Preparation method of acetyl zingiberone

Abstract

The invention discloses a preparation method of acetyl zingiberone, which is characterized by comprising the following steps: S1, 2-methoxyphenol and formaldehyde are used as raw materials, chloromethylation reaction is performed under the action of hydrochloric acid and lewis acid to generate an intermediate I, and the structural formula of the intermediate I is as follows: # imgabs0 #; reacting under the action of alkali to synthesize an acetyl zingiberone crude product; s3, pulping and purifying the obtained crude acetyl zingiberone product by using a mixed solvent composed of alkane and an ester solvent to obtain a pure acetyl zingiberone product. According to the method, 2-methoxyphenol, acetylacetone and formaldehyde are taken as raw materials, and the high-purity acetyzingerone is synthesized in a high-yield, high-specificity and high-selectivity manner through three-step reaction of chloromethylation, coupling and purification. The process route has the advantages of simple process, good reaction selectivity, high yield, cheap and easily available raw materials, low equipment requirement, easy realization of industrial production and the like, and has a wide market application prospect.

Description

Technical Field

[0001] The invention relates to the technical field of organic chemical synthesis, and in particular to a method for preparing acetylgingerone. Background Art

[0002] Acetylgingerone is another active component with super antioxidant activity after vitamin E and resveratrol. It is an all-round antioxidant master that can effectively resist various free radicals and has high antioxidant activity. Its resistance to hydrogen peroxide free radicals is 17.7 times that of vitamin E; its resistance to hydroxyl free radicals is 39.6 times that of vitamin E; and its resistance to nitric oxide free radicals is 126.6 times that of vitamin E. Clinically, it has very good wrinkle removal, spot removal and anti-inflammatory effects. It can also protect our DNA. Using it during the day can provide strong antioxidant protection for DNA, and continue to reduce subsequent DNA mutations caused by daytime ultraviolet radiation at night.

[0003] In the prior art, the synthesis of acetylgingerone mainly includes the following methods:

[0004]

[0005] Xu Jianhua et al. from Fujian Medical University used vanillin and acetylacetone as raw materials, firstly Knovenagel condensed to generate an intermediate, then used palladium carbon as a catalyst, and hydrogen was pressurized to generate acetylgingerone. However, this process requires the use of a hydrogenation kettle, palladium carbon and hydrogen, which has high requirements for equipment and workers, and the process cost is high [CN101434525A, 4-(4-hydroxy-3-methoxybenzyl) curcumin and its use in the preparation of anti-tumor drugs]. Summary of the invention

[0006] The technical problem to be solved by the present invention is to provide a method for preparing acetylgingerone with simple operation, low cost and easy availability of raw materials, low equipment requirements and high yield in view of the deficiencies in the above-mentioned prior art.

[0007] To achieve the above object, the technical solution adopted by the present invention is: a method for preparing acetylgingerone, comprising the following steps:

[0008] S1. Using 2-methoxyphenol (also known as o-methoxyphenol) and formaldehyde as raw materials, a chloromethylation reaction is performed under the action of hydrochloric acid and Lewis acid to generate an intermediate I. The structural formula of the intermediate I is shown below:

[0009]

[0010] S2, using intermediate I and acetylacetone as raw materials, reacting under the action of a base to synthesize a crude product of acetylgingerone;

[0011] S3, purifying the obtained crude acetylglucerone by beating with a mixed solvent consisting of an alkane and an ester solvent to obtain pure acetylglucerone.

[0012] The preparation route is as follows:

[0013]

[0014] Preferably, step S1 specifically includes:

[0015] 2-Methoxyphenol, Lewis acid, hydrochloric acid and the first organic solvent are mixed and cooled to 0-5°C, and a formaldehyde aqueous solution is added dropwise under stirring. After stirring until the raw materials are dissolved, the mixture is heated for reaction for a certain period of time.

[0016] Preferably, step S1 further comprises: cooling after the reaction is completed, separating the liquids, extracting the aqueous phase with the first organic solvent, combining the obtained organic phases, washing with water and brine, drying, filtering, and concentrating the filtrate to obtain intermediate I.

[0017] Preferably, the Lewis acid in step S1 is at least one of zinc chloride, aluminum chloride, tin chloride and ferric chloride, more preferably zinc chloride.

[0018] Preferably, the molar ratio of Lewis acid to 2-methoxyphenol in step S1 is 1 to 1.5:1, for example, 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1 or any number between them, more preferably, the ratio is 1.1:1.

[0019] Preferably, the formaldehyde aqueous solution in step S1 can be replaced by one or both of paraformaldehyde and triformaldehyde.

[0020] Preferably, the molar ratio of formaldehyde to 2-methoxyphenol in step S1 is 1 to 2:1, for example, 1:1, 1.2:1, 1.4:1, 1.6:1, 1.8:1, 2:1 or any value between them, more preferably, the ratio is 1.2:1.

[0021] Preferably, the molar ratio of hydrochloric acid to 2-methoxyphenol in step S1 is 3 to 8:1, for example, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1 or any value between them, more preferably, the ratio is 4:1.

[0022] Preferably, the organic solvent in step S1 is at least one of dichloromethane, toluene and 1,2-dichloroethane. More preferably,

[0023] Preferably, the ratio of the volume of the organic solvent to the mass of 2-methoxyphenol is 4 to 10:1, in terms of volume in mL and weight in g. For example, it is 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1 or any value between them, and more preferably, the ratio is 6:1.

[0024] Preferably, the heating temperature in step S1 is 40-80°C, for example, 40, 50, 60, 70, 80°C or any value therebetween, more preferably, the temperature is 60°C.

[0025] Preferably, the heating reaction time is 2 to 10 hours, for example, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours or any value between any two of them. The reaction endpoint is confirmed by the TLC result that the raw material reaction is complete.

[0026] Preferably, step S2 specifically includes:

[0027] Acetylacetone and the second organic solvent are mixed, cooled to 0-5°C, a base is added, and then stirred for 0.5-1h, the organic solvent of the intermediate I prepared in step S1 is added dropwise, and then the reaction is continued by keeping warm until the raw materials react completely.

[0028] Preferably, step S2 further comprises: after the reaction is completed, adding hydrochloric acid to adjust the pH to 2-3, concentrating under reduced pressure to remove the second organic solvent, filtering, washing the filter cake with water, collecting the filter cake, and drying to obtain crude acetylgingerone.

[0029] Preferably, the molar ratio of acetylacetone to intermediate I in step S2 is 1 to 1.4:1, for example, 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1 or any value between them, more preferably, the ratio is 1.1:1.

[0030] Preferably, the base in step S2 is at least one of sodium methoxide, sodium ethoxide, potassium tert-butoxide, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, and potassium fluoride, and more preferably, sodium ethoxide or potassium tert-butoxide.

[0031] Preferably, the molar ratio of the base to the intermediate I is 2 to 3:1, for example, 2:1, 2.2:1, 2.4:1, 2.6:1, 2.8:1, 3:1 or any value between any two of them, more preferably 2.2:1.

[0032] Preferably, the second organic solvent in step S2 is at least one of methanol, ethanol, tetrahydrofuran, acetone and toluene, more preferably tetrahydrofuran.

[0033] Preferably, the ratio of the volume of the second organic solvent to the mass of the intermediate I is 4 to 8:1, measured in mL by volume and g by weight. For example, it is 4, 5, 6, 7, 8 or any value between them, and more preferably, the ratio is 6:1.

[0034] Preferably, the reaction time in step S2 is 2 to 7 h, for example, 2, 3, 4, 5, 6, 7 h or any value between any two of them. The end point of the reaction is confirmed by TLC (thin layer chromatography) or HPLC (high pressure liquid chromatography) to determine whether the intermediate I has reacted completely.

[0035] Preferably, step S3 specifically includes:

[0036] The crude acetylgingerone is mixed with an alkane and an ester solvent, heated to a certain temperature and stirred for a period of time, and then cooled to room temperature and stirred.

[0037] Preferably, the alkane solvent in step S3 is at least one of petroleum ether, n-hexane and n-heptane, more preferably n-hexane.

[0038] Preferably, the ester solvent is at least one of ethyl acetate, isopropyl acetate and tert-butyl acetate, and more preferably, ethyl acetate.

[0039] Preferably, the volume ratio of the alkane to the ester solvent is 8 to 12:1, for example, 8:1, 9:1, 10:1, 11:1, 12:1 or any value between them, more preferably, the ratio is 10:1.

[0040] Preferably, the heating temperature in step S3 is 60-90°C, for example, 60, 70, 80, 90, 100°C or any value therebetween, more preferably 70°C.

[0041] Preferably, the heating reaction time in step S3 is 2 to 5 hours, for example, 2, 3, 4, 5 hours or any value therebetween, more preferably, 3 hours.

[0042] Preferably, the stirring time after cooling to room temperature in step S3 is 0.5 to 2 h, for example, 0.5, 1, 1.5, 2 h or any value between any two of them, more preferably, 1 h.

[0043] Preferably, the ratio of the volume of the mixed solvent in step S3 to the quality of the crude acetylgingerone is 6 to 14:1, measured in units of volume (mL) and weight (g). The ratio is 6, 8, 10, 12, 14 or any value between them, and more preferably, the ratio is 10.

[0044] Preferably, step S3 specifically includes:

[0045] The obtained crude acetylgingerone is added to a mixed solvent consisting of an alkane solvent and an ester solvent, heated to 60-70°C, reacted for 2-5 hours, then cooled to room temperature, stirred for 0.5-2 hours, filtered, the filter cake is rinsed with an alkane solvent, the filter cake is collected, and dried to obtain pure acetylgingerone.

[0046] The beneficial effects of the present invention are:

[0047] The invention uses 2-methoxyphenol, acetylacetone and formaldehyde as raw materials, and synthesizes high-purity acetylgingerone with high yield, high specificity and selectivity through three-step reactions of chloromethylation, coupling and purification. The process route has the advantages of simple process, good reaction selectivity, high yield, cheap and easy-to-obtain raw materials, low equipment requirements, easy to realize industrial production, etc., and has broad market application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 This is the H NMR spectrum of the pure acetylglucerone prepared in Example 1. DETAILED DESCRIPTION

[0049] The present invention is further described in detail below in conjunction with embodiments so that those skilled in the art can implement the invention with reference to the description.

[0050] It should be understood that the terms such as “having”, “including” and “comprising” used herein do not exclude the existence or addition of one or more other elements or combinations thereof.

[0051] The test methods used in the following examples are conventional methods unless otherwise specified. The materials and reagents used in the following examples are all commercially available unless otherwise specified. In the following examples, if no specific conditions are specified, the experiments were carried out under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used, if the manufacturer is not specified, are all conventional products that can be purchased commercially.

[0052] Example 1

[0053] A method for preparing acetylglucerone comprises the following steps:

[0054] S1. Preparation of intermediate I:

[0055]

[0056] In a 2L three-necked flask, add 100.0g of 2-methoxyphenol, 120.8g of zinc chloride, 270mL of 36% concentrated hydrochloric acid and 600mL of toluene. Then cool to 2°C, add 78.5g of 37% formaldehyde aqueous solution dropwise while stirring, stir until the raw materials are completely dissolved, then heat to 60°C and continue the reaction for 4h.

[0057] The reaction solution was cooled and separated. The aqueous phase was extracted with 400 mL of toluene. The organic phases were combined, washed with 500 mL of water and 500 mL of brine (mass concentration 20%), respectively, dried over anhydrous sodium sulfate, and concentrated to obtain 132.8 g of intermediate I with a yield of 95.5%.

[0058] S2, preparation of crude acetylgingerone:

[0059] Add 84.7 g of acetylacetone and 660 mL of tetrahydrofuran into a 2 L three-necked flask, cool to 2°C, add 189.9 g of potassium tert-butoxide in batches, and stir for 0.5 h. Add dropwise 132 mL of tetrahydrofuran solution containing 132.8 g of intermediate I, and continue to keep warm at 2°C for 2 h.

[0060] The reaction solution was quenched with 2N hydrochloric acid and adjusted to pH = 2, concentrated to remove tetrahydrofuran, cooled to room temperature and filtered, the filter cake was rinsed with a large amount of water, the filter cake was collected and dried to obtain 177.2 g of crude acetylgingerone.

[0061] S3, preparation of pure acetylgingerone:

[0062] 1770 mL of a mixed solvent consisting of n-hexane and ethyl acetate in a volume ratio of 10:1 was added to the crude acetylginkkerone, heated to 70°C for reaction for 3 h, then cooled to room temperature and stirred for 1 h, filtered, the filter cake was rinsed with n-hexane, the filter cake was collected, and dried to obtain 165.0 g of pure acetylginkkerone with a yield of 90.8%.

[0063] The H NMR data of the pure acetylgingerone prepared in this example are shown below. Figure 1 As shown:

[0064] 1 H NMR (400MHz, CDCl3): δ6.80-6.86(m,1H),6.61-6.65(m,2H),5.62(d,J=6.3Hz,1H),3.98(t, J=7.5Hz, 0.45H), 3.86 (s, 3H), 3.59 (s, 1H), 3.08 (d, J=7.5Hz, 1H), 2.13 (s, 3H), 2.08 (s, 3H).

[0065] Example 2

[0066] A method for preparing acetylglucerone comprises the following steps:

[0067] S1. Preparation of intermediate I:

[0068]

[0069] In a 2L three-necked flask, add 100g 2-methoxyphenol, 156.8g ferric chloride, 300mL 36% concentrated hydrochloric acid and 500mL 1,2-dichloroethane. Then cool to 2°C, add 26.6g paraformaldehyde in batches with stirring, stir until the raw materials are completely dissolved, and then heat to 80°C and continue the reaction for 3h.

[0070] The reaction solution was cooled and separated. The aqueous phase was extracted with 400 mL of 1,2-dichloroethane. The organic phases were combined, washed with 500 mL of water and 500 mL of brine (mass concentration 20%), respectively, dried over anhydrous sodium sulfate, and concentrated to obtain 128.4 g of intermediate I with a yield of 92.3%.

[0071] S2, preparation of crude acetylgingerone:

[0072] Add 89.4 g of acetylacetone and 512 mL of methanol into a 2 L three-necked flask, cool to 2°C, add 96.4 g of sodium methoxide in batches, and stir for 0.5 h. Add dropwise a solution of 128.4 g of intermediate I in 128 mL of methanol, and continue to keep warm at 2°C for 2 h.

[0073] The reaction solution was quenched with 2N hydrochloric acid and adjusted to pH = 2, concentrated to remove methanol, cooled to room temperature and filtered, the filter cake was rinsed with a large amount of water, the filter cake was collected and dried to obtain 175.5 g of crude acetylgingerone.

[0074] S3, preparation of pure acetylgingerone:

[0075] 1400 mL of a mixed solvent consisting of petroleum ether and isopropyl acetate in a volume ratio of 9:1 was added to the crude acetylgingerone, heated to 60°C for 4 h, then cooled to room temperature and stirred for 1.5 h, filtered, the filter cake was rinsed with n-hexane, the filter cake was collected, and dried to obtain 158 g of pure acetylgingerone with a yield of 89.9%.

[0076] Example 3

[0077] A method for preparing acetylglucerone comprises the following steps:

[0078] S1. Preparation of intermediate I:

[0079]

[0080] In a 2L three-necked flask, add 100.0g 2-methoxyphenol, 123.5g aluminum chloride, 240mL 36% concentrated hydrochloric acid and 700mL dichloromethane, then cool to 2°C, add 31.5g trioxymethylene in batches with stirring, stir until the raw materials are completely dissolved, then heat to 40°C and continue the reaction for 6h.

[0081] The reaction solution was cooled and separated. The aqueous phase was extracted with 400 mL of dichloromethane. The organic phases were combined, washed with 500 mL of water and 500 mL of brine (mass concentration 20%), respectively, dried over anhydrous sodium sulfate, and concentrated to obtain 126.9 g of intermediate I with a yield of 91.3%.

[0082] S2, preparation of crude acetylgingerone:

[0083] Add 86.3 g of acetylacetone and 762 mL of acetone to a 2 L three-necked flask, cool to 2°C, add 70.6 g of sodium hydroxide, and stir for 0.5 h. Add dropwise a solution of 126.9 g of intermediate I in 127 mL of acetone, and continue to keep warm at 2°C for 2 h.

[0084] The reaction solution was quenched with 2N hydrochloric acid and adjusted to pH = 2, concentrated to remove acetone, cooled to room temperature and filtered, the filter cake was rinsed with a large amount of water, the filter cake was collected and dried to obtain 170.9 g of crude acetylgingerone.

[0085] S3, preparation of pure acetylgingerone:

[0086] Add 1880 mL of n-heptane: tert-butyl acetate in a volume ratio of

[0087] =10:1 mixed solvent, heated to 80 ° C for 2h, then cooled to room temperature and stirred for 1.5h, filtered, the filter cake was rinsed with n-heptane, collected and dried to obtain 155.8g of pure acetylgingerone with a yield of 89.7%.

[0088] Although the embodiments of the present invention have been disclosed as above, they are not limited to the applications listed in the specification and the implementation modes. They can be fully applied to various fields suitable for the present invention. For those familiar with the art, additional modifications can be easily implemented. Therefore, without departing from the general concept defined by the claims and the scope of equivalents, the present invention is not limited to specific details.

Claims

1. A method for preparing acetylgingerone, characterized in that: The following steps are involved: S1. Using 2-methoxyphenol and formaldehyde as raw materials, a chloromethylation reaction is carried out under the action of hydrochloric acid and Lewis acid to generate an intermediate I. The structural formula of the intermediate I is shown below: S2, using intermediate I and acetylacetone as raw materials, reacting under the action of a base to synthesize a crude product of acetylgingerone; S3, purifying the obtained crude acetylglucerone by beating with a mixed solvent consisting of an alkane and an ester solvent to obtain pure acetylglucerone.

2. The method for preparing acetylgingerone according to claim 1, characterized in that: Step S1 specifically includes: 2-methoxyphenol, Lewis acid, hydrochloric acid and the first organic solvent are mixed and cooled to 0-5°C, and a formaldehyde aqueous solution is added dropwise under stirring, and the mixture is stirred until the raw materials are dissolved and then heated for reaction; After the reaction is completed, the temperature is lowered, the liquids are separated, the aqueous phase is extracted with the first organic solvent, the obtained organic phases are combined, washed with water and brine, dried, filtered, and the filtrate is concentrated to obtain intermediate I.

3. The method for preparing acetylgingerone according to claim 2, characterized in that: The Lewis acid in step S1 is at least one of zinc chloride, aluminum chloride, tin chloride and ferric chloride, and the molar ratio of the Lewis acid to 2-methoxyphenol is 1 to 1.5:

1.

4. The method for preparing acetylgingerone according to claim 2, characterized in that: The molar ratio of formaldehyde to 2-methoxyphenol in step S1 is 1 to 2:

1.

5. The method for preparing acetylgingerone according to claim 2, characterized in that: The molar ratio of hydrochloric acid to 2-methoxyphenol in step S1 is 3 to 8:

1.

6. The method for preparing acetylgingerone according to claim 2, characterized in that: The organic solvent in step S1 is at least one of dichloromethane, toluene, and 1,2-dichloroethane. Calculated in units of volume (mL) and weight (g), the ratio of the volume of the organic solvent to the mass of 2-methoxyphenol is 4 to 10:

1.

7. The method for preparing acetylgingerone according to claim 2, characterized in that: The heating temperature in step S1 is 40 to 80° C., and the heating reaction time is 2 to 10 hours.

8. The method for preparing acetylgingerone according to claim 1, characterized in that: Step S2 specifically includes: Mix acetylacetone and the second organic solvent, cool to 0-5°C, add a base, and then stir for 0.5-1h, dropwise add the organic solvent of the intermediate I prepared in step S1, and then continue to keep warm and react for 2-7h; After the reaction is completed, hydrochloric acid is added to adjust the pH to 2-3, and the second organic solvent is removed by concentration under reduced pressure. The mixture is filtered, the filter cake is rinsed with water, the filter cake is collected, and dried to obtain crude acetylgingerone.

9. The method for preparing acetylgingerone according to claim 8, characterized in that: The molar ratio of acetylacetone to intermediate I in step S2 is 1 to 1.4:

1.

10. The method for preparing acetylgingerone according to claim 8, characterized in that: The base in step S2 is at least one of sodium methoxide, sodium ethoxide, potassium tert-butoxide, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, and potassium fluoride, and the molar ratio of the base to the intermediate I is 2 to 3:

1.

11. The method for preparing acetylgingerone according to claim 8, characterized in that: The second organic solvent in step S2 is at least one of methanol, ethanol, tetrahydrofuran, acetone, and toluene. The volume unit is mL and the weight unit is g. The ratio of the volume of the second organic solvent to the mass of the intermediate I is 4 to 8:

1.

12. The method for preparing acetylgingerone according to claim 1, characterized in that: Step S3 specifically includes: The obtained crude acetylgingerone is added to a mixed solvent consisting of an alkane solvent and an ester solvent, heated to 60-90°C, reacted for 2-5 hours, then cooled to room temperature, stirred for 0.5-2 hours, filtered, the filter cake is rinsed with an alkane solvent, the filter cake is collected, and dried to obtain pure acetylgingerone.

13. The method for preparing acetylgingerone according to claim 12, characterized in that: The alkane solvent in step S3 is at least one of petroleum ether, n-hexane, and n-heptane, the ester solvent is at least one of ethyl acetate, isopropyl acetate, and tert-butyl acetate, and the volume ratio of the alkane to the ester solvent is 8 to 12:

1.

14. The method for preparing acetylgingerone according to claim 12, characterized in that: In terms of volume unit as mL and weight unit as g, the ratio of the volume of the mixed solvent in step S3 to the quality of the crude acetylgingerone is 6 to 14:1.

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