Separation and purification method of myclobutanil

Abstract

The invention discloses a separation and purification method of myclobutanil, and belongs to the technical field of pesticides. The method comprises the following steps: adding a myclobutanil liquid-phase crude product into a preheated melt crystallizer for cooling crystallization; then discharging the non-crystallized mother liquor, sweating the remaining crystals, and discharging sweat; further melting the product and discharging into a crystallization kettle; the crystallization kettle is heated firstly and then cooled for crystallization, materials in the crystallization kettle are put into a centrifugal machine to be subjected to centrifugal separation, pure myclobutanil is obtained, and mother liquor is recycled. The method provided by the invention can be used for preparing myclobutanil with the purity of more than or equal to 99%, avoids the use of concentrated nitric acid, reduces the pollution to the environment and the consumption of resources, and improves the product quality of myclobutanil.

Description

Technical Field

[0001] The invention belongs to the technical field of pesticides, and particularly relates to a method for separating and purifying myclobutanil. Background Art

[0002] Myclobutanil, 1-(4-chlorophenyl)-2-(1H-1,2,4-triazole-1-methyl)hexanenitrile, 2-(4-chlorophenyl)-2-(1H,1,2,4-triazole-1-methyl)hexanenitrile, CAS No.: 88671-89-0. It is a triazole fungicide developed in the late 20th century. It has the characteristics of high efficiency, broad spectrum, low toxicity, strong systemicity, and environmental friendliness. It has excellent activity against a variety of fungi.

[0003] The structural formula of myclobutanil is:

[0004]

[0005] The original drug of myclobutanil is a light yellow solid with a melting point of 63-68°C. The pure product is a colorless needle-shaped crystal with a melting point of 68-69°C and a boiling point of 202-208°C / 1mm Hg. Solubility (25°C): soluble in alcohol, aromatic hydrocarbons, esters, and ketones (50-100g / L), poorly soluble in water 142 (mg / L), and insoluble in aliphatic hydrocarbons.

[0006] There are many synthetic routes for myclobutanil (Zeng Qingbin, Research on the Synthesis of Myclobutanil, a Triazole Fungicide [D], Master's Thesis, Zhejiang University of Technology, 2004). The currently used route is to put dimethyl sulfoxide, 50% sodium hydroxide solution and triazole into a reactor to obtain a sodium triazole solution; then, 1-chloro-2-nitrile-2-(4-chlorophenyl)hexane is added dropwise to the sodium triazole solution to obtain the original drug of myclobutanil. The reaction is as follows:

[0007]

[0008] The appearance of the original drug of myclobutanil is brown-red, and the content is more than 90% according to GC analysis, the melting point is 63-68°C, and the yield is about 76%. The document further provides a method for purifying the crude product of myclobutanil, in which the crude product is treated with aliphatic hydrocarbons to remove other organic matter, and then recrystallized with acetone, so that the content of myclobutanil can reach 97%, and the product is a light yellow powder.

[0009] High-purity myclobutanil is crucial for efficacy evaluation and formulation. In the above preparation route, the reaction of 1-chloro-2-nitrile-2-(4-chlorophenyl)hexane with sodium triazole also produces the following by-products:

[0010]

[0011] The structure of the by-product is close to that of the main product. In the prior art, the solution crystallization method is mainly used for purification. For example, Li Xiang, Liu Li, Hu Xiaoli, etc. (New Synthesis Method of Myclobutanil [J] Pesticides, 2001, 40 (30): 11, 16) add water to stir the reaction materials after the reaction is completed, extract with chloroform, desolventize, and recrystallize to obtain the original drug of myclobutanil, with a content of 93% and a yield of 76.23%. Meng Zhaowei (Meng Zhaowei, Research on New Myclobutanil [J] Chemical Engineering and Equipment, 2008 (6) 89-91:) uses xylene as solvent, slowly cools down to 5°C within ten hours at 80-85°C, adds the previous crystal seeds when the temperature drops to 70°C, and filters under nitrogen purification. Wash the agglomerates with xylene, then wash with 5°C isopropanol to obtain the pure product, dry at 90°C, 50mmHg nitrogen replacement, and the final product has a purity of 97%. In the above processes, the purification of myclobutanil is carried out by solution crystallization, but the structure of the by-product is similar to that of the main product, and the improvement of its purity is subject to certain limitations.

[0012] US4366165 discloses a method for separating and purifying myclobutanil using concentrated nitric acid. However, concentrated nitric acid is highly corrosive and volatile, and there are problems such as equipment corrosion and environmental pollution. Summary of the invention

[0013] In order to solve the problems in the prior art, the present invention provides a method for separating and purifying myclobutanil.

[0014] The separation and purification method of myclobutanil of the present invention comprises the following steps:

[0015] Step 1): adding the crude liquid phase of myclobutanil to a preheated melt crystallizer, and after all the materials are melted into liquid, cooling and crystallizing at a cooling rate of 0.1 to 1°C / min, with the final crystallization temperature being 50-58°C;

[0016] Step 2): discharge the uncrystallized mother liquor and sweat the remaining crystals, the temperature rising rate of the sweating process is 0.1-1°C / min, the temperature is raised to 60-62°C, the temperature is kept constant for 0.5-1 hour, and the sweating liquid is discharged;

[0017] Step 3): raising the temperature to melt the crystals treated in step 2), and discharging the molten product into a crystallization kettle pre-filled with ethanol solution;

[0018] Step 4): The crystallization kettle is first heated to dissolve the material, and then cooled and crystallized at a cooling rate of 0.1 to 1°C / min, with a final temperature of 5 to 10°C;

[0019] Step 5): placing the material in the crystallization kettle into a centrifuge, and centrifuging to obtain a pure product of myclobutanil, and recycling the mother liquor.

[0020] Preferably, the mass percentage of myclobutanil in the crude myclobutanil liquid phase product in step 1) is ≥85%. Preferably, the crude myclobutanil liquid phase product is obtained by reacting sodium triazole with 1-chloro-2-nitrile-2-(4-chlorophenyl)hexane.

[0021] According to a preferred embodiment of the present invention, while the temperature is increased in step 2), the bottom valve of the equipment is opened to discharge the sweating liquid into the sweating liquid tank for use as the next batch of raw materials.

[0022] Preferably, in step 4), the mass percentage concentration of the ethanol solution is 30%-60%, and the heating temperature is 40-60°C.

[0023] The present invention also provides a separation and purification system of myclobutanil for implementing the method, the system comprising a melt crystallizer, a mother liquor receiving tank, a product crystallization kettle and a centrifuge; wherein the melt crystallizer receives the myclobutanil liquid phase crude product and performs cooling crystallization, discharges the uncrystallized mother liquor to the mother liquor receiving tank after cooling crystallization, then the melt crystallizer performs sweating treatment on the crystals after the mother liquor is discharged, and the sweating liquid in the sweating treatment process is also discharged to the mother liquor receiving tank; finally, the melt crystallizer heats and melts the crystals after the sweating treatment;

[0024] The product crystallization kettle receives the product after the melting treatment in the melt crystallizer, and cools and crystallizes it to obtain a material containing crystals, which is then transported to a centrifuge;

[0025] The crystals are centrifuged and separated by a centrifuge, and the obtained crystals are pure myclobutanil.

[0026] Furthermore, the melt crystallizer uses an external medium for temperature control, and has both a cold medium flow channel and a hot medium flow channel, and uses a cold medium for cooling and a hot medium for heating.

[0027] Compared with the prior art, the present invention adopts melt crystallization, separates part of the impurities, and then recrystallizes with ethanol-water solution to prepare myclobutanil with a purity of ≥99%. The method of the present invention avoids the use of concentrated nitric acid, reduces environmental pollution and resource consumption, and improves product quality. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 The present invention is a process flow chart for separation and purification of myclobutanil;

[0029] Figure 2 This is the high performance liquid chromatogram of myclobutanil crystals. DETAILED DESCRIPTION

[0030] The following examples provide those of ordinary skill in the art with an understanding of how to make and evaluate the present invention, which are exemplary of the present disclosure and are not intended to limit the scope of the invention. Although every effort has been made to ensure accuracy with respect to numerical values ​​(e.g., amounts, temperatures, etc.), some errors and deviations should be considered. Unless otherwise stated, temperatures are in ° C or at ambient temperature, and pressures are at or near atmospheric pressure.

[0031] like Figure 1 As shown, it is an optional system schematic diagram for implementing the separation and purification method of the present invention, and the system mainly includes a melt crystallizer, a mother liquor receiving tank, a product crystallization kettle, a centrifuge and a centrifugal mother liquor tank; wherein, the melt crystallizer receives the crude liquid phase of myclobutanil and performs cooling crystallization, and after cooling crystallization, the uncrystallized mother liquor is discharged to the mother liquor receiving tank. In addition, the melt crystallizer also performs sweating treatment on the crystals after the mother liquor is discharged, and the sweating liquid in the sweating treatment process is also discharged to the mother liquor receiving tank; the melt crystallizer finally heats up and melts the crystals.

[0032] In the present invention, the melt crystallizer uses an external medium for temperature control, and has both a cold medium flow channel and a hot medium flow channel. The cold medium is used for cooling, and the hot medium is used for heating.

[0033] The product crystallization kettle receives the melted product, adds ethanol and heats it to 40-60°C, then cools and crystallizes it to obtain a material containing crystals, which is then transported to a centrifuge. The centrifuge separates the crystals, and the resulting liquid enters a centrifugal mother liquid tank. The resulting crystals are pure myclobutanil.

[0034] Example 1

[0035] 500 kg of crude liquid phase of myclobutanil (myclobutanil content 85.2%) was added into a preheated melt crystallizer, and after all the materials were melted into liquid, the temperature was lowered at 0.1°C / min, and the final crystallization temperature was 50°C;

[0036] After discharging the uncrystallized mother liquor, the crystals are sweated, the heating rate is 0.1°C / min, the temperature is raised to 60°C, the temperature is kept constant for 0.5 hours, and the sweating liquid is discharged; the temperature is raised until the product melts, and the product is discharged into the product crystallization kettle. A sufficient amount of 30% mass percent ethanol solution is added to the crystallization kettle, the temperature is raised to 40°C, and the crystallization is cooled at a rate of 0.1°C / min, and the final crystallization temperature is 5°C. The material in the crystallization kettle is placed in a centrifuge, and 405 kg of pure myclobutanil is obtained by centrifugation, and the mother liquor is recycled.

[0037] Liquid chromatography analysis conditions: chromatographic column is C18 column, detection wavelength is 225nm, mobile phase is methanol: water = 8:2, flow rate is 1ml / min. Figure 2 The HPLC chromatogram of the myclobutanil crystals in Example 1 shows a content of 99.151%.

[0038] Example 2

[0039] 500 kg of crude liquid phase of myclobutanil (myclobutanil content 85.7%) is added to a preheated melt crystallizer. After all the materials are melted into liquid, the temperature is lowered at 1°C / minute, and the final crystallization temperature is 58°C; after discharging the uncrystallized mother liquor, the crystals are sweated, the heating rate is 1°C / minute, the temperature is raised to 62°C, the temperature is kept constant for 1 hour, and the sweating liquid is discharged; the temperature is raised until the product melts, and the product is discharged to the product crystallization kettle. A sufficient amount of 60% mass percentage concentration of ethanol solution is added to the crystallization kettle, the temperature is raised to 60°C, and cooling and crystallization are carried out at a rate of 1°C / minute, and the final crystallization temperature is 10°C. The material in the crystallization kettle is placed in a centrifuge, and centrifugal separation is performed to obtain 356 kg of pure myclobutanil, and the mother liquor is recycled. The test method is the same as in Example 1, and the myclobutanil content is 99.150%.

[0040] Example 3

[0041] 500 kg of crude liquid phase of myclobutanil (myclobutanil content 90.2%) was added into a preheated melt crystallizer, and after all the materials were melted into liquid, the temperature was lowered at 0.5°C / min, and the final crystallization temperature was 55°C;

[0042] After discharging the uncrystallized mother liquor, the crystals are sweated, the heating rate is 0.5°C / min, the temperature is raised to 61°C, the temperature is kept constant for 1 hour, and the sweating liquid is discharged; the temperature is raised until the product melts, and the product is discharged into the product crystallization kettle. A sufficient amount of 40% mass percent ethanol solution is added to the crystallization kettle, the temperature is raised to 50°C, and cooling crystallization is carried out at a rate of 0.5°C / min. The final crystallization temperature is 8°C. The material in the crystallization kettle is placed in a centrifuge, and centrifugal separation is performed to obtain 435 kg of pure myclobutanil, and the mother liquor is recycled. The test method is the same as in Example 1, and the myclobutanil content is 99.100%.

[0043] Comparative Example 4

[0044] 500 kg of crude liquid phase of myclobutanil (myclobutanil content 85.0%) was added into a preheated melt crystallizer, and after all the materials were melted into liquid, the temperature was lowered at 0.1°C / min, and the final crystallization temperature was 50°C;

[0045] After discharging the uncrystallized mother liquor, the crystals were sweated at a heating rate of 0.1°C / min to 60°C, kept at a constant temperature for 0.5 hours, and the sweating liquid was discharged; the temperature was raised until the product melted, and 415 kg of the product was collected, with a myclobutanil content of 98.5%.

[0046] Comparative Example 5

[0047] In a crystallization kettle, 500 kg of crude liquid phase of myclobutanil (myclobutanil content 90.2%) was added to a 30% mass percent concentration of ethanol solution, the temperature was raised to 40° C., and cooling crystallization was performed at a rate of 0.1° C. / min, and the final crystallization temperature was 5° C. The material in the crystallization kettle was placed in a centrifuge, and centrifugal separation was performed to obtain 430 kg of product, with a myclobutanil content of 96.8%.

[0048] Comparative Example 6

[0049] In a crystallization kettle, 500 kg of crude liquid phase of myclobutanil (myclobutanil content 90.2%) is added to a 30% mass percentage concentration of ethanol solution and heated to 40°C, and cooled and crystallized at a rate of 0.1°C / min, and the final crystallization temperature is 5°C. The material in the crystallization kettle is placed in a centrifuge and centrifuged to obtain myclobutanil. Myclobutanil is added to a preheated melt crystallizer, and after the material is completely melted into a liquid state, the temperature is lowered at 0.5°C / min, and the final crystallization temperature is 55°C; after discharging the uncrystallized mother liquor, the crystals are sweated, the heating rate is 0.5°C / min, the temperature is raised to 61°C, the temperature is kept constant for 1 hour, and the sweating liquid is discharged; the temperature is raised until the product melts, the product is collected, and 425 kg of the product is obtained, and the myclobutanil content is 97.0%.

[0050] Comparative Example 4 did not perform cooling crystallization after the sweating was completed, and the purity of the product obtained could only reach 98.5%, which was lower than the methods of Examples 1 to 3; Comparative Example 5 only adopted the purification method of cooling crystallization, and the content was only 96.8%; Comparative Example 6 adopted the purification method of cooling crystallization, separation, and sweating in sequence, and its content was 97.0%. It can be seen that the order of sweating first and then cooling crystallization adopted in the present invention is crucial to obtaining a high-purity product.

[0051] The above-mentioned embodiments only express several implementation methods of the present invention, and the description is relatively specific and detailed, but it cannot be understood as limiting the scope of the present invention. For ordinary technicians in this field, several modifications and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention.

Claims

1. A method for separating and purifying myclobutanil, characterized in that: The steps include: Step 1): adding the crude liquid phase of myclobutanil to a preheated melt crystallizer, and after all the materials are melted into liquid, cooling and crystallizing at a cooling rate of 0.1 to 1°C / min, with the final crystallization temperature being 50-58°C; Step 2): discharge the uncrystallized mother liquor and sweat the remaining crystals, the temperature rising rate of the sweating process is 0.1-1°C / min, the temperature is raised to 60-62°C, the temperature is kept constant for 0.5-1 hour, and the sweating liquid is discharged; Step 3): raising the temperature to melt the crystals treated in step 2), and discharging the molten product into a crystallization kettle pre-filled with ethanol solution; Step 4): The crystallization kettle is first heated to dissolve the material, and then cooled and crystallized at a cooling rate of 0.1 to 1°C / min, with a final temperature of 5 to 10°C; Step 5): placing the material in the crystallization kettle into a centrifuge, and centrifuging to obtain a pure product of myclobutanil, and recycling the mother liquor.

2. The method for separation and purification of myclobutanil according to claim 1, wherein: The mass percentage of myclobutanil in the myclobutanil liquid phase crude product in step 1) is ≥85%.

3. The method for separation and purification of myclobutanil according to claim 1, wherein: Step 2) While the temperature is rising, the bottom valve of the equipment is opened to discharge the sweating liquid into the sweating liquid tank for use as the next batch of raw materials.

4. The method for separation and purification of myclobutanil according to claim 1, wherein: In step 4), the mass percentage concentration of the ethanol solution is 30%-60%.

5. The method for separation and purification of myclobutanil according to claim 1, wherein: In step 4), the heating temperature is 40-60°C.

6. The method for separating and purifying myclobutanil according to claim 1, wherein: The crude liquid phase product of myclobutanil is obtained by reacting sodium triazole with 1-chloro-2-nitrile-2-(4-chlorophenyl)hexane.

7. A separation and purification system for myclobutanil for implementing the method according to claim 1, characterized in that: The system comprises a melt crystallizer, a mother liquor receiving tank, a product crystallization kettle and a centrifuge; wherein the melt crystallizer receives a crude liquid phase of myclobutanil and performs cooling and crystallization, and discharges the uncrystallized mother liquor to the mother liquor receiving tank after cooling and crystallization, and then the melt crystallizer performs sweating treatment on the crystals after the mother liquor is discharged, and the sweating liquid in the sweating treatment process is also discharged to the mother liquor receiving tank; and finally the melt crystallizer heats and melts the crystals after the sweating treatment; The product crystallization kettle receives the product after the melting treatment in the melt crystallizer, and cools and crystallizes it to obtain a material containing crystals, which is then transported to a centrifuge; The crystals are centrifuged and separated by a centrifuge, and the obtained crystals are pure myclobutanil.

8. The system according to claim 7, characterized in that The melt crystallizer uses an external medium for temperature control. It has both a cold medium flow channel and a hot medium flow channel. The cold medium is used for cooling and the hot medium is used for heating.

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