Method for preparing cyantraniliprole crystal form A

Abstract

The invention belongs to the technical field of crystal form preparation, and particularly relates to a method for preparing a cyantraniliprole crystal form A. The method comprises the following steps that a mixed system of a cyantraniliprole crystal form B and a solvent is prepared, the water content of the mixed system is 0.1 wt% or below, the solvent is one or a combination of multiple of chlorobenzene, n-octane, n-nonane and isooctane, and the solvent is one or more of chlorobenzene, n-octane, n-nonane and isooctane; heating until the temperature in the mixed system is 90 DEG C to the boiling point of the solvent, and cooling to obtain the cyantraniliprole A crystal form. The cyantraniliprole A crystal form prepared through the method is high in quality, the purity of the crystal form can reach 98% or above, even 99% or above, the content of effective components can reach 95% or above, and product competitiveness is powerfully improved. In addition, the method is simple in technological process and can be applied to industrial-scale popularization.

Description

Technical Field

[0001] The invention belongs to the technical field of crystal preparation, and specifically relates to a method for preparing a cyantraniliprole A crystal form. Background Art

[0002] Cyantraniliprole is a second-generation nicotinic acid receptor inhibitor insecticide successfully developed by DuPont after chlorantraniliprole. It is also called cyantraniliprole. In addition to having good permeability, conductivity, chemical stability, and high insecticidal activity, it also has strong systemic activity and kills insects more thoroughly. The structural formula of cyantraniliprole is as follows:

[0003]

[0004] The existence of two or more different crystal structures of the same substance is called polymorphism. The internal cause of its formation, that is, the fundamental reason, is the change of molecular structure and molecular spatial arrangement; the external cause is mainly the change of the environmental state and parameters of the crystal, such as the type and proportion of solvents, supersaturation, as well as temperature and humidity, pressure, cooling rate / crystallization rate, stirring method / speed, etc. These factors may induce the formation of specific crystal forms.

[0005] Different crystal forms of the same substance differ in physical and chemical properties such as appearance, solubility, melting point, dissolution, and biological effectiveness, which in turn affect its stability, bioavailability, and efficacy. Therefore, screening for superior crystal forms and developing their preparation processes to obtain stable, high-purity specific crystal form products has important research value and practical significance.

[0006] It has been found that the A crystal form and the B crystal form of cyantraniliprole are hydrated (i.e., it is relatively easy to combine with water), and the A crystal form of cyantraniliprole is non-hydrated (i.e., it is not easy to combine with water). When exposed to changing air humidity, the water content of the B crystal form will change significantly. Unlike the B crystal form, the water content of the A crystal form will not increase or decrease significantly when experiencing changes in air humidity. In addition, during long-term storage, the A crystal form is usually not converted into the B crystal form. The stability of the A crystal form is also conducive to the consistency of the measurement results of the relevant detection items of cyantraniliprole. The above characteristics make the A crystal form of cyantraniliprole well suitable for the preparation of long-acting and stable solid preparations, and can also be used as a stable active ingredient to limit the content. In addition, the A crystal form of cyantraniliprole has higher filtration performance, and can also save separation costs during industrial production.

[0007] The cyantraniliprole A crystal form can be prepared from the cyantraniliprole B crystal form. For example, CN102216284A discloses a method for preparing the cyantraniliprole A crystal form, wherein the cyantraniliprole B crystal form is suspended in water, n-heptane, 1-chlorobutane, toluene, 1-butanol or 1-pentanol solvent, heated and the crystal seeds of the A crystal form are added for suspension crystallization. Although this method can obtain the A crystal form product, it requires the additional addition of crystal seeds, the process flow is more complicated, and the cost is increased. Summary of the invention

[0008] Problem that the invention aims to solve

[0009] Based on the above problems, WO2023095161A1 discloses a method for preparing an improved cyananthramide A crystal form, that is, heating and crystallization in methylcyclohexane, dimethylbenzene or a mixture of the two, and the method can obtain cyananthramide A crystal form product without the additional addition of crystal seeds. Based on this, the present invention is tested according to the method disclosed in WO2023095161A1 and found that although the method can obtain cyananthramide A crystal form without the additional addition of crystal seeds, the purity of cyananthramide A crystal form obtained by the method is not high enough. Therefore, the present invention aims to overcome the problem of low crystal purity in the preparation method of cyananthramide A crystal form product without the additional addition of crystal seeds at present, from the purity and active ingredient content (absolute content of cyananthramide A crystal form and B crystal form) of A crystal form in cyananthramide product, a simple and stable method for preparing cyananthramide A crystal form is provided.

[0010] Solutions for solving problems

[0011] In order to solve the above problems, the present invention provides a method for preparing a cyantraniliprole A crystal form, which comprises the following steps:

[0012] (1) preparing a mixed system of cyantraniliprole B crystal form and a solvent, wherein the water content of the mixed system is less than 0.1 wt %, and the solvent is a combination of one or more of chlorobenzene, n-octane, n-nonane and isooctane;

[0013] (2) heating the mixed system to a temperature between 90° C. and the boiling point of the solvent, and cooling the system to obtain cyantraniliprole A crystal form.

[0014] In the present invention, the mixed system (i.e., a mixed system of cyantraniliprole B crystal form and a solvent having a water content of less than 0.1wt% in the aforementioned system) can be prepared by a common method in the art. For example, the cyantraniliprole B crystal form is directly mixed with a suitable amount of solvent, and the water content in the suitable amount of solvent must be less than 0.1wt%; for another example, the cyantraniliprole B crystal form is mixed with a solvent and then dehydrated, and the dehydration method includes a physical dehydration method or a chemical dehydration method, including but not limited to evaporation dehydration, azeotropic dehydration, gas dehydration, molecular sieve adsorption dehydration or membrane dehydration.

[0015] Preferably, in step (1), the mixed system is obtained by mixing the cyantraniliprole B crystal form and the solvent and then removing water.

[0016] Preferably, in step (1), the water content of the mixed system is less than 0.07 wt %, preferably less than 0.05 wt %.

[0017] Preferably, in step (2), the heating time is more than 4 hours, preferably 4 to 12 hours.

[0018] Preferably, in step (2), the heating time does not exceed 24 hours, preferably does not exceed 12 hours.

[0019] Preferably, when the solvent is chlorobenzene, n-octane or n-nonane, the heating temperature in step (2) is 90 to 120° C.; or

[0020] When the solvent is isooctane, the heating temperature in step (2) is 90-99°C.

[0021] Preferably, in step (1), the mass ratio of the solvent to the cyantraniliprole B crystal form is 3 to 10, preferably 4 to 6.

[0022] Preferably, in step (1), the water removal method is evaporation, preferably azeotropic distillation.

[0023] Preferably, in step (2), the cooling temperature is 20-40°C, preferably 30-35°C.

[0024] Preferably, in step (2), the cooling further comprises a post-processing step.

[0025] More preferably, the post-treatment step comprises filtering and drying steps.

[0026] More preferably, the drying temperature is 70-120°C.

[0027] More preferably, the drying pressure is -0.06 to -0.1 MPa.

[0028] More preferably, the drying time is 6 to 12 hours.

[0029] Preferably, the water content of the cyantraniliprole B crystal form is 1wt% to 5wt%, preferably 1wt% to 3wt%.

[0030] Preferably, the purity of the cyantraniliprole A crystal form is above 95%, above 98%, and preferably above 99%.

[0031] Effects of the Invention

[0032] The cyantraniliprole A crystal form prepared by the method provided by the present invention has high quality, the crystal purity can reach more than 98%, even more than 99%, and the active ingredient content (i.e., the sum of the absolute contents of cyantraniliprole A crystal form and B crystal form) can reach more than 95%, which greatly improves the competitiveness of the product. In addition, the method provided by the present invention has a simple process flow, and the reagents are cheap and readily available, and can be used for industrial-scale promotion. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 This is the infrared spectrum of cyantraniliprole crystal form A and crystal form B.

[0034] Figure 2 The infrared spectra of cyantraniliprole A crystal products with different contents.

[0035] Figure 3 It is a linear relationship diagram of the cyantraniliprole A crystal form content and the ratio of the characteristic peak area obtained by measurement.

[0036] Figure 4 This is the infrared spectrum of the cyantraniliprole A crystal form prepared in Example 1 (with n-nonane as solvent).

[0037] Figure 5 This is the infrared spectrum of the cyantraniliprole A crystal form prepared in Example 2 (using chlorobenzene as solvent).

[0038] Figure 6 This is the infrared spectrum of the cyantraniliprole A crystal form prepared in Example 3 (using n-octane as solvent).

[0039] Figure 7 This is the infrared spectrum of the cyantraniliprole A crystal form prepared in Example 4 (using isooctane as solvent).

[0040] Figure 8 It is a comparison chart of the XRPD spectra of the cyantraniliprole B crystal form and the cyantraniliprole A crystal form product prepared in Comparative Example 1.

[0041] Fig. 9 This is the XRPD pattern of cyantraniliprole B crystal form.

[0042] Fig.10 This is the XRPD spectrum of the cyantraniliprole A crystal form prepared in Example 1.

[0043] Fig.11 This is the XRPD spectrum of the cyantraniliprole A crystal form obtained according to the preparation method in CN102216284A.

[0044] Fig.12 It is a comparison chart of the XRPD spectra of cyantraniliprole B crystal form, cyantraniliprole A crystal form obtained by the preparation method in CN102216284A, and cyantraniliprole A crystal form prepared in Example 1. DETAILED DESCRIPTION

[0045] Various exemplary embodiments, features and aspects of the present invention will be described in detail below. The word "exemplary" used here means "used as an example, embodiment or illustrative". Any embodiment described here as "exemplary" is not necessarily interpreted as being superior or better than other embodiments.

[0046] In addition, in order to better illustrate the present invention, numerous specific details are provided in the following specific embodiments. It should be understood by those skilled in the art that the present invention can be implemented without certain specific details. In other examples, methods, means, equipment and steps well known to those skilled in the art are not described in detail in order to highlight the subject matter of the present invention.

[0047] Unless otherwise stated, the units used in this specification are all international standard units, and the numerical values ​​and numerical ranges appearing in the present invention should be understood to include the inevitable systematic errors in industrial production.

[0048] In this specification, the word "may" means both performing a certain process and not performing a certain process.

[0049] In this specification, the references to "some specific / preferred embodiments", "other specific / preferred embodiments", "embodiments", etc., mean that the specific elements (e.g., features, structures, properties and / or characteristics) described in connection with the embodiments are included in at least one embodiment described herein, and may or may not exist in other embodiments. In addition, it should be understood that the elements may be combined in various embodiments in any suitable manner.

[0050] In this specification, a numerical range expressed using “a numerical value A to a numerical value B” or “between a numerical value A and a numerical value B” means a range including the endpoints numerical values ​​A and B.

[0051] In this specification, the numerical range expressed using "a numerical value A or more" or "a numerical value A or less" means a range including the numerical value A at the endpoint.

[0052] In this specification, the numerical range expressed as "a numerical value A or less" for the water content means a range including the endpoint numerical value A and being equal to or greater than 0.

[0053] In the present specification, when "normal temperature" or "room temperature" is used, the temperature may be 15 to 30°C, further 15 to 25°C, for example, 20°C.

[0054] In this specification, "A crystal content" or "purity of cyantraniliprole A crystal" refers to the proportion of cyantraniliprole A crystal in the sum of cyantraniliprole A crystal + B crystal in the obtained sample, which is determined by infrared.

[0055] In this specification, "absolute content" refers to the sum of the absolute contents of cyantraniliprole A crystal form and B crystal form in the obtained sample, which is determined by HPLC.

[0056] In this specification, "yield" refers to the sum of the yields of cyantraniliprole A crystal form + B crystal form calculated by absolute content in the preparation method of the present invention.

[0057] Method for preparing crystal form A

[0058] The method for preparing the cyantraniliprole A crystal form provided by the present invention comprises the following steps:

[0059] (1) preparing a mixed system of cyantraniliprole B crystal form and a solvent, wherein the water content of the mixed system is less than 0.1 wt %, and the solvent is a combination of one or more of chlorobenzene, n-octane, n-nonane and isooctane;

[0060] (2) heating the mixed system to a temperature between 90° C. and the boiling point of the solvent, and cooling the system to obtain cyantraniliprole A crystal form.

[0061] In the present invention, the mixed system of cyantraniliprole B crystal form and solvent can be prepared by a common method in the art. For example, the cyantraniliprole B crystal form is directly mixed with a suitable amount of solvent, and the water content of the suitable amount of solvent needs to be less than 0.1wt%; for another example, the cyantraniliprole B crystal form is mixed with a solvent and then dehydrated, and the dehydration method includes a physical dehydration method or a chemical dehydration method, including but not limited to evaporation dehydration, azeotropic dehydration, gas dehydration, molecular sieve adsorption dehydration or membrane dehydration.

[0062] In some embodiments, in step (1), the mixed system is obtained by directly mixing the cyantraniliprole B crystal form and the solvent.

[0063] In some embodiments, in step (1), the mixed system is obtained by mixing the cyantraniliprole B crystal form and the solvent and then removing water.

[0064] In some embodiments, in step (1), the water content of the mixed system is less than 0.1 wt %. In some specific embodiments, the water content of the mixed system is less than 0.07 wt %, preferably less than 0.05 wt %, such as less than 0.03 wt %, less than 0.02 wt %, etc.

[0065] In some embodiments, the heating time in step (2) is 4 hours or more, such as 5 hours, 6 hours, 8 hours, 9 hours, etc. In other embodiments, the heating time in step (2) is 5 hours or more. In other embodiments, the heating time in step (2) is 9 hours or more.

[0066] In some embodiments, the heating time in step (2) does not exceed 24 h, for example, does not exceed 20 h, does not exceed 16 h, does not exceed 12 h, etc.

[0067] In some embodiments, the solvent is a combination of one or more of chlorobenzene and n-nonane.

[0068] In some specific embodiments, when the solvent is chlorobenzene, the heating time in step (2) is more than 4 hours.

[0069] In other specific embodiments, when the solvent is n-nonane, the heating time in step (2) is more than 9 hours.

[0070] In some embodiments, in step (2), the temperature of the mixed system is heated to 95-115°C.

[0071] In some embodiments, when the solvent is chlorobenzene, n-octane or n-nonane, the heating temperature in step (2) is 90-120°C, preferably 95-115°C, and more preferably 100-110°C.

[0072] In some embodiments, when the solvent is isooctane, the heating temperature in step (2) is 90-99°C, preferably 95-99°C.

[0073] In the present invention, the amount of solvent is not a key factor affecting the crystallization effect and the increase in the content of crystal form A. In some embodiments, the mass ratio of the solvent to the cyantraniliprole crystal form B can be 3 to 10, preferably 4 to 6, such as 4.5, 5, 5.5, etc.

[0074] In some embodiments, the solvent is of analytical grade or chromatographic grade and contains almost no water.

[0075] In some embodiments, the mixed system is obtained by mixing the cyantraniliprole B crystal form and the solvent and then removing water, and the water removal method is evaporation removal, preferably azeotropic distillation. In some specific embodiments, evaporation removal will take away a portion of the solvent, and the solvent can be supplemented after evaporation removal. The amount of supplemented solvent can be an amount that makes the mass ratio of the solvent and the cyantraniliprole B crystal form in the system reach 3 to 10 (preferably 4 to 6, such as 4.5, 5, 5.5, etc.); and the level of the supplemented solvent is at least analytically pure, almost free of water, and has little effect on the water in the system.

[0076] In some embodiments, the cooling temperature in step (2) is 20-40°C, preferably 25-40°C, and more preferably 30-35°C.

[0077] In some embodiments, the cooling in step (2) further comprises a post-treatment step.

[0078] In some embodiments, the post-processing step comprises filtering and drying steps.

[0079] In some specific embodiments, the drying temperature is 70-120°C, for example, 75°C, 80°C, 85°C, 90°C, 100°C, etc.

[0080] In some specific embodiments, the drying pressure is -0.06 to -0.1 MPa, such as -0.07 MPa, -0.08 MPa, -0.09 MPa, etc.

[0081] In some specific embodiments, the drying time is 6 to 12 hours, such as 8 hours, 10 hours, etc.

[0082] In some embodiments, the water content of the cyantraniliprole B crystal form used in the present invention is 1 wt% to 5 wt%, preferably 1 wt% to 3 wt%.

[0083] The XRPD spectra of the raw material cyantraniliprole B crystal form used in the present invention, the cyantraniliprole A crystal form in CN102216284A (the solvent is n-heptane), and the product prepared by the present invention (such as Example 1, the solvent used is n-nonane) are shown in the figure. Fig.12 ; The spectrum represented by "n-heptane" is the spectrum of the cyantraniliprole A crystal form in CN102216284A, and the spectrum represented by "n-nonane" is the product prepared in Example 1 of the present invention. Fig.12 It can be seen that the present invention obtains a new crystal form different from the cyantraniliprole B crystal form, and the new crystal form is the cyantraniliprole A crystal form.

[0084] In some embodiments, the purity of the cyantraniliprole A crystal form obtained by the preparation method of the present invention is 95% or more, preferably 98% or more, for example 98.5% or more or 99% or more.

[0085] Infrared measurement method

[0086] Infrared instrument name: Shimadzu Fourier transform infrared spectrometer; Model: IRAffinity-1S; Measurement parameters: Measurement mode: transmittance, apodization function: Happ-Genzel, scan times: 15, resolution: 4 cm -1 , wave number range 400~4500cm -1 ; The determination method is KBr tablet method.

[0087] In addition, when the sample of the present invention is ground and tableted, the crystal form of cyantraniliprole will not change. XRPD detection shows that the crystal form of the sample before and after grinding is consistent, and no crystal transformation occurs.

[0088] A crystal content (purity) determination method

[0089] There are obvious differences between cyantraniliprole A and B in the infrared spectra. The peak positions of the two are different, and some of the peak positions have significant characteristic differences, as shown in Figure 2. Figure 1 . Figure 2 The infrared spectra of some products with different crystal purity are given, and their peak areas are also different, which can be used to determine the crystal content.

[0090] like Figure 1 As shown, the peak positions of the two crystal forms A and B in the infrared spectrum are:

[0091] Table 1 Peak positions of infrared spectra of cyantraniliprole A crystal form

[0092] Serial number <![CDATA[Wavenumber (cm -1 )]]> Serial number <![CDATA[Wavenumber (cm -1 )]]> 1 470.63 15 1465.9 2 594.08 16 1489.05 3 717.52 17 1519.91 4 763.81 18 1581.63 5 810.1 19 1635.64 6 879.54 20 1689.64 7 964.41 21 2237.43 8 1026.13 22 2337.72 9 1041.56 23 2368.59 10 1072.42 24 3387 11 1157.29 25 3649.32 12 1226.73 26 3749.62 13 1303.88 27 3803.63 14 1357.89 28 3903.92

[0093] Table 2 Peak positions of infrared spectra of cyantraniliprole B crystal form

[0094] Serial number <![CDATA[Wavenumber (cm -1 )]]> Serial number <![CDATA[Wavenumber (cm -1 )]]> 1 486.06 15 1535.34 2 586.36 16 1597.06 3 671.23 17 1643.35 4 756.1 18 1674.21 5 802.39 19 1751.36 6 879.54 20 2229.71 7 964.41 21 2337.72 8 1080.14 22 2368.59 9 1149.57 23 3649.32 10 1273.02 24 3680.18 11 1303.88 25 3711.04 12 1357.89 26 3749.62 13 1411.89 27 3803.63 14 1465.9 28 3903.92

[0095] Crystal forms A and B are different crystal forms of the same substance, which leads to the shift of the infrared spectrum peak position, and then the peak positions of the two are different. In the process of quantitative determination of crystal forms, in order to avoid the influence between the two, the characteristic peak of crystal form A at 717.52 cm was selected after comparison. -1 , and the common peak position of A and B crystal forms is 964.41cm -1 As a reference for quantitative determination.

[0096] Quantitative determination process:

[0097] (1) Sample preparation: Weigh 1 g of crystal form A and B samples with known absolute content and crystal form content in different proportions, accurate to 0.001 g, and mix the weighed samples thoroughly on a vortex mixer. Then weigh 0.02 g of the mixed sample and 2 g of dry potassium bromide (accurate to 0.001 g), and grind them thoroughly in an agate mortar. After grinding, weigh about 0.035 g of the sample into a tableting mold, and complete the sample preparation and infrared detection on a 2-ton tablet press. The content of crystal form A and the corresponding characteristic peak area (717.52 cm -1 and 964.41cm -1 ) are shown in the following table:

[0098] Table 3 Ratio of A crystal content to corresponding characteristic peak area

[0099] A crystal content <![CDATA[Corrected area (717.52 cm -1 )]]> <![CDATA[Corrected area (964.41 cm -1 )]]> Area ratio 0.518 8.013 124.335 0.0644 0.665 14.165 129.034 0.1098 0.742 14.087 101.569 0.1387 0.785 18.142 119.396 0.1519 0.816 23.341 147.079 0.1587 0.842 23.843 139.431 0.1710 0.874 24.652 128.373 0.1920 0.974 30.07 138.639 0.2169

[0100] (2) Plotting the content of Form A (as the abscissa) and the ratio of the characteristic peak area obtained by the measurement (as the ordinate), and fitting, an equation y=0.3413x-0.1148 is obtained, see Figure 3 ,from Figure 3 It can be seen that the two have a good linear relationship (R 2 =0.9928);

[0101] (3) Weigh 0.02g of the sample with unknown crystal content and 2g of dry potassium bromide (accurate to 0.001g), and grind them thoroughly in an agate mortar. After grinding, weigh about 0.035g of the sample into a tableting mold, and complete the sample preparation and infrared detection on a 2-ton tablet press to obtain the ratio of characteristic peak areas. According to the above equation, the ratio of characteristic peak areas is substituted into the calculation to obtain the A crystal content in the sample.

[0102] Example

[0103] The embodiments of the present invention will be described in detail below in conjunction with the examples, but those skilled in the art will appreciate that the following examples are only used to illustrate the present invention and should not be considered to limit the scope of the present invention. If no specific conditions are specified in the examples, they are carried out according to normal conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be obtained commercially.

[0104] The cyantraniliprole B crystal form dry product used in the example is obtained by crystallizing cyantraniliprole in acetonitrile-water and drying, with a moisture content of 1.62 wt %, an absolute content of 92.51 wt %, and an XRPD pattern as shown in Fig. 9The peak position and intensity data of the diffraction peak in the XRPD spectrum are shown in Table 4. The deviation of the characteristic peak corresponding to the B crystal form in patent CN102216284A is ±0.3%, proving that the two are the same crystal form, namely, B crystal form.

[0105] Table 4 XRPD data of the dry cyantraniliprole B crystal form used in the examples (only the diffraction peaks with higher peak intensity in the XRPD spectrum are recorded)

[0106] 2θ(°) Peak intensity (%) 7.239 96.3 9.755 97.9 18.456 45.2 19.058 61.1 22.028 49.6 23.131 100 25.39 71.2

[0107] The wet product of cyantraniliprole B crystal form used in the example was obtained by crystallizing cyantraniliprole in acetonitrile-water and washing with acetonitrile, with a moisture content of 2.30 wt%, an acetonitrile content of 9.19 wt%, an absolute content of 82.64 wt%, and was identified as cyantraniliprole B crystal form by XRPD.

[0108] Example 1: Suspended crystallization after evaporation and removal of water in n-nonane

[0109] Weigh 10.5 g of the dry product of cyantraniliprole B crystal form into a flask with a water separator-condensation device and a mechanical stirrer, add 50.80 g of n-nonane, set the stirring speed to 200 rpm, set the external temperature Tj = 110 ° C, start heating, and wait until the system material temperature is heated to 97 ° C. Turn on the vacuum pump, adjust the vacuum degree to -0.07 MPa, evaporate and concentrate, and collect the condensate. After about 20 minutes of evaporation, collect about 5 mL of condensate. It is observed that there is obvious stratification at the bottom of the condensate in the water separator. Remove the vacuum, release the lower layer of liquid (including water, 0.81 g) from the bottom of the water separator, and the upper layer The liquid was poured back into the system, and then continued to evaporate, and the vacuum degree was adjusted to -0.085 MPa. This was repeated twice. After about 40 minutes, the condensate collected in the condenser was clear and transparent without stratification. The vacuum was removed, and all the condensate was released from the bottom of the water separator and poured back into the system. The water content of the system was detected to be 0.04 wt%. The temperature in the system rose to Tr = 100 ° C, and continued to heat and stir. After maintaining heating for 5 hours, the heating was stopped, and the temperature was cooled to 35 ° C and filtered. The product was taken out and weighed in a vacuum drying oven at 80 ° C and -0.085 MPa for 8 hours, and the infrared spectrum was detected by XRPD. Figure 4 , XRPD spectrum see Fig.10 The peak positions and intensity data of the diffraction peaks in the XRPD spectrum are shown in Table 5.

[0110] Table 5 XRPD data of the product obtained after evaporation and dehydration in n-nonane (only some diffraction peaks with higher peak intensity in the XRPD spectrum are recorded)

[0111] 2θ(°) Peak intensity (%) 6.502 100 10.784 35 19.635 27.6 20.665 21 26.282 10 26.647 24.8 31.246 10.3

[0112] According to Example 3 in CN102216284A (using a suspension in n-heptane), Form A was prepared, and the XRPD pattern of the obtained Form A is shown in Fig.11 The peak positions and intensity data of the diffraction peaks in the XRPD spectrum are shown in Table 6.

[0113] Table 6 XRPD data of crystal form A obtained from CN102216284A (only the diffraction peaks with higher peak intensity in the XRPD spectrum are recorded)

[0114] 2θ(°) Peak intensity (%) 6.422 100 10.731 18.4 19.532 69.2 20.607 41.3 26.199 31.2 26.62 20.9 31.164 26.2

[0115] By comparing the data in Table 5 and Table 6, the 2θ (°) deviation of the corresponding characteristic peak in the XRPD spectrum of the product of this embodiment and the A crystal form in CN102216284A is ±0.3%, proving that the two are the same crystal form, that is, the product obtained in this embodiment is cyantraniliprole A crystal form.

[0116] The results of product purity and yield determined by infrared are shown in Table 7. When the solvent is n-nonane, the evaporation and dehydration method can obtain a product with a purity of up to 98.97% of the A crystal form.

[0117] Table 7 Results of evaporation and water removal when the solvent is n-nonane

[0118] Product weight / g Product moisture / % Absolute content / wt% Yield / % A crystal content / wt% 9.61 0.19 95.48 94.46 98.97

[0119] In addition, evaporation and water removal were carried out in n-nonane according to the above method to investigate the effect of different water contents on the purity of the crystal form of the product after crystallization. The results are shown in Table 8 below. The results show that after evaporation and water removal to a system water content of more than 0.1%, the purity of the A crystal form in the product will decrease and cannot reach 98%.

[0120] Table 8 The results of investigating the effect of different water contents on the purity of Form A when the solvent is n-nonane

[0121]

[0122] Example 2: Suspended crystallization after evaporation and removal of water in chlorobenzene

[0123] Weigh 10.0 g of the dry product of cyantraniliprole B crystal form into a flask with a water separator-condensation device and a mechanical stirrer, add 50.0 g of chlorobenzene, set the stirring speed to 200 rpm, set the external temperature Tj = 105 ° C, start heating, and wait until the system material temperature is heated to 95 ° C. Turn on the vacuum pump, adjust the vacuum degree to -0.05 MPa, evaporate and concentrate, collect the condensate, adjust Tj = 110 ° C, and collect about 2 mL of condensate after evaporation for about 20 minutes. It is observed that the condensate in the water separator is milky white and turbid, and there is obvious stratification. Continue evaporation and gradually adjust the vacuum degree to -0.07 MPa. When about 5 mL of condensate is collected, remove the vacuum. The condensate was released from the bottom of the water separator, and then the vacuum was gradually increased to -0.08MPa, and the condensate was continued to evaporate and collected. After about 50 minutes, about 15mL of condensate was collected in the condenser, and it was clear and transparent without turbidity or stratification. The vacuum was removed, and all the condensate was released from the bottom of the water separator. 25g of fresh chlorobenzene was added, and the water content of the system was 0.02wt%. The temperature in the system Tr = 100°C was continued to heat and stir, and the heating was stopped after maintaining heating for 4h. After cooling to 32°C, it was filtered and dried in a vacuum drying oven at 80°C and -0.085MPa for 8h. The product was taken out and weighed. It was identified as A crystal form by XRPD, and then infrared was detected. The infrared spectrum is shown in Figure 5 .

[0124] The results are shown in Table 9. When the solvent is chlorobenzene, the evaporation and dehydration method can obtain a product with a purity of up to 99.42% of Form A.

[0125] Table 9 Results of evaporation and water removal when the solvent is chlorobenzene

[0126] Product weight / g Moisture / wt% Absolute content / wt% Yield / % A crystal content / wt% 9.03 0.08 96.90 94.58 99.42

[0127] Example 3: Suspension crystallization after evaporation and removal of water in n-octane

[0128] Weigh 10.04 g of cyantraniliprole B crystal dry product into a flask with a water separator-condensation device and mechanical stirring, add 50.12 g of n-octane, set the stirring speed to 200 rpm, set the external temperature Tj = 110 ° C, start heating, and wait until the system material temperature is heated to 90 ° C. Turn on the vacuum pump and adjust the vacuum degree to -0.045 MPa for evaporation and concentration. Collect the condensate. After about 20 minutes of evaporation, collect about 7 mL of condensate. It is observed that there is obvious stratification at the bottom of the condensate in the water separator. Remove the vacuum, release the lower layer of liquid from the bottom of the water separator, and pour the upper layer of liquid back into the system. After that, the evaporation was continued and the vacuum degree was adjusted to -0.07MPa. After about 20min, about 5mL of condensate was collected in the condenser, which was clear and transparent without stratification. The vacuum was removed and all the condensate was released from the bottom of the water separator. 4g of fresh n-octane was added. The water content of the system was 0.04wt% and the temperature in the system rose to Tr = 100°C. The heating and stirring were continued and the heating was stopped after maintaining the heating for 5h. The temperature was cooled to 33°C and then filtered. The product was taken out and weighed after being dried in a vacuum drying oven at 80°C and -0.085MPa for 8h. It was identified as A crystal form by XRPD and then infrared was detected. The infrared spectrum was shown in Figure 6 .

[0129] The results are shown in Table 10. When the solvent is n-octane, the evaporation and dehydration method can be used to obtain a product with a purity of up to 98.89% of the A crystal form.

[0130] Table 10 Results of evaporation and water removal when the solvent is n-octane

[0131] Product weight / g Moisture / wt% Absolute content / wt% Yield / % A crystal content / wt% 9.35 0.22 94.75 95.38 98.89

[0132] Example 4: Suspension crystallization after evaporation and removal of water in isooctane

[0133] Weigh 9.97 g of the dry product of cyantraniliprole B crystal form into a flask with a water separator-condensation device and a mechanical stirrer, add 50.24 g of isooctane, set the stirring speed to 200 rpm, set the external temperature Tj = 107 ° C, start heating, and wait until the system material temperature is heated to 95 ° C. Turn on the vacuum pump and slowly adjust the vacuum degree to -0.04 MPa for evaporation and concentration. Collect the condensate. After about 15 minutes of evaporation, collect about 5 mL of condensate. It is observed that there is obvious stratification at the bottom of the condensate in the water separator. Remove the vacuum, release the lower layer of liquid (including water, 0.48 g) from the bottom of the water separator, and pour the upper layer of liquid. Return to the system, then continue evaporation, gradually adjust the vacuum degree to -0.06MPa, about 60min later, collect about 15mL of condensate in the condenser without stratification, remove the vacuum, release all the condensate from the bottom of the water separator, add 15g of fresh isooctane, detect the water content of the system to be 0.08wt%, the temperature in the system rises to Tr = 99°C, continue heating and stirring, maintain heating for 5h and then stop heating, cool to 35°C and filter, dry in a vacuum drying oven at 80°C, -0.085MPa for 8h, take out the product, weigh it, identify it as A crystal form by XRPD, and then detect infrared, infrared spectrum is shown Figure 7 .

[0134] The results are shown in Table 11. When the solvent is isooctane, the water is evaporated to 0.08 wt % of the system water content, and the purity of the obtained A-type product is relatively low, only 94.87%.

[0135] Table 11 Results of evaporation and water removal when the solvent is isooctane

[0136] Product weight / g Product moisture / wt% Absolute content / wt% Yield / % A crystal content / wt% 9.20 0.24 96.59 96.34 94.87

[0137] In addition, water removal and crystallization were carried out in isooctane according to the above method, and the effect of different water contents on the purity of the crystal form of the product after crystallization was investigated. The results are shown in Table 12 below. The results show that when the water content of the system is 0.04% by evaporation, a crystal form A product with a purity of up to 98.89% can be obtained; when the water content of the system is above 0.16% by evaporation, the purity of the crystal form A will be significantly reduced.

[0138] Table 12 Results of the effects of different water contents on product purity when the solvent is isooctane

[0139]

[0140] Example 5: Using the wet product of crystal form B as raw material (suspended in n-nonane for crystallization after evaporation and dehydration)

[0141] Weigh 16.80 g of the wet product of cyantraniliprole B crystal form into a flask with a water separator-condensation device and a mechanical stirrer, add 78 g of n-nonane, set the stirring speed to 200 rpm, set the external temperature Tj = 120 ° C, start heating, and wait until the system material temperature is heated to 100 ° C. Turn on the vacuum pump and slowly adjust the vacuum degree to -0.07 MPa to evaporate and concentrate the condensate. After about 30 minutes of evaporation, about 6 mL of condensate was collected. It was observed that there was obvious stratification at the bottom of the condensate in the water separator. The vacuum was removed, and the lower layer of liquid (including water, 2.48 g) was released from the bottom of the water separator. The upper layer The liquid was poured back into the system, and then continued to evaporate, and the vacuum degree was gradually adjusted to -0.085 MPa. After about 60 minutes, about 20 mL of condensate was collected in the condenser without stratification. The vacuum was removed and all the condensate was released from the bottom of the water separator. 20 g of fresh n-nonane was added, and the water content of the system was detected to be 0.04%. The temperature in the system rose to Tr = 110°C, and stirring was continued. The heating was maintained for 5 hours and then stopped. The temperature was cooled to 30°C and then filtered. The product was taken out and weighed after drying in a vacuum drying oven at 80°C and -0.085 MPa for 8 hours. It was identified as crystal form A by XRPD, and then detected by infrared.

[0142] The results are shown in Table 13. When the solvent is n-nonane, the wet product of Form B can be used as the raw material and the Form A product with a purity of up to 98.25% can be obtained by evaporating and removing water.

[0143] Table 13 Effect of the purity of the product when the solvent is n-nonane and the wet product of Form B is used as the raw material

[0144] Product weight / g Moisture / wt% Absolute content / wt% Yield / % A crystal content / wt% 13.84 0.34 95.58 95.28 98.25

[0145] Example 6: Investigating the effect of crystallization time on the purity of the product crystal form (crystallization by suspension in n-nonane)

[0146] Weigh 20.2 g of the dry product of cyantraniliprole B crystal form into a flask with a water separator-condensation device and a mechanical stirrer, add 110 g of n-nonane, set the stirring speed to 200 rpm, set the external temperature Tj = 125 ° C, start heating, and wait until the system material temperature is heated to 97 ° C. Turn on the vacuum pump and adjust the vacuum degree to -0.075 MPa for evaporation and concentration. Collect the condensate. After about 20 minutes of evaporation, collect about 5 mL of condensate. It is observed that there is obvious stratification at the bottom of the condensate in the water separator, and then continue Evaporate and gradually increase the vacuum degree to -0.085MPa. After about 50 minutes, the water separator is full of condensate and the height of the bottom water phase remains unchanged (the volume of the water separator is 25mL). At this time, stop evaporation and concentration, and detect the water content of the system to be 0.03wt%. The temperature in the system rises to Tr=110℃, continue heating and stirring, and take samples every 1h. The sampling volume is about 2mL. After cooling to 30℃, filter and dry in a vacuum drying oven at 80℃, -0.085MPa for 8h. Then take out the product, weigh it, and detect infrared.

[0147] The results are shown in Table 14. When the solvent is n-nonane and the heating time is more than 5 hours, the purity of Form A can reach more than 98%.

[0148] Table 14 Effect of heating time on product purity when the solvent is n-nonane

[0149] Time / h 1 2 3 4 5 6 7 8 9 10 A crystal purity / wt% 72.23 83.75 88.54 95.7 98.2 98.45 98.77 98.89 99.32 99.34

[0150] Example 7: Investigating the effect of crystallization time on the purity of the product crystal form (suspension crystallization in isooctane)

[0151] Weigh 20.50 g of the dry product of cyantraniliprole B crystal form into a flask with a water separator-condensation device and mechanical stirring, add 110 g of isooctane, set the stirring speed to 200 rpm, set the external temperature Tj = 125 ° C, start heating, and when the system material temperature is heated to 97 ° C, the system boils significantly. After evaporation for about 10 minutes, about 6 mL of condensate is collected. It is observed that there is obvious stratification at the bottom of the condensate in the water separator. Then continue evaporation and collect condensate. After about 40 minutes, the water separator is full of condensate and the height of the bottom water phase remains unchanged (the volume of the water separator is 25 mL). The external temperature Tj is reduced to 110 ° C, and the water content of the system is detected to be 0.07 wt%. The temperature in the system rises to Tr = 99 ° C, and heating and stirring are continued. Sampling is performed at intervals of 1 h. The sampling volume is about 2 mL. After cooling to 35 ° C, it is filtered and dried in a vacuum drying oven at 80 ° C, -0.085 MPa for 8 h. Take out the product, weigh it, and detect infrared.

[0152] The results are shown in Table 15. When the solvent is isooctane and the heating time is more than 9 hours, the purity of Form A can reach more than 98%.

[0153] Table 15 Effect of heating time on product purity when the solvent is isooctane

[0154] Time / h 1 2 3 4 5 6 7 8 9 10 A crystal purity / wt% 26.79 38.59 76.04 87.75 96.53 97.2 97.53 97.8 98.34 98.4

[0155] Comparative Example 1: Suspension crystallization method without evaporation and water removal step

[0156] Weigh 3-3.5 g of the dry product of cyantraniliprole B crystal form into a flask with a condenser, add 15-17 g of a solvent, and heat to a temperature close to the boiling point of the solvent (if the boiling point of the solvent is greater than 100°C, heat to 90-100°C), keep warm for 12 hours, cool to room temperature and stir for 5-7 hours, filter, and vacuum dry at 80°C, -0.085 MPa for 4 hours, then take out the product, and detect the infrared spectrum using the KBr tablet method.

[0157] Experimental results: Cyclohexane, 1,2-dichloroethane, n-nonane, ethylbenzene, ethylene glycol dimethyl ether, sec-butyl acetate, isopropyl acetate, methyl tert-butyl ether, n-octane, isobutanol, chlorobenzene, n-hexane, butyl acetate, tert-butanol, isopentanol, isooctane, 1-chloropentane, 3-pentanol, trimethyl orthoformate, 1,2-dichloropropane, 1,3-dichloropropane, petroleum ether, ethyl acetate, sec-butanol, and 2-pentanone were used as solvents, and the experiment was carried out according to the above-mentioned crystal transformation method. The experimental results show that when ethylbenzene, isobutanol, n-octane, n-nonane, chlorobenzene, sec-butanol, isooctane, 1-chloropentane, 1,2-dichloropropane, and 1,3-dichloropropane are used as solvents, the infrared spectrum of the cyantraniliprole product obtained is different from that of the raw material. Further XRPD detection confirms that the obtained product is crystal form A. The XRPD spectrum of crystal form A corresponding to each solvent is shown in Figure 8 The purity results of Form A corresponding to each solvent are shown in Table 16 below.

[0158] Table 16 Purity results of Form A corresponding to each solvent

[0159]

[0160] Comparative Example 2: Adding seed crystals and suspending and crystallizing in n-nonane, n-octane or 1,3-dichloropropane

[0161] Weigh 3-3.5 g of the dry product of cyantraniliprole B crystal form into a flask with a condenser, add 15-17 g of solvent, and add 0.03-0.04 g of crystal form A seed (crystallized from n-heptane, crystal form A purity 97.6%) and heat to 95-100° C., keep warm for 12 hours, cool to room temperature and stir for 5-7 hours, filter, and vacuum dry at 80° C., -0.085 MPa for about 4 hours, then take out the product, determine its water content, and detect the infrared spectrum using the KBr tablet method.

[0162] The experimental results are shown in Table 17. The results show that after adding seed crystals, the purity of crystal form A is improved compared with Comparative Example 1, but the purity of crystal form A is still low and cannot meet the requirements.

[0163] Table 17 Effect of adding seed crystals on product crystal purity

[0164]

[0165] Comparative Example 3: Raising the crystallization temperature and suspending the crystallization in n-octane or n-nonane

[0166] Weigh 5 g of the dry product of cyantraniliprole B crystal form into a flask with a condenser, add 25 g of n-octane or n-nonane solvent, and heat to 70-120°C. After keeping warm for 12 hours, reduce to 35°C, filter, and vacuum dry at 80°C, -0.085 MPa for about 12 hours. Then take out the product and detect the infrared spectrum using the KBr tablet method.

[0167] The results are shown in Tables 18 and 19. The experimental results show that the higher the heating temperature (i.e., the crystal transformation temperature), the higher the purity of Form A. However, when the heating temperature is close to the boiling point of the solvent, the purity of Form A is still relatively low. For example, when the solvent is n-octane and the heating temperature is 118°C, the purity of Form A is only 94.5%.

[0168] Table 18 Results of increasing the crystallization temperature in n-octane

[0169]

[0170] Table 19 Results of increasing the crystallization temperature in n-nonane

[0171]

[0172] Comparative Example 4:

[0173] According to the examples in WO2023095161A1, a wet product of cyantraniliprole is obtained. The wet product of cyantraniliprole is heated to reflux in methylcyclohexane or xylene and dehydrated by a Dean-Stark device (water separator). After the dehydration is completed, the suspension is cooled to 25-30°C, stirred for 1h and filtered. The solid is dried for 30min and finally dried in a vacuum oven at 60-65°C for 8-10h. The results are shown in Table 20 below. The results show that the purity of the A crystal form obtained by the preparation method disclosed in WO2023095161A1 is low, only about 90%.

[0174] Table 20 Results of crystal form A obtained from WO2023095161A1

[0175]

[0176] It should be noted that, although the technical solution of the present invention is introduced with specific examples, those skilled in the art will appreciate that the present invention should not be limited thereto.

[0177] The embodiments of the present invention have been described above, and the above description is exemplary, not exhaustive, and is not limited to the disclosed embodiments. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments. The selection of terms used herein is intended to best explain the principles of the embodiments, practical applications, or technical improvements in the market, or to enable other persons of ordinary skill in the art to understand the embodiments disclosed herein.

Claims

1. A method for preparing a cyantraniliprole A crystal form, comprising the following steps: (1) preparing a mixed system of cyantraniliprole B crystal form and a solvent, wherein the water content of the mixed system is less than 0.1 wt %, and the solvent is a combination of one or more of chlorobenzene, n-octane, n-nonane and isooctane; (2) heating the mixed system to a temperature between 90° C. and the boiling point of the solvent, and cooling the system to obtain the cyantraniliprole A crystal form.

2. The method for preparing cyantraniliprole A crystal form according to claim 1, characterized in that: In step (1), the mixed system is obtained by mixing the cyantraniliprole B crystal form and the solvent and then removing water.

3. The method for preparing cyantraniliprole A crystal form according to claim 1 or 2, characterized in that: In step (1), the water content of the mixed system is less than 0.07 wt %, preferably less than 0.05 wt %.

4. The method for preparing cyantraniliprole A crystal form according to any one of claims 1 to 3, characterized in that: In step (2), the heating time is more than 4 hours, preferably more than 5 hours.

5. The method for preparing cyantraniliprole A crystal form according to any one of claims 1 to 4, characterized in that: In step (2), the heating time does not exceed 24 hours, preferably does not exceed 12 hours.

6. The method for preparing cyantraniliprole A crystal form according to any one of claims 1 to 5, characterized in that: When the solvent is chlorobenzene, n-octane or n-nonane, the heating temperature in step (2) is 90-120° C.; or When the solvent is isooctane, the heating temperature in step (2) is 90-99°C.

7. The method for preparing cyantraniliprole A crystal form according to any one of claims 1 to 6, characterized in that: In step (1), the mass ratio of the solvent to the cyantraniliprole B crystal form is 3 to 10, preferably 4 to 6.

8. The method for preparing cyantraniliprole A crystal form according to any one of claims 2 to 7, characterized in that: In step (1), the water removal method is evaporation, preferably azeotropic distillation.

9. The method for preparing cyantraniliprole A crystal form according to any one of claims 1 to 8, characterized in that: In step (2), the cooling temperature is 20-40°C, preferably 30-35°C.

10. The method for preparing the cyantraniliprole A crystal form according to any one of claims 1 to 9, characterized in that: In step (2), the cooling further comprises a post-processing step; Preferably, the post-processing step comprises filtering and drying steps; More preferably, the drying temperature is 70 to 120° C., the drying pressure is -0.06 to -0.1 MPa, and the drying time is 6 to 12 hours.

11. The method for preparing cyantraniliprole A crystal form according to any one of claims 1 to 10, characterized in that: The water content of the cyantraniliprole B crystal form is 1 wt% to 5 wt%, preferably 1 wt% to 3.5 wt%.

12. The method for preparing cyantraniliprole A crystal form according to any one of claims 1 to 11, characterized in that: The purity of the cyantraniliprole A crystal form is above 95%, preferably above 98%, and more preferably above 99%.

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