Process for the preparation of crystalline form i of boscalid by melt crystallization

Abstract

The present invention relates to a process for the preparation of crystalline form I of boscalid by melt crystallization, characterized in that it comprises the following steps: A. heating boscalid solids to complete melting and optionally continuing the temperature; B. cooling to complete crystallization of the material; C. again heating the solidified material to a temperature above that of step B and maintaining it; D. cooling and discharging.

Description

Technical Field

[0001] This invention relates to a method for preparing cyazofamid crystal form I by melt-transfer crystallization. Background Technology

[0002] Boscalid has a broad fungicidal spectrum, exhibiting activity against almost all types of fungi. It can be used to prevent powdery mildew, gray mold, root rot, and other diseases, and can be applied to fruit trees, grapes, vegetables, and field crops. Different crystal forms of boscalid have different applications in the formulation field. Boscalid crystal form I can be used to prepare water-dispersible spray-dried or extruded granules.

[0003] Chinese patent CN109071445B discloses a method for preparing crystalline form I of azoxystrobin. This method involves first dissolving crystalline form II of anhydrous azoxystrobin in a first solvent, combining the resulting solution with water, separating the solid from the solvent mixture, and drying to obtain crystalline form I of anhydrous azoxystrobin. This method uses flammable and explosive solvents and generates wastewater containing organic solvents. The production process is cumbersome and inefficient.

[0004] Chinese patent CN114181141A discloses another method for preparing boscalid crystal form I. This method involves dissolving anhydrous boscalid in a non-water-soluble organic solvent to obtain a solution, then adding the solution to hot water for flash evaporation of the solvent, resulting in a wet product of boscalid crystal form I suspended in water. After cooling, filtration, and drying, the boscalid crystal form I product is obtained. This method requires flash evaporation of the organic solvent at temperatures above 100°C, which is not only energy-intensive but also poses a risk of deflagration.

[0005] Chinese patent CN115536581A discloses the following steps for preparing cyazofamid crystal form I: A. Adding cyazofamid solid to an organic solvent and stirring under controlled temperature until completely dissolved; B. Adding purified water and continuing to stir under controlled temperature until dissolved; C. Filtering; D. Adding further purified water and further refluxing to dissolve; E. Cooling and crystallizing; F. Filtering, washing, and drying.

[0006] Chinese patent CN109790124B discloses a method for preparing crystal form I, comprising: (a) dissolving a boscalid starting material in dichloromethane, dichloroethane, chloroform, or chlorobenzene at room temperature or above to provide a boscalid solution; (b) cooling the boscalid solution and stirring it at 400 rpm to 700 rpm for 15 minutes to 2 hours until crystal formation is observed; and (c) achieving crystallization by abruptly cooling the solution to provide a solid crystalline product from the stirred solution, wherein the solution is abruptly cooled to -10°C to 5°C, wherein the solid crystalline product is anhydrous boscalid in form I with a melting point of 144-145°C. This method involves a rapid cooling crystallization operation, which may lead to "agglomeration" problems in actual industrial scale-up, thus affecting the purity of the crystal form and making stable production impossible.

[0007] Existing methods for preparing cyazofamid crystal form I suffer from problems such as unstable crystal form, difficult process operation, and low production efficiency. Summary of the Invention

[0008] In view of the above problems, the present invention aims to provide a new method for preparing boscalid I crystal form by melt-transfer crystallization, which can obtain boscalid I crystal form with high crystal purity, stability and high content.

[0009] The novel preparation method of this invention uses amorphous cytotoxicant, crystal form II, a mixture of crystal form I and crystal form II, or a mixture of amorphous cytotoxicant and crystal form I and / or crystal form II as raw materials, and prepares crystal form I by melt-transfer method.

[0010] The inventors of this application have discovered that in existing methods for preparing boscalid I via solvent crystallization, the drying process of the resulting wet crystals is difficult to control stably in industrial-scale production, potentially leading to crystal transformation and thus introducing instability. The melt preparation method of this invention can better achieve stable large-scale industrial production.

[0011] Specifically, the present invention relates to:

[0012] (1) A method for preparing cyazofamid crystal form I, characterized by comprising the following steps:

[0013] A. Heat the solid boscalid until it is completely melted, and optionally continue to keep it at that temperature;

[0014] B. Cool down until the material has completely crystallized and solidified;

[0015] C. Reheat the solidified material to above the temperature in step B and maintain the temperature;

[0016] D. Cool down and discharge the material;

[0017] The solid boscalid is amorphous boscalid, crystal form II, a mixture of crystal form I and crystal form II, or a mixture of amorphous boscalid with crystal form I and / or crystal form II, preferably crystal form II of boscalid.

[0018] (2) According to the method described in (1) above, in step A, the temperature is heated to 175-200°C, preferably 175-190°C, and optionally kept at that temperature.

[0019] (3) According to the method described in (1) or (2) above, the heat preservation time in step A is controlled to be 1 to 4 hours, preferably 2 hours.

[0020] (4) The method described in any one of (1) to (3) above, wherein the cooling temperature in step B is 80 to 90°C.

[0021] (5) The method described in any one of (1) to (4) above, wherein the heat preservation temperature in step C is 95 to 110°C.

[0022] (6) The method according to any one of (1) to (5) above, wherein the heat preservation time in step C is controlled to be 1 to 4 hours, preferably 2 hours.

[0023] (7) The method described in any one of (1) to (6) above, wherein the cooling temperature in step D is 10 to 40°C. Attached Figure Description

[0024] Figure 1 The DSC curve of the crystalline form I of cytotoxicamine prepared in Example 1 of this application.

[0025] Figure 2 The DSC curve of the crystalline form I of cyazofamid prepared in Example 2 of this application.

[0026] Figure 3 The DSC curve of cytotoxic acetamiprid crystal form I prepared in Example 3 of this application.

[0027] Figure 4 The image shows the X-ray powder diffraction pattern of the crystalline form I of cyazofamid prepared in Example 3 of this application. Detailed Implementation

[0028] This invention provides a method for preparing boscalid crystalline form I, the method comprising the following steps:

[0029] A. Heat the solid boscalid until it is completely melted, and optionally continue to keep it at that temperature;

[0030] B. Allow the material to cool naturally until it has completely crystallized and solidified;

[0031] C. Reheat the solidified material to above the temperature in step B and maintain the temperature;

[0032] D. Cool down and discharge the material.

[0033] In some specific embodiments, step A involves heating to 175–200°C, preferably 175–190°C, and optionally continuing to hold at this temperature to ensure complete melting of the boscalid solid. When the material quantity is small, the solid can be completely melted after heating to the above temperature without the need for holding. However, when the material quantity is large, such as in industrial-scale production, it is preferable to continue holding after heating to ensure that all solids are fully melted.

[0034] In some specific embodiments, when performing heat preservation in step A, the heat preservation time is controlled between 1 and 4 hours, preferably 2 hours. If the heat preservation time is too short, it may lead to incomplete melting; if the heat preservation time is too long, the product may be at risk of degradation, resulting in a decrease in product content.

[0035] In some specific implementations, the temperature is lowered to 80–90°C in step B.

[0036] In some specific embodiments, the holding temperature in step C is 95–110°C. When the temperature is higher than 110°C, it approaches the melting point of cyazofamid, which can cause the solid portion to melt and clump together; when the temperature is lower than 95°C, the crystal transformation is incomplete, which will affect the purity of the crystal form.

[0037] In some specific embodiments, the holding time in step C is controlled to be between 1 and 4 hours, preferably 2 hours. If the holding time is too short, the crystal transformation will be incomplete, which will affect the purity of the crystal form.

[0038] In some specific implementations, the temperature is reduced to 10–40°C in step D.

[0039] Example

[0040] The preferred embodiments of the method of the present invention will be described below with reference to specific examples. However, the present invention is not limited to these embodiments. Any modifications and changes that do not depart from the spirit and scope of the present invention shall fall within the scope of the present invention.

[0041] High performance liquid chromatography conditions:

[0042] Chromatographic column: C18 column, 250 mm × 4.6 mm × 5 μm;

[0043] Mobile phase: Acetonitrile: Water (adjusted to pH 3.7-4.1 with formic acid) = 80:20;

[0044] Column temperature: 30℃; flow rate: 1.0 mL / min; wavelength: 254 nm.

[0045] The crystal purity of the product was determined using differential scanning calorimetry (DSC) under the following conditions:

[0046] Heating range: 20-120℃; heating rate: 4℃ / min;

[0047] Heating range: 120-170℃; heating rate: 1℃ / min.

[0048] The X-ray powder diffraction pattern of the product was determined under the following conditions:

[0049] Scan 2θ: 2.0~90.0°, step: 6° / min, Cu (40kV, 40mA).

[0050] Moisture content in the product was determined by Karl Fischer (KF) titration.

[0051] Example 1

[0052] Take 5 kg of cyazofamid crystal form II raw material, spread it evenly in an aluminum drying tray, place it in an oven, and heat it to 180℃ until it is completely melted. Turn off the heating, cool it to 90℃, and after the cyazofamid is completely solidified, heat it again to 110℃ and hold it at that temperature for 2 hours. Then cool it to 30℃ to obtain a white solid. Differential scanning calorimetry (DSC) confirmed that the product was cyazofamid crystal form I with a crystal purity of 100%. Figure 1 The content was determined to be 98.5% by high performance liquid chromatography and the moisture content was determined to be 0.21% by Karl Fischer (KF) titration.

[0053] Example 2

[0054] Take 5 kg of boscalid crystal form II raw material, spread it evenly in an aluminum drying tray, place it in an oven, and heat it to 190℃ until it is completely melted. Turn off the heating, cool it to 90℃, and after the boscalid is completely solidified, heat it again to 110℃ and hold it at that temperature for 2 hours. Then cool it to 30℃ to obtain a white solid. Differential scanning calorimetry (DSC) confirmed that the product was 100% pure boscalid crystal form I. Figure 2 The content was determined to be 97.8% by high performance liquid chromatography and the moisture content was determined to be 0.28% by Karl Fischer (KF) titration.

[0055] Example 3

[0056] 200 kg of boscalid form II raw material was added to the reactor, heated to 175°C, and held for 1 hour until completely melted. The material was then transferred to aluminum drying trays, 5 kg per tray, placed on a material cart, and allowed to cool naturally to 90°C until the boscalid was completely solidified. The material was then placed in an oven, heated to 100°C, and held for 2 hours. It was then cooled to 30°C to obtain a white solid. Differential scanning calorimetry (DSC) confirmed that the product was 100% pure boscalid form I. Figure 3 The content was determined to be 98.1% by high performance liquid chromatography and the moisture content was determined to be 0.28% by Karl Fischer (KF) titration.

[0057] The X-ray powder diffraction pattern of the product was determined, and the results are as follows: Figure 4 As shown.

[0058] Example 4: Investigation of Crystal Form Thermal Stability

[0059] The product samples from Example 3 were placed under high temperature (54°C) and high humidity (75%) conditions to examine their storage stability. The results are shown in Table 1.

[0060] Table 1

[0061]

[0062] As shown in Table 1, the crystal form I product with a purity of 100% obtained by the method of the present invention still maintains a purity of 100% after being placed under high temperature (54°C) and high humidity (75%) conditions for 30 days, demonstrating good stability.

[0063] Example 5: Effect of Incubation Time on Product Content (Step A)

[0064] Take 5 kg of cyazofamid crystal form II raw material, spread it evenly in an aluminum drying tray, place it in an oven, heat it to 190℃ until it is completely melted, keep it at the temperature, and take samples at different times to detect the change in its content. The results are shown in Table 2.

[0065] Table 2

[0066] Sampling time content% Complete melting 98.5 Keep warm for 1 hour 98.5 Keep warm for 2 hours 98.5 Keep warm for 4 hours 98.1

[0067] Take 5 kg of cyazofamid crystal form II raw material, spread it evenly in an aluminum drying tray, place it in an oven, heat it to 200℃ until it is completely melted, keep it at the temperature, and take samples at different times to detect the change in its content. The results are shown in Table 3.

[0068] Table 3

[0069] Sampling time content% Complete melting 98.6 Keep warm for 2 hours 98.5 Keep warm for 4 hours 97.6 Keep warm for 5 hours 97.4

[0070] The results in Tables 2 and 3 show that when the heat preservation time is greater than 4 hours, the product content tends to decrease as the heat preservation time increases.

[0071] Comparative Example 1

[0072] Take 5 kg of boscalid crystal form II raw material, spread it evenly in an aluminum drying tray, place it in an oven, and heat it to 180℃ until it is completely melted. Turn off the heating and cool it to 90℃ until the boscalid is completely solidified. Control the material temperature to 70℃~80℃ and keep it at this temperature for 2 hours. Finally, cool it to 30℃ to obtain a white solid boscalid crystal form I product, with a crystal purity of 99.55%.

Claims

1. A method for preparing boscalid crystal form I by melt-transfer crystallization, characterized in that, Includes the following steps: A. Heat the solid cyazofamid to 175-200°C until it is completely melted, and optionally continue to keep it at this temperature for 1-4 hours. B. Cool down until the material has completely crystallized and solidified; C. Reheat the solidified material to above the temperature in step B and keep it at that temperature. The holding temperature is 95-110°C and the holding time is controlled between 1 and 4 hours. D. Cool down and discharge the material; The solid boscalid is amorphous boscalid, crystal form II, a mixture of crystal form I and crystal form II, or a mixture of amorphous boscalid with crystal form I and / or crystal form II.

2. The preparation method according to claim 1, wherein in step A, the temperature is heated to 175–190°C, and optionally held at that temperature.

3. The preparation method according to claim 1 or 2, wherein the heat preservation time in step A is controlled at 2 hours.

4. The preparation method according to claim 1 or 2, wherein the temperature is lowered to 80-90°C in step B.

5. The preparation method according to claim 1 or 2, wherein the heat preservation time in step C is controlled at 2 hours.

6. The preparation method according to claim 1 or 2, wherein the temperature is lowered to 10-40°C in step D.

7. The preparation method according to claim 1 or 2, wherein the boscalid solid is boscalid crystal form II.

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