CN110272393B - Prothioconazole solvate and preparation method and application thereof - Google Patents

Prothioconazole solvate and preparation method and application thereof Download PDF

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CN110272393B
CN110272393B CN201810206267.4A CN201810206267A CN110272393B CN 110272393 B CN110272393 B CN 110272393B CN 201810206267 A CN201810206267 A CN 201810206267A CN 110272393 B CN110272393 B CN 110272393B
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solvate
diethylamine
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prothioconazole
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李忠
任国宾
徐晓勇
洪鸣凰
龚成予
胡健
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East China University of Science and Technology
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    • 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
    • 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
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
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Abstract

The invention provides a prothioconazole solvate, application and a preparation method thereof, and particularly relates to a diethylamine solvate of 2- [ (2RS) -2- (1-chlorocyclopropyl) -3- (2-chlorphenyl) -2-hydroxypropyl ] -2H-1,2, 4-triazole-3 (4H) -thione, a preparation method and application. The prothioconazole diethylamine solvate has high purity and excellent crystallization performance, is stable under the conditions of high humidity and illumination, and has excellent solubility. The preparation method is simple, stable in process and capable of realizing large-scale production. The solvate can greatly improve the quality control and industrial application of the prothioconazole-containing pesticide.

Description

Prothioconazole solvate and preparation method and application thereof
Technical Field
The invention belongs to the field of pesticide chemistry, and particularly relates to a prothioconazole solvate and a preparation method and application thereof.
Background
Prothioconazole (compound of formula I),
Figure BDA0001595978960000011
chemical name 2- [ (2RS) -2- (1-chlorocyclopropyl) -3- (2-chlorophenyl) -2-hydroxypropyl]-2H-1,2, 4-triazole-3 (4H) -thione. Prothioconazole was originally published by patent WO 9616048 and its preparation is given. The structure of prothioconazole is described in M.Jautelat et al, Pfalanzenschultz-Nacbrichten Bayer, 57/2004,2, 145-162. Among the crystalline forms of prothioconazole, form I crystals are disclosed in US 5,789,430 and form II crystals are disclosed in US 2006/0106080 a1, form I crystals being metastable at room temperature and form II being thermodynamically stable at room temperature. CN 102083802 discloses a solvate with dimethyl sulfoxide (DMSO) and amorphous prothioconazole.
Prothioconazole is a low-toxicity, highly effective, broad-spectrum fungicide of the triazolothioketone type, used as a fungicide to treat infected crops. The mechanism of action is to inhibit the demethylation at position 14 of lanosterol or 2, 4-methylenedihydrolanostane, precursors of sterols in fungi. The bactericidal composition is mainly used for preventing and treating a plurality of diseases of cereals, wheat and bean crops and the like, such as powdery mildew, banded sclerotial blight, fusarium wilt, leaf spot, rust disease, sclerotinia rot, net blotch, leaf blotch, gray mold, black shank and the like. The crystal forms are different, and the physicochemical properties of the crystal forms are different except appearance and hardness. Stability, solubility, hygroscopicity, melting point, particle density and flowability have a great influence on the drug effect. The new solvate forms of prothioconazole are likely to provide opportunities for improving the performance of the prothioconazole product.
Therefore, the development of new solvates of prothioconazole, which have the requirements of good stability, high solubility, simple preparation method and large-scale production, is urgently needed in the field.
Disclosure of Invention
The invention aims to provide a novel solvate of prothioconazole, which has good stability, high solubility and simple preparation method.
Another object of the present invention is to provide a novel solvate of prothioconazole, its use and a process for its preparation.
In a first aspect of the invention, there is provided a solvate of a compound of formula I, which solvate is a solvate of diethylamine of a compound of formula I, which solvate is a solid,
Figure BDA0001595978960000021
in another preferred embodiment, the molar ratio of the compound of formula I to diethylamine is from 1:0.8 to 1: 1.2.
In another preferred embodiment, the molar ratio of the compound of formula I to diethylamine is 1:1.
In another preferred embodiment, the solvate is crystalline or amorphous.
In another preferred embodiment, the solvate has an X-ray powder diffraction pattern comprising 3 or more 2 Θ values selected from the group consisting of: 5.7 degrees +/-0.2 degrees, 11.4 degrees +/-0.2 degrees, 16.4 degrees +/-0.2 degrees, 17.0 degrees +/-0.2 degrees, 19.9 degrees +/-0.2 degrees, 22.8 degrees +/-0.2 degrees, 26.6 degrees +/-0.2 degrees, 27.0 degrees +/-0.2 degrees, 27.9 degrees +/-0.2 degrees, 31.7 degrees +/-0.2 degrees, 32.9 degrees +/-0.2 degrees, 36.0 degrees +/-0.2 degrees and 38.4 degrees +/-0.2 degrees.
In another preferred embodiment, the solvate has an X-ray powder diffraction pattern comprising 3 or more 2 Θ values selected from the group consisting of: 11.4 degrees +/-0.2 degrees, 16.4 degrees +/-0.2 degrees, 17.0 degrees +/-0.2 degrees and 22.8 degrees +/-0.2 degrees.
In another preferred embodiment, the solvate has an X-ray powder diffraction pattern substantially as characterized in figure 1 (c).
In another preferred embodiment, the solvate has single crystal diffraction analysis data as shown in any one or more of table 2.
TABLE 2 Single Crystal diffraction analysis data for prothioconazole diethylamine solvate
Figure BDA0001595978960000022
In another preferred embodiment, the X-ray powder diffraction pattern is a pattern obtained by CuK α rays.
In another preferred embodiment, the TGA profile of the solvate is substantially as characterized in figure 3.
In another preferred embodiment, the DSC image of the solvate has desolvation peak within the range of 110-121 ℃.
In another preferred embodiment, the solvate has an enthalpy of desolvation of 70 +/-5J/g.
In another preferred embodiment, the solvate lacks a melting peak between 137 ℃ and 145 ℃, i.e. the solvate lacks the melting characteristics of form I and form II of the compound of formula I.
In another preferred embodiment, the DSC diagram of said solvate is substantially as characterized in figure 2 (c).
In another preferred embodiment, the solvate has a bond length and bond angle substantially as shown in table 3.
In a second aspect of the invention, there is provided a process for the preparation of a solvate according to the first aspect of the invention, the process comprising the steps of:
(a) providing a solution of a compound of formula I in diethylamine;
(b) subjecting said solution to a precipitation treatment, thereby precipitating a solvate solution of diethylamine of the compound of formula I; and
(c) separating the precipitated solvate to obtain the solvate according to the first aspect of the present invention.
In another preferred example, the step (a) is performed at normal temperature.
In another preferred embodiment, in step (a), said compound of formula I is selected from the group consisting of: an amorphous compound, form I, form II, or a combination thereof.
In another preferred embodiment, in the step (b), the precipitation treatment is a crystallization treatment.
In another preferred example, in the step (b), the precipitation treatment (e.g., crystallization treatment) is performed under conditions of adding an antisolvent or volatilizing a coating film.
In another preferred embodiment, the precipitation treatment (e.g., crystallization treatment) is carried out with the addition of an anti-solvent selected from the group consisting of: n-hexane, cyclohexane, n-heptane, or combinations thereof.
In another preferred embodiment, in step (b), the anti-solvent is used in an amount added until a solid precipitates.
In another preferred embodiment, in the step (b), the volume ratio of the antisolvent to the diethylamine is 3 to 8: 1.
in another preferred embodiment, in step (c), the separation is filtration to obtain the solvate.
In another preferred example, after step (b) and before step (c), the method further comprises: (d) and (5) standing.
In another preferred example, after step (c), the method further comprises: (e) drying the isolated solvate.
In a third aspect of the invention, there is provided a process for the preparation of a solvate according to the first aspect of the invention, the process comprising the steps of:
(i) providing a solution of a compound of formula I in diethylamine;
(ii) subjecting the solution to standing crystallization under crystallization conditions to obtain the solvate according to the first aspect of the present invention.
In another preferred example, the step (i) is performed at normal temperature.
In another preferred embodiment, in the step (ii), the crystallization is performed under the condition of adding an anti-solvent.
In another preferred embodiment, in step (ii), the antisolvent is selected from the group consisting of: n-hexane, cyclohexane, n-heptane, or combinations thereof.
In another preferred example, in step (ii), the volume ratio of the antisolvent to the diethylamine is 3 to 8: 1.
in another preferred embodiment, in the step (ii), the standing time is 0.5 to 48 hours.
In another preferred example, after step (ii), the method further comprises: (iii) isolating the solvate.
In another preferred embodiment, in step (iii), the separation is filtration to obtain the solvate.
In another preferred example, after step (iii), the method further comprises: (iv) drying the isolated solvate.
In a fourth aspect of the present invention, there is provided a pesticidal composition comprising:
(a) a solvate according to the first aspect of the invention, together with (b) an agriculturally pharmaceutically acceptable carrier.
In a fifth aspect of the present invention, there is provided a use of the solvate according to the first aspect of the present invention or the pesticidal composition according to the fourth aspect of the present invention for preventing or controlling diseases; or for inhibiting harmful microorganisms in agriculture, forestry or horticulture.
In another preferred example, the prevention or control is prevention or control of diseases in agriculture, forestry or horticulture.
In another preferred embodiment, the disease is selected from the group consisting of plant diseases: powdery mildew, banded sclerotial blight, fusarium wilt, leaf spot, rust disease, sclerotinia sclerotiorum, net blotch, leaf blotch, gray mold, black spot, brown spot, black shank or a combination thereof.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Drawings
FIG. 1 shows XRD diffraction patterns of form I crystals, form II crystals and diethylamine solvate of prothioconazole. Wherein (a) represents a crystal of form I, (b) represents a crystal of form II, and (c) represents a diethylamine solvate.
FIG. 2 shows a DSC overlay of the form I crystals, form II crystals and diethylamine solvate of prothioconazole. Wherein (a) represents a crystal of form I, (b) represents a crystal of form II, and (c) represents a diethylamine solvate.
Figure 3 shows a TGA profile of prothioconazole diethylamine solvate.
FIG. 4 shows an NMR chart of prothioconazole diethylamine solvate, wherein FIG. 4(a) represents a carbon spectrum and FIG. 4(b) represents a hydrogen spectrum.
In FIG. 5, (a) shows a projection of the molecular spatial structure of the diethyltoluamide solvate of prothioconazole, and (b) shows a projection of the unit cell stacking of the diethyltoluamide solvate of prothioconazole.
Detailed Description
The present inventors have, through extensive and intensive studies, unexpectedly found a diethylamine solvate of prothioconazole, use thereof and a preparation method thereof for the first time. The prothioconazole diethylamine solvate has good illumination stability, high humidity resistance and excellent solubility, is obviously superior to the existing prothioconazole crystal in the aspect of water solubility, and can be produced in a large scale. The method is suitable for preparing the pesticide composition for inhibiting harmful microorganisms, and the solvate is simple in preparation method, stable in process and suitable for large-scale industrial production. On this basis, the inventors have completed the present invention.
Description of the terms
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
As used herein, the term "about" when used in reference to a specifically recited value means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).
As used herein, the term "comprising" or "includes" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of …," or "consisting of ….
As used herein, the term "n or more than n 2 θ values selected from the group" refers to any positive integer (e.g., n +1, …) including n and greater than n, where the upper limit Nup is the number of all 2 θ peaks in the group. For example, "3 or more" includes not only 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, …, each positive integer of the upper limit Nup, but also ranges such as "4 or more", "5 or more", "6 or more".
A compound of formula I
Prothioconazole (compound of formula I),
Figure BDA0001595978960000061
chemical name 2- [ (2RS) -2- (1-chlorocyclopropyl) -3- (2-chlorophenyl) -2-hydroxypropyl]-2H-1,2, 4-triazole-3 (4H) -thione. The compound is used as a fungicide widely used in the world, and is mainly used for preventing and treating a plurality of diseases of cereals, wheat and bean crops and the like, such as powdery mildew, banded sclerotial blight, fusarium wilt, leaf spot, rust disease, sclerotinia rot, net blotch, leaf blotch, gray mold, black shank and the like.
Crystallization of
Production scale crystallization can be accomplished by manipulating the solution such that the solubility limit of the compound of interest is exceeded. This can be accomplished by a variety of methods, for example, dissolving the compound at relatively high temperatures and then cooling the solution below the saturation limit. Or by boiling, atmospheric evaporation, vacuum drying, or by some other method to reduce the liquid volume. The solubility of the compound of interest may be reduced by adding an anti-solvent or a solvent in which the compound has low solubility or a mixture of such solvents. Another alternative is to adjust the pH to reduce solubility. For a detailed description of the Crystallization see crystallography, third edition, J WMulens, Butterworth-Heineman Ltd., 1993, ISBN 0750611294.
If salt formation is desired to occur simultaneously with crystallization, addition of an appropriate acid or base may result in direct crystallization of the desired salt if the salt is less soluble in the reaction medium than the starting material. Also, in media where the final desired form is less soluble than the reactants, completion of the synthesis reaction can result in direct crystallization of the final product.
Optimization of crystallization may include seeding the crystallization medium with crystals of the desired form. In addition, many crystallization methods use a combination of the above strategies. One example is to dissolve the compound of interest in a solvent at elevated temperature, followed by the addition of an appropriate volume of anti-solvent in a controlled manner so that the system is just below the saturation level. At this point, seeds of the desired form may be added (and the integrity of the seeds maintained) and the system cooled to complete crystallization.
Solvates
In the process of contacting a compound or a drug molecule with a solvent molecule, the solvent molecule and the compound molecule form eutectic crystals and remain in the solid substance due to external condition and internal condition factors, which is difficult to avoid. The material formed after crystallization of the compound with a solvent is known as a solvate or solvate (solvate). The solvent which is easily solvated with organic compounds is selected from water, methanol, benzene, ethanol, ether, aromatic hydrocarbon, heterocyclic aromatic hydrocarbon, etc.
Hydrates are a particular solvate. In the pharmaceutical industry, hydrates have separately discussed value for their specificity, whether in the synthesis of drug substances, pharmaceutical formulations, drug storage, and evaluation of drug activity.
As used herein, the terms "prothioconazole solvate", "prothioconazole diethylamine solvate", "solvate of the present invention" and similar terms refer to solvates described in connection with the first aspect of the present invention. Preferably, the solvent molecules are contained in the crystalline lattice of prothioconazole, in which case the solvent is diethylamine. In this document, the above and similar terms are used interchangeably.
Pesticide composition
The "active ingredient" or "active compound" in the pesticidal composition of the present invention refers to the compound of formula (I) of the present invention, especially a solvate of the compound of formula (I) of the present invention.
The "active ingredient" or "active compound" and the pesticidal composition of the present invention can be used for preventing or controlling diseases; or for inhibiting harmful microorganisms in agriculture, forestry or horticulture.
Differential scanning calorimetry analysis
Also known as differential thermal scanning analysis (DSC), is a technique for measuring the relationship between the energy difference between a measured substance and a reference substance and the temperature during heating. The position, shape and number of peaks on a DSC spectrum are related to the nature of the substance and can be used qualitatively to identify the substance. The method is commonly used in the field to detect various parameters such as phase transition temperature, glass transition temperature, reaction heat and the like of a substance. The temperature ranges mentioned in the examples of the invention are determined by Differential Scanning Calorimetry (DSC) and are based on prothioconazole solvate with a temperature accuracy of +/-0.1 ℃ unless otherwise stated.
Use of
The invention provides a prothioconazole diethylamine solvate and application of a pesticide composition thereof, wherein the solvate has high efficiency and broad spectrum, and is mainly used for preventing and treating a plurality of diseases of cereals, wheat and bean crops and the like, such as powdery mildew, banded sclerotial blight, leaf spot, rust disease, sclerotinia rot, net blotch, leaf spot, gray mold, black shank and the like.
The main advantages of the invention
(1) The diethylamine solvate of the present invention has high purity, excellent crystallization performance, stability under the conditions of high humidity and illumination, and excellent solubility, is obviously superior to the existing prothioconazole crystal in the aspect of water solubility, and is favorable for stable quality control and industrial application.
(2) The preparation method of the diethylamine solvate is simple, easy to control, stable in process, good in reproducibility and suitable for large-scale industrial production.
(3) The diethylamine solvate of the present invention can be used for preventing or controlling diseases; or for inhibiting harmful microorganisms in agriculture, forestry or horticulture.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specific conditions noted in the following examples, generally according to conventional conditions, or according to conditions recommended by the manufacturer. Unless otherwise indicated, percentages and parts are by weight. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only. The test materials and reagents used in the following examples are commercially available without specific reference. The normal temperature or room temperature is 4-25 deg.C, preferably 15-25 deg.C.
Test method
XRD (X-ray powder diffraction) method: the instrument model is as follows: rigaku Ultima IV, target: Cu-K α: (
Figure BDA0001595978960000081
40kV, 40mA), at room temperature using a D/tex Ultra detector. The circulating water pressure is about 0.25-0.3MPa, and the measurement parameters are 40kV, 40mA and 1.6 kV.
The differences in measurements associated with such X-ray powder diffraction analysis results arise from a number of factors including: (a) errors in sample preparation (e.g., sample height), (b) instrument errors, (c) calibration differences, (d) operator errors (including errors in determining peak position), and (e) properties of the substance (e.g., preferred orientation errors). Calibration errors and sample height errors often result in a shift of all peaks in the same direction. When using a flat holder, small differences in sample height will result in large shifts in XRD peak positions. Systematic studies show that sample height differences of 1mm can result in peak shifts of 2 θ up to 1 °. These shifts can be identified from the X-ray diffraction patterns and can be eliminated by compensating for them (using the system calibration factor for all peak position values) or recalibrating the instrument. As described above, measurement errors from different instruments can be corrected by applying a system calibration factor to make the peak positions consistent. In the embodiment of the invention, the X-ray diffraction takes prothioconazole solvate as a measurement object.
TGA (thermogravimetric analysis) method: the instrument model is as follows: TA Q500 thermogravimetric analyzer using N 2 The temperature rise rate is 10 ℃/min under the atmosphere.
DSC (differential scanning calorimetry) method: the instrument model is as follows: TA Q2000, using N 2 The temperature rise rate is 10 ℃/min under the atmosphere.
Example 1 preparation of the diethylamine solvate of prothioconazole
1.1 weighing 50mg of a compound of formula I into a 10mL sample vial, dissolving in 1.0mL diethylamine at room temperature, and shaking slightly to clarify. 5.0mL of n-heptane is dripped, the solution becomes white and turbid, and after standing for 24h, light brown blocky single crystals are separated out from the bottom of the bottle, and the color is darker. Filtering out a part of precipitated single crystals, and placing the single crystals in a vacuum oven for drying for 6 hours to obtain the diethylamine solvate.
1.2 weighing 50mg of the compound of formula I into a 10mL sample vial, dissolving in 1.0mL diethylamine at room temperature, and shaking slightly to clarify. 5.0mL of n-hexane is added dropwise, the solution becomes cloudy, and after standing for 24 hours, a light brown massive single crystal is separated out from the bottom of the bottle. Filtering out a part of precipitated single crystals, and placing the single crystals in a vacuum oven for drying for 6 hours to obtain the diethylamine solvate.
1.3 weighing 50mg of the compound of formula I into a 10mL sample vial, dissolving in 1.0mL diethylamine at room temperature, and shaking slightly to clarify. 5.0mL of cyclohexane is added dropwise, the solution becomes cloudy, and after standing for 24h, a light brown blocky single crystal is separated out from the bottom of the bottle, and the color is light. Filtering and centrifuging, taking a part of precipitated single crystals, and drying in a vacuum oven for 6 hours to obtain the diethylamine solvate.
The XRD diffraction pattern of the obtained diethylamine solvate is substantially as shown in fig. 1(c), part of the XRD peaks of the solvate is shown in table 1, and the data of single crystal diffraction analysis is shown in table 2.
TABLE 1 partial 2 θ values in XRD peaks for prothioconazole diethylamine solvate
2θ(±0.2 2θ)
5.7
11.4 (Weak)
16.4 (Weak)
17.0 (Medium)
19.9
22.8 (Strong)
26.6
27.0
27.9
31.7
32.9
36.0
38.4
TABLE 2 Single Crystal diffraction analysis data for prothioconazole diethylamine solvate
Figure BDA0001595978960000091
Figure BDA0001595978960000101
The bond lengths and bond angles of the prothioconazole diethylamine solvate are shown in table 3, and the parameters are as follows:
TABLE 3 bond length and bond angle of prothioconazole diethylamine solvate
Figure BDA0001595978960000102
Figure BDA0001595978960000111
Figure BDA0001595978960000121
Figure BDA0001595978960000131
The DSC spectrum of the prothioconazole diethylamine solvate is basically as shown in figure 2 (c). In FIG. 2, the melting onset temperature of the form I crystals is 137.71 ℃ and the melting onset temperature of the form II crystals is 138.80 ℃. The diethylamine solvate lacks the melting peak between about 137 ℃ and about 145 ℃, i.e., lacks the melting characteristics of form I and form II of the compound of formula I. The desolvation starting temperature of the prothioconazole diethylamine solvate is 110.81 ℃, and the desolvation peak is within the range of 110.9-120.7 ℃, and the enthalpy value of the desolvation is 70 +/-5J/g.
The TGA profile of the prothioconazole diethylamine solvate is substantially as shown in figure 3. It was observed that the weight loss of the solvate was about 17.54% when heated to 200 ℃, which was roughly calculated to be a mono-solvate (prothioconazole: diethylamine ═ 1: 1).
The solvate was judged to be a 1:1 prothioconazole/diethylamine solvate by TGA, NMR (shown in FIG. 4(a) C spectrum and FIG. 4(b) H spectrum).
In addition, a single crystal structure of the prothioconazole diethylamine solvate was also obtained, as shown in fig. 5(a) and (b).
Example 2 stability Studies of the diethylamine solvate of prothioconazole
Samples of the diethylamine solvate of prothioconazole in example 1 were respectively placed under 90 + -5% humidity and 4500 + -500 lux illumination intensity, and after 5 days and 10 days, respectively, the samples were taken out for XRD test to examine the stability of the samples to humidity and illumination. The result shows that the XRD diffraction patterns of the samples after being placed for 5 days and 10 days have no obvious change, and the solvate is stable under the conditions of high humidity and illumination.
Example 3 solubility examination of the diethylamine solvate of prothioconazole
A sample of the diethylamine solvate of prothioconazole from example 1 was dissolved in 50mL of purified water at pH 7 at 293.15K to give a solubility of 167.82g/L, whereas under the same conditions, the solubility of prothioconazole form I was 0.32g/L and the solubility of prothioconazole form II was 0.18 g/L.
The results show that the diethylamine solvate of the present invention has very excellent solubility, which is significantly superior to the existing prothioconazole crystals in water solubility, and the solubilities are about 524 times and 932 times that of prothioconazole form I and prothioconazole form ii, respectively.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (15)

1. A solvate of a compound of formula I, wherein the solvate is a solvate of diethylamine of a compound of formula I, wherein the solvate is a solid,
Figure FDA0003610892490000011
wherein,
the molar ratio of the compound of the formula I to diethylamine is 1:0.8-1: 1.2;
and, the solvate has an X-ray powder diffraction pattern comprising all 2 θ values selected from the group consisting of: 11.4 ° ± 0.2 °, 16.4 ° ± 0.2 °, 17.0 ° ± 0.2 °, and 22.8 ° ± 0.2 °.
2. The solvate of claim 1, wherein the molar ratio of the compound of formula I to diethylamine is 1:1.
3. The solvate of claim 1, having an X-ray powder diffraction pattern comprising all 2 θ values selected from the group consisting of: 5.7 DEG +/-0.2 DEG, 11.4 DEG +/-0.2 DEG, 16.4 DEG +/-0.2 DEG, 17.0 DEG +/-0.2 DEG, 19.9 DEG +/-0.2 DEG, 22.8 DEG +/-0.2 DEG, 26.6 DEG +/-0.2 DEG, 27.0 DEG +/-0.2 DEG, 27.9 DEG +/-0.2 DEG, 31.7 DEG +/-0.2 DEG, 32.9 DEG +/-0.2 DEG, 36.0 DEG +/-0.2 DEG and 38.4 DEG +/-0.2 deg.
4. The solvate of claim 1, having an X-ray powder diffraction pattern substantially as characterized in figure 1 (c).
5. The solvate of claim 1, having single crystal diffraction analysis data as set forth in any one or more of table 2 below
TABLE 2 Single Crystal diffraction analysis data for prothioconazole diethylamine solvate
Figure FDA0003610892490000012
6. The solvate of claim 1, wherein the TGA profile of the solvate is substantially as characterized in figure 3.
7. The solvate of claim 1, having a DSC profile with a desolvation peak in the range of 110 to 121 ℃.
8. The solvate of claim 1, having a DSC profile substantially as characterized in figure 2 (c).
9. A process for preparing the solvate of claim 1, comprising the steps of:
(a) providing a solution of a compound of formula I in diethylamine;
(b) (ii) a diethylamine solvate of the compound of formula I precipitated by subjecting said solution to a precipitation treatment; and
(c) isolating the precipitated solvate, thereby obtaining the solvate of claim 1.
10. The method of claim 9, wherein the precipitation treatment is carried out with the addition of an anti-solvent selected from the group consisting of: n-hexane, cyclohexane, n-heptane, or combinations thereof.
11. A process for preparing the solvate of claim 1, comprising the steps of:
(i) providing a solution of a compound of formula I in diethylamine;
(ii) subjecting said solution to crystallization by standing under crystallization conditions to obtain the solvate of claim 1.
12. A pesticidal composition, characterized in that the composition comprises:
(a) the solvate of any one of claims 1 to 8, and (b) an agriculturally pharmaceutically acceptable carrier.
13. Use of the solvate according to any one of claims 1 to 8 or the pesticidal composition according to claim 12 for preventing or controlling a plant disease.
14. The use according to claim 13, wherein the plant disease is a plant disease selected from the group consisting of: powdery mildew, banded sclerotial blight, fusarium wilt, leaf spot, rust disease, sclerotinia sclerotiorum, net blotch, leaf blotch, gray mold, black spot, brown spot, black shank or a combination thereof.
15. Use of the solvate according to any one of claims 1 to 8 or the pesticidal composition according to claim 13 for inhibiting harmful microorganisms in agriculture, forestry or horticulture.
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Citations (3)

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CN1681390A (en) * 2002-07-22 2005-10-12 拜尔农作物科学股份公司 Crystal form II 2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione
WO2009153785A2 (en) * 2008-06-17 2009-12-23 Makhteshim Chemical Works Ltd. Crystalline modifications of prothioconazole
US20150064257A1 (en) * 2012-04-25 2015-03-05 Bayer Cropscience Lp Metalaxyl and prothioconazole cocrystals and methods of making and using

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1681390A (en) * 2002-07-22 2005-10-12 拜尔农作物科学股份公司 Crystal form II 2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione
WO2009153785A2 (en) * 2008-06-17 2009-12-23 Makhteshim Chemical Works Ltd. Crystalline modifications of prothioconazole
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