A preparation method of alkyl pyran 3,5-difluorobenzene

Abstract

The present invention relates to the technical field of organic synthesis, and provides a method for preparing alkyl pyran 3,5-difluorobenzene, comprising the following steps: S1. Add a Grignard reagent to an alkyl pyranone solution, conduct a first reaction, perform a first quenching, separate the liquid by liquid separation to obtain an organic phase, add an acidic resin to the organic phase, reflux, filter to obtain a filtrate containing alkyl pyran en-chlorobenzene, and successively add tetramethyldisiloxane and methanesulfonic acid to the filtrate containing alkyl pyran en-chlorobenzene, conduct a second reaction to obtain alkyl pyran chlorobenzene; S2. Add alkyl pyran chlorobenzene, 3,5-difluorobenzeneboronic acid and an acid-binding agent to a solvent, stir, add a catalyst, conduct a third reaction to obtain alkyl pyran 3,5-difluorobenzene; the Grignard reagent is prepared from magnesium chips and p-chlorobromobenzene. Through the above technical solution, the problems of high preparation cost, low purity and low yield of alkyl pyran 3,5-difluorobenzene in the related art are solved.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and specifically, to a preparation method of alkylpyran 3,5-difluorobenzene. Background Art

[0002] Alkylpyran 3,5-difluorobenzene is an important intermediate of existing liquid crystal materials and is widely used in TFT liquid crystal materials. Currently, alkylpyran 3,5-difluorobenzene is prepared by using alkylpyranone as the starting material, selectively debrominating p-dibromobenzene with butyllithium to generate p-bromophenyllithium, reacting at ultra-low temperature, hydrolyzing to generate alkylpyranol bromobenzene, generating alkylpyran bromobenzene after dehydroxy group removal by a silicon reagent, and then reacting alkylpyran bromobenzene with 3,5-difluorophenylboronic acid through Suzuki reaction.

[0003] It can be seen from this that in the preparation of alkylpyran 3,5-difluorobenzene by the existing technology, butyllithium, ultra-low temperature reaction conditions and selective debromination are required, which are all unfavorable factors for organic synthesis. For example, the high price of butyllithium will increase the raw material cost; the ultra-low temperature reaction conditions require liquid nitrogen and special equipment, resulting in increased costs; selective debromination leads to low purity and yield.

[0004] In order to reduce the preparation cost of alkylpyran 3,5-difluorobenzene and improve its purity and yield, it is of great significance to develop a new preparation method of alkylpyran 3,5-difluorobenzene. Summary of the Invention

[0005] The present invention provides a preparation method of alkylpyran 3,5-difluorobenzene, which solves the problems of high preparation cost, low purity and low yield of alkylpyran 3,5-difluorobenzene in the related technology.

[0006] The technical solution of the present invention is as follows:

[0007] The present invention provides a preparation method of alkylpyran 3,5-difluorobenzene, including the following steps:

[0008] S1. Add a Grignard reagent to an alkylpyranone solution, conduct a first reaction, a first quenching, liquid separation, to obtain an organic phase. Add an acidic resin to the organic phase, reflux, filter, to obtain a filtrate containing alkylpyran enol chloride benzene. Add tetramethyldisiloxane and methanesulfonic acid to the filtrate containing alkylpyran enol chloride benzene in sequence, conduct a second reaction, to obtain alkylpyran chloride benzene;

[0009] S2. Add the alkylpyran chloride benzene, 3,5-difluorophenylboronic acid and an acid-binding agent to a solvent, stir, add a catalyst, conduct a third reaction, to obtain alkylpyran 3,5-difluorobenzene;

[0010] The Grignard reagent is prepared from magnesium chips and p-chlorobromobenzene.

[0011] In the present invention, the preparation process route diagram is as follows:

[0012]

[0013] As a further technical solution, the preparation method of the Grignard reagent includes the following steps: adding magnesium chips into tetrahydrofuran, and then adding a tetrahydrofuran solution of p-chlorobromobenzene, and reacting to obtain the Grignard reagent.

[0014] As a further technical solution, during the reaction, the temperature is 10 - 50 °C and the time is 2 - 4 h.

[0015] As a further technical solution, the molar ratio of the magnesium chips to the p-chlorobromobenzene is 1.1 - 1.15:1.

[0016] As a further technical solution, the alkylpyranone solution is an alkylpyranone toluene solution.

[0017] As a further technical solution, the alkylpyranone solution includes one of an ethylpyranone solution, a propylpyranone solution, and a cyclopentylpyranone solution.

[0018] As a further technical solution, the molar ratio of the p-chlorobromobenzene to the alkylpyranone in the alkylpyranone solution is 1.2 - 1.3:1.

[0019] As a further technical solution, during the first reaction, the temperature is -20 - 0 °C and the time is 1.5 - 2.5 h.

[0020] As a further technical solution, the first quenching includes the following steps: adding the reaction solution obtained from the first reaction into ice water and stirring, and acidifying with hydrochloric acid to a pH value of 6.

[0021] As a further technical solution, the weight ratio of the acidic resin to the alkylpyranone in the alkylpyranone solution is 1 - 5:100.

[0022] As a further technical solution, during the reflux, reflux and separate water until no water is generated.

[0023] As a further technical solution, the molar ratio of the tetramethyldisiloxane to the alkylpyranone in the alkylpyranone solution is 1.05 - 1.1:1.

[0024] As a further technical solution, the molar ratio of the methanesulfonic acid to the alkylpyranone in the alkylpyranone solution is 1.2:1.

[0025] As a further technical solution, during the second reaction, the temperature is -10 °C and the time is 2 - 6 h.

[0026] As a further technical solution, after the second reaction is completed, the reaction solution is washed with water until neutral, dried with a desiccant, the desiccant is removed, passed through a silica gel column, the solvent is removed by rotary evaporation, distilled under reduced pressure, the fractions are collected under vacuum, and frozen and crystallized.

[0027] As a further technical solution, the molar ratio of the 3,5-difluorobenzeneboronic acid to the alkyl pyran chlorobenzene is 1.05 - 1.1:1.

[0028] As a further technical solution, the molar ratio of the acid-binding agent to the alkyl pyran chlorobenzene is 1.5:1.

[0029] As a further technical solution, the acid-binding agent includes one of potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, and sodium phosphate, and preferably potassium carbonate.

[0030] As a further technical solution, in step S2, a phase transfer catalyst is further added to the solvent, and the mass ratio of the phase transfer catalyst to the alkyl pyran chlorobenzene is 1:50.

[0031] As a further technical solution, the phase transfer catalyst includes one of tetrabutylammonium bromide, tetrabutylammonium chloride, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride, and tetradecyltrimethylammonium chloride, and preferably tetrabutylammonium bromide.

[0032] As a further technical solution, the mass ratio of the catalyst to the alkyl pyran chlorobenzene is 2 - 4:10000.

[0033] As a further technical solution, the catalyst is a palladium catalyst, and preferably Pd132.

[0034] As a further technical solution, in step S2, the solvent is composed of N,N-dimethylformamide and water with a volume ratio of 2:1.

[0035] As a further technical solution, during the third reaction, the temperature is 30 - 60 °C and the time is 3 h.

[0036] As a further technical solution, after the third reaction is completed, the temperature is lowered, water and toluene are added, stirred, left to stand, separated, the aqueous phase is extracted with toluene, the organic phases are combined, washed with water until neutral, dried with a desiccant, the desiccant is removed, the solvent is removed by rotary evaporation, and crystallization is carried out.

[0037] As a further technical solution, when adding water and toluene, the volume ratio of water to toluene is 18:5.

[0038] The working principle and beneficial effects of the present invention are as follows:

[0039] 1. In the present invention, when preparing alkyl pyran 3,5-difluorobenzene, the Grignard reagent method with mild reaction conditions is selected to replace the butyllithium lithiation method, avoiding the ultra-low temperature reaction conditions, reducing the preparation cost, and improving the reaction safety; the Suzuki coupling reaction of alkyl pyran chlorobenzene and 3,5-difluoroboric acid is selected, significantly improving the yield and purity of alkyl pyran 3,5-difluorobenzene.

[0040] 2. In the present invention, adding the Grignard reagent to the alkyl pyranone solution avoids the defect that a large amount of by-products are generated when adding the alkyl pyranone solution to the Grignard reagent, resulting in the inability of the subsequent reaction to proceed normally.

[0041] 3. In the present invention, an acidic resin is selected as the dehydration catalyst, avoiding the defect that the amount of alkyl pyranene chlorobenzene generated is small due to the too strong acidity of conventional dehydration catalysts such as p-toluenesulfonic acid, thus affecting the preparation of alkyl pyran 3,5-difluorobenzene. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] The present invention will be further described in detail below with reference to the drawings and specific embodiments.

[0043] Figure 1 Gas chromatogram of ethyl pyran chlorobenzene in Example 1;

[0044] Figure 2 Is the gas chromatogram of ethyl pyran 3,5-difluorobenzene in Example 1;

[0045] Figure 3 Is the gas chromatogram of propyl pyran chlorobenzene in Example 4;

[0046] Figure 4 Is the gas chromatogram of propyl pyran 3,5-difluorobenzene in Example 4;

[0047] Figure 5 Is the gas chromatogram of cyclopentyl pyran chlorobenzene in Example 5;

[0048] Figure 6 Is the gas chromatogram of cyclopentyl pyran 3,5-difluorobenzene in Example 5. DETAILED DESCRIPTION OF THE INVENTION

[0049] The technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts fall within the scope of the present invention.

[0050] In the following examples and comparative examples, unless otherwise specified, all reaction raw materials are of reagent grade; the acid resin is of the type 001×7 strong acid cation exchange resin.

[0051] Example 1

[0052] A method for preparing ethyl pyran 3,5-difluorobenzene, comprising the following steps:

[0053] S1. Under nitrogen protection, 100 g (0.781 moL) of ethyl pyranone is dissolved in 200 mL of toluene to obtain an ethyl pyranone toluene solution, which is cooled to -10 °C with cold brine. The Grignard reagent is slowly added from a constant pressure funnel to the ethyl pyranone toluene solution, and the addition is completed within 2.5 h. After the addition is completed, the reaction is carried out at -10 °C for 2 h. The reaction solution after the reaction (the content of ethyl pyranone in the reaction solution is 2.5%, and the content of the by-product tertiary alcohol is 2.3%) is poured into ice water and stirred for 1 h, and then acidified with 10% hydrochloric acid by mass fraction to a pH value of 6. Liquid separation is carried out, and the aqueous phase is extracted twice with 200 mL of toluene. The organic phases are combined, washed with water until neutral, and after the water is completely separated, the organic phase is put into another clean three-necked flask. 5 g of acid resin is added with stirring, and the mixture is heated to reflux. Water is separated by reflux until no water is produced. The acid resin is removed by filtration to obtain a filtrate containing ethyl pyranene chlorobenzene (the content of ethyl pyranene chlorobenzene is 86.2%). The temperature is lowered to -10 °C under nitrogen protection, 115.4 g (0.859 moL) of tetramethyldisiloxane is added to the filtrate containing ethyl pyranene chlorobenzene, and the mixture is stirred at -10 °C for 1 h. Then 90.06 g (0.937 moL) of methanesulfonic acid is added, and the reaction is carried out at -10 °C for 4 h. After the reaction is completed, it is washed with water until neutral, dried over anhydrous sodium sulfate, the desiccant is removed, passed through a silica gel column, the solvent is removed by rotary evaporation, and vacuum distillation is carried out. The fraction is collected at a vacuum of -0.098 MPa and 150 °C, and frozen and crystallized 4 times with absolute ethanol to obtain 108.9 g of ethyl pyran chlorobenzene with a purity of 98.74%. The gas chromatogram is as Figure 1 shown;

[0054] Among them, the preparation method of the Grignard reagent comprises the following steps: 28 g (1.167 moL) of magnesium chips are added to a 1 L three-necked flask, heated and dried under a nitrogen stream, 200 mL of tetrahydrofuran is added, 194.3 g (1.015 moL) of p-chlorobromobenzene is dissolved in 388 mL of tetrahydrofuran for standby. 5 mL of the p-chlorobromobenzene tetrahydrofuran solution is added to the three-necked flask. After the reaction is initiated by stirring, the remaining p-chlorobromobenzene tetrahydrofuran solution is added dropwise at a controlled temperature of 30 °C, and the addition is completed within 2.5 h. After the addition is completed, the temperature is controlled at 30 °C and stirred for 3 h to obtain the Grignard reagent;

[0055] S2. Add 50 g (0.222 moL) of ethyl pyranyl chlorobenzene, 38.5 g (0.244 mol) of 3,5-difluorobenzeneboronic acid, and 46 g (0.333 moL) of potassium carbonate to a solvent composed of 200 mL of N,N-dimethylformamide and 100 mL of water. Under nitrogen protection, stir, add 0.02 g of catalyst Pd132, heat to 50 °C, and react for 3 h. After the reaction is completed, cool to room temperature, add 360 mL of water and 100 mL of toluene, stir, let stand, separate the layers. After the aqueous phase is extracted twice with 100 mL of toluene, combine the organic phases, wash with water until neutral, dry with anhydrous sodium sulfate, remove the desiccant, rotary evaporate the solvent, and crystallize with ethanol to obtain 46.1 g of ethyl pyranyl 3,5-difluorobenzene with a purity of 99.76% and a yield of 68.7%. The gas chromatogram is as shown in Figure 2 shown.

[0056] Example 2

[0057] The difference between this example and Example 1 is only that in step S2 of this example, the addition amount of catalyst Pd132 is 0.04 g, and 58.4 g of ethyl pyranyl 3,5-difluorobenzene is obtained with a purity of 99.81% and a yield of 81.7%.

[0058] Example 3

[0059] The difference between this example and Example 2 is only that in step S2 of this example, 1 g of tetrabutylammonium bromide is further added to the solvent, and 58.3 g of ethyl pyranyl 3,5-difluorobenzene is obtained with a purity of 99.75% and a yield of 86.9%.

[0060] Example 4

[0061] A preparation method of propyl pyranyl 3,5-difluorobenzene, comprising the following steps:

[0062] S1. Under nitrogen protection, dissolve 120 g (0.845 moL) of propylpyranone in 240 mL of toluene to obtain a propylpyranone toluene solution. Cool it to -10 °C with cold brine. Slowly add the Grignard reagent from the constant pressure funnel into the propylpyranone toluene solution. Finish the dropping in 2.5 h. After the dropping is completed, react at -10 °C for 2 h. Pour the reacted reaction solution (the content of propylpyranone in the reaction solution is 1.32%, and the content of the by-product tertiary alcohol is 2.21%) into ice water and stir for 1 h. Add hydrochloric acid with a mass fraction of 10% dropwise until the pH value is 6. Separate the layers. Extract the aqueous phase twice with 240 mL of toluene. Combine the organic phases. Wash the organic phase with water until it is neutral. After separating the water completely, put the organic phase into another clean three-necked flask. Add 5 g of acidic resin under stirring and heat to reflux. Reflux and separate water until no water is produced. Filter to remove the acidic resin to obtain a filtrate containing propylpyranene chlorobenzene (the content of propylpyranene chlorobenzene is 91.6%). Cool it to -10 °C under nitrogen protection. Add 125 g (0.929 moL) of tetramethyldisiloxane to the filtrate containing propylpyranene chlorobenzene. Stir at -10 °C for 1 h. Then add 97.5 g (1.014 moL) of methanesulfonic acid and react at -10 °C for 4 h. After the reaction is completed, wash with water until it is neutral, dry with anhydrous sodium sulfate, remove the desiccant, pass through a silica gel column, rotary evaporate the solvent, and perform vacuum distillation. Collect the fraction at a vacuum of -0.098 MPa and 150 °C. Crystallize with absolute ethanol 4 times to obtain 139.2 g of propylpyran chlorobenzene with a purity of 98.87%. The gas chromatogram is as shown in Figure 3 shown;

[0063] Among them, the preparation method of the Grignard reagent includes the following steps: Add 28 g (1.167 moL) of magnesium chips into a 1 L three-necked flask, heat and dry under a nitrogen stream, add 200 mL of tetrahydrofuran. Dissolve 194.1 g (1.014 moL) of p-chlorobromobenzene in 388 mL of tetrahydrofuran for standby. Add 5 mL of the p-chlorobromobenzene tetrahydrofuran solution to the three-necked flask. After stirring to initiate the reaction, control the temperature at 30 °C and dropwise add the remaining p-chlorobromobenzene tetrahydrofuran solution. Finish the dropping in 2.5 h. After the dropping is completed, control the temperature at 30 °C and stir for 3 h to obtain the Grignard reagent;

[0064] S2. Add 50 g (0.209 moL) of propylpyranyl chlorobenzene, 35.2 g (0.223 mol) of 3,5-difluorobenzeneboronic acid, 43.3 g (0.314 moL) of potassium carbonate and 1 g of tetrabutylammonium bromide to a solvent composed of 200 mL of N,N-dimethylformamide and 100 mL of water. Under nitrogen protection, stir, add 0.04 g of catalyst Pd132, heat to 50 °C, react for 3 h. After the reaction is completed, cool to room temperature, add 360 mL of water and 100 mL of toluene, stir, let stand, separate the layers. After the aqueous phase is extracted twice with 100 mL of toluene, combine the organic phases, wash with water until neutral, dry with anhydrous sodium sulfate, remove the desiccant, rotary evaporate the solvent, and crystallize with ethanol to obtain 57.7 g of propylpyranyl 3,5-difluorobenzene, with a purity of 99.83% and a yield of 87.3%. The gas chromatogram is as shown in Figure 4 shown.

[0065] Example 5

[0066] A preparation method of cyclopentylpyranyl 3,5-difluorobenzene, comprising the following steps:

[0067] S1. Under nitrogen protection, dissolve 132 g (0.785 moL) of cyclopentylpyranone in 264 mL of toluene to obtain a cyclopentylpyranone toluene solution. Cool to -10 °C with cold brine, and slowly add the Grignard reagent from the constant pressure funnel to the cyclopentylpyranone toluene solution. The addition is completed in 2.5 h. After the addition is completed, react at -10 °C for 2 h. Pour the reacted reaction solution (the content of cyclopentylpyranone in the reaction solution is 1.52%, and the content of by-product tertiary alcohol is 2.36%) into ice water and stir for 1 h. Add hydrochloric acid with a mass fraction of 10% dropwise to acidify to pH 6, separate the layers. The aqueous phase is extracted twice with 260 mL of toluene, combine the organic phases, wash the organic phase with water until neutral. After separating the water, put the organic phase into another clean three-necked flask, add 5 g of acidic resin under stirring, heat to reflux, reflux and separate water until no water is produced, filter to remove the acidic resin to obtain a filtrate containing cyclopentylpyranyl enyl chlorobenzene (the content of cyclopentylpyranyl enyl chlorobenzene is 90.42%). Cool to -10 °C under nitrogen protection, add 116.1 g (0.864 moL) of tetramethyldisiloxane to the filtrate containing cyclopentylpyranyl enyl chlorobenzene, stir at -10 °C for 1 h, then add 90.5 g (0.942 moL) of methanesulfonic acid, react at -10 °C for 4 h. After the reaction is completed, wash with water until neutral, dry with anhydrous sodium sulfate, remove the desiccant, pass through a silica gel column, rotary evaporate the solvent, and perform vacuum distillation. Collect the fraction at a vacuum of -0.098 MPa and 150 °C, and perform freeze crystallization with anhydrous ethanol 4 times to obtain 145.3 g of cyclopentylpyranyl chlorobenzene, with a purity of 99.2%. The gas chromatogram is as shown in Figure 5 shown;

[0068] Among them, the preparation method of the Grignard reagent includes the following steps: Add 26 g (1.083 moL) of magnesium shavings to a 1 L three-necked flask, heat and dry under a nitrogen stream, add 200 mL of tetrahydrofuran. Dissolve 180.3 g (0.942 moL) of p-chlorobromobenzene in 360 mL of tetrahydrofuran for standby. Add 5 mL of the p-chlorobromobenzene tetrahydrofuran solution to the three-necked flask. After stirring to initiate the reaction, control the temperature at 30 °C and dropwise add the remaining p-chlorobromobenzene tetrahydrofuran solution. The addition is completed in 2.5 h. After the addition is completed, control the temperature at 30 °C and stir for 3 h to obtain the Grignard reagent;

[0069] S2. Add 50 g (0.19 moL) of cyclopentylpyranyl chlorobenzene, 33 g (0.209 mol) of 3,5-difluorophenylboronic acid, 39.3 g (0.285 moL) of potassium carbonate, and 1 g of tetrabutylammonium bromide to a solvent composed of 200 mL of N,N-dimethylformamide and 100 mL of water. Under nitrogen protection, stir, add 0.04 g of the catalyst Pd132, heat to 50 °C, and react for 3 h. After the reaction is completed, cool to room temperature, add 360 mL of water and 100 mL of toluene, stir, let stand, separate the layers. The aqueous phase is extracted 2 times with 100 mL of toluene, then the organic phases are combined, washed with water until neutral, dried with anhydrous sodium sulfate, the desiccant is removed, the solvent is rotary evaporated, and crystallized with ethanol to obtain 57 g of cyclopentylpyranyl 3,5-difluorobenzene, with a purity of 99.84% and a yield of 87.5%. The gas chromatogram is as Figure 6 shown.

[0070] Comparative Experiment 1 Influence of the addition sequence of the Grignard reagent and ethyl pyranone on the preparation of ethyl pyranyl 3,5-difluorobenzene

[0071] Add 28 g (1.167 moL) of magnesium shavings to a 1 L three-necked flask, heat and dry under a nitrogen stream, add 200 mL of tetrahydrofuran. Dissolve 194.3 g (1.015 moL) of p-chlorobromobenzene in 388 mL of tetrahydrofuran for standby. Add 5 mL of the p-chlorobromobenzene tetrahydrofuran solution to the three-necked flask. After stirring to initiate the reaction, control the temperature at 30 °C and dropwise add the remaining p-chlorobromobenzene tetrahydrofuran solution. The addition is completed in 2.5 h. After the addition is completed, control the temperature at 30 °C and stir for 3 h to obtain the Grignard reagent. Under nitrogen protection, cool with cold brine to -10 °C. Dissolve 100 g (0.781 moL) of ethyl pyranone in 200 mL of toluene to obtain an ethyl pyranone toluene solution. Dropwise add the ethyl pyranone toluene solution to the Grignard reagent. The addition is completed in 2.5 h. After the addition is completed, react at -10 °C for 2 h, and detect the reaction solution after the reaction;

[0072] The test results show that in the reaction of Grignard reagent and ethyl pyranone, 17.85% of ethyl pyranone remained unreacted, and 47.74% of the by-product tertiary alcohol was formed, indicating that ethyl pyranone participated in the reaction in the form of lactone under these conditions. Due to the formation of a large amount of by-products, the preparation of ethyl pyran 3,5-difluorobenzene could not proceed normally.

[0073] Comparative Experiment 2: Influence of Conventional Dehydration Catalysts on the Preparation of Ethyl Pyran 3,5-difluorobenzene

[0074] Under nitrogen protection, 100 g (0.781 moL) of ethyl pyranone was dissolved in 200 mL of toluene to obtain an ethyl pyranone toluene solution. The temperature was lowered to -10 °C with cold brine. The Grignard reagent was slowly added from a constant pressure funnel to the ethyl pyranone toluene solution. The addition was completed in 2.5 h. After the addition was completed, the reaction was carried out at -10 °C for 2 h. The reaction solution after the reaction (the content of ethyl pyranone in the reaction solution was 2.5%, and the content of the by-product tertiary alcohol was 2.3%) was poured into ice water and stirred for 1 h. Hydrochloric acid with a mass fraction of 10% was added dropwise until the pH value reached 6. Liquid separation was carried out. The aqueous phase was extracted twice with 200 mL of toluene. The organic phases were combined, washed with water until neutral, and after separating the water completely, the organic phase was put into another clean three-necked flask. 5 g of p-toluenesulfonic acid was added with stirring, and the mixture was heated to reflux. Reflux and water separation were carried out until no water was produced. The acidic resin was removed by filtration, and the filtrate containing alkyl pyran en chloro benzene was detected;

[0075] Among them, the preparation method of the Grignard reagent includes the following steps: 28 g (1.167 moL) of magnesium chips were added to a 1 L three-necked flask, heated and dried under a nitrogen stream, 200 mL of tetrahydrofuran was added, 194.3 g (1.015 moL) of p-chlorobromobenzene was dissolved in 388 mL of tetrahydrofuran for standby. 5 mL of the p-chlorobromobenzene tetrahydrofuran solution was added to the three-necked flask. After stirring to initiate the reaction, the temperature was controlled at 30 °C and the remaining p-chlorobromobenzene tetrahydrofuran solution was added dropwise. The addition was completed in 2.5 h. After the addition was completed, the temperature was controlled at 30 °C and stirred for 3 h to obtain the Grignard reagent;

[0076] The test results show that the content of ethyl pyran en chloro benzene was 42.6%. It is considered that this is due to the too strong acidity of p-toluenesulfonic acid. The too strong acidity of the conventional dehydration catalyst will affect the normal preparation of ethyl pyran 3,5-difluorobenzene.

[0077] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing alkylpyran 3,5-difluorobenzene, characterized in that: The following steps are involved: S1, adding a Grignard reagent to an alkylpyrone solution, reacting for the first time, quenching for the first time, separating the liquids to obtain an organic phase, adding an acidic resin to the organic phase, refluxing, filtering, obtaining a filtrate containing alkylpyran alkene chlorobenzene, sequentially adding tetramethyldisiloxane and methylsulfonic acid to the filtrate containing alkylpyran alkene chlorobenzene, reacting for the second time, obtaining alkylpyran alkene chlorobenzene; S2, adding the alkylpyranyl chlorobenzene, 3,5-difluorophenylboric acid and an acid binding agent to the solvent, stirring, adding a catalyst, reacting for the third time, and obtaining alkylpyranyl 3,5-difluorobenzene; The Grignard reagent is prepared from magnesium chips and p-chlorobromobenzene; During the first reaction, the temperature is -20~0°C and the time is 1.5~2.5h; During the second reaction, the temperature is -10°C and the time is 2 to 6 hours.

2. A method for preparing alkylpyran 3,5-difluorobenzene according to claim 1, characterized in that, The molar ratio of the magnesium chips to the p-chlorobromobenzene is 1.1-1.15:

1.

3. A method for preparing alkylpyran 3,5-difluorobenzene according to claim 1, characterized in that, The molar ratio of the p-chlorobromobenzene to the alkyl pyrone in the alkyl pyrone solution is 1.2-1.3:

1.

4. A method for preparing alkylpyran 3,5-difluorobenzene according to claim 1, characterized in that, The weight ratio of the acidic resin to the alkyl pyrone in the alkyl pyrone solution is 1-5:

100.

5. A method for preparing alkylpyran 3,5-difluorobenzene according to claim 1, characterized in that, The molar ratio of the tetramethyl disiloxane to the alkyl pyrone in the alkyl pyrone solution is 1.05-1.1:

1.

6. A method for preparing alkylpyran 3,5-difluorobenzene according to claim 1, characterized in that, The molar ratio of the methanesulfonic acid to the alkyl pyrone in the alkyl pyrone solution is 1.2:

1.

7. A method for preparing alkylpyran 3,5-difluorobenzene according to claim 1, characterized in that, The molar ratio of the 3,5-difluorophenylboric acid to the alkylpyranylchlorobenzene is 1.05-1.1:

1.

8. A method for preparing alkylpyran 3,5-difluorobenzene according to claim 1, characterized in that, The molar ratio of the acid binding agent to the alkylpyranylchlorobenzene is 1.5:

1.

9. A method for preparing alkylpyran 3,5-difluorobenzene according to claim 1, characterized in that, In step S2, a phase transfer catalyst is also added to the solvent, and the mass ratio of the phase transfer catalyst to the alkylpyranylchlorobenzene is 1:

50.

10. The method for preparing alkylpyran 3,5-difluorobenzene according to claim 1, characterized in that: The mass ratio of the catalyst to the alkylpyranylchlorobenzene is 2-4:10000.

11. The method for preparing alkylpyran 3,5-difluorobenzene according to claim 8, characterized in that: The acid binding agent includes one of potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate and sodium phosphate.

12. The method for preparing alkylpyran 3,5-difluorobenzene according to claim 9, characterized in that: The phase transfer catalyst includes one of tetrabutylammonium bromide, tetrabutylammonium chloride, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride and tetradecyltrimethylammonium chloride.

13. The method for preparing alkylpyran 3,5-difluorobenzene according to claim 10, characterized in that: The catalyst is a palladium catalyst.

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