Preparation method and application of nicosulfuron Ia crystal form

Abstract

The invention provides a preparation method and application of a nicosulfuron Ia crystal form, and the preparation method comprises the following steps: mixing and stirring a nicosulfuron raw material and an alcoholic solution, and then cooling and filtering to obtain the nicosulfuron Ia crystal form, the nicosulfuron raw material is a product prepared from nicosulfuron or a nicosulfuron active compound. According to the preparation method provided by the invention, the crystal form conversion time is remarkably shortened, the purpose of rapidly preparing the stable crystal form of the nicosulfuron is achieved, additional equipment and facilities do not need to be added, only an original crystallization device needs to be used, the production cost is controlled, and the preparation method is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of pesticide production, and particularly relates to a preparation method of a nicosulfuron Ia crystal form and application thereof. Background Art

[0002] Nicosulfuron is a highly effective, low-toxic sulfonylurea herbicide developed jointly by Ishihara Sangyo Co., Ltd. of Japan and DuPont of the United States for use as a cornfield herbicide. Its pure form is white crystals, and its chemical name is 2-(4,6-dimethoxypyrimidin-2-ylcarbamoylaminosulfonyl)-N,N-dimethylnicotinamide (Nicosulfuron). This sulfonylurea herbicide disrupts the plant's internal structure and physiological balance, inhibiting acetolactate synthase and preventing the synthesis of branched-chain amino acids, which in turn prevents cell division. This prevents sensitive plants from growing normally and eventually causing them to wither and die.

[0003] Currently, the main crystalline forms of nicosulfuron include Forms Ia, II, III, IV, V, and VI, as well as some common solvates. Form Ia is the most common crystalline form of nicosulfuron, exhibiting high thermal and physical stability, making it suitable for long-term storage and processing. However, existing methods for preparing Form Ia of nicosulfuron suffer from complex processes and long production cycles, limiting its industrial application.

[0004] CN111362921A discloses a nicosulfuron crystal form and a preparation method thereof. The nicosulfuron crystal form has an X-ray powder diffraction pattern with reflection angles 2θ of 12.4°±0.2°, 14.1°±0.2°, 15.4°±0.2°, 16.9°±0.2°, 18.3°±0.2°, 18.7°±0.2°, 21.8°±0.2°, 23.9°±0.2°, 24.7°±0.2°, and 25.5°±0.2°. The preparation method comprises: first, recrystallization using acetonitrile, and then water removal using toluene. The crystal form prepared using this method is not easily hygroscopic. Using this crystal form as a standard sample can ensure that the standard sample content used remains unchanged within six months, enabling accurate calibration of the product content and ensuring the stability and accuracy of the nicosulfuron product detection system. The preparation method is scientific, reasonable, simple, and easy to implement.

[0005] CN108299392A discloses a nicosulfuron crystal form and its preparation method. Its DSC spectrum exhibits a characteristic endothermic peak at 187±2°C. The crystal form is prepared using a constant-temperature suspension crystallization method. Crude nicosulfuron is added to ethanol at a mass ratio of nicosulfuron to the ethanol solvent of 0.12-0.17. The constant-temperature suspension crystallization temperature is 40-50°C, and the crystals are stirred for 36-48 hours to form a white solid. The product is filtered while hot and dried to obtain nicosulfuron crystals. The product has well-grown blocky crystal habits, good fluidity, and is not prone to agglomeration. It has a high bulk density of 0.6421 g / mL and an angle of repose of 24°. This method facilitates production operations such as formulation and filtration, and solves the problem of existing needle-shaped crystal habits that are prone to agglomeration and difficult to formulate.

[0006] CN110330480A discloses a nicosulfuron crystalline hydrate and its preparation method and application. The nicosulfuron crystalline hydrate no longer absorbs moisture in the air, has good stability, is easy to dry and subsequently process, and has high chemical purity, uniform particle size distribution, good dispersibility, good stability of subsequent processed preparations, fast disintegration rate, high biological activity, and obvious quality advantages. During the drying, crushing, packaging and downstream processing of the preparation in the production workshop, the material does not absorb moisture and become sticky, which is conducive to clean production and uniform preparation ingredients. It also has the advantages of a simple production process, high yield, and low cost.

[0007] However, none of the above methods involve the preparation of Form Ia of nicosulfuron, nor do they address the problems existing in the prior art preparation of Form Ia. Therefore, current industrial production urgently needs to find a new method for preparing the stable Form Ia of nicosulfuron with simple steps and short reaction time. Summary of the Invention

[0008] In response to the shortcomings of the prior art, the present invention aims to provide a method for preparing the nicosulfuron Ia crystal form and its application. The preparation method provided by the present invention significantly shortens the crystal form conversion time, achieving the goal of rapidly preparing a stable nicosulfuron crystal form. It does not require additional equipment or facilities, requiring only the original crystallization apparatus, thus controlling production costs and making it suitable for industrial production.

[0009] In order to achieve the purpose of the invention, the present invention adopts the following technical solutions:

[0010] In one aspect, the present invention provides a method for preparing nicosulfuron Ia crystal form, the preparation method comprising the following steps:

[0011] The nicosulfuron raw material and the alcohol solution are mixed and stirred, and then cooled and filtered to obtain the nicosulfuron Ia crystal form;

[0012] The nicosulfuron raw material is a nicosulfuron preparation product or a nicosulfuron technical.

[0013] The method provided by the present invention can significantly shorten the crystal form conversion time by using alcohol solution treatment, thereby achieving the purpose of quickly preparing a stable crystal form of nicosulfuron. No additional equipment or facilities are required, and only the original crystallization device needs to be used, thereby controlling production costs and being suitable for industrial production.

[0014] Preferably, the preparation method of the nicosulfuron preparation product comprises:

[0015] Pyrimidinamine and ((3-(N,N-dimethylaminocarbonyl)-2-pyridyl)sulfonamido)phenyl formate (hereinafter referred to as phenyl ester) are mixed and reacted to obtain the nicosulfuron preparation product.

[0016] Preferably, the nicosulfuron raw material is nicosulfuron technical, and before the nicosulfuron raw material is mixed with the alcohol solution, the nicosulfuron raw material is further mixed with phenol and a solvent, and then the solvent is removed.

[0017] Preferably, the molar ratio of the nicosulfuron technical and phenol is (0.8-1.2): (0.8-1.2), wherein the number of parts of the nicosulfuron technical can be 0.8, 0.9, 1, 1.1 or 1.2, etc., and the number of parts of phenol can be 0.8, 0.9, 1, 1.1 or 1.2, etc., but are not limited to the values listed above. Other values not listed within the above numerical range are also applicable.

[0018] Preferably, the mass ratio of the nicosulfuron raw material to the alcohol solution is 1:(1-3), such as 1:1, 1:1.5, 1:2, 1:2.5 or 1:3, etc., but is not limited to the above values. Other values not listed within the above numerical range are also applicable.

[0019] Preferably, the alcohol solution comprises any one of anhydrous ethanol, anhydrous methanol, an ethanol aqueous solution or a methanol aqueous solution, or a combination of at least two thereof, preferably anhydrous ethanol.

[0020] Preferably, the mixing and stirring time is 1 min-2 h, for example, 1 min, 5 min, 10 min, 0.5 h, 1 h, 1.5 h or 2 h, but is not limited to the values listed above. Other values not listed within the above numerical range are also applicable.

[0021] Preferably, the mixing and stirring time is 1-2 minutes.

[0022] The method provided by the present invention can achieve the preparation of Form Ia in a very short time by controlling the stirring time.

[0023] Preferably, the mixing temperature is 25-60°C, for example, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C or 60°C, but is not limited to the values listed above. Other values not listed within the above numerical range are also applicable.

[0024] The above-mentioned specific parameters and reagent selection can further improve the yield and purity of the obtained nicosulfuron Ia crystal form and enhance the effectiveness of the method.

[0025] On the other hand, the present invention also provides the use of the preparation method of the above-mentioned nicosulfuron Ia crystal form in the preparation of nicosulfuron.

[0026] Compared with the prior art, the present invention has the following beneficial effects:

[0027] The present invention provides a method for preparing a nicosulfuron Ia crystal form. By using an alcohol solution for treatment, the crystal form conversion time can be significantly shortened, thereby achieving the purpose of rapidly preparing a stable nicosulfuron crystal form. No additional equipment or facilities are required, and only the original crystallization device needs to be used, thereby controlling production costs and being suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 is the X-ray diffraction pattern of the product of Example 1;

[0029] Figure 2 is the X-ray diffraction pattern of the product of Example 6;

[0030] Figure 3 This is an electron microscope image of the product of Example 1. DETAILED DESCRIPTION

[0031] The technical solution of the present invention is further described below by way of specific embodiments. It should be understood by those skilled in the art that the embodiments are merely to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0032] Example 1

[0033] This embodiment provides a method for rapidly preparing the stable crystalline form Ia of nicosulfuron, the method comprising the following steps:

[0034] 25 g of pyrimidineamine and 50 g of phenyl ester were subjected to a condensation reaction in 200 g of dichloromethane at 50° C.; after the reaction, the dichloromethane solvent was removed by a combination of evaporative crystallization and reduced pressure distillation to obtain a crude nicosulfuron product; the crude nicosulfuron product was added to 60° C. ethanol in a mass ratio of nicosulfuron:ethanol = 1:3, and stirred for 2 minutes; after washing, the material was rapidly cooled, filtered, washed, and dried to obtain a crystalline form Ia product with a product mass of 50.5 g, a yield of 86%, and a crystalline form Ia content of 95%. The diffraction angle 2θ of the X-ray powder diffraction pattern of the crystalline form has characteristic peaks at 5.8°, 7.0°, 8.4°, 9.1°, 11.5°, 12.3°, 14.1°, 15.4°, 16.9°, 18.3°, 18.6°, 19.3°, 20.3°, 21.8°, 23.3°, 24.0°, 24.7°, 25.4°, 25.9°, 26.6°, 27.0°, 27.5°, and 28.5°, which is consistent with the results of the present invention. Figure 1 consistent; the crystal shape is a cuboid, Figure 3 The results were consistent, confirming that the obtained product was nicosulfuron crystal form Ia crystal.

[0035] Example 2

[0036] This embodiment provides a method for rapidly preparing the stable crystalline form Ia of nicosulfuron, the method comprising the following steps:

[0037] 25 g of pyrimidineamine and 50 g of phenyl ester were subjected to a condensation reaction in 200 g of dichloromethane at 50° C.; after the reaction, the dichloromethane solvent was removed by a combination of evaporative crystallization and reduced pressure distillation to obtain a crude nicosulfuron product; the crude nicosulfuron product was added to 60° C. ethanol in a mass ratio of nicosulfuron:ethanol = 1:1 and stirred for 2 minutes; after washing, the product was rapidly cooled, filtered, washed, and dried to obtain a crystalline form Ia product with a product mass of 52.8 g, a yield of 90%, and a crystalline form Ia content of 75%. The diffraction angle 2θ of the X-ray powder diffraction pattern of the crystalline form has characteristic peaks at 5.8°, 7.0°, 8.4°, 9.1°, 11.5°, 12.3°, 14.1°, 15.4°, 16.9°, 18.3°, 18.6°, 19.3°, 20.3°, 21.8°, 23.3°, 24.0°, 24.7°, 25.4°, 25.9°, 26.6°, 27.0°, 27.5°, and 28.5°, which is consistent with the results of the present invention. Figure 1 consistent; the crystal shape is a cuboid, Figure 3 The results were consistent, confirming that the obtained product was nicosulfuron crystal form Ia crystal.

[0038] Example 3

[0039] This embodiment provides a method for rapidly preparing the stable crystalline form Ia of nicosulfuron, the method comprising the following steps:

[0040] 25 g of pyrimidineamine and 50 g of phenyl ester were subjected to a condensation reaction in 200 g of dichloromethane at 50° C.; after the reaction, the dichloromethane solvent was removed by a combination of evaporative crystallization and reduced pressure distillation to obtain a crude nicosulfuron product; the crude nicosulfuron product was added to 25° C. ethanol in a mass ratio of nicosulfuron:ethanol = 1:3 and stirred for 0.5 h; after washing, the material was rapidly cooled, filtered, washed, and dried to obtain a crystalline form Ia product with a product mass of 51.1 g, a yield of 87%, and a crystalline form Ia content of 80%. The diffraction angle 2θ of the X-ray powder diffraction pattern of the crystalline form has characteristic peaks at 5.8°, 7.0°, 8.4°, 9.1°, 11.5°, 12.3°, 14.1°, 15.4°, 16.9°, 18.3°, 18.6°, 19.3°, 20.3°, 21.8°, 23.3°, 24.0°, 24.7°, 25.4°, 25.9°, 26.6°, 27.0°, 27.5°, and 28.5°, which is consistent with the results of the present invention. Figure 1 consistent; the crystal shape is a cuboid, Figure 3 The results were consistent, confirming that the obtained product was nicosulfuron crystal form Ia crystal.

[0041] Example 4

[0042] This embodiment provides a method for rapidly preparing the stable crystalline form Ia of nicosulfuron, the method comprising the following steps:

[0043] 41 g of nicosulfuron technical and 10 g of phenol were dissolved in 180 g of dichloromethane; the dichloromethane solvent was removed by a combination of evaporative crystallization and reduced pressure distillation to obtain a crude nicosulfuron product; the crude nicosulfuron product was added to 25° C. ethanol in a mass ratio of 1:3 and stirred for 0.5 h; after washing, the material was rapidly cooled, filtered, washed, and dried to obtain a crystalline form Ia product with a product mass of 35.7 g, a yield of 87%, and a crystalline form Ia content of 80%. The diffraction angle 2θ of the X-ray powder diffraction pattern of the crystalline form has characteristic peaks at 5.8°, 7.0°, 8.4°, 9.1°, 11.5°, 12.3°, 14.1°, 15.4°, 16.9°, 18.3°, 18.6°, 19.3°, 20.3°, 21.8°, 23.3°, 24.0°, 24.7°, 25.4°, 25.9°, 26.6°, 27.0°, 27.5°, and 28.5°, which is consistent with the results of the present invention. Figure 1 consistent; the crystal shape is a cuboid, Figure 3 The results were consistent, confirming that the obtained product was nicosulfuron crystal form Ia crystal.

[0044] Example 5

[0045] This example provides a method for rapidly preparing the stable crystalline form Ia of nicosulfuron. The method is consistent with Example 3 except that ethanol is replaced with an equal amount of isopropanol in step (3).

[0046] The final product yield was 81%, and the content of Form Ia was 85%.

[0047] Example 6

[0048] This example provides a method for rapidly preparing the stable crystalline form Ia of nicosulfuron. The method is consistent with Example 3 except that ethanol is replaced with an equal amount of 80% ethanol aqueous solution in step (3).

[0049] Finally, the crystal form IV product was obtained with a mass of 51.1 g and a yield of 87%, without the crystal form Ia. The X-ray powder diffraction pattern of this crystal form has characteristic peaks at diffraction angles 2θ of 6.3°, 10.0°, 12.6°, 13.1°, 13.9°, 15.2°, 19.7°, 20.2°, 22.3°, 23.1°, 25.4°, 27.1°, 27.8°, and 31.0°, which are consistent with the results of the present invention. Figure 2 The results were consistent, confirming that the obtained product was nicosulfuron form IV crystal.

[0050] Example 7

[0051] This example provides a method for rapidly preparing the stable crystalline form Ia of nicosulfuron. The method is consistent with Example 3 except that ethanol is replaced with an equal amount of methanol in step (3).

[0052] The final product mass was 52.8 g, the yield was 92%, and there was no Ia crystal form. The X-ray powder diffraction pattern of this crystal form had characteristic peaks at diffraction angles 2θ of 6.3°, 10.0°, 12.6°, 13.1°, 13.9°, 15.2°, 19.7°, 20.2°, 22.3°, 23.1°, 25.4°, 27.1°, 27.8°, and 31.0°, which were consistent with the results of the present invention. Figure 2 The results were consistent, confirming that the obtained product was nicosulfuron form IV crystal.

[0053] Example 8

[0054] This example provides a method for rapidly preparing a stable crystalline form Ia of nicosulfuron. The method is consistent with Example 4 except that phenol is replaced with an equal mole of resorcinol in step (1).

[0055] The final product yield was 70%, and the content of Form Ia was 75%.

[0056] Example 9

[0057] This example provides a method for rapidly preparing the stable crystalline form Ia of nicosulfuron. The method is consistent with Example 4 except that phenol is replaced with an equal mole of o-cresol in step (1).

[0058] The final product yield was 80%, and the content of Form Ia was 75%.

[0059] The above results show that the present invention can effectively improve the product yield and the content of the Ia crystal form by controlling the stirring time and using specific reagents, significantly shorten the crystal form conversion time, and achieve the purpose of quickly preparing a stable crystal form of nicosulfuron.

[0060] The applicant declares that while the present invention uses the above-described embodiments to illustrate the preparation method and application of the nicosulfuron crystal form Ia, the present invention is not limited to the above-described embodiments, and does not necessarily rely on the above-described embodiments for implementation. Those skilled in the art should understand that any improvements to the present invention, equivalent substitutions for the raw materials of the present invention, addition of auxiliary ingredients, and selection of specific methods, etc., fall within the scope of protection and disclosure of the present invention.

[0061] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the scope of protection of the present invention.

[0062] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any appropriate manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.

Claims

1. A method for preparing nicosulfuron Ia crystal form, characterized in that: The preparation method comprises the following steps: The nicosulfuron raw material and the alcohol solution are mixed and stirred, and then cooled and filtered to obtain the nicosulfuron Ia crystal form; The nicosulfuron raw material is a nicosulfuron preparation product or a nicosulfuron technical.

2. The method for preparing the nicosulfuron Ia crystal form according to claim 1, wherein The preparation method of the nicosulfuron preparation product comprises: Pyrimidinamine and ((3-(N,N-dimethylaminocarbonyl)-2-pyridyl)sulfonamido)phenylformate are mixed and reacted to obtain the nicosulfuron preparation product.

3. The method for preparing the nicosulfuron Ia crystal form according to claim 1 or 2, wherein: The nicosulfuron raw material is nicosulfuron technical. Before the nicosulfuron raw material is mixed with the alcohol solution, the nicosulfuron raw material is mixed with phenol and a solvent, and then the solvent is removed.

4. The method for preparing the nicosulfuron Ia crystal form according to claim 3, wherein: The molar ratio of the nicosulfuron technical and phenol is (0.8-1.2):(0.8-1.2).

5. The method for preparing the nicosulfuron Ia crystal form according to any one of claims 1 to 4, characterized in that: The mass ratio of the nicosulfuron raw material to the alcohol solution is 1:(1-3).

6. The method for preparing the nicosulfuron Ia crystal form according to any one of claims 1 to 5, characterized in that: The alcohol solution includes any one of anhydrous ethanol, anhydrous methanol, an ethanol aqueous solution or a combination of at least two of them, preferably anhydrous ethanol.

7. The method for preparing the nicosulfuron Ia crystal form according to any one of claims 1 to 6, characterized in that: The mixing and stirring time is 1 min-2 h.

8. The method for preparing the nicosulfuron Ia crystal form according to claim 7, wherein: The mixing and stirring time is 1-2 minutes.

9. The method for preparing the nicosulfuron Ia crystal form according to any one of claims 1 to 8, characterized in that: The mixing and stirring temperature is 25-60°C.

10. Use of the method for preparing the nicosulfuron Ia crystal form according to any one of claims 1 to 9 in the preparation of nicosulfuron.

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