CN118043308A

CN118043308A - Bond formation methods based on coupling reactions

Info

Publication number: CN118043308A
Application number: CN202280065991.4A
Authority: CN
Inventors: 伊藤太亮
Original assignee: Chugai Pharmaceutical Co Ltd
Current assignee: Chugai Pharmaceutical Co Ltd
Priority date: 2021-09-30
Filing date: 2022-09-30
Publication date: 2024-05-14

Abstract

According to the present invention, there is provided a method for producing a compound by a cross-coupling reaction, comprising the step of reacting a compound 1 having a leaving group X ¹ on a carbon atom of an aromatic ring with a compound 2 having a reactive group capable of undergoing a c—o bond formation reaction or a c—n bond formation reaction based on substitution with the leaving group in a solvent comprising an amide-based solvent represented by the formula a [ formula wherein R ¹、R² and R ³ are each independently a C _1‑4 alkyl group, wherein the total number of carbon atoms of R ¹、R² and R ³ is 4 or more and 6 or less ], in the presence of a catalyst and a base; x ¹ is a halogen atom or-O-SO ₂-R⁴.

Description

Bond formation method based on coupling reaction

Technical Field

The present invention relates to a bond formation method based on a coupling reaction, and in particular, to a method of 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 including a step of forming a bond by a coupling reaction.

Background

Methods for forming carbon-oxygen bonds or carbon-nitrogen bonds by cross-coupling reactions are widely used in the synthesis of compounds for pharmaceutical development and the like. For example, there are many reports on cross-coupling reactions using palladium catalysts for halogenated aryl groups (non-patent documents 1 to 3).

As one of side reactions in the cross-coupling reaction, dehalogenated products are known in which halogen atoms of a reaction substrate such as a halogenated aryl group are substituted with hydrogen atoms (non-patent document 1). There is a report that the formation of dehalogenation can be suppressed by changing the ligand or performing the reaction at a low temperature (non-patent document 2).

In addition, the following reports are reported: in the case of using a substrate containing a functional group having high sensitivity to alkali, for example, a carboxylate structure, etc., in the reaction, it is more preferable to use a P2Et phosphazene base as the base used in the reaction than to use an alkali metal base such as NaOtBu, liHMDS. (non-patent document 6).

There are reports on the influence of solvents in cross-coupling reactions using palladium catalysts (non-patent documents 4 and 5). In addition, regarding N, N-dimethyloctanoamide, an example of adding to a solvent in order to prevent a flow path from being blocked in fluid chemistry is reported (non-patent document 7).

Prior art literature

Patent literature

Patent document 1: US4,453,017

Patent document 2: japanese patent laid-open No. 2006-213692

Non-patent literature

Non-patent document 1: dorel, r.et al, angel.chem.int.ed.2019, 58, 17118.

Non-patent document 2: surry, d.s. et al chem. Sci.2011,2, 27.

Non-patent document 3: anderson, k.w. et al, j.am.chem.soc.2006, 128, 10694.

Non-patent document 4: shermwood, J.et al, green.chem.2019, 21, 2164.

Non-patent document 5: molina De La Torre, j.a.et al, organometallics 2013, 32, 5428.

Non-patent document 6: SANTANILLA, a.b. et al, organic Letters,2015, 17, 3370.

Non-patent document 7: yang, j.c.et al, angel.chem.int.ed.2016, 55, 2531.

Disclosure of Invention

Problems to be solved by the invention

Cross-coupling reactions using palladium catalysts are widely used in the synthesis of compounds such as drug discovery, and a large number of palladium catalysts have been developed. However, the inventors have confirmed that there are problems such as maintaining a low conversion rate and/or mass production of by-products in which the leaving group is replaced with hydrogen depending on the substrate, and there are problems that cannot be confirmed under conventional coupling conditions. For example, in a coupling-based carbon-nitrogen bond formation reaction using a halogenated aryl group and an amine as substrates, even if the conditions described in non-patent document 2 are used as references, problems such as reaction retention at a low conversion rate and significant formation of dehalogenated substances are generated when a specific substrate is used. In addition, in the synthesis of phenols by a carbon-oxygen bond formation reaction by coupling with a halogenated aryl group and water as a matrix, even if the conditions described in non-patent document 3 are used as references, the formation of impurities such as dehalogenation cannot be sufficiently suppressed in some matrices. Further, with reference to non-patent documents 4, 5 and 7, even if the reaction solvents described in the documents are used, the improvement effect cannot be obtained.

The present invention has been made in view of such a situation, and in one aspect, an object of the present invention is to provide a method for forming a carbon-oxygen bond or a carbon-nitrogen bond, which can improve conversion and/or suppress byproducts in a cross-coupling reaction using a palladium catalyst for a halogenated aryl group. In addition, in one aspect, the present invention aims to provide a method for synthesizing a compound comprising the above method. In another aspect, the present invention aims to provide a method for improving conversion and/or a method for inhibiting by-products such as dehalogenation, which can be applied to a cross-coupling reaction using a palladium catalyst for halogenated aryl groups.

Means for solving the problems

The present inventors have found that a specific solvent is used to exhibit preferable reactivity in a cross-coupling reaction using a palladium catalyst, and further found that the solvent can be applied to a carbon-oxygen bond (C-O bond) or a carbon-nitrogen bond (C-N bond) formation reaction, thereby completing the present invention. In one aspect, the invention discloses the following invention.

[ A-1] a method for producing a compound by a cross-coupling reaction, comprising a step of reacting a compound 1 having a leaving group X ¹ on a carbon atom of an aromatic ring with a compound 2 having a reactive group capable of undergoing a C-O bond formation reaction or a C-N bond formation reaction based on substitution with the leaving group in a solvent comprising an amide-based solvent represented by formula A in the presence of a catalyst and a base;

[ chemical formula 1]

[ Wherein R ¹、R² and R ³ are each independently a C _1-4 alkyl group, wherein the total number of carbon atoms of R ¹、R² and R ³ is 4 or more and 6 or less ],

X ¹ is a halogen atom or-O-SO ₂-R⁴;

R ⁴ is a C _1-6 alkyl group which may be substituted with 1 or more fluorine atoms, or a phenyl group which may be substituted with 1 or more fluorine atoms or a C _1-6 alkyl group which may be substituted with a fluorine atom;

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.

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

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

A-4 the method according to any one of [ A-1] to [ A-3], wherein the compound 1 has 1 or 2 or 3 leaving groups which may be the same or different.

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

A-6 the method according to any one of [ A-1] to [ A-5], wherein the compound 2 has 1 or 2 or 3 of the above-mentioned reactive groups, which may be the same or different.

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

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

The method according to any one of [ A-1] to [ A-8], wherein the compound 2 is:

1) Water, or a compound having a hydroxyl group capable of forming a C-O bond as shown in 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-to 10-membered heteroaryl group containing 1 or more ring heteroatoms independently selected from O, N and S, each of which may be substituted with 1 or more groups independently selected from 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, a 5-to 10-membered heteroarylcarbonylamino group containing 1 or more ring heteroatoms independently selected from O, N and S, (C _1-6 alkyl) aminocarbonyl, di (C _1-6 alkyl) aminocarbonyl, and 4-to 8-membered cyclic aminocarbonyl;

2) A compound having an H-N group capable of forming a C-N bond shown by HNR ⁶R⁷,

R ⁶ and R ⁷ together with the nitrogen atom to which they are bonded form a 5-to 7-membered saturated heterocyclic ring which may be substituted with 1 or more substituents independently selected from the group consisting of fluorine atom, cyano group, C _1-6 alkyl group, C _1-6 alkoxy group, (C _1-6 alkoxy) carbonyl group, (C _1-6 alkoxy) carbonylamino group, (C _1-6 alkyl) carbonylamino group, (C _6-10 aryl) carbonylamino group, 5-to 10-membered heteroarylcarbonylamino group comprising 1 or more ring heteroatoms independently selected from O, N and S, di (C _1-6 alkyl) amino group, 4-to 8-membered cyclic amino group, aminocarbonyl group, (C _1-6 alkyl) aminocarbonyl group, di (C _1-6 alkyl) aminocarbonyl group and 4-to 8-membered cyclic aminocarbonyl group,

Or alternatively

R ⁶ and R ⁷ are each independently a hydrogen atom, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _3-8 cycloalkyl group, a (C _1-6 alkyl) carbonyl group, a (C _6-10 aryl) carbonyl group, a 5-to 10-membered heteroarylcarbonyl group comprising 1 or more ring heteroatoms independently selected from O, N and S, a C _7-14 aralkyl group, a C _6-10 aryl group, or a 5-to 10-membered heteroaryl group comprising 1 or more ring heteroatoms independently selected from O, N and S, each of which may be substituted with 1 or more cyclic groups independently selected from 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 group, a 5-to 10-membered heteroarylcarbonylamino group comprising 1 or more ring heteroatoms independently selected from O, N and S, a di (C _1-6 alkyl) amino group, a 4-to 8-membered cyclic amino group, an aminocarbonyl group, a (C _1-6 alkyl) aminocarbonyl group, a di (C _1-6 alkyl) aminocarbonyl group, and a 4-to 8-membered cyclic amino group.

[ A-10] the method according to any one of [ A-1] to [ A-9], wherein the compound 1 is a compound represented by X ¹-Ar²,

X ¹ is a chlorine atom, a bromine atom, an iodine atom, or-O-SO ₂-R⁴;

ar ² is C _6-10 aryl, or a 5-to 10-membered heteroaryl group containing 1 or more ring heteroatoms independently selected from O, N and S, each of which may be substituted with 1 or more groups independently selected from 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-to 10-membered heteroarylcarbonylamino containing 1 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 alkyl) aminocarbonyl, and 4-to 8-membered cyclic aminocarbonyl.

A-11 the method according to any one of [ A-1] to [ A-10], wherein the compound 1 is supported on a resin for solid phase synthesis, and a compound represented by X ¹-Ar² in [ A-10] is contained in a part of the chemical structure.

A-12 the method according to any one of [ A-10] to [ A-11], wherein X ¹ is a chlorine atom, a bromine atom or an iodine atom.

[ A-13] the method according to any one of [ A-10] to [ A-12], wherein Ar ² is independently selected from phenyl, naphthyl, pyrrolyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, triallyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, indolyl, indolinyl, benzothienyl, benzofuranyl, benzisothiazolyl, benzisoxazolyl, indazolyl, benzimidazolyl, benzotriazole, azaindolyl and imidazopyridyl, each of which may be substituted.

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

A-15 the method according to any one of [ A-10] to [ A-14], wherein X ¹ is a bromine atom;

Ar ² is phenyl or pyridinyl, each of which may be substituted with 1 or more groups independently selected from 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-to 10-membered heteroarylcarbonylamino comprising 1 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 alkyl) aminocarbonyl and 4-to 8-membered cyclic aminocarbonyl.

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-diethylacetamide (DEAc) and N, N-diethylpropionamide (DEPr).

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

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

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

A process according to any one of [ A-1] to [ A-19], wherein the cross-coupling reaction is carried out at 0 to 200 ℃,0 to 150 ℃,0 to 100 ℃,10 to 80 ℃, or 25 to 80 ℃.

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

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

[ A-23] the method according to any one of [ A-1] to [ A-22], wherein the catalyst is a catalyst comprising a palladium complex represented by any one of the following general formulae (Cat 1), (Cat 2), (Cat 3), (Cat 4) and (Cat 5),

[ Chemical formula 2]

[ Wherein R ²⁰ is a hydrogen atom, a C _1-6 alkyl group, or a C _6-10 aryl group, R ² is a halogen or-O-SO ₂-CH₃,R²² is a hydrogen atom, a C _1-6 alkyl group which may be substituted with 1 or more fluorine atoms, or a (C _1-6 alkoxy) carbonyl group which may be substituted with a tri (C _1-6 alkyl) silyl group,

L is independently a monodentate ligand (L1), (L2), (L3), (L4), (L5), (L6) or (L7) of the formula, or 2L are bidentate ligands (L8), (L9), (L10), (L11) or (L12):

[ chemical formula 3]

[ Wherein R ²³ is independently t-butyl, cyclohexyl, 2-furyl, 2-thienyl, 2-pyridyl, phenyl (the phenyl group may be substituted with 1 or more fluorine atoms, C _1-6 alkyl group which may be substituted with a fluorine atom, C _1-6 alkoxy group, or dimethylamino group), or adamantyl,

R ²⁴ is C _1-6 alkyl, cyclohexyl, 2-furyl, 2-thienyl, 2-pyridyl, N-phenyl-2-pyrrolyl, N-phenyl-2-indolyl, phenyl (the phenyl may be substituted with 1 or more fluorine atoms, C _1-6 alkyl which may be substituted with fluorine atoms, C _1-6 alkoxy, morpholinyl, or dimethylamino), or adamantyl,

R ²⁵ is a hydrogen atom, a C _1-6 alkyl group, or a C _1-6 alkoxy group,

W ¹ is-C (CH ₃)₂ -, or-NH-,

R ²⁶、R²⁷、R²⁸ and R ²⁹ are each independently a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, or a morpholinyl group,

R ³⁰、R³¹ and R ³² are each independently a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, or a dimethylamino group,

R ³³ is a hydrogen atom, or-SO ₂ -O-M, M is lithium, sodium or potassium,

R ³⁴ is a hydrogen atom, a C _1-6 alkyl group, or a C _1-6 alkoxy group,

R ³⁵ and R ³⁶ are each independently a hydrogen atom, a C _1-6 alkyl group, or a C _1-6 alkoxy group,

R ³⁷ is a hydrogen atom, or a phenyl group which may be substituted by a C _1-6 alkyl group,

R ³⁸ is independently a hydrogen atom, phenyl which may be substituted by C _1-6 alkyl, or-CH (CH ₃)-N(CH₃)₂,

R ³⁹ is tert-butyl, cyclohexyl, or adamantyl,

R ⁴⁰ is a hydrogen atom or a C _1-6 alkyl group, and the arrow indicates a coordinate bond ] ].

[ A-24] the method according to any one of [ A-1] to [ A-22], wherein the catalyst is a catalyst comprising a palladium complex represented by the following general formula (Cat 6) and general formula (Cat 7),

[ Chemical formula 4]

[ Wherein R ⁴¹ is a hydrogen atom or a phenyl group which may be substituted with a C _1-6 alkyl group, R ⁴² is independently a halogen atom, R ⁴³ is a fluorine atom or a chlorine atom, L is an N-heterocyclic carbene ligand represented by the following general formula (L12) or (L13),

[ Chemical formula 5]

R ⁴⁴ and R ⁴⁵ are each independently C _1-6 alkyl, cyclohexyl, adamantyl, or phenyl (which phenyl may be substituted by more than 1C _1-6 alkyl, C _1-6 alkoxy or dimethylamino) with a carbon atom of ·· representing a carbene and an arrow representing a coordination bond.

[ A-25] the method according to any one of [ A-1] to [ A-22], wherein the catalyst is a catalyst comprising a palladium complex formed by combining a palladium compound selected from the group consisting of bis (allyl palladium (II) chloride), tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0) chloroform adduct, palladium chloride (pi-cinnamyl) dimer, (1-methallyl) palladium chloride dimer, (1, 5-cyclooctadiene) bis (trimethylsilylmethyl) palladium (II), (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) mesylate dimer and palladium (II) with a ligand selected from the group consisting of monodentate ligands (L1), (L2), (L3), (L4), (L5), (L6) or (L7) of the following general formulae, or bidentate ligands (L8), (L9), (L10), (L11) or (L12) or a ligand as a salt thereof,

[ Chemical formula 6]

[ Wherein R ²³ is tert-butyl, cyclohexyl, 2-furyl, 2-thienyl, 2-pyridyl, phenyl (the phenyl group may be substituted with 1 or more fluorine atoms, C _-6 alkyl group which may be substituted with a fluorine atom, C _1-6 alkoxy group, or dimethylamino group), or adamantyl,

R ²⁵ is a hydrogen atom, a C _1-6 alkyl group, or a C _1-6 alkoxy group,

W ¹ is-C (CH ₃)₂ -, or-NH-,

R ³³ is a hydrogen atom, or-SO ₂ -O-M, M is lithium, sodium or potassium,

R ³⁴ is a hydrogen atom, a C _1-6 alkyl group, or a C _1-6 alkoxy group,

R ³⁸ is a hydrogen atom, phenyl which may be substituted by C _1-6 alkyl, or-CH (CH ₃)-N(CH₃)₂,

R ³⁹ is tert-butyl, cyclohexyl, or adamantyl,

R ⁴⁰ is a hydrogen atom or a C _1-6 alkyl group, and the arrow represents a coordinate bond ].

The method according to any one of [ A-1] to [ A-23], wherein the catalyst is a catalyst comprising a palladium complex selected from Buchwald 1 st generation catalyst precursor (G1), buchwald 2 nd generation catalyst precursor (G2), buchwald 3 rd generation catalyst precursor (G3), buchwald 4 th generation catalyst precursor (G4), buchwald 5 th generation catalyst precursor (G5), and Buchwald 6 th generation catalyst precursor (G6).

[ A-27] the method according to [ A-25], wherein the above catalyst is a palladium catalyst comprising a combination of a compound represented by the general formula (II) bis (allyl palladium (II)), tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0) chloroform adduct, palladium chloride (pi-cinnamyl) dimer, (1-methallyl) palladium chloride dimer, (1, 5-cyclooctadiene) bis (trimethylsilylmethyl) palladium (II), (2 '-amino-1, 1' -biphenyl-2-yl) methane sulfonate palladium (II) dimer and palladium acetate palladium (II) with a ligand represented by the general formula (L1), (L3) or (L6) and a ligand as a ligand of the salt thereof,

[ Chemical formula 7 ]

[ Wherein R ²³ is independently t-butyl, cyclohexyl, or adamantyl,

R ²⁴ is C _1-6 alkyl, cyclohexyl, N-phenyl-2-indolyl, or adamantyl,

R ³⁰、R³¹ and R ³² are each independently a hydrogen atom, a C _1-6 alkyl group, a C _-6 alkoxy group, or a dimethylamino group,

R ³³ is a hydrogen atom, or-SO ₂ -O-M, M is lithium, sodium or potassium,

R ³⁷ is phenyl which may be substituted by C _1-6 alkyl ].

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

[ A-29] the method according to any one of [ A-1] to [ A-22] and [ A-28], wherein the catalyst is a catalyst comprising 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) trifluoromethane sulfonate, bis (trifluoromethane) 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' -bis (diphenylphosphino) ferrocene and 1, 3-bis (diphenylphosphino) propane.

The method according to any one of [ A-1] to [ A-22], [ A-28] and [ A-29], wherein the catalyst is a catalyst comprising a nickel complex selected from the group consisting of:

Dichloro bis (tricyclohexylphosphine) nickel (II),

Dichloro [1,1' -bis (diphenylphosphino) ferrocene ] nickel (II), and

Dichloro [1, 3-bis (diphenylphosphino) propane ] nickel (II).

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

A-32 the method according to any one of [ A-1] to [ A-31], wherein the base is selected from the group consisting of amidines, guanidines, phosphazenes, alkali metal carbonates, alkali metal phosphates, alkali metal C _1-6 alkoxides and alkali metal hydroxides.

A-33 according to any one of [ A-1] to [ A-32], wherein, the above base is selected from 2-tert-butyl-1, 3-tetramethylguanidine (BTMG), 7-methyl-1, 5, 7-triazabicyclo [4.4.0] dec-5-ene (MTBD) 1-ethyl-2, 4-penta (dimethylamino) -2λ ⁵,4λ⁵ -bis (phosphazene) (P2E), 1-tert-butyl-2, 4-penta (dimethylamino) -2λ ⁵,4⁵ -bis (phosphazene) (P2 tBu) tert-butylimino-tris (dimethylamino) phosphine (P1 tBu), 2-tert-butylimino-2-diethylamino-1, 3-dimethylperf-hydro-1, 3, 2-diaza-phosphorus (BEMP), tert-butylimino-tris (pyrrolidine) phosphine (BTPP), alkali metal carbonates, alkali metal phosphates, alkali metal C _1-6 alkoxides and alkali metal hydroxides.

[ A-34] the method according to any one of [ A-1] to [ A-33], wherein the base is selected from the group consisting of 2-t-butyl-1, 3-tetramethylguanidine (BTMG), 7-methyl-1, 5, 7-triazabicyclo [4.4.0] dec-5-ene (MTBD), 1-t-butyl-2, 4-penta (dimethylamino) -2λ ⁵,4λ⁵ -bis (phosphazene) (P2 tBu), t-butylimino-tris (dimethylamino) phosphine (P1 tBu), 2-t-butylimino-2-diethylamino-1, 3-dimethylperfhydro-1, 3, 2-diazaphosphorus (BEMP), t-butylimino-tris (pyrrolidine) phosphine (BTPP), cesium carbonate, tripotassium phosphate, potassium hydroxide and sodium t-butoxide.

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

[ 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, trifluoromethanesulfonyl imide, tetrafluoroboric acid, hexafluorophosphoric acid, and hexafluoroantimony (V) acid.

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

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

A-39 the method according to any one of [ A-1] to [ A-38], wherein a mixture comprising 2 or more compounds 1 is reacted.

A [ A-40] the method according to any one of [ A-1] to [ A-39], which is used for producing a compound constituting a compound library.

The method according to any one of [ A-1] to [ A-40], wherein 2 or more kinds of the compound 1 are a resin for solid phase synthesis supported via a linking group (Japanese term).

A-42 the method according to any one of [ A-1] to [ A-41], wherein 3 or more, 4 or more, 5 or more, 7 or more, or 10 or more of the compound 1 is a resin for solid phase synthesis supported via a linking group.

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

A-44 the method according to any one of [ A-1] to [ A-43], wherein the compound 1 is a resin for solid phase synthesis having a leaving group X ¹ on a carbon atom of an aromatic ring in a side chain or a resin for solid phase synthesis having a reactive group capable of undergoing a C-O bond formation reaction or a C-N bond formation reaction by substitution with the leaving group in a side chain.

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

[ B-2] the method according to [ B-1], wherein the compound 2 is water or a compound represented by 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-to 10-membered heteroaryl group containing 1 or more ring heteroatoms independently selected from O, N and S, each of which may be substituted with 1 or more groups independently selected from fluorine atom, cyano, C _1-6 alkyl, C _1-6 alkoxy, (C _1-6 alkoxy) carbonyl, (C _1-6 alkoxy) carbonylamino, aminocarbonyl, (C _1-6 alkyl) aminocarbonyl, di (C _1-6 alkyl) aminocarbonyl, and 4-to 8-membered cyclic aminocarbonyl.

[ B-3] the method according to [ B-2], wherein the compound 2 is supported on a solid phase synthesis resin and the compound represented by HO-R ⁵ is contained in a part of the chemical structure.

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

[ B-5] the method according to any one of [ B-1] to [ B-4], wherein the product of the coupling reaction is a compound represented by Ar ² -OH or Ar ²-OR⁵, or a compound containing a compound represented by Ar ² -OH or Ar ²-OR⁵ in a part of the chemical structure, ar ² and R ⁵ are as defined above.

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

[ C-2] the method according to [ C-1], wherein the compound 2 is a compound represented by HNR ⁶R⁷,

Or alternatively

R ⁶ and R ⁷ are each independently a hydrogen atom, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _3-8 cycloalkyl group, a (C _1-6 alkyl) carbonyl group, a (C _6-10) aryl group, a 5-to 10-membered heteroarylcarbonyl group containing 1 or more ring heteroatoms independently selected from O, N and S, a C _7-14 aralkyl group, a C _6-10 aryl group, or a 5-to 10-membered heteroaryl group containing 1 or more ring heteroatoms independently selected from O, N and S, each of which may be substituted with 1 or more substituents independently selected from fluorine atom, 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 alkyl) aminocarbonyl, and 4-to 8-membered cyclic aminocarbonyl.

[ C-3] the method according to [ C-1] or [ C-2], wherein the compound 2 is supported on a resin for solid phase synthesis, and a compound represented by HNR ⁶R⁷ is contained in a part of the chemical structure.

The method according to any one of [ C-1] to [ C-3], wherein the product of the coupling reaction is a compound represented by Ar ²-NR⁶R⁷ or a compound containing a compound represented by Ar ²-NR⁶R⁷ in a part of the chemical structure, ar ²、R⁶ and R ⁷ are as defined above.

A method for producing a compound according to [ D-1] which comprises 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 ].

[ E-1] use of a solvent comprising an amide-based solvent represented by formula A in a cross-coupling reaction,

[ Chemical formula 8 ]

[ Wherein R ¹、R² and R ³ are each independently a C _1-4 alkyl group, and wherein the total number of carbon atoms of R ¹、R² and R ³ is 4 to 6 inclusive ].

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

[ F-1] A method for producing a compound by a cross-coupling reaction in the presence of a palladium catalyst, comprising the step of performing the cross-coupling reaction in a solvent comprising an amide-based solvent represented by formula A in the presence of a palladium catalyst and a base,

[ Chemical formula 9 ]

[ Wherein R ¹、R² and R ³ are each independently a C _1-4 alkyl group, wherein the total number of carbon atoms of R ¹、R² and R ³ is 4 or more and 6 or less ], and the palladium catalyst is a palladium complex containing a phosphine ligand.

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

A method according to any one of [ F-1] and [ F-2], wherein the solvent is N, N-dimethylpropionamide (DMPr).

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

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

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

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

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

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

The method according to any one of [ F-1] to [ F-9], wherein the catalyst is a catalyst comprising a palladium complex selected from Buchwald 1 st generation catalyst precursor (G1), buchwald 2 nd generation catalyst precursor (G2), buchwald 3 rd generation catalyst precursor (G3), buchwald 4 th generation catalyst precursor (G4), buchwald 5 th generation catalyst precursor (G5), and Buchwald 6 th generation catalyst precursor (G6).

[ F-11] the method according to any one of [ F-1] to [ F-8], wherein the catalyst is a catalyst comprising a palladium complex formed by combining a palladium compound selected from the group consisting of bis (allyl palladium (II)) tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0) chloroform adduct, palladium chloride (pi-cinnamyl) dimer, (1-methallyl) palladium chloride dimer, (1, 5-cyclooctadiene) bis (trimethylsilylmethyl) palladium (II), (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) mesylate dimer and palladium (II) with a ligand selected from the group consisting of a monodentate ligand (L1), (L3) or (L6) of the general formula described in [ A-27], and a ligand as a salt thereof.

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

The method according to any one of [ F-1] to [ F-12], wherein the base is selected from the group consisting of amidines, guanidines, phosphazenes, alkali metal carbonates, alkali metal phosphates, alkali metal C _1-6 alkoxides and alkali metal hydroxides.

The method according to any one of [ F-1] to [ F-13], wherein, the above base is selected from 2-tert-butyl-1, 3-tetramethylguanidine (BTMG), 7-methyl-1, 5, 7-triazabicyclo [4.4.0] dec-5-ene (MTBD) 1-ethyl-2, 4-penta (dimethylamino) -2λ ⁵,4λ⁵ -bis (phosphazene) (P2E), 1-tert-butyl-2, 4-penta (dimethylamino) -2λ ⁵,4⁵ -bis (phosphazene) (P2 tBu) tert-butylimino-tris (dimethylamino) phosphine (P1 tBu), 2-tert-butylimino-2-diethylamino-1, 3-dimethylperf-hydro-1, 3, 2-diaza-phosphorus (BEMP), tert-butylimino-tris (pyrrolidine) phosphine (BTPP), alkali metal carbonates, alkali metal phosphates, alkali metal C _1-6 alkoxides and alkali metal hydroxides.

[ F-15] the method according to any one of [ F-1] to [ F-14], wherein the base is selected from the group consisting of 2-t-butyl-1, 3-tetramethylguanidine (BTMG), 7-methyl-1, 5, 7-triazabicyclo [4.4.0] dec-5-ene (MTBD), 1-t-butyl-2, 4-penta (dimethylamino) -2λ ⁵,4λ⁵ -bis (phosphazene) (P2 tBu), t-butylimino-tris (dimethylamino) phosphine (P1 tBu), 2-t-butylimino-2-diethylamino-1, 3-dimethylperfhydro-1, 3, 2-diazaphosphorus (BEMP), t-butylimino-tris (pyrrolidine) phosphine (BTPP), cesium carbonate, tripotassium phosphate, potassium hydroxide and sodium t-butoxide.

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

[ 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, trifluoromethanesulfonyl imide, tetrafluoroboric acid, hexafluorophosphoric acid, and hexafluoroantimony (V) acid.

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

The method according to any one of [ F-1] to [ F-18], wherein the cross-coupling reaction is a C-O bond formation reaction involving the detachment of the leaving group based on the compound 1 having a leaving group and the compound 2 having a hydroxyl group.

[ F-20] the method according to [ F-19], wherein the compound 1 is represented by X ¹-Ar², and X ¹ and Ar ² are as defined above.

[ F-21] the method according to [ F-19] or [ F-20], wherein the compound 2 is water or represented by HO-R ⁵, and R ⁵ is as defined above.

[ F-22] the method according to [ F-19] or [ F-20], wherein the compound 2 is supported on a resin for solid phase synthesis, and a compound represented by HO-R ⁵ is contained in a part of the chemical structure, and R ⁵ is as defined above.

[ F-23] the method according to any one of [ F-19] to [ F-22], wherein the product of the coupling reaction is a compound represented by Ar ² -OH or Ar ²-O-R⁵, or a compound containing a compound represented by Ar ² -OH or Ar ²-O-R⁵ in a part of the chemical structure, ar ² and R ⁵ are as defined above.

The method according to any one of [ F-1] to [ F-18], wherein the cross-coupling reaction is a C-N bond formation reaction involving the separation of the leaving group with the compound 1 having a leaving group and the compound 2 having H-N as a matrix.

[ F-25] the method according to [ F-24], wherein the compound 1 is represented by X ¹-Ar², and X ¹ and Ar ² are as defined above.

[ F-26] the method according to [ F-24] or [ F-25], wherein the compound 2 is represented by HNR ⁶R⁷, and R ⁶ and R ⁷ are as defined above.

[ F-27] the method according to [ F-24] or [ F-25], wherein the compound 2 is supported on a resin for solid phase synthesis, and a compound represented by HNR ⁶R⁷ is contained in a part of the chemical structure, and R ⁶ and R ⁷ are as defined above.

[ F-28] the method according to any one of [ F-24] to [ F-27], wherein the product of the coupling reaction is a compound represented by Ar ²-NR⁶R⁷ or a compound containing a compound represented by Ar ²-NR⁶R⁷ in a part of the chemical structure, ar ²、R⁶ and R ⁷ are as defined above.

A method according to any one of [ F-19] to [ F-28], wherein the compound 1 is carried on a resin for solid phase synthesis, and a compound represented by X ¹-Ar² is contained in a part of the chemical structure, and X ¹ and Ar ² are as defined above.

[ G-1] A method for inhibiting the production of by-products in a cross-coupling reaction, comprising the step of performing the cross-coupling reaction in a solvent comprising an amide-based solvent represented by formula A in the presence of a catalyst and a base,

[ Chemical formula 10 ]

The cross-coupling reaction is a substitution reaction of a leaving group X ¹ in the compound 1 having the leaving group X ¹ at a carbon atom of an aromatic ring, and the by-product is a compound obtained by substitution of the leaving group with a hydrogen atom.

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

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

A method according to any one of [ G-1] to [ G-3], wherein the compound 1 has 1 or 2 or 3 leaving groups which may be the same or different.

A method according to any one of [ G-1] to [ G-4], wherein the compound 1 has 1 leaving group.

The method according to any one of [ G-1] to [ G-5], wherein the compound 2 has 1 or 2 or 3 of the above-mentioned reactive groups, which may be the same or different.

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

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

The method according to any one of [ G-1] to [ G-8], wherein the compound 2 is:

Or alternatively

[ G-10] the method according to any one of [ G-1] to [ G-9], wherein the compound 1 is a compound represented by X ¹-Ar²,

X ¹ is a chlorine atom, a bromine atom, an iodine atom, or-O-SO ₂-R⁴;

Ar ² is C _6-10 aryl, or a 5-to 10-membered heteroaryl group containing 1 or more ring heteroatoms independently selected from O, N and S, each of which may be substituted with 1 or more groups independently selected from 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-to 10-membered heteroarylcarbonylamino containing 1 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 alkyl) aminocarbonyl and 4-to 8-membered cyclic aminocarbonyl,

The by-product is a compound shown as H-Ar ².

The method according to any one of [ G-1] to [ G-10], wherein the compound 1 is supported on a solid phase synthesis resin and the compound represented by X ¹-Ar² in [ G-10] is contained in a part of the chemical structure.

A method according to any one of [ G-10] to [ G-11], wherein X ¹ is a chlorine atom, a bromine atom or an iodine atom.

[ G-13] the method according to any one of [ G-10] to [ G-12], wherein Ar ² is independently selected from phenyl, naphthyl, pyrrolyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, triallyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, indolyl, indolinyl, benzothienyl, benzofuranyl, benzisothiazolyl, benzisoxazolyl, indazolyl, benzimidazolyl, benzotriazole, azaindolyl and imidazopyridyl, each of which may be substituted.

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

The method according to any one of [ G-10] to [ G-14], wherein X ¹ is a bromine atom;

Ar ² is phenyl or pyridinyl, each of which may be substituted with 1 or more groups independently selected from 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-to 10-membered heteroarylcarbonylamino containing 1 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 alkyl) aminocarbonyl, and 4-to 8-membered cyclic aminocarbonyl.

A process 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-diethylacetamide (DEAc) and N, N-diethylpropionamide (DEPr).

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

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

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

[ 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 ℃,0 to 150 ℃,0 to 100 ℃,10 to 80 ℃, or 25 to 80 ℃.

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

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

[ G-23] the method according to any one of [ G-1] to [ G-22], wherein the catalyst is a catalyst comprising a palladium complex represented by any one of the following general formulae (Cat 1), (Cat 2), (Cat 3), (Cat 4) and (Cat 5),

[ Chemical formula 11]

[ Wherein R ²⁰ is a hydrogen atom, a C _1-6 alkyl group, or a C _6-10 aryl group, R ²¹ is a halogen atom or a-O-SO ₂-CH₃,R²² group is a hydrogen atom, a C _1-6 alkyl group which may be substituted with 1 or more fluorine atoms, or a (C _1-6 alkoxy) carbonyl group which may be substituted with a tri-C _1-6 alkylsilyl group, L is independently a monodentate ligand (L1), (L2), (L3), (L4), (L5), (L6), or (L7) of the following general formula, or 2L is a bidentate ligand (L8), (L9), (L10), (L11), or (L12):

[ chemical formula 12]

R ²⁵ is a hydrogen atom, a C _1-6 alkyl group, or a C _1-6 alkoxy group,

W ¹ is-C (CH ₃)₂ -, or-NH-,

R ³³ is a hydrogen atom, or-SO ₂ -O-M, M is lithium, sodium or potassium,

R ³⁴ is a hydrogen atom, a C _1-6 alkyl group, or a C _1-6 alkoxy group,

R ³⁹ is tert-butyl, cyclohexyl, or adamantyl,

[ G-24] the method according to any one of [ G-1] to [ G-22], wherein the catalyst is a catalyst comprising a palladium complex represented by the following general formula (Cat 6) and general formula (Cat 7),

[ Chemical formula 13 ]

[ Chemical formula 14 ]

[ G-25] the method according to any one of [ G-1] to [ G-22], wherein the catalyst is a catalyst comprising a palladium complex formed by combining a palladium compound selected from the group consisting of bis (allyl palladium (II) chloride), tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0) chloroform adduct, palladium chloride (pi-cinnamyl) dimer, (1-methallyl) palladium chloride dimer, (1, 5-cyclooctadiene) bis (trimethylsilylmethyl) palladium (II), (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) mesylate dimer and palladium (II) with a ligand selected from the group consisting of monodentate ligands (L1), (L2), (L3), (L4), (L5), (L6) or (L7) of the following general formulae, or a ligand represented by bidentate ligand (L8), (L9), (L10), (L11) or (L12) or a ligand as a salt thereof,

[ Chemical formula 15 ]

R ²⁵ is a hydrogen atom, a C _1-6 alkyl group, or a C _1-6 alkoxy group,

W ¹ is-C (CH ₃)₂ -, or-NH-,

R ³³ is a hydrogen atom, or-SO ₂ -O-M, M is lithium, sodium or potassium,

R ³⁴ is a hydrogen atom, a C _1-6 alkyl group, or a C _1-6 alkoxy group,

R ³⁹ is tert-butyl, cyclohexyl, or adamantyl,

The method according to any one of [ G-1] to [ G-23], wherein the catalyst is a catalyst comprising a palladium complex selected from the group consisting of Buchwald 1 st generation catalyst precursor (G1), buchwald 2 nd generation catalyst precursor (G2), buchwald 3 rd generation catalyst precursor (G3), buchwald 4 th generation catalyst precursor (G4), buchwald 5 th generation catalyst precursor (G5), and Buchwald 6 th generation catalyst precursor (G6).

[ G-27] the method according to [ G-25], wherein the above catalyst is a palladium catalyst comprising a combination of a compound represented by the general formula (II) bis (allyl palladium (II)), tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0) chloroform adduct, palladium chloride (pi-cinnamyl) dimer, (1-methallyl) palladium chloride dimer, (1, 5-cyclooctadiene) bis (trimethylsilylmethyl) palladium (II), (2 '-amino-1, 1' -biphenyl-2-yl) methane sulfonate palladium (II) dimer and palladium acetate palladium (II) with a ligand represented by the general formula (L1), (L3) or (L6) and a ligand as a ligand of the salt thereof,

[ Chemical formula 16 ]

[ Wherein R ²³ is independently t-butyl, cyclohexyl, or adamantyl,

R ²⁴ is C _1-6 alkyl, cyclohexyl, N-phenyl-2-indolyl, or adamantyl,

R ³³ is a hydrogen atom, or-SO ₂ -O-M, M is lithium, sodium or potassium,

R ³⁷ is phenyl which may be substituted by C _1-6 alkyl ].

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

[ G-29] the method according to any one of [ G-1] to [ G-22] and [ G-28], wherein the catalyst is a catalyst comprising 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) trifluoromethane sulfonate, bis (trifluoromethane) 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' -bis (diphenylphosphino) ferrocene and 1, 3-bis (diphenylphosphino) propane.

The method according to any one of [ G-1] to [ G-22], [ G-28] and [ G-29], wherein the catalyst is a catalyst comprising a nickel complex selected from the group consisting of:

Dichloro bis (tricyclohexylphosphine) nickel (II),

Dichloro [1,1' -bis (diphenylphosphino) ferrocene ] nickel (II), and

Dichloro [1, 3-bis (diphenylphosphino) propane ] nickel (II).

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

The method according to any one of [ G-1] to [ G-31], wherein the base is selected from the group consisting of amidines, guanidines, phosphazenes, alkali metal carbonates, alkali metal phosphates, alkali metal C _1-6 alkoxides and alkali metal hydroxides.

[ G-33] the method according to any one of [ G-1] to [ G-32], wherein, the above base is selected from 2-tert-butyl-1, 3-tetramethylguanidine (BTMG), 7-methyl-1, 5, 7-triazabicyclo [4.4.0] dec-5-ene (MTBD) 1-ethyl-2, 4-penta (dimethylamino) -2λ ⁵,4λ⁵ -bis (phosphazene) (P2E), 1-tert-butyl-2, 4-penta (dimethylamino) -2λ ⁵,4⁵ -bis (phosphazene) (P2 tBu) tert-butylimino-tris (dimethylamino) phosphine (P1 tBu), 2-tert-butylimino-2-diethylamino-1, 3-dimethylperf-hydro-1, 3, 2-diaza-phosphorus (BEMP), tert-butylimino-tris (pyrrolidine) phosphine (BTPP), alkali metal carbonates, alkali metal phosphates, alkali metal C _1-6 alkoxides and alkali metal hydroxides.

[ G-34] the method according to any one of [ G-1] to [ G-33], wherein the base is selected from the group consisting of 2-t-butyl-1, 3-tetramethylguanidine (BTMG), 7-methyl-1, 5, 7-triazabicyclo [4.4.0] dec-5-ene (MTBD), 1-t-butyl-2, 4-penta (dimethylamino) -2λ ⁵,4λ⁵ -bis (phosphazene) (P2 tBu), t-butylimino-tris (dimethylamino) phosphine (P1 tBu), 2-t-butylimino-2-diethylamino-1, 3-dimethylperfhydro-1, 3, 2-diazaphosphorus (BEMP), t-butylimino-tris (pyrrolidine) phosphine (BTPP), cesium carbonate, tripotassium phosphate, potassium hydroxide and sodium t-butoxide.

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

[ 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, trifluoromethanesulfonyl imide, tetrafluoroboric acid, hexafluorophosphoric acid, and hexafluoroantimony (V) acid.

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

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

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

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

[ H-1] A method for producing a compound by a cross-coupling reaction, comprising the step of reacting a compound 1 having a leaving group X ¹ on a carbon atom of an aromatic ring with a compound 2 having a reactive group capable of undergoing a C-O bond formation reaction or a C-N bond formation reaction based on substitution with the leaving group in a solvent comprising an amide-based solvent represented by formula A in the presence of a catalyst and a base,

[ Chemical formula 17 ]

X ¹ is a halogen atom or-O-SO ₂-R⁴;

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;

The compound 1 is a resin for solid phase synthesis having a leaving group X ¹ on a carbon atom of an aromatic ring in a side chain, or a resin for solid phase synthesis having a reactive group capable of undergoing a c—o bond formation reaction or a c—n bond formation reaction based on substitution with the leaving group in a side chain.

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

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

The method according to any one of [ H-1] to [ H-3], wherein the compound 1 has 1 or 2 or 3 leaving groups which may be the same or different.

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

The method according to any one of [ H-1] to [ H-5], wherein the compound 2 has 1 or 2 or 3 of the above-mentioned reactive groups, which may be the same or different.

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

[ H-8] the method according to any one of [ H-1] to [ H-7], wherein a side chain of the resin for solid phase synthesis contains a decomposable linking group,

The method further comprises a step of cleaving out a compound containing a C-O bond or a C-N bond formed by the cross-coupling reaction from the resin for solid phase synthesis by decomposing the linking group after the cross-coupling reaction.

The method according to any one of [ H-1] to [ H-8], wherein the compound 2 is:

1) A resin for solid phase synthesis having a side chain bonded to a compound having a hydroxyl group capable of forming a C-O bond shown in HO-R ⁵ via a linking group,

2) A resin for solid phase synthesis having a side chain bonded to a compound having an H-N group capable of forming a C-N bond shown by HNR ⁶R⁷ via a linking group,

Or alternatively

[ H-10] the method according to any one of [ H-1] to [ H-9], wherein the compound 1 is a resin for solid phase synthesis having a side chain bonded to a compound represented by X ¹-Ar² via a linking group,

X ¹ is a chlorine atom, a bromine atom, an iodine atom, or-O-SO ₂-R⁴;

[ H-11] the method according to [ H-9] or [ H-10], wherein the compound 1 has a chemical structure capable of producing a compound represented by R⁵O-Ar²、HOAr²、R⁶R⁷N-Ar²、Ar¹-Ar²、R⁸R⁹R¹⁰C-Ar²、R¹³R¹⁴R¹⁵C-Ar² or R ¹⁶R¹⁷R¹⁸C-Ar² by decomposing a linking group contained in a side chain after the cross-coupling reaction.

The method according to any one of [ H-10] to [ H-11], wherein X ¹ is a chlorine atom, a bromine atom or an iodine atom.

[ H-13] the method according to any one of [ H-10] to [ H-12], wherein Ar ² is independently selected from phenyl, naphthyl, pyrrolyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, triallyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, indolyl, indolinyl, benzothienyl, benzofuranyl, benzisothiazolyl, benzisoxazolyl, indazolyl, benzimidazolyl, benzotriazole, azaindolyl and imidazopyridyl, each of which may be substituted.

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

[ H-15] the method according to any one of [ H-10] to [ H-14], wherein X ¹ is a bromine atom;

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-diethylacetamide (DEAc) and N, N-diethylpropionamide (DEPr).

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

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

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

[ H-20] the method according to any one of [ H-1] to [ H-19], wherein the cross-coupling reaction is performed at 0 to 200 ℃,0 to 150 ℃,0 to 100 ℃,10 to 80 ℃, or 25 to 80 ℃.

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

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

[ H-23] the method according to any one of [ H-1] to [ H-22], wherein the catalyst is a catalyst comprising a palladium complex represented by any one of the following general formulae (Cat 1), (Cat 2), (Cat 3), (Cat 4) and (Cat 5),

[ Chemical formula 18 ]

[ Wherein R ²⁰ is a hydrogen atom, a C _1-6 alkyl group, or a C _6-10 aryl group, R ²¹ is a halogen or-O-SO ₂-CH₃,R²² is a hydrogen atom, a C _1-6 alkyl group which may be substituted with 1 or more fluorine atoms, or a (C _1-6 alkoxy) carbonyl group which may be substituted with a tri (C _1-6 alkyl) silyl group,

[ chemical formula 19 ]

R ²⁵ is a hydrogen atom, a C _1-6 alkyl group, or a C _1-6 alkoxy group,

W ¹ is-C (CH ₃)₂ -, or-NH-,

R ³³ is a hydrogen atom, or-SO ₂ -O-M, M is lithium, sodium or potassium,

R ³⁴ is a hydrogen atom, a C _1-6 alkyl group, or a C _1-6 alkoxy group,

R ³⁹ is tert-butyl, cyclohexyl, or adamantyl,

[ H-24] the method according to any one of [ H-1] to [ H-22], wherein the catalyst is a catalyst comprising a palladium complex represented by the following general formula (Cat 6) and general formula (Cat 7),

[ Chemical formula 20 ]

[ Chemical formula 21 ]

[ H-25] the method according to any one of [ H-1] to [ H-22], wherein the catalyst is a catalyst comprising a palladium complex formed by combining a palladium compound selected from the group consisting of bis (allyl palladium (II) chloride), tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0) chloroform adduct, palladium chloride (pi-cinnamyl) dimer, (1-methallyl) palladium chloride dimer, (1, 5-cyclooctadiene) bis (trimethylsilylmethyl) palladium (II), (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) mesylate dimer and palladium (II) with a ligand selected from the group consisting of monodentate ligands (L1), (L2), (L3), (L4), (L5), (L6) or (L7) of the following general formulae, or a ligand represented by bidentate ligand (L8), (L9), (L10), (L11) or (L12) or a ligand as a salt thereof,

[ Chemical formula 22 ]

R ²⁵ is a hydrogen atom, a C _1-6 alkyl group, or a C _1-6 alkoxy group,

W ¹ is-C (CH ₃)₂ -, or-NH-,

R ³³ is a hydrogen atom, or-SO ₂ -O-M, M is lithium, sodium or potassium,

R ³⁴ is a hydrogen atom, a C _1-6 alkyl group, or a C _1-6 alkoxy group,

R ³⁹ is tert-butyl, cyclohexyl, or adamantyl,

The method according to any one of [ H-1] to [ H-23], wherein the catalyst is a catalyst comprising a palladium complex selected from Buchwald 1 st generation catalyst precursor (G1), buchwald 2 nd generation catalyst precursor (G2), buchwald 3 rd generation catalyst precursor (G3), buchwald 4 th generation catalyst precursor (G4), buchwald 5 th generation catalyst precursor (G5), and Buchwald 6 th generation catalyst precursor (G6).

[ H-27] the method according to [ H-25], wherein the above catalyst is a palladium catalyst comprising a combination of a palladium compound selected from the group consisting of bis (allyl palladium (II)), tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0) chloroform adduct, palladium chloride (pi-cinnamyl) dimer, (1-methallyl) palladium chloride dimer, (1, 5-cyclooctadiene) bis (trimethylsilylmethyl) palladium (II), (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) mesylate dimer and palladium (II) acetate, and a ligand selected from the group consisting of a ligand represented by the following general formula (L1), (L3) or (L6) and a ligand as a salt thereof,

[ Chemical formula 23 ]

[ Wherein R ²³ is independently t-butyl, cyclohexyl, or adamantyl,

R ²⁴ is C _1-6 alkyl, cyclohexyl, N-phenyl-2-indolyl, or adamantyl,

R ³³ is a hydrogen atom, or-SO ₂ -O-M, M is lithium, sodium or potassium,

R ³⁷ is phenyl which may be substituted by C _1-6 alkyl ].

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

[ H-29] the method according to any one of [ H-1] to [ H-22] and [ H-28], wherein the catalyst is a catalyst comprising 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) triflate, bis (trifluoromethanesulfonyl) 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' -bis (diphenylphosphino) ferrocene and 1, 3-bis (diphenylphosphino) propane.

The method according to any one of [ H-1] to [ H-22], [ H-28] and [ H-29], wherein the catalyst is a catalyst comprising a nickel complex selected from the group consisting of:

Dichloro bis (tricyclohexylphosphine) nickel (II),

Dichloro [1,1' -bis (diphenylphosphino) ferrocene ] nickel (II), and

Dichloro [1, 3-bis (diphenylphosphino) propane ] nickel (II).

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

The method according to any one of [ H-1] to [ H-31], wherein the base is selected from the group consisting of amidines, guanidines, phosphazenes, alkali metal carbonates, alkali metal phosphates, alkali metal C _1-6 alkoxides and alkali metal hydroxides.

[ H-33] the method according to any one of [ H-1] to [ H-32], wherein, the above base is selected from 2-tert-butyl-1, 3-tetramethylguanidine (BTMG), 7-methyl-1, 5, 7-triazabicyclo [4.4.0] dec-5-ene (MTBD) 1-ethyl-2, 4-penta (dimethylamino) -2λ ⁵,4λ⁵ -bis (phosphazene) (P2E), 1-tert-butyl-2, 4-penta (dimethylamino) -2λ ⁵,4⁵ -bis (phosphazene) (P2 tBu) tert-butylimino-tris (dimethylamino) phosphine (P1 tBu), 2-tert-butylimino-2-diethylamino-1, 3-dimethylperf-hydro-1, 3, 2-diaza-phosphorus (BEMP), tert-butylimino-tris (pyrrolidine) phosphine (BTPP), alkali metal carbonates, alkali metal phosphates, alkali metal C _1-6 alkoxides and alkali metal hydroxides.

[ H-34] the method according to any one of [ H-1] to [ H-33], wherein the base is selected from the group consisting of 2-t-butyl-1, 3-tetramethylguanidine (BTMG), 7-methyl-1, 5, 7-triazabicyclo [4.4.0] dec-5-ene (MTBD), 1-t-butyl-2, 4-penta (dimethylamino) -2λ ⁵,4λ⁵ -bis (phosphazene) (P2 tBu), t-butylimino-tris (dimethylamino) phosphine (P1 tBu), 2-t-butylimino-2-diethylamino-1, 3-dimethylperfhydro-1, 3, 2-diazaphosphorus (BEMP), t-butylimino-tris (pyrrolidine) phosphine (BTPP), cesium carbonate, tripotassium phosphate, potassium hydroxide and sodium t-butoxide.

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

[ 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, trifluoromethanesulfonyl imide, tetrafluoroboric acid, hexafluorophosphoric acid, and hexafluoroantimony (V) acid.

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

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

The method according to any one of [ H-1] to [ H-38], wherein a mixture comprising 2 or more compounds 1 is reacted.

The method according to any one of [ H-1] to [ H-39], wherein the method is used for producing a compound constituting a compound library.

The method according to any one of [ H-1] to [ H-40], wherein 2 or more kinds of compound 1 are solid phase synthesis resins supported via a linking group.

The method according to any one of [ H-1] to [ H-41], wherein 3 or more, 4 or more, 5 or more, 7 or more, or 10 or more of the compound 1 are solid phase synthetic resins supported via a linking group.

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

Effects of the invention

According to the present invention, there is provided a method for producing a compound based on a cross-coupling reaction using a palladium catalyst, which improves conversion and/or suppresses the production of by-products.

Detailed Description

In one aspect the invention relates to a method of manufacturing a compound by cross-coupling reactions. The cross-coupling reaction is not particularly limited, and examples thereof include a C-O bond formation reaction or a C-N bond formation reaction based on substitution with the leaving group.

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 may also be a catalyst precursor that converts 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. In the present specification, the catalyst includes 1 or more kinds of compounds such as an active species having catalytic activity, and a catalyst precursor that forms an active species in a reaction system.

In one embodiment of the invention, the cross-coupling reaction is carried out in the presence of a palladium catalyst. As the palladium catalyst, for example, a palladium compound or a palladium complex described in the present specification can be used. In the case of using a palladium catalyst, as a substrate for the C-O bond formation reaction, water, or alcohol, and a compound having a leaving group can be used. As a substrate for the C-N bond formation reaction, ammonia, primary amine, secondary amine may be used.

The palladium catalyst is not particularly limited as long as it is a palladium catalyst that can be used in a cross-coupling reaction in general. As the palladium catalyst, for example, palladium acetate, pd (dba) ₂、Pd₂(dba)₃、Pd₂(dba)₃CHCl₃, allyl palladium chloride dimer, palladium chloride (pi-cinnamyl) dimer, (1-methallyl) palladium chloride dimer, (1, 5-cyclooctadiene) bis (trimethylsilylmethyl) palladium (II), palladium (II) mesylate dimer, and the like can be used.

Ligands may also be used if desired. Examples of the ligand include trialkylphosphine (PCy ₃ (tricyclohexylphosphine), P (tBu) ₃ (tri-t-butylphosphine), di (1-adamantyl) -n-butylphosphine (cataCXium A), di-t-butylmethylphosphine ((tBu) ₂ PMe), triadamantane (P (Ad) ₃), di-t-butylneopentylphosphine (Neopentyl (tBu) ₂ P)), triarylphosphine (triphenylphosphine, tris (o-tolylphosphine) (P (o-Tol) ₃)), and the like.

Further, examples of the ligand include dialkylbiaryl phosphine such as XPhos (2-dicyclohexylphosphino-2 ',4',6 '-triisopropylbiphenyl), SPhos (2-dicyclohexylphosphino-2', 6 '-dimethoxybiphenyl), ruPhos (2-dicyclohexylphosphino-2', 6 '-diisopropyloxybiphenyl), 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-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) dicyclohexylphosphine), tBuDavePhos (2-di-tert-butylphosphino-2 ',4',6 '-triisopropylbiphenyl), CPhos (2-dicyclohexylphosphino-2' - (N, N-dimethylamino) biphenyl, GPhos (3- (tert-butoxy) -2',6' -diisopropylphosphine, 5, 4 '-dicyclohexyl-2' - (N, N-dimethylamino) biphenyl, 4-dicyclohexylphosphino-2 ',4' -dimethylamino-2-biphenyl). 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 number: 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-m-terphenyl) phosphine), and the like), monoalkylmonoaryl biaryl phosphine ((tBu) PhCPhos (2- [ (tert-butyl) phenylphosphino ] -2',6 '-bis (N, N-dimethylamino) biphenyl), diaryl biaryl phosphine (PhCPhos (2-diphenylphosphino-2', 6 '-bis (N, N-dimethylamino) biphenyl), bis (3, 5-bis (trifluoromethyl) phenyl) (2', 6 '-bis (dimethylamino) -3, 6-dimethoxybiphenyl-2-phosphine, bis (3', 5-dimethoxy-2-phosphine), bis (3, 5-bis (3 ', 6-dimethoxy) -biphenyl, bis (3, 6-fluoro-3' -3-propoxy) -biphenyl, and the like JackiePhos (2- { bis [3, 5-bis (trifluoromethyl) phenyl ] phosphino } -3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl)), dialkylmonoaryl phosphine (APhos ((4- (N, N-dimethylamino) phenyl) di-t-butylphosphine), (tBu) ₂ PPh, morDalPhos (2-morpholinophenylbis (1-adamantyl) phosphine), trixiePhos (2- (di-t-butylphosphino) -1,1 '-binaphthyl), meCgPPh (1, 3,5, 7-tetramethyl-6-phenyl-2, 4, 8-trioxa-6-phospha-adamantane)), QPhos (1, 2,3,4, 5-pentamphenyl-1' - (di-t-butylphosphino) ferrocene), cataCXium PICy (2- (dicyclohexylphosphino) -1- (2, 4, 6-trimethylphenyl) -1H-imidazole), cyBippyPhos (5- (dicyclohexylphosphino) -1',3',5 '-triphenyl-1, 4' -bipyrazole), 56 (5- (di-t-butylphosphino) -1, 5 '-tri-phenyl-1', 35 '-bipyrazole), and adamantyl (1, 3, 5' -tri-phenyl-1 '-biphosphino) -1- [3, 4' -tri-t-butyl-6-phosphane ] -1- (3, 35 '-biphosphino) 2, 5' -t-butylphenyl) ferrocene, 3',5' -triphenyl-1 'H-1,4' -bipyrazole), cataCXium PtB (2- (di-t-butylphosphino) -1-phenyl-1H-pyrrole), cataCXium POMetB (2- (di-t-butylphosphino) -1- (2-methoxyphenyl) -1H-pyrrole), cataCXium PIntB (2- (di-t-butylphosphino) -1-phenyl-indole), and the like.

Further, as the ligand, there may be mentioned bidentate phosphine ligands such as dppf (1, 1 '-bis (phenylphosphino) ferrocene), dtbpf (1, 1' -bis (di-t-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), josiphos ((R) -1- [ (Sp) -2- (dicyclohexylphosphino) ferrocene) ethyl di-t-butylphosphine) and the like.

Further, as the ligand, there may be mentioned N-heterocyclic carbene (NHC) ligands such as IPr (1, 3-bis (2, 6-diisopropylphenyl) imidazol-2-ylidene), siPr (1, 3-bis (2, 6-diisopropylphenyl) imidazolidin-2-ylidene), IMes (1, 3-bis (2, 4, 6-trimethylphenyl) imidazol-2-ylidene), IPent (1, 3-bis (2, 6-di-3-pentylphenyl) imidazol-2-ylidene)) and the like.

In addition, the palladium catalyst may be a palladium complex known as a palladium catalyst precursor. As palladium catalyst precursor, buchwald generation 1 catalyst precursor (G1) can be used. Examples thereof include XPhos Pd G1, SPhos Pd G1, ruPhos Pd G1, brettPhos Pd G1, tBuXPhos Pd G1, and the like.

As palladium catalyst precursor, buchwald 2 nd generation catalyst precursor (G2) can be used. As an example thereof, XPhos Pd G2、SPhos Pd G2、RuPhos Pd G2、BrettPhos Pd G2、tBuXPhos Pd G2、CPhos Pd G2、DavePhos Pd G2、CyJohnPhs Pd G2、APhos Pd G2、(tBu)₂PPh Pd G2、MorDalPhos Pd G2、PCy₃ Pd G2、P(tBu)₃Pd G2、cataCXium A Pd G2、(tBu)₂PMe Pd G2、Neopentyl(tBu)₂P Pd G2、P(o-Tol)₃Pd G2、XantPhos Pd G2 and the like are given.

As palladium catalyst precursor, buchwald 3 rd generation catalyst precursor (G3) can be used. Examples thereof include catalog number ：804193)、tBuBrettPhos Pd G3、AdBrettPhos Pd G3、(tBu)PhCPhos Pd G3、PhCPhos Pd G3、APhos Pd G3、(tBu)₂PPh Pd G3、MorDalPhos Pd G3、PCy₃Pd G3、P(tBu)₃Pd G3、cataCXium A Pd G3、(tBu)₂PMe Pd G3、Neopentyl(tBu)₂P Pd G3、P(o-Tol)₃Pd 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 of 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、Me₄tBuXPhos Pd G3、Me₃(OMe)tBuXPhos Pd G3(Sigma-Aldrich, and any solvent may be blended.

As palladium catalyst precursor, buchwald 4 th generation catalyst precursor (G4) may be used. Examples thereof include 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、(tBu)PhCPhos Pd G4、 methanesulfonate (2-bis (3, 5-bis (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)₂PPh Pd G4、MorDalPhos Pd G4、PCy₃ Pd G4、P(tBu)₃Pd G4、cataCXium A Pd G4、(tBu)₂PMe Pd G4、Neopentyl(tBu)₂P Pd G4、meCgPPh Pd G4、dppf Pd G4、BINAP Pd G4、Tol-BINAP Pd G4、XantPhos Pd G4、N-XantPhos Pd G4 and the like.

As palladium catalyst precursor, buchwald 5 th generation catalyst precursor (G5) may be used. Examples thereof include XPhos Pd G5, brettPhos Pd G5, SPhos Pd G, ruPhos Pd G, and the like.

As palladium catalyst precursor, buchwald 6 th generation catalyst precursor (G6) can be used. As an example thereof, tBuBrettPhos Pd G6 TES、tBuBrettPhos Pd G6 Br、AdBrettPhos Pd G6 Br、GPhos Pd G6 TES、AlPhos Pd G6 Br、AlPhos Pd G6 OTf and the like are given.

As palladium catalyst precursor, palladium (II) dichloride complex can be used. As an example thereof, Pd(PPh₃)₂Cl₂、Pd(PCy₃)₂Cl₂、Pd(dppf)Cl₂、Pd(dtbpf)Cl₂、(APhos)₂PdCl₂、(AdBippyPhos)₂PdCl₂ and the like are given.

As palladium catalyst precursor, palladium (0) complex can be used. Examples thereof include tetrakis (triphenylphosphine) palladium (0), bis (tricyclohexylphosphine) palladium (0), bis (tri-t-butylphosphine) palladium (0), and the like.

As palladium catalyst precursor, palladium (I) halide complexes can be used. Examples thereof include a bromine (tri-t-butylphosphine) palladium (I) dimer, an iodine (tri-t-butylphosphine) palladium (I) dimer, and the like.

As palladium catalyst precursor, a phosphine pi-allylpalladium catalyst may be used. As examples thereof, 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' -diisopropyloxy-1, 1' -biphenyl) palladium (II)), [ BrettPhos Pd (crotyl) ] OTf (crotyl (2-dicyclohexylphosphino-2 ',4',6' -triisopropyl-3, 6-dimethoxy-1, 1' -biphenyl) trifluoromethanesulfonic acid palladium (II)), [ tBuXPhos Pd (allyl) ] f (2-di-tert-butylphosphino-2 ',4',6' -triisopropyl-1 ' -biphenyl) trifluoromethanesulfonic acid, [ Broth (3, 6' -triisopropyl-1, 1' -biphenyl) ] Palladium (II)), [ Brethylphosphine (3 ',4' -triisopropyl-1, 1' -biphenyl) palladium (II)) AmPhos Pd (crotyl) Cl (chloro (crotyl) [ (P-dimethylaminophenyl) (di-t-butylphosphine) ] palladium (II)), P (Cy) 3Pd (crotyl) Cl (chloro (crotyl) (tricyclohexylphosphine) palladium (II)), [ P (tBu) 3] Pd (crotyl) Cl (tri-t-butylphosphine (chloro) (crotyl) palladium (II)), [ BINAP Pd (allyl) ] Cl ((R) -BINAP Pd (allyl) ] Cl; allyl [ (R) -2,2 '-bis (diphenylphosphino) -1,1' -binaphthyl ] palladium (II)), [ XantPhosPd (allyl) ] Cl (allyl [4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene ] palladium (II)) and the like.

As palladium catalyst precursor, PEPPSI catalyst may be used. Examples thereof include Pd-PEPPSI IPR, pd-PEPPSI SIPR ((1, 3-bis (2, 6-diisopropylphenyl) imidazolylidene) (3-chloropyridyl) palladium (II) dichloride), pd-PEPPSI IPENT (1, 3-bis (2, 6-di-3-pentylphenyl) imidazol-2-ylidene), and the like.

As palladium catalyst precursor, (NHC) Pd (allyl) Cl catalyst can be used. Examples thereof include allyl [1, 3-bis (2, 6-diisopropylphenyl) imidazol-2-ylidene ] palladium (II) chloride, allyl [1, 3-bis (2, 6-diisopropylphenyl) -2-imidazolidinylidene ] palladium (II) chloride, and [1, 3-bis (2, 6-diisopropylphenyl) imidazol-2-ylidene ] palladium (II) chloride.

As palladium catalyst precursor, NHC-Pd naphthoquinone catalyst may be used. As an example thereof, 1, 3-bis (2, 6-diisopropylphenyl) imidazol-2-ylidene (1, 4-naphthoquinone) palladium (0) dimer and the like can be used as the precursor of the palladium catalyst.

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、Me₄tBuXPhos Pd G3、Me₃(OMe)tBuXPhos Pd G3、tBuBrettPhos Pd G3、AdBrettPhos Pd G3、(tBu)PhCPhos Pd G3、PhCPhos Pd G3、APhos Pd G3、(tBu)₂PPh Pd G3、MorDalPhos Pd G3、PCy₃ Pd G3、P(tBu)₃Pd G3、cataCXium A Pd G3、(tBu)₂PMe Pd G3、Neopentyl(tBu)₂P Pd G3、P(o-Tol)₃Pd 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 G4、DavePhos Pd G4、GPhos Pd G4、tBuDavePhos Pd G4、VPhos Pd G4、EPhos Pd G4、CyJohnPhos Pd G4、tBuBrettPhos Pd G4、(tBu)PhCPhos Pd G4、 methanesulfonate (2-bis (3, 5-bis (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)₂PPh Pd G4、MorDalPhos Pd G4、PCy₃Pd G4、P(tBu)₃Pd G4、cataCXium A Pd G4、(tBu)₂PMe Pd G4、Neopentyl(tBu)₂P 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(PCy₃)₂Cl₂、Pd(dppf)Cl₂、Pd(dtbpf)Cl₂、(APhos)₂PdCl₂、 bis (tricyclohexylphosphine) palladium (0), bis (tri-t-butylphosphine) palladium (0), pd-PEPPSI IPR, pd-PEPPSI SIPR, pd-PEPPI-IPent may be used as the precursor of the palladium catalyst, and RuPhos Pd G4、tBuXPhos Pd G4、RockPhos Pd G3、BrettPhos Pd G4、tBuBrettPhos Pd G4、AdBrettPhos Pd G3、AdBrettPhos Pd G6 Br、(tBu)PhCPhos Pd G4 may be particularly preferably used as the precursor of the palladium catalyst.

In one embodiment of the present invention, XPhos、SPhos、RuPhos、BrettPhos、tBuXPhos、CPhos、DavePhos、GPhos、tBuDavePhos、VPhos、JackiePhos、CyJohnPhos、RockPhos、Me₄tBuXPhos、Me₃(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)₂PPh、MorDalPhos、PCy3、P(tBu)₃、cataCXium A、(tBu)₂PMe、Neopentyl(tBu)₂P、QPhos、TrixiePhos、meCgPPh、dppf、dtbpf、cataCXium PICy、CyBippyPhos、BippyPhos、AdBippyPhos、cataCXium PtB、cataCXium POMetB、cataCXium PIntB, and in particular RuPhos、tBuXPhos、RockPhos、BrettPhos、tBuBrettPhos、AdBrettPhos、(tBu)PhCPhos、BippyPhos、AdBippyPhos、cataCXiumPIntB、meCgPPh, may be preferably used as a ligand of the palladium catalyst.

In one embodiment of the present invention, palladium acetate, pd (dba) ₂、Pd₂(dba)₃、Pd₂(dba)₃CHCl₃, allyl palladium chloride dimer, palladium chloride (pi-cinnamyl) dimer, (1-methallyl) palladium chloride dimer, (1, 5-cyclooctadiene) bis (trimethylsilylmethyl) palladium (II) and palladium (II) mesylate dimer may be used as the palladium catalyst, and in particular, pd ₂(dba)₃CHCl₃ may be preferably used as the palladium catalyst.

The number of equivalents of palladium catalyst used can be set appropriately by those skilled in the art. In one embodiment of the present invention, for example, the number of equivalents of the palladium catalyst may be set to 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 with respect to a compound having a leaving group such as a halogen atom (in this specification, compound 1 or a compound represented by X ¹-Ar²) as one of substrates for the cross-coupling reaction. The number of equivalents of the ligand used may be appropriately set by those skilled in the art, and for example, may be set to 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 with respect to the compound having a leaving group. The number of equivalents of the precursor of the catalyst to be used may be appropriately set by those skilled in the art, and for example, may be set to 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 with respect to the compound having a leaving group.

In one embodiment of the present invention, for example, the number of equivalents of the palladium catalyst may be set to 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 with respect to another substrate (in this specification, a compound also referred to as compound 2) which reacts with the above-mentioned compound having a leaving group in the cross-coupling reaction. The number of equivalents of the ligand to be used may be appropriately set by those skilled in the art, and for example, may be set to 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 with respect to the compound. The number of equivalents of the precursor of the catalyst to be used may be appropriately set by those skilled in the art, and for example, may be set to 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 with respect to the compound.

In one embodiment of the invention, the cross-coupling reaction is carried out in the presence of a nickel catalyst. As the nickel catalyst, for example, a nickel complex described in the present specification can be used. In the case of using a nickel catalyst, as a substrate for the C-O bond formation reaction, water, or alcohol, and a compound having a leaving group may be used. As a substrate for the C-N bond formation reaction, ammonia, primary amine, secondary amine may be used.

The nickel catalyst is not particularly limited as long as it is a nickel catalyst that can be used in a cross-coupling reaction in general. Examples of the nickel catalyst include bis (1, 5-cyclooctadiene) nickel, dichloro (1, 2-dimethoxyethane) nickel, dibromo (1, 2-dimethoxyethane) nickel, nickel (II) chloride, nickel (II) bromide, nickel (II) triflate, bis (trifluoromethanesulfonyl imide) nickel (II), nickel (II) acetylacetonate, and nickel (II) nitrate, and any water may be blended. In one embodiment of the present invention, a nickel catalyst formed of a combination of at least 1 selected from bis (1, 5-cyclooctadiene) nickel and nickel (II) chloride and at least 1 selected from tricyclohexylphosphine, 1' -bis (diphenylphosphino) ferrocene and 1, 3-bis (diphenylphosphino) propane may be used for the cross-coupling catalyst.

The number of equivalents of nickel catalyst used may be suitably set by those skilled in the art. In one embodiment of the present invention, for example, the number of equivalents of the nickel catalyst may be set to 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 with respect to a compound having a leaving group such as a halogen atom (in this specification, compound 1 or a compound shown by X ¹-Ar²) as one of substrates for the cross-coupling reaction. The number of equivalents of the ligand used may be appropriately set by those skilled in the art, and for example, may be set to 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 with respect to the compound having a leaving group. The number of equivalents of the precursor of the catalyst to be used may be appropriately set by those skilled in the art, and for example, may be set to 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 with respect to the compound having a leaving group.

In one embodiment of the present invention, for example, the number of equivalents of the nickel catalyst may be set to 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 with respect to another substrate (in this specification, a compound also referred to as compound 2) that reacts with the above-mentioned compound having a leaving group in the cross-coupling reaction. The number of equivalents of the ligand to be used may be appropriately set by those skilled in the art, and for example, may be set to 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 with respect to the compound. The number of equivalents of the precursor of the catalyst to be used may be appropriately set by those skilled in the art, and for example, may be set to 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 with respect to the compound.

In one aspect of the invention, the cross-coupling reaction may use compound 1 having a leaving group X ¹ on a carbon atom of an aromatic ring as a substrate. The aromatic ring is not particularly limited as long as it has an aromatic cyclic chemical structure, and examples thereof include a C _6-10 aromatic carbocyclic ring and a 5-to 10-membered aromatic heterocyclic ring containing 1 or more ring heteroatoms independently selected from O, N and S. Leaving group X ¹ contains more than 1 in compound 1, for example, compound 1 may have 1 to 10, 1 to 5, or 1 to 3 leaving groups. In the case where a plurality of leaving groups X ¹ are contained in the compound 1, the leaving groups X ¹ may be the same or different. In addition, one aromatic ring may contain 1 or more carbon atoms having a leaving group X ¹, and compound 1 may contain 1 or more aromatic rings containing 1 or more leaving groups X ¹. In one embodiment, compound 1 comprises 1 leaving group X ¹.

In one embodiment of the invention, the leaving group X ¹ is a halogen atom or-O-SO ₂-R⁴. In a preferred form, leaving group X ¹ is a bromine atom or a chlorine atom, and in a more preferred form leaving group X ¹ is a bromine atom.

As the compound for cross-coupling with the compound 1, a compound 2 having a hydroxyl group capable of forming a c—o bond or an h—n group capable of forming a c—n bond can be used. In one aspect of the present invention, compound 2 has 1 or more reactive groups selected from a hydroxyl group capable of forming a c—o bond and an h—n group capable of forming a c—n bond. In the case where the reactive group is plural, they may be the same or different. In one embodiment, compound 1 comprises 1 reactive group.

In one aspect of the present invention, compound 2 is a compound having a hydroxyl group capable of forming a c—o bond, and water and alcohol can be exemplified. As the alcohol, a compound represented by HO-R ⁵ can be exemplified. Here, 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-to 10-membered heteroaryl group containing 1 or more ring heteroatoms independently selected from O, N and S, each of which may be substituted with 1 or more groups independently selected from 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, a 5-to 10-membered heteroarylcarbonylamino group containing 1 or more ring heteroatoms independently selected from O, N and S, aminocarbonyl, (C _1-6 alkyl) aminocarbonyl, di (C _1-6 alkyl) aminocarbonyl, and 4-to 8-membered cyclic aminocarbonyl.

In one embodiment of the present invention, the compound shown in HO-R ⁵ may be used as a cross-coupled matrix. In another mode of the present invention, a compound containing the chemical structure of the compound shown by HO-R ⁵ in the molecule can be used as a cross-coupled matrix. In one embodiment, the compound having the chemical structure of the compound shown by HO-R ⁵ in the molecule does not contain reactive groups other than those derived from HO-R ⁵.

In one embodiment of the present invention, a solid phase synthesis resin having 1 or more compounds represented by HO-R ⁵ or 1 or more compounds having a chemical structure including a compound represented by HO-R ⁵ in a molecule, which is supported via a linking group, may be used as a cross-coupled substrate. The term "supported" as used herein means that the compound is bonded via a linking group. Therefore, in the above-described mode, a resin for solid phase synthesis having a side chain to which the compound is bonded via a linking group can be used as a cross-coupled substrate.

In one aspect of the present invention, the compound 2 is a compound having an h—n group capable of forming a c—n bond, and examples thereof include ammonia and amines. As amines, compounds shown by HNR ⁶R⁷ can be exemplified. Here, R ⁶ and R ⁷ form, together with the nitrogen atom to which they are bonded, a 5-to 7-membered saturated heterocyclic ring which may be substituted with 1 or more substituents independently selected from the group consisting of fluorine atom, cyano group, C _1-6 alkyl group, C _1-6 alkoxy group, (C _1-6 alkoxy) carbonyl group, (C _1-6 alkoxy) carbonylamino group, (C _1-6 alkyl) carbonylamino group, (C _6-10 aryl) carbonylamino group, 5-to 10-membered heteroarylcarbonylamino group containing 1 or more ring hetero atoms independently selected from O, N and S, di (C _1-6 alkyl) amino group, 4-to 8-membered cyclic amino group, aminocarbonyl group, (C _1-6 alkyl) aminocarbonyl group, di (C _1-6 alkyl) aminocarbonyl group and 4-to 8-membered cyclic aminocarbonyl group,

Or alternatively

In one embodiment of the present invention, a compound shown as HNR ⁶R⁷ may be used as a cross-coupled matrix. In another mode of the present invention, a compound containing the chemical structure of the compound shown by HNR ⁶R⁷ in the molecule can be used as a cross-coupled substrate. In one embodiment, the compound having the chemical structure of the compound shown by HNR ⁶R⁷ in the molecule does not contain reactive groups other than those derived from HNR ⁶R⁷.

In one embodiment of the present invention, a solid phase synthesis resin carrying 1 or more compounds represented by HNR ⁶R⁷ or 1 or more compounds having a chemical structure including a compound represented by HNR ⁶R⁷ in a molecule via a linking group may be used as a cross-coupled substrate. The term "supported" as used herein means that the compound is bonded via a linking group. Therefore, in the above-described mode, a resin for solid phase synthesis having a side chain to which the compound is bonded via a linking group can be used as a cross-coupled substrate.

In the present specification, the "5-to 7-membered saturated heterocyclic ring formed by R ⁶ and R ⁷ together with the nitrogen atom to which they are bonded" is not particularly limited as long as it is a 5-to 7-membered saturated heterocyclic ring containing nitrogen, and may be, for example, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, azepane, diazacycloheptane, triazepane, or the like. The heterocycle may have a substituent.

In one aspect of the present invention, the cross-coupling reaction is carried out in a solvent comprising an amide-based solvent of formula A,

[ Chemical formula 24 ]

[ Wherein R ¹、R² and R ³ are each independently a C _1-4 alkyl group, and wherein the total number of carbon atoms of R ¹、R² and R ³ is 4 to 6 inclusive ]. Specifically, N-ethyl-N-methylacetamide, N-diethylacetamide, N-methyl-N-propylacetamide, N-ethyl-N-propylacetamide, N-methyl-N-butylacetamide, N-dimethylpropionamide, N-ethyl-N-methylpropionamide, N, N-diethylpropionamide, N-methyl-N-propylpropionamide, N-ethyl-N-methylbutanamide, N-dimethylbutyrylamide, N-diethylbutyramide, N-dimethylisobutyramide, N-ethyl-N-methylisobutylamide, or N, N-diethylisobutyramide.

In a preferred embodiment of the present invention, the amide-based solvent is N, N-dimethylpropionamide, N-diethylacetamide, or N, N-diethylpropionamide. In one embodiment, a mixed solvent containing 2 or more amide solvents represented by formula a is used as a solvent for the cross-coupling reaction. In one embodiment, 1 solvent selected from amide solvents represented by formula a is used as a solvent for the cross-coupling reaction. In one embodiment, a solvent containing an amide-based solvent represented by formula A of 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 the solvent for the cross-coupling reaction.

The reaction temperature may be appropriately set by those skilled in the art, and may be, for example, 0 to 200 ℃, 0 to 150 ℃, 0 to 100 ℃, 10 to 80 ℃, or 25 to 80 ℃.

In one aspect of the invention, a base may be used in the cross-coupling reaction. The base may be a base commonly used for cross-coupling reactions, or may be a mixture of various bases. In one embodiment, the base is selected from an organic base having a pKa of 23 or more of the conjugate acid in acetonitrile and an inorganic base having a pKa of 9 to 20 of the conjugate acid in water. Examples of the base 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-dimethylaniline, P1-tBu, and P2 tBu. In one of the ways in which the present invention may be used, the base is selected from 2-tert-butyl-1, 3-tetramethylguanidine (BTMG), 7-methyl-1, 5, 7-triazabicyclo [4.4.0] dec-5-ene (MTBD) 1-ethyl-2, 4-penta (dimethylamino) -2λ ⁵,4λ⁵ -di (phosphazene) (P2 Et), 1-tert-butyl-2, 4-penta (dimethylamino) -2λ ⁵,4λ⁵ -di (phosphazene) (P2 tBu) tert-butylimino-tris (dimethylamino) phosphine (P1 tBu), 2-tert-butylimino-2-diethylamino-1, 3-dimethylperf-hydro-1, 3, 2-diaza-phosphorus (BEMP), tert-butylimino-tris (pyrrolidine) phosphine (BTPP), alkali metal carbonates, alkali metal phosphates, alkali metal C _1-6 alkoxides and alkali metal hydroxides. The number of equivalents of the base to be used may be appropriately set by those skilled in the art, and for example, may be 1 to 100 equivalents, 1 to 75 equivalents, 1 to 50 equivalents, 1 to 30 equivalents, or 1 to 10 equivalents with respect to the carboxylic acid containing A.

The reaction time of the cross-coupling reaction may be set appropriately by those skilled in the art, for example, in the range of 1 minute to 96 hours, 5 minutes to 72 hours, 10 minutes to 48 hours, 15 minutes to 48 hours, or 30 minutes to 24 hours.

In the present specification, examples of the aromatic ring include a 5-to 10-membered monocyclic or condensed ring aromatic ring, or a C _6-10 -to 10-membered heteroaromatic ring containing 1 or more ring heteroatoms independently selected from O, N and S, and examples thereof 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, an imidazopyridine ring, and the like.

In the present specification, as the C _6-10 aryl group, phenyl and naphthyl are exemplified. Further, as the 5-to 10-membered heteroaryl group containing 1 or more ring heteroatoms independently selected from O, N and S, there may be exemplified a pyrrolyl group, a thienyl group, a furyl group, a pyridyl group, a thiazolyl group, an isothiazolyl group, a pyrazolyl group, an oxazolyl group, an isoxazolyl group, an imidazolyl group, a triallyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group, a quinolyl group, an isoquinolyl group, a 4H-quinolizinyl group, a phthalazinyl group, a naphthyridinyl group, a quinoxalinyl group, a quinazolinyl group, a cinnolinyl group, a pteridinyl group, an indolyl group, an indolinyl group, a benzothienyl group, a benzofuryl group, a benzisothiazolyl group, a benzisoxazolyl group, an indazolyl group, a benzimidazolyl group, a benzotriazole group, an azaindolyl group, an imidazopyridyl group, and the like.

In the present specification, the C _1-6 alkyl group is a linear or branched 1-valent saturated aliphatic group having 1 to 6 carbon atoms. Specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-methylpropyl, n-pentyl, isopentyl, 2-methylbutyl, 1-dimethylpropyl, 1-ethylpropyl, hexyl, 4-methylpentyl, 2-ethylbutyl and the like are mentioned.

In the present specification, the C _1-4 alkyl group is a linear or branched 1-valent saturated aliphatic group having 1 to 4 carbon atoms. Specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-methylpropyl and the like are mentioned.

In the present specification, the C _2-6 alkenyl group is a chain or branched 1-valent group having 1 or more double bonds and having 2 to 6 carbon atoms. Examples thereof include vinyl (vinyl), 1-propenyl, 2-propenyl (allyl), propen-2-yl, and 3-butenyl (homoallyl (homoallyl)), and the like.

In the present specification, the C _2-6 alkynyl group means a linear or branched 1-valent group having 1 or more 3 bonds and having 2 to 6 carbon atoms, and includes, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl and the like.

In the present specification, a C _3-8 cycloalkyl group means a cyclic saturated aliphatic hydrocarbon group having 3 to 8 carbon atoms. Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

In the present specification, C _1-6 alkoxy means C _1-6 alkyl-O-group, where C _1-6 alkyl is as defined above. Specific examples include methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.

In the present specification, (C _1-6 alkoxy) carbonyl refers to a C _1-6 alkoxy-C (=o) -group, where C _1-6 alkoxy is as defined above.

In the present specification, (C _1-6 alkyl) carbonyl refers to C _1-6 alkyl-C (=o) -group, where C _1-6 alkyl is as defined above.

In the present specification, (C _1-6 alkoxy) carbonylamino "(C _1-6 alkoxy) carbonyl" is as defined above.

In this specification, "C _1-6 alkyl" of a (C _1-6 alkyl) amino group is defined as above.

In the present specification, "C _1-6 alkyl" of di (C _1-6 alkyl) amino group is defined as above, and may be the same or different.

In the present specification, the 4-to 8-membered cyclic amino group includes aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and the like, and is bonded through a nitrogen atom.

In this specification, "C _6-10 aryl" of a (C _6-10 aryl) carbonylamino group is as defined above.

In the present specification, a "5-to 10-membered heteroaryl group containing 1 or more ring heteroatoms independently selected from O, N and S" containing a 5-to 10-membered heteroarylcarbonylamino group independently selected from 1 or more ring heteroatoms in O, N and S is defined as above.

In the present specification, aminocarbonyl refers to-CONH ₂.

"C _1-6 alkyl" of a (C _1-6 alkyl) aminocarbonyl group is as defined above.

In the present specification, "C _1-6 alkyl" of di (C _1-6 alkyl) aminocarbonyl is defined as above, and may be the same or different.

In the present specification, a 4-to 8-membered cyclic amino group of a 4-to 8-membered cyclic aminocarbonyl group is as defined above, and a carbonyl group is bonded via a nitrogen atom.

In this specification, "C _6-10 aryl" of the (C _6-10 aryl) carbonyl group is defined as above.

In the present specification, "5-to 10-membered heteroaryl group containing 1 or more ring heteroatoms independently selected from O, N and S" comprising a 5-to 10-membered heteroarylcarbonyl group independently selected from 1 or more ring heteroatoms in O, N and S is defined as above.

In the present specification, "C _1-6 alkyl" of the tri (C _1-6 alkyl) silyl group is defined as above, and may be the same or different. Examples thereof include trimethylsilyl, triethylsilyl, and t-butyldimethylsilyl.

In the present specification, "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, or the like. In the present invention, when a halogen atom is a substituent such as an aryl group or a heteroaryl group, preferred halogen atoms include a fluorine atom, a chlorine atom and a bromine atom. In the present invention, when the halogen atom is a substituent of an alkyl group or a group (such as an alkoxy group, an alkenyl group, or an alkylthio group) some of which contain an alkyl group, a fluorine atom is preferable as the halogen atom. Specific examples of the group having a halogen atom as a substituent include trifluoromethyl, pentafluoroethyl, trifluoromethoxy, pentafluoroethoxy, trifluoromethylthio, pentafluoroethylthio and the like. Preferred halogen atoms as X ¹ are chlorine atoms, bromine atoms and iodine atoms.

Examples of the C _1-6 alkyl group which may be substituted with 1 or more fluorine atoms include trifluoromethyl.

In the present specification, the C _7-14 aralkyl group means an alkyl group substituted with an aryl group having 7 to 14 carbon atoms in total. Examples thereof include benzyl, 1-phenethyl, 2-phenethyl, 1-naphthylmethyl, 2-naphthylmethyl and the like.

In this specification, alkali metal refers to lithium, sodium, potassium, rubidium, cesium and francium. Examples of the alkali metal forming a salt such as an alkoxide or hydroxide include lithium, sodium and potassium.

In one aspect of the invention, the cross-coupling reaction is carried out in a reaction system that also includes a salt along with the base described above. 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, fluorine-substituted sulfonimide metal salts, and the like, and inorganic acid metal salts, particularly fluorine-containing boric acid metal salts, fluorine-containing phosphoric acid metal salts, and fluorine-containing antimonic acid metal salts, and the like. Examples of the metal salt include alkali metal salts. In embodiment 1 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, trifluoromethanesulfonyl imide, tetrafluoroboric acid, hexafluorophosphoric acid, and hexafluoroantimony (V) acid.

In one aspect of the present invention, the cross-coupling reaction may be performed using a resin for solid phase synthesis carrying either one of the compounds 1 or 2 as a matrix. In addition, in one aspect of the present invention, the resin for solid phase synthesis may be carried out using as a matrix any one of compounds 1 or 2 of 2 or more, 3 or more, 4 or more, 5 or more, 7 or more, or 10 or more, which is supported via a linking group. The solid phase synthesis resin used as the solid phase carrier is not particularly limited as long as it is a resin for solid phase synthesis that is generally used. Examples thereof include solid-phase carriers having any functional group such as carboxyl group, amino group, aminomethyl group, hydroxyl group, and hydroxymethyl group on polystyrene, in addition to carboxilic resin, CTC resin, trt resin, SASRIN resin, rink amide resin, palam resin, seiber amide resin, merrifield resin, wang resin, and 2- (4-bromomethylphenoxy) ethyl polystyrene. In addition, it is also possible to design to use any linking group that links these carriers to the compound 1 or 2 by covalent bond, and to be able to cleave between the linking group and the compound. The carrier is not particularly limited, and examples thereof include PEG (polyethylene glycol) and the like, in addition to polystyrene.

The method and reaction conditions for supporting the compound 1 or 2 on the resin for solid-phase synthesis can be appropriately set by those skilled in the art based on the methods described in the known literature and the like. The reaction conditions for cleaving out the compound from the solid phase synthesis resin can be appropriately set by those skilled in the art based on the chemical structure of the solid phase synthesis resin used. As the reagent for cleavage, for example, a bronsted acid having a pKa of 10 or less in water or any lewis acid may be used in addition to carboxylic acids such as hydrochloric acid and trifluoroacetic acid (TFA), fluoroalcohols such as 2, 2-Trifluoroethanol (TFE) and 1, 3-Hexafluoroisopropanol (HFIP). In one embodiment, a compound cleaved from a solid phase synthesis resin can be used as a screening compound for drug discovery.

In one aspect of the present invention, the cross-coupling reaction can be performed by using, as a substrate, either a solid-phase synthesis resin having a leaving group X ¹ on a carbon atom of an aromatic ring of a side chain as compound 1 or a solid-phase synthesis resin having a reactive group capable of undergoing a c—o bond formation reaction or a c—n bond formation reaction based on substitution with the leaving group as compound 2. In one aspect of the present invention, the resin for solid phase synthesis to which 2 or more, 3 or more, 4 or more, 5 or more, 7 or more or 10 or more different compounds are bonded may be used as a matrix. The solid phase synthesis resin used as the solid phase carrier is not particularly limited as long as it is a resin for solid phase synthesis that is generally used. Examples thereof include solid-phase carriers having any functional group such as carboxyl group, amino group, aminomethyl group, hydroxyl group, and hydroxymethyl group on polystyrene, in addition to carboxilic resin, CTC resin, trt resin, SASRIN resin, rink amide resin, palam resin, seiber amide resin, merrifield resin, wang resin, and 2- (4-bromomethylphenoxy) ethyl polystyrene. In addition, it is also possible to design to use any linking group that links these carriers to the compound 1 or 2 by covalent bond, and to be able to cleave between the linking group and the compound. The carrier is not particularly limited, and examples thereof include PEG (polyethylene glycol) and the like, in addition to polystyrene.

The method and reaction conditions for preparing a resin for solid phase synthesis having a side chain to which a predetermined compound is bonded via a linking group can be appropriately set by those skilled in the art based on the methods described in known documents and the like. The reaction conditions for cleaving out the compound from the solid phase synthesis resin can be appropriately set by those skilled in the art based on the chemical structure of the solid phase synthesis resin used. As the reagent for cleavage, for example, a bronsted acid having a pKa of 10 or less in water or any lewis acid may be used in addition to carboxylic acids such as hydrochloric acid and trifluoroacetic acid (TFA), fluoroalcohols such as 2, 2-Trifluoroethanol (TFE) and 1, 3-Hexafluoroisopropanol (HFIP). In one embodiment, a compound cleaved from a solid phase synthesis resin can be used as a screening compound for drug discovery.

The present invention will be described in more detail with reference to 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 well known methods. Unless otherwise indicated, reagents and solvents were of reagent quality or higher and were used as received from various commercial suppliers. The information on the palladium catalyst such as the obtained source and the catalog number is shown below.

[ Table 1]

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 is suitably used.

As the amino silica gel for column chromatography, biotage (registered trademark) SNAP channel NH2 (50 μm) or Biotage (registered trademark) SNAP CARTRIDGE KP-NH or the like is suitably used.

As the reversed phase silica gel for column chromatography, biotage (registered trademark) SNAP MLTRA C (25 μm) or Biotage (registered trademark) Sfaer C (30 μm) is suitably used.

¹H-NMR、¹³ The C-NMR spectrum was measured using Me ₄ Si as an internal standard, or not, and using ECP-400 (manufactured by JEOL Co.), agilent400-MR (manufactured by Agilent Technologies Co.), AVANCE3 Cryo-TCI, AVANCE3 400, AVANCE3 HD 400, AVANCE NEO 400, AVANCE3 HD 300, AVANCE3 300, AVANCE 2300 or AVANCE NEO 300 (manufactured by Bruker Co.), or the like (s=singlet, brs=broad singlet, d=doublet, t=triplet, q=quartet, dd=doublet, ddd=doublet, dt=doublet triplet, td=triplet, m=multiplet).

Unless otherwise specified, the reaction trace and purity measurement were carried out by measuring the retention time and mass analysis under the analysis conditions shown in the following table using 2020 (Shimadzu).

The following abbreviations are used in the examples.

[ Table 2]

[ Table 3]

[ Table 4]

The analytical conditions for LCMS are set forth in table LC01.

[ Table 5]

[ Table LC01]

The values detected in the positive mode are all described unless otherwise specified, as described in the M/z [ m+h ] ⁺ and (m+h) ⁺, which are described as analysis results of LCMS in examples. The% UV area in LCMS indicates the value at PDA (190-400 nm or 210-400 nm) unless otherwise specified. When a specific wavelength (for example, 299 nm) is described, UV area% at a wavelength ranging from +/-4nm around the described wavelength is described. The blank in the table indicates that the detection limit is not higher than the detection limit.

The expression "concentrating under reduced pressure" means that the solvent is removed by evaporation under reduced pressure by means of a rotary evaporator, a mechanical oil vacuum pump or a mechanical oil-free vacuum pump.

The expression "dried overnight under reduced pressure" means that the solvent is removed by evaporation under reduced pressure by means of a rotary evaporator, a mechanical oil vacuum pump or a mechanical oil-free vacuum pump.

The expressions "overnight" and "overnight" refer to about 8 to 14 hours unless otherwise specified, but are not limited thereto.

The solid phase reaction may be carried out in any suitable vessel, for example a glass vial which can be closed with a lid provided with a Teflon (registered trade mark) packing, a column provided with a frit filter and a suitable plug. The dimensions of the vessel are appropriately selected so that there is sufficient space for the resin to be effectively stirred, considering that there is sufficient space for the solvent and the possibility of some specific resins to be significantly swelled when treated with the organic solvent.

For stirring in the solid phase reaction, a suitable shaker (e.g., EYELA, MMS-320, MMS-220H, or AS ONE, myBL-100CS, or TAITEC, M.BR-104) or stirring device (combination of separable flask and centrifugal stirrer C-mix of Zhongcun scientific instruments, inc., sealing mixer UZU and AQUATECHS, inc.) is suitably used and is carried out at 50-200rpm to ensure adequate mixing of factors that are generally considered to be important for success of the reaction on the resin.

In order to monitor the progress of the reaction on the solid phase, it is necessary to collect the resin from the reaction vessel. At this time, about 10. Mu.L of the resin was collected by sucking it in such a manner as to be necessary to contain the resin, using a micropipette equipped with a pipette tip having a suitable length cut from the tip, and transferred to a filter of a pipette tip with a filter (for example, thermo Scientific, tip with an ART filter ART20P, 2149P-05). Then, the compound supported on the resin was cut from the resin according to the following representative procedure for the resin on the filter. 3 washes with DMF (0.1 mL), 3 washes with MeOH (0.1 mL), 3 washes with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 2 min. After filtration, the solid phase was washed with DMF (0.05 mL), meCN (0.25 mL) was added to the filtrate, and LC samples were prepared and LCMS assay was performed, thereby determining the progress of the reaction.

The expression "cut out" from the solid phase means that the compound supported on the resin is separated from the resin, and means that the resin is treated with, for example, a 10% TFA/DCM solution containing 0.02M pentamethylbenzene, and the supported compound is recovered from the solution.

The compound numbers used in the examples are represented by any combination of letters and numbers and symbols. The compound in a state supported on a solid phase is provided with "R" at the end, and is represented by "A02-1R", for example. In contrast, the compound cleaved from the solid phase is denoted "A02" from which "-1R" is removed.

Used in the chemical structure representation in the examples

[ Chemical formula 25 ]

The label of (2) represents a polystyrene resin and represents a state in which the compound is supported on a solid phase.

The numbers in "-1R" representing the compounds supported on the solid phase used in the examples indicate the types of resins used.

Example of the marks of "-1R")

[ Chemical formula 26 ]

The solid-phase supported compound used in the solid-phase synthesis shows the amount of the compound (mmol/g) to be supported, which indicates the amount calculated assuming that 100% of the compound to be cut is supported on the solid phase.

Even when the solid-phase-supported compounds are the same, the amount to be supported may vary from batch to batch, but the same compound number may be used for the compound number.

Example 1: synthesis of Compounds used in the present specification

Examples 1-1-1: synthesis of tert-butyl 4- [4- [ [4- (4-ethoxycarbonylphenyl) phenoxy ] methyl ] phenoxy ] piperidine-1-carboxylate (Compound a 04)

[ Chemical formula 27 ]

To a 100mL three-necked flask under nitrogen atmosphere were added tert-butyl 4- [4- (hydroxymethyl) phenoxy ] piperidine-1-carboxylate (a 01,1.00g,3.25 mmol), triethylamine (0.499 mL,3.58 mmol) and DCM (16.3 mL), and the reaction vessel was cooled to 0deg.C. Methanesulfonyl chloride (0.266 mL,3.42 mmol) was added and stirred at 0deg.C for 3 hours. To the resulting mixture was added saturated aqueous sodium bicarbonate (4.9 mL). The organic layer was extracted 3 times with dichloromethane (24 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue (a 02), ethyl 4- (4-hydroxyphenyl) benzoate (a 03,0.866g,3.58 mmol), cesium carbonate (2.12 g,6.50 mmol) and NMP (12.0 mL) were mixed under nitrogen atmosphere in a 100mL three-necked flask and stirred at room temperature for 24 hours. To the resulting mixture were added saturated aqueous ammonium chloride (6 mL) and ethyl acetate (12 mL). After the organic layer was extracted 3 times with ethyl acetate (10 mL), the resulting organic layer was mixed, and hexane (20 mL) was added. The organic layer was washed 3 times with water (15 mL), 1 time with saturated aqueous sodium chloride (15 mL), and concentrated under reduced pressure. After the obtained residue was purified by silica gel column chromatography (NH-silica gel, 0-25% ethyl acetate/hexane), the obtained crude product was purified by silica gel column chromatography (NH-silica gel, 0-100% methylene chloride/hexane). The obtained crude product was dissolved in ethyl acetate (100 mL) and hexane (200 mL), washed 3 times with water (200 mL), washed 1 time with a saturated aqueous sodium chloride solution (100 mL), and concentrated under reduced pressure, whereby the title compound a04 (1.44 g,2.71mmol, 83%) was obtained as a white solid.

[ Chemical formula 28 ]

Compound a04

¹H-NMR(400MHz,CDCl₃)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).

LRMS：m/z 554[M+Na]⁺

Retention time: 1.684 minutes (analysis conditions FA05-1, 290 nm).

Examples 1-1-2: synthesis of ethyl 4- [4- [ (4-piperidin-4-yloxyphenyl) methoxy ] phenyl ] benzoate (Compound a 05)

[ Chemical formula 29 ]

To a 5mL screw cap vial under nitrogen was added tert-butyl 4- [4- [ [4- (4-ethoxycarbonylphenyl) phenoxy ] methyl ] phenoxy ] piperidine-1-carboxylate (a 04, 50.0mg, 94.0. Mu. Mol), N-diisopropylethylamine (29.5. Mu.L, 0.169 mmol) and THF (1.88 mL), and the reaction vessel was cooled to 0 ℃. Trimethylsilyl triflate (20.4. Mu.L, 0.113 mmol) was added and stirred at 0deg.C for 3 hours. N, N-diisopropylethylamine (2.95. Mu.L, 16.9. Mu. Mol) and trimethylsilyl triflate (2.0. Mu.L, 11. Mu. Mol) were added and stirred at 0℃for 1.5 hours. To the resulting mixture was added triethylamine (26.2 μl) at 0 ℃ and stirred at room temperature for 30 minutes. Water (847. Mu.L), DMSO (1 mL) and formic acid (12.1. Mu.L, 0.282 mmol) were added and purified by reverse phase column chromatography (C18, 0-60% 0.1% formic acid in acetonitrile/0.1% formic acid in water). The resultant product was dissolved in methylene chloride (100 mL), washed 3 times with saturated aqueous sodium bicarbonate (50 mL), washed 1 time with saturated aqueous sodium chloride (50 mL), and concentrated under reduced pressure, whereby the title compound a05 (19.8 mg,45.9mmol, 49%) was obtained as a white solid.

[ Chemical formula 30 ]

¹H-NMR(400MHz,CDCl₃)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).

LRMS：m/z 432[M+H]⁺

Retention time: 0.904 min (analysis conditions FA05-1, 290 nm).

Examples 1-2-1: synthesis of Compound A02-1R

[ Chemical formula 31 ]

Carboxylic Resin (A01-1R) (Chem-Impex, support 2.19mmol/g,1.00g,2.19 mmol) and NMP (15 mL) were added to a 20mL glass vial under nitrogen atmosphere and shaken at room temperature for 1 hour. Ethyl 4- [4- [ (4-piperidin-4-yloxyphenyl) methoxy ] phenyl ] benzoate (a 05) (0.106 g, 0.248 mmol) and piperidine (0.033 mL,0.329 mmol), HOAt (0.298 g,2.19 mmol), DIC (0.3411 mL,2.19 mmol) were added and the mixture was shaken at room temperature for 4 hours. Piperidine (1.30 mL,13.1 mmol) and HOAt (1.79 g,13.1 mmol), DIC (2.05 mL,13.1 mmol) were added and shaken overnight at room temperature.

Solid phase purification

The reaction solution and the suspension of the solid phase were all transferred to a filter, washed 3 times with NMP (20 mL), 3 times with MeOH (20 mL), 3 times with DCM (20 mL), and the resulting solid phase was dried under reduced pressure overnight to give Compound A02-1R (supported 0.200mmol/g,1.25g,0.250 mmol).

Reaction tracking

The suspension of reaction solution and solid phase (10. Mu.L) was transferred to a filter, washed 3 times with NMP (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.1M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with NMP (0.05 mL), meCN (0.25 mL) was added to the filtrate, and LC samples were prepared and LCMS measurement was performed, thereby measuring the progress of the reaction. As a result, the target a02 was observed to be 100%.

[ Chemical formula 32 ]

LRMS：m/z 243[M+H]⁺

Retention time: 1.085 minutes (analysis conditions FA05-1, 299 nm).

Examples 1-2-2: synthesis of Compound A03-1R

[ Chemical formula 33 ]

To a10 mL glass vial under nitrogen was added compound A02-1R (0.200 mmol/g,1.25g,0.250 mmol) and THF (7.2 mL), meOH (0.8 mL), aqueous sodium hydroxide (5M, 0.8mL,4.0 mmol), and the mixture was shaken at 60℃for 6 hours.

Solid phase purification

The reaction solution and the suspension of the solid phase were all transferred to a filter, washed 3 times with NMP (20 mL), 3 times with water (20 mL), 3 times with HOAt/NMP solution (0.2M, 20 mL), 3 times with NMP (20 mL), 3 times with MeOH (20 mL), 3 times with DCM (20 mL), and the resulting solid phase was dried under reduced pressure overnight to give Compound A03-1R (loading 0.201mmol/g,1.16g,0.232 mmol).

Reaction tracking

The suspension of reaction solution and solid phase (10. Mu.L) was transferred to a filter, washed 3 times with NMP (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.1M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with NMP (0.05 mL), meCN (0.25 mL) was added to the filtrate, and LC samples were prepared and LCMS measurement was performed, thereby measuring the progress of the reaction. As a result, the target a03 was observed to be 100%.

[ Chemical formula 34 ]

Maximum wavelength: 293nm

Retention time: 0.775 min (analysis conditions FA05-1, 299 nm).

Examples 1-2-3: synthesis of Compound A02-2R

[ Chemical formula 35 ]

To a 200mL empty column with a filter under nitrogen atmosphere were added carboxic Resin (A01-2R) (Chem-Impex, supported 1.70mmol/g,10.5g,17.9 mmol), ethyl 4- [4- [ (4-piperidin-4-yloxyphenyl) methoxy ] phenyl ] benzoate (a 05) (1.08 g,2.51 mmol), HOAt (2.43 g,17.9 mmol) and NMP (158 mL), and the mixture was 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 mixture 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 shaken overnight at room temperature.

Solid phase purification

The solid phase was washed 3 times with NMP (150 mL), 3 times with MeOH (150 mL), 3 times with DCM (150 mL), 3 times with heptane (150 mL), and the resulting solid phase was dried under reduced pressure overnight to give Compound A02-2R (loading 0.200mmol/g,12.8g,2.56 mmol).

A02-2R was washed 3 times with DCM (0.1 mL) and immersed in a 10% TFA/DCM solution (0.1 mL) containing 0.05M pentamethylbenzene for 5 min. After filtration, NMP (0.1 mL) was added to the filtrate. In this case, LCMS measurement of a diluted solution was performed by adding MeCN (0.25 mL) to 0.1mL, and thus 100% of the target a02 was observed.

[ Chemical formula 36 ]

LRMS：m/z 243[M+H]⁺

Retention time: 1.081 min (analysis conditions FA05-1, 299 nm).

Examples 1-2-4: synthesis of Compound A03-2R

[ Chemical formula 37 ]

To 200mL of the empty column with the filter under a nitrogen atmosphere were added compound A02-2R (supported 0.200mmol/g,12.8g,2.56 mmol) and NMP (134 mL), 2-methyl-2-butanol (38.4 mL), and the mixture was shaken at room temperature for 1 hour. Aqueous n-tetrabutylammonium hydroxide (1M, 6.40mL,6.40 mmol) was added and the mixture was shaken at room temperature for 14 hours.

Solid phase purification

The solid phase was washed 1 time with NMP (190 mL), 3 times with HOAt/NMP solution (0.1M, 190 mL), 3 times with NMP (190 mL), 3 times with MeOH (190 mL), 3 times with DCM (190 mL), 3 times with heptane (190 mL), and the resulting solid phase was dried under reduced pressure overnight to give Compound A03-2R (loading 0.201mmol/g,12.5g,2.50 mmol).

Reaction tracking

The suspension of reaction solution and solid phase (12. Mu.L) was transferred to a filter, washed 3 times with NMP (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 5 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), meCN (0.25 mL) was added to the filtrate, and LC samples were prepared and LCMS assay was performed, thereby determining the progress of the reaction. As a result, the target a03 was observed to be 100%.

[ Chemical formula 38 ]

Maximum wavelength: 294nm

Retention time: 0.767 min (analysis conditions FA05-1, 299 nm).

Examples 1-2-5: synthesis of Compound A02-3R

[ Chemical formula 39 ]

To 800mL of the empty column with the filter under nitrogen atmosphere were added carboxic Resin (A01-3R) (Rapp Polymer, supporting 1.70mmol/g,40.0g,68.0 mmol) and NMP (600 mL), and the mixture was shaken at room temperature for 1 hour. HOAt (9.26 g,68.0 mmol) and DIC (10.6 mL,68.0 mmol), ethyl 4- [4- [ (4-piperidin-4-yloxyphenyl) methoxy ] phenyl ] benzoate (a 05) (4.13 g,9.58 mmol) were added and the mixture was shaken at room temperature for 3.5 hours. HOAt (18.5 g,136 mmol) and DIC (21.2 mL,136 mmol), piperidine (16.8 mL,170 mmol) were added and shaken overnight at room temperature.

Solid phase purification

The reaction solution and the suspension of the solid phase were all transferred to a 2L separable flask, washed 3 times with NMP (800 mL), 3 times with MeOH (800 mL), 3 times with DCM (800 mL), 3 times with heptane (800 mL), and the resulting solid phase was dried under reduced pressure overnight to give Compound A02-3R (supported 0.200mmol/g,47.9g,9.58 mmol).

Reaction tracking

The suspension of reaction solution and solid phase (10. Mu.L) was transferred to a filter, washed 3 times with NMP (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and immersed in a 10% TFA/DCM solution (0.1 mL) containing 0.05M pentamethylbenzene for 5 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), meCN (0.25 mL) was added to the filtrate, and LC samples were prepared and LCMS assay was performed, thereby determining the progress of the reaction. As a result, the target a02 was observed to be 100%.

[ Chemical formula 40 ]

LRMS：m/z 243[M+H]⁺

Retention time: 1.081 min (analysis conditions FA05-1, 299 nm).

Examples 1-2-6: synthesis of Compound A03-3R

[ Chemical formula 41 ]

To a 2L separable flask, under a nitrogen atmosphere, compound A02-3R (supported 0.200mmol/g,47.9g,9.58 mmol) and NMP (503 mL) were added, and 2-methyl-butanol (144 mL) were stirred at room temperature for 1 hour. After cooling the suspension to 5 ℃, aqueous n-tetrabutylammonium hydroxide (1 m,14.4ml,144 mmol) was added dropwise and stirred at 25 ℃ for 3.5 hours. The procedure of adding dropwise n-tetrabutylammonium hydroxide aqueous solution (1M, 2.39mL,2.39 mmol) and stirring at room temperature for 1 hour was repeated twice.

Solid phase purification

The suspension of reaction solution and solid phase was washed 3 times with HOAt/NMP solution (0.1M, 800 mL), 3 times with NMP (800 mL), 3 times with MeOH (800 mL), 3 times with DCM (800 mL), 3 times with heptane (800 mL), and the resulting solid phase was dried under reduced pressure for 6 days to give Compound A03-3R (loading 0.201mmol/g,49.8g,10.0 mmol).

A03-3R was washed 3 times with DCM (0.05 mL) and immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 5 min. After filtration, LCMS measurement of the diluted solution was performed with DMF (0.05 mL) and MeCN (0.25 mL), whereby 100% of the target a03 was observed.

[ Chemical formula 42 ]

Maximum wavelength: 294nm

Retention time: 0.761 min (analysis conditions FA05-1, 299 nm).

Examples 1-2-7: synthesis of Compound A02-4R

[ Chemical formula 43 ]

To 800mL of the empty column with the filter under nitrogen atmosphere were added carboxic Resin (A01-4R) (carrying 1.70mmol/g,24.7g,42.0 mmol) and NMP (371 mL) and the mixture was shaken at room temperature for 45 minutes. HOAt (5.72 g,42.0 mmol) and DIC (6.55 mL,42.0 mmol), ethyl 4- [4- [ (4-piperidin-4-yloxyphenyl) methoxy ] phenyl ] benzoate (a 05) (2.56 g,5.93 mmol) were added and the mixture was shaken at room temperature for 4.5 hours. HOAt (11.5 g,84.0 mmol) and DIC (13.1 mL,84.0 mmol), piperidine (10.4 mL,105 mmol) were added and the mixture was shaken at room temperature for 21 hours.

Solid phase purification

The reaction solution was discharged from the column, the solid phase was washed 3 times with NMP (500 mL), 3 times with MeOH (500 mL), 3 times with DCM (500 mL), 3 times with heptane (500 mL), and the resulting solid phase was dried under reduced pressure overnight to give Compound A02-4R (supported 0.200mmol/g,30.5g,6.1 mmol).

A02-4R was washed 3 times with DCM (0.10 mL) and immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.2M pentamethylbenzene for 5 min. After filtration, LCMS measurement of the diluted solution was performed with DMF (0.05 mL) and MeCN (0.20 mL), whereby 100% of the target a03 was observed.

[ Chemical formula 44 ]

LRMS：m/z 243[M+H]⁺

Retention time: 1.071 min (analysis conditions FA05-1, 299 nm).

Examples 1-2-8: synthesis of Compound A03-4R

[ Chemical formula 45 ]

To 800mL of the empty column with the filter under a nitrogen atmosphere were added compound A02-4R (supported 0.200mmol/g,29.6g,5.92 mmol) and NMP (311 mL), 2-methyl-2-butanol (89 mL), and the mixture was stirred at room temperature for 1 hour. After cooling the suspension to 5℃an aqueous solution of n-tetrabutylammonium hydroxide (1M, 11.8m,118 mmol) was added dropwise and stirred at 25℃for 7.0 hours.

Solid phase purification

The suspension of reaction solution and solid phase was washed 3 times with HOAt/NMP solution (0.1M, 500 mL), 3 times with NMP (500 mL), 3 times with MeOH (500 mL), 3 times with DCM (500 mL), 3 times with heptane (500 mL), and the resulting solid phase was dried under reduced pressure for 4 days to give Compound A03-4R (supported 0.201mmol/g,30.6g,6.2 mmol).

A03-4R was washed 3 times with DCM (0.10 mL) and immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.2M pentamethylbenzene for 5 min. After filtration, LCMS measurement of the diluted solution was performed with DMF (0.05 mL) and MeCN (0.2 mL), whereby 99.9% of target a03 was observed.

[ Chemical formula 46 ]

Maximum wavelength: 294nm

Retention time: 0.775 min (analysis conditions FA05-1, 299 nm).

Examples 1-3-1: synthesis of Compound B01-1R

[ Chemical formula 47 ]

To a 5mL glass vial under nitrogen was added compound A03-1R (loading 0.201mmol/g,250mg,0.0502 mmol) and NMP (3.75 mL), 3-bromoaniline (b 01) (20. Mu.L, 0.19 mmol), HOAt (26 mg,0.19 mmol), DIC (29. Mu.L, 0.19 mmol), and the mixture was shaken at 60℃for 15 hours. 3-Bromoaniline (b 01) (41. Mu.L, 0.38 mmol), HOAt (51 mg,0.38 mmol), DIC (58. Mu.L, 0.38 mmol) were added and the mixture was shaken at 60℃for 4 hours.

Solid phase purification

The reaction solution and the suspension of the solid phase were all transferred to a filter, washed 3 times with NMP (5 mL), 1 time with NMP/meoh=1:1 (v/v, 5 mL), 3 times with MeOH (5 mL), 3 times with DCM (5 mL), and the resulting solid phase was dried under reduced pressure overnight to give compound B01-1R (supported 0.195mmol/g,248mg,0.0484 mmol).

Reaction tracking

The suspension of reaction solution and solid phase (20. Mu.L) was transferred to a filter, washed 3 times with NMP (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.1M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with NMP (0.05 mL), meCN (0.25 mL) was added to the filtrate, and LC samples were prepared and LCMS measurement was performed, thereby measuring the progress of the reaction. As a result, the target B01 was observed to be 100%.

[ Chemical formula 48 ]

LRMS：m/z 368、370[M+H]⁺

Retention time: 1.166 min (analysis conditions FA05-1, 299 nm).

Examples 1-3-2: synthesis of Compound B02-1R

[ Chemical formula 49 ]

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

B02-1R was immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.1M pentamethylbenzene for 2 minutes, and LCMS measurement of the filtrate after addition of NMP (0.05 mL), meCN (0.25 mL) and filtration was performed, whereby 100% of the objective B02 was observed.

[ Chemical formula 50 ]

LRMS：m/z 382、384[M+H]⁺

Retention time: 1.221 min (analysis conditions FA05-1, 299 nm).

Examples 1-3-3: synthesis of Compound B03-1R

[ Chemical formula 51 ]

To a 20mL empty column with a filter under nitrogen atmosphere, compound A03-1R (supported 0.201mmol/g,1.00g,0.201 mmol) and NMP (15 mL) were added, and the mixture was shaken at room temperature for 1 hour. 3-amino-5-bromopyridine (b 03) (70 mg,0.402 mmol), 1-methylimidazole (64. Mu.L, 0.804 mmol), and PyClU (134 mg,0.402 mmol) were added, and the mixture was stirred at room temperature for 1 hour. 3-amino-5-bromopyridine (b 03) (35 mg,0.201 mmol), 1-methylimidazole (32. Mu.L, 0.402 mmol), and PyClU (67 mg,0.201 mmol) were added, and the mixture was stirred at room temperature for 20 minutes.

Solid phase purification

The solid phase was washed 2 times with NMP (15 mL), 3 times with MeOH (15 mL), 3 times with DCM (15 mL), and the resulting solid phase was dried under reduced pressure overnight to give Compound B03-1R (0.195 mmol/g,1.04g,0.203 mmol).

Reaction tracking

The suspension of reaction solution and solid phase (10. Mu.L) was transferred to a filter, washed 3 times with NMP (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.1M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with NMP (0.1 mL). To the filtrate (50. Mu.L) was added MeCN (0.25 mL), and an LC sample was prepared and LCMS measurement was performed, thereby measuring the progress of the reaction. As a result, the target B03 was observed to be 100%.

[ Chemical formula 52 ]

LRMS：m/z 369、371[M+H]⁺

Retention time: 1.014 minutes (analysis conditions FA05-1, 299 nm).

Examples 1-3-4: synthesis of Compound B01-2R

[ Chemical formula 53 ]

Compound B01-2R (supported amount: 0.195 mmol/g) can be synthesized by the same method as that of compound B03-1R using compound A03-2R (supported amount: 0.201 mmol/g) and 3-bromoaniline (B01).

B01-2R was washed 3 times with DCM (0.1 mL) and immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.05M pentamethylbenzene for 5 min. After filtration, LCMS measurement of the diluted solution was performed with DMF (0.05 mL) and MeCN (0.25 mL), whereby 99.6% of target B01 was observed.

[ Chemical formula 54 ]

LRMS：m/z 368、370[M+H]⁺

Retention time: 1.161 minutes (analysis conditions FA05-1, 299 nm).

Examples 1-3-5: synthesis of Compound B02-2R

[ Chemical formula 55 ]

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

The B02-2R was washed 3 times with DCM (0.1 mL) and immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.05M pentamethylbenzene for 5 min. After filtration, LCMS measurement of a diluted solution with DMF (0.05 mL) and MeCN (0.25 mL) was performed, whereby 100% of the target B02 was observed.

[ Chemical formula 56 ]

LRMS：m/z 382、384[M+H]⁺

Retention time: 1.220 min (analysis conditions FA05-1, 299 nm).

Examples 1-3-6: synthesis of Compound B04-3R

[ Chemical formula 57 ]

Compound B04-3R (supported amount: 0.194 mmol/g) can be synthesized by the same method as compound B03-1R using compound A03-3R (supported amount: 0.201 mmol/g) and 5-bromo-2-methoxy-aniline (B04).

B04-3R was washed 3 times with DCM (0.1 mL) and immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.05M pentamethylbenzene for 5min. After filtration, LCMS measurement of the diluted solution was performed with DMF (0.05 mL) and MeCN (0.25 mL), whereby 99.5% of target B04 was observed.

[ Chemical formula 58 ]

LRMS：m/z398、400[M+H]⁺

Retention time: 1.228 minutes (analysis conditions FA05-1, 299 nm).

Examples 1-3-7: synthesis of Compound B05-2R

[ Chemical formula 59 ]

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

B05-2R was washed 3 times with DCM (0.1 mL) and immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.05M pentamethylbenzene for 5min. After filtration, LCMS measurement of the diluted solution was performed with DMF (0.05 mL) and MeCN (0.25 mL), whereby 99.2% of target B05 was observed.

[ Chemical formula 60 ]

LRMS：m/z 383、385[M+H]⁺

Retention time: 1.029 min (analysis conditions FA05-1, 299 nm).

Examples 1-3-8: synthesis of Compound B06-2R

[ Chemical formula 61 ]

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

B06-2R was washed 3 times with DCM (0.1 mL) and immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.05M pentamethylbenzene for 5 min. After filtration, LCMS measurement of the diluted solution was performed with DMF (0.05 mL) and MeCN (0.25 mL), whereby 99.6% of target B06 was observed.

[ Chemical formula 62 ]

LRMS：m/z 436、438[M+H]⁺

Retention time: 1.335 min (analysis conditions FA05-1, 299 nm).

Examples 1-3-9: synthesis of Compound B07-1R

[ Chemical formula 63 ]

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

Reaction tracking

The suspension of reaction solution and solid phase (10. Mu.L) was transferred to a filter, washed 3 times with NMP (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.1M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with NMP (0.1 mL). LCMS measurement of a solution diluted by adding MeCN (0.25 mL) to the filtrate (0.05 mL) was performed, whereby 96% of the target B07 was observed.

[ Chemical formula 64 ]

LRMS：m/z 424、426[M+H]⁺

Retention time: 1.396 min (analysis conditions FA05-1, 299 nm).

Examples 1-3-10: synthesis of Compound B08-3R

[ Chemical formula 65 ]

Compound B08-3R (supported amount: 0.197 mmol/g) can be synthesized by the same method as that of compound B03-1R using compound A03-3R (supported amount: 0.201 mmol/g) and 3-chloroaniline (B08).

B08-3R was washed 3 times with DCM (0.1 mL) and immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.05M pentamethylbenzene for 5 min. After filtration, LCMS measurement of the diluted solution was performed with DMF (0.05 mL) and MeCN (0.25 mL), whereby 100% of target B08 was observed.

[ Chemical formula 66 ]

LRMS：m/z 324[M+H]⁺

Retention time: 1.141 min (analysis conditions FA05-1, 299 nm).

Examples 1-3-11: synthesis of Compound B09-3R

[ Chemical formula 67 ]

Compound B09-3R (supported amount: 0.193 mmol/g) can be synthesized by the same method as compound B03-1R using compound A03-3R (supported amount: 0.201 mmol/g) and 3-iodoaniline (B09).

B09-3R was washed 3 times with DCM (0.1 mL) and immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.05M pentamethylbenzene for 5 min. After filtration, LCMS measurement of a diluted solution with DMF (0.05 mL) and MeCN (0.25 mL) was performed, whereby 100% of the target B09 was observed.

[ Chemical formula 68 ]

LRMS：m/z 416[M+H]⁺

Retention time: 1.192 min (analysis conditions FA05-1, 299 nm).

Examples 1-3-12: synthesis of Compound B10-3R

[ Chemical formula 69 ]

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

B10-3R was washed 3 times with DCM (0.1 mL) and immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.05M pentamethylbenzene for 5 min. After filtration, LCMS measurement of the diluted solution was performed with DMF (0.05 mL) and MeCN (0.25 mL), whereby 97.2% of target B10 was observed.

[ Chemical formula 70 ]

LRMS：m/z 386、388[M+H]⁺

Retention time: 1.164 min (analysis conditions FA05-1, 299 nm).

Examples 1-3-13: synthesis of Compound B11-3R

[ Chemical formula 71 ]

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

B11-3R was washed 3 times with DCM (0.1 mL) and immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.05M pentamethylbenzene for 5 min. After filtration, LCMS measurement of the diluted solution was performed with DMF (0.05 mL) and MeCN (0.25 mL), whereby 99.1% of target B11 was observed.

[ Chemical formula 72 ]

LRMS：m/z 386、388[M+H]⁺

Retention time: 1.165 minutes (analysis conditions FA05-1, 299 nm).

Examples 1-3-14: synthesis of Compound B12-3R

[ Chemical formula 73 ]

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

B12-3R was washed 3 times with DCM (0.1 mL) and immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.05M pentamethylbenzene for 5 min. After filtration, LCMS measurement of a diluted solution with DMF (0.05 mL) and MeCN (0.25 mL) was performed, whereby 100% of target B12 was observed.

[ Chemical formula 74 ]

LRMS：m/z 398、400[M+H]⁺

Retention time: 1.093 minutes (analysis conditions FA05-1, 299 nm).

Examples 1-3-15: synthesis of Compound B13-3R

[ Chemical formula 75 ]

Compound B13-3R (supporting amount 0.195 mmol/g) can be synthesized by the same method as compound B03-1R using compound A03-3R (supporting amount 0.201 mmol/g) and 6-bromopyridine-3-amine (B13).

B13-3R was washed 3 times with DCM (0.1 mL) and immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.05M pentamethylbenzene for 5 min. After filtration, LCMS measurement of the diluted solution was performed with DMF (0.05 mL) and MeCN (0.25 mL), whereby 99.6% of target B13 was observed.

[ Chemical formula 76 ]

LRMS：m/z 369、371[M+H]⁺

Retention time: 1.011 min (analysis conditions FA05-1, 299 nm).

Examples 1-3-16: synthesis of Compound B14-3R

[ Chemical formula 77 ]

Compound B14-3R (supported 0.194 mmol/g) can be synthesized by the same method as compound B03-1R using compound A03-3R (supported 0.201 mmol/g) and (2-bromothiazol-5-yl) methylamine (B14).

B14-3R was washed 3 times with DCM (0.1 mL) and immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.05M pentamethylbenzene for 5 min. After filtration, LCMS measurement of the diluted solution was performed with DMF (0.05 mL) and MeCN (0.25 mL), whereby 97.8% of target B14 was observed.

[ Chemical formula 78 ]

LRMS：m/z 389、391[M+H]⁺

Retention time: 0.925 min (analysis conditions FA05-1, 299 nm).

Examples 1-3-17: synthesis of Compound B15-1R

[ Chemical formula 79 ]

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

The suspension of reaction solution and solid phase (10. Mu.L) was transferred to a filter, washed 3 times with NMP (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.1M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with NMP (0.1 mL). LCMS measurement of a solution diluted by adding MeCN (0.25 mL) to the filtrate (0.05 mL) was performed, whereby 100% of the target B15 was observed.

[ Chemical formula 80 ]

LRMS：m/z 388、390[M+H]⁺

Retention time: 1.061 min (analysis conditions FA05-1, 299 nm).

Examples 1-3-18: synthesis of Compound H04-3R

[ Chemical formula 81 ]

To a 100mL glass vial under nitrogen atmosphere, compound A03-3R (supported 0.201mmol/g,5.00g,1.01 mmol) and NMP (60 mL) were added and the mixture was shaken at room temperature for 1 hour. 3- (aminomethyl) -N-methylaniline (h 04) (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.

The reaction solution and the solid phase suspension were all transferred to a filter, washed 3 times with NMP (100 mL), 3 times with MeOH (100 mL), 3 times with DCM (100 mL), 3 times with heptane (100 mL), and Compound H04-3R (loading 0.196mmol/g,5.45 g) was obtained.

H04-3R was washed 3 times with DCM (0.1 mL) and immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 5 min. After filtration, LCMS measurement of the diluted solution was performed with DMF (0.05 mL) and MeCN (0.25 mL), whereby 97.2% of target H04 was observed.

[ Chemical formula 82 ]

LRMS：m/z 333[M+H]⁺

Retention time: 0.675 minutes (analysis conditions FA05-1, 299 nm).

Examples 1-3-19: synthesis of Compound H01-4R

[ Chemical formula 83 ]

To a 50mL empty column with a filter under nitrogen atmosphere were added compound A03-4R (supported 0.201mmol/g,2.5g,0.50 mmol) and DCM (37.5 mL), and the mixture was shaken at room temperature for 1 hour. 4- (Fmoc-amino) piperidine hydrochloride (h 01, 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 shaken at room temperature for 6 hours.

The solid phase was washed 3 times with NMP (50 mL), 3 times with NMP/H ₂ o=1/1 (50 mL), 3 times with NMP (50 mL). To the column was added 20% piperidine/DMF solution (50 mL), and the mixture was shaken at room temperature for 2 hours, after the solution was drained, washed 3 times with NMP (50 mL), 3 times with MeOH (50 mL), 3 times with DCM (50 mL), 3 times with heptane (50 mL), to give Compound H01-4R (loading 0.198mmol/g,3.0 g).

H01-4R was washed 3 times with DCM (0.1 mL) and immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.2M pentamethylbenzene for 5 min. After filtration, LCMS measurement of the diluted solution was performed with DMF (0.05 mL) and MeCN (0.20 mL), whereby 98.0% of target H01 was observed.

[ Chemical formula 84 ]

LRMS：m/z 297[M+H]⁺

Retention time: 0.551 min (analysis conditions FA05-1, 299 nm).

Examples 1-3-20: synthesis of Compound H02-4R

[ Chemical formula 85 ]

To a 100mL empty column with a filter under nitrogen atmosphere were added compound A03-4R (supported 0.201mmol/g,6.5g,1.31 mmol) and DCM (98.0 mL), and the mixture was shaken at room temperature for 1 hour. 4-amino-1-N-Fmoc-piperidine hydrochloride (h 02, 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 shaken at room temperature for 2.5 hours.

The solid phase was washed 3 times with NMP (100 mL), 3 times with NMP/H ₂ o=1/1 (100 mL), 3 times with NMP (100 mL). A20% piperidine/DMF solution (100 mL) was added to the column, the mixture was shaken at room temperature for 1 hour, after draining the solution, it was washed 3 times with NMP (100 mL), 3 times with MeOH (100 mL), 3 times with DCM (100 mL), 3 times with heptane (100 mL), and Compound H02-4R (loading 0.198mmol/g,7.3 g) was obtained.

H02-4R was washed 3 times with DCM (0.1 mL) and immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.2M pentamethylbenzene for 5 min. After filtration, LCMS measurement of the diluted solution was performed with DMF (0.05 mL) and MeCN (0.20 mL), whereby 97.4% of target H01 was observed.

[ Chemical formula 86 ]

LRMS：m/z 297[M+H]⁺

Retention time: 0.561 min (analysis conditions FA05-1, 299 nm).

Examples 1-3-21: synthesis of Compound H03-4R

[ Chemical formula 87 ]

To a 50mL empty column with a filter under nitrogen atmosphere were added compound A03-4R (supported 0.201mmol/g,2.5g,0.50 mmol) and DCM (37.5 mL), and the mixture was shaken at room temperature for 1 hour. 3- (aminomethyl) aniline (h 03) (0.307 g,2.51 mmol), DIC (0.389 mL,2.51 mmol) and HOAt (0.348 g,2.51 mmol) were added and the mixture was shaken at room temperature for 18 hours. 3- (aminomethyl) aniline (h 03) (0.123 g,1.00 mmol), DIC (0.156 mL,1.00 mmol) and HOAt (0.137 g,1.00 mmol) were added and the mixture was shaken at room temperature for 4 hours.

The solid phase was washed 3 times with NMP (50 mL), 3 times with NMP/H ₂ O=/1 (50 mL), 3 times with NMP (50 mL), 3 times with MeOH (50 mL), 3 times with DCM (50 mL), 3 times with heptane (50 mL), compound H03-4R (0.197 mmol/g,2.9g supported) was obtained.

H03-4R was washed 3 times with DCM (0.1 mL) and immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.2M pentamethylbenzene for 5 min. After filtration, LCMS measurement of the diluted solution was performed with DMF (0.05 mL) and MeCN (0.20 mL), whereby 98.6% of target H03 was observed.

[ Chemical formula 88 ]

LRMS：m/z 319[M+H]⁺

Retention time: 0.641 min (analysis conditions FA05-1, 299 nm).

Example 2

Example 2-1: investigation of various solvents in hydroxylation of aryl Bromide carried on solid phase

Examples 2-1-1: in the hydroxylation reaction of the compound B01-1R, experiments comparing solvents were performed using AdBrettPhos Pd G Br as palladium catalyst and BTMG as base

[ Chemical formula 89 ]

Experimental operation

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

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), meCN (0.25 mL) was added to the filtrate, and LC samples were prepared and LCMS assay was performed, thereby determining the progress of the reaction. The results (UV area%) are shown in Table 2-1-1.

[ Table 6]

[ Table 2-1-1]

From the above results, it was confirmed that the conversion rate was always higher when DMPr, DEAc, DEPr was used than when a solvent was used in general, and the formation of by-products (H-bodies) in which the leaving group of the substrate was replaced with a hydrogen atom and other impurities was reduced, leading to high yields. When DMAc, which is generally used as an amide solvent, and urea solvents DMI and DMPU, which are excellent in matrix solubility as in the amide solvents, are used, H (C01) is formed in a large amount, and the yield of the target product is low. When NMP, which is generally used as an amide solvent, was used, the yield of the target product was high, but an impurity P01 of 83 more m/z than H was observed. In the case of NMP, even in the case of other substrates, 83 impurities are generated in an amount larger than that of H, and the impurities are generated in a large amount by the substrate, so that the yield of the target product is lowered (examples 2-1-2 and examples 2-1-3 described later). In the case of using DMF, it was observed that the impurity Q01 was more than H-form 57 in m/z, separation from the target D01 became difficult, and the yield of the target was also low. In addition, toluene was added to DMAc for the purpose of confirming the effect of improving the fat-solubility of the entire solvent, and as a result, no trend of improvement over DMAc was observed. On the other hand, in the case of THF and toluene, the reaction is slow, the formation of impurities increases, and the yield of the target product is low. Further, a reported example of DMOc (angel. Chem. Int. Ed.2016, 55, 2531-2535.) was used as an additive to a solvent in a flow reaction of an amide-based solvent and a c—n coupling reaction, but the formation of H-form (C01) was increased to a low yield.

[ Chemical formula 90 ]

LRMS：m/z 306[M+H]⁺

Retention time: 0.864 min (analysis conditions FA05-1, 299 nm)

Retention time: 1.660 min (analysis conditions FA05-long,299 nm).

[ Chemical formula 91 ]

LRMS：m/z 290[M+H]⁺

Retention time: 1.017 min (analysis conditions FA05-1, 299 nm)

Retention time: 2.081 minutes (analysis conditions FA05-long,299 nm).

Compound P01 (Structure undetermined)

LRMS：m/z 373[M+H]⁺

Retention time: 0.923 min (analysis conditions FA05-1, 299 nm).

Compound Q01 (Structure undetermined)

LRMS：m/z 347[M+H]⁺

Retention time: 1.744 minutes (analysis conditions FA05-long,299 nm).

Examples 2-1-2: in the hydroxylation reaction of the compound B03-1R, experiments were conducted in which the solvent was compared with AdBrettPhos Pd G Br as palladium catalyst and BTMG as base

[ Chemical formula 92 ]

Experimental operation

To a 0.6mL glass vial under nitrogen atmosphere was added compound B03-1R (0.195 mmol/g,20mg,0.0039 mmol), solvent (0.4 mL) and water (0.010 mL), and the mixture was shaken at room temperature for 1 hour. AdBrettPhos Pd G6 Br (0.8 mg,0.00078 mmol) and BTMG (11.7. Mu.L, 0.059 mmol) were added and shaken at 80℃for 24 hours.

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), meCN (0.25 mL) was added to the filtrate, and LC samples were prepared and LCMS assay was performed, thereby determining the progress of the reaction. The results (UV area%) are shown in tables 2-1-2.

[ Table 7]

[ Tables 2-1-2]

From the above results, it was confirmed that the conversion rate was always high in DMPr and DEAc, and the production of H-form and other impurities, which are problems, was reduced, and a high yield was obtained. On the other hand, in DMAc, the formation of H-form (C03) is large, and when NMP is used, many impurities P03 having an m/z higher than that of H-form 83 are observed, and the yield of the target product is low.

[ Chemical formula 93 ]

LRMS：m/z 307[M+H]⁺

Retention time: 1.296 min (analysis conditions RPAMIDETFA-long, 299 nm).

[ Chemical formula 94 ]

LRMS：m/z 291[M+H]⁺

Retention time: 1.211 min (analysis conditions RPAMIDETFA-long, 299 nm).

Compound P03 (Structure undetermined)

LRMS：m/z 374[M+H]⁺

Retention time: 1.425 min (analysis conditions RPAMIDETFA-long, 299 nm).

Examples 2-1-3: in the hydroxylation reaction of the compound B04-3R, experiments with comparative solvents were performed using AdBrettPhos Pd G Br as palladium catalyst and P1tBu as base

[ Chemical formula 95 ]

Experimental operation

To a 0.6mL glass vial under nitrogen atmosphere was added compound B04-3R (0.194 mmol/g,20mg,0.0039 mmol), solvent (0.32 mL) and water (0.080 mL), and the mixture was shaken at room temperature for 1 hour. AdBrettPhos Pd G6 Br (0.8 mg,0.00078 mmol) and P1tBu (14.8. Mu.L, 0.058 mmol) were added and shaken at 80℃for 0.5 h.

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), meCN (0.25 mL) was added to the filtrate, and LC samples were prepared and LCMS assay was performed, thereby determining the progress of the reaction. The results (UV area%) are shown in tables 2-1-3.

[ Table 8]

[ Tables 2-1-3]

From the above results, it was confirmed that the conversion rate was always high in DMPr and DEAc, and the production of H-form and other impurities, which are problems, was reduced, and a high yield was obtained. On the other hand, in the case of using DMAc, the reaction proceeds slowly. In addition, when DMF is used, the reaction proceeds slowly, and the formation of H-form (C04) is large, resulting in low yield of the target product. When NMP was used, a large amount of H (C04) and 83 more impurities P04 than H were observed in m/z, and the yield of the target product was low.

[ Chemical formula 96 ]

LRMS：m/z 336[M+H]⁺

Retention time: 0.905 min (analysis conditions FA05-2, 299 nm).

[ Chemical formula 97 ]

LRMS：m/z 320[M+H]⁺

Retention time: 1.077 min (analysis conditions FA05-2, 299 nm).

Compound P04 (Structure undetermined)

LRMS：m/z 403[M+H]⁺

Retention time: 0.935 min (analysis conditions FA05-2, 299 nm).

Example 2-2: investigation of various palladium catalysts in hydroxylation of aryl bromides supported on solid phase

Example 2-2-1: in the hydroxylation reaction of the compound B02-2R, experiments on the palladium catalyst were studied using P2tBu as a base and DMPr as a solvent

[ Chemical formula 98 ]

Experimental operation

To a 0.6mL glass vial under nitrogen atmosphere, compound B02-2R (0.194 mmol/g,20mg,0.0039 mmol), DMPr (0.4 mL) and water (0.010 mL) were added and the mixture was shaken at room temperature for 1 hour. The catalyst described in Table 2-2-1 and a P2tBu/THF solution (2M, 29.1. Mu.L, 0.058 mmol) were added and the mixture was shaken at 80℃for 0.5 hours.

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), meCN (0.25 mL) was added to the filtrate, and LC samples were prepared and LCMS assay was performed, thereby determining the progress of the reaction. The results (UV area%) are shown in Table 2-2-1.

[ Table 9]

[ Table 2-2-1]

From the above results, it was revealed that various palladium catalysts can be utilized in the hydroxylation reaction using DMPr as a solvent. In particular, when a catalyst of RockPhos Pd G, tBuBrettPhos Pd G4, or a combination of AdBippyPhos and Pd ₂dba₃CHCl₃ is used, the yield is high.

[ Chemical formula 99 ]

LRMS：m/z 320[M+H]⁺

Retention time: 0.931 min (analysis conditions FA05-1, 299 nm).

[ Chemical formula 100 ]

LRMS：m/z 304[M+H]⁺

Retention time: 1.075 min (analysis conditions FA05-1, 299 nm).

Examples 2-3: investigation of various bases in hydroxylation of aryl bromides supported on solid phases

Example 2-3-1: in the hydroxylation reaction of the compound B02-2R, experiments with a base were studied using AdBrettPhos Pd G as a palladium catalyst and DMPr as a solvent

Experimental operation

To a 0.6mL glass vial under nitrogen atmosphere, compound B02-2R (0.194 mmol/g,20mg,0.0039 mmol), DMPr (0.4 mL) and water (0.010 mL) were added and the mixture was shaken at room temperature for 1 hour. AdBrettPhos Pd G3 (0.8 mg,0.00078 mmol) and the base described in Table 2-3-1 (0.058 mmol) were added and the mixture was shaken at 80℃for the time described in Table 2-3-1.

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), meCN (0.25 mL) was added to the filtrate, and LC samples were prepared and LCMS assay was performed, thereby determining the progress of the reaction. The results (UV area%) are shown in Table 2-3-1.

[ Table 10]

[ Table 2-3-1]

From the above results, it was found that a wide range of organic bases such as BTMG, MTBD, P1tBu, BEMP, BTPP, P tBu and a wide range of inorganic bases such as Cs ₂CO₃、K₃PO₄ and KOH can be used in the hydroxylation reaction using DMPr as a solvent. The preferred base is phosphazene base such as P1tBu or P2tBu which has a high reaction rate and generates little H-form.

Examples 2 to 4: matrix general

Examples 2-4-1: synthesis of D06-2R by hydroxylation of Compound B06-2R

[ Chemical formula 101 ]

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

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), meCN (0.25 mL) was added to the filtrate, LC samples were prepared, and LCMS assay was performed. As a result, H (C06) was as low as 2.7%, and the yield of the target D06 was 97.3%.

[ Chemical formula 102]

LRMS：m/z 374[M+H]⁺

Retention time: 1.040 min (analysis conditions FA05-1, 299 nm).

[ Chemical formula 103 ]

LRMS：m/z 358[M+H]⁺

Retention time: 1.183 min (analysis conditions FA05-1, 299 nm).

Examples 2 to 5: investigation of various solvents in the C-O coupling reaction of aryl Bromide carried on solid phase

Examples 2-5-1: in the C-O coupling reaction of Compound B02-2R with 3-phenyl-1-propanol (g 01), experiments comparing solvents using AdBippyPhos as a ligand for the palladium catalyst and BTMG as a base

[ Chemical formula 104]

Experimental operation

A solution of compound B02-2R (0.194 mmol/g,15mg,0.0029 mmol) and potassium triflate (5.5 mg,0.029 mmol) dissolved in the solvent (0.3 mL) described in Table 2-5-1 was added to a 0.6mL glass vial under nitrogen atmosphere. 3-phenyl-1-propanol (39.6. Mu.L, 0.291 mmol) was added thereto, and the mixture was shaken at room temperature for 1 hour. A mixed solution of Pd ₂dba₃CHCl₃ (0.025M, 0.00029 mmol) and AdBippyPhos (0.1M, 0.0016 mmol) (prepared by adding 2 compounds to the corresponding solvents and heating with a desiccator for about 1 minute) was added (11.6. Mu.L). BTMG (8.7. Mu.L, 0.044 mmol) was added and the mixture was shaken at 80℃for 24 hours.

The suspension of reaction solution and solid phase (12. Mu.L) was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 1 minute. After filtration, the solid phase was washed with DMF (0.05 mL), meCN (0.25 mL) was added to the filtrate, and LC samples were prepared and LCMS assay was performed, thereby determining the progress of the reaction. The results (UV area%) are shown in Table 2-5-1.

[ Table 11]

[ Table 2-5-1]

From the above results, it was confirmed that the conversion rate was higher in DMPr than in the case of the commonly used solvents, and the formation of H form and by-products (OH form) considered to react with water was reduced, resulting in high yield. On the other hand, when DMAc is used, the reaction proceeds slowly, and the yield of the target product after 24 hours is also low. When NMP is used, H (C02) and OH (D02) are formed in large amounts, and the yield of the target product is low.

[ Chemical formula 105 ]

LRMS：m/z 438[M+H]⁺

Retention time: 1.381 min (analysis conditions FA05-1, 299 nm)

Examples 2-5-2: in the C-O coupling reaction of Compound B02-2R with 2-methylphenol (g 02), experiments comparing solvents were performed using AdBippyPhos as a ligand to the palladium catalyst and BTMG as a base

[ Chemical formula 106]

Experimental operation

A solution of compound B02-2R (0.194 mml/g,15mg,0.0029 mmol) and potassium triflate (5.5 mg,0.029 mmol) dissolved in the solvent (0.3 mL) described in Table 2-5-2 was added to a 0.6mL glass vial under nitrogen atmosphere. 2-methylphenol (30.0. Mu.L, 0.291 mmol) was added and shaken at room temperature for 1 hour. A mixed solution of Pd ₂dba₃CHCl₃ (0.025M, 0.00029 mmol) and AdBippyPhos (0.1M, 0.0016 mmol) (prepared by adding 2 compounds to the corresponding solvents and heating with a desiccator for about 1 minute) was added (11.6. Mu.L). BTMG (8.7. Mu.L, 0.044 mmol) was added and the mixture was shaken at 80℃for 24 hours.

The suspension of reaction solution and solid phase (12. Mu.L) was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 1 minute. After filtration, the solid phase was washed with DMF (0.05 mL), meCN (0.25 mL) was added to the filtrate, and LC samples were prepared and LCMS assay was performed, thereby determining the progress of the reaction. The results (UV area%) are shown in tables 2-5-2.

[ Table 12]

[ Tables 2-5-2]

From the above results, it was confirmed that the conversion rate was higher in DMPr than in the case of the commonly used solvents, and the formation of H form and by-products (OH form) considered to react with water was reduced, resulting in high yield. On the other hand, when DMAc is used, the reaction proceeds slowly, and the yield of the target product is low. When NMP is used, H (C02) is produced in a large amount, and the yield of the target product is low.

[ Chemical formula 107 ]

LRMS：m/z 410[M+H]⁺

Retention time: 1.327 minutes (analysis conditions FA05-1, 299 nm).

Example 3

Example 3-1: investigation of various solvents in C-N coupling reactions of aryl Bromide carried on solid phase

Example 3-1-1: in the C-N coupling reaction of the Compound B02-1R with 4-phenylpiperidine (e 01), experiments in which the solvent was compared with (tBu) PhCPhos Pd G4 as palladium catalyst and P2tBu as base

[ Chemical formula 108 ]

Experimental operation

Compound B02-1R (0.194 mmol/g,20mg,0.0039 mmol) and solvent (0.4 mL) were added to a 0.6mL glass vial under nitrogen atmosphere and shaken at room temperature for 1 hour. 4-phenylpiperidine (e 01) (12.5 mg,0.078 mmol) and (tBu) PhCPhos Pd G (0.6 mg,0.00078 mmol) 4 were added, and the P2tBu/THF solution (2M, 58.2. Mu.L, 0.116 mmol) was shaken at room temperature for 2 hours.

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), meCN (0.25 mL) was added to the filtrate, and LC samples were prepared and LCMS assay was performed, thereby determining the progress of the reaction. The results (UV area%) are shown in Table 3-1-1.

[ Table 13]

[ Table 3-1-1]

From the above results, it was confirmed that the conversion rate was higher in DMPr than in the case of the commonly used solvents, and the formation of H-bodies and other impurities was reduced, resulting in high yields. On the other hand, it was confirmed that the reaction proceeded slowly when DMAc, DMF, DMI or DMPU was used, and that the reaction rate was also slow when THF or toluene (references: organometallics 2013, 32, 5428-5434) whose inhibitory effect on H formation was reported was used. When NMP was used, although the disappearance of the starting material was rapid, the formation of H (C02) was large, and the yield of the target product was low because of the observation that the impurity P02 had an m/z greater than that of H83.

[ Chemical formula 109 ]

LRMS：m/z 463[M+H]⁺

Retention time: 1.340 min (analysis conditions FA05-1, 299 nm).

Compound P02 (Structure undetermined)

LRMS：m/z 387[M+H]⁺

Retention time: 0.905 min (analysis conditions FA05-1, 299 nm).

Examples 3-1-2: in the C-N coupling reaction of the Compound B02-1R with N-methyl-3-phenylpropylamine (e 02), experiments comparing solvents with (tBu) PhCPhos Pd G4 as palladium catalyst and P2tBu as base

[ Chemical formula 110 ]

Experimental operation

Compound B02-1R (0.194 mmol/g,20mg,0.0039 mmol) and solvent (0.4 mL) were added to a 0.6mL glass vial under nitrogen atmosphere and shaken at room temperature for 1 hour. N-methyl-3-phenylpropylamine (e 02) (11.6 mg,0.078 mmol) and (tBu) PhCPhos Pd G4 (0.6 mg,0.00078 mmol), P2tBu/THF solution (2M, 58.2. Mu.L, 0.116 mmol) were added and the mixture was shaken at room temperature for 24 hours.

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), meCN (0.25 mL) was added to the filtrate, and LC samples were prepared and LCMS assay was performed, thereby determining the progress of the reaction. The results are shown in tables 3-1-2.

[ Table 14]

[ Tables 3-1-2]

From the above results, it was confirmed that the conversion rate was higher in DMPr than in the case of the commonly used solvents, and the formation of H-bodies and other impurities was reduced, resulting in high yields. On the other hand, it was confirmed that the reaction rate was slow in the case of using DMAc, DMF, DMI, DMPU, THF and toluene. When NMP was used, the formation of H (C02) was extremely large, and an impurity P02 having an m/z of 83 more than that of H was observed, resulting in a low yield. As solvents for C-N coupling reactions, which are highly polar solvents like amide solvents, studies were conducted using DMSO and tpamyl oh (Organic Letters 2015, 17, 3370-3373.) reported in the examples, but the solid phase did not swell and the reaction did not progress very much. Further, as an additive of an amide-based solvent in a flow reaction of a c—n coupling reaction, a reported DMOc (angel. Chem. Int. Ed.2016, 55, 2531-2535.) was used, but the reaction proceeded slowly and was performed in a low yield.

[ Chemical formula 111 ]

LRMS：m/z 451[M+H]⁺

Retention time: 1.027 min (analysis conditions FA05-1, 299 nm)

Retention time: 2.120 min (analysis conditions FA05-long,299 nm).

[ Chemical formula 112]

LRMS：m/z 304[M+H]⁺

Retention time: 2.257 minutes (analysis conditions FA05-long,299 nm).

Compound P02 (Structure undetermined)

LRMS：m/z 387[M+H]⁺

Retention time: 1.807 min (analysis conditions FA05-long,299 nm).

Examples 3-1-3: in the C-N coupling reaction of the Compound B02-1R with 1-methyl-3-phenylpropylamine (e 06), experiments comparing solvents with (tBu) PhCPhos Pd G4 as palladium catalyst and P2tBu as base

[ Chemical formula 113 ]

Experimental operation

Compound B02-1R (0.194 mmol/g,20mg,0.0039 mmol) and solvent (0.4 mL) were added to a 0.6mL glass vial under nitrogen atmosphere and shaken at room temperature for 1 hour. 1-methyl-3-phenylpropylamine (e 06) (12.5. Mu.L, 0.078 mmol) and (tBu) PhCPhos Pd G4 (0.6 mg,0.00078 mmol), P2tBu/THF solution (2M, 58.2. Mu.L, 0.116 mmol) were added and the mixture was shaken at room temperature for 2 hours.

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), meCN (0.25 mL) was added to the filtrate, and LC samples were prepared and LCMS assay was performed, thereby determining the progress of the reaction. The results (UV area%) are shown in tables 3-1-3.

[ Table 15]

[ Tables 3-1-3]

From the above results, it was confirmed that the conversion rate was higher in DMPr than in the case of the commonly used solvents, and the formation of H-bodies and other impurities was reduced, resulting in high yields. On the other hand, it was confirmed that the reaction rate was slow when DMAc was used. It was confirmed that the formation of H-form (C02) in NMP was large, the reaction rate was slow, and the yield was low.

[ Chemical formula 114 ]

LRMS：m/z 451[M+H]⁺

Retention time: 1.276 min (analysis conditions FA05-1, 299 nm).

Examples 3-1-4: in the C-N coupling reaction of the Compound B01-1R with dipropylamine (e 03), experiments comparing solvents were performed using (tBu) PhCPhos Pd G4 as palladium catalyst and P2tBu as base

[ Chemical formula 115 ]

Experimental operation

Compound B01-1R (0.195 mmol/g,20mg,0.0039 mmol) and solvent (0.4 mL) were added to a 0.6mL glass vial under nitrogen atmosphere and shaken at room temperature for 1 hour. Dipropylamine (e 03) (10.7. Mu.L, 0.078 mmol) and (tBu) PhCPhos Pd G4 (0.6 mg,0.00078 mmol), P2tBu/THF solution (2M, 58.5. Mu.L, 0.117 mmol) were added and the mixture was shaken at room temperature for 24 hours.

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), meCN (0.25 mL) was added to the filtrate, and LC samples were prepared and LCMS assay was performed, thereby determining the progress of the reaction. The results (UV area%) are shown in tables 3-1-4.

[ Table 16]

[ Tables 3-1-4]

From the above results, it was confirmed that the conversion rate was higher in DMPr than in the case of the commonly used solvents, and the formation of H-bodies and other impurities was reduced, resulting in high yields. On the other hand, when DMAc is used, the reaction rate is low, and an impurity R01 having an m/z greater than that of H-form 57 is observed. When NMP was used, the formation of H (C01) was extremely large, and an impurity P01 having an m/z higher than that of H83 was observed, resulting in a low yield.

[ Chemical formula 116 ]

LRMS：m/z 389[M+H]⁺

Retention time: 1.989 minutes (analysis conditions FA05-long,299 nm).

Compound P01 (Structure undetermined)

LRMS：m/z 373[M+H]⁺

Retention time: 1.823 minutes (analysis conditions FA05-long,299 nm).

Compound R01 (Structure undetermined)

LRMS：m/z 347[M+H]⁺

Retention time: 1.720 minutes (analysis conditions FA05-long,299 nm).

Examples 3-1-5: in the C-N coupling reaction of Compound B01-1R with 2-methylpiperidine (e 04), experiments comparing solvents were performed using (tBu) PhCPhos Pd G4 as palladium catalyst and P2tBu as base

[ Chemical formula 117 ]

Experimental operation

Compound B01-1R (0.195 mmol/g,20mg,0.0039 mmol) and solvent (0.4 mL) were added to a 0.6mL glass vial under nitrogen atmosphere and shaken at room temperature for 1 hour. 2-methylpiperidine (e 04) (9.21. Mu.L, 0.078 mmol) and (tBu) PhCPhos Pd G (0.6 mg,0.00078 mmol) were added, and the P2tBu/THF solution (2M, 58.5. Mu.L, 0.117 mmol) was shaken at room temperature for 24 hours.

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), meCN (0.25 mL) was added to the filtrate, and LC samples were prepared and LCMS assay was performed, thereby determining the progress of the reaction. The results (UV area%) are shown in tables 3-1-5.

[ Table 17]

[ Tables 3-1-5]

[ Chemical formula 118 ]

LRMS：m/z 387[M+H]⁺

Retention time: 0.705 min (analysis conditions FA05-01, 299 nm).

Compound R01 (Structure undetermined)

LRMS：m/z 347[M+H]⁺

Retention time: 0.879 min (analysis conditions FA05-01, 299 nm).

Examples 3-1-6: in the C-N coupling reaction of the Compound B02-1R with 2, 6-dimethylaniline (e 13), experiments in which the solvent was compared with (tBu) PhCPhos Pd G4 as the palladium catalyst and P2tBu as the base

[ Chemical formula 119 ]

Compound B02-1R (0.194 mmol/g,20mg,0.0039 mmol) and solvent (0.4 mL) were added to a 0.6mL glass vial under nitrogen atmosphere and shaken at room temperature for 1 hour. 2, 6-dimethylaniline (e 13) (9.6. Mu.L, 0.078 mmol) and (tBu) PhCPhos Pd G (0.6 mg,0.00078 mmol) were added. A solution of P2tBu/THF (2M, 58.2. Mu.L, 0.116 mmol) was added and the mixture was shaken at room temperature for 24 hours.

The suspension of reaction solution and solid phase (12. Mu.L) was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), meCN (0.25 mL) was added to the filtrate, and LC samples were prepared and LCMS assay was performed, thereby determining the progress of the reaction. The results (UV area%) are shown in tables 3-1-6.

[ Table 18]

[ Tables 3-1-6]

From the above results, it was confirmed that the conversion rate was higher in DMPr than in the case of the commonly used solvents, and the formation of H-bodies and other impurities was reduced, resulting in high yields. On the other hand, in the case of using DMAc, it was confirmed that the reaction rate was slow. When NMP was used, the formation of H (C02) was extremely large, and an impurity P02 having an m/z of 83 more than that of H was observed, resulting in a low yield.

[ Chemical formula 120 ]

LRMS：m/z 423[M+H]⁺

Retention time: 1.275 min (analysis conditions FA05-1, 299 nm).

Examples 3-1-7: in the C-N coupling reaction of Compound B01-1R with N-ethylaniline (e 16), experiments in which the solvent was compared with (tBu) PhCPhos Pd G4 as the palladium catalyst and P2tBu as the base

[ Chemical formula 121 ]

Compound B01-1R (0.195 mmol/g,20mg,0.0039 mmol) and solvent (0.4 mL) were added to a 0.6mL glass vial under nitrogen atmosphere and shaken at room temperature for 1 hour. N-ethylaniline (e 16) (9.9. Mu.L, 0.078 mmol) and (tBu) PhCPhos Pd G (0.6 mg,0.00078 mmol) were added. A solution of P2tBu/THF (2M, 58.5. Mu.L, 0.117 mmol) was added and the mixture was shaken at room temperature for 2 hours.

The suspension of reaction solution and solid phase (12. Mu.L) was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), meCN (0.25 mL) was added to the filtrate, and LC samples were prepared and LCMS assay was performed, thereby determining the progress of the reaction. The results (UV area%) are shown in tables 3-1-7.

[ Table 19]

[ Tables 3-1-7]

From the above results, it was confirmed that the conversion rate was higher in DMPr than in the case of the commonly used solvents, and the formation of H-bodies and other impurities was reduced, resulting in high yields. On the other hand, it was confirmed that the reaction rate was slow in the case of using DMAc. When NMP was used, the formation of H (C01) was extremely large, and an impurity P01 having an m/z higher than that of H83 was observed, resulting in a low yield.

[ Chemical formula 122 ]

LRMS：m/z 409[M+H]⁺

Retention time: 1.313 minutes (analysis conditions FA05-1, 299 nm).

Example 3-2: investigation of various catalysts in C-N coupling reactions of aryl bromides supported on solid phases

Example 3-2-1: in the C-N coupling reaction of the Compound B01-2R with piperidine (e 08), experiments with a palladium catalyst were studied using P2tBu as a base and DMPr as a solvent

[ Chemical formula 123 ]

To a 0.6mL glass vial under nitrogen was added compound B01-2R (0.195 mmol/g,20mg,0.0039 mmol) and DMPr (0.4 mL), piperidine (e 08) (3.85. Mu.L, 0.039 mmol), and the mixture was shaken at room temperature for 1 hour. The catalyst described in Table 3-2-1 and a P2tBu/THF solution (2M, 29.3. Mu.L, 0.059 mmol) were added and the mixture was shaken at 80℃for the time described in Table 3-2-1.

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), meCN (0.25 mL) was added to the filtrate, and LC samples were prepared and LCMS assay was performed, thereby determining the progress of the reaction. The results (UV area%) are shown in Table 3-2-1.

[ Table 20]

[ Table 3-2-1]

From the above results, it was shown that a wide range of palladium catalysts can be utilized in the c—n coupling reaction using DMPr as a solvent.

In particular, in the case of using a catalyst of RuPhos Pd G4, tBuXPhos Pd G4, (tBu) PhCPhos Pd G, bippyPhos in combination with Pd ₂dba₃CHCl₃ or cataCXium PIntB in combination with Pd ₂dba₃CHCl₃, a high yield is obtained.

[ Chemical formula 124 ]

LRMS：m/z 373[M+H]⁺

Retention time: 0.757 min (analysis conditions FA05-01, 299 nm).

Examples 3-3: investigation of various bases in C-N coupling reactions of aryl bromides supported on solid phases

Example 3-3-1: in the C-N coupling reaction of Compound B01-2R with piperidine (e 08), the experiment of the base was studied in the case of using (tBu) PhCPhos Pd G4 as palladium catalyst and DMPr as solvent

To a 0.6mL glass vial under nitrogen was added compound B01-2R (0.195 mmol/g,20mg,0.0039 mmol) and DMPr (0.4 mL), piperidine (e 08) (3.85. Mu.L, 0.039 mmol), and the mixture was shaken at room temperature for 1 hour. (tBu) PhCPhos Pd G4 (0.6 mg,0.00078 mmol) and the base (0.0059 mmol) described in Table 3-3-1 were added and the mixture was shaken at 80℃for the time described in Table 3-3-1.

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), meCN (0.25 mL) was added to the filtrate, and LC samples were prepared and LCMS assay was performed, thereby determining the progress of the reaction. The results (UV area%) are shown in Table 3-3-1.

[ Table 21]

[ Table 3-3-1]

From the above results, it was revealed that K ₃PO₄ and NaOtBu as inorganic bases can be used in addition to P2tBu as an organic base in the C-N coupling reaction using DMPr as a solvent. The preferred base is a phosphazene base of P2tBu which has a high reaction rate and generates little H form.

Examples 3-3-2: in the C-N coupling reaction of Compound B02-1R with 4-phenylpiperidine (e 01), experiments with addition of salt Using (tBu) PhCPhos Pd 4 as palladium catalyst, BTMG as base, DMPr as solvent

[ Chemical formula 125 ]

Compound B02-1R (0.194 mmol/g,20mg,0.0039 mmol) and DMPr (0.4 mL) were added to a 0.6mL glass vial under nitrogen atmosphere and shaken at room temperature for 1 hour. 4-phenylpiperidine (e 01) (12.5 mg,0.078 mmol) and (tBu) PhCPhos Pd G4 (0.6 mg,0.00078 mmol) were added. The salts (0.116 mmol) and BTMG (23.2. Mu.L, 0.116 mmol) described in Table 3-3-2 were added and the mixture was shaken at 80℃for 2 hours.

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), meCN (0.25 mL) was added to the filtrate, and LC samples were prepared and LCMS assay was performed, thereby determining the progress of the reaction. The results (UV area%) are shown in Table 3-3-2.

[ Table 22]

[ Table 3-3-2]

From the above results, it was found that in the C-N coupling reaction using DMPr as a solvent, the reaction proceeds faster and the yield is improved by adding salts such as NaTFA and KTFA. The effect of adding the salt is not limited to the matrix used in the experiment.

Examples 3-4: matrix general

Example 3-4-1: synthesis of E0205-1R by C-N coupling reaction of Compound B02-1R with cyclohexylamine (E05)

[ Chemical formula 126 ]

Compound B02-1R (0.194 mmol/g,20mg,0.0039 mmol) and DMPr (0.4 mL) were added to a 0.6mL glass vial under nitrogen atmosphere and shaken at room temperature for 1 hour. Cyclohexylamine (e 05) (8.9. Mu.L, 0.078 mmol) and (tBu) PhCPhos Pd G4 (0.6 mg,0.00078 mmol) were added. A solution of P2tBu/THF (2M, 58.2. Mu.L, 0.116 mmol) was added and the mixture was shaken at room temperature for 0.5 hours.

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), meCN (0.25 mL) was added to the filtrate, LC samples were prepared, and LCMS assay was performed. As a result, object E0205 was observed to be 100%.

[ Chemical formula 127 ]

LRMS：m/z 401[M+H]⁺

Retention time: 1.096 minutes (analysis conditions FA05-1, 299 nm).

Examples 3-4-2: synthesis of E0207-1R by C-N coupling reaction of Compound B02-1R with 3-aminopentane (E07)

[ Formula 128 ]

Compound B02-1R (0.194 mmol/g,20mg,0.0039 mmol) and DMPr (0.4 mL) were added to a 0.6mL glass vial under nitrogen atmosphere and shaken at room temperature for 1 hour. 3-aminopentane (e 07) (9.0. Mu.L, 0.078 mmol) and (tBu) PhCPhos Pd G4 (0.6 mg,0.00078 mmol) were added. A solution of P2tBu/THF (2M, 58.2. Mu.L, 0.116 mmol) was added and the mixture was shaken at room temperature for 24 hours.

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), meCN (0.25 mL) was added to the filtrate, LC samples were prepared, and LCMS assay was performed. As a result, it was observed that target E0207 was 98.6% and H (C02) was 1.4%.

[ Chemical formula 129 ]

LRMS：m/z 389[M+H]⁺

Retention time: 1.229 minutes (analysis conditions FA05-1, 299 nm).

Examples 3-4-3: synthesis of E0209-1R by C-N coupling reaction of Compound B02-1R with o-toluidine (E09)

[ Chemical formula 130]

Compound B02-1R (0.194 mmol/g,20mg,0.0039 mmol) and DMPr (0.4 mL) were added to a 0.6mL glass vial under nitrogen atmosphere and shaken at room temperature for 1 hour. O-toluidine (e 09) (8.3. Mu.L, 0.078 mmol) and (tBu) PhCPhos Pd G4 (0.6 mg,0.00078 mmol) were added. A solution of P2tBu/THF (2M, 58.2. Mu.L, 0.116 mmol) was added and the mixture was shaken at room temperature for 2 hours.

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), meCN (0.25 mL) was added to the filtrate, LC samples were prepared, and LCMS assay was performed. As a result, it was observed that target E0209 was 98.2% and H (C02) was 1.1%.

[ Chemical formula 131 ]

LRMS：m/z 409[M+H]⁺

Retention time: 1.257 minutes (analysis conditions FA05-1, 299 nm).

Examples 3-4-4: synthesis of E0210-1R by C-N coupling reaction of Compound B02-1R with 2-ethylaniline (E10)

[ Chemical formula 132 ]

Compound B02-1R (0.194 mmol/g,20mg,0.0039 mmol) and DMPr (0.4 mL) were added to a 0.6mL glass vial under nitrogen atmosphere and shaken at room temperature for 1 hour. 2-Ethylaniline (e 10) (9.6. Mu.L, 0.078 mmol) and (tBu) PhCPhos Pd G (0.6 mg,0.00078 mmol) were added. A solution of P2tBu/THF (2M, 58.2. Mu.L, 0.116 mmol) was added and the mixture was shaken at room temperature for 24 hours.

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), meCN (0.25 mL) was added to the filtrate, LC samples were prepared, and LCMS assay was performed. As a result, 98.7% of the target E0210 and 1.3% of the H form (C02) were observed.

[ Chemical formula 133 ]

Compound E0210

LRMS：m/z 423[M+H]⁺

Retention time: 1.309 minutes (analysis conditions FA05-1, 299 nm).

Examples 3-4-5: synthesis of E0211-1R by C-N coupling reaction of Compound B02-1R with 2-isopropylaniline (E11)

[ Chemical formula 134 ]

To a 0.6mL glass vial under nitrogen atmosphere, compound B02,1R (0.194 mmol/g,20mg,0.0039 mmol) and DMPr (0.4 mL) were added and the mixture was shaken at room temperature for 1 hour. 2-isopropylaniline (e 11) (10.8. Mu.L, 0.078 mmol) and (tBu) PhCPhos Pd G4 (0.6 mg,0.00078 mmol) were added. A solution of P2tBu/THF (2M, 58.2. Mu.L, 0.116 mmol) was added and the mixture was shaken at room temperature for 24 hours.

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), meCN (0.25 mL) was added to the filtrate, LC samples were prepared, and LCMS assay was performed. As a result, 97.9% of the target E0211 and 2.1% of the H form (C02) were observed.

[ Chemical formula 135 ]

LRMS：m/z 437[M+H]⁺

Retention time: 1.351 minutes (analysis conditions FA05-1, 299 nm).

Examples 3-4-6: synthesis of E0212-1R by C-N coupling reaction of Compound B02-1R with 2- (tert-butyl) aniline (E12)

[ Chemical formula 136 ]

Compound B02-1R (0.194 mmol/g,20mg,0.0039 mmol) and DMPr (0.4 mL) were added to a 0.6mL glass vial under nitrogen atmosphere and shaken at room temperature for 1 hour. 2- (tert-butyl) aniline (e 12) (12.1. Mu.L, 0.078 mmol) and (tBu) PhCPhos Pd G4 (0.6 mg,0.00078 mmol) were added. A solution of P2tBu/THF (2M, 58.2. Mu.L, 0.116 mmol) was added and the mixture was shaken at room temperature for 24 hours.

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), meCN (0.25 mL) was added to the filtrate, LC samples were prepared, and LCMS assay was performed. As a result, 92.9% of the target E0212 and 2.3% of the H form (C02) were observed.

[ Chemical formula 137 ]

LRMS：m/z 451[M+H]⁺

Retention time: 1.407 min (analysis conditions FA05-1, 299 nm).

Examples 3-4-8: synthesis of E0113-1R by C-N coupling reaction of Compound B01-1R with 2, 6-dimethylaniline (E13)

[ Chemical formula 138 ]

To a 0.6mL glass vial under nitrogen was added compound B01-1R (0.195 mmol/g,20mg,0.0039 mmol) and DMPr (0.4 mL), and the mixture was shaken at room temperature for 1 hour. 2, 6-dimethylaniline (e 13) (9.7. Mu.L, 0.078 mmol) and (tBu) PhCPhos Pd G (0.6 mg,0.00078 mmol) were added. A solution of P2tBu/THF (2M, 58.5. Mu.L, 0.117 mmol) was added and the mixture was shaken at room temperature for 24 hours.

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), meCN (0.25 mL) was added to the filtrate, LC samples were prepared, and LCMS assay was performed. As a result, 95.1% of the target E0113 and 1.5% of the H-form (C01) were observed.

[ Chemical formula 139 ]

LRMS：m/z 409[M+H]⁺

Retention time: 1.248 min (analysis conditions FA05-1, 299 nm).

Examples 3-4-9: synthesis of E0114-1R by C-N coupling of Compound B01-1R with 2, 6-diethylaniline (E14)

[ Chemical formula 140]

To a 0.6mL glass vial under nitrogen was added compound B01-1R (0.195 mmol/g,20mg,0.0039 mmol) and DMPr (0.4 mL), and the mixture was shaken at room temperature for 1 hour. 2, 6-diethylaniline (e 14) (12.1. Mu.L, 0.078 mmol) and (tBu) PhCPhos Pd G (0.6 mg,0.00078 mmol) were added. A solution of P2tBu/THF (2M, 58.5. Mu.L, 0.117 mmol) was added and the mixture was shaken at room temperature for 24 hours.

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), meCN (0.25 mL) was added to the filtrate, LC samples were prepared, and LCMS assay was performed. As a result, 90.2% of the target E0114, 3.8% of the matrix B01 and 1.6% of the H-form (C01) were observed.

[ Chemical formula 141 ]

LRMS：m/z 437[M+H]⁺

Retention time: 1.345 min (analysis conditions FA05-1, 299 nm).

Examples 3-4-10: synthesis of E0115-1R by C-N coupling of Compound B01-1R with N-methylaniline (E15)

[ Chemical formula 142 ]

To a 0.6mL glass vial under nitrogen was added compound B01-1R (0.195 mmol/g,20mg,0.0039 mmol) and DMPr (0.4 mL), and the mixture was shaken at room temperature for 1 hour. N-methylaniline (e 15) (8.4. Mu.L, 0.078 mmol) and (tBu) PhCPhos Pd G (0.6 mg,0.00078 mmol) were added. A solution of P2tBu/THF (2M, 58.5. Mu.L, 0.117 mmol) was added and the mixture was shaken at room temperature for 24 hours.

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), meCN (0.25 mL) was added to the filtrate, LC samples were prepared, and LCMS assay was performed. As a result, 95.4% of the target E0115 and 1.1% of the H-form (C01) were observed.

[ Chemical formula 143 ]

LRMS：m/z 395[M+H]⁺

Retention time: 1.259 min (analysis conditions FA05-1, 299 nm).

Examples 3-4-12: synthesis of E0303-1R by C-N coupling of Compound B03-1R with dipropylamine (E03)

[ Chemical formula 144 ]

To a 0.6mL glass vial under nitrogen was added compound B01-1R (0.195 mmol/g,20mg,0.0039 mmol) and DMPr (0.4 mL), and the mixture was shaken at room temperature for 1 hour. Dipropylamine (e 03) (10.7. Mu.L, 0.078 mmol) and (tBu) PhCPhos Pd G4 (0.6 mg,0.00078 mmol) were added. A solution of P2tBu/THF (2M, 58.5. Mu.L, 0.117 mmol) was added and the mixture was shaken at room temperature for 24 hours.

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), meCN (0.25 mL) was added to the filtrate, LC samples were prepared, and LCMS assay was performed. As a result, 89.6% of the target E0303 and 3.9% of the H-form (C03) were observed.

[ Chemical formula 145 ]

LRMS：m/z 390[M+H]⁺

Retention time: 0.825 min (analysis conditions FA05-1, 299 nm).

Examples 3-4-13: synthesis of E0502-2R by C-N coupling reaction of Compound B05-2R with N-methyl-3-phenylpropylamine (E02)

[ Chemical formula 146 ]

To a 0.6mL glass vial under nitrogen was added compound B05-2R (0.194 mmol/g,20mg,0.0039 mmol) and DMPr (0.4 mL), and the mixture was shaken at room temperature for 1 hour. N-methyl-3-phenylpropylamine (e 02) (11.6 mg,0.078 mmol) and (tBu) PhCPhos Pd G4 (0.6 mg,0.00078 mmol) were added. A solution of P2tBu/THF (2M, 58.2. Mu.L, 0.116 mmol) was added and the mixture was shaken at room temperature for 24 hours.

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 2 minutes. After filtration, the solid phase was washed with DMF (0.05 mL), meCN (0.25 mL) was added to the filtrate, LC samples were prepared, and LCMS assay was performed. As a result, the target E0502 was 87.2%, and the H-body (C05) was 4.4%.

[ Chemical formula 147 ]

LRMS：m/z 452[M+H]⁺

Retention time: 0.897 min (analysis conditions FA05-1, 299 nm).

[ Chemical formula 148 ]

LRMS：m/z 305[M+H]⁺

Retention time: 0.605 min (analysis conditions FA05-1, 299 nm).

Examples 3-4-14: synthesis of E0101-3R by C-N coupling reaction of Compound B08-3R with 4-phenylpiperidine (E01)

[ Chemical formula 149 ]

A solution of compound B08-3R (0.197 mmol/g,15mg,0.0029 mmol) and 4-phenylpiperidine (e 01) (4.8 mg,0.030 mmol) in DMPr (0.3 mL) was added to a 0.6mL glass vial under nitrogen atmosphere and shaken at room temperature for 1 hour. RuPhos Pd G4 (0.5 mg,0.00059 mmol) was added. A P2tBu/THF solution (2M, 22.5. Mu.L, 0.045 mmol) was added and the mixture was shaken at 80℃for 24 hours.

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 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), meCN (0.25 mL) was added to the filtrate, LC samples were prepared, and LCMS assay was performed. As a result, it was observed that target E0101 was 51.2%, H (C01) was 7.5%, and raw material (B08) was 39.8%.

[ Chemical formula 150]

LRMS：m/z 449[M+H]⁺

Retention time: 0.999 min (analysis conditions FA05-1, 299 nm)

Retention time: 2.397 minutes (analysis conditions FA05-long,299 nm).

Examples 3-4-15: synthesis of E0101-3R by C-N coupling reaction of Compound B09-3R with 4-phenylpiperidine (E01)

[ Chemical formula 151 ]

A solution of compound B09-3R (0.193 mmol/g,15mg,0.0029 mmol) and 4-phenylpiperidine (e 01) (4.8 mg,0.030 mmol) in DMPr (0.3 mL) was added to a 0.6mL glass vial under nitrogen atmosphere and shaken at room temperature for 1 hour. A DMPr solution (prepared by adding 2 kinds of compounds to DMPr and heating them in a desiccator for about 1 minute) was added, which was mixed with Pd ₂dba₃CHCl₃ (0.025M, 0.0012 mmol) and (tBu) PhCPhos (0.1M, 0.0003 mmol) (12.0. Mu.L). A P2tBu/THF solution (2M, 22.5. Mu.L, 0.045 mmol) was added and the mixture was shaken at 80℃for 24 hours.

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and 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, LC samples were prepared, and LCMS assay was performed. As a result, it was found that the target E0101 was 71.3% and the H form (C01) was 12.6%.

Examples 3-4-16: synthesis of E1001-3R by C-N coupling reaction of Compound B10-3R with 4-phenylpiperidine (E01)

[ Chemical formula 152 ]

A solution of compound B10-3R (0.194 mmol/g,15mg,0.0029 mmol) and 4-phenylpiperidine (e 01) (4.8 mg,0.030 mmol) in DMPr (0.3 mL) was added to a 0.6mL glass vial under nitrogen atmosphere and shaken at room temperature for 1 hour. A DMPr solution (prepared by adding 2 kinds of compounds to DMPr and heating them in a desiccator for about 1 minute) was added, which was mixed with Pd ₂dba₃CHCl₃ (0.025M, 0.0012 mmol) and (tBu) PhCPhos (0.1M, 0.0003 mmol) (12.0. Mu.L). A P2tBu/THF solution (2M, 22.5. Mu.L, 0.045 mmol) was added and the mixture was shaken at 80℃for 24 hours.

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in TFA/HFIP/dcm=2/9/9 (0.05 mL) for1 minute. After filtration, the solid phase was washed with DMF (0.05 m), meCN (0.25 mL) was added to the filtrate, LC samples were prepared, and LCMS assay was performed. As a result, 90.8% of the target E1001 was observed.

[ Chemical formula 153 ]

LRMS：m/z 467[M+H]⁺

Retention time: 1.060 minutes (analysis conditions FA05-1, 299 nm).

Examples 3-4-17: synthesis of E0401-3R by C-N coupling reaction of Compound B04-3R with 4-phenylpiperidine (E01)

[ Chemical formula 154 ]

A solution of compound B04-3R (0.194 mmol/g,15mg,0.0029 mmol) and 4-phenylpiperidine (e 01) (4.8 mg,0.030 mmol) in DMPr (0.3 mL) was added to a 0.6mL glass vial under nitrogen atmosphere and shaken at room temperature for 1 hour. A DMPr solution (prepared by adding 2 kinds of compounds to DMPr and heating them in a desiccator for about 1 minute) was added, which was mixed with Pd ₂dba₃CHCl₃ (0.025M, 0.0012 mmol) and (tBu) PhCPhos (0.1M, 0.0003 mmol) (12.0. Mu.L). A P2tBu/THF solution (2M, 22.5. Mu.L, 0.045 mmol) was added and the mixture was shaken at 80℃for 24 hours.

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and 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, LC samples were prepared, and LCMS assay was performed. As a result, 94.7% of the target E0401 was observed.

[ Chemical formula 155 ]

LRMS：m/z 479[M+H]⁺

Retention time: 0.875 min (analysis conditions FA05-1, 299 nm).

Examples 3-4-18: synthesis of E1101-3R by C-N coupling reaction of Compound B11-3R with 4-phenylpiperidine (E01)

[ Chemical formula 156 ]

A solution of compound B11-3R (0.194 mmol/g,15mg,0.0029 mmol) and 4-phenylpiperidine (e 01) (4.8 mg,0.030 mmol) in DMPr (0.3 mL) was added to a 0.6mL glass vial under nitrogen atmosphere and shaken at room temperature for 1 hour. A DMPr solution (prepared by adding 2 kinds of compounds to DMPr and heating them for about 1 minute in a desiccator) was added to the mixture of Pd ₂dba₃CHCl₃ (0.025M, 0.0012 mmol) and (tBu) PhCPhos (0.1M, 0.0003 mmol) (12.0. Mu.L). A P2tBu/THF solution (2M, 22.5. Mu.L, 0.045 mmol) was added and the mixture was shaken at 80℃for 24 hours.

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and 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, LC samples were prepared, and LCMS assay was performed. As a result, 92.2% of object E1101 was observed.

[ Chemical formula 157 ]

LRMS：m/z 467[M+H]⁺

Retention time: 1.219 min (analysis conditions FA05-1, 299 nm).

Examples 3-4-19: synthesis of E1201-3R by C-N coupling reaction of Compound B12-3R with 4-phenylpiperidine (E01)

[ Chemical formula 158 ]

A solution of compound B12-3R (0.194 mmol/g,15mg,0.0029 mmol) and 4-phenylpiperidine (e 01) (4.8 mg,0.030 mmol) in DMPr (0.3 mL) was added to a 0.6mL glass vial under nitrogen atmosphere and shaken at room temperature for 1 hour. A DMPr solution (prepared by adding 2 kinds of compounds to DMPr and heating them in a desiccator for about 1 minute) was added, which was mixed with Pd ₂dba₃CHCl₃ (0.025M, 0.0012 mmol) and (tBu) PhCPhos (0.1M, 0.0003 mmol) (12.0. Mu.L). A P2tBu/THF solution (2M, 22.5. Mu.L, 0.045 mmol) was added and the mixture was shaken at 80℃for 24 hours.

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and 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, LC samples were prepared, and LCMS assay was performed. As a result, the target E1201 was observed to be 97.7%.

[ Chemical formula 159 ]

LRMS：m/z 479[M+H]⁺

Retention time: 0.867 min (analysis conditions FA05-1, 299 nm).

Examples 3-4-20: synthesis of E1301-3R by C-N coupling reaction of Compound B13-3R with 4-phenylpiperidine (E01)

[ Chemical formula 160]

A solution of compound B13-3R (0.195 mmol/g,15mg,0.0029 mmol) and 4-phenylpiperidine (e 01) (4.8 mg,0.030 mmol) in DMPr (0.3 mL) was added to a 0.6mL glass vial under nitrogen atmosphere and shaken at room temperature for 1 hour. A DMPr solution (prepared by adding 2 kinds of compounds to DMPr and heating them in a desiccator for about 1 minute) was added, which was mixed with Pd ₂dba₃CHCl₃ (0.025M, 0.0012 mmol) and (tBu) PhCPhos (0.1M, 0.0003 mmol) (12.0. Mu.L). A P2tBu/THF solution (2M, 22.5. Mu.L, 0.045 mmol) was added and the mixture was shaken at 80℃for 24 hours.

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and 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, LC samples were prepared, and LCMS assay was performed. As a result, 88.6% of the target E1301 was observed.

[ Chemical formula 161 ]

LRMS：m/z 450[M+H]⁺

Retention time: 0.840 min (analysis conditions FA05-1, 299 nm).

Examples 3-4-21: synthesis of E1401-3R by C-N coupling reaction of Compound B14-3R with 4-phenylpiperidine (E01)

[ Chemical formula 162 ]

A solution of compound B14-3R (0.194 mml/g,15mg,0.0029 mmol) and 4-phenylpiperidine (e 01) (4.8 mg,0.030 mmol) in DMPr (0.3 mL) was added to a 0.6mL glass vial under nitrogen atmosphere and shaken at room temperature for 1 hour. A DMPr solution (prepared by adding 2 kinds of compounds to DMPr and heating them in a desiccator for about 1 minute) was added, which was mixed with Pd ₂dba₃CHCl₃ (0.025M, 0.0012 mmol) and (tBu) PhCPhos (0.1M, 0.0003 mmol) (12.0. Mu.L). A P2tBu/THF solution (2M, 22.5. Mu.L, 0.045 mmol) was added and the mixture was shaken at 80℃for 24 hours.

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and 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, LC samples were prepared, and LCMS assay was performed. As a result, object E1401 was observed to be 79.0%.

[ Chemical formula 163 ]

LRMS：m/z 470[M+H]⁺

Retention time: 0.848 min (analysis conditions FA05-1, 299 nm).

Examples 3-4-22: synthesis of E1501-1R by C-N coupling reaction of Compound B15-1R with 4-phenylpiperidine (E01)

[ Chemical formula 164 ]

A solution of compound B15-1R (0.194 mmol/g,15mg,0.0029 mmol) and 4-phenylpiperidine (e 01) (4.8 mg,0.030 mmol) in DMPr (0.3 mL) was added to a 0.6mL glass vial under nitrogen atmosphere and shaken at room temperature for 1 hour. A DMPr solution (prepared by adding 2 kinds of compounds to DMPr and heating them in a desiccator for about 1 minute) was added, which was mixed with Pd ₂dba₃CHCl₃ (0.025M, 0.0012 mmol) and (tBu) PhCPhos (0.1M, 0.0003 mmol) (12.0. Mu.L). A P2tBu/THF solution (2M, 22.5. Mu.L, 0.045 mmol) was added and the mixture was shaken at 80℃for 24 hours.

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and 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, LC samples were prepared, and LCMS assay was performed. As a result, the target E1501 was observed to be 62.4%.

[ Chemical formula 165 ]

LRMS：m/z 469[M+H]⁺

Retention time: 0.976 min (analysis conditions FA05-1, 299 nm).

Examples 3-4-23: synthesis of G0401-3R by C-N coupling reaction of Compound H04-3R with methyl 4-bromobenzoate (G01)

[ Chemical formula 166 ]

Compound H04-3R (0.196 mmol/g,15mg,0.0029 mmol) and methyl 4-bromobenzoate (g 01) (6.3 mg,0.029 mmol) and DMPr (0.3 mL) were added to a 0.6mL glass vial under nitrogen atmosphere and shaken at room temperature for 1 hour. RuPhos Pd G4 (2.5 mg,0.0029 mmol) and BTPP (13.5. Mu.L, 0.044 mmol) were added and shaken at 80℃for 24 hours.

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 1 minute. After filtration, the solid phase was washed with DMF (0.05 mL), meCN (0.25 mL) was added to the filtrate, LC samples were prepared, and LCMS assay was performed. As a result, 92.9% of the target G0401 was observed.

[ Chemical formula 167 ]

LRMS：m/z 467[M+H]⁺

Retention time: 1.133 min (analysis conditions FA05-1, 299 nm).

Examples 3-4-24: synthesis of G0401-3R by CN coupling of Compound H04-3R with methyl 4-chlorobenzoate (G04)

[ Chemical formula 168 ]

Compound H04-3R (0.196 mmol/g,15mg,0.0029 mmol) and methyl 4-chlorobenzoate (g 04) (5.0 mg,0.029 mmol) and DMPr (0.3 mL) were added to a 0.6mL glass vial under nitrogen atmosphere and shaken at room temperature for 1 hour. RuPhos Pd G4 (2.5 mg,0.0029 mmol) and BTPP (13.5. Mu.L, 0.044 mmol) were added and shaken at 80℃for 24 hours.

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 1 minute. After filtration, the solid phase was washed with DMF (0.05 mL), meCN (0.25 mL) was added to the filtrate, LC samples were prepared, and LCMS assay was performed. As a result, 90.3% of the target G0401 was observed.

Examples 3-4-25: synthesis of G0401-3R by C-N coupling reaction of Compound H04-3R with methyl 4-iodobenzoate (G05)

[ Chemical formula 169 ]

Compound H04-3R (0.196 mmol/g,15mg,0.0029 mmol) and methyl 4-iodobenzoate (g 05) (7.7 mg,0.029 mmol) and DMPr (0.3 mL) were added to a 0.6mL glass vial under nitrogen atmosphere and shaken at room temperature for 1 hour. RuPhos Pd G4 (2.5 mg,0.0029 mmol) and BTPP (13.5. Mu.L, 0.044 mmol) were added and shaken at 80℃for 24 hours.

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 1 minute. After filtration, the solid phase was washed with DMF (0.05 mL), meCN (0.25 mL) was added to the filtrate, LC samples were prepared, and LCMS assay was performed. As a result, 89.8% of the target G0401 was observed.

Examples 3-4-26: G0202-4R Synthesis by C-N coupling reaction of Compound H02-4R with ethyl 4-bromopyridine formate (G02)

[ Chemical formula 170 ]

Compound H02-4R (0.198 mmol/g,15mg,0.0030 mmol) and ethyl 5-bromopyridine formate (g 02) (6.8 mg,0.030 mmol) and DMPr (0.3 mL) were added to a 0.6mL glass vial under nitrogen atmosphere and shaken at room temperature for 1 hour. RuPhos Pd G4 (2.5 mg,0.0030 mmol) and BTPP (13.6. Mu.L, 0.045 mmol) were added and shaken at 80℃for 24 hours.

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 1 minute. After filtration, the solid phase was washed with DMF (0.05 mL), meCN (0.25 mL) was added to the filtrate, LC samples were prepared, and LCMS assay was performed. As a result, 89.5% of target G0202 was observed.

[ Chemical formula 171 ]

Compound G0202

LRMS：m/z 446[M+H]⁺

Retention time: 0.880 min (analysis conditions FA05-1, 299 nm).

Examples 3-4-27: synthesis of G0402-3R by C-N coupling reaction of Compound H04-3R with 5-bromopyridine ethyl formate (G02)

[ Chemical formula 172 ]

Compound H04-3R (0.196 mmol/g,15mg,0.0029 mmol) and ethyl 5-bromopyridine formate (g 02) (6.8 mg,0.029 mmol) and DMPr (0.3 mL) were added to a 0.6mL glass vial under nitrogen atmosphere and shaken at room temperature for 1 hour. RuPhos Pd G4 (2.5 mg,0.0029 mmol) and BTPP (13.5. Mu.L, 0.044 mmol) were added and shaken at 80℃for 24 hours.

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 1 minute. After filtration, the solid phase was washed with DMF (0.05 mL), meCN (0.25 mL) was added to the filtrate, LC samples were prepared, and LCMS assay was performed. As a result, the target G0402 was observed to be 87.0%.

[ Chemical formula 173 ]

LRMS：m/z 482[M+H]⁺

Retention time: 0.983 min (analysis conditions FA05-1, 299 nm).

Examples 3-4-28: G0103-4R Synthesis by C-N coupling of Compound H01-4R with ethyl 2-bromothiazole-4-carboxylate (G03)

[ Chemical formula 174 ]

To a 0.6mL glass vial under nitrogen was added compound H01-4R (0.198 mmol/g,15mg,0.0030 mmol) and ethyl 2-bromothiazole-4-carboxylate (g 03) (7.0 mg,0.030 mmol) and DMPr (0.3 mL), and the mixture was shaken at room temperature for 1 hour. tBuXPhos Pd G4 (2.5 mg,0.0030 mmol) and BTPP (13.6. Mu.L, 0.045 mmol) were added and shaken at 80℃for 24 hours.

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 1 minute. After filtration, the solid phase was washed with DMF (0.05 mL), meCN (0.25 mL) was added to the filtrate, LC samples were prepared, and LCMS assay was performed. As a result, 89.5% of target G0103 was observed.

[ Chemical formula 175 ]

LRMS：m/z 452[M+H]⁺

Retention time: 0.919 min (analysis conditions FA05-1, 299 nm).

Examples 3-4-29: G0303-4R synthesis by C-N coupling of Compound H03-4R with ethyl 2-bromothiazole-4-carboxylate (G03)

[ Chemical formula 176 ]

Compound H03-4R (0.197 mmol/g,15mg,0.0030 mmol) and ethyl 2-bromothiazole-4-carboxylate (g 03) (7.0 mg,0.030 mmol) and DMPr (0.3 mL) were added to a 0.6mL glass vial under nitrogen atmosphere and shaken at room temperature for 1 hour. tBuXPhos Pd G4 (2.4 mg,0.0030 mmol) and BTPP (13.6. Mu.L, 0.045 mmol) were added and shaken at 80℃for 24 hours.

The suspension of reaction solution and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and then immersed in a 10% TFA/DCM solution (0.05 mL) containing 0.02M pentamethylbenzene for 1 minute. After filtration, the solid phase was washed with DMF (0.05 mL), meCN (0.25 mL) was added to the filtrate, LC samples were prepared, and LCMS assay was performed. As a result, the target G0303 was observed to be 87.6%.

[ Chemical formula 177 ]

LRMS：m/z 474[M+H]⁺

Retention time: 1.001 min (analysis conditions FA05-1, 299 nm).

Example 5: application of Pd coupling conditions to mixtures

Example 5-1: synthesis of matrix mixtures

Examples 5-1-1: synthesis of mixture 2-2-B00-0

[ Chemical formula 178 ]

D084-3R and D085-3R can be prepared using separately prepared 2- (3-bromo-5- ((4- (piperidin-4-yloxy) benzyl) oxy) phenyl) propionic acid and 7-bromo-5- ((4- (piperidin-4-yloxy) benzyl) oxy) -1,2,3, 4-tetrahydronaphthalene-1-carboxylic acid under the same conditions as described in example 1-2-1.

To a 200mL column with filter was added compound D084-3R (3.2 g,0.200 mmol/g) and compound D085-3R (3.2 g,0.200 mmol/g), NMP (90 mL), tAmylOH (25.6 mL). The reaction solution was kept from leaking by covering with a cap, and the mixture was shaken at room temperature for 5 minutes. An aqueous TBAOH solution (1M, 256mL,2.56 mmol) was added. The reaction solution was kept from leaking by covering with a cap, and the mixture was shaken at room temperature for 1 hour. The suspension of the reaction solution and the solid phase was filtered with a filter of a column, washed 3 times with NMP/water=1/1 (128 mL), washed 3 times with NMP (128 mL), washed 3 times with an NMP solution (0.05 m,128mL each) mixed with tetrabutylammonium bisulfate and 2, 6-di-tert-butylpyridine, washed 3 times with NMP (128 mL), washed 3 times with MeOH (128 mL), washed 3 times with DCM (128 mL), washed 3 times with heptane (128 mL), and the resulting solid phase was dried under reduced pressure to give a mixture 2-2-B00-0 (6.81 g,0.201 mmol/g).

The compounds contained in mixture 2-2-B00-0 are shown in [ Table 5-1-1 ]. In [ Table 5-1-1], each compound contained in the mixture is represented by ID, and the structure is represented by the corresponding n number in the structural formula representing the mixture. Namely, the n number of the compound 2-2-B00-0-0001 is 0, which means the compound D084-3R, and the n number of the compound 2-2-B00-0-0002 is 1, which means the compound D085-3R.

[ Table 23]

[ Table 5-1-1] Compounds contained in mixture 2-2-B00-0

ID	Number 0
		2-2-B00-0-0001	0
2-2-B00-0-0002	1

Examples 5-1-2: synthesis of mixture 2-2-a1B01-0 to 2-2-a1B05-0

[ Chemical formula 179 ]

To 5 20mL columns with filters were added mixture 2-2-B00-0 (1.28 g,0.201 mmol/g) and DCM (15.4 mL). The amine (1.80 mmol) described in Table 5-1-2-0 was added to each column, and the reaction mixture was allowed to oscillate at room temperature for 1 hour with a cap so as not to leak. A MeCN solution (1M, 0.013mL,0.770mmol each) was added, mixed with PipClU and NMI. The reaction solution was kept from leaking by covering with a cap, and the mixture was shaken at room temperature for 2 hours.

The suspension of the reaction solution and the solid phase was filtered with a filter of a column, washed 3 times with NMP/water=1/1 (25 mL), washed 3 times with NMP (25 mL), washed 3 times with MeOH (25 mL), washed 3 times with DCM (25 mL), washed 1 time with heptane (25 mL), and the resulting solid phase was dried under reduced pressure to give the mixtures described in table 5-1-2-0.

[ Table 24]

[ Tables 5-1-2-0]

The compounds contained in the mixtures 2-2-a1B01-0 to 2-2-a1B05-0 are shown in tables 5-1-2-1 to 5-1-2-5. In [ tables 5-1-2-1] to [ tables 5-1-2-5], each compound contained in the mixture is represented by ID, and the corresponding n number and B moiety in the structural formula of the mixture are represented by symbols, thereby representing the structure. The correspondence of symbols and structural formulas related to part B in this specification is as follows, unless otherwise indicated.

[ Chemical formula 180]

For example, the compounds 2-2-a1B01-0-0001 have the following structure, wherein n is 0 and the moiety B is B01.

[ Chemical formula 1.81 ]

For example, the following structure is shown in the formula 2-2-a1B02-0-0002, wherein n is 1 and B is a moiety B02.

[ Chemical formula 182 ]

[ Table 25]

[ Table 5-1-2-1] Compounds contained in mixture 2-2-a1B01-0

ID	N number	B
			2-2-a1B01-0-0001	0	B01
2-2-a1B01-0-0002	1	B01

[ Table 26]

[ Table 5-1-2-2] Compounds contained in mixture 2-2-a1B02-0

ID	N number	B
			2-2-a1B02-0-0001	0	B02
2-2-a1B02-0-0002	1	B02

[ Table 27]

[ Table 5-1-2-3] Compounds contained in mixture 2-2-a1B03-0

ID	N number	B
			2-2-a1B03-0-0001	0	B03
2-2-a1B03-0-0002	1	B03

[ Table 28]

[ Tables 5-1-2-4] Compounds contained in mixture 2-2-a1B04-0

ID	N number	B
			2-2-a1B04-0-0001	0	B04
2-2-a1B04-0-0002	1	B04

[ Table 29]

[ Tables 5-1-2-5] Compounds contained in mixture 2-2-a1B05-0

ID	N number	B
			2-2-a1B05-0-0001	0	B05
2-2-a1B05-0-0002	1	B05

Examples 5-1-3: preparation of mixture 2-2-C00-0

[ Formula 183 ]

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

[ Table 30]

[ Tables 5-1-3-0]

Mixture of	Usage amount
		2-2-a1B01-0	0.700g
2-2-a1B02-0	0.700g
		2-2-a1B03-0	0.700g
[2-2-a1B04-0	0.700g
		[2-2-a1B05-0	0.700g

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 represented by ID, and the corresponding n number and B moiety in the structural formula of the mixture are represented by symbols, thereby representing the structure. The symbols in part B correspond to the structural formulae shown in examples 5-1-2.

[ Table 31]

[ Table 5-1-3-1] Compounds contained in mixture 2-2-C00-0

ID	N number	B
			2-2-a1B01-0-0001	0	B01
2-2-a1B01-0-0002	1	B01
			2-2-a1B02-0-0001	0	B02
2-2-a1B02-0-0002	1	B02
			2-2-a1B03-0-0001	0	B03
2-2-a1B03-0-0002	1	B03
			2-2-a1B04-0-0001	0	B04
2-2-a1B04-0-0002	1	B04
			2-2-a1B05-0-0001	0	B05
2-2-a1B06-0-0002	1	B06

Example 5-2: application of Pd coupling conditions to mixtures

Example 5-2-1: synthesis of mixture 2-2-b3C00-0 by hydroxylation of mixture 2-2-C00-0

[ Chemical formula 184 ]

To a 15mL glass vial was added mixture 2-2-C00-0 (550 mg,0.196 mmol/g) and DEAc (11.0 mL), water (0.275 mL,15.3 mmol) 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 shaken at 60℃for 15 hours.

The suspension of reaction solution and solid phase was transferred to a column with a filter for filtration, washed 3 times with NMP (11 mL), 3 times with NMP/water=5/1 solution of N-acetyl-L-cysteine (0.2 m,11 mL), 3 times with NMP solution (both 0.05m,11 mL) mixed with tetrabutylammonium bisulfate and 2, 6-di-tert-butylpyridine, 3 times with NMP solution of 4-methylmorpholine (0.05 m,11 mL), 3 times with NMP/water=1/1 (11 mL), 3 times with NMP (11 mL), 3 times with MeOH (11 mL), 3 times with DCM (11 mL), 1 time with heptane (11 mL), and the resulting solid phase was dried under reduced pressure to give a mixture 2-2-b3C00-0.

2-2-B3C00-0 are shown in [ Table 5-2-1-1 ]. In [ Table 5-2-1-1], each compound which can be contained in the mixture is represented by ID, and the corresponding n number and B moiety in the structural formula of the mixture are represented by symbols, thereby representing the structure. The symbols in part B correspond to the structural formulae shown in examples 5-1-2.

[ Table 32]

[ Table 5-2-1-1] Compounds that may be contained in mixture 2-2-b3C00-0

ID	N number	B
			2-2-b3C00-0-0001	0	B01
2-2-b3C00-0-0002	0	B02
			2-2-b3C00-0-0003	0	B03
2-2-b3C00-0-0004	1	B01
			2-2-b3C00-0-0005	1	B02
2-2-b3C00-0-0006	1	B03
			2-2-b3C00-0-0007	0	B04
2-2-b3C00-0-0008	0	B05
			2-2-b3C00-0-0009	1	B04
2-2-b3C00-0-0010	1	B05

[ Chemical formula 185 ]

At the time of 15 hours shaking at 60℃12. Mu.L of the suspension of reaction and solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL) and immersed in a 10% TFA/DCM solution of pentamethylbenzene (0.02M, 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 give a solution of mixture 2-2-b3C 00-1. By performing LCMS measurement of this solution, all the M/z ([ M+H ] +) from the compounds contained in the mixture 2-2-b3C00-1 described in [ Table 5-2-1-2] were observed. In [ Table 5-2-1-2], each compound which can be contained in the mixture is represented by ID, and the corresponding n number and B moiety in the structural formula of the mixture are represented by symbols, thereby representing the structure. This result shows that the mixture 2-2-b3C00-0 described in [ Table 5-2-1-1] can be accurately synthesized.

[ Table 33]

[ Table 5-2-1-2] Compounds that may be contained in mixture 2-2-b3C00-1

ID	Accurate quality	m/z	N number	B
					2-2-b3C00-1-0001	257.105	258[M+H]⁺	0	B01
2-2-b3C00-1-0002	271.121	272[M+H]⁺	0	B02
					2-2-b3C00-1-0003	275.096	276[M+H]⁺	0	B03
2-2-b3C00-1-0004	283.121	284[M+H]⁺	1	B01
					2-2-b3C00-1-0005	297.136	298[M+H]⁺	1	B02
2-2-b3C00-1-0006	301.111	302[M+H]⁺	1	B03
					2-2-b3C00-1-0007	314.073	215[M+H]⁺	0	B04
2-2-b3C00-1-0008	325.093	326[M+H]⁺	0	B05
					2-2-b3C00-1-0009	340.088	341[M+H]⁺	1	B04
2-2-b3C00-1-0010	351.108	352[M+H]⁺	1	B05

From the above results, it was revealed that the hydroxylation reaction using DEAc as a solvent can be applied even in the case where the substrate is not a single compound but a mixture of a plurality of compounds.

Examples 5-2-2: synthesis of mixture 2-2-b1C19-0 by C-N coupling reaction of mixture 2-2-C00-0

[ Chemical formula 186 ]

To a 4mL glass vial was added 2-2-C00-0 (128 mg,0.196 mmol/g) and DMPr (2.56 mL), and the mixture was shaken at room temperature for 1 hour. Ethyl 4- (piperazin-1-yl) benzoate (e 22) (58.9 mg,0.251 mmol) was added. (tBu) PhCPhos Pd G4 (19. Mg,0.025 mmol) and a solution of P2tBu in THF (2M, 0.189mL,0.377 mmol) were added and the mixture was shaken at 25℃for 1 hour.

The suspension of reaction solution and solid phase was transferred to a 6mL filter for filtration, washed 3 times with NMP/water=1/1 (2.6 mL), 3 times with NMP/water=5/1 solution of N-acetyl-L-cysteine (0.2 m,2.6 mL), 3 times with NMP solution (both 0.05m,2.6 mL) mixed with tetrabutylammonium bisulfate and 2, 6-di-tert-butylpyridine, 3 times with NMP solution of 4-methylmorpholine (0.05 m,2.6 mL), 3 times with NMP/water=1/1 (2.6 mL), 3 times with NMP (2.6 mL), 3 times with MeOH (2.8 mL), 3 times with DCM (2.8 mL), 3 times with heptane (2.8 mL), and the resulting solid phase was dried under reduced pressure to give a mixture of 2-2-b1C19-0.

2-2-B1C19-0 may be contained as shown in [ Table 5-2-2-1 ]. In [ Table 5-2-2-1], each compound which can be contained in the mixture is represented by ID, and the corresponding n number and B moiety in the structural formula of the mixture are represented by symbols, thereby representing the structure.

[ Table 34]

[ Table 5-2-2-1] Compounds that may be contained in mixture 2-2-b1C19-0

ID	N number	B
			2-2-b1C19-0-0001	0	B01
2-2-b1C19-0-0002	0	B02
			2-2-b1C19-0-0003	0	B03
2-2-b1C19-0-0004	1	B01
			2-2-b1C19-0-0005	1	B02
2-2-b1C19-0-0006	1	B03
			2-2-b1C19-0-0007	0	B04
2-2-b1C19-0-0008	0	B05
			2-2-b1C19-0-0009	1	B04
2-2-b1C19-0-0010	1	B05

[ Chemical formula 187 ]

At 25℃for 1 hour, 12. Mu.L of the suspension of the reaction solution and the solid phase was transferred to a filter, washed 3 times with DMF (0.1 mL), 3 times with MeOH (0.1 mL), 3 times with DCM (0.1 mL), and immersed in a 10% TFA/DCM solution of pentamethylbenzene (0.02M, 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, thereby obtaining a solution of mixture 2-2-b1C 19-1. By performing LCMS measurement of this solution, all the M/z ([ M+H ] ⁺) from the compounds contained in the mixture 2-2-b1C19-1 described in [ Table 5-2-2 ] were observed. In [ Table 5-2-2-2], each compound which can be contained in the mixture is represented by ID, and the corresponding n number and B moiety in the structural formula of the mixture are represented by symbols, thereby representing the structure. The symbols in part B correspond to the structural formulae shown in examples 5-1-2. This result shows that the mixture 2-2-b1C19-0 described in [ Table 5-2-2-1] can be accurately synthesized.

[ Table 35]

[ Table 5-2-2-1] Compounds that may be contained in mixture 2-2-b1C19-1

ID	Accurate quality	m/z	N number	B
					2-2-b1C19-1-0001	473.231	474[M+H]⁺	0	B01
2-2-b1C19-1-0002	487.247	488[M+H]⁺	0	B02
					2-2-b1C19-1-0003	491.222	492[M+H]⁺	0	B03
2-2-b1C19-1-0004	499.247	500[M+H]⁺	1	B01
					2-2-b1C19-1-0005	513.263	514[M+H]⁺	1	B02
2-2-b1C19-1-0006	517.238	518[M+H]⁺	1	B03
					2-2-b1C19-1-0007	530.199	531[M+H]⁺	0	B04
2-2-b1C19-1-0008	541.219	542[M+H]⁺	0	B05
					2-2-b1C19-1-0009	556.214	557[M+H]⁺	1	B04
2-2-b1C19-1-0010	567.234	568[M+H]⁺	1	B05

From the above results, it was revealed that even in the case where the substrate is not a single compound but a mixture of a plurality of compounds, the c—n coupling reaction using DMPr as a solvent can be applied. It was revealed that in the production of a compound library having a plurality of structures, the compound library can be efficiently constructed by performing a palladium coupling process of a plurality of compounds by applying the reaction conditions shown in this example.

Claims

1. A method for producing a compound by a cross-coupling reaction, comprising a step of reacting a compound 1 having a leaving group X ¹ on a carbon atom of an aromatic ring with a compound 2 having a reactive group capable of undergoing a c—o bond formation reaction or a c—n bond formation reaction based on substitution with the leaving group in a solvent comprising an amide-based solvent represented by formula a in the presence of a catalyst and a base;

Wherein R ¹、R² and R ³ are each independently a C _1-4 alkyl group, wherein the total number of carbon atoms of R ¹、R² and R ³ is 4 to 6,

X ¹ is a halogen atom or-O-SO ₂-R⁴;

R ⁴ is C _1-6 alkyl optionally substituted with 1 or more fluorine atoms, or phenyl optionally substituted with 1 or more fluorine atoms or C _1-6 alkyl optionally substituted with fluorine atoms;

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

3. The method according to any one of claims 1 or 2, wherein the compound 1 is a resin for solid phase synthesis having a leaving group X ¹ on a carbon atom of an aromatic ring in a side chain, or a resin for solid phase synthesis having a reactive group capable of undergoing a C-O bond formation reaction or a C-N bond formation reaction based on substitution with the leaving group in a side chain.

4. A method according to any one of claims 1 to 3, wherein compound 2 is:

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-to 10-membered heteroaryl group containing 1 or more ring heteroatoms independently selected from O, N and S, each of which is optionally substituted with 1 or more groups independently selected from 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, a 5-to 10-membered heteroarylcarbonylamino group containing 1 or more ring heteroatoms independently selected from O, N and S, (C _1-6 alkyl) aminocarbonyl, di (C _1-6 alkyl) aminocarbonyl, and 4-to 8-membered cyclic aminocarbonyl;

R ⁶ and R ⁷ together with the nitrogen atom to which they are bonded form a 5-to 7-membered saturated heterocyclic ring optionally substituted with 1 or more substituents independently selected from the group consisting of 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-to 10-membered heteroarylcarbonylamino comprising 1 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 alkyl) aminocarbonyl and 4-to 8-membered cyclic aminocarbonyl,

Or alternatively

R ⁶ and R ⁷ are each independently a hydrogen atom, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _3-8 cycloalkyl group, a (C _1-6 alkyl) carbonyl group, a (C _6-10 aryl) carbonyl group, a 5-to 10-membered heteroarylcarbonyl group comprising 1 or more ring heteroatoms independently selected from O, N and S, a C _7-14 aralkyl group, a C _6-10 aryl group, or a 5-to 10-membered heteroaryl group comprising 1 or more ring heteroatoms independently selected from O, N and S, each of which is optionally substituted with 1 or more substituents independently selected from 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 group, a 5-to 10-membered heteroarylcarbonylamino group comprising 1 or more ring heteroatoms independently selected from O, N and S, a di (C _1-6 alkyl) amino group, a 4-to 8-membered cyclic amino group, an aminocarbonyl group, (C _1-6 alkyl) aminocarbonyl group, a di (C _1-6 alkyl) aminocarbonyl group, and a 4-to 8-membered cyclic amino group.

5. The method according to any one of claims 1 to 4, wherein the compound 1 is a compound represented by X ¹-Ar²,

X ¹ is a chlorine atom, a bromine atom, an iodine atom, or-O-SO ₂-R⁴;

Ar ² is C _6-10 aryl, or a 5-to 10-membered heteroaryl group containing 1 or more ring heteroatoms independently selected from O, N and S, each of which is optionally substituted with 1 or more groups independently selected from 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-to 10-membered heteroarylcarbonylamino containing 1 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 alkyl) aminocarbonyl, and 4-to 8-membered cyclic aminocarbonyl.

6. The method of any one of claims 1-5, wherein Ar ² is independently selected from phenyl, naphthyl, pyrrolyl, thienyl, furanyl, pyridyl, thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, triallyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, indolyl, indolinyl, benzothienyl, benzofuranyl, benzisothiazolyl, benzisoxazolyl, indazolyl, benzimidazolyl, benzotriazole, azaindolyl, and imidazopyridinyl, each of which is optionally substituted.

7. The method of any one of claims 1-6, wherein the solvent is selected from the group consisting of N, N-dimethylpropionamide (DMPr), N-diethylacetamide (DEAc), and N, N-diethylpropionamide (DEPr).

8. The method of any one of claims 1-7, wherein the solvent is N, N-dimethylpropionamide (DMPr).

9. The method according to any one of claims 1 to 8, wherein the solvent is a solvent containing 30v/v% or more of at least one selected from the group consisting of N, N-dimethylpropionamide (DMPr), N-diethylacetamide (DEAc), and N, N-diethylpropionamide (DEPr).

10. The method according to any one of claims 1 to 9, wherein the catalyst is a catalyst comprising a palladium complex represented by any one of the following general formulae (Cat 1), (Cat 2), (Cat 3), (Cat 4) and (Cat 5):

Wherein R ²⁰ is a hydrogen atom, a C _1-6 alkyl group, or a C _6-10 aryl group, R ²¹ is a halogen or-O-SO ₂-CH₃,R²² is a C _1-6 alkyl group optionally substituted with 1 or more fluorine atoms, or a (C _1-6 alkoxy) carbonyl group optionally substituted with a tri (C _1-6 alkyl) silyl group, L is independently a monodentate ligand (L1), (L2), (L3), (L4), (L5), (L6), or (L7) of the general formula, or 2L is a bidentate ligand (L8), (L9), (L10), (L11), or (I12):

Wherein R ²³ is independently t-butyl, cyclohexyl, 2-furyl, 2-thienyl, 2-pyridyl, phenyl, or adamantyl, the phenyl group being optionally substituted with 1 or more fluorine atoms, C _1-6 alkyl optionally substituted with fluorine atoms, C _1-6 alkoxy, or dimethylamino,

R ²⁴ is C _1-6 alkyl, cyclohexyl, 2-furyl, 2-thienyl, 2-pyridyl, N-phenyl-2-pyrrolyl, N-phenyl-2-indolyl, phenyl or adamantyl, the phenyl group optionally substituted with more than 1 fluorine atom, C _1-6 alkyl optionally substituted with fluorine atom, C _1-6 alkoxy, morpholinyl or dimethylamino,

R ²⁵ is a hydrogen atom, a C _1-6 alkyl group, or a C _1-6 alkoxy group,

W ¹ is-C (CH ₃)₂ -, or-NH-,

R ³³ is a hydrogen atom, or-SO ₂ -O-M, M is lithium, sodium or potassium,

R ³⁴ is a hydrogen atom, a C _1-6 alkyl group, or a C _1-6 alkoxy group,

R ³⁷ is a hydrogen atom, or phenyl optionally substituted by C _1-6 alkyl,

R ³⁸ is independently a hydrogen atom, phenyl optionally substituted by C _1-6 alkyl, or-CH (CH ₃)-N(CH₃)₂,

R ³⁹ is tert-butyl, cyclohexyl, or adamantyl,

R ⁴⁰ is a hydrogen atom or a C _1-6 alkyl group, and the arrow indicates a coordinate bond.

11. The process according to any one of claims 1 to 9, wherein the catalyst is a catalyst comprising a palladium complex represented by the following general formula (Cat 6) and general formula (Cat 7),

Wherein R ⁴¹ is a hydrogen atom or a phenyl group optionally substituted with a C _1-6 alkyl group, R ⁴² is independently a halogen atom, R ⁴³ is a fluorine atom or a chlorine atom, L is an N-heterocyclic carbene ligand represented by the following general formula (L12) or (L13),

R ⁴⁴ and R ⁴⁵ are each independently C _1-6 alkyl, cyclohexyl, adamantyl, or phenyl optionally substituted with more than 1C _1-6 alkyl, C _1-6 alkoxy, or dimethylamino group, with a carbon atom of ·· representing a carbene, and an arrow representing a coordination bond.

12. The process according to any one of claims 1 to 9, wherein the catalyst is a catalyst comprising a palladium complex formed by combining a palladium compound selected from the group consisting of bis (allyl palladium (II) chloride), tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0) chloroform adduct, palladium chloride (pi-cinnamyl) dimer, (1-methallyl) palladium chloride dimer, (1, 5-cyclooctadiene) bis (trimethylsilylmethyl) palladium (II), (2 '-amino-1, 1' -biphenyl-2-yl) methane sulfonic acid palladium (II) dimer and palladium (II) acetate with a ligand selected from the group consisting of monodentate ligands (L1), (L2), (L4), (L5), (L6) or (L7) of the following general formulas, or a ligand represented by bidentate ligand (L8), (L9), (L10), (L11) or (L12) or a ligand as a salt thereof,

Wherein R ²³ is tert-butyl, cyclohexyl, 2-furyl, 2-thienyl, 2-pyridyl, phenyl, or adamantyl, the phenyl group being optionally substituted with 1 or more fluorine atoms, C _-6 alkyl optionally substituted with fluorine atoms, C _1-6 alkoxy, or dimethylamino,

R ²⁵ is a hydrogen atom, a C _1-6 alkyl group, or a C _1-6 alkoxy group,

W ¹ is-C (CH ₃)₂ -, or-NH-,

R ³³ is a hydrogen atom, or-SO ₂ -O-M, M is lithium, sodium or potassium,

R ³⁴ is a hydrogen atom, a C _1-6 alkyl group, or a C _1-6 alkoxy group,

R ³⁷ is a hydrogen atom, or phenyl optionally substituted by C _1-6 alkyl,

R ³⁸ is a hydrogen atom, phenyl optionally substituted by C _1-6 alkyl, or-CH (CH ₃)-N(CH₃)₂,

R ³⁹ is tert-butyl, cyclohexyl, or adamantyl,

13. The process according to any one of claims 1 to 12, wherein the base comprises at least 1 base selected from organic bases having a pKa of 23 or more of the conjugate acid in acetonitrile and inorganic bases having a pKa of 9 to 20 of the conjugate acid in water.

14. The process according to any one of claims 1 to 13, wherein in the reaction system, a salt is further included together with the base.

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, trifluoromethanesulfonyl imide, tetrafluoroboric acid, hexafluorophosphoric acid, hexafluoroantimony (V) acid.

16. A method for producing a compound, comprising the method according to any one of claims 1 to 15.

17. Use of a solvent comprising an amide-based solvent of formula A in a cross-coupling reaction, wherein,

Wherein R ¹、R² and R ³ are each independently a C _1-4 alkyl group, and wherein the total number of carbon atoms of R ¹、R² and R ³ is 4 to 6.