KR20220033677A - Purification method of Azoxystrobin - Google Patents

Abstract

The present specification relates to a purification method of azoxystrobin, comprising a step of recrystallizing azoxystrobin twice or more using a recrystallization solvent containing alcohol. The purification method of azoxystrobin of the present specification can manufacture azoxystrobin with high purity.

Description

Purification method of Azoxystrobin

The present specification relates to a method for purifying azoxystrobin.

Azoxystrobin raw material synthesis is achieved through coupling reaction with 2-cyanophenol from methoxyacrylate intermediate using DABCO catalyst. However, the starting material for methoxyacrylate used as a raw material contains Di-propenoate (hereinafter referred to as DPPA) and other sub-components, and there is a problem that persists even after the azoxystrobin synthesis process. In addition, there is a problem in that the generated subcomponents remain together even in the final synthesis step.

Most of the subcomponents present after the reaction are removed during one recrystallization with IPA or MeOH as a solvent, but 0.3% or more of the DPPA subcomponent remains, and there is a problem that other subcomponents remain in the range of 0.1 to 0.2%. Residual sub-ingredients can become a problem during product registration, so it is essential to develop a process that can be refined to less than 0.1%.

An object of the present specification is to provide a method for purifying azoxystrobin, which includes recrystallizing azoxystrobin twice or more using a recrystallization solvent containing alcohol.

The present specification relates to a primary recrystallization in which azoxystrobin is obtained by adding a first recrystallization solvent containing alcohol to a reaction solution in which the synthesis of azoxystrobin is completed, and then precipitating azoxystrobin using the first recrystallization solvent. step; and

After adding a second recrystallization solvent containing alcohol to the obtained azoxystrobin, a secondary recrystallization step of precipitating azoxystrobin using the second recrystallization solvent to obtain azoxystrobin,

The first recrystallization step and the second recrystallization step are each independently,

raising the temperature to a final temperature of 68°C or higher and 72°C or lower; and

It provides a method for purifying azoxystrobin comprising the step of obtaining azoxystrobin that is precipitated while cooling to 10° C. or less through a temperature maintenance period of three or more steps.

In the purification method of azoxystrobin of the present specification, the temperature maintenance period of the three or more steps is,

a first temperature holding period for maintaining the cooled temperature after cooling to 60° C. or more and 62° C. or less from the final temperature;

After cooling to 30 ℃ or more and 35 ℃ or less, a second temperature maintenance section for maintaining the cooled temperature; and

After cooling to 10° C. or less, it includes a third temperature maintaining section for maintaining the cooled temperature.

In the purification method of azoxystrobin of the present specification, the cooling rate for cooling from the final temperature to 60° C. or more and 62° C. or less is 0.5° C./min or more and 1° C./min or less.

In the purification method of azoxystrobin of the present specification, the cooling rate for cooling to 30° C. or more and 35° C. or less after the end of the first temperature maintenance period is 0.1° C./min or more and 0.3° C./min or less.

In the purification method of azoxystrobin of the present specification, the cooling rate for cooling to 10° C. or less after the end of the second temperature maintenance period is 10° C./min or more and 15° C./min or less.

In the purification method of azoxystrobin of the present specification, the temperature maintenance period of the three or more steps maintains a constant temperature for 30 minutes or more and 3 hours or less, respectively.

In the purification method of azoxystrobin of the present specification, the first recrystallization solvent and the second recrystallization solvent are isopropyl alcohol or methanol, respectively.

In the purification method of azoxystrobin of the present specification, before the first recrystallization step,

washing with water by adding water to the reaction solution in which the synthesis of azoxystrobin is completed; and

After washing with water, the step of separating the organic layer is further included.

In the purification method of azoxystrobin of the present specification, the method further comprises the step of recovering the evaporated solvent by reducing the separated organic layer.

The purification method of azoxystrobin of the present specification has a high removal rate of DPPA.

The purification method of azoxystrobin of the present specification can prepare azoxystrobin with high purity.

Azoxystrobin having a uniform crystal size can be obtained by the purification method of azoxystrobin of the present specification.

Hereinafter, the present specification will be described in detail.

The present specification provides a method for purifying azoxystrobin, comprising the step of recrystallizing azoxystrobin twice or more using a recrystallization solvent containing alcohol to obtain azoxystrobin. In this case, azoxystrobin having a high removal rate of DPPA and a uniform crystal size can be obtained.

The present specification relates to a primary recrystallization in which azoxystrobin is obtained by adding a first recrystallization solvent containing alcohol to a reaction solution in which the synthesis of azoxystrobin is completed, and then precipitating azoxystrobin using the first recrystallization solvent. step; and

After adding a second recrystallization solvent containing alcohol to the obtained azoxystrobin, the second recrystallization solvent is used to precipitate azoxystrobin to obtain azoxystrobin. A purification method is provided.

The first recrystallization solvent and the second recrystallization solvent may be the same as or different from each other. Preferably, the first recrystallization solvent and the second recrystallization solvent may be the same as each other. In this case, since the solvent remaining in the recrystallized crystal is the same, it is easy to remove the solvent.

In the present specification, the first recrystallization step and the second recrystallization step are each independently,

raising the temperature to a final temperature of 68°C or higher and 72°C or lower; and

and obtaining azoxystrobin that is precipitated while cooling to 10° C. or less through a temperature maintenance period of three or more steps.

In the present specification, the synthesis of azoxystrobin does not specify the reactants, solvents, conditions, etc. used, as long as azoxystrobin can be synthesized, and azoxystrobin can be synthesized by a method known in the art.

In the present specification, the first recrystallization step is,

preparing a mixed solution by adding a first recrystallization solvent containing alcohol to the reaction solution in which the synthesis of azoxystrobin is completed;

raising the temperature of the mixed solution to a final temperature of 68°C or higher and 72°C or lower; and

and obtaining azoxystrobin that is precipitated while cooling the mixed solution to 10° C. or less through at least one temperature maintenance section.

In the present specification, the temperature maintenance section of the first recrystallization step is a temperature maintenance section of three or more steps, and specifically is a temperature maintenance section of three steps.

During recrystallization, if the temperature section is set and cooled to a low temperature in a short time without cooling, solid particles are not uniformly formed in the section where the crystals are precipitated, but particles that agglomerate and agglomerate are generated. The solid particles generated by agglomeration have a color close to brown and have a high content of DPPA subcomponents when the purity is analyzed by high performance liquid chromatography (HPLC).

On the other hand, when a temperature range is given, azoxystrobin is uniformly precipitated with light yellow crystals, and particles with poor purity due to agglomeration are suppressed, and when the recrystallization solvent is removed, DPPA has a purification effect that escapes into solution.

In the present specification, the temperature maintenance period of the three or more steps of the first recrystallization step is,

a first temperature holding period for maintaining the cooled temperature after cooling to 60° C. or more and 62° C. or less from the final temperature;

After cooling to 30 ℃ or more and 35 ℃ or less, a second temperature maintenance section for maintaining the cooled temperature; and

After cooling to 10° C. or less, it includes a third temperature maintaining section for maintaining the cooled temperature.

The first temperature maintenance section is a temperature section for dissolving azoxystrobin, the second temperature maintenance section is a temperature section where high-purity crystals are uniformly produced without agglomeration, and the third temperature maintenance section is to be precipitated when maintaining a low temperature. It is a temperature section where possible crystals are precipitated, and most of the crystals are precipitated in the second temperature maintenance section, but it is meaningful to additionally precipitate azoxystrobin remaining in order to improve the yield.

In the present specification, the transparency of the solution changes to cloudy at about 50 ° C. during cooling to the temperature of the first temperature maintaining period and the second temperature maintaining period after the end of the first temperature maintaining period (the stage immediately before crystal precipitation), and precipitation starts at 45 ° C.

The second temperature maintenance section is a section in which the solution cooled to 30°C or more and 35°C or less is left at room temperature without applying additional heat, and the temperature of the solution cooled to 30°C or more and 35°C or less is balanced at room temperature. do. For example, when the temperature of the solution cooled to 30° C. or more and 35° C. or less is higher than room temperature, the temperature of the solution may be cooled to room temperature in the corresponding section. As a result, when the second temperature maintenance period ends, the temperature of the solution is room temperature (25±5° C.), and specifically, the temperature of the solution may be 22° C. or more and 25° C. or less.

The third temperature maintenance section is a section for maintaining a cooled temperature through an ice water bath or a bath of a combination of dry ice and acetone, and can maintain a temperature cooled to -20°C or more and 10°C or less.

In the first recrystallization step, the cooling rate for cooling from the final temperature to 60° C. or more and 62° C. or less is 0.5° C./min or more and 1° C./min or less. Specifically, it may be cooled from 70° C. to 60° C. for about 15 minutes.

In the first recrystallization step, after the end of the first temperature maintenance period, the cooling rate for cooling to 30°C or more and 35°C or less is 0.1°C/min or more and 0.3°C/min or less. Specifically, it can be cooled slowly from 60°C to 35°C using a heating mantle for about 2 hours.

In the first recrystallization step, after the second temperature maintenance period ends, the cooling rate for cooling to 10° C. or less is 10° C./min or more and 15° C./min or less. Specifically, it may be cooled to -20°C or more and 10°C or less through an ice water bath or a bath of a combination of dry ice and acetone.

In the first recrystallization step, the temperature maintenance section of the three or more steps maintains a constant temperature for 30 minutes or more and 3 hours or less, respectively. Through this, there is an advantage in that the yield can be increased by securing sufficient time for the remaining azoxystrobin to precipitate.

In the purification method of azoxystrobin of the present specification, the azoxystrobin is synthesized from a methoxyacrylate intermediate, and the weight ratio of the first recrystallization solvent based on the weight of the methoxyacrylate intermediate is 1 to 3 times. am. As the amount of the solvent used in the first recrystallization solvent is small, the yield of azoxystrobin is high, but on the contrary, the purity of azoxystrobin tends to deteriorate. It is possible to obtain azoxystrobin with a purity of 99% or more.

In the purification method of azoxystrobin of the present specification, the first recrystallization solvent is isopropyl alcohol or methanol.

The purification method of azoxystrobin of the present specification may further include the step of filtration under reduced pressure of azoxystrobin precipitated through the first recrystallization step.

In the present specification, the second recrystallization step may cite the above description of the first recrystallization step, and further may be different or the same as the first recrystallization step. Preferably, in the second recrystallization step, a second recrystallization solvent containing alcohol is added to the azoxystrobin obtained in the first recrystallization step, and the reference of the content of the second recrystallization solvent is the weight of the obtained azoxystrobin. Azoxystrobin can be obtained by precipitating azoxystrobin in the same manner as in the first recrystallization step, except that.

In the present specification, the secondary recrystallization step is,

preparing a mixed solution by adding a second recrystallization solvent containing alcohol to azoxystrobin obtained in the first recrystallization step;

raising the temperature of the mixed solution to a final temperature of 68°C or higher and 72°C or lower; and

and obtaining azoxystrobin that is precipitated while cooling the mixed solution to 10° C. or less through at least one temperature maintenance section.

In the present specification, the temperature maintenance section of the second recrystallization step is a temperature maintenance section of three or more steps, and specifically a three-step temperature maintenance section.

In the present specification, the temperature maintenance period of the three or more steps of the secondary recrystallization step is,

a first temperature holding period for maintaining the cooled temperature after cooling to 60° C. or more and 62° C. or less from the final temperature;

After cooling to 30 ℃ or more and 35 ℃ or less, a second temperature maintenance section for maintaining the cooled temperature; and

After cooling to 10° C. or less, it includes a third temperature maintaining section for maintaining the cooled temperature.

In the second recrystallization step, the cooling rate for cooling from the final temperature to 60° C. or more and 62° C. or less is 0.5° C./min or more and 1° C./min or less. Specifically, it may be cooled from 70° C. to 60° C. for about 15 minutes.

In the secondary recrystallization step, after the end of the first temperature maintenance period, the cooling rate for cooling to 30°C or more and 35°C or less is 0.1°C/min or more and 0.3°C/min or less. Specifically, it can be cooled slowly from 60°C to 35°C using a heating mantle for about 2 hours.

In the second recrystallization step, after the second temperature maintenance period is terminated, the cooling rate for cooling to 10° C. or less is 10° C./min or more and 15° C./min or less. Specifically, it may be cooled to -20°C or more and 10°C or less through an ice water bath or a bath of a combination of dry ice and acetone.

In the second recrystallization step, the temperature maintaining section of the three or more steps maintains a constant temperature for 30 minutes or more and 3 hours or less, respectively. Through this, there is an advantage in that the yield can be increased by securing sufficient time for the remaining azoxystrobin to precipitate.

In the purification method of azoxystrobin of the present specification, the weight ratio of the second recrystallization solvent is 1 to 3 times based on the weight of azoxystrobin obtained in the first recrystallization step.

In the purification method of azoxystrobin of the present specification, the second recrystallization solvent is isopropyl alcohol or methanol.

In the purification method of azoxystrobin of the present specification, before the first recrystallization step, washing with water by adding water to the reaction solution in which the synthesis of azoxystrobin is completed; and after washing with water, separating the organic layer. In this case, there is an advantage in that residual K ₂ CO ₃ and inorganic substances contained in the reaction solution can be removed.

In the purification method of azoxystrobin of the present specification, the method further comprises the step of recovering the evaporated solvent by reducing the separated organic layer.

In the purification method of azoxystrobin of the present specification, the concentration of the reaction solution can be adjusted so that the concentration of the reaction solution is equal to or greater than the saturation concentration while the evaporated solvent is recovered by reducing the pressure of the reaction solution in which the synthesis of azoxystrobin is completed. Specifically, the reaction solution in which the synthesis of azoxystrobin has been completed may be reduced pressure until the saturated concentration of azoxystrobin in the reaction solution is greater than or equal to the saturation concentration of azoxystrobin.

In the present specification, lowering the pressure uses a pump to remove the gas from the container containing the reaction solution to lower the vapor pressure of the gaseous state in the container. In this process, the solvent evaporated from the reaction solution is included in the removed gas due to the lowered vapor pressure, and the solvent may be recovered through a trap for recovering the gaseous solvent from the removed gas as a liquid.

In the purification method of azoxystrobin of the present specification, after obtaining the precipitated azoxystrobin, the obtained azoxystrobin is heated at 8°C to 15°C. The method may further include washing with water by adding it to isopropyl alcohol. In this case, the yield may be improved by about 2% to 3%.

The purification method of azoxystrobin of the present specification includes the steps of filtration under reduced pressure of azoxystrobin precipitated through a secondary recrystallization step; and

It may further comprise the step of drying the filtered azoxystrobin.

In the purification method of azoxystrobin of the present specification, after filtration under reduced pressure through the first recrystallization step and the second recrystallization step, the filtered filtrate may be separated by evaporation and reused as a solvent.

Hereinafter, the present specification will be described in more detail through examples. However, the following examples are only for illustrating the present specification, and not for limiting the present specification.

[Experimental Example 1]

[Example 1]

P-1 (100 g, 0.31 mol) and 500 ml of ethyl acetate (Ethylacetate, EA) were added to the reaction flask and stirred at room temperature for 10 minutes. After that, K ₂ CO ₃ (47.5 g, 0.35 mol) is added, and after 10 minutes, 2-Cyanophenol (2-Cyanophenol) (41.0 g, 0.35 mol) is added and the temperature is raised to 80° C. so that the reaction mixture is refluxed. stirred.

The reaction mixture is stirred under reflux at 80° C. for 6 hours, and when the residual amount of P-1 is less than 2% through high performance liquid chromatography (HPLC) analysis, the reaction is terminated.

The reaction was terminated by adding 200 g of water, and the lower aqueous layer was discarded after standing still for layer separation. After washing by adding 200 g of water again to the obtained upper organic layer, the organic layer was separated, and the separated organic layer was evaporated under reduced pressure.

Slowly add 100 ml of Isopropyl alcohol (IPA) (1.8 times the weight of the injected P-1). Thereafter, the temperature was raised to 70° C. based on the internal temperature, and the mixture was stirred for 1 hour with a stirring rod to completely dissolve the solid.

As the primary recrystallization step, lowered to 60 ℃ and maintained for 30 minutes, the temperature is gradually lowered to drop to 35 ℃ over 2 hours. At this point, crystals begin to precipitate. After aging at 35°C for 3 hours, it was maintained at room temperature (25°C) for 30 minutes. After that, the mixture is stirred for 2 hours more so that crystals are sufficiently precipitated while being cooled in an ice water bath. At this time, the temperature of the solution inside the reactor cooled by the ice water bath is maintained at 4°C to 5°C.

The resulting precipitate was filtered and washed by adding 50 ml of cold IPA at 8°C to 15°C.

After completion of the primary recrystallization, the solid obtained by filtration under reduced pressure was removed from the solvent in a 50 ℃ vacuum oven and the weight was checked. (115.1 g / Yield 91.5%)

Among the solids obtained, 201.8 g of IPA, which is 1.8 times, was added to 112.1 g except for some samples for analysis. Thereafter, the temperature was raised to 70° C. based on the internal temperature, and the mixture was stirred for 1 hour with a stirring rod to completely dissolve the solid.

As a secondary recrystallization step, the temperature is lowered to 60°C, maintained for 30 minutes, and then gradually lowered to 35°C over 2 hours. At this point, crystals begin to precipitate. After aging at 35°C for 3 hours, it was maintained at room temperature (25°C) for 30 minutes. After that, the mixture is stirred for 2 hours more so that crystals are sufficiently precipitated while being cooled in an ice water bath. At this time, the temperature of the solution inside the reactor cooled by the ice water bath is maintained at 4°C to 5°C.

The resulting precipitate was filtered and washed by adding 50 ml of cold IPA at 8°C to 15°C.

After completion of the secondary recrystallization, the resulting solid was filtered under reduced pressure to remove the solvent in a 50°C vacuum oven to obtain 109.9 g of Azoxystrobin. (Total yield = 89.7%, DPPA less than 0.1%)

[Examples 1-1 to 1-12]

Azoxystrobin was obtained by recrystallization twice in the same manner as in Example 1, except that the scale and the amount of IPA used were changed as shown in Table 1 below.

After primary recrystallization and secondary recrystallization, the content and purity of DPPA were analyzed under the following conditions through HPLC (Waters, Inc.). The purity was 99% or more, the yield was 95% or more, and the area percentage (DPPA content) of the peak of DPPA compared to the total peak area is shown in Table 1 below.

- Column: CAPCELL PAK C18, 4.7um, 250mm

- Mobile phase: ACN (Acetonitrile):H ₂ O = 6:4

- Detector wavelength: 254 um

- Mobile phase flow rate: 0.7ml/min

- Mode: Isocratic

- Sample concentration: 1000 ppm

Entry Scale
(g) Solvent (IPA) Primary recrystallization DPPA content (%) Secondary recrystallization DPPA content (%) usage
(g) weight ratio 1-1 20 30 1.5 0.18 0.04 1-2 20 30 1.5 0.18 0.08 1-3 20 30 1.5 0.44 0.37 1-4 20 30 1.5 0.32 0.05 1-5 20 30 1.5 0.32 0.26 1-6 20 30 1.5 0.25 0.01 1-7 20 30 1.5 0.25 0.18 1-8 20 36 1.8 0.25 0.04 1-9 20 36 1.8 0.37 0.05 1-10 100 180 1.8 0.18 0.08 1-11 100 180 1.8 0.31 0.09 1-12 100 180 1.8 0.32 0.06

In this case, the scale of Table 1 is the weight of P-1 during the primary recrystallization, and the weight of azoxystrobin obtained through the primary recrystallization during the secondary recrystallization.

Through Table 1, when the recrystallization solvent was used in a weight ratio of 1.8 times, it was confirmed that the DPPA content was uniformly less than 0.1% after the secondary recrystallization.

[Example 2]

Azoxystrobin was obtained by recrystallization twice in the same manner as in Example 1, except that methanol (MeOH) was used instead of IPA. The yield after the primary recrystallization is 90.8%, the yield after the secondary recrystallization is 96.1%, and the total yield is 87.3%.

[Experimental Example 2]

Examples 3-1 and 3-2 were recrystallized twice in the same manner as in Example 1, except that the scale and the amount of IPA used were changed as shown in Table 2 below to obtain Azoxystrobin.

Meanwhile, in Comparative Example 1, 180 g (1.8 times) of IPA was added as in Example 3-1, the temperature was raised to 70° C. based on the internal temperature, and the mixture was stirred for 1 hour with a stirring rod to completely dissolve the solid.

However, during cooling, the temperature was immediately lowered to 25° C. (room temperature) and stirred for 30 minutes. At this time, it was confirmed that as the temperature rapidly dropped, solid masses with dark colors were formed.

After that, the mixture is stirred for 2 hours more so that crystals are sufficiently precipitated while being cooled in an ice water bath.

After completion of the primary recrystallization, the solid obtained by filtration under reduced pressure was removed by vacuum oven, and the weight was checked.

To 114.0 g of the obtained solid, 208.3 g of IPA, which is 1.8 times thereof, was added. Thereafter, the temperature was raised to 70° C. based on the internal temperature, and the mixture was stirred for 1 hour with a stirring rod to completely dissolve the solid.

Upon cooling, the temperature was immediately lowered to 25° C. (room temperature) and stirred for 30 minutes. At this time, it was confirmed that as the temperature rapidly dropped, solid masses with dark colors were formed.

After that, the mixture is stirred for 2 hours more so that crystals are sufficiently precipitated while being cooled in an ice water bath.

After the secondary recrystallization was completed, the solid obtained by filtration under reduced pressure was removed with a vacuum oven to obtain 111.6 g (97.9%) of Azoxystrobin.

After primary recrystallization and secondary recrystallization, the content and purity of DPPA were analyzed in the same manner as in Experimental Example 1. The purity was 99% or more, the yield was about 90% or more, and the content of DPPA was shown in Table 2 below.

From Table 2, in the case of Comparative Example 1, the content of DPPA after the secondary recrystallization was 3.4 times that of Example 3-1, and it was confirmed that a significant amount of DPPA, an impurity, was not removed.

Claims (9)

A first recrystallization step of adding a first recrystallization solvent containing alcohol to the reaction solution in which the synthesis of azoxystrobin is completed, and then precipitating azoxystrobin using the first recrystallization solvent to obtain azoxystrobin; and
After adding a second recrystallization solvent containing alcohol to the obtained azoxystrobin, a secondary recrystallization step of precipitating azoxystrobin using the second recrystallization solvent to obtain azoxystrobin,
The first recrystallization step and the second recrystallization step are each independently,
raising the temperature to a final temperature of 68°C or higher and 72°C or lower; and
A method for purifying azoxystrobin comprising the step of obtaining azoxystrobin that is precipitated while cooling to 10° C. or less through a temperature maintenance period of three or more steps. The method according to claim 1, wherein the temperature maintenance period of three or more steps,
a first temperature maintenance section for maintaining the cooled temperature after cooling to 60° C. or more and 62° C. or less from the final temperature;
After cooling to 30 ℃ or more and 35 ℃ or less, a second temperature maintenance section for maintaining the cooled temperature; and
After cooling to 10 ° C. or less, the purification method of azoxystrobin comprising a third temperature maintenance section for maintaining the cooled temperature. The method for purifying azoxystrobin according to claim 2, wherein the cooling rate for cooling from the final temperature to 60°C or more and 62°C or less is 0.5°C/min or more and 1°C/min or less. The method for purifying azoxystrobin according to claim 2, wherein the cooling rate for cooling to 30°C or more and 35°C or less after the end of the first temperature maintenance period is 0.1°C/min or more and 0.3°C/min or less. The method for purifying azoxystrobin according to claim 2, wherein the cooling rate for cooling to 10°C or less after the end of the second temperature maintenance period is 10°C/min or more and 15°C/min or less. The method for purifying azoxystrobin according to claim 1, wherein a constant temperature is maintained for 30 minutes or more and 3 hours or less in each of the three or more steps of temperature maintenance. The method according to claim 1, wherein the first recrystallization solvent and the second recrystallization solvent are isopropyl alcohol or methanol, respectively. The method according to claim 1, Before the first recrystallization step,
washing with water by adding water to the reaction solution in which the synthesis of azoxystrobin is completed; and
After washing with water, the purification method of azoxystrobin further comprising the step of separating the organic layer. The method for purifying azoxystrobin according to claim 8, further comprising recovering the evaporated solvent by reducing the separated organic layer.