Separation of intermediates for selective isolation of metribuzin

Abstract

This application relates to intermediates in the isolation of metribuzin and 4-aminomethylated metribuzin. Metribuzin p-toluensulfonate.

Description

[0001] This application is a divisional application of application number 202411838676.8 filed on December 13, 2024, entitled "Method for selective separation of metribuzin and its separation intermediate". Technical Field

[0002] This invention relates to the separation intermediates for the selective separation of metribuzin. Background Technology

[0003] Mefenoxam can be used as a selective herbicide, mainly exerting its weed-killing activity by inhibiting the photosynthesis of sensitive plants. After application, the germination and seedling emergence of sensitive weeds are not affected, but after emergence, the leaves turn pale green and eventually die from nutrient depletion. It is suitable for a variety of broadleaf weeds in field crops such as soybeans, potatoes, tomatoes, sugarcane, and corn, and is also effective against some grass weeds, but its efficacy against perennial weeds is poor.

[0004] One known method for preparing triazine is by reacting triazine with a methylating agent, which may include methyl sulfate, methyl phosphate, or halomethyl ester.

[0005] Chinese patent application CN109503504A reports that during the methylation of triazine to prepare metribuzin, two types of methylmetribuzin impurities are generated. One of these impurities, N-methylated at the 2-position, forms a eutectic with metribuzin, making it difficult to remove. The patent application does not mention any methods for removing these two impurities.

[0006] 4-aminomethylated cypermethrin 2-N-methylated cypermethrin Summary of the Invention

[0007] When the inventors of this application were researching methods for recovering methamidophos from organic solutions containing methamidophos, they discovered that it was difficult to separate methamidophos from the 4-aminomethylated methamidophos in the solution by crystallization, which increased the difficulty and effectiveness of methamidophos separation.

[0008] In view of the above problems, the inventors of this application, through in-depth research, discovered that by adding p-toluenesulfonic acid to an organic solution containing metribuzin and 4-aminomethylated metribuzin, metribuzin p-toluenesulfonate can be selectively generated and crystallized out, while 4-aminomethylated metribuzin is not easily salted and remains in the mother liquor, thereby achieving effective separation of metribuzin and 4-aminomethylated metribuzin; then, the obtained metribuzin p-toluenesulfonate is subjected to operations such as alkali dissociation, water washing, cooling crystallization, filtration, and drying to obtain metribuzin of qualified quality.

[0009] Specifically, the present invention provides:

[0010] (1) The following formula represents methamidophos p-methylbenzenesulfonate:

[0011] .

[0012] (2) Separation method of metribuzin and 4-aminomethylated metribuzin,

[0013] 4-aminomethylated cypermethrin

[0014] The method involves adding an aqueous solution of p-toluenesulfonic acid to an organic solution containing cypermethrin and 4-aminomethylated cypermethrin, stirring, and selectively reacting the p-toluenesulfonic acid with cypermethrin to generate the cypermethrin p-toluenesulfonate shown in (1) above, which then crystallizes out. The p-toluenesulfonate is obtained by filtration and separation, and then the salt is dissociated to obtain cypermethrin.

[0015] (3) According to the method described in (2) above, the molar ratio of p-toluenesulfonic acid to the methamidophos to be separated is (1.0 to 1.5):1.

[0016] (4) According to the method described in (2) or (3) above, the addition of the aqueous solution of p-toluenesulfonic acid is carried out under temperature control, preferably 0 to 50°C, more preferably 10 to 25°C, and even more preferably 10 to 15°C.

[0017] (5) The method according to any one of (2) to (4) above, wherein the organic solution is toluene, xylene or tetrachloroethylene solution.

[0018] (6) According to any one of (2) to (5) above, the dissociation step includes adding an organic solvent and water to methoxyfenozide p-methylbenzenesulfonate, heating, adding liquid alkali to adjust the pH to alkaline, preferably adjusting the pH to 11-12, separating the liquid, adding water to the organic layer for washing, separating the liquid, cooling the organic layer, crystallizing, filtering and obtaining methoxyfenozide.

[0019] (7) The organic solvent described in (6) above is toluene, xylene or tetrachloroethylene.

[0020] (8) The method described in (6) or (7) above, wherein the temperature is raised to 45-50°C.

[0021] (9) A method for post-treatment of the mother liquor of cypermethrin, the method comprising separating cypermethrin from the mother liquor by any one of the methods described in (2) to (8) above.

[0022] (10) According to the method described in (9) above, wherein quinazon is prepared by reacting triazinone with a methylating agent. Detailed Implementation

[0023] In this application, "about" means ±10%.

[0024] This invention provides a method for separating metribuzin and 4-aminomethylated metribuzin.

[0025] 4-aminomethylated cypermethrin

[0026] The method involves adding an aqueous solution of p-toluenesulfonic acid to an organic solution containing cypermethrin and 4-aminomethylated cypermethrin, stirring, selectively reacting p-toluenesulfonic acid with cypermethrin to generate cypermethrin p-toluenesulfonate, which crystallizes out, filtering to separate the p-toluenesulfonate, and then dissociating the salt to obtain cypermethrin.

[0027]

[0028] Mefenoxam p-methylbenzenesulfonate

[0029] The 4-aminomethylated cypermethrin does not readily form a salt with p-toluenesulfonic acid, and therefore remains in organic solutions.

[0030] In a specific embodiment, the molar ratio of p-toluenesulfonic acid to the cypermethrin to be separated is (1.0-1.5):1, preferably about 1.2. When the amount of p-toluenesulfonic acid is too small, the cypermethrin will not react completely, which will lead to a decrease in the product yield; when the amount of p-toluenesulfonic acid is greater than 1.5, further increasing the amount of p-toluenesulfonic acid will no longer improve the product yield.

[0031] The addition of the aqueous solution of p-toluenesulfonic acid is preferably carried out under temperature control, preferably 0–50°C, more preferably 10–25°C, and even more preferably 10–15°C. When the temperature is too high, the solubility of cypermethrin p-toluenesulfonate in the aqueous layer increases, and the yield decreases; when the temperature is too low, the yield of the product no longer increases.

[0032] In a specific embodiment, the organic solution containing metribuzin is toluene, xylene, or tetrachloroethylene solution.

[0033] The separation method of this application preferably further includes the step of dissociating cypermethrin p-methylbenzenesulfonate to obtain cypermethrin. This step includes adding an organic solvent and water to cypermethrin p-methylbenzenesulfonate, heating, adding liquid alkali to adjust the pH to alkaline, separating the liquids, adding water to the organic layer for washing, separating the liquids again, cooling the organic layer, crystallizing, and filtering to obtain cypermethrin.

[0034] The organic solvent added in the dissociation step is preferably toluene, xylene, or tetrachloroethylene.

[0035] In a specific embodiment, the mass ratio of the organic solvent used in the dissociation step to cypermethrin p-toluenesulfonate is (0.75–2.15):1, preferably (1–1.2):1. If the amount of organic solvent is too small, the cypermethrin obtained after dissociation cannot be completely dissolved; if the amount of organic solvent is too large, less cypermethrin will precipitate during cooling crystallization, thereby reducing the yield of cypermethrin. The preferred mass ratio of water added together with the organic solvent to cypermethrin p-toluenesulfonate is (0.4–1):1.

[0036] In the dissociation step, it is preferable to raise the temperature to 45–50°C. When the temperature is below 45°C, the cypermethrin obtained after dissociation with liquid alkali cannot be completely dissolved in the organic layer; when the temperature is above 50°C, cypermethrin will undergo the following hydrolysis side reaction under alkaline conditions, resulting in a decrease in the yield of cypermethrin.

[0037]

[0038] In the dissociation step, liquid alkali is added to adjust the pH to preferably 11-12. Too high a pH will cause hydrolysis of triazine, resulting in a decrease in the yield of triazine; too low a pH will prevent the unreacted triazine from forming a salt, thus preventing triazine from entering the aqueous phase and making it impossible to separate triazine and triazine.

[0039] In a more specific embodiment, the dissociation step includes adding 1.1 times the mass of toluene (based on the mass of toluene-p-methylbenzenesulfonate) and 1 times the mass of water (based on the mass of toluene-p-methylbenzenesulfonate) to the toluene-p-methylbenzenesulfonate, heating to 45-50°C, adding 30% liquid alkali to adjust the pH to 11-12, stirring for 10 minutes, allowing the mixture to stand and separate, adding 1 times the mass of water (based on the mass of toluene-p-methylbenzenesulfonate) to the organic layer, controlling the temperature at 45-50°C, stirring for 10 minutes, allowing the mixture to stand and separate, cooling the organic layer to 0-5°C, stirring for 1 hour, filtering, then rinsing with toluene, and drying at 70-75°C to obtain toluene.

[0040] Another aspect of the present invention relates to a novel intermediate obtained from the above separation, namely, cypermethrin p-methylbenzenesulfonate as shown below.

[0041] Mefenoxam p-methylbenzenesulfonate

[0042] Example

[0043] The present invention will be further described in detail below with reference to specific embodiments, but the present invention is not limited to these specific embodiments. Any modifications or changes within the scope of the present invention fall within the scope of this application.

[0044] In the following examples, the high-performance liquid chromatography (HPLC) analysis conditions were as follows: the instrument was an Agilent 1100LC HPLC system with a UV detector. A C18 column (250 mm × 4.6 mm × 5 μm) was used. The mobile phase was acetonitrile:water (adjusted to pH 3.7-4.1 with formic acid) = 60:40; the column temperature was 30°C; the flow rate was 1.0 mL / min; and the detection wavelength was 254 nm.

[0045] Example 1

[0046] 60g of metribuzin-toluene mother liquor (containing 9.75% metribuzin and 1.64% methyl metribuzin) was added to a four-necked flask. The temperature was maintained at 25℃, and 15.67g of a 30% p-toluenesulfonic acid aqueous solution was added dropwise. After the addition was complete, the mixture was stirred for 0.5h, filtered, and dried at 75℃ to obtain 6.23g of metribuzin-p-toluenesulfonate, with a yield of 58.60%. The content of metribuzin was 55.03%, and the content of 4-aminomethylated metribuzin was 0.82%.

[0047] Example 2

[0048] 60g of metribuzin toluene mother liquor (containing 9.75% metribuzin and 1.64% methyl metribuzin) was added to a four-necked flask. The temperature was maintained at 25℃, and 14.11g of a 30% p-toluenesulfonic acid aqueous solution was added dropwise. After the addition was complete, the mixture was stirred for 0.5h, filtered, and dried at 75℃ to obtain 6.04g of metribuzin p-toluenesulfonate, with a yield of 56.34%. The content of metribuzin was 54.57%, and the content of 4-aminomethylated metribuzin was 0.80%.

[0049] Example 3

[0050] 60g of metribuzin toluene mother liquor (containing 9.75% metribuzin and 1.64% methyl metribuzin) was added to a four-necked flask. The temperature was maintained at 25℃, and 18.81g of a 30% p-toluenesulfonic acid aqueous solution was added dropwise. After the addition was complete, the mixture was stirred for 0.5h, filtered, and dried at 75℃ to obtain 7.51g of metribuzin p-toluenesulfonate, with a yield of 70.33%. The content of metribuzin was 54.79%, and the content of 4-aminomethylated metribuzin was 0.82%.

[0051] Example 4

[0052] 55.63 g of metribuzin toluene mother liquor (containing 9.75% metribuzin and 1.64% methyl metribuzin) was added to a four-necked flask. The temperature was maintained at 25°C, and 33.42 g of a 30% p-toluenesulfonic acid aqueous solution was added dropwise. After the addition was complete, the mixture was stirred for 0.5 h, filtered, and dried at 75°C to obtain 8.48 g of metribuzin p-toluenesulfonate, with a yield of 79.59%. The content of metribuzin was 50.91%, and the content of 4-aminomethylated metribuzin was 0.93%.

[0053] Example molar ratio of p-toluenesulfonic acid / methoxyfenozide Temperature (°C) Yield (%) Mefenoxam content (%) 4-aminomethylated cypermethrin content (%) Example 1 1:1 25 58.60 55.03 0.82 Example 2 0.9:1 25 56.34 54.57 0.80 Example 3 1.2:1 25 70.33 54.79 0.82 Example 4 2.3:1 25 79.59 50.91 0.93

[0054] According to the results of Examples 1, 2, 3, and 4, the product yield gradually increases with the increase of the molar ratio of p-toluenesulfonic acid to metribuzin. When the molar ratio of p-toluenesulfonic acid to metribuzin is 2.3:1, the amount of p-toluenesulfonic acid used increases by 91.67% compared to Example 3, while the product yield only increases by 13% compared to Example 3, indicating a slow increase in yield.

[0055] Example 5

[0056] 60g of metribuzin-toluene mother liquor (containing 9.75% metribuzin and 1.64% methyl metribuzin) was added to a four-necked flask. The temperature was maintained at 10℃, and 18.81g of a 30% p-toluenesulfonic acid aqueous solution was added dropwise. After the addition was complete, the mixture was stirred for 0.5h, filtered, and dried at 75℃ to obtain 8.64g of metribuzin-p-toluenesulfonate, with a yield of 79.37%. The content of metribuzin was 53.74%, and the content of 4-aminomethylated metribuzin was 1.28%.

[0057] Example molar ratio of p-toluenesulfonic acid / methoxyfenozide Temperature (°C) Yield (%) Mefenoxam content (%) Content of 4-aminomethylated cypermethrin (%) Example 3 1.2:1 25 70.33 54.79 0.82 Example 5 1.2:1 10 79.37 53.74 1.28

[0058] According to the results of Examples 3 and 5, the product yield at a controlled temperature of 25°C is lower than that at a controlled temperature of 10°C. This may be because the solubility of methamidophos p-methylbenzenesulfonate in the aqueous layer is greater at 25°C.

[0059] 8.44 g of the obtained metribuzin p-methylbenzenesulfonate was added to 9.9 g of toluene and 8.44 g of water, and the temperature was raised to 45–50 °C. The pH was adjusted to 11–12 with 30% sodium hydroxide solution, the temperature was controlled at 45–50 °C, and the mixture was stirred for 10 min. After standing and separating the layers, the organic layer was washed with water, stirred for 10 min, and allowed to stand and separate again. The organic layer was cooled to 0–5 °C and stirred for crystallization for 1 h. After filtration, the filter cake was washed with toluene and dried at 70–75 °C to obtain 3.9 g of metribuzin, with a yield of 83.49%, of which the content of metribuzin was 97.10% and the content of 4-aminomethylated metribuzin was 0.8%. The overall yield of the two steps was 66.27%.

[0060] Comparative example

[0061] Formic acid, acetic acid, phosphoric acid, or hydrochloric acid were used instead of p-toluenesulfonic acid, and the rest was the same as in Example 1. No crystals were precipitated using any of these acids, making selective separation of metribuzin and 4-aminomethylated metribuzin impossible.

Claims

1. The following formula represents methamidophos p-methylbenzenesulfonate: 。 2. Use of methacin p-methylbenzenesulfonate for the selective separation of methacin from 4-aminomethylated methacin.

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