Method for producing metconazole crystals

Abstract

To provide new technical common sense for a method of producing metconazole that can achieve sufficient yield and cis-isomer ratio. [Solution] A method for producing metconazole crystals, comprising the steps of preparing a mixture containing a solvent containing cycloalkanes and metconazole, and cooling the mixture to crystallize metconazole.

Description

Technical Field

[0005] , ,

[0001] The present invention relates to a method for producing crystals of metconazole.

Background Art

[0002] Metconazole is known as an active ingredient in fungicides for agricultural and horticultural use, and its physical properties and the like are disclosed in, for example, Non-Patent Document 1. Since metconazole has high utility, various production methods thereof have been studied.

[0003] For example, Patent Document 1 discloses that metconazole can be produced by extracting from a solution after subjecting 5-(4-chlorobenzyl)-2,2-dimethylcyclopentanone to an azolization reaction and purifying by column chromatography.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Non-Patent Documents

[0005]

Non-Patent Document 1

[0006] Further investigations by the inventors revealed that the method described in Patent Document 1 resulted in a low yield of metconazole, indicating room for improvement. Furthermore, while it is known that metconazole has stereoisomers, with the cis isomer exhibiting high activity as a pesticide, the proportion of the cis isomer in the manufactured metconazole was not specified in Patent Document 1.

[0007] Therefore, one objective of the present invention is to provide a new technical means that can achieve a sufficient yield and a sufficient ratio of the cis isomer in a method for producing metconazole. [Means for solving the problem]

[0008] The inventors, through diligent research, unexpectedly discovered that metconazole crystals can be produced in sufficient yield and cis-isomer ratio by cooling a mixture containing a solvent with cycloalkanes and metconazole. The present invention is based on this finding.

[0009] According to one embodiment of the present invention, the following is provided. [1] A step of preparing a mixture containing a solvent containing cycloalkanes and metconazole, and The above mixture is cooled to crystallize metconazole. A method for producing metconazole crystals containing [the specified substance]. [2] The method for producing the above cycloalkanes comprising ethylcyclohexane as described in [1]. [3] The manufacturing method according to [1] or [2], wherein the step of preparing the above-mentioned mixture includes a step of heating the temperature of the above-mentioned mixture to 90 to 100°C to bring it into a solution state. [4] A manufacturing method according to any one of [1] to [3], wherein the step of crystallizing the metconazole is further comprising the step of cooling the mixture to 0 to 15°C. [5] The above step of crystallizing metconazole is A step of raising the temperature of the cooled mixture, and The above mixture is cooled again. A manufacturing method according to any one of [1] to [4], comprising each of the above at least once. [6] The manufacturing method according to [5], wherein the cooled mixture in the step of raising the temperature is a mixture cooled to 0 to 40°C. [7] The above heating step includes a step of heating the cooled mixture to 30-60°C. The manufacturing method described in [5] or [6]. [8] The manufacturing method according to any one of [5] to [7], wherein the cooled mixture in the step of raising the temperature is a mixture cooled to 20 to 40°C, and the step of raising the temperature includes a step of raising the temperature of the cooled mixture to 45 to 60°C. [9] The step of crystallizing metconazole is performed after the step of raising the temperature and before the step of cooling again. The process of maintaining the temperature of the above mixture. A manufacturing method according to any one of [5] to [8], further comprising:

[10] The manufacturing method according to [9], wherein the step of maintaining the above temperature includes a step of maintaining the above mixture at 45 to 60°C.

[11] In the powder X-ray diffraction pattern obtained using CuKα radiation, the following applies: 8.7±0.2 degrees (2θ), 13.4±0.2 degrees (2θ), 15.9±0.2 degrees (2θ), 17.5±0.2 degrees (2θ), 18.9±0.2 degrees (2θ), and 19.8±0.2 degrees (2θ) Metconazole crystals containing at least three peaks selected from the group consisting of [the specified group]. A metconazole crystal prepared by any of the methods in

[12] [1] to

[10] , wherein the powder X-ray diffraction pattern obtained using CuKα radiation is as follows: 8.7±0.2 degrees (2θ), 13.4±0.2 degrees (2θ), 15.9±0.2 degrees (2θ), 17.5±0.2 degrees (2θ), 18.9±0.2 degrees (2θ), and 19.8±0.2 degrees (2θ) Metconazole crystals containing at least three peaks selected from the group consisting of [the specified group]. Particles consisting of metconazole crystals as described in

[13]

[11] or

[12] . [Effects of the Invention]

[0010] According to one embodiment of the present invention, a method for producing metconazole crystals that can achieve a sufficient yield and cis ratio can be provided. [Brief explanation of the drawing]

[0011] [Figure 1] An example of the powder X-ray diffraction pattern of metconazole crystals obtained in Example 1 is shown. [Modes for carrying out the invention]

[0012] [Methconazole crystal manufacturing method] According to one embodiment of the present invention, a step of preparing a mixed solution containing a solvent containing cycloalkanes and metconazole (also referred to as the "preparation step" in this specification), and a step of cooling the above mixed solution to crystallize metconazole (also referred to as the "crystallization step" in this specification) A method for producing crystals of metconazole (also referred to as the "production method of the present invention" in this specification) including is provided. According to one embodiment of the present invention, the production method of the present invention is advantageous from the viewpoint of being able to produce crystals of metconazole with a sufficient yield and a ratio of the cis form. Hereinafter, the production method of the present invention will be described in detail.

[0013] In this specification, it is intended that "crystal" be used interchangeably with "crystal form".

[0014] In this specification, the notation "X to Y" (X and Y are arbitrary numerical values) means "X or more and Y or less".

[0015] [[ID=I7]] <Preparation step> According to one embodiment of the present invention, the production method of the present invention includes the above preparation step being carried out.

[0016] The mixed solution containing a solvent containing cycloalkanes and metconazole may be produced by a desired method (for example, a method of mixing a solvent containing cycloalkanes and metconazole under any conditions), may be commercially available, or may be a mixture of a commercially available solvent containing cycloalkanes and metconazole.

[0017] According to one embodiment of the present invention, the above preparation step may include a step of heating the mixture to a temperature at which substantially all of the metconazole is dissolved to bring it into a solution state. The above temperature can be appropriately adjusted by those skilled in the art, taking into consideration the type and amount of cycloalkanes contained in the solvent described later, the amount of metconazole contained in the mixture, etc. In this specification, "substantially all dissolved" means a state in which no undissolved solid metconazole can be observed by visual inspection or the like. More quantitatively, it refers to a state in which, for example, 98% by mass or more, preferably 99% by mass or more, and more preferably 100% by mass of the total weight of metconazole added to the mixture is dissolved. The above mixture containing a solvent containing cycloalkanes and metconazole may contain, for example, salts that may be produced during the metconazole manufacturing process. Therefore, the above mixture may contain undissolved material (for example, fine undissolved material) to the extent that it does not impair the effects of the present invention.

[0018] According to one embodiment of the present invention, the above preparation step may include a step of heating the temperature of the mixture to 90-100°C to a state in which substantially all of the metconazole is dissolved. This temperature range is advantageous from the viewpoint of potentially improving the yield of metconazole crystals and / or the proportion of the cis isomer produced.

[0019] According to one embodiment of the present invention, the above preparation step may include a step of heating the temperature of the mixture to 90-100°C to bring it into a solution state. Bringing it into a solution state is advantageous from the viewpoint that the purity of the manufactured metconazole crystals can be further improved.

[0020] (Solvents containing cycloalkanes) According to one embodiment of the present invention, the above-mentioned mixture contains a solvent containing cycloalkanes.

[0021] The cycloalkanes contained in the above solvent are not particularly limited as long as they can achieve the objectives of the present invention. Examples include cyclopropanes such as cyclopropane, methylcyclopropane, 1,2-dimethylcyclopropane, and ethylcyclopropane; cyclopentanes such as cyclopentane, methylcyclopentane, 1,1-dimethylcyclopentane, and ethylcyclopentane; cyclohexanes such as cyclohexane, methylcyclohexane, 1,1-dimethylcyclohexane, 1,3-dimethylcyclohexane, and ethylcyclohexane; cycloheptanes such as cycloheptane, methylcycloheptane, 1,2-dimethylcycloheptane, and ethylcycloheptane; and cyclooctanes such as cyclooctane, methylcyclooctane, 1,4-dimethylcyclooctane, 1,5-dimethylcyclooctane, and ethylcyclooctane. These may be used individually or in any combination of two or more. From the viewpoint of ensuring a good solubility difference with respect to metconazole even at low temperatures, it is preferable that the above cycloalkanes include cyclohexanes (preferably at least one selected from methylcyclohexane and ethylcyclohexane, more preferably ethylcyclohexane).

[0022] The amount of cycloalkanes contained in the above solvent is not particularly limited as long as the objective of the present invention can be achieved. For example, it may be 50 to 100% by volume, preferably 70 to 100% by volume, more preferably 90 to 100% by volume, and even more preferably 95 to 100% by volume, based on the total volume of the above solvent.

[0023] The above solvent may include other solvents other than cycloalkanes (for example, water; organic solvents such as ethyl acetate, toluene, tetrahydrofuran, and N-methyl-2-pyrrolidone; or any mixed solvents thereof) to the extent that it does not impair the purpose of the present invention.

[0024] The amount of the solvent contained in the above-mentioned mixture is not particularly limited as long as the objective of the present invention can be achieved. For example, it may be 30 to 99% by mass, preferably 40 to 97% by mass, more preferably 50 to 95% by mass, and even more preferably 60 to 90% by mass, based on the total mass of the above-mentioned mixture.

[0025] (Metconazole) Metconazole (5-(4-chlorobenzyl)-2,2-dimethyl-1-(1H-1,2,4-triazole-1-ylmethyl)cyclopentanol) has the following structure: [ka] It is a compound that has [a certain characteristic].

[0026] Furthermore, metconazole has the following stereoisomer: [ka] It is known that...

[0027] In this specification, the cis isomer of metconazole means that it includes the above-mentioned (+)-methconazole-cis(1R,5S) and (-)-methconazole-cis(1S,5R). Furthermore, in this specification, the trans isomer of metconazole means that it includes the above-mentioned (+)-methconazole-trans(1R,5R) and (-)-methconazole-trans(1S,5S). According to one embodiment of the present invention, the above-mentioned cis isomer means a racemic mixture of the above-mentioned (+)-methconazole-cis(1R,5S) and (-)-methconazole-cis(1S,5R). According to one embodiment of the present invention, the above-mentioned trans isomer means a racemic mixture of the above-mentioned (+)-methconazole-trans(1R,5R) and (-)-methconazole-trans(1S,5S).

[0028] In this specification, the ratio of the cis-isomer of metconazole (cis ratio) is given by the following formula:

number

[0029] The metconazole contained in the above mixture may be just one of the stereoisomers, or it may be a mixture of any two or more stereoisomers in any proportion.

[0030] The amount of metconazole contained in the above mixture is not particularly limited as long as the objective of the present invention can be achieved. For example, it may be 1 to 70% by mass, preferably 3 to 60% by mass, more preferably 5 to 50% by mass, and even more preferably 10 to 40% by mass, based on the total mass of the above mixture.

[0031] The above mixture may contain other components besides the solvent and metconazole, to the extent that it does not impair the purpose of the present invention. These other components may include, but are not limited to, water, unavoidable impurities contained in the reagents, raw materials, and solvents used, as well as salts and organic compounds generated during the manufacturing process.

[0032] <Crystallization process> According to one embodiment of the present invention, a crystallization step is performed in the manufacturing method of the present invention. According to one embodiment of the present invention, the crystallization step includes a step of crystallizing metconazole from the mixture by cooling crystallization.

[0033] The crystallization process described above is not particularly limited as long as the conditions (temperature, cooling rate, etc.) are such that metconazole crystals can be obtained. Those skilled in the art can adjust the composition and amount of the mixture, the desired amount of metconazole crystals, etc., as appropriate.

[0034] According to one embodiment of the present invention, the crystallization step may include a step of cooling the mixture to 0 to 15°C (preferably 3 to 14°C, more preferably 5 to 13°C) from the viewpoint that the yield and / or cis ratio of metconazole crystals can be further improved.

[0035] The cooling rate in the crystallization step described above may be, for example, 1 to 40°C / hour, preferably 1 to 35°C / hour, and more preferably 1 to 30°C / hour. The cooling rate may be constant or varied during the crystallization step described above.

[0036] According to one embodiment of the present invention, the crystallization step is performed as follows: A step of raising the temperature of the cooled mixture (also referred to as the "temperature raising step" in this specification), and A step of cooling the above mixture again (also referred to as the "recooling step" in this specification) Each of these steps may be included at least once. According to one embodiment of the present invention, including the heating step and the recooling step in the crystallization step is advantageous in that the yield and / or cis ratio of the resulting metconazole crystals can be further improved. Furthermore, according to one embodiment of the present invention, including the heating step and the recooling step in the crystallization step is advantageous in that larger metconazole crystals (or particles consisting of metconazole crystals) can be obtained.

[0037] Although not bound by theory, it is thought that by raising the temperature of the cooled mixture and then cooling it again, at least a portion of the trans isomer of metconazole may be redissolved in the mixture preferentially over the cis isomer, resulting in an improved cis ratio of the resulting metconazole crystals.

[0038] The temperature of the mixed liquid subjected to the above heating step may be, for example, 0 to 40°C, preferably 15 to 40°C, and more preferably 30 to 40°C. According to one embodiment of the present invention, the cooled mixed liquid in the above heating step may be a mixed liquid cooled to 0 to 40°C (preferably 15 to 40°C, more preferably 20 to 40°C, and even more preferably 30 to 40°C).

[0039] According to one embodiment of the present invention, the crystallization step may include a step of cooling the mixture before the heating step (for example, a step of cooling the mixture to 0 to 40°C (preferably 15 to 40°C, more preferably 30 to 40°C)). According to one embodiment of the present invention, the preparation step may include a step of heating the mixture to 90 to 100°C to make it a solution, and the crystallization step may include a step of cooling the mixture before the heating step (for example, a step of cooling the mixture to 0 to 40°C (preferably 15 to 40°C, more preferably 30 to 40°C)). The rate of cooling in the cooling step is not particularly limited and may be, for example, 1 to 40°C / hour, preferably 1 to 35°C / hour, more preferably 1 to 30°C / hour. The rate of cooling may be constant or varied in the cooling step.

[0040] The temperature to be raised in the above heating step may be, for example, above the temperature of the mixed liquid subjected to the heating step and 60°C or less, preferably above the temperature of the mixed liquid and 55°C or less. The temperature to be raised in the above heating step may be 30 to 60°C, preferably 40 to 60°C, and more preferably 45 to 55°C.

[0041] According to one embodiment of the present invention, the heating step may include a step of heating the mixture, which has been cooled to 0 to 40°C (preferably 15 to 40°C, more preferably 20 to 40°C, and even more preferably 30 to 40°C), to a temperature above the temperature of the mixture but 60°C or less (preferably 45 to 60°C, more preferably 45 to 55°C).

[0042] The heating rate in the above heating step is not particularly limited and may be, for example, 1 to 50°C / hour, preferably 1 to 40°C / hour, and more preferably 1 to 35°C / hour. The heating rate may be constant or varied during the above heating step.

[0043] The cooling temperature in the above recooling step may be, for example, 0°C or higher and less than the temperature of the mixture in the above heating step, preferably 0 to 30°C, more preferably 0 to 15°C. From the viewpoint of further improving the yield and / or cis ratio of metconazole crystals, the cooling temperature in the above recooling step is preferably 0 to 15°C (more preferably 3 to 14°C, even more preferably 5 to 13°C).

[0044] The cooling rate in the above recooling step is not particularly limited and may be, for example, 1 to 40°C / hour, preferably 1 to 35°C / hour, and more preferably 1 to 30°C / hour. The cooling rate may be constant or varied during the above recooling step.

[0045] The heating step and the recooling step described above may each be performed once or multiple times. If the heating step and the recooling step are performed multiple times, the conditions for the heating step and / or recooling step (e.g., heating temperature, heating rate, cooling temperature, cooling rate) may be the same or different.

[0046] According to one embodiment of the present invention, the crystallization step is performed after the heating step and before the recooling step, A step of maintaining the temperature of the above mixture (also referred to as the "first maintenance step" in this specification) It may further include the following. According to one embodiment of the present invention, the crystallization step including the first maintenance step is advantageous in that the yield and / or cis ratio of the metconazole crystals obtained may be further improved. In the first maintenance step, it is sufficient to maintain the temperature within a range of ±2°C of the desired temperature, and preferably within a range of ±1°C of the desired temperature.

[0047] The temperature in the first maintenance step described above can be appropriately adjusted according to the temperature in the heating step described above, as can be said by those skilled in the art. The temperature in the first maintenance step described above may be, for example, 30 to 60°C, preferably 40 to 60°C, more preferably 45 to 60°C, and even more preferably 45 to 55°C.

[0048] The time in the first maintenance step (maintenance time) can be appropriately adjusted by those skilled in the art depending on the purity and / or cis ratio of the metconazole crystals obtained and the production time, for example, it may be 10 minutes to 5 hours or 20 minutes to 3 hours.

[0049] If the above heating step and the above recooling step are performed multiple times, the first maintenance step may be included in each of them, or it may be included only in combinations of some of the heating steps and recooling steps. Also, if the first maintenance step is performed multiple times in accordance with the multiple times the heating step and the above recooling step are performed, the conditions of the first maintenance step (e.g., maintenance time) may be the same or different.

[0050] According to one embodiment of the present invention, the crystallization step is performed as follows: The step of adding metconazole seed crystals (also referred to as the "seed crystal addition step" in this specification) It may also include other things.

[0051] The cis ratio of the seed crystal used in the seed crystal addition step described above is not particularly limited as long as the objective of the present invention can be achieved, and may be, for example, 80% or more.

[0052] The amount of seed crystals added in the seed crystal addition step described above is not particularly limited as long as the objective of the present invention can be achieved. For example, it may be 0.001 to 1% by mass, preferably 0.003 to 0.3% by mass, and more preferably 0.006 to 0.1% by mass, based on the total mass of metconazole contained in the mixture.

[0053] The seed crystal addition step described above may be performed at any timing during the crystallization step (for example, before the heating step, before the recooling step, or simultaneously with the first maintenance step). Furthermore, the seed crystal addition step may be performed once or multiple times. The temperature during the seed crystal addition step should be such that the seed crystal does not dissolve, for example, 0 to 85°C, preferably 20 to 85°C, and more preferably 30 to 75°C.

[0054] According to one embodiment of the present disclosure, the seed crystal addition step may include a step (hereinafter also referred to as the "second maintenance step") of maintaining the temperature of the mixture at a temperature of -10°C or higher and at or below the temperature at which the seed crystal was added, from the viewpoint of performing crystal growth after the addition of the seed crystal (for example, if the temperature at which the seed crystal was added was 55°C, the mixture is maintained at 45-55°C). The duration of the second maintenance step (maintenance time) is not particularly limited, but may be, for example, 0.5 to 5 hours, preferably 0.5 to 3 hours, and more preferably 1 to 2 hours. In the second maintenance step, the temperature should be maintained within a range of ±2°C from the desired temperature, and preferably within a range of ±1°C from the desired temperature.

[0055] According to one embodiment of the present invention, the crystallization step may include a step of cooling the mixture to a desired temperature (e.g., 0 to 15°C) and then maintaining the mixture at that temperature (also referred to herein as the "third maintenance step"). The duration of the third maintenance step (maintenance time) is not particularly limited, but may be, for example, 0.5 to 24 hours, preferably 0.5 to 12 hours, and more preferably 1 to 6 hours. In the third maintenance step, the mixture should be maintained within a range of ±2°C from the desired temperature, and preferably within a range of ±1°C from the desired temperature.

[0056] The manufacturing method of the present invention may include other steps besides those described above, as necessary, as long as they do not impair the objectives of the present invention. Such other steps may be performed at any time before, simultaneously with, or after each of the above steps. For example, from the viewpoint of further improving the yield, cis ratio, and / or particle size of the metconazole crystals obtained, at least one step of maintaining the temperature of the mixture for a desired period of time may be included at any time during the crystallization process, in addition to the first, second, and third maintenance steps. Furthermore, for example, from the viewpoint of recovering the metconazole crystals obtained, a step of separating them from the solvent by filtration or the like may be performed, and a step of drying the metconazole crystals may be performed. The conditions (temperature, time, pressure, etc.) in the step of separating from the solvent and the step of drying the metconazole crystals are not particularly limited as long as they do not impair the objectives of the present invention, and can be appropriately adjusted by those skilled in the art.

[0057] [Metconazole crystals] According to one embodiment of the present invention, in a powder X-ray diffraction pattern obtained using CuKα rays, the following applies: 8.7±0.2 degrees (2θ), 13.4±0.2 degrees (2θ), 15.9±0.2 degrees (2θ), 17.5±0.2 degrees (2θ), 18.9±0.2 degrees (2θ), and 19.8±0.2 degrees (2θ) A crystal of metconazole (hereinafter also referred to as "the crystal of the present invention") is provided, comprising at least three peaks selected from the group consisting of the following. Although not bound by theory, the crystal of the present invention is advantageous in that it may be easier to handle and / or formulate compared to other metconazole crystals.

[0058] According to one embodiment of the present invention, the powder X-ray diffraction pattern can be measured using CuKα rays as the X-ray source. According to a preferred embodiment of the present invention, the powder X-ray diffraction pattern can be measured by the method described in the examples herein.

[0059] The relative intensity of X-ray diffraction peaks may depend on selective orientation and other factors. Therefore, the crystals of the present invention may require processing (for example, grinding the sample with an agate mortar and pestle or by other means) to mitigate these factors. Furthermore, although the position of the peak along the 2θ axis does not change significantly with the selective orientation in principle, slight errors may occur between instruments, so it may be preferable to use the same powder X-ray diffractometer when evaluating different crystals.

[0060] According to one embodiment of the present invention, the crystal of the present invention exhibits the following characteristics in the above powder X-ray diffraction pattern: 8.7±0.2 degrees (2θ), 13.4±0.2 degrees (2θ), 15.9±0.2 degrees (2θ), 17.5±0.2 degrees (2θ), 18.9±0.2 degrees (2θ), and 19.8±0.2 degrees (2θ) It includes at least three (preferably at least four, more preferably at least five) peaks selected from the group consisting of the following.

[0061] According to one embodiment of the present invention, the crystal of the present invention exhibits the following characteristics in the above powder X-ray diffraction pattern: 8.7±0.2 degrees (2θ), 13.4±0.2 degrees (2θ), 15.9±0.2 degrees (2θ), 17.5±0.2 degrees (2θ), 18.9±0.2 degrees (2θ), and 19.8±0.2 degrees (2θ) This includes the peak.

[0062] According to one embodiment of the present invention, the crystal of the present invention exhibits the following characteristics in the above powder X-ray diffraction pattern: 11.5±0.2 degrees (2θ) and 14.8±0.2 degrees (2θ) It further includes at least one peak selected from the above.

[0063] According to one embodiment of the present invention, the crystal of the present invention exhibits the following characteristics in the above powder X-ray diffraction pattern: 11.5±0.2 degrees (2θ) and 14.8±0.2 degrees (2θ) This includes the peak of the peak.

[0064] According to one embodiment of the present invention, the crystal of the present invention exhibits the following characteristics in the above powder X-ray diffraction pattern: 10.6±0.2 degrees (2θ), 12.1±0.2 degrees (2θ), 12.6±0.2 degrees (2θ), 15.3±0.2 degrees (2θ), 20.1±0.2 degrees (2θ), 20.7±0.2 degrees (2θ), 21.3±0.2 degrees (2θ), 23.1±0.2 degrees (2θ), 24.0±0.2 degrees (2θ), 24.4±0.2 degrees (2θ), and 24.9±0.2 degrees (2θ) It further includes at least one peak (preferably at least three, more preferably at least five, even more preferably at least seven, and even more preferably at least ten) selected from the group consisting of the above.

[0065] According to one embodiment of the present invention, the crystal of the present invention exhibits the following characteristics in the above powder X-ray diffraction pattern: 10.6±0.2 degrees (2θ), 12.1±0.2 degrees (2θ), 12.6±0.2 degrees (2θ), 15.3±0.2 degrees (2θ), 20.1±0.2 degrees (2θ), 20.7±0.2 degrees (2θ), 21.3±0.2 degrees (2θ), 23.1±0.2 degrees (2θ), 24.0±0.2 degrees (2θ), 24.4±0.2 degrees (2θ), and 24.9±0.2 degrees (2θ) This includes the peak of the peak.

[0066] According to one embodiment of the present invention, the crystal of the present invention exhibits the following characteristics in the above powder X-ray diffraction pattern: 8.7±0.2 degrees (2θ), 10.6±0.2 degrees (2θ), 11.5±0.2 degrees (2θ), 12.1±0.2 degrees (2θ), 12.6±0.2 degrees (2 θ), 13.4±0.2 degrees (2θ), 14.8±0.2 degrees (2θ), 15.3±0.2 degrees (2θ), 15.9±0.2 degrees (2θ), 17.5±0.2 2θ degrees, 18.9±0.2 degrees (2θ), 19.8±0.2 degrees (2θ), 20.1±0.2 degrees (2θ), 20.7±0.2 degrees (2θ), 21.3±0.2 degrees (2θ), 23.1±0.2 degrees (2θ), 24.0±0.2 degrees (2θ), 24.4±0.2 degrees (2θ), and 24.9±0.2 degrees (2θ) This includes the peak.

[0067] According to one embodiment of the present invention, the powder X-ray diffraction pattern of the crystal of the present invention is as shown in the figure below: [ka] It has the pattern shown by.

[0068] The crystals of the present invention may be produced, for example, by the manufacturing method of the present invention.

[0069] According to one embodiment of the present invention, a crystal of the present invention produced by the manufacturing method of the present invention is provided. According to one embodiment of the present invention, a crystal of the present invention produced by the manufacturing method of the present invention, wherein in the powder X-ray diffraction pattern obtained using CuKα rays, the following: 8.7±0.2 degrees (2θ), 13.4±0.2 degrees (2θ), 15.9±0.2 degrees (2θ), 17.5±0.2 degrees (2θ), 18.9±0.2 degrees (2θ), and 19.8±0.2 degrees (2θ) A crystal of metconazole is provided, containing at least three peaks selected from the group consisting of the following.

[0070] [Particles made of metconazole crystals] According to one embodiment of the present invention, particles comprising the crystal of the present invention (also referred to herein as "particles of the present invention") are provided. In this specification, "particles" as used with respect to the crystal of the present invention means individual particles of the substance, whether they exist individually or in aggregates. In this specification, particles are intended to encompass primary particles and aggregates.

[0071] In this specification, “primary particle” refers to a single entity. Furthermore, “aggregate” refers to a cluster of primary particles. Note that the term “aggregate” in this specification is not intended to limit the nature of the bonding between primary particles and is interchangeable with, for example, “assembly.”

[0072] The particles of the present invention may contain unavoidable impurities in addition to the crystal of the present invention. Therefore, according to one embodiment of the present invention, the particles of the present invention may substantially consist of the crystal of the present invention.

[0073] The particle size of the particles of the present invention is not particularly limited and can be appropriately adjusted by those skilled in the art depending on the purpose.

[0074] [Methconazole crystal manufacturing method] According to one embodiment of the present invention, a step of atomizing metconazole crystals produced by the manufacturing method of the present invention (for example, crystals of the present invention) (also referred to herein as the "atomization step") A method is provided for producing particles (for example, the particles of the present invention) consisting of metconazole crystals containing the present invention. According to one embodiment of the present invention, the particle formation step may include, for example, a step of grinding the particles of the present invention.

[0075] The conditions in the particle formation process (temperature, time, pressure, etc.) are not particularly limited as long as they are conditions that produce particles consisting of metconazole crystals, and those skilled in the art can adjust them as appropriate according to the desired metconazole crystal particles.

[0076] According to one embodiment of the present invention, particles consisting of metconazole crystals (for example, the particles of the present invention) are provided, which are produced by a method for producing particles consisting of metconazole crystals as described above.

[0077] [Agricultural and horticultural chemicals / Industrial material protectants] According to one embodiment of the present invention, an agricultural and horticultural agent and / or industrial material protectant is provided, containing metconazole crystals (e.g., crystals of the present invention) and / or particles made of metconazole crystals (e.g., particles of the present invention). According to one embodiment of the present invention, the agricultural and horticultural agent and / or industrial material protectant contains metconazole crystals (e.g., crystals of the present invention) and / or particles made of metconazole crystals (e.g., particles of the present invention) as an active ingredient.

[0078] The above-mentioned agricultural and horticultural chemicals and / or industrial material protective agents may be used by mixing the above-mentioned metconazole crystals (e.g., the crystals of the present invention) and / or particles consisting of the above-mentioned metconazole crystals (e.g., the particles of the present invention) with a carrier, surfactant and other formulation aids, etc., to formulate them into various forms such as powders, granules, powder-granules, wettable powders, aqueous solvents, emulsions, liquids, oils, aerosols, microencapsulated formulations, pastes, coatings, fumigants, fumigants and trace sprays. Such formulation aids, etc., may be known ones (e.g., those described in International Publication No. 2019 / 093522 and International Publication No. 2020 / 213739), and those skilled in the art can appropriately adjust them according to the desired formulation, etc.

[0079] The above-mentioned agricultural and horticultural chemicals and / or industrial material protectants may contain only metconazole crystals (e.g., the crystals of the present invention) and / or particles made of metconazole crystals (e.g., the particles of the present invention) as active ingredients, or they may contain other active ingredients in addition to these. According to one embodiment of the present invention, the above-mentioned agricultural and horticultural chemicals and / or industrial material protectants can also be used in combination with other known active ingredients to enhance their performance as agricultural and horticultural chemicals. Examples of other known active ingredients include known active ingredients contained in fungicides, insecticides, acaricides, nematicides, and plant growth regulators. Such fungicides, etc., may be known ones (e.g., those described in International Publication No. 2019 / 093522 and International Publication No. 2020 / 213739), and those skilled in the art can appropriately adjust them according to the desired formulation, etc.

[0080] According to one embodiment of the present invention, the above-mentioned agricultural and horticultural agent and / or industrial material protectant may contain other crystals of metconazole in addition to the metconazole crystals (e.g., the crystals of the present invention) and / or particles consisting of the metconazole crystals (e.g., the particles of the present invention). [Examples]

[0081] The manufacturing method of the present invention will be described in more detail below using examples. However, the following examples are not intended to limit the manufacturing method of the present invention in any way. Unless otherwise specified, the percentages and ratios described herein are by mass. Unless otherwise specified, the units and measurement methods described herein are in accordance with the provisions of the Japanese Industrial Standards (JIS).

[0082] [Synthesis example: Synthesis of metconazole (5-(4-chlorobenzyl)-2,2-dimethyl-1-(1H-1,2,4-triazole-1-ylmethyl)cyclopentanol)] The metconazole (concentrate) used in the examples described later was synthesized by the following method.

[0083] A mixture of 42 g of 1,2,4-triazole dissolved in 115 g of N-methyl-2-pyrrolidone was prepared. 40 g of sodium hydroxide and 12 g of water were added to this mixture and dissolved while heating and stirring. 135 mL of toluene was added, and the by-product water was azeotropically dehydrated with the toluene at 135°C under normal pressure. After removing the water, the toluene was removed by distillation to obtain a mixture containing the azole salt.

[0084] To the mixture containing the azole salt obtained above, 141 g of 5-(4-chlorobenzyl)-2,2-dimethylcyclopentanone and 20 g of N-methyl-2-pyrrolidone were added. While maintaining the reaction mixture temperature at 125±2°C, 31 g of t-butoxide and 120 g of trimethylsulfoxonium bromide were added in installments, and the reaction was carried out to obtain a post-reaction solution containing metconazole.

[0085] After cooling the reaction solution obtained above from 80°C to room temperature (30°C), 200 mL of water and 200 mL of toluene were added to extract metconazole into the organic layer. 80 mL of toluene was added to the aqueous layer for re-extraction, and the organic layer and aqueous layer were washed seven times with 220 mL of water.

[0086] After removing toluene under reduced pressure, the procedure of adding 50 mL of water and removing toluene azeotropically was repeated twice to obtain 146.34 g of metconazole concentrate with a toluene concentration of less than 0.1% (116.89 g of metconazole purity, yield 64.16%). Analysis by gas chromatography using a known method showed that the cis isomer accounted for 60.90% and the trans isomer for 13.93% (cis ratio 81.38%).

[0087] [Example 1: Preparation of metconazole crystals 1] The entire amount (146.34 g) of the metconazole concentrate prepared as described above was mixed with 400 mL of ethylcyclohexane. After washing with water and dehydrating, the resulting organic layer was completely dissolved in an oil bath while maintaining the temperature at 90°C. Half of the obtained organic layer (solution) (58.25 g of pure metconazole) was gradually cooled. Midway through the cooling process, 0.02% by mass of metconazole seed crystals (metconazole with a cis ratio of 80% or more) was added based on the total mass of metconazole contained in the organic layer used. The solution was then further cooled to 35°C at a rate of 1°C / 3 minutes. Once 35°C was reached, the solution was heated to 50°C and maintained at 50°C for 30 minutes. Subsequently, the solution was cooled to 10°C at a rate of 1°C / 3 minutes and filtered to obtain metconazole crystals (57.21 g, crystallization yield 98.21%). Analysis of the obtained metconazole crystals by gas chromatography using a known method revealed that the cis isomer was 81.72% and the trans isomer was 16.83% (cis ratio 82.92%).

[0088] [Example 2: Preparation of metconazole crystals 2] Half of the organic layer (solution) obtained in Example 1 (58.64 g of pure metconazole) was gradually cooled. During the cooling process, 0.02% by mass of metconazole seed crystals (metconazole with a cis ratio of 80% or more) was added based on the total mass of metconazole contained in the organic layer used. The mixture was then cooled to 10°C at a rate of 1°C / 3 minutes and filtered to obtain metconazole crystals (57.60 g, crystallization yield 98.22%). Analysis of the obtained metconazole crystals by gas chromatography using a known method revealed that it consisted of 80.69% cis isomer and 17.43% trans isomer (cis ratio 82.23%).

[0089] [Example 3: Preparation of metconazole crystals 3] The metconazole crystals obtained in Example 2 and the filtrate from Example 2 (i.e., the solution obtained by filtering off the metconazole crystals) were mixed and heated to over 90°C to homogenize, thereby obtaining a mixture (solution) containing metconazole and ethylcyclohexane (57.85 g of metconazole purity). This solution was gradually cooled, and at one point, a seed crystal of metconazole (metconazole with a cis ratio of 80% or more) was added at a rate of 0.02% by mass relative to the total mass of metconazole contained in the mixture (solution) used. The solution was then cooled to 10°C at a rate of 1°C / 3 minutes to obtain metconazole crystals (56.81 g, crystallization yield 98.20%). Analysis of the obtained metconazole crystals by gas chromatography using a known method revealed that the cis isomer was 80.74% and the trans isomer was 17.04% (cis ratio 82.58%).

[0090] [Test Example 1: Powder X-ray Diffraction (PXRD) Pattern Measurement] Powder X-ray diffraction (PXRD) pattern measurements were performed on the metconazole crystals obtained in Example 1 under the following measurement conditions. The results are shown in Table 1 and Figure 1. <Measurement conditions> Equipment used:X'Pert PRO MPD X-ray source:CuKα ray Voltage / Current: 45 kV / 40 mA Detector: Pixcel (high-sensitivity multi-channel detector) Step width: 0.026° (2θ) Measurement range: 3~60°(2θ) Measurement temperature: 23℃ [Table 1]

[0091] Based on the results of Examples 1-3, it is considered that metconazole crystals can be produced in sufficient yield and cis ratio by cooling a mixture containing a solvent containing a cycloalkane (preferably ethylcyclohexane) and metconazole.

[0092] Furthermore, the results from Example 1 suggest that by raising the temperature of the above mixture while it is cooling, maintaining it at a desired temperature (e.g., the temperature after raising the temperature) for a desired time as needed, and then cooling the mixture again, it is possible to obtain metconazole crystals with a higher cis ratio. Metconazole is known to have higher activity in the cis isomer compared to other stereoisomers (e.g., the trans isomer), and it is considered extremely difficult in this art to increase the proportion of the cis isomer even slightly. That is, when metconazole is synthesized by known synthesis methods, it is known that the trans isomer is present at a concentration of about 20%. It is also considered common technical knowledge in this art that separating only the cis isomer from the synthesized metconazole (a mixture of cis and trans isomers) is extremely difficult. According to one embodiment of the present invention, in a method for producing metconazole crystals, raising the temperature of the mixture while it is cooling, maintaining it at a desired temperature (e.g., the temperature after raising the temperature) for a desired time as needed, and then cooling the mixture again is particularly advantageous from the viewpoint that the proportion of the cis isomer can be further improved.

Claims

1. A step of preparing a mixture containing a solvent containing cycloalkanes and metconazole, and The process involves cooling the aforementioned mixture to crystallize metconazole. A method for producing metconazole crystals containing [the specified substance].

2. The method for producing the product according to claim 1, wherein the cycloalkanes include ethylcyclohexane.

3. The manufacturing method according to claim 1, wherein the step of preparing the mixed liquid includes a step of heating the mixed liquid to a temperature of 90 to 100°C to bring it into a solution state.

4. The manufacturing method according to claim 1, wherein the step of crystallizing metconazole includes a step of cooling the mixture to 0 to 15°C.

5. The step of crystallizing the metconazole is A step of raising the temperature of the cooled mixture, and The step of cooling the aforementioned mixture again. The manufacturing method according to claim 1, comprising each of these steps at least once.

6. The manufacturing method according to claim 5, wherein the cooled mixed liquid in the step of raising the temperature is a mixed liquid cooled to 0 to 40°C.

7. The step of raising the temperature includes a step of raising the temperature of the cooled mixture to 30 to 60°C. The manufacturing method according to claim 5.

8. The manufacturing method according to claim 5, wherein the cooled mixed liquid in the heating step is a mixed liquid cooled to 20 to 40°C, and the heating step includes a step of heating the cooled mixed liquid to 45 to 60°C.

9. The step of crystallizing metconazole is performed after the step of raising the temperature and before the step of cooling again. The process of maintaining the temperature of the mixture. The manufacturing method according to claim 5, further comprising:

10. The manufacturing method according to claim 9, wherein the step of maintaining the temperature includes a step of maintaining the mixture at 45 to 60°C.

11. In the powder X-ray diffraction pattern obtained using CuKα radiation, the following applies: 8.7±0.2 degrees (2θ), 13.4±0.2 degrees (2θ), 15.9±0.2 degrees (2θ), 17.5±0.2 degrees (2θ), 18.9±0.2 degrees (2θ), and 19.8±0.2 degrees (2θ) A crystal of metconazole containing at least three peaks selected from the group consisting of the following.

12. Particles comprising metconazole crystals as described in claim 11.

Images