Preparation process of 2-[2-(2, 4-difluorophenyl)-2-propylene-1-yl]-1, 3-propylene glycol

Abstract

A preparation process of 2-[2-(2, 4-difluorophenyl)-2-propylene-1-yl]-1, 3-propylene glycol belongs to the field of medical intermediates, and comprises the following steps: step 1, adding 1-[1-(bromomethyl) vinyl]-2, 4-difluoro-benzene and diethyl malonate into N, N-dimethylformamide, and then adding potassium carbonate for reaction; 2, after the reaction in the step 1 is completed, filtering to remove potassium carbonate, and then carrying out acid pickling, toluene extraction, saturated saline solution washing, concentration and rectification to obtain an oily substance; and step 3, adding the oily substance obtained in the step 2 into methanol, mixing, then adding sodium borohydride for reaction, and after the reaction is completed, concentrating, crystallizing and filtering to obtain the 2-[2-(2, 4-difluorophenyl)-2-propylene-1-yl]-1, 3-propylene glycol. According to the method, the cost is effectively reduced, so that the reaction period can be shortened, meanwhile, the reaction yield can be increased, and industrial production is facilitated.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical intermediates, specifically a preparation process for 2-[2-(2,4-difluorophenyl)-2-propen-1-yl]-1,3-propanediol. Background Technology

[0002] [2-(2,4-Difluorophenyl)-2-propen-1-yl]-1,3-propanediol is an important pharmaceutical intermediate that plays a key role in the synthesis of various bioactive drug molecules. For example, in the research and development and production of certain anti-inflammatory and antibacterial drugs, this compound can serve as a core structural unit and, through further chemical modification, construct the molecular skeleton of the target drug. Optimizing its preparation process is of great significance for improving drug synthesis efficiency, reducing production costs, and ensuring drug quality.

[0003] However, the existing production process has the following problems: the synthetic route is relatively long and the overall yield is low, which increases production time and cost; in some routes, when using 1,2,3-trichloropropane as an alkylating agent, there may be poor selectivity, which means that more by-products may be generated, which not only affects the yield but also increases the difficulty of subsequent separation and purification; therefore, there are problems such as long synthetic routes, low overall yield, and sometimes harsh reaction conditions that need to be solved. Summary of the Invention

[0004] This invention provides a preparation process for 2-[2-(2,4-difluorophenyl)-2-propen-1-yl]-1,3-propanediol to overcome the deficiencies in the prior art.

[0005] This invention is achieved through the following technical solution: A process for preparing 2-[2-(2,4-difluorophenyl)-2-propen-1-yl]-1,3-propanediol includes the following steps: Step 1: Add 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene and diethyl malonate to N,N-dimethylformamide, followed by the addition of potassium carbonate to carry out the reaction; Step 2: After the reaction in Step 1 is completed, the potassium carbonate is removed by filtration, followed by acid washing, toluene extraction, washing with saturated brine, adding anhydrous sodium sulfate to remove water, concentration, and distillation to obtain an oily substance; Step 3: The oily substance obtained in Step 2 is added to methanol and mixed, followed by the addition of sodium borohydride to react. After the reaction is completed, the mixture is concentrated, crystallized, and filtered to obtain 2-[2-(2,4-difluorophenyl)-2-propen-1-yl]-1,3-propanediol.

[0006] In the preparation process of 2-[2-(2,4-difluorophenyl)-2-propen-1-yl]-1,3-propanediol as described above, in step one, the molar ratio of 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene to diethyl malonate is 1:1.1-1.3, the molar ratio of 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene to potassium carbonate is 1:2-2.2, and the mass-volume ratio of 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene to N,N-dimethylformamide is 1:6-8.

[0007] In the preparation process of 2-[2-(2,4-difluorophenyl)-2-propen-1-yl]-1,3-propanediol as described above, the reaction temperature in step one is 50-70℃ and the reaction time is 2-3h.

[0008] The preparation process of 2-[2-(2,4-difluorophenyl)-2-propen-1-yl]-1,3-propanediol as described above, wherein the preparation process of 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene includes the following steps: Step 1: Add 2,4-difluoroacetophenone to tetrahydrofuran, then add a tetrahydrofuran solution of methyl magnesium chloride dropwise to react. After the reaction is complete, add sulfuric acid to continue the reaction. Step 2: Add saturated sodium carbonate solution to the solution after the reaction in Step 1 and react. After the reaction is complete, extract with petroleum ether. After extraction, combine the petroleum ether phases and wash with saturated brine. Add anhydrous sodium sulfate to the combined solution to remove water and concentrate to obtain an oily substance. Step 3: Add the oily substance obtained in Step 2 and dibromohydantoin to dimethyl sulfoxide for reaction. After the reaction is completed, add sulfuric acid to continue the reaction. Step 4: Add saturated sodium carbonate solution to the solution after the reaction in Step 3 to carry out the reaction. After the reaction is completed, extract with dichloromethane to combine all the dichloromethane phases. Then wash with water and saturated brine several times alternately. Add anhydrous sodium sulfate to the combined solution to remove water and concentrate to obtain an oily substance. Then obtain 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene by supercritical fluid extraction.

[0009] The preparation process of 2-[2-(2,4-difluorophenyl)-2-propen-1-yl]-1,3-propanediol as described above, wherein in step 1, the molar ratio of 2,4-difluoroacetophenone to methyl magnesium chloride is 1:1.1-1.3, the volume-to-mass ratio of tetrahydrofuran dissolving 2,4-difluoroacetophenone to 2,4-difluoroacetophenone is 4-6:1, and the mass-to-volume ratio of methyl magnesium chloride to tetrahydrofuran in the tetrahydrofuran solution of methyl magnesium chloride is 1:4-5, and the methyl magnesium chloride... The tetrahydrofuran solution was added dropwise in an ice-water bath. After the addition was complete, the reaction was carried out at a stirring speed of 40-60 r / min for 20-30 min. Then, the ice-water bath was removed, and the temperature was raised to room temperature to continue the reaction for 4-5 h. After that, the mixture was transferred to an ice-water bath, and concentrated sulfuric acid with a concentration of 98% was added dropwise. The molar ratio of 2,4-difluoroacetophenone to concentrated sulfuric acid was 1:0.6-0.7. After the addition was complete, the temperature was raised to 50-60℃ to continue the reaction for 3-4 h. The entire reaction was carried out under nitrogen protection.

[0010] In the preparation process of 2-[2-(2,4-difluorophenyl)-2-propen-1-yl]-1,3-propanediol as described above, in step 2, saturated sodium carbonate solution is added dropwise to the solution after the reaction in step 1 until no bubbles are generated. Then, it is extracted 3-4 times with petroleum ether at a volume ratio of 2-3. After combining all petroleum ether phases, it is washed 3-5 times with saturated brine. After adding excess anhydrous sodium sulfate and standing for 4-5 hours, it is filtered and heated under negative pressure to remove the organic solvent.

[0011] The preparation process of 2-[2-(2,4-difluorophenyl)-2-propen-1-yl]-1,3-propanediol as described above, in step 3, the molar ratio of the oil obtained in step 2 to dibromohydantoin is 1:0.5-0.6, and the mass-to-volume ratio of the oil obtained in step 2 to dimethyl sulfoxide is 1:10-12. The stirring speed is 80-100 r / min, the reaction time is 3-4 h, after the reaction is completed, the mixture is transferred to an ice-water bath, and concentrated sulfuric acid with a concentration of 98% is added dropwise. The molar ratio of the oil obtained in step 2 to concentrated sulfuric acid is 1:0.6-0.7. After the addition is completed, the temperature is raised to 50-60℃ and the reaction is continued for 4-5 h. The entire reaction is carried out under nitrogen protection.

[0012] The preparation process of 2-[2-(2,4-difluorophenyl)-2-propen-1-yl]-1,3-propanediol as described above involves the following steps: In step 4, a saturated sodium carbonate solution is added dropwise to the solution after the reaction in step 3 until no more bubbles are generated. The solution is then extracted 3-5 times with dichloromethane at a volume ratio of 3-4, and all dichloromethane phases are combined. The solution is then washed 2-4 times alternately with water and saturated brine. Subsequently, excess anhydrous sodium sulfate is added, and the solution is allowed to stand for 4-5 hours. After filtration and heating under negative pressure, the organic solvent is removed. The concentrated solution is then... The condensed oily substance is loaded into an extraction vessel, using carbon dioxide as the extractant. The extraction pressure is set to 20-25 MPa, the extraction temperature to 40-50℃, the carbon dioxide flow rate to 15-20 L / h, and the extraction time to 2-3 h. The pressure in separation vessel I is controlled at 8-10 MPa and the temperature at 35-40℃, while the pressure in separation vessel II is 5-6 MPa and the temperature at 30-35℃. The fraction in separation vessel II is collected to obtain 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene.

[0013] The preparation process of 2-[2-(2,4-difluorophenyl)-2-propen-1-yl]-1,3-propanediol as described above, in step two, acid washing is performed using 30% hydrochloric acid, followed by two acid washes. Then, extraction is performed 3-4 times with toluene at a volume ratio of 2-3. After the toluene phases are combined, the mixture is washed 3-5 times with saturated brine. After adding excess anhydrous sodium sulfate and allowing it to stand for 4-5 hours, it is heated to remove 60-70% of the solvent before distillation. The specific operation of the distillation is to use a vacuum distillation apparatus, set the vacuum degree to 0.08-0.1 MPa, control the top temperature of the column at 120-130℃, and collect the fraction within this temperature range.

[0014] In the preparation process of 2-[2-(2,4-difluorophenyl)-2-propen-1-yl]-1,3-propanediol as described above, the mass-to-volume ratio of the oil to methanol in step three is 1:5-7, the molar ratio of 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene to sodium borohydride is 1:1.2-1.4, the sodium borohydride is added in 3-4 portions, with an interval of 15-20 minutes between each addition, and after the addition is completed, the mixture is heated in a water bath at 30-40°C at a concentration of 50... The reaction was carried out at a stirring speed of -70 r / min for 3-4 h. Then, the reaction solution was heated under negative pressure to remove 80-90% of the solvent. After cooling to room temperature, it was allowed to stand for crystallization for 2-3 h. Then, it was transferred to an environment of -10 °C and allowed to stand for crystallization for another 18-20 h. After filtration, the filter cake was washed with methanol 2-3 times and then dried at 40-50 °C and a vacuum of 0.08 MPa for 2-3 h to obtain 2-[2-(2,4-difluorophenyl)-2-propen-1-yl]-1,3-propanediol.

[0015] The advantages of this invention are as follows: This invention uses 1-[1-(bromomethyl)vinyl]-2,4-difluoro-benzene as the reactant and reacts it with diethyl malonate in N,N-dimethylformamide solvent, using potassium carbonate as a base catalyst. This route effectively shortens the synthesis steps in the traditional process by optimizing the raw material ratio and reaction conditions. Furthermore, in the crucial intermediate purification stage, supercritical fluid extraction technology replaces the traditional multiple column chromatography or recrystallization operations. Using carbon dioxide as the extractant not only provides good selectivity and separation efficiency but also effectively reduces the amount of organic solvent used and subsequent processing costs, facilitating subsequent industrial production. This invention also achieves self-control over the supply of raw materials by preparing 1-[1-(bromomethyl)vinyl]-2,4-difluoro-benzene, effectively reducing costs, thus shortening the reaction cycle and increasing the reaction yield, facilitating industrial production. Attached Figure Description

[0016] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0017] Figure 1 This is the purity chromatogram of Example 1 of the present invention; Figure 2 This is the purity chromatogram of Example 2 of the present invention; Figure 3 This is the purity chromatogram of Example 3 of the present invention; Figure 4 This is the detection blank control chromatogram of the single solvent in this invention. Detailed Implementation

[0018] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0019] A process for preparing 2-[2-(2,4-difluorophenyl)-2-propen-1-yl]-1,3-propanediol includes the following steps: Step 1: Add 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene and diethyl malonate to N,N-dimethylformamide, followed by the addition of potassium carbonate to carry out the reaction; Step 2: After the reaction in Step 1 is completed, the potassium carbonate is removed by filtration, followed by acid washing, toluene extraction, washing with saturated brine, adding anhydrous sodium sulfate to remove water, concentration, and distillation to obtain an oily substance; Step 3: The oily substance obtained in Step 2 is added to methanol and mixed, followed by the addition of sodium borohydride to react. After the reaction is completed, the mixture is concentrated, crystallized, and filtered to obtain 2-[2-(2,4-difluorophenyl)-2-propen-1-yl]-1,3-propanediol.

[0020] Specifically, in step one of this embodiment, the molar ratio of 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene to diethyl malonate is 1:1.1-1.3, the molar ratio of 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene to potassium carbonate is 1:2-2.2, and the mass-volume ratio of 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene to N,N-dimethylformamide is 1:6-8.

[0021] Specifically, in step one of this embodiment, the reaction temperature is 50-70℃ and the reaction time is 2-3 hours.

[0022] More specifically, the preparation process of 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene described in this embodiment includes the following steps: Step 1: Add 2,4-difluoroacetophenone to tetrahydrofuran, then add a tetrahydrofuran solution of methyl magnesium chloride dropwise to react. After the reaction is complete, add sulfuric acid to continue the reaction. Step 2: Add saturated sodium carbonate solution to the solution after the reaction in Step 1 and react. After the reaction is complete, extract with petroleum ether. After extraction, combine the petroleum ether phases and wash with saturated brine. Add anhydrous sodium sulfate to the combined solution to remove water and concentrate to obtain an oily substance. Step 3: Add the oily substance obtained in Step 2 and dibromohydantoin to dimethyl sulfoxide for reaction. After the reaction is completed, add sulfuric acid to continue the reaction. Step 4: Add saturated sodium carbonate solution to the solution after the reaction in Step 3 to carry out the reaction. After the reaction is completed, extract with dichloromethane to combine all the dichloromethane phases. Then wash with water and saturated brine several times alternately. Add anhydrous sodium sulfate to the combined solution to remove water and concentrate to obtain an oily substance. Then obtain 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene by supercritical fluid extraction.

[0023] More specifically, in step 1 of this embodiment, the molar ratio of 2,4-difluoroacetophenone to methyl magnesium chloride is 1:1.1-1.3, the volume-to-mass ratio of tetrahydrofuran to 2,4-difluoroacetophenone is 4-6:1, and the mass-to-volume ratio of methyl magnesium chloride to tetrahydrofuran in the tetrahydrofuran solution is 1:4-5. The addition of the tetrahydrofuran solution is carried out in an ice-water bath. After the addition is completed, the reaction is carried out for 20-30 minutes with a stirring speed of 40-60 r / min. Then, the ice-water bath is removed, the temperature is raised to room temperature, and the reaction continues for 4-5 hours. Then, the mixture is transferred to an ice-water bath, and concentrated sulfuric acid with a concentration of 98% is added dropwise. The molar ratio of 2,4-difluoroacetophenone to concentrated sulfuric acid is 1:0.6-0.7. After the addition is completed, the temperature is raised to 50-60℃, and the reaction continues for 3-4 hours. The entire reaction is carried out under nitrogen protection.

[0024] More specifically, in step 2 of this embodiment, the saturated sodium carbonate solution is added dropwise to the solution after the reaction in step 1 until no more bubbles are generated. Then, it is extracted 3-4 times with petroleum ether at a volume ratio of 2-3. After combining all the petroleum ether phases, it is washed 3-5 times with saturated brine. Then, excess anhydrous sodium sulfate is added and the mixture is allowed to stand for 4-5 hours. After filtration, it is heated under negative pressure to remove the organic solvent.

[0025] Furthermore, in step 3 of this embodiment, the molar ratio of the oily substance obtained in step 2 to dibromohydantoin is 1:0.5-0.6, and the mass-to-volume ratio of the oily substance obtained in step 2 to dimethyl sulfoxide is 1:10-12. The stirring speed is 80-100 r / min, the reaction time is 3-4 h, and after the reaction is completed, the mixture is transferred to an ice-water bath, and concentrated sulfuric acid with a concentration of 98% is added dropwise. The molar ratio of the oily substance obtained in step 2 to concentrated sulfuric acid is 1:0.6-0.7. After the addition is completed, the temperature is raised to 50-60℃ to continue the reaction for 4-5 h. The entire reaction is carried out under nitrogen protection.

[0026] Furthermore, in step 4 of this embodiment, the saturated sodium carbonate solution is added dropwise to the solution after the reaction in step 3 until no more bubbles are generated. After extraction with dichloromethane at a volume ratio of 3-4 times 3-5 times, all dichloromethane phases are combined. Then, the mixture is washed alternately with water and saturated brine 2-4 times. Subsequently, excess anhydrous sodium sulfate is added and the mixture is allowed to stand for 4-5 hours. After filtration and heating under negative pressure, the organic solvent is removed. The concentrated oily substance is then loaded into an extraction vessel. Carbon dioxide is used as the extractant. The extraction pressure is set to 20-25 MPa, the extraction temperature to 40-50°C, the carbon dioxide flow rate to 15-20 L / h, and the extraction time to 2-3 hours. The pressure in separation vessel I is controlled at 8-10 MPa and the temperature at 35-40°C. The pressure in separation vessel II is controlled at 5-6 MPa and the temperature at 30-35°C. The fraction in separation vessel II is collected to obtain 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene.

[0027] Furthermore, in step two of this embodiment, the acid washing is performed using 30% hydrochloric acid, followed by two acid washes. Then, the product is extracted 3-4 times with toluene at a volume ratio of 2-3. After the toluene phases are combined, the product is washed 3-5 times with saturated brine. After adding excess anhydrous sodium sulfate and letting it stand for 4-5 hours, it is heated to remove 60-70% of the solvent before distillation. The specific operation of the distillation is to use a vacuum distillation apparatus, set the vacuum degree to 0.08-0.1 MPa, and control the top temperature of the column at 120-130°C, collecting the fraction within this temperature range.

[0028] Furthermore, in step three of this embodiment, the mass-to-volume ratio of the oily substance to methanol is 1:5-7, and the molar ratio of 1-[1-(bromomethyl)vinyl]-2,4-difluoro-benzene to sodium borohydride is 1:1.2-1.4. Sodium borohydride is added in 3-4 portions, with an interval of 15-20 minutes between each addition. After the addition is complete, the reaction is carried out at a water bath temperature of 30-40°C and a stirring speed of 50-70 r / min for 3-4 hours. Subsequently, the reaction solution is heated under negative pressure to remove 80-90% of the solvent. After cooling to room temperature, it is allowed to stand for crystallization for 2-3 hours. Then, it is transferred to an environment of -10°C and allowed to stand for crystallization for another 18-20 hours. After filtration, the filter cake is washed with methanol 2-3 times and then dried at 40-50°C under a vacuum of 0.08 MPa for 2-3 hours to obtain 2-[2-(2,4-difluorophenyl)-2-propen-1-yl]-1,3-propanediol.

[0029] Example 1 Step 1: Add 10g of 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene and diethyl malonate to N,N-dimethylformamide, followed by the addition of potassium carbonate for reaction. The molar ratio of 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene to diethyl malonate is 1:1.1, the molar ratio of 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene to potassium carbonate is 1:2, and the mass-to-volume ratio of 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene to N,N-dimethylformamide is 1:6. The reaction temperature is 50℃, and the reaction time is 3h. The preparation process of 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene includes the following steps: Step 1: 2,4-Difluoroacetophenone was added to tetrahydrofuran, followed by the dropwise addition of a tetrahydrofuran solution of magnesium methyl chloride. The molar ratio of 2,4-difluoroacetophenone to magnesium methyl chloride was 1:1.1, the volume-to-mass ratio of the tetrahydrofuran solution to 2,4-difluoroacetophenone was 4:1, and the mass-to-volume ratio of magnesium methyl chloride to tetrahydrofuran in the magnesium methyl chloride tetrahydrofuran solution was 1:4. The dropwise addition of the magnesium methyl chloride tetrahydrofuran solution was carried out in an ice-water bath. After the addition was completed, the reaction was carried out at a stirring speed of 40 r / min for 30 min. Then, the ice-water bath was removed, the temperature was raised to room temperature, and the reaction was continued for 4 h. Then, the mixture was transferred to an ice-water bath, and 98% concentrated sulfuric acid was added dropwise. The molar ratio of 2,4-difluoroacetophenone to concentrated sulfuric acid was 1:0.6. After the addition was completed, the temperature was raised to 50-60℃, and the reaction was continued for 3-4 h. The entire reaction was carried out under nitrogen protection. Step 2: Add saturated sodium carbonate solution to the solution after the reaction in Step 1 and react. Add saturated sodium carbonate solution dropwise to the solution after the reaction in Step 1 until no more bubbles are generated. Then extract three times with petroleum ether at a volume ratio of 3. Combine all petroleum ether phases and wash three times with saturated brine. Add excess anhydrous sodium sulfate and let stand for 4 hours. Filter and heat under negative pressure to remove organic solvents to obtain an oily substance. Step 3: Add the oily substance obtained in Step 2 and dibromohydantoin to dimethyl sulfoxide for reaction. The molar ratio of the oily substance obtained in Step 2 to dibromohydantoin is 1:0.5, and the mass-to-volume ratio of the oily substance obtained in Step 2 to dimethyl sulfoxide is 1:10. The stirring speed is 80 r / min, and the reaction time is 4 h. After the reaction is completed, transfer to an ice-water bath and add 98% concentrated sulfuric acid dropwise. The molar ratio of the oily substance obtained in Step 2 to concentrated sulfuric acid is 1:0.6. After the addition is completed, raise the temperature to 50℃ and continue the reaction for 5 h. The entire reaction is carried out under nitrogen protection. Step 4: Add saturated sodium carbonate solution to the solution after the reaction in Step 3 and react. Add saturated sodium carbonate solution dropwise to the solution after the reaction in Step 3 until no more bubbles are generated. Extract three times with dichloromethane at a volume ratio of 3, then combine all the dichloromethane phases. Wash twice alternately with water and saturated brine. Then add excess anhydrous sodium sulfate and let stand for 4 hours. Filter and heat under negative pressure to remove organic solvent. Load the concentrated oily substance into the extraction vessel. Use carbon dioxide as the extractant. Set the extraction pressure to 20 MPa, the extraction temperature to 50°C, the carbon dioxide flow rate to 15 L / h, and the extraction time to 3 hours. Control the pressure of separation vessel I at 8 MPa and the temperature at 35°C. Control the pressure of separation vessel II at 5 MPa and the temperature at 30°C. Collect the fraction in separation vessel II to obtain 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene. Step 2: After the reaction in Step 1 is completed, the potassium carbonate is removed by filtration. Then, acid washing, toluene extraction, and washing with saturated brine are performed. Anhydrous sodium sulfate is added to remove water, and the product is concentrated and distilled to obtain an oily substance. The acid washing is performed with 30% hydrochloric acid twice. After acid washing, the product is extracted four times with toluene at a volume ratio of 2. After the toluene phases are combined, the product is washed three times with saturated brine. Excess anhydrous sodium sulfate is added and the product is allowed to stand for 4 hours. Then, it is heated to remove 60-70% of the solvent before distillation. The specific operation of the distillation is to use a vacuum distillation apparatus, set the vacuum degree to 0.08 MPa, and control the top temperature of the column at 120-130℃. The fraction in this temperature range is collected. Step 3: The oily substance obtained in Step 2 was mixed with methanol, followed by the addition of sodium borohydride. The mass-to-volume ratio of the oily substance to methanol was 1:5-7, and the molar ratio of 1-[1-(bromomethyl)vinyl]-2,4-difluoro-benzene to sodium borohydride was 1:1.2. Sodium borohydride was added in three portions, with 15-minute intervals between each addition. After the addition was complete, the reaction was carried out at 30°C in a water bath with a stirring speed of 50 rpm for 4 hours. Subsequently, the reaction solution was heated under negative pressure to remove 80-90% of the solvent. After cooling to room temperature, it was allowed to stand for crystallization for 2 hours, followed by further crystallization at -10°C for 18 hours. The mixture was then filtered, and the filter cake was washed twice with methanol and dried at 40°C under a vacuum of 0.08 MPa for 3 hours to obtain 9.75 g of 1-[1-(bromomethyl)vinyl]-2,4-difluoro-benzene, with a yield of 94.4% and a purity of 99.12% (e.g., ...). Figure 1 As shown, the peak between 13-14 min is a solvent-generated peak and therefore is not marked. Figure 4 (As shown).

[0030] Example 2 Step 1: Add 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene and diethyl malonate to N,N-dimethylformamide, followed by the addition of potassium carbonate for reaction. The molar ratio of 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene to diethyl malonate is 1:1.3, the molar ratio of 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene to potassium carbonate is 1:2.2, and the mass-to-volume ratio of 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene to N,N-dimethylformamide is 1:8. The reaction temperature is 70℃, and the reaction time is 2 hours. The preparation process of 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene includes the following steps: Step 1: 2,4-Difluoroacetophenone was added to tetrahydrofuran, followed by the dropwise addition of a tetrahydrofuran solution of magnesium methyl chloride. The molar ratio of 2,4-difluoroacetophenone to magnesium methyl chloride was 1:1.1, the volume-to-mass ratio of the tetrahydrofuran solution to 2,4-difluoroacetophenone was 6:1, and the mass-to-volume ratio of magnesium methyl chloride to tetrahydrofuran in the magnesium methyl chloride tetrahydrofuran solution was 1:5. The dropwise addition of the magnesium methyl chloride tetrahydrofuran solution was carried out in an ice-water bath. After the addition was completed, the reaction was carried out at a stirring speed of 60 r / min for 20 min. Then, the ice-water bath was removed, the temperature was raised to room temperature, and the reaction continued for 5 h. Subsequently, the mixture was transferred to an ice-water bath, and concentrated sulfuric acid with a concentration of 98% was added dropwise. The molar ratio of 2,4-difluoroacetophenone to concentrated sulfuric acid was 1:0.7. After the addition was completed, the temperature was raised to 60 °C, and the reaction continued for 3 h. The entire reaction was carried out under nitrogen protection. Step 2: Add saturated sodium carbonate solution to the solution after the reaction in Step 1 and react. Add saturated sodium carbonate solution dropwise to the solution after the reaction in Step 1 until no more bubbles are generated. Then extract three times with petroleum ether at a volume ratio of 3. Combine all petroleum ether phases and wash five times with saturated brine. Add excess anhydrous sodium sulfate and let stand for 5 hours. Filter and heat under negative pressure to remove organic solvents to obtain an oily substance. Step 3: Add the oily substance obtained in Step 2 and dibromohydantoin to dimethyl sulfoxide for reaction. The molar ratio of the oily substance obtained in Step 2 to dibromohydantoin is 1:0.6, and the mass-to-volume ratio of the oily substance obtained in Step 2 to dimethyl sulfoxide is 1:12. The stirring speed is 100 r / min, and the reaction time is 3 h. After the reaction is completed, transfer to an ice-water bath and add 98% concentrated sulfuric acid dropwise. The molar ratio of the oily substance obtained in Step 2 to concentrated sulfuric acid is 1:0.7. After the addition is completed, raise the temperature to 60℃ and continue the reaction for 4 h. The entire reaction is carried out under nitrogen protection. Step 4: Add saturated sodium carbonate solution to the solution after the reaction in Step 3 and react. Add saturated sodium carbonate solution dropwise to the solution after the reaction in Step 3 until no more bubbles are generated. Extract three times with dichloromethane at a volume ratio of 4, then combine all the dichloromethane phases. Wash four times alternately with water and saturated brine. Then add excess anhydrous sodium sulfate and let stand for 5 hours. Filter and heat under negative pressure to remove organic solvents. Load the concentrated oily substance into an extraction vessel. Use carbon dioxide as the extractant. Set the extraction pressure to 25 MPa, the extraction temperature to 50°C, the carbon dioxide flow rate to 20 L / h, and the extraction time to 2 hours. Control the pressure of separation vessel I at 10 MPa and the temperature at 40°C. Control the pressure of separation vessel II at 6 MPa and the temperature at 35°C. Collect the fraction in separation vessel II to obtain 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene. Step 2: After the reaction in Step 1 is completed, the potassium carbonate is removed by filtration. Then, acid washing, toluene extraction, and washing with saturated brine are performed. Anhydrous sodium sulfate is added to remove water, and the product is concentrated and distilled to obtain an oily substance. The acid washing is performed with 30% hydrochloric acid twice. After acid washing, the product is extracted three times with toluene at a volume ratio of 3. After the toluene phases are combined, the product is washed five times with saturated brine. Excess anhydrous sodium sulfate is added and the product is allowed to stand for 5 hours. Then, it is heated to remove 60-70% of the solvent before distillation. The specific operation of the distillation is to use a vacuum distillation apparatus, set the vacuum degree to 0.1 MPa, and control the top temperature of the column at 120-130℃. The fraction in this temperature range is collected. Step 3: The oily substance obtained in Step 2 was mixed with methanol, followed by the addition of sodium borohydride. The mass-to-volume ratio of the oily substance to methanol was 1:5-7, and the molar ratio of 1-[1-(bromomethyl)vinyl]-2,4-difluoro-benzene to sodium borohydride was 1:1.4. Sodium borohydride was added in four portions, with 20-minute intervals between each addition. After the addition was complete, the reaction was carried out at 40°C in a water bath with a stirring speed of 70 r / min for 4 hours. Subsequently, the reaction solution was heated under negative pressure to remove 80-90% of the solvent. After cooling to room temperature, it was allowed to stand for crystallization for 3 hours, followed by a further standing crystallization at -10°C for 20 hours. The mixture was then filtered, and the filter cake was washed three times with methanol. Finally, it was dried at 50°C under a vacuum of 0.08 MPa for 2 hours. 9.83 g of 1-[1-(bromomethyl)vinyl]-2,4-difluoro-benzene was obtained, with a yield of 95.2% and a purity of 99.13% (e.g., ...). Figure 2 As shown, the peak between 13-14 min is a solvent-generated peak and therefore is not marked. Figure 4 (As shown).

[0031] Example 3 Step 1: Add 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene and diethyl malonate to N,N-dimethylformamide, followed by the addition of potassium carbonate for reaction. The molar ratio of 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene to diethyl malonate is 1:1.2, the molar ratio of 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene to potassium carbonate is 1:2.1, and the mass-to-volume ratio of 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene to N,N-dimethylformamide is 1:7. The reaction temperature is 60℃, and the reaction time is 2.5h. The preparation process of 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene includes the following steps: Step 1: 2,4-Difluoroacetophenone was added to tetrahydrofuran, followed by the dropwise addition of a tetrahydrofuran solution of magnesium methyl chloride. The molar ratio of 2,4-difluoroacetophenone to magnesium methyl chloride was 1:1.2, the volume-to-mass ratio of the tetrahydrofuran solution to 2,4-difluoroacetophenone was 5:1, and the mass-to-volume ratio of magnesium methyl chloride to tetrahydrofuran in the magnesium methyl chloride tetrahydrofuran solution was 1:4.5. The dropwise addition of the magnesium methyl chloride tetrahydrofuran solution was carried out in an ice-water bath. After the addition was completed, the reaction was carried out at a stirring speed of 50 r / min for 25 min. Then, the ice-water bath was removed, the temperature was raised to room temperature, and the reaction was continued for 4.5 h. Subsequently, the mixture was transferred to an ice-water bath, and 98% concentrated sulfuric acid was added dropwise. The molar ratio of 2,4-difluoroacetophenone to concentrated sulfuric acid was 1:0.65. After the addition was completed, the temperature was raised to 55 °C, and the reaction was continued for 3.5 h. The entire reaction was carried out under nitrogen protection. Step 2: Add saturated sodium carbonate solution to the solution after the reaction in Step 1 and react. Add saturated sodium carbonate solution dropwise to the solution after the reaction in Step 1 until no more bubbles are generated. Then extract with petroleum ether at a volume ratio of 2.5 four times. Combine all petroleum ether phases and wash with saturated brine four times. Add excess anhydrous sodium sulfate and let stand for 4.5 hours. Filter and heat under negative pressure to remove organic solvent to obtain an oily substance. Step 3: The oily substance obtained in Step 2 and dibromohydantoin were added to dimethyl sulfoxide for reaction. The molar ratio of the oily substance obtained in Step 2 to dibromohydantoin was 1:0.55, and the mass-to-volume ratio of the oily substance obtained in Step 2 to dimethyl sulfoxide was 1:14. The stirring speed was 90 r / min, and the reaction time was 3.5 h. After the reaction was completed, the mixture was transferred to an ice-water bath, and concentrated sulfuric acid with a concentration of 98% was added dropwise. The molar ratio of the oily substance obtained in Step 2 to concentrated sulfuric acid was 1:0.65. After the addition was completed, the temperature was raised to 55℃ and the reaction was continued for 4.5 h. The entire reaction was carried out under nitrogen protection. Step 4: Add saturated sodium carbonate solution to the solution after the reaction in Step 3 and react. Add saturated sodium carbonate solution dropwise to the solution after the reaction in Step 3 until no more bubbles are generated. Extract with dichloromethane at a volume ratio of 3.5 four times, then combine all the dichloromethane phases. Wash with water and saturated brine three times alternately. Then add excess anhydrous sodium sulfate and let stand for 4.5 hours. Filter and remove organic solvent by heating under negative pressure. Load the concentrated oily substance into the extraction vessel. Use carbon dioxide as the extractant. Set the extraction pressure to 23 MPa, the extraction temperature to 45°C, the carbon dioxide flow rate to 18 L / h, and the extraction time to 2.3 hours. Control the pressure of separation vessel I at 9 MPa and the temperature at 38°C. Control the pressure of separation vessel II at 5.5 MPa and the temperature at 33°C. Collect the fraction in separation vessel II to obtain 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene. Step 2: After the reaction in Step 1 is completed, the potassium carbonate is removed by filtration. Then, acid washing, toluene extraction, and washing with saturated brine are performed. Anhydrous sodium sulfate is added to remove water, and the product is concentrated and distilled to obtain an oily substance. The acid washing is performed with 30% hydrochloric acid twice. After acid washing, the product is extracted four times with toluene at a volume ratio of 2.5. After the toluene phases are combined, the product is washed four times with saturated brine. Excess anhydrous sodium sulfate is added and the product is allowed to stand for 4.5 hours. After heating to remove 60-70% of the solvent, distillation is performed. The specific operation of the distillation is to use a vacuum distillation apparatus, set the vacuum degree to 0.09 MPa, and control the top temperature of the column at 120-130℃. The fraction in this temperature range is collected. Step 3: The oily substance obtained in Step 2 was mixed with methanol, followed by the addition of sodium borohydride. The mass-to-volume ratio of the oily substance to methanol was 1:6, and the molar ratio of 1-[1-(bromomethyl)vinyl]-2,4-difluoro-benzene to sodium borohydride was 1:1.3. Sodium borohydride was added in four portions, with each addition spaced 17 minutes apart. After the addition was complete, the reaction was carried out at a water bath temperature of 35°C and a stirring speed of 60 r / min for 3.5 h. Subsequently, the reaction solution was heated under negative pressure to remove 80-90% of the solvent. After cooling to room temperature, it was allowed to stand for crystallization for 2.5 h, and then transferred to an environment of -10°C for further crystallization for 18 h. After filtration, the filter cake was washed twice with methanol and then dried at 45°C under a vacuum of 0.08 MPa for 2.5 h to obtain 10.03 g of 1-[1-(bromomethyl)vinyl]-2,4-difluoro-benzene, with a yield of 97.1% and a purity of 99.14% (e.g., ...). Figure 3 As shown, the peak between 13-14 min is a solvent-generated peak and therefore is not marked. Figure 4 (As shown).

[0032] As can be seen from Examples 1-3, the preparation process of the present invention is relatively simple and easy to industrialize. At the same time, the 1-[1-(bromomethyl)vinyl]-2,4-difluoro-benzene obtained by the present invention has a high yield and purity, which can effectively improve production efficiency and reduce production costs to a certain extent.

[0033] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A process for preparing 2-[2-(2,4-difluorophenyl)-2-propen-1-yl]-1,3-propanediol, characterized in that: Includes the following steps: Step 1: Add 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene and diethyl malonate to N,N-dimethylformamide, followed by the addition of potassium carbonate to carry out the reaction; Step 2: After the reaction in Step 1 is completed, the potassium carbonate is removed by filtration, followed by acid washing, toluene extraction, washing with saturated brine, adding anhydrous sodium sulfate to remove water, concentration, and distillation to obtain an oily substance; Step 3: The oily substance obtained in Step 2 is added to methanol and mixed, followed by the addition of sodium borohydride to react. After the reaction is completed, the mixture is concentrated, crystallized, and filtered to obtain 2-[2-(2,4-difluorophenyl)-2-propen-1-yl]-1,3-propanediol.

2. The preparation process of 2-[2-(2,4-difluorophenyl)-2-propen-1-yl]-1,3-propanediol according to claim 1, characterized in that: In step one, the molar ratio of 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene to diethyl malonate is 1:1.1-1.3, the molar ratio of 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene to potassium carbonate is 1:2-2.2, and the mass-volume ratio of 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene to N,N-dimethylformamide is 1:6-8.

3. The preparation process of 2-[2-(2,4-difluorophenyl)-2-propen-1-yl]-1,3-propanediol according to claim 1, characterized in that: The reaction temperature in step one is 50-70℃, and the reaction time is 2-3 hours.

4. The preparation process of 2-[2-(2,4-difluorophenyl)-2-propen-1-yl]-1,3-propanediol according to claim 1, characterized in that: The preparation process of 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene includes the following steps: Step 1: Add 2,4-difluoroacetophenone to tetrahydrofuran, then add a tetrahydrofuran solution of methyl magnesium chloride dropwise to react. After the reaction is complete, add sulfuric acid to continue the reaction. Step 2: Add saturated sodium carbonate solution to the solution after the reaction in Step 1 and react. After the reaction is complete, extract with petroleum ether. After extraction, combine the petroleum ether phases and wash with saturated brine. Add anhydrous sodium sulfate to the combined solution to remove water and concentrate to obtain an oily substance. Step 3: Add the oily substance obtained in Step 2 and dibromohydantoin to dimethyl sulfoxide for reaction. After the reaction is completed, add sulfuric acid to continue the reaction. Step 4: Add saturated sodium carbonate solution to the solution after the reaction in Step 3 to carry out the reaction. After the reaction is completed, extract with dichloromethane to combine all the dichloromethane phases. Then wash with water and saturated brine several times alternately. Add anhydrous sodium sulfate to the combined solution to remove water and concentrate to obtain an oily substance. Then obtain 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene by supercritical fluid extraction.

5. The preparation process of 2-[2-(2,4-difluorophenyl)-2-propen-1-yl]-1,3-propanediol according to claim 4, characterized in that: In step 1, the molar ratio of 2,4-difluoroacetophenone to methyl magnesium chloride is 1:1.1-1.3, the volume-to-mass ratio of tetrahydrofuran to 2,4-difluoroacetophenone is 4-6:1, and the mass-to-volume ratio of methyl magnesium chloride to tetrahydrofuran in the methyl magnesium chloride tetrahydrofuran solution is 1:4-5. The addition of the methyl magnesium chloride tetrahydrofuran solution is carried out in an ice-water bath. After the addition is completed, the reaction is carried out for 20-30 minutes with a stirring speed of 40-60 r / min. Then, the ice-water bath is removed, the temperature is raised to room temperature, and the reaction continues for 4-5 hours. Then, the mixture is transferred to an ice-water bath, and concentrated sulfuric acid with a concentration of 98% is added dropwise. The molar ratio of 2,4-difluoroacetophenone to concentrated sulfuric acid is 1:0.6-0.

7. After the addition is completed, the temperature is raised to 50-60℃, and the reaction continues for 3-4 hours. The entire reaction is carried out under nitrogen protection.

6. The preparation process of 2-[2-(2,4-difluorophenyl)-2-propen-1-yl]-1,3-propanediol according to claim 4, characterized in that: In step 2, saturated sodium carbonate solution is added dropwise to the solution after the reaction in step 1 until no more bubbles are generated. Then, it is extracted 3-4 times with petroleum ether at a volume ratio of 2-3. After combining all the petroleum ether phases, it is washed 3-5 times with saturated brine. Then, excess anhydrous sodium sulfate is added and the mixture is allowed to stand for 4-5 hours. After filtration, it is heated under negative pressure to remove the organic solvent.

7. The preparation process of 2-[2-(2,4-difluorophenyl)-2-propen-1-yl]-1,3-propanediol according to claim 4, characterized in that: In step 3, the molar ratio of the oily substance obtained in step 2 to dibromohydantoin is 1:0.5-0.6, and the mass-to-volume ratio of the oily substance obtained in step 2 to dimethyl sulfoxide is 1:10-12. The stirring speed is 80-100 r / min, the reaction time is 3-4 h, and after the reaction is completed, the mixture is transferred to an ice-water bath, and concentrated sulfuric acid with a concentration of 98% is added dropwise. The molar ratio of the oily substance obtained in step 2 to concentrated sulfuric acid is 1:0.6-0.

7. After the addition is completed, the temperature is raised to 50-60℃ and the reaction is continued for 4-5 h. The entire reaction is carried out under nitrogen protection.

8. The preparation process of 2-[2-(2,4-difluorophenyl)-2-propen-1-yl]-1,3-propanediol according to claim 4, characterized in that: In step 4, saturated sodium carbonate solution is added dropwise to the solution after the reaction in step 3 until no more bubbles are generated. The solution is then extracted 3-5 times with dichloromethane at a volume ratio of 3-4. All dichloromethane phases are combined, and the solution is washed 2-4 times alternately with water and saturated brine. Excess anhydrous sodium sulfate is then added, and the solution is allowed to stand for 4-5 hours. After filtration and heating under negative pressure, the organic solvent is removed. The concentrated oily substance is then loaded into an extraction vessel. Carbon dioxide is used as the extractant, and the extraction pressure is set to 20-25 MPa, the extraction temperature to 40-50℃, the carbon dioxide flow rate to 15-20 L / h, and the extraction time to 2-3 hours. The pressure in separation vessel I is controlled at 8-10 MPa and the temperature at 35-40℃, while the pressure in separation vessel II is 5-6 MPa and the temperature at 30-35℃. The fraction in separation vessel II is collected to obtain 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene.

9. The preparation process of 2-[2-(2,4-difluorophenyl)-2-propen-1-yl]-1,3-propanediol according to claim 1, characterized in that: In step two, the acid washing is performed using 30% hydrochloric acid, followed by two acid washes. Then, the product is extracted 3-4 times with toluene at a volume ratio of 2-3. After the toluene phases are combined, the product is washed 3-5 times with saturated brine. After adding excess anhydrous sodium sulfate and letting it stand for 4-5 hours, it is heated to remove 60-70% of the solvent before distillation. The specific operation of the distillation is to use a vacuum distillation apparatus, set the vacuum degree to 0.08-0.1 MPa, and control the top temperature of the column at 120-130℃, collecting the fraction within this temperature range.

10. The preparation process of 2-[2-(2,4-difluorophenyl)-2-propen-1-yl]-1,3-propanediol according to claim 1, characterized in that: In step three, the mass-to-volume ratio of the oily substance to methanol is 1:5-7, and the molar ratio of 1-[1-(bromomethyl)vinyl]-2,4-difluorobenzene to sodium borohydride is 1:1.2-1.

4. Sodium borohydride is added in 3-4 portions, with an interval of 15-20 minutes between each addition. After the addition is complete, the reaction is carried out at a water bath temperature of 30-40°C and a stirring speed of 50-70 r / min for 3-4 hours. Subsequently, the reaction solution is heated under negative pressure to remove 80-90% of the solvent. After cooling to room temperature, it is allowed to stand for crystallization for 2-3 hours. Then, it is transferred to an environment of -10°C and allowed to stand for crystallization for another 18-20 hours. After filtration, the filter cake is washed with methanol 2-3 times and then dried at 40-50°C under a vacuum of 0.08 MPa for 2-3 hours to obtain 2-[2-(2,4-difluorophenyl)-2-propen-1-yl]-1,3-propanediol.

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