CN108948105B - Chemical synthesis method of glycyrrhetinic acid monoglucuronide - Google Patents

Chemical synthesis method of glycyrrhetinic acid monoglucuronide Download PDF

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CN108948105B
CN108948105B CN201810768064.4A CN201810768064A CN108948105B CN 108948105 B CN108948105 B CN 108948105B CN 201810768064 A CN201810768064 A CN 201810768064A CN 108948105 B CN108948105 B CN 108948105B
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glycyrrhetinic acid
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刘洋
程卯生
李慧宁
汪志鹏
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Shenyang Pharmaceutical University
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Abstract

The invention discloses a chemical synthesis method of glycyrrhetinic acid monoglucuronide, belonging to the fields of organic synthesis, pharmaceutical chemistry and food science. The glycyrrhetinic acid with rich sources and low price is used as a starting material, and the glycyrrhetinic acid monoglucuronide is simply and easily synthesized by 5 steps of reaction of forming benzyl ester by carboxyl, forming glucoside by C3 hydroxyl and benzoylated methyl glucuronate glycosyl donor, and then respectively removing methyl, benzoyl and benzyl. The method has the advantages of cheap raw materials and reagents, mild reaction conditions, simple operation and ideal yield, and provides a feasible chemical synthesis method for preparing the glycyrrhetinic acid monoglucuronide.

Description

Chemical synthesis method of glycyrrhetinic acid monoglucuronide
Technical Field
The invention relates to the fields of organic synthesis, pharmaceutical chemistry and food science, and aims to provide a chemical synthesis method which is efficient and can be used for preparing glycyrrhetinic acid monoglucuronide in a large scale.
Background
Licorice is a Chinese medicinal material with wide application. Glycyrrhizic acid (GL) is used as the main bioactive substance in Glycyrrhrizae radix, and has antitumor, antiinflammatory, antiviral, antiallergic, and blood lipid reducing effects. At the same time, it is a sweetener, which is about 170 times as sweet as sucrose. Glycyrrhetinic acid (3-O-mono-beta-D-glucuronide, GAMG) is a product obtained by hydrolysis of glycyrrhizic acid to remove glucuronic acid from the outer end. The two have similar biological activity, GAMG has equal or better antiinflammatory and antiallergic activity than GL, and has good solubility and low toxicity. In addition, GAMG is a novel sweetener, and its sweetness is 5 times that of GL and more than 1000 times that of sucrose. Therefore, GAMG has a wide application prospect in the pharmaceutical and food industries.
Figure BDA0001729539150000011
Currently, the method for preparing GAMG mainly uses partial hydrolysis of the glycoside bond of GL, but a large amount of Glycyrrhetinic Acid (GA) which is an aglycone substance is generated because the hydrolysis degree is not easy to control. Amin et al reported that GAMG can be obtained by hydrolyzing GL with β -glucuronidase (H.A.S.Amin, H.A.El-Menuufy, A.A.El-Mehalawy, et al.J.mol.Catal.B-enzyme 2011,69,54), by optimizing culture production conditions and reaction conditions to give guidance on GAMG production by hydrolysis and minimize GA production, GAMG production (51.5%) is about 2 times higher than GA production (26.8%) under optimal conditions. Chinese patent (CN201210426829.9) of hanbang science and technology ltd, jiang su reports a preparation method in which GL is hydrolyzed with hydrochloric acid to obtain a GAMG crude product, which is further purified by a semi-preparative high performance liquid chromatograph to obtain high purity GAMG, but the yield of GAMG is not mentioned. Although the above method is feasible, the extraction process is complicated in the process of preparing GAMG, and the generation of GA by hydrolysis is inevitable, so that not only separation and purification are difficult, but also mass production is difficult.
Disclosure of Invention
The invention aims to provide a simple method for chemically synthesizing glycyrrhetinic acid monoglucuronide.
The chemical synthesis method of GAMG provided by the invention takes cheap and easily available GA as the starting material, and realizes the preparation of high-purity GAMG with higher yield through 5-step reaction. The invention also provides a feasible method for synthesizing other glucuronic acid saponins.
In order to achieve the purpose, the invention adopts the technical scheme that:
the method comprises the steps of taking glucuronolactone as an initial raw material, and carrying out lactone ring opening, benzoylation, sugar end group bromination, end group hydrolysis and end group trichloroacetimide esterification reaction to obtain the benzoylated glucuronate methyl ester trichloroacetimidate (I). Glycyrrhetinic acid (GA, CAS 471-53-4) is used as an initial raw material, a carboxyl group at the C30 position is protected to obtain a benzyl ester compound (II), the benzyl ester compound (II) reacts with the benzyl ester compound (I) to obtain a 3-O-glucoside compound (III), a methyl group and three benzoyl groups are removed to obtain a compound (IV), and finally, a benzyl group is removed to obtain a target product GAMG.
The method comprises the following specific steps:
(1) preparation of the all-benzoylated glucuronic acid methyl ester trichloroacetimidate (I):
hydrolyzing and ring-opening a methanol solution of glucuronolactone under the action of alkali, reacting with benzoyl chloride at-10-0 ℃, brominating the obtained product on terminal group carbon in hydrobromic acid-acetic acid, further hydrolyzing, and finally reacting with trichloroacetonitrile under the action of DBU to generate the glycosyl donor compound with the structural formula (I).
Figure BDA0001729539150000021
Wherein, the alkali is one of sodium methoxide, sodium hydroxide or potassium hydroxide.
The preferred base is sodium methoxide.
(2) Preparation of benzyl glycyrrhetinate (II): in a mixed solvent system containing a phase transfer catalyst, controlling the temperature to be not higher than 50 ℃ under a certain alkaline condition, and reacting glycyrrhetinic acid with benzyl bromide to generate benzyl ester to obtain a compound with a structural formula (II).
Figure BDA0001729539150000031
Wherein, the phase transfer catalyst is one of tetrabutylammonium bromide or tetrabutylammonium chloride.
Preferably, the phase transfer catalyst is tetrabutylammonium bromide.
Wherein the mixed solvent system comprises dichloromethane-water, chloroform-water, tetrahydrofuran-water and acetone-water, and the volume ratio is 15: 1-5: 1.
the mixed solvent system is preferably dichloromethane-water, and the volume ratio is preferably 15: 1.
wherein the alkali is one of potassium carbonate or sodium carbonate.
Preferably, the base is potassium carbonate.
(3) Preparation of saponin Compound (III): and (3) carrying out a glycoside forming reaction on the compound (II) and a glycosyl donor (I) at the temperature of-78-0 ℃ under the catalysis of Lewis acid to obtain a compound with a structure (III).
Figure BDA0001729539150000032
Wherein the Lewis acid is one of trimethylsilyl trifluoromethanesulfonate or boron trifluoride.
The lewis acid is preferably trimethylsilyl trifluoromethanesulfonate.
(4) Preparation of saponin Compound (IV): and (3) removing methyl and three benzoyl from the compound (III) under an alkaline condition to obtain a compound with a structure (IV).
Figure BDA0001729539150000033
Wherein, the alkali is one or two of sodium methoxide, sodium hydroxide or potassium hydroxide.
Preferred bases are potassium hydroxide and sodium methoxide.
(5) Preparation of GAMG: dissolving the compound (IV) in an organic solvent, reacting with hydrogen at the temperature of 25-80 ℃ under the catalysis of palladium-carbon, and removing benzyl to obtain a target compound GAMG.
Figure BDA0001729539150000041
Wherein the organic solvent is one or more mixed solvents selected from dichloromethane, chloroform, ethyl acetate, methanol and ethanol.
Preferably, the organic solvent is ethyl acetate.
The invention has the technical effects that: establishes a simple preparation method of glycyrrhetinic acid monoglucuronide, and the yield reaches 40.3-55.5 percent (calculated by GA).
Detailed Description
The foregoing and other aspects of the present invention will be apparent from, and elucidated with reference to, the embodiments described hereinafter. It should not be understood to those skilled in the art that the scope of the above-described subject matter of the present invention is limited to the following description of the methods; all the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
EXAMPLE 1 Synthesis of Perbenzoylated glucuronic acid methyl ester trichloroacetimidate (I)
At room temperature in a dark place, dissolving 10.0g of glucuronolactone in 70mL of methanol, adding 2.4mL of 1M sodium methoxide/methanol solution, stirring for reaction for 5 hours, adding a proper amount of glacial acetic acid, adjusting to be neutral, concentrating under reduced pressure to obtain brown viscous liquid, dissolving in 70mL of pyridine, dropwise adding 50mL of benzoyl chloride under an ice bath condition, reacting for 5 hours, adding 200mL of water after the solution is clarified, stirring for 20 minutes, extracting with dichloromethane for 3 times, washing an organic layer for 3 times, adjusting the pH to be 5-6 with dilute hydrochloric acid, washing with saturated sodium bicarbonate to be neutral, washing with saturated sodium chloride for 1 time, and drying with anhydrous sodium sulfate. Filtering, evaporating partial solvent under reduced pressure, dropwise adding 80mLHBr/AcOH solution under ice bath, reacting for 5h, adding 200mL water, stirring for 20min, extracting with dichloromethane for 3 times, washing the organic layer with water for 3 times, washing with saturated sodium bicarbonate to neutrality, washing with saturated sodium chloride for 1 time, and drying with anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was dissolved in acetone-water (10mL/2mL) and stirred at room temperature for 24 hours. The acetone was evaporated under reduced pressure, dichloromethane was added to extract 3 times, the organic layers were combined, washed with saturated sodium chloride 1 time, and dried over anhydrous sodium sulfate. The dichloromethane was evaporated under reduced pressure and the residue was dissolved in dry 20mL dichloromethane, trichloroacetonitrile (0.95mL) and DBU (0.04mL) were added and stirred in an ice bath for 3 h. The reaction solution was concentrated, and the reaction solution was concentrated with petroleum ether: and (3) carrying out column chromatography by using ethyl acetate (5:1), and separating to obtain the compound with the structural formula (I), wherein the yield is 84.0%.1H NMR(600MHz,CDCl3)δ8.68(s,1H),7.97(d,J＝7.2Hz,2H),7.95(d,J＝7.2Hz,2H),7.89(d,J＝7.2Hz,2H),7.56–7.50(m,2H),7.46(t,J＝7.4Hz,1H),7.40(t,J＝7.8Hz,2H),7.36(t,J＝7.8Hz,2H),7.32(t,J＝7.8Hz,2H),6.91(d,J＝3.6Hz,1H),6.29(t,J＝9.9Hz,1H),5.76(t,J＝9.9Hz,1H),5.64(dd,J＝10.1,3.6Hz,1H),4.77(d,J＝10.1Hz,1H),3.69(s,3H).13C NMR(150MHz,CDCl3)δ167.36,165.64,165.42,160.41,133.76,133.75,133.58,130.05,129.91,128.86,128.71,128.64,128.61,128.57,128.56,92.99,71.08,70.34,69.76,69.41,53.22.HRMS(ESI):calcd.for[M+H]+C30H25Cl3NO10:664.0539,found 664.0567.
EXAMPLE 2 Synthesis of Perbenzoylated glucuronic acid methyl ester trichloroacetimidate (I)
At room temperature in a dark place, 10.0g of glucuronolactone is dissolved in 70mL of methanol, 4.8mL of 0.5M sodium hydroxide/methanol solution is added, the mixture is stirred and reacted for 3 hours, a proper amount of diluted hydrochloric acid is added, the mixture is adjusted to be neutral, the mixture is decompressed and concentrated to obtain brown viscous liquid, the brown viscous liquid is dissolved in 70mL of pyridine, 50mL of benzoyl chloride is dropwise added under the ice bath condition to react for 5 hours, 200mL of water is added after the solution is clarified, the mixture is stirred for 20 minutes, dichloromethane is used for extraction for 3 times, an organic layer is washed for 3 times, the pH value of the diluted hydrochloric acid is adjusted to be 5-6, saturated sodium bicarbonate is washed to be neutral, saturated sodium chloride is washed for. Filtering, evaporating partial solvent under reduced pressure, dropwise adding 80mLHBr/AcOH solution under ice bath, reacting for 5h, adding 200mL water, stirring for 20min, extracting with dichloromethane for 3 times, washing the organic layer with water for 3 times, washing with saturated sodium bicarbonate to neutrality, washing with saturated sodium chloride for 1 time, and drying with anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was dissolved in acetone-water (10mL/2mL) and stirred at room temperature for 24 hours. The acetone was evaporated under reduced pressure, dichloromethane was added to extract 3 times, the organic layers were combined, washed with saturated sodium chloride 1 time, and dried over anhydrous sodium sulfate. The dichloromethane was evaporated under reduced pressure and the residue was dissolved in dry 30mL tetrahydrofuran, trichloroacetonitrile (0.95mL) and DBU (0.04mL) were added and stirred in an ice bath for 3 h. The reaction solution was concentrated, and the reaction solution was concentrated with petroleum ether: and (3) carrying out column chromatography by using ethyl acetate (5:1), and separating to obtain the compound with the structural formula (I), wherein the yield is 89.2%. Mass spectrometry and nuclear magnetic data were as in example 2.
EXAMPLE 3 Synthesis of benzyl Glycyrrhetinic acid ester (II)
Glycyrrhetinic acid (10.0g, 21.3mmol), benzyl bromide (5.0mL, 42.5mmol), potassium carbonate (8.8g, 63.8mmol), water (10mL) and tetrabutylammonium bromide (1.37g, 4.3mmol) were sequentially added to 150mL of dichloromethane, heated at 50 ℃ under reflux for 6h, cooled after the reaction, washed to neutral with dilute hydrochloric acid, and concentrated. The crude product is recrystallized by ethyl acetate to obtain white needle-shaped glycyrrhetinic acid benzyl ester (II) with the yield of 90.2 percent.
EXAMPLE 4 Synthesis of Glycyrrhetinic acid benzyl ester 3-O-Perbenzoyl glucuronide methyl ester glycoside (III)
Benzyl glycyrrhetinate (II) (3.0g, 5.4mmol) and benzoylated glucuronic acid methyl ester imidate (I) (4.3g, 6.4mmol) were dissolved in 50mL of dichloromethane, stirred in ice bath for 10min, trimethylsilyl trifluoromethanesulfonate (0.1mL, 0.5mmol) was added dropwise, after stirring in ice bath for 0.5h, the reaction was quenched with 0.2mL of triethylamine, and filtered. The filtrate was concentrated, and subjected to column chromatography using petroleum ether-ethyl acetate (8:1) to give 4.2g of compound (III) with a yield of 73.6%.1H NMR(600MHz,CDCl3)δ7.94(dd,J＝8.3,1.1Hz,2H),7.92(dd,J＝8.3,1.2Hz,2H),7.85(dd,J＝8.3,1.1Hz,2H),7.51(q,J＝7.6Hz,2H),7.44(t,J＝7.4Hz,1H),7.39–7.33(m,9H),7.30(t,J＝7.9Hz,2H),5.91(t,J＝9.7Hz,1H),5.67(t,J＝9.7Hz,1H),5.59(dd,J＝9.8,7.8Hz,1H),5.53(s,1H),5.19(d,J＝12.2Hz,1H),5.09(d,J＝12.2Hz,1H),4.89(d,J＝7.8Hz,1H),4.32(d,J＝9.8Hz,1H),3.72(s,3H),3.20–3.15(m,1H),2.79(dt,J＝13.4,3.3Hz,1H),2.26(s,1H),2.05–1.73(m,8H),1.63–1.40(m,5H),1.37–1.24(m,10H),1.15(s,3H),1.10(s,3H),1.06(s,3H),0.97(d,J＝13.1Hz,1H),0.71(d,J＝1.2Hz,6H),0.66(s,3H),0.62(d,J＝11.5Hz,1H).13C NMR(150MHz,CDCl3)δ200.11,176.33,169.02,167.42,165.92,165.26,164.99,136.25,133.51,133.44,133.25,129.97,129.93,129.89,129.48,129.04,128.91,128.76,128.67,128.57,128.46,128.43,128.41,103.30,90.70,72.99,72.50,71.98,70.51,66.38,61.86,55.30,53.06,48.31,45.44,44.12,43.22,41.19,39.30,39.22,37.77,36.89,32.79,31.89,31.30,28.53,28.44,27.82,26.57,26.51,25.80,23.44,18.77,17.41,16.44,16.34.HRMS(ESI):calcd.for[M+NH4]+C65H78NO13:1080.5468,found 1080.5493.
EXAMPLE 5 Synthesis of Glycyrrhetinic acid benzyl ester 3-O-Perbenzoyl glucuronide methyl ester glycoside (III)
Benzyl glycyrrhetinate (II) (3.0g, 5.4mmol) and total benzoylated glucuronic acid methyl ester imidate (I) (4.3g, 6.4mmol) were dissolved in 50mL of dichloromethane, stirred at-78 ℃ for 10min, boron trifluoride diethyl etherate (0.7mL, 5.4mmol) was added dropwise, and after stirring at 78 ℃ for 0.5h, the reaction was quenched with 0.8mL of triethylamine. Filtration, concentration of the filtrate and column chromatography with petroleum ether-ethyl acetate (8:1) gave 3.9g of compound (III) in 69.4% yield, as in example 4 with mass spectrometry and nuclear magnetic data.
EXAMPLE 6 Synthesis of Glycyrrhetinic acid benzyl ester 3-O-glucuronide (IV)
Compound (III) (4.2g, 3.9mmol) was dissolved in 50mL of acetone-water (10:1v/v), potassium hydroxide powder (0.4g, 7.8mmol) was added with stirring, the mixture was stirred at room temperature for 30min, the solvent was distilled off under reduced pressure, the solid was dissolved in 50mL of methanol, 3.9mL of 1M sodium methoxide-methanol solution was added, the mixture was stirred at room temperature for 2h, and then the pH was adjusted to 6 with a cation exchange resin. The cation exchange resin was removed by filtration, the filtrate was concentrated, and column chromatography was performed using methylene chloride-methanol-formic acid (300:10:1) to obtain 2.7g of the compound (IV) with a yield of 92.1%.1H NMR(600MHz,CD3OD)δ7.41–7.35(m,4H),7.34–7.31(m,1H),5.44(s,1H),5.23(d,J＝12.1Hz,1H),5.08(d,J＝12.1Hz,1H),4.37(d,J＝7.8Hz,1H),3.76(d,J＝9.9Hz,1H),3.51(t,J＝9.4Hz,1H),3.35(t,J＝9.1Hz,1H),3.24(dd,J＝9.2,7.8Hz,1H),3.18(dd,J＝11.6,4.7Hz,1H),2.68(dt,J＝13.2,3.3Hz,1H),2.42(s,1H),2.11(td,J＝13.7,4.4Hz,1H),1.98(ddd,J＝21.9,13.3,3.2Hz,2H),1.87–1.79(m,3H),1.79–1.68(m,3H),1.61(d,J＝13.3Hz,1H),1.50–1.40(m,3H),1.39(s,3H),1.35(dt,J＝14.2,3.1Hz,1H),1.23(ddd,J＝15.3,12.8,5.7Hz,2H),1.15(s,3H),1.13(s,3H),1.10(s,3H),1.06(s,3H),1.01(dd,J＝18.2,8.1Hz,2H),0.87(s,3H),0.78(d,J＝11.2Hz,1H),0.70(s,3H).13C NMR(150MHz,CD3OD)δ202.52,177.79,172.40,137.74,129.66,129.43,128.94,106.97,90.72,77.67,76.57,75.28,73.19,67.35,63.07,56.37,49.69,46.69,45.17,44.55,42.32,40.52,40.17,38.79,38.04,33.76,32.88,32.04,28.99,28.47,28.37,27.53,27.32,26.98,23.76,19.25,18.41,16.98,16.94.HRMS(ESI):calcd.for[M+H]+C43H61O10:737.4259,found 737.4253.
EXAMPLE 7 Synthesis of Glycyrrhetinic acid benzyl ester 3-O-glucuronide (IV)
Compound (III) (4.2g, 3.9mmol) was dissolved in 50mL of acetone-water (10:1v/v), sodium hydroxide powder (0.3g, 7.8mmol) was added with stirring, the mixture was stirred at room temperature for 30min, the solvent was distilled off under reduced pressure, the solid was dissolved in 50mL of methanol, 3.9mL of 1M sodium methoxide-methanol solution was added, the mixture was stirred at room temperature for 2h, then pH was adjusted to 6 with a cation exchange resin, the cation exchange resin was removed by filtration, the filtrate was concentrated, and column chromatography was performed with dichloromethane-methanol-formic acid (300:10:1) to obtain 2.3g of Compound (IV) with a yield of 80.6%, and the mass spectrum and nuclear magnetic data were the same as in example 6.
EXAMPLE 8 Synthesis of Glycyrrhetinic acid benzyl ester 3-O-glucuronide (IV)
Compound (III) (4.2g, 3.9mmol) was dissolved in 50mL of acetone-water (10:1v/v), 3.9mL of 1M sodium methoxide-methanol solution was added, and after stirring at room temperature for 2 hours, the pH was adjusted to 7 with a cation exchange resin, the cation exchange resin was removed by filtration, the filtrate was concentrated, the solid was dissolved in 50mL of acetone, potassium hydroxide powder (0.4g, 7.8mmol) was added with stirring, the mixture was stirred at room temperature for 30min, the pH was adjusted to 6 with a cation exchange resin, the cation exchange resin was removed by filtration, the filtrate was concentrated, and methylene chloride-methanol-formic acid (300:10:1) was subjected to column chromatography to give 2.08g of Compound (IV) with a yield of 71.0%, and the mass spectrum and nuclear magnetic data were the same as in example 6.
EXAMPLE 9 Synthesis of Glycyrrhetinic acid benzyl ester 3-O-glucuronide (IV)
Compound (III) (4.2g, 3.9mmol) was dissolved in 50mL of acetone-water (10:1v/v), potassium hydroxide powder (0.88g, 15.64mmol) was added with stirring, and after stirring at room temperature for 2.5 hours, the pH was adjusted to 6 with dilute hydrochloric acid, the solvent was concentrated under reduced pressure, and dichloromethane-methanol-formic acid (300:10:1) column chromatography was performed to give 2.14g of Compound (IV) with a yield of 73.0%, mass spectrometry and nuclear magnetic data the same as those in example 6.
EXAMPLE 10 Synthesis of Glycyrrhetinic acid Monoglucuronic acid (GAMG)
Compound (IV) (2.7g, 3.6mmol) was dissolved in 100mL of ethyl acetate, 10% Pd/C (0.50g) was added, and the mixture was heated at 60 ℃ and purged with hydrogen. Stirring for reaction for 4 hr, filtering to remove Pd/C, concentrating the filtrate, and performing column chromatography with dichloromethane-methanol-formic acid (150:10:1) to obtain 2.1g GAMG with yield of 90.7%.1H NMR(600MHz,CD3OD)δ5.57(s,1H),5.49(s,1H),4.38(d,J＝7.8Hz,1H),3.76(d,J＝9.8Hz,1H),3.51(t,J＝9.4Hz,1H),3.36(t,J＝9.1Hz,1H),3.24(t,J＝8.5Hz,1H),3.19(dd,J＝11.6,4.5Hz,1H),2.68(d,J＝13.5Hz,1H),2.45(s,1H),2.22–2.10(m,2H),1.98–1.59(m,9H),1.49–1.43(m,2H),1.42(s,3H),1.41–1.37(m,3H),1.24(d,J＝12.9Hz,1H),1.17(s,3H),1.14(s,3H),1.14(s,3H),1.07(s,3H),1.06–1.00(m,2H),0.87(s,3H),0.83(s,3H),0.80(d,J＝11.6Hz,1H)；13C NMR(150MHz,CD3OD)δ202.66,180.38,172.83,128.92,106.97,90.72,77.67,76.55,75.28,73.18,63.10,56.38,54.81,49.91,46.75,44.90,44.61,42.39,40.53,40.17,39.02,38.05,33.78,32.97,31.99,29.20,28.75,28.38,27.58,27.38,26.98,23.82,19.27,18.42,16.98,16.94.HRMS(ESI):calcd.for[M+H]+C36H55O10:647.3790,found 647.3790。

Claims (9)

1. A chemical synthesis method of glycyrrhetinic acid monoglucuronide is characterized in that glucuronolactone is used as a starting material, and the completely benzoylated methyl glucuronate trichloroacetimidate (I) is obtained through lactone ring opening, benzoylation, sugar end group bromination, end group hydrolysis and end group trichloroacetimidate esterification; takes glycyrrhetinic acid as an initial raw material, under the action of a phase transfer catalyst tetrabutylammonium bromide or tetrabutylammonium chloride, protects carboxyl at C30 position to obtain a benzyl ester compound (II), and reacts with the benzyl ester compound (II) to obtain 3-OA glycoside compound (III), methyl and three benzoyl are removed to obtain a compound (IV), and finally benzyl is removed to obtain a target product, namely glycyrrhetinic acid monoglucuronide;
Figure DEST_PATH_IMAGE001
。
2. the method of synthesis according to claim 1, comprising the steps of:
(1) preparation of the all-benzoylated glucuronic acid methyl ester trichloroacetimidate (I):
hydrolyzing and opening the ring of glucuronolactone under alkaline conditions, reacting with benzoyl chloride, brominating on terminal group carbon in hydrobromic acid-acetic acid, hydrolyzing, and finally generating a glycosyl donor compound with a structural formula (I) with trichloroacetonitrile under alkaline conditions;
(2) preparation of benzyl glycyrrhetinate (II):
reacting glycyrrhetinic acid with benzyl bromide in a mixed solvent system containing a phase transfer catalyst under an alkaline condition to generate benzyl ester, and obtaining a compound with a structural formula (II);
(3) preparation of saponin Compound (III):
the compound (II) and glycosyl donor (I) are catalyzed by Lewis acid to generate glycoside-forming reaction to obtain a compound with a structure of (III);
(4) preparation of saponin Compound (IV):
removing methyl and three benzoyl from the compound (III) under an alkaline condition to obtain a compound with a structure (IV);
(5) preparation of GAMG:
and (3) reacting the compound (IV) with hydrogen in an organic solvent under the catalysis of palladium-carbon, and removing benzyl to obtain a target compound GAMG.
3. The synthesis method according to claim 2, wherein in the step (1), the alkali is sodium methoxide, sodium hydroxide or potassium hydroxide, and the reaction temperature is-10 to 0oC。
4. The synthesis method according to claim 2, wherein in the step (2), the mixed solvent is dichloromethane-water, chloroform-water, tetrahydrofuran-water, acetone-water, and the volume ratio is 15: 1-5: 1.
5. the synthesis method of claim 2, wherein in the step (2), the alkali is one of potassium carbonate and sodium carbonate.
6. The synthetic method according to claim 2, wherein in the step (3), the Lewis acid is trimethylsilyl trifluoromethanesulfonate or boron trifluoride, and the reaction temperature is-78 to 0oC。
7. The method according to claim 2, wherein in step (4), the base is sodium methoxide, sodium hydroxide, potassium hydroxide or their mixture.
8. The synthesis method according to claim 2, wherein the organic solvent in step (5) is one or more of dichloromethane, chloroform, ethyl acetate, methanol and ethanol.
9. The synthesis method according to claim 2, wherein the reaction temperature in the step (5) is 25-80%oC。
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