl group) is attached to an oxygen atom as defined herein. Aryloxy groups are, for example, C6-C. 14 Aryloxy group, preferably C6 aryloxy group, C 10 aryloxy groups and C 14 Aryloxy, more preferably C6 aryloxy and C 10 Aryloxy group, most preferably C6 aryloxy group. Specific examples of aryloxy groups include phenoxy, 1-naphthoxy, 2-naphthoxy, tolyloxy, and xyleneoxy.

[0191] As used herein, “amino” means -NRR’, where N represents a nitrogen atom and R and R’ are each independently selected from the group consisting of: hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or R and R’ form a ring together with the nitrogen atom to which they are attached. Examples of amino groups include -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, N-C1-C6 alkyl-N-C2-C6 alkenylamino, N-C1-C6 alkyl-N-C1-C6 alkoxy-C1-C6 alkylamino, and 4- to 9-membered cyclic amino groups.

[0192] As used herein, “monoalkylamino” means an amino (-NRR') group as defined above, where R is a hydrogen atom and R' is an alkyl group. Monoalkylamino groups are, for example, mono-C1-C 20 Alkylamino, preferably mono-C1-C 15 Alkylamino, more preferably mono-C1-C 10 Alkylamino, most preferably mono-C1-C6 alkylamino. Specific examples of mono-alkylamino include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, sec-butylamino, and tert-butylamino.

[0193] As used herein, “dialkylamino” means an amino (-NRR') group as defined above, where R and R' are each independently an alkyl group. Dialkylamino is, for example, a di-C1-C 20 Alkylamino, preferably di-C1-C 15 Alkylamino, more preferably di-C1-C 10 Alkylamino, most preferably di-C1-C6 alkylamino. Specific examples of dialkylamino include dimethylamino, diethylamino, and methylethylamino.

[0194] As used herein, “cyclic amino” is a group of “amino (-NRR’)” as defined herein, wherein R and R’ together with the nitrogen atom to which they are attached form a ring. Cyclic amino groups are, for example, 3- to 14-membered cyclic amino groups, preferably 3- to 12-membered cyclic amino groups, more preferably 3- to 10-membered cyclic amino groups, still more preferably 4- to 9-membered cyclic amino groups, and most preferably 4- to 7-membered cyclic amino groups. Specific examples of cyclic amino groups include 1-azacyclobutane, 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-morpholinyl, 3-oxazolidinyl, 1,1-thiomorpholinyl-4-yl, and 3-oxa-8-azabicyclo[3.2.1]octane-8-yl.

[0195] As used herein, “cyclic aminooxy” is a group (-OR (R for cyclic amino) in which a “cyclic amino” is attached to an oxygen atom as defined herein. Cyclic amino groups are, for example, 3- to 14-membered cyclic aminooxy groups, preferably 3- to 12-membered cyclic aminooxy groups, more preferably 3- to 10-membered cyclic aminooxy groups, still more preferably 4- to 9-membered cyclic aminooxy groups, and most preferably 4- to 7-membered cyclic aminooxy groups. Specific examples of cyclic aminooxy groups include 1-azacyclobutyloxy, 1-pyrrolidinyloxy, 1-piperidinyloxy, 1-piperazinyloxy, 4-morpholinyloxy, 3-oxazolidinyloxy, 1,1-thiomorpholinyl-4-yloxy, and 3-oxa-8-azabicyclo[3.2.1]octane-8-yloxy.

[0196] As used herein, “aminocarbonyl” is a group in which an “amino” group, as defined herein, is attached to a carbon atom of a carbonyl group. It is sometimes also referred to as an amide. Aminocarbonyl groups are, for example, -CONH2, mono-C1-C6 alkylaminocarbonyl, di-C1-C6 alkylaminocarbonyl, N-C1-C6 alkyl-N-C2-C6 alkenylaminocarbonyl, N-C1-C6 alkyl-N-C1-C6 alkoxy-C1-C6 alkylaminocarbonyl, and 4- to 9-membered cyclic aminocarbonyl groups. Specific examples of aminocarbonyl groups include -CONH2, methylaminocarbonyl, ethylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, 1-azacyclobutylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, 1-piperazinylcarbonyl, 4-morpholinylcarbonyl, and 3-oxazolylalkylcarbonyl.

[0197] As used herein, "aminoalkyl" is a group in which one or more hydrogen atoms of an alkyl group as defined herein are substituted with an amino group. Preferably, an aminoalkyl group is a group in which one hydrogen atom of an alkyl group is substituted with an amino group. An aminoalkyl group is, for example, an amino C1-C... 20 Alkyl, preferably amino C1-C 10 Alkyl, more preferably amino C1-C8 alkyl, most preferably amino C1-C6 alkyl. Specific examples of aminoalkyl include aminomethyl, aminoethyl, 4-aminobutyl, methylaminomethyl, dimethylaminomethyl, methylaminoethyl, and dimethylaminoethyl.

[0198] As used herein, "cycloalkylalkyl" is a group in which one or more hydrogen atoms of an alkyl group as defined herein are substituted with a cycloalkyl group. Preferably, a cycloalkylalkyl group is a group in which one hydrogen atom of an alkyl group is substituted with a cycloalkyl group. A cycloalkylalkyl group is, for example, C3-C4. 10 cycloalkyl-C1-C 20 Alkyl, preferably C3-C 10Cycloalkyl-C1-C6 alkyl, more preferably C3-C8 cycloalkyl-C1-C6 alkyl, and most preferably C3-C6 cycloalkyl-C1-C2 alkyl. Specific examples of cycloalkyl alkyl groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, and cyclohexylpropyl.

[0199] As used herein, “cycloalkoxyalkyl” is a group in which one or more hydrogen atoms of an alkyl group as defined herein are substituted with a cycloalkoxy group. Cycloalkoxyalkyl is preferably a group in which one hydrogen atom of an alkyl group is substituted with a cycloalkoxy group. Cycloalkoxyalkyl is, for example, C3-C4. 10 Cycloalkoxy-C1-C6 alkyl, preferably C3-C8 cycloalkoxy-C1-C6 alkyl, more preferably C3-C7 cycloalkoxy-C1-C6 alkyl, and most preferably C3-C6 cycloalkoxy-C1-C6 alkyl. Specific examples of cycloalkoxyalkyl include cyclopropoxymethyl, cyclobutoxymethyl, and cyclopentyloxymethyl.

[0200] As used herein, “heterocyclic alkyl” is a group in which one or more hydrogen atoms of an alkyl group as defined herein are substituted with a “heterocyclic group”. Heterocyclic alkyl is preferably a group in which one hydrogen atom of an alkyl group is substituted with a heterocyclic group. Heterocyclic alkyl is, for example, a 3- to 14-membered heterocyclic-C1-C6 alkyl, preferably a 3- to 12-membered heterocyclic-C1-C6 alkyl, more preferably a 3- to 10-membered heterocyclic-C1-C4 alkyl, and most preferably a 4- to 7-membered heterocyclic-C1-C3 alkyl. Specific examples of heterocyclic alkyl include azirmonobutane-1-ylmethyl, oxadienobutane-3-ylmethyl, 2-(tetrahydrofuran-3-yl)ethyl, (1-methylpyrrolidone-3-yl)methyl, 2-morpholinoethyl, 3-(1-piperidinyl)propyl, and 3-(4-methylpiperazin-1-yl)propyl.

[0201] As used herein, "alkylthioalkyl" is a group in which one or more hydrogen atoms of an alkyl group as defined herein are substituted with an alkylthio group. Alkylthioalkyl is preferably a group in which one hydrogen atom of an alkyl group is substituted with an alkylthio group. Alkylsulfonylalkyl is, for example, C1-C1. 20 Alkylthio-C1-C4 alkyl, preferably C1-C 10 Alkylthio-C1-C4 alkyl, more preferably C1-C8 alkylthio-C1-C4 alkyl, and most preferably C1-C6 alkylthio-C1-C6 alkyl. Specific examples of alkylthioalkyl include methylthiomethyl, ethylthiomethyl, 1-propylthiomethyl, 2-propylthiomethyl, n-butylthiomethyl, isobutylthiomethyl, sec-butylthiomethyl, and tert-butylthiomethyl.

[0202] As used herein, "alkylsulfinylalkyl" is a group in which one or more hydrogen atoms of an alkyl group as defined herein are substituted with an alkylsulfinyl group. Alkylsulfinylalkyl is preferably a group in which one hydrogen atom of an alkyl group is substituted with an alkylsulfinyl group. Alkylsulfinylalkyl is, for example, C1-C1. 20 alkylsulfinyl-C1-C4 alkyl, preferably C1-C 10 Alkylsulfinyl-C1-C4 alkyl, more preferably C1-C8 alkylsulfinyl-C1-C4 alkyl, and most preferably C1-C6 alkylsulfinyl-C1-C6 alkyl. Specific examples of alkylsulfinyl alkyl include methylsulfinylmethyl, ethylsulfinylmethyl, 1-propylsulfinylmethyl, 2-propylsulfinylmethyl, n-butylsulfinylmethyl, isobutylsulfinylmethyl, sec-butylsulfinylmethyl, and tert-butylsulfinylmethyl.

[0203] As used herein, “heteroarylalkyl” is a group in which one or more hydrogen atoms of an alkyl group as defined herein are substituted with a “heteroaryl” group. Heteroarylalkyl is preferably a group in which one hydrogen atom of an alkyl group is substituted with a heteroaryl group. Heteroarylalkyl is, for example, a 5- to 10-membered heteroaryl-C1-C6 alkyl, preferably a 5- to 10-membered heteroaryl-C1-C4 alkyl, more preferably a 5- to 10-membered heteroaryl-C1-C3 alkyl, and most preferably a 5- to 10-membered heteroaryl-C1-C2 alkyl. Specific examples of heteroarylalkyl include 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-furanylmethyl, 2-thienylmethyl, 3-thienylmethyl, and 4-thiazolylmethyl.

[0204] As used herein, “heteroarylalkoxy” is a group in which the alkyl portion of “heteroarylalkyl” as defined herein is attached to an oxygen atom. Heteroarylalkoxy is, for example, a 5- to 10-membered heteroaryl-C1-C6 alkoxy, preferably a 5- to 10-membered heteroaryl-C1-C4 alkoxy, more preferably a 5- to 10-membered heteroaryl-C1-C3 alkoxy, and most preferably a 5- to 10-membered heteroaryl-C1-C2 alkoxy. Specific examples of heteroarylalkoxy include 2-pyridylmethoxy, 3-pyridylmethoxy, 4-pyridylmethoxy, 2-furanylmethoxy, 2-thienylmethoxy, 3-thienylmethoxy, and 4-thiazolylmethoxy.

[0205] As used herein, "alkoxyalkyl" is a group in which one or more hydrogen atoms of an alkyl group as defined herein are substituted with an alkoxy group. Alkoxyalkyl is preferably a group in which one hydrogen atom of an alkyl group is substituted with an alkoxy group. Alkoxyalkyl is, for example, C1-C6 alkoxy-C1-C 20 Alkyl, preferably C1-C6 alkoxy-C1-C 15 Alkyl, more preferably C1-C6 alkoxy-C1-C 10 Alkyl, most preferably C1-C6 alkoxy-C1-C6 alkyl. Specific examples of alkoxyalkyl include methoxymethyl, ethoxymethyl, 1-propoxymethyl, 2-propoxymethyl, n-butoxymethyl, isobutoxymethyl, sec-butoxymethyl, tert-butoxymethyl, pentoxymethyl, 3-methylbutoxymethyl, 1-methoxyethyl, 2-methoxyethyl, and 2-ethoxyethyl.

[0206] As used herein, “heteroarylalkoxyalkyl” means a group in which one or more hydrogen atoms of an alkyl group as defined herein are substituted with a “heteroarylalkoxy” as defined herein. A heteroarylalkoxyalkyl group is preferably a group in which one hydrogen atom of an alkyl group is substituted with a heteroarylalkoxy. A heteroarylalkoxyalkyl group is, for example, a 5- to 10-membered heteroaryl-C1-C6 alkoxy-C1-C6 alkyl, preferably a 5- to 10-membered heteroaryl-C1-C4 alkoxy-C1-C6 alkyl, more preferably a 5- to 10-membered heteroaryl-C1-C3 alkoxy-C1-C6 alkyl, and most preferably a 5- to 10-membered heteroaryl-C1-C2 alkoxy-C1-C6 alkyl. Specific examples of heteroarylalkoxyalkyl groups include 2-pyridylmethoxymethyl, 3-pyridylmethoxymethyl, 4-pyridylmethoxymethyl, 2-furanylmethoxymethyl, 2-thienylmethoxymethyl, 3-thienylmethoxymethyl, and 4-thiazolylmethoxymethyl.

[0207] As used herein, "alkylene" means a divalent group derived by removing any hydrogen atom from an "alkyl" as defined herein. Alkylenes are preferably C1-C8 alkylenes, more preferably C1-C3 alkylenes. Examples of alkylenes specifically include -CH2-, -(CH2)2-, -(CH2)3-, -CH(CH3)CH2-, -C(CH3)2-, -(CH2)4-, -CH(CH3)CH2CH2-, -C(CH3)2CH2-, -CH2CH(CH3)CH2-, -CH2C(CH3)2-, -CH2CH2CH(CH3)-, -CH2CH(CH2CH3)-, -(CH2)5-, -CH(CH3)CH(CH2CH3)-, -(CH2)6-, -(CH2)7-, and -(CH2)8-.

[0208] As used herein, a "peptide compound" means a compound in which two or more amino acid residues are linked by an amide bond. As long as two or more amino acids are linked by an amide bond, the peptide chain may contain another bond, such as an ester bond or a thioester bond. Examples of the number of amino acid residues contained in a peptide include 5 to 30 residues. Peptides can be linear, branched, or cyclic.

[0209] As used herein, a peptide chain refers to the chain-like portion of a peptide in which two or more amino acid residues are linked by amide bonds. A peptide chain may contain another bond, such as an ester bond or a thioester bond, as long as the two or more amino acids are linked by amide bonds. Examples of the number of amino acid residues contained in a peptide chain range from 5 to 30 residues.

[0210] As used herein, "optionally substituted" means that a group and / or an atom may be substituted with optional substituents and / or optional atoms. That is, it encompasses two states: a state in which a particular group and a particular atom are not substituted with any optional substituents or optional atoms, and a state in which a particular group and / or a particular atom are substituted with optional substituents and / or optional atoms. Each of the group and / or the atom may be further substituted with optional substituents and / or optional atoms. The group and optional substituents are not limited and may be freely selected, for example, from groups containing atoms selected from the group consisting of: hydrogen, halogen, carbon, oxygen, sulfur, nitrogen, boron, silicon, and phosphorus. The atom and optional atoms are not limited and may be freely selected, for example, from halogen, carbon, oxygen, sulfur, nitrogen, boron, silicon, and phosphorus. Examples of optional substituents include alkyl, alkoxy, fluoroalkyl, fluoroalkoxy, oxo, aminocarbonyl, alkylsulfonyl, alkylsulfonylamino, cycloalkyl, aryl, heteroaryl, heterocyclic, arylalkyl, heteroarylalkyl, halogen, nitro, amino, monoalkylamino, dialkylamino, cyano, carboxyl, alkoxycarbonyl, and formyl.

[0211] As used herein, the term "optionally protected" means that the group can be protected by any protecting group.

[0212] As used herein, examples of "protecting groups against a carboxyl group" include alkyl ester protecting groups, benzyl ester protecting groups, substituted alkyl ester protecting groups, and alkenyl ester protecting groups. Specific examples of protecting groups against a carboxyl group include methyl groups, ethyl groups, tert-butyl groups, benzyl groups, triphenylmethyl groups, cumyl groups, methoxytriphenylmethyl groups, 2-(trimethylsilyl)ethyl groups, 2,2,2-trichloroethyl groups, and allyl groups.

[0213] As used herein, examples of "protecting groups against amide groups" include phenylamide-type protecting groups, alkylamide-type protecting groups, alkenylamide-type protecting groups, benzylamide-type protecting groups, and alkoxyalkylamide-type protecting groups. Specific examples of protecting groups against amide groups include phenyl groups, tert-butyl groups, allyl groups, benzyl groups, 4-methoxybenzyl groups, triphenylmethyl groups, cumyl groups, methoxymethyl groups, and benzyloxymethyl groups.

[0214] As used herein, examples of "protecting groups against an amino group" include urethane protecting groups, amide protecting groups, arylsulfonamide protecting groups, alkylamine protecting groups, and imide protecting groups. Specific examples of urethane protecting groups include Fmoc, Troc, TSoc, BIBSoc, IPCSoc, BBSoc, CHBSoc, CDBSoc, Boc, Alloc, Cbz, and Teoc groups. Examples of amide protecting groups include pentafluoropropionyl, trifluoroacetyl, acetyl, and benzoyl groups. Examples of arylsulfonamide protecting groups include benzenesulfonyl, 2-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl, p-toluenesulfonyl, nitrobenzenesulfonyl, and dinitronitrobenzenesulfonyl. Examples of alkylamine groups include tert-butyl and triphenylmethyl groups. Examples of imide protecting groups include phthaloyl groups.

[0215] As used herein, “one or more” means one or two or more. When “one or more” is used in a context relating to substituents of a group, the term means a quantity from one to the maximum number of substituents permitted for that group. Specifically, “one or more” includes, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and / or more.

[0216] The compounds described herein, or their salts, may be solvates thereof. Examples of salts of such compounds include: hydrochlorides; hydrobroms; hydroiodates; phosphates; phosphonates; sulfates; sulfonates, such as methanesulfonates, p-toluenesulfonates, and trifluoromethanesulfonates; carboxylates, such as acetates, citrates, maleates, tartrates, succinates, and salicylates; alkali metal salts, such as sodium and potassium salts; alkaline earth metal salts, such as magnesium and calcium salts; and ammonium salts, such as ammonium salts, alkylammonium salts, dialkylammonium salts, trialkylammonium salts, and tetraalkylammonium salts. These salts may be generated, for example, by contacting the compound with an acid or a base. As used herein, a solvate means a molecular aggregate formed by a compound and a solvent, and is not particularly limited, provided that it is a solvate formed by a solvent acceptable for uptake when administered with a drug. Specific examples of solvates include not only solvates formed with a single solvent such as water, alcohol (ethanol, methanol, 1-propanol, 2-propanol, etc.) or dimethyl sulfoxide, but also solvates formed by multiple solvents per molecule of the compound, or solvates formed by multiple types of solvents per molecule of the compound. For example, a solvate formed by the compound and water is called a hydrate. A hydrate is preferred as a solvate of the compound of the present invention. Specifically, the hydrate is preferably 1 to 20 hydrates, more preferably 1 to 10 hydrates, further preferably 1 to 5 hydrates, and most preferably 1 to 3 hydrates.

[0217] As used herein, “amino acid” includes both natural and non-natural amino acids (sometimes referred to as amino acid derivatives). As used herein, “amino acid” can refer to an amino acid residue. As used herein, “natural amino acid” is any L-amino acid selected from the following: Glycine, L-Ala, L-Ser, L-Thr, L-Val, L-Leu, L-Ile, L-Phe, L-Tyr, L-Trp, L-His, L-Glutamic acid, L-Asp, L-Glutamine, L-Asn, L-Cys, L-Met, L-Lys, L-Arg, or L-Pro. As used herein, “non-natural amino acid” is an amino acid other than a natural amino acid. Examples of non-natural amino acids include β-amino acids, γ-amino acids, D-type amino acids, N-substituted amino acids (except Pro), α,α-disubstituted amino acids, and amino acids having side chains different from those of natural amino acids. As amino acids herein, amino acids having any conformation are acceptable. There are no particular limitations on the side chains of amino acids, and each side chain is freely selected from groups such as alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaryl, cycloalkyl, or spiro-bonded cycloalkyl, and / or atoms such as hydrogen atoms. Each group and / or atom may further optionally be substituted. In a non-limiting aspect, amino acids as used herein can be compounds having a carboxyl group and an amino group in the same molecule. Even in this case, compounds in which the nitrogen atom of the amino group of the amino acid and any atom of the side chain together form a ring (such as proline, hydroxyproline, and azircyclobutane-2-carboxylic acid) are included in amino acids.

[0218] The main chain amino group of an amino acid can be unsubstituted (i.e., an NH2 group) or substituted (i.e., a -NHR group, where R represents an alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or cycloalkyl group optionally having a substituent, and one or both non-adjacent methylene groups of any of these groups can be substituted with an oxygen atom, a carbonyl group (-CO-), or a sulfonyl group (-SO2-); and the carbon chain bonded to the N atom and the carbon atom at the α-position can form a ring, as in proline). The substituents of R are selected in the same manner as those for the substituents of the amino acid side chains described above. In the case of a substituted main chain amino group, R is included in "the side chain of the amino acid" as used herein. Such amino acids having substituted skeletal amino groups are referred to herein as "N-substituted amino acids." Examples of "N-substituted amino acids" in this specification preferably include, but are not limited to, N-alkyl amino acids, N-C1-C6 alkyl amino acids, N-C1-C4 alkyl amino acids, and N-methyl amino acids.

[0219] As used herein, “amino acid” includes all isotopes corresponding to each amino acid. An isotope of an amino acid is one in which at least one atom is replaced by atoms having the same atomic number (number of protons) but different mass numbers (total number of protons and neutrons) at an abundance ratio different from that of the natural amino acid. Examples of isotopes contained in “amino acid” herein include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine atoms, and they each include… 2 H, 3 H, 13 C 14 C 15 N、 17 O、 18 O、 32 P, 35 S, 18 F, 36 Cl, etc. For compounds as used herein, all compounds containing radioactive or non-radioactive isotopic elements in any proportion are covered within the scope of this invention.

[0220] As used herein, a “liquid-phase synthesis method” is a method in which a compound undergoes a chemical reaction in a liquid phase (solution) to synthesize a desired compound without using a solid-phase support. In liquid-phase synthesis methods for peptides, amino acids and peptides not bound to a solid-phase support can be used. Liquid-phase synthesis methods for peptides also include the following steps as liquid-phase synthesis methods: during the peptide synthesis reaction, a desired peptide chain is bound to a functional group (tag) to dissolve the peptide in a solvent; and during the separation of the desired peptide, a poor solvent is added to separate the peptide as a solid while the desired peptide chain is bound to the tag (this method may also be called a liquid-phase tagging method or a tagging method). Examples of liquid-phase labeling methods include the following methods using hydrophobic labels (see examples: Y. Okada, H. Suzuki, T. Nakae, S. Fujita, H. Abe, K. Nagano, T. Yamada, N. Ebata, S. Kim and K. Chiba, Tag-Assisted Liquid-Phase Peptide Synthesis Using Hydrophobic Benzyl Alcohols as Supports, J. Org. Chem., 2013, 78, 320-327, or S. Yano et al., Molecules 2021, 26 (12), 3497).

[0221] As used herein, examples of "halogen-derived substituents" include fluorine (-F), chlorine (-Cl), bromine (-Br), and iodine (-I).

[0222] As used herein, examples of "substituents containing oxygen atoms" include hydroxyl (-OH), oxy group (-OR), oxo (=O), carbonyl (-C(=O)-R), carboxyl (-CO2H), oxycarbonyl (-C(=O)-OR), carbonyloxy group (-OC(=O)-R), thiocarbonyl (thiocarbonyl) (-C(=O)-SR), carbonylthio (carbonylthio) group (-SC(=O)-R), aminocarbonyl (-C(=O)-NHR), carbonylamino (-NH-C(=O)-R), oxycarbonylamino (-NH-C(=O)-OR), sulfonylamino (-NH-S(O)2-R), aminosulfonyl (-S(O)2-NHR), aminosulfonylamino (-NH-S(=O)2-NHR), thiocarboxyl (thiocarboxyl) (-C(=O)-SH) And carboxyl carbonyl group (-C(=O)-CO2H).

[0223] Examples of alkoxy groups (-OR) include alkoxy, cycloalkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, and arylalkoxy. Alkoxy groups are preferably C1-C4 alkoxy, C1-C2 alkoxy, and particularly preferably methoxy or ethoxy.

[0224] Examples of carbonyl groups (-C(=O)-R) include formyl (-C(=O)-H), alkyl carbonyl, cycloalkyl carbonyl, alkenyl carbonyl, alkynyl carbonyl, aryl carbonyl, heteroaryl carbonyl, and aralkyl carbonyl.

[0225] Examples of oxycarbonyl groups (-C(=O)-OR) include alkyloxycarbonyl, cycloalkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, and aralkyloxycarbonyl.

[0226] Examples of carbonyloxy groups (-OC(=O)-R) include alkyl carbonyloxy groups, cycloalkyl carbonyloxy groups, alkenyl carbonyloxy groups, alkynyl carbonyloxy groups, aryl carbonyloxy groups, heteroaryl carbonyloxy groups, and aralkyl carbonyloxy groups.

[0227] Examples of thiocarbonyl (also known as thiocarbonyl) (-C(=O)-SR) include alkylthiocarbonyl, cycloalkylthiocarbonyl, alkenylthiocarbonyl, alkynylthiocarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl and aralkylthiocarbonyl.

[0228] Examples of carbonyl thio (also known as carbonyl thio) (-SC(=O)-R) include alkyl carbonyl thio, cycloalkyl carbonyl thio, alkenyl carbonyl thio, alkynyl carbonyl thio, aryl carbonyl thio, heteroaryl carbonyl thio, and aralkyl carbonyl thio.

[0229] Examples of aminocarbonyl groups (-C(=O)-NHR) include alkylaminocarbonyl groups (e.g., C1-C6 or C1-C4 alkylaminocarbonyl groups, specifically ethylaminocarbonyl or methylaminocarbonyl groups), cycloalkylaminocarbonyl groups, alkenylaminocarbonyl groups, alkynylaminocarbonyl groups, arylaminocarbonyl groups, heteroarylaminocarbonyl groups, and aralkylaminocarbonyl groups. Further examples include groups in which the H atom bonded to the N atom in -C(=O)-NHR is further substituted with an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl group.

[0230] Examples of carbonylamino groups (-NH-C(=O)-R) include alkylcarbonylamino, cycloalkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, and aralkylcarbonylamino. Additional examples include groups in which the H atom bonded to the N atom in -NH-C(=O)-R is further substituted with an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl group.

[0231] Examples of oxycarbonylamino groups (-NH-C(=O)-OR) include alkoxycarbonylamino, cycloalkoxycarbonylamino, alkenoxycarbonylamino, alkynoxycarbonylamino, aryloxycarbonylamino, heteroaryloxycarbonylamino, and arylalkoxycarbonylamino. Additional examples include groups in which the H atom bonded to the N atom in -NH-C(=O)-OR is further substituted with an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl group.

[0232] Examples of sulfonylamino (-NH-SO2-R) include alkylsulfonylamino, cycloalkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, and aralkylsulfonylamino. Additional examples include groups in which the H atom bonded to the N atom in -NH-SO2-R is further substituted with an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl group.

[0233] Examples of aminosulfonyl (-SO2-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 -SO2-NHR is further substituted with an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl group.

[0234] Examples of aminosulfonylamino (-NH-SO2-NHR) include alkylaminosulfonylamino, cycloalkylaminosulfonylamino, alkenylaminosulfonylamino, alkynylaminosulfonylamino, arylaminosulfonylamino, heteroarylaminosulfonylamino, and aralkylaminosulfonylamino. Further, the two H atoms bonded to the N atom in -NH-SO2-NHR are optionally substituted with substituents independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl groups, and the two substituents may form a ring comprising the nitrogen atom to which they are attached.

[0235] As used herein, examples of "substituents containing sulfur atoms" include thiols (-SH), thio (thio(-SR)), sulfinyl (-S(=O)-R), sulfonyl (-S(=O)2-R), sulfonyl (-SO3H), pentafluorothio (-SF5), and dithio (-SSR).

[0236] Examples of thio groups (thio(-SR)) include alkylthio, cycloalkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, and aralkylthio.

[0237] Examples of thioyl (-S(=O)-R) groups include alkyl sulfinyl, cycloalkyl sulfinyl, alkenyl sulfinyl, alkynyl sulfinyl, aryl sulfinyl, heteroaryl sulfinyl, and aralkyl sulfinyl.

[0238] Examples of sulfonyl groups (-S(=O)2-R) include alkylsulfonyl, cycloalkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heteroarylsulfonyl, and aralkylsulfonyl.

[0239] As used herein, examples of "nitrogen-containing substituents" include azide (-N3, also known as "azide group"), cyano (-CN), primary amino (-NH2), secondary amino (-NH-R), tertiary amino (-NR(R')), amido (-C(=NH)-NH2), substituted amido (-C(=NR)-NR'R''), guanidino (-NH-C(=NH)-NH2), substituted guanidino (-NR-C(=NR''')-NR'R''), and aminocarbonylamino (-NR-CO-NR'R'').

[0240] Examples of secondary amino groups (-NH-R) include alkylamino, cycloalkylamino, alkenylamino, alkynylamino, arylamino, heteroarylamino, and aralkylamino.

[0241] Examples of tertiary amino groups (-NR(R')) include amino groups having any two substituents independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, etc., such as alkyl (aralkyl)amino, and the two substituents may form a ring including the nitrogen atom to which they are attached.

[0242] Examples of substituted amidoyl groups (C(=NR)-NR'R'') include those in which the three substituents R, R', and R'' on the N atom are each independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl groups, such as alkyl(aralkyl)(aryl)amidinyl.

[0243] Examples of substituted guanidino groups (-NR-C(=NR''')-NR'R'') include groups in which R, R', R'' and R''' are each independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and aralkyl groups, and groups in which these substituents form a ring including the nitrogen atom to which they are attached.

[0244] Examples of aminocarbonylamino (-NR-CO-NR'R'') include groups in which R, R', and R'' are each independently selected from hydrogen atoms, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl groups, and groups in which these substituents form a ring including the nitrogen atom to which they are attached.

[0245] As used in this article, the "amino acid residues" that make up peptide compounds are sometimes simply referred to as "amino acids".

[0246] As used in this article, "to" indicates a range of values ​​that includes both ends of the range. For example, "A to B" means a range of values ​​where A is greater than or equal to B.

[0247] As used in this article, when used in conjunction with a numerical value, the term “approximately” means a range of values ​​between +10% and -10% of that value.

[0248] As used herein, the term “and / or” is intended to include all combinations of the appropriate combinations of the terms “and” and “or”. Specifically, for example, the term “A, B and / or C” includes the following seven variations: (i) A, (ii) B, (iii) C, (iv) A and B, (v) A and C, (vi) B and C, and (vii) A, B and C.

[0249] Method for producing the compound or salt thereof represented by formula (1)

[0250] In one aspect, the present invention relates to a method for producing a compound represented by formula (1) or a salt thereof. The method includes the step of contacting the compound represented by formula (2) or a salt thereof with a catalyst (metathesis step):

[0251] [Formula 8]

[0252]

[0253] Where R 1 R 2 R 3 R 4 , n and X are respectively related to R in the above [1]. 1 R 2 R 3 R 4 , n and X have the same meaning.

[0254] In one aspect, the catalyst used in the metathesis step is a metal-alkylene complex. Examples of metal-alkylene complexes include ruthenium-alkylene complexes, molybdenum-alkylene complexes, and tungsten-alkylene complexes, with ruthenium-alkylene complexes being preferred. When the catalyst is a ruthenium-alkylene complex, it preferably contains phosphine and / or N-heterocyclic carbene as ligands.

[0255] Specific examples of catalysts used in the metathesis step include: first-generation Grubbs catalyst (dichloro(benzyl)bis(tricyclohexylphosphine)ruthenium(II)), second-generation Grubbs catalyst (dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidine](benzyl)(tricyclohexylphosphine)ruthenium(II)), third-generation Grubbs catalyst (dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidine](benzyl)bis(3-bromopyridine)ruthenium(II)), Stewart-Grubbs catalyst (dichloro[1,3-bis(2-methylphenyl)-2-imidazolidine](2-isopropoxyphenylmethylene)ruthenium(II)), nitro-Grela Catalysts (dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinedimethyl][(2-isopropoxy-5-nitrobenzyl)]ruthenium(II)), Zhan Catalyst-1B (dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinedimethyl][[5-[(dimethylamino)sulfonyl]-2-(1-methylethoxy-O)phenyl]methylene-C]ruthenium(II)), Zhan Catalyst-1C ({[2-(isopropoxy)-5-(N,N-dimethylaminosulfonyl)phenyl]methylene}(tricyclohexylphosphine)dichlororuthenium(II)), first-generation Hoveyda-Grubbs catalyst (dichloro(2-isopropoxyphenylmethylene)(tricyclohexylphosphine)ruthenium), second-generation Hoveyda-Grubbs catalyst Catalysts ((1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinedimethyl)dichloro(o-isopropoxyphenylmethylene)ruthenium), [1,3-bis-(2,6-isopropylphenyl)-2-imidazolidinedimethyl]dichloro(2-isopropoxybenzyl)ruthenium(II), bis[1-(2,6-diethylphenyl)-3,5,5-trimethyl-3-phenylpyrrolidine-2-yl](3-phenyl-1H-inden-1-yl)ruthenium chloride, [1-(2,6-diethylphenyl)-3,5,5-trimethyl-3-phenylpyrrolidine-2-yl](2-isopropoxy-5-nitrobenzyl)ruthenium(II) chloride Or [1-[2,4,6-trimethylphenyl]-3,5,5-trimethyl-3-phenyl-2-pyrrolinoside]dichloro(2-isopropoxybenzylidene)ruthenium(II).Among them, the preferred catalysts are the first-generation Hoveyda-Grubbs catalyst (dichloro(2-isopropoxyphenylmethylene)(tricyclohexylphosphine)ruthenium), the second-generation Hoveyda-Grubbs catalyst ((1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinedimethyl)dichloro(o-isopropoxyphenylmethylene)ruthenium) or [1-[2,4,6-trimethylphenyl]-3,5,5-trimethyl-3-phenyl-2-pyrrolidinedimethyl]dichloro(2-isopropoxybenzylidene)ruthenium(II).

[0256] The amount of catalyst used in the metathesis step is not particularly limited, and the amount is, for example, 0.001 molar equivalent to 0.5 molar equivalent, preferably 0.003 molar equivalent to 0.3 molar equivalent, and more preferably 0.05 molar equivalent to 0.1 molar equivalent relative to the compound represented by formula (2).

[0257] In one respect, the compound represented by formula (2) or a salt thereof is a salt of the compound represented by formula (2). The salt of the compound represented by formula (2) is preferably a salt formed with a Bronsted acid having a pKa of 3 or less. Examples of salts include hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, p-toluenesulfonate, trifluoromethanesulfonate, or trifluoroacetate. Among these, hydrochloride is preferred.

[0258] In one aspect, the compound represented by formula (2) or a salt thereof is a compound represented by formula (2), and an acid is used in the metathesis step. The acid used is preferably a Bronsted acid having a pKa of 3 or less, or a Lewis acid, and more preferably a Lewis acid. Examples of Bronsted acids having a pKa of 3 or less include hydrogen chloride, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, or trifluoroacetic acid. Among these, hydrogen chloride is preferred. Examples of Lewis acids include boron trihalides, their solvated complexes (e.g., boron trifluoride-tetrahydrofuran complex and boron trifluoride-diethyl ether complex), titanium tetrahalides (e.g., titanium tetrachloride and titanium tetrabromide), and titanium tetraalkoxy (e.g., titanium tetraisopropoxy and titanium tetrabutoxy). Among these, boron trifluoride-tetrahydrofuran complex or boron trifluoride-diethyl ether complex is preferred.

[0259] When a Bronsted acid with a pKa of 3 or less is used in the metathesis step, its amount is not particularly limited, and relative to the compound represented by formula (2), the amount is, for example, 0.1 molar equivalent to 10.0 molar equivalent, preferably 1.0 molar equivalent to 3.0 molar equivalent, more preferably 1.0 molar equivalent to 2.0 molar equivalent, and still more preferably 1.0 molar equivalent to 1.5 molar equivalent.

[0260] When a Lewis acid is used in the metathesis step, its amount is not particularly limited, and the amount is, for example, 0.1 molar equivalent to 10.0 molar equivalent, preferably 1.0 molar equivalent to 3.0 molar equivalent, more preferably 1.0 molar equivalent to 2.0 molar equivalent, and still more preferably 1.0 molar equivalent to 1.5 molar equivalent, relative to the compound represented by formula (2).

[0261] In one aspect, alcohols and / or bronsted acids are further used as additives in the metathesis step, and the pKa of the additives is 4 to 17. As used herein, “pKa” can be measured using water as a solvent. The pKa used herein can be a measurement already reported as pKa when using water as a solvent. In this case, the value from a measurement taken at 25°C is applied as the pKa measurement. When a pKa measurement is unavailable, pKa can be calculated using ADMETPredictor (Simulations Plus Inc., version 8.0) and is used as pKa herein. Examples of alcohols among additives having pKas of 4 to 17 include 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), 2-propanol, methanol, and 2,2,2-trifluoroethanol (TFE). Examples of bronsted acids among additives having pKas of 4 to 17 include acetic acid. Among the additives, 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) or acetic acid are preferred.

[0262] When alcohols and / or bronsted acids are used as additives in the metathesis step, their amounts are not particularly limited, and the amount is, for example, 0.1 mL to 100 mL per g of the compound represented by formula (2), and preferably 2 mL to 10 mL.

[0263] In one aspect, the metathesis step is carried out via a liquid-phase synthesis method. The solvents used in the liquid-phase synthesis method include at least one selected from the group consisting of: ketone-based solvents, nitrile-based solvents, halogen-based solvents, ether-based solvents, amide-based solvents, ester-based solvents, aromatic hydrocarbon-based solvents, aliphatic hydrocarbon-based solvents, and carbonate-based solvents. Specific examples of ketone-based solvents include acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, cyclopentanone, and diethyl ketone. Specific examples of nitrile-based solvents include acetonitrile and propionitrile. Specific examples of halogen-based solvents include dichloromethane, chloroform, and 1,2-dichloroethane. Specific examples of ether-based solvents include diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentylmethyl ether, 4-methyltetrahydropyran, 1,3-dioxolane, 1,4-dioxane, 1,2-dimethoxyethane, diisopropyl ether, methyl tert-butyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, anisole, and tetraethylene glycol dimethyl ether. Specific examples of amide-based solvents include N,N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), N,N-dimethylacetamide (DMA), N-ethyl-2-pyrrolidone (NEP), N-butyl-2-pyrrolidone (NBP), 1,3-dimethyl-2-imidazolium ketone (DMI), and formamide. Specific examples of ester-based solvents include methyl acetate, ethyl acetate, methyl propionate, butyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, amyl acetate, and γ-valerolactone. Specific examples of solvents based on aromatic hydrocarbons include toluene, o-xylene, m-xylene, p-xylene, mesitylene, chlorobenzene, fluorobenzene, and anisole. Specific examples of solvents based on aliphatic hydrocarbons include pentane, hexane, heptane, octane, and cyclohexane. Specific examples of solvents based on carbonates include dimethyl carbonate, diethyl carbonate, and dibutyl carbonate. The solvent used in the cyclization step is preferably one or more of the group consisting of: acetone, methyl tert-butyl ether, dimethyl carbonate, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, tetrahydrofuran, ethyl acetate, isopropyl acetate, dichloromethane, 1,2-dichloroethane, toluene, chlorobenzene, heptane, and cyclohexane, more preferably one or more of the group consisting of: acetone, methyl tert-butyl ether, dimethyl carbonate, ethyl acetate, toluene, and dichloromethane, still more preferably acetone or toluene, and most preferably acetone.

[0264] When the metathesis step is performed by liquid-phase synthesis, the concentration of the compound represented by formula (2) or its salt is 0.01 mol / L to 0.3 mol / L, preferably 0.02 mol / L to 0.3 mol / L, and more preferably 0.033 mol / L to 0.3 mol / L, relative to the solvent used in the liquid-phase synthesis method.

[0265] On one hand, the metathesis step can be carried out by stirring the reaction mixture at a reaction temperature of 20°C to 100°C, and preferably 30°C to 70°C. The reaction temperature can be the temperature of the reaction mixture in the reaction vessel (internal temperature) or the set temperature of the temperature control device for the reaction vessel (external temperature). The metathesis step can be carried out by stirring the reaction mixture for 10 minutes to 10 hours, preferably 1 hour to 6 hours, and more preferably 1 hour to 4 hours.

[0266] When the metathesis step is carried out by a liquid-phase synthesis method, the reaction mixture can be prepared by any of the following (a) to (d):

[0267] (a) A mixture of a compound represented by formula (2) or its salt, a catalyst, an acid, an additive and a solvent is prepared by adding a solvent mixture containing a compound represented by formula (2) or its salt to a solvent mixture containing a catalyst;

[0268] (b) A mixture of a compound represented by formula (2) or its salt, a catalyst, an acid, an additive and a solvent is prepared by adding a solvent mixture containing a compound represented by formula (2) or its salt to a solvent mixture containing a heated catalyst;

[0269] (c) A mixture of a compound represented by formula (2) or a salt thereof, a catalyst, an acid, an additive, and a solvent is prepared by adding a solvent mixture containing a catalyst to a solvent mixture containing a compound represented by formula (2) or a salt thereof; and

[0270] (d) A mixture is prepared by adding a solvent to a compound represented by formula (2) or a salt thereof, and then adding a catalyst, an acid and an additive.

[0271] On one hand, the compound represented by formula (2) or its salt is obtained by condensing the compound represented by formula (6) and the compound represented by formula (7), and then deprotecting the urethane protecting group.

[0272] [Formula 9]

[0273]

[0274] Where R 2 R 3 R 4 , n and X are respectively related to R in the above [1]. 2 R 3 R 4 , n and X have the same meaning, and X2 It is a urethane protecting group.

[0275] The condensation reaction of the compound represented by formula (6) and the compound represented by formula (7) can be carried out, for example, during solid-phase synthesis and / or liquid-phase synthesis using condensation reagents and / or bases, and preferably during liquid-phase synthesis.

[0276] The condensing reagents and bases used in the condensation reaction and their amounts are not particularly limited, but the condensing reagents and bases commonly used in peptide synthesis and their amounts are preferred (see, for example, Peptide Coupling Reagents, More than a Letter Soup (Chem. Rev. 2011, 111, 6557-6602.)). When no condensing reagent is used in the condensation reaction, compounds in which the carboxyl groups have been pre-converted to active esters, etc., can be used.

[0277] Specific examples of condensing reagents 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), ethyl 2-cyano-2-(hydroxyimino)acetate (oxyma), and 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (HOOBt). Or HODhbt), N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), 2,3,4,5,6-pentafluorophenol (HOPfp), N-hydroxysuccinimide (HOSu), 6-chloro-1-hydroxy-1H-benzotriazole (Cl-HOBt), O-(1H-benzotriazole-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HBTU), O-(7-aza-1H-benzotriazole-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), N-[1 -(cyano-2-ethoxy-2-oxoethyleneaminooxy)dimethylamino(morpholino)] hexafluorophosphate (COMU), O-[(ethoxycarbonyl)cyanoethyleneamino]-N,N,N',N'-tetramethylurea hexafluorophosphate (HOTU), O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethylurea tetrafluoroborate (TBTU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea tetrafluoroborate (TATU), [ethylcyano(hydroxyimino)acetic acid-O 2Tri-1-pyrrolylphosphonium hexafluorophosphate (PyOxim), 2-bromo-1-ethylpyridinium tetrafluoroborate (BEP), 1H-benzotriazol-1-yloxy-tris(pyrrolidine)phosphonium hexafluorophosphate (PyBOP), 1H-benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), bromotri(pyrrolyl)phosphonium hexafluorophosphate (PyBroP), chlorotri(pyrrolyl)phosphonium hexafluorophosphate (PyCloP), (7-azabenzotriazol-1-yloxy)tripyrrolidinephosphonium hexafluorophosphate (PyAOP), bromotri(dimethylamino)phosphonium hexafluorophosphate (Brop), 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazine-4(3H)-one (DEPBT), N, N,N',N'-Tetramethyl-O-(N-succinimide)urea tetrafluoroborate (TSTU), N,N,N',N'-Tetramethyl-O-(N-succinimide)urea hexafluorophosphate (HSTU), O-(3,4-dihydro-4-oxo-1,2,3-benzotriazine-3-yl)-N,N,N',N'-tetramethylurea tetrafluoroborate (TDBTU), Tetramethylthiourea S-(1-oxide-2-pyridyl)-N,N,N',N'-tetrafluoroborate (TOTT), O-(2-oxo-1(2H)pyridyl)-N,N,N',N'-tetramethylurea tetrafluoroborate (TPTU), N,N'-carbonyldiimidazolium (CDI), 1,1'-carbonyl-di(1,2,4-triazole) (CDT), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholine chloride (DMT-MM), propylphosphonic anhydride (T3P), and chloro-N,N,N',N'-tetramethylformamidin hexafluorophosphate. Among them, one or more of the group consisting of HATU, T3P, and TCFH are preferred, and TCFH is more preferred.

[0278] Organic bases are suitable as bases, and in particular, organic bases containing tertiary amines are preferred. Specific examples of such bases include 2,2,6,6-tetramethylpiperidine, N-methylmorpholine, N,N-diisopropylethylamine (DIPEA), 2,4,6-trimethylpyridine, 2,6-dimethylpyridine, pyridine, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), 2,3,6,7-tetrahydro-1H,5H-9-azabenzo[ij]quinazine, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[2.2.2]octane, and 1,5-diazabicyclo[2.2.2]octane. Heterobicyclo[4.3.0]-5-nonene (DBN), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, 1,1,3,3-tetramethylguanidine (TMG), 1,8-bis(tetramethylguanidinyl)naphthalene (TMGN), 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), triethylamine (TEA), trimethylamine, 1-methylpiperidine, N,N'-dimethylpiperazine, N-ethylmorpholine, and p-dimethylaminopyridine (DMAP). Among them, one or more of the group consisting of N-methylmorpholine, 2,6-dimethylpyridine, and N,N-diisopropylethylamine (DIPEA) are preferred, and N,N-diisopropylethylamine (DIPEA) is more preferred.

[0279] On one hand, the condensation reaction is carried out via a liquid-phase synthesis method. Solvents used in liquid-phase synthesis methods can include one or more of the following: nitrile-based solvents, halogen-based solvents, ether-based solvents, amide-based solvents, ester-based solvents, and carbonate-based solvents. Specific examples of nitrile-based solvents include acetonitrile and propionitrile. Specific examples of halogen-based solvents include dichloromethane, chloroform, and 1,2-dichloroethane. Specific examples of ether-based solvents include diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentylmethyl ether, 4-methyltetrahydropyran, 1,3-dioxolane, 1,4-dioxane, 1,2-dimethoxyethane, diisopropyl ether, methyl tert-butyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, anisole, and tetraethylene glycol dimethyl ether. Specific examples of amide-based solvents include DMF, NMP, DMA, NEP, NBP, DMI, and formamide. Specific examples of ester-based solvents include methyl acetate, ethyl acetate, methyl propionate, butyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, amyl acetate, and γ-valerolactone. Specific examples of carbonate-based solvents include dimethyl carbonate, diethyl carbonate, and dibutyl carbonate. Solvents used for condensation reactions are preferably one or more selected from the group consisting of: acetonitrile, dimethyl carbonate, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, tetrahydrofuran, ethyl acetate, isopropyl acetate, dichloromethane, DMF, and anisole; more preferably one or more selected from the group consisting of: acetonitrile, 2-methyltetrahydrofuran, ethyl acetate, and dichloromethane; and still more preferably one or more selected from the group consisting of: acetonitrile and 2-methyltetrahydrofuran.

[0280] The condensation reaction of the compound represented by formula (6) and the compound represented by formula (7) can be carried out, for example, by stirring the reaction mixture at a reaction temperature of 10 to 50°C, preferably 20 to 40°C. The reaction temperature can be the temperature of the reaction mixture in the reaction vessel (internal temperature) or the set temperature of the temperature control device for the reaction vessel (external temperature). The condensation reaction can be carried out by stirring the reaction mixture for 0.5 hours to 8 hours, and preferably 1 hour to 5 hours.

[0281] The urethane protecting groups in the compounds obtained by the condensation reaction of the compounds represented by formula (6) and the compounds represented by formula (7) can be eliminated by methods known to those skilled in the art, and examples of such methods include the following: wherein the reaction mixture is stirred at a reaction temperature of 10°C to 40°C for 1 to 6 hours with or without an acid (such as methanesulfonic acid or trifluoroacetic acid) or a base (DBU or piperidine) in the presence or absence of a solvent (such as 2-methyltetrahydrofuran, acetonitrile or toluene).

[0282] Method for producing the compound represented by formula (3) or its salt

[0283] In one aspect, the present invention relates to a method for producing a compound represented by formula (3) or a salt thereof. The method includes the step of hydrogenating the compound represented by formula (1) or a salt thereof obtained in the above-described production method.

[0284] [Formula 10]

[0285]

[0286] Where R 1 R 2 R 3 R 4 , n and X are respectively related to R in the above [1]. 1 R 2 R 3 R 4 , n and X have the same meaning.

[0287] The hydrogenation step can be performed by those skilled in the art, and examples include the following method: wherein the reaction mixture is stirred in a hydrogen atmosphere at a reaction temperature of 10°C to 40°C for 0.5 hours to 12 hours, preferably 1 hour to 6 hours, with or without a solvent (such as 2-methyltetrahydrofuran, methanol or ethyl acetate) using a catalyst (such as Pd / C, Pd(OH)2 / C or PtO2).

[0288] Method for producing the compound represented by formula (4) or a salt thereof

[0289] In one aspect, the present invention relates to a method for producing a compound represented by formula (4) or a salt thereof. The method comprises the step of protecting the amino group of the compound represented by formula (1) or a salt thereof obtained in the above-described production method with a urethane protecting group.

[0290] [Equation 11]

[0291]

[0292] Where R 2 R 3 R 4 , n and X are respectively related to R in the above [1]. 2 R 3 R 4 , n and X have the same meaning, and X 1 It is a urethane protecting group.

[0293] The step of protecting with a urethane protecting group can be carried out by methods known to those skilled in the art, and examples include the following method: wherein the reaction mixture is stirred at a reaction temperature of 10°C to 40°C for 1 hour to 4 hours with or without a solvent (such as 2-methyltetrahydrofuran, acetonitrile, or toluene) using a urethane esterifying agent (such as di-tert-butyl dicarbonate, N-benzyloxycarbonyloxysuccinimide, or 9-fluorenylmethylchloroformate).

[0294] In one aspect, the present invention relates to a method for producing (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,24,36-octamethyl-10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecoxo-13-propyl-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0] 4,8 .0 26,30 A method for synthesizing, according to International Publication No. WO 2023 / 214576, an amino group of a compound represented by formula (4) or a salt thereof.

[0295] Method for producing the compound represented by formula (5) or a salt thereof

[0296] In one aspect, the present invention relates to a method for producing a compound represented by formula (5) or a salt thereof. The method comprises the step of protecting the amino group of the compound represented by formula (2) or a salt thereof obtained in the above-described production method with a urethane protecting group.

[0297] [Equation 12]

[0298]

[0299] Where R 2 R 3 R 4 , n and X are respectively related to R in the above [1]. 2 R 3 R 4 , n and X have the same meaning, and X 1 It is a urethane protecting group.

[0300] The step of protecting with a urethane protecting group can be carried out by methods known to those skilled in the art, and examples include the following method: wherein the reaction mixture is stirred at a reaction temperature of 10°C to 40°C for 1 hour to 4 hours with or without a solvent (such as 2-methyltetrahydrofuran, acetonitrile, or toluene) using a urethane esterifying agent (such as di-tert-butyl dicarbonate, N-benzyloxycarbonyloxysuccinimide, or 9-fluorenylmethylchloroformate).

[0301] The following is a description of each symbol used in the structural formulas of the compounds represented by equations (1) to (7).

[0302] R 1 It is hydrogen.

[0303] R 2 It is hydrogen or a C1-C6 alkyl group. R 2 Preferably, it is hydrogen or methyl.

[0304] R 3 Hydrogen, optionally substituted C1-C6 alkyl, optionally substituted halo-C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 14 Aryl, optionally substituted 5- to 14-membered heteroaryl, optionally substituted C7-C 14 Aryl groups, optionally substituted 3- to 14-membered heterocyclic groups, optionally substituted 5- to 10-membered heteroaryl-C1-C6 alkyl groups, optionally substituted C1-C6 alkoxy-C1-C6 alkyl groups, optionally substituted C1-C6 alkylthio-C1-C6 alkyl groups, optionally substituted C1-C6 alkylsulfinyl-C1-C6 alkyl groups, optionally substituted carboxyl-C1-C6 alkyl groups, optionally substituted C7-C6 alkyl groups. 14Ararylalkoxy-C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl-C1-C6 alkyl, optionally substituted C3-C8 cycloalkoxy-C1-C6 alkyl, optionally substituted 4- to 7-membered heterocyclic-C1-C3 alkyl, optionally substituted 5- to 10-membered heteroaryl-C1-C6 alkoxy-C1-C6 alkyl, or optionally substituted amino carbonyl (the relevant amino group is selected from the group consisting of: -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, N-C1-C6 alkyl-N-C2-C6 alkenylamino, N-C1-C6 alkyl-N-C1-C6 alkoxy-C1-C6 alkylamino, and 4- to 9-membered cycloamino). R 3 Preferably, it is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C7-C 14 Aryl group, optionally substituted 5- to 10-membered heteroaryl-C1-C6 alkyl group, or optionally substituted 3- to 14-membered heterocyclic group, more preferably hydrogen, C1-C6 alkyl group, or optionally halogenated C1-C3 alkyl group or C7-C alkyl group substituted with C1-C6 alkyl group. 14 Aryl group, and more preferably hydrogen, 2-methylpropyl, p-(trifluoromethyl)benzyl or p-methylbenzyl.

[0305] R 4 OR 5 NHR 5 ', amino acid residues or peptide chains containing 1 to 20 amino acid residues, the amino acid residues and peptide chains may have protecting groups, and R 5 This is a protecting group against the carboxyl group. R 4 Preferably OR 5 NHR 5 ', amino acid residues or peptide chains containing 2 to 13 amino acid residues. R 5 Preferably, the protecting group is an alkyl ester type, a benzyl ester type, a substituted alkyl ester type, or an alkenyl ester type; more preferably, it is a methyl group, an ethyl group, a tert-butyl group, a benzyl group, a triphenylmethyl group, a cumyl group, a methoxytriphenylmethyl group, a 2-(trimethylsilyl)ethyl group, a 2,2,2-trichloroethyl group, or an allyl group; and still more preferably, it is tert-butyl or benzyl. 5The protecting group is a phenylamide type protecting group, an alkylamide type protecting group, an alkenylamide type protecting group, a benzylamide type protecting group, or an alkoxyalkylamide type protecting group, more preferably a phenyl group, a tert-butyl group, an allyl group, a benzyl group, a 4-methoxybenzyl group, a triphenylmethyl group, a cumyl group, a methoxymethyl group, or a benzyloxymethyl group, and still more preferably a phenyl group. The amino acid residue is preferably glycine, alanine, isoleucine, leucine, valine, methionine, phenylalanine, tyrosine, proline, N-methylglycine, N-methylalanine, N-methylisoleucine, N-methylleucine, N-methylvaline, N-methylmethionine, N-methylphenylalanine, N-methyltyrosine, or N-methylproline. More preferably, the amino acid residues are glycine, alanine, isoleucine, leucine, methionine, phenylalanine, tyrosine, N-methylglycine, N-methylalanine, N-methylisoleucine, N-methylleucine, N-methylmethionine, N-methylphenylalanine, or N-methyltyrosine.

[0306] n is an integer from 1 to 4. n is an integer of 1 or 2. The most preferred value for n is 2.

[0307] X is optionally a substituted C1-C3 alkylene, -CH2OCH2-, or -CH2SCH2-. X is preferably an optionally substituted C1-C3 alkylene, or -CH2OCH2-, more preferably an optionally substituted C1-C3 alkylene, still more preferably a C1-C3 alkylene, and most preferably methylene.

[0308] X 1 Choose from the group consisting of: Fmoc group, Cbz group, Troc group, Alloc group, Teoc group, TSoc group, BIBSoc group, IPCSoc group, BBSoc group, CHBSoc group, CDBSoc group, and Boc group. 1 Preferably, it is selected from one of the following groups: Fmoc group, Cbz group, and Boc group. X 1 The most preferred option is the Fmoc group.

[0309] X 2 Choose from the group consisting of: Fmoc group, Cbz group, Troc group, Alloc group, Teoc group, TSoc group, BIBSoc group, IPCSoc group, BBSoc group, CHBSoc group, CDBSoc group, and Boc group. 2Preferably, it is selected from one of the following groups: Fmoc group, Cbz group, and Boc group. X 2 The most preferred option is the Fmoc group.

[0310] As X 1 and X 2 The preferred combination is X. 1 and X 2 Each of the two is selected from the group consisting of: Fmoc group, Cbz group, Troc group, Alloc group, Teoc group, TSoc group, BIBSoc group, IPCSoc group, BBSoc group, CHBSoc group, CDBSoc group, and Boc group. More preferably, X 1 and X 2 Each of them is selected from the group consisting of: Fmoc group, Cbz group, and Boc group. Most preferably, X 1 and X 2 Each of them is an Fmoc group.

[0311] Method for producing cyclic peptide compounds or their salts

[0312] In one aspect, the present invention relates to a method for producing cyclic peptide compounds or salts thereof. The method comprises a process in which the compound or salt thereof, obtained in the above-described production method and represented by each of formulas (1) to (5), or the peptide compound obtained by chemical conversion of the compound or its salt thereof, is cyclized.

[0313] On one hand, cyclic peptides are produced by amide cyclization of the N-terminal amino group and C-terminal carboxyl group of the peptide compound. Amide cyclization can be performed using, for example, condensing agents and / or bases. The condensing agents and bases used in amide cyclization are not particularly limited; commonly used condensing agents and bases in peptide synthesis can be used. Amide cyclization can also be performed by liquid-phase synthesis methods. The solvents used in liquid-phase synthesis methods are not particularly limited; commonly used solvents in peptide synthesis can be used.

[0314] On one hand, cyclic peptide compounds are produced by thioether cyclization of the N-terminal chloroacetyl group and the C-terminal cysteine ​​side chain of the peptide compound.

[0315] In one aspect, the cyclic peptide compound or its salt produced by the method of the present invention contains 8 to 20, preferably 11 to 14, more preferably 11 to 13, and most preferably 11 amino acid residues.

[0316] In one aspect, the cyclic peptide compound or its salt produced by the method of the present invention may contain at least one, at least two, at least three, at least four, or at least five non-natural amino acid residues. In some embodiments, the non-natural amino acid residues contained in the cyclic peptide compound or its salt produced by the method of the present invention are N-methyl amino acid residues.

[0317] In one aspect, the cyclic peptide compounds produced by the method of the present invention may include a cyclic structure (cyclic portion) as a part of their structure. Specific examples of such cyclic structures include those cyclic structures in which the side chain of one amino acid residue is linked to the side chain of another amino acid residue, those cyclic structures in which the N-substituent of one amino acid residue is linked to the side chain of another amino acid residue, and those cyclic structures in which the N-substituent of one amino acid residue is linked to the N-substituent of another amino acid residue. The two amino acid residues involved in the linking of the cyclic structure may be adjacent, or any number of amino acid residues may be present between them, 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 ring sizes formed by ring structures include, but are not intended to be 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. Preferably, the rings formed by the cyclic structure are 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered, 13-membered, 14-membered, 15-membered, 16-membered, 17-membered, 18-membered, 19-membered, or 20-membered rings; more preferably, 10-membered, 11-membered, 12-membered, 13-membered, 14-membered, 15-membered, 16-membered, 17-membered, or 18-membered rings; most preferably, 11-membered, 12-membered, 13-membered, or 14-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.

[0318] In one aspect, the cyclic peptide compound or its salt produced by the method of the present invention may contain a cyclic moiety consisting of 4 or more, 6 or more, 8 or more, or 11 or more amino acid residues. In an embodiment, the cyclic peptide compound or its salt produced by the method of the present invention consists of a cyclic moiety consisting of 4 to 14, preferably 6 to 14, more preferably 8 to 14, and most preferably 11 to 14 amino acid residues. In an embodiment, the cyclic peptide compound or its salt produced by the method of the present invention consists of a cyclic moiety consisting of 11 amino acid residues. In these aspects, the amide bond connecting the amino group of the first amino acid or peptide to the carboxyl group of the second amino acid or peptide is contained at positions 1, 2, 3, 4, 5, 6, or 7 in the cyclic moiety.

[0319] In one aspect, the cyclic peptide compound or its salt produced by the method of the present invention is (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,24,36-octamethyl-10-[(1S)-1-methylpropyl]-3,9,12,15,19,22,25,31,34,37,45-undecoxo-13-propyl-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.0] 4,8 .0 26,30 [42-ene-23,1'-cyclobutane]-17-carboxamide or its salts.

[0320] In one respect, the compound or salt thereof represented by formula (1) produced by the method of the present invention may be a compound or salt thereof represented by formula (1a).

[0321] [Equation 13]

[0322]

[0323] Where Y is a hydroxyl group, optionally substituted C1-C 10 Alkyl groups, optionally substituted C6-C 16 aryloxy groups, optionally substituted C7-C 14 Alkoxy or optionally substituted 3- to 12-membered cyclic aminooxy groups.

[0324] On the one hand, Y in formula (1a) is preferably a C1-C8 alkoxy, C6 aryloxy, or C 10 Aryloxy group, C7-C 16 Aryl alkoxy or 3- to 12-membered cyclic amino oxy, more preferably methoxy, ethoxy, tert-butoxy, phenoxy, 1-naphthoxy, tolyloxy, benzyloxy, phenethoxy, 1-pyrrolidinyloxy, 1-piperidinyloxy or 1-piperazinyloxy, and most preferably tert-butoxy.

[0325] On one hand, the compound represented by formula (1a) or its salt is N-methyl-N-((S)-2-((S)-3-(methylamino)-2-oxo-2,3,4,7-tetrahydro-1H-aza-1-yl)-3-(4-(trifluoromethyl)phenyl)propionyl)glycine tert-butyl ester or its hydrochloride.

[0326] In one respect, the compound or salt thereof represented by formula (1) produced by the method of the present invention may be a compound or salt thereof represented by formula (1b).

[0327] [Formula 14]

[0328]

[0329] Where R 6 It is methyl or trifluoromethyl, and Z is a hydroxyl group, optionally substituted C1-C. 10 Alkyl groups, optionally substituted C6-C 16 aryloxy groups, optionally substituted C7-C 14 Alkoxy or optionally substituted 3- to 12-membered cyclic aminooxy groups.

[0330] On the one hand, Z in formula (1b) is preferably a C1-C8 alkoxy, C6 aryloxy, or C 10 Aryloxy group, C7-C 16 Aryl alkoxy or 3- to 12-membered cyclic amino oxy, more preferably methoxy, ethoxy, tert-butoxy, phenoxy, 1-naphthoxy, tolyloxy, benzyloxy, phenethoxy, 1-pyrrolidinyloxy, 1-piperidinyloxy or 1-piperazinyloxy, and most preferably tert-butoxy.

[0331] On the one hand, R in equation (1b) 6 Preferably, it is methyl. On the other hand, R in formula (1b) 6 The preferred form is trifluoromethyl.

[0332] On one hand, the compound represented by formula (1b) or its salt is N-methyl-N-((S)-2-((S,Z)-3-(methylamino)-2-oxo-3,4,7,8-tetrahydroazacyclooctatetraen-1(2H)-yl)-3-(p-tolyl)propionyl)glycine tert-butyl ester or its hydrochloride.

[0333] On one hand, the compound represented by formula (1b) or its salt is N-methyl-N-((S)-2-((S,Z)-3-(methylamino)-2-oxo-3,4,7,8-tetrahydroazacyclooctatetraen-1(2H)-yl)-3-(4-(trifluoromethyl)phenyl)propionyl)glycine tert-butyl ester or its hydrochloride.

[0334] On one hand, the compound represented by formula (1b) or its salt is N-methyl-N-((S)-2-((S,Z)-3-(methylamino)-2-oxo-2,3,4,5,8,9-hexahydro-1H-azacyclononaten-1-yl)-3-(p-tolyl)propionyl)glycine tert-butyl ester or its hydrochloride.

[0335] On one hand, the compound represented by formula (1b) or its salt is tert-butyl(S)-N,N-dimethyl-2-((S,Z)-3-(methylamino)-2-oxo-3,4,7,8-tetrahydroazacyclooctatetraen-1(2H)-yl)-3-(4-(trifluoromethyl)phenyl)propionamide or its hydrochloride salt.

[0336] On one hand, a method for producing a compound or a salt thereof represented by formula (1) includes a step of contacting a compound or a salt thereof represented by formula (2) with a catalyst (metathesis step). With R in formulas (1) and (2) 1 Compared to cases where the protective group is a urethane ester, the formation of impurities is suppressed.

[0337] On one hand, a method for producing a compound or a salt thereof represented by formula (1) includes a step of contacting a compound or a salt thereof represented by formula (2) with a catalyst (metathesis step). With R in formulas (1) and (2) 1 Compared to the case where the protecting group is a carbamate, dimer formation is suppressed.

[0338] On the one hand, the purity of the compound or its salt represented by formula (1) is 90% or higher, preferably 95% or higher, more preferably 98% or higher, and most preferably 99% or higher, as determined by HPLC analysis via the UVArea value at 210 nm.

[0339] On the one hand, the content of impurities in the compound represented by formula (1) or its salt is less than 10%, preferably less than 5%, more preferably less than 1%, and most preferably less than 0.5% or undetectable, as determined by HPLC analysis using the UVArea value at 210 nm.

[0340] As used herein, examples of impurities may include dimers in which compounds represented by formula (2) are intermolecularly linked. As such dimers, a chain compound obtained by intermolecular olefin metathesis at one position (e.g., the compound represented by formula (8) in Examples 1 to 6) or a cyclic compound obtained by reaction at two positions (e.g., the compound represented by formula (9) in Examples 1 to 6).

[0341] [Formula 15]

[0342]

[0343] In addition to the compounds represented by formulas (8) and (9), impurities may also include compounds in which olefin metathesis reactions occur at different positions, and compounds with double bonds having different E / Z forms.

[0344] All references cited in this paper, including the following patent applications and publications, are incorporated herein by reference in their entirety: International Publication No. WO 2013 / 100132; International Publication No. WO 2018 / 225851; International Publication No. WO 2018 / 225864; International Publication No. WO 2019 / 117274; International Publication No. WO 2020 / 111238; International Publication No. WO 202012 / 2182; International Publication No. WO 2021 / 075478; International Publication No. WO 2021 / 090856; International Publication No. WO 2021132545; International Publication No. WO 2021246471; International Publication No. WO 2022 / 097540; International Publication No. WO 2022 / 138891; International Publication No. WO 20221 / 45444; International Publication No. WO 2022 / 234864; International Publication No. WO 2023 / 127869; International Publication No. WO 2022 / 234853; and International Publication No. WO 2023 / 214576.

[0345] [Example]

[0346] The disclosure will be described in more detail below with reference to examples, but the disclosure is not limited to the examples below.

[0347] In the following examples, high-performance liquid chromatography (HPLC) analysis was performed using any of the analytical conditions described below. A photodiode array detector or mass spectrometer was used for the detection of each compound, although other techniques (such as evaporative light scattering detection) could also be used.

[0348] HPLC analysis conditions: Method 1

[0349] Equipment: Waters ACQUITY UPLC H-Class + ACQUITY QDA

[0350] Column: Ascentis Express 90A C18 (Sigma-Aldrich Co. LLC), 2.1 mm ID × 50mm, 2.7 μm

[0351] Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[0352] Elution method: B) 5% (0 min) → 100% (5 min) → 5% (5.1 min) → 5% (7 min)

[0353] Flow rate: 0.5 mL / min

[0354] Column temperature: 35℃

[0355] Detection wavelength: 210 nm (PDA)

[0356] HPLC Analytical Conditions and Methods 2

[0357] Equipment: Waters ACQUITY UPLC H-level

[0358] Column: Ascentis Express 90A C18 (Sigma-Aldrich Co. LLC), 2.1 mm ID × 50mm, 2.7 μm

[0359] Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[0360] Elution method: B): 5% (0 min) → 100% (5 min) → 5% (5.1 min) → 5% (7 min)

[0361] Flow rate: 0.5 mL / min

[0362] Column temperature: 35℃

[0363] Detection wavelength: 210 nm (PDA)

[0364] HPLC Analytical Conditions and Methods 3

[0365] Equipment: Waters ACQUITY UPLC H-Class + ACQUITY QDA

[0366] Column: Ascentis Express 90A C18 (Sigma-Aldrich Co. LLC), 2.1 mm ID × 50mm, 2.7 μm

[0367] Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[0368] Elution method: B) 50% (0 min) → 100% (3 min) → 100% (5 min) → 50% (5.1 min) → 50% (7 min)

[0369] Flow rate: 0.5 mL / min

[0370] Column temperature: 35℃

[0371] Detection wavelength: 220 nm (PDA)

[0372] HPLC Analytical Conditions and Methods 4

[0373] Equipment: Waters ACQUITY UPLC H-level

[0374] Column: Ascentis Express RP-amide (Sigma-Aldrich Co. LLC), 3.0 mm ID × 50mm, 2.7 μm

[0375] Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[0376] Elution method: B): 5% (0 min) → 100% (5 min) → 5% (5.1 min) → 5% (7 min)

[0377] Flow rate: 0.5 mL / min

[0378] Column temperature: 35℃

[0379] Detection wavelength: 210 nm (PDA)

[0380] HPLC Analytical Conditions and Methods 5

[0381] Equipment: Waters ACQUITY UPLC H-level

[0382] Column: Ascentis Express 90A C18 (Sigma-Aldrich Co. LLC), 2.1 mm ID × 50mm, 2.7 μm

[0383] Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B)

[0384] Elution method: B) 5% (0 min) → 100% (5 min) → 100% (7 min) → 5% (7.1 min) → 5% (9 min)

[0385] Flow rate: 0.5 mL / min

[0386] Column temperature: 35℃

[0387] Detection wavelength: 210 nm (PDA)

[0388] The conversion of the reaction mixture from HPLC analysis and the ratio of dimers formed by intermolecular reactions to the product were calculated as follows.

[0389] Conversion rate (%): {Area value of product / (Area value of product + Area value of starting material)} × 100

[0390] The ratio of dimers to products formed through intermolecular reactions: (sum of the area values ​​of all dimers / area value of the product) × 100

[0391] 1 1H-NMR spectra were measured using an ECX500II nuclear magnetic resonance apparatus (manufactured by JEOL Ltd.) and referenced to a deuterium-locked signal from the sample solvent. Commercially available deuterated solvents were used as sample solvents, depending on the purpose of the measurement. The chemical shift of tetramethylsilane, used as an internal standard, was set to 0 ppm, and the chemical shifts of the signals of the analytes were expressed in ppm. Signal abbreviations were used as follows: s = singlet, brs = broad singlet, d = doublet, t = triplet, q = quadruplet, dd = doublet, and m = multiplet. The split width of the signal was expressed as the J value (Hz). The integral value of the signal was calculated based on the ratio of the signal area intensity of each signal.

[0392] The qNMR measurement method was performed by dissolving the residue containing the target compound and the internal standard in DMSO-d6 and subjecting them to the following analytical conditions.

[0393] Measuring instrument: JNM-ECZ500R

[0394] Internal standard: 3,5-bis(trifluoromethyl)benzoic acid

[0395] Measurement conditions ( 1 H-NMR: DMSO-d6, pulse angle 90°, digital resolution 0.25 Hz, relaxation time 60 seconds, spinless, count 8.

[0396] Example 1-1

[0397] Synthesis of (S)-2-(but-3-en-1-ylamino)-3-(4-(trifluoromethyl)phenyl)propionic acid (compound 1)

[0398] [Formula 16]

[0399]

[0400] Acetonitrile (822 mL), 4-bromo-1-butene (235.07 g), and triethylamine (17.66 g) were added to a nitrogen-filled reaction vessel at an external temperature of 25 °C, and the mixture was stirred for 1 hour. Subsequently, (S)-2-amino-3-(4-(trifluoromethyl)phenyl)propionic acid (135.46 g), water (676 mL), and triethylamine (158.19 g) were added, the external temperature was raised to 70 °C, and the mixture was stirred for 3.5 hours. The reaction mixture was cooled to 25 °C, and the precipitated solid was collected by filtration and washed with a mixture of acetonitrile and water (v:v = 1:1, 676 mL). The resulting wet solid was then further washed with acetonitrile (676 mL). The resulting wet solid was dried under reduced pressure at 40 °C to give compound 1 (124.73 g) as a white solid.

[0401] LCMS (ESI) retention time of compound 1: 2.34 min, m / z = 288 [M+H] + (HPLC analysis conditions: Method 1)

[0402] Example 1-2

[0403] Synthesis of (S)-N-(2-(but-3-en-1-ylamino)-3-(4-(trifluoromethyl)phenyl)propionyl)-N-methylglycine tert-butyl hydrochloride (compound 2-HCl)

[0404]

[0405] At an external temperature of 25°C, compound 1 (107.26 g), sarcosine tert-butyl hydrochloride (102.00 g), acetonitrile (751 mL), and DBU (233.03 g) synthesized in Example 1-1 were added to a first reaction vessel filled with nitrogen, and the mixture was stirred for 10 minutes. After the solution became homogeneous, the external temperature was set to 2°C, and a solution of 50% T3P in 2-MeTHF (309.03 g) was added dropwise over 2 hours and 14 minutes. After the reaction was complete, toluene (751 mL) and a 1 mol / L aqueous sodium hydroxide solution (536 mL) were added to the reaction mixture. After stirring the resulting mixture for 30 minutes, the aqueous layer was drained. The organic layer was stored overnight at approximately 25°C. After storage, a 5% aqueous sodium carbonate solution (536 mL) was added to the organic layer, stirred for 10 minutes, and then the aqueous layer was drained. Subsequently, a 5% sodium dihydrogen phosphate aqueous solution (751 mL) was added to the organic layer, stirred for 10 minutes, and then the aqueous layer was drained. Next, a 5% sodium dihydrogen phosphate aqueous solution (751 mL) was added to the organic layer, stirred for 10 minutes, and then the aqueous layer was drained. Then, a 5% sodium chloride aqueous solution (751 mL) was added to the organic layer, stirred for 10 minutes, and then the aqueous layer was drained. The organic layer was stored overnight at an external temperature of 5°C. After storage, the organic layer was concentrated under reduced pressure at 40°C until the liquid volume of the organic layer reached approximately 215 mL. Toluene (215 mL) was added to the concentrated solution, and the mixture was concentrated under reduced pressure at 40°C to approximately 215 mL, and this operation was repeated twice. The precipitated inorganic salts were filtered, and toluene (276.6 mL) was added to the obtained filtrate. In a second reaction vessel, pyridine hydrochloride (43.28 g) and acetonitrile (148 mL) were added, and the prepared solution was added dropwise over 45 minutes at an external temperature of 25 °C to a solution of compound 2 in toluene. Precipitation of crystals was confirmed during the dropwise addition. The second reaction vessel was rinsed with acetonitrile (74 mL), and the resulting solution was added to the mixture containing compound 2. The resulting mixture was stirred for 1 hour. Subsequently, toluene (1.7 L) was added, and the mixture was stirred for 1 hour, then the external temperature was lowered to 0 °C, and the mixture was stirred for another 2 hours. The obtained crystals were filtered and washed twice with toluene (296 mL), and then cooled to 0 °C. The obtained wet solid was stored at an external temperature of 5 °C for one weekend. After storage, the wet solid was dried under reduced pressure at an external temperature of 40 °C to give compound 2-HCl (98.66 g) as a white solid.

[0406] LCMS (ESI) retention time of compound 2: 3.03 min, m / z = 415 [M+H] + (HPLC analysis conditions: Method 1)

[0407] Example 1-3

[0408] Synthesis of (5S,8S)-5-allyl-7-(but-3-en-1-yl)-1-(9H-fluoren-9-yl)-4,10-dimethyl-3,6,9-trioxo-8-(4-(trifluoromethyl)benzyl)-2-oxa-4,7,10-triazadodecane-12-oic acid tert-butyl (compound Fmoc-3)

[0409] [Formula 18]

[0410]

[0411] Compound 2-HCl (2.70 kg, 6.00 mol) synthesized in Examples 1-2 above was added to the reaction vessel. Then, (S)-2-(((9-H-fluorene-9-yl)methoxy)carbonyl)(methyl)amino)-4-pentenoic acid (2.74 kg), acetonitrile (6.34 kg), and MeTHF (5.74 kg) were added, the external temperature of the reaction vessel was set to 15°C, and DIPEA (3.86 kg) was added. A solution obtained by dissolving TCFH (3.35 kg) in acetonitrile (7.58 kg) was then added to the reaction vessel, the external temperature of the reaction vessel was set to 25°C, and the reaction mixture was stirred for 5 hours. MeTHF (5.74 kg) was added to the reaction vessel, the external temperature of the reaction vessel was set to 15°C, and a 5% aqueous solution of potassium carbonate (13.45 kg) was added, and the reaction mixture was stirred for 30 minutes. The aqueous layer was drained, and the resulting organic layer was then washed with 5% sulfuric acid (13.45 kg). MeTHF (5.74 kg) was added to the reaction vessel, and the organic layer was then washed with 5% potassium carbonate aqueous solution (13.45 kg). The resulting organic layer was concentrated under reduced pressure, acetonitrile (16.91 kg) was added, and the mixture was further concentrated to give a residue containing compound Fmoc-3.

[0412] LC retention time of compound Fmoc-3: 5.442 min (HPLC analysis conditions: Method 2)

[0413] LCMS (ESI) retention time of compound Fmoc-3: 5.491 min, m / z = 770 [M+Na] + (HPLC analysis conditions: Method 1)

[0414] Examples 1-4

[0415] Synthesis of N-((S)-2-((S)-N-(but-3-en-1-yl)-2-(methylamino)pent-4-enamide)-3-(4-(trifluoromethyl)phenyl)propionyl)-N-methylglycine tert-butyl hydrochloride (compound 3-HCl)

[0416] [Formula 19]

[0417]

[0418] The residues containing compound Fmoc-3 obtained in Examples 1-3 above were added to the reaction vessel. DBU (2.59 kg) was then added at 15°C, and the resulting mixture was stirred for 1 hour. Triethylamine (2.29 kg) and sodium bisulfite (2.12 kg) were then added, and the reaction mixture was stirred at 25°C for 1 hour. Toluene (18.38 kg) and 10% ammonia (33.92 kg) were added to the reaction vessel, the mixture was stirred for 10 minutes, and then the aqueous layer was drained. The resulting organic layer was washed three times with 10% ammonia (33.92 kg) and then with 5% sodium chloride aqueous solution (33.92 kg). The resulting organic layer was concentrated under reduced pressure. Toluene (7.7 kg) was added to the obtained residue, and the mixture was concentrated under reduced pressure. The following operation was repeated twice: toluene (7.7 kg) was added to the obtained residue and concentrated under reduced pressure to give a residue containing compound 3.

[0419] Toluene (0.86 kg) was added to the obtained residue, followed by the addition of a solution obtained by dissolving pyridine hydrochloride (0.65 kg) in acetonitrile (3.17 kg) at 25 °C. The resulting mixture was stirred for 1 hour, followed by the addition of MTBE (11.92 kg) and stirring. The resulting precipitate was collected by filtration under reduced pressure, and the obtained wet solid was washed twice with MTBE (3.97 kg). The obtained solid was dried under reduced pressure to give compound 3-HCl (2.60 kg, 4.63 mol, two-step yield from compound 2-HCl: 77.5%).

[0420] UV intensity ratio: 100%

[0421] (Detection wavelength 210 nm, retention time 3.145 min, HPLC analysis conditions: Method 2)

[0422] LCMS (ESI) retention time of compound 3: 3.213 min, m / z = 526 [M+H] + (HPLC analysis conditions: Method 1)

[0423] Examples 1-5

[0424] Fmoc-4 was synthesized via cyclization metathesis of compound Fmoc-3.

[0425] [Formula 20]

[0426]

[0427] Acetonitrile (20 mL) was added to the residue (55 mL) containing compound Fmoc-3 obtained in Examples 1-3 above, and the azeotropic dehydration under reduced pressure was repeated twice. The resulting residue was purified by silica gel column chromatography (mobile phase: heptane / ethyl acetate, v / v ratio 0:100 → 40:60). The collected solution was concentrated, and MTBE (20 mL) was added to the resulting concentrated mixture to precipitate compound Fmoc-3. The obtained solid was filtered to give Fmoc-3 (4.90 g) as a white solid.

[0428] Fmoc-3 (1.00 g, 1.34 mmol) was added to the first reaction vessel and dissolved in acetone (7 mL) and HFIP (4.46 g, 2.8 mL) to prepare a solution of Fmoc-3. Hoveyda-Grubbs catalyst ([1-[2,4,6-trimethylphenyl]-3,5,5-trimethyl-3-phenyl-2-pyrrolinoside]dichloro(2-isopropoxybenzyl)ruthenium(II)) (8.5 mg, 0.013 mmol) and acetone (5 mL) were added to the second reaction vessel. After the second reaction vessel was filled with nitrogen, the solution of compound Fmoc-3 prepared as described above was added dropwise over 2 hours while the solution in the second reaction vessel was heated at 65 °C and refluxed. The first reaction vessel was then washed with acetone (1 mL), and the resulting washing solution was added dropwise to the solution in the second reaction vessel over 10 minutes. After dropwise addition, the reaction mixture was stirred for 4 hours, and a sample was taken for analysis by HPLC. The conversion was confirmed to be 95.2%, and the ratio of the dimer formed via intermolecular reaction to the product (Fmoc-4) was 361%.

[0429] LCMS (ESI) retention time of compound Fmoc-4: 2.784 min, m / z = 742 [M+Na] + (HPLC analysis conditions: Method 3)

[0430] Examples 1-6

[0431] Synthesizing compound 4-HCl via cyclization metathesis of compound 3-HCl

[0432] [Equation 21]

[0433]

[0434] Compound 3-HCl (50.2 mg) obtained in Examples 1-4 above was added to the reaction vessel and dissolved in acetone (0.35 mL) and HFIP (0.14 mL). Separately, the catalyst solution was prepared by dissolving Hoveyda-Grubbs catalyst ([1-[2,4,6-trimethylphenyl]-3,5,5-trimethyl-3-phenyl-2-pyrrololinylidene]dichloro(2-isopropoxybenzyl)ruthenium(II)) (2.8 mg) in acetone (0.25 mL), and the resulting catalyst solution was added to the reaction vessel. The resulting reaction mixture was heated at 65 °C with stirring and refluxed for 5 hours. After the reaction, the reaction mixture was sampled and analyzed by HPLC. The conversion was confirmed to be 99.3%, and the ratio of the dimer formed by the intermolecular reaction to the product (4-HCl) was 0.42%.

[0435] LCMS (ESI) retention time of compound 4: 2.975 min, m / z = 498 [M+H] + (HPLC analysis conditions: Method 1)

[0436] Table 1 shows a comparison between Examples 1-5 and Examples 1-6 above.

[0437]

[0438] [Table 1]

[0439]

[0440] It has been confirmed that, compared with the compound Fmoc-3 protected by Fmoc as shown in Table 1, the use of the unprotected compound 3-HCl allows the reaction to proceed in an intramolecular selective manner.

[0441] Examples 1-7

[0442] Synthesis of N-methyl-N-((S)-2-((S,Z)-3-(methylamino)-2-oxo-3,4,7,8-tetrahydroazacyclooctatetraen-1(2H)-yl)-3-(4-(trifluoromethyl)phenyl)propionyl)glycine tert-butyl hydrochloride (compound 4-HCl)

[0443] [Equation 23]

[0444]

[0445] Compound 3-HCl (0.64 kg) obtained in Examples 1-4 above was added to the first reaction vessel, and the mixture was dissolved in acetone (3.52 kg) and HFIP (2.88 kg) to prepare a solution of compound 3-HCl. In the second reaction vessel, the catalyst solution was prepared using Hoveyda-Grubbs catalyst ([1-[2,4,6-trimethylphenyl]-3,5,5-trimethyl-3-phenyl-2-pyrrolinoside]dichloro(2-isopropoxybenzyl)ruthenium(II)) (7.12 g) and acetone (2.51 kg), and the second reaction vessel was then filled with nitrogen. The compound 3-HCl solution prepared as described above was then added dropwise to the second reaction vessel over 1.5 hours, while the catalyst solution in the second reaction vessel was heated at 65°C and refluxed. After the dropwise addition was complete, the reaction mixture was stirred for 1 hour, allowed to cool to 25°C, and then stirred again for 1 hour. The resulting precipitate was collected by filtration, and the obtained wet solid was washed twice with acetone (2.52 kg). The obtained solid was dried under reduced pressure to give 0.55 kg of compound 4-HCl (yield 90.7%).

[0446] UV intensity ratio: 99.1%

[0447] (Detection wavelength 210 nm, retention time 2.820 min, HPLC analysis conditions: Method 2)

[0448] LCMS (ESI) retention time of compound 4: 2.859 min, m / z = 498 [M+H] + (HPLC analysis conditions: Method 1)

[0449] 1 ¹H-NMR (500 MHz, DMSO-d6, detected as a mixture of rotational isomers) δ 9.74 (brs, 1H), 8.63 (brs, 1H), 7.60–7.39 (m, 4H), 5.78–5.39 (m, 3H), 4.53–4.48 (m, 1H), 4.18–3.74 (m, 3H), 3.61–3.50 (m, 1H), 3.11–2.83 (m, 6H), 2.45–2.41 (m, 1H), 2.30–2.12 (m, 2H), 1.96 (s, 1H), 1.87 (s, 2H), 1.40 (s, 3H), 1.39 (s, 6H)

[0450] Examples 1-8

[0451] Research on additives in the cyclization metathesis of compound 3-HCl

[0452] Compound 3-HCl, obtained in Examples 1-4 above, acetone (10 volumes based on the weight of compound 3-HCl), additives (2 volumes based on the weight of compound 3-HCl), and a second-generation Hoveyda-Grubbs catalyst (5 mol%) were added to the reaction vessel, and the reaction vessel was then filled with nitrogen. The resulting mixture was stirred at an external temperature of 55°C for 3 to 3.5 hours. The resulting reaction mixture was sampled and analyzed by HPLC to determine the conversion. Table 2 below shows a list of the additives used and their conversion rates.

[0453] [Equation 24]

[0454]

[0455] [Table 2]

[0456]

[0457] It was confirmed that even when using a variety of weak acids and alcohols as additives as shown in Table 2, the target 4-HCl was generated at a conversion rate of 70% or higher.

[0458] Examples 1-9

[0459] Synthesis of N-((S)-2-((S,Z)-3-((((9H-fluorene-9-yl)methoxy)carbonyl)(methyl)amino)-2-oxo-3,4,7,8-tetrahydroazacyclooctatetraen-1(2H)-yl)-3-(4-(trifluoromethyl)phenyl)propionyl)-N-methylglycine tert-butyl ester (compound Fmoc-4)

[0460] [Equation 25]

[0461]

[0462] The reaction vessel was filled with nitrogen, and compound 4-HCl (3.14 kg, 5.88 mol) was prepared in the same manner as in Examples 1-7 above, with acetonitrile (7.34 kg), MeTHF (2.54 kg), and DIPEA (1.90 kg) added to the reaction vessel. Then, a solution obtained by dissolving 9-fluorenylmethylchloroformate (1.60 kg) in MeTHF (5.36 kg) was added to the reaction vessel, and the mixture was stirred at 15°C for 1 hour. N,N-dimethylethylenediamine (0.10 kg) was added to the reaction vessel, and the mixture was stirred at 25°C for 0.5 hours. Then, 4% sulfuric acid (31.35 kg) was added at 15°C, the mixture was stirred, and the aqueous layer was removed. MeTHF (5.38 kg) and 4% sulfuric acid (31.47 kg) were added to the obtained organic layer, the mixture was stirred, and the aqueous layer was removed. MeTHF (5.38 kg) and a 5% sodium carbonate aqueous solution (31.39 kg) were added to the obtained organic layer. The mixture was stirred, and the aqueous layer was drained. MeTHF (5.38 kg) and a 5% sodium chloride aqueous solution (31.43 kg) were added to the obtained organic layer. The mixture was stirred, and the aqueous layer was drained. The obtained organic layer was concentrated and subjected to azeotropic dehydration with the addition of MeTHF to obtain a concentrated solution containing compound Fmoc-4.

[0463] LC retention time of compound Fmoc-4: 4.980 min (HPLC analysis conditions: Method 4)

[0464] In the cyclization metathesis of Fmoc-3, the compound derived from the intermolecular reaction is the major product. On the other hand, Fmoc-4 was successfully obtained as the major product via cyclization metathesis of 3-HCl and subsequent N-terminal Fmoc protection of this sequence.

[0465] Example 1-10

[0466] Synthesis of N-methyl-N-((S)-2-((S)-3-(methylamino)-2-oxoazacyclooctane-1-yl)-3-(4-(trifluoromethyl)phenyl)propionyl)glycine tert-butyl hydrochloride (compound 5-HCl)

[0467] [Equation 26]

[0468]

[0469] Compound 4-HCl (240 mg, 0.45 mmol), obtained in Examples 1-7 above, methanol (4.8 mL), and 10% Pd / C (54% water content, 51.8 mg) were added to a reaction vessel, which was then filled with hydrogen. The mixture was stirred at approximately 25 °C for 75 minutes, and the reaction mixture was then filtered. The palladium on carbon separated by filtration was washed with methanol (3 mL). The resulting filtrate was dried under reduced pressure to give compound 5-HCl (221 mg, 0.41 mmol, 91.9% yield) as a white solid.

[0470] UV intensity ratio: 99.5%

[0471] (Detection wavelength 210 nm, retention time 2.808 min, HPLC analysis conditions: Method 1, m / z = 500 [M+H]) + (ESI)

[0472] The compound obtained by cyclization metathesis was successfully converted into the corresponding lactam 5-HCl by hydrogenating the double bond to a single bond.

[0473] Example 1-11

[0474] Synthesis of (S)-2-(but-3-en-1-ylamino)-3-(p-tolyl)propionic acid (compound 6)

[0475] [Equation 27]

[0476]

[0477] (S)-2-amino-3-(p-tolyl)propionic acid (3.45 g, 19.3 mmol), ethanol (20.7 mL), water (17.3 mL), triethylamine (8.05 mL, 57.8 mmol), and 4-bromo-1-butene (5.82 mL, 57.8 mmol) were added to a reaction vessel, and the resulting mixture was stirred at 70 °C for 4 hours. The reaction mixture was cooled to 25 °C, and the resulting precipitate was collected by filtration. The obtained solid was dried under reduced pressure to give compound 6 (2.40 g, 53% yield) as a white solid.

[0478] UV intensity ratio: 99.0%

[0479] (Detection wavelength 210 nm, retention time 1.983 min, HPLC analysis conditions and method 2)

[0480] Example 1-12

[0481] Synthesis of (S)-N-(2-(but-3-en-1-ylamino)-3-(p-tolyl)propionyl)-N-methylglycine tert-butyl ester (compound 7)

[0482] [Equation 28]

[0483]

[0484] Compound 6 (2.05 g, 8.79 mmol), sarcosine tert-butyl hydrochloride (3.20 g, 17.6 mmol), acetonitrile (20 mL), and DIPEA (6.91 mL, 39.5 mmol) obtained in Examples 1-11 above were added to the reaction vessel at approximately 25 °C. After the reaction vessel was filled with nitrogen, chlorotripyrrolidinyl phosphonium hexafluorophosphate (5.60 g, 13.3 mmol) was added, and the mixture was stirred at 72 °C for 5 hours. The reaction mixture was cooled to 25 °C, and then 10% potassium carbonate aqueous solution (10 mL) was added, and the mixture was stirred for 6 hours. The aqueous layer was drained, and the resulting organic layer was washed with 10% sodium bisulfate aqueous solution (16 mL × 2 times). 1 mol / L sodium hydroxide aqueous solution (10 mL) and MeTHF (10 mL) were added to the resulting organic layer, the mixture was stirred, and the aqueous layer was drained. Toluene (10 mL) was added to the obtained organic layer, and the mixture was washed with water (10 mL × 2) and 5% sodium chloride aqueous solution (10 mL). The obtained organic layer was concentrated and subjected to azeotropic dehydration with the addition of toluene (20 mL) to give a residue (5.08 g) containing compound 7.

[0485] LCMS (ESI) retention time of compound 7: 2.756 min, m / z = 361 [M+H] + (HPLC analysis conditions: Method 1)

[0486] Example 1-13

[0487] Synthesis of N-((S)-2-((S)-N-(but-3-en-1-yl)-2-(methylamino)pent-4-enamide)-3-(p-tolyl)propionyl)-N-methylglycine tert-butyl ester (compound 8)

[0488] [Equation 29]

[0489]

[0490] The residue (5.75 g) containing compound 7 (10.6 mmol), obtained by the methods described in Examples 1-12 above, (S)-2-(((9-H-fluorene-9-yl)methoxy)carbonyl)(methyl)amino)-4-pentenoic acid (4.50 g, 12.8 mmol), acetonitrile (19 mL), and DIPEA (7.43 mL) were added to the reaction vessel at approximately 25 °C. After the reaction vessel was filled with nitrogen, TCFH (5.97 g, 21.3 mmol) was added, and the mixture was stirred at 25 °C for 4 hours. Then, MTBE (19 mL), 5% potassium carbonate aqueous solution (19 mL), and 1-methylimidazole (0.85 mL) were added, and the mixture was stirred at approximately 25 °C for 10 minutes. The aqueous layer was drained, and the resulting organic layer was washed with 10% sodium bisulfate aqueous solution (19 mL × 2) and 5% sodium chloride aqueous solution (19 mL). The obtained organic layer was concentrated, and then DBU (4.81 mL) and acetonitrile (7.6 mL) were added. The resulting mixture was stirred at approximately 25°C for 45 minutes. Then, sodium bisulfite (2.76 g), triethylamine (5.93 mL), and water (1.92 mL) were added, and the mixture was stirred at approximately 25°C for 2 hours. Then, toluene (19 mL), isopropyl acetate (19 mL), and 20% ammonia solution (36 mL) were added, and the mixture was stirred. The aqueous layer was drained, and the resulting organic layer was washed with 20% ammonia solution (36 mL × 3) and sodium chloride aqueous solution (19 mL). The obtained organic layer was concentrated under reduced pressure and then subjected to azeotropic dehydration with the addition of toluene (19 mL × 2) to give a residue (9.01 g) containing compound 8.

[0491] LCMS (ESI) retention time of compound 8: 3.038 min, m / z = 472 [M+H] + (HPLC analysis conditions: Method 1)

[0492] Example 1-14

[0493] Synthesis of N-methyl-N-((S)-2-((S,Z)-3-(methylamino)-2-oxo-3,4,7,8-tetrahydroazacyclooctatetraen-1(2H)-yl)-3-(p-tolyl)propionyl)glycine tert-butyl ester (compound 9)

[0494] [Formula 30]

[0495]

[0496] The purified product of compound 8 synthesized in Examples 1-13 above (purified by silica gel column chromatography using dichloromethane / methanol as the mobile phase) (41.6 mg, 0.088 mmol) was added to the reaction vessel. Then, a toluene solution (0.45 mL) containing toluene (2.2 mL), boron trifluoride-tetrahydrofuran complex (9.7 μL, 0.088 mmol), and first-generation Hoveyda-Grubbs catalyst (2.6 mg, 4.4 μmol) was added to the reaction vessel. After the reaction vessel was filled with nitrogen, the resulting mixture was stirred at an external temperature of 40 °C for 3 hours. The reaction mixture was then sampled and analyzed by HPLC. The conversion was confirmed to be 74.8%, and the ratio of the dimer formed by the intermolecular reaction to product (9) was 1.7%.

[0497] LCMS (ESI) retention time of compound 9: 2.492 min, m / z = 444 [M+H] + (HPLC analysis conditions: Method 1)

[0498] Example 1-15

[0499] Synthesis of (5S,8S)-5-allyl-7-(but-3-en-1-yl)-4,10-dimethyl-8-(4-methylbenzyl)-3,6,9-trioxo-1-phenyl-2-oxa-4,7,10-triazadodecane-12-oic acid tert-butyl (compound Cbz-8)

[0500] [Equation 31]

[0501]

[0502] Compound 7 (0.50 g, 1.39 mmol), synthesized by a method similar to Examples 1-12 above, was added to the reaction vessel, followed by (S)-2-((benzyloxy)carbonyl)(methyl)amino)-4-pentenoic acid (0.43 g, 1.66 mmol), acetonitrile (2.5 mL), and DIPEA (1.09 mL). TCFH (0.78 g) was added at approximately 25 °C, and the resulting mixture was stirred at approximately 25 °C for 1 hour. MeTHF (2.5 mL) and a 5% aqueous solution of sodium bicarbonate (5 mL) were then added, the mixture was stirred, and the aqueous layer was drained. The organic layer was washed in this order with a 5% aqueous solution of sodium bicarbonate (5 mL), a 5% aqueous solution of potassium bisulfate (5 mL), and a 2.5% aqueous solution of sodium chloride (5 mL). The obtained organic layer was concentrated to give a residue containing compound Cbz-8. The residue was purified by silica gel column chromatography (mobile phase: heptane / ethyl acetate, v / v ratio 100:0 → 80:20) to give compound Cbz-8 (0.66 g).

[0503] LCMS (ESI) of compound Cbz-8: retention time, 4.867 min, m / z = 628 [M+Na] + (HPLC analysis conditions: Method 1)

[0504] Example 1-16

[0505] Synthesis of N-((S)-2-((S,Z)-3-(((benzyloxy)carbonyl)(methyl)amino)-2-oxo-3,4,7,8-tetrahydroazacyclooctatetraen-1(2H)-yl)-3-(p-tolyl)propionyl)-N-methylglycine tert-butyl ester (compound Cbz-9)

[0506] [Equation 32]

[0507]

[0508] Compound Cbz-8 (48.6 mg, 0.080 mmol), obtained in Examples 1-15 above, toluene (2.67 mL), and the first-generation Hoveyda-Grubbs catalyst (2.3 mg, 3.9 μmol) were added to the reaction vessel. After the reaction vessel was filled with nitrogen, the reaction mixture was stirred at an external temperature of 70°C for 2 hours. The reaction mixture was then sampled and analyzed by HPLC. The conversion was confirmed to be 39.4%, and the ratio of the dimer formed by the intermolecular reaction to the product (Cbz-9) was 35.9%.

[0509] LCMS (ESI) of compound Cbz-9: retention time, 1.877 min, m / z = 600 [M+Na] + (HPLC analysis conditions: Method 3)

[0510] Table 3 below shows a comparison between the cyclization metathesis of the unprotected N-terminus compound 8 (Examples 1-14) and the cyclization metathesis of the Cbz-protected compound Cbz-8 (Examples 1-16).

[0511] [Equation 33]

[0512]

[0513] [Table 3]

[0514]

[0515] It has been confirmed that using the unprotected compound 8 allows the cyclization metathesis reaction to proceed with higher conversion rates and in an intramolecular selective manner compared to using the Cbz-protected compound Cbz-8.

[0516] Example 1-17

[0517] Synthesis of N-((S)-2-((S)-N-(but-3-en-1-yl)-2-(methylamino)pent-4-enamide)-3-(p-tolyl)propionyl)-N-methylglycine tert-butyl hydrochloride (compound 8-HCl)

[0518] [Formula 34]

[0519]

[0520] The residue (9.01 g) containing compound 8 obtained by the methods described in Examples 1-13 above was added to a pyridine hydrochloride solution obtained by dissolving pyridine hydrochloride (0.86 g) in acetonitrile (1.9 mL), followed by the addition of MTBE (11.4 mL). The resulting mixture was stirred at approximately 25 °C for 10 min, and MTBE (7.6 mL) was added. The reaction mixture was stirred for 1 h, then MTBE (19 mL) was added, and the mixture was stirred for 1 h, followed by standing for 15 h. The resulting precipitate was collected by filtration, and the obtained solid was dried under reduced pressure to give 2.79 g of a beige solid of compound 8-HCl (purity 97.5%, NMR content calculated by qNMR and UV intensity ratio).

[0521] UV intensity ratio: 99.1%

[0522] (Detection wavelength 210 nm, retention time 3.042 min, HPLC analysis conditions: Method 1, m / z = 472 [M+H]) + (ESI)

[0523] Example 1-18

[0524] Synthesis of N-methyl-N-((S)-2-((S,Z)-3-(methylamino)-2-oxo-3,4,7,8-tetrahydroazacyclooctatetraen-1(2H)-yl)-3-(p-tolyl)propionyl)glycine tert-butyl hydrochloride (compound 9-HCl)

[0525] [Formula 35]

[0526]

[0527] In a first reaction vessel, compound 8-HCl (1.02 g, 97.5% purity) obtained in Examples 1-17 was dissolved in acetone (5 mL) and HFIP (0.41 mL) to prepare a compound 8-HCl solution. A second-generation Hoveyda-Grubbs catalyst (0.061 g), acetone (15 mL), and HFIP (1.8 mL) were added to a second reaction vessel to prepare a catalyst solution. The second reaction vessel was filled with nitrogen, and the catalyst solution in the second vessel was heated and refluxed at an external temperature of 65°C. The compound 8-HCl solution prepared as described above was then added dropwise to the second reaction vessel over 1 hour. After the dropwise addition was complete, the reaction mixture was stirred for 1 hour, and a sample of the reaction mixture was taken and analyzed by HPLC. The conversion was confirmed to be 99.3%, and the ratio of the dimer formed by intermolecular reaction to the product (9-HCl) was 1.7%. The reaction mixture was cooled to approximately 25°C, MTBE (10 mL) was added to the reaction mixture, and the resulting suspension was then filtered. The resulting wet solid was then washed twice with a mixture of acetone / MTBE (volume ratio 2:1, 5 mL). The resulting solid was dried under reduced pressure to give 0.79 g of the compound 9-HCl as a white solid (81.4%, purity 97.0%, NMR content calculated by qNMR and UV intensity ratio of the product).

[0528] UV intensity ratio: 98.6%

[0529] (Detection wavelength 210 nm, retention time 2.630 min, HPLC analysis conditions: Method 1, m / z = 444 [M+H]) + (ESI)

[0530] 1¹H-NMR (500 MHz, DMSO-d6, detected as a mixture of rotational isomers) δ 8.93–9.54 (br, 1H), 8.29–8.93 (br, 1H), 7.03–7.14 (m, 4H), 5.70–5.36 (m, 3H), 4.49–4.45 (m, 1H), 4.23–3.80 (m, 2H), 3.73–3.67 (m, 1H), 3.59–3.49 (m, 1H), 2.96–2.78 (m, 6H), 2.44–2.40 (m, 1H), 2.28–2.09 (m, 5H), 1.94 (s, 1.2H), 1.92 (s, 1.8H), 1.43 (s, 3.5H), 1.40 (s, 5.5H)

[0531] The cyclization metathesis reaction was successfully carried out using the unprotected N-terminus of the compound 8-HCl to obtain the cyclic compound 9-HCl in ≥80% yield and LC purity ≥98%.

[0532] Example 1-19

[0533] Synthesis of (S)-2-(arylamino)-3-(4-(trifluoromethyl)phenyl)propionic acid (compound 10)

[0534] [Formula 36]

[0535]

[0536] (S)-2-amino-3-(4-(trifluoromethyl)phenyl)propionic acid (3.34 g, 14.3 mmol), acetonitrile (10 mL), water (8.3 mL), triethylamine (5.99 mL, 43.0 mmol), and allyl bromide (3.72 mL, 43.0 mmol) were added to a reaction vessel, and the reaction mixture was stirred at approximately 25 °C for 1 hour. The resulting precipitate was collected by filtration, and the obtained solid was dried under reduced pressure to give compound 10 (3.05 g, 77.9% yield) as a white solid.

[0537] UV intensity ratio: 96.4%

[0538] (Detection wavelength 210 nm, retention time 1.925 min, HPLC analysis conditions: Method 1, m / z = 274 [M+H]) + (ESI)

[0539] Example 1-20

[0540] Synthesis of (S)-N-(2-(arylamino)-3-(4-(trifluoromethyl)phenyl)propionyl)-N-methylglycine tert-butyl ester (compound 11)

[0541] [Formula 37]

[0542]

[0543] At approximately 25°C, compound 10 (2.51 g, 9.19 mmol), sarcosine tert-butyl hydrochloride (2.52 g, 13.9 mmol), acetonitrile (18 mL), and DBU (5.68 mL, 37.7 mmol) obtained in Examples 1-19 above were added to the reaction vessel. Then, at an external temperature of 0°C, T3P (50 wt% MeTHF solution, 7.38 mL) was added to the reaction vessel, and the resulting mixture was stirred at approximately 25°C for 1 hour. Toluene (20 mL) and 1 mol / L sodium hydroxide aqueous solution (13 mL) were added, the mixture was stirred for 15 minutes, and the aqueous layer was drained. The resulting organic layer was washed in this order with 5% sodium carbonate aqueous solution (13 mL), 5% sodium dihydrogen phosphate aqueous solution (20 mL × 3 times), and 10% sodium chloride aqueous solution (5 mL). The obtained organic layer was concentrated under reduced pressure and subjected to azeotropic dehydration with the addition of toluene (20 mL). Filtration and concentration of the resulting mixture yielded a residue (5.80 g) containing compound 11.

[0544] LCMS (ESI) retention time of compound 11: 2.768 min, m / z = 401 [M+H] + (HPLC analysis conditions: Method 1)

[0545] Example 1-21

[0546] Synthesis of (5S,8S)-5,7-diallyl-1-(9H-fluoren-9-yl)-4,10-dimethyl-3,6,9-trioxo-8-(4-(trifluoromethyl)benzyl)-2-oxa-4,7,10-triazadodecane-12-oic acid tert-butyl (compound Fmoc-12)

[0547]

[0548] At room temperature, the following were added to the reaction vessel: a residue (5.41 g) containing compound 11, obtained by the same method as in Examples 1-20 above; (S)-2-((9-H-fluorene-9-yl)methoxy)carbonyl)(methyl)amino)-4-pentenoic acid (3.92 g); acetonitrile (17 mL); MeTHF (9 mL); and DIPEA (7.46 mL). After the reaction vessel was filled with nitrogen, TCFH (4.81 g) was added, and the mixture was stirred at approximately 25°C for 3.5 hours. Then, MeTHF (20 mL) and a 5% aqueous solution of potassium carbonate (17 mL) were added, and the mixture was stirred at approximately 25°C. The aqueous layer was drained, and the resulting organic layer was washed with 5% sulfuric acid (17 mL) and a 5% aqueous solution of potassium carbonate (17 mL). The resulting organic layer was concentrated under reduced pressure, and then acetonitrile (20 mL) was added, and the mixture was concentrated. The resulting concentrated solution was cooled to 0°C, and the resulting precipitate was collected by filtration. The obtained wet solid was washed with acetonitrile (10 mL) and dried under reduced pressure to give compound Fmoc-12 (2.18 g) as a white solid.

[0549] LC retention time of compound Fmoc-12: 5.231 min (HPLC analysis conditions: Method 2)

[0550] Example 1-22

[0551] Synthesis of N-((S)-2-((S)-N-allyl-2-(methylamino)pent-4-enamide)-3-(4-(trifluoromethyl)phenyl)propionyl)-N-methylglycine tert-butyl hydrochloride (compound 12-HCl)

[0552] [Formula 39]

[0553]

[0554] Compound Fmoc-12 (2.18 g, 2.97 mmol), obtained in Examples 1-21 above, acetonitrile (7 mL), and DBU (0.45 mL) were added to a reaction vessel at approximately 25 °C, and the reaction mixture was stirred for 1.5 h. Then, water (0.54 mL), triethylamine (1.66 mL), and sodium bisulfite (0.77 g) were added to the reaction mixture, and the mixture was stirred at approximately 25 °C for 2 h. Toluene (30 mL) and 10% ammonia (16 mL) were added to the reaction mixture, the mixture was stirred, and then the aqueous layer was drained. The resulting organic layer was washed three times with 10% ammonia (16 mL) and then with 5% sodium chloride aqueous solution (10 mL). The resulting organic layer was concentrated under reduced pressure and subjected to three azeotropic dehydration cycles with the addition of toluene (20 mL).

[0555] An acetonitrile solution (1 mL) containing pyridine hydrochloride (0.36 g) was added to the obtained residue. Then MTBE (6 mL) and heptane (6 mL) were added, and the resulting mixture was stirred. The resulting precipitate was collected by filtration, and the obtained wet powder was washed with heptane (5 mL). The obtained solid was dried under reduced pressure to give 1.50 g of compound 12-HCl (2.74 mmol, yield 92.1%).

[0556] UV intensity ratio: 99.5%

[0557] (Detection wavelength 210 nm, retention time 3.030 min, HPLC analysis conditions: Method 1, m / z = 512 [M+H]) + (ESI)

[0558] Example 1-23

[0559] Synthesis of N-methyl-N-((S)-2-((S)-3-(methylamino)-2-oxo-2,3,4,7-tetrahydro-1H-aza-1-yl)-3-(4-(trifluoromethyl)phenyl)propionyl)glycine tert-butyl hydrochloride (compound 13-HCl)

[0560] [Formula 40]

[0561]

[0562] Compound 12-HCl (75.8 mg, 0.14 mmol), obtained in Examples 1-22 above, a second-generation Hoveyda-Grubbs catalyst (4.44 mg), acetone (1.02 mL), and HFIP (0.68 mL) were added to a reaction vessel. After the reaction vessel was filled with nitrogen, the reaction mixture was heated at an external temperature of 65 °C for 1 hour. The reaction mixture was allowed to cool to approximately 25 °C, and then sampled and analyzed by HPLC. The results showed a conversion of 98.1%, and no dimers formed by intermolecular reactions were detected. The reaction mixture was concentrated, and then acetone (1 mL) was added, and the resulting precipitate was filtered. The obtained wet solid was washed with acetone (1 mL), and the obtained solid was dried under reduced pressure to give compound 13-HCl (57.7 mg, 80.2% yield) as a white solid.

[0563] UV intensity ratio: 98.9%

[0564] (Detection wavelength 210 nm, retention time 2.733 min, HPLC analysis conditions: Method 1, m / z = 484 [M+H]) + (ESI)

[0565] 1 H-NMR (500 MHz, DMSO-d6) δ 9.44 (brs, 1H), 8.69 (brs, 1H), 7.62-7.42 (m, 4H), 5.81-5.35 (m, 3H), 4.75-4.70 (m, 1H), 4.38-4.29 (m, 1H), 4.11-3.87 (m, 2H), 3.83-3.60 (m, 1H), 3.14-2.81 (m, 5H), 2.65-2.71 (m, 1H), 2.22-2.07 (m, 4H), 1.40 (s, 9H)

[0566] The cyclization metathesis reaction was successfully carried out using the unprotected N-terminus of compound 12-HCl to obtain cyclic compound 13-HCl in ≥80% yield and LC purity ≥98%.

[0567] Example 1-24

[0568] Synthesis of (S)-N-(2-(but-3-en-1-ylamino)-3-(p-tolyl)propionyl)-N-methylglycine tert-butyl hydrochloride (compound 7-HCl)

[0569] [Formula 41]

[0570]

[0571] Compound 6 (1.10 g, 4.71 mmol), 1,1'-carbonyldiimidazole (0.92 g, 5.66 mmol), and THF (16.5 mL) obtained in Examples 1-11 above were added to the reaction vessel. After the reaction vessel was filled with nitrogen, trifluoromethanesulfonic acid (0.96 mL, 10.8 mmol) was added at 25 °C, and the mixture was stirred at 50 °C for 1.5 h. The mixture was cooled to 25 °C, and then a solution obtained by dissolving sarcosine tert-butyl hydrochloride (1.03 g, 5.66 mmol) in THF (2 mL), acetonitrile (3 mL), and DIPEA (3.8 mL, 21.7 mmol) were added to the mixture. The resulting mixture was stirred for 2 h. Then, 5% potassium carbonate aqueous solution (11 mL) was added, the mixture was stirred for 5 min, and the aqueous layer was removed. The obtained organic layers were washed with 10% sodium bisulfate aqueous solution (11 mL) and 5% sodium bisulfate aqueous solution (11 mL). Each aqueous layer was washed three times with MeTHF (11 mL). All organic layers were mixed and concentrated under reduced pressure. Acetonitrile (12 mL) and 2 M hydrochloric acid (5 mL) were added to the obtained residue, and the mixture was concentrated under reduced pressure. The resulting precipitate was filtered, washed with water, and then dried under reduced pressure to give 0.48 g of compound 7-HCl.

[0572] LCMS (ESI) retention time of compound 7: 2.689 min, m / z = 361 [M+H] + (HPLC analysis conditions: Method 1)

[0573] Example 1-25

[0574] Synthesis of N-((S)-2-((S)-N-(but-3-en-1-yl)-2-(methylamino)hex-5-enamide)-3-(p-tolyl)propionyl)-N-methylglycine tert-butyl hydrochloride (compound 14-HCl)

[0575] [Equation 42]

[0576]

[0577] Compound 7-HCl (0.89 g, 2.25 mmol), obtained by the same method as in Examples 1-24 above, (S)-2-((((9-H-fluorene-9-yl)methoxy)carbonyl)(methyl)amino)-5-hexenoic acid (1.07 g, 2.92 mmol), acetonitrile (4.5 mL), MeTHF (2.3 mL), and DIPEA (1.96 mL, 11.2 mmol) were added to the reaction vessel. TCFH (1.29 g) was added to the reaction mixture, and the mixture was stirred at approximately 25 °C for 2.5 h. Then, MeTHF (18 mL) and 5% aqueous potassium carbonate solution (9 mL) were added, the mixture was stirred, and the aqueous layer was removed. The obtained organic layer was washed with 5% sulfuric acid (5.4 mL) and 5% aqueous potassium carbonate solution (4.5 mL). The obtained organic layer was concentrated, acetonitrile (20 mL) was added, and azeotropic dehydration was performed. Acetonitrile (2 mL) and DBU (0.51 mL) were added to the obtained residue, and the mixture was stirred for 1 hour. DBU (0.34 mL) was added, and the mixture was stirred for 20 minutes. Triethylamine (1.25 mL), water (0.41 mL), and sodium bisulfite (0.58 g) were then added to the reaction mixture, and the mixture was stirred for 1 hour. Triethylamine (0.62 mL) was added to the reaction mixture, and the mixture was stirred for 45 minutes. Toluene (15 mL) and 10% ammonia (20 mL) were then added to the reaction mixture, the mixture was stirred, and the aqueous layer was removed. The obtained organic layer was washed four times with 10% ammonia (10 mL), and then washed with 5% sodium chloride aqueous solution (10 mL). The obtained organic layer was concentrated under reduced pressure, toluene (10 mL) was added, and azeotropic dehydration was performed. The obtained residue was filtered, the filtrate was concentrated, and then acetonitrile (1 mL) containing pyridine hydrochloride (0.27 g) was added. MTBE (10 mL) was added to the mixture, and the resulting mixture was stirred at about 25 °C for 1 hour. The mixture was cooled to 0 °C, and the resulting precipitate was filtered. The obtained wet solid was washed with MTBE (5 mL) and dried under reduced pressure to give compound 14-HCl (0.81 g).

[0578] UV intensity ratio: 99.3%

[0579] (Detection wavelength 210 nm, retention time 3.150 min, HPLC analysis conditions: Method 1, m / z = 486 [M+H]) + (ESI)

[0580] Example 1-26

[0581] Synthesis of N-methyl-N-((S)-2-((S,Z)-3-(methylamino)-2-oxo-2,3,4,5,8,9-hexahydro-1H-azacyclononaten-1-yl)-3-(p-tolyl)propionyl)glycine tert-butyl hydrochloride (compound 15-HCl)

[0582] [Formula 43]

[0583]

[0584] Compound 14-HCl (53.3 mg, 0.10 mmol), obtained in Examples 1-25 above, a second-generation Hoveyda-Grubbs catalyst (3.1 mg, 0.005 mmol), acetone (1 mL), and HFIP (0.12 mL) were added to the reaction vessel. After the reaction vessel was filled with nitrogen, the reaction mixture was heated at an external temperature of 60 °C for 1 hour. The reaction mixture was sampled and analyzed by HPLC. The results showed a conversion of 97.8% and a ratio of 6.1% of the dimer formed by intermolecular reaction to the product (15-HCl). The reaction mixture was stirred for another 1 hour and allowed to cool to approximately 25 °C, and then MTBE (1 mL) was added. The resulting precipitate was filtered, and the resulting wet powder was washed with a mixed solution of acetone and MTBE (0.4 mL, v / v ratio 1:1), and then washed with MTBE (1 mL). The obtained solid was dried under reduced pressure to give compound 15-HCl (19.7 mg, yield 39.1%).

[0585] UV intensity ratio: 98.2%

[0586] (Detection wavelength 210 nm, retention time 2.768 min, HPLC analysis conditions and method 2)

[0587] LCMS (ESI) retention time of compound 15: 2.696 min, m / z = 458 [M+H] + (HPLC analysis conditions: Method 1)

[0588] 1¹H-NMR (500 MHz, DMSO-d6, detected as a mixture of rotational isomers) δ 9.29 (brs, 1H), 8.55 (brs, 1H), 7.15–6.99 (m, 4H), 5.97–5.55 (m, 3H), 4.32–3.72 (m, 4H), 3.54–3.47 (m, 1H), 3.13–3.01 (m, 3H), 2.93–2.78 (m, 2H), 2.27–1.71 (m, 9H), 1.67 (s, 1.8H), 1.52 (s, 1.2H), 1.46 (s, 3.2H), 1.37 (s, 5.8H)

[0589] Example 1-27

[0590] Synthesis of (5S,8S)-5,7-di(but-3-en-1-yl)-1-(9H-fluoren-9-yl)-4,10-dimethyl-3,6,9-trioxo-8-(4-(trifluoromethyl)benzyl)-2-oxa-4,7,10-triazadodecane-12-oic acid tert-butyl (compound Fmoc-16)

[0591] [Formula 44]

[0592]

[0593] Compound 2-HCl (2.53 g, 5.61 mmol), obtained by the methods described in Examples 1-2 above, (S)-2-((((9-H-fluorene-9-yl)methoxy)carbonyl)(methyl)amino)-5-hexenoic acid (1.07 g, 7.03 mmol), acetonitrile (12.5 mL), MeTHF (6.3 mL), and DIPEA (4.89 mL) were added to the reaction vessel. Then, TCFH (3.20 g) was added to the reaction vessel, and the resulting mixture was stirred at approximately 25 °C for 2.5 h, and then allowed to stand for 23 h. Then, MeTHF (25 mL) and a 5% potassium carbonate aqueous solution (18 mL) were added, the mixture was stirred, and the aqueous layer was removed. The resulting organic layer was washed with 5% sulfuric acid (18 mL) and a 5% potassium carbonate aqueous solution (18 mL), and concentrated under reduced pressure. Acetonitrile (20 mL) was added to the obtained residue, and azeotropic dehydration was performed. The resulting precipitate was then filtered, and the obtained wet solid was washed with acetonitrile (10 mL). The obtained solid was dried under reduced pressure to give compound Fmoc-16 (2.32 g).

[0594] UV intensity ratio: 99.4%

[0595] (Detection wavelength 210 nm, retention time 5.590 min, HPLC analysis conditions and method 5)

[0596] Example 1-28

[0597] Research on the synthesis of N-((S)-2-((S,Z)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-2-oxo-2,3,4,5,8,9-hexahydro-1H-azacyclononatetraen-1-yl)-3-(4-(trifluoromethyl)phenyl)propionyl)-N-methylglycine tert-butyl ester (compound Fmoc-17)

[0598] [Formula 45]

[0599]

[0600] Compound Fmoc-16 (71.7 mg, 0.094 mmol), obtained in Examples 1-27 above, second-generation Hoveyda-Grubbs catalyst (2.9 mg, 0.0045 mmol), acetone (0.94 mL), and HFIP (0.11 mL) were added to the reaction vessel. After the reaction vessel was filled with nitrogen, the reaction mixture was heated at 60 °C for 1 hour. The reaction mixture was sampled and analyzed by HPLC. The results showed a conversion of 77.6% and a ratio of 161% between the dimer formed by intermolecular reaction and the product (Fmoc-17).

[0601] LCMS (ESI) retention time of compound Fmoc-17: 2.932 min, m / z = 756 [M+Na] + (HPLC analysis conditions: Method 3)

[0602] Table 4 below shows a comparison between the cyclization metathesis of the unprotected N-terminus compound 14-HCl (Examples 1-26) and the cyclization metathesis of the protected Fmoc compound Fmoc-16 (Examples 1-28).

[0603] [Formula 46]

[0604]

[0605] [Table 4]

[0606]

[0607] It has been confirmed that, compared with Fmoc-protected compound Fmoc-16, the use of compound 14-HCl, in which the N-terminus is unprotected, allows the cyclization metathesis reaction to proceed with higher conversion and in an intramolecular selective manner.

[0608] Example 1-29

[0609] Synthesis of (S)-2-(but-3-en-1-ylamino)-N,N-dimethyl-3-(4-(trifluoromethyl)phenyl)propionamide (compound 18)

[0610] [Formula 47]

[0611]

[0612] At approximately 25°C, compound 1 (2.21 g, 7.69 mmol), dimethylamine (2 M THF solution, 7.69 mL, 15.4 mmol), acetonitrile (6.6 mL), and DBU (3.48 mL) obtained in Example 1-1 above were added to the reaction vessel. Then, at an external temperature of 0°C, T3P (50 wt% MeTHF solution, 6.18 mL) was added to the reaction mixture, and the resulting mixture was stirred at approximately 25°C for 40 minutes. T3P (50 wt% MeTHF solution, 3 mL) and dimethylamine (2 M THF solution, 3.0 mL, 6.0 mmol) were added to the reaction mixture, and the mixture was stirred for 45 minutes. Then, MeTHF (22 mL) and 1 mol / L sodium hydroxide aqueous solution (11 mL) were added to the reaction mixture. After removing the aqueous layer, the obtained organic layer was washed twice with 1 mol / L sodium hydroxide aqueous solution (11 mL), twice with 5% sodium dihydrogen phosphate aqueous solution (11 mL), washed again with 1 mol / L sodium hydroxide aqueous solution (11 mL), and washed with 5% potassium carbonate aqueous solution (11 mL). The obtained organic layer was concentrated, MeTHF (20 mL) was added, and azeotropic dehydration was performed. The obtained residue was filtered and concentrated to give a residue (2.98 g) containing compound 18.

[0613] LCMS (ESI) retention time of compound 18: 2.207 min, m / z = 315 [M+H] + (HPLC analysis conditions: Method 1)

[0614] Example 1-30

[0615] Synthesis of (S)-N-(but-3-en-1-yl)-N-((S)-1-(dimethylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propane-2-yl)-2-(methylamino)pent-4-enamide hydrochloride (compound 19-HCl)

[0616] [Formula 48]

[0617]

[0618] Add to the reaction vessel the residue (2.98 g) containing compound 18 obtained in Examples 1-29 above, (S)-2-((9-H-fluorene-9-yl)methoxy)carbonyl)(methyl)amino)-4-pentenoic acid (2.70 g), acetonitrile (9.6 mL), and DIPEA (4.0 mL). Add TCFH (3.21 g) to the resulting mixture and stir at approximately 25 °C for 2.5 h. Then, add MeTHF (30 mL) and 5% potassium carbonate aqueous solution (12 mL) to the reaction mixture, stir the mixture, and remove the aqueous layer. Wash the obtained organic layer twice with 5% sulfuric acid (12 mL) and 5% potassium carbonate aqueous solution (12 mL). Concentrate the obtained organic layer under reduced pressure. Add MeTHF (30 mL) to the resulting mixture and perform azeotropic dehydration. Add acetonitrile (10 mL) and DBU (1.39 mL) to the obtained residue. The reaction mixture was stirred at approximately 25°C for 75 minutes. Triethylamine (4.29 mL), water (1.39 mL), and sodium bisulfite (1.99 g) were added, and the mixture was stirred for 2 hours. Then, toluene (40 mL) and 10% ammonia (40 mL) were added to the reaction mixture, the mixture was stirred, and the aqueous layer was removed. The resulting organic layer was washed three times with 10% ammonia (40 mL) and then with 5% sodium chloride aqueous solution (20 mL), and the organic layer was concentrated under reduced pressure. The azeotropic dehydration of the residue with toluene (20 mL) was repeated three times. The resulting slurry was filtered and concentrated. A solution prepared by dissolving pyridine hydrochloride (0.81 g) in acetonitrile (3 mL) was added to the residue. After adding MTBE (20 mL), the resulting mixture was stirred for 1 hour. The resulting precipitate was collected by filtration, and the resulting wet solid was washed with MTBE (5 mL). The obtained solid was dried under reduced pressure to give compound 19-HCl (2.05 g).

[0619] UV intensity ratio: 98.9%

[0620] (Detection wavelength 210 nm, retention time 2.560 min, HPLC analysis conditions: Method 1, m / z = 426 [M+H]) + (ESI)

[0621] Example 1-31

[0622] Synthesis of (S)-N,N-dimethyl-2-((S,Z)-3-(methylamino)-2-oxo-3,4,7,8-tetrahydroazacyclooctatetraen-1(2H)-yl)-3-(4-(trifluoromethyl)phenyl)propionamide hydrochloride (compound 20-HCl)

[0623] [Formula 49]

[0624]

[0625] Compound 19-HCl (98.5 mg, 0.21 mmol), obtained in Examples 1-30 above, a second-generation Hoveyda-Grubbs catalyst (6.6 mg, 0.011 mmol), acetone (1.5 mL), and HFIP (0.5 mL) were added to the reaction vessel. After the reaction vessel was filled with nitrogen, the reaction mixture was heated at an external temperature of 65 °C for 1 hour. The reaction mixture was then sampled and analyzed by HPLC. The results showed a conversion of 89.8% and a ratio of 4.6% of the product (20-HCl) to the dimer formed by the intermolecular reaction. After allowing the reaction mixture to cool to approximately 25 °C, the resulting precipitate was filtered, and the obtained wet solid was washed with acetone (2 mL). The obtained solid was dried under reduced pressure to give compound 20-HCl (46.9 mg, yield 50.7%).

[0626] UV intensity ratio: 98.2%

[0627] (Detection wavelength 210 nm, retention time 2.135 min, HPLC analysis conditions: Method 1, m / z = 398 [M+H]) + (ESI)

[0628] 1H-NMR (DMSO-d6, 500 MHz) δ: 9.55 (brs, 1H), 8.57 (brs, 1H), 7.59 (d, J= 8.1Hz, 2H), 7.50 (d, J = 8.1 Hz, 2H), 5.72 (dd, J = 9.7, 5.5 Hz, 1H), 5.62-5.58 (m,1H), 5.42-5.37 (m, 1H), 4.50 (t, J = 8.0 Hz, 1H), 3.79-3.73 (m,1H), 3.59-3.53 (m,1H), 3.11-3.01 (m, 2H), 2.88-2.81 (m, 7H), 2.46-2.41 (m, 1H), 2.22-2.06 (m, 2H), 1.86 (s, 3H)

[0629] Cyclic dipeptide 20-HCl was successfully obtained via a cyclization metathesis reaction with a purity ≥98%.

[0630] Example 1-32

[0631] Synthesis of N-((S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-N-(but-3-en-1-yl)pent-4-enamide)-3-(4-(trifluoromethyl)phenyl)propionyl)-N-methylglycine tert-butyl ester (compound Fmoc-21)

[0632] [Formula 50]

[0633]

[0634] Compound 2-HCl (5.01 g, 11.1 mol), synthesized in Examples 1-2, was added to the reaction vessel. Then, (S)-2-(((9-H-fluorene-9-yl)methoxy)carbonyl)amino)-4-pentenoic acid (4.74 g), 1,3-dimethyl-2-imidazolidineone (25 mL), and 2,4,6-trimethylpyridine (7.35 mL) were added to the reaction vessel. TCFH (4.93 g) was then added to the mixture, and the resulting mixture was stirred at an external temperature of 25 °C for 7 hours, followed by standing of the reaction mixture for 16 hours. A 5% aqueous potassium carbonate solution (25 mL) and MeTHF (30 mL) were added to the reaction vessel, the mixture was stirred, and the aqueous layer was removed. The resulting organic layer was washed in this order with 5% sulfuric acid (25 mL) and 5% aqueous potassium carbonate solution (25 mL). The obtained organic layer was concentrated under reduced pressure, and azeotropic dehydration was repeated twice with the addition of MeTHF (20 mL) to obtain a residue containing compound Fmoc-21. The obtained residue was purified by reversed-phase column chromatography (mobile phase: water / acetonitrile v / v 40:60 → 0:100). The collected solution was concentrated, and azeotropic dehydration was repeated with the addition of acetonitrile to give Fmoc-21 (5.00 g) as a white solid.

[0635] UV intensity ratio: 97.9%

[0636] (Detection wavelength 210 nm, retention time 5.182 min, HPLC analysis conditions: Method 1, m / z = 756 [M+H]) + (ESI)

[0637] Example 1-33

[0638] Synthesis of N-((S)-2-((S)-2-amino-N-(but-3-en-1-yl)pent-4-enamide)-3-(4-(trifluoromethyl)phenyl)propionyl)-N-methylglycine tert-butyl ester (compound 21)

[0639] [Equation 51]

[0640]

[0641] The compound Fmoc-21 (3.02 g) obtained in Examples 1-32 was dissolved in acetonitrile (15 mL) in a reaction vessel. DBU (0.62 mL) was then added, and the resulting mixture was stirred at an external temperature of 25°C for 30 minutes. Triethylamine (2.29 mL), sodium bisulfite (1.06 g), and water (0.74 mL) were then added to the reaction mixture, and the mixture was stirred at an external temperature of 25°C for 1.5 hours. Toluene (40 mL) and 10% ammonia (24 mL) were added to the reaction vessel, and the resulting mixture was stirred for 10 minutes, after which the aqueous layer was drained. The resulting organic layer was washed with 10% ammonia (24 mL) and then with 10% sodium chloride aqueous solution (24 mL). The resulting organic layer was concentrated under reduced pressure. Azeotropic dehydration was performed with the addition of toluene (20 mL) to give a residue containing compound 21. The obtained residue was purified by reversed-phase column chromatography (mobile phase: water / acetonitrile, volume ratio 80:20 → 40:60). The collected solution was concentrated and subjected to repeated azeotropic dehydration with the addition of acetonitrile to give 1.36 g of compound 21 as a pale yellow oil (content 91.6%, NMR content calculated by qNMR and UV intensity ratio).

[0642] UV intensity ratio: 93.7%

[0643] (Detection wavelength 210 nm, retention time 3.171 min, HPLC analysis conditions: Method 2)

[0644] Example 1-34

[0645] Synthesis of N-((S)-2-((S,Z)-3-(((benzyloxy)carbonyl)amino)-2-oxo-3,4,7,8-tetrahydroazacyclooctatetraen-1(2H)-yl)-3-(4-(trifluoromethyl)phenyl)propionyl)-N-methylglycine tert-butyl ester (compound Cbz-22)

[0646] [Equation 52]

[0647]

[0648] Compound 21 (130.8 mg, 91.6%, 0.23 mmol), synthesized in Examples 1-33, acetone (2.34 mL), HFIP (0.24 mL), boron trifluoride-diethyl ether complex (44.5 μL, 0.35 mmol), and the second-generation Hoveyda-Grubbs catalyst (10.3 mg, 16.4 mmol) were added to the reaction vessel. After the reaction vessel was filled with nitrogen, the mixture in the reaction vessel was stirred at an external temperature of 65 °C for 1 hour. The reaction mixture was sampled and analyzed by HPLC. It was confirmed that the conversion was 95.1%, and the ratio of the dimer formed by the intermolecular reaction to product (22) was 7.4%. The reaction mixture was allowed to cool to 25 °C, and then triethylamine (52.3 μL) was added, and the mixture was stirred. MTBE (3 mL) and 5% potassium carbonate aqueous solution (1 mL) were added to the reaction mixture, the mixture was stirred, and then the aqueous layer was drained. The obtained organic layer was concentrated. Acetonitrile (1 mL), N-benzyloxycarbonyloxysuccinimide (58.7 mg), and DIPEA (40.8 μL) were then added to the obtained residue, and the mixture was stirred at an external temperature of 25 °C for 30 min. The reaction mixture was concentrated under reduced pressure, and then MTBE (3 mL) and 1 M sodium hydroxide aqueous solution (1 mL) were added. The resulting mixture was stirred, and then the aqueous layer was removed. The obtained organic layer was washed with 10% potassium bisulfate aqueous solution (1 mL), and then with 5% potassium carbonate aqueous solution (1 mL). The obtained organic layer was concentrated under reduced pressure, and the obtained residue was purified twice by reversed-phase column chromatography (mobile phase: water / acetonitrile, first: v / v 45:55 → 20:80, second: v / v 45:55 → 25:75). The collected solution was concentrated and subjected to repeated azeotropic dehydration in the presence of acetonitrile to give 47.2 mg of compound Cbz-22 (yield: 32.6%) as a white solid.

[0649] UV intensity ratio: 98.3%

[0650] (Detection wavelength 210 nm, retention time 4.398 min, HPLC analysis conditions: Method 1, m / z = 640 [M+H]) + (ESI)

[0651] 1¹H-NMR (500 MHz, DMSO-d6, detected as a mixture of rotational isomers) δ 7.54 (t, J = 7.8 Hz, 2H), 7.46–7.18 (m, 8H), 5.66–5.59 (m, 1.6H), 5.50–5.45 (m, 0.6H), 5.36–5.29 (m, 0.8H), 5.05–5.01 (m, 0.9H), 4.95–4.91 (m, 1.1H), 4.74–4.68 (m, 1H), 4.24 (d, J = 18.5 Hz, 0.4H), 3.98 (d, J = 17.0 Hz, 0.6H), 3.83–3.42 (m, 3H), 3.18–3.08 (m,1H), 2.86-2.74 (m, 4H), 2.64-2.58 (m, 1H), 2.51-2.36 (m, 1H), 2.31-2.08 (m, 2H), 1.46-1.21 (m, 9H)

[0652] Example 1-35

[0653] Synthesis of (S)-(1-oxo-1-(phenylamino)propane-2-yl)carbamate tert-butyl ester (compound Boc-23)

[0654] [Formula 53]

[0655]

[0656] N-(tert-butoxycarbonyl)-L-alanine (3.98 g), acetonitrile (4 mL), aniline (2.11 mL), and N-methylmorpholine (6.94 mL) were added to the reaction vessel. HATU (8.96 g) was then added to the reaction mixture at an external temperature of 0 °C, and the resulting mixture was stirred at an external temperature of 25 °C for 1.5 h. A 5% aqueous solution of potassium carbonate (16 mL) and 4-methyltetrahydropyran (40 mL) were then added to the reaction mixture, and the mixture was stirred. The aqueous layer was drained, and the resulting organic layer was washed twice with 10% ammonia (20 mL) and then twice with 5% sodium dihydrogen phosphate aqueous solution (20 mL). The resulting organic layer was concentrated under reduced pressure, and azeotropic dehydration was repeated twice with the addition of acetonitrile. MTBE (10 mL) was added to the obtained concentrated product, and the mixture was stirred. The resulting solid was collected by filtration, and the obtained wet solid was washed with MTBE (5 mL). The obtained wet solid was dried under reduced pressure to give compound Boc-23 (3.64 g) as a white solid.

[0657] UV intensity ratio: 99.6%

[0658] (Detection wavelength 210 nm, retention time 2.732 min, HPLC analysis conditions: Method 1, m / z = 287 [M+H]) + (ESI)

[0659] Example 1-36

[0660] Synthesis of (S)-2-(amino)-N-phenylpropionamide (compound 23)

[0661] [Formula 54]

[0662]

[0663] Compound Boc-23 (3.64 g) obtained in Examples 1-35 and acetonitrile (15 mL) were added to the reaction vessel. Then, methanesulfonic acid (2.68 mL) was added to the mixture. The resulting mixture was then stirred at an external temperature of 25 °C for 3 hours. At an external temperature of 0 °C, 8 M aqueous sodium hydroxide solution (6.89 mL) and 4-methyltetrahydropyran (15 mL) were added to the reaction mixture, and the mixture was then stirred. The organic layer was collected, and the aqueous layer was extracted with 4-methyltetrahydropyran (20 mL). The obtained organic layers were mixed and concentrated under reduced pressure. Two azeotropic dehydrations were performed with the addition of 4-methyltetrahydropyran (20 mL). The obtained residue was filtered and washed with 4-methyltetrahydropyran (10 mL). The filtrate and washing solution were mixed, and the mixture was then concentrated to give a residue (3.13 g) containing compound 23.

[0664] LCMS (ESI) retention time of compound 23: 1.118 min, m / z = 165 [M+H] + (HPLC analysis conditions: Method 1)

[0665] Example 1-37

[0666] Synthesis of ((S)-1-(allyl((S)-1-oxo-1-(phenylamino)propane-2-yl)amino)-1-oxopent-4-en-2-yl)(methyl)carbamate (9H-fluorene-9-yl)methyl (compound Fmoc-24)

[0667] [Formula 55]

[0668]

[0669] The residue containing compound 23 obtained in Examples 1-36 (2.83 g) and DMF (6.1 mL) were added to the reaction vessel. Then, DIPEA (3.25 mL) and allyl bromide (1.29 mL) were added to the mixture. The mixture was then stirred at an external temperature of 25°C for 2 hours. Next, acetonitrile (6.1 mL), (S)-2-(((9-H-fluorene-9-yl)methoxy)carbonyl)(methyl)amino)-4-pentenoic acid (3.49 g), DIPEA (5.2 mL), and TCFH (4.14 g) were added to the reaction mixture. The resulting mixture was then stirred at an external temperature of 25°C for 3 hours. A 5% aqueous solution of potassium carbonate (20 mL) and MTBE (30 mL) were added to the reaction mixture, the mixture was stirred, and then the aqueous layer was removed. The obtained organic layer was washed in the following order: 20 mL of 5% potassium carbonate aqueous solution, 20 mL of 5% sulfuric acid (twice), and 20 mL of 5% potassium carbonate aqueous solution. The obtained organic layer was concentrated under reduced pressure and subjected to two azeotropic dehydration processes with the addition of acetonitrile (20 mL). The obtained residue was purified by reversed-phase column chromatography (mobile phase: water / acetonitrile v / v ratio 50:50 → 15:85). The collected solution was concentrated and subjected to repeated azeotropic dehydration with the addition of acetonitrile to give compound Fmoc-24 (2.63 g) as a white solid.

[0670] UV intensity ratio: 97.9%

[0671] (Detection wavelength 210 nm, retention time 4.475 min, HPLC analysis conditions: Method 1, m / z = 560 [M+H]) + (ESI)

[0672] Example 1-38

[0673] Synthesis of (S)-N-allyl-2-(methylamino)-N-((S)-1-oxo-1-(phenylamino)propane-2-yl)pent-4-enamide hydrochloride (compound 24-HCl)

[0674] [Formula 56]

[0675]

[0676] Compound Fmoc-24 (2.63 g) obtained in Examples 1-37 and acetonitrile (8 mL) were added to the reaction vessel. DBU (0.37 mL) was then added to the mixture, and the resulting mixture was stirred at an external temperature of 25 °C for 75 min. MTBE (26 mL) and a 5% aqueous solution of potassium carbonate (13 mL) were added to the reaction mixture, which was then stirred and the aqueous layer was removed. 0.5 M hydrochloric acid (15 mL) was added to the obtained organic layer, which was then stirred and the organic layer was removed. Potassium carbonate (1.40 g) was added to the obtained aqueous layer, and the resulting mixture was further stirred. 4-Methyltetrahydropyran (25 mL) was added to the mixture, and the mixture was further stirred. The resulting aqueous layer was removed, and the obtained organic layer was concentrated under reduced pressure. Azeotropic dehydration was performed with the addition of 4-methyltetrahydropyran (20 mL). The resulting residue was then filtered, and the filtrate was concentrated. Acetonitrile (20 mL) and 6M hydrochloric acid (0.73 mL) were added to the obtained residue, and the mixture was concentrated under reduced pressure. Acetonitrile (5 mL) and MTBE (10 mL) were added to the obtained residue, and the mixture was stirred until a solid precipitate formed. MTBE (20 mL) was added, the mixture was stirred further, and the resulting solid was collected by filtration. The obtained wet solid was washed with MTBE (10 mL). The obtained wet solid was dried under reduced pressure to give compound 24-HCl (1.21 g) as a white solid.

[0677] UV intensity ratio: 99.3%

[0678] (Detection wavelength 210 nm, retention time 1.991 min, HPLC analysis conditions: Method 1, m / z = 316 [M+H]) + (ESI)

[0679] Example 1-39

[0680] Synthesis of (S)-2-((S)-3-(methylamino)-2-oxo-2,3,4,7-tetrahydro-1H-aza-1-yl)-N-phenylpropionamide (compound 25)

[0681]

[0682] Compound 24-HCl (86.4 mg, 0.25 mmol), obtained in Examples 1-38, second-generation Hoveyda-Grubbs catalyst (7.69 mg, 0.012 mmol), acetone (2.5 mL), and HFIP (0.28 mL) were added to the reaction vessel. After the reaction vessel was filled with nitrogen, the mixture in the reaction vessel was heated at an external temperature of 65 °C for 2 hours. The reaction mixture was sampled and analyzed by HPLC. The results showed a conversion of 98.8%, and no dimers formed by intermolecular reactions were detected. The reaction mixture was allowed to cool to approximately 25 °C and then concentrated under reduced pressure. MTBE (3 mL) and 0.5 M hydrochloric acid (3 mL) were added to the obtained residue, and the mixture was stirred and the organic layer was removed. Potassium carbonate (0.23 g) was added to the obtained aqueous layer. The mixture was stirred, and the extraction was repeated three times with the addition of 4-methyltetrahydropyran (3 mL). The obtained organic layers were mixed and concentrated under reduced pressure. Azeotropic dehydration was performed with the addition of 10 mL of 4-methyltetrahydropyran. The resulting residue was purified by reversed-phase column chromatography (mobile phase: water / acetonitrile, v / v ratio 95:5 → 65:35). The collected solution was concentrated and azeotropic dehydration was repeated with the addition of acetonitrile to give compound 25 (39.8 mg, yield: 56.4%) as a brown oil.

[0683] UV intensity ratio: 98.8%

[0684] (Detection wavelength 210 nm, retention time 1.643 min, HPLC analysis conditions: Method 1, m / z = 288 [M+H]) + (ESI)

[0685] 1 H-NMR (500 MHz, DMSO-d6) δ 9.75 (s, 1H), 7.54 (d, J = 7.6 Hz, 2H), 7.28 (t, J = 7.6 Hz, 2H), 7.03 (t, J = 7.6 Hz, 1H), 5.73-5.62 (m, 2H), 5.09 (q, J =7.0 Hz, 1H), 4.27-4.23 (m, 1H), 3.82-3.73 (m, 2H), 2.47-2.23 (m, 5H), 2.13-1.91(m, 1H), 1.29 (d, J = 7.0 Hz, 3H)

[0686] [Industrial Applicability]

[0687] This invention provides a method for the efficient production of peptide compounds having a peptide structure with a central ring. The production method of this invention enables the reduction of production costs of peptide compounds and also reduces environmental impact, thus making it particularly useful for large-scale peptide synthesis.

Claims

1. A method for producing a compound or a salt thereof represented by formula (1), said method comprising the step of contacting the compound or a salt thereof represented by formula (2) with a catalyst, i.e., a metathesis step: in R 1 It is hydrogen. R 2 It is hydrogen or C1-C6 alkyl; R 3 Hydrogen, optionally substituted C1-C6 alkyl, optionally substituted halo-C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 ynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 14 Aryl, optionally substituted 5- to 14-membered heteroaryl, optionally substituted C7-C 14 Aryl groups, optionally substituted 3- to 14-membered heterocyclic groups, optionally substituted 5- to 10-membered heteroaryl-C1-C6 alkyl groups, optionally substituted C1-C6 alkoxy-C1-C6 alkyl groups, optionally substituted C1-C6 alkylthio-C1-C6 alkyl groups, optionally substituted C1-C6 alkylsulfinyl-C1-C6 alkyl groups, optionally substituted C1-C6 alkylsulfonyl-C1-C6 alkyl groups, optionally substituted carboxyl-C1-C6 alkyl groups, optionally substituted C7-C6 alkyl groups. 14 Ararylalkoxy-C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl-C1-C6 alkyl, optionally substituted C3-C8 cycloalkoxy-C1-C6 alkyl, optionally substituted 4- to 7-membered heterocyclic-C1-C3 alkyl, optionally substituted 5- to 10-membered heteroaryl-C1-C6 alkoxy-C1-C6 alkyl, or optionally substituted aminocarbonyl, wherein, The relevant amino groups are selected from the group consisting of: -NH2, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, N-C1-C6 alkyl-N-C2-C6 alkenylamino, N-C1-C6 alkyl-N-C1-C6 alkoxy-C1-C6 alkylamino, and 4- to 9-membered cyclic amino groups. R 4 OR 5 NHR 5 ', an amino acid residue or a peptide chain containing 1 to 20 amino acid residues, wherein the amino acid residues and the peptide chain may have protecting groups, R 5 As a protecting group against the carboxyl group, R 5 ' is a protecting group targeting the amide group, n is an integer from 1 to 4, and X is optionally a substituted C1-C3 alkylene, -CH2OCH2-, or -CH2SCH2-.

2. A method for producing a compound or a salt thereof represented by formula (3), the method comprising the step of hydrogenating a compound or a salt thereof represented by formula (1), the compound or a salt thereof being obtained by the method according to claim 1: Where R 1 R 2 R 3 R 4 , n and X are respectively related to R in [1] 1 R 2 R 3 R 4 , n and X have the same meaning.

3. The method according to claim 1 or 2, wherein the catalyst is a metal-alkylene complex.

4. The method according to any one of claims 1 to 3, wherein the compound represented by formula (2) or a salt thereof is a salt of the compound represented by formula (2).

5. The method according to any one of claims 1 to 3, wherein the compound represented by formula (2) or a salt thereof is a compound represented by formula (2), and an acid is used in the metathesis step.

6. The method according to any one of claims 1 to 5, wherein an alcohol and / or a Bronsted acid are further used as additives in the metathesis step, and the pKa of the additive is 4 to 17.

7. The method according to any one of claims 1 to 6, wherein the metathesis step is performed by a liquid-phase synthesis method.

8. The method according to claim 7, wherein the solvent used in the liquid-phase synthesis method is one or more of the group consisting of: acetone, methyl tert-butyl ether, dimethyl carbonate, ethyl acetate, toluene, and dichloromethane.

9. The method according to claim 7 or 8, wherein in the liquid-phase synthesis method, the concentration of the compound represented by formula (2) or a salt thereof is from 0.01 mol / L to 0.5 mol / L.

10. The method according to any one of claims 1 to 9, wherein R 2 It is hydrogen or a straight-chain C1-C3 alkyl group.

11. The method according to any one of claims 1 to 10, wherein R 3 It is hydrogen, C1-C6 alkyl, or optionally C7-C substituted with halogenated C1-C3 alkyl or C1-C6 alkyl. 14 Aryl alkyl group.

12. The method according to any one of claims 1 to 11, wherein R 4 OR 5 NHR 5' , amino acid residues or peptide chains containing 2 to 13 amino acid residues, R 5 As a protecting group against the carboxyl group, R 5 ' is a protecting group against the amide group, and The 2 to 13 amino acid residues are selected from one or more of the following groups: glycine, alanine, isoleucine, leucine, methionine, phenylalanine, tyrosine, N-methylglycine, N-methylalanine, N-methylisoleucine, N-methylleucine, N-methylmethionine, N-methylphenylalanine, and N-methyltyrosine.

13. The method according to any one of claims 1 to 12, wherein n is an integer of 1 or 2.

14. The method according to any one of claims 1 to 13, wherein X 1 The group consisting of the following is selected: Fmoc group, Cbz group, Troc group, Alloc group, Teoc group, TSoc group, BIBSoc group, IPCSoc group, BBSoc group, CHBSoc group, CDBSoc group, and Boc group.

15. The method according to any one of claims 1 to 14, wherein X is an optionally substituted C1-C3 alkylene group.

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