WO2002066423A1 - Process for preparation of polyfluoroalkylsulfenyl compounds - Google Patents

Abstract

The invention aims at providing a process for preparation of polyfluoroalkylsulfenyl compounds by polyfluoroalkylation of a disulfide with a polyfluoroalkyl halide in the presence of an industrially easy-to-use assistant and a process for synthesis of benzyl difluoromethyl sulfide in a high yield by using an industrially easy-to-use solvent. Specifically, a process for preparation of polyfluoro- alkylsulfenyl compounds, characterized by reacting a disulfide with both at least one member selected from among hydrazine and metal borohydrides and a polyfluoroalkyl halide.

Description

 Description Method for producing polyfluoroalkylsulfenyl compounds <Technical field>

 The present invention relates to a method for producing a polyfluoroalkylsulfenyl derivative useful as a medicinal and agricultural chemical. Benzyl useful as a precursor of difluoromethinolesulfenyl chloride used for producing a difluoromethylsulfenyl derivative The present invention relates to a method for producing (difluoromethyl) sulfide, and a 1-arylu 3-cyano 4-trifluoromethylsulfenylvirazole derivative particularly useful as an agricultural or veterinary drug.

<Background technology>

In recent years, compounds having a polyfluoroalkylsulfenyl group, especially a trifluoromethylsulfenyl group (CF ₃ S) and a difluoromethylsulfenyl group (CF ₂ HS) have specific biological activities Attention has been paid to this. In particular, a bisazole derivative having a trifluoromethylsulfenyl group or a pyrazole derivative having a difluoromethylphenyl group (JP-A-62-228065, JP-A-63-316771, JP-A-63-316771, JP-A-3-118369 and JP-A-10-338676) are useful as insecticides and are effective methods for introducing polyfluoroalkylsulfenyl groups, especially trifluoromethylsulfuryl groups and dimethyl groups. There is a need for a method for introducing a fluoromethylphenyl group.

As a method for directly introducing a polyfluoroalkylsulfenyl group, for example, a trifluoromethylsulfuryl group, a method using trifluoromethylsulfuryl chloride (Japanese Patent No. 2669538) is known. However, trimethylsulfur chloride used as a raw material has toxicity and is difficult to industrialize. In addition, a nucleophilic substitution reaction with copper trifluoromethylsulfenyl (Synthesis, 1975, 721) and a nucleophilic substitution reaction with thiophosgene / potassium fluoride (J. Fluorine. Chem., 1997, 169) is known, but there is a problem that it is difficult to industrially produce the reaction reagent.

 Generally, sulfides can also be prepared by nucleophilic substitution of thiols with alkyl halides. However, this nucleophilic substitution reaction is difficult to proceed, and particularly in the case of perfluorinated alkyl halides required for producing a trifluoromethylsulfenyl derivative, various activations are required, which complicates the work. Or toxic substances are used for activation. In addition, thiol is liable to be converted to disulfide by air oxidation, which may cause difficulty in industrial handling, and also has a problem of odor. Therefore, it is difficult to industrially produce a trifluoromethylsulfur derivative by this method.

 When thiol is used as a raw material, the number of steps is increased since thiol is generally produced by reducing an intermediate such as thiocyanatodisulfide. There is also known a method of polyfluoroalkylating a thiosiano group to introduce a polyfluoroalkylsulfenyl group. For example, a method is known in which trifluoromethyltrimethyl / resilane is allowed to act on a thiocyanate compound (Tetrahedron Lett., 1997, 65), but trifluoromethyltrimethylsilane used as a raw material is expensive. It is difficult to industrially produce a trifluoromethylsulfenyl derivative by the method.

 The method for producing a trifluoromethylsulfenyl derivative using disulfide as a raw material is effective in view of the ease of producing the raw material.

 For example, Patent No. 2,746,707 discloses that an excess amount of sodium formate and an excess amount of sulfur dioxide are used to react disulfide with trifluoromethyl halide to obtain the corresponding trifluoromethyl sulfone. A method for producing a fermented body is described. However, sulfur dioxide is irritating and has a negative impact on the environment, which is problematic for industrial use.

In addition, there is no example in Japanese Patent No. 27466707 in which a compound other than trifluoromethyl bromide is used as the trifluoromethyl halide. Trifluoromethyl bromide has been banned from production because it destroys the ozone layer, and is a raw material that is harmful to the global environment. There is a need for a process for producing a trifluoromethylsulfur derivative that can be carried out industrially without using thiol.

 It is known that a method using difluoromethylsulfenyl chloride is effective as a method for introducing a polyfluoroanolekylsulfenyl group, for example, a diphnoleolomethinolesnorephenyl group. I have. G 丄 Moore, J. Org. Chem., 1979, Vol. 44, p. 1708 states that difluoromethylsulfuryl chloride can be synthesized from benzinole (difluoromethyl) sulfide and benzyl (difluoromethyl) sulfide. It is described that can be synthesized by reacting a salt of benzyl mercaptan with difluoromethane in the presence of a specific solvent and sodium hydroxide. The document states that the yield is excellent when N, N-dimethylformamide (hereinafter abbreviated as “DMF”) is used as a reaction solvent when synthesizing benzyl (difluoromethyl) sulfide. ing. However, DMF is known to irritate the skin, eyes, and mucous membranes and cause liver damage by prolonged inhalation.In order to carry out the reaction industrially, it is necessary to substitute a solvent that is easy to handle. It has been demanded. Further, further improvement in yield is required.

 The present invention relates to a polyfluoroalkylsulfuric acid compound obtained by conducting a polyfluoroalkylation reaction with a halogenated polyfluoroalkyl in the presence of a disulfide as a raw material in the presence of an industrially easy-to-use auxiliary agent. And a method for synthesizing benzyl (difluoromethyl) sulfide in a high yield by using a commercially available solvent.

<Disclosure of Invention>

 As a result of the study by the present inventors, it was found that in the reaction between disulfide and halogenated polyfluoroalkyl, the desired polyfluoroalkylsulfenyl compound can be obtained by performing the reaction in the presence of hydrazine or metal borohydride. And completed the first invention.

In addition, in the reaction of benzyl mercaptan or a salt thereof with chlorodifluoromethane, the desired solvent can be obtained by using a mixed solvent of alcohol and water as a reaction solvent. It was found that benzyl (difluoromethyl) sulfide was obtained in good yield.

Completed the second invention.

 That is, a first gist of the present invention is a method for obtaining a polyfluoroalkylsulfenyl compound by reacting disulfide with one or more selected from hydrazine and metal borohydride and a polyfluoroalkyl halide. Exists.

 A second gist of the present invention is to provide a method for producing benzyl (difluoromethyl) sulfide by reacting benzyl mercaptan or a salt thereof with chlorodifluoromethane in the presence of a solvent and a base, wherein a mixed solvent of alcohol and water is used as a solvent. A method for producing benzyl (difluoromethyl) sulfide, which is characterized in that it is used. BEST MODE FOR CARRYING OUT THE INVENTION>

 Hereinafter, the present invention will be described in detail.

 First, the first invention will be described.

The disulfide used in the first invention is represented by the general formula (1). R ⁿ -S-S-R ¹² (1)

R ¹¹ and R ¹² each independently represent a group bonded to a sulfur atom at a carbon atom, and may be bonded to each other to form a ring. Examples of the group bonded to a sulfur atom at a carbon atom include an alkyl group, an aryl group, and a heteroaryl group. These groups may further have a substituent. As R ¹¹ and R ¹² , specifically, dimethinoresin sulfide, getyl disulfide, g-n-propinoresin sulfide, diisopropyl disulfide, g-n-butyl disulfide, — Sec-Petinoresinolefide, diisobutyl / resinose-renofide, g-tert-ptynoresinose-renofide, di-n-amyl disulfide, diisoamyl-disulfide, g-tert-amino-resin-norfide, G-n-heptino Resin-norebuide, di-tert-octinore di-no-sulfide, di-n-decino-resin-no-resulfide, g-tert-dodecyl-disulphide, aryl-disulfide, 2-hydroxyshetyl disulfide, cystamine, de, dicyclohexino Regis Nolefide, Zichoglyco Acid, dithiodipropionic acid, cystine, L-cystine, D-cystine, homocystin, L-homocystin, D-homocystin, penicillamine disosulfide, 4,4, dithiobutanoic acid, thioctic acid, benzyldis / Refido, dihuyeurdisunolide,, —: trinoresulfuride, 2,2'-dithionaphthalene, 412-trofujyldisulfide, 2,2,1-dithiobenzoic acid, 2,2, dithioadi Phosphorus, 2,2'-dithioviridine, 4,4'-dithiopyridine, 6,6,1-dithionicotinic acid, 1,2-dithiane, trans-l, 2-dithiane-1,4,5-diol, diphnorefuryldishu And 2,2,1-dithiobis (benzothiazo ^ /).

The disulfide is preferably a disulfide which is a heterocyclic ring in which at least one of R ¹¹ and R ¹² in the general formula (1) may be substituted. Examples of the heterocyclic ring include pyrazole, pyrrole, imidazole, pyridine, thiophene, and furan. The disulfide is more preferably di (birazolyl) disulfide having a substituent. Pyrazol derivatives having a trifluoromethylsnorrefenyl group obtained from di (birazolyl) disnorefedica having a substituent are useful as agricultural and veterinary drugs. As the disulfide, a compound represented by the general formula (2) or the general formula (3) is particularly preferable.

R ¹ represents a hydrogen atom, a C ¹ -C 4 alkyl group or a C 2 -C 5 acyl group, and _c R ¹ specifically represents a hydrogen atom; a methyl group, an ethyl group, an n-propyl group, C such as isopropyl, n-butyl, isopropyl, sec-butyl, t-butyl, etc. A straight-chain or branched-chain alkyl group of 1 to 4 carbon atoms; or a methylcarbonyl group, an ethylcarbonyl group, an n-propylcarbonyl group, an isopropylcarbonyl group, an n-butylcarboninole group, an isobutylcarbonyl group, a sec-butylcarbonyl group, t represents a C1-C4 linear or branched chain acyl group such as a monobutylcarbonyl group.

R ² represents a hydrogen atom, a hydroxyl group or an alkyl group of C 1 through C 4. R ² is, specifically, a hydrogen atom; a hydroxyl group; or a direct group such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, and a t-butyl group. It represents a chain or branched alkyl group, preferably a hydrogen atom.

R ³ is a hydrogen atom, a hydroxyl group, an alkyl group of C 1 through C 4, a haloalkyl group of C 1 through C 4, C 1 alkoxy group ~ C 4, optionally substituted phenoxy group, a C 1 through C 4 Haloalkoxy group, C 1 -C 4 alkylsulfenyl group, C 1 -C 4 alkylsulfininole group, C 1 -C 4 anolequinolenes olefoninole group, optionally substituted aryl Group or a heteroaryl group. R ³ is preferably an optionally substituted aryl group or a heteroaryl group, and particularly preferably an optionally substituted aryl group or a heteroaryl group represented by the following formula.

R ⁴ is an alkyl group of C 1 through C 4, a haloalkyl group of C 1 through C 4, alkoxy group of C 1 through C 4, optionally substituted phenoxy group, Haroarukoki of C 1 through C 4 And a C 1 -C 4 alkylsulfenyl group, a C 1 -C 4 alkylsulfenyl group, a C 1 -C 4 alkylsulfonyl group, a halogen atom, a nitro group or a cyano group.

 m represents 0, 1 or 2.

 X represents a carbon atom substituted with a nitrogen atom or a halogen atom, preferably a carbon atom substituted with a halogen atom, particularly preferably a carbon atom substituted with a chlorine atom.

 n represents 0, 1 or 2, and preferably represents 1.

 Among the above combinations of substituents, a preferred compound is bis (1-1 (2,6-dichloro-1-41-trifnoroleolomethinolefeninole) _3-canolepo-trinole-1.5_ (pyrazin-12-ylmethylamino) ) Pyrazole (41-yl) is a single disulfide.

X represents a carbon atom substituted with a nitrogen atom or a halogen atom, preferably a carbon atom substituted with a halogen atom, particularly preferably a carbon atom substituted with a chlorine atom.

These disulfides as possible out be synthesized by such a condensation reaction, a condensation reaction with sulfur monochloride, the oxidation reaction of mercaptans with disodium disulfinate de (N a ₂ S _2).

 The polyfluoroalkyl halide used in the first invention is represented by the general formula (4).

R ^{2 1} — X ² (4) X ² represents a chlorine atom, a bromine atom or an iodine atom, preferably a bromine atom or an iodine atom, more preferably an iodine atom.

R ^{2 1} represents a polyfurfuryl O b alkyl group. A polyfluoroalkyl group is an alkyl group substituted by one or more fluorine atoms. The carbon number of the alkyl group of the polyfluoroalkyl group is preferably 1 to 20, more preferably 1 to 10, and particularly preferably 1. R ^{2 1} may have a substituent other than a fluorine atom, as a substituent other than full Tsu atom, preferably a halogen atom other than fluorine, a substituent having a SansoHara child, having a nitrogen atom Substituents and the like are exemplified, and particularly preferably, a halogen atom other than fluorine is exemplified.

R ^{2 1} is preferably all of the hydrogen atoms are halogen atom (however, the full Tsu atom containing 1 or more) perhaloalkyl group substituted with halogen is part of the hydrogen atoms on the alkyl group on the alkyl group And a polyhaloalkyl group substituted with an atom (including one or more fluorine atoms). More preferably, a perfluoroalkyl group in which all hydrogen atoms on the alkyl group are substituted with fluorine atoms, alkyl Examples thereof include a polyfluoroalkyl group in which a part of hydrogen atoms on the group is substituted with a fluorine atom, and particularly preferably a perfluoroalkyl group.

Specific examples of perfluoroalkyl halides include trifluoromethyl chloride, trifluoromethyl bromide, trifluoromethyl iodide, pentafluoroethyl chloride, pentafluoroethyl bromide, Pentaphthalenoyl iodide, heptafluoropropyl chloride, heptafluoropropyl bromide, heptafluoropropyl iodide, heptafluoropropyl iodide, nonafluorobutyl chloride, nonafluorobutyl bromide, nonafluorobutyl iodide Robutyl, perphnoleo chloride pentinole, perphnoleo bromide pentinole, perphnolelopentyl iodide, perfluoro chloride hexyl, perfluoro bromide hexyl, perfluoro iodide hexyl, perfluoro chloride heptyl, perfluoro bromide / Leno mouth hepatic oleo, iodide perfluorinated heptyl, perfluoro octyl chloride, odor Perfluorooctyl iodide, perfluorooctyl iodide, perfluoronyl chloride, perfluorononyl bromide, perfluorononyl bromide, perfluorononyl bromide, perfluorododecyl chloride, perfluorododecyl bromide, perfluorinated dodecyl bromide Perfluorododecyl chloride and the like. Preferably trichloride Halogenated trifluoromethyls such as trifluoromethyl, trifluoromethyl bromide, and iowidani trifluoromethyl are used, more preferably trifluoromethyl bromide and trifluoromethyl bromide, and particularly preferably trifluoromethyl bromide. Trifluoromethyl iodide is used.

 The amount of the polyfluoroalkyl nodogen used is usually at least 2 mol equivalent to disulfide (that is, at least 1 mol equivalent to zeo atom), and usually at most 20 mol equivalent, preferably 8 mol equivalent. Less than the equivalent (that is, less than 4 molar equivalents relative to the iodine atom). Unreacted polyfluoroalkyl halide can be recovered by methods such as volatile separation, distillation, and extraction.

 The first invention is characterized in that the reaction between the disulfide and the polyfluoroalkyl halide is carried out in the presence of hydrazine or metal borohydride. When the reaction between the disulfide and the halogenated polyfluoroalkyl is carried out in the presence of hydrazine, anhydrous hydrazine and hydrazine hydrate can be used as the hydrazine, but hydrazine hydrate is preferred for safety. Is used. The amount of hydrazine to be added is generally at least 0.5 molar equivalent, preferably at least 1.5 molar equivalent, and usually at most 10 molar equivalent, preferably at most 4 molar equivalent, based on disulfide. In the case of hydrazine, there is an advantage that it is not necessary to use an electron transfer catalyst together.

 The reaction between disulfide and polyfluoroalkyl halide, which is carried out in the presence of hydrazine, can be carried out in the absence of a base, but is preferably carried out in the presence of a base. Examples of the base include organic bases such as triethylamine, trimethylamine, and pyridine; and inorganic bases such as potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, sodium hydroxide, and dipotassium hydrogen phosphate. Is an inorganic base, more preferably potassium carbonate. The amount of the base is usually at least 1 molar equivalent, preferably at least 2 molar equivalents, and usually at most 10 molar equivalents, preferably at most 3 molar equivalents, based on disulfide.

Furthermore, in this case, hydrazine is considered to have the function of generating a polyfluoroalkyl anion radical by one-electron reduction of the halogenated polyfluoroalkyl, and further generating a polyfluoroalkyl radical by cleavage. Can be So The resulting polyfluoroalkyl radical acts on the disulfide to form a polyfluorosulfur compound.

 In the first invention, when the reaction between the disulfide and the halogenated polyfluoroalkyl is carried out in the coexistence of a metal borohydride, the metal borohydride may be lithium borohydride, sodium borohydride, or potassium borohydride. Alkali earth metal borohydride, such as calcium borohydride, magnesium borohydride, etc.Typical metal borohydride, such as zinc borohydride, zinc borohydride, lithium cyano borohydride Examples thereof include silane and sodium borohydride such as sodium borohydride, and preferably include alkali metal borohydride, and more preferably sodium borohydride. The amount of the metal borohydride to be used is generally at least 0.5 molar equivalent, preferably at least 1.5 molar equivalent, and usually at most 10 molar equivalent, preferably at most 4 molar equivalent, based on disulfide.

The reaction between disulfide and halogenated polyfluoroalkyl, which is carried out in the presence of a metal borohydride, is preferably carried out in the presence of a bividinium salt derivative. Examples of the biviridinium salt derivative include those known as electron-transfer catalysts described in J. Org. Chem., 1990, 55, 4127 and the like. —Dimethyl-4,4'-biviridinium dichloride (methyl viologen) and other 1,1,1-dialkyl-1,4, —biviridinium salts, 1,1,1-ethylene-1,2,2'-biviridylium Examples include biviridem salt derivatives such as 1,1 ′ dialkyl 1,2,2,1 viridylium salts such as dibromide, and more preferred are viologen dyes that are 1,1′-dimethyl 4,4,1 viridinium salts. Particularly preferred is methyl viologen. The amount of Bibirijiniumu salt derivative, with respect to disulfide, usually 0.0 to 1 mole _^0/0 or more, preferably 1 mol% or more, usually 9 9 mole _^0/0 or less, preferably 2 0 mol% or less It is. The vibidium salt is present in the aqueous layer after oil-water separation at the end of the reaction, and can be recycled.

The reaction between the disulfide and the halogenated polyfluoroalkyl, which is carried out in the presence of a metal borohydride, can be carried out in the absence of a base, but is preferably carried out in the presence of a base. Done below. Examples of the base include organic bases such as triethylamine, trimethylamine, and pyridine; and inorganic bases such as potassium carbonate, potassium hydrogencarbonate, potassium hydroxide, sodium hydroxide, and dipotassium hydrogenphosphate. Organic bases, more preferably, triethylamine are exemplified. The amount of the base is preferably a large excess with respect to the disulfide, more preferably at least 10 molar equivalents and at most 100 molar equivalents.

 The mechanism by which the reaction proceeds due to the presence of the metal borohydride is not clear, but under the reaction conditions of the present invention, the metal borohydride has the function of reducing disulfide to a thiol group. In addition, thiol groups become thiolatwaeons in the presence of a base. Thiolato anion is capable of one-electron reduction of coexisting methyl viologen.Similar to hydrazine, thiolate anion acts on halogenated polyfluoroalkyl to generate polyfluoroalkyl radical, and induces disulfide to polyfluorosulfur compound. It is presumed that you are.

 The reaction between the disulfide and the polyfluoroalkyl halide is usually carried out in the presence of a solvent. The solvent is not particularly limited, but preferably DMF, dimethylacetamide, N-methyl-12-pyrrolidone, DMI (1,3-dimethyl-12-imidazolidinone), HMPA (hexamethylphosphoramide), DMSO (Dimethyl sulfoxide), aprotic polar solvents such as sulfolane, and the like, particularly preferably polar solvents having an amide group such as DMF, dimethylacetamide, and N-methyl-1-pyrrolidone.

 The amount of the solvent used is usually at least 1 fold, preferably at least 2 fold, particularly preferably at least 5 fold, and usually at most 100 fold, preferably at most 1 fold, in terms of volume Z weight ratio to the substrate (disulfide). The range is 100 times or less, particularly preferably 20 times or less.

The reaction method is as follows: 1) a method of dissolving a halogenated polyfluoroalkyl under normal pressure, 2) a blowing method, and 3) in a reaction vessel charged with disulfide, a solvent, hydrazine or metal borohydride, and, if necessary, a base. ) A method of charging and reacting a polyfluoroalkyl halide in a closed vessel such as an autoclave. The reaction temperature is usually −20 ° C. or higher, preferably 0 ° C. or higher, and is usually selected from a range of 120 ° C. or lower and room temperature or lower. The reaction time is generally 1 hour or longer, preferably 10 hours or longer, and usually 120 hours or shorter, preferably 48 hours or shorter.

 After completion of the reaction, the product is isolated by the usual post-treatment method, ie, extraction by oil-water separation, oil-water separation or crystallization by adding water, or distillation, or used in the next step without isolation.

 According to the first invention, a polyfluorinated alkylsulfenyl compound corresponding to the disulfide used as a raw material can be obtained. According to the first invention, for example, pyrazole derivatives represented by general formulas (5) and (6) can be obtained.

(Five)

R \ R ² , R ³ , X, n are as defined in general formula (2). R ⁵ is R ^{2 1} the same meaning in the general formula (4).

—Specific examples of the compound represented by the general formula (5) include: 1,1- (2,6-dichloro-41-trifnoreo methinolefeninole) 1,4-trifleuromethinoles / refenisle- 5-(pyrazine-1 -ylmethylamino) pyrazole-3 -capillonitrile, 1-(2,6 dichloro-1 4-1tri phenolic methinolepheninole) _ 4 -diphnoreomethyl sulphenyl 5-(pyridine 1 -2-) (Methylmethylamino) pyrazole-3 carbonitrile.

X has the same meaning as in general formula (2). R ⁵ has the same meaning as R ²¹ in formula (4).

 Specific examples of the compound represented by the general formula (6) include 1- (2,6-dichloro41-triphenylone methylphenol) -14-trifluoromethylsulfenyl

-5-aminopyrazole-131-carbonitrile.

The pyrazole derivative represented by the general formulas (5) and (6) obtained by the first invention is used as a raw material, and is represented by the general formula (7) by a route such as the reaction formulas 1 and 2. Can be obtained.

Reaction formula 1

Instead of ¾

Reaction formula 2

CF ₃

In the general formula (7), RR \ R ³ , X and n have the same meanings as in the general formula (2). R ⁵ has the same meaning as R ²¹ in formula (4). p represents 1 or 2, and preferably 1. Specific examples of the compound represented by the general formula (7) include 1- (2,6-dichloro-opening—4-trifluoromethylphenyl) -14-trifluoromethylsulfiel-15-1 ( Pyrazine-1-ylmethylamino) pyrazole-13-potunitrile.

In the general formula (8), X has the same meaning as in the general formula (2). R ⁵ has the same meaning as R ^{21 in} formula (4). p represents 1 or 2, and preferably 1. Specific examples of the compound represented by the general formula (8) include 1- (2,6-dichloro-4-trifluoromethyl-phenol) -141-trifnoroleolomethinoresnorefininole-51-aminopyrazo 1-ru 3-carbonitrile.

 Examples of the method of oxidizing the sulfur atom in Reaction Formulas 1 and 2 include a chemical oxidation method using an oxidizing agent and a biochemical oxidation method using enzymes, bacteria, etc., but the chemical oxidation method is generally used. Used. In chemical oxidation, it is usually at least 0.2 molar equivalent, preferably at least 0.25 molar equivalent, and usually at most 5.0 molar equivalent, based on the compound of the general formula (5) or (6). The oxidizing agent is preferably added in an amount of 2.0 molar equivalents or less in the presence or absence of a solvent. The reaction is carried out at a temperature of 120 ° C. or less, usually for 1 hour or more, usually for 48 hours or less, preferably for 6 hours or less. Examples of the oxidizing agent used in this reaction include hydrogen peroxide, oxone, m-chloroperbenzoic acid, peracetic acid, sodium periodate, ruthenium tetroxide, ozone, t-butyl hydroperoxide, nitric acid, and the like. And preferably hydrogen peroxide. Hydrogen peroxide is usually used as a hydrogen peroxide solution, and the concentration of the hydrogen peroxide in the hydrogen peroxide solution is usually 10 weight. /. As described above, it is preferably at least 30% by weight, usually at most 70% by weight, and preferably at most 60% by weight.

As a solvent used in this reaction, an organic solvent generally used for an oxidation reaction can be used, and a hydrocarbon solvent such as toluene and hexane, and a halogenated hydrocarbon solvent such as dichloromethane and chloroform are used. . In particular, in the present invention, it is preferable to carry out the reaction in the presence of an acid. Examples of the acid used include a protonic acid and a Lewis acid, and a protonic acid is preferred. Examples of the protic acid include inorganic acids such as sulfuric acid, hydrochloric acid, nitric acid, and phosphoric acid, and organic acids such as acetic acid, formic acid, and trifluoroacetic acid. Of these, inorganic acids are preferable, and sulfuric acid is more preferable. When sulfuric acid is used, sulfuric acid having a concentration of 60 to 90% by weight is generally used, and sulfuric acid having a concentration of 75 to 85% by weight is preferably used.

A preferred combination of the oxidizing agent and the solvent is a combination of hydrogen peroxide and sulfuric acid. In this reaction, a catalyst that assists oxidation may be added as needed.A catalyst that assists oxidation of sulfide can be generally used as the catalyst. Preferably, a ruthenium compound, a tungsten compound, a vanadium compound, These include molybdenum compounds, titanium compounds, and more preferably ruthenium compounds. Examples of the ruthenium compound include ruthenium trichloride and ruthenium oxide. The amount of these catalysts for Surufui de of starting material, usually 0.0 to 1 mol% or more, or preferably 0.1 mole _^0/0 or more, usually 1 0 0 mol% or less, preferably 2 0 mode % Or less.

 When a catalyst is used, the reaction is usually carried out at a temperature of at least 30 ° C, preferably at least 10 ° C, usually at a temperature of 120 ° C or less, preferably at a temperature of room temperature (25 ° C) or less. It is usually performed for 1 hour or more, usually for 48 hours or less, preferably for 6 hours or less. Next, the second invention will be described.

In the second invention, benzyl mercaptan or a salt thereof is used. Benzyl mercaptan is a compound having a structure of Ph CH ₂ SH (wherein, Ph represents a phenyl group). Examples of the salt of benzyl mercaptan include an alkali metal salt of benzyl mercaptan, an alkaline earth metal salt of benzyl mercaptan, and the like, and an alkali metal salt of benzyl mercaptan is preferably used. The amount of benzyl mercaptan or a salt thereof added is usually 5% or more, preferably 10% or more, when the weight of benzyl mercaptan is expressed as a percentage (%) based on the volume of a mixed solvent of water and alcohol. 0% or less, preferably 50% or less Below.

The chlorodifluoromethane used in the second invention is a compound having a structure of CHF ₂ C 1.

 The amount of difluoromethane added is usually 1 mole or more, usually 5 moles or less, and preferably 3 moles or less, in molar ratio to benzyl mercaptan. The base used in the second invention generally includes an alkali metal hydroxide, an alkaline earth metal hydroxide, ammonia, an organic amine, and the like. Preferably, an alkali metal hydroxide is used, More preferably, sodium hydroxide or hydroxide hydrate is used.

 The amount of the base to be added is usually 1 mole or more, usually 5 moles or less, preferably 2 moles or less in molar ratio to benzyl mercaptan.

 The second invention is characterized in that a water / alcohol mixture is used as a solvent. The alcohol used for the mixed solvent is preferably an alcohol compatible with water, particularly preferably an alcohol having 1 to 3 carbon atoms. Specifically, methanol, ethanol and isopropanol are used, and preferably isopropanol is used.

 The alcohol and the mixing ratio (volume ratio) of the mixed solvent differ depending on the type of alcohol. Alcohol: water = 1: 100 or more, preferably 50: 50 or more, usually 100: 1 or less , Preferably in the range of 95: 5 or less. When isopropanol is used as the alcohol, the range of isopropanol: water = 60: 40 to 90:10 is particularly preferable.

The order of addition of each component to the reactor and the reaction method are not particularly limited, but a preferable example is that a mixed solvent of alcohol and water is first prepared, and benzyl mercaptan or a salt thereof is added thereto. And then add a base to dissolve. Next, the reaction is carried out by introducing chlorodifluoromethane into the mixture, and benzinole (difluoromethyl) sulfide represented by the following formula (CHF ₂ SCH ₂ Ph (where Ph represents a fuel group))

Is obtained. The reaction temperature is usually at least 20 ° C, preferably at least 10 ° C, and usually at most 120 ° C, preferably at most 70 ° C. The reaction time is generally 1 hour or longer, usually 120 hours or shorter, preferably 5 hours or shorter.

 Since benzyl mercaptan is easily oxidized by oxygen, the reaction atmosphere is preferably replaced with an inert gas such as nitrogen or argon, and the solvent used in the reaction is preferably degassed to remove oxygen.

 After completion of the reaction, extraction is performed according to a conventional method. Thereafter, the reaction product may be used in another reaction without isolation or purified by distillation or the like to isolate the reaction product.

By reacting the second benzyl (Jifuruoromechiru) sulfides obtained by the invention and black mouth agent such as _{C l 2, SO 2 C 1} 2, it is possible to obtain the difluoromethyl O b methyl sulphates Eeruku port Li de . This reaction is usually performed without a solvent. The reaction temperature is usually 150 ° C. or higher, preferably 110 ° C. or higher, and usually 150 ° C. or lower, preferably 100 ° C. or lower. The reaction time is generally 10 minutes or longer, preferably 30 minutes or longer, and usually 24 hours or shorter, preferably 10 hours or shorter.

 By reacting the thus obtained difuromethylsulfenyl chloride with the pyrazole compound, a difluoromethylsulfenyl group can be introduced into the pyrazole compound. Examples of the pyrazole compound to be reacted with difluoromethylsulfuryl chloride include a compound represented by the general formula (10).

R \ R ² s R ³ , X and n are as defined in general formula (2).

Difluoromethylsulfenyl chloride and a compound represented by the general formula (10) The compound represented by the general formula (9) can be produced by reacting

R \ RR ³ , X, n have the same meaning as in general formula (2). The compound represented by the general formula (9) is preferably, for example, methylphenyl) -1,4-difluoromethylsulfenyl-5- (pyridine-12-ylmethinoleamino) pyrazole-3-caprolpo-tolyl. No.

 In the reaction of difluoromethylsulfuryl chloride with the compound represented by the general formula (10), difluoromethylsulfuryl chloride reacts with the compound represented by the general formula (10). It is usually at least 0.5 molar equivalent, preferably at least 0.8 molar equivalent, and usually at most 10 molar equivalent, preferably at least 5 molar equivalent. The reaction temperature is usually 0 ° C. or higher, usually 150 ° C. or lower, preferably 100 ° C. or lower. The reaction time is usually 1 hour or longer, usually within 24 hours, preferably within 4 hours.

Solvents used in the reaction between difluoromethylsulfenyl chloride and the compound represented by the general formula (10) include aromatic hydrocarbons such as benzene, toluene and xylene; acetone, methylethylketone and the like. Ketones; halogenated hydrocarbons such as chloroform or methylene chloride; ether solvents such as ether, diisopropyl ether, and tetrahydrofuran; non-protonic polar solvents such as DMF and dimethyl sulfoxide; Of these, toluene and chloromethane are preferred. The reaction is preferably performed in the presence of a base, and the base may be pyridine, Amines such as luminin are used. Examples>

 Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to the following Examples.

[Reference Example 1]

 (Manufacture of disulfide)

 5-Amino-1- (2,6-dichloro-1-41-trifluoromethylphenyl) pyrazole-1-carbonitrile 110 g (0.343 M), 2-formylvirazine 38.5 g (0 0.356 M) and 440 mL of toluene were added with 0.28 g of p-toluenesulfonic acid monohydrate, and the mixture was heated under reflux for 3 hours while removing generated water. After cooling to room temperature, the resulting crystals were collected by filtration. The crystals are further washed with 8 OmL of toluene, and crude 1- (2,6-dichloro-4-trifluoromethylphenyl) -15- (pyrazine-1-2-ylmethylideneimino) pyrazole containing about 8% toluene

There were obtained 50.34 g of 3 _ force lupoetrile.

 Sodium borohydride (8.8 g, 0.221 M) was added to ethanol (53 OmL), and the above-obtained 1- (2,6-dichroic port _4-1 trifluoromethylinophenyl) -15- (pyrazine (1-2-Methylmethylidenimino) Crystals of pyrazole-3-carbonitrile were gradually added at 7 to 15 ° C. After stirring at room temperature for 2 hours, the mixture was gradually added at 10 to 20 ° C. while stirring in 100 mL of 0.6 N hydrochloric acid. After stirring for about 1 hour, the resulting crystals were collected by filtration, washed with water until the washing liquid reached pH 5, and further washed twice with 5 mL of ethanol. The obtained crystals were dissolved in 130 OmL of ethyl acetate, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting crystals were collected by filtration. The obtained crystals are washed with 10 OmL of hexane, and

4- (trifluoromethylphenyl) -5- (pyrazine-1-ylmethylamino) pyrazole-13-carbo-tolyl 16.2 g (0.28 OM) was obtained in a yield of 81.6%. In a nitrogen atmosphere, contains 11- (2,6-dichloro-1-4-trifluoromethylphenyl) -5- (pyrazine-1-ylmethylamino) pyrazole-3-potulonitolinole 5.0 Og (l 2.1 ηιΜ) 80 mL of the anhydrous dichloromethane solution was cooled to 2 ° C, and 2 OmL of a dichloromethane solution containing 0.48 mL (0.817 g, 6.05 mM) of sulfur monochloride was added dropwise thereto. After completion of the dropwise addition, the temperature was returned to room temperature, and the solution was left for 4 hours while stirring. The organic layer was washed with 6 OmL of a saturated aqueous sodium hydrogen carbonate solution and then with 2 OmL of water, and dried over anhydrous magnesium sulfate. After filtration of the magnesium sulfate, the solvent was distilled off under reduced pressure, and the crude product was washed with a mixed solvent of Hex-EtOAc to give 3.88 g of bis (1- (2,6-dichloro-4-trifurno). Leolomethinorefe-nore) -3- 3-carbonitrile-5- (pyrazine-12-inolemethylamino) pyrazole-4 ^^) 1 disulfide was obtained (yield 72%).

[Example 1]

Bis (11- (2,6-dichloro-4-trifluorotrifluoromethyl: tnyl) -1,3-carbo-tolyl-5- (pyrazine-1-2-inolemethinoleamino) pyrazole 4-1-1 produced in Reference Example 1 1) 3.00 g (3.38 mM) of disulfide was dissolved in DMF (6 OmL), and the solution was placed in a 15 OmL SUS autoclave purged with nitrogen. While stirring, an aqueous solution (7. OmL) containing potassium carbonate (1.40 g, 1 0.1 mM) and hydrazine monohydrate (0.684 g, 13.5 mM) was added. The autoclave was cooled to 180 ° C and 2. OmL of trifluoromethyl iodide (4.0 Og, 20.4 mM) was introduced into the reaction solution from a compressed cylinder. The temperature of the reaction solution was returned to room temperature while stirring, and further stirred for one day. Thereafter, 15 OmL of distilled water was poured into the solution while stirring, and extracted with ethyl acetate (200 mL × 3 times). The combined ethyl acetate extracts were washed with distilled water (12 OmL) and dried over anhydrous magnesium sulfate. After filtering the magnesium sulfate, ethyl acetate was distilled off with an evaporator, and volatile substances were removed at a bath temperature of 100 ° C. using a high vacuum pump to remove all high boiling solvents such as DMF. The obtained crude product (3.57 g) was washed with Hex / EtOAc. Objective 1-1 (2,6-dichloro-1-41-trifluoromethylphenyl) — 41-Trifluoromethinoresnorefeneru 51- (pyrazin-1-ylmethylamino) pyrazole-3-carbonitrile was obtained in a yield of 98%.

[Example 2]

Bis (1- (2,6-dichloro-4-1-trifluoromethylphenyl) -1-3-canolepotryl-5_ (pyrazine-1 f-normethy / reamino) pyrazole-14-yl prepared in Reference Example 1 0.200 g (0.224 mM) and DMF (4. OmL) were charged to a 3 OmL SUS autoclave in which nitrogen was replaced. While stirring, an aqueous solution (0.5 mL) containing potassium carbonate (0.093 g, 0.673 mM) and hydrazine monohydrate (0.023 g, 0.447 mM) was added. The autoclave was cooled to -80 ° C, and 0.5 mL of trifluoromethyl iodide (1.0 Og, 5.1 OmM) was introduced into the reaction mixture from a compression pom- bane. The temperature of the reaction solution was returned to room temperature while stirring, and further stirred for one day. Thereafter, the solution was poured into 20 mL of distilled water while stirring, and extracted with ethyl acetate (3 OmL × 3 times). The ethyl acetate extracts were combined, washed with distilled water (10 mL), and dried over anhydrous magnesium sulfate. After filtration of the magnesium sulfate, the ethyl acetate was distilled off with an evaporator, and volatile substances were further removed at a bath temperature of 100 ° C using a high vacuum pump to remove all high boiling solvents such as DMF. The crude product obtained (0.28 g) was washed with MeOH-H ₂ 0. Target substance 11 (2,6-dichloro-4-1 trifluoromethylphenol) -4 1 Trinoleolomethi snorrefue 2 Λ ^ — 5-1 (Virazine 1-inolemethinoleamino) pyrazole-3 Nitril was obtained with a yield of 89%.

[Example 3]

Diooyl disulfide OlOO g (0.916 mM) and DMF (4. OmL) were charged into a nitrogen-substituted 30 mL SUS autocrepe. While stirring, an aqueous solution (0.6 mL) containing potassium carbonate (0.253 g, 1.83 mM) and hydrazine monohydrate (0.185 g, 3.66 mM) was added. The autoclave was cooled to 180, and 0.5 mL of trifluoromethyl iodide (1. 00 g, 5.1 Omm o 1). The temperature of the reaction solution was returned to room temperature with stirring, and the mixture was further stirred for 2 days. Thereafter, the solution was poured into 2 OmL of distilled water with stirring, and extracted with ethyl acetate (30 mL × 3 times). The combined ethyl acetate extracts were washed with distilled water (10 mL) and dried over anhydrous magnesium sulfate. After filtering the magnesium sulfate, ethyl acetate was distilled off with an evaporator. Trifluoromethylsulfuelbenzene was obtained in a yield of 48%.

[Example 4]

 Bis (1- (2,6-dichloro-41-trifnoroleolomethinorefue-norre) 1-3-force ruptonitrile-5- (pyrazine-1 2-^-methylamino) pyrazol-41-yl) disulfy F 0.200 g (0.224 mM), DMF (2 OmL), triethynoleamine 2.OmL (14.3 mM, 64 eq based on raw disulfide), methyl viologen 5.7 mg (0.022 mM, 0.1 eq), sodium polo 22.5 mg (0.59 mM, 2.7 eq) of the hydride was charged into a 50 mL autoclave purged with nitrogen. The autoclave was cooled to 180 ° C, and after introducing 0.18 g (0.92 mM, 4.1 eq) of trifluoromethylinochloride into the reaction solution, the autoclave was sealed. The temperature of the reaction solution was returned to room temperature with stirring, and the mixture was further stirred for 24 hours. The autoclave was opened, the reaction solution was poured into 2 OmL of water, and extracted with getileruthere (2 OmL X 3). The combined ether extracts were washed with distilled water and dried over anhydrous magnesium sulfate. The ether was removed by distillation, and the obtained crude product (0.375 g) was purified by silica gel column chromatography to give 1- (2,6-dichloro-1-41-trinoleolomethinolefeninole)-(1-) 1-triphnolelomethyl Light yellow crystals of sulfenyl-1- (pyrazine-1-ylmethylamino) pyrazole-3-carbonitrile (0.166 g, 0.323 mmo 1) were obtained in a yield of 72%.

[Example 5]

Bis (1— (2,6-dichloro-4-trifnoroleolomethinolefe-nore) 1 3-force Lupotunitryl 51- (pyrazine 2-ylmethylamino) pyrazole-41-yl)-diso-norf Ol OO g (0.1 1 2mM) ヽ DMF (10mL), trietinoreamine (1.0mL), sodium borohydride (9.4 mg, 2.2 eq) was charged into a nitrogen-purged 5 OmL autoclave, and the autoclave was cooled to 180 ° C. 0.5 mL of trifluoromethyl iodide was blown into the reaction solution from a compressed cylinder. The solution temperature was returned to room temperature with stirring, and the mixture was further stirred for 24 hours. When the usual post-treatment is performed, the desired product is obtained as follows: 1,1- (2,6-dichloro-4-trifluorotrifluoromethyl-norphene) 1.4-triphnoleolomethinolesnorrefue-nore-5- (pyrazine-12-ylmethylamino) pyrazole 3_Carbonitrile was obtained with a yield of 33%.

[Example 6]

Bis (1- (2,6-dichloro-4-trihnorololomethylpheninole) — 3-force ruptonitrile 1-51 (pyrazine 1 2 ^^-methylamino) pyrazol 4-yl) —disnoreflide 0.200 g (0.224 mM) _s DMF (10.0 mL), triethylamine (0.25 mL), methyl viologen (5.7 mg), and sodium hydride (16.9 mg, 2.0 eq) were reacted in the same manner as in Example 2. , 1-1 (2, 6-dichloro 1-41-rifenoleolomethinolepheninole)-4 _ triphnoleolomethinolesnole-feninole 5-(pyrazine 1-2-inolemethinoleamino) pyrazonole 3-force olevonitrile was obtained in a yield of 61%.

[Example 7]

Bis (1— (2,6-dichloro_4—triphnoleolomethinolephenyl) —3—force ruptonitrile-5— (pyrazine-1-2-ylmethylamino) pyrazole-1-4-yl) 1-disnosulfide 0.200 g (0.224 mmo 1), DMF (4.0 mL), triethylamine (0.4 mL), methyl viologen (5.7 mg, 10 mol 1% of the amount of disulfide used), sodium borohydride (21 mg, 2.5 mol 1 eq) was reacted in the same manner as in Example 2 except that the reaction required 48 hours, and 1 (2,6-dichloromethane-1 4-1trifluoromethylinorefeninole) 1 4-1trifluoromethylino Lesnorrefue Nil 51 (pyrazine-1-ylmethylamino) pyrazole-3-carbonitrile was obtained in a yield of 41%.

[Example 8]

 Bis (11 (2,6-dichloro-1-41-trifnoroleolomethinolepheninole) 1-3-force norebonitrinole 5-aminopyrazono-le 4-inole) Disinolefide 0.100 g (0.142mM) , DMF (10.0 mL), Triethylamine (1.0 mL), Methylviologen (2.8 mg, 7.7% of the amount of disulfide used), and sodium borohydride (10.7 mg, 2.0 mol eq) The reaction was carried out in the same manner as in Example 1 by charging into a 50 mL autoclave having been purged with nitrogen. After post-treatment by extraction, the desired product 1- (2,6-dichloro-1-41-trifluoromethylphenyl) 1-4-trifluoromethylsnolephenyl 2-l-5-aminopyrazono-l-3 Luponitrinole was obtained in a yield of 21%.

[Example 9]

 5-amino-1,1- (2,6-dichloro-1,4-trifluoromethylphenyl) obtained in Example 8—4-trifluoromethylinoresolefinino-levirazonone-l-carbotrile 200 g, To a mixture of 56.2 g of formylpyrazine and 800 ml of toluene was added 6.0 g of pyridinum p-toluenesulfonate, and the mixture was heated under reflux for 27 hours while removing generated water. Further, 6.0 g of pyridium-p-toluenesulfonate was added, and the mixture was further heated under reflux for 10 hours, cooled with ice, and the generated crystals were filtered. The crystals are washed with 50 Om 1 of toluene, dried and dried. 1- (2,6-dichloro-4-1trifluoromethylphenyl) -14-trifluoromethylsulfinyl 5 -— (pyrazine-12-ino) (Remethylidene imino) pyrazole-3-carbinitol 228 g was obtained.

Sodium borohydride 8.65 g of ethanol in 800 ml of 1 suspension of ice-cooled 1- (2,6-dichloro-1-4-trifluoromethylinophenyl) — 4-trifluoromethylsulfinyl-1-5-1 (pyrazine-1) 2-ilmethylidenimino) pyrazo Rhu 3-Carbonitrile (227 g) was gradually added at 15 ° C or lower. After stirring at room temperature for 1 hour, the mixture was slowly dropped into 160 Oml of 1N hydrochloric acid while stirring. The resulting crystals were filtered, washed with a mixed solution of ethanol 20 Om 1 / water 10 Om 1, then ethanol 400 m 1 / water 10 Om 1 and dried to obtain 183 g. Recrystallized from hexane / ethyl acetate (lZ1), 1337g of 1- (2,6-dichloro-1-41-trifluoromethylinorefue-nore) 1-4-trinoleolomethinoles / refininole 5 — (Pyrazine-2-ylmethylamino) pyrazole-3-potrolnitrile (melting point: 169 ° C) was obtained.

[Example 10]

 25 ml of water and 75 ml of isopropanol (manufactured by Wako Pure Chemical Industries, Ltd.) are added to a 200 ml four-necked flask, and benzyl mercaptan (manufactured by Tokyo Chemical Industry Co., Ltd.) 30 g (0.242mo 1 ) Was added. Further, 14.4 g (0.362 m o 1) of sodium hydroxide (manufactured by Wako Pure Chemical Industries, Ltd.) was added and dissolved. Keep the temperature of the solution at 55 ° C and stir with 10 L of chlorodifluoromethane (manufactured by Daikin Corporation).

(0.45mo1) was introduced in 2 hours, and the reaction was carried out. The reaction was followed by gas chromatography.

 After the reaction was completed, 20 Om1 of water and 200 ml of ethyl acetate were added, and the organic layer was extracted. Further, the aqueous layer was washed with 10 Om 1 of water, and the organic layer was dried over 10 g of anhydrous magnesium sulfate. Magnesium sulfate was filtered off and the solvent was distilled off to obtain 36.5 g (yield 87%) of benzyl (cloguchi difluoromethyl) sulfide having a purity of 98%.

[Comparative Example 1]

In a 20 Om 1 four-necked flask, 24.Og of 50 wt% sodium hydroxide consisting of 12.0 g of water and 12.0 g of sodium hydroxide, and 6 M of DMF (manufactured by Wako Pure Chemical Industries, Ltd.) Then, 24.2 g (0.2 Omo 1) of benzyl mercaptan (manufactured by Tokyo Chemical Industry Co., Ltd.) was added thereto to obtain a homogeneous solution. Solution temperature to 50-65 ° C Example of chlorodifluoromethane (manufactured by Daikin Co., Ltd.) while keeping and stirring

Introduced in 2 hours in the same manner as in 1, and reacted. The reaction was followed by gas chromatography.

 After completion of the reaction, 20 Om1 of water and 3 OOml of ethyl acetate were added, and the organic layer was extracted. The organic layer was washed with 5 Om 1 of water and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off and the solvent was distilled off, thereby obtaining 27.0 g (yield 78%) of benzyl (chlorodifluoromethyl) sulfide having a purity of 95%.

[Example 11]

 (1) Production of 1,1- (2,6-dichroic-1-41-trifnoroleolomethinolefeninole) -1-5- (pyridin-1-2-ylmethylamino) pyrazole-3-carboetril

 (1-1) In a three-necked flask, add 40 ml of dehydrated tonoleene, 1- (2,6-dichloro-4-trifluoromethylinophenyl) -5-aminopyrazole-3-carboditril 10 g (31 .lmmo 1), 4.55 g of 2-pyridinecarboxaldehyde and 0.03 g of p-toluenesulfonic acid were charged and refluxed under nitrogen for 3 hours. After washing the above reaction solution three times with water, the organic phase is dried over magnesium sulfate, magnesium sulfate is removed by filtration, and the solvent is distilled off to obtain 1_ (2,6-dichloro-41-trifnoroleolomethino). (Refeninole) 15- (Pyridine-12-inolemethylidene denimino) pyrazole-3-carbonitrile 12.63 g of solid (purity 98,6 LC%, 30.3 mmo 1, yield 97.3%) I got

(1 -2) Dehydrated methanol in a three-necked flask 200 Om 1, 1-1 (2,6-dichloro-1-41-triphnoleolomethinorefue-nore) 1-5— (pyridine-1 2-inoremethylidenimino) 47.7 g (purity 96%, 109.9 mmo 1) of pyrazole-3-carbonitrile and 2.0 g of sodium tetrahydroborate were charged and reacted under nitrogen for 2 hours. Thereafter, the crystals formed in the reaction solution are collected by filtration, washed with water and methanol, dried in vacuo, and dried in 1- (2,6-dichloro-4-trifluoromethylphenyl) -5- (pyridine 2-Inolemethinoleamino) pyrazole-3-canoleponitrile 42. 84 g of solid (purity 97.5%, 101.3 mm o 1, yield 84. 1%).

 (2) Manufacture of difluoromethylsulfueurc mouth lid

 8.25 g of benzinole (chlorodifluoromethinole) sulfy obtained in Example 10 was cooled to 0 ° C., and 4.2 g of chlorine gas was blown thereinto over 30 minutes while stirring. After stirring at the same temperature for 1 hour, a distillation apparatus was installed and heated to an internal temperature of 65 ° C to obtain 4.3 g of difluoromethylsulfuryl chloride (77% yield) as a fraction.

 (3) Preparation of 1- (2,6-dichloro-1-4-trifthreolomethinolefeninole) 4-difluoromethylthio-5- (pyridine-1-ylmethylamino) pyrazole-3-carbonitrile

 Under a nitrogen atmosphere, 1- (2,6-dichloro-4-trifluoromethylphenyl) -5- (pyridine-1-fluoromethylamino) pyrazole-1-carbonitrile 50 Omg (1.2 lmmo 1) Suspend in 5.OmL of anhydrous dichloromethane and, with stirring, add 2.OmL of anhydrous dichloromethane containing 18Omg (1.52mmo1, 1.25 eq.) Of difluoromethinoresnolefeninolechloride. The mixture was added dropwise at room temperature and reacted for 2 hours. 10 OmL of ethyl acetate was added, and the organic layer was washed with 2 OmL of a saturated aqueous sodium hydrogen carbonate solution, followed by 2 OmL of water, and dried over anhydrous magnesium sulfate. After filtration of the magnesium sulfate, the solvent was distilled off under reduced pressure, and the crude product was recrystallized with a mixed solvent of hexane Z ethyl acetate (3/1) to give 535 mg of 1,2- (2-, 6- Thus, dichloro-4- (triphenylenomethyl methinolefeegle) -4-diphenylenomethylthio-5- (pyridine-1-ylmethylamino) virazole-3-carbonitrile was obtained (yield 90%, purity 96%). Although the present invention has been described in detail and with reference to specific embodiments, it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the invention.

This application was filed on February 22, 2001 (Japanese Patent Application No. 2001-046036), filed on February 22, 2001 (Japanese Patent Application No. 2001-046037), and published on October 16, 2001 (3 It is based on the Japanese patent application (Japanese Patent Application No. 2001-318198), the content of which is here. Captured as a reference. Industrial applicability>

 According to the present invention, a polyfluoroalkylation reaction with a polyfluoroalkyl halide is carried out in the presence of a disulfide as a raw material in the presence of an industrially easy-to-use auxiliary agent, to give a polyfluoroalkylsulfuel compound. Obtainable. Further, it is possible to provide a method for synthesizing benzyl (difluoromethyl) sulfide in good yield by using a commercially available solvent.

Claims

The scope of the claims

1. A process for producing a polyfluoroalkylsulfenyl compound, which comprises reacting a disulfide with one or more halogenated polyfluoroalkyl selected from hydrazine and metal borohydride.

2. Disulphide has general formula (1)

R ¹¹ — S— S— R ¹² (1)

(In the formula, R ¹¹ and R ¹² each independently represent a group bonded to a sulfur atom by a carbon atom, and may be bonded to each other to form a ring)

2. The production method according to claim 1, wherein the method is:

3. disulfide preparation ranging second claim of claim at least one of R ^u and R ¹² is a disulfide bonded to a sulfur atom through a carbon atom of the heterocyclic ring which may be substituted de.

4. The method according to claim 3, wherein the heterocycle is a virazole ring.

5. The method according to any one of claims 1 to 4, wherein the disulphide is a 1- (hetero) aryl-1 3-cyano 5-substituted alkylamino benzoylazole derivative represented by the following general formula (2). Production method as described.

(In the formula, R ^1. R ² showing the Ashiru group hydrogen atom, an alkyl group or a C 2 to C 5 of C 1～C4 represents a hydrogen atom, a hydroxyl group or an alkyl group of C 1~C 4. R ³ Is a hydrogen atom, a hydroxyl group, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, an optionally substituted phenoxy group, a C1-C4 haloalkoxy group, 1-C4 anorekylsnolephenyl group, C1-C4 anolequinolenosolefinyl group, C1-C4 alkylsulfonyl group, optionally substituted aryl group or heteroaryl group X represents a carbon atom substituted by a nitrogen atom or a halogen atom, and n represents 0, 1 or 2.)

6 In general formula (2), R ³ is

(Wherein, R ⁴ is a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, an optionally substituted phenoxy group, a C1-C4 haloalkoxy group And a C 1 -C 4 anoalkylsulfenyl group, a C 1 -C 4 anolexynolesulfinyl group, a C 1 -C 4 alkylsulfonyl group, a halogen atom, a nitro group or a cyano group. Indicates 1 or 2.)

6. The method according to claim 5, wherein:

7. The claim wherein the disnolesulfide is bis (1- (2,6-dichloro-4-trifluoromethylphenyl) -13-carbonitrile-1-51 (pyrazine-1-ylmethylamino) pyrazol-41-yl) disulfide. 6. The production method according to item 6.

8. The method according to any one of claims 1 to 7, wherein the halogenated polyfluoroalkyl is a halogenated perfluoroalkyl.

9. The production method according to claim 8, wherein the polyfluoroalkyl halide is triphnoleolomethinole iodide.

10. The method according to claim 1, wherein at least one selected from hydrazine and metal borohydride is a metal borohydride.

1 1. The metal borohydride is lithium borohydride, sodium borohydride, calcium borohydride, calcium borohydride, magnesium borohydride, zinc borohydride or lithium cyanoborohydride or sodium 12. The production method according to claim 1 or 10, which is a cyanoborohydride.

12. The process according to claim 10, wherein the reaction is carried out in the presence of a biviridinium salt derivative.

13. The production method according to claim 12, wherein the vibidium salt derivative is an electron transfer catalyst.

14. The production method according to claim 13, wherein the biviridinium salt derivative is a viologen dye.

15. The method according to claim 14, wherein the viologen dye is methyl viologen.

16. — 1 _ (hetero) aryl-1 3-cyano 5 -substituted alkylaminopyrazole derivatives represented by the general formula (2).

(Wherein, R ¹ represents a hydrogen atom, a C 1 -C 4 alkyl group or a C 2 -C 5 acyl group. R ² represents a hydrogen atom, a hydroxyl group or a C 1 -C 4 alkyl group. ³ is a hydrogen atom, a hydroxyl group, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, an optionally substituted phenoxy group, a C1-C4 haloalkoxy group, A C1-C4 alkylsulfinyl group, a C1-C4 alkylsulfenyl group, a C1-C4 alkylsulfonyl group, an optionally substituted aryl group or a heteroaryl group X represents a carbon atom substituted by a nitrogen atom or a halogen atom, and n represents 0, 1 or 2.)

7. In the general formula (2),

 Man

 _ £

N

(In the formula, R ⁴ is a C1-C4 alkyl group, a C1-C4 haloalkyl group, C1-

C4 alkoxy group, optionally substituted phenoxy group, C1-C4 haloa It represents a alkoxy group, a C1-C4 alkylsulfenyl group, a C1-C4 alkylsulfonyl group, a C1-C4 alkylsulfonyl group, a halogen atom, a nitro group or a cyano group. m indicates 0, 1 or 2. )

17. The (hetero) aryl-1 3-cyano 5-substituted alkylaminopyrazole derivative according to claim 16, wherein the derivative is:

1 8. Bis (1 _ (2,6-dichloro-4-trifnoroleolomethinolefeninole) — 3-carbonitrile-5— (pyrazine-12-ylmethylamino) pyrazol-4-inole) disizolefide.

1 9. A pyrazole derivative represented by the general formula (5) obtained by the method according to claim 1.

(Wherein, R ¹ represents a hydrogen atom, a C ¹ -C 4 alkyl group or a C 2 -C 5 acyl group. R ² represents a hydrogen atom, a hydroxyl group or a C 1 -C 4 alkyl group. ³ is a hydrogen atom, a hydroxyl group, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, an optionally substituted phenoxy group, a C1-C4 haloalkoxy group, It represents a C1-C4 alkylsulfenyl group, a C1-C4 alkylsulfinyl group, a C1-C4 alkylsulfol group, an optionally substituted aryl group or a heteroaryl group. R ⁵ represents a polyfluoroalkyl group, X represents a nitrogen atom or a carbon atom substituted by a halogen atom, and n represents 0, 1 or Shows 2. )

20. A pyrazole derivative represented by the general formula (7) produced from the virazole derivative obtained by the method according to claim 1.

_tC ^H 2 ^R3 (7)

(Wherein, R ¹ represents a hydrogen atom, a C ¹ -C 4 alkyl group or a C 2 -C 5 acyl group. R ² represents a hydrogen atom, a hydroxyl group or a C 1 -C 4 alkyl group. ³ is a hydrogen atom, a hydroxyl group, a C 1 to C 4 anoalkyl group, a C 1 to C 4 haloalkyl group, a C 1 to C 4 alkoxy group, an optionally substituted phenoxy group, a C 1 to C 4 halo A norecoxy group, a C1-C4 alkylsulfenyl group, a C1-C4 alkylsulfinyl group, a C1-C4 alkylsulfonyl group, an optionally substituted aryl group or a heteroaryl group. R ⁵ represents a polyfluoroalkyl group, X represents a nitrogen atom or a carbon atom substituted by a halogen atom, n represents 0, 1 or 2, and p represents 1 or 2.)

21. A process for producing benzyl (difluoromethyl) sulfide by reacting benzyl mercaptan or a salt thereof with chlorodifluoromethane in the presence of a solvent and a base, characterized in that a mixed solvent of alcohol and water is used as a solvent. For producing benzinole (difluoromethyl) sulfide.

2 2. The alcohol characterized in that the alcohol is an alcohol having 1 to 3 carbon atoms. 22. The method for producing benzyl (difluoromethyl) sulfide according to claim 21.

23. A pyrazole compound represented by the following general formula (9), which is produced from benzyl (difluoromethyl) sulfide obtained by the method according to claim 21.

(Wherein, R ¹ represents a hydrogen atom, a C ¹ -C 4 alkyl group or a C 2 -C 5 acyl group. R ² represents a hydrogen atom, a hydroxyl group or a C 1 -C 4 alkyl group. ³ is a hydrogen atom, a hydroxyl group, a C1-C4 alkyl group, a C1-C4 haloalkyl group, a C1-C4 alkoxy group, an optionally substituted phenoxy group, a C1-C4 haloalkoxy group, alkyl sulphates enyl group C 1 through C 4, an alkyl sul Finiru group, C 1 through C 4 alkylsulfonyl group, optionally substituted Ari group or heteroaryl group C 1~C4. R ⁵ Represents a polyfluoroalkyl group, X represents a nitrogen atom or a carbon atom substituted by a halogen atom, and n represents 0, 1 or 2.)