Process for the preparation of urolithin a

Abstract

The application discloses a preparation method of urolithin A. The method uses urolithin B as a raw material, adopts potassium persulfate to perform Elbs oxidation under alkaline conditions, and obtains urolithin A. A reaction route is as follows: wherein, formula I is a chemical structural formula of urolithin B, and formula II is a chemical structural formula of urolithin A. The preparation method of urolithin A provided by the application effectively reduces a synthesis cost, avoids use of dangerous and toxic reagents, effectively reduces generation of industrial three wastes, and is simple in process, convenient in operation, low in raw material cost, high in yield, and beneficial to large-scale industrial production.

Description

Technical Field

[0001] This invention relates to the field of urolithin A preparation technology, and particularly to a method for preparing urolithin A. Background Technology

[0002] Urolithin A is a secondary metabolite of the natural polyphenol compound ellagitannins (ETs), and its structural formula is shown below:

[0003]

[0004] ETs are mainly found in foods such as pomegranates, raspberries, strawberries, walnuts, and red wine, while UA is a product of ETs metabolism by gut microbiota. Numerous studies have confirmed its diverse biological activities, including antioxidant, anti-inflammatory, anti-aging, estrogen / androgen regulation, and induction of mitophagy. With further research and exploration of related mechanisms, many pharmacological effects of UA have been gradually elucidated. Early studies found it could prevent and treat major diseases such as prostate cancer, colorectal cancer, bladder cancer, endometrial cancer, and pancreatic cancer. UA also protects the kidneys and prevents diseases such as colitis, osteoarthritis, and intervertebral disc degeneration due to its strong anti-inflammatory effects. Recent studies have found significant effects of UA in the treatment of neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Furthermore, UA plays a positive role in the prevention and treatment of many metabolic diseases because it can induce mitophagy, thereby delaying aging and treating cardiovascular diseases. Therefore, UA has broad application prospects in the prevention and treatment of numerous diseases.

[0005] Existing methods for preparing urolithin A typically employ a synthetic route using 2-bromo-5-methoxybenzoic acid as a starting material, which undergoes a copper salt-catalyzed coupling cyclization with resorcinol under alkaline conditions, followed by demethylation with hydrobromic acid, aluminum trichloride, or boron tribromide. However, this route requires high amounts of hydrobromic acid and aluminum trichloride in the second step, generating significant amounts of waste. Boron tribromide, on the other hand, demands sophisticated equipment, requiring ultra-low temperature and anhydrous operation, and is highly toxic. Alternatively, m-hydroxybenzoic acid can be used as a starting material, undergoing liquid bromination followed by copper salt-catalyzed cyclization with resorcinol under alkaline conditions to obtain the product. However, this route suffers from low yields in this step due to competing reactions between the ortho- and halogenated phenolic hydroxyl groups, making separation difficult and requiring multiple column chromatography analyses, resulting in high production costs. Furthermore, the high toxicity and corrosiveness of liquid bromine limit the further development and application of this route. Therefore, it is necessary to propose a new method for preparing ortho-carboxybenzaldehyde to address the problems existing in the above processes. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to provide a method for preparing urolithin A, which addresses the shortcomings of the prior art.

[0007] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is: a method for preparing urolithin A, wherein urolithin B is used as raw material, and potassium persulfate is used for Elbs oxidation under alkaline conditions to obtain urolithin A. The reaction route is as follows:

[0008]

[0009] Wherein, Formula I is the chemical structural formula of urolithin B, and Formula II is the chemical structural formula of urolithin A.

[0010] Preferably, the method for preparing urolithin A includes the following steps:

[0011] S1. Urolithin B is reacted with potassium persulfate in a strongly alkaline aqueous solution. After the reaction is completed, the product is acidified to obtain crude urolithin A.

[0012] S2. The crude urolithin A is hot-beaten with an aqueous acetic acid solution and recrystallized to finally obtain the urolithin A product.

[0013] Preferably, the alkali in the strongly alkaline aqueous solution in step 1 is sodium hydroxide, potassium hydroxide, or lithium hydroxide.

[0014] Preferably, in step 1, the molar ratio of alkali to urolithin B in the strongly alkaline aqueous solution is 6:1 to 3:1.

[0015] Preferably, the reaction time in step 1 is 6-12 hours and the reaction temperature is 30-60°C.

[0016] Preferably, the molar ratio of potassium persulfate and urolithin B in step 1 is 1.5:1 to 1.

[0017] Preferably, in step 1, an acidification treatment is performed using an aqueous sulfuric acid solution, the concentration of which is 10 wt% to 40 wt%.

[0018] Preferably, the hot pulping temperature in step 2 is 80-100℃ and the time is 1-3h.

[0019] Preferably, the method for preparing urolithin A includes the following steps:

[0020] S1. Add urolithin B to an aqueous sodium hydroxide solution and stir until urolithin B is completely dissolved to obtain an alkaline solution of urolithin B. Add the alkaline solution of urolithin B dropwise to a potassium persulfate solution. After the reaction is complete, cool down and then add an aqueous sulfuric acid solution to adjust the pH to 3-4. Stir, filter, and wash the filter cake with water to obtain crude urolithin A.

[0021] S2. Add crude urolithin A to an aqueous acetic acid solution, heat and stir to perform hot pulping, then cool and recrystallize, filter, wash the filter cake with an aqueous acetic acid solution, and vacuum dry to finally obtain the urolithin A product.

[0022] Preferably, the method for preparing urolithin A includes the following steps:

[0023] S1. Add urolithin B to an aqueous sodium hydroxide solution and stir until urolithin B is completely dissolved to obtain an alkaline solution of urolithin B. Add the alkaline solution of urolithin B dropwise to a potassium persulfate solution and react at 40°C for 8 hours. After the reaction is completed, cool down to 5°C and then add 30wt% sulfuric acid aqueous solution to adjust the pH to 3-4. Stir at 25°C for 1 hour, filter, and wash the filter cake with water to obtain crude urolithin A.

[0024] S2. Add crude urolithin A to an aqueous acetic acid solution, heat and stir at 90°C for 2 hours to perform hot slurrying, then cool to room temperature for recrystallization, filter, wash the filter cake with a 50wt% aqueous acetic acid solution, and vacuum dry at 50°C to finally obtain the urolithin A product.

[0025] The beneficial effects of the present invention are: the preparation method of urolithin A provided by the present invention effectively reduces the synthesis cost, avoids the use of dangerous and toxic reagents, effectively reduces the generation of industrial waste, and the process is simple, convenient to operate, the raw materials are cheap and readily available, and the yield is high, which is conducive to large-scale industrial production. Attached Figure Description

[0026] Figure 1 The NMR spectrum of the urolithin A product prepared in Example 1. Detailed Implementation

[0027] The present invention will be further described in detail below with reference to embodiments, so that those skilled in the art can implement it based on the description.

[0028] It should be understood that terms such as “having,” “comprising,” and “including” as used herein do not exclude the presence or addition of one or more other elements or combinations thereof.

[0029] Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, the materials and reagents used in the following examples are commercially available. For examples where specific conditions are not specified, conventional conditions or conditions recommended by the manufacturer are followed. For reagents or instruments whose manufacturers are not specified, they are all commercially available products.

[0030] This invention provides a method for preparing urolithin A. The method uses inexpensive and readily available urolithin B as a raw material and employs potassium persulfate under alkaline conditions for Elbs oxidation to obtain urolithin A in one step. The reaction route is as follows:

[0031]

[0032] Wherein, Formula I is the chemical structural formula of urolithin B, and Formula II is the chemical structural formula of urolithin A.

[0033] The reaction mechanism involves the oxidation of phenol by potassium persulfate under alkaline conditions, followed by hydrolysis, thereby introducing a phenolic hydroxyl group at the para-position of phenol. This is determined by the keto-enol tautomerism of phenol. The oxygen atom of the persulfate undergoes electrophilic substitution at the para-position of phenol, followed by hydrolysis to obtain the target product. The reverse mechanism is shown below:

[0034]

[0035] In a preferred embodiment, the method for preparing urolithin A includes the following steps:

[0036] S1. Urolithin B is reacted with potassium persulfate in a strongly alkaline aqueous solution. After the reaction is completed, the product is acidified to obtain crude urolithin A.

[0037] S2. The crude urolithin A is hot-beaten with an aqueous acetic acid solution and recrystallized to finally obtain the urolithin A product.

[0038] In a preferred embodiment, the alkali in the strongly alkaline aqueous solution in step 1 includes, but is not limited to, sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.

[0039] In a preferred embodiment, in step 1, the molar ratio of alkali to urolithin B in the strongly alkaline aqueous solution is 6:1 to 3:1. For example, it can be 6:1, 5:1, 4:1, 3:1, or any combination thereof, with 5:1 being the most preferred.

[0040] In a preferred embodiment, the reaction time in step 1 is 6-12 hours, for example, it can be 6, 8, 10, 12 hours or any combination thereof, with 8 hours being the most preferred. The reaction temperature is 30-60°C, for example, it can be 30°C, 40°C, 50°C, 60°C or any combination thereof, with 40°C being the most preferred.

[0041] The volume of water used in step 1 is 8 to 15 times the weight of urolithin B, expressed in milliliters per gram. For example, it can be 8, 10, 12, 13, 15 times or any combination thereof, with 12 times being the most preferred.

[0042] In a preferred embodiment, the molar ratio of potassium persulfate and urolithin B in step 1 is 1.5:1 to 1, for example, it can be 1.5:1, 1.3:1, 1.2:1, 1.1:1 or any value formed by any two of them, with 1.2:1 being the most preferred.

[0043] In a preferred embodiment, step 1 involves acidification using an aqueous sulfuric acid solution. The concentration of the aqueous sulfuric acid solution is 10 wt% to 40 wt%, for example, it can be 10%, 20%, 30%, 40%, or any combination thereof, with 30% being the most preferred.

[0044] In a preferred embodiment, the volume of the sulfuric acid aqueous solution in step 1 is 1.5-2.5 times the weight of urolithin B, expressed in milliliters / grams, and can be 1.5, 1.8, 2.0, 2.5 or any combination thereof, with 2.0 times being the most preferred.

[0045] In a preferred embodiment, the acetic acid aqueous solution in step 2 is 5 to 8 times that of urolithin B, in milliliters / gram. For example, it can be 5, 6, 7, 8 times or any combination of these values, with 6 times being the most preferred.

[0046] In a preferred embodiment, the hot beating temperature in step 2 is 80-100℃, for example, it can be 80℃, 85℃, 90℃, 100℃ or any combination thereof, with 90℃ being the most preferred. The beating time is 1-3 hours, for example, it can be 1, 1.5, 2, 2.5, 3 hours or any combination thereof, with 2 hours being the most preferred.

[0047] In a preferred embodiment, the method for preparing urolithin A includes the following steps:

[0048] S1. Add urolithin B to an aqueous sodium hydroxide solution and stir until urolithin B is completely dissolved to obtain an alkaline solution of urolithin B. Add the alkaline solution of urolithin B dropwise to a potassium persulfate solution and react at 30-60℃ for 6-12 hours. After the reaction is completed, cool down and then add an aqueous sulfuric acid solution to adjust the pH to 3-4. Stir, filter, and wash the filter cake with water to obtain crude urolithin A.

[0049] S2. Add crude urolithin A to an aqueous acetic acid solution, heat and stir at 80-100℃ for 1-3 hours to perform hot slurrying, then cool and recrystallize, filter, wash the filter cake with an aqueous acetic acid solution, and vacuum dry to finally obtain the urolithin A product.

[0050] The above is the general concept of the present invention. Based on this, detailed embodiments and comparative examples are provided below to further illustrate the present invention.

[0051] Example 1

[0052] S1. Preparation of crude urolithin A

[0053]

[0054] Add 10L of water to a 20L three-necked flask, then add potassium persulfate (1946g, 7.2mol), and heat to 40℃ to completely dissolve the potassium persulfate to obtain a potassium sulfate solution.

[0055] To prepare an alkaline solution of urolithin B: Add 5L of water and urolithin B (1272g, 6mol) to a 10L flask. After adding the urolithin B, cool the flask to below 10℃. Add sodium hydroxide (1200g, 30mol) in batches slowly. During the addition process, be careful to control the temperature to not exceed 30℃. After adding the urolithin B, keep the temperature at 30℃ and stir thoroughly for 30 minutes until the urolithin B is completely dissolved to obtain the alkaline solution of urolithin B.

[0056] Urolithin B alkaline solution was slowly added dropwise to potassium persulfate solution, with the temperature controlled not to exceed 40°C during the addition. After the addition was complete, the reaction was kept at this temperature for 8 hours. After the reaction was complete by TLC, the temperature was lowered to about 5°C, and 2.5 L of 30 wt% sulfuric acid aqueous solution was slowly added dropwise, with the temperature controlled not to exceed 25°C during the addition. After the addition was complete, the mixture was kept at this temperature and stirred for 1 hour. The mixture was then filtered, and the filter cake was washed with water to obtain crude urolithin A, with a wet weight of 1808 g.

[0057] S2, Preparation of urolithin A product

[0058] Add 3.8L of water and 3.8L of acetic acid to a 20L three-necked flask, then add 1808g of crude urolithin A. Heat to 90℃, keep warm and stir for 2 hours, then let cool naturally to room temperature (25℃). Filter, wash the filter cake twice with a 50wt% acetic acid aqueous solution, and vacuum dry at 50℃ to obtain 1164g of urolithin A product, with a yield of 85.01%.

[0059] The NMR data for urolitholytic A product are as follows:

[0060] 1H NMR(400MHz,DMSO-d6)δ10.17(s,1H,OH),10.10(s,1H,OH),

[0061] 8.04(d,1H,J=8.8Hz,10-H),7.96(d,1H,J=8.4Hz,1-H),

[0062] 7.45(d,1H,J=2.0Hz,7-H),7.26(dd,1H,J=8.8,2.0Hz,9-H),

[0063] 6.74(dd,1H,J=8.4,2.0Hz,2-H), 6.67(d,1H,J=2.0Hz,4-H);

[0064] Nuclear magnetic resonance spectrum as follows Figure 1 As shown.

[0065] Example 2

[0066] S1. Preparation of crude urolithin A

[0067]

[0068] Add 15L of water to a 50L three-necked flask, then add potassium persulfate (2430g, 9mol), and heat to 50℃ to completely dissolve the potassium persulfate to obtain a potassium sulfate solution.

[0069] To prepare an alkaline solution of urolithin B: Add 5L of water and urolithin B (1272g, 6mol) to a 10L flask. After adding the urolithin B, cool the flask to below 10℃. Add potassium hydroxide (2016g, 36mol) in batches slowly. During the addition process, be careful to control the temperature to not exceed 30℃. After adding the urolithin B, keep the flask at 30℃ and stir thoroughly for 30 minutes until the urolithin B is completely dissolved to obtain an alkaline solution of urolithin B.

[0070] Urolithin B alkaline solution was slowly added dropwise to potassium persulfate solution, with the temperature controlled not to exceed 50°C during the addition. After the addition was complete, the reaction was kept at this temperature for 10 hours. After the TLC reaction was complete, the temperature was lowered to about 5°C, and 3.2 L of 20 wt% sulfuric acid aqueous solution was slowly added dropwise, with the temperature controlled not to exceed 25°C during the addition. After the addition was complete, the mixture was kept at 25°C and stirred for 1 hour. The mixture was then filtered, and the filter cake was washed with water to obtain crude urolithin A with a wet weight of 1725 g.

[0071] S2, Preparation of urolithin A product

[0072] Add 5L of water and 5L of acetic acid to a 20L three-necked flask, then add 1725g of crude urolithin A, heat to 100℃, keep warm and stir for 2 hours, then let cool naturally to room temperature of 25℃; filter, wash the filter cake twice with 50wt% acetic acid aqueous solution, and vacuum dry at 50℃ to obtain 1094g of urolithin A product, with a yield of 79.90%.

[0073] Although the embodiments of the present invention have been disclosed above, they are not limited to the applications listed in the specification and embodiments. They can be applied to various fields suitable for the present invention. For those skilled in the art, other modifications can be easily made. Therefore, without departing from the general concept defined by the claims and their equivalents, the present invention is not limited to the specific details.

Claims

1. A method for preparing urolithin A, characterized in that, This method uses urolithin B as a raw material and undergoes Elbs oxidation with potassium persulfate under alkaline conditions to obtain urolithin A. The reaction route is as follows: Wherein, Formula I is the chemical structural formula of urolithin B, and Formula II is the chemical structural formula of urolithin A; The preparation method of the urolithin A includes the following steps: S1. Urolithin B is reacted with potassium persulfate in a strongly alkaline aqueous solution. After the reaction is completed, the product is acidified to obtain crude urolithin A. S2. The crude urolithin A is hot-beaten with an aqueous acetic acid solution, recrystallized, and finally the urolithin A product is obtained. The alkali in the strongly alkaline aqueous solution in step S1 is sodium hydroxide; In step S1, the molar ratio of alkali to urolithin B in the strongly alkaline aqueous solution is 6:1 to 3:

1. The reaction time in step S1 is 6-12 hours, and the reaction temperature is 30-60°C. In step S1, the molar ratio of potassium persulfate and urolithin B is 1.5:1~1. In step S1, an acidification treatment is performed using an aqueous sulfuric acid solution with a concentration of 10wt% to 40wt%.

2. The method for preparing urolithin A according to claim 1, characterized in that, The hot pulping temperature in step S2 is 80-100℃ and the time is 1-3h.

3. The method for preparing urolithin A according to any one of claims 1-2, characterized in that, Includes the following steps: S1. Add urolithin B to an aqueous sodium hydroxide solution and stir until urolithin B is completely dissolved to obtain an alkaline solution of urolithin B. Add the alkaline solution of urolithin B dropwise to a potassium persulfate solution. After the reaction is complete, cool down and then add an aqueous sulfuric acid solution to adjust the pH to 3-4. Stir, filter, and wash the filter cake with water to obtain crude urolithin A. S2. Add crude urolithin A to an aqueous acetic acid solution, heat and stir to perform hot pulping, then cool and recrystallize, filter, wash the filter cake with an aqueous acetic acid solution, and vacuum dry to finally obtain the urolithin A product.

4. The method for preparing urolithin A according to claim 3, characterized in that, Includes the following steps: S1. Add urolithin B to an aqueous sodium hydroxide solution and stir until urolithin B is completely dissolved to obtain an alkaline solution of urolithin B. Add the alkaline solution of urolithin B dropwise to a potassium persulfate solution and react at 40°C for 8 hours. After the reaction is completed, cool down to 5°C and then add 30wt% sulfuric acid aqueous solution to adjust the pH to 3-4. Stir at 25°C for 1 hour, filter, and wash the filter cake with water to obtain crude urolithin A. S2. Add crude urolithin A to an aqueous acetic acid solution, heat and stir at 90°C for 2 hours to perform hot slurrying, then cool to room temperature for recrystallization, filter, wash the filter cake with a 50wt% aqueous acetic acid solution, and vacuum dry at 50°C to finally obtain the urolithin A product.

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