A kind of preparation method of 2-tert-butyl-4-hydroxyanisole

Abstract

The present invention relates to a preparation method of 2-tert-butyl-4-hydroxyanisole, hydroquinone and tert-butyl alcohol are used as starting raw materials to synthesize 2-tert-butyl-4-hydroxyanisole, 4-position hydroxyl with less steric hindrance is protected by tert-butyldimethylchlorosilane (TBSCl), iodomethane is preferentially reacted with 1-position hydroxyl with greater steric hindrance, and finally protecting group is removed under mild conditions to obtain 2-tert-butyl-4-hydroxyanisole (2-BHA) with high yield. Preparation method of the present invention is not prone to side reaction, and reaction conditions are mild, the generation of harmful substances is reduced, and the obtained products have good purity and high yield. Simultaneously, production cost is low, and it is suitable for industrialized large-scale production.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and particularly relates to a method for preparing 2-tert-butyl-4-hydroxyanisole. Background Art

[0002] Butylated hydroxyanisole (BHA), also known as tert-butyl-4-hydroxyanisole, is a waxy solid composed of >98.5% active substances. It is a mixture of 3-tert-butyl-4-hydroxyanisole (3-BHA) and 2-tert-butyl-4-hydroxyanisole (2-BHA). BHA is relatively stable to heat and is not easily destroyed under weak alkaline conditions, so it is a good antioxidant. Due to its good antioxidant activity, BHA is often used as a food additive to enhance the stability of oils and fats during their shelf life. However, recent studies have shown that antioxidants such as BHA, TEMPO and NAC can inhibit the differentiation of monocytes into M2 macrophages by inhibiting the production of reactive oxygen species, thereby inhibiting the occurrence of tumors, and therefore have a certain anti-cancer effect.

[0003] At present, the commercial preparation method of BHA mainly uses p-methoxyphenol as a raw material, and synthesizes it with tert-butyl alcohol, tert-butyl alcohol methyl ether or isobutylene under the catalysis of protonic acid, ion exchange resin, alkoxy aluminum, or aluminum oxide. In addition, there are some new methods for synthesizing BHA recently. For example, Korean patent document KR 2013051653 discloses that 2-tert-butylhydroquinone is used as a raw material, and reacts with dimethyl sulfate under base catalysis in a water / n-hexane two-phase reaction system to synthesize BHA, and the yield after recrystallization is 84% ​​and the purity is 99%. However, since dimethyl sulfate is prone to hydrolysis side reactions when it encounters alkaline water, an excess of dimethyl sulfate is usually required, but the by-products generated by excessive dimethyl sulfate enter the wastewater, which will cause a huge waste of resources. In addition, Chinese patent document CN 108929202 A discloses the use of steric hindrance principle, under the action of a base with steric hindrance, selectively activating the 4-hydroxyl group of 2-tert-butylhydroquinone in a non-protonic solvent, and then further allowing it to undergo an SN1 substitution reaction with a methylating agent, and finally recrystallizing the reaction product to obtain 2-BHA with a purity of up to 99.0%. However, in this method, the base may react with 2-tert-butylhydroquinone to generate water, which affects the reaction process, so the generated water needs to be removed first. Summary of the invention

[0004] In view of the above-mentioned shortcomings of the prior art, the present invention discloses a method for preparing 2-tert-butyl-4-hydroxyanisole, which has the characteristics of mild reaction conditions, high product selectivity and good catalytic effect, and has a simple process and low cost.

[0005] The technical solution adopted by the present invention to solve the technical problem is as follows:

[0006] A method for preparing 2-tert-butyl-4-hydroxyanisole comprises the following steps:

[0007] (1) Hydroquinone and tert-butyl alcohol react in the presence of a catalyst to generate tert-butyl hydroquinone.

[0008]

[0009] Preferably, the catalyst in step (1) is selected from one or more of aminosulfonic acid, AlCl3, FeCl3, and sulfuric acid.

[0010] Preferably, in step (1), the molar ratio of the catalyst, hydroquinone and tert-butyl alcohol is 1:5-10:5-10.

[0011] Preferably, the reaction solvent in step (1) is selected from one or more of toluene and xylene. The reaction conditions are 120-150° C. and the reaction time is 4-12 hours.

[0012] (2) adding tert-butyldimethylsilyl chloride to tert-butylhydroquinone to generate 2-(tert-butyl)-4-((tert-butyldimethylsilyl)oxy)phenol under base catalysis,

[0013]

[0014] Preferably, the reaction solvent in step (2) is selected from one or more of N,N-dimethylformamide (DMF), dichloromethane and tetrahydrofuran.

[0015] Preferably, the reaction condition of step (2) is 60° C. for 2 hours.

[0016] Preferably, the base in step (2) is selected from one or more of imidazole, pyridine and triethylamine.

[0017] Preferably, in step (2), the molar ratio of tert-butylhydroquinone to tert-butyldimethylsilyl chloride is 1:1.5, and the molar ratio of tert-butylhydroquinone to imidazole is 1:2.5.

[0018] (3) 2-(tert-butyl)-4-((tert-butyldimethylsilyl)oxy)phenol reacts with iodomethane under base catalysis to obtain tert-butyl (3-(tert-butyl)-4-methoxyphenoxy)dimethylsilane.

[0019]

[0020] Preferably, the reaction solvent in step (3) is selected from one or more of acetone, toluene and acetonitrile.

[0021] Preferably, the reaction conditions of step (3) are reflux for 12-24 hours.

[0022] Preferably, the base in step (3) is selected from one or more of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium ethoxide, potassium ethoxide, and triethylamine.

[0023] Preferably, the molar ratio of 2-(tert-butyl)-4-((tert-butyldimethylsilyl)oxy)phenol, iodomethane and base in step (3) is 1:2-5:1.

[0024] (4) tert-butyl (3-(tert-butyl)-4-methoxyphenoxy) dimethyl silane is deprotected under the catalysis of a catalyst to obtain 2-tert-butyl-4-hydroxyanisole.

[0025]

[0026] Preferably, the reaction solvent in step (4) is selected from one or more of acetone, tetrahydrofuran and dichloromethane.

[0027] Preferably, the reaction condition of step (4) is 25° C. for 2 hours.

[0028] Preferably, the catalyst in step (4) is selected from one or more of tetrabutylammonium fluoride, hydrochloric acid, and pyridine.

[0029] Preferably, the molar ratio of tert-butyl (3-(tert-butyl)-4-methoxyphenoxy) dimethylsilane to the catalyst in step (4) is 1:2.

[0030] A specific example of the present invention is as follows:

[0031] A method for preparing 2-tert-butyl-4-hydroxyanisole comprises the following steps:

[0032] (1) Hydroquinone, aminosulfonic acid as a catalyst, tert-butyl alcohol, 1,4-dioxane, and a solvent are placed in a reaction flask, heated in an oil bath to 120-150° C., and reacted for 4-12 hours to generate tert-butylhydroquinone. After the reaction is completed, a sufficient amount of ethanol is added to the reaction flask to dissolve the reaction product, and the reaction product is allowed to stand to precipitate aminosulfonic acid, and then the aminosulfonic acid is removed by filtration. The solvent is removed by distillation under reduced pressure to obtain a crude product, and the crude product is purified to obtain tert-butylhydroquinone.

[0033] In this step, toluene or xylene is used as a solvent, and aminosulfonic acid, hydroquinone and tert-butyl alcohol are reacted in a ratio of 1:5-10:5-10, more preferably 1:5:5. The reaction temperature is preferably 135°C, and the reaction time is preferably 8 hours.

[0034] In a preferred embodiment of the present invention, the purification method may be a method such as recrystallization or washing.

[0035] (2) The product tert-butylhydroquinone obtained in step (1) is dissolved in N,N-dimethylformamide (DMF), and imidazole and tert-butyldimethylsilyl chloride (TBSCl) are added at room temperature under nitrogen protection, and heated and stirred at 60°C for 2 hours. After the reaction is completed, the mixture is cooled to room temperature and the reaction solution is quenched with saturated ammonium chloride. The mixture is extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product is purified by column chromatography to obtain 2-(tert-butyl)-4-((tert-butyldimethylsilyl)oxy)phenol.

[0036] In this step, the base selected is imidazole, pyridine, triethylamine, and the preferred base is imidazole.

[0037] The ratio of tert-butyl hydroquinone to TBSCl is 1:1.5, and the ratio of tert-butyl hydroquinone to imidazole is 1:2.5. The reaction temperature is preferably 60° C., and the reaction time is preferably 2 hours.

[0038] (3) Under nitrogen protection, the product 2-(tert-butyl)-4-((tert-butyldimethylsilyl)oxy)phenol obtained in step (2) and potassium carbonate are added to acetone, iodomethane is added to the stirred suspension via a syringe and the mixture is refluxed for about 12-24 hours to quench the reaction, and the mixture is concentrated under reduced pressure. After alkali washing, the product tert-butyl (3-(tert-butyl)-4-methoxyphenoxy) dimethylsilane is purified by column chromatography.

[0039] In this step, the selected quenching solvents are methanol and water, and the base used for washing is NaOH aqueous solution and saturated sodium carbonate solution, preferably 1M NaOH aqueous solution.

[0040] (4) tert-butyl (3-(tert-butyl)-4-methoxyphenoxy) dimethylsilane, methyl iodide and potassium carbonate are reacted in a ratio of 1:2-5:1, more preferably 1:2.5:1. The reaction time is preferably 24 hours.

[0041] The product of step (3), tert-butyl (3-(tert-butyl)-4-methoxyphenoxy) dimethyl silane, was dissolved in tetrahydrofuran and added to a reaction flask. Tetrabutylammonium fluoride (TBAF) was dissolved in tetrahydrofuran and added to the reaction flask. The mixture was stirred at room temperature for 1 hour. After the reaction, the reaction solution was quenched with saturated ammonium chloride, extracted with ethyl acetate three times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by column chromatography to obtain the product 2-tert-butyl-4-hydroxyanisole.

[0042] In this step, the product and tetrabutylammonium fluoride are reacted in a ratio of 1:1-3, more preferably 1:2.

[0043] In this step, the concentration of tetrabutylammonium fluoride is 1M.

[0044] The preparation method of 2-tert-butyl-4-hydroxyanisole of the present invention has the following advantages:

[0045] In the reaction step (1), aminosulfonic acid is used as a catalyst to synthesize tert-butylhydroquinone. Since aminosulfonic acid is inexpensive and has the characteristics of being non-volatile, odorless and extremely low in toxicity to the human body, the process cost is low and the production process is green and clean.

[0046] In reaction step (2), TBSCl is used to first protect the phenolic hydroxyl group with less steric hindrance, so that the base first removes the hydrogen on the phenolic hydroxyl group at the meta position of the tert-butyl group and then attacks iodomethane to prepare 2-BHA with higher purity.

[0047] The preparation method of the present invention is simple, side reactions are not likely to occur, and the yield and purity are high. Compared with the conventional hydroxyl protecting group Bn, the removal of the protecting group needs to be carried out under hydrogen conditions, which is prone to cause safety accidents such as explosions, while the reaction conditions of the present method are mild, the generation of harmful substances is reduced, and it is relatively green and healthy. DETAILED DESCRIPTION

[0048] The preparation method of 2-tert-butyl-4-hydroxyanisole in the present invention is further described by the following examples, but these examples do not constitute any limitation to the present invention.

[0049] Example 1

[0050] Preparation of tert-butylhydroquinone:

[0051] Weigh hydroquinone (1g, 10mmol), catalyst aminosulfonic acid (4.85g, 50mmol), 20mL solvent, tert-butyl alcohol (3.7g, 50mmol), 5mL 1,4-dioxane in a reaction flask, and heat the reaction in an oil bath. After the reaction is completed, cool to room temperature, add ethanol to dissolve the crude product, let it stand until precipitation occurs, then filter and separate the catalyst aminosulfonic acid, and obtain a crude product after removing the solvent by vacuum distillation. Finally, the crude product is washed with ether or recrystallized to obtain the product tert-butyl hydroquinone. The product yield and purity obtained using different solvents are shown in Table 1.

[0052] 1 H NMR (400MHz, Chloroform-d) δ 8.61 (s, 1H), 8.16 (s, 1H), 6.82 (d, J = 7.5Hz, 1H), 6.75 (s, 1H), 6.49 (d, J = 7.5Hz, 1H), 1.40 (s, 9H).

[0053] 13C NMR (400MHz, Chloroform-d) δ149.68,146.66,137.64,117.37,114.21,111.63,36.84,31.90,31.90,31.90.

[0054] Table 1

[0055] Solvents Temperature / ℃ Time / h Yield purity Toluene 120 4 84％ 82％ Xylene 120 4 83％ 80％ Toluene 135 4 92％ 90％ Toluene 150 4 87％ 90％ Toluene 135 8 92％ 95％ Toluene 135 12 95％ 98％

[0056] Preparation of 2-(tert-butyl)-4-((tert-butyldimethylsilyl)oxy)phenol:

[0057] Weigh tert-butylhydroquinone (1.66g, 10mmol) and dissolve in 50mL N, N-dimethylformamide (DMF), under nitrogen protection, add alkali (25mmol) and tert-butyldimethylsilyl chloride (TBSCl) (2.25g, 15mmol) at room temperature, and heat and stir for 2 hours. After the reaction is completed, the mixture is cooled to room temperature and the reaction solution is quenched with saturated ammonium chloride (100mL). Ethyl acetate is extracted three times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography purifies the product to obtain product 2-(tert-butyl)-4-((tert-butyldimethylsilane) oxygen) phenol. The product yield and purity obtained using different alkalis are shown in Table 2.

[0058] 1 H NMR (400MHz, Chloroform-d) δ7.72(s,1H),6.85(d,J=7.5Hz,1H),6.67(d,J=1.5Hz,1H),6.58(dd,J=7.5,1.5Hz,1H),1.6(s,9H),1.01(s,9H),0.4(s,6H).

[0059] 13 C NMR (400MHz, Chloroform-d) δ149.58,147.60,138.61,118.63,115.32,115.48,36.71,0.2,0.2,31.94,25.83,25.83,25.83,30.69,30.69,30.69.

[0060] Table 2

[0061] Alkali Temperature / ℃ Yield purity Imidazole 60 93％ 90％ Pyridine 60 90％ 90％ Triethylamine 60 84％ 86％ Imidazole 25 80％ 85％ Imidazole 80 87％ 82％

[0062] Preparation of tert-butyl (3-(tert-butyl)-4-methoxyphenoxy) dimethyl silane

[0063] Under nitrogen protection, 2-(tert-butyl)-4-((tert-butyldimethylsilane)oxy)phenol (560mg, 2mmol), alkali (2mmol) were added to 10mL solvent, 310μL iodomethane was added to the stirred suspension by syringe, and the mixture was heated to reflux for 24 hours and then cooled to room temperature, and then quenched with methanol and water. Most of the organic solvent was removed by concentration under reduced pressure, and the residue was washed with water and ethyl acetate into a separatory funnel. After separation, the organic layer was washed with 1M NaOH (aqueous solution) and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure by column chromatography to obtain the product tert-butyl (3-(tert-butyl)-4-methoxyphenoxy) dimethylsilane. The product yields and purities obtained using different solvents and alkalis are shown in Table 3.

[0064] 1 H NMR (400MHz, Chloroform-d) δ6.96 (d, J = 1.5 Hz, 1H), 6.87 (d, J = 7.5 Hz, 1H), 6.77 (d, J = 1.5 Hz, 1H), 3.84 (s, 3H), 1.46 (s, 9H), 1.21 (s, 9H), 0.25 (s, 4H).

[0065] 13 C NMR(400MHz,Chloroform-d)δ149.58,147.60,138.61,118.63,115.32,115. 48,56.74,36.71,0.2,0.2,31.94,25.83,25.83,25.83,30.69,30.69,30.69.

[0066] Table 3

[0067] Solvents Alkali Time / h Yield purity acetone Potassium carbonate 12 95％ 93％ Toluene Potassium carbonate 12 92％ 87％ Acetonitrile Potassium carbonate 12 90％ 90％ acetone Sodium hydroxide 12 95％ 98％ acetone Potassium carbonate 24 97％ 98％

[0068] Preparation of 2-tert-butyl-4-hydroxyanisole:

[0069] Weigh tert-butyl (3-(tert-butyl)-4-methoxyphenoxy) dimethylsilane (0.6 g, 2 mmol) and dissolve it in tetrahydrofuran (5 mL) and add it to the reaction bottle. At the same time, dissolve tetrabutylammonium fluoride (TBAF) in tetrahydrofuran (1 M, 4 ml, 4 mmol) and add it to the reaction bottle. Stir and react at room temperature for 1 hour. After the reaction, quench the reaction liquid with saturated ammonium chloride (50 mL), extract with ethyl acetate three times, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the product by column chromatography to obtain 2-tert-butyl-4-hydroxyanisole (yield 98%, purity 95%).

[0070] 1H NMR (400MHz, Chloroform-d) δ8.45(s,1H),6.68(d,J=1.5Hz,1H),6.57(dd,J=7.4,1.6Hz,1H),6.82(d,J=7.5Hz,1H),3.52(s,3H),1.49(s,9H).

[0071] 13 C NMR (400MHz, Chloroform-d) δ150.68,147.60,142.61,115.47,114.28,113.69,56.74,30.69,30.69,30.69.

[0072] Comparative Example 1

[0073] Take hydroquinone (1g, 10mmol), catalyst aminosulfonic acid (4.85g, 50mmol), 20mL xylene, tert-butyl alcohol (3.7g, 50mmol), 5mL 1,4-dioxane in a reaction bottle, heat to 120℃ in an oil bath and react for 4 hours. After the reaction is completed, cool to room temperature, add ethanol to dissolve the crude product, let it stand until a precipitate is precipitated, then filter and separate the catalyst aminosulfonic acid, and remove the solvent by vacuum distillation to obtain a crude product. Finally, the crude product is washed with ether or recrystallized to obtain the product tert-butylhydroquinone (yield 83%, purity about 80%).

[0074] Weigh tert-butylhydroquinone (1.66 g, 10 mmol) and dissolve it in 50 mL N, N-dimethylformamide (DMF). Add pyridine (1.98 g, 25 mmol) and tert-butyldimethylsilyl chloride (TBSCl) (2.25 g, 15 mmol) at room temperature under nitrogen protection, and heat and stir at 60 ° C for 2 hours. After the reaction is completed, the mixture is cooled to room temperature and quenched with saturated ammonium chloride (100 mL). Extract with ethyl acetate three times, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the product by column chromatography to obtain the product 2-(tert-butyl)-4-((tert-butyldimethylsilane)oxy)phenol (yield 90%, purity about 90%).

[0075] Under nitrogen protection, 2-(tert-butyl)-4-((tert-butyldimethylsilane)oxy)phenol (560mg, 2mmol), anhydrous potassium carbonate (277mg, 2mmol) were added to 10mL toluene, 310μL iodomethane was added to the stirred suspension by syringe, and the mixture was heated to reflux for 12 hours and then cooled to room temperature, and then quenched with methanol and water. Most of the organic solvent was removed by concentration under reduced pressure, and the residue was washed with water and ethyl acetate into a separatory funnel. After separation, the organic layer was washed with 1M NaOH (aqueous solution) and brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the product tert-butyl (3-(tert-butyl)-4-methoxyphenoxy) dimethylsilane (yield 92%, purity 87%).

[0076] The above description is only a preferred embodiment of the present invention, and therefore cannot be used to limit the scope of the present invention. That is, equivalent changes and modifications made according to the patent scope of the present invention and the contents of the specification should still fall within the scope of the present invention.

Claims

1. A method for preparing 2-tert-butyl-4-hydroxyanisole, characterized in that, The steps include: (1) hydroquinone and tert-butyl alcohol react in the presence of a catalyst, aminosulfonic acid, to produce tert-butyl hydroquinone, the reaction solvent is selected from toluene, the reaction conditions are 135° C., the reaction time is 4-12 hours, and the molar ratio of hydroquinone, catalyst and tert-butyl alcohol is 1:5-10:5-10; (2) adding tert-butyldimethylsilyl chloride to tert-butylhydroquinone to generate 2-(tert-butyl)-4-((tert-butyldimethylsilyl)oxy)phenol under base catalysis, wherein the base is selected from imidazole, and the reaction solvent is selected from N,N-dimethylformamide, and reacting at 60° C. for 2 hours; (3) 2-(tert-butyl)-4-((tert-butyldimethylsilyl)oxy)phenol reacts with iodomethane under base catalysis to obtain tert-butyl(3-(tert-butyl)-4-methoxyphenoxy)dimethylsilane, wherein the base is selected from potassium carbonate, the reaction solvent is selected from acetone, and the reaction conditions are reflux for 12-24 hours; (4) tert-butyl (3-(tert-butyl)-4-methoxyphenoxy) dimethylsilane is deprotected in the presence of tetrabutylammonium fluoride as a catalyst to obtain 2-tert-butyl-4-hydroxyanisole. The reaction solvent in step (4) is selected from tetrahydrofuran, and the reaction conditions are 25° C. for 2 hours.

2. The method according to claim 1, characterized in that In step (2), the molar ratio of tert-butylhydroquinone to tert-butyldimethylchlorosilane is 1:1.5, and the molar ratio of tert-butylhydroquinone to imidazole is 1:2.

5.

3. The method according to claim 1, characterized in that: In step (3), the molar ratio of 2-(tert-butyl)-4-((tert-butyldimethylsilyl)oxy)phenol, methyl iodide and base is 1:2-5:

1.

4. The method according to claim 1, characterized in that: In step (4), the molar ratio of tert-butyl (3-(tert-butyl)-4-methoxyphenoxy) dimethylsilane to the catalyst is 1:2.

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