CN109020905A - The polymorphic and preparation method thereof of two kinds of Cyproconazoles - Google Patents
The polymorphic and preparation method thereof of two kinds of Cyproconazoles Download PDFInfo
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- CN109020905A CN109020905A CN201710433084.1A CN201710433084A CN109020905A CN 109020905 A CN109020905 A CN 109020905A CN 201710433084 A CN201710433084 A CN 201710433084A CN 109020905 A CN109020905 A CN 109020905A
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- 0 CC(C1CC1)C(*)(C[n]1ncnc1)c(cc1)ccc1Cl Chemical compound CC(C1CC1)C(*)(C[n]1ncnc1)c(cc1)ccc1Cl 0.000 description 1
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- 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
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- 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
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract
The present invention provides the polymorph of Cyproconazole, its application and preparation methods, specifically, the present invention relates to polymorph, preparation method and the purposes of 2- (4 chlorphenyl) -3- cyclopropyl -1- (1H-1,2,4- triazol-1-yls) butyl- 2- alcohol.
Description
Technical field
The invention belongs to field of pesticide chemistry, specifically, the present invention relates to the polymorph of Cyproconazole, its application and
Preparation method.
Background technique
Cyproconazole (compound of formula I), chemical name 2- (4 chlorphenyl) -3- cyclopropyl -1- (1H-1,2,4- triazol-1-yls)
Butyl- 2- alcohol.The compound is ergosterol demethylation inhibitors, can prevent and treat cereal and coffee rust, cereal, fruit tree and grape
Powdery mildew, peanut, beet leaf spot, scab of apple and peanut white rot.Cyproconazole has efficient, low toxicity, broad spectrum activity etc.
Feature.
Same compound, crystal form are different, and solubility may also can have difference, in addition its stability, mobility, can
Compressibility may also can be different.And these physicochemical properties can generate certain influence to the application of the compound.According to primitivation
Preparation method in conjugate patent US4664696A, the crystal form prepared are named as crystal form A, and that there are solubility is low by crystal form A
The case where.
Therefore, this field needs the polymorph of research and development compound of formula I, it is desirable that preparation method is simple, thermal stability is good, inhales
It is moist it is low, dissolubility is high, is produced on a large scale.
Summary of the invention
The purpose of the present invention is to provide polymorphics of a kind of Cyproconazole and preparation method thereof.
The first aspect of the present invention provides a kind of crystal of compound of formula I,
In another preferred example, the crystal is selected from the group: crystal form B and crystal form C.
In another preferred example, the X-ray powder diffraction pattern of the crystal form B includes 3 or 3 or more selected from the group below
2 θ values: 6.5 ± 0.2 °, 9.1 ± 0.2 °, 13.0 ± 0.2 °, 16.4 ± 0.2 °, 18.1 ± 0.2 °, 18.4 ± 0.2 °, 19.4 ±
0.2°、20.8±0.2°、25.5±0.2°、26.1±0.2°、29.2±0.2°。
In another preferred example, the X-ray powder diffraction pattern of the crystal form B can further comprise 3 or 3 or more and select
From 2 θ values of the following group: 7.0 ± 0.2 °, 9.7 ± 0.2 °, 13.5 ± 0.2 °, 18.8 ± 0.2 °, 21.3 ± 0.2 °, 22.6 ± 0.2 °,
23.0±0.2°、23.3±0.2°、24.7±0.2°、24.9±0.2°、26.8±0.2°、27.5±0.2°、27.8±0.2°、
28.5±0.2°、30.0±0.2°、30.8±0.2°、33.0±0.2°、34.9±0.2°、35.3±0.2°、38.0±0.2°、
39.3±0.2°、43.1±0.2°。
In another preferred example, the X-ray powder diffraction pattern of the crystal form B is basic as Fig. 1 is characterized.
In another preferred example, the TGA figure of the crystal form B is basic as Fig. 3 is characterized.
In another preferred example, the DSC figure of the crystal form B has endothermic peak within the scope of 101-109 DEG C.
In another preferred example, the DSC figure of the crystal form B is basic as Fig. 2 is characterized.
In another preferred example, the crystal form B purity is greater than 95%, it is preferable that purity is greater than 97%, it is highly preferred that pure
Degree is greater than 99%, and most preferably, purity is greater than 99.5%.
In another preferred example, the X-ray powder diffraction pattern of the crystal form C includes 3 or 3 or more selected from the group below
2 θ values: 6.4 ± 0.2 °, 9.0 ± 0.2 °, 11.0 ± 0.2 °, 12.9 ± 0.2 °, 15.6 ± 0.2 °, 18.0 ± 0.2 °, 21.2 ±
0.2°、24.1±0.2°。
In another preferred example, the X-ray powder diffraction pattern of the crystal form C can further comprise 3 or 3 or more and select
From 2 θ values of the following group: 7.2 ± 0.2 °, 9.5 ± 0.2 °, 19.1 ± 0.2 °, 22.1 ± 0.2 °, 22.5 ± 0.2 °, 23.0 ± 0.2 °,
25.4±0.2°、26.0±0.2°、27.3±0.2°、28.4±0.2°、28.9±0.2°、30.0±0.2°、30.6±0.2°、
31.6±0.2°、33.4±0.2°、40.1±0.2°、43.3±0.2°。
In another preferred example, the X-ray powder diffraction pattern of the crystal form C is basic as Figure 12 is characterized.
In another preferred example, the TGA figure of the crystal form C is basic as Figure 14 is characterized.
In another preferred example, the DSC figure of the crystal form C has endothermic peak within the scope of 103-109 DEG C.
In another preferred example, the DSC figure of the crystal form C is basic as Figure 13 is characterized.
In another preferred example, the crystal form C purity is greater than 95%, it is preferable that purity is greater than 97%, it is highly preferred that pure
Degree is greater than 99%, and most preferably, purity is greater than 99.5%.
The second aspect of the present invention provides a kind of composition pesticide, and the composition includes: (a) such as first party of the present invention
Crystal described in face, and (b) acceptable carrier in Pesticide Science.
The third aspect of the present invention provides a kind of method for preparing crystal form B described in first aspect present invention, comprising steps of
(i) compound of formula I is provided in the first solution of the first solvent；
(ii) the second solvent is added into the first above-mentioned solution, forms the second solution, and crystallization is carried out to the second solution
Processing, to form crystal form B described in first aspect present invention.
In another preferred example, first solvent is selected from the group: nitromethane, 2,2,2- trifluoroethanols or its group
It closes.
In another preferred example, second solvent is anti-solvent.
In another preferred example, second solvent is normal heptane.
In another preferred example, in step (i), the compound of formula I is selected from the group: amorphous compound, crystal form A,
Crystal form B, crystal form C, or combinations thereof.
In another preferred example, in step (i), the amount ratio of the compound of formula I and first solvent is (5-
500) mg:(0.1-10) ml, preferably (10-200) mg:(0.2-5) ml is more preferably (20-100) mg:(0.5-2) ml.
In another preferred example, in step (ii), the amount ratio of first solvent and second solvent is 1:2-
10, preferably 1:3-8 are more preferably 1:4-6.
In another preferred example, after step (ii), the method also includes: (iii) is from the described molten of previous step
The crystal form B is separated in liquid.
In another preferred example, after step (iii), the method also includes: (iv) to the isolated crystal form B into
Row drying.
The fourth aspect of the present invention provides a kind of method for preparing crystal form C described in first aspect present invention, comprising steps of
(i) compound of formula I is provided in the first solution of the first solvent；
(ii) the second solvent is added into the first above-mentioned solution, forms the second solution, and crystallization is carried out to the second solution
Processing, to form crystal form C described in first aspect present invention.
In another preferred example, first solvent is 2- butanone.
In another preferred example, second solvent is anti-solvent.
In another preferred example, second solvent is n-hexane.
In another preferred example, in step (i), the compound of formula I is selected from the group: amorphous compound, crystal form A,
Crystal form B, crystal form C, or combinations thereof.
In another preferred example, in step (i), the amount ratio of the compound of formula I and first solvent is (5-
500) mg:(0.05-5) ml, preferably (10-200) mg:(0.1-2.5) ml is more preferably (20-100) mg:(0.2-1)
ml。
In another preferred example, in step (ii), the amount ratio of first solvent and second solvent is 1:2-
10, preferably 1:3-8 are more preferably 1:4-6.
In another preferred example, after step (ii), the method also includes: (iii) is from the described molten of previous step
The crystal form C is separated in liquid.
In another preferred example, after step (iii), the method also includes: (iv) to the isolated crystal form C into
Row drying.
The fifth aspect of the present invention provides agriculture described in crystal described in a kind of first aspect present invention or second aspect of the present invention
The purposes of drug composition, for preventing or controlling disease；Or for inhibiting harmful microorganism on agricultural, forestry or gardening.
In another preferred example, the prevention or control are the prevention on agricultural, forestry or gardening or control disease.
In another preferred example, disease plant disease selected from the group below: cereal and coffee rust, cereal, fruit tree
And uncinula necator, peanut, beet leaf spot, scab of apple and peanut white rot, or combinations thereof.
It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention
It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, exist
This no longer tires out one by one states.
Detailed description of the invention
Fig. 1 shows the XRPD map of crystal form B Cyproconazole.
Fig. 2 shows the DSC figure of crystal form B Cyproconazole.
Fig. 3 shows the TGA figure of crystal form B Cyproconazole.
Fig. 4 shows crystal form B molecule stereo structure perspective view.
Fig. 5 shows that crystal form B structure cell accumulates perspective view.
Fig. 6 shows five days high-temperature stability XRPD maps of crystal form B.
Fig. 7 shows ten days high-temperature stability XRPD maps of crystal form B.
Fig. 8 shows crystal form B five days high wet stability XRPD maps.
Fig. 9 shows crystal form B ten days high wet stability XRPD maps.
Figure 10 shows five days light durability XRPD maps of crystal form B.
Figure 11 shows ten days light durability XRPD maps of crystal form B.
Figure 12 shows the XRPD map of crystal form C Cyproconazole.
Figure 13 shows the DSC figure of crystal form C Cyproconazole.
Figure 14 shows the TGA figure of crystal form C Cyproconazole.
Figure 15 shows five days high-temperature stability XRPD maps of crystal form C.
Figure 16 shows ten days high-temperature stability XRPD maps of crystal form C.
Figure 17 shows crystal form C five days high wet stability XRPD maps.
Figure 18 shows crystal form C ten days high wet stability XRPD maps.
Figure 19 shows five days light durability XRPD maps of crystal form C.
Figure 20 shows ten days light durability XRPD maps of crystal form C.
Specific embodiment
The present inventor is surprised to find that polymorph, its application of Cyproconazole by extensive and in-depth research for the first time
And preparation method.The Polvmorph Puritv is high, has good thermal stability and non-hygroscopic, and excellent in terms of solubility
In existing Cyproconazole.Inhibit harmful microbe composition pesticide suitable for preparation, thus to cereal and coffee rust,
Cereal, fruit tree and uncinula necator, peanut, beet leaf spot, the diseases such as scab of apple and peanut white rot have preferably anti-
Effect.In addition, polymorph preparation method of the invention is simple, it is suitble to large-scale industrial production.On this basis, inventor is complete
At the present invention.
Term explanation
Unless otherwise defined, otherwise whole technologies used herein and scientific term all have such as fields of the present invention
The normally understood identical meanings of those of ordinary skill.
As used herein, in use, term " about " means that the value can be from enumerating in mentioning the numerical value specifically enumerated
Value changes not more than 1%.For example, as used herein, statement " about 100 " include 99 and 101 and between whole values (for example,
99.1,99.2,99.3,99.4 etc.).
As used herein, term " containing " or " including (including) " can be open, semi-enclosed and enclosed.It changes
Yan Zhi, the term also include " substantially by ... constitute " or " by ... constitute ".
As used herein, term " n or n or more 2 θ values selected from the group below " refers to including n and any just whole greater than n
Number (such as n, n+1 ...), wherein upper limit Nup is the number of all 2 θ peak values in the group.Such as " 3 or 3 or more " are not only
Including 3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21 ... each positive integer of upper limit Nup, also
Including the ranges such as " 4 or 4 or more ", " 5 or 5 or more ", " 6 or 6 or more ".
Compound of formula I
Cyproconazole (compound of formula I), chemical name 2- (4 chlorphenyl) -3- cyclopropyl -1- (1H-1,2,4- triazol-1-yls)
Butyl- 2- alcohol.The compound is ergosterol demethylation inhibitors, can prevent and treat cereal and coffee rust, cereal, fruit tree and grape
Powdery mildew, peanut, beet leaf spot, scab of apple and peanut white rot.Cyproconazole has efficient, low toxicity, broad spectrum activity etc.
Feature.
Polymorph
It is exactly to exist in the form of crystallization that solid, which is not in the form of unbodied,.In the case where crystal form, molecule is fixed
In three-dimensional lattice case.When compound is crystallized out from solution or slurries, the space lattice that it can be different is arranged
Crystallization (this property is referred to as " polymorphism "), forms the crystal with different crystal forms, this various crystal form
Referred to as " polymorph ".The different polymorphs of given substance can in terms of one or more physical attributes (such as solubility and
Rate of dissolution, true specific gravity, crystalline form, accumulation mode, mobility and/or solid-state stability) it is different from each other.
Crystal of the invention, including crystal form selected from the group below: crystal form B and crystal form C.
Crystallization
It can be by working solution, so that the solubility limit of compound of interest is exceeded, to complete production scale
Crystallization.This can be completed by a variety of methods, for example, dissolved compound at relatively high temperature, then cools down solution
To saturation limit.Or by boiling, atmospheric evaporation, vacuum drying or by some other methods reduce liquid bulk
Product.It can be come by the way that anti-solvent or compound is added in the mixture of solvent or such solvent wherein with low solubility
Reduce the solubility of compound of interest.Another optional method is to adjust pH value to reduce solubility.Related crystallization aspect
It is described in detail and refers to Crystallization, the third edition, J W Mullens, Butterworth-Heineman Ltd.,
1993,ISBN0750611294。
If it is expected that the formation of salt with crystallization occur simultaneously, if salt is smaller than dissolution of raw material degree in reaction medium,
Acid or alkali appropriate, which is added, can lead to the direct crystallization of required salt.Equally, smaller than reactant solubility in finally desired form
Medium in, the completion of synthetic reaction can make final product direct crystallization.
The optimization of crystallization may include that the crystal of required form is used to be inoculated in crystallization medium as crystal seed.In addition, many knots
Crystal method uses the combination of above-mentioned strategy.One embodiment be at high temperature by interested compound dissolution in a solvent, with
The anti-solvent of proper volume is added by controlled way afterwards, so that system is just under saturated level.At this point, needed for being added
The crystal seed (and the integrality for keeping crystal seed) of form, system is cooling to complete to crystallize.
Solvate
In compound or drug molecule and solvent molecule contact process, external condition and interior condition factor cause solvent point
The situation that son forms eutectic with compound molecule and remains in solid matter is difficult to avoid that.It is formed after drug and solvent crystallization
Substance is referred to as solvate (solvate).Readily with organic compound formed solvate solvent type be water, methanol,
Benzene, ethyl alcohol, ether, aromatic hydrocarbons, heterocyclic arene etc..
Hydrate is a kind of special solvate.In pharmaceuticals industry, no matter the synthesis of bulk pharmaceutical chemicals, pharmaceutical preparation,
In medicine storage and pharmaceutical activity evaluation, hydrate all has the value individually discussed because of its particularity.
Composition pesticide
" active constituent " or " reactive compound " in composition pesticide of the present invention refers to Formulas I of the present invention
Object is closed, especially with compound of formula I existing for crystal form of the present invention.
" active constituent " or " reactive compound " and composition pesticide of the present invention can be used for preventing or controlling disease；
Or for inhibiting harmful microorganism on agricultural, forestry or gardening.
Differential scanning calorimetry
Also known as " differential scanning calorimetry " (DSC) is during heating, to measure between measured matter and reference substance
A kind of technology of relationship between energy difference and temperature.The property of peak position, shape and peak number mesh and substance on DSC map has
It closes, therefore can qualitatively be used to identify substance.This method commonly used in the art detects phase transition temperature, the glass transition temperature of substance
The many kinds of parameters such as degree, reaction heat.
Preparation method
The method for preparing Cyproconazole crystal form B, C, it is characterised in that used room temperature volatilization is this to be easy and fast to a large amount of works
The method that industry metaplasia produces.
Purposes
The present invention provides the purposes of crystal form B and C and its composition pesticide, the crystal form high-efficiency broad spectrum can prevent and treat cereal
With coffee rust, cereal, fruit tree and uncinula necator, peanut, beet leaf spot, scab of apple and peanut white rot.
Main advantages of the present invention are:
(1) the compound of the present invention crystal form B and C all has good thermal stability and non-hygroscopic, and in solubility
Aspect is better than existing Cyproconazole.
(2) the compound of the present invention crystal form B and C preparation method is simple, is suitble to large-scale industrial production.
(3) the compound of the present invention crystal form B and C can be used for preventing or controlling disease；Or in agricultural, forestry or garden
Inhibit harmful microorganism in skill.
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip
Part, or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are calculated by weight.
Experimental material used in following embodiment and reagent can obtain unless otherwise instructed from commercially available channel.Room temperature or
Room temperature refers to 4 DEG C -25 DEG C, preferably 15-25 DEG C.
Test method:
XRD (X-ray powder diffraction) method: instrument model: Rigaku Ultima IV, target: Cu-K α (40kV,
40mA), it is carried out at room temperature using D/tex Ultra detector.In 2 sections θ from 3 ° to 45 °, scanning speed is scanning range
20 °/minute.
By including that many factors below generate measurement difference relevant to this kind of X-ray powder diffraction analysis result: (a)
Error in sample preparation object (such as height of specimen), (b) instrument error, (c) calibrate difference, (d) personal error (including
The error occurred when measuring peak position), and (e) property (such as preferred orientation error) of substance.Calibration error and sample
Height error frequently results in displacement of all peaks in the same direction.When using flat bracket, the small difference of height of specimen will
Lead to the big displacement of the peak position XRD.System research shows the peak position that the sample height difference of 1mm can lead to up to 1 ° of 2 θ
It moves.These displacements can be identified from X-ray diffractogram, and can be by compensating for the displacement (by system calibration
The factor is used for all peak position values) or the recalibration instrument elimination displacement.As described above, being made by application system calibration factor
Peak position is consistent, measurement error of the recoverable from different instruments.
TGA (thermogravimetric analysis) method: instrument model: TA Q500 thermogravimetric analyzer, using N2Atmosphere, heating rate 10
℃/min
DSC (differential scanning calorimetry) method: instrument model: TA Q2000, using N2Atmosphere, heating rate be 10 DEG C/
min
The preparation of 1. crystal form A of embodiment
Preparation method in the preparation method referenced patent US4664696A of crystal form A.
The X-ray powder diffraction pattern of gained crystal form A is about at least 6.9 ± 0.2 °, 13.5 ± 0.2 °, 14.6 in 2 θ values
±0.2°、16.0±0.2°、16.5±0.2°、18.4±0.2°、18.7±0.2°、19.1±0.2°、19.5±0.2°、19.8
Have diffraction maximum at ± 0.2 °, 20.7 ± 0.2 °, 22.6 ± 0.2 °, 29.2 ± 0.2 °, further may include positioned at 7.9 ± 0.2 °,
9.9±0.2°、13.1±0.2°、14.1±0.2°、14.4±0.2°、21.1±0.2°、21.4±0.2°、22.1±0.2°、
23.4±0.2°、23.8±0.2°、24.9±0.2°、25.1±0.2°、25.6±0.2°、26.2±0.2°、27.2±0.2°、
28.0±0.2°、28.3±0.2°、30.1±0.2°、30.3±0.2°、30.7±0.2°、31.8±0.2°、32.3±0.2°、
Diffraction maximum at 33.6 ± 0.2 °, 35.1 ± 0.2 °, 37.1 ± 0.2 °.
The preparation of 2. crystal form B Cyproconazole of embodiment
2.1 weigh 50mg compound of formula I in container, and the dissolution of 1ml nitromethane is added, adds the normal heptane of 5ml, quiet
Crystal form B Cyproconazole is obtained after setting volatilization, vacuum drying.
2.2 weigh 50mg compound of formula I in container, and the dissolution of 2,2,2- trifluoroethanol of 0.5ml is added, adds 2.5ml
Normal heptane, stand volatilization, vacuum drying after obtain crystal form B Cyproconazole.
Gained crystal form B is polymorphic, and XRD spectrum is basic as shown in Figure 1, diffraction angular data is substantially as shown in table 1 below.
The XRD data of 1 crystal form B of table
The DSC map of crystal form B is basic as shown in Fig. 2, wherein endothermic peak corresponds to fusion and decomposition process, in 101-109 DEG C of model
There is endothermic peak in enclosing.
The TGA map of crystal form B is basic as shown in figure 3, substantially without weightlessness before decomposition.
In addition, have also obtained crystal form B in embodiment 2 does single crystal X-ray diffraction (SXRD) structure, as shown in Figure 4, Figure 5,
Its parameter is as follows:
The single crystal X-ray diffraction parameter of 2 crystal form B of table
3. crystal form B Cyproconazole study on the stability of embodiment
3.1 high-temperature stability
Crystal form B Cyproconazole sample in embodiment 2 is placed in 60 ± 2 DEG C of baking ovens, is taken out sample after 5 days and 10 days
XRPD test is carried out, to investigate sample to the stability of crystal form of temperature.As shown in Figure 6, Figure 7, the results showed that, crystal form under this condition
B sample is stablized.
3.2 high wet stabilities
Crystal form B Cyproconazole sample in embodiment 2 is placed under 90 ± 5% damp conditions, by sample after 5 days and 10 days
It takes out and carries out XRPD test, to investigate sample to the stability of crystal form of humidity.As shown in Figure 8, Figure 9, the results showed that, under this condition
Crystal form B sample is stablized.
3.3 light durability
Crystal form B Cyproconazole sample in embodiment 2 is placed under 4500 ± 500 lux intensities of illumination, after 5 days and 10 days
Sample is taken out and carries out XRPD test, to investigate sample to the stability of crystal form of illumination.As shown in Figure 10, Figure 11, the results showed that,
Crystal form B sample is stablized under this condition.
The solubility of embodiment 4. crystal form A and crystal form B compares
It weighs excessive crystal form A and crystal form B is suspended in methanol, after concussion for 24 hours, test solubility, test knot using UPLC
Fruit is as shown in table 3 below:
The solubility of table 3 crystal form B and crystal form A
| Crystal form | Solubility (mg/ml) |
| Crystal form A | 200 |
| Crystal form B | 226 |
The preparation of 5. crystal form C Cyproconazole of embodiment
50mg compound of formula I is weighed in sample bottle, the dissolution of 0.5ml 2- butanone is added, adds the n-hexane of 2.5ml,
Crystal form C Cyproconazole is obtained after standing volatilization, vacuum drying.
Gained crystal form C is polymorphic, and XRD spectrum is substantially as shown in figure 12, and diffraction peak data is substantially as shown in table 4 below.
The XRD data of 4 crystal form C of table
The DSC map of crystal form C is substantially as shown in figure 13, and wherein endothermic peak corresponds to fusion and decomposition process, in 103-109 DEG C of model
There is endothermic peak in enclosing.
The TGA map of crystal form C is substantially as shown in figure 14, substantially without weightlessness before decomposition.
6. crystal form C Cyproconazole study on the stability of embodiment
6.1 high-temperature stability
Crystal form C Cyproconazole sample in embodiment 5 is placed in 60 ± 2 DEG C of baking ovens, is taken out sample after 5 days and 10 days
XRPD test is carried out, to investigate sample to the stability of crystal form of temperature.As shown in Figure 15, Figure 16, the results showed that, it is brilliant under this condition
Type C sample is stablized.
6.2 high wet stabilities
Crystal form C Cyproconazole sample in embodiment 5 is placed under 90 ± 5% damp conditions, by sample after 5 days and 10 days
It takes out and carries out XRPD test, to investigate sample to the stability of crystal form of humidity.As shown in Figure 17, Figure 18, the results showed that, this condition
Lower crystal form C sample is stablized.
6.3 light durability
Crystal form C Cyproconazole sample in embodiment 5 is placed under 4500 ± 500lux intensity of illumination, after 5 days and 10 days
Sample is taken out and carries out XRPD test, to investigate sample to the stability of crystal form of illumination.As shown in Figure 19, Figure 20, the results showed that,
Crystal form C sample is stablized under this condition.
The solubility of embodiment 7. crystal form A and crystal form C compares
It weighs excessive crystal form A and crystal form C is suspended in methanol, after concussion for 24 hours, test solubility, test knot using UPLC
Fruit is as follows:
The solubility of table 5 crystal form C and crystal form A
| Crystal form | Solubility (mg/ml) |
| Crystal form A | 200 |
| Crystal form C | 222 |
All references mentioned in the present invention is incorporated herein by reference, independent just as each document
It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can
To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims
It encloses.
Claims (10)
1. a kind of crystal of compound of formula I,
2. crystal as described in claim 1, which is characterized in that the crystal is selected from the group: crystal form B and crystal form C.
3. crystal as described in claim 1, which is characterized in that the crystal is crystal form B, and the x-ray powder of the crystal form B spreads out
Penetrate map include 3 or 3 or more 2 θ values selected from the group below: 6.5 ± 0.2 °, 9.1 ± 0.2 °, 13.0 ± 0.2 °, 16.4 ±
0.2°、18.1±0.2°、18.4±0.2°、19.4±0.2°、20.8±0.2°、25.5±0.2°、26.1±0.2°、29.2±
0.2°。
4. crystal as claimed in claim 3, which is characterized in that the crystal form B also has feature selected from the group below:
(1) X-ray powder diffraction pattern of the crystal form B is basic as Fig. 1 is characterized；And/or
(2) the TGA figure of the crystal form B is basic as Fig. 3 is characterized；And/or
(3) the DSC figure of the crystal form B has endothermic peak within the scope of 101-109 DEG C；And/or
(4) the DSC figure of the crystal form B is basic as Fig. 2 is characterized；And/or
(5) the crystal form B purity is greater than 95%.
5. crystal as described in claim 1, which is characterized in that the crystal is crystal form C, and the x-ray powder of the crystal form C spreads out
Penetrate map include 3 or 3 or more 2 θ values selected from the group below: 6.4 ± 0.2 °, 9.0 ± 0.2 °, 11.0 ± 0.2 °, 12.9 ±
0.2°、15.6±0.2°、18.0±0.2°、21.2±0.2°、24.1±0.2°。
6. crystal as claimed in claim 5, which is characterized in that the crystal form C also has feature selected from the group below:
(1) X-ray powder diffraction pattern of the crystal form C is basic as Figure 12 is characterized；And/or
(2) the TGA figure of the crystal form C is basic as Figure 14 is characterized；And/or
(3) the DSC figure of the crystal form C has endothermic peak within the scope of 103-109 DEG C；And/or
(4) the DSC figure of the crystal form C is basic as Figure 13 is characterized；And/or
(5) the crystal form C purity is greater than 95%.
7. a kind of composition pesticide, the composition includes:
(a) such as crystal as claimed in any one of claims 1 to 6, and (b) acceptable carrier in Pesticide Science.
8. a kind of method for preparing crystal described in claim 1, wherein the crystal is crystal form B, and the method includes steps
It is rapid:
(i) compound of formula I is provided in the first solution of the first solvent；
(ii) the second solvent is added into the first above-mentioned solution, forms the second solution, and crystallization processing is carried out to the second solution,
To form crystal as claimed in claim 3, i.e. crystal form B.
9. a kind of method for preparing crystal described in claim 1, wherein the crystal is crystal form C, and the method includes steps
It is rapid:
(i) compound of formula I is provided in the first solution of the first solvent；
(ii) the second solvent is added into the first above-mentioned solution, forms the second solution, and crystallization processing is carried out to the second solution,
To form crystal described in claim 5, i.e. crystal form C.
10. the purposes of a kind of crystal described in claim 1 or composition pesticide as claimed in claim 7, for preventing or controlling
Disease processed；Or for inhibiting harmful microorganism on agricultural, forestry or gardening.
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