A process for the preparation of 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol

Abstract

The present application belongs to the processing method related to the chemical field, and particularly relates to a preparation method of a monomer polyhydroxy phenolic compound 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol for resin. Under the catalysis of a solvent and a Lewis acid, 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol crude product is generated by the reaction of 2,6-dihydroxymethyl-p-cresol and resorcinol, and the 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol crude product is purified by using an acid-base extraction and a heating dissolution and crystallization post-processing mode, so that 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol pure product is obtained. In the present application, the Lewis acid is used as a catalyst to replace hydrochloric acid, sulfuric acid, p-toluenesulfonic acid and the like, so that the reaction selectivity can be greatly improved, the side reaction is reduced, and the crude product purity can reach 90-95%.

Description

TECHNICAL FIELD

[0001] The present application belongs to the processing method related to the chemical field, and especially relates to a preparation method of a monomer polyhydroxy phenolic compound 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol for resin. BACKGROUND

[0002] 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol, English name: 2,6-Bis(2,4-dihydroxybenzyl)-4-methylphenol, CAS number: 93933-64-3, molecular formula: C 21 H 20 O5, molecular weight: 352, is an important component in a photosensitive resin composition, and is widely used as a crosslinking agent in the photosensitive resin composition.

[0003] 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol is a polyphenolic compound, and the structure is as shown in the following formula, and is an important component of a polyimide photoresist in electronic chemicals, and is reported more in European and American patents, but the synthesis research of the substance is not many:

[0004]

[0005] 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol

[0006] There are few reports on the synthesis of 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol. European Patent EP0117759 reports that 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol is directly synthesized from 2,6-dihydroxymethyl-p-cresol and resorcinol in the presence of p-toluenesulfonic acid as a catalyst and ethanol as a solvent, and the solid product is precipitated by adding water after the ethanol is evaporated. However, the product obtained after the solvent is evaporated is an oil that does not precipitate when added to water, and the product has low purity and contains many impurities, so column chromatography is required to obtain a product with high purity, which is not suitable for industrial scale-up. In the literature Mol Divers (2011) 15:373-381, silica gel loaded with sulfuric acid is used for condensation reaction in 1,4-dioxane, and column chromatography is also required for purification, and the preparation process of silica gel loaded with sulfuric acid is complex and not suitable for industrial production. Patent WO9007538A1 also reports that 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol is directly synthesized from 2,6-dihydroxymethyl-p-cresol and resorcinol in the presence of p-toluenesulfonic acid as a catalyst and water as a solvent, and the product is precipitated directly from water and can be obtained by filtration. However, the patent also mentions that the purity of the product is only 83%, and the subsequent purification is not reported, so the product with such purity is difficult to apply to photosensitive resin. From the above related patent literatures, it can be seen that the main problem of the synthesis of 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol is that the product has low purity, and the post-treatment methods reported at present are not suitable for industrial large-scale production. SUMMARY

[0007] The purpose of the present application is to overcome the problems of low product purity and unsuitability for industrial scale-up in the post-treatment of 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol product preparation in the prior art, and a purification method for preparing 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol with high purity and suitable for industrial scale production is provided.

[0008] In order to achieve the above technical objectives, the present application adopts the following technical solutions:

[0009] A method for preparing 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol, which comprises reacting 2,6-dihydroxymethyl-p-cresol and resorcinol in the presence of a solvent and a Lewis acid catalyst to obtain 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol crude product, and purifying the 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol crude product by acid-base extraction and heating dissolution crystallization, to obtain 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol product.

[0010] Further, 2,6-dihydroxymethyl-p-cresol is added to a solvent, p- resorcinol is added under stirring, then a Lewis acid is added as a catalyst, and condensation reaction is carried out at 60-100℃ for 2-6h, the solvent is evaporated, water is added, and filtration is carried out to obtain 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol crude product.

[0011] The molar ratio of the resorcinol to 2,6-dihydroxymethyl-p-cresol is 10:1-20:1.

[0012] The molar amount of the Lewis acid is 0.1-1 times the molar amount of 2,6-dihydroxymethyl-p-cresol.

[0013] The Lewis acid is one or several of aluminum trichloride, iron trichloride or boron trifluoride.

[0014] The solvent is one or several of toluene, tetrahydrofuran or dichloroethane; the mass of the solvent is 6-10 times the mass of 2,6-dihydroxymethyl-p-cresol.

[0015] Further, the purification is as follows: 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol crude product is added to purified water, a base is added, dissolution is carried out under stirring, liquid separation is carried out after extraction with an organic solvent, the water layer is taken, an acid is added to the filtrate, the solid is precipitated after heating under stirring, dissolution is carried out, the solid is precipitated after cooling and crystallization, filtration is carried out, and drying is carried out to obtain 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol pure product.

[0016] In the purification process, when the crude product is added to purified water, the mass ratio of the purified water to the crude product is 1:5-1:10;

[0017] In the purification process, the base is one or several of sodium carbonate, sodium hydroxide, sodium methoxide or sodium bicarbonate; the molar ratio of the base to 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol crude product is 3:1-6:1.

[0018] In the purification process, the temperature for dissolving the crude product in the base water is 20-30℃.

[0019] In the purification process, the organic solvent used for extraction is one or several of ethyl acetate, toluene, dichloromethane or trichloromethane; the mass of the organic solvent is 5-10 times the mass of 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol crude product.

[0020] In the purification process, the acid added to the filtrate is one or several of hydrochloric acid, sulfuric acid or acetic acid; the molar amount ratio of the acid to the base is 1:1-2:1.

[0021] In the purification process, the temperature for dissolution and heating is 70-100℃.

[0022] The cooling crystallization is natural cooling crystallization or gradient cooling crystallization; wherein the natural cooling crystallization is natural cooling crystallization of the solution at 0-10 DEG C, stirring once for 3-5 hours, standing for 15-48 hours, and crystal washing with purified water, preferably the crystallization temperature condition is 3-5 DEG C, and the crystallization time is 24-36 hours; the gradient cooling crystallization is first constant temperature at 30-50 DEG C for 0.5-2 hours, then gradient cooling to 1-5 DEG C at 1-2 DEG C / min, and standing for 2-15 hours, and crystal washing with purified water.

[0023] The drying temperature in the purification process is 60-90 DEG C, and the drying time is 4-12 hours.

[0024] The present application has the advantages of:

[0025] 1. The present application uses Lewis acid as catalyst, instead of hydrochloric acid, sulfuric acid, p-toluene sulfonic acid, etc., which can greatly improve the reaction selectivity, reduce side reactions, and obtain a crude product with purity of 90-95%.

[0026] 2. The present application uses acid-base extraction and heating dissolution and crystallization for post-treatment and purification, which avoids the use of silica gel chromatographic column in the prior art, improves the product purity, and makes the process more suitable for industrial scale production, is simple to operate, reduces the discharge of three wastes, and reduces the production cost. BRIEF DESCRIPTION OF DRAWINGS

[0027] Figure 1 NMR spectrum of 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol prepared in Example 1. DETAILED DESCRIPTION

[0028] The specific embodiments of the present application are further described below in conjunction with examples, and it should be pointed out that the specific embodiments described herein are only for the purpose of illustrating and explaining the present application, and are not limited to the present application.

[0029] The method for preparing and purifying 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol described in the present application can obtain the target product with high purity and yield through a synthesis and purification process, the solvents used are safe and environmentally friendly, and easy to recycle, and the operation is simple, which is beneficial to large-scale production.

[0030] Example 1:

[0031] 2,6-dihydroxymethyl-p-cresol 100 g was added to solvent toluene 800 g, resorcinol 982 g was added under stirring, after stirring evenly, aluminum chloride 63.6 g was added, heating was started, after heating to 80 °C, temperature was kept for 4 h, HPLC was used to monitor the complete reaction of raw materials, temperature was decreased to room temperature, solvent was evaporated under reduced pressure, 1000 g of water was added, stirring was carried out for 1 h, filtration was carried out, 190.2 g of crude product was obtained, purity was 92.1% (HPLC);

[0032] Crude product purification: the obtained crude product 150 g was added to 750 g of water, sodium hydroxide 52.0 g was added, dissolution was carried out under stirring at 25 °C, 150 g of ethyl acetate was added, extraction and separation were carried out, 135.0 g of 36% hydrochloric acid was added to the water layer, a large amount of solid was precipitated, the temperature was increased to 70 °C under stirring, the solid was completely dissolved, natural cooling crystallization was carried out, the solution was cooled to 5 °C, natural cooling crystallization was carried out, stirring was carried out for 3 h, standing time was 24 h, then filtration was carried out, the filter cake was washed with a small amount of purified water, the product was dried under reduced pressure at 60 °C for 8 h, the weight was kept, 135.3 g of 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol product was obtained, the detection purity was 98.3% (HPLC).

[0033] Example 2:

[0034] 2,6-dihydroxymethyl-p-cresol 100 g was added to solvent dichloroethane 1000 g, resorcinol 654.7 g was added under stirring, after stirring evenly, iron trichloride 48.4 g was added, heating was started, after heating to 90 °C, temperature was kept for 3 h, HPLC was used to monitor the complete reaction of raw materials, temperature was decreased to room temperature, solvent was evaporated under reduced pressure, 1000 g of water was added, stirring was carried out for 1 h, filtration was carried out, 185.5 g of crude product was obtained, purity was 90.8% (HPLC);

[0035] Crude product purification: the crude product 150 g was added to 1000 g of water, sodium hydroxide 70 g was added, dissolution was carried out under stirring at 28 °C, 200 g of dichloromethane was added, extraction and separation were carried out, 160.5 g of 35% hydrochloric acid was added to the water layer, a large amount of solid was precipitated, the temperature was increased to 70 °C under stirring, the solid was completely dissolved, natural cooling crystallization was carried out, the solution was cooled to 5 °C, natural cooling crystallization was carried out, stirring was carried out for 5 h, standing time was 24 h, then filtration was carried out, the filter cake was washed with a small amount of purified water, the product was dried under vacuum at 60 °C for 6 h, the weight was kept, 138.5 g of product was obtained, the detection purity was 97.9% (HPLC).

[0036] Example 3:

[0037] 100g of 2,6-dihydroxymethyl-p-cresol was added to 800g of tetrahydrofuran solvent. 1309.5g of resorcinol was added under stirring. After stirring until homogeneous, 20.2g of boron trifluoride was added. Heating was started, and the temperature was raised to 70℃ and maintained for 5 hours. The reaction of the raw materials was monitored by HPLC until complete. The mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. 1000g of water was added, and the mixture was stirred for 1 hour. After filtration, 187.3g of crude product with a purity of 92.1% (HPLC) was obtained.

[0038] Crude product purification: 150g of the obtained crude product was added to 750g of water, 70.0g of sodium methoxide was added, and the mixture was stirred and dissolved at 22℃. 200g of ethyl acetate was added, and the mixture was extracted and separated. 160.5g of 35% hydrochloric acid was added to the aqueous layer, and a large amount of solid precipitated. The temperature was raised to 70℃ with stirring until all the solid dissolved. The crystallization was carried out by gradient cooling. First, the temperature was kept constant at 30℃ for 2h, and then the temperature was lowered at a gradient of 1℃ / min until it reached 5℃. The crystallization time was 15h. After filtration, the filter cake was washed with a small amount of purified water. The product was vacuum dried at 60℃ for 7h and weighed to constant weight to obtain 140.0g of product. The purity was determined to be 98.7% (HPLC).

[0039] Comparative Example 1

[0040] 100g of 2,6-dihydroxymethyl-p-cresol was added to 800g of toluene solvent. 982g of resorcinol was added while stirring. After stirring evenly, 20.5g of p-toluenesulfonic acid was added. Heating was started and the temperature was raised to 80℃. The temperature was maintained for 4 hours. The reaction of the raw materials was monitored by HPLC until it was complete. The temperature was lowered to room temperature, and the solvent was evaporated under reduced pressure. 1000g of water was added, and the mixture was stirred for 1 hour. After filtration, 150.2g of crude product with a purity of 85.5% (HPLC) was obtained.

[0041] Crude product purification: 150g of the obtained crude product was added to 750g of water, 52.0g of sodium hydroxide was added, and the mixture was stirred and dissolved at 25℃. 150g of ethyl acetate was added, and the mixture was extracted and separated. 135.0g of 36% hydrochloric acid was added to the aqueous layer, and a large amount of solid precipitated. The temperature was raised to 70℃ with stirring until all the solid dissolved. The mixture was allowed to cool naturally for crystallization. The solution was then cooled to 5℃ for natural cooling and crystallization. The mixture was stirred once every 3 hours and allowed to stand for 24 hours. The mixture was then filtered, and the filter cake was washed with a small amount of purified water. The product was dried under vacuum at 60℃ for 8 hours until constant weight was obtained, yielding 120.3g of product with a purity of 93.3% (HPLC).

[0042] Comparing Comparative Example 1 with Examples 1-3 above, it can be seen that when p-toluenesulfonic acid is used as a catalyst in Comparative Example 1, the purity of the crude product is 85.5%, while the purities of the crude products in Examples 1-3 of the present invention are 92.1%, 90.8%, and 92.1%, respectively. The purity of the pure product in Comparative Example 1 is only 93.3%, while the purities of the pure products in Examples 1-3 of the present invention are 98.3%, 97.9%, and 98.7%, respectively. It is evident that using Lewis acids as catalysts in Examples 1-3 of the present invention can significantly improve reaction selectivity and reduce side reactions.

Claims

1. A method for preparing 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol, characterized in that: 2,6-Dihydroxymethyl-4-cresol was added to a solvent, followed by the addition of hydroquinone under stirring. Lewis acid was then added as a catalyst, and the condensation reaction was carried out at 60-100℃ for 2-6 hours. The solvent was evaporated, and the product was added to water and filtered to obtain crude 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol. The crude 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol was purified by acid-base extraction and heating to dissolve and crystallize, thus obtaining pure 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol. The Lewis acid is one or more of aluminum trichloride, ferric trichloride, or boron trifluoride; Purification was performed by adding crude 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol to purified water, adding alkali and stirring to dissolve it, extracting it with an organic solvent, separating the liquid and collecting the aqueous layer, adding acid to the filtrate, precipitating a solid, heating with stirring to dissolve it, cooling to crystallize the precipitate, filtering, and drying to obtain pure 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol.

2. The method for preparing 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol according to claim 1, characterized in that: The molar ratio of resorcinol to 2,6-dihydroxymethyl-p-cresol is 10:1-20:1; the molar amount of Lewis acid is 0.1-1 times the molar amount of 2,6-dihydroxymethyl-p-cresol.

3. The method for preparing 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol according to claim 1, characterized in that: The solvent is one or more of toluene, tetrahydrofuran, or dichloroethane; the mass of the solvent is 6-10 times the mass of 2,6-dihydroxymethyl-p-cresol.

4. The method for preparing 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol according to claim 1, characterized in that: During the purification process, the crude product is added to the purified water, and the mass ratio of the purified water to the crude 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol is 1:5-1:

10. During the purification process, the alkali is one or more of sodium carbonate, sodium hydroxide, sodium methoxide, or sodium bicarbonate; the molar ratio of the alkali to crude 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol is 3:1-6:

1. The temperature at which the crude product dissolves in alkaline water during the purification process is 20-30℃; The organic solvent used in the purification process is one or more of ethyl acetate, toluene, dichloromethane or chloroform, and the mass of the organic solvent is 5-10 times the mass of the crude 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol. The acid added to the filtrate during the purification process is one or more of hydrochloric acid, sulfuric acid, or acetic acid, and the molar ratio of acid to base is 1:1 to 2:

1.

5. The method for preparing 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol according to claim 1, characterized in that: The dissolution temperature during purification is 70-100℃.

6. The method for preparing 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol according to claim 1, characterized in that: The cooling crystallization is either natural cooling crystallization or gradient cooling crystallization. Natural cooling crystallization involves placing the solution at 0-10℃ for natural cooling crystallization, stirring once every 3-5 hours, and letting it stand for 15-48 hours before washing the crystals with purified water. Gradient cooling crystallization involves first maintaining a constant temperature of 30-50℃ for 0.5-2 hours, and then cooling the solution at a gradient of 1-2℃ / min to 1-5℃ for 2-15 hours, followed by washing the crystals with purified water.

7. The method for preparing 2,6-bis(2,4-dihydroxybenzyl)-4-methylphenol according to claim 1, characterized in that: The drying temperature during purification is 60-90℃, and the drying time is 4-12 hours.

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