WO2024001401A1

WO2024001401A1 - Crystal form a of pyroxasulfone, and preparation method therefor and use thereof

Info

Publication number: WO2024001401A1
Application number: PCT/CN2023/086917
Authority: WO
Inventors: 沈运河; 祝玉超
Original assignee: 安徽久易农业股份有限公司
Priority date: 2022-06-28
Filing date: 2023-04-07
Publication date: 2024-01-04
Also published as: CN114989157A

Abstract

A crystal form of pyroxasulfone, and a preparation method therefor and the use thereof. A brand-new crystal form A is obtained by means of a recrystallization method. The crystal form A of pyroxasulfone has the characteristics of a stable structure and stable chemical properties, can be stored at room temperature for a long time, is also more beneficial for preparation processing, has a good preventive effect on annual weeds in wheat fields, and has strong economic value.

Description

A kind of crystal form A of sulfonazole and its preparation method and application

Technical field

The invention belongs to the field of pesticides, and specifically relates to the crystal form A of the herbicide sulfenazole and its preparation method and application.

Background technique

Pyroxasulfone is an isoxazole herbicide developed by Japan Combination Chemical Company. Its chemical name is 3-[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl base) pyrazol-4-ylmethylsulfonyl]-4,5-dihydro-5,5-dimethyl-1,2-isoxazole, the molecular formula is C12H14F5N3O4S, the molecular weight is 391.32, and the CAS registration number is 447399 -55-5.

Mefenacet is mainly used as a pre-emergent sealing treatment agent, supplemented by blocking broad-leaf grasses, mainly grasses. It has many advantages: it is suitable for a wide range of crops, and can be used for wheat, corn, peanuts, rice, soybeans, cotton and other crops; It is safe for the environment and for current and next crops; the validity period can reach about 28 days.

Different crystal structures of the original drug molecules usually have different properties, so their use situations are also different. For example, crystalline forms are generally more stable than amorphous forms, then they can be used for long-term preservation of that solid material, while amorphous forms are generally more soluble than crystalline forms, which makes them more useful for some purposes than crystalline forms in drug administration. . The crystal form of a compound also affects its physicochemical properties, such as melting point, solubility or dissolution rate. It is therefore advantageous that crystalline forms can be obtained with a range of physicochemical properties so that effectiveness can be optimized. At present, there are few reports on the crystal form of sulfapyrazole: 1) CN 112969697 A records the needle-shaped and short columnar crystal forms of sulfopentazole, and gives the corresponding XPRD diffraction spectrum, showing that at 17.8° There are characteristic peaks at the diffraction angles 2θ of 18.0° and 19.9°; 2) CN114213402A discloses the crystal form A and B of sulfapyrazole; 3) WO2021144796 discloses the crystal form A of sulfapyrazole, which shows that at 17.8° There are characteristic peaks at the diffraction angle 2θ of 20.9° and 22.4°.

technical problem

However, the above-mentioned patent documents did not conduct research on the stability and field efficacy tests of the crystalline form. Therefore, developing a new crystal form with high stability and good biological activity is of great significance for the synthesis, use, efficacy and storage of sulfenazole.

Technical solutions

The invention provides a crystal form A of sulfenazole with stable physical and chemical properties and a preparation method thereof. The preparation of the crystal form and the efficacy test of the preparation are provided.

In order to solve the above technical problems, the present invention adopts the following technical solutions:

An object of the present invention is to provide a crystalline form A of sulfenazole. The X-ray powder diffraction pattern of the crystalline form measured with CuKα rays has a 2theta value of 10.0°±0.2°, 20.1°±0.2° and There is a characteristic peak at 30.2°±0.2°.

Furthermore, the X-ray powder diffraction pattern of the crystal form A measured with CuKα rays also has characteristic peaks at one or more of the 2theta values of 20.5°±0.2° and 20.9°±0.2°.

Further, the analytical data of the X-ray powder diffraction pattern measured with CuKα rays for the above-mentioned crystalline form A is shown in Table 1:

Table 1 Diffraction peak data of sulfonazole crystal form A

Further, the X-ray powder diffraction pattern of the above-mentioned crystal form A measured with CuKα rays is basically as shown in Figure 1.

beneficial effects

The preparation method of the above-mentioned sulfapyrazole crystal form A is to add a certain amount of sulfopentazole solid or the reaction concentrate containing sulfopentazole into a suitable solvent, raise the temperature to dissolve, and finally reduce the temperature to a certain level according to a certain cooling rate. The crystallization was carried out at a certain temperature, and the crystal form obtained was Form A.

Further, the organic solvent is selected from one or more mixed solvents selected from water, methanol, ethanol, toluene, ethyl acetate, propyl acetate, dichloroethane, and dichloromethane.

Further, the temperature at which the sulfonazole solid dissolves in a suitable organic solvent is 50-120°C.

Further, the cooling rate is 0.1-10°C/min.

Further, the concentration of the solid sulfonazole or the reaction concentrate containing sulfonazole in the solvent is 10-1000g/L (based on the pure product of sulfonazole).

Further, the solid sulfomenazolin is selected from amorphous sulfomeprazole or mixtures thereof, containing other crystalline forms of sulfomeprazole or mixtures thereof.

Description of drawings

Figure 1: XRPD spectrum of Cu-Kα radiation of crystal form A prepared in Example 5 of the present invention;

Figure 2: XRPD spectrum of Cu-Kα radiation of crystal form B prepared in Example 1 of the present invention.

Embodiments of the invention

Definition and Description

Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular phrase or term should not be considered uncertain or unclear in the absence of a specific definition, but should be understood in its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.

The intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and those skilled in the art. Well-known equivalents and preferred embodiments include, but are not limited to, the embodiments of the present invention.

The chemical reactions of the specific embodiments of the present invention are completed in a suitable solvent. The solvent must be suitable for the chemical changes of the present invention and the required reagents and materials. In order to obtain the compounds of the present invention, it is sometimes necessary for those skilled in the art to modify or select synthetic steps or reaction procedures on the basis of existing embodiments.

All solvents used in the present invention are commercially available and used without further purification.

The invention discloses the crystal form A of sulfopentazolin and its preparation method. Those skilled in the art can learn from the contents of this article and appropriately improve the implementation of process parameters. It should be noted that all similar substitutions and modifications are obvious to those skilled in the art, and they are deemed to be included in the present invention. The methods and products of the present invention have been described through preferred embodiments. Relevant persons can obviously modify or appropriately change and combine the methods described herein without departing from the content, spirit and scope of the present invention to implement and apply the present invention. Invent technology.

The present invention will be described in detail through examples below. These examples do not mean any limitation to the present invention.

The XPRD experimental parameters are as follows:

The present invention provides a crystalline form A of sulfonazole, which crystalline form A is determined by X-ray powder diffraction method based on its diffraction pattern, X-ray powder diffraction recorded at 25°C using Cu-Kα (1.5443Å) radiation Figure (Figure 1), showing characteristic reflections expressed as 2θ values or as interplanar spacing d (d [Å]), as shown in Table 1 below.

Table 1 Diffraction peak data of sulfopyrazole crystal form A

The preparation method of the above-mentioned sulfopenazole crystal form A is to add a certain amount of sulfopenazole solid or concentrated liquid to a suitable solvent, raise the temperature to dissolve, and finally lower the temperature to a certain temperature at a certain cooling rate for crystallization to obtain the crystal. Type A.

Further, the solvent is selected from one or more mixed solvents selected from water, methanol, ethanol, toluene, ethyl acetate, propyl acetate, dichloroethane, and dichloromethane.

The solid sulfapyrazole is selected from the group consisting of amorphous sulfopentazole and mixtures thereof, sulfopentazole containing other crystal forms and mixtures thereof; for example, a reaction mixture containing sulfopentazole obtained by a chemical reaction (removing after other reagents and by-products); the reaction and subsequent treatment are carried out in a solvent or a solvent mixture consisting at least partly, preferably at least 30%, of a suitable crystallizing solvent, removing excess of other reagents and any catalyst present as well as any undesirable A mixture of sulfapyrazole containing other crystal forms is prepared using a suitable solvent such as water; a solution of sulfopentazole is prepared through a chemical reaction of a suitable precursor of sulfopentazole, etc.

The dissolution temperature is preferably 50-120°C, more preferably 60-80°C, and the cooling rate is 0.1-10°C/min, preferably 0.5-8°C/min, and more preferably 2-6°C/min.

Specific steps include:

(1) Add the sulfapyrazole solid into a suitable solvent, stir and dissolve at 50-200°C, especially at at least 60°C, to obtain an organic solution containing the dissolved sulfopentazole solid; wherein, the sulfopentazole solid The suitable concentration in organic solvents is 10-500g/L. The selection of a suitable concentration depends on the nature of the selected organic solvent and the solution temperature, and can be determined by those skilled in the art based on specific experiments.

(2) Crystallization; including ① cooling the solution of sulfopyrazole for crystallization; or ② adding a solvent that reduces the solubility to the sulfopyrazole solution; or other common crystallization methods, etc. The temperature of the crystallization is preferably below 100°C, more preferably below 80°C to achieve slow crystallization.

Further, the cooling rate is 0.1-10°C/min.

Further, the suitable concentration of sulfopentazolin in the solvent is 10-1000g/L. The selection of a suitable concentration depends on the nature of the selected solvent and the solution temperature, and can be determined by those skilled in the art based on specific experiments.

Example 1

Add 150 ml of toluene to the 500 ml four-necked flask, and slowly add 50 g of sulfamethoxazole (content: 98%) while stirring; raise the temperature to reflux, the solution becomes transparent, and keep it warm for 30 minutes; after the heat preservation is completed, slowly cool down at a cooling rate of 2°C /min. When the temperature is lowered to 40°C, solid material begins to precipitate. Continue to lower the temperature to 5°C and keep it warm for 30 minutes. A large amount of white material precipitates. After the heat preservation is completed, filter it to obtain colorless crystal material. The material is dried in an oven at 60°C and weighed: 46.3g, measured content; 98.9%.

X-ray powder diffraction analysis confirmed that the obtained crystalline form B of sulfonazole was shown in Figure 2.

Example 2

(1) Add 150 ml of methanol to a 500 ml four-necked flask, and slowly add 20 g of metapyrazole (content: 98%) while stirring; raise the temperature to reflux, the solution becomes transparent, and keep it warm for 30 minutes; after the heat preservation is completed, slowly cool down at the cooling rate is 2℃/min. When the temperature is lowered to 60°C, solid material begins to precipitate. Continue to lower the temperature to 5°C and keep it warm for 30 minutes. A large amount of white material precipitates. After the heat preservation is completed, filter it to obtain colorless crystal material. The material is dried in an oven at 60°C and weighed: 19.5g, measured content; 99.0%.

X-ray powder diffraction analysis confirmed that what was obtained was the crystal form B of sulfonazole.

(2) Add 150 ml of methanol to the 500 ml four-necked flask, and slowly add 20 g of metapyrazole (content: 98%) while stirring; raise the temperature to reflux, the solution becomes transparent, and keep it warm for 30 minutes; after the heat preservation is completed, slowly cool down, and the cooling rate is 10℃/min. When the temperature is lowered to 60°C, solid material begins to precipitate. Continue to lower the temperature to 5°C and keep it warm for 30 minutes. A large amount of white material precipitates. After the heat preservation is completed, filter it to obtain colorless crystal material. The material is dried in an oven at 60°C and weighed: 19.8g, measured content; 98.3%.

(3) Add 150 ml of methanol to the 500 ml four-necked flask, and slowly add 20 g of metapyrazole (content: 98%) while stirring; raise the temperature to reflux, the solution will become transparent, and keep it for 30 minutes; after the insulation is completed, slowly cool down at the cooling rate is 2℃/min. When the temperature is lowered to 60°C, solid material begins to precipitate. Continue to lower the temperature to -10°C and keep it warm for 30 minutes. A large amount of white material precipitates. After the heat preservation is completed, filter it to obtain colorless crystal material. The material is dried in an oven at 60°C and weighed. : 19.8g, measured content; 99.2%.

Example 3

Add 150 ml of ethyl acetate to the 500 ml four-necked flask, and slowly add 80 g of sulfopentazole (content: 98%) while stirring; raise the temperature to reflux, the solution becomes transparent, and keep it for 30 minutes; after the insulation is completed, slowly cool down at a cooling rate of 2℃/min. When the temperature is lowered to 35°C, solid material begins to precipitate. Continue to lower the temperature to 5°C and keep it warm for 30 minutes. A large amount of white material precipitates. After the heat preservation is completed, filter it to obtain colorless crystal material. The material is dried in an oven at 60°C and weighed: 65g, measured content; 98.1%.

Example 4

Add 150ml of toluene and 30mL of water to the 500ml four-necked flask, slowly add 50g of sulfopyrazole (content: 98%) while stirring; heat up to reflux, the solution becomes transparent (divided into two phases), and keep warm for 30 minutes; after the heat preservation is completed , slowly cool down, the cooling rate is 2℃/min. When the temperature is lowered to 35°C, solid material begins to precipitate. Continue to lower the temperature to 5°C and keep it warm for 30 minutes. A large amount of white material precipitates. After the heat preservation is completed, filter it to obtain colorless crystal material. The material is dried in an oven at 60°C and weighed: 45.2g, measured content; 99.2%.

X-ray powder diffraction analysis confirmed that what was obtained was the crystalline form A of sulfonazole.

Example 5

Add 180ml methanol (containing 30% water) to the 500ml four-necked flask, and slowly add 20g sulfamethoxazole (content: 98%) while stirring; raise the temperature to reflux, the solution becomes transparent, and keep it warm for 30 minutes; after the insulation is completed, slowly cool down the temperature , the cooling rate is 2℃/min. When the temperature is lowered to 55°C, solid material begins to precipitate. Continue to lower the temperature to 5°C and keep it warm for 30 minutes. A large amount of white material precipitates. After the heat preservation is completed, filter it to obtain colorless crystal material. The material is dried in an oven at 60°C and weighed: 18.8g, measured content; 99.6%.

X-ray powder diffraction analysis confirmed that what was obtained was the crystalline form A of sulfonazole (see Figure 1 for the XPRD pattern of crystalline form A).

Example 6

Add 150 ml toluene and 150 mL methanol to the 500 ml four-necked flask, and slowly add 60 g sulfopentazolin (content: 98%) while stirring; raise the temperature to reflux, the solution becomes transparent, and keep it warm for 30 minutes; after the heat preservation is completed, slowly cool down at the cooling rate is 2℃/min. When the temperature is lowered to 50°C, solid material begins to precipitate. Continue to lower the temperature to 5°C and keep it warm for 30 minutes. A large amount of white material precipitates. After the heat preservation is completed, filter it to obtain colorless crystal material. The material is dried in an oven at 60°C and weighed: 56g, measured content; 98.0%.

X-ray powder diffraction analysis confirmed that what was obtained was the mixed crystal form of sulfonazole.

Table 2 Results of crystallization under different conditions

Example 7 Melting Point Determination

The parameters were set according to the differential thermogravimetric method: the starting temperature was 60°C, the temperature was raised to 180°C at a rate of 10°C/min, and kept for 10 minutes. The melting point of each crystal form was measured to be approximately: 133.9-135.0°C.

Example 8 Crystal Form Stability Test

Take about 5 mg of the sulfonazole crystal form A obtained in Example 5, weigh it accurately, and place it in a glass sample bottle. Weigh 2 parts at each time point under each condition as test samples; test XRPD samples Place 1 copy per condition per time point. Wrap the bottle mouth of the above sample with aluminum foil and poke some small holes in the aluminum foil, and then place the sample in a constant temperature and humidity box at 60°C, 92.5% RH and 40°C/75% RH.

Table 3 Stability test of Form A

Referring to the same method as above, the stability test of crystal form B was carried out. The test results are shown in Table 4 below:

Experimental results show that:

Compared with the crystal form B, the sulfonazole crystal form A obtained by the present invention has good stability and its purity changes little. And the appearance and crystal form have not changed.

Example 9: Preparation and field efficacy test of 40% sulfonazole aqueous suspension

1. Formula of 40% sulfonazole aqueous suspension

Table 5. Formula of 40% sulfonazole aqueous suspension

2. Formula index of 40% sulfonazole aqueous suspension

Preparation performance test standards are as follows:

Appearance: Use a 100 mL stoppered transparent glass graduated cylinder for the test. Put 100 mL into the above graduated cylinder. After sealing, place it according to the following conditions: hot storage at 54°C for 14 days, cold storage at 0°C for 7 days, and normal temperature for 14 days. Visually observe the difference in appearance, and there is no stratification. , no precipitation, no turbidity and no significant color difference is considered qualified.

The content of sulfopyrazole at room temperature is the content after being sealed and placed at room temperature for 14 days.

The content of sulfonazole under cold storage is the content after being sealed and placed at 0°C for 7 days.

The content of sulfopyrazole under heat storage is the content after being sealed and placed at 54°C for 14 days.

The pH is measured in accordance with GB/T1603-1993, and a pH of 5-9 is considered qualified.

Durable foaming property: Follow 4.11 in HG/T2467.5-2003.

Suspension rate: According to GB/T14825-2006, the suspension rate is generally required to be >90%.

Pourability: According to HG/T2467.5-2003 4.9, the residue after pourability is ≤5%.

The prevention efficacy test standards are as follows:

Field test test method of using 40% sulfonazole suspension to control annual weeds in wheat fields: conventional field spraying, the dosage is the recommended dosage, the water consumption is 600L/hm2, and the spraying of clean water is used as the blank control (CK). Each treatment was repeated 4 times, with a total of 28 plots, with an area of 30m2, arranged in random blocks. Control effectiveness survey: 4 survey points per plot, 0.25 m2 per point. Calculate the fresh weight control effectiveness of each weed separately.

The performance and preventive effect of the preparation were tested as required, and the results are as follows:

Table 5. Formulation specifications of 40% sulfaconazole aqueous suspension

.

Claims

A kind of crystal form A of sulfonazole, characterized in that: the X-ray powder diffraction pattern of the crystal form measured with CuKα rays has a 2theta value of 10.0°±0.2°, 20.1°±0.2° and 30.2°± There is a characteristic peak at 0.2°.
The sulfonepyrazole crystal form A according to claim 1, characterized in that: the X-ray powder diffraction pattern of the crystal form measured with CuKα rays at 2theta value is: 10.0°±0.2°, 20.1°±0.2 °, there are characteristic peaks at 20.5°±0.2°, 20.9°±0.2° and 30.2°±0.2°.
The crystal form A of sulfonazole according to claim 1, characterized in that: the X-ray powder diffraction pattern of the crystal form measured with CuKα rays is basically as shown in Figure 1.
The crystal form A of sulfonazole according to any one of claims 1 to 3, characterized in that: the melting point of the crystal form A is 131.6-133.5°C.
A kind of sulfapyrazole technical material, is characterized in that, contains the sulfopentazole crystal form A as described in any one of claims 1 to 3, preferably, contains at least 98.5% sulfopentazole crystal form A.
A method for preparing the sulfapyrazole crystal form A according to any one of claims 1 to 4, characterized in that the sulfopentazole solid or the reaction concentrate containing sulfopentazole is dissolved in a suitable solvent , and then perform cooling and crystallization; the organic solvent is selected from one or more mixed solvents among water, methanol, ethanol, toluene, ethyl acetate, propyl acetate, dichloroethane, and dichloromethane.
The preparation method of sulfapyrazole crystal form A according to claim 6, characterized in that the dissolution temperature of the sulfopentazole solid or the reaction concentrate containing sulfopentazole in a suitable organic solvent is 50°C -120°C, preferably 60-80°C, and the rate of cooling crystallization is 0.1-10°C/min, preferably 0.5-8°C/min, more preferably 2-6°C/min.
The preparation method of sulfapyrazole crystal form A according to claim 6, characterized in that the concentration of the sulfopentazole solid or the reaction concentrate containing sulfopentazole in the solvent is 10-500g/L .
The preparation method of sulfopentazolin crystal form A according to claim 6, characterized in that the sulfonepyrazone solid is selected from the group consisting of amorphous sulfonepyrazone or a mixture thereof, and other crystal forms of sulfonepyrazone. or mixtures thereof.
A herbicide, characterized in that it contains at least 90% of the sulfonazole crystal form A according to any one of claims 1 to 3.