Purification method of Azoxystrobin

Abstract

The present specification relates to a method for purifying azoxystrobin, comprising an evaporative crystallization step in which azoxystrobin crystals are introduced into a reaction solution in which the synthesis of azoxystrobin has been completed, and the synthesized azoxystrobin is crystallized while evaporating the solvent in the reaction solution by reducing the pressure.

Description

Technology Field

[0001] This specification relates to a method for purifying azoxystrobin. Background Technology

[0002] The synthesis of the azoxystrobin generic active ingredient is carried out through a coupling reaction between 2-cyanophenol and a methoxyacrylate intermediate using a DABCO catalyst. After the reaction, a process capable of reducing manufacturing costs must be established for the synthesized material to ensure economic viability.

[0003] The methods in the existing prior art literature involve a process of recovering the solvent by reduced pressure after synthesis and performing multiple purification processes to reduce the impurity content.

[0004] However, this method causes an increase in process costs and a decrease in yield.

[0005] Accordingly, it is necessary to secure a purification process that can ensure purity and yield while reducing process costs. The problem to be solved

[0006] This specification aims to provide a method for purifying azoxystrobin by introducing azoxystrobin crystals and performing vacuum distillation. means of solving the problem

[0007] The present specification provides a method for purifying azoxystrobin, comprising an evaporation step of evaporating a solvent in a reaction solution by reducing the pressure of the reaction solution in which the synthesis of azoxystrobin has been completed, and introducing azoxystrobin crystals into the reaction solution before or after the reduction of pressure.

[0008] The method for purifying azoxystrobin according to the present specification further includes the step of, before adding azoxystrobin crystals to the reaction solution, reducing the pressure of the reaction solution in which the synthesis of azoxystrobin has been completed to adjust the concentration so that the concentration of the reaction solution is greater than or equal to the saturation concentration.

[0009] In the method for purifying azoxystrobin according to the present specification, the amount of azoxystrobin crystal added is 0.5% by weight or more and 20% by weight or less based on the weight of azoxystrobin in the reaction solution before adding the azoxystrobin crystal to the reaction solution.

[0010] In the purification method of azoxystrobin of the present specification, the temperature of the reaction solution is controlled to be 40°C or higher and 80°C or lower.

[0011] In the method for purifying azoxystrobin according to the present specification, the purity of the azoxystrobin in the reaction solution after adding azoxystrobin crystals to the reaction solution and performing an evaporation step is higher than the purity of the azoxystrobin in the reaction solution before adding azoxystrobin crystals to the reaction solution.

[0012] In the method for purifying azoxystrobin according to the present specification, the peak area associated with azoxystrobin measured by chromatography of the reaction solution in which azoxystrobin crystals are added and an evaporation step is performed is wider than the peak area associated with azoxystrobin measured by chromatography of the reaction solution in which azoxystrobin crystals are added before the reaction solution in which azoxystrobin crystals are added.

[0013] In the purification method of azoxystrobin of the present specification, the percentage of the amount of solvent recovered through the evaporation step is 90% or more based on the total amount of solvent introduced into the reaction solution. Effects of the invention

[0014] The method for purifying azoxystrobin according to the first embodiment of this specification reduces the cost of the azoxystrobin purification process.

[0015] The method for purifying azoxystrobin according to the second embodiment of this specification reduces the time of the azoxystrobin purification process.

[0016] The method for purifying azoxystrobin according to the third embodiment of this specification has the advantage of a high recovery rate of the solvent introduced during the reaction in the azoxystrobin purification process. Brief explanation of the drawing

[0017] Figure 1 is the crystal size distribution of azoxystrobin used in the example. Specific details for implementing the invention

[0018] The present specification is described in detail below.

[0019] The present specification provides a method for purifying azoxystrobin, comprising an evaporation step of depressurizing a reaction solution in which the synthesis of azoxystrobin has been completed to evaporate a solvent within the reaction solution, and introducing azoxystrobin crystals into the reaction solution before or after depressurization. In this case, depressurization continues during the evaporation step, and the depressurized state continues from the start of depressurization until the end of the evaporation step. "Before depressurization" means introducing azoxystrobin crystals before starting depressurization, and "after depressurization" means introducing azoxystrobin crystals while maintaining depressurization during depressurization, or introducing azoxystrobin crystals after stopping depressurization and applying depressurization again.

[0020] The present specification provides a method for purifying azoxystrobin, comprising the step of adding azoxystrobin crystals to a reaction solution in which the synthesis of azoxystrobin has been completed, and then reducing the pressure.

[0021] The present specification provides a method for purifying azoxystrobin, comprising an evaporation crystallization step of introducing azoxystrobin crystals into a reaction solution in which the synthesis of azoxystrobin has been completed, and crystallizing the synthesized azoxystrobin while evaporating the solvent in the reaction solution by reducing the pressure.

[0022] In one embodiment of the present specification, after azoxystrobin crystals are introduced into a reaction solution in which the synthesis of azoxystrobin has been completed, the pressure inside the container containing the reaction solution is lowered. In other words, a pump is used to remove gas from the container containing the reaction solution, thereby lowering the vapor pressure of the gaseous state inside the container. In this process, the gas removed due to the lowered vapor pressure contains solvent evaporated from the reaction solution, and a trap is installed to recover the gaseous solvent from the removed gas as a liquid.

[0023] When the pressure is reduced without adding azoxystrobin crystals to the reaction solution where the synthesis of azoxystrobin has been completed, the azoxystrobin dissolved in the solution does not precipitate due to the characteristics of azoxystrobin, and as the solvent evaporates, the concentration of azoxystrobin gradually increases, while conversely, as the concentration of the solvent gradually decreases, the rate of solvent evaporation decreases. If the rate of solvent evaporation decreases, the time required to remove the solvent by evaporation increases, and to reduce the time, the temperature must be raised or a higher reduced pressure must be applied.

[0024] Furthermore, as the concentration of azoxystrobin increases, the viscosity of the entire solution rises, transforming it into a viscous liquid that is difficult to transport. Therefore, if evaporation is performed only up to a transportable viscosity, it is difficult to recover a certain amount of solvent. Although it is possible to transport the solution by continuing evaporation and adding an antisolvent that mixes with the solvent to precipitate it, in this case, the reaction solvent added during synthesis that did not evaporate mixes with the antisolvent, making it difficult to separate and recover the reaction solvent and antisolvent for recycling.

[0025] On the other hand, as in the method for purifying azoxystrobin of the present specification, when azoxystrobin crystals are added to a reaction solution in which the synthesis of azoxystrobin has been completed, crystallization of azoxystrobin proceeds along with the evaporation of the solvent under reduced pressure.

[0026] Accordingly, even if the amount of reaction solution decreases as the amount of solvent decreases over time, the rate of increase in the concentration of the reaction solution is reduced, significantly reducing the decrease in the evaporation rate caused by the increase in concentration, and allowing the solvent to evaporate easily.

[0027] According to the method for purifying azoxystrobin of the present specification, when azoxystrobin crystals are introduced into a reaction solution in which the synthesis of azoxystrobin has been completed and the pressure is reduced, a solid product can be obtained in which most of the solvent has evaporated once evaporative crystallization is complete. Subsequently, by adding an antisolvent such as water, the product can be made into a state that is ready for washing and transport simultaneously.

[0028] In this process, the solvent introduced for the synthesis of azoxystrobin can be almost entirely recovered, increasing the solvent reuse rate and significantly improving the recovery rate of azoxystrobin.

[0029] In this specification, the synthesis of azoxystrobin is not specified as long as azoxystrobin can be synthesized, and the reactants, solvents, conditions, etc. used can be synthesized using methods known in the art.

[0030] In this specification, the temperature of the reaction solution may be lower than the boiling point of the reaction solution considering reduced pressure conditions, and the boiling point of the reaction solution may be a temperature considering the phenomenon where it becomes higher than the boiling point of the reaction solvent added during synthesis. Preferably, it may be lower than the boiling point of the reaction solvent added during synthesis. In this specification, the temperature of the reaction solution may be room temperature or higher, specifically 40°C or higher. Here, room temperature refers to the ambient temperature as is without heating or cooling, and may be 20±5°C.

[0031] In the present specification, when ethyl acetate with a boiling point of 77.1°C is used as the reaction solvent added during synthesis, the temperature of the reaction solution may be 80°C or lower, taking into account the boiling point elevation phenomenon, and specifically, may be controlled to be 40°C or higher and 80°C or lower.

[0032] In this specification, the temperature of the reaction solution is controlled to 40°C or higher and 80°C or lower before adding azoxystrobin crystals to the reaction solution in which the synthesis of azoxystrobin has ended, and the temperature of the reaction solution may be maintained at 40°C or higher and 80°C or lower even while performing the evaporation crystallization step.

[0033] The method for purifying azoxystrobin according to the present specification may further include the step of adjusting the concentration of the reaction solution by vacuum distillation of the reaction solution in which the synthesis of azoxystrobin has been completed, before adding azoxystrobin crystals to the reaction solution, so that the concentration of the reaction solution is greater than or equal to the saturation concentration. Specifically, if the saturation concentration of azoxystrobin in the reaction solution is 40g of azoxystrobin per 100g of solvent, the reaction solution in which the synthesis of azoxystrobin has been completed may be vacuum distilled until it reaches a concentration greater than or equal to the saturation concentration.

[0034] In this specification, the step of controlling the concentration may utilize a pump to remove gas from a container holding the reaction solution, thereby lowering the vapor pressure of the gaseous state within the container. In this process, the removed gas, due to the lowered vapor pressure, contains solvent evaporated from the surface of the reaction solution, and a trap is installed to recover the gaseous solvent among the removed gas as a liquid.

[0035] In this specification, the amount of azoxystrobin crystals added is determined by considering the rate at which the crystals precipitate relative to the rate at which the solvent evaporates. Specifically, the amount of azoxystrobin crystals added may be 0.5% by weight or more and 20% by weight or less, based on the weight of azoxystrobin in the reaction solution before adding the azoxystrobin crystals to the reaction solution. In this case, azoxystrobin in a solid form can be obtained by controlling the rate at which the crystals precipitate within an appropriate time for recovering the solvent.

[0036] The amount of azoxystrobin crystal added may be 10% by weight or less, 5% by weight or less, 4% by weight or less, 3% by weight or less, 2% by weight or less, or 1% by weight or less, based on the weight of azoxystrobin in the reaction solution before adding the azoxystrobin crystal to the reaction solution.

[0037] The input amount of the azoxystrobin crystals can control the crystal precipitation rate, and the crystal precipitation rate increases as the input amount of the azoxystrobin crystals increases. If the solvent evaporates faster than the crystal precipitation rate and the liquid does not become viscous before the crystals precipitate, it is desirable to control the input amount of the azoxystrobin crystals to a minimum by considering reduced pressure and temperature conditions. This is because a smaller input amount of azoxystrobin crystals is advantageous for processes following evaporative crystallization, such as re-purification, washing, and drying.

[0038] In this specification, the average size of the azoxystrobin crystals introduced may be 10 μm or more and 500 μm or less. Here, the size is the length of the line connecting two points on the circumference of the crystal, and preferably the length of the longest line connecting two points on the circumference of the crystal. It is preferable that the average size of the azoxystrobin crystals introduced be smaller, as this results in a larger surface area relative to weight, but it may be 10 μm or more and 200 μm or less.

[0039] In this specification, the purity of azoxystrobin in the reaction solution after adding azoxystrobin crystals to the reaction solution and performing an evaporative crystallization step is higher than the purity of azoxystrobin in the reaction solution before adding azoxystrobin crystals to the reaction solution. This means that it has been effectively purified through evaporative crystallization.

[0040] In this specification, the peak area associated with azoxystrobin measured by chromatography of the reaction solution in which azoxystrobin crystals are added and the evaporative crystallization step is performed is wider than the peak area associated with azoxystrobin measured by chromatography of the reaction solution in which azoxystrobin crystals are added and the reaction solution in which the evaporative crystallization step is performed. This means that the purity of azoxystrobin has been improved through evaporative crystallization.

[0041] Area% of a specific peak obtained through chromatographic measurement is a widely used method for measuring sample purity and is used to evaluate the quantitative proportions of substances contained within the sample. For example, if a sample contains substances A, B, and C, the peak area increases depending on the amounts of A, B, and C present. An improvement in the purity of a substance (A) means that the amount of A contained in the sample has increased; more precisely, it means that the relative proportion of A, i.e., A / (A+B+C), has increased. Therefore, an improvement in purity can be evaluated by an increase in Area%.

[0042] In this specification, for the chromatographic measurement, the solution was taken before and after the evaporation crystallization process, respectively, and chromatographically measured. The relative areas of the peaks related to azoxystrobin were determined by chromatographic measurement, and the results before and after the evaporation crystallization process were compared.

[0043] Here, the sample for chromatographic measurement prior to the evaporation crystallization process is taken from the solution immediately before the solvent distillation begins under reduced pressure. Specifically, the solution immediately before the solvent distillation begins under reduced pressure is obtained by adding water to the reaction solution where the synthesis of azoxystrobin has been completed, stirring, and separating the layers to obtain an organic layer; through this preliminary purification process, water-soluble impurities have been removed.

[0044] In addition, the sample for chromatographic measurement after the evaporation crystallization process is a solution obtained by adding an antisolvent after the evaporation crystallization is finished, stirring for about 30 minutes, and then diluting the crystals, which have undergone filtering and drying steps, in a solvent for chromatographic measurement.

[0045] In this specification, when azoxystrobin crystals are introduced, the crystals grow as self-assembly occurs on the surface of the introduced azoxystrobin crystals as seeds of crystals, so the crystals themselves are mostly composed of azoxystrobin. Accordingly, when the evaporation crystallization process is completed, the precipitated crystals and a solution containing impurities between the crystals or on the surface of the crystals remain. Since the residual solution and impurities within the solution can be easily removed by adding an antisolvent that does not dissolve the precipitated crystals well, the peak area % of azoxystrobin increases after evaporation crystallization, thereby improving the purity of azoxystrobin.

[0046] In this specification, the chromatography measured to determine the area % and purity of azoxystrobin may be gas chromatography (GC) or liquid chromatography (LC), and preferably high-performance liquid chromatography (HPLC).

[0047] In this specification, based on the total amount of solvent introduced into the reaction solution, the percentage of the amount of solvent recovered through the evaporation crystallization step may be 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, or 98% or more.

[0048] In this specification, based on the total amount of solvent introduced into the reaction solution, the percentage of the amount of solvent recovered through the concentration control step and the evaporation crystallization step may be 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more, or 98% or more.

[0049] In this specification, the time for performing the evaporation crystallization step can be determined according to the size of the reactor, solvent, temperature, and pressure conditions. For example, when the temperature of the reaction solution is 40°C, the time can be selected to be 2 hours or more and 3 hours or less.

[0050] In this specification, the point at which the evaporation crystallization step is terminated is when most of the solvent is removed by evaporation and the remaining material is in a solid state, or when 90% or more, or even 95% or more, of the weight of the reaction solvent at the end of synthesis has been removed or recovered.

[0051] The method for purifying azoxystrobin according to the present specification may further include an additional purification step after the evaporation crystallization step. The additional purification step may further include at least one step among washing, filtering, drying, and recrystallization steps. At this time, since most of the reaction solvent added for synthesis has been removed, there is a wide range of choices for the recrystallization solvent.

[0052] The present specification will be explained in more detail below through examples. However, the following examples are intended only to illustrate the present specification and are not intended to limit the present specification.

[0053] [Synthetic Example]

[0054]

[0055] P-1 (100g, 0.31 mol) and 500g of ethyl acetate (EA) were added to a reaction flask and stirred at room temperature for 10 minutes. Then, K2CO3 (47.5g, 0.35 mol) was added, and after 10 minutes, 2-cyanophenol (41.0g, 0.35 mol) was added, and the mixture was stirred while raising the temperature to 80°C to reflux the reaction mixture.

[0056] The above reaction mixture is refluxed and stirred at 80°C for 6 hours, and the reaction is terminated when the residual amount of P-1 is less than 2% as determined by high-performance liquid chromatography (HPLC) analysis.

[0057] 200 g of water was added to terminate the reaction, and after standing for layer separation, the lower aqueous layer was discarded. 200 g of water was added again to the obtained upper organic layer to wash it, and the organic layer was separated.

[0058] For a fair comparison, the separated organic layer was divided into 125g portions, and experiments for the Examples and Comparative Examples were conducted separately. Each 125g portion of the organic layer contained approximately 24.21g of azoxystrobin (synthetic yield 96.3%), unreacted material (P-1), by-products (DPPA, etc.), and 100g of ethyl acetate used as the reaction solvent. (See Table 2 below)

[0059] [Example 1]

[0060] In the synthesis example, the temperature of 125g of the reaction solution divided was adjusted to 40℃. Under reduced pressure conditions of approximately 200–300 torr, more than 20g of the solvent was evaporated, and the reduced pressure state was maintained (concentration control step) until the concentration exceeded the saturation concentration. The reduced pressure was briefly stopped, and 0.25g of azoxystrobin crystals (average size approximately 70μm) having the size distribution shown in Fig. 1 (1wt%) based on the weight of azoxystrobin in the reaction solution was added. Approximately 22.5g of solvent (ethyl acetate) was recovered through the concentration control step before adding the azoxystrobin crystals.

[0061] At this time, the saturation concentration at 40℃ was 31.22g of azoxystrobin per 100g of ethyl acetate, and the volume of the reaction solution at the start of reduced pressure was 115mL, and considering the above saturation concentration, the saturation point was determined when the volume became 90mL or less.

[0062] After that, the reduced pressure was restarted under conditions of approximately 200 to 300 torr, and an additional 75.5g of solvent was evaporated along with crystallization (evaporation crystallization step). During this process, the total reduced pressure time was 165 minutes, excluding the time for introducing the crystals.

[0063] After the evaporation crystallization was completed, about 100 ml of isopropyl alcohol was added and the mixture was washed by stirring at room temperature for about 30 minutes. Subsequently, the mixture was filtered and dried to obtain solid azoxystrobin (Az).

[0064] [Examples 2 to 4]

[0065] Except for adding crystals of azoxystrobin (average size about 70 μm) having the size distribution of Fig. 1 with the content of Table 2 below, crystallization was carried out in the same manner as in Example 1 while evaporating the solvent to recover ethyl acetate, and solid azoxystrobin (Az) was obtained.

[0066] [Comparative Example 1]

[0067] The temperature of 125 g of the reaction solution divided in the synthesis example was adjusted to 40°C. The solvent was evaporated for 3 hours under reduced pressure conditions of about 200 to 300 torr, and about 75.5 g of solvent was recovered. Unlike the examples, crystallization did not proceed under the conditions of Comparative Example 1, and a liquid azoxystrobin with high viscosity was obtained.

[0068] [Experimental Example]

[0069] Before the purification below, each sample of Examples 1 to 4 and Comparative Example 1 was measured using HPLC (Waters) under the following conditions, and the area of ​​each component relative to the total peak area was shown as a percentage (%) in Table 1.

[0070] - Column: CAPCELL PAK C18, 4.7um, 250mm

[0071] - Mobile phase: ACN (Acetonitrile):H2O = 6:4

[0072] - Detector wavelength: 254 µm

[0073] - Mobile phase flow rate: 0.7 ml / min

[0074] - Mode: Isocratic

[0075] - Sample concentration: 1000 ppm

[0076] The sample was measured by diluting approximately 20 mg of dried crystals in ACN to a concentration of 1000 ppm. Here, Comparative Example 1 was measured by diluting a high-concentration liquid phase in ACN to the same concentration, and before purification, the organic layer separated after water washing in the above synthesis example, that is, the solution immediately before the start of depressurization, was collected and diluted in ACN to the same concentration for measurement.

[0077] Before purification Example 1 Example 2 Example 3 Example 4 Comparative Example 1 target substance Az 96.30% 99.31% 99.44% 99.38% 99.47% 96.30% reactants P-1 0.20% ND ND ND ND 0.20% major impurities DPPA 1.00% 0.42% 0.35% 0.39% 0.33% 1.00% DPPA and other impurities 2.50% 0.27% 0.21% 0.23% 0.20% 2.50%

[0078] The data in Table 1 was organized and presented in Table 2 along with the experimental conditions of Examples 1 to 4 and Comparative Example 1. The amount of DPPA purity improvement in Table 2 below is the difference between the area% of DPPA before purification and the area% of each DPPA (Amount of DPPA purity improvement = Area% of DPPA before purification - Area% of each DPPA).

[0079] In Table 2, the amount of seed added refers to the amount of azoxystrobin crystals added, and is a percentage of the weight of azoxystrobin in the reaction solution before adding the azoxystrobin crystals to the reaction solution.

[0080] In Table 2, the process time is the time from the start of depressurization to the end of depressurization.

[0081] Example 1 Example 2 Example 3 Example 4 Comparative Example 1 Seed input amount [wt%] 1 3 5 10 0 DPPA Purity Improvement Amount [%] 0.58 0.65 0.61 0.67 0 Process time [min] 165 165 160 150 240 Solvent recovery amount (g) 98.0 95.2 96.7 95.1 75.5

[0082] Through Tables 1 and 2, it was confirmed that Examples 1 to 4, in which azoxystrobin crystals were added, showed increased purity compared to Comparative Example 1, in which azoxystrobin crystals were not added. In addition, in this experiment, it was confirmed that the azoxystrobin crystals were produced quickly, so even if 1% of azoxystrobin crystals were added, there was an effective effect.

Claims

Claim 1 A method for purifying azoxystrobin, comprising an evaporation step of depressurizing a reaction solution in which the synthesis of azoxystrobin has been completed to evaporate a solvent within the reaction solution, wherein, prior to depressurizing, azoxystrobin crystals are introduced into the reaction solution, and prior to introducing azoxystrobin crystals into the reaction solution, a step of depressurizing the reaction solution in which the synthesis of azoxystrobin has been completed to adjust the concentration of the reaction solution to be greater than or equal to the saturation concentration, wherein the evaporation step of depressurizing the reaction solution in which the synthesis of azoxystrobin has been completed to evaporate a solvent within the reaction solution is performed under depressurization conditions of 200 torr to 300 torr, and prior to introducing azoxystrobin crystals into the reaction solution, a step of depressurizing the reaction solution in which the synthesis of azoxystrobin has been completed to adjust the concentration of the reaction solution to be greater than or equal to the saturation concentration is performed under depressurization conditions of 200 torr to 300 torr. Claim 2 delete Claim 3 A method for purifying azoxystrobin according to claim 1, wherein the amount of azoxystrobin crystal added is 0.5% by weight or more and 20% by weight or less based on the weight of azoxystrobin in the reaction solution before adding the azoxystrobin crystal to the reaction solution. Claim 4 A method for purifying azoxystrobin according to claim 1, wherein the temperature of the reaction solution is controlled to be 40°C or higher and 80°C or lower. Claim 5 A method for purifying azoxystrobin according to claim 1, wherein the purity of the azoxystrobin in the reaction solution after adding the azoxystrobin crystal and performing the evaporation step is higher than the purity of the azoxystrobin in the reaction solution before adding the azoxystrobin crystal to the reaction solution. Claim 6 A method for purifying azoxystrobin according to claim 1, wherein the peak area associated with azoxystrobin measured by chromatography of the reaction solution in which azoxystrobin crystals are added and an evaporation step is performed is wider than the peak area associated with azoxystrobin measured by chromatography of the reaction solution in which azoxystrobin crystals are added and the reaction solution in which an evaporation step is performed is wider. Claim 7 A method for purifying azoxystrobin according to claim 1, wherein the percentage of the amount of solvent recovered through the evaporation step is 90% or more based on the total amount of solvent introduced into the reaction solution.

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