阅读说明：本技术 一种2-喹啉基苯基酮化合物的制备方法 (Preparation method of 2-quinolyl phenyl ketone compound ) 是由 赵西梅 王光辉 贾健 刘希光 于 2021-08-10 设计创作，主要内容包括：本发明公开了一种2-喹啉基苯基酮化合物的制备方法,以2-乙炔基苯胺、苯基乙二醛、哌啶为起始原料,通过金催化三组分偶联反应(A～(3) couplings)以及分子内缩合反应,一步合成2-喹啉基苯基酮。此制备方法原料廉价易得、操作步骤简单,反应条件温和,原子经济性高,区域选择性优异,适合规模化工业生产的需要。制备得到的2-喹啉基苯基酮是一种重要的活性药物分子,可以作为大麻素CB-(2)受体兴奋剂。(The invention discloses a preparation method of a 2-quinolyl phenyl ketone compound, which takes 2-ethynyl aniline, phenyl glyoxal and piperidine as initial raw materials and carries out gold-catalyzed three-component coupling reaction (A) 3 couplings) and intramolecular condensation reaction to synthesize the 2-quinolyl phenyl ketone in one step. The preparation method has the advantages of cheap and easily-obtained raw materials, simple operation steps, mild reaction conditions, high atom economy and excellent regioselectivity, and is suitable for the requirement of large-scale industrial production. The prepared 2-quinolyl phenyl ketone is an important active drug molecule and can be used as cannabinoid CB 2 A receptor agonist.)

1. A preparation method of a 2-quinolyl phenyl ketone compound is characterized in that 2-ethynylaniline shown in a formula (II), phenyl glyoxal shown in a formula (III) and piperidine shown in a formula (IV) are used as starting raw materials, AuCl shown in a formula (V) is used as a catalyst, methylbenzene is used as a solvent, and the 2-quinolyl phenyl ketone compound is synthesized through a one-step reaction;

2. a method for producing a 2-quinolylphenylketone compound according to claim 1, which comprises the steps of: adding 2-ethynylaniline, phenyl glyoxal, piperidine and AuCl into a drying container, then adding toluene, heating and stirring for reaction, cooling to room temperature after the reaction is finished, extracting for a plurality of times by using ethyl acetate, combining extract liquor, vacuumizing and decompressing to remove the solvent, and separating by silica gel column chromatography to obtain the 2-quinolylphenyl ketone compound.

3. The method of claim 2, wherein the molar ratio of 2-ethynylaniline, phenylglyoxal, piperidine and AuCl is 1:1.1:1.1: 0.01.

4. A method for producing a 2-quinolylphenylketone compound according to claim 2, wherein the toluene is added in an amount of: 1.0mL of toluene was added to 1.0mmol of 2-ethynylaniline.

5. The method for producing a 2-quinolylphenylketone compound according to claim 2, wherein the heating and stirring reaction is carried out at 50 ℃ for 2 hours.

6. The method for producing a 2-quinolylphenylketone compound according to claim 2, wherein the extraction with ethyl acetate is carried out 3 times at room temperature.

7. A process for producing a 2-quinolylphenylketone compound as claimed in claim 2, wherein the eluent used in the separation by silica gel column chromatography is petroleum ether: ethyl acetate ═ 20: 1.

8. the method of claim 1, wherein the nuclear magnetic spectrum data of the synthesized 2-quinolylphenylketone compound is as follows:¹H NMR(400MHz,CDCl₃):δ8.38(d,J＝8.4Hz,1H),8.30-8.21(m,3H),8.14(d,J＝8.5Hz,1H),7.94(d,J＝8.2Hz,1H),7.85-7.79(m,1H),7.73-7.62(m,2H),7.55(dd,J＝8.4,7.0Hz,2H).¹³C NMR(100MHz,CDCl₃):δ193.9,154.8,146.9,137.2,136.3,133.2,131.6,130.7,130.2,129.0,128.6,128.3,127.8,120.9。

Technical Field

The invention belongs to the technical field of fine chemical engineering, and particularly relates to a preparation method of a 2-quinolyl phenyl ketone compound.

Background

2-quinolylphenyl ketone compound is an important active drug molecule and can be used as cannabinoid CB₂A receptor agonist. At present, the method for synthesizing 2-quinolyl phenyl ketone compound is shown as the following reaction formula, quinoline (VI) is used as initial raw material, quinoline N-oxide intermediate (VII) is obtained by oxidation of m-CPBA, 2-halogenated quinoline is obtained by reaction with acyl chloride, then aryl nucleophilic substitution reaction is carried out on the 2-halogenated quinoline and KCN to generate 2-cyano quinoline (VIII), and then 2-quinolyl phenyl ketone compound is generated by reaction with Grignard reagent(I) In that respect The preparation method not only needs to use highly toxic cyanide, but also has complex operation steps and poor regioselectivity and atom economy. Therefore, the development of a safe and efficient method for synthesizing the 2-quinolylphenyl ketone compound has important research value.

Disclosure of Invention

The invention aims to provide a preparation method of a 2-quinolyl phenyl ketone compound, which overcomes the defects of the prior art, and has the advantages of cheap and easily-obtained raw materials, simple operation steps, mild reaction conditions, high atom economy and excellent regioselectivity, and is suitable for the requirement of large-scale industrial production.

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

a preparation method of a 2-quinolyl phenyl ketone compound comprises the steps of taking 2-ethynylaniline shown in a formula (II), phenyl glyoxal shown in a formula (III) and piperidine shown in a formula (IV) as initial raw materials, taking AuCl shown in a formula (V) as a catalyst and toluene as a solvent, and synthesizing the 2-quinolyl phenyl ketone compound through one-step reaction;

further, the specific steps are as follows: adding 2-ethynylaniline, phenyl glyoxal, piperidine and AuCl into a drying container, then adding toluene, heating and stirring for reaction, cooling to room temperature after the reaction is finished, extracting for a plurality of times by using ethyl acetate, combining extract liquor, vacuumizing and decompressing to remove the solvent, and separating by silica gel column chromatography to obtain the 2-quinolylphenyl ketone compound.

Further, the molar ratio of the 2-ethynylaniline, the phenylglyoxal, the piperidine and the AuCl is 1:1.1:1.1: 0.01.

Further, the addition amount of the toluene is as follows: 1.0mL of toluene was added to 1.0mmol of 2-ethynylaniline.

Further, the temperature of the heating stirring reaction is 50 ℃, and the stirring time is 2 h.

Further, the mixture was cooled to room temperature and extracted with ethyl acetate 3 times.

Further, when the separation is carried out by silica gel column chromatography, the eluent adopts petroleum ether: ethyl acetate ═ 20: 1.

further, the nuclear magnetic spectrum data of the synthesized 2-quinolyl phenyl ketone compound is as follows:¹H NMR(400MHz,CDCl₃):δ8.38(d,J＝8.4Hz,1H),8.30-8.21(m,3H),8.14(d,J＝8.5Hz,1H),7.94(d,J＝8.2Hz,1H),7.85-7.79(m,1H),7.73-7.62(m,2H),7.55(dd,J＝8.4,7.0Hz,2H).¹³C NMR(100MHz,CDCl₃):δ193.9,154.8,146.9,137.2,136.3,133.2,131.6,130.7,130.2,129.0,128.6,128.3,127.8,120.9。

compared with the prior art, the invention has the following beneficial technical effects:

the preparation method provided by the invention starts from a new reaction type, and avoids the problems of the traditional method, such as use of virulent cyanide, complicated operation steps, poor regioselectivity and poor atom economy. The preparation method has the advantages of cheap and easily-obtained raw materials, simple operation steps, mild reaction conditions, high atom economy and excellent regioselectivity, and is suitable for the requirement of large-scale industrial production. The prepared 2-quinolyl phenyl ketone is an important active drug molecule and can be used as cannabinoid CB₂A receptor agonist.

Drawings

The accompanying drawings are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention and not to limit the invention.

FIG. 1 is a schematic representation of 2-quinolylphenyl ketones prepared in accordance with the present invention¹H NMR spectrum.

FIG. 2 is a schematic representation of 2-quinolylphenyl ketones prepared in accordance with the present invention¹³C NMR spectrum.

Detailed Description

The invention is described in further detail below:

a process for preparing 2-quinolyl phenylketone compound safely and efficiently features that 2-ethynyl aniline, phenylglyoxal and piperidine are used as initial raw materials, and three-component coupling reaction is catalyzed by Au (A)³couplings) and intramolecular condensation reaction to synthesize the 2-quinolyl phenyl ketone in one step.

The structural formula of the 2-quinolyl phenyl ketone compound is shown as (I).

The nuclear magnetic spectrum data of the 2-quinolyl phenyl ketone compound are as follows:¹H NMR(400MHz,CDCl₃):δ8.38(d,J＝8.4Hz,1H),8.30-8.21(m,3H),8.14(d,J＝8.5Hz,1H),7.94(d,J＝8.2Hz,1H),7.85-7.79(m,1H),7.73-7.62(m,2H),7.55(dd,J＝8.4,7.0Hz,2H).¹³C NMR(100MHz,CDCl₃):δ193.9,154.8,146.9,137.2,136.3,133.2,131.6,130.7,130.2,129.0,128.6,128.3,127.8,120.9.

the specific preparation scheme of the 2-quinolylphenyl ketone compound is as follows: 2-ethynylaniline, phenyl glyoxal and piperidine are used as starting materials, and a target product is synthesized through one-step reaction. The method comprises the following specific steps: 2-ethynylaniline (II), phenyl glyoxal (III) and piperidine (IV) react for 2h in toluene solvent at 50 ℃ under the catalysis of AuCl (V) (1 mol%) to obtain 2-quinolylphenylketone compound (I). The preparation method does not need anhydrous and anaerobic conditions, has simple operation steps, and has cheap and easily obtained compounds (II), (III) and (IV).

The reaction equation for preparing 2-quinolylphenylketone compounds is as follows:

the present invention will be described in detail with reference to examples. It should be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict.

The following detailed description is illustrative of the embodiments and is intended to provide further details of the invention. Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the invention.

Examples

The preparation method of the 2-quinolyl phenyl ketone compound comprises the following specific steps:

2-ethynylaniline (II) (117.2mg,1.0mmol,1.0eq.), phenylglyoxal (III) (147.6mg,1.1mmol,1.1eq.), piperidine (IV) (93.7mg,1.1mmol,1.1eq.), AuCl (V) (2.32mg, 0.01mmol,0.01eq.), was added to a dried stirred flask, followed by 1.0mL of toluene and stirring with heating at 50 ℃ for 2 h. After cooling to room temperature, extraction was performed with ethyl acetate (10mL × 3 times), the extracts were combined, the solvent was removed under reduced pressure by vacuum filtration, and silica gel column chromatography (petroleum ether: ethyl acetate: 20: 1) was performed to obtain 2-quinolylphenylketone compound (I) (212.3mg, 91%). The nuclear magnetic spectrum data is as follows through nuclear magnetic analysis:¹H NMR(400MHz,CDCl₃):δ8.38(d,J＝8.4Hz,1H),8.30-8.21(m,3H),8.14(d,J＝8.5Hz,1H),7.94(d,J＝8.2Hz,1H),7.85-7.79(m,1H),7.73-7.62(m,2H),7.55(dd,J＝8.4,7.0Hz,2H).¹³C NMR(100MHz,CDCl₃):δ193.9,154.8,146.9,137.2,136.3,133.2,131.6,130.7,130.2,129.0,128.6,128.3,127.8,120.9.

the above-mentioned 2-quinolylphenylketone compound is prepared according to the following reaction equation:

the embodiments described above are merely preferred embodiments of the present invention, and should not be considered as limitations of the present invention, and features in the embodiments and examples in the present application may be arbitrarily combined with each other without conflict. The protection scope of the present invention is defined by the claims, and includes equivalents of technical features of the claims. I.e., equivalent alterations and modifications within the scope hereof, are also intended to be within the scope of the invention.