Multi-substituted acylamino quinoxaline derivative and preparation method thereof

Abstract

The invention discloses a polysubstituted acylamino quinoxaline derivative and a preparation method thereof, and relates to the technical field of organic synthetic chemistry. The structural formula of the multi-substituted acylamino quinoxaline derivative is shown in the specification. The multi-substituted amido quinoxaline derivative is prepared by taking an o-diaryl isonitrile compound, aryl isonitrile and a zwitter-ion trapping agent as substrates and carrying out three-component reaction in water. The preparation method disclosed by the invention is efficient, green, mild in condition, simple to operate, simple and easily available in raw materials and reagents, high in practicability and suitable for synthesizing various acylamino quinoxaline derivatives.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthetic chemistry, and in particular to a polysubstituted amide quinoxaline derivative and a preparation method thereof. Background Art

[0002] Aminoquinoxaline derivatives are a class of nitrogen-containing heterocyclic compounds with unique structures and diverse functions. Due to their excellent biological activity, they have attracted widespread attention in fields such as chemistry, medicine, materials science, and bioengineering. Related research has shown that this class of compounds has broad application prospects in neuromodulation, anti-tumor, antibacterial, and anti-inflammatory applications.

[0003] In medicinal chemistry, the amidoquinoxaline skeleton has been shown to act as an antagonist for a variety of targets. For example, a compound with an amidoquinoxaline nucleus (N-(3-chloro-2-methylphenyl)quinoxaline-2-carboxamide) acts as a 5-HT3 receptor antagonist. It primarily inhibits 5-HT3 receptor activity, reducing central nervous system excitability, thereby alleviating nausea and vomiting symptoms and exhibiting antidepressant and anxiolytic effects. This class of drugs specifically blocks the 5-HT3 receptor, thereby reducing the activity of neurotransmitters and decreasing the sensitivity of the vomiting reflex. N-Tricyclo[3.3.1.13,7]dec-1-yl-2-quinoxalinecarboxamide (NPS-2390) acts as a noncompetitive antagonist for mGluR1 (metabotropic glutamate receptor 1) and mGluR5 (metabotropic glutamate receptor 5). It does not compete with agonists for binding sites at these receptors, but rather affects receptor function through other pathways. In addition, NPS-2390 is also an effective calcium-sensing receptor (CaSR) inhibitor that can regulate physiological processes related to calcium ions. NPR-C antagonists can block the signal transduction pathway mediated by the receptor by binding to the NPR-C receptor. This helps to regulate physiological processes related to the NPR-C receptor, such as regulating vascular tension and affecting cardiac function. In addition, quinoxaline compounds have also shown new uses in the treatment of cardiovascular diseases. Studies have shown that ethyl 2-(4-(amidoquinoxaline)phenyl)acetic acid compounds, as important precursors of NPR-C antagonists, can be used to prepare a series of NPR-C antagonists ( Tetrahedron Letters, 2020,61,151654).

[0004] While existing amidoquinoxaline derivatives have shown promise across multiple targets, they still face several challenges: First, the reported structural types are relatively concentrated and lack novelty; second, many synthetic methods suffer from complex processes, limited availability of raw materials, or low yields, hindering further research in drug development and application expansion. Therefore, developing amidoquinoxaline derivatives with novel structures and simple synthesis remains an important research direction in this field. Summary of the Invention

[0005] In view of the above prior art, the purpose of the present invention is to provide a polysubstituted amide quinoxaline derivative and a preparation method thereof. The structural formula of the polysubstituted amide quinoxaline derivative is The invention relates to a novel quaternaryl isocyanide, a zwitterion scavenger, and an ortho-diaryl isocyanide. The quaternary isocyanide is prepared by a three-component reaction in water using an ortho-diaryl isocyanide compound, an aryl isocyanide, and a zwitterion scavenger as substrates. The preparation method of the invention is efficient and green, has mild conditions, is simple to operate, uses readily available raw materials and reagents, and is highly practical, making it suitable for the synthesis of various amidoquinoxaline derivatives.

[0006] To achieve the above object, the present invention adopts the following technical solutions: In a first aspect of the present invention, a multi-substituted amidoquinoxaline derivative is provided, wherein the structural formula of the multi-substituted amidoquinoxaline derivative is shown in formula (I): Formula (I); In formula (I), R 1 Selected from C1-C20 straight or branched alkyl, aryl, halogen, and hydrogen; R 2 One selected from aryl, fused aryl, heteroaryl or alkyl; R 3 One selected from acyl, aromatic hydrocarbon or alkylthio.

[0007] As a preference, R 1 One selected from 4,5-dimethyl, 6-methyl, 7-methyl, 6,7-dimethoxy, 6,7-dichloro, 6,7-dibromo, and hydrogen atom; R 2 One selected from 4-methoxyphenyl, 4-methyl, 4-methoxy, 4-phenyl, 4-bromo, 4-ethoxy, 4-benzoyl, 3-nitro, 2-phenyl, 2-methyl-2-chloro, 2-ethoxy, 2-cyano, 3-methyl, 3-bromo, 2-methyl, 3,4-dimethyl, 3,5-dimethyl, 2,6-dimethyl, 3,4,5-trimethoxy, 1-naphthyl, 2-naphthyl, 5-quinolyl, 6-quinolyl, cyclohexyl, n-butyl, 2-methyl-3-chlorophenyl, 4-ethoxybenzyl, adamantyl, 4-methylbenzyl, 4-chlorobenzyl, 4-sulfonyl, or a hydrogen atom; R 3 One selected from formyl, benzoyl, benzyl and carbonylthio.

[0008] Preferably, the polysubstituted amidoquinoxaline derivatives are 3-benzoyl-N-(4-methoxyphenyl)-6,7-dimethylamidoquinoxaline, 3-formyl-N-(4-methoxyphenyl)-6,7-dimethylamidoquinoxaline, 3-benzyl-N-(4-methoxyphenyl)-6,7-dimethylamidoquinoxaline and 3-carbonyl-N-(4-methoxyphenyl)-6,7-dimethylamidoquinoxaline, and the structural formulas are shown in Formula (II) to Formula (V): Formula (II); Formula (III); Formula (IV); Formula (V).

[0009] The second aspect of the present invention provides a method for preparing the above-mentioned polysubstituted amidoquinoxaline derivative, comprising the following steps: The o-diaryl isocyanide, aryl isocyanide and zwitterion capture agent are mixed and placed in deionized water for reaction; after the reaction is completed, the reaction system is cooled and filtered, and the filtered solid is collected to obtain a multi-substituted amide quinoxaline derivative.

[0010] Preferably, the structural formula of o-diaryl isonitrile is shown in formula (VI): Formula (VI); Where R 1 Selected from C1-C20 straight or branched alkyl groups, aryl groups, halogen atoms, and hydrogen atoms.

[0011] Furthermore, R 1 One selected from 4,5-dimethyl, 6-methyl, 7-methyl, 6,7-dimethoxy, 6,7-dichloro, 6,7-dibromo or hydrogen atom.

[0012] Preferably, the structural formula of the aromatic isonitrile is shown in formula (VII): Formula (VII); Where R 2 One selected from aryl, fused aryl, heteroaryl or alkyl.

[0013] Furthermore, R 2One selected from 4-methoxyphenyl, 4-methyl, 4-methoxy, 4-phenyl, 4-bromo, 4-ethoxy, 4-benzoyl, 3-nitro, 2-phenyl, 2-methyl-2-chloro, 2-ethoxy, 2-cyano, 3-methyl, 3-bromo, 2-methyl, 3,4-dimethyl, 3,5-dimethyl, 2,6-dimethyl, 3,4,5-trimethoxy, 1-naphthyl, 2-naphthyl, 5-quinolyl, 6-quinolyl, cyclohexyl, n-butyl, 2-methyl-3-chlorophenyl, 4-ethoxybenzyl, adamantyl, 4-methylbenzyl, 4-chlorobenzyl, 4-sulfonyl, or a hydrogen atom.

[0014] Preferably, the zwitterion capture agent is selected from one of sodium benzoate, phenyl acetate, azo compounds, and trimethylsilyl isothiocyanate.

[0015] Preferably, the added amounts of o-diaryl isocyanide, aromatic isocyanide, zwitterion capture agent and deionized water are 1 mmol: (1-2) mmol: (1-3) mmol: (5-15) mL.

[0016] Furthermore, the added amounts of o-diaryl isocyanide, aryl isocyanide, zwitterion capture agent and deionized water are 0.2 mmol: 0.4 mmol: 0.6 mmol: 2 mL.

[0017] Preferably, the reaction temperature is 25-100° C. and the reaction time is 1-24 h.

[0018] Furthermore, the reaction temperature is 60° C. and the reaction time is 1 h.

[0019] Beneficial effects of the present invention: 1. As a nitrogen-containing heterocyclic compound, amidoquinoxaline compounds can be used as organic synthesis intermediates to prepare amidoquinoxaline and as important anti-caking agents. They occupy a very important position in the fields of medicinal chemistry and organic synthesis. The present invention provides a polysubstituted amidoquinoxaline derivative, whose structural formula is The amidoquinoxaline derivatives prepared by the present invention can be used for the derivatization of pesticide drug molecules.

[0020] 2. The present invention utilizes o-diaryl isonitrile compounds, aryl isonitriles, and zwitterion traps as substrates, and reacts in water to produce polysubstituted amidoquinoxaline derivatives without the need for metal reagents or base catalysis, or isolation from water or oxygen. Compared to the prior art, the present invention utilizes a three-component reaction of o-diaryl isonitriles with various isonitriles and a zwitterion trap to produce amidoquinoxaline compounds. The preparation method of the present invention is efficient and green, operates under mild conditions, is simple to operate, uses readily available raw materials and reagents, and is highly practical, making it suitable for the synthesis of various amidoquinoxaline derivatives. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 : H NMR spectrum of the polysubstituted amidoquinoxaline derivative prepared in Example 1; Figure 2 : H NMR spectrum of the polysubstituted amidoquinoxaline derivative prepared in Example 2; Figure 3 : H NMR spectrum of the polysubstituted amidoquinoxaline derivative prepared in Example 3; Figure 4 : H NMR spectrum of the polysubstituted amide-quinoxaline derivative prepared in Example 4. DETAILED DESCRIPTION

[0022] It should be noted that the following detailed descriptions are illustrative and intended to provide further explanation of the present application. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present application belongs.

[0023] Amidoquinoxaline compounds, a class of nitrogen-containing heterocyclic compounds, have important applications in the pharmaceutical and pesticide fields. For example, amidoquinoxaline compounds are also important organic synthesis intermediates, capable of undergoing nucleophilic substitution reactions on the quinoxaline ring and electrophilic substitution reactions on the benzene ring. They can react with many different raw materials to produce a variety of amidoquinoxaline compounds. In addition, amidoquinoxaline derivatives are also several important anti-caking agents. Although existing amidoquinoxaline derivatives have shown potential for multiple targets, there is still a need to develop amidoquinoxaline derivatives with novel structures and simple synthesis.

[0024] Based on this, the present invention provides a polysubstituted amide quinoxaline derivative and a preparation method thereof. The structural formula of the polysubstituted amide quinoxaline derivative is shown in formula (I): Formula (I).

[0025] Where R 1 Selected from C1-C20 straight or branched alkyl, aryl, halogen, and hydrogen; R 2 One selected from aryl, fused aryl, heteroaryl or alkyl; R 3 One selected from formyl, benzoyl or benzyl.

[0026] The invention is based on easily available o-diaryl isonitrile, and realizes a novel multi-component reaction by initiating a multi-component reaction through the chemically selective heterodimerization of o-diphenyl isonitrile and isonitrile, thereby preparing a multi-substituted amide quinoxaline derivative.

[0027] Its synthetic route is as follows: .

[0028] The reaction mechanism is as follows: o-diaryl isonitriles undergo chemoselective heterodimerization with various isonitriles to yield highly reactive zwitterionic intermediates or their resonant 1,4-diazabutriene intermediates. This intermediate then undergoes intramolecular nucleophilic addition to generate quinoxaline-based 1,3-zwitterionic intermediates. Finally, the zwitterionic intermediates are captured by a zwitterion trapping agent, ultimately yielding the key amidoquinoxaline synthon. The reaction process is as follows: .

[0029] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments.

[0030] The experimental materials used in the examples of the present invention are all conventional experimental materials in the art and can be purchased through commercial channels.

[0031] Example 1: Preparation of polysubstituted amidoquinoxaline derivatives The polysubstituted amidoquinoxaline derivative in this embodiment is 3-benzoyl-N-(4-methoxyphenyl)-6,7-dimethylamidoquinoxaline, and its synthesis route is: .

[0032] 1,2-diisocyanato-4,5-dimethylbenzene 1a (31.2 mg, 0.2 mmol), 1-isocyanato-4-methoxybenzene 2a (53.2 mg, 0.4 mmol) and sodium benzoate (86.4 mg, 0.6 mmol) were added to a 15 mL pressure tube in sequence. 2 mL of deionized water and a stirring bar were added. After tightening the stopcock of the pressure tube, the reaction mixture was stirred at room temperature for 30 minutes to allow the reaction system to be uniformly mixed. The mixture was then heated to 60°C by microwave irradiation. o C and stirred for one hour. During the reaction, the reaction mixture was monitored by online TLC. After the reactant 1a was completely consumed, the reaction solution was cooled to room temperature or poured into ice water. After the precipitated solid was filtered and air-dried, a light yellow solid 3a (76.48 mg, 82%) was obtained.

[0033] 1 H NMR (400 MHz, CDCl3): δ 2.47 (s, 6H), 3.81 (s, 3H), 6.92 (d, J = 8.0Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.70-7.71 (m, 5H), 7.76 (s, 2H), 11.46 (s,1H). 13 C NMR (100 MHz, CDCl3): δ HRMS (ESI) m / z: [M+H] + calcd for C 25 H 22 N3O3 + 412.1656; found 412.1655. Figure 1 This is the H NMR spectrum of the amidoquinoxaline derivative obtained in Example 1 of the present invention.

[0034] Example 2: Preparation of polysubstituted amidoquinoxaline derivatives The polysubstituted amidoquinoxaline derivative in this embodiment is 3-formyl-N-(4-methoxyphenyl)-6,7-dimethylamidoquinoxaline, and its synthesis route is: The difference between this example and Example 1 is that phenyl acetate is used instead of sodium benzoate in Example 1. The yield of the obtained polysubstituted amidoquinoxaline derivative is 90% (62.89 mg).

[0035] 1 H NMR (400 MHz, CDCl3): δ 2.10 (s, 3H), 2.47 (s, 6H), 3.81 (s, 3H), 6.92 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.76 (s, 2H), 11.46 (s, 1H). 13 CNMR (100 MHz, CDCl3): δ 18.8, 27.0, 55.8, 114.5, 122.6, 129.2, 130.2, 140.6,149.6, 150.9, 158.9, 160.3, 195.9. HRMS (ESI) m / z: [M+Na] + calcd for C 20 H 20 N3O3 + 350.1499; found 350.1493. Figure 2 This is the H NMR spectrum of the amidoquinoxaline derivative obtained in Example 2 of the present invention.

[0036] Example 3: Preparation of polysubstituted amidoquinoxaline derivatives The polysubstituted amidoquinoxaline derivative in this embodiment is 3-benzyl-N-(4-methoxyphenyl)-6,7-dimethylamidoquinoxaline, and its synthesis route is: The difference between this example and Example 1 is that azoimide is used instead of sodium benzoate in Example 1. The yield of the prepared polysubstituted amidoquinoxaline derivative is 89% (70.75 mg).

[0037] 1 H NMR (400 MHz, CDCl3): δ 2.47 (s, 6H), 3.62 (s, 2H), 3.81 (s, 3H), 6.92(d, J = 8.0 Hz, 2H), 7.20-7.28 (m, 5H), 7.63 (d, J = 8.0 Hz, 2H), 7.75 (s,2H), 9.86 (s, 1H). 13 C NMR (100 MHz, CDCl3): δ 18.8, 37.5, 55.8, 114.5, 122.6,125.7, 127.2, 128.6, 129.0, 129.1, 130.2, 138.5, 138.7, 139.9, 141.4, 147.5,150.0, 150.6, 158.9, 162.6. HRMS (ESI) m / z: [M+H] + calcd for C 25 H 24 N3O2 + 398.1863;found 398.1866. Figure 3 This is the H NMR spectrum of the amidoquinoxaline derivative obtained in Example 3 of the present invention.

[0038] Example 4: Preparation of polysubstituted amidoquinoxaline derivatives The polysubstituted amidoquinoxaline derivative in this embodiment is 3-carbonthio-N-(4-methoxyphenyl)-6,7-dimethylamidoquinoxaline, and its synthesis route is: The difference between this example and Example 1 is that trimethylsilyl isothiocyanate is used instead of sodium benzoate in Example 1. The yield of the obtained polysubstituted amidoquinoxaline derivative is 82% (57.63 mg).

[0039] 1 H NMR (400 MHz, CDCl3): δ 2.38 (s, 3H), 2.42 (s, 3H), 3.88 (s, 3H), 7.07(d, J = 8.8 Hz, 2H), 7.32 (d, J = 8.8 Hz, 2H), 7.56 (s, 1H), 8.36 (s, 1H),8.38 (s, 1H), 8.88 (s, 1H). 13 C NMR (100 MHz, CDCl3): δ 20.55, 20.56, 55.8, 114.5,122.6, 127.8, 129.6, 130.2, 138.8, 141.9, 147.3, 148.6, 150.2, 157.8, 158.9,160.3, 230.2. HRMS (ESI) m / z: [M+H] + calcd for C 25 H 24 N3O2 + 352.1114; found352.1115. Figure 4 This is the H NMR spectrum of the amidoquinoxaline derivative obtained in Example 4 of the present invention.

[0040] The above description is merely a preferred embodiment of the present application and is not intended to limit the present application. Various modifications and variations are possible for those skilled in the art. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present application shall be included within the scope of protection of the present application.

Claims

1. A polysubstituted amidoquinoxaline derivative, characterized in that: The structural formula of the polysubstituted amidoquinoxaline derivative is shown in formula (I): Formula (I); In formula (I), R 1 Selected from C1-C20 straight or branched alkyl, aryl, halogen, and hydrogen; R 2 One selected from aryl, fused aryl, heteroaryl or alkyl; R 3 One selected from acyl, aromatic hydrocarbon or alkylthio.

2. The polysubstituted amidoquinoxaline derivative according to claim 1, wherein R 1 One selected from 4,5-dimethyl, 6-methyl, 7-methyl, 6,7-dimethoxy, 6,7-dichloro, 6,7-dibromo, and hydrogen atom; R 2 One selected from 4-methoxyphenyl, 4-methyl, 4-methoxy, 4-phenyl, 4-bromo, 4-ethoxy, 4-benzoyl, 3-nitro, 2-phenyl, 2-methyl-2-chloro, 2-ethoxy, 2-cyano, 3-methyl, 3-bromo, 2-methyl, 3,4-dimethyl, 3,5-dimethyl, 2,6-dimethyl, 3,4,5-trimethoxy, 1-naphthyl, 2-naphthyl, 5-quinolyl, 6-quinolyl, cyclohexyl, n-butyl, 2-methyl-3-chlorophenyl, 4-ethoxybenzyl, adamantyl, 4-methylbenzyl, 4-chlorobenzyl, 4-sulfonyl, and a hydrogen atom; R 3 One selected from benzoyl, formyl, benzyl and carbonyl.

3. The polysubstituted amidoquinoxaline derivative according to claim 1, wherein The polysubstituted amidoquinoxaline derivatives are 3-benzoyl-N-(4-methoxyphenyl)-6,7-dimethylamidoquinoxaline, 3-formyl-N-(4-methoxyphenyl)-6,7-dimethylamidoquinoxaline, 3-benzyl-N-(4-methoxyphenyl)-6,7-dimethylamidoquinoxaline and 3-carbonylthio-N-(4-methoxyphenyl)-6,7-dimethylamidoquinoxaline, and their structural formulas are shown in Formula (II) to Formula (V), respectively: Formula (II); Formula (III); Formula (IV); Formula (V).

4. The method for preparing a polysubstituted amidoquinoxaline derivative according to any one of claims 1 to 3, characterized in that: The steps include: The o-diaryl isocyanide, aryl isocyanide and zwitterion capture agent are mixed and placed in deionized water for reaction; after the reaction is completed, the reaction system is cooled and filtered, and the filtered solid is collected to obtain a multi-substituted amide quinoxaline derivative.

5. The method for preparing a polysubstituted amidoquinoxaline derivative according to claim 4, wherein: The structural formula of o-diaryl isonitrile is shown in formula (VI): Formula (VI); Where R 1 One selected from 4,5-dimethyl, 6-methyl, 7-methyl, 6,7-dimethoxy, 6,7-dichloro, 6,7-dibromo or hydrogen atom.

6. The method for preparing a polysubstituted amidoquinoxaline derivative according to claim 4, wherein: The structural formula of aromatic isonitrile is shown in formula (VII): Formula (VII); Where R 2 One selected from 4-methoxyphenyl, 4-methyl, 4-methoxy, 4-phenyl, 4-bromo, 4-ethoxy, 4-benzoyl, 3-nitro, 2-phenyl, 2-methyl-2-chloro, 2-ethoxy, 2-cyano, 3-methyl, 3-bromo, 2-methyl, 3,4-dimethyl, 3,5-dimethyl, 2,6-dimethyl, 3,4,5-trimethoxy, 1-naphthyl, 2-naphthyl, 5-quinolyl, 6-quinolyl, cyclohexyl, n-butyl, 2-methyl-3-chlorophenyl, 4-ethoxybenzyl, adamantyl, 4-methylbenzyl, 4-chlorobenzyl, 4-sulfonyl, or a hydrogen atom.

7. The method for preparing a polysubstituted amidoquinoxaline derivative according to claim 4, wherein: The zwitterion capture agent is selected from one of sodium benzoate, phenyl acetate, azo compounds, and trimethylsilyl isothiocyanate.

8. The method for preparing a polysubstituted amidoquinoxaline derivative according to claim 4, wherein: The added amounts of o-diaryl isocyanide, aromatic isocyanide, zwitterion capture agent and deionized water are 1 mmol: (1-2) mmol: (1-3) mmol: (5-15) mL.

9. The method for preparing a polysubstituted amidoquinoxaline derivative according to claim 4, wherein: The reaction temperature is 25-100°C and the reaction time is 1-24h.

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