A chemical synthesis method of 3',5-dimethyl hesperidin chalcone as a methyl hesperidin impurity

Abstract

This invention discloses a chemical synthesis method for the methyl hesperidin impurity 3',5-dimethylhesperidin chalcone, belonging to the field of chemical synthesis technology. The method includes preparing 3',5-dimethylhesperidin chalcone by carrying out a ring-opening reaction under alkaline conditions. After synthesizing the methyl hesperidin impurity 3',5-dimethylhesperidin chalcone, the method of this invention only requires simple extraction, concentration, crystallization, filtration and drying to obtain the high-purity target product.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis technology, specifically to a method for the chemical synthesis of 3',5-dimethylhesperidin chalcone, an impurity of methylhesperidin. Background Technology

[0002] Methyl hesperidin is a water-soluble mixture of various dihydroflavonoid-type methyl hesperidins. It possesses vitamin P-like efficacy, enhances the effects of vitamin C, and has strong antiviral and antibacterial properties; high doses can inhibit the replication of influenza viruses. It can inhibit the action of tyrosinase, which causes skin darkening, and can be used to treat skin diseases such as dark spots and freckles. It maintains normal vascular permeability, improves capillary resistance, enhances capillary elasticity and resilience, and prevents and treats capillary bleeding, gingival bleeding, etc. It has the same pharmacological effects as hesperidin, strengthening capillary resistance, normalizing capillary permeability, and preventing vascular disorders caused by arteriosclerosis; its efficacy is enhanced when used in combination with vitamin C. It can be used for nosebleeds, retinal hemorrhage, gingival bleeding, alveolar bleeding, gastrointestinal bleeding, hemorrhoidal bleeding, and the prevention and treatment of bleeding before or after surgery. Clinically, it mainly plays a preventive, adjunctive, or therapeutic role in vascular diseases caused by hypertension and arteriosclerosis. Methyl hesperidin is used as a raw material in many chemical pharmaceutical preparations in China, such as compound three-dimensional linoleic acid capsules, methyl hesperidin vitamin C chewable tablets, and vitamin C hesperidin granules.

[0003] Methyl hesperidin is produced from hesperidin as a starting material through an alkylation reaction. Methyl hesperidin is a multi-component dihydroflavonoid mixture with 3'-methylhesperidin and 3',5-dimethylhesperidin as the main components, and containing small amounts of lemon balm glycoside and 5-methyl lemon balm glycoside. Currently, the impurity 3',5-dimethylhesperidin chalcone is a process impurity introduced by the ring-opening of the main component 3',5-dimethylhesperidin under alkaline conditions, and therefore must be controlled. The structural formula of the impurity is shown below:

[0004] However, there is currently no reported method for the chemical synthesis of 3',5-dimethylhesperidin chalcone, an impurity of methylhesperidin. Summary of the Invention

[0005] In view of the shortcomings of the prior art described above, the purpose of this invention is to provide a chemical synthesis method for the methyl hesperidin impurity 3',5-dimethylhesperidin chalcone, in order to solve the technical problem that the lack of a chemical synthesis method for the 3',5-dimethylhesperidin chalcone impurity in the prior art leads to the inability to obtain a high-purity impurity reference standard for the quality control of methyl hesperidin.

[0006] This invention provides a chemical synthesis method for the methyl hesperidin impurity 3',5-dimethylhesperidin chalcone, the method comprising preparing 3',5-dimethylhesperidin chalcone by ring-opening reaction under alkaline conditions.

[0007] In one embodiment, the base is sodium hydroxide.

[0008] In one embodiment, the sodium hydroxide is added in the form of an aqueous solution with a concentration of 0.8-1.2 mol / L.

[0009] In one embodiment, the molar ratio of 3',5-dimethylhesperidin to sodium hydroxide is 1:(30-80).

[0010] In one embodiment, the reaction temperature is 20-25°C and the reaction time is 10-15 hours.

[0011] In one embodiment, the process further includes a separation and purification step: adjusting the pH of the reaction solution to 6-8, extracting and concentrating to obtain a crude product, and then crystallizing, filtering and drying to obtain the target product.

[0012] In one embodiment, the extractant used in the extraction is n-butanol.

[0013] In one embodiment, the crystallization is performed by pulping with methanol for 12-14 hours.

[0014] In one embodiment, the drying is vacuum drying, the drying temperature is 50-60°C, and the drying time is 8-10 hours.

[0015] In one embodiment, the HPLC purity of 3',5-dimethylhesperidin chalcone prepared by the method is ≥99.94%.

[0016] This invention provides a chemical synthesis method for the methyl hesperidin impurity 3',5-dimethylhesperidin chalcone, which has the following advantages: The preparation method of the methyl hesperidin impurity 3',5-dimethylhesperidin chalcone of this invention is simple to operate, uses readily available raw materials, has a high yield, and is easy to purify. The prepared impurity can then be used as an impurity standard in the detection and analysis of the methyl hesperidin product, for the quality control of methyl hesperidin, and for the qualitative and quantitative control of 3',5-dimethylhesperidin chalcone. After synthesizing the methyl hesperidin impurity 3',5-dimethylhesperidin chalcone, the preparation method of this invention only requires simple extraction, concentration, crystallization, filtration, and drying to obtain the high-purity target product. Attached Figure Description

[0017] Figure 1The high-performance liquid chromatogram of 3',5-dimethylhesperidin chalcone prepared in Example 1.

[0018] Figure 2 The high-resolution mass spectrum of 3',5-dimethylhesperidin chalcone prepared in Example 1 is shown.

[0019] Figure 3 The infrared spectrum of 3',5-dimethylhesperidin chalcone prepared in Example 1.

[0020] Figure 4 The NMR spectrum of 3',5-dimethylhesperidin chalcone prepared in Example 1 is shown.

[0021] Figure 5 The NMR carbon spectrum of 3',5-dimethylhesperidin chalcone prepared in Example 1. Detailed Implementation

[0022] Reaction formula:

[0023] Example 1 At room temperature, 1 g of 3',5-dimethylhesperidin was added to 60 ml of 1 N sodium hydroxide aqueous solution, and the mixture was stirred for 15 h. The pH of the reaction solution was adjusted to 6-8 with 1 N HCl, and after standing for 5 h, 200 ml of MeOH was added to the crude product obtained by extraction and concentration with n-butanol. The mixture was stirred at room temperature for 12 h, filtered under reduced pressure, and dried under vacuum at 60 °C for 8 h to obtain 265 mg of 3',5-dimethylhesperidin chalcone.

[0024] The structure of 3',5-dimethylhesperidin chalcone prepared in Example 1 was confirmed by high performance liquid chromatography, mass spectrometry, infrared spectroscopy, NMR 1H spectrum and NMR 1C spectrum.

[0025] The NMR 1H and NMR 1C spectra were performed using DMSO-d6 as the solvent; the mass spectrometry detection was performed using DMSO as the solvent and ESI was used as the excitation method; the detailed method for high-performance liquid chromatography detection is as follows: The determination was performed according to the high performance liquid chromatography method (General Chapter 0512, Part IV, Chinese Pharmacopoeia 2020 Edition).

[0026] Preparation of test solution: Accurately weigh an appropriate amount of 3',5-dimethylhesperidin chalcone, dissolve and dilute it with DMSO to prepare a solution containing approximately 2.0 mg per ml, to be tested.

[0027] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the packing material (Agilent Zorbax Eclipse XDB-C18 column, 150×4.6mm, 5µm or equivalent column); methanol-glacial acetic acid aqueous solution (4:57, v / v) = 39:61 was used as the mobile phase; the flow rate was 1.0 mL / min; the detection wavelength was 283 nm; the column temperature was 35 °C; and the injection volume was 5 μL.

[0028] The purity was determined to be 99.94% by HPLC.

[0029] Example 2 At room temperature, 1 g of 3',5-dimethylhesperidin was added to 120 ml of 1 N sodium hydroxide aqueous solution, and the mixture was stirred for 12 h. The pH of the reaction solution was adjusted to 6-8 with 1 N HCl, and after standing for 5 h, 180 ml of MeOH was added to the crude product obtained by extraction and concentration with n-butanol. The mixture was stirred at room temperature for 14 h, filtered under reduced pressure, and dried under vacuum at 50 °C for 10 h to obtain 235 mg of 3',5-dimethylhesperidin chalcone. The purity of the 3',5-dimethylhesperidin chalcone obtained in Example 2 was comparable to that in Example 1.

[0030] The above embodiments are merely illustrative of the principles and effects of the present invention and are not intended to limit the invention. When numerical ranges are given in the embodiments, it should be understood that, unless otherwise stated in the present invention, both endpoints of each numerical range and any value between the two endpoints may be selected. Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those skilled in the art. In addition to the specific methods, devices, and materials used in the embodiments, based on the knowledge of those skilled in the art and the description of the present invention, any prior art methods, devices, and materials similar to or equivalent to those described, used, and materials in the embodiments of the present invention can be used to implement the present invention. Any person skilled in the art can modify or change the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or changes made by those skilled in the art without departing from the spirit and technical concept disclosed in the present invention should still be covered by the claims of the present invention.

Claims

1. A chemical synthesis method for the methyl hesperidin impurity 3',5-dimethylhesperidin chalcone, characterized in that: The method includes preparing 3',5-dimethylhesperidin chalcone by ring-opening reaction under alkaline conditions.

2. The method according to claim 1, characterized in that: The alkali is sodium hydroxide.

3. The method according to claim 2, characterized in that: The sodium hydroxide is added in the form of an aqueous solution, the concentration of which is 0.8-1.2 mol / L.

4. The method according to claim 3, characterized in that: The molar ratio of 3',5-dimethylhesperidin to sodium hydroxide is 1:(30-80).

5. The method according to claim 1, characterized in that: The reaction temperature is 20-25℃, and the reaction time is 10-15 hours.

6. The method according to claim 1, characterized in that, It also includes separation and purification steps: the pH of the reaction solution is adjusted to 6-8, and the crude product is obtained by extraction and concentration, followed by crystallization, filtration and drying to obtain the target product.

7. The method according to claim 6, characterized in that: The extraction process uses n-butanol as the extractant.

8. The method according to claim 6, characterized in that: The crystallization process involves pulping with methanol for 12-14 hours.

9. The method according to claim 6, characterized in that: The drying process is vacuum drying, with a drying temperature of 50-60℃ and a drying time of 8-10 hours.

10. The method according to claim 1, characterized in that: The HPLC purity of 3',5-dimethylhesperidin chalcone prepared by the method is ≥99.94%.

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