Preparation method of urolithin A

Abstract

The invention belongs to the technical field of preparation of urolithin A, and particularly relates to a preparation method of urolithin A. The preparation method comprises the following steps: S1, by taking parachlorophenol and resorcinol as initial raw materials, carrying out coupling reaction under the catalytic action of sodium hydroxide and copper sulfate to obtain an intermediate 1; and S2, reacting the intermediate 1 with carbon dioxide under specific conditions under the action of a catalyst to obtain the product urolithin A. The synthesis process is simple and efficient, the used raw materials are easy to obtain and low in price, reagents can be recycled and reused, generation of three wastes can be greatly reduced, the green chemistry principle is met, and good development prospects are achieved. The method is an efficient, reliable and environment-friendly synthesis method of urolithin A, and is beneficial to industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of preparation of urolithin A, and particularly relates to a method for preparing urolithin A. Background Art

[0002] In the prior art, the preparation of urolithin A is generally carried out at a temperature of 75°C, and resorcinol and 2-bromo-5-hydroxybenzoic acid react under the action of sodium hydroxide and copper sulfate solution to generate crude urolithin A. Urolithin A further reacts under the action of glacial acetic acid to complete the protonation and purification process to generate urolithin A. However, the chemical reagents used in this process are expensive and costly; the reaction efficiency is low, resulting in low yield; the purification steps are complicated and the effect is not ideal, and the purity of the product is difficult to guarantee; the use of strong acids and oxidants poses a threat to the environment and the safety of operators, etc. In addition, the process will also produce a large amount of wastewater, waste gas and waste residue, which increases the difficulty and cost of the three wastes treatment. These factors make the process complex and limit the feasibility of its industrial application.

[0003] Cost: 2-bromo-5-hydroxybenzoic acid is used as the starting material, and its cost and commercial value affect the economic feasibility of the entire synthetic route. In addition, when the amount of glacial acetic acid used is large, the cost will also increase. The product purification steps are cumbersome: including multiple steps of hot filtration, hot water washing, nitrogen drying, drying, etc. These steps are time-consuming and may increase costs. The reason may be that the product is difficult to separate from the by-products or unreacted raw materials, or the initial reaction conditions are not sufficient to achieve efficient conversion. Summary of the invention

[0004] The object of the present invention is to solve the above problems. The present application proposes a method for preparing urolithin A, wherein m-diphenol and p-chlorophenol are used as starting materials, and a coupling reaction is carried out under the catalytic action of sodium hydroxide and copper sulfate, and then reacted with carbon dioxide under specific conditions and under the action of a catalyst to obtain the product urolithin A. m-diphenol and p-chlorophenol are used as starting materials, and not only have obvious advantages in raw material cost, but also have the advantages of high reactivity, multifunctionality, good solubility and chemical stability. A new route for synthesizing urolithin A proposed by the present invention is more convenient, environmentally friendly, high in yield, less three wastes and higher in purity, and is an efficient, reliable and environmentally friendly method for synthesizing urolithin A, which is conducive to industrial production.

[0005] To achieve the above object, the present invention provides the following technical solution: a method for preparing urolithin A, characterized in that: m-diphenol and p-chlorophenol are used as starting materials, and the synthesis route of urolithin A is as follows:

[0006]

[0007] The preparation method of urolithin A comprises the following steps:

[0008] S1. A coupling reaction is carried out between m-diphenol and p-chlorophenol under the catalysis of sodium hydroxide and copper sulfate to obtain intermediate 1 ([1,1'-biphenyl]-2,4,4'-triol). The reaction process of intermediate 1 is as follows:

[0009]

[0010] S2. The intermediate 1 prepared in S1 is reacted with carbon dioxide under specific conditions and in the presence of a catalyst to obtain the product urolithin A. The reaction process is as follows:

[0011]

[0012] The reaction process of intermediate 1 in step S1 comprises the following steps:

[0013] a. Dissolve m-diphenol and p-chlorophenol in solvent 1, and add sodium hydroxide solution to keep the system alkaline;

[0014] b. Add copper sulfate solution, heat and stir to react for several hours to overnight until the reaction is complete, cool the reaction mixture to room temperature, and filter to remove insoluble solids;

[0015] c. Remove most of the solvent by distillation under reduced pressure, and perform multiple crystallizations with an appropriate amount of solvent 2 to remove residual inorganic salts and impurities;

[0016] d. Dry in a vacuum oven to obtain intermediate 1.

[0017] Step S2 The reaction process comprises the following steps:

[0018] a. Place the intermediate 1 and the catalyst in a high pressure reactor and dissolve them with an appropriate amount of solvent 3 to ensure that all solids are completely dissolved;

[0019] b. nitrogen is introduced through the air inlet of the autoclave to replace the air in the autoclave to exclude oxygen and impurities. After the nitrogen replacement is completed, carbon dioxide is introduced through the air inlet of the autoclave to fill the autoclave with carbon dioxide, so that the reaction system is in carbon dioxide gas;

[0020] c. gradually heating the autoclave to a set temperature, and at the same time, adjusting the pressure in the autoclave to a set value, stirring the reaction mixture at the set temperature and pressure, and reacting for several hours;

[0021] d. After the reaction is completed, the reaction mixture is cooled to room temperature, the internal pressure is released, and the product is extracted with solvent 2. The extraction is repeated several times, and most of the solvent is removed by vacuum distillation. The concentrated crude product is recrystallized and dried to obtain urolithin A.

[0022] Preferably: in the reaction process of intermediate 1 in step S1: the ratio of p-chlorophenol to m-diphenol is 1:1-3; the ratio of p-chlorophenol to solvent 1 is 1:3-10; the ratio of catalyst copper sulfate to sodium hydroxide is 1:5-10; the reactor is selected according to the amount of raw materials.

[0023] Preferably, during the reaction of step S2, the ratio of the intermediate 1 to the catalyst is 10-20:1; the ratio of the intermediate 1 to the solvent 3 is 1:2-10.

[0024] Preferably: in the reaction process of step S2, the catalyst is any one of cupric acetate, cupric chloride, cupric sulfate, cuprous chloride and cupric oxide.

[0025] Preferably, in the reaction process of intermediate 1 in step S1, solvent 1 is any one of DMF (N,N-dimethylformamide), DMSO (dimethyl sulfoxide), methanol and ethanol; solvent 2 is any one of diethyl ether, ethyl acetate and dichloromethane.

[0026] Preferably, during the reaction of step S2, solvent 3 is an alcohol organic solvent, including methanol, ethanol, and isopropanol.

[0027] Preferably: during the reaction of intermediate 1 in step S1, the reaction temperature is 50-70°C and the reaction time is 8-12h.

[0028] Preferably, during the reaction in step S2, the temperature of the autoclave is set at 150-200°C, the reaction time is 8-12h, and the pressure is 0.5-1MPa.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] The present invention uses m-diphenol and p-chlorophenol as starting materials, which are not only in sufficient supply and relatively low in price in the market, which helps to reduce the cost of the entire synthesis process, but also have the advantages of high reactivity, multifunctionality, good solubility and chemical stability. The synthetic route is simple to operate, the synthetic process is concise and efficient, the recycling and reuse of reagents can greatly reduce waste generation in accordance with the principle of green chemistry, and the product yield and purity are high, and it has good safety and effectiveness, so it has good development prospects.

[0031] A new route for synthesizing urolithin A is proposed, and the preparation method is more convenient, environmentally friendly, has a high yield, less three wastes and higher purity, which is conducive to industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required for use in the description of the embodiments will be briefly introduced below. Obviously, the drawings in the following description are only for more clearly illustrating the embodiments of the present invention or the technical solutions in the prior art. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0033] Figure 1 Schematic diagram of the chromatogram of urolithin A of the present invention. DETAILED DESCRIPTION

[0034] In order to enable those skilled in the art to better understand and implement the technical solution of the present invention, the present invention is further described below in conjunction with specific examples and data, but the examples are not intended to limit the present invention.

[0035] The experimental methods and detection methods described in the following embodiments are conventional methods unless otherwise specified; the reagents and materials are commercially available unless otherwise specified.

[0036] The present invention provides a method for preparing urolithin A, comprising the following steps:

[0037] S1, subjecting m-diphenol and p-chlorophenol to a coupling reaction under the catalysis of sodium hydroxide and copper sulfate to obtain intermediate 1;

[0038] S2, reacting the intermediate 1 prepared in S1 with carbon dioxide under specific conditions and in the presence of a catalyst to obtain the product urolithin A;

[0039] Its synthetic route is as follows:

[0040]

[0041] The reaction process of intermediate 1 in step S1 comprises the following steps:

[0042] a. dissolving m-diphenol and p-chlorophenol in solvent 1, adding sodium hydroxide solution to keep the system alkaline, wherein the ratio of p-chlorophenol to m-diphenol is 1:1-3, and the ratio of p-chlorophenol to solvent 1 is 1:3-10;

[0043] b. Add copper sulfate solution, heat and stir to react for several hours to overnight until the reaction is completed, cool the reaction mixture to room temperature, filter to remove insoluble solids, the ratio of copper sulfate to sodium hydroxide is 1:5-10, the heating temperature is 50-70°C, and the reaction time is 8-12h;

[0044] c. Remove most of the solvent by distillation under reduced pressure, and use an appropriate amount of solvent 2 for multiple crystallizations to remove residual inorganic salts and impurities.

[0045] d. Dry in a vacuum oven to obtain intermediate 1.

[0046] Step S2 The reaction process comprises the following steps:

[0047] a. Place the intermediate 1 and the catalyst in a ratio of 10-20:1 in an autoclave, dissolve with an appropriate amount of solvent 3 to ensure that all solids are completely dissolved, and the ratio of the intermediate 1 to the solvent 3 is 1:2-10;

[0048] b. Nitrogen is introduced through the air inlet of the high-pressure reactor to replace the air in the reactor to remove oxygen and other impurities; after the nitrogen replacement is completed, carbon dioxide is introduced through the air inlet of the high-pressure reactor to ensure that the reactor is filled with carbon dioxide and the reaction system is in carbon dioxide gas;

[0049] c. Gradually heat the autoclave to a set temperature of 150-200°C. At the same time, adjust the pressure in the autoclave to a set value of 0.5-1MPa. Stir the reaction mixture at the set temperature and pressure to react for 8-12 hours.

[0050] d. After the reaction is completed, the reaction mixture is cooled to room temperature, the internal pressure is released, and the product is extracted with solvent 2. The extraction is repeated several times, and most of the solvent is removed by vacuum distillation. The concentrated crude product is recrystallized and dried to obtain urolithin A.

[0051] Wherein, the solvent 1 is any one of DMF (N,N-dimethylformamide), DMSO (dimethyl sulfoxide), methanol, and ethanol; the solvent 2 is any one of ether, ethyl acetate, and dichloromethane; and the solvent 3 is an alcohol organic solvent, including methanol, ethanol, propanol, and the like.

[0052] The above contents are specifically described below through the following embodiments.

[0053] The specific embodiments are as follows:

[0054] Embodiment 1:

[0055] 1) In a 1L reactor, dissolve 100g of m-diphenol and 100g of p-chlorophenol in 500ml of ethanol, and add 55g of sodium hydroxide to keep the system alkaline;

[0056] 2) Stir and dissolve, then dissolve 9g of copper sulfate in 360ml of water, pump it into the reactor under negative pressure, stir and heat at 70°C for 10h, cool the reaction mixture to room temperature after the reaction is completed, and filter to remove insoluble solids;

[0057] 3) removing most of the solvent by distillation under reduced pressure, and performing multiple crystallizations with 1L of ethyl acetate in batches to remove residual inorganic salts and impurities;

[0058] 4) drying in a vacuum oven to obtain 139 g of intermediate 1;

[0059] The process of generating the product urolithin A in step S2 is as follows:

[0060] 5) 139 g of the intermediate 1 and 8.2 g of copper acetate were placed in an autoclave, dissolved with 800 ml of methanol, and stirred to ensure that all solids were completely dissolved;

[0061] 6) nitrogen is introduced through the air inlet of the high-pressure reactor to replace the air in the reactor to remove oxygen and other impurities. After the nitrogen replacement is completed, carbon dioxide is introduced through the air inlet of the high-pressure reactor to place the reaction system in carbon dioxide gas and ensure that the reactor is filled with carbon dioxide;

[0062] 7) gradually raising the temperature of the autoclave to 200°C and the pressure to 1 MPa, stirring the reaction mixture at the set temperature and pressure, and reacting for 10 hours;

[0063] 8) After the reaction was completed, the mixture was cooled to room temperature, the internal pressure was released, and the reaction mixture was extracted with 1 L of ethyl acetate. The extraction was repeated several times, and most of the solvent was removed by vacuum distillation. The concentrated crude product was recrystallized to obtain 134.9 g of urolithin A after drying, with a yield of 75.7%.

[0064] Embodiment 2:

[0065] 1) In a 25L reactor, 2.4kg of m-diphenol and 2.4kg of p-chlorophenol were dissolved in 12.5L of LMF, and 1.32kg of sodium hydroxide was added to keep the system alkaline;

[0066] 2) Stir and dissolve, then dissolve 165g of copper sulfate in 6.6L of water, pump it into the reactor under negative pressure, stir and heat at 70°C for 10h, cool the reaction mixture to room temperature after the reaction is completed, and filter to remove insoluble solids;

[0067] 3) removing most of the solvent by distillation under reduced pressure, and performing multiple crystallizations with 25 L of ethyl acetate in batches to remove residual inorganic salts and impurities;

[0068] 4) drying in a vacuum oven to obtain 3.1 kg of intermediate 1;

[0069] The process of generating the product urolithin A in step S2 is as follows:

[0070] 5) 3.1 kg of the intermediate 1 and 181 g of copper oxide were placed in a high pressure reactor, dissolved with 25 L of methanol, and stirred to ensure that all solids were completely dissolved;

[0071] 6) nitrogen is introduced through the air inlet of the high-pressure reactor to replace the air in the reactor to remove oxygen and other impurities; after the nitrogen replacement is completed, carbon dioxide is introduced through the air inlet of the high-pressure reactor to place the reaction system in carbon dioxide gas and ensure that the reactor is filled with carbon dioxide;

[0072] 7) gradually raising the temperature of the autoclave to 200°C and the pressure to 1 MPa, stirring the reaction mixture at the set temperature and pressure, and reacting for 10 hours;

[0073] 8) After the reaction is completed, the reaction mixture is cooled to room temperature, the internal pressure is released, and the product is extracted from the reaction mixture with 25 L of ethyl acetate. The extraction is repeated several times, and most of the solvent is removed by distillation under reduced pressure. The concentrated crude product is recrystallized and dried to obtain 3.2 kg of urolithin A with a yield of 74.8%.

[0074] Embodiment 3:

[0075] 1) In a 400L reactor, 40kg of m-diphenol and 35kg of p-chlorophenol were dissolved in 200L of ethanol, and 19kg of sodium hydroxide was added to keep the system alkaline;

[0076] 2) Stir and dissolve, then dissolve 3.2 kg of copper sulfate in 12.6 L of water, pump it into the reactor under negative pressure, stir and heat at 70°C for 12 h, cool the reaction mixture to room temperature after the reaction is completed, and filter to remove insoluble solids;

[0077] 3) removing most of the solvent by distillation under reduced pressure, and performing multiple crystallizations with 400 L of ethyl acetate in batches to remove residual inorganic salts and impurities;

[0078] 4) drying in a vacuum oven to obtain 48 kg of intermediate 1;

[0079] The process of generating the product urolithin A in step S2 is as follows:

[0080] 5) 48 kg of intermediate 1 and 3.2 kg of copper chloride were placed in a high pressure reactor, dissolved in 280 L of methanol, and stirred to ensure that all solids were completely dissolved;

[0081] 6) nitrogen is introduced through the air inlet of the high-pressure reactor to replace the air in the reactor to remove oxygen and other impurities. After the nitrogen replacement is completed, carbon dioxide is introduced through the air inlet of the high-pressure reactor to place the reaction system in carbon dioxide gas and ensure that the reactor is filled with carbon dioxide;

[0082] 7) gradually raising the temperature of the autoclave to 200°C and the pressure to 1 MPa, stirring the reaction mixture at the set temperature and pressure, and reacting for 10 hours;

[0083] 8) After the reaction was completed, the reaction mixture was cooled to room temperature, the internal pressure was released, and the product was extracted with 300 L of ethyl acetate. The extraction was repeated several times, and most of the solvent was removed by distillation under reduced pressure. The concentrated crude product was recrystallized and dried to obtain 47.7 kg of urolithin A with a yield of 76.5%.

[0084] The purity in the above examples is as follows Figure 1 As shown in the chromatogram.

[0085] The contents not described in detail in the present invention are all prior art.

[0086] The above description is only a preferred embodiment of the present invention, and is not limited to the description in the specification and implementation. Therefore, any equivalent changes or modifications made according to the structure, features and principles described in the scope of the present invention should be included in the scope of the present invention.

Claims

1. A method for preparing urolithin A, characterized in that: Using m-diphenol and p-chlorophenol as starting materials, the synthetic route of urolithin A is as follows: The preparation method of urolithin A comprises the following steps: S1. m-Diphenol and p-chlorophenol are subjected to coupling reaction under the catalysis of sodium hydroxide and copper sulfate to obtain intermediate 1 ([1,1'-biphenyl]-2,4,4'-triol). The reaction process of intermediate 1 is: S2. The intermediate 1 prepared in S1 is reacted with carbon dioxide under specific conditions and in the presence of a catalyst to obtain the product urolithin A. The reaction process is as follows:

2. The method for preparing urolithin A according to claim 1, characterized in that: The reaction process of intermediate 1 in step S1 comprises the following steps: a. Dissolve m-diphenol and p-chlorophenol in solvent 1, and add sodium hydroxide solution to keep the system alkaline; b. Add copper sulfate solution, heat and stir the reaction for several hours to overnight until the reaction is complete, cool the reaction mixture to room temperature, and filter to remove insoluble solids; c. Remove most of the solvent by distillation under reduced pressure, and perform multiple crystallizations with an appropriate amount of solvent 2 to remove residual inorganic salts and impurities; d. Dry in a vacuum oven to obtain intermediate 1.

3. The method for preparing urolithin A according to claim 1, characterized in that: In step S2, under the action of a catalyst, the product urolithin A is obtained, and the reaction process is as follows: a. Place the intermediate 1 and the catalyst in a high pressure reactor and dissolve them with an appropriate amount of solvent 3 to ensure that all solids are completely dissolved; b. nitrogen is introduced through the air inlet of the autoclave to replace the air in the autoclave to exclude oxygen and impurities; after the nitrogen replacement is completed, carbon dioxide is introduced through the air inlet of the autoclave, and the carbon dioxide fills the autoclave, so that the reaction system is in carbon dioxide gas; c. gradually heating the autoclave to a set temperature, and at the same time, adjusting the pressure in the autoclave to a set value, stirring the reaction mixture at the set temperature and pressure, and reacting for several hours; d. After the reaction is completed, the reaction mixture is cooled to room temperature and the internal pressure is released; the reaction mixture is extracted with solvent 2 and the extraction is repeated several times; most of the solvent is removed by vacuum distillation, and the concentrated crude product is recrystallized and dried to obtain urolithin A.

4. The method for preparing urolithin A according to claim 2, characterized in that: In the reaction process of intermediate 1 in step S1: the ratio of p-chlorophenol to m-diphenol is 1:1-3; the ratio of p-chlorophenol to solvent 1 is 1:3-10; the ratio of catalyst copper sulfate to sodium hydroxide is 1:1-10; the reactor is selected according to the amount of raw materials.

5. The method for preparing urolithin A according to claim 3, characterized in that: In the reaction process of step S2: the ratio of the intermediate 1 to the catalyst is 10-20:1; the usage ratio of the intermediate 1 to the solvent 3 is 1:1-10.

6. The method for preparing urolithin A according to claim 3, characterized in that: In the reaction process of step S2, the catalyst is any one of cupric acetate, cupric chloride, cupric sulfate, cuprous chloride, cupric oxide, copper powder, cuprous oxide, and basic cupric carbonate.

7. The method for preparing urolithin A according to claim 2, characterized in that: In the reaction process of intermediate 1 in step S1, solvent 1 is any one of DMF (N,N-dimethylformamide), DMSO (dimethyl sulfoxide), NMP (N-methylpyrrolidone), cyclopentane, DMI (1,3-dimethyl-2-imidazolidinone), methanol, n-butanol, isopropanol, and ethanol; the solvent 2 is any one of diethyl ether, ethyl acetate, dichloromethane, acetone, and methyl tert-butyl ether.

8. The method for preparing urolithin A according to claim 3, characterized in that: In the reaction process of step S2, the solvent 3 is an alcohol organic solvent, including methanol, ethanol, and isopropanol.

9. The method for preparing urolithin A according to claim 2, characterized in that: In the reaction process of intermediate 1 in step S1, the reaction temperature is 0-100° C. and the reaction time is 1-12 h.

10. The method for preparing urolithin A according to claim 3, characterized in that: During the reaction in step S2, the temperature of the high-pressure reactor is set at 100-200° C., the reaction time is 1-12 h, and the pressure is 0-2 MPa.

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