Preparation method of phenylethyl resorcinol

Abstract

The invention provides a preparation method of phenethyl resorcinol, which comprises the following steps: under the catalytic action of an acid catalyst, m-hydroxybenzaldehyde and 1-phenylethanol react in a first solvent at the first reaction temperature of 60-110 DEG C to obtain an intermediate, after the intermediate, alkali and a second solvent are added into a first reaction flask, the intermediate is subjected to a reaction at the first reaction temperature of 60-110 DEG C to obtain the phenethyl resorcinol. Hydrogen peroxide is dropwise added into the first reaction bottle, so that phenethyl resorcinol is generated from the intermediate, and the second reaction temperature is 10-25 DEG C. The preparation method provided by the invention is beneficial to improvement of reaction selectivity and reduction of the probability of generation of byproducts.

Description

Technical Field

[0001] The invention relates to the technical field of organic chemical synthesis, and in particular to a method for preparing phenethyl resorcinol. Background Art

[0002] In the currently disclosed synthesis method of phenethyl resorcinol, phenethyl resorcinol is synthesized in one step by alkylation reaction of resorcinol and styrene. The benzene ring in resorcinol is highly active and can react at every position. The generated phenethyl group causes the product to be more active than resorcinol, and then generates disubstituted or even trisubstituted impurities, which leads to low selectivity of the reaction, low raw material utilization, many impurities, low conversion rate, and complex and difficult purification. The molar ratio of resorcinol: styrene is much higher than the theoretical amount of 1:1, which also increases the production cost. Summary of the invention

[0003] In order to overcome the deficiencies of the prior art, the object of the present invention is to provide a method for preparing phenethyl resorcinol which is beneficial to improving reaction selectivity and reducing the probability of generating by-products.

[0004] To solve the above problems, the technical solution adopted by the present invention is as follows:

[0005] A method for preparing phenethyl resorcinol comprises the following steps:

[0006] Under the catalytic action of an acid catalyst, m-hydroxybenzaldehyde and 1-phenylethanol react in a first solvent to obtain an intermediate, and the first reaction temperature is 60° C. to 110° C.;

[0007] After the intermediate, the base and the second solvent are added into the first reaction bottle, hydrogen peroxide is added dropwise into the first reaction bottle so that the intermediate generates phenethyl resorcinol, and the second reaction temperature is 10° C.-25° C.

[0008] In some possible implementations, the acid catalyst is selected from at least one of sulfuric acid, p-toluenesulfonic acid, aminosulfonic acid, phosphoric acid or hydrochloric acid, and the amount of the acid catalyst added is 0.05-0.1 times the molar equivalent of the m-hydroxybenzaldehyde.

[0009] In some possible implementations, the molar ratio of the m-hydroxybenzaldehyde to the 1-phenylethanol is 1.1:1-1.2:1.

[0010] In some possible implementations, the molar ratio of the intermediate, the base and the hydrogen peroxide is 1:1:2-1:1:5.

[0011] In some possible embodiments, the base is selected from at least one of sodium hydroxide, potassium hydroxide, sodium bicarbonate or potassium bicarbonate.

[0012] In some possible embodiments, the first solvent is selected from at least one of toluene, tetrahydrofuran, acetonitrile or N,N-dimethylformamide, and the second solvent is selected from at least one of acetonitrile, tetrahydrofuran, methanol or water.

[0013] In some possible embodiments, the step of obtaining the intermediate comprises:

[0014] Adding the m-hydroxybenzaldehyde, the acid catalyst and the first solvent into the second reaction bottle, heating the reaction bottle to the first reaction temperature and reflux;

[0015] The 1-phenylethanol is added dropwise to the second reaction bottle for reaction, and the reaction is kept warm for 2.8-3.2 hours after the addition is completed.

[0016] In some possible embodiments, the step of obtaining the intermediate further comprises:

[0017] After the reaction of the liquid phase detection reaction system is completed, the pH value of the system is adjusted to 7;

[0018] The first solvent is removed by rotary evaporation to obtain the intermediate.

[0019] In some possible embodiments, the step of obtaining the phenethyl resorcinol comprises:

[0020] Add the intermediate and the second solvent into the first reaction bottle, and cool to 10°C-12°C;

[0021] Then, the alkaline solution is added to the first reaction bottle at a controlled dropping speed so that the dropping temperature is maintained below 15° C. After the dropping is completed, the solution is kept at 15° C. and stirred for 20-40 minutes;

[0022] Then, the hydrogen peroxide is dripped into the first reaction bottle at a controlled dripping speed so that the dripping temperature is maintained below 25° C. After the dripping is completed, the reaction is kept at 25° C. for 1.8-2 hours.

[0023] In some possible embodiments, the step of obtaining the phenethyl resorcinol further comprises:

[0024] After the liquid phase detection reaction is completed, the pH value of the system is adjusted to 7;

[0025] Then, a solid crude product is obtained by extraction and rotary evaporation;

[0026] Add ethyl acetate 3 times the weight of the crude solid product, stir and heat to 77°C for 50-70 minutes, cool to 13°C-17°C and stir for 20-40 minutes, separate the solid and liquid to obtain a separated solid;

[0027] The separated solid was washed with ethyl acetate and dried to obtain solid phenethyl resorcinol.

[0028] Compared with the prior art, the present invention has the following beneficial effects:

[0029] In the present application, the acid catalyst can protonate the hydroxyl group of 1-phenylethanol, and then 1-phenylethanol and m-hydroxybenzaldehyde undergo an electrophilic substitution reaction. Due to the conjugation effect of the hydroxyl group, aldehyde group and benzene ring, the electron cloud density of the para position of the aldehyde group and one of the ortho positions of the hydroxyl group is significantly increased, so that the electrophilic substitution reaction mainly occurs at this site, while the other sites on the benzene ring have the opposite effect of the conjugation effect caused by the hydroxyl group and aldehyde group, resulting in a relatively low electron cloud density, which is not conducive to the occurrence of electrophilic substitution reactions. In addition, the target product can be obtained by alkaline hydrolysis after the aldehyde group and hydrogen peroxide of the intermediate undergo Baeyer-Villiger reaction. Therefore, the present application controls the reaction site by selecting reactants of specific structure to obtain an intermediate of specific structure, and selects a specific reaction so that one of the intermediate sites is reacted and converted to obtain a product, so that the preparation method provided by the present application is conducive to improving the reaction selectivity and reducing the probability of producing by-products.

[0030] The present invention is further described in detail below in conjunction with the accompanying drawings and specific embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 A synthetic route diagram provided for an embodiment of the present application;

[0032] Figure 2 A flow chart of a preparation method provided in one embodiment of the present application;

[0033] Figure 3 H NMR spectrum of the intermediate prepared in this application;

[0034] Figure 4 This is the hydrogen nuclear magnetic resonance spectrum of phenethyl resorcinol prepared in this application. DETAILED DESCRIPTION

[0035] The following will be combined with the drawings in the embodiments of the present application to clearly and completely describe the technical solutions in the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, not all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of this application.

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in the specification of the present invention herein are only for the purpose of describing specific embodiments and are not intended to limit the present invention. In the absence of conflict, the following embodiments and features in the embodiments may be combined with each other.

[0037] An embodiment of the present application provides a method for preparing phenethyl resorcinol, comprising the following steps:

[0038] Step S101: Under the catalytic action of an acid catalyst, m-hydroxybenzaldehyde and 1-phenylethanol react in a first solvent to obtain an intermediate, and the first reaction temperature is 60° C. to 110° C.

[0039] In some embodiments, the step of obtaining the intermediate specifically comprises:

[0040] Add the m-hydroxybenzaldehyde, the acid catalyst and the first solvent into the second reaction bottle, and heat the bottle to the first reaction temperature for reflux.

[0041] The 1-phenylethanol is added dropwise to the second reaction bottle for reaction, and the reaction is kept warm for 2.8-3.2 hours after the addition is completed.

[0042] The process parameters of this step are conducive to improving the conversion rate of the reactants.

[0043] In some embodiments, the step of obtaining the intermediate further comprises:

[0044] After the reaction of the liquid phase detection reaction system is completed, the pH value of the system is adjusted to 7.

[0045] The first solvent is removed by rotary evaporation to obtain the intermediate.

[0046] This step can prevent the first solvent from participating in subsequent reactions and affecting the yield of the target product.

[0047] In some embodiments, the acid catalyst is selected from at least one of sulfuric acid, p-toluenesulfonic acid, aminosulfonic acid, phosphoric acid or hydrochloric acid, and the above acid catalysts have good protonation efficiency, thereby improving the reaction efficiency. The amount of the acid catalyst added is 0.05-0.1 times the molar equivalent of the m-hydroxybenzaldehyde.

[0048] In some embodiments, the molar ratio of the m-hydroxybenzaldehyde to the 1-phenylethanol is 1.1: 1-1.2: 1. The present application can obtain a higher conversion rate through a lower reactant ratio, thereby helping to reduce production costs.

[0049] In some embodiments, the first solvent is selected from at least one of toluene, tetrahydrofuran, acetonitrile, or N,N-dimethylformamide.

[0050] Step S102: After adding the intermediate, the base and the second solvent into the first reaction bottle, hydrogen peroxide is added dropwise into the first reaction bottle to generate phenylethyl resorcinol from the intermediate, and the second reaction temperature is 10° C. to 25° C. For example, the base can be prepared into a base solution before adding to the reaction system.

[0051] In some embodiments, the specific steps of obtaining the phenethyl resorcinol include:

[0052] Add the intermediate and the second solvent into the first reaction bottle and cool to 10°C-12°C.

[0053] Then, the alkaline solution is added to the first reaction bottle at a controlled dropping speed so that the dropping temperature is maintained below 15° C. After the dropping is completed, the solution is kept at 15° C. and stirred for 20-40 minutes.

[0054] Then, the hydrogen peroxide is dripped into the first reaction bottle at a controlled dripping speed so that the dripping temperature is maintained below 25° C. After the dripping is completed, the reaction is kept at 25° C. for 1.8-2 hours.

[0055] In some embodiments, the step of obtaining the phenethyl resorcinol further comprises:

[0056] After the liquid phase detection reaction is completed, the pH value of the system is adjusted to 7.

[0057] Then, a solid crude product was obtained by extraction and rotary evaporation.

[0058] Add ethyl acetate in an amount 3 times the weight of the crude solid product, stir and heat to 77° C. for 50-70 minutes, cool to 13° C.-17° C. and stir for 20-40 minutes, and separate the solid and liquid to obtain a separated solid.

[0059] The separated solid was washed with ethyl acetate and dried to obtain solid phenethyl resorcinol.

[0060] In some embodiments, the molar ratio of the intermediate, the base and the hydrogen peroxide is 1:1:2-1:1:5.

[0061] In some embodiments, the base is selected from at least one of sodium hydroxide, potassium hydroxide, sodium bicarbonate or potassium bicarbonate. Selecting a strong base is beneficial to improving the efficiency of alkaline hydrolysis, thereby improving the efficiency of obtaining the target product.

[0062] In some embodiments, the second solvent is selected from at least one of acetonitrile, tetrahydrofuran, methanol or water. The specific selection of the above solvent is convenient for subsequent removal through relatively simple steps, thereby facilitating the simplicity of purification and separation of the target product.

[0063] In the present application, the acid catalyst can protonate the hydroxyl group of 1-phenylethanol, and then 1-phenylethanol and m-hydroxybenzaldehyde undergo an electrophilic substitution reaction. Due to the conjugation effect of the hydroxyl group, aldehyde group and benzene ring, the electron cloud density of the para position of the aldehyde group and one of the ortho positions of the hydroxyl group is significantly increased, so that the electrophilic substitution reaction mainly occurs at this site, while the other sites on the benzene ring have the opposite effect of the conjugation effect caused by the hydroxyl group and aldehyde group, resulting in a relatively low electron cloud density, which is not conducive to the occurrence of electrophilic substitution reactions. In addition, the target product can be obtained by alkaline hydrolysis after the aldehyde group and hydrogen peroxide of the intermediate undergo Baeyer-Villiger reaction. Therefore, the present application controls the reaction site by selecting reactants of specific structure to obtain an intermediate of specific structure, and selects a specific reaction so that one of the intermediate sites is reacted and converted to obtain a product, so that the preparation method provided by the present application is conducive to improving the reaction selectivity and reducing the probability of producing by-products.

[0064] Specific

[0065] Embodiment 1:

[0066] 599.78g of m-hydroxybenzaldehyde, 41.45g of 36% hydrochloric acid and 1.8L of acetonitrile were added to the second reaction bottle, stirred and heated to 82°C for reflux, 500g of 1-phenylethanol was added dropwise, and the reaction was kept warm for 3 hours after the addition. After the liquid phase detection reaction was completed, the pH value of the system was adjusted to 7 with 10% sodium hydroxide aqueous solution, and the 950g crude intermediate obtained after the acetonitrile was evaporated at 70°C was used for the next step. The content was measured and converted to about 840g of the intermediate in the crude product, and then the amount of material used in the next step was determined. In this step, the corresponding amount of hydrochloric acid added was 0.1 times the molar equivalent of m-hydroxybenzaldehyde. The molar ratio of the m-hydroxybenzaldehyde to the 1-phenylethanol was 1.2:1.

[0067] The intermediate crude product and 4L water are put into the first reaction bottle and cooled to 10 ° C. 148.48g of sodium hydroxide solid is dissolved in 200mL of water and added dropwise to the first reaction bottle. The flow rate is controlled to control the temperature below 15 ° C. After the dripping, stir at 15 ° C for 0.5 hours. 1.87kg of 27% hydrogen peroxide is added dropwise, and the flow rate is controlled to control the temperature below 25 ° C. After the dripping, the reaction is kept at 25 ° C for 2 hours. After the liquid phase detection reaction is completed, the pH value of the system is adjusted to 7 with acetic acid, extracted twice with 4L of dichloromethane, and the organic phase is dried and then the dichloromethane is evaporated at 40 ° C to obtain a solid crude product. Add ethyl acetate 3 times the weight of the crude solid product, stir and heat to 77°C for 1 hour, cool to 15°C and stir for 0.5 hour, separate the solid and liquid to obtain a separated solid, rinse the separated solid once with ethyl acetate, and dry the solid to obtain a beige solid product, phenylethyl resorcinol, with a liquid phase detection purity of 99.2% and a second step molar yield of 86.68%.

[0068] In this step, the molar ratio of the intermediate, the base and the hydrogen peroxide is 1:1:4.

[0069] Embodiment 2:

[0070] 599.78g of m-hydroxybenzaldehyde, 40.13g of concentrated sulfuric acid (concentration of 99% (mass fraction)) and 2.4L of tetrahydrofuran were added to the second reaction bottle, stirred and heated to 66°C for reflux, 500g of 1-phenylethanol was added dropwise, and the reaction was kept warm for 3 hours after the addition. After the liquid phase detection reaction was completed, the pH value of the system was adjusted to 7 with a 10% sodium hydroxide aqueous solution, and 1kg of crude intermediate was obtained after tetrahydrofuran was evaporated at 60°C for the next step. The crude product contained about 827g of intermediate, and the amount of material for the next step was determined. In this step, the amount of concentrated sulfuric acid added was 0.1 times the molar equivalent of m-hydroxybenzaldehyde. The molar ratio of m-hydroxybenzaldehyde to 1-phenylethanol was 1.2:1. The reagents used in the specific embodiments of the present application are all conventional reagents, which can be purchased from the market, so the specific purchase manufacturer and the corresponding CAS number are not repeated.

[0071] Put the intermediate crude product and 3.6L methanol into the first reaction bottle, cool to 10 ° C, dissolve 146.18g sodium hydroxide solid in 200mL water, add it dropwise into the first reaction bottle, control the flow rate to control the temperature below 15 ° C, and stir at 15 ° C for 0.5 hours after the drop is completed. Add 2.3kg of hydrogen peroxide with a concentration of 27%, control the flow rate to control the temperature below 25 ° C, and keep it at 25 ° C for 2 hours after the drop is completed. After the liquid phase detection reaction is completed, adjust the pH to 7 with an appropriate amount of hydrochloric acid, and evaporate the methanol at 60 ° C to obtain a crude product. Extract twice with 4 times the weight of dichloromethane and 4 times the weight of water of the crude product, dry the organic phase, and evaporate the dichloromethane at 40 ° C to obtain a solid crude product. Add ethanol 3 times the weight of the solid crude product, stir and heat to 78°C for 1 hour, cool to 15°C and stir for 0.5 hour, separate the solid and liquid to obtain a separated solid, rinse the separated solid once with ethanol, and dry the solid to obtain a beige solid product, phenylethyl resorcinol, with a liquid phase detection purity of 99.4% and a second step molar yield of 85.51%.

[0072] In this step, the molar ratio of the intermediate, the base and the hydrogen peroxide is 1:1:5.

[0073] The nuclear magnetic resonance hydrogen spectra of the intermediate and phenethyl resorcinol obtained in the above examples of the present application are as follows: Figure 3 and Figure 4 As shown. Through the displacement, splitting fraction and number of peaks in the hydrogen nuclear magnetic resonance spectrum, it can be known that the intermediate and phenethyl resorcinol of the above target structure are prepared in the present application. Specifically, refer to Figure 3 The chemical shift corresponding to region A is 5.61, and the number of hydrogen is 1, which corresponds to the hydrogen at position 6 of the benzene ring. The chemical shift corresponding to region B is 1.59, and the number of hydrogen is 3, which corresponds to the hydrogen on the methyl group. The chemical shifts corresponding to regions C, D, and E are 7.27, 7.35, and 7.44, and the number of hydrogen is 9, which corresponds to the hydrogen at positions 3, 5, 6, 7, 13, 14, 15, 16, and 17. The chemical shift corresponding to region F is 9.93, and the number of hydrogen is 1, which corresponds to the hydrogen at position 8.

[0074] Reference Figure 4 The chemical shift corresponding to region A is 9.13, and the number of hydrogen is 1, which corresponds to the hydrogen at position 8 of the benzene ring. The chemical shift corresponding to region B is 9, and the number of hydrogen is 1, which corresponds to the hydrogen at position 7. The chemical shifts corresponding to regions C, D, E, F, and G are 7.22, 7.11, 6.87, 6.28, and 6.19, and the number of hydrogen is 9, which corresponds to the hydrogen at positions 3, 5, 6, 12, 13, 14, 15, and 16. The chemical shift corresponding to region H is 4.34, and the number of hydrogen is 1, which corresponds to the hydrogen at position 9. The chemical shift corresponding to region I is 1.46, and the number of hydrogen is 3, which corresponds to the hydrogen atoms on the methyl group.

[0075] The above-mentioned embodiments are only preferred embodiments of the present invention and cannot be used to limit the scope of protection of the present invention. Any non-substantial changes and substitutions made by technicians in this field on the basis of the present invention shall fall within the scope of protection required by the present invention.

Claims

1. A method for preparing phenethyl resorcinol, characterized in that: The steps include: Under the catalytic action of an acid catalyst, m-hydroxybenzaldehyde and 1-phenylethanol react in a first solvent to obtain an intermediate, and the first reaction temperature is 60° C. to 110° C.; After adding the intermediate, the base and the second solvent into the first reaction bottle, hydrogen peroxide is added dropwise into the first reaction bottle so that the intermediate generates phenethyl resorcinol, and the second reaction temperature is 10° C.-25° C.

2. The preparation method according to claim 1, characterized in that The acid catalyst is selected from at least one of sulfuric acid, p-toluenesulfonic acid, aminosulfonic acid, phosphoric acid or hydrochloric acid, and the added amount of the acid catalyst is 0.05-0.1 times the molar equivalent of the m-hydroxybenzaldehyde.

3. The preparation method according to claim 1, characterized in that: The molar ratio of the m-hydroxybenzaldehyde to the 1-phenylethanol is 1.1:1-1.2:

1.

4. The preparation method according to claim 3, characterized in that: The molar ratio of the intermediate, the base and the hydrogen peroxide is 1:1:2-1:1:

5.

5. The preparation method according to claim 1, characterized in that: The alkali is selected from at least one of sodium hydroxide, potassium hydroxide, sodium bicarbonate or potassium bicarbonate.

6. The preparation method according to claim 1, characterized in that: The first solvent is selected from at least one of toluene, tetrahydrofuran, acetonitrile and N,N-dimethylformamide, and the second solvent is selected from at least one of acetonitrile, tetrahydrofuran, methanol and water.

7. The preparation method according to claim 6, characterized in that: The steps of obtaining the intermediate include: Adding the m-hydroxybenzaldehyde, the acid catalyst and the first solvent into the second reaction bottle, heating the reaction bottle to the first reaction temperature and reflux; The 1-phenylethanol is added dropwise to the second reaction bottle for reaction, and the reaction is kept warm for 2.8-3.2 hours after the addition is completed.

8. The preparation method according to claim 7, characterized in that: The step of obtaining the intermediate further comprises: After the reaction of the liquid phase detection reaction system is completed, the pH value of the system is adjusted to 7; The first solvent is removed by rotary evaporation to obtain the intermediate.

9. The preparation method according to claim 7 or 8, characterized in that: The step of obtaining the phenethyl resorcinol comprises: Add the intermediate and the second solvent into the first reaction bottle, and cool to 10°C-12°C; Then, the alkaline solution is added to the first reaction bottle at a controlled dropping speed so that the dropping temperature is maintained below 15° C. After the dropping is completed, the solution is kept at 15° C. and stirred for 20-40 minutes; Then, the hydrogen peroxide is dripped into the first reaction bottle at a controlled dripping speed so that the dripping temperature is maintained below 25° C. After the dripping is completed, the reaction is kept at 25° C. for 1.8-2 hours.

10. The preparation method according to claim 9, characterized in that: The step of obtaining the phenethyl resorcinol also includes: After the liquid phase detection reaction is completed, the pH value of the system is adjusted to 7; Then, a solid crude product is obtained by extraction and rotary evaporation; Add ethyl acetate 3 times the weight of the crude solid product, stir and heat to 77°C for 50-70 minutes, cool to 13°C-17°C and stir for 20-40 minutes, separate the solid and liquid to obtain a separated solid; The separated solid was washed with ethyl acetate and dried to obtain solid phenethyl resorcinol.

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