A method for the synthesis of 2,6-difluorostyrene
By using 2,6-dichlorobenzonitrile as a raw material, 2,6-difluorostyrene was synthesized through fluorination, methylation, reduction, and dehydration reactions, solving the problems of expensive raw materials and safety risks, and realizing the efficient and low-cost synthesis of 2,6-difluorostyrene.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- ZHEJIANG ZHONGXIN FLUORIDE MATERIALS CO LTD
- Filing Date
- 2026-04-10
- Publication Date
- 2026-06-26
AI Technical Summary
Existing methods for synthesizing 2,6-difluorostyrene suffer from high raw material costs, poor atom economy, and safety risks, limiting their industrial application.
2,6-Difluorostyrene was synthesized from 2,6-dichlorobenzonitrile via a four-step reaction involving fluorination, methylation, reduction, and dehydration. The use of inexpensive and readily available raw materials and optimization of reaction conditions improved the synthesis efficiency and product purity.
This provides a synthetic route with inexpensive and readily available raw materials, simple reaction operation, high yield, and good purity, which is suitable for industrial application.
Abstract
Description
Technical Field
[0001] This application relates to the field of organic chemical synthesis technology, and more specifically, to a method for synthesizing 2,6-difluorostyrene. Background Technology
[0002] 2,6-Difluorostyrene is an important fluorine-containing fine chemical. The fluorine atoms and unsaturated carbon-carbon double bonds in its molecule give it excellent reactivity and chemical structure expansion capabilities. Therefore, it has important applications in the fields of pharmaceuticals, pesticides, and new materials as a synthetic building block and functional polymer monomer. It is also a key intermediate in the synthesis of novel piperidine fungicides such as fluoxetine.
[0003] There are four main existing methods for synthesizing 2,6-difluorostyrene.
[0004] (1) Patent WO2023007426 discloses the synthesis of 2,6-difluorostyrene from 2,6-difluorobenzaldehyde via a Wittig reaction: .
[0005] This method has a short synthesis step, requiring only one reaction to obtain the target product. However, the raw materials used, such as 2,6-difluorobenzaldehyde and triphenylmethylphosphonium bromide, are expensive and difficult to obtain. At the same time, triphenylmethylphosphonium bromide, used as a Wittig reagent, has low atom utilization in the reaction and generates a large amount of triphenylphosphine oxygenate byproducts, resulting in high synthesis costs and making it difficult to scale up applications.
[0006] (2) Patent CN112961019 discloses the synthesis of 2,6-difluorostyrene from 2,6-difluoroacetophenone via a reduction and dehydration reaction: .
[0007] This method can synthesize the target product in just one step, but the raw materials used, 2,6-difluoroacetophenone, tetramethyldisiloxane and trifluoromethanesulfonic acid, are expensive and hard to obtain, resulting in high synthesis costs and insufficient competitiveness for industrial applications.
[0008] (3) Patent CN119219464 discloses the synthesis of 2,6-difluorostyrene from 2-bromo-1,3-difluorobenzene via Grignard reaction, carbonyl addition, and dehydration reaction: .
[0009] The drawback of this method is that the raw material 2-bromo-1,3-difluorobenzene is expensive and difficult to obtain, resulting in high synthesis costs. In addition, the first step Grignard reaction poses certain safety risks in industrial production.
[0010] (4) Patent CN119306568 discloses the synthesis of 2,6-difluorostyrene from 2,6-difluorobenzaldehyde via carbonyl addition and dehydration reactions: .
[0011] This method has certain advantages over the previous three synthesis methods, but it also has shortcomings such as the high price and difficulty in obtaining the raw material 2,6-difluorobenzaldehyde, and the Grignard reaction involving high safety risks in the synthesis process, which leads to high synthesis costs and potential safety hazards in production, thus limiting its large-scale application. Summary of the Invention
[0012] To address the shortcomings of traditional 2,6-difluorostyrene synthesis, such as high raw material costs, poor atom economy, and high safety risks, this application provides a novel method for synthesizing 2,6-difluorostyrene. Using 2,6-dichlorobenzonitrile, which has a mature market supply in the thousands of tons, as a raw material, 2,6-difluorostyrene is synthesized through a four-step reaction involving fluorination, methylation, reduction, and dehydration. This method offers advantages such as readily available and inexpensive raw materials, good atom economy, simple reaction operation, high synthesis yield, and high product purity, making it suitable for industrial applications.
[0013] The technical solution adopted in this application is as follows: A method for synthesizing 2,6-difluorostyrene includes the following steps: (1) 2,6-Dichlorobenzonitrile (I) undergoes a halogen exchange fluorination reaction with a fluorinating agent in a polar aprotic solvent to give 2,6-difluorobenzonitrile (II). (2) The 2,6-difluorobenzonitrile (II) obtained in step (1) undergoes an addition reaction with methyl magnesium halide in an inert solvent, and is hydrolyzed to obtain 2,6-difluoroacetophenone (III). (3) The 2,6-difluoroacetophenone (III) obtained in step (2) is subjected to carbonyl reduction reaction in a solvent to obtain 1-(2,6-difluorophenyl)ethanol (IV). (4) The 1-(2,6-difluorophenyl)ethanol (IV) obtained in step (3) is dehydrated in an alkane solvent under the catalysis of a protic acid to obtain 2,6-difluorostyrene (V).
[0014] The synthetic route used in this application can be represented by the following reaction formula: .
[0015] The further settings of this application are as follows: In step (1): The polar aprotic solvent refers to a solvent whose molecules have a large dipole moment but do not contain ionizable hydrogen atoms, selected from one or more of the following: N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolinone, dimethyl sulfoxide, dimethyl sulfone, sulfolane, hexamethylphosphoric triamine, acetonitrile, propionitrile, butyronitrile, benzonitrile, dimethyl carbonate, diethyl carbonate, methyl ethyl carbonate, ethylene carbonate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, tert-butyl acetate, and the amount of solvent used is 0.1 to 20 times the mass of 2,6-dichlorobenzonitrile (I).
[0016] The fluorinating agent can be an alkali metal fluoride salt, such as sodium fluoride or potassium fluoride, or a quaternary ammonium fluoride or quaternary phosphonium fluoride salt, such as tetramethylammonium fluoride, tetrabutylammonium fluoride, or tetraphenylphosphonium fluoride. Preferred fluorinating agents are alkali metal fluorides, selected from one or more of the following: lithium fluoride, sodium fluoride, potassium fluoride, rubidium fluoride, and cesium fluoride. The molar ratio of the fluorinating agent to 2,6-dichlorobenzonitrile (I) is 2–6:1.
[0017] During the fluorination reaction, adding appropriate amounts of single or composite catalysts can increase the fluorination reaction rate, lower the fluorination reaction temperature, and reduce the occurrence of side reactions. The main types of catalysts available include: quaternary ammonium salt catalysts, such as tetramethylammonium chloride, tetramethylammonium bromide, tetrabutylammonium bromide, tetrabutylammonium chloride, benzyltriethylammonium chloride, and hexadecyltrimethylammonium chloride; quaternary phosphonium salt catalysts, such as triphenylmethylphosphonium chloride, triphenylethylphosphonium bromide, and tetraphenylphosphonium bromide; and crown ether catalysts, such as 18-crown ether-6 and 15-crown ether-5. The amount of catalyst used is 0 to 0.5 times the mass of 2,6-dichlorobenzonitrile (I).
[0018] The reactivity of fluorination reaction systems varies depending on the type and amount of fluorinating agent, solvent, and catalyst used, thus requiring different fluorination reaction temperatures. Generally, when the fluorination reaction temperature is below 80°C, the reaction rate is slow, which is not conducive to improving synthesis efficiency. Conversely, when the fluorination reaction temperature is above 220°C, side reactions increase rapidly with rising temperature, leading to a more complex reaction system and a rapid decrease in reaction yield and product purity. Therefore, to obtain a suitable reaction rate while minimizing side reactions, the preferred fluorination reaction temperature is 80–220°C.
[0019] In step (2): The methyl magnesium halide is selected from one or more of methyl magnesium chloride, methyl magnesium bromide, and methyl magnesium iodide. Methyl magnesium halide can be prepared in-house or commercially available standard-specification methyl magnesium halide products can be used. When preparing methyl magnesium halide in-house, it is usually obtained by reacting metallic magnesium with chloromethane, bromomethane, or iodomethane in an inert solvent. The molar ratio of methyl magnesium halide to 2,6-difluorobenzonitrile(II) is 1 to 3:1.
[0020] The inert solvent mentioned refers to a solvent that does not react with the raw materials, intermediates, and products during the reaction process, and is selected from one or more of the following: diethyl ether, isopropyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, benzene, toluene, xylene, and ethylbenzene. The amount of solvent used is 0.1 to 20 times the mass of 2,6-difluorobenzonitrile (II).
[0021] 2,6-Difluorobenzonitrile(II) reacts with magnesium methyl halide via an addition reaction to yield the following structural intermediate: .
[0022] The intermediate reacts with water to yield 2,6-difluoroacetophenone (III). Therefore, after the addition reaction, the reaction solution needs to be quenched and hydrolyzed by adding water, i.e., adding an appropriate amount of water dropwise to the reaction solution or adding an appropriate amount of water dropwise to the reaction solution to cause the intermediate to hydrolyze and yield 2,6-difluoroacetophenone (III). The amount of water used is not particularly strict, except for meeting the requirements for quenching the intermediate and excess methyl magnesium halide; it can be adjusted within a reasonable range based on the convenience of post-processing. As an imine metal compound, the reaction intermediate has strong reactivity. To avoid side reactions, the reaction temperature must be strictly controlled. Lowering the reaction temperature helps suppress side reactions, but the reaction rate decreases accordingly, which is not conducive to improving synthesis efficiency. Excessively high reaction temperatures will trigger side reactions, reducing the reaction yield and product quality. The preferred reaction temperature is -30 to 80°C.
[0023] In step (3): The carbonyl reduction reaction method mentioned refers to all reduction methods applicable to the reduction of ketone carbonyl groups to secondary alcohols, including but not limited to metal-catalyzed hydrogenation reduction, metal-catalyzed transfer hydrogenation reduction, metal borohydride (lithium borohydride, sodium borohydride, potassium borohydride and their derivatives) reduction, and lithium aluminum hydride reduction. Considering factors such as reducing synthesis costs, improving atom economy, and reducing pollution emissions, the preferred carbonyl reduction method is metal-catalyzed hydrogenation reduction.
[0024] The metal-catalyzed hydrogenation reduction method uses a metal catalyst selected from noble metals and / or non-noble metals, specifically elements and / or compounds, wherein the metal element is selected from one or more of the following: nickel, palladium, platinum, cobalt, rhodium, iridium, chromium, molybdenum, iron, ruthenium, and copper. The elemental metal catalyst is in the form of porous particles, powder, or a dispersion supported on a carrier surface. The metal compound catalyst is selected from one or more of metal oxides, metal halides, metal sulfides, metal carbides, and metal complexes. The metal catalyst is a homogeneous catalyst or a heterogeneous catalyst, preferably a heterogeneous catalyst, to facilitate catalyst separation and recycling. The amount of metal catalyst used is 0.0001 to 0.5 times the weight of 2,6-difluoroacetophenone(III).
[0025] The metal-catalyzed hydrogenation reduction method is preferably carried out in a solvent, and the solvent is selected from one or more of alcohol solvents, ester solvents, aromatic solvents, alkane solvents, and water. More specifically, the reaction solvent is selected from one or more of the following: methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, tert-butanol, methyl formate, ethyl formate, isopropyl formate, tert-butyl formate, methyl acetate, ethyl acetate, isopropyl acetate, tert-butyl acetate, benzene, toluene, xylene, ethylbenzene, n-hexane, cyclohexane, methylcyclohexane, n-heptane, and water. The amount of solvent used is 0.1 to 20 times the mass of 2,6-difluoroacetophenone (III).
[0026] In the aforementioned metal-catalyzed hydrogen hydrogenation reduction method, hydrogen pressure is one of the key operating parameters. It needs to be coordinated and matched with parameters such as the type and amount of metal catalyst, the type and amount of reaction solvent, and the reaction temperature to ensure that the reaction has good reaction rate and selectivity. The preferred hydrogen pressure range is 0.001 to 3.0 MPa.
[0027] In the metal-catalyzed hydrogenation reduction method, the suitable hydrogenation reaction temperature varies depending on the type and amount of metal catalyst, the type and amount of reaction solvent, and the hydrogen pressure. To obtain an ideal reaction rate and minimize side reactions, a reaction temperature of 0–150°C is preferred.
[0028] In step (4): The alkane solvent is selected from one or more straight-chain, branched, or cyclic alkanes of C5 to C12. Preferred alkane solvents are selected from one or more of the following: n-hexane, cyclohexane, methylcyclohexane, and n-heptane. The amount of alkane solvent used is 0.1 to 100 times the mass of 1-(2,6-difluorophenyl)ethanol (IV).
[0029] It should be noted that aromatic hydrocarbons, such as benzene, toluene, xylene, and ethylbenzene, should not be used as reaction solvents to avoid the following side reactions: .
[0030] The protic acid is selected from one or more of the following: inorganic protic acids, organic protic acids, and protic acid-type resins. Representative inorganic protic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen sulfate, phosphoric acid, and dihydrogen phosphate. Representative organic protic acids include formic acid, acetic acid, propionic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzoic acid, benzenesulfonic acid, and p-toluenesulfonic acid. Representative protic acid-type resins include carboxylic acid-type cation exchange resins and sulfonic acid-type cation exchange resins. The amount of protic acid used is 0.0001 to 1 times the weight of 1-(2,6-difluorophenyl)ethanol (IV).
[0031] The dehydration reaction can be carried out at low temperatures (reaction temperature below the boiling points of water and solvent) by removing the water generated in the reaction with a dehydrating agent, or at high temperatures (reaction temperature equal to the boiling point of the solvent, the azeotropic point of the solvent and water, or the reaction temperature higher than the boiling point of water but lower than the boiling point of the solvent) by distillation to remove the water generated in the reaction, thereby promoting the reaction. Dehydrating agents used for low-temperature dehydration include, but are not limited to, anhydrous calcium chloride, dehydrating molecular sieves, and dehydrating silica gel. The preferred dehydration method is azeotropic dehydration under solvent boiling conditions, with a dehydration reaction temperature of 50–160°C. ℃.
[0032] Compared with the prior art, the beneficial effects of this application are reflected in: (1) A new synthetic method for synthesizing 2,6-difluorostyrene using 2,6-dichlorobenzonitrile as raw material through a four-step reaction of fluorination, methylation, reduction and dehydration was developed, providing a competitive new synthetic route for the industrial production of 2,6-difluorostyrene.
[0033] (2) Using 2,6-dichlorobenzonitrile, which has a mature market supply of thousands of tons, as raw material, compared with the raw materials such as 2,6-difluorobenzaldehyde used in existing synthesis methods, it has the advantages of cheap and readily available raw materials and stable market supply, solving the problem of low-priced, high-quality and stable supply of raw materials, and making the synthesis route truly have industrial application value.
[0034] (3) In the reaction of 1-(2,6-difluorophenyl)ethanol to synthesize 2,6-difluorostyrene, inert alkanes are used as reaction solvents, and aromatic solvents are avoided to prevent aromatic solvents from participating in side reactions, thereby greatly improving the reaction yield and product quality.
[0035] The present application will be further described below with reference to specific embodiments. It should be noted that the following embodiments are only for the purpose of helping to understand the present application and do not constitute a limitation thereof. The specific embodiments may not exhaustively cover all technical features of the present application; as long as the technical features involved in the specification do not conflict with each other, they can be combined to form new embodiments. Detailed Implementation
[0036] Example 1
[0037] 85 g of 2,6-dichlorobenzonitrile, 87 g of potassium fluoride, and 250 g of dimethyl sulfoxide were added to a 1 L reaction flask. The mixture was stirred and heated to 170 °C, and the reaction was maintained at this temperature for 14 hours. The reaction was then stopped and the mixture was cooled. The reaction system was cooled to room temperature, and 500 g of water was added. The mixture was stirred at room temperature and extracted with dichloroethane. The organic phase was removed by atmospheric distillation to remove the solvent. The concentrated liquid was then distilled under reduced pressure to obtain 65.0 g of 2,6-difluorobenzonitrile, with a yield of 94.6% and a purity of 99.5%.
[0038] Example 2
[0039] 100 g of 2,6-dichlorobenzonitrile, 98 g of sodium fluoride, 5 g of cesium fluoride, 5 g of tetraphenylphosphonium bromide, and 600 g of sulfolane were added to a 1 L reaction flask. The mixture was stirred and heated to 210 °C, and the reaction was maintained at this temperature for 12 hours. The reaction was then stopped and the temperature was lowered. The reaction system was distilled under reduced pressure to dryness. The resulting fraction was then purified by reduced pressure distillation to obtain 76.1 g of 2,6-difluorobenzonitrile, with a yield of 94.2% and a purity of 99.6%.
[0040] Example 3
[0041] 60 g of 2,6-dichlorobenzonitrile, 73 g of potassium fluoride, 6 g of tetramethylammonium chloride, and 600 g of N,N-dimethylformamide were added to a 1 L reaction flask. The mixture was stirred and heated to 150 °C, and the reaction was maintained at this temperature for 18 hours. The reaction was then stopped and the mixture was cooled. The reaction system was cooled to room temperature, filtered, and the filter cake was washed with N,N-dimethylformamide. The filtrate and the washing liquid were combined and subjected to vacuum distillation to obtain 46.2 g of 2,6-difluorobenzonitrile, with a yield of 95.2% and a purity of 99.4%.
[0042] Example 4
[0043] 120 g of 2,6-dichlorobenzonitrile, 100 g of potassium fluoride, and 600 g of 1,3-dimethyl-2-imidazolinone were added to a 1 L reaction flask. The mixture was stirred and heated to 190 °C, and the reaction was maintained at this temperature for 16 hours. The reaction was then stopped and the temperature was lowered. The reaction system was distilled under reduced pressure to dryness, and the resulting fraction was further distilled under reduced pressure to obtain 91.7 g of 2,6-difluorobenzonitrile, with a yield of 94.5% and a purity of 99.5%.
[0044] Example 5
[0045] 50 g of 2,6-dichlorobenzonitrile, 85 g of potassium fluoride, 5 g of cesium fluoride, 5 g of tetrabutylammonium bromide, and 600 g of tert-butyl acetate were added to a 1 L reaction flask. The mixture was stirred and heated to 95 °C, and the reaction was maintained at this temperature for 30 hours. The reaction was then stopped and the mixture was cooled. The reaction system was cooled to room temperature, diluted to 400 g of water, stirred at room temperature, and allowed to stand to separate the organic phase. The aqueous phase was extracted with tert-butyl acetate. The organic phases were combined, and the solvent was removed by distillation under normal pressure. The concentrate was then distilled under reduced pressure to obtain 38.3 g of 2,6-difluorobenzonitrile, with a yield of 94.7% and a purity of 99.4%.
[0046] Example 6
[0047] 235 mL of a 3 mol / L methylmagnesium chloride tetrahydrofuran solution was added to a 1 L reaction flask. Under nitrogen protection, the mixture was stirred at room temperature. A mixed solution of 70 g of 2,6-difluorobenzonitrile and 420 g of anhydrous tetrahydrofuran was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 6 hours. The reaction solution was diluted to 400 g of water, and the tetrahydrofuran was recovered by atmospheric distillation. The concentrate was extracted with ethyl acetate, and the organic phases were combined. The solvent was removed by atmospheric distillation, and the concentrate was purified by vacuum distillation to give 70.6 g of 2,6-difluoroacetophenone, with a yield of 89.8% and a purity of 99.6%.
[0048] Example 7
[0049] Add 60 g of 2,6-difluorobenzonitrile and 240 g of anhydrous diethyl ether to a 1-liter reaction flask, under nitrogen protection, stir and cool to -15°C. At -15°C, 260 mL of a 2 mol / L magnesium methyl bromide diethyl ether solution was added dropwise. After the addition was complete, the mixture was stirred at -15°C for 16 hours. 200 g of water was added, and the pH was adjusted to acidic with dilute sulfuric acid. The mixture was allowed to stand and separate into layers. The organic phase was separated, and the aqueous phase was extracted with diethyl ether. The organic phases were combined, and the solvent was removed by distillation under normal pressure. The concentrate was then distilled under reduced pressure to give 60.2 g of 2,6-difluoroacetophenone, with a yield of 89.4% and a purity of 99.4%.
[0050] Example 8
[0051] Add 230 mL of a 2.5 mol / L solution of methylmagnesium chloride in 2-methyltetrahydrofuran to a 1 L reaction flask. Under nitrogen protection, stir and heat to 40 °C. Add dropwise a mixed solution of 50 g of 2,6-difluorobenzonitrile and 400 g of anhydrous 2-methyltetrahydrofuran. After the addition is complete, heat to 40 °C. The reaction mixture was stirred at ℃ for 5 hours. The reaction solution was diluted in 500 g of ice water, the pH was adjusted to acidic with phosphoric acid, and the mixture was allowed to stand to separate into layers. The organic phase was separated, and the aqueous phase was extracted with 2-methyltetrahydrofuran. The organic phases were combined, the solvent was removed by distillation under normal pressure, and the concentrate was distilled under reduced pressure to obtain 51.9 g of 2,6-difluoroacetophenone, with a yield of 92.5% and a purity of 99.5%.
[0052] Example 9
[0053] Add 195 mL of a 3 mol / L tetrahydrofuran solution of methylmagnesium chloride to a 1 L reaction flask, under nitrogen protection, stir and heat to 60 °C. At ℃, a mixed solution of 45 g of 2,6-difluorobenzonitrile and 450 g of anhydrous toluene was added dropwise. After the addition was complete, the solution was heated to 60 °C. The reaction mixture was stirred at ℃ for 5 hours. The reaction solution was cooled to room temperature, diluted in 300 g of water, stirred at room temperature, and the pH was adjusted to acidic with concentrated hydrochloric acid. The mixture was allowed to stand and separate into layers. The organic phase was separated, and the aqueous phase was extracted with toluene. The organic phases were combined, and the solvent was removed by distillation under normal pressure. The concentrate was then distilled under reduced pressure to obtain 46.1 g of 2,6-difluoroacetophenone, with a yield of 91.3% and a purity of 99.3%.
[0054] Example 10
[0055] Add 125 g of 2,6-difluoroacetophenone, 500 g of methanol, and 2.5 g of 5% platinum-carbon to a 1-liter pressure-resistant reactor. Seal the reactor, replace the reactor with hydrogen, and maintain the hydrogen pressure at 0.7–0.8 MPa. Stir and heat to 40°C. The reaction was carried out at ℃ for 14 hours, then stopped and cooled. The reaction system was cooled to room temperature, the reaction solution was removed, the platinum carbon was recovered by filtration, and the solvent was removed by distillation of the filtrate to obtain 126.0 g of 1-(2,6-difluorophenyl)ethanol, with a yield of 99.5% and a purity of 99.3%.
[0056] Example 11
[0057] Add 90 g of 2,6-difluoroacetophenone, 540 g of ethanol, and 4.5 g of Raney nickel to a 1-liter pressure-resistant reactor. Seal the reactor, use a hydrogen purging system to maintain a hydrogen pressure of 0.9–1.0 MPa, and stir while heating to 60°C. The reaction was carried out at ℃ for 18 hours, then stopped and cooled. The reaction system was cooled to room temperature, the reaction solution was removed, Raney nickel was recovered by filtration, and the solvent was removed by distillation of the filtrate to obtain 90.4 g of 1-(2,6-difluorophenyl)ethanol, with a yield of 99.2% and a purity of 99.5%.
[0058] Example 12
[0059] Add 70 g of 2,6-difluoroacetophenone, 560 g of isopropanol, and 7 g of copper chromite to a 1-liter pressure-resistant reactor. Seal the reactor, replace the reactor with hydrogen, and maintain a hydrogen pressure of 1.5–1.6 MPa. Stir and heat to 120°C. The reaction was carried out at ℃ for 15 hours, then stopped and cooled. The reaction system was cooled to room temperature, the reaction solution was removed, copper chromite was recovered by filtration, and the solvent was removed by distillation of the filtrate to obtain 70.5 g of 1-(2,6-difluorophenyl)ethanol, with a yield of 99.4% and a purity of 99.2%.
[0060] Example 13
[0061] Add 60 g of 2,6-difluoroacetophenone, 600 g of ethyl acetate, and 9 g of Raney cobalt to a 1-liter pressure-resistant reactor. Seal the reactor, use a hydrogen purging system to maintain a hydrogen pressure of 2.0–2.1 MPa, and stir while heating to 100°C. The reaction was carried out at ℃ for 16 hours, then stopped and cooled. The reaction system was cooled to room temperature, the reaction solution was removed, Raney cobalt was recovered by filtration, and the solvent was removed by distillation of the filtrate to obtain 60.3 g of 1-(2,6-difluorophenyl)ethanol, with a yield of 99.2% and a purity of 99.4%.
[0062] Example 14
[0063] Add 45 g of 2,6-difluoroacetophenone, 450 g of toluene, 135 g of water, and 0.45 g of 5% palladium on carbon to a 1-liter pressure-resistant reactor. Seal the reactor, replace the reactor with hydrogen, maintain the hydrogen pressure at 0.5–0.6 MPa, and stir while heating to 80°C. The reaction was carried out at ℃ for 12 hours, then stopped and cooled. The reaction system was cooled to room temperature, the reaction solution was removed, palladium on carbon was recovered by filtration, the filtrate was allowed to stand to separate the organic phase, the aqueous phase was extracted with toluene, the organic phases were combined, the solvent was removed by atmospheric distillation, and the concentrate was purified by vacuum distillation to obtain 44.4 g of 1-(2,6-difluorophenyl)ethanol, with a yield of 97.4% and a purity of 99.9%.
[0064] Example 15
[0065] 50 g of 1-(2,6-difluorophenyl)ethanol, 1 g of p-toluenesulfonic acid, and 500 g of n-hexane were added to a 1 L reaction flask. The mixture was stirred and heated to reflux, and the water was removed by reflux for 7 hours. The reaction was then stopped and the temperature was lowered. The reaction system was cooled to room temperature, and 100 g of 2% potassium carbonate solution was added. The mixture was stirred at room temperature for 10 minutes, allowed to stand to separate the aqueous phase, and the organic phase was washed with 100 g of pure water. The solvent was recovered by distillation under normal pressure, and the concentrate was purified by vacuum distillation to obtain 42.2 g of 2,6-difluorostyrene, with a yield of 95.2% and a purity of 99.5%.
[0066] Example 16
[0067] 35 g of 1-(2,6-difluorophenyl)ethanol, 1.75 g of phosphoric acid, and 525 g of n-heptane were added to a 1 L reaction flask. The mixture was stirred and heated to reflux, and the water was removed under reflux for 5 hours. The reaction was then stopped and the temperature was lowered. The reaction system was cooled to room temperature, and 100 g of 5% sodium carbonate solution was added. The mixture was stirred at room temperature for 10 minutes, allowed to stand to separate the aqueous phase, and the organic phase was washed with 100 g of pure water. The solvent was recovered by distillation under normal pressure, and the concentrate was purified by vacuum distillation to obtain 29.4 g of 2,6-difluorostyrene, with a yield of 94.8% and a purity of 99.3%.
[0068] Example 17
[0069] 55 g of 1-(2,6-difluorophenyl)ethanol, 11 g of carboxylic acid-type cation exchange resin, and 1350 g of cyclohexane were added to a 2 L reaction flask. The mixture was stirred and heated to reflux, and the solution was separated under reflux for 5 hours. The reaction was then stopped and the temperature was lowered. The reaction system was cooled to room temperature, and the ion exchange resin was recovered by filtration. The solvent was recovered by atmospheric distillation of the filtrate. The concentrate was then distilled under reduced pressure to obtain 46.4 g of 2,6-difluorostyrene, with a yield of 95.2% and a purity of 99.4%.
[0070] Example 18
[0071] 65 g of 1-(2,6-difluorophenyl)ethanol, 6.5 g of sulfonic acid-type cation exchange resin, and 1300 g of methylcyclohexane were added to a 2 L reaction flask. The mixture was stirred and heated to reflux, and the mixture was refluxed for 4 hours to separate the water. The reaction was then stopped and the temperature was lowered. The reaction system was cooled to room temperature, and the ion exchange resin was recovered by filtration. The filtrate was washed successively with 100 g of 2% potassium carbonate solution and 200 g of pure water. The solvent was recovered by atmospheric distillation, and the concentrate was purified by vacuum distillation to obtain 54.9 g of 2,6-difluorostyrene, with a yield of 95.3% and a purity of 99.5%.
[0072] Example 19
[0073] 6.5 g of sulfonic acid-type cation exchange resin and 1300 g of methylcyclohexane were added to a 2 L reaction flask. The mixture was stirred and heated to reflux. 65 g of 1-(2,6-difluorophenyl)ethanol was added dropwise while refluxing to separate water. After the addition was complete, refluxing to separate water continued for 2 hours. The reaction was then stopped and the temperature was lowered. The reaction system was cooled to room temperature, and the ion exchange resin was recovered by filtration. The filtrate was washed successively with 100 g of 2% potassium carbonate solution and 200 g of pure water. The solvent was recovered by atmospheric distillation, and the concentrate was purified by vacuum distillation to obtain 55.0 g of 2,6-difluorostyrene, with a yield of 95.5% and a purity of 99.6%.
[0074] Comparative Example 1 30 g of 1-(2,6-difluorophenyl)ethanol, 3 g of sulfonic acid-type cation exchange resin, and 600 g of toluene were added to a 1 L reaction flask. The mixture was stirred and heated to reflux, and the water was separated under reflux for 4 hours. The reaction was then stopped and the temperature was lowered. The reaction system was cooled to room temperature, and the ion exchange resin was recovered by filtration. The filtrate was washed successively with 50 g of 2% potassium carbonate solution and 100 g of pure water. The solvent was recovered by atmospheric distillation, and the concentrate was purified by vacuum distillation to obtain 2.8 g of 2,6-difluorostyrene (purity 96.4%), and 35.8 g of a mixture of 1,3-difluoro-2-[1-(o-methylphenyl)ethyl]benzene (byproduct A) and 1,3-difluoro-2-[1-(p-methylphenyl)ethyl]benzene (byproduct B) in an approximately 8:2 ratio.
[0075] Byproduct A: .
[0076] 1H NMR (400 MHz, CDCl3) δ: 7.26 ~ 7.01 (m, 5H), 6.84 ~ 6.72 (m, 2H), 4.56 (q, J = 8 Hz, 1H), 2.28 (s, 3H), 1.71 (d, J = 8 Hz, 3H).
[0077] Byproduct B: .
[0078] 1 H NMR (400 MHz, CDCl3) δ: 7.22 ~ 6.96 (m, 5H), 6.84 ~ 6.72 (m, 2H), 4.63 (q, J = 8 Hz, 1H), 2.29 (s, 3H), 1.69 (d, J = 8 Hz, 3H).
[0079] Comparative Example 2 3 g of sulfonic acid-type cation exchange resin and 600 g of toluene were added to a 1 L reaction flask. The mixture was stirred and heated to reflux. 30 g of 1-(2,6-difluorophenyl)ethanol was added dropwise while refluxing to separate water. After the addition was complete, refluxing to separate water continued for 2 hours. The reaction was then stopped and the temperature was lowered. The reaction system was cooled to room temperature, and the ion exchange resin was recovered by filtration. The filtrate was washed successively with 50 g of 2% potassium carbonate solution and 100 g of pure water. The solvent was recovered by atmospheric distillation, and the concentrate was purified by vacuum distillation to obtain 3.6 g of 2,6-difluorostyrene (purity 96.8%), and 35.2 g of a mixture of 1,3-difluoro-2-[1-(o-methylphenyl)ethyl]benzene (byproduct A) and 1,3-difluoro-2-[1-(p-methylphenyl)ethyl]benzene (byproduct B) in an approximately 8:2 ratio.
[0080] Comparative Examples 18-19 and Comparative Examples 1-2 show that: 1-(2,6-difluorophenyl)ethanol undergoes reflux dehydration under protic acid catalysis to produce 2,6-difluorostyrene. If toluene is used as the reaction solvent, the following side reaction will occur: .
[0081] Therefore, aromatic hydrocarbons are not suitable as the reaction solvent for this reaction; alkanes are preferred.
Claims
1. A method for synthesizing 2,6-difluorostyrene, characterized in that, Includes the following steps: (1) 2,6-Dichlorobenzonitrile undergoes a halogen exchange fluorination reaction with a fluorinating agent in a polar aprotic solvent to obtain 2,6-difluorobenzonitrile; (2) The 2,6-difluorobenzonitrile obtained in step (1) undergoes an addition reaction with methyl magnesium halide in an inert solvent, and is then hydrolyzed to obtain 2,6-difluoroacetophenone; (3) The 2,6-difluoroacetophenone obtained in step (2) is subjected to a carbonyl reduction reaction in a solvent to obtain 1-(2,6-difluorophenyl)ethanol; (4) The 1-(2,6-difluorophenyl)ethanol obtained in step (3) is dehydrated in an alkane solvent under the catalysis of a protic acid to obtain 2,6-difluorostyrene.
2. The method for synthesizing 2,6-difluorostyrene according to claim 1, characterized in that, In step (1), the polar aprotic solvent is selected from one or more of the following: N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolinone, dimethyl sulfoxide, dimethyl sulfone, sulfolane, hexamethylphosphoric triamine, acetonitrile, propionitrile, butyronitrile, benzonitrile, dimethyl carbonate, diethyl carbonate, methyl ethyl carbonate, ethylene carbonate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, tert-butyl acetate, and the amount of solvent used is 0.1 to 20 times the mass of 2,6-dichlorobenzonitrile.
3. The method for synthesizing 2,6-difluorostyrene according to claim 1, characterized in that, In step (1), the fluorinating agent is selected from one or more of the following: lithium fluoride, sodium fluoride, potassium fluoride, rubidium fluoride, cesium fluoride, and the molar ratio of the fluorinating agent to 2,6-dichlorobenzonitrile is 2 to 6:
1.
4. The method for synthesizing 2,6-difluorostyrene according to claim 1, characterized in that, In step (1), the reaction temperature is 80 to 220°C.
5. The method for synthesizing 2,6-difluorostyrene according to claim 1, characterized in that, In step (2), the methyl magnesium halide is selected from one or more of methyl magnesium chloride, methyl magnesium bromide, and methyl magnesium iodide, and the molar ratio of methyl magnesium halide to 2,6-difluorobenzonitrile is 1 to 3:
1.
6. The method for synthesizing 2,6-difluorostyrene according to claim 1, characterized in that, In step (2), the inert solvent is selected from one or more of the following: diethyl ether, isopropyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, benzene, toluene, xylene, ethylbenzene, and the amount of solvent used is 0.1 to 20 times the mass of 2,6-difluorobenzonitrile.
7. The method for synthesizing 2,6-difluorostyrene according to claim 1, characterized in that, In step (2), the reaction temperature is -30 to 80℃.
8. The method for synthesizing 2,6-difluorostyrene according to claim 1, characterized in that, In step (3), the carbonyl reduction reaction is carried out by metal-catalyzed hydrogen hydrogenation reduction.
9. The method for synthesizing 2,6-difluorostyrene according to claim 8, characterized in that, In step (3), the metal catalyst used in the metal catalytic hydrogen hydrogenation reduction method is selected from elemental metals and / or compounds, wherein the metal element is selected from one or more of the following: nickel, palladium, platinum, cobalt, rhodium, iridium, chromium, molybdenum, iron, ruthenium, and copper. The amount of metal catalyst used is 0.0001 to 0.5 times the weight of 2,6-difluoroacetophenone.
10. The method for synthesizing 2,6-difluorostyrene according to claim 8, characterized in that, In step (3), the metal-catalyzed hydrogen hydrogenation reduction method is carried out in a solvent. The solvent used is selected from one or more of alcohol solvents, ester solvents, aromatic solvents, alkane solvents and water. The amount of solvent used is 0.1 to 20 times the mass of 2,6-difluoroacetophenone.
11. The method for synthesizing 2,6-difluorostyrene according to claim 8, characterized in that, In step (3), the hydrogen pressure range of the metal catalytic hydrogen hydrogenation reduction method is 0.001 to 3.0 MPa.
12. The method for synthesizing 2,6-difluorostyrene according to claim 8, characterized in that, In step (3), the metal-catalyzed hydrogen hydrogenation reduction method has a reaction temperature of 0 to 150°C.
13. The method for synthesizing 2,6-difluorostyrene according to claim 1, characterized in that, In step (4), the alkane solvent is selected from one or more straight-chain, branched or cyclic alkanes of C5 to C12, and the amount of solvent used is 0.1 to 100 times the mass of 1-(2,6-difluorophenyl)ethanol.
14. The method for synthesizing 2,6-difluorostyrene according to claim 1, characterized in that, In step (4), the protic acid is selected from one or more of the following: inorganic protic acid, organic protic acid, protic acid type resin, and the amount of protic acid used is 0.0001 to 1 times the weight of 1-(2,6-difluorophenyl)ethanol.
15. The method for synthesizing 2,6-difluorostyrene according to claim 1, characterized in that, In step (4), the dehydration reaction is carried out at a temperature of 50–160 °C.