Two-step process for efficiently synthesizing gingerenone a
The two-step synthesis process of gingerone A utilizes hydrogenation and dehydration reactions, which simplifies the purification process, improves the yield and purity of gingerone A, and solves the problems of complex synthesis process and low yield in existing technologies, making it suitable for industrial production.
Patent Information
- Authority / Receiving Office
- WO · WO
- Patent Type
- Applications
- Current Assignee / Owner
- CHEN YUSONG
- Filing Date
- 2025-02-17
- Publication Date
- 2026-07-23
AI Technical Summary
The existing technology for synthesizing gingerone A has a complex process, low yield, and is not suitable for industrial production, posing environmental and economic problems.
A two-step process for synthesizing gingerone A, including hydrogenation and dehydration reactions, is employed. Using readily available curcumin as the starting material, the purification process is simplified and the yield and purity are improved through hydrogenation and dehydration reactions combined with suitable solvents and catalysts.
The method achieves highly selective synthesis of gingerone A, simplifies purification steps, improves yield and product purity, reduces raw material costs, and meets the environmental and economic requirements of industrial production.
Smart Images
Figure CN2025077568_23072026_PF_FP_ABST
Abstract
Description
A two-step process for efficient synthesis of gingerone A Technical Field
[0001] This invention belongs to the field of chemical synthesis technology, specifically relating to a two-step process for the efficient synthesis of gingerone A. Background Technology
[0002] Gingerone A is a natural product extracted from plants, primarily those in the ginger family, such as ginger. In recent years, this compound has attracted considerable attention in traditional medicine, modern pharmacology, and food science due to its various biological activities, including anti-inflammatory, antioxidant, and antitumor effects.
[0003] While some existing literature reports methods for synthesizing gingerone A, these methods suffer from drawbacks such as complex processes, the need for cumbersome column chromatography, low yields, and poor economic and environmental performance, making them unsuitable for industrial production. Therefore, developing a more economical, environmentally friendly, and high-yield industrial preparation process for gingerone A is an urgent technical challenge, enabling its widespread application in pharmaceuticals, food, and cosmetics. Summary of the Invention
[0004] To address the technical problems existing in the prior art, the purpose of this invention is to provide a two-step, highly efficient process for the synthesis of gingerone A. This invention optimizes the synthesis method of gingerone A as a whole, ensuring high selectivity for the target product in each step, eliminating the need for repeated purification, reducing the number of column chromatography purification steps, and obtaining solid gingerone A that meets product purity requirements. The process utilizes readily available reactants, employs mild and controllable reaction conditions, and allows for easy recovery and reuse of solvents and catalysts. It is safe, reliable, and environmentally friendly, achieving high reaction yields and product purity, and is easily scalable for industrial production.
[0005] To achieve the above objectives, the present invention provides the following technical solution:
[0006] This invention provides a two-step process for the efficient synthesis of gingerone A, comprising the following steps:
[0007] (1) Hydrogenation reaction: Curcumin, solvent and catalyst are mixed evenly and reacted completely in a hydrogen atmosphere. The resulting reaction solution is filtered to recover the catalyst. The resulting filtrate is concentrated and then separated and purified to obtain hexahydrocurcumin.
[0008] (2) Dehydration reaction: Hexahydrocurcumin, solvent and catalyst are mixed evenly, heated and stirred until the reaction is complete, ethyl acetate and water are added to the obtained reaction solution for separation to obtain organic phase, the organic phase is washed with water and concentrated to obtain crude product, the crude product is purified and dried to obtain gingerone A solid.
[0009] As a preferred embodiment, in the hydrogenation reaction, the solvent is selected from any one or a mixture of two or more of the following solvents: methanol, ethanol, isopropanol, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, dichloromethane, 1,2-dichloroethane, acetic acid, ethyl acetate, isopropyl acetate, toluene, or water; and the catalyst is selected from any one or a combination of two or more of the following: palladium on carbon, palladium hydroxide, palladium acetate, palladium chloride, dichloro[1,1'-bis(diphenylphosphine)ferrocene]palladium, platinum on carbon, rhodium on carbon, or Raney nickel.
[0010] As a preferred embodiment, in the dehydration reaction, the solvent is selected from any one or a mixture of two or more of the following solvents: methanol, ethanol, isopropanol, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, dichloromethane, 1,2-dichloroethane, acetic acid, ethyl acetate, isopropyl acetate, or toluene; the catalyst is selected from any one or a combination of two or more of the following: p-toluenesulfonic acid and its hydrate, sulfuric acid, hydrochloric acid, alumina and its hydrate, acetic acid, molecular sieve, or anhydrous sodium sulfate.
[0011] As a preferred embodiment, the hydrogenation reaction is carried out at a temperature of 35-45°C for 20-50 hours, and the dehydration reaction is carried out at a temperature of 40-105°C for 2-10 hours.
[0012] As a preferred embodiment, in the hydrogenation reaction, the solvent is anhydrous ethanol; in the dehydration reaction, the solvent is 1,4-dioxane.
[0013] As a preferred embodiment, in the hydrogenation reaction, the mass ratio of curcumin to solvent is 1:(4-30); in the dehydration reaction, the mass ratio of hexahydrocurcumin to solvent is 1:(5-40).
[0014] As a preferred embodiment, in the hydrogenation reaction, the mass ratio of curcumin to solvent is 1:(5-15); in the dehydration reaction, the mass ratio of hexahydrocurcumin to solvent is 1:(15-25).
[0015] As a preferred embodiment, in the hydrogenation reaction, the mass ratio of curcumin to catalyst is 1:(0.01-0.5); in the dehydration reaction, the molar ratio of hexahydrocurcumin to catalyst is 1:(0.005-0.5).
[0016] As a preferred embodiment, in the hydrogenation reaction, the mass ratio of curcumin to catalyst is 1:(0.15-0.5); in the dehydration reaction, the molar ratio of hexahydrocurcumin to catalyst is 1:(0.01-0.3).
[0017] As a preferred embodiment, in the hydrogenation reaction, the separation and purification method is silica gel column chromatography, and the eluent is a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of 10:1 to 1:10.
[0018] As a preferred embodiment, the specific process of separation and purification in the hydrogenation reaction involves sequential elution using a mixed solvent of petroleum ether and ethyl acetate in volume ratios of 10:1, 3:1, and 1:1.
[0019] As a preferred embodiment, in the dehydration reaction, the volume ratio of the reaction solution, ethyl acetate, and water is 1:(0.5-1.5):(0.5-1.5).
[0020] As a preferred embodiment, the purification method in the dehydration reaction is recrystallization, crystallization, or pulping.
[0021] As a preferred embodiment, in the dehydration reaction, the solvent used in the purification process is selected from any one or a mixture of two or more of the following solvents: methanol, ethanol, isopropanol, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, dichloromethane, 1,2-dichloroethane, acetic acid, ethyl acetate, isopropyl acetate, acetone, n-heptane, n-hexane, cyclohexane, toluene, or water.
[0022] As a preferred embodiment, the purification process is performed 1-10 times during the dehydration reaction.
[0023] As a preferred embodiment, in the dehydration reaction, the mass ratio of the crude product to the purification solvent is 1:(1-20).
[0024] As a preferred embodiment, the temperature during the purification process in the dehydration reaction is controlled between 0-60℃.
[0025] Compared with the prior art, the beneficial effects of adopting the technical solution of the present invention are as follows:
[0026] 1. This invention discloses for the first time a two-step, highly selective process for synthesizing gingerone A. The post-processing of the target product is simple, the impurity content is low, and the yield is significantly improved, greatly saving raw material costs. It effectively replaces the existing low-capacity column chromatography method and achieves technological innovation.
[0027] 2. This invention uses readily available and inexpensive curcumin as a starting material, and obtains gingerone A through hydrogenation and dehydration reactions. The hydrogenation reaction conditions of this invention are mild and highly selective, requiring no pressurization and reducing the risk of adverse reactions. The overall reaction conditions are mild and controllable, and the reaction solvent and catalyst are easy to recycle, effectively reducing waste disposal difficulties. It is safe, reliable, and environmentally friendly, with a product purity of no less than 98.0%. This is a low-cost process that meets energy conservation and emission reduction requirements and is suitable for industrial production. Attached Figure Description
[0028] To more clearly illustrate the embodiments of the present invention, the accompanying drawings involved in the embodiments will be briefly described below.
[0029] Figure 1 is a high-performance liquid chromatogram of hexahydrocurcumin prepared in Example 1.
[0030] Figure 2 shows the mass spectrum of hexahydrocurcumin prepared in Example 1.
[0031] Figure 3 is a high-performance liquid chromatogram of gingerone A prepared in Example 1.
[0032] Figure 4 shows the mass spectrum of gingerone A prepared in Example 1. Detailed Implementation
[0033] The present invention will now be described in detail with reference to the embodiments, but the embodiments do not limit the present invention in any way. Unless otherwise specified, the reagents, methods, and equipment used in the present invention are conventional reagents, methods, and equipment in this technical field. Obviously, the embodiments described below are only some embodiments of the present invention. For those skilled in the art, other similar embodiments can be obtained without creative effort and all fall within the protection scope of the present invention.
[0034] HPLC analysis methods for gingerone A and hexahydrocurcumin:
[0035] Chromatographic column: Shim-pack Velox C18, 2.7 μm, 4.6*150 mm; column temperature: 30℃; mobile phase flow rate: 0.9 mL / min; mobile phase: A: 0.05% TFA aqueous solution, B: 0.05% TFA acetonitrile solution; elution gradient: 0 min 80% A, 7 min 70% A, 29 min 50% A, 32 min 48% A, 35 min 5% A, 40 min 5% A, 40.1 min 80% A, 48 min 80% A, end; detection wavelength: 220 nm.
[0036] Example 1
[0037] (1) Preparation of hexahydrocurcumin:
[0038] 600g of curcumin (ZASM01) was dissolved in 6L of anhydrous ethanol and stirred thoroughly. 120g of palladium catalyst was added, and the mixture was purged with hydrogen. The temperature was raised to 40℃ and maintained for 48h. After passing the central control test, the reaction solution was cooled, filtered, and the catalyst was recovered. 630g of silica gel was added to the filtrate, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography using petroleum ether:ethyl acetate ratios of 10:1, 3:1, and 1:1, with 1.2L of eluent used in each ratio, to obtain a pure solution. The collected pure solution was concentrated to obtain a white solid hexahydrocurcumin (D399-2310-011) with a yield of 65% and an HPLC purity of 97.2%.
[0039] (2) Preparation of gingerone A:
[0040] 300g of D399-2310-011 was dissolved in 6L of 1,4-dioxane and stirred thoroughly. 52.19g of p-toluenesulfonic acid monohydrate was added, the mixture was purged with nitrogen, and the temperature was raised to 100℃ and refluxed for 4 hours. After the reaction was deemed satisfactory, the reaction solution was cooled to 40-50℃, and 5L each of ethyl acetate and water were added for extraction and separation. The organic phase was washed twice with purified water (5L), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by crystallization to obtain the sample, which was then vacuum dried (40-45℃, -0.085MPa) for 16 hours to obtain gingerone A (D399-2310-021) solid, with a yield of 72.5% and an HPLC purity of 98.5%.
[0041] The formula for calculating the yield in the above reaction is as follows: Yield = (Actual yield / Theoretical yield) × 100%;
[0042] The reaction equations for the above reactions are as follows:
[0043] (3) The physicochemical properties of the obtained gingerone A product are shown in the table below:
[0044] Table 1 Physicochemical properties of gingerone A product
[0045] Example 2
[0046] Optimize the amount of palladium catalyst used in the hydrogenation reaction:
[0047] Five batches of experiments were conducted to confirm the effect of palladium catalyst dosage on the reaction conversion rate: 100g of curcumin (ZASM01) was dissolved in ethanol (1L), stirred thoroughly, and then 5%, 10%, 20%, 35%, and 50% of the raw material mass of palladium catalyst were added respectively. Hydrogen was used for replacement, and the temperature was raised to 40℃ and then kept at that temperature for reaction. Samples were taken after 48 hours for HPLC analysis to obtain the conversion rate of raw materials into products and by-products.
[0048] Table 2. Conversion rates of raw materials into products and byproducts
[0049] Considering both the conversion rate of hexahydrocurcumin and the cost of palladium catalyst, the preferred amount of palladium catalyst is 20%–35%.
[0050] Example 3
[0051] (1) Preparation of hexahydrocurcumin:
[0052] 600g of curcumin (ZASM01) was dissolved in 6L of ethanol and stirred thoroughly. 210g of palladium catalyst was added, and the mixture was purged with hydrogen. The temperature was raised to 35℃ and maintained for 40h. After passing the control test, the reaction solution was cooled, filtered, and the catalyst was recovered. 650g of silica gel was added to the filtrate, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography using petroleum ether:ethyl acetate ratios of 10:1, 3:1, and 1:1, with 1.2L of eluent used in each ratio, to obtain a pure solution. The collected pure solution was concentrated to obtain a white solid hexahydrocurcumin (D399-2310-011) with a yield of 76.3% and an HPLC purity of 98.1%.
[0053] (2) Preparation of gingerone A:
[0054] 300g of D399-2310-011 was dissolved in 6L of 1,4-dioxane and stirred thoroughly. Concentrated sulfuric acid (4g) was added, nitrogen was used for purging, and the temperature was raised to 60℃. The reaction was allowed to proceed for 8 hours. After the reaction was deemed acceptable by the control system, the reaction solution was cooled to 30-40℃. Ethyl acetate and water (5L each) were added for extraction and separation. The organic phase was washed twice with purified water (5L). The washed organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by pulping to obtain the sample. The sample was dried under vacuum (40-45℃, -0.085MPa) for 20 hours to obtain gingerone A (D399-2310-021) solid, with a yield of 75.6% and an HPLC purity of 99.0%.
[0055] Example 4
[0056] (1) Preparation of hexahydrocurcumin:
[0057] The experimental procedure was the same as that in Example 1, except that the solvent was a mixed solution of isopropanol and water (the mass ratio of isopropanol to water was 9:1), which yielded a white solid of hexahydrocurcumin with a yield of 48% and a purity of 97.5% according to HPLC analysis.
[0058] (2) Preparation of gingerone A:
[0059] The experimental procedure was the same as that in Example 1, except that the solvent was benzene, the reaction temperature was 40°C, and the crude product was purified by recrystallization to obtain gingerone A solid with a yield of 50.0% and a purity of 98.1% according to HPLC analysis.
[0060] Comparative Example 1
[0061] (1) Preparation of hexahydrocurcumin:
[0062] 60 g of palladium catalyst was added to a methanol solution (46.7 L) containing 600 g of curcumin. The solution was then purged with hydrogen, heated to 40 °C, and stirred for 20 hours. After the reaction was complete as monitored by TLC, the reaction was stopped, the reaction solution was cooled, filtered, and 1.2 kg of silica gel was added to the filtrate. The filtrate was then concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography, eluting with chloroform to obtain an oily substance (yield 13.3%). The HPLC purity was 96.0%.
[0063] (2) Preparation of gingerone A:
[0064] 300g of the oily substance obtained in step (1) was dissolved in methanol and 1M sulfuric acid aqueous solution (6L, 1:1). After stirring at room temperature for 5 hours, the reaction product was post-processed and separated by column chromatography to obtain gingerone A oily substance with a yield of 20.5% and a purity of 96.5% as determined by HPLC.
[0065] Comparative Example 2
[0066] (1) Preparation of hexahydrocurcumin:
[0067] The experimental procedure was the same as that of Comparative Example 1, except that the solvent was 95% ethanol, which yielded an off-white solid of hexahydrocurcumin with a yield of 8.0% and a purity of 98.2% according to HPLC analysis.
[0068] (2) Preparation of gingerone A:
[0069] The experimental procedure was the same as that of Comparative Example 1, except that toluene was used as the solvent. Solid gingerone A was obtained with a yield of 19.8% and a purity of 94.5% as determined by HPLC.
[0070] In summary, in the synthesis of gingerone A in this invention, the preferred solvent for the hydrogenation reaction is anhydrous ethanol, and the reaction temperature is 35-45℃ under the action of a catalyst. Purification is performed using column chromatography. For the dehydration reaction, the preferred solvent is 1,4-dioxane, and the reaction temperature is 40-105℃. Purification is performed by recrystallization, crystallization, or pulping. This yields gingerone A solid powder with high purity, stable properties, and easier transportation, storage, and use. The reaction solvent and catalyst of this invention are recyclable and reusable. The reaction conditions are mild and easily controllable, suitable for industrial production, and the product quality is controllable, meeting the requirements for pharmaceutical raw materials.
[0071] The foregoing examples are merely illustrative, used to explain some features of the methods described in this invention. The appended claims are intended to claim the broadest possible scope, and the embodiments presented herein are demonstrated by the applicant's actual experimental results. Therefore, for those skilled in the art, other similar embodiments obtained without departing from the inventive concept and without inventive effort all fall within the protection scope of this invention.
Claims
1. A process for the efficient synthesis of zingiberone A in two steps, characterized by, Includes the following steps: (1) Hydrogenation reaction: Curcumin, solvent and catalyst are mixed evenly and reacted completely in hydrogen atmosphere. The resulting reaction solution is filtered to recover the catalyst. The filtrate is concentrated and then separated and purified to obtain hexahydrocurcumin. (2) Dehydration reaction: Hexahydrocurcumin, solvent and catalyst are mixed evenly, heated and stirred until the reaction is complete, ethyl acetate and water are added to the obtained reaction solution for separation to obtain organic phase, the organic phase is washed with water and concentrated to obtain crude product, the crude product is purified and dried to obtain gingerone A solid.
2. The process according to claim 1, characterized in that, In the hydrogenation reaction, the solvent is selected from any one or a mixture of two or more of the following solvents: methanol, ethanol, isopropanol, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, dichloromethane, 1,2-dichloroethane, acetic acid, ethyl acetate, isopropyl acetate, toluene, or water; the catalyst is selected from any one or a combination of two or more of the following: palladium on carbon, palladium hydroxide, palladium acetate, palladium chloride, dichloro[1,1'-bis(diphenylphosphine)ferrocene]palladium, platinum on carbon, rhodium on carbon, or Raney nickel. In the dehydration reaction, the solvent is selected from any one or a mixture of two or more of the following solvents: methanol, ethanol, isopropanol, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, dichloromethane, 1,2-dichloroethane, acetic acid, ethyl acetate, isopropyl acetate, or toluene; the catalyst is selected from any one or a combination of two or more of the following: p-toluenesulfonic acid and its hydrate, sulfuric acid, hydrochloric acid, alumina and its hydrate, acetic acid, molecular sieve, or anhydrous sodium sulfate.
3. The process according to claim 2, characterized in that, In the hydrogenation reaction, the solvent is anhydrous ethanol; In the dehydration reaction, the solvent is 1,4-dioxane.
4. The process according to claim 1, characterized in that, In the hydrogenation reaction, the reaction temperature is 35-45℃ and the reaction time is 20-50h; In the dehydration reaction, the reaction temperature is 40–105℃ and the reaction time is 2–10h.
5. The process according to claim 1, characterized in that, In the hydrogenation reaction, the mass ratio of curcumin to solvent is 1:(4-30), and the mass ratio of curcumin to catalyst is 1:(0.01-0.5). In the dehydration reaction, the mass ratio of hexahydrocurcumin to solvent is 1:(5-40), and the molar ratio of hexahydrocurcumin to catalyst is 1:(0.005-0.5).
6. The process of claim 1, wherein, In the hydrogenation reaction, the separation and purification method is silica gel column chromatography, and the eluent is a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of 10:1 to 1:
10.
7. The process of claim 1, wherein, In the dehydration reaction, the volume ratio of the reaction solution, ethyl acetate, and water is 1:(0.5-1.5):(0.5-1.5).
8. The process of claim 1, wherein, In the dehydration reaction, the purification method is recrystallization, crystallization, or pulping.
9. The process of claim 8, wherein, The solvent used in the purification process is selected from any one of methanol, ethanol, isopropanol, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, dichloromethane, 1,2-dichloroethane, acetic acid, ethyl acetate, isopropyl acetate, acetone, n-heptane, n-hexane, cyclohexane, toluene or water or a mixed solvent of two or more thereof, and the number of purification is 1-10 times.
10. The process according to any one of claims 1 to 9, characterized in that, In the dehydration reaction, the mass ratio of the crude product to the purification solvent is 1:(1-20), and the temperature in the purification process is controlled at 0-60℃.