JP2020083797A - Method for producing aromatic halogen derivative - Google Patents

Abstract

To provide a highly efficient and economically advantageous method for producing a halogen compound.SOLUTION: The method produces a halogen compound represented by formula (2) (X is a halogen atom, and b is an integer of 1-5) by reacting an aniline derivative represented by formula (1) (Ris an ester group, a carbonyl group, a nitrile group, a nitro group, an optionally substituted alkyl group or an optionally substituted aralkyl group, and a is an integer of 0-4) with a halogenating agent in the presence of a copper catalyst and a persulfate.SELECTED DRAWING: None

Description

The present invention relates to a novel method for producing an aromatic halogen derivative (hereinafter sometimes simply referred to as “halogen compound”). Specifically, it relates to a novel method for producing a halogen compound, which is highly efficient and economically advantageous.

An aromatic halogen derivative (for example, a compound in which a halogen atom is substituted on a benzene ring) is a compound useful as a lattice component of various physiologically active compounds including pharmaceuticals or a synthetic raw material thereof (see Non-Patent Documents 1 and 2). ). Among them, when the aromatic ring is an aniline derivative, it can be used as various synthetic raw materials.

Various methods for producing an aromatic halogen derivative by introducing a halogen atom into an aromatic ring (hereinafter sometimes referred to simply as “halogenating”) have been studied.

For example, a method using molecular halogen (Cl ₂ , Br ₂ ) is known (see Non-Patent Document 3). However, this method has room for improvement in terms of toxicity of molecular halogen, difficulty in controlling reaction, and difficulty in treating by-product hydrogen halide. In addition, this method halogenates an aromatic raw material having an amino group, a group bonded to an aromatic ring by an ester bond, a group bonded to an aromatic ring by a carbonyl bond, a group bonded to an aromatic ring by an amide bond, or the like. There was room for improvement in that it was difficult.

As a method other than this, a method using N-halosuccinimide (specifically, N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), N-iodosuccinimide (NIS)) has been proposed ( See Non-Patent Document 4, Patent Document 1, and Non-Patent Document 5). According to this method, operability is remarkably improved as compared with the method using a molecular halogen.

However, in these methods using N-halosuccinimide, there is room for improvement because the N-halosuccinimide itself is an expensive reagent. In other words, industrial production that requires mass production required further improvement.

On the other hand, various studies have been conducted on halogenation using an alkali metal halide salt as a low-toxic, easy-to-handle, and inexpensive material. Specifically, it is a method of reacting an aromatic raw material with an alkali metal halide salt (raw material) in the presence of hydrogen peroxide and a molybdenum catalyst (see Non-Patent Document 6). Further, a method (see Non-Patent Document 7) of reacting raw materials with each other in the presence of Oxone ((registered trademark); double salt of potassium hydrogen sulfate and potassium sulfate) is also known. Furthermore, a method is known in which the raw materials are reacted with each other in the presence of Oxone (registered trademark) and sulfuric acid.

However, in these methods, although the alkali metal halide salt which is one of the raw materials is inexpensive, there is room for improvement in that the molybdenum catalyst, Oxone (registered trademark) and the like, which are the catalyst, are expensive. Furthermore, since Oxone (registered trademark) is a high molecular weight substance, there is room for improvement in that it is difficult to handle. Furthermore, in these methods, halogenation with higher selectivity was demanded (it was desired to increase the probability of introducing halogen into a specific position of the aromatic ring).

JP, 2008-076289, A JP, 2008-070601, A

Journal of Chemical Education 2004, 81, 1441-1449. Chemical Reviews 2014, 116, 12564-12649. Organic Synthesis, Coll. Vol. 4, 1963, p. 256-258. Journal of The American Chemical Society 1958, 80, 4327-4330. Organic Letters 2017, 19, 4243-4246. Tetrahedron Letters 2000, 41 2083-2085. Synthetic Communications, 2001, 31, 2021-2027.

Therefore, an object of the present invention is to provide a method capable of efficiently producing a desired halogen compound with a high yield even by using relatively inexpensive reagents/materials and under relatively mild conditions. It is in. Specifically, it is to provide a production method that exhibits excellent effects when the aromatic raw material is an aniline derivative.

The present inventors have earnestly studied to solve the above problems. Then, various reaction systems were tried using an alkali metal halide salt or an ammonium halide salt which is an inexpensive raw material. Then, they found that the above problems can be solved by advancing the reaction in the presence of a copper catalyst and a persulfate, which are relatively inexpensive materials, and completed the present invention.

That is, the present invention is
(1) In the presence of a copper catalyst and persulfate,
Formula (1) below

(In the formula,
R ¹ is a group that bonds to a benzene ring through an ester bond, a group that bonds to a benzene ring through an amide bond, a group that bonds to a benzene ring through a carbonyl bond, a nitrile group, a nitro group, or an alkyl that may have a substituent. A group, or an aralkyl group which may have a substituent,
a is an integer of 0 to 4, and when a is 2 or more, R ¹ may be the same group or different groups. ) An aniline derivative represented by () (hereinafter, the aniline derivative as the raw material may be simply referred to as a “substrate”),
By reacting with at least one halogenating agent selected from an alkali metal halide salt and an ammonium halide salt (hereinafter, sometimes simply referred to as “halogenating agent”),
Formula (2) below

(In the formula,
R ¹ and a have the same meaning as in the above formula (1),
X is a halogen atom,
b is an integer of 1 to 5,
However, a+b is an integer of 1-5. ) Is a method for producing a halogen compound.

In addition, as a matter of course, in the halogen compound represented by the formula (2), the halogen atom of X is determined by the halogen atom of the halogenating agent used as a raw material.

The present invention can have the following aspects.

(2) The method according to (1) above, wherein the persulfate is at least one oxidizing agent selected from alkali metal persulfate and ammonium persulfate.

(3) The copper catalyst is a compound selected from copper halide, copper acetate, copper sulfate, copper oxide, copper trifluoromethanesulfonate, and copper benzoate, a hydrate of the compound, or a solvate of the compound. The method according to (1) or (2) above.

(4) The aniline derivative represented by the formula (1) is
The following formula (1A)

(In the formula,
R ¹ has the same meaning as in formula (1). ) Is a compound represented by
The halogen compound represented by the formula (2) is
The following formula (2A)

(In the formula,
R ¹ has the same meaning as in the above formula (1A),
X has the same meaning as in formula (2). The method in any one of said (1)-(3) which is a compound shown by these.

In addition, as a matter of course, in the halogen compound represented by the formula (2A), the halogen atom of X is determined by the halogen atom of the halogenating agent used as a raw material.

(5) The aniline derivative represented by the formula (1) is
The following formula (1B)

(In the formula,
R ¹ has the same meaning as in formula (1). ) Is a compound represented by
The halogen compound represented by the formula (2) is
The following formula (2B)

(In the formula,
R ¹ has the same meaning as in the above formula (1B),
X has the same meaning as in formula (2) above,
Y is a hydrogen atom or a halogen atom. The method in any one of said (1)-(3) which is a compound shown by these.

In addition, as a matter of course, in the halogen compound represented by the formula (2B), the halogen atoms of X and Y are determined by the halogen atom of the halogenating agent used as a raw material. is there. As will be described in detail below, Y may be a hydrogen atom in the present invention by adjusting the amount of the halogenating agent used and the reaction time.

According to the method of the present invention, a desired halogen compound can be efficiently produced with a high yield using relatively inexpensive reagents/materials and under relatively mild conditions. This method is suitable for industrialization because halogenation is possible using relatively inexpensive reagents and raw materials. Among them, in the aniline derivative (substrate) which is a raw material compound, when a substrate having a substituent at a specific position is used, a halogen atom can be introduced at a specific position. Therefore, the halogen compound obtained by this method has high purity and is inexpensive. As a result, it is useful as a raw material for various reactions.

The present invention comprises an aniline derivative having a specific structure and a specific halogenating agent,
It is a method for producing a desired halogen compound with high efficiency by reacting in the presence of a copper catalyst and a persulfate. Hereinafter, description will be made step by step.

(Copper catalyst)
In the present invention, the following copper compounds can be used. Specific examples include a compound selected from copper halide, copper acetate, copper sulfate, copper oxide, copper trifluoromethanesulfonate, and copper benzoate, a hydrate of the compound, or a solvate of the compound.

Specific examples of the copper halide include copper (I) chloride (CuCl), copper (II) chloride (CuCl ₂ ), copper (I) bromide (CuBr), and copper (II) bromide (CuBr ₂ ). ), copper(I) iodide (CuI), copper(II) iodide (CuI ₂ ) and the like.

Examples of the copper acetate include copper (I) acetate (CuOAc) and copper (II) acetate (Cu(OAc) ₂ ).

The copper sulfate is CuSO ₄ .

Examples of the copper oxide include copper (I) oxide (Cu ₂ O) and copper (II) oxide (CuO).

Examples of the copper trifluoromethanesulfonate include copper (I) trifluoromethanesulfonate (CuOTf) and copper (II) trifluoromethanesulfonate (Cu(OTf) ₂ ).

Examples of the copper benzoate include copper (I) benzoate (CuOBz) and copper (II) benzoate (Cu(OBz) ₂ ).

As described above, the copper catalyst may contain any one of monovalent copper and divalent copper. These copper catalysts can be used alone or as a mixture of plural kinds. When used in multiple types, the reference amount is the total amount of those copper catalysts.

Further, in the present invention, a hydrate of the copper compound or a solvate of the copper compound may be used.

In the present invention, as a copper catalyst exhibiting a particularly excellent effect, a hydrate of copper (II) acetate (Cu(OAc) ₂ .H ₂ O) or a hydrate of copper (II) sulfate (sulfuric acid) is used. Copper pentahydrate) (CuSO ₄ .5H ₂ O).

In the present invention, the amount of copper catalyst used is not particularly limited. Above all, in order to reduce the residue on the obtained halogen compound and to exhibit high productivity, it is preferable to set the amount to 0.001 to 1.00 mol with respect to 1 mol of the aniline derivative (substrate) as a raw material. , 0.05 to 0.5 mol is more preferable.

(Persulfate)
In the present invention, the persulfate is considered to have an action of oxidizing the halogenating agent described in detail below to facilitate the reaction (it is considered to act as an oxidizing agent).

The persulfate is preferably at least one oxidizing agent selected from alkali metal persulfate and ammonium persulfate.

Specific examples of the alkali metal persulfate include sodium persulfate (Na ₂ S ₂ O ₈ ) and potassium persulfate (K ₂ S ₂ O ₈ ). Examples of the ammonium persulfate salt include ammonium persulfate ((NH ₄ ) ₂ S ₂ O ₈ ).

These persulfates can be used alone or in combination of two or more. When used in multiple types, the reference amount is the total amount of those persulfates.

In the present invention, the amount of persulfate used is not particularly limited. Among them, in order to reduce the residue on the obtained halogen compound and to exhibit high productivity, it is preferably 1 to 4 mol per 1 mol of the aniline derivative (substrate) as a raw material, and 1 to 3 mol is preferable. More preferably, it is a mole.

(Substrate; aniline derivative as raw material)
In the present invention, the aniline derivative serving as a substrate (raw material) is a compound represented by the following formula (1).

R ¹ is a group that bonds to a benzene ring through an ester bond, a group that bonds to a benzene ring through an amide bond, a group that bonds to a benzene ring through a carbonyl bond, a nitrile group, a nitro group, or an alkyl that may have a substituent. A group, or an aralkyl group which may have a substituent,
a is an integer of 0 to 4, and when a is 2 or more, R ¹ may be the same group or different groups. ) Is an aniline derivative.

According to the present invention, even an aniline derivative having an electron-withdrawing group such as a group that bonds to a benzene ring through an amide bond, a group that bonds to a benzene ring through a carbonyl bond, a nitrile group, or a nitro group can be efficiently prepared. A halogen compound can be produced.

In addition, a commercially available known compound can be used as these “substrates”. Therefore, the substrate can be synthesized by a known method.

(Explanation of R ¹ )
In the formula (1), a group that bonds to a benzene ring through an ester bond, a group that bonds to a benzene ring through an amide bond, a group that bonds to a benzene ring through a carbonyl bond, a nitrile group, a nitro group, or a substituent And an aralkyl group which may have a substituent.

The group bonded to the benzene ring by an ester bond is not particularly limited as long as it has an ester bond in the molecule of the group and is bonded to the benzene ring by the ester bond. Specifically, an alkyl ester group having an alkyl group having 1 to 10 carbon atoms, an alkoxy ester group having an alkoxy group having 1 to 10 carbon atoms (the "alkoxy" group portion has a carbon number of 1 to 10). It is not particularly limited as long as it is an “aralkyl” group having a carbon number of 7 to 10. Specifically, it is a “benzyloxy” group substituted with an alkyl group having a carbon number of 1 to 3. ), an aralkyl ester group having an aralkyl group having 7 to 20 carbon atoms, an aryl ester group having an aryl group having 6 to 20 carbon atoms, or a carboxyl group. The aryl group and the aralkyl group may have a substituent, and the substituent is preferably an alkyl group having 1 to 10 carbon atoms.

Among the above groups, the group that bonds to the benzene ring through an ester bond is particularly preferably a carboxyl group, a methoxycarbonyloxy group, or a benzyloxycarbonyloxy group.

The group bonded to the benzene ring by an amide bond is not particularly limited as long as it has an amide bond in the molecule of the group and is bonded to the benzene ring by the amide bond. Specifically, an alkylamido group having an alkyl group having 1 to 12 carbon atoms, an alkoxyamido group having an alkoxy group having 1 to 10 carbon atoms (the "alkoxy" group portion has a carbon number range of 1 to 10). It is not particularly limited as long as it is an “aralkyl” group having a carbon number of 7 to 10. Specifically, it is a “benzyloxy” group substituted with an alkyl group having a carbon number of 1 to 3. ), an aralkylamide group having an aralkyl group having 7 to 20 carbon atoms, an arylamide group having an aryl group having 6 to 20 carbon atoms, or a carboxylic acid amide group. The aryl group and the aralkyl group may have a substituent, and the substituent is preferably an alkyl group having 1 to 10 carbon atoms.

Among the above, the group that bonds to the benzene ring through an amide bond is particularly preferably a methoxycarbonylamino group, an ethoxycarbonylamino group, a benzyloxycarbonylamino group, or a tert-butoxycarbonylamino group.

The group bonded to the benzene ring by a carbonyl bond is not particularly limited as long as it has a carbonyl bond in the gas molecule and is bonded to the benzene ring by the carbonyl bond. An alkylcarbonyl group having an alkyl group having 1 to 12 carbon atoms, an alkoxycarbonyl group having an alkoxy group having 1 to 10 carbon atoms (the portion of the "alkoxy" group is particularly preferably in the range of 1 to 10 carbon atoms, It is not limited, and may be an "aralkyl" group having 7 to 10 carbon atoms, specifically, a "benzyloxy" group substituted with an alkyl group having 1 to 3 carbon atoms.) , An aralkylcarbonyl group having an aralkyl group having 7 to 20 carbon atoms, an arylcarbonyl group having an aryl group having 6 to 20 carbon atoms, or an aldehyde group. The aryl group and the aralkyl group may have a substituent, and the substituent is preferably an alkyl group having 1 to 10 carbon atoms or an alkoxy group having 1 to 10 carbon atoms. ..

Among the above, the group that bonds to the benzene ring through the carbonyl bond is particularly preferably a methoxycarbonyl group, an ethoxycarbonyl group, or a benzyloxycarbonyl group.

The alkyl group which may have a substituent preferably has 1 to 10 carbon atoms in the alkyl group portion.

The aralkyl group which may have a substituent preferably has 7 to 20 carbon atoms in the aralkyl group.

The substituents contained in the alkyl group which may have a substituent or the aralkyl group which may have a substituent are preferably the following substituents. Examples of the substituent include the group that bonds to the benzene ring through the ester bond, the group that bonds to the benzene ring through the amide bond, or the group that bonds to the benzene ring through the carbonyl bond, and they are the same groups as those exemplified above. Is preferred. In addition, examples of the substituent include a nitrile group, a nitro group, and a halogen atom.

a represents the number of R ¹ and is an integer of 0 to 4. When a is 0, the substrate is aniline. Further, when a is 2 or more, R ¹ may be the same group or different groups. Above all, a is preferably 1 to 3 in consideration of the usefulness of the obtained halogen compound. Considering the selectivity of the reaction, a is preferably 1.

(Preferable aniline derivative)
In the present invention, the more useful halogen compound, which is a compound (substrate) which is selectively halogenated, includes the following compounds.

<Suitable raw material compound (1A)>
In the present invention, the following formula (1A)

(In the formula,
R ¹ has the same meaning as in formula (1). ) (Hereinafter, sometimes referred to simply as "raw material compound represented by formula (1A)"). When the aniline derivative represented by the formula (1A) is used as a substrate, the halogen compound represented by the formula (2A) described in detail below can be selectively produced.

<Suitable raw material compound (1B)>
In the present invention, the following formula (1B)

(In the formula,
R ¹ has the same meaning as in formula (1). Hereinafter, the compound represented by the formula (1) may be simply referred to as the "raw material compound represented by the formula (1B)". ) Is preferable. When the aniline derivative represented by the formula (1B) is used as a substrate, the halogen compound represented by the formula (2B) described in detail below can be selectively produced.

When the raw material compound represented by the formula (1B) is used, the halogenating agent described in detail below is less than 2 moles relative to 1 mole of the raw material compound, depending on the kind of the raw material compound. However, it is also possible to selectively obtain a disubstituted halogen compound having a halogen atom introduced at the para-position or the ortho-position. Specifically, even if the amount of the halogenating agent is 1.5 mol or more and less than 2.0 mol, based on 1 mol of the raw material compound, a disubstituted halogen compound can be produced.

(Halogenating agent)
In the present invention, the halogenating agent reacted with the substrate is at least one compound selected from alkali metal halide salts and ammonium halide salts.

Examples of the alkyl halide metal salt include alkyl fluoride metal salts such as lithium fluoride (LiF), sodium fluoride (NaF), potassium fluoride (KF), and cesium fluoride (CsF).

Examples thereof include alkyl chloride metal salts such as lithium chloride (LiCl), sodium chloride (NaCl), potassium chloride (KCl), and cesium chloride (CsCl).

Examples thereof include alkyl bromide metal salts such as lithium bromide (LiBr), sodium bromide (NaBr), potassium bromide (KBr), and cesium bromide (CsBr).

Examples thereof include alkyl iodide metal salts such as lithium iodide (LiI), sodium iodide (NaI), potassium iodide (KI), and cesium iodide (CsI).

Examples of the ammonium halide salt include ammonium fluoride (NH ₄ F), ammonium bifluoride (NH ₄ F·HF), tetra-n-butylammonium fluoride (TBAF), tetramethylammonium fluoride (TMAF) and the like. Ammonium fluoride salts may be mentioned.

Examples thereof include ammonium chloride salts such as ammonium chloride (NH ₄ Cl), tetra-n-butylammonium chloride (TBAC), and tetramethylammonium chloride (TMAC).

Ammonium bromide salts such as ammonium bromide (NH ₄ Cl), tetra-n-butylammonium bromide (TBAB), tetramethylammonium bromide (TMAB) and the like can be mentioned.

Examples thereof include ammonium iodide salts such as ammonium iodide (NH ₄ I), tetra-n-butylammonium iodide (TBAI), and tetramethylammonium iodide (TMAI).

The type of these halogenating agents may be appropriately determined according to the intended use of the obtained halogen compound. Therefore, these halogenating agents can be used alone or as a mixture of plural kinds. When used in plural types, the reference amount is the total amount of those halogenating agents.

Among these halogenating agents, it is preferable to use sodium bromide or sodium iodide as a raw material which is inexpensive, easy to handle, and has high halide purity and yield.

The amount of the halogenating agent used may be appropriately determined according to the structure of the desired halogen compound. Considering the ease of removal of unreacted halogenating agent, high production efficiency, etc., it is preferably 1 to 10 moles per 1 mole of the aniline derivative (substrate) as a raw material, More preferably, it is a mole.

Among them, a halogen compound having one halogen atom introduced, such as a halogen compound represented by the formula (2A) described below or a halogen compound represented by the formula (2B), wherein Y is a hydrogen atom, In the case of production, the amount of the halogenating agent used is preferably the following amount. Specifically, the halogenating agent is preferably used in an amount of 1 to 5 mol, and more preferably 1 to 3 mol, based on 1 mol of the aniline derivative (substrate) as a raw material.

Further, in the halogen compound represented by (2B) described in detail below, when the compound in which Y is a halogen atom (compound in which two halogen atoms are introduced) is produced, use of the above halogenating agent The amount is preferably the following amount. Specifically, the halogenating agent is preferably used in an amount of 1.5 to 10 mol, and more preferably 1.5 to 6 mol, based on 1 mol of the aniline derivative (substrate) as a raw material. According to the present invention, if the type of the substrate, the type of the persulfate, the type of the copper catalyst, and the type of the halogenating agent are optimized, the amount of the halogenating agent is 1. Even if the amount is 5 mol or more and less than 2 mol, a compound in which two halogen atoms are selectively introduced can be produced.

<Other reaction conditions>
(solvent)
In the present invention, it is preferably carried out in a solvent. That is, it is preferable to stir and mix the copper catalyst, the persulfate, the substrate, and the halogenating agent in a solvent. The following solvents may be mentioned.

Ester solvents such as ethyl acetate, methyl acetate, butyl acetate and isopropyl acetate.

Nitrile solvents such as acetonitrile and propionitrile.

An ether solvent such as tetrahydrofuran (THF), 2-methyl THF, 1,4-dioxane, tert-butyl methyl ether, dimethoxyethane, diglyme.

Ketone-based solvents such as acetone, diethyl ketone, and methyl ethyl ketone.

Halogen-based solvents such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane and chlorobenzene.

Aromatic solvents such as toluene and xylene.

Hydrocarbon solvents such as hexane and heptane.

Dimethyl sulfoxide (DMSO).

water.

The solvent as described above can be used. These solvents may be used alone or in combination of two or more. When used in multiple types, the reference amount is the total amount of those solvents.

Among them, it is preferable to use water alone or the following mixed solvent. In the future, as the oil ratio, a mixed solvent of water and at least one organic solvent selected from acetonitrile, ethyl acetate, toluene, methylene chloride, and DMSO is preferable. Among these mixed solvents, it is preferable to use a mixed solvent of acetonitrile and water or a mixed solvent of DMSO and water.

When a mixed solvent is used, it is preferable to use 100 to 10,000 ml of the organic solvent with respect to 100 ml of water.

In the present invention, when a solvent is used, it is preferable that the components be used in amounts such that they can be sufficiently stirred and mixed. Therefore, the amount of solvent used is not particularly limited. Above all, in order to efficiently react each component, it is preferable to use 1 to 100 ml of the solvent for 1 g of the substrate. When a mixed solvent is used, the amount of the mixed solvent used is preferably 1 to 100 ml with respect to 1 part by mass of the substrate.

(Reaction conditions)
In the present invention, the substrate and the halogenating agent are reacted in the presence of the copper catalyst and the persulfate, preferably in the solvent. The reaction can be carried out by mixing the components.

The method of mixing the respective components is not particularly limited, and it can be carried out in a reaction vessel equipped with a stirrer. The procedure for adding each component into the reaction vessel is not particularly limited. Among them, the substrate, and the solvent used as necessary are premixed in a reaction vessel, and the copper catalyst, the persulfate, the halogenating agent, the solvent used as necessary You may mix|blend. The copper catalyst, the persulfate, the halogenating agent, and the solvent used if necessary may be mixed in advance. It is also possible to previously mix the copper catalyst, the substrate, and a solvent to be used as necessary in a reaction vessel, and add the halogenating agent and the persulfuric acid to the mixed solution. The halogenating agent and the persulfate can be mixed in the mixed solution separately, or can be mixed in advance. The halogenating agent and the persulfate can be blended using a solvent, or can be blended without using a solvent.

The temperature at the time of mixing the components, that is, the reaction temperature (the temperature in the reaction system) is not particularly limited. Specifically, it can be carried out in the range of -30 to 100°C. Among them, according to the present invention, the reaction can proceed even under relatively mild conditions. Therefore, according to the present invention, impurities such as by-products can be suppressed. In that case, specifically, the reaction temperature is preferably in the range of 0 to 50°C.

The reaction time is not particularly limited, and can be appropriately determined while checking the reaction ratio of the substrate. According to the present invention, since the reaction proceeds in a relatively short time, it is usually 1 minute or more and 48 hours or less, and more preferably 1 hour or more and 24 hours or less. In addition, this reaction time refers to a time during which all of the benzene derivative and the halogenating agent are mixed.

The pressure during the reaction is also not particularly limited. Specifically, the reaction may be carried out under any of atmospheric pressure, reduced pressure, and increased pressure. Considering operability, it is preferable to carry out under atmospheric pressure. Also, the atmosphere during the reaction is not particularly limited. Specifically, it can be carried out in an air atmosphere or an inert gas atmosphere. Considering the operability, it is preferable to carry out under an air atmosphere.

The step after the reaction is not particularly limited. For example, it is preferable to remove the product (halogen compound) from the reaction solution according to the following procedure. Specifically, first, a reducing agent (for example, sodium thiosulfate) is added to the obtained reaction liquid in order to decompose persulfuric acid (salt) which is an oxidizing agent. Then, if necessary, it is neutralized with an alkali (for example, sodium hydroxide). Then, if necessary, an acid (for example, hydrochloric acid) is added to facilitate transfer of the raw material aniline derivative as an acid salt (for example, hydrochloride) to the aqueous layer. Then, it is preferable to extract the product (halide) by an extraction method such that the product (halogen compound) is present in the organic layer.

Further, the obtained product (halogen compound) can be further purified by known means such as recrystallization, column purification, solvent washing, reprecipitation, and water washing, depending on its properties.

(Halogen compound)
By carrying out the reaction under the above conditions,
A halogen compound represented by the following formula (2) can be obtained.

In the formula,
R ¹ and a have the same meaning as in the above formula (1),
X is a halogen atom,
b is an integer of 1 to 5,
However, a+b is an integer of 1-5.

In addition, as a matter of course, in the halogen compound represented by the formula (2), the halogen atom of X is determined by the halogen atom of the halogenating agent used as a raw material.

Among them, b is preferably 1 to 4, and particularly preferably b is 1 to 2 in order to be a useful halogen compound. Further, a+b is preferably 2 to 5, and particularly preferably 2 to 3.

<Suitable halogen compound (2A)>
When the raw material compound represented by the formula (1A) is used, a compound represented by the following formula (2A) can be obtained.

In the formula,
R ¹ has the same meaning as in the above formula (1A),
X has the same meaning as in formula (2). According to the present invention, a halogen compound represented by the above formula (2A) with high purity can be produced by using the raw material compound represented by the above formula (1A).

<Suitable halogen compound (2B)>
When the raw material compound represented by the above formula (1B) is used, a compound represented by the following formula (2B) can be obtained.

In the formula,
R ¹ has the same meaning as in the above formula (1B),
X has the same meaning as in formula (2) above,
Y is a hydrogen atom or a halogen atom.

In the present invention, when the raw material compound represented by the formula (1B) is used, first, a halogen atom is introduced at the para position. That is, first, in the formula (2B), a halogen compound in which Y is a hydrogen atom can be produced. Here, if the reaction is stopped, a halogen compound represented by the formula (2B) in which only the para-position is halogenated (a halogen compound in which Y is a hydrogen atom. Hereinafter, also referred to simply as a “p-position halogen compound”) There is). Depending on the purpose, the reaction can be stopped at this point to obtain the halogen compound at the p-position in high purity.

In the present invention, when the halogenation reaction proceeds next, a halogen compound represented by the formula (2B) in which Y is a halogen atom can be obtained. That is, when the halogenation reaction is further proceeded after the production of the halogen compound at the p-position, the halogen compound introduced by the formula (2B) (a halogen compound in which Y is a halogen atom. , May be simply referred to as a "disubstituted halogen compound"). In this case, a disubstituted halogen compound in which X and Y are the same halogen atom can be obtained by using a halogenating agent having the same halogen atom as in the production of the p-position halogen compound. It is also possible to obtain a disubstituted halogen compound in which X and Y are different halogen atoms by using a halogenating agent having a halogen atom different from that at the time of producing the p-position halogen compound.

Although Y can be a halogen atom under the above conditions, the disubstituted halogen compound can be directly obtained by appropriately selecting the type of substrate, reaction conditions and the like. Specifically, when the raw material compound represented by the formula (1B) in which R ¹ is a cyano group is used, the disubstituted halogen compound can be selectively produced. In this case, the disubstituted halogen compound is produced by using less than 2 mol of the halogenating agent (preferably 1.5 mol or more and less than 2 mol of the halogenating agent) with respect to 1 mol of the raw material compound. it can. In this case, the disubstituted halogen compound can be produced without using an excessive amount of the halogenating agent, which is advantageous in terms of cost and facilitates post-treatment.

As described above, in the present invention, the introduction position of the halogen atom can be controlled by limiting the substrate. Since the obtained halogen compound can be used in various fields, the industrial utility value of the present invention is very high.

Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.

Example 1
The halogenation reaction represented by the following formula was carried out.

An aqueous solution of copper sulfate pentahydrate (1.24 g, 4.97 mmol: copper catalyst) (using 30 ml of water), acetonitrile (60 mL), and methyl 2-aminobenzoate (3.00 g, 19.84 mmol; substrate). Was introduced into the reaction vessel, and these components were mixed with stirring at 40° C. for 10 minutes. A mixture of sodium bromide (3.67 g, 35.67 mmol; halogenating agent) and sodium persulfate (6.62 g, 27.80 mmol; persulfate) was added to the reaction solution at a temperature of 40°C. Was added over a period of 2 hours. Then, this reaction liquid was stirred and mixed at room temperature (23° C.) for 17 hours.

The reaction solution was cooled to 15° C., sodium thiosulfate (1 g) was added, and the mixture was stirred for 10 minutes. Next, the pH was adjusted to 0.91 with concentrated hydrochloric acid. Then, the obtained reaction liquid was transferred to a separating funnel, the aqueous layer was separated, and the organic layer was concentrated under reduced pressure (45° C.) to obtain 5.2 g of a crude product. By purifying 1 g of the crude product by silica gel column chromatography (developing solvent: hexane/ethyl acetate=15:1), methyl 2-amino-5-bromobenzoate was obtained (yield 0.73 g: halogenated compound). The yield considered based on the substrate was 83%.

The melting point, infrared analysis (IR), and ¹ H-NMR measurement results of the obtained methyl 2-amino-5-bromobenzoate are shown.
Melting point: 77-80°C.
IR (KBr): 3364, 1676, 1605 cm< ^-1 >.
¹ H-NMR (CDCl ₃ ) δ 7.97 ppm (s, 1H), 7.30-7.34 ppm (m, 1H), 6.55-6.57 ppm (m, 1H), 5.75 ppm (brs, 1H), 3.87 ppm (s, 3H).

Comparative Example 1
In Example 1, the same reaction as Example 1 was performed except that copper sulfate pentahydrate was not added. However, methyl 2-amino-5-bromobenzoate was not produced.

Example 2
The halogenation reaction represented by the following formula was carried out.

An aqueous solution of copper sulfate pentahydrate (0.21 g, 0.86 mmol: copper catalyst) (using 5 mL of water), acetonitrile (10 mL), and methyl 2-aminobenzoate (0.50 g, 3.31 mmol: substrate). Was introduced into a reaction vessel, and these components were mixed with stirring at 40° C. for 10 minutes.

A mixture of sodium iodide (0.89 g, 5.94 mmol: halogenating agent) and sodium persulfate (1.10 g, 4.62 mmol; persulfate) was added to the reaction solution at a temperature of 40° C. Was added over a period of 2 hours. Then, this reaction liquid was stirred and mixed at room temperature (23° C.) for 17 hours.

The reaction solution was cooled to 15° C., sodium thiosulfate (0.15 g) was added, and the mixture was stirred for 10 minutes. Next, the pH was adjusted to 0.91 with concentrated hydrochloric acid. Then, the reaction solution was transferred to a separating funnel, the aqueous layer was separated, and the organic layer was concentrated under reduced pressure (45° C.) to obtain a crude product. The resulting crude product was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=20:1) to give methyl 2-amino-5-iodobenzoate (0.78 g, based on the substrate). Yield: 85%: halogen compound).

The obtained 2-amino-5-iodo-benzoic acid methyl show a melting point, infrared analysis ^(IR), the results of measurement of 1 H-NMR.
Melting point 77-80[deg.]C.
IR (KBr) 3364, 1676, 1605 cm-1.
¹ H-NMR (CDCl ₃ ) δ 8.13 ppm (s, 1H), 7.45-7.48 ppm (m, 1H), 6.44-6.46 ppm (m, 1H), 5.77 ppm (brs, 1H), 3.86 ppm (s, 3H).

Example 3
The halogenation reaction represented by the following formula was carried out.

An aqueous solution of copper sulfate pentahydrate (450 mg, 1.81 mmol: copper catalyst) (using 10 mL of water), acetonitrile (20 mL), and 2-nitroaniline (1.00 g, 7.24 mmol: substrate) in a reaction vessel. And the components were stirred and mixed at room temperature (23° C.) for 15 minutes.

The temperature of this reaction solution was cooled to 7°C, and sodium persulfate (2.41 g, 10.14 mmol: persulfate) and sodium bromide (1.34 g) were added so that the temperature of the reaction solution was maintained at 7°C. , 13.03 mmol: halogenating agent) was added over 15 minutes. After that, stirring and mixing were performed for 4 hours while maintaining the temperature of the reaction solution at 7°C. Then, this reaction liquid was stirred and mixed at room temperature for 17 hours.

Sodium thiosulfate (0.4 g) was added to the reaction solution at room temperature (23° C.). A 24 mass% aqueous sodium hydroxide solution was added to the obtained reaction solution to adjust the pH of the reaction solution to 9 to 11. A mixed liquid of ethyl acetate (100 mL) and water (100 mL) was added to the obtained adjusted liquid, and the mixture was transferred to a separating funnel. Then, the aqueous layer was removed, and the organic layer was concentrated under reduced pressure to obtain a crude product. The resulting crude product was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=15:1) to give 2-nitro-4-bromoaniline (1.14 g, yield based on the substrate). Rate 72.6%: halogen compound)).

The melting point and ¹ H-NMR measurement results of the obtained 2-nitro-4-bromoaniline are shown.
Melting point 107-108[deg.]C.
¹ H-NMR (CDCl ₃ ) δ 8.28 ppm (s, 1H), 7.42-7.46 ppm (m, 1H), 6.71-6.73 ppm (m, 1H), 6.08 ppm (brs, 1H).

Example 4
The halogenation reaction represented by the following formula was carried out.

In Example 3, except that 2-cyanoaniline (0.855 g, 7.24 mmol: substrate) was used as a substrate, the same operation as in Example 3 was carried out to obtain 2-cyano-4-bromoaniline (1.18 g). , Yield based on substrate, 82.7%; halogen compound) was obtained.

The results of melting point, IR, and ¹ H-NMR of the obtained 2-cyano-4-bromoaniline are shown.
Melting point 92-93[deg.]C.
IR (KBr) 3351, 2217, 1630 cm-1.
¹ H-NMR (CDCl ³ ) δ 7.48 ppm (s, 1H), 7.39-7.42 ppm (m, 1H), 6.63-6.65 ppm (m, 1H), 4.44 ppm (brs, 1H).

Example 5
The halogenation reaction represented by the following formula was carried out.

The same operation as in Example 3 was performed except that 2-methylaniline (0.775 g, 7.24 mmol: substrate) was used as the substrate in Example 3, and 2,4-dibromo-6-methylaniline (0 .959 g, yield 50% based on substrate; halogenated compound) was obtained. In this case, the amount of the halogenating agent was 1.8 mol per mol of the substrate, but the disubstituted halogen compound (2,4-dibromo-6-methylaniline) could be selectively obtained.

The results of ¹ H-NMR measurement of the obtained 2,4-dibromo-6-methylaniline are shown.
¹ H-NMR(CDCl ₃ ) δ 7.42-7.43 ppm (m, 1H), 7.11-7.12 ppm (m, 1H), 4.05 ppm (brs, 1H).

Example 6
The halogenation reaction represented by the following formula was carried out.

In Example 3, the same operation as in Example 3 was performed except that methyl 4-aminobenzoate (1.09 g, 7.24 mmol: substrate) was used as the substrate, and methyl 4-amino-3-bromobenzoate was used. (1.50 g, 90% yield based on the substrate: halogenated compound) was obtained.

With respect to the obtained methyl 4-amino-3-bromobenzoate, IR and ¹ H-NMR measurement results are shown.
IR(KBr)3356, 1684 cm< ^-1 >.
¹ H-NMR (CDCl ₃ ) δ 8.12 ppm (s, 1H), 7.78-7.80 ppm (m, 1H), 6.71-6.74 ppm (m, 1H), 4.52 ppm (brs, 1H), 3.86 ppm (s, 3H).

Claims (5)

In the presence of a copper catalyst and persulfate,
Formula (1) below

(In the formula,
R ¹ is a group that bonds to a benzene ring through an ester bond, a group that bonds to a benzene ring through an amide bond, a group that bonds to a benzene ring through a carbonyl bond, a nitrile group, a nitro group, or an alkyl that may have a substituent. A group, or an aralkyl group which may have a substituent,
a is an integer of 0 to 4, and when a is 2 or more, R ¹ may be the same group or different groups. ) An aniline derivative represented by
By reacting with at least one halogenating agent selected from an alkali metal halide salt and an ammonium halide salt,
Formula (2) below

(In the formula,
R ¹ and a have the same meaning as in the above formula (1),
X is a halogen atom,
b is an integer of 1 to 5,
However, a+b is an integer of 1-5. ) A method for producing a halogen compound represented by the formula (1). The method according to claim 1, wherein the persulfate is at least one oxidizing agent selected from alkali metal persulfate and ammonium persulfate. The copper catalyst is a compound selected from copper halide, copper acetate, copper sulfate, copper oxide, copper trifluoromethanesulfonate, and copper benzoate, a hydrate of the compound, or a solvate of the compound. The method according to 1 or 2. The aniline derivative represented by the formula (1) is
The following formula (1A)

(In the formula,
R ¹ has the same meaning as in formula (1). ) Is a compound represented by
The halogen compound represented by the formula (2) is
The following formula (2A)

(In the formula,
R ¹ has the same meaning as in the above formula (1A),
X has the same meaning as in formula (2). ) The method according to any one of claims 1 to 3, which is a compound represented by the formula (4). The aniline derivative represented by the formula (1) is
The following formula (1B)

(In the formula,
R ¹ has the same meaning as in formula (1). ) Is a compound represented by
The halogen compound represented by the formula (2) is
The following formula (2B)

(In the formula,
R ¹ has the same meaning as in the above formula (1B),
X has the same meaning as in formula (2) above,
Y is a hydrogen atom or a halogen atom. ) The method according to any one of claims 1 to 3, which is a compound represented by the formula (4).