TW200540160A - Process for the production of 5-difluoromethoxy -4-thiomethylpyrazoles - Google Patents

Description

200540160 (1) IX. Description of the invention [Technical field to which the invention belongs] The present invention relates to a method for producing a 5-difluoromethoxy-4-thiomethylpyrazole compound. [Prior art] The 5-difluoromethoxy-4_thiomethylpyrazole compound obtained by the present invention is used as an intermediate for the manufacture of medicine and pesticides. A method for obtaining a 5-difluorinated methoxypyrazole compound. It is known that a 5-hydroxypyrazole compound and chlorodifluoromethane are dissolved in a N, N-dimethylformamide solvent in the presence of potassium bicarbonate. A method of reaction (see Non-Patent Document 1), a method of reacting in a mixed solvent of dioxane and water in the presence of sodium hydroxide (see Patent Document 1). However, a method for obtaining a 5-difluoromethoxy-4-thiomethylpyrazole compound using chlorodifluoromethane for a 5-difluoromethoxy-4 · thiomethylpyrazole compound is unknown. On the one hand, 5-difluorinated methoxy-4-thiomethylpyrazole compounds have ketoenol tautomers, and keto compounds can be understood as the addition of sulfide compounds that possess electron-recovering hydrocarbons. In general, this type of mecca becomes reversible, and when the product is heated simultaneously with a strong base, the sulfur compound is known to be detached (see Non-Patent Document 2). When a chlorodifluoromethane is used under strong base conditions to obtain a 5 · difluoromethoxy-4-thiomethylpyrazole compound from a 5-hydroxy-4-thiomethylpyrazole compound, for example, at When reacting in an alcohol solvent, the reactions proceed in a race to cause decomposition of the raw materials to known ones (see Non-Patent Document 2). 200540160 (2) Patent Document 1: International Publication W09 5 M 9967 Non-Patent Document 1: Fixed Journal of Pharmaceutical Chemistry, Volume 43-1 No. 6 '2975-29 8 1 Μ (2000 $) Non-Patent Document 2: Organic Synthesis Tasks of Sulfur Compounds (Japan Sankyo Publishing Co., Ltd.) Chapter 5.5.2, pages 171-174, (1981) [Summary of the Invention] [Questions to be Solved by the Invention] The present invention provides 5-hydroxy-4-thiomethyl A novel method for efficiently producing 5-difluoromethoxy-4-thiomethylpyrazole compounds using chlorodifluoromethane. [Means for solving the problem] In view of the above-mentioned situation, the present inventors have intensively studied the results of a method for producing a 5-difluoromethoxy-4-thiomethylpyrazole compound, and unexpectedly found that φ will be 5-hydroxy-4 -Thiomethylpyrazole compound and chlorodifluoromethane, sodium hydroxide as base, carbon number 1 to 3 (for carbon numbers below, for example, carbon number 1 to 3, abbreviated as "C1 ~ C3") ( The reaction was performed in the presence of C1 to C3 alkyl) ketone or (C1 to C3 alkyl) nitrile, and it was found that the above-mentioned problems can be solved. The present invention has been completed based on this research. [Effect of the Invention] A novel industrial manufacturing method for providing a 5-difluoromethoxy-4-4-thiomethylpyrazole compound by the method of the present invention, using 5-hydroxy-4-thiomethyl-6-200540160 ( 3) -4 -Sulfur materials or valence ratios of D compounds and fluorinated methyl fluoride as raw materials, 5-difluoromethoxymethylpyrazole compounds can be easily manufactured. Moreover, the reaction time of the product of the method of the present invention is reduced, and the reaction time is greatly shortened, which is industrially advantageous. [Best Mode for Carrying Out the Invention] Hereinafter, the present invention will be described in detail. The present invention was made by the subject of the invention described in the following [1] to [4]. [1] General formula (1)

It has an aromatic hydrocarbon group having 〇 or • (in the formula! Is an alkyl group, an aromatic hydrocarbon group which may have a substituent or a 5-substituent heterocyclic group, R2 is an electron recovering group, R3 is an alkyl group, and an aromatic hydrocarbon group having 5 substituents. Or a heterocyclic group which may have a substituent, wherein η is a 5-hydroxy-4-thiomethylpyrazole compound represented by 2), and a general formula (2) CHF2 X (2) (wherein X is a halogen atom) R2

I

200540160 (4) The halogenated difluoromethane shown in (4) is characterized by the reaction in the presence of bis (C1 ~ C3 alkyl) ketone or C3 alkyl) nitrile, and sodium hydroxide. (3) • S (〇) n— R3, OCHF2 (wherein R], R2, R3 and n have the same meaning as above). Preparation of the 5-difluoromethoxy-4-thiomethylpyrazole compound shown. [2]-The method described in the above [1] where X in general formula (2) is chlorine. [3] The manufacturer described in [1] or [2] where n is 0 [4] The manufacturer described in [1] or [2] where n is 2 [5] The reaction is based on water capture The production method described in any one of [1] to [4] in the presence of a functional additive. [6] The additive having a water-trapping effect is the production method of the above-mentioned [5], which is at least one selected from the group consisting of anhydrous sulfur chloride # § and sodium carbonate. The present invention is described in detail below. The present invention is a 5-hydroxy-4-thiomethyl compound represented by the general formula (1) and a halogenated difluoromethane represented by the general formula (2), in a di-C3 alkyl group, or a ketone or (C1 ~ C3 alkane). The reaction of acrylonitrile and sodium hydroxide is characterized by the reaction of 5-difluorinated methoxy · -8-(C1 ~ general formula), which is characterized by the general formula (3). The method of producing pyrazolyl (C1 ~ 4-thiomethyl 200540160 (5) in the presence of (5) based pyrazole compounds. First, the raw material compound represented by the general formula (1) of the raw material of the method of the present invention will be described. General formula ( Examples of R! In 1) include, for example, methyl, ethyl, η-propyl, isopropyl, η-butyl, sec-butyl, t-butyl, η-pentyl, and η-hexyl. And other straight or branched C1 ~ C6 alkyl groups; for example, monocyclic or condensed C6 ~ C10 aromatic hydrocarbon groups such as phenyl, naphthyl, etc. (the aromatic hydrocarbon groups are halogens having bromine, chlorine, fluorine, iodine, etc. Atom: For example, methyl, ethyl, η-propyl, isopropyl, η-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, etc. C6 alkyl; for example, methoxy, ethoxy Straight-chain or branched C1 ~ C6 alkoxy groups such as methyl, η-propoxy, isopropoxy, etc .; for example, methoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, etc. Branched (C1 ~ C6 alkoxy)-(C1 ~ C6 alkyl) groups; for example, linear or branched C1 ~ C6 halogenated alkyl groups such as fluoromethyl, difluoromethyl, trifluoromethyl, etc .; carboxyl groups; For example, linear or branched (C1 ~ C6 alkoxy) carbonyl groups such as methoxycarbonyl and ethoxycarbonyl; nitro; for example, methoxycarbonylmethyl, 1-methoxycarbonylethyl, 1 · ethoxycarbonylethyl Straight-chain or branched (C1 ~ C6 alkoxy) carbonyl- (C1 ~ C6 alkyl) groups; substituents such as cyano may also be used); for example, furyl, benzofuryl, pyridyl, thiophene Base, benzothienyl, oxazoline, benzoxazoline, thiazolyl, benzothiazolyl, isoxazoline, thiadiazolyl, pyrazinyl, pyrimidinyl, indolyl, D Quinolinyl, pyrazolinyl, imidazolinyl, benzimidazolinyl, triazolyl, sangenyl, etc., having at least one selected from nitrogen atom, oxygen atom, sulfur atom, etc. Heteroatoms with 5 to 1 atoms 4, preferably 5 to -9- 200540160 (6) 10 monocyclic or condensed ring aromatic heterocyclic group (the aromatic heterocyclic group, for example, a halogen atom having bromine, chlorine, fluorine, Yao, etc., such as formazan Straight-chain or branched Cl ~ C6 alkyl groups such as alkyl, ethyl, η · propyl, isopropyl, η-butyl, sec-butyl, t-butyl, η-pentyl, n-hexyl, etc .; for example Linear or branched C1 ~ C6 alkoxy groups such as methoxy, ethoxy, η-propoxy, isopropoxy, etc .; for example, methoxymethyl, 1-methoxyethyl, 1-ethoxyethyl (C1 ~ C6 alkoxy)-(C1 ~ C6 alkyl) groups; such as fluoromethyl, diφfluoromethyl, trifluoromethyl, etc. C6 haloalkyl; carboxyl; linear or branched (C1 ~ C6 alkoxy) carbonyl such as methoxycarbonyl, ethoxycarbonyl, etc .; nitro; for example, methoxycarbonylmethyl, 1-methoxycarbonylethyl Or branched (C1 ~ C6 alkoxy) carbonyl- (C1 ~ C6 alkyl), 1-ethoxycarbonylethyl, etc .; substituents such as cyano may also be used); or, for example, hydrofuryl, pyridine Sulfanyl, thiolanyl, thianyl, pyrrolidinyl, There are at least one heteroatomic atom selected from nitrogen atom, oxygen atom, sulfur atom φ represented by indolyl, tetrahydropyridyl, imidazolinyl, piperazinyl, etc., and the number of atoms constituting the ring is 5 to 14, preferably 5 to 10 monocyclic or condensed ring having no aromatic heterocyclic group (which does not have aromatic heterocyclic group, for example, having 1 or more halogen atoms such as bromine, chlorine, fluorine, iodine, etc. ; Such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, etc., straight or branched C1 ~ C6 Alkyl; straight or branched C1 ~ C6 alkoxy, such as methoxy, ethoxy, η-propoxy, isopropoxy, etc .; straight or branched, such as methylol, hydroxyethyl, etc. Branch C1 ~ C6 hydroxyalkyl; straight or branched (for example, methoxymethyl, methoxyethyl, ethoxyethyl, etc.) (C1 ~ C6 alkoxy)-(C1 ~ C6 -10- 200540160 (7) alkane Radicals); for example, linear or branched C1 to C6 halogenated alkyl groups such as fluoromethyl, difluoromethyl, trifluoromethyl, etc .; carboxyl groups; or alkali metal salts such as sodium, potassium, and lithium salts thereof, or Alkaline earth metals such as calcium, barium, and magnesium salts Representative metal carboxyl salts; such as linear or branched (C1 ~ C6 alkoxy) carbonyl groups such as methoxycarbonyl, ethoxycarbonyl, etc .; halogen atoms such as bromine, chlorine, fluorine, iodine; nitro; amine ; For example, methylamino, dimethylamino, ethylamino, diethylamine, etc., straight or branched mono- or di (C1 ~ C6 alkyl) amine φ group, such as acetamido Straight or branched (C1 ~ C6 alkyl) carbonylamino groups such as propylamino, butyrylamino, etc .; cyano; methylamidino; such as methylcarbonyl, ethylcarbonyl, etc. C1 ~ C6 alkyl) carbonyl group; for example, aryl carbonyl groups such as phenylfluorenyl, naphthyl fluorenyl and the like having an atomic number of 6 to 14, ideally 6 to 10: for example, pyridinecarbonyl, thiophenecarbonyl, furancarbonyl and the like having 1 Substitution of at least one heteroatom atom selected from nitrogen atom, oxygen atom and sulfur atom, and the number of atoms constituting the ring is 5 to 14, preferably 5 to 10, monocyclic or condensed ring heterocyclic aryl carbonyl group May have an aromatic heterocyclic group with or without φ. The electron withdrawing group represented by R2 in the general formula (1) means an atomic group that attracts an electron by an opponent with an inducing effect. Specifically, for example, a straight chain or a branch having one or more difluoromethyl groups, trifluoromethyl groups, and the like Branched C1 ~ C6 haloalkyl groups; carboxyl groups; for example, linear or branched (C1 ~ C6 alkoxy) carbonyl groups such as methoxycarbonyl, ethoxycarbonyl, etc .; halogen atoms such as bromine, chlorine, fluorine, iodine, etc .; Nitro; Formamyl; Linear or branched (C1 ~ C6 alkyl) carbonyl groups such as methylcarbonyl, ethylcarbonyl, etc .; Aminocarbonyl; Linear or branched (C1) groups such as methylaminocarbonyl ~ C6 alkyl) aminocarbonyl group; for example, di-11-200540160 (8) methylaminocarbonyl group, such as linear or branched di (Cl ~ C6 alkyl) aminocarbonyl group; cyano group; for example, chlorophenyl, Substituents represented by acetophenyl, nitrophenyl, acenaphthyl, etc., in order to induce an atomic group that attracts electrons by an opponent (eg, as described in the above example of an atomic group that attracts electrons by an opponent) Chain or branched C1 ~ C6 haloalkyl; carboxyl group; straight chain or branched (C1 ~ C6 alkoxy) carbonyl; halogen Nitro; formamyl; straight or branched (C1 ~ C6 alkyl) carbonyl; amino carbonyl; straight or branched (C1 ~ C6 alkyl) carbonyl; straight or branched di (C1 ~ C6 Alkyl) aminocarbonyl; monocyclic or condensed C6 to C10 aromatic hydrocarbon groups such as cyano and other atomic groups; cyanopyridyl, chlorophenyl, nitrofuranyl, methylpyridyl, etc. Base, having one or more atomic groups that attract electrons from an opponent with an inducing effect (such as the straight or branched C1 ~ C6 haloalkyl groups described above as examples of atomic groups that attract electrons with an opponent from an inducing effect; carboxyl; linear Or branched (C1 ~ C6 alkoxy) carbonyl; halogen atom; nitro; formamyl: straight or branched (C1 ~ C6 alkyl) carbonyl; aminocarbonyl; straight or branched (C1 ~ C6 Alkyl) aminocarbonyl; linear or branched di (C1 ~ C6 alkyl) aminocarbonyl; atomic groups such as cyano), having 1 to 4 at least one selected from nitrogen, oxygen, and sulfur atoms Heterogeneous atoms include monocyclic or condensed heterocyclic aryl groups having 5 to 14 atoms, preferably 5 to 10, and the like. The substituent represented by R3 in the general formula (1) includes, for example, methyl, ethyl, η · propyl, isopropyl, η-butyl, sec-butyl, t-butyl, and η · Straight-chain or branched C1 ~ C6 alkyl groups such as pentyl, η-hexyl, etc .; C6 ~ C10 aromatic hydrocarbon groups of monocyclic or condensed rings such as phenyl, naphthyl (the aromatic-12-200540160 (9) hydrocarbon group For example, halogen atoms having bromine, chlorine, fluorine, iodine, etc .; for example, methyl, ethyl, η-propyl, isopropyl, η-butyl, sec-butyl, t-butyl, η-pentyl, Straight-chain or branched C1 ~ C6 alkyl groups such as η-hexyl; hydroxyl groups; straight-chain or branched C1 ~ C6 alkoxy groups such as methoxy, ethoxy, η-propoxy, isopropoxy, etc. ; Such as methoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, etc., straight or branched (C1 ~ C6 alkoxy)-(Cl ~ C6 alkyl) groups; such as fluoromethyl, Difluoromethyl, trifluoromethyl, etc. linear or branched C1 ~ C6 halogenated alkyl groups; carboxyl groups; such as methoxycarbonyl, ethoxycarbonyl, etc. (C1 ~ C6 alkoxy) Carbonyl; for example, straight chain of methoxycarbonylmethyl, 1-methoxycarbonylethyl, 1-ethoxycarbonylethyl, etc. Or branched (C1 ~ C6 alkoxy) carbonyl- (C1 ~ C6 alkyl); substituents such as cyano may also be used); for example, furyl, benzofuranyl, pyridyl, thienyl, benzothiophene Base, oxazoline, benzoxazoline, thiazolyl, benzothiazolyl, isoxazoline, thiadiazolyl, pyrazinyl, pyrimidinyl, indolyl, quinolinyl, pyrazole Phenyl, imidazoline, benzimidazoline, triazolyl, triazolyl, etc. are represented by φ and have 1 to 4 at least one hetero atom selected from nitrogen, oxygen, and sulfur atoms, and constitute Single-ring or condensed-ring aromatic heterocyclic group having 5 to 14 ring atoms, preferably 5 to 10 (the aromatic heterocyclic group, such as a halogen atom of bromine, chlorine, fluorine, iodine, etc., such as methyl , Ethyl, η-propyl, isopropyl, butyl, sec-butyl, t-butyl, η-pentyl, η-hexyl, etc., straight or branched C1 to C6 alkyl groups; hydroxyl groups; for example Linear or branched C1 ~ C6 alkoxy groups such as methoxy, ethoxy, η-propoxy, isopropoxy, etc .: e.g. methoxymethyl, 1-methoxyethyl, 1-ethoxyethyl Straight chain or branch (C1 ~ C6 alkoxy)-(C1 ~ C6 alkyl) groups; for example, fluoromethyl, -13- 200540160 (10) straight or branched Cl ~ C6 haloalkyl groups such as difluoromethyl, trifluoromethyl; Carboxy; straight or branched (C1 ~ C6 alkoxy) carbonyl such as methoxycarbonyl, ethoxycarbonyl, etc .; nitro; for example, methoxycarbonylmethyl, 1 · methoxycarbonylethyl, 1-ethoxy Linear or branched (C1 ~ C6 alkoxy) such as carbonylethyl, carbonyl- (C1 ~ C6 alkyl); substituents such as cyano may also be used); or, for example, hydrofuryl, pyranyl, tetrahydro Thioranyl, thianyl, pyrrolidinyl, indolyl, tetrahydropyridyl, imidazolinyl, piperazinyl, etc. have 1 to 4 represented by nitrogen, oxygen, sulfur At least one heteroatomic atom selected for the atom, the number of atoms constituting the ring is 5 to 14, preferably 5 to 10, a monocyclic or condensed ring having no aromatic heterocyclic group (which does not have an aromatic heterocyclic group, For example, it has one or more halogen atoms such as bromine, chlorine, fluorine, iodine, etc., such as methyl, ethyl, η-propyl, isopropyl, η-butyl, sec-butyl, t-butyl, η- Amyl, η-hexane And other straight or branched C1 ~ C6 alkyl groups; hydroxyl groups; for example, methoxy, ethoxy, η-propoxy, isopropoxy, etc. straight or branched C1 ~ C6 alkyloxy groups; Linear or branched (C1 ~ C6 alkoxy)-(C1 ~ C6 alkyl) groups such as oxymethyl, methoxyethyl, and ethoxyethyl; for example, fluoromethyl, difluoromethyl, trifluoro A linear or branched C1 ~ C6 haloalkyl group such as a methyl group; a carboxyl group; or an alkali metal salt thereof such as sodium salt, potassium salt, lithium salt, or an alkaline earth metal salt such as calcium salt, barium salt, or magnesium salt; Carboxylic metal salts; linear or branched (C1 ~ C6 alkoxy) carbonyl groups such as methoxycarbonyl, ethoxycarbonyl, etc .; halogen atoms such as bromine, chlorine, fluorine, iodine, etc .; nitro groups; amine groups; Straight-chain or branched mono- or di- (C 1 to C 6 alkyl) amine groups, such as ethylamino, dimethylamino, ethylamino, diethylamino, etc., such as ethylamino, propylamino Aminobutyrylamido-14- 200540160 (11) Linear or branched (C1 ~ C6 alkyl) carbonylamino; cyano; methylamidino; straight chain such as methylcarbonyl, ethylcarbonyl, etc. Or branched (C1 ~ C6 alkyl) carbonyl For example, the number of atoms constituting a ring such as phenylfluorenyl, naphthyl, and the like is 6 to 14, and an arylcarbonyl group, such as 6 to 10, which has 1 to 4 at least one kind selected from a nitrogen atom, an oxygen atom, and a sulfur atom. It is a monocyclic or condensed ring heterocyclic carbonyl substituent of 5 to 14 atoms, preferably 5 to 10 atoms, and may or may not have an aromatic heterocyclic group. When η in formula (1) is 0, the compound represented by general formula (1) is a sulfide, and when η is 2, the compound represented by general formula (2) is a code. The 5-hydroxy-4-thiomethylpyrazole compound represented by the general formula (1) is a known compound or, for example, the reaction of 5-hydroxypyrazoles with formaldehyde and sulfur compounds described in Reference Examples 1 to 4 described later, Can be easily synthesized. Next, a halogenated difluoromethane represented by the general formula (2) will be described. X in the general formula (2) is an atom such as fluorine, chlorine, bromine, or iodine. Therefore, the halogenated difluoromethane of the general formula (2) that can be used in the present reaction can be exemplified by trifluoromethane, chlorodifluoromethane, bromodifluoromethane, and difluoroiodomethane. Desirable examples include chlorodifluoromethane and bromodifluoromethane, and particularly preferred is chlorodifluoromethane. The molar ratio of the halogenated difluoromethane represented by the general formula (2) can be reacted with the 5-hydroxy-4-thiomethylpyrazole compound represented by the general formula (1) at any molar ratio. . Among them, the molar ratio of the 5-hydroxy-4-thiomethylpyrazole compound represented by the general formula (1) is 1 mole ratio. The halogenated difluoromethane represented by the general formula (2) is usually 0.1 to 10.0 mole ratio. The ideal range is -15-200540160 (12) 1.0 to 5.0 mole ratio, and more preferably 1.3 to 2.2 mole ratio. This reaction can be performed using sodium hydroxide. The sodium hydroxide used in the reaction may be solid sodium hydroxide. Commercially available 96% sodium hydroxide or commercially available granular 99% sodium hydroxide is preferred, especially 9 9 % Sodium hydroxide is more desirable. The amount of sodium hydroxide to be used may be any amount as long as the reaction can proceed sufficiently. Among them, it is 1.0 to 20 moles, preferably 1.5 to 10 moles, and more preferably 2.0 to 3.0 moles, with respect to the 5-hydroxy-4 · thiomethylpyrazole compound represented by 1 mole in general formula (1). Range. In this reaction, the additive is presumed to capture the water produced as a by-product with the reaction in the reaction system. Anhydrous sodium sulfate, calcium chloride, and / or sodium carbonate coexist in the reaction system, especially when the yield is enlarged. Improve stability. In addition, the addition of this additive suppresses the hydrolysis of halogenated difluoromethane, and as a result, the reduction in the amount of halogenated difluoromethane used is related. The amount of the additive to be used is not particularly limited, and it is 0.01 to 20 mol, and preferably 0.1 to 10 mol relative to the 5-hydroxy-4-thiomethylpyrazole compound represented by the general formula (1). More preferably, a range of 0.2 to 5.0 mol can exhibit sufficient effects. From the observation of the present inventors, the additive is presumed to be a job for capturing water by-produced with the reaction in the reaction system, and a job for capturing water by-produced with the reaction in the reaction system may use substances other than those exemplified above. These substances. This reaction can be carried out, for example, in the presence of a bis (C1 to C3 alkyl) ketone such as acetone or methyl ethyl ketone; or a (C1 to C3 alkyl) nitrile such as acetonitrile or propiononitrile. Usually, the reaction solvent can also be used for the reaction. The reaction system can fully stir -16-200540160 (13) The excess amount is mixed, and it is usually 0.05 ~ 10 L compared with 1 mole of the raw material compound represented by general formula (1). It is preferably 0.3 to 5 L, and more preferably 0.5 to 2 L. Use bis (C1 ~ C3 alkyl) ketone, (C1 ~ C3 alkyl) nitrile alone, or a solvent that does not hinder the reaction, such as aromatic hydrocarbons that can be mixed with toluene, xylene, chlorobenzene, etc .; dichloromethane, Halogenated aliphatic hydrocarbons such as chloroform; ether solvents such as diethyl ether and diisopropyl ether; and aliphatic φ hydrocarbons such as pentane and hexane are used. However, the mixing ratio of di (C1 ~ C3 alkyl) ketone and (C1 ~ C3 alkyl) nitrile is extremely reduced, and the reaction rate decreases as the reaction rate is not ideal. The mixing ratio (capacity) relative to the mixed solvent of aromatic hydrocarbons and the like Ratio) is 1 or more (that is, the mixed solvent of aromatic hydrocarbons and the like is equal or more), it is desirable to mix di (C1 ~ C3 alkyl) ketone and (C1 ~ C3 alkyl) nitrile with a solvent that does not hinder the reaction When used in combination, the amount used is within the above-mentioned range (relative to the starting compound 1 mol di (C1 ~ C3 alkyl) ketone, (C1 ~ C3 alkyl) nitrile) represented by the general formula (1), and is usually 0 · 〇. 1 ~ 10 L, the ideal φ is 0.3 ~ 5L, more preferably 0.5 ~ 2L). The total solvent amount is preferably an amount sufficient for the reaction system to be sufficiently agitated, and is usually from 0.001 to L, and more preferably from 0.5 to 2 L, relative to the raw compound 1 mole represented by the general formula (1). The reaction temperature of this reaction must be carried out at -10 ° C to 35 ° C, and the reaction rate is preferably 0 t to 10 ° C. The reaction time of this reaction is not particularly limited, and the reaction rate varies depending on the introduction rate of the halogenated difluoromethane represented by the general formula (2). The reaction is usually completed within 1 to 30 hours. -17- 200540160 (14) There is no particular limitation on the order and method of adding each component to the reaction. A suitable example is to add an alkali to the organic layer, add a raw material compound represented by the general formula (1) to a suspension state, and then introduce a halogenated difluoromethane represented by the general formula (2) to react to obtain a general compound. Method of the product represented by formula (3). According to this reaction, a 5-hydroxy-4-thiomethylpyridine compound represented by the general formula (1) and a halogenated difluoromethane represented by the general formula (2) are used in the presence of sodium hydroxide φ. (C1 ~ C3 alkyl) ketones and (C1 ~ C3 alkyl) nitriles generate 5-difluorinated methoxy-4-thiomethylpyrazole compounds represented by the general formula (3), and are used as medicine, Compounds of pesticide intermediates. [Embodiment] The following describes the manufacturing method of the present invention with reference examples and examples. The present invention is not limited to the examples. φ (Reference Example 1) 3-[(5-hydroxy-1-methyl · 3-trifluoromethylpyrazole-4- 醯) -methylsulfan 4,5-dihydro-5,5-dimethyl Synthesis of diisoxazole 5-hydroxy-1 · methyl-3-trifluoromethanepyrazole 1.7 g (10 mmol) and sodium hydroxide K6 g (40 mmol) solvent in 10 ml of water. After the solution was stirred at room temperature, 1.7 g (20 mmol) of a 35% aqueous formaldehyde solution (35% formalin solution) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. Here, 10 ml of an aqueous solution of [5,5-dimethyl (4,5-dihydroisoD-oxazol-3-])] thiocarboxamidine hydrochloride (2.1 g (10 mmol)) was added dropwise. 'Stir for 2 hours. After the reaction, drip at 35 ° /. 5.0 g (50 mmol) of hydrochloric acid. The precipitated crystals were suction-filtered -18- 200540160 (15) and washed twice with 5 ml of water. Drying with a warm air dryer gave 2.5 g (yield 80.1%) of the title compound as pale yellow crystals. The obtained crystals were recrystallized from a η-hexane / 2-propanol mixed solvent to obtain white crystals. ] H-NMR 値 (3 00 MHz, MeOH-d4): 〇 = 4.88 (br, 1H), 4.08 (s, 2H), 3.64 (s, 3H), 2.91 (s, 2H),] 39 (s , 6H) ppm o

LC ~ MS (El) · m / z = 3 09 (M +) »17 7 (base) φ Melting point: 1 1 5-1 1 6 ° C (Reference Example 2) 5 · Hydroxy-1-methyl Synthesis of 4-methylthiomethyl-3-trifluoromethylpyrazole 5-hydroxy-1-methyl-3-trifluoromethanepyrazole 1.7 g (10 mmol) and sodium hydroxide 0.6 g ( 15 mmol) of solvent in 10 ml of water. After the solution was stirred at room temperature, 1.7 g (20 mmol) of a 35% formaldehyde aqueous solution (35% formalin solution) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. At room temperature, 7.1 g (10 mmol) of a 10% sodium sulfur methyl alkoxide aqueous metal solution was added dropwise, and the mixture was stirred for 6 hours. After the reaction, 5.0 g (50 mmol) of 3 5% hydrochloric acid was added dropwise. The precipitated crystals were filtered with suction and washed twice with 5 ml of water. Drying with a warm air dryer gave 1.6 g (yield 72.7%) of the title compound as pale yellow crystals. The obtained crystals were recrystallized from a water-methanol mixed solvent to obtain white crystals. iH-NMR 値 (300 MHz, MeOH-d4): a = 4.86 (br, 1H), 3.64 (s, 3H), 3.56 (s, 2H), 2.02 (s, 3H) ppm. LC-MS (El) · m / z = 226 (M +), 179 (base)

Melting point: 123-124 ° C -19 · 200540160 (16) (Reference Example 3) 4-[(5-hydroxy-p-methyl-3-trifluoromethylpyrazole-4- 醯) · methylsulfonium] toluene Synthesis

5-Hydroxy-1-methyl-3-trifluoromethanepyrazole 8.3 g (50 mmol) and sodium hydroxide 3.0 g (7.5 m m ο 1) were dissolved in 50 m 1 of water. After the solution was stirred at room temperature, 8.5 g (100 mmol) of a 35% formaldehyde aqueous solution (35% formalin solution) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. Here, 9.0 g (50 mmol) of sodium toluenesulfinate was added at room temperature and stirred for 2 hours. After the reaction, 25.0 g (2 50 mmol) of 35% hydrochloric acid was added dropwise, and 100 ml of water was further added. The precipitated crystals were filtered with suction and washed twice with 20 ml of water. Drying with a warm air dryer gave 14.0 g (yield 83.8%) of the title compound as white crystals. j-NMR 値 (3 00 MHz, MeOH-d4) · σ = 7.62 (d; J = 8.4 Hz, 2H), 7.39 (d; J = 8.4 Hz, 2H), 4.85 (br, 1H), 4.32 (s, 2H), 3.63 (s, 3H), 2 · 4 4 (s, 3 H) ppm 〇 LC-MS (El): m / z = 3 34 (M +), 179 (base)

Melting point: 1 3 5 ° C (Reference Example 4) Synthesis of 4- [3-cyano-5-hydroxy-1-phenylpyrazole-4- 醯] -methylsulfo] toluene 5-hydroxy-1 -1.8 g (10 mmol) of methyl-3-trifluoromethanepyrazole and 0.6 g (15 mmol) of sodium hydroxide in 10 ml of water. After the solution was stirred at room temperature, 1.7 g (20 mmol) of a 35% aqueous formaldehyde solution (35% formalin solution) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. Here, 1.8 g (10 mmol) of sodium toluenesulfinate was added at room temperature and stirred for 2 hours. After the reaction, 5.0 g (50 mmol) of 35% hydrochloric acid was added dropwise, and 20 ml of water was further added. The precipitated crystals were filtered with suction -20- 200540160 (17), and washed twice with 20 ml of water. Drying with a warm air dryer gave 3.0 g (yield 85.7%) of the title compound as pale yellow crystals. j-NMR 値 (300 MHz, MeOH-d4): σ = 7.4-7.7 (m; 9H), 4.86 (s, 1H), 4.40 (s, 2H), 2.46 (s, 3H) ppm LC-MS (El): m / z = 3 5 3 (M +), 197 (base)

Melting point: 2 1 4 ° C φ Example 1: 3- [5-Difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4- 醯] -methylsulfide] _4,5 -Synthesis of dihydro-5,5-dimethylisoxazole in 100 ml of acetonitrile, and 3-[(5-hydroxy-1-methyl-3-trifluoromethylpyrazole) synthesized in Reference Example 1 was added 4- 醯) · methylsulfur] -4,5-dihydro-5,5-dimethylisoxazole 33.2 g (purity 93.3%, 0.1 mol) and 99% sodium hydroxide 12.0 g (0.3 mol ), And stirred at room temperature for 1 hour. After the suspension was ice-cooled and kept in the range of 5 to 15 ° C, 17.3 g (0.2 mol) of chlorodifluoromethane was introduced over a period of 4 hours and reacted in the same temperature range for 5 hours. After the reaction is completed, add 100 ml toluene, 50 ml water and 10 ml 35 ° /. Hydrochloric acid, and the organic layer was separated. After the aqueous layer was re-extracted at 50 ml, the combined organic layer was washed in the order of 50 ml of water and 20 ml of saturated saline. The obtained organic layer was dried over sodium sulfate, and the solvent was distilled off to obtain 38.0 g of the title compound (purity: 85%, purity: 90%) as a reddish brown liquid. The product was purified by silica gel column chromatography (developing solvent; hexane / ethyl acetate = 4/1) to obtain the title compound 22.6 as white crystals. 4-NMR 値 (3 00 MHz, CDC13) ·· σ = 6.72 (t; J = 72Hz, 1H), 4.17 (s, 2H), 3.80 (s, 3H), 2.77 (s, 2H), 1.40 21-200540160 (18) (s, 6H) GC-MS (El): m / z = 3 5 9 (M +), 179 (base)

Melting point: 47-48 ° C In the following Examples 2 to 5, the internal standard analysis method (internal standard; η-octylbenzene) of the compound obtained in Example 丨 as a standard was used to calculate the production φ Example 2: 3- The yield of [(5-difluoromethoxy-1-methyl-3 · trifluoromethylpyrazolidine) -methylthio] -4,5-dihydro-5,5-dimethylisoxazole was confirmed at 20 ml of acetonitrile, η · octylbenzene g (internal standard material), 3 · [(5 · hydroxy-1-methyl-3 · trifluoromethylpyrazole-4 ··) synthesized in Reference Example 1 Methylsulfur] -4,5-dihydro-5,5-dimethylisoxazole 1.7 g (purity 93.3%, 0.001 mmol) and 99% sodium hydroxide 1.2 g (0.3 mmol), and stirred at room temperature for 1 hour. After the suspension was kept cold in the range of 0 to 100 ° C, an excessive amount of chlorodifluoromethane was introduced using a balloon, and after 1 hour from the start of blowing, a sample of the reaction solution was taken and a gas chromatograph was used. The reaction yield was calculated according to an internal standard analysis method, and the yield was 89%. Examples 3 to 5 and Comparative Examples 1 to 9 In the same manner as in Example 2, the reaction was performed in various solvents (total amount: 20 ml). The results are summarized in Table 1. In the reaction of the comparative example, 0.05 g of tetrabutylammonium bromide, a related mobile catalyst, was added to each of them. In addition, the solvent term in (Table 1) indicates the capacity ratio by "v · · v". -22- 200540160 (19) [Table 1]

Example No. Solvent reaction time yield (%) • —---- Residue of raw material (%) 2 Acetonitrile 1 89 0 3 Acetone 1 86 0 4 Acetonitrile: toluene (v · · v = 1: 1 ) 5 89 0 5 Acetone: Toluene (v · v = 1 · 1) 3 93 0 Comparative Example 1 Toluene: Water (v: v = 1: 1) 20 28 15 Comparative Example 2 Toluene 20 50 23 Comparative Example 3 Chlorobenzene 20 33 5 5 Comparative example 4 Dimethoxyethane 20 68 0 Comparative example 5 Tetrahydrofuran 20 69 6 Comparative example 6 Diisopropyl ether 20 2 77 Comparative example 7 1-Methyl-2-pyrrolyldione 20 72 11 Comparative Example 8 2-propanol 3 10 11 Comparative Example 9 _4-methyl-2-pentanone 20 41 27 (Comparative Example 10). Except that 99% sodium hydroxide of Example 2 was replaced with 99% potassium hydroxide ( The same mole number was used, and the same reaction was performed as in Example 2. -23- 200540160 (20) Results After 1 hour from the start of the blow-in analysis, only 10% of the target substance was formed, the raw materials had disappeared, and the remaining substances were decomposed products. (Comparative Example 11) A reaction was performed in the same manner as in Example 2 except that the sodium hydroxide of Example 2 was replaced with potassium hydroxide (using the same mole number). As a result, analysis was performed 24 hours after the start of blowing, and only 1% of the target substance was formed, and the remainder was the raw material. Example 6: 5-Difluoromethoxy-1-methyl-4-methylthiomethyl-3 · trifluoro Synthesis of methylpyrazole in 10 ml of acetonitrile, 5-hydroxy-1-methyl-4-methylthiomethyl-3-trifluoromethylpyrazole synthesized in Reference Example 2 1.2 g (5 mmol) And 99% sodium hydroxide 0.6 g (15 mm ο 1), and stirred at room temperature for 1 hour. After the suspension was ice-cooled and kept in the range of 0 to 10 ° C, an excessive amount of chlorodi | fluroin was introduced using a balloon. After 1 hour from the start of blowing, the balloon was disassembled and 20 ml of water was added to the reaction solution. 20 ml of ethyl acetate, and the organic layer was separated. Furthermore, the aqueous layer was re-extracted with 20 ml of ethyl acetate, and the combined organic layer was washed with 10 ml of water and 10 ml of saturated saline in this order. The obtained organic layer was dried over sodium sulfate, and the solvent was distilled off to obtain 1.2 g (yield 88%) of the title compound as a pale yellow liquid. OW-NMR 値 (3 00 MHz, CDC13): 〇 = 6.82 (t; J = 72.6 Ηζ, 1Η), 3.82 (s, 3H), 3.61 (s, 2H), 2.09 (s, 3H) GC-MS (El) · m / z = 276 (M +), 179 (base) -24- 200540160 (21) Example 7: Synthesis of 4-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4 • 醯) -methylsulfonium] toluene 10 ml of acetonitrile, 1.7 g (5 mmol) of 4-[(5 · hydroxy-1-methyl-3-trifluoromethylpyrazole-4- 醯) -methylsulfonium] toluene synthesized in Reference Example 3 and 99% sodium hydroxide 0.6 g (15 mm ο 1), and stirred at room temperature for 1 hour. After the suspension was kept cold at a temperature of 0 to 10 ° C, an excessive amount of chlorodifluoromethane was introduced using a balloon. After 1 hour from the start of blowing, the balloon was disassembled, and 20 ml of water was added to the reaction solution. 20 ml of ethyl acetate, and the organic layer was separated. The aqueous layer was re-extracted with 20 ml of ethyl acetate, and the combined organic layer was washed with 10 mi of water and 10 ml of saturated saline in this order. The obtained organic layer was dried over sodium sulfate, and the solvent was distilled off to obtain 2.1 g (yield: 99%) of the title compound as pale yellow crystals. The obtained crystals were recrystallized from? -Hexane-2-propanol to obtain white crystals. 4-NMR 値 (3 00 MHz, CDC13): a = 7.70 (d; J = 8.4Hz, 2H) »7.35 (d; J = 8.4Hz, 2H) > 6.99 (t; J = 72.4Hz •, 1H ), 4.12 (s, 2H), 3.85 (s, 3H), 2.46 (s, 3H) GC-MS (El): m / z = 384 (M +), 229 (base) Example 8: 4- [ (3-Cyano-5-difluoromethyl-1-phenylpyrazole · 4- 醯) methylsulfonyl] toluene was synthesized in 10 ml of acetonitrile, and 4 in Synthesis of Reference Example 4 [3 -Cyano-5-acyl · 1-phenylpyrazole-4- 醯] • methylsulfo] toluene · 8 g (5 mmol) and 99% sodium hydroxide 0.6 g (15 mmol), Stir at room temperature for 1 hour. The suspension was cooled with ice and kept in the range of 0 to 10 ° C. '-25- 200540160 (22) chlorodifluoromethane was introduced in excess using a balloon, and the balloon was disassembled and reacted after 1 hour from the start of blowing. 20 ml of water and 20 ml of ethyl acetate were added to the solution, and the organic layer was separated. The aqueous layer was re-extracted with ethyl ester, and the combined organic layer was washed with 10 ml of water and 10 ml of saturated saline in this order. The obtained organic layer was dried over sodium sulfate, and the solvent was distilled off to obtain 1.8 g (yield 88%) of the title compound as pale yellow crystals. The obtained crystals were recrystallized from? -Hexane-2-propanol to obtain white crystals. ! H-NMR 値 (300 MHz, CDC13): σ = 7.75 (d; • J = 8.4Hz, 2H), 7.6-7.4 (m, 5H), 7.41 (t; J = 8 · 4Ηζ, 2H) , 6.87 (t; J = 72.4Hz, 1H), 4.31 (s, 2H), 2.49 (s, 3H) GC-MS (El): m / z = 403 (M +), 248 (base) Example 9 : 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4- 醯) -methylsulfide] -4,5-dihydro-5, when using the additive sodium carbonate, Synthesis of 5-dimethylisoxazole from acetonitrile 1,000,000. Addition of 3-[(5-hydroxy-1-φmethyl-3-trifluoromethylpyrazole-4-醯) -Methylsulfur] -4,5 · Dihydro-5,5-dimethylisoxazole 320g (purity 96.8 ° / 〇, 1mol) and 99% sodium hydroxide 1208 (3 mol) and carbonic acid 53 g (0.5 mol) of sodium were stirred at room temperature for 1 hour. After the suspension was kept cold at 5 to 15 ° C, the suspension was introduced with 130 g (1.5 mol) of chlorodifluoromethane over 4 hours, and reacted at the same temperature range for 6 hours. After the reaction was completed, 1,000 ml of water was added, and the organic layer was separated. After the aqueous layer was re-extracted with 300 ml of acetonitrile, the organic layer was combined. The organic layer was analyzed for the reaction yield using a gas chromatograph in accordance with an internal standard analysis method. The yield was 91%. -26- 200540160 (23) [Industrial application field] The present invention provides a 5-difluorinated methoxy-4-thiomethanine manufacturing method. According to the present invention, thiomethylpyrazole and halogenated dihalide are easily used. As a raw material, fluoromethane is used to simplify methoxy-4-thiomethylpyrazole compounds. The intermediates useful in the manufacture of pharmaceuticals and pesticides are obtained in the high yield of the present invention as a 4-thiomethylpyrazole compound. In addition, the present invention refers to the entire specification of the application No. 2004-1 32764 dated April 28, 2004, and the entire contents of the patent application, and is incorporated into the 5-hydroxy-4-operation of the novel pyrazolium compound as the disclosure of the present specification. 5-Difluoride raw material has less decomposition, and 5-difluoromethoxy is available. Japanese Patent Application Scope and Summary of Invention

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Claims (1)

200540160 (1) 10. Scope of patent application 1. A method for producing a 5-difluoromethoxy-4-thiomethylpyrazol compound such as the general formula (3), which is characterized in that the general formula (1) (Where 'R! Is an alkyl group, an aromatic hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, R2 is an electron recovery group, R3 is an alkyl group, an aromatic hydrocarbon group which may have a substituent or may have A heterocyclic group of a substituent, η is 0 or 2) a 5-hydroxy-4-thiomethylpyrazole compound represented by the formula (2) CHF2 X (2) (In the formula, X is a halogen atom.) The halogenated difluoromethane shown in the presence of bis (C1 ~ C3 alkyl) ketone or (C1 ~ e3 alkyl) nitrile, and sodium hydroxide is the reactor R2 plant S { 0) n_R3) T \ ν, ν into 0chf2 I Rl (3) (where Ri, R2, R3 and n have the same meaning as above). -28- 200540160 (2) 2. For example, the method for producing 5-difluorinated methyl 4-difluoride compound of item 1 in the scope of patent application, wherein in the general formula (2) is 〇3. As item 1 or 2 of the scope of patent application 5_ Method for producing difluoroprimary methyl gel compounds, which one. 4 · If the scope of patent application is 1 or 2 of 5 _ two gas production method of methylpyrazole compounds, where η is two. 5. The method for producing an oxy-4-thiomethylpyrazole compound according to any one of items 1 to 4 of the patent application, wherein the additive is carried out in the presence of β water trapping additives. 6. The method for producing 5-dimethoxypyridine difluoride compound according to item 5 of the scope of patent application, which has water trapping water as a group selected from the group consisting of anhydrous sodium sulfate, calcium chloride, and sodium carbonate. 0 I Where X of the methyl-4-thiomethyl group is chlorine, methoxy-4-thiomethoxy-4 -thio 5-difluoromethane [should be at least one of the additives for the 1 kind -29- 200540160 VII. Designated Representative Map: (1) The designated representative map in this case is: None (II) The component representative symbol of this representative map is simply explained: None 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: r2, N; -S (〇) n-R3, OCHF2 Ri (3)