CN111892597B - Quinoxalinyl pyridopyrazine compound and preparation method and application thereof - Google Patents
Quinoxalinyl pyridopyrazine compound and preparation method and application thereof Download PDFInfo
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- A—HUMAN NECESSITIES
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Abstract
The invention provides a quinoxalinyl pyridopyrazine compound and a preparation method thereof, wherein the compound is obtained by directly synthesizing an alkynone compound 3, an amino pyrazinyl ketone compound 1 and a phenylenediamine compound 2 synthesized by alkyne compounds and phenylacetaldehyde under the action of a catalyst and an additive by a one-pot method, has good substrate universality, and the quinoxalinyl pyridopyrazine compound is a brand-new synthesis method provided on the basis of the prior art, and has good antibacterial activity on escherichia coli, shigella dysenteriae, staphylococcus aureus and candida albicans, and provides a new choice for the research and clinical use of antibacterial drugs.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a quinoxalinyl pyridopyrazine compound and a preparation method and application thereof.
Background
The pyrazine compound has important pharmacological activity effects of tuberculosis resistance, anticonvulsant, convulsion resistance, free radical removal, sterilization and the like on medicines, and has important application in the flavor and food industry.
Pyridine compounds are key components and core skeletons of a plurality of natural products, and pyridine skeleton structures are widely existing in synthetic medicines, and have various important physiological activities: such as anticancer, antioxidant, antibacterial, etc., but not all fungi or bacteria are pathogenic, and usually only a small fraction of fungi can cause illness in humans, and the development of antifungal, bacterial drugs is needed to treat these diseases.
In the application of quinoxaline compounds in antibacterial drugs, quinoxaline veterinary drugs with antibacterial and growth promoting effects are synthesized as early as 1967 in German Bayer company, and some quinoxaline drugs for resisting bacteria and promoting growth of livestock such as mequindox, olaquindox and carbadox are also available later, but in terms of long-term use effects, the drugs have problems such as drug residues and reproductive toxicity, so that further development of new drugs is needed to solve the problems.
With the rapid development of combinatorial chemistry and high throughput techniques, thousands of molecules of compounds are rapidly synthesized, and in the face of numerous compounds of unknown activity, it is necessary to identify the lead, and the initial experiments to identify the lead are to conduct drug susceptibility assays to determine whether the compound possesses primary activity for bacteriostasis or sterilization. The invention designs and synthesizes a series of quinoxalinyl pyrido [2,3-b ] pyrazine compounds, and preliminary researches the effect of the quinoxalinyl pyrido [2,3-b ] pyrazine compounds on the aspect of antibiosis, and has wide significance for the further development of future antibacterial drugs.
Disclosure of Invention
The invention aims to provide a quinoxalinyl pyridopyrazine compound and a preparation method thereof, and the antibacterial activity of the compound series on escherichia coli, staphylococcus aureus, candida albicans and shigella dysenteriae is studied.
The quinoxalinyl pyridopyrazine compound has the following structural general formula:
wherein R is 1 ＝H、Me、Cl；R 2 ＝H、Me、OMe、Ph、4-MePh；R 3 ＝H、Me、Br、Cl、CF 3 、COOH；R 4 ＝Ph、4-MePh、4-ClPh、t-Bu、n-Bu、cyclopropyl、trimethylsilyl；R 3 The substituted benzene ring may be a pyridine ring;
preferably, the quinoxalinyl pyridopyrazine compounds include the following:
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 obtained by the following method:
the quinoxalinyl pyridopyrazine compound is directly synthesized by an alkyne compound 3 synthesized by alkyne compounds and phenylacetaldehyde, an amino pyrazinyl ketone compound 1 and a phenylenediamine compound 2 through 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, 3-amino-6-chloropyrazin-2-carboxylic acid methyl ester, 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-bromophthalenediamine, 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-dimethyl-1-phenyl-3-hexyn-2-one, 1-phenyl-4- (trimethylsilyl) -3-butyn-2-one.
The preparation reaction general formula of the quinoxalinyl pyridopyrazine compound is as follows:
the preparation method of the quinoxalinyl pyridopyrazine compound comprises the following steps:
1. adding the amino pyrazinyl ketone compound 1 and the alkynone compound 3 into a reaction tube, adding a solvent, a catalyst and an additive, carrying out reflux reaction for 3-5h, adding the phenylenediamine compound 2, continuing stirring reaction, detecting by TLC, and completely reacting for 4-6 h;
2. and (3) cooling the reaction liquid in the step (I) to room temperature, filtering by diatomite, concentrating the filtrate under reduced pressure, and separating and purifying by silica gel column chromatography to obtain the quinoxalinyl pyridopyrazine compound.
Preferably, the catalyst in the first step is RuCl 3 The 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 step one is 1.0:1.1-1.3:1.1-1.3:0.1-0.2:1.2-1.4.
Preferably, the developing agent used in the column chromatography purification method in the second step is ethyl acetate: n-hexane=1:8-1:12.
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 preparation method of the quinoxalinyl pyridopyrazine compound is simple and has good substrate universality.
3. The quinoxalinyl pyridopyrazine compound has good antibacterial activity on escherichia coli, shigella dysenteriae, staphylococcus aureus and candida albicans, and provides a new choice for the research and clinical use of antibacterial drugs.
Detailed Description
The following is a further detailed description of the present invention in conjunction with specific embodiments, so that those skilled in the art may better understand and practice the present invention, but the examples are not intended to limit the present invention.
The structural formula of the quinoxalinyl pyridopyrazine compound is as follows:
preparation of starting compound 3: adding alkyne compounds and solvent anhydrous tetrahydrofuran into a reaction bottle under the protection of nitrogen, cooling to-20 ℃, taking 1.1 equivalent of n-butyllithium to be added into the solution dropwise, stirring for 1h at-20 ℃, then adding 1.0 equivalent of aldehyde compounds into the reaction solution, gradually heating to room temperature, continuously stirring for 12h, slowly adding water at 0 ℃ for quenching reaction after the reaction is finished, extracting the solution by diethyl ether, merging organic phases, washing by saturated saline water, drying by anhydrous sodium sulfate, concentrating the solvent under reduced pressure, and separating by column chromatography to obtain alkyne alcohol compounds. Dissolving the obtained alkynol compound in anhydrous dichloromethane, cooling to 0 ℃, then slowly adding 1.2 equivalents of Dess-Martin oxidant in batches, continuing the reaction for 1h, and then adding excessive saturated Na 2 S 2 O 3 Solution and saturated NaHCO 3 Quenching the solution, extracting the mixed solution with diethyl ether, mixing the 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, sun Y L, wei Y, shi M. Phosphine-Catalyzed Intermolecular Annulations of Fluorinated ortho-Aminophenones with Alkynones-The Switchable [4+2 ]]or[4+2]/[3+2]Cycloaddition[J].Advanced Synthesis&Catalysis.2019,361,2129-2135.)
Example 1
Preparation of compound 4 a: 2mmol of 1- (3-aminopyrazin-2-yl) ethanone, 2.2mmol of 1, 4-diphenyl-3-butyn-2-one are added to a reaction tube, 10mL of acetic acid, 0.2mmol of RuCl are added 3 And 2.4mmol of NBS, stirring for 3h under reflux, adding 2.2mmol of o-phenylenediamine, continuing stirring for reaction, detecting the reaction by TLC, cooling the reaction liquid to room temperature after 4h, filtering by diatomite, washing by ethyl acetate, concentrating the filtrate under reduced pressure, separating by silica gel column chromatography, and using ethyl acetate as a developing agent: n-hexane=1:10, the title compound was obtained as a light brown solid, having the following structural formula and characterization:
8-methyl-7-phenyl-6- (3-phenylquinoxalin-2-yl) pyrido [2,3-b]Pyrazine; 1 H NMR(400MHz,CDCl 3 )δ8.70–8.67(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). 13 C NMR(101MHz,CDCl 3 )δ153.96,152.80,149.60,147.56,146.42,143.76,143.58,142.91,139.97,138.12,135.64,133.73,130.56,129.96,129.80,127.65,127.53,126.87,126.38,124.45,123.95,15.87.HRMS(ESI):calcd for C 28 H 20 N 5 + [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 and compound 3 is 1, 4-diphenyl-3-butyn-2-one, for a specific experimental procedure reference example 1:
2, 8-dimethyl-7-phenyl-6- (3-phenylquinoxalin-2-yl) pyrido [2,3-b]Pyrazine; 1 H NMR(400MHz,CDCl 3 )δ8.60(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). 13 C NMR(101MHz,CDCl 3 )δ155.06,154.89,151.16,150.78,147.03,146.58,146.16,145.92,145.67,143.83,138.86,136.89,133.39,132.65,131.88,128.62,127.95,127.34,126.71,125.18,124.51,21.36,15.74.HRMS(ESI):calcd for C 29 H 22 N 5 + [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, and compound 3 is 1, 4-diphenyl-3-butyn-2-one, for a specific experimental procedure reference example 1:
2-chloro-8-methyl-7-phenyl-6- (3-phenylquinoxalin-2-yl) pyrido [2,3-b]Pyrazine; 1 H NMR(400MHz,CDCl 3 )δ8.69(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). 13 C NMR(101MHz,CDCl 3 )δ154.31,149.64,149.09,146.67,145.32,144.87,143.76,142.20,141.34,140.82,136.25,134.07,131.12,130.35,129.85,129.01,128.79,128.53,128.08,127.85,126.46,14.69.HRMS(ESI):calcd for C 28 H 19 ClN 5 + [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, and compound 3 is 1, 4-diphenyl-3-butyn-2-one, for a specific experimental procedure reference example 1:
7, 8-diphenyl-6- (3-phenylquinoxalin-2-yl) pyrido [2,3-b]Pyrazine; 1 H NMR(400MHz,CDCl 3 )δ8.75–8.64(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). 13 C NMR(101MHz,CDCl 3 )δ155.26,154.13,149.79,149.05,148.09,146.24,145.77,144.28,142.69,139.95,137.90,136.97,134.98,132.37,131.85,131.41,130.70,129.76,129.58,129.35,129.21,127.83,127.64.HRMS(ESI):calcd for C 33 H 22 N 5 + [M+H] + 488.1870,found 488.1872.
example 5
Preparation of compound 4 e: compound 1 is (3-amino-6-chloropyrazin-2-yl) (phenyl) methanone, compound 2 is o-phenylenediamine, compound 3 is 1, 4-diphenyl-3-butyn-2-one, and reference is made to example 1 for a specific experimental procedure:
2-chloro-7, 8-diphenyl-6- (3-phenylquinoxalin-2-yl) pyrido [2,3-b]Pyrazine; 1 H NMR(400MHz,CDCl 3 )δ8.70(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). 13 C NMR(101MHz,CDCl 3 )δ153.24,150.96,147.82,145.76,144.17,143.73,142.26,141.89,139.86,138.65,135.56,135.05,133.43,130.28,129.96,129.82,129.59,129.36,128.08,127.86,127.34,127.06,126.75.HRMS(ESI):calcd for C 33 H 21 ClN 5 + [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, and compound 3 is 1, 4-diphenyl-3-butyn-2-one, for a specific experimental procedure reference example 1:
2, 3-dichloro-7-phenyl-6- (3-phenylquinoxalin-2-yl) pyrido [2,3-b]Pyrazine; 1 H NMR(400MHz,CDCl 3 )δ8.75(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). 13 C NMR(101MHz,CDCl 3 )δ155.46,148.06,146.18,145.80,144.86,143.63,143.49,142.14,142.02,136.94,135.87,134.78,131.66,131.43,131.02,130.29,129.27,128.84,128.61,128.17,127.65,126.06.HRMS(ESI):calcd for C 27 H 16 Cl 2 N 5 + [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, and compound 3 is 1, 4-diphenyl-3-butyn-2-one, for a specific experimental procedure reference example 1:
2, 3-dichloro-8-methyl-7-phenyl-6- (3-phenylquinoxalin-2-yl) pyrido [2,3-b]Pyrazine; 1 H NMR(400MHz,CDCl 3 )δ8.10(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). 13 C NMR(101MHz,CDCl 3 )δ156.58,153.39,151.02,147.55,147.07,146.63,145.92,143.55,143.08,138.78,137.82,136.52,133.42,132.92,132.46,131.38,130.94,130.26,129.87,128.76,125.31,15.77.HRMS(ESI):calcd for C 28 H 18 Cl 2 N 5 + [M+H] + 494.0934,found494.0935.
example 8
Preparation of Compound 4 h: compound 1 is 1- (3-aminopyrazin-2-yl) ethanone, compound 2 is 3, 4-diaminotoluene, compound 3 is 1, 4-diphenyl-3-butyn-2-one, and reference is made to example 1 for a specific experimental procedure:
8-methyl-6- (6-methyl-3-phenylquinoxalin-2-yl) -7-phenylpyrido [2,3-b ]]Pyrazine; 1 H NMR(400MHz,CDCl 3 )δ8.76–8.71(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). 13 C NMR(101MHz,CDCl 3 )δ153.89,153.30,149.57,148.09,145.24,144.17,143.76,142.59,140.28,139.83,138.62,135.45,133.43,131.35,130.56,129.79,129.37,129.26,128.98,128.64,127.83,127.36,126.78,20.62,14.58.HRMS(ESI):calcd for C 29 H 22 N 5 + [M+H] + 440.1870,found 440.1876.
example 9
Preparation of compound 4 i: compound 1 is 1- (3-aminopyrazin-2-yl) ethanone, compound 2 is 4-bromophthalenediamine, compound 3 is 1, 4-diphenyl-3-butyn-2-one, and reference is made to example 1 for a specific experimental procedure:
6- (6-bromo-3-phenylquinoxalin-2-yl) -8-methyl-7-phenylpyrido [2,3-b ]]Pyrazine; 1 H NMR(400MHz,CDCl 3 )δ8.72–8.67(m,2H),8.28–8.21(m,3H),7.89–7.47(m,4H),7.41–7.28(m,6H),2.47(s,3H). 13 C NMR(101MHz,CDCl 3 )δ154.17,152.80,151.06,150.64,147.54,145.68,144.84,143.57,140.91,139.14,136.76,135.23,133.14,130.94,130.37,129.56,128.78,128.65,128.18,127.93,127.64,127.03,124.73,15.62.HRMS(ESI):calcd for C 28 H 19 BrN 5 + [M+H] + 504.0818,found504.0822.
example 10
Preparation of Compound 4 j: compound 1 is 1- (3-aminopyrazin-2-yl) ethanone, compound 2 is 3, 4-diaminobenzotrifluoride and compound 3 is 1, 4-diphenyl-3-butyn-2-one, for a specific experimental procedure reference example 1:
8-methyl-7-phenyl-6- (3-phenyl-6- (trifluoromethyl) quinoxalin-2-yl) pyrido [2,3-b]Pyrazine; 1 H NMR(400MHz,CDCl 3 )δ8.76–8.62(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).δ154.60,152.31,150.67,149.75,147.60,144.51,143.27,140.28,139.32,136.66,134.87,132.52,130.91(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 C 29 H 19 F 3 N 5 + [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, and reference is made to example 1 for a specific experimental procedure:
2- (8-methyl-7-phenylpyrido [2, 3-b)]Pyrazin-6-yl) -3-phenylquinoxaline-6-carboxylic acid; 1 H NMR(400MHz,CDCl 3 )δ8.80–8.73(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). 13 C NMR(101MHz,CDCl 3 )δ167.06,154.15,153.12,150.76,149.83,147.54,145.35,145.16,143.23,141.74,139.76,136.86,134.67,133.78,131.26,130.84,129.56,128.63,128.31,127.08,126.83,126.56,126.27,125.25,15.63.HRMS(ESI):calcd for C 29 H 20 N 5 O 2 + [M+H] + 470.1612,found 470.1615.
example 12
Preparation of Compound 4 l: compound 1 is 3-amino-6-chloropyrazine-2-carboxylic acid methyl ester, compound 2 is o-phenylenediamine, compound 3 is 1, 4-diphenyl-3-butyn-2-one, and reference is made to example 1 for a specific experimental procedure:
2-chloro-8-methoxy-7-phenyl-6- (3-phenylquinoxalin-2-yl) pyrido [2,3-b]Pyrazine; 1 H NMR(400MHz,CDCl 3 )δ8.77(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). 13 C NMR(101MHz,CDCl 3 )δ165.64,153.47,148.54,145.72,144.19,143.09,142.21,141.56,140.24,138.10,132.80,131.49,129.93,129.19,129.08,127.71,127.46,126.53,126.32,119.64,57.46.HRMS(ESI):calcd for C 28 H 19 ClN 5 O + [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, and compound 3 was 1, 4-diphenyl-3-butyn-2-one, for a detailed description of the experimental procedure, reference example 1:
2-phenyl-3- (6-phenyl-7- (p-tolyl) -1H-imidazo [4,5-b]Pyridin-5-yl) quinoxalines; 1 H NMR(400MHz,CDCl 3 )δ12.89(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). 13 C NMR(101MHz,CDCl 3 )δ153.66,152.86,145.27,144.36,143.65,143.08,142.41,137.51,135.86,134.30,133.93,131.66,130.26,129.98,128.87,128.78,128.37,127.69,127.31,127.04,126.67,126.08,120.33,20.53.HRMS(ESI):calcd for C 33 H 24 N 5 + [M+H] + 490.2026,found 490.2028.
example 14
Preparation of compound 4 n: compound 1 is 1- (3-aminopyrazin-2-yl) ethanone, compound 2 is 2, 3-diaminotoluene, and compound 3 is 1, 4-diphenyl-3-butyn-2-one, for a specific experimental procedure reference example 1:
8-methyl-6- (5-methyl-3-phenylquinoxalin-2-yl) -7-phenylpyrido [2,3-b ]]Pyrazine; 1 H NMR(400MHz,CDCl 3 )δ8.76(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).
13 C NMR(101MHz,CDCl 3 )δ154.49,152.38,149.68,148.75,145.13,144.60,142.92,142.67,138.70,137.99,137.05,134.69,133.12,130.49,129.65,127.55,127.36,125.77,125.56,125.21,124.86,124.31,123.44,16.58,14.75.HRMS(ESI):calcd for C 29 H 22 N 5 + [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, and reference is made to example 1 for a specific experimental procedure:
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6- (6, 7-dichloro-3-phenylquinoxalin-2-yl) -8-methyl-7-phenylpyrido [2,3-b ]]Pyrazine; 1 H NMR(400MHz,CDCl 3 )δ8.72–8.66(m,2H),8.17(s,1H),8.09–7.88(m,3H),7.50–7.13(m,8H),2.48(s,3H). 13 C NMR(101MHz,CDCl 3 )δ154.30,152.75,150.68,149.37,147.14,144.56,141.79,139.47,139.06,136.77,136.40,134.63,131.75,130.17,129.47,129.31,129.09,128.38,128.54,127.38,126.69,15.08.HRMS(ESI):calcd for C 28 H 18 Cl 2 N 5 + [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, and reference is made to example 1 for a specific experimental procedure:
8-methyl-7-phenyl-6- (3-phenylpyrido [3, 4-b)]Pyrazin-2-yl) pyrido [2,3-b]Pyrazine; 1 H NMR(400MHz,CDCl 3 )δ8.94(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). 13 C NMR(101MHz,CDCl 3 )δ154.22,153.89,153.22,150.46,150.10,149.05,147.36,147.03,145.97,144.32,142.37,137.58,136.34,134.65,130.99,129.28,128.97,127.76,127.44,126.90,126.34,119.89,14.89.HRMS(ESI):calcd for C 27 H 19 N 6 + [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, and compound 3 is 1-phenyl-3-octyn-2-one, for a specific experimental procedure reference example 1:
6- (3-butylquinoxalin-2-yl) -8-methyl-7-phenylpyrido [2,3-b ]]Pyrazine; 1 H NMR(400MHz,CDCl 3 )δ8.82–8.78(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). 13 C NMR(101MHz,CDCl 3 )δ154.68,151.78,151.43,149.12,148.35,146.93,145.28,143.46,140.25,138.65,136.49,131.74,130.55,129.86,129.57,128.86,128.43,128.01,126.57,35.00,31.07,21.80,15.60,13.83.HRMS(ESI):calcd for C 26 H 24 N 5 + [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, and compound 3 is 5, 5-dimethyl-1-phenyl-3-hexyn-2-one, for a specific experimental procedure reference example 1:
6- (3- (tert-butyl) quinoxalin-2-yl) -8-methyl-7-phenylpyrido [2,3-b ]]Pyrazine; 1 H NMR(400MHz,CDCl 3 )δ8.73–8.62(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). 13 C NMR(101MHz,CDCl 3 )δ162.81,155.47,152.38,151.24,149.39,147.88,145.47,141.42,140.64,140.36,138.68,132.56,132.34,131.41,129.42,128.67,126.51,37.69,26.60,15.26.HRMS(ESI):calcd for C 26 H 24 N 5 + [M+H] + 406.2026,found 406.2023.
example 19
Preparation of compound 4 s: compound 1 is 1- (3-aminopyrazin-2-yl) ethanone, compound 2 is o-phenylenediamine, and compound 3 is 1-phenyl-4- (trimethylsilyl) -3-butyn-2-one, for a specific experimental procedure reference example 1:
8-methyl-7-phenyl-6- (3- (trimethylsilyl) quinoxalin-2-yl) pyrido [2,3-b]Pyrazine; 1 H NMR(400MHz,CDCl 3 )δ8.87–8.65(m,3H),8.31–8.13(m,2H),7.80–7.17(m,6H),2.57(s,3H),0.16(s,9H). 13 C NMR(101MHz,CDCl 3 )δ157.52,156.95,153.60,150.22,149.20,148.97,146.85,142.02,141.32,138.76,133.56,133.22,132.84,132.01,131.72,131.62,130.40,129.14,20.64,-1.49.HRMS(ESI):calcd for C 25 H 24 N 5 Si + [M+H] + 422.1795,found 422.1799.
example 20
Preparation of compound 4 t: compound 1 is 1- (3-aminopyrazin-2-yl) ethanone, compound 2 is o-phenylenediamine, and compound 3 is 1-phenyl-4- (p-tolyl) -3-butyn-2-one, for a detailed description of the experimental procedure, reference example 1:
8-methyl-7-phenyl-6- (3- (p-tolyl) quinoxalin-2-yl) pyrido [2,3-b]Pyrazine; 1 H NMR(400MHz,CDCl 3 )δ8.74–8.66(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). 13 C NMR(101MHz,CDCl 3 )δ154.39,153.90,151.05,149.86,146.84,144.37,144.12,143.65,142.01,141.76,138.47,135.30,131.56,130.26,130.10,129.83,128.89,128.30,127.34,126.76,126.18,20.75,15.18.HRMS(ESI):calcd for C 29 H 22 N 5 + [M+H] + 440.1870,found 440.1874.
example 21
Preparation of compound 4 u: compound 1 is 1- (3-aminopyrazin-2-yl) ethanone, compound 2 is o-phenylenediamine, and compound 3 is 4- (4-chlorophenyl) -1-phenyl-3-butyn-2-one, for a specific experimental procedure reference example 1:
6- (3- (4-chlorophenyl) quinoxalin-2-yl) -8-methyl-7-phenylpyrido [2,3-b ]]Pyrazine; 1 H NMR(400MHz,CDCl 3 )δ8.71–8.63(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). 13 C NMR(101MHz,CDCl 3 )δ154.48,154.01,150.98,149.76,146.70,144.26,144.07,143.38,141.86,139.15,136.18,135.68,131.47,130.05,129.79,129.63,129.15,128.55,127.62,126.87,125.77,15.02.HRMS(ESI):calcd for C 28 H 19 ClN 5 + [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, and compound 3 is 4-cyclopropyl-1-phenyl-3-butyn-2-one, for a specific experimental procedure reference example 1:
6- (3-Cyclopropylquinoxalin-2-yl) -8-methyl-7-phenylpyrido [2,3-b ]]Pyrazine; 1 H NMR(400MHz,CDCl 3 )δ8.75–8.69(m,2H),7.86–7.79(m,2H),7.63–7.30(m,7H),2.77(s,3H),1.24–0.78(m,5H). 13 C NMR(101MHz,CDCl 3 )δ155.05,152.89,151.06,150.24,148.72,147.54,147.32,144.65,140.42,140.34,137.76,132.52,132.37,130.85,129.74,129.55,128.30,127.99,127.14,15.84,12.36,10.08.HRMS(ESI):calcd for C 25 H 20 N 5 + [M+H] + 390.1713,found 390.1717.
example 23
Example 1 was repeated, except that no catalyst RhCl was added 3 The reaction does not produce the target product 4a, or RhCl 3 Change to FeCl 3 、ZnCl 2 、AlCl 3 、Pd(OAc) 2 With AlCl only 3 Trace amounts of the product 4a were obtained for the catalyst, and the target product 4a was not obtained for the rest.
Example 24
Example 1 was repeated except that no NBS was added and no product 4a was obtained by the reaction; or when the addition amount of NBS is 0.5-1.5mmol, the product 4a is still not obtained; when the amount of NBS was 1.8, 2.0mmol, 42%, 52% of product 4a was obtained, respectively; when the amount of NBS was 3.0mmol, the yield of 4a was 28%.
Example 25
When example 1 was repeated and the solvent was changed to absolute ethanol or absolute dimethyl sulfoxide or absolute toluene or absolute dichloroethane, the desired product 4a could not be obtained.
The compounds listed in the above examples are part of the synthetic compounds of the present invention.
Biological activity test:
the compounds 4a-4v were tested for their inhibitory effect on E.coli, shigella dysenteriae, staphylococcus aureus and Candida albicans.
Antibacterial performance of each compound is detected by adopting a bacteriostasis circle method:
1. preparation of compound solution: weighing 10mg of compound, dripping one drop of DMSO 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. the experimental escherichia coli BNCC337357, shigella dysenteriae BNCC340633, staphylococcus aureus BNCC186335 and candida albicans BNCC176009 are all purchased from North Nanopsis; inoculating the strain into a solid culture medium (pH 7.5), culturing at 37deg.C for 24 hr, inoculating single colony into a liquid culture medium (pH 7.5), shake culturing at 37deg.C overnight, and keeping the bacterial liquid for later use;
3. injecting a certain amount of bacterial liquid into the 45 ℃ flat culture medium, uniformly mixing and leading the concentration of viable bacteria to be 10 5 CFU/mL, then pouring 20mL into a flat plate, and standing horizontally for solidification (the four bacterial liquids are the same in operation);
4. taking dry sterile filter paper sheets (diameter is 5 mm), dropwise adding 40 mu L of compound solution into each filter paper 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 a cover, culturing at 37 ℃ for 24-48h, observing and measuring the existence and the size of a bacteriostasis ring, measuring the diameter of the bacteriostasis ring by a crisscross method, wherein the diameter of the bacteriostasis ring is less than or equal to 7mm, and repeating each experiment for three times; (the results are detailed in Table 1)
6. Preparing a solution with the same volume by adopting a drop of DMSO and distilled water in a blank group, dripping 40 mu L of the solution on filter paper, drying the solution at room temperature, and placing the solution in the center of a culture medium; the solutions on the control filters were 0.1% of the solutions prepared from commercial ibupromycin, fluconazole, cefminox sodium and clarithromycin, respectively.
Table 1 inhibition of E.coli, candida albicans, staphylococcus aureus and Shigella dysenteriae by various compounds
As can be seen from the data in table 1, the distilled water in the blank group 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, and the diameters of the inhibition zones respectively reach 24 mm, 27 mm and 28mm, which are higher than the inhibition activity of cefminox sodium on escherichia coli, the inhibition activity of fluconazole on candida albicans and the inhibition activity of clarithromycin on shigella dysenteriae; the antibacterial activity of the compound 4j on staphylococcus aureus is strongest, the diameter of a bacteriostasis ring reaches 26mm, and the antibacterial activity of the compound 4g, 4i-4m, 4o, 4p, 4r, 4s and 4n compounds on staphylococcus aureus is higher than the inhibitory activity of the medicines of each control group on staphylococcus aureus.
As shown by the data in Table 1, the antibacterial activity of the compound 4a-4v of the invention on escherichia coli, candida albicans, staphylococcus aureus and shigella dysenteriae is strong, the antibacterial activity on shigella dysenteriae is strong, the diameter of the antibacterial circle is 14-28mm, and the diameters of the antibacterial circles of 4a-4e, 4g, 4i-4m, 4o-4p and 4s are all more than 20 mm.
The data show that the quinoxalinyl pyridopyrazine compound has 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 foregoing description is only of the preferred embodiments of the present invention, and is not intended to limit the scope of the invention, but rather is intended to cover any equivalents of the structures disclosed herein or modifications in the equivalent processes, or any application of the structures disclosed herein, directly or indirectly, in other related arts.
Claims (5)
1. A compound is characterized by having a structural general formula:
wherein R is 1 ＝H、Me、Cl；R 2 =h, me, OMe, phenyl, 4-methylphenyl; r is R 3 ＝H、Me、Br、Cl、CF 3 、COOH；R 4 Phenyl, 4-methylphenyl, 4-chlorophenyl, t-Bu, n-Bu, cyclopropyl, trimethylsilyl.
2. A compound, characterized in that it is selected from the group consisting of:
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. A process for the preparation of a compound according to claim 1 or 2, characterized in that it comprises the following reaction steps:
1. adding the compound 1 and the compound 3 into a reaction tube, adding a solvent, a catalyst and an additive, carrying out reflux reaction for 3-5h, adding the compound 2, continuing stirring for reaction, detecting by TLC, carrying out complete reaction for 4-6h,
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, 3-amino-6-chloropyrazine-2-carboxylic acid methyl ester, 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,
the compound 2 is o-phenylenediamine, 2, 3-diaminotoluene, 3, 4-diaminotoluene, 4-bromophthalenediamine, 3, 4-diaminobenzotrifluoride, 3, 4-diaminobenzoic acid, 4, 5-dichloro-1, 2-phenylenediamine, 3, 4-diaminopyridine,
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-dimethyl-1-phenyl-3-hexyn-2-one, 1-phenyl-4- (trimethylsilyl) -3-butyn-2-one,
the catalyst is RuCl 3 The additive is N-bromosuccinimide, and the solvent is acetic acid;
2. and (3) cooling the reaction liquid in the step (I) to room temperature, filtering by using diatomite, concentrating the filtrate under reduced pressure, and separating and purifying by using silica gel column chromatography to obtain the compound.
4. The method according to claim 3, wherein 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; the developing agent used in the column chromatography purification method in the second step is ethyl acetate: n-hexane=1:8-1:12.
5. The use of a compound according to claim 1 or 2 for the preparation of an antibacterial agent against escherichia coli, shigella dysenteriae, staphylococcus aureus and candida albicans.
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| US4933342A (en) * | 1988-04-11 | 1990-06-12 | Nisshin Flour Milling Co., Ltd. | Quinoxaline derivatives and antiulcer agents |
| CN101330918A (en) * | 2005-11-11 | 2008-12-24 | 阿特纳赞塔里斯有限公司 | Pyridopyrazine derivatives and use thereof as modulators of the signal transduction paths |
| WO2017060406A1 (en) * | 2015-10-09 | 2017-04-13 | Janssen Pharmaceutica Nv | Quinoxaline and pyridopyrazine derivatives as pi3kbeta inhibitors |
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| US4933342A (en) * | 1988-04-11 | 1990-06-12 | Nisshin Flour Milling Co., Ltd. | Quinoxaline derivatives and antiulcer agents |
| CN101330918A (en) * | 2005-11-11 | 2008-12-24 | 阿特纳赞塔里斯有限公司 | Pyridopyrazine derivatives and use thereof as modulators of the signal transduction paths |
| WO2017060406A1 (en) * | 2015-10-09 | 2017-04-13 | Janssen Pharmaceutica Nv | Quinoxaline and pyridopyrazine derivatives as pi3kbeta inhibitors |
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