CN114478657B

CN114478657B - Synthesis method of neohesperidin

Info

Publication number: CN114478657B
Application number: CN202210149786.8A
Authority: CN
Inventors: 黎四芳; 钟艺琼
Original assignee: Xiamen University
Current assignee: Xiamen University
Priority date: 2022-02-18
Filing date: 2022-02-18
Publication date: 2023-03-31
Anticipated expiration: 2042-02-18
Also published as: CN114478657A

Abstract

A method for synthesizing neohesperidin, which relates to the field of fine chemical engineering. Dissolving radicel acetophenone-4' -beta-neohesperidin and isovanillin in absolute ethanol, adding a composite catalyst consisting of L-proline and catechol, heating to 70-85 ℃, performing reflux reaction for 8-13 h, cooling to room temperature, performing suction filtration, washing a filter cake with cold ethanol for multiple times, and performing vacuum drying to obtain a white solid powdery product neohesperidin. The catechol and the L-proline are added into a reaction system to form a composite catalyst, the catechol has strong complexing ability and can form a ring-shaped complex with an oxygen atom of an aldehyde group of the isovanillin through a hydrogen bond, so that the aldehyde group of the isovanillin is activated and can be easily reacted with a transition substance generated by the L-proline and the phloretin-4 '-beta-neohesperidin to obtain the neohesperidin, the reaction effect is improved, the phloretin-4' -beta-neohesperidin is nearly completely converted, and the yield and the purity are obviously improved.

Description

Synthesis method of neohesperidin

Technical Field

The invention relates to the field of fine chemical engineering, in particular to a synthesis method for synthesizing neohesperidin by reacting phloretin acetophenone-4' -beta-neohesperidin with isovanillin under the action of a catalyst.

Background

Neohesperidin is a flavonoid compound naturally existing in plants of Rutaceae and Rubiaceae, and has the following chemical structural formula:

the neohesperidin is a key raw material for synthesizing the high-sweetness sweetener neohesperidin dihydrochalcone. Neohesperidin also has excellent physiological functions of reducing blood fat, lowering blood pressure, eliminating free radicals, resisting inflammation, inhibiting bacteria, resisting cancer, protecting cardiovascular and cerebrovascular systems and the like, and is widely applied to the fields of food, medicine and feed. Although neohesperidin can be extracted from traditional Chinese medicinal materials such as fructus aurantii, the yield is limited, and the increasing demand cannot be met. The neohesperidin can also be obtained by chemical conversion of naringin. The naringin is more abundant in source than the neohesperidin, can be extracted from citrus peels and shaddock peels, and China has abundant citrus and shaddock resources, so that the synthesis of the neohesperidin from the naringin can change waste into valuable, and has wide prospects.

The naringin opens a flavone ring in an alkaline environment to generate phloretin acetophenone-4' -beta-neohesperidin, which then has an aldol condensation reaction with isovanillin under the action of a catalyst to generate neohesperidin, wherein the reaction formula is as follows:

the key of the technological process is how to efficiently catalyze the aldol condensation reaction of the phloem acetophenone-4' -beta-neohesperidoside and the isovanillin. U.S. Pat. No. 3,3375242 uses KOH as catalyst, and uses large excess (12 times mole number) of isovanillin to react with phloretin-4' -beta-neohesperidin, and then obtains neohesperidin by acidifying with concentrated hydrochloric acid. However, the method has the advantages of low reaction yield, large dosage of the raw material isovanillin, difficult recovery and high preparation cost, and is not suitable for industrial production.

US patent 3947405 carries out the reaction of phloroacetophenone-4' - β -neohesperidoside with isovanillin with a secondary amine and organic acid catalytic system, tetrahydropyrrole being found to be optimal by comparing the lower alkylamines (dimethylamine, diethylamine and diisopropylamine), the aromatic amines (methylaniline, diphenylamine), the alkanolamines (diethanolamine), the cyclic amines (imidazoline, piperazine, tetrahydropyrrole); acetic acid has also been found to be the most preferred as compared to the catalytic properties of lower alkane carboxylic acids (formic, acetic and propionic) and aromatic carboxylic acids (benzoic), etc. Taking pyrrolidine and acetic acid as a catalytic system and isopropanol as a solvent, and reacting for 15 hours at a reflux temperature to obtain neohesperidin with the yield of 87% and the purity of 92%. The method has the advantages of low product yield and purity, easy volatilization of tetrahydropyrrole, pungent odor and easy environmental pollution.

Chinese patent CN103408620B proposes that the activity of the catalyst can be improved by changing the feeding mode of the catalyst under the catalysis system of pyrrolidine and acetic acid, the yield of the obtained neohesperidin is more than or equal to 85%, and the purity is more than or equal to 98%. Although the purity of the method is improved, the yield is reduced, and the method still has the defects of easy volatilization, pungent odor and easy environmental pollution of the tetrahydropyrrole.

Chinese patent CN101863940B takes L-proline as a catalyst to catalyze the reaction of radicle acetophenone-4' -beta-neohesperidin and isovanillin to obtain pale yellow solid powder neohesperidin, wherein the yield is more than or equal to 95 percent, and the purity is more than or equal to 96 percent. The method improves the yield of neohesperidin, but still cannot obtain high-purity products, and the products are light yellow solid powder in appearance, so that white solid powder products cannot be obtained.

Disclosure of Invention

The invention aims to provide a synthesis method of neohesperidin, which can effectively improve the product yield and purity.

The method comprises the following specific steps:

dissolving radicel acetophenone-4' -beta-neohesperidin and isovanillin in absolute ethyl alcohol, adding a composite catalyst consisting of L-proline and catechol, heating to 70-85 ℃, performing reflux reaction for 8-13 h, cooling to room temperature, performing suction filtration, washing a filter cake with cold ethyl alcohol for multiple times, and performing vacuum drying to obtain a white solid powdery product neohesperidin.

The mol ratio of the L-proline to the catechol in the composite catalyst can be 1: 0.2-1.

The mass ratio of the radicle acetophenone-4' -beta-neohesperidin to the absolute ethyl alcohol can be 0.05-0.12: 1.

The molar ratio of the radicel acetophenone-4' -beta-neohesperidin glycoside to the isovanillin can be 1: 0.9-1.5.

The molar ratio of the L-proline to the phlorizin-4' -beta-neohesperidoside can be 0.5-1.5: 1.

The temperature of the reaction may be 70 to 85 ℃.

The temperature of the ethanol may be 4 ℃.

The multiple washing can be carried out by 3 times of washing the filter cake.

In the invention, catechol and L-proline are added into a reaction system to form a composite catalyst, the catechol has strong complexing ability and can form a cyclic complex with an oxygen atom of an aldehyde group of isovanillin through a hydrogen bond, so that the aldehyde group of the isovanillin is activated, and the aldehyde group of the isovanillin is easier to react with a transition product generated by the L-proline and the phloretin acetophenone-4 '-beta-neohesperidin to obtain the neohesperidin, therefore, the reaction effect is improved, the phloretin acetophenone-4' -beta-neohesperidin is nearly completely converted, and the yield and the purity of the neohesperidin product are remarkably improved compared with the prior method. Meanwhile, the obtained neohesperidin product has no residual unreacted orange-yellow phlorizin-4' -beta-neohesperidin, so that the product is white solid powder in appearance.

Drawings

FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of neohesperidin prepared by the synthesis method of the present invention;

FIG. 2 is an infrared spectrum of neohesperidin prepared by the synthesis method of the present invention.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the following embodiments will be further described with reference to the accompanying drawings. It should be understood that the specific embodiments described herein are merely illustrative of the invention and do not delimit the invention. On the contrary, the invention is intended to cover alternatives, modifications, equivalents and alternatives which may be included within the spirit and scope of the invention as defined by the appended claims. Furthermore, in the following detailed description of the present invention, certain specific details are set forth in order to provide a better understanding of the present invention. It will be apparent to one skilled in the art that the present invention may be practiced without these specific details.

Example 1:

adding 48g of absolute ethyl alcohol into a 100mL four-neck flask with an electric stirrer, a thermometer and a reflux condenser in a constant-temperature water bath, starting stirring, adding 4g (0.0084 mol) of phloroacetophenone-4' -beta-neohesperidin and 1.28g (0.0084 mol) of isovanillin, after complete dissolution, sequentially adding 0.97g (0.0084 mol) of L-proline and 0.46g (0.0042 mol) of catechol, heating to 78.5 ℃, keeping the temperature under reflux for reaction for 12 hours, stopping heating, cooling to room temperature, generating a large amount of white precipitates at the bottom of the flask, performing suction filtration by using a Buchner funnel, washing a filter cake by using 30mL of cold ethyl alcohol (4 ℃) for 3 times, performing suction drying, then placing the filter cake in a vacuum drying oven, and drying for 12 hours at 45 ℃ to obtain a white solid powdery substance neohesperidin, wherein the yield is 93.79%, and the purity of the product is 99.45% by using high performance liquid chromatography.

Example 2:

adding 42g of absolute ethyl alcohol into a 100mL four-neck flask with an electric stirrer, a thermometer and a reflux condenser in a constant-temperature water bath, starting stirring, adding 4g (0.0084 mol) of phloretin-4' -beta-neohesperidin and 1.54g (0.0101 mol) of isovanillin, after complete dissolution, sequentially adding 0.97g (0.0084 mol) of L-proline and 0.28g (0.0025 mol) of catechol, heating to 78.5 ℃, keeping the temperature under reflux for reaction for 11 hours, stopping heating, cooling to room temperature, generating a large amount of white precipitates at the bottom of the flask, performing suction filtration by using a Buchner funnel, washing a filter cake by using 30mL of cold ethyl alcohol (4 ℃) for 3 times, performing suction drying, then placing the filter cake in a vacuum drying oven, and drying for 12 hours at 45 ℃ to obtain a white solid powdery substance neohesperidin, wherein the yield is 96.90%, and the product purity is 99.54% by high performance liquid chromatography.

Example 3:

the reaction apparatus and the operation method were the same as in example 2. The difference lies in that the reaction temperature is 72 ℃, and the result is that the yield of the neohesperidin is 90.26% and the purity is 99.30%.

Example 4:

the reaction apparatus and the operation method were the same as in example 2. The difference lies in that the reaction time is 12 hours, and the result is that the yield of the neohesperidin is 96.50 percent and the purity is 99.46 percent.

Example 5:

the reaction apparatus and the operation method were the same as in example 2. The difference is that the mol ratio of L-proline to catechol in the composite catalyst is 1: 0.2; the mass ratio of the radicel acetophenone-4' -beta-neohesperidoside to the absolute ethyl alcohol is 0.05: 1.

Example 6:

the reaction apparatus and the operation method were the same as in example 2. The difference is that the mol ratio of L-proline to catechol in the composite catalyst is 1: 1; the mass ratio of the radicle acetophenone-4' -beta-neohesperidin to the absolute ethyl alcohol is 0.12: 1.

Example 7:

the reaction apparatus and the operation method were the same as in example 1. The difference is that the molar ratio of the radicle acetophenone-4' -beta-neohesperidin to the isovanillin is 1: 0.9. The mol ratio of the L-proline to the phlorizin acetyl benzene-4' -beta-neohesperidoside is 0.5: 1.

Example 8:

the reaction apparatus and the operation method were the same as in example 1. The difference is that the molar ratio of the radicel acetophenone-4' -beta-neohesperidin to the isovanillin is 1: 1.5. The molar ratio of the L-proline to the phlorizin-4' -beta-neohesperidoside is 1.5: 1.

Example 9:

the reaction apparatus and the operation method were the same as in example 2. The difference is that the molar ratio of the radicel acetophenone-4' -beta-neohesperidin to the isovanillin is 1: 1.2. The molar ratio of the L-proline to the phlorizin acetyl benzene-4' -beta-neohesperidoside is 1: 1.

Comparative example:

the reaction apparatus and the operation method were the same as in example 1. The difference is that in this case no catechol is added. As a result, neohesperidin was obtained as a pale yellow solid powder with a yield of 85.41% and a purity of 96.10% as determined by HPLC.

FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of neohesperidin prepared by the synthesis method of the present invention; fig. 2 is an infrared spectrum of neohesperidin prepared by the synthesis method of the present invention. As can be seen from the above, the invention adds catechol and L-proline to form a composite catalyst in the reaction system, thereby significantly improving the yield and the product purity of the neohesperidin product.

The above-described embodiments are merely preferred embodiments of the present invention, and should not be considered as limiting the scope of the invention. All equivalent changes and modifications made within the scope of the present invention shall fall within the scope of the present invention.

Claims

1. The synthesis method of neohesperidin is characterized by comprising the following specific steps:

dissolving phlorizin-4' -beta-neohesperidin and isovanillin in absolute ethyl alcohol, adding a composite catalyst consisting of L-proline and catechol, heating to 70-85 ℃, performing reflux reaction for 8-13 h, cooling to room temperature, performing suction filtration, washing a filter cake with cold ethanol for multiple times, and performing vacuum drying to obtain a white solid powdery product neohesperidin.

2. The method for synthesizing neohesperidin according to claim 1, wherein the molar ratio of L-proline to catechol in the composite catalyst is 1: 0.2-1.

3. The method for synthesizing neohesperidin as claimed in claim 1, wherein the mass ratio of the radiculoacetophenon-4' - β -neohesperidin to the absolute ethyl alcohol is 0.05-0.12: 1.

4. The method for synthesizing neohesperidin according to claim 1, wherein the molar ratio of phloretin-4' - β -neohesperidin to isovanillin is 1: 0.9-1.5.

5. A synthesis method of neohesperidin as claimed in claim 1, wherein the molar ratio of L-proline to phloretin-4' - β -neohesperidin is 0.5-1.5: 1.

6. A process for the synthesis of neohesperidin as claimed in claim 1, wherein the temperature of the ethanol is 4 ℃.

7. A process for the synthesis of neohesperidin according to claim 1, wherein the washing of the filter cake for the plurality of washes is carried out 3 times.