A microwave-assisted synthesis method of 18α-glycyrrhetinic acid and its derivatives

Abstract

The present invention provides a synthetic method for efficiently preparing 18α-glycyrrhetinic acid and its derivatives. This method uses 18β-glycyrrhetinic acid as the starting material, and under microwave-assisted conditions, realizes the inversion of the chiral center at the 18th position from the β configuration to the α configuration to prepare 18α-glycyrrhetinic acid. Further, using H2O2 as a green oxidant and CeBr3 as a catalyst, the 3-OH of 18α-glycyrrhetinic acid is oxidized to a carbonyl group to prepare a very crucial cyclic ketone intermediate. This method has the characteristics of high efficiency, rapidity, and low cost, and is a very green and environmentally friendly synthetic method for 18α-glycyrrhetinic acid and its oxidized derivatives, with broad application prospects.

Description

Technical Field

[0001] The present invention belongs to the technical fields of green chemistry and organic synthesis. Specifically, it relates to a method for preparing 18α-glycyrrhetinic acid by realizing the inversion of the configuration at the 18th position from β to α using 18β-glycyrrhetinic acid as a raw material under microwave assistance. Further, using H2O2 as an oxidant and CeBr3 as a catalyst, the 3-OH group is oxidized to a carbonyl group to prepare an oxidized derivative of cyclic ketone type 18α-glycyrrhetinic acid. Background Art

[0002] Licorice is the dried root and rhizome of the leguminous plant Glycyrrhiza uralensis Fisch., Glycyrrhiza inflata Bat., or Glycyrrhiza glabra L. Glycyrrhetinic acid is the main component in licorice and has various pharmacological effects such as anti-inflammatory, anti-tumor, and immunomodulatory effects.

[0003] Glycyrrhetinic acid has two configurations, α and β, at the 18th position. It has been reported in the literature that compared with 18β-glycyrrhetinic acid, 18α-glycyrrhetinic acid has stronger pharmacological effects in protecting nerve cells, targeting the protection of liver cells, etc. However, most of the glycyrrhetinic acid naturally produced in licorice is in the 18β configuration, and the content of 18α-glycyrrhetinic acid is extremely low, which leads to its high price and great difficulty in large-scale development and utilization. Therefore, chemical synthesis is an important way to obtain 18α-glycyrrhetinic acid. Conventional methods for preparing 18α-glycyrrhetinic acid require high-temperature heating, and the reaction time is 2 - 4 h, which is relatively long. With the aid of microwave assistance, the inversion of the configuration at the 18th position from β to α requires a lower temperature and a shorter time. In addition, realizing the oxidation of 3-OH to a carbonyl group can prepare a key cyclic ketone intermediate, which is of great significance for the further structural derivatization of 18α-glycyrrhetinic acid and the discovery of monomers with higher activity. Summary of the Invention

[0004] The object of the present invention is to develop a synthesis method for 18α-glycyrrhetinic acid and its derivatives with low cost, high yield, greenness, and easy operation. The specific synthesis route is as follows:

[0005]

[0006] The technical solution adopted by the present invention is:

[0007] (1) Synthesis of 18α-glycyrrhetinic acid: Using 18β-glycyrrhetinic acid as the raw material, and using diethylene glycol, n-butanol, glycerol, isopropanol, N,N-dimethylformamide, dimethyl sulfoxide, acetone, acetonitrile, tert-butanol and other organic solvents as solvents, adding strong bases such as KOH, NaOH, sodium methoxide, and sodium ethoxide, in the same container, after microwave reaction for 0.2 - 0.5 h, adding deionized water and concentrated hydrochloric acid, and filtering to obtain a solid. After washing with acetone, the solid is recrystallized with ethanol to obtain pure 18α-glycyrrhetinic acid.

[0008] (2) Synthesis of 18α-glycyrrhetinic acid derivatives: Adding 18α-glycyrrhetinic acid, CeBr3 and H2O2 to an organic solvent, and stirring at room temperature for 2 h until the reaction is complete. Extracting with organic solvents such as ethyl acetate in multiple times, filtering, and concentrating under reduced pressure to obtain the target product.

[0009] Advantages of the present invention:

[0010] Compared with the prior art, the present invention has the following advantages and effects:

[0011] The present invention realizes for the first time the synthesis of 18α-glycyrrhetinic acid from 18β-glycyrrhetinic acid through microwave assistance, improves the reaction efficiency, greatly shortens the reaction time, and reduces the reaction temperature. Using environmentally friendly reagents in the oxidation reaction reduces the environmental pressure and embodies the idea of green environmental protection. Description of the Drawings

[0012] Figure 1 is the 1H NMR spectrum of 18α-glycyrrhetinic acid synthesized by the present invention

[0013] Figure 2 is the 13C NMR spectrum of 18α-glycyrrhetinic acid synthesized by the present invention

[0014] Figure 3 is the IR spectrum of 18α-glycyrrhetinic acid synthesized by the present invention

[0015] Figure 4 is the 1H NMR spectrum of the oxidized derivative of 18α-glycyrrhetinic acid synthesized by the present invention

[0016] Figure 5 is the 13C NMR spectrum of the oxidized derivative of 18α-glycyrrhetinic acid synthesized by the present invention

[0017] Figure 6 is the IR spectrum of the oxidized derivative of 18α-glycyrrhetinic acid synthesized by the present invention Detailed Embodiments

[0018] The present invention will be described in detail below with specific implementation examples, but the protection scope of the present invention is not limited thereto.

[0019] In the following examples1 H-NMR and 13 C-NMR spectra were measured at room temperature and recorded on a 400 MHz spectrometer. 1 The frequency for H was 400 MHz, 13 and the frequency for C was 100 MHz. The spectrometer was from Bruker.

[0020] (1) Step 1: Synthesis of 18α-glycyrrhetinic acid

[0021] (3) 18β-glycyrrhetinic acid (2.12 mmol, 1.0 g) and a strong base (7.63 mmol) were added to diethylene glycol, n-butanol, glycerol, isopropanol, N,N-dimethylformamide, dimethyl sulfoxide, acetone, acetonitrile, tert-butanol, and other organic solvents. The microwave power was 50 - 300 W, the heating temperature was 50 - 100 °C, and the reaction time was 0.2 - 0.5 h. After the reaction, deionized water (13 ml) and concentrated hydrochloric acid were added to adjust the pH value to 2 - 3, and the solid was obtained by suction filtration. After washing with acetone (10 ml) at 40 °C, the solid was recrystallized with absolute ethanol (100 ml) to obtain 0.481 g of pure 18α-glycyrrhetinic acid, with a yield of 48.1%.

[0022] (4) Synthesis of 18α-glycyrrhetinic acid derivatives: The above product 18α-glycyrrhetinic acid, MBr x (M is Fe 2+ 、Fe 3+ 、Ce 3+ 、Ce 4+ , x is 2 - 3) (0.1 mmol) and an aqueous H2O2 solution (30 wt%, 3 mmol, 0.31 ml) were added to an organic solvent, and the mixture was stirred at room temperature for 2 h until the reaction was complete. The target product (0.398 g) was obtained by extracting with organic solvents such as ethyl acetate in multiple times, filtering, and concentrating under reduced pressure, with a yield of 83.2%

[0023] The total yield of the two-step reaction was 40.02%.

[0024] 18α-glycyrrhetinic acid: The molecular formula is: C 30 H 46 O4

[0025]

[0026] Proton spectrum 11H-NMR (400 MHz, DMSO-d6) δ: 12.16 (s, 1H), 5.33 (s, 1H), 3.01 (dd, 1H, ), 2.44, 2.29 - 2.27, 1.89, 1.79, 1.69 - 1.18, 1.16, 1.09, 1.04, 1.04 - 0.90, 0.90, 0.72 - 0.67, 0.69, 0.65;

[0027] Carbon spectrum 13 13C-NMR (100 MHz, DMSO-d6) δ: 199.2 (C-11), 179.9 (C-29), 166.5 (C-13), 123.5 (C-12), 77.0 (C-3), 60.4, 54.6, 45.1, 43.8, 42.0, 40.6, 39.1, 38.9, 37.1, 36.9, 35.7, 35.6, 33.7, 31.9, 28.8, 28.6, 27.4, 26.7, 21.1, 20.9, 18.7, 17.7, 16.9, 16.5, 16.1.

[0028] Mass spectrum MS: In the MS of the target compound, the measured value m / z = 471.3471, the theoretical value: m / z = 471.3474, which is consistent with the molecular weight of the target compound.

[0029] 18α-Glycyrrhetinic acid derivative: The molecular formula is: C 30 H 44 O4

[0030]

[0031] Proton spectrum 1 1H-NMR (400 MHz, CDCl3) δ: 1 1H NMR (400 MHz, CDCl3) δ 5.64 (s, 1H), 5.64, 5.35, 5.33, 5.32, 5.29, 4.83, 4.81, 2.87, 2.86, 2.38, 2.36, 2.34, 2.25, 2.02, 2.00, 1.99, 1.97, 1.95, 1.75, 1.72, 1.69, 1.66, 1.61, 1.58, 1.55, 1.50, 1.48, 1.47, 1.46, 1.44, 1.39, 1.38, 1.34, 1.32, 1.30, 1.29, 1.27, 1.25, 1.20, 1.18, 1.17, 1.09, 1.06, 0.80, 0.79, 0.74.

[0032] Carbon spectrum 1313C-NMR (400 MHz, CDCl3) δ: 217.28, 199.49, 183.62, 166.43, 129.90, 126.02, 124.00, 77.36, 77.25, 77.04, 76.73, 72.26, 71.65, 59.94, 55.49, 47.72, 45.06, 43.73, 42.39, 40.49, 39.69, 37.57, 36.52, 35.94, 35.59, 34.67, 34.22, 33.19, 32.65, 31.59, 29.78, 29.70, 29.32, 28.78, 28.31, 27.22, 26.75, 26.46, 25.47, 22.69, 21.53, 21.38, 20.73, 20.55, 19.45, 18.89, 18.45, 16.07, 15.82, 14.13, 9.68, 1.02.

[0033] Mass spectrometry MS: In the MS of the target compound, the measured value: m / z = 467.3152, the theoretical value: m / z = 467.3162, which is consistent with the molecular weight of the target compound.

Claims

1. A synthesis method of a microwave-assisted 18α-glycyrrhetinic acid oxidation derivative, characterized in that, The method includes: using 18β-glycyrrhetinic acid as a raw material, adding KOH and a solvent, and under microwave conditions, achieving inversion of the 18-configuration to prepare 18α-glycyrrhetinic acid; the solvent is diethylene glycol, the reaction temperature is 100 °C, and the reaction time is 0.5 h; further oxidative derivatization of 18α-glycyrrhetinic acid: using 18α-glycyrrhetinic acid as a raw material, CeBr3 as a catalyst, and H2O2 as the sole oxidant, oxidizing 3-OH to a carbonyl group to prepare 3-oxo-18α-glycyrrhetinic acid.

2. The synthesis method of the 18α-glycyrrhetinic acid oxidation derivative according to claim 1, characterized in that: For the reaction of oxidizing 3-OH to a carbonyl group, the reaction temperature is room temperature; the reaction is carried out under open conditions; the reaction time is 2 h.

Images