A preparation method of new eriocin

Abstract

The present invention relates to a method for preparing a new eriocin. The method solves the technical problems of the existing method for preparing new eriocin, such as low yield, complicated operation, long time consumption, and being unfavorable for industrial production. The method for preparing a new eriocin of the present invention comprises the following steps: 1) uniformly mixing neohesperidin with an alkaline solution in proportion, heating and performing a hydrolysis and ring-opening reaction, and cooling to room temperature after the reaction is completed; adjusting the pH to neutral, cooling, filtering, and drying in sequence to obtain an intermediate; 2) mixing the intermediate with protocatechuic aldehyde in proportion, dissolving in an organic solvent, adding aniline catalyst, heating and performing a condensation reaction under nitrogen protection, reacting until the intermediate content is less than 0.5%, and stopping the reaction; 3) recovering the solvent under reduced pressure until the solvent is near zero, washing and filtering to obtain a crude new eriocin; and 4) refining with ethanol to obtain a refined new eriocin. The method of the present invention can quickly and efficiently prepare a high-purity refined new eriocin.

Description

Technical Field

[0001] The present invention relates to a preparation method of new eriocin. Background Art

[0002] Eriocitrin, a key component of the traditional Chinese medicine (Gou Citrus aurantium), is a flavonoid compound also known as eriocitrin or eriocitrin. Studies have shown that eriocitrin exhibits a wide range of pharmacological activities, including anti-tumor, anti-viral, anti-free radical, vascular relaxant, and antioxidant properties. According to relevant literature, the main active ingredients in the Chinese medicinal herb Drynaria Rhizome are naringin and eriocitrin, with the following structure:

[0003]

[0004] Existing literature rarely describes methods for preparing eriocin. Some literature reports extracting eriocin from Rhizoma Drynariae using ethanol as a solvent, followed by purification by column chromatography and other methods to obtain a small amount of product. This method is cumbersome, has a low yield, and is time-consuming. Another method for extracting eriocin from plants is limited by the low effective content and complex composition of the plant raw materials, resulting in small preparation quantities, low yields, and low purity, making it difficult to manufacture industrially. Therefore, developing a new method for preparing eriocin is of great significance. Summary of the Invention

[0005] The purpose of the present invention is to solve the technical problems of the existing preparation method of new eriocin, such as low purity, low yield, complicated operation, long time consumption, and being unfavorable for industrial production, and to provide a preparation method of new eriocin.

[0006] The preparation method of a new eriocin of the present invention is to use neohesperidin as a starting material, to carry out ring opening and hydrolysis in an alkaline solvent to obtain an intermediate, and then to carry out a condensation reaction of the intermediate with protocatechuic aldehyde. The synthesis route is as follows:

[0007]

[0008] The technical solution of the present invention is:

[0009] A method for preparing a new eriocin is characterized in that it comprises the following steps:

[0010] 1) uniformly mixing neohesperidin and an alkaline solution in a certain proportion, heating to 70-120° C., performing a hydrolysis ring-opening reaction, stopping the reaction after 3-8 hours, and cooling to room temperature; adjusting the pH to neutral, cooling, filtering, and drying in sequence to obtain an intermediate;

[0011] 2) mixing the intermediate and protocatechuic aldehyde in a proportion, dissolving them in an organic solvent, then adding aniline catalyst, and heating to 50° C. to 100° C. under nitrogen protection to carry out a condensation reaction. Sampling and testing are performed during the reaction. The reaction is stopped when the content of the intermediate is less than 0.5%, thereby obtaining a reaction mixture;

[0012] 3) the reaction mixture was decompressed to recover the solvent until dry, and the mixture was washed with water and filtered to obtain a crude product of eriocin;

[0013] 4) The crude product of the new eriocin is purified by using ethanol to obtain the refined product of the new eriocin.

[0014] Furthermore, in step 1), the alkaline solution is a sodium hydroxide solution or a potassium hydroxide solution, and the concentration of the alkaline solution is 7% to 15%.

[0015] Furthermore, in step 1), the mass ratio of neohesperidin to alkaline solution is 1:10-15.

[0016] Furthermore, in step 2), the organic solvent is DMF.

[0017] Furthermore, in step 2), the material ratio of the condensation reaction is: the mass ratio of protocatechuic aldehyde to the intermediate is 1-1.5:3.3, the amount of aniline is 5% of the mass of protocatechuic aldehyde, and the amount of DMF is 3-8 times the mass of the intermediate.

[0018] Furthermore, in step 2), the amount of DMF is 3 to 5 times the mass of the intermediate; the temperature is raised to 60° C. to 80° C.;

[0019] In step 1), between cooling and filtering, the step of adding 2 times the amount of 50% ethanol and beating for 2 hours is also included.

[0020] Furthermore, in step 2), the content of the intermediate in the condensation reaction is monitored by high performance liquid chromatography.

[0021] Furthermore, step 1) is specifically as follows: neohesperidin is mixed uniformly with a 12% sodium hydroxide solution in a mass ratio of 1:10, the mixture is heated to 100° C. for hydrolysis and ring-opening reaction, the reaction is stopped after 4 hours, and the mixture is cooled to room temperature; hydrochloric acid is added to adjust the pH to neutral, the solid is cooled to obtain a solid, 50% ethanol is added twice as much as the solid, and the solid is beaten for 2 hours, filtered, and dried to obtain an intermediate;

[0022] Step 2) is specifically as follows: the intermediate and protocatechuic aldehyde are mixed in a mass ratio of 1:3.3, dissolved in DMF (4 times the mass of the intermediate), and then aniline catalyst (5% by mass of protocatechuic aldehyde) is added. Under nitrogen protection, the temperature is raised to 60° C. to carry out condensation reaction, and sampling is performed to stop the reaction when the raw material is less than 0.5%.

[0023] Beneficial effects of the present invention:

[0024] 1. The present invention provides a method for preparing neoerioctoside, which uses neohesperidin and protocatechuic aldehyde as raw materials and is prepared by aniline as a catalyst. The method has low raw material cost, simple process, high product purity, and is suitable for large-scale industrial production. The crude neoerioctoside obtained can be purified to obtain a pure product with a content of more than 98%.

[0025] 2. The preparation method of a new eriocin of the present invention uses a sodium hydroxide solution or a potassium hydroxide solution with a concentration of 7%-15%, which has rapid hydrolysis, a short reaction cycle, and cheap and readily available raw materials.

[0026] 3. In the preparation method of a new eriocin of the present invention, adding 2 times the amount of 50% ethanol for pulping between cooling and filtration can better remove impurities and make the subsequent reaction more rapid and complete. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 The present invention is a liquid chromatogram of a method for preparing a new eriocin in accordance with the present invention. DETAILED DESCRIPTION

[0028] The present invention will be described in detail below with reference to the accompanying drawings and examples.

[0029] Example 1

[0030] In a clean 1000ml reaction flask, add neohesperidin and an alkaline solution at a mass ratio of 1:10-15. In this example, 50g of neohesperidin and 500g of a 12% sodium hydroxide solution were added. The temperature was raised to 70-120°C for hydrolysis and ring-opening. The reaction was stopped after 3-8 hours. In this example, the temperature was raised to 100°C. After 4 hours, the reaction was stopped, the temperature was cooled to room temperature, and hydrochloric acid was added to adjust the pH to neutral. The solid was cooled to a khaki color. The solid was slurried with twice the amount of 50% ethanol for 2 hours, filtered, and dried to obtain 21.3g of the intermediate, a pale yellow solid.

[0031] In a clean 500ml reaction flask, add protocatechuic aldehyde and the intermediate in a mass ratio of 1-1.5:3.3. In this example, 21.3g of the intermediate and 6.4g of protocatechuic aldehyde are added, along with an organic solvent 3-8 times the mass of the intermediate. In this example, 85g of DMF is added and stirred to dissolve. Aniline (5% by mass of protocatechuic aldehyde) is then added. In this example, 0.3g of aniline is added, and nitrogen is introduced. The condensation reaction is carried out at a temperature of 50-100°C. High-performance liquid chromatography (HPLC) sampling and monitoring are performed throughout the reaction. The reaction is stopped when the intermediate content is less than 0.5%. In this example, the reaction is started at 60°C. After 6 hours, sampling is performed and the raw material content is less than 0.5%, stopping the reaction to obtain a reaction mixture. The reaction mixture is decompressed and the solvent is recovered until near dryness. 200ml of water is added, the temperature is raised to 60°C, and the mixture is stirred for 1 hour. Filter while hot to obtain 33.4g of crude product. The crude product of new eriocin was purified by ethanol to obtain 24.9 g of new eriocin with a content greater than 98.0%. The liquid chromatogram is as follows: Figure 1 shown.

[0032] Example 2

[0033] In a clean 2000ml reaction flask, add 50g of neohesperidin and 750g of 8% sodium hydroxide solution. Heat to 70°C and react. After 3 hours, cool to room temperature, adjust the pH to neutral with hydrochloric acid, and cool to obtain a khaki solid. Add twice the amount of 50% ethanol and slurry for 2 hours. Filter and dry to obtain 23.2g of a light yellow solid.

[0034] In a clean 500ml reaction flask, add 23.2g of the intermediate, 10.5g of protocatechuic aldehyde, and 185g of DMF. Stir and dissolve. Add 0.53g of aniline and purge with nitrogen. Heat to 60°C to initiate the reaction. Samples are taken during the reaction. After 2 hours, if the starting material concentration is less than 0.5%, the reaction is stopped to obtain a reaction mixture. The reaction mixture is decompressed and the solvent is recovered to near dryness. Add 250ml of water, heat to 60°C, stir for 1 hour, and filter while hot to obtain 29.2g of crude product. The crude erythroposide is purified with ethanol to obtain 23.9g of erythroposide with a content greater than 98.0%.

[0035] Example 3

[0036] In a clean 2000ml reaction flask, add 50g of neohesperidin and 600g of 7% sodium hydroxide solution. Heat to 100°C and allow to react. After 8 hours, cool to room temperature, adjust the pH to neutral with hydrochloric acid, and cool to obtain a khaki solid. Add twice the amount of 50% ethanol and slurry for 2 hours. Filter and dry to obtain 20.2g of a light yellow solid.

[0037] In a clean 500ml reaction flask, add 20.2g of the intermediate, 7.3g of protocatechuic aldehyde, and 61g of DMF. Stir and dissolve. Add 0.4g of aniline and purge with nitrogen. Heat to 80°C to initiate the reaction. Samples are taken during the reaction. After 4 hours, if the starting material concentration is less than 0.1%, the reaction is stopped to obtain a reaction mixture. The reaction mixture is decompressed and the solvent is recovered to near dryness. Add 250ml of water, heat to 60°C, stir for 1 hour, and filter while hot to obtain 32.2g of crude product. The crude erythroposide is purified with ethanol to obtain 22.7g of erythroposide with a content greater than 98.0%.

[0038] Example 4

[0039] In a clean 2000ml reaction flask, add 80g of neohesperidin and 800g of 15% sodium hydroxide solution. Heat to 120°C and react. After 6 hours, cool to room temperature, adjust the pH to neutral with hydrochloric acid, and cool to obtain a khaki solid. Add twice the amount of 50% ethanol and slurry for 2 hours. Filter and dry to obtain 35.8g of a light yellow solid.

[0040] In a clean 500ml reaction flask, add 35.8g of the intermediate, 13.0g of protocatechuic aldehyde, and 215g of DMF. Stir and dissolve. Add 0.7g of aniline and purge with nitrogen. Heat to 70°C to initiate the reaction. Samples are taken during the reaction. After 4 hours, if the raw material concentration is less than 0.1%, the reaction is stopped to obtain a reaction mixture. The reaction mixture is decompressed and the solvent is recovered to near dryness. Add 350ml of water, heat to 60°C, stir for 1 hour, and filter while hot to obtain 56.4g of crude product. The crude erythroposide is purified with ethanol to obtain 34.9g of erythroposide with a content greater than 98.0%.

[0041] Example 5

[0042] In a clean 2000ml reaction flask, add 80g of neohesperidin and 800g of 15% sodium hydroxide solution. Heat to 105°C and react. After 3 hours, cool to room temperature. Add hydrochloric acid to adjust the pH to neutral. Cool to obtain a khaki solid. Add twice the amount of 50% ethanol and slurry for 2 hours. Filter and dry to obtain 34.5g of a light yellow solid.

[0043] In a clean 500ml reaction flask, add 34.5g of the intermediate, 13.6g of protocatechuic aldehyde, and 270g of DMF. Stir and dissolve. Add 0.7g of aniline and purge with nitrogen. Heat to 60°C to initiate the reaction. Samples are taken during the reaction. After 5 hours, if the starting material concentration is less than 0.1%, the reaction is stopped to obtain a reaction mixture. The reaction mixture is decompressed and the solvent is recovered to near dryness. Add 350ml of water, heat to 60°C, stir for 1 hour, and filter while hot to obtain 48.7g of crude product. The crude product is purified with ethanol to obtain 35.1g of new eriocin with a content greater than 98.0%.

[0044] Example 6

[0045] In a clean 2000ml reaction flask, add 120g of neohesperidin and 1500g of 10% sodium hydroxide solution. Heat to 105°C and react. After 3.5 hours, cool to room temperature, adjust the pH to neutral with hydrochloric acid, and cool to obtain a khaki solid. Add twice the amount of 50% ethanol and slurry for 2 hours. Filter and dry to obtain 49.6g of a light yellow solid.

[0046] In a clean 500ml reaction flask, add 49.6g of the intermediate, 16.3g of protocatechuic aldehyde, and 250g of DMF. Stir and dissolve. Add 0.8g of aniline and introduce nitrogen. Heat to 50°C to initiate the reaction. Samples are taken during the reaction. After 8 hours, if the raw material concentration is less than 0.1%, the reaction is stopped to obtain a reaction mixture. The reaction mixture is decompressed and the solvent is recovered to near dryness. Add 500ml of water, heat to 60°C, stir for 1 hour, and filter while hot to obtain 63.7g of crude product. The crude erythroposide is purified with ethanol to obtain 43.2g of erythroposide with a content greater than 98.0%.

[0047] Example 7

[0048] In a clean 2000ml reaction flask, add 120g of neohesperidin and 1200g of 10% sodium hydroxide solution. Heat to 105°C and react. After 4 hours, cool to room temperature. Add hydrochloric acid to adjust the pH to neutral. Cool to obtain a khaki solid. Add twice the amount of 50% ethanol and slurry for 2 hours. Filter and dry to obtain 48.7g of a light yellow solid.

[0049] In a clean 500ml reaction flask, add 48.7g of the intermediate, 15.6g of protocatechuic aldehyde, and 250g of DMF. Stir and dissolve. Add 0.8g of aniline and introduce nitrogen. Heat to 100°C to initiate the reaction. Samples are taken during the reaction. After 2 hours, if the raw material concentration is less than 0.1%, the reaction is stopped to obtain a reaction mixture. The reaction mixture is decompressed and the solvent is recovered until near dryness. Add 500ml of water, heat to 60°C, stir for 1 hour, and filter while hot to obtain 52.3g of crude product. The crude erythroposide is purified with ethanol to obtain 38.4g of erythroposide with a content greater than 98.0%.

[0050] The liquid chromatograms of Examples 2 to 7 are the same as those in Example 1. Figure 1 near.

[0051] The conditions for liquid phase detection in the above embodiment are: chromatographic column: Luna C18, 4.6 mm × 250 mm, 5 μm; mobile phase: water: methanol = 50:50; column temperature: 25°C; flow rate: 1.0 mL / min; detection wavelength: 254 nm.

Claims

1. A method for preparing a new eriocin, characterized in that: The following steps are involved: 1) Neohesperidin was mixed with a 12% sodium hydroxide solution at a mass ratio of 1:10, heated to 100°C for hydrolysis and ring-opening reaction, and the reaction was stopped after 4 hours. The mixture was cooled to room temperature. Hydrochloric acid was added to adjust the pH to neutral, and the solid was cooled to obtain a solid. 50% ethanol was added twice as much and the mixture was beaten for 2 hours. The solid was filtered and dried to obtain an intermediate. 2) The intermediate and protocatechuic aldehyde were mixed in a mass ratio of 1:3.3 and dissolved in DMF (4 times the mass of the intermediate). Aniline catalyst (5% by mass of protocatechuic aldehyde) was then added. Under nitrogen protection, the temperature was raised to 60°C for condensation reaction. Sampling was performed until the amount of the starting material was less than 0.5%, and the reaction was stopped to obtain a reaction mixture. 3) The reaction mixture was decompressed to recover the solvent until dryness, and then washed with water and filtered to obtain a crude product of Eriobotrya japonica; 4) The crude product of the new eriocin is purified by using ethanol to obtain the refined product of the new eriocin.

2. The method for preparing a new eriocin according to claim 1, wherein: In step 2), the content of the intermediate in the condensation reaction is monitored by high performance liquid chromatography.

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