A total synthesis method of kavalactone compounds

Abstract

The present invention provides a kind of total synthesis method of kavalactone compounds, including: step (1), using methyl acetoacetate as raw material, using pyridine as solvent, under the catalysis of sodium hydroxide and anhydrous potassium carbonate, reaction, obtain dehydroacetic acid;Step (2), by dehydroacetic acid, add sulfuric acid, reaction, solid-liquid separation, obtain 4-hydroxy-6-methyl-2H-pyran-2-one;Step (3), 4-hydroxy-6-methyl-2H-pyran-2-one, dimethyl sulfate, acetone, anhydrous potassium carbonate are mixed, reaction, reaction solution is distilled under reduced pressure, obtains 4-methoxy-6-methyl-2H-pyran-2-one;Step (4), 4-methoxy-6-methyl-2H-pyran-2-one, aromatic aldehyde, sodium hydroxide and anhydrous potassium carbonate are mixed, reaction, obtain kavalactone compounds.The method has short reaction time, high reaction efficiency, easy-to-control reaction conditions, high product purity, simple and easy-to-get raw materials, and is easy to separate.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis and relates to a total synthesis method of kava lactone compounds. Background Art

[0002] Kavalactones, a natural product extracted from the root of Kava kava, possess potent biological activity and are abundant in abundance. They possess important biological properties, including promoting relaxation without impairing cognitive function or inducing addictive behaviors. They also possess a range of medicinal properties, including alleviating menopausal symptoms, neuroprotection, antibacterial, antifungal, antiepileptic, antispasmodic, analgesic, local anesthetic, diuretic, and hypnotic properties. In addition to the naturally occurring kavalactones that have been discovered, the synthetic synthesis of kavalactone derivatives with similar structures has also attracted extensive research interest.

[0003] Modern use of kava root as a natural medicine has shown more favorable results in the treatment of anxiety disorders compared to various prescription medications, including benzodiazepines. Kava extracts are as effective as standard therapies for anxiety disorders, with less toxicity and minimal physical and psychological dependence. Oxidative stress is implicated in the pathogenesis of neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. Isolated natural kavalactones can activate the antioxidant response element pathway, thereby enhancing the expression of related antioxidant enzymes such as heme oxygenase-1 (HO-1), achieving therapeutic effects.

[0004] At present, there are no reports on the total synthesis of kavalactone and its derivatives. Currently, kavalactone and its derivatives are mainly obtained by solvent extraction from kava roots and other piperine roots. The yield is greatly affected by the planting area, and the extraction efficiency of different solvents is also different. It has the disadvantages of high cost, difficulty in obtaining, high impurities, and severe environmental pollution. Summary of the Invention

[0005] The present invention aims to provide a method for the total synthesis of kava lactone compounds, which has short reaction time, high reaction efficiency, easy-to-control reaction conditions, high product purity, simple and readily available raw materials, and simple separation.

[0006] The present invention is achieved through the following technical solutions:

[0007] A total synthesis method of kavalactone compounds comprises:

[0008] Step (1) is to use methyl acetoacetate as a raw material and pyridine as a solvent, stir and heat the reaction under the catalysis of sodium hydroxide and anhydrous potassium carbonate, after the reaction is completed, cool the reaction solution to room temperature, adjust the pH to neutral, let it stand, precipitate, separate the solid and liquid, and obtain dehydroacetic acid;

[0009] Step (2), adding sulfuric acid to dehydroacetic acid, stirring, heating to react, pouring the resulting reaction solution into ice, precipitating, and solid-liquid separation to obtain 4-hydroxy-6-methyl-2H-pyran-2-one;

[0010] Step (3), mixing 4-hydroxy-6-methyl-2H-pyran-2-one, dimethyl sulfate, acetone, and anhydrous potassium carbonate, stirring, heating, and distilling the reaction solution under reduced pressure to obtain 4-methoxy-6-methyl-2H-pyran-2-one;

[0011] Step (4), mixing 4-methoxy-6-methyl-2H-pyran-2-one, aromatic aldehyde, sodium hydroxide and anhydrous potassium carbonate, and reacting to obtain a kavalactone compound;

[0012] Among them, the aromatic aldehyde structural formula is Ar-CHO, Ar is

[0013] Preferably, in step (1), the molar ratio of methyl acetoacetate, sodium hydroxide and anhydrous potassium carbonate is 1.0:(0.5-2.5):(0.25-1.0).

[0014] Preferably, in step (1), the reaction temperature is 60°C to 85°C, and the reaction time is 1.5h to 3.5h.

[0015] Preferably, in step (2), the molar ratio of dehydroacetic acid to sulfuric acid is 1.0:(5.0-30.0).

[0016] Preferably, in step (2), the reaction temperature is 110° C. to 135° C., and the reaction time is 1.5 h to 2.0 h.

[0017] Preferably, in step (3), the molar ratio of 4-hydroxy-6-methyl-2H-pyran-2-one, dimethyl sulfate and anhydrous potassium carbonate is 1.0:(1.0-1.5):(0.5-1.2).

[0018] Preferably, in step (3), the reaction temperature is 15°C to 35°C, and the reaction time is 1.0h to 3.0h.

[0019] Preferably, in step (4), the molar ratio of 4-methoxy-6-methyl-2H-pyran-2-one, aromatic aldehyde, sodium hydroxide and anhydrous potassium carbonate is 1.0:(1.0-2.0):(0.5-1.0):(0.25-1.0).

[0020] Preferably, in step (4), the reaction is carried out using a solid phase grinding method, and the reaction time is 0.5 h to 2.0 h.

[0021] Preferably, in steps (1) to (4), the reaction progress is monitored by TLC.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] The present invention uses methyl acetoacetate as the starting material, undergoes nucleophilic addition dehydrogenation under alkaline conditions to generate dehydroacetic acid, then deacetylates the dehydroacetic acid to generate 4-hydroxy-6-methyl-2H-pyran-2-one, then undergoes hydroxymethylation to generate 4-methoxy-6-methyl-2H-pyran-2-one, and finally reacts with aromatic aldehydes to synthesize kavalactone compounds. The present invention provides a total synthesis method for kavalactone compounds, which is the first report in the world on a chemical synthesis method for kavalactone compounds. The method has the advantages of short reaction time, high reaction efficiency, easy control of reaction conditions, high product purity, simple and easy-to-obtain raw materials, and simple separation. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 is the FT-IR spectrum of dehydroacetic acid (first intermediate compound);

[0025] Figure 2 is the FT-IR spectrum of 4-hydroxy-6-methyl-2H-pyran-2-one (second intermediate compound);

[0026] Figure 3 is the FT-IR spectrum of 4-methoxy-6-methyl-2H-pyran-2-one (third intermediate compound);

[0027] Figure 4 is the FT-IR spectrum of kavalactone;

[0028] Figure 5 4-hydroxy-6-methyl-2H-pyran-2-one (second intermediate compound) 1 H NMR spectrum;

[0029] Figure 6 4-methoxy-6-methyl-2H-pyran-2-one (third intermediate compound) 1 H NMR spectrum;

[0030] Figure 7 4-hydroxy-6-methyl-2H-pyran-2-one (second intermediate compound) 13 C NMR spectrum;

[0031] Figure 8 4-methoxy-6-methyl-2H-pyran-2-one (third intermediate compound) 13 C NMR spectrum. DETAILED DESCRIPTION

[0032] In order to further understand the present invention, the present invention is described below in conjunction with embodiments. These descriptions are only for further explaining the features and advantages of the present invention and are not intended to limit the claims of the present invention.

[0033] The structural formula of the kavalactone compound of the present invention is shown in (1):

[0034]

[0035] Among them, Ar is

[0036] The present invention provides a method for the total synthesis of kava lactone compounds, comprising the following steps:

[0037] Step (1) using methyl acetoacetate as a raw material and pyridine as a solvent, stirring and heating the reaction under the catalysis of sodium hydroxide and anhydrous potassium carbonate. After the reaction is completed, the reaction solution is cooled to room temperature, the pH is adjusted to neutral, and the solution is allowed to stand to precipitate a light yellow precipitate, which is filtered, washed with water, and dried to obtain dehydroacetic acid (a first intermediate compound);

[0038]

[0039] Step (2), adding concentrated H2SO4 to the first intermediate compound produced in step (1), stirring, heating and reacting, pouring the resulting reaction solution into ice, precipitating a large amount of milky white precipitate, filtering, washing with water, and drying to obtain 4-hydroxy-6-methyl-2H-pyran-2-one (second intermediate compound);

[0040]

[0041] Step (3), mixing the second intermediate compound generated in step (2), dimethyl sulfate, acetone, and anhydrous potassium carbonate, stirring, and heating to react, and distilling the reaction solution under reduced pressure to remove the solvent to obtain a white 4-methoxy-6-methyl-2H-pyran-2-one (third intermediate compound) solid;

[0042]

[0043] Step (4), subjecting the third intermediate compound generated in step (3), aromatic aldehyde, sodium hydroxide and anhydrous potassium carbonate to solid phase grinding reaction until the reaction is complete; washing the crude product with water, filtering and drying to obtain a kava lactone compound;

[0044]

[0045] In the total synthesis method of the kava lactone compounds of the present invention, in step (1), the molar ratio of each substance is methyl acetoacetate: sodium hydroxide: anhydrous potassium carbonate = 1.0: (0.5-1.0): (0.25-1.0); the reaction temperature is 60° C. to 85° C., and the reaction time is 1.5 h to 3.5 h.

[0046] In the total synthesis method of the kava lactone compounds of the present invention, in step (2), the molar ratio of each substance is the first intermediate compound: sulfuric acid = 1.0: (5.0-30.0); the reaction temperature is 110° C. to 135° C., and the reaction time is 1.5 h to 2.0 h.

[0047] In the total synthesis method of the kava lactone compounds of the present invention, in step (3), the molar ratio of each substance is the second intermediate compound: dimethyl sulfate: anhydrous potassium carbonate = 1.0: (1.0-1.5): (0.5-1.2); the reaction temperature is 15° C. to 35° C., and the reaction time is 1.0 h to 3.0 h.

[0048] In the total synthesis method of the kavalactone compounds of the present invention, in step (4), the molar ratio of each substance is the third intermediate compound: aromatic aldehyde: sodium hydroxide: anhydrous potassium carbonate = 1.0: (1.0-1.5): (0.5-1.0): (0.25-1.0); and the reaction time is 0.5h-2.0h.

[0049] In any of the above steps, TLC can be used to monitor the progress of the reaction. When the detection results show no raw material point, the reaction is complete. The TLC developing solvent used is preferably a mixed developing solvent with a volume ratio of petroleum ether:ethyl acetate = 3:1.

[0050] Example 1

[0051] In a dry three-necked flask, add 0.1 mol of methyl acetoacetate, use pyridine as solvent, and stir under the catalysis of 0.05 mol of sodium hydroxide and 0.05 mol of anhydrous potassium carbonate. Raise the temperature to 60°C for reaction. Monitor the progress of the reaction by TLC. The reaction time is 2 hours until the reaction is complete. Cool the reaction solution to room temperature, adjust the pH to neutral, and let it stand. A light yellow precipitate will precipitate. Filter, wash with water, and dry to obtain dehydroacetic acid (the first intermediate compound). Its FT-IR spectrum is shown below. Figure 1 The yield was 89.5%, mp: 111.3~111.6℃.

[0052] Example 2

[0053] To a dry three-necked flask, add 0.1 mol of methyl acetoacetate, pyridine as the solvent, and, under the catalysis of 0.1 mol of sodium hydroxide and 0.025 mol of anhydrous potassium carbonate, stir and heat to 80°C. Monitor the reaction progress by TLC and complete the reaction for 3 hours. Cool the reaction solution to room temperature, adjust the pH to neutral, and allow it to stand. A pale yellow precipitate will precipitate. Filter, wash with water, and dry to obtain dehydroacetic acid (the first intermediate compound). The yield is 82.3%, and the mp is 110.7-111.4°C.

[0054] Example 3

[0055] In a dry three-necked flask, 0.1 mol of the first intermediate compound prepared in Example 1 was added, along with 5 ml of concentrated H2SO4. The mixture was stirred and heated to 110°C for reaction. The reaction progress was monitored by TLC. The reaction time was 2 h until completion. The reaction solution was poured onto ice to precipitate a large amount of milky white precipitate. The precipitate was filtered, washed with water, and dried to obtain 4-hydroxy-6-methyl-2H-pyran-2-one (second intermediate compound). Its FT-IR spectrum is shown below. Figure 2 As shown, 1 H NMR spectrum Figure 5 As shown, 13 C NMR spectrum Figure 7 The yield was 86.1%, mp: 182.1~182.4℃.

[0056] Example 4

[0057] To a dry three-necked flask, add 0.1 mol of the first intermediate compound prepared in Example 1 and 10 ml of concentrated H₂SO₄. Stir and heat to 130°C for reaction. Monitor the reaction progress by TLC, and the reaction time is 1.5 hours until completion. Pour the reaction solution onto ice to precipitate a large amount of milky white precipitate. Filter, wash with water, and dry to obtain 4-hydroxy-6-methyl-2H-pyran-2-one (second intermediate compound). The yield is 93.4%, mp: 182.3-182.9°C.

[0058] Example 5

[0059] In a dry three-necked flask, 0.1 mol of the second intermediate compound prepared in Example 3, 0.1 mol of dimethyl sulfate, and 0.1 mol of anhydrous potassium carbonate were added to the reaction flask, stirred, and reacted at 20°C. The reaction progress was monitored by TLC. The reaction time was 1.0 h until the reaction was complete. The reaction solution was distilled under reduced pressure to remove the solvent to obtain a white solid of 4-methoxy-6-methyl-2H-pyran-2-one (the third intermediate compound). Its FT-IR spectrum is shown below. Figure 3 As shown, 1 H NMR spectrum Figure 6 As shown,13 C NMR spectrum Figure 8 The yield was 87.3%, mp: 81.7~82.1℃.

[0060] Example 6

[0061] To a dry three-necked flask, add 0.1 mol of the second intermediate compound prepared in Example 3, 0.15 mol of dimethyl sulfate, and 0.05 mol of anhydrous potassium carbonate. Stir and react at 30°C. Monitor the reaction progress by TLC. The reaction time is 3.0 h until completion. The reaction solution is distilled under reduced pressure to remove the solvent, yielding 4-methoxy-6-methyl-2H-pyran-2-one (the third intermediate compound) as a white solid. The yield is 86.9%, mp: 81.2-81.6°C.

[0062] Example 7

[0063] 0.1 mol of the third intermediate compound prepared in Example 5, 0.1 mol of benzaldehyde, 0.05 mol of sodium hydroxide, and 0.05 mol of anhydrous potassium carbonate were added to a dry mortar for solid phase grinding. The reaction progress was monitored by TLC. The reaction time was 1.0 h until the reaction was complete. The crude product was washed with water, filtered, and dried to obtain kavalactone, whose FT-IR spectrum is shown as follows: Figure 4 The yield was 94.6%, mp: 234.1~234.7℃.

[0064] Example 8

[0065] 0.1 mol of the third intermediate compound, 0.15 mol of o-aminobenzaldehyde, 0.1 mol of sodium hydroxide, and 0.05 mol of anhydrous potassium carbonate were added to a dry mortar and ground into a solid phase. TLC monitored the reaction progress, which lasted 2.0 hours until completion. The crude product was washed with water, filtered, and dried to obtain the kavalactone. The yield was 97.7%, and the mp was 234.6-234.9°C.

Claims

1. A method for the total synthesis of kavalactone compounds, characterized in that: include: Step (1) is to use methyl acetoacetate as a raw material and pyridine as a solvent, stir and heat the reaction under the catalysis of sodium hydroxide and anhydrous potassium carbonate, after the reaction is completed, cool the reaction solution to room temperature, adjust the pH to neutral, let it stand, precipitate, separate the solid and liquid, and obtain dehydroacetic acid; Step (2), adding sulfuric acid to dehydroacetic acid, stirring, heating to react, pouring the resulting reaction solution into ice, precipitating, and solid-liquid separation to obtain 4-hydroxy-6-methyl-2H-pyran-2-one; Step (3), mixing 4-hydroxy-6-methyl-2H-pyran-2-one, dimethyl sulfate, acetone, and anhydrous potassium carbonate, stirring, heating, and distilling the reaction solution under reduced pressure to obtain 4-methoxy-6-methyl-2H-pyran-2-one; Step (4), mixing 4-methoxy-6-methyl-2H-pyran-2-one, aromatic aldehyde, sodium hydroxide and anhydrous potassium carbonate, and reacting to obtain a kavalactone compound; Among them, the aromatic aldehyde structural formula is Ar-CHO, Ar is 2. The total synthesis method of kavalactone compounds according to claim 1, characterized in that: In step (1), the molar ratio of methyl acetoacetate, sodium hydroxide and anhydrous potassium carbonate is 1.0:(0.5-2.5):(0.25-1.0).

3. The total synthesis method of kavalactone compounds according to claim 1, characterized in that: In step (1), the reaction temperature is 60°C to 85°C, and the reaction time is 1.5h to 3.5h.

4. The total synthesis method of kavalactone compounds according to claim 1, characterized in that: In step (2), the molar ratio of dehydroacetic acid to sulfuric acid is 1.0:(5.0-30.0).

5. The total synthesis method of kavalactone compounds according to claim 1, characterized in that: In step (2), the reaction temperature is 110° C. to 135° C., and the reaction time is 1.5 h to 2.0 h.

6. The method for the total synthesis of kavalactone compounds according to claim 1, characterized in that: In step (3), the molar ratio of 4-hydroxy-6-methyl-2H-pyran-2-one, dimethyl sulfate and anhydrous potassium carbonate is 1.0:(1.0-1.5):(0.5-1.2).

7. The method for the total synthesis of kavalactone compounds according to claim 1, characterized in that: In step (3), the reaction temperature is 15°C to 35°C, and the reaction time is 1.0h to 3.0h.

8. The method for the total synthesis of kavalactone compounds according to claim 1, characterized in that: In step (4), the molar ratio of 4-methoxy-6-methyl-2H-pyran-2-one, aromatic aldehyde, sodium hydroxide and anhydrous potassium carbonate is 1.0:(1.0-2.0):(0.5-1.0):(0.25-1.0).

9. The method for the total synthesis of kavalactone compounds according to claim 1, characterized in that: In step (4), the reaction is carried out using a solid phase grinding method, and the reaction time is 0.5 h to 2.0 h.

10. The method for the total synthesis of kavalactone compounds according to claim 1, characterized in that: In steps (1) to (4), the reaction progress was monitored by TLC.

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