Process for efficiently synthesizing zingiberenone A by two-step method

Abstract

The invention discloses a process for efficiently synthesizing zingiberenone A by a two-step method, and belongs to the technical field of chemical synthesis. Compared with the prior art, the preparation process for synthesizing zingiberenone A by adopting a two-step method has the advantages that the target product synthesized in each step has high selectivity and does not need to be repeatedly purified, the yield is obviously improved, and the raw material cost is greatly saved. The hydrogenation reaction catalyst and the solvent can be recycled, so that the waste treatment difficulty can be effectively reduced. The process disclosed by the invention can be applied to industrial production of zingiberenone A, and lays a foundation for realizing raw material conversion of zingiberenone A.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis, and particularly relates to a two-step process for efficiently synthesizing gingerol A. Background Art

[0002] Gingerone A is a natural product extracted from plants, mainly from Zingiberaceae plants, such as ginger. In recent years, this compound has attracted much attention in traditional medicine, modern pharmacology, food science and other fields due to its anti-inflammatory, antioxidant, anti-tumor and other biological activities.

[0003] Although some methods for synthesizing gingerol A have been reported in some existing literature, they all have the problems of complex process, cumbersome column chromatography, low yield, poor economy and environmental protection, and unsuitability for industrial production. Therefore, research and development of a more economical, environmentally friendly and high-yield industrial preparation process for gingerol A has become a technical problem that needs to be solved urgently, so that gingerol A can be widely used in the fields of medicine, food, cosmetics, etc. Summary of the invention

[0004] In view of the technical problems existing in the above-mentioned prior art, the purpose of the present invention is to provide a two-step process for efficiently synthesizing gingerol A. The present invention optimizes the synthesis method as a whole, and the target product synthesized in each step has high selectivity, does not need to be repeatedly purified, reduces the number of column chromatography purifications, and obtains solid gingerol A that meets the product purity requirements. The process reaction raw materials are easily available, the reaction conditions are mild and controllable, the solvents and catalysts are easy to recycle and reuse, it is safe, reliable and environmentally friendly, the reaction yield and product purity are high, and it is easy to expand industrial production.

[0005] To achieve the above object, the present invention provides the following technical solutions:

[0006] The present invention provides a two-step process for efficiently synthesizing gingerol A, comprising the following steps:

[0007] (1) Hydrogenation reaction: Curcumin, solvent and catalyst are mixed uniformly, and after the reaction is completed in a hydrogen atmosphere, the catalyst is filtered and recovered, and the filtrate is concentrated and separated and purified to obtain hexahydrocurcumin;

[0008] (2) Dehydration reaction: Hexahydrocurcumin, a solvent and a catalyst are mixed uniformly, heated and stirred to react until the reaction is complete, ethyl acetate and water are added to the obtained reaction solution, the liquids are separated, the obtained organic phase is washed with water, concentrated, the crude product is purified, and dried to obtain gingerol A solid.

[0009] As a preferred embodiment, in the hydrogenation reaction, the solvent is selected from any one of 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, or a mixed solvent of two or more thereof; the catalyst is selected from any one of palladium carbon, palladium hydroxide, palladium acetate, palladium chloride, dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium, platinum carbon, rhodium carbon, or Raney nickel, or a combination of two or more thereof.

[0010] As a preferred scheme, in the dehydration reaction, the solvent is selected from any one of 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, or a mixed solvent of two or more thereof; the catalyst is selected from any one of p-toluenesulfonic acid and its hydrate, sulfuric acid, hydrochloric acid, aluminum oxide and its hydrate, acetic acid, molecular sieves or anhydrous sodium sulfate, or a combination of two or more thereof.

[0011] As a preferred solution, in the hydrogenation reaction, the reaction temperature is 35-45°C, and the reaction time is 20 to 50 hours. In the dehydration reaction, the reaction temperature is 40 to 105°C, and the reaction time is 2 to 10 hours.

[0012] As a preferred solution, in the hydrogenation reaction, the solvent is anhydrous ethanol; in the dehydration reaction, the solvent is 1,4-dioxane.

[0013] As a preferred solution, in the hydrogenation reaction, the mass ratio of curcumin to the solvent is 1:(4-30); in the dehydration reaction, the mass ratio of hexahydrocurcumin to the solvent is 1:(5-40).

[0014] As a preferred embodiment, in the hydrogenation reaction, the mass ratio of curcumin to the solvent is 1:(5-15); in the dehydration reaction, the mass ratio of hexahydrocurcumin to the solvent is 1:(15-25).

[0015] As a preferred embodiment, in the hydrogenation reaction, the mass ratio of curcumin to the catalyst is 1:(0.01-0.5); in the dehydration reaction, the molar ratio of hexahydrocurcumin to the catalyst is 1:(0.005-0.5).

[0016] As a preferred embodiment, in the hydrogenation reaction, the mass ratio of curcumin to the catalyst is 1:(0.15-0.5); in the dehydration reaction, the molar ratio of hexahydrocurcumin to the catalyst is 1:(0.01-0.3).

[0017] As a preferred solution, in the hydrogenation reaction, the separation and purification method is silica gel column chromatography separation and purification, and the eluent is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 10:1-1:10.

[0018] As a preferred solution, in the hydrogenation reaction, the specific process of separation and purification is to use a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of 10:1, 3:1 and 1:1 in sequence for elution.

[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 solution, in the dehydration reaction, the purification method 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 mixed solvent of two or more 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.

[0022] As a preferred solution, in the dehydration reaction, the number of purifications is 1-10 times.

[0023] As a preferred solution, in the dehydration reaction, the mass ratio of the crude product to the purification solvent is 1:(1-20).

[0024] As a preferred solution, in the dehydration reaction, the temperature is controlled at 0-60°C during the purification process.

[0025] Compared with the prior art, the beneficial effects of the technical solution of the present invention are:

[0026] 1. The present invention discloses for the first time a two-step, highly selective process for synthesizing gingerol A. The post-processing for preparing the target product is simple, the impurity content is low, and the yield is significantly improved, which greatly saves the cost of raw materials, effectively replaces the existing low-capacity column chromatography method, and realizes technological innovation.

[0027] 2. The present invention uses cheap and easily available curcumin as a starting material, and obtains gingerol A through hydrogenation and dehydration reactions. The hydrogenation reaction conditions of the present invention are mild, the selectivity is high, and no pressurization is required, thereby reducing the reaction risk factor. The overall reaction conditions of the present invention are mild and controllable, and the reaction solvent and the catalyst are easy to recycle, which can effectively reduce the difficulty of waste treatment. The present invention is safe, reliable and environmentally friendly, and the product purity is not less than 98.0%. The process is low-cost, meets the requirements of energy conservation and emission reduction, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] In order to more clearly illustrate the embodiments of the present invention, the drawings related to the embodiments are briefly introduced below.

[0029] Figure 1 The HPLC chromatogram of hexahydrocurcumin prepared in Example 1.

[0030] Figure 2 The mass spectrum of hexahydrocurcumin prepared in Example 1.

[0031] Figure 3 This is the high performance liquid chromatogram of gingerol A prepared in Example 1.

[0032] Figure 4 This is the mass spectrum of gingerol A prepared in Example 1. DETAILED DESCRIPTION

[0033] The present invention is described in detail below in conjunction with embodiment, but embodiment does not limit the present invention in any form. Unless otherwise specified, the reagent, method and equipment adopted in the present invention are conventional reagents, methods and equipment in the art. Obviously, the embodiment in the following description is only a partial embodiment of the present invention, and for those skilled in the art, without paying creative labor, obtaining other similar embodiments all falls into protection scope of the present invention.

[0034] HPLC analysis method of gingerolone A and hexahydrocurcumin:

[0035] Chromatographic column: Shim-pack Velox C18, 2.7μm, 4.6*150mm; column temperature: 30℃; mobile phase flow rate: 0.9mL / min; mobile phase: A: 0.05% TFA aqueous solution, B: 0.05% TFA acetonitrile solution; elution gradient: 0min80%A, 7min 70%A, 29min 50%A, 32min 48%A, 35min 5%A, 40min 5%A, 40.1min80%A, 48min80%A, end; detection wavelength: 220nm.

[0036] Example 1

[0037] (1) Preparation of hexahydrocurcumin:

[0038] 600g of curcumin (ZASM01) was dissolved in 6L of anhydrous ethanol, stirred thoroughly, 120g of palladium catalyst was added, hydrogen was replaced, the temperature was raised to 40°C, and the reaction was kept warm for 48h. The central control test was qualified, the temperature was lowered, the catalyst was filtered and recovered, 630g of silica gel was added to the filtrate, and the filtrate was concentrated to a crude product, which was separated and purified by silica gel column chromatography, and eluted in turn with petroleum ether: ethyl acetate = 10:1, 3:1 and 1:1 eluents, using 1.2L respectively. The collected pure product solution was concentrated to obtain an off-white solid of hexahydrocurcumin (D399-2310-011), with a yield of 65% and an HPLC analysis purity of 97.2%.

[0039] (2) Preparation of gingerolone A:

[0040] Dissolve 300g D399-2310-011 in 6L 1,4-dioxane, stir well, add p-toluenesulfonic acid monohydrate (52.19g), replace with nitrogen, heat to 100℃, reflux for 4h. The reaction is qualified in the control test, cool to 40-50℃, add 5L of ethyl acetate and water, extract and separate, wash the organic phase with purified water (5L) twice, dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate to obtain a crude product, purify the crude product by crystallization to obtain a sample, vacuum dry (40-45℃, -0.085MPa) for 16h, and obtain gingerol A (D399-2310-021) solid, with a yield of 72.5% and a purity of 98.5% by HPLC analysis.

[0041] The calculation formula of the yield in the above reaction is as follows: yield = (actual yield / theoretical yield) × 100%;

[0042] The reaction formula of the above reaction is as follows:

[0043]

[0044] (3) The physicochemical properties of the obtained gingerol A product are shown in the following table:

[0045] Table 1 Physical and chemical properties of gingerol A products

[0046]

[0047] Example 2

[0048] Optimize the amount of palladium catalyst used in hydrogenation reaction:

[0049] Through 5 batches of experiments, the effect of the amount of palladium catalyst used on the reaction conversion rate was confirmed: 100g of curcumin (ZASM01) was dissolved in ethanol (1L), and after sufficient stirring, 5%, 10%, 20%, 35% and 50% of the raw material mass of palladium catalyst were added respectively, hydrogen was replaced, and the temperature was raised to 40°C for insulation reaction. Samples were taken for HPLC analysis after 48 hours to obtain the conversion rate of raw materials into products and by-products.

[0050] Table 2 Conversion rate results of raw materials into products and by-products

[0051]

[0052] Taking into consideration the conversion rate of hexahydrocurcumin and the cost of the palladium catalyst, the preferred amount of the palladium catalyst is 20% to 35%.

[0053] Example 3

[0054] (1) Preparation of hexahydrocurcumin:

[0055] 600g of curcumin (ZASM01) was dissolved in 6L of ethanol, stirred thoroughly, 210g of palladium catalyst was added, hydrogen was replaced, the temperature was raised to 35°C, the reaction was kept warm for 40h, the central control test was qualified, the temperature was lowered, the catalyst was filtered and recovered, 650g of silica gel was added to the filtrate, and the filtrate was concentrated to a crude product, which was separated and purified by silica gel column chromatography, and eluted in turn with an eluent of petroleum ether: ethyl acetate = 10:1, 3:1 and 1:1, using 1.2L respectively. The collected pure product solution was concentrated to obtain an off-white solid of hexahydrocurcumin (D399-2310-011), with a yield of 76.3% and a purity of 98.1% by HPLC analysis.

[0056] (2) Preparation of gingerolone A:

[0057] 300g D399-2310-011 was dissolved in 6L 1,4-dioxane, stirred thoroughly, concentrated sulfuric acid (4g) was added, nitrogen was replaced, the temperature was raised to 60°C, the reaction was carried out for 8h, the reaction control test was qualified, the temperature was lowered to 30-40°C, 5L of ethyl acetate and water were added, the liquid was extracted, the organic phase was washed twice with purified water (5L), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by pulping to obtain a sample, and vacuum dried (40-45°C, -0.085MPa) for 20h to obtain gingerolone A (D399-2310-021) as a solid with a yield of 75.6% and a purity of 99.0% by HPLC analysis.

[0058] Example 4

[0059] (1) Preparation of hexahydrocurcumin:

[0060] The experimental process is the same as the steps of Example 1, except that the solvent is a mixed solution of isopropanol and water (the mass ratio of isopropanol to water is 9:1), and an off-white hexahydrocurcumin solid is obtained with a yield of 48% and an HPLC analysis purity of 97.5%.

[0061] (2) Preparation of gingerolone A:

[0062] The experimental process was the same as that of Example 1, except that the solvent was benzene, the reaction temperature was 40° C., and the crude product was purified by recrystallization to obtain solid gingerol A with a yield of 50.0% and a purity of 98.1% according to HPLC analysis.

[0063] Comparative Example 1

[0064] (1) Preparation of hexahydrocurcumin:

[0065] 60 g of palladium catalyst was added to a methanol solution (46.7 L) containing curcumin (600 g), hydrogen was replaced, the temperature was raised to 40 ° C, and the reaction was stirred for 20 hours. After the reaction was completed by TLC monitoring, the reaction was stopped, the temperature was lowered, and the filtrate was filtered. 1.2 kg of silica gel was added to the filtrate and the filtrate was concentrated to a crude product. The crude product was separated and purified by silica gel column chromatography with chloroform as the eluent to obtain an oily product (yield 13.3%). The purity of the product by HPLC was 96.0%.

[0066] (2) Preparation of gingerolone A:

[0067] 300 g of the oil obtained in step (1) was dissolved in methanol and 1 M sulfuric acid aqueous solution (6 L, 1:1), stirred at room temperature for 5 hours, post-treated and separated by column chromatography to obtain gingerol A as an oil with a yield of 20.5% and a purity of 96.5% by HPLC analysis.

[0068] Comparative Example 2

[0069] (1) Preparation of hexahydrocurcumin:

[0070] The experimental process was the same as that of Comparative Example 1, except that the solvent was 95% ethanol, and an off-white hexahydrocurcumin solid was obtained with a yield of 8.0% and a purity of 98.2% by HPLC analysis.

[0071] (2) Preparation of gingerolone A:

[0072] The experimental process was the same as that of Comparative Example 1, except that the solvent was toluene, and gingerol A solid was obtained with a yield of 19.8% and a purity of 94.5% according to HPLC analysis.

[0073] In summary, in the synthesis of gingerolone A, the preferred reaction solvent for hydrogenation reaction is anhydrous ethanol, under the action of a catalyst, the reaction temperature is 35-45°C, and purification is performed by column chromatography separation; the preferred reaction solvent for dehydration reaction is 1,4-dioxane, the reaction temperature is 40-105°C, and purification is performed by recrystallization, crystallization or pulping, so that gingerolone A solid powder with high purity, stable properties, and easier transportation, storage and use can be obtained. The reaction solvent and catalyst are recyclable and reusable, the reaction conditions are mild and easy to control, suitable for industrial production, and the product quality is controllable, meeting the requirements of raw materials.

[0074] The foregoing examples are merely illustrative and are used to explain some features of the method of the present invention. The attached claims are intended to require the widest possible range that can be imagined, and the embodiments presented herein are demonstrated by the applicant's actual experimental results. Therefore, for those skilled in the art, without departing from the concept of the present invention and without paying creative labor, other similar embodiments are obtained and fall within the scope of protection of the present invention.

Claims

1. A two-step process for efficiently synthesizing gingerol A, characterized in that: The following steps are involved: (1) Hydrogenation reaction: Curcumin, solvent and catalyst are mixed uniformly, and after the reaction is completed in a hydrogen atmosphere, the catalyst is filtered and recovered, and the filtrate is concentrated and separated and purified to obtain hexahydrocurcumin; (2) Dehydration reaction: Hexahydrocurcumin, a solvent and a catalyst are mixed uniformly, heated and stirred to react until the reaction is complete, ethyl acetate and water are added to the obtained reaction solution, the liquids are separated, the obtained organic phase is washed with water, concentrated, the crude product is purified, and dried to obtain gingerol A solid.

2. The process according to claim 1, characterized in that In the hydrogenation reaction, the solvent is selected from any one of 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, or a mixed solvent of two or more thereof; the catalyst is selected from any one of palladium carbon, palladium hydroxide, palladium acetate, palladium chloride, dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium, platinum carbon, rhodium carbon, or Raney nickel, or a combination of two or more thereof; In the dehydration reaction, the solvent is selected from any one of 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, or a mixed solvent of two or more thereof; the catalyst is selected from any one of p-toluenesulfonic acid and its hydrate, sulfuric acid, hydrochloric acid, aluminum oxide and its hydrate, acetic acid, molecular sieves or anhydrous sodium sulfate, or a combination of two or more thereof.

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°C and the reaction time is 20-50h; in the dehydration reaction, the reaction temperature is 40-105°C 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 the solvent is 1:(4-30); in the dehydration reaction, the mass ratio of hexahydrocurcumin to the solvent is 1:(5-40); In the hydrogenation reaction, the mass ratio of curcumin to the catalyst is 1:(0.01-0.5); in the dehydration reaction, the molar ratio of hexahydrocurcumin to the catalyst is 1:(0.005-0.5).

6. The process according to claim 1, characterized in that In the hydrogenation reaction, the separation and purification method is silica gel column chromatography separation and purification, and the eluent is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 10:1-1:

10.

7. The process according to claim 1, characterized in that 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 according to claim 1, characterized in that In the dehydration reaction, the purification method is recrystallization, crystallization or beating.

9. The process according to claim 8, characterized in that In the dehydration reaction, the solvent used in the purification process is selected from any one or a mixed solvent of two or more 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; the number of purifications 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 is controlled at 0-60°C during the purification process.

Images