Preparation method of high-purity 2-bromo-4-tert-butyl-3, 5-difluorophenol

Abstract

The invention provides a method for synthesizing 2-bromo-4-tert-butyl-3, 5-difluorophenol, and belongs to the field of fine chemical engineering. The preparation method comprises the following steps: firstly preparing a high-purity 4-tert-butyl-3, 5-difluorophenol intermediate by using an ionic liquid (3-(1-methyl-1H-imidazole-3-onium-3-yl) propyl) zirconium chloride (V) (IL-Zr) as a Friedel-Crafts alkylation catalyst, and then brominating the high-purity 4-tert-butyl-3, 5-difluorophenol intermediate with bromine to obtain a high-purity 2-bromo-4-tert-butyl-3, 5-difluorophenol product; the method overcomes the problems of low reaction yield, incapability of recycling the catalyst, large wastewater amount, difficulty in product purification, high cost, difficulty in operation and the like in the prior art, has the advantages of recyclable catalyst, small wastewater discharge amount, high yield, low comprehensive cost, high product purity and the like, and is more suitable for industrial production. According to the technical scheme provided by the invention, a feasible method is provided for the preparation of the high-content intermediate 4-tert-butyl-3, 5-difluorophenol and the high-content 2-bromo-4-tert-butyl-3, 5-difluorophenol.

Description

Technical Field

[0001] The invention belongs to the technical field of fine chemicals, and in particular relates to a method for synthesizing high-purity 2-bromo-4-tert-butyl-3,5-difluorophenol. Background Art

[0002] 2-Bromo-4-tert-butyl-3,5-difluorophenol is an important intermediate for organic synthesis, pharmaceutical intermediates, and molecular modification and derivatization of drugs and pesticides. High-purity 2-bromo-4-tert-butyl-3,5-difluorophenol is a colorless to light yellow oil. Currently, there is no high-purity 2-bromo-4-(tert-butyl)-3,5-difluorophenol for sale in the market. The process reported in the literature is mainly to use 3,5-difluorophenol and methyl tert-butyl ether as starting materials, slowly add solid catalyst zirconium tetrachloride into the reaction system, first synthesize the intermediate 4-tert-butyl-3,5-difluorophenol, and then slowly add N-bromosuccinimide (NBS) solid in batches under the conditions of acetonitrile as solvent and monohydrated p-toluenesulfonic acid as catalyst to prepare 2-bromo-4-tert-butyl-3,5-difluorophenol; the reaction equation is as follows:

[0003]

[0004] This process method has the disadvantages of being unable to recycle zirconium tetrachloride and p-toluenesulfonic acid monohydrate catalyst, large amount of wastewater, difficulty in purifying the product, low yield, high cost, and complex operation, and is therefore not suitable for large-scale industrial production.

[0005] Therefore, the development of a better tert-butylation catalytic system and a simpler bromination reaction system is of great significance for solving the recycling of catalysts, reducing wastewater discharge, improving reaction yields, reducing production costs, and improving product purity. Summary of the invention

[0006] In order to overcome the above technical defects, the object of the present invention is to provide a method for synthesizing 2-bromo-4-tert-butyl-3,5-difluorophenol.

[0007] The preparation method of 2-bromo-4-tert-butyl-3,5-difluorophenol of the present invention comprises the following steps: adding 3,5-difluorophenol to a tert-butyl ether solvent, then dripping an ionic liquid catalyst, after the reaction is completed, standing to separate the liquid, stripping the lower layer with a tert-butyl ether solvent, combining and concentrating the organic phases to obtain an intermediate 4-tert-butyl-3,5-difluorophenol, adding an organic solvent to dissolve, slowly dripping bromine, completing the reaction, adding a terminator, standing to separate the liquid, and concentrating the organic phase to obtain high-purity 2-bromo-4-tert-butyl-3,5-difluorophenol.

[0008] Specifically, it can be divided into two specific steps:

[0009]

[0010] The first step is to add tert-butyl ether solvent and 3,5-difluorophenol to the reaction kettle, stir until dissolved, slowly dropwise add ionic liquid catalyst at a certain temperature, the reaction is completed, stand and separate, add ether to the ionic liquid layer for back extraction, and apply the lower ionic liquid layer to the next kettle; after the extract is combined with the upper organic phase, it is washed with a saturated sodium chloride aqueous solution, the organic layer is concentrated under reduced pressure to remove the solvent, and the residue in the kettle is distilled under reduced pressure. The obtained product fraction is placed at 20-25° C. overnight to obtain a high-purity intermediate white needle-shaped crystal 4-tert-butyl-3,5-difluorophenol.

[0011]

[0012] Step 2: Add the 4-tert-butyl-3,5-difluorophenol obtained by flash evaporation into an organic solvent to dissolve it, slowly add bromine dropwise, and when the reaction is finished, add a terminator to terminate the reaction, let it stand to separate the liquids, desolventize the organic phase, and perform vacuum distillation to obtain high-purity 2-bromo-4-tert-butyl-3,5-difluorophenol.

[0013] Furthermore, in the above technical solution, the ether is one of methyl tert-butyl ether, ethyl tert-butyl ether, di-tert-butyl ether, or a combination of the two.

[0014] Furthermore, in the above technical solution, the ionic liquid catalyst is (3-(1-methyl-1H-imidazol-3-ium-3-yl)propyl)zirconium (V) chloride, abbreviated as IL-Zr.

[0015] Furthermore, in the above technical solution, the molar ratio of the catalyst IL-Zr to 3,5-difluorophenol is 0.5-0.75:1, preferably 0.6-0.7:1.

[0016] Furthermore, in the above technical solution, the molar ratio of ether to 3,5-difluorophenol is 1.5-2.5:1, preferably 1.8-2.2:1.

[0017] Furthermore, in the above technical solution, the solvent used in the bromination reaction is one or a combination of dichloromethane, 1,2-dichloroethane, chloroform, 1,1,2,2-tetrachloroethylene, and 1,1,2,2-tetrachloroethane.

[0018] Furthermore, in the above technical solution, the molar ratio of bromine to 4-tert-butyl-3,5-difluorophenol is 1.0-1.8:1, preferably 1.0-1.2:1.

[0019] Furthermore, in the above technical solution, the mass ratio of the solvent to 4-tert-butyl-3,5-difluorophenol is 2-5:1, preferably 3-4:1.

[0020] Furthermore, in the above technical solution, the alkylation reaction time is 20-50h, preferably 30-40h; the bromination reaction time is 1-5h, preferably 2-3h.

[0021] Furthermore, in the above technical solution, the alkylation reaction temperature is 0-50°C, preferably 20-30°C; the bromination reaction temperature is -5°C-50°C, preferably 10-30°C.

[0022] Furthermore, in the above technical solution, the typical reaction operation is as follows:

[0023] 1) Add ether and 3,5-difluorophenol to a four-necked reaction bottle with a stirring tube and a thermometer sleeve. After stirring to dissolve, slowly add the ionic liquid IL-Zr dropwise at a certain temperature. After the addition is completed, keep warm and stir for 40 hours;

[0024] 2) the two-phase reaction liquid obtained in step 1) is allowed to stand for separation, the lower ionic liquid phase is recovered and reused, the upper organic phase is concentrated, and then flash evaporated under reduced pressure;

[0025] 3) adding the material after flash evaporation in step 2) into the bromination reaction solvent, stirring at a certain temperature to dissolve, keeping the temperature and slowly adding bromine, and continuing to keep the temperature and stirring for 1 hour after the addition is completed, adding sodium bisulfite aqueous solution to wash the organic phase, standing to separate and concentrating the organic phase, and performing vacuum distillation to obtain 2-bromo-4-tert-butyl-3,5-difluorophenol.

[0026] Advantageous Effects of the Invention

[0027] 1. The present invention overcomes the problems in the prior art of low yield of 3,5-difluorophenol Friedel-Crafts alkylation reaction, difficult post-treatment, complicated operation, inability to recycle the catalyst, and high impurities in the subsequent bromination reaction and difficulty in purification.

[0028] 2. The method provided by the present invention is relatively simple to operate, has high product purity, high product yield, is safe, has less harm to the human body, and has less environmental pollution, and provides a feasible method for the preparation of high-content 2-bromo-4-tert-butyl-3,5-difluorophenol. DETAILED DESCRIPTION

[0029] The following examples may enable those skilled in the art to more fully understand the present invention, but are not intended to limit the present invention in any way.

[0030] Preparation of (3-(1-methyl-1H-imidazol-3-yl)propyl)zirconium(V) chloride

[0031] In a four-necked flask, under argon protection, N-methylimidazole (8.21 g, 0.10 mol) and a large amount of excess n-butyl chloride (46.29 g, 0.50 mmol) were added, and refluxed with stirring for 24 hours. After the reflux reaction was completed, the reaction solution was concentrated to remove excess n-butyl chloride to obtain crude N-methyl-3-propylimidazole chloride. The crude product was recrystallized using acetonitrile: ethyl acetate = 1:1 to obtain 10.05 g of high-purity N-methyl-3-propylimidazole chloride, with a yield of 63%.

[0032] In a four-necked flask, under the protection of dry argon, add N-methyl-3-propyl imidazole chloride (10.05 g, 63 mmol), raise the temperature in the kettle to 70 ° C, and when the solid in the kettle reaches a molten state, slowly add zirconium tetrachloride solid (14.68 g, 63 mmol), stir until it becomes clear under a dry argon atmosphere, and obtain (3-(1-methyl-1H-imidazol-3-ium-3-yl)propyl)zirconium chloride (V), i.e. IL-Zr.

[0033] Comparative Example 1

[0034] Under nitrogen protection, ZrCl4 (5.826 g, 25 mmol) was slowly added to a solution of methyl tert-butyl ether (9.70 g, 110 mmol) with 3,5-difluorophenol (6.505 g, 50 mmol) in a reaction flask to keep the reaction mixture at 30-40°C. The reaction was stirred at room temperature for 2 hours and then at 50°C for 48 hours; the reaction solution was quenched with a saturated aqueous ammonium chloride solution, allowed to stand for separation, the aqueous layer was extracted with ether, the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous MgSO4, and the solvent was evaporated under reduced pressure; 5.29 g of light brown liquid 4-tert-butyl-3,5-difluorophenol was obtained by purification by SiO2 column chromatography, with a yield of 57% and a GC analysis content of 97.9%.

[0035] Comparative Example 2

[0036] To a stirred reaction flask, add 4-tert-butyl-3,5-difluorophenol (2.2 g, 11.8 mol), p-toluenesulfonic acid monohydrate (2.035 g, 11.8 mmol) and acetonitrile (11.8 g, 290 mmol). Under stirring, cool the reaction mixture to 0-10°C with an ice-water bath, and slowly add N-bromosuccinimide (2.103 g, 11.8 mmol) in batches while keeping warm. After the addition, slowly heat the reaction solution to 20-25°C and keep warm and stir overnight. Concentrate the reaction solution under reduced pressure to remove the solvent, and purify the residue by SiO2 column chromatography to obtain 2.04 g of light brown liquid 2-bromo-4-tert-butyl-3,5-difluorophenol with a yield of 65.2% and a content of 96.1% according to GC analysis.

[0037] Example 1

[0038] In a four-necked bottle, under nitrogen protection, methyl tert-butyl ether (192.03 g, 2.18 mol) and 3,5-difluorophenol (130 g, 999.31 mmol) were added, stirred to dissolve, the temperature in the kettle was raised to 45 ° C and stirred for 0.5 h, and the ionic liquid IL-Zr (274.67 g, 699.52 mmol, 0.7 eq) was slowly added dropwise, and after the addition was completed, the mixture was kept warm and stirred for 40 h. After the reaction was completed, the reaction solution was heated at 20- The mixture was allowed to stand at 30°C for separation, and the lower ionic liquid layer was stripped with methyl tert-butyl ether, and the lower ionic liquid layer was applied to the next kettle; the extract was combined with the upper organic phase, washed with a saturated sodium chloride aqueous solution, the organic layer was concentrated under reduced pressure to remove the solvent, and the residue in the kettle was distilled under reduced pressure. The obtained product fraction was placed at 20-25°C overnight to obtain 165g of white needle-shaped crystals of 4-tert-butyl-3,5-difluorophenol, with a yield of 88.7% and a content of 99.5% according to GC analysis.

[0039] Example 2

[0040] In a four-necked bottle, under nitrogen protection, methyl tert-butyl ether (192.03 g, 2.18 mol) and 3,5-difluorophenol (130 g, 999.31 mmol) were added, stirred to dissolve, the temperature in the kettle was raised to 45 ° C and stirred for 0.5 h, and the ionic liquid IL-Zr (294.29 g, 749.48 mmol, 0.75 eq) recycled in Example 1 was slowly added dropwise, and the mixture was stirred for 40 h at room temperature; after the reaction was completed, the reaction mixture was reacted. The reaction solution was allowed to stand at 20-30°C for separation, the lower ionic liquid layer was stripped with methyl tert-butyl ether, and the lower ionic liquid layer was applied to the next kettle; the extract was combined with the upper organic phase, washed with a saturated sodium chloride aqueous solution, the organic layer was concentrated under reduced pressure to remove the solvent, and the residue in the kettle was distilled under reduced pressure. The obtained product fraction was placed at 20-25°C overnight to obtain 173g of white needle-shaped crystals of 4-tert-butyl-3,5-difluorophenol, with a yield of 92.9% and a content of 99.1% according to GC analysis.

[0041] Example 3

[0042] In a four-necked bottle, under nitrogen protection, di-tert-butyl ether (192.03 g, 2.18 mol) and 3,5-difluorophenol (130 g, 999.31 mmol) were added, stirred to dissolve, the temperature in the kettle was raised to 45 ° C and stirred for 0.5 h, and the ionic liquid IL-Zr (306.06 g, 779.46 mol, 0.78 eq) was slowly added dropwise, and after the addition was completed, the mixture was kept warm and stirred for 40 h. After the reaction was completed, the reaction solution was heated at 20- The mixture was allowed to stand at 30°C for separation, and the lower ionic liquid layer was back-extracted with di-tert-butyl ether, and the lower ionic liquid layer was applied to the next kettle; the extract was combined with the upper organic phase, washed with a saturated sodium chloride aqueous solution, the organic layer was concentrated under reduced pressure to remove the solvent, and the residue in the kettle was distilled under reduced pressure. The obtained product fraction was placed at 20-25°C overnight to obtain 163g of white needle-shaped crystals of 4-tert-butyl-3,5-difluorophenol, with a yield of 87.3% and a content of 99.7% according to GC analysis.

[0043] Example 4

[0044] In a four-necked flask, add 4-tert-butyl-3,5-difluorophenol (10 g, 53.7 mmol) and chloroform (25 g) in turn, keep the reaction system at 20°C and start to add bromine (9.0 g, 56.4 mmol, 1.05 eq) dropwise. After the addition is completed, keep stirring at 20°C for 1 hour. After confirming that the reaction is complete, add sodium bisulfite aqueous solution dropwise to the reaction solution while keeping warm, stir for 0.5 h, let stand to separate the liquids, take the upper organic phase, concentrate under reduced pressure to remove the solvent, and subject the residue to vacuum distillation to obtain a white to light yellow liquid 2-bromo-4-tert-butyl-3,5-difluorophenol, with a mass of 12.9 g, a yield of 90.6%, and a content of 99.2% according to GC analysis.

[0045] The above are only preferred embodiments of the present invention. It should be noted that the above preferred embodiments should not be regarded as limiting the present invention, and the protection scope of the present invention should be based on the scope defined by the claims. For ordinary technicians in this technical field, several improvements and modifications can be made without departing from the spirit and scope of the present invention, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. A method for synthesizing a high-purity intermediate 2-bromo-4-tert-butyl-3,5-difluorophenol, characterized in that: The method comprises the following steps: adding 3,5-difluorophenol to a tert-butyl ether solvent, then dripping a catalyst, after the reaction is finished, standing to separate the liquids, stripping the lower layer with a tert-butyl ether solvent, combining and concentrating the organic phases to obtain an intermediate 4-tert-butyl-3,5-difluorophenol, adding an organic solvent to dissolve the intermediate, slowly dripping bromine, finishing the reaction, adding a terminator, standing to separate the liquids, concentrating the organic phase, and obtaining high-purity 2-bromo-4-tert-butyl-3,5-difluorophenol.

2. The method for preparing 2-bromo-4-tert-butyl-3,5-difluorophenol according to claim 1, characterized in that: The tert-butyl ether solvent is selected from methyl tert-butyl ether, ethyl tert-butyl ether, di-tert-butyl ether or a combination of several thereof.

3. The method for preparing 2-bromo-4-tert-butyl-3,5-difluorophenol according to claim 1, characterized in that: The catalyst is (3-(1-methyl-1H-imidazol-3-ium-3-yl)propyl)zirconium (V) chloride, and the specific structure is as follows:

4. The method for preparing 2-bromo-4-tert-butyl-3,5-difluorophenol according to claim 1, characterized in that: The molar ratio of the catalyst IL-Zr to 3,5-difluorophenol is 0.5-0.75:1, preferably 0.6-0.7:

1.

5. The method for preparing 2-bromo-4-tert-butyl-3,5-difluorophenol according to claim 1, characterized in that: The molar ratio of the tert-butyl ether solvent to 3,5-difluorophenol is 1.5-2.5:1, preferably 1.8-2.2:

1.

6. The method for preparing 2-bromo-4-tert-butyl-3,5-difluorophenol according to claim 1, characterized in that: The organic solvent is selected from the group consisting of dichloromethane, 1,2-dichloroethane, chloroform, 1,1,2,2-tetrachloroethylene, and 1,1,2,2-tetrachloroethane, or a combination thereof.

7. The method for preparing 2-bromo-4-tert-butyl-3,5-difluorophenol according to claim 1, characterized in that: The molar ratio of bromine to 4-tert-butyl-3,5-difluorophenol is 1.0-1.5:1, preferably 1.0-1.2:

1.

8. The method for preparing 2-bromo-4-tert-butyl-3,5-difluorophenol according to claim 1, characterized in that: The mass ratio of the organic solvent to 4-tert-butyl-3,5-difluorophenol is 2-5:1, preferably 3-4:

1.

9. The method for preparing 2-bromo-4-tert-butyl-3,5-difluorophenol according to claim 1, characterized in that: The reaction time of Friedel-Crafts alkylation is 20-50 h, preferably 30-40 h; the reaction time of bromination is 1-5 h, preferably 2-3 h.

10. The method for preparing 2-bromo-4-tert-butyl-3,5-difluorophenol according to claim 1, characterized in that: The alkylation reaction temperature is 0-50°C, preferably 20-30°C; the bromination reaction temperature is -5°C-50°C, preferably 10-30°C.

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