Process for the preparation of a new hesperidin intermediate

Abstract

The application discloses a preparation method of a new hesperidin intermediate. The method comprises the following steps: dissolving naringin in dimethyl sulfoxide to prepare a solution, adding powder potassium hydroxide dissolved in dimethyl sulfoxide to the solution as a basic catalyst, and hydrolyzing the solution to obtain a new hesperidin intermediate, i.e., phloretin acetyl benzene-4'-neohesperidoside. The preparation method of the new hesperidin intermediate has almost no side reaction during the hydrolysis reaction, and finally, the target product with high yield and high purity is obtained. Compared with the prior art, the method has the advantages of simple technical operation, low cost, good product quality, high yield and easy industrial production.

Description

Technical Field

[0001] This invention relates to a method for preparing a novel hesperidin intermediate, specifically a method for preparing a novel hesperidin intermediate, root bark acetylphenyl-4'-neohesperidin. Background Technology

[0002] Neohesperidin, CAS number 13241-33-3, is a dihydroflavonoid compound commonly found alongside naringin and hesperidin in plants of the Rutaceae and Rubiaceae families. Its primary use in the pharmaceutical field is in gastrointestinal medications, where it is used to relieve phlegm, reduce bloating, and alleviate abdominal distension. Furthermore, neohesperidin is a key raw material for the industrial synthesis of the sweetener dihydrochalcone. The structure of neohesperidin is as follows:

[0003]

[0004] Currently, there are two industrially available methods for preparing neohesperidin: plant extraction and semi-synthesis of naringin. The semi-synthesis method using naringin as a raw material is the most important method. Root bark acetylphenyl-4'-neohesperidin is a key intermediate in the preparation of neohesperidin from naringin. The structural formula of the intermediate root bark acetylphenyl-4'-neohesperidin is as follows:

[0005]

[0006] The existing preparation process involves ring-opening hydrolysis of naringin in an alkaline solution to generate naringin-4'-neohesperidin, which then reacts with isovandin to generate neohesperidin. The key to this process lies in the step of preparing naringin-4'-neohesperidin from naringin. Chinese patent CN201710585715 discloses the preparation of naringin-4'-neohesperidin in an alcoholic solution using sodium alkoxide as an alkaline catalyst. However, existing technologies typically require high reaction temperatures, use large amounts of alkaline solution, generate significant amounts of reaction wastewater, and generally have low yields, typically 60-70%. Therefore, developing a new process for preparing naringin-4'-neohesperidin from naringin is of great significance. Summary of the Invention

[0007] The purpose of this invention is to solve the technical problems of high temperature, large amount of alkali, large amount of wastewater and low yield in existing preparation methods, and to provide a new method for preparing hesperidin intermediates. The method uses naringin as the main raw material and dimethyl sulfoxide, methanol and potassium hydroxide as excipients to prepare root bark acetylphenyl-4'-neohesperidin. The method is simple to operate, low in cost, produces high-quality products, has a high yield and is easy to industrialize.

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

[0009] A novel method for preparing a hesperidin intermediate, characterized by:

[0010] Dimethyl sulfoxide (DMSO) and methanol were mixed to obtain a DMSO solvent. Potassium hydroxide dissolved in the DMSO solvent was used as an alkaline catalyst to completely dissolve naringin in the DMSO solvent for hydrolysis. Then, the solution was purified to obtain a neohesperidin intermediate, namely root bark acetylphenyl-4'-neohesperidin.

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

[0012] Step 2: Cool the solution to room temperature and adjust the pH to 5-6;

[0013] Step 3: After slowly adding purified water, heat the mixture to reflux. When white needle-like solids begin to precipitate, continue to slowly cool the mixture to 0℃~5℃ and maintain the temperature.

[0014] Step 4: Filter and rinse with ice water, then dry to obtain the neohesperidin intermediate root bark acetylphenyl-4'-neohesperidin.

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

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

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

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

[0019] Furthermore, in step 1, potassium hydroxide is added in 4 to 6 separate applications, with each application spaced 30 minutes apart.

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

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

[0022] Furthermore, the potassium hydroxide is in powder form.

[0023] Compared with the prior art, the present invention has the following beneficial technical effects:

[0024] 1. The method for preparing the new hesperidin intermediate of the present invention utilizes the super-alkalinity of potassium hydroxide dissolved in dimethyl sulfoxide reaction solvent, and the characteristic that naringin can be completely dissolved in a low amount of dimethyl sulfoxide solvent at a relatively low temperature. Dimethyl sulfoxide and methanol are mixed as reaction solvents, and potassium hydroxide is used as an alkaline catalyst to hydrolyze naringin to prepare the new hesperidin intermediate, namely root bark acetylphenyl-4'-neohesperidin.

[0025] 2. The method for preparing the novel hesperidin intermediate of this invention, according to the liquid phase control display, shows that almost no side reactions are generated during the hydrolysis reaction, and the target product with high yield and high purity is finally obtained. The technology is simple to operate, low in cost, good in product quality, high in yield, and easy to industrialize.

[0026] 3. The method for preparing the novel hesperidin intermediate of this invention uses less alkali and generates less wastewater, which not only reduces production costs but is also environmentally friendly. Attached Figure Description

[0027] Figure 1 This is an example of a method for preparing a novel hesperidin intermediate according to the present invention - a liquid chromatogram of naringin;

[0028] Figure 2 This is a liquid chromatogram of the reaction solution in Example 1 of the preparation method of a novel hesperidin intermediate of the present invention;

[0029] Figure 3 This is a liquid chromatogram of a novel hesperidin intermediate, as described in Example 1 of the preparation method of a novel hesperidin intermediate according to the present invention. Detailed Implementation

[0030] Example 1

[0031] In a 500-liter reactor, 100 kg of naringin, 112.5 kg of dimethyl sulfoxide, and 37.5 kg of 90% methanol were added. The mixture was heated to 30°C and stirred until the contents were completely dissolved. The liquid chromatography analysis of naringin showed the following... Figure 3 As shown, 8 kg of powdered potassium hydroxide was added in four portions, 30 minutes apart. After each addition, the temperature was raised to 40°C to initiate the reaction. After 4 hours, the raw material disappeared from the liquid phase, at which point the reaction was stopped. Figure 2 As shown. The solution was cooled to room temperature, and the pH was adjusted to 5 with glacial acetic acid. 50 kg of purified water was slowly added dropwise, completing the addition in about 1 hour. The solution was then refluxed for 1 hour, followed by cooling with water. Needle-like crystals began to precipitate at 50°C. The solution was further cooled to 0°C and held at that temperature for 4 hours. The solution was centrifuged, and the solid was washed with a small amount of cold water. The solid was then dried under reduced pressure at 60°C. 79.3 kg of a snow-white needle-like solid (neohesperidin intermediate) with a purity of 99.3% was obtained. Figure 3 As 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 added. The mixture was heated to 28°C and stirred until the materials were completely dissolved. 10 kg of powdered potassium hydroxide was added in five portions, 30 minutes apart. After each addition, the temperature was raised to 60°C to initiate the reaction. After 2 hours, the raw materials disappeared from the liquid phase, and the reaction was stopped. The mixture was cooled to room temperature, and the pH was adjusted to 5 with glacial acetic acid. 50 kg of purified water was slowly added dropwise, completing the addition over approximately 1 hour. The mixture was refluxed for 1 hour, then cooled with cooling water. Needle-like crystals began to precipitate at 45°C. The temperature was further lowered to 0°C and maintained for 4 hours. The mixture was centrifuged, and the solid was washed with a small amount of cold water. The solid was dried under reduced pressure at 60°C. 78.8 kg of a snow-white needle-like solid (neohesperidin intermediate) was obtained, with a purity of 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 added. The mixture was heated to 30°C and stirred until the materials were completely dissolved. 12 kg of powdered potassium hydroxide was added in six portions, 30 minutes apart. After each addition, the temperature was raised to 50°C to initiate the reaction. After 6 hours, the raw materials disappeared from the liquid phase, and the reaction was stopped. The mixture was cooled to room temperature, and the pH was adjusted to 5 with glacial acetic acid. 80 kg of purified water was slowly added dropwise, completing the addition over approximately 2 hours. The mixture was then refluxed for 1 hour, followed by cooling with water. Needle-like crystals began to precipitate at 50°C. The temperature was further lowered to 3°C and maintained for 4 hours. The mixture was centrifuged, and the solid was washed with a small amount of cold water. The solid was then dried under reduced pressure at 60°C. 77.5 kg of a snow-white needle-like solid (neohesperidin intermediate) was obtained, with a purity of 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 added. The mixture was heated to 32°C and stirred until the materials were completely dissolved. 10 kg of powdered potassium hydroxide was added in five portions, 30 minutes apart. After each addition, the temperature was raised to 60°C to initiate the reaction. After 3 hours, the raw materials disappeared from the liquid phase, and the reaction was stopped. The mixture was cooled to room temperature, and the pH was adjusted to 6 with glacial acetic acid. 50 kg of purified water was slowly added dropwise, completing the addition in about 1 hour. The mixture was refluxed for 1 hour, then cooled with cooling water. Needle-like crystals began to precipitate at 55°C. The temperature was further lowered to 0°C and maintained for 4 hours. The mixture was centrifuged, and the solid was washed with a small amount of cold water. The solid was dried under reduced pressure at 60°C. 80.2 kg of a snow-white needle-like solid (neohesperidin intermediate) was obtained, with a purity of 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 added. The mixture was heated to 30°C and stirred until the materials were completely dissolved. 9 kg of powdered potassium hydroxide was added in four portions, 30 minutes apart. After each addition, the temperature was raised to 50°C to initiate the reaction. After 2 hours, the raw materials disappeared from the liquid phase, and the reaction was stopped. The mixture was cooled to room temperature, and the pH was adjusted to 6 with glacial acetic acid. 75 kg of purified water was slowly added dropwise, completing the addition over approximately 2 hours. The mixture was refluxed for 1 hour, then cooled with cooling water. Needle-like crystals began to precipitate at 40°C. The temperature was further lowered to 0°C and maintained for 4 hours. The mixture was centrifuged, and the solid was washed with a small amount of cold water. The solid was dried under reduced pressure at 60°C. 77.0 kg of a snow-white needle-like solid (neohesperidin intermediate) was obtained, with a purity of 99.0%.

[0040] The above description is merely a specific embodiment of the present invention, but the scope of protection 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 scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A method for preparing a new hesperidin intermediate, characterized in that: a dimethyl sulfoxide solvent is obtained by mixing dimethyl sulfoxide and methanol, 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 performed to obtain the new hesperidin intermediate, i.e. phloretin acetylphenyl-4'-neohesperidoside, and the specific reaction steps are as follows: Step 1, naringin, methanol and dimethyl sulfoxide are added to a reaction kettle, stirred uniformly, heated to 28-32℃, potassium hydroxide is added, and the hydrolysis reaction is continued at 40-60℃; the liquid phase control naringin is less than 0.5%, and the reaction is ended; the methanol is a methanol solution with a mass concentration of more than 80%; Step 2, cool to room temperature, adjust the solution pH to 5-6; Step 3, after slowly adding purified water, warm up to reflux, when white needle-shaped solid begins to precipitate, continue to slowly cool to 0-5℃ for incubation; Step 4, filter and wash with ice water, dry to obtain the new hesperidin intermediate phloretin acetylphenyl-4'-neohesperidoside.

2. The process for the preparation of neohesperidose intermediates as claimed in claim 1, wherein: In step 1, the mass ratio of methanol to dimethyl sulfoxide is 1:2.5-1:

3.

3. The process for the preparation of neohesperidose intermediates as claimed in claim 2, wherein: In step 1, the mass ratio of methanol to naringin is 1:1.4-1:2.

67.

4. The method for preparing the new hesperidin intermediate according to claim 3, characterized in that: In step 1, the mass ratio of potassium hydroxide to naringin is 0.08:1-0.12:

1.

5. The process for the preparation of neohesperidose intermediates as claimed in claim 4, wherein: In step 3, the mass ratio of purified water to naringin is 0.5:1-0.8:

1.

6. The process for the preparation of neohesperidose intermediates as claimed in claim 5, wherein: In step 1, the potassium hydroxide is added in 4-6 times, and the interval time is 30 min each time.

7. The process for the preparation of neohesperidose intermediates as claimed in claim 1, wherein: In step 2, ice acetic acid is used to adjust the solution pH.

8. The process for the preparation of neohesperidose intermediates as claimed in claim 1, wherein: In step 1, the methanol is a methanol solution with a mass concentration of 80-90%.

9. The process for the preparation of neohesperidose intermediates as claimed in claim 8, wherein: The potassium hydroxide is a powdered potassium hydroxide.

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