A method for preparing urolithin a

Abstract

This invention discloses a method for preparing urolithin A, comprising using 2-bromo-5-hydroxybenzoic acid and 4-boronic acid resorcinol as raw materials, and reacting them under reflux in the presence of a first palladium catalyst and a copper-containing catalyst to obtain urolithin A. Specifically, 4-bromoresorcinol and trimethyl borate are used as raw materials, reacting in the presence of a second palladium catalyst and a potassium salt to obtain 4-boronic acid resorcinol; and 3-hydroxybenzoic acid is used as a raw material, reacting with a brominating reagent under acidic conditions to generate 2-bromo-5-hydroxybenzoic acid. The preparation method provided by this invention has the advantages of simple operation, high product purity, high yield, short synthetic route, low equipment requirements, and high input-output ratio, making it easier to industrialize.

Description

Technical Field

[0001] This invention belongs to the field of bioactive substance synthesis technology, specifically relating to a method for preparing urolithin A. Background Technology

[0002] Urolithin A is a natural compound produced by gut microbiota metabolizing ellagitannins in food, and is widely found in plants such as pomegranates, nuts, strawberries, and raspberries. Studies have shown that urolithin A has potential health benefits such as anti-inflammatory effects, anti-aging properties, and protection of mitochondrial function. It falls under the category of "post-biotics," meaning active substances produced by gut microbiota after metabolizing food, and can be used as a raw material for health supplements, cosmetics, and food additives. After ingesting food containing ellagitannins, specific gut microbiota (such as Akkermansia) can convert ellagitannins into urolithin A. However, approximately 40% of the population lacks the relevant functional gut microbiota and cannot effectively produce this substance in their bodies.

[0003] The traditional industrial production route for urolithin A primarily uses 2-bromo-5-hydroxybenzoic acid and resorcinol as starting materials, constructing the parent structure via Ullmann coupling reaction, and then obtaining urolithin A through acetic acid release. However, the 2-bromo-5-hydroxybenzoic acid process requires two steps: methyl protection and high-temperature demethylation with anhydrous aluminum trichloride, generating large amounts of aluminum salt solid waste and acidic wastewater, resulting in high environmental treatment costs. Furthermore, the resorcinol aromatic ring has two equivalent coupling sites, which, under copper catalysis, randomly generate positional isomers with similar polarity to the target product, posing a potential risk to the quality control of high-purity pharmaceutical-grade products. Additionally, the entire process uses a high-temperature, strongly alkaline aqueous phase system, which easily leads to the oxidation of polyphenols to form dark quinone impurities. Excessive use of resorcinol also increases raw material waste and the burden of wastewater treatment. Therefore, existing urolithin A preparation technologies generally suffer from low yields, high production costs, and long synthetic routes, limiting its large-scale application in health products, cosmetics, and food additives.

[0004] Therefore, developing a high-yield, low-cost method for preparing urolithin A with a short synthetic route has significant practical application value. Summary of the Invention

[0005] The purpose of this invention is to overcome the shortcomings and deficiencies of the prior art and provide a high-yield preparation method for urolithin A. This preparation method uses 2-bromo-5-hydroxybenzoic acid and 4-boronic acid resorcinol as substrates, and utilizes 4-boronic acid resorcinol as a site-specific coupling substrate. By leveraging the site specificity of Suzuki coupling, carbon-carbon bonds are specifically formed at the boric acid substitution sites, eliminating the risk of the formation of positional isomers of urolithin A from the reaction source. It has the advantages of short synthetic route, high reaction conversion rate, low equipment requirements, simple operation, low production cost, and easier industrialization.

[0006] To achieve the above objectives, the present invention provides a method for preparing urolithin A, comprising the steps of: using 2-bromo-5-hydroxybenzoic acid and 4-boronic acid resorcinol as raw materials, and reacting under reflux in the presence of a first palladium catalyst and a copper-containing catalyst to obtain urolithin A.

[0007] In one specific embodiment, during the reflux reaction to obtain urolithin A, the molar ratio of 2-bromo-5-hydroxybenzoic acid to 4-boronic acid resorcinol is 1:1 to 1:2.5, the molar ratio of 2-bromo-5-hydroxybenzoic acid to the first palladium catalyst is 1:0.001 to 1:0.1, and the molar ratio of 2-bromo-5-hydroxybenzoic acid to the copper-containing catalyst is 1:3 to 1:5. Preferably, the reflux reaction temperature in this step is 80℃ to 100℃, and the reaction time is 3 to 6 hours. Thus, the core aromatic ring skeleton of urolithin A is constructed via palladium catalysis in the second organic phase at 80℃ to 100℃, with only a short-term auxiliary lactone ring closure by low-concentration copper sulfate, effectively avoiding the severe oxidation side reactions of polyhydroxyphenols under traditional high-temperature, strong-alkali conditions. The yield of urolithin A obtained by this method can reach over 75%, and even over 94%.

[0008] To obtain high-purity urolithin A, and with convenient operation and low cost, the preparation method of urolithin A also includes purifying urolithin A using an acid-adjusted crystallization method. Specifically, the reaction solution containing urolithin A obtained after the reflux reaction to synthesize urolithin A is added to water, the pH value of the system is adjusted to 2-6, and after stirring to crystallize, filtering, and drying, the finished urolithin A product is obtained.

[0009] To further reduce costs, the preparation method of 4-boronic acid resorcinol includes: using 4-bromoresorcinol and trimethyl borate as raw materials, reacting them under the action of a second palladium catalyst and potassium salt to obtain 4-boronic acid resorcinol.

[0010] In one specific embodiment, the method for preparing 4-boronic acid resorcinol includes: reacting 4-bromoresorcinol and trimethyl borate under reflux at 50°C to 100°C in the presence of a second palladium catalyst and a potassium salt; then cooling to 30°C to 50°C, adding acid to adjust the pH to 1 to 3, and stirring for 2 to 5 hours to synthesize 4-boronic acid resorcinol; wherein the molar ratio of 4-bromoresorcinol to trimethyl borate is 1:2 to 1:3, the molar ratio of the second palladium catalyst to 4-bromoresorcinol is 0.005:1 to 0.05:1, and the molar ratio of 4-bromoresorcinol to potassium salt is 1:0.5 to 1:2. Preferably, the reaction time for this step is 4 to 7 hours. The yield of 4-boronic acid resorcinol obtained by this method reaches over 73%, and even over 95%.

[0011] To further improve the purity of 4-boronic acid resorcinol, and to achieve convenient operation and low cost, the preparation method of 4-boronic acid resorcinol also includes a step of purifying 4-boronic acid resorcinol using a solution-crystallization method. Specifically, the reaction solution containing 4-boronic acid resorcinol obtained after the reaction synthesis of 4-boronic acid resorcinol is mixed with water, stirred to induce crystallization, filtered, and dried to obtain purified 4-boronic acid resorcinol.

[0012] To further shorten the synthesis route of urea A and achieve green production, a method for preparing 2-bromo-5-hydroxybenzoic acid includes: reacting 3-hydroxybenzoic acid as a raw material with a brominating reagent under acidic conditions to generate 2-bromo-5-hydroxybenzoic acid. This preparation method directly produces 2-bromo-5-hydroxybenzoic acid from 3-hydroxybenzoic acid via a one-step unprotected regioselective bromination, completely eliminating the methyl protection and aluminum trichloride deprotection steps, and generating no aluminum salt hazardous waste.

[0013] In one specific embodiment, the method for preparing 2-bromo-5-hydroxybenzoic acid includes: reacting 3-hydroxybenzoic acid and the brominating reagent under acidic conditions (pH 2-6) to undergo a bromination reaction to synthesize 2-bromo-5-hydroxybenzoic acid; wherein the molar ratio of 3-hydroxybenzoic acid to the brominating reagent is 1:1 to 1:2. Preferably, the reaction time for this step is 4-7 hours. The yield of 2-bromo-5-hydroxybenzoic acid obtained by this method reaches over 83%, and even over 94%.

[0014] To further improve the purity of 2-bromo-5-hydroxybenzoic acid, and to achieve convenient operation and low cost, the preparation steps of 2-bromo-5-hydroxybenzoic acid also include a step of purifying 2-bromo-5-hydroxybenzoic acid by a solution-crystallization method. Specifically, the reaction solution containing 2-bromo-5-hydroxybenzoic acid obtained after the bromination reaction is mixed with water, stirred to induce crystallization, filtered, and dried to obtain purified 2-bromo-5-hydroxybenzoic acid.

[0015] This invention also provides a urolithin A product obtained by the above preparation method. This urolithin A product can be used as a raw material in the preparation of health products, cosmetics, or food additives.

[0016] Compared with the prior art, the technical solution provided by the present invention has the following characteristics:

[0017] 1) Short synthesis route: The target product urolithin A can be obtained in a maximum of three core reactions, which greatly shortens the production cycle;

[0018] 2) Simple operation: The reaction conditions in each step are mild and the purification method is simple (all adopt crystallization method), requiring no complicated equipment;

[0019] 3) High product yield: The yields of all intermediate products and target products are at a high level;

[0020] 4) Low production cost: The raw materials used are readily available, the amount of catalyst used is small, and the purification process does not require expensive reagents, resulting in a high input-output ratio;

[0021] 5) High product purity: By precisely controlling reaction conditions and crystallization parameters, high-purity finished products can be obtained, meeting the raw material requirements of health products, cosmetics, and food additives, and making it easier to achieve industrial application. Attached Figure Description

[0022] Figure 1 This is the 2-bromo-5-hydroxybenzoic acid product prepared in Example 1. 1 H NMR spectrum;

[0023] Figure 2 This is the 4-boronic acid resorcinol product prepared in Example 3. 1 H NMR spectrum;

[0024] Figure 3 This is the urolithin A product prepared in Example 7. 1 H NMR spectrum. Detailed Implementation

[0025] The present invention will be further described in detail below with reference to the embodiments and accompanying drawings, but the embodiments of the present invention are not limited thereto.

[0026] To make the objectives, technical solutions, and advantages 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.

[0027] The endpoints and any values ​​of the ranges disclosed in this invention are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this invention.

[0028] Unless otherwise specified, all terms used in this invention are commonly used in the relevant field, and all raw materials, equipment, preparation processes, testing methods, etc., unless otherwise specified, are existing technologies in the relevant field. All raw materials and reagents used in this invention are of industrial grade purity.

[0029] To address the problems of low yield, high production cost, and long synthesis routes commonly found in the industrial production of urolithin A, this invention mainly designs a method for preparing urolithin A. This method has advantages such as a short synthesis route, inexpensive and readily available raw materials, high reaction conversion rate, low equipment requirements, simple operation, low production cost, and easier industrialization. Specifically, the specific embodiments of this invention adopt the following technical solutions:

[0030] A method for preparing urolithin A, comprising the following steps:

[0031]

[0032] Preparation of 2-bromo-5-hydroxybenzoic acid: 3-hydroxybenzoic acid and a brominating reagent are reacted in an acidic environment with a pH of 2-6 at a molar ratio of 1:1 to 1:2 for 4-7 h to obtain a reaction solution containing 2-bromo-5-hydroxybenzoic acid; the reaction solution containing 2-bromo-5-hydroxybenzoic acid is added to 2-5 times the volume of water and stirred to induce crystallization. After filtration, the crystals are dried at 30-80℃ for 6-10 h to obtain a 2-bromo-5-hydroxybenzoic acid product with a purity of not less than 95%. Preferably, the brominating reagent is selected from one of N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, carbon tetrabromide, N-bromo-o-sulfonylbenzeneimide, 1,3,5-tribromo-1,3,5-thiazinane-2,4,6-trione, N-bromophthalimide, and Br2; the acid used in the acidic conditions is selected from one of hydrochloric acid, sulfuric acid, nitric acid, and trifluoroacetic acid.

[0033] Preparation of 4-boronic acid resorcinol: 4-bromoresorcinol and trimethyl borate are mixed in a molar ratio of 1:2 to 1:3 and refluxed at 50℃ to 100℃ for 3 to 7 h under the action of a second palladium catalyst and potassium salt; then the temperature is lowered to 30℃ to 50℃, acid is added to adjust the pH to 1 to 3, and the mixture is stirred for 2 to 5 h to obtain a reaction solution containing 4-boronic acid resorcinol; the reaction solution containing 4-boronic acid resorcinol is added to 3 to 8 times the volume of water and stirred to induce crystallization, filtered, and the crystals are dried at 30 to 80℃ for 7 to 10 h to obtain a 4-boronic acid resorcinol product with a purity of not less than 95%. In the synthesis of 4-boronic acid resorcinol, the second palladium catalyst activates the C-Br bond on the benzene ring, mediating the transfer of boron groups. Potassium salt provides anion to replace Br, forming an intermediate containing a methyl borate group. The detached Br reacts with potassium ions to form potassium bromide. The methyl ester group on the intermediate hydrolyzes at pH 1-3 to synthesize the target intermediate, 4-boronic acid resorcinol, while also preventing the oxidation of the phenolic hydroxyl group and the decomposition of the borate group on the target product. During this borylation reaction, the potassium salt also neutralizes acidic byproducts in the reaction system, preventing palladium catalyst poisoning. Without palladium or potassium salt, the borylation reaction is difficult to carry out effectively. To ensure adequate crystallization and crystal purity during the purification of 4-boronic acid resorcinol, the volume of water used for crystallization is preferably 3-8 times the volume of the reaction liquid containing 4-boronic acid resorcinol, such as 2, 3, 4, 5, 6, 7, or 8 times.

[0034] In the synthesis of 4-boronic acid resorcinol, the reaction conversion rate is extremely low or even non-reactive when the reflux reaction temperature is below 50℃, and the reaction conversion rate no longer increases above 100℃, and may even decrease with further increases in temperature. Therefore, the preferred reaction temperatures are 50℃, 60℃, 70℃, 80℃, 90℃, and 100℃. To ensure the successful synthesis and yield of 4-boronic acid resorcinol, the preferred molar ratio of the second palladium catalyst to 4-bromoresorcinol is 0.005:1 to 0.05:1, such as 0.005:1, 0.01:1, 0.02:1, 0.03:1, 0.04:1, 0.05:1, etc.; the preferred molar ratio of 4-bromoresorcinol to potassium salt is 1:0.5 to 1:2, such as 1:0.5, 1:0.8, 1:1, 1:1.2, 1:1.5, 1:1.8, 1:2, etc.; the second palladium catalyst is selected from one of 1,1-bis(diphenylphosphino)ferrocene palladium(II) dichloride, palladium(II) chloride, palladium(II) acetate; the potassium salt is selected from one of potassium acetate, potassium carbonate, potassium chloride, potassium sulfate, potassium nitrate; the acid used to adjust the pH of the system is hydrochloric acid, sulfuric acid, trifluoromethanesulfonic acid, etc.

[0035] Preparation of urolithin A: 2-bromo-5-hydroxybenzoic acid and 4-boronic acid resorcinol are reacted at a molar ratio of 1:1 to 1:2.5 under the combined action of a first palladium catalyst and a copper-containing catalyst at 80-100 °C for 3-6 h to obtain a reaction solution containing urolithin A. This reaction solution containing urolithin A is then added to water at 2-7 times its volume to adjust the pH to 2-6. The mixture is stirred to induce crystallization, filtered, and the crystals are dried at 30-80 °C for 6-10 h to obtain urolithin A product with a purity of 99% or higher. In the preparation of urolithin A, 2-bromo-5-hydroxybenzoic acid and 4-boronic acid resorcinol first undergo Suzuki-Miyaura coupling under the catalysis of the first palladium catalyst, connecting the benzene rings of the two raw materials. Then, a copper-containing catalyst is added to perform copper-catalyzed cyclization to obtain the target product, urolithin A. To ensure that the purity of the crystallized crystals meets the standards during the purification of urolithin A, the volume of water used for crystallization is preferably 2 to 7 times the volume of the reaction liquid containing urolithin A, such as 2, 3, 4, 5, 6, or 7 times.

[0036] To ensure efficient and low-cost synthesis of urolithin A, the molar ratio of 2-bromo-5-hydroxybenzoic acid to the first palladium catalyst is preferably 1:0.001 to 1:0.1, such as 0.001:1, 0.005:1, 0.01:1, 0.03:1, 0.05:1, 0.08:1, 0.1:1, etc.; the molar ratio of 2-bromo-5-hydroxybenzoic acid to the copper-containing catalyst is preferably 1:3 to 1:5, such as 1:3, 1:3.5, 1:4, 1:4.5, 1:5, etc.; the first palladium catalyst is selected from tetrakis(triphenylphosphine)palladium, palladium(II) chloride, palladium(II) acetate, 1,1-bis(diphenylphosphine)di... One of ferrocene palladium dichloride (II); the copper-containing catalyst mainly acts as a single-electron oxidant and as a Lewis acid to complete the cyclization esterification process of carboxyl and phenolic hydroxyl groups, and can be selected from copper powder, copper-bronze tree, CuSO4 hydrate, CuSO4 pentahydrate, anhydrous CuSO4, CuBr, CuCl2, CuBr2, CuOTf (copper trifluoromethanesulfonate (I) toluene complex), Cu(acac)2 (copper acetylacetone), CuCN, Cu2O, CuCl, CuI, CuO and mixtures thereof; the acid used to adjust the pH value is selected from hydrochloric acid, sulfuric acid, nitric acid, trifluoroacetic acid.

[0037] The urolithin A product obtained by the above preparation method can be used as a raw material for preparing health products, cosmetics or food additives.

[0038] Example 1: Preparation of 2-bromo-5-hydroxybenzoic acid

[0039]

[0040] 1 kg of 3-hydroxybenzoic acid (approximately 7.25 mol) was dissolved in 10 L of acetonitrile, followed by the addition of 0.66 kg of concentrated sulfuric acid (98%) and stirring for 30 min. Subsequently, 1.51 kg of N-bromosuccinimide (approximately 8.48 mol) was added, and the reaction was continued with stirring for 5 h. The reaction solution was poured into 30 L of water, stirred to induce crystallization, filtered, and the white filter residue was dried under vacuum at 70 °C for 8 h to obtain 1.5 kg of 2-bromo-5-hydroxybenzoic acid, with a yield of 94.57% and a purity of 98.67%.

[0041] Figure 1 shown 1 H NMR (d-DMSO): δ 7.04 (1H, dd, J = 8.5, 2.5 Hz), 7.47-7.63(2H, 7.53 (dd, J = 2.5, 0.5 Hz), 7.57 (dd, J = 8.5, 0.5 Hz)), δ 9.96 (1H, 0.5Hz), δ 13.21 (1H, 0.5Hz).

[0042] Example 2 Preparation of 2-bromo-5-hydroxybenzoic acid

[0043] 1 kg (approximately 7.25 mol) of 3-hydroxybenzoic acid was dissolved in 10 L of acetonitrile, followed by the addition of 1.0 kg of concentrated sulfuric acid (98%) and stirring for 30 min. Subsequently, 2.0 kg (approximately 8.85 mol) of N-bromophthalimide was added, and the reaction was continued with stirring for 5 h. The reaction solution was poured into 40 L of water, stirred to induce crystallization, filtered, and the white filter residue was dried under vacuum at 70 °C for 8 h to obtain 1.32 kg of 2-bromo-5-hydroxybenzoic acid, with a yield of 83.07% and a purity of 98.48%.

[0044] 1 H NMR (d-DMSO): δ 7.04 (1H, dd, J = 8.5, 2.5 Hz), 7.47-7.63 (2H, 7.53(dd, J = 2.5, 0.5 Hz), 7.57 (dd, J = 8.5, 0.5 Hz)), δ 9.96 (1H, 0.5Hz), δ13.21 (1H, 0.5Hz).

[0045] Example 3 Preparation of 4-Borate Resorcinol

[0046]

[0047] 1 kg (approximately 5.32 mol) of 4-bromoresorcinol was dissolved in 10 kg of N,N-dimethylformamide. Then, 1.34 kg of trimethyl borate (approximately 12.86 mol), 0.039 kg (approximately 0.05 mol) of 1,1-bis(diphenylphosphino)ferrocene palladium(II) dichloride, and 0.78 kg (approximately 7.96 mol) of potassium acetate were added sequentially. The mixture was heated to 100 °C and refluxed for 5 h. The temperature was then lowered to 40 °C, and 5.45 kg of hydrochloric acid (approximately 25.72 mol) was added and stirred for 3 h. After cooling to room temperature, 50 kg of water was added and stirred to induce crystallization. The crystals were filtered, and the residue was dried at 70 °C for 8 h to obtain 0.79 kg of 4-boronic acid resorcinol, with a yield of 95.24% and a purity of 98.73%.

[0048] Figure 2 shown 1 H NMR (d-DMSO): δ 6.44-6.50 (2H, dd, J = 4, 0.5 Hz), 7.51-7.53 (1H, dd, J = 8.0, 0.5 Hz).

[0049] Example 4 Preparation of 4-Borate Resorcinol

[0050] 1 kg (approximately 5.32 mol) of 4-bromoresorcinol was dissolved in 10 kg of N,N-dimethylformamide. Then, 1.78 kg (approximately 17.14 mol) of trimethyl borate, 0.012 kg (approximately 0.05 mol) of palladium(II) acetate, and 1.1 kg (approximately 7.97 mol) of potassium carbonate were added sequentially. The mixture was heated to 80 °C and refluxed for 5 h. The temperature was then lowered to 40 °C, and 7.26 kg (approximately 34.28 mol) of hydrochloric acid was added and stirred for 3 h. After cooling to room temperature, 60 kg of water was added and stirred to induce crystallization. The crystals were filtered, and the residue was dried at 60 °C for 10 h to obtain 0.61 kg of 4-boronic acid resorcinol, with a yield of 73.26% and a purity of 98.36%.

[0051] 1 H NMR (d-DMSO): δ 6.44-6.50 (2H, dd, J = 4, 0.5 Hz), 7.51-7.53 (1H, dd, J = 8.0, 0.5 Hz).

[0052] Example 5 Preparation of 4-Borate Resorcinol

[0053] Take 1 kg of 4-bromoresorcinol (approximately 5.32 mol), dissolve it in 10 kg of N,N-dimethylformamide, then add 1.34 kg (approximately 12.86 mol) of trimethyl borate, 0.02 kg (approximately 0.03 mol) of 1,1-bis(diphenylphosphino)ferrocene palladium(II) dichloride, and 0.78 kg (approximately 4.48 mol) of potassium sulfate sequentially. The mixture is heated to 100 °C and refluxed for 5 h. The temperature is then lowered to 40 °C, and 5.45 kg of hydrochloric acid (approximately 25.72 mol) is added and stirred for 3 h. After cooling to room temperature, 50 kg of water is added and stirred to induce crystallization. After filtration, the filter residue crystals are dried at 70 °C for 8 h to obtain 0.67 kg of 4-boronic acid resorcinol, with a yield of 79.63% and a purity of 97.01%.

[0054] 1 H NMR (d-DMSO): δ 6.44-6.50 (2H, dd, J = 4, 0.5 Hz), 7.51-7.53 (1H, dd, J = 8.0, 0.5 Hz).

[0055] Example 6 Preparation of Urolithin A

[0056]

[0057] Take 1.02 kg of 2-bromo-5-hydroxybenzoic acid (98% purity, approximately 4.72 mol) and 1.22 kg of 4-boronic acid resorcinol (98% purity, approximately 7.76 mol), dissolve them in 20 kg of 1,4-dioxane, then add 0.054 kg (approximately 0.05 mol) of tetrakis(triphenylphosphine)palladium, and reflux at 80 °C for 2 h; then add 20 kg of 20% copper sulfate aqueous solution (approximately 25 mol), heat to 100 °C and reflux for 2 h; after cooling to room temperature, add 30 kg of water, adjust the pH of the system to 3 with sulfuric acid, and stir to precipitate crystals; after filtration, dry the filter residue crystals at 70 °C for 8 h to obtain 0.805 kg of solid urolithin A, with a yield of 75.76% and a purity of 99.38%.

[0058] 1 H NMR (d-DMSO): δ 6.88-6.89 (1H, J = 4, 0.5 Hz), 6.75-6.78 (1H, dd, J= 4, 0.5 Hz)), 7.47-7.48 (1H, dd, J = 4, 0.5Hz), 7.98 (1H, 0.5 Hz), 8.05-8.07 (2H, dd, J = 8, 0.5 Hz), 10.08-10.15 (2H, dd, J = 28, 0.5 Hz).

[0059] Example 7 Preparation of Urolithin A

[0060] Take 1.02 kg of 2-bromo-5-hydroxybenzoic acid (98% purity, approximately 4.72 mol) and 1.09 kg of 4-boronic acid resorcinol (98% purity, approximately 6.94 mol), dissolve them in 20 kg of 1,4-dioxane, then add 0.012 kg (approximately 0.05 mol) of palladium(II) acetate, and reflux at 80 °C for 2 h; then add 20 kg of 15% cuprous chloride aqueous solution (approximately 30.30 mol), heat to 100 °C and reflux for 2 h; after cooling to room temperature, add 30 kg of water, adjust the pH of the system to 3 with hydrochloric acid, and stir to precipitate crystals; after filtration, dry the filter residue crystals at 60 °C for 10 h to obtain 1.01 kg of solid urolithin A, with a yield of 94.70% and a purity of 99.01%.

[0061] Figure 3 shown 1 H NMR (d-DMSO): δ 6.88-6.89 (1H, J = 4, 0.5 Hz), 6.75-6.78 (1H, dd, J = 4, 0.5 Hz)), 7.47-7.48 (1H, dd, J = 4, 0.5Hz), 7.98 (1H, 0.5Hz), 8.05-8.07 (2H, dd, J = 8, 0.5 Hz), 10.08-10.15 (2H, dd, J = 28, 0.5 Hz).

[0062] Example 8 Preparation of urolithin A

[0063] Take 1.02 kg of 2-bromo-5-hydroxybenzoic acid (98% purity, approximately 4.72 mol) and 1.5 kg of 4-boronic acid resorcinol (98% purity, approximately 9.55 mol), dissolve them in 20 kg of 1,4-dioxane, then add 0.037 kg (approximately 0.05 mol) of 1,1-bis(diphenylphosphino)ferrocene palladium(II) dichloride, and reflux at 80 °C for 2 h; then add 20 kg of 20% copper bromide aqueous solution (approximately 17.94 mol), heat to 100 °C and reflux for 2 h; after cooling to room temperature, add 30 kg of water, adjust the pH of the system to 5 with nitric acid, and stir to precipitate crystals; after filtration, dry the filter residue crystals at 70 °C for 8 h to obtain 0.855 kg of solid urolithin A, with a yield of 80.49% and a purity of 99.42%.

[0064] 1H NMR (d-DMSO): δ 6.88-6.89 (1H, J = 4, 0.5 Hz), 6.75-6.78 (1H, dd, J= 4, 0.5 Hz)), 7.47-7.48 (1H, dd, J = 4, 0.5Hz), 7.98 (1H, 0.5 Hz), 8.05-8.07 (2H, dd, J = 8, 0.5 Hz), 10.08-10.15 (2H, dd, J = 28, 0.5 Hz).

[0065] In summary, the method for preparing urolithin A provided in this embodiment of the invention includes the preparation of urolithin A precursor molecules: 2-bromo-5-hydroxybenzoic acid and 4-boronic acid resorcinol, the synthesis and purification of urolithin A, and by optimizing the ratio of reaction raw materials, catalyst selection and process parameters, a three-step method for efficient synthesis of urolithin A is achieved. The total yield of urolithin A synthesized by this three-step method can reach more than 85%, and the purity can reach more than 99%. It has the characteristics of simple operation, high product purity, high yield, short synthesis route, low equipment requirements and high input-output ratio, and is easier to industrialize.

[0066] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them; although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications can still be made to the specific implementation of the present invention or equivalent substitutions can be made to some technical features without departing from the spirit of the technical solutions of the present invention, and all such modifications and substitutions should be covered within the scope of the technical solutions claimed in the present invention.

Claims

1. A method for preparing urolithin A, comprising the steps of: using 2-bromo-5-hydroxybenzoic acid and 4-boronic acid resorcinol as raw materials, and reacting under reflux at 80℃~100℃ in the presence of a first palladium catalyst and a copper-containing catalyst to obtain urolithin A; wherein, The first palladium catalyst is selected from one of tetra(triphenylphosphine)palladium, palladium(II) chloride, palladium(II) acetate, and 1,1-bis(diphenylphosphine)ferrocene palladium(II) chloride.

2. The preparation method according to claim 1, characterized in that, The molar ratio of 2-bromo-5-hydroxybenzoic acid to 4-boronic acid resorcinol is 1:1 to 1:2.5, the molar ratio of 2-bromo-5-hydroxybenzoic acid to the first palladium catalyst is 1:0.001 to 1:0.1, and the molar ratio of 2-bromo-5-hydroxybenzoic acid to the copper-containing catalyst is 1:3 to 1:

5.

3. The preparation method according to claim 1 or 2, characterized in that, It also includes the purification of urolithin A by acid-adjusted crystallization: the reaction solution containing urolithin A obtained after the synthesis of urolithin A by reflux reaction is mixed with 2 to 7 times the volume of the reaction solution of water, the pH value of the system is adjusted to 2 to 6, and after stirring, crystallization, filtration and drying, the urolithin A product is obtained.

4. The preparation method according to claim 1 or 2, characterized in that, The preparation method of 4-boronic acid resorcinol includes: using 4-bromoresorcinol and trimethyl borate as raw materials, reacting them in the presence of a second palladium catalyst and a potassium salt to obtain 4-boronic acid resorcinol; wherein, the second palladium catalyst is selected from one of 1,1-bis(diphenylphosphino)ferrocene palladium(II) chloride, palladium(II) chloride, and palladium(II) acetate, and the potassium salt is selected from one of potassium acetate, potassium carbonate, potassium chloride, potassium sulfate, and potassium nitrate.

5. The preparation method according to claim 4, characterized in that, The preparation method of 4-boronic acid resorcinol includes: 4-bromoresorcinol and trimethyl borate reacted under reflux at 50℃~100℃ in the presence of the second palladium catalyst and potassium salt; then the temperature was lowered to 30℃~50℃, acid was added to adjust the pH value to 1~3, and the mixture was stirred for 2~5 h to synthesize 4-boronic acid resorcinol.

6. The preparation method according to claim 5, characterized in that, The molar ratio of 4-bromoresorcinol to trimethyl borate is 1:2 to 1:3, the molar ratio of the second palladium catalyst to 4-bromoresorcinol is 0.005:1 to 0.05:1, and the molar ratio of 4-bromoresorcinol to potassium salt is 1:0.5 to 1:

2.

7. The preparation method according to claim 5 or 6, characterized in that, The method for preparing 4-boronic acid resorcinol also includes purifying 4-boronic acid resorcinol by a solution-crystallization method: the reaction solution containing 4-boronic acid resorcinol obtained after the reaction synthesis of 4-boronic acid resorcinol is mixed with 3 to 8 times the volume of water of the reaction solution, stirred to induce crystallization, filtered, and dried to obtain the purified 4-boronic acid resorcinol product.

8. The preparation method according to claim 1 or 2, characterized in that, The preparation method of 2-bromo-5-hydroxybenzoic acid includes: using 3-hydroxybenzoic acid as a raw material, reacting it with a brominating reagent under acidic conditions to generate 2-bromo-5-hydroxybenzoic acid.

9. The preparation method according to claim 8, characterized in that, The method for preparing 2-bromo-5-hydroxybenzoic acid includes: 3-hydroxybenzoic acid and the brominating reagent undergoing a bromination reaction under acidic conditions of pH 2 to 6 to synthesize 2-bromo-5-hydroxybenzoic acid; wherein the molar ratio of 3-hydroxybenzoic acid to the brominating reagent is 1:1 to 1:

2.

10. The preparation method according to claim 9, characterized in that, The preparation steps of 2-bromo-5-hydroxybenzoic acid also include purifying 2-bromo-5-hydroxybenzoic acid by dissolution crystallization: the reaction solution containing 2-bromo-5-hydroxybenzoic acid obtained after the bromination reaction is mixed with 2 to 5 times the volume of water of the reaction solution, stirred to precipitate crystals, filtered, and dried to obtain the purified 2-bromo-5-hydroxybenzoic acid product.

Images