CN116283761B

CN116283761B - A 3-alkenyl ketone substituted quinoline-2-one and a green synthesis method thereof

Info

Publication number: CN116283761B
Application number: CN202310090527.7A
Authority: CN
Inventors: 胡方芝; 王保桂; 李帅帅; 王鹏
Original assignee: Qingdao Agricultural University
Current assignee: Qingdao Agricultural University
Priority date: 2023-02-02
Filing date: 2023-02-02
Publication date: 2024-06-28
Anticipated expiration: 2043-02-02
Also published as: CN116283761A

Abstract

The invention discloses a 3-alkenyl ketone substituted quinoline-2-ketone skeleton with biological activity and a green synthesis method thereof. The invention provides a structure of a 3-alkenyl ketone substituted quinoline-2-ketone bioactive framework. The structural formula of the 3-alkenyl ketone substituted quinoline-2-ketone bioactive framework is as follows: Wherein R ² is any one of ethyl and n-propyl; r ³ is any one of hydrogen atom, alkyl, halogen, trifluoromethyl and cyano. The invention provides a synthesis method thereof, which comprises the following steps: reacting an anthranilaldehyde compound with 4-hydroxy-6-methyl-2-pyrone under a certain condition to prepare the 3-alkenyl ketone substituted quinoline-2-ketone compound. The invention provides a method for synthesizing 3-alkenyl ketone substituted quinoline-2-ketone compounds with various structures.

Description

3-Alkenyl ketone substituted quinoline-2-ketone and green synthesis method thereof

Technical Field

The invention relates to the technical field of pharmaceutical intermediates and chemical synthesis, in particular to a 3-alkenyl ketone substituted quinoline-2-ketone structure with bioactivity and a green synthesis method thereof.

Background

The quinoline-2-ketone and the derivative thereof are important heterocyclic compounds, have good biological activity, are widely applied in the field of medicine, and play an important role in the treatment of diseases such as cancer, atherosclerosis, schizophrenia, parkinson, alzheimer disease and the like. For example, aripiprazole is a novel atypical antipsychotic marketed in the united states in 2002 for the treatment of schizophrenia; rebamipide plays an important role in promoting regeneration of mucosal tissue, reducing tissue inflammatory reaction, enhancing mucosal barrier function, etc., and is a novel antiulcer agent marketed in japan in 1990; tipirfenib is a novel antitumor drug which can be used for treating myeloma and other cancers, and enters into clinical research of III phase in the United states at present, and the drugs are all quinoline-2-ketone derivatives. In view of the importance of the quinolin-2-one skeleton in the medical field, it is important to efficiently construct quinolin-2-one, especially a multi-functional substituted quinolin-2-one skeleton.

In 2014, the professor "Xiaoqu" of Henan university of industry used benzoyl formic acid and alkenylamide as raw materials and silver nitrate as a catalyst, and constructed a 3, 4-dihydro-3-benzoyl-2 (1H) -quinolinone skeleton by radical reaction (J.org.chem., 2014,79,8094-8102). However, the reaction requires 2 equivalents of potassium thiosulfate as the oxidizing agent and requires a high temperature of 100 degrees to be carried out.

In 2019, the central university of ethnic group life and environmental sciences institute Luo Feixian doctor reported that the transition metal Pd/Cu synergistically catalyzes the tandem hydrocarbon arylation and intramolecular amination reaction, and a one-pot method was used to synthesize a 3, 4-dihydro-2 (1H) -quinolinone backbone (org.lett., 2019,21,1668-1671). The reaction requires not only a relatively expensive metal catalyst, but also a reaction at 140 degrees.

Although the above reactions can synthesize quinolin-2-one frameworks with high efficiency, expensive metal catalysts or high temperature reaction conditions greatly limit the application of these reactions, especially limiting the further industrialization of pharmaceutical manufacturing enterprises.

Therefore, how to use cheap and easily available raw materials, green and mild reaction conditions to efficiently construct the quinoline-2-ketone skeleton, solves the problems existing in the current organic synthesis method, and synthesizes a series of quinoline-2-ketone derivatives is the problem to be solved at present.

Disclosure of Invention

The invention aims at overcoming the defects of the prior art and provides a 3-alkenyl ketone substituted quinoline-2-ketone structure with bioactivity and a green synthesis method thereof. The novel 3-alkenyl ketone substituted quinoline-2-ketone bioactive skeleton provided by the invention provides a novel model molecule for drug development. The synthesis method of the 3-alkenyl ketone substituted quinoline-2-ketone bioactive framework is based on the hydrogen migration process, the framework is efficiently synthesized in one step, the operation is simple, the efficiency is high, the practicability is high, the constructed framework contains various functional groups, and the later synthesis application of the framework is facilitated.

The technical scheme of the invention is realized as follows:

The 3-alkenyl ketone substituted quinoline-2-ketone bioactive framework has the structural formula shown as follows:

wherein R ¹,R² is any one of ethyl and n-propyl; r ³ is any one of hydrogen atom, alkyl, halogen, trifluoromethyl and cyano.

The compounds of the present invention may exist in the form of one or more stereoisomers. The various isomers include tautomers, geometric isomers, enantiomers, diastereomers and the like. These isomers and mixtures of these isomers are all within the scope of the present invention.

The invention also provides a synthesis method of the 3-alkenyl ketone substituted quinoline-2-ketone bioactive framework, and a synthetic process route diagram of the invention is shown in figure 1, and the synthesis method comprises the following steps:

Uniformly mixing an anthranilate compound and 4-hydroxy-6-methyl-2-pyrone in a solvent, and reacting at 100-120 ℃ to prepare a 3-alkenyl ketone substituted quinoline-2-ketone compound;

Wherein, the structural formula of the o-aminobenzaldehyde compound is shown as follows:

Wherein the structural formula of the 4-hydroxy-6-methyl-2-pyrone is as follows:

the reaction condition can be detected by thin layer chromatography, and the purification is carried out after the reaction is finished, so as to obtain the purified product of the 3-alkenyl ketone substituted quinoline-2-ketone compound.

The reaction process specifically comprises the following steps:

O-aminobenzaldehyde compound and 4-hydroxy-6-methyl-2-pyrone are subjected to Knoevenagel condensation reaction to form intermediate product electron-deficient olefin, the electron-deficient olefin is used as driving force to initiate intramolecular hydrogen migration to form an imine intermediate, then the imine intermediate containing amino and lactone is generated through dealkylation in the process of imine hydrolysis, and finally the final product 3-alkenyl ketone substituted quinoline-2-ketone is generated through intramolecular acylation reaction. The synthetic route is specifically as follows:

preferably, the synthesis process as described above is carried out at 120 ℃.

Preferably, the solvent used in the above reaction is green and pollution-free water. The solvent is used in the following amount: 10-20L of solvent is added to each mole of o-aminobenzaldehyde compound.

Preferably, the synthesis reaction does not adopt a catalyst, so that the product synthesis cost is effectively reduced.

The compounds of the present invention may exist in the form of one or more stereoisomers. The various isomers include geometric isomers. These isomers, including mixtures of these isomers, are within the scope of the present invention.

The beneficial effects of the invention are as follows:

1. according to the invention, under mild reaction conditions, the 3-alkenyl ketone substituted quinoline-2-ketone skeleton is efficiently synthesized by one-step reaction, and the technical scheme of the invention provides a convenient and concise synthesis method for the 3-alkenyl ketone substituted quinoline-2-ketone skeleton, so that the 3-alkenyl ketone substituted quinoline-2-ketone skeleton is efficiently constructed through a hydrogen migration process for the first time.

2. The invention develops a method for efficiently synthesizing 3-alkenyl ketone substituted quinoline-2-ketone compounds with multiple functional groups and multiple structures, provides a compound library with multiple structures and 3-alkenyl ketone substituted quinoline-2-ketone frameworks, and provides a novel model molecule for drug development.

3. The method has mild reaction conditions, the 3-alkenyl ketone substituted quinoline-2-ketone compound is synthesized in water through one-step reaction, the substrate universality is good, the substrate substituent can be an electron-withdrawing group or an electron-donating group, and the position of the substituent has no obvious influence on the reaction yield. The invention provides experimental basis for the efficient construction of 3-alkenyl ketone substituted quinoline-2-ketone skeleton with good biological activity, and has good practical significance and application value.

Drawings

FIG. 1 is a synthetic process scheme of the present invention.

Detailed Description

The following description of the embodiments of the present invention will clearly and fully describe the technical solutions of the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and/or" as used in this specification includes any and all combinations of one or more of the associated listed items.

The experimental methods used in the following examples are all conventional methods unless otherwise specified; reagents, materials, instruments, etc. used in the examples described below are all commercially available unless otherwise specified; the reaction vessel used in the examples below was a 25mL thick-walled pressure-resistant tube.

Example 1

The embodiment provides a synthesis method of a 3-alkenyl ketone substituted quinoline-2-ketone bioactive framework, which comprises the following steps:

taking 0.1mmol of N-diethyl substituted o-aminobenzaldehyde compound in a reaction tube, sequentially adding 1mL of solvent, adding 0.12mmol of 4-hydroxy-6-methyl-2-pyrone, controlling the reaction temperature of the system, continuously stirring, and carrying out sample application tracking reaction through a thin layer chromatography plate until the raw materials are completely reacted. After the reaction is completed, separating and purifying by using a silica gel column, and rotary steaming the purified product to obtain a target product. The reaction formula is as follows:

2. according to the method, the following 10 parallel test groups are set, and different reaction conditions are respectively adopted, such as: different raw material proportions, different solvents, different solvent volumes, different temperatures. The specific settings for the different test groups are shown in Table 1:

TABLE 1 reaction yield of anthranilaldehyde with 4-hydroxy-6-methyl-2-pyruvic ketone under different conditions

From the above analysis of parallel test results, it can be seen that: when water is used as a solvent in the synthesis reaction, 10-20L of the solvent is added per mol of the o-aminobenzaldehyde compound, and the reaction can be carried out; when 10L of water is added to each mole of o-aminobenzaldehyde compound, the yield is highest; the reaction temperature is 120 ℃, and the yield is the highest. In addition, under the optimal reaction conditions, 30% of acetic acid or triethylamine is added as a catalyst in the reaction, the reaction yield is low,

In the following examples 2 to 10, reactions were carried out according to the procedure of example 1; in the reaction system, raw materials of o-aminobenzaldehyde compound and 4-hydroxy-6-methyl-2-pyrone are respectively 0.1mmol and 0.12mmol, water is used as a solvent, and the reaction is continuously stirred at 120 ℃ until the raw materials are completely reacted, so that corresponding target products are respectively obtained.

Example 2

Raw materials: n-diethyl-substituted anthranilic acid, 4-hydroxy-6-methyl-2-pyrone

The product is: the chemical formula: c ₁₅H₁₇NO₃

Molecular weight: 259.1208

Structural formula:

Yield: 85%

¹H NMR(500MHz,CDCl₃)δ15.04(s,1H),7.22–7.17(m,1H),7.13(t,J＝7.2Hz,1H),6.96(dd,J＝13.4,7.0Hz,2H),5.57(s,1H),4.02–3.87(m,2H),3.46(t,J＝6.8Hz,1H),3.25(dd,J＝15.6,7.7Hz,1H),2.97(dd,J＝15.6,5.8Hz,1H),1.95(s,3H),1.21(dd,J＝15.8,7.9Hz,3H).¹³C NMR(125MHz,CDCl₃)δ191.5,188.5,166.9,138.6,128.4,127.8,124.7,123.2,114.7,99.8,50.7,37.9,28.2,23.9,12.6.HRMS(ESI)m/z:[M+Na]⁺calcd.for C₁₅H₁₇NNaO₃:282.1101,found:282.1097.

Example 3

Raw materials: N-di-N-propyl substituted anthranilic acid, 4-hydroxy-6-methyl-2-pyrone

The product is: the chemical formula: c ₁₆H₁₉NO₃

Molecular weight: 273.1365

Structural formula:

yield: 65%

¹H NMR(500MHz,CDCl₃)δ15.09(s,1H),7.24(d,J＝7.8Hz,1H),7.20(d,J＝7.2Hz,1H),7.01(dd,J＝19.4,7.7Hz,2H),5.64(s,1H),3.98–3.85(m,2H),3.55(t,J＝6.5Hz,1H),3.31(dt,J＝16.2,8.2Hz,1H),3.04(dd,J＝15.6,5.7Hz,1H),2.02(s,3H),1.69(dt,J＝15.6,7.7Hz,2H),0.97(t,J＝7.7Hz,3H).¹³CNMR(125MHz,CDCl₃)δ191.6,188.3,167.1,138.7,128.4,127.7,124.8,123.2,114.9,99.8,50.8,44.3,28.2,23.9,20.4,11.3.HRMS(ESI)m/z:[M+H]⁺calcd.for C₁₆H₂₀NO₃:274.1438,found:274.1434.

Example 4

Raw materials: n, N-diethyl-2-amino-6-fluorobenzaldehyde, 4-hydroxy-6-methyl-2-pyrone

The product is: the chemical formula: c ₁₅H₁₆FNO₃

Molecular weight: 277.1114

Structural formula:

Yield: 63%

¹H NMR(500MHz,CDCl₃)δ15.04(s,1H),7.21(dd,J＝14.8,7.3Hz,1H),6.80(t,J＝8.7Hz,2H),5.66(s,1H),4.00(m,2H),3.55(t,J＝6.2Hz,1H),3.40(dd,J＝16.1,7.0Hz,1H),3.02(dd,J＝16.1,5.6Hz,1H),2.03(s,3H),1.27(d,J＝7.7Hz,3H).¹³C NMR(125MHz,CDCl₃)δ191.4,188.2,166.5,160.0(d,J＝242.5Hz),140.34(d,J＝6.4Hz),128.44(d,J＝9.5Hz),112.1(d,J＝21.3Hz),110.3(d,J＝8.8Hz),110.2(d,J＝11.2Hz),99.6,49.9,38.3,23.8,20.4(d,J＝4.1Hz),12.6.HRMS(ESI)m/z:[M+Na]⁺calcd.for C₁₅H₁₆FNNaO₃:300.1006,found:300.1006.

Example 5

Raw materials: n, N-diethyl-2-amino-6-bromobenzaldehyde, 4-hydroxy-6-methyl-2-pyrone

The product is: the chemical formula: c ₁₅H₁₆BrNO₃

Molecular weight: 337.0314

Structural formula:

Yield: 60 percent of

¹H NMR(500MHz,CDCl₃)δ15.02(s,1H),7.27(s,1H),7.12(t,J＝7.7Hz,1H),6.97(d,J＝7.9Hz,1H),5.66(s,1H),3.99(m,2H),3.61–3.47(m,2H),3.14(d,J＝12.9Hz,1H),2.03(s,3H),1.30–1.24(m,3H).¹³C NMR(125MHz,CDCl₃)δ191.2,188.2,166.5,139.9,128.6,127.4,124.8,124.1,114.0,99.7,50.2,38.4,27.9,23.9,12.6.HRMS(ESI)m/z:[M+H]⁺calcd.for C₁₅H₁₇BrNO₃:338.0386,found:338.0389.

Example 6

Raw materials: n, N-diethyl-2-amino-4-chlorobenzaldehyde, 4-hydroxy-6-methyl-2-pyrone

The product is: the chemical formula: c ₁₅H₁₆ClNO₃

Molecular weight: 293.0819

Structural formula:

Yield: 50 percent of

¹H NMR(500MHz,CDCl₃)δ15.05(s,1H),7.12(d,J＝7.7Hz,1H),6.99(s,2H),5.63(s,1H),3.98(m,2H),3.54(s,1H),3.29(dd,J＝15.5,6.0Hz,1H),3.02(dd,J＝15.6,4.3Hz,1H),2.03(s,3H),1.29(t,J＝7.1Hz,3H).¹³C NMR(125MHz,CDCl₃)δ191.3,188.3,166.7,139.7,133.4,129.4,123.1,123.0,115.0,99.6,50.5,38.1,27.6,23.8,12.5.HRMS(ESI)m/z:[M+H]⁺calcd.for C₁₅H₁₇ClNO₃:294.0891,found:294.0895.

Example 7

Raw materials: n, N-diethyl-2-amino-4-methylbenzaldehyde, 4-hydroxy-6-methyl-2-pyrone

The product is: the chemical formula: c ₁₆H₁₉NO₃

Molecular weight: 273.1365

Structural formula:

Yield: 62 percent of

¹H NMR(500MHz,CDCl₃)δ15.11(s,1H),7.07(d,J＝7.1Hz,1H),6.83(d,J＝9.4Hz,2H),5.63(s,1H),3.99(m,2H),3.51(t,J＝6.4Hz,1H),3.27(dd,J＝15.6,7.4Hz,1H),3.00(dd,J＝15.5,5.5Hz,1H),2.36(s,3H),2.02(s,3H),1.29(t,J＝7.5Hz,3H).¹³C NMR(125MHz,CDCl₃)δ191.7,188.5,166.9,138.5,137.6,128.2,123.9,121.6,115.4,99.8,50.9,37.9,27.9,23.9,21.6,12.7.HRMS(ESI)m/z:[M+Na]⁺calcd.for C₁₆H₁₉NNaO₃:296.1257,found:296.1258.

Example 8

Raw materials: n, N-diethyl-2-amino-4-trifluoromethylbenzaldehyde, 4-hydroxy-6-methyl-2-pyrone

The product is: the chemical formula: c ₁₆H₁₆F₃NO₃

Molecular weight: 327.1082

Structural formula: (in the form of enol)

Yield: 72 percent of

¹H NMR(500MHz,DMSO)δ11.81(s,1H),7.31(dd,J＝8.5,1.8Hz,1H),7.24(d,J＝2.0Hz,1H),6.60(d,J＝8.5Hz,1H),6.08(d,J＝0.6Hz,1H),3.46(s,2H),3.13(d,J＝7.2Hz,2H),2.19(s,3H),1.23(t,J＝7.1Hz,3H).¹³C NMR(125MHz,DMSO)δ167.2,166.1,161.6,149.7,125.9(q,J＝268.8Hz),126.4(q,J＝3.8Hz),124.8(q,J＝3.8Hz),123.7,115.2(q,J＝31.3Hz),108.9,100.4,98.8,37.9,25.2,19.8,14.5.HRMS(ESI)m/z:[M+H]⁺calcd.for C₁₆H₁₇F₃NO₃:328.1155,found:328.1159.

Example 9

Raw materials: n, N-diethyl-2-amino-4-cyanobenzaldehyde, 4-hydroxy-6-methyl-2-pyrone

The product is: the chemical formula: c ₁₆H₁₆N₂O₃

Molecular weight: 284.1161

Structural formula: (in the form of enol)

Yield: 68%

¹H NMR(500MHz,DMSO)δ11.75(s,1H),7.06(d,J＝7.7Hz,1H),6.90(dd,J＝7.6,1.2Hz,1H),6.80(s,1H),6.08(s,1H),3.45(s,2H),3.11(q,J＝7.1Hz,2H),2.19(s,3H),1.22(t,J＝7.1Hz,3H).¹³C NMR(125MHz,DMSO)δ167.2,165.9,161.6,147.3,130.1,129.5,120.4,119.4,111.6,109.9,100.4,98.3,37.9,25.5,19.8,14.4.HRMS(ESI)m/z:[M+H]⁺calcd.for C₁₆H₁₇N₂O₃:285.1234,found:285.1222.

Example 10

Raw materials: n, N-diethyl-2-amino-5-cyanobenzaldehyde, 4-hydroxy-6-methyl-2-pyrone

The product is: the chemical formula: c ₁₆H₁₆N₂O₃

Molecular weight: 284.1161

Structural formula: (in the form of enol)

Yield: 67%

¹H NMR(500MHz,DMSO)δ11.83(s,1H),7.41(dd,J＝8.5,2.1Hz,1H),7.19(d,J＝2.0Hz,1H),6.58(d,J＝8.6Hz,1H),6.09(s,1H),3.41(s,2H),3.16(q,J＝7.1Hz,2H),2.20(s,3H),1.22(t,J＝7.2Hz,3H).¹³C NMR(125MHz,DMSO)δ167.3,165.9,161.8,150.3,132.7,132.3,124.1,121.3,109.5,100.4,98.3,95.8,37.7,25.0,19.8,14.4.HRMS(ESI)m/z:[M+H]⁺calcd.for C₁₆H₁₇N₂O₃:285.1234,found:285.1226.

The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.

Claims

The synthesis method of the 3-alkenyl ketone substituted quinoline-2-ketone bioactive framework is characterized by comprising the following steps:

uniformly mixing an anthranilate compound and 4-hydroxy-6-methyl-2-pyrone in water, and reacting at 100-120 ℃ to obtain a 3-alkenyl ketone substituted quinoline-2-ketone compound;

Wherein, the structural formula of the o-aminobenzaldehyde compound is as follows:

，

Wherein R ¹,R² is any one of ethyl and n-propyl; r ³ is any one of hydrogen atom, halogen, trifluoromethyl and cyano;

Wherein the structural formula of the 4-hydroxy-6-methyl-2-pyrone is as follows:

；

Wherein, the structural formula of the 3-alkenyl ketone substituted quinoline-2-ketone bioactive framework is as follows:

，

wherein R ² is any one of ethyl and n-propyl; r ³ is any one of hydrogen atom, halogen, trifluoromethyl and cyano.
2. The method according to claim 1, wherein the molar ratio of the anthranilate compound to 4-hydroxy-6-methyl-2-pyrone is 1: (1-5).
3. The method of claim 1, wherein the solvent is used in an amount of: 10 to 20L solvent is added to each mole of o-aminobenzaldehyde compound.
4. The synthetic method of claim 1 wherein the catalyst is added prior to the reaction, the catalyst being a bronsted acid.
5. The method according to claim 1 or 4, wherein the catalyst is used in an amount of 5 to 50 mol%.