JP2019048879A - Cocrystal containing 3-(difluoromethyl)-1-methyl-n-[(3r)-1,1,3-trimethyl-2,3-dihydro-1h-indene-4-yl]-1h-pyrazole-4-carboxamide - Google Patents

Abstract

To provide a cocrystal having an excellent control effect on plant disease.SOLUTION: A cocrystal contains 3-(difluoromethyl)-1-methyl-N-[(3R)-1,1,3-trimethyl-2,3-dihydro-1H-indene-4-yl]-1H-pyrazole-4-carboxamide, and one monocyclic aromatic compound selected from the following group A: a benzene compound having one or more group selected from the group consisting of a halogen atom, a hydroxy group, a cyano group, a nitro group, a formyl group, an acetyl group, a carboxy group and a carboxymethyl group; and a pyridine compound having one or more group selected from the group consisting of a halogen atom, a hydroxy group, a cyano group, a nitro group, a formyl group, an acetyl group, a carboxy group and a carboxymethyl group.SELECTED DRAWING: None

Description

  The present invention provides novel 3- (difluoromethyl) -N-[(R) -2,3-dihydro-1,1,3-trimethyl-1H-inden-4-yl] -1-methyl-1H-pyrazole- The present invention relates to a co-crystal composed of 4-carboxamide and a monocyclic aromatic compound and an agricultural chemical preparation containing the co-crystal.

  3- (Difluoromethyl) -1-methyl-N-[(3R) -1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl] -1H-pyrazole-4-carboxamide (Referred to as the present amide compound) is known to have a controlling effect against plant pathogens (Patent Document 1) and is known to form solvates with various solvents (Patent Document 2). .

PCT Publication WO2011 / 162397 PCT Publication WO2015 / 118793

  The subject of this invention is providing the substance containing this amide compound which shows the outstanding control effect with respect to a plant disease.

As a result of intensive studies to solve the above problems, the present inventor has found that a co-crystal composed of the present amide compound and a certain monocyclic aromatic compound exhibits an excellent control effect against plant diseases. Was completed.
That is, the present invention is as follows.
[1] A co-crystal (hereinafter referred to as the present co-crystal) comprising the present amide compound and any one monocyclic aromatic compound selected from the following group A (hereinafter referred to as the present mono-cyclic aromatic compound). .
Group A: a benzene compound having one or more groups selected from the group consisting of halogen atoms, hydroxyl groups, cyano groups, nitro groups, formyl groups, acetyl groups, carboxy groups and carboxymethyl groups; and halogen atoms, hydroxyl groups, cyano groups, A pyridine compound having one or more groups selected from the group consisting of a nitro group, a formyl group, an acetyl group, a carboxy group, and a carboxymethyl group.
[2] A co-crystal comprising the present amide compound and any one monocyclic aromatic compound selected from the following group B.
Group B: Benzoic acid, chlorobenzene, acetophenone, and salicylaldehyde.
[3] An agrochemical formulation containing the co-crystal.

  This co-crystal shows an excellent control effect against plant diseases.

The powder X-ray-diffraction pattern of the co-crystal of this amide compound and benzoic acid. The powder X-ray-diffraction pattern of the co-crystal of this amide compound and acetophenone. The powder X-ray-diffraction pattern of the co-crystal of this amide compound and chlorobenzene. The powder X-ray-diffraction pattern of the co-crystal of this amide compound and salicylaldehyde. TG-DTA trace of co-crystal of this amide compound and benzoic acid. TG-DTA trace of co-crystal of this amide compound and acetophenone. TG-DTA trace of co-crystal of this amide compound and chlorobenzene. TG-DTA trace of co-crystal of this amide compound and salicylaldehyde. TG-DTA trace of co-crystal of this amide compound and ethylbenzene. Co-crystal structure diagram of this amide compound and acetophenone obtained from the analysis result of single crystal X-ray diffraction (4 molecules of this amide compound and 2 molecules of acetophenone) Stereo view of the co-crystal structure of this amide compound and acetophenone (two molecules of this amide compound and one molecule of acetophenone; hydrogen omitted) Co-crystal structure diagram of the present amide compound and chlorobenzene obtained from the analysis result of single crystal X-ray diffraction (4 molecules of this amide compound and 2 molecules of acetophenone) Stereo view of the co-crystal structure of this amide compound and chlorobenzene (two molecules of this amide compound and one molecule of chlorobenzene: hydrogen omitted)

This co-crystal consists of the present amide compound and the present monocyclic aromatic compound.
This amide compound is a compound described in WO2011 / 162397. This monocyclic aromatic compound is a publicly known compound.

One embodiment of the present monocyclic aromatic compound that forms a co-crystal with the present amide compound includes a monocyclic aromatic compound selected from Group A. As one aspect | mode of this monocyclic aromatic compound, the monocyclic aromatic compound chosen from the group B is mentioned.

  Examples of the monocyclic aromatic compound that forms a co-crystal with the amide compound include toluene, o-xylene, m-xylene, p-xylene, ethylbenzene, chlorobenzene, o-dichlorobenzene, p-dichlorobenzene, 2, 4 , 5,6-tetrachloro-1,3-benzenedicarbonitrile, acetaldehyde, acetophenone, benzoic acid, o-toluic acid, m-toluic acid, p-toluic acid, 2,3,6-trichlorobenzoic acid, 3 , 6-dichloro-2-methoxybenzoic acid, phenol, o-cresol, m-cresol, p-cresol, dinitrophenol, 2-cyanophenol, 3-cyanophenol, 4-cyanophenol, 2,6-dichloro-4 -Cyanophenol, 2,6-dibromo-4-cyanophenol, 2,6-diiodo-4-si Anophenol, 4,6-dinitro-o-cresol, pentachlorophenol, salicylaldehyde, 3-methoxy-4-hydroxybenzaldehyde, (4-chlorophenoxy) acetic acid, (2,4-dichlorophenoxy) acetic acid, (3, Benzene compounds such as 4-dichlorophenoxy) acetic acid; pyridine compounds such as picolinic acid and 3,6-dichloro-2-picolinic acid.

  The co-crystal is considered to be formed by stabilizing the amide compound and the monocyclic aromatic compound through interactions such as intermolecular hydrogen bonding, π orbital stacking, and van der Waals forces. In the present co-crystal, the molar ratio of the monocyclic aromatic compound to the amide compound is usually in the range of 0.2 to 2.0, preferably in the range of 0.3 to 1.5, and 0.4 to 0.8. The range of is more preferable.

The formation of the co-crystal was confirmed by thermal analysis (TG / DTA), differential scanning calorimetry (DSC), infrared absorption spectrum (IR), X-ray diffraction pattern, ¹³ C-CP / MAS-solid state NMR spectrum, etc. Can be confirmed. The composition of the co-crystal is confirmed by thermal analysis, differential scanning calorimetry (DSC), ¹ H-NMR spectrum, ¹³ C-NMR spectrum, gel filtration chromatography (GPC), high performance liquid chromatography (HPLC), elemental analysis, etc. can do.

As a method for producing the co-crystal, specifically,
(I) a method comprising mixing the present amide compound, the present monocyclic aromatic compound and an auxiliary component as required, and subjecting the mixture to a mechanochemical solid phase reaction;
(Ii) A method of heating and stirring a suspension obtained by suspending the present amide compound, the present monocyclic aromatic compound and, if necessary, an auxiliary component in a solvent;
(Iii) a method by dissolving the present amide compound, the present monocyclic aromatic compound and, if necessary, an auxiliary component in a solvent and then precipitating a co-crystal; or (iv) the present amide compound and the present monocyclic aromatic. Examples thereof include a method of mixing a group compound with auxiliary components as necessary, heating and melting.
Of these, the method (ii) or (iii) is preferred.

  Examples of auxiliary components used as necessary in the method for producing the co-crystal include surfactants, extenders, auxiliary agents for enhancing efficacy, antioxidants, ultraviolet absorbers, stabilizers and the like.

In the method (i), the mechanochemical solid phase reaction is preferably performed by dry pulverization.

The solvent used in the method (ii) is not particularly limited, but a liquid medium capable of dissolving the present amide compound and the present monocyclic aromatic compound at a solubility of 100 ppm or more is preferable. Specific examples of the solvent include monohydric alcohols such as water, methanol, ethanol, propanol, isopropanol, and butanol, glycols such as ethylene glycol, diethylene glycol, propylene glycol, and glycerin, and ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone. Etc. These solvents can be used alone or in combination of two or more. Among these, water is preferably used as the solvent.
After suspending the present amide compound and the present monocyclic aromatic compound in a solvent, they may be stirred for a certain period of time or may be allowed to stand without stirring. After suspension, heat and stir for a certain time. The time for stirring or the time for heating is not particularly limited, but each is preferably 30 minutes or more and 1 day or less. This time depends on the purpose of use of the co-crystal, the present amide compound and the present monocyclic aromatic compound, preferably 10% by mass or more and 100% by mass or less of the total amount of the present amide compound and the present monocyclic aromatic compound. Preferably, 50% by mass or more and 100% by mass or less, particularly preferably 90% by mass or more and 100% by mass or less, may be sufficient time for forming a co-crystal. This time can be determined by the above-described method for confirming the formation of the co-crystal or by measuring the change with time of the solid particle diameter in the suspension. The heating temperature is preferably 40 ° C. or higher and not higher than the boiling point of the solvent, more preferably 60 ° C. or higher and not higher than the boiling point of the solvent.
The heating and stirring steps of the suspension are preferably performed in the presence of a surfactant. As the surfactant, those described later can be used, and are selected from the group consisting of nonionic surfactants such as polyoxyethylene glycol tristyryl phenyl ether, lignin sulfonate, and dialkyl sulfosuccinate. It is preferable to use at least one of the above.

The solvent used in the method (iii) is not particularly limited as long as it can dissolve all of the present amide compound and the present monocyclic aromatic compound. Specific examples of the solvent include acetone, acetonitrile, methanol, ethanol, ethyl acetate, dichloromethane, chloroform, tetrahydrofuran, n-hexane, cyclohexane, benzene, toluene, xylene and the like. These solvents can be used alone or in combination of two or more. Of these, acetone is preferred. If the monocyclic aromatic compound is a liquid at room temperature that can dissolve the amide compound, the amide compound is dissolved in an excess amount of the monocyclic aromatic compound, and a co-crystal is obtained from the resulting solution. It may be formed.
The co-crystal can be precipitated by mixing with a poor solvent or cooling. Although strictly different from recrystallization, a co-crystal can be obtained simply by distilling off the solvent.

In the method (iv), the heating temperature is at least equal to or higher than the temperature at which the mixture of the amide compound and the monocyclic aromatic compound melts, and the amide compound and the monocyclic aromatic compound diamide are heated. Any temperature may be used as long as it does not decompose. This temperature does not necessarily mean that both of the above components are higher than the melting temperature exhibited by each of them, and a lower temperature is possible depending on the properties of the mixture. The heating temperature is preferably 85 ° C. or higher, more preferably 90 ° C. or higher, and even more preferably 100 ° C. or higher.

The cocrystal thus produced can be used in the production of the agrochemical formulation of the present invention in the form in which it is produced, or after further purification of the cocrystal, depending on the application.
The agrochemical formulation containing this co-crystal can contain other agrochemical active ingredients. Other agrochemical active ingredients that can be included include insecticides, acaricides, nematicides, fungicides, herbicides, plant growth regulators, resistance inducers, pest repellents, antiviral agents, etc. Can be illustrated.

The dosage form of the agrochemical formulation of the present invention is not particularly limited as long as the cocrystal can exist in a cocrystal state, and specifically, powder, wettable powder, granular wettable powder, Examples thereof include suspensions and tablets, and concentrated suspensions are preferred for seed treatment applications.

Specific examples of auxiliary components used in the agricultural chemical formulation of the present invention include surfactants, extenders, auxiliary agents for enhancing efficacy, antioxidants, ultraviolet absorbers, stabilizers and the like.
Examples of the use of the agrochemical formulation of the present invention include agricultural and horticultural use and home and garden use.

In the agrochemical formulation of the present invention, a solid carrier, a liquid carrier, oil, and / or a surfactant are usually mixed with the co-crystal, and if necessary, formulation adjuvants such as a fixing agent, a dispersant, and a stabilizer are added. Manufactured. The preparation contains the present co-crystal in a weight ratio of usually 0.1 to 99%, preferably 0.2 to 90%.

Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to the examples.

First, specific examples of the method for producing the co-crystal are shown below.
Production Example 1
After adding 333 mg of the present amide compound and 61 mg of benzoic acid to 600 μL of ethyl acetate to prepare a homogeneous solution, the solution is allowed to stand at room temperature for 24 hours under open conditions. A co-crystal of the compound and benzoic acid (hereinafter sometimes referred to as the present co-crystal 1) was obtained.

Production Example 2
1 g of this amide compound was added to 1 mL of acetophenone, and this amide compound was dissolved by heating with a dryer to prepare a uniform solution. To this solution, 2 mg of a xylene solvate of the present amide compound (described in Reference Example 14 of International Publication No. WO2015 / 118793) was added and allowed to stand at room temperature for 24 hours. Crystals formed in the solution were filtered and dried at room temperature and normal pressure for 24 hours to obtain 0.49 g of crude crystals.
Next, 9 g of the amide compound was added to 9 mL of acetophenone, and the amide compound was dissolved by heating with a dryer to prepare a uniform solution. To the solution, 30 mg of the crude crystals obtained by the above procedure was added and allowed to stand at room temperature for 24 hours. Crystals produced in the solution were filtered and dried at room temperature and normal pressure for 24 hours to obtain 4.5 g of a co-crystal of the present amide compound and acetophenone (hereinafter sometimes referred to as the present co-crystal 2). .

Production Example 3
1 g of the amide compound was added to 1 mL of chlorobenzene, and the amide compound was dissolved by heating with a dryer to prepare a uniform solution. 2 mg of the amide compound xylene hydrate (described in Reference Example 14 of International Publication No. WO2015 / 118793) was added to the solution, left at room temperature for 30 minutes, further cooled to 5 ° C., For 2 hours. Crystals formed in the solution were filtered and dried at room temperature and normal pressure for 24 hours to obtain 0.76 g of crude crystals.
Next, 9 g of the amide compound was added to 9 mL of chlorobenzene, and the amide compound was dissolved by heating with a dryer to prepare a uniform solution. To the solution, 10 mg of the crude crystals obtained by the above procedure was added and allowed to stand at room temperature for 24 hours. Crystals formed in the solution were filtered and dried at room temperature and normal pressure for 24 hours to obtain 7.6 g of a co-crystal of the present amide compound and chlorobenzene (hereinafter sometimes referred to as the present co-crystal 3).

Production Example 4
1 g of this amide compound was added to 1 mL of salicylaldehyde, and this amide compound was dissolved by heating with a dryer to prepare a uniform solution. To this solution, 10 mg of a xylene hydrate of the present amide compound (described in Reference Example 14 of International Publication No. WO2015 / 118793) was added and allowed to stand at room temperature for 24 hours. Crystals formed in the solution were filtered and dried at room temperature and normal pressure for 24 hours to obtain 0.44 g of crude crystals.
Next, 9 g of this amide compound was added to 9 mL of salicylaldehyde, and this amide compound was dissolved by heating with a dryer to prepare a uniform solution. To the solution, 30 mg of the crude crystals obtained by the above procedure was added and allowed to stand at room temperature for 24 hours. Crystals generated in the solution were filtered and dried at room temperature and normal pressure for 24 hours to obtain 4.5 g of a co-crystal of the present amide compound and salicylaldehyde (hereinafter sometimes referred to as the present co-crystal 4). .

Next, formulation examples of agricultural chemical formulations using this co-crystal are shown below.
Formulation Example 1
75 parts of any one of the co-crystals 1 to 4, 15 parts of propylene glycol (manufactured by Nacalai Tesque), 15 parts of Soprophor FLK (manufactured by Rhodia Nikka), and 0.6 part of anti-form C emulsion (Dow Corning) And a mixture of ion-exchanged water at a ratio of 120 parts, and the slurry is wet-pulverized to obtain a wet-pulverized slurry. Separately, 0.3 part of Kelzan S (manufactured by Kelco), 0.6 part of Veegum granules (manufactured by RT Vanderbilt) and 0.6 part of Proxel GXL (manufactured by Arch Chemicals) are added and mixed in 72.9 parts of ion-exchanged water. A thickener aqueous solution is obtained. The wet pulverized slurry (75.2 parts) and the thickener aqueous solution (24.8 parts) are mixed to obtain a flowable preparation.

Formulation Example 2
15 parts of any one of the co-crystals 1 to 4, 1.5 parts of sorbitan trioleate, and 28.5 parts of an aqueous solution containing 2 parts of polyvinyl alcohol were mixed and pulverized by a wet pulverization method. Thereafter, 45 parts of an aqueous solution containing 0.05 part of xanthan gum and 0.1 part of aluminum magnesium silicate is added thereto, and further 10 parts of propylene glycol is added and stirred to obtain a flowable preparation.

Formulation Example 3
45 parts of any one of the co-crystals 1 to 4, 5 parts of propylene glycol (manufactured by Nacalai Tesque), 5 parts of Soprophor FLK (manufactured by Rhodia Nikka), and 0.2 part of anti-form C emulsion (Dow Corning) Co., Ltd.), Proxel GXL 0.3 parts (manufactured by Arch Chemical Co., Ltd.), and ion-exchanged water are mixed at a ratio of 49.5 parts to prepare a base slurry. 150 parts of glass beads (Φ = 1 mm) are added to 100 parts of the slurry, and pulverized for 2 hours while cooling with cooling water. After grinding, the glass beads are removed by filtration to obtain a flowable formulation.

Formulation Example 4
50.5 parts of any one of the co-crystals 1 to 4, 38.5 parts of NN kaolin clay (manufactured by Takehara Chemical Industries), 10 parts of Morwet D425, 1.5 parts of Morwer EFW (manufactured by Akzo Nobel) ) To obtain an AI premix. The premix is pulverized with a jet mill to obtain a powder.

Formulation Example 5
5 parts of any one of the co-crystals 1 to 4, 1 part of synthetic hydrous silicon oxide, 2 parts of calcium lignin sulfonate, 30 parts of bentonite, and 62 parts of kaolin clay are mixed well and mixed well with water. After combining, granule drying is performed to obtain a granule.

Formulation Example 6
Each powder is obtained by thoroughly pulverizing and mixing 3 parts of any one of the present co-crystals 1 to 4, 87 parts of kaolin clay, and 10 parts of talc.

Next, a specific example shows that the agrochemical formulation containing the co-crystal has excellent efficacy against plant diseases.
Test Example 1 Soybean rust (Phakopsora pachyrhizi) control plastic pots were filled with soil, sowed with soybeans, grown in a greenhouse for 10 days, and sprayed with an aqueous suspension of soybean rust spores. After inoculation, the soybean was placed in a humid room at 23 ° C for night and night at 20 ° C for 1 day, and then cultivated for 2 days in the greenhouse. Then, the preparation containing the co-crystal prepared according to the above formulation example was This amide compound was diluted with water so that the amount of application in terms of amide compound would be the following amount, and the diluted solution was sprayed on the foliage so that it sufficiently adhered to the leaves of soybean. After spraying, the spray solution on the leaf surface was air-dried, and the soybean was continuously cultivated in a greenhouse (23 ° C.). The lesion area on the leaf surface was examined 14 days after the inoculation. From the lesion area in the treated area and the untreated area, the efficacy of the treated area was calculated by the following formula 1. The results are summarized in Table 1.

Formula 1

※本アミド化合物が上記記載の薬量となるように処理した。

* The amide compound was treated so as to have the dosage described above.

Excellent control when cocrystals of the present amide compound and the above monocyclic aromatic compound are used compared to the case where the same application rate in terms of the present amide compound is used with crystals composed of the present amide compound alone. Efficacy was shown.

Test Example 2 Measurement of apparent water solubility In a beaker containing water, an amount of the co-crystal of the present amide compound and benzoic acid that does not completely dissolve at room temperature is added and dissolved in water after a certain time with stirring. The concentration of the amide compound was analyzed. As a result of analysis after about 0.5 hours, the concentration of the present amide compound dissolved in water was about 1.5 times the concentration in the case of using crystals composed of the present amide compound alone. After about 19 hours, the concentration of the present amide compound dissolved in water was almost the same as that when a crystal composed of the present amide compound alone was used.

Next, measurement conditions of powder X-ray diffraction of a co-crystal of the present amide compound and a monocyclic aromatic compound are shown below.
X-ray diffractometer: SmartLab; target: Cu; X-ray tube current: 200 mA; X-ray tube voltage: 45 kV

The measured powder X-ray diffraction pattern of each co-crystal is shown in a separate drawing. The peak position and relative intensity of the diffraction pattern are shown below.

Next, measurement conditions of single crystal X-ray diffraction of a co-crystal of the present amide compound and a monocyclic aromatic compound, and analysis results of the crystal structure (crystal structure parameters) are shown below.

Measurement conditions a)
Single crystal X-ray diffraction data was collected with Rigaku R-AXIS RAPID using MoKα radiation.
The structure was resolved by the direct method, refined and expanded by using the Fourier method in the SHELX software package.
Absorption correction was performed using ABSCOR software.

Measurement conditions b)
Single crystal X-ray diffraction data was collected with Rigaku R-AXIS RAPID using CuKα radiation.
The structure was resolved by the direct method, refined and expanded by using the Fourier method in the CRYSTALS software package.
Absorption correction was performed using ABSCOR software.

As can be seen from the crystal parameters shown in Tables 6 and 7, the co-crystals of this monoamide compound and four different monocyclic aromatic compounds have crystal structures that are very similar crystallographically. Further, from the diagrams shown in FIGS. 10 to 13, the co-crystal of the present invention has a crystal structure in which the position of the amide compound is almost the same and only the monocyclic aromatic compound as a guest molecule is replaced. It can be said that these co-crystals have a so-called isomorphic structure. Cocrystals with relatively weak interactions between the drug substance and coformer have been reported to form cocrystals with isomorphic structure even when the coformer is replaced with molecules of similar structure (CrystEngComm, 2018, 20 volumes, 362-369pp). It is presumed that the co-crystal of the amide compound and the monocyclic aromatic compound will also be a co-crystal of the isomorphic structure.

  This co-crystal has an excellent control effect against plant diseases and is useful as an active ingredient contained in an agrochemical formulation.

Claims (3)

3- (Difluoromethyl) -1-methyl-N-[(3R) -1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl] -1H-pyrazole-4-carboxamide and A co-crystal comprising any one monocyclic aromatic compound selected from Group A.
Group A: a benzene compound having one or more groups selected from the group consisting of halogen atoms, hydroxyl groups, cyano groups, nitro groups, formyl groups, acetyl groups, carboxy groups and carboxymethyl groups; and halogen atoms, hydroxyl groups, cyano groups, A pyridine compound having one or more groups selected from the group consisting of a nitro group, a formyl group, an acetyl group, a carboxy group, and a carboxymethyl group. 3- (Difluoromethyl) -1-methyl-N-[(3R) -1,1,3-trimethyl-2,3-dihydro-1H-inden-4-yl] -1H-pyrazole-4-carboxamide and A cocrystal comprising any one monocyclic aromatic compound selected from Group B.
Group B: Benzoic acid, chlorobenzene, acetophenone, and salicylaldehyde. An agrochemical formulation containing the co-crystal according to claim 1 or 2.

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