CN117263875A - Tebuconazole crystal and continuous crystallization method and application thereof - Google Patents
Tebuconazole crystal and continuous crystallization method and application thereof Download PDFInfo
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- 239000013078 crystal Substances 0.000 title claims abstract description 201
- PXMNMQRDXWABCY-UHFFFAOYSA-N 1-(4-chlorophenyl)-4,4-dimethyl-3-(1H-1,2,4-triazol-1-ylmethyl)pentan-3-ol Chemical compound C1=NC=NN1CC(O)(C(C)(C)C)CCC1=CC=C(Cl)C=C1 PXMNMQRDXWABCY-UHFFFAOYSA-N 0.000 title claims abstract description 126
- 239000005839 Tebuconazole Substances 0.000 title claims abstract description 124
- 238000002425 crystallisation Methods 0.000 title claims abstract description 93
- 230000008025 crystallization Effects 0.000 claims abstract description 73
- 238000001816 cooling Methods 0.000 claims abstract description 60
- 239000002002 slurry Substances 0.000 claims abstract description 28
- 238000003756 stirring Methods 0.000 claims abstract description 26
- 239000002245 particle Substances 0.000 claims abstract description 25
- 239000012452 mother liquor Substances 0.000 claims abstract description 18
- 238000001035 drying Methods 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 238000000926 separation method Methods 0.000 claims description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 4
- 239000000575 pesticide Substances 0.000 claims description 4
- 230000009467 reduction Effects 0.000 claims description 4
- 238000000034 method Methods 0.000 abstract description 22
- 230000008569 process Effects 0.000 abstract description 16
- 238000009826 distribution Methods 0.000 abstract description 11
- 230000006872 improvement Effects 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 46
- 230000000052 comparative effect Effects 0.000 description 18
- 230000003287 optical effect Effects 0.000 description 11
- 238000012360 testing method Methods 0.000 description 10
- 238000010899 nucleation Methods 0.000 description 8
- 230000006911 nucleation Effects 0.000 description 7
- 238000010900 secondary nucleation Methods 0.000 description 7
- 235000013339 cereals Nutrition 0.000 description 6
- 238000004581 coalescence Methods 0.000 description 6
- 230000002776 aggregation Effects 0.000 description 5
- 230000001965 increasing effect Effects 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000010998 test method Methods 0.000 description 5
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- 238000004140 cleaning Methods 0.000 description 4
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- 239000007787 solid Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- 238000000879 optical micrograph Methods 0.000 description 3
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 description 2
- 244000052616 bacterial pathogen Species 0.000 description 2
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- 230000001276 controlling effect Effects 0.000 description 2
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- 230000005923 long-lasting effect Effects 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- OILXMJHPFNGGTO-UHFFFAOYSA-N (22E)-(24xi)-24-methylcholesta-5,22-dien-3beta-ol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(C)C(C)C)C1(C)CC2 OILXMJHPFNGGTO-UHFFFAOYSA-N 0.000 description 1
- RQOCXCFLRBRBCS-UHFFFAOYSA-N (22E)-cholesta-5,7,22-trien-3beta-ol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CCC(C)C)CCC33)C)C3=CC=C21 RQOCXCFLRBRBCS-UHFFFAOYSA-N 0.000 description 1
- OQMZNAMGEHIHNN-UHFFFAOYSA-N 7-Dehydrostigmasterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CC(CC)C(C)C)CCC33)C)C3=CC=C21 OQMZNAMGEHIHNN-UHFFFAOYSA-N 0.000 description 1
- 235000017060 Arachis glabrata Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000018262 Arachis monticola Nutrition 0.000 description 1
- 240000002791 Brassica napus Species 0.000 description 1
- 235000006008 Brassica napus var napus Nutrition 0.000 description 1
- DNVPQKQSNYMLRS-NXVQYWJNSA-N Ergosterol Natural products CC(C)[C@@H](C)C=C[C@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@@H]3CC[C@]12C DNVPQKQSNYMLRS-NXVQYWJNSA-N 0.000 description 1
- 244000141359 Malus pumila Species 0.000 description 1
- 240000008790 Musa x paradisiaca Species 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
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- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 241000220324 Pyrus Species 0.000 description 1
- 241000221662 Sclerotinia Species 0.000 description 1
- 240000006394 Sorghum bicolor Species 0.000 description 1
- 235000011684 Sorghum saccharatum Nutrition 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 244000098338 Triticum aestivum Species 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 229910001870 ammonium persulfate Inorganic materials 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 235000021016 apples Nutrition 0.000 description 1
- 235000021015 bananas Nutrition 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000012407 engineering method Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- DNVPQKQSNYMLRS-SOWFXMKYSA-N ergosterol Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H](CC[C@]3([C@H]([C@H](C)/C=C/[C@@H](C)C(C)C)CC[C@H]33)C)C3=CC=C21 DNVPQKQSNYMLRS-SOWFXMKYSA-N 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 238000000399 optical microscopy Methods 0.000 description 1
- 235000020232 peanut Nutrition 0.000 description 1
- 235000021017 pears Nutrition 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000010903 primary nucleation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000004781 supercooling Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/64—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with three nitrogen atoms as the only ring hetero atoms
- A01N43/647—Triazoles; Hydrogenated triazoles
- A01N43/653—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
- A01P3/00—Fungicides
Landscapes
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Environmental Sciences (AREA)
- Wood Science & Technology (AREA)
- Plant Pathology (AREA)
- Zoology (AREA)
- Engineering & Computer Science (AREA)
- Pest Control & Pesticides (AREA)
- General Health & Medical Sciences (AREA)
- Dentistry (AREA)
- Health & Medical Sciences (AREA)
- Agronomy & Crop Science (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a tebuconazole crystal, a continuous crystallization method and application thereof, comprising the following steps: (1) Under the stirring condition, adding the tebuconazole mother liquor with the temperature of 65-75 ℃ into a crystallization kettle, cooling to 60-65 ℃, adding tebuconazole seed crystals, cooling to 50-60 ℃ for crystal growth, and then enabling crystal slurry to enter a secondary crystallization kettle; (2) After the crystal slurry enters a secondary crystallization kettle, cooling to 40-50 ℃ under the stirring condition, growing crystals, and then entering a tertiary crystallization kettle; (3) After the crystal slurry enters a three-stage crystallization kettle, cooling to 20-30 ℃ under the stirring condition, and growing crystals to obtain the tebuconazole crystals; the tebuconazole crystal obtained by the method has narrow particle size distribution, the main particle size of the product after the process improvement can reach 400 mu m, the D50 is 300-360 mu m, the D90 is 650-680 mu m, the tebuconazole crystal has good anti-caking property, the process is simple, and the industrialization can be realized.
Description
Technical Field
The invention belongs to the technical field of crystallization in chemical engineering industry, and particularly relates to a tebuconazole crystal, a continuous crystallization method and application thereof.
Background
Tebuconazole (CAS: 107534-96-3) chemical name 4, 4-dimethyl-3- (1H-1, 2, 4-triazol-1-ylmethyl) -1- (4-chlorophenyl) -3-pentanol English name Tebuconazole, molecular formula C 16 H 22 ClN 3 O is a high-efficiency broad-spectrum systemic triazole bactericidal pesticide, has three functions of protection, treatment and eradication, and has wide bactericidal spectrum and long lasting period; the bactericidal composition is used as a seed treatment agent and foliar spray worldwide, has wide bactericidal spectrum, high activity and long lasting period. Tebuconazole is mainly used for preventing and controlling various fungal diseases on crops such as wheat, rice, peanut, vegetables, bananas, apples, pears, corn and sorghum, and is registered and widely applied on more than 60 crops in more than 50 countries worldwide. The product is used for preventing and treating sclerotinia rot of colza, and has the advantages of good prevention effect, lodging resistance, obvious yield increasing effect, etc., and has the function mechanism of inhibiting demethylation of ergosterol on cell membrane, so that cell membrane can not be formed by the pathogenic bacteria, and the pathogenic bacteria can be killed.
The product crystallized by the traditional tebuconazole crystallization process is in a rod shape, the granularity of the product is between 20 and 30 mu m, the granularity is generally smaller, and the problems of serious agglomeration, poor anti-caking property and the like exist in the crystal. In CN102659696a, a method for improving the anti-caking property of tebuconazole crystals by increasing the grain size of tebuconazole crystals by cooling crystallization is mentioned, and the tebuconazole crystals D90 obtained by the method is 280-300 μm, but the grain size and the anti-caking property of tebuconazole crystals obtained by the method are still further improved.
Therefore, it is necessary to find a crystallization method capable of further increasing the particle size of tebuconazole crystals, reducing the crystal aggregation phenomenon and improving the anti-caking ability thereof.
Disclosure of Invention
The invention aims to solve the problems of small granularity, poor anti-caking property and serious agglomeration of the existing tebuconazole product, and provides a method for improving the anti-granularity of tebuconazole, wherein the obtained product is not easy to agglomerate, has strong anti-caking property, uses a small amount of seed crystals in the process and is beneficial to amplification.
A continuous crystallization method of tebuconazole crystals, the continuous crystallization method comprising the steps of:
(1) Under the stirring condition, adding the tebuconazole mother liquor with the temperature of 65-75 ℃ into a primary crystallization kettle, cooling to 60-65 ℃, adding tebuconazole seed crystals, cooling to 50-60 ℃ for crystal growth, and then enabling crystal slurry to enter a secondary crystallization kettle;
(2) After the crystal slurry enters a secondary crystallization kettle, cooling to 40-50 ℃ under the stirring condition, growing crystals, and then entering a tertiary crystallization kettle;
(3) And after the crystal slurry enters a three-stage crystallization kettle, cooling to 20-30 ℃ under the stirring condition, and growing crystals to obtain the tebuconazole crystals.
Preferably, the solute of the tebuconazole mother liquor in the step (1) is tebuconazole, and the solution is cyclohexane;
the concentration of the tebuconazole mother liquor solute in the step (1) is 8-20wt%.
Preferably, the grain diameter of the tebuconazole seed crystal in the step (1) is 500-1300 meshes;
the adding amount of the tebuconazole seed crystal in the step (1) is 1-8wt% of tebuconazole crystals.
Preferably, the stirring speed in the step (1) is 150-300 r/min;
the tebuconazole mother liquor in the step (1) is added into a primary crystallization kettle in a dropwise adding mode, and the dropwise adding speed is 1-8 ml/min;
the cooling rate of the step (1) to 50-60 ℃ is 5-15 ℃/h;
the crystal growing time in the step (1) is 0.5-2 h.
Preferably, the rate of the crystal slurry entering the secondary crystallization kettle in the step (2) is 1-8 ml/min;
the stirring speed of the step (2) is 150-300 r/min;
the temperature reduction rate of the step (2) for cooling to 40-50 ℃ is 5-15 ℃/h;
and (3) the time for growing the crystals in the step (2) is 0.5-2.5 h.
Preferably, the rate of the crystal slurry entering the three-stage crystallization kettle in the step (3) is 1-8 ml/min;
the stirring speed of the step (3) is 150-300 r/min;
the temperature reduction rate of the step (3) for cooling to 20-30 ℃ is 5-15 ℃/h;
and (3) the time for growing the crystals is 0.5-2.5 h.
Preferably, the step (3) further comprises solid-liquid separation and drying of the mixture obtained after crystal growth;
the solid-liquid separation mode is filtration;
the drying temperature is 50 ℃, the drying time is 24 hours, and the drying is carried out at normal pressure.
A tebuconazole crystal is prepared according to a continuous crystallization method of tebuconazole crystal.
Preferably, the main particle size of the tebuconazole crystal product reaches 400 mu m, D50 is 300-360 mu m, and D90 is 650-680 mu m.
The application of tebuconazole crystals is the application of tebuconazole crystals in preparing pesticides.
The invention has the technical characteristics and beneficial effects that:
1. the invention adopts the cooling crystallization technology to prepare the tebuconazole crystal, does not need repeated temperature return, and has simple process; the cost is low, and the grain size of the obtained product is far larger than that obtained by the traditional process;
2. the invention adopts continuous crystallization, so that the crystallization operation can be continuous, the engineering method is easy, and the crystal grain size distribution range can be regulated and controlled by adjusting the seed crystal adding and stirring rate, thereby realizing the accurate control of the grain size distribution of the product;
3. according to molecular thermodynamics of tebuconazole and kinetic parameters of crystal growth, different cooling rates are designed in different temperature intervals; in a higher temperature range (more than 50 ℃), the nucleation of tebuconazole is obviously inhibited, and the growth is improved; under the reasonable cooling rate, secondary nucleation can be inhibited by adding a trace amount of seed crystal, and under the condition of 50 ℃, although nucleation is improved, under the same supersaturation degree, the system is easier to nucleate, the seed crystal added in the earlier stage is obviously grown up, and more crystal faces are consumed for bearing the supersaturation degree, so that the cooling rate can be gradually accelerated; by reasonably designing a cooling curve, the wide particle size distribution caused by secondary nucleation can be obviously inhibited;
4. after crystallization is finished according to the preparation method provided by the invention, the obtained tebuconazole crystal has narrow particle size distribution, the main particle size of the product after the process improvement can reach about 400 mu m, the D50 is 300-360 mu m, the D90 is 650-680 mu m, and the tebuconazole crystal has good anti-caking property.
Drawings
FIG. 1 is a photograph of an optical microscope of tebuconazole crystals of experimental example 1;
FIG. 2 is a photograph of a conventional process of optical microscopy of tebuconazole crystals;
FIG. 3 is a photograph of an optical microscope of tebuconazole crystals of experimental example 2;
FIG. 4 is a photograph of an optical microscope of tebuconazole crystals of Experimental example 3;
FIG. 5 is a photograph of a light microscope of tebuconazole crystals of Experimental example 4;
FIG. 6 is a photograph of a light microscope of tebuconazole crystals of Experimental example 5;
FIG. 7 is an optical microscope photograph of tebuconazole crystals of comparative example 1;
FIG. 8 is an optical microscope photograph of tebuconazole crystals of comparative example 2;
FIG. 9 is an optical microscope photograph of tebuconazole crystals of comparative example 3;
figure 10 XRD patterns of tebuconazole crystals of experiment 1 and original conventional process products.
The specific embodiment is as follows:
the technical scheme of the invention is further described by the following specific embodiments. It will be apparent to those skilled in the art that the examples are merely to aid in understanding the invention and are not to be construed as a specific limitation thereof.
Example 1:
it is an object of the present invention to provide a continuous crystallization method of tebuconazole crystals, comprising the steps of:
(1) Under stirring, adding tebuconazole mother liquor with the temperature of 65-75 ℃ (such as 65 ℃, 66 ℃, 67 ℃, 68 ℃, 69 ℃, 70 ℃, 71 ℃, 72 ℃, 73 ℃, 74 ℃, 75 ℃ and the like) into a primary crystallization kettle, cooling to 60-65 ℃ (such as 60 ℃, 61 ℃, 62 ℃, 63 ℃, 64 ℃, 65 ℃ and the like), adding tebuconazole seed crystal, cooling to 50-60 ℃ (such as 50 ℃, 51 ℃, 52 ℃, 53 ℃, 54 ℃, 55 ℃, 56 ℃, 57 ℃, 58 ℃, 59 ℃, 60 ℃ and the like) for crystal growth, and then feeding crystal slurry into a secondary crystallization kettle;
preferably, the solute of the tebuconazole mother liquor in the step (1) is tebuconazole, and the solution is cyclohexane;
preferably, the concentration of the tebuconazole mother liquor solute of step (1) is 8 to 20wt% (e.g. 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, etc.), preferably 11.5 to 17.5wt%.
The grain diameter of the tebuconazole seed crystal in the step (1) is 500-1300 meshes (such as 500 meshes, 600 meshes, 700 meshes, 800 meshes, 900 meshes, 1000 meshes, 1100 meshes, 1200 meshes, 1300 meshes and the like);
preferably, the tebuconazole seed crystals in step (1) are added in an amount of 1 to 8wt% (e.g., 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, etc.), preferably 2.5 to 5wt%, of tebuconazole crystals.
The stirring speed in the step (1) is 150-300 r/min (for example, 150r/min, 170r/min, 190r/min, 210r/min, 230r/min, 250r/min, 270r/min, 300 revolutions, etc.);
preferably, the tebuconazole mother liquor in the step (1) is added into the primary crystallization kettle in a dropwise manner, wherein the dropwise adding speed is 1-8 ml/min (such as 1ml/min, 2ml/min, 3ml/min, 4ml/min, 5ml/min, 6ml/min, 7ml/min, 8ml/min and the like);
preferably, the cooling rate of the cooling to 50-60 ℃ in the step (1) is 5-15 ℃/h (such as 5 ℃/h, 6 ℃/h, 7 ℃/h, 8 ℃/h, 9 ℃/h, 10 ℃/h, 11 ℃/h, 12 ℃/h, 13 ℃/h, 14 ℃/h, 15 ℃/h, etc.);
preferably, the seeding time in step (1) is 0.5-2 h (e.g. 0.5h, 0.75h, 1h, 1.25h, 1.5h, 1.75h, 2h, etc.), preferably 0.5-1.5 h.
(2) After the crystal slurry enters a secondary crystallization kettle, the crystal slurry is cooled to 40-50 ℃ (40 ℃, 41 ℃, 42 ℃, 43 ℃, 44 ℃, 45 ℃, 46 ℃, 47 ℃, 48 ℃, 49 ℃, 50 ℃ and the like) under the stirring condition, and then the crystal slurry enters a tertiary crystallization kettle;
preferably, the rate of the crystal slurry entering the secondary crystallization kettle in the step (2) is 1-8 ml/min (such as 1ml/min, 2ml/min, 3ml/min, 4ml/min, 5ml/min, 6ml/min, 7ml/min, 8ml/min, etc.);
preferably, the stirring speed in the step (2) is 150-300 r/min (for example, 150r/min, 170r/min, 190r/min, 210r/min, 230r/min, 250r/min, 270r/min, 300 revolutions, etc.);
preferably, the cooling rate of the step (2) to 40-50 ℃ is 5-15 ℃/h;
preferably, the time for growing the crystals in the step (2) is 0.5-2.5 h (e.g. 0.5h, 0.75h, 1h, 1.25h, 1.5h, 1.75h, 2h, 2.5h, etc.), preferably 0.5-2 h.
(3) After the crystal slurry enters a three-stage crystallization kettle, the temperature is reduced to 20-30 ℃ (for example, 20 ℃, 21 ℃, 22 ℃, 23 ℃, 24 ℃, 25 ℃, 26 ℃, 27 ℃, 28 ℃, 29 ℃, 30 ℃ and the like) under the stirring condition, and the tebuconazole crystals are obtained by crystal growth.
Preferably, the rate of the crystal slurry entering the three-stage crystallization kettle in the step (3) is 1-8 ml/min (such as 1ml/min, 2ml/min, 3ml/min, 4ml/min, 5ml/min, 6ml/min, 7ml/min, 8ml/min, etc.);
preferably, the stirring speed in the step (3) is 150-300 r/min (for example, 150r/min, 170r/min, 190r/min, 210r/min, 230r/min, 250r/min, 270r/min, 300 revolutions, etc.);
preferably, the cooling rate of the cooling to 20-30 ℃ in the step (3) is 5-15 ℃/h (such as 5 ℃/h, 6 ℃/h, 7 ℃/h, 8 ℃/h, 9 ℃/h, 10 ℃/h, 11 ℃/h, 12 ℃/h, 13 ℃/h, 14 ℃/h, 15 ℃/h, etc.);
preferably, the time for growing the crystals in the step (3) is 0.5-2.5 h (for example, 0.5h, 0.75h, 1h, 1.25h, 1.5h, 1.75h, 2h, 2.5h, etc.), preferably 0.5-2 h.
Preferably, the step (3) further comprises solid-liquid separation and drying of the mixture obtained after crystal growth;
preferably, the solid-liquid separation mode is filtration;
preferably, the drying temperature is 50 ℃, the drying time is 24 hours, and the drying is carried out at normal pressure.
The second object of the present invention is to provide a continuous crystallization method for preparing tebuconazole crystals according to the above-mentioned method.
Preferably, the main particle size of the tebuconazole crystal product reaches 400 mu m, D50 is 300-360 mu m, and D90 is 650-680 mu m.
It is a further object of the present invention to provide a use of the tebuconazole crystals in the preparation of a pesticide.
In the present invention, solution crystallization is an effective way to obtain the target crystal form, crystal habit, particle size and particle size distribution. Solubility data and thermodynamic properties of tebuconazole are essential to control its crystal form, crystal habit and particle size distribution. Solid-liquid phase equilibrium data are also fundamental data for continuous crystallization industry design and scale-up.
The solubility data of tebuconazole were determined as follows:
| temperature (. Degree. C.) | Concentration (g/100 g solution) | Crystallization amount (g/100 g solvent) |
| 25 | 0.60 | 0.61 |
| 30 | 0.99 | 1.00 |
| 35 | 1.32 | 1.33 |
| 40 | 1.58 | 1.61 |
| 45 | 2.30 | 2.35 |
| 50 | 3.37 | 3.49 |
| 55 | 5.53 | 5.85 |
| 60 | 8.44 | 9.22 |
| 65 | 13.50 | 15.61 |
| 70 | 19.91 | 24.86 |
The solution in the metastable zone containing solute in excess of the saturation amount is called supersaturated solution, and the ultimate solubility of the solute when the solution is in supersaturation and the nucleation is to be spontaneously generated is called the super-solubility of the solute. The region between the solubility curve and the super-solubility curve is the metastable region of the solute. In a defined solution system, the solubility curve is fixed, while the super-solubility curve varies with changing conditions, the position of which is related to various factors such as the rate of cooling, the intensity of stirring, and the presence or absence of impurities.
The metastable zone width refers to the distance between the super-solubility and solubility of a solute, and can be generally expressed in terms of either extreme supersaturation or extreme supercooling. A larger metastable zone width indicates that the more stable supersaturated solution of the species is, the less prone to crystallization, but a wider metastable zone will also tend to result in severe burst nucleation. The solution is in a metastable zone state, and the crystal with good crystal form and uniform granularity can be obtained by adding seed crystal or slowly cooling to promote primary nucleation, so that the measurement of the data of the metastable zone of the crystalline substance has very important significance for crystallization operation. In the crystallization process, it is generally desired to control the operation path of crystallization in the metastable region, promote crystal growth to inhibit secondary nucleation, reduce the generation of fine particles, and obtain a product with large and uniform particle size.
The data for the metastable zone were determined as follows:
by measuring these basic data, we can know that the solubility of tebuconazole in cyclohexane is greatly influenced by temperature, especially that the solubility of tebuconazole increases rapidly with the increase of temperature in a high temperature region, and that the influence of temperature on the solubility of tebuconazole becomes smaller gradually with the decrease of temperature, and the main effect is that the solubility of tebuconazole is smaller in a low temperature region. Therefore, it is important to control the crystallization of tebuconazole in the high temperature zone. Meanwhile, by measuring the nucleation metastable zone of tebuconazole, the temperature difference between saturation temperature points and crystallization temperature points with different concentrations is between 12 and 18 ℃, which shows that the metastable zone at different temperatures is stable and wider, so that the crystallization operation path can be controlled in the nucleation metastable zone by adding seed crystals and controlling the cooling rate, the nucleation is inhibited, the growth is promoted, and the product with large and uniform granularity is obtained.
Experimental example 1:
(1) Adding tebuconazole mother liquor with the mass fraction of 13.5% at the temperature of 70 ℃ into a crystallization kettle at the time of 4ml/min, cooling to 65 ℃, adding seed crystals with the particle size of 450 meshes, which are 2.5% compared with the product mass, for crystal growth for 0.5 hour, cooling the crystallization kettle at the speed of 10 ℃/h, and cooling to 60 ℃ at the rotating speed of 250r/min;
(2) Adding the crystal slurry obtained in the step (1) into a secondary crystallization kettle at a cooling rate of 10 ℃/h to 50 ℃, and adding the crystal slurry into a tertiary crystallization kettle at a cooling rate of 4ml/min after crystal growth for 1 hour;
(3) And cooling the three-stage kettle to 25 ℃ at a cooling rate of 10 ℃/h, and growing the crystal for 1 hour, wherein the rotating speed is 250r/min, so as to finally obtain a crystal mixture.
(4) Filtering the crystallization mixture obtained in the step (3) to obtain a solid, and then cleaning and drying to obtain tebuconazole crystals.
The tebuconazole crystals obtained in this experimental example were subjected to a particle size distribution test (the test instrument was a Markov MS3000 laser particle sizer), and it was found that the obtained tebuconazole crystals D90 was 653 μm.
The integral optical microscope picture of the product is shown in fig. 1, and compared with the original traditional process product picture (see fig. 2), the coalescence condition of the crystal product can be obviously slowed down.
Experimental example 2:
the difference from experimental example 1 is that the mass fraction of the tebuconazole mother liquor is 17.5%, the added seed crystal is about 800 meshes, the mass is 5% of the product mass, and the other preparation methods are the same as experimental example 1.
As a result of the same test method as in Experimental example 1, it was found that the obtained tebuconazole crystal D90 was 658. Mu.m.
The integral optical microscope picture of the product is shown in fig. 3, and the coalescence condition of the crystal product is obviously slowed down.
Experimental example 3:
(1) Adding tebuconazole mother liquor with the mass fraction of 20% at the temperature of 75 ℃ into a crystallization kettle at the time of 8ml/min, cooling to 63 ℃, adding seed crystals with the granularity of 1300 meshes, which are 8% in mass compared with the product, for crystal growth for 0.5 hour, cooling the crystallization kettle at the speed of 15 ℃/h, and cooling to 55 ℃ at the rotating speed of 300r/min;
(2) Adding the crystal slurry obtained in the step (1) into a secondary crystallization kettle at a cooling rate of 15 ℃/h to 45 ℃, and adding the crystal slurry into a tertiary crystallization kettle at 8ml/min after growing crystals for 2.5 hours;
(3) And cooling the three-stage kettle to 30 ℃ at a cooling rate of 15 ℃/h, and growing the crystal for 2.5 hours, wherein the rotating speed is 300r/min, so as to finally obtain the crystal mixture.
(4) Filtering the crystallization mixture obtained in the step (3) to obtain a solid, and then cleaning and drying to obtain tebuconazole crystals.
The tebuconazole crystals obtained in this experimental example were subjected to a particle size distribution test (the test instrument was a Markov MS3000 laser particle sizer), and it was found that the obtained tebuconazole crystals D90 was 651. Mu.m.
The bulk optical microscope image of the product is shown in fig. 4, and the coalescence of the crystal product is significantly slowed down.
Experimental example 4:
(1) Adding tebuconazole mother liquor with the mass fraction of 8% at the temperature of 65 ℃ into a crystallization kettle in the time of 2ml/min, cooling to 60 ℃, adding seed crystals with the granularity of 800 meshes and the mass of 1% compared with the product, carrying out crystal growth for 1 hour, cooling the crystallization kettle at the speed of 5 ℃/h, and cooling to 50 ℃ at the rotating speed of 150r/min;
(2) Adding the crystal slurry obtained in the step (1) into a secondary crystallization kettle at a cooling rate of 5 ℃/h to 40 ℃, and adding the crystal slurry into a tertiary crystallization kettle at a cooling rate of 2ml/min after crystal growth for 1 hour;
(3) And cooling the three-stage kettle to 20 ℃ at a cooling rate of 5 ℃/h, and growing the crystal for 1 hour, wherein the rotating speed is 150r/min, so as to finally obtain a crystal mixture.
(4) Filtering the crystallization mixture obtained in the step (3) to obtain a solid, and then cleaning and drying to obtain tebuconazole crystals.
The tebuconazole crystals obtained in this experimental example were subjected to a particle size distribution test (the test instrument was a Markov MS3000 laser particle sizer), and it was found that the obtained tebuconazole crystals D90 was 660. Mu.m.
The integral optical microscope picture of the product is shown in fig. 5, and the coalescence condition of the crystal product is obviously slowed down.
Experimental example 5:
(1) Adding tebuconazole mother liquor with the mass fraction of 11.5% at the temperature of 70 ℃ into a crystallization kettle at the time of 5ml/min, cooling to 63 ℃, adding seed crystals with the particle size of 800 meshes and the mass of 5% compared with the product, and carrying out crystal growth for 1.5 hours, wherein the crystallization kettle is cooled at the speed of 10 ℃/h, and the temperature is reduced to 60 ℃ and the rotating speed is 250r/min;
(2) Adding the crystal slurry obtained in the step (1) into a secondary crystallization kettle at a cooling rate of 10 ℃/h to 50 ℃, and adding the crystal slurry into a tertiary crystallization kettle at a cooling rate of 5ml/min after growing the crystal for 2 hours;
(3) And cooling the three-stage kettle to 30 ℃ at a cooling rate of 10 ℃/h, and growing the crystal for 2 hours, wherein the rotating speed is 250r/min, so that a crystal mixture is finally obtained.
(4) Filtering the crystallization mixture obtained in the step (3) to obtain a solid, and then cleaning and drying to obtain tebuconazole crystals.
The tebuconazole crystals obtained in this experimental example were subjected to a particle size distribution test (the test instrument was a Markov MS3000 laser particle sizer), and it was found that the obtained tebuconazole crystals D90 was 677. Mu.m.
The bulk optical microscope image of the product is shown in fig. 6, and the coalescence of the crystal product is significantly slowed down.
Reference is made to comparative example 1:
see CN102659696a.
The ammonium persulfate crystal obtained in this comparative example was subjected to the same test method as in experimental example 1, and the obtained tebuconazole crystal D90 was 291. Mu.m.
Under the conditions of an applied pressure of 10300Pa and an added water amount of 1%, the samples of experimental example 1 and reference comparative example 1 were placed in a agglomeration mold for 3 days, to prepare A, B two identical sets of cylindrical agglomerated samples, respectively, having a diameter of 3.6cm and a height of 2cm. The caking samples were allowed to fall freely from the same height and the degree of breakage was compared, i.e. the caking strength was tested as follows:
| experiment | Sample of | Free drop height | Rate of fracture |
| 1 | Experimental example 1 caking sample A | 1m | 100％ |
| 2 | Experimental example 1 caking sample B | 2m | 100％ |
| 3 | Reference comparative example 1 caking sample A | 1m | 30％ |
| 4 | Reference to comparative example 1 caking sample B | 2m | 45％ |
As can be seen from table 1, comparing the caking strength test 1 with the tests 3 and 4, the caking sample prepared from the product of experimental example 1 can be completely crushed already when freely falling at a height of 1 m; whereas the agglomerated sample obtained from the product of comparative example 1 had a breakage of less than 50% at a height of 2m when freely dropped. From the experimental results, the anti-caking performance of the tebuconazole product prepared by the invention is far better than that of the tebuconazole product in the patent CN102659696A. Comparative example 1:
the difference from experimental example 1 is only that no seed crystal was added during the continuous crystallization, and the remaining crystallization methods are the same as experimental example 1.
The same test method as in experimental example 1 was used for the tebuconazole crystals obtained in this comparative example, and it was found that the obtained perpivazol crystals D90 was 331. Mu.m.
The integral optical microscope picture of the product is shown in fig. 7, and comparison of experimental example 1 and comparative example 1 shows that the supersaturation cannot be consumed in time due to the absence of seed crystals, and a large amount of secondary nucleation occurs. Therefore, the product granularity is not uniform, more fine particles exist in the product, and the fact that secondary nucleation is serious in the crystallization process and the final product coalescence is serious is shown.
Comparative example 2:
the difference from experimental example 1 was only that the amount of seed crystal added in the process was 10% of the product mass, and the rest of the preparation method was the same as experimental example 1.
The tebuconazole crystals obtained in this comparative example were subjected to the same test method as in experimental example 1, and it was found that tebuconazole crystals D90 was 446. Mu.m.
As can be seen from the comparison of experimental example 1 and comparative example 2, the product obtained by adding 10% of seed crystals has a particle size which is not expected although the particle size is increased, and the agglomeration of the product is serious due to the increase of seed crystals, and the flowability and anti-caking ability are low. Comparative example 3:
the difference from experimental example 1 is that the amount of seed crystals added in the process is 10% of the product mass, the rotation speed of the crystallization kettle is 400r/min, and the rest preparation methods are the same as experimental example 1.
The tebuconazole crystals obtained in this comparative example were subjected to the same test method as in experimental example 1, and it was found that the obtained tebuconazole crystals D90 was 355 μm, and the bulk optical microscope picture of the product was shown in FIG. 7.
As can be seen from comparison of experimental example 1 and comparative example 3, the bulk optical microscope image of the product shows that there are a large number of fine particles in the crystals under this condition, because the stirring speed is too high, a large number of crystals are broken up during crystallization, and the stirring is intense to cause secondary nucleation of the crystals, so that the stirring speed is increased during intermittent cooling crystallization to break up the crystals, the secondary nucleation is serious, and the fine particles are more.
The crystal form refers to the arrangement mode of crystal molecules in the crystal, is important physicochemical properties of the crystal, and for polymorphic substances, certain physicochemical properties (such as melting point, solubility and stability) may be different due to different crystal forms; under different conditions, the crystal forms may be mutually converted, and the crystal transformation phenomenon occurs. In order to verify whether the crystalline form difference of the tebuconazole crystals obtained by the novel process is compared with the crystalline form of the workshop product crystals, XRD characterization is carried out on the product obtained in the experimental example 1 and the workshop product crystals, the XRD chart is shown in figure 10, and according to the specification of P372 in 2015 of Chinese pharmacopoeia, if the crystalline form substances of two crystalline samples are judged to be the same, the diffraction peak position error range of the crystalline form substances is within +/-0.2 degrees. In fig. 10, it can be seen that the peak positions of two tebuconazole crystals with different morphologies correspond to the same diffraction angle, so that it can be considered that the tebuconazole crystals in the patent are consistent compared with the crystals of workshop products, and the crystallization process does not generate the phenomenon of crystal transformation.
The applicant declares that the above is only a specific embodiment of the present invention, but the scope of the present invention is not limited thereto, and it should be apparent to those skilled in the art that any changes or substitutions that are easily conceivable within the technical scope of the present invention disclosed by the present invention fall within the scope of the present invention and the disclosure.
Claims (10)
1. A continuous crystallization method of tebuconazole crystals, characterized in that the continuous crystallization method comprises the steps of:
(1) Under the stirring condition, adding the tebuconazole mother liquor with the temperature of 65-75 ℃ into a primary crystallization kettle, cooling to 60-65 ℃, adding tebuconazole seed crystals, cooling to 50-60 ℃ for crystal growth, and then enabling crystal slurry to enter a secondary crystallization kettle;
(2) After the crystal slurry enters a secondary crystallization kettle, cooling to 40-50 ℃ under the stirring condition, growing crystals, and then entering a tertiary crystallization kettle;
(3) And after the crystal slurry enters a three-stage crystallization kettle, cooling to 20-30 ℃ under the stirring condition, and growing crystals to obtain the tebuconazole crystals.
2. The continuous crystallization method of tebuconazole crystals according to claim 1, wherein the solute of the tebuconazole mother liquor in the step (1) is tebuconazole, and the solution is cyclohexane;
the concentration of the tebuconazole mother liquor solute in the step (1) is 8-20wt%.
3. The continuous crystallization method of tebuconazole crystals according to claim 1, wherein the grain size of tebuconazole seed crystals in the step (1) is 500 to 1300 mesh;
the adding amount of the tebuconazole seed crystal in the step (1) is 1-8wt% of tebuconazole crystals.
4. The continuous crystallization method of tebuconazole crystals according to claim 1, wherein the stirring rate in the step (1) is 150 to 300r/min;
the tebuconazole mother liquor in the step (1) is added into a primary crystallization kettle in a dropwise adding mode, and the dropwise adding speed is 1-8 ml/min;
the cooling rate of the step (1) to 50-60 ℃ is 5-15 ℃/h;
the crystal growing time in the step (1) is 0.5-2 h.
5. The continuous crystallization method of tebuconazole crystals according to claim 1, wherein the rate of the crystal slurry entering the secondary crystallization kettle in the step (2) is 1-8 ml/min;
the stirring speed of the step (2) is 150-300 r/min;
the temperature reduction rate of the step (2) for cooling to 40-50 ℃ is 5-15 ℃/h;
and (3) the time for growing the crystals in the step (2) is 0.5-2.5 h.
6. The continuous crystallization method of tebuconazole crystals according to claim 1, wherein the rate of the crystal slurry entering the three-stage crystallization kettle in the step (3) is 1-8 ml/min;
the stirring speed of the step (3) is 150-300 r/min;
the temperature reduction rate of the step (3) for cooling to 20-30 ℃ is 5-15 ℃/h;
and (3) the time for growing the crystals is 0.5-2.5 h.
7. The continuous crystallization method of tebuconazole crystals as claimed in claim 1, wherein the step (3) further comprises subjecting the mixture obtained after the crystallization to solid-liquid separation and drying;
the solid-liquid separation mode is filtration;
the drying temperature is 50 ℃, the drying time is 24 hours, and the drying is carried out at normal pressure.
8. Tebuconazole crystals prepared by a continuous crystallization method of tebuconazole crystals according to any one of claims 1 to 7.
9. The tebuconazole crystal according to claim 8, wherein the tebuconazole crystal product has a bulk particle size of 400 μm, a D50 of 300 to 360 μm and a D90 of 650 to 680 μm.
10. Use of tebuconazole crystals according to any of claims 8-9 for the preparation of pesticides.
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