CN110776550B - C3 and C20 double-esterified glycyrrhetinic acid derivative and preparation method and application thereof - Google Patents
C3 and C20 double-esterified glycyrrhetinic acid derivative and preparation method and application thereof Download PDFInfo
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Abstract
The invention providesA C3 and C20 doubly esterified glycyrrhetinic acid derivative has a structure shown in formula I, or pharmaceutically acceptable salt, solvate, optical isomer or polymorph thereof. Experimental results show that the C3 and C20 double-esterified glycyrrhetinic acid derivative provided by the invention has a good bacteriostatic action on staphylococcus aureus, can inhibit staphylococcus aureus ATCC 6538, staphylococcus aureus ATCC 12228 and staphylococcus aureus ATCC 29213, and provides a new choice for an anti-infective drug of staphylococcus aureus.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a C3 and C20 double-esterified glycyrrhetinic acid derivative and a preparation method and application thereof.
Background
Staphylococcus aureus is a significant cause of morbidity and mortality worldwide. Such ubiquitous gram-positive bacteria can cause mild to life threatening diseases, with the common in-situ symptoms of pyogenic disease, food poisoning, pneumonia and sepsis. Chemotherapy is commonly used for s. However, the emergence of methicillin-resistant staphylococcus aureus (MRSA) represents a problem that has become very acute in the treatment of staphylococcus aureus infections. The increased morbidity and mortality caused by infection with multidrug resistant pathogens has highlighted an urgent need to develop new antibacterial agents to protect human and plant life health.
A significant portion of the approved drugs currently designed as novel antimicrobial agents are natural products or scaffolds derived from natural products. Natural products and derivatives thereof with unique and diverse chemical structures generally have broad-spectrum bactericidal activity, and particularly have very significant inhibitory activity against antibiotic-resistant strains, which provides a reasonable design and development idea for novel antibacterial therapies.
Glycyrrhetinic acid is the main component of Glycyrrhrizae radix extract. Previous studies have shown that glycyrrhetinic acid has a number of properties, including anti-inflammatory, anti-allergic, anti-peptic ulcer and anti-viral activity. Glycyrrhetinic acid has antibacterial effects on some bacteria, but the underlying mechanism of this activity is not clear. In order to further explore the antibacterial mechanism of glycyrrhetinic acid, the glycyrrhetinic acid needs to be modified to provide more useful activity data.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide a glycyrrhetinic acid derivative that is di-esterified with C3 and C20, and a preparation method and an application thereof, for further exploring the effect of glycyrrhetinic acid on gram-positive bacteria.
In order to solve the technical problems, the invention provides a C3 and C20 double-esterified glycyrrhetinic acid derivative which has a structure shown in a formula I, or pharmaceutically acceptable salt, solvate, optical isomer or polymorphic substance thereof:
wherein R is C1-C10 alkyl;
r' is C1-C10 alkyl, substituted or unsubstituted five-membered or six-membered aromatic group.
The invention carries out esterification modification on the carbon atom No. 3 (C3) and the carbon atom No. 20 (C20) of glycyrrhetinic acid.
Wherein R' in the esterification group modified by C3 is preferably C1-C10 alkyl, substituted or unsubstituted five-membered or six-membered aromatic group.
The C1-C10 alkyl group is more preferably a C1-C5 alkyl group, and still more preferably a methyl group, an ethyl group, a propyl group or an n-butyl group.
In the invention, the five-membered aromatic group refers to a five-membered aromatic ring or aromatic heterocyclic group containing carbon atoms and heteroatoms; the six-membered aromatic group means a six-membered aromatic ring or aromatic heterocyclic group containing a carbon atom and a heteroatom.
In the substituted or unsubstituted five-membered or six-membered aromatic group, the substituent is preferably C1-C5 alkyl or C1-C5 alkoxy; the five-or six-membered aromatic group is preferably phenyl, furyl, pyrrolyl or thienyl.
Further preferably, the substituted or unsubstituted five-or six-membered aromatic group is phenyl, p-methylphenyl, o-methylphenyl, m-methylphenyl, p-methoxyphenyl, o-methoxyphenyl or m-methoxyphenyl.
R in the C20-modified esterifying group is preferably C1-C10 alkyl, more preferably C1-C5 alkyl, and even more preferably methyl, ethyl, propyl or n-butyl.
The invention discloses a preparation method of the C3 and C20 double esterified glycyrrhetinic acid derivative, which comprises the following steps:
a) mixing glycyrrhetinic acid shown as a formula II with an anhydride compound, a benzene anhydride compound or a benzene acyl chloride compound, and carrying out a first esterification reaction under the catalysis of 4-dimethylaminopyridine to obtain a C3 esterified derivative shown as a formula III;
b) adding an alcohol compound into the derivative shown in the formula III under a strong acid condition, and carrying out a second esterification reaction to obtain a compound shown in the formula I in which C3 and C20 are esterified;
or comprises the following steps:
c) adding an alcohol compound into glycyrrhetinic acid shown in a formula II under a strong acid condition, and carrying out a third esterification reaction to obtain a C20 esterified derivative shown in a formula IV;
d) mixing the derivative shown as the formula IV with an anhydride compound, a benzene anhydride compound or a benzene acyl chloride compound, and carrying out fourth esterification reaction under the catalytic action of 4-dimethylaminopyridine to obtain a compound shown as the formula I, wherein C3 and C20 are esterified;
wherein R is C1-C10 alkyl;
r' is C1-C10 alkyl, substituted or unsubstituted five-membered or six-membered aromatic group.
In the present invention, the reaction equations of steps a) and b) are as follows:
firstly, glycyrrhetinic acid shown as a formula II is taken as a raw material, the glycyrrhetinic acid is dissolved in an organic solvent, an anhydride compound, a benzene anhydride compound or a benzene acyl chloride compound is added at normal temperature, and a first esterification reaction is carried out under the catalysis of 4-dimethylaminopyridine, so that the esterified derivative of C3 shown as a formula III is obtained.
The temperature of the first esterification reaction is preferably 10-40 ℃, and the reaction time is preferably 4-6 h.
The preferable molar ratio of the glycyrrhetinic acid to the anhydride compound or the benzene anhydride compound is 1: 1.5-3.0; the preferable molar ratio of the glycyrrhetinic acid to the benzoyl chloride compounds is 1: 2.0-4.0.
The organic solvent is preferably pyridine.
Then, the derivative shown in the formula III is dissolved in an organic solvent, and an alcohol compound is added under the strong acid condition to carry out a second esterification reaction, so that the compound shown in the formula I with esterified C3 and C20 is obtained.
The temperature of the second esterification reaction is preferably 10-40 ℃, and the reaction time is preferably 6-12 h.
The molar ratio of the derivative shown in the formula III to the alcohol compound is preferably 1: 2.0-4.5.
The organic solvent is preferably methanol or ethanol.
In the present invention, the reaction equations of the steps c) and d) are as follows:
firstly, glycyrrhetinic acid shown in formula II is used as a raw material, the glycyrrhetinic acid is dissolved in an organic solvent, and an alcohol compound is added under a strong acid condition to carry out a third esterification reaction, so that a derivative with esterified C20 shown in formula IV is obtained.
The temperature of the third esterification reaction is preferably 10-40 ℃, and the reaction time is preferably 12-24 h.
The preferable molar ratio of the glycyrrhetinic acid to the alcohol compound is 1: 2.0-4.5.
The organic solvent is preferably methanol or ethanol.
And then dissolving the derivative shown as the formula IV in an organic solvent, adding an anhydride compound, a benzene anhydride compound or a benzene acyl chloride compound at normal temperature, and carrying out fourth esterification reaction under the catalytic action of 4-dimethylaminopyridine to obtain the compound shown as the formula I in which C3 and C20 are esterified.
The temperature of the fourth esterification reaction is preferably 10-40 ℃, and the reaction time is preferably 12-18 h.
The mole ratio of the derivative shown in the formula IV to the anhydride compound or the benzene anhydride compound is preferably 1: 1.5-3.0; the mol ratio of the derivative shown in the formula IV to the benzoyl chloride compound is preferably 1: 2.0-4.0.
The organic solvent is preferably pyridine.
In the present invention, the acid anhydride compound is preferably formic anhydride, acetic anhydride, propionic anhydride, or butyric anhydride; the benzene acid anhydride compound is preferably phenyl acid anhydride or benzyloxy acid anhydride; the benzoyl chloride compound is preferably o-methylbenzoyl chloride, m-methylbenzoyl chloride, o-methoxybenzoyl chloride or m-methoxybenzoyl chloride; the alcohol compound is preferably methanol, ethanol, propanol or n-butanol.
In the present invention, after the second esterification reaction or the fourth esterification reaction is completed, it is preferable to further include a purification step.
Preferably, the purification step comprises evaporating the solvent and purifying by column chromatography.
In some embodiments of the invention, the purification step specifically comprises:
filtering, evaporating the solvent under reduced pressure, extracting with distilled water, drying, collecting a solid layer, adding alkali to the solid layer to adjust the pH value to 7-8, washing with water to be neutral, filtering, collecting the solid, drying the solid, and purifying by silica gel column chromatography.
All derivatives prepared according to the invention are white solids.
In the above structural formula of the present invention, a single bond represents a methyl group.
The invention discloses application of the C3 and C20 double-esterified glycyrrhetinic acid derivatives or the C3 and C20 double-esterified glycyrrhetinic acid derivatives prepared by the preparation method in preparation of an anti-staphylococcus preparation.
The invention discloses an anti-staphylococcus preparation, which comprises the C3 and C20 double-esterified glycyrrhetinic acid derivatives or the C3 and C20 double-esterified glycyrrhetinic acid derivatives prepared by the preparation method.
The administration method of the anti-staphylococcus preparation can be oral administration, injection administration, spray inhalation, local administration, rectal administration, nasal administration, buccal administration, administration through an implanted kit and the like.
The dosage form of the anti-staphylococcus preparation can be oral dosage forms, such as capsules, tablets, pills, powder, granules, aqueous suspension or solution and the like.
The anti-staphylococcal agent may further comprise a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or combination thereof.
The above pharmaceutically acceptable carriers, excipients, diluents, adjuvants and vehicles can be selected according to the common general knowledge of those skilled in the art, and the present invention is not particularly limited thereto.
Compared with the prior art, the invention provides a C3 and C20 double-esterified glycyrrhetinic acid derivative which has a structure shown in a formula I, or pharmaceutically acceptable salt, solvate, optical isomer or polymorphic substance thereof. Experimental results show that the C3 and C20 double-esterified glycyrrhetinic acid derivative provided by the invention has a good bacteriostatic action on staphylococcus aureus, can inhibit staphylococcus aureus ATCC 6538, staphylococcus aureus ATCC 12228 and staphylococcus aureus ATCC 29213, and provides a new choice for an anti-infective drug of staphylococcus aureus.
Drawings
FIG. 1 is a high resolution mass spectrum of compound 4a prepared according to the present invention;
FIG. 2 is a high resolution mass spectrum of compound 4b prepared according to the present invention.
Detailed Description
In order to further illustrate the present invention, the following examples are provided to describe the C3 and C20 diacrylated glycyrrhetinic acid derivatives of the present invention and their preparation and use in detail.
EXAMPLE 1 preparation of Compound 2a
Glycyrrhetinic acid (compound 1) (470mg, 1mmol) is weighed into a 100mL round-bottom flask with magnetons, then 20mL of anhydrous methanol is weighed into the flask, the mixture is stirred for 3min at room temperature until the anhydrous methanol is completely dissolved, 1.5mL of concentrated sulfuric acid is sucked by a glass pipette and slowly added into the system, and then the esterification reaction is carried out for 24h under the condition of normal temperature. Finally, the methanol solvent was distilled off under reduced pressure at 45 ℃ to obtain a crude product of Compound 2 a. Compound 2a was obtained as a white solid in 90% yield by silica gel column chromatography (eluent: petroleum ether: ethyl acetate (vol): 2: 1).
To carry out1HNMR 13C NMR and high resolution mass spectrometry analysis, results are:1H NMR(400MHz,CDCl3)δ5.66(s,1H),3.68(s,3H),3.27–3.17(m,1H),2.85–2.75(m,1H),2.33(s,1H),2.10–1.96(m,3H),1.94–1.87(m,1H),1.87–1.77(m,1H),1.67–1.55(m,5H),1.49(d,J＝6.6Hz,2H),1.46–1.37(m,3H),1.36(s,3H),1.30(d,J＝9.7Hz,2H),1.21–1.16(m,1H),1.14(s,3H),1.13(s,3H),1.12(s,3H),1.00(s,3H),0.98–0.93(m,1H),0.80(s,6H),0.72–0.67(m,1H).13C NMR(400MHz,CDCl3)δ200.22,176.94,169.17,128.57,78.78,61.84,54.98,51.79,48.41,45.40,44.06,43.21,41.13,39.15,37.76,37.11,32.79,31.85,31.16,28.53,28.34,28.11,27.33,26.50,26.44,23.41,18.69,17.50,16.38,15.59.HRMS(ESI)C31H49O4(485.3625)；485.3625(M+H)+。
EXAMPLE 2 preparation of Compound 2b
Glycyrrhetinic acid (compound 1) (470.0mg, 1mmol) was weighed into a 100mL round-bottomed flask with magnetons, then 20mL absolute ethanol was weighed into the flask, stirred at room temperature for 3min until completely dissolved, 1.5mL concentrated sulfuric acid was sucked by a glass pipette, slowly added into the system, and then placed at room temperature for esterification reaction for 24 h. Finally, the ethanol solvent was distilled off under reduced pressure at 45 ℃ to obtain a crude product of compound 2 b. Compound 2b was obtained as a white solid in 88% yield by silica gel column chromatography (eluent: petroleum ether: ethyl acetate (vol): 2: 1).
To carry out1H NMR 13C NMR and high resolution mass spectrometry analysis, results are:1H NMR(400MHz,CDCl3)δ5.62(s,1H),4.23–4.07(m,2H),3.25–3.17(m,1H),2.81–2.72(m,1H),2.32(s,1H),2.12–2.04(m,1H),2.04–1.93(m,2H),1.93–1.86(m,1H),1.85–1.75(m,1H),1.70–1.49(m,6H),1.46–1.38(m,2H),1.38–1.28(m,6H),1.24(t,J＝7.1Hz,3H),1.17(d,J＝12.6Hz,1H),1.12(s,3H),1.12(s,3H),1.10(s,3H),1.03–0.99(m,1H),0.98(s,3H),0.96–0.90(m,1H),0.78(s,6H),0.68(d,J＝11.5Hz,1H).13C NMR(400MHz,CDCl3)δ200.23,176.39,169.32,128.51,78.74,61.83,60.32,54.95,48.39,45.39,43.84,43.22,41.09,39.14,37.73,37.10,32.78,31.82,31.13,28.57,28.33,28.11,27.31,26.50,26.43,23.40,18.68,17.50,16.37,15.60,14.34.HRMS(ESI)C32H51O4(499.3782)；499.3787(M+H)+。
EXAMPLE 3 preparation of Compound 3a
Glycyrrhetinic acid (compound 1) (470.0mg, 1mmol) was weighed into a 100mL magneton round-bottomed flask, then 20mL pyridine was weighed as a solvent, stirred at room temperature for 2min until completely dissolved, 4-dimethylaminopyridine (155.7mg,1.2mmol) was added, after stirring to homogeneity, acetic anhydride (86.8mg,0.85mmol) was finally added, and after 6h of reaction, the reaction end point was detected by TLC. The pyridine solvent was distilled off under reduced pressure at 55 ℃ to obtain a crude product of compound 3 a. Compound 3a was obtained as a white solid in 80% yield by silica gel column chromatography (eluent: petroleum ether: ethyl acetate (vol): 2: 1).
To carry out1H NMR 13C NMR and high resolution mass spectrometry analysis, results are:1H NMR(400MHz,CDCl3)δ5.71(s,1H),4.60–4.49(m,1H),2.86–2.76(m,1H),2.36(d,J＝7.7Hz,1H),2.22–2.16(m,1H),2.05(s,3H),2.03–1.89(m,3H),1.88–1.80(m,1H),1.71–1.57(m,5H),1.47(t,J＝9.1Hz,1H),1.44–1.39(m,3H),1.37(s,3H),1.26(s,3H),1.23(s,3H),1.17(s,3H),1.13(s,3H),1.05(s,1H),1.01(s,1H),0.88(s,6H),0.83(d,J＝5.6Hz,3H),0.80(d,J＝5.9Hz,1H).13C NMR(400MHz,CDCl3)δ200.26,180.84,171.02,169.33,128.50,80.66,61.73,55.06,48.27,45.48,43.77,43.23,40.92,38.81,38.08,37.73,36.98,32.75,31.88,30.96,29.69,28.53,28.42,28.06,26.44,23.59,23.36,21.29,18.71,17.40,16.69,16.40.HRMS(ESI)C32H48O5Na(535.3394)；535.3403(M+Na)+。
EXAMPLE 4 preparation of Compound 3b
Glycyrrhetinic acid (compound 1) (470.0mg, 1mmol) was weighed into a 100mL round-bottomed flask with magnetons, then 20mL of pyridine was weighed as a solvent, stirred at room temperature for 2min until completely dissolved, 4-dimethylaminopyridine (155.7mg,1.2mmol) was added, after stirring to homogeneity, benzoic anhydride (192.3mg,0.85mmol) was finally added, and after 6h of reaction, the reaction end point was detected by TLC. The pyridine solvent was distilled off under reduced pressure at 55 ℃ to obtain a crude product of compound 3 b. Compound 3b was obtained as a white solid in 75% yield by silica gel column chromatography (eluent: petroleum ether: ethyl acetate (vol): 2: 1).
To carry out1H NMR 13C NMR and high resolution mass spectrometry analysis, results are:1H NMR(400MHz,CDCl3)δ8.07–8.01(m,2H),7.55(t,J＝7.4Hz,1H),7.44(t,J＝7.6Hz,2H),5.73(s,1H),4.83–4.73(m,1H),2.91–2.81(m,1H),2.42(s,1H),2.24–2.17(m,1H),2.09–1.95(m,3H),1.95–1.87(m,1H),1.87–1.72(m,3H),1.72–1.59(m,3H),1.56–1.48(m,1H),1.46–1.38(m,6H),1.37–1.31(m,1H),1.26(d,J＝1.4Hz,1H),1.24(s,3H),1.22(s,3H),1.18(d,J＝4.7Hz,1H),1.16(s,3H),1.14–1.08(m,1H),1.04(s,3H),0.96(s,3H),0.89(d,J＝10.3Hz,1H),0.85(s,3H).13C NMR(400MHz,CDCl3)δ200.27,181.11,180.97,169.37,166.29,132.71,130.98,129.55,128.52,128.31,81.29,61.74,55.15,48.28,45.51,43.79,43.27,40.93,38.83,38.48,37.74,37.04,32.76,31.89,30.97,28.55,28.43,28.24,26.46,23.66,23.40,18.74,17.44,16.98,16.43.HRMS(ESI)C37H50O5Na(597.3550)；597.3565(M+Na)+。
EXAMPLE 5 preparation of Compound 3c
Glycyrrhetinic acid (compound 1) (470.0mg, 1mmol) was weighed into a 100mL round-bottomed flask with magnetons, then 20mL pyridine was weighed as solvent, stirred at room temperature for 2min until completely dissolved, then 4-dimethylaminopyridine (155.7mg,1.2mmol) and pyridine (100.7mg,1.2mmol) were added, after stirring well, finally p-methylphenylchloride (295.4mg,1.9mmol) was added, and after 6h reaction, the reaction end point was detected by TLC. The pyridine solvent was distilled off under reduced pressure at 55 ℃ to obtain a crude product of compound 3 c. Compound 3c was obtained as a white solid in 92% yield by silica gel column chromatography (eluent: petroleum ether: ethyl acetate (vol): 3: 1).
To carry out1H NMR 13C NMR and high resolution mass spectrometry analysis, results are:1H NMR(400MHz,CDCl3)δ7.91(s,1H),7.89(s,1H),7.30(s,1H),7.28(s,1H),5.69(s,1H),3.29–3.16(m,1H),2.83–2.71(m,1H),2.43(s,3H),2.35–2.26(m,2H),2.12–1.99(m,3H),1.91–1.81(m,1H),1.75(t,J＝13.7Hz,1H),1.70–1.51(m,5H),1.51–1.39(m,4H),1.38(s,3H),1.34(s,3H),1.30–1.22(m,1H),1.17(d,J＝12.1Hz,1H),1.13(s,6H),1.05(d,J＝13.8Hz,1H),1.00(s,3H),0.98–0.90(m,1H),0.86(s,3H),0.80(s,3H),0.70(d,J＝11.5Hz,1H).13C NMR(400MHz,CDCl3)δ200.06,172.11,168.54,162.42,145.67,130.46,129.63,128.81,126.15,78.78,61.86,54.96,48.16,45.51,45.40,43.23,40.98,39.17,39.15,37.46,37.12,32.78,32.04,30.96,28.39,28.12,27.54,27.29,26.47,26.41,23.47,21.84,18.71,17.51,16.37,15.59.HRMS(ESI)C38H52O5Na(611.3707)；611.3711(M+Na)+。
EXAMPLE 6 preparation of Compound 3d
Glycyrrhetinic acid (compound 1) (470.0mg, 1mmol) was weighed into a 100mL round-bottomed flask with magnetons, then 20mL pyridine was weighed as solvent, stirred at room temperature for 2min until completely dissolved, then 4-dimethylaminopyridine (155.7mg,1.2mmol) and pyridine (100.7mg,1.2mmol) were added, after stirring to homogeneity, finally o-methoxyphenylacyl chloride (311.5mg,1.9mmol) was added, and after 6h reaction, the reaction end point was detected by TLC. The pyridine solvent was distilled off under reduced pressure at 55 ℃ to give compound 3d as a crude product. Compound 3d was obtained as a white solid in 95% yield by silica gel column chromatography (eluent: petroleum ether: ethyl acetate (vol): 3: 1).
To carry out1H NMR 13C NMR and high resolution mass spectrometry analysis, results are:1H NMR(400MHz,CDCl3)δ7.83(dd,J＝7.8,1.7Hz,1H),7.59–7.52(m,1H),7.04(d,J＝7.6Hz,1H),7.00(d,J＝8.4Hz,1H),5.66(s,1H),3.90(s,3H),3.28–3.17(m,1H),2.84–2.73(m,1H),2.37–2.28(m,2H),2.12–1.95(m,3H),1.90–1.80(m,1H),1.72(t,J＝11.3Hz,1H),1.66–1.54(m,5H),1.49–1.39(m,4H),1.37(s,3H),1.32(s,3H),1.24(d,J＝8.6Hz,1H),1.20(d,J＝12.2Hz,1H),1.13(s,6H),1.08–1.02(m,1H),1.00(s,3H),0.97–0.91(m,1H),0.86(s,3H),0.80(s,3H),0.69(d,J＝11.6Hz,1H).13C NMR(400MHz,CDCl3)δ200.04,172.30,168.65,161.72,160.21,135.41,132.73,128.76,120.36,118.30,112.23,78.78,61.86,55.94,54.98,47.98,45.38,45.20,43.20,40.92,39.17,39.15,37.43,37.13,32.78,31.98,30.92,28.41,28.11,27.45,27.32,26.48,26.44,23.48,18.72,17.51,16.36,15.57.HRMS(ESI)C38H52O6Na(627.3656)；627.3658(M+Na)+。
EXAMPLE 7 preparation of Compound 4a
Weighing the compound 3c (616.3mg, 1mmol) in a 100mL round-bottom flask with magnetons, then weighing 20mL absolute ethyl alcohol in the flask, stirring for 3min at room temperature until the absolute ethyl alcohol is completely dissolved, sucking 1.5mL concentrated sulfuric acid by a glass pipette, slowly adding the concentrated sulfuric acid into the system, and then placing the system under the condition of normal temperature for esterification reaction for 24 h. Finally, the ethanol solvent was distilled off under reduced pressure at 45 ℃ to obtain a crude product of compound 4 a. Compound 4a was obtained as a white solid in 77% yield by silica gel column chromatography (eluent: petroleum ether: ethyl acetate (vol): 15: 1).
To carry out1H NMR 13C NMR and high resolution mass spectrometry analysis, results are:1H NMR(400MHz,CDCl3)δ7.88-7.75(m,1H),7.65(s,1H),7.25(s,1H),7.20-7.15(d,1H),5.68(s,1H),4.20–4.05(m,2H)3.18–3.06(m,1H),2.80–2.75(d,1H),2.40(s,3H),2.38–2.29(m,2H),2.22–2.02(m,3H),1.95–1.86(m,1H),1.78(t,J＝13.7Hz,1H),1.70–1.58(m,4H),1.55–1.42(m,5H),1.37(s,3H),1.31(s,3H),1.28–1.20(m,4H),1.15(d,J＝12.1Hz,1H),1.12(s,6H),1.02(d,J＝13.8Hz,1H),0.99(s,3H),0.97–0.92(m,1H),0.85(s,3H),0.82(s,3H),0.73(d,J＝11.5Hz,1H).13C NMR(400MHz,CDCl3)δ201.16,170.01,165.34,160.48,146.66,132.11,124.63,127.71,125.18,78.88,62.16,60.40,55.06,47.86,45.99,45.30,42.21,40.58,39.44,39.05,37.88,37.18,32.01,31.84,30.99,28.80,28.22,27.34,27.09,26.93,26.54,23.66,21.32,18.55,17.56,16.99,16.05,14.93.HRMS(ESI)C40H51O5(616.4028)；615.4062(M-H)-
FIG. 1 is a high resolution mass spectrum of compound 4 a.
EXAMPLE 8 preparation of Compound 4b
Weighing the compound 3d (632.5mg, 1mmol) in a 100mL round-bottom flask with magnetons, then weighing 20mL absolute ethyl alcohol in the flask, stirring for 3min at room temperature until the absolute ethyl alcohol is completely dissolved, sucking 1.5mL concentrated sulfuric acid by a glass pipette, slowly adding the concentrated sulfuric acid into the system, and then placing the system under the condition of normal temperature for esterification reaction for 24 h. Finally, the ethanol solvent was distilled off under reduced pressure at 45 ℃ to obtain a crude product of compound 4 b. Compound 4b was obtained as a white solid in 68% yield by silica gel column chromatography (eluent: petroleum ether: ethyl acetate (vol): 10: 1).
To carry out1H NMR 13C NMR and high resolution mass spectrometry analysis, results are:1H NMR(400MHz,CDCl3)δ7.82–7.77(m,1H),7.48–7.42(m,1H),6.98(d,J＝5.0Hz,1H),6.96(d,J＝6.7Hz,1H),5.65(s,1H),4.82–4.69(m,1H),4.23–4.07(m,2H),3.89(s,3H),2.89–2.79(m,1H),2.40(s,1H),2.14–1.85(m,5H),1.85–1.75(m,3H),1.73–1.56(m,4H),1.53–1.41(m,2H),1.38(s,3H),1.36–1.30(m,2H),1.26(t,J＝7.1Hz,4H),1.19(s,3H),1.14(s,3H),1.14(s,3H),1.06(d,J＝18.8Hz,1H),0.99(s,3H),0.99(s,3H),0.87(d,J＝10.8Hz,1H),0.80(s,3H).13C NMR(400MHz,CDCl3)δ200.16,176.41,169.36,166.09,159.22,133.26,131.58,128.50,120.85,120.07,112.00,81.15,61.76,60.33,55.82,55.13,48.45,45.46,43.87,43.26,41.09,38.86,38.40,37.74,37.02,32.76,31.85,31.15,28.58,28.33,28.12,26.51,26.46,23.63,23.40,18.72,17.44,16.94,16.45,14.35.HRMS(APCI)C40H55O6(631.4015)；631.4012(M-H)-。
FIG. 2 is a high resolution mass spectrum of compound 4 b.
The reaction equation and the compound formula of the above example are shown below:
example 9
The compounds obtained in the above examples were subjected to a bacteriostatic test against staphylococcus aureus (ATCC 12228), and MIC data of the compounds are shown in table 1. Glycyrrhetic acid (GA, CAS number: 471-53-4) has an MIC value of 0.4. mu.M for Staphylococcus aureus (ATCC 12228).
Bacteriostatic effect of the compounds of Table 1 on Staphylococcus aureus (ATCC 12228)
| Compound (I) | MIC(μM) | Compound (I) | MIC(μM) |
| 2a | 0.2 | 3c | 0.05 |
| 2b | 0.2 | 3d | 0.05 |
| 3a | 0.2 | 4a | 0.0125 |
| 3b | 0.1 | 4b | 0.0125 |
Example 10
The compounds obtained in the above examples were subjected to a bacteriostatic test against staphylococcus aureus (ATCC 6538), and MIC data of the compounds are shown in table 2. Glycyrrhetic acid (GA, CAS number: 471-53-4) has an MIC value of 0.4. mu.M for Staphylococcus aureus (ATCC 6538).
TABLE 2 bacteriostatic effect of the compounds on Staphylococcus aureus (ATCC 6538)
| Compound (I) | MIC(μM) | Compound (I) | MIC(μM) |
| 2a | 0.2 | 3c | 0.1 |
| 2b | 0.1 | 3d | 0.05 |
| 3a | 0.2 | 4a | 0.025 |
| 3b | 0.05 | 4b | 0.0125 |
Example 11
The compounds obtained in the above examples were subjected to bacteriostatic test against Staphylococcus aureus (ATCC 29213), and MIC data of the compounds are shown in Table 3. Glycyrrhetic acid (GA, CAS number: 471-53-4) has an MIC value of 0.4. mu.M for Staphylococcus aureus (ATCC 29213).
TABLE 3 bacteriostatic Effect of Compounds on Staphylococcus aureus (ATCC 29213)
| Compound (I) | MIC(μM) | Compound (I) | MIC(μM) |
| 2a | 0.1 | 3c | 0.1 |
| 2b | 0.2 | 3d | 0.05 |
| 3a | 0.2 | 4a | 0.025 |
| 3b | 0.1 | 4b | 0.0125 |
As can be seen from the above examples and comparative examples, the invention performs esterification modification on the carbon atom No. 3 and the carbon atom No. 20 of glycyrrhetinic acid simultaneously, so that the bacteriostatic effect is greatly improved.
The above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.
Claims (6)
1. A C3 and C20 di-esterified glycyrrhetinic acid derivative having the structure shown in formula I, or a pharmaceutically acceptable salt or an optical isomer thereof:
wherein R is ethyl;
r' is p-methylphenyl or o-methoxyphenyl.
2. The process for the preparation of C3 and C20 diacrylated glycyrrhetinic acid derivatives of claim 1, comprising the steps of:
a) mixing glycyrrhetinic acid shown as a formula II with a phthalic anhydride compound or a benzoyl chloride compound, and carrying out a first esterification reaction under the catalytic action of 4-dimethylaminopyridine to obtain a C3 esterified derivative shown as a formula III;
b) adding an alcohol compound into the derivative shown in the formula III under a strong acid condition, and carrying out a second esterification reaction to obtain a compound shown in the formula I in which C3 and C20 are esterified;
or comprises the following steps:
c) adding an alcohol compound into glycyrrhetinic acid shown in a formula II under a strong acid condition, and carrying out a third esterification reaction to obtain a C20 esterified derivative shown in a formula IV;
d) mixing the derivative shown as the formula IV with a benzene anhydride compound or a benzene acyl chloride compound, and carrying out fourth esterification reaction under the catalytic action of 4-dimethylaminopyridine to obtain a compound shown as a formula I, wherein C3 and C20 are esterified;
the phthalic anhydride compound is selected from p-methyl phenyl anhydride or o-methoxy phenyl anhydride;
the benzoyl chloride compound is selected from p-methyl phenyl acyl chloride or o-methoxy benzoyl chloride;
the alcohol compound is ethanol;
wherein R is ethyl;
r' is p-methylphenyl or o-methoxyphenyl.
3. The method of claim 2, wherein the temperature of the first esterification reaction in step a) is 10 ℃ to 40 ℃; the temperature of the second esterification reaction in the step b) is 10-40 ℃; the temperature of the third esterification reaction in the step c) is 10-40 ℃; the temperature of the fourth esterification reaction in the step d) is 10-40 ℃.
4. The preparation method according to claim 2, wherein in the step a), the molar ratio of the glycyrrhetinic acid to the phthalic anhydride compound is 1:1.5 to 3.0; the molar ratio of the glycyrrhetinic acid to the benzoyl chloride compounds is 1: 2.0-4.0; in the step b), the molar ratio of the derivative shown as the formula III to the alcohol compound is 1: 2.0-4.5;
in the step c), the molar ratio of the glycyrrhetinic acid to the alcohol compound is 1: 2.0-4.5; in the step d), the molar ratio of the derivative shown as the formula IV to the benzene anhydride compound is 1: 1.5-3.0; the molar ratio of the derivative shown in the formula IV to the benzoyl chloride compound is 1: 2.0-4.0.
5. Use of the C3 and C20 diesterified glycyrrhetinic acid derivative of claim 1 or the C3 and C20 diesterified glycyrrhetinic acid derivative prepared by the preparation method of any one of claims 2 to 4 in the preparation of an anti-staphylococcal preparation.
6. An anti-staphylococcal agent comprising the C3 and C20 di-esterified glycyrrhetinic acid derivative of claim 1 or the C3 and C20 di-esterified glycyrrhetinic acid derivative prepared by the preparation method of any one of claims 2 to 4.
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