CN111892597A - Quinoxalinyl pyridopyrazine compound and preparation method and application thereof - Google Patents

Quinoxalinyl pyridopyrazine compound and preparation method and application thereof Download PDF

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CN111892597A
CN111892597A CN202010905381.3A CN202010905381A CN111892597A CN 111892597 A CN111892597 A CN 111892597A CN 202010905381 A CN202010905381 A CN 202010905381A CN 111892597 A CN111892597 A CN 111892597A
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朱继强
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Abstract

The invention provides a quinoxalinyl pyridopyrazine compound and a preparation method thereof, the compound is directly synthesized by an alkyne ketone compound 3, an amino pyrazinyl ketone compound 1 and a phenylenediamine compound 2 which are synthesized by an alkyne compound and phenylacetaldehyde under the action of a catalyst and an additive by a one-pot method, and has good substrate universality.

Description

Quinoxalinyl pyridopyrazine compound and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a quinoxalinyl pyridopyrazine compound as well as a preparation method and application thereof.
Background
The pyrazine compounds mainly play important pharmacological activities of resisting tuberculosis, expelling winged insects, resisting convulsion, eliminating free radicals, sterilizing and the like in medicaments, and also have important application in the flavor and food industry.
Pyridine compounds are key components and core frameworks of a plurality of natural products, and the pyridine framework structure widely exists in synthetic drugs and has a plurality of important physiological activities: such as anticancer, antioxidant, antibacterial, etc., but not all fungi or bacteria are pathogenic, and usually only a small fraction of them can cause diseases in human body, and the development of antifungal and antibacterial drugs is needed for treating the diseases.
The application of quinoxaline compounds in antibacterial drugs is as early as 1967, quinoxaline veterinary drugs with antibacterial and growth-promoting effects are synthesized by German Bayer, and some quinoxaline drugs for antibacterial and growth-promoting effects of livestock, such as mequindox, olaquindox, carba and the like are available later, but from the aspect of long-term use effects, the drugs have the problems of drug residues, reproductive toxicity and the like, so that a new drug needs to be further developed to solve the problem.
With the rapid development of combinatorial chemistry and high-throughput technology, thousands of compound molecules are rapidly synthesized, and in the face of numerous compounds with unknown activities, it is necessary to determine the lead, and the initial experiment for determining the lead is to perform drug sensitivity assay to determine whether the compound has primary activity for bacteriostasis or sterilization. The invention designs and synthesizes a series of quinoxalinyl pyrido [2,3-b ] pyrazine compounds, preliminarily researches the antibacterial effect of the quinoxalinyl pyrido [2,3-b ] pyrazine compounds, and has wide significance for further development of future antibacterial drugs.
Disclosure of Invention
The invention aims to provide a quinoxalinyl pyridopyrazine compound and a preparation method thereof, and researches the antibacterial activity of the series of compounds on escherichia coli, staphylococcus aureus, candida albicans and shigella dysenteriae.
The quinoxalinyl pyridopyrazine compound has the following structural general formula:
Figure BDA0002661231550000011
wherein R is1＝H、Me、Cl；R2＝H、Me、OMe、Ph、4-MePh；R3＝H、Me、Br、Cl、CF3、COOH；R4＝Ph、4-MePh、4-ClPh、t-Bu、n-Bu、cyclopropyl、trimethylsilyl；R3The substituted benzene ring may be a pyridine ring;
preferably, the quinoxalinyl pyridopyrazines comprise the following compounds:
8-methyl-7-phenyl-6- (3-phenylquinoxalin-2-yl) pyrido [2,3-b ] pyrazine;
2, 8-dimethyl-7-phenyl-6- (3-phenylquinoxalin-2-yl) pyrido [2,3-b ] pyrazine;
2-chloro-8-methyl-7-phenyl-6- (3-phenylquinoxalin-2-yl) pyrido [2,3-b ] pyrazine;
7, 8-diphenyl-6- (3-phenylquinoxalin-2-yl) pyrido [2,3-b ] pyrazine;
2-chloro-7, 8-diphenyl-6- (3-phenylquinoxalin-2-yl) pyrido [2,3-b ] pyrazine;
2, 3-dichloro-7-phenyl-6- (3-phenylquinoxalin-2-yl) pyrido [2,3-b ] pyrazine;
2, 3-dichloro-8-methyl-7-phenyl-6- (3-phenylquinoxalin-2-yl) pyrido [2,3-b ] pyrazine;
8-methyl-6- (6-methyl-3-phenylquinoxalin-2-yl) -7-phenylpyrido [2,3-b ] pyrazine;
6- (6-bromo-3-phenylquinoxalin-2-yl) -8-methyl-7-phenylpyrido [2,3-b ] pyrazine;
8-methyl-7-phenyl-6- (3-phenyl-6- (trifluoromethyl) quinoxalin-2-yl) pyrido [2,3-b ] pyrazine;
2- (8-methyl-7-phenylpyrido [2,3-b ] pyrazin-6-yl) -3-phenylquinoxaline-6-carboxylic acid;
2-chloro-8-methoxy-7-phenyl-6- (3-phenylquinoxalin-2-yl) pyrido [2,3-b ] pyrazine;
2-phenyl-3- (6-phenyl-7- (p-tolyl) -1H-imidazo [4,5-b ] pyridin-5-yl) quinoxaline;
8-methyl-6- (5-methyl-3-phenylquinoxalin-2-yl) -7-phenylpyrido [2,3-b ] pyrazine;
6- (6, 7-dichloro-3-phenylquinoxalin-2-yl) -8-methyl-7-phenylpyrido [2,3-b ] pyrazine;
8-methyl-7-phenyl-6- (3-phenylpyrido [3,4-b ] pyrazin-2-yl) pyrido [2,3-b ] pyrazine;
6- (3-butylquinoxalin-2-yl) -8-methyl-7-phenylpyrido [2,3-b ] pyrazine;
6- (3- (tert-butyl) quinoxalin-2-yl) -8-methyl-7-phenylpyrido [2,3-b ] pyrazine;
8-methyl-7-phenyl-6- (3- (trimethylsilyl) quinoxalin-2-yl) pyrido [2,3-b ] pyrazine;
8-methyl-7-phenyl-6- (3- (p-tolyl) quinoxalin-2-yl) pyrido [2,3-b ] pyrazine;
6- (3- (4-chlorophenyl) quinoxalin-2-yl) -8-methyl-7-phenylpyrido [2,3-b ] pyrazine;
6- (3-Cyclopropylquinoxalin-2-yl) -8-methyl-7-phenylpyrido [2,3-b ] pyrazine.
The quinoxalinyl pyridopyrazine compound can be prepared into a product by the following method:
an alkynone compound 3 synthesized by an alkynone compound and phenylacetaldehyde, an amino pyrazinyl ketone compound 1 and a phenylenediamine compound 2 are directly synthesized into the quinoxalinyl pyridopyrazine compound by a one-pot method under the action of a catalyst and an additive.
Preferably, the compound 1 is 1- (3-aminopyrazin-2-yl) ethanone, 1- (3-amino-6-methylpyrazin-2-yl) ethanone, 1- (3-amino-6-chloropyrazin-2-yl) ethanone, 1- (3-amino-5, 6-dichloropyrazin-2-yl) ethanone, methyl 3-amino-6-chloropyrazin-2-carboxylate, 3-amino-5, 6-dichloropyrazin-2-carbaldehyde, (3-amino-6-chloropyrazin-2-yl) (phenyl) methanone, (3-aminopyrazin-2-yl) (phenyl) methanone, (4-amino-1H-imidazol-5-yl) (p-tolyl) methanone;
preferably, the compound 2 is o-phenylenediamine, 2, 3-diaminotoluene, 3, 4-diaminotoluene, 4-bromoo-phenylenediamine, 3, 4-diaminobenzotrifluoride, 3, 4-diaminobenzoic acid, 4, 5-dichloro-1, 2-phenylenediamine, 3, 4-diaminopyridine;
preferably, the compound 3 is 1, 4-diphenyl-3-butyn-2-one, 1-phenyl-4- (p-tolyl) -3-butyn-2-one, 4- (4-chlorophenyl) -1-phenyl-3-butyn-2-one, 4-cyclopropyl-1-phenyl-3-butyn-2-one, 1-phenyl-3-octyn-2-one, 5, 5-dimethyl-1-phenyl-3-hexyn-2-one, 1-phenyl-4- (trimethylsilyl) -3-butyn-2-one.
The general formula of the preparation reaction of the quinoxalinyl pyridopyrazine compound is as follows:
Figure BDA0002661231550000031
the preparation method of the quinoxalinyl pyridopyrazine compound comprises the following steps:
adding an amino pyrazinyl ketone compound 1 and an alkynone compound 3 into a reaction tube, adding a solvent, a catalyst and an additive, performing reflux reaction for 3-5h, adding a phenylenediamine compound 2, continuously stirring for reaction, detecting by TLC (thin layer chromatography), and reacting completely for 4-6 h;
and secondly, cooling the reaction liquid obtained in the step one to room temperature, filtering by using diatomite, concentrating the filtrate under reduced pressure, and then separating and purifying by using silica gel column chromatography to obtain the quinoxalinyl pyridopyrazine compound.
Preferably, the catalyst in step one is RuCl3The additive is N-bromosuccinimide, and the solvent is acetic acid.
Preferably, the molar mass ratio of the compound 1, the compound 2, the compound 3, the catalyst and the additive in the first step is 1.0:1.1-1.3:1.1-1.3:0.1-0.2: 1.2-1.4.
Preferably, the developing solvent used in the column chromatography purification method in the second step is ethyl acetate: n-hexane 1:8 to 1: 12.
Compared with the prior art, the invention has the following beneficial effects:
1. the quinoxalinyl pyridopyrazine compound synthesized by the one-pot method is a brand new synthesis method provided on the basis of the prior art.
2. The quinoxalinyl pyridopyrazine compound disclosed by the invention is simple in preparation method and has good substrate universality.
3. The quinoxalinyl pyridopyrazine compound disclosed by the invention has good antibacterial activity on escherichia coli, shigella dysenteriae, staphylococcus aureus and candida albicans, and provides a new choice for research and clinical use of antibacterial drugs.
Detailed Description
The technical solutions of the present invention are further described in detail with reference to specific examples so that those skilled in the art can better understand the present invention and can implement the present invention, but the examples are not intended to limit the present invention.
The quinoxalinyl pyridopyrazine compound has the structural formula as follows:
Figure BDA0002661231550000041
preparation of starting compound 3: under the protection of nitrogen, adding an alkyne compound and a solvent anhydrous tetrahydrofuran into a reaction bottle, cooling to-20 ℃, dropwise adding 1.1 equivalent of n-butyllithium into the solution, stirring at-20 ℃ for 1h, then adding 1.0 equivalent of an aldehyde compound into the reaction solution, gradually raising the temperature to room temperature, continuously stirring for 12h, after the reaction is finished, slowly adding water at 0 ℃ to quench the reaction, extracting the solution with diethyl ether, combining organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating the solvent under reduced pressure, and separating by column chromatography to obtain the alkynol compound. Dissolving the obtained alkynol compound in anhydrous dichloromethane, cooling to 0 ℃, then slowly adding 1.2 equivalents of Dess-Martin oxidant in batches, continuing to react for 1h, and then adding excessive saturated Na2S2O3Solution and saturated NaHCO3Quenching the solution for reaction, extracting the mixed solution with diethyl ether, combining organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, concentrating the solvent under reduced pressure, and separating by silica gel column chromatography to obtain the alkynone compound. Reference (Zhang Y S, SunY L, Wei Y, Shi M. Phospholine-Catalyzed Intermolecular associations of fluorinate endorphes with Alkynones-The Switchant [4+2]or[4+2]/[3+2]Cycloaddition[J].Advanced Synthesis&Catalysis.2019,361,2129-2135.)
Figure BDA0002661231550000051
Example 1
Preparation of compound 4 a: 2mmol of 1- (3-aminopyrazin-2-yl) ethanone and 2.2mmol of 1, 4-diphenyl-3-butyn-2-one were added to a reaction tube, and 10mL of acetic acid and 0.2mmol of RuCl were added3And 2.4mmol NBS, refluxing and stirring for 3h, adding 2.2mmol o-phenylenediamine, continuing to stir for reaction, detecting the reaction by TLC, completely reacting after 4h, cooling the reaction solution to room temperature, filtering by diatomite, washing by ethyl acetate, decompressing the filtrate, and performing reaction by using a stirrerConcentrating, separating by silica gel column chromatography, and separating with ethyl acetate: n-hexane 1:10 to obtain the target compound as a light brown solid, and the structural formula and the characteristics are as follows:
Figure BDA0002661231550000052
8-methyl-7-phenyl-6- (3-phenylquinoxalin-2-yl) pyrido [2,3-b]Pyrazine;1H NMR(400MHz,CDCl3)8.70–8.67(m,2H),8.20(dd,J＝6.8,0.8Hz,1H),8.06–7.94(m,3H),7.75–7.63(m,4H),7.50–7.37(m,6H),2.54(s,3H).13C NMR(101MHz,CDCl3)153.96,152.80,149.60,147.56,146.42,143.76,143.58,142.91,139.97,138.12,135.64,133.73,130.56,129.96,129.80,127.65,127.53,126.87,126.38,124.45,123.95,15.87.HRMS(ESI):calcd forC28H20N5 +[M+H]+426.1713,found 426.1715.
example 2
Preparation of compound 4 b: compound 1 is 1- (3-amino-6-methylpyrazin-2-yl) ethanone, compound 2 is o-phenylenediamine, compound 3 is 1, 4-diphenyl-3-butyn-2-one, the specific experimental procedure is as in example 1:
Figure BDA0002661231550000061
2, 8-dimethyl-7-phenyl-6- (3-phenylquinoxalin-2-yl) pyrido [2,3-b]Pyrazine;1H NMR(400MHz,CDCl3)8.60(s,1H),8.26(dd,J＝8.4,1.2Hz,1H),8.08–7.84(m,3H),7.76–7.59(m,4H),7.59–7.33(m,6H),2.62(s,3H),2.51(s,3H).13C NMR(101MHz,CDCl3)155.06,154.89,151.16,150.78,147.03,146.58,146.16,145.92,145.67,143.83,138.86,136.89,133.39,132.65,131.88,128.62,127.95,127.34,126.71,125.18,124.51,21.36,15.74.HRMS(ESI):calcd for C29H22N5 +[M+H]+440.1870,found 440.1875.
example 3
Preparation of compound 4 c: compound 1 is 1- (3-amino-6-chloropyrazin-2-yl) ethanone, compound 2 is o-phenylenediamine, compound 3 is 1, 4-diphenyl-3-butyn-2-one, the specific experimental procedure is as in example 1:
Figure BDA0002661231550000062
2-chloro-8-methyl-7-phenyl-6- (3-phenylquinoxalin-2-yl) pyrido [2,3-b]Pyrazine;1H NMR(400MHz,CDCl3)8.69(s,1H),8.13(dd,J＝6.8,1.0Hz,1H),8.10–8.00(m,3H),7.80–7.67(m,4H),7.59–7.38(m,6H),2.56(s,3H).13C NMR(101MHz,CDCl3)154.31,149.64,149.09,146.67,145.32,144.87,143.76,142.20,141.34,140.82,136.25,134.07,131.12,130.35,129.85,129.01,128.79,128.53,128.08,127.85,126.46,14.69.HRMS(ESI):calcd forC28H19ClN5 +[M+H]+460.1323,found 460.1327.
example 4
Preparation of compound 4 d: compound 1 is (3-aminopyrazin-2-yl) (phenyl) methanone, compound 2 is o-phenylenediamine, compound 3 is 1, 4-diphenyl-3-butyn-2-one, the specific experimental procedure is as in example 1:
Figure BDA0002661231550000071
7, 8-Diphenyl-6- (3-phenylquinoxalin-2-yl) pyrido [2,3-b]Pyrazine;1H NMR(400MHz,CDCl3)8.75–8.64(m,2H),8.51–8.16(m,4H),7.87–7.76(m,2H),7.68–7.59(m,4H),7.52–7.29(m,9H).13C NMR(101MHz,CDCl3)155.26,154.13,149.79,149.05,148.09,146.24,145.77,144.28,142.69,139.95,137.90,136.97,134.98,132.37,131.85,131.41,130.70,129.76,129.58,129.35,129.21,127.83,127.64.HRMS(ESI):calcd for C33H22N5 +[M+H]+488.1870,found 488.1872.
example 5
Preparation of compound 4 e: compound 1 was (3-amino-6-chloropyrazin-2-yl) (phenyl) methanone, compound 2 was o-phenylenediamine, compound 3 was 1, 4-diphenyl-3-butyn-2-one, the specific experimental procedure was as in example 1:
Figure BDA0002661231550000072
2-chloro-7, 8-diphenyl-6- (3-phenylquinoxalin-2-yl) pyrido [2,3-b]Pyrazine;1H NMR(400MHz,CDCl3)8.70(s,1H),8.48–8.04(m,4H),7.90–7.79(m,2H),7.67–7.46(m,4H),7.44–7.19(m,9H).13C NMR(101MHz,CDCl3)153.24,150.96,147.82,145.76,144.17,143.73,142.26,141.89,139.86,138.65,135.56,135.05,133.43,130.28,129.96,129.82,129.59,129.36,128.08,127.86,127.34,127.06,126.75.HRMS(ESI):calcd for C33H21ClN5 +[M+H]+522.1480,found 522.1481.
example 6
Preparation of compound 4 f: compound 1 is 3-amino-5, 6-dichloropyrazine-2-carbaldehyde, compound 2 is o-phenylenediamine, compound 3 is 1, 4-diphenyl-3-butyn-2-one, the specific experimental procedures refer to example 1:
Figure BDA0002661231550000073
2, 3-dichloro-7-phenyl-6- (3-phenylquinoxalin-2-yl) pyrido [2,3-b]Pyrazine;1H NMR(400MHz,CDCl3)8.75(s,1H),8.41(dd,J＝7.6,1.8Hz,1H),8.23–8.02(m,3H),7.89–7.67(m,4H),7.68–7.32(m,6H).13C NMR(101MHz,CDCl3)155.46,148.06,146.18,145.80,144.86,143.63,143.49,142.14,142.02,136.94,135.87,134.78,131.66,131.43,131.02,130.29,129.27,128.84,128.61,128.17,127.65,126.06.HRMS(ESI):calcd for C27H16Cl2N5 +[M+H]+480.0777,found 480.0780.
example 7
Preparation of compound 4 g: compound 1 is 1- (3-amino-5, 6-dichloropyrazin-2-yl) ethanone, compound 2 is o-phenylenediamine, compound 3 is 1, 4-diphenyl-3-butyn-2-one, the specific experimental procedure is as in example 1:
Figure BDA0002661231550000081
2, 3-dichloro-8-methyl-7-phenyl-6- (3-phenylquinoxalin-2-yl) pyrido [2,3-b]Pyrazine;1H NMR(400MHz,CDCl3)8.10(dd,J＝8.0,1.4Hz,1H),7.94–7.87(m,2H),7.67–7.51(m,5H),7.45–7.30(m,6H),2.47(s,3H).13C NMR(101MHz,CDCl3)156.58,153.39,151.02,147.55,147.07,146.63,145.92,143.55,143.08,138.78,137.82,136.52,133.42,132.92,132.46,131.38,130.94,130.26,129.87,128.76,125.31,15.77.HRMS(ESI):calcd for C28H18Cl2N5 +[M+H]+494.0934,found494.0935.
example 8
Preparation of compound 4 h: compound 1 was 1- (3-aminopyrazin-2-yl) ethanone, compound 2 was 3, 4-diaminotoluene, compound 3 was 1, 4-diphenyl-3-butyn-2-one, the specific experimental procedure was as in example 1:
Figure BDA0002661231550000082
8-methyl-6- (6-methyl-3-phenylquinoxalin-2-yl) -7-phenylpyrido [2,3-b]Pyrazine;1H NMR(400MHz,CDCl3)8.76–8.71(m,2H),8.34(d,J＝10.2Hz,1H),7.98(dd,J＝7.2,1.4Hz,2H),7.78(d,J＝1.8Hz,1H),7.50–7.29(m,9H),2.57(s,3H),2.34(s,3H).13C NMR(101MHz,CDCl3)153.89,153.30,149.57,148.09,145.24,144.17,143.76,142.59,140.28,139.83,138.62,135.45,133.43,131.35,130.56,129.79,129.37,129.26,128.98,128.64,127.83,127.36,126.78,20.62,14.58.HRMS(ESI):calcd for C29H22N5 +[M+H]+440.1870,found440.1876.
example 9
Preparation of compound 4 i: compound 1 is 1- (3-aminopyrazin-2-yl) ethanone, compound 2 is 4-bromoo-phenylenediamine, compound 3 is 1, 4-diphenyl-3-butyn-2-one, the specific experimental procedure is as in example 1:
Figure BDA0002661231550000091
6- (6-bromo-3-phenylquinoxalin-2-yl) -8-methyl-7-phenylpyrido [2,3-b]Pyrazine;1H NMR(400MHz,CDCl3)8.72–8.67(m,2H),8.28–8.21(m,3H),7.89–7.47(m,4H),7.41–7.28(m,6H),2.47(s,3H).13C NMR(101MHz,CDCl3)154.17,152.80,151.06,150.64,147.54,145.68,144.84,143.57,140.91,139.14,136.76,135.23,133.14,130.94,130.37,129.56,128.78,128.65,128.18,127.93,127.64,127.03,124.73,15.62.HRMS(ESI):calcd forC28H19BrN5 +[M+H]+504.0818,found504.0822.
example 10
Preparation of compound 4 j: compound 1 was 1- (3-aminopyrazin-2-yl) ethanone, compound 2 was 3, 4-diaminobenzotrifluoride, compound 3 was 1, 4-diphenyl-3-butyn-2-one, the specific experimental procedure was as in example 1:
Figure BDA0002661231550000092
8-methyl-7-phenyl-6- (3-phenyl-6- (trifluoromethyl) quinoxalin-2-yl) pyrido [2,3-b]Pyrazine;1HNMR(400MHz,CDCl3)8.76–8.62(m,3H),8.46(d,J＝7.1Hz,1H),8.06–7.98(m,3H),7.49–7.25(m,8H),2.48(s,3H).154.60,152.31,150.67,149.75,147.60,144.51,143.27,140.28,139.32,136.66,134.87,132.52,130.91(q,J＝3.8Hz),129.71,129.38,128.55,128.50(q,J＝24.2Hz),128.40,127.67,127.25,125.14(q,J＝7.6Hz),124.39(q,J＝6.7Hz),15.68.HRMS(ESI):calcd for C29H19F3N5 +[M+H]+494.1587,found 494.1585.
example 11
Preparation of compound 4 k: compound 1 is 1- (3-aminopyrazin-2-yl) ethanone, compound 2 is 3, 4-diaminobenzoic acid, compound 3 is 1, 4-diphenyl-3-butyn-2-one, the specific experimental procedure is as in example 1:
Figure BDA0002661231550000101
2- (8-methyl-7-phenylpyrido [2,3-b ]]Pyrazin-6-yl) -3-phenylquinoxaline-6-carboxylic acid;1H NMR(400MHz,CDCl3)8.80–8.73(m,2H),8.60–8.43(m,1H),8.08(dd,J＝7.2,1.6Hz,2H),7.58–7.37(m,8H),2.68(s,3H).13C NMR(101MHz,CDCl3)167.06,154.15,153.12,150.76,149.83,147.54,145.35,145.16,143.23,141.74,139.76,136.86,134.67,133.78,131.26,130.84,129.56,128.63,128.31,127.08,126.83,126.56,126.27,125.25,15.63.HRMS(ESI):calcd for C29H20N5O2 +[M+H]+470.1612,found 470.1615.
example 12
Preparation of compound 4 l: compound 1 is methyl 3-amino-6-chloropyrazine-2-carboxylate, compound 2 is o-phenylenediamine, compound 3 is 1, 4-diphenyl-3-butyn-2-one, the specific experimental procedure is as in example 1:
Figure BDA0002661231550000102
2-chloro-8-methoxy-7-phenyl-6- (3-phenylquinoxalin-2-yl) pyrido [2,3-b]Pyrazine;1H NMR(400MHz,CDCl3)8.77(s,1H),8.33(dd,J＝8.4,0.8Hz,1H),8.20–7.90(m,3H),7.83–7.64(m,4H),7.62–7.34(m,6H),3.78(s,3H).13C NMR(101MHz,CDCl3)165.64,153.47,148.54,145.72,144.19,143.09,142.21,141.56,140.24,138.10,132.80,131.49,129.93,129.19,129.08,127.71,127.46,126.53,126.32,119.64,57.46.HRMS(ESI):calcd for C28H19ClN5O+[M+H]+476.1273,found 476.1271.
example 13
Preparation of compound 4 m: compound 1 was (4-amino-1H-imidazol-5-yl) (p-tolyl) methanone, compound 2 was o-phenylenediamine, compound 3 was 1, 4-diphenyl-3-butyn-2-one, the specific experimental procedure was as in example 1:
Figure BDA0002661231550000111
2-phenyl-3- (6-phenyl-7- (p-tolyl) -1H-imidazo [4, 5-b)]Pyridin-5-yl) quinoxaline;1H NMR(400MHz,CDCl3)12.89(s,1H),8.53–8.38(m,2H),8.11(dd,J＝6.8,1.8Hz,2H),7.90–7.69(m,3H),7.65–7.29(m,12H),2.32(s,3H).13C NMR(101MHz,CDCl3)153.66,152.86,145.27,144.36,143.65,143.08,142.41,137.51,135.86,134.30,133.93,131.66,130.26,129.98,128.87,128.78,128.37,127.69,127.31,127.04,126.67,126.08,120.33,20.53.HRMS(ESI):calcd for C33H24N5 +[M+H]+490.2026,found 490.2028.
example 14
Preparation of compound 4 n: compound 1 was 1- (3-aminopyrazin-2-yl) ethanone, compound 2 was 2, 3-diaminotoluene, compound 3 was 1, 4-diphenyl-3-butyn-2-one, the specific experimental procedure was as in example 1:
Figure BDA0002661231550000112
8-methyl-6- (5-methyl-3-phenylquinoxalin-2-yl) -7-phenylpyrido [2,3-b]Pyrazine;1H NMR(400MHz,CDCl3)8.76(dd,J＝27.7,7.5Hz,2H),8.14–7.99(m,3H),7.70–7.46(m,3H),7.46–7.17(m,7H),2.60(s,3H),2.51(s,3H).
13C NMR(101MHz,CDCl3)154.49,152.38,149.68,148.75,145.13,144.60,142.92,142.67,138.70,137.99,137.05,134.69,133.12,130.49,129.65,127.55,127.36,125.77,125.56,125.21,124.86,124.31,123.44,16.58,14.75.HRMS(ESI):calcd forC29H22N5 +[M+H]+440.1870,found 440.1873.
example 15
Preparation of compound 4 o: compound 1 is 1- (3-aminopyrazin-2-yl) ethanone, compound 2 is 4, 5-dichloro-1, 2-phenylenediamine, compound 3 is 1, 4-diphenyl-3-butyn-2-one, the specific experimental procedure is as in example 1:
Figure BDA0002661231550000121
6- (6, 7-dichloro-3-phenylquinoxalin-2-yl) -8-methyl-7-phenylpyrido [2,3-b]Pyrazine;1H NMR(400MHz,CDCl3)8.72–8.66(m,2H),8.17(s,1H),8.09–7.88(m,3H),7.50–7.13(m,8H),2.48(s,3H).13C NMR(101MHz,CDCl3)154.30,152.75,150.68,149.37,147.14,144.56,141.79,139.47,139.06,136.77,136.40,134.63,131.75,130.17,129.47,129.31,129.09,128.38,128.54,127.38,126.69,15.08.HRMS(ESI):calcd for C28H18Cl2N5 +[M+H]+494.0934,found 494.0937.
example 16
Preparation of compound 4 p: compound 1 is 1- (3-aminopyrazin-2-yl) ethanone, compound 2 is 3, 4-diaminopyridine, compound 3 is 1, 4-diphenyl-3-butyn-2-one, the specific experimental procedure is as in example 1:
Figure BDA0002661231550000122
8-methyl-7-phenyl-6- (3-phenylpyrido [3, 4-b)]Pyrazin-2-yl) pyrido [2,3-b]Pyrazine;1HNMR(400MHz,CDCl3)8.94(s,1H),8.72–8.48(m,3H),7.77(dd,J＝7.1,1.8Hz,2H),7.40–7.05(m,9H),2.37(s,3H).13C NMR(101MHz,CDCl3)154.22,153.89,153.22,150.46,150.10,149.05,147.36,147.03,145.97,144.32,142.37,137.58,136.34,134.65,130.99,129.28,128.97,127.76,127.44,126.90,126.34,119.89,14.89.HRMS(ESI):calcd forC27H19N6 +[M+H]+427.1666,found427.1671.
example 17
Preparation of compound 4 q: compound 1 is 1- (3-aminopyrazin-2-yl) ethanone, compound 2 is o-phenylenediamine, compound 3 is 1-phenyl-3-octyn-2-one, the specific experimental procedure is as in example 1:
Figure BDA0002661231550000123
6- (3-butylquinoxalin-2-yl) -8-methyl-7-phenylpyrido [2,3-b]Pyrazine;1H NMR(400MHz,CDCl3)8.82–8.78(m,2H),8.10–8.07(m,2H),7.67–7.36(m,7H),3.03–2.63(m,5H),1.84(p,J＝12.6Hz,2H),1.49(dd,J＝14.3,7.8Hz,2H),1.09(t,J＝6.6Hz,3H).13C NMR(101MHz,CDCl3)154.68,151.78,151.43,149.12,148.35,146.93,145.28,143.46,140.25,138.65,136.49,131.74,130.55,129.86,129.57,128.86,128.43,128.01,126.57,35.00,31.07,21.80,15.60,13.83.HRMS(ESI):calcd for C26H24N5 +[M+H]+406.2026,found 406.2023.
example 18
Preparation of compound 4 r: compound 1 is 1- (3-aminopyrazin-2-yl) ethanone, compound 2 is o-phenylenediamine, compound 3 is 5, 5-dimethyl-1-phenyl-3-hexyn-2-one, the specific experimental procedure is as in example 1:
Figure BDA0002661231550000131
6- (3- (tert-butyl) quinoxalin-2-yl) -8-methyl-7-phenylpyrido [2,3-b]Pyrazine;1H NMR(400MHz,CDCl3)8.73–8.62(m,2H),8.09–7.75(m,2H),7.55(dd,J＝8.8,2.4Hz,2H),7.45–7.10(m,5H),2.54(s,3H),1.36(s,9H).13C NMR(101MHz,CDCl3)162.81,155.47,152.38,151.24,149.39,147.88,145.47,141.42,140.64,140.36,138.68,132.56,132.34,131.41,129.42,128.67,126.51,37.69,26.60,15.26.HRMS(ESI):calcd for C26H24N5 +[M+H]+406.2026,found 406.2023.
example 19
Preparation of compound 4 s: compound 1 was 1- (3-aminopyrazin-2-yl) ethanone, compound 2 was o-phenylenediamine, compound 3 was 1-phenyl-4- (trimethylsilyl) -3-butyn-2-one, the specific experimental procedure was as in example 1:
Figure BDA0002661231550000132
8-methyl-7-phenyl-6- (3- (trimethylsilyl) quinoxalin-2-yl) pyrido [2,3-b]Pyrazine;1HNMR(400MHz,CDCl3)8.87–8.65(m,3H),8.31–8.13(m,2H),7.80–7.17(m,6H),2.57(s,3H),0.16(s,9H).13C NMR(101MHz,CDCl3)157.52,156.95,153.60,150.22,149.20,148.97,146.85,142.02,141.32,138.76,133.56,133.22,132.84,132.01,131.72,131.62,130.40,129.14,20.64,-1.49.HRMS(ESI):calcd for C25H24N5Si+[M+H]+422.1795,found422.1799.
example 20
Preparation of compound 4 t: compound 1 was 1- (3-aminopyrazin-2-yl) ethanone, compound 2 was o-phenylenediamine, compound 3 was 1-phenyl-4- (p-tolyl) -3-butyn-2-one, the specific experimental procedure was as in example 1:
Figure BDA0002661231550000141
8-methyl-7-phenyl-6- (3- (p-tolyl) quinoxalin-2-yl) pyrido [2,3-b]Pyrazine;1H NMR(400MHz,CDCl3)8.74–8.66(m,2H),8.35–8.22(m,2H),7.92(d,J＝11.4Hz,2H),7.75–7.23(m,9H),2.65(s,3H),2.32(s,3H).13C NMR(101MHz,CDCl3)154.39,153.90,151.05,149.86,146.84,144.37,144.12,143.65,142.01,141.76,138.47,135.30,131.56,130.26,130.10,129.83,128.89,128.30,127.34,126.76,126.18,20.75,15.18.HRMS(ESI):calcdfor C29H22N5 +[M+H]+440.1870,found 440.1874.
example 21
Preparation of compound 4 u: compound 1 was 1- (3-aminopyrazin-2-yl) ethanone, compound 2 was o-phenylenediamine, compound 3 was 4- (4-chlorophenyl) -1-phenyl-3-butyn-2-one, the specific experimental procedure was as described in example 1:
Figure BDA0002661231550000142
6- (3- (4-chlorophenyl) quinoxalin-2-yl) -8-methyl-7-phenylpyrido [2,3-b]Pyrazine;1H NMR(400MHz,CDCl3)8.71–8.63(m,2H),8.20–8.11(m,2H),7.84(d,J＝10.8Hz,2H),7.69–7.15(m,9H),2.49(s,3H).13C NMR(101MHz,CDCl3)154.48,154.01,150.98,149.76,146.70,144.26,144.07,143.38,141.86,139.15,136.18,135.68,131.47,130.05,129.79,129.63,129.15,128.55,127.62,126.87,125.77,15.02.HRMS(ESI):calcd for C28H19ClN5 +[M+H]+460.1323,found460.1325.
example 22
Preparation of compound 4 v: compound 1 is 1- (3-aminopyrazin-2-yl) ethanone, compound 2 is o-phenylenediamine, compound 3 is 4-cyclopropyl-1-phenyl-3-butyn-2-one, the specific experimental procedure is as in example 1:
Figure BDA0002661231550000143
6- (3-Cyclopropylquinoxalin-2-yl) -8-methyl-7-phenylpyrido [2,3-b]Pyrazine;1H NMR(400MHz,CDCl3)8.75–8.69(m,2H),7.86–7.79(m,2H),7.63–7.30(m,7H),2.77(s,3H),1.24–0.78(m,5H).13C NMR(101MHz,CDCl3)155.05,152.89,151.06,150.24,148.72,147.54,147.32,144.65,140.42,140.34,137.76,132.52,132.37,130.85,129.74,129.55,128.30,127.99,127.14,15.84,12.36,10.08.HRMS(ESI):calcd for C25H20N5 +[M+H]+390.1713,found390.1717.
example 23
Example 1 was repeated, except that no catalyst RhCl was added3The target product 4a is not obtained in the reaction, or RhCl is added3Exchanged for FeCl3、ZnCl2、AlCl3、Pd(OAc)2With AlCl only3When it is a catalystA trace amount of product 4a was obtained, and the target product 4a was not obtained in the rest.
Example 24
Example 1 was repeated, except that no NBS was added and no product 4a was obtained from the reaction; or when the addition amount of NBS is 0.5-1.5mmol, the product 4a can not be obtained; when the amount of NBS is 1.8 and 2.0mmol, 42 percent and 52 percent of the product 4a are obtained respectively; when the amount of NBS was 3.0mmol, the yield of 4a was 28%.
Example 25
Example 1 was repeated, and when the solvent was changed to absolute ethanol or absolute dimethyl sulfoxide or absolute toluene or absolute dichloroethane, the reaction did not give the objective product 4 a.
The compounds listed in the above examples are part of the synthetic compounds of the present invention.
And (3) biological activity test:
the compounds 4a-4v were tested for their inhibitory effects against E.coli, Shigella dysenteriae, Staphylococcus aureus and Candida albicans.
The antibacterial performance of each compound is detected by adopting a bacteriostatic ring method:
1. preparation of compound solution: weighing 10mg of compound, dropwise adding a drop of DMSO (dimethyl sulfoxide) into a rubber head dropper, and adding distilled water to prepare a compound solution with the mass fraction of 0.1 per mill for later use;
2. coli BNCC337357, Shigella dysenteriae BNCC340633, Staphylococcus aureus BNCC186335 and Candida albicans BNCC176009 for the experiment were purchased from North Nara organisms; inoculating the strain in a solid culture medium (pH7.5), culturing at 37 deg.C for 24 hr, selecting single colony, inoculating in a liquid culture medium (pH7.5), and culturing at 37 deg.C in a shaking table overnight to obtain bacterial liquid;
3. injecting a certain amount of bacteria liquid into a 45 ℃ plate culture medium, uniformly mixing and ensuring the concentration of viable bacteria to be 105CFU/mL, then pouring 20mL into the flat plate, horizontally standing and solidifying for later use (the four bacterial liquids operate the same);
4. taking a dry sterile filter paper sheet (diameter is 5mm), dripping 40 mu L of the prepared compound solution into each sheet, and drying at room temperature for later use;
5. placing the prepared filter paper sheet in the center of a culture medium flat plate, covering the culture medium flat plate, culturing at 37 ℃ for 24-48h, observing and measuring the existence and the size of an inhibition zone, measuring the diameter of the inhibition zone by adopting a cross method, and repeating each experiment for three times, wherein the diameter of the inhibition zone is less than or equal to 7mm and has no inhibition effect; (results are detailed in Table 1)
6. Preparing a solution with the same volume by adopting a drop of DMSO and distilled water in the blank group, taking 40 mu L of the solution to be dropped on filter paper, drying at room temperature and then placing the filter paper in the center of a culture medium; the solutions on the filter paper of the control group are 0.1 per mill solutions prepared by commercially available venezumycin, fluconazole, cefminox sodium and clarithromycin respectively.
TABLE 1 inhibition of E.coli, Candida albicans, Staphylococcus aureus and Shigella dysenteriae by each compound
Figure BDA0002661231550000161
Figure BDA0002661231550000171
As can be seen from the data in Table 1, the blank group of distilled water had no antibacterial activity against Escherichia coli, Candida albicans, Staphylococcus aureus and Shigella dysenteriae; the compound 4m has the highest antibacterial activity on escherichia coli, candida albicans and shigella dysenteriae, the diameters of inhibition zones respectively reach 24 mm, 27 mm and 28mm, the inhibition activity of the compound is higher than that of cefminox sodium on escherichia coli, that of fluconazole on candida albicans and that of clarithromycin on shigella dysenteriae; the compound 4j has the strongest antibacterial activity on staphylococcus aureus, the diameter of a bacteriostatic zone reaches 26mm, and the antibacterial activity of the compounds 4g, 4i-4m, 4o, 4p, 4r, 4s and 4n on staphylococcus aureus is higher than that of the control group medicaments.
The data in Table 1 show that the compounds 4a-4v have stronger antibacterial activity on Shigella dysenteriae in the antibacterial activity on Escherichia coli, Candida albicans, Staphylococcus aureus and Shigella dysenteriae, and the diameters of the inhibition zones are 14-28mm, wherein the diameters of the inhibition zones 4a-4e, 4g, 4i-4m, 4o-4p and 4s are all more than 20 mm.
The data show that the quinoxalinyl pyridopyrazine compound obtained by the invention has a good application prospect in the aspect of synthesis and application of antibacterial drugs, and can provide beneficial help for preparing bactericides in the future.
The above description is only a preferred embodiment of the present invention, and not intended to limit the scope of the present invention, and all modifications of equivalent structures and equivalent processes, which are made by the present specification, or directly or indirectly applied to other related technical fields, are included in the scope of the present invention.

Claims (10)

1. A quinoxalinyl pyridopyrazine compound is characterized in that the general structural formula of the quinoxalinyl pyridopyrazine compound is as follows:
Figure FDA0002661231540000011
wherein R is1＝H、Me、Cl；R2＝H、Me、OMe、Ph、4-MePh；R3＝H、Me、Br、Cl、CF3、COOH；R4＝Ph、4-MePh、4-ClPh、t-Bu、n-Bu、cyclopropyl、trimethylsilyl；R3The substituted benzene ring may be a pyridine ring.
2. The quinoxalinyl pyridopyrazines according to claim 1, comprising the following compounds:
8-methyl-7-phenyl-6- (3-phenylquinoxalin-2-yl) pyrido [2,3-b ] pyrazine;
2, 8-dimethyl-7-phenyl-6- (3-phenylquinoxalin-2-yl) pyrido [2,3-b ] pyrazine;
2-chloro-8-methyl-7-phenyl-6- (3-phenylquinoxalin-2-yl) pyrido [2,3-b ] pyrazine;
7, 8-diphenyl-6- (3-phenylquinoxalin-2-yl) pyrido [2,3-b ] pyrazine;
2-chloro-7, 8-diphenyl-6- (3-phenylquinoxalin-2-yl) pyrido [2,3-b ] pyrazine;
2, 3-dichloro-7-phenyl-6- (3-phenylquinoxalin-2-yl) pyrido [2,3-b ] pyrazine;
2, 3-dichloro-8-methyl-7-phenyl-6- (3-phenylquinoxalin-2-yl) pyrido [2,3-b ] pyrazine;
8-methyl-6- (6-methyl-3-phenylquinoxalin-2-yl) -7-phenylpyrido [2,3-b ] pyrazine;
6- (6-bromo-3-phenylquinoxalin-2-yl) -8-methyl-7-phenylpyrido [2,3-b ] pyrazine;
8-methyl-7-phenyl-6- (3-phenyl-6- (trifluoromethyl) quinoxalin-2-yl) pyrido [2,3-b ] pyrazine;
2- (8-methyl-7-phenylpyrido [2,3-b ] pyrazin-6-yl) -3-phenylquinoxaline-6-carboxylic acid;
2-chloro-8-methoxy-7-phenyl-6- (3-phenylquinoxalin-2-yl) pyrido [2,3-b ] pyrazine;
2-phenyl-3- (6-phenyl-7- (p-tolyl) -1H-imidazo [4,5-b ] pyridin-5-yl) quinoxaline;
8-methyl-6- (5-methyl-3-phenylquinoxalin-2-yl) -7-phenylpyrido [2,3-b ] pyrazine;
6- (6, 7-dichloro-3-phenylquinoxalin-2-yl) -8-methyl-7-phenylpyrido [2,3-b ] pyrazine;
8-methyl-7-phenyl-6- (3-phenylpyrido [3,4-b ] pyrazin-2-yl) pyrido [2,3-b ] pyrazine;
6- (3-butylquinoxalin-2-yl) -8-methyl-7-phenylpyrido [2,3-b ] pyrazine;
6- (3- (tert-butyl) quinoxalin-2-yl) -8-methyl-7-phenylpyrido [2,3-b ] pyrazine;
8-methyl-7-phenyl-6- (3- (trimethylsilyl) quinoxalin-2-yl) pyrido [2,3-b ] pyrazine;
8-methyl-7-phenyl-6- (3- (p-tolyl) quinoxalin-2-yl) pyrido [2,3-b ] pyrazine;
6- (3- (4-chlorophenyl) quinoxalin-2-yl) -8-methyl-7-phenylpyrido [2,3-b ] pyrazine;
6- (3-Cyclopropylquinoxalin-2-yl) -8-methyl-7-phenylpyrido [2,3-b ] pyrazine.
3. The quinoxalinyl pyridopyrazines according to claim 1, characterized in that they comprise the product obtained by the following process:
an alkynone compound 3 synthesized by an alkynone compound and phenylacetaldehyde, an amino pyrazinyl ketone compound 1 and a phenylenediamine compound 2 are directly synthesized into the quinoxalinyl pyridopyrazine compound by a one-pot method under the action of a catalyst and an additive.
4. The quinoxalinyl pyridopyrazines according to claim 3, wherein said aminopyrazinones are 1- (3-aminopyrazin-2-yl) ethanone, 1- (3-amino-6-methylpyrazin-2-yl) ethanone, 1- (3-amino-6-chloropyrazin-2-yl) ethanone, 1- (3-amino-5, 6-dichloropyrazin-2-yl) ethanone, methyl 3-amino-6-chloropyrazin-2-carboxylate, 3-amino-5, 6-dichloropyrazin-2-carbaldehyde, (3-amino-6-chloropyrazin-2-yl) (phenyl) methanone, (3-aminopyrazin-2-yl) (phenyl) methanone, (4-amino-1H-imidazol-5-yl) (p-tolyl) methanone.
5. The quinoxalinyl pyridopyrazines according to claim 3, wherein compound 2 is o-phenylenediamine, 2, 3-diaminotoluene, 3, 4-diaminotoluene, 4-bromoo-phenylenediamine, 3, 4-diaminobenzotrifluoride, 3, 4-diaminobenzoic acid, 4, 5-dichloro-1, 2-phenylenediamine, 3, 4-diaminopyridine.
6. Quinoxalinyl pyridopyrazines according to claim 3, the compound 3 is 1, 4-diphenyl-3-butyn-2-one, 1-phenyl-4- (p-tolyl) -3-butyn-2-one, 4- (4-chlorophenyl) -1-phenyl-3-butyn-2-one, 4-cyclopropyl-1-phenyl-3-butyn-2-one, 1-phenyl-3-octyn-2-one, 5, 5-dimethyl-1-phenyl-3-hexyn-2-one, 1-phenyl-4- (trimethylsilyl) -3-butyn-2-one.
7. A process for the preparation of quinoxalinyl pyridopyrazines according to claims 1 to 6, characterized in that it comprises the following reaction steps:
adding an amino pyrazinyl ketone compound 1 and an alkynone compound 3 into a reaction tube, adding a solvent, a catalyst and an additive, performing reflux reaction for 3-5h, adding a phenylenediamine compound 2, continuously stirring for reaction, detecting by TLC (thin layer chromatography), and reacting completely for 4-6 h;
and secondly, cooling the reaction liquid obtained in the step one to room temperature, filtering by using diatomite, concentrating the filtrate under reduced pressure, and then separating and purifying by using silica gel column chromatography to obtain the quinoxalinyl pyridopyrazine compound.
8. The method of claim 7, wherein the catalyst in step one is RuCl3The additive is N-bromosuccinimide, and the solvent is acetic acid.
9. The method for preparing quinoxalinyl pyridopyrazine compound according to claim 7, wherein the molar mass ratio of compound 1, compound 2, compound 3, catalyst and additive in step one is 1.0:1.1-1.3:1.1-1.3:0.1-0.2: 1.2-1.4; and the developing agent used by the column chromatography purification method in the step two is ethyl acetate: n-hexane 1:8 to 1: 12.
10. The use of a compound according to any one of claims 1 to 9 for the preparation of an antibacterial medicament for inhibiting escherichia coli, shigella dysenteriae, staphylococcus aureus and candida albicans.
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CN114478405B (en) * 2021-02-08 2023-08-15 中国科学院成都生物研究所 Preparation method of chiral nitrogen substituted tetrahydroquinoxaline

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