阅读说明：本技术 一种羟基喹啉化合物的绿色合成方法 (Green synthesis method of hydroxyquinoline compound ) 是由 唐晓冬 吴银容 梁恩 于 2019-08-26 设计创作，主要内容包括：本发明公开了一种羟基喹啉化合物的绿色合成方法。所述羟基喹啉化合物的结构如式Ⅰ所示；其制备过程为：以R<Sub>1</Sub>取代2-甲基喹啉化合物和R<Sub>2</Sub>取代的苯甲醛化合物为原料,以酸为催化剂,以水作溶剂,加热反应,即可生成式Ⅰ所示羟基喹啉化合物。本发明所述方法以取代2-甲基喹啉类和取代苯甲醛化合物为原料,以酸为催化剂,以水作为溶剂进行反应,经一步反应即可得到羟基喹啉化合物；所述方法以水作为溶剂,避免了有机溶剂的使用,以酸为催化剂,避免了使用复杂性或高毒性的催化剂；反应条件温和、反应过程简单,符合绿色化学理念；所述反应的后处理简单,仅需简单的萃取、浓缩和柱层析即可获得高纯度的羟基喹啉化合物。<Image he="255" wi="564" file="DDA0002179388330000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses a green synthesis method of a hydroxyquinoline compound. The structure of the hydroxyquinoline compound is shown as a formula I; the preparation process comprises the following steps: with R 1 Substituted 2-methylquinoline compounds and R 2 The substituted benzaldehyde compound is used as a raw material, acid is used as a catalyst, water is used as a solvent, and the mixture is heated to react to generate the hydroxyquinoline compound shown as the formula I. The method takes substituted 2-methylquinoline and substituted benzaldehyde compounds as raw materials, takes acid as a catalyst, takes water as a solvent for reaction, and can obtain a hydroxyquinoline compound through one-step reaction; the method takes water as a solvent, avoids the use of an organic solvent, takes acid as a catalyst, and avoids the use of a complex or highly toxic catalyst; the reaction condition is mild, the reaction process is simple, and the green chemical concept is met; the reactionThe post-treatment is simple, and the high-purity hydroxyquinoline compound can be obtained only by simple extraction, concentration and column chromatography.)

1. The green synthesis method of the hydroxyquinoline compound is characterized in that the hydroxyquinoline compound has a structure shown in a formula I:

wherein R is₁Is hydrogen, halogen, C_1～4Alkyl radical, C_1～4Haloalkyl, C_1～4Alkoxy or C_1～4A haloalkoxy group; r₂Is hydrogen, phenyl, naphthyl or substituted phenyl; the substituent in the substituted phenyl is halogen and C_1～4Alkyl radical, C_1～4Haloalkyl, C_1～4Alkoxy radical, C_1～4One or more of haloalkoxy, cyano or phenyl;

the preparation process comprises the following steps: with R₁Substituted 2-methylquinoline compounds and R₂The substituted benzaldehyde compound is used as a raw material, acid is used as a catalyst, water is used as a solvent, and the mixture is heated to react to generate the hydroxyquinoline compound shown as the formula I.

2. The green synthesis method of a hydroxyquinoline compound according to claim 1, wherein R is₁The structure of the substituted 2-methylquinoline compound is shown as the formula II:

wherein R is₁Is hydrogen, halogen, C_1～4Alkyl radical, C_1～4Haloalkyl, C_1～4Alkoxy or C_1～4A haloalkoxy group.

3. The green synthesis method of a hydroxyquinoline compound according to claim 1, wherein R is₂The structure of the substituted benzaldehyde compound is shown as a formula III:

wherein R is₂Is hydrogen, phenyl, naphthyl or substituted phenyl; the substituent in the substituted phenyl is halogen and C_1～4Alkyl radical, C_1～4Haloalkyl, C_1～4Alkoxy radical, C_1～4One or more of haloalkoxy, cyano or phenyl.

4. A green synthesis method of a hydroxyquinoline compound according to any one of claims 1 to 3, wherein R is₁Is hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, propoxy, trifluoromethoxy, or trifluoroethoxy; r₂Is hydrogen, phenyl, naphthyl or substituted phenyl; the substituent in the substituted phenyl is one or more of halogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, propoxy, trifluoromethoxy, trifluoroethoxy, cyano or phenyl.

5. The green synthesis method of the hydroxyquinoline compound according to claim 1, wherein the acid is one or more of glacial acetic acid, hydrochloric acid, hydrobromic acid, trifluoroacetic acid, pivalic acid, nitric acid, L-proline, ferric chloride, or zinc chloride.

6. A green synthesis method of a hydroxyquinoline compound according to claim 5, wherein the acid is one or more of glacial acetic acid, hydrochloric acid, pivalic acid or nitric acid.

7. The green synthesis method of the hydroxyquinoline compound according to claim 1, wherein the temperature of the heating reaction is 80 ℃ to 120 ℃.

8. The green synthesis method of a hydroxyquinoline compound according to claim 1, wherein R is₁Substituted 2-methylquinoline compounds and R₂The molar ratio of the substituted benzaldehyde compound is 1-2: 1;

the R is₁The molar ratio of the substituted 2-methylquinoline compound to the acid is 1: 0.1-0.3.

9. The green synthesis method of the hydroxyquinoline compound according to any one of claims 1 to 8, characterized in that, after the reaction is finished, the reaction solution is extracted with ethyl acetate, the organic phase is collected and concentrated to obtain a crude product; and then carrying out column chromatography separation on the crude product to obtain the hydroxyquinoline compound shown in the formula I.

10. The green synthesis method of the hydroxyquinoline compound as claimed in claim 9, wherein the mobile phase of the column chromatography is petroleum ether and ethyl acetate, and gradient elution is performed at a volume ratio of (5-30): 1.

Technical Field

The invention relates to the technical field of organic synthesis, and particularly relates to a green synthesis method of a hydroxyquinoline compound.

Background

In organic synthesis, the use of a large amount of flammable, explosive and volatile organic solvents brings great harm to the environment, so how to reduce the use of the organic solvents or find a substitute for the organic solvents plays a very important role in organic synthesis. In recent years, organic synthesis using water as a solvent has been a focus of research. With the discovery of more and more aqueous phase reaction catalysts, there are increasingly relevant aqueous phase organic reactions reported (Butler, r.n. and Coyne, a.g. chem.rev.2010,110, 6302-6337; kitanoson, t.; Masuda, k.; Xu, p.and Kobayashi, s.chem.rev.2018,118, 679-746). Compared with the traditional solvent, water as the organic reaction solvent has the unique advantages of safety, low price, no toxicity, no pollution and the like, and accords with the concept of green chemistry.

The greatest advantages of the organic small molecule catalyst compared with the metal catalyst are that: metal catalysts are not only expensive, but also sensitive to water and air, and thus the reaction conditions are generally severe. The organic small molecular catalyst has the advantages of simple and mild catalytic reaction conditions, environmental friendliness, stability, easy obtainment and recovery, low toxicity, low price and the like, and is widely concerned by chemists (Chauhan, P.; Mahajan, S.and Enders, D.Acc.chem.Res.2017,50, 2809-.

Quinoline compounds are an important nitrogen heterocyclic compound, are widely distributed in natural products and pharmaceutically active molecules, and are a hot spot of current pharmaceutical research. On the other hand, hydroxyl groups are not only one of the most common functional groups in organic synthesis, but can be further converted into other various functional groups, and are also common groups in pharmaceutically active molecules. Therefore, it is very important to research the green synthesis method of the hydroxyquinoline compound for the development of synthesis methodology and pharmaceutical chemistry.

Disclosure of Invention

The invention aims to provide a green synthetic method of a hydroxyquinoline compound, aiming at the defects that in the prior art, the preparation of the hydroxyquinoline compound needs to be carried out in multiple steps, each step of reaction needs to consume a large amount of organic solvent, metal catalyst and the like, the 2-methylquinoline compound has a single conversion mode, harsh reaction conditions, multiple side reactions, difficult product separation and the like. The method takes substituted 2-methylquinolines and substituted benzaldehyde compounds as raw materials, takes acid as a catalyst, takes water as a solvent to carry out reaction, and then the hydroxyquinoline compound can be prepared; the preparation method avoids the use of organic solvents, has simple reaction conditions, uses small molecules as the used catalyst, avoids the use of complex or highly toxic catalysts, and accords with the green chemical concept.

The above object of the present invention is achieved by the following scheme:

a green synthesis method of a hydroxyquinoline compound is disclosed, wherein the structure of the hydroxyquinoline compound is shown as a formula I:

wherein R is₁Is hydrogen, halogen, C_1～4Alkyl radical, C_1～4Haloalkyl, C_1～4Alkoxy or C_1～4A haloalkoxy group; r₂Is hydrogen, phenyl, naphthyl or substituted phenyl; the substituent in the substituted phenyl is halogen and C_1～4Alkyl radical, C_1～4Haloalkyl, C_1～4Alkoxy radical, C_1～4One or more of haloalkoxy, cyano or phenyl;

the preparation process comprises the following steps: with R₁Substituted 2-methylquinoline compounds and R₂The substituted benzaldehyde compound is used as a raw material, acid is used as a catalyst, water is used as a solvent, and the mixture is heated to react to generate the hydroxyquinoline compound shown as the formula I.

In the preparation method of the invention, R₁Substituted dimethylquinolines are firstly isomerized into enamines under the catalysis of acid; then, enamine and substituted benzaldehyde undergo nucleophilic substitution reaction to obtain a hydroxyquinoline compound; the preparation method adopts specific raw materials, takes acid as a catalyst and water as a solvent, the substituted 2-methylquinoline can perform nucleophilic addition reaction with the substituted benzaldehyde compound, the hydroxyquinoline compound can be prepared by one-step reaction, the reaction process is simple, a large amount of organic solvent and metal catalyst are not needed in the reaction, and the reaction condition is mild, simple and convenientIs simple and environment-friendly, and accords with the green chemical concept.

Preferably, said R is₁The structure of the substituted 2-methylquinoline compound is shown as the formula II:

wherein R is₁Is hydrogen, halogen, C_1～4Alkyl radical, C_1～4Haloalkyl, C_1～4Alkoxy or C_1～4A haloalkoxy group.

Preferably, said R is₂The structure of the substituted benzaldehyde compound is shown as a formula III:

wherein R is₂Is hydrogen, phenyl, naphthyl or substituted phenyl; the substituent in the substituted phenyl is halogen and C_1～4Alkyl radical, C_1～4Haloalkyl, C_1～4Alkoxy radical, C_1～4One or more of haloalkoxy, cyano or phenyl.

More preferably, said R₁Is hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, propoxy, trifluoromethoxy, or trifluoroethoxy; r₂Is hydrogen, phenyl, naphthyl or substituted phenyl; the substituent in the substituted phenyl is one or more of halogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, propoxy, trifluoromethoxy, trifluoroethoxy, cyano or phenyl.

More preferably, said R₁Is hydrogen, halogen, methyl, ethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, trifluoromethoxy or trifluoroethoxy; r₂Is hydrogen, phenyl, naphthyl or substituted phenyl; the substituent in the substituted phenyl is halogen, methyl, ethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, propoxy, trifluoromethoxy, methoxy, ethoxy, trifluoromethyl,one or more of trifluoroethoxy, cyano, or phenyl.

Preferably, the acid is one or more of glacial acetic acid, hydrochloric acid, hydrobromic acid, trifluoroacetic acid, pivalic acid, nitric acid, L-proline, ferric chloride or zinc chloride.

Preferably, the acid is one or more of glacial acetic acid, hydrochloric acid, pivalic acid or nitric acid; more preferably, the acid is glacial acetic acid.

Preferably, the temperature of the heating reaction is 80-120 ℃; more preferably, the temperature of the heating reaction is 100 ℃.

Preferably, said R is₁Substituted 2-methylquinoline compounds and R₂The molar ratio of the substituted benzaldehyde compound is 1-2: 1; more preferably, the molar ratio is 1.5: 1.

Preferably, said R is₁The molar ratio of the substituted 2-methylquinoline compound to the acid is 1: 0.1-0.3; more preferably, the molar ratio is 1: 0.2.

Preferably, after the reaction is finished, extracting the reaction solution by using ethyl acetate, collecting an organic phase, and concentrating to obtain a crude product; and then carrying out column chromatography separation on the crude product to obtain the hydroxyquinoline compound shown in the formula I.

Preferably, the mobile phase of the column chromatography is petroleum ether and ethyl acetate, and gradient elution is carried out according to the volume ratio of (5-30): 1; more preferably, the mobile phase is a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 20: 1.

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

the method takes substituted 2-methylquinoline and substituted benzaldehyde compounds as raw materials, takes acid as a catalyst, takes water as a solvent for reaction, and can obtain a hydroxyquinoline compound through one-step reaction; the method takes water as a solvent, avoids the use of an organic solvent, takes acid as a catalyst, and avoids the use of a complex or highly toxic catalyst; the reaction condition is mild, the reaction process is simple, and the green chemical concept is met;

the post-treatment of the reaction is simple, and the high-purity hydroxyquinoline compound can be obtained only by simple extraction, concentration and column chromatography; has wide application prospect for the preparation and the application of the hydroxyquinoline compound.

Detailed Description

The present invention is further described in detail below with reference to specific examples, which are provided for illustration only and are not intended to limit the scope of the present invention. The test methods used in the following examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are, unless otherwise specified, commercially available reagents and materials.