HK1162501B

HK1162501B - Process for producing phenyl-substituted heterocyclic derivative through coupling using transition metal catalyst

Info

Publication number: HK1162501B
Application number: HK12102980.4A
Authority: HK
Inventors: Masato Komiyama; Naoki Yajima; Masayuki Kurokawa
Original assignee: Teijin Limited
Priority date: 2009-02-27
Filing date: 2010-02-26
Publication date: 2015-09-25

Description

Method for producing phenyl-substituted heterocyclic derivative by coupling method using transition metal catalyst

Technical Field

The present invention relates to a method for producing a phenyl-substituted heterocyclic derivative by a novel coupling method of a phenyl derivative and a heterocyclic derivative using a transition metal catalyst. More specifically, the present invention relates to a process for producing a phenyl-substituted heterocyclic derivative or an intermediate thereof, which is useful as a xanthine oxidase inhibitor such as a therapeutic agent for gout and hyperuricemia, and which is excellent.

Background

Gout is a disease based on hyperuricemia, and an improvement therapy for hyperuricemia is performed after onset of remission. Therapeutic agents for hyperuricemia are roughly classified into uricosuric agents and uric acid synthesis inhibitors (xanthine oxidase inhibitors), and are appropriately selected depending on the form and degree of the disease.

Examples of Xanthine Oxidase (XOD) inhibitors include 2-phenylthiazole derivatives (patent documents 1 to 6 and non-patent document 1), 3-phenylisothiazole derivatives (patent documents 7 and 8), phenylpyrazole derivatives (patent documents 9 to 11), and 2-phenylpyrazole derivativesAzole derivatives (patent document 12) and phenyl heteroaryl derivatives (patent document 13). The production methods described in patent documents 1 to 12 are methods for constructing a heterocyclic ring by a production method in which reactions are continuously performed in series, and the number of steps is large. The production method described in patent document 13 is a method of constructing a skeleton by directly coupling a benzene ring and a heterocycle, and the number of steps is small. However, this method requires production of a boron compound, and therefore is expensive, and is not a satisfactory method in terms of a production method with a small number of steps and a low cost.

As a production method in which a C — H bond on a heterocyclic ring is directly bonded to a benzene ring without using a boron compound, a coupling method using palladium (non-patent documents 2 to 10), rhodium (non-patent document 11), iridium (non-patent document 12), copper (non-patent document 13), nickel (non-patent documents 14 to 15), cobalt (non-patent document 16), palladium-copper (non-patent documents 17 to 19), and palladium-silver (non-patent document 20) as a catalyst has been reported. Among them, the production method using a nickel catalyst relates to a method for synthesizing a phenyl-substituted heterocyclic derivative as a Xanthine Oxidase (XOD) inhibitor (non-patent document 9). However, no example of synthesizing the phenyl-substituted heterocyclic derivative of the present invention using a metal catalyst other than a nickel catalyst has been reported. Further, the above reaction is not a reaction which satisfies the requirements in terms of substrate restriction, cost and yield.

Documents of the prior art

Patent document

Patent document 1: international publication No. 92/09279 pamphlet

Patent document 2: japanese patent laid-open No. 6-293746

Patent document 3: japanese patent laid-open No. 6-329647

Patent document 4: japanese patent laid-open No. 6-345724

Patent document 5: japanese patent laid-open No. Hei 10-139770

Patent document 6: japanese patent laid-open No. Hei 11-60552

Patent document 7: japanese patent laid-open No. 57-85379

Patent document 8: japanese patent laid-open No. 6-211815

Patent document 9: japanese patent laid-open No. 59-95272

Patent document 10: international publication pamphlet No. 98-18765

Patent document 11: japanese patent laid-open No. Hei 10-310578

Patent document 12: japanese patent laid-open No. Hei 6-65210

Patent document 13: international publication No. 2007-097403 pamphlet

Non-patent document

Non-patent document 1: heterocycles 1998: 47, 857

Non-patent document 2: j.am.chem.soc.2003: 125, 1700

Non-patent document 3: j.am.chem.soc.2006: 128, 16496

Non-patent document 4: angew.chem., int.ed.2007: 46, 7996

Non-patent document 5: j.org.chem.2009: 74, 1826

Non-patent document 6: org.lett.2009: 10(13),2909

Non-patent document 7: tetrahedron Letters, 2008: 49(6),1045

Non-patent document 8: tetrahedron Letters, 2003: 59(30),5685

Non-patent document 9: bull. chem.soc.jpn., 1998: 71, 467

Non-patent document 10: chem.a.eur.j., 2009: 15(6),1337

Non-patent document 11: j.am.chem.soc.2008: 130, 14926

Non-patent document 12: chem.comm.2004: 1926

Non-patent document 13: j.am.chem.soc.2007: 129(41),12404

Non-patent document 14: org.lett.2009: 11(8),1733

Non-patent document 15: org.lett.2009: 11(8),1737

Non-patent document 16: org.lett.2003: 5(20),3607

Non-patent document 17: tetrahedron, 2007: 63(9),1970

Non-patent document 18: org.lett.2004: 6(12),2011

Non-patent document 19: j.am.chem.soc.2003: 125, 1700

Non-patent document 20: angew.chem.int.ed.2007: 46, 7996

Disclosure of Invention

Problems to be solved by the invention

The present invention has been made to solve the above-mentioned problems, and an object of the present invention is to provide a process for producing a phenyl-substituted heterocyclic derivative which is useful as a xanthine oxidase inhibitor such as a therapeutic agent for gout and hyperuricemia, or a good process for producing an intermediate thereof, which is different from the above-mentioned known processes.

Means for solving the problems

The present inventors have conducted extensive studies to solve the above problems, and as a result, have found that a benzene ring of a phenyl derivative can be directly coupled to a C — H bond on a heterocyclic derivative with good selectivity by using a transition metal compound.

That is, the present invention relates to the following technical matters.

[1] A process for producing a phenyl-substituted heterocyclic derivative represented by the following formula (3),

produced by reacting a compound represented by the following formula (1) with a compound represented by the following formula (2) in the presence of a transition metal compound;

in the formula (1), the reaction mixture is,

R¹represents a hydrogen atom orA halogen atom;

R²represents a hydrogen atom, a cyano group, a nitro group, a halogen atom, a formyl group or a halomethyl group;

a represents a hydrogen atom, C₁～C₈Alkyl radical, C₃～C₆Cycloalkyl groups, phenyl groups, fluorine atoms (only in the case where X is a bond) or protecting groups for hydroxyl groups (only in the case where X is an oxygen atom);

a may be substituted with 1 to 3 substituents selected from a halogen atom, C₁～C₄Alkyl radical, C₁～C₄Alkoxy radical, C₁～C₄Alkylthio radical, C₃～C₆Cycloalkyl, phenyl, phenoxy and pyridyl groups;

x represents a bond (only when A is a phenyl group or a fluorine atom) or an oxygen atom;

y represents a leaving group, and Y represents a leaving group,

in the formula (2), the reaction mixture is,

h represents a hydrogen atom;

b represents a group selected from the following formulae;

R³represents COOR^3aOr COR^3b；

R^3aRepresents a hydrogen atom, C₁～C₄Ester protecting groups for alkyl or carboxyl groups;

R^3ban amide-type protecting group representing a carboxyl group which forms an amide with an adjacent carbonyl group;

R⁴represents a hydrogen atom, a halogen atom or C₁～C₄An alkyl group;

w represents an oxygen atom or a sulfur atom,

in the formula (3), the reaction mixture is,

A、X、R¹and R²Is as defined for formula (1), B and R³The definition of (3) is the same as that of the formula (2).

[2][1]The production process described above, wherein A is C₁～C₅An alkyl group.

[3] [1] the production method according to, wherein A is isobutyl.

[4] The production method according to any one of [1] to [3], wherein X is an oxygen atom.

[4][1]～[4]The production process of any one of the above, wherein R¹Is a hydrogen atom.

[6][1]～[5]The production process of any one of the above, wherein R²Is cyano.

[7] The production method according to any one of [1] to [6], wherein,

y represents a halogen atom, -OCO₂-(C₁～C₄Alkyl), -OCO₂- (phenyl), -OSO₂-(C₁～C₄Alkyl), -OSO₂- (phenyl) or diazo;

c in Y₁～C₄The alkyl group may be substituted with 1 to 3 halogen atoms, and the phenyl group in Y may be substituted with 1 to 3 halogen atoms or C₁～C₄Alkyl substitution.

[8] The production method according to any one of [1] to [7], wherein B represents the following group.

[9][1]～[8]The production process of any one of the above, wherein R⁴Is methyl.

[10] The production process according to any one of [1] to [9], wherein the transition metal compound is a salt of 0-valent copper or 1-valent copper.

[11] The production process according to any one of [1] to [9], wherein the transition metal compound is 0-valent palladium or a salt of 1-valent or 2-valent palladium.

[12] The production process according to any one of [1] to [9], wherein the transition metal compound is a salt of palladium having a valence of 0 or 2.

[13] The production process according to any one of [1] to [9], wherein the transition metal compound is a salt of cobalt having a valence of 0 or cobalt having a valence of 2.

[14] The production method according to any one of [1] to [9], wherein the transition metal compound is copper (I) iodide (CuI).

[15][1]～[9]The production process according to any one of the above processes, wherein the transition metal compound is palladium (II) acetate (Pd (OAc))₂) Palladium (II) propionate (Pd (O (C ═ O) CH)₂CH₃)₂) Palladium (II) 2-methylpropionate (Pd (O (C ═ O) CH (CH)₃)₂)₂) Palladium trimethyl acetate (Pd (OPiv))₂) Palladium (II) chloride (PdCl)₂) Palladium (I) bromide (Pd)₂Br₂) Or palladium (II) hydroxide (Pd (OH)₂)。

[16][1]～[9]The production process according to any one of the above processes, wherein the transition metal compound is palladium (II) acetate (Pd (OAc))₂) Palladium (II) propionate (Pd (O (C ═ O) CH)₂CH₃)₂) Palladium (II) 2-methylpropionate (Pd (O (C ═ O) CH (CH)₃)₂)₂) Or trimethylpalladium acetate (Pd (OPiv)₂)。

[17][1]～[9]Zhong renThe process according to the above, wherein the transition metal compound is palladium (II) acetate (Pd (OAc)₂) Palladium (II) chloride (PdCl)₂) Or palladium (II) hydroxide (Pd (OH)₂)。

[18][1]～[9]The production process according to any one of the above processes, wherein the transition metal compound is cobalt (II) acetate (Co (OAc))₂)。

[19] The production process according to any one of [1] to [18], wherein a ligand capable of coordinating to the transition metal compound is further present during the reaction.

[20] [19] the production method according to [19], wherein the ligand is triphenylphosphine, tri-tert-butylphosphine, di-tert-butylmethylphosphine, tert-butyldicyclohexylphosphine, di-tert-butylcyclohexylphosphine, tricyclohexylphosphine, 2-dicyclohexylphosphino-2 ', 6' -diisopropoxy-1, 1 '-biphenyl, 2-dicyclohexylphosphino-2', 4 ', 6' -triisopropyl-1, 1 '-biphenyl, phenanthroline, 1' -bis (diphenylphosphino) ferrocene, or a salt thereof.

[21] [19] the production method according to [19], wherein the ligand is triphenylphosphine, tri-tert-butylphosphine, di-tert-butylmethylphosphine, tert-butyldicyclohexylphosphine, di-tert-butylcyclohexylphosphine, tricyclohexylphosphine, phenanthroline, or 1, 1' -bis (diphenylphosphino) ferrocene.

[22] [19] the production method according to any one of [1] to [19], wherein the ligand is triphenylphosphine, phenanthroline, or 1, 1' -bis (diphenylphosphino) ferrocene.

[23] [19] the production method according to, wherein the ligand is a phosphine ligand.

[24] [23] the production method according to [23], wherein the ligand is tri-tert-butylphosphine, tert-butyldicyclohexylphosphine, di-tert-butylmethylphosphine, di-tert-butylcyclohexylphosphine, tricyclohexylphosphine, 2-dicyclohexylphosphino-2 ', 6 ' -diisopropoxy-1, 1 ' -biphenyl, 2-dicyclohexylphosphino-2 ', 4 ', 6 ' -triisopropyl-1, 1 ' -biphenyl, or a salt thereof.

[25] [23] the production method according to [23], wherein the ligand is tri-tert-butylphosphine, tert-butyldicyclohexylphosphine, di-tert-butylmethylphosphine, di-tert-butylcyclohexylphosphine, or tricyclohexylphosphine.

[26] The production method according to any one of [1] to [25], wherein a base is further present in the reaction.

[27] [26] the production method according to, wherein the base is lithium tert-butoxide.

[28] [26] the production method according to, wherein the base is potassium carbonate or cesium carbonate.

[29] The production method according to any one of [1] to [28], wherein a silver salt is further present in the reaction.

[30] [29] the production method according to any one of the above methods, wherein the silver salt is silver carbonate.

[31][1]～[30]The production method of any one of the above, wherein C is further present in the reaction₁～C₁₂Or a salt thereof.

[32][1]～[30]The production method of any one of the above, wherein C is further present in the reaction₁～C₆Or a salt thereof.

[33] [32] the production method according to any one of the above methods, wherein the carboxylic acid or a salt thereof is 2-methylpropionic acid, trimethylacetic acid or a salt thereof.

[34] [32] the production method according to, wherein the carboxylic acid or a salt thereof is trimethylacetic acid.

ADVANTAGEOUS EFFECTS OF INVENTION

According to the present invention, a phenyl-substituted heterocyclic derivative (compound represented by formula (3)) can be obtained with a reduced number of steps by selectively performing a coupling reaction between a phenyl derivative (compound represented by formula (1)) and a heterocyclic derivative (compound represented by formula (2)) using a transition metal catalyst.

Further, since the number of steps is small, the phenyl-substituted heterocyclic derivative (the compound represented by the formula (3)) can be produced in a high yield at a low cost.

Detailed Description

The following description will discuss terms used in the present specification either singly or in combination. Unless otherwise specified, the description of each substituent is common to each site. Combinations of substituents and variables are permissible only if such combinations result in chemically stable compounds. When the substituent itself is substituted with 2 or more groups, these plural groups may be present on the same carbon or different carbons as long as they can form a stable structure.

In the present invention, "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

In the present invention, "C₁～C₈The "alkyl group" refers to a saturated straight-chain or branched aliphatic hydrocarbon group having 1 to 8 carbon atoms, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl, 1-dimethylbutyl, 2-dimethylbutyl, 3-dimethylbutyl, n-heptyl, and n-octyl.

In the present invention, "C₁～C₄Alkoxy "means a radical consisting of₁～C₄Examples of the group consisting of alkyl and oxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy.

In the present invention, "C₃～C₆The "cycloalkyl group" refers to a cyclic alkyl group having 3 to 6 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In the present invention, "C₁～C₄Alkylthio "means a radical consisting of₁～C₄Examples of the "alkyl" and "thio" group include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio and isobutylthioAnd tert-butylthio.

In the present invention, the "halomethyl group" means a methyl group substituted with 1 or more halogen atoms, and examples thereof include a trifluoromethyl group, a difluoromethyl group, a fluoromethyl group, a trichloromethyl group, a dichloromethyl group, a chloromethyl group, a tribromomethyl group, a dibromomethyl group, and a bromomethyl group.

In the present invention, the "leaving group" refers to an atom or a group of atoms detached from a reaction substrate in a substitution reaction, an elimination reaction, or the like. Examples of the "leaving group" may include a halogen atom and an-OCO₂-(C₁～C₄Alkyl), -OCO₂- (phenyl), -OSO₂-(C₁～C₄Alkyl), -OSO₂- (phenyl) or diazo (-N)⁺N), etc. C constituting a leaving group₁～C₄The alkyl group may be substituted with 1 to 3 halogen atoms, and the phenyl group constituting the leaving group may be substituted with 1 to 3 halogen atoms or C₁～C₄Alkyl substitution. But is not limited thereto.

"protecting group for hydroxyl group" means a group protecting a hydroxyl group. The "protecting group for a hydroxyl group" is well known in the art and can be classified into an ether protecting group, a silicon ether protecting group, an ester protecting group, a carbonate protecting group, a phosphine protecting group, a sulfonate protecting group and the like, and examples thereof include benzyloxymethyl, methoxyethoxymethyl, phenylthiomethyl, phenacylmethyl, 4-bromobenzoylmethylmethyl, cyclopropylmethyl, allyl, propargyl, cyclohexyl, benzyl, O-nitrobenzyl, 4- (dimethylamino) carbonylbenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl, 4-pyridylmethyl, trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, formyl, - (C ═ O) - (C₁～C₄Alkyl), benzoyl, 4-oxopentanoyl, pivaloyl, methylester, 1-adamantyloxycarbonyl, tert-butoxycarbonyl, 4-methylsulfinylbenzyloxycarbonyl, 2, 4-dimethylpent-3-yloxycarbonyl, 2, 2, 2-trichloroethoxycarbonyl, vinyloxycarbonyl, benzyloxycarbonyl, - (C ═ O) NH- (C ═ O)₁～C₄Alkyl Groups), methanesulfonyl Groups, and toluenesulfonyl Groups, and the like, and Groups described in the "phenol protecting group of Protective Groups in Organic Synthesis" (3 rd edition, 1994), (4 th edition, 2006) "in Green (T.W.Greene) and Wutz (P.G.M.Wuts). However, the group is not limited to the groups exemplified herein, as long as it can be used as a protecting group for a hydroxyl group. Here, the protecting group of a hydroxyl group is a group which functions as a protecting group of a hydroxyl group when X is an oxygen atom. For example, when benzyl is a protecting group, A-X-is PhCH₂-O-。

The "ester-protecting group of a carboxyl group" in the present invention means a group for protecting a carboxyl group, which is bonded to an oxygen atom of the protected carboxyl group to form an ester. Examples of the "ester-protecting group for a carboxyl group" may include C₁～C₆Alkyl, 9-fluorenylmethyl, methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, benzyloxymethyl, pivaloyloxymethyl, phenylacetyloxymethyl, triisopropylsilylmethyl, p-bromobenzoylmethyl, α -methylbenzoylmethyl, p-methoxybenzoylmethyl, decyl, carboxamidomethyl, p-azobenzamidomethyl, N-phthalimidomethyl, 2, 2, 2-trichloroethyl, 2-haloethyl, ω -chloroalkyl, 2- (triethylsilyl) ethyl, 2-methylthioethyl, 1, 3-dithianyl-2-methyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (p-toluenesulfonyl) ethyl, tetrahydrofuranyl, methoxyethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, decyl, N-phthaloylaminomethyl, N-phthalimidomethyl, 2, 2, 2-trichloroethyl, 2-haloethyl, ω -chloroalkyl, 2- (2' -pyridyl) ethyl, 2- (p-methoxyphenyl) ethyl, 2- (diphenylphosphino) ethyl, 1-methyl-1-phenylethyl, 2- (4-acetyl-2-nitrophenyl) ethyl, 2-cyanoethyl, dicyclopropylmethyl, cyclopentyl, cyclohexyl, allyl, methallyl, 2-methylbut-3-en-2-yl, 3-methylbut-2-isoprenyl, 3-buten-1-yl, 4- (trimethylsilyl) -2-buten-1-yl, cinnamyl, alpha-methylcinnamyl, prop-2-ynylpropargyl, phenyl, 2, 6-dimethylphenyl, 2, 6-diisopropylphenyl, 2, 6-di-tert-butyl-4-methylphenyl, 2, 6-di-tert-butyl-4-methoxyphenyl, p- (methylthio) phenyl, pentafluoroPhenyl, benzyl, triphenylmethyl, diphenylmethyl, bis (o-nitrophenyl) methyl, 9-anthrylmethyl, 2- (9, 10-dioxo) anthrylmethyl, 5-dibenzocycloheptyl, 1-pyrenylmethyl, 2- (trifluoromethyl) -6-chromonylmethyl, 2, 4, 6-trimethylbenzyl, P-bromobenzyl, o-nitrobenzyl, P-methoxybenzyl, 2, 6-dimethoxybenzyl, 4- (methylsulfinyl) benzyl, 4-sulfobenzyl, 4-azidomethoxybenzyl, piperonyl, 4-picolinyl, P-P-benzyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, isopropyldimethylsilyl, phenyldimethylsilyl, P-toluenesulfonyl, P-nitrobenzyl, Di (tert-butyl) methylsilyl, triisopropylsilyl, C₁～C₆Alkylthio, alkylthio,Azolyl, 2-alkyl-1, 3-Oxazolinyl, 4-alkyl-5-oxo-1, 3-Oxazolidinyl, 2-bis-trifluoromethyl-4-alkyl-5-oxo-1, 3-Oxazolidinyl, 5-alkyl-4-oxo-1, 3-dioxolanyl, dioxanone, and the like, and Groups described in the ester protecting group of carboxyl group in Guilin (T.W.Greene) and Wutz (P.G.M.Wuts), "Protective Groups in Organic Synthesis (3 rd edition, 1994), (4 th edition, 2006)". However, the group is not limited to the groups exemplified herein, as long as it can be used as a protecting group for a carboxyl group.

The "amide-type protecting group for carboxyl group" in the present invention refers to a group for protecting carboxyl group, which is bonded to the carbonyl carbon atom of the protected carboxyl group to form an amide. Examples of the "amide-type protecting group for a carboxyl group" include Groups described in the "protecting group for a carboxyl group" in Guilin (T.W.Greene) and Wuzhez (P.G.M.Wuts) "and" Protective Groups in organic Synthesis (Protective Groups in organic Synthesis) (3 rd edition, 1994) ", and" 4 th edition, 2006) ", such as N, N-dimethylamino group, pyrrolidinyl group, piperidinyl group, 5, 6-dihydrophenanthridinyl group, o-nitrophenylamino group, N-7-nitroindolyl group, N-8-nitro-1, 2, 3, 4-tetrahydroquinolinyl group, N-phenylhydrazino group, N' -diisopropylhydrazino group. However, the amino group is not limited to the groups exemplified herein as long as it can be used as a protecting group for a carboxyl group.

In the present invention, for example, "C₁"C" of "etc. represents a carbon atom, and the numbers attached thereafter represent the carbon number. For example, "C₁～C₆"represents a range of 1 to 6 carbon atoms. It is apparent that, in the present invention, if the carbon number is different, this group having the carbon number is represented. For example, "C₁～C₄Alkyl "means" C₁～C₈The alkyl group is defined as a group having 1 to 4 carbon atoms. The same applies to the treatment of carbon numbers in other groups.

The "diazo" in the present invention may form a salt. Examples of the salt include a fluoride salt, a chloride salt, a bromide salt, an iodide salt, and a tetrafluoroborate salt.

Abbreviations used in the present invention are as follows.

TfO: trifluoromethanesulfonyloxy, MsO: methanesulfonyloxy group, TsO: tosyloxy, Me: methyl group, Et: ethyl group, n-Pr: n-propyl group, i-Pr: isopropyl group, i-Bu: isobutyl, t-Bu: tert-butyl, MeO: methoxy group, Ph: phenyl, OAc: acetoxy, 4-MeO-Ph: 4-methoxyphenyl, Cy: cyclohexyl, Piv: pivaloyl radical

The present invention relates to the following formula (3)

A process for producing a phenyl-substituted heterocyclic derivative represented by the formula (1)

A compound represented by the formula (2)

The compounds represented are reacted in the presence of a transition metal compound.

In the above formulae (1) and (3), R¹Represents a hydrogen atom or a halogen atom.

As R¹The "halogen atom" in (1) is preferably a chlorine atom or a fluorine atom, and more preferably a fluorine atom.

As R¹In general, hydrogen atoms are preferred.

In the above formulae (1) and (3), R²Represents a hydrogen atom, a cyano group, a nitro group, a halogen atom, a formyl group or a halomethyl group.

As R²The "halogen atom" in (1) is preferably a bromine atom.

As R²The "halomethyl group" in (1) is preferably chloromethyl, dichloromethyl, trichloromethyl or trifluoromethyl.

As R²As a whole, a cyano group, a nitro group or a formyl group is preferable, and a cyano group is preferable.

In the formulas (1) and (3), A represents a hydrogen atom and C₁～C₈Alkyl radical, C₃～C₆Cycloalkyl groups, phenyl groups, fluorine atoms (only when X is a bond) or protecting groups for hydroxyl groups (only when X is an oxygen atom). Here, the protecting group of a hydroxyl group is a group which functions as a protecting group of a hydroxyl group when X is an oxygen atom. For example, when the protecting group is benzyl, A-X-is PhCH₂-O-。

A may be substituted with 1 to 3 substituents selected from a halogen atom, C₁～C₄Alkyl radical, C₁～C₄Alkoxy radical, C₁～C₄Alkylthio radical, C₃～C₆Cycloalkyl, phenyl, phenoxy and pyridyl.

As "C" in A₁～C₈Alkyl ", preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl or neopentyl, with isobutyl or neopentyl being preferred and isobutyl being more preferred.

As A as a whole, C is preferred₁～C₅An alkyl group.

In the formulae (1) and (3), X represents a bond (only when A is a phenyl group or a fluorine atom) or an oxygen atom. Among them, oxygen atom is preferred.

In the formula (1), Y represents a leaving group. Among them, preferred is a halogen atom, -OCO₂-(C₁～C₄Alkyl), -OCO₂- (phenyl), -OSO₂-(C₁～C₄Alkyl), -OSO₂- (phenyl) or diazo.

Leaving group as Y being-OCO₂-(C₁～C₄Alkyl) "or" -OSO₂-(C₁～C₄Alkyl) "as" C "in Y₁～C₄Alkyl ", preferably methyl.

Leaving group as Y being-OCO₂-(C₁～C₄Alkyl) "or" -OSO₂-(C₁～C₄Alkyl), "C" in Y₁～C₄The alkyl group "may be substituted with 1 to 3 halogen atoms. The "halogen atom" is preferably a fluorine atom, and particularly preferably 3 fluorine atoms.

Leaving group as Y being-OCO₂- (phenyl)' or "-OSO₂- (phenyl)', the "phenyl" in Y mayBy 1 to 3 halogen atoms or C₁～C₄Alkyl substitution. As the "C₁～C₄Alkyl ", preferably methyl.

When the leaving group for Y is a "halogen atom", the "halogen atom" is preferably an iodine atom, a bromine atom or a chlorine atom, and among them, an iodine atom or a bromine atom is preferred.

"diazo" groups may form salts. When the leaving group of Y represents a "diazo group", the salt of the "diazo group" is preferably tetrafluoroborate.

As the whole Y, an iodine atom, a bromine atom, a trifluoromethanesulfonyloxy group or the like is preferable.

In the formula (2), H represents a hydrogen atom.

In the formulas (2) and (3), B represents a group selected from the following formulas. The right-hand bonds of the formulae are with R³The bond on the left side is a bond to a hydrogen atom in formula (2), and a bond to a phenyl group in formula (3).

Among them, the following groups are preferred.

In the above formulae (2) and (3), R³Represents COOR^3aOr COR^3b。

R^3aRepresents a hydrogen atom, C₁～C₄Ester protecting groups for alkyl or carboxyl groups. Here, as R^3aThe ester protecting group of the carboxyl group is a protecting group R^3aThe group of substituted carboxyl groups.

As R^3aPreferably a hydrogen atom or C₁～C₄An alkyl group.

R^3bRepresents an amide-type protecting group of a carboxyl group which forms an amide with an adjacent carbonyl group.

As R³Overall, preferably COOR^3a。

In the above formulae (2) and (3), R⁴Represents a hydrogen atom, a halogen atom or C₁～C₄An alkyl group.

As R⁴The "halogen atom" in (1) is preferably a fluorine atom.

As R⁴In (1), "C₁～C₄Alkyl ", preferably methyl.

As R⁴Integer, preferably C₁～C₄Alkyl groups, among which methyl is preferred.

In the formulae (2) and (3), W represents an oxygen atom or a sulfur atom.

In the above formula (3), A, X, R¹And R²Are the same as those in the formula (1), B and R are³The definitions and preferred groups of (3) are the same as in formula (2), respectively.

Specific examples of the compound represented by the formula (1) are shown in tables 1 to 4, and specific examples of the compound represented by the formula (2) are shown in tables 5 to 7. However, the compounds represented by the formulae (1) and (2) are not limited to the specific examples.

[ Table 1]

[ Table 2]

[ Table 3]

[ Table 4]

[ Table 5]

[ Table 6]

[ Table 7]

The production method of the present invention is characterized by using a transition metal compound as a catalyst. The transition metal in the transition metal compound used in the production method of the present invention does not include nickel, and examples thereof include copper, palladium, cobalt, iron, rhodium, ruthenium, and iridium. Among them, copper, palladium or cobalt is preferable. Examples of copper include 0-valent Cu (0), 1-valent Cu (I), and 2-valent Cu (II), and preferably 0-valent Cu (0) or 1-valent Cu (I). Palladium is preferably Pd (0) in the valence state 0, Pd (I) in the valence state 1 or Pd (II) in the valence state 2. Cobalt may be exemplified by 0-valent Co (0), 1-valent Co (I), 2-valent Co (II) and 3-valent Co (III), and 0-valent Co (0), 1-valent Co or 2-valent Co (II) is preferable. Iron may be exemplified by 0-valent Fe (0), 2-valent Fe (II) and 3-valent Fe (III), preferably 2-valent Fe (II) or 3-valent Fe (III). Rhodium is preferably Rh (0) having a valence of 0 or Rh (I) having a valence of 1. Ruthenium is preferably 0-valent Ru (0) or 2-valent Ru (II). Examples of iridium include 0-valent Ir (0), 1-valent Ir (I), 2-valent Ir (II), 3-valent Ir (III) and 4-valent Ir (IV), and preferably 3-valent Ir (III).

Examples of the salt of cu (I) include copper (I) chloride, copper (I) bromide, copper (I) iodide, copper (I) acetate, copper tetrafluoroborate, copper thiophene-2-carboxylate, hydrates thereof, and mixtures thereof.

Examples of the salt of cu (II) include copper (II) fluoride, copper (II) chloride, copper (II) bromide, copper (II) iodide, copper (II) acetate, copper (II) formate, copper (II) hydroxide, copper (II) nitrate, copper (II) carbonate, copper (II) acetylacetonate, copper (II) borate, copper (II) oxalate, copper (II) phthalate, copper (II) tartrate, copper (II) trifluoromethanesulfonate, copper (II) benzoate, a hydrate thereof, and a mixture thereof.

Among them, copper (I) iodide (CuI) is preferable.

The salt of pd (I) may, for example, be palladium (I) dibromide or a hydrate thereof.

Examples of the salt of Pd (II) include palladium (II) acetate, palladium (II) propionate, palladium (II) butyrate, palladium (II) 2-methylpropionate, palladium (II) 3-methylbutyrate, palladium (II) 2-ethylbutyrate, palladium (II) trimethylacetate, palladium (II) 3, 3-dimethylbutyrate, palladium (II) 2, 2, 3, 3-tetramethylbutyrate, palladium (II) trifluoroacetate, palladium (II) nitrate, palladium (II) chloride, palladium (II) bromide, palladium (II) iodide, palladium (II) acetylacetonate, palladium (II) perchlorate, palladium (II) citrate, palladium (II) oxalate, palladium (II) cyclohexanebutyrate, palladium (II) benzoate, palladium (II) stearate, palladium (II) sulfamate, palladium (II) carbonate, palladium (II) thiocyanate, palladium (II) trifluoromethanesulfonate (II), Bis (4-diethylaminodithiobenzyl) palladium (II), palladium (II) cyanide, palladium (II) fluoride, palladium (II) boride, palladium (II) borate, palladium (II) hypophosphite, palladium (II) ammonium sulfate, palladium (II) hydroxide, cyclopentadienyl palladium (II) hydrate, and a mixture thereof. Of these, palladium (II) acetate (Pd (OAc) is preferred₂) Palladium (II) propionate (Pd (O (C ═ O) CH)₂CH₃)₂) Palladium (II) 2-methylpropionate (Pd (O (C ═ O) CH (CH)₃)₂)₂) Palladium trimethyl acetate (Pd (OPiv))₂) Palladium (II) chloride (PdCl)₂) Palladium (I) bromide (Pd)₂Br₂) Or palladium (II) hydroxide (Pd (OH)₂) Palladium (II) acetate (Pd (OAc)₂) Palladium (II) propionate (Pd (O (C ═ O) CH)₂CH₃)₂) Palladium (II) 2-methylpropionate (Pd (O (C ═ O) CH (CH)₃)₂)₂) Or trimethylpalladium acetate (Pd (OPiv)₂)。

Examples of the salt of cobalt (II) include cobalt (II) acetate, cobalt (II) nitrate, cobalt (II) chloride, cobalt (II) bromide, cobalt (II) iodide, cobalt (II) acetylacetonate, cobalt (II) perchlorate, cobalt (II) citrate, cobalt (II) oxalate, cobalt (II) fumarate, cobalt (II) gluconate, cobalt (II) benzoate, cobalt (II) lactate, cobalt (II) stearate, cobalt (II) sulfamate, cobalt (II) carbonate, cobalt (II) thiocyanate, cobalt (II) fluoride, cobalt (II) phosphate, cobalt (II) sulfate, cobalt (II) hydroxide, cobalt (II) sulfide, hydrates thereof, and mixtures thereof. Of these, cobalt (II) acetate (Co (OAc) is preferred₂)。

Examples of the salt of cobalt (III) include cobalt (III) fluoride, cobalt (III) chloride, cobalt (III) bromide, cobalt (III) iodide, cobalt (III) acetylacetonate, cobalt (III) sulfate, cobalt (III) nitrate, cobalt (III) phosphate, cobalt (III) perchlorate, cobalt (III) citrate, hydrates thereof, and mixtures thereof.

Examples of the salt of iron (II) Include Iron (II) fluoride, iron (II) chloride, iron (II) bromide, iron (II) iodide, iron (II) sulfate, iron (II) nitrate, iron (II) oxalate, iron (II) fumarate, iron (II) acetate, iron (II) lactate, iron (II) gluconate, iron (II) benzoate, iron (II) stearate, iron (II) acetylacetonate, iron (II) sulfide, hydrates thereof, and mixtures thereof.

Examples of the salt of iron (III) include iron (III) fluoride, iron (III) chloride, iron (III) bromide, iron (III) iodide, iron (III) sulfate, iron (III) phosphate, iron (III) perchlorate, hydrates thereof, and mixtures thereof.

The rhodium (I) salt may, for example, be rhodium (I) chloride, a hydrate thereof or a mixture thereof.

Examples of the salt of ruthenium (II) include ruthenium (II) chloride, hydrates thereof, and mixtures thereof.

Examples of the salt of iridium (III) include iridium (III) chloride, iridium (III) bromide, iridium (III) acetate, iridium (III) carbonyl, iridium (III) acetylacetonate, potassium hexachloroiridium (III), potassium nitrosyl pentachlorodide (III), iridium (III) 2, 4-pentanedionate, dichloropentamethylcyclopentadienylidium (III) dimer, iridium (III) dichloride (pentamethylcyclopentadienyl) dimer, [ (pentamethylcyclopentadienyl) iridium ] chloride dimer, hydrates thereof, and mixtures thereof.

These transition metal compounds can also be used in the form of mixtures.

Among these transition metal compounds, palladium is a particularly preferred metal species.

As these transition metal compounds, compounds having ligands previously coordinated thereto can be used. Examples of the transition metal compound to which the ligand is coordinated include the following transition metal compounds. But is not limited thereto.

In the production method of the present invention, a ligand capable of coordinating with a transition metal may be present together with a transition metal compound. In the reaction, the presence of a ligand capable of coordinating with the transition metal compound allows the benzene ring of the phenyl derivative and the C-H bond of the heterocyclic derivative to be coupled with good selectivity, and the yield of the compound represented by formula (3) can be improved. The ligand used in the above-mentioned production method of the present invention may, for example, be carboxylic acids, amides, phosphines, oximes, thioethers, sulfonic acids, 1, 3-diketones, Schiff bases,Oxazoline, diamine, hydrocarbon, carbon monoxide, carbene ligands, and the like. But is not limited thereto. The coordinating atoms in the ligand are nitrogen atom, phosphorus atom, oxygen atom, sulfur atom, etc., and there are monodentate ligands having only 1 coordinating atom and polydentate ligands having 2 or more coordinating atoms. For hydrocarbons, carbon monoxide and carbenes, carbon atoms are used as coordinating atoms. These ligands can also be used in the form of salts.

The monodentate ligand may, for example, be PR⁵R⁶R⁷Phosphine ligands represented by the formula, triethylamine, pyridine, etc.; here, R⁵、R⁶And R⁷Each independently represents C₁～C₈Alkyl radical, C₁～C₄Alkoxy radical, C₃～C₈Cycloalkyl, phenyl, biphenyl, phenoxy, furanyl; c₃～C₈Cycloalkyl radicals may also be substituted by C₁～C₄Alkyl substitution; phenyl may also be substituted with methyl, sulfonic acid or salts thereof; the biphenyl radicals may also each independently be C₁～C₄Alkyl radical, C₁～C₄Alkoxy and dimethylamino.

As by PR⁵R⁶R⁷Examples of the phosphine ligand include t-butyldicyclohexylphosphine, isobutyldicyclohexylphosphine, n-butyldicyclohexylphosphine, isopropyldicyclohexylphosphine, n-propyldicyclohexylphosphine, ethyldicyclohexylphosphine, methyldicyclohexylphosphine, cyclopropyldicyclohexylphosphine, cyclobutyldicyclohexylphosphine, t-butylbicyclooctylphosphine, t-butylbicycloheptylphosphine, t-butyldicyclopentylphosphine, t-butylbicyclobutylphosphine, t-butyldicyclopropylphosphine, triethylphosphine, tri-n-propylphosphine, triisopropylphosphine, tri-t-butylphosphine, tri-n-octylphosphine, tricyclohexylphosphine, tricyclopentylphosphine, tricyclopropylphosphine, di-t-butylmethylphosphine, di-t-butylethylphosphine, di-t-butyl-propylphosphine, di-t-butylisopropylphosphine, di-t-butyl-n-butylphosphine, di-t-butylisobutylphosphine, Di-tert-butylneopentyl phosphine, triphenylphosphine, tri (o-tolyl) phosphine, tris (o-tolyl) phosphineYl) phosphine, tris (phenoxy) phosphine, tris (2-furyl) phosphine, trimethoxy phosphine, triethoxy phosphine, tri-n-propoxy phosphine, triisopropoxy phosphine, tri-n-butoxy phosphine, triisobutoxy phosphine, tri-t-butoxy phosphine, di-t-butyl cyclohexyl phosphine, diisobutyl cyclohexyl phosphine, di-n-butyl cyclohexyl phosphine, diisopropyl cyclohexyl phosphine, di-n-propyl cyclohexyl phosphine, diethyl cyclohexyl phosphine, dimethyl cyclohexyl phosphine, di-t-butyl cyclopentyl phosphine, diisobutyl cyclopentyl phosphine, di-n-butyl cyclopentyl phosphine, diisopropyl cyclopentyl phosphine, di-n-propyl cyclopentyl phosphine, diethyl cyclopentyl phosphine, dimethyl cyclopentyl phosphine, di-t-butyl cyclooctyl phosphine, di-t-butyl cycloheptyl phosphine, di-t-butyl cyclopentyl phosphine, di-t-butyl cyclobutyl phosphine, di-t-butyl cyclopropyl phosphine, dimethyl phenyl phosphine, diethyl phenyl phosphine, di-n-propyl phenyl phosphine, Diisopropylphenylphosphine, di-n-butylphenyl phosphine, diisobutylphenylphosphine, di-t-butylphenyl phosphine, bicyclooctylphenylphosphine, bicycloheptylphenylphosphine, dicyclohexylphenylphosphine, dicyclopentylphenylphosphine, dicyclobutylphenylphosphine, dicyclopropylphenylphosphine, dicyclohexyl- (p-tolyl) -phosphine, dicyclohexyl- (o-tolyl) phosphine, dicyclohexyl- (p-tolyl) phosphine, dicyclohexyl- (2, 4, 6-trimethylphenyl) phosphine, methyldiphenylphosphine, ethyldiphenylphosphine, n-propyldiphenylphosphine, isopropyldiphenylphosphine, n-butyldiphenylphosphine, isobutyldiphenylphosphine, t-butyldiphenylphosphine, cyclooctyldiphenylphosphine, cycloheptyldiphenylphosphine, cyclohexyldiphenylphosphine, cyclopentyldiphenylphosphine, cyclobutyldiphenylphosphine, cyclopropyldiphenylphosphine, bis (p-sulfophenyl) phenylphosphine potassium salt, cBRIDP, BippyPhos, TrippyPhos, XPhos (2-dicyclohexylphosphino-2 ', 4 ', 6-triisopropyl-1, 1-biphenyl), t-Bu-XPhos, john Phos, Cy-john Phos, MePhos, t-Bu-MePhos, DavePhos, t-Bu-DavePhos, SPhos, RuPhos (2-dicyclohexylphosphino-2 ', 6 ' -diisopropoxy-1, 1 ' -biphenyl), cataCXium a, catacxiumban, cataCXium PtB, cataCXium PCy, cataCXium metpob, catacxiumpyc, cataCXium PIntB, catacxpicium, Q-Phos, josphos, and the like, and mixtures thereof.

Examples of the bidentate ligand include 2, 2 '-bipyridyl, 4' -tert-butylbipyridyl, phenanthroline, 2, 2 '-bipyrimidinyl, 1, 4-diazabicyclo [2, 2, 2] octane, 2- (dimethylamino) ethanol, tetramethylethylenediamine, N-dimethylethylenediamine, N' -dimethylethylenediamine, 2-aminomethylpyridine, (NE) -N- (pyridin-2-ylmethylene) aniline, 1 '-bis (diphenylphosphino) ferrocene, 1' -di-tert-butylferrocene, diphenylphosphinomethane, 1, 2-bis (diphenylphosphino) ethane, 1, 3-bis (diphenylphosphino) propane, 1, 5-bis (diphenylphosphino) pentane, 1, 2-bis (dipentafluorophenylphosphino) ethane, and the like, 1, 2-bis (dicyclohexylphosphino) ethane, 1, 3- (dicyclohexylphosphino) propane, 1, 2-bis (di-t-butylphosphino) ethane, 1, 3-bis (di-t-butylphosphino) propane, 1, 2-bis (diphenylphosphino) benzene, 1, 5-cyclooctadiene, BINAP, BIPHEMP, PROPHOS, DIOP, DEGUPHOS, DIPAMP, DuPHOS, NORPHOS, PNNP, SKEWPHOS, BPPFA, SEGPHOS, CHIRAPHOS, DPEphos, Xantphos, and the like, and mixtures thereof.

The BINAP also includes derivatives of BINAP, and specific examples thereof include 2, 2 ' -bis (diphenylphosphino) -1,1 ' -binaphthyl, 2 ' -bis (di-p-tolylphosphino) -1,1 ' -binaphthyl, 2 ' -bis (di-p-tert-butylphenyl phosphino) -1,1 ' -binaphthyl, 2 ' -bis (di-p-tolylphosphino) -1,1 ' -binaphthyl, 2 ' -bis (di-3, 5-dimethylphenylphosphino) -1,1 ' -binaphthyl, 2 ' -bis (di-p-methoxyphenyl phosphino) -1,1 ' -binaphthyl, 2 ' -bis (dicyclopentylphosphino) -1,1 ' -binaphthyl, 2 ' -bis (dicyclohexylphosphino) -1,1 ' -binaphthyl, 2-di (. beta. -naphthyl) phosphino-2 ' -diphenylphosphino-1, 1 ' -binaphthyl, and 2-diphenylphosphino-2 ' -di (p-trifluoromethylphenyl) phosphino-1, 1 ' -binaphthyl, and the like.

The BIPHEMP also includes derivatives of BIPHEMP, and specific examples thereof include 2, 2 '-dimethyl-6, 6' -bis (diphenylphosphino) -1,1 '-biphenyl, 2' -dimethyl-6, 6 '-bis (dicyclohexylphosphino) -1, 1' -biphenyl, 2 '-dimethyl-4, 4' -bis (dimethylamino) -6, 6 '-bis (diphenylphosphino) -1, 1' -biphenyl, 2 ', 4, 4' -tetramethyl-6, 6 '-bis (diphenylphosphino) -1, 1' -biphenyl, 2 '-dimethoxy-6, 6' -bis (diphenylphosphino) -1,1 '-biphenyl, 2', 3, 3 ' -tetramethoxy-6, 6 ' -bis (diphenylphosphino) -1,1 ' -biphenyl, 2 ', 4, 4 ' -tetramethyl-3, 3 ' -dimethoxy-6, 6 ' -bis (diphenylphosphino) -1,1 ' -biphenyl, 2 ' -dimethyl-6, 6 ' -bis (di-p-tolylphosphino) -1,1 ' -biphenyl, 2 ' -dimethyl-6, 6 ' -bis (di-p-tert-butylphenyl phosphino) -1,1 ' -biphenyl, 2 ', 4, 4 ' -tetramethyl-3, 3 ' -dimethoxy-6, 6 ' -bis (di-p-methoxyphenyl phosphino) -1,1 ' -biphenyl, and the like.

The ligand used in the reaction of the present invention may be used in the form of a salt, and examples of the salt include hydrochloride, hydrobromide and tetrafluoroborate.

When a palladium catalyst is used, a phosphine ligand is preferred as the ligand. Among them, PR is preferred⁵R⁶R⁷Phosphine ligand shown in the specification. Specifically, tri-tert-butylphosphine, tricyclohexylphosphine, tert-butyldicyclohexylphosphine, di-tert-butylcyclohexylphosphine, di-tert-butylmethylphosphine, 2-dicyclohexylphosphino-2 ', 6 ' -diisopropoxy-1, 1 ' -biphenyl, 2-dicyclohexylphosphino-2 ', 4 ', 6 ' -triisopropyl-1, 1 ' -biphenyl or a salt thereof is preferable, tri-tert-butylphosphine, di-tert-butylcyclohexylphosphine or a salt thereof is more preferable, and di-tert-butylcyclohexylphosphine or a salt thereof is particularly preferable.

When the ligand is previously coordinated, a preferred ligand may be used after being coordinated to palladium.

The ligands can also be used in the form of mixtures. The ligand may be used by being previously coordinated to the transition metal compound. If necessary, the ligand used in the reaction of the present invention may not be used.

In the production method of the present invention, a base may be used in combination with the transition metal compound. By combining a base, the yield of the compound represented by the formula (3) can be increased. The base used in the above-mentioned production method of the present invention is not particularly limited, but among them, lithium hydride, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium fluoride, cesium fluoride, tripotassium phosphate, sodium acetate, potassium acetate and the like, and C are preferable₁～C₆Metal salts (lithium salt, sodium salt, potassium salt, magnesium salt) of alcoholate of (1), C₁～C₆Metal salts (lithium salt, sodium salt, potassium salt, magnesium salt) of alkyl anion of (A), tetra (C)₁～C₄Alkyl) ammonium salts (fluoride, chloride, bromide), diisopropylethylamine, tributylamine, N-methylmorpholine, diazabicycloundecene, diazabicyclooctane, imidazole, etc.

"C" as a base used in the production method of the present invention₁～C₆In the metal salt (lithium salt, sodium salt, potassium salt, magnesium salt) "of the alcoholate₁～C₆Examples of the alcoholate of (a) include methylate, ethylate, n-propylate, isopropylate, n-butylate, iso-butylate, tert-butylate, n-amylate, iso-amylate, neopentylglycolate, 1-methylpropanoate, n-hexylate, iso-hexylate, 1-dimethylbutanoate, 2-dimethylbutanoate and 3, 3-dimethylbutanoate. Mixtures thereof may also be used.

"C" as a base used in the reaction of the present invention₁～C₆In the metal salt (lithium salt, sodium salt, potassium salt, magnesium salt) "of an alkyl anion₁～C₆Examples of the "alkyl anion" may include methyl anion, ethyl anion, n-propyl anion, isopropyl anion, n-butyl anion, isobutyl anion, tert-butyl anion, n-pentyl anion, isopentyl anion, neopentyl anion, 1-methylpropyl anion, n-hexyl anion, and isohexyl anion1, 1-dimethylbutyl anion, 2-dimethylbutyl anion, and 3, 3-dimethylbutyl anion. Mixtures thereof may also be used.

When a palladium catalyst is used, the base is preferably potassium carbonate, potassium bicarbonate, cesium carbonate or tetra-n-butylammonium fluoride, and particularly preferably potassium carbonate or cesium carbonate.

The preferred base when using a copper catalyst is potassium phosphate and the preferred base when using a cobalt catalyst is cesium fluoride.

The base used in the reaction of the present invention may be omitted if necessary.

In the production method of the present invention, a reducing agent for reducing a transition metal may be used in combination with the transition metal compound. Examples thereof may include zinc.

In the production method of the present reaction, a silver salt may be added. By adding a silver salt, the yield of the compound represented by formula (3) can be further improved. The silver salt may, for example, be silver carbonate.

In the production method of the present reaction, C may be added₁～C₁₂Or a salt thereof. By adding C₁～C₁₂The carboxylic acid or a salt thereof of (2) can further improve the yield and/or the reaction rate of the compound represented by the formula (3). These C₁～C₁₂Mixtures of the carboxylic acids or salts thereof may also be used. C₁～C₁₂The carboxylic acid (b) is a carboxylic acid having 1 to 12 carbon atoms including the carbon of the carboxyl group, and may contain a halogen atom, an oxo group, and an ether bond. Examples thereof may include formic acid, acetic acid, propionic acid, butyric acid, 2-methylpropionic acid, valeric acid, 3-methylbutyric acid, 2-methylbutyric acid, pivalic acid, 3, 3-dimethylbutyric acid, 2-methylpentanoic acid, 2-methylhexanoic acid, 2-methylheptanoic acid, pentanecarboxylic acid, hexanoic acid, 4-methylpentanoic acid, 3, 3-dimethylbutyric acid, 2-ethylbutyric acid, 2-methylpentanoic acid, 3-methylpentanoic acid, 2-dimethylbutyric acid, 2, 3-dimethylbutyric acid, heptanoic acid, 2-methylhexanoic acid, 3-methylhexanoic acid, 4-methylhexanoic acid, 5-methylhexanoic acid, 2-dimethylpentanoic acid, 2, 3, 3-trimethylbutyric acid, octanoValeric acid, 2-ethylhexanoic acid, 2-methylheptanoic acid, 3-methylheptanoic acid, 4-methylheptanoic acid, 6-methylheptanoic acid, 2-dimethylheptanoic acid, 3-methylheptanoic acid, 2-diethylbutyric acid, 2, 4-trimethylpentanoic acid, 2-methyloctanoic acid, 2-methylundecanoic acid, 2-methylnonanoic acid, alpha-methylcinnamic acid, cyclopropylacetic acid, 3-cyclopropylpropionic acid, cyclobutylacetic acid, cyclopentylacetic acid, cyclohexylacetic acid, cyclopentylpropionic acid, (2-methylcyclopentyl) acetic acid, cyclopentanecarboxylic acid, 3-oxocyclopentanecarboxylic acid, cyclopropanecarboxylic acid, cyclobutanecarboxylic acid, cyclohexanecarboxylic acid, cycloheptanecarboxylic acid, 1-methylcyclopropanecarboxylic acid, 2-dimethylcyclopropanecarboxylic acid, 2, 2, 3, 3-tetramethylcyclopropanecarboxylic acid, 2-octylcyclopropanecarboxylic acid, 1- (4-methylphenyl) -1-cyclopropanecarboxylic acid, 2-p-tolylcyclopropanecarboxylic acid, 1- (2-fluorophenyl) -cyclopropanecarboxylic acid, 1- (3-fluorophenyl) -cyclopropanecarboxylic acid, 1- (4-chlorophenyl) -cyclopropanecarboxylic acid, 1- (3-chlorophenyl) -cyclopropanecarboxylic acid, 2- (4-chlorophenyl) -cyclopropanecarboxylic acid, 1- (2, 4-dichlorophenyl) -cyclopropanecarboxylic acid, 1- (3, 4-dichlorophenyl) -cyclopropanecarboxylic acid, 2-fluoro-2-phenylcyclopropanecarboxylic acid, methyl ethyl ester, ethyl ester, 1- (4-methoxyphenyl) -cyclopropanecarboxylic acid, 2- (4-tert-butylphenyl) -cyclopropanecarboxylic acid, 2-difluorocyclopropanecarboxylic acid, 2-dichlorocyclopropanecarboxylic acid, 2-chloro-2-fluorocyclopropanecarboxylic acid, 1-trifluoromethylcyclopropanecarboxylic acid, 2-dichloro-1-methylcyclopropanecarboxylic acid, cyclopropane-1, 1-dicarboxylic acid, 2' -oxydiacetic acid, 1, 2-dimethylcyclopropanedicarboxylic acid, 4-methylcyclobutanecarboxylic acid, 4-ethylcyclopropanecarboxylic acid, 3-methoxycyclobutanecarboxylic acid, 3-chlorocyclobutanecarboxylic acid, 4-chlorobutanecarboxylic acid, 3-oxocyclobutanecarboxylic acid, 3-dimethylcyclobutanecarboxylic acid, 1-methylcyclopentane carboxylic acid, 3-cyclopentene carboxylic acid, 1-methylcyclopentane carboxylic acid, 1-methylcyclohexane carboxylic acid, 4-methylcyclohexane carboxylic acid, 2-methylcyclohexane carboxylic acid, 3-methylcyclohexane carboxylic acid, cyclooctane carboxylic acid, spiro [2.2 ]]Pentane-1-carboxylic acid, spiro [2.3 ]]Hexane-1-carboxylic acid, bicyclo [4.1.0 ]]Heptane-7-carboxylic acid, tricyclo [3.2.1.0 ]^*2，4^*]Octane-3-carboxylic acid, bicyclo [6.1.0 ]]Nonane-9-carboxylic acid, bicyclo [2.2.1 ]]Heptane-1-carboxylic acid, bicyclo [2.2.1 ]]Heptane-2-carboxylic acid, 7-dimethyltricyclo [2.2.1.0(2, 6)]Heptane (Heptane)-1-carboxylic acid, 5-norbornene-2-carboxylic acid, norbornane-2-carboxylic acid, 1-adamantanecarboxylic acid, 3-methyladamantane-1-carboxylic acid, 3-fluoroadamantane-1-carboxylic acid, 3, 5-dimethyladamantane-1-carboxylic acid, 3-ethyladamantane-1-carboxylic acid, 3-chloroadamantane-1-carboxylic acid, 3, 5, 7-trimethyladamantane-1-carboxylic acid, 3-bromoadamantane-1-carboxylic acid, 5-bromo-3-methyladamantane-1-carboxylic acid, 5-bromo-3-ethyladamantane-1-carboxylic acid, tetrahydrofuran-2-carboxylic acid, and mixtures thereof, Tetrahydrofuran-3-carboxylic acid, tetrahydropyran-4-carboxylic acid, tetrahydropyran-3-carboxylic acid, methoxyacetic acid, trichloroacetic acid, dichloroacetic acid, chloroacetic acid, fluoroacetic acid, 2-fluoro-2-methylpropionic acid, difluoroacetic acid, 2-chloropropionic acid, 3-fluoropropionic acid, 2-chloropropionic acid, 3-chloropropionic acid, 2-chlorobutyric acid, 3-chlorobutyric acid, 4-chlorobutyric acid, 2-chloro-2-methylpropionic acid, 3-chloro-2, 2-dimethylpropionic acid, 5-chloropentanoic acid, 2-chloro-3-methylbutyric acid, dichloroacetic acid, 1-fluoro-1-chloroacetic acid, 2-difluoropropionic acid, 2-difluorobutyric acid, 2, 2-dichloropropionic acid, 2, 3-dichloropropionic acid, chlorodifluoroacetic acid, trifluoroacetic acid, 3, 3, 3-trifluoropropionic acid, 2-methyl-4, 4, 4-trifluorobutanoic acid, 2, 3, 3-tetrafluoropropionic acid, and the like. But is not limited thereto.

As C₁～C₁₂The carboxylic acid (b) is preferably a carboxylic acid in which the carbon atom in the α -position of the carboxyl group is not a carbon atom on the aromatic ring, and more preferably a carboxylic acid containing a halogen atom and an ether bond. Examples thereof may include acetic acid, propionic acid, 2-methylpropionic acid, 2-ethylbutyric acid, trimethylacetic acid, cyclopropanoic acid, 2, 3, 3-tetramethylcyclopropanoic acid, cyclopentanecarboxylic acid, 1-adamantanecarboxylic acid, 2-chloro-2-methylpropionic acid, tetrahydrofuran-2-carboxylic acid, 2' -oxydiacetic acid and cyclopropane-1, 1-dicarboxylic acid.

Among them, carboxylic acids having one carboxyl group are preferable. Examples thereof may include acetic acid, propionic acid, 2-methylpropionic acid, 2-ethylbutyric acid, trimethylacetic acid, cyclopropanoic acid, 2, 3, 3-tetramethylcyclopropanoic acid, cyclopentanecarboxylic acid, 1-adamantanecarboxylic acid, 2-chloro-2-methylpropionic acid and tetrahydrofuran-2-carboxylic acid.

More preferably a carboxylic acid having 0 or 1 hydrogen atom bonded to the carbon atom at the α -position of the carboxyl group. Examples thereof may include 2-methylpropanoic acid, 2-ethylbutyric acid, trimethylacetic acid, cyclopropanoic acid, 2, 3, 3-tetramethylcyclopropanoic acid, cyclopentanecarboxylic acid, 2-chloro-2-methylpropanoic acid and tetrahydrofuran-2-carboxylic acid.

Particularly preferred is a carboxylic acid consisting of only carbon atoms and hydrogen atoms other than the carboxyl group. Examples thereof may include 2-methylpropanoic acid, 2-ethylbutyric acid, trimethylacetic acid, cyclopropanoic acid, 2, 3, 3-tetramethylcyclopropanoic acid, cyclopentanecarboxylic acid and 1-adamantanecarboxylic acid.

Particularly preferred are carboxylic acids having 1 to 8 carbon atoms, and more preferred are carboxylic acids having 1 to 6 carbon atoms. Examples thereof may include 2-methylpropanoic acid, 2-ethylbutyric acid, trimethylacetic acid, cyclopropanoic acid and cyclopentanecarboxylic acid. More particularly, 2-methylpropionic acid or trimethylacetic acid is preferable.

C used in the reaction of the present invention₁～C₁₂The carboxylic acids of (a) can also be used in the form of salts. Examples of the salt include alkali metal salts such as sodium salt, potassium salt and lithium salt, alkaline earth metal salts such as calcium salt and magnesium salt, metal salts such as aluminum salt and iron salt, inorganic salts such as ammonium salt, organic salts such as tert-octylamine salt, dibenzylamine salt, morpholine salt, glucamine salt, glycylalkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N' -dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine (フエネルアミン) salt, piperazine salt, tetramethylammonium salt and tris (hydroxymethyl) aminomethane salt.

C used in the reaction of the present invention₁～C₁₂Carboxylic acids and their salts are generally useful as additives, but if available in the form of or readily manufactured as carboxylates of transition metal compounds, such as palladium (II) propionate, carboxylates of transition metal compounds may also be used.

The manufacturing method of the present invention can be carried out in a wide temperature range. Usually from 0 ℃ to 200 ℃ and preferably from 0 ℃ to 150 ℃. The reaction is desirably carried out under normal pressure, but may be carried out under increased pressure or reduced pressure. The reaction time is 0.1 to 72 hours, preferably 0.1 to 48 hours. The reaction can be carried out in air, but it is preferable to carry out the reaction in a gas atmosphere such as argon or nitrogen which does not adversely affect the reaction. In addition, the reaction may be irradiated with microwaves.

Examples of the solvent used in the production method of the present invention include aliphatic hydrocarbons (hexane, cyclohexane, heptane, etc.), aliphatic halogenated hydrocarbons (dichloromethane, chloroform, carbon tetrachloride, dichloroethane, etc.), aromatic hydrocarbons (benzene, toluene, xylene, 1, 3, 5-trimethylbenzene, chlorobenzene, etc.), ethers (diethyl ether, dibutyl ether, Dimethoxyethane (DME), cyclopentyl methyl ether (CPME), tert-butyl methyl ether, tetrahydrofuran, di-n-butyl methyl ether, n-butyl etherAlkanes, etc.), esters (ethyl acetate, ethyl propionate, etc.), amides (dimethylformamide (DMF), Dimethylacetamide (DMA), N-methylpyrrolidone (NMP), etc.), nitriles (acetonitrile, propionitrile, etc.), Dimethylsulfoxide (DMSO), and mixed solvents thereof.

The amount of the compound of formula (2) used in the production method of the present invention may be in the range of 1 mol% to 1000 mol% relative to the amount of the compound of formula (1). The amount is preferably 50 to 200 mol%, more preferably 80 to 120 mol%.

The amount of the transition metal compound or ligand used in the production method of the present invention may be in the range of 100 mol% or less of the compound of formula (1) or the compound of formula (2) used. Preferably 20 mol% or less. The ligand may not be used as the case may be.

The amount of the base used in the production method of the present invention may be in the range of 1000 mol% or less of the compound of formula (1) or the compound of formula (2). Preferably, the amount is 500 mol% or less.

The amount of the solvent used in the production method of the present invention may be 1000 times or less the weight of the compound of formula (1) or the compound of formula (2). Preferably 100 times or less. More preferably 20 times or less.

The compound of formula (1), the compound of formula (2), the transition metal compound, the ligand, the base, and C used in the production method of the present invention₁～C₁₂The order of addition of the carboxylic acid and the solvent (b) is arbitrary, and the optimum order can be selected depending on the combination of the reagents used.

C used in the production method of the present invention₁～C₁₂The amount of the carboxylic acid (b) used may be 50000 mol% or less of the transition metal compound used. Preferably 5000 mol% or less, more preferably 1000 mol% or less, and particularly preferably 500 mol% or less.

The amount of the silver salt used in the production method of the present invention is 500 mol% or less of the compound of formula (1). Preferably 200 mol% or less.

"mol%" indicates the concentration of a substance expressed by dividing the number of moles of the substance by 100 moles of the substance.

The compound represented by formula (1) used in the production method of the present invention can be produced by the following method.

Synthesis method (1)

In the reaction formula, X is an oxygen atom, R¹、R²A, Y are as defined in formula (1). L is¹Examples of the leaving group include a halogen atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group and a p-toluenesulfonyloxy group.

Specifically, the compound (a) may be reacted with the compound (b) in the presence of a suitable base in a suitable solvent under suitable temperature conditions to produce the compound represented by formula (1).

The solvent to be used is not particularly limited, and examples thereof include aliphatic hydrocarbons (hexane, cyclohexane, and hexane,Heptane, etc.), aliphatic halogenated hydrocarbons (dichloromethane, chloroform, carbon tetrachloride, dichloroethane, etc.), aromatic hydrocarbons (benzene, toluene, xylene, chlorobenzene, 1, 3, 5-trimethylbenzene, etc.), ethers (diethyl ether, dibutyl ether, Dimethoxyethane (DME), cyclopentyl methyl ether (CPME), tetrahydrofuran, di-n-butyl ether, etc.), and the likeAlkanes, etc.), esters (ethyl acetate, ethyl propionate, etc.), amides (dimethylformamide (DMF), Dimethylacetamide (DMA), N-methylpyrrolidone (NMP), etc.), nitriles (acetonitrile, propionitrile, etc.), Dimethylsulfoxide (DMSO), water, and mixed solvents thereof.

Examples of the base to be used include lithium hydride, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium fluoride, cesium fluoride, tripotassium phosphate, sodium acetate, potassium acetate and the like, and C₁～C₆Metal salt (lithium salt, sodium salt, potassium salt) of alcoholate of (1), C₁～C₆The alkyl anion of (a) a metal salt (lithium salt, sodium salt, potassium salt), diisopropylethylamine, tributylamine, N-methylmorpholine, diazabicycloundecene, diazabicyclooctane, imidazole, etc.

Reference may be made, for example, to the reference examples of the present invention or "bioorg.med.chem.lett.2004: 14, 2547-2550 ", etc.

Synthesis method (2)

In the reaction formula, X is an oxygen atom, R¹、R²A, Y are as defined in formula (1). The reaction may be a mitsunobu reaction. For example, in the presence of diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), 1 '- (azodicarbonyl) dipiperidine (ADDP), 1' -azobis (N, N-dimethylformamide) (TMAD), or the like, and in the presence of triphenylphosphine, tributylphosphine, or the like, tetrahydrofuran, or the like,The reaction is carried out in a solvent such as ethyl ether, 1, 2-dimethoxyethane, dichloromethane or toluene at the temperature of 0-150 ℃.

The compound represented by the formula (1) can be produced by carrying out the reaction using the mitsunobu reaction and the like "Bull. chem.Soc.Jpn., 1967, Vol.40, p.2380", "Synthesis, 1981, P.1", "org.React., 1992, Vol.42, p.335".

The compound represented by formula (1) can also be synthesized by a conventional ether synthesis method. Can be synthesized by referring to a conventional organic synthesis chemistry book such as "the 4 th edition of the laboratory chemistry lecture 20, organic Synthesis of alcohol II, amine 187-.

Among the compounds represented by the formula (2), compounds in which B is a thiazole ring are also commercially available, but can be synthesized, for example, by referring to the following reaction scheme.

In the above reaction scheme, R³And R⁴The definition of (3) is the same as that of the formula (2) of the present invention. X' represents a halogen atom.

The 2-aminothiazole derivative produced by the thiazole cyclization reaction in the step 1 can be synthesized by referring to "Pharmaceutical Chemistry Journal, 2007, Vol.41, p.105-108", "Pharmaceutical Chemistry Journal, 2001, Vol.35, p.96-98", "pamphlet of International publication No. 2005/075435", "pamphlet of International publication No. 2005/026137", and the like. The reaction of step 2 can be performed by referring to "Journal of Heterocyclic Chemistry, 1985, Vol.22, pp.1621-1630", "Journal of the Chemical Society, PerkinTransactions 1: organic and Bio-Organic Chemistry, 1982, Vol.1, 159-. In addition, the thiazole derivative represented by the formula (2) can be synthesized, for example, by referring to "pamphlet of International publication No. 2002/051849" and "pamphlet of International publication No. 2001/062250".

Among the compounds represented by the formula (2), compounds in which B is a pyridine ring are commercially available in many forms, and a large number of synthetic methods have been reported and can be synthesized by these techniques.

In the compound represented by the formula (2), B is isoAn azole ring or an isothiazole ring [ formula (2) wherein W is an oxygen atom or a sulfur atom]The compounds of (a) are also commercially available, but can be synthesized by referring to the methods described, for example, in "tetrahedron letters, 1968, 5209-5213", "Synthesis, 1970, 344-350", "Angewandte Chemie, 1967, vol 79, 471-472", "Chemische Berichte, 1973, vol 106, 3291-3311".

Examples

The present invention will be specifically described below with reference to examples and the like. It is not intended that the scope of the present invention be limited in any way by these examples.

In this example, the following devices were used for analysis and purification.

TLC: merck silica gel 60F₂₅₄(0.25mm)

Flash column chromatography: biotage Flash, Si40

Preparative Thin Layer Chromatography (PTLC): merck silica gel 60F₂₅₄(1mm)

Liquid chromatography/Mass Spectrometry (LC/MS)

An analysis system: SHIIMAZU LCMS-2010A

Software: LCMS Solution

The experimental conditions are as follows:

column: phenomenex Gemini 3 μm 4.6mm x 30mm

Flow rate: 1.2mL/min

Measuring temperature: 40 deg.C

A, solvent A: 5% MeCN/95% H₂O+0.05％TFA

B, solvent: 95% MeCN/5% H₂O+0.05％TFA

MS mode: ESI +

ESI voltage: 4.5KV

Source temperature: 130 deg.C

Desolvation temperature: 320 deg.C

[ Table 8]

Using a double column mode

Nuclear Magnetic Resonance (NMR): JEOL JNM-AL400(¹H 400MHz)¹The chemical shift of H-NMR was expressed in ppm based on the chemical shift of tetramethylsilane (0.0 ppm). Data are represented by the following abbreviations.

s ═ singlet, d ═ doublet, dd ═ doublet, t ═ triplet, q ═ quartet, m ═ multiplet, br ═ broad signal.

Reference examples and examples¹In H-NMR, a proton signal in a carboxylic acid may not be confirmed under measurement conditions such as a solvent.

[ reference example 1]

Synthesis of 4-methylthiazole-5-carboxylic acid tert-butyl ester

A mixture of 4-methyl-5-thiazolecarboxylic acid (1.36g, 9.48mmol) and thionyl chloride (28.7mL) was stirred at 80 ℃ for 1 hour. The reaction mixture was concentrated under reduced pressure to remove thionyl chloride, and the resulting crude product was dried under reduced pressure. To a solution of the crude product in dichloromethane (5.68mL) were added tert-butanol (2.84mL) and pyridine (16.9mL), and the mixture was stirred at 60 ℃ overnight. After the reaction, the reaction solution was concentrated under reduced pressure, a saturated aqueous sodium carbonate solution and ethyl acetate were added to the obtained crude product, ethyl acetate was separated, and ethyl acetate was further added to a saturated aqueous sodium bicarbonate solution to conduct extraction. The combined organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate. After magnesium sulfate was filtered off, the solvent was concentrated under reduced pressure, and the resulting crude product was purified by silica gel chromatography (hexane/ethyl acetate ═ 85/15) to give the title compound (964 mg). The yield thereof was found to be 51%.

¹H-NMR(400MHz，CDCl₃)8.72(s，1H)，2.74(s，3H)，1.58(s，9H).

[ reference example 2]

Synthesis of 5-iodo-2-isobutoxybenzonitrile

A solution of 2-methyl-1-propanol (0.56mL, 6.06mmol) in N, N-dimethylformamide (10mL) was cooled to 0 deg.C and sodium hydride (242mg, 60% suspension in mineral oil, 6.06mmol) was added in small portions. The suspended reaction solution was stirred at 0 ℃ for 5 minutes, then the temperature was raised to 23 ℃, stirred at room temperature for 10 minutes, and cooled again to 0 ℃. 2-fluoro-5-iodobenzonitrile (1.0g, 4.04mmol) was added to the reaction solution, and the reaction solution was warmed to room temperature and stirred for 1.5 hours. After completion of the reaction, water (20mL) was added to the reaction mixture, which was then extracted with ethyl acetate (3X 30 mL). The organic phases were combined, washed with saturated brine (3X 30mL), and dried over anhydrous magnesium sulfate. After magnesium sulfate was filtered off, the solvent was concentrated under reduced pressure, and the resulting crude product was purified by silica gel chromatography (hexane/ethyl acetate ═ 98/2) to give the title compound (950 mg). The yield thereof was found to be 78%.

¹H-NMR(400MHz，CDCl₃)7.81(d，J＝2.2Hz，1H)，7.76(dd，J＝8.8Hz，2.2Hz，1H)，6.72(d，J＝8.8Hz，1H)，3.80(d，J＝6.3Hz，2H)，2.21-2.11(m、1H)，1.06(d，J＝6.8Hz，6H).

[ reference example 3]

Synthesis of 5-bromo-2-isobutoxybenzonitrile

A suspension of sodium hydride (1.64g, 60% suspension in mineral oil, 37.5mmol) in N, N-dimethylformamide (50mL) was cooled to 0 ℃ and then 2-methyl-1-propanol (3.47mL, 37.5mmol) was added in small portions. The reaction was stirred at room temperature for 20 minutes. The reaction solution was cooled to 0 ℃ again, and 2-fluoro-5-bromobenzonitrile (5.00g, 25.0mmol) was added in small portions, followed by stirring at room temperature for 15 hours. After completion of the reaction, water (100mL) was added and extracted with ethyl acetate (3X 100 mL). The organic phases were combined, washed with saturated brine (2X 50mL), and dried over anhydrous sodium sulfate. After sodium sulfate was filtered off, the solvent was concentrated under reduced pressure, and the resulting crude product was purified by silica gel chromatography (hexane/ethyl acetate ═ 9/1) to give the title compound (6.04 g). The yield thereof was found to be 95%.

¹H-NMR(400MHz，CDCl₃)7.65(d，J＝2.4Hz，1H)，7.60(d，J＝9.0Hz，2.4Hz，1H)，6.84(d，J＝8.8Hz，1H)，3.81(d，J＝6.6Hz，2H)，2.22-2.12(m、1H)，1.06(d，J＝6.6Hz，6H).

[ example 1]

Synthesis of tert-butyl 2- (3-cyano-4-isobutoxyphenyl) -4-methylthiazole-5-carboxylate

To a reaction vessel were added tert-butyl 4-methylthiazole-5-carboxylate (49.8mg, 0.25mmol) obtained in reference example 1, 5-iodo-2-isobutoxybenzonitrile (112.9mg, 0.375mmol) obtained in reference example 2, and anhydrous N, N-dimethylformamide (1.25 mL). Lithium tert-butoxide (40.0mg, 0.5mmol) and copper (I) iodide (9.5mg, 0.05mmol) were added under a nitrogen atmosphere, and then the mixture was heated to 140 ℃ and stirred for 30 minutes. After completion of the reaction, the reaction mixture was cooled to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine and dried over magnesium sulfate. After magnesium sulfate was filtered off, the organic solvent was concentrated under reduced pressure, and the resulting crude product was purified by thin layer silica gel chromatography (hexane/ethyl acetate 4/1) to give the title compound (29.2 mg). The yield thereof was found to be 31%.

¹H-NMR(400MHz，CDCl₃)8.16(d，J＝2.4Hz，1H)，8.08(dd，J＝8.8Hz，2.4Hz，1H)，7.00(d，J＝8.8Hz，1H)，3.89(d，J＝6.8Hz，2H)，2.73(s，3H)，2.24-2.16(m，1H)，1.59(s，9H)，1.09(d，J＝6.8Hz，6H).

[ example 2]

To a reaction vessel were added tert-butyl 4-methylthiazole-5-carboxylate (49.8mg, 0.25mmol) obtained in reference example 1, 5-iodo-2-isobutoxybenzonitrile (112.9mg, 0.375mmol) obtained in reference example 2, and water (0.5 mL). Dicomplexed 1, 1' -bis (diphenylphosphino) ferrocene complex [ PdCl ] of palladium (II) chloride was added under nitrogen atmosphere₂(dppf)](20.7mg, 0.025mmol), triphenylphosphine (39.3mg, 0.15mmol) and silver carbonate (138.4mg, 0.5mmol), heated to 60 ℃ and stirred for 24 h. After completion of the reaction, the reaction mixture was cooled to room temperature, ethyl acetate (2.5mL) was added to the reaction mixture, and insoluble matter was filtered off and washed with ethyl acetate. Will be provided withThe filtrate was extracted 2 times with ethyl acetate. The combined organic phases were washed with saturated brine and dried over magnesium sulfate. After magnesium sulfate was filtered off, the organic solvent was concentrated under reduced pressure, and the resulting crude product was purified by thin layer silica gel chromatography (hexane/ethyl acetate 3/1) to give the title compound (87.6 mg). The yield thereof was found to be 94%.

[ example 3]

After tert-butyl 4-methylthiazole-5-carboxylate (598mg, 3.0mmol) obtained in reference example 1, 5-bromo-2-isobutoxybenzonitrile (762mg, 3.0mmol) obtained in reference example 3, palladium acetate (67.4mg, 0.30mmol), tricyclohexylphosphine (168mg, 0.60mmol), cesium carbonate (1.95g, 6.0mmol) and toluene (11mL) were added to a test tube type reaction vessel (50mL), the reaction vessel was charged with nitrogen and then was heated to 120 ℃ with the lid tightly, and stirred for 19 hours. After completion of the reaction, ethyl acetate (30mL) was added to the reaction mixture, and insoluble matter was filtered off. To the filtrate was added 0.1mol/L hydrochloric acid (20mL), and the organic phase was extracted and separated. The aqueous phase was extracted with additional ethyl acetate (20 mL). The combined organic phases were washed with water (30mL) and saturated brine (30mL), and dried over sodium sulfate. After sodium sulfate was filtered off, the organic solvent was concentrated under reduced pressure, and the resulting crude product was purified by silica gel chromatography (hexane/ethyl acetate ═ 7/1) to give the title compound (930 mg). The yield thereof was found to be 83%.

¹H-NMR(400MHz，CDCl₃)8.16(d，J＝2.44Hz，1H)，8.08(dd，J＝8.78Hz，2.20Hz，1H)，7.00(d，J＝8.78Hz，1H)，3.90(d，J＝6.59Hz，2H)，2.73(s，3H)，2.25-2.16(m，1H)，1.59(s，9H)，1.09(d，J＝6.83Hz，6H).

[ example 4]

To a test tube-type reaction vessel were added tert-butyl 4-methylthiazole-5-carboxylate (180mg, 0.903mmol) obtained in reference example 1, 5-bromo-2-isobutoxybenzonitrile (230mg, 0.903mmol) obtained in reference example 3, palladium hydroxide (31.7mg, 0.045mmol), tricyclohexylphosphine (12.7mg, 0.045mmol), potassium carbonate (250mg, 1.81mmol), copper iodide (172mg, 0.903mmol), and dimethyl sulfoxide (3.0mL), and the reaction vessel was charged with nitrogen gas and covered tightly, heated to 120 ℃ and stirred for 20 hours. After completion of the reaction, ethyl acetate (10mL) and water (10mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The solution was filtered through celite, washing with ethyl acetate (20mL), water (10 mL). The organic phase was separated from the filtrate and the aqueous phase was further extracted with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine (10mL) and dried over sodium sulfate. After sodium sulfate was filtered off, the organic solvent was concentrated under reduced pressure, and the obtained crude product was purified by silica gel chromatography (hexane/ethyl acetate 49/1-4/1) to obtain a crude product of the title compound (188 mg). The mixture was dissolved in ethanol (3mL) under heating (80 ℃ C.), cooled to 10 ℃ C., and the precipitated solid was separated by filtration and washed with ethanol (2 mL). The solid was dried under reduced pressure at room temperature to give the title compound (132 mg). The yield thereof was found to be 39%.

¹H-NMR(400MHz，CDCl₃)8.17(d，J＝2.20Hz，1H)，8.08(dd，J＝8.90Hz，2.32Hz，1H)，7.00(d，J＝9.02Hz，1H)，3.90(d，J＝6.59Hz，2H)，2.73(s，3H)，2.24-2.15(m，1H)，1.59(s，9H)，1.09(d，J＝6.83Hz，6H).

[ example 5]

To a reaction vessel were added tert-butyl 4-methylthiazole-5-carboxylate (598mg, 3.0mmol) obtained in reference example 1, 5-bromo-2-isobutoxybenzonitrile (762mg, 3.0mmol) obtained in reference example 3, palladium acetate (67.4mg, 0.30mmol), tricyclohexylphosphine (168mg, 0.60mmol), potassium carbonate (829mg, 6.0mmol), toluene (10mL), and trimethylacetic acid (92mg, 0.90mmol), followed by stirring at room temperature for 30 minutes under a nitrogen atmosphere, further heating and refluxing, and stirring for 9 hours. After completion of the reaction, water (20mL) and ethyl acetate (20mL) were added to the reaction mixture, and the organic phase was extracted and separated. The aqueous phase was extracted with additional ethyl acetate (20 mL). The combined organic phases were dried over magnesium sulfate. After magnesium sulfate was filtered off, the organic solvent was concentrated under reduced pressure, and the resulting crude product was purified by silica gel chromatography (hexane/ethyl acetate 100/0 → 0/100) to give the title compound (880 mg). The yield thereof was found to be 79%.

¹H-NMR(400MHz，CDCl₃)8.16(d，J＝2.20Hz，1H)，8.08(dd，J＝8.78Hz，2.20Hz，1H)，7.00(d，J＝8.78Hz，1H)，3.90(d，J＝6.34Hz，2H)，2.73(s，3H)，2.25-2.15(m，1H)，1.59(s，9H)，1.09(d，J＝6.59Hz，6H).

[ example 6]

Synthesis of ethyl 2- (3-cyano-4-isobutoxyphenyl) -4-methylthiazole-5-carboxylate

To a reaction vessel were added ethyl 4-methylthiazole-5-carboxylate (514mg, 3.0mmol), 5-bromo-2-isobutoxybenzonitrile (762mg, 3.0mmol) obtained in reference example 3, palladium acetate (67.4mg, 0.30mmol), tricyclohexylphosphine (168mg, 0.60mmol), potassium carbonate (829mg, 6.0mmol), toluene (10mL), and trimethylacetic acid (92mg, 0.90mmol), followed by stirring at room temperature for 30 minutes under a nitrogen atmosphere, further heating and refluxing, and stirring for 10 hours. After completion of the reaction, water (20mL) and ethyl acetate (20mL) were added to the reaction mixture, and the organic phase was extracted and separated. The aqueous phase was extracted with additional ethyl acetate (20 mL). The combined organic phases were dried over magnesium sulfate. After magnesium sulfate was filtered off, the organic solvent was concentrated under reduced pressure, and the resulting crude product was purified by silica gel chromatography (hexane/ethyl acetate 100/0 → 0/100) to give the title compound (734 mg). The yield thereof was found to be 71%.

¹H-NMR(400MHz，CDCl₃)8.18(d，J＝2.44Hz，1H)，8.09(dd，J＝8.78Hz，2.20Hz，1H)，7.01(d，J＝8.78Hz，1H)，4.36(q，J＝7.07Hz，2H)，3.90(d，J＝6.34Hz，2H)，2.77(s，3H)，2.26-2.16(m，1H)，1.39(t，J＝7.19Hz，3H)，1.09(d，J＝6.83Hz，6H).

[ example 7]

To a reaction vessel were added tert-butyl 4-methylthiazole-5-carboxylate (598mg, 3.0mmol) obtained in reference example 1, 5-bromo-2-isobutoxybenzonitrile (801mg, 3.15mmol) obtained in reference example 3, palladium acetate (67.4mg, 0.30mmol), di-tert-butylcyclohexylphosphine (137mg, 0.60mmol), potassium carbonate (829mg, 6.0mmol), and toluene (10mL), followed by stirring at room temperature for 30 minutes under a nitrogen atmosphere, further heating under reflux, and stirring for 24 hours. After completion of the reaction, water (15mL) and ethyl acetate (20mL) were added to the reaction mixture, and the organic phase was extracted and separated. The aqueous phase was extracted with additional ethyl acetate (20 mL). The combined organic phases were dried over magnesium sulfate. After magnesium sulfate was filtered off, the organic solvent was concentrated under reduced pressure to obtain a crude product. Toluene (1mL) was added to the crude product, which was dissolved at 70 ℃, and heptane (9mL) was added at 70 ℃, allowed to cool to room temperature, and cooled to 0 ℃. The precipitated solid was separated by filtration and washed with heptane (20mL) to give the title compound (611mg, 1.64 mmol). The filtrate was concentrated under reduced pressure again, and the resulting crude product was purified by silica gel chromatography (hexane/ethyl acetate ═ 100/0 → 0/100) to give the title compound (405mg, 1.09 mmol). The yield thereof was found to be 91%.

¹H-NMR(400MHz，CDCl₃)8.17(d，J＝2.20Hz，1H)，8.09(dd，J＝8.90Hz，2.32Hz，1H)，7.00(d，J＝8.78Hz，1H)，3.90(d，J＝6.34Hz，2H)，2.73(s，3H)，2.24-2.17(m，1H)，1.59(s，9H)，1.09(d，J＝6.83Hz，6H).

[ example 8]

To a reaction vessel were added ethyl 4-methylthiazole-5-carboxylate (1.71g, 10.0mmol), 5-bromo-2-isobutoxybenzonitrile obtained in reference example 3 (2.54g, 10.0mmol), palladium acetate (22.4mg, 0.10mmol), tetrafluoroborate salt of tri-tert-butylphosphine (87.0mg, 0.30mmol), potassium carbonate (1.45g, 10.5mmol), and xylene (10mL), followed by stirring at room temperature for 30 minutes under a nitrogen atmosphere, further heating and refluxing, and stirring for 17 hours. After the reaction was completed, hot filtration was performed, and the mixture was washed with toluene and dichloromethane. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified to give the title compound (2.69 g). The yield thereof was found to be 78%.

[ example 9]

To a reaction vessel were added ethyl 4-methylthiazole-5-carboxylate (1.71g, 10.0mmol), 5-bromo-2-isobutoxybenzonitrile obtained in reference example 3 (2.69g, 10.5mmol), palladium acetate (22.4mg, 0.10mmol), di-tert-butylcyclohexylphosphine (68.5mg, 0.30mmol), potassium carbonate (1.45g, 10.5mmol), and xylene (10mL), followed by stirring at room temperature for 30 minutes under a nitrogen atmosphere, reflux heating, and stirring for 24 hours. After the reaction was completed, hot filtration was performed, and the mixture was washed with toluene and dichloromethane. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified to give the title compound (2.83 g). The yield thereof was found to be 82%.

[ example 10]

After adding tert-butyl 4-methylthiazole-5-carboxylate (59.8mg, 0.3mmol) obtained in reference example 1, 5-bromo-2-isobutoxybenzonitrile (76.2mg, 0.3mmol) obtained in reference example 3, palladium acetate (6.7mg, 0.030mmol), a ligand, a base (0.60mmol), and a solvent (1mL) to a test tube type reaction vessel (10mL), the reaction vessel was filled with nitrogen gas and was tightly closed, and then heated to 120 ℃ and stirred. After completion of the reaction, a part of the reaction solution was diluted with DMSO, the resulting solution was measured by HPLC, and the calculated yield of the target substance was calculated from the HPLC area% of the target substance with the sum of the HPLC area% of compounds a to D and TM corrected to 100%. The calculated yield of the target substance was calculated from the HPLC area% of the target substance by substituting the following equation.

Yield (%) of TM [ { B total amount (mol)/[ { B total amount (mol) }/2+ { a total amount (mol) × 2+ TM total amount (mol) }/2+ { a total amount (mol) × 100 total amount (mol) × C (mol) × 2+ TM)

Total amount of each compound (mol) ═ area value in HPLC (mAU)/area value in HPLC per 1mol of each compound (mAU/mol)

High performance liquid chromatography

An analysis system: G1315A Hewlett Packard series 1100

Software: ChemStation for LC 3D

The experimental conditions are as follows:

column: imtakt Cadenza CD-C184.6X 100mm

Flow rate: 1.0mL/min

Wavelength: 254nm

Temperature: 40 deg.C

A, solvent A: 5% MeCN/95% H₂O+0.05％TFA

B, solvent: 95% MeCN/5% H₂O+0.05％TFA

Gradient:

b solvent

B solvent

The results of this example are shown below.

[ Table 9]

The abbreviations in the tables have the following meanings.

DME: dimethoxyethane

NMP: n-methyl pyrrolidone

EA: ethyl acetate

CPME: cyclopentyl methyl ether

HBF₄: tetrafluoroboric acid

dppp: 1, 1' -bis (diphenylphosphino) propane

dppe: 1, 1' -bis (diphenylphosphino) ethane

dppb: 1, 1' -bis (diphenylphosphino) butane

dppf: 1, 1' -bis (diphenylphosphino) ferrocene

PCy 3: tricyclohexylphosphine

PivOH: trimethylacetic acid

n-Oct.: n-octyl radical

[ example 11]

To a test tube-type reaction vessel (10mL) were added ethyl 4-methylthiazole-5-carboxylate (85.5mg, 0.5mmol), 5-bromo-2-isobutoxybenzonitrile (127.1mg, 0.5mmol) obtained in reference example 3, a palladium seed, a ligand, a base (1.0mmol), an additive (0.15mmol), and a solvent (1.7mL), and the reaction vessel was charged with nitrogen gas and then heated to 120 ℃ with being tightly covered, and stirred. After completion of the reaction, a part of the reaction solution was diluted with DMSO, the resulting solution was measured by HPLC, and the calculated yield of the target substance was calculated from the HPLC area% of the target substance with the sum of the HPLC area% of compounds a to D and TM corrected to 100%. The results are shown in Table 10.

High performance liquid chromatography

An analysis system: G1315A Hewlett Packard series 1100

Software: ChemStation for LC 3D

The experimental conditions are as follows:

column: phenomenex Luna Phenyl-Hexyl 5um 4.6X 100mm

Flow rate: 1.0mL/min

Wavelength: 240nm

Temperature: 40 deg.C

A, solvent A: 5% MeCN/95% H₂O+0.05％TFA

B, solvent: 95% MeCN/5% H₂O+0.05％TFA

Gradient:

b solvent

B solvent

[ Table 10]

[ example 12]

Ethyl 4-methylthiazole-5-carboxylate (381.2mg, 1.5mmol), 5-bromo-2-isobutoxybenzonitrile (256.8mg, 1.5mmol) obtained in reference example 3, palladium acetate (6.7mg, 0.030mmol), di-tert-butylcyclohexylphosphine (13.7mg, 0.060mmol), potassium carbonate (414.6mg, 3.0mmol), an additive (0.45mmol), and xylene (5.0mL) were added to a test tube-type reaction vessel (20mL), and then the reaction vessel was charged with nitrogen gas and was tightly closed, heated to 120 ℃ and stirred for 5 hours. After completion of the reaction, a part of the reaction solution was diluted with DMSO, the resulting solution was measured by HPLC, and the calculated yield of the target substance was calculated from the HPLC area% of the target substance with the sum of the HPLC area% of compounds a to D and TM corrected to 100%. The results are shown in Table 11.

High performance liquid chromatography

An analysis system: G1315A Hewlett Packard series 1100

Software: ChemStation for LC 3D

The experimental conditions are as follows:

column: phenomenex Luna Phenyl-Hexyl 5um 4.6X 100mm

Flow rate: 1.0mL/min

Wavelength: 240nm

Temperature: 40 deg.C

A, solvent A: 5% MeCN/95% H₂O+0.05％TFA

B, solvent: 95% MeCN/5% H₂O+0.05％TFA

Gradient:

b solvent

B solvent

[ Table 11]

INDUSTRIAL APPLICABILITY

The novel coupling method of the present invention, in which a phenyl derivative represented by formula (1) and a heterocyclic derivative represented by formula (2) are coupled in the presence of a transition metal compound to obtain a phenyl-substituted heterocyclic derivative represented by formula (3), can be used for producing a xanthine oxidase inhibitor or an intermediate thereof, which is a therapeutic agent for hyperuricemia, in a small number of steps and at a high yield and at a low cost.

Claims

1. A process for producing a phenyl-substituted heterocyclic derivative represented by the following formula (3),

in (i) a transition metal compound selected from 0-valent palladium or a salt of 1-valent or 2-valent palladium, and (ii) C₁～C₁₂Is produced by reacting a compound represented by the following formula (1) with a compound represented by the following formula (2) in the presence of a carboxylic acid of (a) or a salt thereof;

in the formula (1), Y represents a halogen atom, -OCO₂-(C₁～C₄Alkyl), -OCO₂- (phenyl), -OSO₂-(C₁～C₄Alkyl), -OSO₂- (phenyl) or diazo;

c in Y₁～C₄The alkyl group may be substituted with 1 to 3 halogen atoms, and the phenyl group in Y may be substituted with 1 to 3 halogen atoms or C₁～C₄The substitution of the alkyl group is carried out,

in the formula (2), the reaction mixture is,

h represents a hydrogen atom;

R³represents COOR^3aOr COR^3b；

R⁴represents a hydrogen atom, a halogen atom or C₁～C₄An alkyl group, a carboxyl group,

in the formula (3), the reaction mixture is,

R³and R⁴The definition of (3) is the same as in the formula (2).

2. The method of claim 1, wherein R is⁴Is methyl.

3. The process according to claim 1, wherein the transition metal compound is palladium (II) acetate (Pd (OAc))₂) Palladium (II) propionate (Pd (O (C = O) CH)₂CH₃)₂) Palladium (II) 2-methylpropionate (Pd (O (C = O) CH (CH)₃)₂)₂) Palladium trimethyl acetate (Pd (OPiv))₂) Palladium (II) chloride (PdCl)₂) Palladium (I) bromide (Pd)₂Br₂) Or palladium (II) hydroxide (Pd (OH)₂)。

4. The process according to claim 1, wherein the transition metal compound is palladium (II) acetate (Pd (OAc))₂) Palladium (II) propionate (Pd (O (C = O) CH)₂CH₃)₂) Palladium (II) 2-methylpropionate (Pd (O (C = O) CH (CH)₃)₂)₂) Or trimethylpalladium acetate (Pd (OPiv)₂)。

5. The production process according to any one of claims 1 to 4, wherein a ligand capable of coordinating with the transition metal compound is further present in the reaction.

6. The process according to claim 5, wherein the ligand is a phosphine ligand.

7. The process according to claim 6, wherein the phosphine ligand is tri-tert-butylphosphine, di-tert-butylmethylphosphine, tert-butyldicyclohexylphosphine, di-tert-butylcyclohexylphosphine, tricyclohexylphosphine, 2-dicyclohexylphosphino-2 ', 6 ' -diisopropoxy-1, 1 ' -biphenyl, 2-dicyclohexylphosphino-2 ', 4 ', 6 ' -triisopropyl-1, 1 ' -biphenyl, or a salt thereof.

8. The production process according to any one of claims 1 to 4, wherein a base is further present in the reaction.

9. The process according to claim 8, wherein the base is potassium carbonate, potassium hydrogencarbonate, cesium carbonate or tetra-n-butylammonium fluoride.

10. The production process according to any one of claims 1 to 4, wherein a silver salt is further present in the reaction.

11. The method of claim 10, wherein the silver salt is silver carbonate.

12. The process according to claim 1, wherein the carboxylic acid or a salt thereof is 2-methylpropanoic acid, trimethylacetic acid or a salt thereof.