CN108947858A - A kind of preparation method and application of chalcone, dihydrochalcone and chromocor compound - Google Patents

Abstract

The invention discloses the preparation method and applications of a kind of chalcone, dihydrochalcone and chromocor compound, the 3 of synthetic method synthesis through the invention, 4 ', 6 '-trihydroxy -4- methoxyl group chalcones are stronger to the inhibitory effect of a- glucuroide, can be used for reducing postprandial hyperglycemia；4- dimethylamino chalcone, 4-HC, 3- hydroxyl -4- methoxyl group chalcone and 3,4 ', 6 '-trihydroxy -4- methoxyl group chalcones are obvious to the inhibitory effect of non-glycosylation, can be used for the treatment to diabetes, atherosclerosis.

Description

A kind of preparation method and application of chalcone, dihydrochalcone and flavonoid compound

technical field

The invention relates to the preparation technology of chalcone compounds, in particular to a preparation method and application of chalcone, dihydrochalcone and flavone compounds.

Background technique

Diabetes mellitus is a syndrome of glucose, protein and lipid metabolism disorder caused by lack of insulin in the body or increase of hormones that antagonize insulin, or that insulin cannot exert normal physiological functions in target cells. Traditional oral hypoglycemic drugs have limited curative effect, and basic research on new natural sources of diabetes drugs is an urgent and urgent task. With the in-depth study of the basic theory of diabetes, antidiabetic drugs with various mechanisms of action have been used in clinical evaluation and treatment, among which insulin secretagogues have attracted widespread attention.

Chalcones and their derivatives are products of cross-aldol condensation of aromatic aldehydes and ketones, and are important organic synthesis intermediates for the synthesis of various natural compounds. The chemical structure of chalcone is 1,3-diphenylpropenone. Natural compounds based on it exist in licorice, safflower and other plants. These natural chalcones often contain phenolic hydroxyl groups. Due to its flexible molecular structure, chalcone can bind to different receptors, so it has a wide range of biological activities, such as anti-tumor, inhibition and scavenging of oxygen free radicals, antibacterial, anti-allergic, anti-viral, anti-ulcer and antispasmodic, etc. The classic synthesis method of chalcone is to use strong base or strong acid to catalyze the aldol condensation of acetophenone and its derivatives with aromatic aldehydes, with a yield of 10%-70%. In recent years, with the continuous discovery of various catalysts and the extensive exploration of reaction conditions, the synthesis methods of chalcones have tended to be diversified.

Contents of the invention

The purpose of the present invention is to provide a preparation method and application of chalcone, dihydrochalcone and flavonoids, so as to solve the problems raised in the above-mentioned background technology.

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

1. Chalcone: the synthesis of 4-dimethylaminochalcone comprises the following steps:

The synthesis of A, 2,4-dihydroxyacetophenone;

B. Synthesis of 4-dimethylaminochalcone: Dissolve 2,4-dihydroxyacetophenone (0.02mol) in 10ml of absolute ethanol, add 20ml of 10% NaOH under stirring, keep the reaction temperature <10°C, gradually Add (0.02mol) 20ml of absolute ethanol solution of p-dimethylaminobenzaldehyde dropwise, then raise the temperature to 25°C for reaction; Wash with absolute ethanol.

2. The synthesis of 4-hydroxychalcone comprises the following steps:

The synthesis of A, 2,4-dihydroxyacetophenone;

B. Synthesis of 4-hydroxychalcone: 2.4g (0.02mol) of 2,4-dihydroxyacetophenone was dissolved in 20ml of absolute ethanol, slowly added dropwise to 10% ice-cold NaOH solution, and then the same Add 10ml of 4-hydroxybenzaldehyde solution in absolute ethanol dropwise at a high speed, raise the temperature to 25°C and stir to react, let stand after the reaction is complete, filter with suction, and wash with ice-cold absolute ethanol at least twice.

3. Dihydrochalcone: the synthesis of 3-hydroxyl-4-methoxychalcone comprises the following steps:

The synthesis of A, 2,4-dihydroxyacetophenone;

B. Synthesis of 3-hydroxy-4-methoxychalcone: Dissolve 2,4-dihydroxyacetophenone (0.014mol) in 10ml of absolute ethanol, add 5ml of 10% NaOH under stirring, and keep the reaction temperature < 10°C, after fully stirring for about 20min, slowly add (0.014mol) vanillin 10ml absolute ethanol solution dropwise, then raise the temperature to 25°C for reaction, after the reaction is complete, filter with suction, the filter residue is light pink, use ice-cold anhydrous Hydro-ethanol washes at least twice.

4. Flavonoids: the synthesis of 3,4',6'-trihydroxy-4-methoxychalcone, comprising the following steps:

The synthesis of A, 2,4-dihydroxyacetophenone;

B. Synthesis of 3,4',6'-trihydroxy-4-methoxychalcone: Dissolve 2,4-dihydroxyacetophenone (0.014mol) in 25ml absolute ethanol, drop by drop 5ml 50% KOH, then add vanillin (0.014mol) in small amounts in batches, stir the reaction at 30°C, and detect the reaction is complete by TLC; pour the reactant into crushed ice, adjust the pH value to 2 with 1M HCl, Stand still, extract with CH2Cl2, combine the organic layers, wash with water, and evaporate the solvent by rotary evaporation.

As a further solution of the present invention: the synthesis method of 2,4-dihydroxyacetophenone is: after mixing anhydrous zinc chloride and acetic acid evenly, add 4 molecular sieves, slowly add (0.1mol) finely ground methane in batches in small amounts Hydroquinone was refluxed at 100°C for 5 hours. After the reactant was cooled to room temperature, it was poured into 120ml of crushed ice. The product crystallized, filtered with suction, and washed twice with ice water.

Application of the above-mentioned 3,4',6'-trihydroxy-4-methoxychalcone in the preparation of a drug for reducing postprandial hyperglycemia.

For the above-mentioned 4-dimethylaminochalcone, 4-hydroxychalcone, 3-hydroxy-4-methoxychalcone and 3,4',6'-trihydroxy-4-methoxychalcone Application in the preparation of drugs for treating diabetes and atherosclerosis.

Compared with the prior art, the beneficial effects of the present invention are: 3,4',6'-trihydroxy-4-methoxychalcone has a stronger inhibitory effect on a-glucosidase, and can be used to reduce postprandial Hyperglycemia; 4-dimethylaminochalcone, 4-hydroxychalcone, 3-hydroxy-4-methoxychalcone, and 3,4',6'-trihydroxy-4-methoxychalcone Ketones have obvious inhibitory effects on non-enzyme glycosylation, and can be used for the treatment of diabetes and atherosclerosis.

Description of drawings

Figure 1 is a chromatogram of the inhibitory effect of chalcones 1 to 4 on α-glucosidase.

Figure 2 is a chromatogram of the inhibitory effect of chalcones 1-4 on protein non-enzymatic glycosylation.

Detailed ways

The following will clearly and completely describe the technical solutions in the embodiments of the present invention with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only some, not all, embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by persons of ordinary skill in the art without making creative efforts belong to the protection scope of the present invention.

Embodiment one,

A. Synthesis of 2,4-dihydroxyacetophenone: Mix anhydrous zinc chloride and acetic acid evenly, add 4 molecular sieves, slowly add (0.1mol) finely ground resorcinol in batches, and heat at 100°C The reaction was carried out under reflux for 5 hours. After the reactant was cooled to room temperature, it was poured into 120 ml of crushed ice. The product crystallized, filtered with suction, and washed twice with ice water to obtain a crude product.

B. Synthesis of 4-dimethylaminochalcone 1: Dissolve 2,4-dihydroxyacetophenone (0.02mol) in 10ml of absolute ethanol, add 20ml of 10% NaOH under stirring, and keep the reaction temperature <10°C. Add (0.02mol) 20ml of absolute ethanol solution of p-dimethylaminobenzaldehyde dropwise, then raise the temperature to 25°C for reaction; after the reaction is complete, pour the reactant into ice water, orange precipitate appears, suction filter, and water and washed with absolute ethanol. Yield 76.3%, melting point 108-110°C. Spectral data: MS: m/z=252 (M+1, 100%). IR: 3433cm-1, 1614cm-1. 1HNMR: δ=3.04 (s, 6H, NMe2), 6.72 (d, 2H, H3, H5), 7.34 (d, 1H, Hα), 7.47 (d, 2H, H2 , H6), 7.54 (m, 3H, H3', H4', H5'), 7.79 (d, 1H, Hβ), 8.00 (d, 2H, H2', H6').

Embodiment two,

The synthesis of A, 2,4-dihydroxyacetophenone;

B. Synthesis of 4-hydroxychalcone 2: 2.4g (0.02mol) of 2,4-dihydroxyacetophenone was dissolved in 20ml of absolute ethanol, slowly added dropwise to 10% ice-cold NaOH solution, and then Add 2.4 g of 4-hydroxybenzaldehyde in 10 ml of absolute ethanol solution dropwise at the same speed, heat up to 25° C. and stir to react. After the reaction is complete, let it stand still, filter it with suction, and wash it with ice-cold absolute ethanol two to three times. The yield is 10%, and the melting point is 328°C. Spectral data: MS: m/z=121 (100%). IR: 3433cm-1, 1614cm-1. 1HNMR: δ=6.92 (d, 2H, H3, H5), 7.26 (m, 3H, H3', H4', H5'), 7.50 (d, 1H, Hα), 7.59 (d, 1H, Hβ), 7.98 (m, 2H, H2, H6), 8.20 (d, 2H, H2', H6'), 9.85 (s, 1H, OH).

Embodiment three,

The synthesis of A, 2,4-dihydroxyacetophenone;

B. Synthesis of 3-hydroxy-4-methoxychalcone 3: 1.68g (0.014mol) of 2,4-dihydroxyacetophenone was dissolved in 10ml of absolute ethanol, and 5ml of 10% NaOH was added under stirring to keep Reaction temperature <10°C. After fully stirring for about 20 minutes, slowly dropwise add 2.13g (0.014mol) of vanillin in 10ml of absolute ethanol solution, and then raise the temperature to 25°C for reaction. After the reaction is complete, filter with suction, the filter residue is light pink, and wash with ice-cold absolute ethanol two to three times. Yield 5.1%. Spectral data: MS: m/z=151 (100%). IR: 3433cm-1, 1659cm-1. 1H NMR: δ=3.74 (s, 3H, OCH3), 6.50~6.51 (m, 3H, ArH), 7.22 (d, 1H, CH), 7.30~7.40 (m, 4H, ArH), 9.27 (s, 1H, OH).

Embodiment four,

The synthesis of A, 2,4-dihydroxyacetophenone;

B. Synthesis of 3,4',6'-trihydroxy-4-methoxychalcone 4: Dissolve 2,4-dihydroxyacetophenone (0.014mol) in 25ml absolute ethanol, drop by drop Add 5ml of 50% KOH, then add vanillin (0.014mol) in small amounts in batches, stir the reaction at 30°C, and use TLC to detect that the reaction is complete; pour the reactant into crushed ice, and adjust the pH value to 2 with 1M HCl , stood still, extracted with CH2Cl2, combined the organic layers, washed with water, evaporated the solvent by rotary evaporation, and obtained 2.08 g of brown yellow solid powder, with a yield of 51.8%, and a melting point of 79-80°C. Spectral data: MS: m/z=151 (100%). IR: 3433cm-1, 1614cm-1. 1H NMR: δ=3.87 (s, 3H, OCH3), 6.44~6.95 (m, 3H, ArH), 7.43 (d, 1H, CH), 7.85 (m, 3H, ArH), 7.91 (d, 1H, CH), 12.70 (s, 1H, OH), 13.50 (s, 1H, OH).

Draw the chalcone compound solution (2mg/ml) and 50ul-glucosidase solution (3mg/5ml) respectively in the above-mentioned examples, dissolve them in 0.05M phosphate buffer solution with pH=7.28, and prepare them in JASCD J Tested on -810 circular dichroism spectrometer, scanning range (180-300nm). The scanning results are shown in Figures 1 and 2. The results show that 3,4',6'-trihydroxy-4-methoxychalcone has a strong inhibitory effect on a-glucosidase and can be used to reduce postprandial hyperglycemia; 4-Dimethylaminochalcone, 4-hydroxychalcone, 3-hydroxy-4-methoxychalcone and 3,4',6'-trihydroxy-4-methoxychalcone The inhibitory effect of enzyme glycosylation is relatively obvious, and can be used for the treatment of diabetes and atherosclerosis.

It will be apparent to those skilled in the art that the invention is not limited to the details of the above-described exemplary embodiments, but that the invention can be embodied in other specific forms without departing from the spirit or essential characteristics of the invention. Accordingly, the embodiments should be regarded in all points of view as exemplary and not restrictive, the scope of the invention being defined by the appended claims rather than the foregoing description, and it is therefore intended that the scope of the invention be defined by the appended claims rather than by the foregoing description. All changes within the meaning and range of equivalents of the elements are embraced in the present invention. Any reference sign in a claim should not be construed as limiting the claim concerned.

In addition, it should be understood that although this specification is described according to implementation modes, not each implementation mode only contains an independent technical solution, and this description in the specification is only for clarity, and those skilled in the art should take the specification as a whole , the technical solutions in the various embodiments can also be properly combined to form other implementations that can be understood by those skilled in the art.

Claims (10)

1. chalcone: the synthetic method of 4-dimethylaminochalcone is characterized in that: comprise the following steps: The synthesis of A, 2,4-dihydroxyacetophenone; B. Synthesis of 4-dimethylaminochalcone: Dissolve 2,4-dihydroxyacetophenone (0.02mol) in 10ml of absolute ethanol, add 20ml of 10% NaOH under stirring, keep the reaction temperature <10°C, gradually Add (0.02mol) 20ml of absolute ethanol solution of p-dimethylaminobenzaldehyde dropwise, then raise the temperature to 25°C for reaction; Wash with absolute ethanol. 2. chalcone: the synthetic method of 4-hydroxychalcone, is characterized in that: comprise the following steps: The synthesis of A, 2,4-dihydroxyacetophenone; B. Synthesis of 4-hydroxychalcone: 2.4g (0.02mol) of 2,4-dihydroxyacetophenone was dissolved in 20ml of absolute ethanol, slowly added dropwise to 10% ice-cold NaOH solution, and then the same Add 10ml of 4-hydroxybenzaldehyde solution in absolute ethanol dropwise at a high speed, raise the temperature to 25°C and stir to react, let stand after the reaction is complete, filter with suction, and wash with ice-cold absolute ethanol at least twice. 3. Dihydrochalcone: the synthetic method of 3-hydroxyl-4-methoxychalcone, is characterized in that: comprise the following steps: The synthesis of A, 2,4-dihydroxyacetophenone; B. Synthesis of 3-hydroxy-4-methoxychalcone: Dissolve 2,4-dihydroxyacetophenone (0.014mol) in 10ml of absolute ethanol, add 5ml of 10% NaOH under stirring, and keep the reaction temperature < 10°C, after fully stirring for about 20min, slowly add (0.014mol) vanillin 10ml absolute ethanol solution dropwise, then raise the temperature to 25°C for reaction, after the reaction is complete, filter with suction, the filter residue is light pink, use ice-cold anhydrous Hydro-ethanol washes at least twice. 4. Flavonoids: 3,4 ', the synthetic method of 6'-trihydroxy-4-methoxychalcone, is characterized in that: comprise the following steps: The synthesis of A, 2,4-dihydroxyacetophenone; B. Synthesis of 3,4',6'-trihydroxy-4-methoxychalcone: Dissolve 2,4-dihydroxyacetophenone (0.014mol) in 25ml absolute ethanol, drop by drop 5ml 50% KOH, then add vanillin (0.014mol) in small amounts in batches, stir the reaction at 30°C, and detect the reaction is complete by TLC; pour the reactant into crushed ice, adjust the pH value to 2 with 1M HCl, Stand still, extract with CH2Cl2, combine the organic layers, wash with water, and evaporate the solvent by rotary evaporation. 5. according to the arbitrary described synthetic method of claim 1-4, it is characterized in that: the synthetic method of 2,4-dihydroxyacetophenone is: add 4 molecular sieves after anhydrous zinc chloride and acetic acid are mixed, Slowly add (0.1mol) finely ground resorcinol in small amounts in batches, and reflux at 100°C for 5 hours. After the reactant is cooled to room temperature, pour it into 120ml of crushed ice. The product crystallizes out. Suction filter and wash with ice water twice. 6. the synthetic method as claimed in claim 4 3,4', the application of 6'-trihydroxyl-4-methoxychalcone for the preparation of medicines for reducing postprandial hyperglycemia. 7. The application of the 4-dimethylaminochalcone synthesized by the synthetic method as claimed in claim 1 in the preparation of medicines for treating diabetes and atherosclerosis. 8. The application of the 4-hydroxychalcone synthesized by the synthetic method as claimed in claim 2 in the preparation of medicines for treating diabetes and atherosclerosis. 9. The application of the 3-hydroxyl-4-methoxychalcone synthesized by the synthetic method as claimed in claim 3 in the preparation of medicines for treating diabetes and atherosclerosis. 10. The synthesis method as claimed in claim 4 and 3,4',6'-trihydroxyl-4-methoxychalcone are used for the preparation of the application of the medicine for treating diabetes and atherosclerosis.