Preparation method of neohesperidin intermediate

Abstract

According to the preparation method of the neohesperidin intermediate, dimethyl sulfoxide and methanol are mixed to serve as a reaction solvent, powdery potassium hydroxide dissolved in dimethyl sulfoxide serves as a basic catalyst, naringin is completely dissolved in the dimethyl sulfoxide solvent for hydrolysis, and the neohesperidin intermediate, namely, phloem acetylbenzene-4 '-neohesperidoside, is obtained. According to the preparation method of the neohesperidin intermediate disclosed by the invention, almost no side reaction is generated during hydrolysis reaction, and a target product with high yield and high purity is finally obtained. Compared with the prior art, the technical operation is simple, the cost is low, the product quality is good, the yield is high, and industrial production is easy.

Description

Technical Field

[0001] The present invention relates to a preparation method of neohesperidin intermediate, and particularly to a preparation method of neohesperidin intermediate p-hydroxyacetophenone-4'-neohesperidoside. Background Art

[0002] Neohesperidin, with the English name Hesperidin and the cas number 13241-33-3, is a dihydroflavonoid compound and usually exists in Rutaceae and Rubiaceae plants together with naringin and hesperidin. The most important use of neohesperidin in the pharmaceutical field is in gastrointestinal drugs, which has the effects of resolving phlegm and eliminating indigestion, breaking qi and relieving fullness, etc. In addition, neohesperidin is also the main raw material for the industrial synthesis of the sweetener dihydrochalcone. The structure of neohesperidin is as follows:

[0003]

[0004] Currently, the industrialized preparation methods of neohesperidin include two methods: plant extraction and semi-synthesis from naringin. Among them, the semi-synthesis method using naringin as the raw material is the main preparation method. P-hydroxyacetophenone-4'-neohesperidoside is the key intermediate for the preparation of neohesperidin from naringin. The structural formula of the intermediate p-hydroxyacetophenone-4'-neohesperidoside is as follows:

[0005]

[0006] The existing preparation process is that naringin is ring-opened and hydrolyzed in an alkaline solution to generate p-hydroxyacetophenone-4'-neohesperidoside, and then p-hydroxyacetophenone-4'-neohesperidoside reacts with isovanillin to generate neohesperidin. The key to this process lies in the step of preparing p-hydroxyacetophenone-4'-neohesperidoside from naringin. Chinese Patent CN201710585715 discloses the preparation of p-hydroxyacetophenone-4'-neohesperidoside using sodium alkoxide as the alkaline catalyst in an alcohol solution. However, the existing technology usually requires a relatively high reaction temperature, uses a large amount of alkaline solution, generates a large amount of reaction wastewater, and the yield is generally not high, usually 60-70%. Therefore, it is very meaningful to develop a new process for preparing p-hydroxyacetophenone-4'-neohesperidoside from naringin. Summary of the Invention

[0007] The purpose of the present invention is to solve the technical problems of high temperature, large amount of alkali used, a large amount of wastewater, and low yield in the existing preparation methods, and to provide a preparation method of neohesperidin intermediate. Using naringin as the main raw material, and using dimethyl sulfoxide, methanol, and potassium hydroxide as auxiliary materials to prepare p-hydroxyacetophenone-4'-neohesperidoside, the operation is simple, the cost is low, the product quality is good, the yield is high, and it is easy to industrialize.

[0008] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0009] A preparation method of neohesperidin intermediate, which is characterized in that:

[0010] Dimethyl sulfoxide and methanol are mixed to obtain a dimethyl sulfoxide solvent, and potassium hydroxide dissolved in the dimethyl sulfoxide solvent is used as a basic catalyst. Naringin is completely dissolved in the dimethyl sulfoxide solvent for hydrolysis reaction, and then purification treatment is carried out to obtain the neohesperidin intermediate, namely phloretin acetylbenzene-4'-neohesperidoside.

[0011] Further, in step 1, naringin, methanol and dimethyl sulfoxide are added to a reaction kettle, stirred evenly, heated to 28°C to 32°C, potassium hydroxide is added, and the temperature is continued to be raised to 40°C to 60°C for hydrolysis reaction; in the liquid phase, the content of naringin is controlled to be less than 0.5%, and the reaction is ended; the methanol is a methanol solution with a mass concentration greater than 80%;

[0012] In step 2, the temperature is lowered to room temperature, and the pH of the solution is adjusted to 5 to 6;

[0013] In step 3, after slowly adding purified water, heating under reflux is carried out. When white needle-like solids begin to precipitate, the temperature is slowly lowered to 0°C to 5°C for heat preservation;

[0014] In step 4, filtration and washing with ice water are carried out, and drying is carried out to obtain the neohesperidin intermediate phloretin acetylbenzene-4'-neohesperidoside.

[0015] Further, in step 1, the mass ratio of methanol to dimethyl sulfoxide is 1:2.5 to 1:3.

[0016] Further, in step 1, the mass ratio of methanol to naringin is 1:1.4 to 1:2.67.

[0017] Further, in step 1, the mass ratio of potassium hydroxide to naringin is 0.08:1 to 0.12:1.

[0018] Further, in step 3, the mass ratio of purified water to naringin is 0.5:1 to 0.8:1.

[0019] Further, in step 1, the addition of potassium hydroxide is completed in 4 to 6 times, and the interval time between each addition is 30 min.

[0020] Further, in step 2, glacial acetic acid is used to adjust the pH value of the solution.

[0021] Further, in step 1, the methanol is an 80%-90% methanol solution.

[0022] Further, the potassium hydroxide is powdered potassium hydroxide.

[0023] Compared with the prior art, the beneficial technical effects of the present invention are as follows:

[0024] 1. The preparation method of the neohesperidin intermediate of the present invention utilizes the super strong alkalinity shown by potassium hydroxide dissolved in dimethyl sulfoxide as the reaction solvent, and the characteristic that naringin can be completely dissolved in a low multiple of dimethyl sulfoxide solvent at a relatively low temperature. Dimethyl sulfoxide and methanol are used as the mixed reaction solvent, and potassium hydroxide is used as the alkaline catalyst to carry out the hydrolysis of naringin to prepare the neohesperidin intermediate, that is, phloretin-4'-neohesperidoside.

[0025] 2. The preparation method of the neohesperidin intermediate of the present invention shows that according to the liquid phase control display, almost no side reactions occur during the hydrolysis reaction, and finally the target product with high yield and high purity is obtained. The technical operation is simple, the cost is low, the product quality is good, the yield is high, and it is easy to industrialize.

[0026] 3. The preparation method of the neohesperidin intermediate of the present invention uses less alkali and produces less wastewater, which not only reduces the production cost but also is environmentally friendly. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 is the liquid chromatogram of naringin in the example of the preparation method of a neohesperidin intermediate of the present invention;

[0028] Figure 2 is the liquid chromatogram of the reaction solution in the first example of the preparation method of a neohesperidin intermediate of the present invention;

[0029] Figure 3 is the liquid chromatogram of the neohesperidin intermediate in the first example of the preparation method of a neohesperidin intermediate of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0030] Example 1

[0031] In a 500-liter reaction kettle, 100 kg of naringin, 112.5 kg of dimethyl sulfoxide, and 37.5 kg of 90% methanol were added. The temperature was raised to 30 °C and stirred until the materials were dissolved clearly. Among them, the liquid chromatogram of naringin is as Figure 3 shown. 8 kg of powdered potassium hydroxide was added in 4 portions at intervals of 30 minutes. After adding, the temperature was raised to 40 °C to start the reaction. After 4 h, the raw materials disappeared under liquid phase control, and the reaction was stopped, as Figure 2 shown. The temperature was lowered to room temperature, and the pH was adjusted to 5 with glacial acetic acid. 50 kg of purified water was slowly dropped in, and it took about 1 h to finish dropping. The temperature was raised to reflux for 1 h, and the cooling water was turned on to cool down. Needle-shaped crystals began to precipitate at 50 °C. The temperature was continuously lowered to 0 °C and kept warm for 4 h. Centrifuged, and the solid was rinsed with a small amount of cold water. The solid was dried under reduced pressure at 60 °C. 79.3 kg of snow-white needle-shaped solid (neohesperidin intermediate) was obtained, with a purity of 99.3%, as Figure 3 shown.

[0032] Example 2

[0033] In a 500-liter reactor, 100 kg of naringin, 120 kg of dimethyl sulfoxide, and 40 kg of 80% methanol were charged. The temperature was raised to 28°C and stirred until the materials were dissolved clearly. 10 kg of powdered potassium hydroxide was added in 5 portions at 30-minute intervals. After addition, the temperature was raised to 60°C to start the reaction. After 2 hours, the raw materials in the liquid phase control disappeared, and the reaction was stopped. The temperature was lowered to room temperature, and the pH was adjusted to 5 with glacial acetic acid. 50 kg of purified water was slowly dropped in, and it was dropped completely in about 1 hour. The temperature was raised to reflux for 1 hour, and then the cooling water was turned on to cool down. Needle-shaped crystals began to precipitate at 45°C. The temperature was continued to be lowered to 0°C and kept warm for 4 hours. Centrifuged, and the solid was rinsed with a small amount of cold water. The solid was dried under reduced pressure at 60°C in a vacuum. 78.8 kg of snow-white needle-shaped solid (neohesperidin intermediate) was obtained. The purity was 99.1%.

[0034] Example 3

[0035] In a 500-liter reactor, 100 kg of naringin, 179 kg of dimethyl sulfoxide, and 71 kg of 80% methanol were charged. The temperature was raised to 30°C and stirred until the materials were dissolved clearly. 12 kg of powdered potassium hydroxide was added in 6 portions at 30-minute intervals. After addition, the temperature was raised to 50°C to start the reaction. After 6 hours, the raw materials in the liquid phase control disappeared, and the reaction was stopped. The temperature was lowered to room temperature, and the pH was adjusted to 5 with glacial acetic acid. 80 kg of purified water was slowly dropped in, and it was dropped completely in about 2 hours. The temperature was raised to reflux for 1 hour, and then the cooling water was turned on to cool down. Needle-shaped crystals began to precipitate at 50°C. The temperature was continued to be lowered to 3°C and kept warm for 4 hours. Centrifuged, and the solid was rinsed with a small amount of cold water. The solid was dried under reduced pressure at 60°C in a vacuum. 77.5 kg of snow-white needle-shaped solid (neohesperidin intermediate) was obtained. The purity was 99.4%.

[0036] Example 4

[0037] In a 500-liter reactor, 100 kg of naringin, 150 kg of dimethyl sulfoxide, and 50 kg of 80% methanol were charged. The temperature was raised to 32°C and stirred until the materials were dissolved clearly. 10 kg of powdered potassium hydroxide was added in 5 portions at 30-minute intervals. After addition, the temperature was raised to 60°C to start the reaction. After 3 hours, the raw materials in the liquid phase control disappeared, and the reaction was stopped. The temperature was lowered to room temperature, and the pH was adjusted to 6 with glacial acetic acid. 50 kg of purified water was slowly dropped in, and it was dropped completely in about 1 hour. The temperature was raised to reflux for 1 hour, and then the cooling water was turned on to cool down. Needle-shaped crystals began to precipitate at 55°C. The temperature was continued to be lowered to 0°C and kept warm for 4 hours. Centrifuged, and the solid was rinsed with a small amount of cold water. The solid was dried under reduced pressure at 60°C in a vacuum. 80.2 kg of snow-white needle-shaped solid (neohesperidin intermediate) was obtained. The purity was 99.2%.

[0038] Example 5

[0039] In a 500-liter reactor, 100 kg of naringin, 150 kg of dimethyl sulfoxide, and 60 kg of 80% methanol were charged. The temperature was raised to 30 °C and stirred until the materials were completely dissolved. 9 kg of powdered potassium hydroxide was added in 4 portions at 30-minute intervals. After addition, the temperature was raised to 50 °C to start the reaction. After 2 h, the raw materials disappeared in the in-liquid control, and the reaction was stopped. The temperature was lowered to room temperature, and the pH was adjusted to 6 with glacial acetic acid. 75 kg of purified water was slowly added dropwise over about 2 h. The temperature was raised to reflux for 1 h, and then cooled with cooling water. Needle-like crystals began to precipitate at 40 °C. The temperature was further lowered to 0 °C and held for 4 h. Centrifugation was carried out, and the solid was rinsed with a small amount of cold water. The solid was dried under reduced pressure at 60 °C. 77.0 kg of snow-white needle-like solid (neohesperidin intermediate) was obtained. The purity was 99.0%.

[0040] As described above, the above is only the specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any changes or substitutions within the technical scope disclosed in the present invention should be covered within the protection scope of the present invention. Therefore, the protection scope of the present invention should be subject to the protection scope of the claims described above.

Claims

1. A method for preparing a new hesperidin intermediate, characterized in that: Dimethyl sulfoxide and methanol are mixed to obtain a dimethyl sulfoxide solvent, potassium hydroxide dissolved in the dimethyl sulfoxide solvent is used as an alkaline catalyst, naringin is completely dissolved in the dimethyl sulfoxide solvent for hydrolysis reaction, and then purified to obtain a neohesperidin intermediate, namely, radix acetophenone-4'-neohesperidin.

2. The method for preparing the neohesperidin intermediate according to claim 1, characterized in that: The specific steps include: Step 1, adding naringin, methanol and dimethyl sulfoxide into a reaction kettle, stirring evenly, heating to 28°C to 32°C, adding potassium hydroxide, and continuing to heat to 40°C to 60°C for hydrolysis reaction; controlling naringin in the liquid phase to be less than 0.5%, and ending the reaction; the methanol is a methanol solution with a mass concentration greater than 80%; Step 2, cooling to room temperature and adjusting the solution pH to 5-6; Step 3, after slowly dropping purified water, the temperature is raised to reflux, and when white needle-shaped solids begin to precipitate, the temperature is slowly lowered to 0°C to 5°C for insulation; Step 4, filtering, rinsing with ice water, and drying to obtain the neohesperidin intermediate root acetophenone-4'-neohesperidin.

3. The method for preparing the neohesperidin intermediate according to claim 2, characterized in that: In step 1, the mass ratio of methanol to dimethyl sulfoxide is 1:2.5 to 1:

3.

4. The method for preparing the neohesperidin intermediate according to claim 2, characterized in that: In step 1, the mass ratio of methanol to naringin is 1:1.4 to 1:2.

67.

5. The method for preparing the neohesperidin intermediate according to claim 2, characterized in that: In step 1, the mass ratio of potassium hydroxide to naringin is 0.08:1 to 0.12:

1.

6. The method for preparing the neohesperidin intermediate according to claim 2, characterized in that: In step 3, the mass ratio of purified water to naringin is 0.5:1 to 0.8:

1.

7. The method for preparing the neohesperidin intermediate according to claim 2, characterized in that: In step 1, potassium hydroxide is added in 4 to 6 times, with an interval of 30 minutes each time.

8. The method for preparing the neohesperidin intermediate according to claim 2, characterized in that: In step 2, glacial acetic acid is used to adjust the pH value of the solution.

9. The method for preparing the neohesperidin intermediate according to claim 2, characterized in that: In step 1, methanol is 80%-90% methanol solution.

10. The method for preparing the neohesperidin intermediate according to claim 8, characterized in that: The potassium hydroxide is powdered potassium hydroxide.

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