CN108546251A - The novel crystal forms of prothioconazoles - Google Patents
The novel crystal forms of prothioconazoles Download PDFInfo
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- CN108546251A CN108546251A CN201810280882.XA CN201810280882A CN108546251A CN 108546251 A CN108546251 A CN 108546251A CN 201810280882 A CN201810280882 A CN 201810280882A CN 108546251 A CN108546251 A CN 108546251A
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- Prior art keywords
- prothioconazoles
- crystal forms
- toluene
- crystallization
- novel crystal
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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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
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention discloses a kind of novel crystal forms of prothioconazoles --- the crystallization toluene solvate of prothioconazoles; the compound is usually than amorphous stabilization; them are made to can be used for the long-term preservation of the solid matter; and comparing II types crystalline solid and the more easily dissolving of crystallization DMSO solvates for the foreign patent protection that compares, this so that they are more more useful in terms of dispenser than other crystal types for certain purposes.
Description
Technical field
The present invention relates to a kind of new solid forms more particularly to rosickyite bacterium of new type bactericide prothioconazoles
The crystallization toluene solvate of the novel crystal forms of azoles --- prothioconazoles.
Background technology
Its molecule of prothioconazoles crystal is recorded in earliest in US5789430 and related patents bulletin.Two kinds of prothioconazoles
Crystalline form I types and II types, II types are published in patent CN1681390B, and the crystallization DMSO solvates of prothioconazoles exist
It is on the books in CN102083802.
The different crystal forms of general important molecule usually have different property, in the case of can be used for difference.Such as
Crystal type makes them can be used for the long-term preservation of the solid matter usually than amorphous stabilization, and amorphous usually compares crystallinity
It more easily dissolves, this so that they are more more useful in terms of dispenser than crystal type for certain purposes.
The crystal form of compound influences its physicochemical property, such as fusing point, solubility or dissolution rate.It is therefore advantageous that can
To obtain that there is the crystal form of a certain range of physicochemical property, to may make validity to optimize.Therefore in some applications, example
If it may be advantageous for the lower form of more stable but solubility, and the form of higher-energy, more high-dissolvability can be answered at other
Different benefits is provided with middle.
Invention content
It is an object of the invention to overcome the deficiencies of the prior art and provide a kind of novel crystal forms of prothioconazoles, to provide
A kind of replacement crystal form of new stabilization.
The present invention is achieved by the following technical solutions：
A kind of novel crystal forms of prothioconazoles, the crystal form are embodied by the crystallization toluene solvate form of prothioconazoles, institute
It states solvate to be determined based on its diffraction pattern by x-ray powder diffraction, be radiated using Cu-K αAt 25 DEG C
The X-ray powder diffraction figure of record, display is using 2 θ values or as interplanar distanceThe feature of expression reflects, such as following table
Shown, crystal form D includes at least three, and generally at least 5, specifically at least seven, especially whole following features reflect.
Further, the crystallization toluene solvate of above-mentioned prothioconazoles by by prothioconazoles in toluene solvant or toluene
It is formed with being crystallized in the mixed solution of water.The temperature of crystallization is for 120 DEG C hereinafter, preferably 80 DEG C hereinafter, more preferably 60 DEG C
Hereinafter, to realize slow crystallization rate.
The preparation process of the crystallization toluene solvant of above-mentioned prothioconazoles includes：
(1) prothioconazoles of form known are added in toluene solvant or the mixed solution of toluene and water and are dissolved；
(2) it crystallizes；The solution for including the 1. cooling prothioconazoles containing dissolving, is crystallized；Or 2. to containing dissolving
Being added in the solution of prothioconazoles reduces the solvent of solubility, such as water；Or 3. concentration contains the solution of the prothioconazoles of dissolving；Or
3. 1. any combination mode or other common method for crystallising etc.；Further, cooling speed is in 2-8 DEG C/min.
Further, suitable concentration of the prothioconazoles of the form known in the solution for crystallization is 100-
150g/L, the selection of suitable concentration depend on the property and solution temperature of the organic solvent of selection, can be by people in the art
Member determines according to specific experiment.
Further, the purity of the prothioconazoles of the form known is 90% or more, preferably 92% or more, further
Preferably 95% or more, i.e., be toluene solvant toluene impurities content based on prothioconazoles existing for the dissolving in solvent not
More than 10%, preferably no more than 8%, further preferably it is no more than 5%.
Further, the prothioconazoles of the form known be selected from armorphous prothioconazoles or different crystal forms mixture,
Or the single crystal form and its mixture of the mixture or prothioconazoles of amorphous and crystallization prothioconazoles.Such as：Pass through chemical reaction
The obtained reaction mixture containing prothioconazoles；In toluene solvant or at least partly, preferably at least 40% by suitable crystalline
It is reacted and is handled in the solvent mixture of solvent composition, remove excessive reagent and any existing catalyst and any
There are the prothioconazoles mixture for other crystal forms that improper solvent such as water etc. prepares, other crystal forms here refer to and this hair
The different other known crystal form of bright crystal form；The solution of prothioconazoles is prepared by the chemical reaction of the appropriate precursors of prothioconazoles
Deng；It can also use and be similar to method described in the prior art progress cited in background technology, these prior arts are herein
Entirety is as reference.
Further, the temperature of the dissolving be 0-110 DEG C, preferably 50 DEG C or more, but for dissolving temperature cannot
More than the boiling point of solvent, therefore, usually carried out at 50-110 DEG C, further preferably at 50-100 DEG C hereinafter, more preferably in 50-
It is carried out at 60 DEG C.
A kind of prothioconazoles, the prothioconazoles contain at least 90% (weight), the rosickyite of especially at least 95% (weight)
The crystallization toluene solvate of bacterium azoles.
A kind of fungicide, the crystallization toluene solvant of the above-mentioned prothioconazoles containing at least 95% (weight), less than 5%
Ingredient is to be usually used in the additive of fungicide configuration, such as solubilizer, surfactant.The fungicide is in aqueous suspension concentrate
Form or non-aqueous suspension concentrate form or the powder or particle form being dispersed among in water are used to prepare and kill microorganism
Drug.
The present invention has the following advantages compared with prior art：The present invention obtains a kind of prothioconazoles by suitable method
Novel crystal forms --- the crystallization toluene solvate of prothioconazoles, the compound usually than amorphous stabilization, make them can be used for
The long-term preservation of the solid matter, and compare the II types crystalline solid for the foreign patent protection that compares and crystallize DMSO solvates and more hold
Soluble, this so that they are more more useful in terms of dispenser than other crystal types for certain purposes.
Description of the drawings
Fig. 1：The XRPD figures of the toluene solvate of prothioconazoles crystallization.
Specific implementation mode
Following embodiment method therefor is known to those skilled in the art the conventional method of dawn unless otherwise instructed, institute
The materials such as reagent are commercially available products unless otherwise instructed.
The present invention provides a kind of crystallization toluene solvate of prothioconazoles, the solvate can be by X-ray powder
Last diffraction approach is determined based on its diffraction pattern, is radiated using Cu-K αThe X-ray powder diffraction recorded at 25 DEG C
Figure, as shown in Figure 1, it is shown that using 2 θ values or as interplanar distanceAll features reflection indicated：
Wherein, the solvate includes at least three, especially whole usually from least five, especially at least 7
Feature reflects.
The preparation method of the prothioconazoles of above-mentioned crystallization, by the prothioconazoles of form known in toluene solvant or toluene and water
Mixed solution in crystallize and carry out, wherein：
The prothioconazoles of form known：Mixture or amorphous selected from armorphous prothioconazoles or different crystal forms and crystallization
The mixture of prothioconazoles or the single crystal form and its mixture of prothioconazoles.Its purity be 90% or more, preferably 92% with
On, further preferably 95% or more；
Crystallization：The temperature of crystallization be 120 DEG C hereinafter, preferably 80 DEG C hereinafter, more preferably 60 DEG C hereinafter, it is slow to realize
Slow crystallization rate.
Specific steps include：
(1) prothioconazoles of form known are added in suitable organic solvent, at 0-110 DEG C, especially at least 50
Stirring and dissolving at DEG C obtains the solution of the prothioconazoles containing dissolving, the boiling point of solution is no more than for the temperature of dissolving, therefore
Further, carried out at 50-110 DEG C, further preferably at 50-100 DEG C hereinafter, more preferably at 50-60 DEG C stirring and dissolving；
It is known that the suitable concentration of the prothioconazoles of form in organic solvent is preferably 100-150g/L, but not limited to this, depend on
In the property and solution temperature of the organic solvent of selection, can be determined according to specific experiment by those skilled in the art.
(2) it crystallizes；Solution including the 1. cooling prothioconazoles containing dissolving is crystallized, cooling speed 2-8 DEG C/
min；Or the solvent for reducing solubility is 2. added into the solution of the prothioconazoles containing dissolving, such as non-polar organic solvent or
Water；Or 3. concentration contains the solution of the prothioconazoles of dissolving；Or 1.-any combination method 3. or other known crystallization side
Method.
Embodiment 1
160ml toluene is added in 500ml four-hole boiling flasks, and stirring is slowly added to 60g prothioconazoles, and material is evenly dispersed,
Stir 5min；It begins to warm up, is to slowly warm up to 100 DEG C (used time about 12min), the slow dissolved clarification of material, reaction solution is that shallow white is saturating
Bright state maintains 80 DEG C, keeps the temperature 5min；After heat preservation, slow cooling has a small amount of solid material to start to analyse when being cooled to 54 DEG C
Go out, continues to be cooled to 35 DEG C (used time about 30min)；Begin to use ice water cooling to continue to be cooled to 5 DEG C (used time about 5min), and ties up
5 DEG C of heat preservation 40min are held, there are a large amount of white mass to be precipitated；After heat preservation, negative pressure leaching obtains white crystal material, 54 DEG C of material
Baking oven is dried, and is weighed, and content is surveyed；
Submitted sample XRPA collection of illustrative plates, feature based reflection, is confirmed as the toluene solvate of prothioconazoles crystallization.
Embodiment 2
160ml toluene is added in 500ml four-hole boiling flasks, and stirring is slowly added to that the prothioconazoles of 60g are added, and material is equal
5min is stirred in even dispersion；It begins to warm up, is to slowly warm up to 90 DEG C (used time about 12min), the slow dissolved clarification of material, reaction solution is shallow
White clear state maintains 90 DEG C, keeps the temperature 5min；After heat preservation, slow cooling has a small amount of solid material when being cooled to 52 DEG C
Start to be precipitated, continues to be cooled to 35 DEG C (used time about 30min)；Beginning to use ice water cooling to continue to be cooled to 5 DEG C, (used time is about
5min), and 5 DEG C of heat preservation 40min are maintained, there are a large amount of white mass to be precipitated；After heat preservation, negative pressure leaching obtains white crystal object
Material, 50 DEG C of baking oven drying of material, weighs, surveys content；
Submitted sample XRPA collection of illustrative plates, feature based reflection, is confirmed as the toluene solvate of prothioconazoles crystallization.
Embodiment 3
500ml four-hole boiling flasks, are added 120ml toluene, and stirring is slowly added to the prothioconazoles of the other crystal forms of 60g, object
Expect evenly dispersed, stirring 5min；It begins to warm up, is to slowly warm up to 70 DEG C (used time about 12min), the slow dissolved clarification of material, reaction solution
For brownish red pellucidity, 90 DEG C are maintained, keeps the temperature 5min；After heat preservation, slow cooling is added 30mL's when being cooled to 50 DEG C
Water has a small amount of solid material to start to be precipitated, and continues to be cooled to 35 DEG C (used time about 30min)；Ice water cooling is begun to use to continue to drop
Temperature maintains 5 DEG C of heat preservation 30min to 5 DEG C (used time about 5min), has a large amount of white mass to be precipitated；After heat preservation, negative pressure is taken out
Filter, obtains white crystal material, and 50 DEG C of baking oven drying of material weigh, survey content；
Submitted sample XRPA, feature based reflection, is confirmed as the toluene solvate of prothioconazoles crystallization.
Measure the solubility of the various crystal forms of prothioconazoles at 20 DEG C in the water of the buffering of pH=7 using fask oscillating method：I
Type：28ppm；II types：15ppm；It is amorphous:34ppm；DMSO solvates：30ppm；Toluene solvate:38ppm.Further
Measurement obtains essentially identical value, and keeps the relative solubility of same order in all cases.As a result this hair is shown
Bright novel crystal forms have relatively high solubility.
It is a kind of detailed embodiment and specific operating process of the present invention above, is before being with technical solution of the present invention
It puts and is implemented, but protection scope of the present invention is not limited to the above embodiments.
Claims (10)
1. a kind of novel crystal forms of prothioconazoles, which exists in the form of the crystallization toluene solvate of prothioconazoles, feature
Be, in the X-ray powder diffraction figure of the solvate comprising 2 θ values be 10.9 ± 0.2 °, 12.7 ± 0.2 °, 14.8 ± 0.2 °,
15.5±0.2°、16.7±0.2°、17.1±0.2°、18.0±0.2°、18.6±0.2°、19.4±0.2°、20.4±0.2°、
21.2±0.2°、21.6±0.2°、22.5±0.2°、23.2±0.2°、23.6±0.2°、24.4±0.2°、24.9±0.2°、
25.9 ± 0.2 °, 27.3 ± 0.2 °, 30.3 ± 0.2 °, 32.3 ± 0.2 ° or 33.7 ± 0.2 ° of feature reflects at least three.
2. a kind of novel crystal forms of prothioconazoles according to claim 1, which is characterized in that the X-ray powder of the solvate
Last diffraction pattern includes the feature reflection of all 2 θ values as described in claim 1.
3. a kind of novel crystal forms of prothioconazoles according to claim 1, which is characterized in that the crystallization first of the prothioconazoles
Solvate is formed by being crystallized in the mixed solution of toluene solvant or toluene and water by the prothioconazoles of form known.
4. a kind of novel crystal forms of prothioconazoles according to claim 3, which is characterized in that the rosickyite bacterium of the form known
A concentration of 100-150g/L of the azoles in the mixed solution of toluene solvant or toluene and water.
5. a kind of novel crystal forms of prothioconazoles according to claim 3, which is characterized in that the rosickyite bacterium of the form known
The purity of azoles is 90% or more.
6. a kind of novel crystal forms of prothioconazoles according to claim 3, which is characterized in that the rosickyite bacterium of the form known
Azoles is selected from the mixture or amorphous of armorphous prothioconazoles or different crystal forms and crystallizes mixture or the rosickyite bacterium of prothioconazoles
The single crystal form and its mixture of azoles.
7. a kind of novel crystal forms of prothioconazoles according to claim 3, which is characterized in that the rosickyite bacterium of the form known
Solution temperature of the azoles in the mixed solution of toluene solvant or toluene and water is 0-110 DEG C.
8. a kind of prothioconazoles, which is characterized in that the prothioconazoles contain the as described in claim 1 of at least 90% (weight)
Prothioconazoles crystallization toluene solvate.
9. a kind of fungicide, which is characterized in that the crystallization toluene solvant of the above-mentioned prothioconazoles containing at least 95% (weight).
10. a kind of fungicide as claimed in claim 9 is preparing the application in killing microbial medicine.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810280882.XA CN108546251A (en) | 2018-04-02 | 2018-04-02 | The novel crystal forms of prothioconazoles |
| PCT/CN2019/072879 WO2019192246A1 (en) | 2018-04-02 | 2019-01-24 | Novel crystal form of prothioconazole |
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| CN201810280882.XA CN108546251A (en) | 2018-04-02 | 2018-04-02 | The novel crystal forms of prothioconazoles |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110372617A (en) * | 2019-08-08 | 2019-10-25 | 北京颖泰嘉和生物科技股份有限公司 | A kind of Pharmaceutical composition, the crystal form and preparation method thereof of prothioconazoles, application |
| CN110903256A (en) * | 2019-04-23 | 2020-03-24 | 江苏七洲绿色化工股份有限公司 | Crystal form of prothioconazole and preparation method and application thereof |
| CN110981822A (en) * | 2019-11-27 | 2020-04-10 | 海利尔药业集团股份有限公司 | Preparation method of prothioconazole I-type crystal form |
| WO2020174432A1 (en) * | 2019-02-28 | 2020-09-03 | Hikal Limited | Dioxane solvate of prothioconazole and process for preparation thereof |
| CN113444053A (en) * | 2021-06-04 | 2021-09-28 | 安徽久易农业股份有限公司 | Prothioconazole crystal form and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1274349A (en) * | 1997-10-10 | 2000-11-22 | 拜尔公司 | Process for preparing triazoline thione derivatives |
| CN102083802A (en) * | 2008-06-17 | 2011-06-01 | 马克特辛姆化学工厂有限公司 | Crystalline modifications of prothioconazole |
-
2018
- 2018-04-02 CN CN201810280882.XA patent/CN108546251A/en active Pending
-
2019
- 2019-01-24 WO PCT/CN2019/072879 patent/WO2019192246A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1274349A (en) * | 1997-10-10 | 2000-11-22 | 拜尔公司 | Process for preparing triazoline thione derivatives |
| CN102083802A (en) * | 2008-06-17 | 2011-06-01 | 马克特辛姆化学工厂有限公司 | Crystalline modifications of prothioconazole |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020174432A1 (en) * | 2019-02-28 | 2020-09-03 | Hikal Limited | Dioxane solvate of prothioconazole and process for preparation thereof |
| CN110903256A (en) * | 2019-04-23 | 2020-03-24 | 江苏七洲绿色化工股份有限公司 | Crystal form of prothioconazole and preparation method and application thereof |
| CN110903256B (en) * | 2019-04-23 | 2022-04-08 | 江苏七洲绿色化工股份有限公司 | Crystal form of prothioconazole and preparation method and application thereof |
| CN110372617A (en) * | 2019-08-08 | 2019-10-25 | 北京颖泰嘉和生物科技股份有限公司 | A kind of Pharmaceutical composition, the crystal form and preparation method thereof of prothioconazoles, application |
| WO2021022604A1 (en) * | 2019-08-08 | 2021-02-11 | 北京颖泰嘉和生物科技股份有限公司 | Pharmaceutical composition, crystal form of prothioconazole, preparation method and application thereof |
| CN110981822A (en) * | 2019-11-27 | 2020-04-10 | 海利尔药业集团股份有限公司 | Preparation method of prothioconazole I-type crystal form |
| CN113444053A (en) * | 2021-06-04 | 2021-09-28 | 安徽久易农业股份有限公司 | Prothioconazole crystal form and preparation method and application thereof |
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| WO2019192246A1 (en) | 2019-10-10 |
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Application publication date: 20180918 |