WO2008066033A1

WO2008066033A1 - Alkylthio-substituted benzene derivative and process for production thereof

Info

Publication number: WO2008066033A1
Application number: PCT/JP2007/072839
Authority: WO
Inventors: Shinya Maehara; Hideyuki Murakami; Satoshi Hobara
Original assignee: Hokko Chemical Industry Co., Ltd.
Priority date: 2006-11-29
Filing date: 2007-11-27
Publication date: 2008-06-05

Abstract

Disclosed is a process for producing an industrially useful alkylthio-substituted benzene derivative by using an aqueous solution of an alkali metal salt of a lower alkanethiol which is available at a low cost. Specifically disclosed is a process for producing an alkylthio-substituted benzene derivative represented by the general formula (6) by reacting a halogenated benzene derivative represented by the general formula (1) with an alkanethiol alkali metal salt represented by the general formula (2). The process comprises: a first reaction step for conducting the reaction by adding an aqueous solution of the alkali metal salt of the lower alkanethiol to a mixed solution of the halogenated benzene derivative, a reaction solvent and an azeotropic solvent (a solvent which can be removed together with water from a reaction system by distillation) which may be the same as the halogenated benzene derivative represented by the formula (1), while distilling a mixture of water and the azeotropic solvent to remove water present in the reaction system continuously so that the water content of the reaction mixture becomes 10 mass% or less; and, optionally, a second reaction step for adding an alkyl halide represented by the general formula (3), an alkyl sulfate ester represented by the general formula (4) or an alkyl carbonate ester represented by the general formula (5) to the reaction system.

Description

Specification

Method for producing alkylthio group-substituted benzene derivative

Technical field

[0001] The present invention relates to a novel method for producing a substituted benzene derivative having an alkylthio group, which is important as an intermediate for pharmaceuticals and agricultural chemicals. Background art

[0002] Several methods for producing substituted benzene derivatives having an alkylthio group have been known so far. As a general method, a method of reacting an alkali metal salt of a lower alkanethiol with a halogen-substituted benzene derivative is known. For example, by reacting dichlorobenzene or dichlorotoluenes with hexanethiol phosphoric triamide (HMPA) at 100 ° C with 1.5-fold mol of methanethiol sodium salt, followed by treatment with methyl iodide. It has been reported that methylthio group-substituted benzene derivatives can be obtained in a yield of 92% (Non-patent document 1, Non-patent document 2). In this case, the methanethiol sodium salt used is anhydrous, and no examples of using aqueous solutions have been reported.

[0003] In addition, a polyethylene glycol solvent and xylene as surfactants were added to 1,2-dibromobenzene, reacted with a 30% aqueous solution of methanethiol sodium salt while dehydrating, and then purified by distillation to obtain 63% The power S, which describes that 2-methylthiobromobenzene can be obtained in a yield, is not yet sufficient in terms of economy for industrial use (Patent Document 1, Implementation) Example 9).

[0004] Further, 1,2-dichlorobenzene was added dropwise in polyethylene glycol at 135 ° C over 1 hour with 1 / 3-fold moles of 30% aqueous methanethiol sodium salt solution over 1,4 dichlorobenzene over 135 hours. After reacting to 2-methylthiochlorobenzene, water was added to oxidize the chlorine to obtain 2-chromiumbenzenesulfurolide with a yield of 68.2%, or polyethylene glycol It has been reported that tetra-n-butylammonium bromide is added without using bismuth and the same reaction is carried out to obtain 2-chlorobenzene benzenesulfur chloride in a yield of 66.7% (patented) Reference 2, Example 1 and Example 9).

In the same way, in the presence of tetra-n-butylphosphonium bromide, 1,4-dichloro It has been reported that 4-chlorothiophenol can be obtained in a yield of 87.1% by reacting benzene with 30% aqueous methanethiol sodium salt solution and then reacting with chlorine without adding water (patent) Reference 3, Example 2).

In these cases, the ability to increase the reaction efficiency of methanethiol sodium salt by using excess dichlorobenzene as a raw material or adding a surfactant S, isolation of chlorothioanisoles Yields are not described. The use of surfactants, to use multilingual tool industrially case of difficult recovery of anti応溶medium is still a problem force ^s in terms of economy.

In general, lower alkanethiols have a low boiling point and have a unique odor that is difficult to handle, requiring special equipment.

Alkaline metal salts of lower alkanethiols are easier to handle! / Than thiols themselves, but they are expensive as anhydrides and have problems in terms of economy in industrial production. An aqueous salt solution is easy to synthesize and is inexpensive. The reaction yield decreases because the reactivity decreases due to the presence of a large amount of water. It is necessary to use a large excess of alkali metal salt in order to obtain the desired product in high yield. It is also known that alkylthio group dealkylation occurs as a side reaction due to the presence of excess alkanethiol alkali metal salt. Therefore, the use of a large excess of an alkanethiolalkali metal salt is not an efficient method for synthesizing alkylthio group-substituted benzene derivatives. Therefore, establishment of an economical production method for economically advantageous lower alkylthio group-substituted benzene derivatives is desired!

Non-Patent Document 1: Synthesis, 1982, Vol. 6, 475–478

Non-Patent Document 2: Tetrahedron Letters, 21, 3099-3100, 1980 Patent Document 1: JP-A-9 40636

Patent Document 2: Japanese Patent Laid-Open No. 948752

Patent Document 3: Japanese Patent Laid-Open No. 2001-302616

Disclosure of the invention

Problems to be solved by the invention [0006] As described above, the ability to use an aqueous solution of a lower alkanethiol alkali metal salt from the economical aspect is advantageous in producing an alkylthio group-substituted benzene derivative. Generally available lower alkanethiol alkali metal salts. The concentration of the aqueous solution is about 10 to 30%. If it is used as it is, the reactivity decreases due to the presence of a large amount of water, and it is difficult to use it industrially because the reaction efficiency is poor. Therefore, an industrially advantageous method for producing an alkylthio group-substituted benzene derivative using an aqueous solution of a lower alkanethiol alkali metal salt that is available at low cost is desired. Means for solving the problem

[0007] The inventors of the present invention have made extensive studies to achieve the above object. As a result, by using an aqueous solution of a lower alkanethiol alkali metal salt, water is continuously reacted by azeotropic dehydration in the presence of a certain organic solvent so that the water content in the reaction system is below a certain water content. It was found that an alkylthio group-substituted benzene derivative was obtained in a high yield when reacted with a halogenated benzene derivative while removing it, and the present invention was completed.

Here, “azeotropic dehydration” means that water and an azeotropic solvent (which is a solvent that can be removed from the reaction system by distillation together with water) are distilled simultaneously to distill water present in the reaction system. It means to remove.

That is, the present invention provides the following general formula (1)

[Chemical 1]

(Wherein R, R, R, R and R are the same or different hydrogen atoms;

1 2 3 4 5

A linear or branched alkyl group having 1 to 6 carbon atoms; a linear or branched alkoxy group having 1 to 6 carbon atoms; a nitrogen atom; a trifluoromethyl group; a phenyl group; or a carbon number; 1 to 3 substituents selected from the group consisting of 6 linear or branched alkyl groups, 1 to 6 carbon linear or branched alkoxy groups, and halogen atoms. X represents a halogen atom. )

A halogenated benzene derivative represented by the following general formula (2)

R SM (2)

(In the formula, R represents a methyl group or an ethyl group, and M represents an alkali metal cation.

6

. And a lower alkanethiol alkali metal salt represented by the following general formula (6)

( ₆₎

(Wherein R, R, R, R, R and R are as defined above)

1 2 3 4 5 6

A process for producing an alkylthio group-substituted benzene derivative represented by:

An azeotropic solvent (which can be removed from the reaction system by distillation together with water) which may be the same as the halogenated benzene derivative, the reaction solvent and the halogenated benzene derivative represented by the formula (1); The mixture of water and azeotropic solvent was distilled by distillation while adding an aqueous solution of the above lower alkanethiol alkali metal salt without adding a surfactant to the mixed solution of Including the first reaction step in which the reaction is carried out by removing the water present to reduce the water content in the reaction mixture to 10% by mass or less, and if necessary, the following general formula (3)

R Υ (3)

6

(Υ represents a halogen atom.)

An alkyl halide represented by

The following general formula (4)

(R O) SO (4)

6 2 2

An alkyl sulfate represented by

The following general formula (5) (RO) CO (5)

6 2

A method for producing an alkylthio group-substituted benzene derivative comprising a second reaction step in which an alkyl carbonate represented by the formula

The invention's effect

[0008] According to the present invention, it is possible to produce an industrially useful alkylthio group-substituted benzene derivative in high yield by using an inexpensive aqueous solution of a lower alkanethiol alkali metal salt, which is available at low cost. Monkey.

Hereinafter, the present invention will be described in more detail.

BEST MODE FOR CARRYING OUT THE INVENTION

[0009] The process for producing an alkylthio group-substituted benzene derivative, which is particularly useful in the present invention, first comprises a halogenated benzene derivative represented by the above general formula (1) and a lower alkyl represented by the above general formula (2). Reacting the lucanthiol strength metal salt.

[0010] In the present invention, the halogenated benzene derivative represented by the above general formula (1), R, R,

1 2

R, R and R can each independently be any of the substituents described above.

3 4 5

Examples of the straight-chain or branched alkyl group having 1 to 6 carbon atoms include, for example, methyl group, ethyl group, n propyl group, isopropyl group, n butyl group, isobutyl group, sec butanol group, tert butyl group, n pentyl group, isopentyl group, 2-methylbutyl group, neopentyl group, n-hexyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 3,3-dimethylbutyl group, 1,1-dimethylbutyl group, 1 , 3-dimethylenobutyl group, 2,3-dimethylbutyl group, 1-ethylbutyl group, 1-methyl-1-ethylenopropyl group, 1,2-dimethylbutyl group, 2-methyl-1-ethylpropyl group, 2,2-dimethylbutyl group, etc.

Examples of the linear or branched alkoxy group having 1 to 6 carbon atoms include methoxy group, ethoxy group, n propoxy group, isopropoxy group, n butoxy group, isobutoxy group, se c butoxy group, tert butoxy group, n Pentyloxy group, isopentyloxy group, 2-methylbutoxy group, neopentyloxy group, n-hexyloxy group, 4-methylpentyl-oxy group, 3 methino-repentino-reoxy group, 2-methino-repentino-reoxy group, 3, 3— dimethylbutoxy group, 1, 1-dimethylbutoxy group, 1, 3 dimethylbutoxy group, 2, 3— Dimethylbutoxy group, 1-ethylbutoxy group, 1-methyl-1-ethylpropoxy group, 1,2-dimethylenobutoxy group, 2-methinole-1-ethinorepropoxy group, 2,2-dimethylenobutoxy group, etc.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. A linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkoxy group having 1 to 6 carbon atoms. And a phenyl group substituted at 1 to 3 positions with a substituent selected from the group consisting of halogen atoms include, for example, 2 methylphenyl group, 3 methylphenyl group, 4 methylphenyl group, 2, 3 dimethylphenyl group, 2 , 4 Dimethyl phenyl group, 2, 5 Dimethyl phenyl group, 2, 6 Dimethyl phenyl group, 3, 4 Dimethyl phenyl group, 3, 5 Dimethino fenenore group, 2, 4, 6 Trimethino fenenore group, 3 , 4, 5 Trimethylolenyl, 2 ethenylphenyl, 3 ethenylphenyl, 4 ethenylphenyl, 2, 3 jetylphenyl, 2, 4 jetylphenyl, 2, 6 jetylphenyl Group, 3, 5 Jetyl phenyl group, 3, 4, 5 Trimethyl phenyl group, 2-n-propyl phenyl group, 3 Isopropyl phenyl group, 2-n Butyl phenyl group, 4-tert Butyl phenyl group, 3-Isoiso Pentylphenyl group, 4 (1,1-dimethylpropynole) phenyl group, 4 —n hexylphenyl group, 2 methoxyphenyl group, 3 methoxyphenyl group, 4-methoxyphenyl group, 3, 4-dimethoxyphenol Diyl group, 3-ethoxyphenyl group, 4 ethoxyphenyl group, 3-isopropoxyphenyl group, 4-tert-butoxyphenyl group, 3-methyl-4-methoxyphenyl group, 3-chlorophenyl group, etc. .

Examples of the halogen atom for X in the general formula (1) include a fluorine atom, a chlorine atom, and a bromine atom. Among them, a chlorine atom and a bromine atom are preferable from the viewpoint of easy availability. As the halogenated benzene derivative represented by the general formula (1), for example,

1,2-dihalogenated benzene, 1,3-dihalogenated benzene, 1,4-dihalogenated benzene, 1,2,3 trihalogen benzene, 1,2,4 trihalogen benzene, 1,3, 5-trichlorobenzene, hexanologenbenzene, 2-alkyleno-benzene, 3-alkyl halogenated benzene, 4-alkyl halogenated benzene, 2-alkoxy halogenated benzene, 3-alkoxy halogenated Benzene, 4-alkoxy halogenated Benzene, 2 trifluoromethyl halogenated benzene, 3 trifluoromethyl halogenated benzene, 4 trifluoromethyl halogenated benzene, 4 phenyl halogenated benzene, 3 phenyl 1,2 dihalogenated benzene, 4 phenol 2-luo 1,2 dihalogenated benzene, 5-phenyl di-luodium 1,2 di-halogenated benzene, 4 alkyl phenyl di-roodium 1, 2 di-halogenated benzene, 5-alkoxy phenol di-roodium 1,2 di-halogenated benzene, 2-phenyl-1,3 dihalogen Benzene, 4-alkylphenyl- 1,3 dihalogenated benzene, 5 phenyl 1,3 dihalogenated benzene, 2 alkoxy phenylolene, 1,4-dihalogenated benzene, 3-halogenated phenyl 1,3 4 Dihalogenated benzene, 3 Alkyl 1,2 Dihalogenated benzene, 4 Alkyl 1,2 Dihalogenated benzene, 5 Luky 1,2 dihalogenated benzene, 2 alkyl 1,3 dihalogenated benzene, 4 alkyl 1,3-dihalogenated benzene, 5-alkyl 1,3-dihalogenated benzene, 2 alkyl 1,4-dihalogenated benzene, 3 alkyl 1,4-dihalogenated benzene, 3 alkoxy 1,2 dihalogenated benzene, 4-ananoloxy 1,2-dihalogenated benzene, 5-an alcoholoxy 1,2-dihalogenated benzene, 2 alkoxy 1,3 dihalogenated benzene, 4 Alkoxy 1,3 dihalogenated benzene, 5 Ananoloxy 1,3 Dihalogen benzene, 2 Ananoloxy 1,4-Dihalogenated benzene, 3-Alkoxy 1,4-Dihalogenated benzene, 3-Trifluoromethyl-1,2, Dihalogenated benzene, 4 trifluoromethyl-1,2 dihalogenated benzene, 5 trifluoromethyl- 1,2 dihalogenated benzene, 2 trifluoromethylolene 1,3-dihalogenated benzene, 4 trifluoromethyl 1,3-dihalogenated benzene, 5 trifluoromethyl; 1,3 dihalogenated benzene, 2 trifluoromethyl -1,4-dihalogenated benzene, 3-trifluoromethyl-1,4 dihalogenated benzene, 3 phenyl 1,2 dihalogenated benzene, 4 alkyl phenyl benzene 1,2 dihalogenated benzene, 5 phenyl 1,2-dihalogenated benzene, 2 phenyl 1,3-dihalogenated benzene, 2 alkyl phenyl, 1,3 dihalogenated benzene, 2-alkoxy phenyl 1,3-dihalogenated benzene, 4-phenyl two 1 , 3-Dihalogenated benzene, 5-Fluorine 1,3-Dihalogenated benzene, 5-Halogenated phenyl 1,3 Dihalogenated benzene, 2 Phenyl Over 1,4 Jiharogen benzene, 3 Anore Kirufeniru 1,4-dihalogenated benzene, 2,3 dialkyl halogenated benzene, 2,4 dialkyl halogenated benzene, 2,5 dialkyl halogenated benzene, 2,6-dialkyl halogenated benzene, 3,4-dialkyl halogenated Benzene, 3,5-dialkyl halogenated benzene, 2,3 dialkoxy halogenated benzene, 2,4 dialkoxy halogenated benzene, 2,5 dialkoxy halogenated benzene, 2,6 dialkoxy halogenated benzene, 3, 4-Dialkoxy halogenated benzene, 3,5-Dialkoxy halogenated benzene, 2,4 Ditrifluoromethyl halogenated benzene, 3,5-Ditrifluoromethyl halogenated benzene, 2 Alkyl 3 alkoxy halogenated benzene , 2 alkyl 4 alkoxy halogenated benzene, 2 alkyl 5 alkoxy Rogenated benzene, 2 alkyl-6 alkoxy halogenated benzene, 3 alkynole 4 alkoxy halogenated benzene, 3-alkyl 5-alkoxy halogenated benzene, 2 alkyl-4 phenyl halogenated benzene, 2 alkyl-4 alkyl phenyl halogenated benzene, 2 alkyl 4 alkoxyphenyl halogenated benzene, 2 alkyl-6 phenyl halogenated benzene, 3 alkyl-5 halogenated phenyl halogenated benzene, 2 alkoxy 4 phenyl halogenated benzene, 2-alkoxy 6-phenyl halogen Benzene, 3 -alkoxy 5 -alkylphenyl halogenated benzene, 2,3,4 trialkyl halogenated benzene, 3,4,5-triazolealkyl halogenated benzene, 2,3,4 trialkoxy halogenated benzene, 3 , 4,5-Trialkoxyhalo Such as emissions of benzene, and the like.

In this paragraph, when referring to dihalogenation, the two halogen atoms may be the same or different.

More specifically, chlorobenzene, bromobenzene, fluorobenzene, odobenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1,4-dichlorobenzene, 1,3-difunoleobenzene, 1-bromo 2 Black mouth benzene, 1-Bromo 3 Black mouth benzene, 1-Bromo 4—Black mouth benzene, 1—Funoleo 2—Black mouth benzene, 1—Funoleo One mouth 3 Chlo mouth benzene, 1—Funoleo mouth one 4 Head Benzene, 1-odd 2 Black mouth benzene, 1-yod 3-Black-mouthed benzene, 1-yod 4 Black-mouthed benzene, 1 Bromo 2 Funole-aged lobenzene, 1-Bromo 3 Funore-aged robenzene, 1-Bromo 4-Funore O-benzene, 1-bromo-2 oodobenzene, 1-bromo-3 oodobenzene, 1—bromo-4 oodobenzene, 1—funoleoro 2 oodobenzene, 1—funoleolo 3 oodobenzene, 1-nooroleo 4 oodobenzene, 1,3,5—trichloro-benzene, 1-bromo 3,5 Dichlorodiethyl benzene, 1-bromo-2,4 difluorobenzene, 1-diethyl methane 3,5-diphenolobenzene, bromopentafluorobenzene, pentafluororeobenzene, 2 bromotonolene, 3 bromotonolene, 4-bromotonolene 2 chlorotoluene, 3 chlorotoluene, 4 chlorotoluene, 2 fluorotoluene, 3 fluorotoluene, 4 fluorotoluene, 2 ydnotorenen, 3 iodotonoren, 4 iodotonorenen, 2 bromon—propinole , 3 bromo-isopropino benzene, 4 bromo-tert butynolebenzene, 2 chloro-isopropino benzene, 3 chloro-n-butino benzene, 4 chloro-tert butino benzene, 4 odo tert butinoreben sen, 3 funoleol tert butino benzene , 4-n hexenorefnoroleo benzene, 2, 3 dichroic toluene, 2, 4 dichroic toluene, 2, 5 dichroic toluene, 2, 6 dichroic toluene, 3, 4 dichroic toluene, 3, 5 dichroic toluene 2, 3 Jib mouth moto noren, 2, 4 Jib mouth moto noren, 2, 5 Jib mouth moto noren, 2, 6 Jib mouth moto no ren, 3, 4 dibromo toluene, 3, 5 bromotoluene, 2 bromo 3 Mouth Mor 4 Chlorotonolene, 2F, Mouth Moe 5 Chlorotolenen, 2F, Mouth Mor 6 Chlorotono 2, 3 Bromo-5 chlorotoluene, 2 Fluoro-6 bromotoluene, 2 Fluoro4 chlorotolenene, 2 bromo-6 ododonorene, 2 chloro-6 ododonorene, 2,4,6 Trichloromouth toluene, 2, 4 dichlorophenylbenzene, 2, 6 Dichlorophenol Ninobenzene, 3 Bromo 5 Black mouth phenylobenzene, 2 Bromoanisonore, 3 —Bromoanisonore, 4 Bromoanisonore, 2 Chloroanisonore, 3 Chloroanisonore, 4 Chloroanisole Sonore, 2-Hunoleoloanisonore, 4-Hunoleoloanisonore, 2-Hanianisole, 3-Hodoanisole, 2-Ethoxybromobenzene, 3-Ethoxychlorobenzene, 4-n-propoxyfluorobenzene, 2-Black Nzotrifluoride, 3 Black Mouth Benzotrifluoride, 4 Black mouth Benzotrifluoride, 2 Bromobenzotri Benzene, 2,4 Dimethylchlorobenzene, 3,4 Dimethylchlorobenzene, 3,5 Dimethylchlorobenzene, 2,4 Dimethylfluorobenzene, 3,5 Jetyl bromobenzene, 2 Phenylol bromobenzene, 3 Phenylol bromobenzene, 4 Phenyl bromobenzene, 2 Phenyl chlorobenzene, 3 Phenyl chlorobenzene, 4 ph 'mouth morpheno benzene, 2 Phenyl chloro benzene, 4 Phenyl chlorobenzene, 2— (2 -Methylphenyl) bromobenzene, 3- (3 methylphenyl) bromobenzene, 2- (2-methylphenyl) chlorobenzene, 4-one (4-methylphenol) bromobenzene, 4-one (4 tert butynolephenol) Funoleo-mouth benzene, 4-one (4-tert-butynolefuenore) black-mouthed benzene, 4-one (4-tert-butyl) Eninore) odobenzene, 4-one (4-tert-butylphenol) 1, 3 dichlorobenzene, 2- (3 methoxyphenol) bromobenzene, 4- (4-tert-butoxyphenol) oleoreno benzene, 4 1- (4-tert-butoxyphenyl) black benzene, 4- (4-tert-butoxyphenyl) chlorobenzene, 4-one (2-chlorobutenyl)

[0013] Regarding the alkali metal salt of the lower alkanethiol represented by the general formula (2), R is

6 represents a til group or an ethyl group, and the alkali metal cation represents a lithium ion, a sodium ion, a potassium ion, a noredium ion, a cesium ion or the like.

Examples of the alkali metal salt of the lower alkanethiol represented by the general formula (2) include, for example, a lithium salt of methanethiol, a sodium salt of methanethiol, a power methanethiol salt, a lithium salt of ethanethiol, and an ethanethiol. And sodium salt of ethane and the like.

[0014] The reaction solvent is a solvent that enables a reaction between a halogenated benzene derivative and a lower alkanethiol alkali metal salt without adding a surfactant, and has a high affinity for a cation and promotes the reaction. Aprotic polar solvents that are preferably aprotic polar solvents from the standpoint of effectiveness include 1,3 dimethyl-2 imidazolidinone, N methyl-2-pyrrolidinone, N, N dimethylformamide, N, N dimethyl Amide solvents such as acetoamide and hexamethylphosphoric triamide; Sulfoxide or sulfone solvents such as dimethyl sulfoxide or phosphorane; Pyridine; 2 Methyl pyridine, 3 Methyl pyridine, 4 Methyl pyridine, 2, 6 dimethyl pyridine, 2 , 4 1-5 such as dimethyl pyridine Pyridine substituted with a linear or branched alkyl group having 1 to 6 carbon atoms; quinoline; and 1 to 5 linear or branched carbon atoms having 1 to 6 carbon atoms such as 2 methylquinoline Use force S to use one or more solvents selected from the group consisting of quinoline substituted with alkyl groups.

[0015] The reaction solvent is usually used in a mass ratio of from 0.5 to 100 times the mass ratio of the halogenated benzene derivative as the raw material, but preferably from 0.5 to 10 times the amount. is there.

In the production method of the present invention, the reaction between the halogenated benzene derivative and the lower alkanethiol alkali metal salt is performed by distilling and distilling water derived from the aqueous solution of the lower alkanethiol alkali metal salt together with the azeotropic solvent. , While removing continuously from the reaction system.

[0017] As a method for removing water, for example, using a Dean-Stark apparatus usually used in a laboratory or a similar apparatus, an azeotropic solvent distilled off can be used. Separation of the mixture with water can be performed using a mechanism in which only water is removed. At this time, the separated azeotropic solvent can be returned to the reaction system.

[0018] Therefore, it is preferable that the azeotropic solvent has a low solubility in water and quickly separates from water. Such a solvent is selected from benzene; a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkoxy group having 1 to 6 carbon atoms, or a trifluoromethyl group. Benzenes substituted with 1 to 3 substituents; 5 to 15 carbon atoms; linear, branched or cyclic aliphatic alkanes having 15 to 15 carbon atoms; Is preferably one or more solvents selected from the group consisting of cyclic ethers; and halogenated benzene derivatives represented by the general formula (1).

Examples of benzenes include, for example, benzene, toluene, orthoxylene, metaxylene, noraxylene, mesitylene, ethynolebenzene, isopropylenobenzene, benzotrinoleolide, and anisole.

Examples of aliphatic alkanes include n-hexane, n-heptane, n-octane, n-decane, isooctane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, decalin, methylcyclohexane, etc. Is mentioned. Examples of ethers include methyl-tert butyl ether, di-n-propyl ether. Tenole, G-n-Butinoreetenole, G-tert-Butinoreetenore, Ethenore n-Butinoreether, Cyclopentyl methyl ether, 1,2-Dimethoxypropane, 1,3-Dimethoxybutane bread, 1,2-Dimethoxybutane And diethylene glycol di-n-butyl ether.

Among these solvents, when the proportion of water in the azeotrope with water is relatively high and the specific gravity is smaller than that of water, it is separated into an upper solvent such as benzene, toluene, orthoxylene, One or more solvents selected from the group consisting of meta-xylene and para-xylene are preferred from the viewpoints of dehydration efficiency, reaction efficiency, and operability! /.

In addition, when the halogenated benzene derivative represented by the general formula (1), which is the reaction substrate, can be azeotroped with water, it is used as an azeotropic solvent, and the azeotropic solvent is added separately. The ability to carry out the reaction without the addition. Usually, in order to remove water more efficiently, an azeotropic solvent having a lower boiling point than the halogenated benzene derivative as the reaction substrate is added separately.

The addition amount of the azeotropic solvent is an amount by which the reflux of the mixture of water and the azeotropic solvent derived from the aqueous solution is maintained during the addition of the aqueous solution of the lower alkanethiol alkali metal salt, and varies depending on the capacity of the reactor. It is preferable to add within the range of the force S and the ratio with the reaction solvent described later.

Furthermore, the above-described reaction solvent and azeotropic solvent can be arbitrarily mixed and used. Usually, it is desirable to use a mixture of a reaction solvent and an azeotropic solvent one by one from the viewpoint of solvent recovery and economy.

From the standpoint of reactivity, the ratio of the reaction solvent to the azeotropic solvent is the mass ratio at the start of the reaction, and the reaction solvent: azeotropic solvent = 200:;! Is in the range of 20:;! To 2: 1, more preferably in the range of 8:;! To 3: 1.

Reaction solvent: Azeotropic solvent = When the azeotropic solvent is larger than 1: 1, dehydration efficiency is improved, but the relative amount of the reaction solvent is decreased, so that the reactivity may be lowered. Conversely, when the amount of azeotropic solvent is less than reaction solvent: azeotropic solvent = 200: 1, dehydration is not performed efficiently, and as a result, the remaining moisture increases and the reactivity may decrease. In this case, it is necessary to increase the reaction temperature or extend the reaction time in order to increase the dehydration efficiency. This causes problems such as increased response. Therefore, in order to efficiently perform dehydration and maintain sufficient reactivity, the ratio of the reaction solvent to the azeotropic solvent is preferably within the above range.

If the azeotropic solvent is the same as the halogenated benzene derivative represented by the above general formula (1), which is the reaction substrate, and other azeotropic solvents belonging to the above group are not added separately, In the definition of the above ratio with the solvent, the “azeotropic solvent” means the halogenated benzene derivative represented by the general formula (1).

[0020] The reaction temperature between the halogenated benzene derivative and the aqueous solution of the lower alkanethiol alkali metal salt is preferably a force capable of using a temperature of 50 ° C to 200 ° C, more preferably the boiling point of the azeotropic solvent, or The temperature at which the solvent can be distilled off with water is used.

In the production method of the present invention, a preferred embodiment of the method for adding an aqueous solution of a lower alkanethiol alkali metal salt includes mixing the compound of formula (1), a reaction solvent and an azeotropic solvent, and adding the mixture with the azeotropic solvent. It is preferable to add an aqueous solution of a lower alkanethiol alkali metal salt in advance so that the mixture with water derived from the aqueous solution is heated in advance so that the mixture rapidly refluxs. At that time, the moisture contained in the reaction mixture is substantially 10% by mass or less, preferably substantially 5% by mass or less, more preferably substantially less than 5% by mass with respect to the entire reaction mixture. Add 3% by mass or less so that the reflux of the mixture of azeotropic solvent and water is maintained.

Here, “substantially” means a range that does not affect the yield, and specifically, an amount of 50% by mass or more is preferably added to the amount of the lower alkanethiol alkali metal salt aqueous solution to be added. More preferably, it is a range in which an amount of 80% by mass or more is added, and most preferably a range in which an amount of 90% by mass or more is added.

That is, if azeotropic dehydration is continuously performed, it is allowed to temporarily exceed the above-mentioned water content when adding an aqueous solution of a lower alkanethiolalkali metal salt.

As a specific method for controlling the amount of water in the reaction mixture, the amount of water to be added and the amount of water to be added, which can be dropped or added intermittently, either continuously or intermittently, are distilled. This should be done while measuring the amount of distilled water. In the case of continuous dripping, the amount of water added and distillate In the case of intermittent addition, where it is desirable to add dropwise so that the amount is almost the same amount, the amount of water added to the reaction mixture by one addition calorie should not exceed 10% by mass of the total reaction mixture The power to do S is desirable. More preferably, it should be added in a range not exceeding 5% by mass, and most preferably not exceeding 3% by mass. By quickly reducing the water content in the reaction mixture to 10% by mass or less, the reaction temperature rises, the reaction proceeds sufficiently, and high-yield production becomes possible.

The amount of the lower alkanethiol alkali metal salt aqueous solution added is preferably 0.;! To 4 times the amount of the lower alkanethiol alkali metal salt as a lower alkanethiol alkali metal salt with respect to 1 mol of the compound of the formula (1) which is the substrate used in the reaction. More preferably 0.5 to 3 times the amount is used, still more preferably 0.7 to 2 times the amount.

As the lower alkanethiol alkali metal salt aqueous solution to be added, a commercially available product can be used as it is, or an aqueous solution of the corresponding alkali metal hydroxide, alkanethiol, and other components prepared separately can be used. The concentration of the lower alkanethiol alkali metal salt contained in the aqueous solution can be used in the range of 1% by mass to 80% by mass. Usually, the concentration is in the range of 5% by mass to 50% by mass.

The production method of the present invention is represented by the above formula (3), formula (4), or formula (5) where the alkyl group part is the same as the lower alkanethiol alkali metal salt used, if necessary. It includes a second reaction step in which the alkylthio group-substituted benzene derivative represented by the formula (6) is obtained by adding and alkylating an alkylating agent.

When the reaction between the compound represented by formula (1) and the lower alkanethiol alkali metal salt is completed, depending on the excess amount of the alkanethiol alkali metal salt used and the reaction temperature, the alkylthiol introduced as a side reaction may be used. In some cases, a thiol derivative in which a part of the group is dealkylated is produced, but even in this case, as shown in the second reaction step, the thiol derivative by-produced by adding an alkylating agent is It can be easily converted into an alkylthio group-substituted benzene derivative represented by the formula (I), and the target product can be obtained in high yield.

The alkylating agent is added in a molar ratio of 0.1 to 5.0 times, preferably 0.3 to 1.5 times with respect to 1 mol of the compound represented by the formula (1) as a substrate. The alkylating agent may be any of the compounds represented by formula (3), formula (4), or formula (5), but is preferably an alkylnolide power that is a compound of formula (3). Desirable in terms of ease and economy.

The reaction temperature of the alkylation with the alkylating agent is preferably a force at which a temperature from 0 ° C to 200 ° C can be used, more preferably from room temperature to 100 ° C.

[0023] After completion of the reaction, the organic phase is separated by a method such as distilling off the solvent under reduced pressure as necessary, adding water to the residue for liquid separation, or adding an organic solvent for extraction. Further, if necessary, purification using means such as distillation, recrystallization, column chromatography and the like can provide a high-purity alkylthio group-substituted benzene derivative in a high yield. Example

Hereinafter, the present invention will be described in detail based on examples, but the present invention is not limited to the following examples.

[Example 1] 4 Production of chlorothioanisole

Charge a 4-liter flask with 1,4 dichlorobenzene 147. Og (l.0 monole), 1,3 dimethyl-2-imidazolidinone 640 g, and xylene 210 g. Warmed to 130 ° C. Next, 64 g of 15% -methanethiol sodium salt aqueous solution was added all at once, and refluxing started by azeotropy. Dean—Stark apparatus was used to remove 135% of water, while maintaining the temperature at 135 ° -145 ° C. A force of dropping a total of 11 Og of 15% aqueous solution of sodium methanethiol over 1 hour. Almost the same amount of water distilled. After confirming that about 80 g of water was distilled in 1 hour, the dropping was continued in the same manner while checking the amount of distillation. A total of 561 g (l. 2 mol) of 15% aqueous methanethiol sodium salt solution was added dropwise over 7 hours, and after completion of the addition, the mixture was aged at the same temperature for 1 hour (the water content in the reaction mixture was substantially less than 5% by mass). there were). Finally, 467g of water distills. Next, after cooling to room temperature, 30.2 g (0.6 mol) of chloromethane was blown at 25-35 ° C and stirred for 1 hour at the same temperature. The dealkylated product disappeared by gas chromatography. The reaction was completed after confirming that the title compound was obtained. The reaction solution was transferred to a 2 L eggplant flask and concentrated under reduced pressure using a rotary evaporator.

900 g of water and 520 g of xylene were added to the residue and extracted at room temperature. The aqueous phase is separated and removed. The organic phase was washed twice with 600 g of water. The solvent was removed by a rotary evaporator to obtain 175.3 g of a concentrated product. Distillation and purification under reduced pressure yielded the highly pure title compound.

Yield 139 · 5g Yield 88 · 0% (1.4-dichlorobenzene level)

(1) Boiling point 114-116 ° C / 2400Pa (18torr)

(2) — NMR spectrum (δ in CDC1) 7. 25, 6. 92 (dd, 4H), 2. 36 (s, 3H)

Three

[Example 2] Production of 2-chloro-6-methylthiotoluene

A 2 L 4-neck flask was charged with 2,6-diclonal orifice 161. Og (l. 0 monole), 1,3-dimethyl 2-640 imidazolidinone, and 160 g of toluene. Heated to an internal temperature of 130 ° C with a heater. Next, 35 g of 20% sodium methanethiol salt solution was added all at once, and refluxing began by azeotropy. While removing the distilled water using a Dean-Stark apparatus, dropwise addition of a 20% -methanethiol sodium salt aqueous solution was continued so as to maintain 125-135 ° C. A force S in which a total amount of 120 g was dripped over 1 hour, and at the same time as dripping, approximately the same amount of water was distilled. After confirming that 79 g of water was distilled in 1 hour, the dropping was continued in the same manner while checking the amount of distillation. A total of 527 g (l.5 mol) of 20% -methanethiol sodium salt aqueous solution was added dropwise over 7 hours, and after completion of the addition, the mixture was aged at the same temperature for 1 hour (the water content in the reaction mixture was substantially 3% by mass). Below). The total amount of distilled water was 414g. Next, after cooling to room temperature, 40.0 g (0.8 mol) of chloromethane was blown at 25-35 ° C, stirred at the same temperature for 1 hour, and the demethylated product disappeared by gas chromatography. The reaction was completed after confirming that the title compound was obtained. The reaction solution was transferred to a 2 L eggplant flask and concentrated under reduced pressure using a rotary evaporator.

900 g of water and 500 g of toluene were added to the residue, and the mixture was extracted at room temperature. The aqueous phase was separated and the organic phase was washed twice with 600 g of water. The solvent was distilled off with a rotary evaporator to obtain 166.7 g of a concentrated product. Distillation and purification under reduced pressure yielded the highly pure title compound.

Yield 144.5 g Yield 83.7% (2.6 — Dichlorodiethyl toluene level)

(1) Boiling point 100-101. C / 800Pa (6torr)

(Z ^ H—NMR spectrum (δ in CDC1) 7. 20— 6. 92 (m, 3H) 2. 40 (s, 3H)

Three

2.32 (s, 3H)

[Example 3] ¾ of 2-chloro-6-methylthiotoluene A 2 L 4-neck flask was charged with 161 g (1.0 mol) of 2,6-dichlorotoluene, 640 g of N-methylpyrrolidinone, and 80 g of toluene.

Warmed to 30 ° C. Next, 120 g of 20% -methanethiol sodium salt aqueous solution was added all at once, and it was confirmed that refluxing started by azeotropy by continuing heating. Heating was continued to maintain 115-135 ° C while removing the distilled water using the Dean-Stark apparatus. After that, when the water distills to some extent, about 50g was added intermittently every 30 minutes.

. When the amount of water distilled every 30 minutes was confirmed, it was about 40 g. Thereafter, the intermittent addition was continued while confirming the amount of distillate. 20% —Methanethiol sodium salt aqueous solution total 6

31 g (l. 8 mol) was added over 7 hours, and after completion of addition, the mixture was aged at the same temperature for 1 hour (the water content in the reaction mixture was substantially 10% by mass or less). The total amount of distilled water is 4

It was 70 g. Next, after cooling to room temperature, add 40.0 g (0.8 monole) of chloromethane to 25

The mixture was blown at 0 ° C., stirred at the same temperature for 1 hour, and the reaction was completed after confirming that the demethylated product had disappeared by gas chromatography and that all were the title compound. The reaction solution was transferred to a 2 L eggplant flask and concentrated under reduced pressure using a rotary evaporator.

To the residue were added 980 g of water and 540 g of toluene, and the mixture was extracted at room temperature. The aqueous phase was separated and the organic phase was washed twice with 600 g of water. The solvent was removed by a rotary evaporator to obtain 186. lg of a concentrate. Distillation and purification under reduced pressure yielded the highly pure title compound.

Yield 121. 3e Yield 70. 3% (2.6-dichlorotoluene level)

(1) Boiling point 100-101. C / 800Pa (6torr)

(Z ^ H—NMR spectrum (δ in CDC1) 7. 20— 6. 92 (m, 3H), 2. 40 (s, 3H)

Three

2.32 (s, 3H)

[Example 4] Production of 3-methoxythioadisol

A 2L 4-neck flask was charged with 71 · 3g (0.5 mol) of 3-chloroanisole, 300g of hexamethylphosphoric triamide, and 70g of toluene, and heated to a temperature of 130 ° C with a mantle heater in a nitrogen atmosphere. did. Next, when 15% -methanethiol sodium salt aqueous solution was slowly dropped, refluxing started by azeotropy. The dripping was continued to maintain 125-135 ° C while removing the water distilled by the Dean-Stark apparatus. When about 80 g was dropped over 1 hour, 60 g of water was distilled off, and thereafter dropping was continued while confirming the amount of distillation. 15% A total of 327 g (0.7 mol) of tanthiol sodium salt aqueous solution was added dropwise over 6 hours, and after completion of the addition, the mixture was aged at the same temperature for 1 hour (the water content in the reaction mixture was substantially 3% by mass or less) . After allowing to cool to 30 ° C, 20.0 g (0.4 mol) of chloromethane was blown at 30–45 ° C, stirred at the same temperature for 1 hour, and the demethylated product disappeared by gas chromatography. The reaction was completed after confirming that all were the title compounds. After adding 600 g of water and 200 g of toluene to the reaction solution, shaking with a separatory funnel, the aqueous phase was separated and removed, and the organic phase was further washed twice with 300 g of water. Concentration under reduced pressure using a rotary evaporator gave 80.6 g of concentrate. Distillation and purification under reduced pressure yielded the highly pure title compound.

Yield 66.4 g Yield 78. 3% (3 Chloroanisole standard)

(1) Boiling point 121-123 ° C / 2130Pa (16torr)

(2 ^ 1— NMR spectrum (δ in CDC1) 7. 20— 6. 52 (m, 4H), 3. 66 (s, 3H)

Three

2.35 (s, 3H)

[Example 5] Production of 3-chlorothioanisole

Charge a 4-liter flask with 1,3-dichloro-benzene 147 · Og (1.0 monole), 1,3-dimethyl 2, imidazolidinone 640 g, and toluene 320 g in a nitrogen heater with a mantle heater. The internal temperature was heated to 120 ° C. Next, 110 g of a 10% sodium methanethiol salt solution was added over 5 minutes, and refluxing began by azeotropy. Except for the water distilled by the Dean-Stark apparatus, after confirming that 98 g of water was distilled, the same amount as the water added 1 hour later, 110 g of 10% -methanethiol sodium salt aqueous solution was continuously added. The water distilled by azeotropy was removed. The reaction temperature was maintained at 110 ° C. to 135 ° C., and thereafter the distillation amount was confirmed in the same manner and the operation was repeated. A total of 981 g (l.4 mol) of 10% -methanethiol sodium salt aqueous solution was added over 9 hours. After completion of the dropwise addition, the mixture was aged at the same temperature for 1 hour (the water content in the mixture was substantially 8% by mass or less). Finally, 840 g of water was distilled. Next, after cooling to room temperature, 40.0 g (0.8 mol) of chloromethane was blown at 25 35 ° C, stirred for 1 hour at the same temperature, and the dealkylated product disappeared by gas chromatography. It was confirmed that the reaction was completed. After distilling off the solvent by distillation under reduced pressure, 900 g of water and 520 g of toluene were added to the residue, followed by extraction at room temperature. The aqueous phase was separated and the organic phase was washed twice with 600 g of water. Rotary evaporation The solvent was distilled off with one ter to obtain 175.3 g of a concentrate. When purified by distillation under reduced pressure, the highly pure title compound was obtained.

Yield 134 · 8g Yield 85 · 0% (1.3-dichlorobenzene level)

(1) Boiling point 108-110 ° C / 2400Pa (18torr)

(Z ^ H— NMR spectrum (δ in CDC1)

3, 7. 22— 6. 90 (m, 4H), 2. 42 (s, 3H

)

[Example 6] Production of 2-chlorothioanisole

A 1L 4-neck flask is charged with 73.5 g (0.5 mol) of 1,2-dichlorobenzene, 320 g of N-methyl-2-pyrrolidinone, and 80 g of benzene, and the internal temperature is 110 ° C with a mantle heater in a nitrogen atmosphere. Until warmed. Next, when 18 g of a 15% -methanethiol sodium salt aqueous solution was added dropwise, refluxing started by azeotropy. The dropping was continued to maintain 110-120 ° C with the power of removing water from the Dean-Stark apparatus. When 18 g of 15% -methanethiol sodium salt aqueous solution was dropped, a part of the reaction solution was taken out and the moisture was measured with a Karl Fischer moisture measuring device, which was about 1.1%. Subsequently, 90 g of 15% -methanethiol sodium salt aqueous solution was added dropwise over 1 hour, and at the same time as dripping, approximately the same amount of water was distilled off. After confirming that 68 g of water was distilled in 1 hour, the dropping was continued in the same manner while checking the amount of distillation. A total of 374 g (0.8 mol) of 15% -methanethiol sodium salt aqueous solution was added dropwise over 6 hours. there were). Finally, 304 g of water was distilled. Next, after cooling to room temperature, 10.0 g (0.2 mol) of chloromethane was blown at 25-35 ° C, stirred at the same temperature for 1 hour, and the dealkylated product disappeared by gas chromatography. The reaction was completed after confirming that all were the title compounds. The reaction solution was transferred to a 2 L volume of Nasflasco and concentrated under reduced pressure using a rotary evaporator.

To the residue were added 500 g of water and 250 g of benzene, and the mixture was extracted at room temperature. The aqueous phase was separated and the organic phase was washed twice with 300 g of water. The solvent was distilled off using a rotary evaporator to obtain 88. lg of a concentrate. Distillation and purification under reduced pressure yielded the highly pure title compound.

Yield 67.2g Yield 84.7% (1.2-dichlorobenzene level)

(1) Boiling point 119—121 ° C / 2400Pa (18torr) (2) — NMR spectrum (δ in CDCl) 7. 31, 6. 92 (m, 4H), 2. 46 (s, 3H)

Three

[Examples 7 to 12] The raw material was a halogenated benzene derivative shown in Table 1, and in Example 8, a 20% -ethanethiol potassium salt aqueous solution was used instead of 15% -methanethiol sodium salt, and The reaction was carried out in the same manner as in Example 4 except that odoethane was added dropwise instead of blowing methane to obtain the corresponding alkylthio group-substituted benzene derivative. The results are shown in Table 1. The yield was calculated based on the halogenated benzene derivative as a raw material.

[0031] [Table 1]

0036 is ^ i $ 22s

2,6—Dichlorotonolene 32.2g (0.2 monole), 1,3—Dimethylolene 2—Imidazo, Lydinone 120g, 30 ^ο / _ο — Methanic acid-nore sodium salt in water 24 mol) was heated with a mantle heater under a nitrogen atmosphere, and the internal temperature was maintained at the reflux temperature of 101 ° C (the amount of water with respect to the reaction mixture was about 20% by mass). After 8 hours, it was confirmed by gas chromatography that there was almost no decrease in raw materials, and the reaction was completed. Next, after cooling to room temperature, 5 g (0.1 mol) of chloromethane was blown at 25-35 ° C and stirred at the same temperature for 1 hour. The dealkylated product disappeared by gas chromatography, and all the title compounds It was confirmed that the reaction was completed. 300 g of water and 150 g of toluene were added to the reaction solution, and the mixture was extracted at room temperature. The aqueous phase was separated and the organic phase was washed twice with 100 g of water. The solvent was distilled off by a rotary evaporator to obtain 43.2 g of a concentrate. The content of the title compound was analyzed by gas chromatography and found to be 9.9 g (yield 28.9%, based on 2,6-dichloromouth toluene).

[0033] Reference Production Example 2 Production of 2-chloro-6-methylthiotoluene

Charge a 2L 4-neck flask with 2,6-diclonal orifice 161.0 g (1.0 mono), 1,3-dimethyl 2-imidazolidinenone 640 g and toluene 320 g with a mantle heater in a nitrogen atmosphere. Heated to 115 ° C.

Next, 200 g of a 20% -methanethiol sodium salt aqueous solution was added over 10 minutes, and the mixture was heated and refluxed by azeotropy. Heating was continued to maintain 93-120 ° C while removing the water distilled by the Dean-Stark apparatus. After confirming that about 20 g of water had distilled off, about 25 g of 20% -methanethiol sodium salt aqueous solution was added. In the same manner, while confirming the amount of water distilled, the addition was continued so that the amount of water in the reaction mixture was maintained at 10 to 20% by mass, and 490 g (1.4 mol) of 20% -methanethiol sodium salt over 6 hours. The aqueous solution was intermittently added, and the reaction was terminated by heating for 1 hour after addition of the entire amount.

Subsequently, the same operation as in Example 2 was performed to obtain 190 g of a concentrate. When the content of the title compound was analyzed by gas chromatography, it was 65.4 g (yield 37.9%, based on 2,6-dichloronitrone).

[0034] Reference Production Example 3 Production of 2-chloro-6-methylthiotoluene

2, 6-Dichlorophlegm Nolen 161 · 0g (1 .0 monole), 1, 3——Dimethyl in a 2L 4-neck flask Lou 2—imidazolidinone 320 g and toluene 420 g were charged and heated to 115 ° C. with a mantle heater in a nitrogen atmosphere. Next, 20% -methanethiol sodium salt aqueous solution 2 Og was slowly added dropwise, and refluxing started by azeotropy. The dropping was continued to maintain 93-120 ° C while removing the water distilled by the Dean-Stark apparatus. When about 80 g was dropped over 1 hour, about 55 g of water was distilled. In the same manner, the dropwise addition was continued, and a total amount of 490 g (1.4 mol) was added dropwise over 5.5 hours, followed by heating for an additional hour to complete the reaction (the water content in the reaction mixture was substantially 3% or less). )

Subsequently, the same operation as in Example 2 was performed to obtain 172 g of a concentrate. When the content of the title compound was analyzed by gas chromatography, it was 65 g (yield 37.5%, 2,6-dichroic toluene based on toluene).

Claims

The scope of the claims

The following general formula (1)

[Chemical 3]

(Wherein R, R, R, R and R are the same or different hydrogen atoms;

1 2 3 4 5

A halogenated benzene derivative represented by

The following general formula (2)

R SM (2)

6

. )

Is reacted with an alkali metal salt of a lower alkanethiol represented by the following general formula (6):

(Wherein R, R, R, R, R and R are as defined above)

1 2 3 4 5 6

A process for producing an alkylthio group-substituted benzene derivative represented by: An aqueous solution of the lower alkanethiol alkali metal salt is added to a mixed solution of the halogenated benzene derivative, the reaction solvent, and the azeotropic solvent which may be the same as the halogenated benzene derivative represented by the formula (1). However, the reaction is carried out by distilling the mixture of water and the azeotropic solvent by distillation and continuously removing the water present in the system so that the water content in the reaction mixture is 10% by mass or less. A method for producing an alkylthio group-substituted benzene derivative comprising a step.

[2] After the reaction step, the following general formula (3)

R Y (3)

6

(Y represents a halogen atom)

The following general formula (4)

(R O) SO (4)

6 2 2

An alkyl sulfate represented by

The following general formula (5)

(R O) CO (5)

6 2

The method for producing an alkylthio group-substituted benzene derivative according to claim 1, further comprising a second reaction step of adding an alkyl carbonate represented by the formula:

[3] The method for producing an alkylthio group-substituted benzene derivative according to [1] or [2], wherein the reaction solvent is an aprotic polar solvent.

[4] The aprotic polar solvent is 1, 3 dimethyl-2-imidazolidinone, N methyl 2 pyrrolidinone, hexamethylphosphoric triamide, N, N dimethylformamide, N, N dimethylacetamide, dimethyl sulfoxide, Phosphorane, pyridine, quinoline, linear or branched alkyl group having 1 to 6 carbon atoms;!-To 5-substituted pyridine, and linear or branched alkyl group having 1 to 6 carbon atoms The method for producing an alkylthio group-substituted benzene derivative according to claim 3, which is one or more solvents selected from the group consisting of quinoline substituted by!

[5] The azeotropic solvent is benzene; a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkoxy group having 1 to 6 carbon atoms, and a trifluoromethyl group. Benzene substituted with 1 to 3 substituents selected from the group consisting of force; 5 to 5 carbon atoms; A linear, branched or cyclic aliphatic alkane; and a linear, branched or cyclic ether having 5 to 15 carbon atoms; and a halogenated benzene derivative represented by the general formula (1) The method for producing an alkylthio group-substituted benzene derivative according to any one of claims 1 to 5 and claim 4, wherein the solvent is one or more solvents selected from the group consisting of:

The alkylthio group-substituted benzene according to any one of claims 1 to 5, wherein a mass ratio at the start of the reaction between the reaction solvent and the azeotropic solvent is 200:;! To 1: 1. A method for producing a derivative.