Method for producing amide compound

Abstract

The present invention provides a method that is for producing an amide compound, that comprises obtaining an amide compound by causing a reaction between a carboxylic acid compound and an amine compound in the presence of a condensing agent and a first base, and in which the first base is a compound represented by formula A, and the molar ratio (first base / condensing agent) of the first base with respect to the condensing agent is 1.8 or less.

Description

Method for producing amide compounds

[0001] The present invention relates to a method for forming an amide bond from an amine compound and a carboxylic acid compound. The present invention further relates to a method for producing a compound, which comprises a step of forming an amide bond from an amine compound and a carboxylic acid compound.

[0002] The formation of an amide bond from an amine compound and a carboxylic acid compound is an extremely important reaction for forming the basic skeleton of various organic compounds such as pharmaceuticals, agricultural chemicals, and polymer compounds. This reaction has been studied for a long time, and many condensing agents have been developed (Non-Patent Document 1).

[0003] In amide bond-forming reactions, when the reactivity is low, such as with sterically hindered substrates, a method using a haluronium-based condensing agent has been reported (Non-Patent Document 2).As a condensation method for improving reactivity, a method using N-methylimidazole (NMI) together with a haluronium-based condensing agent to form an N-acylimidazolium intermediate has been reported (Non-Patent Document 3).

[0004] Valeur, E. et al., Chem. Soc. Rev. 2009, 38, 606-631. Due-Hansen, ME et al., Org. Biomol. Chem. 2016, 14, 430-433. Beutner, GL et al., Org. Lett. 2018, 20, 4218-4222.

[0005] The method of forming an amide bond from an amine compound and a carboxylic acid compound is widely applied in the development and production of pharmaceuticals, and many condensing agents have been developed. In addition, methods for improving the reactivity of condensing agents for sterically hindered substrates have been reported (Non-Patent Documents 2 and 3).

[0006] However, when forming an amide bond with extremely low reactivity, such as with a carboxylic acid compound with high steric hindrance and / or an amine compound with low nucleophilicity, even when the above-mentioned existing methods using a haluronium-based condensing agent are used, the target amide compound cannot be obtained in sufficient yield and / or a large amount of by-products are generated, and there are problems that have not yet been resolved by the conventional methods. Therefore, a method for forming an amide bond with greater versatility is desired.

[0007] In view of these circumstances, the present inventors have conducted extensive research and completed the present invention. In one aspect, the present invention aims to provide a method for producing an amide compound, which can improve the yield and / or suppress the production of by-products in a reaction for forming an amide bond from an amine compound and a carboxylic acid compound. In another aspect, the present invention aims to provide a method for synthesizing a compound, which includes the above method. In another aspect, the present invention aims to provide a method for improving the yield and / or suppressing the production of by-products, which can be applied to a method for forming an amide bond from an amine compound and a carboxylic acid compound.

[0008] The present inventors have discovered that in a reaction for preparing an amide compound from an amine compound and a carboxylic acid compound by forming an amide bond through a dehydration condensation reaction of an amino group and a carboxyl group using a condensing agent, the reaction can proceed in high yield and / or with reduced by-product generation by using a specific condensing agent and adjusting the amount of base used. Specifically, the inventors investigated the equivalent amounts used for the uronium-based condensing agent or 2-halo-N-alkylpyridinium-based condensing agent, first base (e.g., NMI), and optionally, second base (e.g., dimethylaniline). As a result, they found that the desired amide compound can be produced in higher yield and / or with reduced by-product generation than previously reported reaction conditions (e.g., the conditions described in Non-Patent Document 3). Furthermore, they found that these conditions are applicable to reactions for forming an amide bond from various amine compounds and carboxylic acids, leading to the completion of the present invention.

[0009] The present specification includes the disclosure of the following inventions: [A-1] A method for producing an amide compound, comprising reacting a carboxylic acid compound with an amine compound in the presence of a condensing agent and a first base to obtain an amide compound, wherein the first base is a compound represented by Formula A:

[0010]

[0011] [In the formula, R １ is C １－６ Alkyl and C ６－１０ aryl, R ２ , R ３ , and R ４ are each independently a hydrogen atom, a halogen atom, or C １－６ Alkyl, and C ６－１０ aryl, or R １ and R ２ is R １ and the nitrogen atom to which R ２ and the condensing agent is a 5- to 6-membered non-aromatic heterocycle, and two or more of the condensing agent may be used, and the molar ratio of the first base to the condensing agent (first base / condensing agent) is 1.8 or less.

[0012] [A-2] The method according to [A-1], wherein the molar ratio of the first base to the condensing agent is 1.7 or less, 1.6 or less, 1.5 or less, 1.4 or less, 1.3 or less, 1.2 or less, 1.1 or less, or 1.0 or less.

[0013] [A-3] The method according to [A-1] or [A-2], wherein the condensing agent is at least one selected from a uronium-based condensing agent and a 2-halo-N-alkylpyridinium-based condensing agent. [A-4] The method according to [A-1] or [A-2], wherein the condensing agent is a uronium-based condensing agent.

[0014] [A-5] The uronium-based condensing agent is a haluronium-based condensing agent, such as fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TFFH), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH), 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium hexafluorophosphate (PyClU), 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium tetrafluoroborate (TPyClU), chlorodipiperidinocarbenium hexafluorophosphate (PipClU), 2-chloro-1,3-dimethylimidazolinium chloride (DMC), 2-chloro-1,3-dimethylimidazolinium hexafluorophosphate (CIP), and The method according to any one of [A-1] to [A-4], wherein the haluronium-based condensing agent is selected from the group consisting of 2-chloro-1,3-dimethylimidazolinium tetrafluoroborate (CIB), and two or more of them may be used.

[0015] [A-6] The method according to [A-1] or [A-2], wherein the condensing agent is a 2-halo-N-alkylpyridinium condensing agent. [A-7] The method according to [A-6], wherein the 2-halo-N-alkylpyridinium condensing agent is, for example, a 2-halo-N-alkylpyridinium condensing agent selected from the group consisting of 2-chloro-1-methylpyridinium iodide, 2-bromo-1-ethylpyridinium tetrafluoroborate, and 2-fluoro-1-methylpyridinium p-toluenesulfonate, and two or more kinds may be used.

[0016] [A-8] The method according to any one of [A-1] to [A-7], wherein the reaction is further carried out in the presence of a second base. [A-9] The method according to any one of [A-1] to [A-8], wherein the reaction is carried out in the presence of an amine compound in an excess amount relative to the carboxylic acid compound as a second base.

[0017] [A-10] The method according to [A-8] or [A-9], wherein the second base is an organic base whose conjugate acid in water has a pKa of 11 or less. [A-11] The method according to any one of [A-8] to [A-10], wherein the conjugate acid of the second base in water has a pKa of 0 to 11, 1 to 9, 2 to 8, 3 to 8, or 3.7 to 7.9.

[0018] [A-12] The second base is represented by the formula B1 and B2:

[0019]

[0020] [In the formula, R ５ and R ６ together with the nitrogen atom to which it is attached form a 5- to 7-membered saturated heterocycle, which may further contain heteroatoms selected from O and S, or R ５ and R ７ , and / or R ６ and R １１ together with the nitrogen atom and carbon atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, which may further contain heteroatoms selected from O and S, or R ５ and R ６ are each independently, C １－６ Alkyl, and C ６－１０ aryl, R ７ , R ８ , R ９ , R １０ and R １１ are each independently a hydrogen atom, C １－６ Alkyl, C ６－１０ aryl, halogen atom, or cyano; R １２ , R １３ , R １４ , R １５ and R １６ are each independently a hydrogen atom, C １－６ Alkyl, and C ６－１０ aryl, wherein C １－６ Alkyl, and C ６－１０The method according to any one of [A-1] to [A-11], wherein two or more of the aryl groups may be used, and the aryl group may be selected from the group consisting of:

[0021] [A-13] The second base is represented by formula B1:

[0022]

[0023] [In the formula, R ５ and R ６ together with the nitrogen atom to which it is attached form a 5- to 7-membered saturated heterocycle, which may further contain heteroatoms selected from O and S, or R ５ and R ７ , and / or R ６ and R １１ together with the nitrogen atom and carbon atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, which may further contain heteroatoms selected from O and S, or R ５ and R ６ are each independently, C １－６ Alkyl, and C ６－１０ aryl, R ７ , R ８ , R ９ , R １０ and R １１ are each independently a hydrogen atom, C optionally substituted with one or more halogen atoms, １－６ alkyl, C optionally substituted with one or more halogen atoms; ６－１０ The method according to any one of [A-8] to [A-12], wherein two or more of the above may be used.

[0024] [A-14]R ５ and R ６ together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocycle, or R ５ and R ７ , and R ６ and R １１together with the nitrogen atom and carbon atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, or R ５ and R ６ are each independently, C １－６ alkyl, R ７ , R ８ , R ９ , R １０ and R １１ each independently represents a hydrogen atom, C optionally substituted with one or more halogen atoms, １－６ alkyl or halogen atom, R １２ , R １３ , R １４ , R １５ and R １６ each independently represents a C optionally substituted with a hydrogen atom or one or more halogen atoms; １－６ The method according to either [A-12] or [A-13], wherein the alkyl is alkyl.

[0025] [A-15] The method according to any one of [A-8] to [A-12], wherein the second base is selected from the group consisting of N,N-dimethylaniline, N,N,2,4,6-pentamethylaniline, julolidine, collidine, and 2,6-lutidine, the benzene ring of which may be substituted with a halogen atom or trifluoromethyl, and two or more of these may be used.

[0026] [A-16] The R in the first base １ is C １－６ Alkyl or C ６－１０ aryl, and the R ２ , R ３ and R ４ are each independently a hydrogen atom, C １－６ Alkyl or C ６－１０ The method according to any one of [A-8] to [A-15], wherein the aryl is aryl.

[0027] [A-17] The method according to any one of [A-8] to [A-16], wherein the first base is selected from the group consisting of N-methylimidazole, tetramethylimidazole, and N-phenylimidazole, and two or more of them may be used.

[0028] [A-18] The method according to any one of [A-1] to [A-17], wherein the amine compound is used in an amount of 2 equivalents or more relative to the carboxylic acid compound. [A-19] The method according to any one of [A-1] to [A-18], wherein the reaction is carried out in the presence of a solvent.

[0029] [A-20] The method according to [A-19], wherein the solvent is selected from the group consisting of halogen-based solvents, nitrile-based solvents, amide-based solvents, ether-based solvents, and aromatic hydrocarbon-based solvents, and two or more of them may be used.

[0030] [A-21] The method according to [A-19] or [A-20], wherein the solvent is selected from the group consisting of halogenated solvents, nitrile solvents, ether solvents, and amide solvents, and two or more of them may be used.

[0031] [A-22] The method according to any one of [A-19] to [A-21], wherein the solvent is selected from the group consisting of halogenated solvents, nitrile solvents, and amide solvents, and two or more of them may be used.

[0032] [A-23] The method according to any one of [A-20] to [A-22], wherein the halogen-based solvent is selected from the group consisting of dichloromethane, chloroform, and 1,2-dichloroethane, and two or more of them may be used. [A-24] The method according to any one of [A-20] to [A-23], wherein the halogen-based solvent is dichloromethane.

[0033] [A-25] The method according to any one of [A-20] to [A-22], wherein the nitrile solvent is selected from the group consisting of acetonitrile, propionitrile, and benzonitrile, and two or more of them may be used. [A-26] The method according to any one of [A-20] to [A-22], wherein the nitrile solvent is acetonitrile.

[0034] [A-27] The method according to any one of [A-20] to [A-22], wherein the amide solvent is selected from the group consisting of N-methylpyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, N,N-dimethylpropionamide, N,N-dimethylisobutyramide, N,N-diethylacetamide, N,N-diethylpropionamide, 1-ethyl-2-pyrrolidinone, 1-octyl-2-pyrrolidinone, 1-cyclohexyl-2-pyrrolidinone, and N-methylcaprolactam, and two or more of them may be used.

[0035] [A-28] The method according to [A-20] or [A-21], wherein the ether solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,3-dioxolane, diisopropyl ether, cyclopentyl methyl ether, t-butyl methyl ether, and 4-methyltetrahydropyran, and two or more of these may be used. [A-29] The method according to [A-20] or [A-21], wherein the ether solvent is tetrahydrofuran.

[0036] [A-30] The method according to [A-20], wherein the aromatic hydrocarbon solvent is selected from the group consisting of benzene, toluene, and xylene, and two or more of them may be used. [A-31] The method according to any one of [A-1] to [A-30], wherein the equivalent ratio of the condensing agent to the carboxylic acid compound is condensing agent / carboxylic acid compound = 20 / 1 to 1 / 1.

[0037] [A-32] The method according to any one of [A-1] to [A-31], wherein the molar ratio of the condensing agent to the carboxylic acid is condensing agent / carboxylic acid=15 / 1 to 1 / 1, 10 / 1 to 1 / 1, or 5 / 1 to 1 / 1.

[0038] [A-33] The method according to any one of [A-1] to [A-32], wherein the reaction is carried out at a reaction temperature of 0° C. to 100° C. [A-34] The method according to [A-33], wherein the reaction temperature is 10° C. to 80° C., 10° C. to 60° C., 15° C. to 50° C., 15° C. to 40° C., or 20° C. to 40° C. [A-35] The method according to [A-33], wherein the reaction temperature is 10° C. to 80° C., 10° C. to 60° C., 15° C. to 40° C., or 20° C. to 30° C.

[0039] [A-36] The method according to any one of [A-1] to [A-35], wherein the carboxylic acid compound is a resin for solid phase synthesis to which a carboxylic acid compound is bound via a linker, or the amine compound is a resin for solid phase synthesis to which an amine compound is bound via a linker.

[0040] [A-37] The method according to any one of [A-1] to [A-36], wherein the carboxylic acid compound is a resin for solid phase synthesis to which two or more different carboxylic acid compounds are bound via linkers, or the amine compound is a resin for solid phase synthesis to which two or more different amine compounds are bound via linkers.

[0041] [A-38] The method according to any one of [A-1] to [A-37], wherein the carboxylic acid compound is a resin for solid phase synthesis to which the carboxylic acid compound is bound via a linker. [A-39] The method according to any one of [A-1] to [A-37], wherein the amine compound is a resin for solid phase synthesis to which the amine compound is bound via a linker.

[0042] [A-40] The carboxylic acid compound of formula A1 or A2:

[0043]

[0044] [In the formula, R ２０ , R ２１ , R ２２ , R ２３ , R ２４ , R ２５ , R ２６ and R ２７ are each independently a hydrogen atom, a halogen atom, cyano, C １－６ Alkyl, C １－６ Alkoxy, (C１－６ alkoxy)carbonyl, (C １－６ alkoxy)carbonylamino, (C １－６ alkyl)carbonylamino, (C ６－１０ aryl)carbonylamino, di(C １－６ alkyl)amino, 4- to 8-membered cyclic amino, aminocarbonyl, (C １－６ alkyl)aminocarbonyl, di(C １－６ alkyl)aminocarbonyl, 4- to 8-membered cyclic aminocarbonyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ Cycloalkyl, C ７－１４ Aralkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl containing one or more ring heteroatoms independently selected from O, N, and S, each of which may be substituted by a substituent; or a mixture of two or more of these compounds, or a resin for solid phase synthesis to which the compound is bound via a linker, wherein the carboxylic acid compound does not have any group participating in an amide bond-forming reaction other than the carboxy group represented by Formula A1 or Formula A2.

[0045] [A-41] The method according to [A-40], wherein the carboxylic acid compound is one type of compound represented by formula A1, or a mixture of two or more types, or a resin for solid phase synthesis to which the compound is bound via a linker, and wherein the carboxylic acid compound does not have any group participating in an amide bond-forming reaction other than the carboxy group represented by formula A1.

[0046] [A-42] In the carboxylic acid compound, the R ２０ and R ２４ are each independently C １－６ Alkyl or C ６－１０ [A-43] The method according to [A-41], wherein the amine compound is of formula A3 or A4:

[0047]

[0048] [In the formula, R ４０ , R ４６ and R４７ are each independently a hydrogen atom, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ Cycloalkyl, C ７－１４ Aralkyl, C ６－１０ aryl, and 5-10 membered heteroaryl containing one or more ring heteroatoms independently selected from O, N, and S; or ４０ and R ４５ together with the nitrogen atom and carbon atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, which may further contain heteroatoms selected from O and S, or R ４６ and R ４７ together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocycle, which may further contain a heteroatom selected from O and S; R ４１ , R ４２ , R ４３ , R ４４ , and R ４５ are each independently a hydrogen atom, a halogen atom, cyano, nitro, C １－６ Alkyl, C １－６ Alkoxy, (C １－６ alkoxy)carbonyl, (C １－６ alkoxy)carbonylamino, (C １－６ alkyl)carbonylamino, (C ６－１０ aryl)carbonylamino, di(C １－６ alkyl)amino, 4- to 8-membered cyclic amino, aminocarbonyl, (C １－６ alkyl)aminocarbonyl, di(C １－６ alkyl)aminocarbonyl, 4- to 8-membered cyclic aminocarbonyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ Cycloalkyl, C ７－１４ Aralkyl, C ６－１０aryl, and 5- to 10-membered heteroaryl containing one or more ring heteroatoms independently selected from O, N, and S, each of which may be substituted by a substituent; or a mixture of two or more of these compounds, or a resin for solid phase synthesis to which the compound is bound via a linker, wherein the amine compound does not have any group participating in an amide bond-forming reaction other than the amino group represented by Formula A3 or Formula A4.

[0049] [A-44] The method according to [A-43], wherein the amine compound is one type of compound represented by formula A3, or a mixture of two or more types, or a resin for solid phase synthesis to which the compound is bound via a linker, wherein the amine compound has no group participating in an amide bond-forming reaction other than the amino group represented by formula A3.

[0050] [A-45] The R ４１ and R ４５ are each independently C １－６ Alkyl or C ６－１０ [A-46] The method according to [A-44], wherein the uronium-based condensing agent is a compound represented by formula C1:

[0051]

[0052] [In the formula, R ３０ , R ３１ , R ３２ , R ３３ are each independently, C １－６ alkyl, or R ３０ and R ３１ , and / or R ３２ and R ３３ form a 5- to 7-membered saturated heterocycle, which may contain one ring heteroatom selected from O or S, or R ３１ and R ３２form a 5- to 7-membered saturated heterocycle, the heterocycle optionally containing one ring heteroatom selected from O and S; X is a leaving group; and Z is a counter anion; or a mixture of two or more compounds represented by the following formula (1):

[0053] [A-47] The method according to any one of [A-46], wherein X is a halogen atom. [A-48] The method according to [A-46] or [A-42], wherein X is a fluorine atom or a chlorine atom. [A-49] The method according to [A-49], wherein the 2-halo-N-alkylpyridinium condensing agent is a compound represented by the formula C3:

[0054] [In the formula, R ３５ is C １－６ is alkyl, and X １ is a halogen, and Y is a counter anion; or a mixture of two or more compounds represented by the formula (I).

[0055] [A-50] The method according to any one of [A-1] to [A-49], wherein the reaction is carried out in a mixture containing two or more different carboxylic acid compounds and / or two or more different amine compounds as substrates.

[0056] [A-51] The method according to any one of [A-1] to [A-50], wherein the reaction is carried out in a mixture containing two or more different carboxylic acid compounds as substrates. [A-52] The method according to any one of [A-1] to [A-51], wherein the reaction is carried out in a mixture containing two or more different amine compounds as substrates.

[0057] [A-53] The method according to any one of [A-45] to [A-52], wherein the mixture comprises, as a substrate, a resin for solid phase synthesis to which two or more different carboxylic acid compounds are bound via a linker, or a resin for solid phase synthesis to which two or more different amine compounds are bound via a linker, and the carboxylic acid compounds or amine compounds bound to the individual resins are the same.

[0058] [A-54] The method according to any one of [A-1] to [A-11] and [A-18] to [A-53], wherein the reaction is carried out in the presence of an excess amount of the amine compound relative to the carboxylic acid compound as a second base, and the amine compound is one type of compound represented by formula A3 according to [A-43], or a mixture of two or more types.

[0059] [A-55] A method for producing a compound constituting a compound library, the method comprising producing an amide compound by the method according to any one of [A-1] to [A-54].

[0060] [B-1] A method for forming an amide bond by dehydration condensation of a carboxy group and an amino group, comprising reacting a carboxylic acid compound with an amine compound in the presence of a condensing agent and a first base to form an amide bond, wherein the first base is a compound represented by the formula A:

[0061]

[0062] [In the formula, R １ is C １－６ Alkyl and C ６－１０ aryl, R ２ , R ３ , and R ４ are each independently a hydrogen atom, a halogen atom, or C １－６ Alkyl, and C ６－１０ aryl, or R １ and R ２ is R １ and the nitrogen atom to which R ２ and a molar ratio of the first base to the condensing agent (first base / condensing agent) is 1.8 or less.

[0063] [B-2] The method according to [B-1], wherein the molar ratio of the first base to the condensing agent is 1.7 or less, 1.6 or less, 1.5 or less, 1.4 or less, 1.3 or less, 1.2 or less, 1.1 or less, or 1.0 or less.

[0064] [B-3] The method according to [B-1] or [B-2], wherein the condensing agent is at least one selected from the group consisting of a uronium-based condensing agent and a 2-halo-N-alkylpyridinium-based condensing agent. [B-4] The method according to [B-1] or [B-2], wherein the condensing agent is a uronium-based condensing agent.

[0065] [B-5] The uronium-based condensing agent is a haluronium-based condensing agent, such as fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TFFH), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH), 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium hexafluorophosphate (PyClU), 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium tetrafluoroborate (TPyClU), chlorodipiperidinocarbenium hexafluorophosphate (PipClU), 2-chloro-1,3-dimethylimidazolinium chloride (DMC), 2-chloro-1,3-dimethylimidazolinium hexafluorophosphate (CIP), and The method according to [B-1] or [B-2], wherein the haluronium-based condensing agent is selected from the group consisting of 2-chloro-1,3-dimethylimidazolinium tetrafluoroborate (CIB), and two or more of them may be used.

[0066] [B-6] The method according to [B-1] or [B-2], wherein the condensing agent is a 2-halo-N-alkylpyridinium condensing agent. [B-7] The method according to [B-1] or [B-2], wherein the 2-halo-N-alkylpyridinium condensing agent is a halo-N-alkylpyridinium condensing agent selected from the group consisting of, for example, 2-chloro-1-methylpyridinium iodide, 2-bromo-1-ethylpyridinium tetrafluoroborate, and 2-fluoro-1-methylpyridinium p-toluenesulfonate, and two or more of these may be used.

[0067] [B-8] The method according to any one of [B-1] to [B-7], wherein the reaction is further carried out in the presence of a second base. [B-9] The method according to any one of [B-1] to [B-8], wherein the reaction is carried out in the presence of an excess amount of the amine compound as a second base.

[0068] [B-10] The method according to [B-8] or [B-9], wherein the second base is an organic base whose conjugate acid in water has a pKa of 11 or less. [B-11] The method according to any one of [B-8] to [B-10], wherein the conjugate acid of the second base in water has a pKa of 0 to 11, 1 to 9, 2 to 8, 3 to 8, or 3.7 to 7.9.

[0069] [B-12] The second base is represented by the formula B1 and B2:

[0070]

[0071] [In the formula, R ５ and R ６ together with the nitrogen atom to which it is attached form a 5- to 7-membered saturated heterocycle, which may further contain heteroatoms selected from O and S, or R ５ and R ７ , and / or R ６ and R １１ together with the nitrogen atom and carbon atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, which may further contain heteroatoms selected from O and S, or R ５ and R ６ are each independently, C １－６ Alkyl, and C ６－１０ aryl, R ７ , R ８ , R ９ , R １０ and R １１ are each independently a hydrogen atom, C １－６ Alkyl, C ６－１０ aryl, halogen atom, or cyano; R １２ , R １３ , R １４ , R １５ and R １６ are each independently a hydrogen atom, C１－６ Alkyl, and C ６－１０ aryl, wherein C １－６ Alkyl, and C ６－１０ The method according to any one of [B-8] to [B-11], wherein two or more of the aryl groups may be used, and the aryl group may be selected from the group consisting of:

[0072] [B-13] The second base is represented by formula B1:

[0073]

[0074] [In the formula, R ５ and R ６ together with the nitrogen atom to which it is attached form a 5- to 7-membered saturated heterocycle, which may further contain heteroatoms selected from O and S, or R ５ and R ７ , and / or R ６ and R １１ together with the nitrogen atom and carbon atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, which may further contain heteroatoms selected from O and S, or R ５ and R ６ are each independently, C １－６ Alkyl, and C ６－１０ aryl, R ７ , R ８ , R ９ , R １０ and R １１ are each independently a hydrogen atom, C optionally substituted with one or more halogen atoms, １－６ alkyl, C optionally substituted with one or more halogen atoms; ６－１０ The method according to any one of [B-8] to [B-12], wherein two or more of the above may be used.

[0075] [B-14]R ５ and R ６ together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocycle, or R ５ and R ７, and R ６ and R １１ together with the nitrogen atom and carbon atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, or R ５ and R ６ are each independently, C １－６ alkyl, R ７ , R ８ , R ９ , R １０ and R １１ each independently represents a hydrogen atom, C optionally substituted with one or more halogen atoms, １－６ alkyl or halogen atom, R １２ , R １３ , R １４ , R １５ and R １６ each independently represents a C optionally substituted with a hydrogen atom or one or more halogen atoms; １－６ The method according to either [B-12] or [B-13], wherein the alkyl is alkyl.

[0076] [B-15] The method according to any one of [B-8] to [B-12], wherein the second base is selected from the group consisting of N,N-dimethylaniline, N,N,2,4,6-pentamethylaniline, julolidine, collidine, and 2,6-lutidine, the benzene ring of which may be substituted with a halogen atom or trifluoromethyl, and two or more of these may be used.

[0077] [B-16] The R in the first base １ is C １－６ Alkyl or C ６－１０ aryl, and the R ２ , R ３ and R ４ are each independently a hydrogen atom, C １－６ Alkyl or C ６－１０ The method according to any one of [B-8] to [B-15], wherein the aryl is aryl.

[0078] [B-17] The method according to any one of [B-8] to [B-16], wherein the first base is selected from the group consisting of N-methylimidazole, tetramethylimidazole, and N-phenylimidazole, and two or more of them may be used.

[0079] [B-18] The method according to any one of [B-1] to [B-17], wherein the amine compound is used in an amount of 2 equivalents or more relative to the carboxylic acid compound. [B-19] The method according to any one of [B-1] to [B-18], wherein the reaction is carried out in the presence of a solvent.

[0080] [B-20] The method according to [B-19], wherein the solvent is selected from the group consisting of halogen-based solvents, nitrile-based solvents, amide-based solvents, ether-based solvents, and aromatic hydrocarbon-based solvents, and two or more of them may be used.

[0081] [B-21] The method according to [B-19] or [B-20], wherein the solvent is selected from the group consisting of halogen-based solvents, nitrile-based solvents, ether-based solvents, and amide-based solvents, and two or more of these may be used. [B-22] The method according to any one of [B-19] to [B-21], wherein the solvent is selected from the group consisting of halogen-based solvents, nitrile-based solvents, and amide-based solvents, and two or more of these may be used.

[0082] [B-23] The method according to any one of [B-20] to [B-22], wherein the halogen-based solvent is selected from the group consisting of dichloromethane, chloroform, and 1,2-dichloroethane, and two or more of them may be used.

[0083] [B-24] The method according to any one of [B-20] to [B-22], wherein the halogen-based solvent is dichloromethane. [B-25] The method according to any one of [B-20] to [B-22], wherein the nitrile-based solvent is selected from the group consisting of acetonitrile, propionitrile, and benzonitrile, and two or more of them may be used. [B-26] The method according to any one of [B-20] to [B-22], wherein the nitrile-based solvent is acetonitrile.

[0084] [B-27] The method according to any one of [B-20] to [B-22], wherein the amide solvent is selected from the group consisting of N-methylpyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, N,N-dimethylpropionamide, N,N-dimethylisobutyramide, N,N-diethylacetamide, N,N-diethylpropionamide, 1-ethyl-2-pyrrolidinone, 1-octyl-2-pyrrolidinone, 1-cyclohexyl-2-pyrrolidinone, and N-methylcaprolactam, and two or more of them may be used.

[0085] [B-28] The method according to [B-20] or [B-21], wherein the ether solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,3-dioxolane, diisopropyl ether, cyclopentyl methyl ether, t-butyl methyl ether, and 4-methyltetrahydropyran, and two or more of them may be used.

[0086] [B-29] The method according to [B-20] or [B-21], wherein the ether solvent is tetrahydrofuran. [B-30] The method according to any one of [B-20] to [B-22], wherein the aromatic hydrocarbon solvent is selected from the group consisting of benzene, toluene, and xylene, and two or more of them may be used. [B-31] The method according to any one of [B-1] to [B-30], wherein the equivalent ratio of the condensing agent to the carboxylic acid compound is condensing agent / carboxylic acid compound = 20 / 1 to 1 / 1.

[0087] [B-32] The method according to any one of [B-1] to [B-31], wherein the molar ratio of the condensing agent to the carboxylic acid is condensing agent / carboxylic acid=15 / 1 to 1 / 1, 10 / 1 to 1 / 1, or 5 / 1 to 1 / 1.

[0088] [B-33] The method according to any one of [B-1] to [B-32], wherein the reaction is carried out at a reaction temperature of 0° C. to 100° C. [B-34] The method according to [B-33], wherein the reaction temperature is 10° C. to 80° C., 10° C. to 60° C., 15° C. to 50° C., 15° C. to 40° C., or 20° C. to 40° C. [B-35] The method according to [B-33], wherein the reaction temperature is 10° C. to 80° C., 10° C. to 60° C., 15° C. to 40° C., or 20° C. to 30° C.

[0089] [B-36] The method according to any one of [B-1] to [B-35], wherein the carboxylic acid compound is a resin for solid phase synthesis to which a carboxylic acid compound is bound via a linker, or the amine compound is a resin for solid phase synthesis to which an amine compound is bound via a linker.

[0090] [B-37] The method according to any one of [B-1] to [B-36], wherein the carboxylic acid compound is a resin for solid phase synthesis to which two or more different carboxylic acid compounds are bound via linkers, or the amine compound is a resin for solid phase synthesis to which two or more different amine compounds are bound via linkers.

[0091] [B-38] The method according to any one of [B-1] to [B-37], wherein the carboxylic acid compound is a resin for solid phase synthesis to which the carboxylic acid compound is bound via a linker. [B-39] The method according to any one of [B-1] to [B-37], wherein the amine compound is a resin for solid phase synthesis to which the amine compound is bound via a linker.

[0092] [B-40] The carboxylic acid compound of formula A1 or A2:

[0093]

[0094] [In the formula, R ２０ , R ２１ , R ２２ , R ２３ , R ２４ , R ２５ , R ２６ and R ２７ are each independently a hydrogen atom, a halogen atom, cyano, C １－６ Alkyl, C １－６ Alkoxy, (C１－６ alkoxy)carbonyl, (C １－６ alkoxy)carbonylamino, (C １－６ alkyl)carbonylamino, (C ６－１０ aryl)carbonylamino, di(C １－６ alkyl)amino, 4- to 8-membered cyclic amino, aminocarbonyl, (C １－６ alkyl)aminocarbonyl, di(C １－６ alkyl)aminocarbonyl, 4- to 8-membered cyclic aminocarbonyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ Cycloalkyl, C ７－１４ Aralkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl containing one or more ring heteroatoms independently selected from O, N, and S, each of which may be substituted by a substituent; or a mixture of two or more of these compounds, or a resin for solid phase synthesis to which the compound is bound via a linker, wherein the carboxylic acid compound does not have any group participating in an amide bond-forming reaction other than the carboxy group represented by Formula A1 or Formula A2.

[0095] [B-41] The method according to [B-40], wherein the carboxylic acid compound is one type of compound represented by formula A1, or a mixture of two or more types, or a resin for solid phase synthesis to which the compound is bound via a linker, and wherein the carboxylic acid compound does not have any group participating in an amide bond-forming reaction other than the carboxy group represented by formula A1.

[0096] [B-42] In the carboxylic acid compound, the R ２０ and R ２４ are each independently C １－６ Alkyl or C ６－１０ [B-43] The method according to [B-41], wherein the amine compound is a compound represented by the formula A3 or A4:

[0097]

[0098] [In the formula, R ４０ , R ４６ and R４７ are each independently a hydrogen atom, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ Cycloalkyl, C ７－１４ Aralkyl, C ６－１０ aryl, and 5-10 membered heteroaryl containing one or more ring heteroatoms independently selected from O, N, and S; or ４０ and R ４５ together with the nitrogen atom and carbon atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, which may further contain heteroatoms selected from O and S, or R ４６ and R ４７ together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocycle, which may further contain a heteroatom selected from O and S; R ４１ , R ４２ , R ４３ , R ４４ , and R ４５ are each independently a hydrogen atom, a halogen atom, cyano, nitro, C １－６ Alkyl, C １－６ Alkoxy, (C １－６ alkoxy)carbonyl, (C １－６ alkoxy)carbonylamino, (C １－６ alkyl)carbonylamino, (C ６－１０ aryl)carbonylamino, di(C １－６ alkyl)amino, 4- to 8-membered cyclic amino, aminocarbonyl, (C １－６ alkyl)aminocarbonyl, di(C １－６ alkyl)aminocarbonyl, 4- to 8-membered cyclic aminocarbonyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ Cycloalkyl, C ７－１４ Aralkyl, C ６－１０aryl, and 5- to 10-membered heteroaryl containing one or more ring heteroatoms independently selected from O, N, and S, each of which may be substituted by a substituent], or a mixture of two or more of these, or a resin for solid phase synthesis to which the compound is bound via a linker, wherein the amine compound does not have any group participating in an amide bond-forming reaction other than the amino group represented by Formula A3 or Formula A4.

[0099] [B-44] The method according to [B-44], wherein the amine compound is one type of compound represented by formula A3, or a mixture of two or more types, or a resin for solid phase synthesis to which the compound is bound via a linker, and the amine compound does not have any group participating in an amide bond-forming reaction other than the amino group represented by formula A3.

[0100] [B-45] The R ４１ and R ４５ are each independently C １－６ Alkyl or C ６－１０ [B-46] The method according to [B-44], wherein the uronium-based condensing agent is a compound represented by formula C1:

[0101]

[0102] [In the formula, R ３０ , R ３１ , R ３２ , R ３３ are each independently, C １－６ alkyl, or R ３０ and R ３１ , and / or R ３２ and R ３３ form a 5- to 7-membered saturated heterocycle, which may contain one ring heteroatom selected from O or S, or R ３１ and R ３２ form a 5- to 7-membered non-aromatic heterocycle, which may contain one ring heteroatom selected from O or S; X is a leaving group; Z －is a counter anion], or a mixture of two or more compounds represented by the formula [B-1] to [B-45].

[0103] [B-47] The method according to any one of [B-46], wherein X is a halogen atom. [B-48] The method according to [B-46] or [B-47], wherein X is a fluorine atom or a chlorine atom.

[0104] [B-49] The 2-halo-N-alkylpyridinium-based condensing agent is represented by formula C3:

[0105] [In the formula, R ３５ is C １－６ is alkyl, and X １ is a halogen, and Y is a counter anion; or a mixture of two or more compounds represented by the formula (B-1), (B-2), and (B-6) to (B-48).

[0106] [B-50] The method according to any one of [B-1] to [B-49], wherein the reaction is carried out in a mixture containing two or more different carboxylic acid compounds and / or two or more different amine compounds as substrates.

[0107] [B-51] The method according to any one of [B-1] to [B-50], wherein the reaction is carried out in a mixture containing two or more different carboxylic acid compounds as substrates. [B-52] The method according to any one of [B-1] to [B-41], wherein the reaction is carried out in a mixture containing two or more different amine compounds as substrates.

[0108] [B-53] The method according to any one of [B-50] to [B-52], wherein the mixture comprises, as a substrate, a resin for solid phase synthesis to which two or more different carboxylic acid compounds are bound via a linker, or a resin for solid phase synthesis to which two or more different amine compounds are bound via a linker, and the carboxylic acid compounds or amine compounds bound to the individual resins are the same.

[0109] [B-54] The method according to any one of [B-1] to [B-11] and [B-18] to [B-53], wherein the reaction is carried out in the presence of an excess amount of the amine compound relative to the carboxylic acid compound as a second base, and the amine compound is one type of compound represented by formula A3 according to [B-43], or a mixture of two or more types.

[0110] [C-1] A composition containing a condensing agent for use in a method for forming an amide bond by dehydration condensation of a carboxy group and an amino group, the method comprising reacting a carboxylic acid compound with an amine compound in the presence of a condensing agent and a first base to form an amide bond, wherein the first base is a compound represented by Formula A:

[0111]

[0112] [In the formula, R １ is C １－６ Alkyl and C ６－１０ aryl, R ２ , R ３ , and R ４ are each independently a hydrogen atom, a halogen atom, or C １－６ Alkyl, and C ６－１０ aryl, or R １ and R ２ is R １ and the nitrogen atom to which R ２ and a molar ratio of the first base to the condensing agent (first base / condensing agent) is 1.8 or less.

[0113] [C-2] The composition according to [C-1], wherein the molar ratio of the first base to the uronium-based condensing agent is 1.7 or less, 1.6 or less, 1.5 or less, 1.4 or less, 1.3 or less, 1.2 or less, 1.1 or less, or 1.0 or less. [C-3] The method according to [C-1] or [C-2], wherein the condensing agent is at least one selected from a uronium-based condensing agent and a 2-halo-N-alkylpyridinium-based condensing agent. [C-4] The method according to [C-1] or [C-2], wherein the condensing agent is a uronium-based condensing agent.

[0114] [C-5] The uronium-based condensing agent is a haluronium-based condensing agent, such as fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TFFH), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH), 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium hexafluorophosphate (PyClU), 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium tetrafluoroborate (TPyClU), chlorodipiperidinocarbenium hexafluorophosphate (PipClU), 2-chloro-1,3-dimethylimidazolinium chloride (DMC), 2-chloro-1,3-dimethylimidazolinium hexafluorophosphate (CIP), and The composition according to [C-1] or [C-2], wherein the haluronium-based condensing agent is selected from the group consisting of 2-chloro-1,3-dimethylimidazolinium tetrafluoroborate (CIB), and two or more of them may be used.

[0115] [C-6] The method according to [C-1] or [C-2], wherein the condensing agent is a 2-halo-N-alkylpyridinium condensing agent. [C-7] The method according to [C-1] or [C-2], wherein the 2-halo-N-alkylpyridinium condensing agent is, for example, a halo-N-alkylpyridinium condensing agent selected from the group consisting of 2-chloro-1-methylpyridinium iodide, 2-bromo-1-ethylpyridinium tetrafluoroborate, and 2-fluoro-1-methylpyridinium p-toluenesulfonate, and two or more of these may be used.

[0116] [C-8] The composition according to any one of [C-1] to [C-7], wherein the reaction is further carried out in the presence of a second base. [C-9] The composition according to any one of [C-1] to [C-8], wherein the reaction is carried out in the presence of an excess amount of the amine compound as a second base.

[0117] [C-10] The composition according to [C-8] or [C-9], wherein the second base is an organic base whose conjugate acid in water has a pKa of 11 or less. [C-11] The composition according to any one of [C-8] to [C-10], wherein the conjugate acid of the second base has a pKa in water of 0 to 11, 1 to 9, 2 to 8, 3 to 8, or 3.7 to 7.9.

[0118] [C-12] The second base is a base represented by the formula B1 and B2:

[0119]

[0120] [In the formula, R ５ and R ６ together with the nitrogen atom to which it is attached form a 5- to 7-membered saturated heterocycle, which may further contain heteroatoms selected from O and S, or R ５ and R ７ , and / or R ６ and R １１ together with the nitrogen atom and carbon atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, which may further contain heteroatoms selected from O and S, or R ５ and R ６ are each independently, C １－６ Alkyl, and C ６－１０ aryl, R ７ , R ８ , R ９ , R １０ and R １１ are each independently a hydrogen atom, C １－６ Alkyl, C ６－１０ aryl, halogen atom, or cyano; R １２ , R １３ , R １４ , R １５ and R １６ are each independently a hydrogen atom, C １－６ Alkyl, and C ６－１０ aryl, wherein C １－６ Alkyl, and C ６－１０and aryl is optionally substituted with one or more halogen atoms], and two or more of them may be used.

[0121] [C-13] The second base is a base represented by formula B1:

[0122]

[0123] [In the formula, R ５ and R ６ together with the nitrogen atom to which it is attached form a 5- to 7-membered saturated heterocycle, which may further contain heteroatoms selected from O and S, or R ５ and R ７ , and / or R ６ and R １１ together with the nitrogen atom and carbon atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, which may further contain heteroatoms selected from O and S, or R ５ and R ６ are each independently, C １－６ Alkyl, and C ６－１０ aryl, R ７ , R ８ , R ９ , R １０ and R １１ are each independently a hydrogen atom, C optionally substituted with one or more halogen atoms, １－６ alkyl, C optionally substituted with one or more halogen atoms; ６－１０ The composition according to any one of [C-8] to [C-12], wherein two or more of the above groups may be used.

[0124] [C-14]R ５ and R ６ together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocycle, or R ５ and R ７ , and R ６ and R １１together with the nitrogen atom and carbon atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, or R ５ and R ６ are each independently, C １－６ alkyl, R ７ , R ８ , R ９ , R １０ and R １１ each independently represents a hydrogen atom, C optionally substituted with one or more halogen atoms, １－６ alkyl or halogen atom, R １２ , R １３ , R １４ , R １５ and R １６ each independently represents a C optionally substituted with a hydrogen atom or one or more halogen atoms; １－６ The composition according to either [C-12] or [C-13], wherein the alkyl is alkyl.

[0125] [C-15] The composition according to any one of [C-8] to [C-12], wherein the second base is selected from the group consisting of N,N-dimethylaniline, N,N,2,4,6-pentamethylaniline, julolidine, collidine, and 2,6-lutidine, the benzene ring of which may be substituted with a halogen atom or trifluoromethyl, and two or more of these may be used.

[0126] [C-16] The R in the first base １ is C １－６ Alkyl or C ６－１０ aryl, and the R ２ , R ３ and R ４ are each independently a hydrogen atom, C １－６ Alkyl or C ６－１０ The composition according to any one of [C-8] to [C-15], wherein the aryl is aryl.

[0127] [C-17] The composition according to any one of [C-8] to [C-16], wherein the first base is selected from the group consisting of N-methylimidazole, tetramethylimidazole, and N-phenylimidazole, and two or more of them may be used.

[0128] [C-18] The composition according to any one of [C-1] to [C-17], wherein the amine compound is used in an amount of 2 equivalents or more relative to the carboxylic acid compound. [C-19] The composition according to any one of [C-1] to [C-18], wherein the reaction is carried out in the presence of a solvent.

[0129] [C-20] The composition according to [C-19], wherein the solvent is selected from the group consisting of halogen-based solvents, nitrile-based solvents, amide-based solvents, ether-based solvents, and aromatic hydrocarbon-based solvents, and two or more of these may be used.

[0130] [C-21] The composition according to [C-19] or [C-20], wherein the solvent is selected from the group consisting of halogen-based solvents, nitrile-based solvents, ether-based solvents, and amide-based solvents, and two or more of these may be used. [C-22] The composition according to any one of [C-19] to [C-21], wherein the solvent is selected from the group consisting of halogen-based solvents, nitrile-based solvents, and amide-based solvents, and two or more of these may be used.

[0131] [C-23] The composition according to any one of [C-20] to [C-22], wherein the halogen-based solvent is selected from the group consisting of dichloromethane, chloroform, and 1,2-dichloroethane, and two or more of them may be used. [C-24] The composition according to any one of [C-20] to [C-22], wherein the halogen-based solvent is dichloromethane.

[0132] [C-25] The composition according to any one of [C-20] to [C-22], wherein the nitrile solvent is selected from the group consisting of acetonitrile, propionitrile, and benzonitrile, and two or more of them may be used.

[0133] [C-27] The composition according to any one of [C-20] to [C-22], wherein the amide solvent is selected from the group consisting of N-methylpyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, N,N-dimethylpropionamide, N,N-dimethylisobutyramide, N,N-diethylacetamide, N,N-diethylpropionamide, 1-ethyl-2-pyrrolidinone, 1-octyl-2-pyrrolidinone, 1-cyclohexyl-2-pyrrolidinone, and N-methylcaprolactam, and two or more of these may be used.

[0134] [C-28] The composition according to [C-20], wherein the ether solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,3-dioxolane, diisopropyl ether, cyclopentyl methyl ether, t-butyl methyl ether, and 4-methyltetrahydropyran, and two or more of these may be used.

[0135] [C-29] The composition according to [C-20] or [C-21], wherein the ether solvent is tetrahydrofuran. [C-30] The composition according to any one of [C-20] to [C-22], wherein the aromatic hydrocarbon solvent is selected from the group consisting of benzene, toluene, and xylene, and two or more of them may be used. [C-31] The composition according to any one of [C-1] to [C-30], wherein the equivalent ratio of the condensing agent to the carboxylic acid compound is condensing agent / carboxylic acid compound = 20 / 1 to 1 / 1.

[0136] [C-32] The composition according to any one of [C-1] to [C-31], wherein the molar ratio of the condensing agent to the carboxylic acid is condensing agent / carboxylic acid = 15 / 1 to 1 / 1, 10 / 1 to 1 / 1, or 5 / 1 to 1 / 1.

[0137] [C-33] The composition according to any one of [C-1] to [C-32], wherein the reaction is carried out at a reaction temperature of 0° C. to 100° C. [C-34] The composition according to [C-33], wherein the reaction temperature is 10° C. to 80° C., 10° C. to 60° C., 15° C. to 40° C., or 20° C. to 30° C.

[0138] [C-35] The composition according to [C-33], wherein the reaction temperature is 10° C. to 80° C., 10° C. to 60° C., 15° C. to 40° C., or 20° C. to 30° C. [C-36] The composition according to any one of [C-1] to [C-35], wherein the carboxylic acid compound is a resin for solid phase synthesis to which a carboxylic acid compound is bound via a linker, or the amine compound is a resin for solid phase synthesis to which an amine compound is bound via a linker.

[0139] [C-37] The composition according to any one of [C-1] to [C-36], wherein the carboxylic acid compound is a resin for solid phase synthesis to which two or more different carboxylic acid compounds are bound via linkers, or the amine compound is a resin for solid phase synthesis to which two or more different amine compounds are bound via linkers.

[0140] [C-38] The composition according to any one of [C-1] to [C-37], wherein the carboxylic acid compound is a resin for solid phase synthesis to which the carboxylic acid compound is bound via a linker. [C-39] The composition according to any one of [C-1] to [C-37], wherein the amine compound is a resin for solid phase synthesis to which the amine compound is bound via a linker.

[0141] [C-40] The carboxylic acid compound of formula A1 or A2:

[0142]

[0143] [In the formula, R ２０ , R ２１ , R ２２ , R ２３ , R ２４ , R ２５ , R ２６ and R ２７ are each independently a hydrogen atom, a halogen atom, cyano, C １－６ Alkyl, C １－６ Alkoxy, (C １－６ alkoxy)carbonyl, (C １－６ alkoxy)carbonylamino, (C １－６ alkyl)carbonylamino, (C ６－１０ aryl)carbonylamino, di(C １－６ alkyl)amino, 4- to 8-membered cyclic amino, aminocarbonyl, (C１－６ alkyl)aminocarbonyl, di(C １－６ alkyl)aminocarbonyl, 4- to 8-membered cyclic aminocarbonyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ Cycloalkyl, C ７－１４ Aralkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl containing one or more ring heteroatoms independently selected from O, N, and S, each of which may be substituted with an optional substituent; or a mixture of two or more compounds represented by the formula [C-1] to [C-39], wherein the carboxylic acid compound does not have any group participating in an amide bond-forming reaction other than the carboxy group represented by formula A1 or formula A2.

[0144] [C-41] The composition according to [C-40], wherein the carboxylic acid compound is one type of compound represented by formula A1, or a mixture of two or more types, or a resin for solid phase synthesis to which the compound is bound via a linker, wherein the carboxylic acid compound does not have any group participating in an amide bond-forming reaction other than the carboxy group represented by formula A1.

[0145] [C-42] In the carboxylic acid compound, the R ２０ and R ２４ are each independently C １－６ Alkyl or C ６－１０ [C-43] The composition according to [C-41], wherein the amine compound is a compound of Formula A3 or Formula A4:

[0146]

[0147] [In the formula, R ４０ , R ４６ and R ４７ are each independently a hydrogen atom, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ Cycloalkyl, C ７－１４ Aralkyl, C ６－１０aryl, and 5-10 membered heteroaryl containing one or more ring heteroatoms independently selected from O, N, and S; or ４０ and R ４５ together with the nitrogen atom and carbon atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, which may further contain heteroatoms selected from O and S, or R ４６ and R ４７ together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocycle, which may further contain a heteroatom selected from O and S; R ４１ , R ４２ , R ４３ , R ４４ , and R ４５ are each independently a hydrogen atom, a halogen atom, cyano, nitro, C １－６ Alkyl, C １－６ Alkoxy, (C １－６ alkoxy)carbonyl, (C １－６ alkoxy)carbonylamino, (C １－６ alkyl)carbonylamino, (C ６－１０ aryl)carbonylamino, di(C １－６ alkyl)amino, 4- to 8-membered cyclic amino, aminocarbonyl, (C １－６ alkyl)aminocarbonyl, di(C １－６ alkyl)aminocarbonyl, 4- to 8-membered cyclic aminocarbonyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ Cycloalkyl, C ７－１４ Aralkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl containing one or more ring heteroatoms independently selected from O, N, and S, each of which may be substituted by a substituent; or a mixture of two or more compounds represented by the formula [A-1] to [C-42], wherein the amine compound does not have any group participating in an amide bond-forming reaction other than the amino group represented by formula A3 or A4.

[0148] [C-44] The composition according to [C-43], wherein the amine compound is one type of compound represented by formula A3, or a mixture of two or more types, or a resin for solid phase synthesis to which the compound is bound via a linker, wherein the amine compound has no group participating in an amide bond-forming reaction other than the carboxy group represented by formula A3.

[0149] [C-45] In the amine compound, the R ４１ and R ４５ are each independently C １－６ Alkyl or C ６－１０ [C-46] The composition according to [C-44], wherein the uronium-based condensing agent is a compound represented by formula C1:

[0150]

[0151] [In the formula, R ３０ , R ３１ , R ３２ , R ３３ are each independently, C １－６ alkyl, or R ３１ and R ３２ , and / or R ３２ and R ３３ form a 5- to 7-membered non-aromatic heterocycle, which may contain one ring heteroatom selected from O or S, or R ３１ and R ３２ form a 5- to 7-membered non-aromatic heterocycle, which may contain one ring heteroatom selected from O or S; X is a leaving group; Z － is a counter anion], or a mixture of two or more compounds represented by the formula (C-1) to (C-45).

[0152] [C-47] The composition according to any one of [C-46], wherein X is a halogen atom. [C-48] The composition according to [C-46] or [C-47], wherein X is a fluorine atom or a chlorine atom.

[0153] [C-49] The 2-halo-N-alkylpyridinium-based condensing agent is a compound represented by formula C3:

[0154] [In the formula, R ３５ is C １－６ is alkyl, and X １ is a halogen, and Y is a counter anion; or a mixture of two or more compounds represented by the formula (C-1), (C-2), and (C-6) to (C-48).

[0155] [C-50] The composition according to any one of [C-1] to [C-49], wherein the reaction is carried out in a mixture containing two or more different carboxylic acid compounds and / or two or more different amine compounds as substrates.

[0156] [C-51] The composition according to any one of [C-1] to [C-50], wherein the reaction is carried out in a mixture containing two or more different carboxylic acid compounds as substrates. [C-52] The composition according to any one of [C-1] to [C-50], wherein the reaction is carried out in a mixture containing two or more different amine compounds as substrates.

[0157] [C-53] The composition according to any one of [C-50] to [C-52], wherein the mixture comprises, as a substrate, a resin for solid phase synthesis to which two or more different carboxylic acid compounds are bound via a linker, or a resin for solid phase synthesis to which two or more different amine compounds are bound via a linker, and the carboxylic acid compounds or amine compounds bound to each resin are the same.

[0158] [C-54] The composition according to any one of [C-1] to [C-11] and [C-18] to [C-53], wherein the reaction is carried out in the presence of an excess amount of the amine compound as a second base relative to the carboxylic acid compound, and the amine compound is one type of compound represented by formula A3 according to [C-48], or a mixture of two or more types.

[0159] [C-55] The composition according to any one of [C-1] to [C-54] for use in the method according to any one of [A-1] to [A-54] and [B-1] to [B-54].

[0160] [D-1] Use of a condensing agent in a method for forming an amide bond by dehydration condensation of a carboxy group and an amino group, the method comprising reacting a carboxylic acid compound with an amine compound in the presence of a condensing agent and a first base to form an amide bond, wherein the first base is a compound represented by Formula A:

[0161]

[0162] [In the formula, R １ is C １－６ Alkyl and C ６－１０ aryl, R ２ , R ３ , and R ４ are each independently a hydrogen atom, a halogen atom, or C １－６ Alkyl, and C ６－１０ aryl, or R １ and R ２ is R １ and the nitrogen atom to which R ２ and a molar ratio of the first base to the condensing agent (first base / condensing agent) is 1.8 or less.

[0163] [D-2] The use according to [D-1], wherein the molar ratio of the first base to the condensing agent is 1.7 or less, 1.6 or less, 1.5 or less, 1.4 or less, 1.3 or less, 1.2 or less, 1.1 or less, or 1.0 or less.

[0164] [D-3] The method according to [D-1] or [D-2], wherein the condensing agent is at least one selected from a uronium-based condensing agent and a 2-halo-N-alkylpyridinium-based condensing agent. [D-4] The method according to [D-1] or [D-2], wherein the condensing agent is a uronium-based condensing agent.

[0165] [D-5] The uronium-based condensing agent is a haluronium-based condensing agent, such as fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TFFH), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH), 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium hexafluorophosphate (PyClU), 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium tetrafluoroborate (TPyClU), chlorodipiperidinocarbenium hexafluorophosphate (PipClU), 2-chloro-1,3-dimethylimidazolinium chloride (DMC), 2-chloro-1,3-dimethylimidazolinium hexafluorophosphate (CIP), and The use according to [D-1] or [D-2], wherein the haluronium-based condensing agent is selected from the group consisting of 2-chloro-1,3-dimethylimidazolinium tetrafluoroborate (CIB), and two or more of them may be used.

[0166] [D-6] The method according to [D-1] or [D-2], wherein the condensing agent is a 2-halo-N-alkylpyridinium condensing agent. [D-7] The method according to [D-1] or [D-2], wherein the 2-halo-N-alkylpyridinium condensing agent is, for example, a halo-N-alkylpyridinium condensing agent selected from the group consisting of 2-chloro-1-methylpyridinium iodide, 2-bromo-1-ethylpyridinium tetrafluoroborate, and 2-fluoro-1-methylpyridinium p-toluenesulfonate, and two or more of these may be used.

[0167] [D-8] The use according to any one of [D-1] to [D-7], wherein the reaction is further carried out in the presence of a second base. [D-9] The use according to any one of [D-1] to [D-8], wherein the reaction is carried out in the presence of an amine compound in an excess amount relative to the carboxylic acid compound as a second base.

[0168] [D-10] The use according to [D-8] or [D-9], wherein the second base is an organic base whose conjugate acid in water has a pKa of 11 or less. [D-11] The use according to any one of [D-8] to [D-10], wherein the conjugate acid of the second base has a pKa in water of 0 to 11, 1 to 9, 2 to 8, 3 to 8, or 3.7 to 7.9.

[0169] [D-12] The second base is represented by the formula B1 and B2:

[0170]

[0171] [In the formula, R ５ and R ６ together with the nitrogen atom to which it is attached form a 5- to 7-membered saturated heterocycle, which may further contain heteroatoms selected from O and S, or R ５ and R ７ , and / or R ６ and R １１ together with the nitrogen atom and carbon atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, which may further contain heteroatoms selected from O and S, or R ５ and R ６ are each independently, C １－６ Alkyl, and C ６－１０ aryl, R ７ , R ８ , R ９ , R １０ and R １１ are each independently a hydrogen atom, C １－６ Alkyl, C ６－１０ aryl, halogen atom, or cyano; R １２ , R １３ , R １４ , R １５ and R １６ are each independently a hydrogen atom, C １－６ Alkyl, and C ６－１０ aryl, wherein C １－６ Alkyl, and C ６－１０The use according to any one of [D-8] to [D-11], wherein two or more of the aryl groups may be used, and the aryl group is selected from the group consisting of:

[0172] [D-13] The second base is represented by formula B1:

[0173]

[0174] [In the formula, R ５ and R ６ together with the nitrogen atom to which it is attached form a 5- to 7-membered saturated heterocycle, which may further contain heteroatoms selected from O and S, or R ５ and R ７ , and / or R ６ and R １１ together with the nitrogen atom and carbon atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, which may further contain heteroatoms selected from O and S, or R ５ and R ６ are each independently, C １－６ Alkyl, and C ６－１０ aryl, R ７ , R ８ , R ９ , R １０ and R １１ are each independently a hydrogen atom, C optionally substituted with one or more halogen atoms, １－６ alkyl, C optionally substituted with one or more halogen atoms; ６－１０ The use according to any one of [D-8] to [D-12], wherein two or more of the above may be used.

[0175] [D-14]R ５ and R ６ together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocycle, or R ５ and R ７ , and R ６ and R １１together with the nitrogen atom and carbon atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, or R ５ and R ６ are each independently, C １－６ alkyl, R ７ , R ８ , R ９ , R １０ and R １１ each independently represents a hydrogen atom, C optionally substituted with one or more halogen atoms, １－６ alkyl or halogen atom, R １２ , R １３ , R １４ , R １５ and R １６ each independently represents a C optionally substituted with a hydrogen atom or one or more halogen atoms; １－６ The use according to either [D-12] or [D-13], wherein the aryl group is alkyl.

[0176] [D-15] The use according to any one of [D-8] to [D-12], wherein the second base is selected from the group consisting of N,N-dimethylaniline, N,N,2,4,6-pentamethylaniline, julolidine, collidine, and 2,6-lutidine, the benzene ring of which may be substituted with a halogen atom or trifluoromethyl, and two or more of these may be used.

[0177] [D-16] The R in the first base １ is C １－６ Alkyl or C ６－１０ aryl, and the R ２ , R ３ and R ４ are each independently a hydrogen atom, C １－６ Alkyl or C ６－１０ The use according to any one of [D-8] to [D-15], wherein the compound is aryl.

[0178] [D-17] The use according to any one of [D-8] to [D-16], wherein the first base is selected from the group consisting of N-methylimidazole, tetramethylimidazole, and N-phenylimidazole, and two or more of them may be used.

[0179] [D-18] The use according to any one of [D-1] to [D-17], wherein the molar ratio of the amine compound to the carboxylic acid compound is 2.0 or more. [D-19] The use according to any one of [D-1] to [D-18], wherein the reaction is carried out in the presence of a solvent.

[0180] [D-20] The use according to [D-19], wherein the solvent is selected from the group consisting of halogen-based solvents, nitrile-based solvents, amide-based solvents, ether-based solvents, and aromatic hydrocarbon-based solvents, and two or more of them may be used.

[0181] [D-21] The use according to [D-19] or [D-20], wherein the solvent is selected from the group consisting of halogen-based solvents, nitrile-based solvents, ether-based solvents, and amide-based solvents, and two or more of these may be used. [D-22] The use according to any of [D-19] to [D-21], wherein the solvent is selected from the group consisting of halogen-based solvents, nitrile-based solvents, and amide-based solvents, and two or more of these may be used.

[0182] [D-23] The use according to any one of [D-20] to [D-22], wherein the halogen-based solvent is selected from the group consisting of dichloromethane, chloroform, and 1,2-dichloroethane, and two or more of them may be used. [D-24] The use according to any one of [D-20] to [D-22], wherein the halogen-based solvent is dichloromethane.

[0183] [D-25] The use according to any one of [D-20] to [D-23], wherein the nitrile solvent is selected from the group consisting of acetonitrile, propionitrile, and benzonitrile, and two or more of them may be used. [D-26] The use according to any one of [D-20] to [D-22], wherein the nitrile solvent is acetonitrile.

[0184] [D-27] The use according to any one of [D-20] to [D-22], wherein the amide solvent is selected from the group consisting of N-methylpyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, N,N-dimethylpropionamide, N,N-dimethylisobutyramide, N,N-diethylacetamide, N,N-diethylpropionamide, 1-ethyl-2-pyrrolidinone, 1-octyl-2-pyrrolidinone, 1-cyclohexyl-2-pyrrolidinone, and N-methylcaprolactam, and two or more of these may be used.

[0185] [D-28] The use according to [D-20] or [D-21], wherein the ether solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,3-dioxolane, diisopropyl ether, cyclopentyl methyl ether, t-butyl methyl ether, and 4-methyltetrahydropyran, and two or more of them may be used.

[0186] [D-29] The use according to [D-20] or [D-21], wherein the ether solvent is tetrahydrofuran. [D-30] The use according to any of [D-20] to [D-22], wherein the aromatic hydrocarbon solvent is selected from the group consisting of benzene, toluene, and xylene, and two or more of them may be used. [D-31] The use according to any of [D-1] to [D-30], wherein the equivalent ratio of the condensing agent to the carboxylic acid compound is condensing agent / carboxylic acid compound = 20 / 1 to 1 / 1.

[0187] [D-32] The use according to any one of [D-1] to [D-31], wherein the molar ratio of the uronium-based condensing agent to the carboxylic acid is uronium-based condensing agent / carboxylic acid = 15 / 1 to 1 / 1, 10 / 1 to 1 / 1, or 5 / 1 to 1 / 1.

[0188] [D-33] The use according to any one of [D-1] to [D-32], wherein the reaction is carried out at a reaction temperature of 0° C. to 100° C. [D-34] The use according to [D-33], wherein the reaction temperature is 10° C. to 80° C., 10° C. to 60° C., 15° C. to 40° C., or 20° C. to 30° C.

[0189] [D-35] The use according to [D-33], wherein the reaction temperature is 10° C. to 80° C., 10° C. to 60° C., 15° C. to 40° C., or 20° C. to 30° C. [D-36] The use according to any of [D-1] to [D-35], wherein the carboxylic acid compound is a resin for solid phase synthesis to which a carboxylic acid compound is bound via a linker, or the amine compound is a resin for solid phase synthesis to which an amine compound is bound via a linker.

[0190] [D-37] The use according to any one of [D-1] to [D-36], wherein the carboxylic acid compound is a resin for solid phase synthesis to which two or more different carboxylic acid compounds are bound via linkers, or the amine compound is a resin for solid phase synthesis to which two or more different amine compounds are bound via linkers.

[0191] [D-38] The use according to any one of [D-1] to [D-37], wherein the carboxylic acid compound is a resin for solid phase synthesis to which the carboxylic acid compound is bound via a linker. [D-39] The use according to any one of [D-1] to [D-37], wherein the amine compound is a resin for solid phase synthesis to which the amine compound is bound via a linker.

[0192] [D-40] The carboxylic acid compound of formula A1 or A2:

[0193]

[0194] [In the formula, R ２０ , R ２１ , R ２２ , R ２３ , R ２４ , R ２５ , R ２６ and R ２７ are each independently a hydrogen atom, a halogen atom, cyano, C １－６ Alkyl, C １－６ Alkoxy, (C １－６ alkoxy)carbonyl, (C １－６ alkoxy)carbonylamino, (C １－６ alkyl)carbonylamino, (C ６－１０ aryl)carbonylamino, di(C １－６alkyl)amino, 4- to 8-membered cyclic amino, aminocarbonyl, (C １－６ alkyl)aminocarbonyl, di(C １－６ alkyl)aminocarbonyl, 4- to 8-membered cyclic aminocarbonyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ Cycloalkyl, C ７－１４ Aralkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl containing one or more ring heteroatoms independently selected from O, N, and S, each of which may be substituted with any substituent; or a mixture of two or more of these compounds, or a resin for solid phase synthesis to which the compound is bound via a linker, wherein the carboxylic acid compound does not have any group participating in an amide bond-forming reaction other than the carboxy group represented by Formula A1 or Formula A2.

[0195] [D-41] The use according to [D-40], wherein the carboxylic acid compound is one type of compound represented by formula A1, or a mixture of two or more types, or the resin for solid phase synthesis is one to which the compound is bound via a linker, and wherein the carboxylic acid compound does not have any group participating in an amide bond-forming reaction other than the carboxy group represented by formula A1.

[0196] [D-42] In the carboxylic acid compound, the R ２０ and R ２４ are each independently C １－６ Alkyl or C ６－１０ [D-43] The use according to [D-41], wherein the amine compound is of formula A3 or A4:

[0197]

[0198] [In the formula, R ４０ , R ４６ and R ４７ are each independently a hydrogen atom, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ Cycloalkyl, C ７－１４ Aralkyl, C６－１０ aryl, and 5-10 membered heteroaryl containing one or more ring heteroatoms independently selected from O, N, and S; or ４０ and R ４５ together with the nitrogen atom and carbon atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, which may further contain heteroatoms selected from O and S, or R ４６ and R ４７ together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocycle, which may further contain a heteroatom selected from O and S; R ４１ , R ４２ , R ４３ , R ４４ , and R ４５ are each independently a hydrogen atom, a halogen atom, cyano, nitro, C １－６ Alkyl, C １－６ Alkoxy, (C １－６ alkoxy)carbonyl, (C １－６ alkoxy)carbonylamino, (C １－６ alkyl)carbonylamino, (C ６－１０ aryl)carbonylamino, di(C １－６ alkyl)amino, 4- to 8-membered cyclic amino, aminocarbonyl, (C １－６ alkyl)aminocarbonyl, di(C １－６ alkyl)aminocarbonyl, 4- to 8-membered cyclic aminocarbonyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ Cycloalkyl, C ７－１４ Aralkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl containing one or more ring heteroatoms independently selected from O, N, and S, each of which may be substituted by a substituent], or a mixture of two or more of these compounds, or a resin for solid phase synthesis to which the compound is bound via a linker, wherein the amine compound does not have any group participating in an amide bond-forming reaction other than the amino group represented by Formula A3 or Formula A4.

[0199] [D-44] The use according to [D-43], wherein the amine compound is one type of compound represented by formula A3, or a mixture of two or more types, or the resin for solid phase synthesis is one to which the compound is bound via a linker, and the amine compound does not have any group participating in an amide bond-forming reaction other than the amino group represented by formula A3.

[0200] [D-45] In the amine compound, the R ４１ and R ４５ are each independently C １－６ Alkyl or C ６－１０ [D-46] The use according to [D-44], wherein the uronium-based condensing agent is a compound represented by formula C1:

[0201]

[0202] [In the formula, R ３０ , R ３１ , R ３２ , R ３３ are each independently, C １－６ alkyl, or R ３１ and R ３２ , and / or R ３２ and R ３３ form a 5- to 7-membered non-aromatic heterocycle, which may contain one ring heteroatom selected from O or S, or R ３１ and R ３２ form a 5- to 7-membered non-aromatic heterocycle, which may contain one ring heteroatom selected from O or S; X is a leaving group; Z － is a counter anion], or a mixture of two or more compounds represented by the formula (D-1) to (D-45).

[0203] [D-47] The use according to any one of [D-46], wherein X is a halogen atom. [D-48] The use according to [D-46] or [D-47], wherein X is a fluorine atom or a chlorine atom.

[0204] [D-49] The 2-halo-N-alkylpyridinium-based condensing agent is a compound represented by formula C3: [In the formula, R ３５is C １－６ is alkyl, and X １ is a halogen, and Y is a counter anion; or a mixture of two or more compounds represented by the formula (I).

[0205] [D-50] The use according to any one of [D-1] to [D-49], wherein the reaction is carried out in a mixture containing two or more different carboxylic acid compounds and / or two or more different amine compounds as substrates.

[0206] [D-51] The use according to any one of [D-1] to [D-50], wherein the reaction is carried out in a mixture containing two or more different carboxylic acid compounds as substrates. [D-52] The use according to any one of [D-1] to [D-51], wherein the reaction is carried out in a mixture containing two or more different amine compounds as substrates.

[0207] [D-53] The use according to any one of [D-50] to [D-52], wherein the mixture comprises, as a substrate, a resin for solid phase synthesis to which two or more different carboxylic acid compounds are bound via a linker, or a resin for solid phase synthesis to which two or more different amine compounds are bound via a linker, and the carboxylic acid compounds or amine compounds bound to the individual resins are the same.

[0208] [D-54] Use according to any one of [D-1] to [D-11] and [D-18] to [D-53], wherein the reaction is carried out in the presence of an excess amount of the amine compound as a second base relative to the carboxylic acid compound, and the amine compound is one compound represented by formula A3 according to [D-43], or a mixture of two or more compounds.

[0209] [D-55] Use of any one of [D-1] to [D-54] in the method described in any one of [A-1] to [A-54] and [B-1] to [B-54].

[0210] [E-1] A method for producing an amide compound, comprising reacting a carboxylic acid compound with an amine compound in the presence of a uronium-based condensing agent and a first base to obtain an amide compound, wherein the first base is a compound represented by Formula A:

[0211]

[0212] [In the formula, R １ is C １－６ Alkyl and C ６－１０ aryl, R ２ , R ３ , and R ４ are each independently a hydrogen atom, a halogen atom, or C １－６ Alkyl, and C ６－１０ aryl, or R １ and R ２ is R １ and the nitrogen atom to which R ２ forms a 5- to 6-membered non-aromatic heterocycle together with the carbon atom to which it is bonded, and two or more of these may be used, and the molar ratio of the first base to the uronium condensing agent (first base / uronium condensing agent) is 1.8 or less.

[0213] [E-2] The method according to [E-1], wherein the uronium-based condensing agent is a halouronium-based condensing agent. [E-3] The method according to [E-1] or [E-2], wherein the reaction is further carried out in the presence of a second base.

[0214] [E-4] The method according to any one of [E-1] to [E-3], wherein the reaction is carried out in the presence of an excess amount of the amine compound as a second base. [E-5] The method according to [E-3] or [E-4], wherein the second base is an organic base whose conjugate acid has a pKa in water of 11 or less.

[0215] [E-6] The second base is represented by the formula B1 and B2:

[0216]

[0217] [In the formula, R ５ and R ６ together with the nitrogen atom to which it is attached form a 5- to 7-membered saturated heterocycle, which may further contain heteroatoms selected from O and S, or R ５ and R ７ , and / or R ６ and R １１together with the nitrogen atom and carbon atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, which may further contain heteroatoms selected from O and S, or R ５ and R ６ are each independently, C １－６ Alkyl, and C ６－１０ aryl, R ７ , R ８ , R ９ , R １０ and R １１ are each independently a hydrogen atom, C １－６ Alkyl, C ６－１０ aryl, halogen atom, or cyano; R １２ , R １３ , R １４ , R １５ and R １６ are each independently a hydrogen atom, C １－６ Alkyl, and C ６－１０ aryl, wherein C １－６ Alkyl, and C ６－１０ The method according to any one of [E-3] to [E-5], wherein two or more of the aryl groups may be used, and the aryl group may be selected from the group consisting of:

[0218] [E-7] The method according to any one of [E-1] to [E-6], wherein the first base is selected from the group consisting of N-methylimidazole, tetramethylimidazole, and N-phenylimidazole, and two or more of them may be used.

[0219] [E-8] The method according to any one of [E-1] to [E-7], wherein the reaction is carried out in the presence of a solvent, and the solvent is selected from the group consisting of halogen-based solvents, nitrile-based solvents, amide-based solvents, ether-based solvents, and aromatic hydrocarbon-based solvents, and two or more of these solvents may be used.

[0220] [E-9] The method according to any one of [E-1] to [E-8], wherein the carboxylic acid compound is a resin for solid phase synthesis to which a carboxylic acid compound is bound via a linker, or the amine compound is a resin for solid phase synthesis to which an amine compound is bound via a linker.

[0221] [E-10] The carboxylic acid compound is represented by formula A1 or A2:

[0222]

[0223] [In the formula, R ２０ , R ２１ , R ２２ , R ２３ , R ２４ , R ２５ , R ２６ and R ２７ are each independently a hydrogen atom, a halogen atom, cyano, C １－６ Alkyl, C １－６ Alkoxy, (C １－６ alkoxy)carbonyl, (C １－６ alkoxy)carbonylamino, (C １－６ alkyl)carbonylamino, (C ６－１０ aryl)carbonylamino, di(C １－６ alkyl)amino, 4- to 8-membered cyclic amino, aminocarbonyl, (C １－６ alkyl)aminocarbonyl, di(C １－６ alkyl)aminocarbonyl, 4- to 8-membered cyclic aminocarbonyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ Cycloalkyl, C ７－１４ Aralkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl containing one or more ring heteroatoms independently selected from O, N, and S, each of which may be substituted by a substituent; or a mixture of two or more of these compounds, or a resin for solid phase synthesis to which the compound is bound via a linker, wherein the carboxylic acid compound does not have any group participating in an amide bond-forming reaction other than the carboxy group represented by Formula A1 or Formula A2.

[0224] [E-11] The amine compound is represented by formula A3 or A4:

[0225]

[0226] [In the formula, R ４０ , R４６ and R ４７ are each independently a hydrogen atom, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ Cycloalkyl, C ７－１４ Aralkyl, C ６－１０ aryl, and 5-10 membered heteroaryl containing one or more ring heteroatoms independently selected from O, N, and S; or ４０ and R ４５ together with the nitrogen atom and carbon atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, which may further contain heteroatoms selected from O and S, or R ４６ and R ４７ together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocycle, which may further contain a heteroatom selected from O and S; R ４１ , R ４２ , R ４３ , R ４４ , and R ４５ are each independently a hydrogen atom, a halogen atom, cyano, nitro, C １－６ Alkyl, C １－６ Alkoxy, (C １－６ alkoxy)carbonyl, (C １－６ alkoxy)carbonylamino, (C １－６ alkyl)carbonylamino, (C ６－１０ aryl)carbonylamino, di(C １－６ alkyl)amino, 4- to 8-membered cyclic amino, aminocarbonyl, (C １－６ alkyl)aminocarbonyl, di(C １－６ alkyl)aminocarbonyl, 4- to 8-membered cyclic aminocarbonyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ Cycloalkyl, C ７－１４ Aralkyl, C ６－１０aryl, and 5- to 10-membered heteroaryl containing one or more ring heteroatoms independently selected from O, N, and S, each of which may be substituted by a substituent; or a mixture of two or more of these compounds, or a resin for solid phase synthesis to which the compound is bound via a linker, wherein the amine compound does not have any group participating in an amide bond-forming reaction other than the amino group represented by Formula A3 or Formula A4.

[0227] [E-12] The uronium-based condensing agent is represented by formula C1:

[0228]

[0229] [In the formula, R ３０ , R ３１ , R ３２ , R ３３ are each independently, C １－６ alkyl, or R ３０ and R ３１ , and / or R ３２ and R ３３ form a 5- to 7-membered saturated heterocycle, which may contain one ring heteroatom selected from O or S, or R ３１ and R ３２ form a 5- to 7-membered saturated heterocycle, the heterocycle optionally containing one ring heteroatom selected from O and S; X is a leaving group; and Z is a counter anion; or a mixture of two or more compounds represented by the formula (I) above.

[0230] [E-13] The method according to any one of [E-1] to [E-12], wherein the reaction is carried out in a mixture containing two or more different carboxylic acid compounds and / or two or more different amine compounds as substrates.

[0231] [E-14] A method for producing a compound constituting a compound library, the method comprising producing an amide compound by the method described in any one of [E-1] to [E-13].

[0232] [E-15] A method for forming an amide bond by dehydration condensation of a carboxy group and an amino group, comprising reacting a carboxylic acid compound with an amine compound in the presence of a uronium-based condensing agent and a first base to form an amide bond, wherein the first base is a compound represented by formula A:

[0233]

[0234] [In the formula, R １ is C １－６ Alkyl and C ６－１０ aryl, R ２ , R ３ , and R ４ are each independently a hydrogen atom, a halogen atom, or C １－６ Alkyl, and C ６－１０ aryl, or R １ and R ２ is R １ and the nitrogen atom to which R ２ forms a 5- to 6-membered non-aromatic heterocycle together with the carbon atom to which it is bonded, or a mixture of two or more compounds thereof, wherein the molar ratio of the first base to the uronium-based condensing agent (first base / uronium-based condensing agent) is 1.8 or less.

[0235] In one aspect, the present invention makes it possible to improve the conversion rate in an amide-forming reaction between an amine compound and a carboxylic acid compound using a condensing agent, and / or to efficiently produce an amide compound through said reaction.

[0236] In one aspect, the present invention provides a method for producing an amide compound, comprising reacting a carboxylic acid compound with an amine compound in the presence of a uronium-based condensing agent or a 2-halo-N-alkylpyridinium-based condensing agent and a first base to obtain an amide compound. The carboxylic acid compound is not particularly limited as long as it has one or more carboxy groups that serve as reaction sites for an amide bond-forming reaction. In one embodiment, the carboxylic acid compound has 1 to 5, 1 to 4, 1 to 3, 1 or 2, or 1 carboxy group in its molecule. The amine compound is not particularly limited as long as it has one or more amino groups that serve as reaction sites for an amide bond-forming reaction. In one embodiment, the amine compound has 1 to 5, 1 to 4, 1 to 3, 1 or 2, or 1 amino group in its molecule. The carboxylic acid compound and the amine compound can be synthesized by known methods, or commercially available compounds can be used.

[0237] In one aspect, the method for producing an amide compound of the present invention can be applied to an amide-forming reaction of a compound having a carboxy group and an amino group in one molecule. In one embodiment, the amide-forming reaction is a cyclization reaction, and the resulting compound is a 4- to 40-membered, 4- to 34-membered, 4- to 12-membered, or 5- to 10-membered cyclic amide compound, and the ring-constituting atoms may contain one or more heteroatoms selected from O, N, and S.

[0238] In one aspect of the present invention, the uronium-based condensing agent is not particularly limited as long as it is a uronium compound that can be used for dehydration condensation in an amide bond-forming reaction. In one embodiment, the uronium compound can be a known uronium salt, for example, a commercially available uronium compound as a condensing agent. In one embodiment of the present invention, the uronium-based condensing agent can be one type of uronium compound, or a mixture of two or more types of uronium compounds.

[0239] In this specification, uronium compounds include compounds called amidinium compounds. In one aspect of the present invention, the uronium-based condensing agent is represented by formula C1:

[0240]

[0241] [In the formula, R ３０ , R ３１ , R ３２ , R ３３ are each independently, C １－６ alkyl, or R ３０ and R ３１ , and / or R ３２ and R ３３ form a 5- to 7-membered non-aromatic heterocycle, which may contain one ring heteroatom selected from O or S, or R ３１ and R ３２ form a 5- to 7-membered non-aromatic heterocycle, which may contain one ring heteroatom selected from O or S; X is a leaving group; Z － is a counter anion] can be used.

[0242] As used herein, the compound of formula C1 may be a compound of formula C2:

[0243] The compound may exist as an isomer, for example a tautomer, represented by the formula:

[0244] In the present specification, the leaving group represented by X is not particularly limited, and examples thereof include a halogen atom and a group represented by the following formula:

[0245]

[0246] [In the formula, R ３４ is C １－６ The benzene ring and the pyridine ring in the formula are C １－６ and the like. The alkyl group may be substituted with one or more substituents selected from alkyl and halogen atoms.

[0247] According to one aspect of the present invention, a halouronium compound is used as the uronium-based condensing agent. In one embodiment, the group represented by X in formula C1 is a halogen atom, specifically a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, or the like, more specifically a fluorine atom or a chlorine atom.

[0248] In this specification, Z －The counter anion represented by the formula (I) is not particularly limited, but examples thereof include halide anions (e.g., fluoride ion, chloride ion, bromide ion, iodide ion, etc.), hexafluorophosphate ion (PF ６ － ), tetrafluoroborate ion (BF ４ － More specifically, examples of the counter anion include chloride ions and hexafluorophosphate ions (PF ６ － ), tetrafluoroborate ion (BF ４ － ) is an example.

[0249] In one embodiment of the present invention, one or a mixture of two or more different uronium compounds listed below can be used as the uronium-based condensing agent: 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide hexafluorophosphate (HBTU); 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide tetrafluoroborate (TBTU); 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU); 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide tetrafluoroborate (TATU); O-(6-chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TCTU); O-(6-chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HCTU); N,N,N',N'-tetramethyl-O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)uronium tetrafluoroborate (TDBTU); O-(benzotriazol-1-yl)-N,N,N',N'-bis(tetramethylene)uronium hexafluorophosphate (HBPyU); O-(benzotriazol-1-yl)-N,N,N',N'-bis(pentamethylene)uronium hexafluorophosphate (HBPipU); O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU); O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N',N'-tetramethyluronium hexafluorophosphate (HOTU); (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (COMU); O-[2-oxo-1(2H)-pyridyl]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TPTU);2-(5-norbornene-2,3-dicarboximido)-1,1,3,3-tetramethyluronium tetrafluoroborate (TNTU); O-(N-succinimidyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TSTU); O-(N-succinimidyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HSTU); dipyrrolidino(N-succinimidyloxy)carbenium hexafluorophosphate (HSPyU); N,N,N',N'-tetramethyl-S-(1-oxido-2-pyridyl)thiouronium tetrafluoroborate (TOTT); N,N,N',N'-tetramethyl-S-(1-oxido-2-pyridyl)thiouronium hexafluorophosphate (HOTT); fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TFFH); chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH); 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium hexafluorophosphate (PyClU); 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium tetrafluoroborate (TPyClU); chlorodipiperidinocarbenium hexafluorophosphate (PipClU); 2-chloro-1,3-dimethylimidazolinium chloride (DMC); 2-chloro-1,3-dimethylimidazolinium hexafluorophosphate (CIP); and 2-chloro-1,3-dimethylimidazolinium tetrafluoroborate (CIB);

[0250] In one embodiment of the present invention, one or a mixture of two or more different halouronium compounds described below can be used as the uronium-based condensing agent: fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TFFH); chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH); 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium hexafluorophosphate (PyClU); 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium tetrafluoroborate (TPyClU); chlorodipiperidinocarbenium hexafluorophosphate (PipClU); 2-chloro-1,3-dimethylimidazolinium chloride (DMC); 2-chloro-1,3-dimethylimidazolinium hexafluorophosphate (CIP); and 2-chloro-1,3-dimethylimidazolinium tetrafluoroborate (CIB).

[0251] In one aspect of the present invention, the 2-halo-N-alkylpyridinium condensing agent is not particularly limited as long as it is a 2-halo-N-alkylpyridinium compound that can be used for dehydration condensation in an amide bond-forming reaction. In one embodiment, the 2-halo-N-alkylpyridinium compound can be a known 2-halo-N-alkylpyridinium salt, for example, a commercially available 2-halo-N-alkylpyridinium compound that can be used as a condensing agent. In one embodiment of the present invention, the 2-halo-N-alkylpyridinium condensing agent can be a single 2-halo-N-alkylpyridinium compound, or a mixture of two or more 2-halo-N-alkylpyridinium compounds.

[0252] In one aspect of the present invention, the 2-halo-N-alkylpyridinium condensing agent is represented by formula C3:

[0253]

[0254] [In the formula, R ３５ is C １－６ is alkyl, and X １In one embodiment of the present invention, a compound represented by the formula C3, wherein X is a halogen and Y is a counter anion, can be used. １ The group represented by the formula (I) is a halogen atom, specifically a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, or the like, and more specifically a fluorine atom, a chlorine atom, or a bromine atom.

[0255] In this specification, Y － The counter anion represented by the formula (I) is not particularly limited, but examples thereof include halide anions (e.g., fluoride ion, chloride ion, bromide ion, iodide ion, etc.), hexafluorophosphate ion (PF ６ － ), tetrafluoroborate ion (BF ４ － ), p-toluenesulfonate ion (pTsO － More specifically, examples of the counter anion include iodide ion and tetrafluoroborate ion (BF ４ － ), p-toluenesulfonate ion (pTsO － ) is an example.

[0256] In one embodiment of the present invention, one or a mixture of two or more different 2-halo-N-alkylpyridinium compounds described below can be used as the 2-halo-N-alkylpyridinium condensing agent: 2-chloro-1-methylpyridinium iodide; 2-bromo-1-ethylpyridinium tetrafluoroborate; and 2-fluoro-1-methylpyridinium p-toluenesulfonate.

[0257] In one embodiment of the present invention, one type of uronium compound, one type of haluronium compound, or one type of 2-halo-N-alkylpyridinium compound can be used as the condensing agent. In one aspect of the present invention, the amide bond forming reaction is carried out by reacting a carboxylic acid compound with an amine compound in the presence of a condensing agent and a first base.

[0258] In one embodiment of the present invention, one type of uronium compound or one type of haluronium compound can be used as the uronium-based condensing agent. In one aspect of the present invention, the amide bond-forming reaction is carried out by reacting a carboxylic acid compound with an amine compound in the presence of a condensing agent and a first base.

[0259] wherein the first base is of formula A:

[0260]

[0261] [In the formula, R １ is C １－６ Alkyl and C ６－１０ aryl, R ２ , R ３ , and R ４ are each independently a hydrogen atom, a halogen atom, or C １－６ Alkyl, and C ６－１０ aryl, or R １ and R ２ is R １ and the nitrogen atom to which R ２ together with the carbon atom to which it is attached form a 5- to 6-membered non-aromatic heterocycle, or a mixture of two or more different compounds represented by the formula: １－６ Alkyl is, for example, methyl; C ６－１０ Aryl is, for example, phenyl. In one embodiment of the invention, R １ is methyl or phenyl, and R ２ , R ３ , and R ４ are each independently a hydrogen atom or methyl.

[0262] Examples of compounds that can be used as the first base include N-methylimidazole, tetramethylimidazole, N-phenylimidazole, 1-isopropylimidazole, 1-tert-butylimidazole, 1-(2,6-diisopropylphenyl)imidazole, 1,2-dimethylimidazole, 1,4-dimethylimidazole, 5-chloro-1-methylimidazole, 5-bromo-1-methylimidazole, 5-iodo-1-methylimidazole, 2-iodo-1-methylimidazole, 1-methyl-2-(methylthio)imidazole, 1-methylbenzimidazole, 4-methyl-1,2,4-triazole, and imidazo[1,5-a]pyridine, and specific examples include N-methylimidazole, tetramethylimidazole, and N-phenylimidazole.

[0263] In one embodiment of the present invention, the molar ratio of the first base to the condensing agent (first base / condensing agent) is 1.8 or less, 1.7 or less, 1.6 or less, 1.5 or less, 1.4 or less, 1.3 or less, 1.2 or less, or 1.1 or less. In one embodiment, the molar ratio (first base / condensing agent) is 0.1 or more, 0.2 or more, 0.3 or more, 0.4 or more, 0.5 or more, 0.6 or more, 0.7 or more, 0.8 or more, or 0.9 or more.

[0264] In one embodiment of the present invention, the molar ratio of the first base to the uronium-based condensing agent (first base / uronium-based condensing agent) is 1.8 or less, 1.7 or less, 1.6 or less, 1.5 or less, 1.4 or less, 1.3 or less, 1.2 or less, or 1.1 or less. In another embodiment, the molar ratio (first base / uronium-based condensing agent) is 0.1 or more, 0.2 or more, 0.3 or more, 0.4 or more, 0.5 or more, 0.6 or more, 0.7 or more, 0.8 or more, or 0.9 or more.

[0265] In one aspect of the present invention, the amide bond-forming reaction can be carried out in the presence of a second base different from the first base. In one aspect of the present invention, the second base is an organic base whose conjugate acid has a pKa in water of 11 or less, 10 or less, 9 or less, 8 or less, or 7.9 or less, and 0 or more, 1 or more, 2 or more, 3 or more, or 3.7 or more. In one aspect of the present invention, the pKa in water of the conjugate acid of the second base is 0 to 11, 1 to 9, 2 to 8, 3 to 8, or 3.7 to 7.9. The pKa of the conjugate acid of the base can be determined by conventional methods, for example, a value measured at 25°C according to the method described in "Experimental Chemistry Lectures 5, Thermal Measurements and Equilibria," p. 460 (edited by the Chemical Society of Japan, published by Maruzen Co., Ltd.). As reference values, values ​​described in the publicly known literature Eur. J. Org. Chem. 2019, 6735-6748, Advanced Chemistry Development (ACD / Labs) Software V11.02 ((c) 1994-2019 ACD / Labs), calculated values ​​using ADMET predictor (version 9.5, parameters are all default values), values ​​described in the Sigma-Aldrich catalog, values ​​described in Chemical Book (https: / / www.chemicalbook.com), or values ​​described in PubChem (https: / / pubchem.ncbi.nlm.nih.gov) can be appropriately referenced. The calculated pKa values ​​of the conjugate acids in water using ADMET predictor (version 9.5) are, for example, 3.71 for 3-chloro-N,N-dimethylaniline, 3.75 for N,N-dimethyl-4-(trifluoromethyl)aniline, 3.81 for N,N-dimethyl-3-(trifluoromethyl)aniline, 4.45 for 3-bromo-N,N-dimethylaniline, 4.65 for N,N,2,4,6-pentamethylaniline, 4.7 for 4-bromo-N,N-dimethylaniline, 4.8 for 4-fluoro-N,N-dimethylaniline, 5.12 for N,N-dimethyl-p-toluidine, 5.19 for N,N-dimethylaniline, 5.63 for julolidine, 6.64 for N,N-diethylaniline, 6.73 for 2,6-lutidine, and 7.86 for N-methylmorpholine.

[0266] In one embodiment of the invention, the second base is represented by formula B1 and B2:

[0267]

[0268] [In the formula, R ５ and R ６ together with the nitrogen atom to which it is attached form a 5- to 7-membered saturated heterocycle, which may further contain heteroatoms selected from O and S, or R ５ and R ７ , and / or R ６ and R １１ together with the nitrogen atom and carbon atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, which may further contain heteroatoms selected from O and S, or R ５ and R ６ are each independently, C １－６ Alkyl, and C ６－１０ aryl, R ７ , R ８ , R ９ , R １０ and R １１ are each independently a hydrogen atom, C １－６ Alkyl, C ６－１０ aryl, halogen atom, or cyano; R １２ , R １３ , R １４ , R １５ and R １６ are each independently a hydrogen atom, C １－６ Alkyl, and C ６－１０ aryl, wherein C １－６ Alkyl, and C ６－１０ and wherein aryl is optionally substituted with one or more halogen atoms], or a mixture of two or more different compounds.

[0269] In one embodiment, R ５ and R ７ , and R ６ and R １１form a 6-membered non-aromatic heterocycle together with the nitrogen atom and carbon atom to which they are attached, or R ５ and R ６ are each independently, C １－６ alkyl, and R ７ , R ８ , R ９ , R １０ and R １１ are each independently a hydrogen atom, a C optionally substituted with one or more fluorine atoms, １－６ alkyl, halogen atom, or cyano; R １２ , R １３ , R １４ , R １５ and R １６ each independently represents a hydrogen atom and a C optionally substituted with one or more fluorine atoms; １－６ alkyl.

[0270] In one embodiment, R ５ and R ７ , and R ６ and R １１ form a 6-membered non-aromatic heterocycle together with the nitrogen atom and carbon atom to which they are attached, or R ５ and R ６ are all methyl, and R ７ , R ８ , R ９ , R １０ and R １１ are each independently selected from a hydrogen atom, trifluoromethyl, methyl, a fluorine atom, a chlorine atom, and a bromine atom; R １２ , R １３ , R １４ , R １５ and R １６ are each independently selected from a hydrogen atom, trifluoromethyl, and methyl.

[0271] Compounds utilized as second bases include N,N-dimethylaniline, 4-bromo-N,N-dimethylaniline, 4-fluoro-N,N-dimethylaniline, 3-bromo-N,N-dimethylaniline, 3-chloro-N,N-dimethylaniline, N,N-dimethyl-3-(trifluoromethyl)aniline, N,N,2,4,6-pentamethylaniline, julolidine, collidine, and 2,6-lutidine.

[0272] In one embodiment of the present invention, the molar ratio of the second base to the first base (second base / first base) is 100 or less, 70 or less, 50 or less, 20 or less, 10 or less, 5 or less, or 3.5 or less. In one embodiment, the molar ratio (second base / first base) is 0 or more, 0.1 or more, 0.2 or more, 0.5 or more, 0.7 or more, or 1.0 or more.

[0273] In one aspect of the present invention, an amine compound serving as a substrate for an amide-forming reaction can be used as a second base in an excess amount relative to a carboxylic acid compound. Here, the term "excess amount" is not particularly limited, but may be, for example, an amount greater than the number of equivalents relative to the carboxylic acid compound. In one embodiment, by using an equivalent amount of the amine compound in addition to an amine compound corresponding to a predetermined molar ratio relative to the previously specified uronium compound or first base, an amine compound exceeding an equivalent amount can be used as a second base. In one embodiment of the present invention, when an amine compound serving as a substrate is used as a second base, the amine compound is used in an amount of 2 to 100 equivalents, 3 to 80 equivalents, 5 to 50 equivalents, 5 to 20 equivalents, or 5 to 12 equivalents relative to the carboxylic acid. Here, the number of equivalents relative to the carboxylic acid compound is calculated taking into account the number of carboxy groups contained in the carboxylic acid compound.

[0274] In one embodiment of the present invention, the molar ratio of the second base to the condensing agent (second base / condensing agent) is 20 or less, 10 or less, 7 or less, 5 or less, 4 or less, 3.5 or less, 2 or less, or 1 or less. In one embodiment, the molar ratio (second base / condensing agent) is 0 or more, 0.1 or more, 0.2 or more, 0.5 or more, 0.7 or more, or 1 or more.

[0275] In one embodiment of the present invention, the molar ratio of the second base to the uronium-based condensing agent (second base / uronium-based condensing agent) is 20 or less, 10 or less, 7 or less, 5 or less, 4 or less, 3.5 or less, 2 or less, or 1 or less. In one embodiment, the molar ratio (second base / uronium-based condensing agent) is 0 or more, 0.1 or more, 0.2 or more, 0.5 or more, 0.7 or more, or 1 or more.

[0276] In one aspect of the invention, the carboxylic acid compound has Formula A1 or Formula A2:

[0277]

[0278] [In the formula, R ２０ , R ２１ , R ２２ , R ２３ , R ２４ , R ２５ , R ２６ and R ２７ are each independently a hydrogen atom, a halogen atom, cyano, C １－６ Alkyl, C １－６ Alkoxy, (C １－６ alkoxy)carbonyl, (C １－６ alkoxy)carbonylamino, (C １－６ alkyl)carbonylamino, (C ６－１０ aryl)carbonylamino, di(C １－６ alkyl)amino, 4- to 8-membered cyclic amino, aminocarbonyl, (C １－６ alkyl)aminocarbonyl, di(C １－６ alkyl)aminocarbonyl, 4- to 8-membered cyclic aminocarbonyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ Cycloalkyl, C ７－１４ Aralkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl containing one or more ring heteroatoms independently selected from O, N, and S, each of which may be substituted by an optional substituent.

[0279] In one aspect of the present invention, the carboxylic acid compound used is a resin for solid phase synthesis to which one type of carboxylic acid compound or two, three, or four or more different carboxylic acid compounds are bound via linkers. In one aspect of the present invention, the carboxylic acid compound is a resin for solid phase synthesis to which one type of compound represented by Formula A1 or Formula A2 or two or more compounds are bound via linkers. In one embodiment, the carboxylic acid compound does not have a group participating in an amide bond-forming reaction other than the carboxy group represented by Formula A1 or A2.

[0280] In one aspect of the present invention, the molar ratio of the condensing agent to the carboxylic acid compound is condensing agent / carboxylic acid = 20 / 1 to 1 / 1, 15 / 1 to 1 / 1, 10 / 1 to 1 / 1, or 5 / 1 to 1 / 1. When the carboxylic acid compound is a resin for solid phase synthesis, the molar ratio of the condensing agent to the carboxylic acid contained in the compound bound to the resin is condensing agent / carboxylic acid = 20 / 1 to 1 / 1, 15 / 1 to 1 / 1, 10 / 1 to 1 / 1, or 5 / 1 to 1 / 1.

[0281] In one aspect of the present invention, the molar ratio of the uronium condensing agent to the carboxylic acid compound is uronium condensing agent / carboxylic acid compound=20 / 1 to 1 / 1, 15 / 1 to 1 / 1, 10 / 1 to 1 / 1, or 5 / 1 to 1 / 1. When the carboxylic acid compound is a resin for solid phase synthesis, the molar ratio of the uronium condensing agent to the carboxylic acid contained in the compound bound to the resin is uronium condensing agent / carboxylic acid=20 / 1 to 1 / 1, 15 / 1 to 1 / 1, 10 / 1 to 1 / 1, or 5 / 1 to 1 / 1.

[0282] In one aspect of the invention, the amine compound has formula A3 or A4:

[0283]

[0284] [In the formula, R ４０ , R ４６ and R ４７ are each independently a hydrogen atom, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ Cycloalkyl, C ７－１４ Aralkyl, C ６－１０aryl, and 5-10 membered heteroaryl containing one or more ring heteroatoms independently selected from O, N, and S; or ４０ and R ４５ together with the nitrogen atom and carbon atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, which may further contain heteroatoms selected from O and S, or R ４６ and R ４７ together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocycle, which may further contain a heteroatom selected from O and S; R ４１ , R ４２ , R ４３ , R ４４ , and R ４５ are each independently a hydrogen atom, a halogen atom, cyano, nitro, C １－６ Alkyl, C １－６ Alkoxy, (C １－６ alkoxy)carbonyl, (C １－６ alkoxy)carbonylamino, (C １－６ alkyl)carbonylamino, (C ６－１０ aryl)carbonylamino, di(C １－６ alkyl)amino, 4- to 8-membered cyclic amino, aminocarbonyl, (C １－６ alkyl)aminocarbonyl, di(C １－６ alkyl)aminocarbonyl, 4- to 8-membered cyclic aminocarbonyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ Cycloalkyl, C ７－１４ Aralkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl containing one or more ring heteroatoms independently selected from O, N, and S, each of which may be substituted by a substituent, or a mixture of two, three, or four or more different compounds. In one embodiment, the amine compound has no group participating in an amide bond-forming reaction other than the amino group represented by formula A3 or A4.

[0285] In one aspect of the present invention, a resin for solid-phase synthesis to which one amine compound or two, three, or four or more amine compounds are bound via linkers is used as the amine compound. In one embodiment, the amine compound does not have any group participating in an amide bond-forming reaction other than the amino group represented by Formula A3 or A4.

[0286] In the present specification, the group participating in the amide bond-forming reaction is not particularly limited. Specifically, the group participating in the amide bond-forming reaction is a carboxy group or an amino group capable of forming an amide bond.

[0287] In one aspect of the present invention, the molar ratio of the condensing agent to the amine compound is condensing agent / amine compound=20 / 1 to 1 / 1, 15 / 1 to 1 / 1, 10 / 1 to 1 / 1, or 5 / 1 to 1 / 1. When the amine compound is a resin for solid phase synthesis, the molar ratio of the condensing agent to the amine contained in the compound bound to the resin is condensing agent / amine=20 / 1 to 1 / 1, 15 / 1 to 1 / 1, 10 / 1 to 1 / 1, or 5 / 1 to 1 / 1.

[0288] In one aspect of the present invention, the molar ratio of the uronium condensing agent to the amine compound is uronium condensing agent / amine compound=20 / 1 to 1 / 1, 15 / 1 to 1 / 1, 10 / 1 to 1 / 1, or 5 / 1 to 1 / 1. When the amine compound is a resin for solid phase synthesis, the molar ratio of the uronium condensing agent to the amine contained in the compound bound to the resin is uronium condensing agent / amine=20 / 1 to 1 / 1, 15 / 1 to 1 / 1, 10 / 1 to 1 / 1, or 5 / 1 to 1 / 1.

[0289] In one embodiment of the present invention, the amide bond forming reaction is carried out at a reaction temperature of 0° C. to 100° C., 10° C. to 80° C., 10° C. to 60° C., 15° C. to 40° C., or 20° C. to 30° C. In one aspect of the present invention, the amide bond forming reaction is carried out in a mixture containing two, three or more, or four or more carboxylic acid compounds and / or two, three or more, or four or more amine compounds as substrates.

[0290] In one aspect, the present invention provides the following: A method for producing an amide compound, comprising reacting a carboxylic acid compound and an amine compound with fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TFFH), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH), 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium hexafluorophosphate (PyClU), 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium tetrafluoroborate (TPyClU), chlorodipiperidinocarbenium hexafluorophosphate (PipClU), 2-chloro-1,3-dimethylimidazolinium chloride (DMC), 2-chloro-1,3-dimethyl the method comprising reacting imidazolinium hexafluorophosphate (CIP) with at least one condensing agent selected from the group consisting of 2-chloro-1,3-dimethylimidazolinium tetrafluoroborate (CIB), 2-chloro-1-methylpyridinium iodide, 2-bromo-1-ethylpyridinium tetrafluoroborate, and 2-fluoro-1-methylpyridinium p-toluenesulfonate in the presence of at least one first base selected from the group consisting of N-methylimidazole, tetramethylimidazole, and N-phenylimidazole to obtain an amide compound, wherein the molar ratio of the first base to the condensing agent (first base / condensing agent) is 1.5 or less.

[0291] In one aspect, the present invention provides the following: A method for producing an amide compound, comprising reacting a carboxylic acid compound and an amine compound with fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TFFH), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH), 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium hexafluorophosphate (PyClU), 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium tetrafluoroborate (TPyClU), chlorodipiperidinocarbenium hexafluorophosphate (PipClU), 2-chloro-1,3-dimethyl The method comprises reacting at least one uronium-based condensing agent selected from the group consisting of imidazolinium chloride (DMC), 2-chloro-1,3-dimethylimidazolinium hexafluorophosphate (CIP), and 2-chloro-1,3-dimethylimidazolinium tetrafluoroborate (CIB) in the presence of at least one first base selected from the group consisting of N-methylimidazole, tetramethylimidazole, and N-phenylimidazole to obtain an amide compound, wherein the molar ratio of the first base to the uronium-based condensing agent (first base / uronium-based condensing agent) is 1.5 or less.

[0292] In one aspect, the present invention provides a method for producing an amide compound, comprising reacting a carboxylic acid compound and an amine compound with a fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TFFH), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH), 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium hexafluorophosphate (PyClU), 1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium tetrafluoroborate (TPyClU), chlorodipiperidinocarbenium hexafluorophosphate (PipClU), 2-chloro-1,3-dimethylimidazolinium chloride (DMC), 2-chloro-1,3-dimethylimidazolinium hexafluorophosphate (CIP), and 2-chloro-1,3-dimethylimidazolinium tetrafluoroborate. and at least one first base selected from the group consisting of N-methylimidazole, tetramethylimidazole, and N-phenylimidazole, in the presence of at least one second base selected from the group consisting of N,N-dimethylaniline, 4-bromo-N,N-dimethylaniline, 4-fluoro-N,N-dimethylaniline, 3-bromo-N,N-dimethylaniline, 3-chloro-N,N-dimethylaniline, N,N-dimethyl-3-(trifluoromethyl)aniline, N,N,2,4,6-pentamethylaniline, julolidine, collidine, and 2,6-lutidine, to obtain an amide compound, wherein the molar ratio of the first base to the uronium-based condensing agent (first base / uronium-based condensing agent) is 1.2 or less.

[0293] In this specification, C ６－１０Examples of aryl include phenyl and naphthyl. Examples of 5-10 membered heteroaryl containing one or more ring heteroatoms independently selected from O, N, and S include pyrrolyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, triallyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, indolyl, indolinyl, benzothiophenyl, benzofuranyl, benzisothiazolyl, benzisoxazolyl, indazolyl, benzimidazolyl, benzotriazolyl, azaindolyl, and imidazopyridyl.

[0294] In this specification, a 5- to 7-membered saturated heterocycle is a saturated heterocycle having 5 to 7 ring atoms, and containing one or more heteroatoms selected from O and S as ring atoms. Examples thereof include pyrrolidine, piperidine, morpholine, thiomorpholine, and azepane.

[0295] In this specification, the term "5- to 7-membered non-aromatic heterocycle" refers to a non-aromatic heterocycle having 5 to 7 ring atoms, and includes a 5- to 7-membered saturated heterocycle. The term "5- to 7-membered non-aromatic heterocycle" includes a 5- to 7-membered saturated heterocycle in which one single bond is replaced with a double bond.

[0296] In this specification, C １－６ Alkyl is a linear or branched monovalent saturated aliphatic group having 1 to 6 carbon atoms. Specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, 1-methylpropyl, n-pentyl, isopentyl, 2-methylbutyl, 1,1-dimethylpropyl, 1-ethylpropyl, hexyl, 4-methylpentyl, and 2-ethylbutyl.

[0297] In this specification, C ２－６Alkenyl is a straight- or branched-chain monovalent group of 2 to 6 carbon atoms having one or more double bonds. Examples include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), propen-2-yl, and 3-butenyl (homoallyl).

[0298] In this specification, C ２－６ Alkynyl means a straight or branched monovalent group of 2 to 6 carbon atoms having one or more triple bonds, and includes, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl.

[0299] In this specification, C ３－８ Cycloalkyl means a cyclic saturated aliphatic hydrocarbon group having 3 to 8 carbon atoms, examples of which include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0300] In this specification, C ７－１４ Aralkyl means an alkyl substituted with an aryl having a total of 7 to 14 carbon atoms, examples of which include benzyl, 1-phenethyl, 2-phenethyl, 1-naphthylmethyl, 2-naphthylmethyl, and the like.

[0301] In this specification, C １－６ Alkoxy is C １－６ means an alkyl-O- group, where C １－６ Alkyl is as defined above. Specific examples include methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, i-butoxy, sec-butoxy, and t-butoxy.

[0302] In this specification, (C １－６ Alkoxy)carbonyl is C １－６ means an alkoxy-C(═O)— group, where C １－６ Alkoxy is as defined above. １－６ Alkyl)carbonyl is C １－６ means an alkyl-C(═O)— group, where C １－６ Alkyl is as previously defined.

[0303] In this specification, (C １－６ alkoxy)carbonylamino "(C １－６ The term "alkoxy)carbonyl" is as defined above. １－６ alkyl)amino "C １－６ "Alkyl" is as previously defined.

[0304] In this specification, di(C １－６ alkyl)amino "C １－６ The "alkyl" is as defined above and may be the same or different. In this specification, the 4- to 8-membered cyclic amino includes groups such as aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, which are bonded at a nitrogen atom.

[0305] In this specification, (C ６－１０ aryl)carbonylamino "C ６－１０ The term "aryl" is as defined above. As used herein, the term "5- to 10-membered heteroaryl containing one or more ring heteroatoms independently selected from O, N, and S" in the context of 5- to 10-membered heteroarylcarbonylamino containing one or more ring heteroatoms independently selected from O, N, and S is as defined above.

[0306] As used herein, aminocarbonyl refers to -CONH ２ (C １－６ alkyl)aminocarbonyl "C １－６ "Alkyl" is as previously defined.

[0307] In this specification, di(C １－６ alkyl)aminocarbonyl "C １－６ "Alkyl" is as defined above and may be the same or different. As used herein, the 4- to 8-membered cyclic amino of the 4- to 8-membered cyclic aminocarbonyl is as defined above, and is bonded to the carbonyl via a nitrogen atom.

[0308] In this specification, (C ６－１０ aryl)carbonyl "C ６－１０The term "aryl" is as defined above. As used herein, the term "5- to 10-membered heteroaryl containing one or more ring heteroatoms independently selected from O, N, and S" in the context of a 5- to 10-membered heteroarylcarbonyl containing one or more ring heteroatoms independently selected from O, N, and S is as defined above.

[0309] As used herein, avian (C １－６ Alkyl)silyl "C １－６ "Alkyl" is as defined above and may be the same or different. Examples thereof include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, etc.

[0310] In the present specification, the term "halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc. In the present invention, when a halogen atom is a substituent of an aryl, a heteroaryl, etc., preferred examples of the halogen atom include a fluorine atom, a chlorine atom, and a bromine atom. In the present invention, when a halogen atom is a substituent of an alkyl or a group containing an alkyl as a part thereof (alkoxy, alkenyl, alkylthio, etc.), preferred examples of the halogen atom include a fluorine atom. Specific examples of groups having a halogen atom as a substituent include trifluoromethyl, pentafluoroethyl, trifluoromethoxy, pentafluoroethoxy, trifluoromethylthio, and pentafluoroethylthio.

[0311] C optionally substituted with one or more fluorine atoms １－６ In one aspect of the present invention, the reaction time for the amide bond-forming reaction can be appropriately set by those skilled in the art, and is set within the range of, for example, 1 minute to 96 hours, 5 minutes to 72 hours, 10 minutes to 48 hours, 15 minutes to 48 hours, or 30 minutes to 24 hours.

[0312] In one embodiment of the present invention, the production method includes removing impurities after amidation. Impurity removal can be performed by a method commonly used in the technical field of the present invention. Examples of impurities include impurities derived from reaction reagents consumed in the reaction, unreacted reaction reagents, decomposition products resulting from the reaction, coexisting bases, and reaction solvents. Specific examples of impurities include condensing agents such as 2-chloro-1,3-dimethylimidazolinium hexafluorophosphate (CIP), decomposition products derived from condensing agents such as 1,3-dimethyl-2-imidazolidinone, first bases such as NMI, and second bases such as N,N-dimethylaniline. Examples of methods for removing impurities include liquid-liquid separation, distillation under reduced pressure, a method using a solid-phase reagent, purification by normal-phase or reverse-phase silica gel column chromatography, and purification by GPC (molecular sieve chromatography).

[0313] Liquid-liquid separation for removing impurities can be carried out by a method commonly used in the technical field of the present invention. Liquid-liquid separation is not particularly limited as long as it is a combination of solvents that separate into multiple layers for the purpose of separating desired products from impurities (unwanted substances). For example, liquid-liquid separation can be carried out by combining a solvent selected from ester solvents such as ethyl acetate and isopropyl acetate; ether solvents such as diethyl ether, diisopropyl ether, t-butyl methyl ether (TBME), cyclopentyl methyl ether (CPME), 2-methyltetrahydrofuran, and 4-methyltetrahydropyran; halogenated solvents such as dichloromethane, chloroform, and 1,2-dichloroethane; aromatic hydrocarbon solvents such as benzene and toluene; and hydrocarbon solvents such as hexane, cyclohexane, and heptane; with a solvent selected from water, an acidic aqueous solution such as an aqueous hydrochloric acid solution, and a basic aqueous solution such as an aqueous sodium bicarbonate solution. A single solvent may be used, or a mixture of multiple solvents may be used. Furthermore, if it is consistent with the purpose of separating desired products from impurities (unwanted substances), it can be carried out by combining organic solvents that separate into layers, such as a combination of hexane and acetonitrile.

[0314] The vacuum distillation to remove impurities can be carried out by a method commonly used in the technical field of the present invention. The vacuum distillation conditions can be appropriately set depending on the impurities to be removed. For example, the pressure may be 100 to 400 mbar, 50 to 100 mbar, 5 to 50 mbar, or 0.1 to 5 mbar, and the temperature may be 20 to 100°C, 25 to 50°C, or 35 to 45°C.

[0315] The removal of impurities using a solid-phase reagent can be carried out by a method commonly used in the technical field of the present invention, such as macroporous triethylammonium methylpolystyrene carbonate, macroporous polystyrene sulfonic acid, amine-supported silica gel, carboxylic acid-supported silica gel, etc.

[0316] In one aspect of the present invention, an amide compound-forming reaction can be carried out by reacting a solid-phase synthesis resin having a side chain containing a carboxy group as a carboxylic acid compound in a liquid containing an amine compound. In one embodiment, the amine compound is used in an excess amount relative to the carboxy groups present, for example, 2 equivalents or more, 3 equivalents or more, 5 equivalents or more, 7 equivalents or more, or 10 equivalents or more. Here, the excess amine compound can act as the second base.

[0317] In one aspect of the present invention, an amide compound-forming reaction can be carried out by reacting a solid-phase synthesis resin having a side chain containing an amino group as an amine compound in a liquid containing a carboxylic acid compound. In one embodiment, the carboxylic acid compound is used in an excess amount relative to the amino groups present, for example, 1.1 equivalents or more, 1.5 equivalents or more, 2 equivalents or more, 3 equivalents or more, 5 equivalents or more, 7 equivalents or more, or 10 equivalents or more of the carboxylic acid compound.

[0318] Conversion of a carboxyl group or amino group contained in a solid-phase synthesis resin to an amide group can be carried out using a reaction apparatus known to those skilled in the art. In one embodiment, the side chain contains a linker moiety that can be cleaved to produce a compound containing an amide group by reaction.

[0319] In one aspect of the present invention, the amide bond-forming reaction can be carried out using a solid-phase synthesis resin to which an amine compound or a carboxylic acid compound is bound via a linker as a substrate. In one embodiment, the amine compound or the carboxylic acid compound is supported via a linker on the solid-phase synthesis resin used as a solid support, and the linker moiety is decomposed under predetermined reaction conditions after the amide bond reaction to produce a compound containing an amide moiety.

[0320] The solid-phase synthesis resin used as the solid-phase support is not particularly limited as long as it is a commonly used resin. Examples include carboxylic resin, CTC resin, Trt resin, SASRIN resin, Rink amide resin, PAL AM resin, Seiber amide resin, Merrifield resin, Wang resin, 2-(4-bromomethylphenoxy)ethyl polystyrene, and solid-phase supports having any functional group on polystyrene, such as a carboxy group, an amino group, an aminomethyl group, a hydroxy group, or a hydroxymethyl group. Furthermore, any linker that covalently bonds these supports to Compound 1 or 2 may be used, allowing for cleavage between the linker and the compound. The support is also not particularly limited, and examples thereof include polystyrene and PEG (polyethylene glycol).

[0321] Techniques for binding a compound to a solid-phase synthesis resin and reaction conditions can be appropriately determined by those skilled in the art based on methods described in publicly known literature. Reaction conditions for cleaving a compound from a solid-phase synthesis resin can be appropriately determined by those skilled in the art based on the chemical structure of the solid-phase synthesis resin used. Reagents used for cleavage include, for example, hydrochloric acid, carboxylic acids such as trifluoroacetic acid (TFA), fluoroalcohols such as 2,2,2-trifluoroethanol (TFE) and 1,1,1,3,3,3-hexafluoroisopropyl alcohol (HFIP), as well as Bronsted acids with a pKa of 10 or less in water or any Lewis acid. In one embodiment, the compound cleaved from the solid-phase synthesis resin can be used as a screening compound for drug discovery.

[0322] The present invention will be described in more detail below with reference to the following reference examples and examples, but the present invention is not limited to these examples. EXAMPLES All starting materials, reagents, and solvents were obtained from commercial suppliers or synthesized using known methods. Reagents and solvents were of reagent quality or better and were used as obtained from various commercial sources unless otherwise specified.

[0323] As silica gel for column chromatography, Biotage® SNAP MLtra, Biotage® Sfaer D (Duo) (60 μm), or Biotage® Sfaer HC D (Duo) (20 μm) was appropriately used. As amino silica gel for column chromatography, Biotage® SNAP Isolute NH2 (50 μm) or Biotage® SNAP Cartridge KP-NH was appropriately used. As reverse-phase silica gel for column chromatography, Biotage® SNAP MLtra C18 (25 μm) or Biotage® Sfaer C18 (30 μm) was appropriately used.

[0324] １ H-NMR, １３ C-NMR spectra were measured using Me as an internal standard. ４ Measurements were carried out with or without Si using an appropriate instrument such as ECP-400 (manufactured by JEOL), Agilent 400-MR (manufactured by Agilent Technologies), AVANCE3 Cryo-TCI, AVANCE3 400, AVANCE3 HD 400, AVANCE NEO 400, AVANCE3 HD 300, AVANCE3 300, AVANCE2 300, or AVANCE NEO 300 (manufactured by Bruker) (s = singlet, brs = broad singlet, d = doublet, t = triplet, q = quartet, dd = double doublet, ddd = double double doublet, dt = double triplet, td = triple doublet, m = multiplet).

[0325] ​Unless otherwise specified, reaction tracking and purity measurement were performed by measuring retention times and performing mass spectrometry using 2020 (Shimadzu) under the analytical conditions shown in the table below.

[0326] The following abbreviations are used in the examples:

[0327]

[0328] The LCMS analysis conditions are shown in the table below.

[0329]

[0330] The m / z [M+H] shown in the LCMS analysis results in the examples ＋ and (M+H) ＋ Unless otherwise specified, all values ​​shown are those detected in positive mode. Furthermore, the UV area % in LCMS is the value in PDA (190-400 nm or 210-400 nm) unless otherwise specified. When a specific wavelength (e.g., 299 nm) is listed, the UV area % is shown at wavelengths up to + / - 4 nm from the listed wavelength. Blank cells in the tables indicate values ​​below the detection limit.

[0331] The term "concentrated under reduced pressure" refers to removal of solvent by evaporation under reduced pressure using a rotary evaporator, a mechanical oil vacuum pump, or a mechanical oil-free vacuum pump. The term "dried overnight under reduced pressure" refers to removal of solvent by evaporation under reduced pressure using a rotary evaporator, a mechanical oil vacuum pump, or a mechanical oil-free vacuum pump.

[0332] The terms "overnight" and "overnight" refer to approximately 8 to 14 hours unless otherwise specified. The terms "room temperature" and "rt" refer to approximately 20 to 25°C unless otherwise specified. The solid-phase reaction can be carried out in any appropriate container, such as a glass vial that can be sealed with a cap equipped with Teflon (registered trademark) packing, a fritted filter, and a column with an appropriate stopper. The size of the container is appropriately selected so that there is sufficient space for the solvent and that there is enough room for effective stirring of the resin, taking into consideration that certain resins may swell significantly when treated with organic solvents.

[0333] Agitation in solid-phase reactions was carried out at 50-200 rpm using a suitable shaker (e.g., EYELA MMS-320, MMS-220H, Tokyo Rika Kikai Co., Ltd., or MyBL-100CS, AS ONE, or M-BR-104, TAITEC) or a stirring device (a combination of a separable flask, manufactured by Asahi Seisakusho Co., Ltd., and a sealing mixer UZU, manufactured by Nakamura Scientific Instruments Co., Ltd., and a centrifugal stirrer C-mix, manufactured by Aquatex Co., Ltd.) to ensure sufficient mixing, a factor generally recognized as important for the success of reactions on resins.

[0334] To monitor the progress of the reaction on the solid phase, the resin must be removed from the reaction vessel. To do so, a micropipette equipped with a pipette tip cut to an appropriate length was used to aspirate approximately 10 μL of resin, ensuring that the resin was included. The resin was then transferred onto the filter of a filter-equipped pipette tip (e.g., Thermo Scientific, ART Filter Tip ART20P, 2149P-05). The resin-supported compound was then cleaved from the resin using the following typical procedure for resin on a filter: After washing three times with DMF (0.1 mL), three times with MeOH (0.1 mL), and three times with DCM (0.1 mL), the resin was immersed in 0.02 M pentamethylbenzene in 10% TFA / DCM (0.05 mL) for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), MeCN (0.25 mL) was added to the filtrate, an LC sample was prepared, and the reaction progress was measured by LCMS measurement.

[0335] The term "cleavage" from the solid phase refers to the desorption of a compound supported on the resin from the resin, for example, by treating the resin with a 10% TFA / DCM solution containing 0.02 M pentamethylbenzene, and recovering the supported compound in solution.

[0336] The compound numbers used in the examples are indicated by a combination of arbitrary letters, numbers, and symbols. Compounds supported on a solid phase are indicated by adding an "R" to the end, for example, "A02-1R." In contrast, compounds cleaved from the solid phase are indicated by "A02," omitting the "-1R."

[0337] Used in the chemical structure notation in the examples:

[0338] The notation indicates a polystyrene resin, and indicates that the compound is supported on a solid phase.

[0339] In the examples, the number in "-1R" indicates that the compound is supported on a solid phase, and indicates the lot of the resin used.

[0340] Example of "-1R"

[0341]

[0342] The amount of supported solid-phase compounds used in solid-phase synthesis is shown as a supported amount (mmol / g), which is calculated assuming that 100% of the extracted compound is supported on the solid phase.

[0343] Even when the compound supported on the solid phase is the same, the amount supported may differ depending on the lot, but the same compound number may be used.

[0344] Example 1: Substrate synthesis Example 1-1: Synthesis of solid-phase carboxylic acid compound Example 1-1-1: Synthesis of compound D03-1R

[0345]

[0346] Amidation Reaction: Under a nitrogen atmosphere, carboxylic resin (D01-1R) (2.19 mmol / g, 12.0 g) and NMP (120 mL) were added to two 150 mL glass vials and shaken at room temperature for 1 hour. Ethyl 4-[4-[(4-piperidin-4-yloxyphenyl)methoxy]phenyl]benzoate (B08) (1.28 g, 2.96 mmol), piperidine (2.08 mL, 21.0 mmol), HOAt (3.58 g, 26.3 mmol), and DIC (4.09 mL, 26.3 mmol) were added to each vial and shaken at 40°C for 3 days. Piperidine (5.20 mL, 52.6 mmol), HOAt (7.15 g, 52.6 mmol), and DIC (8.19 mL, 52.6 mmol) were added to each vial, and the mixture was shaken at room temperature overnight.

[0347] The reaction solution and the solid phase suspension in the two vials were all transferred to a 400 mL filter-equipped column, washed three times with NMP (240 mL), three times with MeOH (240 mL), and three times with DCM (240 mL), and the obtained solid phase was dried under reduced pressure to obtain compound D02-1R (loading amount 0.200 mmol / g).

[0348] Hydrolysis: Under a nitrogen atmosphere, the entire amount of compound D02-1R obtained, THF (360 mL), MeOH (40 mL), and aqueous KOH solution (5 M, 40 mL, 200 mmol) were added to an 800 mL filter column and shaken at 50 °C for 21 hours. A portion of the reaction solution and solid phase suspension was transferred onto a filter tip and washed three times with NMP (0.1 mL), three times with MeOH (0.1 mL), and three times with DCM (0.1 mL). The column was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 5 minutes, filtered, and the filtrate was diluted with NMP (0.25 mL). The reaction progress was measured by LCMS measurement of a solution 50 μL of which was diluted with MeCN (0.25 mL). As a result, 100% D03 was observed. However, the analysis was performed by cutting out at a wavelength of 290 nm (±4 nm).

[0349] Furthermore, the reaction solution and the solid phase suspension were all filtered through a column filter, and the filtered solution was washed three times with water (500 mL), three times with a solution of HOAt in NMP (0.2 M, 500 mL), three times with NMP (500 mL), three times with MeOH (500 mL), and three times with DCM (500 mL). The obtained solid phase was dried under reduced pressure to obtain compound D03-1R (0.201 mmol / g, 28.7 g).

[0350]

[0351] Compound D03 Maximum wavelength: 294 nm Retention time: 0.773 minutes (Analysis conditions FA05-1)

[0352] Example 1-1-2: Synthesis of compound D05-1R

[0353]

[0354] Amidation Reaction: Under a nitrogen atmosphere, compound D03-1R (0.201 mmol / g, 1.00 g) and NMP (15 mL) were added to a 20 mL filter column and shaken at room temperature for 1 hour. Methyl 3-amino-2,6-dimethylbenzoate (B09) (72.0 mg, 0.402 mmol), NMI (64.0 μL, 0.804 mmol), and PyClU (0.134 g, 0.402 mmol) were added and shaken at room temperature for 18 hours. A 10 μL aliquot of the reaction mixture and solid phase suspension was transferred onto a filter tip and washed three times with NMP (0.1 mL), three times with MeOH (0.1 mL), and three times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 5 minutes, filtered, and washed with NMP (0.1 mL). 50 μL of the combined filtrate was diluted with MeCN (0.25 mL) and the reaction progress was measured by LCMS. As a result, 100% D04 was observed. However, analysis was performed by cutting out at a wavelength of 290 nm (±4 nm).

[0355] Furthermore, the reaction solution and the solid phase suspension were all filtered through a column filter, washed twice with NMP (15 mL), three times with MeOH (15 mL), and three times with DCM (15 mL), and the obtained solid phase was dried under reduced pressure to obtain compound D04-1R (0.195 mmol / g, 1.01 g).

[0356] Hydrolysis: Under a nitrogen atmosphere, the entire amount of compound D04-1R obtained, THF (12 mL), MeOH (1.5 mL), and aqueous NaOH (5 M, 1.5 mL, 7.5 mmol) were added to a 20 mL filter column and shaken at 50 °C for 22 hours. The reaction mixture and solid phase suspension were filtered through the column filter and washed three times with water (15 mL), three times with a solution of HOAt in NMP (0.2 M, 15 mL), three times with NMP (15 mL), three times with MeOH (15 mL), and three times with DCM (15 mL). The resulting solid phase was dried under reduced pressure. THF (12 mL), MeOH (1.5 mL), and aqueous NaOH (5 M, 1.5 mL, 7.5 mmol) were added, and the mixture was shaken at 50 °C for 16 hours. Potassium trimethylsilanolate (0.759 g, 5.92 mmol) was added and the mixture was shaken at room temperature for 20 hours. Potassium trimethylsilanolate (0.759 g, 5.92 mmol) was added and the mixture was shaken at 60°C for 18 hours and then at 80°C for 2 days. A 10 μL aliquot of the reaction mixture and solid phase suspension was transferred onto a filter tip and washed three times with NMP (0.1 mL), three times with MeOH (0.1 mL), and three times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.2 M, 0.05 mL) for 5 minutes, filtered, washed with NMP (0.05 mL), and the combined filtrate was diluted with NMP (250 μL). A 50 μL aliquot was diluted with MeCN (0.25 mL) and the reaction progress was measured by LCMS. As a result, D05 was observed at 83%. However, the analysis was performed by cutting out at a wavelength of 290 nm (±4 nm).

[0357] Furthermore, the reaction solution and the solid phase suspension were all filtered through a column filter, and washed three times with water (15 mL), three times with a solution of HOAt in NMP (0.2 M, 15 mL), three times with NMP (15 mL), three times with MeOH (15 mL), and three times with DCM (15 mL). The obtained solid phase was dried under reduced pressure to obtain compound D05-1R (0.195 mmol / g).

[0358]

[0359] Compound D04 LRMS: m / z 376 [M+H] ＋ Retention time: 1.021 minutes (Analysis conditions FA05-1)

[0360]

[0361] Compound D05 LRMS: m / z 362 [M+H] ＋ Retention time: 0.849 minutes (Analysis conditions FA05-1)

[0362] Example 1-1-3: Synthesis of compound D07-1R

[0363]

[0364] Amidation Reaction: Under a nitrogen atmosphere, compound D03-1R (0.201 mmol / g, 1.00 g) and NMP (15 mL) were added to a 20 mL filter column and shaken at room temperature for 1 hour. Methyl 3-amino-4-piperidin-1-ylbenzoate (B10) (94.0 mg, 0.402 mmol), NMI (64.0 μL, 0.804 mmol), and PyClU (0.134 g, 0.402 mmol) were added, and the column was shaken at room temperature for 18 hours. A 10 μL aliquot of the reaction mixture and solid phase suspension was transferred onto a filter tip and washed three times with NMP (0.1 mL), three times with MeOH (0.1 mL), and three times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 5 minutes, filtered, and washed with NMP (0.1 mL). 50 μL of the combined filtrate was diluted with MeCN (0.25 mL) and the reaction progress was measured by LCMS. As a result, 100% D06 was observed. However, analysis was performed by cutting out at a wavelength of 299 nm (±4 nm).

[0365] Furthermore, the reaction solution and the solid phase suspension were all filtered through a column filter, washed twice with NMP (15 mL), three times with MeOH (15 mL), and three times with DCM (15 mL), and the obtained solid phase was dried under reduced pressure to obtain compound D06-1R (0.193 mmol / g, 1.02 g).

[0366] Hydrolysis: Under a nitrogen atmosphere, the entire amount of compound D06-1R obtained, THF (12 mL), MeOH (1.5 mL), and aqueous NaOH (5 M, 1.5 mL, 7.5 mmol) were added to a 20 mL filter column and shaken at 50 °C for 22 hours. 10 μL of the reaction mixture and solid phase suspension was transferred onto a filter tip and washed three times with NMP (0.1 mL), three times with MeOH (0.1 mL), and three times with DCM (0.1 mL). The column was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.2 M, 0.05 mL) for 5 minutes, filtered, washed with NMP (0.05 mL), and the combined filtrate was diluted with NMP (250 μL). The reaction progress was measured by LCMS analysis of a solution of 50 μL diluted with MeCN (0.25 mL). As a result, 84% D07 was observed. The analysis was performed using a wavelength of 299 nm (±4 nm). The reaction mixture and the solid phase suspension were all filtered through a column filter and washed three times with water (15 mL), three times with a solution of HOAt in NMP (0.2 M, 15 mL), three times with NMP (15 mL), three times with MeOH (15 mL), and three times with DCM (15 mL). The resulting solid phase was dried under reduced pressure to obtain compound D07-1R (0.193 mmol / g).

[0367]

[0368] Compound D06 LRMS: m / z 431 [M+H] ＋ Retention time: 1.330 minutes (Analysis conditions FA05-1)

[0369]

[0370] Compound D07 LRMS: m / z 417 [M+H] ＋ Retention time: 1.120 minutes (Analysis conditions FA05-1)

[0371] Example 1-1-4: Synthesis of compound D09-1R

[0372]

[0373] Amidation Reaction: Under a nitrogen atmosphere, compound D03-1R (0.201 mmol / g, 1.00 g) and NMP (15 mL) were added to a 20 mL filter column and shaken at room temperature for 1 hour. 4-(4-bromophenyl)piperidine-4-carboxylate methyl hydrochloride (B11) (135 mg, 0.402 mmol), NMI (64.0 μL, 0.804 mmol), DIPEA (70.0 μL, 0.402 mmol), and PyClU (0.134 g, 0.402 mmol) were added and shaken at room temperature for 18 hours. A 10 μL aliquot of the reaction mixture and solid phase suspension was transferred onto a filter tip and washed three times with NMP (0.1 mL), three times with MeOH (0.1 mL), and three times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 5 minutes, filtered, and washed with NMP (0.1 mL). 50 μL of the combined filtrate was diluted with MeCN (0.25 mL) and the reaction progress was measured by LCMS. As a result, 100% D08 was observed. However, analysis was performed by cutting out at a wavelength of 290 nm (±4 nm).

[0374] Furthermore, the reaction solution and the solid phase suspension were all filtered through a column filter, washed twice with NMP (15 mL), three times with MeOH (15 mL), and three times with DCM (15 mL), and the obtained solid phase was dried under reduced pressure to obtain compound D08-1R (0.190 mmol / g, 1.04 g).

[0375] Hydrolysis: Under a nitrogen atmosphere, the entire amount of compound D08-1R obtained, THF (12 mL), MeOH (1.5 mL), and aqueous NaOH (5 M, 1.5 mL, 7.5 mmol) were added to a 20 mL filter column and shaken at 50 °C for 22 hours. 10 μL of the reaction mixture and solid phase suspension was transferred onto a filter tip and washed three times with NMP (0.1 mL), three times with MeOH (0.1 mL), and three times with DCM (0.1 mL). The column was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.2 M, 0.05 mL) for 5 minutes, filtered, washed with NMP (0.05 mL), and the combined filtrate was diluted with NMP (250 μL). The reaction progress was measured by LCMS analysis of a solution of 50 μL diluted with MeCN (0.25 mL). As a result, 96% D09 was observed. However, the analysis was performed by cutting out at a wavelength of 290 nm (±4 nm).

[0376] Furthermore, the reaction solution and the solid phase suspension were all filtered through a column filter, and washed three times with water (15 mL), three times with a solution of HOAt in NMP (0.2 M, 15 mL), three times with NMP (15 mL), three times with MeOH (15 mL), and three times with DCM (15 mL). The obtained solid phase was dried under reduced pressure to obtain compound D09-1R (0.193 mmol / g).

[0377]

[0378] Compound D08 LRMS: m / z 494,496 [M+H] ＋ Retention time: 1.198 minutes (Analysis conditions FA05-1)

[0379]

[0380] Compound D09 LRMS: m / z 480,482 [M+H] ＋ Retention time: 1.028 minutes (Analysis conditions FA05-1)

[0381] Example 1-1-5: Synthesis of compound D10-1R

[0382]

[0383] Under a nitrogen atmosphere, 2.00 g of carboxylic resin (D01-1R) (2.19 mmol / g) and 30 mL of NMP were added to a 60 mL glass vial and shaken at room temperature for 1 hour. 4-[4-[(4-bromophenoxy)methyl]phenoxy]piperidine (B15) (176 mg, 0.486 mmol), piperidine (0.217 mL, 2.19 mmol), HOAt (0.656 g, 4.82 mmol), and DIC (0.751 mL, 4.82 mmol) were added and shaken at room temperature for 21 hours. 0.867 mL, 8.76 mmol), HOAt (1.19 g, 8.76 mmol), and DIC (1.37 mL, 8.76 mmol) were added and shaken at room temperature for 14 hours. 10 μL of the reaction solution and solid phase suspension was transferred onto a filter tip and washed three times with NMP (0.1 mL), three times with methanol (0.1 mL), and three times with DCM (0.1 mL). The chip was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.02 M, 0.05 mL) for 5 minutes, filtered, and washed with NMP (0.05 mL). The combined filtrate was diluted with MeCN (0.25 mL) and the reaction progress was measured by LCMS. As a result, 100% D10 was observed. However, analysis was performed by cutting out at a wavelength of 280 nm (± 4 nm).

[0384] Furthermore, the reaction solution and the suspension of the solid phase were all transferred onto a filter and washed three times with NMP (30 mL), three times with methanol (30 mL), and three times with DCM (30 mL). The obtained solid phase was dried overnight under reduced pressure to obtain compound D10-1R (loading amount 0.200 mmol / g, 2.87 g).

[0385]

[0386] Compound D10 Maximum wavelength: 226,281 nm. Retention time: 0.880 minutes (Analysis conditions FA05-1)

[0387] Example 1-1-6: Synthesis of compound D11-1R

[0388]

[0389] Compound D10-1R (0.200 mmol / g, 1.05 g) and NMP (21.0 mL) were placed in a 30 mL glass vial under a nitrogen atmosphere and shaken at room temperature for 1 hour. Bis(pinacolato)diboron (CAS No.: 73183-34-3) (1.07 g, 4.20 mmol), potassium acetate (618 mg, 6.30 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (CAS No.: 95464-05-4) (171 mg, 0.21 mmol) were added, and the mixture was shaken at 80°C for 2 hours.

[0390] 12 μL of the reaction solution and solid phase suspension was transferred onto a filter tip and washed three times with NMP (0.1 mL), three times with MeOH (0.1 mL), and three times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.02 M, 0.05 mL) for 5 minutes, filtered, and washed with NMP (0.05 mL). The combined filtrate was diluted with MeCN (0.25 mL) and the reaction progress was measured by LCMS. As a result, 99.4% of D11 was observed. However, the analysis was performed by cutting out at a wavelength of 250 nm (± 4 nm).

[0391] Furthermore, a suspension of the reaction solution and solid phase was transferred onto a filter using NMP (60 mL), and the filter was washed three times with NMP (21 mL), three times with NMP / water=1 / 1 (21 mL), three times with water (21 mL), three times with NMP / water=1 / 1 (21 mL), three times with NMP (21 mL), three times with methanol (21 mL), three times with DCM (21 mL), and three times with heptane (21 mL). The obtained solid phase was dried overnight under reduced pressure to obtain compound D11-1R (loading amount 0.198 mmol / g, 1.13 g).

[0392]

[0393] Compound D11 Maximum wavelength: 238 nm Retention time: 0.999 minutes (Analysis conditions FA05-1)

[0394] Example 1-1-7: Synthesis of compound D12-1R

[0395] Compound D11-1R (0.198 mmol / g, 509 mg), 4-bromo-2,6-dimethylbenzoic acid (A06) (69.3 mg, 0.302 mmol), and THF (7.64 mL) were added to a 20 mL glass vial under a nitrogen atmosphere and shaken at room temperature for 1 hour. Water (27.2 μL, 1.51 mmol), cataCXium Pd G4 (CAS No.: 2230788-67-5, Aldrich Product No.: 900349) (37.4 mg, 50.0 μmol), and P2tBu / THF solution (2.0 M, 0.227 mL, 0.454 mmol) were added, and the mixture was shaken at 60°C for 1 hour.

[0396] The suspension of the reaction solution and solid phase was transferred onto two filters using NMP, and each filter was washed three times with NMP (5 mL), three times with a solution of N-acetylcysteine ​​in NMP / water = 5 / 1 (0.2 M, 5 mL), three times with NMP (5 mL), three times with MeOH (5 mL), three times with DCM (5 mL), and three times with heptane (5 mL). The obtained solid phase was dried under reduced pressure overnight to obtain compound D12-1R (loading amount 0.198 mmol / g, 485 mg).

[0397] A portion of compound D12-1R was washed three times with DCM (0.10 mL), immersed in a 0.05 M pentamethylbenzene 10% TFA / DCM solution (0.05 M, 0.05 mL) for 5 minutes, filtered, and washed with NMP (0.10 mL). The combined filtrate was diluted with MeCN (0.25 mL) and subjected to LCMS measurement, whereby 97.3% of the target compound D12 was observed. However, the analysis was performed by cutting out at a wavelength of 270 nm (± 4 nm).

[0398]

[0399] Compound D12 LRMS: m / z 225 [M+H] ＋ Retention time: 0.823 minutes (Analysis conditions FA05-1)

[0400] Example 1-2: Synthesis of solid phase amine compound Example 1-2-1: Synthesis of compound F01-1R

[0401]

[0402] Under a nitrogen atmosphere, compound D03-1R (0.201 mmol / g, 1.00 g) and NMP (15 mL) were placed in a 20 mL glass vial and shaken at room temperature for 1 hour. 3-(aminomethyl)aniline (B12) (197 mg, 1.61 mmol), Oxyma (229 mg, 1.61 mmol), and DIC (252 μL, 1.61 mmol) were added, and the mixture was shaken at room temperature for 15 hours.

[0403] The reaction solution and the solid phase suspension were all transferred to a filter-equipped column, filtered, and then washed three times with NMP (15 mL), three times with MeOH (15 mL), and three times with DCM (15 mL). The resulting solid phase was dried under reduced pressure to obtain compound F01-1R (0.197 mmol / g, 1.01 g). A portion of compound F01-1R was transferred onto a filter-equipped chip and washed with DCM (0.1 mL). The chip was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.02 M, 0.05 mL) for 5 minutes, filtered, washed with NMP (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) and analyzed by LCMS. 97% of F01 was observed. However, the analysis was performed by cutting out at a wavelength of 290 nm (± 4 nm).

[0404]

[0405] Compound F01 LRMS: m / z 319 [M+H] ＋ Retention time: 0.708 minutes (analysis conditions: RPamide TFA05) Example 1-2-2: Synthesis of compound F02-1R

[0406]

[0407] Under a nitrogen atmosphere, compound D03-1R (0.201 mmol / g, 1.00 g) and NMP (15 mL) were added to a 20 mL glass vial and shaken at room temperature for 1 hour. 3-((methylamino)methyl)aniline (B13) (219 mg, 1.61 mmol), Oxyma (229 mg, 1.61 mmol), and DIC (252 μL, 1.61 mmol) were added, and the mixture was shaken at room temperature for 15 hours.

[0408] The reaction mixture and the solid phase suspension were transferred to a filter-equipped column, filtered, and washed three times with NMP (15 mL), three times with MeOH (15 mL), and three times with DCM (15 mL). The resulting solid phase was dried under reduced pressure to obtain compound F02-1R (0.196 mmol / g, 1.05 g). A portion of compound F02-1R was transferred onto a filter-equipped chip and washed with DCM (0.1 mL). The chip was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.02 M, 0.05 mL) for 5 minutes, filtered, washed with NMP (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) and analyzed by LCMS. 98% of F02 was observed. However, the analysis was performed by cutting out at a wavelength of 290 nm (± 4 nm).

[0409]

[0410] Compound F02 LRMS: m / z 333 [M+H] ＋ Retention time: 0.723 minutes (Analysis conditions RPAmideTFA05)

[0411] Example 1-2-3: Synthesis of compound F04-1R

[0412]

[0413] Under a nitrogen atmosphere, compound D03-1R (0.201 mmol / g, 100 mg) and NMP (1.5 mL) were added to each of 24 4 mL glass vials and shaken at room temperature for 1 hour. An NMP solution of piperazine-1-allyl carboxylate (B14) (0.4 M, 101 μL, 0.040 mmol), an NMP solution of NMI (0.8 M, 101 μL, 0.080 mmol), and an NMP solution of PyClU (0.4 M, 101 μL, 0.04 mmol) were added to each vial and shaken at room temperature for 3 hours.

[0414] The reaction mixture and the solid suspension were transferred to 24 filter columns using NMP, filtered, washed twice with NMP (2 mL), three times with MeOH (2 mL), three times with DCM (2 mL), and three times with heptane (2 mL), and the resulting solid was dried under reduced pressure. All the solids were combined to give compound F03-1R (0.195 mmol / g, 2.64 g).

[0415] Under a nitrogen atmosphere, compound F03-1R (0.195 mmol / g, 108 mg), a 1,2-dichloroethane solution of pyrrolidine (1 M, 0.632 mL, 0.632 mmol), and 1,2-dichloroethane (0.864 mL) were placed in a 4 mL glass vial and shaken at room temperature for 1 hour. A 1,2-dichloroethane solution of tetrakis(triphenylphosphine)palladium(0) (0.1 M, 10.5 μL, 1.05 μmol) was added, and the mixture was shaken at room temperature for 7.5 hours.

[0416] 10 μL of the reaction mixture and solid phase suspension was transferred onto a filter tip and washed three times with NMP (0.1 mL), three times with MeOH (0.1 mL), and three times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.02 M, 0.05 mL) for 5 minutes, filtered, washed with NMP (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) to measure the reaction progress by LCMS. As a result, 98% of F04 was observed. However, the analysis was performed by cutting out at a wavelength of 290 nm (± 4 nm).

[0417] The reaction mixture and solid suspension were transferred to a filter column and filtered. The mixture was washed three times with NMP (2 mL), three times with a 0.3 M N-acetyl-L-cysteine ​​solution in NMP / water (5 / 1), three times with a 0.2 M DIPEA solution in NMP (2 mL), three times with NMP (2 mL), three times with MeOH (2 mL), three times with DCM (2 mL), and three times with heptane (2 mL). The solid was then dried under reduced pressure. The entire solid phase was combined to give compound F04-1R (0.198 mmol / g, 105 mg).

[0418]

[0419] Compound F04 LRMS: m / z 283 [M+H] ＋ Retention time: 0.549 minutes (Analysis conditions FA05-1)

[0420] Example 1-2-4: Synthesis of compound F06-1R

[0421] Compound D03-1R (0.201 mmol / g, 1.00 g) and DCM (15 mL) were added to a 30 mL glass vial under a nitrogen atmosphere and shaken at room temperature for 1 hour. tert-Butyl N-methyl-N-piperidin-4-ylcarbamate (B29) (86 mg, 0.402 mmol), NMI (63.5 μL, 0.804 mmol), DIPEA (70.2 μL, 0.402 mmol), and PipClU (0.145 g, 0.402 mmol) were added and shaken at room temperature for 3.5 hours. A 12 μL aliquot of the reaction mixture and solid phase suspension was transferred onto a filter tip and washed three times with DMF (0.1 mL), three times with MeOH (0.1 mL), and three times with DCM (0.1 mL). The reaction mixture was immersed in a 10% TFA / DCM solution (0.10 M, 0.05 mL) of pentamethylbenzene for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) and analyzed by LCMS. As a result, 93% of F05 was observed. However, analysis was performed by cutting out at a wavelength of 299 nm (±4 nm).

[0422] Furthermore, a suspension of the reaction solution and solid phase was transferred onto a filter using NMP (20 mL), and washed three times with NMP / water=1 / 1 (20 mL), three times with NMP (20 mL), three times with methanol (20 mL), three times with DCM (20 mL), and three times with heptane (20 mL). The obtained solid phase was dried overnight under reduced pressure to obtain compound F05-1R (loading amount 0.194 mmol / g, 1.18 g).

[0423] Under a nitrogen atmosphere, compound F05-1R (0.194 mmol / g, 1.11 g) and 2-methyltetrahydrofuran (22 mL) were added to a 30 mL glass vial and shaken at room temperature for 1 hour. Tin(II) trifluoromethanesulfonate (CAS number: 62086-04-8) (1.12 g, 2.68 mmol) and 2,6-lutidine (468 μL, 4.02 mmol) were added, and the mixture was shaken at 80°C for 14.5 hours. A solution of 4,4'-di-tert-butyl-2,2'-bipyridine in NMP (0.1 M, 6.0 mL) was added to the reaction mixture, and the mixture was shaken at room temperature for 1.5 hours.

[0424] 12 μL of the reaction mixture and solid phase suspension was transferred onto a filter tip and washed three times with DMF (0.1 mL), three times with MeOH (0.1 mL), and three times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.10 M, 0.05 mL) for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) to measure the reaction progress by LCMS. As a result, 99% of F06 was observed. However, the analysis was performed by cutting out at a wavelength of 299 nm (± 4 nm).

[0425] The reaction mixture and the solid phase suspension were transferred to a filter column and filtered, and then washed three times with a 2,2'-bipyridine NMP solution (0.1 M, 22 mL), three times with NMP (22 mL), and three times with TBAHSO ４ The solid phase was washed three times with an NMP solution (0.05 M, 22 mL) of a mixture of tetrabutylammonium hydrogen sulfate (BTMG) and DTBP (2,6-di-tert-butylpyridine), three times with an NMP solution (0.05 M, 22 mL) of BTMG (2-tert-butyl-1,1,3,3-tetramethylguanidine), three times with an NMP solution (0.05 M, 22 mL), three times with an NMP solution of DTBP (0.05 M, 22 mL), three times with NMP / water = 1 / 1 (22 mL), three times with NMP (22 mL), three times with MeOH (22 mL), three times with DCM (22 mL), and three times with heptane (22 mL), and the resulting solid phase was dried under reduced pressure to obtain compound F06-1R (loading amount 0.197 mmol / g, 1.11 g).

[0426]

[0427] Compound F05 LRMS: m / z 411 [M+H] ＋ Retention time: 1.057 minutes (Analysis conditions FA05-1)

[0428]

[0429] Compound F06 LRMS: m / z 311 [M+H] ＋ Retention time: 0.537 minutes (Analysis conditions FA05-1)

[0430] Example 2: Amidation reaction in liquid phase Example 2-1: Investigation of amidation conditions Example 2-1-1: Investigation of amidation conditions for 1 equivalent of amine substrate (3-aminobiphenyl (B01)) and 3 equivalents of carboxylic acid (2,6-dimethylbenzoic acid (A01))

[0431]

[0432] Under a nitrogen atmosphere, 3-aminobiphenyl (B01) (3.4 mg, 0.020 mmol, 1 eq.) and 2,6-dimethylbenzoic acid (A01) (9.0 mg, 0.060 mmol, 3 eq.) were added to a 0.6 mL glass vial. For Runs 1, 3, and 5 to 9, DCM (0.1 mL) and MeCN (0.1 mL) were added. For Runs 2 and 4, DCM (0.2 mL) and MeCN (0.2 mL) were added. A first base, a second base, and a condensing agent listed in Table 2-1-1 were added, and the mixture was shaken at room temperature for the reaction time listed in the table. However, for Runs 1, 3, and 6 to 9, the condensing agent was added as a DCM / MeCN = 1 / 1 solution (0.2 M). For Run 5, DCM (0.1 mL) and MeCN (0.1 mL) were further added. A portion of the reaction mixture was dispensed and subjected to LCMS measurement to measure the reaction progress. The results are shown in Table 2-1-1. However, the yield in Table 2-1-1 is calculated assuming the total of identified peaks excluding peaks not attributable to B01 as 100%. Analysis was also performed by cutting out at a wavelength of 305 nm (±95 nm).

[0433]

[0434] The above results demonstrate that the yield is higher under conditions in which 1 equivalent of the first base (NMI or 1-phenylimidazole) is used relative to the haluronium-based condensing agent (PyC1U or CIP) and a second base (N,N-dimethylaniline or N,N-dimethyl-3-(trifluoromethyl)aniline) is added (Runs 3, 6, and 8) than under conditions in which 4.5 equivalents of a base (NMI, 1-phenylimidazole, N,N-dimethylaniline, or DIPEA) is used relative to the haluronium-based condensing agent (PyC1U or CIP) (Runs 1, 2, 4, 5, and 7).

[0435]

[0436] Compound C0101 LRMS: m / z 302 [M+H] ＋ Retention time: 1.287 minutes (Analysis conditions FA05-1) Retention time: 2.799 minutes (Analysis conditions FA05-long)

[0437] Example 2-1-2: Investigation of amidation conditions for 1 equivalent of carboxylic acid substrate (2,6-dimethylbenzoic acid (A01)) and 2 equivalents of amine (aniline (B02))

[0438]

[0439] Under a nitrogen atmosphere, 2,6-dimethylbenzoic acid (A01) (3.0 mg, 0.020 mmol, 1 eq.), aniline (B02) (3.7 mg, 0.040 mmol, 2 eq.), DCM (0.1 mL), and MeCN (0.1 mL) were added to a 0.6 mL glass vial. The first base, second base, and condensing agent listed in Table 2-1-2 were added, and the mixture was shaken at room temperature for 24 hours. However, the condensing agent was added as a DCM / MeCN = 1 / 1 solution (0.2 M). A portion of the reaction solution was dispensed, and the reaction progress was measured by LCMS measurement. The results are shown in Table 2-1-2. However, the yield in Table 2-1-2 is calculated by assuming the total of identified peaks excluding peaks not attributable to A01 as 100%. In addition, the analysis was performed by cutting out at a wavelength of 270 nm (±4 nm).

[0440]

[0441] The above results indicate that the yield was higher under the conditions (Runs 4, 5, 7, 8) in which the amount of the first base (NMI) used relative to the haluronium-based condensing agent (PyC1U) was 0.8 to 1.0 equivalent and a second base (N,N-dimethylaniline or N,N-dimethyl-3-(trifluoromethyl)aniline) was added than under the conditions (Runs 1, 2, 3, 6) in which 2 equivalents of a base (NMI, N,N-dimethylaniline, DIPEA, N,N-dimethyl-3-(trifluoromethyl)aniline) relative to the haluronium-based condensing agent (PyC1U).

[0442]

[0443] Compound C0102 LRMS: m / z 226 [M+H] ＋ Retention time: 1.043 minutes (Analysis conditions FA05-1)

[0444] Example 2-1-3: Investigation of amidation conditions for 1 equivalent of amine substrate (3-aminobiphenyl (B01)) and 3 equivalents of carboxylic acid (2,6-dimethylbenzoic acid (A01))

[0445]

[0446] Under a nitrogen atmosphere, 3-aminobiphenyl (B01) (3.4 mg, 0.020 mmol, 1 eq.), 2,6-dimethylbenzoic acid (A01) (9.0 mg, 0.060 mmol, 3 eq.), DCM (0.2 mL), and MeCN (0.2 mL) were added to a 0.6 mL glass vial. The first base, second base, and condensing agent listed in Table 2-1-3 were added, and the mixture was shaken at room temperature for the reaction time listed in the table. A portion of the reaction solution was dispensed, and the reaction progress was measured by LCMS analysis. The results are shown in Table 2-1-3. However, the yield in Table 2-1-3 is calculated assuming the total of identified peaks excluding those not attributable to B01 as 100%. Furthermore, the analysis was performed by cutting out the peaks at a wavelength of 305 nm (±95 nm).

[0447]

[0448] The above results indicate that, as described in Non-Patent Document 3, the conditions in which 1 equivalent of the first base (NMI) is used relative to the haluronium condensing agent (TCFH) or the Mukaiyama reagent (2-halo-N-alkylpyridinium salt) (BEP) and a second base (N,N-dimethylaniline) is added (Runs 3, 4, and 6) provide a higher yield than the conditions in which 4.5 equivalents of the base (NMI) are used relative to the haluronium condensing agent (TCFH) or the Mukaiyama reagent (2-halo-N-alkylpyridinium salt) (BEP) (Runs 1, 2, and 5).

[0449] Reference Example: Amidation reaction of 2,6-dimethylbenzoic acid (A01) and 3-aminobiphenyl (B01) using a BTFFH / DIPEA system (conditions in Non-Patent Document 2)

[0450]

[0451] Under a nitrogen atmosphere, 2,6-dimethylbenzoic acid (A01) (3.9 mg, 0.026 mmol, 1.3 eq.) and DCM (0.2 mL) were added to a 0.6 mL glass vial. BTFFH (9.5 mg, 0.030 mmol, 1.5 eq.) and DIPEA (15.7 μL, 0.090 mmol, 4.5 eq.) were added and the mixture was shaken at room temperature for 1 hour. A solution of 3-aminobiphenyl (B01) (3.4 mg, 0.020 mmol, 1 eq.) in DCM (0.2 mL) was added and the mixture was shaken at 80°C for 24 hours. A portion of the reaction mixture was dispensed and the reaction progress was measured by LCMS. As a result, 4% of the target product (C0101), 63% of the raw material (B01), and 33% of a by-product thought to be the reaction between the raw material (B01) and the condensing agent BTFFH were observed. However, the yield was calculated assuming the total of identified peaks excluding peaks not attributable to B01 as 100%. Analysis was also performed by cutting out at a wavelength of 305 nm (±95 nm).

[0452] This result indicates that the amidation reaction between 2,6-dimethylbenzoic acid (A01) and 3-aminobiphenyl (B01) cannot be carried out efficiently in the BTFFH / DIPEA system (conditions in Non-Patent Document 2).

[0453] Example 2-2: Investigation of the range of application of haluronium-based condensing agents, first bases, and second bases Example 2-2-1: Investigation of the range of application of haluronium-based condensing agents, first bases, and second bases in the amidation of 1 equivalent of amine substrate (3-aminobiphenyl (B01)) and 3 equivalents of carboxylic acid (2,6-dimethylbenzoic acid (A01))

[0454]

[0455] Under a nitrogen atmosphere, 3-aminobiphenyl (B01) (3.4 mg, 0.020 mmol, 1 eq.), 2,6-dimethylbenzoic acid (A01) (9.0 mg, 0.060 mmol, 3 eq.), DCM (0.1 mL), and MeCN (0.1 mL) were added to a 0.6 mL glass vial. The first base, second base, and condensing agent listed in Table 2-2-1 were added, and the mixture was shaken at room temperature for the reaction time listed in the table. However, for Runs 1 to 5, 8, 9, 12, and 13, the condensing agent was added as a 1 / 1 DCM / MeCN solution (0.2 M). For Runs 6, 7, 10, 11, 14, and 15, the condensing agent was added as a 0.4 M MeCN solution, and the first base was added as a 0.4 M DCM solution. For Runs 16 to 21, the condensing agent was added as a MeCN solution (0.4 M), the first base was added as a DCM solution (0.8 M), and DCM (0.05 mL) was then added. A portion of the reaction solution was dispensed and the reaction progress was measured by LCMS. The results are shown in Table 2-2-1. However, the yield in Table 2-2-1 is calculated as 100% by excluding peaks that are not derived from B01 among the identified peaks. In addition, the analysis was performed by cutting out at a wavelength of 305 nm (±95 nm).

[0456]

[0457] These results demonstrate that CIP, PyClU, and PipClU can be used as haluronium-based condensing agents. NMI and tetramethylimidazole can be used as first bases. A wide range of bases, including N,N-dimethylaniline, N,N,2,4,6-pentamethylaniline, julolidine, 2,6-lutidine, 4-bromo-N,N-dimethylaniline, 4-fluoro-N,N-dimethylaniline, N,N-dimethyl-4-(trifluoromethyl)aniline, 3-bromo-N,N-dimethylaniline, 3-chloro-N,N-dimethylaniline, and N,N-dimethyl-3-(trifluoromethyl)aniline, can be used as second bases.

[0458] Example 2-3: Investigation of Substrate Applicability Example 2-3-1: Investigation of Substrate Applicability When Amine Substrates Are Used Under a nitrogen atmosphere, a carboxylic acid (0.084 mmol) and an amine (0.040 mmol) listed in Table 2-3-1 were added to a 0.6 mL glass vial. A DCM solution of NMI (0.8 M, 0.10 mL, 0.080 mmol), a DCM solution of 4-bromo-N,N-dimethylaniline (1.6 M, 0.10 mL, 0.16 mmol), and a DCM solution of PyClU (0.4 M, 0.20 mL, 0.080 mmol) were added and the mixture was shaken at room temperature for the reaction time listed in the table. A portion of the reaction solution was dispensed, and the reaction progress was measured by LCMS. The results are shown in the yields listed in Table 2-3-1. However, the yields in Table 2-3-1 are calculated assuming the total of identified peaks excluding those not derived from amines as 100%. In addition, the analysis was performed by cutting out the signal at a wavelength of 305 nm (±95 nm).

[0459]

[0460]

[0461]

[0462] Example 3: Amidation reaction on solid phase Example 3-1: Investigation of amidation conditions Example 3-1-1: Investigation of amidation conditions for solid phase carboxylic acid substrate (D05-1R) and aniline (B02)

[0463]

[0464] Under a nitrogen atmosphere, D05-1R (0.195 mmol / g, 20 mg, purity 83%), aniline (B02) (3.6 μL, 0.039 mmol), and DCM (0.4 mL) were added to a 0.6 mL glass vial. For Run 2, DIPEA (4.1 μL, 0.023 mmol) was added, and for Run 3, NMI (1.9 μL, 0.023 mmol) was added. Runs 1 to 3 were all shaken at room temperature for 1 hour. For Run 1, a MeCN solution containing PipClU and NMI (1 M, 7.8 μL, 0.0078 mmol) was added, and the mixture was shaken at room temperature for 24 hours. For Runs 2 and 3, PipClU (2.8 mg, 0.0078 mmol) was added, and the mixture was shaken at room temperature for 24 hours.

[0465] A 12 μL aliquot of the reaction mixture and solid phase suspension was transferred onto a filter-equipped tip and washed three times with DMF (0.1 mL), three times with MeOH (0.1 mL) (EtOH was used instead of MeOH in Runs 2 and 3), and three times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) and the reaction progress was measured by LCMS analysis. The results are shown in Table 3-1-1. However, the yield in Table 3-1-1 is calculated as 100% excluding peaks derived from impurities originally contained in D05-1R (83% purity). Analysis was also performed by cutting out at a wavelength of 299 nm (±4 nm).

[0466]

[0467] The above results indicate that the condition of using 1 equivalent of base (NMI) relative to the condensing agent (Run 1) gives a higher yield than the condition of using 3 equivalents of base (DIPEA or NMI) relative to the condensing agent (Runs 2 and 3).

[0468]

[0469] Compound E0502 LRMS: m / z 437 [M+H] ＋ Retention time: 2.207 minutes (Analysis conditions FA05-long)

[0470] Example 3-2: Investigation of the applicability of haluronium-based condensing agents, first base, second base, and solvent Example 3-2-1: Investigation of the applicability of haluronium-based condensing agents in the amidation of solid-phase carboxylic acid substrate (D03-1R) and 2,6-diisopropylaniline (B03)

[0471]

[0472] Under a nitrogen atmosphere, D03-1R (0.201 mmol / g, 20 mg) and DCM (0.35 mL) were placed in a 0.6 mL glass vial and shaken at room temperature for 1 hour. A DCM solution (0.050 mL) of 2,6-diisopropylaniline (B03) (0.4 M, 0.020 mmol), NMI (0.4 M, 0.020 mmol), and N,N-dimethyl-3-(trifluoromethyl)aniline (0.8 M, 0.040 mmol) was added. A haluronium-based condensing agent (0.020 mmol) listed in Table 3-2-1 was added, and the mixture was shaken at room temperature for 2 hours.

[0473] 10 μL of the reaction solution and solid phase suspension was transferred onto a filter-equipped tip and washed three times with NMP (0.1 mL), three times with MeOH (0.1 mL), and three times with DCM (0.1 mL). The sample was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 1 minute, filtered, washed with NMP (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) and subjected to LCMS measurement to measure the reaction progress. The results are shown in Table 3-2-1. However, the analysis was performed by cutting out at a wavelength of 290 nm (± 4 nm).

[0474]

[0475] The above results demonstrate that PyClU, TPyClU, PipClU, CIP, and CIB can be used as haluronium-based condensing agents.

[0476]

[0477] Compound E0303 LRMS: m / z 374 [M+H] ＋ Retention time: 1.210 minutes (Analysis conditions FA05-1)

[0478] Example 3-2-2: Investigation of the range of solvents applicable to the amidation of solid-phase carboxylic acid substrate (D03-1R) and 2,6-diisopropylaniline (B03)

[0479]

[0480] Under a nitrogen atmosphere, D03-1R (0.201 mmol / g, 20 mg) and the solvent listed in Table 3-2-2 were added to a 0.6 mL glass vial and shaken at room temperature for 1 hour. A DCM solution (0.050 mL) of 2,6-diisopropylaniline (B03) (0.4 M, 0.020 mmol), NMI (0.4 M, 0.020 mmol), and N,N-dimethyl-3-(trifluoromethyl)aniline (0.8 M, 0.040 mmol) was added. PipClU (7.3 mg, 0.020 mmol) was added in Runs 1 to 5, and a DCM solution of PyClU (0.4 M, 0.050 mL, 0.020 mmol) was added in Runs 6 to 14. The mixture was then shaken at room temperature for 2 hours.

[0481] 10 μL of the reaction solution and solid phase suspension was transferred onto a filter-equipped tip and washed three times with NMP (0.1 mL), three times with MeOH (0.1 mL), and three times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 1 minute, filtered, washed with NMP (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) and the reaction progress was measured by LCMS measurement. The results are shown in Table 3-2-2. However, the analysis was performed by cutting out at a wavelength of 290 nm (± 4 nm).

[0482]

[0483] Example 3-3: Examination of substrate applicability Example 3-3-1: Synthesis of E0305-1R by amidation of compound D03-1R and 4-nitroaniline (B05)

[0484]

[0485] Under a nitrogen atmosphere, D03-1R (0.201 mmol / g, 20 mg) and DCM (0.4 mL) were placed in a 0.6 mL glass vial and shaken at room temperature for 1 hour. 4-Nitroaniline (B05) (5.6 mg, 0.040 mmol) was added. A MeCN solution (8.0 μL) of PipClU (1.1 M, 0.0088 mmol) and NMI (1.0 M, 0.0080 mmol) was added, and the mixture was shaken at room temperature for 28 hours.

[0486] 12 μL of the reaction solution and solid phase suspension was transferred onto a filter tip and washed five times with DMF (0.1 mL), five times with MeOH (0.1 mL), and five times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) to measure the reaction progress by LCMS. As a result, 98% of E0305 was observed. However, the analysis was performed by cutting out at a wavelength of 290 nm (± 4 nm).

[0487]

[0488] Compound E0305 LRMS: m / z 335 [M+H] ＋ Retention time: 1.085 minutes (Analysis conditions FA05-1)

[0489] Example 3-3-2: Synthesis of E0306-1R by amidation of compound D03-1R and N-methyl-4-nitroaniline (B06)

[0490]

[0491] Under a nitrogen atmosphere, D03-1R (0.201 mmol / g, 20 mg) and DCM (0.4 mL) were placed in a 0.6 mL glass vial and shaken at room temperature for 1 hour. N-methyl-4-nitroaniline (B06) (6.1 mg, 0.040 mmol) was added. A MeCN solution (8.0 μL) of PipClU (1.1 M, 0.0088 mmol) and NMI (1.0 M, 0.0080 mmol) was added, and the mixture was shaken at room temperature for 28 hours.

[0492] 12 μL of the reaction solution and solid phase suspension was transferred onto a filter tip and washed five times with DMF (0.1 mL), five times with MeOH (0.1 mL), and five times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) to measure the reaction progress by LCMS. As a result, 99% of E0306 was observed. However, the analysis was performed by cutting out at a wavelength of 290 nm (± 4 nm).

[0493]

[0494] Compound E0306 LRMS: m / z 349 [M+H] ＋ Retention time: 0.999 minutes (Analysis conditions FA05-1)

[0495] Example 3-3-3: Synthesis of E0307-1R by amidation of compound D03-1R and N-isopropylbenzylamine (B07)

[0496]

[0497] Under a nitrogen atmosphere, D03-1R (0.201 mmol / g, 20 mg) and DCM (0.4 mL) were placed in a 0.6 mL glass vial and shaken at room temperature for 1 hour. N-isopropylbenzylamine (B07) (6.6 μL, 0.040 mmol) was added. A MeCN solution (8.0 μL) of PipClU (1.1 M, 0.0088 mmol) and NMI (1.0 M, 0.0080 mmol) was added, and the mixture was shaken at room temperature for 2 hours.

[0498] 12 μL of the reaction solution and solid phase suspension was transferred onto a filter tip and washed five times with DMF (0.1 mL), five times with MeOH (0.1 mL), and five times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) to measure the reaction progress by LCMS. As a result, 99% of E0307 was observed. However, the analysis was performed by cutting out at a wavelength of 290 nm (± 4 nm).

[0499]

[0500] Compound E0307 LRMS: m / z 346 [M+H] ＋ Retention time: 1.137 minutes (Analysis conditions FA05-1)

[0501] Example 3-3-4: Synthesis of E0703-1R by amidation of compound D07-1R and 2,6-diisopropylaniline (B03)

[0502]

[0503] Under a nitrogen atmosphere, D07-1R (0.193 mmol / g, 20 mg, purity 84%) and DCM (0.4 mL) were placed in a 0.6 mL glass vial and shaken at room temperature for 1 hour. 2,6-Diisopropylaniline (B03) (7.3 μL, 0.039 mmol) was added. A MeCN solution (7.7 μL) of PipClU (1.1 M, 0.0085 mmol) and NMI (1.0 M, 0.0077 mmol) was added, and the mixture was shaken at room temperature for 2 hours.

[0504] 12 μL of the reaction solution and solid phase suspension was transferred onto a filter tip and washed five times with DMF (0.1 mL), five times with MeOH (0.1 mL), and five times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) and the reaction progress was measured by LCMS analysis. As a result, 99% E0703 was observed. However, the total amount calculated excluding peaks derived from impurities originally contained in D07-1R (84% purity) was set at 100%. The analysis was also performed by cutting out at a wavelength of 299 nm (± 4 nm).

[0505]

[0506] Compound E0703 LRMS: m / z 576 [M+H] ＋ Retention time: 1.461 minutes (Analysis conditions FA05-1)

[0507] Example 3-3-5: Synthesis of E0705-1R by amidation of compound D07-1R and 4-nitroaniline (B05)

[0508]

[0509] Under a nitrogen atmosphere, D07-1R (0.193 mmol / g, 20 mg, purity 84%) and DCM (0.4 mL) were placed in a 0.6 mL glass vial and shaken at room temperature for 1 hour. 4-Nitroaniline (B05) (5.3 mg, 0.039 mmol) was added. A MeCN solution (7.7 μL) of PipClU (1.1 M, 0.0085 mmol) and NMI (1.0 M, 0.0077 mmol) was added, and the mixture was shaken at room temperature for 24 hours.

[0510] 12 μL of the reaction solution and solid phase suspension was transferred onto a filter tip and washed five times with DMF (0.1 mL), five times with MeOH (0.1 mL), and five times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) and the reaction progress was measured by LCMS analysis. As a result, 99% E0705 was observed. However, the total amount calculated excluding peaks derived from impurities originally contained in D07-1R (84% purity) was set at 100%. The analysis was also performed by cutting out at a wavelength of 299 nm (± 4 nm).

[0511]

[0512] Compound E0705 LRMS: m / z 537 [M+H] ＋ Retention time: 1.365 minutes (Analysis conditions FA05-1)

[0513] Example 3-3-6: Synthesis of E0706-1R by amidation of compound D07-1R and N-methyl-4-nitroaniline (B06)

[0514]

[0515] Under a nitrogen atmosphere, D07-1R (0.193 mmol / g, 20 mg, purity 84%) and DCM (0.4 mL) were placed in a 0.6 mL glass vial and shaken at room temperature for 1 hour. N-methyl-4-nitroaniline (B06) (5.9 mg, 0.039 mmol) was added. A MeCN solution (7.7 μL) of PipClU (1.1 M, 0.0085 mmol) and NMI (1.0 M, 0.0077 mmol) was added, and the mixture was shaken at room temperature for 24 hours.

[0516] 12 μL of the reaction mixture and solid phase suspension was transferred onto a filter tip and washed five times with DMF (0.1 mL), five times with MeOH (0.1 mL), and five times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) and the reaction progress was measured by LCMS analysis. As a result, 100% E0706 was observed. However, the total amount calculated excludes peaks derived from impurities originally contained in D07-1R (84% purity). The analysis was also performed by cutting out at a wavelength of 299 nm (± 4 nm).

[0517]

[0518] Compound E0706 LRMS: m / z 551 [M+H] ＋ Retention time: 1.284 minutes (Analysis conditions FA05-1)

[0519] Example 3-3-7: Synthesis of E0707-1R by amidation of compound D07-1R and N-isopropylbenzylamine (B07)

[0520]

[0521] Under a nitrogen atmosphere, D07-1R (0.193 mmol / g, 20 mg, purity 84%) and DCM (0.4 mL) were placed in a 0.6 mL glass vial and shaken at room temperature for 1 hour. N-isopropylbenzylamine (B07) (6.3 μL, 0.039 mmol) was added. A MeCN solution (7.7 μL) of PipClU (1.1 M, 0.0085 mmol) and NMI (1.0 M, 0.0077 mmol) was added, and the mixture was shaken at room temperature for 30 minutes.

[0522] 12 μL of the reaction mixture and solid phase suspension was transferred onto a filter tip and washed five times with DMF (0.1 mL), five times with MeOH (0.1 mL), and five times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) and analyzed by LCMS. As a result, 99% E0707 was observed. However, the total amount calculated excluding peaks derived from impurities originally contained in D07-1R (84% purity) was set at 100%. The analysis was also performed by cutting out at a wavelength of 299 nm (± 4 nm).

[0523]

[0524] Compound E0707 LRMS: m / z 548 [M+H] ＋ Retention time: 1.420 minutes (Analysis conditions FA05-1)

[0525] Example 3-3-8: Synthesis of E0903-1R by amidation of compound D09-1R and 2,6-diisopropylaniline (B03)

[0526]

[0527] Under a nitrogen atmosphere, D09-1R (0.191 mmol / g, 20 mg, purity 96%) and DCM (0.4 mL) were placed in a 0.6 mL glass vial and shaken at room temperature for 1 hour. 2,6-Diisopropylaniline (B03) (7.2 μL, 0.038 mmol) was added. A MeCN solution (7.6 μL) of PipClU (1.1 M, 0.0084 mmol) and NMI (1.0 M, 0.0076 mmol) was added, and the mixture was shaken at room temperature for 24 hours.

[0528] 12 μL of the reaction solution and solid phase suspension was transferred onto a filter tip and washed five times with DMF (0.1 mL), five times with MeOH (0.1 mL), and five times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) and the reaction progress was measured by LCMS analysis. As a result, 94% E0903 was observed. However, the total amount calculated excluding peaks derived from impurities originally contained in D09-1R (96% purity) was set at 100%. The analysis was also performed by cutting out at a wavelength of 290 nm (± 4 nm).

[0529]

[0530] Compound E0903 LRMS: m / z 639,641 [M+H] ＋ Retention time: 1.359 minutes (Analysis conditions FA05-1)

[0531] Example 3-3-9: Synthesis of E0905-1R by amidation of compound D09-1R and 4-nitroaniline (B05)

[0532]

[0533] Under a nitrogen atmosphere, D09-1R (0.191 mmol / g, 20 mg, purity 96%) and DCM (0.4 mL) were placed in a 0.6 mL glass vial and shaken at room temperature for 1 hour. 4-Nitroaniline (B05) (5.3 mg, 0.038 mmol) was added. A MeCN solution (7.6 μL) of PipClU (1.1 M, 0.0084 mmol) and NMI (1.0 M, 0.0076 mmol) was added, and the mixture was shaken at room temperature for 24 hours.

[0534] 12 μL of the reaction mixture and solid phase suspension was transferred onto a filter tip and washed five times with DMF (0.1 mL), five times with MeOH (0.1 mL), and five times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) and the reaction progress was measured by LCMS analysis. As a result, 95% E0905 was observed. However, the total amount calculated excluding peaks derived from impurities originally contained in D09-1R (96% purity) was set at 100%. The analysis was also performed by cutting out at a wavelength of 290 nm (± 4 nm).

[0535]

[0536] Compound E0905 LRMS: m / z 600,602 [M+H] ＋ Retention time: 1.253 minutes (Analysis conditions FA05-1)

[0537] Example 3-3-10: Synthesis of G0101-1R by amidation of compound F01-1R and 2,6-dimethylbenzoic acid (A01)

[0538]

[0539] Under a nitrogen atmosphere, F01-1R (0.197 mmol / g, 20 mg, purity 97%) and DCM (0.4 mL) were placed in a 0.6 mL glass vial and shaken at room temperature for 1 hour. 2,6-Dimethylbenzoic acid (A01) (7.1 mg, 0.047 mmol) and N,N-dimethyl-p-toluidine (17.0 μL, 0.118 mmol) were added. A MeCN solution (39.4 μL) of PipClU (1.0 M, 0.039 mmol) and NMI (1.1 M, 0.043 mmol) was added, and the mixture was shaken at room temperature for 90 hours.

[0540] 12 μL of the reaction solution and solid phase suspension was transferred onto a filter-equipped tip and washed five times with DMF (0.1 mL), five times with MeOH (0.1 mL), and five times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) to measure the reaction progress by LCMS measurement. As a result, 69% G0101 was observed. However, the total amount calculated is 100% excluding peaks derived from impurities originally contained in F01-1R (purity 97%). The analysis was also performed by cutting out at a wavelength of 290 nm (± 4 nm).

[0541]

[0542] Compound G0101 LRMS: m / z 451 [M+H] ＋ Retention time: 1.037 minutes (Analysis conditions FA05-1)

[0543] Example 3-3-11: Synthesis of G0105-1R by amidation of compound F01-1R and 4-dimethylaminobenzoic acid (A05)

[0544]

[0545] Under a nitrogen atmosphere, F01-1R (0.197 mmol / g, 20 mg, purity 97%) and DCM (0.4 mL) were added to a 0.6 mL glass vial and shaken at room temperature for 1 hour. 4-Dimethylaminobenzoic acid (A05) (7.8 mg, 0.047 mmol) and N,N-dimethyl-p-toluidine (17.0 μL, 0.118 mmol) were added. A MeCN solution (39.4 μL) of PipClU (1.0 M, 0.039 mmol) and NMI (1.1 M, 0.043 mmol) was added, and the mixture was shaken at room temperature for 90 hours.

[0546] 12 μL of the reaction solution and solid phase suspension was transferred onto a filter-equipped tip and washed five times with DMF (0.1 mL), five times with MeOH (0.1 mL), and five times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) to measure the reaction progress by LCMS measurement. As a result, 98% G0105 was observed. However, the total amount calculated excluding peaks derived from impurities originally contained in F01-1R (purity 97%) was 100%. The analysis was also performed by cutting out at a wavelength of 290 nm (± 4 nm).

[0547]

[0548] Compound G0105 LRMS: m / z 466 [M+H] ＋ Retention time: 1.023 minutes (Analysis conditions FA05-1)

[0549] Example 3-3-12: Synthesis of G0104-1R by amidation of compound F01-1R and 2-methyl-2-phenylpropanoic acid (A04)

[0550]

[0551] Under a nitrogen atmosphere, F01-1R (0.197 mmol / g, 20 mg, purity 97%) and DCM (0.4 mL) were placed in a 0.6 mL glass vial and shaken at room temperature for 1 hour. 2-Methyl-2-phenylpropanoic acid (A04) (7.8 mg, 0.047 mmol) and N,N-dimethyl-p-toluidine (17.0 μL, 0.118 mmol) were added. A MeCN solution (39.4 μL) of PipClU (1.0 M, 0.039 mmol) and NMI (1.1 M, 0.043 mmol) was added, and the mixture was shaken at room temperature for 30 minutes.

[0552] 12 μL of the reaction solution and solid phase suspension was transferred onto a filter-equipped tip and washed five times with DMF (0.1 mL), five times with MeOH (0.1 mL), and five times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) to measure the reaction progress by LCMS. As a result, 100% G0104 was observed. However, the total amount excluding peaks derived from impurities originally contained in F01-1R (purity 97%) was calculated as 100%. The analysis was also performed by cutting out at a wavelength of 290 nm (± 4 nm).

[0553]

[0554] Compound G0104 LRMS: m / z 465 [M+H] ＋ Retention time: 1.105 minutes (Analysis conditions FA05-1)

[0555] Example 3-3-13: Synthesis of G0201-1R by amidation of compound F02-1R and 2,6-dimethylbenzoic acid (A01)

[0556]

[0557] Under a nitrogen atmosphere, F02-1R (0.196 mmol / g, 20 mg, purity 98%) and DCM (0.4 mL) were added to a 0.6 mL glass vial and shaken at room temperature for 1 hour. 2,6-Dimethylbenzoic acid (A01) (7.1 mg, 0.047 mmol) and N,N-dimethyl-p-toluidine (16.9 μL, 0.118 mmol) were added. A MeCN solution (39.2 μL) of PipClU (1.0 M, 0.039 mmol) and NMI (1.1 M, 0.043 mmol) was added, and the mixture was shaken at room temperature for 90 hours.

[0558] 12 μL of the reaction solution and solid phase suspension was transferred onto a filter tip and washed five times with DMF (0.1 mL), five times with MeOH (0.1 mL), and five times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) to measure the reaction progress by LCMS. As a result, 91% G0201 was observed. However, the total amount calculated excluding peaks derived from impurities originally contained in F02-1R (98% purity) was set at 100%. The analysis was also performed by cutting out at a wavelength of 290 nm (± 4 nm).

[0559]

[0560] Compound G0201 LRMS: m / z 465 [M+H] ＋ Retention time: 1.000 minutes, 1.060 minutes (bimodal) (Analysis conditions FA05-1)

[0561] Example 3-3-14: Synthesis of G0205-1R by amidation of compound F02-1R and 4-dimethylaminobenzoic acid (A05)

[0562]

[0563] Under a nitrogen atmosphere, F02-1R (0.196 mmol / g, 20 mg, purity 98%) and DCM (0.4 mL) were placed in a 0.6 mL glass vial and shaken at room temperature for 1 hour. 4-Dimethylaminobenzoic acid (A05) (7.8 mg, 0.047 mmol) and N,N-dimethyl-p-toluidine (16.9 μL, 0.118 mmol) were added. A MeCN solution (39.2 μL) of PipClU (1.0 M, 0.039 mmol) and NMI (1.1 M, 0.043 mmol) was added, and the mixture was shaken at room temperature for 90 hours.

[0564] 12 μL of the reaction solution and solid phase suspension was transferred onto a filter tip and washed five times with DMF (0.1 mL), five times with MeOH (0.1 mL), and five times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) to measure the reaction progress by LCMS. As a result, 98% G0205 was observed. However, the total amount calculated excluding peaks derived from impurities originally contained in F02-1R (98% purity) was set at 100%. The analysis was also performed by cutting out at a wavelength of 290 nm (± 4 nm).

[0565]

[0566] Compound G0205 LRMS: m / z 480 [M+H] ＋ Retention time: 0.975 minutes (Analysis conditions FA05-1)

[0567] Example 3-3-15: Synthesis of G0204-1R by amidation of compound F02-1R and 2-methyl-2-phenylpropanoic acid (A04)

[0568]

[0569] Under a nitrogen atmosphere, F02-1R (0.196 mmol / g, 20 mg, purity 98%) and DCM (0.4 mL) were placed in a 0.6 mL glass vial and shaken at room temperature for 1 hour. 2-Methyl-2-phenylpropanoic acid (A04) (7.7 mg, 0.047 mmol) and N,N-dimethyl-p-toluidine (16.9 μL, 0.118 mmol) were added. A MeCN solution (39.2 μL) of PipClU (1.0 M, 0.039 mmol) and NMI (1.1 M, 0.043 mmol) was added, and the mixture was shaken at room temperature for 30 minutes.

[0570] 12 μL of the reaction solution and solid phase suspension was transferred onto a filter tip and washed five times with DMF (0.1 mL), five times with MeOH (0.1 mL), and five times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) and the reaction progress was measured by LCMS analysis. As a result, 99% G0204 was observed. However, the total amount calculated excluding peaks derived from impurities originally contained in F02-1R (98% purity) was set at 100%. The analysis was also performed by cutting out at a wavelength of 290 nm (± 4 nm).

[0571]

[0572] Compound G0204 LRMS: m / z 479 [M+H] ＋ Retention time: 1.113 minutes (Analysis conditions FA05-1)

[0573] Example 3-3-16: Synthesis of G0401-1R by amidation of compound F04-1R and 2,6-dimethylbenzoic acid (A01)

[0574]

[0575] Under a nitrogen atmosphere, F04-1R (0.198 mmol / g, 20 mg) and DCM (0.4 mL) were added to a 0.6 mL glass vial and shaken at room temperature for 1 hour. 2,6-Dimethylbenzoic acid (A01) (7.1 mg, 0.048 mmol) and N-methylmorpholine (13.1 μL, 0.119 mmol) were added. A MeCN solution (39.6 μL) of PipClU (1.0 M, 0.040 mmol) and NMI (1.1 M, 0.044 mmol) was added, and the mixture was shaken at room temperature for 2 hours.

[0576] 12 μL of the reaction solution and solid phase suspension was transferred onto a filter tip and washed five times with DMF (0.1 mL), five times with MeOH (0.1 mL), and five times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) to measure the reaction progress by LCMS. As a result, 95% of G0401 was observed. However, the analysis was performed by cutting out at a wavelength of 290 nm (± 4 nm).

[0577]

[0578] Compound G0401 LRMS: m / z 415 [M+H] ＋ Retention time: 0.941 minutes (Analysis conditions FA05-1)

[0579] Example 3-3-17: Synthesis of G0405-1R by amidation of compound F04-1R and 4-dimethylaminobenzoic acid (A05)

[0580]

[0581] Under a nitrogen atmosphere, F04-1R (0.198 mmol / g, 20 mg) and DCM (0.4 mL) were added to a 0.6 mL glass vial and shaken at room temperature for 1 hour. 4-Dimethylaminobenzoic acid (A05) (7.9 mg, 0.048 mmol) and N-methylmorpholine (13.1 μL, 0.119 mmol) were added. A MeCN solution (39.6 μL) of PipClU (1.0 M, 0.040 mmol) and NMI (1.1 M, 0.044 mmol) was added, and the mixture was shaken at room temperature for 2 hours.

[0582] 12 μL of the reaction solution and solid phase suspension was transferred onto a filter tip and washed five times with DMF (0.1 mL), five times with MeOH (0.1 mL), and five times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) to measure the reaction progress by LCMS. As a result, 98% of G0405 was observed. However, the analysis was performed by cutting out at a wavelength of 290 nm (± 4 nm).

[0583]

[0584] Compound G0405 LRMS: m / z 430 [M+H] ＋ Retention time: 0.885 minutes (Analysis conditions FA05-1)

[0585] Example 3-3-18: Synthesis of G0404-1R by amidation of compound F04-1R and 2-methyl-2-phenylpropanoic acid (A04)

[0586]

[0587] Under a nitrogen atmosphere, F04-1R (0.198 mmol / g, 20 mg) and DCM (0.4 mL) were placed in a 0.6 mL glass vial and shaken at room temperature for 1 hour. 2-Methyl-2-phenylpropanoic acid (A04) (7.8 mg, 0.048 mmol) and N-methylmorpholine (13.1 μL, 0.119 mmol) were added. A MeCN solution (39.6 μL) of PipClU (1.0 M, 0.040 mmol) and NMI (1.1 M, 0.044 mmol) was added, and the mixture was shaken at room temperature for 30 minutes.

[0588] 12 μL of the reaction solution and solid phase suspension was transferred onto a filter tip and washed five times with DMF (0.1 mL), five times with MeOH (0.1 mL), and five times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) to measure the reaction progress by LCMS. As a result, 100% G0404 was observed. However, the analysis was performed by cutting out at a wavelength of 290 nm (± 4 nm).

[0589]

[0590] Compound G0404 LRMS: m / z 429 [M+H] ＋ Retention time: 1.027 minutes (Analysis conditions FA05-1)

[0591] Example 3-3-19: Synthesis of E1202-1R by amidation of compound D12-1R and aniline (B02)

[0592]

[0593] Under a nitrogen atmosphere, D12-1R (0.190 mmol / g, 10 mg, purity 96%) and DCM (0.2 mL) were placed in a 0.6 mL glass vial and shaken at room temperature for 1 hour. Aniline (B02) (1.8 mg, 0.019 mmol) was added. A MeCN solution (3.8 μL) of PipClU (1.0 M, 0.0038 mmol) and NMI (1.0 M, 0.0038 mmol) was added, and the mixture was shaken at room temperature for 24 hours.

[0594] 12 μL of the reaction mixture and solid phase suspension was transferred onto a filter tip and washed five times with DMF (0.1 mL), five times with MeOH (0.1 mL), and five times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) and analyzed by LCMS. As a result, 96% E1202 was observed. However, the total amount calculated was 100% excluding the peaks derived from impurities originally contained in D12-1R (96% purity) and the pentamethylbenzene peak. The analysis was also performed by cutting out at a wavelength of 270 nm (± 4 nm).

[0595]

[0596] Compound E1202 LRMS: m / z 318 [M+H] ＋ Retention time: 1.065 minutes (Analysis conditions FA05-1)

[0597] Example 3-3-20: Synthesis of E1216-1R by amidation of compound D12-1R and N-methylaniline (B16)

[0598]

[0599] Under a nitrogen atmosphere, D12-1R (0.190 mmol / g, 10 mg, purity 96%) and DCM (0.2 mL) were placed in a 0.6 mL glass vial and shaken at room temperature for 1 hour. N-methylaniline (B16) (2.0 mg, 0.019 mmol) was added. A MeCN solution (3.8 μL) of PipClU (1.0 M, 0.0038 mmol) and NMI (1.0 M, 0.0038 mmol) was added, and the mixture was shaken at room temperature for 24 hours.

[0600] 12 μL of the reaction mixture and solid phase suspension was transferred onto a filter tip and washed five times with DMF (0.1 mL), five times with MeOH (0.1 mL), and five times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) and analyzed by LCMS. As a result, 95% E1216 was observed. However, the total amount calculated was 100% excluding the peaks derived from impurities originally contained in D12-1R (96% purity) and the pentamethylbenzene peak. The analysis was also performed by cutting out at a wavelength of 270 nm (± 4 nm).

[0601]

[0602] Compound E1216 LRMS: m / z 332 [M+H] ＋ Retention time: 1.023 minutes, 1.045 minutes (bimodal) (analysis conditions FA05-1)

[0603] Example 3-3-21: Synthesis of E1217-1R by amidation of compound D12-1R and 2-methylaniline (B17)

[0604]

[0605] Under a nitrogen atmosphere, D12-1R (0.190 mmol / g, 10 mg, purity 96%) and DCM (0.2 mL) were placed in a 0.6 mL glass vial and shaken at room temperature for 1 hour. 2-Methylaniline (B17) (2.0 mg, 0.019 mmol) was added. A MeCN solution (3.8 μL) of PipClU (1.0 M, 0.0038 mmol) and NMI (1.0 M, 0.0038 mmol) was added, and the mixture was shaken at room temperature for 24 hours.

[0606] 12 μL of the reaction mixture and solid phase suspension was transferred onto a filter tip and washed five times with DMF (0.1 mL), five times with MeOH (0.1 mL), and five times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) and analyzed by LCMS. As a result, 90% E1217 was observed. However, the total amount calculated was 100% excluding the peaks derived from impurities originally contained in D12-1R (96% purity) and the pentamethylbenzene peak. The analysis was also performed by cutting out at a wavelength of 270 nm (± 4 nm).

[0607]

[0608] Compound E1217 LRMS: m / z 332 [M+H] ＋ Retention time: 1.065 minutes (Analysis conditions FA05-1)

[0609] Example 3-3-22: Synthesis of E1219-1R by amidation of compound D12-1R and 2,6-dimethylaniline (B19)

[0610]

[0611] Under a nitrogen atmosphere, D12-1R (0.190 mmol / g, 10 mg, purity 96%) and DCM (0.2 mL) were placed in a 0.6 mL glass vial and shaken at room temperature for 1 hour. 2,6-Dimethylaniline (B19) (2.3 mg, 0.019 mmol) was added. A MeCN solution (3.8 μL) of PipClU (1.0 M, 0.0038 mmol) and NMI (1.0 M, 0.0038 mmol) was added, and the mixture was shaken at room temperature for 24 hours.

[0612] 12 μL of the reaction mixture and solid phase suspension was transferred onto a filter tip and washed five times with DMF (0.1 mL), five times with MeOH (0.1 mL), and five times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) and analyzed by LCMS. As a result, 90% E1219 was observed. However, the total amount calculated was 100%, excluding the peaks derived from impurities originally contained in D12-1R (96% purity) and the pentamethylbenzene peak. The analysis was also performed by cutting out at a wavelength of 270 nm (± 4 nm).

[0613]

[0614] Compound E1219 LRMS: m / z 346 [M+H] ＋ Retention time: 1.081 minutes (Analysis conditions FA05-1)

[0615] Example 3-3-23: Synthesis of E1220-1R by amidation of compound D12-1R and N-propan-2-ylaniline (B20)

[0616]

[0617] Under a nitrogen atmosphere, D12-1R (0.190 mmol / g, 10 mg, purity 96%) and DCM (0.2 mL) were placed in a 0.6 mL glass vial and shaken at room temperature for 1 hour. N-propan-2-ylaniline (B20) (2.6 mg, 0.019 mmol) was added. A MeCN solution (3.8 μL) of PipClU (1.0 M, 0.0038 mmol) and NMI (1.0 M, 0.0038 mmol) was added, and the mixture was shaken at room temperature for 24 hours.

[0618] 12 μL of the reaction mixture and solid phase suspension was transferred onto a filter tip and washed five times with DMF (0.1 mL), five times with MeOH (0.1 mL), and five times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) to measure the reaction progress by LCMS. As a result, 88% E1220 was observed. However, the total amount calculated was 100% excluding the peaks derived from impurities originally contained in D12-1R (96% purity) and the pentamethylbenzene peak. The analysis was also performed by cutting out at a wavelength of 270 nm (± 4 nm).

[0619]

[0620] Compound E1220 LRMS: m / z 360 [M+H] ＋ Retention time: 1.135 minutes (Analysis conditions FA05-1)

[0621] Example 3-3-24: Synthesis of E1221-1R by amidation of compound D12-1R and 2-tert-butyl-N-methylaniline (B21)

[0622]

[0623] Under a nitrogen atmosphere, D12-1R (0.190 mmol / g, 10 mg, purity 96%) and DCM (0.2 mL) were placed in a 0.6 mL glass vial and shaken at room temperature for 1 hour. 2-tert-Butyl-N-methylaniline (B21) (3.1 mg, 0.019 mmol) was added. A MeCN solution (3.8 μL) of PipClU (1.0 M, 0.0038 mmol) and NMI (1.0 M, 0.0038 mmol) was added, and the mixture was shaken at room temperature for 24 hours.

[0624] 12 μL of the reaction mixture and solid phase suspension was transferred onto a filter tip and washed five times with DMF (0.1 mL), five times with MeOH (0.1 mL), and five times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) and analyzed by LCMS. As a result, 87% E1221 was observed. However, the total amount calculated was 100%, excluding the peaks derived from impurities originally contained in D12-1R (96% purity) and the pentamethylbenzene peak. The analysis was also performed by cutting out at a wavelength of 270 nm (± 4 nm).

[0625]

[0626] Compound E1221 LRMS: m / z 388 [M+H] ＋ Retention time: 1.281 minutes (Analysis conditions FA05-1)

[0627] Example 3-3-25: Synthesis of E1222-1R by amidation of compound D12-1R and 4-(methylamino)benzonitrile (B22)

[0628]

[0629] Under a nitrogen atmosphere, D12-1R (0.190 mmol / g, 10 mg, purity 96%) and DCM (0.2 mL) were placed in a 0.6 mL glass vial and shaken at room temperature for 1 hour. 4-(Methylamino)benzonitrile (B22) (2.5 mg, 0.019 mmol) was added. A MeCN solution (3.8 μL) of PipClU (1.0 M, 0.0038 mmol) and NMI (1.0 M, 0.0038 mmol) was added, and the mixture was shaken at room temperature for 24 hours.

[0630] 12 μL of the reaction mixture and solid phase suspension was transferred onto a filter tip and washed five times with DMF (0.1 mL), five times with MeOH (0.1 mL), and five times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) and analyzed by LCMS. As a result, 62% E1222 was observed. However, the total amount calculated was 100%, excluding the peaks derived from impurities originally contained in D12-1R (96% purity) and the pentamethylbenzene peak. The analysis was also performed by cutting out at a wavelength of 270 nm (± 4 nm).

[0631]

[0632] Compound E1222 LRMS: m / z 357 [M+H] ＋ Retention time: 2.033 minutes (Analysis conditions FA05-long)

[0633] Example 3-3-26: Synthesis of E1223-1R by amidation of compound D12-1R and 2,6-diethylaniline (B23)

[0634]

[0635] Under a nitrogen atmosphere, D12-1R (0.190 mmol / g, 10 mg, 96% purity) and DCM (0.2 mL) were added to a 0.6 mL glass vial and shaken at room temperature for 1 hour. 2,6-Diethylaniline (B23) (2.8 mg, 0.019 mmol) was added. A MeCN solution (3.8 μL) of PipClU (1.0 M, 0.0038 mmol) and NMI (1.0 M, 0.0038 mmol) was added and shaken at room temperature for 24 hours. 12 μL of the reaction mixture and solid phase suspension was transferred onto a filter tip and washed five times with DMF (0.1 mL), five times with MeOH (0.1 mL), and five times with DCM (0.1 mL). The reaction mixture was immersed in a 10% TFA / DCM solution (0.1 M, 0.05 mL) of pentamethylbenzene for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) and analyzed by LCMS. As a result, 91% E1223 was observed. However, the calculation was based on a total of 100% excluding the peaks derived from impurities originally contained in D12-1R (purity 96%) and the pentamethylbenzene peak. Analysis was also performed by cutting out at a wavelength of 270 nm (±4 nm).

[0636]

[0637] Compound E1223 LRMS: m / z 374 [M+H] ＋ Retention time: 1.176 minutes (Analysis conditions FA05-1)

[0638] Example 3-3-27: Synthesis of E1224-1R by amidation of compound D12-1R and 4-(ethylamino)benzonitrile (B24)

[0639]

[0640] Under a nitrogen atmosphere, D12-1R (0.190 mmol / g, 10 mg, purity 96%) and DCM (0.2 mL) were placed in a 0.6 mL glass vial and shaken at room temperature for 1 hour. 4-(Ethylamino)benzonitrile (B24) (2.8 mg, 0.019 mmol) was added. A MeCN solution (3.8 μL) of PipClU (1.0 M, 0.0038 mmol) and NMI (1.0 M, 0.0038 mmol) was added, and the mixture was shaken at room temperature for 24 hours.

[0641] 12 μL of the reaction mixture and solid phase suspension was transferred onto a filter tip and washed five times with DMF (0.1 mL), five times with MeOH (0.1 mL), and five times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) and analyzed by LCMS. As a result, 54% E1224 was observed. However, the total amount calculated is 100% excluding the peaks derived from impurities originally contained in D12-1R (96% purity) and the pentamethylbenzene peak. The analysis was also performed by cutting out at a wavelength of 270 nm (± 4 nm).

[0642]

[0643] Compound E1224 LRMS: m / z 371 [M+H] ＋ Retention time: 1.043 minutes (Analysis conditions FA05-1)

[0644] Example 3-3-28: Synthesis of E1225-1R by amidation of compound D12-1R and 4-(propan-2-ylamino)benzonitrile (B25)

[0645]

[0646] Under a nitrogen atmosphere, D12-1R (0.190 mmol / g, 10 mg, purity 96%) and DCM (0.2 mL) were placed in a 0.6 mL glass vial and shaken at room temperature for 1 hour. 4-(propan-2-ylamino)benzonitrile (B25) (3.0 mg, 0.019 mmol) was added. A MeCN solution (3.8 μL) of PipClU (1.0 M, 0.0038 mmol) and NMI (1.0 M, 0.0038 mmol) was added, and the mixture was shaken at room temperature for 24 hours.

[0647] 12 μL of the reaction mixture and solid phase suspension was transferred onto a filter tip and washed five times with DMF (0.1 mL), five times with MeOH (0.1 mL), and five times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) and analyzed by LCMS. As a result, 15% E1225 was observed. However, the total amount calculated was 100% excluding the peaks derived from impurities originally contained in D12-1R (96% purity) and the pentamethylbenzene peak. The analysis was also performed by cutting out at a wavelength of 270 nm (± 4 nm).

[0648]

[0649] Compound E1225 LRMS: m / z 385 [M+H] ＋ Retention time: 2.269 minutes (Analysis conditions FA05-long)

[0650] Example 3-3-29: Synthesis of E1226-1R by amidation of compound D12-1R and 4-amino-3-methylbenzonitrile (B26)

[0651]

[0652] Under a nitrogen atmosphere, D12-1R (0.190 mmol / g, 10 mg, purity 96%) and DCM (0.2 mL) were placed in a 0.6 mL glass vial and shaken at room temperature for 1 hour. 4-Amino-3-methylbenzonitrile (B26) (2.5 mg, 0.019 mmol) was added. A MeCN solution (3.8 μL) of PipClU (1.0 M, 0.0038 mmol) and NMI (1.0 M, 0.0038 mmol) was added, and the mixture was shaken at room temperature for 24 hours.

[0653] 12 μL of the reaction mixture and solid phase suspension was transferred onto a filter tip and washed five times with DMF (0.1 mL), five times with MeOH (0.1 mL), and five times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) and analyzed by LCMS. As a result, 66% E1226 was observed. However, the total amount calculated was 100%, excluding the peaks derived from impurities originally contained in D12-1R (96% purity) and the pentamethylbenzene peak. The analysis was also performed by cutting out at a wavelength of 270 nm (± 4 nm).

[0654]

[0655] Compound E1226 LRMS: m / z 357 [M+H] ＋ Retention time: 1.055 minutes (Analysis conditions FA05-1)

[0656] Example 3-3-30: Synthesis of E1227-1R by amidation of compound D12-1R and N-methyl-4-(trifluoromethyl)aniline (B27)

[0657]

[0658] Under a nitrogen atmosphere, D12-1R (0.190 mmol / g, 10 mg, purity 96%) and DCM (0.2 mL) were placed in a 0.6 mL glass vial and shaken at room temperature for 1 hour. N-methyl-4-(trifluoromethyl)aniline (B27) (3.3 mg, 0.019 mmol) was added. A MeCN solution (3.8 μL) of PipClU (1.0 M, 0.0038 mmol) and NMI (1.0 M, 0.0038 mmol) was added, and the mixture was shaken at room temperature for 24 hours.

[0659] 12 μL of the reaction mixture and solid phase suspension was transferred onto a filter tip and washed five times with DMF (0.1 mL), five times with MeOH (0.1 mL), and five times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) and analyzed by LCMS. As a result, 83% E1227 was observed. However, the total amount calculated was 100%, excluding the peaks derived from impurities originally contained in D12-1R (96% purity) and the pentamethylbenzene peak. The analysis was also performed by cutting out at a wavelength of 270 nm (± 4 nm).

[0660]

[0661] Compound E1227 LRMS: m / z 400 [M+H] ＋ Retention time: 1.153 minutes (Analysis conditions FA05-1)

[0662] Example 3-3-31: Synthesis of E1206-1R by amidation of compound D12-1R and N-methyl-4-nitroaniline (B06)

[0663]

[0664] Under a nitrogen atmosphere, D12-1R (0.190 mmol / g, 10 mg, purity 96%) and DCM (0.2 mL) were placed in a 0.6 mL glass vial and shaken at room temperature for 1 hour. N-methyl-4-nitroaniline (B06) (2.9 mg, 0.019 mmol) was added. A MeCN solution (3.8 μL) of PipClU (1.0 M, 0.0038 mmol) and NMI (1.0 M, 0.0038 mmol) was added, and the mixture was shaken at room temperature for 24 hours.

[0665] 12 μL of the reaction mixture and solid phase suspension was transferred onto a filter tip and washed five times with DMF (0.1 mL), five times with MeOH (0.1 mL), and five times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) and analyzed by LCMS. As a result, 58% E1206 was observed. However, the total amount calculated was 100% excluding the peaks derived from impurities originally contained in D12-1R (96% purity) and the pentamethylbenzene peak. The analysis was also performed by cutting out at a wavelength of 270 nm (± 4 nm).

[0666]

[0667] Compound E1206 LRMS: m / z 377 [M+H] ＋ Retention time: 1.051 minutes (Analysis conditions FA05-1)

[0668] Example 3-3-32: Synthesis of E1228-1R by amidation of compound D12-1R and N-ethyl-4-nitroaniline (B28)

[0669]

[0670] Under a nitrogen atmosphere, D12-1R (0.190 mmol / g, 10 mg, purity 96%) and DCM (0.2 mL) were placed in a 0.6 mL glass vial and shaken at room temperature for 1 hour. N-ethyl-4-nitroaniline (B28) (3.2 mg, 0.019 mmol) was added. A MeCN solution (3.8 μL) of PipClU (1.0 M, 0.0038 mmol) and NMI (1.0 M, 0.0038 mmol) was added, and the mixture was shaken at room temperature for 24 hours.

[0671] 12 μL of the reaction mixture and solid phase suspension was transferred onto a filter tip and washed five times with DMF (0.1 mL), five times with MeOH (0.1 mL), and five times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) and analyzed by LCMS. As a result, 34% E1228 was observed. However, the total amount calculated was 100%, excluding the peaks derived from impurities originally contained in D12-1R (96% purity) and the pentamethylbenzene peak. The analysis was also performed by cutting out at a wavelength of 270 nm (± 4 nm).

[0672]

[0673] Compound E1228 LRMS: m / z 391 [M+H] ＋ Retention time: 1.093 minutes (Analysis conditions FA05-1)

[0674] Example 3-3-33: Synthesis of E1218-1R by amidation of compound D12-1R and 4-aminobenzonitrile (B18)

[0675]

[0676] Under a nitrogen atmosphere, D12-1R (0.190 mmol / g, 10 mg, purity 96%) and DCM (0.2 mL) were placed in a 0.6 mL glass vial and shaken at room temperature for 1 hour. 4-Aminobenzonitrile (B18) (2.2 mg, 0.019 mmol) was added. A MeCN solution (3.8 μL) of PipClU (1.0 M, 0.0038 mmol) and NMI (1.0 M, 0.0038 mmol) was added, and the mixture was shaken at room temperature for 24 hours.

[0677] 12 μL of the reaction mixture and solid phase suspension was transferred onto a filter tip and washed five times with DMF (0.1 mL), five times with MeOH (0.1 mL), and five times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) and analyzed by LCMS. As a result, 92% E1218 was observed. However, the total amount calculated was 100% excluding the peaks derived from impurities originally contained in D12-1R (96% purity) and the pentamethylbenzene peak. The analysis was also performed by cutting out at a wavelength of 270 nm (± 4 nm).

[0678]

[0679] Compound E1218 LRMS: m / z 343 [M+H] ＋ Retention time: 1.052 minutes (Analysis conditions FA05-1)

[0680] Example 3-3-34: Synthesis of E1203-1R by amidation of compound D12-1R and 2,6-di(propan-2-yl)aniline (B03)

[0681]

[0682] Under a nitrogen atmosphere, D12-1R (0.190 mmol / g, 10 mg, purity 96%) and DCM (0.2 mL) were placed in a 0.6 mL glass vial and shaken at room temperature for 1 hour. 2,6-Di(propan-2-yl)aniline (B03) (3.4 mg, 0.019 mmol) was added. A MeCN solution (3.8 μL) of PipClU (1.0 M, 0.0038 mmol) and NMI (1.0 M, 0.0038 mmol) was added, and the mixture was shaken at room temperature for 24 hours.

[0683] 12 μL of the reaction mixture and solid phase suspension was transferred onto a filter tip and washed five times with DMF (0.1 mL), five times with MeOH (0.1 mL), and five times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) and analyzed by LCMS. As a result, 79% E1203 was observed. However, the total amount calculated is 100% excluding the peaks derived from impurities originally contained in D12-1R (96% purity) and the pentamethylbenzene peak. The analysis was also performed by cutting out at a wavelength of 270 nm (± 4 nm).

[0684]

[0685] Compound E1203 LRMS: m / z 402 [M+H] ＋ Retention time: 1.247 minutes (Analysis conditions FA05-1)

[0686] Example 3-3-35: Synthesis of G0607-1R by amidation of compound F06-1R and 2-methylbenzoic acid (A07)

[0687]

[0688] Under a nitrogen atmosphere, F06-1R (0.197 mmol / g, 10 mg, purity 99%) and DCM (0.15 mL) were placed in a 0.6 mL glass vial and shaken at room temperature for 1 hour. A THF solution (39.5 μL) of 2-methylbenzoic acid (A07) (0.3 M, 0.012 mmol) was added. A MeCN solution (9.87 μL) of PipClU (1.0 M, 0.0099 mmol) and NMI (1.0 M, 0.0099 mmol) and DIPEA (2.068 μL, 0.012 mmol) were added, followed by shaking at 40°C for 24 hours.

[0689] 12 μL of the reaction solution and solid phase suspension was transferred onto a filter tip and washed five times with DMF (0.1 mL), five times with MeOH (0.1 mL), and five times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) to measure the reaction progress by LCMS. As a result, 79% of G0607 was observed. However, the analysis was performed by cutting out at a wavelength of 299 nm (± 4 nm).

[0690]

[0691] Compound G0607 LRMS: m / z 429 [M+H] ＋ Retention time: 0.932 minutes (Analysis conditions FA05-1)

[0692] Example 3-3-36: Synthesis of G0608-1R by amidation of compound F06-1R and 4-methoxybenzoic acid (A08)

[0693]

[0694] Under a nitrogen atmosphere, F06-1R (0.197 mmol / g, 10 mg, purity 99%) and DCM (0.15 mL) were placed in a 0.6 mL glass vial and shaken at room temperature for 1 hour. A THF solution (39.5 μL) of 4-methoxybenzoic acid (A08) (0.3 M, 0.012 mmol) was added. A MeCN solution (9.87 μL) of PipClU (1.0 M, 0.0099 mmol) and NMI (1.0 M, 0.0099 mmol) and DIPEA (2.068 μL, 0.012 mmol) were added, followed by shaking at 40°C for 24 hours.

[0695] 12 μL of the reaction mixture and solid phase suspension was transferred onto a filter tip and washed five times with DMF (0.1 mL), five times with MeOH (0.1 mL), and five times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) and analyzed by LCMS. As a result, 100% G0608 was observed. However, the total amount excluding peaks derived from identifiable impurities was calculated as 100%. The analysis was also performed by cutting out at a wavelength of 299 nm (± 4 nm).

[0696]

[0697] Compound G0608 LRMS: m / z 445 [M+H] ＋ Retention time: 0.908 minutes (Analysis conditions FA05-1)

[0698] Example 3-3-37: Synthesis of G0609-1R by amidation of compound F06-1R and (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-methylbutanoic acid (A09)

[0699]

[0700] Under a nitrogen atmosphere, F06-1R (0.197 mmol / g, 10 mg, 99% purity) and DCM (0.15 mL) were added to a 0.6 mL glass vial and shaken at room temperature for 1 hour. A THF solution (39.5 μL) of (2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-3-methylbutanoic acid (A09) (0.3 M, 0.012 mmol) was added. A MeCN solution (9.87 μL) of PipClU (1.0 M, 0.0099 mmol) and NMI (1.0 M, 0.0099 mmol) and DIPEA (2.068 μL, 0.012 mmol) were added, followed by shaking at 40°C for 24 hours.

[0701] 12 μL of the reaction mixture and solid phase suspension was transferred onto a filter tip and washed five times with DMF (0.1 mL), five times with MeOH (0.1 mL), and five times with DCM (0.1 mL). The mixture was immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.1 M, 0.05 mL) for 1 minute, filtered, washed with DMF (0.05 mL), and the combined filtrate was diluted with MeCN (0.25 mL) and analyzed by LCMS. As a result, 89% G0609 was observed. However, the total amount excluding peaks derived from identifiable impurities was calculated as 100%. The analysis was also performed by cutting out at a wavelength of 299 nm (± 4 nm).

[0702]

[0703] Compound G0609 LRMS: m / z 646 [M+H] ＋ Retention time: 1.271 minutes (Analysis conditions FA05-1)

[0704] Example 4: Application of amidation conditions to mixtures Example 4-1: Synthesis of mixture 2-2-c1D01-0 by amidation reaction of mixture 2-2-D00-0 and confirmation of its production Example 4-1-1: Synthesis of mixture 2-2-c1D01-0 by amidation reaction of mixture 2-2-D00-0

[0705]

[0706] The compounds that can be contained in the separately prepared mixture 2-2-D00-0 are shown in Table 4-1-1-1. In Table 4-1-1-1, each compound that can be contained in the mixture is shown by an ID, and the structure is represented by a symbol that represents the combination of the corresponding n number and part B, part b, and part C in the structural formula of the mixture.

[0707] In this specification, the correspondence between symbols and structural formulae in parts B, b, C and c is as shown below.

[0708]

[0709] Structural formula and symbol corresponding to part B of the structural formula in Example 4

[0710]

[0711]

[0712]

[0713] For example, compound 2-2-D00-0-0001 has the following structure, where n is 0, B is B01, b is b1, and C is C01.

[0714]

[0715] Furthermore, for example, compound 2-2-D00-0-0049 has the following structure, in which the number n is 1, B is B02, b is b4, and C is C12.

[0716]

[0717] The 25 types of mixture were added to a 20 mL glass vial to give mixture 2-2-D00-0 (800 mg), followed by DCM (12.0 mL) and shaking at room temperature for 1 hour. 4-Fluoro-3-nitroaniline (B15) (0.242 g, 1.55 mmol) was added. A mixture of PipClU (0.224 g, 0.621 mmol), NMI (0.049 mL, 0.621 mmol), and MeCN (0.50 mL) was added and the mixture was shaken at room temperature for 17 hours.

[0718] The suspension of the reaction liquid and solid phase was transferred to a filter-equipped column and filtered, and washed three times with NMP / water = 1 / 1 (16 mL), three times with an NMP solution of tetrabutylammonium hydrogen sulfate and 2,6-di-tert-butylpyridine mixed (each 0.05 M, 16 mL), three times with an NMP solution of 4-methylmorpholine (0.05 M, 16 mL), three times with NMP / water = 1 / 1 (16 mL), three times with NMP (16 mL), three times with MeOH (16 mL), three times with DCM (16 mL), and three times with heptane (16 mL). The obtained solid phase was dried under reduced pressure to obtain mixture 2-2-c1D01-0.

[0719] The compounds that can be included in mixture 2-2-c1D01-0 are shown in Table 4-1-1-2. In Table 4-1-1-2, each compound that can be included in the mixture is shown by an ID, and the structure is represented by a symbol that represents the corresponding n number in the structural formula of the mixture and the combination of parts B, b, and C. The correspondence between the symbols and structural formulas for parts B, b, and C has already been shown.

[0720]

[0721]

[0722]

[0723]

[0724]

[0725]

[0726]

[0727]

[0728]

[0729]

[0730]

[0731]

[0732]

[0733]

[0734]

[0735]

[0736] Example 4-1-2: Synthesis of mixture 2-2-c2D02-0 by acylsulfonamidation reaction of mixture 2-2-D00-0

[0737]

[0738] The 25 types of mixture were added to a 20 mL glass vial to give mixture 2-2-D00-0 (832 mg), followed by addition of NMP (12.0 mL) and shaking at room temperature for 1 hour. 2,6-Lutidine (0.108 mL, 0.931 mmol) and HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, CAS number: 148893-10-1) (0.354 g, 0.931 mmol) were added, followed by shaking at 45°C for 17 hours. 4-Fluoro-3-nitrobenzenesulfonamide (B16) (0.239 g, 1.09 mmol) and P1tBu (tert-butylimino-tris(dimethylamino)phosphorane, CAS number: 81675-81-2) (0.592 mL, 2.33 mmol) were added, and the mixture was shaken at room temperature for 18 hours.

[0739] The suspension of the reaction liquid and solid phase was transferred to a filter-equipped column and filtered, and washed three times with NMP / water = 1 / 1 (16 mL), three times with an NMP solution of tetrabutylammonium hydrogen sulfate and 2,6-di-tert-butylpyridine mixed (each 0.05 M, 16 mL), three times with an NMP solution of 4-methylmorpholine (0.05 M, 16 mL), three times with NMP / water = 1 / 1 (16 mL), three times with NMP (16 mL), three times with MeOH (16 mL), three times with DCM (16 mL), and three times with heptane (16 mL). The obtained solid phase was dried under reduced pressure to obtain mixture 2-2-c2D02-0.

[0740] The compounds that can be included in mixture 2-2-c2D02-0 are shown in Table 4-1-2-1. In Table 4-1-2-1, each compound that can be included in the mixture is shown by an ID, and the structure is represented by a symbol that represents the corresponding n number in the structural formula of the mixture and the combination of parts B, b, and C. The correspondence between the symbols and structural formulas for parts B, b, and C has already been shown.

[0741]

[0742]

[0743]

[0744]

[0745]

[0746]

[0747]

[0748]

[0749] Example 4-1-3: Synthesis of mixture 2-2-d1E01-0

[0750]

[0751] Mixture 2-2-c1D01-0 (100 mg) and mixture 2-2-c2D02-0 (100 mg) were placed in a 4 mL glass vial, and NMP (2.0 mL) was added, followed by shaking at room temperature for 1 hour. Cyclohexylamine (B17) (37.2 mg, 0.375 mmol) and 1,8-bis(dimethylamino)naphthalene (121 mg, 0.563 mmol) were added, followed by shaking at 80°C for 18 hours.

[0752] The suspension of the reaction solution and solid phase was transferred to a filter-equipped column and filtered, and washed three times with NMP / water = 1 / 1 (4 mL), three times with NMP (4 mL), three times with an NMP solution of tetrabutylammonium hydrogen sulfate and 2,6-di-tert-butylpyridine mixed (each 0.05 M, 4 mL), three times with an NMP solution of 4-methylmorpholine (0.05 M, 4 mL), three times with NMP / water = 1 / 1 (4 mL), three times with NMP (4 mL), three times with MeOH (4.5 mL), three times with DCM (4.5 mL), and three times with heptane (4.5 mL). The obtained solid phase was dried under reduced pressure to obtain mixture 2-2-d1E01-0.

[0753] The compounds that can be included in mixture 2-2-d1E01-0 are shown in Table 4-1-3-1. In Table 4-1-3-1, each compound that can be included in the mixture is indicated by an ID, and the structure is represented by a symbol that represents the combination of the corresponding n number and part B, part b, part C, and part c in the structural formula of the mixture. The correspondence between the symbols and structural formulas for part B, part b, part C, and part c has already been shown. For example, compound 2-2-d1E01-0-0001 has an n number of 0, B is B01, b is b1, C is C01, and c is c01, and has the following structure.

[0754]

[0755]

[0756]

[0757]

[0758]

[0759]

[0760]

[0761]

[0762]

[0763]

[0764]

[0765]

[0766]

[0767]

[0768]

[0769]

[0770] Example 4-1-4: Confirmation of progress of amidation reaction in Example 4-1-1 by analysis of mixture 2-2-d1E01-1

[0771]

[0772] Mixture 2-2-d1E01-0 (50 mg) was placed in a 2 mL glass vial. A solution of pentamethylbenzene in DCM (0.08 M, 1.0 mL) was added, and the mixture was shaken at room temperature for 30 minutes. TFA (0.10 mL) was added, and the mixture was shaken at room temperature for 30 minutes. The reaction mixture and solid suspension were transferred to a 3 mL filter column using two 0.5 mL portions of DMI, and then filtered. The mixture was washed twice with 0.5 mL of DMI, and the combined filtrate was collected in a 15 mm x 75 mm test tube. The solution was evaporated in a Genevac. Solid-supported morpholine (Aldrich catalog number: 493813) (80 mg) and 0.4 mL of DMI were added, and the mixture was shaken at 1500 rpm for 15 minutes. The solution and solid suspension were transferred to a 3 mL filter column using two 0.4 mL portions of DMI, and then filtered. The mixture was washed twice with DMI (0.2 mL) and twice with MeCN (0.2 mL), and the combined filtrate was placed in a 0.5-2 mL microwave vessel. The solution was evaporated under reduced pressure (using a Genevac vacuum concentrator). The residue was dissolved in dimethyl sulfoxide (0.185 mL) to obtain a solution of mixture 2-2-d1E01-1. Retention time measurements and mass spectrometry of the compounds in mixture 2-2-d1E01-1 were performed under the analytical conditions shown below, and analysis was performed using Compound Discoverer 3.2 (Thermo Fisher Scientific).

[0773]

[0774] As a result, as shown in Table 4-1-4, the m / z and retention times of 499 out of 500 compounds that could be contained in mixture 2-2-d1E01-1 were observed. This indicates that mixture 2-2-d1E01-0 was synthesized in 99.8% success rate, and that the previous step, mixture 2-2-c1D01-0, was also synthesized in 99.6% or more success rate.

[0775] The above results demonstrated that the amidation reaction of mixture 2-2-D00-0 in Example 4-1-1 proceeded without any problems. Furthermore, it was demonstrated that the amidation reaction conditions are applicable even when the substrate is not a single substrate but a mixture of multiple substrates.

[0776]

[0777]

[0778]

[0779]

[0780]

[0781]

[0782]

[0783]

[0784]

[0785]

[0786]

[0787]

[0788]

[0789] In the production of a compound library having diverse structures, it was shown that a compound library can be efficiently constructed by applying the reaction conditions shown in this example and performing an amidation step on multiple compounds.

Claims

1. A method for producing an amide compound, comprising reacting a carboxylic acid compound with an amine compound in the presence of a condensing agent and a first base to obtain the amide compound, wherein the first base is a compound represented by Formula A: 【Chemistry 1】 [In the formula, R １ is C １－６ Alkyl and C ６－１０ aryl, R ２ , R ３ , and R ４ are each independently a hydrogen atom, a halogen atom, or C １－６ Alkyl, and C ６－１０ aryl, or R １ and R ２ is R １ and the nitrogen atom to which R ２ and the condensing agent is a 5- to 6-membered non-aromatic heterocycle, and two or more of the condensing agent may be used, and the molar ratio of the first base to the condensing agent (first base / condensing agent) is 1.8 or less.

2. 2. The method according to claim 1, wherein the condensing agent is a uronium-based condensing agent or a 2-halo-N-alkylpyridinium-based condensing agent.

3. The method of claim 1 , wherein the reaction is further carried out in the presence of a second base.

4. 10. The method of claim 1, wherein the reaction is carried out in the presence of an excess of the amine compound as a second base.

5. 4. The method of claim 3, wherein the second base is an organic base whose conjugate acid has a pKa in water of 11 or less.

6. The second base is represented by formula B1 and B2: 【Chemistry 2】 [In the formula, R ５ and R ６ together with the nitrogen atom to which it is attached form a 5- to 7-membered saturated heterocycle, which may further contain heteroatoms selected from O and S, or R ５ and R ７ , and / or R ６ and R １１ together with the nitrogen atom and carbon atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, which may further contain heteroatoms selected from O and S, or R ５ and R ６ are each independently, C １－６ Alkyl, and C ６－１０ aryl; R ７ , R ８ , R ９ , R １０ and R １１ are each independently a hydrogen atom, C １－６ Alkyl, C ６－１０ aryl, halogen atom, or cyano; R １２ , R １３ , R １４ , R １５ and R １６ are each independently a hydrogen atom, C １－６ Alkyl, and C ６－１０ aryl; Said C １－６ Alkyl, and C ６－１０ The method according to claim 3, wherein the aryl is selected from the group consisting of:

7. The method according to any one of claims 1 to 6, wherein the first base is selected from the group consisting of N-methylimidazole, tetramethylimidazole, and N-phenylimidazole, and two or more of them may be used.

8. The method according to any one of claims 1 to 6, wherein the reaction is carried out in the presence of a solvent, and the solvent is selected from the group consisting of halogen-based solvents, nitrile-based solvents, amide-based solvents, ether-based solvents, and aromatic hydrocarbon-based solvents, and two or more of these solvents may be used.

9. The method according to any one of claims 1 to 6, wherein the carboxylic acid compound is a resin for solid phase synthesis to which a carboxylic acid compound is bound via a linker, or the amine compound is a resin for solid phase synthesis to which an amine compound is bound via a linker.

10. The carboxylic acid compound is of formula A1 or A2: 【Transformation 3】 [In the formula, R ２０ , R ２１ , R ２２ , R ２３ , R ２４ , R ２５ , R ２６ and R ２７ are each independently a hydrogen atom, a halogen atom, cyano, C １－６ Alkyl, C １－６ Alkoxy, (C １－６ alkoxy)carbonyl, (C １－６ alkoxy)carbonylamino, (C １－６ alkyl)carbonylamino, (C ６－１０ aryl)carbonylamino, di(C １－６ alkyl)amino, 4- to 8-membered cyclic amino, aminocarbonyl, (C １－６ alkyl)aminocarbonyl, di(C １－６ alkyl)aminocarbonyl, 4- to 8-membered cyclic aminocarbonyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ Cycloalkyl, C ７－１４ Aralkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl containing one or more ring heteroatoms independently selected from O, N, and S, each of which may be substituted by a substituent; or a mixture of two or more of these compounds, or a resin for solid phase synthesis to which said compound is bound via a linker, wherein the carboxylic acid compound does not have a group participating in an amide bond-forming reaction other than the carboxy group represented by Formula A1 or Formula A2.

11. The amine compound is of formula A3 or A4: 【Chemistry 4】 [In the formula, R ４０ , R ４６ and R ４７ are each independently a hydrogen atom, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ Cycloalkyl, C ７－１４ Aralkyl, C ６－１０ aryl, and 5-10 membered heteroaryl containing one or more ring heteroatoms independently selected from O, N, and S; or R ４０ and R ４５ together with the nitrogen atom and carbon atom to which they are attached form a 5- to 7-membered non-aromatic heterocycle, which may further contain heteroatoms selected from O and S, or R ４６ and R ４７ together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocycle, which may further contain heteroatoms selected from O and S; R ４１ , R ４２ , R ４３ , R ４４ , and R ４５ are each independently a hydrogen atom, a halogen atom, cyano, nitro, C １－６ Alkyl, C １－６ Alkoxy, (C １－６ alkoxy)carbonyl, (C １－６ alkoxy)carbonylamino, (C １－６ alkyl)carbonylamino, (C ６－１０ aryl)carbonylamino, di(C １－６ alkyl)amino, 4- to 8-membered cyclic amino, aminocarbonyl, (C １－６ alkyl)aminocarbonyl, di(C １－６ alkyl)aminocarbonyl, 4- to 8-membered cyclic aminocarbonyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ Cycloalkyl, C ７－１４ Aralkyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl containing one or more ring heteroatoms independently selected from O, N, and S, each of which may be substituted by a substituent; or a mixture of two or more of these compounds, or a resin for solid phase synthesis to which the compound is bound via a linker, wherein the amine compound does not have a group participating in an amide bond-forming reaction other than the amino group represented by Formula A3 or Formula A4.

12. The uronium-based condensing agent is represented by formula C1: 【Transformation 5】 [In the formula, R ３０ , R ３１ , R ３２ , R ３３ are each independently, C １－６ is alkyl, or R ３０ and R ３１ , and / or R ３２ and R ３３ form a 5- to 7-membered saturated heterocycle, which may contain one ring heteroatom selected from O or S, or R ３１ and R ３２ form a 5- to 7-membered saturated heterocycle, which may contain one ring heteroatom selected from O or S; X is a leaving group, Z is a counter anion; or The 2-halo-N-alkylpyridinium condensing agent is represented by formula C3: 【Transformation 6】 [In the formula, R ３５ is C １－６ is alkyl, and X １ is a halogen, and Y is a counter anion; or a mixture of two or more compounds represented by the formula (I).

13. The method according to any one of claims 1 to 6, wherein the reaction is carried out in a mixture containing two or more different carboxylic acid compounds and / or two or more different amine compounds as substrates.

14. A method for producing compounds constituting a compound library, the method comprising producing an amide compound by the method according to any one of claims 1 to 6.

15. A method for forming an amide bond by dehydration condensation of a carboxy group and an amino group, comprising reacting a carboxylic acid compound with an amine compound in the presence of a condensing agent and a first base to form an amide bond, wherein the first base is a compound represented by Formula A: 【Transformation 7】 [In the formula, R １ is C １－６ Alkyl and C ６－１０ aryl, R ２ , R ３ , and R ４ are each independently a hydrogen atom, a halogen atom, or C １－６ Alkyl, and C ６－１０ aryl, or R １ and R ２ is R １ and the nitrogen atom to which R ２ and a molar ratio of the first base to the condensing agent (first base / condensing agent) is 1.8 or less.

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