Method for producing peptide compound having ring structure

Abstract

The present invention provides a novel ring-closing metathesis reaction for constructing a peptide structure having a medium ring. The present invention provides a method for performing the ring-closing metathesis reaction, wherein the ring-closing metathesis reaction is carried out at a low dilution condition (for example, a concentration of 0.1 mol / L). The present invention provides a method for performing a ring-closing metathesis reaction suitable for mass production.

Description

Method for producing peptide compounds having a ring structure

[0001] The present invention relates to a method for producing a peptide compound having a ring structure by utilizing a ring-closing metathesis reaction.

[0002] In recent years, it has been discovered that some cyclic peptide compounds containing unnatural amino acids have improved metabolic stability and membrane permeability (Non-Patent Documents 1 and 2). Some of these cyclic peptides have a dipeptide structure containing a medium-sized ring (Patent Document 1). Among these medium-sized rings, those with 5- to 7-membered rings are called Friedinger lactams. Friedinger lactams have the property of being able to change pharmacological activity and metabolic stability by constraining their conformation, and are structures that are sometimes encountered in drug design (Non-Patent Document 3).

[0003] Medium-sized rings are typically formed by ring-closing metathesis reactions using ruthenium-alkylidene complexes, such as the Hoveyda-Grubbs catalyst. When performing this reaction, substrates whose N-terminal amino groups are protected with Boc or Fmoc are typically used (Non-Patent Documents 4 and 5). However, these methods require high dilution conditions (e.g., 0.01 mol / L) or less, as intermolecular reactions compete with the desired ring-closing metathesis reaction (i.e., intramolecular reaction), resulting in poor yields of the target product. On the other hand, when ring-closing metathesis reactions are performed under high dilution conditions, the low substrate concentration reduces the rate of the desired ring-closing metathesis reaction, leading to catalyst deactivation and potentially requiring an increased catalyst amount and an additional catalyst removal step. Furthermore, high dilution conditions require the use of large amounts of solvent, making them unsuitable for mass synthesis, such as the production of active pharmaceutical ingredients, from a productivity perspective.

[0004] International Publication No. 2022 / 234853

[0005] Acc. Chem. Res., 2008, 41,1331-1342.Angew. Chem. Int. Ed., 2013, 52,254-269.Science, 1980, 210, 676-658.J.Org.Chem.,2003,68,62-69.J.Org.Chem.,2015,80,4904-4918.

[0006] The present invention has been made in view of these circumstances. In one aspect, an object is to establish a novel ring-closing metathesis reaction for constructing a peptide structure containing a medium-sized ring. In another aspect, an object is to establish a method for performing the ring-closing metathesis reaction under low dilution conditions (e.g., 0.1 mol / L). In another aspect, an object is to establish a method for performing the ring-closing metathesis reaction in high yield. In another aspect, an object is to establish a method for performing the ring-closing metathesis reaction in which the generation of by-products is suppressed. In another aspect, an object is to establish a method for performing the ring-closing metathesis reaction suitable for mass production.

[0007] As a result of extensive investigations aimed at solving the above-mentioned problems, the present inventors have found that, in the presence of a catalyst such as a metal-alkylidene complex, a ring-closing metathesis reaction can proceed while maintaining high intramolecular reaction selectivity even under low dilution conditions by using a substrate that is an amino acid with an unprotected N-terminal amino group.

[0008] In one non-limiting specific embodiment, the present invention includes the following: [1] A method for producing a compound represented by formula (1) or a salt thereof, the method comprising a step of contacting a compound represented by formula (2) or a salt thereof with a catalyst (metathesis step). [In the formula, R １ is hydrogen, and R ２ is hydrogen or C １ -C ６ alkyl, R ３ is hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted haloC １ -C ６ Alkyl, optionally substituted C ２ -C ６Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C ３ -C ８ Cycloalkyl, optionally substituted C ６ -C １４ Aryl, optionally substituted 5- to 14-membered heteroaryl, optionally substituted C ７ -C １４ Aralkyl, optionally substituted 3- to 14-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl C １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkoxy C １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkylsulfanyl C １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkylsulfinyl C １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkylsulfonyl C １ -C ６ Alkyl, optionally substituted carboxy C １ -C ６ Alkyl, optionally substituted C ７ -C １４ Aralkoxy C １ -C ６ Alkyl, optionally substituted C ３ -C ８ Cycloalkyl C １ -C ６ Alkyl, optionally substituted C ３ -C ８ Cycloalkoxy C １ -C ６ Alkyl, optionally substituted 4- to 7-membered heterocyclyl C １ -C ３ Alkyl, optionally substituted 5- to 10-membered heteroaryl C １ -C６ Alkoxy C １ -C ６ alkyl, or optionally substituted aminocarbonyl (wherein the amino is —NH ２ , Mono C １ -C ６ Alkylamino, DiC １ -C ６ Alkylamino, N—C １ -C ６ Alkyl-N—C ２ -C ６ Alkenylamino, N—C １ -C ６ Alkyl-N—C １ -C ６ Alkoxy C １ -C ６ alkylamino, and 4- to 9-membered cyclic amino; ４ is OR ５ , N.H.R. ５ R', an amino acid residue, or a peptide chain containing 1 to 20 amino acid residues, the amino acid residue and the peptide chain may have a protecting group; ５ is a protecting group for a carboxy group, R ５ ' is a protecting group for an amide group, n is an integer of 1 to 4, and X is an optionally substituted C １ -C ３ Alkylene, —CH ２ OCH ２ - or -CH ２ SCH ２ [2] A method for producing a compound represented by formula (3) or a salt thereof, the method comprising a step of hydrogenating a compound represented by formula (1) or a salt thereof obtained by the method according to [1]. [In the formula, R １ , R ２ , R ３ , R ４ , n, and X are R in [1] １ , R ２ , R ３ , R ４, n, and X.] [3] A method for producing a compound represented by formula (4) or a salt thereof, the method comprising a step of protecting an amino group of a compound represented by formula (1) or a salt thereof obtained by the method described in [1] with a carbamate protecting group. [In the formula, R ２ , R ３ , R ４ , n, and X are R in [1] ２ , R ３ , R ４ , n, and X; １ is a carbamate protecting group.] [4] A method for producing a compound represented by formula (5) or a salt thereof, the method comprising a step of protecting an amino group of a compound represented by formula (3) or a salt thereof obtained by the method described in [2] with a carbamate protecting group. [In the formula, R ２ , R ３ , R ４ , n, and X are R in [1] ２ , R ３ , R ４ , n, and X; １is a carbamate protecting group.] [5] The method according to any one of [1] to [4], wherein the catalyst is a metal-alkylidene complex. [6] The method according to any one of [1] to [5], wherein the catalyst is a ruthenium-alkylidene complex, a molybdenum-alkylidene complex, or a tungsten-alkylidene complex. [7] The method according to any one of [1] to [6], wherein the catalyst is a ruthenium-alkylidene complex. [8] The method according to any one of [1] to [7], wherein the catalyst is a ruthenium-alkylidene complex having a phosphine and / or an N-heterocyclic carbene as a ligand. [9] The catalyst is a first-generation Grubbs catalyst (dichloro(benzylidene)bis(tricyclohexylphosphine)ruthenium(II)), a second-generation Grubbs catalyst (dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](benzylidene)(tricyclohexylphosphine)ruthenium(II)), a third-generation Grubbs catalyst (dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](benzylidene)bis(3-bromopyridine)ruthenium(II)), a Stewart-Grubbs catalyst (dichloro[1,3-bis(2-methylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II)), a nitro-Grela catalyst (dichloro bis[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene][(2-isopropoxy-5-nitrobenzylidene)]ruthenium(II)), Zhan catalyst-1B (dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene][[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 catalysts ((1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium), [1,3-bis(2,6-isopropylphenyl)-2-imidazolidinylidene]dichloro(2-isopropoxybenzylidene)ruthenium(II), bis[1-(2,6-diethylphenyl)-3,5,5-trimethyl-3-phenylpyrrolidin-2-ylidene](3-phenyl

[10] The method according to any one of [1] to [8], wherein the compound is [1-(2,6-diethylphenyl)-3,5,5-trimethyl-3-phenyl-2-pyrrolidin-2-yl](2-isopropoxy-5-nitrobenzylidene)ruthenium(II) chloride, [1-(2,4,6-trimethylphenyl)-3,5,5-trimethyl-3-phenyl-2-pyrrolidin-2-yl](2-isopropoxy-5-nitrobenzylidene)ruthenium(II).

[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-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium), or [1-[2,4,6-trimethylphenyl]-3,5,5-trimethyl-3-phenyl-2-pyrrolinylidene]dichloro(2-isopropoxybenzylidene)ruthenium(II).

[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).

[12] The method according to

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

[13] The method according to

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

[14] The method according to

[12] , wherein the salt of the compound represented by formula (2) is a hydrochloride.The method according to

[12] or

[13] .

[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.

[16] The method according to

[15] , wherein the acid is a Brønsted acid having a pKa of 3 or less. [16-1] The method according to

[16] , wherein the Brønsted acid is at least one Brønsted acid selected from the group consisting of hydrogen chloride, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, paratoluenesulfonic acid, trifluoromethanesulfonic acid, and trifluoroacetic acid.

[17] The method according to

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

[18] The method according to

[15] , wherein the acid is a Lewis acid. [18-1] The method according to

[18] , wherein the Lewis acid is at least one Lewis acid selected from the group consisting of boron trihalides and solvated complexes thereof, titanium tetrahalides, and tetraalkoxytitaniums.

[19] The method according to

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

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

[10] , wherein an alcohol and / or a Bronsted acid is further used as an additive in the metathesis step, and the additive has a pKa of 4 to 17. [20-1] The method according to any one of

[12] ,

[16] , or

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

[21] The method according to

[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.

[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.

[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 1 g of the compound represented by formula (2). [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 1 g of the compound represented by formula (2).

[24] The metathesis step is carried out by a liquid phase synthesis method.

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

[23] .

[25] The method according to

[24] , wherein the solvent used in the liquid phase synthesis method comprises one or more selected from the group consisting of ketone solvents, nitrile solvents, halogenated solvents, ether solvents, amide solvents, ester solvents, aromatic hydrocarbon solvents, aliphatic hydrocarbon solvents, and carbonate ester solvents.

[26] 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, the nitrile-based solvent is one or more selected from the group consisting of acetonitrile and propionitrile, the halogen-based solvent is one or more selected from the group consisting of dichloromethane, chloroform, and 1,2-dichloroethane, the ether-based solvent is one or more selected from the group consisting of diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, 4-methyltetrahydropyran, 1,3-dioxolane, 1,4-dioxane, 1,2-dimethoxyethane, diisopropyl ether, methyl t-butyl ether, diglyme, triglyme, anisole, and tetraglyme, The amide solvent is one or more selected from the group consisting of 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-imidazolidinone (DMI), and formamide; the ester solvent is one or more selected from the group consisting of methyl acetate, ethyl acetate, methyl propionate, butyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, pentyl acetate, and γ-valerolactone; the aromatic hydrocarbon solvent is one or more selected from the group consisting of toluene, o-xylene, m-xylene, p-xylene, mesitylene, chlorobenzene, fluorobenzene, and anisole; and the aliphatic hydrocarbon solvent is one or more selected from the group consisting of pentane, hexane, heptane, octane, and cyclohexane. The carbonate ester solvent is dimethyl carbonate, diethyl carbonate,and dibutyl carbonate.

[27] The method according to any one of

[24] to

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

[28] The method according to any one of

[24] to

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

[29] The method according to any one of

[24] to

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

[30] The method according to any one of

[24] to

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

[31] The method according to any one of

[25] to

[30] , wherein the concentration of the compound represented by formula (2) or a salt thereof in the solvent used in the liquid phase synthesis is 0.01 to 0.3 mol / L. [31-1] The method according to any one of

[25] to

[31] , wherein the concentration of the compound represented by formula (2) or a salt thereof in the solvent used in the liquid phase synthesis is 0.02 to 0.3 mol / L. [31-2] The method according to any one of

[25] to [31-1], wherein the concentration of the compound represented by formula (2) or a salt thereof in the solvent used in the liquid phase synthesis is 0.033 to 0.3 mol / L. [31-3] The method according to any one of

[25] to [31-2], wherein the reaction mixture in the liquid phase synthesis is prepared by any one of the following (a) to (d): (a) A mixture of a solvent containing a compound represented by formula (2) or a salt thereof is added to a mixture of a solvent containing a catalyst, thereby preparing a mixture of a compound represented by formula (2) or a salt thereof, a catalyst, an acid, an additive, and a solvent. (b) A mixture of a solvent containing a compound represented by formula (2) or a salt thereof is added to a heated mixture of a solvent containing a catalyst, thereby preparing a mixture of a compound represented by formula (2) or a salt thereof, a catalyst, an acid, an additive, and a solvent.and a solvent to prepare a mixture. (c) A mixture of a solvent containing a catalyst is added to a mixture of a solvent containing a compound represented by formula (2) or a salt thereof, to prepare a mixture of a compound represented by formula (2) or a salt thereof, a catalyst, an acid, an additive, and a solvent. (d) A solvent is added to a compound represented by formula (2) or a salt thereof, and then a catalyst, an acid, and an additive are added to prepare a mixture. [31-4] The method according to (b) of [31-3], in which heating is carried out at a temperature near the boiling point of the solvent.

[32] The method according to any one of [1] to [31-4], in which a compound represented by formula (2) or a salt thereof is obtained by condensing a compound represented by formula (6) with a compound represented by formula (7), and then deprotecting the carbamate protecting group. [In the formula, R ２ , R ３ , R ４ , n, and X are R in [1] ２ , R ３ , R ４ , n, and X; ２ is a carbamate protecting group.]

[33] R ２ is hydrogen or linear C １ -C ３

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

[32] , wherein R is alkyl. ２

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

[33] , wherein R is hydrogen or methyl. ３ is hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C ３ -C ８ Cycloalkyl, optionally substituted C ７ -C １４ Aralkyl, optionally substituted 5- to 10-membered heteroaryl C １ -C ６

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

[34] , wherein R is alkyl, or an optionally substituted 3- to 14-membered heterocyclyl. ３ But hydrogen, C １-C ６ Alkyl or haloC １ -C ３ Alkyl or C １ -C ６ C optionally substituted with alkyl ７ -C １４

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

[35] , wherein R is aralkyl. ３

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

[36] , wherein R is hydrogen, 2-methylpropyl, p-trifluoromethylbenzyl, or p-methylbenzyl. ４ But OR ５ , N.H.R. ５ ', an amino acid residue, or a peptide chain containing 2 to 13 amino acid residues, R ５ 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 t-Bu group, a benzyl group, a trityl group, a cumyl group, a methoxytrityl group, a 2-(trimethylsilyl)ethyl group, a 2,2,2-trichloroethyl group, or an allyl group, more preferably tert-butyl or benzyl; R ５

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

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

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

[39] , wherein n is an integer of 1 to 2, and n is an integer of 1 to 2.

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

[39] , wherein n is an integer of 1 to 2.

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

[39] , wherein n is 2.

[41] X is an optionally substituted C １ -C ３

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

[40] , wherein X is alkylene. １ -C ３

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

[42] , wherein X is methylene. [43-1] The method according to any one of [1] to

[42] , wherein X is methylene and n is an integer of 1 to 2. [43-2] The method according to any one of [1] to

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

[44] X １ is one selected from the group consisting of an Fmoc group, a Cbz group, a Troc group, an Alloc group, a Teoc group, a TSoc group, a BIBSoc group, an IPCSoc group, a BBSoc group, a CHBSoc group, a CDBSoc group, and a Boc group. １

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

[44] , wherein X is one selected from the group consisting of an Fmoc group, a Cbz group, and a Boc group. １

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

[45] , wherein X is an Fmoc group. ２is one selected from the group consisting of an Fmoc group, a Cbz group, a Troc group, an Alloc group, a Teoc group, a TSoc group, a BIBSoc group, an IPCSoc group, a BBSoc group, a CHBSoc group, a CDBSoc group, and a Boc group. ２

[49] The method according to any one of

[32] to

[47] , wherein X is one selected from the group consisting of an Fmoc group, a Cbz group, and a Boc group. ２is an Fmoc group.

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

[49] , wherein the cyclic peptide compound or a salt thereof comprises, as a partial structure, a residue of a peptide produced by the steps of any one of [1] to

[49] .

[51] The method of

[50] , wherein the cyclic peptide compound or a salt thereof comprises 8 to 20 amino acid residues.

[52] The method of

[50] or

[51] , wherein the cyclic peptide compound or a salt thereof comprises 11 to 14 amino acid residues.

[53] The method of any one of

[50] to

[52] , wherein the cyclic peptide compound comprises at least one unnatural amino acid residue.

[54] The method of any one of

[50] to

[53] , wherein the cyclic peptide compound comprises at least four unnatural amino acid residues.

[55] The method of any one of

[50] to

[54] , wherein the cyclic peptide compound comprises at least five unnatural amino acid residues.

[56] The method of any 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.

[57] The method of any 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.

[58] The method of any of

[53] to

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

[59] The cyclic peptide compound to be 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-undecaoxo-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

[60] The method according to any one of

[50] to

[58] , wherein the compound 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-undecaoxo-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 ]pentatetracont-42-ene-23,1'-cyclobutane]-17-carboxamide.

[61] A compound represented by formula (1a) or a salt thereof. [wherein Y represents a hydroxyl group, an optionally substituted C １ -C １０ Alkoxy, optionally substituted C ６ -C １６ Aryloxy, optionally substituted C ７ -C １４ aralkoxy, or an optionally substituted 3- to 12-membered cyclic aminooxy.]

[62] The compound according to

[61] or a salt thereof, wherein Y is tert-butoxy.

[63] tert-butyl N-methyl-N-((S)-2-((S)-3-(methylamino)-2-oxo-2,3,4,7-tetrahydro-1H-azepin-1-yl)-3-(4-(trifluoromethyl)phenyl)propanoyl)glycinate or hydrochloride thereof.

[64] A compound represented by formula (1b) or a salt thereof. [In the formula, R ６ is methyl or trifluoromethyl, Z is a hydroxyl group, an optionally substituted C １ -C １０ Alkoxy, optionally substituted C ６ -C １６Aryloxy, optionally substituted C ７ -C １４

[65] The compound or salt thereof according to

[64] , wherein Z is tert-butoxy.

[66] R ６

[67] The compound or salt thereof according to

[64] or

[65] , wherein R is methyl. ６ is trifluoromethyl.

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

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

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

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

[72] A method for producing a compound represented by formula (1) or a salt thereof, comprising a step of contacting a compound represented by formula (2) or a salt thereof with a catalyst (metathesis step), wherein R in formulas (1) and (2) １

[73] A method for producing a compound represented by formula (1) or a salt thereof, comprising a step of contacting a compound represented by formula (2) or a salt thereof with a catalyst (metathesis step), wherein R in formulas (1) and (2) is a carbamate protecting group, and the formation of impurities is suppressed compared to when R １is a carbamate protecting group, the formation of a dimer is suppressed compared to when

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

[75] a compound represented by formula (1) or a salt thereof, the content of impurities contained in which is less than 10%, preferably less than 5%, more preferably less than 1%, even more preferably less than 0.5%, and most preferably undetectable, as determined by the UVArea value at 210 nm by HPLC analysis. In the above numbering, numbers cited in dependent claims include their subnumbers unless otherwise specified. For example,

[31] cited in a dependent claim indicates that it includes

[31] as well as its subnumbers [31-1], [31-2], and [31-3]. The same applies to other numbering schemes.

[0009] According to the present invention, a peptide compound having a peptide structure containing a medium-sized ring can be efficiently produced. The production method of the present invention can reduce the production cost of a peptide compound and reduce the environmental load, and is therefore particularly useful for large-scale peptide synthesis.

[0010] Abbreviations The abbreviations used in this specification are listed below. MTBE: Methyl tert-butyl ether HFIP: 1,1,1,3,3,3-hexafluoro-2-propanol MeTHF: 2-methyltetrahydrofuran DBU: 1,8-diazabicyclo[5.4.0]-7-undecene TFE: 2,2,2-trifluoroethanol TCFH: Chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate DIPEA: Diisopropylethylamine Fmoc: 9-Fluorenylmethyloxycarbonyl Cbz: Benzyloxycarbonyl Troc: 2,2,2-Trichloroethoxycarbonyl Alloc: Allyloxycarbonyl Teoc: 2-(Trimethylsilyl)ethoxycarbonyl TSoc: Triisopropylsilyloxycarbonyl BIBSoc: Di-t-butylisobutylsilyloxycarbonyl IPCSoc: Di-i-propyl-t-butylsilyloxycarbonyl BBSoc: benzyl-di-t-butylsilyloxycarbonyl CHBSoc: di-t-butylcyclohexylsilyloxycarbonyl CDBSoc: t-butyloctadecylsilyloxycarbonyl Boc: t-butoxycarbonyl

[0011] Definitions of functional groups, etc. (The terms exemplified below are merely examples and are not intended to be particularly limiting and are commonly understood by those skilled in the art.)

[0012] In the present specification, examples of "halogen" include fluorine, chlorine, bromine, and iodine. In addition, in the specification, F represents fluorine, Cl represents chlorine, Br represents bromine, and I represents iodine. Examples of halogen include fluorine, chlorine, and bromine, and preferred examples are fluorine and chlorine.

[0013] In this specification, "alkyl" refers to a linear or branched monovalent saturated hydrocarbon group derived from an aliphatic saturated hydrocarbon by removing any one hydrogen atom, and does not contain heteroatoms (atoms other than carbon and hydrogen atoms) or unsaturated carbon-carbon bonds in the skeleton, but has a hydrocarbyl or hydrocarbon group structure subset containing hydrogen atoms and carbon atoms. Alkyl includes not only linear ones but also branched ones. Specific examples of alkyl include alkyls having 1 to 20 carbon atoms (C １ -C ２０ , hereinafter referred to as “C ｐ -C ｑ " means that the number of carbon atoms is p to q), and preferably C １ -C １０ Alkyl, more preferably C １ -C ６ Specific examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, isobutyl (2-methylpropyl), n-pentyl, s-pentyl (1-methylbutyl), t-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. １ -C ６ Specific examples of alkyl include methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl. １ -C ３ Specific examples of alkyl include methyl, ethyl, and n-propyl. ３ -C ６Specific examples of alkyl include i-propyl, s-butyl, t-butyl, isobutyl (2-methylpropyl), s-pentyl (1-methylbutyl), t-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, 2-ethylbutyl, and the like.

[0014] As used herein, "haloalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" as defined herein are substituted with halogen. As the haloalkyl, a group in which 1 to 6 hydrogen atoms, which are allowed to be substituted, are substituted with halogen is preferred. Examples of haloalkyl include haloC １ -C ２０ alkyl and haloC １ -C １０ Alkyl is preferred, haloC １ -C ８ Alkyl is more preferred, haloC １ -C ６ Alkyl is more preferred, haloC １ -C ３ Alkyl is most preferred. HaloC １ -C ６ The alkyl is, for example, a group in which 1 to 6 hydrogen atoms, which are permissible for substitution, are substituted with fluorine, preferably a group in which 1 to 5 hydrogen atoms are substituted with fluorine, more preferably a group in which 1 to 4 hydrogen atoms are substituted with fluorine, and most preferably a group in which 1 to 3 hydrogen atoms are substituted with fluorine. Specific examples of haloalkyl include difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3-difluoropropyl, 4,4-difluorobutyl, 5,5-difluoropentyl, etc.

[0015] As used herein, "alkenyl" refers to a straight-chain or branched-chain monovalent unsaturated hydrocarbon group having one or more carbon-carbon double bonds (bonds between two adjacent sp2 carbon atoms). Depending on the configuration of the atom or atomic group bonded to the sp2 carbon atom, the geometry of the double bond can be entgegen (E) or zusammen (Z), cis or trans. Examples of alkenyl include C ２ -C １０ alkenyl, C ２ -C ８ Alkenyl is preferred, C ２ -C ７ Alkenyl is more preferred, C ２ -C ６ Alkenyl is most preferred. Specific examples of alkenyl include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), isopropenyl, 1-butenyl, 2-butenyl (including cis and trans), 3-butenyl, pentenyl, and hexenyl.

[0016] As used herein, the term "alkynyl" refers to a linear or branched monovalent unsaturated hydrocarbon group having one or more carbon-carbon triple bonds (bonds between two adjacent sp carbon atoms). Examples of alkynyl include C ２ -C １０ alkynyl, C ２ -C ８ Alkynyl is preferred, C ２ -C ７ Alkynyl is more preferred, C ２ -C ６ Alkynyl is most preferred, and specific examples of alkynyl include ethynyl, 1-propynyl, propargyl (2-propynyl), 1-butynyl, 2-butynyl, 3-butynyl, pentynyl, and hexynyl.

[0017] As used herein, the term "cycloalkyl" refers to a saturated or partially saturated cyclic monovalent non-aromatic hydrocarbon ring group (alicyclic ring group). The carbon atoms constituting the ring may be oxidized to include a carbonyl. The cycloalkyl may be selected from the group consisting of a monocyclic ring, a fused ring, and a spiro ring. As used herein, a cycloalkyl containing a monocyclic ring is referred to as a monocyclic cycloalkyl, i.e., a monocyclic alicyclic ring group; a cycloalkyl containing a fused ring is referred to as a fused ring cycloalkyl, i.e., a fused ring alicyclic ring group; and a cycloalkyl containing a spiro ring is referred to as a spirocyclic cycloalkyl, i.e., a spirocyclic alicyclic ring group. A cycloalkyl may form a fused ring with a saturated alicyclic ring such as a cyclopentane ring or a cyclohexane ring, an unsaturated alicyclic ring such as a cyclopentene ring or a cyclohexene ring, or an aromatic hydrocarbon ring such as a benzene ring or a naphthalene ring. A cycloalkyl may form a spiro ring with a saturated alicyclic ring such as a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring. Examples of cycloalkyl include C ３ -C １０ is cycloalkyl, and C ３ -C ８ Cycloalkyl is preferred, C ３ -C ７ Cycloalkyl is more preferred, C ３ -C ６ Cycloalkyl is most preferred. Specific examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, spiro[3.3]heptyl, and cyclohexenyl.

[0018] In the present specification, the term "aryl" refers to a monovalent aromatic hydrocarbon ring group consisting of a single ring or fused rings that exhibits monovalent aromaticity. In the present specification, an aryl consisting of a single ring is referred to as a monocyclic aryl, and an aryl consisting of a fused ring is referred to as a fused ring aryl. Examples of aryl include C ６ -C １４ aryl, C ６ Aryl, C １０ Aryl and C １４ Aryl is preferred, C ６ Aryl and C１０ Aryl is more preferred, C ６ Aryl is most preferred. Specific examples of aryl include phenyl, 1-naphthyl, 2-naphthyl, tolyl, and xylyl.

[0019] As used herein, "aralkyl (arylalkyl)" refers to a group in which one or more hydrogen atoms of an "alkyl" as defined herein are substituted with an "aryl" as defined herein. Examples of aralkyl include C ７ -C ２０ aralkyl, C ７ -C １８ Aralkyl is preferred, C ７ -C １６ Aralkyl is more preferred, C ７ -C １４ Aralkyl is most preferred. ７ -C ２０ Examples of aralkyl include C ６ -C １０ Aryl C １ -C １０ alkyl, C ６ -C １０ Aryl C １ -C ８ Alkyl is preferred, C ６ Aryl C １ -C ８ Alkyl or C １０ Aryl C １ -C ８ Alkyl is more preferred, C ６ Aryl C １ -C ８ Alkyl is most preferred. ７ -C １８ Examples of aralkyl include C ６ -C １０ Aryl C １ -C ８ alkyl, C ６ -C １０ Aryl C １ -C ６ Alkyl is preferred, C ６ Aryl C １ -C ６ Alkyl or C １０ Aryl C １-C ６ Alkyl is more preferred, C ６ Aryl C １ -C ６ Alkyl is most preferred. ７ -C １６ As the aralkyl, for example, C ６ -C １０ Aryl C １ -C ６ alkyl, C ６ -C １０ Aryl C １ -C ４ Alkyl is preferred, C ６ Aryl C １ -C ４ Alkyl or C １０ Aryl C １ -C ４ Alkyl is more preferred, C ６ Aryl C １ -C ４ Alkyl is most preferred. ７ -C １４ As the aralkyl, for example, C ６ -C １０ Aryl C １ -C ４ alkyl, C ６ -C １０ Aryl C １ -C ３ Alkyl is preferred, C ６ Aryl C １ -C ３ Alkyl or C １０ Aryl C １ -C ３ Alkyl is more preferred, C ６ Aryl C １ -C ３ Alkyl is most preferred. Specific examples of aralkyl include benzyl, phenethyl, and 3-phenylpropyl.

[0020] As used herein, the term "heterocyclyl" refers to a heterocyclic group containing, in addition to carbon atoms, preferably 1 to 5, and more preferably 1 to 3, heteroatoms selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms as ring-constituting atoms, and which may have a double and / or triple bond within the ring. A carbon atom within the heterocyclyl ring may be oxidized to form a carbonyl. As used herein, a heterocyclyl containing a single ring is referred to as a monocyclic heterocyclyl, a heterocyclyl containing a fused ring is referred to as a fused-ring heterocyclyl, and a heterocyclyl containing a spiro ring is referred to as a spirocyclic heterocyclyl. A heterocyclyl may form a fused ring or a spiro ring with, for example, a saturated alicyclic ring such as a cyclopentane ring or a cyclohexane ring, or a saturated heterocycle such as a tetrahydropyran ring, a dioxane ring, or a pyrrolidine ring. The number of atoms constituting the heterocyclyl ring is, for example, 3 to 14 (3- to 14-membered heterocyclyl), preferably 3 to 12 (3- to 12-membered heterocyclyl), more preferably 3 to 10 (3- to 10-membered heterocyclyl), and most preferably 4 to 7 (4- to 7-membered heterocyclyl). Specific examples of heterocyclyl include azetidinyl, oxiranyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, thiadiazolidinyl, oxazolidonyl, dioxolanyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, 4-oxopyrrolidinyl, piperidinyl, 4-oxopiperidinyl, piperazinyl, dioxanyl, and rings in which one or more single bonds in these saturated heterocycles are replaced with double bonds or triple bonds.

[0021] As used herein, the term "heteroaryl" refers to a monovalent aromatic heterocyclic group that contains at least one heteroatom in addition to carbon atoms and is composed of a monocyclic or fused ring that exhibits aromaticity. In this specification, a heteroaryl composed of a single ring is referred to as a monocyclic heteroaryl, and a heteroaryl composed of a fused ring is referred to as a fused-ring heteroaryl. The number of atoms constituting the heteroaryl ring is, for example, 5 to 14 (5- to 14-membered heteroaryl), preferably 5 to 13 (5- to 13-membered heteroaryl), more preferably 5 to 10 (5- to 10-membered heteroaryl), and most preferably 5 to 7 (5- to 7-membered heteroaryl). Specific examples of heteroaryl include 5-membered heteroaryls such as furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, and tetrazolyl; 6-membered heteroaryls such as pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, and triazinyl; 9-membered heteroaryls such as benzofuranyl, benzothienyl, benzothiazolyl, benzimidazolyl, benzotriazolyl, indolyl, indazolyl, and pyrazolopyridyl; and 10-membered heteroaryls such as quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, and quinoxalinyl.

[0022] As used herein, "alkoxy" refers to a group in which an "alkyl" as defined herein is bonded to an oxygen atom (-OR (R is alkyl)). Examples of alkoxy include C １ -C ２０ Alkoxy, C １ -C １０ Alkoxy is preferred, C １ -C ８ Alkoxy is more preferred, C １ -C ６ Alkoxy is most preferred, and specific examples of alkoxy include methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, i-butoxy, sec-butoxy, tert-butoxy, pentyloxy, and 3-methylbutoxy.

[0023] As used herein, "alkylsulfanyl" refers to a group in which an "alkyl" as defined herein is bonded to a sulfur atom (-SR (R is alkyl)). It is also called alkylthio. Examples of alkylsulfanyl include C １ -C ２０ alkylsulfanyl, C １ -C １０ Alkylsulfanyl is preferred, C １ -C ８ Alkylsulfanyl is more preferred, C １ -C ６ Specific examples of alkylsulfanyl include methylsulfanyl, ethylsulfanyl, 1-propylsulfanyl, 2-propylsulfanyl, n-butylsulfanyl, i-butylsulfanyl, s-butylsulfanyl, t-butylsulfanyl, pentylsulfanyl, and 3-methylbutylsulfanyl.

[0024] As used herein, "alkylsulfinyl" refers to a sulfinyl group (-S(=O)-R (R is alkyl)) to which an "alkyl" as defined herein is bonded. Examples of alkylsulfinyl include C １ -C ２０ alkylsulfinyl, C １ -C １０ Alkylsulfinyl is preferred, C １ -C ８ Alkyl sulfinyl is more preferred, C １ -C ６ Specific examples of alkylsulfinyl include methylsulfinyl, ethylsulfonyl, 1-propylsulfinyl, 2-propylsulfinyl, n-butylsulfinyl, i-butylsulfinyl, s-butylsulfinyl, t-butylsulfinyl, pentylsulfinyl, and 3-methylbutylsulfinyl.

[0025] As used herein, "alkylsulfonyl" refers to a sulfonyl group (-S(=O)) bonded to an "alkyl" as defined herein. ２ -R (where R is alkyl). Examples of alkylsulfonyl include C１ -C ２０ alkylsulfonyl, C １ -C １０ Alkylsulfonyl is preferred, C １ -C ８ Alkylsulfonyl is more preferred, C １ -C ６ Specific examples of alkylsulfonyl include methylsulfonyl, ethylsulfonyl, 1-propylsulfonyl, 2-propylsulfonyl, n-butylsulfonyl, i-butylsulfonyl, s-butylsulfonyl, t-butylsulfonyl, pentylsulfonyl, and 3-methylbutylsulfonyl.

[0026] As used herein, "carboxyalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" as defined herein are substituted with "carboxy". Preferred carboxyalkyl groups are those in which one hydrogen atom of an alkyl is substituted with carboxy. Examples of carboxyalkyl include carboxyC １ -C ２０ alkyl and carboxy C １ -C １５ Alkyl is preferred, and carboxy C １ -C １０ Alkyl is more preferred, and carboxy C １ -C ６ Alkyl is most preferred. Specific examples of carboxyalkyl include carboxymethyl and carboxyethyl.

[0027] As used herein, "aralkoxy" refers to a group in which the alkyl moiety of an "aralkyl" defined herein is bonded to an oxygen atom (-O-R-Ar (R is alkylene)). Examples of aralkoxy include C ７ -C ２０ Aralkoxy, C ７ -C １８ Aralkoxy is preferred, C ７ -C １６ Aralkoxy is more preferred, C ７ -C １４ Aralkoxy is most preferred. ７ -C ２０Examples of aralkoxy include C ６ -C １０ Aryl C １ -C １０ Alkoxy, C ６ -C １０ Aryl C １ -C ８ Alkoxy is preferred, C ６ Aryl C １ -C ８ Alkoxy or C １０ Aryl C １ -C ８ Alkoxy is more preferred, C ６ Aryl C １ -C ８ Alkoxy is most preferred. ７ -C １８ Examples of aralkoxy include C ６ -C １０ Aryl C １ -C ８ Alkoxy, C ６ -C １０ Aryl C １ -C ６ Alkoxy is preferred, C ６ Aryl C １ -C ６ Alkoxy or C １０ Aryl C １ -C ６ Alkoxy is more preferred, C ６ Aryl C １ -C ６ Alkoxy is most preferred. ７ -C １６ As the aralkoxy, for example, C ６ -C １０ Aryl C １ -C ６ Alkoxy, C ６ -C １０ Aryl C １ -C ４ Alkoxy is preferred, C ６ Aryl C １ -C ４ Alkoxy or C １０ Aryl C １ -C ４ Alkoxy is more preferred, C６ Aryl C １ -C ４ Alkoxy is most preferred. ７ -C １４ As the aralkoxy, for example, C ６ -C １０ Aryl C １ -C ４ Alkoxy, C ６ -C １０ Aryl C １ -C ３ Alkoxy is preferred, C ６ Aryl C １ -C ３ Alkoxy or C １０ Aryl C １ -C ３ Alkoxy is more preferred, C ６ Aryl C １ -C ３ Alkoxy is most preferred. Specific examples of aralkoxy include benzyloxy, phenethyloxy, and 3-phenylpropoxy.

[0028] As used herein, "aralkoxyalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" as defined herein are substituted with an "aralkoxy" as defined herein. Aralkoxyalkyl includes C ７ -C １４ Aralkoxy C １ -C ６ Alkyl is preferred, C ７ -C １４ Aralkoxy C １ -C ２ Alkyl is more preferred. Specific examples of aralkoxyalkyl include benzyloxymethyl and 1-(benzyloxy)ethyl.

[0029] As used herein, "cycloalkoxy" refers to a group in which a "cycloalkyl" as defined herein is bonded to an oxygen atom (-OR (R is cycloalkyl)). Examples of cycloalkoxy include C ３ -C １０ cycloalkoxy, C ３ -C ８ Cycloalkoxy is preferred, C ３ -C７ Cycloalkoxy is more preferred, C ３ -C ６ Cycloalkoxy is most preferred. Specific examples of cycloalkoxy include cyclopropoxy, cyclobutoxy, cyclopentyloxy, and the like.

[0030] As used herein, "aryloxy" refers to a group in which an "aryl" as defined herein is bonded to an oxygen atom (-OAr (Ar is aryl)). Examples of aryloxy include C ６ -C １４ aryloxy, C ６ Aryloxy, C １０ Aryloxy and C １４ Aryloxy is preferred, C ６ Aryloxy and C １０ Aryloxy is more preferred, C ６ Aryloxy is most preferred. Specific examples of aryloxy include phenoxy, 1-naphthyloxy, 2-naphthyloxy, tolyloxy, and xylyloxy.

[0031] As used herein, "amino" refers to -NRR', where N represents a nitrogen atom, and R and R' are each independently selected from the group consisting of a hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or R and R' are groups that form a ring together with the nitrogen atom to which they are attached. ２ , Mono C １ -C ６ Alkylamino, DiC １ -C ６ Alkylamino, N—C １ -C ６ Alkyl-N—C ２ -C ６ Alkenylamino, N—C １ -C ６ Alkyl-N—C １ -C ６ Alkoxy C １ -C ６ Examples include alkylamino and 4- to 9-membered cyclic amino.

[0032] As used herein, "monoalkylamino" refers to a group in which R is a hydrogen atom and R' is an "alkyl" in the "amino (-NRR')" defined herein. Examples of monoalkylamino include monoC １ -C ２０ alkylamino, mono C １ -C １５ Alkylamino is preferred, mono C １ -C １０ Alkylamino is more preferred, and mono C １ -C ６ Alkylamino is most preferred. Specific examples of monoalkylamino include methylamino, ethylamino, n-propylamino, i-propylamino, n-butylamino, s-butylamino, and t-butylamino.

[0033] As used herein, "dialkylamino" refers to a group in which R and R' are each independently "alkyl" within the "amino (-NRR')" defined herein. Examples of dialkylamino include diC １ -C ２０ alkylamino, diC １ -C １５ Alkylamino is preferred, diC １ -C １０ Alkylamino is more preferred, diC １ -C ６ Alkylamino is most preferred. Specific examples of dialkylamino include dimethylamino, diethylamino, and methylethylamino.

[0034] As used herein, "cyclic amino" refers to the "amino (-NRR')" defined herein, in which R and R' form a ring together with the nitrogen atom to which they are bonded. Examples of cyclic amino include 3- to 14-membered cyclic amino, preferably 3- to 12-membered cyclic amino, more preferably 3- to 10-membered cyclic amino, even more preferably 4- to 9-membered cyclic amino, and most preferably 4- to 7-membered cyclic amino. Specific examples of cyclic amino include 1-azetidyl, 1-pyrrolidyl, 1-piperidyl, 1-piperazyl, 4-morpholinyl, 3-oxazolidyl, 1,1-dioxidethiomorpholinyl-4-yl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, and the like.

[0035] As used herein, "cyclic aminooxy" refers to a group in which a "cyclic amino" as defined herein is bonded to an oxygen atom (-OR (R is cyclic amino)). Examples of cyclic aminooxy include 3- to 14-membered cyclic aminooxy, preferably 3- to 12-membered cyclic aminooxy, more preferably 3- to 10-membered cyclic aminooxy, even more preferably 4- to 9-membered cyclic aminooxy, and most preferably 4- to 7-membered cyclic aminooxy. Specific examples of cyclic amino include 1-azetidyloxy, 1-pyrrolidyloxy, 1-piperidyloxy, 1-piperazyloxy, 4-morpholinyloxy, 3-oxazolidyloxy, 1,1-dioxidethiomorpholinyl-4-yloxy, 3-oxa-8-azabicyclo[3.2.1]octan-8-yloxy, and the like.

[0036] As used herein, "aminocarbonyl" refers to a group in which an "amino" as defined herein is bonded to the carbon atom of a carbonyl. It may also be called an amide. Examples of aminocarbonyl include -CONH ２ , Mono C １ -C ６ Alkylaminocarbonyl, diC １ -C ６ Alkylaminocarbonyl, N—C １ -C ６ Alkyl-N—C ２ -C ６ Alkenylaminocarbonyl, N—C １ -C ６ Alkyl-N—C１ -C ６ Alkoxy C １ -C ６ alkylaminocarbonyl, and 4- to 9-membered cyclic aminocarbonyl. Specific examples of aminocarbonyl include -CONH ２ methylaminocarbonyl, ethylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, 1-piperazinylcarbonyl, 4-morpholinylcarbonyl, 3-oxazolidinylcarbonyl and the like.

[0037] As used herein, "aminoalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" as defined herein are substituted with "amino". As the aminoalkyl, a group in which one hydrogen atom of an alkyl is substituted with amino is preferred. Examples of aminoalkyl include amino C １ -C ２０ alkyl and amino C １ -C １０ Alkyl is preferred, and amino C １ -C ８ Alkyl is more preferred, and amino C １ -C ６ Alkyl is most preferred. Specific examples of aminoalkyl include aminomethyl, aminoethyl, 4-aminobutyl, methylaminomethyl, dimethylaminomethyl, methylaminoethyl, and dimethylaminoethyl.

[0038] As used herein, "cycloalkylalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" as defined herein are substituted with a "cycloalkyl". As the cycloalkylalkyl, a group in which one hydrogen atom of an alkyl is substituted with a cycloalkyl is preferred. Examples of cycloalkylalkyl include C ３ -C １０ Cycloalkyl C １ -C ２０ alkyl, C ３ -C １０ Cycloalkyl C １ -C ６ Alkyl is preferred, C ３-C ８ Cycloalkyl C １ -C ６ Alkyl is more preferred, C ３ -C ６ Cycloalkyl C １ -C ２ Alkyl is most preferred. Specific examples of cycloalkylalkyl include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, and cyclohexylpropyl.

[0039] As used herein, "cycloalkoxyalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" as defined herein are substituted with "cycloalkoxy". As the cycloalkoxyalkyl, a group in which one hydrogen atom of an alkyl is substituted with cycloalkoxy is preferred. Examples of cycloalkoxyalkyl include C ３ -C １０ Cycloalkoxy C １ -C ６ alkyl, C ３ -C ８ Cycloalkoxy C １ -C ６ Alkyl is preferred, C ３ -C ７ Cycloalkoxy C １ -C ６ Alkyl is more preferred, C ３ -C ６ Cycloalkoxy C １ -C ６ Alkyl is most preferred. Specific examples of cycloalkoxyalkyl include cyclopropoxymethyl, cyclobutoxymethyl, cyclopentyloxymethyl, and the like.

[0040] As used herein, "heterocyclylalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" as defined herein are substituted with a "heterocyclyl". Preferred heterocyclylalkyl groups are those in which one hydrogen atom of an alkyl is substituted with a heterocyclyl. Examples of heterocyclylalkyl include 3- to 14-membered heterocyclyl C １ -C ６alkyl and 3- to 12-membered heterocyclyl C １ -C ６ Alkyl is preferred, and 3- to 10-membered heterocyclyl C １ -C ４ Alkyl is more preferred, and 4- to 7-membered heterocyclyl C １ -C ３ Specific examples of heterocyclylalkyl include azetidin-1-ylmethyl, oxetan-3-ylmethyl, 2-(tetrahydrofuran-3-yl)ethyl, (1-methylpyrrolidin-3-yl)methyl, 2-morpholinoethyl, 3-(1-piperidinyl)propyl, and 3-(4-methylpiperazin-1-yl)propyl.

[0041] As used herein, "alkylsulfanylalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" as defined herein are substituted with "alkylsulfanyl". As the alkylsulfanylalkyl, a group in which one hydrogen atom of an alkyl is substituted with alkylsulfanyl is preferred. For example, C １ -C ２０ Alkylsulfanyl C １ -C ４ alkyl, C １ -C １０ Alkylsulfanyl C １ -C ４ Alkyl is preferred, C １ -C ８ Alkylsulfanyl C １ -C ４ Alkyl is more preferred, C １ -C ６ Alkylsulfanyl C １ -C ６ Specific examples of alkylsulfanylalkyl include methylsulfanylmethyl, ethylsulfanylmethyl, 1-propylsulfanylmethyl, 2-propylsulfanylmethyl, n-butylsulfanylmethyl, i-butylsulfanylmethyl, s-butylsulfanylmethyl, and t-butylsulfanylmethyl.

[0042] As used herein, "alkylsulfinylalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" as defined herein are substituted with "alkylsulfinyl". As the alkylsulfenylalkyl, a group in which one hydrogen atom of an alkyl is substituted with alkylsulfinyl is preferred. For example, C １ -C ２０ Alkylsulfinyl C １ -C ４ alkyl, C １ -C １０ Alkylsulfinyl C １ -C ４ Alkyl is preferred, C １ -C ８ Alkylsulfinyl C １ -C ４ Alkyl is more preferred, C １ -C ６ Alkylsulfinyl C １ -C ６ Specific examples of alkylsulfinylalkyl include methylsulfinylmethyl, ethylsulfinylmethyl, 1-propylsulfinylmethyl, 2-propylsulfinylmethyl, n-butylsulfinylmethyl, i-butylsulfinylmethyl, s-butylsulfinylmethyl, and t-butylsulfinylmethyl.

[0043] As used herein, "heteroarylalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" as defined herein are substituted with a "heteroaryl". As the heteroarylalkyl, a group in which one hydrogen atom of an alkyl is substituted with a heteroaryl is preferred. Examples of heteroarylalkyl include 5- to 10-membered heteroaryl C １ -C ６ alkyl and 5-10 membered heteroaryl C １ -C ４ Alkyl is preferred, and 5- to 10-membered heteroaryl C １ -C ３ Alkyl is more preferred, and 5- to 10-membered heteroaryl C １ -C ２Specific examples of heteroarylalkyl include 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-furanylmethyl, 2-thienylmethyl, 3-thienylmethyl, and 4-thiazolylmethyl.

[0044] As used herein, "heteroarylalkoxy" refers to a group in which the alkyl moiety of "heteroarylalkyl" as defined herein is bonded to an oxygen atom. Examples of heteroarylalkoxy include 5- to 10-membered heteroaryl C １ -C ６ alkoxy and 5-10 membered heteroaryl C １ -C ４ Alkoxy is preferred, and 5- to 10-membered heteroaryl C １ -C ３ Alkoxy is more preferred, and 5- to 10-membered heteroaryl C １ -C ２ Alkoxy is most preferred. Specific examples of heteroarylalkoxy include 2-pyridylmethoxy, 3-pyridylmethoxy, 4-pyridylmethoxy, 2-furanylmethoxy, 2-thienylmethoxy, 3-thienylmethoxy, and 4-thiazolylmethoxy.

[0045] As used herein, "alkoxyalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" as defined herein are substituted with "alkoxy". Preferred alkoxyalkyl groups are those in which one hydrogen atom of an alkyl is substituted with alkoxy. Examples of alkoxyalkyl include C １ -C ６ Alkoxy C １ -C ２０ alkyl, C １ -C ６ Alkoxy C １ -C １５ Alkyl is preferred, C １ -C ６ Alkoxy C １ -C １０ Alkyl is more preferred, C １ -C ６ Alkoxy C １ -C ６Specific examples of alkoxyalkyl include methoxymethyl, ethoxymethyl, 1-propoxymethyl, 2-propoxymethyl, n-butoxymethyl, i-butoxymethyl, s-butoxymethyl, t-butoxymethyl, pentyloxymethyl, 3-methylbutoxymethyl, 1-methoxyethyl, 2-methoxyethyl, and 2-ethoxyethyl.

[0046] As used herein, "heteroarylalkoxyalkyl" refers to a group in which one or more hydrogen atoms of an "alkyl" as defined herein are substituted with a "heteroarylalkoxy" as defined herein. As the heteroarylalkoxyalkyl, a group in which one hydrogen atom of an alkyl is substituted with a heteroarylalkoxy is preferred. As the heteroarylalkoxyalkyl, for example, a 5- to 10-membered heteroaryl C １ -C ６ Alkoxy C １ -C ６ alkyl and 5-10 membered heteroaryl C １ -C ４ Alkoxy C １ -C ６ Alkyl is preferred, and 5- to 10-membered heteroaryl C １ -C ３ Alkoxy C １ -C ６ Alkyl is more preferred, and 5- to 10-membered heteroaryl C １ -C ２ Alkoxy C １ -C ６ Specific examples of heteroarylalkoxyalkyl include 2-pyridylmethoxymethyl, 3-pyridylmethoxymethyl, 4-pyridylmethoxymethyl, 2-furanylmethoxymethyl, 2-thienylmethoxymethyl, 3-thienylmethoxymethyl, and 4-thiazolylmethoxymethyl.

[0047] As used herein, "alkylene" refers to a divalent group derived from an "alkyl" as defined herein by further removing one optional hydrogen atom. １ -C ８ Alkylene is preferred, C １ -C３ Alkylene is more preferred. Specific examples of alkylene include —CH ２ -, -(CH ２ ) ２ -, -(CH ２ ) ３ -, -CH(CH ３ ) CH ２ -, -C(CH ３ ) ２ -, -(CH ２ ) ４ -, -CH(CH ３ ) CH ２ CH ２ -, -C(CH ３ ) ２ CH ２ -, -CH ２ CH (CH ３ ) CH ２ -, -CH ２ C(CH ３ ) ２ -, -CH ２ CH ２ CH (CH ３ ) -, -CH ２ CH (CH ２ CH ３ ) -, -(CH ２ ) ５ -, -CH(CH ３ ) CH(CH ２ CH ３ ) -, -(CH ２ ) ６ -, -(CH ２ ) ７ -, -(CH ２ ) ８ - and others.

[0048] As used herein, the term "peptide compound" refers to a compound in which two or more amino acid residues are linked by amide bonds. As long as two or more amino acids are linked by amide bonds, the peptide chain may contain other bonds (e.g., ester bonds, thioester bonds, etc.). The number of amino acid residues contained in a peptide is, for example, 5 to 30. A peptide may be linear, branched, or cyclic.

[0049] As used herein, the term "peptide chain" refers to a chain-like portion of a peptide in which two or more amino acid residues are linked by amide bonds. As long as two or more amino acids are linked by amide bonds, the peptide chain may contain other bonds (e.g., ester bonds, thioester bonds, etc.). The number of amino acid residues contained in the peptide chain is, for example, 5 to 30 residues.

[0050] As used herein, the term "optionally substituted" means that a certain group and / or a certain atom may be substituted with any substituent and / or any atom. That is, either a state in which the certain group and the certain atom are not substituted with any substituent or any atom, or a state in which the certain group and / or the certain atom are substituted with any substituent and / or any atom, can be selected. Each of the certain group and / or the certain atom may be further substituted with any substituent and / or any atom. That is, either a state in which the certain group and the certain atom are not substituted with any substituent or any atom, or a state in which the certain group and / or the certain atom are substituted with any substituent and / or any atom, can be selected. The certain group and the certain substituent are not limited and may be freely selected, for example, from groups containing atoms selected from the group consisting of hydrogen atoms, halogen atoms, carbon atoms, oxygen atoms, sulfur atoms, nitrogen atoms, boron atoms, silicon atoms, and phosphorus atoms. The certain atom and the optional atom are not limited and may be freely selected from, for example, a halogen atom, a carbon atom, an oxygen atom, a sulfur atom, a nitrogen atom, a boron atom, a silicon atom, or a phosphorus atom. Examples of the optional substituent include alkyl, alkoxy, fluoroalkyl, fluoroalkoxy, oxo, aminocarbonyl, alkylsulfonyl, alkylsulfonylamino, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, halogen, nitro, amino, monoalkylamino, dialkylamino, cyano, carboxyl, alkoxycarbonyl, formyl, etc.

[0051] As used herein, the term "optionally protected" means that a group may be protected by any protecting group.

[0052] As used herein, the term "protecting group for a carboxy group" includes alkyl ester type protecting groups, benzyl ester type protecting groups, substituted alkyl ester type protecting groups, alkenyl ester type protecting groups, etc. Specific examples of the protecting group for a carboxy group include a methyl group, an ethyl group, a t-Bu group, a benzyl group, a trityl group, a cumyl group, a methoxytrityl group, a 2-(trimethylsilyl)ethyl group, a 2,2,2-trichloroethyl group, an allyl group, etc.

[0053] As used herein, the term "amide group-protecting group" includes phenylamide-type protecting groups, alkylamide-type protecting groups, alkenylamide-type protecting groups, benzylamide-type protecting groups, alkoxyalkylamide-type protecting groups, etc. Specific examples of the amide group-protecting group include a phenyl group, a t-Bu group, an allyl group, a benzyl group, a 4-methoxybenzyl group, a trityl group, a cumyl group, a methoxymethyl group, a benzyloxymethyl group, etc.

[0054] As used herein, "amino-protecting groups" include carbamate-protecting groups, amide-protecting groups, arylsulfonamide-protecting groups, alkylamine-protecting groups, and imide-protecting groups. Specific examples of carbamate-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, tosyl, nosyl, and dinitronosyl groups. Examples of alkylamine-protecting groups include t-Bu and trityl groups. Examples of imide-protecting groups include phthaloyl groups.

[0055] As used herein, "one or more" means one or more than one. When "one or more" is used in the context of substituents on a group, the term means a number from one to the maximum number of substituents permitted by that group. Specific examples of "one or more" include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and / or more.

[0056] The compounds or salts thereof described herein may be solvates thereof. Examples of salts of the compounds include hydrochlorides, hydrobromides, hydroiodides, phosphates, phosphonates, sulfates, sulfonates such as methanesulfonates, paratoluenesulfonates, and trifluoromethanesulfonates; carboxylates such as acetates, citrates, malates, tartrates, succinates, salicylates, and trifluoroacetates; alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as magnesium salts and calcium salts; and ammonium salts such as ammonium salts, alkylammonium salts, dialkylammonium salts, trialkylammonium salts, and tetraalkylammonium salts. These salts can be produced, for example, by contacting the compound with an acid or a base. In this specification, the term "solvate" refers to a compound that forms a molecular group together with a solvent, and is not particularly limited as long as it is a solvate formed with a solvent that is acceptable for ingestion accompanying the administration of a drug. Specific examples of solvates include solvates with a single solvent such as water, alcohol (ethanol, methanol, 1-propanol, 2-propanol, etc.), dimethyl sulfoxide, etc., as well as solvates formed with multiple solvents per molecule of the compound, or solvates formed with multiple types of solvents per molecule of the compound. For example, a solvate formed with water of a compound is called a hydrate. As the solvate of the compound of the present invention, hydrates are preferred. Specific examples of such hydrates include mono- to 20-hydrates, more preferably mono- to deca-hydrates, even more preferably mono- to penta-hydrates, and most preferably mono- to tri-hydrates.

[0057] As used herein, "amino acid" includes natural amino acids and unnatural amino acids (sometimes referred to as amino acid derivatives). Furthermore, as used herein, "amino acid" may refer to an amino acid residue. As used herein, "natural amino acid" refers to any L-amino acid selected from the group consisting of Gly (glycine), L-Ala (alanine), L-Ser (serine), L-Thr (threonine), L-Val (valine), L-Leu (leucine), L-Ile (isoleucine), L-Phe (phenylalanine), L-Tyr (tyrosine), L-Trp (tryptophan), L-His (histidine), L-Glu (glutamic acid), L-Asp (aspartic acid), L-Gln (glutamine), L-Asn (asparagine), L-Cys (cysteine), L-Met (methionine), L-Lys (lysine), L-Arg (arginine), and L-Pro (proline). As used herein, "unnatural amino acid" refers to an amino acid other than natural amino acids. Examples of unnatural amino acids include β-amino acids, γ-amino acids, D-amino acids, N-substituted amino acids other than Pro, α,α-disubstituted amino acids, and amino acids whose side chains differ from those of natural amino acids. The amino acids referred to herein may have any configuration. The side chains of the amino acids are not particularly limited and may be freely selected from groups such as alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, and spiro-linked cycloalkyl, and / or atoms such as hydrogen atoms. Each of these groups and / or atoms may be further substituted. In a non-limiting embodiment, the amino acids referred to herein may be compounds having a carboxy group and an amino group in the same molecule. Even in this case, amino acids also include proline, hydroxyproline, azetidine-2-carboxylic acid, and the like, in which the nitrogen atom of the amino group and any atom in the side chain of the amino acid form a ring.

[0058] The main chain amino group of the amino acid is unsubstituted (NH ２group), and may be substituted (i.e., an —NHR group: R represents an alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or cycloalkyl group which may have a substituent, and one or two non-adjacent methylene groups in these groups are replaced by an oxygen atom, a carbonyl group (—CO—), or a sulfonyl group (—SO ２ -), or, as in proline, the carbon chain bonded to the N atom may form a ring with the carbon atom at the α-position.) The substituent of R is selected in the same manner as the substituent in the amino acid side chain described above. When the main chain amino group is substituted, R is included in the "amino acid side chain" in this specification. An amino acid in which such a main chain amino group is substituted is referred to as an "N-substituted amino acid" in this specification. As used herein, the "N-substituted amino acid" is preferably an N-alkyl amino acid, an N-C １ -C ６ Alkyl amino acids, N-C １ -C ４ Examples include, but are not limited to, alkyl amino acids and N-methyl amino acids.

[0059] As used herein, "amino acid" includes all corresponding isotopes. An isotope of an "amino acid" is one in which at least one atom is replaced with an atom having the same atomic number (number of protons) but a different mass number (sum of the number of protons and neutrons) in an abundance ratio different from the natural abundance ratio. Examples of isotopes included in "amino acids" as used herein include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, and chlorine atoms, each of which is 2 H, 3 H, 13 C. 14 C. 15 N, 17 O. 18 O. 32 P, 35 S, 18 F, 36 Cl, etc. Compounds herein containing all proportions of radioactive or non-radioactive isotopes are within the scope of the present invention.

[0060] As used herein, "liquid phase synthesis" refers to a method for synthesizing a target compound by chemically reacting a compound in a liquid phase (solution) without using a solid phase support. Liquid phase peptide synthesis can be performed using amino acids and peptides that are not bound to a solid phase support. Such liquid phase peptide synthesis also includes a method in which a target peptide chain is synthesized in a state in which a functional group (tag) that solubilizes the peptide in a solvent is bound to the peptide during the peptide synthesis reaction, and then, during isolation of the target peptide, a poor solvent is added to isolate the target peptide chain as a solid in a state in which the target peptide chain is bound to the tag (sometimes referred to as a liquid phase tag method or tag method). Examples of liquid-phase tagging methods include the following methods using hydrophobic tags (see, for example, 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).

[0061] As used herein, the term "substituent derived from halogen" includes fluoro (-F), chloro (-Cl), bromo (-Br), iodo (-I), and the like.

[0062] As used herein, the term "substituent containing an oxygen atom" includes hydroxy (-OH), oxy (-OR), oxo (=O), carbonyl (-C(=O)-R), carboxy (-COH), oxycarbonyl (-C(=O)-OR), carbonyloxy (-OC(=O)-R), sulfanylcarbonyl (thiocarbonyl) (-C(=O)-SR), carbonylsulfanyl (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), sulfamoylamino (-NH-S(=O)2-NHR), sulfanylcarboxy (thiocarboxy) (-C(=O)-SH), and carboxycarbonyl (-C(=O)-COH).

[0063] Examples of oxy (—OR) include alkoxy, cycloalkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, aralkyloxy, etc. Alkoxy includes C １ ~C ４ Alkoxy, C １ ~C ２ Alkoxy is preferred, and methoxy or ethoxy is particularly preferred.

[0064] Examples of carbonyl (-C(=O)-R) include formyl (-C(=O)-H), alkylcarbonyl, cycloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, and the like.

[0065] Examples of oxycarbonyl (-C(=O)-OR) include alkyloxycarbonyl, cycloalkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl, and the like.

[0066] Examples of carbonyloxy (-OC(=O)-R) include alkylcarbonyloxy, cycloalkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, and aralkylcarbonyloxy.

[0067] Examples of sulfanylcarbonyl (also called thiocarbonyl) (-C(=O)-SR) include alkylsulfanylcarbonyl, cycloalkylsulfanylcarbonyl, alkenylsulfanylcarbonyl, alkynylsulfanylcarbonyl, arylsulfanylcarbonyl, heteroarylsulfanylcarbonyl, aralkylsulfanylcarbonyl, and the like.

[0068] Examples of carbonylsulfanyl (also called carbonylthio) (-SC(=O)-R) include alkylcarbonylsulfanyl, cycloalkylcarbonylsulfanyl, alkenylcarbonylsulfanyl, alkynylcarbonylsulfanyl, arylcarbonylsulfanyl, heteroarylcarbonylsulfanyl, aralkylcarbonylsulfanyl, and the like.

[0069] Examples of aminocarbonyl (-C(=O)-NHR) include alkylaminocarbonyl (e.g., C １ ~C ６ or C １ ~C ４ Examples thereof include alkylaminocarbonyl, specifically ethylaminocarbonyl, methylaminocarbonyl, etc.), cycloalkylaminocarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl, etc. In addition to these, examples thereof 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.

[0070] Examples of carbonylamino (-NH-C(=O)-R) include alkylcarbonylamino, cycloalkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, aralkylcarbonylamino, etc. In addition to these, groups in which the H atom bonded to the N atom in -NH-C(=O)-R is further substituted with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl are also included.

[0071] Examples of oxycarbonylamino (-NH-C(=O)-OR) include alkoxycarbonylamino, cycloalkoxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, aryloxycarbonylamino, heteroaryloxycarbonylamino, aralkyloxycarbonylamino, etc. In addition to these, groups in which the H atom bonded to the N atom in -NH-C(=O)-OR is further substituted with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl are also included.

[0072] Examples of sulfonylamino (-NH-SO2-R) include alkylsulfonylamino, cycloalkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, aralkylsulfonylamino, etc. In addition to these, groups in which the H atom bonded to the N atom in -NH-SO2-R is further substituted with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl are also included.

[0073] Examples of aminosulfonyl (-SO2-NHR) include alkylaminosulfonyl, cycloalkylaminosulfonyl, alkenylaminosulfonyl, alkynylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, etc. In addition to these, groups in which the H atom bonded to the N atom in -SO2-NHR is further substituted with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl are also included.

[0074] Examples of sulfamoylamino (-NH-SO-NHR) include alkylsulfamoylamino, cycloalkylsulfamoylamino, alkenylsulfamoylamino, alkynylsulfamoylamino, arylsulfamoylamino, heteroarylsulfamoylamino, aralkylsulfamoylamino, etc. Furthermore, the two H atoms bonded to the N atom in -NH-SO-NHR may be substituted with substituents independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, and these two substituents may form a ring together with the nitrogen atom to which they are bonded.

[0075] As used herein, examples of a "substituent containing a sulfur atom" include thiol (-SH), sulfanyl (thio(-SR)), sulfinyl (-S(=O)-R), sulfonyl (-S(=O)2-R), sulfo (-SOH), pentafluorosulfanyl (-SF5), and disulfanyl (-SSR).

[0076] Examples of sulfanyl (thio(-SR)) are selected from alkylsulfanyl, cycloalkylsulfanyl, alkenylsulfanyl, alkynylsulfanyl, arylsulfanyl, heteroarylsulfanyl, aralkylsulfanyl, and the like.

[0077] Examples of sulfinyl (-S(=O)-R) include alkylsulfinyl, cycloalkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heteroarylsulfinyl, aralkylsulfinyl, and the like.

[0078] Examples of sulfonyl (-S(=O)2-R) include alkylsulfonyl, cycloalkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, and the like.

[0079] Examples of a "substituent containing a nitrogen atom" in this specification include azide (-N3, also referred to as an "azido group"), cyano (-CN), primary amino (-NH2), secondary amino (-NH-R), tertiary amino (-NR(R')), amidino (-C(=NH)-NH2), substituted amidino (-C(=NR)-NR'R''), guanidino (-NH-C(=NH)-NH2), substituted guanidino (-NR-C(=NR''')-NR'R''), and aminocarbonylamino (-NR-CO-NR'R'').

[0080] Examples of secondary amino (-NH-R) include alkylamino, cycloalkylamino, alkenylamino, alkynylamino, arylamino, heteroarylamino, and aralkylamino.

[0081] Examples of tertiary amino (—NR(R′)) include an amino group having any two substituents independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, etc., such as alkyl(aralkyl)amino, and these two substituents may form a ring together with the nitrogen atom to which they are bonded.

[0082] Examples of substituted amidino (-C(=NR)-NR'R'') include groups in which the three substituents R, R', and R'' on the N atom are each independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, such as alkyl(aralkyl)(aryl)amidino.

[0083] Examples of substituted guanidino (-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, or groups in which these groups form a ring together with the nitrogen atom to which they are bonded.

[0084] Examples of aminocarbonylamino (-NR-CO-NR'R'') include groups in which R, R', and R'' are each independently selected from a hydrogen atom, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, or groups in which these groups form a ring together with the nitrogen atom to which they are bonded.

[0085] In this specification, the "amino acid residues" that constitute a peptide compound may be simply referred to as "amino acids".

[0086] In this specification, the term "to" indicating a numerical range includes both ends of the range. For example, "A to B" means a numerical range that is equal to or greater than A and equal to or less than B.

[0087] As used herein, the term "about" when used in conjunction with a numerical value means a range of values ​​of plus or minus 10% of that numerical value.

[0088] As used herein, the term "and / or" includes any combination of "and" and "or." Specifically, for example, "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.

[0089] Method for Producing a Compound Represented by Formula (1) or a Salt Thereof In one aspect, the present invention relates to a method for producing a compound represented by formula (1) or a salt thereof, the method comprising a step of contacting a compound represented by formula (2) or a salt thereof with a catalyst (metathesis step). [In the formula, R １ , R ２ , R３ , R ４ , n, and X are R in [1] above. １ , R ２ , R ３ , R ４ , n, and X.]

[0090] In one embodiment, the catalyst used in the metathesis step is a metal-alkylidene complex. Examples of metal-alkylidene complexes include ruthenium-alkylidene complexes, molybdenum-alkylidene complexes, and tungsten-alkylidene complexes, with ruthenium-alkylidene complexes being preferred. When the catalyst is a ruthenium-alkylidene complex, it is preferred that the catalyst has a phosphine and / or an N-heterocyclic carbene as a ligand.

[0091] Specific examples of catalysts used in the metathesis step include first-generation Grubbs catalyst (dichloro(benzylidene)bis(tricyclohexylphosphine)ruthenium(II)), second-generation Grubbs catalyst (dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](benzylidene)(tricyclohexylphosphine)ruthenium(II)), and third-generation Grubbs catalyst (dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](benzylidene)bis(3-bromo 2-isopropoxyphenylmethylene)ruthenium(II)), Stewart-Grubbs catalyst (dichloro[1,3-bis(2-methylphenyl)-2-imidazolidinylidene](2-isopropoxyphenylmethylene)ruthenium(II)), Nitro-Grela catalyst (dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene][(2-isopropoxy-5-nitrobenzylidene)]ruthenium(II)), Zhan catalyst-1B (dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene][(2-isopropoxy-5-nitrobenzylidene)]ruthenium(II)), den][[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 ((1,3 -bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium), [1,3-bis(2,6-isopropylphenyl)-2-imidazolidinylidene]dichloro(2-isopropoxybenzylidene)ruthenium(II), bis[1-(2,6-diethylphenyl)-3,5,5-trimethyl-3-phenylpyrrolidin-2-ylidene](3-phenyl-1H-inden-1-ylidene)ruthenium chloride, [1-(2,6-diethylphenyl)-3,5,5-trimethyl-3-phenylpyrrolidin-2-yl](2-isopropoxy-5-nitrobenzylidene)ruthenium(II) chloride, or [1-[2,4,6-trimethylphenyl]-3,5,5-trimethyl-3-phenyl-2-pyrrolinylidene]dichloro(2-isopropoxybenzylidene)ruthenium(II). Among these, 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-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium), or [1-[2,4,6-trimethylphenyl]-3,5,5-trimethyl-3-phenyl-2-pyrrolinylidene]dichloro(2-isopropoxybenzylidene)ruthenium(II) is preferred.

[0092] The amount of the catalyst used in the metathesis step is not particularly limited, and is, for example, 0.001 to 0.5 molar equivalents, preferably 0.003 to 0.3 molar equivalents, and more preferably 0.05 to 0.1 molar equivalents, relative to the compound represented by formula (2).

[0093] In one embodiment, 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 with a Bronsted acid having a pKa of 3 or less. Examples of such salts include hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, paratoluenesulfonate, trifluoromethanesulfonate, and trifluoroacetate, and among these, hydrochloride is preferred.

[0094] In one embodiment, 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 Brønsted acid or a Lewis acid having a pKa of 3 or less, more preferably a Lewis acid. Examples of Brønsted acids having a pKa of 3 or less include hydrogen chloride, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, paratoluenesulfonic acid, trifluoromethanesulfonic acid, and trifluoroacetic acid, with hydrogen chloride being preferred. Examples of Lewis acids include boron trihalides and solvated complexes thereof (e.g., boron trifluoride tetrahydrofuran complex, boron trifluoride diethyl ether complex), titanium tetrahalides (e.g., titanium tetrachloride, titanium tetrabromide), and tetraalkoxytitanium (e.g., tetra i-propoxytitanium, tetra n-butoxytitanium), with boron trifluoride tetrahydrofuran complex or boron trifluoride tetrahydrofuran complex being preferred.

[0095] When a Bronsted acid having a pKa of 3 or less is used in the metathesis step, its amount is not particularly limited and is, for example, 0.1 to 10.0 molar equivalents, preferably 1.0 to 3.0 molar equivalents, more preferably 1.0 to 2.0 molar equivalents, and even more preferably 1.0 to 1.5 molar equivalents, relative to the compound represented by formula (2).

[0096] When a Lewis acid is used in the metathesis step, the amount used is not particularly limited, and is, for example, 0.1 to 10.0 molar equivalents, preferably 1.0 to 3.0 molar equivalents, more preferably 1.0 to 2.0 molar equivalents, and even more preferably 1.0 to 1.5 molar equivalents, relative to the compound represented by formula (2).

[0097] In one embodiment, an alcohol and / or a Bronsted acid is further used as an additive in the metathesis step, and the additive has a pKa of 4 to 17. The "pKa" herein can be measured using water as a solvent. The pKa herein may be a previously reported measured value when water is used as a solvent, in which case the measured value at 25°C is used. If the measured pKa value is not available, it may be calculated using ADMETPredictor (Simulations Plus Inc., version 8.0), and the calculated value may be used as the pKa herein. Examples of alcohols among additives having a pKa 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 a pKa of 4 to 17 include acetic acid. Among the additives, 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) or acetic acid is preferred.

[0098] When an alcohol and / or a Bronsted acid is used as an additive in the metathesis step, the amount used is not particularly limited and is, for example, 0.1 mL to 100 mL, and preferably 2 mL to 10 mL, per 1 g of the compound represented by formula (2).

[0099] In one embodiment, the metathesis step is carried out by a liquid phase synthesis method. The solvent used in the liquid phase synthesis method includes one or more 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 solvents include diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, 4-methyltetrahydropyran, 1,3-dioxolane, 1,4-dioxane, 1,2-dimethoxyethane, diisopropyl ether, methyl t-butyl ether, diglyme, triglyme, anisole, and tetraglyme. Specific examples of amide 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-imidazolidinone (DMI), and formamide. Specific examples of ester solvents include methyl acetate, ethyl acetate, methyl propionate, butyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, pentyl acetate, and γ-valerolactone. Specific examples of aromatic hydrocarbon solvents include toluene, o-xylene, m-xylene, p-xylene, mesitylene, chlorobenzene, fluorobenzene, anisole, etc. Specific examples of aliphatic hydrocarbon solvents include pentane, hexane, heptane, octane, cyclohexane, etc. Specific examples of carbonate ester solvents include dimethyl carbonate, diethyl carbonate, dibutyl carbonate, etc.The solvent used in the liquid phase synthesis method is preferably one or more selected from the group consisting of acetone, methyl t-butyl ether, dimethyl carbonate, 2-methyltetrahydropyran, 4-methyltetrahydropyran, tetrahydrofuran, ethyl acetate, isopropyl acetate, dichloromethane, 1,2-dichloroethane, toluene, chlorobenzene, heptane, and cyclohexane, more preferably one or more selected from the group consisting of acetone, methyl t-butyl ether, dimethyl carbonate, ethyl acetate, toluene, and dichloromethane, even more preferably acetone or toluene, and most preferably acetone.

[0100] When the metathesis step is carried out by a liquid phase synthesis method, the concentration of the compound represented by formula (2) or a salt thereof in the solvent used in the liquid phase synthesis method is 0.01 to 0.3 mol / L, preferably 0.02 to 0.3 mol / L, and more preferably 0.033 to 0.3 mol / L.

[0101] In one embodiment, the metathesis step can be carried out by stirring the reaction mixture at a reaction temperature of 20 to 100°C, preferably 30 to 70°C. The reaction temperature may be the temperature of the reaction mixture in the reaction vessel (internal temperature) or the temperature set in the temperature control device of 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 to 6 hours, and more preferably 1 to 4 hours.

[0102] When the metathesis step is carried out by a liquid phase synthesis method, the reaction mixture may be prepared in any of the following ways (a) to (d): (a) A mixture of a solvent containing a compound represented by formula (2) or a salt thereof is added to a mixture of a solvent containing a catalyst to prepare a mixture of a compound represented by formula (2) or a salt thereof, a catalyst, an acid, an additive, and a solvent; (b) A mixture of a solvent containing a compound represented by formula (2) or a salt thereof is added to a heated mixture of a solvent containing a catalyst to prepare a mixture of a compound represented by formula (2) or a salt thereof, a catalyst, an acid, an additive, and a solvent; (c) A mixture of a solvent containing a catalyst is added to a mixture of a solvent containing a compound represented by formula (2) or a salt thereof, a catalyst, an acid, an additive, and a solvent; (d) A solvent is added to a compound represented by formula (2) or a salt thereof, and then a catalyst, an acid, and an additive are added to prepare a mixture.

[0103] In one embodiment, the compound represented by formula (2) or a salt thereof is obtained by condensing a compound represented by formula (6) with a compound represented by formula (7), followed by deprotecting the carbamate protecting group. [In the formula, R ２ , R ３ , R ４ , n, and X are R in [1] above. ２ , R ３ , R ４ , n, and X; ２ is a carbamate protecting group.

[0104] The condensation reaction of the compound represented by formula (6) and the compound represented by formula (7) can be carried out, for example, using a condensation reagent and / or a base in solid phase synthesis and / or liquid phase synthesis, and is preferably carried out in liquid phase synthesis.

[0105] The condensation reagent, base, and amounts thereof used in the condensation reaction are not particularly limited, and condensation reagents, bases, and amounts thereof generally used in peptide synthesis are preferred (e.g., Peptide Coupling Reagents, More than a Letter Soup (Chem. Rev. 2011, 111, 6557-6602.)). On the other hand, when no condensation reagent is used in the condensation reaction, a compound in which the carboxyl group has been converted into an active ester or the like in advance may be used.

[0106] Specific examples of the condensation reagent include N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), HCl), 1-hydroxy-1H-benzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), ethyl 2-cyano-2-(hydroxyimino)acetate (oxyma), 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (HOOB or HODhbt), N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), 2,3,4,5,6-pentafluorophenol (HOPfp), N-hydroxysuccinimide (HOSu), 6-chloro-1-hydroxy-1H-benzotriazole (Cl-HOBt), O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-(7-aza-1H- Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), N-[1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino(morpholino)]uronium hexafluorophosphate (COMU), O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N',N'-tetramethyluronium hexafluorophosphate (HOTU), O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TATU), [ethylcyano(hydroxyimino)acetato-O 2]tri-1-pyrrolidinylphosphonium hexafluorophosphate (PyOxim), 2-bromo-1-ethylpyridinium tetrafluoroborate (BEP), 1H-benzotriazol-1-yloxy-tri(pyrrolidino)phosphonium hexafluorophosphate (PyBOP), 1H-benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), bromotri(pyrrolidino)phosphonium hexafluorophosphate (PyBroP), Chlorotri(pyrrolidino)phosphonium hexafluorophosphate (PyCloP), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), bromotris(dimethylamino)phosphonium hexafluorophosphate (Brop), 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT), N,N,N',N'-tetramethyl-O-(N-succinimidyl)uronium tetrafluoro Boric acid (TSTU), N,N,N',N'-tetramethyl-O-(N-succinimidyl)uronium hexafluorophosphate (HSTU), O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TDBTU), tetramethylthiuronium S-(1-oxido-2-pyridyl)-N,N,N',N'-tetrafluoroborate (TOTT), O-(2-oxo-1(2H)pyridyl)-N, Examples include N,N',N'-tetramethyluronium tetrafluoroborate (TPTU), N,N'-carbonyldiimidazole (CDI), 1,1'-carbonyl-di-(1,2,4-triazole) (CDT), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM), propylphosphonic anhydride (T3P), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH), etc. Among these, one or more selected from the group consisting of HATU, T3P, and TCFH are preferred, with TCFH being more preferred.

[0107] As the base, an organic base is preferably used, and among them, an organic base containing a tertiary amine is preferred. Specific examples of such bases include 2,2,6,6-tetramethylpiperidine, N-methylmorpholine, N,N-diisopropylethylamine (DIPEA), 2,4,6-collidine, 2,6-lutidine, pyridine, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), 2,3,6,7-tetrahydro-1H,5H-9-azabenzo[ij]quinolizine, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]-5-non ... Examples of suitable amines include naphthalene (DBN), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, 1,1,3,3-tetramethylguanidine (TMG), 1,8-bis(tetramethylguanidino)naphthalene (TMGN), 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), triethylamine (TEA), trimethylamine, 1-methylpiperidine, N,N'-dimethylpiperazine, N-ethylmorpholine, and p-dimethylaminopyridine (DMAP). Among these, one or more amines selected from the group consisting of N-methylmorpholine, 2,6-lutidine, and N,N-diisopropylethylamine (DIPEA) are preferred, with N,N-diisopropylethylamine (DIPEA) being more preferred.

[0108] In certain embodiments, the condensation reaction is carried out by a liquid phase synthesis method. The solvent used in the liquid phase synthesis method may include one or more solvents selected from the group consisting of nitrile solvents, halogenated solvents, ether solvents, amide solvents, ester solvents, and carbonate ester solvents. Specific examples of nitrile solvents include acetonitrile and propionitrile. Specific examples of halogenated solvents include dichloromethane, chloroform, and 1,2-dichloroethane. Specific examples of ether solvents include diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentyl methyl ether, 4-methyltetrahydropyran, 1,3-dioxolane, 1,4-dioxane, 1,2-dimethoxyethane, diisopropyl ether, methyl t-butyl ether, diglyme, triglyme, anisole, and tetraglyme. Specific examples of amide solvents include DMF, NMP, DMA, NEP, NBP, DMI, and formamide. Specific examples of ester solvents include methyl acetate, ethyl acetate, methyl propionate, butyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, pentyl acetate, and γ-valerolactone. Specific examples of carbonate ester solvents include dimethyl carbonate, diethyl carbonate, and dibutyl carbonate. The solvent for the condensation reaction is 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 even more preferably one or more selected from the group consisting of acetonitrile and 2-methyltetrahydrofuran.

[0109] 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 may be the temperature of the reaction mixture in the reaction vessel (internal temperature), or the temperature set in the temperature regulator of the reaction vessel (external temperature). The condensation reaction can be carried out by stirring the reaction mixture for 0.5 to 8 hours, preferably 1 to 5 hours.

[0110] The carbamate protecting group in the compound obtained by the condensation reaction of the compound represented by formula (6) and the compound represented by formula (7) can be deprotected by a method known to those skilled in the art, and examples thereof include a method in which the reaction mixture is stirred using an acid such as methanesulfonic acid or trifluoroacetic acid; or a base such as DBU or piperidine, in the presence or absence of a solvent such as 2-methyltetrahydrofuran, acetonitrile, or toluene, at a reaction temperature of 10 to 40° C. for 1 to 6 hours.

[0111] Method for Producing a Compound Represented by Formula (3) or a Salt Thereof In one aspect, the present invention relates to a method for producing a compound represented by formula (3) or a salt thereof, the method comprising a step of hydrogenating a compound represented by formula (1) or a salt thereof obtained by the above production method. [In the formula, R １ , R ２ , R ３ , R ４ , n, and X are R in [1] above. １ , R ２ , R ３ , R ４ , n, and X.]

[0112] The hydrogenation step can be carried out by a method known to those skilled in the art, and examples thereof include a method in which the reaction mixture is stirred using a catalyst such as Pd / C, Pd(OH) / C, or PtO in the presence or absence of a solvent such as 2-methyltetrahydrofuran, methanol, or ethyl acetate under a hydrogen atmosphere at a reaction temperature of 10 to 40° C. for 0.5 to 12 hours, preferably 1 to 6 hours.

[0113] Method for Producing a Compound Represented by Formula (4) or a Salt Thereof In one aspect, the present invention relates to a method for producing a compound represented by formula (4) or a salt thereof, the method comprising a step of protecting the amino group of the compound represented by formula (1) or a salt thereof obtained by the above production method with a carbamate protecting group. [In the formula, R ２ , R ３ , R ４ , n, and X are R in [1] above. ２ , R ３ , R ４ , n, and X; １ is a carbamate protecting group.

[0114] The step of protecting with a carbamate protecting group can be carried out by a method known to those skilled in the art, and examples thereof include a method in which a carbamate-forming reagent such as di-tert-butyl dicarbonate, N-carbobenzoxysuccinimide, or 9-fluorenylmethyl chloroformate is used, and the reaction mixture is stirred in the presence or absence of a solvent such as 2-methyltetrahydrofuran, acetonitrile, or toluene at a reaction temperature of 10 to 40° C. for 1 to 4 hours.

[0115] In one embodiment, the present invention provides (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-undecaoxo-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 The present invention relates to a method for producing pentatetracont-42-ene-23,1'-cyclobutane]-17-carboxamide or a salt thereof, which method comprises synthesizing the amino group of the compound represented by formula (4) or a salt thereof obtained by the above-mentioned production method according to WO 2023 / 214576.

[0116] Method for Producing a Compound Represented by Formula (5) or a Salt Thereof In one aspect, the present invention relates to a method for producing a compound represented by formula (5) or a salt thereof, the method comprising a step of protecting the amino group of the compound represented by formula (2) or a salt thereof obtained by the above production method with a carbamate protecting group. [In the formula, R ２ , R ３ , R ４ , n, and X are R in [1] above. ２ , R ３ , R ４ , n, and X; １ is a carbamate protecting group.

[0117] The step of protecting with a carbamate protecting group can be carried out by a method known to those skilled in the art, and examples thereof include a method in which a carbamate-forming reagent such as di-tert-butyl dicarbonate, N-carbobenzoxysuccinimide, or 9-fluorenylmethyl chloroformate is used, and the reaction mixture is stirred in the presence or absence of a solvent such as 2-methyltetrahydrofuran, acetonitrile, or toluene at a reaction temperature of 10 to 40° C. for 1 to 4 hours.

[0118] Each symbol used in the structural formula of the compounds represented by formulas (1) to (7) will be explained below.

[0119] R １ is hydrogen.

[0120] R ２ is hydrogen or C １ -C ６ It is alkyl. ２ is preferably hydrogen or methyl.

[0121] R ３ is hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted haloC １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C３ -C ８ Cycloalkyl, optionally substituted C ６ -C １４ Aryl, optionally substituted 5- to 14-membered heteroaryl, optionally substituted C ７ -C １４ Aralkyl, optionally substituted 3- to 14-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl C １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkoxy C １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkylsulfanyl C １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkylsulfinyl C １ -C ６ Alkyl, optionally substituted carboxy C １ -C ６ Alkyl, optionally substituted C ７ -C １４ Aralkoxy C １ -C ６ Alkyl, optionally substituted C ３ -C ８ Cycloalkyl C １ -C ６ Alkyl, optionally substituted C ３ -C ８ Cycloalkoxy C １ -C ６ Alkyl, optionally substituted 4- to 7-membered heterocyclyl C １ -C ３ Alkyl, optionally substituted 5- to 10-membered heteroaryl C １ -C ６ Alkoxy C １ -C ６ Alkyl or optionally substituted aminocarbonyl (the amino is -NH ２ , Mono C １ -C ６ Alkylamino, DiC １-C ６ Alkylamino, N—C １ -C ６ Alkyl-N—C ２ -C ６ Alkenylamino, N—C １ -C ６ Alkyl-N—C １ -C ６ Alkoxy C １ -C ６ R is selected from the group consisting of alkylamino, and 4- to 9-membered cyclic amino. ３ is preferably hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C ３ -C ８ Cycloalkyl, optionally substituted C ７ -C １４ Aralkyl, optionally substituted 5- to 10-membered heteroaryl C １ -C ６ alkyl, or optionally substituted 3- to 14-membered heterocyclyl, more preferably hydrogen, C １ -C ６ Alkyl, or C １ -C ３ Haloalkyl or C １ -C ６ C optionally substituted with alkyl ７ -C １４ It is preferably aralkyl, more preferably hydrogen, 2-methylpropyl, p-trifluoromethylbenzyl, or p-methylbenzyl.

[0122] R ４ is OR ５ , N.H.R. ５ ', an amino acid residue, or a peptide chain containing 1 to 20 amino acid residues, the amino acid residue and the peptide chain may have a protecting group, R ５ is a protecting group for the carboxy group. ４ is preferably OR ５ , N.H.R.５ ', an amino acid residue, or a peptide chain containing 2 to 13 amino acid residues. ５ is preferably 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, more preferably a methyl group, an ethyl group, a t-Bu group, a benzyl group, a trityl group, a cumyl group, a methoxytrityl group, a 2-(trimethylsilyl)ethyl group, a 2,2,2-trichloroethyl group, or an allyl group, and even more preferably tert-butyl or benzyl. ５ is preferably 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 t-Bu group, an allyl group, a benzyl group, a 4-methoxybenzyl group, a trityl group, a cumyl group, a methoxymethyl group, or a benzyloxymethyl group, and even 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. The amino acid residue is more preferably glycine, alanine, isoleucine, leucine, methionine, phenylalanine, tyrosine, N-methylglycine, N-methylalanine, N-methylisoleucine, N-methylleucine, N-methylmethionine, N-methylphenylalanine, or N-methyltyrosine.

[0123] n is an integer of 1 to 4. n is preferably an integer of 1 to 2. n is most preferably 2.

[0124] X is an optionally substituted C １ -C ３ Alkylene, —CH ２ OCH ２ - or -CH ２ SCH ２ X is preferably an optionally substituted C １ -C３ Alkylene or —CH ２ OCH ２ -, more preferably optionally substituted C １ -C ３ alkylene, more preferably C １ -C ３ It is preferably alkylene, and most preferably methylene.

[0125] X １ is one 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. １ is preferably one selected from the group consisting of an Fmoc group, a Cbz group, and a Boc group. １ is most preferably an Fmoc group.

[0126] X ２ is one 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. ２ is preferably one selected from the group consisting of an Fmoc group, a Cbz group, and a Boc group. ２ is most preferably an Fmoc group.

[0127] X １ and X ２ As a combination of １ and X ２ Both are one 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. １ and X ２ Both are one selected from the group consisting of an Fmoc group, a Cbz group, and a Boc group. １ and X ２ Both are Fmoc groups.

[0128] In one aspect, the present invention relates to a method for producing a cyclic peptide compound or a salt thereof. The method includes, for example, a method of cyclizing the compound represented by any of Formulas (1) to (5) or a salt thereof obtained by the above-mentioned production method, or a peptide compound obtained by chemically converting the compound or a salt thereof.

[0129] In one embodiment, a cyclic peptide compound is produced by amide cyclization of the N-terminal amino group and the C-terminal carboxyl group of a peptide compound. Amide cyclization can be carried out, for example, using a condensation reagent and / or a base. The condensation reagent and base used in amide cyclization are not particularly limited, and condensation reagents and bases commonly used in peptide synthesis can be used. Alternatively, amide cyclization can be carried out by liquid phase synthesis. The solvent used in liquid phase synthesis is not particularly limited, and solvents commonly used in peptide synthesis can be used.

[0130] In some embodiments, cyclic peptide compounds are prepared by thioether cyclization of the N-terminal chloroacetyl and C-terminal cysteine ​​side chains of the peptide compounds.

[0131] In one embodiment, the cyclic peptide compound or salt thereof produced by the method of the present invention contains 8 to 20 amino acid residues, preferably 11 to 14 amino acid residues, more preferably 11 to 13 amino acid residues, and most preferably 11 amino acid residues.

[0132] In some embodiments, the cyclic peptide compound or salt thereof produced by the methods of the present invention can contain at least 1, at least 2, at least 3, at least 4, or at least 5 unnatural amino acid residues. In certain embodiments, the unnatural amino acid residue contained in the cyclic peptide compound or salt thereof produced by the methods of the present invention is an N-methyl amino acid residue.

[0133] In some embodiments, the cyclic peptide compound produced by the method of the present invention may contain a cyclic structure (cyclic portion) as a partial structure. Specific examples of cyclic structures include a structure in which the side chain of one amino acid residue is linked to the side chain of another amino acid residue, a structure in which the N-substituent of one amino acid residue is linked to the side chain of another amino acid residue, or a structure 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 linkage for the cyclic structure may be adjacent, or any number of amino acid residues, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 amino acid residues, may be present between them. The size of the ring formed by the cyclic structure is not particularly limited, and examples include a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, a 12-membered ring, a 13-membered ring, a 14-membered ring, a 15-membered ring, a 16-membered ring, a 17-membered ring, an 18-membered ring, a 19-membered ring, a 20-membered ring, a 21-membered ring, a 22-membered ring, a 23-membered ring, a 24-membered ring, a 25-membered ring, a 26-membered ring, a 27-membered ring, a 28-membered ring, a 29-membered ring, a 30-membered ring, a 31-membered ring, a 32-membered ring, a 33-membered ring, a 34-membered ring, or a 35-membered ring. Preferably, the ring is a 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19-, or 20-membered ring, more preferably a 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, or 18-membered ring, and most preferably an 11-, 12-, 13-, or 14-membered ring. When a peptide compound has a cyclic structure, the number of cyclic structures is not limited, but it is preferred that one, two, three, four, or five cyclic structures be present.

[0134] In certain aspects, the cyclic peptide compound or salt thereof produced by the method of the present invention can comprise a cyclic portion composed of 4 or more, 6 or more, 8 or more, or 11 or more amino acid residues. In certain embodiments, the cyclic peptide compound or salt thereof produced by the method of the present invention comprises a cyclic portion composed of 4 to 14 amino acid residues, preferably 6 to 14 amino acid residues, more preferably 8 to 14 amino acid residues, and most preferably 11 to 14 amino acid residues. In certain embodiments, the cyclic peptide compound or salt thereof produced by the method of the present invention comprises a cyclic portion composed of 11 amino acid residues. In these aspects, the cyclic portion contains one, two, three, four, five, six, or seven amide bonds linking the amino group of a first amino acid or peptide with the carboxy group of a second amino acid or peptide.

[0135] In one embodiment, the cyclic peptide compound or salt thereof 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-undecaoxo-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 ]pentatetracont-42-ene-23,1'-cyclobutane]-17-carboxamide.

[0136] In one embodiment, the compound represented by formula (1) or a salt thereof produced by the method of the present invention may be a compound represented by formula (1a) or a salt thereof. [wherein Y represents a hydroxyl group, an optionally substituted C １ -C １０ Alkoxy, optionally substituted C ６ -C １６Aryloxy, optionally substituted C ７ -C １４ aralkoxy, or an optionally substituted 3- to 12-membered cyclic aminooxy.]

[0137] In one embodiment, Y in formula (1a) is preferably C １ -C ８ Alkoxy, C ６ Aryloxy and C １０ Aryloxy, C ７ -C １６ Aralkoxy and 3- to 12-membered cyclic aminooxy are preferred, with methoxy, ethoxy, tert-butoxy, phenoxy, 1-naphthyloxy, tolyloxy, benzyloxy, phenethyloxy, 1-pyrrolidyloxy, 1-piperidyloxy and 1-piperazyloxy being most preferred, and tert-butoxy being most preferred.

[0138] In one embodiment, the compound represented by Formula (1a) or a salt thereof is tert-butyl N-methyl-N-((S)-2-((S)-3-(methylamino)-2-oxo-2,3,4,7-tetrahydro-1H-azepin-1-yl)-3-(4-(trifluoromethyl)phenyl)propanoyl)glycinate or its hydrochloride salt.

[0139] In one embodiment, the compound represented by formula (1) or a salt thereof produced by the method of the present invention may be a compound represented by formula (1b) or a salt thereof. [In the formula, R ６ is methyl or trifluoromethyl, Z is a hydroxyl group, optionally substituted C １ -C １０ Alkoxy, optionally substituted C ６ -C １６ Aryloxy, optionally substituted C ７ -C １４ aralkoxy, or an optionally substituted 3- to 12-membered cyclic aminooxy.]

[0140] In one embodiment, Z in formula (1b) is preferably C １ -C ８ Alkoxy, C ６Aryloxy and C １０ Aryloxy, C ７ -C １６ Aralkoxy and 3- to 12-membered cyclic aminooxy are preferred, with methoxy, ethoxy, tert-butoxy, phenoxy, 1-naphthyloxy, tolyloxy, benzyloxy, phenethyloxy, 1-pyrrolidyloxy, 1-piperidyloxy and 1-piperazyloxy being most preferred, and tert-butoxy being most preferred.

[0141] In one embodiment, R in formula (1b) ６ is preferably methyl. In another embodiment, R in formula (1b) ６ is preferably trifluoromethyl.

[0142] In one embodiment, the compound represented by Formula (1b) or a salt thereof is tert-butyl N-methyl-N-((S)-2-((S,Z)-3-(methylamino)-2-oxo-3,4,7,8-tetrahydroazocin-1(2H)-yl)-3-(p-tolyl)propanoyl)glycinate or its hydrochloride salt.

[0143] In one embodiment, the compound represented by Formula (1b) or a salt thereof is tert-butyl N-methyl-N-((S)-2-((S,Z)-3-(methylamino)-2-oxo-3,4,7,8-tetrahydroazocin-1(2H)-yl)-3-(4-(trifluoromethyl)phenyl)propanoyl)glycinate or its hydrochloride salt.

[0144] In one embodiment, the compound represented by Formula (1b) or a salt thereof is tert-butyl N-methyl-N-((S)-2-((S,Z)-3-(methylamino)-2-oxo-2,3,4,5,8,9-hexahydro-1H-azonin-1-yl)-3-(p-tolyl)propanoyl)glycinate or its hydrochloride salt.

[0145] In one embodiment, the compound represented by formula (1b) or a salt thereof is (S)—N,N-dimethyl-2-((S,Z)-3-(methylamino)-2-oxo-3,4,7,8-tetrahydroazocin-1(2H)-yl)-3-(4-(trifluoromethyl)phenyl)propanamide or its hydrochloride salt.

[0146] In one embodiment, a method for producing a compound represented by formula (1) or a salt thereof includes a step of contacting a compound represented by formula (2) or a salt thereof with a catalyst (metathesis step), and R １ is a carbamate protecting group, the formation of impurities is suppressed.

[0147] In one embodiment, a method for producing a compound represented by formula (1) or a salt thereof includes a step of contacting a compound represented by formula (2) or a salt thereof with a catalyst (metathesis step), and R １ is a carbamate protecting group, the formation of a dimer is suppressed.

[0148] In one embodiment, the purity of the compound represented by formula (1) or a salt thereof is 90% or more, preferably 95% or more, more preferably 98% or more, and most preferably 99% or more, as determined by the UVArea value at 210 nm by HPLC analysis.

[0149] In one embodiment, the content of impurities contained in the compound represented by formula (1) or a salt thereof is less than 10%, preferably less than 5%, more preferably less than 1%, and most preferably less than 0.5% or an undetectable amount, as determined by UVArea value at 210 nm by HPLC analysis.

[0150] In this specification, an example of an "impurity" is a dimer formed by intermolecular bonding between compounds represented by formula (2). Such a dimer is presumed to be a chain compound obtained by an intermolecular olefin metathesis reaction proceeding at one site (for example, in the case of Example 1-6, the compound represented by the following formula (8)) or a cyclic compound obtained by an intermolecular olefin metathesis reaction proceeding at two sites (for example, in the case of Example 1-6, the compound represented by the following formula (9)).

[0151] In addition to the compounds represented by formula (8) and formula (9), possible impurities include compounds in which the olefin metathesis reaction occurs at different positions, compounds with different E / Z configurations of double bonds, and the like.

[0152] All references cited herein, including patent applications and publications, are hereby incorporated by reference in their entirety, including the following: WO 2013 / 100132, WO 2018 / 225851, WO 2018 / 225864, WO 2019 / 117274, WO 2020 / 111238, WO 202012 / 2182, WO 2021 / 0 75478, WO 2021 / 090856, WO 2021 / 132545, WO 2021 / 246471, WO 2022 / 097540, WO 2022 / 138891, WO 2022 / 145444, WO 2022 / 234864, WO 2023 / 127869, WO 2022 / 234853, WO 2023 / 214576.

[0153] The present disclosure will be described in more detail below based on examples, but the present disclosure is not limited to the following examples.

[0154] In the following examples, high performance liquid chromatography (HPLC) analysis was performed using one of the analytical conditions described below. Detection of each compound was performed using a photodiode array detector or a mass spectrometer, but other techniques such as evaporative light scattering detection may also be used.

[0155] HPLC analysis conditions, method 1. Apparatus: Waters ACQUITY UPLC H-Class + ACQUITY QDA. Column: Ascentis Express 90A C18 (Sigma-Aldrich), 2.1 mm ID × 50 mm, 2.7 μm. Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B). Elution method: B) 5% (0 min) → 100% (5 min) → 5% (5.1 min) → 5% (7 min). Flow rate: 0.5 mL / min. Column temperature: 35 °C. Detection wavelength: 210 nm (PDA).

[0156] HPLC analysis conditions, method 2. Apparatus: Waters ACQUITY UPLC H-Class. Column: Ascentis Express 90A C18 (Sigma-Aldrich), 2.1 mm ID x 50 mm, 2.7 μm. Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B). Elution method: B) 5% (0 min) → 100% (5 min) → 5% (5.1 min) → 5% (7 min). Flow rate: 0.5 mL / min. Column temperature: 35 °C. Detection wavelength: 210 nm (PDA).

[0157] HPLC analysis conditions, method 3. Apparatus: Waters ACQUITY UPLC H-Class + ACQUITY QDA. Column: Ascentis Express 90A C18 (Sigma-Aldrich), 2.1 mm ID × 50 mm, 2.7 μm. Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B). Elution method: B) 50% (0 min) → 100% (3 min) → 100% (5 min) → 50% (5.1 min) → 50% (7 min). Flow rate: 0.5 mL / min. Column temperature: 35 °C. Detection wavelength: 220 nm (PDA).

[0158] HPLC analysis conditions, method 4. Apparatus: Waters ACQUITY UPLC H-Class. Column: Ascentis Express RP-amide (Sigma-Aldrich), 3.0 mm ID x 50 mm, 2.7 μm. Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B). Elution method: B) 5% (0 min) → 100% (5 min) → 5% (5.1 min) → 5% (7 min). Flow rate: 0.5 mL / min. Column temperature: 35 °C. Detection wavelength: 210 nm (PDA).

[0159] HPLC analysis conditions, method 5. Apparatus: Waters ACQUITY UPLC H-Class. Column: Ascentis Express 90A C18 (Sigma-Aldrich), 2.1 mm ID x 50 mm, 2.7 μm. Mobile phase: 0.05% TFA / water (A), 0.05% TFA / MeCN (B). Elution method: B) 5% (0 min) → 100% (5 min) → 100% (7 min) → 5% (7.1 min) → 5% (9 min). Flow rate: 0.5 mL / min. Column temperature: 35 °C. Detection wavelength: 210 nm (PDA).

[0160] The conversion rate of the reaction mixture was analyzed by HPLC, and the ratio of the dimer formed by the intermolecular reaction to the product was calculated as follows: Conversion rate (%): {area value of product / (area value of product+area value of raw material)} x 100 Ratio of the dimer formed by the intermolecular reaction to the product: (total area values ​​of all dimers / area value of product) x 100

[0161] 1 ​H-NMR spectra were measured using a nuclear magnetic resonance spectrometer ECX500II (JEOL) and referenced to the deuterium lock 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 analyte signals were expressed in ppm. Signal abbreviations are s = singlet, brs = broad singlet, d = doublet, t = triplet, q = quartet, dd = double doublet, and m = multiplet. Signal splitting widths are expressed as J values ​​(Hz). Signal integration values ​​were calculated based on the ratio of the signal area intensities of each signal.

[0162] The qNMR measurement was carried out by dissolving the residue containing the target compound and the internal standard in DMSO-d6 under the following analytical conditions. Measurement equipment: JNM-ECZ500R Internal standard: 3,5-bis(trifluoromethyl)benzoic acid Measurement conditions ( 1 H-NMR): DMSO-d6, pulse angle 90°C, digital resolution 0.25Hz, relaxation time 60 seconds, no spin, number of accumulations 8

[0163] Example 1-1 Synthesis of (S)-2-(but-3-en-1-ylamino)-3-(4-(trifluoromethyl)phenyl)propionic acid (Compound 1)

[0164] Acetonitrile (822 mL), 4-bromo-1-butene (235.07 g), and triethylamine (17.66 g) were added to a nitrogen-purged reactor at an external temperature of 25 °C and stirred for 1 hour. (S)-2-amino-3-(4-(trifluoromethyl)phenyl)propionic acid (135.46 g), water (676 mL), and triethylamine (158.19 g) were then added, and the mixture was heated to 70 °C and 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 (1:1 volume ratio, 676 mL). The resulting wet powder was then further washed with acetonitrile (676 mL). The resulting wet powder was dried under reduced pressure with the filter set to an external temperature of 40 °C. The dried powder was collected, yielding compound 1 as a white solid (124.73 g). LCMS (ESI) retention time of compound 1: 2.34 min, m / z=288 [M+H] + (HPLC analysis conditions method 1)

[0165] Example 1-2 Synthesis of tert-butyl (S)-N-(2-(but-3-en-1-ylamino)-3-(4-(trifluoromethyl)phenyl)propanoyl)-N-methylglycinate hydrochloride (Compound 2-HCl)

[0166] Compound 1 (107.26 g) synthesized in Example 1-1, sarcosine tert-butyl ester hydrochloride (102.00 g), acetonitrile (751 mL), and DBU (233.03 g) were added to a first reaction vessel purged with nitrogen at an external temperature of 25°C and stirred for 10 minutes. After confirming that the solution had become homogeneous, the external temperature was set to 2°C, and a 50% solution of T3P in 2-MeTHF (309.03 g) was added dropwise over 2 hours and 14 minutes. After confirming completion of the reaction, toluene (751 mL) and 1 mol / L aqueous sodium hydroxide solution (536 mL) were added to the reaction mixture, stirred for 30 minutes, and the aqueous layer was discarded. The organic layer was stored overnight at around 25°C. After storage, 5% aqueous sodium carbonate solution (536 mL) was added to the organic layer, stirred for 10 minutes, and the aqueous layer was discarded. Next, 5% aqueous sodium dihydrogen phosphate (751 mL) was added to the organic layer and stirred for 10 minutes, after which the aqueous layer was discarded. 5% aqueous sodium dihydrogen phosphate (751 mL) was added to the organic layer and stirred for 10 minutes, after which the aqueous layer was discarded. 5% brine (751 mL) was added to the organic layer and stirred for 10 minutes, after which the aqueous layer was discarded. 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 organic layer volume was approximately 215 mL. Toluene (215 mL) was added to the concentrated solution, and the solution was concentrated under reduced pressure at 40°C until the organic layer volume was approximately 215 mL. This procedure was repeated twice. The precipitated inorganic salts were filtered, and toluene (276.6 mL) was added to the resulting filtrate. In a second reaction vessel, a solution prepared by adding acetonitrile (148 mL) to pyridine hydrochloride (43.28 g) was added dropwise over 45 minutes to the toluene solution of compound 2 obtained above at an external temperature of 25°C. Crystal precipitation was observed in the reaction vessel during the dropwise addition. Furthermore, acetonitrile (74 mL) was used to rinse the second reaction vessel containing the pyridine hydrochloride solution, and the resulting solution was added to the first reaction vessel containing compound 2 and stirred for 1 hour. Subsequently, toluene (1.7 L) was added to the first reaction vessel containing compound 2, and after stirring for 1 hour, the external temperature was lowered to 0°C and stirred for an additional 2 hours. The resulting crystals were filtered and washed twice with toluene (296 mL) cooled to 0°C. The resulting wet powder was stored at an external temperature of 5°C over the weekend. After storage, the wet powder was dried under reduced pressure at an external temperature of 40°C.The dried powder was collected to give compound 2-HCl as a white solid (98.66 g). LCMS (ESI) retention time for compound 2: 3.03 min, m / z=415 [M+H]. + (HPLC analysis conditions method 1)

[0167] Example 1-3 Synthesis of tert-butyl (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-triazadodecan-12-oate (compound Fmoc-3)

[0168] The compound 2-HCl (2.70 kg, 6.00 mol) synthesized in Example 1-2 above was added to a reaction vessel. Next, (S)-2-(((9-H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-pentenoic acid (2.74 kg), acetonitrile (6.34 kg), and MeTHF (5.74 kg) were added, and the external temperature of the reaction vessel was set to 15°C. DIPEA (3.86 kg) was then added. Next, a solution of TCFH (3.35 kg) dissolved in acetonitrile (7.58 kg) was added to the reaction vessel. The reaction mixture was stirred for 5 hours after the external temperature of the reaction vessel was set to 25°C. MeTHF (5.74 kg) was added to the reaction vessel, and the external temperature of the reaction vessel was then set to 15°C. A 5% aqueous potassium carbonate solution (13.45 kg) was then added, and the reaction mixture was stirred for 30 minutes. The aqueous layer was then discharged, and the resulting organic layer was washed with 5% sulfuric acid (13.45 kg). After adding MeTHF (5.74 kg) to the reaction vessel, the organic layer was washed with 5% aqueous potassium carbonate solution (13.45 kg). The resulting organic layer was concentrated under reduced pressure, and acetonitrile (16.91 kg) was added and further concentrated to obtain a concentrate containing compound Fmoc-3. LC retention time of compound Fmoc-3: 5.442 minutes (HPLC analysis condition method 2). LCMS (ESI) retention time of compound Fmoc-3: 5.491 minutes, m / z = 770 [M+Na]. + (HPLC analysis conditions method 1)

[0169] Example 1-4 Synthesis of tert-butyl N-((S)-2-((S)-N-(but-3-en-1-yl)-2-(methylamino)pent-4-enamido)-3-(4-(trifluoromethyl)phenyl)propanoyl)-N-methylglycinate hydrochloride (Compound 3-HCl)

[0170] The concentrate containing compound Fmoc-3 obtained in Example 1-3 above was added to a reaction vessel, and DBU (2.59 kg) was added at 15°C. The mixture was stirred for 1 hour. Next, triethylamine (2.29 kg) and sodium bisulfite (2.12 kg) were added to the reaction vessel, and the reaction mixture was stirred at 25°C for 1 hour. Toluene (18.38 kg) and 10% aqueous ammonia (33.92 kg) were added to the reaction vessel, and the reaction mixture was stirred for 10 minutes, after which the aqueous layer was discharged. The resulting organic layer was washed three times with 10% aqueous ammonia (33.92 kg) and then with 5% brine (33.92 kg). The resulting organic layer was concentrated under reduced pressure, and toluene (7.7 kg) was added to the resulting residue and concentrated under reduced pressure. The addition of toluene (7.7 kg) to the resulting residue and concentration under reduced pressure were repeated twice to obtain a concentrate containing compound 3. Toluene (0.86 kg) was added to the resulting concentrate, followed by the addition of a solution of pyridine hydrochloride (0.65 kg) in acetonitrile (3.17 kg) at 25°C. The reaction mixture was stirred for 1 hour, after which MTBE (11.92 kg) was added and stirred. The resulting precipitate was collected by filtration under reduced pressure, and the resulting wet powder was washed twice with MTBE (3.97 kg). The resulting solid was dried under reduced pressure to obtain compound 3-HCl (2.60 kg, 4.63 mol, 77.5% yield over two steps from compound 2-HCl). UV intensity ratio: 100% (detection wavelength: 210 nm, retention time: 3.145 min, HPLC analysis condition: method 2). LCMS (ESI) retention time of compound 3-HCl: 3.213 min, m / z = 526 [M+H]. + (HPLC analysis conditions method 1)

[0171] Example 1-5 Synthesis of Compound Fmoc-4 by Ring-Closing Metathesis of Compound Fmoc-3

[0172] Acetonitrile (20 mL) was added to the concentrated solution (55 mL) containing Fmoc-3 obtained in Example 1-3 above, and azeotropic dehydration under reduced pressure was repeated twice. The resulting residue was purified by silica gel column chromatography (mobile phase: heptane / ethyl acetate, volume ratio 0:100 → 40:60). The collected solution was concentrated, and MTBE (20 mL) was added to the resulting concentrated solution to precipitate compound Fmoc-3. The resulting solid was filtered to obtain Fmoc-3 (4.90 g) as a white solid. Fmoc-3 (1.00 g, 1.34 mmol) was added to a first reaction vessel and dissolved in acetone (7 mL) and HFIP (4.46 g, 2.8 mL) to prepare a solution of Fmoc-3. A second reaction vessel was charged with Hoveyda-Grubbs catalyst ([1-[2,4,6-trimethylphenyl]-3,5,5-trimethyl-3-phenyl-2-pyrrolinylidene]dichloro(2-isopropoxybenzylidene)ruthenium(II)) (8.5 mg, 0.013 mmol) and acetone (5 mL). After purging the atmosphere in the second reaction vessel with nitrogen, the solution in the second reaction vessel was heated to reflux at 65 °C while the solution of compound Fmoc-3 prepared above was added dropwise over 2 h. The first reaction vessel was then washed with acetone (1 mL), and the resulting wash solution was added dropwise to the solution in the second reaction vessel over 10 min. After the addition was complete, the reaction mixture was stirred for 4 h. A sample was taken from the reaction mixture and analyzed by HPLC. The conversion was 95.2%, and the ratio of the dimer formed by the intermolecular reaction to the product (Fmoc-4) was 361%. LCMS (ESI) retention time of compound Fmoc-4: 2.784 min, m / z=742[M+Na] + (HPLC analysis conditions method 3)

[0173] Example 1-6 Synthesis of Compound 4-HCl by Ring-Closing Metathesis of Compound 3-HCl

[0174] The compound 3-HCl (50.2 mg) obtained in Example 1-4 above was added to a reaction vessel and dissolved using acetone (0.35 mL) and HFIP (0.14 mL). A catalyst solution was prepared separately by dissolving Hoveyda-Grubbs catalyst ([1-[2,4,6-trimethylphenyl]-3,5,5-trimethyl-3-phenyl-2-pyrrolinylidene]dichloro(2-isopropoxybenzylidene)ruthenium(II)) (2.8 mg) in acetone (0.25 mL), and the catalyst solution was added to the reaction vessel. The reaction mixture was then stirred while the external temperature of the reaction vessel was set to 65°C and heated to reflux for 5 hours. HPLC analysis of a sample from the reaction mixture confirmed a conversion rate of 99.3% and a ratio of the dimer formed by the intermolecular reaction to the product (4-HCl) of 0.42%. LCMS (ESI) retention time of compound 4-HCl: 2.975 min, m / z=498 [M+H] + (HPLC analysis conditions method 1)

[0175] A comparison of Examples 1-5 and 1-6 above is shown in Table 1 below.

[0176]

[0177] As shown in Table 1, it was confirmed that the use of unprotected compound 3-HCl resulted in intramolecular selective reaction compared to the use of Fmoc-protected compound Fmoc-3.

[0178] Example 1-7 Synthesis of tert-butyl N-methyl-N-((S)-2-((S,Z)-3-(methylamino)-2-oxo-3,4,7,8-tetrahydroazocin-1(2H)-yl)-3-(4-(trifluoromethyl)phenyl)propanoyl)glycinate hydrochloride (Compound 4-HCl)

[0179] Compound 3-HCl (0.64 kg) obtained in Example 1-4 above was added to a first vessel and dissolved using acetone (3.52 kg) and HFIP (2.88 kg) to prepare a solution of compound 3-HCl. A catalyst solution was prepared in a second reaction vessel using Hoveyda-Grubbs catalyst ([1-[2,4,6-trimethylphenyl]-3,5,5-trimethyl-3-phenyl-2-pyrrolinylidene]dichloro(2-isopropoxybenzylidene)ruthenium(II)) (7.12 g) and acetone (2.51 kg), and the atmosphere in the second reaction vessel was then purged with nitrogen. Next, while the catalyst solution in the second reaction vessel was heated to reflux at an external temperature of 65°C, the compound 3-HCl solution prepared above was added dropwise over 1.5 hours. After the dropwise addition, the reaction mixture was stirred for 1 hour, allowed to cool to 25°C, and then stirred for another hour. The resulting precipitate was collected by filtration under reduced pressure, and the resulting wet powder was rinsed twice with acetone (2.52 kg). The resulting solid was dried under reduced pressure to obtain 0.55 kg of compound 4-HCl (yield 90.7%). UV intensity ratio: 99.1% (detection wavelength 210 nm, retention time 2.820 min, HPLC analysis condition method 2). LCMS (ESI) retention time of compound 4-HCl: 2.859 min, m / z = 498 [M+H]. + (HPLC analysis conditions method 1) 1 H-NMR (500 MHz, DMSO-d6, detected as rotamer mixture) 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)

[0180] Example 1-8: Investigation of Additives in the Ring-Closing Metathesis of Compound 3-HCl. Compound 3-HCl obtained in Example 1-4 above, acetone (10 times the amount), additive (2 times the amount), and second-generation Hoveyda-Grubbs catalyst (5 mol%) were added to a reaction vessel, and the atmosphere in the reaction vessel was replaced with nitrogen. The external temperature of the reaction vessel was then set to 55°C, and the mixture was stirred for 3 to 3.5 hours. The reaction mixture was sampled and analyzed by HPLC to determine the conversion rate. The additives used and their conversion rates are listed in Table 2 below.

[0181]

[0182] As shown in Table 2, it was confirmed that the target product 4-HCl was produced with a conversion rate of 70% or more even when multiple types of weak acids or alcohols were used as additives.

[0183] Example 1-9 Synthesis of tert-butyl N-((S)-2-((S,Z)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-2-oxo-3,4,7,8-tetrahydroazocin-1(2H)-yl)-3-(4-(trifluoromethyl)phenyl)propanoyl)-N-methylglycinate (compound Fmoc-4)

[0184] The reaction vessel was purged with nitrogen, and compound 4-HCl (3.14 kg, 5.88 mol), obtained by the same method as in Example 1-7 above, acetonitrile (7.34 kg), MeTHF (2.54 kg), and DIPEA (1.90 kg) were added. Next, a solution of 9-fluorenylmethyl chloroformate (1.60 kg) dissolved in MeTHF (5.36 kg) was added to the reaction vessel at 15°C and stirred for 1 hour. N,N-dimethylethylenediamine (0.10 kg) was added to the reaction vessel and stirred at 25°C for 0.5 hours. Next, 4% sulfuric acid (31.35 kg) was added to the reaction vessel at 15°C and stirred, and the aqueous layer was discharged. MeTHF (5.38 kg) and 4% sulfuric acid (31.47 kg) were added to the resulting organic layer and stirred, and the aqueous layer was discharged. MeTHF (5.38 kg) and 5% aqueous sodium carbonate solution (31.39 kg) were added to the obtained organic layer and stirred, and the aqueous layer was discharged. MeTHF (5.38 kg) and 5% saline solution (31.43 kg) were added to the obtained organic layer and stirred, and the aqueous layer was discharged. The obtained organic layer was concentrated and subjected to azeotropic dehydration with addition of MeTHF to obtain a concentrate containing compound Fmoc-4. LC retention time of compound Fmoc-4: 4.980 minutes (HPLC analysis condition method 4).

[0185] In the ring-closing metathesis of Fmoc-3, the main product is a compound derived from an intermolecular reaction, but by ring-closing metathesis with 3-HCl and subsequent Fmocation of the N-terminus, we succeeded in obtaining Fmoc-4 as the main product.

[0186] Example 1-10 Synthesis of tert-butyl N-methyl-N-((S)-2-((S)-3-(methylamino)-2-oxoazocane-1-yl)-3-(4-(trifluoromethyl)phenyl)propanoyl)glycinate hydrochloride (Compound 5-HCl)

[0187] Compound 4-HCl (240 mg, 0.45 mmol) obtained in Example 1-7 above, methanol (4.8 mL), and 10% palladium-carbon (water content 54%, 51.8 mg) were added to a reaction vessel, and the atmosphere inside the reaction vessel was replaced with a hydrogen atmosphere. After stirring at around 25°C for 75 minutes, the reaction mixture was filtered, and the filtered palladium-carbon was washed with methanol (3 mL). The resulting filtrate was concentrated under reduced pressure to obtain compound 5-HCl (221 mg, 0.41 mmol, yield 91.9%) as a white solid. UV intensity ratio: 99.5% (detection wavelength 210 nm, retention time 2.808 minutes, HPLC analysis conditions: method 1, m / z = 500 [M+H] + (ESI)

[0188] The compound obtained by ring-closing metathesis was successfully converted from its double bond to a single bond by hydrogenation, leading to the corresponding lactam 5-HCl.

[0189] Example 1-11 Synthesis of (S)-2-(but-3-en-1-ylamino)-3-(p-tolyl)propanoic acid (Compound 6)

[0190] (S)-2-Amino-3-(p-tolyl)propanoic 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 stirred at 70 °C for 4 hours. After cooling to 25 °C, the resulting precipitate was collected by filtration and the resulting solid was dried under reduced pressure to give compound 6 (2.40 g, 53% yield) as a white solid. UV intensity ratio: 99.0% (detection wavelength: 210 nm, retention time: 1.983 min, HPLC analysis condition: method 2).

[0191] Example 1-12 Synthesis of tert-butyl (S)-N-(2-(but-3-en-1-ylamino)-3-(p-tolyl)propanoyl)-N-methylglycinate (Compound 7)

[0192] Compound 6 (2.05 g, 8.79 mmol) obtained in Example 1-11 above, tert-butyl sarcosine hydrochloride (3.20 g, 17.6 mmol), acetonitrile (20 mL), and DIPEA (6.91 mL, 39.5 mmol) were added to a reaction vessel at approximately 25°C. After purging the reaction vessel with nitrogen, chlorotripyrrolidinophosphonium hexafluorophosphate (5.60 g, 13.3 mmol) was added and the mixture was stirred at 72°C for 5 hours. After cooling to 25°C, 10% aqueous potassium carbonate solution (10 mL) was added and the mixture was stirred for 6 hours. The aqueous layer was discarded, and the resulting organic layer was washed with 10% aqueous sodium hydrogen sulfate solution (16 mL x 2). 1 mol / L aqueous sodium hydroxide solution (10 mL) and MeTHF (10 mL) were added to the resulting organic layer, followed by stirring, and the aqueous layer was discarded. Toluene (10 mL) was added to the resulting organic layer, which was then washed with water (10 mL × 2) and 5% brine (10 mL). The resulting organic layer was concentrated, followed by azeotropic dehydration with toluene (20 mL) to obtain a residue containing compound 7 (5.08 g). LCMS (ESI) retention time of compound 7: 2.756 min, m / z = 361 [M+H]. + (HPLC analysis conditions method 1)

[0193] Example 1-13 Synthesis of tert-butyl N-((S)-2-((S)-N-(but-3-en-1-yl)-2-(methylamino)pent-4-enamido)-3-(p-tolyl)propanoyl)-N-methylglycinate (Compound 8)

[0194] The residue (5.75 g) containing compound 7 (10.6 mmol) obtained by the method of Example 1-12 above, (S)-2-(((9-H-fluoren-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 a reaction vessel at approximately 25°C. After the atmosphere in the reaction vessel was replaced with nitrogen, TCFH (5.97 g, 21.3 mmol) was added and the mixture was stirred at 25°C for 4 hours. Next, MTBE (19 mL), 5% aqueous potassium carbonate 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 discarded, and the resulting organic layer was washed with 10% aqueous sodium hydrogen sulfate solution (19 mL × 2) and 5% brine (19 mL). The resulting organic layer was concentrated, and DBU (4.81 mL) and acetonitrile (7.6 mL) were added. The mixture was stirred at around 25°C for 45 minutes. Sodium bisulfite (2.76 g), triethylamine (5.93 mL), and water (1.92 mL) were then added, followed by stirring at around 25°C for 2 hours. Toluene (19 mL), isopropyl acetate (19 mL), and 20% aqueous ammonia (36 mL) were then added and stirred. After the aqueous layer was discarded, the resulting organic layer was washed with 20% aqueous ammonia (36 mL x 3) and brine (19 mL). The resulting organic layer was concentrated under reduced pressure, followed by azeotropic dehydration with toluene (19 mL x 2) to obtain a residue containing compound 8 (9.01 g). LCMS (ESI) retention time for compound 8: 3.038 minutes, m / z = 472 [M+H]. + (HPLC analysis conditions method 1)

[0195] Example 1-14 Synthesis of tert-butyl N-methyl-N-((S)-2-((S,Z)-3-(methylamino)-2-oxo-3,4,7,8-tetrahydroazocin-1(2H)-yl)-3-(p-tolyl)propanoyl)glycinate (Compound 9)

[0196] The purified product of compound 8 (41.6 mg, 0.088 mmol) synthesized in Example 1-13 above (purified by a silica gel column using dichloromethane / methanol as the mobile phase) was added to the reaction vessel. Then, toluene (2.2 mL), boron trifluoride tetrahydrofuran complex (9.7 μL, 0.088 mmol), and a toluene solution (0.45 mL) containing the first-generation Hoveyda-Grubbs catalyst (2.6 mg, 4.4 μmol) were added to the reaction vessel, and the atmosphere inside the reaction vessel was replaced with nitrogen. The reaction mixture was then stirred for 3 hours after the external temperature of the reaction vessel was set to 40°C. A sample was taken from the reaction mixture and analyzed by HPLC. The conversion rate was 74.8%, and the ratio of the dimer formed by the intermolecular reaction to the product (9) was confirmed to be 1.7%. LCMS (ESI) retention time of compound 9: 2.492 min, m / z = 444 [M+H] + (HPLC analysis conditions method 1)

[0197] Example 1-15 Synthesis of tert-butyl (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-triazadodecan-12-oate (compound Cbz-8)

[0198] Compound 7 (0.50 g, 1.39 mmol), synthesized by a method similar to that described in Example 1-12, was added to a 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 mixture was stirred at approximately 25°C for 1 hour. MeTHF (2.5 mL) and 5% aqueous sodium bicarbonate solution (5 mL) were then added and the mixture was stirred. The aqueous layer was then discarded. The organic layer was washed sequentially with 5% aqueous sodium bicarbonate solution (5 mL), 5% aqueous potassium hydrogen sulfate solution (5 mL) × 2, and 5% brine (5 mL). The resulting organic layer was concentrated to obtain a concentrated solution of compound Cbz-8. The residue was purified using a silica gel column (mobile phase: heptane / ethyl acetate, volume ratio 100:0 → 80:20) to obtain compound Cbz-8 (0.66 g). LCMS (ESI) retention time of compound Cbz-8: 4.867 minutes, m / z = 628 [M + Na] + (HPLC analysis conditions method 1)

[0199] Example 1-16 Synthesis of tert-butyl N-((S)-2-((S,Z)-3-(((benzyloxy)carbonyl)(methyl)amino)-2-oxo-3,4,7,8-tetrahydroazocin-1(2H)-yl)-3-(p-tolyl)propanoyl)-N-methylglycinate (compound Cbz-9)

[0200] Compound Cbz-8 (48.6 mg, 0.080 mmol) obtained in Example 1-15 above, toluene (2.67 mL), and first-generation Hoveyda-Grubbs catalyst (2.3 mg, 3.9 μmol) were added to a reaction vessel, and the atmosphere inside the reaction vessel was replaced with nitrogen. The external temperature of the reaction mixture was then set to 70°C, and the mixture was stirred for 2 hours. A sample of the reaction mixture was then taken and analyzed by HPLC. The conversion rate was confirmed to be 39.4%, and the ratio of the dimer formed by the intermolecular reaction to the product (Cbz-9) was confirmed to be 35.9%. LCMS (ESI) retention time of compound Cbz-9: 1.877 minutes, m / z=600 [M+Na] +(HPLC analysis conditions method 3)

[0201] A comparison of the ring-closing metathesis of N-terminally unprotected compound 8 (Examples 1-14) and the ring-closing metathesis of Cbz-protected compound Cbz-8 (Examples 1-16) is shown in Table 3 below.

[0202]

[0203] It was confirmed that the use of unprotected compound 8 resulted in a higher conversion rate and intramolecular selectivity in the ring-closing metathesis reaction compared to the use of the Cbz-protected compound Cbz-8.

[0204] Example 1-17 Synthesis of tert-butyl N-((S)-2-((S)-N-(but-3-en-1-yl)-2-(methylamino)pent-4-enamido)-3-(p-tolyl)propanoyl)-N-methylglycinate hydrochloride (Compound 8-HCl)

[0205] To the residue (9.01 g) containing compound 8 obtained by the method of Example 1-13 above, a pyridine hydrochloride solution prepared by dissolving pyridine hydrochloride (0.86 g) in acetonitrile (1.9 mL) and MTBE (11.4 mL) were added. The reaction mixture was stirred at around 25°C for 10 minutes, and MTBE (7.6 mL) was added. The reaction mixture was stirred for 1 hour, and then MTBE (19 mL) was added. The mixture was stirred for 1 hour and then allowed to stand for 15 hours. The resulting precipitate was collected by filtration, and the resulting solid was dried under reduced pressure to obtain 2.79 g of compound 8-HCl (content 97.5%, product of the NMR content calculated by qNMR and the UV intensity ratio) as a beige solid. UV intensity ratio: 99.1% (detection wavelength 210 nm, retention time 3.042 minutes, HPLC analysis conditions method 1, m / z = 472 [M+H] + (ESI)

[0206] Example 1-18 Synthesis of tert-butyl N-methyl-N-((S)-2-((S,Z)-3-(methylamino)-2-oxo-3,4,7,8-tetrahydroazocin-1(2H)-yl)-3-(p-tolyl)propanoyl)glycinate hydrochloride (Compound 9-HCl)

[0207] In a first reaction vessel, compound 8-HCl (1.02 g, 97.5% content) obtained in Example 1-17 was dissolved in acetone (5 mL) and HFIP (0.41 mL) to prepare a compound 8-HCl solution. In a second reaction vessel, second-generation Hoveyda-Grubbs catalyst (0.061 g), acetone (15 mL), and HFIP (1.8 mL) were added to prepare a catalyst solution. The atmosphere in the second reaction vessel was then purged with nitrogen. The external temperature of the second reaction vessel was then set to 65°C, and the compound 8-HCl solution prepared above was added dropwise to the catalyst solution over 1 hour while heating the catalyst solution in the second reaction vessel to reflux. After the addition, the reaction mixture was stirred for 1 hour. A sample was taken and analyzed by HPLC. The conversion was confirmed to be 99.3%, with the ratio of dimers formed by intermolecular reaction to the product (9-HCl) being 1.7%. The reaction mixture was allowed to cool to approximately 25°C, and MTBE (10 mL) was added to the reaction mixture. The resulting suspension was then filtered. The resulting wet powder was then washed twice with a mixed solution of acetone / MTBE (volume ratio 2:1, 5 mL). The resulting solid was dried under reduced pressure to obtain 0.79 g of compound 9-HCl (81.4%, content 97.0%, product of the NMR content calculated by qNMR and the UV intensity ratio) as a white solid. UV intensity ratio: 98.6% (detection wavelength 210 nm, retention time 2.630 min, HPLC analysis conditions method 1, m / z = 444 [M+H] + (ESI) 1 H-NMR (500 MHz, DMSO-d6, detected as rotamer mixture) 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)

[0208] By using the N-terminal unprotected compound 8-HCl, we were able to carry out a ring-closing metathesis reaction with a yield of over 80% and an LC purity of over 98%, and successfully obtained the cyclic compound 9-HCl.

[0209] Example 1-19 Synthesis of (S)-2-(allylamino)-3-(4-(trifluoromethyl)phenyl)propanoic acid (Compound 10)

[0210] (S)-2-Amino-3-(4-(trifluoromethyl)phenyl)propanoic 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 h. The resulting precipitate was collected by filtration, and the resulting solid was dried under reduced pressure to give compound 10 (3.05 g, 77.9% yield) as a white solid. UV intensity ratio: 96.4% (detection wavelength: 210 nm, retention time: 1.925 min, HPLC analysis conditions: method 1, m / z = 274 [M+H]). + (ESI)

[0211] Example 1-20 Synthesis of tert-butyl (S)-N-(2-(allylamino)-3-(4-(trifluoromethyl)phenyl)propanoyl)-N-methylglycinate (Compound 11)

[0212] Compound 10 (2.51 g, 9.19 mmol) obtained in Example 1-19 above, tert-butyl sarcosine hydrochloride (2.52 g, 13.9 mmol), acetonitrile (18 mL), and DBU (5.68 mL, 37.7 mmol) were added to a reaction vessel at approximately 25°C. The external temperature of the reaction vessel was then set to 0°C, and T3P (50 wt% MeTHF solution, 7.38 mL) was added, followed by stirring at approximately 25°C for 1 hour. Toluene (20 mL) and 1 mol / L aqueous sodium hydroxide solution (13 mL) were added, followed by stirring for 15 minutes, and the aqueous layer was discarded. The resulting organic layer was washed sequentially with 5% aqueous sodium carbonate solution (13 mL), 5% aqueous sodium dihydrogen phosphate solution (20 mL x 3), and 10% brine (5 mL). The resulting organic layer was concentrated under reduced pressure, and toluene (20 mL) was added for azeotropic dehydration. Subsequently, filtration and concentration were performed to obtain 5.80 g of a residue containing compound 11. LCMS (ESI) retention time of compound 11: 2.768 min, m / z = 401 [M+H] + (HPLC analysis conditions method 1)

[0213] Example 1-21 Synthesis of tert-butyl (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-triazadodecan-12-oate (compound Fmoc-12)

[0214] The residue (5.41 g) containing compound 11 obtained by the same method as in Example 1-20 above, (S)-2-(((9-H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-pentenoic acid (3.92 g), acetonitrile (17 mL), MeTHF (9 mL), and DIPEA (7.46 mL) were added to a reaction vessel at room temperature. After the atmosphere in the reaction vessel was replaced with nitrogen, TCFH (4.81 g) was added and the mixture was stirred at around 25°C for 3.5 hours. Next, MeTHF (20 mL) and 5% aqueous potassium carbonate solution (17 mL) were added and the mixture was stirred at around 25°C. The aqueous layer was discarded, and the resulting organic layer was washed with 5% sulfuric acid (17 mL) and 5% aqueous potassium carbonate solution (17 mL). The resulting organic layer was concentrated under reduced pressure, and then acetonitrile (20 mL) was added and the mixture was concentrated. After cooling to 0°C, the resulting precipitate was collected by filtration, and the resulting wet powder was washed with acetonitrile (10 mL). The resulting solid was dried under reduced pressure to obtain compound Fmoc-12 (2.18 g) as a white solid. LC retention time of compound Fmoc-12: 5.231 minutes (HPLC analysis condition method 2).

[0215] Example 1-22 Synthesis of tert-butyl N-((S)-2-((S)-N-allyl-2-(methylamino)pent-4-enamido)-3-(4-(trifluoromethyl)phenyl)propanoyl)-N-methylglycinate hydrochloride (Compound 12-HCl)

[0216] Compound Fmoc-12 (2.18 g, 2.97 mmol) obtained in Example 1-21 above, acetonitrile (7 mL), and DBU (0.45 mL) were added to a reaction vessel at around 25°C, and the reaction mixture was stirred for 1.5 hours. Next, 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 around 25°C for 2 hours. Toluene (30 mL) and 10% aqueous ammonia (16 mL) were added to the reaction mixture, and the mixture was stirred. The aqueous layer was then discarded. The resulting organic layer was washed three times with 10% aqueous ammonia (16 mL), followed by 5% brine (10 mL). The resulting organic layer was concentrated under reduced pressure, and azeotropic dehydration was performed three times with toluene (20 mL). To the resulting concentrate, an acetonitrile solution (1 mL) containing pyridine hydrochloride (0.36 g) was added. MTBE (6 mL) and heptane (6 mL) were then added to the reaction mixture, and the mixture was stirred. The resulting precipitate was collected by filtration under reduced pressure, and the resulting wet powder was washed with heptane (5 mL). The resulting solid was dried under reduced pressure to obtain 1.50 g (2.74 mmol, 92.1% yield) of compound 12-HCl. UV intensity ratio: 99.5% (detection wavelength: 210 nm, retention time: 3.030 min, HPLC analysis conditions: method 1, m / z = 512 [M+H]). + (ESI)

[0217] Example 1-23 Synthesis of tert-butyl N-methyl-N-((S)-2-((S)-3-(methylamino)-2-oxo-2,3,4,7-tetrahydro-1H-azepin-1-yl)-3-(4-(trifluoromethyl)phenyl)propanoyl)glycinate hydrochloride (Compound 13-HCl)

[0218] Compound 12-HCl (75.8 mg, 0.14 mmol) obtained in Example 1-22 above, second-generation Hoveyda-Grubbs catalyst (4.44 mg), acetone (1.02 mL), and HFIP (0.68 mL) were added to a reaction vessel. After replacing the atmosphere in the reaction vessel with nitrogen, the reaction mixture was heated for 1 hour after the external temperature of the reaction vessel was set to 65°C. The reaction mixture was allowed to cool to approximately 25°C, and a sample was taken and analyzed by HPLC. The conversion rate was 98.1%, and no dimer formed by intermolecular reaction was detected. The reaction mixture was concentrated, and acetone (1 mL) was added. The resulting precipitate was filtered. The resulting wet powder was washed with acetone (1 mL), and the resulting solid was dried under reduced pressure to obtain compound 13-HCl (57.7 mg, yield 80.2%) as a white solid. UV intensity ratio: 98.9% (detection wavelength 210 nm, retention time 2.733 minutes, HPLC analysis conditions method 1, m / z=484[M+H] + (ESI) 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)

[0219] Using the N-terminal unprotected compound 12-HCl, we successfully performed a ring-closing metathesis reaction to obtain the cyclic compound 13-HCl with a yield of over 80% and a purity of over 98%.

[0220] Example 1-24 Synthesis of tert-butyl (S)-N-(2-(but-3-en-1-ylamino)-3-(p-tolyl)propanoyl)-N-methylglycinate hydrochloride (Compound 7-HCl)

[0221] Compound 6 (1.10 g, 4.71 mmol), 1,1'-carbonyldiimidazole (0.92 g, 5.66 mmol), and THF (16.5 mL), obtained by a method similar to that described in Example 1-11, were added to a reaction vessel, and the atmosphere inside the reaction vessel was replaced 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 hours. After cooling to 25°C, a solution of tert-butyl sarcosine hydrochloride (1.03 g, 5.66 mmol) in THF (2 mL), acetonitrile (3 mL), and DIPEA (3.8 mL, 21.7 mmol) was added to the reaction mixture and stirred for 2 hours. A 5% aqueous potassium carbonate solution (11 mL) was then added, the mixture was stirred for 5 minutes, and the aqueous layer was discarded. The resulting organic layer was washed with 10% aqueous sodium hydrogen sulfate (11 mL) and 5% aqueous sodium hydrogen sulfate (11 mL), and each aqueous layer was washed three times with MeTHF (11 mL). All organic layers were combined and concentrated under reduced pressure. Acetonitrile (12 mL) and 2 M hydrochloric acid (5 mL) were added to the resulting residue, and the mixture was concentrated under reduced pressure. The resulting precipitate was filtered, washed with water, and then dried under reduced pressure to obtain 0.48 g of compound 7-HCl. LCMS (ESI) retention time of compound 7-HCl: 2.689 min, m / z=361 [M+H] + (HPLC analysis conditions method 1)

[0222] Example 1-25 Synthesis of tert-butyl N-((S)-2-((S)-N-(but-3-en-1-yl)-2-(methylamino)hex-5-enamido)-3-(p-tolyl)propanoyl)-N-methylglycinate hydrochloride (Compound 14-HCl)

[0223] Compound 7-HCl (0.89 g, 2.25 mmol), (S)-2-((((9-H-fluoren-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 a reaction vessel. TCFH (1.29 g) was added to the reaction mixture, and the mixture was stirred at about 25°C for 2.5 hours. Next, MeTHF (18 mL) and 5% aqueous potassium carbonate solution (9 mL) were added, and the mixture was stirred. The aqueous layer was then discarded. The resulting organic layer was washed with 5% sulfuric acid (5.4 mL) and 5% aqueous potassium carbonate solution (4.5 mL). The resulting organic layer was concentrated, and acetonitrile (20 mL) was added to perform azeotropic dehydration. Acetonitrile (2 mL) and DBU (0.51 mL) were added to the resulting residue and stirred for 1 hour. DBU (0.34 mL) was added and stirred for 20 minutes. Next, triethylamine (1.25 mL), water (0.41 mL), and sodium bisulfite (0.58 g) were added to the reaction mixture and stirred for 1 hour. Triethylamine (0.62 mL) was added to the reaction mixture and stirred for 45 minutes. Next, toluene (15 mL) and 10% aqueous ammonia (20 mL) were added to the reaction mixture and stirred, and the aqueous layer was discarded. The resulting organic layer was washed four times with 10% aqueous ammonia (10 mL) and then with 5% brine (10 mL). The resulting organic layer was concentrated under reduced pressure, and toluene (10 mL) was added and azeotropically dehydrated. The resulting residue was filtered, and the filtrate was concentrated, followed by the addition of pyridine hydrochloride (0.27 g) in acetonitrile (1 mL). MTBE (10 mL) was added, and the mixture was stirred at around 25 °C for 1 hour. After cooling to 0°C, the resulting precipitate was filtered, and the resulting wet powder was washed with MTBE (5 mL). The resulting solid was dried under reduced pressure to give compound 14-HCl (0.81 g). UV intensity ratio: 99.3% (detection wavelength: 210 nm, retention time: 3.150 min, HPLC analysis conditions: method 1, m / z = 486 [M+H]). + (ESI)

[0224] Example 1-26 Synthesis of tert-butyl N-methyl-N-((S)-2-((S,Z)-3-(methylamino)-2-oxo-2,3,4,5,8,9-hexahydro-1H-azonin-1-yl)-3-(p-tolyl)propanoyl)glycinate hydrochloride (Compound 15-HCl)

[0225] Compound 14-HCl (53.3 mg, 0.10 mmol) obtained in Example 1-25 above, second-generation Hoveyda-Grubbs catalyst (3.1 mg, 0.005 mmol), acetone (1 mL), and HFIP (0.12 mL) were added to a reaction vessel. After replacing the atmosphere inside the reaction vessel with nitrogen, the reaction mixture was heated to 60°C for 1 hour. A sample of the reaction mixture was taken and analyzed by HPLC. The conversion rate was 97.8%, and the ratio of the dimer formed by intermolecular reaction to the product (15-HCl) was 6.1%. The reaction mixture was stirred for an additional hour and allowed to cool to approximately 25°C. MTBE (1 mL) was then added to the reaction mixture. The resulting precipitate was filtered, and the resulting wet powder was washed with a mixed solution of acetone and MTBE (0.4 mL, 1:1 by volume), followed by MTBE (1 mL). The resulting solid was dried under reduced pressure to obtain compound 15-HCl (19.7 mg, 39.1% yield). UV intensity ratio: 98.2% (detection wavelength 210 nm, retention time 2.768 minutes, HPLC analysis conditions method 2) LCMS (ESI) retention time of compound 15-HCl: 2.696 minutes, m / z=458 [M+H] + (HPLC analysis conditions method 1) 1H-NMR (500 MHz, DMSO-d6, detected as rotamer mixture) 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)

[0226] Example 1-27 Synthesis of tert-butyl (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-triazadodecan-12-oate (compound Fmoc-16)

[0227] The compound 2-HCl (2.53 g, 5.61 mmol) obtained by the method of Example 1-2 above, (S)-2-((((9-H-fluoren-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 a reaction vessel. TCFH (3.20 g) was then added to the reaction mixture, which was stirred at around 25°C for 2.5 hours and then allowed to stand for 23 hours. MeTHF (25 mL) and 5% aqueous potassium carbonate solution (18 mL) were then added and stirred, and the aqueous layer was discarded. The resulting organic layer was washed with 5% sulfuric acid (18 mL) and 5% aqueous potassium carbonate solution (18 mL) and concentrated under reduced pressure. Acetonitrile (20 mL) was added to the resulting residue and azeotropically dehydrated. The resulting precipitate was filtered, and the resulting wet powder was washed with acetonitrile (10 mL). The resulting solid was dried under reduced pressure to obtain compound Fmoc-16 (2.32 g). UV intensity ratio: 99.4% (detection wavelength 210 nm, retention time 5.590 min, HPLC analysis condition method 5).

[0228] Example 1-28 Synthesis of tert-butyl N-((S)-2-((S,Z)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-2-oxo-2,3,4,5,8,9-hexahydro-1H-azonin-1-yl)-3-(4-(trifluoromethyl)phenyl)propanoyl)-N-methylglycinate (compound Fmoc-17)

[0229] Compound Fmoc-16 (71.7 mg, 0.094 mmol) obtained in Example 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 a reaction vessel. After replacing the atmosphere in the reaction vessel with nitrogen, the reaction mixture was heated for 1 hour after setting the external temperature of the reaction vessel to 60°C. A sample of the reaction mixture was taken and analyzed by HPLC. The conversion rate was 77.6%, and the ratio of the dimer formed by the intermolecular reaction to the product (Fmoc-17) was 161%. LCMS (ESI) retention time of compound Fmoc-17: 2.932 min, m / z = 756 [M+Na] + (HPLC analysis conditions: method 3)

[0230] A comparison of the results of the ring-closing metathesis of N-terminally unprotected compound 14-HCl (Example 1-26) and the ring-closing metathesis of Fmoc-protected compound Fmoc-16 (Example 1-28) is shown in Table 4 below.

[0231]

[0232] Compared with the case where the Fmoc-protected compound Fmoc-16 was used, the ring-closing metathesis reaction proceeded with higher conversion and intramolecular selectivity when the N-terminal unprotected compound 14-HCl was used.

[0233] Example 1-29 Synthesis of (S)-2-(but-3-en-1-ylamino)-N,N-dimethyl-3-(4-(trifluoromethyl)phenyl)propanamide (Compound 18)

[0234] Compound 1 (2.21 g, 7.69 mmol) obtained in Example 1-1 above, dimethylamine (2 M THF solution, 7.69 mL, 15.4 mmol), acetonitrile (6.6 mL), and DBU (3.48 mL) were added to a reaction vessel containing a stirrer at approximately 25 °C. The external temperature of the reaction vessel was then set to 0 °C, and T3P (50 wt% MeTHF solution, 6.18 mL) was added to the reaction mixture, followed by stirring 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 then added to the reaction mixture, followed by stirring for an additional 45 minutes. 2MeTHF (22 mL) and 1 mol / L aqueous sodium hydroxide solution (11 mL) were then added to the reaction mixture, and the stirrer and aqueous layer were discarded. The resulting organic layer was washed twice with 1 mol / L aqueous sodium hydroxide (11 mL), twice with 5% aqueous sodium dihydrogen phosphate (11 mL), 1 mol / L aqueous sodium hydroxide (11 mL), and 5% aqueous potassium carbonate (11 mL). The resulting organic layer was concentrated, and MeTHF (20 mL) was added for azeotropic dehydration. The resulting residue was filtered and concentrated to obtain a residue containing compound 18 (2.98 g). LCMS (ESI) retention time of compound 18: 2.207 min, m / z = 315 [M+H]. + (HPLC analysis conditions method 1)

[0235] Example 1-30 Synthesis of (S)—N-(but-3-en-1-yl)-N-((S)-1-(dimethylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-yl)-2-(methylamino)pent-4-enamide hydrochloride (Compound 19-HCl)

[0236] The residue containing compound 18 obtained in Example 1-29 (2.98 g), (S)-2-(((9-H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-pentenoic acid (2.70 g), acetonitrile (9.6 mL), and DIPEA (4.0 mL) were added to a reaction vessel. TCFH (3.21 g) was added to the reaction mixture, which was then stirred at around 25°C for 2.5 hours. MeTHF (30 mL) and 5% aqueous potassium carbonate solution (12 mL) were then added to the reaction mixture, which was then stirred, and the aqueous layer was discarded. The resulting organic layer was washed twice with 5% sulfuric acid (12 mL) and 5% aqueous potassium carbonate solution (12 mL) and concentrated under reduced pressure. MeTHF (30 mL) was added and azeotropic dehydration was performed. Acetonitrile (10 mL) and DBU (1.39 mL) were added to the resulting residue. The reaction mixture was stirred at approximately 25 °C for 75 min, after which triethylamine (4.29 mL), water (1.39 mL), and sodium bisulfite (1.99 g) were added and stirred for 2 h. Toluene (40 mL) and 10% aqueous ammonia (40 mL) were then added to the reaction mixture, followed by stirring. The aqueous layer was then discarded. The resulting organic layer was washed three times with 10% aqueous ammonia (40 mL) and 5% brine (20 mL), and then concentrated under reduced pressure. The residue was subjected to azeotropic dehydration three times with toluene (20 mL), and the resulting slurry was filtered and concentrated. A solution of pyridine hydrochloride (0.81 g) in acetonitrile (3 mL) was added to the resulting concentrate. MTBE (20 mL) was then added to the reaction mixture, followed by stirring for 1 h. The resulting precipitate was collected by filtration, and the resulting wet powder was washed with MTBE (5 mL). The resulting solid was dried under reduced pressure to give compound 19-HCl (2.05 g). UV intensity ratio: 98.9% (detection wavelength 210 nm, retention time 2.560 minutes, HPLC analysis conditions method 1, m / z=426[M+H] + (ESI)

[0237] Example 1-31 Synthesis of (S)-N,N-dimethyl-2-((S,Z)-3-(methylamino)-2-oxo-3,4,7,8-tetrahydroazocin-1(2H)-yl)-3-(4-(trifluoromethyl)phenyl)propanamide hydrochloride (Compound 20-HCl)

[0238] Compound 19-HCl (98.5 mg, 0.21 mmol) obtained in Example 1-30 above, second-generation Hoveyda-Grubbs catalyst (6.6 mg, 0.011 mmol), acetone (1.5 mL), and HFIP (0.5 mL) were added to a reaction vessel. After replacing the atmosphere in the reaction vessel with nitrogen, the mixture in the reaction vessel was heated to an external temperature of 65°C for 1 hour. A sample of the reaction mixture was taken and analyzed by HPLC. The conversion rate was 89.8%, and the ratio of the dimer formed by intermolecular reaction to the product (20-HCl) was 4.6%. After allowing the reaction mixture to cool to around 25°C, the resulting precipitate was filtered, and the resulting wet powder was washed with acetone (2 mL). The resulting solid was dried under reduced pressure to obtain compound 20-HCl (46.9 mg, yield 50.7%). UV intensity ratio: 98.2% (detection wavelength 210 nm, retention time 2.135 minutes, HPLC analysis conditions method 1, m / z=398[M+H] + (ESI) 1 H-NMR(DMSO-d6,500 MHz) δ: 9.55 (brs, 1H), 8.57 (brs, 1H), 7.59 (d, J= 8.1 Hz, 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)

[0239] Even with the cyclic compound 20-HCl consisting of a dipeptide, we were able to successfully obtain the target product with a purity of over 98% by ring-closing metathesis reaction.

[0240] Example 1-32 Synthesis of tert-butyl N-((S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-N-(but-3-en-1-yl)pent-4-enamido)-3-(4-(trifluoromethyl)phenyl)propanoyl)-N-methylglycinate (compound Fmoc-21)

[0241] The compound 2-HCl (5.01 g, 11.1 mmol) synthesized in Example 1-2 was added to a reaction vessel. (S)-2-(((9-H-fluoren-9-yl)methoxy)carbonyl)amino)-4-pentenoic acid (4.74 g), 1,3-dimethyl-2-imidazolidinone (25 mL), and 2,4,6-trimethylpyridine (7.35 mL) were then added to the reaction vessel. TCFH (4.93 g) was then added to the reaction vessel and stirred at an external temperature of 25°C for 7 hours. The reaction mixture was then allowed to stand for 16 hours. 5% aqueous potassium carbonate solution (25 mL) and 2-MeTHF (30 mL) were added to the reaction vessel and stirred, and the aqueous layer was then discarded. The resulting organic layer was washed sequentially with 5% sulfuric acid (25 mL) and 5% aqueous potassium carbonate solution (25 mL). The resulting organic layer was concentrated under reduced pressure, and azeotropic dehydration with 2-MeTHF (20 mL) was repeated twice to obtain a residue containing compound Fmoc-21. The resulting residue was purified by reverse-phase column chromatography (mobile phase: water / acetonitrile, volume ratio 40:60 → 0:100). The collected solution was concentrated, and azeotropic dehydration with acetonitrile was repeated to obtain Fmoc-21 (5.00 g) as a white solid. UV intensity ratio: 97.9% (detection wavelength 210 nm, retention time 5.182 min, HPLC analysis conditions: method 1, m / z = 756 [M+Na]). + (ESI)

[0242] Example 1-33 Synthesis of tert-butyl N-((S)-2-((S)-2-amino-N-(but-3-en-1-yl)pent-4-enamido)-3-(4-(trifluoromethyl)phenyl)propanoyl)-N-methylglycinate (Compound 21)

[0243] Compound Fmoc-21 (3.02 g) obtained in Example 1-32 and acetonitrile (15 mL) were added to a reaction vessel to dissolve Fmoc-21. DBU (0.62 mL) was then added, and the reaction mixture was stirred at an external temperature of 25°C for 30 minutes. Next, triethylamine (2.29 mL), sodium bisulfite (1.06 g), and water (0.74 mL) were added to the reaction vessel, and the reaction mixture was stirred at an external temperature of 25°C for 1.5 hours. Toluene (40 mL) and 10% aqueous ammonia (24 mL) were added to the reaction vessel, and the resulting mixture was stirred for 10 minutes, after which the aqueous layer was discarded. The resulting organic layer was washed with 10% aqueous ammonia (24 mL) and then with 10% brine (24 mL). The resulting organic layer was concentrated under reduced pressure, toluene (20 mL) was added, and the mixture was again concentrated under reduced pressure and subjected to azeotropic dehydration to obtain a residue containing compound 21. The resulting residue was purified by reverse-phase column chromatography (mobile phase: water / acetonitrile, volume ratio 80:20 → 40:60). The collected solution was concentrated, and azeotropic dehydration with acetonitrile was repeated to obtain 1.36 g of compound 21 (content 91.6%, product of NMR content calculated by qNMR and UV intensity ratio) as a pale yellow oil. UV intensity ratio: 93.7% (detection wavelength 210 nm, retention time 3.171 min, HPLC analysis conditions: method 2).

[0244] Example 1-34 Synthesis of tert-butyl N-((S)-2-((S,Z)-3-(((benzyloxy)carbonyl)amino)-2-oxo-3,4,7,8-tetrahydroazocin-1(2H)-yl)-3-(4-(trifluoromethyl)phenyl)propanoyl)-N-methylglycinate (Compound Cbz-22)

[0245] Compound 21 (130.8 mg, 91.6% content, 0.23 mmol) synthesized in Example 1-33, acetone (2.34 mL), HFIP (0.24 mL), boron trifluoride diethyl ether complex (44.5 μL, 0.35 mmol), and second-generation Hoveyda-Grubbs catalyst (10.3 mg, 16.4 μmol) were added to a reaction vessel. The pressure inside the reaction vessel was reduced and then restored with nitrogen. The external temperature of the reaction vessel was set to 65°C, and the reaction mixture was stirred for 1 hour. A sample of the reaction mixture was taken and analyzed by HPLC. This confirmed that the conversion was 95.1% and that the ratio of the dimer formed by the intermolecular reaction to the product (22) was 7.4%. The reaction mixture was allowed to cool to 25°C, after which triethylamine (52.3 μL) was added and stirred. MTBE (3 mL) and 5% aqueous potassium carbonate solution (1 mL) were then added to the reaction mixture, followed by stirring, and the aqueous layer was discarded. The resulting organic layer was concentrated, and then acetonitrile (1 mL), N-carbobenzoxysuccinimide (58.7 mg), and DIPEA (40.8 μL) were added to the concentrate and stirred at an external temperature of 25 °C for 30 min. The reaction mixture was concentrated under reduced pressure, followed by the addition of MTBE (3 mL) and 1 M aqueous sodium hydroxide (1 mL). After stirring, the aqueous layer was discarded. The resulting organic layer was washed with 10% aqueous potassium hydrogen sulfate (1 mL) and then with 5% aqueous potassium carbonate (1 mL). The resulting organic layer was concentrated under reduced pressure, and the residue was purified twice by reverse-phase column chromatography (mobile phase: water / acetonitrile, first: 45:55 → 20:80 (volume ratio), second: 45:55 → 25:75 (volume ratio)). The collected solution was concentrated, and azeotropic dehydration with acetonitrile was repeated to obtain compound Cbz-22 (47.2 mg, yield 32.6%) as a white solid. UV intensity ratio: 98.3% (detection wavelength 210 nm, retention time 4.398 minutes, HPLC analysis conditions method 1, m / z=640 [M+Na] + (ESI) 1H-NMR (500 MHz, DMSO-d6, detected as rotamer mixture) 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)

[0246] Example 1-35 Synthesis of tert-butyl (S)-(1-oxo-1-(phenylamino)propan-2-yl)carbamate (compound Boc-23)

[0247] N-(tert-butoxycarbonyl)-L-alanine (3.98 g), acetonitrile (4 mL), aniline (2.11 mL), and N-methylmorpholine (6.94 mL) were added to a reaction vessel. The external temperature of the reaction vessel was then set to 0 °C, and HATU (8.96 g) was added to the reaction mixture. The mixture was stirred at an external temperature of 25 °C for 1.5 hours. 5% aqueous potassium carbonate (16 mL) and 4-methyltetrahydropyran (40 mL) were then added to the reaction mixture and stirred. After the aqueous layer was drained, the resulting organic layer was washed twice with 10% aqueous ammonia (20 mL) and then twice with 5% aqueous sodium dihydrogen phosphate (20 mL). The resulting organic layer was concentrated under reduced pressure and subjected to azeotropic dehydration twice with acetonitrile. MTBE (10 mL) was added to the resulting concentrate and stirred. The resulting solid was collected by filtration, and the resulting wet powder was washed with MTBE (5 mL). The resulting wet powder was dried under reduced pressure to obtain compound Boc-23 (3.64 g) as a white solid. UV intensity ratio: 99.6% (detection wavelength: 210 nm, retention time: 2.732 min, HPLC analysis conditions: method 1, m / z = 287 [M+Na]). + (ESI)

[0248] Example 1-36 Synthesis of (S)-2-amino-N-phenylpropanamide (Compound 23)

[0249] Compound Boc-23 (3.64 g) obtained in Example 1-35 and acetonitrile (15 mL) were added to a reaction vessel. Methanesulfonic acid (2.68 mL) was then added to the reaction mixture, and the external temperature of the reaction vessel was set to 25°C. The mixture was then stirred for 3 hours. The external temperature of the reaction vessel was then set to 0°C. 8 M aqueous sodium hydroxide solution (6.89 mL) and 4-methyltetrahydropyran (15 mL) were then added to the reaction mixture, followed by stirring. The organic layer was recovered, and the aqueous layer was extracted with 4-methyltetrahydropyran (20 mL). The organic layer was recovered. The resulting organic layers were combined and concentrated under reduced pressure. The mixture was then subjected to azeotropic dehydration twice with 4-methyltetrahydropyran (20 mL). The resulting residue was filtered and washed with 4-methyltetrahydropyran (10 mL). The filtrate and washings were combined and concentrated to obtain a residue containing compound 23 (3.13 g). LCMS (ESI) retention time of compound 23: 1.118 min, m / z=165 [M+H] + (HPLC analysis conditions method 1)

[0250] Example 1-37 Synthesis of (9H-fluoren-9-yl)methyl ((S)-1-(allyl((S)-1-oxo-1-(phenylamino)propan-2-yl)amino)-1-oxopent-4-en-2-yl)(methyl)carbamate (compound Fmoc-24)

[0251] The residue containing compound 23 obtained in Example 1-36 (2.83 g) and DMF (6.1 mL) were added to a reaction vessel. DIPEA (3.25 mL) and allyl bromide (1.29 mL) were then added to the reaction mixture. The external temperature of the reaction vessel was set to 25°C, and the mixture was stirred for 2 hours. Acetonitrile (6.1 mL), (S)-2-(((9-H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)-4-pentenoic acid (3.49 g), DIPEA (5.2 mL), and TCFH (4.14 g) were then added to the reaction mixture. The external temperature of the reaction vessel was set to 25°C, and the mixture was stirred for 3 hours. 5% aqueous potassium carbonate solution (20 mL) and MTBE (30 mL) were added to the reaction mixture, and the mixture was stirred. The aqueous layer was then discarded. The resulting organic layer was washed sequentially with 5% aqueous potassium carbonate solution (20 mL), 5% sulfuric acid (20 mL x 2), and 5% aqueous potassium carbonate solution (20 mL). The resulting organic layer was concentrated under reduced pressure, and azeotropic dehydration with acetonitrile (20 mL) was repeated twice. The resulting residue was purified by reversed-phase column chromatography (mobile phase: water / acetonitrile volume ratio 50:50 → 15:85). The collected solution was concentrated, and azeotropic dehydration with acetonitrile was repeated until compound Fmoc-24 was solidified and dried. Compound Fmoc-24 (2.63 g) was obtained as a white solid. UV intensity ratio: 97.9% (detection wavelength: 210 nm, retention time: 4.475 min, HPLC analysis conditions: method 1, m / z = 560 [M+Na]). + (ESI)

[0252] Example 1-38 Synthesis of (S)-N-allyl-2-(methylamino)-N-((S)-1-oxo-1-(phenylamino)propan-2-yl)pent-4-enamide hydrochloride (Compound 24-HCl)

[0253] Compound Fmoc-24 (2.63 g) obtained in Example 1-37 and acetonitrile (8 mL) were added to a reaction vessel. DBU (0.37 mL) was then added to the reaction mixture, and the external temperature of the reaction vessel was set to 25°C and stirred for 75 minutes. MTBE (26 mL) and 5% aqueous potassium carbonate solution (13 mL) were added to the reaction mixture, followed by stirring, and the aqueous layer was discarded. 0.5 M hydrochloric acid (15 mL) was added to the resulting organic layer, followed by stirring, and the organic layer was discarded. Potassium carbonate (1.40 g) was added to the resulting aqueous layer while stirring, and the mixture was further stirred. 4-Methyltetrahydropyran (25 mL) was added to the aqueous layer, followed by further stirring. After discarding the aqueous layer, the resulting organic layer was concentrated under reduced pressure. 4-Methyltetrahydropyran (20 mL) was added and azeotropic dehydration was performed, and the resulting residue was filtered, and the filtrate was concentrated. Acetonitrile (20 mL) and 6 M hydrochloric acid (0.73 mL) were added to the resulting concentrate, followed by concentration under reduced pressure. Acetonitrile (5 mL) and MTBE (10 mL) were added to the resulting residue and stirred until a solid formed. MTBE (20 mL) was added and further stirred, after which the resulting solid was collected by filtration, and the wet powder was washed with MTBE (10 mL). The wet powder was dried under reduced pressure to obtain compound 24-HCl (1.21 g) as a white solid. UV intensity ratio: 99.3% (detection wavelength: 210 nm, retention time: 1.991 min, HPLC analysis conditions: method 1, m / z=316 [M+H] + (ESI)

[0254] Example 1-39 Synthesis of (S)-2-((S)-3-(methylamino)-2-oxo-2,3,4,7-tetrahydro-1H-azepin-1-yl)-N-phenylpropanamide (Compound 25)

[0255] Compound 24-HCl (86.4 mg, 0.25 mmol) obtained in Example 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 a reaction vessel. The pressure inside the reaction vessel was reduced and then restored with nitrogen. The external temperature of the reaction vessel was set to 65°C, and the reaction mixture was heated for 2 hours. A sample of the reaction mixture was taken and analyzed by HPLC. The conversion rate was 98.8%, and no dimer formed by intermolecular reaction was detected. The reaction mixture was allowed to cool to around 25°C and then concentrated under reduced pressure. MTBE (3 mL) and 0.5 M hydrochloric acid (3 mL) were added to the resulting concentrate, followed by stirring. The organic layer was then discarded. Potassium carbonate (0.23 g) was added to the resulting aqueous layer with stirring, and the mixture was further stirred. This extraction procedure was repeated three times with the addition of 4-methyltetrahydropyran (3 mL). The resulting organic layers were combined and concentrated under reduced pressure, followed by azeotropic dehydration with 4-methyltetrahydropyran (10 mL). The resulting residue was purified by reverse-phase column chromatography (mobile phase: water / acetonitrile volume ratio 95:5 → 65:35). The collected solution was concentrated, and azeotropic dehydration with acetonitrile was repeated to obtain compound 25 (39.8 mg, 56.4% yield) as a brown oil. UV intensity ratio: 98.8% (detection wavelength: 210 nm, retention time: 1.643 min, HPLC analysis conditions: method 1, m / z = 288 [M+H]). + (ESI) 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)

[0256] The present invention provides a method for efficiently producing a peptide compound having a peptide structure containing a medium-sized ring. The production method of the present invention can reduce the production cost of peptide compounds and reduce the environmental load, and is therefore particularly useful for large-scale peptide synthesis.

Claims

1. A method for producing a compound represented by formula (1) or a salt thereof, comprising a step of contacting a compound represented by formula (2) or a salt thereof with a catalyst (metathesis step). [In the formula, R １ is hydrogen, and R ２ is hydrogen or C １ -C ６ alkyl, R ３ is hydrogen, optionally substituted C １ -C ６ Alkyl, optionally substituted haloC １ -C ６ Alkyl, optionally substituted C ２ -C ６ Alkenyl, optionally substituted C ２ -C ６ Alkynyl, optionally substituted C ３ -C ８ Cycloalkyl, optionally substituted C ６ -C １４ Aryl, optionally substituted 5- to 14-membered heteroaryl, optionally substituted C ７ -C １４ Aralkyl, optionally substituted 3- to 14-membered heterocyclyl, optionally substituted 5- to 10-membered heteroaryl C １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkoxy C １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkylsulfanyl C １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkylsulfinyl C １ -C ６ Alkyl, optionally substituted C １ -C ６ Alkylsulfonyl C １ -C ６ Alkyl, optionally substituted carboxy C １ -C ６ Alkyl, optionally substituted C ７ -C １４ Aralkoxy C １ -C ６ Alkyl, optionally substituted C ３ -C ８ Cycloalkyl C １ -C ６ Alkyl, optionally substituted C ３ -C ８ Cycloalkoxy C １ -C ６ Alkyl, optionally substituted 4- to 7-membered heterocyclyl C １ -C ３ Alkyl, optionally substituted 5- to 10-membered heteroaryl C １ -C ６ Alkoxy C １ -C ６ alkyl, or optionally substituted aminocarbonyl (wherein the amino is —NH ２ , Mono C １ -C ６ Alkylamino, DiC １ -C ６ Alkylamino, N—C １ -C ６ Alkyl-N—C ２ -C ６ Alkenylamino, N—C １ -C ６ Alkyl-N—C １ -C ６ Alkoxy C １ -C ６ alkylamino, and 4- to 9-membered cyclic amino; ４ is OR ５ , N.H.R. ５ R', an amino acid residue, or a peptide chain containing 1 to 20 amino acid residues, the amino acid residue and the peptide chain may have a protecting group; ５ is a protecting group for a carboxy group, R ５ ' is a protecting group for an amide group, n is an integer of 1 to 4, and X is an optionally substituted C １ -C ３ Alkylene, —CH ２ OCH ２ - or -CH ２ SCH ２ - is.] 2. A method for producing a compound represented by formula (3) or a salt thereof, comprising a step of hydrogenating a compound represented by formula (1) or a salt thereof obtained by the method according to claim 1. [In the formula, R １ , R ２ , R ３ , R ４ , n, and X are R in [1] １ , R ２ , R ３ , R ４ , n, and X.] 3. The method of claim 1 or 2, wherein the catalyst is a metal-alkylidene type 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 is further used as an additive in the metathesis step, and the additive has a pKa of 4 to 17.

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

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

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

10. R ２ is hydrogen or linear C １ -C ３ The method according to any one of claims 1 to 9, wherein the alkyl is alkyl.

11. R ３ But hydrogen, C １ -C ６ Alkyl or haloC １ -C ３ Alkyl or C １ -C ６ C optionally substituted with alkyl ７ -C １４ The method according to any one of claims 1 to 10, wherein the aryl group is aralkyl.

12. R ４ But OR ５ , N.H.R. ５ ', an amino acid residue, or a peptide chain containing 2 to 13 amino acid residues, R ５ is a protecting group for a carboxy group, and R ５ 12. The method according to claim 1, wherein ' is a protecting group for an amide group, and the 2 to 13 amino acid residues are one or more selected from the group consisting of 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 of any one of claims 1 to 12, wherein n is an integer from 1 to 2.

14. X １ is one selected from the group consisting of an Fmoc group, a Cbz group, a Troc group, an Alloc group, a Teoc group, a TSoc group, a BIBSoc group, an IPCSoc group, a BBSoc group, a CHBSoc group, a CDBSoc group, and a Boc group.

15. X is optionally substituted C １ -C ３ The method according to any one of claims 1 to 14, wherein the alkylene is alkylene.

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