Improved synthesis, separation and purification method of 3, 3 '-dimethoxy-5, 5'-dimethyl-2, 2 '-diphenol

Abstract

The invention discloses an improved method for synthesis, separation and purification of 3, 3 '-dimethoxy-5, 5'-dimethyl-2, 2 '-diphenol. The invention relates to a method for preparing 3, 3 '-dimethoxy-5, 5'-dimethyl-2, 2 '-diphenol by taking 2-methoxy-4-methylphenol as a raw material and improving a synthetic route and a post-treatment method of the 2-methoxy-4-methylphenol on the basis of an existing synthetic method. According to the present invention, the single-pass yield of the 3, 3 '-dimethoxy-5, 5'-dimethyl-2, 2 '-diphenol can achieve about 75% under the optimal condition, the feeding amount is substantially reduced, the post-treatment operation is simple, the product can be obtained only through the simple operations such as distillation, neutralization, filtration, recrystallization and the like, and the high energy consumption tedious operations such as rectification, liquid-liquid extraction, column chromatography and the like are not required;

Description

Technical Field

[0001] The invention relates to the field of organic synthesis, and in particular to a novel synthesis and post-treatment method of 3,3'-dimethoxy-5,5'-dimethyl-2,2'-biphenol. Background Art

[0002] 2,2'-Biphenol derivatives are a very important class of organic chemical products. Biphenol is widely used, mainly in the preparation of various phosphorus-containing catalysts. For example, biphenol is used to prepare a catalyst system for synthesizing adiponitrile through hydrocyanation reaction using butadiene as raw material. Compared with the traditional nickel / phosphine ligand catalyst system, the catalyst system prepared by biphenol has a lower reaction temperature and higher selectivity in this synthesis reaction. At the same time, in recent years, phosphorus-containing catalyst ligands based on biphenol have also been widely used in the hydroformylation reaction of butene. In addition, biphenol can be used as a monomer to synthesize high polymers, and can also be used as plastic antioxidants, rubber antioxidants, etc.

[0003] Most of the 2,2'-biphenol derivatives reported so far are 2,2'-biphenols with alkyl substituents, such as 3,3',5,5'-tetramethyl-2,2'-biphenol, 3,3',5,5'-tetra-tert-butyl-2,2'-biphenol, etc., and their synthesis is mainly prepared by oxidative coupling reaction of phenol derivatives. For example, patents US6077979A, CN101155768A and Organometallics 2015,34,4102-4108 reported the preparation of 3,3',5,5'-tetramethyl-2,2'-biphenol using Na2S2O8 / FeSO4 as an oxidation system, but the oxidation system has a strong oxidation ability. When the applicant used it to oxidize 2-methoxy-4-methylphenol, the oxidation selectivity and yield were very poor. Patents CN106916053A and Chem.Eur.J.2019,25,8279-8288 and other documents report the preparation method of 3,3',5,5'-tetra-tert-butyl-2,2'-biphenol, but the catalytic system is too complicated or the preparation cost of the catalyst is high, so the operability of actual production is too poor. Patent CN1800127A discloses the synthesis of 3,3',6,6'-tetraalkyl-2,2'-biphenol, but it needs to go through halogenation, coupling, and dehalogenation steps. The synthesis route is long, and the dehalogenation step requires the use of precious metal catalysts, so the cost is high. Patent CN101817713A and Patent CN105272826A disclose oxidative coupling routes using tert-butyl hydroperoxide or selenium dioxide as oxidants, but the cost of tert-butyl hydroperoxide and selenium dioxide is significantly higher than that of conventional catalysts. Patent CN1615287A discloses a method for preparing 3,3',5,5'6,6'-hexaalkyl-2,2'-biphenol using a copper complex as an oxidant, but the final yield is generally not high.

[0004] The electron-donating capacity of the methoxy group is better than that of the alkyl chain, so methoxy-substituted phenols are more easily oxidized. Therefore, the method for preparing alkyl-substituted 2,2'-biphenol has poor oxidation selectivity when oxidizing methoxyphenol derivatives, and may further oxidize phenol to quinone derivatives. A milder oxidation system is required to prepare methoxy-substituted 2,2'-biphenol derivatives. There are relatively many reports on the preparation of 3,3'-di-tert-butyl-5,5'-dimethoxy-2,2'-biphenol. For example, J.Org.Chem.2011,76,8376–8385 reported that 3,3'-di-tert-butyl-5,5'-dimethoxy-2,2'-biphenol was prepared with high yield using K3Fe(CN)6 as an oxidant under alkaline conditions. However, K3Fe(CN)6 has a large molecular weight, and even if it is measured according to the stoichiometric ratio, its feed mass is still twice the mass of the raw material monophenol, and the production cost is obviously high. In addition, K3Fe(CN)6 molecules contain cyano groups, and the highly toxic hydrocyanic acid is involved in the post-treatment acidification process, which poses a high safety risk. There are relatively few reports on 3,3'-dimethoxy-substituted 2,2'-biphenol derivatives. 3,3'-dimethoxy-5,5'-dimethyl-2,2'-biphenol, as a 3,3'-dimethoxy-substituted 2,2'-biphenol derivative, is an excellent structure for the preparation of high-performance hydrocyanation and hydroformylation phosphorus ligands, and there are relatively few reports on its preparation. Muhammet Uyanik et al. reported in Chem. Commun., 2021, 57, 11625–11628 a method for synthesizing 3,3'-dimethoxy-5,5'-dimethyl-2,2'-biphenol using 2-methoxy-4-methylphenol as raw material and hydrogen peroxide as oxidant. Although a high conversion rate was achieved, the amount of raw material 2-methoxy-4-methylphenol added in the reaction stage was less than 1g, and the amount of oxidant added was 1.2 times the raw material stoichiometric ratio. In the post-treatment stage, a large amount of saturated NaHSO3 solution was used to quench the reaction, and then liquid-liquid extraction and column chromatography were used to separate and purify the product. Liquid-liquid extraction is cumbersome, requires a large amount of solvent, and consumes a lot of energy for subsequent solvent recovery. Column chromatography is only suitable for laboratory preparation and not for large-scale industrial production.

[0005] Therefore, the present invention is an improvement based on the research of Muhammet Uyanik. First, the feeding amount of the oxidant hydrogen peroxide in the preparation stage is that when hydrogen peroxide oxidatively couples the phenol derivative, theoretically one molecule of H2O2 can remove two H atoms, that is, two molecules of phenol derivatives are oxidatively coupled to one molecule of 2,2'-biphenol derivative. Therefore, the theoretical stoichiometric ratio of H2O2 is half of that of the phenol derivative, and the molar feeding amount of hydrogen peroxide can be compressed to 0.5 to 0.55 times of the molar feeding amount of the phenol derivative, thereby reducing the probability of further oxidation of 2,2'-biphenol. In the post-treatment stage, the feeding amount of the reducing agent is mainly used to quench the unreacted H2O2 and the trace amount of I2 generated in the system. After reducing the feeding amount of hydrogen peroxide, the molar feeding amount of the reducing agent can be compressed to less than 10% of the molar feeding amount of the phenol derivative, and its feeding amount is greatly reduced. In addition, the present invention abandons the original liquid-liquid extraction and column chromatography separation and purification methods, and directly adopts the separation and purification method of distillation and recovery of solvent under alkaline conditions, and further neutralization, solid-liquid extraction, and recrystallization, which not only reduces the amount of solvent used, but also the operation method is suitable for large-scale production.

[0006] The improved method for the synthesis, separation and purification of 3,3'-dimethoxy-5,5'-dimethyl-2,2'-biphenol of the present invention greatly reduces the amount of oxidant and reducing agent in the post-treatment process; the material system is in a powder state in most cases during the whole process, which greatly improves the convenience of the treatment process; in terms of post-treatment operations, only simple operations such as distillation, neutralization, filtration, and recrystallization are required, which greatly avoids the limitations brought by liquid-liquid extraction and column chromatography methods and is suitable for large-scale production. Summary of the invention

[0007] The technical problem to be solved by the present invention is to provide an improved method for the synthesis and separation and purification of 3,3'-dimethoxy-5,5'-dimethyl-2,2'-biphenol. The synthesis method and post-treatment process reduce material costs and are simple and easy to operate.

[0008] An improved method for the synthesis, separation and purification of 3,3'-dimethoxy-5,5'-dimethyl-2,2'-biphenol, the synthesis route of which is shown in the following formula, is characterized in that it comprises the following steps:

[0009]

[0010] (1) 2-methoxy-4-methylphenol, Bu4NI, sodium carbonate, and hydrogen peroxide are reacted in ethyl acetate. After the reaction is completed, a reducing agent is added to the reaction solution to quench the unreacted hydrogen peroxide and iodine intermediates, and then a weak base sodium carbonate is added to ensure that the reaction solution is alkaline, and then the solvent is recovered by reduced pressure distillation to obtain a light yellow solid.

[0011] (2) After adding distilled water to the light yellow solid, neutralize it with hydrochloric acid, stir it at a certain temperature for a period of time, and then filter it to obtain a yellow solid.

[0012] (3) Add a low-polarity solvent to the yellow solid for solid-liquid extraction, and filter to obtain solid 1.

[0013] (4) The solid 1 is recrystallized with a mixed solvent, cooled, filtered, and dried to obtain the target product 3,3'-dimethoxy-5,5'-dimethyl-2,2'-biphenol.

[0014] Wherein, the molar amount of hydrogen peroxide in the hydrogen peroxide in step (1) is 0.5 to 0.55 times the molar amount of 2-methoxy-4-methylphenol.

[0015] Furthermore, in step (1), the reducing agent is one or a mixture of sodium bisulfite, sodium sulfite or sodium thiosulfate.

[0016] Furthermore, in the step (1), the molar ratio of the reducing agent to the raw material 2-methoxy-4-methylphenol is 1:10 to 1:30.

[0017] Furthermore, in the step (1), the molar ratio of the sodium carbonate added after the reducing agent to the reducing agent feed amount is 1.2:1 to 2:1.

[0018] Furthermore, in the step (2), the neutralization reaction temperature is 40-60° C., the neutralization reaction time is 1-3 hours, and the pH is finally controlled at pH<3.

[0019] Furthermore, in step (3), the low polarity solvent is a low boiling point alkane solvent, such as petroleum ether, n-hexane, cyclohexane, etc.

[0020] Furthermore, in step (4), the recrystallization mixed solvent is toluene / petroleum ether or ethanol / water or ethanol / petroleum ether.

[0021] Furthermore, in the step (4), the volume ratio of the good solvent to the poor solvent in the recrystallization mixed solvent is between 4:1 and 1:4.

[0022] Beneficial effects of the present invention:

[0023] The amount of oxidant and reductant used in the present invention is greatly reduced compared with the original route; in the post-treatment process of the present invention, the material system is in a powder state in most cases, which greatly improves the convenience of the treatment process; the post-treatment operation provided by the present invention only requires simple operations such as distillation, neutralization, filtration, and recrystallization, which greatly avoids the limitations brought by liquid-liquid extraction and column chromatography methods and is suitable for large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 The present invention is a schematic flow diagram of a synthesis scheme of 3,3'-dimethoxy-5,5'-dimethyl-2,2'-biphenol.

[0025] Figure 2 It is a yellow solid powder filtered after solid-liquid extraction of petroleum ether and its corresponding 1 H NMR.

[0026] Figure 3 The white solid powder obtained by recrystallization and its corresponding 1 H NMR. DETAILED DESCRIPTION

[0027] The embodiments of the present invention will be described in detail below with reference to examples.

[0028] Embodiment 1:

[0029] The improved method for the synthesis, separation and purification of 3,3'-dimethoxy-5,5'-dimethyl-2,2'-biphenol and the post-treatment process include the following steps:

[0030] (1) 13.82 g of 2-methoxy-4-methylphenol and 100 mL of ethyl acetate were added to a 250 mL single-necked flask and stirred at room temperature. Subsequently, 3.69 g of Bu4NI and 10.60 g of anhydrous sodium carbonate were added. A total of 6.80 g of 27.5% hydrogen peroxide was added dropwise in three batches within 3 h and reacted at room temperature for 3 h.

[0031] (2) After the reaction is completed, sodium bisulfite solution (0.7 g of sodium bisulfite dissolved in 5 mL of water) is added to the reaction solution and stirred for 0.5 h. Subsequently, sodium carbonate solution (1.07 g of sodium carbonate dissolved in 5 mL of water) is added, and the solution is then rotary evaporated to obtain a light yellow solid.

[0032] (3) After adding 300 mL of water to the light yellow solid, hydrochloric acid was added dropwise to neutralize it. The solution was stirred at 45° C. for 1 h. During the process, the pH of the solution was always controlled to be <3. The solution was filtered and the filter cake was dried to obtain 13.75 g of a yellow solid.

[0033] (4) 13.75 g of the yellow solid was added to petroleum ether for solid-liquid extraction, stirred at 45 °C for 2 h, and then filtered to obtain a crude product of 3,3'-dimethoxy-5,5'-dimethyl-2,2'-biphenol.

[0034] (5) The crude product 3,3'-dimethoxy-5,5'-dimethyl-2,2'-biphenol was recrystallized with a mixed solvent of toluene and petroleum ether (58 mL of toluene and 58 mL of petroleum ether were added), and the precipitated solid was cooled and filtered, washed with a mixed solvent of toluene and petroleum ether, and the filter cake was dried to obtain a white solid, namely 3,3'-dimethoxy-5,5'-dimethyl-2,2'-biphenol, with a mass of 8.87 g and a yield of 64.65%.

[0035] Embodiment 2:

[0036] The improved method for the synthesis, separation and purification of 3,3'-dimethoxy-5,5'-dimethyl-2,2'-biphenol and the post-treatment process include the following steps:

[0037] (1) 34.54 g of 2-methoxy-4-methylphenol and 250 mL of ethyl acetate were added to a 500 mL single-necked flask and stirred at room temperature. Subsequently, 9.23 g of Bu4NI and 26.5 g of anhydrous sodium carbonate were added. A total of 15.46 g of 27.5% hydrogen peroxide was added dropwise in three batches within 3 h, and the mixture was reacted at room temperature for 3 h.

[0038] (2) After the reaction is completed, sodium bisulfite solution (1.30 g of sodium bisulfite dissolved in 10 mL of water) is added to the reaction solution and stirred for 0.5 h, followed by addition of sodium carbonate solution (2.12 g of sodium carbonate dissolved in 10 mL of water), and the solution is then rotary evaporated to obtain a light yellow solid.

[0039] (3) After adding 500 mL of water to the light yellow solid, hydrochloric acid was added dropwise to neutralize it. The solution was stirred at 50° C. for 2 h. During the process, the pH of the solution was always controlled to be <3. The solution was filtered and the filter cake was dried to obtain 34.30 g of a yellow solid.

[0040] (4) 34.30 g of the yellow solid was added to n-hexane for solid-liquid extraction, stirred at 45° C. for 2 h, and then filtered to obtain a crude product of 3,3'-dimethoxy-5,5'-dimethyl-2,2'-biphenol.

[0041] (5) The crude product 3,3'-dimethoxy-5,5'-dimethyl-2,2'-biphenol was recrystallized with ethanol-water solution (112 mL ethanol and 56 mL water were added), and the precipitated solid was cooled and filtered, washed with ethanol-water solution, and the filter cake was dried to obtain a white solid, namely 3,3'-dimethoxy-5,5'-dimethyl-2,2'-biphenol, with a mass of 19.62 g and a yield of 57.22%.

[0042] Embodiment 3:

[0043] The improved method for the synthesis, separation and purification of 3,3'-dimethoxy-5,5'-dimethyl-2,2'-biphenol and the post-treatment process include the following steps:

[0044] (1) 27.63 g of 2-methoxy-4-methylphenol and 200 mL of ethyl acetate were added to a 500 mL single-necked flask and stirred at room temperature. Subsequently, 7.39 g of Bu4NI and 21.20 g of anhydrous sodium carbonate were added. A total of 13.60 g of 27.5% hydrogen peroxide was added dropwise in three batches within 3 h, and the mixture was reacted at room temperature for 3 h.

[0045] (2) After the reaction is completed, sodium thiosulfate solution (1.26 g of sodium thiosulfate dissolved in 10 mL of water) is added to the reaction solution and stirred for 0.5 h, followed by addition of sodium carbonate solution (1.53 g of sodium carbonate dissolved in 10 mL of water), and the solution is then rotary evaporated to obtain a light yellow solid.

[0046] (3) After adding 400 mL of water to the light yellow solid, hydrochloric acid was added dropwise to neutralize it. The solution was stirred at 55° C. for 3 h. During the process, the pH of the solution was always controlled to be <3. The solution was filtered and the filter cake was dried to obtain 27.43 g of a yellow solid.

[0047] (4) 27.43 g of the yellow solid was added to cyclohexane for solid-liquid extraction, stirred at 45° C. for 2 h, and then filtered to obtain a crude product of 3,3'-dimethoxy-5,5'-dimethyl-2,2'-biphenol.

[0048] (5) The crude product 3,3'-dimethoxy-5,5'-dimethyl-2,2'-biphenol was recrystallized from a mixed solution of ethanol and petroleum ether (72 mL of ethanol and 36 mL of petroleum ether were added), and the precipitated solid was cooled and filtered, washed with ethanol aqueous solution, and the filter cake was dried to obtain a white solid, namely 3,3'-dimethoxy-5,5'-dimethyl-2,2'-biphenol, with a mass of 20.38 g and a yield of 74.30%.

[0049] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the embodiments of the present invention may have various modifications and variations. Any modification, equivalent replacement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A novel improved method for the synthesis and separation and purification of 3,3'-dimethoxy-5,5'-dimethyl-2,2'-biphenol, characterized in that: The steps include: (1) 2-methoxy-4-methylphenol, Bu4NI, sodium carbonate, and hydrogen peroxide are reacted in ethyl acetate. After the reaction is completed, a reducing agent is added to the reaction solution to quench the unreacted hydrogen peroxide and iodine intermediates, and then a weak base sodium carbonate is added to ensure that the reaction solution is alkaline, and then the solvent is recovered by reduced pressure distillation to obtain a light yellow solid. (2) After adding distilled water to the light yellow solid, neutralize it with hydrochloric acid, stir it at a certain temperature for a period of time, and then filter it to obtain a yellow solid. (3) A low-polarity solvent was added to the yellow solid for extraction, and the solid 1 was obtained by filtration. (4) The solid 1 is recrystallized with a mixed solvent, cooled, filtered, and dried to obtain the target product 3,3'-dimethoxy-5,5'-dimethyl-2,2'-biphenol.

2. The improved method for the synthesis and separation and purification of 3,3'-dimethoxy-5,5'-dimethyl-2,2'-biphenol according to claim 1, characterized in that The molar amount of hydrogen peroxide in the hydrogen peroxide in step (1) is 0.5 to 0.55 times the molar amount of 2-methoxy-4-methylphenol.

3. The improved method for the synthesis and separation and purification of 3,3'-dimethoxy-5,5'-dimethyl-2,2'-biphenol according to claim 1, characterized in that The reducing agent in step (1) is one or a mixture of sodium bisulfite, sodium sulfite or sodium thiosulfate.

4. The improved method for the synthesis and separation and purification of 3,3'-dimethoxy-5,5'-dimethyl-2,2'-biphenol according to claim 1, characterized in that In the step (1), the molar ratio of the reducing agent to the raw material 2-methoxy-4-methylphenol is 1:10 to 1:

30.

5. The improved method for the synthesis and separation and purification of 3,3'-dimethoxy-5,5'-dimethyl-2,2'-biphenol according to claim 1, characterized in that The molar ratio of the sodium carbonate added after the reducing agent in the step (1) to the reducing agent feed amount is 1.2:1 to 2:

1.

6. The improved method for the synthesis and separation and purification of 3,3'-dimethoxy-5,5'-dimethyl-2,2'-biphenol according to claim 1, characterized in that The neutralization reaction temperature in step (2) is 40-60° C., the neutralization reaction time is 1-3 hours, and the pH is finally controlled at pH<3.

7. The improved method for the synthesis and separation and purification of 3,3'-dimethoxy-5,5'-dimethyl-2,2'-biphenol according to claim 1, characterized in that The low polarity solvent in step (3) is a low boiling point alkane solvent, such as petroleum ether, n-hexane, cyclohexane, etc.

8. The improved method for the synthesis and separation and purification of 3,3'-dimethoxy-5,5'-dimethyl-2,2'-biphenol according to claim 1, characterized in that The recrystallization mixed solvent in step (4) is toluene / petroleum ether or ethanol / water or ethanol / petroleum ether.

9. The improved method for synthesizing and separating and purifying 3,3'-dimethoxy-5,5'-dimethyl-2,2'-biphenol according to claim 1, characterized in that The volume ratio of the good solvent to the poor solvent in the recrystallization mixed solvent in step (4) is between 4:1 and 1:4.

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