CN112409124B - Preparation method and application of epoxiconazole intermediate - Google Patents
Preparation method and application of epoxiconazole intermediate Download PDFInfo
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- CN112409124B CN112409124B CN202011445745.0A CN202011445745A CN112409124B CN 112409124 B CN112409124 B CN 112409124B CN 202011445745 A CN202011445745 A CN 202011445745A CN 112409124 B CN112409124 B CN 112409124B
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- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
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- C07C29/147—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof
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Abstract
The invention relates to the field of chemical industry, and particularly discloses a preparation method and application of a epoxiconazole intermediate, wherein the preparation method of the epoxiconazole intermediate adopts p-fluorobenzonitrile and o-chlorobenzaldehyde as raw materials, and the p-epoxiconazole key intermediate 2- (4-fluorophenyl) -3- (2-chlorophenyl) chloropropene is obtained through condensation, esterification, reduction and chlorination in sequence.
Description
Technical Field
The invention relates to the field of chemical industry, in particular to a preparation method and application of a epoxiconazole intermediate.
Background
Epoxiconazole (epoxiconazole) is a novel broad-spectrum bactericide with broad spectrum and long lasting period, has preventive and therapeutic effects, and is used as a novel important triazole fluorine-containing bactericide, and the epoxiconazole has the advantages of high efficiency, low toxicity and safety, accords with the residual toxicity standard of the medicament of the world health organization, and has very good market prospect.
Of these, 2- (4-fluorophenyl) -3- (2-chlorophenyl) -chloropropene is the most typical intermediate for synthesizing the bactericide epoxiconazole. Along with the continuous development of technology, people's attention to environmental problems is also continuously increasing. The preparation method of 2- (4-fluorophenyl) -3- (2-chlorophenyl) -chloropropene in the prior art has the following defects in actual use: the existing preparation methods of 2- (4-fluorophenyl) -3- (2-chlorophenyl) -chloropropene mostly have the problems of great environmental pollution, harm to human health and low content and yield of target products. For example, one production route in the prior art is to react o-chlorobenzyl chloride with triphenylphosphine to form o-chlorobenzyl phosphate, and then to react the o-chlorobenzyl phosphate with p-fluoroacetophenone under strongly alkaline conditions to form the target product; the triphenylphosphine used as a raw material is high in price, so that the cost is high; most of the byproducts generated in the reaction are phosphorus-containing compounds, so that the pollution to the environment is large, and finally, the content and the yield of the target product are low (up to 13 percent), so that the industrial production is difficult to realize. At present, the main stream process at home and abroad is to carry out Grignard reaction on fluoro-acetophenone or 4-fluoro-chloroacetophenone and o-chlorobenzyl chloride, then carrying out dehydration reaction, and then carrying out chlorination to obtain 2- (4-fluorophenyl) -3- (2-chlorophenyl) -chloropropene; the above route has the disadvantages of huge pollution, serious influence on the production environment, low yield and low quality.
Disclosure of Invention
The embodiment of the invention aims to provide a preparation method of a epoxiconazole intermediate, which aims to solve the problems that the existing preparation method of 2- (4-fluorophenyl) -3- (2-chlorophenyl) -chloropropene has larger environmental pollution and lower content and yield of target products.
In order to achieve the above object, the embodiment of the present invention provides the following technical solutions:
a preparation method of a epoxiconazole intermediate comprises the following steps:
1) Condensing p-fluorobenzonitrile (4-fluorobenzonitrile) and o-chlorobenzaldehyde to generate 2- (4-fluorophenyl) -3- (2-chlorophenyl) acrylonitrile;
2) Esterifying 2- (4-fluorophenyl) -3- (2-chlorophenyl) acrylonitrile to obtain methyl 2- (4-fluorophenyl) -3- (2-chlorophenyl) acrylate;
3) Reducing 2- (4-fluorophenyl) -3- (2-chlorophenyl) methyl acrylate in an alcohol solvent by using a reducing agent to obtain 2- (4-fluorophenyl) -3- (2-chlorophenyl) allyl alcohol;
4) The 2- (4-fluorophenyl) -3- (2-chlorophenyl) propenol is subjected to chlorination reaction in an organic solvent to obtain the epoxiconazole intermediate, specifically the epoxiconazole key intermediate 2- (4-fluorophenyl) -3- (2-chlorophenyl) chloropropene, also called 2- (4-fluorophenyl) -3- (2-chlorophenyl) chloropropene.
As a further scheme of the invention: the reaction temperature of the condensation is 0 to 80 ℃, more preferably 30 to 45 ℃.
As still further aspects of the invention: the reaction temperature of the esterification is 25-65 ℃, preferably 45-55 ℃.
As still further aspects of the invention: the reaction temperature of the reduction reaction is 20-40 ℃.
As still further aspects of the invention: the reaction temperature of the chlorination reaction is 0 to 50 ℃, more preferably 10 to 25 ℃.
The invention also aims to provide the epoxiconazole key intermediate 2- (4-fluorophenyl) -3- (2-chlorophenyl) chloropropene prepared by the preparation method of the epoxiconazole intermediate.
Another object of the embodiment of the invention is to provide an application of the preparation method of the epoxiconazole intermediate in preparation of broad-spectrum bactericides.
Compared with the prior art, the invention has the beneficial effects that:
the preparation method of the epoxiconazole intermediate provided by the embodiment of the invention adopts the p-fluorobenzonitrile and the o-chlorobenzaldehyde as raw materials, and the 2- (4-fluorophenyl) -3- (2-chlorophenyl) chloropropene serving as the key intermediate of the epoxiconazole is obtained through condensation, esterification, reduction and chlorination in sequence.
Detailed Description
The present invention will be described in further detail with reference to specific examples. The following examples will assist those skilled in the art in further understanding the present invention, but are not intended to limit the invention in any way. It should be noted that variations and modifications could be made by those skilled in the art without departing from the inventive concept. These are all within the scope of the present invention.
The embodiment of the invention provides a preparation method of a epoxiconazole intermediate, in particular to a simple preparation method of the epoxiconazole intermediate, which comprises the following steps:
1) Condensing p-fluorobenzonitrile (4-fluorobenzonitrile) and o-chlorobenzaldehyde to generate 2- (4-fluorophenyl) -3- (2-chlorophenyl) acrylonitrile;
2) Esterifying 2- (4-fluorophenyl) -3- (2-chlorophenyl) acrylonitrile to obtain methyl 2- (4-fluorophenyl) -3- (2-chlorophenyl) acrylate;
3) Reducing 2- (4-fluorophenyl) -3- (2-chlorophenyl) methyl acrylate in an alcohol solvent by using a reducing agent to obtain 2- (4-fluorophenyl) -3- (2-chlorophenyl) allyl alcohol;
4) The 2- (4-fluorophenyl) -3- (2-chlorophenyl) propenol is subjected to chlorination reaction in an organic solvent to obtain the epoxiconazole intermediate, specifically the epoxiconazole key intermediate 2- (4-fluorophenyl) -3- (2-chlorophenyl) chloropropene, also called 2- (4-fluorophenyl) -3- (2-chlorophenyl) chloropropene.
As another preferred embodiment of the present invention, in the process for producing a epoxiconazole intermediate, the reaction temperature of the condensation is 0 to 80 ℃, more preferably 30 to 45 ℃.
As another preferred embodiment of the present invention, in the preparation method of the epoxiconazole intermediate, the condensation is carried out in a reaction solvent under the catalysis of alkali to generate 2- (4-fluorophenyl) -3- (2-chlorophenyl) acrylonitrile.
As another preferred embodiment of the present invention, the reaction solvent is any one selected from methanol, ethanol, isopropanol, dichloroethane, toluene, etc.
As another preferred embodiment of the present invention, the reaction solvent is preferably an alcohol, more preferably methanol.
As another preferred embodiment of the present invention, the reaction solvent is used in an amount of 1 to 10 times by weight, preferably 2 to 3 times by weight, the weight of the p-fluorophenylacetonitrile.
As another preferred embodiment of the present invention, the base used for the base catalysis is any one of sodium hydroxide, potassium carbonate, sodium methoxide, sodium amide, sodium ethoxide, and the like. Of course, other oxides or salts of alkali metals, alkaline earth metals, and some rare earth elements may be selected according to the needs, and are not limited herein.
As another preferred embodiment of the present invention, the base used for the base catalysis is sodium hydroxide or potassium hydroxide.
As another preferred embodiment of the present invention, the base is used in an amount of 0.1 to 1 compound equivalent, more preferably 0.15 compound equivalent, to the fluorobenzonitrile.
As another preferred embodiment of the present invention, in the process for producing a epoxiconazole intermediate, the esterification is carried out in the presence of an acid with an esterification solvent and a small amount of water.
As another preferred embodiment of the present invention, the acid is any one of sulfuric acid, hydrochloric acid, phosphoric acid, etc., more preferably hydrogen chloride gas, or an aqueous solution of 80wt% to 95wt% sulfuric acid.
As another preferred embodiment of the present invention, the esterification solvent is selected from any one of methanol, ethanol, isopropanol, toluene, dichloroethane, ethyl acetate, etc.
As another preferred embodiment of the present invention, the esterification solvent is preferably an alcohol, more preferably methanol and ethanol.
As another preferred embodiment of the present invention, the esterifying solvent is used in an amount of 1 to 10 times by weight of 2- (4-fluorophenyl) -3- (2-chlorophenyl) acrylonitrile, preferably 2 to 4 times by weight of 2- (4-fluorophenyl) -3- (2-chlorophenyl) acrylonitrile.
As another preferred embodiment of the present invention, the reaction temperature of the esterification is 25 to 65℃and preferably 45 to 55 ℃.
Preferably, in the preparation method of the epoxiconazole intermediate, the esterification is carried out in the presence of acid methanol (hydrogen chloride methanol, ch3oh. Hcl) and a small amount of water.
As another preferred embodiment of the present invention, in the preparation method of the epoxiconazole intermediate, the reaction temperature of the reduction reaction is 20 to 40 ℃.
As another preferred embodiment of the invention, in the preparation method of the epoxiconazole intermediate, the implementation process of the step 3) is to dissolve 2- (4-fluorophenyl) -3- (2-chlorophenyl) methyl acrylate in an alcohol solvent, keep the temperature at 10 ℃ to 15 ℃, add a reducing agent, heat up to 20 ℃ to 40 ℃ after the addition, keep the temperature for 1 to 2 hours, and finish the reaction to obtain 2- (4-fluorophenyl) -3- (2-chlorophenyl) propenol.
As another preferred embodiment of the invention, in the preparation method of the epoxiconazole intermediate, the feeding mole ratio of the 2- (4-fluorophenyl) -3- (2-chlorophenyl) methyl acrylate and the reducing agent is 1:0.38-1.
As another preferred embodiment of the present invention, the alcoholic solvent is selected from one or more of methanol, ethanol and isopropanol. More preferably methanol or ethanol.
As another preferred embodiment of the present invention, the reducing agent is any one of sodium borohydride, potassium borohydride, lithium aluminum hydride, and the like. More preferably potassium borohydride.
As another preferred embodiment of the present invention, in the process for producing a epoxiconazole intermediate, the reaction temperature of the chlorination reaction is 0 to 50℃and more preferably 10 to 25 ℃.
As another preferred embodiment of the present invention, in the process for producing a epoxiconazole intermediate, the organic solvent used in step 4) is any one of dichloroethane, dichloromethane, toluene, methylcyclohexane, etc.
As another preferred embodiment of the present invention, the organic solvent is more preferably dichloroethane, or dichloromethane.
In another preferred embodiment of the present invention, in the method for preparing a epoxiconazole intermediate, the chlorinating reagent used in the chlorination reaction is any one of thionyl chloride, aqueous hydrogen chloride solution, sulfonyl chloride, phosphorus trichloride, phosphorus pentachloride, and the like.
As another preferred embodiment of the present invention, the chlorinating agent is more preferably thionyl chloride, or sulphuryl chloride.
As another preferred embodiment of the present invention, in the process for producing a epoxiconazole intermediate, the chlorinating agent is used in an amount of 1 to 3 compound equivalents of 2- (4-fluorophenyl) -3- (2-chlorophenyl) propenol, more preferably 1.1 to 1.5 compound equivalents.
In the embodiment of the invention, p-fluorobenzonitrile and o-chlorobenzaldehyde are adopted as raw materials, and the epoxiconazole intermediate, in particular to 2- (4-fluorophenyl) -3- (2-chlorophenyl) chloropropene which is a key epoxiconazole intermediate, is obtained through condensation, esterification, reduction and chlorination in sequence. The preparation method is a new route for synthesizing the epoxiconazole intermediate 2- (4-fluorophenyl) -3- (2-chlorophenyl) chloropropene, the process is relatively simple, each step of reaction can be completed under mild conditions, the cost is low, the pollution is less, the raw material sources are convenient, the content and the yield of target products are higher, and the method is suitable for industrial production.
The embodiment of the invention also provides an application of the preparation method of the epoxiconazole intermediate in epoxiconazole processing.
The embodiment of the invention also provides an application of the preparation method of the epoxiconazole intermediate in the preparation of broad-spectrum bactericides.
The technical effects of the process for producing a epoxiconazole intermediate of the present invention are further illustrated below by way of specific examples.
Example 1
The preparation method of the epoxiconazole intermediate specifically comprises the following steps:
1) Parafluorobenzonitrile (i.e., 4-fluorobenzonitrile) and o-chlorobenzaldehyde are put in a reaction solvent (methanol, ethanol, isopropanol, dichloroethane, toluene, etc., more preferably methanol) and condensed under the catalysis of a base at a reaction temperature of 0 to 80 ℃, more preferably 30 to 45 ℃. After the reaction, adding a proper amount of water, cooling and filtering to obtain the 2- (4-fluorophenyl) -3- (2-chlorophenyl) acrylonitrile.
The specific flow is represented by the following reaction formula (1):
2) 2- (4-fluorophenyl) -3- (2-chlorophenyl) acrylonitrile is added into a methanol-hydrogen chloride solvent (CH 3OH. HCl), a certain amount of water is added, the mixture is heated and stirred to react to a terminal point, the mixture is neutralized to be neutral by alkali, methanol is distilled off under reduced pressure, the residue is dissolved by toluene, and the mixture is washed by water and desolventized under reduced pressure to obtain 2- (4-fluorophenyl) -3- (2-chlorophenyl) methyl acrylate.
The specific flow is represented by the following reaction formula (2):
3) Dissolving methyl 2- (4-fluorophenyl) -3- (2-chlorophenyl) acrylate in an alcohol solvent, maintaining the temperature at 10-15 ℃, adding a reducing agent, heating to 20-40 ℃, preserving the temperature for 1-2h, ending the reaction, decompressing, desolventizing, adding water for dilution, filtering to obtain a crude product of 2- (4-fluorophenyl) -3- (2-chlorophenyl) propenol, and recrystallizing with methylcyclohexane to obtain a pure product of 2- (4-fluorophenyl) -3- (2-chlorophenyl) propenol.
The specific flow is represented by the following reaction formula (3):
4) Dissolving 2- (4-fluorophenyl) -3- (2-chlorophenyl) propenol into dichloroethane, slowly dropwise adding thionyl chloride, keeping the temperature until the end of the dropwise adding reaction, distilling off the solvent under negative pressure, dissolving the residue with toluene, washing with water until the residue is neutral, and cooling for crystallization to obtain 2- (4-fluorophenyl) -3- (2-chlorophenyl) chloropropene.
The specific flow is represented by the following reaction formula (4):
example 2
135 g (1 mol) of 4-fluorobenzonitrile and 140.5 g (1 mol) of o-chlorobenzaldehyde are added into 400 g of absolute methanol, the mixture is stirred uniformly, then 5 g of 30wt% sodium hydroxide aqueous solution is dripped, the PH=10 or more is regulated, the mixture is slowly heated to 35-40 ℃ for reaction for 2 hours, the 4-fluorobenzonitrile is sampled and analyzed to be less than 0.5% and qualified, 250 g of water is dripped, the mixture is slowly cooled to 10 ℃ under stirring, the mixture is filtered, a small amount of water is washed to be neutral, and the mixture is naturally dried, thus 253 g of 2- (4-fluorophenyl) -3- (2-chlorophenyl) acrylonitrile is obtained, the content of which is 97.5% and the molar yield of which is 95.8%.
Example 3
130 g (0.5 mol) of 2- (4-fluorophenyl) -3- (2-chlorophenyl) acrylonitrile obtained in example 2 is weighed and slowly added into 13wt% hydrogen chloride-methanol solution (480 g) in batches, the mixture is completely dissolved under stirring, 13 g of water is then dropwise added, the mixture is reacted for 2 hours at normal temperature, then slowly heated to 45-50 ℃ to the end point, the temperature is reduced to 0 ℃ after the reaction is finished, 15% alkali liquor is slowly dropwise added to adjust the pH to be neutral, the temperature is not more than 15 ℃, the methanol is distilled off under reduced pressure after the pH is adjusted to be neutral, 300 g of toluene is added for extraction and dissolution, 130 g of water is added for 2 times, the upper toluene solution is distilled under reduced pressure for concentration and recovery of toluene, and 136 g of methyl 2- (4-fluorophenyl) -3- (2-chlorophenyl) acrylate is obtained, the content of which is 98.2% and the molar yield is 92%.
Example 4
Preparation of methyl 2- (4-fluorophenyl) -3- (2-chlorophenyl) acrylate was carried out according to the method in example 3 by weighing 148 g (0.5 mol) of methyl 2- (4-fluorophenyl) -3- (2-chlorophenyl) acrylate, adding to 300 g of methanol, stirring and dissolving to be clear, cooling to 10-15 ℃ and adjusting the pH to about 10, then adding 28 g of a reducing agent potassium borohydride solid in batches, releasing heat when adding, controlling the temperature not to exceed 30 ℃, after the addition, detecting that the pH value of the reaction solution is stable to about 9-10 and preserving the temperature for 2 hours, sampling and analyzing the reaction completely, distilling under reduced pressure to recover the methanol, adding 300 g of water to the residue, stirring and solidifying, filtering at normal temperature, washing a filter cake to be neutral by water, adding to 200 g of methylcyclohexane, heating and dissolving at zero-5 ℃, cooling to be filtered at-5 ℃, rinsing the filter cake by cold methylcyclohexane, applying a time to the filter cake, and naturally airing at normal temperature to obtain 126 g of white solid, wherein the yield of 2- (4-fluorophenyl) -3- (2-chlorophenyl) allyl alcohol is 93 mol%, and the yield is 89.5%.
Example 5
Preparation of 2- (4-fluorophenyl) -3- (2-chlorophenyl) propenol was carried out according to the method in example 4, 136 g (0.5 mol) of 2- (4-fluorophenyl) -3- (2-chlorophenyl) propenol was weighed and added to 300 g of anhydrous dichloroethane, 65 g of freshly distilled thionyl chloride was dropwise added at 15℃and the tail gas was absorbed with liquid base, the dropwise addition temperature was controlled between 15 and 25℃and the reaction was carried out for 3 hours at the end of the dropwise addition, then 130 g of water was dropwise added, stirring was carried out for 20 minutes, the water layer was separated off at rest, the oil layer was washed with dilute alkali water to neutrality, the water layer was separated off, dichloroethane layer was recovered under reduced pressure, 200 g of toluene was added to the residue, the residue was cooled to about-3℃and filtered, and naturally dried to obtain 143 g of 2- (4-fluorophenyl) -3- (2-chlorophenyl) chloropropene as an off-white solid, the content was 97% by mol yield was 92.8%.
According to the embodiment, the invention adopts the p-fluorobenzonitrile and the o-chlorobenzaldehyde as raw materials, and the 2- (4-fluorophenyl) -3- (2-chlorophenyl) chloropropene which is a key intermediate of the epoxiconazole is obtained through condensation, esterification, reduction and chlorination in sequence, so that the process is relatively simple, the reactions of all the steps can be completed under mild conditions, the cost is lower, the pollution is less, the sources of the raw materials are convenient, the content and the yield of target products are higher, and the method is suitable for industrial production.
Example 6
A preparation method of a epoxiconazole intermediate, in particular to a simple preparation method of the epoxiconazole intermediate, which comprises the following steps:
1) Placing p-fluorobenzonitrile (4-fluorobenzonitrile) and o-chlorobenzaldehyde into a reaction solvent and condensing the p-fluorobenzonitrile (4-fluorobenzonitrile) and the o-chlorobenzaldehyde under the catalysis of alkali to generate 2- (4-fluorophenyl) -3- (2-chlorophenyl) acrylonitrile;
2) Esterifying 2- (4-fluorophenyl) -3- (2-chlorophenyl) acrylonitrile in the presence of an acid and an esterification solvent with a small amount of water to obtain methyl 2- (4-fluorophenyl) -3- (2-chlorophenyl) acrylate;
3) Reducing 2- (4-fluorophenyl) -3- (2-chlorophenyl) methyl acrylate in an alcohol solvent by using a reducing agent to obtain 2- (4-fluorophenyl) -3- (2-chlorophenyl) allyl alcohol;
4) And (3) carrying out chlorination reaction on the 2- (4-fluorophenyl) -3- (2-chlorophenyl) propenol in an organic solvent to obtain the epoxiconazole intermediate, in particular to 2- (4-fluorophenyl) -3- (2-chlorophenyl) chloropropene which is a key epoxiconazole intermediate.
In this example, the reaction temperature of the condensation in step 1) is 0 ℃. The reaction solvent is methanol. The dosage of the reaction solvent is 1 time of the weight of the p-fluorobenzonitrile. The alkali used for the alkali catalysis is sodium hydroxide. The amount of the base used for the base catalysis is 0.1 compound equivalent of the p-fluorobenzonitrile.
In this example, the reaction temperature of the esterification in step 2) was 25 ℃. The acid is an aqueous 80wt% sulfuric acid solution. The esterification solvent is methanol. The amount of the esterification solvent is 1 time of the weight of the 2- (4-fluorophenyl) -3- (2-chlorophenyl) acrylonitrile.
In the embodiment, the implementation process of the step 3) specifically comprises the steps of dissolving methyl 2- (4-fluorophenyl) -3- (2-chlorophenyl) acrylate in an alcohol solvent, keeping the temperature at 10 ℃, adding a reducing agent, wherein the feeding mole ratio of the methyl 2- (4-fluorophenyl) -3- (2-chlorophenyl) acrylate to the reducing agent is 1:0.38, heating to 20 ℃ after the addition, carrying out reduction reaction, preserving heat for 1h, and ending the reaction to obtain the 2- (4-fluorophenyl) -3- (2-chlorophenyl) propenol. The alcohol solvent is methanol. The reducing agent is sodium borohydride.
In this example, the reaction temperature of the chlorination reaction in step 4) was 0 ℃. The organic solvent is dichloroethane. The chlorinating reagent used in the chlorination reaction is thionyl chloride. The chlorinating agent is used in an amount of 1 compound equivalent of 2- (4-fluorophenyl) -3- (2-chlorophenyl) propenol.
Example 7
A preparation method of a epoxiconazole intermediate, in particular to a simple preparation method of the epoxiconazole intermediate, which comprises the following steps:
1) Placing p-fluorobenzonitrile (4-fluorobenzonitrile) and o-chlorobenzaldehyde into a reaction solvent and condensing the p-fluorobenzonitrile (4-fluorobenzonitrile) and the o-chlorobenzaldehyde under the catalysis of alkali to generate 2- (4-fluorophenyl) -3- (2-chlorophenyl) acrylonitrile;
2) Esterifying 2- (4-fluorophenyl) -3- (2-chlorophenyl) acrylonitrile in the presence of an acid and an esterification solvent with a small amount of water to obtain methyl 2- (4-fluorophenyl) -3- (2-chlorophenyl) acrylate;
3) Reducing 2- (4-fluorophenyl) -3- (2-chlorophenyl) methyl acrylate in an alcohol solvent by using a reducing agent to obtain 2- (4-fluorophenyl) -3- (2-chlorophenyl) allyl alcohol;
4) The 2- (4-fluorophenyl) -3- (2-chlorophenyl) propenol is subjected to chlorination reaction in an organic solvent to obtain the epoxiconazole intermediate, specifically the epoxiconazole key intermediate 2- (4-fluorophenyl) -3- (2-chlorophenyl) chloropropene, also called 2- (4-fluorophenyl) -3- (2-chlorophenyl) chloropropene.
In this example, the reaction temperature of the condensation in step 1) is 80℃and the reaction solvent is ethanol. The dosage of the reaction solvent is 10 times of the weight of the p-fluorobenzonitrile. The base used for the base catalysis is potassium hydroxide. The amount of the base used for the base catalysis is 1 compound equivalent of the p-fluorobenzonitrile.
In this example, the reaction temperature of the esterification in step 2) was 65 ℃. The acid is hydrogen chloride gas. The esterification solvent is ethanol. The amount of the esterification solvent is 10 times of the weight of the 2- (4-fluorophenyl) -3- (2-chlorophenyl) acrylonitrile.
In the embodiment, the implementation process of the step 3) specifically comprises the steps of dissolving methyl 2- (4-fluorophenyl) -3- (2-chlorophenyl) acrylate in an alcohol solvent, maintaining the temperature at 15 ℃, adding a reducing agent, wherein the feeding mole ratio of the methyl 2- (4-fluorophenyl) -3- (2-chlorophenyl) acrylate to the reducing agent is 1:1, heating to 40 ℃ after the addition, carrying out reduction reaction, preserving heat for 2 hours, and ending the reaction to obtain 2- (4-fluorophenyl) -3- (2-chlorophenyl) propenol. The alcohol solvent is ethanol. The reducing agent is potassium borohydride.
In this example, the reaction temperature of the chlorination reaction in step 4) was 50 ℃. The organic solvent is methylene chloride. The chlorinating reagent used in the chlorination reaction is aqueous hydrogen chloride. The chlorinating agent is used in an amount of 3 compound equivalents of 2- (4-fluorophenyl) -3- (2-chlorophenyl) propenol.
Example 8
In comparison with example 6, the procedure was as in example 6 except that the reaction temperature of the condensation in step 1) was 40 ℃, the reaction solvent was isopropanol, the reaction solvent was used in an amount 5 times the weight of p-fluorophenylacetonitrile, the base used for the base catalysis was potassium carbonate, and the base used for the base catalysis was used in an amount of 0.5 compound equivalent of p-fluorophenylacetonitrile.
Example 9
In comparison with example 6, the procedure was as in example 6 except that the reaction temperature of the condensation in step 1) was 30 ℃, the reaction solvent was dichloroethane, the reaction solvent was used in an amount of 2 times the weight of p-fluorophenylacetonitrile, the base used for the base catalysis was sodium methoxide, and the base used for the base catalysis was used in an amount of 0.15 compound equivalent of p-fluorophenylacetonitrile.
Example 10
In comparison with example 6, the procedure was as in example 6 except that the reaction temperature of the condensation in step 1) was 45 ℃, the reaction solvent was toluene, the reaction solvent was used in an amount of 3 times by weight of p-fluorophenylacetonitrile, the base used for the base catalysis was sodium amide, and the base used for the base catalysis was used in an amount of 0.5 compound equivalent of p-fluorophenylacetonitrile.
Example 11
In comparison with example 6, the procedure was as in example 6 except that the reaction temperature of the condensation in step 1) was 40 ℃, the reaction solvent was toluene, the reaction solvent was used in an amount of 3 times by weight of p-fluorophenylacetonitrile, the base used for the base catalysis was sodium ethoxide, and the base used for the base catalysis was used in an amount of 0.5 compound equivalent of p-fluorophenylacetonitrile.
Example 12
In comparison with example 8, the procedure was as in example 8 except that the reaction temperature of the esterification in step 2) was 45℃and the acid was phosphoric acid, the esterification solvent was isopropanol and the amount of the esterification solvent was 2 times the weight of 2- (4-fluorophenyl) -3- (2-chlorophenyl) acrylonitrile.
Example 13
In comparison with example 8, the procedure was as in example 8 except that the reaction temperature of the esterification in step 2) was 55℃and the acid was phosphoric acid, the esterification solvent was toluene and the amount of the esterification solvent was 4 times the weight of 2- (4-fluorophenyl) -3- (2-chlorophenyl) acrylonitrile.
Example 14
The procedure of example 8 was repeated except that the reaction temperature for the esterification in step 2) was 50℃and the acid was phosphoric acid, the esterification solvent was dichloroethane, and the amount of the esterification solvent was 3 times the weight of 2- (4-fluorophenyl) -3- (2-chlorophenyl) acrylonitrile.
Example 15
In comparison with example 8, the procedure was as in example 8 except that the reaction temperature of the esterification in step 2) was 45℃and the acid was phosphoric acid, the esterification solvent was ethyl acetate, and the amount of the esterification solvent was 2 times the weight of 2- (4-fluorophenyl) -3- (2-chlorophenyl) acrylonitrile.
Example 16
In comparison with example 8, the procedure of step 3) was carried out by dissolving methyl 2- (4-fluorophenyl) -3- (2-chlorophenyl) acrylate in an alcohol solvent, maintaining the temperature at 12℃and adding a reducing agent in a molar ratio of 1:0.5, heating to 30℃after the addition, and then conducting the reduction reaction, keeping the temperature for 1.5 hours, wherein the alcohol solvent is isopropyl alcohol and the reducing agent is lithium aluminum hydride, and the procedure is otherwise the same as in example 8.
Example 17
In comparison with example 16, the procedure is as in example 16 except that the alcoholic solvent in step 3) is an equal weight mixture of methanol and ethanol.
Example 18
In comparison with example 8, the same procedure as in example 8 was followed except that the reaction temperature of the chlorination reaction in step 4) was 10℃and the organic solvent was toluene, the chlorinating agent used in the chlorination reaction was sulfonyl chloride, and the amount of the chlorinating agent was 1.1 equivalent of 2- (4-fluorophenyl) -3- (2-chlorophenyl) propenol.
Example 19
In comparison with example 8, the same procedure as in example 8 was repeated except that the reaction temperature of the chlorination reaction in step 4) was 25℃and the organic solvent was methylcyclohexane, the chlorinating agent used in the chlorination reaction was phosphorus trichloride, and the amount of the chlorinating agent was 1.5 compound equivalents of 2- (4-fluorophenyl) -3- (2-chlorophenyl) propenol.
Example 20
In comparison with example 8, the same procedure as in example 8 was followed except that the reaction temperature of the chlorination reaction in step 4) was 20℃and the organic solvent was toluene, the chlorinating agent used in the chlorination reaction was phosphorus pentachloride, and the amount of the chlorinating agent was 1.3 compound equivalents of 2- (4-fluorophenyl) -3- (2-chlorophenyl) propenol.
Comparative example 1
U.S. patent document (publication No. US 4464381) discloses a preparation method of 2- (4-fluorophenyl) -3- (2-chlorophenyl) -propylene, which is characterized in that o-chlorobenzyl chloride is generated by chlorating o-chlorotoluene serving as a raw material by chlorine, then o-chlorobenzyl chloride and triphenylphosphine react to generate o-chlorobenzyl phosphate, and then the o-chlorobenzyl phosphate and p-fluoro acetophenone react under a strong alkaline condition to generate target products 2- (4-fluorophenyl) -3- (2-chlorophenyl) -propylene (namely 2- (4-fluorophenyl) -3- (2-chlorophenyl) chloropropene). However, the triphenylphosphine used therein is expensive, resulting in a relatively high cost. Most of the byproducts generated in the reaction are phosphorus-containing compounds, so that the pollution to the environment is large, and finally, the content and the yield of the target product 2- (4-fluorophenyl) -3- (2-chlorophenyl) -propylene are low (up to only 13 percent), so that the industrial production is difficult to realize.
Comparative example 2
The main process for producing 2- (4-fluorophenyl) -3- (2-chlorophenyl) chloropropene at home and abroad is to carry out Grignard reaction on p-fluoro-acetophenone or 4-fluoro-chloroacetophenone and o-chlorobenzyl, then carrying out dehydration reaction, and then carrying out chlorination to obtain the 2- (4-fluorophenyl) -3- (2-chlorophenyl) chloropropene. The specific flow is represented by the following reaction formula (5):
the Grignard reaction needed by the route belongs to a high-risk reaction, a large amount of solvent is needed, a lot of magnesium chloride or magnesium sulfate waste salt is difficult to treat, and the yield and quality of the Grignard reaction are low, which is difficult to succeed. The second step of dehydration reaction needs to add acetic anhydride, acetic acid, concentrated sulfuric acid and the like, and is also pollution-free and seriously affects the production environment.
Comparative example 3
One prior art route for the production of 2- (4-fluorophenyl) -3- (2-chlorophenyl) chloropropene is shown in the following formula (6):
the route can generate a large amount of phosphorus-containing wastewater, is also a high-pollution process, and is difficult to follow and is not suitable for industrial production.
Evaluation of Performance
The methods in examples 2 to 5 and comparative examples 1 to 3 were evaluated for performance. Specifically, the product yield and the process characteristics are seen, wherein the yield results are shown in the following table 1.
TABLE 1 yield results for the preparation of different epoxiconazole intermediates
| Group of | Yield of 2- (4-fluorophenyl) -3- (2-chlorophenyl) -propylene |
| Example 5 | 92.8% |
| Comparative example 1 | 13% |
According to the results, the epoxiconazole intermediate, in particular the epoxiconazole key intermediate 2- (4-fluorophenyl) -3- (2-chlorophenyl) chloropropene, is obtained by adopting p-fluorobenzonitrile and o-chlorobenzaldehyde as raw materials and sequentially carrying out condensation, esterification, reduction and chlorination. The method has the advantages of relatively simple process, mild reaction conditions, wide and cheap raw material sources, safe process, few three wastes, environmental protection, higher content and yield of target products, suitability for industrial production, and wide market prospect, and solves the problems of larger environmental pollution and lower content and yield of the target products in the existing preparation method of the 2- (4-fluorophenyl) -3- (2-chlorophenyl) -chloropropene.
While the preferred embodiments of the present invention have been described in detail, the present invention is not limited to the above embodiments, and various changes can be made without departing from the spirit of the present invention within the knowledge of those skilled in the art. It is not necessary here nor is it exhaustive of all embodiments. And obvious variations or modifications thereof are contemplated as falling within the scope of the present invention.
Claims (10)
1. The preparation method of the epoxiconazole intermediate is characterized by comprising the following steps of:
1) Condensing p-fluorobenzonitrile and o-chlorobenzaldehyde to generate 2- (4-fluorophenyl) -3- (2-chlorophenyl) acrylonitrile;
2) Esterifying 2- (4-fluorophenyl) -3- (2-chlorophenyl) acrylonitrile to obtain methyl 2- (4-fluorophenyl) -3- (2-chlorophenyl) acrylate;
3) Reducing 2- (4-fluorophenyl) -3- (2-chlorophenyl) methyl acrylate in an alcohol solvent by using a reducing agent, wherein the feeding molar ratio of the 2- (4-fluorophenyl) -3- (2-chlorophenyl) methyl acrylate to the reducing agent is 1:0.38-1, so as to obtain 2- (4-fluorophenyl) -3- (2-chlorophenyl) allyl alcohol;
4) And (3) carrying out chlorination reaction on the 2- (4-fluorophenyl) -3- (2-chlorophenyl) propenol in an organic solvent, wherein the dosage of a chlorinating reagent is 1-3 compound equivalents of the 2- (4-fluorophenyl) -3- (2-chlorophenyl) propenol, and obtaining the epoxiconazole intermediate.
2. The process for producing a epoxiconazole intermediate according to claim 1, wherein in the process for producing a epoxiconazole intermediate, p-fluorobenzonitrile and o-chlorobenzaldehyde are placed in a reaction solvent and condensed at 0 to 80 ℃ under the catalysis of a base to produce 2- (4-fluorophenyl) -3- (2-chlorophenyl) acrylonitrile.
3. The method for producing a epoxiconazole intermediate according to claim 2, wherein the reaction solvent is any one selected from the group consisting of methanol, ethanol, isopropanol, dichloroethane, and toluene.
4. The method for preparing a epoxiconazole intermediate according to claim 2, wherein in the method for preparing a epoxiconazole intermediate, the base used for the base catalysis is any one of sodium hydroxide, potassium carbonate, sodium methoxide, sodium amide and sodium ethoxide.
5. The process for producing a epoxiconazole intermediate according to claim 1, wherein the esterification is carried out by esterifying 2- (4-fluorophenyl) -3- (2-chlorophenyl) acrylonitrile in the presence of an acid, an esterification solvent and water at 25 to 65 ℃.
6. The method for preparing epoxiconazole intermediate according to claim 5, wherein the esterification solvent is selected from any one of methanol, ethanol, isopropanol, toluene, dichloroethane, and ethyl acetate.
7. The method for producing a epoxiconazole intermediate according to claim 1, wherein the reaction temperature of the reduction reaction is 20 to 40 ℃.
8. The method for producing a epoxiconazole intermediate according to claim 1, wherein in the method for producing a epoxiconazole intermediate, the reducing agent is any one of sodium borohydride, potassium borohydride, lithium aluminum hydride.
9. The method for producing a epoxiconazole intermediate according to claim 1, wherein the reaction temperature of the chlorination reaction is 0 to 50 ℃, and the chlorinating reagent used in the chlorination reaction is any one of thionyl chloride, aqueous hydrogen chloride, sulfonyl chloride, phosphorus trichloride, and phosphorus pentachloride.
10. Use of a process for the preparation of a epoxiconazole intermediate according to any of claims 1 to 9 in the preparation of a broad-spectrum fungicide.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JPH10291995A (en) * | 1997-02-18 | 1998-11-04 | Mitsui Chem Inc | Production of iminotris(disubstituted amino) phosphorane |
| WO2010148207A2 (en) * | 2009-06-18 | 2010-12-23 | Arena Pharmaceuticals, Inc. | Processes for the preparation of 5-ht2c receptor agonists |
| CN105130757A (en) * | 2015-08-12 | 2015-12-09 | 大连九信生物化工科技有限公司 | Epoxiconazole intermediate 1-chloro-3-(2-chlorophenyl)-2-(4-fluorophenyl)-2-propanol synthesis process |
| CN110317122A (en) * | 2019-07-19 | 2019-10-11 | 东南大学 | A method of Z-type is converted by E type epoxiconazole intermediate |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH10291995A (en) * | 1997-02-18 | 1998-11-04 | Mitsui Chem Inc | Production of iminotris(disubstituted amino) phosphorane |
| WO2010148207A2 (en) * | 2009-06-18 | 2010-12-23 | Arena Pharmaceuticals, Inc. | Processes for the preparation of 5-ht2c receptor agonists |
| CN105130757A (en) * | 2015-08-12 | 2015-12-09 | 大连九信生物化工科技有限公司 | Epoxiconazole intermediate 1-chloro-3-(2-chlorophenyl)-2-(4-fluorophenyl)-2-propanol synthesis process |
| CN110317122A (en) * | 2019-07-19 | 2019-10-11 | 东南大学 | A method of Z-type is converted by E type epoxiconazole intermediate |
Non-Patent Citations (1)
| Title |
|---|
| Guohua Zhao et al..Synthesis and SAR of potent and selective tetrahydropyrazinoisoquinolinone 5-HT2C receptor agonists.《Bioorganic & Medicinal Chemistry Letters》.2013,第23卷第3914-3919页. * |
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