阅读说明：本技术 一种查尔酮衍生物QNL-Chalcone的制备方法及应用 (Preparation method and application of Chalcone derivatives QNL-Chalcone ) 是由 关丽萍 彭鼎新 张珊珊 何丽雅 于 2019-09-29 设计创作，主要内容包括：本发明涉及药物合成领域,针对现有技术的发明物分子活性不足及合成路线较长的问题,公开了一种新型查尔酮衍生物QNL-Chalcone的制备方法及应用,包括以下步骤：(1)、1-(2-甲基-4-苯基喹啉-3-基)乙酮的合成；(2)、QNL-Chalcone的合成,以乙酰丙酮按、2-氨基二苯甲酮、2-溴苯甲醛为原料,通过上述两个制备步骤制得QNL-Chalcone。本发明既引入了喹啉母核,又保留了查尔酮活性必须基团—丙烯酮结构,到抗抑郁活性强,副作用低的化合物QNL-Chalcone；该药物的合成路线短,且成本较低,并且该工艺的可控性好,易于实际大规模工业化量产,制得的产品收率高,纯度高。(The invention relates to the field of drug synthesis, and discloses a preparation method and application of novel Chalcone derivatives QNL-Chalcone aiming at the problems of insufficient molecular activity and long synthetic route of the invention in the prior art, which comprises the following steps of (1) synthesis of 1- (2-methyl-4-phenylquinoline-3-yl) ethanone, and (2) synthesis of QNL-Chalcone, wherein acetylacetone, 2-aminobenzophenone and 2-bromobenzaldehyde are used as raw materials, and the QNL-Chalcone is prepared through the two preparation steps.)

The preparation method of Chalcone derivatives QNL-Chalcone is characterized by comprising the following steps:

(1) and synthesis of 1- (2-methyl-4-phenylquinolin-3-yl) ethanone:

(2) and synthesis of QNL-Chalcone:

2. the method for preparing Chalcone derivatives QNL-Chalcone according to claim 1, wherein in the step (1), the raw materials are selected from acetylacetone 4.8mmol, citric acid 2-2.2mmol, 2-aminobenzophenone 4-4.5mmol, 1, 4-dioxane 15-18ml, 2-2.5mol KOH solution 10-15ml, ethyl acetate 90-96ml, water and anhydrous Na in terms of acetylacetone 4.8mmol₂SO₄；

The specific process of the step (1) is as follows:

mixing 4.8mmol of acetylacetone and 2-2.2mmol of citric acid in a container to obtain a mixed solution, and stirring and refluxing; dissolving 4-4.5mmol of 2-aminobenzophenone in 15-18ml of 1, 4-dioxane under heating, slowly dripping into the mixed solution under stirring, adding 1.9-2.1mol of KOH solution into the reaction system after the reaction is finished, extracting with 30-32ml of ethyl acetate, washing with water to neutrality, and adding anhydrous Na₂SO₄Drying, suction filtering, spin drying, and ethanol recrystallization to obtain the compound 1- (2-methyl-4-phenylquinoline-3-yl) ethanone.

3. The method for preparing Chalcone derivatives QNL-Chalcone according to claim 2, wherein the heating temperature under the heating condition is 95-110 ℃.

4. The method for preparing novel Chalcone derivative QNL-Chalcone according to claim 2, wherein the number of times of ethyl acetate extraction is 3-4.

5. The method for preparing novel Chalcone derivative QNL-Chalcone according to claim 1, wherein in the step (2), the raw materials are charged in a ratio of 1- (2-methyl-4-phenylquinolin-3-yl) ethanone to 2mmol of 2-bromobenzaldehyde to 2.2-2.6mmol of 4-4.5% KOH in ethanol to 28-32ml of ice water to HCl to ether;

the specific process of the step (2) is as follows: mixing 2mmol of 1- (2-methyl-4-phenylquinoline-3-yl) ethanone and 2.2-2.6mmol of 2-bromobenzaldehyde in a container, adding 28-32ml of ethanol solution of 4-4.5% KOH, stirring for reaction, pouring the reaction solution into ice water after the reaction is finished, adjusting the pH of the solution to be neutral by using HCl, extracting by using ether, removing the ether, firstly spreading a column and then passing the column to finally obtain QNL-Chalcone.

6. The method for preparing Chalcone derivatives QNL-Chalcone according to claim 5, wherein the silica gel with 300-400 mesh size is used for the column.

7. The method for preparing Chalcone derivatives QNL-Chalcone according to claim 5, wherein the mixture of petroleum ether and ethyl acetate is used for the column, and the volume ratio of petroleum ether to ethyl acetate in the mixture is 20-22: 1.

8. The method for preparing Chalcone derivative QNL-Chalcone according to claim 5, wherein the ether is removed by combining ether layers and evaporating the ether under reduced pressure.

9. Use of the Chalcone derivative QNL-Chalcone according to of claims 1-8 for the preparation of a medicament with antidepressant activity.

10. The use according to claim 9, wherein the medicament is an injectable medicament.

Technical Field

The invention relates to the field of drug synthesis, in particular to a preparation method and application of Chalcone derivatives QNL-Chalcone.

Background

Depression is a disorder of affective activity manifested by abnormally low mood, often with a strong tendency to suicide, accompanied by symptoms associated with autonomic nerves or somatization. The clinical manifestations of the disease are unhappy, easy stimulation, sadness, uneasiness and bitterness, the indifference and lack of interest of surrounding things, the inhibition of thought and action and the signs of insomnia, the depression can have serious influence on the body functions of the human body, and the disease has the characteristics of high morbidity, difficult cure, high recurrence rate and the like. The treatment effect of the existing antidepressant is not ideal.

The compounds containing quinoline ring have antidepressant activity according to literature reports, and the chalcone compounds are important α -unsaturated ketones, have various activities and low toxicity, and researches show that the chalcone compounds have antidepressant activity.

The patent number CN201811494253.3, the patent name of which is "quinoline substituted chalcone compounds, a preparation method and an application thereof", discloses quinoline substituted chalcone novel compounds, medicinal salts thereof, a preparation method thereof, medicinal compositions which comprise a therapeutically effective amount of quinoline substituted chalcone novel compounds and/or medicinal salts thereof, and pharmaceutically acceptable carriers.

The method has the disadvantages of insufficient molecular activity, long synthetic route, high cost, high reaction control requirement and more side reactions in the synthetic process.

Disclosure of Invention

The invention provides a preparation method and application of Chalcone derivatives QNL-Chalcone in order to overcome the problems of insufficient molecular activity and long synthetic route of the invention in the prior art, which not only introduces quinoline nucleus, but also reserves an essential group of Chalcone activity, namely an propenone structure, so that the compound QNL-Chalcone has strong antidepressant activity and low side effect.

In order to achieve the purpose, the invention adopts the following technical scheme:

A method for preparing Chalcone derivative QNL-Chalcone, comprising the following steps:

(1) and synthesis of 1- (2-methyl-4-phenylquinolin-3-yl) ethanone:

(2) and synthesis of QNL-Chalcone:

preferably, in the step (1), the charging ratio of each raw material based on acetylacetone in 4.8mmol is as follows: acetylacetone, 4.8 mmol; 2-2.2mmol of citric acid; 4-4.5mmol of 2-aminobenzophenone; 15-18ml of 1, 4-dioxane; 2-2.5mol of KOH solution, 10-15 ml; ethyl acetate, 90-96 ml; water; anhydrous Na₂SO₄；

The specific process of the step (1) is as follows:

mixing 4.8mmol of acetylacetone and 2-2.2mmol of citric acid in a container to obtain a mixed solution, and stirring and refluxing; dissolving 4-4.5mmol of 2-aminobenzophenone in 15-18ml of 1, 4-dioxane under heating, slowly dripping into the mixed solution under stirring, adding 1.9-2.1mol of KOH solution into the reaction system after the reaction is finished, extracting with 30-32ml of ethyl acetate, washing with water to neutrality, and adding anhydrous Na₂SO₄Drying, suction filtering, spin drying, and ethanol recrystallization to obtain the compound 1- (2-methyl-4-phenylquinoline-3-yl) ethanone.

Preferably, the heating temperature of the heating condition is 95 to 110 ℃.

Preferably, the number of times of extraction with ethyl acetate is 3 to 4.

The synthesis mechanism of 1- (2-methyl-4-phenylquinolin-3-yl) ethanone:

acetyl acetone and 2-aminobenzophenone are subjected to nucleophilic addition-elimination reaction under the action of citric acid as a catalyst to obtain the 1- (2-methyl-4-phenylquinoline-3-yl) ethanone.

Preferably, in the step (2), the charging ratio of each raw material based on 2mmol of 1- (2-methyl-4-phenylquinolin-3-yl) ethanone is as follows: 1- (2-methyl-4-phenylquinolin-3-yl) ethanone, 2 mmol; 2-bromobenzaldehyde, 2.2-2.6 mmol; 4-4.5% KOH ethanol solution, 28-32 ml; ice water; HCl; diethyl ether;

the specific process of the step (2) is as follows: mixing 2mmol of 1- (2-methyl-4-phenylquinoline-3-yl) ethanone and 2.2-2.6mmol of 2-bromobenzaldehyde in a container, adding 28-32ml of ethanol solution of 4-4.5% KOH, stirring for reaction, pouring the reaction solution into ice water after the reaction is finished, adjusting the pH of the solution to be neutral by using HCl, extracting by using ether, removing the ether, firstly spreading a column and then passing the column to finally obtain QNL-Chalcone.

Preferably, the column is laid by using silica gel with the specification of 300-400 meshes.

Preferably, the column chromatography adopts a mixture of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate in the mixture is 20-22: 1.

Preferably, the ether is removed by combining the ether layers and distilling off the ether under reduced pressure.

Mechanism for the synthesis of QNL-Chalcone:

acetyl of 1- (2-methyl-4-phenylquinoline-3-yl) ethanone forms carbanion under the catalysis of potassium hydroxide, and then nucleophilic addition-elimination reaction (claisen-Schmidt condensation reaction) is carried out on carbonyl of m-bromobenzaldehyde to obtain the target compound

The Chalcone derivative QNL-Chalcone is applied to preparation of antidepressant active drugs.

Preferably, the medicament is an injectable medicament.

Therefore, the invention has the following beneficial effects:

(1) not only a quinoline mother nucleus is introduced, but also an acrylketone structure which is an essential group for Chalcone activity is reserved, so that the compound QNL-Chalcone with strong antidepressant activity and low side effect is obtained;

(2) the invention takes acetylacetone, 2-aminobenzophenone and 2-bromobenzaldehyde which are easy to obtain and low in price as raw materials, and the QNL-Chalcone is obtained by two-step synthesis, wherein the synthesis route of the medicine is short, and the cost is low;

(3) the process has good controllability, is easy for actual large-scale industrial mass production, and the prepared product has high yield and high purity.

Detailed Description

The present invention is further described in conjunction with the detailed description below.