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CN119080732A - Industrial scale preparation method of urolithin compounds - Google Patents

Industrial scale preparation method of urolithin compounds Download PDF

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Publication number
CN119080732A
CN119080732A CN202411190402.2A CN202411190402A CN119080732A CN 119080732 A CN119080732 A CN 119080732A CN 202411190402 A CN202411190402 A CN 202411190402A CN 119080732 A CN119080732 A CN 119080732A
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Prior art keywords
compound
reaction
urolithin
acid
hydroxy
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Inventor
宣露露
余建军
沈强
高省
徐钦源
刘佳玲
李阳
凌德彬
丁云康
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Yinfu Pharmaceutical Technology Shanghai Co ltd
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Yinfu Pharmaceutical Technology Shanghai Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本发明涉及一种一种尿石素类化合物的工业规模制备方法，具体地，所述方法包括步骤：以羟基‑9‑芴酮为原料，经过包括羟基保护、Baeyer‑Villiger反应、羟基脱保护等步骤合成了多型号尿石素，包括尿石素A、尿石素B、尿石素C、尿石素D、尿石素E。本发明中的方法提供了一种新颖的合成尿石素类化合物的方法，合成步骤简单，原料廉价易得，对环境污染小，收率高、适合大规模生产，对尿石素类化合物工业化生产具有重要意义。The present invention relates to an industrial-scale preparation method of a urolithin compound. Specifically, the method comprises the steps of: using hydroxy-9-fluorenone as a raw material, synthesizing multiple types of urolithins through steps including hydroxyl protection, Baeyer-Villiger reaction, hydroxyl deprotection, etc., including urolithin A, urolithin B, urolithin C, urolithin D, and urolithin E. The method of the present invention provides a novel method for synthesizing urolithin compounds, with simple synthesis steps, cheap and easily available raw materials, low environmental pollution, high yield, and suitability for large-scale production, which is of great significance to the industrial production of urolithin compounds.

Description

Industrial scale preparation method of urolithin compound
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a novel industrial scale preparation method of urolithin compounds.
Background
Ellagitannins and ellagic acid are polyphenols antioxidants widely distributed in various vegetables, fruits and nuts, which are poorly absorbed in the gastrointestinal tract and have low bioavailability, but are partly converted by mammalian intestinal microorganisms into more readily absorbable urolithin metabolites. Natural urolithin is not common in nature, but is widely distributed in urine, feces and bile of mammals such as humans, rats, mice, cows, pigs, etc., as a metabolite of ellagitannin or ellagic acid. Urolithin is produced by the action of the intestinal flora. Urolithin A (Urolithin A) and urolithin B (Urolithin B) were at the earliest ellagic acid metabolites isolated from sheep kidney stones.
In recent years, research on the biological activity, tissue distribution and in vivo metabolic processes of urolithin compounds at home and abroad is increasing. It has been reported that the substance named urolithin A (Urolithin A) in punica granatum and other fruits can help slow down specific aging processes by improving the function of cell mitochondria, and furthermore, the intake of this compound is not a risk for human body health. Studies have shown that urolithin A stimulates mitochondrial biogenesis in the same manner as regular exercise, is a compound capable of reestablishing cell recirculation to defective mitochondria, and has antioxidant, anti-inflammatory, anticancer and intestinal flora regulating biological activities. However, uroliths naturally occurring in nature are not common, and thus, development of a method for artificially synthesizing uroliths is urgently required.
Patents WO2015100213A2 and WO2019168972A1 disclose the synthesis of urolithin A by Ullmann coupling of 2-bromo-5-methoxybenzoic acid, 2-bromo-5-hydroxybenzoic acid with resorcinol under copper sulphate catalysis, respectively, with low overall yields (WO 2015100213A2 reports a maximum overall yield of 67.6% for the two steps and WO2019168972A reports a maximum overall yield of 52.9% for the two steps). CN111978282a discloses that the coupling reaction is performed by using boric acid compound as raw material, and then the synthetic urolithin a is subjected to deprotection, sulfonylation, lactonization, deprotection, and synthesis route is complicated, and the more expensive raw material boric acid compound is used, which is not better than Ullmann coupling reaction route.
Therefore, the invention needs to provide a new synthesis method of urolithin compounds with easily available raw materials and high yield.
Disclosure of Invention
The invention aims to provide a novel method for synthesizing urolithin compounds by taking hydroxy-9-fluorenone as a raw material and carrying out three steps of hydroxy protection, baeyer-Villiger reaction and hydroxy deprotection.
The invention provides a method for preparing a compound (I), which comprises the following steps of S2, carrying out oxidation reaction on a compound (II) in the presence of peroxyacid to generate the compound (I):
Compound (II):
Compound (I):
wherein R 1′,R2′,R3′,R4′,R5′,R6′,R7 'and R 8' are each independently selected from the group consisting of H, OH, C1-C4 alkyl, C1-C4 haloalkyl, OR, R is independently selected from the group consisting of C1-C4 alkyl, hydroxy protecting group, OR R forms a heterocycloalkyl group containing at least one O heteroatom with the O atom attached, OR two R together form-C1-C3 alkylene-when two OR are in adjacent positions;
And optionally S3, when the-O-hydroxyl protecting group exists in the compound (II), the product obtained in the step (1) is subjected to a hydroxyl deprotection reaction to generate the compound (I).
In another preferred embodiment, prior to S2, the method further comprises the step S1 of reacting-OH in R 1′,R2′,R3′,R4′,R5′,R6′,R7 'and R 8' with a hydroxyl protecting reagent to produce compound II having an-O-hydroxyl protecting group.
In another preferred embodiment, the peroxyacid is peroxytrifluoroacetic acid, p-nitroperoxybenzoic acid, m-chloroperoxybenzoic acid, peroxybenzoic acid, peroxyacetic acid, and the preferred peroxyacid is m-chloroperoxybenzoic acid.
In another preferred embodiment, the hydroxyl protecting group is selected from the group consisting of methyl, t-butyl (tBu), benzyl (Bn), 3, 4-Dihydropyranyl (DHP), p-methoxybenzyl, trityl, and C1-C6 alkylsilyl.
In another preferred embodiment, the reaction in S2 is performed in the presence of another protic acid, such as trifluoroacetic acid, trichloroacetic acid, tribromoacetic acid, or a combination thereof.
In another preferred embodiment, in compound (I), R 7' is OH.
In another preferred embodiment, in compound (II), R 1′、R5 'and R 6' are both H, and R 2′、R3′、R4′、R7 'and R 8' are independently selected from H, OH, OBn or O-DHP.
In another preferred embodiment, in compound (I), R 1′、R5 'and R 6' are both H, and R 2′、R3′、R4′、R7 'and R 8' are independently selected from H and OH.
In another preferred embodiment, in compound (II), R 1′、R3′、R4′、R5′、R6 'and R 8' are both H, and R 2 'and R 7' are both OBn or O-DHP.
In another preferred embodiment, compound (I) is urolithin A
In another preferred embodiment, in compound (II), R 1′,R2′,R3′,R4′,R5′,R6 ' and R 8 ' are both H and R 7 ' is OBn or O-DHP.
In another preferred embodiment, compound (I) is urolithin B
In another preferred embodiment, in compound (II), R 1′,R4′,R5′,R6 'and R 8' are both H, and R 2′,R3 'and R 7' are both OBn or O-DHP.
In another preferred embodiment, compound (I) is urolithin C
In another preferred embodiment, in compound (II), R 1′,R4′,R5 'and R 6' are both H, and R 2′,R3′,R7 'and R 8' are both OBn or O-DHP.
In another preferred embodiment, compound (I) is urolithin D
In another preferred embodiment, in compound (II), R 1′,R3′,R5 'and R 6' are both H, and R 2′,R4′,R7 'and R 8' are both OBn or O-DHP.
In another preferred embodiment, compound (I) is urolithin E
In another preferred embodiment, the method comprises the steps of:
s1, in an inert solvent, hydroxy-9-fluorenone and a hydroxy protecting reagent perform hydroxy protection reaction to obtain a compound II;
S2, in an inert solvent, in the presence of peroxyacid, carrying out Baeyer-Villiger reaction on the compound II to obtain a compound III;
and S3, in an inert solvent, performing hydroxyl deprotection reaction on the compound III to obtain the compound shown in the formula I.
Those skilled in the art understand that the hydroxy-9-fluorenone differs from compound II only in that one or more of the hydroxy groups in the hydroxy-9-fluorenone are present in compound II in the form of an-O-hydroxy protecting group. The structural difference between compound III and compound I is only that the-O-hydroxy protecting group in compound III is present in the form of-OH in compound I.
In another preferred embodiment, the method comprises the steps of:
S1, in an inert solvent, in the presence of alkali, hydroxyl-9-fluorenone and a hydroxyl protecting reagent perform a hydroxyl protecting reaction to obtain a compound II;
s2, in an inert solvent, in the presence of trifluoroacetic acid and peroxyacid, carrying out Baeyer-Villiger reaction on the compound II to obtain a compound III;
and S3, in an inert solvent, carrying out hydroxyl deprotection reaction on the compound III in the presence of alkali and a catalyst to obtain the compound shown in the formula I.
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.
In another preferred embodiment, the hydroxyl protecting agent in step S1 is benzyl chloride, benzyl bromide, dihydropyran, preferably benzyl chloride.
In another preferred embodiment, in step S1, the base is selected from the group consisting of potassium carbonate, sodium bicarbonate, potassium bicarbonate, or a combination thereof.
In another preferred example, in the step S1, the molar ratio of the hydroxy-9-fluorenone to the hydroxy protecting agent is 1:2 to 1:5, and the preferred molar ratio is 1:3 to 1:4.
In another preferred example, in the step S1, the molar ratio of the alkali of the hydroxyl-9-fluorenone is 1:2-1:5, and the preferred molar ratio is 1:3-1:5.
In another preferred embodiment, in step S1, the temperature of the reaction is 50-90 ℃, preferably 60-85 ℃.
In another preferred embodiment, in step S1, the reaction time is 3 to 12 hours, preferably 5 to 8 hours.
In another preferred example, the step S1 further comprises a post-treatment step of cooling the reaction solution obtained in the step S1, filtering, pulping the filter cake by adding water, filtering, and drying to obtain the compound II.
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.
In another preferred example, in step S2, the peroxyacid is peroxytrifluoroacetic acid, paranitroperoxybenzoic acid, m-chloroperoxybenzoic acid, peroxybenzoic acid, peracetic acid, and the preferred peroxyacid is m-chloroperoxybenzoic acid.
In another preferred example, in the step S2, 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.
In another preferred example, in the step S2, the molar ratio of the compound II to trifluoroacetic acid is 1:1-1:5, and the preferred molar ratio is 1:1-1:2.
In another preferred embodiment, step S2 is performed under inert gas such as nitrogen or helium.
In another preferred embodiment, in step S2, the temperature of the reaction is 30.+ -. 10 ℃, preferably 30.+ -. 5 ℃.
In another preferred embodiment, in step S2, the reaction time is from 6 to 24 hours, preferably from 8 to 15 hours.
In another preferred example, the step S2 further comprises a post-treatment step of cooling the reaction solution in the step S2, adding an aqueous solution (10+/-5 wt%) of sodium sulfite, stirring and quenching the reaction, adding an aqueous solution (10+/-5 wt%) of sodium carbonate, stirring (0.5-1 h), standing and separating the solution, washing the aqueous layer with water, washing the aqueous layer with saturated saline, standing and separating the solution, collecting the organic layer, and removing dichloromethane to obtain the compound III.
In another preferred embodiment, in step S3, the inert solvent is selected from the group consisting of absolute methanol, absolute ethanol, acetonitrile, methylene chloride, tetrahydrofuran, N-dimethylformamide, or a combination thereof, and the preferred solvent is absolute methanol.
In another preferred example, in step S3, the catalyst is palladium carbon, platinum carbon or raney nickel, and the preferred catalyst is raney nickel or palladium carbon. Wherein the metal content in the palladium carbon and the platinum carbon can be 3-10wt%, preferably 5wt%.
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.
In another preferred embodiment, in step S3, the temperature of the reaction is 40.+ -. 10 ℃, preferably 40.+ -. 5 ℃.
In another preferred embodiment, in step S3, the base is formic acid amine or acetic acid amine.
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, more preferably 1:4.
In another preferred embodiment, in step S3, the reaction time is 4 to 16 hours, preferably 5 to 10 hours. In another preferred example, the step S3 further comprises a post-treatment step, namely cooling the reaction solution in the step S3, adding N, N-dimethylformamide, stirring (0.5-1 hour), filtering, adding water into the filtrate for crystallization, filtering, and drying to obtain the compound I.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Drawings
FIG. 1 is an HPLC purity profile of urolithin A prepared in example 5.
FIG. 2 is a 1 H NMR spectrum of urolithin A prepared in example 5.
Detailed Description
The inventor provides an industrial scale preparation method of urolithin compounds through extensive and intensive research and massive screening and testing. Specifically, hydroxyl-9-fluorenone is used as a raw material, and the urolithin compound is synthesized through three steps of hydroxyl protection, baeyer-Villiger reaction and hydroxyl deprotection, the method has the advantages of simple synthesis steps, low cost and easy obtainment of raw materials, small environmental pollution, high yield, suitability for large-scale production and great significance for industrial production of the urolithin compounds. The present invention has been completed on the basis of this finding.
Terminology
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.
As used herein, when used in reference to a specifically recited value, the term "about" means that the value can vary no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values therebetween (e.g., 99.1, 99.2, 99.3, 99.4, etc.).
As used herein, the term "comprising" or "including" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of, or" consisting of.
As used herein, the term "room temperature" or "normal temperature" refers to a temperature of 4-40 ℃, preferably 25±5 ℃.
Preparation method
The present invention provides a process for preparing compound (I), comprising the steps of:
s2, in the presence of peroxyacid, the compound (II) is subjected to oxidation reaction to generate a compound (I):
Compound (II):
Compound (I):
wherein R 1′,R2′,R3′,R4′,R5′,R6′,R7 'and R 8' are each independently selected from the group consisting of H, OH, C1-C4 alkyl, C1-C4 haloalkyl, OR, R is independently selected from the group consisting of C1-C4 alkyl, hydroxy protecting group, OR R forms a heterocycloalkyl group containing at least one O heteroatom with the O atom attached, OR two R together form-C1-C3 alkylene-when two OR are in adjacent positions;
And optionally S3, when the-O-hydroxyl protecting group exists in the compound (II), the product obtained in the step (1) is subjected to a hydroxyl deprotection reaction to generate the compound (I).
In the present invention, carbonyl groups are converted into lactones mainly by the Baeyer-Villiger reaction of 9-fluorenones.
While the substituents on the ring are not particularly limited and may be selected according to the desired product to be produced. Optionally, when the substituents on the ring are present with reactive groups such as OH, the Baeyer-Villiger reaction is followed by respective deprotection and deprotection steps, which are common to those skilled in the art and may be chosen as desired. For example, common hydroxyl protecting groups include, but are not limited to, methyl, t-butyl (tBu), benzyl (Bn), 3, 4-Dihydropyranyl (DHP), p-methoxybenzyl, trityl, and C1-C6 alkylsilyl.
In another preferred embodiment, prior to S2, the method further comprises the step S1 of reacting-OH in R 1′,R2′,R3′,R4′,R5′,R6′,R7 'and R 8' with a hydroxyl protecting reagent to produce compound II having an-O-hydroxyl protecting group.
Typically, urolithin-like compounds may be prepared by the methods of the present invention including, but not limited to, urolithin A, B, C, D and E.
More specifically, the method comprises the steps of:
s1, in an inert solvent, hydroxy-9-fluorenone and a hydroxy protecting reagent perform hydroxy protection reaction to obtain a compound II;
S2, in an inert solvent, in the presence of peroxyacid, carrying out Baeyer-Villiger reaction on the compound II to obtain a compound III;
and S3, in an inert solvent, performing hydroxyl deprotection reaction on the compound III to obtain the compound shown in the formula I.
Those skilled in the art understand that the hydroxy-9-fluorenone differs from compound II only in that one or more of the hydroxy groups in the hydroxy-9-fluorenone are present in compound II in the form of an-O-hydroxy protecting group. The structural difference between compound III and compound I is only that the-O-hydroxy protecting group in compound III is present in the form of-OH in compound I.
In another preferred embodiment, the method comprises the steps of:
S1, in an inert solvent, in the presence of alkali, hydroxyl-9-fluorenone and a hydroxyl protecting reagent perform a hydroxyl protecting reaction to obtain a compound II;
s2, in an inert solvent, in the presence of trifluoroacetic acid and peroxyacid, carrying out Baeyer-Villiger reaction on the compound II to obtain a compound III;
and S3, in an inert solvent, carrying out hydroxyl deprotection reaction on the compound III in the presence of alkali and a catalyst to obtain the compound shown in the formula I.
In another preferred embodiment, the hydroxyl protecting agent in step S1 is benzyl chloride, benzyl bromide, dihydropyran, preferably benzyl chloride.
In another preferred example, in step S2, the peroxyacid is peroxytrifluoroacetic acid, paranitroperoxybenzoic acid, m-chloroperoxybenzoic acid, peroxybenzoic acid, peracetic acid, and the preferred peroxyacid is m-chloroperoxybenzoic acid.
In another preferred example, in step S3, the catalyst is palladium carbon, platinum carbon or raney nickel, and the preferred catalyst is raney nickel or palladium carbon. Wherein the metal content in the palladium carbon and the platinum carbon can be 3-10wt%, preferably 5wt%.
The main advantages of the invention include:
(1) The method of the invention uses (poly) hydroxy-9-fluorenone as the initial raw material, and has low price.
(2) The method has the advantages of simple steps, mild conditions, high total yield, small environmental pollution, suitability for large-scale production and great significance for industrial production of the urolithin compounds.
The invention is further described below in conjunction with the specific embodiments. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
Example 1
The preparation of the compound II comprises the following specific steps:
Synthesis of Compound II by adding 2, 7-dihydroxy-9-fluorenone (50 g,0.23 mol) to 500mL of acetonitrile, adding potassium carbonate (127.7 g,0.92 mol) with stirring, adding 3, 4-dihydropyran (68.1 g,0.81 mol) after stirring uniformly, heating the system to reflux, reacting for 5-8 hours, monitoring the reaction endpoint by TLC, cooling to room temperature, filtering, adding 500mL of purified water into the filter cake, pulping for 1 hour, filtering, and drying by 45 ℃ air blast to constant weight to obtain 72.8g (yield 81.2%) of brick red solid powder, namely Compound II.
Example 2
The preparation of the compound II comprises the following specific steps:
(1) Synthesis of Compound II by adding 2, 7-dihydroxy-9-fluorenone (50 g,0.23 mol) to 500mL of acetonitrile, adding potassium carbonate (127.7 g,0.92 mol) under stirring, adding benzyl bromide (138.5 g,0.81 mol) after stirring uniformly, heating the system to reflux, reacting for 5-8 hours, monitoring the reaction endpoint by TLC, cooling to room temperature, filtering, adding 500mL of purified water into the filter cake, pulping for 1 hour, filtering, and drying to constant weight by 45 ℃ air blast to obtain 85.1g (yield 88.4%) of brick red solid powder, namely Compound II.
Example 3
The new method for synthesizing urolithin A specifically comprises the following steps:
(1) Synthesis of Compound II by adding 2, 7-dihydroxy-9-fluorenone (50 g,0.23 mol) to 500mL of acetonitrile, adding potassium carbonate (127.7 g,0.92 mol) under stirring, adding benzyl chloride (102.3 g,0.81 mol) after stirring uniformly, heating the system to reflux, reacting for 5-8 hours, monitoring the reaction endpoint by TLC, cooling to room temperature, filtering, adding 500mL of purified water into the filter cake, pulping for 1 hour, filtering, and drying to constant weight by 45 ℃ air blast to obtain 86.9g (yield 92.1%) of brick red solid powder, namely Compound II.
(2) Synthesis of Compound III, namely adding compound II into 800mL of dichloromethane, adding m-chloroperoxybenzoic acid (173 g,0.852 mol) under stirring, dropwise adding trifluoroacetic acid (24.1 g,0.21 mol), heating to 30 ℃, introducing nitrogen for protection reaction for 10-15 hours, monitoring the reaction end point by TLC, cooling to room temperature, adding 100mL of 10% sodium sulfite aqueous solution, stirring for 1 hour, quenching the reaction, adding 10% sodium carbonate aqueous solution, stirring for 0.5 hour, standing for separating, washing the water layer twice with purified water, washing once with saturated saline, standing for separating, and distilling the organic layer under reduced pressure to remove dichloromethane. 76.8g (yield 84.9%) of compound III was obtained as a tan solid.
(3) Synthesis of urolithin A by adding 768mL of anhydrous methanol to compound III, adding 5% palladium-carbon catalyst (7.7 g), adding ammonium formate (47.4 g,0.75 mol) under stirring, heating to 40 ℃ for reaction for 5-10 hours, TLC monitoring the reaction end point, cooling to room temperature, adding N, N-dimethylformamide, stirring for 0.5 hours, filtering, adding purified water to filtrate for crystallization for 1 hour, filtering, drying to obtain yellow solid (40.7 g, yield: 94.9%), namely urolithin A, and HPLC purity of 99.25%.
Example 4
The new method for synthesizing urolithin A specifically comprises the following steps:
(1) The synthesis of the compound II comprises the steps of adding 2, 7-dihydroxyl-9-fluorenone (5 kg,23 mol) into 50L of acetonitrile, adding potassium carbonate (12.7 kg,92 mol) under stirring, adding benzyl chloride (10.2 kg,81 mol) after stirring uniformly, heating a system to reflux, reacting for 5-8 hours, monitoring the reaction endpoint by TLC, cooling to room temperature, filtering, adding 50L of purified water into a filter cake, pulping for 1 hour, filtering, and drying to constant weight by 45 ℃ air blast to obtain 8.5kg (yield 92%) of brick red solid powder, namely the compound II.
(2) The synthesis of the compound III comprises the steps of adding 80L of dichloromethane into the compound II, adding m-chloroperoxybenzoic acid (17 kg,8.5 mol) under stirring, dropwise adding trifluoroacetic acid (2.4 kg,2.1 mol), heating to 30 ℃, introducing nitrogen for protecting reaction for 10-15 hours, monitoring the reaction end point by TLC, cooling to room temperature, adding 10% sodium sulfite aqueous solution, stirring for 1 hour, quenching the reaction, adding 10% sodium carbonate aqueous solution, stirring for 0.5 hour, standing for separating, washing the water layer twice with purified water, washing with saturated saline water, standing for separating, and distilling the organic layer under reduced pressure to remove the dichloromethane. 7.8kg of a brown yellow solid is obtained, namely the compound III.
(3) The synthesis of urolithin A comprises the steps of adding 78L of anhydrous methanol into a compound III, adding 5% of palladium-carbon catalyst (0.7 kg), adding ammonium formate (4.8 kg,7.6 mol) into the mixture under stirring, heating the mixture to 40 ℃ for reacting for 5 to 10 hours, monitoring the reaction end point by TLC, cooling the mixture to room temperature, adding N, N-dimethylformamide into the mixture, stirring the mixture for 0.5 hour, filtering the mixture, adding purified water into the filtrate for crystallization for 1 hour, filtering the filtrate, and drying the filtrate to obtain yellow solid (4.09 kg) which is urolithin A, wherein the liquid phase purity is 99.08 percent.
Example 5
The new method for synthesizing urolithin A specifically comprises the following steps:
(1) The synthesis of the compound II comprises the steps of adding 2, 7-dihydroxyl-9-fluorenone (200 kg) into 2000L acetonitrile, adding potassium carbonate (508 kg) under stirring, adding benzyl chloride (408 kg) after stirring uniformly, heating a system to reflux, reacting for 5-8 hours, monitoring the reaction end point by TLC, cooling to room temperature, filtering, adding 2000L of purified water into a filter cake, pulping for 1 hour, filtering, and drying to constant weight by 45 ℃ in a blowing way to obtain 348.5kg of brick red solid powder, namely the compound II.
(2) The synthesis of the compound III comprises the steps of adding 3200L of dichloromethane into the compound I, adding m-chloroperoxybenzoic acid (680 kg) into the mixture under stirring, dropwise adding trifluoroacetic acid (96 kg), heating to 30 ℃, introducing nitrogen for protecting and reacting for 10-15 hours, monitoring the reaction end point by TLC, cooling to room temperature, adding 10% sodium sulfite aqueous solution into the mixture, stirring for 1 hour, quenching the reaction, adding 10% sodium carbonate aqueous solution into the mixture, stirring for 0.5 hour, standing for separating, washing the water layer twice with purified water, washing the water layer once with saturated saline, standing for separating, and distilling the organic layer under reduced pressure to remove the dichloromethane. 313kg of a brown yellow solid is obtained, namely the compound III.
(3) And (3) synthesizing urolithin A, namely adding 3120L of anhydrous methanol into a compound II, adding 5% of palladium-carbon catalyst (28 kg), adding ammonium formate (193 kg) under stirring, heating to 40 ℃ for reacting for 5-10 hours, monitoring the reaction end point by TLC, cooling to room temperature, adding N, N-dimethylformamide, stirring for 0.5 hour, filtering, adding purified water into filtrate for crystallization for 1 hour, filtering, and drying to obtain 165.2kg of yellow solid, namely urolithin A. HPLC purity 99.19% (fig. 1).
Example 6
The new method for synthesizing urolithin B specifically comprises the following steps:
(1) Synthesis of Compound II 7-hydroxy-9-fluorenone (50 g,0.255 mol) was added to 500mL of acetonitrile, potassium carbonate (52.8 g,0.38 mol) was added with stirring, benzyl chloride (35.3 g,0.28 mol) was added after stirring well, the system was heated to reflux, the reaction was allowed to proceed for 5-8 hours, TLC was monitored for the end point of the reaction, cooled to room temperature and then filtered, 500mL of purified water was added to the filter cake, slurried for 1 hour, filtered, and air-dried at 45℃until the weight was constant, to give 66.0g (yield 90.6%) of a brick-red solid powder, namely Compound II.
(2) Synthesis of Compound III, namely adding compound II into 800mL of dichloromethane, adding m-chloroperoxybenzoic acid (173 g,0.852 mol) under stirring, dropwise adding trifluoroacetic acid (24.1 g,0.21 mol), heating to 30 ℃, introducing nitrogen for protection reaction for 10-15 hours, monitoring the reaction end point by TLC, cooling to room temperature, adding 100mL of 10% sodium sulfite aqueous solution, stirring for 1 hour, quenching the reaction, adding 10% sodium carbonate aqueous solution, stirring for 0.5 hour, standing for separating, washing the water layer twice with purified water, washing once with saturated saline, standing for separating, and distilling the organic layer under reduced pressure to remove dichloromethane. 61.0g (yield 87.5%) of compound III are obtained as a tan solid.
(3) Synthesis of urolithin B by adding 768mL of anhydrous methanol to compound III, adding 5% palladium-carbon catalyst (7.7 g), adding ammonium formate (19.1 g,0.30 mol) under stirring, heating to 40 ℃ for reaction for 5-10 hours, TLC monitoring the reaction end point, cooling to room temperature, adding N, N-dimethylformamide, stirring for 0.5 hours, filtering, adding purified water to filtrate for crystallization for 1 hour, filtering, drying to obtain yellow solid 40.76g (yield: 95.2%), namely urolithin B, and HPLC purity of 99.42%.
Example 7
The new method for synthesizing urolithin C specifically comprises the following steps:
(1) Synthesis of Compound II by adding 2,3, 7-trihydroxy-9-fluorenone (50 g,0.204 mol) to 500mL of acetonitrile, adding potassium carbonate (135.1 g,0.98 mol) while stirring, adding benzyl chloride (84.8 g,0.673 mol) after stirring uniformly, heating the system to reflux, reacting for 5-8 hours, monitoring the reaction endpoint by TLC, cooling to room temperature, filtering, adding 500mL of purified water into the filter cake, pulping for 1 hour, filtering, and drying by 45 ℃ air blast to constant weight to obtain 92.7g (yield 91.4%) of brick red solid powder, namely Compound II.
(2) Synthesis of Compound III, namely adding compound II into 800mL of dichloromethane, adding m-chloroperoxybenzoic acid (173 g,0.852 mol) under stirring, dropwise adding trifluoroacetic acid (24.1 g,0.21 mol), heating to 30 ℃, introducing nitrogen for protection reaction for 10-15 hours, monitoring the reaction end point by TLC, cooling to room temperature, adding 100mL of 10% sodium sulfite aqueous solution, stirring for 1 hour, quenching the reaction, adding 10% sodium carbonate aqueous solution, stirring for 0.5 hour, standing for separating, washing the water layer twice with purified water, washing once with saturated saline, standing for separating, and distilling the organic layer under reduced pressure to remove dichloromethane. 85.6g (89.4% yield) of a tan solid was obtained as compound III.
(3) Synthesis of urolithin C by adding 768mL of anhydrous methanol to compound III, adding 5% palladium-carbon catalyst (7.7 g), adding ammonium formate (46.5 g,0.75 mol) under stirring, heating to 40 ℃ for reaction for 5-10 hours, TLC monitoring the reaction end point, cooling to room temperature, adding N, N-dimethylformamide, stirring for 0.5 hours, filtering, adding purified water to filtrate for crystallization for 1 hour, filtering, drying to obtain yellow solid 38.3g (yield: 94.7%), namely urolithin C, and HPLC purity of 99.28%.
Example 8
The new method for synthesizing urolithin D specifically comprises the following steps:
(1) Synthesis of Compound II by adding 2,3,7, 8-tetrahydroxy-9-fluorenone (50 g,0.192 mol) to 500mL of acetonitrile, adding potassium carbonate (126.9 g,0.92 mol) while stirring, adding benzyl chloride (102.4 g,0.81 mol) after stirring uniformly, heating the system to reflux, reacting for 5-8 hours, monitoring the reaction endpoint by TLC, cooling to room temperature, filtering, adding 500mL of purified water into the filter cake, pulping for 1 hour, filtering, and drying by 45 ℃ air blast to constant weight to obtain 111.8g (yield 90.8%) of brick-red solid powder, namely Compound II.
(2) Synthesis of Compound III, namely adding compound II into 800mL of dichloromethane, adding m-chloroperoxybenzoic acid (173 g,0.852 mol) under stirring, dropwise adding trifluoroacetic acid (24.1 g,0.21 mol), heating to 30 ℃, introducing nitrogen for protection reaction for 10-15 hours, monitoring the reaction end point by TLC, cooling to room temperature, adding 100mL of 10% sodium sulfite aqueous solution, stirring for 1 hour, quenching the reaction, adding 10% sodium carbonate aqueous solution, stirring for 0.5 hour, standing for separating, washing the water layer twice with purified water, washing once with saturated saline, standing for separating, and distilling the organic layer under reduced pressure to remove dichloromethane. 102.1g (89.0% yield) of a tan solid was obtained as compound III.
(3) Synthesis of urolithin D by adding 768mL of anhydrous methanol to compound III, adding 5% palladium-carbon catalyst (7.7 g), adding ammonium formate (71.1 g,1.12 mol) under stirring, heating to 40 ℃ for reaction for 5-10 hours, TLC monitoring the end point of the reaction, cooling to room temperature, adding N, N-dimethylformamide, stirring for 0.5 hour, filtering, adding purified water to filtrate for crystallization for 1 hour, filtering, drying to obtain yellow solid 40.71g (yield: 95.1%), namely urolithin D, and HPLC purity of 99.43%.
Example 9
The new method for synthesizing urolithin E specifically comprises the following steps:
(1) Synthesis of Compound II by adding 2,4,7,8-tetrahydroxy-9-fluorenone (50 g,0.192 mol) to 500mL of acetonitrile, adding potassium carbonate (127.7 g,0.92 mol) under stirring, adding benzyl chloride (102.3 g,0.81 mol) after stirring uniformly, heating the system to reflux, reacting for 5-8 hours, monitoring the reaction endpoint by TLC, cooling to room temperature, filtering, adding 500mL of purified water into the filter cake, pulping for 1 hour, filtering, and drying to constant weight by 45 ℃ air blast to obtain 115.3g (yield 93.2%) of brick red solid powder, namely Compound II.
(2) Synthesis of Compound III, namely adding compound II into 800mL of dichloromethane, adding m-chloroperoxybenzoic acid (173 g,0.852 mol) under stirring, dropwise adding trifluoroacetic acid (24.1 g,0.21 mol), heating to 30 ℃, introducing nitrogen for protection reaction for 10-15 hours, monitoring the reaction end point by TLC, cooling to room temperature, adding 100mL of 10% sodium sulfite aqueous solution, stirring for 1 hour, quenching the reaction, adding 10% sodium carbonate aqueous solution, stirring for 0.5 hour, standing for separating, washing the water layer twice with purified water, washing once with saturated saline, standing for separating, and distilling the organic layer under reduced pressure to remove dichloromethane. 98.7g (yield 83.4%) of compound III are obtained as a tan solid.
(3) Synthesis of urolithin E by adding 768mL of anhydrous methanol to compound III, adding 5% palladium-carbon catalyst (7.7 g), adding ammonium formate (68.2 g,1.08 mol) under stirring, heating to 40 ℃ for reaction for 5-10 hours, TLC monitoring the end point of the reaction, cooling to room temperature, adding N, N-dimethylformamide, stirring for 0.5 hour, filtering, adding purified water to filtrate for crystallization for 1 hour, filtering, drying to obtain 39.5g of yellow solid (yield: 95.5%), namely urolithin E, and HPLC purity of 99.14%.
From the above, the method can synthesize the urolithin compounds on an industrial scale, and has the advantages of easily available raw materials, simple operation, mild reaction conditions, high yield and high product purity, and is very suitable for industrial production.
All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims (10)

1.一种制备化合物(I)的方法，其特征在于，所述方法包括以下步骤：S2：在过氧酸存在下，化合物(II)发生氧化反应生成化合物(I)：1. A method for preparing compound (I), characterized in that the method comprises the following steps: S2: in the presence of a peracid, compound (II) undergoes an oxidation reaction to generate compound (I): 化合物(II)： Compound (II): 化合物(I)： Compound (I): 式中，R1′，R2′，R3′，R4′，R5′，R6′，R7′和R8′分别独立地选自下组：H，OH、C1-C4烷基、C1-C4卤代烷基、OR；R独立地选自下组：C1-C4烷基、羟基保护基、或R与连接地O原子形成至少含有一个O杂原子的杂环烷基；或当两个OR在相邻的位置时，两个R共同形成-C1-C3亚烷基-；In the formula, R 1 ′, R 2 ′, R 3 ′, R 4 ′, R 5 ′, R 6 ′, R 7 ′ and R 8 ′ 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-; 和任选地S3：当化合物(II)中存在-O-羟基保护基时，将步骤(1)所得产物经羟基脱保护反应生成化合物(I)。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.如权利要求1所述的方法，其特征在于，所述方法还包括步骤：S1：使R1′，R2′，R3′，R4′，R5′，R6′，R7′和R8′中的-OH与羟基保护试剂反应，从而生成具有-O-羟基保护基的化合物II。2. The method according to claim 1, characterized in that the method further comprises the step: S1: reacting -OH in R 1 ′, R 2 ′, R 3 ′, R 4 ′, R 5 ′, R 6 ′, R 7 ′ and R 8 ′ with a hydroxyl protecting agent to generate a compound II having an -O-hydroxyl protecting group. 3.如权利要求1所述的方法，其特征在于，所述过氧酸为过氧三氟乙酸、对硝基过氧苯甲酸、间氯过氧苯甲酸、过氧苯甲酸、过氧乙酸，优选的过氧酸为间氯过氧苯甲酸。3. The method according to claim 1, wherein 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.如权利要求1所述的方法，其特征在于，化合物(II)中，R1′、R5′和R6′都是H，R2′、R3′、R4′、R7'和R8′独立地选自：H，OH，OBn或O-DHP。4. The method according to claim 1, wherein 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.如权利要求1所述的方法，其特征在于，化合物(I)是尿石素A5. The method according to claim 1, characterized in that compound (I) is urolithin A 尿石素E尿石素C尿石素D或尿石素E Urolithin E Urolithin C Urolithin D Urolithin E 6.如权利要求1所述的方法，其特征在于，所述方法包括步骤：6. The method according to claim 1, characterized in that the method comprises the steps of: S1：在惰性溶剂中，羟基-9-芴酮和羟基保护试剂发生羟基保护反应，得化合物II；S1: In an inert solvent, hydroxy-9-fluorenone and a hydroxy protecting agent undergo a hydroxy protecting reaction to obtain compound II; S2：在惰性溶剂中，在过氧酸存在下，化合物II发生Baeyer-Villiger反应得化合物III；S2: Compound II undergoes Baeyer-Villiger reaction in an inert solvent in the presence of a peracid to obtain compound III; S3：在惰性溶剂中，化合物III发生羟基脱保护反应，得到式I化合物。S3: In an inert solvent, compound III undergoes a hydroxyl deprotection reaction to obtain a compound of formula I. 7.如权利要求1所述的方法，其特征在于，所述方法包括步骤：7. The method according to claim 1, characterized in that the method comprises the steps of: S1：在惰性溶剂中，在碱存在下，羟基-9-芴酮和羟基保护试剂发生羟基保护反应，得化合物II；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：在惰性溶剂中，在三氟乙酸和过氧酸存在下，化合物II发生Baeyer-Villiger反应得化合物III；S2: Compound II undergoes Baeyer-Villiger reaction in an inert solvent in the presence of trifluoroacetic acid and peracid to obtain compound III; S3：在惰性溶剂中，在碱和催化剂存在下，化合物III发生羟基脱保护反应，得到式I化合物。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.如权利要求7所述的方法，其特征在于，步骤S1包括一个或多个选自下组的技术特征：8. The method of claim 7, wherein step S1 comprises one or more technical features selected from the group consisting of: 所述惰性溶剂为丙酮、乙腈、四氢呋喃、二氧六环、甲苯、二甲苯，或其组合，优选的溶剂为丙酮或者乙腈；The inert solvent is acetone, acetonitrile, tetrahydrofuran, dioxane, toluene, xylene, or a combination thereof, and the preferred solvent is acetone or acetonitrile; 所述羟基保护试剂为氯化苄、溴化苄、二氢吡喃，优选氯化苄；The hydroxyl protecting agent is benzyl chloride, benzyl bromide, dihydropyran, preferably benzyl chloride; 所述碱选自下组：碳酸钾、碳酸钠、碳酸氢钠、碳酸氢钾，或其组合；The base is selected from the group consisting of potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, or a combination thereof; 羟基-9-芴酮和羟基保护试剂的摩尔比为1：2～1：5，优选的摩尔比为1：3-1：4；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; 羟基-9-芴酮所述碱的摩尔比为1：2～1：5，优选的摩尔比为1：3-1：5；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; 所述反应的温度为50-90℃，优选为60-85℃；The reaction temperature is 50-90°C, preferably 60-85°C; 所述反应的时间为3-12h，优选为5-8h；和/或The reaction time is 3-12 hours, preferably 5-8 hours; and/or 步骤S1后还包括后处理步骤：将步骤S1的反应液降温后过滤，滤饼加入水打浆，过滤，干燥得化合物II。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.如权利要求7所述的方法，其特征在于，步骤S2包括一个或多个选自下组的技术特征：9. The method of claim 7, wherein step S2 comprises one or more technical features selected from the group consisting of: 所述惰性溶剂为二氯甲烷、丙酮、乙腈、四氢呋喃、二氧六环、甲苯、二甲苯，或其组合，优选的溶剂为二氯甲烷；The inert solvent is dichloromethane, acetone, acetonitrile, tetrahydrofuran, dioxane, toluene, xylene, or a combination thereof, and the preferred solvent is dichloromethane; 所述过氧酸为过氧三氟乙酸、对硝基过氧苯甲酸、间氯过氧苯甲酸、过氧苯甲酸、过氧乙酸，优选的过氧酸为间氯过氧苯甲酸；The peracid is trifluoroacetic acid, p-nitroperbenzoic acid, m-chloroperbenzoic acid, perbenzoic acid, or peracetic acid, and the preferred peracid is m-chloroperbenzoic acid; 所述化合物II和过氧酸的摩尔比为1：1～1：5，优选的摩尔比为1：3～1：4；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; 所述化合物II和三氟乙酸的摩尔比为1：1～1：5，优选的摩尔比为1：1～1：2；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; 步骤S2在惰性气体保护下反应，如氮气、氦气；Step S2: reacting under the protection of an inert gas, such as nitrogen or helium; 所述反应的温度为30±10℃，优选为30±5℃；The reaction temperature is 30±10°C, preferably 30±5°C; 所述反应的时间为6-24h，优选为8-15h；和/或The reaction time is 6-24h, preferably 8-15h; and/or 步骤S2后还包括后处理步骤：将步骤S2的反应液降温，加入亚硫酸钠水溶液(10±5wt％)搅拌淬灭反应，加入碳酸钠水溶液(10±5wt％)搅拌(0.5-1h)，静置分液，水层用水洗涤后用饱和食盐水洗涤，静置分液，收集有机层并除去二氯甲烷得化合物III。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.如权利要求7所述的方法，其特征在于，步骤S3包括一个或多个选自下组的技术特征：10. The method of claim 7, wherein step S3 comprises one or more technical features selected from the following group: 所述惰性溶剂选自下组：无水甲醇、无水乙醇、乙腈、二氯甲烷、四氢呋喃、N，N-二甲基甲酰胺，或其组合，优选的溶剂为无水甲醇；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; 所述催化剂为钯碳、铂碳或者雷尼镍，优选的催化剂为雷尼镍或钯碳；The catalyst is palladium carbon, platinum carbon or Raney nickel, and the preferred catalyst is Raney nickel or palladium carbon; 所述化合物III和催化剂的质量比为100：5～100：20，优选的质量比为100：7～100：15，如100：10；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; 所述反应的温度为40±10℃，优选为40±5℃；The reaction temperature is 40±10°C, preferably 40±5°C; 所述碱为甲酸胺或乙酸胺；The base is ammonium formate or ammonium acetate; 所述化合物III和碱的摩尔比为1：2～1：8，优选为1：2～1：5，更优选为1：4；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; 所述反应的时间为4-16h，优选为5-10h；和/或The reaction time is 4-16 hours, preferably 5-10 hours; and/or 步骤S3后还包括后处理步骤：将步骤S3的反应液降温后加入N，N-二甲基甲酰胺搅拌(0.5-1小时)，过滤，滤液加入水析晶，过滤，干燥，得化合物I。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.
CN202411190402.2A 2024-08-27 2024-08-27 Industrial scale preparation method of urolithin compounds Pending CN119080732A (en)

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