Industrial-scale preparation method of urolithin compound

Abstract

The invention relates to an industrial-scale preparation method of a urolithin compound, and particularly, the method comprises the following steps: taking hydroxy-9-fluorenone as a raw material, and synthesizing various types of urolithin, including urolithin A, urolithin B, urolithin C, urolithin D and urolithin E, through the steps of hydroxyl protection, Baeyer-Villiger reaction, hydroxyl deprotection and the like. The novel method for synthesizing the urolithin compound is provided, synthesis steps are simple, raw materials are low in price and easy to obtain, pollution to the environment is small, the yield is high, and the method is suitable for large-scale production and has important significance on industrial production of the urolithin compound.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a new industrial-scale preparation method of urolithin compounds. Background Art

[0002] Ellagitannins and ellagic acid are polyphenolic antioxidants widely distributed in a variety of vegetables, fruits and nuts. They are poorly absorbed in the gastrointestinal tract and have low bioavailability, but some of them are converted into more easily absorbed urolithin metabolites by mammalian intestinal microorganisms. Natural urolithins are not common in nature, but as metabolites of ellagic tannins or ellagic acid, they are widely distributed in the urine, feces and bile of mammals such as humans, rats, mice, cattle and pigs. Urolithins are produced under the action of intestinal flora. Urolithin A and Urolithin B were first isolated as ellagic acid metabolites from sheep kidney stones.

[0003] In recent years, there has been an increasing number of studies on the biological activity, tissue distribution, and in vivo metabolic processes of urolithin compounds at home and abroad. Studies have reported that a substance called urolithin A in pomegranates and other fruits may help slow down certain aging processes by improving the function of cell mitochondria; in addition, the intake of this compound does not pose a risk to human health. Studies have shown that urolithin A can stimulate mitochondrial biogenesis in the same way as regular exercise. It is a compound that can rebuild the recycling of defective mitochondria in cells and has biological activities such as antioxidant, anti-inflammatory, anti-cancer, and regulation of intestinal flora. However, naturally occurring urolithin is not common in nature, so there is an urgent need to develop methods for artificially synthesizing urolithin.

[0004] Patents WO2015100213A2 and WO2019168972A1 disclose the synthesis of urolithin A by Ullmann coupling reaction of 2-bromo-5-methoxybenzoic acid and 2-bromo-5-hydroxybenzoic acid with resorcinol under the catalysis of copper sulfate. Although the steps are simple, the total yield is low (WO2015100213A2 reports that the maximum total yield of two steps is 67.6%, and WO2019168972A reports that the maximum total yield of two steps is 52.9%). CN111978282A discloses the synthesis of urolithin A by coupling reaction using boric acid compounds as raw materials, and then "deprotection->sulfonylation->lactonization->re-deprotection". The synthesis route is cumbersome and uses more expensive raw material boric acid compounds, which is not better than the Ullmann coupling reaction route.

[0005] Therefore, the present invention needs to provide a new synthesis method of urolithin compounds with easy-to-obtain raw materials and high yield. Summary of the invention

[0006] The purpose of the present invention is to provide a new method for synthesizing urolithin compounds by using hydroxy-9-fluorenone as a raw material through three steps including hydroxyl protection, Baeyer-Villiger reaction and hydroxyl deprotection.

[0007] The present invention provides a method for preparing compound (I), the method comprising the steps of: S2: in the presence of a peracid, compound (II) undergoes an oxidation reaction to generate compound (I):

[0008] Compound (II):

[0009] Compound (I):

[0010] In the formula, R1′, R2′, R3′, R4′, R5′, R6′, R7′ and R8′ are independently selected from the following groups: H, OH, C1-C4 alkyl, C1-C4 haloalkyl, OR; R is independently selected from the following group: C1-C4 alkyl, hydroxyl protecting group, or R and the connected O atom form a heterocyclic alkyl group containing at least one O heteroatom; or when two ORs are in adjacent positions, the two Rs together form -C1-C3 alkylene-;

[0011] and optionally S3: when there is an -O-hydroxy protecting group in compound (II), subjecting the product obtained in step (1) to hydroxyl deprotection reaction to generate compound (I).

[0012] In another preferred embodiment, before S2, the method further includes the step: S1: reacting -OH in R1′, R2′, R3′, R4′, R5′, R6′, R7′ and R8′ with a hydroxyl protecting agent to generate a compound II having an -O-hydroxyl protecting group.

[0013] In another preferred embodiment, the peracid is peroxytrifluoroacetic acid, p-nitroperbenzoic acid, meta-chloroperbenzoic acid, perbenzoic acid, or peracetic acid, and the preferred peracid is meta-chloroperbenzoic acid.

[0014] In another preferred embodiment, the hydroxyl protecting group is selected from the following group: methyl, tert-butyl (tBu), benzyl (Bn), 3,4-dihydropyranyl (DHP), p-methoxybenzyl, trityl and C1-C6 alkylsilyl.

[0015] In another preferred embodiment, the reaction in S2 is carried out in the presence of another protic acid, such as trifluoroacetic acid, trichloroacetic acid, tribromoacetic acid, or a combination thereof.

[0016] In another preferred embodiment, in compound (I), R7′ is OH.

[0017] In another preferred embodiment, in compound (II), R1′, R5′ and R6′ are all H, and R2′, R3′, R4′, R7′ and R8′ are independently selected from: H, OH, OBn or O-DHP.

[0018] In another preferred embodiment, in compound (I), R1′, R5′ and R6′ are all H, and R2′, R3′, R4′, R7′ and R8′ are independently selected from: H and OH.

[0019] In another preferred embodiment, in compound (II), R1′, R3′, R4′, R5′, R6′ and R8′ are all H, and R2′ and R7′ are all OBn or O-DHP.

[0020] In another preferred embodiment, compound (I) is urolithin A

[0021] In another preferred embodiment, in compound (II), R1′, R2′, R3′, R4′, R5′, R6′ and R8′ are all H, and R7′ is OBn or O-DHP.

[0022] In another preferred embodiment, compound (I) is urolithin B

[0023] In another preferred embodiment, in compound (II), R1′, R4′, R5′, R6′ and R8′ are all H, and R2′, R3′ and R7′ are all OBn or O-DHP.

[0024] In another preferred embodiment, compound (I) is urolithin C

[0025] In another preferred embodiment, in compound (II), R1′, R4′, R5′ and R6′ are all H, and R2′, R3′, R7′ and R8′ are all OBn or O-DHP.

[0026] In another preferred embodiment, compound (I) is urolithin D

[0027] In another preferred embodiment, in compound (II), R1′, R3′, R5′ and R6′ are all H, and R2′, R4′, R7′ and R8′ are all OBn or O-DHP.

[0028] In another preferred embodiment, compound (I) is urolithin E

[0029] In another preferred embodiment, the method comprises the steps of:

[0030] S1: In an inert solvent, hydroxy-9-fluorenone and a hydroxy protecting agent undergo a hydroxy protecting reaction to obtain compound II;

[0031] S2: Compound II undergoes Baeyer-Villiger reaction in an inert solvent in the presence of a peracid to obtain compound III;

[0032] S3: In an inert solvent, compound III undergoes a hydroxyl deprotection reaction to obtain a compound of formula I.

[0033] Those skilled in the art will appreciate that the structural difference between the hydroxy-9-fluorenone and compound II is that one or more hydroxyl groups in the hydroxy-9-fluorenone exist in the form of -O-hydroxyl protecting groups in compound II. The structural difference between compound III and compound I is that the -O-hydroxyl protecting group in compound III exists in the form of -OH in compound I.

[0034] In another preferred embodiment, the method comprises the steps of:

[0035] S1: In an inert solvent and in the presence of a base, hydroxy-9-fluorenone and a hydroxy protecting agent undergo a hydroxy protecting reaction to obtain compound II;

[0036] S2: Compound II undergoes Baeyer-Villiger reaction in an inert solvent in the presence of trifluoroacetic acid and peracid to obtain compound III;

[0037] S3: In an inert solvent, in the presence of a base and a catalyst, compound III undergoes a hydroxyl deprotection reaction to obtain a compound of formula I.

[0038] In another preferred embodiment, in step S1, the inert solvent is acetone, acetonitrile, tetrahydrofuran, dioxane, toluene, xylene, or a combination thereof, and the preferred solvent is acetone or acetonitrile.

[0039] In another preferred embodiment, the hydroxyl protecting agent in step S1 is benzyl chloride, benzyl bromide, or dihydropyran, preferably benzyl chloride.

[0040] In another preferred embodiment, in step S1, the base is selected from the group consisting of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, or a combination thereof.

[0041] In another preferred embodiment, the molar ratio of hydroxy-9-fluorenone to the hydroxyl protecting agent in step S1 is 1:2 to 1:5, and the preferred molar ratio is 1:3-1:4.

[0042] In another preferred embodiment, the molar ratio of hydroxy-9-fluorenone to the base in step S1 is 1:2 to 1:5, and the preferred molar ratio is 1:3-1:5.

[0043] In another preferred embodiment, in step S1, the reaction temperature is 50-90°C, preferably 60-85°C.

[0044] In another preferred embodiment, in step S1, the reaction time is 3-12 hours, preferably 5-8 hours.

[0045] In another preferred embodiment, step S1 further includes a post-treatment step: cooling the reaction solution of step S1 and filtering it, adding water to the filter cake to slurry, filtering, and drying to obtain compound II.

[0046] In another preferred embodiment, in step S2, the inert solvent is dichloromethane, acetone, acetonitrile, tetrahydrofuran, dioxane, toluene, xylene, or a combination thereof, and the preferred solvent is dichloromethane.

[0047] In another preferred embodiment, in step S2, the peracid is peroxytrifluoroacetic acid, p-nitroperbenzoic acid, meta-chloroperbenzoic acid, perbenzoic acid, or peracetic acid, and the preferred peracid is meta-chloroperbenzoic acid.

[0048] In another preferred embodiment, in step S2, the molar ratio of compound II to peracid is 1:1 to 1:5, and the preferred molar ratio is 1:3 to 1:4.

[0049] In another preferred embodiment, in step S2, the molar ratio of compound II to trifluoroacetic acid is 1:1 to 1:5, and the preferred molar ratio is 1:1 to 1:2.

[0050] In another preferred embodiment, step S2 is reacted under the protection of an inert gas, such as nitrogen or helium.

[0051] In another preferred embodiment, in step S2, the reaction temperature is 30±10°C, preferably 30±5°C.

[0052] In another preferred embodiment, in step S2, the reaction time is 6-24 hours, preferably 8-15 hours.

[0053] In another preferred embodiment, step S2 further includes a post-treatment step: cooling the reaction solution of step S2, adding an aqueous sodium sulfite solution (10±5wt%) and stirring to quench the reaction, adding an aqueous sodium carbonate solution (10±5wt%) and stirring (0.5-1h), standing to separate the liquids, washing the aqueous layer with water and then with saturated brine, standing to separate the liquids, collecting the organic layer and removing dichloromethane to obtain compound III.

[0054] In another preferred embodiment, in step S3, the inert solvent is selected from the following group: anhydrous methanol, anhydrous ethanol, acetonitrile, dichloromethane, tetrahydrofuran, N,N-dimethylformamide, or a combination thereof, and the preferred solvent is anhydrous methanol.

[0055] In another preferred embodiment, in step S3, the catalyst is palladium carbon, platinum carbon or Raney nickel, preferably Raney nickel or palladium carbon, wherein the metal content of the palladium carbon or platinum carbon can be 3-10wt%, preferably 5wt%.

[0056] In another preferred embodiment, in step S3, the mass ratio of the compound III to the catalyst is 100:5 to 100:20, and the preferred mass ratio is 100:7 to 100:15, such as 100:10.

[0057] In another preferred embodiment, in step S3, the reaction temperature is 40±10°C, preferably 40±5°C.

[0058] In another preferred embodiment, in step S3, the base is ammonium formate or ammonium acetate.

[0059] In another preferred example, the molar ratio of the compound III to the base is 1:2 to 1:8, preferably 1:2 to 1:5, and more preferably 1:4.

[0060] In another preferred embodiment, in step S3, the reaction time is 4-16 hours, preferably 5-10 hours. In another preferred embodiment, step S3 further includes a post-treatment step: cooling the reaction solution of step S3, adding N,N-dimethylformamide and stirring (0.5-1 hour), filtering, adding water to the filtrate for crystallization, filtering, and drying to obtain compound I.

[0061] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0062] Figure 1 This is the HPLC purity profile of urolithin A prepared in Example 5.

[0063] Figure 2 The urolithin A prepared in Example 5 1 H NMR spectrum. DETAILED DESCRIPTION

[0064] The inventors have conducted extensive and in-depth research, and through a large number of screenings and tests, provided an industrial-scale preparation method for urolithin compounds. Specifically, hydroxy-9-fluorenone is used as a raw material, and urolithin compounds are synthesized through three steps including hydroxyl protection, Baeyer-Villiger reaction, and hydroxyl deprotection. The method of the present invention has simple synthesis steps, cheap and easy-to-obtain raw materials, low environmental pollution, high yield, and is suitable for large-scale production, which is of great significance to the industrial production of urolithin compounds. The present invention was completed on this basis.

[0065] the term

[0066] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0067] As used herein, when used in reference to a specific recited numerical value, the term "about" means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0068] As used herein, the term "comprising" or "including (comprising)" may be open, semi-closed and closed. In other words, the term also includes "consisting essentially of" or "consisting of".

[0069] As used herein, the term "room temperature" or "normal temperature" refers to a temperature of 4-40°C, preferably, 25±5°C.

[0070] Preparation method

[0071] The present invention provides a method for preparing compound (I), the method comprising the steps of:

[0072] S2: In the presence of peroxyacid, compound (II) undergoes oxidation reaction to generate compound (I):

[0073] Compound (II):

[0074] Compound (I):

[0075] In the formula, R1′, R2′, R3′, R4′, R5′, R6′, R7′ and R8′ are independently selected from the following groups: H, OH, C1-C4 alkyl, C1-C4 haloalkyl, OR; R is independently selected from the following group: C1-C4 alkyl, hydroxyl protecting group, or R and the connected O atom form a heterocyclic alkyl group containing at least one O heteroatom; or when two ORs are in adjacent positions, the two Rs together form -C1-C3 alkylene-;

[0076] and optionally S3: when there is an -O-hydroxy protecting group in compound (II), subjecting the product obtained in step (1) to hydroxyl deprotection reaction to generate compound (I).

[0077] In the present invention, the carbonyl group is converted into lactone mainly by subjecting the 9-fluorenone compound to Baeyer-Villiger reaction.

[0078] As for the substituents on the ring, there is no particular restriction and they can be selected according to the product to be prepared. Optionally, when there is an active group such as OH in the substituents on the ring, protection and deprotection steps are respectively performed before and after the Baeyer-Villiger reaction, and the protection and deprotection operations are common to those skilled in the art and can be selected as needed. For example, common hydroxyl protecting groups include but are not limited to: methyl, tert-butyl (tBu), benzyl (Bn), 3,4-dihydropyranyl (DHP), p-methoxybenzyl, trityl and C1-C6 alkylsilyl.

[0079] In another preferred embodiment, before S2, the method further includes the step: S1: reacting -OH in R1′, R2′, R3′, R4′, R5′, R6′, R7′ and R8′ with a hydroxyl protecting agent to generate a compound II having an -O-hydroxyl protecting group.

[0080] Typically, urolithin compounds that can be prepared by the method of the present invention include but are not limited to: urolithin A, B, C, D and E.

[0081] More specifically, the method comprises the steps of:

[0082] S1: In an inert solvent, hydroxy-9-fluorenone and a hydroxy protecting agent undergo a hydroxy protecting reaction to obtain compound II;

[0083] S2: Compound II undergoes Baeyer-Villiger reaction in an inert solvent in the presence of a peracid to obtain compound III;

[0084] S3: In an inert solvent, compound III undergoes a hydroxyl deprotection reaction to obtain a compound of formula I.

[0085] Those skilled in the art will appreciate that the structural difference between the hydroxy-9-fluorenone and compound II is that one or more hydroxyl groups in the hydroxy-9-fluorenone exist in the form of -O-hydroxyl protecting groups in compound II. The structural difference between compound III and compound I is that the -O-hydroxyl protecting group in compound III exists in the form of -OH in compound I.

[0086] In another preferred embodiment, the method comprises the steps of:

[0087] S1: In an inert solvent and in the presence of a base, hydroxy-9-fluorenone and a hydroxy protecting agent undergo a hydroxy protecting reaction to obtain compound II;

[0088] S2: Compound II undergoes Baeyer-Villiger reaction in an inert solvent in the presence of trifluoroacetic acid and peracid to obtain compound III;

[0089] S3: In an inert solvent, in the presence of a base and a catalyst, compound III undergoes a hydroxyl deprotection reaction to obtain a compound of formula I.

[0090] In another preferred embodiment, the hydroxyl protecting agent in step S1 is benzyl chloride, benzyl bromide, or dihydropyran, preferably benzyl chloride.

[0091] In another preferred embodiment, in step S2, the peracid is peroxytrifluoroacetic acid, p-nitroperbenzoic acid, meta-chloroperbenzoic acid, perbenzoic acid, or peracetic acid, and the preferred peracid is meta-chloroperbenzoic acid.

[0092] In another preferred embodiment, in step S3, the catalyst is palladium carbon, platinum carbon or Raney nickel, preferably Raney nickel or palladium carbon, wherein the metal content of the palladium carbon or platinum carbon can be 3-10wt%, preferably 5wt%.

[0093] The main advantages of the present invention include:

[0094] (1) The starting material used in the method of the present invention is (poly)hydroxy-9-fluorenone, which is cheap.

[0095] (2) The method of the present invention has simple steps, mild conditions, high total yield, and little environmental pollution, and is very suitable for large-scale production, which is of great significance for the industrial production of urolithin compounds.

[0096] The present invention will be further described below in conjunction with specific implementation. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0097] Example 1

[0098] A preparation of compound II, the specific steps are as follows:

[0099]

[0100] Synthesis of compound II: 2,7-dihydroxy-9-fluorenone (50 g, 0.23 mol) was added to 500 mL of acetonitrile, and potassium carbonate (127.7 g, 0.92 mol) was added under stirring. After stirring evenly, 3,4-dihydropyran (68.1 g, 0.81 mol) was added, and the system was heated to reflux. The reaction was reacted for 5-8 hours, and the reaction endpoint was monitored by TLC. The mixture was cooled to room temperature and filtered. 500 mL of purified water was added to the filter cake, and the mixture was slurried for 1 hour, filtered, and dried at 45°C to constant weight to obtain 72.8 g of brick-red solid powder (yield 81.2%), which was compound II.

[0101] Example 2

[0102] A preparation of compound II, the specific steps are as follows:

[0103]

[0104] (1) Synthesis of Compound II: 2,7-dihydroxy-9-fluorenone (50 g, 0.23 mol) was added to 500 mL of acetonitrile, and potassium carbonate (127.7 g, 0.92 mol) was added under stirring. After stirring evenly, benzyl bromide (138.5 g, 0.81 mol) was added, and the system was heated to reflux and reacted for 5-8 hours. The reaction endpoint was monitored by TLC. The mixture was cooled to room temperature and filtered. 500 mL of purified water was added to the filter cake, and the mixture was slurried for 1 hour. The mixture was filtered and dried at 45° C. to constant weight to obtain 85.1 g of a brick-red solid powder (yield 88.4%), which was Compound II.

[0105] Example 3

[0106] A novel method for synthesizing urolithin A specifically comprises the following steps:

[0107]

[0108] (1) Synthesis of Compound II: 2,7-dihydroxy-9-fluorenone (50 g, 0.23 mol) was added to 500 mL of acetonitrile, and potassium carbonate (127.7 g, 0.92 mol) was added under stirring. After stirring evenly, benzyl chloride (102.3 g, 0.81 mol) was added, and the system was heated to reflux and reacted for 5-8 hours. The reaction endpoint was monitored by TLC. The mixture was cooled to room temperature and filtered. 500 mL of purified water was added to the filter cake, and the mixture was slurried for 1 hour. The mixture was filtered and dried at 45° C. to constant weight to obtain 86.9 g of a brick-red solid powder (yield 92.1%), which was Compound II.

[0109] (2) Synthesis of Compound III: Compound II was added to 800 mL of dichloromethane, and meta-chloroperbenzoic acid (173 g, 0.852 mol) was added under stirring, and trifluoroacetic acid (24.1 g, 0.21 mol) was added dropwise. The temperature was raised to 30°C, and nitrogen was introduced to protect the reaction for 10-15 hours. The reaction end point was monitored by TLC, and the temperature was lowered to room temperature. 100 mL of 10% sodium sulfite aqueous solution was added and stirred for 1 hour to quench the reaction, and 10% sodium carbonate aqueous solution was added and stirred for 0.5 hour. The mixture was allowed to stand for separation, and the aqueous layer was washed twice with purified water and once with saturated brine. The mixture was allowed to stand for separation, and dichloromethane was removed from the organic layer under reduced pressure. 76.8 g of brownish yellow solid (yield 84.9%) was obtained, which was Compound III.

[0110] (3) Synthesis of Urolithin A: Compound III was added to 768 mL of anhydrous methanol, 5% palladium-carbon catalyst (7.7 g) was added, and ammonium formate (47.4 g, 0.75 mol) was added under stirring. The temperature was raised to 40° C. and the reaction was carried out for 5-10 hours. The reaction endpoint was monitored by TLC. The temperature was lowered to room temperature, N,N-dimethylformamide was added, and the mixture was stirred for 0.5 hour. The mixture was filtered, and purified water was added to the filtrate for crystallization for 1 hour. The mixture was filtered and dried to obtain 40.7 g of a yellow solid (yield: 94.9%), which was Urolithin A with a HPLC purity of 99.25%.

[0111] Example 4

[0112] A novel method for synthesizing urolithin A specifically comprises the following steps:

[0113]

[0114] (1) Synthesis of Compound II: 2,7-dihydroxy-9-fluorenone (5 kg, 23 mol) was added to 50 L of acetonitrile, and potassium carbonate (12.7 kg, 92 mol) was added under stirring. After stirring, benzyl chloride (10.2 kg, 81 mol) was added, and the system was heated to reflux and reacted for 5-8 hours. The reaction endpoint was monitored by TLC. The mixture was cooled to room temperature and filtered. 50 L of purified water was added to the filter cake, and the mixture was slurried for 1 hour. The mixture was filtered and dried at 45°C to constant weight to obtain 8.5 kg of brick-red solid powder (yield 92%), which was Compound II.

[0115] (2) Synthesis of Compound III: Compound II was added to 80 L of dichloromethane, and meta-chloroperbenzoic acid (17 kg, 8.5 mol) was added under stirring, and trifluoroacetic acid (2.4 kg, 2.1 mol) was added dropwise, and the temperature was raised to 30°C, and nitrogen was introduced to protect the reaction for 10-15 hours. The reaction end point was monitored by TLC, and the temperature was lowered to room temperature, and a 10% aqueous sodium sulfite solution was added and stirred for 1 hour to quench the reaction, and a 10% aqueous sodium carbonate solution was added and stirred for 0.5 hour, and the mixture was allowed to stand for separation, and the aqueous layer was washed twice with purified water and once with saturated brine, and the mixture was allowed to stand for separation, and the organic layer was distilled under reduced pressure to remove dichloromethane. 7.8 kg of brownish yellow solid was obtained, which was Compound III.

[0116] (3) Synthesis of Urolithin A: Compound III was added to 78 L of anhydrous methanol, 5% palladium-carbon catalyst (0.7 kg) was added, and ammonium formate (4.8 kg, 7.6 mol) was added under stirring. The temperature was raised to 40° C. and the reaction was carried out for 5-10 hours. The reaction endpoint was monitored by TLC. The temperature was lowered to room temperature, N,N-dimethylformamide was added, and the mixture was stirred for 0.5 hour. The mixture was filtered, and purified water was added to the filtrate for crystallization for 1 hour. The mixture was filtered and dried to obtain 4.09 kg of a yellow solid, which was Urolithin A. The liquid phase purity was 99.08%.

[0117] Example 5

[0118] A novel method for synthesizing urolithin A specifically comprises the following steps:

[0119]

[0120] (1) Synthesis of Compound II: 2,7-dihydroxy-9-fluorenone (200 kg) was added to 2000 L of acetonitrile, and potassium carbonate (508 kg) was added under stirring. After stirring evenly, benzyl chloride (408 kg) was added, and the system was heated to reflux and reacted for 5-8 hours. The reaction endpoint was monitored by TLC. The mixture was cooled to room temperature and filtered. 2000 L of purified water was added to the filter cake, and the mixture was slurried for 1 hour. The mixture was filtered and dried at 45° C. to constant weight to obtain 348.5 kg of brick-red solid powder, which was Compound II.

[0121] (2) Synthesis of Compound III: Compound I was added to 3200 L of dichloromethane, and meta-chloroperbenzoic acid (680 kg) was added under stirring, and trifluoroacetic acid (96 kg) was added dropwise, and the temperature was raised to 30°C, and nitrogen was introduced to protect the reaction for 10-15 hours. The reaction end point was monitored by TLC, and the temperature was lowered to room temperature, and a 10% aqueous sodium sulfite solution was added and stirred for 1 hour to quench the reaction, and a 10% aqueous sodium carbonate solution was added and stirred for 0.5 hour, and the mixture was allowed to stand for separation, and the aqueous layer was washed twice with purified water and once with saturated brine, and the mixture was allowed to stand for separation, and the organic layer was distilled under reduced pressure to remove dichloromethane. 313 kg of brownish yellow solid was obtained, which was Compound III.

[0122] (3) Synthesis of Urolithin A: Compound II was added to 3120 L of anhydrous methanol, 5% palladium carbon catalyst (28 kg) was added, and ammonium formate (193 kg) was added under stirring. The temperature was raised to 40°C for reaction for 5-10 hours. The reaction endpoint was monitored by TLC. The temperature was lowered to room temperature, N,N-dimethylformamide was added, and stirred for 0.5 hours. The mixture was filtered. Purified water was added to the filtrate for crystallization for 1 hour. The mixture was filtered and dried to obtain 165.2 kg of a yellow solid, which was Urolithin A. The HPLC purity was 99.19% ( Figure 1 ).

[0123] Example 6

[0124] A novel method for synthesizing urolithin B specifically comprises the following steps:

[0125]

[0126] (1) Synthesis of Compound II: 7-Hydroxy-9-fluorenone (50 g, 0.255 mol) was added to 500 mL of acetonitrile, and potassium carbonate (52.8 g, 0.38 mol) was added under stirring. After stirring, benzyl chloride (35.3 g, 0.28 mol) was added, and the system was heated to reflux and reacted for 5-8 hours. The reaction endpoint was monitored by TLC. The mixture was cooled to room temperature and filtered. 500 mL of purified water was added to the filter cake, and the mixture was slurried for 1 hour. The mixture was filtered and dried at 45° C. to constant weight to obtain 66.0 g of a brick-red solid powder (yield 90.6%), which was Compound II.

[0127] (2) Synthesis of Compound III: Compound II was added to 800 mL of dichloromethane, and meta-chloroperbenzoic acid (173 g, 0.852 mol) was added under stirring, and trifluoroacetic acid (24.1 g, 0.21 mol) was added dropwise. The temperature was raised to 30°C, and nitrogen was introduced to protect the reaction for 10-15 hours. The reaction end point was monitored by TLC, and the temperature was lowered to room temperature. 100 mL of 10% sodium sulfite aqueous solution was added and stirred for 1 hour to quench the reaction, and 10% sodium carbonate aqueous solution was added and stirred for 0.5 hour. The mixture was allowed to stand for separation, and the aqueous layer was washed twice with purified water and once with saturated brine. The mixture was allowed to stand for separation, and dichloromethane was removed from the organic layer under reduced pressure. 61.0 g of brownish yellow solid (yield 87.5%) was obtained, which was Compound III.

[0128] (3) Synthesis of Urolithin B: Compound III was added to 768 mL of anhydrous methanol, 5% palladium carbon catalyst (7.7 g) was added, and ammonium formate (19.1 g, 0.30 mol) was added under stirring. The temperature was raised to 40° C. and the reaction was carried out for 5-10 hours. The reaction endpoint was monitored by TLC. The temperature was lowered to room temperature, N,N-dimethylformamide was added, and the mixture was stirred for 0.5 hour. The mixture was filtered, and purified water was added to the filtrate for crystallization for 1 hour. The mixture was filtered and dried to obtain 40.76 g of a yellow solid (yield: 95.2%), which was Urolithin B with an HPLC purity of 99.42%.

[0129] Example 7

[0130] A novel method for synthesizing urolithin C specifically comprises the following steps:

[0131]

[0132] (1) Synthesis of Compound II: 2,3,7-trihydroxy-9-fluorenone (50 g, 0.204 mol) was added to 500 mL of acetonitrile, and potassium carbonate (135.1 g, 0.98 mol) was added under stirring. After stirring evenly, benzyl chloride (84.8 g, 0.673 mol) was added, and the system was heated to reflux and reacted for 5-8 hours. The reaction endpoint was monitored by TLC. The mixture was cooled to room temperature and filtered. 500 mL of purified water was added to the filter cake, and the mixture was slurried for 1 hour. The mixture was filtered and dried at 45° C. to constant weight to obtain 92.7 g of a brick-red solid powder (yield 91.4%), which was Compound II.

[0133] (2) Synthesis of Compound III: Compound II was added to 800 mL of dichloromethane, and meta-chloroperbenzoic acid (173 g, 0.852 mol) was added under stirring, and trifluoroacetic acid (24.1 g, 0.21 mol) was added dropwise. The temperature was raised to 30°C, and nitrogen was introduced to protect the reaction for 10-15 hours. The reaction end point was monitored by TLC, and the temperature was lowered to room temperature. 100 mL of 10% sodium sulfite aqueous solution was added and stirred for 1 hour to quench the reaction, and 10% sodium carbonate aqueous solution was added and stirred for 0.5 hour. The mixture was allowed to stand for separation, and the aqueous layer was washed twice with purified water and once with saturated brine. The mixture was allowed to stand for separation, and dichloromethane was removed from the organic layer under reduced pressure. 85.6 g of brownish yellow solid (yield 89.4%) was obtained, which was Compound III.

[0134] (3) Synthesis of Urolithin C: Compound III was added to 768 mL of anhydrous methanol, 5% palladium carbon catalyst (7.7 g) was added, and ammonium formate (46.5 g, 0.75 mol) was added under stirring. The temperature was raised to 40° C. and the reaction was carried out for 5-10 hours. The reaction endpoint was monitored by TLC. The temperature was lowered to room temperature, N,N-dimethylformamide was added, and the mixture was stirred for 0.5 hour. The mixture was filtered, and purified water was added to the filtrate for crystallization for 1 hour. The mixture was filtered and dried to obtain 38.3 g of a yellow solid (yield: 94.7%), which was Urolithin C with an HPLC purity of 99.28%.

[0135] Example 8

[0136] A novel method for synthesizing urolithin D specifically comprises the following steps:

[0137]

[0138] (1) Synthesis of Compound II: 2,3,7,8-Tetrahydroxy-9-fluorenone (50 g, 0.192 mol) was added to 500 mL of acetonitrile, and potassium carbonate (126.9 g, 0.92 mol) was added under stirring. After stirring evenly, benzyl chloride (102.4 g, 0.81 mol) was added, and the system was heated to reflux and reacted for 5-8 hours. The reaction endpoint was monitored by TLC. The mixture was cooled to room temperature and filtered. 500 mL of purified water was added to the filter cake, and the mixture was slurried for 1 hour. The mixture was filtered and dried at 45° C. to constant weight to obtain 111.8 g of a brick-red solid powder (yield 90.8%), which was Compound II.

[0139] (2) Synthesis of Compound III: Compound II was added to 800 mL of dichloromethane, and meta-chloroperbenzoic acid (173 g, 0.852 mol) was added under stirring, and trifluoroacetic acid (24.1 g, 0.21 mol) was added dropwise. The temperature was raised to 30°C, and nitrogen was introduced to protect the reaction for 10-15 hours. The reaction end point was monitored by TLC, and the temperature was lowered to room temperature. 100 mL of 10% sodium sulfite aqueous solution was added and stirred for 1 hour to quench the reaction, and 10% sodium carbonate aqueous solution was added and stirred for 0.5 hour. The mixture was allowed to stand for separation, and the aqueous layer was washed twice with purified water and once with saturated brine. The mixture was allowed to stand for separation, and dichloromethane was removed from the organic layer under reduced pressure. 102.1 g of brownish yellow solid (yield 89.0%) was obtained, which was Compound III.

[0140] (3) Synthesis of Urolithin D: Compound III was added to 768 mL of anhydrous methanol, 5% palladium carbon catalyst (7.7 g) was added, and ammonium formate (71.1 g, 1.12 mol) was added under stirring. The temperature was raised to 40° C. and the reaction was carried out for 5-10 hours. The reaction endpoint was monitored by TLC. The temperature was lowered to room temperature, N,N-dimethylformamide was added, and the mixture was stirred for 0.5 hour. The mixture was filtered, and purified water was added to the filtrate for crystallization for 1 hour. The mixture was filtered and dried to obtain 40.71 g of a yellow solid (yield: 95.1%), which was Urolithin D. The HPLC purity was 99.43%.

[0141] Example 9

[0142] A novel method for synthesizing urolithin E specifically comprises the following steps:

[0143]

[0144] (1) Synthesis of Compound II: 2,4,7,8-Tetrahydroxy-9-fluorenone (50 g, 0.192 mol) was added to 500 mL of acetonitrile, and potassium carbonate (127.7 g, 0.92 mol) was added under stirring. After stirring evenly, benzyl chloride (102.3 g, 0.81 mol) was added, and the system was heated to reflux and reacted for 5-8 hours. The reaction endpoint was monitored by TLC. The mixture was cooled to room temperature and filtered. 500 mL of purified water was added to the filter cake, and the mixture was slurried for 1 hour. The mixture was filtered and dried at 45° C. to constant weight to obtain 115.3 g of a brick-red solid powder (yield 93.2%), which was Compound II.

[0145] (2) Synthesis of Compound III: Compound II was added to 800 mL of dichloromethane, and meta-chloroperbenzoic acid (173 g, 0.852 mol) was added under stirring, and trifluoroacetic acid (24.1 g, 0.21 mol) was added dropwise. The temperature was raised to 30°C, and nitrogen was introduced to protect the reaction for 10-15 hours. The reaction end point was monitored by TLC, and the temperature was lowered to room temperature. 100 mL of 10% sodium sulfite aqueous solution was added and stirred for 1 hour to quench the reaction, and 10% sodium carbonate aqueous solution was added and stirred for 0.5 hour. The mixture was allowed to stand for separation, and the aqueous layer was washed twice with purified water and once with saturated brine. The mixture was allowed to stand for separation, and dichloromethane was removed from the organic layer under reduced pressure. 98.7 g of brownish yellow solid (yield 83.4%) was obtained, which was Compound III.

[0146] (3) Synthesis of Urolithin E: Compound III was added to 768 mL of anhydrous methanol, 5% palladium carbon catalyst (7.7 g) was added, and ammonium formate (68.2 g, 1.08 mol) was added under stirring. The temperature was raised to 40° C. and the reaction was carried out for 5-10 hours. The reaction endpoint was monitored by TLC. The temperature was lowered to room temperature, N,N-dimethylformamide was added, and the mixture was stirred for 0.5 hour. The mixture was filtered, and purified water was added to the filtrate for crystallization for 1 hour. The mixture was filtered and dried to obtain 39.5 g of a yellow solid (yield: 95.5%), which was Urolithin E with an HPLC purity of 99.14%.

[0147] It can be seen from the above that urolithin compounds can be synthesized on an industrial scale by the method of the present invention, and the method has readily available raw materials, simple operation, mild reaction conditions, high yield, and high product purity, and is very suitable for industrial production.

[0148] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A method for preparing compound (I), characterized in that: The method The following steps are involved: S2: In the presence of peroxyacid, compound (II) undergoes oxidation reaction to generate compound (I): Compound (II): Compound (I): In the formula, R1′, R2′, R3′, R4′, R5′, R6′, R7′ and R8′ are independently selected from the following groups: H, OH, C1-C4 alkyl, C1-C4 haloalkyl, OR; R is independently selected from the following group: C1-C4 alkyl, hydroxyl protecting group, or R and the connected O atom form a heterocyclic alkyl group containing at least one O heteroatom; or when two ORs are in adjacent positions, the two Rs together form -C1-C3 alkylene-; and optionally S3: when there is an -O-hydroxy protecting group in compound (II), subjecting the product obtained in step (1) to hydroxyl deprotection reaction to generate compound (I).

2. The method according to claim 1, characterized in that The method also includes the step: S1: reacting the -OH in R1′, R2′, R3′, R4′, R5′, R6′, R7′ and R8′ with a hydroxyl protecting agent to generate a compound II having an -O-hydroxyl protecting group.

3. The method according to claim 1, characterized in that The peracid is trifluoroacetic acid, p-nitroperbenzoic acid, meta-chloroperbenzoic acid, perbenzoic acid, or peracetic acid, and the preferred peracid is meta-chloroperbenzoic acid.

4. The method according to claim 1, characterized in that In compound (II), R1′, R5′ and R6′ are all H, and R2′, R3′, R4′, R7′ and R8′ are independently selected from: H, OH, OBn or O-DHP.

5. The method according to claim 1, characterized in that Compound (I) is urolithin A Urolithin E Urolithin C Urolithin D Urolithin E 6. The method according to claim 1, characterized in that The method comprises the steps of: S1: In an inert solvent, hydroxy-9-fluorenone and a hydroxy protecting agent undergo a hydroxy protecting reaction to obtain compound II; S2: Compound II undergoes Baeyer-Villiger reaction in an inert solvent in the presence of a peracid to obtain compound III; S3: In an inert solvent, compound III undergoes a hydroxyl deprotection reaction to obtain a compound of formula I.

7. The method according to claim 1, characterized in that The method comprises the steps of: S1: In an inert solvent and in the presence of a base, hydroxy-9-fluorenone and a hydroxy protecting agent undergo a hydroxy protecting reaction to obtain compound II; S2: Compound II undergoes Baeyer-Villiger reaction in an inert solvent in the presence of trifluoroacetic acid and peracid to obtain compound III; S3: In an inert solvent, in the presence of a base and a catalyst, compound III undergoes a hydroxyl deprotection reaction to obtain a compound of formula I.

8. The method according to claim 7, characterized in that Step S1 includes one or more technical features selected from the following group: The inert solvent is acetone, acetonitrile, tetrahydrofuran, dioxane, toluene, xylene, or a combination thereof, and the preferred solvent is acetone or acetonitrile; The hydroxyl protecting agent is benzyl chloride, benzyl bromide, dihydropyran, preferably benzyl chloride; The base is selected from the group consisting of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, or a combination thereof; The molar ratio of hydroxy-9-fluorenone to the hydroxyl protecting agent is 1:2 to 1:5, and the preferred molar ratio is 1:3 to 1:4; The molar ratio of the hydroxy-9-fluorenone base is 1:2 to 1:5, and the preferred molar ratio is 1:3 to 1:5; The reaction temperature is 50-90°C, preferably 60-85°C; The reaction time is 3-12 hours, preferably 5-8 hours; and / or The method further comprises a post-treatment step after step S1: cooling the reaction solution of step S1 and filtering it, adding water to the filter cake to make a pulp, filtering it, and drying it to obtain compound II.

9. The method according to claim 7, characterized in that Step S2 comprises one or more technical features selected from the following group: The inert solvent is dichloromethane, acetone, acetonitrile, tetrahydrofuran, dioxane, toluene, xylene, or a combination thereof, and the preferred solvent is dichloromethane; The peracid is trifluoroacetic acid, p-nitroperbenzoic acid, m-chloroperbenzoic acid, perbenzoic acid, or peracetic acid, and the preferred peracid is m-chloroperbenzoic acid; The molar ratio of the compound II to the peroxyacid is 1:1 to 1:5, and the preferred molar ratio is 1:3 to 1:4; The molar ratio of the compound II to trifluoroacetic acid is 1:1 to 1:5, and the preferred molar ratio is 1:1 to 1:2; Step S2: reacting under the protection of an inert gas, such as nitrogen or helium; The reaction temperature is 30±10°C, preferably 30±5°C; The reaction time is 6-24h, preferably 8-15h; and / or The method further includes a post-treatment step after step S2: cooling the reaction solution of step S2, adding a sodium sulfite aqueous solution (10±5wt%) and stirring to quench the reaction, adding a sodium carbonate aqueous solution (10±5wt%) and stirring (0.5-1h), standing to separate the liquids, washing the aqueous layer with water and then with saturated brine, standing to separate the liquids, collecting the organic layer and removing dichloromethane to obtain compound III.

10. The method according to claim 7, characterized in that Step S3 includes one or more technical features selected from the following group: The inert solvent is selected from the group consisting of anhydrous methanol, anhydrous ethanol, acetonitrile, dichloromethane, tetrahydrofuran, N,N-dimethylformamide, or a combination thereof, preferably anhydrous methanol; The catalyst is palladium carbon, platinum carbon or Raney nickel, and the preferred catalyst is Raney nickel or palladium carbon; The mass ratio of the compound III to the catalyst is 100:5 to 100:20, and the preferred mass ratio is 100:7 to 100:15, such as 100:10; The reaction temperature is 40±10°C, preferably 40±5°C; The base is ammonium formate or ammonium acetate; The molar ratio of the compound III to the base is 1:2 to 1:8, preferably 1:2 to 1:5, more preferably 1:4; The reaction time is 4-16 hours, preferably 5-10 hours; and / or The method further includes a post-treatment step after step S3: cooling the reaction solution of step S3, adding N,N-dimethylformamide and stirring (0.5-1 hour), filtering, adding water to the filtrate for crystallization, filtering, and drying to obtain compound I.

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