WO2021193432A1

WO2021193432A1 - Method for producing production intermediate of cyclaniliprole

Info

Publication number: WO2021193432A1
Application number: PCT/JP2021/011379
Authority: WO
Inventors: 堅一浅川; 祐介熊倉; 祐樹高橋; 大介森戸; 美樹菅田; 文浩福井
Original assignee: 石原産業株式会社
Priority date: 2020-03-25
Filing date: 2021-03-19
Publication date: 2021-09-30
Also published as: KR20220157967A; JPWO2021193432A1; CN115335368A

Abstract

Provided is a method for producing a production intermediate of high-purity cyclaniliprole.　According to this method, a production intermediate of high-purity cyclaniliprole can be produced at a high yield by reacting a compound represented by formula (II) or a salt thereof with a compound represented by formula (III) or a salt thereof in the presence of a condensing agent and/or a base. By using this intermediate, high-purity cyclaniliprole can be produced.

Description

Manufacturing method of cyclaniliprol manufacturing intermediate

The present invention relates to a method for producing an intermediate for producing cyclaniliprol. Furthermore, the present invention also relates to a method for producing cyclaniliprol using the intermediate for producing cyclaniliprol.

Cycraniliprole (3-bromo-N- [2-bromo-4-chloro-6-[[(1-cyclopropylethyl) amino] carbonyl] phenyl] -1- (3-chloropyridin-2-) (Il) -1H-pyrazole-5-carboxamide; a compound represented by the formula (IV) described later) is described as Compound No. 16 in Patent Document 1, and is useful as an active ingredient of a commercially available agricultural pesticide. Compound. As a method for producing cyclaniliprol, for example, Patent Documents 2 to 4 are known. Further, a compound having a structure similar to that of cyclaniliprol and a method for producing the same are also known (for example, Patent Documents 5 to 10).

International Publication No. 2005/077934 International Publication No. 2008/072745 International Publication No. 2008/072743 International Publication No. 2008/155990 International Publication No. 2003/016283 International Publication No. 2004/011453 International Publication No. 2006/062978 International Publication No. 2008/070158 International Publication No. 2019/207595 Chinese Patent Application Publication No. 102285964

When cyclaniliprol is industrially manufactured as an active ingredient for pesticides, it must comply with the prescribed standards. The problem to be solved by the present invention is to produce high-purity cyclaniliprol in high yield and at low cost. More specifically, it is intended to suppress the inclusion of the impurity (B) described later in cyclaniliprol as an active ingredient of pesticides, and to produce cyclaniliprol with high yield and high purity.

Patent Document 1 describes a method that can be used for producing cyclaniliprol as reaction [A]. However, when the present inventors produce cyclaniliprol represented by the formula (IV) according to the following scheme according to this reaction [A], the compounds represented by the formula (B) which are impurities (hereinafter referred to as “B”). Impurity (B) is produced as a by-product, and it is very difficult to remove this impurity (B) from the obtained cyclaniliprol. It was found that it is not suitable for the production of high-purity cyclaniliprol that meets the above standards.

There is no description about the by-product of the impurity (B) in Patent Document 1, and the problem regarding the formation of the impurity (B) is not recognized in the same document.

As a result of further studies to solve the above problems, the present inventors have also found that the formation of the impurity (B) is due to the presence of Br on the benzene ring. Therefore, it was considered that the method described in Patent Document 1 could not sufficiently suppress the by-product of the impurity (B).

On the other hand, Patent Document 2 discloses a method for producing cyclaniliprol via reaction [N] as a method for producing cyclaniliprol using a raw material having no Br on the benzene ring. .. However, in the specific example corresponding to the reaction [N] in Patent Document 2, for example, the yield of Example 17 (4) is very low, about 14%, and the yield of Example 19 (2) is very low, about 37%. In order to use it as an industrial production method for cyclaniliprol, it was necessary to significantly improve the yield. Further, the problem concerning the generation of the impurity (B) is not described in Patent Document 2 and is not recognized.

As a result of various studies conducted by the present inventors in order to solve the above problems, it was found that the formation of the impurity (B) is due to the presence of Br on the benzene ring, and there is no Br on the benzene ring. It was considered necessary to produce cyclaniliprol via raw materials. Then, even when a raw material having no Br on the benzene ring is used, by selecting a specific reaction reagent, cyclaniliprol with a high yield and a very low impurity content can be produced. We have found a manufacturing method capable of manufacturing an intermediate. It was also found that high-purity cyclaniliprol conforming to the standard as an active ingredient for pesticides can be produced from the production intermediate of cyclaniliprol produced in this manner.

That is, the present invention is a compound represented by the formula (I) or a salt thereof (hereinafter, also simply referred to as a compound (I)):

The compound represented by the formula (II) or a salt thereof (hereinafter, also simply referred to as compound (II)):

And a compound represented by the formula (III) or a salt thereof (hereinafter, also simply referred to as compound (III)):

[In formula (III), R is OH or halogen]
Provided is a production method for reacting with and in the presence of a condensing agent and / or a base. Furthermore, the present invention also provides a method for producing cyclaniliprol, in which the compound (I) thus produced is reacted with a brominating agent.

According to the present invention, compound (I) useful for producing cyclaniliprol can be produced in high yield and high purity. Furthermore, from the compound (I) obtained by the present invention, high-purity cyclaniliprol satisfying the specifications as an active ingredient for pesticides can be produced.

[Method for producing compound (I)]
The method for producing compound (I) of the present invention is characterized by reacting compound (II) with compound (III) in the presence of a condensing agent and / or a base. Here, when R is OH, the compound (II) and the compound (III) are preferably reacted in the presence of a condensing agent and a base, and when R is a halogen, the compound (II) and the compound (II) are reacted. It is preferable to react with compound (III) in the presence of a base. This reaction may be carried out in the presence of a solvent.

The salt of the compound (I), the compound (II) or the compound (III) includes any pesticide-acceptable salt, for example, an alkali metal salt (sodium salt, potassium salt, etc.), alkaline earth. Metal salts (magnesium salts, calcium salts, etc.), ammonium salts, alkylammonium salts (dimethylammonium salts, triethylammonium salts, etc.), acid addition salts (salt salts, perchlorates, sulfates, nitrates, acetates, methanesulfones) (Salt, etc.) and the like. Examples of the halogen represented by R include chlorine, bromine, iodine and the like, and chlorine is preferable.

The amount of compound (II) and compound (III) to be used is not particularly limited as long as the reaction proceeds, but is, for example, 0.8 to 1.2 mol, preferably 0. 9 to 1.1 mol, more preferably 0.95 to 1.05 mol of compound (III) can be used.

The compound (II) and the compound (III) in the present invention can be produced by a method known in the art, for example, the method described in Patent Documents 2, 5, 7 or the like, or a method similar thereto, or commercially available. Goods can also be used. When a compound (III) in which R is halogen is used, the compound (III) in which R is halogen is a halogenating agent (III) in which R is OH according to a method well known in the art. It can also be obtained by reacting with an acid halide such as thionyl chloride or oxalyl chloride).

As the condensing agent used in this reaction, sulfonyl chloride (methanesulfonyl chloride, p-toluenesulfonyl chloride, etc.) and acid halide (thionyl chloride, oxalyl chloride, etc.) are preferable, and among these, the yield and the obtained compound From the viewpoint of the purity of (I), sulfonyl chloride is more preferable, and methanesulfonyl chloride is particularly preferable. The amount of the condensing agent used is not particularly limited as long as the reaction proceeds, but is, for example, 1 to 2 mol, preferably 1 to 1.8 mol, more preferably 1 to 1 to 1 mol of the compound (II). It is 1.5 mol.

The bases used in this reaction include organic bases such as pyridine and picoline (for example, 2-picoline, 3-picoline, 4-picoline), alkali metal carbonates or alkali metal hydrogen carbonates, and alkaline earths. Inorganic bases such as metal carbonates or alkaline earth metal carbonates are preferred, among which pyridine, picoline (eg, 2-picoline, 3) are preferred from the standpoint of yield and purity of the resulting compound (I). -Picoline, 4-picoline), alkali metal carbonates or alkali metal carbonates are more preferred, and pyridine or picoline (eg 2-picoline, 3-picoline, 4-picoline) are even more preferred, among which 3-picoline. Is particularly preferable. The above-mentioned base used in this reaction may be one kind or two or more kinds.
The amount of the base used is not particularly limited as long as the reaction proceeds, but is, for example, 0 to 10 mol, preferably 1 to 7 mol, and more preferably 1 to 4 mol with respect to 1 mol of the compound (II). be.

The solvent that may be used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and is, for example, ketones (acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, etc.), nitriles (acetoyl, propionitrile, etc.). ), Ethers (tetratetra, diethyl ether, etc.), halogenated hydrocarbons (dichloromethane, dichloroethane, chloroform, chlorobenzene, etc.), esters (ethyl acetate, isopropyl acetate, etc.), polar solvents (dimethylformamide, dimethylacetamide, N. -Methylpyrrolidone, dimethylsulfoxide, etc.), aromatic hydrocarbons (toluene, xylene, etc.), pyridines (pyridine, picolin, etc.), or a mixed solvent thereof. Among these, one selected from the group consisting of ketones, nitriles, ethers, halogenated hydrocarbons, polar solvents, and pyridines from the viewpoint of yield and purity of the obtained compound (I). Alternatively, the number is preferably two or more, and more preferably one or two or more selected from the group consisting of ketones, nitriles, ethers, polar solvents, and pyridines. The amount of the solvent used is not particularly limited as long as the reaction proceeds, but is, for example, 0 to 50 times the amount (V / W), preferably 0 to 30 times the amount (V / W) of the compound (II). It is more preferably 0 to 20 times the amount (V / W), and further preferably 1 to 20 times the amount (V / W).

In this reaction, the order of addition of compound (II), compound (III), condensing agent and base, and optionally solvent is not particularly limited, and may be added and mixed in any order. The addition of these components to the reaction system may be carried out all at once or in portions, or may be continuous. For example, as the order of addition, all the components may be mixed at once, or some components may be added later, and specific examples of such addition include, for example, (i). ) Mix compound (II), base and solvent, and add compound (III) and condensing agent to it. (Ii) Mix compound (II), compound (III) base and solvent, and add condensing agent there. Addition and the like can be mentioned.

The temperature of this reaction is usually about 0 to 50 ° C, preferably about 0 to 30 ° C. The reaction time is usually about 1 to 24 hours, preferably about 1 to 5 hours. In addition, in this specification, "room temperature" usually means about 0 to 40 degreeC, more specifically, 10 to 30 degreeC.

After completion of this reaction, compound (I) can be isolated by performing post-treatment by a conventional method such as neutralization, extraction, washing and drying, if necessary. Then, if necessary, compound (I) may be purified by a conventional method such as recrystallization and repulp. Alternatively, it can be used as it is in the next reaction without isolating compound (I) or purifying the isolated compound (I).

The purity of compound (I) obtained by this reaction is usually 95% by weight or more, preferably 97% by weight or more, and more preferably 98.5% by weight or more. In addition to the compound (I) obtained by this reaction, a compound represented by the following formula (A) or a salt thereof (hereinafter, also simply referred to as an impurity (A)) contained as an impurity:

The content of the compound is usually 1% by weight or less, preferably 0.3% by weight or less, based on the total amount of the compound represented by the formula (I) or a salt thereof and the impurity (A). Preferably, it is substantially free of impurities (A). Here, substantially not contained means that an amount of an impurity or the like may be mixed, and for example, the content ratio of the impurity (A) is less than 0.1% by weight. By producing cyclaniliprol using such compound (I), high-purity cyclaniliprol satisfying the specifications as an active ingredient of pesticides can be produced.

[Manufacturing method of cyclani lipol]
Cyclaniliprol can be produced by reacting the compound (I) obtained as described above with a brominating agent. This reaction may be carried out in the presence of a base and a solvent.
Examples of the brominating agent used in this method include bromine and hypobromous acid, and bromine is particularly preferable.

The amount of the brominating agent used is not particularly limited as long as the reaction proceeds, but for 1 mol of compound (I), for example, 0.5 to 5 mol, preferably 1 to 3 mol, more preferably 1 mol. Up to 2 moles of brominating agent can be used.

Bases that may be used in this reaction include metal hydroxides (sodium hydroxide, potassium hydroxide, calcium hydroxide, etc.), metal hydrides (sodium hydride, potassium hydride, etc.), and metal alkoxides (sodium methoxy). Do, sodium ethoxyoxide, potassium t-butoxide, etc.) are preferable, among these, metal hydroxide is more preferable, and sodium hydroxide and potassium hydroxide are further preferable. The above-mentioned base used in this reaction may be one kind or two or more kinds.
The amount of the base used is not particularly limited as long as the reaction proceeds, but is, for example, 1 to 10 mol, preferably 1.5 to 5 mol, more preferably 1.5 mol, per 1 mol of compound (I). ~ 3.5 mol.

The solvent that may be used in this reaction is not particularly limited as long as it does not adversely affect the reaction, but ethers (diethyl ether, butylmethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, etc.) and halogenated hydrocarbons (chlorobenzene). , Dichlorobenzene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, trichloroethane, dichloroethylene, etc.), aromatic hydrocarbons (benzene, toluene, xylene, etc.), aliphatic hydrocarbons (pentane, hexane, heptane, octane, cyclohexane, etc.) ), Esters (methyl acetate, ethyl acetate, propyl acetate (isopropyl acetate, normal propyl acetate, etc.), butyl acetate, etc.), ketones (acetone, methyl ethyl ketone, cyclohexanone, etc.), nitriles (acetamide, propionitrile, etc.), Amides (eg, N, N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, dimethylacetamide, N-methylpyrrolidone, etc.), or a mixed solvent thereof can be mentioned. Among these, from the viewpoint of yield and purity of the obtained cyclaniliprol, one or more selected from the group consisting of ethers, halogenated hydrocarbons and esters is preferable, and esters More preferably, it is one kind or two or more kinds selected from the group consisting of the kind. The amount of the solvent used is not particularly limited as long as the reaction proceeds, but is, for example, 0 to 50 times the amount (V / W), preferably 1 to 30 times the amount (V / W) of the compound (I). The amount is 3 to 20 times (V / W).

In this reaction, the order of adding the compound (I), the brominating agent, and if necessary, the base and the solvent is not particularly limited, and the compounds may be mixed in any order. The addition of these components to the reaction system may be carried out all at once or in portions, or may be continuous. For example, the order of addition is as follows: (i) compound (I) and a brominating agent, if necessary, a solvent is mixed and a base is added thereto, or (ii) compound (I) and a base, and if necessary, a solvent is mixed. Then, a brominating agent may be added thereto.

The temperature of this reaction is usually about −20 to 120 ° C., preferably about 0 to 50 ° C. The reaction time is generally about 0.5 to 48 hours, preferably about 1 to 24 hours.

After completion of this reaction, cyclaniliprol can be isolated by performing post-treatment by a conventional method such as neutralization, extraction, washing and drying, if necessary. Further, due to the conditions of the reaction and / or post-treatment, cyclaniliprol may be isolated as a salt or a solvate, in which case, for example, a conventional method such as neutralization and solvation. Can be converted into a free cyclaniliprol. Then, if necessary, cyclaniliprol can be purified by a conventional method such as recrystallization or repulp. The purity of cyclaniliprol obtained by this reaction is usually 90% by weight or more, preferably 95% by weight or more, and more preferably 97% by weight or more. In addition to the cyclaniliprol obtained by this reaction, the compound represented by the following formula (B) or a salt thereof contained as an impurity:

The content of is usually 1% by weight or less, preferably 0.3% by weight or less, and more preferably impurities, based on the total amount of cyclaniliprol and the compound represented by the formula (B). (B) is substantially not contained. Here, substantially not contained means that an amount of impurities may be mixed, and for example, the content ratio of impurities (B) is less than 0.1% by weight.

The various components in the method of the present invention are appropriately selected from the above-mentioned plurality of examples and conditions, for example, not only the above-mentioned examples and conditions in the normal range but also the examples and conditions in a preferable range. Can be combined with each other.

Examples of preferred embodiments of the present invention are listed below, but the present invention is not limited thereto.
[1] A compound represented by the formula (I) or a salt thereof:

It is a manufacturing method of
The compound represented by the formula (II) or a salt thereof:

And the compound represented by the formula (III) or a salt thereof:

[In formula (III), R is OH or halogen]
A production method in which and is reacted in the presence of a condensing agent and / or a base.
[2] When R is OH, the compound represented by the formula (II) or a salt thereof is reacted with the compound represented by the formula (III) or a salt thereof in the presence of a condensing agent and a base. , [1].
[3] When R is a halogen, the compound represented by the formula (II) or a salt thereof is reacted with the compound represented by the formula (III) or a salt thereof in the presence of a base [1]. ] The manufacturing method described in.
[4] The production method according to [1] or [2], wherein the condensing agent is a sulfonyl chloride or an acid halide.
[5] The production method according to [1] or [2], wherein the condensing agent is sulfonyl chloride.
[6] The production method according to [1] or [2], wherein the condensing agent is methanesulfonyl chloride.
[7] Any one of [1] to [6], wherein the base is one or more selected from the group consisting of pyridine, picoline, alkali metal carbonate and alkali metal hydrogen carbonate. The manufacturing method described in.
[8] The production method according to any one of [1] to [6], wherein the base is pyridine or picoline.
[9] The production method according to any one of [1] to [6], wherein the base is pyridine or 3-picoline.
[10] The production method according to any one of [1] to [9], wherein the reaction is carried out in the presence of a solvent.
[11] The solvent is one or more selected from the group consisting of ketones, nitriles, ethers, halogenated hydrocarbons, polar solvents, pyridines and aromatic hydrocarbons. 10] The manufacturing method according to.
[12] The method according to [10], wherein the solvent is one or more selected from the group consisting of ketones, nitriles, ethers, halogenated hydrocarbons, polar solvents, and pyridines. Production method.
[13] The production method according to [10], wherein the solvent is one or more selected from the group consisting of ketones, nitriles, ethers, polar solvents, and pyridines.
[14] The production method according to [10], wherein the solvent is one or more selected from the group consisting of tetrahydrofuran, N-methylpyrrolidone, acetone, acetonitrile, 3-picoline and pyridine.
[15] The method according to any one of [1] to [14], wherein the obtained compound represented by the formula (I) or a salt thereof has a purity of 95% by weight or more.
[16] In addition to the obtained compound represented by the formula (I) or a salt thereof, the compound represented by the following formula (A) or a salt thereof contained as an impurity:

The content ratio of [1] to [15] is 1% by weight or less based on the total amount of the compound represented by the formula (I) or a salt thereof and the compound represented by the formula (A) or a salt thereof. ] The manufacturing method according to any one of the items.
[17] Any one of [1] to [15], which does not substantially contain the compound represented by the formula (A) or a salt thereof as an impurity in addition to the obtained compound of the formula (I) or a salt thereof. The manufacturing method described in the section.

[18] A compound represented by the formula (I) obtained by the production method according to any one of [1] to [17] or a salt thereof is reacted with a brominating agent to form cyclaniliprol. Production method.
[19] The production method according to [18], wherein the brominating agent is bromine or hypobromous acid.
[20] The production method according to [18] or [19], wherein the reaction is carried out in the presence of a base.
[21] The production method according to [20], wherein the base is one or more selected from the group consisting of metal hydroxides, metal hydrides and metal alkoxides.
[22] The production method according to [20], wherein the base is a metal hydroxide.
[23] The production method according to any one of [18] to [22], wherein the reaction is carried out in the presence of a solvent.
[24] One or two solvents selected from the group consisting of ethers, halogenated hydrocarbons, aromatic hydrocarbons, aliphatic hydrocarbons, esters, ketones, nitriles and amides. The manufacturing method according to [23] described above.
[25] The production method according to [23], wherein the solvent is one or more selected from the group consisting of ethers, halogenated hydrocarbons and esters.
[26] The production method according to [23], wherein the solvent is one or more selected from the group consisting of esters.
[27] The production method according to [23], wherein the solvent is one or more selected from the group consisting of methyl acetate, ethyl acetate, propyl acetate and butyl acetate.
[28] The production method according to [23], wherein the solvent is one or more selected from the group consisting of methyl acetate, ethyl acetate, isopropyl acetate and butyl acetate.
[29] The method according to any one of [18] to [28], wherein the obtained cyclaniliprol has a purity of 90% by weight or more.
[30] In addition to the obtained cyclaniliprol, a compound represented by the following formula (B) or a salt thereof contained as an impurity:

The production method according to any one of [18] to [29], wherein the content ratio of is 1% by weight or less based on the total amount of cyclaniliprol and the compound represented by the formula (B). ..
[31] The production according to any one of [18] to [28], which does not substantially contain the compound represented by the formula (B) or a salt thereof as an impurity other than the obtained cyclaniliprol. Method.

Next, examples of the present invention will be described, but the present invention is not construed as being limited thereto.
The structures of compounds (IIIa), (IIIb) and compound (V) used in this example are shown below.
-Compound (IIIa):

-Compound (IIIb):

-Compound (V)

The HPLC analysis conditions in this example are as follows.
-Equipment used: Nexera XS series manufactured by Shimadzu Corporation-Column: SunShell C18 manufactured by Chromanic Technologies Co., Ltd. (2.6 μm, 2.1 x 100 mm)
-Detection: UV detector (240 nm)
-Column temperature: 40 ° C
・ Flow velocity: 0.5 mL / min
-Mobile phase: Liquid A: 0.1% aqueous formic acid solution, and Liquid B: acetonitrile Gradient conditions are as follows.

The purity (content ratio) is indicated by an area% value by high performance liquid chromatography (HPLC) and / or a weight% value converted from the area%.
The area% value is obtained by measuring the reaction product obtained by the synthetic experiment by HPLC.
The weight% value is calculated by, for example, the conversion method described below. A measurement solvent is added to the cyclaniliprol standard product to prepare a cyclaniliprol standard solution, and the standard solution is measured three times by HPLC. The average value of the area values obtained by the HPLC measurement is calculated, and the average value is divided by the weight of the cyclaniliprol standard product used in the measurement to calculate the unit area value. In the same manner, the unit area value of the compound (I) standard product, the impurity (A) standard product, or the impurity (B) standard product is calculated respectively. For the reaction products described in the examples, the unit area value is calculated in the same manner. The unit area value of the reaction product and the unit area value of the standard product are compared, the ratio is calculated, and the weight% value is calculated. It is also possible to calculate the sensitivity ratio from the unit area value of each of the above standard products and convert it from the sensitivity ratio to obtain the impurity content.

[Example 1] Synthesis of compound (I) A mixture of 0.5 g of compound (II), 0.6 g of compound (IIIa), 0.59 g of 3-picoline and 10 mL of tetrahydrofuran is ice-cooled, and 0.31 g of methanesulfonyl chloride is used. Was slowly added dropwise under ice cooling. After completion of the dropping, the temperature was raised to room temperature, the mixture was stirred overnight at the same temperature, and then the reaction was checked by HPLC. As a result, compound (I) was produced in an area% of 88.1. At that time, no impurity (A) was detected.

[Example 2] Synthesis of compound (I) A mixture of 0.5 g of compound (II), 0.6 g of compound (IIIa), 0.59 g of 3-picoline and 10 mL of N-methylpyrrolidone is ice-cooled and methanesulfonyl chloride. 0.31 g was slowly added dropwise under ice cooling. After completion of the dropping, the temperature was raised to room temperature, the mixture was stirred overnight at the same temperature, and then the reaction was checked by HPLC. As a result, compound (I) was produced in an area% of 98.6. At that time, no impurity (A) was detected.

[Example 3] Synthesis of compound (I) 0.5 g of methanesulfonyl chloride at room temperature was added to a mixed solution of 0.83 g of compound (II), 1.0 g of compound (IIIa), 0.81 g of 3-picoline and 10 mL of acetone. Dropped slowly. When the reaction was checked by HPLC after stirring overnight at the same temperature, compound (I) was produced in an area% of 89.7. At that time, no impurity (A) was detected.

[Example 4] Synthesis of compound (I) 0.5 g of methanesulfonyl chloride at room temperature was added to a mixed solution of 0.83 g of compound (II), 1.0 g of compound (IIIa), 0.81 g of 3-picoline and 10 mL of acetonitrile. Dropped slowly. When the reaction was checked by HPLC after stirring overnight at the same temperature, compound (I) was produced in an area% of 88.9. At that time, no impurity (A) was detected.

[Example 5] Synthesis of compound (I) 1.04 g of compound (IIIb) under an ice bath was slowly added dropwise to a mixed solution of 0.83 g of compound (II), 0.78 g of 3-picoline and 10 mL of acetone. After completion of the dropping, the temperature was raised to room temperature, the mixture was stirred overnight at the same temperature, and then the reaction was checked by HPLC. As a result, compound (I) was produced in an area% of 89.4. At that time, no impurity (A) was detected.

[Example 6] Synthesis of compound (I) 1.04 g of compound (IIIb) under an ice bath was slowly added dropwise to a mixed solution of 0.83 g of compound (II), 0.78 g of 3-picoline and 10 mL of acetonitrile. After completion of the dropping, the temperature was raised to room temperature, the mixture was stirred overnight at the same temperature, and then the reaction was checked by HPLC. As a result, compound (I) was produced at 91.0 area%. At that time, no impurity (A) was detected.

[Example 7] Synthesis of compound (I) 8.9 g of methanesulfonyl chloride at room temperature was slowly added dropwise to a mixed solution of 16.9 g of compound (II), 20 g of compound (IIIa), 12.3 g of pyridine and 98 mL of acetone. .. When the reaction was checked by HPLC after stirring at the same temperature overnight, compound (I) was produced in 93.3 area%. At that time, no impurity (A) was detected. After confirming the completion of the reaction, 49 g of water was slowly added dropwise, and the mixture was stirred at the same temperature for 45 minutes. The slurry was filtered, the obtained solid was washed with acetone water, and dried overnight in a warm air dryer to obtain 32.6 g of compound (I) (yield: 92%; purity: 96% by weight, 98.4 area%).
The conversion method from the area% of purity to the weight% is as follows.
15.41 mg of the cyclaniliprol standard product was weighed in a 25 mL volumetric flask, 1 mL of dimethylformamide, 2 mL of water and 20 mL of acetonitrile were added and dissolved, and the standard solution was prepared by measuring with acetonitrile. The prepared standard solution was measured by HPLC three times. The average value of the area values obtained by the measurement of HPLC was calculated. The calculated average value was divided by 15.41, which is the mass value of the standard cyclaniliprol product, to calculate the unit area value of 66069. In the same manner, the unit area values 72447, 91829 and 81242 of the compound (I), the impurity (A) and the impurity (B) were calculated. Next, the compound (I) obtained by synthesis is also calculated by comparing the area value obtained by the HPLC measurement with the unit area value of the standard product in the same manner, and the weight% value indicating the content ratio of impurities is calculated. Was calculated.

[Example 8] Synthesis of compound (I) 0.45 g of methanesulfonyl chloride at room temperature was slowly added to a mixed solution of 0.79 g of compound (II), 1.0 g of compound (IIIa), 0.39 g of sodium carbonate and 10 mL of acetone. Dropped. When the reaction was checked by HPLC after stirring at the same temperature for 1 hour, compound (I) was produced in 75.5 area%. At that time, no impurity (A) was detected. Subsequently, 0.15 g of sodium carbonate and 0.15 g of methanesulfonyl chloride were added to the reaction solution, and the mixture was stirred overnight at room temperature. As a result, compound (I) was produced in an area% of 97.2. At that time, no impurity (A) was detected.

[Example 9] Synthesis of cyclaniliprol A mixed solution of 11.6 g of compound (I) and 58 mL of ethyl acetate obtained according to Example 3 was ice-cooled, and 5.2 g of bromine was slowly added dropwise. Next, 13.8 g of an aqueous sodium hydroxide solution was slowly added dropwise, and the mixture was stirred at the same temperature for 1 hour. After confirming that the reaction was completed, 12.7 g of an aqueous sodium sulfite solution under an ice bath was added dropwise, and the mixture was stirred at the same temperature for 1 hour. The slurry was filtered and the solid was washed with 11.6 g of water. 17.4 mL of methanol was added to the obtained solid, and the mixture was refluxed for 1 hour and then cooled to room temperature. The slurry was filtered and the solid was dried overnight in a warm air dryer to give 12.9 g of cyclaniliprol (yield: 95%). In addition, no impurity (B) was detected in the obtained cyclaniliprol (purity: 98% by weight, 97.6 area%).
The conversion method from the area% of the purity to the weight% was carried out in the same manner as in Example 7.

[Example 10] Synthesis of compound (I) A mixture of 0.5 g of compound (II), 0.67 g of compound (IIIa), 0.59 g of 3-picoline, and 2 mL of 3-picoline as a solvent is ice-cooled and chloride. 0.29 g of methanesulfonyl was slowly added dropwise under ice cooling. After completion of the dropping, the temperature was raised to room temperature, the mixture was stirred overnight at the same temperature, and then the reaction was checked by HPLC. As a result, compound (I) was produced in an area% of 97.8. At that time, no impurity (A) was detected.

[Example 11] Synthesis of compound (I) A mixture of 0.5 g of compound (II), 0.63 g of compound (IIIa), 0.39 g of 3-picoline, and 5 mL of pyridine as a solvent is ice-cooled and methanesulfonyl chloride. 0.26 g was slowly added dropwise under ice cooling. After completion of the dropping, the temperature was raised to room temperature, the mixture was stirred at the same temperature for 1 hour, and then the reaction was checked by HPLC. As a result, compound (I) was produced in an area% of 96.8. At that time, no impurity (A) was detected.

[Example 12] Synthesis of compound (I) A mixture of 0.5 g of compound (II), 0.63 g of compound (IIIa), 0.39 g of 3-picoline and 5 mL of acetone was ice-cooled and 0.26 g of methanesulfonyl chloride. Was slowly added dropwise under ice cooling. After completion of the dropping, the temperature was raised to room temperature, the mixture was stirred at the same temperature for 66 hours, and then the reaction was checked by HPLC. As a result, compound (I) was produced in an area% of 93.0. At that time, no impurity (A) was detected.

[Example 13] Synthesis of compound (I) A mixture of 0.5 g of compound (II), 0.63 g of compound (IIIa), 0.39 g of 3-picoline and 5 mL of dimethylformamide was ice-cooled to obtain methanesulfonyl chloride 0. 26 g was slowly added dropwise under ice cooling. After completion of the dropping, the temperature was raised to room temperature, the mixture was stirred at the same temperature for 2 hours, and then the reaction was checked by HPLC. As a result, compound (I) was produced in an area% of 97.6. At that time, no impurity (A) was detected.

[Example 14] Synthesis of compound (I) A mixture of 0.5 g of compound (II), 0.63 g of compound (IIIa), 0.39 g of 3-picoline and 5 mL of N-methylpyrrolidone is ice-cooled and methanesulfonyl chloride. 0.26 g was slowly added dropwise under ice cooling. After completion of the dropping, the temperature was raised to room temperature, the mixture was stirred at the same temperature for 2 hours, and then the reaction was checked by HPLC. As a result, compound (I) was produced in 92.4 area%. At that time, no impurity (A) was detected.

[Comparative Example 1] Synthesis of cyclaniliprol 0.5 g of methanesulfonyl chloride at room temperature was added to a mixed solution of 1.11 g of compound (V), 1.0 g of compound (IIIa), 0.81 g of 3-picoline and 10 mL of acetone. Dropped slowly. When the reaction was checked by HPLC after stirring overnight at the same temperature, cyclaniliprol was produced in an area% of 42.9. At that time, the amount of the impurity (B) produced was 0.3 area%.

[Comparative Example 2] Synthesis of cyclaniliprol 0.5 g of methanesulfonyl chloride at room temperature was added to a mixed solution of 1.11 g of compound (V), 1.0 g of compound (IIIa), 0.81 g of 3-picoline, and 10 mL of acetonitrile. Dropped slowly. When the reaction was checked by HPLC after stirring overnight at the same temperature, cyclaniliprol was produced in an area% of 79.9. At that time, the amount of the impurity (B) produced was 5.3 area%.

[Comparative Example 3] Synthesis of cyclaniliprol 1.09 g of compound (IIIb) under an ice bath was slowly added dropwise to a mixed solution of 1.11 g of compound (V), 0.78 g of 3-picoline, and 13 mL of acetone. After completion of the dropping, the temperature was raised to room temperature, the mixture was stirred overnight at the same temperature, and then the reaction was checked by HPLC. As a result, cyclaniliprol was produced at 73.0 area%. At that time, the amount of the impurity (B) produced was 4.2 area%.

[Comparative Example 4] Synthesis of cyclaniliprol 1.09 g of compound (IIIb) under an ice bath was slowly added dropwise to a mixed solution of 1.11 g of compound (V), 0.78 g of 3-picoline, and 13 mL of acetonitrile. After completion of the dropping, the temperature was raised to room temperature, the mixture was stirred overnight at the same temperature, and then the reaction was checked by HPLC. As a result, cyclaniliprol was produced in an area% of 57.7. At that time, the amount of the impurity (B) produced was 6.4 area%.

In Examples 1 to 14, no impurity (A) was detected. Furthermore, unlike Comparative Examples 1 to 4, the cyclaniliprol of Example 9 obtained from the compound (I) obtained by the method of the present invention was confirmed to produce an impurity (B). However, it was possible to produce high-purity cyclaniliprol that meets the specifications as a pesticide drug substance.
The entire contents of the specification, claims, and abstract of Japanese Patent Application No. 2020-054157 filed on March 25, 2020 are cited here and incorporated as disclosure of the specification of the present invention. It is a thing.

Claims

The compound represented by the formula (I) or a salt thereof:

It is a manufacturing method of
The compound represented by the formula (II) or a salt thereof:

And the compound represented by the formula (III) or a salt thereof:

[In formula (III), R is OH or halogen]
A production method in which and is reacted in the presence of a condensing agent and / or a base.
Claim that when R is OH, the compound represented by the formula (II) or a salt thereof is reacted with the compound represented by the formula (III) or a salt thereof in the presence of a condensing agent and a base. The manufacturing method according to 1.
The first aspect of the present invention, wherein when R is a halogen, the compound represented by the formula (II) or a salt thereof is reacted with the compound represented by the formula (III) or a salt thereof in the presence of a base. Manufacturing method.
The production method according to claim 1 or 2, wherein the condensing agent is sulfonyl chloride.
The production method according to any one of claims 1 to 4, wherein the base is one or more selected from the group consisting of pyridine, picoline, alkali metal carbonate and alkali metal hydrogen carbonate. ..
The method according to any one of claims 1 to 5, wherein the obtained compound represented by the formula (I) or a salt thereof has a purity of 95% by weight or more.
In addition to the obtained compound represented by the formula (I) or a salt thereof, the compound represented by the following formula (A) or a salt thereof contained as an impurity:

1 to 6 by weight or less based on the total amount of the compound represented by the formula (I) or a salt thereof and the compound represented by the formula (A) or a salt thereof. The manufacturing method according to any one of the following items.
In addition to the obtained compound represented by the formula (I) or a salt thereof, as an impurity, the compound represented by the formula (A) or a salt thereof:

The method according to any one of claims 1 to 6, which does not substantially contain.
A method for producing cyclaniliprol, wherein the compound represented by the formula (I) obtained by the production method according to any one of claims 1 to 8 or a salt thereof is reacted with a brominating agent.