Preparation method of phenyl 4-hydroxybenzoate

Abstract

The invention provides a preparation method of phenyl 4-hydroxybenzoate, which comprises the following steps: step S1, reacting 4-hydroxybenzoic acid with Boc anhydride under the action of Lewis acid to obtain 4-t-butyloxycarbonyloxybenzoic acid; s2, enabling the 4-tert-butyloxycarbonyloxy benzoic acid to react with phenol under the action of a condensation reagent, so as to obtain 4-tert-butyloxycarbonyloxy phenyl benzoate; and S3, carrying out a reaction on the 4-tert-butyloxycarbonyloxy phenyl benzoate under an alkaline condition to remove Boc so as to obtain the 4-hydroxybenzoic acid phenyl ester. According to the preparation method provided by the embodiment of the invention, the reaction condition is mild, the process is green and environment-friendly, the use risk of a chlorination reagent is avoided, and the reaction safety coefficient is improved.

Description

Technical Field

[0001] This invention relates to the field of compound preparation technology, and specifically to a method for preparing phenyl 4-hydroxybenzoate. Background Technology

[0002] Parabens, also known as p-hydroxybenzoic acid esters, are a class of broad-spectrum preservatives widely used in the food, pharmaceutical, and cosmetic industries. Phenyl 4-hydroxybenzoate is also a paraben, possessing antibacterial and preservative properties, and also exhibits good UV absorption capabilities, making it suitable for use as a sunscreen.

[0003] Currently, there are two main methods for synthesizing phenyl 4-hydroxybenzoate:

[0004] 1. A direct synthesis method was adopted, in which 4-hydroxybenzoic acid and phenol were reacted under the action of RE-Y zeolite (10% w / w of acid) and o-dichlorobenzene was used as the medium to directly obtain phenyl 4-hydroxybenzoate (Formula 1, Synth. Commun. 2002, 32, 2149-2153).

[0005] The synthetic route has a yield of 63%, and o-dichlorobenzene has a boiling point of 179°C. The reaction temperature requires reflux and has high requirements for reaction equipment, making it unsuitable for industrial production.

[0006] (1)

[0007] 2. 4-Hydroxybenzoic acid reacts with acetyl chloride to protect the phenolic hydroxyl group, and then reacts with phenol in the presence of Lewis acid and phosphorus oxychloride in a dichlorobenzene medium to obtain phenyl 4-acetoxybenzoate. Finally, it is deacetylated in an ammonia solution to obtain phenyl 4-hydroxybenzoate (Formula 2, CN107129432).

[0008] This route uses a large number of chlorinating reagents, posing certain safety risks, and the reaction produces hydrogen chloride gas, which is environmentally unfriendly. Furthermore, this route also uses dichlorobenzene as a reaction solvent, making post-processing operations more complicated, and overall, it is not suitable for large-scale production.

[0009] (2) Summary of the Invention

[0010] In view of this, the purpose of this invention is to provide a method for preparing phenyl 4-hydroxybenzoate that is simple to operate, environmentally friendly, safe, and suitable for large-scale production.

[0011] To solve the above-mentioned technical problems, the present invention adopts the following technical solution:

[0012] The preparation method of phenyl 4-hydroxybenzoate according to an embodiment of the present invention includes the following steps:

[0013] The method for preparing phenyl 4-hydroxybenzoate is characterized by comprising the following steps:

[0014] Step S1 involves reacting 4-hydroxybenzoic acid with Boc anhydride under the action of a Lewis acid to obtain 4-tert-butoxycarbonyloxybenzoic acid.

[0015] Step S2 involves reacting the 4-tert-butoxycarbonyloxybenzoic acid with phenol under the action of a condensing agent to obtain phenyl 4-tert-butoxycarbonyloxybenzoic acid.

[0016] Step S3 involves reacting the 4-tert-butoxycarbonyloxybenzoic acid phenyl ester under alkaline conditions to remove Boc, yielding 4-hydroxybenzoic acid phenyl ester.

[0017] Furthermore, the reaction in step S1 is carried out under the action of a Lewis acid, wherein the Lewis acid is one or more of iodide ketone, cobalt chloride hydrate, zinc acetate, and magnesium bromide.

[0018] Furthermore, in step S1, the molar ratio of 4-hydroxybenzoic acid: Boc anhydride: Lewis acid is 1:(0.9~1.2):(0.01~0.5); the reaction temperature is 0~60℃; and the reaction time is 4~16 h.

[0019] Furthermore, in step S1, the solvent includes any one or more of dichloromethane, acetonitrile, and tetrahydrofuran.

[0020] Furthermore, in step S2, the reaction is carried out under the action of a condensing agent, which is one or more of DIC, DCC, and EDCI.

[0021] Furthermore, in step S2, the molar ratio of 4-tert-butoxycarbonyloxybenzoic acid:phenol:condensing reagent is 1:(1.0~1.5):(1.0~1.5); the reaction temperature is 0~40℃; and the reaction time is 2~8 h.

[0022] Furthermore, in step S2, the solvent includes any one or more of dichloromethane, acetonitrile, and tetrahydrofuran.

[0023] Further, in step S3, the reaction is carried out under alkaline conditions, the base is tetrahydropyrrole, the molar ratio of 4-tert-butoxycarbonyloxybenzoic acid phenyl ester to base is 1:(0.5~2.0); the reaction temperature is 0~60℃; and the reaction time is 3~12 h.

[0024] Furthermore, the solvent includes any one or more of methanol, tetrahydrofuran, and dichloromethane.

[0025] The above-described technical solution of the present invention has at least one of the following beneficial effects:

[0026] According to the preparation method of this invention, 4-hydroxybenzoic acid is used as the raw material. Boc anhydride is selected to protect the phenolic hydroxyl group. Under the promotion of a condensation reagent, the carboxyl group esterifies with phenol. Finally, the Boc group is removed under alkaline conditions to obtain phenyl 4-hydroxybenzoate. This method provides mild reaction conditions, avoids the use of hazardous reagents and high-boiling-point solvents, reduces operational difficulty, and improves reaction safety.

[0027] The method described in this invention is simple to operate and is green and safe. Detailed Implementation

[0028] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the described embodiments of the present invention are within the scope of protection of the present invention.

[0029] The preparation method of phenyl 4-hydroxybenzoate according to embodiments of the present invention will be described in detail below.

[0030] The preparation method of phenyl 4-hydroxybenzoate according to an embodiment of the present invention includes the following steps:

[0031] Step S1 involves reacting 4-hydroxybenzoic acid with Boc anhydride under the action of a Lewis acid to obtain 4-tert-butoxycarbonyloxybenzoic acid.

[0032] Step S2 involves reacting the 4-tert-butoxycarbonyloxybenzoic acid with phenol under the action of a condensing agent to obtain phenyl 4-tert-butoxycarbonyloxybenzoic acid.

[0033] Step S3 involves reacting the 4-tert-butoxycarbonyloxybenzoic acid phenyl ester under alkaline conditions to remove Boc, yielding 4-hydroxybenzoic acid phenyl ester.

[0034] Specifically, the preparation method of this application has the following synthetic route as shown in formula (3):

[0035] (3)

[0036] In other words, according to the preparation method of this embodiment of the invention, 4-hydroxybenzoic acid is used as the raw material, Boc anhydride is selected to protect the phenolic hydroxyl group, and the carboxyl group is esterified with phenol under the promotion of a condensation reagent. Finally, the Boc group is removed under alkaline conditions to obtain phenyl 4-hydroxybenzoate. This scheme has mild reaction conditions, avoids the use of dangerous reagents and high-boiling-point solvents, not only reducing the difficulty of operation, but also improving the safety factor of the reaction.

[0037] The following section will explain each step in detail.

[0038] In step S1, the reaction is carried out under the action of a Lewis acid, which is one or more of iodide ketone, cobalt chloride hydrate, zinc acetate, and magnesium bromide. Preferably, the Lewis acid is cobalt chloride hydrate, which is inexpensive, highly active, and can efficiently promote the reaction using only a catalytic amount.

[0039] Further, the molar ratio of 4-hydroxybenzoic acid:Boc anhydride:Lewis acid is 1:(0.9~1.2):(0.01~0.5). Preferably, the molar ratio of 4-hydroxybenzoic acid:Boc anhydride:Lewis acid is 1:1.0:0.05. That is, the same amount of raw material can be completely consumed under the catalysis of Lewis acid, and increasing the amount of Lewis acid will not bring a significant positive effect to the reaction.

[0040] Furthermore, the reaction temperature is 0~60℃, preferably 40~45℃; the reaction time is 4~16 h, preferably 10 h. Reacting at a temperature slightly above room temperature can accelerate the reaction efficiency while preventing side reactions and reduced product yield due to excessively high temperatures.

[0041] Furthermore, the reaction solvent includes any one or more of dichloromethane, acetonitrile, and tetrahydrofuran, preferably acetonitrile, as acetonitrile has good solubility for the raw materials and Lewis acids, which is beneficial for the reaction.

[0042] In step S2, the reaction is carried out under the action of a condensing agent, which is one or more of DIC, DCC, and EDCI. EDCI is preferred, as its byproducts are water-soluble and easily removed.

[0043] Further, the molar ratio of 4-tert-butoxycarbonyloxybenzoic acid:phenol:condensing agent is 1:(1.0~1.5):(1.0~1.5). Preferably, the molar ratio of 4-tert-butoxycarbonyloxybenzoic acid:phenol:condensing agent is 1:1.05:1.1. A slight excess of phenol can ensure that the main raw materials react completely.

[0044] The reaction temperature is 0~40℃, preferably 0~10℃; the reaction time is 2~8 h, preferably 4 h. Condensation reactions are typically carried out at lower temperatures to reduce the occurrence of side reactions.

[0045] Furthermore, the solvent includes any one or more of dichloromethane, acetonitrile, and tetrahydrofuran. Dichloromethane is preferred.

[0046] In step S3, the reaction is carried out under alkaline conditions, the base is tetrahydropyrrole, and the molar ratio of 4-tert-butoxycarbonyloxybenzoic acid phenyl ester to base is 1:(0.5~2.0). Preferably, the molar ratio of 4-tert-butoxycarbonyloxybenzoic acid phenyl ester to base is 1:1.0. If the amount of base is too low, the reaction time will be too long and the reaction will be incomplete. If the amount of base is too high, some ester groups will be hydrolyzed.

[0047] The reaction temperature is 0~60℃, preferably 35~40℃, and the reaction time is 3~12 h, preferably 7 h. Appropriately increasing the reaction temperature can accelerate the reaction rate.

[0048] Furthermore, the reaction solvent includes any one or more of methanol, tetrahydrofuran, and dichloromethane, preferably a mixed solvent of methanol and dichloromethane. Methanol has poor solubility for the intermediate and the target product, so some dichloromethane needs to be added to improve its solubility to ensure the smooth progress of the reaction. At the same time, the product can be obtained by crystallization after the reaction is completed, which is simple and convenient.

[0049] As described above, this invention provides a simple and effective method for preparing phenyl 4-hydroxybenzoate. Furthermore, the preparation method of this invention is simple to operate, feasible in its route, environmentally friendly, and safer.

[0050] The preparation method of phenyl 4-hydroxybenzoate according to the present invention will be further described below with reference to specific embodiments. Example 1

[0051] (I) Preparation of 4-tert-butoxycarbonyloxybenzoic acid

[0052] In a 1000 mL three-necked round-bottom flask, add 300 mL of acetonitrile, then add 40 g of 4-hydroxybenzoic acid, 63.21 g of Boc anhydride and 3.45 g of cobalt chloride hexahydrate in sequence. Heat to 40-45 °C and maintain the temperature for 10 h.

[0053] Post-treatment: The reaction solution was concentrated, and then 250 mL of ethyl acetate was added to the concentrated residue. The mixture was washed twice with 100 mL of water, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 63.48 g of 4-tert-butoxycarbonyloxybenzoic acid, with a yield of 92.0%.

[0054] (II) Preparation of 4-tert-butoxycarbonyloxybenzoic acid phenyl ester

[0055] In a 1000 mL three-necked round-bottom flask, add 350 mL of dichloromethane, then add 40 g of 4-tert-butoxycarbonyloxybenzoic acid and 16.59 g of phenol in sequence. Lower the temperature to an ice-water bath, then add 35.40 g of EDCI and keep the reaction at this temperature for 4 h.

[0056] Post-processing: Wash twice with 150 mL of water, dry with anhydrous sodium sulfate, evaporate to dryness, and slurry the crude product with a mixed solvent (150 mL of petroleum ether and 15 mL of ethyl acetate) to obtain 47.13 g of 4-tert-butoxycarbonyloxybenzoic acid phenyl ester, with a yield of 89.3%.

[0057] (III) Preparation of phenyl 4-hydroxybenzoate

[0058] In a 500 mL three-necked round-bottom flask, add a mixed solvent (160 mL methanol and 20 mL dichloromethane), then add 40 g of 4-tert-butoxycarbonyloxybenzoic acid phenyl ester and 9.05 g of tetrahydropyrrole sequentially, and heat to 35-40 °C and maintain the temperature for 7 h.

[0059] Post-processing: Cool to an ice-water bath, stir for 1 h, filter, wash the filter cake with 40 mL of methanol, dry, and obtain 23.66 g of phenyl 4-hydroxybenzoate, with a yield of 86.8%. Example 2

[0060] (I) Preparation of 4-tert-butoxycarbonyloxybenzoic acid

[0061] In a 1000 mL three-necked round-bottom flask, add 300 mL of acetonitrile, then add 40 g of 4-hydroxybenzoic acid, 63.21 g of Boc anhydride and 6.89 g of cobalt chloride hexahydrate in sequence. Heat to 40-45 °C and maintain the temperature for 10 h.

[0062] Post-treatment: The reaction solution was concentrated, and then 250 mL of ethyl acetate was added to the concentrated residue. The mixture was washed twice with 100 mL of water, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 63.68 g of 4-tert-butoxycarbonyloxybenzoic acid, with a yield of 92.3%.

[0063] (II) Preparation of 4-tert-butoxycarbonyloxybenzoic acid phenyl ester

[0064] In a 1000 mL three-necked round-bottom flask, add 350 mL of dichloromethane, then add 40 g of 4-tert-butoxycarbonyloxybenzoic acid and 16.59 g of phenol in sequence. Lower the temperature to an ice-water bath, then add 41.84 g of EDCI and keep the reaction at this temperature for 4 h.

[0065] Post-processing: Wash twice with 150 mL of water, dry with anhydrous sodium sulfate, evaporate to dryness, and slurry the crude product with a mixed solvent (150 mL of petroleum ether and 15 mL of ethyl acetate) to obtain 46.34 g of phenyl 4-tert-butoxycarbonyloxybenzoate, with a yield of 87.8%.

[0066] (III) Preparation of phenyl 4-hydroxybenzoate

[0067] In a 500 mL three-necked round-bottom flask, add a mixed solvent (160 mL methanol and 20 mL dichloromethane), then add 40 g of 4-tert-butoxycarbonyloxybenzoic acid phenyl ester and 10.86 g of tetrahydropyrrole sequentially, and heat to 35-40 °C and maintain the temperature for 7 h.

[0068] Post-processing: Cool to an ice-water bath, stir for 1 h, filter, wash the filter cake with 40 mL of methanol, dry, and obtain 22.93 g of phenyl 4-hydroxybenzoate, with a yield of 84.1%. Example 3

[0069] (I) Preparation of 4-tert-butoxycarbonyloxybenzoic acid

[0070] In a 1000 mL three-necked round-bottom flask, add 300 mL of acetonitrile, then add 40 g of 4-hydroxybenzoic acid, 63.21 g of Boc anhydride and 2.66 g of zinc acetate in sequence. Heat to 40-45 °C and maintain the temperature for 10 h.

[0071] Post-treatment: The reaction solution was concentrated, and then 250 mL of ethyl acetate was added to the concentrated residue. The mixture was washed twice with 100 mL of water, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 61.13 g of 4-tert-butoxycarbonyloxybenzoic acid, with a yield of 88.6%.

[0072] (II) Preparation of 4-tert-butoxycarbonyloxybenzoic acid phenyl ester

[0073] In a 1000 mL three-necked round-bottom flask, add 350 mL of dichloromethane, then add 40 g of 4-tert-butoxycarbonyloxybenzoic acid and 16.59 g of phenol in sequence. Lower the temperature to an ice-water bath, then add 23.31 g of DIC and keep the reaction at this temperature for 4 h.

[0074] Post-processing: Wash twice with 150 mL of water, dry with anhydrous sodium sulfate, evaporate to dryness, and slurry the crude product with a mixed solvent (80 mL of petroleum ether and 80 mL of ethyl acetate) to obtain 44.70 g of 4-tert-butoxycarbonyloxybenzoic acid phenyl ester, with a yield of 84.7%.

[0075] (III) Preparation of phenyl 4-hydroxybenzoate

[0076] In a 500 mL three-necked round-bottom flask, add 180 mL of methanol, then add 40 g of 4-tert-butoxycarbonyloxybenzoic acid phenyl ester and 9.05 g of tetrahydropyrrole in sequence, and heat to 35-40 °C and maintain the temperature for 7 h.

[0077] Post-processing: Cool to an ice-water bath, stir for 1 h, filter, wash the filter cake with 40 mL of methanol, dry, and obtain 21.43 g of phenyl 4-hydroxybenzoate, yield 78.6%. Example 4

[0078] (I) Preparation of 4-tert-butoxycarbonyloxybenzoic acid

[0079] In a 1000 mL three-necked round-bottom flask, add 300 mL of acetonitrile, then add 40 g of 4-hydroxybenzoic acid, 63.21 g of Boc anhydride and 3.45 g of cobalt chloride hexahydrate in sequence. Heat to 55-60 °C and maintain the temperature for 10 h.

[0080] Post-treatment: The reaction solution was concentrated, and then 250 mL of ethyl acetate was added to the concentrated residue. The mixture was washed twice with 100 mL of water, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 59.47 g of 4-tert-butoxycarbonyloxybenzoic acid, with a yield of 86.2%.

[0081] (II) Preparation of 4-tert-butoxycarbonyloxybenzoic acid phenyl ester

[0082] In a 1000 mL three-necked round-bottom flask, add 350 mL of dichloromethane, then add 40 g of 4-tert-butoxycarbonyloxybenzoic acid and 16.59 g of phenol in sequence. Lower the temperature to an ice-water bath, then add 35.40 g of EDCI, and then heat to 30-35 °C and maintain the temperature for 4 h.

[0083] Post-processing: Wash twice with 150 mL of water, dry with anhydrous sodium sulfate, evaporate to dryness, and slurry the crude product with a mixed solvent (150 mL of petroleum ether and 15 mL of ethyl acetate) to obtain 43.17 g of 4-tert-butoxycarbonyloxybenzoic acid phenyl ester, with a yield of 81.8%.

[0084] (III) Preparation of phenyl 4-hydroxybenzoate

[0085] In a 500 mL three-necked round-bottom flask, add a mixed solvent (160 mL methanol and 20 mL dichloromethane), then add 40 g of 4-tert-butoxycarbonyloxybenzoic acid phenyl ester and 9.05 g of tetrahydropyrrole sequentially, and keep the mixture at 20-25 °C for 7 h.

[0086] Post-processing: Cool to an ice-water bath, stir for 1 h, filter, wash the filter cake with 40 mL of methanol, dry, and obtain 22.24 g of phenyl 4-hydroxybenzoate, yield 81.6%.

[0087] In summary, the method for preparing phenyl 4-hydroxybenzoate of the present invention has the advantages of simple operation, high safety, and green environmental protection.

[0088] The above description represents the preferred embodiments of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A process for the preparation of phenyl 4-hydroxybenzoate, characterized in that, The method comprises the following steps: Step S1, reacting 4-hydroxybenzoic acid with Boc anhydride under the action of Lewis acid to obtain 4-tert-butoxycarbonyloxybenzoic acid; Step S2, reacting the 4-tert-butoxycarbonyloxybenzoic acid with phenol under the action of condensation reagent to obtain 4-tert-butoxycarbonyloxybenzoic acid phenyl ester; Step S3, removing Boc of the 4-tert-butoxycarbonyloxybenzoic acid phenyl ester under alkaline conditions to obtain 4-hydroxybenzoic acid phenyl ester.

2. The production method according to claim 1, characterized by, In the step S1, the reaction is carried out under the action of Lewis acid, and the Lewis acid is one or more of iodous potassium, cobalt chloride hydrate, zinc acetate, and magnesium bromide.

3. The production method according to claim 1, characterized by, In the step S1, the molar ratio of 4-hydroxybenzoic acid, Boc anhydride, and Lewis acid is 1:(0.9-1.2):(0.01-0.5), the reaction temperature is 0-60°C, and the reaction time is 4-16 h.

4. The method of claim 1, wherein, In the step S1, the solvent comprises any one or more of dichloromethane, acetonitrile, and tetrahydrofuran.

5. The preparation method according to claim 1, characterized in that, In the step S2, the reaction is carried out under the action of condensation reagent, and the condensation reagent is one or more of DIC, DCC, and EDCI.

6. The method of claim 1, wherein, In the step S2, the molar ratio of 4-tert-butoxycarbonyloxybenzoic acid, phenol, and condensation reagent is 1:(1.0-1.5):(1.0-1.5), the reaction temperature is 0-40°C, and the reaction time is 2-8 h.

7. The preparation method according to claim 1, characterized in that, In the step S2, the solvent comprises any one or more of dichloromethane, acetonitrile, and tetrahydrofuran.

8. The method of claim 1, wherein, In the step S3, the reaction is carried out under alkaline conditions, the base is tetrahydro-pyrrole, the molar ratio of 4-tert-butoxycarbonyloxybenzoic acid phenyl ester and base is 1:(0.5-2.0), the reaction temperature is 0-60°C, and the reaction time is 3-12 h.

9. The method of claim 1, wherein, In the step S3, the solvent comprises any one or more of methanol, tetrahydrofuran, and dichloromethane.