Method for selectively separating metribuzin and separated intermediate thereof

Abstract

The invention relates to a separation method of metribuzin and 4-amino methylated metribuzin and a separation intermediate thereof. The separation method comprises the following steps: adding a p-toluene sulfonic acid aqueous solution into an organic solution containing metribuzin and 4-amino methylated metribuzin, stirring, selectively reacting p-toluene sulfonic acid with metribuzin to generate metribuzin p-toluene sulfonate, crystallizing and separating out, filtering and separating to obtain p-toluene sulfonate, and then dissociating the p-toluene sulfonate to obtain metribuzin. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a method for selectively separating metribuzin and its separation intermediate, and a method for treating metribuzin mother liquor by adopting the selective separation method. Background Art

[0002] Methicone can be used as a selective herbicide, which mainly exerts its weed-killing activity by inhibiting the photosynthesis of sensitive plants. After application, the germination of sensitive weeds is not affected. After germination, the leaves turn green and finally die due to nutrient depletion. It is suitable for a variety of broad-leaved weeds in field crops such as soybeans, potatoes, tomatoes, sugarcane, and corn, and is also suitable for some grass weeds. It is less effective against perennial weeds.

[0003] One of the known methods for preparing metribuzin is to prepare it by reacting triazone with a methylating agent, wherein the methylating agent includes methyl sulfate, methyl phosphate, methyl halide, and the like.

[0004] Chinese patent application CN109503504A reported that in the reaction of preparing metribuzin by methylation of triazone, the following two methyl metribuzin impurities are produced, among which the 2-position N-methylated metribuzin impurity forms a eutectic with metribuzin and is difficult to remove. The patent application does not mention the removal methods of these two impurities.

[0005] Summary of the invention

[0006] When the inventors of the present application studied how to recover metribuzin from an organic solution containing metribuzin, they found that it was difficult to separate metribuzin in the solution from metribuzin with 4-aminomethylation by crystallization, which increased the difficulty and effect of separating metribuzin.

[0007] In view of the above problems, the inventors of the present application have conducted in-depth research and found that by adding p-toluenesulfonic acid to an organic solution containing metribuzin and 4-aminomethylated metribuzin, p-toluenesulfonate of metribuzin can be selectively generated and crystallized, while 4-aminomethylated metribuzin is not easy to form salts and remains in the mother liquor, thereby achieving effective separation of metribuzin and 4-aminomethylated metribuzin; the obtained p-toluenesulfonate of metribuzin is then subjected to alkali dissociation, water washing, cooling crystallization, filtration, drying and other operations to obtain metribuzin of qualified quality.

[0008] Specifically, the present invention provides:

[0009] (1) metribuzin-p-toluenesulfonate represented by the following formula:

[0010]

[0011] (2) A method for separating metribuzin and 4-aminomethylated metribuzin,

[0012] 4-aminomethylated metribuzin

[0013] The method comprises adding an aqueous p-toluenesulfonic acid solution to an organic solution containing metribuzin and 4-aminomethylated metribuzin, stirring, allowing p-toluenesulfonic acid to selectively react with metribuzin to form the p-toluenesulfonate of metribuzin shown in (1) above and crystallize out, filtering and separating to obtain the p-toluenesulfonate, and then dissociating the salt to obtain metribuzin.

[0014] (3) The method according to (2) above, wherein the molar ratio of p-toluenesulfonic acid to metribuzin to be separated is (1.0-1.5):1.

[0015] (4) The method according to (2) or (3) above, wherein the addition of the p-toluenesulfonic acid aqueous solution is carried out under temperature control conditions, and the temperature control temperature is preferably 0 to 50°C, more preferably 10 to 25°C, and further preferably 10 to 15°C.

[0016] (5) The method according to any one of (2) to (4) above, wherein the organic solvent is toluene, xylene or tetrachloroethylene solution.

[0017] (6) The method according to any one of (2) to (5) above, wherein the dissociation step comprises adding an organic solvent and water to the metribuzin-p-toluenesulfonate, heating, adding liquid alkali to adjust the pH to alkaline, preferably adjusting the pH to 11-12, separating the liquids, adding water to the organic layer to wash, separating the liquids, cooling the organic layer, crystallizing, and filtering to obtain metribuzin.

[0018] (7) The method according to (6) above, wherein the organic solvent is toluene, xylene or tetrachloroethylene.

[0019] (8) The method according to (6) or (7) above, wherein the temperature is raised to 45 to 50°C.

[0020] (9) A method for post-treating a metribuzin mother liquor, the method comprising separating metribuzin from the mother liquor by the method described in any one of (2) to (8) above.

[0021] (10) The method according to (9) above, wherein metribuzin is prepared by reacting a triazone with a methylating agent. DETAILED DESCRIPTION

[0022] In this application, "about" means ±10%.

[0023] In one aspect, the present invention provides a method for separating metribuzin and 4-aminomethylated metribuzin.

[0024] 4-aminomethylated metribuzin

[0025] The method comprises adding an aqueous p-toluenesulfonic acid solution to an organic solution containing metribuzin and 4-aminomethylated metribuzin, stirring, allowing the p-toluenesulfonic acid to selectively react with metribuzin to generate metribuzin p-toluenesulfonate and crystallize out, filtering and separating to obtain the p-toluenesulfonate, and then dissociating the salt to obtain metribuzin.

[0026]

[0027] Methiazole-p-Toluenesulfonate

[0028] The 4-aminomethylated metribuzin does not readily form a salt with p-toluenesulfonic acid and therefore remains in the organic solution.

[0029] In a specific embodiment, the molar ratio of p-toluenesulfonic acid to metribuzin to be separated is (1.0-1.5):1, preferably about 1.2. When the amount of p-toluenesulfonic acid is too small, metribuzin is not completely reacted, resulting in a reduced yield of the product; when the amount of p-toluenesulfonic acid is greater than 1.5, further increasing the amount of p-toluenesulfonic acid can no longer increase the yield of the product.

[0030] The addition of the p-toluenesulfonic acid aqueous solution is preferably carried out under temperature control conditions, and the temperature control temperature is preferably 0-50° C., more preferably 10-25° C., and further preferably 10-15° C. When the temperature is too high, the solubility of metribuzin p-toluenesulfonate in the water layer increases and the yield decreases; when the temperature is too low, the yield of the product no longer increases.

[0031] In a specific embodiment, the organic solution containing metribuzin is a toluene, xylene or tetrachloroethylene solution.

[0032] The separation method of the present application preferably further includes the step of dissociating metribuzin-p-toluenesulfonate to obtain metribuzin, which step includes adding an organic solvent and water to metribuzin-p-toluenesulfonate, heating, adding liquid alkali to adjust the pH to alkaline, separating the liquids, adding water to the organic layer for washing, separating the liquids, cooling the organic layer, crystallizing, and filtering to obtain metribuzin.

[0033] The organic solvent added in the dissociation step is preferably toluene, xylene or tetrachloroethylene.

[0034] In a specific embodiment, the mass ratio of the organic solvent used in the dissociation step to the metribuzin-p-toluenesulfonate is (0.75-2.15):1, preferably (1-1.2):1. When the amount of the organic solvent is too small, the metribuzin obtained after the dissociation cannot be completely dissolved; when the amount of the organic solvent is too large, less metribuzin is precipitated during the cooling crystallization, thereby reducing the yield of metribuzin. The mass ratio of the amount of water added together with the organic solvent to the metribuzin-p-toluenesulfonate is preferably (0.4-1):1.

[0035] In the dissociation step, the temperature is preferably raised to 45-50° C. When the temperature is lower than 45° C., the metribuzin obtained after the dissociation by adding liquid alkali cannot be completely dissolved in the organic layer; when the temperature is higher than 50° C., metribuzin will undergo a hydrolysis side reaction as shown below under alkaline conditions, resulting in a decrease in the yield of metribuzin.

[0036]

[0037] In the dissociation step, liquid alkali is added to adjust the pH to preferably 11 to 12. A high pH may cause a hydrolysis side reaction of metribuzin, resulting in a reduced yield of metribuzin; a low pH may cause the unreacted raw material triazone to fail to form a salt, resulting in the triazone failing to enter the aqueous phase and failing to separate triazone and metribuzin.

[0038] In a more specific embodiment, the dissociation step comprises adding 1.1 times by mass (based on the mass of methicillin-p-toluenesulfonate) of toluene and 1 times by mass (based on the mass of methicillin-p-toluenesulfonate) of water to methicillin-p-toluenesulfonate, heating to 45-50° C., adding a 30% mass concentration of liquid alkali to adjust the pH to 11-12, stirring for 10 minutes and then standing to separate the liquids, adding 1 times by mass (based on the mass of methicillin-p-toluenesulfonate) of water to the organic layer, controlling the temperature at 45-50° C. and stirring for 10 minutes and then standing to separate the liquids, cooling the organic layer to 0-5° C., stirring for 1 hour and then filtering, then eluting with toluene, and drying at 70-75° C. to obtain methicillin.

[0039] Another aspect of the present invention relates to a novel intermediate obtained in the above separation, namely, metribuzin-p-toluenesulfonate as shown below.

[0040] Methiazole-p-Toluenesulfonate

[0041] Example

[0042] The present invention is further described in detail below in conjunction with specific embodiments, but the present invention is not limited to these specific embodiments, and any modifications or changes within the scope of the present invention fall within the scope of this application.

[0043] In the following examples, the conditions for high performance liquid chromatography analysis are as follows: the instrument is Agilent 1100LC liquid chromatograph, UV detector. The chromatographic column is C18 column, 250mm×4.6mm×5um. The mobile phase is acetonitrile: water (adjusted with formic acid to pH=3.7-4.1)=60:40; the column temperature is 30°C, the flow rate is 1.0mL / min; the detection wavelength is 254nm.

[0044] Example 1

[0045] Add 60g of metribuzin toluene mother liquor (wherein the content of metribuzin is 9.75% and the content of methyl metribuzin is 1.64%) to a four-necked bottle, control the temperature at 25°C, and drop 15.67g of 30% p-toluenesulfonic acid aqueous solution. After the addition is complete, stir for 0.5h, filter, and dry at 75°C to obtain 6.23g of metribuzin p-toluenesulfonate, with a yield of 58.60%, of which the content of metribuzin is 55.03% and the content of 4-aminomethylated metribuzin is 0.82%.

[0046] Example 2

[0047] Add 60g of metribuzin toluene mother liquor (wherein the content of metribuzin is 9.75% and the content of methyl metribuzin is 1.64%) to a four-necked bottle, control the temperature at 25°C, and drop 14.11g of 30% p-toluenesulfonic acid aqueous solution. After the addition is complete, stir for 0.5h, filter, and dry at 75°C to obtain 6.04g of metribuzin p-toluenesulfonate, with a yield of 56.34%, of which the content of metribuzin is 54.57% and the content of 4-aminomethylated metribuzin is 0.80%.

[0048] Example 3

[0049] Add 60g of metribuzin toluene mother liquor (wherein the content of metribuzin is 9.75% and the content of methyl metribuzin is 1.64%) to a four-necked bottle, control the temperature at 25°C, and drop 18.81g of 30% p-toluenesulfonic acid aqueous solution. After the addition is complete, stir for 0.5h, filter, and dry at 75°C to obtain 7.51g of metribuzin p-toluenesulfonate, with a yield of 70.33%, of which the content of metribuzin is 54.79% and the content of 4-aminomethylated metribuzin is 0.82%.

[0050] Example 4

[0051] Add 55.63g of metribuzin toluene mother liquor (wherein the content of metribuzin is 9.75% and the content of methyl metribuzin is 1.64%) to a four-necked bottle, control the temperature at 25°C, and drop 33.42g of 30% p-toluenesulfonic acid aqueous solution. After the addition is complete, stir for 0.5h, filter, and dry at 75°C to obtain 8.48g of metribuzin p-toluenesulfonate, with a yield of 79.59%, of which the content of metribuzin is 50.91% and the content of 4-aminomethylated metribuzin is 0.93%.

[0052]

[0053] According to the results of Examples 1, 2, 3, and 4, as the molar ratio of p-toluenesulfonic acid to metribuzin increases, the yield of the product gradually increases; when the molar ratio of p-toluenesulfonic acid to metribuzin is 2.3:1, the amount of p-toluenesulfonic acid increases by 91.67% relative to Example 3, while the yield of the product increases by only 13% relative to Example 3, and the yield increases slowly.

[0054] Example 5

[0055] Add 60g of metribuzin toluene mother liquor (wherein the content of metribuzin is 9.75% and the content of methyl metribuzin is 1.64%) to a four-necked bottle, control the temperature at 10°C, and drop 18.81g of 30% p-toluenesulfonic acid aqueous solution. After the addition is complete, stir for 0.5h, filter, and dry at 75°C to obtain 8.64g of metribuzin p-toluenesulfonate, with a yield of 79.37%, of which the content of metribuzin is 53.74% and the content of 4-aminomethylated metribuzin is 1.28%.

[0056]

[0057] According to the results of Examples 3 and 5, the product yield when the temperature is controlled at 25°C is lower than the product yield when the temperature is controlled at 10°C. The reason may be that the solubility of metribuzin-p-toluenesulfonate in the water layer is greater at 25°C.

[0058] 8.44g of the above-obtained metribuzin p-toluenesulfonate was added to 9.9g of toluene and 8.44g 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, stirred for 10min, and allowed to stand for stratification. The organic layer was washed with water, stirred for 10min, allowed to stand for stratification, the organic layer was cooled to 0-5°C, stirred for crystallization for 1h, filtered, the filter cake was rinsed with toluene, and dried at 70-75°C to obtain 3.9g 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 comprehensive yield of the two steps was 66.27%.

[0059] Comparative Example

[0060] Formic acid, acetic acid, phosphoric acid or hydrochloric acid were used to replace p-toluenesulfonic acid, and the rest was the same as in Example 1. No crystals were precipitated using the above acids, and the selective separation of metribuzin and 4-aminomethylated metribuzin could not be achieved.

Claims

1. Methichloridone p-toluenesulfonate shown in the following formula:

2. A method for separating metribuzin and 4-aminomethylated metribuzin. 4-aminomethylated metribuzin The method comprises adding an aqueous p-toluenesulfonic acid solution to an organic solution containing metribuzin and 4-aminomethylated metribuzin, stirring, allowing p-toluenesulfonic acid to react selectively with metribuzin to generate the p-toluenesulfonate of metribuzin as shown in claim 1 and crystallize out, filtering and separating to obtain the p-toluenesulfonate, and then dissociating the salt to obtain metribuzin.

3. The method according to claim 2, wherein the molar ratio of p-toluenesulfonic acid to metribuzin to be separated is (1.0-1.5):

1.

4. The method according to any one of claims 2 or 3, wherein the addition of the p-toluenesulfonic acid aqueous solution is carried out under temperature control conditions, and the temperature control temperature is preferably 0 to 50°C, more preferably 10 to 25°C, and further preferably 10 to 15°C.

5. The method according to any one of claims 2 to 4, wherein the organic solvent is toluene, xylene or tetrachloroethylene solution.

6. The method according to any one of claims 2 to 5, wherein the dissociation step comprises adding an organic solvent and water to metribuzin-p-toluenesulfonate, heating, adding liquid alkali to adjust the pH to alkaline, preferably adjusting the pH to 11-12, separating the liquids, adding water to the organic layer to wash, separating the liquids, cooling the organic layer, crystallizing, and filtering to obtain metribuzin.

7. The method according to claim 6, wherein the organic solvent is toluene, xylene or tetrachloroethylene.

8. The method according to claim 6 or 7, wherein the temperature is raised to 45-50°C.

9. A method for post-treating a metribuzin mother liquor, the method comprising separating metribuzin from the mother liquor by the method according to any one of claims 2 to 8.

10. The method according to claim 9, wherein metribuzin is prepared by reacting a triazone with a methylating agent.

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