CN101565406A - Preparation process for cyproconazole - Google Patents
Preparation process for cyproconazole Download PDFInfo
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- CN101565406A CN101565406A CNA2009100313448A CN200910031344A CN101565406A CN 101565406 A CN101565406 A CN 101565406A CN A2009100313448 A CNA2009100313448 A CN A2009100313448A CN 200910031344 A CN200910031344 A CN 200910031344A CN 101565406 A CN101565406 A CN 101565406A
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Abstract
The invention discloses a preparation process for high-purity cyproconazole, which comprises the following steps that: 1-(4-chlorphenyl)-2-cyclopropyl-1-acetone is taken as a raw material which performs an epoxidation reaction with a sulphur Fourier agent in a weak polarity organic solvent in the presence of alkali; the mixture is subjected to washing and desolvation to obtain 2-(4-chlorphenyl)-2-(1-cyclopropyl ethyl)epoxy ethane which is condensed and desolventized with 1,2,4-triazole in the presence of a catalyst to obtain a crude product; the crude product is directly dissolved into an organic solvent without processing, and the mixture reacts with inorganic acid by heating to generate salts of the cyproconazole; the salts of the cyproconazole are filtered and washed to obtain a salt; and the salt is dried and heated in a ceratin amount of water for deacidifying, and then the salt is subjected to filtration, washing and drying to obtain a finished product with high content and yield. The process is not only economical and environment-friendly, but also has the advantages of high purity and yield of the product, no need of recrystalization for a plurality of times, safe operation, convenience and the like.
Description
Technical field
The present invention relates to a kind of preparation technology of agricultural chemicals cyproconazole.
Background technology
Cyproconazole: (2RS, 3RS, )-2-(4-chloro-phenyl-)-3-cyclopropyl-1-(1H-1,2, the 4-triazol-1-yl) fourth-2-alcohol (hereinafter to be referred as I) is a kind of important triazole bactericidal agent, be sterol demethylation inhibitor, have prevention and therapeutic action, the foliar treatment and the seed that are used for important cash crop spray.
Its structural formula is:
Major impurity is in the synthetic cyproconazole: (2RS, 3RS, )-2-(4-chloro-phenyl-)-3-cyclopropyl-1-(1H-1,3, the 4-triazol-1-yl) fourth-2-alcohol (hereinafter to be referred as II), because (I) He (II) character is close, carrying out simple recrystallization with general solvent is difficult to separate, so general crude product purity has only about 70-80%, and the same viscosity with syrup is very big, be difficult to solidify.Because 1,2,1 bit substituent derivative just has fungicidal activity in the 4-triazole bactericidal agent, so we should control the generation of other position derivative in building-up process as far as possible, improves the quality of products the purpose that reduces production costs so that reach.
The synthesis technique of cyproconazole is U.S. Pat 4664696 (1987), German patent DE 3406993 (1984) and " modern agricultural chemicals " 2004 the 3rd the 4th phases of volume (author: all done comparatively detailed description trip south China), the consumption of but above-mentioned several pieces of documents sulphur Li Yede reagent when epoxidation reaction is all very big, contaminate environment not only, and yield is low, seems very uneconomical.A large amount of Anhydrous potassium carbonate catalysis have been used during condensation reaction, bring many troubles to aftertreatment, especially nearly all used silicagel column to carry out chromatographic separation during final refining, carry out the product that recrystallization has just obtained 95% above content with solvent again, so not only waste time and energy, and seriously having limited the industrial scale of this product, cost is high especially.
Summary of the invention
Technical problem to be solved by this invention is the defective that overcomes above-mentioned prior art, and the industrial preparation process of a kind of product purity height, yield height, cost is low and unit operation is more simple and safe cyproconazole is provided.
Technical conceive of the present invention is as follows: 1,2, and the 4-triazole has two kinds of isomer, 1H-1,2,4-triazole (hereinafter to be referred as IV) and 4H-1,2,4-triazole (hereinafter to be referred as V), wherein IV is comparatively stable, is main isomer; We select to have the generation that good optionally catalyzer is controlled II as far as possible in reaction process.We find when refining in the back, I and II can generate salt with many mineral acids and some organic acid, the salt less stable of II, and these two kinds of salt solubleness in some specific solvent has very big difference, the purpose that we utilize the nature difference of their salt to reach separation and purify just.
The concrete technical scheme that the present invention adopts is: the preparation technology of described cyproconazole comprises the steps:
(1) epoxidation reaction
Select for use in thioether, benzene, toluene or the hexanaphthene any for solvent, with 1-(4-chloro-phenyl-)-2-cyclopropyl-1-acetone is raw material, with sulphur Li Yede reagent epoxidation reaction takes place in the presence of alkali, reaction is after wash and slough 2-(4-chloro-phenyl-)-2-(the 1-cyclopropyl ethyl) oxyethane that obtains behind the solvent;
Wherein: the configuration of sulphur Li Yede reagent is disposed in the presence of the trimethyl carbinol or isopropylcarbinol by thioether and methyl-sulfate and is formed, and the mol ratio of thioether and methyl-sulfate is 1.0～2.5: 1; The consumption of solvent is 1～4 times of 1-(4-chloro-phenyl-)-2-cyclopropyl-1-acetone weight, and the mol ratio of sulphur Li Yede reagent and 1-(4-chloro-phenyl-)-2-cyclopropyl-1-acetone is 1.0～3.6: 1; The mole proportioning of alkali and methyl-sulfate is 2.0～5.2: 1;
(2) condensation reaction
2-(4-chloro-phenyl-)-2-(1-cyclopropyl ethyl) oxyethane that step () is obtained is in polar solvent, controlled temperature is 70～120 ℃, in the presence of catalyzer with 1,2, the 4-triazole carries out condensation reaction, obtains the cyproconazole crude product after the reaction again after sloughing solvent;
Wherein: polar solvent is selected from N, dinethylformamide, N, in N-N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone or the dimethyl sulfoxide (DMSO) any, the consumption of polar solvent are 2～5 times of weight of 2-(4-chloro-phenyl-)-2-(1-cyclopropyl ethyl) oxyethane; Catalyzer is selected from any one in potassium hydroxide, sodium hydroxide, sodium methylate or the sodium ethylate, and catalyst consumption is 0.05～0.3 times of 2-(4-chloro-phenyl-)-2-(1-cyclopropyl ethyl) oxyethane weight; 1,2, the consumption of 4-triazole is 1.0～3.5 molar equivalents of 2-(4-chloro-phenyl-)-2-(1-cyclopropyl ethyl) oxyethane;
(3) salify
The cyproconazole crude product that step (two) is obtained is dissolved in second solvent, and adds mineral acid, finally obtains the salt of cyproconazole;
Wherein: second solvent is selected from a kind of in methylene dichloride, ethylene dichloride, chloroform, toluene, benzene or the Virahol, and the consumption of second solvent is 2～4 times of cyproconazole crude product weight; Mineral acid is selected from any in sulfuric acid, hydrochloric acid, phosphoric acid or the nitric acid, and the consumption of mineral acid is 1.0～3.0 molar equivalents of cyproconazole crude product;
(4) refining
The salt of the cyproconazole that step (three) is obtained adds depickling behind the water, and temperature is controlled at 40～90 ℃, at last after filtration, obtain the cyproconazole finished product after the drying.
Epoxidation reaction temperature is 10～50 ℃ in the above-mentioned steps (), and the reaction times can be 5～30 hours, and the preferred thioether of described solvent, described alkali are potassium hydroxide.
Polar solvent in the above-mentioned steps (two) is preferably N, dinethylformamide, and catalyzer is preferably potassium hydroxide.The time of condensation reaction can be 3～12 hours.Setting-up point is preferably 80～90 ℃.
The preferred hydrochloric acid of mineral acid in the above-mentioned steps (three), preferred ethylene dichloride of second solvent or chloroform; The temperature of salification process is 0～70 ℃, is preferably 50～65 ℃.Salt time can be 2～3 hours.
The weight of the water in the above-mentioned steps (four) is preferably 3～4 times of weight of the salt of cyproconazole.The depickling temperature is 40～90 ℃ in the step (four), and the time is 3～7 hours.
The invention has the beneficial effects as follows: the product purity height, content is more than 97% basically; The yield height, total molar yield about 80%; Product color is good, need not carry out silicagel column purifying, repeatedly recrystallization; Easy to operate and safe, environmental pollution is little, is more suitable for suitability for industrialized production.
Embodiment
The present invention is described further below in conjunction with specific embodiment, but the present invention should not only limit to these embodiment.
Embodiment one
In 500 milliliters of there-necked flasks, add thioether 250 grams, drip the 30 gram trimethyl carbinols, stir then, temperature is added dropwise to 50 gram methyl-sulfates in keeping below 35 ℃, finish, stirred 4 hours, add 1-(4-chloro-phenyl-)-2-cyclopropyl-1-acetone 75 grams then, potassium hydroxide 50 grams are kept about 40 ℃ and were stirred 20 hours, and the sampling analysis raw material should be below 1%, reaction solution is poured in the cold water, stirring and dissolving is complete, static layering, and organic layer washs neutrality with suitable quantity of water, elder generation's normal pressure precipitation, low-boiling point material is taken off in decompression again, obtains about 2-(4-chloro-phenyl-)-2-(1-cyclopropyl ethyl) oxyethane 82 grams content 90% (chromatogram ration analysis, external standard method).
Above-mentioned 2-(4-chloro-phenyl-)-2-(1-cyclopropyl ethyl) oxyethane 82 grams are dissolved into 205 gram exsiccant N, in dinethylformamide (the being called for short DMF) solvent, add 1,2,4-triazole 32 grams, potassium hydroxide powder 7 grams are kept then about 85 ℃ and were stirred 4-5 hour, the sampling analysis raw material is below 3%, stop to stir, filter, then vacuum distillation recovered solvent, remaining object adds chloroform 200 grams, be heated to 50-55 ℃ of dissolving fully, keep the concentrated hydrochloric acid that this temperature drips 40 grams 35% then, dropwised in about 1 hour, stirred then 2 hours, cooling is filtered, the minimum of chloroform washing, drying obtains cyproconazole hydrochloride 92 grams.
Above-mentioned cyproconazole hydrochloride 88 grams add 330 gram distilled water, are heated to 80 ℃ then and stir 3 hours, and cooling is filtered, and filter cake washes neutrality with water, and 60 ℃ of vacuum-dryings obtain 82 gram cyproconazole finished products, white solid, content 97.5%.
Implementation column 2:
In 1000 milliliters of there-necked flasks, add thioether 375 grams, drip 30 gram isopropylcarbinols, stir then, temperature is added dropwise to 75 gram methyl-sulfates in keeping below 25 ℃, finishes, stirred 4 hours, add 1-(4-chloro-phenyl-)-2-cyclopropyl-1-acetone 112 grams then, potassium hydroxide 80 grams are kept about 40 ℃ and were stirred 20 hours, the sampling analysis raw material should be below 1%, reaction solution is poured in the cold water, and stirring and dissolving is complete, static layering, organic layer washs neutrality with suitable quantity of water, elder generation's normal pressure precipitation, low-boiling point material is taken off in decompression again, obtains about 2-(4-chloro-phenyl-)-2-(1-cyclopropyl ethyl) oxyethane 126 grams, content 91.5% (GC, normalization method).
Above-mentioned 2-(4-chloro-phenyl-)-2-(1-cyclopropyl ethyl) oxyethane 126 grams are dissolved into 373 gram exsiccant N, in dinethylformamide (the being called for short DMF) solvent, add 1,2,4-triazole 49 grams, potassium hydroxide powder 7 grams are kept then about 90 ℃ and were stirred 4 hours, the sampling analysis raw material is below 3%, stop to stir, filter, then vacuum distillation recovered solvent, remaining object adds chloroform 335 grams, be heated to 50-55 ℃ of dissolving fully, keep the concentrated hydrochloric acid that this temperature drips 63 grams 35% then, dropwised in about 1 hour, stirred then 2 hours, cooling is filtered, the minimum of chloroform washing, drying obtains cyproconazole hydrochloride 140 grams.
Above-mentioned cyproconazole hydrochloride 140 grams add 560 gram distilled water, are heated to 85 ℃ then and stir 3 hours, and cooling is filtered, and filter cake washes neutrality with water, and 60 ℃ of vacuum-dryings obtain 125 gram cyproconazole finished products, white solid, content 97.2%.
Claims (7)
1, the preparation technology of cyproconazole is characterized in that: comprise the steps:
(1) epoxidation reaction
Select for use in thioether, benzene, toluene or the hexanaphthene any for solvent, with 1-(4-chloro-phenyl-)-2-cyclopropyl-1-acetone is raw material, with sulphur Li Yede reagent epoxidation reaction takes place in the presence of alkali, reaction is after wash and slough 2-(4-chloro-phenyl-)-2-(the 1-cyclopropyl ethyl) oxyethane that obtains behind the solvent;
Wherein: the configuration of sulphur Li Yede reagent is disposed in the presence of the trimethyl carbinol or isopropylcarbinol by thioether and methyl-sulfate and is formed, and the mol ratio of thioether and methyl-sulfate is 1.0～2.5: 1; The consumption of solvent is 1～4 times of 1-(4-chloro-phenyl-)-2-cyclopropyl-1-acetone weight, and the mol ratio of sulphur Li Yede reagent and 1-(4-chloro-phenyl-)-2-cyclopropyl-1-acetone is 1.0～3.6: 1; The mole proportioning of alkali and methyl-sulfate is 2.0～5.2: 1;
(2) condensation reaction
2-(4-chloro-phenyl-)-2-(1-cyclopropyl ethyl) oxyethane that step () is obtained is in polar solvent, controlled temperature is 70～120 ℃, in the presence of catalyzer with 1,2, the 4-triazole carries out condensation reaction, and reaction is after obtain the cyproconazole crude product after sloughing solvent;
Wherein: polar solvent is selected from N, dinethylformamide, N, in N-N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone or the dimethyl sulfoxide (DMSO) any, the consumption of polar solvent are 2～5 times of weight of 2-(4-chloro-phenyl-)-2-(1-cyclopropyl ethyl) oxyethane; Catalyzer is selected from any one in potassium hydroxide, sodium hydroxide, sodium methylate or the sodium ethylate, and catalyst consumption is 0.05～0.3 times of 2-(4-chloro-phenyl-)-2-(1-cyclopropyl ethyl) oxyethane weight; 1,2, the consumption of 4-triazole is 1.0～3.5 molar equivalents of 2-(4-chloro-phenyl-)-2-(1-cyclopropyl ethyl) oxyethane;
(3) salify
The cyproconazole crude product that step (two) is obtained is dissolved in second solvent, and adds mineral acid, finally obtains the salt of cyproconazole;
Wherein: second solvent is selected from a kind of in methylene dichloride, ethylene dichloride, chloroform, toluene, benzene or the Virahol, and the consumption of second solvent is 2～4 times of cyproconazole crude product weight; Mineral acid is selected from any in sulfuric acid, hydrochloric acid, phosphoric acid or the nitric acid, and the consumption of mineral acid is 1.0～3.0 molar equivalents of cyproconazole crude product;
(4) refining
The salt of the cyproconazole that step (three) is obtained adds depickling behind the water, and temperature is controlled at 40～90 ℃, at last after filtration, obtain the cyproconazole finished product after the drying.
2, the preparation technology of cyproconazole according to claim 1 is characterized in that: epoxidation reaction temperature is 10～50 ℃ in the step (), and the preferred thioether of described solvent, described alkali are potassium hydroxide.
3, the preparation technology of cyproconazole according to claim 1 is characterized in that: the polar solvent in the step (two) is preferably N, dinethylformamide, and catalyzer is preferably potassium hydroxide.
4, the preparation technology of cyproconazole according to claim 1 is characterized in that: the preferred hydrochloric acid of mineral acid in the step (three), preferred ethylene dichloride of second solvent or chloroform; The temperature of salification process is 0～70 ℃.
5, the preparation technology of cyproconazole according to claim 1 is characterized in that: the weight of the water in the step (four) is preferably 3～4 times of weight of the salt of cyproconazole.
6, the preparation technology of cyproconazole according to claim 1 or 5 is characterized in that: the depickling temperature is 40～90 ℃ in the step (four), and the time is 3～7 hours.
7, the preparation technology of cyproconazole according to claim 4 is characterized in that: the temperature of step (three) salification process is 50～65 ℃.
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| CN101798290A (en) * | 2010-04-02 | 2010-08-11 | 北京欧凯纳斯科技有限公司 | Method for synthesizing chiral cyproconazole |
| CN101857576A (en) * | 2010-06-18 | 2010-10-13 | 中国科学院上海有机化学研究所 | Simple method for preparing cyproconazole by cyclopropyl methyl ketone |
| CN102382068A (en) * | 2011-08-09 | 2012-03-21 | 湖南大学 | Method for preparing 1-(1, 2, 4-triazole-1-yl)-2-aryl-2-alkanol |
| CN103113203A (en) * | 2013-03-12 | 2013-05-22 | 黑龙江大学 | Synthetic method for 1-(4-chlorphenyl)-2-cyclopropyl-1-acetone |
| CN105523873A (en) * | 2014-10-24 | 2016-04-27 | 中国科学院上海有机化学研究所 | Fluorine-containing three-membered ring compound, preparation method of fluorine-containing three-membered ring compound and preparation method of fluoroalkyl sulfonium salt |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH658654A5 (en) * | 1983-03-04 | 1986-11-28 | Sandoz Ag | AZOLE DERIVATIVES, METHOD FOR THEIR PRODUCTION AND MEANS THAT CONTAIN THESE COMPOUNDS. |
| GB8729107D0 (en) * | 1987-12-14 | 1988-01-27 | Ici Plc | Chemical process |
| GB9126832D0 (en) * | 1991-12-18 | 1992-02-19 | Sandoz Ltd | Separation process |
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| CN101798290B (en) * | 2010-04-02 | 2012-03-07 | 北京欧凯纳斯科技有限公司 | Method for synthesizing chiral cyproconazole |
| CN101857576A (en) * | 2010-06-18 | 2010-10-13 | 中国科学院上海有机化学研究所 | Simple method for preparing cyproconazole by cyclopropyl methyl ketone |
| CN101857576B (en) * | 2010-06-18 | 2012-07-25 | 中国科学院上海有机化学研究所 | Method for preparing cyproconazole by cyclopropyl methyl ketone |
| CN102382068A (en) * | 2011-08-09 | 2012-03-21 | 湖南大学 | Method for preparing 1-(1, 2, 4-triazole-1-yl)-2-aryl-2-alkanol |
| CN102382068B (en) * | 2011-08-09 | 2013-11-27 | 湖南大学 | Method for preparing 1-(1, 2, 4-triazole-1-yl)-2-aryl-2-alkanol |
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| CN105523873B (en) * | 2014-10-24 | 2019-03-15 | 中国科学院上海有机化学研究所 | The preparation method of fluorine-containing ternary cycle compound, preparation method and fluoroalkyl sulfonium salt |
| CN105523873A (en) * | 2014-10-24 | 2016-04-27 | 中国科学院上海有机化学研究所 | Fluorine-containing three-membered ring compound, preparation method of fluorine-containing three-membered ring compound and preparation method of fluoroalkyl sulfonium salt |
| CN105820128B (en) * | 2015-01-05 | 2018-01-19 | 江西华士药业有限公司 | A kind of preparation method of cyproconazole |
| CN105820128A (en) * | 2015-01-05 | 2016-08-03 | 湖南大学 | Preparation method of cyproconazole |
| CN109020905A (en) * | 2017-06-09 | 2018-12-18 | 华东理工大学 | The polymorphic and preparation method thereof of two kinds of Cyproconazoles |
| CN109020905B (en) * | 2017-06-09 | 2022-12-23 | 华东理工大学 | Two polymorphic forms of cyproconazole and preparation method thereof |
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| CN115490645A (en) * | 2022-11-16 | 2022-12-20 | 江苏七洲绿色化工股份有限公司 | Preparation method of 1- (1H-1, 2,4 triazole) -2, 3-bis (4-chlorphenyl) -butan-2-ol |
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