Preparation method of alkylpyran 3, 5-difluorobenzene

Abstract

The invention relates to the technical field of organic synthesis, and provides a preparation method of alkylpyran-3, 5-difluorobenzene, which comprises the following steps: S1, adding a Grignard reagent into an alkylpyrone solution, reacting for the first time, quenching for the first time, separating liquid to obtain an organic phase, adding acidic resin into the organic phase, refluxing, and filtering to obtain filtrate containing alkylpyranene chlorobenzene, sequentially adding tetramethyldisiloxane and methanesulfonic acid into the filtrate containing the alkylpyran chlorobenzene, and carrying out a second reaction to obtain alkylpyran chlorobenzene; s2, adding alkylpyran chlorobenzene, 3, 5-difluorophenylboronic acid and an acid-binding agent into the solvent, stirring, adding a catalyst, and carrying out a third reaction to obtain alkylpyran 3, 5-difluorobenzene; the Grignard reagent is prepared from magnesium chips and p-chlorobromobenzene. According to the technical scheme, the problems of high preparation cost and low purity and yield of the alkylpyran 3, 5-difluorobenzene in the prior art are solved.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for preparing 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. At present, alkylpyran 3,5-difluorobenzene is prepared by using alkylpyrone as the starting material, and reacting with p-bromobenzene lithium generated by selective bromination of p-dibromobenzene with butyl lithium at ultra-low temperature and hydrolyzing to generate alkylpyranol bromobenzene, and alkylpyranol bromobenzene is hydroxylated by silicon reagent to generate alkylpyran bromobenzene, and alkylpyran bromobenzene is then reacted with 3,5-difluorophenylboric acid by Suzuki reaction to obtain it.

[0003] It can be seen that the existing technology requires butyl lithium, ultra-low temperature reaction conditions and selective bromination when preparing alkylpyran 3,5-difluorobenzene, which are all unfavorable factors for organic synthesis. For example, the high price of butyl lithium will increase the cost of raw materials; ultra-low temperature reaction conditions require the use of liquid nitrogen and special equipment, which will increase the cost; and selective bromination 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 invention provides a method for preparing 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 art.

[0006] The technical solution of the present invention is as follows: The present invention provides a method for preparing alkylpyran 3,5-difluorobenzene, comprising the following steps: 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.

[0007] In the present invention, the preparation process route diagram is as follows:

[0008] As a further technical solution, the preparation method of the Grignard reagent comprises the following steps: adding magnesium chips into tetrahydrofuran, then adding a tetrahydrofuran solution of p-chlorobromobenzene, and reacting to obtain the Grignard reagent.

[0009] As a further technical solution, during the reaction, the temperature is 10-50°C and the time is 2-4h.

[0010] As a further technical solution, the molar ratio of the magnesium chips to the p-chlorobromobenzene is 1.1-1.15:1.

[0011] As a further technical solution, the alkyl pyrone solution is an alkyl pyrone toluene solution.

[0012] As a further technical solution, the alkyl pyrone solution includes one of an ethyl pyrone solution, a propyl pyrone solution, and a cyclopentyl pyrone solution.

[0013] As a further technical solution, the molar ratio of the p-chlorobromobenzene to the alkyl pyrone in the alkyl pyrone solution is 1.2-1.3:1.

[0014] As a further technical solution, during the first reaction, the temperature is -20~0°C and the time is 1.5~2.5h.

[0015] As a further technical solution, the first quenching comprises the following steps: adding the reaction solution obtained from the first reaction into ice water, stirring, and acidifying to a pH value of 6 with hydrochloric acid.

[0016] As a further technical solution, the weight ratio of the acidic resin to the alkyl pyrone in the alkyl pyrone solution is 1-5:100.

[0017] As a further technical solution, during the reflux, the reflux water is separated until no water is produced.

[0018] As a further technical solution, the molar ratio of the tetramethyldisiloxane to the alkylpyrone in the alkylpyrone solution is 1.05-1.1:1.

[0019] As a further technical solution, the molar ratio of the methanesulfonic acid to the alkyl pyrone in the alkyl pyrone solution is 1.2:1.

[0020] As a further technical solution, during the second reaction, the temperature is -10°C and the time is 2 to 6 hours.

[0021] As a further technical solution, after the second reaction is completed, the reaction solution is washed with water to neutrality, dried with a desiccant, the desiccant is removed, passed through a silica gel column, the solvent is removed by rotation, distilled under reduced pressure, the fractions are collected in vacuo, and frozen for crystallization.

[0022] As a further technical solution, the molar ratio of the 3,5-difluorophenylboric acid to the alkylpyranylchlorobenzene is 1.05-1.1:1.

[0023] As a further technical solution, the molar ratio of the acid binding agent to the alkylpyranylchlorobenzene is 1.5:1.

[0024] As a further technical solution, the acid binding agent includes one of potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, and sodium phosphate, preferably potassium carbonate.

[0025] 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 alkylpyranylchlorobenzene is 1:50.

[0026] As a further technical solution, the phase transfer catalyst includes one of tetrabutylammonium bromide, tetrabutylammonium chloride, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride, and tetradecyltrimethylammonium chloride, preferably tetrabutylammonium bromide.

[0027] As a further technical solution, the mass ratio of the catalyst to the alkylpyranylchlorobenzene is 2-4:10000.

[0028] As a further technical solution, the catalyst is a palladium catalyst, preferably Pd132.

[0029] As a further technical solution, in step S2, the solvent consists of N,N-dimethylformamide and water in a volume ratio of 2:1.

[0030] As a further technical solution, during the third reaction, the temperature is 30-60°C and the time is 3h.

[0031] As a further technical solution, after the third reaction is completed, the temperature is lowered, water and toluene are added, stirred, allowed to stand, and separated. The aqueous phase is extracted with toluene, and the organic phases are combined, washed with water until neutral, dried with a desiccant, the desiccant is removed, the solvent is removed by rotation, and crystallization is performed.

[0032] As a further technical solution, when water and toluene are added, the volume ratio of water to toluene is 18:5.

[0033] The working principle and beneficial effects of the present invention are: 1. In the present invention, when preparing alkylpyran 3,5-difluorobenzene, a Grignard reagent method with mild reaction conditions is used instead of a butyl lithium lithium substitution method, thereby avoiding ultra-low temperature reaction conditions, reducing the preparation cost, and improving the reaction safety; alkylpyran chlorobenzene and 3,5-difluoroboric acid are used for Suzuki coupling reaction, which significantly improves the yield and purity of alkylpyran 3,5-difluorobenzene.

[0034] 2. In the present invention, the Grignard reagent is added to the alkyl pyrone solution, which avoids the defect that a large amount of by-products are generated due to the addition of the alkyl pyrone solution to the Grignard reagent, resulting in the subsequent reaction not being able to proceed normally.

[0035] 3. In the present invention, an acidic resin is selected as a dehydration catalyst, thereby avoiding the defect that the conventional dehydration catalyst such as p-toluenesulfonic acid is too strong, resulting in a small amount of alkylpyran chlorobenzene produced, thereby affecting the preparation of alkylpyran 3,5-difluorobenzene. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] The present invention will be further described in detail below in conjunction with the accompanying drawings and specific embodiments.

[0037] Figure 1 The gas chromatogram of ethylpyranylchlorobenzene in Example 1; Figure 2 is the gas chromatogram of ethylpyran 3,5-difluorobenzene in Example 1; Figure 3 Is the gas chromatogram of propylpyranylchlorobenzene in Example 4; Figure 4 is the gas chromatogram of propylpyran 3,5-difluorobenzene in Example 4; Figure 5 Is the gas chromatogram of cyclopentylpyranylchlorobenzene in Example 5; Figure 6 This is the gas chromatogram of cyclopentylpyran 3,5-difluorobenzene in Example 5. DETAILED DESCRIPTION

[0038] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0039] In the following examples and comparative examples, unless otherwise specified, all reaction raw materials are of reagent grade; the model of the acidic resin is 001×7 strongly acidic cation exchange resin.

[0040] Example 1 A method for preparing ethylpyran 3,5-difluorobenzene comprises the following steps: S1. Under nitrogen protection, 100g (0.781 mol) of ethylpyrone was dissolved in 200mL of toluene to obtain ethylpyrone toluene solution. The cold brine was cooled to -10°C. The Grignard reagent was slowly added from the constant pressure funnel to the ethylpyrone toluene solution. The addition was completed in 2.5 hours. After the addition was completed, the reaction was carried out at -10°C for 2 hours. The reaction solution (the content of ethylpyrone 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 hour. 10% hydrochloric acid was added dropwise to acidify to pH 6. The liquid was separated. The aqueous phase was extracted twice with 200mL of toluene. The organic phases were combined and washed with water until neutral. After the water was separated, the organic phase was put into another clean three-necked flask, 5g of acidic resin was added under stirring, and heated to reflux. , reflux water until no water is produced, filter to remove the acidic resin, and obtain a filtrate containing ethylpyranene chlorobenzene (the content of ethylpyranene chlorobenzene is 86.2%), cool to -10°C under nitrogen protection, add 115.4g (0.859moL) of tetramethyldisiloxane to the filtrate containing ethylpyranene chlorobenzene, control the temperature at -10°C and stir for 1h, then add 90.06g (0.937moL) of methylsulfonic acid, react at -10°C for 4h, after the reaction is completed, wash with water until neutral, dry with anhydrous sodium sulfate, remove the desiccant, pass through a silica gel column, spin to remove the solvent, distill under reduced pressure, collect the fractions at a vacuum of -0.098MPa and 150°C, freeze crystallize with anhydrous ethanol 4 times, and obtain 108.9g of ethylpyranene chlorobenzene with a purity of 98.74%. The gas chromatogram is as shown in Figure 1 As shown; The preparation method of the Grignard reagent comprises the following steps: adding 28g (1.167moL) of magnesium chips into a 1L three-necked flask, heating and drying under a nitrogen flow, adding 200mL of tetrahydrofuran, dissolving 194.3g (1.015moL) of p-chlorobromobenzene in 388mL of tetrahydrofuran for later use, adding 5mL of p-chlorobromobenzene tetrahydrofuran solution into the three-necked flask, stirring to initiate a reaction, controlling the temperature at 30°C to dropwise add the remaining p-chlorobromobenzene tetrahydrofuran solution, and completing the dropwise addition in 2.5h. After the dropwise addition is completed, controlling the temperature at 30°C, stirring, and reacting for 3h to obtain the Grignard reagent; S2. Add 50 g (0.222 mol) of ethylpyranyl chlorobenzene, 38.5 g (0.244 mol) of 3,5-difluorophenylboric acid and 46 g (0.333 mol) of potassium carbonate to a solvent consisting of 200 mL of N,N-dimethylformamide and 100 mL of water. Stir under nitrogen protection, add 0.02 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, stand, separate the liquids, extract the aqueous phase twice with 100 mL of toluene, combine the organic phases, wash with water to neutrality, dry with anhydrous sodium sulfate, remove the desiccant, spin off the solvent, and crystallize with ethanol to obtain 46.1 g of ethylpyranyl 3,5-difluorobenzene with a purity of 99.76% and a yield of 68.7%. The gas chromatogram is as follows: Figure 2 shown.

[0041] Example 2 The only difference between this embodiment and embodiment 1 is that in step S2 of this embodiment, the amount of catalyst Pd132 added is 0.04 g, and 58.4 g of ethylpyran 3,5-difluorobenzene is obtained with a purity of 99.81% and a yield of 81.7%.

[0042] Example 3 The only difference between this embodiment and embodiment 2 is that in step S2 of this embodiment, 1 g of tetrabutylammonium bromide is further added to the solvent to obtain 58.3 g of ethylpyranyl 3,5-difluorobenzene with a purity of 99.75% and a yield of 86.9%.

[0043] Example 4 A method for preparing propylpyranyl 3,5-difluorobenzene comprises the following steps: S1. Under nitrogen protection, 120g (0.845moL) of propylpyrone was dissolved in 240mL of toluene to obtain a propylpyrone toluene solution. The cold brine was cooled to -10°C. The Grignard reagent was slowly added from the constant pressure funnel to the propylpyrone toluene solution. The addition was completed in 2.5 hours. After the addition was completed, the reaction was carried out at -10°C for 2 hours. The reaction solution (the content of propylpyrone in the reaction solution was 1.32%, and the content of the by-product tertiary alcohol was 2.21%) was poured into ice water and stirred for 1 hour. 10% hydrochloric acid was added dropwise to acidify to pH 6. The liquid was separated. The aqueous phase was extracted twice with 240mL of toluene. The organic phases were combined and washed with water until neutral. After the water was separated, the organic phase was put into another clean three-necked flask, and 5g of acidic resin was added under stirring. The mixture was heated. The mixture was refluxed and water was separated until no water was produced. The acidic resin was filtered to obtain a filtrate containing propylpyranylchlorobenzene (the content of propylpyranylchlorobenzene was 91.6%). The mixture was cooled to -10°C under nitrogen protection. 125g (0.929moL) of tetramethyldisiloxane was added to the filtrate containing propylpyranylchlorobenzene. The mixture was stirred at -10°C for 1h. Then, 97.5g (1.014moL) of methylsulfonic acid was added and the mixture was reacted at -10°C for 4h. After the reaction was completed, the mixture was washed with water until neutral, dried over anhydrous sodium sulfate, the desiccant was removed, and the mixture was passed through a silica gel column. The solvent was removed by rotation and distillation under reduced pressure. The fractions were collected at a vacuum of -0.098MPa and 150°C. The fractions were crystallized 4 times with anhydrous ethanol to obtain 139.2g of propylpyranylchlorobenzene with a purity of 98.87%. The gas chromatogram was as shown in FIG. Figure 3 As shown; The preparation method of the Grignard reagent comprises the following steps: adding 28g (1.167moL) of magnesium chips into a 1L three-necked flask, heating and drying under a nitrogen flow, adding 200mL of tetrahydrofuran, dissolving 194.1g (1.014moL) of p-chlorobromobenzene in 388mL of tetrahydrofuran for later use, adding 5mL of p-chlorobromobenzene tetrahydrofuran solution into the three-necked flask, stirring to initiate a reaction, controlling the temperature at 30°C to dropwise add the remaining p-chlorobromobenzene tetrahydrofuran solution, and completing the dropwise addition in 2.5h. After the dropwise addition is completed, controlling the temperature at 30°C, stirring, and reacting for 3h to obtain the Grignard reagent; S2. Add 50 g (0.209 mol) of propylpyranyl chlorobenzene, 35.2 g (0.223 mol) of 3,5-difluorophenylboric acid, 43.3 g (0.314 mol) of potassium carbonate and 1 g of tetrabutylammonium bromide to a solvent consisting of 200 mL of N,N-dimethylformamide and 100 mL of water. Stir under nitrogen protection, 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, stand, separate the liquids, extract the aqueous phase twice with 100 mL of toluene, combine the organic phases, wash with water to neutrality, dry with anhydrous sodium sulfate, remove the desiccant, spin-dry 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 follows: Figure 4 shown.

[0044] Example 5 A method for preparing cyclopentylpyran 3,5-difluorobenzene comprises the following steps: S1. Under nitrogen protection, 132 g (0.785 mol) of cyclopentylpyrone was dissolved in 264 mL of toluene to obtain a cyclopentylpyrone toluene solution. The cold brine was cooled to -10 °C, and the Grignard reagent was slowly added from the constant pressure funnel to the cyclopentylpyrone toluene solution. The addition was completed in 2.5 hours. After the addition was completed, the reaction was carried out at -10 °C for 2 hours. The reaction solution (the content of cyclopentylpyrone in the reaction solution was 1.52%, and the content of the by-product tertiary alcohol was 2.36%) was poured into ice water and stirred for 1 hour. 10% hydrochloric acid was added dropwise to acidify to pH 6. The liquid was separated, and the aqueous phase was extracted twice with 260 mL of toluene. The organic phases were combined, and the organic phases were washed with water until neutral. After the water was separated, the organic phase was put into another clean three-necked flask, and 5 g of acidic resin was added under stirring. The reaction mixture was heated to 40 °C. Reflux, reflux water until no water is produced, filter to remove the acidic resin, and obtain a filtrate containing cyclopentylpyranene chlorobenzene (the content of cyclopentylpyranene chlorobenzene is 90.42%), cool to -10°C under nitrogen protection, add 116.1g (0.864moL) of tetramethyldisiloxane to the filtrate containing cyclopentylpyranene chlorobenzene, control the temperature at -10°C and stir for 1h, then add 90.5g (0.942moL) of methylsulfonic acid, react at -10°C for 4h, after the reaction is completed, wash with water until neutral, dry over anhydrous sodium sulfate, remove the desiccant, pass through a silica gel column, spin-dry the solvent, distill under reduced pressure, collect the fractions at a vacuum of -0.098MPa and 150°C, freeze-crystallize with anhydrous ethanol 4 times, and obtain 145.3g of cyclopentylpyranene chlorobenzene with a purity of 99.2%. The gas chromatogram is as follows Figure 5 As shown; The preparation method of the Grignard reagent comprises the following steps: adding 26g (1.083moL) of magnesium chips into a 1L three-necked flask, heating and drying under a nitrogen flow, adding 200mL of tetrahydrofuran, dissolving 180.3g (0.942moL) of p-chlorobromobenzene in 360mL of tetrahydrofuran for later use, adding 5mL of p-chlorobromobenzene tetrahydrofuran solution into the three-necked flask, stirring to initiate a reaction, controlling the temperature at 30°C to dropwise add the remaining p-chlorobromobenzene tetrahydrofuran solution, and completing the dropwise addition in 2.5h. After the dropwise addition is completed, controlling the temperature at 30°C, stirring, and reacting for 3h to obtain the Grignard reagent; S2. Add 50 g (0.19 mol) of cyclopentylpyranyl chlorobenzene, 33 g (0.209 mol) of 3,5-difluorophenylboric acid, 39.3 g (0.285 mol) of potassium carbonate and 1 g of tetrabutylammonium bromide to a solvent consisting of 200 mL of N,N-dimethylformamide and 100 mL of water. Stir under nitrogen protection, 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, stand, separate the liquids, extract the aqueous phase twice with 100 mL of toluene, combine the organic phases, wash with water until neutral, dry with anhydrous sodium sulfate, remove the desiccant, spin-dry the solvent, and crystallize 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 follows: Figure 6 shown.

[0045] Comparative experiment 1 Effect of the order of adding Grignard reagent and ethylpyrone on the preparation of ethylpyranyl 3,5-difluorobenzene Add 28g (1.167moL) magnesium chips to a 1L three-necked flask, heat and dry under nitrogen flow, add 200mL tetrahydrofuran, dissolve 194.3g (1.015moL) p-chlorobromobenzene in 388mL tetrahydrofuran for later use, add 5mL p-chlorobromobenzene tetrahydrofuran solution to the three-necked flask, stir to initiate the reaction, control the temperature at 30℃ and drop the remaining p-chlorobromobenzene tetrahydrofuran solution, add the solution at 30℃, add the solution at 30℃, stir and react for 3h to obtain Grignard reagent, cool the cold brine to -10℃ under nitrogen protection, dissolve 100g (0.781moL) ethylpyrone in 200mL toluene to obtain ethylpyrone toluene solution, add the ethylpyrone toluene solution to the Grignard reagent, add the solution at 30℃, add the solution at 2.5h, react at -10℃ for 2h, and test the reaction solution after the reaction; The test results show that in the reaction of Grignard reagent and ethylpyrone, the remaining 17.85% of ethylpyrone did not react, and 47.74% of the by-product tertiary alcohol was generated, indicating that under this condition, ethylpyrone participated in the reaction as lactone. Due to the generation of a large amount of by-products, the preparation of ethylpyran 3,5-difluorobenzene could not proceed normally.

[0046] Comparative Experiment 2 Effect of conventional dehydration catalysts on the preparation of ethylpyran 3,5-difluorobenzene Under nitrogen protection, 100g (0.781moL) of ethylpyrone was dissolved in 200mL of toluene to obtain an ethylpyrone toluene solution. The cold brine was cooled to -10°C, and the Grignard reagent was slowly added to the ethylpyrone toluene solution from a constant pressure funnel. The addition was completed in 2.5 hours. After the addition was completed, the reaction was carried out at -10°C for 2 hours. The reaction solution (the content of ethylpyrone 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 hour. 10% hydrochloric acid was added dropwise to acidify to a pH value of 6. The liquid was separated, and the aqueous phase was extracted twice with 200mL of toluene. The organic phases were combined, and the organic phases were washed with water until neutral. After the water was separated, the organic phase was put into another clean three-necked flask, and 5g of p-toluenesulfonic acid was added under stirring. The reaction solution was heated to reflux, and the water was separated by reflux until no water was produced. The acidic resin was removed by filtration, and the filtrate containing alkylpyranene chlorobenzene was tested. The preparation method of the Grignard reagent comprises the following steps: adding 28g (1.167moL) of magnesium chips into a 1L three-necked flask, heating and drying under a nitrogen flow, adding 200mL of tetrahydrofuran, dissolving 194.3g (1.015moL) of p-chlorobromobenzene in 388mL of tetrahydrofuran for later use, adding 5mL of p-chlorobromobenzene tetrahydrofuran solution into the three-necked flask, stirring to initiate a reaction, controlling the temperature at 30°C to dropwise add the remaining p-chlorobromobenzene tetrahydrofuran solution, and completing the dropwise addition in 2.5h. After the dropwise addition is completed, controlling the temperature at 30°C, stirring, and reacting for 3h to obtain the Grignard reagent; The test results show that the content of ethylpyranyl chlorobenzene is 42.6%. Analysis shows that this is due to the strong acidity of p-toluenesulfonic acid. The strong acidity of conventional dehydration catalysts will affect the normal preparation of ethylpyranyl 3,5-difluorobenzene.

[0047] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should 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.

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 alkylpyranyl chlorobenzene is 1.5:1; Preferably, the acid binding agent includes one of potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate and sodium phosphate.

9. A method for preparing alkylpyran 3,5-difluorobenzene according to claim 1, characterized in that, In step S2, a phase transfer catalyst is further added to the solvent, and the mass ratio of the phase transfer catalyst to the alkylpyranylchlorobenzene is 1:50; Preferably, the phase transfer catalyst includes one of tetrabutylammonium bromide, tetrabutylammonium chloride, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride and tetradecyltrimethylammonium chloride.

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

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