CN116082245A - Enconazole crystal and preparation method and application thereof - Google Patents
Enconazole crystal and preparation method and application thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 15
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- 238000001228 spectrum Methods 0.000 claims abstract description 6
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- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 15
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- 238000000034 method Methods 0.000 claims description 12
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- 238000010438 heat treatment Methods 0.000 claims description 10
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 10
- 239000012279 sodium borohydride Substances 0.000 claims description 10
- VYWPPRLJNVHPEU-UHFFFAOYSA-N 2-chloro-1-(2,4-dichlorophenyl)ethanone Chemical compound ClCC(=O)C1=CC=C(Cl)C=C1Cl VYWPPRLJNVHPEU-UHFFFAOYSA-N 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 8
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- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 claims description 5
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- 230000035484 reaction time Effects 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 230000001105 regulatory effect Effects 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- LEZWWPYKPKIXLL-UHFFFAOYSA-N 1-{2-(4-chlorobenzyloxy)-2-(2,4-dichlorophenyl)ethyl}imidazole Chemical compound C1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 LEZWWPYKPKIXLL-UHFFFAOYSA-N 0.000 claims description 3
- 229960003913 econazole Drugs 0.000 claims description 3
- DSFHXKRFDFROER-UHFFFAOYSA-N 2,5,8,11,14,17-hexaoxabicyclo[16.4.0]docosa-1(22),18,20-triene Chemical compound O1CCOCCOCCOCCOCCOC2=CC=CC=C21 DSFHXKRFDFROER-UHFFFAOYSA-N 0.000 claims description 2
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- PZBPKYOVPCNPJY-UHFFFAOYSA-N 1-[2-(allyloxy)-2-(2,4-dichlorophenyl)ethyl]imidazole Chemical compound ClC1=CC(Cl)=CC=C1C(OCC=C)CN1C=NC=C1 PZBPKYOVPCNPJY-UHFFFAOYSA-N 0.000 description 7
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- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/60—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms
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- A61P31/02—Local antiseptics
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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Abstract
The invention discloses an Enconazole crystal and a preparation method and application thereof. The main peak 2 theta of the X-ray diffraction spectrum of the Enconazole crystal is 13.64 degrees+/-0.2 degrees, 15.14 degrees+/-0.2 degrees, 20.94 degrees+/-0.2 degrees, 23.02 degrees+/-0.2 degrees, 23.48 degrees+/-0.2 degrees, 24.72 degrees+/-0.2 degrees, 25.60 degrees+/-0.2 degrees and 28.72 degrees+/-0.2 degrees. The invention improves the preparation process of the Enconazole bulk drug, uses crown ether as a catalyst, uses NaOH to replace dangerous NaH as alkali, improves the reaction yield and reduces the use of a high-boiling solvent DMF. The prepared En Kangjing type has good stability on the basis of keeping bactericidal activity, and is suitable for further processing into pharmaceutical preparations. Meanwhile, the preparation method is simple and easy to implement, has good reproducibility and is suitable for mass production.
Description
Technical Field
The invention belongs to the technical field of pharmacy, and particularly relates to an Enconazole crystal and a preparation method and application thereof.
Background
Enilconazol (ECZ) is a broad-spectrum antifungal agent developed by Poisson (Janssen) Inc. of Belgium. The Enconazole structurally belongs to imidazole bactericides, and has higher bactericidal activity on dermatophytes and aspergillus of different animals clinically, in particular to steam state. The action mechanism of the Enconazole is to interfere the biosynthesis of fungal cell membranes, the bioavailability of the Enconazole after the Enconazole is orally taken by animals is high, the Enconazole has no adverse effect on animal reproduction, and no teratogenesis, carcinogenesis and delayed neurotoxicity, and is an efficient green veterinary drug.
The three-step method adopted by the original research process patent GB2063857 (corresponding US 3658813) of Yansen is moderate in process yield, but the final step uses DMF as a solvent NaH as alkali, the reaction conditions are severe, more alkaline waste water is produced by post-treatment, and the environmental pollution is great.
Enconazole is a pale yellow to brown yellow solid, is slightly soluble in water, and is easily dissolved in solvents such as acetone, dichloromethane, methanol, toluene and the like. Due to the solubility problem, the Enconazole needs to be prepared into a proper dosage form by adding auxiliary materials to improve the permeability and the bioavailability. The crystal forms of the raw materials have different degrees of influence on the stability, permeability and bioavailability of the medicine, the acquisition of crystal form data and corresponding properties are necessary, and the application potential is huge especially in the aspect of preparation. To date, no relevant data has been reported and studied on the crystalline form of Enconazole.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide an Enconazole crystal, a preparation method and application thereof, wherein the method has good repeatability and high yield, and the prepared crystal form improves the stability on the basis of keeping the sterilizing activity of Enconazole.
The aim of the invention is achieved by the following technical scheme:
an crystalline form of Enconazole having main peaks 2 theta of 13.64 DEG + -0.2 DEG, 15.14 DEG + -0.2 DEG, 20.94 DEG + -0.2 DEG, 23.02 DEG + -0.2 DEG, 23.48 DEG + -0.2 DEG, 24.72 DEG + -0.2 DEG, 25.60 DEG + -0.2 DEG, and 28.72 DEG + -0.2 DEG in an X-ray diffraction spectrum.
The preparation method of the Enconazole crystal comprises the following steps:
(1) Adding alpha, 2, 4-trichloroacetophenone and imidazole into a solvent, heating the mixture to react, removing the solvent by screwing, adding dichloromethane, washing with water, and removing the dichloromethane by screwing; adding methanol, adding concentrated nitric acid to form salt, filtering, drying, regulating the pH value of the system to 8-9, filtering, and drying to obtain an intermediate ECZ1;
(2) Dissolving an intermediate ECZ1 in a solvent, adding sodium borohydride in batches, stirring at room temperature, refluxing, screwing off the solvent, adding a hydrochloric acid solution, adjusting the pH of the system to 8-9, filtering, and drying to obtain an intermediate ECZ2;
(3) Mixing an N, N-dimethylformamide solution of an intermediate ECZ2 with a crown ether catalyst, sodium hydroxide and a tetrahydrofuran solution of propylene chloride, heating to 60-100 ℃ for reaction, adding diethyl ether after the reaction is finished, washing for several times with water, removing diethyl ether by screwing, adding methanol, adding concentrated nitric acid dropwise to form salt, filtering and drying, regulating the pH of the system to 8-9, filtering and drying to obtain amorphous ECZ;
(4) Adding amorphous ECZ into solvent, heating to dissolve, cooling to room temperature for crystallization, filtering, and drying to obtain yellowish Enconazole crystal.
Preferably, the molar ratio of α,2, 4-trichloroacetophenone to imidazole in step (1) is 1:1 to 10.
Preferably, the solvent in the step (1) is methanol or ethanol.
Preferably, the heating reaction time in the step (1) is 2-6 hours, and the heating reaction temperature is 60-100 ℃.
Preferably, the molar ratio of the addition amount of the concentrated nitric acid in the step (1) to the alpha, 2, 4-trichloroacetophenone is 2-1: 1.
preferably, the solvent in the step (2) is methanol or ethanol.
Preferably, the molar ratio of the added amount of sodium borohydride to ECZ1 in the step (2) is 0.5-2: 1.
preferably, the stirring time at room temperature in the step (2) is 1h, and the refluxing time is 1h.
Preferably, the molar ratio of the addition amount of the crown ether catalyst to ECZ2 in the step (3) is 0.1-1: 1.
preferably, the crown ether catalyst of step (3) is 18-crown-6 or benzo 18-crown-6.
Preferably, the molar ratio of the addition amount of the sodium hydroxide to the ECZ2 in the step (3) is 1-10: 1.
preferably, the molar ratio of the addition amount of the propylene chloride to the ECZ2 in the step (3) is 1-5: 1.
preferably, the reaction time in the step (3) is 12-48 hours.
Preferably, the molar ratio of the adding amount of the concentrated nitric acid to ECZ2 in the step (3) is 2-1: 1.
preferably, the solvent in the step (4) is one or a mixed solution of toluene, acetone, methanol and ethanol.
The application of the Enconazole crystal in preparing Enconazole emulsifiable concentrates, suspending agents and fumigants.
Compared with the prior art, the invention has the beneficial effects that:
(1) The invention improves the preparation process of the Enconazole bulk drug, uses crown ether as a catalyst, uses NaOH to replace dangerous NaH as alkali, improves the reaction yield and reduces the use of a high-boiling solvent DMF.
(2) The En Kangjing type prepared by the invention has good stability on the basis of keeping bactericidal activity, and is suitable for further processing into pharmaceutical preparations.
(3) The preparation method of the crystal form is simple, convenient and easy to implement, has good reproducibility, can obtain the Enconazole with uniform crystal form with higher yield, and is convenient for large-scale production.
Drawings
Fig. 1 is a powder X-ray diffraction pattern of amorphous form of econazole prepared in example 1.
FIG. 2 is a powder X-ray diffraction pattern of pale yellow crystals prepared in example 1.
FIG. 3 is a powder X-ray diffraction pattern of pale yellow crystals prepared in example 2.
FIG. 4 is a powder X-ray diffraction pattern of pale yellow crystals prepared in example 3.
FIG. 5 is a gas chromatogram of an amorphous solid in a stability test.
FIG. 6 is a gas chromatogram of a crystal in a stability test.
FIG. 7 is a schematic illustration of the reaction scheme of the present invention.
Detailed Description
The present invention will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
The concentration of the concentrated nitric acid is 65-68%.
Example 1
A preparation method of an Enconazole crystal comprises the following steps:
(1) Alpha, 2, 4-trichloroacetophenone (111.7 g,0.5 mol) and excess imidazole (102.1 g,1.5 mol) were added to methanol (250 mL), heated to 60℃and reacted for 3 hours. The solvent was removed by spinning, dichloromethane (300 mL) was added and the mixture was washed three times with water. The dichloromethane was removed by spinning, methanol (250 mL) was added, concentrated nitric acid (40.8 g) was added dropwise to form a salt, which was filtered and dried. Adjusting pH to 8-9 with ammonia water, filtering, and drying to obtain intermediate ECZ1.
(2) Intermediate ECZ1 (102.0 g,0.4 mol) was dissolved in methanol (600 mL), sodium borohydride (9.1 g,0.24 mol) was added in portions, stirred at room temperature for 1 hour, and refluxed for 1 hour. The solvent was removed by spinning, 10% hydrochloric acid (300 mL) was added and the excess sodium borohydride was quenched. Adjusting pH to 8-9 with ammonia water, filtering, and drying to obtain intermediate ECZ2.
(3) To a solution of intermediate ECZ2 (77.1 g,0.3 mol) in DMF (50 mL) was added a solution of 18-crown-6 (7.93 g,0.03 mol), sodium hydroxide (24.0 g,0.6 mol) and propylene chloride (34.4 g,0.45 mol) in tetrahydrofuran (250 mL), which was heated to 60℃and reacted for 48 hours. Diethyl ether (500 mL) was added and the mixture was washed five times with water. The solvent was removed by spinning, methanol (30 mL) was added, concentrated nitric acid was added dropwise to form a salt, and the salt was filtered and dried. Adjusting pH to 8-9 with ammonia water, filtering, and drying to obtain amorphous ECZ.
The obtained powder was characterized by X-ray diffraction spectrum, using X-ray diffractometer, cu target, tube voltage 40kV, tube current 40mA, of the company X' Pert PRO of the family Panalytical B.V. of the Netherlands. The powder X-ray diffraction diagram is shown in figure 1, and the obtained product is mainly amorphous Enconazole as shown in figure 1.
(4) 100g of amorphous Enconazole obtained in the above-mentioned manner is added into 50mL of ethanol, heated to 60 ℃ for dissolution, cooled to room temperature for crystallization. Filtering and drying to obtain pale yellow crystal.
The powder obtained was characterized by X-ray diffraction spectrum, and the powder X-ray diffraction pattern is shown in fig. 2. The main peaks and their relative intensities in the obtained diffraction patterns are shown in table 1.
TABLE 1X-ray diffraction pattern of the target product prepared in example 1
Example 2
A preparation method of an Enconazole crystal comprises the following steps:
(1) Alpha, 2, 4-trichloroacetophenone (111.7 g,0.5 mol) and excess imidazole (68.1 g,1.0 mol) were added to methanol (250 mL), heated to 70℃and reacted for 4 hours. The solvent was removed by spinning, dichloromethane (300 mL) was added and the mixture was washed three times with water. Methylene chloride was removed, methanol (250 mL) was added, concentrated nitric acid (39.5 g) was added dropwise to form a salt, and the salt was filtered and dried. Adjusting pH to 8-9 with ammonia water, filtering, and drying to obtain intermediate ECZ1.
(2) Intermediate ECZ1 (102.0 g,0.4 mol) was dissolved in methanol (600 mL), sodium borohydride (7.6 g,0.2 mol) was added in portions, stirred at room temperature for 1 hour, and refluxed for 1 hour. The solvent was removed by spinning, 10% hydrochloric acid (250 mL) was added and the excess sodium borohydride was quenched. Adjusting pH to 8-9 with ammonia water, filtering, and drying to obtain intermediate ECZ2.
(3) To a solution of intermediate ECZ2 (77.1 g,0.3 mol) in DMF (50 mL) was added a solution of 18-crown-6 (39.6 g,0.15 mol), sodium hydroxide (60.0 g,1.5 mol) and propylene chloride (45.9 g,0.6 mol) in tetrahydrofuran (250 mL), which was heated to 60℃and reacted for 24 hours. Diethyl ether (500 mL) was added and the mixture was washed five times with water. The solvent was removed by spinning, methanol (30 mL) was added, concentrated nitric acid was added dropwise to form a salt, and the salt was filtered and dried. Adjusting pH to 8-9 with ammonia water, filtering, and drying to obtain amorphous ECZ.
(4) 100g of amorphous Enconazole obtained in the above was added to 45mL of acetone, heated to 45℃for dissolution, cooled to room temperature for crystallization. Filtering and drying to obtain pale yellow crystal.
The powder obtained was characterized by X-ray diffraction spectrum, and the powder X-ray diffraction pattern is shown in fig. 3. The main peaks and their relative intensities in the obtained diffraction patterns are shown in table 2.
TABLE 2X-ray diffraction pattern of the target product prepared in example 2
Example 3
A preparation method of an Enconazole crystal comprises the following steps:
(1) Alpha, 2, 4-trichloroacetophenone (111.7 g,0.5 mol) and excess imidazole (170.2 g,2.5 mol) were added to methanol (250 mL), heated to 60℃and reacted for 6 hours. The solvent was removed by spinning, dichloromethane (300 mL) was added and the mixture was washed three times with water. Methylene chloride was removed, methanol (250 mL) was added, concentrated nitric acid (42.3 g) was added dropwise to form a salt, and the salt was filtered and dried. Adjusting pH to 8-9 with ammonia water, filtering, and drying to obtain intermediate ECZ1.
(2) Intermediate ECZ1 (102.0 g,0.4 mol) was dissolved in methanol (600 mL), sodium borohydride (30.3 g,0.8 mol) was added in portions, stirred at room temperature for 1 hour, and refluxed for 1 hour. The solvent was removed by spinning, 10% hydrochloric acid (600 mL) was added and the excess sodium borohydride was quenched. Adjusting pH to 8-9 with ammonia water, filtering, and drying to obtain intermediate ECZ2.
(3) To a solution of intermediate ECZ2 (77.1 g,0.3 mol) in DMF (50 mL) was added a solution of 18-crown-6 (79.3 g,0.3 mol), sodium hydroxide (60.0 g,1.5 mol) and propylene chloride (68.9 g,0.9 mol) in tetrahydrofuran (250 mL), which was heated to 60℃and reacted for 12 hours. Diethyl ether (500 mL) was added and the mixture was washed five times with water. The solvent was removed by spinning, methanol (30 mL) was added, concentrated nitric acid was added dropwise to form a salt, and the salt was filtered and dried. Adjusting pH to 8-9 with ammonia water, filtering, and drying to obtain amorphous ECZ.
(4) 100g of amorphous Enconazole obtained in the above was added to 40mL of toluene, heated to 90℃for dissolution, and cooled to room temperature for crystallization. Filtering and drying to obtain pale yellow crystal.
The powder obtained was characterized by X-ray diffraction spectra, the powder X-ray diffraction pattern being shown in figure 4. The main peaks and their relative intensities in the obtained diffraction patterns are shown in table 3.
TABLE 3X-ray diffraction pattern of the target product prepared in example 3
Stability test:
the stability test was performed on amorphous solids and crystals before and after crystallization in example 1, as follows:
the samples were sealed in sample bottles, stored in an incubator at 54 ℃ + -2deg.C for 14 days, placed in a dry box, cooled to room temperature, and the purity of the Enconazole was checked by GC. The results showed that the purity of the amorphous solid was reduced to 95.0% (as shown in fig. 5), while the purity of the crystal was 96.8% (as shown in fig. 6). The statistical results are shown in Table 4.
Table 4 crystal purity statistics table
The above-described embodiments of the present invention do not limit the scope of the present invention. Any other corresponding changes and modifications made in accordance with the technical idea of the present invention shall be included in the scope of the claims of the present invention.
Claims (10)
1. An crystalline form of Enconazole characterized in that the main peak 2 theta in the X-ray diffraction spectrum is 13.64 DEG + -0.2 DEG, 15.14 DEG + -0.2 DEG, 20.94 DEG + -0.2 DEG, 23.02 DEG + -0.2 DEG, 23.48 DEG + -0.2 DEG, 24.72 DEG + -0.2 DEG, 25.60 DEG + -0.2 DEG and 28.72 DEG + -0.2 deg.
2. The method for preparing the Enconazole crystal according to claim 1, comprising the steps of:
(1) Adding alpha, 2, 4-trichloroacetophenone and imidazole into a solvent, heating the mixture to react, removing the solvent by screwing, adding dichloromethane, washing with water, and removing the dichloromethane by screwing; adding methanol, adding concentrated nitric acid to form salt, filtering, drying, regulating the pH value of the system to 8-9, filtering, and drying to obtain an intermediate ECZ1;
(2) Dissolving an intermediate ECZ1 in a solvent, adding sodium borohydride in batches, stirring at room temperature, refluxing, screwing off the solvent, adding a hydrochloric acid solution, adjusting the pH of the system to 8-9, filtering, and drying to obtain an intermediate ECZ2;
(3) Mixing an N, N-dimethylformamide solution of an intermediate ECZ2 with a crown ether catalyst, sodium hydroxide and a tetrahydrofuran solution of propylene chloride, heating to 60-100 ℃ for reaction, adding diethyl ether after the reaction is finished, washing for several times with water, removing diethyl ether by screwing, adding methanol, adding concentrated nitric acid dropwise to form salt, filtering and drying, regulating the pH of the system to 8-9, filtering and drying to obtain amorphous ECZ;
(4) Adding amorphous ECZ into solvent, heating to dissolve, cooling to room temperature for crystallization, filtering, and drying to obtain yellowish Enconazole crystal.
3. The method for preparing the crystal of Enconazole according to claim 2, wherein the molar ratio of said α,2, 4-trichloroacetophenone to imidazole in step (1) is 1:1 to 10;
the molar ratio of the adding amount of the sodium borohydride to ECZ1 in the step (2) is 0.5-2: 1.
4. the method for preparing the Enconazole crystal according to claim 2, wherein the molar ratio of the addition amount of said crown ether catalyst to ECZ2 in step (3) is 0.1-1: 1, a step of;
the molar ratio of the addition amount of the sodium hydroxide to the ECZ2 in the step (3) is 1-10: 1.
5. the method for preparing the crystalline of Enconazole according to any one of claims 2-4, wherein the molar ratio of said propylene chloride added in step (3) to ECZ2 is 1-5: 1, a step of;
the molar ratio of the adding amount of the concentrated nitric acid to ECZ2 in the step (3) is 2-1: 1.
6. the method for preparing the Enconazole crystal according to claim 5, wherein the heating reaction time in step (1) is 2-6 hours, and the heating reaction temperature is 60-100 ℃;
the molar ratio of the adding amount of the concentrated nitric acid to the alpha, 2, 4-trichloroacetophenone in the step (1) is 2-1: 1.
7. the method for preparing a crystal of Enconazole according to any one of claims 2-4, wherein said solvent in step (1) is methanol or ethanol;
the solvent in the step (2) is methanol or ethanol.
8. The method for preparing the crystal of Enconazole according to claim 7, wherein said crown ether catalyst in step (3) is 18-crown-6 or benzo 18-crown-6;
the solvent in the step (4) is one or a mixed solution of toluene, acetone, methanol and ethanol.
9. The method for preparing a crystal of Enconazole according to claim 8, wherein said stirring time at room temperature in step (2) is 1h, and said refluxing time is 1h;
the reaction time in the step (3) is 12-48 h.
10. The use of the crystalline form of econazole of claim 1 for the preparation of emulsifiable concentrates, suspensions and smokable media of econazole.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4380546A (en) * | 1980-05-19 | 1983-04-19 | Basf Aktiengesellschaft | Azole compounds, their preparation, their use for crop treatment, and agents for this purpose |
| CN102180835A (en) * | 2011-03-02 | 2011-09-14 | 合肥华方医药科技有限公司 | Synthesis of imidazole aromatic alcohol derivatives and preparations of imidazole aromatic alcohol derivatives |
| CN104610155A (en) * | 2015-02-06 | 2015-05-13 | 临海市利民化工有限公司 | Preparation method for imazalil |
| CN108191765A (en) * | 2017-12-26 | 2018-06-22 | 湖北回盛生物科技有限公司 | A kind of preparation method of enilconazole |
| CN110437154A (en) * | 2019-09-10 | 2019-11-12 | 武汉川泰科技有限公司 | A kind of preparation method of enilconazole bulk pharmaceutical chemicals |
| CN114409600A (en) * | 2022-01-19 | 2022-04-29 | 武汉回盛生物科技股份有限公司 | Synthetic method of enilconazole |
| CN115433132A (en) * | 2022-10-20 | 2022-12-06 | 武汉回盛生物科技股份有限公司 | Enconazole crystal form, preparation method and application |
-
2022
- 2022-12-26 CN CN202211682523.XA patent/CN116082245A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4380546A (en) * | 1980-05-19 | 1983-04-19 | Basf Aktiengesellschaft | Azole compounds, their preparation, their use for crop treatment, and agents for this purpose |
| CN102180835A (en) * | 2011-03-02 | 2011-09-14 | 合肥华方医药科技有限公司 | Synthesis of imidazole aromatic alcohol derivatives and preparations of imidazole aromatic alcohol derivatives |
| CN104610155A (en) * | 2015-02-06 | 2015-05-13 | 临海市利民化工有限公司 | Preparation method for imazalil |
| CN108191765A (en) * | 2017-12-26 | 2018-06-22 | 湖北回盛生物科技有限公司 | A kind of preparation method of enilconazole |
| CN110437154A (en) * | 2019-09-10 | 2019-11-12 | 武汉川泰科技有限公司 | A kind of preparation method of enilconazole bulk pharmaceutical chemicals |
| CN114409600A (en) * | 2022-01-19 | 2022-04-29 | 武汉回盛生物科技股份有限公司 | Synthetic method of enilconazole |
| CN115433132A (en) * | 2022-10-20 | 2022-12-06 | 武汉回盛生物科技股份有限公司 | Enconazole crystal form, preparation method and application |
Non-Patent Citations (1)
| Title |
|---|
| 黄永明等: "杀菌剂抑霉唑的合成", 《精细化工》, vol. 12, no. 3, 31 December 1995 (1995-12-31), pages 1 - 3 * |
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