A kind of preparation method of butylated hydroxyanisole

Abstract

The present invention relates to a preparation method of butylated hydroxyanisole, and belongs to the field of pharmaceutical chemistry. The preparation method comprises taking 2-tert-butylphenol as a raw material, reacting with sodium methoxide solution under the conditions of a catalyst and / or a co-catalyst by bromination reaction, and preparing butylated hydroxyanisole. The preparation method provided by the present invention does not need to use a large amount of toxic reagents, is safe and environmentally friendly, is not easy to cause harm to production personnel and the environment, has high reaction selectivity, and is conducive to industrial implementation.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical chemistry, and in particular to a method for preparing butylated hydroxyanisole. Background Art

[0002] Butylated hydroxyanisole (BHA), also known as butylated hydroxyanisole, has been used as an antioxidant in food, cosmetics, feed and pharmaceutical industries since 1941. BHA consists of two isomers, 3-tert-butyl-4-hydroxyanisole (3-BHA) and 2-tert-butyl-4-hydroxyanisole (2-BHA). The phenolic hydroxyl group of 3-BHA is affected by the steric hindrance of the tert-butyl group, and its antioxidant performance is 1.5-2 times higher than that of 2-BHA. BHA has been included in the Chinese, American and European Pharmacopoeia. The Chinese Pharmacopoeia (2020 edition) requires that the 2-BHA content shall not exceed 10.0%, while the European Pharmacopoeia (EP 10.0) requires that the 2-BHA content shall not exceed 10.0% of the 3-BHA content. The Joint Expert Committee on Food Additives (JECFA) under the Food and Agriculture Organization of the United Nations and the World Health Organization stipulates that the 3-BHA content in BHA shall not be less than 85%. The melting point of 3-BHA (99.5%) is 60°C-61.5°C, which is higher than the melting point of 2-BHA (99.0%) of 50-51.5°C. 3-BHA is more conducive to eliminating free radicals, has better antioxidant activity, and has good physical and chemical stability. Its stability is mainly reflected in its good fluidity, not easy to agglomerate, and not easy to change color in the environment.

[0003] At present, the research direction of BHA synthesis is to reduce the generation of 2-BHA and other impurities. There are two main synthesis methods: one is to use p-hydroxyanisole as substrate, tert-butyl alcohol, methyl tert-butyl ether and isobutylene as alkylating agents, and synthesize BHA in the presence of a catalyst. The commonly used catalysts are proton acids or Lewis acids, such as H2SO4, H3PO4, ion exchange resins, BF3, ZnCl2, solid heteropoly acids, etc. US Patent US2410902 uses n-hexane as solvent and H3PO4 as catalyst to react p-hydroxyanisole with tert-butyl alcohol or isobutylene at 50°C to obtain a product containing 75% BHA and 15% impurity 2,5-di-tert-butyl-4-hydroxyanisole. Chinese patent CN108238857 reported the use of p-hydroxyanisole, tert-butyl alcohol, phosphoric acid to synthesize BHA in a ratio of 200:90:60 and 300:110:80. In addition, an appropriate amount of concentrated sulfuric acid was added at a temperature of 30°C-40°C. The product yield and isomer content were not reported, but it can be seen that more proton acid catalysts were used in the reaction. Xia Yingzi et al. used p-hydroxyanisole as a substrate, methyl tert-butyl ether as an alkylating agent, a cation exchange resin as a catalyst, toluene and butanone (volume ratio 5:1) as solvents, and a temperature of 80-90°C to obtain a BHA yield of 47.1% and a 3-BHA content of 89.1%. U.S. Patent No. 2,616,931 uses p-hydroxyanisole and butanol in a molar ratio of 2:1, SiO2-AlO3 as a catalyst, and reacts at 150° C. under pressure to obtain 88% 3-BHA and 12% 2-BHA. This method uses a proton acid as a catalyst, which is used in a large amount and has poor reaction selectivity. The catalyst used is a Lewis acid, which has a small source of catalysts and harsh reaction conditions, and is not suitable for large-scale production.

[0004] The second method for synthesizing BHA is to use tert-butylhydroquinone (TBHQ) as a substrate, dimethyl sulfate, methyl iodide, and dimethyl carbonate as alkylating agents to synthesize BHA, or to react with methanol in the presence of a catalyst to obtain BHA. U.S. Patent No. 2776321 uses TBHQ as a substrate, xylene as a solvent, zinc powder and water, and dimethyl sulfate as a methylating agent, and reacts at 90.5°C-91.5°C to obtain 89.5% BHA, of which the 3-BHA content is 72% and the 2-BHA content is 28%. British Patent No. GB1366441 also uses TBHQ as a substrate, dimethyl sulfate as an alkylating agent, and reacts at 30-40°C to obtain a product BHA yield of 84.1%, of which the 3-BHA content is 92.8% and the 2-BHA content is 5.3%. Chinese patent CN 108314609 uses tert-butylhydroquinone (TBHQ) and dimethyl carbonate (DMC) with low toxicity as raw materials, uses self-made double alkali metal as catalyst, and synthesizes BHA at a temperature of 180°C and a pressure of 1.2MPa. The conversion rate of TBHQ is only 28-40%, and the selectivity of the target product 3-tert-butyl-4-hydroxyanisole (3-BHA) is 84-100%. Chinese patent CN101613260 uses TBHQ as a substrate, methanol as a solvent and an alkylating agent, adds concentrated sulfuric acid and metal chloride for reflux reaction, and extracts to obtain a BHA content of 90-94%, the isomer content is not reported, and the yield is 78-81%. This method uses highly toxic dimethyl sulfate and methyl iodide, or generates methyl sulfate substances during the reaction process, which is not friendly to the human body and the environment; using dimethyl carbonate with low toxicity, the conversion rate is low and the cost is high.

[0005]

[0006] The methods for preparing butylated hydroxyanisole (BHA) disclosed in the above prior art have at least one of the following defects:

[0007] (1) The reaction process uses a large amount of protonic acid or highly toxic alkylating agent;

[0008] (2) The reaction produces toxic substances, which are unfriendly to the human body and the environment;

[0009] (3) Poor reaction selectivity and low conversion rate;

[0010] (4) The reaction product is impure, producing 2-BHA or 2-substituted products.

[0011] Therefore, there is still a need to develop a method for preparing butylated hydroxyanisole (3-BHA) that is environmentally friendly, highly selective and has good product purity. Summary of the invention

[0012] The invention provides a method for preparing butylated hydroxyanisole (3-BHA).

[0013] A method for preparing butylated hydroxyanisole (3-BHA) comprises: subjecting 4-bromo-2-tert-butylphenol to a substitution reaction with sodium methoxide in the presence of a copper catalyst and an amide and / or ester co-catalyst, and performing post-treatment after the reaction to prepare butylated hydroxyanisole (3-BHA).

[0014] In some embodiments, a method for preparing butylated hydroxyanisole (3-BHA) comprises: 2-tert-butylphenol is subjected to a bromination reaction to obtain 4-bromo-2-tert-butylphenol, 4-bromo-2-tert-butylphenol is subjected to a substitution reaction with sodium methoxide under the conditions of a copper catalyst, an amide and / or an ester co-catalyst, and after the reaction is completed, post-treatment is performed to prepare butylated hydroxyanisole (3-BHA), and the reaction route is as follows:

[0015]

[0016] The method provided by the invention can obtain butylated hydroxyanisole with a purity of 3-BHA (i.e. 3-tert-butyl-4-hydroxyanisole) greater than 95.0%, 97.0%, 98.0% or 99.0%.

[0017] In some embodiments, the butylated hydroxyanisole obtained by the method provided by the present invention is pure butylated hydroxyanisole (3-BHA), wherein the purity of 3-BHA (i.e., 3-tert-butyl-4-hydroxyanisole) is greater than 99.0%.

[0018] The bromination reagent of the bromination reaction can be tetrabutylammonium tribromide, Br2, N-bromosuccinimide, dibromohydantoin, etc., preferably tetrabutylammonium tribromide.

[0019] The copper catalyst includes at least one selected from cuprous halide, cupric halide, basic copper carbonate, copper sulfate, copper nitrate, cupric acetate or its monohydrate, cuprous acetate, cupric oxalate, and cupric citrate. In some embodiments, the copper catalyst is anhydrous cupric sulfate or anhydrous cuprous chloride, which is beneficial to the acquisition of the product. In some embodiments, the copper catalyst is cupric acetate or its monohydrate, which is beneficial to the acquisition of the product.

[0020] The halogen element in the cuprous halide in the copper catalyst includes one of fluorine, chlorine, bromine and iodine.

[0021] The ester co-catalyst includes at least one selected from methyl formate, methyl acetate, ethyl formate, ethyl acetate, butyl formate, n-butyl acetate, isobutyl acetate, isopropyl acetate, and ethyl oxalate. In some embodiments, the ester co-catalyst is methyl acetate. In some embodiments, the ester co-catalyst is ethyl acetate, which is beneficial to the operation and the acquisition of the product.

[0022] The amide co-catalyst includes at least one selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, hexamethylphosphorotriamide, and 1,3-dimethyl-2-imidazolidinone. In some embodiments, the amide co-catalyst is N,N-dimethylacetamide, which is beneficial to operation control and obtaining the target product.

[0023] The molar ratio of the co-catalyst to 4-bromo-2-tert-butylphenol may be 0.4-10:1. In some embodiments, the molar ratio of the co-catalyst to 4-bromo-2-tert-butylphenol is 0.4-8:1. In some embodiments, the molar ratio of the co-catalyst to 4-bromo-2-tert-butylphenol is 0.4-6:1. In some embodiments, the molar ratio of the co-catalyst to 4-bromo-2-tert-butylphenol is 1-10:1. In some embodiments, the molar ratio of the co-catalyst to 4-bromo-2-tert-butylphenol is 1-6:1. In some embodiments, the molar ratio of the co-catalyst to 4-bromo-2-tert-butylphenol is 1-4:1. In some embodiments, the molar ratio of the co-catalyst to 4-bromo-2-tert-butylphenol is 1-2:1.

[0024] The molar ratio of the sodium methoxide to 4-bromo-2-tert-butylphenol is 2-5:1. In some embodiments, the molar ratio of the sodium methoxide to 4-bromo-2-tert-butylphenol is 2-4:1. In some embodiments, the molar ratio of the sodium methoxide to 4-bromo-2-tert-butylphenol is 2-3:1. In some embodiments, the molar ratio of the sodium methoxide to 4-bromo-2-tert-butylphenol is 3-4:1. In some embodiments, the molar ratio of the sodium methoxide to 4-bromo-2-tert-butylphenol is 3-5:1. In some embodiments, the molar ratio of the sodium methoxide to 4-bromo-2-tert-butylphenol is 4-5:1.

[0025] The molar ratio of the copper catalyst to 4-bromo-2-tert-butylphenol is 0.01-0.20: 1. In some embodiments, the molar ratio of the copper catalyst to 4-bromo-2-tert-butylphenol is 0.03-0.15: 1. In some embodiments, the molar ratio of the copper catalyst to 4-bromo-2-tert-butylphenol is 0.05-0.10: 1. In some embodiments, the molar ratio of the copper catalyst to 4-bromo-2-tert-butylphenol is 0.04-0.08: 1.

[0026] The temperature range of the substitution reaction is 50°C-130°C. In some embodiments, the temperature range of the substitution reaction is 70°C-130°C. In some embodiments, the temperature range of the substitution reaction is 90°C-130°C. In some embodiments, the temperature range of the substitution reaction is 110°C-130°C. In some embodiments, the temperature range of the substitution reaction is 50°C-110°C. In some embodiments, the temperature range of the substitution reaction is 70°C-110°C. In some embodiments, the temperature range of the substitution reaction is 90°C-110°C. In some embodiments, the temperature range of the substitution reaction is 55°C-115°C. In some embodiments, the temperature range of the substitution reaction is 75°C-115°C. In some embodiments, the temperature range of the substitution reaction is 95°C-115°C. In some embodiments, the temperature range of the substitution reaction is 50°C-90°C. In some embodiments, the temperature range of the substitution reaction is 70°C-90°C. In some embodiments, the temperature range of the substitution reaction is 50°C. In some embodiments, the temperature range of the substitution reaction is 60°C. In some embodiments, the temperature range of the substitution reaction is 70°C. In some embodiments, the temperature range of the substitution reaction is 80°C. In some embodiments, the temperature range of the substitution reaction is 90°C. In some embodiments, the temperature range of the substitution reaction is 100°C. In some embodiments, the temperature range of the substitution reaction is 110°C. In some embodiments, the temperature range of the substitution reaction is 120°C. In some embodiments, the temperature range of the substitution reaction is 130°C.

[0027] The reaction time of the substitution reaction is 0.5h-24h. In some embodiments, the reaction time is 0.5h-20h. In some embodiments, the reaction time is 0.5h-16h. In some embodiments, the reaction time is 0.5h-12h. In some embodiments, the reaction time is 0.5h-8h. In some embodiments, the reaction time is 0.5h-4h. In some embodiments, the reaction time is 4h-20h. In some embodiments, the reaction time is 4h-16h. In some embodiments, the reaction time is 4h-12h. In some embodiments, the reaction time is 4h-8h. In some embodiments, the reaction time is 4h-6h.

[0028] The post-treatment comprises: concentrating the reaction solution, neutralizing the obtained product with a hydrochloric acid solution until the pH test paper shows neutrality, adding an alkane solvent for extraction, then washing with an EDTA-2Na aqueous solution and water, taking an organic layer, cooling the temperature to -5°C-15°C, precipitating a solid, and adding a crystallization solvent for crystallization after the solid is dried to obtain butylated hydroxyanisole.

[0029] In some embodiments, during the post-treatment, the temperature is lowered to -5°C-10°C, which is conducive to the acquisition of the product. In some embodiments, during the post-treatment, the temperature is lowered to -5°C-5°C. In some embodiments, during the post-treatment, the temperature is lowered to -5°C-0°C; in some embodiments, during the post-treatment, the temperature is lowered to 0°C-10°C; in some embodiments, during the post-treatment, the temperature is lowered to 0°C-5°C; in some embodiments, during the post-treatment, the temperature is lowered to 5°C-10°C; in some embodiments, the temperature is lowered to -5°C, 0°C, 5°C or 10°C.

[0030] The alkane solvent is a mixed solvent of at least one of heptane, hexane, pentane and petroleum ether and cyclohexane.

[0031] The crystallization solvent is a mixed solvent of at least one of heptane, hexane, pentane and petroleum ether and cyclohexane.

[0032] The volume percentage of cyclohexane in the mixed solvent is 10%-99%. In the mixed solvent, in some embodiments, the volume percentage of cyclohexane is 10%-90%; in some embodiments, the volume percentage of cyclohexane is 10%-80%; in some embodiments, the volume percentage of cyclohexane is 10%-60%, which is conducive to the acquisition of high-purity products; in some embodiments, the volume percentage of cyclohexane is 10%-40%; in some embodiments, the volume percentage of cyclohexane is 10%-30%. In the mixed solvent, in some embodiments, the volume percentage of cyclohexane is 20%-99%; in some embodiments, the volume percentage of cyclohexane is 20%-80%; in some embodiments, the volume percentage of cyclohexane is 20%-60%, which is conducive to the acquisition of high-purity products; in some embodiments, the volume percentage of cyclohexane is 20%-40%. In some embodiments, the volume percentage of cyclohexane is 25%-99%; in some embodiments, the volume percentage of cyclohexane is 25%-75%; in some embodiments, the volume percentage of cyclohexane is 25%-60%, which is conducive to the acquisition of high-purity products. In the mixed solvent, in some embodiments, the volume percentage of cyclohexane is 25%-50%, which is conducive to the acquisition of high-purity products. In the mixed solvent, in some embodiments, the volume percentage of cyclohexane is 25%-30%, which is conducive to the acquisition of high-purity products.

[0033] The amount of the crystallization solvent used ranges from 4 to 20 times the mass of the solid after drying. In some embodiments, the amount of the crystallization solvent used ranges from 5 to 15 times the mass of the solid after drying. In some embodiments, the amount of the crystallization solvent used ranges from 6 to 10 times the mass of the solid after drying. In some embodiments, the amount of the crystallization solvent used ranges from 8 to 10 times the mass of the solid after drying. In some embodiments, the amount of the crystallization solvent used ranges from 8 to 15 times the mass of the solid after drying. In some embodiments, the amount of the crystallization solvent used ranges from 8 to 20 times the mass of the solid after drying. In some embodiments, the amount of the crystallization solvent used ranges from 10 to 15 times the mass of the solid after drying. In some embodiments, the amount of the crystallization solvent used ranges from 12 to 15 times the mass of the solid after drying. In some embodiments, the amount of the crystallization solvent used ranges from 4 times the mass of the solid after drying. In some embodiments, the amount of the crystallization solvent used ranges from 6 times the mass of the solid after drying. In some embodiments, the amount of the crystallization solvent used ranges from 8 times the mass of the solid after drying. In some embodiments, the amount of the crystallization solvent used ranges from 10 times the mass of the solid after drying. In some embodiments, the amount of the crystallization solvent used ranges from 12 times the mass of the solid after drying. In some embodiments, the amount of the crystallization solvent used ranges from 15 times the mass of the solid after drying. In some embodiments, the amount of the crystallization solvent used ranges from 18 times the mass of the solid after drying. In some embodiments, the amount of the crystallization solvent used ranges from 20 times the mass of the solid after drying.

[0034] In some embodiments, a method for preparing butylated hydroxyanisole comprises: 4-bromo-2-tert-butylphenol undergoes a substitution reaction with sodium methoxide at 50°C-130°C under the conditions of a copper catalyst, an amide and / or an ester co-catalyst, and post-processing after the reaction to prepare butylated hydroxyanisole; wherein the copper catalyst is copper sulfate, cuprous chloride, copper acetate, or a combination thereof; the ester co-catalyst is methyl formate, ethyl formate, methyl acetate, or a combination thereof; the amide co-catalyst is N,N-dimethylformamide, N,N-dimethylformamide Acetamide, N-methylpyrrolidone or a combination thereof; the post-treatment comprises: concentrating the reaction solution, neutralizing the obtained product with a hydrochloric acid solution until the pH test paper shows neutrality, then adding n-heptane-cyclohexane for extraction, then washing with an EDTA-2Na aqueous solution and water in sequence, taking an organic layer, cooling it to -5°C-10°C, precipitating crystals, and adding n-heptane-cyclohexane for crystallization after drying to obtain butylated hydroxyanisole, wherein the volume percentage of cyclohexane in the n-heptane-cyclohexane is 20%-60%; the purity of 3-BHA in the prepared butylated hydroxyanisole is greater than 99.0%.

[0035] In the above method, the hydrochloric acid solution can be of any suitable concentration; the EDTA-2Na aqueous solution can be of any suitable concentration.

[0036] In the present invention, high performance liquid chromatography (HPLC) can be used to monitor the reaction endpoint; when the detection shows that the peak area of ​​the raw material 2-tert-butylphenol is ≤1.0%, the reaction can be regarded as completed, and the reaction time is usually within 2 hours; in the substitution reaction, when the detection shows that the peak area of ​​4-bromo-2-tert-butylphenol is ≤1.0%, the reaction can be regarded as completed, and the reaction time is usually within 24 hours.

[0037] The method provided by the present invention can obtain purer butyl hydroxyanisole by controlling appropriate reaction conditions, and the purity of 3-BHA (i.e., 3-tert-butyl-4-hydroxyanisole) in the obtained butyl hydroxyanisole is greater than 95.0%, 97.0%, 98.0%, or 99.0%, and the reaction conditions are safe and friendly, suitable for large-scale industrial production; compared with the prior art, the technical scheme of the present invention has at least the following technical effects:

[0038] (1) The reaction process does not require the use of large amounts of protonic acids or highly toxic alkylating agents;

[0039] (2) The reaction conversion rate is high and the selectivity is good, which is conducive to industrial production;

[0040] (3) The reagents used are safe and environmentally friendly and are unlikely to cause harm to production personnel and the environment;

[0041] (4) The reaction product is 3-BHA, and no 2-BHA or 2-substituted products are produced;

[0042] (5) The product has high purity. The purity of 3-BHA (i.e., 3-tert-butyl-4-hydroxyanisole) in the obtained product butyl hydroxyanisole is greater than 95% or 99%.

[0043] Definition of terms

[0044] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0045] The term "room temperature" refers to a temperature between about 20°C and 35°C, or between about 23°C and 28°C, or about 25°C.

[0046] The reaction involved in the present invention can be monitored by high performance liquid chromatography (HPLC) to monitor the reaction endpoint. When the detection shows that the reaction raw material compound is less than 1.0%, the reaction is considered to be completed. The reaction time is usually within 24 hours.

[0047] The method of the present invention can use high performance liquid chromatography (HPLC) to monitor the purity of the reactants. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 shows the HPLC-DAD diagram of the crude butyl hydroxyanisole in Example 2;

[0049] Figure 2 The HPLC-DAD diagram of the refined butyl hydroxyanisole product in Example 2 is shown;

[0050] Figure 3 shows a polarizing microscope image of butylated hydroxyanisole in Example 2;

[0051] Figure 4 The HPLC-DAD diagram of the crude butyl hydroxyanisole in Example 3 is shown;

[0052] Figure 5 The HPLC-DAD diagram of the refined butyl hydroxyanisole product in Example 3 is shown;

[0053] Figure 6 shows a polarizing microscope image of butylated hydroxyanisole in Example 3;

[0054] Figure 7 shows the HPLC-DAD chart of the crude butyl hydroxyanisole in Example 4;

[0055] Figure 8 The HPLC-DAD diagram of the refined butyl hydroxyanisole product in Example 4 is shown;

[0056] Fig. 9 A polarizing microscope image of butylated hydroxyanisole in Example 4 is shown. DETAILED DESCRIPTION

[0057] In order to enable those skilled in the art to better understand the technical solution of the present invention, some non-limiting embodiments are further disclosed below to further describe the present invention in detail.

[0058] The reagents used in the present invention can be purchased from the market or prepared by the method described in the present invention.

[0059] In the present invention, mL means milliliter, h means hour, g means gram, mg means milligram, ℃ means degree Celsius, HPLC means high performance liquid chromatography, v:v means volume ratio, wt means weight ratio, and EDTA-2Na refers to disodium ethylenediaminetetraacetate.

[0060] Example 1

[0061] 100.00g 2-tert-butylphenol was mixed with 1000mL dichloromethane, stirred at 0°C, and 321.50g tetrabutylammonium tribromide was added in batches, and stirred for 1h. 1000mL 5% sodium thiosulfate was added to quench the reaction, the water layer was removed, and the dichloromethane was removed under reduced pressure. 500mL ethyl acetate was added, and the mixture was washed twice with 500mL purified water each time, and once with 500mL 5%wt sodium chloride solution. The organic layer was decompressed to remove the solvent to obtain 142.35g 4-bromo-2-tert-butylphenol, with a yield of 93.2% and a purity of 98.5%.

[0062] Example 2

[0063] Add 28.35g 4-bromo-2-tert-butylphenol, 86.40g 30%wt sodium methoxide-methanol, 17.54g N,N-dimethylformamide, 0.96g anhydrous copper sulfate to a 500mL flask, heat to 115°C (internal temperature 95.5°C) for reflux reaction for 4.5h, remove the solvent under reduced pressure and cool to room temperature, add hydrochloric acid to neutralize to pH neutrality. Add 130mL n-heptane-cyclohexane (3:1, v:v) to the resulting neutral solution for extraction, wash with 5%wt EDTA-2Na aqueous solution, wash twice with purified water, cool the organic layer to 0°C, filter to obtain a filter cake, and recrystallize the filter cake in 250mL n-heptane-cyclohexane (3:1, v:v) to obtain 13.78g BHA product, 3-BHA purity 99.52%, total yield 61.5%. The HPLC spectrum of the obtained crude butyl hydroxyanisole is as follows Figure 1 As shown, the HPLC spectrum of the refined product is as follows Figure 2 As shown in the polarizing microscope image Figure 3 shown.

[0064] Example 3

[0065] Add 28.35g 4-bromo-2-tert-butylphenol, 86.40g 30%wt sodium methoxide-methanol, 26.69g methyl acetate, 1.10g cuprous chloride to a 500mL flask, heat to 115°C (internal temperature 95°C) for reflux reaction for 4.5h, remove the solvent under reduced pressure and cool to room temperature, add hydrochloric acid to neutralize to pH neutrality. Add 130mL n-heptane-cyclohexane (3:1, v:v) for extraction, wash with 5%wt EDTA-2Na aqueous solution, wash twice with purified water, cool the organic layer to 0°C, filter to obtain a filter cake, and recrystallize the filter cake in 300mL n-heptane-cyclohexane (3:1, v:v) to obtain 16.22g BHA product, 3-BHA purity 99.16%, total yield 72.2%. The HPLC spectrum of the obtained crude butyl hydroxyanisole is as follows Figure 4 As shown, the HPLC spectrum of the refined product is as follows Figure 5 As shown in the polarizing microscope image Figure 6 shown.

[0066] Example 4

[0067] Add 28.35g 4-bromo-2-tert-butylphenol, 86.40g 30%wt sodium methoxide-methanol, 31.36g N,N-dimethylacetamide, 10.57g ethyl acetate, 1.20g copper acetate monohydrate to a 500mL flask, heat to 120°C (internal temperature 100°C) for reflux reaction for 4.5h, remove the solvent under reduced pressure and cool to room temperature, add hydrochloric acid to neutralize to pH neutrality. Add 130mL n-heptane-cyclohexane (1:1, v:v) for extraction, wash with 5%wt EDTA-2Na aqueous solution, wash twice with purified water, cool the organic layer to 0°C, filter to obtain a filter cake, and recrystallize the filter cake in 300mL n-heptane-cyclohexane (1:1, v:v) to obtain 13.43g BHA product, 3-BHA purity 99.72%, total yield 60.10%. The HPLC spectrum of the obtained crude butyl hydroxyanisole is as follows Figure 7 As shown, the HPLC spectrum of the refined product is as follows Figure 8 As shown in the polarizing microscope image Fig. 9 shown.

[0068] Instrument parameters, test conditions and characterization results

[0069] 1. Instrument information: Aglient 1260 HPLC high performance liquid chromatograph (DAD detector)

[0070] Test method:

[0071] 1) Take 1-2 drops of the reaction solution and dilute it to 5 mL with mobile phase, and inject 2.0 uL;

[0072] 2) Take 5 mg of the finished product and dilute it to 10 mL using the mobile phase, and inject 2.0 uL;

[0073] The specific chromatographic conditions are as follows:

[0074] Chromatographic column: Waters Atlantis T3, 5um*4.6mm*150mm;

[0075] Flow rate: 0.65 mL / min;

[0076] Detector wavelength: 290nm;

[0077] Injection volume: 2 μL;

[0078] Column temperature: 30°C;

[0079] Running time: 25min;

[0080] Gradient elution:

[0081]

[0082] Post-run: 5min;

[0083] Mobile phase A: acetonitrile: 5% acetic acid = 45:55;

[0084] Mobile phase B: acetonitrile;

[0085] In the detection results, the main peak RT≈7.46 minutes is 3-BHA, and the rest are impurities.

[0086] 2. Instrument information: Polarized light microscope (PLM)--DM1000

[0087] The method of the present invention has been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods and applications described herein within the content, spirit and scope of the present invention to implement and apply the technology of the present invention. Those skilled in the art can refer to the content of this article and appropriately improve the process parameters. It is particularly important to point out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.

Claims

1. A method for preparing butylated hydroxyanisole, comprising: 4-bromo-2-tert-butylphenol undergoes substitution reaction with sodium methoxide in the presence of a copper catalyst and an ester co-catalyst, and after the reaction, the butylated hydroxyanisole is post-treated to prepare the butylated hydroxyanisole; wherein the purity of 3-BHA in the prepared butylated hydroxyanisole is greater than 95.0%; the ester co-catalyst is methyl acetate; the copper catalyst is cuprous halide; and the halogen element of the cuprous halide is one of fluorine, chlorine, bromine and iodine.

2. The method according to claim 1, comprising: 2-tert-butylphenol is subjected to bromination reaction to obtain 4-bromo-2-tert-butylphenol. 4-bromo-2-tert-butylphenol is subjected to substitution reaction with sodium methoxide under the conditions of copper catalyst and ester co-catalyst. After the reaction, butylated hydroxyanisole is prepared by post-treatment. The reaction route is as follows:

3. The method according to claim 1, wherein: The molar ratio of the copper catalyst to 4-bromo-2-tert-butylphenol is 0.01-0.20:

1.

4. according to any described method of claim 1-3, the molar ratio of described sodium methoxide to 4-bromo-2-tert-butylphenol is 2-5:

1.

5. The method according to any one of claims 1 to 3, wherein the temperature range of the substitution reaction is 50°C-130°C.

6. The method according to any one of claims 1 to 3, wherein the post-processing comprises: The reaction solution is concentrated, and then the resultant is neutralized with a hydrochloric acid solution until the pH test paper shows neutrality, and then an alkane solvent is added for extraction, and then washed with an EDTA-2Na aqueous solution and water, and the organic layer is taken and cooled to -5°C-15°C to precipitate a solid. After the solid is dried, a crystallization solvent is added for crystallization to obtain butylated hydroxyanisole.

7. The method according to claim 6, wherein the alkane solvent and the crystallization solvent are independently a mixed solvent of at least one of heptane, hexane, pentane and petroleum ether and cyclohexane, wherein: The volume percentage of cyclohexane in the mixed solvent is 10% to 99%.

8. The method according to claim 6, wherein the amount of the crystallization solvent is 4-20 times the mass of the dried solid.

9. The method according to any one of claims 1-2, wherein: The post-treatment comprises: concentrating the reaction solution, neutralizing the obtained product with a hydrochloric acid solution until the pH test paper shows neutrality, adding n-heptane-cyclohexane for extraction, then washing with an EDTA-2Na aqueous solution and water in sequence, taking an organic layer, cooling the temperature to -5°C-10°C, precipitating crystals, and adding n-heptane-cyclohexane for crystallization after drying to obtain butylated hydroxyanisole, wherein the volume percentage of cyclohexane in the n-heptane-cyclohexane is 20%-60%; and the purity of 3-BHA in the prepared butylated hydroxyanisole is greater than 99.0%.

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