CN111978282A - Synthesis method of urolithin A - Google Patents

Synthesis method of urolithin A Download PDF

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CN111978282A
CN111978282A CN202010944874.8A CN202010944874A CN111978282A CN 111978282 A CN111978282 A CN 111978282A CN 202010944874 A CN202010944874 A CN 202010944874A CN 111978282 A CN111978282 A CN 111978282A
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room temperature
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马小燕
张长飞
李伟
吴雀群
胡新军
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Sichuan University of Science and Engineering
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Sichuan University of Science and Engineering
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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
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    • Y02P20/00—Technologies relating to chemical industry
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Abstract

The invention discloses a method for synthesizing urolithin A, which comprises the steps of coupling, primary protecting group removal, sulfonylation, carboxylation-lactonization, secondary protecting group removal and the like. The method provided by the invention provides a novel method for synthesizing the urolithin A, the raw materials are cheap and easy to obtain, the used reaction reagent has little pollution to the environment, the route is simple, and the method can be used for large-scale preparation of the urolithin A.

Description

Synthesis method of urolithin A
Technical Field
The invention belongs to the technical field of preparation of urolithin, and particularly relates to a synthetic method of urolithin A.
Background
Ellagitannins are a class of natural polyphenolic substances that are widely found in most nuts and fruits such as pomegranates, chestnuts, blueberries, grapes, and the like, and can produce ellagic acid upon hydrolysis. Human and animal experiments show that ellagitannin and ellagic acid have multiple biological activities of resisting oxidation, resisting inflammation, resisting cancer, regulating intestinal flora and the like, and have potential prevention or treatment effects on chronic diseases such as cancer, diabetes, cardiovascular and cerebrovascular diseases, nervous lesion and the like. However, ellagitannins and ellagic acids have very low bioavailability, the concentration of ellagic acid distributed in tissues and blood is often lower than the effective concentration at which it exerts its biological effect, while unabsorbed ellagitannins are metabolized by the intestinal flora into urolithin-like compounds that are more easily absorbed. Therefore, it has been reported in the literature that the urolithins-type components may be molecular forms of ellagitannins that exert biological activity in vivo. The urolithin is a dibenzopyran-6-one derivative containing different phenolic hydroxyl groups, and has multiple biological activities of oxidation resistance, anti-inflammation, anti-tumor, protein glycosylation inhibition and the like. In recent years, research on the biological activity, tissue distribution and in vivo metabolic process of urolithin compounds has been increasing at home and abroad.
It has been reported that a substance known as urolithin a (urolithin a) in pomegranate and other fruits can help slow down a particular aging process by improving the function of cellular mitochondria; furthermore, the intake of this compound is not at risk to the health of the human organism. Urolithin a has been shown to stimulate mitochondrial biogenesis in the same manner as regular exercise, and is the only compound that can reestablish cell-to-defective mitochondrial recycling. However, since the content of urolithin a naturally occurring in nature is low and the cost of natural extraction is high, it is necessary to develop a method for artificially synthesizing urolithin a.
Disclosure of Invention
Aiming at the prior art, the invention provides a method for synthesizing urolithin A, which aims to solve the problem of difficult extraction of urolithin A.
In order to achieve the purpose, the invention adopts the technical scheme that: the method for synthesizing the urolithin A is characterized by comprising the following steps:
s1: mixing a compound I and a compound II according to a molar ratio of 1: 1-1: 3, dissolving the mixture in a solvent, adding an alkali and a catalyst into the obtained solution, uniformly mixing, and carrying out reflux reaction at room temperature for 15-20 hours to obtain a compound III; the molar ratio of the added alkali to the added catalyst to the compound I is 5-15: 1 and 0.02-0.1: 1 respectively;
Figure BDA0002674956390000011
wherein R is1Is trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, methyl, benzyl, p-methoxybenzyl, methoxymethyl, 2-methoxyethoxyMethyl or benzyloxymethyl, R2Is methyl, benzyl, p-methoxybenzyl, methoxymethyl, benzyloxymethyl or 2-methoxyethoxymethyl, and R1、R2Different; x is Cl, Br, I or OTf;
s2: r in the compound III2Removing radicals to obtain a compound IV,
Figure BDA0002674956390000021
s3: mixing the compound IV with a sulfonylation reagent and alkali according to a molar ratio of 1: 2-4: 2-5, dissolving the mixture in a solvent, reacting at room temperature for 10-15 h to obtain a compound V,
Figure BDA0002674956390000022
s4: mixing the compound V with a transition metal catalyst, a photocatalyst, a ligand, a reducing agent and an additive according to a molar ratio of 1: 0.05-0.2: 0.01-0.05: 0.1-0.3: 1-5, dissolving the mixture in a solvent, reacting for 35-40 h under illumination to obtain a compound VI,
Figure BDA0002674956390000023
s5: r in compound VI1Removing radicals to obtain the product.
On the basis of the technical scheme, the invention can be further improved as follows.
Further, compound II was prepared by the following steps: mixing the compound I with a lithium reagent and boric acid ester at the temperature of-78 ℃ according to a molar ratio of 1: 1-3: 2-5, heating to room temperature, and reacting for 3-5 hours to obtain the lithium borate lithium ion battery; the lithium reagent is lithium, n-butyl lithium or tert-butyl lithium, and the borate is methyl borate, ethyl borate, triisopropyl borate or tri-n-butyl borate.
Further, the base used in S1 is Cs2CO3、K2CO3、Na2CO3、Li2CO3、NaHCO3、K3PO4、KOAc、Ba(OH)2NaOH or CsF; the catalyst used is Pd2dba3、Pd(PPh3)4、Pd(OAc)2、PdCl2、PdCl2(dppf) or Pd (PPh)3)2Cl2。
Further, compound III removes R2The method of the group is as follows:
when R is2In the case of methyl, compound III is reacted with BBr3、BCl3、BF3、TMSI、AlBr3Or AlCl3Mixing and dissolving the components in a solvent according to a molar ratio of 1: 2-5, and reacting at-78-room temperature for 20-25 h to obtain the compound;
when R is2When the benzyl group is used, mixing the compound III with a catalyst according to a mass ratio of 4-5: 1, dissolving the mixture in a solvent, adding a hydrogen source, and reacting at room temperature for 4-5 hours to obtain the benzyl group; the catalyst is 5% Pd/C, 10% Pd/C or Raney nickel, and the hydrogen source is hydrogen, formic acid or ammonium formate;
when R is2When the compound is p-methoxybenzyl, mixing the compound III with trifluoroacetic acid, triethylsilylhydride, boron trifluoride diethyl etherate, dichloro dicyano benzoquinone or ceric ammonium nitrate according to the molar ratio of 1: 2-5, dissolving in a solvent, and reacting at-0-room temperature for 20-25 h to obtain the p-methoxybenzyl compound;
when R is2When the compound is methoxymethyl, benzyloxymethyl or 2-methoxyethoxymethyl, dissolving the compound III in an acidic solvent, and reacting at 55-60 ℃ for 25-35 min to obtain the compound.
Further, the sulfonylation reagent used in S3 is trifluoromethanesulfonyl chloride or trifluoromethanesulfonic anhydride; the base used is triethylamine, pyridine, 2, 6-dimethylpyridine, diisopropylethylamine or 1, 8-diazabicycloundecen-7-ene.
Further, the transition metal catalyst used in S4 is Ni (COD)2、NiBr2、NiBr2·glyme、Pd(PPh3)4、Pd2(dba)3、Pd(PPh3)2Cl2Or Pd (OAc)2(ii) a The photocatalyst used was Ir (dF (CF)3)ppy)2(dtbpy)(PF6)、Ir(4-F-ppy)2(dtbpy)(PF6)、Ir(ppy)2(dtbpy)(PF6)、Ru(bpy)3Cl2·6H2O or 4 CzIPN; the ligand is Xantphos, Xphos, t-BuXPhos, Johnphos, RuPhos, Davephos, Sphos or Neocuprine; the reducing agent is triethanolamine, hanster, N-diisopropylethylamine or 1-adamantane carboxylic acid; the additive is Cs2CO3、K2CO3、Na2CO3、NaHCO3Or
Figure BDA0002674956390000031
And (3) a molecular sieve.
Further, compound VI is freed from R1The method of the group is as follows:
when R is1When the compound is trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl or triisopropylsilyl, mixing the compound VI with tetra-n-butylammonium fluoride, dilute hydrofluoric acid or acetic acid according to the molar ratio of 1: 1.5-3.5, dissolving in a solvent, and reacting at room temperature for 20-25 h to obtain the compound;
when R is1When it is methyl, compound VI is reacted with BBr3、BCl3、BF3、TMSI、AlBr3Or AlCl3Mixing and dissolving the components in a solvent according to a molar ratio of 1: 2-5, and reacting at-78-room temperature for 20-25 h to obtain the compound;
when R is1When the benzyl group is used, mixing a compound VI and a hydrogenation catalyst according to a mass ratio of 4-5: 1, dissolving in a solvent, adding a hydrogen source, and reacting at room temperature for 4-5 hours to obtain the benzyl group; the hydrogenation catalyst is 5% Pd/C, 10% Pd/C or Raney nickel, and the hydrogen source is hydrogen, formic acid or ammonium formate;
when R is1When the compound is p-methoxybenzyl, mixing a compound VI with trifluoroacetic acid, triethylsilylhydride, boron trifluoride diethyl etherate, dichloro dicyano benzoquinone or ammonium ceric nitrate according to a molar ratio of 1: 2-5, dissolving in a solvent, and reacting at-0-room temperature for 20-25 h to obtain the p-methoxybenzyl compound;
when R is1When the compound is methoxymethyl, benzyloxymethyl or 2-methoxyethoxymethyl, dissolving the compound VI in an acidic solvent,and reacting at 55-60 ℃ for 25-35 min to obtain the catalyst.
The invention has the beneficial effects that: the patent provides a novel method for synthesizing the urolithin A, raw materials are cheap and easy to obtain or chemical reaction is easy to prepare, the used reaction reagent has little pollution to the environment, and the route is simple.
Detailed Description
The synthetic route of the urolithin A disclosed by the invention is as follows:
Figure BDA0002674956390000041
the specific operation is as follows:
(1) preparation of the compound of formula II: reacting the compound shown in the formula I with boric acid ester in the presence of a lithium reagent, and carrying out aftertreatment on a reaction system by using dilute hydrochloric acid to obtain a compound shown in the formula II; the lithium reagent is lithium, n-butyl lithium or tert-butyl lithium, and the equivalent weight of the lithium reagent is 1-3; the borate is methyl borate, ethyl borate, triisopropyl borate or tri-n-butyl borate, and the equivalent weight is 2-5; the adopted solvents are tetrahydrofuran and diethyl ether; the reaction temperature is-78-room temperature; the concentration of the dilute hydrochloric acid is 1-4N.
(2) Coupling reaction: the compound of formula I and the compound of formula II are reacted under the action of alkali and palladium catalyst to obtain the compound of formula III; the mass ratio of the compound of the formula I to the compound of the formula II is 1: 1-1: 3; the alkali adopted is Cs2CO3、K2CO3、Na2CO3、Li2CO3、NaHCO3、K3PO4、KOAc、Ba(OH)2NaOH or CsF, the equivalent weight of the alkali is 5-15; the palladium catalyst is Pd2dba3、Pd(PPh3)4、Pd(OAc)2、PdCl2、PdCl2(dppf) or Pd (PPh)3)2Cl2The equivalent weight of the catalyst is 0.02-0.1; the adopted solvent is tetrahydrofuran, 1, 4-dioxane, glycol dimethyl ether, toluene, benzene, dimethylformamide, N-methylpyrrolidone, acetone, acetonitrile or a mixed solution of the solvent and water (v: v ═ 5: 1-1: 1); the reaction condition is room temperature reflux, and the reaction time is 15 to20h。
(3) de-R2Protecting groups: removal of the phenolic hydroxy protecting group R from the compound of formula III2To give a compound of formula IV wherein 1) methyl: can use BBr3、BCl3、BF3、TMSI、AlBr3Or AlCl3Removing the reagents with the equivalent weight of 2-5, wherein the adopted solvents are dichloromethane, trichloromethane, acetonitrile and mercaptan; the reaction temperature is-78-room temperature; 2) benzyl: the catalyst can be removed by hydrogenation under the action of 5 percent Pd/C, 10 percent Pd/C and Raney Ni, hydrogen source is provided by hydrogen, formic acid and ammonium formate, the adopted reaction solvent is methanol, ethanol and ethyl acetate, and the reaction is carried out at room temperature; 3) p-methoxybenzyl group: can be removed under the conditions of trifluoroacetic acid, triethylhydrosilicon, boron trifluoride diethyl etherate, dichlorodicyano benzoquinone, ceric ammonium nitrate and the like, and the equivalent weight is 2-5; the method comprises the following steps of (1) adopting a solvent of dimethyl carbonate, acetonitrile, dichloromethane, acetonitrile or a mixed solution of dichloromethane and water (v: v ═ 20: 1-10: 1); the reaction temperature is 0-room temperature; 4) methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl: can be removed in an acidic environment, the acidic condition is provided by hydrochloric acid and acetic acid, and the reaction solvent is methanol, isopropanol and water.
(4) Sulfonylation reaction: reacting the compound shown in the formula IV with a sulfonylation reagent under an alkaline condition to obtain a compound shown in the formula V; the sulfonylation reagent is trifluoromethanesulfonyl chloride or trifluoromethanesulfonic anhydride, and the equivalent weight is 2-4; the base is triethylamine, pyridine, 2, 6-dimethylpyridine, diisopropylethylamine or 1, 8-diazabicycloundecen-7-ene, and the equivalent weight is 2-5; 4-dimethylamino pyridine with catalytic amount can be added into the reaction system; the adopted reaction solvents are dichloromethane, trichloromethane and normal hexane; the reaction was carried out at room temperature.
(5) Carboxylation-lactonization reaction: introducing carbon dioxide into a vacuum system in which a compound of the formula V, a transition metal catalyst, a photocatalyst, a ligand, a reducing agent, an additive and a reaction solvent exist, and carrying out a light irradiation reaction to obtain a compound of the formula VI; the transition metal catalyst is Ni (COD)2、NiBr2、NiBr2·glyme、Pd(PPh3)4、Pd2(dba)3、Pd(PPh3)2Cl2Or Pd (OAc)2The equivalent weight is 0.05-0.2; the photocatalyst is selected from the following compounds a (Ir (dF (CF)3)ppy)2(dtbpy)(PF6) Compound b (Ir (4-F-ppy)2(dtbpy)(PF6) Compound c (Ir) (ppy)2(dtbpy)(PF6) Compound d (Ru (bpy))3Cl2·6H2O) or 4CzIPN, equivalent weight is 0.01 to 0.05,
Figure BDA0002674956390000051
the ligand is selected from Xantphos, Xphos, t-BuXPhos, Johnphos, RuPhos, Davephos, Sphos or Neocuprine with equivalent weight of 0.1-0.3,
Figure BDA0002674956390000052
the reducing agent is selected from triethanolamine, hanster, N-diisopropylethylamine or 1-adamantane carboxylic acid, and the equivalent weight is 1-5; the additive is selected from Cs2CO3、K2CO3、Na2CO3、NaHCO3Or
Figure BDA0002674956390000062
A molecular sieve having an equivalent weight of 1 to 5; the solvent adopts dimethylformamide, dimethyl sulfoxide, dimethylacetamide and N-methylpyrrolidone; the reaction was carried out under sealed conditions at room temperature, and the light source was a blue light emitting diode (blue LED).
(6) Removing the R1 protecting group: removing the protecting group R1 of phenolic hydroxyl group from the compound shown in the formula VI to obtain the urolithin A, wherein 1) trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and triisopropylsilyl: can be removed by using reagents such as tetra-n-butylammonium fluoride, dilute hydrofluoric acid or acetic acid, and the equivalent weight is 1.5-3.5; adopting a solvent of tetrahydrofuran, acetonitrile, water and a mixed solution of tetrahydrofuran and water (v: v is 10: 1-1: 1); the reaction temperature is room temperature; 2) methyl group: can use BBr3、BCl3、BF3、TMSI、AlBr3Or AlCl3Removing the reagentRemoving, wherein the equivalent weight is 2-5, the adopted solvents are dichloromethane, trichloromethane, acetonitrile and mercaptan, and the reaction temperature is-78-room temperature; 3) benzyl: the catalyst can be removed by hydrogenation under the action of 5% Pd/C, 10% Pd/C or Raney Ni, hydrogen source is provided by hydrogen, formic acid and ammonium formate, the adopted reaction solvent is methanol, ethanol and ethyl acetate, and the reaction is carried out at room temperature; 4) p-methoxybenzyl group: the catalyst can be removed under the conditions of trifluoroacetic acid, triethylsilylhydride, boron trifluoride ethyl ether, dichlorodicyano benzoquinone or ceric ammonium nitrate, the equivalent weight is 2-5, a solvent is dimethyl carbonate, acetonitrile, dichloromethane, acetonitrile or a mixed solution of dichloromethane and water (v: v is 20: 1-10: 1), and the reaction temperature is 0-room temperature; 5) methoxymethyl, benzyloxymethyl or 2-methoxyethoxymethyl: can be removed in an acidic environment, the acidic condition is provided by hydrochloric acid and acetic acid, and the reaction solvent is methanol, isopropanol and water.
The following examples are provided to illustrate specific embodiments of the present invention.
Example 1
A synthetic method of urolithin A comprises the following steps:
Figure BDA0002674956390000061
the method specifically comprises the following steps:
(1) synthesis of Compound 2-1: dissolving compound 1-1(5.84g, 20mmol) in 50mL tetrahydrofuran, adding n-butyllithium in n-hexane (8.0mL, 2.5M, 20mmol) at-78 deg.C, stirring at 78 deg.C for 25min, adding triisopropyl borate (16.2mL, 70mmol) in 50mL tetrahydrofuran through a constant pressure funnel; the reaction system is heated to room temperature for reaction for 3 hours, and the TLC monitors the reaction end point; then poured into 100mL of 3N hydrochloric acid, extracted with ethyl acetate (3X 200mL), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to give a yellow oil (2.63g, 52% yield), compound 2-1, whose NMR was as follows:1H NMR(300MHz,CDCl3)3.83(s,3H),5.11(s,2H),5.46(s,2H),6.54(d,J＝2.1Hz,1H),6.58(dd,J＝8.1,2.1Hz,1H),7.41(m,5H),7.79(d,J＝8.1Hz,1H)；13C NMR(75MHz,CDCl3)55.3,70.7,99.1,105.7,127.8,128.6,129.0,135.9,138.2,163.6,165.2。
(2) synthesis of Compound 3-1: mixing compound 1-1(2.86g, 9.8mmol), compound 2-1(2.63g, 10.2mmol) and Pd2dba3(0.31g, 0.34mmol) was dissolved in 40mL of ethylene glycol dimethyl ether, and 40mL of 2M aqueous sodium carbonate solution was added; the obtained reaction system is refluxed and reacted for 16h, and the end point of the reaction is detected by TLC. After cooling to room temperature, ethyl acetate extraction (3 × 100mL), drying over anhydrous sodium sulfate, concentration and purification by column chromatography gave a pale yellow solid (3.51g, 84% yield), compound 3-1, whose nuclear magnetic assay results were as follows:1H NMR(300MHz,CDCl3)3.81(s,6H),4.98(s,4H),6.55(m,4H),7.21(m,12H)；13C NMR(75MHz,CDCl3)55.4,70.3,100.7,104.9,121.2,126.7,127.4,128.3,132.2,137.5,157.4,160.0。
(3) synthesis of Compound 4-1: dissolving the compound 3-1(3.51g, 8.2mmol) in 50mL of ethanol, adding 10% Pd/C (0.88g), vacuumizing to replace hydrogen for 3 times, reacting the reaction system for 4h at room temperature under a hydrogen atmosphere, and monitoring the reaction end point by TLC. Celite filtration and concentration of the filtrate afforded a white solid (1.92g, 95% yield), compound 4-1, with the following nuclear magnetic assay:1H NMR(300MHz,CDCl3)3.81(s,6H),5.78(br,2H),6.61(m,4H),7.12(d,J＝8.7Hz,2H).13C NMR(75MHz,CDCl3)55.4,101.9,107.7,115.3,131.9,154.3,161.0。
(5) synthesis of Compound 5-1: compound 4-1(1.92g, 7.8mmol) was dissolved in 50mL of dichloromethane, and pyridine (1.6mL, 19.5mmol) and trifluoromethanesulfonic anhydride (3.3mL, 19.5mmol) were added in that order at 0 ℃. Then, the reaction was warmed to room temperature for 12 hours, and the end of the reaction was monitored by TLC. The reaction mixture was poured into 50mL of 1N hydrochloric acid, extracted with dichloromethane (3 × 50mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to give a pale yellow oil (3.66g, 92% yield) as compound 5-1, whose nuclear magnetic assay results were as follows:1H NMR(300MHz,CDCl3)3.88(s,6H),6.92(d,J＝2.4Hz,2H),7.00(dd,J＝8.7,2.4Hz,2H),7.32(d,J＝8.7Hz,2H)；13C NMR(75MHz,CDCl3)55.8,107.6,118.3,121.2,133.1,147.5,160.9。
(6) synthesis of Compound 6-1: mixing compound 5-1(0.51g, 1.0mmol), palladium acetate (11mg, 0.05mmol), ligand Davephos (39mg, 0.1mmol), photocatalyst Ir (ppy)2(dtbpy)(PF6) (18mg, 0.02mmol), cesium carbonate (0.65g, 2.0mmol), diisopropylethylamine (0.35mL, 2mmol) were dissolved in 10mL of dimethylacetamide, and carbon dioxide was replaced by vacuum extraction 3 times. The reaction system is reacted for 36h at room temperature under the atmosphere of carbon dioxide and the irradiation of a blue LED, and the TLC is used for monitoring the reaction end point. The reaction was quenched with 20mL of 2N hydrochloric acid, extracted with ethyl acetate (3X 25mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to give a yellow solid (0.14g, 55% yield) which was compound 6-1, and its NMR was as follows:1H NMR(300MHz,CDCl3)7.90(d,J＝9.0Hz,1H),7.85(d,J＝8.7Hz,1H),7.75(d,J＝2.7Hz,1H),7.36(dd,J＝8.8,3.0Hz,1H),6.90(dd,J＝9.0,2.5Hz,1H),6.85(d,J＝2.4Hz,1H),3.92(s,3H),3.87(s,3H).13C NMR(75MHz,CDCl3)161.5,160.6,159.0,151.5,128.5,124.3,123.1,122.7,120.9,112.3,111.2,110.9,101.4,55.6(2C)。
(7) synthesis of urolithin a: compound 6-1(0.14g, 0.55mmol) was dissolved in dry dichloromethane and BBr was added at-78 deg.C3(0.21mL, 2.2mmol) and then warmed to room temperature for 24h, and the end of the reaction was monitored by TLC. 30mL of 2N hydrochloric acid was added, the mixture was extracted with ethyl acetate (3X 20mL), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to give a dark yellow solid (79mg, 63% yield), urolithin A, as follows:1H NMR(300MHz,DMSO-d6)10.20(br s,1H),8.10(d,J＝9.0Hz,1H),8.01(d,J＝8.7Hz,1H),7.50(d,J＝2.7Hz,1H),7.31(dd,J＝8.7,2.7Hz,1H),6.79(dd,J＝8.5,2.4Hz,1H),6.71(d,J＝2.1Hz,1H).13C NMR(75MHz,DMSO-d6)160.6,159.8,152.1,135.3,135.1,129.7,127.7,124.8,121.6,118.9,113.2,109.4,102.9。
example 2
A synthetic method of urolithin A comprises the following steps:
Figure BDA0002674956390000081
the method specifically comprises the following steps:
(1) synthesis of Compound 2-2: compound 1-2(7.28g, 20mmol) was dissolved in 50mL tetrahydrofuran, a solution of n-butyllithium in n-hexane (8.8mL, 2.5M, 22mmol) was added at-78 deg.C, stirred at 78 deg.C for 25min and then a solution of trimethyl borate (7.8mL, 70mmol) in 50mL tetrahydrofuran was added via a constant pressure funnel. The reaction system is heated to room temperature for reaction for 3h, and the end point of the reaction is monitored by TLC. Then poured into 100mL of 3N hydrochloric acid, extracted with ethyl acetate (3 × 200mL), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to give a yellow oil (2.26g, 40% yield), compound 2-2, whose structural analysis is as follows:1H NMR(300MHz,CDCl3)7.68(d,J＝8.0Hz,1H),6.50(dd,J＝2.1,8.0Hz,1H),6.40(d,J＝2.1Hz,1H),5.69(s,2H),3.87(s,3H),0.99(s,9H),0.23(s,6H)；MS(ESI)m/z 283.1(M+H+)。
(2) synthesis of Compound 3-2: mixing compound 1-2(1.97g, 5.4mmol), compound 2-2(2.26g, 8.0mmol), Pd (PPh)3)4(0.13g, 0.11mmol) was dissolved in 30mL of ethylene glycol dimethyl ether, and 20mL of 2M aqueous sodium carbonate solution was added. The obtained reaction system is refluxed and reacted for 43 hours, and the end point of the reaction is detected by TLC. Cooled to room temperature, extracted with ethyl acetate (3 × 100mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to give a yellow solid (2.38g, 93% yield) which is compound 3-2, and mass-resolved as follows: MS (ESI) M/z 475.3(M + H)+)。
(3) Synthesis of Compound 4-2: compound 3-2(2.38g, 5.0mmol) is dissolved in dry 20mL of dichloromethane and BBr is added at-78 deg.C3(1.9mL, 20.0mmol) and then warmed to room temperature for 24h, and the end of the reaction was monitored by TLC. 50mL of 2N hydrochloric acid was added and methylene chloride was extracted (3X 50mL), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to give a pale yellow solid (1.65, 74% yield) which was compound 4-2, as determined by mass spectrometry: MS (ESI) M/z 469.2(M + Na)+)。
(4) Synthesis of Compound 5-2: compound 4-2(1.65g, 3.7mmol) was dissolved in 30mL of dichloromethane, and pyridine (0) was added in that order at 0 deg.C8mL, 9.2mmol), trifluoromethanesulfonic anhydride (1.6mL, 9.2 mmol). Then, the reaction was warmed to room temperature for 12 hours, and the end of the reaction was monitored by TLC. The reaction mixture was poured into 30mL of 1N hydrochloric acid, extracted with dichloromethane (3 × 50mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to give a yellow oil (2.27g, yield 87%) as compound 5-2, which was analyzed by mass spectrometry as follows: MS (ESI) M/z 711.1(M + H)+)。
(5) Synthesis of Compound 6-2: mixing compound 5-2(0.71g, 1.0mmol), palladium acetate (11mg, 0.05mmol), ligand Davephos (39mg, 0.1mmol), photocatalyst Ir (ppy)2(dtbpy)(PF6) (18mg, 0.02mmol), cesium carbonate (0.65g, 2.0mmol), diisopropylethylamine (0.35mL, 2mmol) were dissolved in 10mL of dimethylacetamide, and carbon dioxide was replaced by vacuum extraction 3 times. The reaction system is reacted for 36h at room temperature under the atmosphere of carbon dioxide and the irradiation of a blue LED, and the TLC is used for monitoring the reaction end point. The reaction was quenched with 20mL of 2N hydrochloric acid, extracted with ethyl acetate (3X 25mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to give a yellow solid (0.22g, 49% yield) which was compound 6-2, and mass-analyzed as follows: MS (ESI) M/z 457.2(M + H)+)。
(6) Synthesis of urolithin a: compound 6-2(0.22g, 0.49mmol) was dissolved in 5mL of tetrahydrofuran, tetra-n-butylammonium fluoride (0.38g, 1.47mmol) was added, and the reaction was allowed to proceed at room temperature for 24 hours, and the end of the reaction was monitored by TLC. 30mL of water was added, extracted with ethyl acetate (3X 20mL), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to give a brown solid (0.11mg, 98% yield) which was urolithin A.
Example 3
A synthetic method of urolithin A comprises the following steps:
Figure BDA0002674956390000091
Figure BDA0002674956390000101
the method specifically comprises the following steps:
(1) synthesis of Compounds 2-3: compound 1-3(6.46g, 20mmol) was dissolved in 50mL of tetrahydrofuran, a solution of n-butyllithium in n-hexane (8.0mL, 2.5M, 20mmol) was added at-78 deg.C, and after stirring at 78 deg.C for 25min, a solution of triisopropyl borate (16.2mL, 70mmol) in 50mL of tetrahydrofuran was added via a constant pressure funnel. The reaction system is heated to room temperature for reaction for 3h, and the end point of the reaction is monitored by TLC. Then poured into 100mL of 3N hydrochloric acid, extracted with ethyl acetate (3 × 200mL), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to give a yellow oil (2.71g, 47% yield) as compound 2-3, which was mass-analyzed as follows: MS (ESI) M/z 311.1(M + Na)+)。
(2) Synthesis of Compounds 3-3: mixing compound 1-3(2.91g, 9.0mmol), compound 2-3(2.71g, 9.4mmol), Pd2dba3(0.29g, 0.32mmol) was dissolved in 40mL of ethylene glycol dimethyl ether, and 40mL of 2M aqueous sodium carbonate solution was added. The obtained reaction system is refluxed and reacted for 16h, and the end point of the reaction is detected by TLC. Cooled to room temperature, extracted with ethyl acetate (3 × 100mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to give a pale yellow solid (3.46g, 79% yield), compound 3-3, which was mass-analyzed as follows: MS (ESI) M/z 487.2(M + H)+)。
(3) Synthesis of Compounds 4-3: compound 3-3(3.46g, 7.1mmol) was dissolved in 50mL of methanol, 20 drops of concentrated HCl were added, the reaction system was reacted at 60 ℃ for 30min, and the end of the reaction was monitored by TLC. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give compound 4-3 as a yellow solid (2.69g, 95% yield) which was analyzed by mass spectrometry as follows: MS (ESI) M/z 421.1(M + Na)+)。
(4) Synthesis of Compounds 5-3: compound 4-3(2.69g, 6.8mmol) was dissolved in 50mL of dichloromethane, and pyridine (1.4mL, 17.0mmol) and trifluoromethanesulfonic anhydride (2.7mL, 17.0mmol) were added in that order at 0 ℃. Then, the reaction was warmed to room temperature for 12 hours, and the end of the reaction was monitored by TLC. The reaction mixture was poured into 50mL of 1N hydrochloric acid, extracted with dichloromethane (3 × 50mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to give a pale yellow oil (4.28g, 95% yield) as compound 5-3, which was analyzed by mass spectrometry as follows: MS (ESI) M/z 663.0(M + H)+)。
(5) Synthesis of Compounds 6-3: mixing compound 5-3(0.66g, 1.0mmol), palladium acetate (11mg, 0.05mmol), ligand Davephos (39mg, 0.1mmol), photocatalyst Ir (ppy)2(dtbpy)(PF6) (18mg, 0.02mmol), cesium carbonate (0.65g, 2.0mmol), diisopropylethylamine (0.35mL, 2mmol) were dissolved in 10mL of dimethylacetamide, and carbon dioxide was replaced by vacuum extraction 3 times. The reaction system is reacted for 36h at room temperature under the atmosphere of carbon dioxide and the irradiation of a blue LED, and the TLC is used for monitoring the reaction end point. The reaction was quenched with 20mL of 2N hydrochloric acid, extracted with ethyl acetate (3X 25mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to give a yellow solid (0.16g, 40% yield) which was compound 6-3, as follows by mass spectrometry: MS (ESI) M/z 409.1(M + H)+).
(6) Synthesis of urolithin a: dissolving the compound 6-3(0.16g, 0.40mmol) in 5mL ethyl acetate, adding 10% Pd/C (64mg), vacuumizing to replace hydrogen for 3 times, reacting the reaction system for 10h at room temperature under a hydrogen atmosphere, and monitoring the reaction end point by TLC. Celite filtration and concentration of the filtrate afforded a brown solid (90g, 99% yield), urolithin a.
While the present invention has been described in detail with reference to the embodiments, it should not be construed as limited to the scope of the patent. Various modifications and changes may be made by those skilled in the art without inventive step within the scope of the appended claims.

Claims (7)

1. A method for synthesizing urolithin A is characterized by comprising the following steps:
s1: mixing a compound I and a compound II according to a molar ratio of 1: 1-1: 3, dissolving the mixture in a solvent, adding an alkali and a catalyst into the obtained solution, uniformly mixing, and carrying out reflux reaction at room temperature for 15-20 hours to obtain a compound III; the molar ratio of the added alkali to the added catalyst to the compound I is 5-15: 1 and 0.02-0.1: 1 respectively;
Figure FDA0002674956380000011
wherein，R1Is trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, methyl, benzyl, p-methoxybenzyl, methoxymethyl, 2-methoxyethoxymethyl or benzyloxymethyl, R2Is methyl, benzyl, p-methoxybenzyl, methoxymethyl, benzyloxymethyl or 2-methoxyethoxymethyl, and R1、R2Different; x is Cl, Br, I or OTf;
s2: r in the compound III2Removing radicals to obtain a compound IV,
Figure FDA0002674956380000012
s3: mixing the compound IV with a sulfonylation reagent and alkali according to a molar ratio of 1: 2-4: 2-5, dissolving the mixture in a solvent, reacting at room temperature for 10-15 h to obtain a compound V,
Figure FDA0002674956380000013
s4: mixing the compound V with a transition metal catalyst, a photocatalyst, a ligand, a reducing agent and an additive according to a molar ratio of 1: 0.05-0.2: 0.01-0.05: 0.1-0.3: 1-5, dissolving the mixture in a solvent, reacting for 35-40 h under illumination to obtain a compound VI,
Figure FDA0002674956380000014
s5: r in compound VI1Removing radicals to obtain the product.
2. The method for synthesizing urolithin a according to claim 1, wherein said compound II is prepared by the following steps: mixing the compound I with a lithium reagent and boric acid ester at the temperature of-78 ℃ according to a molar ratio of 1: 1-3: 2-5, heating to room temperature, and reacting for 3-5 hours to obtain the lithium borate lithium ion battery; the lithium reagent is lithium, n-butyl lithium or tert-butyl lithium, and the borate is methyl borate, ethyl borate, triisopropyl borate or tri-n-butyl borate.
3. The method for synthesizing urolithin a according to claim 1, wherein: the base used in S1 is Cs2CO3、K2CO3、Na2CO3、Li2CO3、NaHCO3、K3PO4、KOAc、Ba(OH)2NaOH or CsF; the catalyst used is Pd2dba3、Pd(PPh3)4、Pd(OAc)2、PdCl2、PdCl2(dppf) or Pd (PPh)3)2Cl2。
4. The method for synthesizing urolithin A according to claim 1, wherein said compound III removes R2The method of the group is as follows:
when R is2In the case of methyl, compound III is reacted with BBr3、BCl3、BF3、TMSI、AlBr3Or AlCl3Mixing and dissolving the components in a solvent according to a molar ratio of 1: 2-5, and reacting at-78-room temperature for 20-25 h to obtain the compound;
when R is2When the benzyl group is used, mixing the compound III with a catalyst according to a mass ratio of 4-5: 1, dissolving the mixture in a solvent, adding a hydrogen source, and reacting at room temperature for 4-5 hours to obtain the benzyl group; the catalyst is 5% Pd/C, 10% Pd/C or Raney nickel, and the hydrogen source is hydrogen, formic acid or ammonium formate;
when R is2When the compound is p-methoxybenzyl, mixing the compound III with trifluoroacetic acid, triethylsilylhydride, boron trifluoride diethyl etherate, dichloro dicyano benzoquinone or ceric ammonium nitrate according to the molar ratio of 1: 2-5, dissolving in a solvent, and reacting at-0-room temperature for 20-25 h to obtain the p-methoxybenzyl compound;
when R is2When the compound is methoxymethyl, benzyloxymethyl or 2-methoxyethoxymethyl, dissolving the compound III in an acidic solvent, and reacting at 55-60 ℃ for 25-35 min to obtain the compound.
5. The method for synthesizing urolithin a according to claim 1, wherein: the sulfonylation reagent used in S3 is trifluoromethanesulfonyl chloride or trifluoromethanesulfonic anhydride; the base used is triethylamine, pyridine, 2, 6-dimethylpyridine, diisopropylethylamine or 1, 8-diazabicycloundecen-7-ene.
6. The method for synthesizing urolithin a according to claim 1, wherein: the transition metal catalyst used in S4 is Ni (COD)2、NiBr2、NiBr2·glyme、Pd(PPh3)4、Pd2(dba)3、Pd(PPh3)2Cl2Or Pd (OAc)2(ii) a The photocatalyst used was Ir (dF (CF)3)ppy)2(dtbpy)(PF6)、Ir(4-F-ppy)2(dtbpy)(PF6)、Ir(ppy)2(dtbpy)(PF6)、Ru(bpy)3Cl2·6H2O or 4 CzIPN; the ligand is Xantphos, Xphos, t-BuXPhos, Johnphos, RuPhos, Davephos, Sphos or Neocuprine; the reducing agent is triethanolamine, hanster, N-diisopropylethylamine or 1-adamantane carboxylic acid; the additive is Cs2CO3、K2CO3、Na2CO3、NaHCO3Or
Figure FDA0002674956380000021
And (3) a molecular sieve.
7. The method for synthesizing urolithin A according to claim 1, wherein said compound VI is depleted of R1The method of the group is as follows:
when R is1When the compound is trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl or triisopropylsilyl, mixing the compound VI with tetra-n-butylammonium fluoride, dilute hydrofluoric acid or acetic acid according to the molar ratio of 1: 1.5-3.5, dissolving in a solvent, and reacting at room temperature for 20-25 h to obtain the compound;
when R is1When it is methyl, compound VI is reacted with BBr3、BCl3、BF3、TMSI、AlBr3Or AlCl3Mixing and dissolving the components in a solvent according to a molar ratio of 1: 2-5, and reacting at-78-room temperature for 20-25 h to obtain the compound;
when R is1When the benzyl group is used, mixing a compound VI and a hydrogenation catalyst according to a mass ratio of 4-5: 1, dissolving in a solvent, adding a hydrogen source, and reacting at room temperature for 4-5 hours to obtain the benzyl group; the hydrogenation catalyst is 5% Pd/C, 10% Pd/C or Raney nickel, and the hydrogen source is hydrogen, formic acid or ammonium formate;
when R is1When the compound is p-methoxybenzyl, mixing a compound VI with trifluoroacetic acid, triethylsilylhydride, boron trifluoride diethyl etherate, dichloro dicyano benzoquinone or ammonium ceric nitrate according to a molar ratio of 1: 2-5, dissolving in a solvent, and reacting at-0-room temperature for 20-25 h to obtain the p-methoxybenzyl compound;
when R is1When the compound is methoxymethyl, benzyloxymethyl or 2-methoxyethoxymethyl, dissolving the compound VI in an acidic solvent, and reacting at 55-60 ℃ for 25-35 min to obtain the compound VI.
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CN115747098A (en) * 2022-10-09 2023-03-07 江苏海洋大学 Streptococcus thermophilus FUA329 and method for producing urolithin A by fermenting same
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