A method for preparing 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol)

Abstract

The application proposes a new method for preparing 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol), including the following reaction steps: the first step: using 2-X-6-methylphenol as raw material, wherein X is selected from one of chlorine, bromine, and iodine, and 2-X-6-methylphenol is reacted with formaldehyde under the conditions of a first alkaline solution or an acidic solution to prepare 4,4'-methylenebis(2-X-6-methylphenol); the second step: 4,4'-methylenebis(2-X-6-methylphenol) is subjected to a dehalogenation reaction to prepare 4,4'-methylenebis(2-methylphenol); the third step: 4,4'-methylenebis(2-methylphenol) is reacted with formaldehyde under the conditions of a second alkaline solution to prepare 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol). The method for preparing 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) of the embodiment of the application has the characteristics of simple operation, few product by-products, and high purity in each step reaction.

Description

Technical Field

[0001] The present application relates to the field of chemical synthesis, in particular to the field of synthesis of phenolic hydroxymethyl compounds, and specifically to a method for preparing 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol). Background Art

[0002] 4,4'-Methylenebis(2-hydroxymethyl-6-methylphenol) is a dihydroxymethyl compound of phenol, and its chemical structure is shown in Structural Formula 1. This compound can be used as a starting material for condensation reactions in organic synthesis, and is also an important intermediate widely used in chemical, pharmaceutical, and optoelectronic materials; in the microelectronics industry, it is mainly one of the important raw materials for diazonaphthoquinone-type photosensitizers in positive photoresists.

[0003] Structural formula 1

[0004] At present, the literature reports that the synthesis method of this compound is mainly prepared by a one-step method of reacting the raw material o-cresol with formaldehyde solution under alkaline conditions (such as sodium hydroxide, potassium carbonate, etc.). However, since o-cresol has two active sites at positions 2 and 4, and the generated hydroxymethyl intermediate product will undergo condensation, it will result in a large number of by-products and low product purity. Subsequent purification requires multiple recrystallizations, resulting in a very low yield. Barclay MG (1944), Hanus Franz (1940), Sprengling GR (1954) and others have reported on the synthesis of this compound, and there are generally problems such as long reaction time, low product purity, and many by-products. Heng Xuhong et al. (CN113831224B) explored a simple synthetic process to prepare 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol). They dissolved o-cresol in dichloromethane solvent, first reacted with formaldehyde using acid catalysis, and separated the liquids after keeping the reaction warm for a period of time; the oil phase was adjusted to pH with sodium hydroxide and then reacted with formaldehyde using alkaline solution catalysis. After the reaction, the pH of the reaction liquid was adjusted with acid, and 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) was obtained after filtration. The yield was up to 72%, and the product purity was up to 96.32%. There were many by-products in the reaction process; however, this method required adjusting the pH of the reaction system twice, and a large amount of acid and base were used in the preparation process, and the product purity could not meet the requirements of the raw material purity required for the photosensitizer. Therefore, finding a simple synthetic route to achieve the preparation of high-purity 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) is a technical problem that needs to be solved urgently. Summary of the invention

[0005] Based on the above background technology, the embodiments of the present application propose a new method for preparing 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol). The embodiments of the present application can achieve the preparation of high-purity 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol). The synthetic route of the present application uses 2-X-6-methylphenol as a raw material. The chemical structure of 2-X-6-methylphenol is shown in Structural Formula 2, wherein X is selected from one of chlorine, bromine, and iodine. Compared with the two reactive sites in the o-cresol molecule, the reactive site in the 2-X-6-methylphenol molecule is reduced to one, generating the product 4,4'-methylenebis(2-X-6-methylphenol), while reducing the generation of by-products during the polycondensation reaction with formaldehyde under the catalysis of acid or base. The chemical structure of the product 4,4'-methylenebis(2-X-6-methylphenol) is shown in Structural Formula 3. Subsequently, the halogen atom (one of chlorine, bromine, and iodine) is removed by dehalogenation reaction. Since the ortho-position reaction activity of the hydroxyl group in the 4,4'-methylenebis(2-methylphenol) structural molecule is the same, high-purity 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) can be obtained in high yield under the catalysis of base. Although the method requires three steps of reaction, each step of the reaction has the characteristics of simple operation, high selectivity, high yield and easy purification, and can meet the high purity requirements for preparing diazonaphthoquinone photosensitizers for positive photoresists.

[0006] Structural formula II Structural formula 3

[0007] According to one aspect of the present application, a method for preparing 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) is provided, comprising the following reaction steps: the first step: using 2-X-6-methylphenol as a raw material, wherein X is selected from one of chlorine, bromine, and iodine, and reacting 2-X-6-methylphenol with formaldehyde under the conditions of a first alkaline solution or an acidic solution to prepare 4,4'-methylenebis(2-X-6-methylphenol); the second step: subjecting 4,4'-methylenebis(2-X-6-methylphenol) to a dehalogenation reaction to prepare 4,4'-methylenebis(2-methylphenol); the third step: reacting 4,4'-methylenebis(2-methylphenol) with formaldehyde under the conditions of a second alkaline solution to prepare 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol). It should be understood that the formaldehyde mentioned in the present application is a formaldehyde solution or paraformaldehyde (CH2O) 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.

[0008] In some embodiments, 4,4'-methylenebis(2-X-6-methylphenol) can undergo a reduction reaction with a transition metal catalyst / reducing agent system in a third alkaline solution to perform a dehalogenation reaction. In some preferred embodiments, 4,4'-methylenebis(2-X-6-methylphenol) reacts with a nickel-aluminum alloy in a third alkaline solution to prepare 4,4'-methylenebis(2-methylphenol). In other preferred embodiments, 4,4'-methylenebis(2-X-6-methylphenol) reacts with palladium-carbon formic acid in a third alkaline solution to prepare 4,4'-methylenebis(2-methylphenol). In other preferred embodiments, aluminum or formic acid is a reducing agent in a transition metal catalyst / reducing agent system, which can undergo a reduction reaction to produce hydrogen to catalyze the hydrogenolysis of 4,4'-methylenebis(2-X-6-methylphenol) for a dehalogenation reaction, and nickel or palladium-carbon is a catalyst for capturing a hydrogen source in a transition metal catalyst / reducing agent system.

[0009] In some embodiments, the third alkaline solution can be one or more of sodium hydroxide, potassium hydroxide, sodium methoxide, potassium tert-butoxide, or tetrabutylammonium hydroxide aqueous solution. In some embodiments, the amount of the third alkaline solution is 10 to 20 times the amount of 4,4'-methylenebis(2-X-6-methylphenol).

[0010] In some embodiments, 4,4'-methylenebis(2-X-6-methylphenol) reacts with a nickel-aluminum alloy at 90-100°C in a third alkaline solution, and the molar ratio of 4,4'-methylenebis(2-X-6-methylphenol) to the nickel-aluminum alloy is 1:2.5-4.0. Preferably, the molar ratio of 4,4'-methylenebis(2-X-6-methylphenol) to the nickel-aluminum alloy can be 1:3.0-3.5.

[0011] In some embodiments, in the first step, the molar ratio of the reactants is: 2-X-6-methylphenol: formaldehyde = 1: 1.2-2.0.

[0012] In some embodiments, in the third step, the molar ratio of the reactants is: 4,4'-methylenebis(2-methylphenol):formaldehyde=1:2.0~4.0. Preferably, in the third step, the molar ratio of the reactants is: 4,4'-methylenebis(2-methylphenol):formaldehyde=1:2.0~3.0.

[0013] In some embodiments, the first step reaction is performed at 10-30°C, and the third step reaction is performed at 5-35°C. Preferably, the first step reaction is performed at 10-20°C, and the third step reaction is performed at 10-15°C.

[0014] In some embodiments, the first alkaline solution may be one or more of sodium hydroxide, potassium carbonate, sodium carbonate, potassium hydroxide, sodium methoxide or tetrabutylammonium hydroxide; the acidic solution may be one or more of hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid or p-toluenesulfonic acid; the second alkaline solution may be one or more of sodium hydroxide, potassium carbonate, sodium carbonate, potassium hydroxide, sodium metaborate tetrahydrate or tetrabutylammonium hydroxide. In some embodiments, preferably, the amount of the first alkaline solution is 0.5 to 1.2 times the amount of substance of 2-X-6-methylphenol. In some embodiments, preferably, the amount of the acidic solution is 0.10 to 1.0 times the amount of substance of 2-X-6-methylphenol. In some embodiments, preferably, the amount of the second alkaline solution is 0.5 to 1.2 times the amount of substance of 4,4'-methylenebis(2-methylphenol).

[0015] In some embodiments, o-cresol is used as a raw material to prepare 2-X-6-methylphenol.

[0016] In a preferred embodiment, o-cresol and diisopropylamine (DIPA) can be dissolved in a solvent, and then a solution of NX-substituted succinimide (NXS) is added dropwise, wherein X is selected from one of chlorine, bromine, and iodine, and stirred until the o-cresol reaction is complete, and the pH value of the reaction system is adjusted with an acidic solution, mixed, and separated to obtain 2-X-6-methylphenol. The chemical structure of NX-substituted succinimide is shown in structural formula 4. Among them, the solvent can be a dichloromethane solvent, and the solution of NX-substituted succinimide can be a solution of NX-substituted succinimide dissolved in dichloromethane. In some embodiments, a solution of NX-substituted succinimide is added dropwise at 15 to 30°C, wherein the molar ratio of the reactants is: o-cresol: diisopropylamine: NX-substituted succinimide = 1: 0.1 to 0.3: 1.0 to 1.3.

[0017] Structural Formula 4

[0018] In other embodiments, o-cresol is used as a raw material, first undergoes a sulfonation reaction with concentrated sulfuric acid to generate 4-hydroxy-3-methylbenzenesulfonic acid, then undergoes a bromination reaction with liquid bromine to obtain 2-bromo-4-hydroxy-6-methylbenzenesulfonic acid, and finally is heated in a dilute sulfuric acid solution to remove the sulfonic acid group to obtain 2-bromo-6-methylphenol. The liquid bromine can also be replaced with other halogen elements to obtain 2-chloro-6-methylphenol and 2-iodo-6-methylphenol.

[0019] Compared with the prior art, the above technical solutions conceived by the present application have the following advantages and effects:

[0020] (1) Compared with the prior art method of preparing 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) by reacting o-cresol as a raw material with formaldehyde, the preparation method of the present application creatively proposes a new method of using 2-X-6-methylphenol as a raw material, reacting with formaldehyde in the first step, undergoing a dehalogenation reaction, and then reacting with formaldehyde in the second step. In addition, each step of the preparation method of the present application has the advantages of simple operation, high selectivity and high yield, and the product purity can meet the raw material purity requirements of the photosensitizer. The method of the present application has the characteristics of simple operation, less product by-products and high purity.

[0021] (2) The technical solution of the present application proposes to introduce a halogen atom at the ortho position of o-cresol, so that the reactive sites of o-cresol are reduced from 2 to 1, thereby avoiding the formation of by-products during the condensation reaction with formaldehyde under the catalysis of acid or base, thereby improving the yield and purity of the final product 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol).

[0022] (3) In the preparation of the compound 4,4'-methylenebis(2-methylphenol), although the preparation of 4,4'-methylenebis(2-methylphenol) from o-cresol as the starting material requires three steps, the total yield can be greater than 87%.

[0023] (4) The present application controls the selectivity by using DIPA together with NXS so that the halogen atom can only be located at the ortho position of the phenolic hydroxyl group of o-cresol, thereby reducing the formation of by-products in the preparation of 2-X-6-methylphenol from o-cresol and improving the yield and purity of the product. DETAILED DESCRIPTION

[0024] In order to make the purpose, technical solutions and advantages of the present application clearer and more understandable, and to fully convey the scope of the present application 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 the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art belong to the scope of protection of the present 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.

[0025] The present application provides a method for preparing 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol), comprising the following steps:

[0026] Step 1: Preparation of 4,4'-methylenebis(2-X-6-methylphenol)

[0027] 2-X-6-methylphenol is used as a raw material, wherein X is selected from one of chlorine, bromine, and iodine, and 2-X-6-methylphenol is reacted with formaldehyde under the conditions of a first alkaline solution or an acidic solution, and the reaction is carried out at 10 to 30°C (preferably at 10 to 20°C) for 12 to 36 hours. The product is precipitated from the system and can be directly filtered to obtain 4,4'-methylenebis(2-X-6-methylphenol). If the reaction temperature is lower than 10°C, the reaction rate slows down and the raw material conversion will be incomplete. If the reaction temperature is too high, the selectivity of the reaction decreases and the number of by-products increases. In some embodiments, the molar ratio of the reactants can be: 2-X-6-methylphenol: formaldehyde = 1: 1.2 to 2.0. If base catalysis is performed, in some embodiments, the first alkaline solution can be one or more of sodium hydroxide, potassium carbonate, sodium carbonate, potassium hydroxide, sodium methoxide, or tetrabutylammonium hydroxide. In some embodiments, preferably, the first alkaline solution is used in an amount of 0.5 to 1.2 times the amount of the substance of 2-X-6-methylphenol. If acid catalysis is performed, in some embodiments, the acidic solution can be one or more of hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid or p-toluenesulfonic acid. In some embodiments, preferably, the acidic solution is used in an amount of 0.10 to 1.0 times the amount of the substance of 2-X-6-methylphenol.

[0028] Step 2: Preparation of 4,4'-methylenebis(2-methylphenol)

[0029] 4,4'-methylenebis(2-X-6-methylphenol) is subjected to a dehalogenation reaction to prepare 4,4'-methylenebis(2-methylphenol). In some embodiments, 4,4'-methylenebis(2-X-6-methylphenol) can undergo a reduction reaction with a transition metal catalyst / reducing agent system in a third alkaline solution to perform a dehalogenation reaction. In some embodiments, the third alkaline solution can be one or more of sodium hydroxide, potassium hydroxide, sodium methoxide, potassium tert-butoxide, or tetrabutylammonium hydroxide aqueous solution. In some embodiments, the amount of the third alkaline solution is 10 to 20 times the amount of 4,4'-methylenebis(2-X-6-methylphenol).

[0030] In some preferred embodiments, 4,4'-methylenebis(2-X-6-methylphenol) reacts with nickel-aluminum alloy in a third alkaline solution to prepare 4,4'-methylenebis(2-methylphenol). In some embodiments, 4,4'-methylenebis(2-X-6-methylphenol) reacts with nickel-aluminum alloy in a third alkaline solution at 90-100°C for 0.5-3 hours, ethyl acetate is added after the reaction is completed, and the organic phase is dried and desolventized after separation to obtain 4,4'-methylenebis(2-methylphenol), wherein the molar ratio of 4,4'-methylenebis(2-X-6-methylphenol) to nickel-aluminum alloy can be 1:2.5-4.0, preferably, the molar ratio of 4,4'-methylenebis(2-X-6-methylphenol) to nickel-aluminum alloy can be 1:3.0-3.5. Among them, if the molar ratio of 4,4'-methylenebis(2-X-6-methylphenol) to nickel-aluminum alloy is greater than 1:2.5, the raw material will not be completely hydrogenated; if the molar ratio of 4,4'-methylenebis(2-X-6-methylphenol) to nickel-aluminum alloy is less than 1:4, the use of excessive reducing agent will bring pressure to post-processing; further controlling the molar ratio of 4,4'-methylenebis(2-X-6-methylphenol) to nickel-aluminum alloy to 1:3.0~3.5 can ensure complete conversion of the substrate without causing too much pressure on the post-processing process.

[0031] In some other preferred embodiments, 4,4'-methylenebis(2-X-6-methylphenol) can be reacted with palladium carbon formic acid in a third alkaline solution to prepare 4,4'-methylenebis(2-methylphenol).

[0032] That is, aluminum or formic acid is a reducing agent in the transition metal catalyst / reducing agent system, which can undergo a reduction reaction to produce hydrogen to catalyze the hydrogenolysis of 4,4'-methylenebis(2-X-6-methylphenol) for dehalogenation reaction, and nickel or palladium carbon is a catalyst for capturing hydrogen sources in the transition metal catalyst / reducing agent system.

[0033] Step 3: Preparation of 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol)

[0034] 4,4'-methylenebis(2-methylphenol) reacts with formaldehyde under the condition of a second alkaline solution to prepare 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol). In some embodiments, 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) is prepared by reacting at 5 to 35°C (preferably at 10 to 15°C). If the reaction temperature is lower than 5°C, the reaction rate slows down and the raw material conversion will be incomplete. If the reaction temperature is too high, the selectivity of the reaction decreases and the by-products increase. In some embodiments, the molar ratio of the reactants is: 4,4'-methylenebis(2-methylphenol): formaldehyde = 1: 2.0 to 4.0. Preferably, the molar ratio of the reactants is: 4,4'-methylenebis(2-methylphenol): formaldehyde = 1: 2.0 to 3.0. Among them, if the molar ratio of 4,4'-methylenebis(2-methylphenol) to formaldehyde is greater than 1:2.0, the reaction raw materials will not be completely converted. If the molar ratio of 4,4'-methylenebis(2-methylphenol) to formaldehyde is greater than 1:4.0, too much formaldehyde will bring environmental pressure; the molar ratio of 4,4'-methylenebis(2-methylphenol) to formaldehyde is further controlled to 1:2.0~3.0. On the one hand, it can ensure the complete conversion of the substrate bisphenol and improve the reaction yield. On the other hand, there is less excess formaldehyde and the environmental pressure is small. In some embodiments, the second alkaline solution can be one or more of sodium hydroxide, potassium carbonate, sodium carbonate, potassium hydroxide, sodium metaborate tetrahydrate or tetrabutylammonium hydroxide. In some embodiments, preferably, the amount of the second alkaline solution is 0.5~1.2 times the amount of 4,4'-methylenebis(2-methylphenol).

[0035] In some embodiments, before the first step, o-cresol can be used as a raw material to prepare 2-X-6-methylphenol.

[0036] In a preferred embodiment, o-cresol and diisopropylamine (DIPA) can be dissolved in a solvent (e.g., dichloromethane, with 0.3-1 L of dichloromethane used per mole of o-cresol), and then a solution of NX-substituted succinimide (NXS) (e.g., a dichloromethane solution of NXS, with 0.5-2 L of dichloromethane used per mole of NXS) is added dropwise, wherein X is selected from one of chlorine, bromine, and iodine, and stirring is continued for about 2-3 hours after the addition is completed, until the o-cresol reaction is completed, and the pH value of the reaction system is adjusted to 1-2 with an acidic solution (e.g., 1M hydrochloric acid), mixed, separated, and the organic phase is dried and desolvated to obtain 2-X-6-methylphenol. Among them, 2% or even less by-products (2,4-diX-6-methylphenol) may be contained. During the reaction, diisopropylamine first reacts with NXS to form N-halogenated diisopropylamine, which acts as an actual halogenating agent and interacts with the hydrogen bond between the substrate phenolic hydroxyl group, resulting in the halogen atom preferentially transferred to the ortho position of the hydroxyl group. In some embodiments, a solution of NX-substituted succinimide is added dropwise at 15-30° C., wherein the molar ratio of the reactants is: o-cresol: diisopropylamine: NX-substituted succinimide = 1: 0.1-0.3: 1.0-1.3. If the content of diisopropylamine is too low, the amount of N-halogenated diisopropylamine generated is insufficient, so that NXS will act as a halogenating agent to undergo a competitive halogenation reaction with poor selectivity, resulting in a decrease in the selectivity of the reaction and an increase in by-products; although an excessive amount of diisopropylamine does not affect the selectivity of the reaction, the reaction cost increases.

[0037] In other embodiments, o-cresol is used as a raw material, first undergoes a sulfonation reaction with concentrated sulfuric acid to generate 4-hydroxy-3-methylbenzenesulfonic acid, then undergoes a bromination reaction with liquid bromine to obtain 2-bromo-4-hydroxy-6-methylbenzenesulfonic acid, and finally is heated in a dilute sulfuric acid solution to remove the sulfonic acid group to obtain 2-bromo-6-methylphenol. The liquid bromine can also be replaced with other halogen elements to obtain 2-chloro-6-methylphenol and 2-iodo-6-methylphenol.

[0038] The present application creatively proposes to use 2-X-6-methylphenol as a raw material. Compared with the two reactive sites in the o-cresol molecule when o-cresol is used as a raw material, the reactive site in the 2-X-6-methylphenol molecule is reduced to one, thereby reducing the generation of by-products during the polycondensation reaction with formaldehyde under the catalysis of acid or base. After the first step reaction with formaldehyde, the product 4,4'-methylenebis(2-X-6-methylphenol) is generated, and the halogen atoms are subsequently removed by a dehalogenation reaction, and then the second step reaction is carried out with formaldehyde. Since the ortho-position reaction activity of the phenolic hydroxyl group in the 4,4'-methylenebis(2-methylphenol) structural molecule is the same, high-purity 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) can be obtained in high yield. Although the method requires three steps of reaction, each step of the reaction is simple to operate, highly selective, highly yielding and easy to purify. The total yield can be greater than 78%, and the purity of the product 4,4'-methylenebis(3-methylphenol) is greater than 99%, which can meet the high purity requirements for the preparation of diazonaphthoquinone-type photosensitizers for positive photoresists.

[0039] The present application will be described in more detail below through examples.

[0040] Example 1

[0041] Preparation of 2-bromo-6-methylphenol: o-cresol (10.8 g) and DIPA (1.52 g) were dissolved in dichloromethane (100 mL), and a dichloromethane (200 mL) solution of NBS (N-bromosuccinimide, 17.8 g) was added dropwise at 20 °C. The mixture was stirred and reacted for 3 hours. After the reaction of the raw material o-cresol was completed, the pH of the reaction system was adjusted to 1-2 with 1 M hydrochloric acid, and then separated with a separatory funnel. The organic phase was dried with anhydrous sodium sulfate and then desolventized in vacuum to obtain 18.2 g of the product with a yield of 97%. The NMR results of the product 2-bromo-6-methylphenol were as follows: 1 H NMR (400 MHz, CDCl3): δ 2.30 (s, 3H), 5.56 (s, 1H), 6.71 (t, J = 8.0 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H).

[0042] Preparation of 4,4'-methylenebis(2-bromo-6-methylphenol): Sodium hydroxide (2 g) was dissolved in 100 mL of water, 2-bromo-6-methylphenol (18.7 g) was added, and then 37% formaldehyde solution (9.7 g) was added dropwise at 20 °C for reaction. After the addition was completed, the reaction was continued for 36 hours. The product precipitated from the system and could be directly filtered to obtain the compound 4,4'-methylenebis(2-bromo-6-methylphenol); the crude product was washed with 0.005 M hydrochloric acid (100 mL), then washed with water (100 mL) twice, and dried to obtain 18.7 g of the product with a yield of 97%. The NMR results of the product 4,4'-methylenebis(2-bromo-6-methylphenol) are 1 H NMR (400MHz, CDCl3): δ 2.25 (s, 3H), 3.70 (s, 1H), 5.44 (s, 1H), 6.85 (s, 1H), 7.07 (s1H); 13 C NMR (100.1 MHz, CDCl3): δ 16.7, 39.6, 110.0, 125.8, 129.2, 130.8,133.9, 148.8.

[0043] Preparation of 4,4'-methylenebis(2-methylphenol): Add 4,4'-methylenebis(2-bromo-6-methylphenol) (11.58 g) and nickel-aluminum alloy (7.84 g) to a 10% sodium hydroxide (200 mL) solution, control the reaction temperature at 95 °C and continue the reaction for 1 hour. After the reaction is completed, add ethyl acetate (100 mL) and extract three times. Combine the organic phases and dry them with anhydrous sodium sulfate. Filter and vacuum desolventize to obtain 4,4'-methylenebis(2-methylphenol); after drying, the product is 6.2 g, with a yield of 91%. The NMR results of the product 4,4'-methylenebis(2-methylphenol) are 1 H NMR (400 MHz, CDCl3): δ 2.22(s, 6H), 3.78 (s, 2H), 4.65 (s, 2H), 6.68 (d, J = 7.6 Hz, 2H), 6.88 (d, J =8.0 Hz, 2H), 6.94 (s 2H); 13 C NMR (100.1 MHz, CDCl3): δ 15.8, 40.2, 114.8, 123.6, 127.3, 131.4, 133.9, 152.0.

[0044] Preparation of 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol): Sodium hydroxide (3 g) was dissolved in 80 mL of water, and then 4,4'-methylenebis(2-methylphenol) (22.8 g) was added. When the temperature of the reaction system was controlled to 10 °C, 37% formaldehyde solution (20 g) was added. The reaction system was continued for 48 hours and then directly filtered. The filter cake was washed with 200 mL of 0.005 M hydrochloric acid, and then washed twice with water (100 mL). After drying, 28.1 g of the product was obtained, with a yield of 97% and a purity greater than 99%. The NMR results of the product 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) are 1 H NMR (DMSO-d6): δ 2.10 (s, 6H), 3.63 (s, 2H), 4.50 (s, 4H), 5.23 (brs, 2H), 6.78 (s, 2H), 6.87 (s, 2H), 8.18 (s,2H); 13 C NMR (100.1 MHz, CDCl3): δ 16.2, 39.7, 59.8, 123.9, 125.1, 127.9, 129.2, 132.3, 150.5.

[0045] Example 2

[0046] Preparation of 2-bromo-6-methylphenol: o-cresol (10.8 g) and DIPA (2.02 g) were dissolved in dichloromethane (100 mL). A solution of NBS (N-bromosuccinimide, 17.8 g) in dichloromethane (200 mL) was slowly added dropwise at 20 °C. The mixture was stirred and reacted for 3 hours. After the reaction of the raw material o-cresol was completed, the pH of the reaction system was adjusted to 1-2 with 1 M hydrochloric acid. The mixture was then separated with a separatory funnel. The organic phase was dried over anhydrous sodium sulfate and desolventized in vacuo to obtain 17.9 g of the product with a yield of 96%.

[0047] Preparation of 4,4'-methylenebis(2-bromo-6-methylphenol): Sodium hydroxide (4 g) was dissolved in 100 mL of water, 2-bromo-6-methylphenol (18.7 g) was added, and then paraformaldehyde (3 g) was added at 20 °C for reaction. The reaction was continued for 36 hours. The product precipitated from the system and could be directly filtered to obtain compound 4,4'-methylenebis(2-bromo-6-methylphenol). The crude product was washed with 0.005 M hydrochloric acid (100 mL), and then washed with water (100 mL) twice. After drying, 18.5 g of the product was obtained, with a yield of 96%.

[0048] Preparation of 4,4'-methylenebis(2-methylphenol): Add 4,4'-methylenebis(2-bromo-6-methylphenol) (11.58 g) and nickel-aluminum alloy (9.2 g) to a 10% sodium hydroxide (200 mL) solution, control the reaction temperature at 95 °C and continue the reaction for 1 hour. After the reaction is completed, add ethyl acetate (100 mL) and extract three times. Combine the organic phases and dry them with anhydrous sodium sulfate. Filter and vacuum desolventize to obtain 4,4'-methylenebis(2-methylphenol); after drying, 6.3 g of the product is obtained with a yield of 92%.

[0049] Preparation of 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol): Sodium hydroxide (2 g) was dissolved in 80 mL of water, and then 4,4'-methylenebis(2-methylphenol) (22.8 g) was added. When the temperature of the reaction system was controlled to 10 °C, 37% formaldehyde solution (24 g) was added. The reaction system was continued for 48 hours and then directly filtered. The filter cake was washed with 200 mL of 0.005 M hydrochloric acid and then washed twice with water (100 mL). The crude product was washed with 10% ethanol aqueous solution (100 mL) and dried to obtain 27.5 g of the product with a yield of 95% and a purity greater than 99%.

[0050] Example 3

[0051] The preparation process of 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) is the same as that of Example 1, except that the reaction temperature of dropping N-bromosuccinimide during the preparation of 2-bromo-6-methylphenol is 15°C. The product 2-bromo-6-methylphenol 17.8 g was obtained with a yield of 95%. On this basis, the final product 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) 11.7 g was obtained with a total yield of 81% and a purity greater than 99%.

[0052] Example 4

[0053] The preparation process of 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) is the same as that of Example 1, except that the reaction temperature of dripping N-bromosuccinimide during the preparation of 2-bromo-6-methylphenol is 30°C. 17.6 g of 2-bromo-6-methylphenol was obtained with a yield of 94%. On this basis, 11.6 g of the final product 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) was obtained with a total yield of 80% and a purity greater than 99%.

[0054] Example 5

[0055] The preparation process of 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) is the same as that of Example 1, except that in the preparation process of 2-bromo-6-methylphenol, the molar ratio of the reactants is: o-cresol: diisopropylamine: N-bromosuccinimide = 1:0.1:1.0. The product 2-bromo-6-methylphenol 17.5 g was obtained with a yield of 93%. On this basis, the final product 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) 11.5 g was obtained with a total yield of 80% and a purity greater than 99%.

[0056] Example 6

[0057] The preparation process of 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) is the same as that of Example 1, except that in the preparation process of 2-bromo-6-methylphenol, the molar ratio of the reactants is: o-cresol: diisopropylamine: N-bromosuccinimide = 1:0.3:1.0. On this basis, 17.2 g of the product 2-bromo-6-methylphenol was obtained with a yield of 92%. On this basis, 11.3 g of the final product 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) was obtained with a total yield of 78% and a purity greater than 99%.

[0058] Example 7

[0059] The preparation process of 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) is the same as that of Example 1, except that in the preparation process of 2-bromo-6-methylphenol, the molar ratio of the reactants is: o-cresol: diisopropylamine: N-bromosuccinimide = 1:0.1:1.3. The product 2-bromo-6-methylphenol 17.4 g was obtained with a yield of 93%. On this basis, the final product 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) 11.5 g was obtained with a total yield of 79% and a purity greater than 99%.

[0060] Example 8

[0061] The preparation process of 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) is the same as that of Example 1, except that in the preparation process of 2-bromo-6-methylphenol, the molar ratio of the reactants is: o-cresol: diisopropylamine: N-bromosuccinimide = 1:0.3:1.3. The product 2-bromo-6-methylphenol 18.0 g was obtained with a yield of 96%. On this basis, the final product 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) 11.9 g was obtained with a total yield of 82% and a purity greater than 99%.

[0062] Example 9

[0063] The preparation process of 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) is the same as that of Example 1, except that the reaction temperature is 10°C during the preparation of 4,4'-methylenebis(2-bromo-6-methylphenol). 18.0 g of the product 4,4'-methylenebis(2-bromo-6-methylphenol) was obtained with a yield of 93%. On this basis, 11.9 g of the final product 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) was obtained with a total yield of 82% and a purity greater than 99%.

[0064] Example 10

[0065] The preparation process of 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) is the same as that of Example 1, except that the reaction temperature is 30°C during the preparation of 4,4'-methylenebis(2-bromo-6-methylphenol). 17.6 g of the product 4,4'-methylenebis(2-bromo-6-methylphenol) was obtained with a yield of 86%. On this basis, 11.6 g of the final product 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) was obtained with a total yield of 80% and a purity greater than 99%.

[0066] Embodiment 11

[0067] The preparation process of 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) is the same as that of Example 1, except that in the preparation process of 4,4'-methylenebis(2-methylphenol), the molar ratio of the reactants is: 4,4'-methylenebis(2-X-6-methylphenol): nickel-aluminum alloy = 1:2.5. The product 4,4'-methylenebis(2-methylphenol) 5.9 g was obtained with a yield of 87%. On this basis, the final product 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) 7.2 g was obtained with a total yield of 84% and a purity greater than 99%.

[0068] Example 12

[0069] The preparation process of 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) is the same as that of Example 1, except that in the preparation process of 4,4'-methylenebis(2-methylphenol), the molar ratio of the reactants is: 4,4'-methylenebis(2-X-6-methylphenol): nickel-aluminum alloy = 1:3.5. The product 4,4'-methylenebis(2-methylphenol) 6.1 g was obtained with a yield of 90%. On this basis, the final product 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) 7.4 g was obtained with a total yield of 87% and a purity greater than 99%.

[0070] Example 13

[0071] The preparation process of 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) is the same as that of Example 1, except that in the preparation process of 4,4'-methylenebis(2-methylphenol), the molar ratio of the reactants is: 4,4'-methylenebis(2-X-6-methylphenol): nickel-aluminum alloy = 1:4.0. The product 4,4'-methylenebis(2-methylphenol) 6.0 g was obtained with a yield of 88%. On this basis, the final product 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) 7.3 g was obtained with a total yield of 85% and a purity greater than 99%.

[0072] Embodiment 14

[0073] The preparation process of 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) is the same as that of Example 1, except that in the preparation process of 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol), 4,4'-methylenebis(2-methylphenol) reacts with 37% formaldehyde solution at 5° C. The final product 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) 26.0 g is obtained with a yield of 89% and a purity greater than 99%.

[0074] Embodiment 15

[0075] The preparation process of 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) is the same as that of Example 1, except that in the preparation process of 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol), 4,4'-methylenebis(2-methylphenol) is reacted with 37% formaldehyde solution at 15° C. The final product 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) 27.3 g is obtained with a yield of 94% and a purity greater than 99%.

[0076] Example 16

[0077] The preparation process of 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) is the same as that of Example 1, except that in the preparation process of 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol), 4,4'-methylenebis(2-methylphenol) reacts with 37% formaldehyde solution at 35° C. The final product 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) 25.8 g is obtained with a yield of 88% and a purity greater than 99%.

[0078] Embodiment 17

[0079] The preparation process of 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) is the same as that of Example 1, except that in the preparation process of 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol), the molar ratio of the reactants is: 4,4'-methylenebis(2-methylphenol): formaldehyde = 1:2.0. The final product 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) 26.5 g is obtained with a yield of 91% and a purity greater than 99%.

[0080] Embodiment 18

[0081] The preparation process of 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) is the same as that of Example 1, except that in the preparation process of 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol), the molar ratio of the reactants is: 4,4'-methylenebis(2-methylphenol): formaldehyde = 1:3.0. The final product 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) 28.0 g is obtained with a yield of 97% and a purity greater than 99%.

[0082] Embodiment 19

[0083] The preparation process of 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) is the same as that of Example 1, except that in the preparation process of 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol), the molar ratio of the reactants is: 4,4'-methylenebis(2-methylphenol): formaldehyde = 1:4.0. The final product 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol) 27.9 g is obtained with a yield of 96% and a purity greater than 99%.

[0084] The above embodiments are merely exemplary embodiments and are not intended to limit the present application. Various changes, substitutions and modifications may be made without departing from the spirit and scope of the present application. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present application shall be included in the scope of protection of the present application.

Claims

1. A method for preparing 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol), comprising the following reaction steps: The first step: using 2-X-6-methylphenol as a raw material, reacting the 2-X-6-methylphenol with formaldehyde under the condition of a first alkaline solution or an acidic solution to prepare 4,4'-methylenebis(2-X-6-methylphenol); Step 2: The 4,4'-methylenebis(2-X-6-methylphenol) is subjected to a dehalogenation reaction to prepare 4,4'-methylenebis(2-methylphenol); Step 3: The 4,4'-methylenebis(2-methylphenol) is reacted with formaldehyde under the condition of a second alkaline solution to prepare the 4,4'-methylenebis(2-hydroxymethyl-6-methylphenol); in, The X is selected from chlorine, bromine and iodine.

2. The method according to claim 1, characterized in that The 4,4'-methylenebis(2-X-6-methylphenol) undergoes a reduction reaction with a transition metal catalyst / reducing agent system in a third alkaline solution to perform the dehalogenation reaction.

3. The method according to claim 2, characterized in that The 4,4'-methylenebis(2-X-6-methylphenol) reacts with the nickel-aluminum alloy in the third alkaline solution to prepare the 4,4'-methylenebis(2-methylphenol).

4. The method according to claim 2, characterized in that: The 4,4'-methylenebis(2-X-6-methylphenol) reacts with palladium carbon formic acid in the third alkaline solution to prepare the 4,4'-methylenebis(2-methylphenol).

5. The method according to claim 1, characterized in that In the first step, the molar ratio of the reactants is: the 2-X-6-methylphenol: the formaldehyde=1:1.2-2.

0.

6. The method according to claim 1, characterized in that In the third step, the molar ratio of the reactants is: the 4,4'-methylenebis(2-methylphenol): the formaldehyde=1:2.0-4.

0.

7. The method according to claim 6, characterized in that In the third step, the molar ratio of the reactants is: the 4,4'-methylenebis(2-methylphenol): the formaldehyde=1:2.0-3.

0.

8. The method according to claim 1, characterized in that The reaction of the first step is carried out at 10-30°C, and the reaction of the third step is carried out at 5-35°C.

9. The method according to claim 8, characterized in that The reaction of the first step is carried out at 10-20°C, and the reaction of the third step is carried out at 10-15°C.

10. The method according to claim 1, characterized in that The first alkaline solution is one or more of sodium hydroxide, potassium carbonate, sodium carbonate, potassium hydroxide, sodium methoxide or tetrabutylammonium hydroxide; the acidic solution is one or more of hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid or p-toluenesulfonic acid; the second alkaline solution is one or more of sodium hydroxide, potassium carbonate, sodium carbonate, potassium hydroxide, sodium metaborate tetrahydrate or tetrabutylammonium hydroxide.

11. The method according to claim 10, characterized in that The amount of the first alkaline solution is 0.5 to 1.2 times the amount of the 2-X-6-methylphenol.

12. The method according to claim 10, characterized in that The amount of the acidic solution is 0.10 to 1.0 times the amount of the 2-X-6-methylphenol.

13. The method according to claim 10, characterized in that The amount of the second alkaline solution is 0.5 to 1.2 times the amount of the 4,4'-methylenebis(2-methylphenol).

14. The method according to claim 2, characterized in that The third alkaline solution is one or more of sodium hydroxide, potassium hydroxide, sodium methoxide, potassium tert-butoxide or tetrabutylammonium hydroxide aqueous solution.

15. The method according to claim 14, characterized in that The amount of the third alkaline solution is 10 to 20 times the amount of the 4,4'-methylenebis(2-X-6-methylphenol).

16. The method according to claim 3, characterized in that The 4,4'-methylenebis(2-X-6-methylphenol) reacts with the nickel-aluminum alloy at 90-100° C., and the molar ratio of the 4,4'-methylenebis(2-X-6-methylphenol) to the nickel-aluminum alloy is 1:2.5-4.

0.

17. The method according to claim 16, characterized in that The molar ratio of the 4,4'-methylenebis(2-X-6-methylphenol) to the nickel-aluminum alloy is 1:3.0-3.

5.

18. The method according to claim 1, characterized in that O-cresol is used as a raw material to prepare the 2-X-6-methylphenol.

19. The method according to claim 18, characterized in that The 2-X-6-methylphenol is obtained by dissolving the o-cresol and diisopropylamine in a solvent, then dropping a solution of N-substituted succinimide, stirring until the o-cresol is completely reacted, adjusting the pH of the reaction system with an acidic solution, mixing, and separating the liquids.

20. The method according to claim 19, characterized in that The solution of the NX-substituted succinimide is added dropwise at 15-30° C., wherein the molar ratio of the reactants is: the o-cresol: the diisopropylamine: the NX-substituted succinimide = 1: 0.1-0.3: 1.0-1.3.