Method for preparing praeruptorin B from praeruptorin A

Abstract

The invention discloses a method for preparing praeruptorin B from praeruptorin A. The method comprises the following steps: dissolving the praeruptorin A in a first solvent at 0-80 DEG C, adding a metal hydroxide aqueous solution, cooling after the reaction is finished, adjusting the pH value to 2-3, extracting by using ethyl acetate, combining the ethyl acetate phase, drying by using anhydrous sodium sulfate, concentrating until no liquid is evaporated, and filtering to obtain the praeruptorin B; performing column chromatography purification to obtain a white or light yellow solid key intermediate; and dissolving the key intermediate in a second solvent at 0-60 DEG C, adding angelica acid, adding an organic phosphine compound, dropwise adding an azodicarboxylate solution, stirring, adding ethyl acetate for dilution, washing with water, drying with anhydrous sodium sulfate, concentrating until no liquid is evaporated, and performing column chromatography purification to obtain white or light yellow solid peucedanin. By adopting the steps, the invention provides the novel preparation method of the praeruptorin B, the preparation steps are simple, and the praeruptorin B can be rapidly prepared from the praeruptorin A.

Description

Technical Field

[0001] The invention relates to the technical field of praeruptorin preparation, and in particular to a method for preparing praeruptorin from praeruptorin A. Background Art

[0002] Peucedanum praeruptorum is the dried root of the white flower peucedanum of the Umbelliferae family. It is also one of the key varieties of the new "Eight Flavors of Zhejiang" in Zhejiang Province. It has the effects of dispersing wind-heat, lowering qi and resolving phlegm. The latest edition of the "Chinese Pharmacopoeia" identifies its active ingredients as mainly white flower peucedanum A and white flower peucedanum B, and stipulates that the content of the former in the dry variety is not less than 0.9%, and the latter is not less than 0.24%. Studies have shown that the content of peucedanum A in related products on the market is relatively high, but the content of peucedanum B is often near the minimum limit (Chinese Traditional Patent Medicine, 2022, 41, 318-321.).

[0003] Recent studies have also revealed that praeruptorin B monomers have anti-platelet aggregation and anti-tumor effects (Phytochemical Analysis, 2018, 29, 425-431.). However, the acquisition of praeruptorin B currently relies mainly on extraction and separation, and its low content makes its purification process more cumbersome and difficult to meet the growing needs. At the same time, since the activity of praeruptorin A with a larger content in antitussive and other aspects is weaker than that of praeruptorin B, it is often regarded as a separation by-product with lower economic value. Therefore, how to quickly and efficiently convert praeruptorin A into high-value-added praeruptorin B is an urgent problem to be solved. Summary of the invention

[0004] The purpose of the present invention is to provide a method for preparing praeruptorin B from praeruptorin A, which can quickly and efficiently prepare praeruptorin B from praeruptorin A.

[0005] To achieve the above object, the present invention provides a method for preparing praeruptorin B from praeruptorin A, comprising the following steps:

[0006] S1. Dissolve praeruptorin A in a first solvent at 0-80° C., add 1.0-5.0 molar equivalents of a metal hydroxide aqueous solution, and stir rapidly for 5-60 min. After the reaction is completed, cool down, adjust the pH to 2-3, extract with ethyl acetate, combine the ethyl acetate phases, dry over anhydrous sodium sulfate, and concentrate until no liquid is evaporated. Purify with column chromatography to obtain a key intermediate as a white or light yellow solid;

[0007] S2. At 0-60°C, the key intermediate obtained in S1 is dissolved in a second solvent, and angelic acid is added at a molar ratio of 1.0-3.0 to the key intermediate while stirring, and an organic phosphine compound is added at a molar ratio of 1.0-3.0 to the key intermediate. Subsequently, a solution of azodicarboxylic acid ester is added dropwise at a molar ratio of 1.0-3.0 to the key intermediate, and the mixture is stirred for 6-24 hours. Ethyl acetate is added to dilute the mixture, and the mixture is washed with water and dried over anhydrous sodium sulfate. The mixture is concentrated until no liquid is evaporated, and purified by column chromatography to obtain white or light yellow solid praeruptolide.

[0008]

[0009] Preferably, in S1, the first solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, ethyl ether, isopropyl ether, toluene and dichloromethane.

[0010] Preferably, in S1, the metal hydroxide is one or more of sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, and tetrabutylammonium hydroxide.

[0011] Preferably, in S1, the concentration of the metal hydroxide aqueous solution is 10-40%.

[0012] Preferably, in S2, the second solvent is one or more of an ether solvent, a benzene solvent and a chlorinated solvent.

[0013] Preferably, in S2, the organic phosphine compound is one or more of triphenylphosphine, diphenylmethylphosphine, diphenylethylphosphine, phenyldimethylphosphine, phenyldiethylphosphine, tri-n-butylphosphine and tricyclohexylphosphine.

[0014] Preferably, in S2, the azodicarboxylic acid ester is one of dimethyl azodicarboxylate, diethyl azodicarboxylate, diisopropyl azodicarboxylate, diisobutyl azodicarboxylate and di-tert-butyl azodicarboxylate.

[0015] The praeruptorin B is prepared by the above-mentioned preparation method of praeruptorin B from praeruptorin A.

[0016] Therefore, the present invention adopts a method for preparing praeruptorin B from praeruptorin A using the above steps, and its beneficial effects are: providing a new method for preparing praeruptor B, the preparation steps are simple, and praeruptor B can be quickly prepared from praeruptorin A.

[0017] The technical solution of the present invention is further described in detail below through the accompanying drawings and embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 is the H NMR spectrum of the key intermediate in Example 1 of the present invention;

[0019] Figure 2 It is the H NMR spectrum of purpurogenol in Example 2 of the present invention. DETAILED DESCRIPTION

[0020] The technical solution of the present invention is further described below through the accompanying drawings and embodiments.

[0021] The present invention can be explained in more detail by the following examples. The purpose of disclosing the present invention is to protect all changes and improvements within the scope of the present invention. The present invention is not limited to the following examples.

[0022] Example 1

[0023] S1, the preparation route of this step is as follows:

[0024]

[0025] At room temperature, praeruptorin 1 (1.5 g, 4 mmol) was dissolved in 60 mL tetrahydrofuran, 20% sodium hydroxide aqueous solution (2.4 g, 12 mmol) was added, and the mixture was stirred rapidly for 60 min. After the reaction, the pH was adjusted to between 1 and 2 with 3 M hydrochloric acid, and the ethyl acetate phases were combined after extraction with 20 mL ethyl acetate three times, dried over anhydrous sodium sulfate, and concentrated until no liquid was evaporated to obtain a yellow oily liquid. After purification by column chromatography (petroleum ether / ethyl acetate = 4:1), 0.86 g of the key intermediate 2 was obtained as a white or light yellow solid, with a yield of 63%.

[0026] The NMR hydrogen spectrum of the key intermediate is shown in Figure 1 As shown,

[0027] 1 H NMR (500MHz, CDCl3) δ7.67(d,J=9.5Hz,1H),7.35(d,J=8.6Hz,1H),6.83(d,J=8.6Hz,1H),6.29-6.22(m,1H),6.15-6.07(m,1H),5.3 2-5.23(m,1H),5.09(d,J=3.5Hz,1H),3.74(dd,J=7.5,4.3Hz,1H),1.94-1.91(m,3H),1.88-1.83(m,3H),1.51(s,3H),1.42(s,3H). HRMS(ESI)m / z Calcd.for C 19 H 20 O6Na([M+Na] + )367.1152,Found 367.1155.

[0028] S2, the preparation route of this step is as follows:

[0029]

[0030] At room temperature, 0.34 g of the key intermediate 2 (1.0 mmol) obtained in S1 was dissolved in 10 mL of anhydrous tetrahydrofuran, angelic acid (1.5 mmol) and diphenylmethylphosphine (1.5 mmol) were added, and stirred at room temperature for 5 min. Diisopropyl azodicarboxylate (DIAD) (1.5 mmol) was slowly added dropwise, stirred at room temperature for 6 h, ethyl acetate was added to dilute the reaction solution, washed with water, dried over anhydrous sodium sulfate, and concentrated until no liquid was evaporated to obtain a yellow oily liquid. Purification by column chromatography (petroleum ether / ethyl acetate = 4:1) gave 0.20 g of white or light yellow solid purpurogenol 3, with a yield of 50%.

[0031] Example 2

[0032] S1. At 40°C, praeruptorin 1 (1.5 g, 4 mmol) was dissolved in 60 mL 1,4-dioxane, 20% aqueous lithium hydroxide solution (1.4 g, 12 mmol) was added, and the reaction was stirred rapidly until the reaction was completed and then cooled. 3M hydrochloric acid was used to adjust the pH to between 1 and 2. The ethyl acetate phase was combined after extraction with 20 mL ethyl acetate three times, dried over anhydrous sodium sulfate, and concentrated until no liquid was evaporated to obtain a yellow oily liquid. After purification by column chromatography (petroleum ether / ethyl acetate = 4:1), 0.96 g of the key intermediate 2 was obtained as a white or light yellow solid with a yield of 70%.

[0033] S2, the preparation route of this step is as follows:

[0034]

[0035] At room temperature, 0.34 g of the key intermediate 2 (1.0 mmol) obtained in S1 was dissolved in 10 mL of toluene, angelic acid (1.5 mmol) was added and stirred, diphenylethylphosphine (1.5 mmol) was added, and stirred at room temperature for 10 min. Di-tert-butyl azodicarboxylate (DBAD) (1.5 mmol) was slowly added dropwise, stirred at room temperature for 13 h, ethyl acetate was added to dilute the reaction solution, washed with water and dried over anhydrous sodium sulfate, concentrated until no liquid was evaporated, and a yellow oily liquid was obtained. Purification by column chromatography (petroleum ether / ethyl acetate = 4:1) gave 0.25 g of white or light yellow solid purpurogenol 3, with a yield of 62%.

[0036] The H NMR spectrum of purpurogenol is shown in Figure 2 As shown,

[0037] 1H NMR(500MHz, CDCl3)δ7.60(d,J=9.5Hz,1H),7.37(d,J=8.6Hz,1H),6.82(d, J=8.6Hz,1H),6.72(d,J=4.9Hz,1H),6.23(d,J=9.5Hz,1H),6.18–6.12(m,1H ),6.07-6.01(m,1H),5.46(d,J=4.9Hz,1H),2.03–1.94(m,6H),1.89–1.86( m,3H),1.85–1.81(m,3H),1.51(s,3H),1.46(d,J=7.2Hz,3H); HRMS(ESI)m / z Calcd.for C 24 H 26 O7Na([M+Na] + )449.1571,Found449.1572.

[0038] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that they can still modify or replace the technical solution of the present invention with equivalents, and these modifications or equivalent replacements cannot cause the modified technical solution to deviate from the spirit and scope of the technical solution of the present invention.

Claims

1. A method for preparing praeruptorin B from praeruptorin A, characterized in that: The method comprises the following steps: S1, dissolving praeruptorin A in a first solvent at 0-80° C., adding 1.0-5.0 molar equivalents of a metal hydroxide aqueous solution, and rapidly stirring for 5-60 minutes. After the reaction is completed, cooling is performed, and the pH value is adjusted to 2-3. After extraction with ethyl acetate, the ethyl acetate phases are combined, dried over anhydrous sodium sulfate, and concentrated until no liquid is evaporated. After purification by column chromatography, a key intermediate in the form of a white or light yellow solid is obtained. S2. At 0-60°C, the key intermediate obtained in S1 is dissolved in a second solvent, and angelic acid is added at a molar ratio of 1.0-3.0 to the key intermediate while stirring, and an organic phosphine compound is added at a molar ratio of 1.0-3.0 to the key intermediate. Subsequently, a solution of azodicarboxylic acid ester is added dropwise at a molar ratio of 1.0-3.0 to the key intermediate, and the mixture is stirred for 6-24 hours. Ethyl acetate is added to dilute the mixture, and the mixture is washed with water and dried over anhydrous sodium sulfate. The mixture is concentrated until no liquid is evaporated, and purified by column chromatography to obtain white or light yellow solid praeruptolide.

2. The method for preparing praeruptorin B from praeruptorin A according to claim 1, characterized in that: In S1, the first solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, ethyl ether, isopropyl ether, toluene and dichloromethane.

3. The method for preparing praeruptorin B from praeruptorin A according to claim 1, characterized in that: In S1, the metal hydroxide is one or more of sodium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, and tetrabutylammonium hydroxide.

4. The method for preparing praeruptorin B from praeruptorin A according to claim 1, characterized in that: In S1, the concentration of the metal hydroxide aqueous solution is 10-40%.

5. The method for preparing praeruptorin B from praeruptorin A according to claim 1, characterized in that: In S2, the second solvent is one or more of an ether solvent, a benzene solvent and a chlorinated solvent.

6. The method for preparing praeruptorin B from praeruptorin A according to claim 1, characterized in that: In S2, the organic phosphine compound is one or more of triphenylphosphine, diphenylmethylphosphine, diphenylethylphosphine, phenyldimethylphosphine, phenyldiethylphosphine, tri-n-butylphosphine and tricyclohexylphosphine.

7. The method for preparing praeruptorin B from praeruptorin A according to claim 1, characterized in that: In S2, the azodicarboxylic acid ester is one of dimethyl azodicarboxylate, diethyl azodicarboxylate, diisopropyl azodicarboxylate, diisobutyl azodicarboxylate and di-tert-butyl azodicarboxylate.

8. Praeruptorin prepared according to the method for preparing praeruptorin B from praeruptorin A according to any one of claims 1 to 7.

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