Preparation method of pyraclostrobin crystal form II

Abstract

This invention relates to a method for preparing pyraclostrobin crystal form II, characterized by comprising the following steps: A. Adding solid pyraclostrobin to tert-butanol and stirring until completely dissolved under controlled temperature of 40-60°C; B. Cooling to 20-30°C and stirring until crystals precipitate; C. Further cooling to 0-15°C to grow crystals; D. Filtering and drying.

Description

Technical Field

[0001] This invention relates to a method for preparing pyraclostrobin crystal form II. Background Technology

[0002] Pyraclostrobin, also known as azoxystrobin, is a broad-spectrum fungicide belonging to the methyl methacrylate class, discovered by BASF in Germany in 1993. It possesses a pyrazole structure. Pyraclostrobin is a mitochondrial respiration inhibitor; it inhibits mitochondrial respiration by blocking electron transfer between cytochrome b and c1, preventing mitochondria from producing and providing the energy (ATP) needed for normal cellular metabolism, ultimately leading to cell death. It exhibits protective, curative, systemic, and rain-washable properties, with a long residual effect and a wide range of applications. Different crystalline forms of pyraclostrobin have different applications in the formulation field; pyraclostrobin crystal form II can be used to prepare aqueous suspension concentrates.

[0003] Chinese patent application CN110590672A discloses a method for preparing pyraclostrobin crystal form II. This method uses isopropanol or a mixture of isopropyl ether and ethanol as a solvent, heats and stirs at 50°C or 80°C for 2 hours, then filters while hot. The filtrate is then cooled to room temperature and allowed to stand for 3-4 days. This method requires natural cooling to room temperature and maintaining this temperature for 3-4 days to obtain crystals. On the one hand, this method has low production efficiency; on the other hand, natural cooling is greatly affected by environmental factors, and different weather conditions or seasons may influence the experiment.

[0004] Chinese patent CN101203136B also discloses a method for preparing pyraclostrobin crystal form II. This method involves heating 100g of isopropanol to 60°C, adding 15g of azoxystrobin while stirring, and stirring the mixture until all substances are dissolved. The mixture is then cooled to 20°C and stirred for another 4 hours, followed by cooling to 10°C and stirring for another 1 hour. The crystals are immediately separated and dried under reduced pressure and ambient temperature for 16 hours. This method provides a rough description of the preparation process, without specifying details such as the cooling rate. Furthermore, this method uses a large amount of solvent and has a low yield. Summary of the Invention

[0005] In view of the above problems, the present invention aims to provide a new method for preparing pyraclostrobin crystal form II. The method of the present invention uses less solvent, is simple to operate, and produces pyraclostrobin crystal form II with high purity and yield, high stability, regular crystal habit, no aggregation, no solvent residue, larger particle size, and more uniform particle size distribution.

[0006] Specifically, the present invention relates to:

[0007] (1) A method for preparing pyraclostrobin crystal form II, characterized by comprising the following steps:

[0008] A. Add pyraclostrobin solid to tert-butanol and stir until completely dissolved under controlled temperature of 40-60℃;

[0009] B. Cool to 20-30℃ and stir until crystals precipitate;

[0010] C. Continue cooling to 0-15℃ for crystal growth;

[0011] D. Filtering, drying.

[0012] (2) According to the preparation method described in (1) above, the mass ratio of tert-butanol to pyraclostrobin solid in step A is (3-10):1, preferably (3-6):1.

[0013] (3) According to the preparation method described in (1) or (2) above, the temperature control temperature in step A is 45 to 55°C.

[0014] (4) The preparation method according to any one of (1) to (3) above, wherein step B is cooled to 20-25°C.

[0015] (5) The preparation method according to any one of (1) to (4) above, wherein the cooling rate in step B is 2 to 3 min / ℃.

[0016] (6) The preparation method according to any one of (1) to (5) above, wherein the stirring time in step B is 1 to 6 hours, preferably 1 to 4 hours.

[0017] (7) According to any one of (1) to (6) above, in step B, a solvent or seed crystal is preferably added to promote crystallization. The amount of solvent is preferably 10 to 50% of the amount of tert-butanol, and the amount of seed crystal is 0.5 to 1% of the amount of pyraclostrobin solid feed.

[0018] (8) According to the preparation method described in (7) above, the solvent in step B is water, cyclohexane, n-hexane, or heptane, preferably water.

[0019] (9) The preparation method according to any one of (1) to (8) above, wherein step C is further cooled to 5 to 10°C; crystallization is carried out for 0.5 to 1 hour.

[0020] (10) The preparation method according to any one of (1) to (9) above, wherein the drying temperature in step D is 30 to 40°C and the drying time is 2 to 8 hours, preferably 2 to 4 hours. Attached Figure Description

[0021] Figure 1 The X-ray powder diffraction pattern is shown for pyraclostrobin crystal form II prepared in Example 1 of this application.

[0022] Figure 2 The DSC curve of pyraclostrobin crystal form II prepared in Example 1 of this application.

[0023] Figure 3 The stability test spectra of pyraclostrobin crystal form II prepared in Example 1 of this application are compared, with X-ray powder diffraction spectra from bottom to top representing 0 days, 30 days, 60 days, and 90 days.

[0024] Figure 4 The image shows the X-ray powder diffraction pattern of the product of Comparative Example 3 of this application.

[0025] Figure 5 This is a schematic diagram showing the particle size distribution of pyraclostrobin crystal form II prepared in Example 1 of this application and the product of Comparative Example 1.

[0026] Figure 6 Scanning electron microscope image of pyraclostrobin crystal form II prepared in Example 1 of this application.

[0027] Figure 7 This is a scanning electron microscope image of the product of Comparative Example 1 of this application.

[0028] Figure 8 The gas phase spectrum is that of pyraclostrobin crystal form II prepared in Example 1 of this application.

[0029] Figure 9 This is the gas phase spectrum of the product of Comparative Example 1 of this application.

[0030] Figure 10 The gas chromatograms of tert-butanol and isopropanol determined by the internal standard method are shown.

[0031] Figure 11 This is an oil separation photograph of Comparative Example 7 of this application. Detailed Implementation

[0032] This invention provides a method for preparing pyraclostrobin crystal form II, the method comprising the following steps:

[0033] A. Add pyraclostrobin solid to tert-butanol and stir until completely dissolved under controlled temperature of 40-60℃;

[0034] B. Cool to 20-30℃ and stir until crystals precipitate;

[0035] C. Continue cooling to 0-15℃ for crystal growth;

[0036] D. Filtering, drying.

[0037] Step A uses tert-butanol as a single solvent, which is simple to operate and easy to control.

[0038] In some specific embodiments, the mass ratio of tert-butanol to pyraclostrobin solid in step A is (3-10):1, preferably (3-6):1. If the amount of tert-butanol is too small, the pyraclostrobin solid will not dissolve easily, and the subsequent cooling process will easily lead to oil precipitation due to the high supersaturation of the system, thus affecting the purity and yield of the crystal form; if the amount of tert-butanol is too large, it will cause waste and reduce production capacity.

[0039] Using tert-butanol as a solvent has two advantages: firstly, it requires less solvent to produce the same yield of pyraclostrobin crystal form II, which aligns with the low-carbon and environmentally friendly production concept; secondly, it has a larger production capacity per unit equipment volume per hour than other containers, meaning that the equipment volume required to produce the same yield of pyraclostrobin crystal form II per unit time is smaller.

[0040] In some specific embodiments, the temperature control in step A is 40–60°C, preferably 45–55°C. Low temperatures will result in insufficient dissolution of the pyraclostrobin solids; high temperatures will lead to prolonged cooling and crystallization time, reducing production efficiency.

[0041] In some specific embodiments, the temperature is lowered to 20–30°C, preferably 20–25°C, in step B. When the temperature drops above 30°C, crystals are less likely to precipitate, and the operation time is prolonged; when the temperature drops below 20°C, oil will precipitate from the system, affecting the purity of the crystal form. Lowering the temperature to the above range can effectively prevent pyraclostrobin from precipitating crystals and prevent pyraclostrobin from precipitating oil.

[0042] In some specific implementations, the cooling rate in step B is 2–3 min / ℃. Cooling too quickly will affect the quality and yield of the crystals; cooling too slowly will result in low production efficiency.

[0043] In some specific embodiments, a solvent can be added in step B to promote crystallization. The solvent can be water, cyclohexane, n-hexane, or heptane, with water being preferred. Preferably, the amount of solvent used is 10-50% of the amount of organic solvent by mass ratio. Excessive use of solvent can cause drastic changes in the supersaturation of the system, leading to rapid crystal growth and oil precipitation, thus affecting crystal quality. It can also hinder solvent recovery.

[0044] In some specific embodiments, seed crystals may be added in step B to promote crystallization. The preferred amount of seed crystals, by mass ratio, is 0.5–1% of the solid feed amount of pyraclostrobin. Insufficient seed crystal addition will result in slow crystal growth; excessive seed crystal addition will affect the purity and quality of the crystals.

[0045] In some specific embodiments, the stirring time in step B is 1 to 6 hours, preferably 1 to 4 hours. Too long a stirring time will reduce production efficiency and may cause crystal form II to transform into crystals; too short a stirring time will cause oil to precipitate from the system.

[0046] In some specific embodiments, step C involves further cooling to 0–15°C, preferably 5–10°C; and crystal growth for 0.5–1 hour. This secondary cooling and crystal growth process helps improve the yield.

[0047] By controlling the temperature of the two-step cooling process, oil precipitation was avoided, allowing the system to crystallize smoothly.

[0048] In some specific embodiments, the drying temperature in step D is 30-40°C, and the drying time is 2-8 hours, preferably 2-4 hours.

[0049] Example

[0050] The present invention will be further described in detail below with reference to specific embodiments, but the present invention is not limited to these specific embodiments. Any modifications or changes within the scope of the present invention fall within the scope of this application.

[0051] In the following examples, the high-performance liquid chromatography (HPLC) analysis conditions were as follows: the instrument was an Agilent 1100LC HPLC system with a UV detector; the chromatographic column was a Kromasil 100-5-C18, 4.6 × 250 mm; the mobile phase was acetonitrile:water (adjusted to pH 3.7-4.1 with formic acid) = 80:20; the column temperature was 30 °C; the flow rate was 1.0 mL / min; and the wavelength was 260 nm.

[0052] Example 1

[0053] Take 20g of pyraclostrobin raw material into a four-necked flask, add 80g of tert-butanol, control the temperature at 50℃, and stir for 0.5 hours until completely dissolved; control the stirring speed at 200r / min and cool down the system, first cooling the system temperature to 20℃ at a cooling rate of 2-3min / ℃, add 30g of deionized water using a constant pressure dropping funnel, stir for 1 hour, and then continue to cool to 5℃ and grow crystals for 1 hour; filter; place in an oven at 40℃ and dry for 2 hours to obtain 18.7g of white crystals, with a yield of 93.5% and a purity of 99%.

[0054] The X-ray powder diffraction (XRD) determination conditions are as follows, and the results are as follows: Figure 1 As shown.

[0055] Scan 2θ range: 2.0~50.0°, step: 0.02° / sec, Cu (40kV, 100mA).

[0056] The 2θ values ​​of the XRD characteristic peaks of the white crystals are: 9.34°±0.2, 11.66°±0.2, 14.16°±0.2, 14.56°±0.2, 14.78°±0.2, 15.84°±0.2, 16.90°±0.2, 18.04°±0.2, 18.44°±0.2, 18.76°±0.2, 19.54°±0.2, 19.98°±0.2, 20.86°±0.2, 22.26°±0.2, 22.70°±0.2, 23.46°±0.2, 24.78°±0.2, 25.10°±0.2, 25.88°±0.2, 26.58°±0.2, and 30.50°±0.2.

[0057] The interplanar spacing d of the XRD characteristic peaks of white crystals is:

[0058] The above d-values ​​were compared with the d-values ​​of pyraclostrobin crystal form II recorded in sections

[0080] -

[0090] of CN101203136B, and were respectively in

[0059] The locations overlapped, confirming that the white crystals were pyraclostrobin crystal form II.

[0060] The measurement conditions for differential scanning calorimetry (DSC) are as follows, and the results are as follows. Figure 2 As shown.

[0061] Heating range: 30-110℃; heating rate: 5℃ / min.

[0062] Example 2

[0063] Take 20g of pyraclostrobin raw material into a four-necked flask, add 80g of tert-butanol, control the temperature at 45℃, and stir for 0.5 hours until completely dissolved; control the stirring speed at 200r / min and cool down the system, first cooling the system to 25℃ at a cooling rate of 2-3min / ℃, stirring for 4 hours, and then continue to cool down to 5℃ and crystallize for 1 hour; filter; place in an oven at 40℃ and dry for 2 hours to obtain 18.3g of white pyraclostrobin crystal form II product, with a yield of 91.5% and a purity of 99%.

[0064] Example 3

[0065] Take 38.7g of pyraclostrobin raw material into a four-necked flask, add 154.8g of tert-butanol, control the temperature at 50℃, and stir for 0.5 hours until completely dissolved; control the stirring speed at 200r / min and cool down the system to 25℃ at a cooling rate of 2-3min / ℃, add 0.387g of pyraclostrobin crystal form II seed crystals, stir for 1 hour, and then continue to cool to 5℃ and grow crystals for 1 hour; filter, place in an oven at 40℃ and dry for 2 hours to obtain 36.5g of white pyraclostrobin crystal form II product, with a yield of 94.3% and a purity of 99%.

[0066] Comparative Example 1 via isopropanol crystallization

[0067] The preparation was carried out according to Example 4 of CN101203136B as follows: 100g of isopropanol was heated to 60°C, and then 15g of pyraclostrobin was added with stirring and the mixture was stirred until all substances were dissolved; the mixture was cooled to 20°C and stirred for 4 hours, and then cooled to 10°C and stirred for another hour; the crystals were immediately separated and dried under reduced pressure for 16 hours to obtain 10.8g of white solid, with a yield of 72% and a purity of 99%.

[0068] Comparative Example 2 via isopropanol crystallization

[0069] According to Example 1 in CN110590672A, the following preparation was carried out: 38.7g of pyraclostrobin crystal form IV raw material was placed in a round-bottom flask, 300ml of isopropanol was added, and the mixture was heated and stirred in an 80℃ water bath for 2 hours. The mixture was filtered while hot, and the filtrate was cooled to room temperature and allowed to stand for 3 days before the precipitated solid phase was collected to obtain 29.7g of pyraclostrobin crystal form II product, with a yield of 76.7% and a purity of 98%.

[0070] Example 4: Stability Study of Crystal Form

[0071] The product from Example 1 was placed at room temperature for 0, 30, 60, and 90 days, respectively. XRD analysis was performed on the product using the same method as in Example 1 to examine the stability of crystal form II. The results are as follows: Figure 3 As shown.

[0072] according to Figure 3 The XRD patterns shown represent the XRD values ​​of the target product, pyraclostrobin crystal form II, obtained in this invention, after being stored at room temperature for 0 days, 30 days, 60 days, and 90 days, respectively. Figure 1 As a result, no crystallization occurred during storage, therefore pyraclostrobin crystal form II exhibits good stability.

[0073] Example 5: Particle size analysis of the crystal form

[0074] The particle size of the product from Example 1 and the product from Comparative Example 1 were measured using a Master size 3000 Malvern particle size analyzer. The particle size distribution diagram is shown below. Figure 5 As shown in Table 1, the main particle size and pitch data are as follows.

[0075] Table 1

[0076] Comparative Example 1 19.277 11.228 Example 1 270.821 1.757

[0077] According to the data in Table 1, the target product pyraclostrobin crystal form II obtained in this invention has a larger particle size and a more uniform particle size distribution compared to the crystals obtained in Comparative Example 1.

[0078] Example 6: Examination of the appearance of the crystal form

[0079] The appearance of the product of Example 1 and the product of Comparative Example 1 were examined using a scanning electron microscope (SEM). The results for the product of Example 1 are as follows: Figure 6 As shown, the results for Comparative Example 1 are as follows: Figure 7 As shown.

[0080] according to Figure 6 and Figure 7 As shown in the scanning electron microscope images, the crystal form II of the target product pyraclostrobin obtained in this invention has a more regular crystal structure than that of Comparative Example 1, and there is no aggregation phenomenon.

[0081] Example 7: Investigation of Residual Solvent in Crystal Form

[0082] The conditions for gas chromatography analysis were as follows: Agilent 6890 gas chromatograph; PEG-20M column; column temperature 55℃, ramped to 200℃ at a rate of 11.5℃ / min; vaporization chamber: 200℃; detector: 200℃.

[0083] Solvent residues in the product of Example 1 and the product of Comparative Example 1 were detected using gas chromatography. The results for the product of Example 1 are as follows: Figure 8 As shown, the results for Comparative Example 1 are as follows: Figure 9 As shown. The gas phase peak positions of tert-butanol and isopropanol were determined using the internal standard method, and the results are as follows. Figure 10 As shown.

[0084] Analysis revealed that the peak at 11.05 was N,N-dimethylformamide, the solvent used to dissolve the product during injection; the peak at 7.24 was toluene, the internal standard; the peak at 5.40 was isopropanol; and the peak at 5.03 was tert-butanol.

[0085] according to Figure 8 and Figure 9As shown in the gas phase spectrum, the target product pyraclostrobin crystal form II obtained in Example 1 of the present invention has no tert-butanol residue, while the pyraclostrobin crystal form II obtained in Comparative Example 1 has isopropanol residue.

[0086] Comparative Example 3 examines the effect of cooling temperature on crystal form.

[0087] 20g of pyraclostrobin raw material was placed in a four-necked flask, and 80g of tert-butanol was added. The temperature was controlled at 45℃, and the mixture was stirred for 0.5 hours until completely dissolved. The stirring speed was controlled at 200r / min, and the temperature was lowered to 15℃. Oil was observed to emerge from the bottom of the flask. After maintaining this temperature for a period of time, the oil solidified, and crystals precipitated on the oil. After filtration and drying, white crystals were obtained, and XRD was performed using the same method as in Example 1. The results are as follows. Figure 4 As shown.

[0088] The 2θ values ​​of the XRD characteristic peaks of the white crystals are: 14.736°±0.2, 18.580°±0.2, 22.178°±0.2, 14.557°±0.2, 24.982°±0.2, and 29.687°±0.2.

[0089] The interplanar spacing d of the XRD characteristic peaks of white crystals is:

[0090] The above d values ​​were found to be completely consistent with the d values ​​of pyraclostrobin crystal form IV recorded in paragraphs

[0008] -

[0012] of CN101203136B, confirming that the white crystals are pyraclostrobin crystal form IV.

[0091] The temperature was lowered to 10°C, and other conditions were the same as in Comparative Example 3. XRD was detected using the same method as in Example 1. The obtained crystal was found to be crystal form IV upon comparison.

[0092] The temperature was lowered to 5°C, and other conditions were the same as in Comparative Example 3. XRD was detected using the same method as in Example 1. The obtained crystal was found to be crystal form IV upon comparison.

[0093] Comparative Example 4 examines the effect of a single organic solvent on crystal form.

[0094] Take 20g of pyraclostrobin raw material into a four-necked flask, add 80g of methanol, control the temperature at 45℃, and stir for 0.5 hours until completely dissolved; control the stirring speed at 200r / min and cool down, first lower the system temperature to 25℃ at a cooling rate of 2-3min / ℃, stir for 4 hours, then cool down to 5℃, grow crystals for 1 hour and filter; place in an oven at 40℃ and dry for 2 hours to obtain crystals, and test XRD in the same way as in Example 1. The obtained crystals were found to be crystal form IV after comparison.

[0095] The solvent was replaced with ethanol, and other conditions were the same as in Comparative Example 4. XRD was detected using the same method as in Example 1, and the obtained crystals were found to be crystal form IV upon comparison.

[0096] The solvent was replaced with n-propanol, and other conditions were the same as in Comparative Example 4. XRD was detected using the same method as in Example 1, and the obtained crystals were found to be crystal form IV upon comparison.

[0097] The solvent was replaced with dichloromethane, and other conditions were the same as in Comparative Example 4. XRD was detected using the same method as in Example 1, and the obtained crystals were found to be crystal form IV upon comparison.

[0098] The solvent was replaced with ethyl acetate, and other conditions were the same as in Comparative Example 4. XRD was detected using the same method as in Example 1, and the obtained crystals were found to be crystal form IV upon comparison.

[0099] The solvent was replaced with anisole, and other conditions were the same as in Comparative Example 4. XRD was detected using the same method as in Example 1, and the obtained crystals were found to be crystal form IV upon comparison.

[0100] The solvent was replaced with acetone, and other conditions were the same as in Comparative Example 4. XRD was detected using the same method as in Example 1, and the obtained crystals were found to be crystal form IV upon comparison.

[0101] Comparative Example 5 investigated the effect of shared solvent and precipitant water on crystal form.

[0102] Dissolve 80g of dichloromethane and 20g of pyraclostrobin completely at room temperature. While maintaining a stirring speed of 200 rpm, cool the mixture until it reaches 20°C. Then add 30g of deionized water and stir for 1 hour. Continue cooling to 5°C and allow crystals to grow for 1 hour before filtering. Dry the crystals in a 40°C oven for 2 hours. Perform XRD analysis using the same method as in Example 1. The obtained crystals were found to be crystal form IV upon comparison.

[0103] The solvent was replaced with ethyl acetate, and other conditions were the same as in Comparative Example 5. XRD was detected using the same method as in Example 1, and the obtained crystals were found to be crystal form IV upon comparison.

[0104] The solvent was replaced with anisole, and other conditions were the same as in Comparative Example 5. XRD was detected using the same method as in Example 1, and the obtained crystals were found to be crystal form IV upon comparison.

[0105] The solvent was replaced with acetone, and other conditions were the same as in Comparative Example 5. XRD was detected using the same method as in Example 1, and the obtained crystals were found to be crystal form IV upon comparison.

[0106] The solvent was replaced with methanol, and other conditions were the same as in Comparative Example 5. XRD was detected using the same method as in Example 1, and the obtained crystals were found to be crystal form IV upon comparison.

[0107] The solvent was replaced with ethanol, and other conditions were the same as in Comparative Example 5. XRD was detected using the same method as in Example 1, and the obtained crystals were found to be crystal form IV upon comparison.

[0108] The solvent was replaced with n-propanol, and other conditions were the same as in Comparative Example 5. XRD was detected using the same method as in Example 1, and the obtained crystals were found to be crystal form IV upon comparison.

[0109] Comparative Example 6 investigated the effects of tert-butanol and pyraclostrobin dosage and temperature.

[0110] 5g of pyraclostrobin and 25g of tert-butanol were stirred at 30℃. After stirring for 2 hours, the mixture still could not be completely dissolved. When the temperature was raised to 45℃, the pyraclostrobin was completely dissolved within 0.5 hours.

[0111] When 5g of pyraclostrobin was stirred with 10g of tert-butanol at 50℃, pyraclostrobin was difficult to stir and did not dissolve easily.

[0112] Comparative Example 7 investigated the effect of the amount of solvent water on the crystal form.

[0113] 20g of pyraclostrobin raw material was placed in a four-necked flask, and 80g of tert-butanol was added. The temperature was controlled at 50℃, and the mixture was stirred for 0.5 hours until completely dissolved. The temperature was then lowered to 20℃ by controlling the stirring speed at 200r / min. 100g of deionized water was added using a constant pressure dropping funnel, and the mixture was stirred for 1 hour. Oil was observed to appear at the bottom of the flask, which is not conducive to obtaining crystals. The oil separation photograph is shown below. Figure 11 As shown.

Claims

1. A method for preparing pyraclostrobin crystal form II, characterized in that, Includes the following steps: A. Add pyraclostrobin solid to tert-butanol and stir until completely dissolved under controlled temperature of 45-55℃; B. Cool to 20-25℃ and stir until crystals precipitate; C. Continue cooling to 5-10℃ and allow crystals to grow for 0.5-1 hour; D. Filtration, drying; The mass ratio of tert-butanol to pyraclostrobin solid in step A is (3-6):1; The cooling rate in step B is 2-3 min / ℃, and the stirring time is 1-4 hours; The drying temperature in step D is 30-40℃, and the drying time is 2-4 hours.

2. The preparation method according to claim 1, wherein a solvent or seed crystal is added in step B to promote crystallization.

3. According to the preparation method of claim 2, the amount of solvent added in step B is 10-50% of the amount of tert-butanol, and the amount of seed crystals is 0.5-1% of the amount of pyraclostrobin solid feed.

4. The preparation method according to claim 2, wherein the solvent in step B is water, cyclohexane, n-hexane, or heptane.

5. The preparation method according to claim 4, wherein the solvent in step B is water.

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