Crystal form of L-glufosinate-ammonium salt and preparation method thereof

Abstract

The invention discloses a crystal form of L-glufosinate-ammonium salt and a preparation method thereof, an X-ray diffraction pattern of the crystal form of L-glufosinate-ammonium salt comprises at least one characteristic peak in 2theta of 10.696 + / -0.2 degrees, 18.34 + / -0.2 degrees, 18.598 + / -0.2 degrees, 20.185 + / -0.2 degrees, 21.893 + / -0.2 degrees and 32.428 + / -0.2 degrees, and tests show that the crystal form of L-glufosinate-ammonium salt is stored for 10 days under the conditions of humidity of 65% and room temperature, the mass change is below 0.5%, and the crystal form of L-glufosinate-ammonium salt can be used as a crystal form of L-glufosinate-ammonium salt. The compound has no obvious hygroscopicity and no obvious change in crystal form, so that the compound can be kept dry in the storage and use processes, and deterioration or activity reduction caused by humidity is avoided. Meanwhile, the crystal form is excellent in performance in a stability test, and the structure of the crystal form is not changed after long-time storage. The high stability ensures the lasting effect of the crystal form of the L-glufosinate-ammonium salt in herbicidal drug products.

Description

Technical Field

[0001] This application relates to the technical field of pesticides, and specifically to a crystal form of L-glufosinate salt and a preparation method thereof. Background Art

[0002] As an organophosphorus non-selective herbicide, L-glufosinate has the characteristics of high efficiency, low toxicity and environmental friendliness, and shows great application potential in modern agriculture. Compared with the traditional glufosinate containing a mixture of L- and D-isomers, only the L-configuration has herbicidal activity. Its herbicidal efficiency is doubled, so that the field application rate can be reduced by 50%, significantly reducing the residue of ineffective components and the ecological load, which is of great significance for reducing agricultural production costs and alleviating the pressure on the environment.

[0003] At present, the mainstream product L-glufosinate ammonium salt on the market dominates due to its environmental compatibility and high-efficiency herbicidal characteristics. However, L-glufosinate ammonium salt has poor hygroscopicity and stability. Therefore, L-glufosinate ammonium salt crystals with strong hygroscopicity and stability and easy to store are highly anticipated by the market. It will promote the development of new salt-type herbicides towards high efficiency and precision, and provide 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 salt and a preparation method thereof, which is a crystal form of L-glufosinate salt with strong hygroscopicity and better stability.

[0005] To achieve the above purpose, this application provides the following technical solution: A crystal form of L-glufosinate salt, the X-ray diffraction pattern of the crystal form of L-glufosinate salt includes at least one characteristic peak of 2θ at 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 includes at least three peaks.

[0006] After testing, the crystal form of this L-glufosinate salt is stored for 10 days at a humidity of 65% and room temperature, and the mass change is below 0.5%, without obvious hygroscopicity, and the crystal form does not change significantly. This is beneficial to keeping it dry during storage and use, and avoiding deterioration or reduction of activity caused by humidity. At the same time, this crystal form shows excellent performance in the stability test. After long-term storage, the crystal structure will not change. This high stability ensures the long-lasting efficacy of the crystal form of L-glufosinate salt in herbicidal drug products.

[0007] At present, the research and development of other salt forms of L-glufosinate, such as isopropylamine salt, dimethylamine salt, and sodium salt, is still in the stage of technical breakthroughs, and there are relatively few reports. Compared with the ammonium salt system, L-glufosinate dimethylamine salt shows significant advantages in solubility and chemical stability. The strong polar characteristics of the dimethylamine group in its molecular structure can increase water solubility by more than 40%, which is of great value for improving the persistence of herbicide efficacy in complex field environments. Therefore, further, the L-glufosinate salt of this application is L-glufosinate dimethylamine salt.

[0008] Further, the X-ray diffraction pattern of the crystal form of the L-glufosinate salt contains at least three characteristic peaks in 2θ of 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°, 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 this form contains at least six peaks.

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

[0011] This application also provides a method for preparing the crystal form of the L-glufosinate salt, which is used to prepare the crystal form of the L-glufosinate salt as described above, including: reacting L-glufosinate acid with an aqueous dimethylamine solution, and after the solution is concentrated, purified, crystallized, and separated and dried, the crystal form of the L-glufosinate salt is obtained. Precise removal of impurities is achieved through preliminary purification by water removal → solvent crystallization → azeotropic water removal and impurity removal; Among them, the L-glufosinate acid raw material can be L-glufosinate acid prepared by conventional methods in the art. The purity of L-glufosinate acid reaches more than 98%, and it can be used for the above reaction; The concentration of the aqueous dimethylamine solution is 10-40%, the molar ratio of L-glufosinate acid to the aqueous dimethylamine solution is 1:1.05-1:10.0, and the reaction of L-glufosinate acid with the aqueous dimethylamine solution is controlled at 0-40°C; During concentration and purification, the solution is concentrated by distillation while removing free dimethylamine to obtain the crude L-glufosinate dimethylamine, and the water content of the crude L-glufosinate dimethylamine is controlled at 5-30%; The crystallization steps include: Step 1: Mix the solvent that is easy to form an azeotrope with water and whose temperature is raised to 40 - 70°C with the crude L - glufosinate - dimethylamine obtained after concentration and purification; Step 2: Raise the temperature of the system to 60 - 90°C and then cool it down for crystallization in a gradient manner; The gradient cooling includes three stages. In the first stage, cool down at a cooling rate with a temperature difference of 1 - 3K between the inside and outside, and cool down to 50 - 60°C. In the second stage, cool down at a cooling rate with a temperature difference of 5 - 8K between the inside and outside, and cool down to 15 - 25°C. In the third stage, cool down at a cooling rate with a temperature difference of 10 - 15K between the inside and outside, and cool down to - 5 - 5°C, and stir until crystals precipitate; Filter the material obtained after crystallization, wash the obtained filter cake with an organic solvent, and dry the obtained wet powder of L - glufosinate - dimethylamine salt to obtain the crystal form of L - glufosinate salt.

[0012] Furthermore, the concentration of the dimethylamine aqueous solution is 0 - 40%, the molar ratio of L - glufosinate acid to the dimethylamine aqueous solution is 1:1.1 - 1:2.0, and the reaction of L - glufosinate acid with the dimethylamine aqueous solution is controlled at 10 - 30°C.

[0013] Furthermore, the solvent that is easy to form an azeotrope with water is selected from at least one of acetonitrile, ethanol, isopropanol, ethyl acetate, n - butanol, iso - pentanol, and n - propanol.

[0014] Furthermore, the water content of the crude L - glufosinate - dimethylamine obtained after concentration and purification is controlled at 8 - 20%.

[0015] Furthermore, the mass ratio of the solvent to the crude L - glufosinate - dimethylamine is 1:1 - 10:1.

[0016] Furthermore, the mass ratio of the solvent to the crude L - glufosinate - dimethylamine is 2:1 - 4:1.

[0017] Furthermore, during crystallization: Step 1: Mix the solvent that is easy to form an azeotrope with water and whose temperature is raised to 50 - 65°C with the crude L - glufosinate - dimethylamine obtained after concentration and purification; Step 2: Raise the temperature of the system to 75 - 85°C and then cool it down for crystallization in a gradient manner.

[0018] Furthermore, the organic solvent is selected from at least one of acetonitrile, ethanol, isopropanol, ethyl acetate, n - butanol, iso - pentanol, or n - propanol.

[0019] Compared with the prior art, the beneficial effects of this application are: 1. The crystal form of the L-glufosinate salt of the present application was tested. When stored at a humidity of 65% and room temperature for 10 days, the mass change was less than 0.5%, there was no obvious hygroscopicity, and the crystal form did not change significantly. At the same time, this crystal form performed excellently in the stability test, and the crystal structure would not change after long-term storage.

[0020] 2. The crystal form of the L-glufosinate dimethylamine salt of the present application showed significant characteristic peaks in the X-ray diffraction pattern. By optimizing the coordination ratio and crystallization process, the molar ratio of dimethylamine ions to L-glufosinate in the crystal form was 1:1, significantly improving the stability of the crystal structure, and the crystal form did not change after long-term storage.

[0021] 3. The crystal form of the L-glufosinate salt of the present application is more prone to hygroscopic deliquescence compared with the traditional L-glufosinate dimethylamine salt. When the relative humidity > 60%, the water absorption 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%.

[0022] 4. The preparation method of the crystal form of the L-glufosinate salt of the present application realizes the precise removal of impurities through low-temperature reaction and staged purification, effectively inhibiting the generation of free amine impurities. Compared with the single concentration crystallization process, the product purity reaches 99.41%. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 It is the X-ray diffraction pattern of the crystal form of the L-glufosinate salt prepared in Example 1 of the present application; Figure 2 It is the hygroscopicity comparison experimental chart of the L-glufosinate salt prepared in Example 1 of the present application, Comparative Example 1 and Comparative Example 2. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0024] Next, the technical solutions in the embodiments of the present application will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present application.

[0025] Example 1

[0026] Currently, there are two major technical bottlenecks in other salt forms of L-glufosinate: 1. Strong hygroscopicity leads to difficult formulation processing. In an environment with a relative humidity > 60%, the water absorption can reach more than 25% of its own mass, easily causing crystal deliquescence and polymerization of active ingredients; 2. The high-purity preparation process is complex. In the conventional synthesis route, incomplete coordination of dimethylamine will generate free amine impurities (content > 5%), which not only reduces the biological activity but also increases the decomposition risk during the storage period. To address these problems, the present application provides a method for preparing a crystal form of L-glufosinate-ammonium salt, which specifically includes: Add L-glufosinate acid (55.4 g, 0.3 mol) to an aqueous solution of dimethylamine (40.57 g, 40%, 0.36 mol), control the reaction temperature in the range of 15 ± 1 °C, keep stirring for 3 h, and concentrate under reduced pressure to obtain 74.2 g of crude L-glufosinate dimethylamine salt with a water content of 10.01%.

[0027] Heat isopropanol to 65 °C, add it to the crude L-glufosinate dimethylamine salt, stir evenly, raise the temperature to 82 °C, cool down to 60 °C at a cooling rate with an internal and external temperature difference of 2 K, cool down to 20 °C at a cooling rate with an internal and external temperature difference of 8 K, cool down to 0 °C at a cooling rate with an internal and external temperature difference of 15 K, keep stirring for 24 h, filter, wash the filter cake with isopropanol, and dry to obtain 66.85 g of L-glufosinate dimethylamine salt product with an HPLC purity of 99.41%, a ratio of L-glufosinate to dimethylamine ions of 1:1.03, and a dry powder yield of 98.6%.

[0028] Perform X-ray powder diffraction test on the L-glufosinate dimethylamine salt product obtained in this example. The spectrum is as Figure 1 shown, and it has 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%, and the relative intensities of all other characteristic peaks are ≤ 5% based on the intensity of the main peak. The X-ray powder diffraction data is shown in Table 1: Table 1: .

[0029] Example 2

[0030] A method for preparing a crystal form of L-glufosinate-ammonium salt, which specifically includes: Add L-glufosinate acid (55.4 g, 0.3 mol) to an aqueous solution of dimethylamine (43.87 g, 40%, 0.39 mol), control the reaction temperature in the range of 20 ± 1 °C, keep stirring for 3 h, and concentrate under reduced pressure to obtain 77.05 g of crude L-glufosinate dimethylamine salt with a water content of 12%. Heat isopropanol to 60 °C, add it to the crude product of L-glufosinate dimethylamine salt, stir evenly, heat up to 83 °C, cool down to 55 °C at a cooling rate with an internal-external temperature difference of 1 K, cool down to 15 °C at a cooling rate with an internal-external temperature difference of 5 K, cool down to 3 °C at a cooling rate with an internal-external temperature difference of 13 K, keep warm and stir for 24 h, filter, wash the filter cake with isopropanol, and dry to obtain 67.24 g of L-glufosinate dimethylamine salt product, with an HPLC purity of 99.52% and a dry powder yield of 98.7%.

[0031] Perform X-ray powder diffraction test on the L-glufosinate dimethylamine salt product obtained in this example. The test spectrum is Figure 1 Basically the same, and the 2θ angle error of each characteristic peak is within 0.2°, confirming that it has the same crystal form as Example 1.

[0032] Example 3

[0033] A preparation method of a crystal form of L-glufosinate salt, specifically including: Add L-glufosinate acid (55.4 g, 0.3 mol) to aqueous dimethylamine solution (54 g, 30%, 0.36 mol), control the reaction temperature in the range of 10 ± 1 °C, keep warm and stir for 3 h, and concentrate under reduced pressure to obtain 79.76 g of crude L-glufosinate dimethylamine salt, with a water content of 15%.

[0034] Heat acetonitrile to 50 °C, add it to the crude product of L-glufosinate dimethylamine salt, stir evenly, heat up to 80 °C, cool down to 50 °C at a cooling rate with an internal-external temperature difference of 3 K, cool down to 25 °C at a cooling rate with an internal-external temperature difference of 6 K, cool down to -2 °C at a cooling rate with an internal-external temperature difference of 10 K, keep warm and stir for 24 h, filter, wash the filter cake with acetonitrile, and dry 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%.

[0035] Perform X-ray powder diffraction test on the L-glufosinate dimethylamine salt product obtained in this example. The test spectrum is Figure 1 Basically the same, and the 2θ angle error of each characteristic peak is within 0.2°, confirming that it has the same crystal form as Example 1.

[0036] Comparative Example 1 A preparation method of L-glufosinate dimethylamine salt, specifically including: Add L-glufosinate acid (55.4 g, 0.3 mol) to aqueous dimethylamine solution (40.57 g, 40%, 0.36 mol), stir and react for 8 h, remove water by rotary evaporation, and dry 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%.

[0037] Comparative Example 2 A method for preparing L-glufosinate ammonium salt specifically comprises: referring to the preparation method of patent example 3 with 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 warm at 40° C. for 7 h, filtering and drying to obtain 50.1 g of L-glufosinate ammonium salt product, with HPLC purity of 96.2% and dry powder yield of 95.8%.

[0038] 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 tested for hygroscopicity and stability: 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 appearance was observed for obvious changes to determine whether different crystal forms were hygroscopic, and their mass and crystal form were retested for obvious changes to determine their stability. The results are shown in Table 2: Table 2: .

[0039] Hygroscopicity and stability test results show that the L-phosphinothionine dimethylamine salt product prepared by the present embodiment 1-3 is stored for 10 days under humidity 65% ​​and room temperature, and the mass change is all below 0.5%, without obvious hygroscopicity, and the crystal formation has no obvious change, which is conducive to keeping it dry during storage and use, avoiding deterioration or activity reduction due to humidity. The crystal formation performs well in stability test, and after long-term storage, the crystal structure will not change. This high stability ensures the lasting effectiveness of L-phosphinothionine dimethylamine salt in herbicidal drug products.

[0040] like Figure 2 As shown, it can be clearly seen that the L-glufosinate dimethylamine salt product of Example 1 has better stability than the L-glufosinate ammonium salt products obtained in Comparative Examples 1 and 2.

Claims

1. A crystal form of L-glufosinate salt, characterized in that: The X-ray diffraction pattern of the crystal form of L-glufosinate salt contains at least one characteristic peak at 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°.

2. The crystalline form of an L-glufosinate salt according to claim 1, characterized in that: The L-glufosinate salt is L-glufosinate dimethylamine salt.

3. The crystalline form of an L-glufosinate salt according to claim 1 or 2, characterized in that: The X-ray diffraction pattern of the crystal form of L-glufosinate salt contains at least three characteristic peaks at 2θ of 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°, 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°.

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

5. The crystalline form of an L-glufosinate salt according to claim 1 or 2, characterized in that: The X-ray diffraction pattern of the crystal form of L-glufosinate salt is shown in Figure 1.

6. A method for preparing a crystal form of L-glufosinate salt, which is used to prepare the crystal form of L-glufosinate salt as described in any one of claims 1-5, and is characterized in that: After reacting L-glufosinate acid with an aqueous dimethylamine solution, the solution is concentrated, purified, crystallized, and separated and dried to obtain the crystal form of L-glufosinate salt.

7. The method for preparing the crystal form of L-glufosinate salt according to claim 6, characterized in that: The purity of L-glufosinate acid is at least 98%, the concentration of the aqueous dimethylamine solution is 10-40%, the molar ratio of L-glufosinate acid to the aqueous dimethylamine solution is 1:1.05-1:10.0, and the reaction of L-glufosinate acid with the aqueous dimethylamine solution is controlled at 0-40°C.

8. A method for preparing a crystal form of L-glufosinate salt according to claim 6 or 7, characterized in that: During concentration and purification, the solution is concentrated by distillation while removing free dimethylamine to obtain crude L-glufosinate dimethylamine, and the water content of the crude L-glufosinate dimethylamine is controlled at 5-30%.

9. The method for preparing a crystal form of L-glufosinate salt according to claim 6 or 7, characterized in that: The crystallization step includes: Step 1: Mix the crude L-glufosinate dimethylamine obtained after concentration and purification with a solvent that is easy to form an azeotrope with water and whose temperature is raised to 40-70°C. Step 2: Raise the temperature of the system to 60-90°C and then cool it down stepwise for crystallization. The stepwise cooling includes three stages. In the first stage, the temperature is decreased at a cooling rate with an internal-external temperature difference of 1-3K until it reaches 50-60°C. In the second stage, the temperature is decreased at a cooling rate with an internal-external temperature difference of 5-8K until it reaches 15-25°C. In the third stage, the temperature is decreased at a cooling rate with an internal-external temperature difference of 10-15K until it reaches -5-5°C, and stirring is continued until crystals precipitate.

10. A method for preparing a crystal form of L-glufosinate salt according to claim 6 or 7, characterized in that: Filter the material obtained after crystallization, wash the resulting filter cake with an organic solvent, and dry the obtained wet powder of L-glufosinate dimethylamine salt to obtain the crystal form of L-glufosinate salt.

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