CN109400541B - Process for the preparation of cyproconazole from 1-chloro-2- (4-chlorophenyl) -3-methyl-4-penten-2-ol - Google Patents
Process for the preparation of cyproconazole from 1-chloro-2- (4-chlorophenyl) -3-methyl-4-penten-2-ol Download PDFInfo
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Abstract
The invention relates to the field of organic synthesis, in particular to a method for preparing cyproconazole by 1-chloro-2- (4-chlorphenyl) -3-methyl-4-pentene-2-alcohol, which comprises the following steps: (1) nucleophilic addition reaction of 2, 4' -dichloroacetophenone and Grignard reagent or organic zinc reagent to produce 1-chloro-2- (4-chlorophenyl) -3-methyl-4-pentene-2-ol, 2- (4-chlorophenyl) -2- (but-3-en-2-yl) -ethylene oxide or their mixture; (2) cyclizing the product obtained in the step (1) and methylene dihalide to obtain 1-chloro-2- (4-chlorphenyl) -3-cyclopropyl butyl-2-alcohol, 2- (4-chlorphenyl) -2- (1-cyclopropyl ethyl) -ethylene oxide or a mixture of the two; (3) and (3) performing nucleophilic substitution reaction on the product obtained in the step (2) and 1,2, 4-triazole or 1,2, 4-triazole salt to obtain cyproconazole. The preparation method of cyproconazole provided by the invention has the advantages of short route and high yield, does not use a sulfur reagent with foul smell, a highly toxic reagent and a noble metal catalyst in the reaction process, and is suitable for large-scale industrial production.
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to a method for preparing cyproconazole by 1-chloro-2- (4-chlorphenyl) -3-methyl-4-pentene-2-alcohol and/or 2- (4-chlorphenyl) -2- (1-cyclopropylethyl) -ethylene oxide.
Background
Cyproconazole is a triazole fungicide developed by Sandoz AG (Sandoz AG), is an ergosterol demethylation inhibitor, has the effects of preventing and treating powdery mildew, rust fungi, botrytis, corallospora, corallinia, septoria and cladosporium pathogenic bacteria on cereal crops, coffee, beet, fruit trees and grapes, can prevent and treat cereal and coffee rust, cereal, fruit tree and grape powdery mildew, peanut and beet leaf spot, apple scab and peanut white rot, and can be mixed with other fungicides. The lasting period for preventing and treating the rust disease of wheat is 4-6 weeks, and the lasting period for preventing and treating the powdery mildew is 3-4 weeks. Cyproconazole was first introduced as a fungicide for foliar application to wheat in france in 1989, and was later used as a seed treatment agent for seed treatment of winter wheat and cotton in western europe and the united states.
The structural formula of cyproconazole is:
for the synthesis of cyproconazole, there are two main industrial processes, namely p-chlorobenzaldehyde grignard reaction and chlorobenzene friedel-crafts reaction, which are based on different reaction raw materials and reaction types.
The p-chlorobenzaldehyde Grignard reaction method starts from p-chlorobenzaldehyde, leads in allyl group through reaction with allyl Grignard reagent to obtain alcohol I, and further obtains a compound II through Simmons-Smith cyclopropanation reaction. The alcohol is then subjected to Swern oxidation to give the aryl ketone III, and the methyl group is introduced with methyl iodide in the presence of sodium methoxide to give the compound IV. Epoxy compound V is obtained by Darzens condensation of sulfonium salt, and finally epoxy-opened substitution reaction is carried out on triazole under alkaline condition to obtain cyproconazole.
The chlorobenzene Friedel-crafts reaction method starts from p-chlorobenzene, leads in cyclopropyl directly through Friedel-crafts reaction with cyclopropyl acetyl chloride to obtain ketone III, and then obtains the cyproconazole through the same route as the Grignard reaction method.
In addition, the chinese patent publication No. CN101857576A discloses a simple method for preparing cyproconazole from cyclopropyl methyl ketone, which comprises preparing p-chlorobenzyl chloride vi as a starting material into a grignard reagent, and then performing nucleophilic substitution reaction with cyclopropyl methyl ketone to generate alcohol vii; dehydrating in the presence of phosphorus oxychloride to form conjugated olefin VIII, and introducing hydroxyl group into a benzyl position through hydroboration oxidation reaction to obtain alcohol IX; the obtained alcohol is oxidized by Dess-Martin to obtain ketone IV, and then the ketone IV and sulfonium iodide are subjected to Darzens condensation under an alkaline condition and further subjected to triazole epoxidization to obtain cyproconazole.
For the first and second synthesis methods, a large amount of highly toxic reagents such as heavy metal copper, methyl iodide, dimethyl sulfate and the like are used in the reaction process; for the third method, although the use of highly toxic reagents is avoided, the reaction steps are as high as six steps, the total yield is only 37%, and the reaction economy is poor.
Disclosure of Invention
The present invention has been made keeping in mind the above problems occurring in the prior art, and an object of the present invention is to provide a method for preparing cyproconazole from 1-chloro-2- (4-chlorophenyl) -3-methyl-4-penten-2-ol.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a process for the preparation of cyproconazole from 1-chloro-2- (4-chlorophenyl) -3-methyl-4-penten-2-ol comprising the steps of:
(1) performing nucleophilic addition reaction on 2, 4' -dichloroacetophenone and a 3-halo-1-butene Grignard reagent, a 3-halo-1-butene organic zinc reagent, a 1-halo-2-butene Grignard reagent or a 1-halo-2-butene organic zinc reagent to obtain one or a mixture of two of products, namely 1-chloro-2- (4-chlorophenyl) -3-methyl-4-penten-2-ol and 2- (4-chlorophenyl) -2- (but-3-en-2-yl) -ethylene oxide;
(2) cyclizing the product obtained in the step (1) with methylene dihalide to obtain one or a mixture of two of products 1-chloro-2- (4-chlorphenyl) -3-cyclopropyl butyl-2-alcohol and 2- (4-chlorphenyl) -2- (1-cyclopropyl ethyl) -ethylene oxide;
(3) a, performing nucleophilic substitution reaction on the product obtained in the step (2) and 1,2, 4-triazole or 1,2, 4-triazole salt to obtain cyproconazole;
or the like, or, alternatively,
(3) b, reacting the 1-chloro-2- (4-chlorphenyl) -3-cyclopropyl butyl-2-alcohol in the product in the step (2) with alkali to generate 2- (4-chlorphenyl) -2- (1-cyclopropyl ethyl) oxirane, and then performing ring-opening reaction with 1,2, 4-triazole to obtain cyproconazole;
the reaction formula is as follows:
wherein X is chlorine, bromine or iodine; m is hydrogen, sodium, potassium or lithium; y is magnesium or zinc.
The above-mentioned (3) A and 3(B) steps are two alternative solutions in parallel.
Preferably, in the step (1), the molar ratio of the 2, 4' -dichloroacetophenone to the 3-halo-1-butene grignard reagent, the 3-halo-1-butene organozinc reagent, the 1-halo-2-butene grignard reagent or the 1-halo-2-butene organozinc reagent is 1: 0.8 to 3.0.
Preferably, the methylene dihalide in step (2) includes diiodomethane, dibromomethane, bromochloromethane, iodochloromethane, iodobromomethane or a mixture thereof.
Preferably, the reaction reagent in the step (2) further comprises zinc powder and copper salt; the mol ratio of 1-chloro-2- (4-chlorphenyl) -3-methyl-4-penten-2-ol to the sum of 2- (4-chlorphenyl) -2- (butyl-3-alkene-2-group) -ethylene oxide, zinc powder and copper salt is 1: 0.8-4.0: 0.01 to 0.8.
Preferably, the copper salt comprises cuprous chloride, cupric sulfate, cuprous sulfate, cupric acetate, cupric nitrate, cupric bromide, cuprous bromide, cupric iodide or cuprous iodide.
Preferably, in the step (3), the molar ratio of the sum of the 1-chloro-2- (4-chlorophenyl) -3-cyclopropylbutan-2-ol and the 2- (4-chlorophenyl) -2- (1-cyclopropylethyl) ethylene oxide to the sum of the 1,2, 4-triazole and the 1,2, 4-triazole salt is 1: 0.8 to 2.2.
Preferably, when the reaction raw materials in the step (3) A contain 1-chloro-2- (4-chlorophenyl) -3-cyclopropylbutan-2-ol and 1,2, 4-triazole, the reactants further include alkali; the molar ratio of the alkali to the 1-chloro-2- (4-chlorophenyl) -3-cyclopropylbutan-2-ol is 0.8-2.0: 1.
preferably, the base comprises sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium methoxide, potassium methoxide, lithium methoxide, sodium ethoxide, potassium ethoxide, lithium ethoxide, sodium isopropoxide, potassium isopropoxide, isopropanol, lithium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, sodium hydride, sodium amide, triethylamine or pyridine.
Preferably, the specific reaction process of step (3) a is as follows:
(a) dissolving 1,2, 4-triazole and alkali in a solvent according to a measured part, and uniformly stirring to obtain a triazole solution;
(b) dissolving 1-chloro-2- (4-chlorphenyl) -3-cyclopropyl butyl-2-alcohol in a solvent, dropwise adding the solution into the triazole solution obtained in the step (a), and performing reflux reaction after dropwise adding until the content of the 1-chloro-2- (4-chlorphenyl) -3-cyclopropyl butyl-2-alcohol is less than 1%;
(c) after the reaction is finished, carrying out reduced pressure distillation to remove the solvent, and washing and filtering the residual materials to obtain a crude product of cyproconazole; refining to obtain white solid cyproconazole.
Preferably, the specific reaction process of step (3) B is as follows:
(a) dissolving metered parts of 1-chloro-2- (4-chlorphenyl) -3-cyclopropyl butan-2-ol and alkali in a solvent, and reacting under stirring to obtain 2- (4-chlorphenyl) -2- (1-cyclopropylethyl) oxirane;
(b) dissolving 1,2, 4-triazole in a solvent, dropwise adding the solution into the 2- (4-chlorophenyl) -2- (1-cyclopropylethyl) oxirane solution obtained in the step (a), and performing reflux reaction after the dropwise adding is finished until the content of the 2- (4-chlorophenyl) -2- (1-cyclopropylethyl) oxirane is less than 1%;
(c) after the reaction is finished, carrying out reduced pressure distillation to remove the solvent, and washing and filtering the residual materials to obtain a crude product of cyproconazole; refining to obtain white solid cyproconazole.
In a second aspect of the invention there is provided the use of 1-chloro-2- (4-chlorophenyl) -3-cyclopropylbutan-2-ol and/or 2- (4-chlorophenyl) -2- (1-cyclopropylethyl) -oxirane in the preparation of cyproconazole.
The invention has the beneficial effects that: the preparation method of cyproconazole provided by the invention has the advantages of short route and high yield, no use of highly toxic reagents in the reaction process, no need of expensive noble metal catalysts, and suitability for large-scale industrial production.
Detailed Description
Example 1
(1) Preparation of 1-chloro-2- (4-chlorophenyl) -3-methyl-4-penten-2-ol
10.0mmol of 2, 4' -dichloroacetophenone is dissolved in 20.0ml of anhydrous ether, the mixture is cooled to 0 ℃ in an ice bath, 12.0mmol of prepared 3-chloro-1-butene Grignard reagent is slowly dripped, and after dripping, the reaction solution is heated to room temperature and stirred for 1.0 h. After the reaction is finished, adding saturated ammonium chloride aqueous solution, extracting with diethyl ether, combining organic phases, and obtaining 1-chloro-2- (4-chlorphenyl) -3-methyl-4-pentene-2-alcohol after desolventizing, wherein the yield is 95%, and the qualitative purity is 98%; the 3-chloro-1-butene Grignard reagent is prepared by a conventional method;
(2) preparation of 1-chloro-2- (4-chlorophenyl) -3-cyclopropylbutan-2-ol
At room temperature, taking 40ml of dichloromethane, sequentially adding 0.12mol of zinc powder, 0.012mol of cuprous chloride and 0.04mol of dibromomethane, then adding 0.0024mol of catalyst acetyl chloride, and stirring for 10-15 min; dissolving 0.10mol of 1-chloro-2- (4-chlorophenyl) -3-methyl-4-pentene-2-alcohol in 15ml of dichloromethane to form a solution, and dropwise adding the solution into the dibromomethane solution for about 15 min; dropwise adding 0.2mol of dibromomethane into the solution, heating to about 40 ℃ after dropwise adding, reacting for 5-6h, cooling after the reaction is finished, adding 30mL of 2M hydrochloric acid, stirring, layering, extracting a water layer with 30mL of dichloromethane, and combining organic layers; the organic layer was washed once more with saturated aqueous sodium chloride solution; the solvent is recovered by organic phase decompression, the yield of crude product is 95 percent, and the qualitative content is 90 percent;
(3) preparation of cyproconazole (reaction with 1,2, 4-triazole sodium salt)
Adding 120ml of DMF (dimethyl formamide) and 1,2, 4-triazole sodium salt (18.5g and 203mmol) into a 250ml four-mouth reaction bottle provided with a thermometer, a condenser tube and a stirring device, adding 1-chloro-2- (4-chlorophenyl) -3-cyclopropyl butan-2-ol (44g and 170mmol), heating to 100 ℃, reacting for 60-100min, sampling and analyzing, and judging that the reaction is finished when the content of the 1-chloro-2- (4-chlorophenyl) -3-cyclopropyl butan-2-ol is less than 1%. Cooling to room temperature, dropwise adding the reaction solution into 120ml of cold water, stirring to separate out a solid, filtering, washing with water, and drying to obtain the cyproconazole with the content of 96% and the weight yield of 90%.
Example 2
(1) Preparation of 1-chloro-2- (4-chlorophenyl) -3-methyl-4-penten-2-ol
10.0mmol of 2, 4' -dichloroacetophenone is dissolved in 20.0ml of anhydrous ether, the mixture is cooled to 0 ℃ in an ice bath, the prepared 11.0mmol of 3-chloro-1-butene organic zinc reagent is slowly dripped, after dripping, the reaction solution is heated to room temperature and stirred for 1.0 h. After the reaction is finished, adding saturated ammonium chloride aqueous solution, stirring for 10min, separating out an organic phase, extracting a water layer by using diethyl ether, combining the organic phases, and desolventizing to obtain the 1-chloro-2- (4-chlorophenyl) -3-methyl-4-pentene-2-ol, wherein the yield is 90 percent, and the qualitative purity is 98 percent; the organic zinc reagent of 3-chloro-1-butene is prepared by a conventional method;
(2) preparing 1-chloro-2- (4-chlorophenyl) -3-cyclopropylbutan-2-ol;
at room temperature, taking 40ml of dichloromethane, sequentially adding 0.10mol of zinc powder, 0.01mol of cuprous chloride and 0.03mol of dibromomethane, then adding 0.001mol of catalyst acetyl chloride, and stirring for 10-15 min; dissolving 0.10mol of 1-chloro-2- (4-chlorophenyl) -3-methyl-4-pentene-2-alcohol in 15ml of dichloromethane to form a solution, and dropwise adding the solution into the dibromomethane solution for about 15 min; dropwise adding 0.2mol of dibromomethane into the solution, heating to about 40 ℃ after dropwise adding, reacting for 5-6h, cooling after the reaction is finished, adding 30mL of 2M hydrochloric acid, stirring, layering, extracting a water layer with 30mL of dichloromethane, and combining organic layers; the organic layer was washed once more with saturated aqueous sodium chloride solution. The solvent is recovered by organic phase decompression, the yield of crude product is 95 percent, and the qualitative content is 90 percent;
(3) adding 18ml of methanol, 3.2g (0.06mol) of sodium methoxide and 4.2g (0.06mol) of 1,2, 4-triazole into a four-neck flask provided with a thermometer, a condenser and a stirring device in sequence, and stirring for 1h at room temperature; dissolving 13.0g (0.05mol) of 1-chloro-2- (4-chlorophenyl) -3-cyclopropylbutan-2-ol in 50ml of methanol to form a solution, dropwise adding the solution into the triazole solution, heating the reaction solution to reflux after the dropwise adding is finished, reacting for 90-120min at the temperature, sampling and analyzing, and judging that the reaction is finished when the content of the 1-chloro-2- (4-chlorophenyl) -3-cyclopropylbutan-2-ol is less than 1%. And (3) after the reaction is finished, removing the methanol by reduced pressure distillation, stirring and washing the residual materials by 100ml of water, filtering to obtain a crude product of cyproconazole, and recrystallizing normal hexane to obtain a white solid cyproconazole, wherein the weight yield is 90% and the purity is 97%.
Example 3
(1) Preparation of 1-chloro-2- (4-chlorophenyl) -3-methyl-4-penten-2-ol
10.0mmol of 2, 4' -dichloroacetophenone is dissolved in 20.0ml of anhydrous ether, the mixture is cooled to 0 ℃ in an ice bath, the prepared 13.0mmol of 1-chloro-2-butene Grignard reagent is slowly dripped, after dripping, the reaction solution is heated to room temperature and stirred for 1.0 h. After the reaction is finished, adding saturated ammonium chloride aqueous solution, extracting with diethyl ether, combining organic phases, and obtaining 1-chloro-2- (4-chlorphenyl) -3-methyl-4-pentene-2-alcohol after desolventizing, wherein the yield is 95%, and the qualitative purity is 98%; the 1-chloro-2-butene Grignard reagent is prepared by a conventional method;
(2) preparing 1-chloro-2- (4-chlorophenyl) -3-cyclopropylbutan-2-ol;
taking 40ml of dichloromethane, sequentially adding 0.14mol of zinc powder, 0.014mol of cuprous chloride and 0.03mol of dibromomethane into the dichloromethane at room temperature, then adding 0.01mol of catalyst acetyl chloride, and stirring for 10-15 min; dissolving 0.10mol of 1-chloro-2- (4-chlorophenyl) -3-methyl-4-pentene-2-alcohol in 15ml of dichloromethane to form a solution, and dropwise adding the solution into the dibromomethane solution for about 15 min; dropwise adding 0.2mol of dibromomethane into the solution, heating to about 40 ℃ after dropwise adding, reacting for 5-6h, cooling after the reaction is finished, adding 30mL of 2M hydrochloric acid, stirring, layering, extracting a water layer with 30mL of dichloromethane, and combining organic layers; the organic layer was washed once more with saturated aqueous sodium chloride solution. The solvent is recovered by organic phase decompression, the yield of crude product is 95 percent, and the qualitative content is 90 percent;
(3) 18ml of methanol, 4.1g (0.075mol) of sodium methoxide and 7.6g (0.11mol) of 1,2, 4-triazole are sequentially added into a four-neck flask provided with a thermometer, a condenser and a stirring device, and stirred for 1h at room temperature; dissolving 13.0g (0.05mol) of 1-chloro-2- (4-chlorophenyl) -3-cyclopropyl butan-2-ol in 50ml of methanol to form a solution, dropwise adding the solution into the triazole solution, heating the reaction solution to reflux after the dropwise adding is finished, reacting for 90-120min at the temperature, sampling and analyzing, and judging that the reaction is finished when the content of the 1-chloro-2- (4-chlorophenyl) -3-cyclopropyl butan-2-ol is less than 1%. And (3) after the reaction is finished, removing the methanol by reduced pressure distillation, stirring and washing the residual materials by using 100ml of water, filtering to obtain a crude product of cyproconazole, and recrystallizing normal hexane to obtain a white solid cyproconazole, wherein the weight yield is 91 percent, and the purity is 98 percent.
Example 4
(1) Preparation of 1-chloro-2- (4-chlorophenyl) -3-methyl-4-penten-2-ol
10.0mmol of 2, 4' -dichloroacetophenone is dissolved in 20.0ml of anhydrous ether, the mixture is cooled to 0 ℃ in an ice bath, the prepared organic zinc reagent of 20.0mmol of 1-chloro-2-butene is slowly dripped, and after dripping, the reaction solution is heated to room temperature and stirred for 1.0 h. After the reaction is finished, adding saturated ammonium chloride aqueous solution, stirring for 10min, separating out an organic phase, extracting a water layer by using diethyl ether, combining the organic phases, and desolventizing to obtain the 1-chloro-2- (4-chlorophenyl) -3-methyl-4-pentene-2-ol, wherein the yield is 90 percent, and the qualitative purity is 98 percent; the organic zinc reagent of the 1-chloro-2-butene is prepared by a conventional method;
(2) preparing 1-chloro-2- (4-chlorophenyl) -3-cyclopropylbutan-2-ol;
at room temperature, taking 40ml of dichloromethane, sequentially adding 0.18mol of zinc powder, 0.018mol of cuprous chloride and 0.03mol of dibromomethane, then adding 0.0001mol of catalyst acetyl chloride, and stirring for 10-15 min; dissolving 0.10mol of 1-chloro-2- (4-chlorophenyl) -3-methyl-4-pentene-2-alcohol in 15ml of dichloromethane to form a solution, and dropwise adding the solution into the dibromomethane solution for about 15 min; dropwise adding 0.06mol of dibromomethane into the solution, heating to about 40 ℃ after dropwise adding, reacting for 5-6h, cooling after the reaction is finished, adding 30mL of 2M hydrochloric acid, stirring, layering, extracting a water layer with 30mL of dichloromethane, and combining organic layers; the organic layer was washed once more with saturated aqueous sodium chloride solution. The solvent is recovered by organic phase decompression, the yield of crude product is 95 percent, and the qualitative content is 90 percent;
(3) 18ml of methanol and 4.1g (0.075mol) of sodium methoxide were sequentially added to a four-necked flask equipped with a thermometer, a condenser and a stirrer, 13.0g (0.05mol) of 1-chloro-2- (4-chlorophenyl) -3-cyclopropylbutan-2-ol was dissolved in 50ml of methanol to prepare a solution, which was added dropwise to the sodium methoxide solution, and after completion of the addition, the reaction mixture was heated to reflux and reacted at this temperature for 60 to 90 minutes, and the reaction was terminated when the content of 1-chloro-2- (4-chlorophenyl) -3-cyclopropylbutan-2-ol was less than 1% by sampling analysis, whereby a solution of 2- (4-chlorophenyl) -2- (1-cyclopropylethyl) oxirane was obtained with a qualitative purity of 97%.
(4) Adding 7.6g (0.11mol) of 1,2, 4-triazole into the solution of the 2- (4-chlorophenyl) -2- (1-cyclopropylethyl) oxirane, heating to reflux, reacting for 60-90min at the temperature, sampling and analyzing, judging that the reaction is finished when the content of the 2- (4-chlorophenyl) -2- (1-cyclopropylethyl) oxirane is less than 1%, distilling under reduced pressure to remove methanol after the reaction is finished, stirring and washing the rest materials with 100ml of water, filtering to obtain a crude product of cyproconazole, and recrystallizing n-hexane to obtain a white solid cyproconazole, wherein the weight yield is 91%, and the purity is 98%.
Example 5
(1)2- (4-chlorophenyl) -2- (but-3-en-2-yl) -oxirane
10.0mmol of 2, 4' -dichloroacetophenone is dissolved in 20.0ml of anhydrous ether, the mixture is cooled to 0 ℃ in an ice bath, 11.0mmol of the prepared Grignard reagent of 3-chloro-1-butene is slowly dripped, and after dripping, the reaction solution is heated to room temperature and stirred for 1.0 h. Continuously heating to about 40 ℃ for reaction for 3h, adding saturated ammonium chloride aqueous solution, stirring for 10min after the reaction is finished, separating out an organic phase, extracting a water layer by using diethyl ether, combining the organic phases, and desolventizing to obtain the 2- (4-chlorphenyl) -2- (butyl-3-alkene-2-yl) -ethylene oxide, wherein the yield is 89%, and the qualitative purity is 98%; the organic zinc reagent of 3-chloro-1-butene is prepared by a conventional method;
(2)2- (4-chlorophenyl) -2- (1-cyclopropylethyl) -oxirane
At room temperature, taking 40ml of dichloromethane, sequentially adding 0.12mol of zinc powder, 0.012mol of cuprous chloride and 0.04mol of dibromomethane, then adding 0.0024mol of catalyst acetyl chloride, and stirring for 10-15 min; dissolving 0.10mol of 2- (4-chlorophenyl) -2- (but-3-en-2-yl) -oxirane in 15ml of dichloromethane to obtain a solution, and dropwise adding the solution into the dibromomethane solution for about 15 min; dropwise adding 0.2mol of dibromomethane into the solution, heating to about 40 ℃ after dropwise adding, reacting for 5-6h, cooling after the reaction is finished, adding 30mL of 2M hydrochloric acid, stirring, layering, extracting a water layer with 30mL of dichloromethane, and combining organic layers; the organic layer was washed once more with saturated aqueous sodium chloride solution; the solvent is recovered by organic phase decompression, the yield of crude product is 95 percent, and the qualitative content is 90 percent;
(3) preparation of cyproconazole
Adding 120ml of DMF (dimethyl formamide) and 1,2, 4-triazole sodium salt (203mmol) into a 250ml four-mouth reaction bottle provided with a thermometer, a condenser tube and a stirring device, adding 2- (4-chlorphenyl) -2- (1-cyclopropyl ethyl) -ethylene oxide (170mmol), heating to 100 ℃, reacting for 60-100min, sampling and analyzing, and judging that the reaction is finished when the content of the 1-chloro-2- (4-chlorphenyl) -3-cyclopropyl butan-2-ol is less than 1%. Cooling to room temperature, dropwise adding the reaction solution into 120ml of cold water, stirring to separate out a solid, filtering, washing with water, and drying to obtain the cyproconazole with the content of 96% and the weight yield of 90%.
Example 6
(1)2- (4-chlorophenyl) -2- (but-3-en-2-yl) -oxirane
10.0mmol of 2, 4' -dichloroacetophenone is dissolved in 20.0ml of anhydrous ether, the mixture is cooled to 0 ℃ in an ice bath, the prepared 11.0mmol of 3-chloro-1-butene organic zinc reagent is slowly dripped, after dripping, the reaction solution is heated to room temperature and stirred for 1.0 h. Continuously heating to about 40 ℃ for reaction for 3h, adding saturated ammonium chloride aqueous solution, stirring for 10min after the reaction is finished, separating out an organic phase, extracting a water layer by using diethyl ether, combining the organic phases, and desolventizing to obtain the 2- (4-chlorphenyl) -2- (butyl-3-alkene-2-yl) -ethylene oxide, wherein the yield is 89%, and the qualitative purity is 98%; the organic zinc reagent of 3-chloro-1-butene is prepared by a conventional method;
(2)2- (4-chlorophenyl) -2- (1-cyclopropylethyl) -oxirane
At room temperature, taking 40ml of dichloromethane, sequentially adding 0.12mol of zinc powder, 0.012mol of cuprous chloride and 0.04mol of dibromomethane, then adding 0.0024mol of catalyst acetyl chloride, and stirring for 10-15 min; dissolving 0.10mol of 2- (4-chlorophenyl) -2- (but-3-en-2-yl) -oxirane in 15ml of dichloromethane to obtain a solution, and dropwise adding the solution into the dibromomethane solution for about 15 min; dropwise adding 0.2mol of dibromomethane into the solution, heating to about 40 ℃ after dropwise adding, reacting for 5-6h, cooling after the reaction is finished, adding 30mL of 2M hydrochloric acid, stirring, layering, extracting a water layer with 30mL of dichloromethane, and combining organic layers; the organic layer was washed once more with saturated aqueous sodium chloride solution; the solvent is recovered by organic phase decompression, the yield of crude product is 95 percent, and the qualitative content is 90 percent;
(3) preparation of cyproconazole
18ml of methanol, 4.1g (0.075mol) of sodium methoxide and 7.6g (0.11mol) of 1,2, 4-triazole are sequentially added into a four-neck flask provided with a thermometer, a condenser and a stirring device, and stirred for 1h at room temperature; dissolving 12.8g (0.05mol) of 2- (4-chlorophenyl) -2- (1-cyclopropylethyl) -oxirane in 50ml of methanol to form a solution, dropwise adding the solution into the triazole solution, heating the reaction solution to reflux after the dropwise adding is finished, reacting for 90-120min at the temperature, sampling and analyzing, and judging that the reaction is finished when the content of the 2- (4-chlorophenyl) -2- (1-cyclopropylethyl) -oxirane is less than 1%. And (3) after the reaction is finished, removing the methanol by reduced pressure distillation, stirring and washing the residual materials by using 100ml of water, filtering to obtain a crude product of cyproconazole, and recrystallizing normal hexane to obtain a white solid cyproconazole, wherein the weight yield is 91 percent, and the purity is 98 percent.
Example 7
(1) Preparation of 1-chloro-2- (4-chlorophenyl) -3-methyl-4-penten-2-ol
10.0mmol of 2, 4' -dichloroacetophenone is dissolved in 20.0ml of anhydrous ether, cooled to 0 ℃ in an ice bath, prepared Grignard reagent mixed by 12.0mmol of 3-chloro-1-butene and 1-chloro-2-butene is slowly dripped, and after dripping, the reaction solution is heated to room temperature and stirred for 1.0 h. After the reaction is finished, adding saturated ammonium chloride aqueous solution, extracting with diethyl ether, combining organic phases, and obtaining 1-chloro-2- (4-chlorphenyl) -3-methyl-4-pentene-2-alcohol after desolventizing, wherein the yield is 95%, and the qualitative purity is 98%; the 3-chloro-1-butene Grignard reagent is prepared by a conventional method;
(2) preparation of 1-chloro-2- (4-chlorophenyl) -3-cyclopropylbutan-2-ol
At room temperature, taking 40ml of dichloromethane, sequentially adding 0.12mol of zinc powder, 0.012mol of cuprous chloride and 0.04mol of dibromomethane, then adding 0.0024mol of catalyst acetyl chloride, and stirring for 10-15 min; dissolving 0.10mol of 1-chloro-2- (4-chlorophenyl) -3-methyl-4-pentene-2-alcohol in 15ml of dichloromethane to form a solution, and dropwise adding the solution into the dibromomethane solution for about 15 min; dropwise adding 0.2mol of dibromomethane into the solution, heating to about 40 ℃ after dropwise adding, reacting for 5-6h, cooling after the reaction is finished, adding 30mL of 2M hydrochloric acid, stirring, layering, extracting a water layer with 30mL of dichloromethane, and combining organic layers; the organic layer was washed once more with saturated aqueous sodium chloride solution; the solvent is recovered by organic phase decompression, the yield of crude product is 95 percent, and the qualitative content is 90 percent;
(3) preparation of cyproconazole
18ml of methanol, 4.1g (0.075mol) of sodium methoxide and 7.6g (0.11mol) of 1,2, 4-triazole are sequentially added into a four-neck flask provided with a thermometer, a condenser and a stirring device, and stirred for 1h at room temperature; dissolving 12.8g (0.05mol) of 1-chloro-2- (4-chlorophenyl) -3-cyclopropylbutan-2-ol in 50ml of methanol to form a solution, dropwise adding the solution into the triazole solution, heating the reaction solution to reflux after the dropwise adding is finished, reacting for 90-120min at the temperature, sampling and analyzing, and judging that the reaction is finished when the content of the 1-chloro-2- (4-chlorophenyl) -3-cyclopropylbutan-2-ol is less than 1%. And (3) after the reaction is finished, removing the methanol by reduced pressure distillation, stirring and washing the residual materials by using 100ml of water, filtering to obtain a crude product of cyproconazole, and recrystallizing normal hexane to obtain a white solid cyproconazole, wherein the weight yield is 91 percent, and the purity is 98 percent.
Example 8
(1) Preparation of 1-chloro-2- (4-chlorophenyl) -3-methyl-4-penten-2-ol
10.0mmol of 2, 4' -dichloroacetophenone is dissolved in 20.0ml of anhydrous ether, the mixture is cooled to 0 ℃ in an ice bath, 12.0mmol of prepared 3-chloro-1-butene Grignard reagent is slowly dripped, and after dripping, the reaction solution is heated to room temperature and stirred for 1.0 h. After the reaction is finished, adding saturated ammonium chloride aqueous solution, extracting with diethyl ether, combining organic phases, and obtaining 1-chloro-2- (4-chlorphenyl) -3-methyl-4-pentene-2-alcohol after desolventizing, wherein the yield is 95%, and the qualitative purity is 98%; the 3-chloro-1-butene Grignard reagent is prepared by a conventional method;
(2) preparation of 1-chloro-2- (4-chlorophenyl) -3-cyclopropylbutan-2-ol
At room temperature, taking 40ml of dichloromethane, sequentially adding 0.12mol of zinc powder, 0.012mol of cuprous chloride and 0.04mol of diiodomethane, adding 0.0024mol of catalyst acetyl chloride, and stirring for 10-15 min; dissolving 0.10mol of 1-chloro-2- (4-chlorophenyl) -3-methyl-4-pentene-2-alcohol in 15ml of dichloromethane to form a solution, and dropwise adding the solution into the diiodomethane solution for about 15 min; dropwise adding 0.2mol of diiodomethane into the solution, heating to about 40 ℃ after dropwise adding, reacting for 5-6h, cooling after the reaction is finished, adding 30mL of 2M hydrochloric acid, stirring, layering, extracting a water layer with 30mL of dichloromethane, and combining organic layers; the organic layer was washed once more with saturated aqueous sodium chloride solution; the solvent is recovered by organic phase decompression, the yield of crude product is 98 percent, and the qualitative content is 93 percent;
(3) preparation of cyproconazole
18ml of methanol, 4.1g (0.075mol) of sodium methoxide and 7.6g (0.11mol) of 1,2, 4-triazole are sequentially added into a four-neck flask provided with a thermometer, a condenser and a stirring device, and stirred for 1h at room temperature; dissolving 12.8g (0.05mol) of 1-chloro-2- (4-chlorophenyl) -3-cyclopropylbutan-2-ol in 50ml of methanol to form a solution, dropwise adding the solution into the triazole solution, heating the reaction solution to reflux after the dropwise adding is finished, reacting for 90-120min at the temperature, sampling and analyzing, and judging that the reaction is finished when the content of the 1-chloro-2- (4-chlorophenyl) -3-cyclopropylbutan-2-ol is less than 1%. And (3) after the reaction is finished, removing the methanol by reduced pressure distillation, stirring and washing the residual materials by using 100ml of water, filtering to obtain a crude product of cyproconazole, and recrystallizing normal hexane to obtain a white solid cyproconazole, wherein the weight yield is 91 percent, and the purity is 98 percent.
Example 9
(1) Preparation of 1-chloro-2- (4-chlorophenyl) -3-methyl-4-penten-2-ol
10.0mmol of 2, 4' -dichloroacetophenone is dissolved in 20.0ml of anhydrous ether, the mixture is cooled to 0 ℃ in an ice bath, 12.0mmol of prepared 3-chloro-1-butene Grignard reagent is slowly dripped, and after dripping, the reaction solution is heated to room temperature and stirred for 1.0 h. After the reaction is finished, adding saturated ammonium chloride aqueous solution, then extracting with diethyl ether, combining organic phases, and obtaining 1-chloro-2- (4-chlorophenyl) -3-methyl-4-pentene-2-ol after desolventizing, wherein the yield is 95 percent, and the qualitative purity is 98 percent; the 3-chloro-1-butene Grignard reagent is prepared by a conventional method;
(2) preparation of 1-chloro-2- (4-chlorophenyl) -3-cyclopropylbutan-2-ol
At room temperature, taking 40ml of dichloromethane, sequentially adding 0.12mol of zinc powder, 0.012mol of cuprous chloride and 0.04mol of bromochloromethane, then adding 0.0024mol of catalyst acetyl chloride, and stirring for 10-15 min; dissolving 0.10mol of 1-chloro-2- (4-chlorophenyl) -3-methyl-4-pentene-2-alcohol in 15ml of dichloromethane to form a solution, and dropwise adding the solution into the bromochloromethane solution for about 15 min; dropwise adding 0.3mol of bromochloromethane into the solution, heating to about 40 ℃ after dropwise adding, reacting for 8-10h, cooling after the reaction is finished, adding 30mL of 2M hydrochloric acid, stirring, layering, extracting a water layer with 30mL of dichloromethane, and combining organic layers; the organic layer was washed once more with saturated aqueous sodium chloride solution; the organic phase is decompressed and used for recovering the solvent, the yield of the crude product is 90 percent, and the qualitative content is 90 percent;
(3) preparation of cyproconazole
18ml of methanol, 4.1g (0.075mol) of sodium methoxide and 7.6g (0.11mol) of 1,2, 4-triazole are sequentially added into a four-neck flask provided with a thermometer, a condenser and a stirring device, and stirred for 1h at room temperature; dissolving 12.8g (0.05mol) of 1-chloro-2- (4-chlorophenyl) -3-cyclopropylbutan-2-ol in 50ml of methanol to form a solution, dropwise adding the solution into the triazole solution, heating the reaction solution to reflux after the dropwise adding is finished, reacting for 90-120min at the temperature, sampling and analyzing, and judging that the reaction is finished when the content of the 1-chloro-2- (4-chlorophenyl) -3-cyclopropylbutan-2-ol is less than 1%. And (3) after the reaction is finished, removing the methanol by reduced pressure distillation, stirring and washing the residual materials by using 100ml of water, filtering to obtain a crude product of cyproconazole, and recrystallizing normal hexane to obtain a white solid cyproconazole, wherein the weight yield is 91 percent, and the purity is 98 percent.
Example 10
(1) Preparation of 1-chloro-2- (4-chlorophenyl) -3-methyl-4-penten-2-ol
10.0mmol of 2, 4' -dichloroacetophenone is dissolved in 20.0ml of anhydrous ether, the mixture is cooled to 0 ℃ in an ice bath, 12.0mmol of prepared 3-chloro-1-butene Grignard reagent is slowly dripped, and after dripping, the reaction solution is heated to room temperature and stirred for 1.0 h. After the reaction is finished, adding saturated ammonium chloride aqueous solution, extracting with diethyl ether, combining organic phases, and obtaining 1-chloro-2- (4-chlorphenyl) -3-methyl-4-pentene-2-alcohol after desolventizing, wherein the yield is 95%, and the qualitative purity is 98%; the 3-chloro-1-butene Grignard reagent is prepared by a conventional method;
(2) preparation of 1-chloro-2- (4-chlorophenyl) -3-cyclopropylbutan-2-ol
At room temperature, taking 40ml of dichloromethane, sequentially adding 0.12mol of zinc powder, 0.012mol of cuprous chloride and 0.04mol of chloroiodomethane, adding 0.0024mol of catalyst acetyl chloride, and stirring for 10-15 min; dissolving 0.10mol of 1-chloro-2- (4-chlorophenyl) -3-methyl-4-pentene-2-alcohol in 15ml of dichloromethane to form a solution, and dropwise adding the solution into the bromochloromethane solution for about 15 min; dropwise adding 0.3mol of chloroiodomethane into the solution, heating to about 40 ℃ after dropwise adding, reacting for 8-10h, cooling after the reaction is finished, adding 30mL of 2M hydrochloric acid, stirring, layering, extracting a water layer with 30mL of dichloromethane, and combining organic layers; the organic layer was washed once more with saturated aqueous sodium chloride solution; the solvent is recovered by organic phase decompression, the yield of crude product is 89%, and the qualitative content is 90%;
(3) preparation of cyproconazole
Adding 18ml of methanol, 4.1g (0.075mol) of sodium methoxide and 7.6g (0.11mol) of 1,2, 4-triazole into a four-neck flask with a thermometer, a condenser and a stirring device in sequence, and stirring for 1h at room temperature; dissolving 12.8g (0.05mol) of 1-chloro-2- (4-chlorophenyl) -3-cyclopropylbutan-2-ol in 50ml of methanol to form a solution, dropwise adding the solution into the triazole solution, heating the reaction solution to reflux after the dropwise adding is finished, reacting for 90-120min at the temperature, sampling and analyzing, and judging that the reaction is finished when the content of the 1-chloro-2- (4-chlorophenyl) -3-cyclopropylbutan-2-ol is less than 1%. And (3) after the reaction is finished, removing the methanol by reduced pressure distillation, stirring and washing the residual materials by using 100ml of water, filtering to obtain a crude product of cyproconazole, and recrystallizing normal hexane to obtain a white solid cyproconazole, wherein the weight yield is 91 percent, and the purity is 98 percent.
The above description is only for the specific embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are included in the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the appended claims.
Claims (3)
1. A process for the preparation of cyproconazole from 1-chloro-2- (4-chlorophenyl) -3-methyl-4-penten-2-ol comprising the steps of:
(1) performing nucleophilic addition reaction on 2, 4' -dichloroacetophenone and a 3-halo-1-butene Grignard reagent, a 3-halo-1-butene organic zinc reagent, a 1-halo-2-butene Grignard reagent or a 1-halo-2-butene organic zinc reagent to obtain one or a mixture of two of products, namely 1-chloro-2- (4-chlorophenyl) -3-methyl-4-penten-2-ol and 2- (4-chlorophenyl) -2- (but-3-en-2-yl) -ethylene oxide; the molar ratio of the 2, 4' -dichloroacetophenone to the 3-halo-1-butene Grignard reagent, the 3-halo-1-butene organic zinc reagent, the 1-halo-2-butene Grignard reagent or the 1-halo-2-butene organic zinc reagent is 1: 0.8 to 3.0;
(2) cyclizing the product obtained in the step (1) and methylene dihalide to obtain one or a mixture of two of products 1-chloro-2- (4-chlorphenyl) -3-cyclopropyl butyl-2-alcohol and 2- (4-chlorphenyl) -2- (1-cyclopropyl ethyl) -ethylene oxide; the reaction also comprises zinc powder, copper salt and catalyst acetyl chloride, wherein the copper salt is selected from cuprous chloride; the methylene dihalide is selected from methylene diiodide, methylene dibromide, bromochloromethane, iodochloromethane, iodobromomethane or the mixture thereof; and the mol ratio of the 1-chloro-2- (4-chlorphenyl) -3-methyl-4-penten-2-ol to the sum of the 2- (4-chlorphenyl) -2- (butyl-3-en-2-yl) -ethylene oxide, zinc powder and copper salt is 1: 0.8-4.0: 0.01 to 0.8;
(3) a, performing nucleophilic substitution reaction on the product obtained in the step (2) and 1,2, 4-triazole or 1,2, 4-triazole salt to obtain cyproconazole; wherein, when the reaction raw materials in the step (3) A contain 1-chloro-2- (4-chlorphenyl) -3-cyclopropyl butyl-2-alcohol and 1,2, 4-triazole, the reactants also comprise alkali; the molar ratio of the alkali to the 1-chloro-2- (4-chlorophenyl) -3-cyclopropylbutan-2-ol is 0.8-2.0: 1; the alkali is selected from sodium methoxide and sodium ethoxide;
or the like, or, alternatively,
(3) b, reacting the 1-chloro-2- (4-chlorophenyl) -3-cyclopropylbutan-2-ol in the product obtained in the step (2) with alkali to generate 2- (4-chlorophenyl) -2- (1-cyclopropylethyl) ethylene oxide, and then performing ring-opening reaction with 1,2, 4-triazole to obtain cyproconazole; the alkali is selected from sodium methoxide and sodium ethoxide;
the reaction formula is as follows:
wherein X is chlorine or bromine; m is hydrogen, sodium, potassium or lithium; y is magnesium or zinc.
2. The method for preparing cyproconazole from 1-chloro-2- (4-chlorophenyl) -3-methyl-4-penten-2-ol according to claim 1, wherein the step (3) A comprises the following steps:
(a) dissolving 1,2, 4-triazole and alkali in a solvent according to a measured part, and uniformly stirring to obtain a triazole solution;
(b) dissolving 1-chloro-2- (4-chlorphenyl) -3-cyclopropyl butyl-2-alcohol in a solvent, dropwise adding the solution into the triazole solution obtained in the step (a), and performing reflux reaction after dropwise adding until the content of the 1-chloro-2- (4-chlorphenyl) -3-cyclopropyl butyl-2-alcohol is less than 1%;
(c) after the reaction is finished, carrying out reduced pressure distillation to remove the solvent, and washing and filtering the residual materials to obtain a crude product of cyproconazole; refining to obtain white solid cyproconazole.
3. The method for preparing cyproconazole from 1-chloro-2- (4-chlorophenyl) -3-methyl-4-penten-2-ol according to claim 1, wherein the step (3) B comprises the following specific reaction processes:
(a) dissolving metered parts of 1-chloro-2- (4-chlorphenyl) -3-cyclopropyl butan-2-ol and alkali in a solvent, and reacting under stirring to obtain 2- (4-chlorphenyl) -2- (1-cyclopropylethyl) oxirane;
(b) dissolving 1,2, 4-triazole in a solvent, dropwise adding the solution into the 2- (4-chlorophenyl) -2- (1-cyclopropylethyl) oxirane solution obtained in the step (a), and performing reflux reaction after the dropwise adding is finished until the content of the 2- (4-chlorophenyl) -2- (1-cyclopropylethyl) oxirane is less than 1%;
(c) after the reaction is finished, carrying out reduced pressure distillation to remove the solvent, and washing and filtering the residual materials to obtain a crude product of cyproconazole; refining to obtain white solid cyproconazole.
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