JP2018076289A - Method for producing halogenated benzene derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a halogenated benzene derivative, which is highly efficient and economically advantageous.SOLUTION: The method produces a halogenated benzene derivative represented by formula (2) by reacting a benzene derivative represented by formula (1) with a halogenating agent selected from N-halogen succinimide and the like in the presence of an acid selected from sulfuric acid and methanesulfonic acid. (Ris H, a hydroxyl group, or an alkoxy group; Rand Rare each independently H or a hydrocarbon group; a is an integer of 1-4; b is an integer of 1-4; a+b is an integer of 2-5; X is a halogen atom; c is an integer of 1-4; and a+b+c is an integer of 3-6).SELECTED DRAWING: None

Description

  The present invention relates to a novel method for producing a halogenated benzene derivative, and particularly to a novel method for producing an iodobenzene derivative. Specifically, the present invention relates to a novel method for producing a halogenated benzene derivative, particularly an iodobenzene derivative, which is highly efficient and economically advantageous.

  An iodobenzene derivative, which is one type of halogenated benzene derivative, is a compound useful as a raw material or raw material for pharmaceuticals and agricultural chemicals (see Patent Document 1 and Non-Patent Document 1).

  As a method for synthesizing these iodobenzene derivatives, a direct iodination method is generally used. For example, a benzene derivative and N-iodosuccinimide (hereinafter sometimes referred to as “NIS”) in an ionic fluid (ionic liquid) or methylene chloride solvent with iron (III) chloride as a catalyst. Is known (see, for example, Non-Patent Document 2). According to this method, iodine can be introduced into the para position of the benzene derivative having an electron withdrawing group such as a hydroxyl group or an aldehyde group (para position of the electron withdrawing group).

  It may be preferable that the raw material benzene derivative into which iodine is introduced is not only a compound having an electron-withdrawing group as a substituent but also a compound having another substituent. For example, when a benzene derivative in which both an electron-withdrawing group and a group having an active hydrogen at the benzyl position (for example, an alkyl group) are used is used, the resulting iodobenzene derivative has high utility value. Become.

  Thus, the present inventors applied the method described in Non-Patent Document 2 to a benzene derivative substituted with an electron-withdrawing group and a group having an active hydrogen at the benzyl position. Then, it was found that the reaction did not proceed well depending on the structure of the benzene derivative used.

  In contrast, various studies have been made on the iodination of benzene derivatives substituted with an electron-withdrawing group and a group having an active hydrogen at the benzyl position. For example, a method is known that has a nitro group as an electron-withdrawing group and a methyl group as a group having an active hydrogen at the benzyl position, that is, iodine is introduced into nitrotoluene. Specifically, in the presence of sulfuric acid, nitrotoluene and the above-mentioned NIS or 1,3-diiodo-5,5-dimethylhydantoin (1,3-Diiodo-5,5-dimethylhydantoin, hereinafter referred to as “DIH” as an iodinating agent. In some cases (see, for example, Non-Patent Documents 3 and 4).

  However, even in these methods, the yield of the target product is moderate (about 40 to 50%). In particular, the selectivity of 4-iodo-2-nitrotoluene is low, and the selectivity of the methyl group is high. There was room for improvement in order to obtain a compound in which iodine was introduced at the position.

  On the other hand, a method is proposed in which iodine is reacted with the benzene derivative (a benzene derivative having an electron-withdrawing group and a group having an active hydrogen at the benzyl position, such as 2-methylbenzoic acid) in the presence of a porous compound. (For example, see Patent Documents 2 and 3). Since the porous compound is present, iodine can be introduced at a specific position according to these methods.

  In these methods, sulfuric acid (in combination with acetic acid) is actually used, periodic acid, iodic acid, and sodium persulfate are used as oxidizing agents, and iodine and benzene derivatives are converted into specific porous compounds. In the presence of. This method is considered to be a problem of the reagent used, but in these methods, in order to complete the reaction, a relatively long time of about 10 hours is required at a relatively high temperature (specifically, 110 to 130 ° C.). there were.

US Patent Application Publication No. 2010/0099883 International Publication No. WO 2004/069722 International publication WO2005 / 003073

Tohnishi, M .; Etc. J. et al. Plastic. Sci. 2005, 30, 354 Racys, D.M. T.A. Etc. J. et al. Organic Lett. 2015, 17, 4782 Chaikovskii, V.M. K. Russ. J. et al. Org. Chem. 2007, 43, 1278 Chaikovskii, V.M. K. Russ. J. et al. Org. Chem. 2009, 45, 1349

  Accordingly, an object of the present invention is to provide a method capable of producing a desired halogenated benzene derivative efficiently at a high yield even under relatively mild conditions.

  The present inventors have made extensive studies to solve the above problems. Then, a benzene derivative having a specific substituent is used, and the benzene derivative, at least one selected from N-halogen succinimide and 1,3-dihalogen-5,5-dimethylhydantoin as a halogenating agent The present inventors have found that the above-mentioned problems can be solved by reacting a kind of compound (for example, “NIS” or “DIH” which is an iodinating agent) in the presence of an acid, and the present invention has been completed.

That is, the present invention
(1) In the presence of at least one acid selected from sulfuric acid and methanesulfonic acid,
Following formula (1)

(Where
R ¹ is a hydrogen atom, a hydroxyl group, or an alkoxy group,
R ² and R ³ are each a hydrogen atom or a hydrocarbon group,
a is an integer of 1 to 4,
b is an integer of 1 to 4,
However, a + b is an integer of 2-5. )
A benzene derivative represented by
By reacting with N-halogen succinimide and at least one halogenating agent selected from 1,3-dihalogen-5,5-dimethylhydantoin,
Following formula (2)

(Where
R ¹ , R ² , a, and b have the same meaning as in the above formula (1),
X is a halogen atom,
c is an integer of 1 to 4,
However, a + b + c is an integer of 3-6. )
A method for producing a halogenated benzene derivative represented by the formula:

In the present invention, in order to reduce impurities such as isomers and increase the yield of the target product,
(2) Furthermore, it is preferable to react the benzene derivative represented by the formula (1) with the halogenating agent in the presence of a porous compound.

Further, in the present invention, in order to obtain a target with higher yield and higher purity,
(3) Furthermore, it is preferable to react the benzene derivative represented by the formula (1) with the halogenating agent in the presence of nitromethane.

In the present invention,
(4) The reaction between the benzene derivative represented by the formula (1) and the halogenating agent is preferably performed in a temperature range of −20 ° C. or higher and 30 ° C. or lower. According to the present invention, the target product can be obtained in high yield even under such relatively mild conditions, and impurities can be further reduced.

In the present invention,
(5) The benzene derivative represented by the formula (1) is
Following formula (3)

(Where
R ¹ , R ² , and R ³ have the same meanings as in the formula (1). )
A compound represented by
The resulting halogenated benzene derivative is
Following formula (4)

(Where
R ¹ , R ² , and R ³ have the same meanings as in the formula (1),
X is a halogen atom. )
It is preferable that it is a compound shown by these. According to the present invention, when producing the compound represented by the formula (4), a particularly excellent effect is exhibited.

  According to the method of the present invention, a desired halogenated benzene derivative, for example, an iodine compound, can be produced efficiently at a high yield even under relatively mild conditions. In addition, the presence of a porous compound and / or a polar solvent such as nitromethane in the reaction system can increase the yield of the target product more effectively and also increase the purity. From the above, the present invention has high industrial utility value.

  The present invention aims at high efficiency by reacting a benzene derivative having a specific structure with a specific halogenating agent in the presence of at least one acid selected from sulfuric acid and methanesulfonic acid. This is a method for producing a halogenated benzene derivative. In the following, description will be given in order.

(acid)
In the present invention, at least one acid selected from sulfuric acid and methanesulfonic acid is used. By using these acids in combination with a halogenating agent described later, it is considered that the reaction can proceed even under relatively mild conditions. As these acids, commercially available products sold as reagents can be used. These acids can also be used as a medium (role of a solvent) so that the components can be easily mixed and contacted depending on the temperature used. In the present invention, sulfuric acid and methanesulfonic acid are two acids. For this reason, other substances generally positioned as acids, such as acetic acid, do not correspond to the acids in the present invention. In this invention, acetic acid is classified into the solvent mentioned later.

  In the present invention, when sulfuric acid is used, it may be sulfuric acid containing water. In the present invention, sulfuric acid not containing water (100% by mass of sulfuric acid), commercially available dilute sulfuric acid, and concentrated sulfuric acid can be used.

  In the present invention, the amount of acid used is not particularly limited, and the benzene derivative used (hereinafter may be simply referred to as “substrate”), the halogenating agent, and the desired halogenated benzene derivative are used. It can be determined accordingly. Among these, in order to increase productivity and facilitate subsequent steps such as purification, it is preferable to use 0.01 to 100 parts by mass of acid with respect to 1 part by mass of the substrate. As a matter of course, the mass of the acid is the mass of the acid itself. For example, when sulfuric acid containing water (aqueous solution) is used, the mass of sulfuric acid contained in the aqueous solution falls within the above range. I should be satisfied.

(Substrate; benzene derivative)
In the present invention, the benzene derivative as a substrate (raw material) is
Following formula (1)

(Where
R ¹ is a hydrogen atom, a hydroxyl group, or an alkoxy group,
R ² and R ³ are each a hydrogen atom or a hydrocarbon group,
a is an integer of 1 to 4, b is an integer of 1 to 4,
However, a + b is an integer of 2-5. )
It is a benzene derivative shown by.

  In the present invention, it is important to use the benzene derivative represented by the formula (1). By using the benzene derivative represented by the formula (1) as a substrate (raw material), an iodobenzene derivative (halogenated benzene derivative) in which a halogen atom, for example, an iodine atom is introduced into a benzene ring can be efficiently produced. According to the present invention, a halogen atom can be introduced into a benzene ring even in a benzene derivative having an electron-withdrawing group having a ketone bond or an ester bond and an active hydrogen at the benzyl position. In addition, the obtained halogenated benzene derivative has many uses as an intermediate and has high utility value.

(Description of R ¹ )
In the formula (1), R ¹ is a hydrogen atom, a hydroxyl group, or an alkoxy group. That is, the —COR ¹ group is an electron-withdrawing group. As a matter of course, in the -COR ¹ group, C is a carbon atom and O is a hydrogen atom.

The alkoxy group is preferably a group having 1 to 6 carbon atoms, and specific examples include groups such as a methoxy group and an ethoxy group. Among these, methoxy group or ethoxy group is preferable in consideration of reactivity, selectivity, and effectiveness of the resulting iodobenzene derivative. In the case of an alkoxy group, it becomes a benzene derivative having an ester bond. A benzene derivative having an ester bond is also obtained when R ¹ is a hydroxyl group.

Among these, R ¹ is preferably a hydroxyl group.

a shows the number of -COR ¹ groups and is an integer of 1-4. When a is 2 or more, the —COR ¹ groups may be the same group or different groups. In consideration of the usefulness of the obtained halogenated benzene derivative, a is preferably 1 to 3.

(Explanation of R ² and R ³ )
R ² and R ³ are each a hydrogen atom or a hydrocarbon group. The —CH (R ² ) (R ³ ) group refers to a group having an active hydrogen at the benzyl position (hydrogen atom at the α position). As a matter of course, in the —CH (R ² ) (R ³ ) group, C is a carbon atom, and H is a hydrogen atom. This hydrogen atom corresponds to an active hydrogen at the benzyl position (hydrogen atom at the α position).

  The hydrocarbon group is not particularly limited, but is preferably an alkyl group having 1 to 12 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, or an aryl group having 6 to 20 carbon atoms. The aralkyl group and the aryl group may have a substituent. When the aralkyl group and the aryl group have a substituent, the substituent is preferably an alkyl group having 1 to 12 carbon atoms.

Among them, in order to obtain a highly useful halogenated benzene derivative in the present invention, R ² and R ³ are both hydrogen atoms, or one of them is a hydrogen atom and the other has 1 to 12 carbon atoms. It is preferably an alkyl group, an aralkyl group having 7 to 20 carbon atoms which may have a substituent, or an aryl group having 6 to 20 carbon atoms which may have a substituent.

b ^{is, -CH (R 2) (R} 3) and indicates the number of groups, an integer of 1 to 4. When b is 2 or more, the —CH (R ² ) (R ³ ) group may be the same group or different groups. In consideration of the usefulness of the resulting benzyl iodide derivative, b is preferably 1 to 3.

(Total number of substituents a + b)
In the benzene derivative represented by the formula (1), the sum (a + b) of the —COR ¹ group and the —CH (R ² ) (R ³ ) group must be an integer of 2 to 5. That is, the benzene derivative must have at least one hydrogen atom as a substituent. This hydrogen atom is substituted with a halogen atom, for example, an iodine atom, to obtain a desired halogenated benzene derivative (iodinated benzene derivative). In view of the usefulness of the obtained halogenated benzene derivative, a + b is preferably 2 to 4.

(Suitable benzene derivative)
In the present invention, in order to produce a more useful halogen benzene derivative, the benzene derivative represented by the formula (1) is represented by the following formula (3):

(Where
R ¹ , R ² , and R ³ have the same meanings as in the formula (1). It is preferable that it is a compound shown by this.

  In the compound represented by the formula (3), a is 1, b is 1, and there are four hydrogen atoms substituted by the halogenating agent. The halogenated benzene derivative obtained using this compound as a raw material can be used in various fields.

(Halogenating agent)
In the present invention, the halogenating agent to be reacted with the substrate is at least one compound selected from N-halogen succinimide and 1,3-dihalogen-5,5-dimethylhydantoin. Specifically, N-chlorosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, N-iodosuccinimide (NIS) ), 1,3-diiodochloro-5,5-dimethylhydantoin (DIH). Considering the usefulness of the resulting halogenated benzene derivative, N-bromosuccinimide (NBS), 1,3-dibromo-5,5-dimethylhydantoin (DBH), N-iodosuccinimide (NIS), 1,3 -Diiodochloro-5,5-dimethylhydantoin (DIH) is preferable, and N-iodosuccinimide (NIS) and 1,3-diiodochloro-5,5-dimethylhydantoin (DIH) are more preferable. Commercially available compounds can be used for these compounds.

(Amount of halogenating agent used)
The amount of the halogenating agent used is not particularly limited, and may be appropriately determined according to the benzene derivative used and the target halogenated benzene derivative. For example, when one halogen atom, for example, an iodine atom is substituted for the benzene derivative, 1 to 4 mol of the halogenating agent (iodinating agent) is used for 1 mol of the benzene derivative. It is preferable to do. Note that the number of moles of the halogenating agent to be used may be appropriately increased according to the number of halogen atoms to be substituted. Specifically, in the present invention, a maximum of 4 halogen atoms can be substituted on the benzene derivative. In this case, 4 to 16 mol of the halogenating agent is used per 1 mol of the benzene derivative. It is preferable to do.

  The present invention is a method of reacting the benzene derivative and the halogenating agent in the presence of the acid. Therefore, the reaction can be carried out using only the above components, but the following can also be present in the reaction system. Next, these components will be described.

(Porous compound)
In the present invention, a porous compound may be present in the reaction system. As the porous compound, a known porous compound that is used when halogenating, for example, iodinating a benzene derivative can be used. For example, the porous compounds described in Patent Documents 2 and 3 can be used. By allowing these porous compounds to be present in the reaction system, purification of the isomer can be suppressed, and the purity and yield of the target product can be further increased.

  Specifically, synthetic zeolite such as β-type zeolite, ZSM-type zeolite, mordenite-type zeolite, L-type zeolite, and Y-type zeolite, for example, trade name: Molecular Sieves 3Å, 4Å, or 13X can be mentioned.

  In addition, a porous compound made of a synthetic resin can be used. Specifically, a synthetic adsorbent (ion exchange resin) containing styrene-divinylbenzene, for example, trade names Dowx 50WX4, Amberlyst 15 and the like can be mentioned.

  In the present invention, the amount of the porous compound used is not particularly limited. Among them, in consideration of productivity and a range where the effect is exhibited, it is preferable to use 0.001 to 10 parts by mass of a porous compound with respect to 1 part by mass of the benzene derivative, and further 0.1 to 1 part by mass is used. It is preferable to do.

(solvent)
In the present invention, if the acid is liquid at the reaction temperature, the reaction can be carried out using the acid as a medium. However, in this reaction, a liquid (solvent) other than the acid used in the present invention can be used in combination with the acid.

The solvent to be used is not particularly limited as long as it does not affect the reaction. In particular,
Halogenated solvents such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,2-trichloroethane;
Alcohol solvents such as methanol, ethanol, 2-propanol, butanol;
Solvents having heteroatoms such as dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, nitromethane, nitroethane;
Examples thereof include carboxylic acid such as acetic acid or water. These solvents can be used alone or in combination of a plurality of types.

  Among these, in order to further increase the purity of the obtained halogenated benzene derivative, it is preferable to use a polar solvent such as nitromethane and water, and it is preferable to use nitromethane in consideration of subsequent steps.

  The amount of solvent used is not particularly limited. Especially, in order to make each component react efficiently, it is preferable to use 0.01-100 mass parts of said solvent with respect to 1 mass part of said benzene derivative, and also 0.1-5 mass parts is used. It is preferable.

(Reaction conditions)
In the present invention, the benzene derivative and the halogenating agent are reacted in the presence of the acid and, if necessary, the porous compound further present in the system and the solvent. The reaction can be carried out by mixing each component.

  The method for mixing the components is not particularly limited, and can be carried out in a reaction vessel equipped with a stirring device. The procedure for adding each component into the reaction vessel is that the acid, the iodinating agent, and if necessary, the solvent and the porous compound are charged in the reaction vessel in advance and stirred, and then the benzene derivative is added. The method is desirable.

  The temperature at which each component is mixed, that is, the reaction temperature (temperature in the reaction system) is not particularly limited. Specifically, it can implement in the range of -50-200 degreeC. 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, reaction temperature becomes like this. Preferably it is the range of -30-100 degreeC, More preferably, it is the range of -30-30 degreeC. In particular, in the present invention, the reaction can be performed in a temperature range of -20 ° C or higher and 30 ° C or lower. Even under such relatively mild conditions, the yield of the target product can be increased, so that the production of by-products due to decomposition or the like can be further suppressed.

  The reaction time is not particularly limited, and can be appropriately determined while confirming the reaction rate of the raw material benzene derivative. According to the present invention, since the reaction proceeds in a relatively short time, it is usually preferably from 1 minute to 72 hours, more preferably from 5 minutes to 16 hours, and more preferably from 30 minutes to 30 minutes. More preferably, it is 8 hours or less. In addition, this reaction time points out the time when the whole quantity of the said benzene derivative and the said halogenating agent is mixed.

  The pressure during the reaction is not particularly limited. Specifically, the reaction may be carried out in any atmosphere under atmospheric pressure, reduced pressure, or increased pressure. In consideration of operability, it is preferably carried 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. In consideration of operability, it is preferable to carry out in an air atmosphere.

  In addition, in the present invention, in order to reduce by-products and the like, it is preferable to carry out the reaction under light shielding.

  The process after completion of the reaction is not particularly limited. For example, after completion of the reaction, the product obtained can be crystallized by further cooling or addition of a poor solvent (for example, water) or the like, separated from other components, and purified. When a porous compound is used, it is preferable to separate the porous compound first by means of centrifugation, filtration or the like before the crystallization.

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

(Halogenated benzene derivative)
By carrying out the reaction under the above conditions,
Following formula (2)

(Where
R ¹ , R ² , a, and b have the same meaning as in the above formula (1),
X is a halogen atom,
c is an integer of 1 to 4,
However, a + b + c is an integer of 3-6. Can be produced. As a matter of course, R ¹ , R ² , a, and b are determined by the benzene derivative to be used, and these preferable groups and numerical values are as described in the benzene derivative. X is determined by the halogenating agent to be used, and is preferably a fluorine atom, a chlorine atom, a bromine atom or an iodine source, more preferably a bromine atom or an iodine atom, and further preferably an iodine atom.

When the preferred benzene derivative is used as a raw material, the resulting halogenated benzene derivative is
Following formula (4)

(Where
R ¹ , R ² , and R ³ have the same meaning as in the formula (1), and X has the same meaning as in the formula (2). ). Since this compound can be used in various fields, the industrial utility value of the present invention is very high.

  EXAMPLES Hereinafter, the present invention will be described in detail with reference to examples. However, the present invention is specific examples, and the present invention is not limited thereto.

Example 1
Sulfuric acid (6.0 ml, 11 g) was charged into a reaction vessel equipped with a magnetic stir bar and cooled on ice (the temperature of sulfuric acid in the reaction vessel (in the reaction system) was 5 ° C.). Then, under stirring, NIS (N-iodosuccinimide; halogenating agent) (0.23 g, 1.0 mmol active oxygen content 1.0 mmol) was added into the reaction vessel, and stirring was continued for 30 minutes.

  Thereafter, with stirring, while maintaining the temperature in the reaction system at 5 ° C., o-toluic acid; “2-methylbenzoic acid” (0.14 g; 1.0 mmol) was added to the reaction vessel under light shielding. Stirring was continued for 2 hours (reaction carried out).

  When the reaction product was confirmed by high performance liquid chromatography (HPLC), the conversion rate of iodinated o-toluic acid was 99%. The molar ratio of the target product ((5-I) in the following formula) to the isomer ((3-I) in the following formula) was target product: isomer = 3.4: 1. The reaction conditions and results are summarized in Table 1.

Example 2
Sulfuric acid (6.0 ml, 11 g) was charged into a reaction vessel equipped with a magnetic stir bar and cooled on ice (the temperature of sulfuric acid in the reaction vessel (in the reaction system) was 5 ° C.). Next, under stirring, DIH (1,3-diiodo-5,5-dimethylhydantoin; halogenating agent) (0.19 g, 0.5 mmol active oxygen content 1.0 mmol) was added into the reaction vessel, and the mixture was added for 2 hours. Stirring was continued (reaction carried out).
Thereafter, with stirring, while maintaining the temperature in the reaction system at 5 ° C., o-toluic acid; “2-methylbenzoic acid” (0.14 g; 1.0 mmol) was added to the reaction vessel under light shielding. The stirring was continued for 2 hours at the same temperature (reaction was carried out).

  When the reaction product was confirmed by high performance liquid chromatography (HPLC), the conversion rate of i-toluic acid was 98%. The molar ratio of the target product ((5-I) in the following formula) to the isomer ((3-I) in the following formula) was target product: isomer = 3.3: 1. The reaction conditions and results are summarized in Table 1.

Example 3
Sulfuric acid (24.0 ml, 44 g) and nitromethane (6.0 ml, 7.0 g) were charged into a reaction vessel equipped with a magnetic stirring bar, and the temperature in the reaction system was adjusted to 5 ° C. while stirring. Then, while stirring, while maintaining the temperature in the reaction system at 5 ° C., NIS (N-iodosuccinimide; halogenating agent) (1.24 g, 5.5 mmol active oxygen amount 5.5 mmol), and synthetic zeolite; The trade name “Molecular Sieves 13X” (0.17 g) was added into the reaction vessel and stirred for 30 minutes.

  Thereafter, while stirring, maintaining the temperature in the reaction system at 5 ° C., o-toluic acid; “2-methylbenzoic acid” (0.68 g; 5.0 mmol) was added to the reaction vessel under light shielding. Stirring was continued for 2 hours (reaction carried out).

  When the reaction product was confirmed by high performance liquid chromatography (HPLC), the conversion rate of iodinated o-toluic acid was 99%. The molar ratio of the target product ((5-I) exemplified in Example 1) to the isomer ((3-I) exemplified in Example 1) was as follows: target product: isomer = 3.7: 1 Met. The reaction conditions and results are summarized in Table 1.

Example 4
In Example 3, the same operation was performed except that sulfuric acid was changed to methanesulfonic acid (24 ml, 36 g) to obtain a target product. The conversion of o-toluic acid was 99%, and the molar ratio of the target product to the isomer was target product: isomer = 4: 1. The reaction conditions and results are summarized in Table 1.

Comparative Example 1 (Further examination of Non-Patent Document 2)
In a reaction vessel equipped with a magnetic stir bar, NIS (N-iodosuccinimide) (0.45 g, 2.0 mmol active oxygen amount 2.0 mmol), 1-butyl-3-methylimidazolium bis (trifluoromethanesulfonyl) imide (5.76 g) and iron (III) chloride (0.016 g, 0.1 mmol)) were added and stirred and dispersed at 25 ° C. for 60 minutes. Subsequently, o-toluic acid; “2-methylbenzoic acid” (0.27 g; 2.0 mmol) was added, and the mixture was stirred at 38 ° C. for 17 hours. When the reaction product was confirmed by high performance liquid chromatography (HPLC), the reaction conditions and results confirmed that o-toluic acid was not iodinated are summarized in Table 1.

Comparative Example 2 (Further examination of Non-Patent Document 2)
In Comparative Example 2, the same operation was performed except for adding o-toluic acid; “2-methylbenzoic acid” and stirring at 80 ° C. for 6 hours and 120 ° C. for 6 hours. When the reaction product was confirmed by HPLC, the conversion of o-toluic acid was 75%, and the molar ratio of the target product to the isomer was target product: isomer = 3: 1. The reaction conditions and results are summarized in Table 1.

Comparative Example 3 (Further examination of Non-Patent Document 2)
In a reaction vessel equipped with a magnetic stir bar, NIS (N-iodosuccinimide) (2.25 g, 10.0 mmol, active oxygen content 10.0 mmol), methylene chloride (44 ml, 70 g) and iron (III) chloride (1. 62 g, 10.0 mmol)) was added and stirred and dispersed at 38 ° C. for 60 minutes. Then, o-toluic acid; “2-methylbenzoic acid” (1.36 g; 10.0 mmol) was added and stirred at 38 ° C. for 6 hours. When the reaction product was confirmed by high performance liquid chromatography (HPLC), the reaction conditions and results confirmed that o-toluic acid was not iodinated are summarized in Table 1.

Claims (5)

In the presence of at least one acid selected from sulfuric acid and methanesulfonic acid,
Following formula (1)

(Where
R ¹ is a hydrogen atom, a hydroxyl group, or an alkoxy group,
R ² and R ³ are each a hydrogen atom or a hydrocarbon group,
a is an integer of 1 to 4,
b is an integer of 1 to 4,
However, a + b is an integer of 2-5. )
A benzene derivative represented by
By reacting with N-halogen succinimide and at least one halogenating agent selected from 1,3-dihalogen-5,5-dimethylhydantoin,
Following formula (2)

(Where
R ¹ , R ² , a, and b have the same meaning as in the above formula (1),
X is a halogen atom,
c is an integer of 1 to 4,
However, a + b + c is an integer of 3-6. )
A method for producing a halogenated benzene derivative represented by the formula:   Furthermore, the method according to claim 1, wherein the benzene derivative represented by the formula (1) and the halogenating agent are reacted in the presence of a porous compound.   Furthermore, the method according to claim 1 or 2, wherein the benzene derivative represented by the formula (1) and the halogenating agent are reacted in the presence of nitromethane.   The method according to any one of claims 1 to 3, wherein the reaction between the benzene derivative represented by the formula (1) and the halogenating agent is performed in a temperature range of -20 ° C to 30 ° C. The benzene derivative represented by the formula (1) is
Following formula (3)

(Where
R ¹ , R ² , and R ³ have the same meanings as in the formula (1). )
A compound represented by
The resulting halogenated benzene derivative is
Following formula (4)

(Where
R ¹ , R ² , and R ³ have the same meanings as in the formula (1),
X is a halogen atom. )
The method according to claim 1, wherein the compound is represented by the formula: