CN112225698A - Mesotrione impurity, salt thereof, tautomer thereof or salt of tautomer thereof and preparation method - Google Patents
Mesotrione impurity, salt thereof, tautomer thereof or salt of tautomer thereof and preparation method Download PDFInfo
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- CN112225698A CN112225698A CN202011225462.5A CN202011225462A CN112225698A CN 112225698 A CN112225698 A CN 112225698A CN 202011225462 A CN202011225462 A CN 202011225462A CN 112225698 A CN112225698 A CN 112225698A
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- C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
- C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
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Abstract
The invention relates to the technical field of chemical synthesis, and particularly discloses a mesotrione impurity compound 1, a salt thereof, a tautomer thereof or a salt of the tautomer thereof and a preparation method thereof. The structural formula of the mesotrione impurity is shown as a formula 1. The preparation method comprises the following steps: in a solvent, carrying out reduction reaction on mesotrione and reducing metal powder under an acidic condition until the HPLC content of the mesotrione is less than 1%, heating to 50-70 ℃, and carrying out cyclization reaction to obtain the compound shown in formula 1, a salt thereof, a tautomer thereof or a salt of the tautomer thereof. The invention provides a brand-new impurity compound of mesotrione, provides a reference substance for impurity analysis and research of mesotrione and a preparation thereof, can be used for reference positioning, qualitative or quantitative use of impurities in a mesotrione raw material and a preparation thereof, is favorable for improving the medication safety of mesotrione and reducing toxic and side effects.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, and particularly relates to a mesotrione impurity, a salt thereof, a tautomer thereof or a salt of the tautomer thereof and a preparation method thereof.
Background
Mesotrione is a pre-emergent and post-emergent broad-spectrum selective herbicide capable of inhibiting hydroxyphenylpyruvate dioxygenase (HPPD) and is effective in controlling major broadleaf weeds and some gramineous weeds. The mesotrione is easy to conduct in the xylem and phloem of the plant, and has contact killing effect and specificity. The results of field efficacy tests prove that the 100 g/L mesotrione suspending agent has better control effect on annual broadleaf weeds and partial gramineous weeds in corn fields, such as piemarker, amaranth, chenopodium album, polygonum, cockspur grass, crabgrass and the like, and has poorer control effect on copperleaf amaranth and some gramineous weeds. The structural formula of mesotrione is as follows.
The mesotrione can generate impurities in the production and use processes, the appearance and the properties of the mesotrione can be changed due to the impurities, the stability of the mesotrione is influenced, the effective content of the product can be reduced due to the high impurity content, the use effect is influenced, the toxic and side effects of the mesotrione are increased, even negative effects on crops can be generated, the biological community structure of the soil is interfered, and the soil function is influenced. Therefore, the detection of impurities in the product is an important link for ensuring the weeding effect of mesotrione and reducing toxic and side effects. Currently, mesotrione impurities specified in the european union are mainly two types, 4-methylsulfonyl-2-nitrobenzoic acid (MNBA) and 2-amino-4-methylsulfonylbenzoic acid (AMBA). In order to improve the medication safety of mesotrione and ensure the weeding effect, it is necessary to fully research the impurities contained in mesotrione.
Disclosure of Invention
In view of the above problems in the prior art, the present invention provides a mesotrione impurity, a salt thereof, a tautomer thereof or a salt of the tautomer, and a preparation method thereof.
In order to solve the technical problems, the technical scheme provided by the invention is as follows:
a mesotrione impurity compound 1, a salt thereof, a tautomer thereof or a salt of the tautomer and a process for preparation:
the invention provides a brand-new impurity compound of mesotrione, provides a reference substance for impurity analysis and research of mesotrione and a preparation thereof, can be used for reference positioning, qualitative or quantitative use of impurities in a mesotrione raw material and a preparation thereof, provides a research basis for monitoring production quality and improving production process, has very important practical value for improving quality controllability of mesotrione and the preparation thereof, is beneficial to improving medication safety of mesotrione and reducing toxic and side effects.
The invention also provides a process for preparing mesotrione impurity compound 1, a salt thereof, a tautomer thereof or a salt of the tautomer, comprising the steps of:
in a solvent, carrying out reduction reaction on mesotrione and reducing metal powder under an acidic condition until the HPLC content of the mesotrione is less than 1%, heating to 50-70 ℃, and carrying out cyclization reaction to obtain the compound shown in formula 1, a salt thereof, a tautomer thereof or a salt of the tautomer thereof.
The specific reaction process is as follows:
the preparation method of the mesotrione impurity compound 1, the salt thereof, the tautomer thereof or the salt of the tautomer thereof, provided by the invention, uses mesotrione and reducing metal powder as starting materials, has the advantages of wide raw material sources and low cost, can obtain a target product by a one-pot method only through reduction reaction and cyclization reaction, does not need special equipment in the reaction process, has mild reaction conditions, and is favorable for realizing expanded production.
Preferably, the pH of the acidic condition is 1-5 and the temperature of the reduction reaction is 20-30 ℃.
Preferably, in the reduction reaction, the acid used in the acidic condition is at least one of hydrochloric acid, sulfuric acid, phosphoric acid or acetic acid.
More preferably, in the reduction reaction, the acid used in the acidic condition is hydrochloric acid.
The acid may be a commercially available chemically pure acid or a dilute acid solution, preferably a dilute acid solution having a concentration of 30-40 wt%.
Preferably, in the reduction reaction, the solvent is at least one of water, acetonitrile, tetrahydrofuran, N-dimethylformamide, methyl tert-butyl ether or diethoxymethane.
Preferably, the reducing metal powder is iron powder, zinc powder or magnesium powder.
Preferably, the mass ratio of the mesotrione to the reducing metal powder is 1: 1-3.
More preferably, the mass ratio of the mesotrione to the reducing metal powder is 1: 1.5-2.
Preferably, the mass ratio of the solvent to mesotrione in the reduction reaction is 5-20: 1.
More preferably, the mass ratio of the solvent to mesotrione during the reduction reaction is 5: 1.
The optimized reaction conditions are favorable for fully carrying out the reduction reaction and the cyclization reaction, and the conversion rate of the raw materials is improved, so that the yield and the purity of the target product are improved.
Preferably, the preparation method of the mesotrione impurity compound 1, the salt thereof, the tautomer thereof or the salt of the tautomer thereof, further comprises the following refining steps:
step a, washing the obtained crude product with a washing solvent, then adding an alkaline solution, adjusting the pH to be more than or equal to 13, carrying out a salt forming reaction, and filtering to obtain a filtrate;
b, adding acid into the filtrate, adjusting the pH value to 1-3, cooling, crystallizing and filtering to obtain a primary refined product;
and c, adding acid into the primary refined product, adjusting the pH value to 1-3, heating to 50-100 ℃, preserving the temperature for 0.5-1h, filtering, cooling and crystallizing the filtrate, filtering, washing and drying to obtain the product.
The preferred refining step is favorable for improving the yield and the purity of the target product, the HPLC purity of the refined mesotrione impurity 1 is more than 99%, and the yield can reach 94-98%.
Preferably, in step a, the alkaline solution is sodium methoxide solution, potassium methoxide solution, sodium ethoxide solution, potassium ethoxide solution, sodium hydroxide solution or potassium hydroxide solution.
More preferably, the alkaline solution is a potassium hydroxide solution.
Preferably, the concentration of the alkaline solution is 30 to 35 wt%.
Preferably, in step a, the washing solvent is water, methanol, ethanol or isopropanol.
More preferably, in step a, the washing solvent is methanol.
More preferably, in step a, the amount of washing solvent added is 2-6 times the mass of mesotrione.
Further preferably, the addition amount of the washing solvent is 4 times of the mass of the mesotrione.
Preferably, the temperature of the cyclization reaction is 60 ℃.
Preferably, the time of the cyclization reaction is 2-4 h.
Preferably, in the step a, the temperature of the salt forming reaction is 50-90 ℃, and the time of the salt forming reaction is 0.5-1 h.
More preferably, in step a, the temperature of the salt formation reaction is 65-75 ℃.
Optionally, in step b, the acid is hydrochloric acid, sulfuric acid, acetic acid or phosphoric acid.
More preferably, in step b, the acid is hydrochloric acid.
Preferably, in the step b, the temperature for cooling and crystallizing is 0-30 ℃ and the time is 0.5-2 h.
More preferably, in the step b, the temperature for cooling and crystallization is 5-10 ℃.
Preferably, in the step c, the temperature for cooling and crystallizing is 0-30 ℃ and the time is 0.5-2 h.
More preferably, in step c, the temperature for cooling and crystallization is 5-10 ℃.
Preferably, in the step c, the temperature is raised to 60-85 ℃, and the temperature is kept for 0.5-1 h.
Preferably, in step c, the acid is hydrochloric acid or sulfuric acid.
More preferably, in step b, the acid is hydrochloric acid.
The acid may be a commercially available chemically pure acid or a dilute acid solution, preferably a dilute acid solution having a concentration of 30-40 wt%.
According to the preparation method of the impurity compound 1 of mesotrione, the salt thereof, the tautomer thereof or the salt of the tautomer thereof, provided by the invention, the selected reagents and solvents are all reagents commonly used in the industrial field, the reagents are cheap and easy to obtain, the operation is simple, the reaction conditions are mild, the HPLC purity of the prepared product can reach 99.9%, the yield can reach 94-98%, the quality requirement of impurities is met, the preparation method can be used as a reference substance for the quality research of mesotrione, and the guarantee is provided for the production and the medication safety of mesotrione.
Drawings
Figure 1 is a mass spectrum of mesotrione impurity compound 1 prepared in example 1 of the present invention;
figure 2 is a liquid chromatogram of mesotrione impurity compound 1 prepared in example 1 of the present invention;
figure 3 is an infrared spectrum of mesotrione impurity compound 1, prepared as in example 1 of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
In order to better illustrate the invention, the following examples are given by way of further illustration.
Example 1
A process for preparing mesotrione impurity compound 1, a salt thereof, a tautomer thereof, or a salt of the tautomer thereof:
adding 40g of mesotrione and 800g of water into a 1000mL reaction bottle at the temperature of 20 ℃, starting stirring, adding a hydrochloric acid solution with the mass concentration of 30 wt% to adjust the pH value to 1.1, adding 40g of iron powder, controlling the sample liquid phase in the reaction process, heating to 50 ℃ when the HPLC content of the mesotrione is less than 1%, carrying out cyclization reaction, reacting for 4 hours, filtering while the solution is hot, washing the obtained filter cake with 240g of isopropanol, filtering after the washing is finished, adding the filter cake into a four-mouth bottle, adding 500g of water for dissolving, then adding a potassium hydroxide solution with the mass concentration of 30 wt%, adjusting the pH value to 13.8, stirring and heating to 90 ℃, carrying out heat preservation reaction for 0.5 hours, filtering while the solution is hot, adding a hydrochloric acid solution with the mass concentration of 30 wt% into the filtrate, adjusting the pH value to 1.2, cooling to 30 ℃ for crystallization for 2 hours, and filtering to obtain a crude product. Adding 500g of water into a reaction bottle, adding 30 wt% of hydrochloric acid aqueous solution to adjust the pH value to 1.5, heating to 50 ℃ under the condition of stirring, preserving heat for 1h, filtering while hot, adding 500g of ice blocks into the filtrate, cooling to 30 ℃, crystallizing for 1h, separating out yellow products, filtering again, washing the products with ice water, and then drying under reduced pressure at 50 ℃ to obtain 33g of target products, wherein the purity of the liquid phase is 99.23%, and the yield is 95.9%.
1HNMR(43MHz，DMSO)：δ12.04(1H,s)，δ8.41-7.31(3H,m)，δ2.80(2H,s)，δ2.55(3H,s)，δ2.10-1.87(11H,d)。
ESI-MS：[M+1]+The theoretical calculation value is 291.8, the experimental measurement value is 291.8, and the actual value is consistent with the theoretical value. The mass spectrum is shown in FIG. 1, and the liquid phase spectrum is shown in FIG. 2.
The infrared spectrum of the prepared target product is shown in fig. 3.
Example 2
A process for preparing mesotrione impurity compound 1, a salt thereof, a tautomer thereof, or a salt of the tautomer thereof:
adding 40g of mesotrione and 400g of diethoxymethane into a 1000mL reaction bottle at the temperature of 30 ℃, starting stirring, adding a sulfuric acid solution with the mass concentration of 30 wt% to adjust the pH value to 4.8, adding 120g of zinc powder, controlling the sample liquid phase in the reaction process, heating to 70 ℃ when the HPLC content of mesotrione is less than 1%, carrying out cyclization reaction, reacting for 2 hours, filtering while the solution is hot, washing the obtained filter cake with 90g of ethanol, filtering after the washing is finished, adding the filter cake into a four-mouth bottle, adding 100g of water for dissolving, then adding a sodium hydroxide solution with the mass concentration of 30 wt%, adjusting the pH value to 14.1, stirring and heating to 50 ℃, carrying out heat preservation reaction for 1 hour, filtering while the solution is hot, adding a hydrochloric acid solution with the mass concentration of 30 wt% into the filtrate, adjusting the pH value to 2.8, cooling to 0 ℃ for crystallization for 0.5 hour, and filtering to obtain a crude product. Adding the crude product into a reaction bottle, adding 200g of water, adding a hydrochloric acid aqueous solution with the mass concentration of 30 wt% to adjust the pH value to 2.7, heating to 100 ℃ under the condition of stirring, preserving the temperature for 0.5h, filtering while the solution is hot, adding 200g of ice blocks into the filtrate, cooling to 0 ℃, crystallizing for 0.5h, separating out a yellow product, filtering again, washing the product with ice water, and then drying under reduced pressure at 50 ℃ to obtain 32.5g of a target product, wherein the purity of a liquid phase is 99.55%, and the yield is 94.6%.
1HNMR(43MHz，DMSO)：δ12.04(1H,s)，δ8.41-7.31(3H,m)，δ2.80(2H,s)，δ2.55(3H,s)，δ2.10-1.87(11H,d)。
ESI-MS：[M+1]+The theoretical calculation value is 291.8, the experimental measurement value is 291.8, and the actual value is consistent with the theoretical value.
Example 3
A process for preparing mesotrione impurity compound 1, a salt thereof, a tautomer thereof, or a salt of the tautomer thereof:
adding 40g of mesotrione and 200g of methyl tert-butyl ether into a 1000mL reaction bottle at 25 ℃, starting stirring, adding a hydrochloric acid solution with the mass concentration of 30 wt% to adjust the pH value to 2.5, adding 60g of iron powder, controlling the sample liquid phase in the reaction process, heating to 60 ℃ when the HPLC content of the mesotrione is less than 1%, carrying out cyclization reaction, reacting for 3 hours, filtering while the solution is hot, washing the obtained filter cake with 80g of methanol, filtering after the washing is finished, adding the filter cake into a four-mouth bottle, adding 350g of water for dissolving, then adding a sodium methoxide solution with the mass concentration of 35 wt%, adjusting the pH value to 13.8, stirring to 70 ℃, carrying out heat preservation reaction for 0.5 hour, filtering while the solution is hot, adding a hydrochloric acid solution with the mass concentration of 30 wt% into the filtrate, adjusting the pH value to 1.8, cooling to 5 ℃ for crystallization for 1 hour, and filtering to obtain a crude product. Adding the crude product into a reaction bottle, adding 200g of water, adding a hydrochloric acid aqueous solution with the mass concentration of 30 wt% to adjust the pH value to 1.2, heating to 75 ℃ under the condition of stirring, preserving the temperature for 1h, filtering while the solution is hot, adding 500g of ice blocks into the filtrate, cooling to 10 ℃, crystallizing for 1h, separating out a yellow product, filtering again, washing the product with ice water, and then drying under reduced pressure at 50 ℃ to obtain 33.8g of a target product, wherein the purity of a liquid phase is 99.90%, and the yield is 98.2%.
1HNMR(43MHz，DMSO)：δ12.04(1H,s)，δ8.41-7.31(3H,m)，δ2.80(2H,s)，δ2.55(3H,s)，δ2.10-1.87(11H,d)。
ESI-MS：[M+1]+The theoretical calculation value is 291.8, the experimental measurement value is 291.8, and the actual value is consistent with the theoretical value.
The reaction conditions, such as temperature, time, solvent and the like, in the example 1 of the present invention are replaced by other conditions defined in the specification of the present invention, and all the technical effects basically equivalent to those in the example 1 can be achieved.
Comparative example 1
The present comparative example provides a method of synthesizing mesotrione impurity compound 1:
adding 50g of mesotrione into a four-mouth bottle, adding 400mL of water, starting stirring, and dropwise adding a potassium hydroxide solution with the mass concentration of 40 wt% at 50 ℃ until the solution is clear. After the solution was dissolved, the feed solution was put into an autoclave, 5g of Raney nickel was put into the autoclave, the autoclave was closed, and the gas in the autoclave was replaced with nitrogen and hydrogen in this order. Then heating to 50-60 ℃, slowly introducing hydrogen, maintaining the pressure at 0.3-0.4MPa and the temperature at 50-60 ℃ until the pressure is not reduced any more, and ending the reaction. And (2) extruding the feed liquid through a filter by using nitrogen, acidifying the extruded feed liquid to be neutral by using a sulfuric acid solution with the mass concentration of 30 wt% under the protection of nitrogen, heating to 80-90 ℃, adding 5g of ferric trichloride as a catalyst, carrying out heat preservation reaction, sampling in the reaction process, carrying out HPLC detection, carrying out central control until the content of an intermediate is less than 1%, ending the reaction, cooling to room temperature, filtering, and washing to obtain a mesotrione impurity compound 1, wherein the HPLC content is 46%, the residual 36% of the mesotrione raw material and 6.95% of main unknown impurities. The specific reaction process is as follows:
the detection method for controlling the content of the intermediate in the reaction process comprises the following steps: a chromatographic column: c18 column (4.6X 250mm, 5 μm);
mobile phase: mobile phase A: mobile phase B40: 60; the mobile phase A is methanol; the mobile phase B is 0.02mol/L KH2PO4Aqueous solution (H)3PO4Adjusting the pH value to 3);
detection wavelength: 220 nm;
flow rate: 0.8 mL/min.
Comparative example 2
The present comparative example provides a method of synthesizing mesotrione impurity compound 1:
4.87g of triphosgene is dissolved in 10.94g of tetrahydrofuran and is used after being dissolved and cleaned. 10.11g of o-amino-p-methylsulfonylbenzoic acid and 10.94g of tetrahydrofuran are added into a four-necked bottle, the temperature is raised to 50-60 ℃, and a tetrahydrofuran solution of triphosgene is added dropwise. And (4) filtering after the content of the HPLC (high performance liquid chromatography) neutral control raw material is less than 0.5%, and dissolving a filter cake in tetrahydrofuran to obtain a tetrahydrofuran solution of an intermediate for later use.
And adding 1.09g of cyclohexanedione, 5.00g of tetrahydrofuran and 1.30g of NaH into another four-mouth bottle, heating to 90 ℃, slowly dropwise adding a tetrahydrofuran solution of the intermediate, keeping the temperature for a middle control after dropwise adding is finished until the content of the intermediate is less than 1%, finishing the reaction, cooling to room temperature, filtering, and washing with water to obtain the mesotrione impurity compound 1, wherein the HPLC content is 78.0%, the intermediate content is 9.88%, and the content of the main unknown impurity is 10.10%. The specific reaction process is as follows:
the detection method for controlling the content of the intermediate in the reaction process comprises the following steps: a chromatographic column: c18 column (4.6X 250mm, 5 μm);
mobile phase: mobile phase A: mobile phase B40: 60; the mobile phase A is methanol; the mobile phase B is 0.02mol/L KH2PO4Aqueous solution (H)3PO4Adjusting the pH value to 3);
detection wavelength: 220 nm;
flow rate: 0.8 mL/min.
Comparative example 3
The present comparative example provides a method of synthesizing mesotrione impurity compound 1:
adding 5.0g of o-amino-p-methylsulfonylbenzaldehyde, 20.0g of water and 2.0g of hydrochloric acid solution with the mass concentration of 32% into a four-mouth bottle, uniformly stirring, heating to 50 ℃, adding 3.0g of cyclohexanedione and 1.0g of ferric trichloride, maintaining the temperature at 50 ℃, keeping the temperature for central control, reacting for 6 hours, cooling to room temperature, filtering and washing with water to obtain a mesotrione impurity compound 1, wherein the total area content of a target product liquid phase is 25.36%, the residual content of the o-amino-p-methylsulfonylbenzaldehyde is 46%, the residual content of the cyclohexanedione is 10.1%, and the content of main unknown impurities is 12.80%. The specific reaction process is as follows:
the HPLC method for detecting the mesotrione impurity compound 1 and the content of impurities therein in examples 1-3 and comparative examples 1-3 is as follows:
a chromatographic column: c18 column (4.6X 250mm, 5 μm);
mobile phase: mobile phase A: mobile phase B40: 60; the mobile phase A is methanol; the mobile phase B is 0.02mol/L KH2PO4Aqueous solution (H)3PO4Adjusting the pH value to 3);
detection wavelength: 220 nm;
flow rate: 0.8 mL/min.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents or improvements made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (10)
1. A mesotrione impurity compound 1, a salt thereof, a tautomer thereof or a salt of the tautomer thereof:
2. a process for preparing mesotrione impurity compound 1, a salt thereof, a tautomer thereof or a salt of the tautomer thereof, as claimed in claim 1, comprising the steps of:
in a solvent, carrying out reduction reaction on mesotrione and reducing metal powder under an acidic condition until the HPLC content of the mesotrione is less than 1%, heating to 50-70 ℃, and carrying out cyclization reaction to obtain the compound shown in formula 1, a salt thereof, a tautomer thereof or a salt of the tautomer thereof.
3. The process for preparing mesotrione impurity compound 1, a salt thereof, a tautomer thereof or a salt of the tautomer thereof, as claimed in claim 2, wherein the acidic conditions are at a pH of 1-5 and the temperature of the reduction reaction is 20-30 ℃.
4. The process for preparing mesotrione impurity compound 1, a salt thereof, a tautomer thereof, or a salt of the tautomer, as claimed in claim 2, wherein the acid used in the reduction reaction is at least one of hydrochloric acid, sulfuric acid, phosphoric acid or acetic acid; and/or
In the reduction reaction, the solvent is at least one of water, acetonitrile, tetrahydrofuran, N-dimethylformamide, methyl tert-butyl ether or diethoxymethane.
5. The process for preparing mesotrione impurity compound 1, a salt thereof, a tautomer thereof or a salt of the tautomer, as claimed in claim 2, wherein the reducing metal powder is iron, zinc or magnesium powder; and/or
The mass ratio of the mesotrione to the reducing metal powder is 1: 1-3; and/or
In the reduction reaction, the mass ratio of the solvent to the mesotrione is 5-20: 1.
6. The process for preparing mesotrione impurity compound 1, a salt thereof, a tautomer thereof or a salt of the tautomer thereof, as claimed in claim 2, further comprising the refining step of:
step a, washing the obtained crude product with a washing solvent, then adding an alkaline solution, adjusting the pH to be more than or equal to 13, carrying out a salt forming reaction, and filtering to obtain a filtrate;
b, adding acid into the filtrate, adjusting the pH value to 1-3, cooling, crystallizing and filtering to obtain a primary refined product;
and c, adding acid into the primary refined product, adjusting the pH value to 1-3, heating to 50-100 ℃, preserving the temperature for 0.5-1h, filtering, cooling and crystallizing the filtrate, filtering, washing and drying to obtain the product.
7. The process for preparing mesotrione impurity compound 1, a salt thereof, a tautomer thereof or a salt of the tautomer thereof, as claimed in claim 6, wherein in step a, the basic solution is sodium methoxide solution, potassium methoxide solution, sodium ethoxide solution, potassium ethoxide solution, sodium hydroxide solution or potassium hydroxide solution; and/or
In step a, the washing solvent is water, methanol, ethanol or isopropanol.
8. The process for preparing mesotrione, impurity compound 1, a salt thereof, a tautomer thereof, or a salt of the tautomer, as claimed in claim 6, wherein in step a, the temperature of the salt-forming reaction is between 50 ℃ and 90 ℃ and the time of the salt-forming reaction is between 0.5h and 1 h.
9. The process for preparing mesotrione impurity compound 1, a salt thereof, a tautomer thereof or a salt of the tautomer thereof, as claimed in claim 6, wherein in step b the acid is hydrochloric acid, sulfuric acid, acetic acid or phosphoric acid; and/or
In the step b, the temperature for cooling and crystallizing is 0-30 ℃ and the time is 0.5-2 h.
10. The process for preparing mesotrione impurity compound 1, a salt thereof, a tautomer thereof or a salt of the tautomer thereof, as claimed in claim 6, wherein in step c, the temperature of the reduced temperature crystallization is from 0 ℃ to 30 ℃ for from 0.5 to 2 hours; and/or
In step c, the acid is hydrochloric acid or sulfuric acid.
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| CN112225698B (en) | 2022-02-11 |
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