CN114516818A - Cyclopropylflufenoxam crystal form and preparation method and application thereof - Google Patents

Cyclopropylflufenoxam crystal form and preparation method and application thereof Download PDF

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CN114516818A
CN114516818A CN202011307401.3A CN202011307401A CN114516818A CN 114516818 A CN114516818 A CN 114516818A CN 202011307401 A CN202011307401 A CN 202011307401A CN 114516818 A CN114516818 A CN 114516818A
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cyflumetofen
crystal form
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杨丙连
吕亮
洪湖
黄超群
张照军
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Cac Nantong Chemical Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • 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
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/44—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a nitrogen atom attached to the same carbon skeleton by a single or double bond, this nitrogen atom not being a member of a derivative or of a thio analogue of a carboxylic group, e.g. amino-carboxylic acids
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    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
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Abstract

The invention provides four new crystal forms of cyflumetofen, including a cyflumetofen crystal form I, a cyflumetofen crystal form II, a cyflumetofen crystal form III and a cyflumetofen crystal form IV, and preparation methods and applications of the four crystal forms. The four novel crystal forms of the cyflumetofen, provided by the invention, have the advantages of high purity, good stability and simple preparation method, can be used as active ingredients of the cyflumetofen preparation, can obviously improve the thermal stability of the preparation, reduce the water precipitation rate of the cyflumetofen suspension preparation, and have good application prospects.

Description

Cyclopropylflufenoxuron crystal form and preparation method and application thereof
Technical Field
The invention belongs to the technical field of pesticides, and particularly relates to a cyflumetofen crystal form and a preparation method and application thereof.
Background
Pests are one of the important factors causing the yield reduction of crops and economic crops, and the development of pesticides with higher activity, lower dosage and more environmental friendliness is an important subject which needs to be continuously researched in the field of pesticides. The m-diamide pesticide represented by Broflanilide has the characteristics of unique action mechanism, novel action target, environmental friendliness and the like, gradually becomes a hot product in the market and the research community, and becomes one of the most potential pesticide development directions.
Cyflumetofen is a novel insecticide developed on the basis of Broflanilide, and has the chemical name of 2' -bromo-2-fluoro-3- [ N- (cyclopropylmethyl) -4-fluorobenzoyl ] -4' - [1,2,2, 2-tetrafluoro-1- (trifluoromethyl) ethyl ] -6' - (trifluoromethyl) benzamide, and the structural formula is as follows:
Figure BDA0002788712190000011
the cyflumetofen has excellent insecticidal activity at low dose, takes effect quickly, can exert the insecticidal activity after being applied for one day, can reach high insecticidal activity within three days, has good quick-acting performance and has good use reverberation on the market.
The active substance can exist in different crystalline forms or in amorphous form, a phenomenon known as polymorphism; in a particular crystalline form, the molecules are uniformly stacked and arranged in a certain order. The polymorphism of the drug is a ubiquitous phenomenon in solid drugs, and the crystal form or solvate of the drug has certain influence on the physicochemical property, specific performance and preparation method of the drug.
In the active substances of insecticides, different crystal forms of one identical compound can sometimes exhibit different physicochemical and use properties, including: solubility, vapor pressure, dissolution rate, stability of phase transition to another crystal form, stability during milling, suspension stability, optical and mechanical properties, hygroscopicity, crystal shape and size, filterability, density, melting point, decomposition stability and color, and even differences in chemical reactions or biological activities. Therefore, the screening and research of the crystal form of the active substance have very important significance for the scale production and the deep application of the active substance.
In recent years, with the progress of the research of pesticide chemistry, people have made a staged achievement in the synthesis process of active substances such as cyflumetofen and the like, for example, CN109497062A discloses a meta-diamide compound, a preparation method and an application thereof, wherein the meta-diamide compound comprises cyflumetofen (compound number 62), and specifically discloses a process method for obtaining cyflumetofen by using 2-fluoro-3- [ N- (cyclopropromethyl) -4-fluoro-benzamide ] benzoic acid as a starting material, reacting with acyl chloride to generate corresponding benzoyl chloride, and further reacting with 2-bromo-6-trifluoromethyl-4-heptafluoroisopropyl aniline. However, in the prior art, the crystal forms of the cyflumetofen cannot be distinguished, the prepared product is usually an unstable crystal form or a mixture of different crystal forms, the properties of the product are irregular solids, and the performance differences of crystallinity, stability and the like among different crystal forms are extremely large; the preparation prepared by the raw material medicine has various indexes such as stability and the like, and can not meet the technical requirements of the existing preparation.
Therefore, it is desirable in the art to develop a new crystal form of cyflumetofen and a preparation method thereof to obtain a more stable cyflumetofen preparation.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a plurality of cyflumetofen crystal forms and a preparation method and application thereof, wherein the cyflumetofen crystal forms have the characteristics of high purity and high stability, can fully meet the requirements on the stability and the bioactivity of a cyflumetofen preparation, and have wide application prospects.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the invention provides a cyflumetofen crystal form I, which has characteristic peaks at diffraction angles 2 theta of 6.7 +/-0.2 degrees, 8.3 +/-0.2 degrees, 9.8 +/-0.2 degrees, 11.3 +/-0.2 degrees, 11.9 +/-0.2 degrees, 14.1 +/-0.2 degrees, 15.2 +/-0.2 degrees, 18.7 +/-0.2 degrees, 19.3 +/-0.2 degrees and 20.2 +/-0.2 degrees in a powder X-ray diffraction pattern under Cu-Ka radiation.
Preferably, in the powder X-ray diffraction pattern of the crystalline form I of the cyflufenamide under Cu-Ka radiation, the diffraction angles 2 theta are 6.7 +/-0.2 degrees, 8.3 +/-0.2 degrees, 9.8 +/-0.2 degrees, 11.3 +/-0.2 degrees, 11.9 +/-0.2 degrees, 12.6 +/-0.2 degrees, 13.7 +/-0.2 degrees, 14.1 +/-0.2 degrees, 14.9 +/-0.2 degrees, 15.2 +/-0.2 degrees, 16,6 +/-0.2 degrees, 17.1 +/-0.2 degrees, 17.5 +/-0.2 degrees, 18.0 +/-0.2 degrees, 18.4 +/-0.2 degrees, 18.7 +/-0.2 degrees, 19.3 +/-0.2 degrees, 19.8 +/-0.2 degrees, 20.2 +/-0.2 degrees, 20.8 +/-0.2 degrees, 20 +/-0.2 degrees, 22.3 +/-0.2 degrees, 22.6 +/-0.2.4 +/-0.23.8 +/-0.2 degrees, 2.2 degrees, 20.8 +/-0.2.2 degrees, 2 degrees, 2.2 +/-0.2 degrees, 2.2 degrees, 2 degrees, 2.3 +/-0.2.2.2 degrees, 2 degrees, 2.2 +/-0.2, 2 +/-0.2 degrees, 2 +/-0.2.2, 2 degrees, 2.2 +/-0.2 degrees, 2 +/-0.2 degrees, 2 degrees, 2.2 +/-0.2 degrees, 3 +/-0.2.2 +/-0.2 degrees, 3 +/-0.2 degrees, 2 +/-0.2 degrees, 3 +/-0.2 degrees, 2.2.2 degrees, 2, 2.2.2.2 +/-0.2 degrees, 2 +/-0.2 degrees, 2 +/-0.2.2 +/-0.2 degrees, 2 +/-0.2 degrees, 2 degrees, 3 +/-0.2 degrees, 2 +/-0.2 degrees, 3 +/-0.2 degrees, 3 +/-0, 3 +/-0.2 degrees, 3 +/-0.2 degrees, 3 +/-0.2 degrees, 3 +/-0.2 degrees, 3 +/-0.2 degrees, 3 +/-0.2, The characteristic peak is at 39.3 +/-0.2 degrees.
Preferably, the differential scanning calorimetry curve of the cyhalodiamide crystal form I has an endothermic peak at 150-157 ℃; the temperature rise rate in the differential scanning calorimetry curve test is 10 ℃/min.
The single crystal research of the cyhalodiamide crystal form I shows that the crystal structure is a triclinic crystal system, and the crystallographic data are shown in Table 1.
TABLE 1
Figure BDA0002788712190000021
Figure BDA0002788712190000031
In an infrared spectrogram of the cyflumetofen crystal form I, the absorption peaks are at the following wave numbers: (KBr pellet, cm)-1，±0.5)，3362.2，3093.6，3076.1，3022.3，2930.6，1679.6，1651.4，1604.9，1581，1509.2，1488，1453.9，1429.6，1412.7，1385.7，1339.4，1325.6，1302.9，1278.7，1263.6，1240，1202.5，1168.4，1157.5，1139.6，1078，1052.5，1005.7，983.9，944.1，932.6，921.9，894.5，847，832，817.3，797.8，758.4，729.1，717.5，702.5，683.3，646.7，625.8，602.6，587.3，563.5，546.7，512.5，467.7，435.4，418.3。
In a second aspect, the present invention provides a process for the preparation of crystalline form I of cyflumetofen as described in the first aspect, the process comprising: crystallizing a cyflumetofen solution to obtain a cyflumetofen crystal form I; the solvent of the cyflufenamid solution is selected from any one or the combination of at least two of ethanol, n-propanol, isopropanol, n-hexane, n-heptane, aromatic hydrocarbon solvents, halogenated hydrocarbon solvents or ether solvents.
Preferably, the concentration of the cyflumetofen solution is 10-300 g/L, such as 15g/L, 20g/L, 25g/L, 30g/L, 35g/L, 40g/L, 45g/L, 50g/L, 60g/L, 70g/L, 80g/L, 90g/L, 100g/L, 110g/L, 130g/L, 150g/L, 170g/L, 190g/L, 200g/L, 210g/L, 230g/L, 250g/L, 270g/L or 290g/L, and specific values therebetween are limited in space and for the sake of brevity, and the specific values included in the range are not exhaustive.
Preferably, the purity of the cyflumetofen in the cyflumetofen solution is more than or equal to 85%, such as 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% or 100%, and the like, and more preferably more than or equal to 90%.
The cyflumetofen solution can be prepared by any one of the following methods: (1) dissolving cyflumetofen in the solvent; or, (2) a solution of cyflumetofen is prepared by chemical reaction and transfer of the reaction mixture (after removal of reagents and/or by-products, if appropriate) into the solvent.
Any known form of cyflumetofen can be used for cyflumetofen in the cyflumetofen solution. Amorphous cyflumetofen, mixtures of different crystalline forms or mixtures of amorphous and crystalline cyflumetofen are generally used.
The dissolving process of the cyflumetofen solution is generally carried out at a temperature of 40 to 80 ℃ (e.g., 42 ℃, 45 ℃, 48 ℃, 50 ℃, 52 ℃, 55 ℃, 58 ℃, 60 ℃, 62 ℃, 65 ℃, 68 ℃, 70 ℃, 72 ℃, 75 ℃ or 78 ℃. As a preferred embodiment of the invention, the dissolution of cyflumetofen is carried out at elevated temperature, in particular at least 50 ℃, but the temperature used for the dissolution does not naturally exceed the boiling point of the solvent. The dissolving process is usually carried out at a temperature of 50-80 ℃.
Preferably, the crystallization temperature is 10 to 35 ℃, such as 11 ℃, 13 ℃, 15 ℃, 17 ℃, 19 ℃, 20 ℃, 21 ℃, 23 ℃, 25 ℃, 27 ℃, 29 ℃, 30 ℃, 31 ℃, 33 ℃ or 34 ℃.
The crystallization may be carried out in any one of the following manners or a combination of at least two of the following manners, for example: (1) cooling the cyflumetofen solution; (2) concentrating the cyflumetofen solution; (3) adding a poor solvent to the solution containing the cyflumetofen; (4) the above measures are combined.
The crystallization is generally carried out until at least 80% by weight, preferably at least 90% by weight, of the employed cyflumetofen has crystallized out.
Preferably, the crystallization may also be promoted or accelerated by adding seeds of form I of cyflumetofen, for example by adding seeds of form I of cyflumetofen before or during crystallization.
Preferably, the amount of the seed crystal is 0.001 to 10%, for example, 0.002%, 0.005%, 0.008%, 0.01%, 0.03%, 0.05%, 0.08%, 0.1%, 0.3%, 0.5%, 0.8%, 1%, 1.5%, 2%, 4%, 6%, 8%, or 9%, more preferably 0.005 to 5%, and still more preferably 0.01 to 1%, based on 100% by mass of the cyhalothrin in the cyhalothrin solution.
Preferably, the seed crystals are added at a temperature at which the saturation concentration of cyflumetofen in the solvent is reached, i.e. at or below the temperature at which the dissolved amount of cyflumetofen forms a saturated solution in the solvent. The temperature dependence of the saturation concentration in the solvent can be determined by the person skilled in the art by routine experiments.
Preferably, the crystallization is followed by a step of solid-liquid separation, and the solid-liquid separation method is a common technique, such as filtration, centrifugation and the like.
Preferably, the solid-liquid separation further comprises a step of washing the solid. The washing solvent may be a crystallization solvent, water or a mixture of a crystallization organic solvent and water. The washing may be carried out in one or more stages, usually with water washing in the final washing stage. The washing is usually carried out at a temperature below 30 c, preferably below 25 c, further preferably below 20 c, in order to keep the loss of valuable product as low as possible.
Preferably, the crystalline form I of cyflumetofen is dried after washing and sent for further processing; the moist ciprofloxacin crystal form I obtained after washing, in particular the moist aqueous ciprofloxacin crystal form I, is usually fed directly to further processing.
Preferably, the aromatic hydrocarbon solvent is selected from any one of benzene, toluene or xylene or a combination of at least two thereof.
Preferably, the halogenated hydrocarbon solvent is selected from any one of or a combination of at least two of dichloromethane, trichloromethane, bromoethane or 1, 2-dichloroethane.
Preferably, the ether solvent is selected from any one or a combination of at least two of tetrahydrofuran, diethyl ether, isopropyl ether or methyl tert-butyl ether.
Preferably, the purity of the cyflumetofen crystal form I is more than or equal to 90 percent, such as 91 percent, 92 percent, 93 percent, 94 percent, 95 percent, 96 percent, 97 percent, 98 percent, 99 percent, 99.5 percent or 100 percent and the like.
In a third aspect, the invention provides a cyflumetofen crystal form II, and characteristic peaks exist at diffraction angles 2 theta of 7.8 +/-0.2 degrees, 10.1 +/-0.2 degrees, 11.2 +/-0.2 degrees, 13.4 +/-0.2 degrees, 15.6 +/-0.2 degrees, 19.4 +/-0.2 degrees, 20.0 +/-0.2 degrees and 20.6 +/-0.2 degrees in a powder X-ray diffraction pattern of the cyflumetofen crystal form II under Cu-Ka radiation.
Preferably, in a powder X-ray diffraction pattern of the cyflumetofen crystal form II under Cu-Ka radiation, the diffraction angle 2 theta has the characteristic peaks of 7.8 +/-0.2 degrees, 10.1 +/-0.2 degrees, 11.2 +/-0.2 degrees, 12.0 +/-0.2 degrees, 12.4 +/-0.2 degrees, 13.4 +/-0.2 degrees, 13.9 +/-0.2 degrees, 14.5 +/-0.2 degrees, 15.6 +/-0.2 degrees, 16.2 +/-0.2 degrees, 17.0 +/-0.2 degrees, 17.7 +/-0.2 degrees, 18.1 +/-0.2 degrees, 18.5 +/-0.2 degrees, 19.4 +/-0.2 degrees, 20.0 +/-0.2 degrees, 20.6 +/-0.2 degrees, 21.3 +/-0.2 degrees, 22.2 +/-0.2 degrees, 23.1 +/-0.2 degrees, 24.2 degrees, 24.8 +/-0.2 degrees, 25.1 +/-0.2 degrees, 21.3 +/-0.2 degrees, 22.2 degrees, 2 degrees, 22.2 +/-0.2 degrees, 2 +/-0.2 degrees, 29.2 degrees, 2 degrees, 29.2 +/-0.2 degrees, 2 degrees, 29.2 degrees, 2 degrees, are included.
Preferably, the differential scanning calorimetry curve of the cyhalodiamide crystal form II has an endothermic peak at 149.7-154.5 ℃; the temperature rise rate in the differential scanning calorimetry curve test is 10 ℃/min.
In an infrared spectrogram of the cyflumetofen crystal form II, the crystal form II has absorption peaks at the following wave numbers: (KBr pellet, cm)-1，±0.5)，3361.7，3094.4，3013.8，2926，1736.4，1680.7，1652.1，1606.4，1581.6，1509.8，1489.2，1454.2，1429.2，1412.4，1384.9，1322.8，1304.7，1279.2，1238.5，1203.8，1169.7，1158.1，1121.5，1078.2，1050，1005.7，984.7，943.3，933.5，922，893.3，846.9，817.8，797.9，760.2，728.7，718.4，703，677.5，646.5，626.5，605.3，587，564.2，539.6，512.3，467.6，418.9，409.8。
In a fourth aspect, the present invention provides a preparation method of cyflumetofen crystal form II as described in the third aspect, the preparation method comprising: crystallizing a cyflumetofen solution to obtain a cyflumetofen crystal form II; the solvent for preparing the cyflumetofen solution contains an ester solvent.
The solvent for preparing the cyflumetofen solution contains an ester solvent, which means that the solvent is an ester solvent or a mixture of the ester solvent and other solvents (such as acetone, water, aliphatic alkane solvents or ether solvents and the like).
Preferably, the concentration of the cyflumetofen solution is 10-300 g/L, such as 15g/L, 20g/L, 25g/L, 30g/L, 35g/L, 40g/L, 45g/L, 50g/L, 60g/L, 70g/L, 80g/L, 90g/L, 100g/L, 110g/L, 130g/L, 150g/L, 170g/L, 190g/L, 200g/L, 210g/L, 230g/L, 250g/L, 270g/L or 290g/L, and specific values therebetween are limited in space and for the sake of brevity, and the specific values included in the range are not exhaustive.
Preferably, the purity of the cyflumetofen in the cyflumetofen solution is more than or equal to 85%, such as 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% or 100%, and the like, and more preferably more than or equal to 90%.
Any known form of cyflumetofen can be used for cyflumetofen in the cyflumetofen solution. Amorphous cyflumetofen, mixtures of different crystalline forms or mixtures of amorphous and crystalline cyflumetofen are generally used.
Preferably, the crystallization temperature is 20 to 40 ℃, for example, 21 ℃, 23 ℃, 25 ℃, 27 ℃, 29 ℃, 30 ℃, 31 ℃, 33 ℃, 35 ℃, 37 ℃ or 39 ℃, and the specific values therebetween are limited by space and for the sake of brevity, and the invention is not intended to be exhaustive of the specific values included in the scope.
Preferably, the method of crystallization comprises natural evaporation and/or concentration.
Specifically, the natural volatilization is slow volatilization at room temperature, and the concentration is performed at 25-40 ℃.
Preferably, the crystallization process further comprises the steps of solid-liquid separation, washing and drying, and the specific method of the steps is the same as that of the second aspect.
Preferably, the solvent is an ester solvent.
Preferably, the ester solvent is selected from any one of ethyl formate, ethyl acetate or isopropyl acetate or a combination of at least two of them.
Preferably, the purity of the cyflumetofen crystal form II is more than or equal to 90 percent, such as 91 percent, 92 percent, 93 percent, 94 percent, 95 percent, 96 percent, 97 percent, 98 percent, 99 percent, 99.5 percent or 100 percent and the like.
In a fifth aspect, the invention provides a cyflumetofen crystal form III, which is a crystal form containing a crystallization solvent, and has characteristic peaks at diffraction angles 2 theta of 5.5 +/-0.2 degrees, 8.3 +/-0.2 degrees, 9.4 +/-0.2 degrees, 11.5 +/-0.2 degrees, 12.6 +/-0.2 degrees, 13.9 +/-0.9 degrees, 15.4 +/-0.2 degrees, 16.1 +/-0.2 degrees, 20.5 +/-0.2 degrees and 27.0 +/-0.2 degrees in a powder X-ray diffraction pattern under Cu-Ka radiation; the crystallization solvent is methanol.
Preferably, in the powder X-ray diffraction pattern of the cyflumetofen crystal form III under Cu-Ka radiation, the diffraction angle 2 theta has the characteristic + -0.3 + -0.2 DEG, 8.3 + -0.2 DEG, 9.4 + -0.2 DEG, 11.5 + -0.2 DEG, 12.6 + -0.2 DEG, 13.9 + -0.9 DEG, 15.4 + -0.2 DEG, 16.1 + -0.2 DEG, 17.2 + -0.2 DEG, 17.4 + -0.2 DEG, 18.8 + -0.2 DEG, 19.7 + -0.2 DEG, 20.20 + -0.2 DEG, 20.5 + -0.2 DEG, 21.5 + -0.2 DEG, 21.8 + -0.2 DEG, 22.3 + -0.2 DEG, 22.6 + -0.2 DEG, 23.5 + -0.2 DEG, 24.1 + -0.2 DEG, 24.6 + -0.2 DEG, 24.7 + -0.2 DEG, 25.3 + -0.2 DEG, 27.0 + -0 + -0.2 DEG, 27.5 + -0 + -0.28.0 + -0.2 DEG, 2 + -0 + -0.34 + -0 + -0.2 DEG, 2 + -0.34 + -0 + -0.2 DEG, 2 + -0.2 DEG, 2 + -0.3 + -0.2 DEG, 2 + -0.2 + -0 + -0.2 DEG, 2 + -0.2 DEG, 2 + -0.2 DEG, 2 + -0.2 DEG, 2.2 + -0.2 DEG, 2 + -0.2 DEG, 2 + -0.2 DEG, 2 + -0.2 + -0 + -0.2 DEG, 2 + -0.2 DEG, 2 DEG, and 32 DEG, 34 DEG, 32 DEG, 34 DEG, 2 + -0.2 + -0.2.2.2 + -0.2 DEG, 32 DEG, 2.2.2 DEG, 2 + -0.2 DEG, 34 DEG, 32 DEG, 2.2.2 DEG, 2 + -0.2.2.2.2 + -0 + -0.2 DEG, 32 DEG, 11 + -0.2 DEG, 2 + -0.2 DEG, 32 DEG, 2 DEG, 2.2.2 + -0.2.2 DEG, 34 DEG, and 32 + -0.2.2 DEG, and 32 + -0.2 DEG, and 32 DEG, 34 DEG, and 32 DEG, 34 DEG, and 11.2.2.2.2.2.2.2.2.2 + -0.2.2.2.2..
The single crystal research of the cyhalodiamide crystal form III shows that the crystal structure is a monoclinic system, and the crystallographic data are shown in Table 2.
TABLE 2
Test temperature (T) 296K
Crystal system Monoclinic crystal
Space group P 21/c
a 16.9717(15)pm
b 14.1550(14)pm
c 13.0223(12)pm
α 90°
β 101.285(3)°
γ 90°
Volume of 3067.9(5)nm3
Z 4
Density (calculated value) 1.629mg/m3
Wavelength of light 0.71073nm
Preferably, the differential scanning calorimetry curve of the cyhalodiamide crystal form III has endothermic peaks at 104-114 ℃ and 151-154.8 ℃; the temperature rise rate in the differential scanning calorimetry curve test is 10 ℃/min. Wherein the endothermic peak at 104 to 114 ℃ has an initial temperature of 104 ℃ and a termination temperature of 114 ℃, and thereafter the crystallization solvent methanol is lost, crystal transformation occurs, and after the crystal transformation, the endothermic peak at 151 to 154.8 ℃ has a peak value at about 152.98 ℃.
In an infrared spectrogram of the cyflumetofen crystal form III, the absorption peaks are at the following wave numbers: (KBr pellet, cm)-1，±0.5)，3362.2，3093.7，3076.2，3022.5，2930.7，1679.6，1651.2，1604.9，1580.9，1509.1，1487.8，1453.7，1429.6，1412.6，1385.6，1339.3，1325.4，1302.8，1278.6，1263.6，1239.8，1202.4，1168.4，1157.4，1139.6，1077.9，1052.5，1005.6，983.8，944.1，932.6，921.9，894.4，846.9，817.2，797.8，758.3，729，717.5，702.5，683.3，646.6，625.8，602.6，587.3，563.4，546.8，512.5，467.8，435.3。
In a sixth aspect, the present invention provides a preparation method of cyflumetofen crystal form III as described in the fifth aspect, wherein the preparation method comprises: crystallizing a cyflumetofen solution to obtain a cyflumetofen crystal form III; the solvent of the cyflumetofen solution is methanol.
Preferably, the concentration of the cyflumetofen solution is 10-300 g/L, such as 15g/L, 20g/L, 25g/L, 30g/L, 35g/L, 40g/L, 45g/L, 50g/L, 60g/L, 70g/L, 80g/L, 90g/L, 100g/L, 110g/L, 130g/L, 150g/L, 170g/L, 190g/L, 200g/L, 210g/L, 230g/L, 250g/L, 270g/L or 290g/L, and specific points between the above points are limited in space and included in the range for brevity, which is not exhaustive list.
Preferably, the purity of the cyflumetofen in the cyflumetofen solution is more than or equal to 85%, such as 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% or 100%, and the like, and more preferably more than or equal to 90%.
Any known form of cyflumetofen can be used for cyflumetofen in the cyflumetofen solution. Amorphous cyflumetofen, mixtures of different crystalline forms or mixtures of amorphous and crystalline cyflumetofen are generally used.
Preferably, the crystallization temperature is 15-35 ℃, such as 16 ℃, 18 ℃, 20 ℃, 21 ℃, 23 ℃, 25 ℃, 27 ℃, 29 ℃, 30 ℃, 31 ℃, 33 ℃ or 34 ℃.
Preferably, the crystallization time is 0.1 to 7 days, such as 0.25 day, 0.5 day, 0.75 day, 1 day, 1.5 day, 2 days, 2.5 days, 3 days, 3.5 days, 4 days, 4.5 days, 5 days, 5.5 days, 6 days, or 6.5 days, etc.
Preferably, the crystallization may be carried out in any one of the following manners or a combination of at least two of the following manners, for example: (1) cooling the ciprofloxacin solution (the solvent is methanol) to room temperature and slowly volatilizing the solvent; (2) concentrating the cyflumetofen solution (methanol is used as a solvent) at room temperature; (3) the above measures are combined; further, it is preferable to carry out crystallization by slow evaporation at room temperature.
Preferably, the crystallization process further comprises the steps of solid-liquid separation, washing and drying, and the specific method of the steps is the same as that of the second aspect.
Preferably, the purity of the cyflumetofen crystal form III is more than or equal to 90 percent, such as 91 percent, 92 percent, 93 percent, 94 percent, 95 percent, 96 percent, 97 percent, 98 percent, 99 percent, 99.5 percent or 100 percent and the like.
In a seventh aspect, the invention provides a cyflumetofen crystal form IV, which has characteristic peaks at diffraction angles 2 θ of 6.7 ± 0.2 °, 7.1 ± 0.2 °, 8.3 ± 0.2 °, 11.3 ± 0.2 °, 11.8 ± 0.2 °, 16.5 ± 0.2 °, 18.6 ± 0.2 °, 19.3 ± 0.2 °, 20.2 ± 0.2 °, 20.8 ± 0.2 °, 21.4 ± 0.2 °, 28.3 ± 0.2 °, 28.6 ± 0.2 ° and 28.9 ± 0.2 ° in a powder X-ray diffraction pattern under Cu-Ka radiation.
Preferably, in the powder X-ray diffraction pattern of the cyflumetofen crystal form IV under Cu-Ka radiation, the diffraction angle 2 theta has the characteristic + -0.2 DEG, 7.1 + -0.2 DEG, 8.3 + -0.2 DEG, 9.7 + -0.2 DEG, 11.3 + -0.2 DEG, 11.8 + -0.2 DEG, 12.5 + -0.2 DEG, 14.1 + -0.2 DEG, 14.9 + -0.2 DEG, 15.2 + -0.2 DEG, 16.5 + -0.2 DEG, 17.1 + -0.2 DEG, 17.5 + -0.2 DEG, 18.0 + -0.2 DEG, 18.3 + -0.2 DEG, 18.6 + -0.2 DEG, 19.3 + -0.2 DEG, 19.8 + -0.2 DEG, 20.2 + -0.2 DEG, 21.4 + -0.2 DEG, 22.1 + -0.2 DEG, 22.6 + -0.2 DEG, 23.4 + -0.2 DEG, 23.7 + -0.2 + -0.24.9 + -0.25.2 DEG, 28 + -0.28 + -0.9 + -0 + -0.26 DEG, 2 + -0.9 + -0.2 DEG, 2 + -0.2 DEG, 2 + -0.2 DEG, 2 + -0.2 DEG, 2.2 DEG, 2 + -0.2 DEG, 2.2 + -0.2 DEG, 2 + -0.2 DEG, 2 + -0.2 DEG, 14 + -0.2 DEG, 2 DEG, 14 + -0.2 DEG, 2 + -0.2 DEG, 2 + -0.2 DEG, and 14 + -0.2 + -0.2.2 + -0.2 DEG, 14 + -0.2 + -0.2.2 + -0.2 DEG, 14 + -0.2 + -0.2.2 DEG, 14 + -0.2 DEG, 14 + -0.2 + -0.2.2 DEG, 14.2 + -0.2 + -0.2.2.2 + -0.2 + -.
Preferably, the differential scanning calorimetry curve of the cyhalodiamide crystal form IV has an endothermic peak at 148-154 ℃; the temperature rise rate in the differential scanning calorimetry curve test is 10 ℃/min.
In the infrared spectrogram of the cyflumetofen crystal form IV, the crystal form IV is as followsAbsorption peaks at wavenumbers: (KBr pellet, cm)-1，±0.5)，3362.2，3093.6，3076.2，3022.8，2930.4，1679.3，1650.9，1604.8，1581，1509.1，1488，1453.7，1429.6，1412.5，1385.8，1339.1，1326，1303.8，1278.8，1263.7，1240.4，1202.5，1167.8，1157.4，1140.2，1077.8，1052.5，1005.8，983.7，944.2，932.6，921.9，894.4，847，832.1，817.1，797.9，758.3，728.9，717.4，702.4，683.4，646.8，625.7，602.6，587.2，563.8，546.8，512.5，467.8，435.5，418.5。
In an eighth aspect, the present invention provides a preparation method of cyflumetofen crystal form IV as described in the seventh aspect, wherein the preparation method comprises: crystallizing a cyflumetofen solution to obtain a cyflumetofen crystal form IV; the solvent of the cyflumetofen solution is a mixed solvent of petroleum ether and ether solvents.
Preferably, the concentration of the cyflumetofen solution is 10-300 g/L, such as 15g/L, 20g/L, 25g/L, 30g/L, 35g/L, 40g/L, 45g/L, 50g/L, 60g/L, 70g/L, 80g/L, 90g/L, 100g/L, 110g/L, 130g/L, 150g/L, 170g/L, 190g/L, 200g/L, 210g/L, 230g/L, 250g/L, 270g/L or 290g/L, and specific values therebetween are limited in space and for the sake of brevity, and the specific values included in the range are not exhaustive.
Preferably, the purity of the cyflumetofen in the cyflumetofen solution is more than or equal to 85%, such as 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% or 100%, and the like, and more preferably more than or equal to 90%.
Any known form of cyflumetofen can be used for cyflumetofen in the cyflumetofen solution. Amorphous cyflumetofen, mixtures of different crystalline forms or mixtures of amorphous and crystalline cyflumetofen are generally used.
Preferably, the crystallization temperature is 15 to 40 ℃, for example, 16 ℃, 18 ℃, 20 ℃, 21 ℃, 23 ℃, 25 ℃, 27 ℃, 29 ℃, 30 ℃, 31 ℃, 33 ℃, 35 ℃, 37 ℃ or 39 ℃, and the specific values therebetween are not exhaustive for the sake of brevity and simplicity.
Preferably, the crystallization can be carried out in any one of the following ways or in a combination of at least two of the following ways, for example: (1) cooling the cyflumetofen solution to room temperature and slowly volatilizing the solvent; (2) concentrating the cyflumetofen solution at room temperature; (3) the above measures are combined; further preferably, the crystallization is carried out by concentration at room temperature.
Preferably, the crystallization process further comprises the steps of solid-liquid separation, washing and drying, and the specific method of the steps is the same as that of the second aspect.
Preferably, the volume ratio of the petroleum ether to the ether solvent is 1:2.3, 1:2.5, 1:2.8, 1:3, 1:3.2, 1:3.5, 1:3.8, 1:4, 1:4.2, 1:4.5, 1:4.8, 1:5, 1:5.2, 1:5.5, 1:5.7 or 1:5.9, etc.
Preferably, the ethereal solvent is selected from any one or a combination of at least two of tetrahydrofuran, diethyl ether, isopropyl ether or methyl tert-butyl ether, and further preferably tetrahydrofuran.
Preferably, the purity of the cyflumetofen crystal form IV is more than or equal to 90 percent, such as 91 percent, 92 percent, 93 percent, 94 percent, 95 percent, 96 percent, 97 percent, 98 percent, 99 percent, 99.5 percent or 100 percent and the like.
In a ninth aspect, the present invention provides a crystalline form I of cyhalodiamide as in the first aspect, a crystalline form II of cyhalodiamide as in the third aspect, a crystalline form III of cyhalodiamide as in the fifth aspect or a crystalline form IV of cyhalodiamide as in the seventh aspect for use in a pesticide.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides four new crystal forms of cyflumetofen, including a cyflumetofen crystal form I, a cyflumetofen crystal form II, a cyflumetofen crystal form III and a cyflumetofen crystal form IV, and a preparation method of the four crystal forms. The four crystal forms of the cyflumetofen have high purity, good stability and simple preparation method, and can be used as active ingredients of the cyflumetofen preparation, remarkably improve the thermal stability of the preparation and reduce the water precipitation rate of the cyflumetofen suspension preparation.
The four cyflumetofen crystal forms provided by the invention are used as the suspending agent preparation of active ingredients, the water-separating rate after the cyflumetofen is stored for 14 days at 54 ℃ is not higher than 12%, even is lower than 8%, the passing rate of a wet sieve test reaches 97.9-99.9%, and the stability of the cyflumetofen new crystal form preparation is obviously higher than that of an amorphous cyflumetofen preparation, so that the suspending agent preparation has a good application prospect.
Drawings
Figure 1 is an X-ray powder diffraction pattern of crystalline form I of cyflumetofen as provided in example 1;
FIG. 2 is a differential scanning calorimetry trace of the crystalline form I of cyflumetofen provided in example 1;
FIG. 3 is a single crystal diffractogram of crystalline form I of cyhalodiamide provided in example 1;
FIG. 4 is an infrared spectrum of crystalline form I of cyflumetofen provided in example 1;
figure 5 is an X-ray powder diffraction pattern of crystalline form II of cyflumetofen provided in example 4;
FIG. 6 is a differential scanning calorimetry trace of crystalline form II of cyflumetofen provided in example 4;
FIG. 7 is an infrared spectrum of crystalline form II of cyhalodiamide provided in example 4;
figure 8 is an X-ray powder diffraction pattern of crystalline form III of cyflumetofen provided in example 6;
FIG. 9 is a differential scanning calorimetry trace of form III of cyflumetofen provided in example 6;
figure 10 is a single crystal diffractogram of crystalline form III of cyflumetofen provided in example 6;
FIG. 11 is an infrared spectrum of crystalline form III of cyflumetofen provided in example 6;
figure 12 is an X-ray powder diffraction pattern of crystalline form IV of cyflumetofen provided in example 7;
FIG. 13 is a differential scanning calorimetry trace of form IV of cyflumetofen provided in example 7;
figure 14 is an infrared spectrum of crystalline form IV of cyflumetofen provided in example 7;
figure 15 is a graph of the stability test results for crystalline form I of cyflumetofen provided in example 1;
figure 16 is a graph of the stability test results for crystalline form II of cyflumetofen provided in example 4;
figure 17 is a stability test result chart of ciprofloxacin crystalline form III provided in example 6;
figure 18 is a graph of the stability test results for crystalline form IV of cyflumetofen provided in example 7.
Detailed Description
The technical solution of the present invention is further described below by way of specific embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitation of the present invention.
The test instrument and the detection method used by the invention are as follows:
(1) x-ray powder diffraction pattern: the Bruker X-ray powder diffractometer is a Cu target, the scanning speed is 0.02 DEG/s, and the angle range is 3-45 deg.
(2) Differential scanning calorimetry curve: differential scanning calorimeter Mettler-Toledo DSC3+, the test conditions were as follows: the crucible is an aluminum crucible with a small hole on the pot cover; the purge gas is nitrogen; the heating rate is 10 ℃/min, and the temperature testing range is 25-200 ℃.
(3) Infrared spectrum: bruker sensor 27 model infrared spectrometer; and (3) correcting the instrument: the wave number of the instrument is corrected by the infrared spectrum absorption peak of the polystyrene film (refer to appendix IV C of the 2010 version two parts of Chinese pharmacopoeia), and the test method is a KBr tabletting method.
(4) Single crystal diffraction experiments: the single crystal samples to be tested in the crystalline state were prepared to dimensions of 0.3mm × 0.3mm × 0.3mm and tested by a single crystal diffractometer of the Bruker D8 QUEST type under the following test conditions: the Mo-Ka ray is selected from the Mo-Ka ray,
Figure BDA0002788712190000111
the temperature was 296(2) K.
Example 1
The present example provides cyflumetofen crystal form I, which is prepared as follows: adding 3.0g of cyflumetofen into 25mL of ethanol, heating, refluxing and dissolving, slowly cooling to room temperature, and filtering to separate out a product; and drying the obtained product at 40 ℃ under reduced pressure overnight to obtain the cyhalothrin crystal form I.
The cyflumetofen crystal form I provided in the embodiment is tested, and the X-ray powder diffraction pattern is shown in fig. 1, so that the crystal form structure of the cyflumetofen crystal form I is confirmed; the differential scanning calorimetry graph is shown in FIG. 2, and it can be seen from FIG. 2 that the endothermic peak has an onset temperature of 150.34 deg.C, a peak temperature of 154.02 deg.C, and an end temperature of 157.05 deg.C; the single crystal diffraction pattern is shown in fig. 3, the crystal structure is a triclinic system, and the crystallographic data are in accordance with those in table 1; the infrared spectrum is shown in FIG. 4, and has absorption peaks at the following wave numbers: (KBr pellet,. + -. 0.5), 3362.2cm-1，3093.6cm-1，3076.1cm-1，3022.3cm-1，2930.6cm-1，1679.6cm-1，1651.4cm-1，1604.9cm-1，1581cm-1，1509.2cm-1，1488cm-1，1453.9cm-1，1429.6cm-1，1412.7cm-1，1385.7cm-1，1339.4cm-1，1325.6cm-1，1302.9cm-1，1278.7cm-1，1263.6cm-1，1240cm-1，1202.5cm-1，1168.4cm-1，1157.5cm-1，1139.6cm-1，1078cm-1，1052.5cm-1，1005.7cm-1，983.9cm-1，944.1cm-1，932.6cm-1，921.9cm-1，894.5cm-1，847cm-1，832cm-1，817.3cm-1，797.8cm-1，758.4cm-1，729.1cm-1，717.5cm-1，702.5cm-1，683.3cm-1，646.7cm-1，625.8cm-1，602.6cm-1，587.3cm-1，563.5cm-1，546.7cm-1，512.5cm-1，467.7cm-1，435.4cm-1，418.3cm-1。
Example 2
This example provides cyflumetofen form I prepared as follows: adding 3.0g of cyflumetofen into 20mL of tetrahydrofuran, heating, refluxing and dissolving, slowly cooling to room temperature, and filtering to separate out a product; and drying the obtained product at 40 ℃ under reduced pressure overnight to obtain the cyhalothrin crystal form I.
The product obtained in the example was tested by an X-ray powder diffractometer, and the crystal structure was confirmed to be ciprofloxacin crystal form I.
Example 3
The present example provides cyflumetofen crystal form I, which is prepared as follows: adding 3.0g of cyflumetofen into 50mL of mixed solvent of ethanol and n-heptane (the volume ratio of the ethanol to the n-heptane is 4:1), heating, refluxing, dissolving, slowly cooling to room temperature, and filtering to obtain a precipitated product; and drying the obtained product at 40 ℃ under reduced pressure overnight to obtain the cyhalothrin crystal form I.
The product obtained in the example was tested by an X-ray powder diffractometer, and the crystal structure was confirmed to be ciprofloxacin crystal form I.
Example 4
The embodiment provides a cyflumetofen crystal form II, which is prepared by the following steps: adding 500mg of cyflumetofen into 25mL of isopropyl acetate, dissolving at room temperature, filtering through a 0.22-micron organic filter membrane, and slowly volatilizing the filtrate at room temperature for one week to obtain crystals; and drying the obtained crystal overnight at 40 ℃ under reduced pressure to obtain the cyhalothrin crystal form II.
The cyflumetofen crystal form II provided in this example is tested, and the X-ray powder diffraction pattern thereof is shown in fig. 5, so that the crystal form structure thereof is confirmed to be cyflumetofen crystal form II; the differential scanning calorimetry graph is shown in FIG. 6, and it can be seen from FIG. 6 that the endothermic peak has an onset temperature of 149.72 deg.C, a peak temperature of 152.08 deg.C, and an end temperature of 154.44 deg.C; the infrared spectrum is shown in FIG. 7, and has absorption peaks at the following wave numbers: (KBr pellet,. + -. 0.5), 3361.7cm-1，3094.4cm-1，3013.8cm-1，2926cm-1，1736.4cm-1，1680.7cm-1，1652.1cm-1，1606.4cm-1，1581.6cm-1，1509.8cm-1，1489.2cm-1，1454.2cm-1，1429.2cm-1，1412.4cm-1，1384.9cm-1，1322.8cm-1，1304.7cm-1，1279.2cm-1，1238.5cm-1，1203.8cm-1，1169.7cm-1，1158.1cm-1，1121.5cm-1，1078.2cm-1，1050cm-1，1005.7cm-1，984.7cm-1，943.3cm-1，933.5cm-1，922cm-1，893.3cm-1，846.9cm-1，817.8cm-1，797.9cm-1，760.2cm-1，728.7cm-1，718.4cm-1，703cm-1，677.5cm-1，646.5cm-1，626.5cm-1，605.3cm-1，587cm-1，564.2cm-1，539.6cm-1，512.3cm-1，467.6cm-1，418.9cm-1，409.8cm-1。
Example 5
The embodiment provides a cyflumetofen crystal form II, which is prepared by the following steps: adding 1.0g of cyflumetofen into 25mL of ethyl acetate, dissolving at room temperature, filtering through a 0.22-micron organic filter membrane, evaporating the solvent from the filtrate through a rotary evaporator, and drying the obtained product at 40 ℃ under reduced pressure overnight to obtain the cyflumetofen crystal form II.
The product obtained in this example was tested by an X-ray powder diffractometer, and it was confirmed that its crystal structure was ciprofloxacin crystal form II.
Example 6
The embodiment provides a cyflumetofen crystal form III, which is prepared by the following steps: adding 400mg of cyflumetofen into 10mL of methanol, filtering the solution through a 0.22 mu m organic filter membrane after the solution is dissolved, and slowly volatilizing the filtrate at room temperature for 5 days to obtain long rod-shaped crystals; drying the long rod-shaped crystal at 40 ℃ under reduced pressure overnight to obtain the cyhalothrin crystal form III.
The cyflumetofen crystal form III provided in this example was tested, and the X-ray powder diffraction pattern obtained is shown in fig. 8, which confirms that the crystal structure is cyflumetofen crystal form III. As shown in FIG. 9, it can be seen from FIG. 9 that the cyflumetofen crystal form III contains cyflumetofenA crystallization solvent, which is a solvate, having 2 endothermic peaks, one endothermic peak having an onset temperature of 104.31 ℃, a melting peak temperature of 110.48 ℃, and an end temperature of 113.91 ℃; the methanol solvent is lost, crystal transformation occurs, the initial temperature after crystal transformation is 151.08 ℃, the melting peak temperature is 152.98 ℃, and the termination temperature is 154.75 ℃. The single crystal diffraction pattern is shown in fig. 10, the crystal structure is monoclinic, and the crystallographic data are as shown in table 2. The infrared spectrum is shown in FIG. 11, and has absorption peaks at the following wavenumbers: (KBr pellet,. + -. 0.5), 3362.2cm-1，3093.7cm-1，3076.2cm-1，3022.5cm-1，2930.7cm-1，1679.6cm-1，1651.2cm-1，1604.9cm-1，1580.9cm-1，1509.1cm-1，1487.8cm-1，1453.7cm-1，1429.6cm-1，1412.6cm-1，1385.6cm-1，1339.3cm-1，1325.4cm-1，1302.8cm-1，1278.6cm-1，1263.6cm-1，1239.8cm-1，1202.4cm-1，1168.4cm-1，1157.4cm-1，1139.6cm-1，1077.9cm-1，1052.5cm-1，1005.6cm-1，983.8cm-1，944.1cm-1，932.6cm-1，921.9cm-1，894.4cm-1，846.9cm-1，817.2cm-1，797.8cm-1，758.3cm-1，729cm-1，717.5cm-1，702.5cm-1，683.3cm-1，646.6cm-1，625.8cm-1，602.6cm-1，587.3cm-1，563.4cm-1，546.8cm-1，512.5cm-1，467.8cm-1，435.3cm-1。
Example 7
This example provides cyflumetofen form IV prepared as follows: adding 40mg of cyflumetofen into 2mL of mixed solvent of tetrahydrofuran and petroleum ether (the volume ratio of the tetrahydrofuran to the petroleum ether is 4:1), filtering by using a 0.22 mu m organic filter membrane after dissolving, and slowly volatilizing the filtrate at room temperature for 4 days to obtain a solid product; drying the solid product at 40 ℃ under reduced pressure overnight to obtain the cyhalothrin crystal form IV.
The crystal form IV of cyflumetofen provided in this example was tested, and the obtained X-ray powder diffractogram is shown in fig. 12, confirming that the crystal form structure is cyflumetofen crystal form IV; FIG. 13 shows a differential scanning calorimetry chart, in which FIG. 13 shows that the endothermic peak start temperature is 148.71 ℃, the peak temperature is 151.27 ℃ and the termination temperature is 153.85 ℃; the infrared spectrum is shown in FIG. 14, and has absorption peaks at the following wave numbers: (KBr pellet,. + -. 0.5), 3362.2cm-1，3093.6cm-1，3076.2cm-1，3022.8cm-1，2930.4cm-1，1679.3cm-1，1650.9cm-1，1604.8cm-1，1581cm-1，1509.1cm-1，1488cm-1，1453.7cm-1，1429.6cm-1，1412.5cm-1，1385.8cm-1，1339.1cm-1，1326cm-1，1303.8cm-1，1278.8cm-1，1263.7cm-1，1240.4cm-1，1202.5cm-1，1167.8cm-1，1157.4cm-1，1140.2cm-1，1077.8cm-1，1052.5cm-1，1005.8cm-1，983.7cm-1，944.2cm-1，932.6cm-1，921.9cm-1，894.4cm-1，847cm-1，832.1cm-1，817.1cm-1，797.9cm-1，758.3cm-1，728.9cm-1，717.4cm-1，702.4cm-1，683.4cm-1，646.8cm-1，625.7cm-1，602.6cm-1，587.2cm-1，563.8cm-1，546.8cm-1，512.5cm-1，467.8cm-1，435.5cm-1，418.5cm-1。
Test example 1
The test example is a stability test experiment of four cyflumetofen crystal forms, and the specific method is as follows:
placing the crystal form I of the cyflumetofen provided in the example 1, the crystal form II of the cyflumetofen provided in the example 4, the crystal form III of the cyflumetofen provided in the example 6 and the crystal form IV of the cyflumetofen provided in the example 7 in a stability test box for one month under the conditions that the temperature is 40 ℃ and the humidity is 75%, and then performing powder diffraction test to compare X-ray powder diffraction patterns before and after the stability test to obtain respective stability results.
The stability test result graph of the cyhalodiamide crystal form I is shown in figure 15, the stability test result graph of the cyhalodiamide crystal form II is shown in figure 16, the stability test result graph of the cyhalodiamide crystal form III is shown in figure 17, and the stability test result graph of the cyhalodiamide crystal form IV is shown in figure 18; the diffraction peak information of FIGS. 15 to 18 are summarized in Table 3.
TABLE 3
Figure BDA0002788712190000141
Figure BDA0002788712190000151
Application example 1
The cyflumetofen preparation comprises the following components in a formula shown in a table 4:
TABLE 4
Figure BDA0002788712190000152
The preparation method comprises the following steps: firstly, putting the crystal form I of the active ingredient ciprofloxacin into a crusher to be crushed for 1min to below 60 meshes for later use; the materials are respectively put into a 200mL sanding barrel, the addition amount of zirconium beads is 2 times of the raw material amount, the rotational speed of the sanding machine is 2100rpm, and the particle size is detected after 60min, 120min, 180min and 240min, so that the suspending agent preparation A is obtained.
Application example 2
The cyflumetofen preparation comprises the following components in a formula shown in a table 5:
TABLE 5
Figure BDA0002788712190000153
Figure BDA0002788712190000161
The preparation method comprises the following steps: firstly, putting the crystal form II of the active ingredient ciprofloxacin into a crusher to be crushed for 1min to below 60 meshes for later use; the materials are respectively put into a 200mL sanding barrel, the addition amount of zirconium beads is 2 times of the raw material amount, the rotational speed of the sanding machine is 2100rpm/min, the materials are respectively grinded for 60min, 120min, 180min and 240min, and then the particle size is detected, so that the suspending agent preparation B is obtained.
Application example 3
The cyflumetofen preparation comprises the following components in a table 6:
TABLE 6
Figure BDA0002788712190000162
The preparation method comprises the following steps: firstly, putting the crystal form III of the active ingredient ciprofloxacin into a crusher to be crushed for 1min until the particle size is below 60 meshes for later use; the materials are respectively put into a 200mL sanding barrel, the addition amount of zirconium beads is 2 times of the raw material amount, the rotational speed of the sanding machine is 2100rpm/min, the materials are respectively grinded for 60min, 120min, 180min and 240min, and then the particle size is detected, so that the suspending agent preparation C is obtained.
Application example 4
A cyflumetofen formulation has the components shown in Table 7:
TABLE 7
Figure BDA0002788712190000171
The preparation method comprises the following steps: firstly, putting the crystal form IV of the active ingredient of the cyflumetofen into a crusher to be crushed for 1min to below 60 meshes for later use; and (3) respectively putting the materials formed by the formula into 200mL sanding barrels, wherein the addition amount of zirconium beads is 2 times of the amount of the raw materials, the rotation speed of the sanding machine is 2100rpm/min, and the particle size is detected after respectively grinding for 60min, 120min, 180min and 240min to obtain a suspending agent preparation D.
Comparative example 1
The cyflumetofen preparation is only different from application example 1 in that the active ingredient cyflumetofen crystal form I is replaced by the same amount of amorphous cyflumetofen, and the specific formula composition and the preparation process are as follows:
TABLE 8
Figure BDA0002788712190000172
The preparation method comprises the following steps: firstly, putting the active ingredient amorphous cyflumetofen into a crusher to be crushed for 1min to below 60 meshes for later use; the materials are respectively put into a 200mL sanding barrel, the addition amount of zirconium beads is 2 times of the raw material amount, the rotational speed of the sanding machine is 2100rpm/min, the materials are respectively grinded for 60min, 120min, 180min and 240min, and then the particle size is detected, so that the suspending agent preparation E is obtained.
Water separation and wet sieve pass test
The cyclopropanimidan formulations provided in application examples 1 to 4 and comparative example 1 were stored at 54 ℃ for a while, and then the water evolution was observed and the water evolution rate (water evolution rate: water evolution amount/sample amount × 100%) was calculated, and the passing rate was obtained by a 75 μm wet sieve to evaluate the quality thereof. The specific wet sieve passing rate test method comprises the following steps: respectively placing the samples in a beaker for wetting and diluting, pouring the samples into a wetted test sieve, and directly washing the samples by using mild tap water; drying, weighing and screening the residues, and calculating the wet screening test passing rate; the test results are shown in table 9.
TABLE 9
Figure BDA0002788712190000181
Figure BDA0002788712190000191
According to the data in table 9, compared with the preparation using amorphous cyflumetofen as an active ingredient in comparative example 1, the four novel cyflumetofen crystal forms provided by the invention have more excellent stability, the water precipitation rate of the cyflumetofen suspension preparation containing the same after being stored for 14 days is less than or equal to 12%, the wet sieve test passing rate reaches 97.9-99.9%, and the stability requirement of the preparation can be more fully met.
The applicant states that the invention is illustrated by the above examples to the crystalline form of cyflumetofen of the invention and the preparation method and application thereof, but the invention is not limited to the above process steps, i.e. it does not mean that the invention must rely on the above process steps to be carried out. It will be apparent to those skilled in the art that any modification of the present invention, equivalent substitutions of selected materials and additions of auxiliary components, selection of specific modes and the like, which are within the scope and disclosure of the present invention, are contemplated by the present invention.

Claims (10)

1. The cyflumetofen crystal form I is characterized by having characteristic peaks at diffraction angles 2 theta of 6.7 +/-0.2 degrees, 8.3 +/-0.2 degrees, 9.8 +/-0.2 degrees, 11.3 +/-0.2 degrees, 11.9 +/-0.2 degrees, 14.1 +/-0.2 degrees, 15.2 +/-0.2 degrees, 18.7 +/-0.2 degrees, 19.3 +/-0.2 degrees and 20.2 +/-0.2 degrees in a powder X-ray diffraction pattern under Cu-Ka radiation.
2. The crystalline form I of cyhalodiamide according to claim 1, characterized in that in the powder X-ray diffraction pattern of the crystalline form I of cyhalodiamide under Cu-Ka radiation, at diffraction angles 2 θ of 6.7 ± 0.2 °, 8.3 ± 0.2 °, 9.8 ± 0.2 °, 11.3 ± 0.2 °, 11.9 ± 0.2 °, 12.6 ± 0.2 °, 13.7 ± 0.2 °, 14.1 ± 0.2 °, 14.9 ± 0.2 °, 15.2 ± 0.2 °, 16,6 ± 0.2 °, 17.1 ± 0.2 °, 17.5 ± 0.2 °, 18.0 ± 0.2 °, 18.4 ± 0.2 °, 18.7 ± 0.2 °, 19.3 ± 0.2 °, 19.8 ± 0.2 °, 20.2 ± 0.2 °, 20.8 ± 0.2 °, 22.3 ± 0.2 °, 22.2 ± 0.2 °, 22 ± 0.2 °,2 ± 0.7 ± 0.2 °,2 ± 0.2 °,2 ± 0.23.3 ± 0.2 °,2 ± 0.2 °,2 ± 0.2 °,2 ± 0.2 °,2 ± 0.2 °,2 °, 2.2 ± 0.2 °,2 ± 0.2 °, 2.2 °,2 °, 2.2 ± 0.2 °,2 ± 0.2 °,2 °, 2.2 °,2 ± 0.2 °,2 °, 2.2.2 °,2 °, 2.2 °,2 ± 0.2 °,2 ± 0.2 °,2 ± 0.2.2 ± 0.2 °,2 ± 0.2 °,2 ± 0.2 °, 2.2.2 ± 0.2 °,2 ± 0.2.2.2.2 ± 0.2 ± 0.2.2 °,2 °, 2.2.2 ± 0.2 °,2 ± 0.2.2 °, 2.2.2 °, 2.3 ± 0.2.2.2 °,2 °, 2.2.2.2.2 °,2 °, 2.2 °,2 ± 0.2 °, 2.2.2 °,2 ° 0.2 °,2 °, 2.2 ± 0.2 °,2 °, 2.2 °,2 °, 2.2 °,2 ± 0.2.2.2 °,2 ± 0, Characteristic peaks are at 32.4 +/-0.2 degrees, 32.8 +/-0.2 degrees, 33.5 +/-0.2 degrees, 34.1 +/-0.2 degrees, 36.0 +/-0.2 degrees and 39.3 +/-0.2 degrees;
preferably, the differential scanning calorimetry curve of the cyhalodiamide crystal form I has an endothermic peak at 150-157 ℃.
3. A process for the preparation of crystalline form I of cyflumetofen according to claim 1 or 2, wherein the process comprises: crystallizing a cyflumetofen solution to obtain a cyflumetofen crystal form I; the solvent of the cyflumetofen solution is selected from any one or the combination of at least two of ethanol, n-propanol, isopropanol, n-hexane, n-heptane, aromatic hydrocarbon solvents, halogenated hydrocarbon solvents or ether solvents;
preferably, the concentration of the cyflumetofen solution is 10-300 g/L;
preferably, the purity of the cyflumetofen in the cyflumetofen solution is more than or equal to 85 percent, and more preferably more than or equal to 90 percent;
preferably, the temperature of the crystallization is 10-35 ℃;
preferably, the aromatic hydrocarbon solvent is selected from any one of benzene, toluene or xylene or a combination of at least two of the same;
preferably, the halogenated hydrocarbon solvent is selected from any one or a combination of at least two of dichloromethane, trichloromethane, bromoethane or 1, 2-dichloroethane;
preferably, the ether solvent is selected from any one of tetrahydrofuran, diethyl ether, isopropyl ether or methyl tert-butyl ether or a combination of at least two of the tetrahydrofuran, the diethyl ether, the isopropyl ether and the methyl tert-butyl ether;
preferably, the purity of the cyflumetofen crystal form I is more than or equal to 90%.
4. The cyflumetofen crystal form II is characterized in that characteristic peaks exist at diffraction angles 2 theta of 7.8 +/-0.2 degrees, 10.1 +/-0.2 degrees, 11.2 +/-0.2 degrees, 13.4 +/-0.2 degrees, 15.6 +/-0.2 degrees, 19.4 +/-0.2 degrees, 20.0 +/-0.2 degrees and 20.6 +/-0.2 degrees in a powder X-ray diffraction pattern of the cyflumetofen crystal form II under Cu-Ka radiation;
preferably, in a powder X-ray diffraction pattern of the cyflumetofen crystal form II under Cu-Ka radiation, the diffraction angle 2 theta has the characteristic peaks of +/-0.2 degrees, 10.1 +/-0.2 degrees, 11.2 +/-0.2 degrees, 12.0 +/-0.2 degrees, 12.4 +/-0.2 degrees, 13.4 +/-0.2 degrees, 13.9 +/-0.2 degrees, 14.5 +/-0.2 degrees, 15.6 +/-0.2 degrees, 16.2 +/-0.2 degrees, 17.0 +/-0.2 degrees, 17.7 +/-0.2 degrees, 18.1 +/-0.2 degrees, 18.5 +/-0.2 degrees, 19.4 +/-0.2 degrees, 20.0 +/-0.2 degrees, 20.6 +/-0.2 degrees, 21.3 +/-0.2 degrees, 22.2 +/-0.2 degrees, 23.1 +/-0.2 degrees, 24.2 degrees, 24.8 +/-0.2 degrees, 25.1 +/-0.2 degrees, 21.3 +/-0.2 degrees, 22.2 +/-0.2 degrees, 2 degrees, 29.0.2 degrees, 2 +/-0.2 degrees, 2.2 degrees, 29.2 degrees, 2 degrees, 28.2 degrees, 2 degrees, 29.2 degrees, 2 degrees, 29 +/-0.2 degrees, 2 degrees, 28 degrees, 2 degrees, 28 degrees, 29.2 degrees, 2 degrees, 0 degrees, 2 degrees, 0 degrees, 2 degrees, 0 degrees, 2 degrees, 0 degrees, are included in diffraction angles, 0 degrees, 2 degrees, are included in diffraction angle 2 degrees, 7 theta;
preferably, the differential scanning calorimetry curve of the cyhalodiamide crystal form II has an endothermic peak at 149.7-154.5 ℃.
5. A method for preparing crystalline form II of cyhalodiamide, according to claim 4, comprising: crystallizing a cyflumetofen solution to obtain a cyflumetofen crystal form II; the solvent of the cyflumetofen solution contains an ester solvent;
preferably, the concentration of the cyflumetofen solution is 10-300 g/L;
preferably, the purity of the cyflumetofen in the cyflumetofen solution is more than or equal to 85 percent, and more preferably more than or equal to 90 percent;
preferably, the temperature of the crystallization is 20-40 ℃;
preferably, the method of crystallization comprises natural evaporation and/or concentration;
preferably, the solvent is an ester solvent;
preferably, the ester solvent is selected from any one or a combination of at least two of ethyl formate, ethyl acetate or isopropyl acetate;
preferably, the purity of the cyflumetofen crystal form II is more than or equal to 90 percent.
6. The cyhalodiamide crystal form III is characterized by comprising a crystallization solvent, and in a powder X-ray diffraction pattern under Cu-Ka radiation, characteristic peaks are formed at diffraction angles 2 theta of 5.5 +/-0.2 degrees, 8.3 +/-0.2 degrees, 9.4 +/-0.2 degrees, 11.5 +/-0.2 degrees, 12.6 +/-0.2 degrees, 13.9 +/-0.9 degrees, 15.4 +/-0.2 degrees, 16.1 +/-0.2 degrees, 20.5 +/-0.2 degrees and 27.0 +/-0.2 degrees; the crystallization solvent is methanol;
preferably, in the powder X-ray diffraction pattern of the cyflumetofen crystal form III under Cu-Ka radiation, the diffraction angle 2 theta has the characteristic +/-0.3 +/-0.2 DEG, 8.3 +/-0.2 DEG, 9.4 +/-0.2 DEG, 11.5 +/-0.2 DEG, 12.6 +/-0.2 DEG, 13.9 +/-0.9 DEG, 15.4 +/-0.2 DEG, 16.1 +/-0.2 DEG, 17.2 +/-0.2 DEG, 17.4 +/-0.2 DEG, 18.8 +/-0.2 DEG, 19.7 +/-0.2 DEG, 20.20 +/-0.2 DEG, 20.5 +/-0.2 DEG, 21.5 +/-0.2 DEG, 21.8 +/-0.2 DEG, 22.3 +/-0.2 DEG, 22.6 +/-0.2 DEG, 23.5 +/-0.2 DEG, 24.1 +/-0.2 DEG, 24.6 +/-0.2 DEG, 24.7 +/-0.2 DEG, 25.3 +/-0.2 DEG, 27.0 +/-0.2 DEG, 27.2 DEG, 27.5 +/-0.2.2.28.0 +/-0.28.28 DEG, 34 +/-0.34 DEG, 2.34 +/-0.30.30.2 DEG, 2 DEG, 2.34 +/-0.34 +/-0.2.2.2 DEG, 2.2 DEG, 2 DEG, 2.2.2 DEG, 2.2.2.2 + -0 +/-0.2 DEG, 2 DEG, 2.2 DEG, 2 DEG, 2.2.2.2 DEG, 2 + -0.2 + -0 +/-0.2.2.2 DEG, 2 + -0 +/-0.2 DEG, 2 DEG, 2.2.2.2 + -0.2 DEG, 2.2 + -0.2 + -0 +/-0.2 DEG, 2.2 DEG, 2 + -0.2 DEG, 2 DEG, 2.2.2 DEG, 2 DEG, 2.2.2.2.2 DEG, 2 + -0.2 + -0 +/-0.2 DEG, 2.2.2 + -0.2.2.2 + -0 +/-0.2 DEG, 2 DEG, 2.2 + -0 +/-0.2.2 DEG, 2 + -0.2 DEG, 2 + -0 + -0.2.2.2 + -0.2 DEG, 2.2 DEG, 2 DEG, 34 + -0 + -0.2 DEG, 2 DEG, 2.2 DEG, 2 DEG, 2.2.2.2 + -0.2 DEG, 34 + -0.2 + -0.2.2.2.2 + -0.2 + -0.2.2 + -0 + -0.2 DEG, 2 + -0.2 DEG, 34 + -0.2 + -0 + -0.2.2.2.2 + -0 + -0.2 + -0 + -0.2.2 + -0 + -0.2 + -0.2.2 + -0 + -0.2.2.2.2.2.2 DEG, and 32 + -0.2 + -0 + -0.2.2.2.2.2 + -0.2 DEG, 34 + -0.2.2.2 + -0.2.2.2.2.2.2 + -0.2.2.2.2 DEG, 34 + -0 + -0.2;
preferably, the differential scanning calorimetry curve of the crystalline form III of the cyflumetofen has endothermic peaks at 104-114 ℃ and 151-154.8 ℃.
7. A process for preparing crystalline form III of cyflumetofen according to claim 6, wherein the process comprises: crystallizing a cyflumetofen solution to obtain a cyflumetofen crystal form III; the solvent of the cyflumetofen solution is methanol;
preferably, the concentration of the cyflumetofen solution is 10-300 g/L;
preferably, the purity of the cyflumetofen in the cyflumetofen solution is more than or equal to 85 percent, and more preferably more than or equal to 90 percent;
preferably, the temperature of the crystallization is 15-35 ℃;
preferably, the crystallization time is 0.1-7 days;
preferably, the purity of the cyflumetofen crystal form III is more than or equal to 90%.
8. A cyflumetofen crystal form IV is characterized in that the cyflumetofen crystal form IV has characteristic peaks at diffraction angles 2 theta of 6.7 +/-0.2 degrees, 7.1 +/-0.2 degrees, 8.3 +/-0.2 degrees, 11.3 +/-0.2 degrees, 11.8 +/-0.2 degrees, 16.5 +/-0.2 degrees, 18.6 +/-0.2 degrees, 19.3 +/-0.2 degrees, 20.2 +/-0.2 degrees, 20.8 +/-0.2 degrees, 21.4 +/-0.2 degrees, 28.3 +/-0.2 degrees, 28.6 +/-0.2 degrees and 28.9 +/-0.2 degrees in a powder X-ray diffraction pattern under Cu-Ka radiation;
preferably, in the powder X-ray diffraction pattern of the cyflumetofen crystal form IV under Cu-Ka radiation, the diffraction angle 2 theta has the characteristic + -0.2 DEG, 7.1 + -0.2 DEG, 8.3 + -0.2 DEG, 9.7 + -0.2 DEG, 11.3 + -0.2 DEG, 11.8 + -0.2 DEG, 12.5 + -0.2 DEG, 14.1 + -0.2 DEG, 14.9 + -0.2 DEG, 15.2 + -0.2 DEG, 16.5 + -0.2 DEG, 17.1 + -0.2 DEG, 17.5 + -0.2 DEG, 18.0 + -0.2 DEG, 18.3 + -0.2 DEG, 18.6 + -0.2 DEG, 19.3 + -0.2 DEG, 19.8 + -0.2 DEG, 20.2 + -0.2 DEG, 21.4 + -0.2 DEG, 22.1 + -0.2 DEG, 22.6 + -0.2 DEG, 23.4 + -0.2 DEG, 23.7 + -0.2 + -0.24.9 + -0.25.2 DEG, 28 + -0.28 + -0.9 + -0.28 + -0.2 DEG, 28 + -0.9 + -0.2 DEG, 2 + -0.9 + -0.2 DEG, 2 + -0.2 DEG, 2 + -0.2 DEG, 14 + -0.2 DEG, 2 DEG, 14 + -0.2 DEG, 2 + -0.2 DEG, 2 + -0.2 DEG, 2.2 DEG, 2 + -0.2 DEG, 2 + -0.2 DEG, 2 + -0.2 DEG, 2 + -0.2 DEG, 14 + -0.2 DEG, and 14 + -0.2 DEG, 14 + -0.2 DEG, 14 + -0.2 DEG, 14 + -0.2 + -0.2.2 + -0.2 DEG, 14 + -0.2 + -0.2.2 DEG, 14 + -0.2 DEG, 14 + -0.2 + -0.2.2 + -0.2 DEG, 14.2 + -0.2;
preferably, the differential scanning calorimetry curve of the crystalline form IV of the cyflumetofen has an endothermic peak at 148-154 ℃.
9. A process for preparing form IV of cyflumetofen according to claim 8, wherein the process comprises: crystallizing a cyflumetofen solution to obtain a cyflumetofen crystal form IV; the solvent of the cyflumetofen solution is a mixed solvent of petroleum ether and an ether solvent;
preferably, the concentration of the cyflumetofen solution is 10-300 g/L;
preferably, the purity of the cyflumetofen in the cyflumetofen solution is more than or equal to 85 percent, and more preferably more than or equal to 90 percent;
preferably, the temperature of the crystallization is 15-40 ℃;
preferably, the volume ratio of the petroleum ether to the ether solvent is 1 (2-6);
preferably, the ether solvent is selected from any one or a combination of at least two of tetrahydrofuran, diethyl ether, isopropyl ether or methyl tert-butyl ether, and further preferably tetrahydrofuran;
preferably, the purity of the cyflumetofen crystal form IV is more than or equal to 90%.
10. Use of the crystalline form I of cyhalodiamide of claim 1, the crystalline form II of cyhalodiamide of claim 4, the crystalline form III of cyhalodiamide of claim 6, or the crystalline form IV of cyhalodiamide of claim 8 in an insecticide.
CN202011307401.3A 2020-11-19 2020-11-19 Cyclopropylflufenoxam crystal form and preparation method and application thereof Pending CN114516818A (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110810413A (en) * 2018-08-10 2020-02-21 上海泰禾国际贸易有限公司 Pharmaceutical composition containing m-diamide compound and application thereof
CN112707836A (en) * 2019-10-25 2021-04-27 南通泰禾化工股份有限公司 Preparation method of m-diamide compound

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110810413A (en) * 2018-08-10 2020-02-21 上海泰禾国际贸易有限公司 Pharmaceutical composition containing m-diamide compound and application thereof
CN112707836A (en) * 2019-10-25 2021-04-27 南通泰禾化工股份有限公司 Preparation method of m-diamide compound

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