Method for forming bond through coupling reaction

Abstract

The present invention provides a method for producing a compound through a cross-coupling reaction, wherein: the method for producing a compound includes reacting a compound 1 having a leaving group X1 on a carbon atom of an aromatic ring, and a compound 2 having a reactive group capable of a C-O bond-forming reaction or a C-N bond-forming reaction through substitution with the aforementioned leaving group, in a solvent that includes an amide solvent represented by formula A [in the formula, R1, R2, and R3 each independently represent a C1-4 alkyl, where the total number of carbon atoms in R1, R2, and R3 is 4-6] in the presence of a catalyst and a base; and X1 is a halogen atom or -O-SO2-R4.

Description

Bond formation method by coupling reaction

[0001] The present invention relates to a method for forming a bond by a coupling reaction, specifically a method for forming a carbon-oxygen bond (C—O bond) or a carbon-nitrogen bond (C—N bond).The present invention also relates to a method for producing a compound, which includes a step of forming a bond by a coupling reaction.

[0002] Cross-coupling reactions to form carbon-oxygen or carbon-nitrogen bonds are widely used in the synthesis of compounds, such as pharmaceutical development. For example, there have been many reports on the cross-coupling reaction of aryl halides using a palladium catalyst (Non-Patent Documents 1 to 3).

[0003] It is known that one of the side reactions in the above cross-coupling reaction is the generation of a dehalogenated product in which a halogen atom in the reaction substrate, such as an aryl halide, is replaced with a hydrogen atom (Non-Patent Document 1). It has been reported that the generation of the dehalogenated product can be suppressed by changing the ligand or performing the reaction at a low temperature (Non-Patent Document 2).

[0004] Furthermore, when a substrate containing a functional group highly sensitive to bases, such as a carboxylic acid ester structure, is used in a reaction, it has been reported that the use of a P2Et phosphazene base is preferable to the use of an alkali metal base such as NaOtBu or LiHMDS (Non-Patent Document 6).

[0005] The effect of solvents on palladium-catalyzed cross-coupling reactions has been reported (Non-Patent Documents 4 and 5). In addition, the addition of N,N-dimethyloctanamide to a solvent to prevent clogging in flow channels has been reported (Non-Patent Document 7).

[0006] US4,453,017 JP2006-213692

[0007] Dorel, R. et al., Angew. Chem. Int. Ed. 2019, 58, 17118.Surry, DS et al. Chem. Sci. 2011, 2, 27.Anderson, KW et al., J. Am. Chem. Soc. 2006, 128, 10694.Sherwood, J. et al., Green. Chem. 2019, 21, 2164. Molina De La Torre, JA et al., Organometallics 2013, 32, 5428. Santanilla, AB et al., Organic Letters, 2015, 17, 3370. Yang, JC et al., Angew. Chem. Int. Ed. 2016, 55, 2531.

[0008] Palladium-catalyzed cross-coupling reactions are widely used in the synthesis of compounds, including pharmaceutical development, and numerous palladium catalysts have been developed. However, the inventors have confirmed that, depending on the substrate, problems remain, such as low conversion rates and / or the generation of numerous by-products in which the leaving group is replaced by hydrogen. These problems remain unresolved under conventional coupling conditions. For example, in the carbon-nitrogen bond-forming reaction of coupling aryl halides with amines as substrates, even when conditions based on Non-Patent Document 2 are used, problems such as low conversion rates and significant formation of dehalogenated products have been observed when certain substrates are used. Furthermore, in the synthesis of allenols via carbon-oxygen bond-forming coupling reactions of aryl halides with water as substrates, even when conditions based on Non-Patent Document 3 are used, the formation of impurities such as dehalogenated products cannot be sufficiently suppressed with certain substrates. Furthermore, even when using reaction solvents as described in Non-Patent Documents 4, 5, and 7, no improvement was observed.

[0009] The present invention has been made in view of these circumstances, and an object of the present invention is to provide a method for forming a carbon-oxygen bond or a carbon-nitrogen bond in a cross-coupling reaction of an aryl halide using a palladium catalyst, which method can improve the conversion rate and / or suppress the production of by-products. Another object of the present invention is to provide a method for synthesizing a compound, which method includes the above method. Another object of the present invention is to provide a method for improving the conversion rate and / or suppressing the production of by-products such as dehalogenated products, which can be applied to a cross-coupling reaction of an aryl halide using a palladium catalyst.

[0010] The present inventors have discovered that the use of a specific solvent exhibits favorable reactivity in a cross-coupling reaction using a palladium catalyst, and further discovered that this solvent is applicable to reactions for forming carbon-oxygen bonds (C-O bonds) or carbon-nitrogen bonds (C-N bonds), thereby completing the present invention.

[0011] [A-1] A method for producing a compound by cross-coupling reaction, comprising reacting a compound of formula A:

[0012]

[0013] [In the formula, R １ , R ２ and R ３ are each independently C １－４ alkyl, provided that R １ , R ２ and R ３ and the total number of carbon atoms of the aromatic rings is 4 or more and 6 or less. １ with a compound 2 having a reactive group capable of a C—O bond forming reaction or a C—N bond forming reaction by substitution with the leaving group; １ represents a halogen atom or —O—SO ２ -R ４ and R ４C may be substituted with one or more fluorine atoms １－６ Alkyl, or one or more fluorine atoms or C optionally substituted with fluorine atoms １－６ The above method, wherein Compound 2 is phenyl optionally substituted with alkyl; and Compound 2 has a hydroxy capable of forming a C—O bond or an H—N group capable of forming a C—N bond.

[0014] [A-2] The method according to [A-1], wherein the catalyst is a palladium catalyst or a nickel catalyst.

[0015] [A-3] The method according to [A-1] or [A-2], wherein the catalyst is a palladium catalyst.

[0016] [A-4] The method according to any one of [A-1] to [A-3], wherein compound 1 has one leaving group, or two or three leaving groups which may be the same or different.

[0017] [A-5] The method according to any one of [A-1] to [A-4], wherein compound 1 has one leaving group.

[0018] [A-6] The method according to any one of [A-1] to [A-5], wherein compound 2 has one of the reactive groups, or two or three of the reactive groups, which may be the same or different.

[0019] [A-7] The method according to any one of [A-1] to [A-6], wherein compound 2 has one of the reactive groups.

[0020] [A-8] The method according to any one of [A-1] to [A-7], wherein either compound 1 or 2 is supported on a resin for solid phase synthesis.

[0021] [A-9] Compound 2 is: 1) water or HO—R ５ is a compound having a hydroxyl capable of forming a C—O bond, represented by R ５ is C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ Cycloalkyl, C ７－１４ Aralkyl, C ６－１０aryl, or a 5-10 membered heteroaryl containing one or more ring heteroatoms independently selected from O, N and S, each of which is selected from fluorine atoms, 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, 5-10 membered heteroarylcarbonylamino containing one or more ring heteroatoms independently selected from O, N and S, aminocarbonyl, (C １－６ alkyl)aminocarbonyl, di(C １－６ 2) HNR, which may be substituted by one or more groups independently selected from the group consisting of HNR, HNR alkyl, HNR cyclic ... ６ R ７ R is a compound having an H—N group capable of forming a C—N bond, ６ and R ７ together with the nitrogen atom to which they are attached to form a 5- to 7-membered saturated heterocycle, and the heterocycle is not limited to a fluorine atom, a cyano, a 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, 5-10 membered heteroarylcarbonylamino containing one or more ring heteroatoms independently selected from O, N and S, di(C １－６ alkyl)amino, 4- to 8-membered cyclic amino, aminocarbonyl, (C １－６ alkyl)aminocarbonyl, di(C １－６ or R ６ and R ７ are each independently a hydrogen atom, C １－６ Alkyl, C ２－６Alkenyl, C ２－６ Alkynyl, C ３－８ cycloalkyl, (C １－６ alkyl)carbonyl, (C ６－１０ aryl)carbonyl, 5-10 membered heteroarylcarbonyl containing one or more ring heteroatoms independently selected from O, N and S, C ７－１４ Aralkyl, C ６－１０ aryl, or a 5-10 membered heteroaryl containing one or more ring heteroatoms independently selected from O, N and S, each of which is selected from fluorine atoms, 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, 5-10 membered heteroarylcarbonylamino containing one or more ring heteroatoms independently selected from O, N and S, di(C １－６ alkyl)amino, 4- to 8-membered cyclic amino, aminocarbonyl, (C １－６ alkyl)aminocarbonyl, di(C １－６ The method according to any one of [A-1] to [A-8], which is optionally substituted with one or more substituents independently selected from the group consisting of alkylaminocarbonyl and 4- to 8-membered cyclic aminocarbonyl.

[0022] [A-10] Compound 1 is X １ -Ar ２ is a compound represented by the formula: １ represents a chlorine atom, a bromine atom, an iodine atom, or —O—SO ２ -R ４ and R ４ C may be substituted with one or more fluorine atoms １－６ Alkyl, or one or more fluorine atoms or C optionally substituted with fluorine atoms １－６ phenyl optionally substituted with alkyl; Ar ２ is C ６－１０aryl, or a 5-10 membered heteroaryl containing one or more ring heteroatoms independently selected from O, N and S, each of which is selected from fluorine atoms, 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, 5-10 membered heteroarylcarbonylamino containing one or more ring heteroatoms independently selected from O, N and S, di(C １－６ alkyl)amino, 4- to 8-membered cyclic amino, aminocarbonyl, (C １－６ alkyl)aminocarbonyl, di(C １－６ The method according to any one of [A-1] to [A-9], wherein the amino group is optionally substituted with one or more groups independently selected from the group consisting of alkyl)aminocarbonyl, and 4- to 8-membered cyclic aminocarbonyl.

[0023] [A-11] Compound 1 is supported on a resin for solid phase synthesis, and X described in [A-10] １ -Ar ２ The method according to any one of [A-1] to [A-10], wherein the compound represented by the formula (I) is a compound represented by the formula (I) in a part of its chemical structure.

[0024] [A-12] X １ is a chlorine atom, a bromine atom, or an iodine atom.

[0025] [A-13] Ar ２are independently selected from the group consisting of phenyl, naphthyl, 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, each of which is optionally substituted.

[0026] [A-14] Ar ２ The method according to any one of [A-10] to [A-13], wherein is phenyl or pyridyl, each of which may be substituted.

[0027] [A-15]X １ is a bromine atom; Ar ２ is phenyl, or pyridyl, each of which is selected from the group consisting of a fluorine 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, 5-10 membered heteroarylcarbonylamino containing one or more ring heteroatoms independently selected from O, N and S, di(C １－６ alkyl)amino, 4- to 8-membered cyclic amino, aminocarbonyl, (C １－６ alkyl)aminocarbonyl, di(C １－６ The method according to any one of [A-10] to [A-14], which is optionally substituted with one or more groups independently selected from the group consisting of (alkyl)aminocarbonyl, and 4- to 8-membered cyclic aminocarbonyl.

[0028] [A-16] The method according to any one of [A-1] to [A-15], wherein the solvent is selected from the group consisting of N,N-dimethylpropionamide (DMPr), N,N-diethylacetamide (DEAc), and N,N-diethylpropionamide (DEPr).

[0029] [A-17] The method according to any one of [A-1] to [A-16], wherein the solvent is N,N-dimethylpropionamide (DMPr).

[0030] [A-18] The method according to any one of [A-1] to [A-17], wherein the solvent contains at least one selected from the group consisting of N,N-dimethylpropionamide (DMPr), N,N-diethylacetamide (DEAc), and N,N-diethylpropionamide (DEPr) in an amount of 30 v / v % or more, 50 v / v % or more, 70 v / v % or more, or 90 v / v % or more.

[0031] [A-19] The method according to any one of [A-1] to [A-18], wherein the solvent contains N,N-dimethylpropionamide (DMPr) at a concentration of 30 v / v % or more, 50 v / v % or more, 70 v / v % or more, or 90 v / v % or more.

[0032] [A-20] The method according to any one of [A-1] to [A-19], wherein the cross-coupling reaction is carried out at 0 to 200°C, 0 to 150°C, 0 to 100°C, 10 to 80°C, or 25 to 80°C.

[0033] [A-21] The method according to any one of [A-1] to [A-20], wherein the molar ratio of compound 1 to compound 2 used is compound 1 / compound 2=0.0005 to 500, 0.005 to 200, or 0.05 to 20.

[0034] [A-22] The method according to any one of [A-1] to [A-21], wherein the molar ratio of the catalyst used is 0.01 to 100 mol %, 0.1 to 50 mol %, or 1 to 25 mol % relative to compound 1 or compound 2.

[0035] [A-23] The catalyst is represented by the following general formulae (Cat 1), (Cat 2), (Cat 3), (Cat 4) and (Cat 5):

[0036]

[0037] [In the formula, R ２０ is a hydrogen atom, C １－６ Alkyl, or C ６－１０ aryl, and R ２ is halogen or -O-SO ２ -CH ３ and R ２２ is a hydrogen atom, a C group optionally substituted with one or more fluorine atoms １－６ Alkyl, or tri(C １－６ alkyl) may be substituted by silyl (C １－６ L is independently a monodentate ligand (L1), (L2), (L3), (L4), (L5), (L6) or (L7) of the following general formula: or two L are bidentate ligands (L8), (L9), (L10), (L11) or (L12):

[0038]

[0039] [In the formula, R ２３ are independently tert-butyl, cyclohexyl, 2-furanyl, 2-thienyl, 2-pyridyl, phenyl (the phenyl is one or more fluorine atoms, C optionally substituted with fluorine atoms). １－６ Alkyl, C １－６ alkoxy, or dimethylamino), or adamantyl, R ２４ is C １－６ alkyl, cyclohexyl, 2-furanyl, 2-thienyl, 2-pyrryl, N-phenyl-2-pyrrolyl, N-phenyl-2-indolyl, phenyl (the phenyl is one or more fluorine atoms, C optionally substituted with fluorine atoms). １－６ Alkyl, C １－６ R is an alkyl group, optionally substituted with alkoxy, morpholino, or dimethylamino, or adamantyl; ２５ is a hydrogen atom, C １－６ Alkyl, or C １－６ Alkoxy, W １ is -C(CH ３ ) ２ - or -NH-, R２６ , R ２７ , R ２８ , and R ２９ are each independently a hydrogen atom, C １－６ Alkyl, C １－６ alkoxy, or morpholino, R ３０ , R ３１ , and R ３２ are each independently a hydrogen atom, C １－６ Alkyl, C １－６ alkoxy, or dimethylamino; R ３３ is a hydrogen atom or -SO ２ -O-M, where M is lithium, sodium, or potassium; R ３４ is a hydrogen atom, C １－６ Alkyl, or C １－６ is alkoxy, and R ３５ and R ３６ are each independently a hydrogen atom, C １－６ Alkyl, or C １－６ is alkoxy, and R ３７ is a hydrogen atom, or C １－６ phenyl optionally substituted with alkyl, R ３８ are independently a hydrogen atom, C １－６ Phenyl optionally substituted with alkyl, or —CH(CH ３ )-N(CH ３ ) ２ and R ３９ is tert-butyl, cyclohexyl, or adamantyl; R ４０ is a hydrogen atom, or C １－６ The method according to any one of [A-1] to [A-22], wherein the catalyst comprises a palladium complex represented by any one of the following formulae:

[0040] [A-24] The catalyst is represented by the following general formula (Cat 6) and general formula (Cat 7):

[0041]

[0042] [In the formula, R ４１ is a hydrogen atom or C １－６phenyl optionally substituted with alkyl, and R ４２ are independently halogen, and R ４３ represents a fluorine atom or a chlorine atom, and L represents an N-heterocyclic carbene ligand represented by the following general formula (L12) or (L13):

[0043]

[0044] R ４４ and R ４５ are each independently １－６ alkyl, cyclohexyl, adamantyl, or phenyl (wherein the phenyl is one or more C １－６ Alkyl, C １－６ The method according to any one of [A-1] to [A-22], wherein the catalyst comprises a palladium complex represented by the following formula:

[0045] [A-25] The catalyst is a palladium compound selected from the group consisting of bis(allylchloropalladium(II)), tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct, palladium(π-cinnamyl)chloride dimer, (1-methylallyl)palladium chloride dimer, (1,5-cyclooctadiene)bis(trimethylsilylmethyl)palladium(II), (2'-amino-1,1'-biphenyl-2-yl)methanesulfonatopalladium(II) dimer, and palladium(II) acetate, and a monodentate ligand (L1), (L2), (L3), (L4), (L5), (L6), or (L7) of the following general formula, or a bidentate ligand (L8), (L9), (L10), (L11), or (L12):

[0046]

[0047] [In the formula, R ２３ is tert-butyl, cyclohexyl, 2-furanyl, 2-thienyl, 2-pyridyl, phenyl (the phenyl is one or more fluorine atoms, C －６ Alkyl, C １－６alkoxy, or dimethylamino), or adamantyl, R ２４ is C １－６ alkyl, cyclohexyl, 2-furanyl, 2-thienyl, 2-pyridyl, N-phenyl-2-pyrrolyl, N-phenyl-2-indolyl, phenyl (the phenyl is one or more fluorine atoms, C optionally substituted with fluorine atoms). １－６ Alkyl, C １－６ R is an alkyl group, optionally substituted with alkoxy, morpholino, or dimethylamino, or adamantyl; ２５ is a hydrogen atom, C １－６ Alkyl, or C １－６ Alkoxy, W １ is -C(CH ３ ) ２ - or -NH-, R ２６ , R ２７ , R ２８ , and R ２９ are each independently a hydrogen atom, C １－６ Arles, C １－６ alkoxy, or morpholino, R ３０ , R ３１ , and R ３２ are each independently a hydrogen atom, C １－６ Alkyl, C １－６ alkoxy, or dimethylamino; R ３３ is a hydrogen atom or -SO ２ -O-M, where M is lithium, sodium, or potassium; R ３４ is a hydrogen atom, C １－６ Alkyl, or C １－６ is alkoxy, and R ３５ and R ３６ are each independently a hydrogen atom, C １－６ Alkyl, or C １－６ is alkoxy, and R ３７ is a hydrogen atom, or C １－６ phenyl optionally substituted with alkyl, R ３８ is a hydrogen atom, C １－６ Phenyl optionally substituted with alkyl, or —CH(CH ３)-N(CH ３ ) ２ and R ３９ is tert-butyl, cyclohexyl, or adamantyl; R ４０ is a hydrogen atom, or C １－６ The method according to any one of [A-1] to [A-22], wherein the catalyst comprises a palladium complex formed in combination with a ligand selected from the group consisting of a ligand represented by the formula:

[0048] [A-26] The method according to any one of [A-1] to [A-23], wherein the catalyst comprises a palladium complex selected from a Buchwald first generation catalyst precursor (G1), a Buchwald second generation catalyst precursor (G2), a Buchwald third generation catalyst precursor (G3), a Buchwald fourth generation catalyst precursor (G4), a Buchwald fifth generation catalyst precursor (G5), or a Buchwald sixth generation catalyst precursor (G6).

[0049] [A-27] The catalyst is a palladium compound selected from the group consisting of bis(allylchloropalladium(II)), tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct, palladium(π-cinnamyl)chloride dimer, (1-methylallyl)palladium chloride dimer, (1,5-cyclooctadiene)bis(trimethylsilylmethyl)palladium(II), (2'-amino-1,1'-biphenyl-2-yl)methanesulfonatopalladium(II) dimer, and palladium(II) acetate, and a monodentate ligand (L1), (L3), or (L6) represented by the following general formula:

[0050]

[0051] [In the formula, R ２３ are independently tert-butyl, cyclohexyl, or adamantyl; R ２４ is C １－６ alkyl, cyclohexyl, N-phenyl-2-indolyl, or adamantyl; R ２６ , R ２７ , R２８ , and R ２９ are each independently a hydrogen atom, C １－６ Alkyl, C １－６ alkoxy, or morpholino, R ３０ , R ３１ , and R ３２ are each independently a hydrogen atom, C １－６ Alkyl, C －６ alkoxy, or dimethylamino; R ３３ is a hydrogen atom or -SO ２ -O-M, where M is lithium, sodium, or potassium; R ３７ is C １－６ The method according to [A-25], wherein the catalyst is a palladium complex formed in combination with a ligand selected from the group consisting of a ligand represented by the formula (I) and a salt thereof, and a palladium catalyst formed in combination with a compound represented by the formula (I),

[0052] [A-28] The method according to any one of [A-1] to [A-22], wherein the catalyst is a nickel catalyst.

[0053] [A-29] The method according to any one of [A-1] to [A-22] and [A-28], wherein the catalyst comprises a nickel complex formed by combining a nickel compound selected from the group consisting of bis(1,5-cyclooctadiene)nickel, dichloro(1,2-dimethoxyethane)nickel, dibromo(1,2-dimethoxyethane)nickel, nickel(II) trifluoromethanesulfonate, bis(trifluoromethanesulfonimide)nickel(II), nickel(II) acetylacetonate, nickel(II) nitrate, nickel(II) bromide, nickel(II) chloride, and hydrates thereof, with a ligand selected from the group consisting of tricyclohexylphosphine, 1,1′-bis(diphenylphosphino)ferrocene, and 1,3-bis(diphenylphosphino)propane.

[0054] [A-30] The method according to any one of [A-1] to [A-22], [A-28] and [A-29], wherein the catalyst comprises a nickel complex selected from the group consisting of dichlorobis(tricyclohexylphosphine)nickel(II), dichloro[1,1'-bis(diphenylphosphino)ferrocene]nickel(II), and dichloro[1,3-bis(diphenylphosphino)propane]nickel(II).

[0055] [A-31] The method according to any one of [A-1] to [A-30], wherein the base comprises at least one base selected from the group consisting of organic bases having a conjugate acid with a pKa of 23 or more in acetonitrile and inorganic bases having a conjugate acid with a pKa of 9 to 20 in water.

[0056] [A-32] The base is selected from the group consisting of amidines, guanidines, phosphazenes, alkali metal carbonates, alkali metal phosphates, and alkali metal C １－６ The method according to any one of [A-1] to [A-31], wherein the compound is selected from the group consisting of alkali metal alkoxides and hydroxides of alkali metals.

[0057] [A-33] The base is 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), 1-ethyl-2,2,4,4,4-pentakis(dimethylamino)-2λ ５ ,4λ ５ -catenadi(phosphazene) (P2E), 1-tert-butyl-2,2,4,4,4-pentakis(dimethylamino)-2λ ５ ,4 ５ -catenadi(phosphazene) (P2tBu), tert-butylimino-tris(dimethylamino)phosphorane (P1tBu), 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP), tert-butylimino-tri(pyrrodino)phosphorane (BTPP), alkali metal carbonates, alkali metal phosphates, alkali metal C １－６The method according to any one of [A-1] to [A-32], wherein the compound is selected from the group consisting of alkali metal alkoxides and hydroxides of alkali metals.

[0058] [A-34] The base is 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), 1-tert-butyl-2,2,4,4,4-pentakis(dimethylamino)-2λ ５ ,4λ ５ The method according to any one of [A-1] to [A-33], wherein the compound is selected from the group consisting of tert-butylimino-tris(dimethylamino)phosphorane (P1tBu), 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP), tert-butylimino-tris(pyrrolidino)phosphorane (BTPP), cesium carbonate, tripotassium phosphate, potassium hydroxide, and sodium tert-butoxide.

[0059] [A-35] The method according to any one of [A-1] to [A-34], wherein the reaction system further contains a salt together with the base.

[0060] [A-36] The method according to [A-35], wherein the salt is an alkali metal salt of an acid selected from the group consisting of trifluoroacetic acid, trifluoromethanesulfonic acid, trifluoromethanesulfonimide, tetrafluoroboric acid, hexafluorophosphoric acid, and hexafluoroantimony(V) acid.

[0061] [A-37] The method according to [A-35], wherein the salt is sodium trifluoroacetate or potassium trifluoroacetate.

[0062] [A-38] The method according to any one of [A-1] to [A-37], wherein the molar ratio of the base to compound 1 or compound 2 is 0.05 to 100, 0.2 to 50, or 1 to 30.

[0063] [A-39] The method according to any one of [A-1] to [A-38], in which a mixture containing two or more types of compound 1 is reacted.

[0064] [A-40] A method according to any one of [A-1] to [A-39] for producing a compound constituting a compound library.

[0065] [A-41] The method according to any one of [A-1] to [A-40], wherein the resin for solid phase synthesis is one on which two or more types of compound 1 are supported via a linker.

[0066] [A-42] The method according to any one of [A-1] to [A-41], wherein the resin for solid phase synthesis has three or more, four or more, five or more, seven or more, or ten or more types of Compound 1 supported thereon via linkers.

[0067] [A-43] A method for producing a compound constituting a compound library, the method comprising producing the compound by the method according to any one of [A-1] to [A-42].

[0068] [A-44] Compound 1 has a leaving group X on the carbon atom of the aromatic ring in the side chain １ or a resin for solid phase synthesis having, in a side chain, a reactive group capable of undergoing a C—O bond forming reaction or a C—N bond forming reaction by substitution with the leaving group.

[0069] [B-1] The method according to any one of [A-1] to [A-44], wherein the cross-coupling reaction is a C—O bond forming reaction, and compound 2 has a hydroxyl capable of forming a C—O bond.

[0070] [B-2] Compound 2 is water or HO—R ５ R ５ is C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ Cycloalkyl, C ７－１４ Aralkyl, C ６－１０ aryl, or a 5-10 membered heteroaryl containing one or more ring heteroatoms independently selected from O, N and S, each of which is selected from fluorine atoms, cyano, C １－６ Alkyl, C １－６ Alkoxy, (C １－６alkoxy)carbonyl, (C １－６ alkoxy)carbonylamino, aminocarbonyl, (C １－６ alkyl)aminocarbonyl, di(C １－６ The method according to [B-1], wherein the amino group is optionally substituted with one or more groups independently selected from the group consisting of alkyl)aminocarbonyl, and 4- to 8-membered cyclic aminocarbonyl.

[0071] [B-3] Compound 2 is supported on a resin for solid phase synthesis, and HO-R ５ The method according to [B-2], wherein the compound represented by the formula (I) is contained as part of the chemical structure.

[0072] [B-4] The method according to [B-2] or [B-3], wherein compound 2 is water.

[0073] [B-5] The product of the coupling reaction is Ar ２ —OH or Ar ２ -OR ５ or a compound represented by Ar ２ —OH or Ar ２ -OR ５ A compound having a compound represented by the formula: ２ , and R ５ The method according to any one of [B-1] to [B-4], wherein is as defined above.

[0074] [C-1] The method according to any one of [A-1] to [A-44], wherein the cross-coupling reaction is a C—N bond forming reaction, and compound 2 has an H—N group capable of forming a C—N bond.

[0075] [C-2] Compound 2 is HNR ６ R ７ R ６ and R ７ together with the nitrogen atom to which they are attached to form a 5- to 7-membered saturated heterocycle, and the heterocycle is not limited to a fluorine atom, a cyano, a C １－６ Alkyl, C １－６ Alkoxy, (C １－６ alkoxy)carbonyl, (C １－６ alkoxy)carbonylamino, (C １－６alkyl)carbonylamino, (C ６－１０ aryl)carbonylamino, 5-10 membered heteroarylcarbonylamino containing one or more ring heteroatoms independently selected from O, N and S, di(C １－６ alkyl)amino, 4- to 8-membered cyclic amino, aminocarbonyl, (C １－６ alkyl)aminocarbonyl, di(C １－６ or R ６ and R ７ are each independently a hydrogen atom, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ cycloalkyl, (C １－６ alkyl)carbonyl, (C ６－１０ aryl)carbonyl, 5-10 membered heteroarylcarbonyl containing one or more ring heteroatoms independently selected from O, N and S, C ７－１４ Aralkyl, C ６－１０ aryl, or a 5-10 membered heteroaryl containing one or more ring heteroatoms independently selected from O, N and S, each of which is selected from fluorine atoms, cyano, C １－６ Alkyl, C １－６ Alkoxy, (C １－６ alkoxy)carbonyl, (C １－６ alkoxy)carbonylamino, di(C １－６ alkyl)amino, 4- to 8-membered cyclic amino, aminocarbonyl, (C １－６ alkyl)aminocarbonyl, di(C １－６ The method according to [C-1], wherein the aminocarbonyl group is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, cyclic, 4- to 8-membered aminocarbonyl, and cyclic aminocarbonyl.

[0076] [C-3] Compound 2 is supported on a resin for solid phase synthesis, and HNR ６ R ７ The method according to [C-1] or [C-2], wherein the compound represented by the formula (I) is a compound represented by the formula (I) in a part of its chemical structure.

[0077] [C-4] The product of the coupling reaction is Ar ２ -NR ６ R ７ or a compound represented by Ar ２ -NR ６ R ７ A compound having a compound represented by the formula: ２ , R ６ and R ７ The method according to any one of [C-1] to [C-3], wherein is as defined above.

[0078] [D-1] A method for producing a compound, comprising the method described in any one of [A-1] to [A-44], [B-1] to [B-5], [C-1] to [C-4], and [H-1] to [H-44].

[0079] [E-1] Formula A:

[0080]

[0081] [In the formula, R １ , R ２ and R ３ are each independently C １－４ alkyl, provided that R １ , R ２ and R ３ wherein the total number of carbon atoms is 4 or more and 6 or less, in a cross-coupling reaction.

[0082] [E-2] The use according to [E-1], wherein the solvent is used in any one of the methods described in [A-1] to [A-44], [B-1] to [B-4], and [C-1] to [C-3].

[0083] [F-1] A method for producing a compound by a cross-coupling reaction in the presence of a palladium catalyst, comprising reacting a compound of formula A:

[0084]

[0085] [In the formula, R １ , R ２ and R ３ are each independently C １－４ alkyl, provided that R１ , R ２ and R ３ wherein the total number of carbon atoms is 4 or more and 6 or less, and the palladium catalyst is a palladium complex containing a phosphine ligand.

[0086] [F-2] The method according to [F-1], wherein the solvent is selected from the group consisting of N,N-dimethylpropionamide (DMPr), N,N-diethylacetamide (DEAc), and N,N-diethylpropionamide (DEPr).

[0087] [F-3] The method according to either [F-1] or [F-2], wherein the solvent is N,N-dimethylpropionamide (DMPr).

[0088] [F-4] The method according to any one of [F-1] to [F-3], wherein the solvent contains at least one selected from the group consisting of N,N-dimethylpropionamide (DMPr), N,N-diethylacetamide (DEAc), and N,N-diethylpropionamide (DEPr) in an amount of 30 v / v % or more, 50 v / v % or more, 70 v / v % or more, or 90 v / v % or more.

[0089] [F-5] The method according to any one of [F-1] to [F-4], wherein the solvent contains N,N-dimethylpropionamide (DMPr) at a concentration of 30 v / v % or more, 50 v / v % or more, 70 v / v % or more, or 90 v / v % or more.

[0090] [F-6] The method according to any one of [F-1] to [F-5], wherein the cross-coupling reaction is carried out at 0 to 200°C, 0 to 150°C, 0 to 100°C, 0 to 80°C, or 25 to 80°C.

[0091] [F-7] The method according to any one of [F-1] to [F-6], wherein the catalyst is a catalyst containing a palladium complex represented by any one of general formulas (Cat 1), (Cat 2), (Cat 3), (Cat 4), and (Cat 5) described in [A-23].

[0092] [F-8] The method according to any one of [F-1] to [F-7], wherein the catalyst is a catalyst containing a palladium catalyst represented by any one of general formula (Cat 6) and general formula (Cat 7) described in [A-24].

[0093] [F-9] The catalyst is selected from the group consisting of bis(allylchloropalladium(II)), tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct, palladium(π-cinnamyl)chloride dimer, (1-methylallyl)palladium chloride dimer, (1,5-cyclooctadiene)bis(trimethylsilylmethyl)palladium(II), (2'-amino-1,1'-biphenyl-2-yl)methanesulfonyl The method according to any one of [F-1] to [F-8], wherein the catalyst comprises a palladium complex formed by combining at least one selected from the group consisting of palladium(II) dimer and palladium(II) acetate with a ligand selected from the group consisting of monodentate ligand (L1), (L2), (L3), (L4), (L5), (L6), or (L7) of the general formula described in [A-25], or bidentate ligand (L8), (L9), (L10), (L11), or (L12) or a salt thereof.

[0094] [F-10] The method according to any one of [F-1] to [F-9], wherein the catalyst comprises a palladium complex selected from the group consisting of a Buchwald first generation catalyst precursor (G1), a Buchwald second generation catalyst precursor (G2), a Buchwald third generation catalyst precursor (G3), a Buchwald fourth generation catalyst precursor (G4), a Buchwald fifth generation catalyst precursor (G5), or a Buchwald sixth generation catalyst precursor (G6).

[0095] [F-11] The method according to any one of [F-1] to [F-8], wherein the catalyst comprises a palladium complex formed by combining a palladium compound selected from the group consisting of bis(allylchloropalladium(II)), tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct, palladium(π-cinnamyl)chloride dimer, (1-methylallyl)palladium chloride dimer, (1,5-cyclooctadiene)bis(trimethylsilylmethyl)palladium(II), (2'-amino-1,1'-biphenyl-2-yl)methanesulfonatopalladium(II) dimer, and palladium(II) acetate, with a ligand selected from the monodentate ligands represented by the general formula (L1), (L3), or (L6) described in [A-27], and salts thereof.

[0096] [F-12] The method according to any one of [F-1] to [F-11], wherein the base comprises at least one base selected from the group consisting of organic bases whose conjugate acids have a pKa of 23 or more in acetonitrile and inorganic bases whose conjugate acids have a pKa of 9 to 20 in water.

[0097] [F-13] The base is selected from the group consisting of amidines, guanidines, phosphazenes, alkali metal carbonates, alkali metal phosphates, and alkali metal C １－６ The method according to any one of [F-1] to [F-12], wherein the compound is selected from the group consisting of alkali metal alkoxides and alkali metal hydroxides.

[0098] [F-14] The base is 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), 1-ethyl-2,2,4,4,4-pentakis(dimethylamino)-2λ ５ ,4λ ５ -catenadi(phosphazene) (P2E), 1-tert-butyl-2,2,4,4,4-pentakis(dimethylamino)-2λ ５ ,4 ５-catenadi(phosphazene) (P2tBu), tert-butylimino-tris(dimethylamino)phosphorane (P1tBu), 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP), tert-butylimino-tri(pyrrodino)phosphorane (BTPP), alkali metal carbonates, alkali metal phosphates, alkali metal C １－６ The method according to any one of [F-1] to [F-13], wherein the compound is selected from the group consisting of alkali metal alkoxides and alkali metal hydroxides.

[0099] [F-15] The base is 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), 1-tert-butyl-2,2,4,4,4-pentakis(dimethylamino)-2λ ５ ,4λ ５ The method according to any one of [F-1] to [F-14], wherein the compound is selected from the group consisting of tert-butylimino-tris(dimethylamino)phosphorane (P1tBu), 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP), tert-butylimino-tris(pyrrolidino)phosphorane (BTPP), cesium carbonate, tripotassium phosphate, potassium hydroxide, and sodium tert-butoxide.

[0100] [F-16] The method according to any one of [F-1] to [F-15], wherein the reaction system further contains a salt together with the base.

[0101] [F-17] The method according to [F-16], wherein the salt is an alkali metal salt of an acid selected from the group consisting of trifluoroacetic acid, trifluoromethanesulfonic acid, trifluoromethanesulfonimide, tetrafluoroboric acid, hexafluorophosphoric acid, and hexafluoroantimony(V) acid.

[0102] [F-18] The method according to [F-17], wherein the salt is sodium trifluoroacetate or potassium trifluoroacetate.

[0103] [F-19] The method according to any one of [F-1] to [F-18], wherein the cross-coupling reaction is a C—O bond-forming reaction involving elimination of the leaving group, using compound 1 having a leaving group and compound 2 having a hydroxy as substrates.

[0104] [F-20] Compound 1 is X １ -Ar ２ and X １ and Ar ２ The method according to [F-19], wherein is as defined above.

[0105] [F-21] Compound 2 is water or HO—R ５ and R ５ The method according to [F-19] or [F-20], wherein

[0106] [F-22] Compound 2 is supported on a resin for solid phase synthesis, and HO-R ５ The compound represented by R ５ The method according to [F-19] or [F-20], wherein

[0107] [F-23] The product of the coupling reaction is Ar ２ —OH or Ar ２ -O-R ５ or a compound represented by Ar ２ —OH or Ar ２ -O-R ５ A compound having a compound represented by the formula: ２ , and R ５ The method according to any one of [F-19] to [F-22], wherein

[0108] [F-24] The method according to any one of [F-1] to [F-18], wherein the cross-coupling reaction is a C—N bond-forming reaction involving elimination of the leaving group, using compound 1 having a leaving group and compound 2 having H—N as substrates.

[0109] [F-25] Compound 1 is X １ -Ar ２ and X １ and Ar ２The method according to [F-24], wherein is as defined above.

[0110] [F-26] Compound 2 is HNR ６ R ７ and R ６ , and R ７ The method according to [F-24] or [F-25], wherein

[0111] [F-27] Compound 2 is supported on a resin for solid phase synthesis, and HNR ６ R ７ The compound represented by R ６ , and R ７ The method according to [F-24] or [F-25], wherein

[0112] [F-28] The product of the coupling reaction is Ar ２ -NR ６ R ７ or a compound represented by Ar ２ -NR ６ R ７ A compound having a compound represented by the formula: ２ , R ６ , and R ７ The method according to any one of [F-24] to [F-27], wherein

[0113] [F-29] Compound 1 is supported on a resin for solid phase synthesis, and X １ -Ar ２ The compound represented by X is included in a part of the chemical structure. １ and Ar ２ The method according to any one of [F-19] to [F-28], wherein the formula (I) is as defined above.

[0114] [G-1] A method for suppressing the generation of by-products in a cross-coupling reaction, comprising reacting a compound represented by formula A:

[0115]

[0116] [In the formula, R １ , R ２ and R ３ are each independently C １－４alkyl, provided that R １ , R ２ and R ３ wherein the total number of carbon atoms in the aromatic ring is 4 or more and 6 or less, and the cross-coupling reaction is carried out in a solvent containing an amide solvent represented by the formula (I) １ wherein the by-product is a compound in which the leaving group has been replaced with a hydrogen atom.

[0117] [G-2] The method according to [G-1], wherein the catalyst is a palladium catalyst or a nickel catalyst.

[0118] [G-3] The method according to [G-1] or [G-2], wherein the catalyst is a palladium catalyst.

[0119] [G-4] The method according to any one of [G-1] to [G-3], wherein compound 1 has one leaving group, or two or three leaving groups which may be the same or different.

[0120] [G-5] The method according to any one of [G-1] to [G-4], wherein compound 1 has one leaving group.

[0121] [G-6] The method according to any one of [G-1] to [G-5], wherein compound 2 has one reactive group, or two or three reactive groups which may be the same or different.

[0122] [G-7] The method according to any one of [G-1] to [G-6], wherein compound 2 has one of the reactive groups.

[0123] [G-8] The method according to any one of [G-1] to [G-7], wherein either compound 1 or 2 is supported on a resin for solid phase synthesis.

[0124] [G-9] Compound 2 is: 1) water or HO—R ５ is a compound having a hydroxyl capable of forming a C—O bond, represented by R ５ is C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ Cycloalkyl, C７－１４ Aralkyl, C ６－１０ aryl, or a 5-10 membered heteroaryl containing one or more ring heteroatoms independently selected from O, N and S, each of which is selected from fluorine atoms, 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, 5-10 membered heteroarylcarbonylamino containing one or more ring heteroatoms independently selected from O, N and S, aminocarbonyl, (C １－６ alkyl)aminocarbonyl, di(C １－６ 2) HNR, which may be substituted by one or more groups independently selected from the group consisting of HNR, HNR alkyl, HNR cyclic ... ６ R ７ R is a compound having an H—N group capable of forming a C—N bond, ６ and R ７ together with the nitrogen atom to which they are attached to form a 5- to 7-membered saturated heterocycle, and the heterocycle is not limited to a fluorine atom, a cyano, a 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, 5-10 membered heteroarylcarbonylamino containing one or more ring heteroatoms independently selected from O, N and S, di(C １－６ alkyl)amino, 4- to 8-membered cyclic amino, aminocarbonyl, (C １－６ alkyl)aminocarbonyl, di(C １－６ or R ６ and R ７ are each independently a hydrogen atom, C１－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ cycloalkyl, (C １－６ alkyl)carbonyl, (C ６－１０ aryl)carbonyl, 5-10 membered heteroarylcarbonyl containing one or more ring heteroatoms independently selected from O, N and S, C ７－１４ Aralkyl, C ６－１０ aryl, or a 5-10 membered heteroaryl containing one or more ring heteroatoms independently selected from O, N and S, each of which is selected from fluorine atoms, 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, 5-10 membered heteroarylcarbonylamino containing one or more ring heteroatoms independently selected from O, N and S, di(C １－６ alkyl)amino, 4- to 8-membered cyclic amino, aminocarbonyl, (C １－６ alkyl)aminocarbonyl, di(C １－６ The method according to any one of [G-1] to [G-8], wherein the aminocarbonyl is optionally substituted with one or more substituents independently selected from the group consisting of (alkyl)aminocarbonyl, and 4- to 8-membered cyclic aminocarbonyl.

[0125] [G-10] Compound 1 is X １ -Ar ２ is a compound represented by the formula: １ represents a chlorine atom, a bromine atom, an iodine atom, or —O—SO ２ -R ４ and R ４ C may be substituted with one or more fluorine atoms １－６ Alkyl, or one or more fluorine atoms or C optionally substituted with fluorine atoms １－６ phenyl optionally substituted with alkyl; Ar ２ is C ６－１０aryl, or a 5-10 membered heteroaryl containing one or more ring heteroatoms independently selected from O, N and S, each of which is selected from fluorine atoms, sia, 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, 5-10 membered heteroarylcarbonylamino containing one or more ring heteroatoms independently selected from O, N and S, (C １－６ alkyl)aminocarbonyl, di(C １－６ alkyl)amino, 4- to 8-membered cyclic amino, aminocarbonyl, (C １－６ alkyl)aminocarbonyl, di(C １－６ and the by-product is H—Ar, optionally substituted with one or more groups independently selected from the group consisting of H—Ar, ... ２ The method according to any one of [G-1] to [G-9], wherein the compound is represented by the formula:

[0126] [G-11] Compound 1 is supported on a resin for solid phase synthesis, and X described in [G-10] １ -Ar ２ The method according to any one of [G-1] to [G-10], wherein the compound represented by the formula (I) is contained as part of the chemical structure.

[0127] [G-12] X １ is a chlorine atom, a bromine atom, or an iodine atom.

[0128] [G-13] Ar ２are independently selected from the group consisting of phenyl, naphthyl, 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, each of which is optionally substituted.

[0129] [G-14]Ar ２ The method according to any one of [G-10] to [G-13], wherein is phenyl or pyridyl, each of which may be substituted.

[0130] [G-15]X １ is a bromine atom; Ar ２ is phenyl, or pyridyl, each of which is selected from the group consisting of a fluorine 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, 5-10 membered heteroarylcarbonylamino containing one or more ring heteroatoms independently selected from O, N and S, (C １－６ alkyl)aminocarbonyl, di(C １－６ alkyl)amino, 4- to 8-membered cyclic amino, aminocarbonyl, (C １－６ alkyl)aminocarbonyl, di(C １－６ The method according to any one of [G-10] to [G-14], which is optionally substituted with one or more groups independently selected from the group consisting of (alkyl)aminocarbonyl, and 4- to 8-membered cyclic aminocarbonyl.

[0131] [G-16] The method according to any one of [G-1] to [G-15], wherein the solvent is selected from the group consisting of N,N-dimethylpropionamide (DMPr), N,N-diethylacetamide (DEAc), and N,N-diethylpropionamide (DEPr).

[0132] [G-17] The method according to any one of [G-1] to [G-16], wherein the solvent is N,N-dimethylpropionamide (DMPr).

[0133] [G-18] The method according to any one of [G-1] to [G-17], wherein the solvent contains at least one selected from the group consisting of N,N-dimethylpropionamide (DMPr), N,N-diethylacetamide (DEAc), and N,N-diethylpropionamide (DEPr) in an amount of 30 v / v % or more, 50 v / v % or more, 70 v / v % or more, or 90 v / v % or more.

[0134] [G-19] The method according to any one of [G-1] to [G-18], wherein the solvent contains N,N-dimethylpropionamide (DMPr) at a concentration of 30 v / v % or more, 50 v / v % or more, 70 v / v % or more, or 90 v / v % or more.

[0135] [G-20] The method according to any one of [G-1] to [G-19], wherein the cross-coupling reaction is carried out at 0 to 200°C, 0 to 150°C, 0 to 100°C, 10 to 80°C, or 25 to 80°C.

[0136] [G-21] The method according to any one of [G-1] to [G-20], wherein the molar ratio of compound 1 to compound 2 used is compound 1 / compound 2=0.0005 to 500, 0.005 to 200, or 0.05 to 20.

[0137] [G-22] The method according to any one of [G-1] to [G-21], wherein the molar ratio of the catalyst used is 0.01 to 100 mol %, 0.1 to 50 mol %, or 1 to 25 mol % relative to compound 1 or compound 2.

[0138] [G-23] The catalyst is represented by the following general formulae (Cat 1), (Cat 2), (Cat 3), (Cat 4) and (Cat 5):

[0139]

[0140] [In the formula, R ２０ is a hydrogen atom, C １－６ Alkyl, or C ６－１０ aryl, and R ２１ is halogen or -O-SO ２ -CH ３ and R ２２ is a hydrogen atom, a C group optionally substituted with one or more fluorine atoms １－６ Alkyl, or tri C １－６ may be substituted by alkylsilyl (C １－６ L is independently a monodentate ligand (L1), (L2), (L3), (L4), (L5), (L6) or (L7) of the following general formula:

[0141]

[0142] [In the formula, R ２３ are independently tert-butyl, cyclohexyl, 2-furanyl, 2-thienyl, 2-pyridyl, phenyl (the phenyl is one or more fluorine atoms, C optionally substituted with fluorine atoms). １－６ Alkyl, C １－６ alkoxy, or dimethylamino), or adamantyl, R ２４ is C １－６ alkyl, cyclohexyl, 2-furanyl, 2-thienyl, 2-pyridyl, N-phenyl-2-pyrrolyl, N-phenyl-2-indolyl, phenyl (the phenyl is one or more fluorine atoms, C optionally substituted with fluorine atoms). １－６ Alkyl, C １－６ R is an alkyl group, optionally substituted with alkoxy, morpholino, or dimethylamino, or adamantyl; ２５ is a hydrogen atom, C １－６ Alkyl, or C １－６ Alkoxy, W １ is -C(CH ３ ) ２ - or -NH-, R２６ , R ２７ , R ２８ , and R ２９ are each independently a hydrogen atom, C １－６ Arles, C １－６ alkoxy, or morpholino, R ３０ , R ３１ , and R ３２ are each independently a hydrogen atom, C １－６ Alkyl, C １－６ alkoxy, or dimethylamino; R ３３ is a hydrogen atom or -SO ２ -O-M, where M is lithium, sodium, or potassium; R ３４ is a hydrogen atom, C １－６ Alkyl, or C １－６ is alkoxy, and R ３５ and R ３６ are each independently a hydrogen atom, C １－６ Alkyl, or C １－６ is alkoxy, and R ３７ is a hydrogen atom, or C １－６ phenyl optionally substituted with alkyl, R ３８ are independently a hydrogen atom, C １－６ Phenyl optionally substituted with alkyl, or —CH(CH ３ )-N(CH ３ ) ２ and R ３９ is tert-butyl, cyclohexyl, or adamantyl; R ４０ is a hydrogen atom, or C １－６ The method according to any one of [G-1] to [G-22], wherein the catalyst comprises a palladium complex represented by any one of the following formulae:

[0143] [G-24] The catalyst is represented by the following general formula (Cat 6) and general formula (Cat 7):

[0144]

[0145] [In the formula, R ４１ is a hydrogen atom or C １－６phenyl optionally substituted with alkyl, and R ４２ are independently halogen, and R ４３ represents a fluorine atom or a chlorine atom, and L represents an N-heterocyclic carbene ligand represented by the following general formula (L12) or (L13):

[0146]

[0147] R ４４ and R ４５ are each independently １－６ alkyl, cyclohexyl, adamantyl, or phenyl (wherein the phenyl is one or more C １－６ Alkyl, C １－６ The method according to any one of [G-1] to [G-22], wherein the catalyst comprises a palladium complex represented by the following formula:

[0148] [G-25] The catalyst is a palladium compound selected from the group consisting of bis(allylchloropalladium(II)), tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct, palladium(π-cinnamyl)chloride dimer, (1-methylallyl)palladium chloride dimer, (1,5-cyclooctadiene)bis(trimethylsilylmethyl)palladium(II), (2'-amino-1,1'-biphenyl-2-yl)methanesulfonatopalladium(II) dimer, and palladium(II) acetate, and a monodentate ligand (L1), (L2), (L3), (L4), (L5), (L6), or (L7) of the following general formula, or a bidentate ligand (L8), (L9), (L10), (L11), or (L12):

[0149]

[0150] [In the formula, R ２３ is tert-butyl, cyclohexyl, 2-furanyl, 2-thienyl, 2-pyridyl, phenyl (the phenyl is one or more fluorine atoms, C －６ Alkyl, C １－６R is an alkyl group optionally substituted with alkoxy or dimethylamino, or adamantyl; ２４ is C １－６ alkyl, cyclohexyl, 2-furanyl, 2-thienyl, 2-pyridyl, N-phenyl-2-pyrrolyl, N-phenyl-2-indolyl, phenyl (the phenyl is one or more fluorine atoms, C optionally substituted with fluorine atoms). １－６ Alkyl, C １－６ R is an alkyl group, optionally substituted with alkoxy, morpholino, or dimethylamino, or adamantyl; ２５ is a hydrogen atom, C １－６ Alkyl, or C １－６ Alkoxy, W １ is -C(CH ３ ) ２ - or -NH-, R ２６ , R ２７ , R ２８ , and R ２９ are each independently a hydrogen atom, C １－６ Alkyl, C １－６ alkoxy, or morpholino, R ３０ , R ３１ , and R ３２ are each independently a hydrogen atom, C １－６ Alkyl, C １－６ alkoxy, or dimethylamino; R ３３ is a hydrogen atom or -SO ２ -O-M, where M is lithium, sodium, or potassium; R ３４ is a hydrogen atom, C １－６ Alkyl, or C １－６ is alkoxy, and R ３５ and R ３６ are each independently a hydrogen atom, C １－６ Alkyl, or C １－６ is alkoxy, and R ３７ is a hydrogen atom, or C １－６ phenyl optionally substituted with alkyl, R ３８ is a hydrogen atom, C １－６ Phenyl optionally substituted with alkyl, or —CH(CH ３)-N(CH ３ ) ２ and R ３９ is tert-butyl, cyclohexyl, or adamantyl; R ４０ is a hydrogen atom, or C １－６ The method according to any one of [G-1] to [G-22], wherein the catalyst comprises a palladium complex formed in combination with a ligand selected from the group consisting of a ligand represented by the formula:

[0151] [G-26] The method according to any one of [G-1] to [G-23], wherein the catalyst comprises a palladium complex selected from a Buchwald first generation catalyst precursor (G1), a Buchwald second generation catalyst precursor (G2), a Buchwald third generation catalyst precursor (G3), a Buchwald fourth generation catalyst precursor (G4), a Buchwald fifth generation catalyst precursor (G5), or a Buchwald sixth generation catalyst precursor (G6).

[0152] [G-27] The catalyst is a palladium compound selected from the group consisting of bis(allylchloropalladium(II)), tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct, palladium(π-cinnamyl)chloride dimer, (1-methylallyl)palladium chloride dimer, (1,5-cyclooctadiene)bis(trimethylsilylmethyl)palladium(II), (2'-amino-1,1'-biphenyl-2-yl)methanesulfonatopalladium(II) dimer, and palladium(II) acetate, and a monodentate ligand (L1), (L3), or (L6) represented by the following general formula:

[0153]

[0154] [In the formula, R ２３ are independently tert-butyl, cyclohexyl, or adamantyl; R ２４ is C １－６ alkyl, cyclohexyl, N-phenyl-2-indolyl, or adamantyl; R ２６ , R ２７ , R２８ , and R ２９ are each independently a hydrogen atom, C １－６ Alkyl, C １－６ alkoxy, or morpholino, R ３０ , R ３１ , and R ３２ are each independently a hydrogen atom, C １－６ Alkyl, C １－６ alkoxy, or dimethylamino; R ３３ is a hydrogen atom or -SO ２ -O-M, where M is lithium, sodium, or potassium; R ３７ is C １－６ The method according to [G-25], wherein the catalyst is a palladium complex formed in combination with a ligand selected from the group consisting of a ligand represented by the formula (I) and a salt thereof, and a palladium catalyst formed in combination with a compound represented by the formula (I),

[0155] [G-28] The method according to any one of [G-1] to [G-22], wherein the catalyst is a nickel catalyst.

[0156] [G-29] The method according to any one of [G-1] to [G-22] and [G-28], wherein the catalyst comprises a nickel complex formed by combining a nickel compound selected from the group consisting of bis(1,5-cyclooctadiene)nickel, dichloro(1,2-dimethoxyethane)nickel, dibromo(1,2-dimethoxyethane)nickel, nickel(II) trifluoromethanesulfonate, bis(trifluoromethanesulfonimide)nickel(II), nickel(II) acetylacetonate, nickel(II) nitrate, nickel(II) bromide, nickel(II) chloride, and hydrates thereof, with a ligand selected from the group consisting of tricyclohexylphosphine, 1,1′-bis(diphenylphosphino)ferrocene, and 1,3-bis(diphenylphosphino)propane.

[0157] [G-30] The method according to any one of [G-1] to [G-22], [G-28] and [G-29], wherein the catalyst comprises a nickel complex selected from the group consisting of dichlorobis(tricyclohexylphosphine)nickel(II), dichloro[1,1'-bis(diphenylphosphino)ferrocene]nickel(II), and dichloro[1,3-bis(diphenylphosphino)propane]nickel(II).

[0158] [G-31] The method according to any one of [G-1] to [G-30], wherein the base comprises at least one base selected from the group consisting of organic bases having a conjugate acid with a pKa of 23 or more in acetonitrile and inorganic bases having a conjugate acid with a pKa of 9 to 20 in water.

[0159] [G-32] The base is selected from the group consisting of amidines, guanidines, phosphazenes, alkali metal carbonates, alkali metal phosphates, and alkali metal C １－６ The method according to any one of [G-1] to [G-31], wherein the compound is selected from the group consisting of alkali metal alkoxides and alkali metal hydroxides.

[0160] [G-33] The base is 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), 1-ethyl-2,2,4,4,4-pentakis(dimethylamino)-2λ ５ ,4λ ５ -catenadi(phosphazene) (P2E), 1-tert-butyl-2,2,4,4,4-pentakis(dimethylamino)-2λ ５ ,4 ５ -catenadi(phosphazene) (P2tBu), tert-butylimino-tris(dimethylamino)phosphorane (P1tBu), 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP), tert-butylimino-tri(pyrrodino)phosphorane (BTPP), alkali metal carbonates, alkali metal phosphates, alkali metal C １－６The method according to any one of [G-1] to [G-32], wherein the compound is selected from the group consisting of alkali metal alkoxides and hydroxides of alkali metals.

[0161] [G-34] The base is 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), 1-tert-butyl-2,2,4,4,4-pentakis(dimethylamino)-2λ ５ ,4λ ５ The method according to any one of [G-1] to [G-33], wherein the compound is selected from the group consisting of tert-butylimino-tris(dimethylamino)phosphorane (P1tBu), 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP), tert-butylimino-tris(pyrrolidino)phosphorane (BTPP), cesium carbonate, tripotassium phosphate, potassium hydroxide, and sodium tert-butoxide.

[0162] [G-35] The method according to any one of [G-1] to [G-34], wherein the reaction system further contains a salt together with the base.

[0163] [G-36] The method according to [G-35], wherein the salt is an alkali metal salt of an acid selected from the group consisting of trifluoroacetic acid, trifluoromethanesulfonic acid, trifluoromethanesulfonimide, tetrafluoroboric acid, hexafluorophosphoric acid, and hexafluoroantimony(V) acid.

[0164] [G-37] The method according to [G-35], wherein the salt is sodium trifluoroacetate or potassium trifluoroacetate.

[0165] [G-38] The method according to any one of [G-1] to [G-37], wherein the molar ratio of the base to compound 1 or compound 2 is 0.05 to 100, 0.2 to 50, or 1 to 30.

[0166] [G-39] The method according to any one of [G-1] to [G-38], wherein compound 2 is a compound defined in any one of [B-1] to [B-4], and [C-1] to [C-3].

[0167] [G-40] The method according to any one of [G-1] to [G-38], wherein the product of the coupling reaction is a compound defined in any one of [B-5] and [C-4].

[0168] [H-1] A method for producing a compound by cross-coupling reaction, comprising reacting a compound of formula A:

[0169]

[0170] [In the formula, R １ , R ２ and R ３ are each independently C １－４ alkyl, provided that R １ , R ２ and R ３ and the total number of carbon atoms of the aromatic rings is 4 or more and 6 or less. １ with a compound 2 having a reactive group capable of a C—O bond forming reaction or a C—N bond forming reaction by substitution with the leaving group; １ represents a halogen atom or —O—SO ２ -R ４ and R ４ C may be substituted with one or more fluorine atoms １－６ Alkyl, or one or more fluorine atoms or C optionally substituted with fluorine atoms １－６ Compound 2 has a hydroxyl group capable of forming a C—O bond or an H—N group capable of forming a C—N bond; Compound 1 has a leaving group X on a carbon atom of an aromatic ring in a side chain. １ or a resin for solid phase synthesis having, in a side chain, a reactive group capable of undergoing a C—O bond forming reaction or a C—N bond forming reaction by substitution with the leaving group.

[0171] [H-2] The method according to [H-1], wherein the catalyst is a palladium catalyst or a nickel catalyst.

[0172] [H-3] The method according to [H-1] or [H-2], wherein the catalyst is a palladium catalyst.

[0173] [H-4] The method according to any one of [H-1] to [H-3], wherein compound 1 has one leaving group, or two or three leaving groups which may be the same or different.

[0174] [H-5] The method according to any one of [H-1] to [H-4], wherein compound 1 has one of the leaving groups.

[0175] [H-6] The method according to any one of [H-1] to [H-5], wherein compound 2 has one reactive group, or two or three reactive groups which may be the same or different.

[0176] [H-7] The method according to any one of [H-1] to [H-6], wherein compound 2 has one of the reactive groups.

[0177] [H-8] The method according to any one of [H-1] to [H-7], wherein the side chain of the solid-phase synthesis resin contains a degradable linker; and the method further comprises degrading the linker after the cross-coupling reaction to cleave a compound containing a C—O bond or a C—N bond formed by the cross-coupling reaction from the solid-phase synthesis resin.

[0178] [H-9] Compound 2 is: 1) HO—R ５ a resin for solid phase synthesis having a side chain to which a compound having a hydroxy capable of forming a C—O bond is bound via a linker, represented by R ５ is C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ Cycloalkyl, C ７－１４ Aralkyl, C ６－１０ aryl, or a 5-10 membered heteroaryl containing one or more ring heteroatoms independently selected from O, N and S, each of which is selected from fluorine atoms, cyano, C １－６ Alkyl, C １－６Alkoxy, (C １－６ alkoxy)carbonyl, (C １－６ alkoxy)carbonylamino, (C １－６ alkyl)carbonylamino, (C ６－１０ aryl)carbonylamino, 5-10 membered heteroarylcarbonylamino containing one or more ring heteroatoms independently selected from O, N and S, aminocarbonyl, (C １－６ alkyl)aminocarbonyl, di(C １－６ 2) HNR, which may be substituted by one or more groups independently selected from the group consisting of HNR, HNR alkyl, HNR cyclic ... ６ R ７ a resin for solid phase synthesis having a side chain to which a compound having an H—N group capable of forming a C—N bond is bound via a linker, represented by R ６ and R ７ together with the nitrogen atom to which they are attached to form a 5- to 7-membered saturated heterocycle, and the heterocycle is not limited to a fluorine atom, a cyano, a 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, 5-10 membered heteroarylcarbonylamino containing one or more ring heteroatoms independently selected from O, N and S, di(C １－６ alkyl)amino, 4- to 8-membered cyclic amino, aminocarbonyl, (C １－６ alkyl)aminocarbonyl, di(C １－６ or R ６ and R ７ are each independently a hydrogen atom, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ cycloalkyl, (C １－６ alkyl)carbonyl, (C６－１０ aryl)carbonyl, 5-10 membered heteroarylcarbonyl containing one or more ring heteroatoms independently selected from O, N and S, C ７－１４ Aralkyl, C ６－１０ aryl, or a 5-10 membered heteroaryl containing one or more ring heteroatoms independently selected from O, N and S, each of which is selected from fluorine atoms, 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, 5-10 membered heteroarylcarbonylamino containing one or more ring heteroatoms independently selected from O, N and S, di(C １－６ alkyl)amino, 4- to 8-membered cyclic amino, aminocarbonyl, (C １－６ alkyl)aminocarbonyl, di(C １－６ The method according to any one of [H-1] to [H-8], wherein the aminocarbonyl is optionally substituted with one or more substituents independently selected from the group consisting of 4- to 8-membered cyclic aminocarbonyl, 4- to 8-membered cyclic aminocarbonyl, and 4- to 8-membered cyclic aminocarbonyl.

[0179] [H-10] Compound 1 is X １ -Ar ２ a resin for solid phase synthesis having a side chain to which a compound represented by the formula: １ represents a chlorine atom, a bromine atom, an iodine atom, or —O—SO ２ -R ４ and R ４ C may be substituted with one or more fluorine atoms １－６ Alkyl, or one or more fluorine atoms or C optionally substituted with fluorine atoms １－６ phenyl optionally substituted with alkyl; Ar ２ is C ６－１０ aryl, or a 5-10 membered heteroaryl containing one or more ring heteroatoms independently selected from O, N and S, each of which is selected from fluorine atoms, cyano, C １－６ Alkyl, C １－６Alkoxy, (C １－６ alkoxy)carbonyl, (C １－６ alkoxy)carbonylamino, (C １－６ alkyl)carbonylamino, (C ６－１０ aryl)carbonylamino, 5-10 membered heteroarylcarbonylamino containing one or more ring heteroatoms independently selected from O, N and S, di(C １－６ alkyl)amino, 4- to 8-membered cyclic amino, aminocarbonyl, (C １－６ alkyl)aminocarbonyl, di(C １－６ The method according to any one of [H-1] to [H-9], wherein the aminocarbonyl group is optionally substituted with one or more groups independently selected from the group consisting of alkyl, 4- to 8-membered cyclic aminocarbonyl, and 4- to 8-membered cyclic aminocarbonyl.

[0180] [H-11] Compound 1 is decomposed by the cross-coupling reaction to form R ５ O-Ar ２ , HOAr ２ , R ６ R ７ N-Ar ２ , Ar １ -Ar ２ , R ８ R ９ R １０ C-Ar ２ , R １３ R １４ R １５ C-Ar ２ or R １６ R １７ R １８ C-Ar ２ The method according to [H-9] or [H-10], wherein the compound has a chemical structure that enables the production of a compound represented by the formula:

[0181] [H-12]X １ is a chlorine atom, a bromine atom, or an iodine atom.

[0182] [H-13]Ar ２are independently selected from the group consisting of phenyl, naphthyl, 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, each of which is optionally substituted.

[0183] [H-14]Ar ２ The method according to any one of [H-10] to [H-13], wherein is phenyl or pyridyl, each of which is optionally substituted.

[0184] [H-15]X １ is a bromine atom; Ar ２ is phenyl, or pyridyl, each of which is selected from the group consisting of a fluorine 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, 5-10 membered heteroarylcarbonylamino containing one or more ring heteroatoms independently selected from O, N and S, di(C １－６ alkyl)amino, 4- to 8-membered cyclic amino, aminocarbonyl, (C １－６ alkyl)aminocarbonyl, di(C １－６ The method according to any one of [H-10] to [H-14], which is optionally substituted with one or more groups independently selected from the group consisting of (alkyl)aminocarbonyl, and 4- to 8-membered cyclic aminocarbonyl.

[0185] [H-16] The method according to any one of [H-1] to [H-15], wherein the solvent is selected from the group consisting of N,N-dimethylpropionamide (DMPr), N,N-diethylacetamide (DEAc), and N,N-diethylpropionamide (DEPr).

[0186] [H-17] The method according to any one of [H-1] to [H-16], wherein the solvent is N,N-dimethylpropionamide (DMPr).

[0187] [H-18] The method according to any one of [H-1] to [H-17], wherein the solvent contains at least one selected from the group consisting of N,N-dimethylpropionamide (DMPr), N,N-diethylacetamide (DEAc), and N,N-diethylpropionamide (DEPr) at a concentration of 30 v / v % or more, 50 v / v % or more, 70 v / v % or more, or 90 v / v % or more.

[0188] [H-19] The method according to any one of [H-1] to [H-18], wherein the solvent contains N,N-dimethylpropionamide (DMPr) at a concentration of 30 v / v % or more, 50 v / v % or more, 70 v / v % or more, or 90 v / v % or more.

[0189] [H-20] The method according to any one of [H-1] to [H-19], wherein the cross-coupling reaction is carried out at 0 to 200°C, 0 to 150°C, 0 to 100°C, 10 to 80°C, or 25 to 80°C.

[0190] [H-21] The method according to any one of [H-1] to [H-20], wherein the molar ratio of compound 1 to compound 2 used is compound 1 / compound 2=0.0005 to 500, 0.005 to 200, or 0.05 to 20.

[0191] [H-22] The method according to any one of [H-1] to [H-21], wherein the molar ratio of the catalyst used is 0.01 to 100 mol %, 0.1 to 50 mol %, or 1 to 25 mol % relative to compound 1 or compound 2.

[0192] [H-23] The catalyst is represented by the following general formulae (Cat 1), (Cat 2), (Cat 3), (Cat 4) and (Cat 5):

[0193]

[0194] [In the formula, R ２０ is a hydrogen atom, C １－６ Alkyl, or C ６－１０ aryl, and R ２１ is halogen or -O-SO ２ -CH ３ and R ２２ is a hydrogen atom, a C group optionally substituted with one or more fluorine atoms １－６ Alkyl, or tri(C １－６ alkyl) may be substituted by silyl (C １－６ L is independently a monodentate ligand (L1), (L2), (L3), (L4), (L5), (L6) or (L7) of the following general formula: or two L are bidentate ligands (L8), (L9), (L10), (L11) or (L12):

[0195]

[0196] [In the formula, R ２３ are independently tert-butyl, cyclohexyl, 2-furanyl, 2-thienyl, 2-pyridyl, phenyl (the phenyl is one or more fluorine atoms, C optionally substituted with fluorine atoms). １－６ Alkyl, C １－６ alkoxy, or dimethylamino), or adamantyl, R ２４ is C １－６ alkyl, cyclohexyl, 2-furanyl, 2-thienyl, 2-pyridyl, N-phenyl-2-pyrrolyl, N-phenyl-2-indolyl, phenyl (the phenyl is one or more fluorine atoms, C optionally substituted with fluorine atoms). １－６ Alkyl, C １－６ R is an alkyl group, optionally substituted with alkoxy, morpholino, or dimethylamino, or adamantyl; ２５ is a hydrogen atom, C １－６ Alkyl, or C １－６ Alkoxy, W １ is -C(CH ３ ) ２ - or -NH-, R２６ , R ２７ , R ２８ , and R ２９ are each independently a hydrogen atom, C １－６ Alkyl, C １－６ alkoxy, or morpholino, R ３０ , R ３１ , and R ３２ are each independently a hydrogen atom, C １－６ Alkyl, C １－６ alkoxy, or dimethylamino; R ３３ is a hydrogen atom or -SO ２ -O-M, where M is lithium, sodium, or potassium; R ３４ is a hydrogen atom, C １－６ Alkyl, or C １－６ is alkoxy, and R ３５ and R ３６ are each independently a hydrogen atom, C １－６ Alkyl, or C １－６ is alkoxy, and R ３７ is a hydrogen atom, or C １－６ phenyl optionally substituted with alkyl, R ３８ are independently a hydrogen atom, C １－６ Phenyl optionally substituted with alkyl, or —CH(CH ３ )-N(CH ３ ) ２ and R ３９ is tert-butyl, cyclohexyl, or adamantyl; R ４０ is a hydrogen atom, or C １－６ The method according to any one of [H-1] to [H-22], wherein the catalyst comprises a palladium complex represented by any one of the following formulae:

[0197] [H-24] The catalyst is represented by the following general formula (Cat 6) and general formula (Cat 7):

[0198]

[0199] [In the formula, R ４１ is a hydrogen atom or C １－６phenyl optionally substituted with alkyl, and R ４２ are independently halogen, and R ４３ represents a fluorine atom or a chlorine atom, and L represents an N-heterocyclic carbene ligand represented by the following general formula (L12) or (L13):

[0200]

[0201] R ４４ and R ４５ are each independently １－６ alkyl, cyclohexyl, adamantyl, or phenyl (wherein the phenyl is one or more C １－６ Alkyl, C １－６ The method according to any one of [H-1] to [H-22], wherein the catalyst comprises a palladium complex represented by the following formula:

[0202] [H-25] The catalyst is a palladium compound selected from the group consisting of bis(allylchloropalladium(II)), tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct, palladium(π-cinnamyl)chloride dimer, (1-methylallyl)palladium chloride dimer, (1,5-cyclooctadiene)bis(trimethylsilylmethyl)palladium(II), (2'-amino-1,1'-biphenyl-2-yl)methanesulfonatopalladium(II) dimer, and palladium(II) acetate, and a monodentate ligand (L1), (L2), (L3), (L4), (L5), (L6), or (L7) of the following general formula, or a bidentate ligand (L8), (L9), (L10), (L11), or (L12):

[0203]

[0204] [In the formula, R ２３ is tert-butyl, cyclohexyl, 2-furanyl, 2-thienyl, 2-pyridyl, phenyl (the phenyl is one or more fluorine atoms, C －６ Alkyl, C １－６R is an alkyl group optionally substituted with alkoxy or dimethylamino, or adamantyl; ２４ is C １－６ alkyl, cyclohexyl, 2-furanyl, 2-thienyl, 2-pyridyl, N-phenyl-2-pyrrolyl, N-phenyl-2-indolyl, phenyl (the phenyl is one or more fluorine atoms, C optionally substituted with fluorine atoms). １－６ Alkyl, C １－６ R is an alkyl group, optionally substituted with alkoxy, morpholino, or dimethylamino, or adamantyl; ２５ is a hydrogen atom, C １－６ Alkyl, or C １－６ Alkoxy, W １ is -C(CH ３ ) ２ - or -NH-, R ２６ , R ２７ , R ２８ , and R ２９ are each independently a hydrogen atom, C １－６ Alkyl, C １－６ alkoxy, or morpholino, R ３０ , R ３１ , and R ３２ are each independently a hydrogen atom, C １－６ Alkyl, C １－６ alkoxy, or dimethylamino; R ３３ is a hydrogen atom or -SO ２ -O-M, where M is lithium, sodium, or potassium; R ３４ is a hydrogen atom, C １－６ Alkyl, or C １－６ is alkoxy, and R ３５ and R ３６ are each independently a hydrogen atom, C １－６ Alkyl, or C １－６ is alkoxy, and R ３７ is a hydrogen atom, or C １－６ phenyl optionally substituted with alkyl, R ３８ is a hydrogen atom, C １－６ Phenyl optionally substituted with alkyl, or —CH(CH ３)-N(CH ３ ) ２ and R ３９ is tert-butyl, cyclohexyl, or adamantyl; R ４０ is a hydrogen atom, or C １－６ The method according to any one of [H-1] to [H-22], wherein the catalyst comprises a palladium complex formed in combination with a ligand selected from the group consisting of a ligand represented by the formula (I) and a salt thereof, wherein the arrow represents a coordinate bond.

[0205] [H-26] The method according to any one of [H-1] to [H-23], wherein the catalyst comprises a palladium complex selected from a Buchwald first generation catalyst precursor (G1), a Buchwald second generation catalyst precursor (G2), a Buchwald third generation catalyst precursor (G3), a Buchwald fourth generation catalyst precursor (G4), a Buchwald fifth generation catalyst precursor (G5), or a Buchwald sixth generation catalyst precursor (G6).

[0206] [H-27] The catalyst is a palladium compound selected from the group consisting of bis(allylchloropalladium(II)), tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct, palladium(π-cinnamyl)chloride dimer, (1-methylallyl)palladium chloride dimer, (1,5-cyclooctadiene)bis(trimethylsilylmethyl)palladium(II), (2'-amino-1,1'-biphenyl-2-yl)methanesulfonatopalladium(II) dimer, and palladium(II) acetate, and a monodentate ligand (L1), (L3), or (L6) represented by the following general formula:

[0207]

[0208] [In the formula, R ２３ are independently tert-butyl, cyclohexyl, or adamantyl; R ２４ is C １－６ alkyl, cyclohexyl, N-phenyl-2-indolyl, or adamantyl; R ２６ , R ２７ , R２８ , and R ２９ are each independently a hydrogen atom, C １－６ Alkyl, C １－６ alkoxy, or morpholino, R ３０ , R ３１ , and R ３２ are each independently a hydrogen atom, C １－６ Alkyl, C １－６ alkoxy, or dimethylamino; R ３３ is a hydrogen atom or -SO ２ -O-M, where M is lithium, sodium, or potassium; R ３７ is C １－６ The method according to [H-25], wherein the catalyst is a palladium complex formed in combination with a ligand selected from the group consisting of a ligand represented by the formula (I) and a salt thereof, and a palladium catalyst formed in combination with a compound represented by the formula (I),

[0209] [H-28] The method according to any one of [H-1] to [H-22], wherein the catalyst is a nickel catalyst.

[0210] [H-29] The method according to any one of [H-1] to [H-22] and [H-28], wherein the catalyst comprises a nickel complex formed by combining a nickel compound selected from the group consisting of bis(1,5-cyclooctadiene)nickel, dichloro(1,2-dimethoxyethane)nickel, dibromo(1,2-dimethoxyethane)nickel, nickel(II) trifluoromethanesulfonate, bis(trifluoromethanesulfonimide)nickel(II), nickel(II) acetylacetonate, nickel(II) nitrate, nickel(II) bromide, nickel(II) chloride, and hydrates thereof, and a ligand selected from the group consisting of tricyclohexylphosphine, 1,1′-bis(diphenylphosphino)ferrocene, and 1,3-bis(diphenylphosphino)propane.

[0211] [H-30] The method according to any one of [H-1] to [H-22], [H-28] and [H-29], wherein the catalyst comprises a nickel complex selected from the group consisting of dichlorobis(tricyclohexylphosphine)nickel(II), dichloro[1,1'-bis(diphenylphosphino)ferrocene]nickel(II), and dichloro[1,3-bis(diphenylphosphino)propane]nickel(II).

[0212] [H-31] The method according to any one of [H-1] to [H-30], wherein the base comprises at least one base selected from the group consisting of organic bases whose conjugate acids have a pKa of 23 or more in acetonitrile and inorganic bases whose conjugate acids have a pKa of 9 to 20 in water.

[0213] [H-32] The base is selected from the group consisting of amidines, guanidines, phosphazenes, alkali metal carbonates, alkali metal phosphates, and alkali metal C １－６ The method according to any one of [H-1] to [H-31], wherein the compound is selected from the group consisting of alkali metal alkoxides and alkali metal hydroxides.

[0214] [H-33] The base is 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), 1-ethyl-2,2,4,4,4-pentakis(dimethylamino)-2λ ５ ,4λ ５ -catenadi(phosphazene) (P2E), 1-tert-butyl-2,2,4,4,4-pentakis(dimethylamino)-2λ ５ ,4 ５ -catenadi(phosphazene) (P2tBu), tert-butylimino-tris(dimethylamino)phosphorane (P1tBu), 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP), tert-butylimino-tri(pyrrodino)phosphorane (BTPP), alkali metal carbonates, alkali metal phosphates, alkali metal C １－６The method according to any one of [H-1] to [H-32], wherein the compound is selected from the group consisting of alkali metal alkoxides and hydroxides of alkali metals.

[0215] [H-34] The base is 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), 1-tert-butyl-2,2,4,4,4-pentakis(dimethylamino)-2λ ５ ,4λ ５ The method according to any one of [H-1] to [H-33], wherein the compound is selected from the group consisting of tert-butylimino-tris(dimethylamino)phosphorane (P1tBu), 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP), tert-butylimino-tris(pyrrolidino)phosphorane (BTPP), cesium carbonate, tripotassium phosphate, potassium hydroxide, and sodium tert-butoxide.

[0216] [H-35] The method according to any one of [H-1] to [H-34], wherein the reaction system further contains a salt together with the base.

[0217] [H-36] The method according to [H-35], wherein the salt is an alkali metal salt of an acid selected from the group consisting of trifluoroacetic acid, trifluoromethanesulfonic acid, trifluoromethanesulfonimide, tetrafluoroboric acid, hexafluorophosphoric acid, and hexafluoroantimony(V) acid.

[0218] [H-37] The method according to [H-35], wherein the salt is sodium trifluoroacetate or potassium trifluoroacetate.

[0219] [H-38] The method according to any one of [H-1] to [H-37], wherein the molar ratio of the base used to compound 1 or compound 2 is 0.05 to 100, 0.2 to 50, or 1 to 30.

[0220] [H-39] The method according to any one of [H-1] to [H-38], in which a mixture containing two or more types of compound 1 is reacted.

[0221] [H-40] A method according to any one of [H-1] to [H-39] for producing a compound constituting a compound library.

[0222] [H-41] The method according to any one of [H-1] to [H-40], wherein the resin for solid phase synthesis is one on which two or more types of compound 1 are supported via a linker.

[0223] [H-42] The method according to any one of [H-1] to [H-41], wherein the resin for solid phase synthesis has three or more, four or more, five or more, seven or more, or ten or more types of Compound 1 supported thereon via linkers.

[0224] [H-43] A method for producing a compound constituting a compound library, the method comprising producing the compound by the method described in any one of [H-1] to [H-42].

[0225] According to the present invention, there is provided a method for preparing a compound by a cross-coupling reaction using a palladium catalyst, which improves the conversion rate and / or reduces the generation of by-products.

[0226] One aspect of the present invention relates to a method for producing a compound by a cross-coupling reaction. The cross-coupling reaction is not particularly limited, but examples thereof include a C—O bond-forming reaction or a C—N bond-forming reaction by substitution with the leaving group.

[0227] In one aspect of the present invention, the catalyst added to the reaction system may be an active species that functions as a catalyst, or a catalyst precursor that is converted to the active species in the reaction system, or a metal compound (e.g., a palladium compound or a nickel compound) and a ligand that form the active species in the reaction system. As used herein, the term "catalyst" encompasses one or more compounds, such as an active species having catalytic activity and a catalyst precursor that forms the active species in the reaction system.

[0228] In one embodiment of the present invention, the cross-coupling reaction is carried out in the presence of a palladium catalyst. Examples of the palladium catalyst that can be used include the palladium compounds and palladium complexes described herein. When a palladium catalyst is used, the substrates for the C—O bond-forming reaction include water, an alcohol, and a compound having a leaving group. The substrates for the C—N bond-forming reaction include ammonia, a primary amine, and a secondary amine.

[0229] The palladium catalyst is not particularly limited as long as it is one that can be commonly used in cross-coupling reactions. Examples of the palladium catalyst include palladium acetate and Pd(dba). ２ , Pd ２ (dba) ３ , Pd ２ (dba) ３ CHCl ３ , allylpalladium chloride dimer, palladium (π-cinnamyl) chloride dimer, (1-methylallyl)palladium chloride dimer, (1,5-cyclooctadiene)bis(trimethylsilylmethyl)palladium(II), (2'-amino-1,1'-biphenyl-2-yl)methanesulfonatopalladium(II) dimer, and the like can be used.

[0230] The palladium catalyst may contain a ligand if necessary. Examples of the ligand include trialkylphosphine (PCy ３ (tricyclohexylphosphine), P(tBu) ３ (tri-tert-butylphosphine), di(1-adamantyl)-n-butylphosphine (cataCXium A), di-tert-butylmethylphosphine ((tBu) ２ PMe), triadamantylphosphine (P(Ad) ３ ), di-tert-butylneopentylphosphine (Neopentyl(tBu) ２ P)), triarylphosphines (triphenylphosphine, tri(o-tolyl)phosphine (P(o-Tol) ３ )) etc.

[0231] Further ligands include dialkylbiarylphosphines such as XPhos (2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl), SPhos (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl), RuPhos (2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl), BrettPhos (2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl), tBuXPhos (2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl), CPhos (2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl ...3,6-diisopropylbiphenyl), tBuXPhos (2-di-tert-butylphosphino-3,6-diisopropylbiphenyl), tBuXPhos (2-dicyclohexylphosphino-3,6-diisopropylbiphenyl), tBuXPhos (2-dicyclohexylphosphino-3,6-diisopropylbiphenyl), tBuXPhos (2-dicyclohexylphosphino-3,6-diisopropylbiphenyl), tBuXPhos (2-di-tert-butylphosphino-3,6-diisopropylbiphenyl), tBuXPhos (2-dicyclohexylphosphino-3,6-diisopropylbiphenyl), tBuXPhos ( dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)biphenyl), DavePhos (2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl), GPhos (3-(tert-butoxy)-2',6'-diisopropyl-6-methoxy[1,1'-biphenyl]-2-yl)dicyclohexylphosphane), tBuDavePhos (2-di-tert-butylphosphino-2'-(N,N-dimethylamino)biphenyl), VPhos (4,6-di-tert-butyl-2'-dicyclohexylphosphino-2-methoxybiphenyl), EPhos (dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl- [1,1'-biphenyl]-2-yl)phosphine), CyJohnPhos (2-biphenyldicyclohexylphosphine), RockPhos (2-di(tert-butyl)phosphino-2',4',6'-triisopropyl-3-methoxy-6-methylbiphenyl, di-tert-butyl(2',4',6'-triisopropyl-3-methoxy-6-methyl-[1,1'-biphenyl]-2-yl)phosphine), Me ４ tBuXPhos (2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl), Me ３(OMe)tBuXPhos (Sigma-Aldrich catalog code: 792470), tBuBrettPhos (2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl), AdBrettPhos (2-(di-1-adamantylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl), AlPhos (di-1-adamantyl(4''-butyl-2'',3'',5'',6''-tetrafluoro-2',4',6'-triisopropyl-2-methoxy-meta-terphenyl)phosphine), etc.), monoalkylmonoarylbiarylphosphines ((tBu)PhCPhos (2-[(tert-butyl)phenylphosphino] -2',6'-bis(N,N-dimethylamino)biphenyl)), diarylbiarylphosphine (PhCPhos (2-diphenylphosphino-2',6'-bis(N,N-dimethylamino)biphenyl), bis(3,5-bis(trifluoromethyl)phenyl)(2',6'-bis(dimethylamino)-3,6-dimethoxybiphenyl-2-yl)phosphine, bis(3,5-bis(trifluoromethyl)phenyl)(2', 6'-bis(isopropoxy)-3,6-dimethoxybiphenyl-2-yl)phosphine, JackiePhos (2-{bis[3,5-bis(trifluoromethyl)phenyl]phosphino}-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)), dialkylmonoarylphosphine (APhos((4-(N,N-dimethylamino)phenyl)di-tert-butylphosphine), (tBu) ２PPh, MorDalPhos (2-morpholinophenyldi(1-adamantyl)phosphine), TrixiePhos (2-(di-tert-butylphosphino)-1,1'-binaphthyl), meCgPPh (1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane)), QPhos (1,2,3,4,5-pentaphenyl-1'-(di-t-butylphosphino)ferrocene), cataCXium PICy (2-(dicyclohexylphosphino)-1-(2,4,6-trimethylphenyl)-1H-imidazole), CyBippyPhos (5-(dicyclohexylphosphino)-1',3',5'-triphenyl-1'H-1,4'-bipyrazole), BippyPhos (5-(di-tert-butylphosphino)-1',3',5'-triphenyl-1'H-1,4'-bipyrazole), AdBippyPhos (5-[di(1-adamantyl)phosphino]-1',3',5'-triphenyl-1'H-1,4'-bipyrazole), cataCXium PtB (2-(di-tert-butylphosphino)-1-phenyl-1H-pyrrole), cataCXium Examples include POMetB (2-(di-tert-butylphosphino)-1-(2-methoxyphenyl)-1H-pyrrole), cataCXium PIntB (2-(di-tert-butylphosphino)-1-phenyl-indole), and the like.

[0232] Further, examples of the ligand include bidentate phosphine ligands, such as dppf (1,1'-bis(phenylphosphino)ferrocene), dtbpf (1,1'-bis(di-tert-butylphosphino)ferrocene), BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl), Tol-BINAP (2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl), XantPhos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene), N-XantPhos (4,6-bis(diphenylphosphino)phenoxazine), and Josiphos ((R)-1-[(Sp)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine).

[0233] Further examples of the ligand include N-heterocyclic carbene (NHC) ligands, such as IPr (1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene), SIPr (1,3-bis(2,6-di-i-propylphenyl)imidazolidine-2-ylidene), IMes (1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene), and IPent (1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene)).

[0234] The palladium catalyst may also be a palladium complex known as a palladium catalyst precursor. Examples of the palladium catalyst precursor include Buchwald first generation catalyst precursors (G1). Examples include XPhos Pd G1, SPhos Pd G1, RuPhos Pd G1, BrettPhos Pd G1, and tBuXPhos Pd G1.

[0235] The palladium catalyst precursor may be a Buchwald second generation catalyst precursor (G2), such as XPhos Pd G2, SPhos Pd G2, RuPhos Pd G2, BrettPhos Pd G2, tBuXPhos Pd G2, CPhos Pd G2, DavePhos Pd G2, CyJohnPhos Pd G2, APhos Pd G2, (tBu) ２ PPh Pd G2, MorDalPhos Pd G2, PCy ３ Pd G2, P(tBu) ３ Pd G2, cataCXium A Pd G2, (tBu) ２ PMe Pd G2, Neopentyl (tBu) ２ P Pd G2, P(o-Tol) ３ Pd G2, XantPhos Pd G2, etc.

[0236] The palladium catalyst precursor may be a Buchwald third generation catalyst precursor (G3), such as XPhos Pd G3, SPhos Pd G3, RuPhos Pd G3, BrettPhos Pd G3, tBuXPhos Pd G3, CPhos Pd G3, DavePhos Pd G3, GPhos Pd G3, tBuDavePhos Pd G3, VPhos Pd G3, JackiePhos Pd G3, CyJohnPhos Pd G3, RockPhos Pd G3, Me ４ tBuXPhos Pd G3, Me ３ (OMe) tBuXPhos Pd G3 (Sigma-Aldrich Catalog: 804193), tBuBrettPhos Pd G3, AdBrettPhos Pd G3, (tBu) PhCPhos Pd G3, PhCPos Pd G3, APhos Pd G3, (tBu) ２ PPh Pd G3, MorDalPhos Pd G3, PCy ３ Pd G3, P(tBu) ３ Pd G3, cataCXium A Pd G3, (tBu) ２ PMe Pd G3, Neopentyl (tBu) ２ P Pd G3, P (o-Tol) ３ Pd G3, QPhos Pd G3, TrixiePhos Pd G3, meCgPPh Pd G3, dppf Pd G3, dtbpf Pd G3, BINAP Pd G3, Tol-BINAP Pd G3, XantPhos Pd G3, N-XantPhos Pd G3, Josiphos Pd G3, and the like, and any solvent may be coordinated.

[0237] The palladium catalyst precursor may be a Buchwald fourth generation catalyst precursor (G4), such as XPhos Pd G4, SPhos Pd G4, RuPhos Pd G4, BrettPhos Pd G4, tBuXPhos Pd G4, CPhos Pd G4, DavePhos Pd G4, GPhos Pd G4, tBuDavePhos Pd G4, VPhos Pd G4, EPhos Pd G4, CyJohnPhos Pd G4, tBuBrettPhos Pd G4, or (tBu)PhCPhos Pd G4, methanesulfonato(2-bis(3,5-di(trifluoromethyl)phenylphosphino)-3,6-dimethoxy-2',6'-bis(dimethylamino)-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II), APhos Pd G4, (tBu) ２ PPh Pd G4, MorDalPhos Pd G4, PCy ３ Pd G4, P(tBu) ３ Pd G4, cataCXium A Pd G4, (tBu) ２ PMe Pd G4, Neopentyl (tBu) ２ Examples include P Pd G4, meCgPPh Pd G4, dppf Pd G4, BINAP Pd G4, Tol-BINAP Pd G4, XantPhos Pd G4, and N-XantPhos Pd G4.

[0238] Palladium catalyst precursors can be Buchwald fifth generation catalyst precursors (G5), such as XPhos Pd G5, BrettPhos Pd G5, SPhos Pd G5, and RuPhos Pd G5.

[0239] Palladium catalyst precursors can be Buchwald sixth generation catalyst precursors (G6), such as tBuBrettPhos Pd G6 TES, tBuBrettPhos Pd G6 Br, AdBrettPhos Pd G6 Br, GPhos Pd G6 TES, AlPhos Pd G6 Br, and AlPhos Pd G6 OTf.

[0240] As the palladium catalyst precursor, a dichloropalladium(II) complex can be used. An example of such a complex is Pd(PPh ３ ) ２ Cl ２ , Pd(PCy ３ ) ２ Cl ２ , Pd(dppf)Cl ２ , Pd(dtbpf)Cl ２ , (APhos) ２ PdCl ２ , (AdBippyPhos) ２ PdCl ２ Examples include:

[0241] Palladium catalyst precursors that can be used include palladium(0) complexes, such as tetrakistriphenylphosphinepalladium(0), bis(tricyclohexylphosphine)palladium(0), and bis(tri-tert-butylphosphine)palladium(0).

[0242] Palladium catalyst precursors that can be used include halide palladium(I) complexes, such as bromo(tri-tert-butylphosphine)palladium(I) dimer and iodo(tri-tert-butylphosphine)palladium(I) dimer.

[0243] As the palladium catalyst precursor, a phosphine π-allylpalladium catalyst can be used. Examples thereof include XPhos Pd(crotyl)Cl (chloro(crotyl)(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II)), SPhos Pd(crotyl)Cl (chloro(crotyl)(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)palladium(II)), RuPhos Pd(crotyl)Cl (chloro(crotyl)(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)palladium(II)), [BrettPhos [Pd(crotyl)]OTf (crotyl(2-dicyclohexylphosphino-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl)palladium(II) triflate), [tBuXPhos Pd(allyl)]OTf (allyl(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II) triflate), [tBuBrettPhos Pd(allyl)]OTf (allyl(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)palladium(II) triflate), AmPhos Examples of such compounds include Pd(crotyl)Cl (chloro(crotyl)[(p-dimethylaminophenyl)(di-tert-butylphosphine)]palladium(II)), P(Cy)Pd(crotyl)Cl (chloro(crotyl)(tricyclohexylphosphine)palladium(II)), [P(tBu)Pd(crotyl)Cl (tri-tert-butylphosphine(chloro)(crotyl)palladium(II)), [BINAP Pd(allyl)]Cl ((R)-BINAP Pd(allyl)]Cl; allyl[(R)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene]palladium(II) chloride), and [XantPhosPd(allyl)]Cl (allyl[4,5-bis(diphenylphosphino)-9,9-dimethylxanthene]palladium(II) chloride).

[0244] The palladium catalyst precursor can be a PEPPSI catalyst, examples of which include Pd-PEPPSI IPr, Pd-PEPPSI SIPr ((1,3-bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl)palladium(II) dichloride), and Pd-PEPPSI IPent (1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene).

[0245] Palladium catalyst precursors that can be used include (NHC)Pd(allyl)Cl catalysts, such as allyl[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]chloropalladium(II), allyl[1,3-bis(2,6-diisopropylphenyl)-2-imidazolidinylidene]chloropalladium(II), and [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]chloro[3-phenylallyl]palladium(II).

[0246] As the palladium catalyst precursor, an NHC-Pd naphthoquinone catalyst can be used, for example, 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene(1,4-naphthoquinone)palladium(0) dimer, etc. can be used as the palladium catalyst precursor.

[0247] In one embodiment of the present invention, XPhos Pd G3, SPhos Pd G3, RuPhos Pd G3, BrettPhos Pd G3, tBuXPhos Pd G3, CPhos Pd G3, DavePhos Pd G3, GPhos Pd G3, tBuDavePhos Pd G3, VPhos Pd G3, JackiePhos Pd G3, CyJohnPhos Pd G3, RockPhos Pd G3, Me ４ tBuXPhos Pd G3, Me ３ (OMe) tBuXPhos Pd G3, tBuBrettPhos Pd G3, AdBrettPhos Pd G3, (tBu) PhCPhos Pd G3, PhCPos Pd G3, APhos Pd G3, (tBu)２ PPh Pd G3, MorDalPhos Pd G3, PCy ３ Pd G3, P(tBu) ３ Pd G3, cataCXium A Pd G3, (tBu) ２ PMe Pd G3, Neopentyl (tBu) ２ P Pd G3, P (o-Tol) ３ Pd G3, QPhos Pd G3, TrixiePhos Pd G3, meCgPPh Pd G3, dppf Pd G3, dtbpf Pd G3, XPhos Pd G4, SPhos Pd G4, RuPhos Pd G4, BrettPhos Pd G4, tBuXPhos Pd G4, CPhos Pd G4DavePhos Pd G4, GPhos Pd G4, tBuDavePhos Pd G4, VPhos Pd G4, EPhos Pd G4, CyJohnPhos Pd G4, tBuBrettPhos Pd G4, (tBu)PhCPhos Pd G4, methanesulfonato(2-bis(3,5-di(trifluoromethyl)phenylphosphino)-3,6-dimethoxy-2′,6′-bis(dimethylamino)-1,1′-biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II), APhos Pd G4, (tBu) ２ PPh Pd G4, MorDalPhos Pd G4, PCy ３ Pd G4, P(tBu) ３ Pd G4, cataCXium A Pd G4, (tBu) ２ PMe Pd G4, Neopentyl (tBu) ２ P Pd G4, meCgPPh Pd G4, dppf Pd G4, tBuBrettPhos Pd G6 TES, tBuBrettPhos Pd G6 Br, AdBrettPhos Pd G6 Br, GPhos Pd G6 TES, AlPhos Pd G6 Br, AlPhos Pd G6 OTf, Pd(PCy ３ ) ２ Cl ２ , Pd(dppf)Cl ２ , Pd(dtbpf)Cl２ , (APhos) ２ PdCl ２、 Bis(tricyclohexylphosphine)palladium(0), bis(tri-tert-butylphosphine)palladium(0), Pd-PEPPSI IPr, Pd-PEPPSI SIPr, and Pd-PEPPSI-IPent can be used as precursors of the palladium catalyst, and in particular, RuPhos Pd G4, tBuXPhos Pd G4, RockPhos Pd G3, BrettPhos Pd G4, tBuBrettPhos Pd G4, AdBrettPhos Pd G3, AdBrettPhos Pd G6 Br, and (tBu)PhCPhos Pd G4 can be preferably used as precursors of the palladium catalyst.

[0248] In one embodiment of the present invention, XPhos, SPhos, RuPhos, BrettPhos, tBuXPhos, CPhos, DavePhos, GPhos, tBuDavePhos, VPhos, JackiePhos, CyJohnPhos, RockPhos, Me ４ tBuXPhos,Me ３ (OMe)tBuXPhos, tBuBrettPhos, AdBrettPhos, (tBu)PhCPhos, PhCPhos, bis(3,5-bis(trifluoromethyl)phenyl)(2',6'-bis(dimethylamino)-3,6-dimethoxybiphenyl-2-yl)phosphine, bis(3,5-bis(trifluoromethyl)phenyl)(2',6'-bis(isopropoxy)-3,6-dimethoxybiphenyl-2-yl)phosphine, APhos, (tBu) ２ PPh, MorDalPhos, PCy ３ , P(tBu) ３ , cataCXium A, (tBu) ２ PMe, Neopentyl (tBu) ２P, QPhos, TrixiePhos, meCgPPh, dppf, dtbpf, cataCXium PICy, CyBippyPhos, BippyPhos, AdBippyPhos, cataCXium PtB, cataCXium POMetB, cataCXium PIntB can be used as a ligand for the palladium catalyst, and in particular, RuPhos, tBuXPhos, RockPhos, BrettPhos, tBuBrettPhos, AdBrettPhos, (tBu)PhCPhos, BippyPhos, AdBippyPhos, cataCXiumPIntB, and meCgPPh can be preferably used as ligands for the palladium catalyst.

[0249] In one embodiment of the present invention, palladium acetate, Pd(dba) ２ , Pd ２ (dba) ３ , Pd ２ (dba) ３ CHCl ３ , allylpalladium chloride dimer, palladium (π-cinnamyl) chloride dimer, (1-methylallyl)palladium chloride dimer, (1,5-cyclooctadiene)bis(trimethylsilylmethyl)palladium(II), (2'-amino-1,1'-biphenyl-2-yl)methanesulfonatopalladium(II) dimer can be used as the palladium catalyst, and in particular Pd ２ (dba) ３ CHCl ３ can be preferably used as the palladium catalyst.

[0250] The number of equivalents of the palladium catalyst to be used can be appropriately determined by those skilled in the art. In one embodiment of the present invention, for example, a compound having a leaving group such as a halogen atom, which is one of the substrates in the cross-coupling reaction (referred to herein as Compound 1 or X) is used. １ -Ar ２The number of equivalents of the palladium catalyst relative to the compound having a leaving group (a compound represented by the formula (I)) can be 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents. The number of equivalents of the ligand used can be appropriately determined by those skilled in the art, and can be, for example, 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents relative to the compound having a leaving group. The number of equivalents of the catalyst precursor used can be appropriately determined by those skilled in the art, and can be, for example, 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents relative to the compound having a leaving group.

[0251] In one embodiment of the present invention, for example, the number of equivalents of the palladium catalyst relative to the other substrate (herein also referred to as compound 2) that reacts with the compound having the leaving group in the cross-coupling reaction can be 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents. The number of equivalents of the ligand used can be appropriately determined by one skilled in the art, and can be, for example, 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents relative to the compound. The number of equivalents of the catalyst precursor to be used can be appropriately determined by a person skilled in the art, and can be, for example, 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents relative to the compound.

[0252] In one embodiment of the present invention, the cross-coupling reaction is carried out in the presence of a nickel catalyst. For example, the nickel complexes described herein can be used as the nickel catalyst. When a nickel catalyst is used, the substrates for the C—O bond-forming reaction can be water or an alcohol, and a compound having a leaving group. The substrates for the C—N bond-forming reaction can be ammonia, a primary amine, or a secondary amine.

[0253] The nickel catalyst is not particularly limited as long as it is one that can be commonly used in cross-coupling reactions. Examples of nickel catalysts that can be used include bis(1,5-cyclooctadiene)nickel, dichloro(1,2-dimethoxyethane)nickel, dibromo(1,2-dimethoxyethane)nickel, nickel(II) chloride, nickel(II) bromide, nickel(II) trifluoromethanesulfonate, bis(trifluoromethanesulfonimide)nickel(II), nickel(II) acetylacetonate, and nickel(II) nitrate, and any of these may be coordinated with water. In one embodiment of the present invention, a nickel catalyst formed by combining at least one selected from the group consisting of bis(1,5-cyclooctadiene)nickel and nickel(II) chloride with at least one selected from the group consisting of tricyclohexylphosphine, 1,1′-bis(diphenylphosphino)ferrocene, and 1,3-bis(diphenylphosphino)propane can be used as the cross-coupling catalyst.

[0254] The number of equivalents of the nickel catalyst to be used can be appropriately determined by those skilled in the art. In one embodiment of the present invention, for example, a compound having a leaving group such as a halogen atom, which is one of the substrates in the cross-coupling reaction (referred to herein as Compound 1 or X) is used. １ -Ar ２ The number of equivalents of the nickel catalyst relative to the compound having a leaving group (a compound represented by the formula (I)) can be 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents. The number of equivalents of the ligand used can be appropriately determined by those skilled in the art, and can be, for example, 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.0 to 5 equivalents, or 0.01 to 3 equivalents relative to the compound having a leaving group. The number of equivalents of the catalyst precursor used can be appropriately determined by those skilled in the art, and can be, for example, 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents relative to the compound having a leaving group.

[0255] In one embodiment of the present invention, for example, the number of equivalents of the nickel catalyst relative to the other substrate (herein also referred to as compound 2) that reacts with the compound having the leaving group in the cross-coupling reaction can be 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents. The number of equivalents of the ligand used can be appropriately determined by one skilled in the art, and can be, for example, 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents relative to the compound. The number of equivalents of the catalyst precursor to be used can be appropriately determined by a person skilled in the art, and can be, for example, 0.001 to 10 equivalents, 0.001 to 7.5 equivalents, 0.001 to 5 equivalents, 0.01 to 5 equivalents, or 0.01 to 3 equivalents relative to the compound.

[0256] In one aspect of the invention, the cross-coupling reaction is carried out by adding a leaving group X to a carbon atom of an aromatic ring. １ The aromatic ring is not particularly limited as long as it has an aromatic ring chemical structure, and for example, ６－１０ An aromatic carbocycle or a 5- to 10-membered aromatic heterocycle containing one or more ring heteroatoms independently selected from O, N, and S. Leaving group X １ Compound 1 may contain one or more leaving groups, for example, 1 to 10, 1 to 5, or 1 to 3 leaving groups. １ When a plurality of leaving groups X are contained in Compound 1, １ may be the same or different. １ and may contain two or more carbon atoms having one or more leaving groups X １ In one embodiment, compound 1 has one or more aromatic rings containing one leaving group X １ Includes.

[0257] In one embodiment of the present invention, the leaving group X １ is a halogen atom or —O—SO ２ -R ４ In a preferred embodiment, the leaving group X １is a bromine atom or a chlorine atom, and in a more preferred embodiment, the leaving group X １ is a bromine atom.

[0258] Compound 2 having a hydroxyl capable of forming a C—O bond or an H—N group capable of forming a C—N bond can be used as the compound used for cross-coupling with compound 1. In one aspect of the present invention, compound 2 has one or more reactive groups selected from a hydroxyl capable of forming a C—O bond and an H—N group capable of forming a C—N bond. When compound 2 has multiple reactive groups, they may be the same or different. In one embodiment, compound 1 contains one reactive group.

[0259] In one aspect of the present invention, compound 2 is a compound having a hydroxyl capable of forming a C—O bond, and examples thereof include water and alcohols. ５ Examples include compounds represented by the formula: ５ is C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ Cycloalkyl, C ７－１４ Aralkyl, C ６－１０ aryl, or a 5-10 membered heteroaryl containing one or more ring heteroatoms independently selected from O, N and S, each of which is selected from fluorine atoms, 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, 5-10 membered heteroarylcarbonylamino containing one or more ring heteroatoms independently selected from O, N and S, aminocarbonyl, (C １－６ alkyl)aminocarbonyl, di(C １－６ It may be substituted with one or more groups independently selected from the group consisting of alkyl)aminocarbonyl, and 4- to 8-membered cyclic aminocarbonyl.

[0260] In one embodiment of the present invention, HO-R ５ In another embodiment of the present invention, a compound represented by the formula: ５ In one embodiment, a compound having a chemical structure represented by the formula: ５ The compound containing in its molecule the chemical structure of the compound represented by HO-R ５ It does not contain any reactive groups other than those derived from

[0261] In one embodiment of the present invention, one or more HO-R ５ or a compound represented by one or more of HO—R ５ A solid-phase synthesis resin carrying a compound having a chemical structure represented by the formula (I) above in its molecule, supported via a linker, can be used as a substrate for cross-coupling. Here, "supported" means that the compound is bound via a linker. Therefore, in the above-mentioned embodiment, a solid-phase synthesis resin having a side chain to which the compound is bound via a linker can be used as a substrate for cross-coupling.

[0262] In one aspect of the present invention, compound 2 is a compound having an H—N group capable of forming a C—N bond, and examples thereof include ammonia, amines, and the like. ６ R ７ Examples include compounds represented by the formula: ６ and R ７ together with the nitrogen atom to which they are attached to form a 5- to 7-membered saturated heterocycle, and the heterocycle is not limited to a fluorine atom, a cyano, a 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, 5-10 membered heteroarylcarbonylamino containing one or more ring heteroatoms independently selected from O, N and S, di(C １－６alkyl)amino, 4- to 8-membered cyclic amino, aminocarbonyl, (C １－６ alkyl)aminocarbonyl, di(C １－６ or R ６ and R ７ are each independently a hydrogen atom, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ cycloalkyl, (C １－６ alkyl)carbonyl, (C ６－１０ aryl)carbonyl, 5-10 membered heteroarylcarbonyl containing one or more ring heteroatoms independently selected from O, N and S, C ７－１４ Aralkyl, C ６－１０ aryl, or a 5-10 membered heteroaryl containing one or more ring heteroatoms independently selected from O, N and S, each of which is selected from fluorine atoms, 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, 5-10 membered heteroarylcarbonylamino containing one or more ring heteroatoms independently selected from O, N and S, di(C １－６ alkyl)amino, 4- to 8-membered cyclic amino, aminocarbonyl, (C １－６ alkyl)aminocarbonyl, di(C １－６ The aminocarbonyl may be substituted by one or more substituents independently selected from the group consisting of alkyl, aminocarbonyl, and 4- to 8-membered cyclic aminocarbonyl.

[0263] In one embodiment of the present invention, HNR ６ R ７ can be used as a substrate for cross-coupling. ６ R ７In one embodiment, a compound having a chemical structure represented by HNR ６ R ７ The compound containing the chemical structure of the compound represented by HNR ６ R ７ It does not contain any reactive groups other than those derived from

[0264] In one embodiment of the present invention, one or more HNR ６ R ７ or a compound represented by one or more HNR ６ R ７ A solid-phase synthesis resin carrying a compound having a chemical structure represented by the formula (I) above, supported via a linker, can be used as a substrate for cross-coupling. Here, "supported" means that the compound is bound via a linker. Therefore, in the above-mentioned embodiment, a solid-phase synthesis resin having a side chain to which the compound is bound via a linker can be used as a substrate for cross-coupling.

[0265] As used herein, "R ６ and R ７ or together with the nitrogen atom to which they are bonded form a 5- to 7-membered saturated heterocycle" is not particularly limited as long as it is a 5- to 7-membered nitrogen-containing saturated heterocycle, and may be, for example, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, azacycloheptane, diazacycloheptane, triazacycloheptane, etc. The heterocycle may have a substituent.

[0266] In one aspect of the invention, the cross-coupling reaction is carried out according to formula A:

[0267]

[0268] [In the formula, R １ , R ２ and R ３ are each independently C １－４ alkyl, provided that R １ , R ２ and R ３wherein the total number of carbon atoms is 4 or more and 6 or less. Specifically, the reaction is carried out in a solvent containing an amide solvent represented by the formula (I) above.

[0269] In a preferred embodiment of the present invention, the amide solvent is N,N-dimethylpropionamide, N,N-diethylacetamide, or N,N-diethylpropionamide. In one embodiment, a mixed solvent containing two or more amide solvents represented by Formula A is used as a solvent for the cross-coupling reaction. In one embodiment, one solvent selected from the amide solvents represented by Formula A is used as a solvent for the cross-coupling reaction. In one embodiment, a solvent containing the amide solvent represented by Formula A at 30% v / v or more, 40% v / v or more, 50% v / v or more, 60% v / v or more, 70% v / v or more, 80% v / v or more, 85% v / v or more, 90% v / v or more, or 95% v / v or more is used as a solvent for the cross-coupling reaction.

[0270] The reaction temperature can be appropriately set by those skilled in the art and can be, for example, 0 to 200°C, 0 to 150°C, 0 to 100°C, 10 to 80°C, or 25 to 80°C. In one aspect of the present invention, a base can be used in the cross-coupling reaction. Bases typically used in cross-coupling reactions can be used, or a mixture of multiple bases can be used. In one embodiment, the base is selected from the group consisting of organic bases whose conjugate acids have a pKa of 23 or higher in acetonitrile and inorganic bases whose conjugate acids have a pKa of 9 to 20 in water. Examples of such bases include pyridine, 2,6-lutidine, 2,4,6-collidine, DTBP, DTBMP, triethylamine, DIPEA, 4-methylmorpholine, DBU, DBN, MTBD, BTMG, TMG, 1,8-bis(dimethylamino)naphthalene, N,N-dimethylaniline, P1-tBu, and P2tBu. In one embodiment, the base is 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), 1-ethyl-2,2,4,4,4-pentakis(dimethylamino)-2λ ５ ,4λ ５ -catenadi(phosphazene) (P2Et, 1-tert-butyl-2,2,4,4,4-pentakis(dimethylamino)-2λ ５ ,4λ-catenadi(phosphazene) (P2tBu), tert-butylimino-tris(dimethylamino)phosphorane (P1tBu), 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (BEMP), tert-butylimino-tri(pyrrolino)phosphorane (BTPP), alkali metal carbonates, alkali metal phosphates, alkali metal C １－６ The number of equivalents of the base to be used can be appropriately determined by those skilled in the art, and can be, for example, 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents relative to the carboxylic acid containing A.

[0271] The reaction time for the cross-coupling 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 to 48 hours, or 30 minutes to 24 hours.

[0272] In the present specification, examples of aromatic rings include 5- to 10-membered monocyclic or fused aromatic rings, or C ６－１０ Examples of such heteroaromatic rings include aromatic rings and 5- to 10-membered heteroaromatic rings containing one or more ring heteroatoms independently selected from O, N, and S. Examples of such heteroaromatic rings include a benzene ring, a naphthalene ring, a pyrrole ring, a thiophene ring, a furan ring, a pyridine ring, a thiazole ring, an isothiazole ring, a pyrazole ring, an oxazole ring, an isoxazole ring, an imidazole ring, a triazole ring, a pyrimidine ring, a uridine ring, a pyrazine ring, a pyridazine ring, a quinoline ring, an isoquinoline ring, a 4H-quinolizine ring, a phthalazine ring, a naphthyridine ring, a quinoxaline ring, a quinazoline ring, a cinnoline ring, a pteridine ring, an indole ring, an indoline ring, a benzothiophene ring, a 1-methyl-1H-indole ring, a benzofuran ring, a benzisothiazole ring, a benzisoxazole ring, an indazole ring, a benzimidazole ring, a benzotriazole ring, an azaindole ring, and an imidazopyridine ring.

[0273] In this specification, C ６－１０ Examples of aryl include phenyl and naphthyl. Examples of 5- to 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.

[0274] In this specification, C １－６Alkyl 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.

[0275] In this specification, C １－４ Alkyl is a linear or branched monovalent saturated aliphatic group having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, and 1-methylpropyl.

[0276] In this specification, C ２－６ Alkenyl is a linear or branched 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).

[0277] 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.

[0278] 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.

[0279] 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.

[0280] 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 previously defined.

[0281] In this specification, (C １－６ Alkyl)carbonyl is C １－６ means an alkyl-C(═O)— group, where C １－６ Alkyl is as previously defined.

[0282] In this specification, (C １－６ Alkoxy)carbonylamino "(C １－６ The term "alkoxy)carbonyl" is as previously defined.

[0283] In this specification, (C １－６ alkyl)amino "C １－６ "Alkyl" is as previously defined.

[0284] In this specification, di(C １－６ alkyl)amino "C １－６ "Alkyl" is as previously defined and may be the same or different.

[0285] In this specification, 4- to 8-membered cyclic amino includes groups such as aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl, which are bonded via a nitrogen atom.

[0286] In this specification, (C ６－１０ aryl)carbonylamino "C ６－１０ "Aryl" is as previously defined.

[0287] As used herein, the "5- to 10-membered heteroaryl containing one or more ring heteroatoms independently selected from O, N, and S" in the 5- to 10-membered heteroarylcarbonylamino containing one or more ring heteroatoms independently selected from O, N, and S is as defined above.

[0288] As used herein, aminocarbonyl refers to -CONH ２ (C１－６ alkyl)aminocarbonyl "C １－６ "Alkyl" is as previously defined.

[0289] In this specification, di(C １－６ alkyl)aminocarbonyl "C １－６ "Alkyl" is as previously defined and may be the same or different.

[0290] 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 the nitrogen atom.

[0291] In this specification, (C ６－１０ aryl)carbonyl "C ６－１０ "Aryl" is as previously defined.

[0292] As used herein, the "5- to 10-membered heteroaryl containing one or more ring heteroatoms independently selected from O, N, and S" of the 5- to 10-membered heteroarylcarbonyl containing one or more ring heteroatoms independently selected from O, N, and S is as defined above.

[0293] 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.

[0294] In this specification, "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc. In the present invention, when a halogen atom is a substituent for aryl, 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 for alkyl or a group containing 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. X １ Preferred halogen atoms for are chlorine, bromine, and iodine atoms.

[0295] C optionally substituted with one or more fluorine atoms １－６ Alkyl includes, for example, trifluoromethyl.

[0296] 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.

[0297] In this specification, alkali metals refer to lithium, sodium, potassium, rubidium, cesium, and francium. Examples of alkali metals that form salts such as alkoxides and hydroxides include lithium, sodium, and potassium.

[0298] In one aspect of the present invention, the cross-coupling reaction is carried out in a reaction system that further contains a salt in addition to the base. The salt is not particularly limited, and examples thereof include organic acid metal salts, particularly fluorine-substituted carboxylic acid metal salts, fluorine-substituted sulfonic acid metal salts, and fluorine-substituted sulfonimide metal salts, and inorganic acid metal salts, particularly fluorine-containing borates, fluorine-containing phosphates, and fluorine-containing antimonates. Examples of metal salts include alkali metal salts. In one aspect of the present invention, the salt is, for example, an alkali metal salt of an acid selected from the group consisting of trifluoroacetic acid, trifluoromethanesulfonic acid, trifluoromethanesulfonimide, tetrafluoroboric acid, hexafluorophosphoric acid, and hexafluoroantimony(V) acid.

[0299] In one aspect of the present invention, a cross-coupling reaction can be carried out using a solid-phase synthesis resin supported with either Compound 1 or 2 as a substrate. In another aspect of the present invention, a cross-coupling reaction can be carried out using a solid-phase synthesis resin supported with two or more, three or more, four or more, five or more, seven or more, or ten or more types of either Compound 1 or 2 via linkers as a substrate. The solid-phase synthesis resin used as the solid support is not particularly limited as long as it is a commonly used resin. Examples of such a resin include carboxylic resin, CTC resin, Trt resin, SASRIN resin, Rink amide resin, PAL AM resin, Seiber amide resin, Merrifield resin, Wang resin, and 2-(4-bromomethylphenoxy)ethyl polystyrene, as well as solid supports having any functional group, such as a carboxy group, an amino group, an aminomethyl group, a hydroxy group, or a hydroxymethyl group, on the polystyrene. Furthermore, any linker that covalently connects the carrier to Compound 1 or 2 may be used, and the design may allow cleavage between the linker and the compound. The carrier is not particularly limited, and examples thereof include polystyrene and PEG (polyethylene glycol).

[0300] The method and reaction conditions for supporting compound 1 or 2 on a solid-phase synthesis resin can be appropriately determined by one of ordinary skill in the art based on methods described in publicly known literature. The reaction conditions for cleaving a compound from a solid-phase synthesis resin can be appropriately determined by one of ordinary skill 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.

[0301] In one aspect of the present invention, the cross-coupling reaction is carried out by adding a leaving group X to a carbon atom of an aromatic ring in a side chain of Compound 1. １or a solid phase synthesis resin carrying, as compound 2, a reactive group in the side chain capable of undergoing a C-O bond forming reaction or a C-N bond forming reaction by substitution with the leaving group. In one aspect of the present invention, a solid phase synthesis resin to which two or more, three or more, four or more, five or more, seven or more, or ten or more different compounds are bound can be used as the substrate. 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 of such solid supports include carboxylic resin, CTC resin, Trt resin, SASRIN resin, Rink amide resin, PAL AM resin, Seiber amide resin, Merrifield resin, Wang resin, and 2-(4-bromomethylphenoxy)ethyl polystyrene, as well as solid supports having any functional group on the polystyrene, such as a carboxyl group, an amino group, an aminomethyl group, a hydroxy group, or a hydroxymethyl group. Furthermore, any linker may be used to covalently link these supports to Compound 1 or 2, allowing for cleavage between the linker and the compound. The support is not particularly limited, and examples thereof include polystyrene and PEG (polyethylene glycol).

[0302] Techniques and reaction conditions for preparing a solid-phase synthesis resin having a side chain to which a predetermined compound is bound via a linker 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.

[0303] The present invention will be described in more detail below using 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 suppliers unless otherwise specified. Information on the palladium catalysts, such as their source and catalog code, is provided below.

[0304]

[0305] As silica gel for column chromatography, Biotage (registered trademark) SNAP MLtra, Biotage (registered trademark) Sfaer D (Duo) (60 μm), Biotage (registered trademark) Sfaer HC D (Duo) (20 μm), or the like was used appropriately.

[0306] The amino silica gel used in the column chromatography was Biotage (registered trademark) SNAP Isolute NH2 (50 μm) or Biotage (registered trademark) SNAP Cartridge KP-NH, etc., as appropriate.

[0307] As the reversed-phase silica gel for column chromatography, Biotage (registered trademark) SNAP MLtra C18 (25 μm) or Biotage (registered trademark) Sfaer C18 (30 μm) or the like was used appropriately.

[0308] 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 = quart, dd = double doublet, ddd = double double doublet, dt = double triplet, td = triple doublet, m = multiplet).

[0309] 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.

[0310] The following abbreviations are used in the examples:

[0311]

[0312]

[0313]

[0314] The LCMS analysis conditions are shown in Table LC01.

[0315]

[0316] 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.

[0317] 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.

[0318] The terms "overnight" and "overnight" refer to approximately 8 to 14 hours unless otherwise specified, but are not limited to this. The solid-phase reaction can be carried out in any suitable 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 equipped 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.

[0319] 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.

[0320] 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.

[0321] 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.

[0322] 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."

[0323] Used in the chemical structure notation in the examples:

[0324]

[0325] The notation "-1R" indicates a polystyrene resin, and indicates that the compound is supported on a solid phase. The number in "-1R" indicates that the compound is supported on a solid phase, and indicates the lot number of the resin used in the examples.

[0326] Example of "-1R"

[0327]

[0328] 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.

[0329] 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.

[0330] Example 1: Synthesis of compounds used in the present specification Example 1-1-1: Synthesis of tert-butyl 4-[4-[[4-(4-ethoxycarbonylphenyl)phenoxy]methyl]phenoxy]piperidine-1-carboxylate (compound a04)

[0331]

[0332] Under a nitrogen atmosphere, tert-butyl 4-[4-(hydroxymethyl)phenoxy]piperidine-1-carboxylate (a01, 1.00 g, 3.25 mmol), triethylamine (0.499 mL, 3.58 mmol), and DCM (16.3 mL) were placed in a 100 mL three-neck flask, and the reaction vessel was cooled to 0°C. Methanesulfonyl chloride (0.266 mL, 3.42 mmol) was added, and the mixture was stirred at 0°C for 3 hours. A saturated aqueous solution of sodium bicarbonate (4.9 mL) was added to the resulting mixture. The organic layer was extracted three times with dichloromethane (24 mL), dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue (a02), ethyl 4-(4-hydroxyphenyl)benzoate (a03, 0.866 g, 3.58 mmol), cesium carbonate (2.12 g, 6.50 mmol), and NMP (12.0 mL) were mixed in a 100 mL three-neck flask under a nitrogen atmosphere and stirred at room temperature for 24 hours. Saturated aqueous ammonium chloride solution (6 mL) and ethyl acetate (12 mL) were added to the resulting mixture. The organic layer was extracted three times with ethyl acetate (10 mL), and the resulting organic layers were combined and hexane (20 mL) was added. The organic layer was washed three times with water (15 mL) and once with saturated aqueous sodium chloride solution (15 mL), and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (NH-silica gel, 0-25% ethyl acetate / hexane), and the resulting crude product was purified by silica gel column chromatography (NH-silica gel, 0-100% dichloromethane / hexane). The obtained crude product was dissolved in ethyl acetate (100 mL) and hexane (200 mL), washed three times with water (200 mL) and once with a saturated aqueous sodium chloride solution (100 mL), and concentrated under reduced pressure to obtain the title compound a04 (1.44 g, 2.71 mmol, 83%) as a white solid.

[0333]

[0334] Compound a04 １ H-NMR (400MHz, CDCl ３) δ8.08 (d, J=8.4Hz, 2H), 7.61 (d, J=8.4Hz, 2H), 7.57 (d, J=8.8Hz, 2H), 7.37 ( d, J=8.4Hz, 2H), 7.06 (d, J=8.8Hz, 2H), 6.94 (d, J=8.4Hz, 2H), 5.04 (s, 1H), 4 .. 50-4.45 (m, 1H), 4.40 (q, J = 7.2Hz, 2H), 3.73-3.67 (m, 2H), 3.38-3.31 (m, 2H ), 1.96-1.88 (m, 2H), 1.80-1.71 (m, 2H), 1.47 (s, 9H), 1.41 (t, J = 7.2Hz, 3H).

[0335] LRMS: m / z 554 [M+Na] ＋ Retention time: 1.684 minutes (analysis conditions FA05-1, 290 nm).

[0336] Example 1-1-2: Synthesis of ethyl 4-[4-[(4-piperidin-4-yloxyphenyl)methoxy]phenyl]benzoate (compound a05)

[0337]

[0338] Under a nitrogen atmosphere, tert-butyl 4-[4-[[4-(4-ethoxycarbonylphenyl)phenoxy]methyl]phenoxy]piperidine-1-carboxylate (a04, 50.0 mg, 94.0 μmol), N,N-diisopropylethylamine (29.5 μL, 0.169 mmol), and THF (1.88 mL) were added to a 5 mL screw-cap vial, and the reaction vessel was cooled to 0°C. Trimethylsilyl trifluoromethanesulfonate (20.4 μL, 0.113 mmol) was added, and the mixture was stirred at 0°C for 3 hours. N,N-diisopropylethylamine (2.95 μL, 16.9 μmol) and trimethylsilyl trifluoromethanesulfonate (2.0 μL, 11 μmol) were added, and the mixture was stirred at 0°C for 1.5 hours. Triethylamine (26.2 μL) was added to the resulting mixture at 0°C, and the mixture was stirred at room temperature for 30 minutes. Water (847 μL), DMSO (1 mL), and formic acid (12.1 μL, 0.282 mmol) were added, and the mixture was purified by reverse-phase column chromatography (C18, 0-60% 0.1% formic acid in acetonitrile / 0.1% formic acid in water). The resulting product was dissolved in dichloromethane (100 mL), washed three times with saturated aqueous sodium bicarbonate (50 mL), and once with saturated aqueous sodium chloride (50 mL). The mixture was concentrated under reduced pressure to give the title compound a05 (19.8 mg, 45.9 mmol, 49%) as a white solid.

[0339]

[0340] Compound a05 １ H-NMR (400MHz, CDCl ３ ) δ8.08 (d, J=8.4Hz, 2H), 7.61 (d, J=8.8Hz, 2H), 7.57 (d, J=8.8Hz, 2H), 7.36 (d, J=8.8Hz, 2H), 7.06 (d, J=8.8Hz, 2H), 6.94 (d, J=8.8Hz, 2H), 5.03 (s, 1H) , 4.42-4.36 (m, 3H), 3.15 (ddd, J=13.6, 4.8, 4.8Hz, 2H), 2.74 (ddd, J=13.6, 9.2, 3.2Hz, 2H), 2.06-1.99 (m, 2H), 173-1.64 (m, 2H), 1.41 (t, J = 7.2Hz, 3H).

[0341] LRMS: m / z 432 [M+H] ＋ Retention time: 0.904 minutes (Analysis conditions FA05-1, 290 nm).

[0342] Example 1-2-1: Synthesis of compound A02-1R

[0343]

[0344] Under a nitrogen atmosphere, carboxylic resin (A01-1R) (Chem-Impex, loading 2.19 mmol / g, 1.00 g, 2.19 mmol) and NMP (15 mL) were added to a 20 mL glass vial and shaken at room temperature for 1 hour. Ethyl 4-[4-[(4-piperidin-4-yloxyphenyl)methoxy]phenyl]benzoate (a05) (0.106 g, 0.246 mmol), piperidine (0.033 mL, 0.329 mmol), HOAt (0.298 g, 2.19 mmol), and DIC (0.341 mL, 2.19 mmol) were added and shaken at room temperature for 4 hours. Piperidine (1.30 mL, 13.1 mmol), HOAt (1.79 g, 13.1 mmol), and DIC (2.05 mL, 13.1 mmol) were added, and the mixture was shaken at room temperature overnight.

[0345] Solid-phase purification The reaction solution and the solid phase suspension were all transferred onto a filter and washed three times with NMP (20 mL), three times with MeOH (20 mL), and three times with DCM (20 mL). The obtained solid phase was dried overnight under reduced pressure to obtain compound A02-1R (loading amount 0.200 mmol / g, 1.25 g, 0.250 mmol).

[0346] Reaction tracking: A suspension (10 μL) of the reaction mixture and solid phase was transferred onto a filter 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 filter was then immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.1 M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with NMP (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and the reaction progress was measured by LCMS. As a result, 100% of the target product A02 was observed.

[0347]

[0348] Compound A02 LRMS: m / z 243 [M+H] ＋ Retention time: 1.085 minutes (analysis conditions FA05-1, 299 nm).

[0349] Example 1-2-2: Synthesis of compound A03-1R

[0350]

[0351] Under a nitrogen atmosphere, compound A02-1R (loading amount 0.200 mmol / g, 1.25 g, 0.250 mmol), THF (7.2 mL), MeOH (0.8 mL), and an aqueous sodium hydroxide solution (5 M, 0.8 mL, 4.0 mmol) were placed in a 10 mL glass vial, and the mixture was shaken at 60° C. for 6 hours.

[0352] Solid-Phase Purification The reaction solution and the solid phase suspension were all transferred onto a filter and washed three times with NMP (20 mL), three times with water (20 mL), three times with HOAt / NMP solution (0.2 M, 20 mL), three times with NMP (20 mL), three times with MeOH (20 mL), and three times with DCM (20 mL). The obtained solid phase was dried under reduced pressure overnight to obtain compound A03-1R (loading amount 0.201 mmol / g, 1.16 g, 0.232 mmol).

[0353] Reaction tracking: A suspension (10 μL) of the reaction mixture and solid phase was transferred onto a filter 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 filter was then immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.1 M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with NMP (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared, and the reaction progress was measured by LCMS. As a result, 100% of the target product A03 was observed.

[0354]

[0355] Compound A03 Maximum wavelength: 293 nm Retention time: 0.775 minutes (Analysis conditions FA05-1, 299 nm).

[0356] Example 1-2-3: Synthesis of compound A02-2R

[0357]

[0358] Under a nitrogen atmosphere, a 200 mL empty column equipped with a filter was charged with Carboxylic Resin (A01-2R) (Chem-Impex, loading 1.70 mmol / g, 10.5 g, 17.9 mmol), ethyl 4-[4-[(4-piperidin-4-yloxyphenyl)methoxy]phenyl]benzoate (a05) (1.08 g, 2.51 mmol), HOAt (2.43 g, 17.9 mmol), and NMP (158 mL) and shaken at room temperature for 1 hour. Piperidine (0.884 mL, 8.93 mmol) and DIC (2.78 mL, 17.9 mmol) were added, and the column was shaken at room temperature for 20 hours. HOAt (4.86 g, 35.7 mmol), DIC (5.56 mL, 35.7 mmol) and piperidine (3.53 mL, 35.7 mmol) were added, and the mixture was shaken at room temperature overnight.

[0359] Solid-phase purification The solid phase was washed three times with NMP (150 mL), three times with MeOH (150 mL), three times with DCM (150 mL), and three times with heptane (150 mL), and the obtained solid phase was dried under reduced pressure overnight to obtain compound A02-2R (loading amount 0.200 mmol / g, 12.8 g, 2.56 mmol).

[0360] A02-2R was washed three times with DCM (0.1 mL) and immersed in a 10% TFA / DCM solution (0.1 mL) containing 0.05 M pentamethylbenzene for 5 minutes. After filtration, NMP (0.1 mL) was added to the filtrate. 0.1 mL of this solution was diluted with MeCN (0.25 mL) and analyzed by LCMS. 100% of the target product A02 was observed.

[0361]

[0362] Compound A02 LRMS: m / z 243 [M+H] ＋ Retention time: 1.081 minutes (analysis conditions FA05-1, 299 nm).

[0363] Example 1-2-4: Synthesis of compound A03-2R

[0364]

[0365] Under a nitrogen atmosphere, compound A02-2R (loading amount 0.200 mmol / g, 12.8 g, 2.56 mmol), NMP (134 mL), and 2-methyl-2-butanol (38.4 mL) were placed in a 200 mL empty column equipped with a filter, and the column was shaken at room temperature for 1 hour. An aqueous solution of n-tetrabutylammonium hydroxide (1 M, 6.40 mL, 6.40 mmol) was added, and the column was shaken at room temperature for 14 hours.

[0366] Solid-phase purification The solid phase was washed once with NMP (190 mL), three times with HOAt / NMP solution (0.1 M, 190 mL), three times with NMP (190 mL), three times with MeOH (190 mL), three times with DCM (190 mL), and three times with heptane (190 mL), and the obtained solid phase was dried under reduced pressure overnight to obtain compound A03-2R (loading amount 0.201 mmol / g, 12.5 g, 2.50 mmol).

[0367] Reaction tracking: A suspension of the reaction mixture and solid phase (12 μL) was transferred onto a filter 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 filter was then immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.02 M pentamethylbenzene for 5 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and the reaction progress was measured by LCMS. As a result, 100% of the target product A03 was observed.

[0368]

[0369] Compound A03 Maximum wavelength: 294 nm Retention time: 0.767 minutes (Analysis conditions FA05-1, 299 nm).

[0370] Example 1-2-5: Synthesis of compound A02-3R

[0371]

[0372] Under a nitrogen atmosphere, carboxylic resin (A01-3R) (Rapp Polymer, loading 1.70 mmol / g, 40.0 g, 68.0 mmol) and NMP (600 mL) were added to an empty 800 mL filter column and shaken at room temperature for 1 hour. HOAt (9.26 g, 68.0 mmol), DIC (10.6 mL, 68.0 mmol), and ethyl 4-[4-[(4-piperidin-4-yloxyphenyl)methoxy]phenyl]benzoate (a05) (4.13 g, 9.58 mmol) were added and shaken at room temperature for 3.5 hours. HOAt (18.5 g, 136 mmol), DIC (21.2 mL, 136 mmol), and piperidine (16.8 mL, 170 mmol) were added and shaken at room temperature overnight.

[0373] Solid-Phase Purification The reaction solution and the solid phase suspension were all transferred to a 2-L separable flask and washed three times with NMP (800 mL), three times with MeOH (800 mL), three times with DCM (800 mL), and three times with heptane (800 mL). The obtained solid phase was dried overnight under reduced pressure to obtain compound A02-3R (loading amount 0.200 mmol / g, 47.9 g, 9.58 mmol).

[0374] Reaction tracking: A suspension (10 μL) of the reaction mixture and solid phase was transferred onto a filter 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 filter was then immersed in a 10% TFA / DCM solution (0.1 mL) containing 0.05 M pentamethylbenzene for 5 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and the reaction progress was measured by LCMS. As a result, 100% of the target product A02 was observed.

[0375]

[0376] Compound A02 LRMS: m / z 243 [M+H] ＋ Retention time: 1.081 minutes (analysis conditions FA05-1, 299 nm).

[0377] Example 1-2-6: Synthesis of compound A03-3R

[0378]

[0379] Under a nitrogen atmosphere, compound A02-3R (loading amount 0.200 mmol / g, 47.9 g, 9.58 mmol), NMP (503 mL), and 2-methyl-butanol (144 mL) were added to a 2 L separable flask and stirred at room temperature for 1 hour. After the suspension was cooled to 5°C, an aqueous solution of normal tetrabutylammonium hydroxide (1 M, 14.4 mL, 144 mmol) was added dropwise and the mixture was stirred at 25°C for 3.5 hours. An aqueous solution of normal tetrabutylammonium hydroxide (1 M, 2.39 mL, 2.39 mmol) was added dropwise and the mixture was stirred at room temperature for 1 hour. This procedure was repeated twice.

[0380] Solid-phase purification The suspension of the reaction solution and solid phase was washed three times with HOAt / NMP solution (0.1 M, 800 mL), three times with NMP (800 mL), three times with MeOH (800 mL), three times with DCM (800 mL), and three times with heptane (800 mL), and the obtained solid phase was dried under reduced pressure for 6 days to obtain compound A03-3R (loading amount 0.201 mmol / g, 49.8 g, 10.0 mmol).

[0381] A03-3R was washed three times with DCM (0.05 mL) and immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.02 M pentamethylbenzene for 5 minutes. After filtration, the solution was diluted with DMF (0.05 mL) and MeCN (0.25 mL) and analyzed by LCMS. 100% of the target product A03 was observed.

[0382]

[0383] Compound A03 Maximum wavelength: 294 nm Retention time: 0.761 min (Analysis conditions FA05-1, 299 nm).

[0384] Example 1-2-7: Synthesis of compound A02-4R

[0385]

[0386] Under a nitrogen atmosphere, carboxylic resin (A01-4R) (Watanabe Chemical Industries, loading 1.70 mmol / g, 24.7 g, 42.0 mmol) and NMP (371 mL) were added to an empty 800 mL filter column and shaken at room temperature for 45 minutes. HOAt (5.72 g, 42.0 mmol), DIC (6.55 mL, 42.0 mmol), and ethyl 4-[4-[(4-piperidin-4-yloxyphenyl)methoxy]phenyl]benzoate (a05) (2.56 g, 5.93 mmol) were added and shaken at room temperature for 4.5 hours. HOAt (11.5 g, 84.0 mmol), DIC (13.1 mL, 84.0 mmol), and piperidine (10.4 mL, 105 mmol) were added and shaken at room temperature for 21 hours.

[0387] Solid-phase purification The reaction solution was discharged from the column, and the solid phase was washed three times with NMP (500 mL), three times with MeOH (500 mL), three times with DCM (500 mL), and three times with heptane (500 mL). The obtained solid phase was dried under reduced pressure overnight to obtain compound A02-4R (loading amount 0.200 mmol / g, 30.5 g, 6.1 mmol).

[0388] A02-4R was washed three times with DCM (0.10 mL) and immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.2 M pentamethylbenzene for 5 minutes. After filtration, the solution was diluted with DMF (0.05 mL) and MeCN (0.20 mL) and analyzed by LCMS. 100% of the target product A03 was observed.

[0389]

[0390] Compound A02 LRMS: m / z 243 [M+H] ＋ Retention time: 1.071 minutes (analysis conditions FA05-1, 299 nm).

[0391] Example 1-2-8: Synthesis of compound A03-4R

[0392]

[0393] Under a nitrogen atmosphere, compound A02-4R (loading amount 0.200 mmol / g, 29.6 g, 5.92 mmol), NMP (311 mL), and 2-methyl-2-butanol (89 mL) were placed in an empty 800 mL column equipped with a filter, and the mixture was stirred at room temperature for 1 hour. After the suspension was cooled to 5°C, an aqueous solution of n-tetrabutylammonium hydroxide (1 M, 11.8 m, 118 mmol) was added dropwise, and the mixture was stirred at 25°C for 7.0 hours.

[0394] Solid-Phase Purification The suspension of the reaction solution and solid phase was washed three times with an HOAt / NMP solution (0.1 M, 500 mL), three times with NMP (500 mL), three times with MeOH (500 mL), three times with DCM (500 mL), and three times with heptane (500 mL), and the obtained solid phase was dried under reduced pressure for four days to obtain compound A03-4R (loading amount 0.201 mmol / g, 30.6 g, 6.2 mmol).

[0395] A03-4R was washed three times with DCM (0.10 mL) and immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.2 M pentamethylbenzene for 5 minutes. After filtration, the solution was diluted with DMF (0.05 mL) and MeCN (0.2 mL) and analyzed by LCMS. The target product A03 was observed at 99.9%.

[0396]

[0397] Compound A03 Maximum wavelength: 294 nm Retention time: 0.775 minutes (Analysis conditions FA05-1, 299 nm).

[0398] Example 1-3-1: Synthesis of compound B01-1R

[0399]

[0400] Under a nitrogen atmosphere, compound A03-1R (loading amount 0.201 mmol / g, 250 mg, 0.0502 mmol), NMP (3.75 mL), 3-bromoaniline (b01) (20 μL, 0.19 mmol), HOAt (26 mg, 0.19 mmol), and DIC (29 μL, 0.19 mmol) were placed in a 5 mL glass vial, and the mixture was shaken at 60° C. for 15 hours. 3-Bromoaniline (b01) (41 μL, 0.38 mmol), HOAt (51 mg, 0.38 mmol), and DIC (58 μL, 0.38 mmol) were added, and the mixture was shaken at 60° C. for 4 hours.

[0401] Solid-Phase Purification The reaction solution and the solid phase suspension were all transferred onto a filter and washed three times with NMP (5 mL), once with NMP / eOH=1:1 (v / v, 5 mL), three times with MeOH (5 mL), and three times with DCM (5 mL). The obtained solid phase was dried under reduced pressure overnight to obtain compound B01-1R (loading amount 0.195 mmol / g, 248 mg, 0.0484 mmol).

[0402] Reaction tracking: The reaction mixture and solid phase suspension (20 μL) was transferred onto a filter 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 filter was then immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.1 M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with NMP (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and the reaction progress was measured by LCMS. As a result, 100% of the target product B01 was observed.

[0403]

[0404] Compound B01 LRMS: m / z 368, 370 [M+H] ＋ Retention time: 1.166 minutes (analysis conditions FA05-1, 299 nm).

[0405] Example 1-3-2: Synthesis of compound B02-1R

[0406]

[0407] Compound B02-1R (loading amount 0.194 mmol / g) can be synthesized using compound A03-1R (loading amount 0.201 mmol / g) and 3-bromo-4-methylaniline (b02) by the same method as for compound B01-1R.

[0408] B02-1R was immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.1 M pentamethylbenzene for 2 minutes, and NMP (0.05 mL) and MeCN (0.25 mL) were added thereto. The filtrate was then filtered and subjected to LCMS measurement. 100% of the target substance B02 was observed.

[0409]

[0410] Compound B02 LRMS: m / z 382, ​​384 [M+H] ＋ Retention time: 1.221 minutes (analysis conditions FA05-1, 299 nm).

[0411] Example 1-3-3: Synthesis of compound B03-1R

[0412]

[0413] Under a nitrogen atmosphere, compound A03-1R (loading amount 0.201 mmol / g, 1.00 g, 0.201 mmol) and NMP (15 mL) were added to a 20 mL empty column equipped with a filter, and the column was shaken at room temperature for 1 hour. 3-amino-5-bromopyridine (b03) (70 mg, 0.402 mmol), 1-methylimidazole (64 μL, 0.804 mmol), and PyClU (134 mg, 0.402 mmol) were added, and the column was shaken at room temperature for 1 hour. 3-amino-5-bromopyridine (b03) (35 mg, 0.201 mmol), 1-methylimidazole (32 μL, 0.402 mmol), and PyClU (67 mg, 0.201 mmol) were added, and the column was shaken at room temperature for 20 minutes.

[0414] Solid-phase purification The solid phase was 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 overnight to obtain compound B03-1R (loading amount 0.195 mmol / g, 1.04 g, 0.203 mmol).

[0415] Reaction tracking: A suspension (10 μL) of the reaction mixture and solid phase was transferred onto a filter 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 filter was then immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.1 M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with NMP (0.1 mL). MeCN (0.25 mL) was added to the filtrate (50 μL), and an LC sample was prepared. The reaction progress was measured by LCMS. As a result, 100% of the target product B03 was observed.

[0416]

[0417] Compound B03 LRMS: m / z 369, 371 [M+H] ＋ Retention time: 1.014 minutes (analysis conditions FA05-1, 299 nm).

[0418] Example 1-3-4: Synthesis of compound B01-2R

[0419]

[0420] Compound B01-2R (loading amount 0.195 mmol / g) can be synthesized using compound A03-2R (loading amount 0.201 mmol / g) and 3-bromoaniline (b01) by the same method as for compound B03-1R.

[0421] B01-2R was washed three times with DCM (0.1 mL) and immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.05 M pentamethylbenzene for 5 minutes. After filtration, the solution was diluted with DMF (0.05 mL) and MeCN (0.25 mL) and analyzed by LCMS. The target product B01 was observed at 99.6%.

[0422]

[0423] Compound B01 LRMS: m / z 368, 370 [M+H] ＋ Retention time: 1.161 minutes (analysis conditions FA05-1, 299 nm).

[0424] Example 1-3-5: Synthesis of compound B02-2R

[0425]

[0426] Compound B02-2R (loading amount 0.194 mmol / g) can be synthesized using compound A03-2R (loading amount 0.201 mmol / g) and 3-bromo-4-methylaniline (b02) by the same method as for compound B03-1R.

[0427] B02-2R was washed three times with DCM (0.1 mL) and immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.05 M pentamethylbenzene for 5 minutes. After filtration, the solution was diluted with DMF (0.05 mL) and MeCN (0.25 mL) and analyzed by LCMS. 100% of the target product B02 was observed.

[0428]

[0429] Compound B02 LRMS: m / z 382, ​​384 [M+H] ＋ Retention time: 1.220 minutes (Analysis conditions FA05-1, 299 nm).

[0430] Example 1-3-6: Synthesis of compound B04-3R

[0431]

[0432] Compound B04-3R (loading amount 0.194 mmol / g) can be synthesized using compound A03-3R (loading amount 0.201 mmol / g) and 5-bromo-2-methoxy-aniline (b04) in the same manner as compound B03-1R.

[0433] B04-3R was washed three times with DCM (0.1 mL) and immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.05 M pentamethylbenzene for 5 minutes. After filtration, the solution was diluted with DMF (0.05 mL) and MeCN (0.25 mL) and analyzed by LCMS. The target product B04 was observed at 99.5%.

[0434]

[0435] Compound B04 LRMS: m / z 398, 400 [M+H] ＋ Retention time: 1.228 minutes (analysis conditions FA05-1, 299 nm).

[0436] Example 1-3-7: Synthesis of compound B05-2R

[0437]

[0438] Compound B05-2R (loading amount 0.194 mmol / g) can be synthesized using compound A03-2R (loading amount 0.201 mmol / g) and 5-bromo-6-methylpyridin-3-amine (b05) by the same method as for compound B03-1R.

[0439] B05-2R was washed three times with DCM (0.1 mL) and immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.05 M pentamethylbenzene for 5 minutes. After filtration, the solution was diluted with DMF (0.05 mL) and MeCN (0.25 mL) and analyzed by LCMS. The target product B05 was observed at 99.2%.

[0440]

[0441] Compound B05 LRMS: m / z 383, 385 [M+H] ＋ Retention time: 1.029 minutes (analysis conditions FA05-1, 299 nm).

[0442] Example 1-3-8: Synthesis of compound B06-2R

[0443]

[0444] Compound B06-2R (loading amount 0.192 mmol / g) can be synthesized using compound A03-2R (loading amount 0.201 mmol / g) and 5-bromo-2-methoxyaniline (b06) by the same method as for compound B03-1R.

[0445] B06-2R was washed three times with DCM (0.1 mL) and immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.05 M pentamethylbenzene for 5 minutes. After filtration, the solution was diluted with DMF (0.05 mL) and MeCN (0.25 mL) and analyzed by LCMS. The target product B06 was observed at 99.6%.

[0446]

[0447] Compound B06 LRMS: m / z 436, 438 [M+H]＋ Retention time: 1.335 minutes (analysis conditions FA05-1, 299 nm).

[0448] Example 1-3-9: Synthesis of compound B07-1R

[0449]

[0450] Compound B07-1R (loading amount 0.193 mmol / g) can be synthesized using compound A03-1R (loading amount 0.201 mmol / g) and 3-bromo-4-(tert-butyl)aniline (b07) by the same method as for compound B03-1R.

[0451] Reaction tracking: A suspension (10 μL) of the reaction mixture and solid phase was transferred onto a filter 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 filter was then immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.1 M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with NMP (0.1 mL). The filtrate (0.05 mL) was diluted with MeCN (0.25 mL) and analyzed by LCMS. 96% of the target product B07 was observed.

[0452]

[0453] Compound B07 LRMS: m / z 424, 426 [M+H] ＋ Retention time: 1.396 minutes (analysis conditions FA05-1, 299 nm).

[0454] Example 1-3-10: Synthesis of compound B08-3R

[0455]

[0456] Compound B08-3R (loading amount 0.197 mmol / g) can be synthesized using compound A03-3R (loading amount 0.201 mmol / g) and 3-chloroaniline (b08) in the same manner as compound B03-1R. B08-3R was washed three times with DCM (0.1 mL) and immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.05 M pentamethylbenzene for 5 minutes. After filtration, the solution was diluted with DMF (0.05 mL) and MeCN (0.25 mL), and LCMS analysis showed 100% of the target product B08.

[0457]

[0458] Compound B08 LRMS: m / z 324 [M+H] ＋ Retention time: 1.141 minutes (analysis conditions FA05-1, 299 nm).

[0459] Example 1-3-11: Synthesis of compound B09-3R

[0460]

[0461] Compound B09-3R (loading amount 0.193 mmol / g) can be synthesized using compound A03-3R (loading amount 0.201 mmol / g) and 3-iodoaniline (b09) by the same method as for compound B03-1R.

[0462] B09-3R was washed three times with DCM (0.1 mL) and immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.05 M pentamethylbenzene for 5 minutes. After filtration, the solution was diluted with DMF (0.05 mL) and MeCN (0.25 mL) and analyzed by LCMS. 100% of the target product B09 was observed.

[0463]

[0464] Compound B09 LRMS: m / z 416 [M+H] ＋ Retention time: 1.192 minutes (analysis conditions FA05-1, 299 nm).

[0465] Example 1-3-12: Synthesis of compound B10-3R

[0466]

[0467] Compound B10-3R (loading amount 0.194 mmol / g) can be synthesized using compound A03-3R (loading amount 0.201 mmol / g) and 5-bromo-2-fluoroaniline (b10) by the same method as for compound B03-1R.

[0468] B10-3R was washed three times with DCM (0.1 mL) and immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.05 M pentamethylbenzene for 5 minutes. After filtration, the solution was diluted with DMF (0.05 mL) and MeCN (0.25 mL) and analyzed by LCMS. 97.2% of the target compound B10 was observed.

[0469]

[0470] Compound B10 LRMS: m / z 386, 388 [M+H] ＋ Retention time: 1.164 minutes (analysis conditions FA05-1, 299 nm).

[0471] Example 1-3-13: Synthesis of compound B11-3R

[0472]

[0473] Compound B11-3R (loading amount 0.194 mmol / g) can be synthesized using compound A03-3R (loading amount 0.201 mmol / g) and 5-bromo-4-fluoroaniline (b11) by the same method as for compound B03-1R.

[0474] B11-3R was washed three times with DCM (0.1 mL) and immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.05 M pentamethylbenzene for 5 minutes. After filtration, the solution was diluted with DMF (0.05 mL) and MeCN (0.25 mL) and analyzed by LCMS. The target product B11 was observed at 99.1%.

[0475]

[0476] Compound B11 LRMS: m / z 386, 388 [M+H] ＋ Retention time: 1.165 minutes (analysis conditions FA05-1, 299 nm).

[0477] Example 1-3-14: Synthesis of compound B12-3R

[0478]

[0479] Compound B12-3R (loading amount 0.194 mmol / g) can be synthesized using compound A03-3R (loading amount 0.201 mmol / g) and 5-bromo-4-methoxyaniline (b12) by the same method as for compound B03-1R.

[0480] B12-3R was washed three times with DCM (0.1 mL) and immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.05 M pentamethylbenzene for 5 minutes. After filtration, the solution was diluted with DMF (0.05 mL) and MeCN (0.25 mL) and analyzed by LCMS. 100% of the target product B12 was observed.

[0481]

[0482] Compound B12 LRMS: m / z 398, 400 [M+H] ＋ Retention time: 1.093 minutes (analysis conditions FA05-1, 299 nm).

[0483] Example 1-3-15: Synthesis of compound B13-3R

[0484]

[0485] Compound B13-3R (loading amount 0.195 mmol / g) can be synthesized using compound A03-3R (loading amount 0.201 mmol / g) and 6-bromopyridin-3-amine (b13) by the same method as for compound B03-1R.

[0486] B13-3R was washed three times with DCM (0.1 mL) and immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.05 M pentamethylbenzene for 5 minutes. After filtration, the solution was diluted with DMF (0.05 mL) and MeCN (0.25 mL) and analyzed by LCMS. The target product B13 was observed at 99.6%.

[0487]

[0488] Compound B13 LRMS: m / z 369, 371 [M+H] ＋Retention time: 1.011 minutes (Analysis conditions FA05-1, 299 nm).

[0489] Example 1-3-16: Synthesis of compound B14-3R

[0490]

[0491] Compound B14-3R (loading amount 0.194 mmol / g) can be synthesized using compound A03-3R (loading amount 0.201 mmol / g) and (2-bromothiazol-5-yl)methanamine (b14) in the same manner as compound B03-1R.

[0492] B14-3R was washed three times with DCM (0.1 mL) and immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.05 M pentamethylbenzene for 5 minutes. After filtration, the solution was diluted with DMF (0.05 mL) and MeCN (0.25 mL) and analyzed by LCMS. The target compound B14 was observed at 97.8%.

[0493]

[0494] Compound B14 LRMS: m / z 389, 391 [M+H] ＋ Retention time: 0.925 minutes (Analysis conditions FA05-1, 299 nm).

[0495] Example 1-3-17: Synthesis of compound B15-1R

[0496]

[0497] Compound B15-1R (loading amount 0.194 mmol / g) can be synthesized using compound A03-3R (loading amount 0.201 mmol / g) and (4-bromothiophen-2-yl)methanamine (b15) by the same method as for compound B03-1R.

[0498] The reaction mixture and solid suspension (10 μL) were transferred onto a filter 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 filter was then immersed in 0.1 M pentamethylbenzene in 10% TFA / DCM solution (0.05 mL) for 2 minutes. After filtration, the solid phase was washed with NMP (0.1 mL). The filtrate (0.05 mL) was diluted with MeCN (0.25 mL) and analyzed by LCMS. 100% of the target product B15 was observed.

[0499]

[0500] Compound B15 LRMS: m / z 388, 390 [M+H] ＋ Retention time: 1.061 minutes (analysis conditions FA05-1, 299 nm).

[0501] Example 1-3-18: Synthesis of compound H04-3R

[0502]

[0503] Under a nitrogen atmosphere, compound A03-3R (loading amount 0.201 mmol / g, 5.00 g, 1.01 mmol) and NMP (60 mL) were placed in a 100 mL glass vial and shaken at room temperature for 1 hour. 3-(aminomethyl)-N-methylaniline (h04) (0.411 g, 3.02 mmol), HOAt (0.410 g, 3.02 mmol), and DIC (0.467 mL, 3.02 mmol) were added, and the mixture was shaken at room temperature for 96 hours.

[0504] The reaction mixture and the solid phase suspension were all transferred onto a filter and washed three times with NMP (100 mL), three times with MeOH (100 mL), three times with DCM (100 mL), and three times with heptane (100 mL) to obtain compound H04-3R (loading amount 0.196 mmol / g, 5.45 g). H04-3R was washed three times with DCM (0.1 mL) and immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.02 M pentamethylbenzene for 5 minutes. After filtration, the target compound H04 was observed at 97.2% by LCMS measurement of the diluted solution with DMF (0.05 mL) and MeCN (0.25 mL).

[0505]

[0506] Compound H04 LRMS: m / z 333 [M+H] ＋ Retention time: 0.675 minutes (Analysis conditions FA05-1, 299 nm).

[0507] Example 1-3-19: Synthesis of compound H01-4R

[0508]

[0509] Compound A03-4R (loading amount 0.201 mmol / g, 2.5 g, 0.50 mmol) and DCM (37.5 mL) were added to a 50 mL empty column equipped with a filter under a nitrogen atmosphere, and the column was shaken at room temperature for 1 hour. 4-(Fmoc-amino)piperidine hydrochloride (h01, CAS number: 221352-86-9) (0.361 g, 1.00 mmol), DIPEA (0.175 mL, 1.00 mmol), NMI (0.160 mL, 2.01 mmol), and PipClU (0.361 g, 1.00 mmol) were added, and the column was shaken at room temperature for 6 hours. The solid phase was washed three times with NMP (50 mL), and then with NMP / H ２ The column was washed three times with 0=1 / 1 (50 mL) and three times with NMP (50 mL). A 20% piperidine / DMF solution (50 mL) was added to the column, and the mixture was shaken at room temperature for 2 hours. After the solution was discharged, the column was washed three times with NMP (50 mL), three times with MeOH (50 mL), three times with DCM (50 mL), and three times with heptane (50 mL) to obtain compound H01-4R (loading amount 0.198 mmol / g, 3.0 g).

[0510] H01-4R was washed three times with DCM (0.1 mL) and immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.2 M pentamethylbenzene for 5 minutes. After filtration, the solution was diluted with DMF (0.05 mL) and MeCN (0.20 mL) and analyzed by LCMS. The target compound H01 was observed at 98.0%.

[0511]

[0512] Compound H01 LRMS: m / z 297 [M+H] ＋ Retention time: 0.551 min (analysis conditions FA05-1, 299 nm).

[0513] Example 1-3-20: Synthesis of compound H02-4R

[0514]

[0515] Compound A03-4R (loading amount 0.201 mmol / g, 6.5 g, 1.31 mmol) and DCM (98.0 mL) were added to a 100 mL empty column equipped with a filter under a nitrogen atmosphere, and the column was shaken at room temperature for 1 hour. 4-Amino-1-N-Fmoc-piperidine hydrochloride (h02, CAS number: 811841-89-1) (0.938 g, 2.61 mmol), DIEA (0.455 mL, 2.61 mmol), NMI (0.417 mL, 5.23 mmol), and PipClU (0.943 g, 2.61 mmol) were added, and the column was shaken at room temperature for 2.5 hours.

[0516] The solid phase was washed three times with NMP (100 mL), ２ The column was washed three times with 100 mL of 0=1 / 1 hexanes (100 mL) and three times with NMP (100 mL). A 20% piperidine / DMF solution (100 mL) was added to the column, and the column was shaken at room temperature for 1 hour. After the solution was drained, the column was washed three times with NMP (100 mL), three times with MeOH (100 mL), three times with DCM (100 mL), and three times with heptane (100 mL) to obtain compound H02-4R (loading amount 0.198 mmol / g, 7.3 g).

[0517] H02-4R was washed three times with DCM (0.1 mL) and immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.2 M pentamethylbenzene for 5 minutes. After filtration, the solution was diluted with DMF (0.05 mL) and MeCN (0.20 mL) and analyzed by LCMS. The target compound H01 was observed at 97.4%.

[0518]

[0519] Compound H02 LRMS: m / z 297 [M+H] ＋ Retention time: 0.561 minutes (analysis conditions FA05-1, 299 nm).

[0520] Example 1-3-21: Synthesis of compound H03-4R

[0521]

[0522] Compound A03-4R (loading amount 0.201 mmol / g, 2.5 g, 0.50 mmol) and DCM (37.5 mL) were added to a 50 mL empty column equipped with a filter under a nitrogen atmosphere and shaken at room temperature for 1 hour. 3-(aminomethyl)aniline (h03) (0.307 g, 2.51 mmol), DIC (0.389 mL, 2.51 mmol), and HOAt (0.342 g, 2.51 mmol) were added and shaken at room temperature for 18 hours. 3-(aminomethyl)aniline (h03) (0.123 g, 1.00 mmol), DIC (0.156 mL, 1.00 mmol), and HOAt (0.137 g, 1.00 mmol) were added and shaken at room temperature for 4 hours.

[0523] The solid phase was washed three times with NMP (50 mL) and NMP / H ２ The mixture was washed three times with 0= / 1 (50 mL), three times with NMP (50 mL), three times with MeOH (50 mL), three times with DCM (50 mL), and three times with heptane (50 mL) to obtain compound H03-4R (loading amount 0.197 mmol / g, 2.9 g).

[0524] H03-4R was washed three times with DCM (0.1 mL) and immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.2 M pentamethylbenzene for 5 minutes. After filtration, the solution was diluted with DMF (0.05 mL) and MeCN (0.20 mL) and analyzed by LCMS. The target product H03 was observed at 98.6%.

[0525]

[0526] Compound H03 LRMS: m / z 319 [M+H] ＋ Retention time: 0.641 min (analysis conditions FA05-1, 299 nm).

[0527] Example 2 Example 2-1: Investigation of various solvents in the hydroxylation reaction of aryl bromide supported on a solid phase Example 2-1-1: Experiment comparing solvents when AdBrettPhos Pd G6 Br was used as the palladium catalyst and BTMG was used as the base in the hydroxylation reaction of compound B01-1R

[0528]

[0529] Compound B01-1R (0.195 mmol / g, 20 mg, 0.0039 mmol), solvent (0.4 mL), and water (0.010 mL) were added to a 0.6 mL glass vial under a nitrogen atmosphere and shaken at room temperature for 1 hour. AdBrettPhos Pd G6 Br (0.8 mg, 0.00078 mmol) and BTMG (11.7 μL, 0.059 mmol) were added, and the mixture was shaken at 80°C for 0.5 to 24 hours.

[0530] The reaction mixture and solid phase suspension were transferred onto a filter and washed three times with DMF (0.1 mL), three times with MeOH (0.1 mL), and three times with DCM (0.1 mL), after which the filter was immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.02 M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and the reaction progress was measured by LCMS. The results (UV surface %) are shown in Table 2-1-1.

[0531]

[0532] From the above results, it was confirmed that, compared to commonly used solvents, when DMPr, DEAc, or DEPr was used, the conversion rate was consistently high, and the production of by-products (H-forms) in which the leaving group of the substrate was replaced with a hydrogen atom and other impurities was reduced, resulting in high yields. When DMAc, which is commonly used as an amide solvent, or urea-based solvents DMI and DMPU, which have excellent substrate solubility like amide-based solvents, were used, the production of the H-form (C01) was high, and the yield of the target product was low. When NMP, which is commonly used as an amide solvent, was used, the yield of the target product was high, but the impurity P01, whose m / z is 83 higher than that of the H-form, was observed. When NMP was used, even in the case of other substrates, an impurity whose m / z is 83 higher than that of the H-form was produced, and depending on the substrate, this impurity was produced in large amounts, resulting in a decrease in the yield of the target product (Examples 2-1-2 and 21-3 described below). When DMF was used, the impurity Q01, whose m / z is 57 higher than that of the H-form, was observed, making separation from the target product D01 difficult and also resulting in a low yield of the target product. Furthermore, when toluene was added to DMAc to confirm the effect of improving the lipid solubility of the entire solvent, no improvement was observed compared to DMAc. On the other hand, in THF and toluene, the reaction was slow, the production of impurities increased, and the yield of the target product was low. Furthermore, although an investigation was conducted using DMOc (Angew. Chem. Int. Ed. 2016, 55, 2531-2535.), an amide solvent that has been reported as an additive to solvents in flow reactions for C-N coupling reactions, the production of the H-form (C01) increased, resulting in a low yield.

[0533]

[0534] Compound D01 LRMS: m / z 306 [M+H] ＋ Retention time: 0.864 minutes (analysis conditions FA05-1, 299 nm) Retention time: 1.660 minutes (analysis conditions FA05-long, 299 nm).

[0535]

[0536] Compound C01 LRMS: m / z 290 [M+H] ＋Retention time: 1.017 minutes (analysis conditions FA05-1, 299 nm) Retention time: 2.081 minutes (analysis conditions FA05-long, 299 nm).

[0537] Compound P01 (structure undetermined) LRMS: m / z 373 [M+H] ＋ Retention time: 0.923 minutes (analysis conditions FA05-1, 299 nm).

[0538] Compound Q01 (structure undetermined) LRMS: m / z 347 [M+H] ＋ Retention time: 1.744 minutes (analysis conditions FA05-long, 299 nm).

[0539] Example 2-1-2: Experiment comparing solvents when AdBrettPhos Pd G6 Br was used as a palladium catalyst and BTMG was used as a base in the hydroxylation reaction of compound B03-1R

[0540]

[0541] Under a nitrogen atmosphere, compound B03-1R (0.195 mmol / g, 20 mg, 0.0039 mmol), solvent (0.4 mL), and water (0.010 mL) were added to a 0.6 mL glass vial and shaken at room temperature for 1 hour. AdBrettPhos Pd G6 Br (0.8 mg, 0.00078 mmol) and BTMG (11.7 μL, 0.059 mmol) were added, and the mixture was shaken at 80°C for 24 hours.

[0542] The reaction mixture and solid phase suspension were transferred onto a filter and washed three times with DMF (0.1 mL), three times with MeOH (0.1 mL), and three times with DCM (0.1 mL), after which the filter was immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.02 M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and the reaction progress was measured by LCMS. The results (UV area %) are shown in Table 2-1-2.

[0543]

[0544] From the above results, it was confirmed that DMPr and DEAc consistently showed high conversion rates, reduced the production of the problematic H-isomer and other impurities, and provided high yields. On the other hand, when DMAc was used, the H-isomer (C03) was produced in large amounts, and when NMP was used, the impurity P03, which has an m / z value 83 higher than that of the H-isomer, was observed in large amounts, and the yield of the target product was low.

[0545]

[0546] Compound D03 LRMS: m / z 307 [M+H] ＋ Retention time: 1.296 minutes (Analysis conditions RPAmideTFA05-long, 299 nm).

[0547]

[0548] Compound C03 LRMS: m / z 291 [M+H] ＋ Retention time: 1.211 minutes (analysis conditions RPAmideTFA05-long, 299 nm).

[0549] Compound P03 (structure undetermined) LRMS: m / z 374 [M+H] ＋ Retention time: 1.425 minutes (Analysis conditions RPAmideTFA05-long, 299 nm).

[0550] Example 2-1-3: Experiment comparing solvents when AdBrettPhos Pd G6 Br was used as the palladium catalyst and P1tBu was used as the base in the hydroxylation reaction of compound B04-3R

[0551]

[0552] Under a nitrogen atmosphere, compound B04-3R (0.194 mmol / g, 20 mg, 0.0039 mmol), solvent (0.32 mL), and water (0.080 mL) were added to a 0.6 mL glass vial and shaken at room temperature for 1 hour. AdBrettPhos Pd G6 Br (0.8 mg, 0.00078 mmol) and P1tBu (14.8 μL, 0.058 mmol) were added, and the mixture was shaken at 80°C for 0.5 hours.

[0553] The reaction mixture and solid phase suspension were transferred onto a filter and washed three times with DMF (0.1 mL), three times with MeOH (0.1 mL), and three times with DCM (0.1 mL), after which the filter was immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.02 M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and the reaction progress was measured by LCMS. The results (UV area %) are shown in Table 2-1-3.

[0554]

[0555] From the above results, it was confirmed that DMPr and DEAc consistently provided high conversion rates, reduced the production of the problematic H-form and other impurities, and provided high yields. On the other hand, when DMAc was used, the reaction progressed slowly. Furthermore, when DMF was used, the reaction progressed slowly and the H-form (C04) was produced in large amounts, resulting in a low yield of the target product. When NMP was used, the H-form (C04) and the impurity P04, which has an m / z value 83 higher than that of the H-form, were observed in large amounts, resulting in a low yield of the target product.

[0556]

[0557] Compound D04 LRMS: m / z 336 [M+H] ＋ Retention time: 0.905 minutes (analysis conditions FA05-2, 299 nm).

[0558]

[0559] Compound C04 LRMS: m / z 320 [M+H] ＋ Retention time: 1.077 minutes (Analysis conditions FA05-2, 299 nm).

[0560] Compound P04 (structure undetermined) LRMS: m / z 403 [M+H] ＋ Retention time: 0.935 minutes (Analysis conditions FA05-2, 299 nm).

[0561] Example 2-2: Examination of various palladium catalysts in the hydroxylation reaction of aryl bromides supported on a solid phase Example 2-2-1: Experiments examining palladium catalysts when P2tBu was used as the base and DMPr was used as the solvent in the hydroxylation reaction of compound B02-2R

[0562]

[0563] Experimental procedure: Under a nitrogen atmosphere, compound B02-2R (0.194 mmol / g, 20 mg, 0.0039 mmol), DMPr (0.4 mL), and water (0.010 mL) were placed in a 0.6 mL glass vial and shaken at room temperature for 1 hour. A catalyst listed in Table 2-2-1 and a P2tBu / THF solution (2 M, 29.1 μL, 0.058 mmol) were added, and the mixture was shaken at 80°C for 0.5 hours.

[0564] The reaction mixture and solid phase suspension were transferred onto a filter and washed three times with DMF (0.1 mL), three times with MeOH (0.1 mL), and three times with DCM (0.1 mL), after which the filter was immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.02 M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and the reaction progress was measured by LCMS. The results (UV area %) are shown in Table 2-2-1.

[0565]

[0566] These results demonstrate that various palladium catalysts can be used in the hydroxylation reaction using DMPr as a solvent. In particular, high yields were obtained using RockPhos Pd G3, tBuBrettPhos Pd G4, or the combination of AdBippyPhos and Pd2dba3CHCl3.

[0567]

[0568] Compound D02 LRMS: m / z 320 [M+H] ＋ Retention time: 0.931 min (analysis conditions FA05-1, 299 nm).

[0569]

[0570] Compound C02 LRMS: m / z 304 [M+H] ＋ Retention time: 1.075 minutes (Analysis conditions FA05-1, 299 nm).

[0571] Example 2-3: Examination of various bases in the hydroxylation reaction of aryl bromide supported on a solid phase Example 2-3-1: Experiments examining bases when AdBrettPhos Pd G3 was used as the palladium catalyst and DMPr was used as the solvent in the hydroxylation reaction of compound B02-2R

[0572] Experimental Procedure: Under a nitrogen atmosphere, compound B02-2R (0.194 mmol / g, 20 mg, 0.0039 mmol), DMPr (0.4 mL), and water (0.010 mL) were added to a 0.6 mL glass vial and shaken at room temperature for 1 hour. AdBrettPhos Pd G3 (0.8 mg, 0.00078 mmol) and a base (0.058 mmol) listed in Table 2-3-1 were added, and the mixture was shaken at 80°C for the time listed in Table 2-3-1.

[0573] The reaction mixture and solid phase suspension were transferred onto a filter and washed three times with DMF (0.1 mL), three times with MeOH (0.1 mL), and three times with DCM (0.1 mL), after which the filter was immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.02 M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and the reaction progress was measured by LCMS. The results (UV area %) are shown in Table 2-3-1.

[0574]

[0575] From the above results, in the hydroxylation reaction using DMPr as a solvent, a wide range of organic bases such as BTMG, MTBD, P1tBu, BEMP, BTPP, and P2tBu, as well as Cs ２ CO ３ , K. ３ P.O. ４It was shown that a wide range of inorganic bases, such as , and KOH, can be used. The preferred bases were phosphazene bases such as PtBu and PtBu, which have a fast reaction rate and produce little H-isomer.

[0576] Example 2-4: Substrate generality Example 2-4-1: Synthesis of D06-2R by hydroxylation reaction of compound B06-2R

[0577]

[0578] Compound B06-2R (0.193 mmol / g, 20 mg, 0.0038 mmol), DMPr (0.4 mL), and water (0.010 mL) were added to a 0.6 mL glass vial under a nitrogen atmosphere and shaken at room temperature for 1 hour. AdBrettPhos Pd G6 Br (0.7 mg, 0.00077 mmol) and BTMG (11.5 μL, 0.058 mmol) were added, and the mixture was shaken at 80°C for 2 hours.

[0579] The reaction mixture and solid phase suspension were transferred onto a filter 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 filter was then immersed in 10% TFA / DCM solution (0.05 mL) containing 0.02 M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and subjected to LCMS measurement. As a result, the H-form (C06) was low at 2.7%, and the target product D06 was obtained in a high yield of 97.3%.

[0580]

[0581] Compound D06 LRMS: m / z 374 [M+H] ＋ Retention time: 1.040 minutes (Analysis conditions FA05-1, 299 nm).

[0582]

[0583] Compound C06 LRMS: m / z 358 [M+H] ＋ Retention time: 1.183 minutes (analysis conditions FA05-1, 299 nm).

[0584] Example 2-5: Investigation of various solvents in the C-O coupling reaction of aryl bromides supported on a solid phase Example 2-5-1: Experiment comparing solvents in the C-O coupling reaction of compound B02-2R and 3-phenyl-1-propanol (g01) when AdBippyPhos was used as a ligand for the palladium catalyst and BTMG was used as a base

[0585]

[0586] Experimental Procedure: Under a nitrogen atmosphere, compound B02-2R (0.194 mmol / g, 15 mg, 0.0029 mmol) and a solution of potassium trifluoromethanesulfonate (5.5 mg, 0.029 mmol) dissolved in a solvent (0.3 mL) listed in Table 2-5-1 were added to a 0.6 mL glass vial. 3-Phenyl-1-propanol (39.6 μL, 0.291 mmol) was added, and the mixture was shaken at room temperature for 1 hour. Pd ２ dba ３ CHCl ３ A mixed solution (11.6 μL) of AdBippyPhos (0.025 M, 0.00029 mmol) and AdBippyPhos (0.1 M, 0.0016 mmol) (prepared by adding the two compounds to the corresponding solvent and heating with a hair dryer for approximately 1 minute) was added to the mixture. BTMG (8.7 μL, 0.044 mmol) was then added, and the mixture was shaken at 80°C for 24 hours.

[0587] The reaction mixture and solid phase suspension (12 μL) was transferred onto a filter 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 filter was then immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.02 M pentamethylbenzene for 1 minute. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and the reaction progress was measured by LCMS. The results (UV area %) are shown in Table 2-5-1.

[0588]

[0589] From the above results, it was confirmed that, compared with commonly used solvents, DMPr has a higher conversion rate, reduces the production of by-products (OH forms) that are thought to be the H form and reaction with water, and gives a high yield. On the other hand, when DMAc was used, the reaction progressed slowly, and the yield of the target product was low even after 24 hours. When NMP was used, the H form (C02) and OH form (D02) were produced in large amounts, and the yield of the target product was low.

[0590]

[0591] Compound G0201 LRMS: m / z 438 [M+H] ＋ Retention time: 1.381 minutes (Analysis conditions FA05-1, 299 nm)

[0592] Example 2-5-2: Experiment comparing solvents when AdBippyPhos was used as a ligand for the palladium catalyst and BTMG was used as a base in the CO coupling reaction of compound B02-2R and 2-methylphenol (g02)

[0593]

[0594] Experimental Procedure: Under a nitrogen atmosphere, compound B02-2R (0.194 mml / g, 15 mg, 0.0029 mmol) and a solution of potassium trifluoromethanesulfonate (5.5 mg, 0.029 mmol) dissolved in a solvent (0.3 mL) listed in Table 2-5-2 were added to a 0.6 mL glass vial. 2-Methylphenol (30.0 μL, 0.291 mmol) was added, and the mixture was shaken at room temperature for 1 hour. Pd ２ dba ３ CHCl ３ A mixed solution (11.6 μL) of AdBippyPhos (0.025 M, 0.00029 mmol) and AdBippyPhos (0.1 M, 0.0016 mmol) (prepared by adding the two compounds to the corresponding solvent and heating with a hair dryer for approximately 1 minute) was added to the mixture. BTMG (8.7 μL, 0.044 mmol) was then added, and the mixture was shaken at 80°C for 24 hours.

[0595] The reaction mixture and solid phase suspension (12 μL) was transferred onto a filter 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 filter was then immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.02 M pentamethylbenzene for 1 minute. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and the reaction progress was measured by LCMS. The results (UV area %) are shown in Table 2-5-2.

[0596]

[0597] From the above results, it was confirmed that, compared with commonly used solvents, DMPr has a higher conversion rate, reduces the production of by-products (OH forms) that are thought to be the H form or a reaction with water, and provides a high yield. On the other hand, when DMAc was used, the reaction progressed slowly and the yield of the target product was low. When NMP was used, the H form (C02) was produced in large amounts, and the yield of the target product was low.

[0598]

[0599] Compound G0202 LRMS: m / z 410 [M+H] ＋ Retention time: 1.327 minutes (analysis conditions FA05-1, 299 nm).

[0600] Example 3 Example 3-1: Investigation of various solvents in the C-N coupling reaction of aryl bromide supported on a solid phase Example 3-1-1: Experiment comparing solvents in the C-N coupling reaction of compound B02-1R and 4-phenylpiperidine (e01) when (tBu)PhCPhos Pd 4 was used as the palladium catalyst and P2tBu was used as the base

[0601]

[0602] Experimental Procedure: Under a nitrogen atmosphere, compound B02-1R (0.194 mmol / g, 20 mg, 0.0039 mmol) and solvent (0.4 mL) were placed in a 0.6 mL glass vial and shaken at room temperature for 1 hour. 4-Phenylpiperidine (e01) (12.5 mg, 0.078 mmol), (tBu)PhCPhos Pd G4 (0.6 mg, 0.00078 mmol), and P2tBu / THF solution (2 M, 58.2 μL, 0.116 mmol) were added, and the mixture was shaken at room temperature for 2 hours.

[0603] The reaction mixture and solid phase suspension were transferred onto a filter and washed three times with DMF (0.1 mL), three times with MeOH (0.1 mL), and three times with DCM (0.1 mL), after which the filter was immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.02 M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and the reaction progress was measured by LCMS. The results (UV area %) are shown in Table 3-1-1.

[0604]

[0605] From the above results, it was confirmed that, compared with commonly used solvents, DMPr provides a higher conversion rate, reduces the production of H-isomers and other impurities, and gives a high yield. On the other hand, when DMAc, DMF, DMI, or DMPU was used, the reaction progressed slowly. It was also confirmed that the reaction rate was slow when THF or toluene, which have been reported to suppress the production of H-isomers (Reference: Organometallics 2013, 32, 5428-5434.), was used. When NMP was used, the raw materials disappeared quickly, but the H-isomer (C02) was produced in large quantities, and the impurity P02, which has an m / z 83 higher than that of the H-isomer, was observed, resulting in a low yield of the desired product.

[0606]

[0607] Compound E0201 LRMS: m / z 463 [M+H] ＋ Retention time: 1.340 minutes (Analysis conditions FA05-1, 299 nm).

[0608] Compound P02 (structure undetermined) LRMS: m / z 387 [M+H] ＋ Retention time: 0.905 minutes (Analysis conditions FA05-1, 299 nm).

[0609] Example 3-1-2: Experiment comparing solvents when (tBu)PhCPhos Pd G4 was used as a palladium catalyst and P2tBu was used as a base in the C-N coupling reaction of compound B02-1R and N-methyl-3-phenylpropylamine (e02)

[0610]

[0611] Experimental Procedure: Under a nitrogen atmosphere, compound B02-1R (0.194 mmol / g, 20 mg, 0.0039 mmol) and solvent (0.4 mL) were placed in a 0.6 mL glass vial and shaken at room temperature for 1 hour. N-methyl-3-phenylpropylamine (e02) (11.6 mg, 0.078 mmol), (tBu)PhCPhos Pd G4 (0.6 mg, 0.00078 mmol), and P2tBu / THF solution (2 M, 58.2 μL, 0.116 mmol) were added, and the mixture was shaken at room temperature for 24 hours.

[0612] The reaction mixture and solid phase suspension were transferred onto a filter and washed three times with DMF (0.1 mL), three times with MeOH (0.1 mL), and three times with DCM (0.1 mL), followed by immersion in 0.02 M pentamethylbenzene in 10% TFA / DCM solution (0.05 mL) for 2 minutes. After filtration, the phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. LC samples were prepared and analyzed by LCMS to determine the reaction progress. The results are shown in Table 3-1-2.

[0613]

[0614] These results confirmed that, compared with commonly used solvents, DMPr provides a higher conversion rate, reduces the production of the H-isomer and other impurities, and provides a high yield. On the other hand, it was confirmed that the reaction rate was slow when DMAc, DMF, DMI, DMPU, THF, and toluene were used. When NMP was used, the H-isomer (C02) was produced in extremely large quantities, and the impurity P02, which has an m / z value 83 higher than that of the H-isomer, was also observed, resulting in a low yield. Similar to amide solvents, DMSO and tAmylOH (Organic Letters 2015, 17, 3370-3373.), which are highly polar solvents and have been reported as solvents for C-N coupling reactions, were also used, but the solid phase did not swell and the reaction hardly progressed. Furthermore, an investigation was conducted using DMOc (Angew. Chem. Int. Ed. 2016, 55, 2531-2535.), an amide solvent that has been reported as an additive to solvents in flow reactions for C—N coupling reactions, but the reaction proceeded slowly and in a low yield.

[0615]

[0616] Compound E0202 LRMS: m / z 451 [M+H] ＋ Retention time: 1.027 minutes (analysis conditions FA05-1, 299 nm) Retention time: 2.120 minutes (analysis conditions FA05-long, 299 nm).

[0617]

[0618] Compound C02 LRMS: m / z 304 [M+H] ＋ Retention time: 2.257 minutes (analysis conditions FA05-long, 299 nm).

[0619] Compound P02 (structure undetermined) LRMS: m / z 387 [M+H] ＋ Retention time: 1.807 minutes (analysis conditions FA05-long, 299 nm).

[0620] Example 3-1-3: Experiment comparing solvents when (tBu)PhCPhos Pd G4 was used as a palladium catalyst and P2tBu was used as a base in the C-N coupling reaction of compound B02-1R and 1-methyl-3-phenylpropylamine (e06)

[0621]

[0622] Experimental Procedure: Under a nitrogen atmosphere, compound B02-1R (0.194 mmol / g, 20 mg, 0.0039 mmol) and solvent (0.4 mL) were placed in a 0.6 mL glass vial and shaken at room temperature for 1 hour. 1-Methyl-3-phenylpropylamine (e06) (12.5 μL, 0.078 mmol), (tBu)PhCPhos Pd G4 (0.6 mg, 0.00078 mmol), and P2tBu / THF solution (2 M, 58.2 μL, 0.116 mmol) were added, and the mixture was shaken at room temperature for 2 hours.

[0623] The reaction mixture and solid phase suspension were transferred onto a filter and washed three times with DMF (0.1 mL), three times with MeOH (0.1 mL), and three times with DCM (0.1 mL), after which the filter was immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.02 M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and the reaction progress was measured by LCMS. The results (UV area %) are shown in Table 3-1-3.

[0624]

[0625] From the above results, it was confirmed that, compared with commonly used solvents, DMPr had a high conversion rate, reduced production of H-isomer and other impurities, and provided a high yield. On the other hand, it was confirmed that the reaction rate was slow when DMAc was used. With NMP, the H-isomer (C02) was produced in large amounts, and the reaction rate was confirmed to be slow, resulting in a low yield.

[0626]

[0627] Compound E0206 LRMS: m / z 451 [M+H] ＋Retention time: 1.276 minutes (analysis conditions FA05-1, 299 nm).

[0628] Example 3-1-4: Experiment comparing solvents when (tBu)PhCPhos Pd G4 was used as a palladium catalyst and P2tBu was used as a base in the C-N coupling reaction of compound B01-1R and dipropylamine (e03)

[0629]

[0630] Under a nitrogen atmosphere, compound B01-1R (0.195 mmol / g, 20 mg, 0.0039 mmol) and solvent (0.4 mL) were placed in a 0.6 mL glass vial and shaken at room temperature for 1 hour. Dipropylamine (e03) (10.7 μL, 0.078 mmol), (tBu)PhCPhos Pd G4 (0.6 mg, 0.00078 mmol), and P2tBu / THF solution (2 M, 58.5 μL, 0.117 mmol) were added, and the mixture was shaken at room temperature for 24 hours.

[0631] The reaction mixture and solid phase suspension were transferred onto a filter and washed three times with DMF (0.1 mL), three times with MeOH (0.1 mL), and three times with DCM (0.1 mL), after which the filter was immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.02 M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and the reaction progress was measured by LCMS. The results (UV area %) are shown in Table 3-1-4.

[0632]

[0633] From the above results, it was confirmed that, compared with commonly used solvents, DMPr provides a higher conversion rate, reduces the production of H-isomer and other impurities, and provides a high yield. On the other hand, when DMAc was used, the reaction rate was slow, and impurity R01, whose m / z is 57 higher than that of the H-isomer, was observed. When NMP was used, the H-isomer (C01) was produced in extremely large amounts, and impurity P01, whose m / z is 83 higher than that of the H-isomer, was observed, resulting in a low yield.

[0634]

[0635] Compound E0103 LRMS: m / z 389 [M+H] ＋ Retention time: 1.989 minutes (analysis conditions FA05-long, 299 nm).

[0636] Compound P01 (structure undetermined) LRMS: m / z 373 [M+H] ＋ Retention time: 1.823 minutes (analysis conditions FA05-long, 299 nm).

[0637] Compound R01 (structure undetermined) LRMS: m / z 347 [M+H] ＋ Retention time: 1.720 minutes (analysis conditions FA05-long, 299 nm).

[0638] Example 3-1-5: Experiment comparing solvents when (tBu)PhCPhos Pd G4 was used as a palladium catalyst and P2tBu was used as a base in the C-N coupling reaction of compound B01-1R and 2-methylpiperidine (e04)

[0639]

[0640] Experimental Procedure: Under a nitrogen atmosphere, compound B01-1R (0.195 mmol / g, 20 mg, 0.0039 mmol) and solvent (0.4 mL) were placed in a 0.6 mL glass vial and shaken at room temperature for 1 hour. 2-Methylpiperidine (e04) (9.21 μL, 0.078 mmol), (tBu)PhCPhos Pd G4 (0.6 mg, 0.00078 mmol), and P2tBu / THF solution (2 M, 58.5 μL, 0.117 mmol) were added, and the mixture was shaken at room temperature for 24 hours.

[0641] The reaction mixture and solid phase suspension were transferred onto a filter and washed three times with DMF (0.1 mL), three times with MeOH (0.1 mL), and three times with DCM (0.1 mL), after which the filter was immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.02 M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and the reaction progress was measured by LCMS. The results (UV area %) are shown in Table 3-1-5.

[0642]

[0643] From the above results, it was confirmed that, compared with commonly used solvents, DMPr provides a higher conversion rate, reduces the production of H-isomer and other impurities, and provides a high yield. On the other hand, when DMAc was used, the reaction rate was slow, and impurity R01, whose m / z is 57 higher than that of the H-isomer, was observed. When NMP was used, the H-isomer (C01) was produced in extremely large amounts, and impurity P01, whose m / z is 83 higher than that of the H-isomer, was observed, resulting in a low yield.

[0644]

[0645] Compound E0104 LRMS: m / z 387 [M+H] ＋ Retention time: 0.705 minutes (Analysis conditions FA05-01, 299 nm).

[0646] Compound R01 (structure undetermined) LRMS: m / z 347 [M+H] ＋ Retention time: 0.879 minutes (analysis conditions FA05-01, 299 nm).

[0647] Example 3-1-6: Experiment comparing solvents when (tBu)PhCPhos Pd G4 was used as a palladium catalyst and P2tBu was used as a base in the C—N coupling reaction of compound B02-1R with 2,6-dimethylaniline (e13)

[0648]

[0649] Compound B02-1R (0.194 mmol / g, 20 mg, 0.0039 mmol) and solvent (0.4 mL) were placed in a 0.6 mL glass vial under a nitrogen atmosphere and shaken at room temperature for 1 hour. 2,6-Dimethylaniline (e13) (9.6 μL, 0.078 mmol) and (tBu)PhCPhos Pd G4 (0.6 mg, 0.00078 mmol) were added. P2tBu / THF solution (2 M, 58.2 μL, 0.116 mmol) was added, and the mixture was shaken at room temperature for 24 hours. The reaction mixture and solid phase suspension (12 μL) was transferred onto a filter 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 filter was then immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.02 M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and the reaction progress was measured by LCMS. The results (UV area%) are shown in Table 3-1-6.

[0650]

[0651] From the above results, it was confirmed that, compared with commonly used solvents, DMPr provides a high conversion rate, reduces the production of H-isomer and other impurities, and gives a high yield. On the other hand, it was confirmed that the reaction rate is slow when DMAc is used. When NMP is used, the production of H-isomer (C02) is extremely high, and the impurity P02, which has an m / z value 83 higher than that of the H-isomer, is also observed, resulting in a low yield.

[0652]

[0653] Compound E0213 LRMS: m / z 423 [M+H] ＋ Retention time: 1.275 minutes (analysis conditions FA05-1, 299 nm).

[0654] Example 3-1-7: Experiment comparing solvents when (tBu)PhCPhos Pd G4 was used as a palladium catalyst and P2tBu was used as a base in the C-N coupling reaction of compound B01-1R and N-ethylaniline (e16)

[0655]

[0656] Compound B01-1R (0.195 mmol / g, 20 mg, 0.0039 mmol) and solvent (0.4 mL) were placed in a 0.6 mL glass vial under a nitrogen atmosphere and shaken at room temperature for 1 hour. N-Ethylaniline (e16) (9.9 μL, 0.078 mmol) and (tBu)PhCPhos Pd G4 (0.6 mg, 0.00078 mmol) were added. P2tBu / THF solution (2 M, 58.5 μL, 0.117 mmol) was added, and the mixture was shaken at room temperature for 2 hours.

[0657] The reaction mixture and solid phase suspension (12 μL) was transferred onto a filter 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 filter was then immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.02 M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and the reaction progress was measured by LCMS. The results (UV area%) are shown in Table 3-1-7.

[0658]

[0659] From the above results, it was confirmed that, compared with commonly used solvents, DMPr provides a high conversion rate, reduces the production of H-isomer and other impurities, and gives a high yield. On the other hand, it was confirmed that the reaction rate is slow when DMAc is used. When NMP is used, the production of H-isomer (C01) is extremely high, and the impurity P01, which has an m / z value 83 higher than that of the H-isomer, is also observed, resulting in a low yield.

[0660]

[0661] Compound E0116 LRMS: m / z 409 [M+H] ＋ Retention time: 1.313 minutes (analysis conditions FA05-1, 299 nm).

[0662] Example 3-2: Examination of various catalysts in the C-N coupling reaction of aryl bromides supported on a solid phase Example 3-2-1: Experiments examining palladium catalysts when P2tBu was used as the base and DMPr was used as the solvent in the C-N coupling reaction of compound B01-2R and piperidine (e08)

[0663]

[0664] Under a nitrogen atmosphere, compound B01-2R (0.195 mmol / g, 20 mg, 0.0039 mmol), DMPr (0.4 mL), and piperidine (e08) (3.85 μL, 0.039 mmol) were placed in a 0.6 mL glass vial and shaken at room temperature for 1 hour. A catalyst and a P2tBu / THF solution (2 M, 29.3 μL, 0.059 mmol) shown in Table 3-2-1 were added, and the mixture was shaken at 80° C. for the time shown in Table 3-2-1.

[0665] The reaction mixture and solid phase suspension were transferred onto a filter 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 filter was then 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), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and the reaction progress was measured by LCMS. The results (UV area %) are shown in Table 3-2-1.

[0666]

[0667] These results demonstrate that a wide range of palladium catalysts can be used in C-N coupling reactions using DMPr as a solvent. In particular, high yields were obtained using RuPhos Pd G4, tBuXPhos Pd G4, (tBu)PhCPhos Pd G4, a combination of BippyPhos and Pd2dba3CHCl3, or a combination of cataCXium PIntB and Pd2dba3CHCl3.

[0668]

[0669] Compound E0108 LRMS: m / z 373 [M+H] ＋ Retention time: 0.757 minutes (analysis conditions FA05-01, 299 nm).

[0670] Example 3-3: Examination of various bases in the C-N coupling reaction of aryl bromides supported on a solid phase Example 3-3-1: Experiments examining bases in the C-N coupling reaction of compound B01-2R and piperidine (e08) when (tBu)PhCPhos Pd G4 was used as a palladium catalyst and DMPr was used as a solvent

[0671] Compound B01-2R (0.195 mmol / g, 20 mg, 0.0039 mmol), DMPr (0.4 mL), and piperidine (e08) (3.85 μL, 0.039 mmol) were added to a 0.6 mL glass vial under a nitrogen atmosphere and the mixture was shaken at room temperature for 1 hour. (tBu)PhCPhos Pd G4 (0.6 mg, 0.00078 mmol) and a base (0.0059 mmol) listed in Table 3-3-1 were added, and the mixture was shaken at 80°C for the time listed in Table 3-3-1.

[0672] The reaction mixture and solid phase suspension were transferred onto a filter and washed three times with DMF (0.1 mL), three times with MeOH (0.1 mL), and three times with DCM (0.1 mL), after which the filter was immersed in a 10% TFA / DCM solution (0.05 mL) containing 0.02 M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and the reaction progress was measured by LCMS. The results (UV area %) are shown in Table 3-3-1.

[0673]

[0674] From the above results, in the C-N coupling reaction using DMPr as a solvent, in addition to the organic base P2tBu, the inorganic base K ３ P.O. ４ It was shown that NaOtBu and NaOtBu could be used. The preferred base was the phosphazene base P2tu, which has a fast reaction rate and produces little H-isomer.

[0675] Example 3-3-2: Experiment in which a salt was added when (tBu)PhCPhos Pd 4 was used as a palladium catalyst, BTMG was used as a base, and DMPr was used as a solvent in the C-N coupling reaction of compound B02-1R and 4-phenylpiperidine (e01)

[0676]

[0677] Compound B02-1R (0.194 mmol / g, 20 mg, 0.0039 mmol) and DMPr (0.4 mL) were placed in a 0.6 mL glass vial under a nitrogen atmosphere and shaken at room temperature for 1 hour. 4-Phenylpiperidine (e01) (12.5 mg, 0.078 mmol) and (tBu)PhCPhos Pd G4 (0.6 mg, 0.00078 mmol) were added. A salt (0.116 mmol) listed in Table 3-3-2 and BTMG (23.2 μL, 0.116 mmol) were added, and the mixture was shaken at 80°C for 2 hours.

[0678] The reaction mixture and solid phase suspension were transferred onto a filter 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 filter was then 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), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and the reaction progress was measured by LCMS. The results (UV area %) are shown in Table 3-3-2.

[0679]

[0680] These results suggest that the addition of salts such as NaTFA and KTFA to the C-N coupling reaction using DMPr as a solvent can accelerate the reaction and improve the yield. The effect of adding salts is not limited to the substrates used in this experiment.

[0681] Example 3-4: Substrate generality Example 3-4-1: Synthesis of E0205-1R by C—N coupling reaction of compound B02-1R with cyclohexylamine (e05)

[0682]

[0683] Compound B02-1R (0.194 mmol / g, 20 mg, 0.0039 mmol) and DMPr (0.4 mL) were added to a 0.6 mL glass vial under a nitrogen atmosphere and shaken at room temperature for 1 hour. Cyclohexylamine (e05) (8.9 μL, 0.078 mmol) and (tBu)PhCPhos Pd G4 (0.6 mg, 0.00078 mmol) were added. P2tBu / THF solution (2 M, 58.2 μL, 0.116 mmol) was added, and the mixture was shaken at room temperature for 0.5 hours.

[0684] The reaction mixture and solid phase suspension were transferred onto a filter 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 filter was then 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), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and subjected to LCMS analysis. The target product E0205 was observed in 100%.

[0685]

[0686] Compound E0205 LRMS: m / z 401 [M+H] ＋ Retention time: 1.096 minutes (analysis conditions FA05-1, 299 nm).

[0687] Example 3-4-2: Synthesis of E0207-1R by C—N coupling reaction of compound B02-1R and 3-aminopentane (e07)

[0688]

[0689] Compound B02-1R (0.194 mmol / g, 20 mg, 0.0039 mmol) and DMPr (0.4 mL) were placed in a 0.6 mL glass vial under a nitrogen atmosphere and shaken at room temperature for 1 hour. 3-Aminopentane (e07) (9.0 μL, 0.078 mmol) and (tBu)PhCPhos Pd G4 (0.6 mg, 0.00078 mmol) were added. P2tBu / THF solution (2 M, 58.2 μL, 0.116 mmol) was added, and the mixture was shaken at room temperature for 24 hours.

[0690] The reaction mixture and solid phase suspension were transferred onto a filter 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 filter was then immersed in 0.02M pentamethylbenzene in 10% TFA / DCM solution (0.05 mL) for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and subjected to LCMS analysis. As a result, 98.6% of the target product E0207 and 1.4% of the H-form (C02) were observed.

[0691]

[0692] Compound E0207 LRMS: m / z 389 [M+H] ＋ Retention time: 1.229 minutes (analysis conditions FA05-1, 299 nm).

[0693] Example 3-4-3: Synthesis of E0209-1R by C—N coupling reaction of compound B02-1R and o-toluidine (e09)

[0694]

[0695] Compound B02-1R (0.194 mmol / g, 20 mg, 0.0039 mmol) and DMPr (0.4 mL) were placed in a 0.6 mL glass vial under a nitrogen atmosphere and shaken at room temperature for 1 hour. o-Toluidine (e09) (8.3 μL, 0.078 mmol) and (tBu)PhCPhos Pd G4 (0.6 mg, 0.00078 mmol) were added. P2tBu / THF solution (2 M, 58.2 μL, 0.116 mmol) was added, and the mixture was shaken at room temperature for 2 hours.

[0696] The reaction mixture and solid phase suspension were transferred onto a filter 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 filter was then immersed in 0.02M pentamethylbenzene in 10% TFA / DCM solution (0.05 mL) for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and subjected to LCMS analysis. As a result, 98.2% of the target product E0209 and 1.1% of the H-form (C02) were observed.

[0697]

[0698] Compound E0209 LRMS: m / z 409 [M+H] ＋ Retention time: 1.257 minutes (analysis conditions FA05-1, 299 nm).

[0699] Example 3-4-4: Synthesis of E0210-1R by C—N coupling reaction of compound B02-1R and 2-ethylaniline (e10)

[0700]

[0701] Compound B02-1R (0.194 mmol / g, 20 mg, 0.0039 mmol) and DMPr (0.4 mL) were placed in a 0.6 mL glass vial under a nitrogen atmosphere and shaken at room temperature for 1 hour. 2-Ethylaniline (e10) (9.6 μL, 0.078 mmol) and (tBu)PhCPhos Pd G4 (0.6 mg, 0.00078 mmol) were added. P2tBu / THF solution (2 M, 58.2 μL, 0.116 mmol) was added, and the mixture was shaken at room temperature for 24 hours.

[0702] The reaction mixture and solid phase suspension were transferred onto a filter 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 filter was then immersed in 0.02M pentamethylbenzene in 10% TFA / DCM solution (0.05 mL) for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and subjected to LCMS analysis. As a result, 98.7% of the target product E0210 and 1.3% of the H-form (C02) were observed.

[0703]

[0704] Compound E0210 LRMS: m / z 423 [M+H] ＋ Retention time: 1.309 minutes (analysis conditions FA05-1, 299 nm).

[0705] Example 3-4-5: Synthesis of E0211-1R by C—N coupling reaction of compound B02-1R and 2-isopropylaniline (e11)

[0706]

[0707] Compound B02-1R (0.194 mmol / g, 20 mg, 0.0039 mmol) and DMPr (0.4 mL) were placed in a 0.6 mL glass vial under a nitrogen atmosphere and shaken at room temperature for 1 hour. 2-Isopropylaniline (e11) (10.8 μL, 0.078 mmol) and (tBu)PhCPhos Pd G4 (0.6 mg, 0.00078 mmol) were added. P2tBu / THF solution (2 M, 58.2 μL, 0.116 mmol) was added, and the mixture was shaken at room temperature for 24 hours.

[0708] The reaction mixture and solid phase suspension were transferred onto a filter 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 filter was then immersed in 0.02M pentamethylbenzene in 10% TFA / DCM solution (0.05 mL) for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and subjected to LCMS analysis. As a result, 97.9% of the target product E0211 and 2.1% of the H-form (C02) were observed.

[0709]

[0710] Compound E0211 LRMS: m / z 437 [M+H] ＋ Retention time: 1.351 minutes (analysis conditions FA05-1, 299 nm).

[0711] Example 3-4-6: Synthesis of E0212-1R by C—N coupling reaction of compound B02-1R and 2-(tert-butyl)aniline (e12)

[0712]

[0713] Compound B02-1R (0.194 mmol / g, 20 mg, 0.0039 mmol) and DMPr (0.4 mL) were placed in a 0.6 mL glass vial under a nitrogen atmosphere and shaken at room temperature for 1 hour. 2-(tert-butyl)aniline (e12) (12.1 μL, 0.078 mmol) and (tBu)PhCPhos Pd G4 (0.6 mg, 0.00078 mmol) were added. P2tBu / THF solution (2 M, 58.2 μL, 0.116 mmol) was added, and the mixture was shaken at room temperature for 24 hours.

[0714] The reaction mixture and solid phase suspension were transferred onto a filter 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 filter was then immersed in 0.02M pentamethylbenzene in 10% TFA / DCM solution (0.05 mL) for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and analyzed by LCMS. The target product E0212 was found to be 92.9% and the H-form (C02) was found to be 2.3%.

[0715]

[0716] Compound E0212 LRMS: m / z 451 [M+H] ＋ Retention time: 1.407 minutes (analysis conditions FA05-1, 299 nm).

[0717] Example 3-4-8: Synthesis of E0113-1R by C-coupling reaction of compound B01-1R and 2,6-dimethylaniline (e13)

[0718]

[0719] Compound B01-1R (0.195 mmol / g, 20 mg, 0.0039 mmol) and DMPr (0.4 mL) were placed in a 0.6 mL glass vial under a nitrogen atmosphere and shaken at room temperature for 1 hour. 2,6-Dimethylaniline (e13) (9.7 μL, 0.078 mmol) and (tBu)PhCPhos Pd G4 (0.6 mg, 0.00078 mmol) were added. P2tBu / THF solution (2 M, 58.5 μL, 0.117 mmol) was added, and the mixture was shaken at room temperature for 24 hours.

[0720] The reaction mixture and solid phase suspension were transferred onto a filter 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 filter was then immersed in 0.02 M pentamethylbenzene in 10% TFA / DCM solution (0.05 mL) for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and subjected to LCMS measurement. As a result, 95.1% of the target product E0113 and 1.5% of the H-form (C01) were observed.

[0721]

[0722] Compound E0113 LRMS: m / z 409 [M+H] ＋ Retention time: 1.248 minutes (analysis conditions FA05-1, 299 nm).

[0723] Example 3-4-9: Synthesis of E0114-1R by C—N coupling reaction of compound B01-1R and 2,6-diethylaniline (e14)

[0724]

[0725] Compound B01-1R (0.195 mmol / g, 20 mg, 0.0039 mmol) and DMPr (0.4 mL) were placed in a 0.6 mL glass vial under a nitrogen atmosphere and shaken at room temperature for 1 hour. 2,6-Diethylaniline (e14) (12.1 μL, 0.078 mmol) and (tBu)PhCPhos Pd G4 (0.6 mg, 0.00078 mmol) were added. P2tBu / THF solution (2 M, 58.5 μL, 0.117 mmol) was added, and the mixture was shaken at room temperature for 24 hours.

[0726] The reaction mixture and solid phase suspension were transferred onto a filter 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 filter was then immersed in 10% TFA / DCM solution (0.05 mL) containing 0.02 M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and subjected to LCMS measurement. As a result, 90.2% of the target product E0114, 3.8% of the substrate B01, and 1.6% of the H-form (C01) were observed.

[0727]

[0728] Compound E0114 LRMS: m / z 437 [M+H] ＋ Retention time: 1.345 minutes (analysis conditions FA05-1, 299 nm).

[0729] Example 3-4-10: Synthesis of E0115-1R by C—N coupling reaction of compound B01-1R and N-methylaniline (e15)

[0730]

[0731] Compound B01-1R (0.195 mmol / g, 20 mg, 0.0039 mmol) and DMPr (0.4 mL) were placed in a 0.6 mL glass vial under a nitrogen atmosphere and shaken at room temperature for 1 hour. N-methylaniline (e15) (8.4 μL, 0.078 mmol) and (tBu)PhCPhos Pd G4 (0.6 mg, 0.00078 mmol) were added. P2tBu / THF solution (2 M, 58.5 μL, 0.117 mmol) was added, and the mixture was shaken at room temperature for 24 hours.

[0732] The reaction mixture and solid phase suspension were transferred onto a filter 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 filter was then immersed in 0.02M pentamethylbenzene in 10% TFA / DCM solution (0.05 mL) for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and subjected to LCMS measurement. As a result, 95.4% of the target product E0115 and 1.1% of the H-form (C01) were observed.

[0733]

[0734] Compound E0115 LRMS: m / z 395 [M+H] ＋ Retention time: 1.259 minutes (analysis conditions FA05-1, 299 nm).

[0735] Example 3-4-12: Synthesis of E0303-1R by C—N coupling reaction of compound B03-1R and dipropylamine (e03)

[0736]

[0737] Compound B01-1R (0.195 mmol / g, 20 mg, 0.0039 mmol) and DMPr (0.4 mL) were added to a 0.6 mL glass vial under a nitrogen atmosphere and shaken at room temperature for 1 hour. Dipropylamine (e03) (10.7 μL, 0.078 mmol) and (tBu)PhCPhos Pd G4 (0.6 mg, 0.00078 mmol) were added. P2tBu / THF solution (2 M, 58.5 μL, 0.117 mmol) was added, and the mixture was shaken at room temperature for 24 hours.

[0738] The reaction mixture and solid phase suspension were transferred onto a filter 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 filter was then 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), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and analyzed by LCMS. The target product E0303 was found to be 89.6% and the H-form (C03) was found to be 3.9%.

[0739]

[0740] Compound E0303 LRMS: m / z 390 [M+H] ＋ Retention time: 0.825 minutes (analysis conditions FA05-1, 299 nm).

[0741] Example 3-4-13: Synthesis of E0502-2R by C—N coupling reaction of compound B05-2R and N-methyl-3-phenylpropylamine (e02)

[0742]

[0743] Compound B05-2R (0.194 mmol / g, 20 mg, 0.0039 mmol) and DMPr (0.4 mL) were placed in a 0.6 mL glass vial under a nitrogen atmosphere and shaken at room temperature for 1 hour. N-methyl-3-phenylpropylamine (e02) (11.6 mg, 0.078 mmol) and (tBu)PhCPhos Pd G4 (0.6 mg, 0.00078 mmol) were added. P2tBu / THF solution (2 M, 58.2 μL, 0.116 mmol) was added, and the mixture was shaken at room temperature for 24 hours.

[0744] The reaction mixture and solid suspension were transferred onto a filter 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 filter was then 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), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and analyzed by LCMS. The target product E0502 was found to be 87.2% and the H-form (C05) was found to be 4.4%.

[0745]

[0746] Compound E0502 LRMS: m / z 452 [M+H] ＋ Retention time: 0.897 minutes (analysis conditions FA05-1, 299 nm).

[0747]

[0748] Compound C05 LRMS: m / z 305 [M+H] ＋ Retention time: 0.605 minutes (Analysis conditions FA05-1, 299 nm).

[0749] Example 3-4-14: Synthesis of E0101-3R by C—N coupling reaction of compound B08-3R with 4-phenylpiperidine (e01)

[0750]

[0751] Under a nitrogen atmosphere, a DMPr solution (0.3 mL) of compound B08-3R (0.197 mmol / g, 15 mg, 0.0029 mmol) and 4-phenylpiperidine (e01) (4.8 mg, 0.030 mmol) was added to a 0.6 mL glass vial and shaken at room temperature for 1 hour. RuPhos Pd G4 (0.5 mg, 0.00059 mmol) was added. P2tBu / THF solution (2 M, 22.5 μL, 0.045 mmol) was added, and the mixture was shaken at 80°C for 24 hours.

[0752] The reaction mixture and solid phase suspension were transferred onto a filter, washed three times with DMF (0.1 mL), three times with MeOH (0.1 mL), and three times with DCM (0.1 mL), and then immersed in a 10% TFA / DCM solution (0.05 mL) for 1 minute. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and subjected to LCMS measurement. As a result, 51.2% of the target product E0101, 7.5% of the H-form (C01), and 39.8% of the raw material (B08) were observed.

[0753]

[0754] Compound E0101 LRMS: m / z 449 [M+H] ＋ Retention time: 0.999 minutes (analysis conditions FA05-1, 299 nm) Retention time: 2.397 minutes (analysis conditions FA05-long, 299 nm).

[0755] Example 3-4-15: Synthesis of E0101-3R by C—N coupling reaction of compound B09-3R and 4-phenylpiperidine (e01)

[0756]

[0757] Under a nitrogen atmosphere, a DMPr solution (0.3 mL) of compound B09-3R (0.193 mmol / g, 15 mg, 0.0029 mmol) and 4-phenylpiperidine (e01) (4.8 mg, 0.030 mmol) was added to a 0.6 mL glass vial, and the mixture was shaken at room temperature for 1 hour. ２ dba ３ CHCl ３ A DMPr solution (12.0 μL) of (tBu)PhCPhos (0.1 M, 0.0003 mmol) and (tBu)PhCPhos (0.025 M, 0.0012 mmol) was added. A PtBu / THF solution (2 M, 22.5 μL, 0.045 mmol) was added, and the mixture was shaken at 80° C. for 24 hours.

[0758] The reaction mixture and solid phase suspension were transferred onto a filter and washed three times with DMF (0.1 mL), three times with MeOH (0.1 mL), and three times with DCM (0.1 mL), then immersed in TFA / HFIP / DCM = 2 / 9 / 9 (0.05 mL) for 1 minute. 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 LCMS measurement was performed. As a result, 71.3% of the target product E0101 and 12.6% of the H-form (C01) were observed.

[0759] Example 3-4-16: Synthesis of E1001-3R by C—N coupling reaction of compound B10-3R with 4-phenylpiperidine (e01)

[0760]

[0761] Under a nitrogen atmosphere, a DMPr solution (0.3 mL) of compound B10-3R (0.194 mmol / g, 15 mg, 0.0029 mmol) and 4-phenylpiperidine (e01) (4.8 mg, 0.030 mmol) was added to a 0.6 mL glass vial, and the mixture was shaken at room temperature for 1 hour. ２ dba ３ CHCl ３ A DMPr solution (12.0 μL) of (tBu)PhCPhos (0.1 M, 0.0003 mmol) and (tBu)PhCPhos (0.025 M, 0.0012 mmol) was added. A PtBu / THF solution (2 M, 22.5 μL, 0.045 mmol) was added, and the mixture was shaken at 80° C. for 24 hours.

[0762] The reaction mixture and solid phase suspension were transferred onto a filter and washed three times with DMF (0.1 mL), three times with MeOH (0.1 mL), and three times with DCM (0.1 mL), followed by immersion in TFA / HFIP / DCM = 2 / 9 / 9 (0.05 mL) for 1 minute. 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 LCMS measurement was performed. As a result, the target product E1001 was observed at 90.8%.

[0763]

[0764] Compound E1001 LRMS: m / z 467 [M+H] ＋ Retention time: 1.060 minutes (Analysis conditions FA05-1, 299 nm).

[0765] Example 3-4-17: Synthesis of E0401-3R by C—N coupling reaction of compound B04-3R and 4-phenylpiperidine (e01)

[0766]

[0767] Under a nitrogen atmosphere, a DMPr solution (0.3 mL) of compound B04-3R (0.194 mmol / g, 15 mg, 0.0029 mmol) and 4-phenylpiperidine (e01) (4.8 mg, 0.030 mmol) was added to a 0.6 mL glass vial, and the mixture was shaken at room temperature for 1 hour. ２ dba ３ CHCl ３ A DMPr solution (12.0 μL) of (tBu)PhCPhos (0.1 M, 0.0003 mmol) and (tBu)PhCPhos (0.025 M, 0.0012 mmol) was added. A PtBu / THF solution (2 M, 22.5 μL, 0.045 mmol) was added, and the mixture was shaken at 80° C. for 24 hours.

[0768] The reaction mixture and solid phase suspension were transferred onto a filter and washed three times with DMF (0.1 mL), three times with MeOH (0.1 mL), and three times with DCM (0.1 mL), followed by immersion in TFA / HFIP / DCM = 2 / 9 / 9 (0.05 mL) for 1 minute. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and subjected to LCMS measurement. As a result, the target product E0401 was observed at 94.7%.

[0769]

[0770] Compound E0401 LRMS: m / z 479 [M+H] ＋ Retention time: 0.875 minutes (Analysis conditions FA05-1, 299 nm).

[0771] Example 3-4-18: Synthesis of E1101-3R by C—N coupling reaction of compound B11-3R with 4-phenylpiperidine (e01)

[0772]

[0773] Under a nitrogen atmosphere, a DMPr solution (0.3 mL) of compound B11-3R (0.194 mmol / g, 15 mg, 0.0029 mmol) and 4-phenylpiperidine (e01) (4.8 mg, 0.030 mmol) was added to a 0.6 mL glass vial, and the mixture was shaken at room temperature for 1 hour. ２ dba ３ CHCl ３ A DMPr solution (12.0 μL) of (tBu)PhCPhos (0.1 M, 0.0003 mmol) and (tBu)PhCPhos (0.025 M, 0.0012 mmol) was added. A PtBu / THF solution (2 M, 22.5 μL, 0.045 mmol) was added, and the mixture was shaken at 80° C. for 24 hours.

[0774] The reaction mixture and solid phase suspension were transferred onto a filter and washed three times with DMF (0.1 mL), three times with MeOH (0.1 mL), and three times with DCM (0.1 mL), followed by immersion in TFA / HFIP / DCM = 2 / 9 / 9 (0.05 mL) for 1 minute. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and subjected to LCMS measurement. As a result, the target product E1101 was observed at 92.2%.

[0775]

[0776] Compound E1101 LRMS: m / z 467 [M+H] ＋ Retention time: 1.219 minutes (analysis conditions FA05-1, 299 nm).

[0777] Example 3-4-19: Synthesis of E1201-3R by C—N coupling reaction of compound B12-3R with 4-phenylpiperidine (e01)

[0778]

[0779] Under a nitrogen atmosphere, a DMPr solution (0.3 mL) of compound B12-3R (0.194 mmol / g, 15 mg, 0.0029 mmol) and 4-phenylpiperidine (e01) (4.8 mg, 0.030 mmol) was added to a 0.6 mL glass vial, and the mixture was shaken at room temperature for 1 hour. ２ dba ３ CHCl ３ A DMPr solution (12.0 μL) of (tBu)PhCPhos (0.1 M, 0.0003 mmol) and (tBu)PhCPhos (0.025 M, 0.0012 mmol) was added. A PtBu / THF solution (2 M, 22.5 μL, 0.045 mmol) was added, and the mixture was shaken at 80° C. for 24 hours.

[0780] The reaction mixture and solid phase suspension were transferred onto a filter and washed three times with DMF (0.1 mL), three times with MeOH (0.1 mL), and three times with DCM (0.1 mL), followed by immersion in TFA / HFIP / DCM = 2 / 9 / 9 (0.05 mL) for 1 minute. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and subjected to LCMS measurement. As a result, the target product E1201 was observed at 97.7%.

[0781]

[0782] Compound E1201 LRMS: m / z 479 [M+H] ＋ Retention time: 0.867 minutes (analysis conditions FA05-1, 299 nm).

[0783] Example 3-4-20: Synthesis of E1301-3R by C—N coupling reaction of compound B13-3R with 4-phenylpiperidine (e01)

[0784]

[0785] Under a nitrogen atmosphere, a DMPr solution (0.3 mL) of compound B13-3R (0.195 mmol / g, 15 mg, 0.0029 mmol) and 4-phenylpiperidine (e01) (4.8 mg, 0.030 mmol) was added to a 0.6 mL glass vial, and the mixture was shaken at room temperature for 1 hour. ２ dba ３CHCl ３ A DMPr solution (12.0 μL) of (tBu)PhCPhos (0.1 M, 0.0003 mmol) and (tBu)PhCPhos (0.025 M, 0.0012 mmol) was added. A PtBu / THF solution (2 M, 22.5 μL, 0.045 mmol) was added, and the mixture was shaken at 80° C. for 24 hours.

[0786] The reaction mixture and solid phase suspension were transferred onto a filter and washed three times with DMF (0.1 mL), three times with MeOH (0.1 mL), and three times with DCM (0.1 mL), followed by immersion in TFA / HFIP / DCM = 2 / 9 / 9 (0.05 mL) for 1 minute. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and subjected to LCMS measurement. As a result, the target product E1301 was observed at 88.6%.

[0787]

[0788] Compound E1301 LRMS: m / z 450 [M+H] ＋ Retention time: 0.840 minutes (analysis conditions FA05-1, 299 nm).

[0789] Example 3-4-21: Synthesis of E1401-3R by C—N coupling reaction of compound B14-3R with 4-phenylpiperidine (e01)

[0790]

[0791] Under a nitrogen atmosphere, a DMPr solution (0.3 mL) of compound B14-3R (0.194 mml / g, 15 mg, 0.0029 mmol) and 4-phenylpiperidine (e01) (4.8 mg, 0.030 mmol) was added to a 0.6 mL glass vial, and the mixture was shaken at room temperature for 1 hour. ２ dba ３ CHCl ３A DMPr solution (12.0 μL) of (tBu)PhCPhos (0.1 M, 0.0003 mmol) and (tBu)PhCPhos (0.025 M, 0.0012 mmol) was added. A PtBu / THF solution (2 M, 22.5 μL, 0.045 mmol) was added, and the mixture was shaken at 80° C. for 24 hours.

[0792] The reaction mixture and solid phase suspension were transferred onto a filter and washed three times with DMF (0.1 mL), three times with MeOH (0.1 mL), and three times with DCM (0.1 mL), followed by immersion in TFA / HFIP / DCM = 2 / 9 / 9 (0.05 mL) for 1 minute. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and subjected to LCMS measurement. As a result, the target product E1401 was observed at 79.0%.

[0793]

[0794] Compound E1401 LRMS: m / z 470 [M+H] ＋ Retention time: 0.848 minutes (Analysis conditions FA05-1, 299 nm).

[0795] Example 3-4-22: Synthesis of E1501-1R by C—N coupling reaction of compound B15-1R and 4-phenylpiperidine (e01)

[0796]

[0797] Under a nitrogen atmosphere, a DMPr solution (0.3 mL) of compound B15-1R (0.194 mmol / g, 15 mg, 0.0029 mmol) and 4-phenylpiperidine (e01) (4.8 mg, 0.030 mmol) was added to a 0.6 mL glass vial, and the mixture was shaken at room temperature for 1 hour. ２ dba ３ CHCl ３A DMPr solution (12.0 μL) of (tBu)PhCPhos (0.1 M, 0.0003 mmol) and (tBu)PhCPhos (0.025 M, 0.0012 mmol) was added. A PtBu / THF solution (2 M, 22.5 μL, 0.045 mmol) was added, and the mixture was shaken at 80° C. for 24 hours.

[0798] The reaction mixture and solid phase suspension were transferred onto a filter and washed three times with DMF (0.1 mL), three times with MeOH (0.1 mL), and three times with DCM (0.1 mL), followed by immersion in TFA / HFIP / DCM = 2 / 9 / 9 (0.05 mL) for 1 minute. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and subjected to LCMS measurement. As a result, the target product E1501 was observed at 62.4%.

[0799]

[0800] Compound E1501 LRMS: m / z 469 [M+H] ＋ Retention time: 0.976 minutes (analysis conditions FA05-1, 299 nm).

[0801] Example 3-4-23: Synthesis of G0401-3R by C—N coupling reaction of compound H04-3R and methyl 4-bromobenzoate (g01)

[0802]

[0803] Compound H04-3R (0.196 mmol / g, 15 mg, 0.0029 mmol), methyl 4-bromobenzoate (g01) (6.3 mg, 0.029 mmol), and DMPr (0.3 mL) were added to a 0.6 mL glass vial under a nitrogen atmosphere and shaken at room temperature for 1 hour. RuPhos Pd G4 (2.5 mg, 0.0029 mmol) and BTPP (13.5 μL, 0.044 mmol) were added, and the mixture was shaken at 80°C for 24 hours.

[0804] The reaction mixture and solid phase suspension were transferred onto a filter 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 filter was then immersed in 0.02 M pentamethylbenzene in 10% TFA / DCM solution (0.05 mL) for 1 minute. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and subjected to LCMS measurement. As a result, the target product G0401 was observed at 92.9%.

[0805]

[0806] Compound G0401 LRMS: m / z 467 [M+H] ＋ Retention time: 1.133 minutes (analysis conditions FA05-1, 299 nm).

[0807] Example 3-4-24: Synthesis of G0401-3R by CN coupling reaction of compound H04-3R and methyl 4-chlorobenzoate (g04)

[0808]

[0809] Compound H04-3R (0.196 mmol / g, 15 mg, 0.0029 mmol), methyl 4-chlorobenzoate (g04) (5.0 mg, 0.029 mmol), and DMPr (0.3 mL) were added to a 0.6 mL glass vial under a nitrogen atmosphere and shaken at room temperature for 1 hour. RuPhos Pd G4 (2.5 mg, 0.0029 mmol) and BTPP (13.5 μL, 0.044 mmol) were added, and the mixture was shaken at 80°C for 24 hours.

[0810] The reaction mixture and solid phase suspension were transferred onto a filter 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 filter was then immersed in 0.02 M pentamethylbenzene in 10% TFA / DCM solution (0.05 mL) for 1 minute. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and subjected to LCMS measurement. As a result, the target product G0401 was observed at 90.3%.

[0811] Example 3-4-25: Synthesis of G0401-3R by C—N coupling reaction of compound H04-3R and methyl 4-iodobenzoate (g05)

[0812]

[0813] Compound H04-3R (0.196 mmol / g, 15 mg, 0.0029 mmol), methyl 4-iodobenzoate (g05) (7.7 mg, 0.029 mmol), and DMPr (0.3 mL) were added to a 0.6 mL glass vial under a nitrogen atmosphere and shaken at room temperature for 1 hour. RuPhos Pd G4 (2.5 mg, 0.0029 mmol) and BTPP (13.5 μL, 0.044 mmol) were added, and the mixture was shaken at 80°C for 24 hours.

[0814] The reaction mixture and solid phase suspension were transferred onto a filter 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 filter was then immersed in 0.02 M pentamethylbenzene in 10% TFA / DCM solution (0.05 mL) for 1 minute. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and subjected to LCMS measurement. As a result, the target product G0401 was observed at 89.8%.

[0815] Example 3-4-26: Synthesis of G0202-4R by C—N coupling reaction of compound H02-4R and ethyl 4-bromopicolinate (g02)

[0816]

[0817] Compound H02-4R (0.198 mmol / g, 15 mg, 0.0030 mmol), ethyl 5-bromopicolinate (g02) (6.8 mg, 0.030 mmol), and DMPr (0.3 mL) were added to a 0.6 mL glass vial under a nitrogen atmosphere and shaken at room temperature for 1 hour. RuPhos Pd G4 (2.5 mg, 0.0030 mmol) and BTPP (13.6 μL, 0.045 mmol) were added, and the mixture was shaken at 80°C for 24 hours.

[0818] The reaction mixture and solid phase suspension were transferred onto a filter 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 filter was then immersed in 0.02M pentamethylbenzene in 10% TFA / DCM solution (0.05 mL) for 1 minute. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and subjected to LCMS measurement. As a result, the target product G0202 was observed at 89.5%.

[0819]

[0820] Compound G0202 LRMS: m / z 446 [M+H] ＋ Retention time: 0.880 minutes (Analysis conditions FA05-1, 299 nm).

[0821] Example 3-4-27: Synthesis of G0402-3R by C—N coupling reaction of compound H04-3R and ethyl 5-bromopicolinate (g02)

[0822]

[0823] Compound H04-3R (0.196 mmol / g, 15 mg, 0.0029 mmol), ethyl 5-bromopicolinate (g02) (6.8 mg, 0.029 mmol), and DMPr (0.3 mL) were added to a 0.6 mL glass vial under a nitrogen atmosphere and shaken at room temperature for 1 hour. RuPhos Pd G4 (2.5 mg, 0.0029 mmol) and BTPP (13.5 μL, 0.044 mmol) were added, and the mixture was shaken at 80°C for 24 hours.

[0824] The reaction mixture and solid phase suspension were transferred onto a filter 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 filter was then immersed in 0.02 M pentamethylbenzene in 10% TFA / DCM (0.05 mL) for 1 minute. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and subjected to LCMS analysis. The target product G0402 was observed at 87.0%.

[0825]

[0826] Compound G0402 LRMS: m / z 482 [M+H] ＋ Retention time: 0.983 minutes (Analysis conditions FA05-1, 299 nm).

[0827] Example 3-4-28: Synthesis of G0103-4R by C—N coupling reaction of compound H01-4R and ethyl 2-bromothiazole-4-carboxylate (g03)

[0828]

[0829] Compound H01-4R (0.198 mmol / g, 15 mg, 0.0030 mmol), ethyl 2-bromothiazole-4-carboxylate (g03) (7.0 mg, 0.030 mmol), and DMPr (0.3 mL) were placed in a 0.6 mL glass vial under a nitrogen atmosphere and shaken at room temperature for 1 hour. tBuXPhos Pd G4 (2.5 mg, 0.0030 mmol) and BTPP (13.6 μL, 0.045 mmol) were added, and the mixture was shaken at 80°C for 24 hours.

[0830] The reaction mixture and solid phase suspension were transferred onto a filter 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 filter was then immersed in 0.02 M pentamethylbenzene in 10% TFA / DCM solution (0.05 mL) for 1 minute. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and subjected to LCMS measurement. As a result, the target product G0103 was observed at 89.5%.

[0831]

[0832] Compound G0103 LRMS: m / z 452 [M+H] ＋ Retention time: 0.919 minutes (analysis conditions FA05-1, 299 nm).

[0833] Example 3-4-29: Synthesis of G0303-4R by C—N coupling reaction of compound H03-4R with ethyl 2-bromothiazole-4-carboxylate (g03)

[0834]

[0835] Compound H03-4R (0.197 mmol / g, 15 mg, 0.0030 mmol), ethyl 2-bromothiazole-4-carboxylate (g03) (7.0 mg, 0.030 mmol), and DMPr (0.3 mL) were added to a 0.6 mL glass vial under a nitrogen atmosphere and shaken at room temperature for 1 hour. tBuXPhos Pd G4 (2.4 mg, 0.0030 mmol) and BTPP (13.6 μL, 0.045 mmol) were added, and the mixture was shaken at 80°C for 24 hours.

[0836] The reaction mixture and solid phase suspension were transferred onto a filter 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 filter was then immersed in 0.02 M pentamethylbenzene in 10% TFA / DCM (0.05 mL) for 1 minute. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate. An LC sample was prepared and subjected to LCMS analysis. The target product G0303 was observed at 87.6%.

[0837]

[0838] Compound G0303 LRMS: m / z 474 [M+H] ＋ Retention time: 1.001 minutes (Analysis conditions FA05-1, 299 nm).

[0839] Example 5: Application of Pd coupling conditions to mixtures Example 5-1: Synthesis of substrate mixture Example 5-1-1: Synthesis of mixture 2-2-B00-0

[0840]

[0841] D084-3R and D085-3R can be prepared under the same conditions as described in Example 1-2-1 using separately prepared methyl 2-(3-bromo-5-((4-(piperidin-4-yloxy)benzyl)oxy)phenyl)propanoate and methyl 7-bromo-5-((4-(piperidin-4-yloxy)benzyl)oxy)-1,2,3,4-tetrahydronaphthalene-1-carboxylate.

[0842] Compound D084-3R (3.2 g, 0.200 mmol / g), compound D085-3R (3.2 g, 0.200 mmol / g), NMP (90 mL), and tAmylOH (25.6 mL) were added to a 200 mL column equipped with a filter. The reaction solution was capped to prevent leakage and shaken at room temperature for 5 minutes. A TBAOH aqueous solution (1 M, 256 mL, 2.56 mmol) was added. The reaction solution was capped to prevent leakage and shaken at room temperature for 1 hour. The suspension of the reaction liquid and solid phase was filtered through a column filter, washed three times with NMP / water = 1 / 1 (128 mL), three times with NMP (128 mL), three times with an NMP solution of tetrabutylammonium hydrogen sulfate and 2,6-di-tert-butylpyridine mixed (all 0.05 M, 128 mL), three times with NMP (128 mL), three times with MeOH (128 mL), three times with DCM (128 mL), and three times with heptane (128 mL), and the obtained solid phase was dried under reduced pressure to obtain a mixture 2-2-B00-0 (6.81 g, 0.201 mmol / g).

[0843] The compounds contained in mixture 2-2-B00-0 are as shown in Table 5-1-1. In Table 5-1-1, each compound contained in the mixture is indicated by an ID, and its structure is represented by the corresponding n number in the structural formula of the mixture. That is, compound 2-2-B00-0-0001 has an n number of 0 and represents compound D084-3R, and compound 2-2-B00-0-0002 has an n number of 1 and represents compound D085-3R.

[0844]

[0845] Example 5-1-2: Synthesis of mixtures 2-2-a1B01-0 to 2-2-a1B05-0

[0846]

[0847] Mixture 2-2-B00-0 (1.28 g, 0.201 mmol / g) and DCM (15.4 mL) were added to five 20 mL columns equipped with filters. The amines (1.80 mmol) listed in Table 5-1-2-0 were added separately to each column, the columns were capped to prevent leakage, and the columns were shaken at room temperature for 1 hour. A solution of PipClU and NMI in MeCN (both 1 M, 0.013 mL, 0.770 mmol) was added. The columns were capped to prevent leakage, and the columns were shaken at room temperature for 2 hours.

[0848] The suspension of the reaction liquid and solid phase was filtered through a column filter and washed three times with NMP / water = 1 / 1 (25 mL), three times with NMP (25 mL), three times with MeOH (25 mL), three times with DCM (25 mL), and once with heptane (25 mL), and the obtained solid phase was dried under reduced pressure to obtain the mixture described in Table 5-1-2-0.

[0849]

[0850] The compounds contained in mixtures 2-2-a1B01-0 to 2-2-a1B05-0 are as shown in Tables 5-1-2-1 to 5-1-2-5. In Tables 5-1-2-1 to 5-1-2-5, each compound contained in the mixture is indicated by an ID, and the corresponding n number and part B in the structural formula of the mixture are indicated by a symbol to represent the structure. Unless otherwise specified, the correspondence between the symbols and structural formulas for part B in this specification is as shown below.

[0851]

[0852] For example, compound 2-2-a1B01-0-0001 has the number n of 0, the moiety B is B01, and has the following structure:

[0853]

[0854] For example, compound 2-2-a1B02-0-0002 has the number n of 1, the moiety B is B02, and has the following structure.

[0855]

[0856]

[0857]

[0858]

[0859]

[0860]

[0861] Example 5-1-3: Preparation of Mixture 2-2-C00-0

[0862]

[0863] The five mixtures listed in Table 5-1-3-0 and DCM (70 mL) were added to a 120 mL filter column. After 1 minute, the suspension of the solvent and solid phase was filtered through the column filter and washed once with heptane (70 mL). The resulting solid phase was dried under reduced pressure to obtain mixture 2-2-C00-0 (3.67 g, 0.196 mmol / g).

[0864]

[0865] The compounds contained in mixture 2-2-C00-0 are shown in Table 5-1-3-1. In Table 5-1-3-1, each compound contained in the mixture is shown by ID, and the structure is represented by a symbol for the corresponding n number in the structural formula of the mixture and part B. The correspondence between the symbols and structural formulas in part B is as shown in Example 5-1-2.

[0866]

[0867] Example 5-2: Application of Pd coupling conditions to mixture Example 5-2-1: Synthesis of mixture 2-2-b3C00-0 by hydroxylation of mixture 2-2-C00-0

[0868]

[0869] Mixture 2-2-C00-0 (550 mg, 0.196 mmol / g), DEAc (11.0 mL), and water (0.275 mL, 15.3 mmol) were added to a 15 mL glass vial and shaken at room temperature for 1 hour. AdBrettPhos Pd G6 Br (21.0 mg, 0.022 mmol) and BTMG (0.275 mL, 1.38 mmol) were added, and the mixture was shaken at 60°C for 15 hours.

[0870] The suspension of the reaction solution and solid phase was transferred to a filter-equipped column and filtered, and washed three times with NMP (11 mL), three times with a solution of N-acetyl-L-cysteine ​​in NMP / water = 5 / 1 (0.2 M, 11 mL), three times with a solution of tetrabutylammonium hydrogen sulfate and 2,6-di-tert-butylpyridine in NMP (both 0.05 M, 11 mL), three times with a solution of 4-methylmorpholine in NMP (0.05 M, 11 mL), three times with NMP / water = 1 / 1 (11 mL), three times with NMP (11 mL), three times with MeOH (11 mL), three times with DCM (11 mL), and once with heptane (11 mL). The obtained solid phase was dried under reduced pressure to obtain mixture 2-2-b3C00-0.

[0871] The compounds that can be included in 2-2-b3C00-0 are shown in [Table 5-2-1-1]. In [Table 5-2-1-1], each compound that can be included in the mixture is shown by ID, and the structure is represented by the corresponding n number in the structural formula of the mixture and the symbol for part B. The correspondence between the symbol and the structural formula for part B is as shown in Example 5-1-2.

[0872]

[0873]

[0874] After 15 hours of shaking at 60 °C, 12 μL of the reaction mixture and solid phase suspension was transferred onto a filter 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 filter was then immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.02 M, 0.05 mL) for 1 minute. After filtration, the solid phase was washed with DMF (0.05 mL), and MeCN (0.25 mL) was added to the filtrate to obtain a solution of mixture 2-2-b3C00-1. LCMS analysis of this solution revealed all m / z ([M+H]+) values ​​derived from compounds potentially contained in mixture 2-2-b3C00-1 listed in Table 5-2-1-2. In [Table 5-2-1-2], each compound that can be contained in the mixture is shown by ID, and the structure is represented by a symbol for the corresponding n number and part B in the structural formula of the mixture. This result showed that the mixture 2-2-b3C00-0 described in [Table 5-2-1-1] was synthesized correctly.

[0875]

[0876] The above results demonstrate that the hydroxylation reaction using DEAc as a solvent is applicable even when the substrate is not a single substance but a mixture of multiple substances.

[0877] Example 5-2-2: Synthesis of mixture 2-2-b1C19-0 by C—N coupling reaction of mixture 2-2-C00-0

[0878]

[0879] 2-2-C00-0 (128 mg, 0.196 mmol / g) and DMPr (2.56 mL) were placed in a 4 mL glass vial and shaken at room temperature for 1 hour. Ethyl 4-(piperazin-1-yl)benzoate (e22) (58.9 mg, 0.251 mmol) was added. (tBu)PhCPhos Pd G4 (19 mg, 0.025 mmol) and a THF solution of P2tBu (2 M, 0.189 mL, 0.377 mmol) were added, and the mixture was shaken at 25°C for 1 hour.

[0880] The reaction solution and solid phase suspension was transferred to a 6 mL filter and filtered, and washed three times with NMP / water = 1 / 1 (2.6 mL), three times with NMP (2.6 mL), three times with a solution of N-acetyl-L-cysteine ​​in NMP / water = 5 / 1 (0.2 M, 2.6 mL), three times with an NMP solution of tetrabutylammonium hydrogen sulfate and 2,6-di-tert-butylpyridine mixed therein (all 0.05 M, 2.6 mL), three times with an NMP solution of 4-methylmorpholine (0.05 M, 2.6 mL), three times with NMP / water = 1 / 1 (2.6 mL), three times with NMP (2.6 mL), three times with MeOH (2.8 mL), three times with DCM (2.8 mL), and three times with heptane (2.8 mL). The resulting solid phase was dried under reduced pressure to obtain mixture 2-2-b1C19-0.

[0881] The compounds that can be included in 2-2-b1C19-0 are shown in [Table 5-2-2-1]. In [Table 5-2-2-1], each compound that can be included in the mixture is shown by ID, and the structure is represented by a symbol for the corresponding n number and part B in the structural formula of the mixture.

[0882]

[0883]

[0884] After shaking at 25°C for 1 hour, 12µL of the reaction mixture and solid phase suspension was transferred onto a filter and washed three times with DMF (0.1mL), three times with MeOH (0.1mL), and three times with DCM (0.1mL). The filter was then immersed in a 10% TFA / DCM solution of pentamethylbenzene (0.02M, 0.05mL) for 1 minute. After filtration, the solid phase was washed with DMF (0.05mL), and MeCN (0.25mL) was added to the filtrate to obtain a solution of mixture 2-2-b1C19-1. LCMS analysis of this solution revealed the m / z ([M+H]) of compounds potentially contained in mixture 2-2-b1C19-1 described in [Table 5-2-2-2]. ＋) were all observed. In [Table 5-2-2-2], each compound that may be contained in the mixture is indicated by an ID, and the structure is represented by a symbol indicating the corresponding n number and part B in the structural formula of the mixture. The correspondence between the symbols and structural formulas in part B is as shown in Example 5-1-2. This result demonstrated that the mixture 2-2-b1C19-0 described in [Table 5-2-2-1] was synthesized correctly.

[0885]

[0886] The above results demonstrate that the C-N coupling reaction using DMPr as a solvent is applicable even when the substrate is not a single compound but a mixture of multiple compounds. The present example also demonstrates that the efficient construction of a compound library is possible by applying the reaction conditions shown in the present example to the production of a compound library with diverse structures and performing a palladium coupling step on multiple compounds.

Claims

1. A method for producing a compound by a cross-coupling reaction In the presence of a catalyst and a base, a compound of formula A: 【Chemistry 1】 [In the formula, R １ , R ２ and R ３ are each independently C １－４ alkyl, provided that R １ , R ２ and R ３ and the total number of carbon atoms of the aromatic rings is 4 or more and 6 or less. １ with a compound 2 having a reactive group capable of a C—O bond forming reaction or a C—N bond forming reaction by substitution with the leaving group; X １ represents a halogen atom or —O—SO ２ -R ４ and R ４ C may be substituted with one or more fluorine atoms １－６ Alkyl, or one or more fluorine atoms or C optionally substituted with fluorine atoms １－６ phenyl optionally substituted with alkyl; The method, wherein compound 2 has a hydroxy capable of forming a C—O bond or an H—N group capable of forming a C—N bond.

2. The method of claim 1 , wherein the catalyst is a palladium catalyst or a nickel catalyst.

3. Compound 1 has a leaving group X on the carbon atom of the aromatic ring in the side chain. １ or a solid phase synthesis resin having, in a side chain, a reactive group capable of undergoing a C—O bond forming reaction or a C—N bond forming reaction by substitution with the leaving group.

4. Compound 2 is 1) Water or HO-R ５ is a compound having a hydroxyl capable of forming a C—O bond, represented by R ５ is C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ Cycloalkyl, C ７－１４ Aralkyl, C ６－１０ aryl, or a 5-10 membered heteroaryl containing one or more ring heteroatoms independently selected from O, N and S, each of which is selected from fluorine atoms, 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, 5-10 membered heteroarylcarbonylamino containing one or more ring heteroatoms independently selected from O, N and S, aminocarbonyl, (C １－６ alkyl)aminocarbonyl, di(C １－６ optionally substituted with one or more groups independently selected from the group consisting of alkyl)aminocarbonyl, and 4- to 8-membered cyclic aminocarbonyl; 2) HNR ６ R ７ is a compound having an H—N group capable of forming a C—N bond, represented by R ６ and R ７ together with the nitrogen atom to which they are attached to form a 5- to 7-membered saturated heterocycle, and the heterocycle is not limited to a fluorine atom, a cyano, a 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, 5- to 10-membered heteroarylcarbonylamino containing one or more ring heteroatoms independently selected from O, N, and S, di(C １－６ alkyl)amino, 4- to 8-membered cyclic amino, aminocarbonyl, (C １－６ alkyl)aminocarbonyl, di(C １－６ optionally substituted by one or more substituents independently selected from the group consisting of alkyl)aminocarbonyl, and 4- to 8-membered cyclic aminocarbonyl; R ６ and R ７ are each independently a hydrogen atom, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－８ cycloalkyl, (C １－６ alkyl)carbonyl, (C ６－１０ aryl)carbonyl, 5-10 membered heteroarylcarbonyl containing one or more ring heteroatoms independently selected from O, N and S, C ７－１４ Aralkyl, C ６－１０ aryl, or a 5-10 membered heteroaryl containing one or more ring heteroatoms independently selected from O, N and S, each of which is selected from fluorine atoms, 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, 5- to 10-membered heteroarylcarbonylamino containing one or more ring heteroatoms independently selected from O, N, and S, di(C １－６ alkyl)amino, 4- to 8-membered cyclic amino, aminocarbonyl, (C １－６ alkyl)aminocarbonyl, di(C １－６ optionally substituted by one or more substituents independently selected from the group consisting of alkyl)aminocarbonyl, and 4- to 8-membered cyclic aminocarbonyl; The method according to any one of claims 1 to 3.

5. Compound 1 is X １ -Ar ２ is a compound represented by X １ represents a chlorine atom, a bromine atom, an iodine atom, or —O—SO ２ -R ４ and R ４ C may be substituted with one or more fluorine atoms １－６ Alkyl, or one or more fluorine atoms or C optionally substituted with fluorine atoms １－６ phenyl optionally substituted with alkyl; Ar ２ is C ６－１０ aryl, or a 5-10 membered heteroaryl containing one or more ring heteroatoms independently selected from O, N and S, each of which is selected from fluorine atoms, 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, 5- to 10-membered heteroarylcarbonylamino containing one or more ring heteroatoms independently selected from O, N, and S, di(C １－６ alkyl)amino, 4- to 8-membered cyclic amino, aminocarbonyl, (C １－６ alkyl)aminocarbonyl, di(C １－６ The method according to any one of claims 1 to 3, wherein the amino group is optionally substituted with one or more groups independently selected from the group consisting of alkyl)aminocarbonyl, and 4- to 8-membered cyclic aminocarbonyl.

6. Ar ２ is independently selected from the group consisting of phenyl, naphthyl, 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, each of which is optionally substituted.

7. 4. The method of claim 1, wherein the solvent is selected from the group consisting of N,N-dimethylpropionamide (DMPr), N,N-diethylacetamide (DEAc) and N,N-diethylpropionamide (DEPr).

8. The method according to any one of claims 1 to 3, wherein the solvent is N,N-dimethylpropionamide (DMPr).

9. The method according to any one of claims 1 to 3, wherein the solvent contains 30 v / v % or more of at least one selected from the group consisting of N,N-dimethylpropionamide (DMPr), N,N-diethylacetamide (DEAc), and N,N-diethylpropionamide (DEPr).

10. The catalysts are represented by the following general formulae (Cat 1), (Cat 2), (Cat 3), (Cat 4) and (Cat 5): 【Chemistry 2】 In the formula, R ２０ is a hydrogen atom, C １－６ Alkyl, or C ６－１０ aryl, and R ２１ is halogen or -O-SO ２ -CH ３ and R ２２ C may be substituted with one or more fluorine atoms １－６ Alkyl, or tri(C １－６ alkyl) may be substituted by silyl (C １－６ L is independently a monodentate ligand (L1), (L2), (L3), (L4), (L5), (L6) or (L7) of the following general formula: 【Transformation 3】 [In the formula, R ２３ are independently tert-butyl, cyclohexyl, 2-furanyl, 2-thienyl, 2-pyridyl, phenyl (the phenyl is one or more fluorine atoms, C optionally substituted with fluorine atoms). １－６ Alkyl, C １－６ alkoxy, or dimethylamino), or adamantyl; R ２４ is C １－６ alkyl, cyclohexyl, 2-furanyl, 2-thienyl, 2-pyridyl, N-phenyl-2-pyrrolyl, N-phenyl-2-indolyl, phenyl (the phenyl is one or more fluorine atoms, C optionally substituted with fluorine atoms). １－６ alkyl, C 1-6 alkoxy, morpholino, or dimethylamino), or adamantyl; R ２５ is a hydrogen atom, C １－６ Alkyl, or C １－６ is an alkoxy; W １ is -C(CH ３ ) ２ - or -NH-, R ２６ , R ２７ , R ２８ , and R ２９ are each independently a hydrogen atom, C １－６ Alkyl, C １－６ alkoxy, or morpholino; R ３０ , R ３１ , and R ３２ are each independently a hydrogen atom, C １－６ Alkyl, C １－６ alkoxy, or dimethylamino; R ３３ is a hydrogen atom or -SO ２ -O-M, where M is lithium, sodium, or potassium; R ３４ is a hydrogen atom, C １－６ Alkyl, or C １－６ is an alkoxy; R ３５ and R ３６ are each independently a hydrogen atom, C １－６ Alkyl, or C １－６ is an alkoxy; R ３７ is a hydrogen atom, or C １－６ phenyl optionally substituted with alkyl; R ３８ are independently a hydrogen atom, C １－６ Phenyl optionally substituted with alkyl, or —CH(CH ３ )-N(CH ３ ) ２ and R ３９ is tert-butyl, cyclohexyl, or adamantyl; R ４０ is a hydrogen atom, or C １－６ The method according to any one of claims 1 to 3, wherein the catalyst comprises a palladium complex represented by any one of the following formulas:

11. The catalyst is represented by the following general formula (Cat 6) and general formula (Cat 7): 【Chemistry 4】 [In the formula, R ４１ is a hydrogen atom or C １－６ phenyl optionally substituted with alkyl, and R ４２ are independently halogen, and R ４３ represents a fluorine atom or a chlorine atom, and L represents an N-heterocyclic carbene ligand represented by the following general formula (L12) or (L13): 【Transformation 5】 R ４４ and R ４５ are each independently １－６ alkyl, cyclohexyl, adamantyl, or phenyl (wherein the phenyl is one or more C １－６ Alkyl, C １－６ The method according to any one of claims 1 to 3, wherein the catalyst comprises a palladium complex represented by the formula:

12. The catalyst is a palladium compound selected from the group consisting of bis(allylchloropalladium(II)), tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct, palladium(π-cinnamyl)chloride dimer, (1-methylallyl)palladium chloride dimer, (1,5-cyclooctadiene)bis(trimethylsilylmethyl)palladium(II), (2′-amino-1,1′-biphenyl-2-yl)methanesulfonatopalladium(II) dimer, and palladium(II) acetate, and a monodentate ligand (L1), (L2), (L), (L4), (L5), (L6), or (L7) of the following general formula, or a bidentate ligand (L8), (L9), (L10), (L11), or (L12): 【Transformation 6】 In the formula, R ２３ is tert-butyl, cyclohexyl, 2-furanyl, 2-thienyl, 2-pyridyl, phenyl (the phenyl is one or more fluorine atoms, C 1-6 alkyl optionally substituted with fluorine atoms, C １－６ alkoxy, or dimethylamino), or adamantyl; R ２４ is C １－６ alkyl, cyclohexyl, 2-furanyl, 2-thienyl, 2-pyridyl, N-phenyl-2-pyrrolyl, N-phenyl-2-indolyl, phenyl (the phenyl is one or more fluorine atoms, C optionally substituted with fluorine atoms). １－６ alkyl, C 1-6 alkoxy, morpholino, or dimethylamino), or adamantyl; R ２５ is a hydrogen atom, C １－６ Alkyl, or C １－６ is an alkoxy; W １ is -C(CH ３ ) ２ - or -NH-, R ２６ , R ２７ , R ２８ , and R ２９ are each independently a hydrogen atom, C １－６ Alkyl, C １－６ alkoxy, or morpholino; R ３０ , R ３１ , and R ３２ are each independently a hydrogen atom, C １－６ Alkyl, C １－６ alkoxy, or dimethylamino; R ３３ is a hydrogen atom or -SO ２ -O-M, where M is lithium, sodium, or potassium; R ３４ is a hydrogen atom, C １－６ Alkyl, or C １－６ is an alkoxy; R ３５ and R ３６ are each independently a hydrogen atom, C １－６ Alkyl, or C １－６ is an alkoxy; R ３７ is a hydrogen atom, or C １－６ phenyl optionally substituted with alkyl; R ３８ is a hydrogen atom, C １－６ Phenyl optionally substituted with alkyl, or —CH(CH ３ )-N(CH ３ ) ２ and R ３９ is tert-butyl, cyclohexyl, or adamantyl; R ４０ is a hydrogen atom, or C １－６ The method according to any one of claims 1 to 3, wherein the catalyst comprises a palladium complex formed in combination with a ligand selected from the group consisting of a ligand represented by the formula:

13. The method according to any one of claims 1 to 3, wherein the base comprises at least one base selected from the group consisting of organic bases whose conjugate acids have a pKa of 23 or more in acetonitrile and inorganic bases whose conjugate acids have a pKa of 9 to 20 in water.

14. The method according to any one of claims 1 to 3, wherein the reaction system further contains a salt together with the base.

15. 15. The method of claim 14, wherein the salt is an alkali metal salt of an acid selected from the group consisting of trifluoroacetic acid, trifluoromethanesulfonic acid, trifluoromethanesulfonimide, tetrafluoroboric acid, hexafluorophosphoric acid, and hexafluoroantimony(V) acid.

16. A method for producing a compound, comprising the method according to any one of claims 1 to 3.

17. Formula A: 【Transformation 7】 [In the formula, R １ , R ２ and R ３ are each independently C １－４ alkyl, provided that R １ , R ２ and R ３ wherein the total number of carbon atoms is 4 or more and 6 or less, in a cross-coupling reaction.