WO2004048346A1

WO2004048346A1 - Process for producing 1-substituted 4-carbamoyl-1,2,4-triazol-5-one derivative

Info

Publication number: WO2004048346A1
Application number: PCT/JP2003/015189
Authority: WO
Inventors: Hiroyuki Okita; Tsunehiro Kido
Original assignee: Hokko Chemical Industry Co., Ltd.
Priority date: 2002-11-28
Filing date: 2003-11-27
Publication date: 2004-06-10
Also published as: JP4397579B2; JP2004175756A

Abstract

A process for producing a 1-substituted 4-carbamoyl-1,2,4-triazol-5-one derivative represented by the following general formula (I): (I) (wherein X represents halogeno or lower alkyl; Y represents halogeno; R represents lower alkyl; and n and m each is an integer of 0 to 5), characterized by reacting a 1-substituted 1,2,4-triazol-5-one derivative with a carbamoyl chloride compound in an organic solvent and/or water in the presence of a dehydrochlorinating agent and a phase-transfer catalyst.

Description

Method for producing 1-substituted-4 triazole-5-one derivatives

Technical field

Light

The present invention relates to a method for producing a 1-substituted-4-carbamyl-1,2,4-triazole-5-one derivative. More specifically, the present invention relates to a 1-substituted-4 __________________________. The present invention relates to a method for producing a high-yield and high-quality product in a simple and low-cost manner by a reaction to be used.

Background art

The following general formula (I)

[Wherein, X represents a halogen atom or a lower alkyl group, Y represents a nitrogen atom, R represents a lower alkyl group, and n and m each represent an integer of 0-5. The mono-substituted-4--4-carbamoyl-1,2,4-triazol-5-one derivative represented by the formula [1] is a compound useful as an active ingredient of a herbicide. Wherein the following general formula (II)

[Wherein, X and n are as defined above. 1-substituted-1,2,4-triazole-5-one derivative represented by the following general formula (III)

[Wherein, Y, R and m are as defined above. Is known in the art in the presence of a dehydrochlorinating agent (see WO 98/38176, pamphlet (pp. 85-87)).

However, in the production method described in this document, considering the reactivity and the like, for example, a combination of an organic solvent, acetonitrile, and a dehydrochlorination agent, carbon dioxide lime, and the role of both the solvent and the dehydrochlorination agent It may be necessary to use a relatively expensive combination of an organic solvent and a dehydrochlorinating agent, such as pyridine. Further, depending on the combination of the organic solvent and the dehydrochlorinating agent, the reaction rate may be low, and even if the reaction proceeds, the desired product may not be obtained in a satisfactory yield, or the reaction may not proceed at all.

Still, in the purification step of the target product, the operation is complicated, for example, after the reaction solvent is distilled off and the extraction solvent is added again, the cost may be high due to complicated operations. I'm sorry. Therefore, in order to provide the desired product at a lower cost, the 1-substituted-4-substituted-l-bamoyl-1,2-, 4-triazole of the general formula (I), which is intended to be simpler, lower-cost and higher in yield, is desired. The development of an industrial method capable of producing 5-one derivatives has been desired.

The present invention seeks to solve the above-mentioned problems associated with the prior art, and is simple, low-cost, high-yield, and high-quality 1-substituted-4-carbamoyl-1,2,2. It is intended to provide a method for producing a 4-triazol-5-one derivative. Disclosure of the invention

The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, by using an inexpensive reaction solvent and a combination of a dehydrochlorinating agent by using a phase-transfer catalyst, the formula (I) was used. That the 1-substituted-4-carbamyl-1,2,4-triazol-5-one derivatives used are obtained in high yield, high purity and high quality, and can be produced industrially advantageously. And found the present invention.

That is, the method for producing the 1-substituted-4-carbamoyl-1,2,4-triazol-5-one derivative according to the present invention comprises the 1-substituted-1,2 represented by the general formula (II). , 4 Triazol-5-one derivative and carpamoyl chloride represented by the above general formula (III) are subjected to a dehydrochlorination reaction in a solvent in the presence of a dehydrochlorinating agent to give a compound of the above general formula (I) The production of 1-substituted-4- 4-rubbamoyl-1,2,4-triazol-5-one derivatives is characterized by reacting with a phase transfer catalyst.

In the present invention, in the above production method, an aromatic hydrocarbon and a solvent may be used as the solvent. It is preferable to use water and / or alkali metal hydroxide or alkaline metal carbonate as a dehydrochlorinating agent.

In the present invention, in the above production method, the phase transfer catalyst may be any one selected from the group consisting of quaternary ammonium salts, phosphonium salts, amines, crown ethers, cryptands, linear polyethylene glycol derivatives, and cyclodextrins. It is preferable to use such a compound.

According to the present invention, a 1-substituted--carpamoyl-1,2,4-triazol-5-one derivative, which is a compound useful as an active ingredient of a herbicide, can be prepared simply and at low cost by a reaction using a phase transfer catalyst. Therefore, it can be manufactured with high yield and high quality. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described specifically. The scheme of the reaction of the present invention is as follows.

In the present invention, as shown in the following scheme, a 1-substituted-1,2,4-triazol-5-one derivative represented by the following general formula (II) (hereinafter, 1-substituted-1,2,4- A triazole-5-one derivative (11), also referred to as compound (II), etc.) is converted to a carbamoyl chloride represented by the following general formula (III) (hereinafter, carbamoyl chloride (クロ), a compound ( III), etc.) and in a solvent or Z or water, in the presence of a dehydrochlorinating agent, by adding a phase transfer catalyst and reacting at room temperature or under heating conditions to obtain a compound represented by the following general formula (I). 1-substitution-4-carbamoyl-1,2,4-triazole-5 -one derivative (hereinafter, 1-substitution-4-carpamoyl-1, 2, 4-triazole-5 _one derivative (1 ), Compound (I), etc.) can be produced.

I ") (in) (1)

[In the formula, X represents a halogen atom or a lower alkyl group, γ represents a halogen atom, .R represents a lower alkyl group, and n and m each represent an integer of 0-5. Π. X pieces! ! !丫 may be the same as each other and may be different from each other. When X and Y are halogen atoms, they may be the same or different. When X and R are lower alkyl 'groups, they may be the same or different from each other. ]

In the above general formulas (1) and (II), the “lower alkyl group” in the definition of X includes a linear or branched one having 1 to 6 carbon atoms. Specifically, for example, methyl, ethyl, n-propyl, isopropyl, n-butino, isobutenole, s-butyl, t-butynole, n-pentyl, isopennole, 2-methinoleptyl, neopentinole, n-hexyl, 4 -Methynorpentyl, 3-methylpentyl, 2-methylpentyl, 3,3-dimethylbutynole, 1,1-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1-ethylbutyl, 1-ethyl -2 -Methylpropynole, 1-methylol- 1-methylpropyl, 1-methyl-ethylpropyl, 2-methyl-1-ethylpropyl, 2-methyl-2-ethylpropyl and the like. In the above general formulas (1) and '(III), the “lower alkyl group” in the definition of R includes, for example, the same as the lower alkyl group for X described above. Replacement form (Rule 26) In the above general formulas (1), (11) and (III), in the definition of X and Y

As the “halogen atom”, specifically, each atom of fluorine, chlorine, bromine or iodine is used.

In particular, X is preferably a chlorine atom, a fluorine atom or a methyl group, and those in which X is bonded to the 2,4-, 2,3- or 2-position of the phenyl group are preferred from the viewpoint of product yield. .

In particular, Y is preferably a fluorine atom or a chlorine atom, and those bonded to the 2, 4- or 4-position of the phenyl group are preferable from the viewpoint of the yield of the product.

As the 1-substituted-1,2,4 triazol-5-one derivative of the above general formula (II), specifically, for example, 1-phenyl-1,2,4-triazol-5-one, 1— ( 2—Black mouth feninole) — 1, 2,4—Triazonole — 5—one, 1— (3—Black mouth phenyl)-1,2,4—Triazonole — 5—year-old, one-one (2— Full-year lofenyl) -1,2,4-triazonole — 5—on, 1— (2-bromopheny: le)-1,2,4-triasol — 5—on, 1- (2-3 ) — 1,2,4— Triazole — 5 -one, 1-(2-methylphenyl) — 1,2,4-Triazole — 5 -one, 1-(2,4-Dichlophenyl)-1,2, 4-Triazole-5-one, 1-(2,4-diphenyl phenyl)-1,2,4-Triazole-5-one, 1-(2,4-diphenyl mophenyl)-1,2, 4- Triazole-5-one, 1-(2,4-di 1- (2,4-Dimethylphenyl)-1,2,4-Triazole-5 -one, 1-(2,4-Dimethylphenyl)-1,2,4-Triazole-5 -one, 1-(2,3 -Dimethylphenyl) -1,2,4-Triazole-5-ON, 1-(2-Fluoro-

4 ク σ-rophenyl) -1,2,4-triazo, Loro — 4-methinolepheninole) — 1,2,4—triazonole-5 — on, 1 — (2-funoleo mouth — 4-methylpheninole) — 1,2,4 — triazonole — 5 — on, 1 — (2— bromo — 4 — methinolepheninole)-1,2, 4-Tori,-Nore — 5 — on, 1 — (2-odo — 4 — methinolefeninole)-1, 2, 4 -Triazonole — 5—On, 1— (2-Methinole — 4 — Black Mouth Feninole) — 1, 2, 4 Triazonole — 5—On, 1 — (2—Methyl—4 —Fluorophenylinole )-1, 2, 4-triazonole — 5 — on, 1 — (2 — methinole-4-bromophenonele)-1, 2, 4-triazonole — 5 — on, 1 — (2 — methinole — 4 フ 4- 4--1, 2, 4-Triazole-5-On and fist. Specific examples of the carbamoyl cyclites represented by the general formula (III) include, for example, N-methynole-N-2,4-diphnoleolophenylcanolebamoinolechloride, N-ethyl-N- 2,4-diphneorolophenylcarbamoinolycide, N-n-propyl-N-2,4_difluorophenylcarbamoylk, N-isopropyl-N-2,4-difluorophenylcarba Moy lechloride, N-methinole — N—4—Fluorophenylcarpamoinoletaroide, N-ethyl-N-4_fluorophenylcarbamoyl chloride, N-n-propyl _N-4 -Fluorocarbalmoyl chloride And N-isopropyl-N-4-fluorophenylcarbamoyl chloride, N-isopropyl-N-phenylcarbamoyl chloride and the like.

Examples of the 1-substituted-4- 4-rubamoyl-1,2, triazol-5-one derivative of the general formula (I) which can be produced by the above reaction include, specifically, for example, 1-pheninole-4- ( N—Isopropynole-N-4-fluoro or 2,4-di-phnoreolophenylcanolepamoyle) -1,2,4-triazole — 5—one, 1 One (2 — Black mouth Feninole) — 4 — (N — Isopropinole one N — 4 — Funoleo Mouth or 2,4-difluorophenylcarbamoy ^ ")-1,2,4-Triazo one-5- ON, 1 — (3-cloth feninole) -4- (N — isopropyl -N-4-fluoro or 2,4-difluorophenylcarbamoyl)-1,2,4-triazole — 5 — ON, 1 — (2,4 — dichloropheninole) 1 4-(N-isopropyl — N-4-phenoleo mouth or 2, 4 — diphnoleolofe dinorecanoleno moinole) — 1,2,4 — triazoline / le-5 -one , 1 — (2 — Fluorenopheninole)-4-(N-Isopropyl-N-4-Fluoro or 2,4-Difluorophenisrecanolevamoinole) — 1,2,4 — Triazole — 5 — ON, 1 — (2, 4— diphnolelophenyl) — 4-(N— isopropylinole — N-4-Fluoro or 2,4-difluorophenylcarbamoyl)-1,2,4 Triazonole-5-on, 1 — (2 — Funoleo mouth — 4 — Black mouth fuenore) — 4-(N -Isopropinole-N _ 4 — phenoleo or 2,4-diphnoreo phenylcarbamoyl)-1,2,4-triazole-5 — on, 1-(2-methylphenyl)--(N — isopropyl-N- 4-fluoro or 2,4-difluorofuninylcarbamoyl) -1,2,4_triazole-5-one, 1— (2,3—dimethylphenyl) —4— (N-isopropyl-N-4-fluoro or 2,4-Diphnoleolopheninolecanolebamoinole)-1,2,4-Triazonole-5 -one, 1-(2-black mouth-4-methinolepheninole)-4-(N-isopropyl-N -4-Fluoro or 2,4-difluorophenyldicarbamoyl - 1,2, 4 - Toriazoru - 5 - one, such as the Ru mentioned.

Examples of the dehydrochlorinating agent include alkali metal hydroxides such as sodium hydroxide, alkali metal carbonates such as potassium carbonate, and organic bases such as pyridine. Is raised. Of these, alkali metal hydroxides and alkali metal carbonates are preferred, and sodium hydroxide is particularly preferred in terms of cost.

The amount of the dehydrochlorinating agent is preferably used in an equivalent amount or a slight excess with respect to the 1-substituted-1,2,4-triazol-5-one derivative (II).

The phase transfer catalyst and the solvent will be described later.

In the present invention, as shown in the above scheme, a 1-substituted-1,2,4-triazol-5-one derivative (II) and a carbamoyl chloride (III) are converted into an organic solvent and / or The desired 1-substituted-4--4-albamoyl-1,2,4-triazole-5-one derivative (I) is obtained by reacting with a phase transfer catalyst in water in the presence of a dehydrochlorinating agent. Can be obtained.

In the present invention, since the reaction shown in the above scheme is carried out by adding a phase transfer catalyst to the reaction system, the alkali of the 1-substituted-1,2,4-triazol-5-one derivative (II) Promoting the reaction by solubilizing the metal salt in the organic phase or collecting it at the water phase interface, or solubilizing the carbamoyl chloride (III) in the aqueous phase or collecting it at the organic phase interface, or It is possible to cause a reaction, and as a result, it is possible to improve the reaction yield of the target compound (I).

In the present invention, such a reaction is carried out in a two-phase system of an organic phase containing carbamoyl alcohol mouth compounds (III) and an aqueous phase containing a derivative (II) and a dehydrochlorinating agent, or an organic solvent or water. It is also possible to proceed with only a single-phase system.

In the present specification, the term "interface" means a single-phase system containing only an organic solvent or water in the vicinity of a contact interface between an organic phase and an aqueous phase when a reaction is performed in a two-phase system of an organic phase and an aqueous phase. When the reaction is carried out in the above, it means near the surface of the solvent. The following is a detailed explanation with preferred examples. As the combination of the acid agents, the organic solvent is, for example, an aromatic hydrocarbon such as toluene or xylene, and the dehydrochlorinating agent is an alkali metal hydroxide such as sodium hydroxide or an alkali such as lithium carbonate. An embodiment that is a metal carbonate is mentioned. In the present invention, even in such a combination of a relatively inexpensive solvent and a dehydrochlorinating agent, since the phase transfer catalyst is used as described above, the desired derivative (I) can be obtained in high yield. it can.

If the above reaction is carried out in the absence of a phase transfer catalyst, the reaction rate is slow with such a combination of an organic solvent and a dehydrochlorinating agent, the reaction proceeds, and the desired product is obtained in a satisfactory yield with τ. Or the reaction may not progress at all. This is because the 1-substituted-1,2,4-triazol-5-one derivative (Π) of the reaction raw material and the dehydrochlorinating agent have low solubility in the organic phase, and the other reaction raw material, carbamoylc. Mouth-rides (ΠΙ) have low solubility in the aqueous phase and are not uniformly mixed in the solvent.

More specifically, the 1-substituted-1,2,4-triazol-5-one derivative (II), which is the starting material in this reaction, is an acidic substance, and is stable and soluble in an aqueous alkali solution at an appropriate concentration. It is. In other words, in the presence of dehydrochlorinating agents such as alkali metal hydroxides and alkali metal carbonates, the solubility in organic solvents is low due to the formation of alkali metal salts, and in the presence of water, Many are in dissolved state.

However, the other raw material, carbamoyl chloride (ΙΠ), is present in the organic phase, so for example, 1-substitution-1,2,4-triazole-5 -When the alkali metal salt of the on derivative (Π) is solubilized in the organic phase or collected at the interface, and conversely, when the For example, it is necessary to solubilize the carbamoyl lip (III) in the aqueous phase or collect it at the interface to provide conditions for contacting and masticating the two kinds of reactants. In addition, the carbamoyl sulfides (III) are gradually decomposed by the dehydrochlorinating agent, so that the slower the reaction rate, the more the decomposition occurs, which leads to a decrease in the reaction yield. Therefore, there is a need to improve the reaction speed.

Therefore, in the present invention, in order to solve the above-mentioned problem, by performing a phase transfer catalytic reaction in which a phase transfer catalyst is added to the reaction system, the 1-substituted-1,2,4-triazole-5-one derivative ( The alkali metal salt of (II) is solubilized in the organic phase or collected at the interface, or the carbamoyl sulfides (III) are solubilized in the aqueous phase or collected at the interface to promote the reaction or promote the reaction. As a result, it is possible to improve the reaction yield of the target compound, 1-substituted-4- 4-rubbamoyl-1,2,4-triazol-5-one derivative (I). ing.

Phase transfer catalysis is the reaction of a solubilizing one of the reactive species in the organic phase in the form of an ion pair with the catalyst, or gathering at the interface, in a two-phase reaction between the substrates and reagents that do not mix with each other. For example, it is used for alkylation reaction, cyanation reaction, oxidation reaction, etc., but there is no example used for the reaction shown in the above scheme so far. . The phase transfer catalyst used in the present invention exhibits a catalytic action of forming a phase pair with the raw material compound for reaction and performing phase transfer. By returning to the phase transfer catalyst, the catalyst is regenerated so that the next reaction raw material compound can exhibit a phase transfer catalytic action. In this way, the phase transfer catalyst acts as a catalyst by repeating phase transfer, and disperses and stabilizes the oil phase in the water phase or the water phase in the oil phase like an emulsifier such as fatty acid soap. To be distinguished.

The phase transfer catalyst used in this reaction is not particularly limited, and examples thereof include quaternary ammonium salts, phosphonium salts, amines, crown ethers, cryptands, linear polyethylene glycol derivatives, and cyclodextrins.

When an organic solvent is used for the reaction, the phase transfer catalyst is preferably a quaternary ammonium salt or a phosphonium salt.

When water is used as the reaction solvent, amines are preferred as the phase transfer catalyst.

When an organic solvent and ice are used together as a solvent, a quaternary ammonium salt or a phosphonium salt is preferable as the phase transfer catalyst.

Specific examples of the quaternary ammonium salts include, for example, tetra-n-butylaminoammonium bromide, tetra-n-butynoleammonium hydrogen sanolate, trioctylmethylammonium-ammonium chloride, and benzinoletriethylammonium. Muchloride and the like.

Specific examples of the phosphonium salt include, for example, tetra-n-butylphosphonium bromide, tetraphenylphosphonium bromide, tetraoctylphosphonium bromide and the like.

Specific examples of the amines include 4-dimethylaminopyridine.

The crown ether is a cyclic polyether, for example, 18-crown-6, 15-crown-2, and the like. Crown ether It is thought that it acts as a phase transfer catalyst by attracting the metal to the crown center, ie, the approximate midpoint between oxygen molecules in the cyclic structure. When the cation is attracted and becomes slightly positively charged, the crown ether is thought to exert its phase transfer catalytic function.

Specific examples of the chain polyethylene glycol and its derivative include polyethylene glycolone, polyethylene glycol / leethenole, and polyethylene glycol ester.

Linear polyethylene dalicol and its derivatives contain two or more ether bonds because they are composed of oxidized styrene structural units, and, like crown ethers, are catalyzed by attracting a cation to the ether bond. It is thought that it acts as a catalyst, thereby exerting a phase transfer catalysis.

Cyclodextrin is a capsule-shaped compound that acts as a phase transfer catalyst by introducing hydrophobic compound (III) into water while being encapsulated inside the hydrophobic capsule, and reacting with compound (II). It is thought that. In the present invention, one of the above phase transfer catalysts may be used alone, or two or more may be used in combination.

The amount of the phase transfer catalyst is usually 1 to 10% by mole, preferably 1 to 5% by mole based on the number of moles of the carbamoyl chloride (III) used as one of the starting compounds.

The equivalence relationship of the reaction is to more efficiently react rubamoyl chlorides (III) with 1-substituted-1,2,4-triazol-5-one derivatives (II) for the reasons listed above. In addition, the 1-substituted-1,2,4-triazole-5-one derivative (Π) may be equivalent to carbamoyl chloride (III). It is preferable to use a slightly excessive amount.

The organic solvent used in this reaction is not particularly limited, but it serves as both a reaction solvent and an extraction solvent, and facilitates washing and liquid separation during the purification process, such as toluene, xylene, and benzene. Aromatic hydrocarbons such as are especially preferred.

The amount of the organic solvent used in this reaction is such that the starting compounds (11), (III), etc. can be dissolved during the reaction, and the target substance, 1_substituted-4-butyrubamoyl-1,2,2, The 4-triazole-5-one derivative (I) must be soluble in amount, for example, 1 mole of the original 1-substituted-1,2,4-triazol-5-one derivative (II). On the other hand, it is used in an amount of 1.0 to 20 liters, but use of a solvent exceeding the required amount is not preferable from the viewpoint of reactor efficiency and cost. In addition, when performing liquid separation, it is effective to perform the liquid separation operation at a temperature of Caro in order to reduce the amount of solvent used and improve the liquid separation properties.

When water is used as the reaction solvent, the amount of water used must be sufficient to produce the desired 1-substituted-4-carpamoyl-1,2,4-triazole-5-one derivative (I). Yes, and a sufficient amount is necessary to solidify and disperse the desired product (I) as necessary. Desirably, for example, it is used in an amount of 1.0 to 10 liters per 1 mol of the 1-substituted-1,2,4-triazol-5-one derivative (II) of the raw material.

In the present invention, the reaction is carried out under the above conditions in an organic solvent and / or water using the above-mentioned compounds (11) and (111), a dehydrochlorinating agent, and a phase transfer catalyst. When the reaction is carried out using an organic solvent, for example, compound (II), a dehydrochlorinating agent and a phase transfer catalyst are dispersed or dissolved in an organic solvent, and if necessary, the mixed solution is heated and stirred, Next, compound (III) Is preferably added while washing with an organic solvent, if necessary, to cause a reaction.

When the above reaction is carried out using an organic solvent and water as a solvent, for example, the compound (II) and a dehydrochlorinating agent are dissolved or dispersed in water, then a phase transfer catalyst is added, and then the compound (III) And an organic solvent, preferably in a mixed state, and then reacted.

When the above reaction is carried out using only water as a solvent, the compound (II) and the dehydrochlorinating agent are dissolved or dispersed in water, and then the phase transfer catalyst and the compound (111) are added in this order. It is preferable to add and react.

The reaction temperature is usually in the range from room temperature to 150 ° C, preferably 20 to 90 ° C. The reaction time varies depending on the reaction temperature and the type of the compound (11), (111), solvent, catalyst, etc., but is usually completed in 30 minutes to 4 hours.

The main by-product of this reaction is aniline, which is a by-product of the decomposition of carbamoyl lip (III). In addition, excess 1-substituted-1,2,4-triazol-5-one derivatives (11) and phase transfer catalysts used in the reaction remain in the reaction product. Excess 1-substituted-1,2,4-triazol-5-one derivative (II) is dissolved and dispersed in water when the dehydrochlorinating agent is used in excess The crude crystals of the 1-substituted-4-carbamyl-1,2,4-triazol-5-one derivative (I) of the target compound can be easily removed as an aqueous alkaline solution by filtering and washing with water. The 1-substituted-1,2,4-triazole-5-one derivative (Π) removed as an aqueous alkali solution precipitates as crystals by acidifying the aqueous solution with hydrochloric acid, sulfuric acid, etc. Recycling and reuse are possible by filtering. In addition, anilines produced as a by-product of the decomposition of carbamoyl clorides (III) are mixed solids obtained by distilling off the solvent after the washing operation in the purification step, or the target substance dispersed in water. Which are contained in a mixture with the derivative (I), can be easily removed by washing or recrystallization with an appropriate solvent. The loss of the target product (I) by washing or recrystallization of the solid mixture is negligible, and the yield of the target product is 1-substituted-4-caprolbumoyl-1,2,4-triazole-5 in high yield and purity. -An on derivative (I) is obtained.

The method of removing the phase transfer catalyst varies depending on the nature of the catalyst used, but the highly water-soluble catalyst removes the mono-substituted-1,2,4-triazole-5-one derivative (Π) described above. Can be simultaneously removed into water.

A catalyst having high solubility in an organic solvent can be similarly removed by the above-mentioned operation of removing anilines produced as a result of the decomposition of the carpamoyl lip (III). Example

Hereinafter, specific embodiments of the present invention will be described in more detail with reference to Examples, but the present invention is not limited to the following Examples as long as the gist of the present invention is not exceeded.

As described above, various compounds of the general formula (II), compounds of the general formula (III), a dehydrochlorinating agent, a solvent, and a phase transfer catalyst are arbitrarily selected and used in accordance with the following examples. By the above method, a desired compound of the general formula (I) can be produced, and the same effects as in the examples can be obtained.

[Example 1]

1 1 _ (2,4-dichlorophenyl) — 4 —— (N — isopropylinole-N-2,4 -di Preparation of fluorophenylcarbamoyl)-1,2,4_ triazonole-5-one

A 50 ml four-necked flask equipped with a stirrer, thermometer, and Dimroth condenser was used as a reaction vessel. 10 ml of water was added to the reaction vessel, and 1- (2,4-dichlorophenyl) -1,2,4-triazonole — 5 — 2.0 g (8.7 mmol) of ON and 0.38 g (9.1 mmol) of sodium hydroxide were sequentially added at room temperature, and the mixture was stirred at the same temperature for 5 minutes. Then, 0.27 g (0.79 t ol) of tetra n-butynoleammonium hydroxide sanolefate was added at room temperature, and the mixture was further stirred at the same temperature for 10 minutes. Then, a solution prepared by dissolving 1.85 g (7.9 mmol) of N-isopropyl-N-2,4-difluorophenylcarbamoyl mouth in 20 ml of toluene at once at room temperature is added vigorously to the mixed solution. The mixture was heated at 90 ° C for 3 hours using a mantle heater with stirring. After the completion of the reaction, the temperature of the mixed solution of the two layers was allowed to cool to 50 ° C with vigorous stirring, then transferred to a separating funnel, the lower alkaline aqueous layer was extracted, and the toluene layer was returned to the reaction vessel. To the reaction vessel containing the toluene layer, add 10 ml of a 1N aqueous solution of sodium hydroxide, heat with vigorous stirring using a mantle heater, maintain the temperature of the mixed solution of the two layers at 50 ° C for 5 minutes, and remove the toluene layer. Washed. Further, the toluene layer was separated and washed twice with 10 ml of 10% saline and finally with 10 ml of water in the same manner as described above. The separated toluene layer was transferred to an eggplant-shaped flask and concentrated under reduced pressure. The solid obtained by concentration was washed with 20 ml of hexane, and the solid was suction-filtered using a Kiriyama funnel. 10 ml of hexane was washed while being suctioned from above the collected solid, and then dried to obtain 3.0 g (yield 90%) of the title compound as the target compound.

[Example 2.]

1-_ (2,4-dichlorophenyl)-4-(N-isopropyl-N-2._4-di Preparation of 1,1,2,4-triazole 5-one (fluoropheninolecanolevamoyl)

A 300 ml four-necked flask equipped with a stirrer, thermometer, and Dimroth condenser was used as a reaction vessel. 150 ml of toluene was added to the reaction vessel, and 1- (2,4-dichroic fermenter) — 1, 2, 4 — Triazo 1 / re — 5-one 22.5 g (0.098 mol), sodium hydroxide 4.3 g (0.103 mol), tetra-n-butylphosphonium bromide 1.7 g (4.9 ol) The mixture was added sequentially at room temperature, and heated at 90 ° C for 1 hour using a mantle heater with vigorous stirring. Allow the mixed solution to cool to 60 ° C while stirring, and wash 22.9 g (0.098 mol) of N-isopropyl-N-2,4-difluorophenylcanolepamoid liquid with 10 ml of toluene. The solution was added to the solution at a time, and heated at 90 ° C. for 4 hours using a mantle heater with vigorous stirring again. After the completion of the reaction, the mixed solution in which NaCl was precipitated was allowed to cool to 50 ° C with vigorous stirring, then 1N-sodium hydroxide aqueous solution 70ral was added, and the mixture was heated with a mantle heater while vigorously stirring. The temperature of the mixed solution of the two layers was kept at 50 ° C for 5 minutes, and the toluene layer was washed. The mixed solution of the two layers was transferred to a separating funnel, the lower alkaline aqueous layer was extracted, and the toluene layer was returned to the reaction vessel. Further, the toluene layer was separated and washed twice with 70 ml of 10% saline and finally with 70 ml of water in the same manner as described above. The toluene layer after liquid separation was transferred to an eggplant flask and concentrated under reduced pressure. The solid obtained by concentration was recrystallized from 300 ml of methanol. The precipitated crystals were suctioned and filtered using a Kiriyama funnel. From the collected solid, 50 ml of methanol was washed while flowing while suctioning, and then dried to obtain 38.5 _g (yield: 92%) of the title compound as the target compound.

[Example 3] 1 1 (2,4-Diphenyl phenyl)-4-(N — Isopropinole-N-2,4 -Diphenyl / Leo phenyl canolebamoyl) — 1, 2, 4 — Triazole-5 ~ Manufacture

A 100 ml four-necked flask equipped with a stirrer, thermometer, and Dimroth condenser was used as a reaction vessel. 50 ml of water was added to the reaction vessel, and 1- (2,4-dichlorophenyl) — 1, 2, 4-triazole — 9.3 g (0.04 mol) of 5-one, 1.8 g (0.042 mol) of sodium hydroxide, 0.49 g (4.Ommol) of 4-dimethylaminopyridine are added sequentially at room temperature, and the mixture is added at the same temperature for 10 minutes. Stirred. Then, add 9.4 g (0.04raol) of N-isopropyl-N-2,4-difluorophenylcarbamoyl chloride at room temperature at a time to this mixed solution, and use a mantle heater with vigorous stirring. And heated at 90 ° C for 2 hours. After the completion of the reaction, the solid dispersed in the aqueous solution was suction-filtered using a Kiriyama funnel. The solid collected by filtration was washed by flowing 50 ml of water while sucking it, and then air-dried. The air-dried solid was recrystallized from 100 ml of methanol. The precipitated crystals were collected by suction filtration using a Kiriyama funnel. After washing with 20 ml of methanol while suction was applied thereto, the crystals were dried and dried to obtain 15.2 _g (yield: 83%) of the title compound of the title.

[Example 4]

1 1 (2-Chloropheninole) 1 4 1 (N—Isopropinole — N—2,4, -Diphnore Orofe-Norecanole Pamoinole) ― 1,2,4-Triazonole

A 300ml four-necked flask equipped with a stirrer, thermometer and Dimroth condenser was used as a reaction vessel. 150ml of toluene was added to the reaction vessel, and 1- (2-chlorophenyl) -1,2,4-triazole — 5—on 20 g (0.1 mol), 4.2 g (0.105 mol) of sodium hydroxide, 1.7 g (5.O mmol) of tetra-n-butylphosphonium bromide are added in sequence at room temperature. The mixture was heated at 90 ° C for 1 hour using a thermometer. Cool the nearly homogeneous mixed solution to 60 ° C with stirring, wash 23.4 g (O.lOmol) of N-isopropyl-N-2,4-difluorophenylcarbamoyl quenched with 10 ml of toluene. The solution was added to the solution at one time, and heated at 90 ° C for 4 hours using a mantle heater with vigorous stirring again. After the reaction was completed, the temperature of the mixed solution in which NaCl was precipitated was allowed to cool to 50 ° C while being vigorously stirred, and then a 70N aqueous solution of 1N-sodium hydroxide was added, and the mixture was heated with a mantle heater while vigorously stirring. The temperature of the mixed solution of the two layers was kept at 50 ° C for 5 minutes, and the toluene layer was washed. The mixed solution of the two layers was transferred to a separating funnel, the lower alkaline aqueous layer was extracted, and the toluene layer was returned to the reaction vessel. Further, the toluene layer was separated and washed twice with 70 ml of 10% saline and finally with 70 ml of water in the same manner as described above. The toluene layer after liquid separation was transferred to an eggplant flask and concentrated under reduced pressure. The solid obtained by concentration was recrystallized from 300 ml of methanol. The precipitated crystals were suctioned and filtered using a Kiriyama funnel. 50 ml of methanol was flown from above the collected crystals while sucking, washed, and dried to obtain 36 lg (yield: 90%) of the title compound crystals.

[Example 5]

1 1 (2 — methinolefeninole) 1 4 1 (N-isopropyl-N-2,4-diphnole orofe-norekanorevamoinole)-1,2,4-triazonole 5 — on manufacture of 50 ml A four-necked flask equipped with a stirrer, thermometer, and Dimroth condenser was used as a reaction vessel, and 10 ml of water was added to the reaction vessel. 1- (2-methylphenyl) -1,2,4-triazole_5—on 2. 0 g (11.4 mmol) and 0.48 g (12.0 mmol) of sodium hydroxide were sequentially added at room temperature, and the mixture was stirred at the same temperature for 5 minutes. Next, 0.35 g (1.04 mmol) of tetra-n-butynoleammonium hydrogen sanophosphate was added at room temperature, and the mixture was further stirred at the same temperature for 10 minutes. Then, A solution obtained by dissolving 2.42 g (10.4 mmol) of N-isopropyl-N-2,4-difluorophenylcarbamoyl chloride in 20 ml of toluene was added all at once to the combined solution at room temperature. The mixture was heated at 90 ° C for 3 hours using a mantle heater with vigorous stirring. After the completion of the reaction, the temperature of the mixed solution of the two layers was allowed to cool to 50 ° C. with vigorous stirring, then transferred to a separating funnel, the lower alkaline aqueous layer was extracted, and the toluene layer was returned to the reaction vessel. Add 10 ml of a 1N aqueous solution of sodium hydroxide to the reaction vessel containing the toluene layer, heat the mixture using a mantle heater with vigorous stirring, and maintain the temperature of the mixed solution of the two layers at 50 ° C for 5 minutes. Washed. Furthermore, the toluene layer was separated and washed twice with 10 ml of 10% saline and finally with 10 ml of water in the same manner as described above. The toluene layer after liquid separation was transferred to a NASFRASCO and concentrated under reduced pressure. The solid obtained by concentration was washed with 20 ml of hexane, and the solid was filtered off with suction using a Kiriyama funnel. Hexane was washed with 10 ml of hexane while being suctioned from above the collected solid, and then dried to obtain 3.8 g (yield 90%) of the title compound as the target compound.

[Reference Example 1]

Production of 1- (2,4-dichlorophenyl) -4- (N-isopropyl-N-2,4-difluorophenylcarbamoyl) -1,2,4-triazole-5-one (Patent Document 1 The method described in WO98 / 38176 pamphlet) A 100 ml four-necked flask was equipped with a stirrer, a thermometer, and a Dimroth condenser to prepare a reaction vessel. Dissolve 2.3 g (0. Olmol) of 1- (2,4-dichlorophenyl) -1,2,4-triazole-5-one in 50 ml of acetonitrile and then l-7 g of potassium carbonate (0.012 mol) ) Was added at room temperature. After stirring the obtained mixed solution at room temperature for 30 minutes, 3.0 g (0.013 mol) of N-isopropyl-N-2,4-difluorophenylcarbamoyl chloride was added to the solution at room temperature. In addition, the mixture was heated and stirred at 80 ° C for 1 hour using a mantle heater. After the completion of the reaction, inorganic salts were removed from the reaction solution by suction filtration using a Kiriyama funnel. Then, acetonitrile was distilled off from the filtrate under reduced pressure. The obtained residue was dissolved in toluene (80 ml), transferred to a separating funnel, the toluene layer was washed with water (40 ml), and then separated. After the toluene layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (3.4 g, yield 80%) as a solid.

[Reference Example 2]

Production of 1- (2,4-dioctanol feninole)--(N-isopropyl-N-2,4-difluorophenylcarbamoyl)-1,2,4-triazole-5-one (Patent Document 1 (Method described in WO 98/38176 pamphlet) A 100 ml four-necked flask was equipped with a stirrer, a thermometer, and a Dimroth condenser to prepare a reaction vessel. 2.3 g (0. Olmol) of 1- (2,4 dichlorophenyl) -1,2,4-triazol-5-one is dissolved in 50 ml of pyridine, and then N-isopropyl-N-2, 3.0 g (0.013 mol) of 4-difluorophenylcarbamoinolechloride was added at room temperature. The mixed solution was left at the same temperature for 20 hours. After completion of the reaction, pyridine was distilled off under reduced pressure. The obtained residue was dissolved in toluene (80 ml), transferred to a separating funnel, and the toluene layer was washed with 1N hydrochloric acid (40 ml) and then with water (40 ml), and then separated. After the toluene layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (3 lg, yield 71%) as a target compound.

Claims

The scope of the claims

eon The following general formula (I)

[In the formula, X represents a halogen atom or a lower alkyl group, γ represents a halogen atom, R represents a lower alkyl group, and n and m each represent an integer of 0-5. The method for producing a 1-substituted-4--4-carbamoyl-1,2,4-triazol-5-one derivative represented by the following general formula (II):

[Wherein, X and n are as defined above. 1 represented by

The 1, 2, 4-triazole-5-one derivative is converted to a compound represented by the following general formula (III)

[Wherein, Y, R and m are as defined above. ] Carno represented by 1-Substitution-4-Force Rubamoyl-1, 2, 4-Characterized by the reaction of Moiruku mouth-rides with an organic solvent and Z or water in the presence of a dehydrochlorinating agent by adding a phase transfer catalyst A method for producing a triazole-5-one derivative. 2. The 1-substituted -4 according to claim 1, wherein an aromatic hydrocarbon and / or water is used as a solvent, and an alkali metal hydroxide or an alkali metal carbonate is used as a dehydrochlorinating agent. -Method for producing carpamoyl-1,2,4-triazol-5-one derivative. 3. As the phase transfer catalyst, any compound selected from the group consisting of quaternary ammonium salts, phosphonium salts, amines, crown ethers, cryptands, linear polyethylene glycol derivatives, and cyclodextrins 3. The method for producing a 1-substituted-4-carbamyl-1,2,4-triazol-5-one derivative according to claim 1 or 2, which is used.