Process for the preparation of hydroxyl ortho-oligomethylated substituted phenols and polyphenols comprising a plurality of phenolic units

Abstract

Embodiments of the present application provide a method for preparing a hydroxyl ortho-hydroxymethyl-substituted methylene-bridged substituted phenol, the method comprising the following steps: A1, reacting a substituted phenol with formaldehyde in the presence of a Lewis acid catalyst to prepare a substituted salicylaldehyde compound (2); A2, condensing the substituted salicylaldehyde compound (2) in a system containing formaldehyde and a Brønsted acid catalyst to prepare a methylene-bridged substituted salicylaldehyde compound (3); A3, reducing the methylene-bridged substituted salicylaldehyde compound (3) to prepare a hydroxyl ortho-hydroxymethyl-substituted methylene-bridged substituted phenol (4). Embodiments of the present application can improve the yield and chemical purity of the prepared hydroxyl ortho-hydroxymethyl-substituted methylene-bridged substituted phenol. According to other embodiments of the present application, a method for preparing a polyphenol compound containing multiple phenol units is also provided.

Description

Technical Field

[0001] The present application relates to the field of chemical synthesis, and in particular to a method for preparing a methylene-bridged substituted phenol substituted with a hydroxymethyl group at the ortho-hydroxyl group, and a method for preparing a polyphenol compound containing multiple phenol units. Background Art

[0002] Polyphenol compounds containing multiple phenol units can be directly used in fields such as photoresist production and further applied to the manufacture of integrated circuits and computer chips. An existing patent (JP 2005139087A) discloses a method for preparing bis(4-hydroxy-3-(4-hydroxy-3-methylbenzyl)-5-methylphenyl)methane via a Friedel-Crafts alkylation of 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) with o-cresol in the presence of phosphoric acid. The reaction principle is as follows:

[0003] .

[0004] The synthesis of the starting material, 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol), relies on the traditional acid-base catalyzed reaction of phenol with formaldehyde. Japan's Honshu Chemical Industry Co., Ltd. (US2007 / 0232839A1) and my country's Liaoning Jingfan New Materials Co., Ltd. (CN113831224A) have respectively disclosed patented methods for the stepwise preparation of o-cresol and formaldehyde via sequential acid- and base-catalyzed reactions. However, these earlier methods suffer from poor chemical selectivity (producing numerous byproducts), the need to adjust the pH of the reaction system twice, the use of large amounts of acid and base during the preparation process, and the difficulty in controlling reaction conditions to achieve the desired effect. These drawbacks severely impact synthesis efficiency and product quality, making them difficult to meet the high chemical purity requirements required in the photoresist industry. Therefore, it is a technical problem that needs to be solved urgently to find a simple synthetic route to prepare substituted phenols with methylene bridges substituted by hydroxymethyl-substituted ortho-hydroxymethyl and polyphenol compounds containing multiple phenol units, and to improve the yield and chemical purity of substituted phenols with methylene bridges substituted by hydroxymethyl-substituted ortho-hydroxymethyl and polyphenol compounds containing multiple phenol units. Summary of the Invention

[0005] In response to the above problems existing in the prior art, the embodiments of the present application propose a method for preparing a substituted phenol with a methylene bridge substituted by a hydroxyl group ortho-hydroxymethyl and a method for preparing a polyphenol compound containing multiple phenol units, aiming to improve the synthesis process, enhance the selectivity and efficiency of the preparation method, be suitable for industrial-scale preparation, and be able to increase the yield and chemical purity of the substituted phenol with a methylene bridge substituted by a hydroxyl group ortho-hydroxymethyl and polyphenol compounds containing multiple phenol units.

[0006] According to one aspect of the present application, a method for preparing a methylene-bridged substituted phenol substituted with a hydroxymethyl group at the ortho-hydroxy position is provided, and the synthetic route is as follows:

[0007] ;

[0008] Specifically, the method comprises the following steps: A1, a substituted phenol (1) undergoes a highly selective formylation reaction with formaldehyde in the presence of a Lewis acid catalyst, and then a first quencher is added to the system to complete the formylation reaction and prepare a substituted salicylaldehyde compound (2); A2, the substituted salicylaldehyde compound (2) undergoes a condensation reaction in a system containing formaldehyde and a Brønsted acid catalyst, solid is precipitated after cooling, and the condensation reaction is completed to prepare a methylene-bridged substituted salicylaldehyde compound (3); A3, the methylene-bridged substituted salicylaldehyde compound (3) is reduced to prepare a methylene-bridged substituted phenol (4) substituted with a hydroxymethyl group ortho to the hydroxyl group; wherein n represents an integer from 1 to 3, and each R0 independently represents a linear or branched hydrocarbon group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a linear or branched alkoxy group having 1 to 6 carbon atoms, or a halogen atom. It should be understood that the formaldehyde mentioned in this application is formaldehyde solution or paraformaldehyde (HCHO) n The formaldehyde solution can be a formaldehyde solution with a mass fraction of 37%, or a formaldehyde solution with other appropriate mass fractions. Since paraformaldehyde is in a solid state, it is more convenient to weigh in experiments or production.

[0009] In some embodiments, the general formula of substituted phenol (1) can be (n is 1), (n is 2), (n is 2) or (n is 3), wherein each R0 independently represents a linear or branched hydrocarbon group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a linear or branched alkoxy group having 1 to 6 carbon atoms, or a halogen atom. The synthetic route of the methylene-bridged substituted phenol in which the hydroxyl group ortho-hydroxymethyl is substituted is as follows:

[0010] .

[0011] In a preferred embodiment, n in the substituted phenol (1) is 1, R0 is methyl, and the substituted phenol (1) is ; or n in the substituted phenol (1) is 2, R0 is methyl, and the substituted phenol (1) is 、 ; or n in the substituted phenol (1) is 1, R0 is ethyl, and the substituted phenol (1) is ; or n in the substituted phenol (1) is 2, R0 is ethyl, and the substituted phenol (1) is 、 ; or n in the substituted phenol (1) is 2, one R0 is methyl and the other R0 is ethyl, the substituted phenol (1) is 、 、 、 .

[0012] In some embodiments, the general formula of substituted phenol (1) can be (n is 1), (n is 2) or (n is 3), wherein each R0 independently represents a linear or branched hydrocarbon group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a linear or branched alkoxy group having 1 to 6 carbon atoms, or a halogen atom. The synthetic route of the methylene-bridged substituted phenol in which the hydroxyl group ortho-hydroxymethyl is substituted is as follows:

[0013] .

[0014] In a preferred embodiment, n in the substituted phenol (1) is 1, R0 is methyl, and the substituted phenol (1) is ; or n in the substituted phenol (1) is 1, R0 is ethyl, and the substituted phenol (1) is .

[0015] In some embodiments, in step A1, one or more of the following features may be included:

[0016] 1) The molar ratio of the substituted phenol (1) to the Lewis acid catalyst is 1:1~2;

[0017] 2) The Lewis acid catalyst is one or more of ZnCl2, FeCl3, NiCl2, CaCl2, and MgCl2;

[0018] 3) The molar ratio of the substituted phenol (1) to the formylation reagent formaldehyde is 1:2~10;

[0019] 4) The substituted phenol (1) reacts with the formylation reagent formaldehyde at 25-85°C in the presence of a Lewis acid catalyst;

[0020] 5) The substituted phenol (1) reacts with the formylation reagent formaldehyde in the presence of a first solvent, wherein the amount of the first solvent is 1 to 20 times the mass of the substituted phenol (1), and the first solvent is selected from one or more of halogenated hydrocarbons, ethers, nitriles, esters, and aromatic hydrocarbons.

[0021] In some embodiments, in step A2, one or more of the following features may be included:

[0022] 1) The molar ratio of the substituted salicylaldehyde compound (2) to the Brønsted acid catalyst is 1: 0.01-0.5;

[0023] 2) The Brønsted acid catalyst is one or more of hydrochloric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, and a strong acid resin;

[0024] 3) The molar ratio of the substituted salicylaldehyde compound (2) to formaldehyde is 1:0.5-0.8;

[0025] 4) contacting a mixture of the substituted salicylaldehyde compound (2) and formaldehyde in the presence of a Brønsted acid catalyst at a reaction temperature of 25 to 100°C;

[0026] 5) The substituted salicylaldehyde compound (2), formaldehyde and a Brønsted acid catalyst react in the presence of a second solvent, wherein the amount of the second solvent is 1 to 5 times the mass of the substituted salicylaldehyde compound (2), and the second solvent is selected from one or more of halogenated hydrocarbons, aromatic hydrocarbons, carboxylic acids and carboxylic acid esters.

[0027] In some embodiments, in step A3, the reduction reaction is carried out using a reduction method such as metal hydride reduction, catalytic hydrogenation, or transfer hydrogenation.

[0028] In some embodiments, in step A3, the reduction reaction is performed by metal hydride reduction, and the methylene-bridged substituted salicylaldehyde compound (3) undergoes a reduction reaction with the metal hydride reducing agent. After the reaction is completed, a second quenching agent is added to quench the reaction, and then extraction, desolventization, and recrystallization are performed to complete the reduction step to prepare a methylene-bridged substituted phenol (4) substituted with hydroxymethyl at the ortho-hydroxy position.

[0029] In some embodiments, in step A3, one or more of the following features are included:

[0030] 1) Metal hydride reducing agents are NaBH4, KBH4, LiAlH4;

[0031] 2) the molar ratio of the methylene-bridged substituted salicylaldehyde compound (3) to the metal hydride reducing agent is 1:1 to 3;

[0032] 3) The contact reaction temperature of the methylene-bridged substituted salicylaldehyde compound (3) and the metal hydride reducing agent is -10~80℃;

[0033] 4) The solvent used to dissolve the methylene-bridged substituted salicylaldehyde compound (3) is a halogenated hydrocarbon, an alcohol or a mixed solvent of the two.

[0034] In some embodiments, the solvent used to dissolve the methylene-bridged substituted salicylaldehyde compound (3) is dichloromethane, methanol, ethanol, a dichloromethane / methanol mixed solvent with a volume ratio of 1:1, or a dichloromethane / ethanol mixed solvent with a volume ratio of 1:1.

[0035] According to another aspect of the present application, a method for preparing a polyphenol compound containing multiple phenol units is provided. The method uses the above-mentioned methylene-bridged substituted phenol (4) substituted with hydroxymethyl at the ortho-hydroxy position. The synthesis route is as follows:

[0036] ;

[0037] Specifically, the method comprises step A4: a methylene-bridged substituted phenol (4) substituted with a hydroxymethyl group at the ortho-hydroxy position undergoes a Friedel-Crafts alkylation reaction with a substituted phenol (5) in the presence of an acidic catalyst to prepare a polyphenol compound (6) containing multiple phenol units; wherein m represents an integer from 1 to 3, and each R1 independently represents a linear or branched hydrocarbon group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or a linear or branched alkoxy group having 1 to 6 carbon atoms; or m is 1 and R1 is a hydroxyl group.

[0038] In some embodiments, the general formula of substituted phenol (5) can be (m is 1), (m is 2), (m is 2), (m is 3), (m is 3) or (m is 3), wherein each R1 independently represents a linear or branched hydrocarbon group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or a linear or branched alkoxy group having 1 to 6 carbon atoms; or substituted phenol (5) is or The synthetic route of polyphenol compounds containing multiple phenol units is as follows:

[0039] .

[0040] In a preferred embodiment, m in the substituted phenol (5) is 1, R1 is methyl, and the substituted phenol (5) is ; or m in the substituted phenol (5) is 1, R1 is ethyl, and the substituted phenol (5) is ; or m in the substituted phenol (5) is 2, and both R1 are methyl, the substituted phenol (5) is ; or m in substituted phenol (5) is 2, and both R1 are ethyl, substituted phenol (5) is ; or m in the substituted phenol (5) is 2, one R1 is a methyl group and the other R1 is an ethyl group, the substituted phenol (5) is 、 .

[0041] In some embodiments, the general formula of substituted phenol (5) can be (m is 1), (m is 2) or (m is 3), wherein each R1 independently represents a linear or branched hydrocarbon group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or a linear or branched alkoxy group having 1 to 6 carbon atoms. The synthesis route of the polyphenol compound containing multiple phenol units is as follows:

[0042] .

[0043] In some embodiments, in step A4, one or more of the following features are included:

[0044] 1) The molar ratio of the methylene-bridged substituted phenol (4) substituted with hydroxymethyl at the ortho-hydroxyl group to the acidic catalyst is 1: 0.05-0.5;

[0045] 2) The acidic catalyst is one or more of hydrochloric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, and strong acidic resin;

[0046] 3) The molar ratio of the methylene-bridged substituted phenol (4) substituted with a hydroxymethyl group at the ortho-hydroxy position to the substituted phenol (5) is 1:10-25;

[0047] 4) The reaction temperature of the methylene-bridged substituted phenol (4) substituted with hydroxymethyl at the ortho-hydroxy position and the substituted phenol (5) is 25~65℃.

[0048] Compared with the prior art, the above technical solutions conceived in this application have the following advantages and effects:

[0049] Compared with the prior art, the preparation method of the present application first utilizes a Lewis acid-catalyzed formylation strategy to highly selectively introduce a formyl group at the ortho position of the phenolic hydroxyl group to prepare a substituted salicylaldehyde compound (2), then utilizes the positional and enhanced positioning effects of the formyl group to jointly position the hydroxyl group and the formyl group in the substituted salicylaldehyde compound (2) to determine the reaction site of step A2 (the presence of the hydroxyl group on the benzene ring allows the substitution reaction to occur at the ortho and para positions of the hydroxyl group, and the presence of the formyl group on the benzene ring allows the substitution reaction to occur at the meta position of the formyl group), thereby highly selectively preparing a methylene-bridged substituted salicylaldehyde compound (3), and finally directly converting the formyl group into a hydroxymethyl group, thereby avoiding the step of introducing the hydroxymethyl group by the acid-base catalyzed reaction of phenol and formaldehyde with poor chemical selectivity from the source, thereby greatly improving the chemical purity and yield of the methylene-bridged substituted phenol substituted with the hydroxymethyl group at the ortho position of the hydroxyl group. Furthermore, the present application provides a method for preparing a polyphenol compound containing multiple phenol units. The method utilizes the aforementioned hydroxyl-ortho-hydroxymethyl-substituted methylene-bridged substituted phenol (4) and substituted phenol (5) to undergo Friedel-Crafts alkylation under acid catalysis to prepare a high-purity polyphenol compound (6) containing multiple phenol units. The high-quality polyphenol compound (6) is capable of meeting the high chemical purity requirements required in the field of photoresists and other electronic chemical materials. DETAILED DESCRIPTION

[0050] In order to make the purpose, technical solutions and advantages of the present application clearer and more understandable, the scope of the present application will be fully conveyed to those skilled in the art. The exemplary embodiments are fully described in detail below. However, these exemplary embodiments can be implemented in different ways and should not be construed as being limited to the embodiments described in this application. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all of them. Based on the embodiments in this application, all other embodiments obtained by those of ordinary skill in the art fall within the scope of protection of this application. It should be understood that the technical features involved in the various embodiments of the present application described below can be combined with each other as long as they do not conflict with each other. Specific experimental conditions or operating conditions not specified in the embodiments can be made under conventional conditions, or made under the conditions recommended by the material supplier.

[0051] Furthermore, it should be understood that the one or more method steps mentioned herein do not exclude the presence of other method steps before or after the combination step, or the insertion of other method steps between the steps explicitly mentioned, unless otherwise specified. In the following examples, all reagents, materials, and instruments used are commercially available unless otherwise specified.

[0052] The examples of the present application provide a method for preparing a methylene-bridged substituted phenol substituted with a hydroxymethyl group at the ortho-hydroxy position. The synthetic route is as follows:

[0053] ;

[0054] The specific steps include:

[0055] A1. The substituted phenol (1) undergoes a highly selective formylation reaction with formaldehyde in the presence of a Lewis acid catalyst, and then a first quencher is added to the system to complete the formylation reaction to prepare a substituted salicylaldehyde compound (2); A2. The substituted salicylaldehyde compound (2) undergoes a condensation reaction in a system containing formaldehyde and a Brønsted acid catalyst, and a solid is precipitated after cooling to complete the condensation reaction to prepare a methylene-bridged substituted salicylaldehyde compound (3); A3. The methylene-bridged substituted salicylaldehyde compound (3) is reduced to prepare a methylene-bridged substituted phenol (4) substituted with a hydroxymethyl group ortho to the hydroxyl group; wherein n represents an integer from 1 to 3, and each R0 independently represents a linear or branched hydrocarbon group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a linear or branched alkoxy group having 1 to 6 carbon atoms, or a halogen atom. In some embodiments, each R0 can independently represent methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, n-pentoxy, n-hexyl, bromine, chlorine, fluorine, or iodine.

[0056] The embodiment of the present application improves the synthesis process. First, the substituted phenol (1) can react with formaldehyde in the presence of a Lewis acid catalyst to formyl at the ortho position of the hydroxyl group with high selectivity to prepare a substituted salicylaldehyde compound (2). The substituted salicylaldehyde compound (2) prepared in this way can not only obtain high chemical purity, but also has a yield much higher than the classical Reimer-Tiemann reaction and Duff reaction methods of introducing formyl groups. The introduction of the ortho-formyl group not only shields the reaction site at the ortho position of the hydroxyl group by occupying the position, but also has the same reaction effect as the hydroxyl group. The positioning effect is achieved to enhance the positioning, thereby fundamentally improving the chemical selectivity of the reaction of the substituted salicylaldehyde compound (2) with formaldehyde under acid catalysis to prepare the methylene-bridged substituted salicylaldehyde compound (3); directly reducing the formyl group of the methylene-bridged substituted salicylaldehyde compound (3) to a hydroxymethyl group to prepare the hydroxyl-ortho-hydroxymethyl-substituted methylene-bridged substituted phenol (4). The embodiment of the present application avoids the step of introducing hydroxymethyl groups into phenol and formaldehyde under acid-base catalysis with poor chemical selectivity and low yield from the source, thereby conveniently preparing the high-purity hydroxyl-ortho-hydroxymethyl-substituted methylene-bridged substituted phenol (4).

[0057] Wherein, based on the co-positioning of the hydroxyl group and the formyl group in the substituted salicylaldehyde compound (2), the methylene group in the methylene-bridged substituted salicylaldehyde compound (3) is connected to the ortho position or the para position of the hydroxyl group, depending on the number, substitution position and group type of R0 in the substituted phenol (1).

[0058] In some embodiments, the general formula of substituted phenol (1) can be 、 、 or , wherein each R0 independently represents a linear or branched hydrocarbon group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a linear or branched alkoxy group having 1 to 6 carbon atoms, or a halogen atom, and R0 occupies the ortho position of the hydroxyl group. After the formylation reaction is completed in step A1, the formyl group occupies the other ortho position of the hydroxyl group, and the hydroxyl group and the formyl group have a consistent positioning effect. The methylene group in the methylene-bridged substituted salicylaldehyde compound (3) is highly selectively connected to the para position of the hydroxyl group. The synthetic route of the methylene-bridged substituted phenol substituted with a hydroxymethyl group ortho to the hydroxyl group is as follows:

[0059] .

[0060] In a preferred embodiment, the substituted phenol (1) can be 、 、 、 、 、 、 、 、 or .

[0061] In some embodiments, the general formula of substituted phenol (1) can be 、 or , wherein each R0 independently represents a linear or branched hydrocarbon group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a linear or branched alkoxy group having 1 to 6 carbon atoms, or a halogen atom, and R0 occupies the para position to the hydroxyl group. After the formylation reaction is completed in step A1, the formyl group occupies the ortho position to the hydroxyl group, and the hydroxyl group and the formyl group have a consistent positioning effect. The methylene group in the methylene-bridged substituted salicylaldehyde compound (3) is highly selectively connected to the other ortho position of the hydroxyl group. The synthetic route of the methylene-bridged substituted phenol substituted with a hydroxymethyl group ortho to the hydroxyl group is as follows:

[0062] .

[0063] In a preferred embodiment, the substituted phenol (1) can be or .

[0064] Optionally, the substituted phenol (1) reacts with formaldehyde in the presence of a first solvent, which can be selected from one or more of halogenated hydrocarbons, ethers, nitriles, esters, and aromatic hydrocarbons. Specifically, the first solvent can be selected from dichloroethane, tetrahydrofuran, ether, acetonitrile, ethyl acetate, toluene, etc., with dichloroethane and acetonitrile being preferred. Optionally, the amount of the first solvent used is 1 to 20 times the mass of the substituted phenol (1), and can be 1 to 5 times, 3 to 10 times, 10 to 20 times, and preferably 3 to 10 times. The amount of the first solvent used can be determined based on factors such as the solubility of the reactants and the reaction rate.

[0065] Optionally, the molar ratio of the substituted phenol (1) to the formylating agent formaldehyde is 1:2 to 10, wherein the molar ratio of the substituted phenol (1) to the formylating agent formaldehyde can be 1:2, 1:4, 1:6, 1:8, 1:10, preferably 1:4 to 8. If the amount of formaldehyde is too low, the conversion of the substituted phenol (1) is incomplete, affecting the yield; if the amount of formaldehyde is too high, the production cost will increase.

[0066] Optionally, the Lewis acid catalyst may be one or more of ZnCl2, FeCl3, NiCl2, CaCl2, and MgCl2, and the Lewis acid catalyst is preferably CaCl2, MgCl2, or ZnCl2. Optionally, the molar ratio of the substituted phenol (1) to the Lewis acid catalyst is 1:1 to 2, wherein the molar ratio of the substituted phenol (1) to the Lewis acid catalyst may be 1:1, 1:1.2, 1:1.5, 1:1.8, or 1:2, and is preferably 1:1.1 to 1.3. If the amount of the Lewis acid catalyst is too low, the conversion of the substituted phenol (1) is incomplete, affecting the yield. If the amount of the Lewis acid catalyst is too high, the production cost will increase.

[0067] Optionally, the substituted phenol (1) reacts with the formylation agent formaldehyde under the catalysis of a Lewis acid catalyst at 25-85°C, specifically 25-35°C, 35-45°C, 45-55°C, 55-65°C, 65-75°C, or 75-85°C, with the preferred reaction temperature being 75-85°C. When the reaction temperature is too low, the reaction time needs to be extended to wait for the complete reaction of the raw materials, which often results in a low reaction conversion rate. When the reaction temperature is too high, side reactions will increase and the purity of the product will be reduced.

[0068] After the reaction of the substituted phenol (1) and formaldehyde is completed, a first quenching agent is added to quench the reaction and complete the formylation reaction. The first quenching agent can be an acidic aqueous solution such as hydrochloric acid or sulfuric acid. For example, 0.5-2 mol / L hydrochloric acid can be added to quench the reaction, and the pH value can be adjusted to 1-4. Then, ethyl acetate is added for extraction, and the mixture is washed with saturated brine. After drying to remove the solvent, a pure substituted salicylaldehyde compound (2) is obtained.

[0069] Optionally, the substituted salicylaldehyde compound (2) undergoes a condensation reaction in a reaction system containing formaldehyde and a Brønsted acid catalyst, specifically by contacting the substituted salicylaldehyde compound (2) with a mixed solution containing formaldehyde and a Brønsted acid catalyst. Optionally, the substituted salicylaldehyde compound (2), formaldehyde, and the Brønsted acid catalyst react in the presence of a second solvent, which can be selected from one or more of halogenated hydrocarbons, aromatic hydrocarbons, carboxylic acids, and carboxylic acid esters. Specifically, the second solvent can be selected from dichloroethane, toluene, acetic acid, ethyl acetate, etc., with acetic acid being preferred. Optionally, the amount of the second solvent used is 1 to 5 times, preferably 2 to 3 times, the mass of the substituted salicylaldehyde compound (2). The amount of the second solvent used can be determined based on factors such as the solubility of the reactants and the reaction rate.

[0070] Optionally, the molar ratio of the substituted salicylaldehyde compound (2) to formaldehyde is 1:0.5 to 0.8, wherein the molar ratio of the substituted salicylaldehyde compound (2) to formaldehyde can be 1:0.5, 1:0.6, 1:0.7, 1:0.8, and preferably 1:0.5 to 0.55. If the amount of formaldehyde is too low, the conversion of the substituted salicylaldehyde compound (2) is incomplete, affecting the yield. If the amount of formaldehyde is too high, the production cost will increase.

[0071] Optionally, the Brønsted acid catalyst can be one or more of hydrochloric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, and a strong acid resin, and the Brønsted acid catalyst is preferably sulfuric acid or methanesulfonic acid. Optionally, the molar ratio of the substituted salicylaldehyde compound (2) to the Brønsted acid catalyst is 1: 0.01-0.5, wherein the molar ratio of the substituted salicylaldehyde compound (2) to the Brønsted acid catalyst can be 1: 0.05-0.2, 1: 0.2-0.3, 1: 0.3-0.4, 1: 0.4-0.5, preferably 1: 0.2-0.3. If the amount of the Brønsted acid catalyst is too low, the conversion of the substituted salicylaldehyde compound (2) is incomplete, affecting the yield. If the amount of the Brønsted acid catalyst is too high, the production cost will increase.

[0072] Optionally, the reaction temperature of the mixture of the substituted salicylaldehyde compound (2) and formaldehyde in the presence of a Brønsted acid catalyst is 25-100°C, specifically 25-30°C, 30-40°C, 40-50°C, 50-60°C, 60-70°C, 70-80°C, 80-90°C, 90-100°C, with the preferred reaction temperature being 80-90°C. When the reaction temperature is too low, the reaction time needs to be extended to wait for the complete reaction of the raw materials, which often results in a low reaction conversion rate. When the reaction temperature is too high, side reactions may increase, reducing the purity of the product.

[0073] The substituted salicylaldehyde compound (2) can be contacted with a mixture of formaldehyde and a Brønsted acid catalyst to react, and the obtained mixture system is cooled to room temperature to complete product precipitation, and the methylene-bridged substituted salicylaldehyde compound (3) is obtained by filtration.

[0074] In some embodiments, in step A3, the reduction reaction may be performed by a reduction method such as metal hydride reduction, catalytic hydrogenation, or transfer hydrogenation.

[0075] In some embodiments, in step A3, a metal hydride reduction method is preferred, that is, the methylene-bridged substituted salicylaldehyde compound (3) undergoes a reduction reaction with a metal hydride reducing agent, and after the reaction is completed, a second quenching agent is added for quenching, and then extraction, desolventization, and recrystallization are performed to complete the reduction step to prepare a methylene-bridged substituted phenol (4) substituted with hydroxymethyl ortho-hydroxymethyl. The second quenching agent can be an acidic aqueous solution such as hydrochloric acid or sulfuric acid. The first quenching agent and the second quenching agent can be the same or different. For example, hydrochloric acid can be used for quenching, and the molar concentration of hydrochloric acid can be 0.5-2 mol / L, and can be 0.5 mol / L, 1.0 mol / L, 1.5 mol / L, 2 mol / L, preferably 1 mol / L, and the pH value of the mixture system is adjusted to 1-4. The quenched system can be extracted with ethyl acetate, washed with saturated brine, and after removing the solvent, the product is recrystallized with ethanol / ethyl acetate (v / v=1:6) to obtain a methylene-bridged substituted phenol (4) substituted with hydroxymethyl ortho-hydroxymethyl.

[0076] Optionally, the metal hydride reducing agent may be NaBH4, KBH4, or LiAlH4. Optionally, the molar ratio of the methylene-bridged substituted salicylaldehyde compound (3) to the metal hydride reducing agent may be 1:1-3, and the molar ratio of the methylene-bridged substituted salicylaldehyde compound (3) to the metal hydride reducing agent may be 1:1-1.5, 1:1.5-2, 1:2-2.5, or 1:2.5-3, preferably 1:1.5-2. If the amount of the metal hydride reducing agent is too low, the conversion of the methylene-bridged substituted salicylaldehyde compound (3) is incomplete, affecting the yield. If the amount of the metal hydride reducing agent is too high, the production cost will increase.

[0077] Optionally, the contact reaction temperature of the methylene-bridged substituted salicylaldehyde compound (3) and the metal hydride reducing agent is -10~80°C, specifically -10~-5°C, -5~0°C, 0~10°C, 10~25°C, 25~80°C, and preferably -5~25°C. When the reaction temperature is too low, the reaction proceeds slowly and is incomplete; when the reaction temperature is too high, the reaction is too violent, the risk increases, and side reactions increase, thereby reducing the purity of the product.

[0078] Optionally, the solvent used to dissolve the methylene-bridged substituted salicylaldehyde compound (3) is a halogenated hydrocarbon, an alcohol, or a mixture thereof. In some embodiments, the solvent used to dissolve the methylene-bridged substituted salicylaldehyde compound (3) is dichloromethane, methanol, ethanol, a dichloromethane / methanol mixed solvent with a volume ratio of 1:1, or a dichloromethane / ethanol mixed solvent with a volume ratio of 1:1.

[0079] The present invention also provides a method for preparing a polyphenol compound containing multiple phenol units. The method uses the above-mentioned methylene-bridged substituted phenol (4) substituted with hydroxymethyl at the ortho-hydroxy position. The synthesis route is as follows:

[0080] ;

[0081] Specifically, the method comprises step A4: a substituted phenol (4) having a methylene bridge substituted with a hydroxymethyl group ortho-hydroxyl group undergoes a Friedel-Crafts alkylation reaction with a substituted phenol (5) in the presence of an acidic catalyst to prepare a polyphenol compound (6) containing multiple phenol units; wherein m represents an integer from 1 to 3, and each R1 independently represents a linear or branched hydrocarbon group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms; or m is 1 and R1 is a hydroxyl group. In some embodiments, each R1 can independently represent a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, an n-pentyl group, an n-hexyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, an n-pentyl group, or an n-hexyl group.

[0082] In the embodiment of the present application, the above-mentioned high-purity hydroxyl-ortho-hydroxymethyl-substituted methylene-bridged substituted phenol (4) is used as a raw material to react with the substituted phenol (5) under acid catalysis to obtain a high-purity polyphenol compound (6) containing multiple phenol units through a Friedel-Crafts alkylation reaction. The synthesis efficiency of the polyphenol compound (6) containing multiple phenol units is greatly improved. The high-purity polyphenol compound (6) containing multiple phenol units can be used in the preparation of photoresists and other electronic chemical materials.

[0083] In some embodiments, the general formula of substituted phenol (5) can be 、 、 、 、 、 , wherein each R1 independently represents a linear or branched hydrocarbon group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or a linear or branched alkoxy group having 1 to 6 carbon atoms, and R1 occupies the para position to the hydroxyl group. After step A4, the methylene group is connected to the ortho position of the hydroxyl group of the substituted phenol (5) (the ortho position of the hydroxyl group in the substituted phenol (5) is the reaction site), thereby obtaining a polyphenol compound (6) containing multiple phenol units. The synthesis route is as follows:

[0084] .

[0085] In a preferred embodiment, the substituted phenol (5) can be 、 、 、 、 or .

[0086] In some embodiments, the substituted phenol (5) is or The synthetic route of polyphenolic compounds (6) with symmetrical structure and unique substitution position and containing multiple phenol units is as follows:

[0087] .

[0088] In some embodiments, the general formula of substituted phenol (5) can be 、 、 Wherein, each R1 independently represents a linear or branched hydrocarbon group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or a linear or branched alkoxy group having 1 to 6 carbon atoms. The substitution reaction preferentially occurs at the para position of the hydroxyl group of the substituted phenol (5) (the para position of the hydroxyl group in the substituted phenol (5) is the reaction site). The synthesis route of the polyphenol compound (6) containing multiple phenol units is as follows:

[0089] .

[0090] Optionally, the acidic catalyst can be one or more of hydrochloric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, and a strong acidic resin, and the acidic catalyst is preferably sulfuric acid or methanesulfonic acid. Optionally, the molar ratio of the methylene-bridged substituted phenol (4) substituted with hydroxymethyl groups at the ortho-hydroxy position to the acidic catalyst is 1: 0.05-0.5, wherein the molar ratio of the methylene-bridged substituted phenol (4) substituted with hydroxymethyl groups at the ortho-hydroxy position to the acidic catalyst can be 1: 0.05-0.15, 1: 0.15-0.3, 1: 0.3-0.5: 1, preferably 1: 0.1-0.25. If the amount of the acidic catalyst is too low, the conversion of the methylene-bridged substituted phenol (4) substituted with hydroxymethyl groups at the ortho-hydroxy position to the acidic catalyst is incomplete, affecting the yield. If the amount of the acidic catalyst is too high, the production cost will increase.

[0091] Optionally, the molar ratio of the substituted phenol (4) with a hydroxymethyl group substituted at the ortho-hydroxy position to the methylene bridged substituted phenol (5) is 1:10 to 25, wherein the molar ratio of the substituted phenol (4) with a hydroxymethyl group substituted at the ortho-hydroxy position to the methylene bridged substituted phenol (5) can be 1:10, 1:15, 1:20, 1:25, and preferably 1:20. If the amount of the substituted phenol (5) is too low, the conversion of the substituted phenol (4) with a hydroxymethyl group substituted at the ortho-hydroxy position to the methylene bridged substituted phenol (4) will be incomplete, affecting the yield. If the amount of the substituted phenol (5) is too high, the production cost will increase.

[0092] Optionally, the reaction temperature of the methylene-bridged substituted phenol (4) substituted with a hydroxymethyl group ortho-hydroxy and the substituted phenol (5) is 25-65°C, specifically 25-35°C, 35-45°C, 45-55°C, 55-65°C, preferably 45-55°C. When the reaction temperature is too low, the reaction time needs to be extended to wait for the complete reaction of the raw materials, and the reaction conversion rate is often low; when the reaction temperature is too high, side reactions will increase and the purity of the product will be reduced.

[0093] The methylene-bridged substituted phenol (4) substituted with hydroxymethyl at the ortho-hydroxy position is contacted with the substituted phenol (5), and the obtained mixture system can be added with stirring to a poor solvent hexane to precipitate the crude product, washed with water, and then recrystallized from methanol / water (v / v=2:1) ​​to obtain a high-purity polyphenol compound (6) containing multiple phenol units.

[0094] The present application will be described in more detail below through more specific embodiments.

[0095] Example 1

[0096] Preparation of 5,5'-methylenebis(2-hydroxy-3-methylbenzaldehyde):

[0097] .

[0098] In a 2 L four-necked round-bottom flask, o-methylphenol (54.1 g, 0.5 mol), MgCl2 (57.1 g, 0.6 mol, 1.2 equiv), and triethylamine (Et3N) (190.9 g, 1.875 mol, 3.75 equiv) were added, and toluene (500 mL) was added while stirring. The mixture was heated to reflux (80°C), and paraformaldehyde (HCHO) was added. n ) (90.1 g, 3 mol, 6 equiv) and reflux for 3 h. After cooling the reaction to room temperature, a mixture of concentrated hydrochloric acid (200 mL) and ice water (500 mL) was added to adjust the pH to 1–4. The resulting clear solution was transferred to a separatory funnel, diluted 5-fold with water, and extracted with ethyl acetate (200 mL x 3). The combined organic phases were washed with saturated brine, dried, and the solvent removed under reduced pressure to yield 64.7 g of 2-hydroxy-3-methylbenzaldehyde as a yellow, transparent liquid with a yield of 95%. It should be understood that equiv represents equivalents, as is well known in the art.

[0099] 2-Hydroxy-3-methylbenzaldehyde (27.2 g, 0.2 mol), paraformaldehyde (3.1 g, 0.104 mol, 0.52 equiv), acetic acid (AcOH) (50 mL), and 93% sulfuric acid (3.4 mL) were added to a 500 mL four-necked flask. The reaction mixture was heated to 90°C for 1 h. After the reaction, the mixture was cooled to room temperature to precipitate a solid, which was then filtered under reduced pressure. The filtrate was reused as solvent for the next reaction. The filter cake was washed with water and then dried to obtain 22.2 g of 5,5'-methylenebis(2-hydroxy-3-methylbenzaldehyde) as a yellow solid in a 78% yield. The melting point (MP) was 140–141°C. The H NMR spectrum of the product, 5,5'-methylenebis(2-hydroxy-3-methylbenzaldehyde), was as follows: 1 H NMR (400 MHz,CDCl3): δ 11.17 (s,2 H),9.83 (s,2 H),7.21 (s,2H),7.17 (s,2 H),3.88 (s,2 H),2.24 (s,6 H); The data of the carbon NMR spectrum of the product 5,5'-methylenebis(2-hydroxy-3-methylbenzaldehyde) are 13 C NMR (101 MHz,CDCl3):δ 196.6,158.6,138.5,131.6,130.7,127.2,119.8,39.6,15.1. The product 5,5'-methylenebis(2-hydroxy-3-methylbenzaldehyde) was analyzed by high resolution mass spectrometry (HRMS) in electrospray ionization (ESI) mode. The molecular formula of 5,5'-methylenebis(2-hydroxy-3-methylbenzaldehyde) is C17 H 16 O4, 5,5'-methylenebis(2-hydroxy-3-methylbenzaldehyde) ion C after adding a proton 17 H 17 O4[M+H] + The theoretical calculated value of the mass-to-charge ratio is 285.1121, and the actual experimental value is 285.1122. The theoretical calculated value is highly consistent with the measured value: HRMS (ESI):calcd for C 17 H 17 O4 [M+H] + 285.1121, found285.1122. The above data confirmed the successful preparation of the target product 5,5'-methylenebis(2-hydroxy-3-methylbenzaldehyde).

[0100] Preparation of 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) (i.e., a methylene-bridged substituted phenol substituted with a hydroxymethyl group at the ortho-hydroxy position):

[0101] .

[0102] A 250 mL four-necked flask was charged with 5,5'-methylenebis(2-hydroxy-3-methylbenzaldehyde) (14.2 g, 50 mmol), dichloromethane (10 mL), and methanol (10 mL). After stirring to dissolve, NaBH4 (3.8 g, 100 mmol, 2 equiv) was added portionwise in an ice-water bath. The mixture was allowed to react at 0°C for 2 h. The reaction was quenched with 1M HCl and the pH of the reaction mixture was adjusted to 1–4. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine, dried, and the solvent removed under reduced pressure. The crude product was recrystallized from ethanol / ethyl acetate (v / v = 1:6) to obtain 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) as a light yellow solid (12.8 g, 89% yield, >98% purity). The melting point (MP) was 152–153°C. The data of the H NMR spectrum of the product 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) are 1 H NMR (400 MHz, DMSO-d6): δ 8.20 (s, 2 H), 6.89 (s, 2 H), 6.80 (s, 2 H), 5.26 (s, 2 H), 4.52 (s, 4 H), 3.65 (s, 2 H), 2.12 (s, 6 H); The data of the carbon NMR spectrum of the product 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) are 13C NMR (101 MHz, DMSO-d6): δ 150.6, 132.4, 129.2, 127.9, 125.2, 124.0, 59.9, 40.2, 16.31. The product 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) was analyzed by high resolution mass spectrometry (HRMS) in electrospray ionization (ESI) mode. C 17 H 24 NO4[M+NH4] + The theoretical calculated value is 306.1700, and the measured value is 306.1693, which is in good agreement with the measured value: HRMS (ESI):calcd for C 17 H 24 NO4[M+NH4] + 306.1700, found 306.1693. The above data confirmed that the target product 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) was successfully prepared.

[0103] Preparation of 4,4'-methylenebis(2-(2-hydroxy-5-methylbenzyl)-6-methylphenol) (i.e., a polyphenolic compound containing multiple phenol units):

[0104] .

[0105] To a 250 mL four-necked round-bottom flask, add p-cresol (21.6 g, 200 mmol, 20 equiv) and p-toluenesulfonic acid (0.2 g, 1.1 mmol, 0.11 equiv). Heat to 50°C in a water bath. Add 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) (2.9 g, 10 mmol, 1 equiv) in portions with stirring. Continue the reaction for 2 h. After the reaction is complete, add 100 mL of petroleum ether (60-90°C) while maintaining stirring at 50°C to precipitate a solid. Filter the solid, and evaporate the filtrate to remove the solvent and recover 12.9 g of p-cresol. The filter cake was washed with water (100 mL) to remove p-toluenesulfonic acid (TsOH) and residual p-cresol. The product was then purified by recrystallization from methanol / water (v / v = 2:1) to obtain 3.5 g of the light pink powder, 4,4'-methylenebis(2-(2-hydroxy-5-methylbenzyl)-6-methylphenol). The yield was 75% and the purity was 96%. The melting point (MP) was 185-186°C. The H NMR spectrum of the product, 4,4'-methylenebis(2-(2-hydroxy-5-methylbenzyl)-6-methylphenol, was: 1H NMR (400 MHz, DMSO-d6): δ 9.38 (s, 2 H), 8.09 (s, 2 H), 6.79 (d, J=8.0 Hz, 2 H), 6.76-6.68 (m, 6 H), 6.65 (s, 2 H), 3.74 (s, 4 H), 3.53 (s, 2 H), 2.10 (s, 6 H), 2.09 (s, 6 H); The data of the carbon NMR spectrum of the product 4,4'-methylenebis(2-(2-hydroxy-5-methylbenzyl)-6-methylphenol) are as follows: 13 C NMR (101 MHz, DMSO-d6): δ152.1, 150.7, 132.4, 130.6, 128.6, 128.2, 127.4, 127.3, 127.2, 126.9, 124.2, 114.7, 39.9, 29.7, 20.3, 16.8. The product 4,4'-methylenebis(2-(2-hydroxy-5-methylbenzyl)-6-methylphenol) was analyzed by high resolution mass spectrometry (HRMS) in electrospray ionization (ESI) mode. C 31 H 36 NO4 [M+NH4] + The theoretical calculated value is 486.2639, and the measured value is 486.2630. The theoretical calculated value is highly consistent with the measured value: HRMS (ESI):calcd forC 31 H 36 NO4 [M+NH4] + 486.2639, found 486.2630. The above data confirmed the successful preparation of the target product 4,4'-methylenebis(2-(2-hydroxy-5-methylbenzyl)-6-methylphenol).

[0106] Example 2

[0107] Preparation of 3,3'-methylenebis(2-hydroxy-5-methylbenzaldehyde):

[0108] .

[0109] A 2 L four-necked round-bottom flask was charged with p-methylphenol (54.1 g, 0.5 mol), MgCl₂ (57.1 g, 0.6 mol, 1.2 equiv), and triethylamine (190.9 g, 1.875 mol, 3.75 equiv). Acetonitrile (MeCN) (500 mL) was added with stirring, and the mixture was heated to reflux (80°C). Paraformaldehyde (90.1 g, 3 mol, 6 equiv) was then added, and the reaction was continued at reflux for 3 h. After cooling to room temperature, a mixture of concentrated hydrochloric acid (200 mL) and ice water (500 mL) was added to adjust the pH of the reaction mixture to 1–4. The resulting clear solution was transferred to a separatory funnel, diluted with 5 volumes of water, and extracted with ethyl acetate (200 mL x 3). The combined organic phases were washed with saturated brine, dried, and the solvent removed under reduced pressure to yield 64.7 g of 2-hydroxy-5-methylbenzaldehyde as a yellow, transparent liquid in a 95% yield.

[0110] 2-Hydroxy-5-methylbenzaldehyde (27.2 g, 0.2 mol), paraformaldehyde (3.1 g, 0.104 mol, 0.52 equiv), acetic acid (50 mL), and 93% sulfuric acid (3.4 mL) were added to a 500 mL four-necked flask. The reaction mixture was heated to 90°C for 1 h. After the reaction, the mixture was cooled to room temperature to precipitate a solid, which was then filtered under reduced pressure. The filtrate was reused as solvent for the next reaction. The filter cake was washed with water and dried to yield 3,3'-methylenebis(2-hydroxy-5-methylbenzaldehyde) as a yellow solid (21.9 g, 77% yield). The melting point (MP) was 231–232°C. The H NMR spectrum of the product, 3,3'-methylenebis(2-hydroxy-5-methylbenzaldehyde), was as follows: 1 H NMR (400 MHz,CDCl3):δ 11.16 (s,2 H),9.83 (s,2 H),7.29 (d,J=2.0Hz,2 H),7.21 (d,J=2.0 Hz,2H),3.99 (s,2 H),2.29 (s,6 H); The data of the carbon NMR spectrum of the product 3,3'-methylenebis(2-hydroxy-5-methylbenzaldehyde) are 13 C NMR (101 MHz,CDCl3):δ 196.6,157.6,139.1,131.7,128.8,128.3,120.1,27.9,20.3. The product 3,3'-methylenebis(2-hydroxy-5-methylbenzaldehyde) was analyzed by high resolution mass spectrometry (HRMS) in electrospray ionization (ESI) mode. C 17 H 17 O4 [M+H] +The theoretical calculated value is 285.1121, and the measured value is 285.1122. The theoretical calculated value is highly consistent with the measured value: HRMS (ESI):calcdfor C 17 H 17 O4 [M+H] + 285.1121, found 285.1122. The above data confirmed that the target product 3,3'-methylenebis(2-hydroxy-5-methylbenzaldehyde) was successfully prepared.

[0111] Preparation of 6,6'-methylenebis(2-hydroxymethyl-4-methylphenol) (i.e., a methylene-bridged substituted phenol substituted with a hydroxymethyl group at the ortho-hydroxy position):

[0112] .

[0113] A 250 mL four-necked flask was charged with 3,3'-methylenebis(2-hydroxy-5-methylbenzaldehyde) (14.2 g, 50 mmol), dichloromethane (10 mL), and methanol (10 mL). After stirring to dissolve, NaBH4 (3.8 g, 100 mmol, 2 equiv) was added portionwise under ice-water cooling. The reaction was continued at 0°C for 2 h. The reaction was then quenched with 1M HCl, and the pH of the reaction mixture was adjusted to 1–4. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine, dried, and the solvent removed under reduced pressure. The crude product was recrystallized from ethanol / ethyl acetate (v / v = 1:6) to obtain 6,6'-methylenebis(2-hydroxymethyl-4-methylphenol) as a white solid (13.3 g, 92% yield, >98% purity). The melting point (MP) was 125–126°C. The data of the H NMR spectrum of the product 6,6'-methylenebis(2-hydroxymethyl-4-methylphenol) are as follows: 1 H NMR (400MHz,DMSO-d6):δ 9.02 (s,2 H),7.07 (s,2 H),6.90 (s,2 H),6.73 (s,2 H),4.56 (s,4H),3.80 (s,2 H),2.14 (s,6 H); The data of the carbon NMR spectrum of the product 6,6'-methylenebis(2-hydroxymethyl-4-methylphenol) are 13 C NMR (101 MHz, DMSO-d6): δ 149.7, 129.1, 128.1, 127.6, 127.5, 125.9, 59.9, 29.4, 20.5. The product 6,6'-methylenebis(2-hydroxymethyl-4-methylphenol) was analyzed by high resolution mass spectrometry (HRMS) in electrospray ionization (ESI) mode. C 17 H20 NaO4 [M+Na] + The theoretical calculated value is 311.1254, and the measured value is 311.1250. The theoretical calculated value is highly consistent with the measured value: HRMS (ESI):calcd for C 17 H 20 NaO4 [M+Na] + 311.1254, found 311.1250. The above data confirmed the successful preparation of the target product 6,6'-methylenebis(2-hydroxymethyl-4-methylphenol).

[0114] Preparation of 6,6'-methylenebis(2-(2-hydroxy-5-methylbenzyl)-4-methylphenol) (i.e., a polyphenolic compound containing multiple phenol units):

[0115] .

[0116] To a 250 mL four-necked round-bottom flask, add p-cresol (21.6 g, 200 mmol, 20 equiv) and p-toluenesulfonic acid (0.2 g, 1.1 mmol, 0.11 equiv). Heat to 50°C in a water bath. Add 6,6'-methylenebis(2-hydroxymethyl-4-methylphenol) (2.9 g, 10 mmol, 1 equiv) in portions with stirring. Continue the reaction for 2 h. After the reaction is complete, add n-hexane (100 mL) while maintaining stirring at 50°C to precipitate a solid. Filter the solid, and evaporate the filtrate to remove the n-hexane to recover 12.9 g of p-cresol. The filter cake was washed with water (100 mL) to remove p-toluenesulfonic acid and residual p-cresol. The product was then recrystallized from methanol / water (v / v = 2:1) to obtain 3.3 g of 6,6'-methylenebis(2-(2-hydroxy-5-methylbenzyl)-4-methylphenol) as a yellow powder with a yield of 71% and a purity of 96%. The melting point (MP) was 174–175°C. The H NMR spectrum of the product 6,6'-methylenebis(2-(2-hydroxy-5-methylbenzyl)-4-methylphenol was as follows: 1 H NMR (400 MHz, DMSO-d6): δ 9.42 (s, 2 H), 8.37 (s, 2 H), 6.83-6.81 (m, 4 H), 6.74-6.72 (m, 2 H), 6.66 (s, 4 H), 3.85 (s, 2 H), 3.80 (s, 4 H), 2.14 (s, 6 H), 2.08 (s, 6 H); The data of the carbon NMR spectrum of the product 6,6'-methylenebis(2-(2-hydroxy-5-methylbenzyl)-4-methylphenol) are as follows: 13C NMR (101 MHz, DMSO-d6): δ 152.2, 149.8, 130.8, 128.4, 127.8, 127.7, 127.5, 127.3, 126.8, 114.8, 30.3, 29.8, 20.4, 20.3. The product 6,6'-methylenebis(2-(2-hydroxy-5-methylbenzyl)-4-methylphenol) was analyzed by high resolution mass spectrometry (HRMS) in electrospray ionization (ESI) mode. C 31 H 36 NO4 [M+NH4] + The theoretical calculated value is 486.2639, and the measured value is 486.2632. The theoretical calculated value is highly consistent with the measured value: HRMS (ESI):calcd for C 31 H 36 NO4 [M+NH4] + The above data confirmed the successful preparation of the target product 6,6'-methylenebis(2-(2-hydroxy-5-methylbenzyl)-4-methylphenol).

[0117] Example 3

[0118] Preparation of 5,5'-methylenebis(2-hydroxy-3,4-dimethylbenzaldehyde):

[0119] .

[0120] To a 2 L four-necked round-bottom flask, add 2,3-dimethylphenol (61.1 g, 0.5 mol), MgCl2 (57.1 g, 0.6 mol, 1.2 equiv), and triethylamine (190.9 g, 1.875 mol, 3.75 equiv). Acetonitrile (500 mL) was added with stirring and the mixture was heated to reflux (80°C). Paraformaldehyde (90.1 g, 3 mol, 6 equiv) was then added and the reaction was continued at reflux for 3 h. After cooling the reaction mixture to room temperature, a mixture of concentrated hydrochloric acid (200 mL) and ice water (500 mL) was added to adjust the pH of the reaction mixture to 1–4. The resulting mixture was transferred to a separatory funnel, diluted with 5 times the volume of water, and extracted with ethyl acetate (200 mL × 3). The combined organic phases were washed with saturated brine, dried, and the solvent was removed under reduced pressure to obtain 2-hydroxy-3,4-dimethylbenzaldehyde as a yellow transparent liquid (71.4 g) with a yield of 95%.

[0121] 2-Hydroxy-3,4-dimethylbenzaldehyde (30.0 g, 0.2 mol), paraformaldehyde (3.1 g, 0.104 mol, 0.52 equiv), acetic acid (50 mL), and 93% sulfuric acid (3.4 mL) were added to a 500 mL four-necked flask. The reaction mixture was heated to 90°C for 1 h. After the reaction, the mixture was cooled to room temperature to precipitate a solid, which was then filtered under reduced pressure. The filtrate was reused as solvent for the next reaction. The filter cake was washed with water and dried to yield 5,5'-methylenebis(2-hydroxy-3,4-dimethylbenzaldehyde) as a yellow solid (26.6 g, 85% yield). The melting point (MP) was 230–231°C. The H NMR spectrum of the product, 5,5'-methylenebis(2-hydroxy-3,4-dimethylbenzaldehyde), was as follows: 1 H NMR (400 MHz,CDCl3):δ 11.32 (s,2 H),9.69 (s,2 H),6.87(s,2 H),3.91 (s,2 H),2.25 (s,6 H),2.24 (s,6 H); The data of the carbon NMR spectrum of the product 5,5'-methylenebis(2-hydroxy-3,4-dimethylbenzaldehyde) are 13 C NMR (101 MHz,CDCl3):δ 196.2,158.5,145.8,130.8,129.5,125.6,118.1,36.6,16.6,11.3. The product 5,5'-methylenebis(2-hydroxy-3,4-dimethylbenzaldehyde) was analyzed by high resolution mass spectrometry (HRMS) in electrospray ionization (ESI) mode. C 19 H 21 O4 [M+H] + The theoretical calculated value is 313.1434, and the measured value is 313.1431. The theoretical calculated value is highly consistent with the measured value: HRMS (ESI): calcd for C 19 H 21 O4 [M+H] + 313.1434, found 313.1431. The above data confirmed the successful preparation of the target product 5,5'-methylenebis(2-hydroxy-3,4-dimethylbenzaldehyde).

[0122] Preparation of 4,4'-methylenebis(6-hydroxymethyl-2,3-dimethylphenol) (i.e., a methylene-bridged substituted phenol substituted with a hydroxymethyl group at the ortho-hydroxy position):

[0123] .

[0124] A 250 mL four-necked flask was charged with 5,5'-methylenebis(2-hydroxy-3,4-dimethylbenzaldehyde) (15.6 g, 50 mmol), dichloromethane (10 mL), and methanol (10 mL). After stirring to dissolve, NaBH4 (3.8 g, 100 mmol, 2 equiv) was added portionwise under ice-water cooling. The reaction was continued at 0°C for 2 h. The reaction was then quenched with 1M HCl and the pH of the reaction mixture was adjusted to 1–4. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine, dried, and the solvent removed under reduced pressure. The crude product was recrystallized from ethanol / ethyl acetate (v / v = 1:6) to obtain 4,4'-methylenebis(6-hydroxymethyl-2,3-dimethylphenol) as a white solid (15.0 g, 95% yield, >98% purity). The melting point (MP) was 168–169°C. The data of the H NMR spectrum of the product 4,4'-methylenebis(6-hydroxymethyl-2,3-dimethylphenol) are 1 H NMR (400 MHz, DMSO-d6): δ 8.18 (s, 2 H), 6.54 (s, 2 H), 5.29 (s, 2 H), 4.47 (s, 4H), 3.73 (s, 2 H), 2.11 (s, 6 H), 2.07 (s, 6 H); The data of the carbon NMR spectrum of the product 4,4'-methylenebis(6-hydroxymethyl-2,3-dimethylphenol) are 13 C NMR (101 MHz, DMSO-d6): δ 150.7, 129.4, 125.3, 124.5, 123.1, 60.5, 36.6, 15.4, 12.4, 12.3. The product 4,4'-methylenebis(6-hydroxymethyl-2,3-dimethylphenol) was analyzed by high resolution mass spectrometry (HRMS) in electrospray ionization (ESI) mode. C 19 H 28 NO4[M+NH4] + The theoretical calculated value is 334.2013, and the measured value is 334.2010. The theoretical calculated value and the measured value are highly consistent: HRMS (ESI):calcd for C 19 H 28 NO4 [M+NH4] + 334.2013, found 334.2010. The above data confirmed the successful preparation of the target product 4,4'-methylenebis(6-hydroxymethyl-2,3-dimethylphenol).

[0125] Preparation of 4,4'-methylenebis(6-(2-hydroxy-5-methylbenzyl)-2,3-dimethylphenol) (i.e., a polyphenolic compound containing multiple phenol units):

[0126] .

[0127] To a 250 mL four-necked round-bottom flask, add p-cresol (21.6 g, 200 mmol, 20 equiv) and p-toluenesulfonic acid (0.2 g, 1.1 mmol, 0.11 equiv). Heat the mixture to 50°C in a water bath. Add 4,4'-methylenebis(6-hydroxymethyl-2,3-dimethylphenol) (3.2 g, 10 mmol, 1 equiv) in portions with stirring. Continue the reaction for 2 h. After the reaction is complete, add n-hexane (100 mL) while maintaining stirring at 50°C to precipitate a solid. Filter the solid, and evaporate the filtrate to remove the n-hexane to recover 12.9 g of p-cresol. The filter cake was washed with water (100 mL) to remove p-toluenesulfonic acid and residual p-cresol. The product was then recrystallized from methanol / water (v / v = 2:1) to obtain 3.6 g of 4,4'-methylenebis(6-(2-hydroxy-5-methylbenzyl)-2,3-dimethylphenol) as a white solid with a yield of 73% and a purity of 97%. The melting point (MP) was 192–193°C. The H NMR spectrum of the product 4,4'-methylenebis(6-(2-hydroxy-5-methylbenzyl)-2,3-dimethylphenol) was as follows: 1 H NMR (400 MHz, DMSO-d6): δ 9.39 (s, 2H), 7.94 (s, 2 H), 6.76 (dd, J = 8.0, 2.4 Hz, 2H), 6.67 (s, 1 H), 6.65 (s, 1 H), 6.61 (s, 2H), 6.38 (s, 2 H), 3.65 (s, 4 H), 3.64 (s, 2 H), 2.10 (s, 6 H), 2.07 (s, 6 H), 1.98 (s, 6H); The data of the carbon NMR spectrum of the product 4,4'-methylenebis(6-(2-hydroxy-5-methylbenzyl)-2,3-dimethylphenol) are as follows: 13 C NMR (101 MHz, DMSO-d6): δ151.8, 150.4, 133.1, 130.2, 129.7, 129.5, 128.2, 127.3, 127.0, 124.2, 123.2, 114.6, 36.8, 29.7, 20.2, 15.4, 12.8. The product 4,4'-methylenebis(6-(2-hydroxy-5-methylbenzyl)-2,3-dimethylphenol) was analyzed by high resolution mass spectrometry (HRMS) in electrospray ionization (ESI) mode. C 33 H 40 NO4 [M+NH4] +The theoretical calculated value is 514.2952, and the measured value is 514.2951. The theoretical calculated value is highly consistent with the measured value: HRMS (ESI):calcd for C 33 H 40 NO4 [M+NH4] + 514.2952, found 514.2951. The above data confirmed the successful preparation of the target product 4,4'-methylenebis(6-(2-hydroxy-5-methylbenzyl)-2,3-dimethylphenol).

[0128] Example 4

[0129] Preparation of 5,5'-methylenebis(2-hydroxy-3,6-dimethylbenzaldehyde):

[0130] .

[0131] To a 2 L four-necked round-bottom flask, add 2,5-dimethylphenol (61.1 g, 0.5 mol), MgCl2 (57.1 g, 0.6 mol, 1.2 equiv), and triethylamine (190.9 g, 1.875 mol, 3.75 equiv). Acetonitrile (500 mL) was added with stirring and the mixture was heated to reflux (80°C). Paraformaldehyde (90.1 g, 3 mol, 6 equiv) was then added and the reaction was continued at reflux for 3 h. The reaction mixture was then cooled to room temperature and a mixture of concentrated hydrochloric acid (200 mL) and ice water (500 mL) was added to adjust the pH of the reaction mixture to 1–4. The resulting mixture was transferred to a separatory funnel, diluted with 5 volumes of water, and extracted with ethyl acetate (200 mL × 3). The combined organic phases were washed with saturated brine, dried, and the solvent was removed under reduced pressure to obtain 71.4 g of 2-hydroxy-3,6-dimethylbenzaldehyde as a yellow transparent liquid with a yield of 95%.

[0132] 2-Hydroxy-3,6-dimethylbenzaldehyde (30.0 g, 0.2 mol), paraformaldehyde (3.1 g, 0.104 mol, 0.52 equiv), acetic acid (50 mL), and 93% sulfuric acid (3.4 mL) were added to a 500 mL four-necked flask. The reaction mixture was heated to 90°C for 1 h. After the reaction, the mixture was cooled to room temperature to precipitate a solid, which was filtered under reduced pressure. The filtrate was reused as solvent for the next reaction. The filter cake was washed with water and dried to yield 5,5'-methylenebis(2-hydroxy-3,6-dimethylbenzaldehyde) as a yellow solid (21.2 g, 68% yield). The melting point (MP) was 198–199°C. The H NMR spectrum of the product, 5,5'-methylenebis(2-hydroxy-3,6-dimethylbenzaldehyde), was as follows: 1H NMR (400 MHz,CDCl3):δ 12.30 (s,2 H),10.42 (s,2H),6.91 (s,2 H),3.81 (s,2 H),2.47 (s,6 H),2.16 (s,6 H); The data of the carbon NMR spectrum of the product 5,5'-methylenebis(2-hydroxy-3,6-dimethylbenzaldehyde) are 13 C NMR (101 MHz,CDCl3):δ 195.9,160.4,139.4,137.1,128.5,124.6,118.1,35.1,15.0,13.3. The product 5,5'-methylenebis(2-hydroxy-3,6-dimethylbenzaldehyde) was analyzed by high resolution mass spectrometry (HRMS) in electrospray ionization (ESI) mode. C 19 H 21 O4 [M+H] + The theoretical calculated value is 313.1434, and the measured value is 313.1434, which is in good agreement with the measured value: HRMS (ESI):calcd for C 19 H 21 O4 [M+H] + 313.1434, found 313.1434. The above data confirmed the successful preparation of the target product 5,5'-methylenebis(2-hydroxy-3,6-dimethylbenzaldehyde).

[0133] Preparation of 4,4'-methylenebis(2-hydroxymethyl-3,6-dimethylphenol) (i.e., a methylene-bridged substituted phenol substituted with a hydroxymethyl group at the ortho-hydroxy position):

[0134] .

[0135] A 250 mL four-necked flask was charged with 5,5'-methylenebis(2-hydroxy-3,6-dimethylbenzaldehyde) (15.6 g, 50 mmol), dichloromethane (10 mL), and methanol (10 mL). After stirring to dissolve, NaBH4 (3.8 g, 100 mmol, 2 equiv) was added portionwise under ice-water cooling. The reaction was continued at 0°C for 2 h. The reaction was then quenched with 1M HCl and the pH of the reaction mixture was adjusted to 1–4. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine, dried, and the solvent removed under reduced pressure. The crude product was recrystallized from ethanol / ethyl acetate (v / v = 1:6) to obtain 4,4'-methylenebis(2-hydroxymethyl-3,6-dimethylphenol) as a yellow solid (13.1 g, 83% yield, >98% purity). The melting point (MP) was 156–157°C. The data of the H NMR spectrum of the product 4,4'-methylenebis(2-hydroxymethyl-3,6-dimethylphenol) are 1 H NMR (400 MHz, DMSO-d6): δ 8.58 (s, 2 H), 6.48 (s, 2 H), 5.24 (t, J = 5.0 Hz, 2 H), 4.67 (d, J = 5.0 Hz, 4 H), 3.66 (s, 2 H), 2.08 (s, 6 H), 2.02 (s, 6 H); The data of the carbon NMR spectrum of the product 4,4'-methylenebis (2-hydroxymethyl-3,6-dimethylphenol) are as follows: 13 C NMR (101 MHz, DMSO-d6): δ152.0, 132.7, 130.0, 129.4, 125.2, 121.4, 57.3, 40.1, 16.4, 14.5. The product 4,4'-methylenebis(2-hydroxymethyl-3,6-dimethylphenol) was analyzed by high resolution mass spectrometry (HRMS) in electrospray ionization (ESI) mode. C 19 H 28 NO4[M+NH4] + The theoretical calculated value is 334.2013, and the measured value is 334.2008. The theoretical calculated value is highly consistent with the measured value: HRMS (ESI):calcd for C 19 H 28 NO4[M+NH4] + 334.2013, found 334.2008. The above data confirmed that the target product 4,4'-methylenebis(2-hydroxymethyl-3,6-dimethylphenol) was successfully prepared.

[0136] Preparation of 4,4'-methylenebis(2-(2-hydroxy-5-methylbenzyl)-3,6-dimethylphenol) (i.e., a polyphenolic compound containing multiple phenol units):

[0137] .

[0138] To a 250 mL four-necked round-bottom flask, add p-cresol (21.6 g, 200 mmol, 20 equiv) and p-toluenesulfonic acid (0.2 g, 1.1 mmol, 0.11 equiv). Heat to 50°C in a water bath. Add 4,4'-methylenebis(2-hydroxymethyl-3,6-dimethylphenol) (3.2 g, 10 mmol, 1 equiv) in portions with stirring. Continue the reaction for 2 h. After the reaction is complete, add n-hexane (100 mL) while maintaining stirring at 50°C to precipitate a solid. Filter the solid, and evaporate the filtrate to remove the n-hexane to recover 12.9 g of p-cresol. The filter cake was washed with water (100 mL) to remove p-toluenesulfonic acid and residual p-cresol, and then recrystallized from methanol / water (v / v = 2:1) to obtain 3.5 g of the product 4,4'-methylenebis(2-(2-hydroxy-5-methylbenzyl)-3,6-dimethylphenol) as a white solid with a yield of 70% and a purity of 95%. The Mp (melting point) was 200°C (decomposition). The H NMR spectrum of the product 4,4'-methylenebis(2-(2-hydroxy-5-methylbenzyl)-3,6-dimethylphenol) was: 1 H NMR (400 MHz, DMSO-d6): δ 9.21 (s, 2 H), 7.93 (s, 2 H), 6.75-6.73 (m, 2 H), 6.69-6.67 (m, 2 H), 6.48 (s, 2 H), 6.34 (s, 2 H), 3.88 (s, 4 H), 3.68 (s, 2 H), 2.09 (s, 6 H), 2.02 (s, 6 H), 1.92 (s, 6 H); The data of the carbon NMR spectrum of the product 4,4'-methylenebis(2-(2-hydroxy-5-methylbenzyl)-3,6-dimethylphenol) are as follows: 13 C NMR (101 MHz, DMSO-d6): δ 152.5, 151.3, 133.4, 129.9, 129.0, 128.4, 126.8, 126.6, 126.5, 126.0, 121.1, 114.3, 36.3, 25.6, 20.4, 16.9, 15.0. The product 4,4'-methylenebis(2-(2-hydroxy-5-methylbenzyl)-3,6-dimethylphenol) was analyzed by high resolution mass spectrometry (HRMS) in electrospray ionization (ESI) mode. C 33 H 40NO4[M+NH4] + The theoretical calculated value is 514.2952, and the measured value is 514.2945. The theoretical calculated value is highly consistent with the measured value: HRMS (ESI):calcd for C 33 H 40 NO4[M+NH4] + 514.2952, found 514.2945. The above data confirmed the successful preparation of the target product 4,4'-methylenebis(2-(2-hydroxy-5-methylbenzyl)-3,6-dimethylphenol).

[0139] Example 5

[0140] Preparation of 4,4'-methylenebis(2-(2,4-dihydroxybenzyl)-6-methylphenol) (i.e., a polyphenolic compound containing multiple phenol units):

[0141] .

[0142] Resorcinol (22.0 g, 200 mmol, 20 equiv) and p-toluenesulfonic acid (0.2 g, 1.1 mmol, 0.11 equiv) were added to a 250 mL four-necked round-bottom flask. The mixture was heated to 50°C in a water bath. 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) (2.9 g, 10 mmol, 1 equiv) was added portionwise with stirring. The reaction was continued for 2 h. After the reaction, n-hexane (100 mL) was added while stirring at 50°C to precipitate a solid. The filtrate was filtered, and the n-hexane was evaporated to recover 13.2 g of resorcinol. The filter cake was washed with water (100 mL) to remove p-toluenesulfonic acid and residual resorcinol. The product was then purified by recrystallization from methanol / water (v / v = 2:1) to obtain 3.2 g of 4,4'-methylenebis(2-(2,4-dihydroxybenzyl)-6-methylphenol) as a gray solid with a yield of 67% and a purity of 96%. The melting point (MP) was 203–204°C. The H NMR spectrum of the product, 4,4'-methylenebis(2-(2,4-dihydroxybenzyl)-6-methylphenol, was as follows: 1H NMR (400 MHz, DMSO-d6): δ 9.48 (s, 2 H), 9.00 (s, 2 H), 8.02 (s, 2 H), 6.72 (d, J = 8.0 Hz, 2 H), 6.66 (s, 2 H), 6.65 (s, 2 H), 6.30 (d, J = 2.4 Hz, 2 H), 6.14 (dd, J = 8.0 Hz, 2 H), 3.65 (s, 4 H), 3.51 (s, 2 H), 2.09 (s, 6 H); The data of the carbon NMR spectrum of the product 4,4'-methylenebis(2-(2,4-dihydroxybenzyl)-6-methylphenol) are as follows: 13 C NMR (101MHz, DMSO-d6):δ 156.4, 155.0, 150.6, 132.3, 130.5, 128.4, 128.0, 127.8, 124.1, 117.6, 106.4, 102.3, 39.9, 29.1, 16.7. The product 4,4'-methylenebis(2-(2,4-dihydroxybenzyl)-6-methylphenol) was analyzed by high resolution mass spectrometry (HRMS) in electrospray ionization (ESI) mode. C 29 H 32 NO6 [M+NH4] + The theoretical calculated value is 490.2224, and the measured value is 490.2212. The theoretical calculated value is highly consistent with the measured value: HRMS (ESI):calcdfor C 29 H 32 NO6 [M+NH4] + 490.2224, found 490.2212. The above data confirmed the successful preparation of the target product 4,4'-methylenebis(2-(2,4-dihydroxybenzyl)-6-methylphenol).

[0143] Example 6

[0144] Preparation of 4,4'-methylenebis(2-(2-hydroxy-3,5-dimethylbenzyl)-6-methylphenol) (i.e., a polyphenolic compound containing multiple phenol units):

[0145] .

[0146] To a 250 mL four-necked round-bottom flask, add 2,4-dimethylphenol (24.4 g, 200 mmol, 20 equiv) and p-toluenesulfonic acid (0.2 g, 1.1 mmol, 0.11 equiv). Heat to 50°C in a water bath. Add 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) (2.9 g, 10 mmol, 1 equiv) in portions with stirring. Continue the reaction for 2 h. After the reaction is complete, add n-hexane (100 mL) while maintaining stirring at 50°C to precipitate a solid. Filter the filtrate, and evaporate the n-hexane to recover 13.5 g of 2,4-dimethylphenol. The filter cake was washed with water (100 mL) to remove p-toluenesulfonic acid and residual p-cresol. The product was then recrystallized from methanol / water (v / v = 2:1) to obtain 3.1 g of 4,4'-methylenebis(2-(2-hydroxy-3,5-dimethylbenzyl)-6-methylphenol) as a yellow solid with a yield of 63% and a purity of 98%. The melting point (MP) was 177–178°C. The H NMR spectrum of the product, 4,4'-methylenebis(2-(2-hydroxy-3,5-dimethylbenzyl)-6-methylphenol, was as follows: 1 H NMR (400 MHz, DMSO-d6): δ8.31 (s, 4 H), 6.72 (d, J = 9.2 Hz, 4 H), 6.66 (s, 2 H), 6.62 (s, 2 H), 3.77 (s, 4 H), 3.54 (s, 2 H), 2.13 (s, 6 H), 2.09 (s, 6 H) ), 2.08 (s, 6 H); The data of the carbon NMR spectrum of the product 4,4'-methylenebis(2-(2-hydroxy-3,5-dimethylbenzyl)-6-methylphenol) are as follows: 13 C NMR (101 MHz, DMSO-d6): δ 150.4, 150.0, 132.5, 128.9, 128.6, 128.2, 128.0, 127.7, 127.6, 127.5, 124.2 (2C), 39.8, 30.2, 20.2, 16. 7, 16.6. The 124.2 (2C) in the carbon NMR spectrum is because the data are the same after rounding when taking the value, so it is recorded as having 2 carbons at 124.2. The product 4,4'-methylenebis(2-(2-hydroxy-3,5-dimethylbenzyl)-6-methylphenol) was analyzed by high-resolution mass spectrometry (HRMS) in electrospray ionization (ESI) mode. C 33 H 40 NO4 [M+NH4] +The theoretical calculated value is 514.2952, and the measured value is 514.2945. The theoretical calculated value is highly consistent with the measured value: HRMS (ESI):calcd for C 33 H 40 NO4 [M+NH4] + 514.2952, found514.2945. The above data confirmed the successful preparation of the target product 4,4'-methylenebis(2-(2-hydroxy-3,5-dimethylbenzyl)-6-methylphenol).

[0147] The synthesis strategy adopted in the present application greatly improves the chemical selectivity of each step, and has simple process operation, simple post-treatment, high synthesis efficiency and product purity, and less three wastes.

[0148] The above description is only a preferred embodiment of the present application and is not intended to limit the present application. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present application should be included in the scope of protection of the present application.

Claims

1. A method for preparing a methylene-bridged substituted phenol substituted with hydroxymethyl at the ortho-hydroxy position, characterized in that: The synthetic route is as follows: The specific steps include: A1, a substituted phenol (1) undergoes a highly selective formylation reaction with formaldehyde in the presence of a Lewis acid catalyst, and then a first quencher is added to the system to complete the formylation reaction to prepare a substituted salicylaldehyde compound (2); A2, the substituted salicylaldehyde compound (2) contains formaldehyde and A condensation reaction is carried out in an acid catalyst system, and a solid is precipitated after cooling, completing the condensation reaction to prepare a methylene-bridged substituted salicylaldehyde compound (3); A3, reducing the methylene-bridged substituted salicylaldehyde compound (3) to prepare a methylene-bridged substituted phenol (4) substituted with hydroxymethyl at the ortho-hydroxy position; wherein n represents an integer from 1 to 3, and each R0 independently represents a linear or branched hydrocarbon group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a linear or branched alkoxy group having 1 to 6 carbon atoms, or a halogen atom; wherein one R0 in the substituted phenol (1) occupies at least the ortho position of the hydroxyl group, so that the methylene group in the obtained methylene-bridged substituted salicylaldehyde compound (3) is connected to the para position of the hydroxyl group; or one R0 in the substituted phenol (1) occupies at least the para position of the hydroxyl group, so that the methylene group in the obtained methylene-bridged substituted salicylaldehyde compound (3) is connected to the ortho position of the hydroxyl group.

2. The preparation method according to claim 1, characterized in that The synthetic route is as follows: Where n is 1, the general formula of substituted phenol (1) is Alternatively, n is 2, and the general formula of substituted phenol (1) is Alternatively, n is 3, and the general formula of substituted phenol (1) is Each R0 independently represents a linear or branched hydrocarbon group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a linear or branched alkoxy group having 1 to 6 carbon atoms, or a halogen atom.

3. The preparation method according to claim 2, characterized in that Substituted phenol (1) is or 4. The preparation method according to claim 1, characterized in that The synthetic route is as follows: Where n is 1, the general formula of substituted phenol (1) is Alternatively, n is 2, and the general formula of substituted phenol (1) is Alternatively, n is 3, and the general formula of substituted phenol (1) is Each R0 independently represents a linear or branched hydrocarbon group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a linear or branched alkoxy group having 1 to 6 carbon atoms, or a halogen atom.

5. The preparation method according to claim 4, characterized in that Substituted phenol (1) is or 6. The preparation method according to claim 1, characterized in that In step A1, one or more of the following features are included: 1) The molar ratio of the substituted phenol (1) to the Lewis acid catalyst is 1:1-2; 2) The Lewis acid catalyst is one or more of ZnCl2, FeCl3, NiCl2, CaCl2, and MgCl2; 3) The molar ratio of the substituted phenol (1) to the formylation reagent formaldehyde is 1:2-10; 4) reacting the substituted phenol (1) with the formylation agent formaldehyde at 25-85° C. under the catalysis of the Lewis acid catalyst; 5) The substituted phenol (1) reacts with a formylation agent, formaldehyde, in the presence of a first solvent, wherein the amount of the first solvent is 1 to 20 times the mass of the substituted phenol (1), and the first solvent is selected from one or more of halogenated hydrocarbons, ethers, nitriles, esters, and aromatic hydrocarbons.

7. The preparation method according to claim 1, characterized in that In step A2, one or more of the following features are included: 1) The substituted salicylaldehyde compound (2) and the The molar ratio of the acid catalyst is 1:0.01 to 0.5; 2) The acid catalyst is one or more of hydrochloric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, and a strong acid resin; 3) The molar ratio of the substituted salicylaldehyde compound (2) to formaldehyde is 1:0.5-0.8; 4) The substituted salicylaldehyde compound (2) and formaldehyde are The contact reaction temperature of the acid catalyst mixture is 25 to 100°C; 5) the substituted salicylaldehyde compound (2), formaldehyde and the The acid catalyst reacts in the presence of a second solvent, the amount of the second solvent is 1 to 5 times the mass of the substituted salicylaldehyde compound (2), and the second solvent is selected from one or more of halogenated hydrocarbons, aromatic hydrocarbons, carboxylic acids, and carboxylic acid esters.

8. The preparation method according to claim 1, characterized in that In step A3, the reduction reaction occurs by a reduction method such as metal hydride reduction, catalytic hydrogenation or transfer hydrogenation.

9. The preparation method according to claim 8, characterized in that In step A3, the reduction reaction is carried out by metal hydride reduction, wherein the methylene-bridged substituted salicylaldehyde compound (3) undergoes a reduction reaction with a metal hydride reducing agent, and after the reaction is completed, a second quenching agent is added to quench the reaction, and then extraction, desolventization, and recrystallization are performed to complete the reduction step, thereby preparing a methylene-bridged substituted phenol (4) substituted with hydroxymethyl at the ortho-hydroxy position of the hydroxyl group.

10. The preparation method according to claim 9, characterized in that Include one or more of the following characteristics: 1) The metal hydride reducing agent is NaBH4, KBH4, or LiAlH4; 2) the molar ratio of the methylene-bridged substituted salicylaldehyde compound (3) to the metal hydride reducing agent is 1:1 to 3; 3) the contact reaction temperature of the methylene-bridged substituted salicylaldehyde compound (3) and the metal hydride reducing agent is -10 to 80° C.; 4) The solvent used to dissolve the methylene-bridged substituted salicylaldehyde compound (3) is a halogenated hydrocarbon, an alcohol or a mixed solvent thereof.

11. A method for preparing a polyphenol compound containing multiple phenol units, characterized in that: Using the methylene-bridged substituted phenol (4) substituted with hydroxymethyl substituted at the ortho-hydroxy position as described in any one of claims 1 to 10, the synthesis route is as follows: Specifically, the method comprises step A4: the methylene-bridged substituted phenol (4) substituted with hydroxymethyl at the ortho-hydroxyl group undergoes a Friedel-Crafts alkylation reaction with the substituted phenol (5) under the action of an acidic catalyst to prepare a polyphenol compound (6) containing multiple phenol units; wherein m represents an integer from 1 to 3, and each R1 independently represents a straight-chain or branched hydrocarbon group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or a straight-chain or branched alkoxy group having 1 to 6 carbon atoms; or m is 1 and R1 is a hydroxyl group.

12. The preparation method according to claim 11, characterized in that The synthetic route is as follows: m is 1, and the general formula of substituted phenol (5) is Alternatively, m is 2, and the general formula of substituted phenol (5) is Alternatively, m is 3, and the general formula of substituted phenol (5) is wherein each R1 independently represents a linear or branched hydrocarbon group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or a linear or branched alkoxy group having 1 to 6 carbon atoms; Alternatively, the substituted phenol (5) is 13. The preparation method according to claim 12, characterized in that Substituted phenol (5) is or 14. The preparation method according to claim 11, characterized in that The synthetic route is as follows: m is 1, and the general formula of substituted phenol (5) is Alternatively, m is 2, and the general formula of substituted phenol (5) is Alternatively, m is 3, and the general formula of substituted phenol (5) is Here, each R1 independently represents a linear or branched hydrocarbon group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or a linear or branched alkoxy group having 1 to 6 carbon atoms.

15. The preparation method according to claim 11, characterized in that In step A4, one or more of the following features are included: 1) The molar ratio of the methylene-bridged substituted phenol (4) substituted with hydroxymethyl at the ortho-hydroxy position to the acidic catalyst is 1:0.05-0.5; 2) The acidic catalyst is one or more of hydrochloric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, and a strong acidic resin; 3) the molar ratio of the methylene-bridged substituted phenol (4) substituted with hydroxymethyl at the ortho-hydroxyl group to the substituted phenol (5) is 1:10 to 25; 4) The reaction temperature of the methylene-bridged substituted phenol (4) substituted with hydroxymethyl at the ortho-hydroxyl group and the substituted phenol (5) is 25-65°C.

Images