A crystal form of L-glufosinate ammonium salt and preparation method thereof

Abstract

The invention discloses a kind of crystal formation of L glufosinate ammonium salt and preparation method thereof, the X-ray diffraction pattern of the crystal formation of L glufosinate ammonium salt includes 10.696 ± 0.2 °, 18.34 ± 0.2 °, 18.598 ± 0.2 °, 20.185 ± 0.2 °, 21.893 ± 0.2 ° and 32.428 ± 0.2 ° 2θ at least one characteristic peak, after testing, the crystal formation of this L glufosinate ammonium salt is stored 10 days at room temperature under humidity 65%, mass change is all below 0.5%, without obvious hygroscopicity, and crystal formation has no obvious change, which is conducive to it keeping dry during storage and use, avoids deterioration or activity reduction due to humidity. Meanwhile, the crystal formation performs well in stability test, and after long-term storage, crystal structure also does not change. This high stability ensures the lasting effectiveness of the crystal formation of L glufosinate ammonium salt in herbicidal drug products.

Description

Technical Field

[0001] The present application relates to the field of pesticide technology, and specifically to a crystal form of L-glufosinate ammonium salt and a preparation method thereof. Background Art

[0002] L-glufosinate, an organophosphine-based herbicide, demonstrates significant potential for application in modern agriculture due to its high efficacy, low toxicity, and environmental friendliness. Compared to traditional glufosinate, which contains a mixture of L- and D-isomers, only the L-form possesses herbicidal activity, resulting in a two-fold increase in herbicidal efficiency. This allows for a 50% reduction in field application rates, significantly reducing residual ineffective components and ecological burdens. This has far-reaching implications for lowering agricultural production costs and alleviating environmental pressures.

[0003] L-glufosinate ammonium, the mainstream product on the market, dominates the market due to its environmental compatibility and highly effective weed control. However, L-glufosinate ammonium has poor hygroscopicity and stability. Therefore, the market is highly anticipating the development of L-glufosinate ammonium crystals, which are highly hygroscopic, stable, and easy to store. They will drive the development of new salt-based herbicides towards higher efficiency and precision, providing a more competitive technical solution for the control of resistant weeds. Summary of the Invention

[0004] The purpose of this application is to provide a crystal form of L-glufosinate ammonium salt and a preparation method thereof, which is a crystal form of L-glufosinate ammonium salt that is highly hygroscopic and more stable.

[0005] To achieve the above-mentioned objectives, the present application provides the following technical solutions: a crystalline form of L-glufosinate ammonium salt, the X-ray diffraction pattern of the crystalline form of L-glufosinate ammonium salt comprising at least one characteristic peak in 2θ of 10.696±0.2°, 18.34±0.2°, 18.598±0.2°, 20.185±0.2°, 21.893±0.2° and 32.428±0.2°. In some embodiments, the XRPD pattern of this form comprises at least three peaks.

[0006] Testing has shown that the L-glufosinate crystalline form exhibits less than 0.5% mass change after 10 days of storage at room temperature and humidity of 65%. The crystal form exhibits no significant hygroscopicity and crystal form changes, which helps it remain dry during storage and use, preventing deterioration or loss of activity due to humidity. Furthermore, the crystal form exhibited excellent stability testing, maintaining its structure even after prolonged storage. This high stability ensures the long-lasting effectiveness of the L-glufosinate crystalline form in herbicide products.

[0007] Currently, the research and development of other salt forms of L-glufosinate, such as isopropylamine, dimethylamine, and sodium salts, is still in the technical research stage, with relatively few reports. Compared to ammonium salt systems, L-glufosinate dimethylamine salt exhibits significant advantages in solubility and chemical stability. The strong polarity of the dimethylamine group in its molecular structure can increase water solubility by more than 40%, which is of great value in improving the herbicide's sustained efficacy in complex field environments. Therefore, the L-glufosinate salt of this application is L-glufosinate dimethylamine salt.

[0008] Further, the X-ray diffraction pattern of the crystalline form of L-glufosinate salt includes 10.241±0.2°, 10.696±0.2°, 14.168±0.2°, 18.34±0.2°, 18.598±0.2°, 19.527±0.2°, 20.185±0.2°, 21.457±0.2°, 21.673±0.2°, 21.893±0.2°, At least three characteristic peaks in 2θ of 23.461±0.2°, 24.031±0.2°, 25.164±0.2°, 27.487±0.2°, 28.162±0.2°, 28.541±0.2°, 30.528±0.2°, 31.631±0.2°, 32.428±0.2°, 33.8±0.2° and 37.784±0.2°.

[0009] In some embodiments, the XRPD pattern of the form comprises at least six peaks.

[0010] Furthermore, the 2θ angle of the main diffraction peak of the crystalline form of L-glufosinate ammonium salt is 10.696°±0.2°, and the relative intensities of all other characteristic peaks are ≤5% based on the main peak intensity.

[0011] The present application also provides a method for preparing a crystal form of L-glufosinate ammonium salt, which is used to prepare the crystal form of L-glufosinate ammonium salt as described above, comprising: reacting L-glufosinate acid with an aqueous dimethylamine solution, concentrating and purifying the solution, crystallizing it, and separating and drying it to obtain the crystal form of L-glufosinate ammonium salt, and performing preliminary purification by water removal → solvent crystallization → azeotropic water removal and impurity removal to achieve precise removal of impurities;

[0012] Wherein, the L-glufosinate raw material can be L-glufosinate prepared by conventional methods in the art, and the purity of L-glufosinate reaches more than 98%, which can be used for the preparation of the above reaction;

[0013] The concentration of the dimethylamine aqueous solution is 10-40%, the molar ratio of L-glufosinate to the dimethylamine aqueous solution is 1:1.05-1:10.0, and the reaction of L-glufosinate and the dimethylamine aqueous solution is controlled at 0-40°C;

[0014] During the concentration and purification, the solution is concentrated by distillation while removing free dimethylamine to obtain crude L-phosphinothricin dimethylamine, wherein the water content of the crude L-phosphinothricin dimethylamine is controlled at 5-30%;

[0015] The crystallization steps include:

[0016] Step 1: Mixing a solvent that easily forms an azeotrope with water and is heated to 40-70° C. with the crude L-phosphinothionyl dimethylamine obtained after concentration and purification;

[0017] Step 2: Raise the system temperature to 60-90°C and then gradually cool down for crystallization;

[0018] Gradient cooling includes three stages: in the first stage, the temperature is lowered to 50-60°C at a cooling rate of 1-3K between the internal and external temperatures; in the second stage, the temperature is lowered to 15-25°C at a cooling rate of 5-8K between the internal and external temperatures; in the third stage, the temperature is lowered to -5-5°C at a cooling rate of 10-15K between the internal and external temperatures, and stirred until crystals precipitate;

[0019] The material obtained after crystallization is filtered, the filter cake obtained is washed with an organic solvent, and the obtained L-glufosinate dimethylamine salt wet powder is dried to obtain the crystalline form of L-glufosinate ammonium salt.

[0020] Furthermore, the concentration of the dimethylamine aqueous solution is 0-40%, the molar ratio of L-glufosinate ammonium to the dimethylamine aqueous solution is 1:1.1-1:2.0, and the reaction of L-glufosinate ammonium and the dimethylamine aqueous solution is controlled at 10-30°C.

[0021] Furthermore, the solvent that easily forms an azeotrope with water is selected from at least one of acetonitrile, ethanol, isopropanol, ethyl acetate, n-butanol, isopentanol, and n-propanol.

[0022] Furthermore, the water content of the crude L-phosphinothionyl dimethylamine obtained by concentration and purification is controlled at 8-20%.

[0023] Furthermore, the mass ratio of the solvent to the crude L-phosphinothionyl dimethylamine is 1:1-10:1.

[0024] Furthermore, the mass ratio of the solvent to the crude L-phosphinothionyl dimethylamine is 2:1-4:1.

[0025] Furthermore, during crystallization:

[0026] Step 1: Mixing a solvent that easily forms an azeotrope with water and is heated to 50-65° C. with the crude L-phosphinothionyl dimethylamine obtained after concentration and purification;

[0027] Step 2: Raise the system temperature to 75-85°C and then gradually cool it down for crystallization.

[0028] Furthermore, the organic solvent is selected from at least one of acetonitrile, ethanol, isopropanol, ethyl acetate, n-butanol, isopentanol or n-propanol.

[0029] Compared with the prior art, the present invention has the following advantages:

[0030] 1. The crystal form of the L-glufosinate ammonium salt of the present application has been tested and stored for 10 days at a humidity of 65% and room temperature. The mass change is less than 0.5%, there is no obvious hygroscopicity, and the crystal form has no obvious change. At the same time, the crystal form performs well in the stability test, and the crystal structure will not change after long-term storage.

[0031] 2. The L-glufosinate dimethylamine salt crystal form of the present application shows significant characteristic peaks in the X-ray diffraction pattern. By optimizing the coordination ratio and crystallization process, the molar ratio of dimethylamine ion to L-glufosinate in the crystal form is 1:1, which significantly improves the stability of the crystal structure, and the crystal form does not change after long-term storage.

[0032] 3. The crystal form of the L-glufosinate ammonium salt of the present application is more hygroscopic and deliquescent than the traditional L-glufosinate dimethylamine salt. When the relative humidity is >60%, the water absorption amount reaches more than 25%. The equilibrium moisture absorption rate of this crystal form is controlled within 2%, and the dry powder yield is increased to 98.6%.

[0033] 4. The crystalline preparation method of L-glufosinate ammonium salt of the present application achieves precise removal of impurities through low-temperature reaction and staged purification, effectively inhibiting the generation of free amine impurities. Compared with a single concentration crystallization process, the product purity reaches 99.41%. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 The X-ray diffraction pattern of the crystalline form of L-glufosinate prepared in Example 1 of the present application;

[0035] Figure 2 This is a comparative experimental diagram of the hygroscopicity of the L-glufosinate prepared in Example 1 of the present application and comparative examples 1 and 2. DETAILED DESCRIPTION

[0036] The following will be combined with the drawings in the embodiments of this application to clearly and completely describe the technical solutions in the embodiments of this application. Obviously, the embodiments described are only part of the embodiments of this application, not all of the embodiments. Based on the embodiments in this application, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of this application.

[0037] Example 1

[0038] Currently, there are two major technical bottlenecks in the development of other salts of L-glufosinate:

[0039] 1. Strong hygroscopicity makes preparation processing difficult. In an environment with relative humidity greater than 60%, the water absorption can reach more than 25% of its own weight, which can easily cause crystal deliquescence and polymerization of active ingredients;

[0040] 2. The high-purity preparation process is complex. In the conventional synthesis route, incomplete dimethylamine coordination will produce free amine impurities (content > 5%), which not only reduces biological activity but also increases the risk of decomposition during storage. To address these difficulties, this application provides a method for preparing a crystalline form of L-glufosinate ammonium salt, which specifically includes:

[0041] L-glufosinate (55.4 g, 0.3 mol) was added to a dimethylamine aqueous solution (40.57 g, 40%, 0.36 mol). The reaction temperature was controlled within the range of 15±1°C. The mixture was stirred for 3 h and concentrated under reduced pressure to obtain 74.2 g of crude L-glufosinate dimethylamine salt with a moisture content of 10.01%.

[0042] Isopropanol was heated to 65°C, added to the crude L-glufosinate dimethylamine salt, stirred evenly, heated to 82°C, cooled to 60°C at a cooling rate of 2K with an internal and external temperature difference, cooled to 20°C at a cooling rate of 8K with an internal and external temperature difference, cooled to 0°C at a cooling rate of 15K with an internal and external temperature difference, kept warm and stirred for 24 hours, filtered, the filter cake was washed with isopropanol, and dried to obtain 66.85g of L-glufosinate dimethylamine salt product with an HPLC purity of 99.41%, a ratio of L-glufosinate to dimethylamine ion of 1:1.03, and a dry powder yield of 98.6%.

[0043] The L-phosphinothionine dimethylamine salt product obtained in this embodiment was subjected to X-ray powder diffraction test, and the spectrum was as follows: Figure 1 As shown, there are characteristic diffraction peaks at 2θ angles of 10.696±0.2°, 18.34±0.2°, 18.598±0.2°, 20.185±0.2°, 21.893±0.2°, and 32.428±0.2°. The main diffraction peak is located at 10.696±0.2° with a relative intensity of 100%. The relative intensities of all other characteristic peaks are ≤5% based on the main peak intensity. Its X-ray powder diffraction data are shown in Table 1:

[0044] Table 1:

[0045] .

[0046] Example 2

[0047] A method for preparing a crystalline form of L-glufosinate ammonium salt, specifically comprising:

[0048] L-glufosinate (55.4 g, 0.3 mol) was added to a dimethylamine aqueous solution (43.87 g, 40%, 0.39 mol). The reaction temperature was controlled at 20 ± 1°C, stirred for 3 h, and concentrated under reduced pressure to yield 77.05 g of crude L-glufosinate dimethylamine salt with a moisture content of 12%.

[0049] Heat isopropanol to 60°C, add it to the crude L-glufosinate dimethylamine salt, stir evenly, raise the temperature to 83°C, cool it to 55°C at a cooling rate of 1K with an internal and external temperature difference, cool it to 15°C at a cooling rate of 5K with an internal and external temperature difference, cool it to 3°C at a cooling rate of 13K with an internal and external temperature difference, keep warm and stir for 24 hours, filter, rinse the filter cake with isopropanol, and dry to obtain 67.24g of L-glufosinate dimethylamine salt product with HPLC purity of 99.52% and dry powder yield of 98.7%.

[0050] The L-phosphinothionyl dimethylamine salt product obtained in this embodiment was subjected to X-ray powder diffraction test, and the test spectrum was consistent with Figure 1 The results are basically consistent, and the 2θ angle error of each characteristic peak is within 0.2°, confirming that it is the same crystal form as Example 1.

[0051] Example 3

[0052] A method for preparing a crystalline form of L-glufosinate ammonium salt, specifically comprising:

[0053] L-glufosinate (55.4 g, 0.3 mol) was added to a dimethylamine aqueous solution (54 g, 30%, 0.36 mol). The reaction temperature was controlled within the range of 10±1°C. The mixture was stirred for 3 h and concentrated under reduced pressure to obtain 79.76 g of crude L-glufosinate dimethylamine salt with a moisture content of 15%.

[0054] Acetonitrile was heated to 50°C, added to the crude L-glufosinate dimethylamine salt, stirred evenly, heated to 80°C, cooled to 50°C at a cooling rate of 3K with an internal and external temperature difference, cooled to 25°C at a cooling rate of 6K with an internal and external temperature difference, cooled to -2°C at a cooling rate of 10K with an internal and external temperature difference, kept warm and stirred for 24 hours, filtered, and the filter cake was washed with acetonitrile and dried to obtain 66.79 g of L-glufosinate dimethylamine salt product with an HPLC purity of 99.47% and a dry powder yield of 98%.

[0055] The L-phosphinothionine dimethylamine salt product obtained in this embodiment was subjected to X-ray powder diffraction test, and the test spectrum was consistent with Figure 1 The results are basically consistent, and the 2θ angle error of each characteristic peak is within 0.2°, confirming that it is the same crystal form as Example 1.

[0056] Comparative Example 1

[0057] A method for preparing L-glufosinate dimethylamine salt specifically comprises: adding L-glufosinate acid (55.4 g, 0.3 mol) to a dimethylamine aqueous solution (40.57 g, 40%, 0.36 mol), stirring and reacting for 8 hours, rotary evaporation to remove water, and drying to obtain 66.95 g of crude L-glufosinate dimethylamine salt with an HPLC purity of 95.3% and a dry powder yield of 94.1%.

[0058] Comparative Example 2

[0059] A method for preparing an L-glufosinate ammonium salt specifically comprises: referring to the preparation method of Example 3 of patent publication number CN110452264 A, first weighing 50.0 g of 92.0% refined glufosinate ammonium and 125 g of methanol into a four-necked flask and mixing them with each other, adding 40 g of 28% ammonia water, keeping the temperature at 40° C. for 7 hours, filtering and drying to obtain 50.1 g of L-glufosinate ammonium salt product with an HPLC purity of 96.2% and a dry powder yield of 95.8%.

[0060] The L-glufosinate dimethylamine salt products obtained in Examples 1-3 and the L-glufosinate ammonium salt obtained in Comparative Examples 1 and 2 were subjected to hygroscopicity and stability tests: 20 g of each of the L-glufosinate dimethylamine salt products obtained in Examples 1-3 and the L-glufosinate ammonium salt obtained in Comparative Examples 1 and 2 were stored at different temperatures and humidities for 10 days, and their appearances were observed for significant changes to determine whether different crystal forms had hygroscopicity. The mass and crystal form were retested for significant changes to determine their stability. The results are shown in Table 2:

[0061] Table 2:

[0062] .

[0063] Hygroscopicity and stability test results show that the L-glufosinate dimethylamine salt product prepared by the present embodiment 1-3 is stored 10 days under humidity 65%, room temperature, and mass change is all below 0.5%, without obvious hygroscopicity, and crystal formation does not have obvious change, which is conducive to it keeping dry during storage and use, avoids deterioration or activity reduction due to humidity. The crystal formation performs well in stability test, and after long-term storage, crystal structure also can not change. This high stability ensures the lasting effectiveness of L-glufosinate dimethylamine salt in herbicidal drug products.

[0064] like Figure 2 As shown, it can be clearly seen that the L-glufosinate dimethylamine salt product of Example 1 is more stable than the L-glufosinate ammonium salt products obtained in Comparative Examples 1 and 2.

Claims

1. A crystalline form of L-glufosinate ammonium salt, characterized in that: The X-ray diffraction pattern of the crystalline form of L-glufosinate has characteristic peaks at 2θ angles of 10.241±0.2°, 10.696±0.2° and 32.428±0.2°, and contains at least one characteristic peak at 2θ of 18.34±0.2°, 18.598±0.2°, 20.185±0.2° or 21.893±0.2°. The L-glufosinate is L-glufosinate dimethylamine salt.

2. A crystalline form of L-glufosinate-ammonium salt according to claim 1, characterized in that: The X-ray diffraction pattern of the crystalline form of L-glufosinate salt comprises at least three characteristic peaks in 2θ of 14.168±0.2°, 18.34±0.2°, 18.598±0.2°, 19.527±0.2°, 20.185±0.2°, 21.457±0.2°, 21.673±0.2°, 21.893±0.2°, 23.461±0.2°, 24.031±0.2°, 25.164±0.2°, 27.487±0.2°, 28.162±0.2°, 28.541±0.2°, 30.528±0.2°, 31.631±0.2°, 33.8±0.2° and 37.784±0.2°.

3. A crystalline form of L-glufosinate-ammonium salt according to claim 1 or 2, characterized in that: The 2θ angle of the main diffraction peak of the crystalline form of L-glufosinate ammonium salt is 10.696°±0.2°, and the relative intensities of all other characteristic peaks are ≤5% based on the main peak intensity.

4. A crystalline form of L-glufosinate-ammonium salt according to claim 1 or 2, characterized in that: The X-ray diffraction pattern of the crystalline form of L-glufosinate ammonium salt is shown in FIG1 .

5. A method for preparing a crystal form of L-glufosinate ammonium salt, for preparing the crystal form of L-glufosinate ammonium salt according to any one of claims 1 to 4, characterized in that: After L-glufosinate-ammonium reacts with a dimethylamine aqueous solution, the solution is concentrated, purified, crystallized, separated and dried to obtain a crystalline form of L-glufosinate-ammonium salt.

6. The method for preparing a crystalline form of L-glufosinate-ammonium salt according to claim 5, wherein: The purity of L-glufosinate is at least 98%, the concentration of the dimethylamine aqueous solution is 10-40%, the molar ratio of L-glufosinate to the dimethylamine aqueous solution is 1:1.05-1:10.0, and the reaction of L-glufosinate and the dimethylamine aqueous solution is controlled at 0-40°C.

7. The method for preparing a crystalline form of L-glufosinate-ammonium salt according to claim 5 or 6, wherein: During the concentration and purification, the solution is concentrated by distillation while removing free dimethylamine to obtain crude L-phosphinothricin dimethylamine. The water content of the crude L-phosphinothricin dimethylamine is controlled at 5-30%.

8. The method for preparing a crystalline form of L-glufosinate-ammonium salt according to claim 5 or 6, wherein: The crystallization steps include: Step 1: Mixing a solvent that easily forms an azeotrope with water and is heated to 40-70° C. with the crude L-phosphinothionyl dimethylamine obtained after concentration and purification; Step 2: Raise the system temperature to 60-90°C and then perform gradient cooling and crystallization; the gradient cooling includes three stages: in the first stage, the temperature is cooled at a cooling rate of 1-3K with an internal and external temperature difference of 5-8K to 15-25°C; in the third stage, the temperature is cooled at a cooling rate of 10-15K with an internal and external temperature difference of 10-15K to -5-5°C, and stirred until crystals precipitate.

9. The method for preparing a crystalline form of L-glufosinate-ammonium salt according to claim 5 or 6, characterized in that: The material obtained after crystallization is filtered, the filter cake obtained is washed with an organic solvent, and the obtained L-glufosinate dimethylamine salt wet powder is dried to obtain the crystalline form of L-glufosinate ammonium salt.

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