A preparation method and application of polysubstituted quinolinone compounds

Abstract

This patent application provides a preparation method and application of a polysubstituted quinolinone compound. Specifically, under inert solvent conditions, by the oxidation Heck reaction of N-aryl nitrosamide and acrylate catalyzed by trivalent rhodium, the cascade reaction of amidation, while releasing small molecules (nitrous oxide, water, alcohol), various polysubstituted quinolinone compounds are quickly constructed. This method has the characteristics of green oxidation, chemical selectivity, and compatible strong coordination. At the same time, the method only uses simple and readily available aromatic amine derivatives as traceless internal oxidative directing groups, reacts with bulk chemicals acrylates, and realizes the one-step construction of fine chemicals such as bioactive molecules and drug molecules. The conversion steps are few and the operation is simple, and the obtained product is easy to further convert in the future.

Description

Technical Field

[0001] The present patent application relates to the technical field of organic compound synthesis, and more specifically, to a preparation method and application of a polysubstituted quinolone compound. Background Art

[0002] Quinolinone and its derivatives are an important nitrogen-containing fused heterocycle, which is the dominant skeleton in natural products, drug molecules and functional materials. Because of its unique lactam structure, it plays an important role in organic synthesis and drug molecule research and development. Its biological activity mainly manifests in: anti-tumor (Chem. Lett. 2007, 17, 86-93.), anti-hepatitis virus (J. Med. Chem. 2006, 49, 971-983.), anti-allergy (Eur. J. Pharmacol. 2009, 602, 138-142.), anti-mental disorder (J. Med. Chem. 1994, 37, 1402-1404.), etc. Drugs containing quinolinone skeletons have been used in the treatment of cancer, Alzheimer's disease, gastric ulcer, schizophrenia and other fields.

[0003] Quinolinone compounds can also be used as important synthetic intermediates for the construction of drug molecules and fused heterocyclic compounds (J.Org.Chem.2005,70,3864-3868.). The biological activities and functions of the compounds are different when modified at different positions. Among them, quinolinone substituted at the N1 position is widely used in the fields of biomedicine and semiconductor manufacturing. Typical molecules include: (R)-6-amino[(4-chlorophenyl)(1-methyl-1H-5-imidazolemethyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone (R115777) is an effective and selective inhibitor of farnesyl protein transferase, which can control tumors. cell growth; Araliopsine is an alkaloid extracted from Rutaceae plants, with an angled and linear fusion structure, with antimalarial, antidiuretic and sedative biological activities, and is mainly used in traditional Chinese medicine; NMDA receptor antagonists can be used to treat various central nervous system diseases, including Parkinson's disease, head injury, epilepsy and Alzheimer's disease; TA-270 is a delayed hypersensitivity inhibitor that can be used to treat asthma, allergic rhinitis and other allergies caused by allergies; Flucarbamide is a muscle relaxant and analgesic; Cilostamide is a potent and selective PDE3 inhibitor with anti-thrombotic and intramedullary hyperplasia activities.

[0004] Therefore, how to simply and quickly construct the molecular skeleton of polysubstituted quinolinone to enrich its molecular library in the fields of biomedicine and functional materials has been a topic of continuous concern to scientists. Literature research found that the main methods for synthesizing quinolinone are:

[0005] 1) Aniline derivatives are subjected to electrophilic substitution and intramolecular condensation to construct polysubstituted quinolinone products, including Friedlander synthesis (J. Heterocycl. Chem., 2003, 40, 601-605.) and Knorr synthesis (J. Org. Chem., 2007, 72, 9761–9764.). These two synthetic strategies provided people with inspiration for the industrial large-scale production of quinolinone compounds in the early days, but their routes are complicated, and the atom economy and step economy are poor. It is worth noting that the reaction uses an equivalent amount of strong acid as a protonating agent, which is difficult to handle after the reaction, has high toxicity, pollutes the environment, and has a low yield and poor economy, which does not conform to the concept of green chemistry.

[0006] 2) The quinolinone product is obtained by oxidation of quinoline derivatives, such as quinoline nitrogen oxide (ACSSustainable Chem. Eng., 2017, 5, 10407-10412.) or N-alkylquinoline amine salt (J. Am. Chem. Soc., 2017, 139, 14237-14243.) The reaction of generating quinolinone has good substrate compatibility, but the stoichiometric strong base is used in this type of reaction system, which is not environmentally friendly. In addition, the raw materials need to be prepared in advance, and the green and simple synthesis of polysubstituted quinoline substrates has the limitation of poor atom and step economy.

[0007] 3) The development of green and efficient synthesis methods with higher atom, step economy and selectivity is still very much worth looking forward to. In recent years, people have developed transition metal-catalyzed carbon-hydrogen bond activation reactions of aniline derivatives to expand the molecular library of quinolinone synthesis. The advantages of these reactions are high atom economy and chemical selectivity. Their aniline derivatives can include acetylaniline (Org. Lett., 2014, 16, 3568-3571.), formylaniline (Eur. J. Org. Chem., 2021, 4477–4484.), aniline (Org. Lett., 2015, 17, 222-225.), phenylhydrazine compounds (Org. Lett., 2016, 18, 2427-2430.), etc. However, the above-mentioned transition metal-catalyzed quinolinone synthesis often has the following problems: the product structure is single, often a lactam quinolinone skeleton molecule containing a free NH bond, and it is impossible to further synthesize the N1-functionalized quinolinone product, and the raw materials need to be prepared in advance, which hinders the continued application potential of this type of method in the synthesis of biologically active molecules; when the reaction constructs the quinolinone molecule through multiple dehydrogenation strategies, stoichiometric amounts of metal oxidants and proton acids are often required, which is not in line with the concept of green chemistry and also limits the application of this method in industrial large-scale production; the multi-step reaction to obtain the N-functionalized quinolinone product has poor step economy.

[0008] Based on the research of our group on the activation of carbon-hydrogen bonds assisted by easily converted weakly coordinating functional groups (ACS Catal., 2019, 9, 8749-8756; ChemCatChem, 2020, 12, 2358-2384 (invited review); Org.Chem.Front., 2019, 6, 284-289. (title paper); Chem.Commun., 2020, 56, 11255-11258. Chin.J.Chem.2020, 38, 929-934. (title paper, selected as "Breaking Report”) Chem. Commun., 2021, 57, 8075-8078; Org. Chem. Front., 2021, 8, 6484–6490 (title page paper); Org. Chem. Front., 2022, 9, 2746-2752.), we believe that developing a traceless directing group that is easy to introduce and transform and can serve as an intramolecular oxidant, using acrylic acid derivatives as coupling reagents, and through oxidative Heck reactions and amidation cascade reactions, regioselectively obtaining multi-substituted quinolinone products, thereby realizing the transformation from bulk chemicals to fine chemicals, can not only solve the problems of atom economy and step economy, but also use molecular oxygen as a co-oxidant to reduce costs while significantly reducing the use of stoichiometric metal salts, which has great theoretical and practical value. It is worth noting that there has been no report on the one-step synthesis of quinolinone and its biologically active molecules through a cascade strategy of oxidative Heck reaction and amidation using molecular oxygen-assisted, intramolecular oxidative traceless directing groups with acrylic acid derivatives.

[0009] It should be noted that in the metal-catalyzed inert bond activation reaction achieved by conventional directing strategies, strongly coordinated compounds are difficult to synthesize selective target products due to their easy complexation with metals and difficulty in dissociation.

[0010] Patent application content

[0011] In order to overcome at least one problem existing in the prior art, the present patent application provides a method for preparing a polysubstituted quinolinone compound. The present patent application uses a simple and readily available N-aryl nitrosamide and an acrylate compound as reaction substrates under inert solvent conditions, through trivalent rhodium catalysis, to achieve chemical selectivity (the examples of the present application can obtain a target molecule with a single product structure with a good yield, and has good chemical selectivity) and regioselectivity (when the reaction substrate of the present application has a strong coordinating heterocycle, it has multiple reactive sites, and the reaction can still obtain a selective single product, proving that it has good regioselectivity) modular synthesis of polysubstituted quinolinone compounds with good application prospects in the field of bioactive molecules and drug molecules.

[0012] Another purpose of the present patent application is to provide the application of the above-mentioned polysubstituted quinolinones. Through this strategy for synthesizing polysubstituted quinolinones, we have quickly and simply synthesized analgesics (Flecarbamide and its analogs), antithrombotic inhibitors (cilostamide) and alkaloids (Romantocin analogs).

[0013] In order to solve the above technical problems, the technical solution adopted by this patent application is:

[0014] A method for preparing a polysubstituted quinolinone compound: in an inert solvent and under the action of a trivalent rhodium catalyst, an N-aryl nitrosamide compound (Formula II) and an acrylate compound (Formula III) are reacted to obtain a polysubstituted quinolinone compound (Formula I), and the reaction equation is as follows:

[0015]

[0016] Where Ar is a polysubstituted aromatic ring compound such as para-position or ortho-position, or a condensed ring compound, R 3 is H or substituted phenyl, R 2 is a methyl, ethyl, tert-butyl, adamantyl, trifluoroethyl, hexafluoroisopropyl substituted with a functional group, R 1 It is a benzene ring substituted with a (cyclo)alkyl group or a functional group.

[0017] This patent application also provides a drug molecule or a bioactive molecule, which are antithrombotic inhibitors, analgesics and alkaloids, respectively, and the drug molecule and the bioactive molecule are polysubstituted quinolinone compounds prepared by the above-mentioned preparation method.

[0018] Compared with the prior art, the beneficial effects of this patent application are:

[0019] The preparation method of the polysubstituted quinolinone compound provided in this patent application has the characteristics of traceless guidance, green oxidation, Heck reaction, and amidation cascade reaction. Through this synthetic strategy, a variety of biologically active molecules and drug molecules can be quickly constructed. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 The hydrogen nuclear magnetic resonance spectrum of compound 1a prepared in Example 1 of the present patent application;

[0021] Figure 2 The carbon NMR spectrum of compound 1a prepared in Example 1 of the present patent application;

[0022] Figure 3 This is the hydrogen nuclear magnetic resonance spectrum of compound 1b prepared in Example 2 of this patent application;

[0023] Figure 4 The carbon NMR spectrum of compound 1b prepared in Example 2 of the present patent application;

[0024] Figure 5 This is the hydrogen nuclear magnetic resonance spectrum of compound 1c prepared in Example 3 of this patent application;

[0025] Figure 6 The carbon NMR spectrum of compound 1c prepared in Example 3 of the present patent application;

[0026] Figure 7 The NMR fluorine spectrum of compound 1c prepared in Example 3 of this patent application

[0027] Figure 8 This is the hydrogen nuclear magnetic resonance spectrum of compound 1d prepared in Example 4 of this patent application;

[0028] Fig. 9 The carbon NMR spectrum of compound 1d prepared in Example 4 of the present patent application;

[0029] Fig.10 The NMR fluorine spectrum of compound 1d prepared in Example 4 of the present patent application;

[0030] Fig.11 This is the hydrogen nuclear magnetic resonance spectrum of compound 1e prepared in Example 5 of this patent application;

[0031] Fig.12 The carbon NMR spectrum of compound 1e prepared in Example 5 of the present patent application;

[0032] Fig.13 This is the hydrogen nuclear magnetic resonance spectrum of compound 1f prepared in Example 6 of this patent application;

[0033] Fig.14 The carbon NMR spectrum of compound 1f prepared in Example 6 of the present patent application;

[0034] Fig.15This is the hydrogen nuclear magnetic resonance spectrum of compound 1g prepared in Example 7 of this patent application;

[0035] Fig.16 The carbon NMR spectrum of compound 1g prepared in Example 7 of the present patent application;

[0036] Fig.17 This is the hydrogen nuclear magnetic resonance spectrum of compound 1h prepared in Example 8 of this patent application;

[0037] Fig.18 The carbon NMR spectrum of compound 1h prepared in Example 8 of the present patent application;

[0038] Fig.19 This is the hydrogen nuclear magnetic resonance spectrum of compound 1i prepared in Example 9 of this patent application;

[0039] Fig. 20 The carbon NMR spectrum of compound 1i prepared in Example 9 of the present patent application;

[0040] Fig.21 The hydrogen nuclear magnetic resonance spectrum of compound 1j-1 prepared in Example 10 of the present patent application;

[0041] Fig. 22 The carbon NMR spectrum of compound 1j-1 prepared in Example 10 of the present patent application;

[0042] Fig.23 The hydrogen nuclear magnetic resonance spectrum of compound 1j-2 prepared in Example 10 of the present patent application;

[0043] Fig.24 The carbon NMR spectrum of compound 1j-2 prepared in Example 10 of the present patent application;

[0044] Fig.25 This is the hydrogen nuclear magnetic resonance spectrum of compound 1p prepared in Example 10 of this patent application;

[0045] Fig.26 This is the carbon nuclear magnetic resonance spectrum of compound 1p prepared in Example 10 of this patent application. DETAILED DESCRIPTION

[0046] The embodiments of the present patent application will be described in detail below in conjunction with the examples, but those skilled in the art will appreciate that the following examples are only used to illustrate the present patent application and should not be considered to limit the scope of the present patent application. If the specific conditions are not specified in the examples, they are carried out according to the normal conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be purchased commercially.

[0047] It should be noted that:

[0048] In this patent application, unless otherwise specified, all implementation methods and preferred implementation methods mentioned herein can be combined with each other to form a new technical solution.

[0049] In this patent application, unless otherwise specified, each reaction or operation step can be carried out sequentially or in a sequential manner. Preferably, the reaction method herein is carried out sequentially.

[0050] Unless otherwise specified, the professional and scientific terms used herein are the same as those familiar to those skilled in the art. In addition, any method or material similar or equivalent to the described content may also be applied to this patent application.

[0051] The present patent application provides a method for preparing a polysubstituted quinolinone compound: in an inert solvent and under the action of a trivalent rhodium catalyst, an N-aryl nitrosamide compound (Formula II) and an acrylate compound (Formula III) are reacted to obtain a polysubstituted quinolinone compound (Formula I). ​​The reaction equation in the preparation method is as follows:

[0052]

[0053] Where Ar is a polysubstituted aromatic ring compound such as para-position or ortho-position, or a condensed ring compound, R 3 is H or substituted phenyl, R 2 is a methyl, ethyl, tert-butyl, adamantyl, trifluoroethyl, hexafluoroisopropyl substituted with a functional group, R 1 It is a benzene ring substituted with a (cyclo)alkyl group or a functional group.

[0054] This patent application discloses a metal-catalyzed traceless (N-nitroso group is used as a traceless directing group, which directs CH activation and then converts itself into a part of the target molecule) and intramolecular oxidant (referring to N-nitroso group)-promoted multi-substituted quinolinone synthesis reaction achieved by an oxidation Heck and intramolecular amide tandem strategy. Specifically, under inert solvent conditions, through the oxidation Heck and intramolecular amide tandem reaction of N-aryl nitrosamide and aromatic ethylene catalyzed by trivalent rhodium, small molecules (nitrous oxide, water, alcohol) are released while various multi-substituted quinolinone compounds are quickly constructed. This method has the characteristics of green oxidation, chemical selectivity, and strong coordination compatibility. At the same time, this method only uses simple and easily available aromatic amine derivatives as traceless internal oxidative directing groups to achieve oxidation Heck reaction and amidation tandem reaction with bulk chemical acrylate. The conversion steps are few and the operation is simple. The obtained product is easy to further transform. More importantly, we also use this strategy to quickly construct fine compounds such as bioactive molecules and drug molecules, which has excellent atom economy and step economy.

[0055] In some embodiments, the inert solvent is any one or more of toluene, tetrahydrofuran, 1,4-dioxane, N,N'-dimethylformamide, N,N'-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, 1,2-dichloroethane, ethanol, and water.

[0056] In some embodiments, the trivalent rhodium catalyst is any one or more of pentamethylcyclopentadienylrhodium chloride dimer and triacetonitrile-pentamethylcyclopentadienylrhodium chloride dimer.

[0057] In some embodiments, the reaction further requires the addition of a halide ion extractor, wherein the halide ion extractor is any one or more of silver hexafluoroantimonate and silver bistrifluoromethanesulfonimide.

[0058] In some embodiments, the reaction further requires the addition of an additive, wherein the additive is any one or more of sodium acetate, sodium trifluoroacetate, sodium pivalate, sodium glycine, sodium propionate, and sodium 2,4,6-trimethylbenzoate.

[0059] In some embodiments, the reaction molar ratio of the N-aryl nitrosamide compound (Formula II) to the acrylate (Formula III) is 1:1.5 to 1:2.

[0060] In some embodiments, the amount of the trivalent rhodium catalyst used is 2 mol % of the amount of the N-aryl nitrosamide compound (Formula II) used.

[0061] In some embodiments, the reaction is carried out at 80-120° C.; the reaction is carried out for 12-24 hours.

[0062] Next, the preparation method of the polysubstituted quinolinone compound of the present patent application is described in detail with specific examples.

[0063] 1. Preparation Example

[0064] Example 1 Preparation of 1-methylquinolinone (1a)

[0065] In an atmospheric pressure air atmosphere, N-methyl-N-phenylnitrosamide 2a (27.2 mg, 0.20 mmol), methyl acrylate 3a (25.8 mg, 0.30 mmol), trivalent rhodium catalyst [Cp*Rh(CH3CN)3Cl2]2 (3.3 mg, 0.004 mmol), silver trifluoromethanesulfonimide (3.9 mg, 0.01 mmol), sodium acetate (27.2 mg, 0.2 mmol), 1,2-dichloroethane (DCE, 1.0 mL) were added to a 15 mL Schlenk reaction tube in sequence, and the mixture was reacted at 100°C for 12 hours. The crude product was separated by chromatography using a prepared silica gel plate, and the selected developing solvent or eluent was a volume ratio of petroleum ether to ethyl acetate of 3:1, to obtain the product 1-methylquinolinone (1a, 20.1 mg), with a yield of 63%. The chemical reaction equation corresponding to this embodiment is as follows:

[0066]

[0067] The H-NMR spectrum and C-NMR spectrum of the compound prepared in Example 1 are as follows: Figure 1 and Figure 2 As shown. Figure 1 It can be seen that: 1 HNMR (400MHz,CDCl3)δ7.66(d,J=9.6Hz,1H),7.59–7.54(m,2H),7.36(dd,J=1.2Hz,8.4Hz,1H),7.25–7.21(m,1H),6.71(d,J=9.6Hz,1H),3.72(s,3H). The molecular hydrogen spectrum peaks can correspond to the target product one by one, and the quantity is reasonable. Figure 2 It can be seen 13 C NMR (100MHz, CDCl3) δ162.3, 140.0, 138.9, 130.6, 128.7, 122.0, 121.6, 120.6, 114.1, 29.3. The molecular carbon spectrum peaks can correspond to the target product one by one, and the number is reasonable. Combining the results of the above nuclear magnetic hydrogen spectrum and carbon spectrum, it can be seen that the product prepared in Example 1 is 1-methylquinolinone (1a).

[0068] In this example, N-methyl-N-phenylnitrosamide 2a and acrylate compound methyl acrylate 3a were subjected to a metal-catalyzed traceless, intramolecular oxidant-promoted oxidative Heck reaction and an amidation cascade reaction to achieve an efficient synthesis of a polysubstituted quinolinone compound 1-methylquinolinone (1a).

[0069] The polysubstituted quinolinone compound synthesis reaction in this embodiment has the characteristics of green oxidation, chemical selectivity, and compatible strong coordination. At the same time, the method only uses easily available aromatic amine derivatives as traceless internal oxidative directing groups to react with bulk chemical acrylates to achieve the one-step construction of fine chemicals such as bioactive molecules and drug molecules. The conversion steps are few and the operation is simple and easy, and the obtained product is easy to be further converted later. The chemical conversion of this application can quickly construct polysubstituted 2-quinolinone molecules of important molecular fragments in the field of drugs and functional materials.

[0070] Example 2 Preparation of 2,3-dihydropyridine-3,2,1-hydroxyquinoline (1b)

[0071] Under an atmospheric pressure air atmosphere, 1-nitroso-1,2,3,4-tetrahydroquinoline 2b (32.4 mg, 0.20 mmol), tert-butyl acrylate 3b (38.4 mg, 0.30 mmol), trivalent rhodium catalyst [Cp*RhCl2]2 (2.5 mg, 0.004 mmol), silver trifluoromethanesulfonimide (3.9 mg, 0.01 mmol), sodium acetate (27.2 mg, 0.2 mmol), copper acetate (12.0 mg, 0.06 mmol), and 1,2-dichloroethane (DCE, 1.0 mL) were added sequentially to a 15 mL Schlenk reaction tube and reacted at 100 °C for 12 hours. The crude product was separated by chromatography on a prepared silica gel plate, and the selected developing solvent or eluent was a volume ratio of petroleum ether to ethyl acetate of 3:1, to obtain 24.5 mg of the product, and the product 2,3-dihydropyridine-3,2,1-hydroxyquinoline (1b) was obtained with a yield of 66%. The chemical reaction equation corresponding to this example is as follows:

[0072]

[0073] The H NMR spectrum and C NMR spectrum of the compound prepared in Example 2 are as follows: Figure 3 , Figure 4 As shown. Figure 3 It can be seen that: 1 HNMR (400MHz, CDCl3) δ7.66 (d, J = 9.2Hz, 1H), 7.39 (dd, J = 1.2Hz, 8.0Hz, 1H), 7.30 (dd, J = 1.2Hz, 6.4Hz, 1H), 7.12 (t, J = 7.6Hz, 1H), 6.69 (d, J = 9.6Hz, 1H), 4.21–4.18 (m, 2H), 2.98 (t, J = 6.4Hz, 2H), 2.12 (dt, J = 6.0Hz, 12.0Hz, 2H). The molecular hydrogen spectrum peaks can correspond to the target product one by one, and the quantity is reasonable. Figure 4 It can be seen that: 13C NMR (100MHz, CDCl3) δ162.0, 138.9, 136.7, 129.9, 126.6, 124.9, 121.8, 121.3, 120.5, 42.2, 27.6, 20.7. The molecular carbon spectrum peaks can correspond to the target product one by one, and the number is reasonable. Combining the results of the above nuclear magnetic hydrogen spectrum and nuclear magnetic carbon spectrum, it can be seen that the product prepared in Example 2 is 2,3-dihydropyridine-3,2,1-hydroxyquinoline (1b).

[0074] In this embodiment, the N-nitroso group in 1-nitroso-1,2,3,4-tetrahydroquinoline 2b is used as a traceless directing group that is easy to introduce and can serve as an intramolecular oxidant, thereby assisting the tandem reaction of oxidative Heck and intramolecular amide with tert-butyl acrylate 3b, and constructing the regioselective quinolinone compound 2,3-dihydropyridine-3,2,1-hydroxyquinoline (1b) in one step, and synthesizing a multi-substituted quinolinone compound under the catalysis of a trivalent iridium catalyst [Cp*IrCl2]2. The chemical transformation in this embodiment has efficient step economy and atom economy. In addition, the chemical transformation in this embodiment can be applied to the synthesis of condensed ring functional material molecules.

[0075] Example 3 Preparation of Flucarbamide-1-methyl-6-trifluoromethylquinolinone (1c)

[0076] Under an atmospheric pressure air atmosphere, N-methyl-4-trifluoromethylphenylnitrosamide 2c (40.8 mg, 0.20 mmol), 2,2,2-trifluoroethyl acrylate 3c (46.2 mg, 0.30 mmol), trivalent rhodium catalyst [Cp*RhCl2]2 (2.5 mg, 0.004 mmol), silver trifluoromethanesulfonimide (3.9 mg, 0.01 mmol), sodium trifluoroacetate (27.2 mg, 0.2 mmol), copper acetate (12.0 mg, 0.06 mmol), and 1,2-dichloroethane (DCE, 1.0 mL) were added sequentially to a 15 mL Schlenk reaction tube and reacted at 100 °C for 12 hours. The crude product was separated by chromatography on a prepared silica gel plate, and the selected developing solvent or eluent was a volume ratio of petroleum ether to ethyl acetate of 3:1, to obtain the product flucarbamide-1-methyl-6-trifluoromethylquinolinone (1c, 21.6 mg), with a yield of 51%. The chemical reaction equation corresponding to this embodiment is as follows:

[0077]

[0078] The H NMR spectrum, C NMR spectrum and F NMR spectrum of the compound prepared in Example 3 are as follows: Figure 5 , Figure 6 and Figure 7 As shown. Figure 5It can be seen that: 1 H NMR (400MHz, CDCl3) δ7.83 (d, J = 2.4Hz, 1H), 7.78 (dd, J = 2.4Hz, 8.8Hz, 1H), 7.71 (d, J = 9.2Hz, 1H), 7.46 (d, J = 8.8Hz, 1H), 6.79 (d, J = 9.6Hz, 1H), 3.75 (s, 3H), molecular hydrogen spectrum peaks can correspond to the target product one by one, and the quantity is reasonable. Figure 6 It can be seen that: 13 C NMR (100MHz, CDCl3) δ162.1, 142.1, 138.5, 127.0 (q, J = 3.0Hz), 126.0 (q, J = 4.0Hz), 126.0, 123.3, 120.6, 120.2, 117.9, 114.7, 29.7. 19 F NMR (376MHz, CDCl3) δ-61.9. The molecular carbon spectrum peaks can correspond to the target product one by one, and the number is reasonable. Combining the results of the above nuclear magnetic hydrogen spectrum, carbon spectrum and fluorine spectrum, it can be seen that the product prepared in Example 3 is flucarbamide-1-methyl-6-trifluoromethylquinolinone (1c).

[0079] In this embodiment, a multi-substituted quinolinone compound with good application prospects in the field of drug molecules, the analgesic - flucarbamide, is modularly synthesized in an inert solvent under the catalysis of a trivalent rhodium catalyst [Cp*RhCl2]2, using easily available N-methyl-4-trifluoromethylphenylnitrosamide 2c and 2,2,2-trifluoroethyl acrylate 3c as reaction substrates, to achieve chemical selectivity (the example of the present application can obtain a target molecule with a single product structure in good yield, having good chemical selectivity) and regioselectivity (when the reaction substrate of the present application has a strongly coordinated heterocycle and has multiple reactive sites, the reaction can still obtain a selective single product, proving its good regioselectivity).

[0080] The chemical transformation in this embodiment can quickly construct the drug molecule of the analgesic, flecarbamide, in one step.

[0081] Example 4 Preparation of 1-methyl-6-trifluoromethylthioquinolinone (1d)

[0082] Under an atmospheric pressure air atmosphere, N-methyl-4-trifluoromethylthiophenylnitrosamide 2d (47.2 mg, 0.20 mmol), 1,1,1,3,3,3-hexafluoropropane-2-yl acrylate 3d (66.6 mg, 0.30 mmol), trivalent rhodium catalyst [Cp*RhCl2]2 (2.5 mg, 0.004 mmol), silver trifluoromethanesulfonimide (3.9 mg, 0.01 mmol), sodium acetate (27.2 mg, 0.2 mmol), and 1,2-dichloroethane (DCE, 1.0 mL) were added sequentially to a 15 mL Schlenk reaction tube and reacted at 100 ° C for 12 hours. The crude product was separated by chromatography on a prepared silica gel plate, and the selected developing solvent or eluent was a volume ratio of petroleum ether to ethyl acetate of 3:1, to obtain the product 1-methyl-6-trifluoromethylthioquinolinone (1d, 28.0 mg), with a yield of 54%. The chemical reaction equation corresponding to this embodiment is as follows:

[0083]

[0084] The H NMR spectrum, C NMR spectrum and F NMR spectrum of the compound prepared in Example 4 are as follows: Figure 8 , Fig. 9 and Fig.10 As shown. Figure 8 It can be seen that: 1 H NMR (400 MHz, CDCl3) δ7.80 (d, J = 2.0 Hz, 1H), 7.74 (dd, J = 2.0 Hz, 6.8 Hz, 1H), 7.60 (d, J = 9.6 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 6.70 (d, J = 9.2 Hz, 1H), 3.67 (s, 3H). Fig. 9 It can be seen that: 13 C NMR (100MHz, CDCl3) δ162.1, 141.7, 138.2, 137.9, 137.1, 128.0, 123.1, 121.3, 117.2 (q, J = 2.0Hz), 115.39, 29.7. Combining the results of the above nuclear magnetic hydrogen spectrum, carbon spectrum and fluorine spectrum, it can be seen that the product prepared in Example 4 is 1-methyl-6-trifluoromethylthioquinolinone (1d).

[0085] The chemical synthesis method in this embodiment has atom and step economy, and directly uses the commonly available N-aryl nitrosamide N-methyl-4-trifluoromethylthiophenyl nitrosamide 2d and as raw materials, and easily obtains 1,1,1,3,3,3-hexafluoropropane-2-yl acrylate 3d as a reaction substrate, while participating in the construction of the nitrogen-containing fused heterocycle as a traceless directing group.

[0086] The chemical transformation in this embodiment has the characteristics of traceless guidance, green oxidation, Heck reaction, and amidation cascade reaction. Through this synthetic strategy, a molecular library of analogs of flucarbamide can be quickly constructed, providing a new strategy for the development of related new drugs.

[0087] Example 5 Preparation of 1,6-dimethyl-3-phenylquinolinone (1e)

[0088] Under an atmospheric pressure air atmosphere, N-methyl-N-p-tolylnitrosamide 2e (30.0 mg, 0.20 mmol), tert-butyl 2-phenylacrylate 3e (61.2 mg, 0.30 mmol), trivalent rhodium catalyst [Cp*RhCl2]2 (2.5 mg, 0.004 mmol), silver trifluoromethanesulfonimide (3.9 mg, 0.01 mmol), sodium pivalate (28.4 mg, 0.2 mmol), copper acetate (12.0 mg, 0.06 mmol), and 1,2-dichloroethane (DCE, 1.0 mL) were added sequentially to a 15 mL Schlenk reaction tube and reacted at 100 °C for 12 hours. The crude product was separated by chromatography on a prepared silica gel plate, and the selected developing solvent or eluent was a volume ratio of petroleum ether to ethyl acetate of 3:1, to obtain the product 1,6-dimethyl-3-phenylquinolinone (1e, 30.9 mg), with a yield of 62%. The chemical reaction equation corresponding to this embodiment is as follows:

[0089]

[0090] The H-NMR spectrum and C-NMR spectrum of the compound prepared in Example 5 are as follows: Fig.11 and Fig.12 As shown. Fig.11 It can be seen that: 1 H NMR (400MHz, CDCl3) δ7.74 (s, 1H), 7.72–7.68 (m, 2H), 7.45–7.36 (m, 5H), 7.27 (d, J=8.4Hz, 1H), 3.78 (s, 3H), 2.43 (s, 3H). Fig.12 It can be seen that: 13 C NMR (100MHz, CDCl3) δ161.4, 137.6, 136.9, 136.6, 132.4, 131.7, 131.5, 129.0, 128.6, 128.1, 127.9, 120.7, 113.9, 29.9, 20.6. Combining the results of the above H NMR spectrum and C NMR spectrum, it can be seen that the product obtained in Example 5 is 1,6-dimethyl-3-phenylquinolinone (1e).

[0091] In this embodiment, a polysubstituted quinolinone compound is synthesized by a trivalent rhodium catalyst [Cp*RhCl2]2 and silver trifluoromethanesulfonyl imide, sodium pivalate and copper acetate under the conditions of an inert solvent 1,2-dichloroethane DCE. This method has high atom economy and step economy, and uses N-nitroso as a traceless directing group that is easy to introduce and can serve as an intramolecular oxidant, thereby assisting the tandem reaction of oxidative Heck and intramolecular amide with acrylic acid derivatives, and constructing a quinolinone compound with regional selectivity in one step.

[0092] The chemical transformation in this example can rapidly construct 3-phenyl multi-substituted quinolinone compounds, and can provide a platform for the construction of more complex molecules.

[0093] Example 6 Preparation of 1-methyl-6-pyridine-3-quinolinone (1f)

[0094] In an atmospheric pressure air atmosphere, N-methyl-4-pyridine-3-phenylnitrosamide 2f (42.6 mg, 0.20 mmol), ethyl acrylate 3f (30.0 mg, 0.30 mmol), trivalent rhodium catalyst [Cp*RhCl2]2 (2.5 mg, 0.004 mmol), silver hexafluoroantimonate (3.6 mg, 0.01 mmol), sodium acetate (27.2 mg, 0.2 mmol), 1,2-dichloroethane (DCE, 1.0 mL) were added to a 15 mL Schlenk reaction tube in sequence, and the mixture was reacted at 100°C for 12 hours. The crude product was separated by chromatography using a prepared silica gel plate, and the selected developing solvent or eluent was a volume ratio of petroleum ether to ethyl acetate of 3:1, to obtain the product 1-methyl-6-pyridine-3-quinolinone (1f, 32.1 mg), with a yield of 68%. The chemical reaction equation corresponding to this embodiment is as follows:

[0095]

[0096] The H-NMR spectrum and C-NMR spectrum of the compound prepared in Example 6 are as follows: Fig.13 and Fig.14 As shown. Fig.13 It can be seen that: 1 H NMR (400MHz, CDCl3) δ8.69 (d, J=2.0Hz, 1H), 8.54–8.52 (m, 1H), 7.82 (ddd, J=1.2Hz, 2.4Hz, 3.6Hz,1H),7.60(d,J=9.2Hz,1H),7.35–7.18(m,4H),6.75(d,J=9.6Hz,1H),3.71(s,3H). From Fig.14 It can be seen that: 13C NMR (100MHz, CDCl3) δ162.2, 150.9, 147.8, 139.9, 138.8, 138.5, 130.5, 128.6, 124.7, 122.0, 121.6, 120.8, 120.6, 114.0, 29.3. Combining the results of the above H NMR spectrum and C NMR spectrum, it can be seen that the product obtained in Example 6 is 1-methyl-6-pyridine-3-quinolinone (1f).

[0097] In this embodiment, a polysubstituted quinolinone compound is prepared in the presence of an inert solvent, 1,2-dichloroethane, by the promotion of a trivalent rhodium catalyst [Cp*RhCl2]2, silver hexafluoroantimonate and sodium acetate.

[0098] This method overcomes the problem that the reaction activity and site selectivity of pyridine substrates, which are extremely challenging in traditional metal-catalyzed carbon-hydrogen bond activation, such as N-methyl-4-pyridine-3-phenylnitrosamide 2f in this example (which has multiple reactive sites when a strongly coordinated heterocyclic pyridine ring is present), are often difficult to obtain. A target molecule with a single product structure and a selective single product 1-methyl-6-pyridine-3-quinolinone (1f) are obtained with a high yield of 68%, demonstrating that it has good chemical selectivity and regioselectivity.

[0099] The chemical transformation in this example can be applied to the biomedical field of pyridine-containing molecules. It is worth noting that this transformation overcomes the limitations of strongly coordinated heterocycles in metal-catalyzed carbon-hydrogen bond activation reactions assisted by conventional directing strategies.

[0100] Example 7 Preparation of ethyl 1-methyl-2-oxo-1-oxo-1,2-dihydroquinoline-6-carboxylate (1 g)

[0101] Under an atmospheric pressure air atmosphere, 2 g (46.8 mg, 0.20 mmol) of tert-butyl-2-but-1-4-nitrosoaminobenzoate, tert-butyl acrylate 3b (38.4 mg, 0.30 mmol), trivalent rhodium catalyst [Cp*RhCl2]2 (2.5 mg, 0.004 mmol), silver trifluoromethanesulfonimide (3.9 mg, 0.01 mmol), sodium acetate (27.2 mg, 0.2 mmol), copper acetate (12.0 mg, 0.06 mmol), and 1,2-dichloroethane (DCE, 1.0 mL) were added to a 15 mL Schlenk reaction tube in sequence, and the mixture was reacted at 100 °C for 12 hours. The crude product was separated by chromatography on a prepared silica gel plate, and the selected developing solvent or eluent was a volume ratio of petroleum ether to ethyl acetate of 3:1, to obtain the product 1-methyl-2-oxo-1-oxo-1,2-dihydroquinoline-6-carboxylic acid ethyl ester (1 g, 35.5 mg), with a yield of 69%. The chemical reaction equation corresponding to this embodiment is as follows:

[0102]

[0103] The H-NMR spectrum and C-NMR spectrum of the compound prepared in Example 7 are as follows: Fig.15 and Fig.16 As shown. Fig.15 It can be seen that: 1 H NMR (400MHz, CDCl3) δ8.26(d,J=2.0Hz,1H),8.21(dd,J=2.0Hz,8.8Hz,1H),7.72(d,J=9.6Hz,1H),7.38(d,J=8.8Hz,1H), From Fig.16 It can be seen that: 13 CNMR (100MHz, CDCl3) δ165.5, 162.3, 143.0, 139.1, 131.7, 131.4, 130.8, 125.0, 124.2, 122.5, 120.1, 114.1, 65.9, 29.7, 17.8. Combining the results of the above nuclear magnetic hydrogen spectrum and carbon spectrum, it can be seen that the product obtained in Example 7 is 1-methyl-2-oxo-1-oxo-1,2-dihydroquinoline-6-carboxylic acid ethyl ester (1g).

[0104] In this embodiment, a polysubstituted quinolinone compound is prepared in the presence of an inert solvent 1,2-dichloroethane (DCE) by the promotion of a trivalent rhodium catalyst [Cp*RhCl2]2, silver trifluoromethanesulfonimide, sodium acetate and copper acetate.

[0105] This method has high atom economy and step economy. It uses molecular oxygen to participate in the intramolecular oxidative traceless directing group to assist with acrylic acid derivatives, and achieves the synthesis of multi-substituted quinolinone compounds in one step through a cascade strategy of oxidative Heck reaction and amidation.

[0106] The chemical transformation in this embodiment can quickly construct a quinolinone molecule containing a crotyl alcohol fragment, which can be used to manufacture pesticides, plasticizers, medicines, coatings, etc.

[0107] Example 8 Preparation of 4-(N,N-dipropylaminosulfonamido)benzyl 1-methyl-2-oxo-1,2-dihydroquinoline-6-carboxylate (1h)

[0108] Under an atmospheric pressure air atmosphere, 4-(N,N,N-dipropylaminosulfonyl)benzyl 4-(methylnitrosoamino)benzoate 2h (86.6 mg, 0.20 mmol), tert-butyl acrylate 3b (38.4 mg, 0.30 mmol), trivalent rhodium catalyst [Cp*RhCl2]2 (2.5 mg, 0.004 mmol), silver trifluoromethanesulfonimide (3.9 mg, 0.01 mmol), sodium acetate (27.2 mg, 0.2 mmol), copper acetate (12.0 mg, 0.06 mmol), and 1,2-dichloroethane (DCE, 1.0 mL) were added sequentially into a 15 mL Schlenk reaction tube and reacted at 100 °C for 12 hours. The crude product was separated by chromatography on a prepared silica gel plate, and the selected developing solvent or eluent was a volume ratio of petroleum ether to ethyl acetate of 2:1, to obtain the product 4-(N,N-dipropylaminoamido)benzyl 1-methyl-2-oxo-1,2-dihydroquinoline-6-carboxylate (1h, 64.8mg), with a yield of 71%. The chemical reaction equation corresponding to this embodiment is as follows:

[0109]

[0110] The H-NMR and C-NMR spectra of the compound prepared in Example 8 are as follows: Fig.17 and Fig.18 As shown. Fig.17 It can be seen that: 1HNMR (400MHz, CDCl3) δ8.27(d,J=2.0Hz,1H),8.22(dd,J=2.0Hz,8.8Hz,1H),7.81(d,J=8.0Hz,2H),7.72(d,J=9.6Hz,1H),7.56(d,J=8.0Hz,2 H),7.40(d,J=8.8Hz,1H),6.74(d,J=9.6Hz,1H),5.43(s,2H),3.72(s,3H),3.08–3.04(m,4H),1.54(q,J=7.6Hz,4H),0.85(t,J=7.6Hz,6H). From Fig.18 It can be seen that: 13 C NMR (100MHz, CDCl3) δ165.3, 162.2, 143.2, 140.3, 140.0, 139.0, 131.4, 130.9, 128.2, 127.3, 123.3, 122.5, 120.1, 114.3, 65.7, 50.1, 29.7, 22.0, 11.1. Combining the results of the above H NMR spectrum and C NMR spectrum, it can be seen that the product obtained in Example 8 is 4-(N,N-dipropylaminoamido)benzyl 1-methyl-2-oxo-1,2-dihydroquinoline-6-carboxylate (1h).

[0111] This embodiment is a metal-catalyzed traceless (N-nitroso group is used as a traceless directing group, which directs CH activation and then converts itself into a part of the target molecule) and promoted by an intramolecular oxidant (referring to N-nitroso group) through an oxidative Heck and intramolecular amide tandem strategy to achieve a polysubstituted quinolinone synthesis reaction. Specifically, under inert solvent conditions, through the oxidative Heck and intramolecular amide tandem reaction of N-aryl nitrosamide and aromatic ethylene catalyzed by trivalent rhodium, small molecules (nitrous oxide, water, alcohol) are released while rapidly constructing various polysubstituted quinolinone compounds.

[0112] The chemical transformation in this example can rapidly modify probenecid drug molecules to enrich the library of drugs and bioactive molecules.

[0113] Example 9 Preparation of 1-methyl-6-(3-methyl-2-en-1-oxy)quinolinone (1i)

[0114] Under an atmospheric pressure air atmosphere, N-methyl-4-(3-methylbut-2-en-1-yl)oxyphenylnitrosamide 2i (44.1 mg, 0.20 mmol), tert-butyl acrylate 3b (38.4 mg, 0.30 mmol), trivalent rhodium catalyst [Cp*RhCl2]2 (2.5 mg, 0.004 mmol), silver trifluoromethanesulfonimide (3.9 mg, 0.01 mmol), sodium acetate (27.2 mg, 0.2 mmol), copper acetate (12.0 mg, 0.06 mmol), and 1,2-dichloroethane (DCE, 1.0 mL) were added sequentially to a 15 mL Schlenk reaction tube and reacted at 100 °C for 12 hours. The crude product was separated by chromatography on a prepared silica gel plate, and the selected developing solvent or eluent was a volume ratio of petroleum ether to ethyl acetate of 1:1, to obtain the product 1-methyl-6-(3-methyl-2-ene-1-oxy)quinolinone (1i, 27.7 mg), with a yield of 57%. The chemical reaction equation corresponding to this embodiment is as follows:

[0115]

[0116] The H-NMR spectrum and C-NMR spectrum of the compound prepared in Example 9 are shown in the following order: Fig.19 and Fig. 20 As shown. Fig.19 It can be seen that: 1 H NMR (400MHz, CDCl3) δ7.60(d,J=9.6Hz,1H),7.29(d,J=9.2Hz,1H),7.20(dd,J=2.8Hz,9.2Hz,1H),7.02(d,J=2.8Hz,1H),6 From Fig. 20 It can be seen that: 13 C NMR (100MHz, CDCl3) δ162.0, 153.9, 138.7, 138.5, 134.6, 122.3, 121.4, 119.9, 119.3, 115.4, 111.5, 65.3, 29.5, 25.8, 18.3. Combining the results of the above H NMR spectrum and C NMR spectrum, it can be seen that the product obtained in Example 9 is 1-methyl-6-(3-methyl-2-ene-1-oxy)quinolinone (1i).

[0117] The preparation method in this embodiment has the characteristics of green oxidation, chemical selectivity, and strong coordination compatibility. At the same time, the method only uses simple and readily available aromatic amine derivatives as traceless internal oxidative directing groups to achieve oxidation Heck reaction and amidation tandem reaction with bulk chemical acrylate. The transformation steps are few and the operation is simple, and the obtained product is easy to further transform; more importantly, the bioactive molecular alkaloid-mandrake analogue is also quickly constructed through this strategy, which has excellent atom economy and step economy.

[0118] The chemical transformation in this embodiment can quickly construct the alkaloid-mandrake analogues for application in the field of biologically active molecules.

[0119] Example 10 Novel Synthesis Method of Cilostamide (1p)

[0120] Step 1: In an atmospheric pressure air atmosphere, methyl 4-(4-(nitrosoamino)methylphenoxybutyrate 2j (50.4 mg, 0.20 mmol), tert-butyl acrylate 3b (38.4 mg, 0.30 mmol), trivalent rhodium catalyst [Cp*RhCl2]2 (2.5 mg, 0.004 mmol), silver trifluoromethanesulfonimide (3.9 mg, 0.01 mmol), sodium acetate (27.2 mg, 0.2 mmol), copper acetate (12. 0mg, 0.06mmol), 1,2-dichloroethane (DCE, 1.0mL), react at a temperature of 100°C for 12 hours. The crude product was separated by chromatography using the prepared silica gel plate, and the selected developing solvent or eluent was a volume ratio of petroleum ether to ethyl acetate of 1:1 to obtain the product 4-(1-methyl-2-oxo-1,2-dihydroquinoline-6-oxy)butyric acid methyl ester (1j-1, 36.3mg), with a yield of 66%. The chemical reaction equation corresponding to this embodiment is as follows:

[0121]

[0122] The NMR hydrogen spectrum and carbon spectrum of the compound prepared in step 1 are shown in sequence as follows: Fig.21 and Fig. 22 As shown. Fig.21 It can be seen that: 1H NMR (400MHz, CDCl3) δ7.58(d,J=9.6Hz,1H),7.28(d,J=9.2Hz,1H),7.16(dd,J=2.8Hz,9.2Hz,1H),6.99(d,J=2.8Hz,1 H), 6.70 (d, J = 9.2Hz, 1H), 4.06 (t, J = 6.0Hz, 2H), 3.70 (s, 3H), 3.69 (s, 3H), 2.56 (t, J = 7.2Hz, 2H), 2.19–2.10 (m, 2H). From Fig. 22 It can be seen that: 13 CNMR (100MHz, CDCl3) δ173.5,161.8,153.8,138.3,134.6,122.2,121.3,119. 5,119.5,115.3,111.3,77.3,77.0,76.7,67.2,51.6,30.4,29.4,24.5,21.8. HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 15 H 17 NO4:275.1158,Found:275.1156. Combining the results of the above H NMR spectrum, C NMR spectrum and mass spectrometry analysis, it can be seen that the product obtained in the above step 1 is methyl 4-(1-methyl-2-oxo-1,2-dihydroquinoline-6-oxy)butyrate (1j-1).

[0123] Step 2: In an atmospheric pressure air atmosphere, methyl 4-(1-methyl-2-oxo-1,2-dihydroquinoline-6-oxy)butyrate (1j-1) (55.0 mg, 0.20 mmol) was added to a 15 mL Schlenk reaction tube, and 2.0 mL of a 20% hydrochloric acid solution was added, and the mixture was reacted at 90° C. for 1 hour. After cooling to room temperature, the crude product was washed with water, and the precipitated crystals were collected by filtration to obtain the product 4-(1-methyl-2-oxo-1,2-dihydroquinoline-6-oxy)butyric acid (1j-2, 51.2 mg), with a yield of 98%. The chemical reaction equation corresponding to this embodiment is as follows:

[0124]

[0125] The H-NMR spectrum and C-NMR spectrum of compound 1j-2 prepared in step 2 are shown in the following order: Fig.23 and Fig.24 As shown. Fig.23It can be seen that: 1H NMR (400MHz, DMSO-d6) δ12.17 (s, 1H), 7.83 (d, J = 9.6Hz, 1H), 7.45 (d, J = 9.2Hz, 1H), 7.31-7.21 (m, 2H), 6.60 (d, J = 9.6Hz, 1H), 4.04 (t, J = 6.4Hz, 2H), 3.59 (s, 3H), 2.41 (t, J = 7.2Hz, 2H), 1.97 (p, J = 6.8Hz, 2H). Fig.24 It can be seen that: 13 C NMR (100 MHz, DMSO-d6) δ 174.1, 160.72, 153.4, 138.7, 134.3, 121.6, 120.9, 120.0, 116.0, 111.4, 67.1, 30.1, 29.1, 24.3. Combined with the results of the above H NMR and C NMR spectra, it can be seen that the product obtained in the above step 2 is 4-(1-methyl-2-oxo-1,2-dihydroquinoline-6-oxy)butanoic acid (1j-2).

[0126] Step 3: In an atmospheric pressure air atmosphere, 4-(1-methyl-2-oxo-1,2-dihydroquinolin-6-oxy)butanoic acid (1j-2) (130.6 mg, 0.50 mmol) was added to a 15 mL Schlenk reaction tube in sequence. After adding 3.0 mL of N,N-dimethylformamide, oxalyl chloride (95.2 mg, 0.75 mmol) was added dropwise at 0°C. After reacting for 2 hours, a dichloromethane solution (DCM, 2.0 mL) of triethylamine (75.9 mg, 0.75 mmol) was added. Then, N-methylcyclohexylamine (113.2 mg, 1 mmol) was added dropwise at 0°C and reacted at this temperature for 3 hours. The crude product was separated by chromatography on a prepared silica gel plate, and the selected developing solvent or eluent was a volume ratio of petroleum ether to ethyl acetate of 1:1, to obtain the product N-cyclohexyl-N-methyl-4-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yl)oxybutyramide (1p, 123.0 mg), with a yield of 69%. The chemical reaction equation corresponding to this embodiment is as follows:

[0127]

[0128] The NMR hydrogen spectrum and carbon spectrum of the compound prepared in step 3 are shown in sequence as follows: Fig.25 and Fig.26 As shown. Fig.25 It can be seen that: 1H NMR (400MHz, CDCl3) δ7.52(d,J=9.6Hz,1H),7.22(dd,J=1.6Hz,9.2Hz,1H),7.14-7.10(m,1H),6.96(d,J=2.8Hz,1H),6.64(d,J=9.6Hz,1H),4. 43–3.47(m,1H),4.03(t,J=6.0Hz,2H),3.63(s,3H),2.76(d,J=10.8Hz ,3H),2.47(m,2H),2.11(m,2H),1.81–1.50(m,6H),1.24–1.16(m,4H).From Fig.26 It can be seen that: 13 C NMR (100MHz, CDCl3) δ171.6,161.9,154.0,138.4,134.5,122.3,121.4,119.5,115.3,111. 4(d,J=2.0Hz),67.8(d,J=8.0Hz),54.4(d,J=41.4Hz),30.9,30.1(d,J=28.0Hz),29.7(d,J =5.0Hz), 29.4(d,J=10.0Hz), 25.7(d,J=16.0Hz), 25.5(d,J=30.0Hz), 24.9(d,J=31.0Hz). Combining the results of the above H-NMR and C-NMR spectra, it can be seen that the product obtained in step 3 is N-cyclohexyl-N-methyl-4-(1-methyl-2-oxo-1,2-dihydroquinolin-6-yl)oxybutyramide (1p).

[0129] In this embodiment, a polysubstituted quinolinone compound is synthesized by a trivalent rhodium catalyst [Cp*RhCl2]2 and silver trifluoromethanesulfonyl imide, sodium pivalate and copper acetate under the conditions of an inert solvent 1,2-dichloroethane DCE. This method has high atom economy and step economy, and uses N-nitroso as a traceless directing group that is easy to introduce and can serve as an intramolecular oxidant, thereby assisting the tandem reaction of oxidative Heck and intramolecular amide with acrylic acid derivatives, and constructing a quinolinone compound with regional selectivity in one step.

[0130] The chemical transformation of this example can rapidly construct the drug Cilostamide, which is an effective and selective PDE3 inhibitor with anti-thrombotic and intramedullary hyperplasia activities.

[0131] In addition, the inventors of this patent application found through systematic screening of acrylic acid derivatives that electron-withdrawing groups such as trifluoroethyl ester, hexafluoroisopropyl ester and large steric hindrances such as tert-butyl ester and adamantane ester have significant advantages when used as substrates; while methyl ester, ethyl ester and N-tert-butyl amide are slightly less efficient when used as substrates; and no product is generated when acrylic acid, acryloyl chloride, etc. are used as substrates.

[0132] As described above, the present patent application uses trivalent rhodium as the catalyzer under inert solvent conditions, and uses easily available N-aryl nitrosamide and acrylate as reaction substrates to achieve chemical selectivity (the examples of the present application can obtain target molecules with a single product structure in good yield, and have good chemical selectivity) and regioselectivity (when the reaction substrate of the present application has a strongly coordinated heterocycle, it has multiple reactive sites, and the reaction can still obtain a selective single product, proving that it has good regioselectivity) to modularly synthesize polysubstituted quinolinone compounds with good application prospects in the field of biologically active molecules and drug molecules.

[0133] In summary, this patent application discloses a metal-catalyzed traceless (N-nitroso group is used as a traceless directing group, which directs CH activation and then converts itself into a part of the target molecule) and intramolecular oxidant (referring to N-nitroso group)-promoted multi-substituted quinolinone synthesis reaction achieved by an oxidative Heck and intramolecular amidation tandem strategy. Specifically, under inert solvent conditions, through the oxidative Heck and intramolecular amidation tandem reaction of N-aryl nitrosamide and aromatic ethylene catalyzed by trivalent rhodium, small molecules (nitrous oxide, water, alcohol) are released while various multi-substituted quinolinone compounds are rapidly constructed. This method has the characteristics of green oxidation, chemical selectivity, and strong coordination compatibility. At the same time, this method only uses simple and readily available aromatic amine derivatives as traceless internal oxidative directing groups to achieve oxidative Heck reactions and amidation tandem reactions with bulk chemical acrylates.

[0134] This transformation has few steps and is easy to operate. The products obtained are easy to further transform. More importantly, we also use this strategy to quickly construct fine compounds such as bioactive molecules and drug molecules with excellent atom economy and step economy.

[0135] Through this strategy, this patent application achieves a one-step simple synthesis of the analgesic - flucarbamide, and also achieves the rapid construction of the alkaloid - romantoin analogue and the anti-thrombotic inhibitor - cilostamide, which greatly enriches the existing molecular library in the fields of biomedicine and functional materials, and provides a new green strategy for the rapid and accurate construction of drug molecules.

[0136] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "illustrative embodiments", "examples", "specific examples", or "some examples" means that the specific features, structures, materials or characteristics described in conjunction with the embodiments or examples are included in at least one embodiment or example of this patent application. In this specification, the schematic representation of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner.

[0137] Although several embodiments of the present patent application have been shown and described, those skilled in the art will appreciate that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present patent application, and the scope of the present patent application is defined by the claims and their equivalents.

Claims

1. A method for preparing a polysubstituted quinolone compound, characterized in that: The specific steps include: S1: In a reactor, 2.5 mg of pentamethylcyclopentadiene iridium dichloride dimer, 3.9 mg of silver trifluoromethanesulfonimide, 27.2 mg of sodium acetate, 1.0 mL of 1,2-dichloroethane, 27.2 mg of N-methyl-N-phenylnitrosamide, and 38.4 mg of tert-butyl acrylate were added in sequence in air; S2: reacting the reaction solution at 100° C. for 12 hours; S3: After the reaction is completed, the mixture is separated by column chromatography to obtain the target compound.

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