Method for producing compounds

Abstract

This method for producing a compound represented by formula (2) comprises bringing at least one acid catalyst, which is selected from organic Brønsted acids and activated clay that is activated by a Brønsted acid, into contact with a compound represented by formula (1) at a temperature equal to or higher than 70°C. In formula (1) and formula (2), X represents an oxygen atom, -NH-, or a sulfur atom, Z represents CH or a nitrogen atom, R1 represents an aprotic substituent, R2 represents a substituent, and n represents an integer of 0-3. However, among the two carbon atoms adjacent to the carbon atom substituted with X in the aromatic ring in formula (1), at least the carbon atom bound to Z and to the carbon atom substituted with X has a hydrogen atom. The aromatic ring in each of the formulae may be fused with another ring to form a fused ring.

Description

Technical Field

[0001] The present invention relates to a method for producing an aromatic compound in which an active hydrogen-containing group and a ketone group are substituted on adjacent carbon atoms of an aromatic ring.

Background Art

[0002] Acylphenol compounds such as hydroxyacetophenone are compounds having a structure in which a hydroxy group as an active hydrogen-containing group and an acyl group as a ketone group are bonded to a benzene ring. Such aromatic compounds substituted with an active hydrogen-containing group and a ketone group are known as synthetic intermediates for pharmaceuticals, agricultural chemicals and chemical products. Among these compounds, aromatic compounds in which an active hydrogen-containing group and a ketone group are substituted on adjacent carbon atoms of an aromatic ring, for example, ortho-acylphenol compounds such as 2-hydroxyacetophenone, are important synthetic intermediates, and various production methods (synthesis methods) thereof have been studied. For example, as a general method for producing an ortho-acylphenol compound, Fries rearrangement, in which a Lewis acid such as aluminum chloride is used and an acyl group is rearranged to the ortho position using acyloxybenzene as a raw material compound, is known (for example, Non-Patent Document 1). However, in Fries rearrangement, the acyl group rearranges not only to the ortho position but also to the para position due to the orientation property of the acyl group. Although the orientation property of the acyl group can be changed depending on temperature, preferential rearrangement to the ortho position cannot be achieved unless a high temperature of 200° C. or higher is set. Moreover, even if the temperature is set high, there is a problem that it is difficult to selectively rearrange the acyl group only to the ortho position.

[0003] However, in studies on the Fries rearrangement of acyloxybenzene (phenyl carboxylate), a method of rearranging an acyl group to the 2-position of a benzene ring by heating 4-hydroxyacylbenzene in the presence of aluminum chloride has also been investigated. For example, Non-Patent Document 2 describes that heating a mixture of 5 g of 4-acetylnaphthol and 5 g of aluminum chloride to 100 to 120°C gives 3 g of 2-acetylnaphthol (yield: 60%). In addition, Non-Patent Document 3 describes that 0.041 g (yield: 8.2%) of 2-hydroxy-3-methylphenyl benzyl ketone [9] can be obtained by adding aluminum chloride (2.21 mol) to a chlorobenzene solution of 4-hydroxy-3-methylphenyl benzyl ketone [8] (2.21 mmol) and refluxing the mixture, and that 2-hydroxy-4-methylphenyl benzyl ketone

[15] can be obtained in a yield of 56.9% by adding aluminum chloride to a nitromethane solution of 4-hydroxy-2-methylphenyl benzyl ketone

[16] and refluxing the mixture, respectively.

Prior Art Documents

Non-Patent Documents

[0004]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Summary of the Invention

Problems to be Solved by the Invention

[0005] As mentioned above, the Fries rearrangement requires high temperature conditions and even aquatic conditions, making it impossible to produce orthoacylphenol compounds using simple methods and conditions, and furthermore, the yield and selectivity are not sufficient. On the other hand, the methods described in Non-Patent Documents 2 and 3 can produce aromatic compounds having acyl and hydroxyl groups on carbon atoms adjacent to the benzene ring, but they also require aquatic conditions. Moreover, considering the usefulness of these aromatic compounds as synthetic intermediates, the yields of the methods described in Non-Patent Documents 2 and 3, which are around 8.2-60%, are not sufficient.

[0006] The object of this invention is to provide a method for producing aromatic compounds in which an active hydrogen-containing group and a ketone group are substituted on adjacent carbon atoms of an aromatic ring, in a simple manner while achieving high yield. [Means for solving the problem]

[0007] The above-mentioned problems of the present invention were solved by the following means. <1> A method for producing a compound represented by the following formula (2), comprising contacting at least one acidic catalyst selected from organic Brønsted acids and activated clays activated with Brønsted acids with a compound represented by the following formula (1) at a temperature of 70°C or higher. [ka] In formulas (1) and (2), X represents an oxygen atom, -NH-, or sulfur atom. Z represents a CH or nitrogen atom. 1 R indicates an aprotic substituent. 2 'x' represents a substituent. n is an integer between 0 and 3. However, in the aromatic ring in formula (1), at least one of the two carbon atoms adjacent to the carbon atom substituted with X is bonded to Z, and the aromatic ring in each formula may be fused with other rings to form a fused ring. <2> Organic Brønsted acids are organic sulfonic acids. <1> The manufacturing method described above. <3> The acidic catalyst and the compound represented by formula (1) are brought into contact in a solvent. <1> or <2> The manufacturing method described above. <4> R 1 is an alkyl group having 1 to 6 carbon atoms. <1> ~ <3> A manufacturing method described in any one of the following. <5> A method for producing a compound represented by the following formula (2), comprising contacting a fluid 1 containing at least one organic Brønsted acid as an acidic catalyst with a fluid 2 containing a compound represented by the following formula (1) in a flow reactor at a temperature of 70°C or higher. [ka] In formulas (1) and (2), X represents an oxygen atom, -NH-, or sulfur atom. Z represents a CH or nitrogen atom. 1 R indicates an aprotic substituent. 2 'x' represents a substituent. n is an integer between 0 and 3. However, in the aromatic ring in formula (1), at least one of the two carbon atoms adjacent to the carbon atom substituted with X is bonded to Z, and the aromatic ring in each formula may be fused with other rings to form a fused ring. <6> Organic Brønsted acids are organic sulfonic acids. <5> The manufacturing method described above. <7> A method for producing a compound represented by the following formula (2), comprising flowing a fluid 3 containing a compound represented by the following formula (1) through a solid support containing at least one activated clay activated with Brønsted acid as an acidic catalyst, thereby bringing the activated clay and the compound represented by formula (1) into contact in a flow reactor at a temperature of 70°C or higher. [ka] In formulas (1) and (2), X represents an oxygen atom, -NH-, or sulfur atom. Z represents a CH or nitrogen atom. 1 R indicates an aprotic substituent. 2 'x' represents a substituent. n is an integer between 0 and 3. However, in the aromatic ring in formula (1), at least one of the two carbon atoms adjacent to the carbon atom substituted with X is bonded to Z, and the aromatic ring in each formula may be fused with other rings to form a fused ring. [Effects of the Invention]

[0008] According to the manufacturing method of the present invention, aromatic compounds in which active hydrogen-containing groups and ketone groups are substituted on adjacent carbon atoms of an aromatic ring can be produced in a simple method with high yield. The above and other features and advantages of the present invention will become more apparent from the following description, with reference to the accompanying drawings as appropriate. [Modes for carrying out the invention]

[0009] In this invention, when describing reaction conditions, amounts of raw material compounds, etc., by indicating numerical ranges, if the upper and lower limits of the numerical range are described separately, either upper or lower limit can be appropriately combined to form a specific numerical range. On the other hand, when describing multiple numerical ranges represented by "~", the upper and lower limits forming the numerical range are not limited to the specific combinations written before and after "~" as a specific numerical range, but can be a numerical range formed by appropriately combining the upper and lower limits of each numerical range. In this invention, a numerical range represented by "~" means a range that includes the values ​​written before and after "~" as the lower and upper limits.

[0010] In this invention, the designation of a compound (for example, when referring to it with "compound" at the end) includes not only the compound itself, but also its salts and ions. It also includes derivatives in which parts have been altered, such as by introducing substituents, to the extent that the effects of this invention are not impaired.

[0011] In the present invention, substituents, linking groups, etc. (hereinafter abbreviated as substituents, etc.) that are not specified as substituted or unsubstituted mean that the group may have appropriate substituents. Therefore, in the present invention, even when simply referred to as a YYY group, this YYY group includes not only the unsubstituted form but also the form with substituents. The same applies to compounds that are not specified as substituted or unsubstituted. Preferred substituents include, for example, groups selected from substituent Z described later. In the present invention, when there are a plurality of substituents or the like represented by specific symbols, or when a plurality of substituents or the like are defined at the same time, this means that each of said substituents or the like may be the same as or different from each other. Additionally, even unless otherwise specified, when a plurality of substituents or the like are adjacent to each other, this means that they may be linked to each other or form a condensed ring to constitute (form) a ring. In the present invention, when the number of carbon atoms of a group is specified, this number of carbon atoms means the number of carbon atoms of the group itself unless otherwise specifically stated in the present invention. That is, when the said group further has a substituent (excluding groups wherein a form further having a substituent can be interpreted as one single group, such as branched alkyl groups), this means the number of carbon atoms when counted without including the number of carbon atoms of said substituent.

[0012] [Production Method of the Present Invention] The method for producing a compound represented by the following formula (2) of the present invention (which may also be simply referred to as "the production method of the present invention") comprises a step of bringing at least one acidic catalyst selected from organic Brønsted acids and activated clays activated with a Brønsted acid into contact with a compound represented by the following formula (1) at a temperature of 70°C or higher. Unlike the Fries rearrangement reaction, the production method of the present invention comprising this step does not require anhydrous conditions as an essential requirement, does not by-produce gas such as hydrogen chloride, and as will be described later, various solvents including aromatic hydrocarbon solvents that cannot be used in Fries rearrangement reactions, other than halogenated solvents, can also be used. In addition, the production method of the present invention does not require the application of high-temperature conditions unlike the Fries rearrangement reaction, and the reaction proceeds under relatively mild temperature conditions while suppressing excessive heat generation. And the production method of the present invention, despite employing simple methods and conditions, provides R 1 -CO- group transferred to the ortho position of the H-X- group, the compound represented by formula (2) can be produced in high yield, preferably with a high purity of 95% or more. Therefore, the production method of the present invention is simple, has high safety, has great industrial robustness, and enables application of a continuous process (flow synthesis method) and industrialization (mass production). In the present invention, from the compound represented by formula (1), R 1The ability to produce the compound represented by formula (2), in which the -CO- group is transferred to the ortho position of the HX- group, in high yield means that the yield of the compound represented by formula (2) relative to the compound represented by formula (1) is 75.0 mol% or more, preferably 80 mol% or more.

[0013] In the present invention, producing a compound represented by formula (2) from a compound represented by formula (1) usually means producing R from a compound represented by formula (1). 1 This refers to the production of a compound represented by formula (2) in which a -CO- group is transferred to the ortho position of an HX- group. However, in embodiments using a compound represented by formula (1) in which Z is a nitrogen atom and the two carbon atoms adjacent to the carbon atom substituted with X in the aromatic ring of formula (1) have hydrogen atoms (at the ortho position), the production of a compound represented by formula (2) from a compound represented by formula (1) means producing a compound represented by formula (1) from R 1 This includes producing a compound represented by formula (2) in which a -CO- group is transferred to the ortho position of one of the HX- groups, and a compound represented by formula (2A) described later (a mixture of both compounds). In this embodiment, the yield of the compound represented by formula (2) refers to the total yield including the yield of the compound represented by formula (2A), but it is preferable that the yield of the compound represented by formula (2) alone is within the above range.

[0014] [ka] In formulas (1) and (2), X represents an oxygen atom, -NH-, or sulfur atom, and Z represents a CH or nitrogen atom. R 1 R indicates an aprotic substituent, 2 represents a substituent, and n is an integer between 0 and 3. However, in the aromatic ring in formula (1) above, at least one of the two carbon atoms adjacent to the carbon atom substituted with X is bonded to Z, and that carbon atom has a hydrogen atom. In addition, the aromatic rings in each formula may be fused with other rings to form fused rings.

[0015] The manufacturing method of the present invention will be described below, in order, including the compounds used, the target compound, and the reaction steps. Each compound or component used in the manufacturing method of the present invention may be one or more.

[0016] <Compound represented by formula (1)> The raw material compound used in the manufacturing method of the present invention is the compound represented by the above formula (1). This compound consists of an active hydrogen-containing group (the "HX-" group in formula (1)) and a ketone group (the "R" group in formula (1)). 1 This is an aromatic compound in which a -CO- group is substituted at the 1st and 4th positions of an aromatic ring. Here, for convenience, the ring-constituting carbon atom to which the active hydrogen-containing group is bonded is designated as "position 1" and Z is designated as "position 3" among the carbon atoms forming the aromatic ring (hereinafter sometimes referred to as ring-constituting carbon atoms), and Z is designated as "position 3". In addition, in the compound represented by formula (1), if X in formula (1) is an oxygen atom, it is called an aromatic hydroxyketone compound; if X in formula (1) is -NH-, it is called an aromatic aminoketone compound; and if X in formula (1) is a sulfur atom, it is sometimes called an aromatic thiohydroxyketone compound.

[0017] In formula (1), X is an oxygen atom, an -NH-, or a sulfur atom. From the standpoint of the reaction that occurs in the production method of the present invention (hereinafter, for convenience, this may be referred to as "the rearrangement reaction that occurs in the present invention"), yield, etc., an oxygen atom is preferred.

[0018] In formula (1), Z is either CH or a nitrogen atom, and CH is preferred in terms of the rearrangement reaction and yield that occur in the present invention. The possible "CH" for Z is the substituent R, which will be discussed later. 2 Replaced by CR 2 It's fine if it's like that.

[0019] In equation (1), R 1 R indicates an aprotic substituent. In this invention, "aprotic substituent" means a substituent that does not have an active hydrogen atom. 1The aprotic substituents that can be used are not particularly limited, but electron-donating groups are preferred. In the present invention, an electron-donating group is a group whose Hammett value (Hammett substituent constant σp) is 0 or less. In the present invention, the Hammett value is the σ value at the para position (σp value) from the σ values ​​described in the literature "The Effect of Structure upon the Reactions of Organic Compounds. Benzene Derivatives" (J.Am.Chem.Soc.1937, 59, 1, 96-103), and for substituents not specifically described in the above literature, the value calculated according to the calculation method described in the above literature is adopted.

[0020] R 1 The electron-donating group that can be used is not particularly limited and can be selected from among the substituent Z described later, and is preferably a hydrocarbon group or a group derived from a heterogeneous compound. The hydrocarbon group includes aliphatic hydrocarbon groups and aromatic hydrocarbon groups, with aliphatic hydrocarbon groups being preferred. The aliphatic hydrocarbon group may be a chain hydrocarbon group or a cyclic hydrocarbon group, and may be a saturated hydrocarbon group or an unsaturated hydrocarbon group (except for aromatic hydrocarbon groups). The chain hydrocarbon group includes a linear hydrocarbon group and a branched hydrocarbon group. Examples of aliphatic hydrocarbon groups include alkyl groups (including cycloalkyl groups), alkenyl groups, and alkynyl groups, and alkyl groups are preferred in terms of the rearrangement reaction and yield that occurs in the present invention. There are no particular restrictions on the number of carbon atoms or structure of each group that can be taken as an aliphatic hydrocarbon group, and it is preferable that it is the corresponding group in substituent Z described later. However, the number of carbon atoms of the alkyl group is preferably 1 to 12, and more preferably 1 to 6, among the number of carbon atoms of the alkyl group in substituent Z. Groups derived from heterocyclic compounds include groups obtained by removing one hydrogen atom from a heterocyclic compound. Heterocyclic compounds include compounds having at least one heteroatom such as oxygen, sulfur, nitrogen, or phosphorus, and not having an active hydrogen atom, and may be chain-like or cyclic compounds. In cyclic compounds, the heteroatom may be located outside the cyclic structure, but heterocyclic compounds having at least one heteroatom within the cyclic structure are preferred. Examples of groups derived from heterocyclic compounds include the heterocyclic group in substituent Z, which will be described later. R 1 As for the aprotic substituents that can be used, electron-donating groups are preferred in terms of the rearrangement reaction that occurs in the present invention, yield, etc., groups derived from hydrocarbon groups or heterocompounds are more preferred, aliphatic hydrocarbon groups are even more preferred, alkyl groups are particularly preferred, and alkyl groups having 1 to 6 carbon atoms are most preferred. R 1 It may have further substituents, but it is preferable that it be unsubstituted. 1 The substituents that may further be present are not particularly limited as long as they do not inhibit the rearrangement reaction that occurs in the present invention, and include substituents Z described later (excluding groups having an active hydrogen atom), among which aprotic substituents and halogen atoms are preferred, and alkyl groups and aryl groups are more preferred.

[0021] In equation (1), R 2 R indicates a substituent. 2 The substituents that can be used are not particularly limited as long as they do not inhibit the rearrangement reaction that occurs in the present invention, and include substituents Z described later (excluding groups having an active hydrogen atom), among which aprotic substituents are preferred, and alkyl groups, alkenyl groups, aryl groups, etc. are more preferred. The compound represented by formula (1) has multiple R 2 If they have [certain characteristics], they may be identical or different from each other.

[0022] In equation (1), n ​​is the substituent R 2This is the number of substitutions, and is usually an integer between 0 and 3, preferably between 0 and 2. However, if Z is a nitrogen atom, n is an integer between 0 and 2, and if the aromatic ring in formula (1) forms a fused ring, it will be the value of m described later.

[0023] In the compound represented by formula (1), of the two carbon atoms adjacent to the X-substituted carbon atom (ortho position) in the aromatic ring (aromatic ring containing Z) in formula (1), at least one carbon atom is bonded to the X-substituted carbon atom and Z (in the compound represented by formula (2), R 1 The carbon atom corresponding to the carbon atom to which the -CO- group is bonded has a hydrogen atom. That is, this carbon atom is unsubstituted. When Z in formula (1) is a nitrogen atom, in the aromatic ring in formula (1), of the two carbon atoms adjacent to the carbon atom substituted with X, the carbon atom bonded to the X-substituted carbon atom and Z has a hydrogen atom, and the carbon atom in the para position relative to Z may or may not have a hydrogen atom.

[0024] In the compound represented by formula (1), the aromatic ring in formula (1) may condense with other rings to form a fused ring. The positions where other rings condense with the aromatic ring in formula (1) are positions 5 and 6, when the carbon atom to which X is bonded in the aromatic ring in formula (1) is designated as position 1 and Z as position 3. When the aromatic ring condenses with other rings to form a fused ring, the compound represented by formula (1) and the compound represented by formula (2) can be expressed as shown in the following formula (1α) or formula (2α).

[0025] [ka]

[0026] In formulas (1α) and (2α), X represents an oxygen atom, -NH-, or sulfur atom, and Z represents a CH or nitrogen atom. 1 R indicates an aprotic substituent, 2'x' represents a substituent, and m is an integer from 0 to 4. α represents another ring fused to the aromatic ring in each formula. However, in formula (1α) above, the carbon atom substituted with X and the carbon atom bonded to Z in the aromatic ring have hydrogen atoms. X, Z, and R in equations (1α) and (2α) 1 and R 2 X, Z, and R in equation (1) are shown. 1 and R 2 It is the same as m, where m is a substituent R, which is appropriately set depending on the type of other ring represented by α. 2 This is the number of substitutions, and can be an integer from 0 to 4, for example. Note that the substituent R of the aromatic ring containing Z in formulas (1α) and (2α) 2 The number of substitutions is either 1 (when Z is CH) or 0 (when Z is a nitrogen atom).

[0027] The other ring α that forms the fused ring with the aromatic ring in each formula is not particularly limited and may be monocyclic or polycyclic, and may include aliphatic hydrocarbon rings or aliphatic heterocyclic rings, aromatic hydrocarbon rings or aromatic heterocyclic rings. Examples of aliphatic hydrocarbon rings include cycloalkanes and cycloalkenes that form the cycloalkyl group of substituent Z described later. Examples of cycloalkenes include cycloalkenes having 3 to 20 carbon atoms, with cycloalkenes having 5 to 7 carbon atoms being preferred. Examples of aromatic hydrocarbon rings include rings that form the aryl group of substituent Z described later. Examples of aliphatic heterocyclic rings and aromatic heterocyclic rings include rings that form the heterocyclic group of substituent Z described later. As for the other rings, in terms of the rearrangement reaction that occurs in the present invention and yield, aliphatic hydrocarbon rings and aromatic hydrocarbon rings are preferred, aliphatic hydrocarbon rings are more preferred, and cycloalkenes are even more preferred. The number of members of each ring constituting the other ring is not particularly limited and can be, for example, 3 to 7 members, but 5 or 6 members are preferred. The fused ring formed by the aromatic ring and other rings in formula (1) is not particularly limited, and any suitable fused ring can be applied. The number of rings constituting the fused ring can be 2 to 4, and 2 or 3 is preferred. Preferred condensed rings that the compound represented by formula (1) can form include a tetraline ring (1,2,3,4-tetrahydronaphthalene ring), a naphthalene ring, an isoquinoline ring, and the like.

[0028] In equation (1), X, Z and R 1 The combinations are not particularly limited, and include any appropriate combination of substituents or atoms indicated by each sign, with preferred combinations of substituents or atoms indicated by each sign being preferred, and in particular X, Z and R 1 Preferably, the group is a combination of an oxygen atom, CH, and a group derived from a hydrocarbon group or a heterogene (paraacylphenol compound), and among these, paraalkylcarbonylphenol compounds are preferred. X, Z, and R 1 and R 2 There are no particular restrictions on the combinations with X, Z, and R. 1 The preferred combination of and R 2 Examples of preferred substituent combinations include: In addition, in the above combinations, the aromatic ring in formula (1) may be a fused ring.

[0029] - Substituent Z - Alkyl groups (preferably C1-C20 alkyl groups, e.g., methyl, ethyl, isopropyl, t-butyl, pentyl, heptyl, 1-ethylpentyl, benzyl, 2-ethoxyethyl, 1-carboxymethyl, etc.), alkenyl groups (preferably C2-C20 alkenyl groups, e.g., vinyl, allyl, oleyl, etc.), alkynyl groups (preferably C2-C20 alkynyl groups, e.g., ethynyl, butadiinyl, phenylethynyl, etc.), cycloalkyl groups (preferably C3-C20 cycloalkyl groups, e.g., cyclopropyl, cyclopentyl, In this specification, alkyl groups usually include cycloalkyl groups, such as cyclohexyl and 4-methylcyclohexyl, but are described separately here.), aryl groups (preferably aryl groups having 6 to 26 carbon atoms, for example, phenyl, 1-naphthyl, 4-methoxyphenyl, 2-chlorophenyl, 3-methylphenyl, etc.), heterocyclic groups (preferably heterocyclic groups having 2 to 20 carbon atoms, more preferably 5 or 6-membered heterocyclic groups having at least one oxygen atom, sulfur atom, or nitrogen atom as ring constituent atoms. Heterocyclic groups include aromatic heterocyclic groups and lipids. Contains aliphatic heterocyclic groups. For example, tetrahydropyran ring group, tetrahydrofuran ring group, 2-pyridyl, 4-pyridyl, 2-imidazolyl, 2-benzimidazolyl, 2-thiazolyl, 2-oxazolyl, pyrrolidone group, etc.), alkoxy groups (preferably alkoxy groups having 1 to 20 carbon atoms, for example, methoxy, ethoxy, isopropyloxy, benzyloxy, etc.), aryloxy groups (preferably aryloxy groups having 6 to 26 carbon atoms, for example, phenoxy, 1-naphthyloxy, 3-methylphenoxy, 4-methoxyphenoxy, etc.), heterocyclic oxy groups (the above heterooxy groups). Groups in which an -O- group is bonded to a telocyclic group), alkoxycarbonyl groups (preferably alkoxycarbonyl groups having 2 to 20 carbon atoms, for example, ethoxycarbonyl, 2-ethylhexyloxycarbonyl, dodecyloxycarbonyl, etc.), aryloxycarbonyl groups (preferably aryloxycarbonyl groups having 7 to 26 carbon atoms, for example, phenoxycarbonyl, 1-naphthyloxycarbonyl, 3-methylphenoxycarbonyl, 4-methoxyphenoxycarbonyl, etc.), heterocyclic oxycarbonyl groups (groups in which an -O-CO- group is bonded to the above heterocyclic group), amino groups,Substituted amino groups (preferably including alkylamino groups having 1 to 20 carbon atoms and arylamino groups having 6 to 26 carbon atoms, for example, N,N-dimethylamino, N,N-diethylamino, N-ethylamino, anilino, etc.), sulfamoyl groups (-SO2NH2), substituted sulfamoyl groups (preferably including sulfamoyl groups having 1 to 20 carbon atoms, for example, N,N-dimethylsulfamoyl, N-phenylsulfamoyl, etc.), acyl groups (including alkylcarbonyl groups, alkenylcarbonyl groups, alkynylcarbonyl groups, arylcarbonyl groups, and heterocyclic carbonyl groups) Preferably, acyl groups having 1 to 20 carbon atoms, for example, acetyl, propionyl, butyryl, octanoyl, hexadecanoyl, acryloyl, methacryloyl, crotonoyl, benzoyl, naphthoyl, nicotinoyl, etc., and acyloxy groups (including alkylcarbonyloxy groups, alkenylcarbonyloxy groups, alkynylcarbonyloxy groups, heterocyclic carbonyloxy groups), preferably acyloxy groups having 1 to 20 carbon atoms, for example, acetyloxy, propionyloxy, butyryloxy, octanoyloxy, hexadecanoyloxy, acrylo (Iloxy, methacryloyloxy, crotonoyloxy, nicotinoyloxy, etc.), allyloxy group (preferably an allyloxy group having 7 to 23 carbon atoms, for example, benzoyloxy, naphthoyloxy, etc.), carbamoyl group (preferably a carbamoyl group having 1 to 20 carbon atoms, for example, N,N-dimethylcarbamoyl, N-phenylcarbamoyl, etc.), acylamino group (preferably an acylamino group having 1 to 20 carbon atoms, for example, acetylamino, benzoylamino, etc.), alkylthio group (preferably an alkylthio group having 1 to 20 carbon atoms, for example , methylthio, ethylthio, isopropylthio, benzylthio, etc.), arylthio group (preferably an arylthio group having 6 to 26 carbon atoms, for example phenylthio, 1-naphthylthio, 3-methylphenylthio, 4-methoxyphenylthio, etc.), heterocyclic thio group (a group in which an -S- group is bonded to the above heterocyclic group), alkylsulfonyl group (preferably an alkylsulfonyl group having 1 to 20 carbon atoms, for example methylsulfonyl, ethylsulfonyl, etc.), arylsulfonyl group (preferably an arylsulfonyl group having 6 to 22 carbon atoms, for example benzenesulfonyl, etc.),Alkylsilyl groups (preferably alkylsilyl groups having 1 to 20 carbon atoms, e.g., monomethylsilyl, dimethylsilyl, trimethylsilyl, triethylsilyl, etc.), arylsilyl groups (preferably arylsilyl groups having 6 to 42 carbon atoms, e.g., triphenylsilyl, etc.), alkoxysilyl groups (preferably alkoxysilyl groups having 1 to 20 carbon atoms, e.g., monomethoxysilyl, dimethoxysilyl, trimethoxysilyl, triethoxysilyl, etc.), aryloxysilyl groups (preferably aryloxysilyl groups having 6 to 42 carbon atoms, e.g., triphenyloxysilyl, etc.), phosphite groups (-OPH(=O)(-OH)), substituted phosphite groups (preferably phosphite groups having 1 to 20 carbon atoms, e.g., -OP(=O)(-OH)(R, P )), phosphoryl group (-OPH2(=O)), substituted phosphoryl group (preferably a phosphate group having 1 to 20 carbon atoms, for example, -OP(=O)(R P 2) A phosphonyl group (preferably a phosphonyl group having 1 to 20 carbon atoms, for example, -P(=O)(R P 2) A phosphinyle group (-PH2), a substituted phosphinyle group (preferably a phosphinyle group having 1 to 20 carbon atoms, for example, -P(R P )2) Phosphonic acid group (-PO(OH)2), Substituted phosphonic acid group (preferably a phosphonic acid group having 1 to 20 carbon atoms, for example, -PO(OR P 2) Examples include sulfo groups (sulfonic acid groups), carboxyl groups, hydroxyl groups, sulfanyl groups, cyano groups, and halogen atoms (e.g., fluorine atoms, chlorine atoms, bromine atoms, iodine atoms, etc.). P is a substituent (preferably a group selected from substituent Z). Furthermore, each of the groups listed as substituent Z may be further substituted with the substituent Z mentioned above.

[0030] Among the above, substituent Z is preferably a group that does not have an active hydrogen atom, for example, R 2 Each of the above groups that can be preferably taken is more preferable.

[0031] The compound represented by formula (1) above can be synthesized as appropriate, or commercially available products can be used. Synthesis methods include various known synthesis reactions or combinations thereof. For example, a Fries rearrangement reaction of the compound represented by formula (3), preferably a carboxylic acid aromatic ester compound, can be performed in the presence of a Lewis acid.

[0032] <Acidic catalyst> The present invention uses an organic Brønsted acid or activated clay activated with a Brønsted acid as an acidic catalyst. By using such an acidic catalyst, the compound represented by formula (2) can be produced in high yield while suppressing gas by-production and excessive heat generation, without requiring water-restricted conditions. Furthermore, various solvents that cannot be used in the Fries rearrangement reaction can be used.

[0033] Organic Brønsted acids can be any organic compound that functions as an "acid" in the Brønsted-Lowry definition, such as organic carboxylic acids and organic sulfonic acids. Examples of organic carboxylic acids include acetic acid, citric acid, gluconic acid, and oxalic acid. Examples of organic sulfonic acids include aliphatic sulfonic acids (alkyl sulfonic acids) such as methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, and camphorsulfonic acid, and aromatic sulfonic acids (aryl sulfonic acids) such as benzenesulfonic acid, p-toluenesulfonic acid (tosylic acid), and naphthalenesulfonic acid. The number of carbon atoms in the alkyl group (excluding substituents) of alkyl sulfonic acids is not particularly limited, but is preferably 1 to 12, and more preferably 1 to 4. The number of carbon atoms in the aryl group (excluding substituents) of aryl sulfonic acids is not particularly limited, but is preferably 6 to 10. The organic Brønsted acid may be a polybasic acid, but it is preferably a monobasic acid. Furthermore, the production method of the present invention can also use an organic Brønsted acid having crystal water, water of hydration, etc. Examples of such hydrated organic Brønsted acids (hydrated catalysts) include organic sulfonic acid hydrates such as p-toluenesulfonic acid monohydrate and camphorsulfonic acid n-hydrate. As for the organic Brønsted acid, organic sulfonic acids or their hydrates are preferred in terms of the rearrangement reaction that occurs in the present invention and yield, and methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, camphorsulfonic acid, p-toluenesulfonic acid, and p-toluenesulfonic acid monohydrate are more preferred.

[0034] Any activated clay can be used, as long as it is clay that has been activated with Brønsted acid; various types of activated clay can be used. The clay is not particularly limited, and various types of clay or clay minerals can be used, such as kaolinite, smectite, talc, zeolite, bentonite, halloysite, and acid clay. Acid clay is an active catalyst based on layered silicates, and an example is montmorillonite activated by a mineral acid such as sulfuric acid and / or hydrochloric acid. Among these, acid clay is preferred in terms of catalytic activity and other factors. Examples of Brønsted acids used to activate clay include organic or inorganic compounds that function as "acids" in the Brønsted-Lowry definition, with inorganic Brønsted acids being preferred. Examples of organic Brønsted acids include the organic Brønsted acids mentioned above. Examples of inorganic Brønsted acids include hydrogen halides, halogen oxoacids, sulfuric acid, fluorosulfonic acid, nitric acid, phosphoric acid, boric acid, etc., with sulfuric acid being preferred.

[0035] There are no particular limitations on the combination of clay and Brønsted acid, and any suitable combination of clay and Brønsted acid is mentioned, with preferred combinations being preferable. For example, a combination of acid clay or halloysite, which mainly consists of clay minerals such as montmorillonite and halloysite, and Brønsted acid, i.e., activated clay obtained by treating acid clay or halloysite with Brønsted acid, is one of the more preferred forms, and a combination of acid clay or bentonite and sulfuric acid, i.e., sulfuric acid-treated activated clay obtained by treating acid clay or bentonite with sulfuric acid, is one of the more preferred forms.

[0036] As activated clay, it may be manufactured by appropriately treating clay with Brønsted acid, or a commercially available product may be used.

[0037] <Solvent> The manufacturing method of the present invention can be carried out without a solvent or in a solvent, regardless of whether the reaction is a batch method or a continuous method. Since the manufacturing method of the present invention does not require water-restricted conditions, it is not necessary to remove a high degree of water from the solvent used beforehand (dehydration treatment). Various organic solvents can be used as solvents in the manufacturing method of the present invention, and organic solvents that do not inhibit the rearrangement reaction that occurs in the present invention are selected. Such organic solvents include organic solvents that are commonly used in the Fries rearrangement reaction, as well as organic solvents that cannot be used in the Fries rearrangement reaction. Examples of organic solvents commonly used in the Fries rearrangement reaction include solvents of electron-withdrawing group-containing compounds, specifically halogenated hydrocarbon compounds such as chlorobenzene, dichlorobenzene, fluorobenzene, difluorobenzene, bromobenzene, dibromobenzene, dichloromethane, dichloroethane, trichloroethane, and chloroform, nitrated hydrocarbon compounds such as nitromethane and nitrobenzene, and various solvents such as carbon disulfide. Examples of organic solvents that cannot be used in the Fries rearrangement reaction include various solvents such as aromatic hydrocarbon compounds, electron-donating group-containing compounds, and aqueous compounds, specifically various solvents such as toluene, xylene, anisole, and other electron-donating group-containing aromatic hydrocarbon compounds. Here, an electron-withdrawing group is a group whose Hammett value (Hammett substituent constant σp) is greater than 0, while an electron-donating group is as described above.

[0038] In the manufacturing method of the present invention, the solvent may include a solvent having active hydrogen, and for example, a mixed solvent of a solvent without active hydrogen and a solvent having active hydrogen may be used. The solvent without active hydrogen is not particularly limited and includes, for example, the organic solvents mentioned above, and the solvent having active hydrogen is not particularly limited and includes, for example, water, alcohol compounds, and amine compounds. If the solvent contains a solvent having active hydrogen, the rearrangement reaction that occurs in the present invention can be promoted. The content of the solvent having active hydrogen in the solvent is preferably small, and for example, it is preferably within the following range. When the above-mentioned aqueous compound is used as a solvent, and when the solvent contains an active hydrogen, the amount of water (water content) in the solvent and the amount of the active hydrogen-containing solvent are not particularly limited, but are preferably 5% by mass or less in order to allow the rearrangement reaction that occurs in the present invention to proceed rapidly.

[0039] The solvent is preferably an aromatic hydrocarbon compound, and more preferably an aromatic hydrocarbon compound containing an electron-donating group.

[0040] <Other ingredients> In the manufacturing method of the present invention, other components may be present in addition to the above-mentioned compound, catalyst, and solvent. Examples of other components include flow gas used in the continuous method described later, magnesium sulfate, sodium sulfate, molecular sieves used as dehydrating agents, and solvents used in azeotropic dehydration. The solvent used in azeotropic dehydration is not limited to any solvent that has the property of forming an azeotrope with water, and examples include acetonitrile, ethyl acetate, pentane, hexane, heptane, cyclohexane, and cumene. If the reaction solvent is a solvent that has the property of forming an azeotrope with water, the reaction solvent can be used as the solvent for azeotropic dehydration. Furthermore, when applying the multi-step synthesis method (one-pot reaction) described later in the manufacturing method of the present invention, examples of compounds that may coexist in the contact step described later in the manufacturing method of the present invention include raw material compounds for synthesizing the compound represented by formula (1) above, such as carboxylic acid aromatic esters, and products from the synthesis reaction in the preceding step, such as the compound represented by formula (2) below.

[0041] <Compound represented by formula (2)> The compound produced by the manufacturing method of the present invention is a compound represented by the following formula (2). This compound consists of an active hydrogen-containing group (the "HX-" group in formula (2)) and a ketone group (the "R" group in formula (2)). 1 It is an aromatic compound in which a -CO- group is substituted at the 1st and 2nd positions (adjacent ring constituent carbon atoms) of an aromatic ring. Furthermore, if the aromatic ring in formula (2) is fused with another ring to form a fused ring, it can be represented by the above formula (2α).

[0042] [ka]

[0043] In equation (2), X is an oxygen atom, an -NH- or a sulfur atom, and is the same as X in equation (1) above. In equation (2), Z is CH or a nitrogen atom, and is the same as Z in equation (1) above. In equation (2), R 1 is an aprotic substituent, and R in formula (1) above 1 It is the same as this. In equation (2), R 2 is a substituent, and R in formula (1) above 2 It is the same as this. In equation (2), n represents an integer between 0 and 3, and is the same as n in equation (1) above.

[0044] In the compound represented by formula (2), the fact that the aromatic ring in formula (2) may condense with other rings to form a fused ring is the same as the fact that the aromatic ring in formula (1) may condense with other rings to form a fused ring.

[0045] Furthermore, in the compound represented by formula (2), X, Z and R 1 Combinations, and further R 2 The combination is X, Z, and R in the compound represented by formula (1). 1 Combinations, and further R 2 This is the same as the combination. Therefore, the compound represented by formula (2) is preferably an orthoacylphenol compound, and among these, an orthoalkylcarbonylphenol compound is more preferred.

[0046] The compound represented by formula (2) can be identified by various identification methods, such as spectral identification methods including nuclear magnetic resonance (NMR) and infrared absorption spectroscopy (IR), mass spectrometry (MASS), and chromatography.

[0047] <Compound represented by formula (2A)> In the manufacturing method of the present invention, when a compound represented by formula (1) above, in which Z is a nitrogen atom and the two carbon atoms adjacent to the carbon atom substituted with X in the aromatic ring of formula (1) (at the ortho position) have hydrogen atoms, a compound represented by the following formula (2A) may be produced along with the compound represented by formula (2) above. This compound consists of an active hydrogen-containing group (the "HX-" group in formula (2A)) and a ketone group (the "R" group in formula (2A)). 1 This is an aromatic compound in which a -CO- group is substituted at the 1st and 2nd positions (adjacent carbon atoms) of an aromatic ring. Note that the aromatic ring in formula (2A) is not fused with any other ring to form a fused ring.

[0048] [ka]

[0049] In formula (2A), X is an oxygen atom, an -NH- or a sulfur atom, and is the same as X in formula (1) above. In formula (2A), Z is CH or a nitrogen atom, and is the same as Z in formula (1) above. In equation (2A), R 1 is an aprotic substituent, and R in formula (1) above 1 It is the same as this. In equation (2A), R 2 is a substituent, and R in formula (1) above 2 It is the same as this. In equation (2A), n represents an integer between 0 and 3, and is the same as n in equation (1) above.

[0050] In the compound represented by formula (2A), X, Z and R 1 Combinations, and further R 2 The combination is X, Z, and R in the compound represented by formula (1). 1 Combinations, and further R 2 This is the same as the combination. Therefore, the compound represented by formula (2A) is preferably an orthoacylphenol compound, and among these, an orthoalkylcarbonylphenol compound is more preferred.

[0051] The compound represented by formula (2A) can be identified in the same manner as the compound represented by formula (2).

[0052] In the production method of the present invention, the production ratio (selectivity) of the compound represented by formula (2) and the compound represented by formula (2A) is determined by the type of compound represented by formula (1), for example, R of formula (1). 1 The choice of X, as well as changes in various reaction conditions, do not determine the result uniquely.

[0053] <Contact process> In the manufacturing method of the present invention, the compound represented by formula (1) and the acidic catalyst are brought into contact with each other in a solvent or in a solvent at a temperature of 70°C or higher. This contact brings about the "R" in the compound represented by formula (1). 1 The -CO- group rearranges from position 4 to position 2 on the aromatic ring in formula (1), resulting in the compound represented by formula (2). In the contact step, one or more compounds represented by formula (1), acidic catalysts, solvents, etc., can be used.

[0054] The contact conditions can be appropriately set depending on the type of compound represented by formula (1) and the acidic catalyst, the presence and type of solvent, etc. For example, the reaction system does not need to be under water-restricted conditions, such as a closed system, as in the Fries rearrangement reaction; it can be in an atmospheric environment, such as an open system. The amount of acidic catalyst used can be, for example, 0.7 or more as the molar ratio of active hydrogen atoms in the acidic catalyst to the "HX-" group in the compound represented by formula (1) [moles of active hydrogen atoms / molars of HX- groups], and is preferably 1.0 or more, more preferably 2.0 or more, and even more preferably 4.0 or more in terms of the rearrangement reaction and yield that occur in the present invention. The upper limit of the above molar ratio is not particularly limited and can be determined as appropriate, for example, it can be 50 or less, preferably 30 or less, and more preferably 20 or less. When activated clay is used as an acidic catalyst, the amount of activated clay used is preferably 0.02 parts by mass or more, more preferably 0.1 parts by mass or more, and even more preferably 0.2 parts by mass or more, with the compound represented by formula (1) being 1 part by mass. The upper limit of the above parts by mass is not particularly limited and can be determined as appropriate, for example, it can be 10 parts by mass or less, preferably 5 parts by mass or less, and more preferably 2 parts by mass or less.

[0055] The contact temperature (reaction temperature) is 70°C or higher, preferably 75°C or higher in terms of the rearrangement reaction and yield that occur in the present invention, and more preferably 80°C or higher in terms of promoting the rearrangement reaction and completing the rearrangement reaction in a short time. The upper limit of the reaction temperature is not particularly limited and can be 200°C or lower, but considering the suppression of side reactions, cost reduction, and application to industrialization, it is preferably 150°C or lower and more preferably 120°C or lower. When the contact process is carried out by batch method, the upper limit of the reaction temperature is as described above, but it can also be 110°C or lower, and even more preferably 100°C or lower. The contact time (reaction time) can be appropriately set according to the type of compound represented by formula (1) and the acidic catalyst, the presence and type of solvent, and the reaction temperature, and is not particularly limited. The reaction time is preferably 10 minutes or more, more preferably 30 minutes or more, and even more preferably 60 minutes or more, in terms of the rearrangement reaction that occurs in the present invention and the yield. Since the compound represented by formula (2) is stable in the reaction system, extending the reaction time beyond what is necessary does not contribute to improving the yield. Therefore, the upper limit of the reaction time can be, for example, 400 minutes or less, taking productivity into consideration, and is preferably 120 minutes or less, taking cost reduction and application to industrialization into consideration. When the compound represented by formula (1) is brought into contact with an acidic catalyst in a solvent, the concentrations of the compound represented by formula (1) and the acidic catalyst in the solvent can be set as appropriate. For example, the concentration of the compound represented by formula (1) in the solvent can be 0.5 to 80% by mass, and is preferably 10 to 40% by mass.

[0056] The method of contacting the compound represented by formula (1) with the above-mentioned acidic catalyst may be either a batch method or a continuous method (flow synthesis method). In particular, since no gas is produced as a by-product in the production method of the present invention, the production method of the present invention can be safely carried out even if a continuous method is applied. When applying the batch method, a general batch reaction configuration can be used. For example, the compound represented by formula (1), an acidic catalyst, and a solvent (if necessary) can be placed in a reaction vessel and brought into contact and rearranged under stirring. The contact conditions are as described above, and the stirring conditions are not particularly limited.

[0057] The flow synthesis method applicable to the manufacturing method of the present invention is not particularly limited, and examples include a homogeneous catalyst type flow synthesis method in which a mixture of an acidic catalyst and a compound represented by formula (1) is passed through the flow path and subjected to contact and rearrangement reaction, and a heterogeneous catalyst type flow synthesis method in which a compound represented by formula (1) is passed through the flow path and subjected to contact and rearrangement reaction. One example of a manufacturing method of the present invention that applies a homogeneous catalytic flow synthesis method is a method (sometimes referred to as the homogeneous catalytic flow synthesis method of the present invention) in which a fluid 1 containing at least one organic Brønsted acid as an acidic catalyst and a fluid 2 containing the compound represented by formula (1) are brought into contact in a flow reactor to produce the compound represented by formula (2). In the homogeneous catalytic flow synthesis method of the present invention, the flow passage (contact region) in the flow reactor in which fluid 1 and fluid 2 are brought into contact is set to the above-mentioned contact conditions, particularly the contact temperature, flow time, and amount of acidic catalyst used. As the compound represented by formula (1) flows through this contact region, it undergoes a rearrangement reaction to become the compound represented by formula (2), and is discharged from the contact region and the flow reactor. In the homogeneous catalytic flow synthesis method of the present invention, fluid 1 and fluid 2 only need to be mixed as they pass through the contact region in the flow reactor. Alternatively, they may be pre-mixed under conditions that prevent the rearrangement reaction occurring in the present invention, and then the mixed fluid of fluid 1 and fluid 2 may be introduced into the contact region and brought into contact, or they may be mixed and brought into contact within the contact region. In the homogeneous catalytic flow synthesis method of the present invention, when referring to mixing or contacting fluid 1 and fluid 2, it is equivalent to mixing or contacting the compound represented by formula (1) in fluid 1 with the organic Brønsted acid in fluid 2.

[0058] The compound represented by formula (1), the organic Brønsted acid, and the compound represented by formula (2) produced in the homogeneous catalytic flow synthesis method of the present invention are as described above. In the homogeneous catalytic flow synthesis method of the present invention, methods, conditions, and reaction equipment such as flow reactors, other than the synthesis conditions (contact conditions), can be those that are commonly used in homogeneous catalytic flow synthesis methods. For example, it is preferable that fluid 1 contains a medium such as a solvent or an inert gas in addition to the compound represented by formula (1) above, in terms of the reactivity of the compound represented by formula (1), the uniformity of the rearrangement reaction, and the yield. Similarly, it is preferable that fluid 2 contains a medium such as a solvent or an inert gas in addition to the acidic catalyst, in terms of the reactivity of the compound represented by formula (1), the uniformity of the rearrangement reaction, and the yield. The solvent used as the medium is as described above. The inert gas used as the medium is not particularly limited, but examples include nitrogen gas, helium gas, and argon gas.

[0059] In the homogeneous catalytic flow synthesis method of the present invention, the concentration and flow rate of each fluid supplied to the flow reactor are appropriately determined considering stoichiometry, the contact conditions described above, the size of the flow reactor, and so on. An example is described below. When supplying a compound represented by formula (1) mixed with a medium, the content (concentration) of the compound represented by formula (1) in the medium (fluid 1) can be 0.5 to 80% by mass, and preferably 10 to 40% by mass. When supplying an organic Brønsted acid as an acidic catalyst mixed with a medium, the content (concentration) of the organic Brønsted acid in this medium (fluid 2) can be 0.5 to 80% by mass, and preferably 40 to 80% by mass. The flow rates of fluid 1 and fluid 2 are, for example, 0.1 to 1000 mL (cm³). 3The flow rate can be 0.5 to 100 mL / min, and is preferable. The pressure inside the flow reactor is not particularly limited and can be set as appropriate, either under open conditions (atmospheric pressure) or under pressurized conditions. For example, it can be set from 1 to 10,000,000 Pa.

[0060] In the homogeneous catalytic flow synthesis method of the present invention, the contact time (reaction time) between fluid 1 and fluid 2 can be appropriately set according to the type of compound represented by formula (1) and the acidic catalyst, the presence and type of solvent, and the reaction temperature, and is not particularly limited. Specific examples of reaction times include those described for the batch method, and the flow rates of fluid 1 and fluid 2, as well as the length of the flow path through which fluid 1 and fluid 2 come into contact (react), can be appropriately set to achieve such reaction times. The diameter (inner diameter) of each flow path through which each liquid flows can be set appropriately according to the flow rate, production volume, etc., and is not particularly limited. For example, the equivalent diameter of each flow path through which each liquid flows can be 1 to 50 mm, preferably 1 to 30 mm, and more preferably 1 to 10 mm. The above-mentioned "equivalent diameter" is also called the equivalent (straight) diameter and is a term used in the field of mechanical engineering. When an equivalent circular pipe is assumed for a pipe or flow path with an arbitrary internal cross-sectional shape, the diameter of the internal cross-section of that equivalent circular pipe is called the equivalent diameter. The equivalent diameter (deq) is defined as deq = 4A / p, where A is the internal cross-sectional area of ​​the pipe and p is the wet edge length (internal circumference) of the pipe. When applied to a circular pipe, this equivalent diameter coincides with the diameter of the internal cross-section of the circular pipe. The equivalent diameter is used to estimate the flow or heat transfer characteristics of the pipe based on the data of the equivalent circular pipe, and represents the spatial scale (representative length) of the phenomenon. The equivalent diameter is deq = 4a for a square pipe with a side length of a. 2 / 4a=a, in an equilateral triangular tube with side length a, deq=a / 3¹ / 2, and in flow between parallel plates with flow path height h, deq=2h (see, for example, "Dictionary of Mechanical Engineering" edited by the Japan Society of Mechanical Engineers (1997, Maruzen Co., Ltd.)).

[0061] Although the homogeneous catalytic flow synthesis method of the present invention is a two-liquid mixing method using the above-mentioned fluids 1 and 2, a one-liquid method can also be applied in which the compound represented by formula (1) and the organic Brønsted acid are brought into contact in a flow reactor using a fluid containing the compound represented by formula (1) and the organic Brønsted acid.

[0062] One example of a manufacturing method of the present invention that applies a heterogeneous catalytic flow synthesis method is a method for producing the compound represented by formula (2) by flowing a fluid 3 containing the compound represented by formula (1) through a solid support bed containing at least one activated clay activated with Brønsted acid as an acidic catalyst (sometimes referred to as the heterogeneous catalytic flow synthesis method of the present invention). In the heterogeneous catalytic flow synthesis method of the present invention, the flow passage (contact region) in the flow reactor where the solid support bed is installed is set to the above-mentioned contact conditions, particularly the contact temperature, flow time, and amount of acidic catalyst used. As the compound represented by formula (1) flows through this contact region (solid support bed), it undergoes a rearrangement reaction to become the compound represented by formula (2), and is discharged from the contact region and the flow reactor.

[0063] The compound represented by formula (1), the activated clay, and the compound represented by formula (2) produced in the heterogeneous catalytic flow synthesis method of the present invention are as described above. In the heterogeneous catalytic flow synthesis method of the present invention, methods, conditions, and reaction equipment such as flow reactors, other than the synthesis conditions (contact conditions), can be those that are commonly used in heterogeneous catalytic flow synthesis methods. For example, it is preferable that fluid 3 contains a medium such as a solvent or an inert gas in addition to the compound represented by formula (1) above, in terms of the reactivity of the compound represented by formula (1), the uniformity of the rearrangement reaction, and the yield. The solvent and inert gas used as the medium are as described above. Furthermore, the solid support layer is a region in which activated clay is fixedly arranged within the flow channel, and the activated clay can be fixedly arranged in the flow channel in a mesh or porous manner, or the activated clay can be supported and fixed on commonly used supports, such as a mesh or porous body. Commonly used meshes and porous bodies can be used without particular limitation.

[0064] In the heterogeneous catalytic flow synthesis method of the present invention, the concentration and flow rate of the fluid 3 supplied to the flow reactor, and the amount of activated clay fixedly placed in the flow reactor are appropriately determined considering stoichiometry, the contact conditions described above, the size of the flow reactor, etc. An example is described below. When supplying a compound represented by formula (1) mixed with a medium, the content (concentration) of the compound represented by formula (1) in the medium (fluid 3) can be 0.5 to 50% by mass, and preferably 1 to 30% by mass. The flow rate of fluid 3 can be, for example, 0.1 to 1000 mL (cm³). 3 The flow rate can be 0.5 to 100 mL / min, and is preferable. The pressure inside the flow reactor is not particularly limited and can be set as appropriate, either under open conditions (atmospheric pressure) or under pressurized conditions. For example, it can be set from 1 to 10,000,000 Pa. A specific example of reaction time in heterogeneous catalytic flow synthesis is the same as that in homogeneous catalytic flow synthesis. Specific examples of the equivalent diameter of each flow channel through which each liquid flows include examples similar to those in the homogeneous catalytic flow synthesis method. The length of the region (column) in which the activated clay is fixedly arranged can be 1 to 50 cm, but it is preferably 5 to 30 cm.

[0065] The above contact step allows for the production of the compound represented by formula (2) from the compound represented by formula (1). Although the details of the reaction mechanism are not yet clear, it is thought to be as follows: In the production method of the present invention, hydrogen ions generated from an acidic catalyst, which is a stronger acid than Lewis acid, bond to the aromatic ring in formula (1), particularly the carbon atom at position 4, and proceed through a transition state (coordination state) where aromaticity is lost, similar to the Fries rearrangement reaction, resulting in the formation of an acyl cation (R 1 -C + Without releasing =O), R 1 It is thought that the -CO- group undergoes an intramolecular rearrangement. One of the driving forces behind this rearrangement reaction is the active hydrogen H bonded to X in equation (2), and the rearranged R. 1 The reason for this is thought to be that the compound becomes more stable than the compound represented by formula (1) due to hydrogen bonding with the carbonyl oxygen atom of the -CO- group.

[0066] <Other processes> The manufacturing method of the present invention may include steps other than the contact step described above. Other steps include, for example, a step of separating or purifying the compound represented by formula (2) that has been manufactured, a step of synthesizing the compound represented by formula (1), and a step of manufacturing the next compound without separating or purifying the compound represented by formula (2) that has been manufactured.

[0067] (Multi-stage manufacturing method) The compound represented by formula (1) used in the manufacturing method of the present invention may be one that has been manufactured (isolated) or prepared in advance, and it is also preferable to use a compound represented by formula (1) that has been synthesized directly, taking into consideration productivity, industrialization, etc. That is, the multi-stage manufacturing process of manufacturing the compound represented by formula (1) and manufacturing the compound represented by formula (2) can be carried out in succession. In the present invention, "carrying out in succession" does not mean carrying out the process continuously over time, but rather means that after manufacturing the compound represented by formula (1), the compound represented by formula (1) is used to manufacture the compound represented by formula (2) without isolating it, preferably a one-pot reaction.

[0068] In this multi-step manufacturing method, the process typically involves a Fries rearrangement reaction of the compound represented by formula (3) in the presence of a Lewis acid, followed by the manufacturing method of the present invention. The manufacturing process in this multi-step manufacturing method is shown below. Note that the compound represented by formula (2), which is a by-product of the Fries rearrangement reaction, is omitted from the description of the manufacturing process below. [ka]

[0069] In equations (1) to (3), X is an oxygen atom, an -NH-, or a sulfur atom, and is the same as X described in equation (1) above. In equation (2), Z is CH or a nitrogen atom, and is the same as Z as explained in equation (1) above. In equation (2), R 1 R is an aprotic substituent, as explained in formula (1) above. 1 It is the same as this. In equation (2), R 2 R is a substituent, as explained in formula (1) above. 2 It is the same as this. In equation (2), n represents an integer between 0 and 3, and is the same as the n explained in equation (1) above.

[0070] The Fries rearrangement reaction in the multi-step manufacturing method can be carried out by appropriately referring to known methods and conditions, and the process is completed by deactivating the Lewis acid after the rearrangement reaction. Since the manufacturing method of the present invention does not require water-restricted conditions, the manufacturing method of the present invention can be carried out even if water is used to deactivate the Lewis acid. Furthermore, since the compound represented by formula (2) is stable under the conditions of the manufacturing method of the present invention, the manufacturing method of the present invention can be carried out even if it is produced as a by-product in the Fries rearrangement reaction. The manufacturing method of the present invention is as described above. When attempting to produce the compound represented by formula (2) by the Fries rearrangement reaction, the low ortho-para directing ability (selectivity) generally results in a mixture of the compound represented by formula (1) and the compound represented by formula (2) as reaction products, and the yield of the target compound represented by formula (2) is not sufficient. However, in the above multi-step manufacturing method, the unintended compound represented by formula (1) produced in the Fries rearrangement reaction can be effectively utilized to produce the target compound represented by formula (2) in high yield. In other words, in the above multi-step manufacturing method, the problem of low ortho-para directing ability (selectivity) in the Fries rearrangement reaction can be resolved by converting the para-oriented compound represented by formula (1) into the ortho-oriented compound represented by formula (2) in high yield in the next step.

[0071] As described above, the manufacturing method of the present invention allows for the production of the compound represented by formula (2) in a simple manner with high yield. Moreover, because the manufacturing method of the present invention is simple, highly safe, and industrially robust, it can be applied as a continuous process (flow synthesis method) and industrialized (mass production). [Examples]

[0072] The present invention will be described in more detail below based on examples, but the present invention is not to be construed as being limited thereto. In the following examples, "parts" and "%" representing composition are by mass unless otherwise specified. In the present invention, "room temperature" means 25°C.

[0073] [ Reference example 1] Compound E2 was prepared by heating compound E1 at 90°C for 1 hour in the presence of methanesulfonic acid. Specifically, 10.0 g (52.6 mmol) of compound E1 and 20.2 g (210.2 mmol) of methanesulfonic acid were added to a reaction vessel and contacted at 90°C for 1 hour with stirring. HPLC analysis revealed an area ratio of compound E1:compound E2 = 7.0:93.0. The reaction product was then cooled to 20°C, and 200 mL of toluene and 100 mL of saturated sodium bicarbonate solution were added. After stirring for 30 minutes and allowing to stand, liquid-liquid separation was performed to recover the toluene layer. 3 g of magnesium sulfate was added to the toluene layer and stirred for 30 minutes. After filtration, 50 mL of toluene was added to the filtration residue to wash and obtain the filtered toluene solution. After concentration to dryness using a rotary evaporator, column chromatography purification was performed using a silica gel column with Wako Gel(R) 60N (150~425 μm) using hexane and ethyl acetate as eluents. The fraction containing compound E2 was concentrated to dryness using a rotary evaporator to obtain 9.30 g of compound E2 (yield 93.0%).

[0074] <Identification of Compound E1> Compound E1, prepared as a starting material, was identified by the following method and results. 1 H-NMR(CDCl3=7.26ppm)δ(ppm):1.77(4H,m),2.53(3H,s),2.65(2H,t),3.03(2H,t),5.47(1H,br),6.67(1H,d),7.52(1H,d) <Identification of Compound E2> The obtained compound E2 was identified by the following method and results. 1 H-NMR(CDCl3=7.26ppm)δ(ppm):1.79(4H,br),2.58(3H,s),2.72(4H,m),6.61(1H,d),7.45(1H,d),12.71(1H,s)

[0075] [Example 2] Compound E2 was prepared by heating a toluene solution containing compound E1 at 90°C for 1 hour in the presence of methanesulfonic acid. Specifically, 20.0 g of anhydrous toluene, 10.0 g of compound E1 (52.6 mmol, 19.9% ​​by mass), and 20.2 g of methanesulfonic acid (210.2 mmol, 40.2% by mass) were added to a reaction vessel. The resulting mixture was contacted at 90°C for 1 hour while stirring. After that, the reaction product was cooled to 20°C, and 200 mL of toluene and 100 mL of saturated sodium bicarbonate solution were added. After stirring for 30 minutes and allowing to stand, liquid-liquid extraction was performed to recover the toluene layer. 3 g of magnesium sulfate was added to the toluene layer and stirred for 30 minutes. After filtration, 50 mL of toluene was added to the filtration residue to wash it and obtain the filtered toluene solution. After concentrating to dryness using a rotary evaporator, column chromatography purification was performed using a silica gel column with Wako Gel(R) 60N (150~425 μm) using hexane and ethyl acetate as eluents. The fraction containing compound E2 was concentrated to dryness using a rotary evaporator to obtain 9.72 g of compound E2 (yield 97.2%). Reference example In the same way as in 1 (Hereafter, in the identification of compounds E1 and E2, we will refer to this as "in the same manner as in Example 1" for convenience.) Compound E2 was identified.

[0076] [Example 3] Compound E2 was prepared by heating an aqueous toluene solution containing compound E1 at 90°C for 1 hour in the presence of methanesulfonic acid. Specifically, 20.0 g of toluene, pre-adjusted to a water content of 300 ppm, 10.0 g of compound E1 (52.6 mmol, concentration 19.9% ​​by mass), and 20.2 g of methanesulfonic acid (210.2 mmol, concentration 40.2% by mass) were added to a reaction vessel. The resulting mixture was contacted at 90°C for 1 hour while stirring. After that, the reaction product was cooled to 20°C, and 200 mL of toluene and 100 mL of saturated sodium bicarbonate solution were added. After stirring for 30 minutes and allowing to stand, liquid-liquid treatment was performed and the toluene layer was recovered. 3 g of magnesium sulfate was added to the toluene layer and stirred for 30 minutes. After filtration, 50 mL of toluene was added to the filtration residue to wash it and obtain the filtered toluene solution. After concentrating to dryness using a rotary evaporator, column chromatography purification was performed using a silica gel column with Wako Gel(R) 60N (150~425 μm) using hexane and ethyl acetate as eluents. The fraction containing compound E2 was concentrated to dryness using a rotary evaporator to obtain 9.82 g of compound E2 (yield 98.2%). Compound E2 was identified in the same manner as in Example 1.

[0077] [Example 4] Compound E2 was prepared by heating an aqueous toluene solution containing compound E1 at 90°C for 1 hour in the presence of methanesulfonic acid. Specifically, 0.4 g of water, 20.0 g of anhydrous toluene, 10.0 g of compound E1 (52.6 mmol, 19.8% by mass), and 20.2 g of methanesulfonic acid (210.2 mmol, 39.9% by mass) were added to a reaction vessel. The resulting mixture was contacted at 90°C for 1 hour while stirring. After that, the reaction product was cooled to 20°C, and 200 mL of toluene and 100 mL of saturated sodium bicarbonate solution were added. After stirring for 30 minutes and allowing to stand, liquid-liquid treatment was performed and the toluene layer was recovered. 3 g of magnesium sulfate was added to the toluene layer and stirred for 30 minutes. After filtration, 50 mL of toluene was added to the filtration residue to wash it and obtain the filtered toluene solution. After concentrating to dryness using a rotary evaporator, column chromatography purification was performed using a silica gel column with Wako Gel(R) 60N (150~425 μm) using hexane and ethyl acetate as eluents. The fraction containing compound E2 was concentrated to dryness using a rotary evaporator to obtain 9.80 g of compound E2 (yield 98.0%). Compound E2 was identified in the same manner as in Example 1.

[0078] [Example 5] Compound E2 was prepared by heating a chlorobenzene solution containing compound E1 at 90°C for 1 hour in the presence of methanesulfonic acid. Specifically, 20.0 g of anhydrous chlorobenzene, 10.0 g of compound E1 (52.6 mmol, 19.9% ​​by mass), and 20.2 g of methanesulfonic acid (210.2 mmol, 40.2% by mass) were added to a reaction vessel. The resulting mixture was contacted at 90°C for 1 hour while stirring. After that, the reaction product was cooled to 20°C, and 200 mL of toluene and 100 mL of saturated sodium bicarbonate solution were added. After stirring for 30 minutes and allowing to stand, liquid-liquid extraction was performed, and the toluene layer was recovered. 3 g of magnesium sulfate was added to the toluene layer and stirred for 30 minutes. After filtration, 50 mL of toluene was added to the filtration residue to wash it and obtain the filtered toluene solution. After concentrating to dryness using a rotary evaporator, column chromatography purification was performed using a silica gel column with Wako Gel(R) 60N (150~425 μm) using hexane and ethyl acetate as eluents. The fraction containing compound E2 was concentrated to dryness using a rotary evaporator to obtain 9.77 g of compound E2 (yield 97.7%). Compound E2 was identified in the same manner as in Example 1.

[0079] [Example 6] Compound E2 was prepared by heating a toluene solution containing compound E1 at 90°C for 1 hour in the presence of p-toluenesulfonic acid monohydrate. Specifically, 20.0 g of anhydrous toluene, 10.0 g of compound E1 (52.6 mmol, 19.9% ​​by mass), and 20.2 g of p-toluenesulfonic acid monohydrate (106.2 mmol, 40.2% by mass) were added to a reaction vessel. The resulting mixture was contacted at 90°C for 1 hour while stirring. After that, the reaction product was cooled to 20°C, and 200 mL of toluene and 100 mL of saturated sodium bicarbonate solution were added. After stirring for 30 minutes and allowing to stand, liquid-liquid treatment was performed and the toluene layer was recovered. 3 g of magnesium sulfate was added to the toluene layer and stirred for 30 minutes. After filtration, 50 mL of toluene was added to the filtration residue to wash it and obtain the filtered toluene solution. After concentrating to dryness using a rotary evaporator, column chromatography purification was performed using a silica gel column with Wako Gel(R) 60N (150~425 μm) using hexane and ethyl acetate as eluents. The fraction containing compound E2 was concentrated to dryness using a rotary evaporator to obtain 9.27 g of compound E2 (yield 92.7%). Compound E2 was identified in the same manner as in Example 1.

[0080] [Example 7] Compound E2 was produced by heating a toluene solution containing compound E1 at 90°C for 1 hour in the presence of activated clay (product name: FULCAT-22B, manufactured by BYK, acid value 28 mg KOH / g) as an activated clay catalyst activated with Brønsted acid. Specifically, 20.0 g of anhydrous toluene, 10.0 g of compound E1 (52.6 mmol, concentration 33.3% by mass), and 2.00 g of FULCAT-22B were added to a reaction vessel. The resulting mixture was contacted at 90°C for 1 hour while stirring. After that, the reaction product was cooled to 20°C and filtered. The filtration residue was then washed with 50 mL of toluene to obtain the filtered toluene solution. After concentrating to dryness using a rotary evaporator, the solution was purified by column chromatography using a silica gel column with Wako Gel(R) 60N (150-425 μm) with hexane and ethyl acetate as eluents. The fraction containing compound E2 was concentrated to dryness using a rotary evaporator to obtain 8.02 g of compound E2 (yield 80.2%). Compound E2 was identified in the same manner as in Example 1.

[0081] [Example 8] 0.30 g of activated clay (product name: FULCAT-22B, manufactured by BYK, acid value 28 mg KOH / g) activated with Brønsted acid was packed into a flow reactor (column) with an inner diameter of 3 mm and a length of 50 mm to form a solid support layer. This solid support layer was heated to 120°C. Next, a toluene solution of compound E1 (compound E1 concentration 4.0 mass%, 0.210 mmol / g, corresponding to fluid 3 above), consisting of 0.83 g of compound E1 and 20 g of toluene, was flowed through the flow reactor at a flow rate of 0.1 mL / min to bring compound E1 into contact with the activated clay on the solid support layer. After collecting 10 g of the fluid that flowed out of the flow reactor, it was concentrated to dryness using a rotary evaporator, and then purified by column chromatography using a silica gel column with Wako Gel(R) 60N (150~425 μm) with hexane and ethyl acetate as eluents. The fraction containing compound E2 was concentrated to dryness using a rotary evaporator to obtain 0.31 g of compound E2 (yield 75.2%). Compound E2 was identified in the same manner as in Example 1.

[0082] [Example 9] Compound E2 was produced in a flow reactor using fluids 1 and 2, which were prepared as described below. Specifically, fluid 1 was prepared, consisting of 10.0 g of toluene (pre-adjusted to a water content of 300 ppm) and 10.0 g of compound E1 (concentration 50.0 mass%), and set in flow channel 1 of the flow reactor. Next, fluid 2 was prepared, consisting of 20.2 g of methanesulfonic acid (concentration 66.9 mass%) and 10.0 g of toluene, and set in flow channel 2 of the flow reactor. The solutions from flow channel 1 and flow channel 2 were each delivered at a rate of 0.1 mL / min and mixed with a mixer to obtain a reaction solution (compound E1 concentration 19.1 mass%, 1.05 mmol / g). This solution was then passed through a pipe-type reaction bed (made of PEEK, inner diameter 1 mm, flow channel length 10 m) heated at 100°C. After collecting 10 g of fluid effluent from the flow reactor, it was concentrated to dryness using a rotary evaporator. Column chromatography purification was then performed using a silica gel column with Wako Gel(R) 60N (150-425 μm) using hexane and ethyl acetate as eluents. The fraction containing compound E2 was concentrated to dryness using a rotary evaporator to obtain 0.194 g of compound E2 (yield 97.5%). Compound E2 was identified in the same manner as in Example 1.

[0083] [Example 10] Compound E3 was subjected to a Fries rearrangement to produce compounds E1 and E2. Then, an organic Brønsted acid was added to the reaction system, and compound E2 was produced from compound E1 in the presence of compound E2. Specifically, compound E3 was subjected to a Fries rearrangement reaction in the same manner as in Comparative Example 1 described later. HPLC analysis revealed no residual compound E3, and the area percentage ratio of compounds E1 and E2 was E1:E2 = 25.6:74.6%. Next, the reaction mixture was cooled to 20°C, 20.2g of methanesulfonic acid was added, and the mixture was contacted at 90°C for 1 hour with stirring. HPLC analysis revealed no residual compound E3, and the area percentage ratio of compounds E1 and E2 was E1:E2 = 2.0:98.0%. Subsequently, the reaction product was cooled to 20°C, and 200mL of toluene and 300mL of saturated sodium bicarbonate solution were added. After stirring for 30 minutes and allowing to stand, liquid-liquid extraction was performed to recover the toluene layer. 3g of magnesium sulfate was added to the toluene layer and stirred for 30 minutes. After filtration, 50mL of toluene was added to the filtration residue to wash it and obtain the filtered toluene solution. After concentration to dryness using a rotary evaporator, the compound E2 was purified by column chromatography using a silica gel column with Wako Gel (R) 60N (150-425 μm) with hexane and ethyl acetate as eluents. The fraction containing compound E2 was concentrated to dryness using a rotary evaporator to obtain 9.02 g of compound E2 (90.2% yield of compound E2 relative to compound E3). Compounds E1 and E2 were identified in the same manner as in Example 1. The manufacturing scheme for Example 10 is shown below. [ka]

[0084] [Example 11] Compound E5 was prepared by heating a toluene solution containing compound E4 at 90°C for 1 hour in the presence of methanesulfonic acid. Specifically, 20.0 g of anhydrous toluene, 10.0 g of compound E4 (60.9 mmol, 19.9% ​​by mass), and 20.2 g of methanesulfonic acid (210.2 mmol, 40.2% by mass) were added to a reaction vessel. The resulting mixture was contacted at 90°C for 1 hour while stirring. After that, the reaction product was cooled to 20°C, and 200 mL of toluene and 100 mL of saturated sodium bicarbonate solution were added. After stirring for 30 minutes and allowing to stand, liquid-liquid extraction was performed to recover the toluene layer. 3 g of magnesium sulfate was added to the toluene layer and stirred for 30 minutes. After filtration, 50 mL of toluene was added to the filtration residue to wash it and obtain the filtered toluene solution. After concentrating to dryness using a rotary evaporator, column chromatography purification was performed using a silica gel column with Wako Gel(R) 60N (150~425 μm) using hexane and ethyl acetate as eluents. The fraction containing compound E5 was concentrated to dryness using a rotary evaporator to obtain 9.80 g of compound E5 (yield 98.0%). [ka]

[0085] <Identification of Compound E4> Compound E4, prepared as a starting material, was identified by the following method and results. 1 H-NMR(CDCl3=7.26ppm)δ(ppm):2.18(3H,s),2.31(3H,s),2.60(3H,s),6.71(1H,s),7.49(1H,d),12.68(1H,s) <Identification of Compound E5> The obtained compound E5 was identified by the following method and results. 1 H-NMR(CDCl3=7.26ppm)δ(ppm):2.18(3H,s),2.31(3H,s),2.60(3H,s),6.71(1H,s),7.49(1H,d),12.68(1H,s)

[0086] [Example 12] Compound E5 was prepared by heating a chlorobenzene solution containing compound E4 at 90°C for 1 hour in the presence of methanesulfonic acid. Specifically, 20.0 g of anhydrous chlorobenzene, 10.0 g of compound E4 (60.9 mmol, concentration 19.9% ​​by mass), and 20.2 g of methanesulfonic acid (210.2 mmol, concentration 40.2% by mass) were added to a reaction vessel. The resulting mixture was contacted at 90°C for 1 hour while stirring. After that, the reaction product was cooled to 20°C, and 200 mL of toluene and 100 mL of saturated sodium bicarbonate solution were added. After stirring for 30 minutes and allowing to stand, liquid-liquid treatment was performed and the toluene layer was recovered. 3 g of magnesium sulfate was added to the toluene layer and stirred for 30 minutes. After filtration, 50 mL of toluene was added to the filtration residue to wash it and obtain the filtered toluene solution. After concentrating to dryness using a rotary evaporator, column chromatography purification was performed using a silica gel column with Wako Gel(R) 60N (150~425 μm) using hexane and ethyl acetate as eluents. The fraction containing compound E5 was concentrated to dryness using a rotary evaporator to obtain 9.53 g of compound E5 (yield 95.3%).

[0087] [Comparative Example 1] The chlorobenzene solution of compound E3 was heated and stirred at 120°C for 1 hour in the presence of aluminum chloride. Specifically, 26.0 g of anhydrous chlorobenzene, 10.0 g of compound E3 (52.6 mmol, concentration 22.5% by mass), and 8.41 g of aluminum chloride (63.1 mmol, concentration 18.9% by mass) were added to the reaction vessel. The resulting mixture was contacted at 120°C for 1 hour while stirring. Analysis by HPLC showed that no compound E3 remained, and the area percentage ratio of compound E1 and compound E2 was compound E1:compound E2 = 25.6:74.6%. Subsequently, the reaction product was cooled to 20°C, and 200 mL of toluene and 100 mL of saturated sodium bicarbonate solution were added. After stirring for 30 minutes and allowing to stand, liquid-liquid extraction was performed, and the toluene layer was recovered. 3 g of magnesium sulfate was added to the toluene layer and stirred for 30 minutes. After filtration, 50 mL of toluene was added to the filtration residue to wash it and obtain the filtered toluene solution. After concentration to dryness using a rotary evaporator, the compound E2 was purified by column chromatography using a silica gel column with Wako Gel (R) 60N (150-425 μm) with hexane and ethyl acetate as eluents. The fraction containing compound E2 was concentrated to dryness using a rotary evaporator to obtain 7.46 g of compound E2 (yield 74.6%). Compounds E1 and E2 were identified in the same manner as in Example 1.

[0088] [Comparative Example 2] Compound E2 was produced by heating a toluene solution containing compound E1 at 90°C for 1 hour in the presence of sulfuric acid. Specifically, 20.0 g of anhydrous toluene, 10.0 g of compound E1 (52.6 mmol, 19.8% by mass), and 20.6 g of sulfuric acid (210.3 mmol, 40.7% by mass) were added to a reaction vessel. The resulting mixture was contacted at 90°C for 1 hour while stirring. After that, the reaction product was cooled to 20°C, and 200 mL of toluene and 200 mL of saturated sodium bicarbonate solution were added. After stirring for 30 minutes and allowing to stand, liquid-liquid treatment was performed and the toluene layer was recovered. 3 g of magnesium sulfate was added to the toluene layer and stirred for 30 minutes. After filtration, 50 mL of toluene was added to the filtration residue to wash it and obtain the filtered toluene solution. After concentrating to dryness using a rotary evaporator, column chromatography purification was performed using a silica gel column with Wako Gel(R) 60N (150~425 μm) using hexane and ethyl acetate as eluents. The fraction containing compound E2 was concentrated to dryness using a rotary evaporator to obtain 2.03 g of compound E2 (yield 20.3%). Compounds E1 and E2 were identified in the same manner as in Example 1.

[0089] [Comparative Example 3] A chlorobenzene solution containing compound E1 was heated at 90°C for 1 hour in the presence of aluminum chloride. Specifically, 20.0 g of anhydrous chlorobenzene, 10.0 g of compound E1 (52.6 mmol, concentration 17.2% by mass), and 28.0 g of aluminum chloride (210.3 mmol, concentration 48.3% by mass) were added to a reaction vessel. The resulting mixture was contacted at 90°C for 1 hour while stirring. Analysis of the reaction solution revealed that compound E2 had not been formed.

[0090] [Comparative Example 4] A chlorobenzene solution containing the above compound E4 was heated at 90°C for 1 hour in the presence of aluminum chloride. Specifically, 20.0 g of anhydrous chlorobenzene, 10.0 g of compound E4 (60.9 mmol, concentration 17.2% by mass), and 28.0 g of aluminum chloride (210.3 mmol, concentration 48.3% by mass) were added to the reaction vessel. The resulting mixture was contacted at 90°C for 1 hour while stirring. Analysis of the reaction solution revealed that compound E5 was not formed.

[0091] Reference Example 1, Example 2 The results for steps 12 and Comparative Examples 1-4 are shown in Table 1. [Table 1]

[0092] <Notes in Table 1> In Table 1, "Compound (1)" refers to the compound represented by formula (1), and "Compound (2)" refers to the compound represented by formula (2). Note that Example 10 and Comparative Example 1 use compound E3, a precursor of the compound represented by formula (1), but for convenience, they are listed in the "Compound (1)" column. Furthermore, when toluene and water were used together as solvents, the "Solvent" column in Table 1 was indicated as "Tol / Water". The symbols in Table 1 are as follows: E1~E5: Compounds E1~E5 represented by the above chemical formulas. Ms: Methanesulfonic acid Ts:p-toluenesulfonic acid monohydrate 22B: Activated clay (FULCAT-22B (product name)) Tol: Toluene CB: Chlorobenzene

[0093] From the above results, the following can be concluded. Comparative Example 1 is a method of performing a Fries rearrangement reaction on compound E3, as described in Non-Patent Document 1. However, both compound E1 and compound E2 are produced, making it impossible to produce the target compound E2 in high yield. Moreover, it requires a water-restricted condition and generates hydrogen chloride, so it is not a simple method and raises safety concerns. In Comparative Example 2, which uses sulfuric acid, an inorganic acid, as an acidic catalyst, the rearrangement reaction of compound E1 does not proceed quickly, making it impossible to produce compound E2 in high yield. Furthermore, in Comparative Examples 3 and 4, the rearrangement reaction that occurs in the present invention does not occur at all, and it is not possible to produce the target compound E2 or compound E5.

[0094] In contrast, methanesulfonic acid or p-toluenesulfonic acid monohydrate was used. Reference Example 1, Example 2 Methods 6 and 9-12, regardless of the reaction mode, do not require aquatic conditions, do not produce gaseous by-products, and are simple methods that allow for the production of compound E2 or compound E5 from compound E1 or compound E4 in high yield. In particular, contacting compound E1 with an acidic catalyst in a solvent promotes the rearrangement reaction that occurs in this invention, resulting in a higher yield of the target compound E2 compared to contact in a solvent-free environment (for example, Reference example (Comparison results between Example 1 and Example 2). In this case, if water is used in combination with the organic solvent (using an aqueous organic solvent), the rearrangement reaction that occurs in the present invention is further promoted and the yield of compound E2 is further improved (for example, comparison results between Example 2 and Example 3 or Example 4). Furthermore, in Examples 7 and 8, which use activated clay, compound E2 can be easily produced from compound E1 in high yield even when a continuous process is applied. Furthermore, Example 10, which involves the production of compound E2 in a multi-step process, demonstrates that compound E2 can be produced from compound E1 in high yield using a simple method, even in the presence of compound E2. This overcomes the problem of the Fries rearrangement reaction (e.g., Comparative Example 1) where compound E2 cannot be produced in high yield. Thus, the manufacturing method of the present invention is simple, highly safe, and industrially robust, making it possible to apply a continuous process (flow synthesis method) and industrialize (mass production) it.

[0095] Although we have described the present invention along with its embodiments, we do not intend to limit our invention in any detail of the description unless specifically designated, and we believe that it should be interpreted broadly without contradicting the spirit and scope of the invention as set forth in the appended claims.

[0096] This application claims priority based on Japanese Patent Application No. 2023-136138, filed in Japan on 24 August 2023, the contents of which are incorporated herein by reference as part of this specification.

Claims

1. A method for producing a compound represented by the following formula (2), comprising contacting at least one acidic catalyst selected from organic Brønsted acids and activated clays activated with Brønsted acids with a compound represented by the following formula (1) in a solvent at a temperature of 70°C or higher. 【Chemistry 1】 In formulas (1) and (2), X represents an oxygen atom, -NH-, or a sulfur atom, Z represents a CH or a nitrogen atom, and R １ R represents an alkyl group having 1 to 6 carbon atoms. ２ ' represents a substituent. n represents an integer between 0 and 3. However, in the aromatic ring in formula (1), at least one of the two carbon atoms adjacent to the carbon atom substituted with X is bonded to Z, and the aromatic ring in each formula may condense with other rings to form a fused ring.

2. The method for producing an organic Brønsted acid according to claim 1, wherein the organic Brønsted acid is an organic sulfonic acid.

3. The manufacturing method according to claim 1, wherein the activated clay is acid clay.

4. The method for producing the compound represented by formula (2) in a yield of 75.0 mol% or more, as described in Claim 1.

5. A method for producing a compound represented by the following formula (2), comprising contacting a fluid 1 containing at least one organic Brønsted acid as an acidic catalyst with a fluid 2 containing a compound represented by the following formula (1) and a solvent in a flow reactor at a temperature of 70°C or higher. 【Chemistry 2】 In formulas (1) and (2), X represents an oxygen atom, -NH-, or a sulfur atom, Z represents a CH or a nitrogen atom, and R １ R represents an alkyl group having 1 to 6 carbon atoms. ２ ' represents a substituent. n represents an integer between 0 and 3. However, in the aromatic ring in formula (1), at least one of the two carbon atoms adjacent to the carbon atom substituted with X is bonded to Z, and the aromatic ring in each formula may condense with other rings to form a fused ring.

6. The manufacturing method according to claim 5, wherein the organic Brønsted acid is an organic sulfonic acid.

7. A method for producing a compound represented by the following formula (2), comprising flowing a fluid 3 containing a compound represented by the following formula (1) and a solvent through a solid support containing at least one activated clay activated with Brønsted acid as an acidic catalyst, thereby bringing the activated clay and the compound represented by the following formula (1) into contact at a temperature of 70°C or higher in a flow reactor. 【Transformation 3】 In formulas (1) and (2), X represents an oxygen atom, -NH-, or a sulfur atom, Z represents a CH or a nitrogen atom, and R １ R represents an alkyl group having 1 to 6 carbon atoms. ２ ' represents a substituent. n represents an integer between 0 and 3. However, in the aromatic ring in formula (1), at least one of the two carbon atoms adjacent to the carbon atom substituted with X is bonded to Z, and the aromatic ring in each formula may condense with other rings to form a fused ring.

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