阅读说明：本技术 甘草次酸糖苷的制备方法和在甜味剂中的应用 (Preparation method of glycyrrhetinic acid glucoside and application of glycyrrhetinic acid glucoside in sweetener ) 是由 朱振元 王鹤颖 王淮旭 于 2019-01-14 设计创作，主要内容包括：本发明涉及甘草次酸糖苷的合成路线,以及其在甜味剂中的应用,属于新型甜味剂合成领域。以甘草次酸和三种单糖(葡萄糖、半乳糖、葡萄糖醛酸)为原料,制备新型、甜度更高的甜味剂。进行以下步骤：(1)甘草次酸30位羧基保护；(2)糖的全苯甲酰化保护；(3)糖一位溴代反应；(4)缩合反应；(5)脱保护反应。最终得到单葡萄糖醛酸甘草次酸苷(GAMG)、甘草次酸葡萄糖苷(GA-β-D-glc)、甘草次酸半乳糖苷(GA-β-D-Gal),并进一步延伸到各中间产物和终产物的纯化工艺。本发明为甘草次酸糖苷的化学合成提供了一种新思路,同时为开发甜味剂新产品提供理论基础。(The invention relates to a synthetic route of glycyrrhetinic acid glucoside and application thereof in a sweetener, belonging to the field of novel sweetener synthesis.A novel sweetener with higher sweetness is prepared by taking glycyrrhetinic acid and three monosaccharides (glucose, galactose and glucuronic acid) as raw materials, and the method comprises the following steps of (1) protecting 30-bit carboxyl of the glycyrrhetinic acid, (2) protecting all benzoylation of sugar, (3) carrying out one-bit bromination reaction of sugar, (4) carrying out condensation reaction, and (5) carrying out deprotection reaction, and finally obtaining the glycyrrhetinic acid glycoside monoglucuronide (GAMG), the glycyrrhetinic acid glucoside (GA- β -D-glc) and the glycyrrhetinic acid galactoside (GA- β -D-Gal), and further extending to purification processes of various intermediate products and final products.)

1. A synthetic route of glycyrrhetinic acid glucoside is characterized by comprising the following steps:

(1) dissolving a certain amount of glycyrrhetinic acid in methanol, dropwise adding concentrated sulfuric acid, heating and refluxing, monitoring the reaction process by using T L C, dissolving a solid by using dichloromethane after the reaction is finished, washing the solid by using a sodium carbonate aqueous solution and distilled water, concentrating and drying to obtain a crude product.

(2) Purifying the crude product obtained in the step (1): recrystallizing the crude product obtained in the step (1) with methanol for a plurality of times to obtain a pure product of glycyrrhetinic acid methyl ester

(3) The total benzoylation protection of sugar is that a certain amount of sugar (glucose, galactose and glucuronic acid) is dissolved by pyridine under the condition of low temperature, then benzoyl chloride is dropped in, after a certain time of stirring, an ice water bath is removed, the reaction is carried out at room temperature, T L C is monitored, after the reaction is finished, part of pyridine is removed by rotary evaporation, dichloromethane is added to completely dissolve the pyridine, and an organic phase is washed by HCl solution, NaHCO3 solution and sodium chloride solution in turn, and is dried to obtain a crude product.

(4) And (3) dissolving the sample obtained in the step (3) with dichloromethane solution at low temperature, adding HBr acetic acid solution, stirring for a certain time, removing the mixture from an ice water bath, reacting at room temperature, monitoring at T L C, neutralizing with sodium bicarbonate solution after the reaction is finished, adding a proper amount of dichloromethane, extracting for several times, combining organic phases, and drying to obtain a crude product of the bromo sugar.

(5) Purifying the crude product obtained in the step (4): and (4) eluting the crude product obtained in the step (4) by using cyclohexane and ethyl acetate in a certain proportion as developing agents to obtain a pure product.

(6) And (3) glycosidation condensation reaction, namely dissolving the samples obtained in the step (2) and the step (5) by using dichloromethane respectively, filling nitrogen for protection, adding silver trifluoromethanesulfonate after reacting for a period of time, transferring the silver trifluoromethanesulfonate into a low-temperature medium, keeping out of the sun, stirring, monitoring reaction by T L C, filtering after the reaction is finished, neutralizing by using triethylamine, washing by using sodium bicarbonate and water, and drying to obtain a crude product.

(7) Purifying the crude product obtained in the step (6): eluting and purifying by using dimethylbenzene and ethyl acetate as developing agents according to a certain proportion to obtain a pure product.

(8) And (3) deprotection, namely dissolving the sample obtained in the step (7) by using dichloromethane, dissolving sodium methoxide in methanol solution, adding the sodium methoxide solution into the sample solution, reacting for a plurality of hours at room temperature, tracking the reaction progress by T L C, and neutralizing by using cation exchange resin after the reaction is finished.

(9) Purifying the crude product obtained in step (7): eluting and purifying with ethyl acetate and methanol at a certain ratio as developing agent to obtain pure product

(10) The three compounds obtained, Glycyrrhetinic Acid Monoglucuronide (GAMG), glycyrrhetinic acid glucoside (GA- β -D-glc) (GA- β -D-Gal), and glycyrrhetinic acid galactoside (GA- β -D-Gal), were subjected to sweetness evaluation.

2. The synthetic route of glycyrrhetinic acid glycoside sweetener according to claim 1, characterized in that neutralization with cationic resins is carried out at the end of the reaction in step (8).

3. The synthetic route of glycyrrhetinic acid glycoside sweeteners according to claim 1, characterized in that step (6) uses silver trifluoromethanesulfonate as catalyst, under nitrogen protection at-20 ℃ medium.

4. The synthetic route for glycyrrhetinic acid glycoside sweeteners according to claim 1, characterized by the design of the whole synthetic concept.

5. The synthetic route to glycyrrhetinic acid glycoside sweeteners according to claim 1, characterized in that the three glycosides prepared serve as the basis for the development of novel sweeteners.

Technical Field

The invention relates to a synthetic route of glycyrrhetinic acid glucoside and application thereof in a sweetener, belonging to the field of synthesis of novel sweeteners.

Background

With the living standard of people in the modern society being remarkably improved, diseases caused by excessive intake of high calorie foods, especially saccharides, become a big social problem, and more people are seeking low calorie sweet additives to meet the demand of sweet foods. The number of sweeteners widely used in the world at present is few, and the sweeteners can be divided into two types according to sources: the first type is natural sweetener, which is a component naturally synthesized in various organisms in the nature and obtained by extraction and processing. The second type is a chemically synthesized sweetener, which refers to a compound with sweet taste synthesized by a chemical method.

The liquorice is common food used as both medicine and food. Licorice extract is widely used as a natural sweetener in confectionery and canned foods. Glycyrrhizic acid is an ancient natural sweetener product, has low heat energy, safety, no toxicity and strong medical care efficacy, and is the most ideal sweetener for patients with hypertension, obesity, diabetes and heart disease. It can make up the disadvantages of cane sugar saccharin and other sweetening agents which induce the above-mentioned diseases. Glycyrrhizic acid has long been one of the legally used plant sweeteners in the western world.

Glycyrrhetinic acid is one of the extracts of licorice and is also an important source of its sweetness. The introduction of glycosyl into the 3-position hydroxyl can improve the solubility and improve the utilization degree of biological activity. Meanwhile, a basic theory is provided for the development of the novel sweetener. Shenyang university of pharmacy is applying for "a chemical synthesis method of glycyrrhetinic acid monoglucuronide", which is different from the chemical synthesis method of glycyrrhetinic acid monoglucuronide: in the synthesis method, benzyl esterification protection is carried out on 30-site carboxyl of glycyrrhetinic acid, and the methyl esterification protection is carried out, so that the reaction is simpler and more convenient; in the synthesis method, trichloroacetimide esterification is used in the condensation reaction, and silver trifluoromethanesulfonate is used as a catalyst in the method, so that the reaction is more efficient. The three patents only synthesize glycyrrhetinic acid monoglucuronide, and the patent connects three monosaccharides (galactose, glucose and glucuronic acid) to the glycyrrhetinic acid to form three compounds with sweetness.

Disclosure of Invention

The invention mainly provides a new idea for the synthesis of glycyrrhetinic acid glucoside. The reaction route of the preparation method is shown as follows (taking glycyrrhetinic acid glucoside as an example):

experiments show that the three compounds have relatively high sweetness, compared with the sweetness analysis of cane sugar, the sweetness of glycyrrhizic acid is about 154 times that of cane sugar, the sweetness of GAMG is about 627 times that of cane sugar, the sweetness of GA- β -D-glc is about 257 times that of cane sugar, the sweetness of the two compounds is higher than that of glycyrrhizic acid, and the sweetness of GA- β -D-Gal is about 128 times that of cane sugar.

Compared with the prior art, the invention has the beneficial effects that:

1. the invention uses benzoyl to protect sugar, with high yield and less impurity.

2. The invention uses the silver trifluoromethanesulfonate as a catalyst for glycosylation reaction, thereby greatly accelerating the reaction process. The success rate of the reaction is also much higher.

3. The invention utilizes the glycyrrhetinic acid which is a natural sweetener as a raw material, and carries out structural modification on the glycyrrhetinic acid to prepare the novel sweetener with higher sweetness.

4. According to the synthetic route of the invention, the yield of the obtained final product is high, and the production can be expanded.

Detailed Description

The present invention will be described in further detail below with reference to specific examples, which are given below as examples of synthetic routes for GA- β -D-glc and GA- β -D-Gal, respectively.