A method for synthesizing 4-[1,1-bis-(4-hydroxy-3-methylphenyl)-ethyl]-benzene-1,2-diol

Abstract

The invention relates to the field of chemical synthesis, and provides a method for synthesizing 4-[1,1-bis-(4-hydroxy-3-methylphenyl)-ethyl]-benzene-1,2-diol, comprising the following steps: 3,4-dimethoxyacetophenone and o-cresol react under an acidic catalyst to obtain an intermediate 4-[1,1-bis-(4-hydroxy-3-methylphenyl)-ethyl]-benzene-1,2-dimethyl ether, and then undergo a deetherification reaction to obtain a target product. The product has high purity, greater than 98%, and good economic practicality; a new and efficient synthesis method is provided for 4-[1,1-bis-(4-hydroxy-3-methylphenyl)-ethyl]-benzene-1,2-diol, which is simple to operate, has good process stability, and has a high reaction yield.

Description

Technical Field

[0001] The invention relates to the field of chemical synthesis, in particular to the field of synthesis of phenolic hydroxymethyl compounds, and specifically to a method for synthesizing 4-[1,1-bis-(4-hydroxy-3-methylphenyl)-ethyl]-benzene-1,2-diol. Background Art

[0002] 4-[1,1-Bis-(4-hydroxy-3-methylphenyl)-ethyl]-benzene-1,2-diol is a polyphenol compound that can be widely used in the synthesis of intermediates in chemical, pharmaceutical, and optoelectronic materials. In the microelectronics industry, it is mainly a synthetic material for photoresist sensitizer intermediates.

[0003] There is no literature report on the synthesis of this structure. There are some literatures with similar structures, but none of their processes can produce the target product. JPH06107577 discloses a method for reacting p-hydroxyacetophenone with o-cresol to obtain the following compound:

[0004]

[0005] Patent JP2014015446 discloses a method for reacting acetophenone with o-cresol to obtain the following compound:

[0006]

[0007] The synthesis reaction of the target compound belongs to the electrophilic substitution reaction of acetophenone derivatives and o-cresol. At the beginning of the research process, 3,4-dihydroxyacetophenone was used as a raw material to react with o-cresol, but most conditions did not produce the target product, and the main content of the product obtained under some conditions was very low. From the perspective of reaction mechanism, phenolic hydroxyl group has electron-donating property. When there are multiple (2 or more) phenolic hydroxyl groups on the substituent of acetophenone derivatives, the phenolic oxygen anion reduces the positive charge of the ketone carbon cation, reducing its reaction activity, so the target product cannot be obtained.

[0008] This problem is solved by using 3,4-dimethoxyacetophenone as a raw material. The derivative of acetophenone smoothly undergoes an electrophilic substitution reaction with o-cresol, and then a deetherification reaction is carried out using a known process to obtain the target product. Summary of the invention

[0009] Based on the above background technology, the purpose of the present invention is to provide a method for synthesizing 4,4'-methylenebis(2-hydroxymethyl-3,6-dimethylphenol), which has the characteristics of simple operation, economical and practical, few product by-products, high purity and high yield.

[0010] The present invention adopts the following technical solutions:

[0011] A method for synthesizing 4-[1,1-bis-(4-hydroxy-3-methylphenyl)-ethyl]-benzene-1,2-diol, wherein the following reaction occurs:

[0012]

[0013] The invention uses 3,4-dimethoxyacetophenone and o-cresol as raw materials, uses an acidic catalyst to catalyze, synthesizes an intermediate 4-[1,1-bis-(4-hydroxy-3-methylphenyl)-ethyl]-benzene-1,2-dimethyl ether, and then carries out a deetherification reaction through a known process to obtain a target product 4-[1,1-bis-(4-hydroxy-3-methylphenyl)-ethyl]-benzene-1,2-diol.

[0014] The invention has the beneficial effects of: high product purity, greater than 95%, good economical practicability; and provides a new synthesis method with simple operation, good process stability and high reaction yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 (a) Mass spectrum and (b) H NMR spectrum of the intermediate;

[0016] Figure 2 (a) Mass spectrum and (b) H NMR spectrum of the product. DETAILED DESCRIPTION

[0017] The present invention is specifically described below in conjunction with specific embodiments: the raw materials used are commercially available analytical grade reagents.

[0018] Example 1, Synthesis of Intermediates

[0019] In a 250ml four-necked bottle equipped with a thermometer, stirring and condensing device, add 27g (0.245mol) of o-cresol, 20g of dichloromethane, 4.7g (0.049mol) of methanesulfonic acid (catalyst), 10.12g (0.049mol) of dodecanethiol (co-catalyst), 9g (0.049mol) of 3,4-dimethoxyacetophenone, stir at elevated temperature, and react at an internal temperature of 40°C for 2h until the reaction is complete. After the reaction is complete, add 80ml of ethyl acetate, separate the layers, and wash the ethyl acetate layer with 1M sodium hydroxide solution, 0.5M hydrochloric acid, and water in turn; remove ethyl acetate by rotary evaporation at 40°C, cool and add 30ml of n-hexane, precipitate and filter to obtain 15.6g of white solid, HPLC98.05%, yield 84.32%. Liquid chromatography-mass spectrometry detection, negative mode 17.65min molecular weight 377, nuclear magnetic hydrogen spectrum confirms that the structure is correct and is the target intermediate (such as Figure 1 As shown) 4-[1,1-bis-(4-hydroxy-3-methylphenyl)-ethyl]-benzene-1,2-dimethyl ether.

[0020] Example 2, Synthesis of target product

[0021] The intermediate 4-[1,1-bis-(4-hydroxy-3-methylphenyl)-ethyl]-benzene-1,2-dimethyl ether 1g (0.00259mol) was added dropwise to a dichloromethane solution of boron tribromide (2.6g (0.01mol) of boron tribromide in dichloromethane 5ml) at -35°C. After the addition was completed, the mixture was stirred at room temperature for 3 hours and deetherified to obtain the target product, 4-[1,1-bis-(4-hydroxy-3-methylphenyl)-ethyl]-benzene-1,2-diol 0.82g, with a content of 98% and a yield of 88.5%. The structure was confirmed by LC-MS and NMR. LC-MS detection, negative mode 8.30min, molecular weight 349; NMR hydrogen spectrum confirmed that the structure was correct and was the target product (such as Figure 2 4-[1,1-bis-(4-hydroxy-3-methylphenyl)-ethyl]-benzene-1,2-diol.

[0022] Comparative Example:

[0023] The process and conditions are the same as those in Example 1, except that the main reaction raw material is 3,4-dihydroxyacetophenone, the amount of 3,4-dihydroxyacetophenone and o-cresol, as well as the types of acidic catalyst and co-catalyst, the specific reaction conditions and the raw materials and product structures are shown in the table below.

[0024]

[0025] 3,4-Dihydroxyacetophenone reacts with o-cresol, catalyzed by an acidic catalyst, as shown in the table.

[0026]

[0027] Example 3 Synthesis of Intermediate (4-[1,1-bis-(4-hydroxy-3-methylphenyl)-ethyl]-benzene-1,2-dimethyl ether)

[0028] In a 250ml four-necked bottle equipped with a thermometer, stirring and condensing device, add 43.2g (0.392mol) of o-cresol, 20g of dichloroethane, 2.35g (0.024mol) of methanesulfonic acid (catalyst), 5.05g (0.024mol) of dodecanethiol (cocatalyst), 9g (0.049mol) of 3,4-dimethoxyacetophenone, stir at elevated temperature, and react at an internal temperature of 60°C for 1.5h until the reaction is complete. After the reaction is complete, add 80ml of dichloroethane, separate the layers, and wash the organic layer with 1M sodium hydroxide solution, 0.5M hydrochloric acid, and water in turn; remove ethyl acetate by rotary evaporation at 40°C, cool and add 30ml of n-hexane, precipitate and filter to obtain 15g of white solid, HPLC97.5%, yield 81.08%.

[0029] Example 4 Synthesis of Intermediate (4-[1,1-bis-(4-hydroxy-3-methylphenyl)-ethyl]-benzene-1,2-dimethyl ether)

[0030] In a 250ml four-necked bottle equipped with a thermometer, stirring and condensing device, add 84.7g (0.783mol) of o-cresol, 4.7g (0.049mol) of methanesulfonic acid (catalyst), 2.53g (0.012mol) of dodecanethiol (co-catalyst), 9g (0.049mol) of 3,4-dimethoxyacetophenone, stir at elevated temperature, and react at an internal temperature of 40°C for 2.5h until the reaction is complete. After the reaction is complete, add 80ml of ethyl acetate, separate the layers, and wash the organic layer with 1M sodium hydroxide solution, 0.5M hydrochloric acid, and water in sequence; remove ethyl acetate by rotary evaporation at 40°C, cool and add 30ml of n-hexane, precipitate and filter to obtain 14.3g of white solid, HPLC97.2%, yield 77.3%.

[0031] Example 5 Synthesis of Intermediate (4-[1,1-bis-(4-hydroxy-3-methylphenyl)-ethyl]-benzene-1,2-dimethyl ether)

[0032] In a 250ml four-necked bottle equipped with a thermometer, stirring and condensing device, add 42.34g (0.392mol) of o-cresol, 20g of toluene, 0.941g (0.010mol) of methanesulfonic acid (catalyst), 2.02g (0.010mol) of dodecanethiol (cocatalyst), 9g (0.049mol) of 3,4-dimethoxyacetophenone, stir at elevated temperature, and react at an internal temperature of 40°C for 3h until the reaction is complete. After the reaction is complete, add 80ml of ethyl acetate, separate the layers, and wash the organic layer with 1M sodium hydroxide solution, 0.5M hydrochloric acid, and water in turn; remove ethyl acetate by rotary evaporation at 40°C, cool and add 30ml of n-hexane, precipitate and filter to obtain 11.5g of white solid, HPLC97.2%, yield 62.16%.

[0033] Example 6 Synthesis of Intermediate (4-[1,1-bis-(4-hydroxy-3-methylphenyl)-ethyl]-benzene-1,2-dimethyl ether)

[0034] In a 250ml four-necked bottle equipped with a thermometer, stirring and condensing device, add 42.34g (0.392mol) of o-cresol, 20g of acetonitrile, 1.41g (0.015mol) of methanesulfonic acid (catalyst), 9g (0.049mol) of 3,4-dimethoxyacetophenone, stir at a temperature of 40℃, and react for 3h until the reaction is completed. After the reaction is completed, add 80ml of ethyl acetate, separate the layers, and wash the organic layer with 1M sodium hydroxide solution, 0.5M hydrochloric acid, and water in sequence; remove the ethyl acetate by rotary evaporation at 40℃, cool down and add 30ml of n-hexane, precipitate and filter to obtain 10.5g of white solid, HPLC 97.5%, yield 56.76%.

[0035] Example 7 Synthesis of Intermediate (4-[1,1-bis-(4-hydroxy-3-methylphenyl)-ethyl]-benzene-1,2-dimethyl ether)

[0036] In a 250ml four-necked bottle equipped with a thermometer, stirring and condensing device, add 26.46g (0.245mol) of o-cresol, 20g of acetonitrile, 4.7g (0.049mol) of methanesulfonic acid (catalyst), 4.65g (0.049mol) of 3-mercaptopropionic acid (co-catalyst), 9g (0.049mol) of 3,4-dimethoxyacetophenone, stir at a temperature of 40°C, and react for 3h until the reaction is completed. After the reaction is completed, add 80ml of ethyl acetate, separate the layers, and wash the organic layer with 1M sodium hydroxide solution, 0.5M hydrochloric acid, and water in turn; remove ethyl acetate by rotary evaporation at 40°C, cool and add 30ml of n-hexane, precipitate and filter to obtain 11.7g of white solid, HPLC96.5%, yield 63.24%.

[0037] Example 8, Synthesis of Intermediate (4-[1,1-bis-(4-hydroxy-3-methylphenyl)-ethyl]-benzene-1,2-dimethyl ether)

[0038] In a 250ml four-necked bottle equipped with a thermometer, stirring and condensing device, add 27g (0.245mol) of o-cresol, 20g of dichloromethane, 8.43g (0.049mol) of p-toluenesulfonic acid (catalyst), 10.12g (0.049mol) of dodecanethiol (cocatalyst), 9g (0.049mol) of 3,4-dimethoxyacetophenone, stir at a temperature of 40℃, and react for 2h until the reaction is completed. After the reaction is completed, add 80ml of dichloromethane, separate the layers, and wash the organic layer with 1M sodium hydroxide solution, 0.5M hydrochloric acid, and water in turn; remove ethyl acetate by rotary evaporation at 40℃, cool and add 30ml of n-hexane, precipitate and filter to obtain 12.1g of white solid, HPLC97.2%, yield 65.414%.

[0039] Example 9 Synthesis of Intermediate (4-[1,1-bis-(4-hydroxy-3-methylphenyl)-ethyl]-benzene-1,2-dimethyl ether)

[0040] In a 250ml four-necked bottle equipped with a thermometer, stirring and condensing device, add 13.5g (0.122mol) of o-cresol, 20g of dichloromethane, 4.7g (0.049mol) of methanesulfonic acid (catalyst), 10.11g (0.049mol) of dodecanethiol (cocatalyst), 9g (0.049mol) of 3,4-dimethoxyacetophenone, stir at the temperature of 40℃, and react for 2h until the reaction is completed. After the reaction is completed, add 80ml of dichloromethane, separate the layers, and wash the organic layer with 1M sodium hydroxide solution, 0.5M hydrochloric acid, and water in turn; remove ethyl acetate by rotary evaporation at 40℃, cool down and add 30ml of n-hexane, precipitate and filter to obtain 6.9g of white solid, HPLC45.7%, yield 37.30%.

[0041] Example 10 Synthesis of Intermediate (4-[1,1-bis-(4-hydroxy-3-methylphenyl)-ethyl]-benzene-1,2-dimethyl ether)

[0042] In a 250ml four-necked bottle equipped with a thermometer, stirring and condensing device, add 27g (0.245mol) of o-cresol, 20g of dichloromethane, 0.47g (0.0049mol) of methanesulfonic acid (catalyst), 1.01g (0.0049mol) of dodecanethiol (cocatalyst), 9g (0.049mol) of 3,4-dimethoxyacetophenone, stir at elevated temperature, and react at an internal temperature of 40°C for 4h until the reaction is complete. After the reaction is complete, add 80ml of dichloromethane, separate the layers, and wash the organic layer with 1M sodium hydroxide solution, 0.5M hydrochloric acid, and water in turn; remove ethyl acetate by rotary evaporation at 40°C, cool and add 30ml of n-hexane, precipitate and filter to obtain 5.2g of white solid, HPLC97.6%, yield 28.11%.

[0043] Example 11 Synthesis of Intermediate (4-[1,1-bis-(4-hydroxy-3-methylphenyl)-ethyl]-benzene-1,2-dimethyl ether)

[0044] In a 250ml four-necked bottle equipped with a thermometer, stirring and condensing device, add 27g (0.245mol) of o-cresol, 20g of acetonitrile, 4.83g (0.049mol) of concentrated hydrochloric acid (catalyst) with a mass concentration of 37%, 10.11g (0.049mol) of dodecanethiol (cocatalyst), 9g (0.049mol) of 3,4-dimethoxyacetophenone, stir at a temperature of 40℃, and react for 4h. After the reaction, add 80ml of ethyl acetate, separate the layers, and wash the organic layer with 1M sodium hydroxide solution, 0.5M hydrochloric acid, and water in turn; remove ethyl acetate by rotary evaporation at 40℃, cool and add 30ml of n-hexane, precipitate and filter to obtain 3.5g of white solid, HPLC 35.6%, yield 18.92%.

[0045] Example 12 Synthesis of Intermediate (4-[1,1-bis-(4-hydroxy-3-methylphenyl)-ethyl]-benzene-1,2-dimethyl ether)

[0046] In a 250ml four-necked bottle equipped with a thermometer, stirring and condensing device, add 27g (0.245mol) of o-cresol, 20g of toluene, 4.83g (0.049mol) of methanesulfonic acid (catalyst), 10.11g (0.049mol) of dodecanethiol (cocatalyst), 9g (0.049mol) of 3,4-dimethoxyacetophenone, stir at elevated temperature, and react at an internal temperature of 80°C for 2h until the reaction is complete. After the reaction is complete, add 80ml of ethyl acetate, separate the layers, and wash the organic layer with 1M sodium hydroxide solution, 0.5M hydrochloric acid, and water in turn; remove ethyl acetate by rotary evaporation at 40°C, cool and add 30ml of n-hexane, precipitate and filter to obtain 8.9g of white solid, HPLC 75.4%, yield 48.11%.

[0047] Example 13 Synthesis of Intermediate (4-[1,1-bis-(4-hydroxy-3-methylphenyl)-ethyl]-benzene-1,2-dimethyl ether)

[0048] In a 250ml four-necked bottle equipped with a thermometer, stirring and condensing device, add 27g (0.245mol) of o-cresol, 20g of toluene, 4.83g (0.049mol) of methanesulfonic acid (catalyst), 10.11g (0.049mol) of dodecanethiol (co-catalyst), 9g (0.049mol) of 3,4-dimethoxyacetophenone, stir at elevated temperature, and react at an internal temperature of 20°C for 5h until the reaction is complete. After the reaction is complete, add 80ml of ethyl acetate, separate the layers, and wash the organic layer with 1M sodium hydroxide solution, 0.5M hydrochloric acid, and water in turn; remove ethyl acetate by rotary evaporation at 40°C, cool and add 30ml of n-hexane, precipitate and filter to obtain 6.5g of white solid, HPLC 75.4%, yield 35.14%.

[0049] Intermediate Example Data Table:

[0050]

[0051] Note: "mol ratio" in the above table refers to the mol ratio to 3,4-dimethoxyacetophenone.

[0052] From the results in the table above, we can see that: as a catalyst, methanesulfonic acid is better than p-toluenesulfonic acid; better than concentrated hydrochloric acid; the yield is low without adding a promoter, and the promoter dodecanethiol is better than 3-mercaptopropionic acid; too much or too little amount of catalyst and promoter affects the yield. The yield is the best at 40℃, the yield is low at 80℃, and the yield is low at 20℃.

[0053] Of course, the above description is not a limitation of the present invention, and the present invention is not limited to the above examples. Changes, modifications, additions or substitutions made by technicians in this technical field within the essential scope of the present invention should also fall within the protection scope of the present invention.

Claims

1. A method for synthesizing 4-[1,1-bis-(4-hydroxy-3-methylphenyl)-ethyl]-benzene-1,2-diol, characterized in that: The intermediate 4-[1,1-bis-(4-hydroxy-3-methylphenyl)-ethyl]-benzene-1,2-dimethyl ether was synthesized with 3,4-dimethoxyacetophenone and o-cresol as raw materials, and then the target product 4-[1,1-bis-(4-hydroxy-3-methylphenyl)-ethyl]-benzene-1,2-diol was obtained through deetherification reaction.

2. The synthesis method according to claim 1, characterized in that The following reaction occurs:

3. The synthesis method according to claim 1, characterized in that The process of synthesizing the intermediate 4-[1,1-bis-(4-hydroxy-3-methylphenyl)-ethyl]-benzene-1,2-dimethyl ether is carried out in the presence of a catalyst, and the catalyst is an acidic catalyst, such as one or more of an inorganic acid and an organic acid such as sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, etc.; The molar ratio of the acid catalyst to 3,4-dimethoxyacetophenone is 0.2-5, preferably 0.5-4, more preferably 0.8-2.

4. The synthesis method according to claim 1, characterized in that In the process of synthesizing the intermediate 4-[1,1-bis-(4-hydroxy-3-methylphenyl)-ethyl]-benzene-1,2-dimethyl ether, no solvent or a solvent may be added to the reaction system, and the added solvent is one or more organic solvents selected from the group consisting of dichloromethane, dichloroethane, chloroform, acetonitrile, benzene, toluene, chlorobenzene, nitrobenzene, methyl tert-butyl ether and the like.

5. The synthesis method according to claim 1 or 3, characterized in that: In the process of synthesizing the intermediate 4-[1,1-bis-(4-hydroxy-3-methylphenyl)-ethyl]-benzene-1,2-dimethyl ether, a promoter may be added or not added to the reaction system, the acid catalyst may be used together with the promoter, and the promoter is one or more of mercaptan derivatives or mercaptopropionic acids, such as one or more of ethyl mercaptan, dodecanethiol, 3-mercaptopropionic acid, etc.; The molar ratio of the co-catalyst to 3,4-dimethoxyacetophenone is 0.2-5, preferably 0.5-4, more preferably 1-3.

6. The synthesis method according to claim 1, characterized in that The molar ratio of o-cresol to 3,4-dimethoxyacetophenone is 4-20, preferably 4-10, more preferably 5-8.

7. The synthesis method according to claim 1 or 4, characterized in that: The mass ratio of 3,4-dimethoxyacetophenone to the solvent is 1:1-1:5, preferably 1:1-1:4, and more preferably 1:2-1:

3.

8. The synthesis method according to any one of claims 1 to 7, characterized in that: The process of synthesizing the intermediate 4-[1,1-bis-(4-hydroxy-3-methylphenyl)-ethyl]-benzene-1,2-dimethyl ether, the reaction conditions are: the reaction temperature is 20-100° C., preferably 30-75° C., more preferably 40-60° C.; The reaction time is 1-40 h, preferably 1-10 h, more preferably 2-6 h.

9. The synthesis method according to claim 1, characterized in that After the process of synthesizing the intermediate 4-[1,1-bis-(4-hydroxy-3-methylphenyl)-ethyl]-benzene-1,2-dimethyl ether is completed, dichloromethane or ethyl acetate is added, and the organic layers are separated and washed with 0.3-1.5M sodium hydroxide solution, 0.05-1M hydrochloric acid, and water in sequence; the solvent is removed by rotary evaporation, n-hexane is added at a reduced temperature, and the precipitate is filtered to obtain a solid product.

10. The synthesis method according to claim 1, characterized in that Deetherification reaction: 1 g of the intermediate 4-[1,1-bis-(4-hydroxy-3-methylphenyl)-ethyl]-benzene-1,2-dimethyl ether is dissolved in 5-50 ml of a solvent (one or more of dichloromethane, dioxane, tetrahydrofuran, dichloroethane, anhydrous ethers, etc.), and 0.3-3 g of boron tribromide (preferably 0.65-2, more preferably 0.98-1.63) is added. The reaction is catalyzed by boron tribromide and the reaction is carried out at a low temperature of -80 to 30°C (preferably -80 to 25, more preferably -70 to 20) to remove the ether, thereby obtaining the target product.

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