CN108948105A - A kind of chemical synthesis process of Glycyrrhetic acid 3-O-mono-BETA-D-glucuronide - Google Patents
A kind of chemical synthesis process of Glycyrrhetic acid 3-O-mono-BETA-D-glucuronide Download PDFInfo
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Abstract
The present invention discloses a kind of chemical synthesis process of Glycyrrhetic acid 3-O-mono-BETA-D-glucuronide, belongs to organic synthesis, pharmaceutical chemistry and field of food science.Using abundance, cheap enoxolone as starting material; by to carboxyl at benzyl ester; the glucuronic acid methyl ester glycosyl donor of C3 hydroxyl and full benzoylation is at glycosides; distinguishing demethylating, benzoyl and benzyl again, totally 5 steps are reacted, and have easily synthesized Glycyrrhetic acid 3-O-mono-BETA-D-glucuronide.The raw materials used in the present invention and reagent price are cheap, and reaction condition is mild, easy to operate, ideal yield coefficient, provide feasible chemical synthesis process for the preparation of Glycyrrhetic acid 3-O-mono-BETA-D-glucuronide.
Description
Technical field
The present invention relates to organic synthesis, pharmaceutical chemistry and field of food science, it is therefore an objective to provide it is a kind of efficiently, can largely make
The chemical synthesis process of standby Glycyrrhetic acid 3-O-mono-BETA-D-glucuronide.
Background technique
Radix Glycyrrhizae is simply using extremely wide Chinese medicine.Glycyrrhizic acid (Glycyrrhizin, GL) is as the master in Radix Glycyrrhizae
Bioactive substance is wanted, there are various effects such as antitumor, anti-inflammatory, antiviral, antiallergy, reducing blood lipid.Meanwhile it is still
A kind of sweetener, sugariness are about 170 times of sucrose.Glycyrrhetic acid 3-O-mono-BETA-D-glucuronide (glycyrrtinic acid 3-O-
Mono- β-D-glucuronide, GAMG) to be glycyrrhizic acid lose the resulting product of outer end glucuronic acid through hydrolysis.The two has
Similar bioactivity, GAMG is equivalent on anti-inflammatory and antiallergic activity or is better than GL, has the spies such as dissolubility is good, toxicity is low
Point.In addition, GAMG is a kind of novel sweetener, it is more than 1000 times of sucrose that sugariness, which is 5 times of GL,.Therefore, GAMG is being cured
It has broad application prospects in medicine and food industry.
Currently, the method for preparing GAMG mainly uses the glycosidic bond of partial hydrolysis GL to obtain, but since hydrolysis degree is not easy
It controls and a large amount of aglycon substance enoxolone (Glycyrrhetinic acid, GA) can be generated.Amin et al. reported via
Beta-glucuronidase enzyme hydrolysis GL obtains method (H.A.S.Amin, H.A.El-Menoufy, the A.A.El- of GAMG
Mehalawy, et al.J.Mol.Catal.B-Enzym 2011,69,54), by culture working condition and reaction item
Part optimizes, and is hydrolyzed with guidance and generates based on GAMG and as far as possible minimize the generation of GA, at optimum conditions, GAMG yield
(51.5%) about 2 times higher than GA yield (26.8%).The Chinese patent of Hanbon Sci. & Tech. Co., Ltd.
(CN201210426829.9) it reports GL and obtains GAMG crude product through hydrochloric acid water solution, then pass through semipreparative high performance liquid chromatography instrument
The preparation method of high-purity GAMG is obtained after being further purified, but does not refer to the yield of GAMG.The above method although practical,
But during preparing GAMG, extraction operation is complicated, while hydrolyzing that generate GA inevitable, not only isolates and purifies difficulty, and
And it is difficult to largely prepare.
Summary of the invention
The object of the present invention is to provide a kind of short-cut methods of chemical synthesis Glycyrrhetic acid 3-O-mono-BETA-D-glucuronide.
The chemical synthesis process of GAMG provided by the invention, be using GA cheap and easy to get as starting material, it is anti-by 5 steps
It answers, the preparation of high-purity GAMG is realized with higher yields.The present invention also mentions simultaneously for the synthesis of other glucuronic acid saponins
Feasible method is supplied.
To achieve the above object, the technical scheme adopted by the invention is as follows:
Using glucurone as starting material, by opening lactonic ring, benzoylation, sugared end group bromo, end group water
Solution, end group tri- chloroacetimidateization reaction, obtains the glucuronic acid methyl ester tri- chloroacetimidate (I) of full benzoylation.
With enoxolone (GA, CAS 471-53-4) for starting material, its C30 carboxyl is protected to obtain Bian ester compounds (II), with (I)
Reaction obtains 3-O- glycoside compounds (III), and demethylating and three benzoyls obtain compound (IV), finally slough benzyl
Obtain target product GAMG.
It comprises the concrete steps that:
(1) preparation of the glucuronic acid methyl ester tri- chloroacetimidate (I) of full benzoylation:
The methanol solution of glucurone hydrolysis in the presence of alkali, it is anti-with chlorobenzoyl chloride at -10~0 DEG C
Answer, the bromo on end group carbon occurs in hydrobromic acid-acetic acid for products therefrom, and then hydrolyzes, finally and Tritox DBU work
It is the glycosyl donor compound of (I) with lower generation structural formula.
Wherein, the alkali is one kind of sodium methoxide or sodium hydroxide or potassium hydroxide.
It is preferred that alkali is sodium methoxide.
(2) preparation of enoxolone benzyl ester (II): in the mixed solvent system containing phase transfer catalyst, certain alkalinity
Under the conditions of, control temperature is not higher than 50 DEG C, and enoxolone is reacted with bromobenzyl generates benzyl ester, obtains the chemical combination that structural formula is (II)
Object.
Wherein, the phase transfer catalyst is one kind of tetrabutylammonium bromide or tetrabutylammonium chloride.
It is preferred that phase transfer catalyst is tetrabutylammonium bromide.
Wherein, the mixed solvent system has methylene chloride-water, chloroform-water, tetrahydrofuran-water, acetone-water, described
Volume ratio is 15:1~5:1.
It is preferred that mixed solvent system is methylene chloride-water, preferred volume ratio 15:1.
Wherein, the alkali is one kind of potassium carbonate or sodium carbonate.
It is preferred that alkali is potassium carbonate.
(3) preparation of saponin compound (III): compound (II) and glycosyl donor (I), at -78~0 DEG C, through Louis
Glycosidation occurs for this acid catalysis, obtains the compound that structure is (III).
Wherein, the lewis acid is one kind of Trimethylsilyl trifluoromethanesulfonate or boron trifluoride.
Preferred Lewis acids are Trimethylsilyl trifluoromethanesulfonate.
(4) preparation of saponin compound (IV): compound (III) demethylating and three benzoyls under alkaline condition
Afterwards, the compound that structure is (IV) is obtained.
Wherein, the alkali is the one or two of sodium methoxide or sodium hydroxide or potassium hydroxide.
It is preferred that alkali is potassium hydroxide and sodium methoxide.
(5) preparation of GAMG: compound (IV) is dissolved in organic solvent, at 25~80 DEG C, is catalyzed with hydrogen in palladium carbon
Lower reaction sloughs benzyl and obtains target compound GAMG.
Wherein, the organic solvent is selected from one of methylene chloride, chloroform, ethyl acetate, methanol and ethyl alcohol or a kind of
Above mixed solvent.
Preferable organic solvent is ethyl acetate.
The solution have the advantages that: establish a kind of simple and convenient process for preparing of Glycyrrhetic acid 3-O-mono-BETA-D-glucuronide, yield
Reach 40.3%~55.5% (calculating with GA).
Specific embodiment
By the description of following specific embodiments, above content of the invention is described in further detail.For
For those skilled in the art, the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to the following method description；
The techniques implemented on the basis of the foregoing are all within the scope of the present invention.
The synthesis of the full benzoylation glucuronic acid methyl ester tri- chloroacetimidate (I) of embodiment 1
It is protected from light at room temperature, glucurone 10.0g is dissolved in 70mL methanol, sodium methoxide/methanol that 1M is added is molten
Liquid 2.4mL is stirred to react 5 hours, appropriate glacial acetic acid is added, is adjusted to neutrality, brown viscous liquid is concentrated under reduced pressure to obtain, is dissolved in 70mL
In pyridine, 50mL chlorobenzoyl chloride is added dropwise under condition of ice bath, reacts 5h, after solution clarification, 200mL water is added and stirs 20min, uses
Methylene chloride extracts 3 times, and organic layer is washed 3 times, and dilute hydrochloric acid tune pH to 5-6, saturated sodium bicarbonate is washed till neutrality, saturated sodium-chloride
It washes 1 time, anhydrous sodium sulfate is dry.Filtering removes partial solvent under reduced pressure, 80mLHBr/AcOH solution is added dropwise under ice bath, reacts 5h,
200mL water is added, stirs 20min, is extracted with dichloromethane 3 times, organic layer is washed 3 times, and saturated sodium bicarbonate is washed till neutrality, is satisfied
It is washed 1 time with sodium chloride, anhydrous sodium sulfate is dry.Filtering, evaporating solvent under reduced pressure, residue are dissolved in acetone-water (10mL/2mL),
It is stirred at room temperature for 24 hours.It removes acetone under reduced pressure, methylene chloride is added and extracts 3 times, merge organic layer saturated sodium-chloride and wash 1 time, anhydrous sulphur
Sour sodium is dry.Remove methylene chloride under reduced pressure, residue is dissolved in dry 20mL methylene chloride, is added Tritox (0.95mL)
With DBU (0.04mL), ice bath stirring 3h.Reaction solution concentration, with petroleum ether: ethyl acetate (5:1) column chromatography, isolated structure
Formula is the compound of (I), yield 84.0%.1H NMR(600MHz,CDCl3) δ 8.68 (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.
The synthesis of the full benzoylation glucuronic acid methyl ester tri- chloroacetimidate (I) of embodiment 2
It is protected from light at room temperature, glucurone 10.0g is dissolved in 70mL methanol, sodium hydroxide/first of 0.5M is added
Alcoholic solution 4.8mL is stirred to react 3 hours, appropriate dilute hydrochloric acid is added, is adjusted to neutrality, brown viscous liquid is concentrated under reduced pressure to obtain, is dissolved in
In 70mL pyridine, 50mL chlorobenzoyl chloride is added dropwise under condition of ice bath, reacts 5h, after solution clarification, the stirring of 200mL water is added
20min is extracted with dichloromethane 3 times, and organic layer is washed 3 times, and dilute hydrochloric acid tune pH to 5-6, saturated sodium bicarbonate is washed till neutrality, satisfies
It is washed 1 time with sodium chloride, anhydrous sodium sulfate is dry.Filtering, removes partial solvent under reduced pressure, and it is molten that 80mLHBr/AcOH is added dropwise under ice bath
Liquid reacts 5h, and 200mL water is added, and stirs 20min, is extracted with dichloromethane 3 times, and organic layer is washed 3 times, saturated sodium bicarbonate
It is washed till neutrality, saturated sodium-chloride is washed 1 time, and anhydrous sodium sulfate is dry.Filtering, evaporating solvent under reduced pressure, residue are dissolved in acetone-water
(10mL/2mL), is stirred at room temperature for 24 hours.It removes acetone under reduced pressure, methylene chloride is added and extracts 3 times, merges organic layer saturated sodium-chloride
It washes 1 time, anhydrous sodium sulfate is dry.Remove methylene chloride under reduced pressure, residue is dissolved in dry 30mL tetrahydrofuran, and trichlorine is added
Acetonitrile (0.95mL) and DBU (0.04mL), ice bath stirring 3h.Reaction solution concentration, with petroleum ether: ethyl acetate (5:1) column chromatography,
Isolated structural formula is the compound of (I), yield 89.2%.Mass spectrum and nuclear magnetic data are the same as embodiment 2.
The synthesis of 3 enoxolone benzyl ester (II) of embodiment
By enoxolone (10.0g, 21.3mmol), bromobenzyl (5.0mL, 42.5mmol), potassium carbonate (8.8g,
63.8mmol), water (10mL) and tetrabutylammonium bromide (1.37g, 4.3mmol) sequentially add in 150mL methylene chloride, and 50 DEG C add
Heat reflux 6h, after end of reaction is cooling, dilute hydrochloric acid is washed till neutrality, concentration.Crude product is recrystallized with ethyl acetate, is obtained white
Spicule enoxolone benzyl ester (II), yield 90.2%.
The synthesis of the full benzoyl glucuronic acid methyl ester glycosides (III) of 4 enoxolone benzyl ester 3-O- of embodiment
By enoxolone benzyl ester (II) (3.0g, 5.4mmol) and full benzoylation glucuronic acid methyl ester imines ester (I)
(4.3g, 6.4mmol) is dissolved in 50mL methylene chloride, ice bath stirring 10min, and Trimethylsilyl trifluoromethanesulfonate is added dropwise
(0.1mL, 0.5mmol), after ice bath stirring 0.5h, with 0.2mL triethylamine quenching reaction, filtering.Filtrate is concentrated, petroleum ether-
Ethyl acetate (8:1) column chromatography, obtains 4.2g compound (III), yield 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.
The synthesis of the full benzoyl glucuronic acid methyl ester glycosides (III) of 5 enoxolone benzyl ester 3-O- of embodiment
By enoxolone benzyl ester (II) (3.0g, 5.4mmol) and full benzoylation glucuronic acid methyl ester imines ester (I)
(4.3g, 6.4mmol) is dissolved in 50mL methylene chloride, -78 DEG C of stirring 10min, dropwise addition boron trifluoride ether (0.7mL,
5.4mmol), after -78 DEG C of stirring 0.5h, with 0.8mL triethylamine quenching reaction.Filtering, filtrate concentration, petroleum ether-ethyl acetate
(8:1) column chromatography, obtains 3.9g compound (III), yield 69.4%, mass spectrum and nuclear magnetic data are the same as embodiment 4.
The synthesis of 6 enoxolone benzyl ester 3-O- glucuronide (IV) of embodiment
Compound (III) (4.2g, 3.9mmol) is dissolved in 50mL acetone-water (10:1v/v), potassium hydroxide is added in stirring
30min, evaporating solvent under reduced pressure is stirred at room temperature in powder (0.4g, 7.8mmol), and solid 50mL methanol dissolves, and 1M methanol is added
Sodium-methanol solution 3.9mL is 6 with cation exchange resin tune pH value after 2h is stirred at room temperature.It is filtered to remove cation exchange tree
Rouge, filtrate concentration, methylene chloride-methanol-formic acid (300:10:1) column chromatography obtain 2.7g compound (IV), yield 92.1%
。1H NMR(600MHz,CD3OD) δ 7.41-7.35 (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)δ
202.52,177.79,172.40,137.74,129.66,129.43,128.94,106.97,90.72,77.67,76.57,
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.
The synthesis of 7 enoxolone benzyl ester 3-O- glucuronide (IV) of embodiment
Compound (III) (4.2g, 3.9mmol) is dissolved in 50mL acetone-water (10:1v/v), sodium hydroxide is added in stirring
30min, evaporating solvent under reduced pressure is stirred at room temperature in powder (0.3g, 7.8mmol), and solid 50mL methanol dissolves, and 1M methanol is added
Sodium-methanol solution 3.9mL after 2h is stirred at room temperature, is 6 with cation exchange resin tune pH value, is filtered to remove cation exchange tree
Rouge, filtrate concentration, methylene chloride-methanol-formic acid (300:10:1) column chromatography obtain 2.3g compound (IV), yield 80.6%,
Mass spectrum and nuclear magnetic data are the same as embodiment 6.
The synthesis of 8 enoxolone benzyl ester 3-O- glucuronide (IV) of embodiment
Compound (III) (4.2g, 3.9mmol) is dissolved in 50mL acetone-water (10:1v/v), 1M sodium methoxide-first is added
Alcoholic solution 3.9mL after 2h is stirred at room temperature, is 7 with cation exchange resin tune pH value, is filtered to remove cation exchange resin, filter
Liquid concentration, solid are dissolved in 50mL acetone, and potassium hydroxide powder (0.4g, 7.8mmol) is added in stirring, and 30min is stirred at room temperature, and are used
Cation exchange resin tune pH value is 6, is filtered to remove cation exchange resin, filtrate concentration, methylene chloride-methanol-formic acid
(300:10:1) column chromatography, obtains 2.08g compound (IV), yield 71.0%, mass spectrum and nuclear magnetic data are the same as embodiment 6.
The synthesis of 9 enoxolone benzyl ester 3-O- glucuronide (IV) of embodiment
Compound (III) (4.2g, 3.9mmol) is dissolved in 50mL acetone-water (10:1v/v), potassium hydroxide is added in stirring
Powder (0.88g, 15.64mmol) after 2.5h is stirred at room temperature, is 6 with dilute hydrochloric acid tune pH value, solvent, methylene chloride-is concentrated under reduced pressure
Methyl alcohol-formic acid (300:10:1) column chromatography, obtains 2.14g compound (IV), yield 73.0%, and mass spectrum and nuclear magnetic data are the same as implementation
Example 6.
The synthesis of 10 Glycyrrhetic acid 3-O-mono-BETA-D-glucuronide of embodiment (GAMG)
Compound (IV) (2.7g, 3.6mmol) is dissolved in 100mL ethyl acetate, is added 10%Pd/C (0.50g), 60
DEG C heating, be passed through hydrogen.It is stirred to react 4h, is filtered to remove palladium carbon, filtrate concentration, methylene chloride-methanol-formic acid (150:10:1)
Column chromatography, obtains 2.1g GAMG, yield 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)δ
202.66,180.38,172.83,128.92,106.97,90.72,77.67,76.55,75.28,73.18,63.10,56.38,
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 (10)
1. a kind of chemical synthesis process of Glycyrrhetic acid 3-O-mono-BETA-D-glucuronide, which is characterized in that be with glucurone
Beginning raw material, by opening lactonic ring, benzoylation, sugared end group bromo, end group hydrolysis, the reaction of end group tri- chloroacetimidateization,
Obtain the glucuronic acid methyl ester tri- chloroacetimidate (I) of full benzoylation；Using enoxolone as starting material, it is protected
C30 carboxyls obtain Bian ester compounds (II), react to obtain 3-O- glycoside compounds (III) with (I), demethylating and three benzene
Formoxyl obtains compound (IV), finally sloughs benzyl and obtains target product Glycyrrhetic acid 3-O-mono-BETA-D-glucuronide；
2. synthetic method as described in claim 1, which comprises the steps of:
(1) preparation of the glucuronic acid methyl ester tri- chloroacetimidate (I) of full benzoylation:
Glucurone hydrolysis under alkaline condition, reacts, then end occurs in hydrobromic acid-acetic acid with chlorobenzoyl chloride
Bromo on base carbon, and then hydrolyze, it is finally generated under alkaline condition with Tritox and obtains the glycosyl donor that structural formula is (I)
Compound；
(2) preparation of enoxolone benzyl ester (II):
In the mixed solvent system containing phase transfer catalyst, under alkaline condition, enoxolone is reacted with bromobenzyl generates benzyl ester,
Obtain the compound that structural formula is (II)；
(3) preparation of saponin compound (III):
Through Louis acid catalysis glycosidation occurs for compound (II) and glycosyl donor (I), obtains the chemical combination that structure is (III)
Object；
(4) preparation of saponin compound (IV):
Compound (III) after demethylating and three benzoyls, obtains the compound that structure is (IV) under alkaline condition；
(5) preparation of GAMG:
Compound (IV) reacts under palladium carbon catalysis in organic solvent, with hydrogen, sloughs benzyl and obtains target compound GAMG.
3. synthetic method as claimed in claim 2, which is characterized in that in step (1), the alkali is sodium methoxide, hydroxide
Sodium or potassium hydroxide, reaction temperature are -10~0 DEG C.
4. synthetic method as claimed in claim 2, which is characterized in that in step (2), the phase transfer catalyst is four fourths
Base ammonium bromide or tetrabutylammonium chloride.
5. synthetic method as claimed in claim 2, which is characterized in that in step (2), the mixed solvent is dichloromethane
Alkane-water, chloroform-water, tetrahydrofuran-water, acetone-water, volume ratio are 15:1~5:1.
6. synthetic method as claimed in claim 2, which is characterized in that in step (2), the alkali is potassium carbonate, sodium carbonate
One of.
7. synthetic method as claimed in claim 2, which is characterized in that in step (3), the lewis acid is trifluoro methylsulphur
Sour trimethylsilyl group or boron trifluoride, reaction temperature are -78~0 DEG C.
8. synthetic method as claimed in claim 2, which is characterized in that in step (4), the alkali is sodium methoxide, hydroxide
Sodium, potassium hydroxide or their mix reagent.
9. synthetic method as claimed in claim 2, which is characterized in that organic solvent described in step (5) be methylene chloride,
One of chloroform, ethyl acetate, methanol and ethyl alcohol or more than one mixed solvent.
10. synthetic method as claimed in claim 2, which is characterized in that the reaction temperature of step (5) is 25~80 DEG C.
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| CN107012156A (en) * | 2016-01-28 | 2017-08-04 | 刘春生 | The related glycosyltransferase gene of glycyrrhizic acid biosynthesis and its coded product and application |
| CN107286218A (en) * | 2017-06-01 | 2017-10-24 | 亿利耐雀生物科技有限公司 | A kind of preparation method of new oleanane-type triterpene saponin derivative |
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| CN107012156A (en) * | 2016-01-28 | 2017-08-04 | 刘春生 | The related glycosyltransferase gene of glycyrrhizic acid biosynthesis and its coded product and application |
| CN107286218A (en) * | 2017-06-01 | 2017-10-24 | 亿利耐雀生物科技有限公司 | A kind of preparation method of new oleanane-type triterpene saponin derivative |
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| CN111434672A (en) * | 2019-01-14 | 2020-07-21 | 天津科技大学 | Preparation method of glycyrrhetinic acid glucoside and application of glycyrrhetinic acid glucoside in sweetener |
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