Preparation method of 3-hydroxyquinoline-2, 4-diketone compound

Abstract

The invention discloses a preparation method of a 3-hydroxylated quinoline-2, 4-diketone compound, which comprises the following steps: in the presence of an oxidant and a solvent, taking an N-o-cyano aryl acrylamide compound as a substrate, stirring and reacting at 80-120 DEG C, and separating and purifying the reaction product to obtain the 3-hydroxylated quinoline-2, 4-diketone compound. According to the method, hydroxylation is realized through carbon-carbon double bond breakage, a simple and effective method is provided for synthesizing the 3-hydroxylated quinoline-2, 4-diketone compound, acid, alkali and transition metal are not needed for catalysis, and the method has the advantages of being easy to operate, high in step economical efficiency, high in functional group tolerance and the like.

Description

Technical Field

[0001] This invention belongs to the field of organic synthetic chemistry technology, specifically relating to a method for preparing 3-hydroxylated quinoline-2,4-dione compounds. Background Technology

[0002] Nitrogen-containing heterocycles are widely found in bioactive natural products, drug molecules, and functional materials, serving as important structural units in organic compounds and capable of being transformed into a series of valuable structural units. Therefore, the efficient construction of nitrogen-containing heterocycles has always been a hot topic in organic synthesis research. Among them, quinoline-2,4-diketones are an important class of nitrogen-containing fused heterocyclic compounds with rich pharmacological activities, such as anticancer, antiviral, and antitumor effects. They are not only widely found in various natural products and drug molecules but also have broad applications in pharmaceuticals and agrochemicals.

[0003] Existing methods for synthesizing 3-hydroxyquinoline-2,4-dione compounds are not yet fully developed, and mainly rely on 4-hydroxyquinoline-2(1 H The 4-hydroxyquinoline-2(1-ketone) was prepared using aniline as a substrate. The most typical synthetic method employed by J. Košmrlj's group involved the thermal condensation of aniline with substituted diethyl malonate to prepare 4-hydroxyquinoline-2(1-ketone). H )-ketone, then 4-hydroxyquinoline-2(1)-ketone was reacted with peracetic acid in alkaline water. H )-keto is oxidized to 3-hydroxyquinoline-2,4-dione ( Tetrahedron , 2013, 69(51) (10826-10835) Although this method effectively synthesized 3-hydroxyquinoline-2,4-dione, the reaction temperature is high. Thermal condensation requires heating in a metal bath at 220-230℃ for 1 hour, followed by heating to 260-270℃ for 3-6 hours, which limits the application of this reaction to some extent. Besides the above method, T. Kappe's group has previously used 4-hydroxyquinoline-2 (1... H Using 3-chloroquinoline-2,4-dione as a substrate, 3-chloroquinoline-2,4-dione was obtained in a solution containing thionyl chloride and 1,4-dioxane. Monatshefte für Chemie / Chemical Monthly , 1992, 123(6) (617-636), followed by hydrolysis with ammonia, successfully yielded 3-hydroxyquinoline-2,4-dione; additionally, 4-hydroxyquinoline-2 (1 H Nitration of 3-hydroxyquinoline-2,4-dione can also be successfully obtained by raising the temperature to 118°C. Journal of heterocyclic chemistry ,1992, 29(6): 1535-1540). However, current reports on methods for synthesizing 3-hydroxyquinoline-2,4-dione compounds suffer from a lack of diversity. Existing literature reports only a limited range of methods for preparing 3-hydroxyquinoline-2,4-dione compounds, except for those using 4-hydroxyquinoline-2 (1 H Aside from methods using quinoline-2,4-diones as substrates, no other synthetic methods have been reported. Therefore, developing an efficient and simple synthetic method to address the limitation of limited methods for synthesizing quinoline-2,4-dione compounds is of great significance. Summary of the Invention

[0004] To address the problems of existing technologies, this invention provides a method for preparing 3-hydroxylated quinoline-2,4-diketone compounds, solving the issues of limited method availability and low atom economy in the synthesis of these compounds. This method is simple and effective, using N-o-cyanoarylacrylamide compounds as substrates. The target product can be obtained in a one-pot process. The oxidant used is inexpensive, readily available, and environmentally friendly. Furthermore, the reaction system does not contain acids, bases, or metals, and features simple operation, high procedural economy, and good functional group tolerance.

[0005] The preparation of 3-hydroxylated quinoline-2,4-dione compounds according to the present invention involves adding an N-o-cyanoarylacrylamide compound, an oxidant, and a solvent to a reactor, followed by stirring the reaction under air atmosphere at 80-120°C. After the reaction is complete, the reaction product is concentrated, and the concentrate is then separated and purified to obtain 3-hydroxylated quinoline-2,4-dione compounds. The chemical reaction formula is as follows:

[0006] In the formula, 1 is an N-o-cyanoarylacrylamide compound, 2 is a 3-hydroxylated quinoline-2,4-dione compound, and R... 1 Selected from H, halogens, CH3, OCH3, thiophene heterocycles; R 2 Selected from H, butyl, benzyl, CH3, propyl, CH2CO2C2H5; R 3 Selected from benzyl, phenyl, CH3, and ethyl.

[0007] The oxidant is selected from potassium persulfate complex salt, ammonium persulfate, and the molar ratio of N-o-cyanoarylacrylamide compound to the oxidant is 1:4-6.

[0008] The solvent is selected from acetone, tetrahydrofuran, acetone-hexafluoroisopropanol-tetrahydrofuran mixed solvent (volume ratio 1:1-3:2-4), acetone-hexafluoroisopropanol-tetrahydrofuran mixed solvent, acetone-isopropanol-tetrahydrofuran mixed solvent (volume ratio 1:1-3:2-4), and acetone-N,N-dimethylformamide-tetrahydrofuran mixed solvent (volume ratio 1:1-3:2-4).

[0009] Separation and purification were performed using column chromatography or thin-layer chromatography, with the eluent being a mixture of petroleum ether and ethyl acetate in a volume ratio of 2:1 to 1:1.

[0010] The N-o-cyanoarylacrylamide compounds used in the preparation method are N-(5-chloro-2-cyanophenyl)-2-methylene-N-propylbutyramide, N-(2-cyano-5-methylphenyl)-2-methylene-N-propylbutyramide, N-(2-cyano-5-methoxyphenyl)-2-methylene-N-propylbutyramide, N-(2-cyano-4-fluorophenyl)-2-methylene-N-propylbutyramide, N-(2-cyanophenyl)-N-methyl-2-phenylacrylamide, and N-(4-bromo-2-cyanophenyl)-2-methylene-N-propylbutyramide. 2-Benzyl-N-(2-cyanophenyl)-N-methylacrylamide, N-(2-cyanophenyl)-2-methylene-N-propylbutyramide, N-benzyl-N-(2-cyanophenyl)-2-methylenebutyramide, N-(2-cyanophenyl)-N-(2-methylenebutyryl)glycine ester, N-butyl-N-(2-cyanophenyl)-2-methylenebutyramide, N-(2-cyano-4-(thiophen-2-yl)phenyl)-2-methylene-N-propylbutyramide, N-(2-cyanophenyl)-2-methylenebutyramide.

[0011] The N-o-cyanoarylacrylamide compounds were prepared by conventional methods, referring to the literature ( Organic Letters , 2021, 23(15) It is prepared by the method described in 6158-6163.

[0012] The present invention has at least the following beneficial effects: This invention uses N-o-cyanoarylacrylamide compounds and oxidants as reactants to achieve the hydroxylation of quinoline-2,4-diketone compounds under heat-promoted oxidation conditions, preparing a series of hydroxylated quinoline-2,4-diketone compounds. Although the variety of quinoline-2,4-diketone compounds has been continuously enriched, current methods for synthesizing 3-hydroxylated quinoline-2,4-diketone compounds not only suffer from limitations in their diversity but also from lengthy and complex synthetic routes and low atom economy. The method for preparing 3-hydroxylated quinoline-2,4-diketone compounds provided by this invention features a simple reaction operation. Furthermore, the synthetic method used in this invention does not require acid, base, or transition metal catalysis; it utilizes a tandem cyclization reaction of free radicals to achieve the synthesis of the target compounds, making it more environmentally friendly and exhibiting higher atom and step economy. The oxidant used is inexpensive, readily available, and environmentally friendly, making the technical solution of this invention more economical, and the obtained products have potential application prospects. Detailed Implementation

[0013] The present invention will be further described in detail below through embodiments, but the scope of protection of the present invention is not limited to the content described. Unless otherwise specified, the methods in the embodiments are performed according to conventional operations, and the reagents used are all commercially available reagents or reagents prepared according to conventional methods.

[0014] Example 1: Preparation of 3-hydroxylated quinoline-2,4-dione compounds

[0015] An N-o-cyanoarylacrylamide compound (0.2 mmol), potassium persulfate complex salt (Oxone, 1 mmol), and a mixed solvent of acetone-hexafluoroisopropanol-tetrahydrofuran (volume ratio 1:2:3, 3 mL) were added to a 15 mL pressure-resistant tube. After mixing, the mixture was stirred in air at 110 °C for 12 hours. After the reaction was complete, the reaction mixture was concentrated and then separated by silica gel column chromatography (the eluent was prepared by mixing petroleum ether and ethyl acetate in a volume ratio of 2:1) to obtain the target product 2.

[0016] Following the above method, experiments were conducted using N-o-cyanoarylacrylamide compounds, and the corresponding products 2a~2m were successfully obtained. The compound structures and data characterization of the target products 2a~2m are as follows: 7-Chloro-3-ethyl-3-hydroxy-1-propylquinoline-2,4(1 H , 3 H )-Diketone (2a)

[0017] White solid (yield: 53%, column chromatography eluent: petroleum ether: ethyl acetate = 2:1), mp 71–72 °C. 1 HNMR (600 MHz, CDCl3) δ 7.89 (d, J = 8.3 Hz, 1H), 7.16 (dd, J = 8.3, 1.7 Hz, 1H), 7.09 (d, J = 1.6 Hz, 1H), 4.13–3.98 (m, 1H), 3.91–3.76 (m, 1H), 1.95–1.77 (m,2H), 1.75–1.65 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H), 0.91 (t, J = 7.4 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 193.7, 172.3, 142.8, 142.5, 129.5, 123.8, 119.0, 115.3,82.8, 44.8, 34.7, 20.4, 11.1, 7.3. HRMS (ESI): m / z calcd. for C 14 H 16 ClNO3Na[M +Na] + 304.0711, found 304.0720. 3-Ethyl-3-hydroxy-7-methyl-1-propylquinoline-2,4(1 H , 3 H )-Diketone (2b)

[0018] White solid (yield: 71%, column chromatography eluent: petroleum ether: ethyl acetate = 2:1), mp 66–68 °C. 1 HNMR (600 MHz, CDCl3) δ 7.81 (d, J = 7.8 Hz, 1H), 6.98 (d, J 0.99 (t, J= 7.4 Hz, 3H), 0.89 (t, J = 7.4 Hz, 3H). 13 C NMR(151 MHz, CDCl3) δ 194.5, 172.5, 147.5, 141.8, 128.2, 124.5, 118.4, 115.4,82.5, 44.4, 34.7, 22.4, 20.5, 11.1, 7.3. HRMS (ESI): m / z calcd. for C 15 H 20 NO3[M+ H] + 262.1438, found 262.1442. 3-Ethyl-3-hydroxy-7-methoxy-1-propylquinoline-2,4(1 H , 3 H )-Diketone (2c)

[0019] Yellow liquid (yield: 47%, column chromatography eluent: petroleum ether: ethyl acetate = 2:1); 1 H NMR (600MHz, CDCl3) δ 7.91 (d, J = 8.6 Hz, 1H), 6.67 (dd, J = 8.7, 2.2 Hz, 1H), 6.55 (d, J = 2.2 Hz, 1H), 4.05–3.98 (m, 1H), 3.89 (s, 3H), 3.86–3.74 (m, 2H), 1.93–1.76(m, 2H), 1.74–1.60 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H), 0.88 (t, J = 7.4 Hz, 3H). 13 HRMS (ESI): m / z calcd. forC 15 H 19 NO4Na [M + Na] +300.1206, found 300.1213. 3-Ethyl-6-fluoro-3-hydroxy-1-propylquinoline-2,4(1 H , 3 H )-Diketone (2d)

[0020] White solid (yield: 64%, column chromatography eluent: petroleum ether: ethyl acetate = 2:1), mp 109–111℃. 1 H NMR (600 MHz, CDCl3) δ 7.61 (dd, J = 7.7, 3.1 Hz, 1H), 7.35–7.30 (m, 1H), 7.10 (dd, J = 9.1, 3.9 Hz, 1H), 4.09–4.02 (m, 1H), 3.89–3.81 (m, 1H), 1.95–1.78 (m, 2H), 1.74–1.63 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H), 0.91 (t, J = 7.4 Hz, 3H). 13 CNMR (151 MHz, CDCl3) δ 193.85, 172.03, 158.44 (d, J = 246.6 Hz), 138.00, 122.89(d, J = 23.3 Hz), 122.10 (d, J = 6.4 Hz), 116.85 (d, J = 7.2 Hz), 114.16 (d, J = 23.4Hz), 82.71, 44.89, 34.48, 20.37, 11.08, 7.22. HRMS (ESI): m / z calcd. forC 14 H 16 FNO3Na [M + Na] + 288.1006, found 288.1015. 3-Hydroxy-1-methyl-3-phenylquinoline-2,4(1 H ,3 H )-Diketone (2e)

[0021] Yellow solid (yield: 54%, column chromatography eluent: petroleum ether: ethyl acetate = 2:1), mp > 200℃. 1 HNMR (600 MHz, CDCl3) δ 7.92 (d, J = 7.5 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.39–7.31 (m, 2H), 7.27 (dd, J = 7.2, 2.8 Hz, 3H), 7.18 (t, J = 9.0 Hz, 2H), 4.38 (s,1H), 3.59 (s, 3H). 13 C NMR (151 MHz, CDCl3) δ 192.6, 171.0, 142.3, 137.8,136.3, 129.3, 129.1, 128.5, 125.7, 124.0, 121.0, 115.2, 83.1, 30.5. HRMS(ESI): m / z [M + Na] + calcd for C 16 H 13 NO3Na, 290.0788; found, 290.0794. 6-Bromo-3-ethyl-3-hydroxy-1-propylquinoline-2,4(1 H , 3 H )-Diketone (2f)

[0022] White solid (yield: 68%, column chromatography eluent: petroleum ether: ethyl acetate = 2:1), mp 131–133℃. 1 H NMR (600 MHz, CDCl3) δ 8.05 (d, J = 2.4 Hz, 1H), 7.70 (dd, J = 8.8, 2.5 Hz, 1H), 7.01 (d, J = 8.9 Hz, 1H), 4.05–4.02 (m, 1H), 3.89–3.83 (m, 1H), 3.80 (s,1H), 1.94-1.79 (m, 2H), 1.68 (dd, J = 15.2, 7.6 Hz, 2H), 1.00 (t, J= 7.4 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 193.6, 172.1, 140.7,138.5, 130.7, 122.2, 116.9, 116.4, 82.9, 44.8, 34.5, 20.4, 11.1, 7.3. HRMS(ESI): m / z calcd. for C 14 H 16 BrNO3Na [M + Na] + 348.0206, found 348.0214. 1-Methyl-3-benzyl-3-hydroxyquinoline-2,4(1 H ,3 H )-Diketone (2g)

[0023] White solid (yield: 60%, column chromatography eluent: petroleum ether: ethyl acetate = 2:1), mp 123–124 °C. 1 H NMR (600 MHz, CDCl3) δ 7.97–7.85 (m, 1H), 7.69–7.58 (m, 1H), 7.21 (t, J = 7.6Hz, 1H), 7.19–7.15 (m, 3H), 7.06 (d, J = 8.3 Hz, 1H), 7.01–6.91 (m, 2H), 3.88(s, 1H), 3.43 (s, 3H), 3.17 (d, J = 13.4 Hz, 1H), 3.10 (d, J = 13.4 Hz, 1H). 13 CNMR (151 MHz, CDCl3) δ 194.0, 171.3, 142.5, 136.3, 132.7, 130.0, 128.0,127.9, 127.6, 123.7, 120.7, 114.9, 82.9, 48.0, 30.1. HRMS (ESI): m / z [M + Na] + calcd for C 17 H 15NO3Na, 304.0944; found, 304.0952. 3-Ethyl-3-hydroxy-1-propylquinoline-2,4(1 H, 3 H )-Diketone (2h)

[0024] White solid (yield: 77%, column chromatography eluent: petroleum ether: ethyl acetate = 2:1), mp 91–93 °C. 1 HNMR (600 MHz, CDCl3) δ 7.92 (d, J = 7.6 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.17(t, J = 7.5 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 4.10–4.02 (m, 1H), 3.85 (dd, J =16.4, 9.3 Hz, 2H), 2.03–1.76 (m, 2H), 1.76–1.53 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H), 0.90 (t, J = 7.4 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 194.9, 172.3, 141.6,136.0, 128.1, 123.5, 120.7, 115.0, 82.7, 44.5, 34.5, 20.4, 11.1, 7.3. HRMS(ESI): m / z calcd. for C 14 H 17 NO3Na [M + Na] + 270.1101, found 270.1109. 1-Benzyl-3-ethyl-3-hydroxyquinoline-2,4(1 H , 3 H )-Diketone (2i)

[0025] Yellow solid (yield: 73%, column chromatography eluent: petroleum ether: ethyl acetate = 2:1), mp 127–128 °C. 1H NMR (600 MHz, CDCl3) δ 7.95 (dd, J = 7.7, 1.6 Hz, 1H), 7.55–7.44 (m, 1H),7.35 (t, J = 7.5 Hz, 2H), 7.29 (d, J = 7.3 Hz, 1H), 7.25 (d, J = 7.4 Hz, 2H), 7.17(t, J = 7.5 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 5.60 (d, J = 16.4 Hz, 1H), 4.94 (d, J = 16.3 Hz, 1H), 3.94 (s, 1H), 2.15–1.90 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H). 13 CNMR (151 MHz, CDCl3) δ 194.7, 172.7, 141.9, 136.0, 135.6, 129.0, 128.0,127.7, 126.3, 123.8, 120.7, 115.9, 82.9, 46.9, 34.7, 7.3. HRMS (ESI): m / zcalcd. for C 18 H 17 NO3Na [M + Na] + 318.1101, found 318.1108. 2-(3-ethyl-3-hydroxy-2,4-dioxo-3,4-dihydroquinoline-1(2) H )-ethyl acetate (2j)

[0026] Yellow liquid (yield: 69%, column chromatography eluent: petroleum ether: ethyl acetate = 2:1); 1 H NMR (600MHz, CDCl3) δ 7.77 (d, J = 7.6 Hz, 1H), 7.73 (d, J = 6.5 Hz, 1H), 7.67–7.60 (m,1H), 7.23 (t, J = 7.5 Hz, 1H), 5.47 (d,J = 15.2 Hz, 2H), 5.04 (s, 1H), 4.38–4.13(m, 2H), 2.57–2.30 (m, 2H), 1.21 (t, J = 7.1 Hz, 3H), 1.17 (t, J = 7.4 Hz, 3H). 13 CNMR (151 MHz, CDCl3) δ 191.1, 169.6, 166.5, 146.2, 137.7, 125.7, 124.6,121.3, 117.7, 86.9, 63.7, 25.8, 13.9, 11.5. HRMS (ESI): m / z calcd.forC 15 H 17 NO5Na [M + Na] + 314.0999, found 314.1008. 1-Butyl-3-ethyl-3-hydroxyquinoline-2,4(1 H ,3 H )-Diketone (2kJ)

[0027] Yellow liquid (yield: 44%, column chromatography eluent: petroleum ether: ethyl acetate = 2:1); 1 H NMR (600MHz, CDCl3) δ 7.90 (dd, J = 7.6, 1.4 Hz, 1H), 7.66–7.54 (m, 1H), 7.15 (t, J = 7.5Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 4.19–4.01 (m, 1H), 3.98–3.75 (m, 2H), 1.94–1.73 (m, 2H), 1.69–1.53 (m, 2H), 1.49–1.31 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H), 0.88 (t, J = 7.4 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 194.8, 172.2, 141.6, 136.0,128.1, 123.4, 120.7, 114.9, 82.7, 42.8, 34.4, 29.1, 19.9, 13.7, 7.2. HRMS(ESI): m / z calcd. for C 15 H 19 NO3Na[M + Na] + 284.1257, found 284.1264. 3-Propyl-3-ethyl-3-hydroxy-6-(thien-2-yl)quinoline-2,4(1 H ,3 H )-Diketone (2l)

[0028] Yellow solid (yield: 53%, column chromatography eluent: petroleum ether: ethyl acetate = 2:1), mp 94–95 °C. 1 HNMR (600 MHz, CDCl3) δ 8.15 (d, J = 2.1 Hz, 1H), 7.84 (dd, J = 8.6, 2.2 Hz, 1H),7.55–7.48 (m, 1H), 7.46–7.37 (m, 2H), 7.15 (d, J = 8.6 Hz, 1H), 4.14–4.03 (m,1H), 3.97–3.80 (m, 2H), 1.97–1.82 (m, 2H), 1.79–1.65 (m, 2H), 1.01 (t, J = 7.4Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 194.9, 172.2,140.4, 139.7, 133.6, 131.5, 126.9, 125.7, 125.5, 121.1, 120.8, 115.6, 82.8,44.7, 34.6, 20.5, 11.1, 7.3.HRMS (ESI): m / z calcd. for C 18 H 19 NO3SNa[M + Na] + 352.0978, found 352.0986. 3-Ethyl-3-hydroxyquinoline-2,4(1 H ,3 H )-Diketone (2m)

[0029] White solid (yield: 53%, column chromatography eluent: petroleum ether: ethyl acetate = 2:1), mp 170–171 °C. 1 H NMR (600 MHz, MeOD) δ 7.82 (dd, J = 7.8, 1.0 Hz, 1H), 7.65–7.51 (m, 1H),7.15 (t, J = 7.3 Hz, 1H), 7.05 (d, J = 8.1 Hz, 1H), 3.31 (s, 1H), 1.96–1.89 (m,1H), 1.88–1.78 (m, 1H), 0.92 (t, J = 7.4 Hz, 3H). 13 C NMR (151 MHz, MeOD) δ197.8, 175.0, 142.7, 137.3, 128.2, 124.3, 120.8, 117.34, 84.1, 34.8, 7.7. HRMS (ESI): m / z calcd. for C 11 H 11 NO3Na[M + Na] + 228.0631, found 228.0630. Example 2: The method for preparing 3-hydroxylated quinoline-2,4-dione compounds according to the present invention is not limited to the above method; taking product 2n as an example... 1. Add N-o-cyanoarylacrylamide compound (0.2 mmol), ammonium persulfate oxidant (1 mmol), and acetone-hexafluoroisopropanol-tetrahydrofuran mixed solvent (volume ratio 1:2:3, 3 mL) to a 15 mL pressure-resistant tube. Then, stir the reaction mixture in air at 110 °C for 12 hours. After the reaction is complete, concentrate the reaction mixture and separate it by silica gel column chromatography to obtain the target product 2n in 20% yield.

[0030] 2. Add N-o-cyanoarylacrylamide compound (0.2 mmol), oxidant Oxone (1 mmol), and solvent acetone-isopropanol-tetrahydrofuran (volume ratio 1:2:3, 3 mL) or acetone-N,N-dimethylformamide-tetrahydrofuran (volume ratio 1:2:3, 3 mL) to a 15 mL pressure-resistant tube. Then, stir the reaction mixture in air at 110 °C for 12 hours. After the reaction is complete, concentrate the reaction mixture and then separate and purify it by silica gel column chromatography to obtain the target product 2n, with yields of 22% and 38%, respectively.

[0031] 3. When the solvent is acetone or tetrahydrofuran, the remaining operations are the same as in step 2, and the yields of target product 2n are 13% and 11%, respectively.

[0032] 4. Add N-o-cyanoarylacrylamide compound (0.2 mmol), oxidant Oxone (1 mmol), and solvent acetone-hexafluoroisopropanol-tetrahydrofuran (volume ratio 1:2:3, 3 mL) to a 15 mL pressure-resistant tube. Then, stir the reaction mixture for 12 hours under air atmosphere and 90 °C. After the reaction is complete, concentrate the reaction mixture and separate it by silica gel column chromatography. The yield of the target product 2n is 54%. 3-Ethyl-3-hydroxy-1-methylquinoline-2,4(1 H ,3 H )-Diketone(2n)

[0033] White solid (eluent for column chromatography: petroleum ether: ethyl acetate = 2:1), mp 139–141℃. 1 H NMR (600 MHz, CDCl3) δ 7.98 (d, J = 7.6 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H), 7.22 (t, J =7.5 Hz, 1H), 7.17 (d, J = 8.3 Hz, 1H), 3.91 (s, 1H), 3.49 (s, 3H), 1.60 (s, 3H). 13 C NMR (151 MHz, CDCl3) δ 195.0, 172.9, 142.5, 136.3, 128.2, 123.7,120.0, 115.09, 79.3, 30.3, 28.8. HRMS (ESI): m / z [M + Na] + calcd forC11 H 11 NO3Na, 228.0631; found, 228.0638. Example 3: Application Experiment (1) 1-Acetyl-3a,5-dimethylfurano[2,3-c]quinoline-2,4(3a) H 5 H The synthesis of 3-dione is as follows: In a 25 mL three-necked flask, compound 2n (123 mg, 0.6 mmol), 4 mL of toluene, and 0.2 mL of triethylamine (Et3N) were added. The mixture was heated to 60 °C, and diene (100.8 mg, 1.2 mmol) was slowly added. After the addition was complete, the temperature was raised to 70 °C and the reaction was carried out for 5 hours. The reaction progress was monitored by TLC. After the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure. The residue was separated by silica gel column chromatography using petroleum ether / ethyl acetate (v / v) as the eluent to obtain 141 mg of 1-acetyl-3a,5-dimethylfurano[2,3-c]quinoline-2,4(3a) H 5 H )-Diketone 3, the reaction equation is as follows:

[0034] Yellow solid (yield: 87%, column chromatography eluent: petroleum ether: ethyl acetate = 2:1), mp > 180℃. 1 HNMR (600 MHz, CDCl3) δ 8.40 (dd, J = 7.8, 1.5 Hz, 1H), 7.65–7.59 (m, 1H), 7.36–7.20 (m, 1H), 7.17 (d, J = 8.3 Hz, 1H), 3.43 (s, 3H), 2.60 (s, 3H), 1.67 (s, 3H). 13 C NMR (151 MHz, CDCl3) δ 193.9, 168.4, 165.9, 165.8, 139.5, 134.7,131.4, 123.8, 122.5, 116.8, 115.5, 83.1, 30.3, 30.3, 25.5. HRMS (ESI): m / z [M+ Na] + calcd for C 15 H 13 NO4Na, 294.0737; found, 294.0741. (2) 1,6-Dimethyl-3-thio-2,6-dihydroimidazo[1,5-c]quinazolin-5(3 H The synthesis of 4-keto-4 involves the following steps: A mixture of 2n (103 mg, 0.5 mmol) and ammonium thiocyanate (291 mg, 3 mmol) in acetic acid (1.5 mL) was heated under reflux for 7 hours. The reaction progress was monitored by thin-layer chromatography (TLC). After the reaction was completed, the mixture was cooled to room temperature and then poured onto ice. It was extracted with ethyl acetate, and the extract was washed successively with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography using petroleum ether-ethyl acetate (v / v 2:1) as the eluent to obtain 64 mg of 1,6-dimethyl-3-thio-2,6-dihydroimidazo[1,5-c]quinazolin-5(3 H )-Ketone 4, the reaction equation is as follows:

[0035] Yellow liquid (yield: 52%, column chromatography eluent: petroleum ether / ethyl acetate = 2:1). 1 H NMR (600MHz, CDCl3) δ 7.52 (s, 1H), 7.49 (dd, J = 12.4, 4.4 Hz, 2H), 7.31 (d, J = 8.5Hz, 1H), 7.19 (t, J = 7.5 Hz, 1H), 3.72 (s, 3H), 2.25 (s, 3H). 13 C NMR (151 MHz, CDCl3) δ 162.9, 139.0, 135.6, 130.0, 129.2, 127.7, 125.4, 121.9, 120.7,113.8, 29.6, 17.7. HRMS (ESI): m / z [M + Na] + calcd for C 12 H 11 N3OSNa, 268.2892; found, 268.2887. (3) The synthesis of 3-hydroxy-1,3-dimethylindoline-2-one 5 is carried out in the following steps: 2n (103 mg, 0.5 mmol) was dissolved in 1.3 M potassium hydroxide aqueous solution and 6 mL toluene solution, and the mixture was refluxed in air for 0.5 h. After the reaction was complete, the mixture was cooled to room temperature, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography using petroleum ether-ethyl acetate (v / v) as the eluent to give 50 mg of 5-hydroxy-1,3-dimethylindolin-2-one. The reaction equation is as follows:

[0036] Yellow solid (yield: 56%, column chromatography eluent: petroleum ether / ethyl acetate = 2 / 1), mp 148-150℃. 1 H NMR (600 MHz, CDCl3) δ 7.41 (dd, J = 7.3, 0.7 Hz, 1H), 7.34–7.28 (m, 1H),7.13–7.05 m, 1H), 6.83 (d, J = 7.8 Hz, 1H), 3.68 (s, 1H), 3.18 (s, 3H), 1.60(s, 3H). 13 C NMR (151 MHz, CDCl3) δ 178.8, 142.7, 131.5, 129.5, 123.4, 123.2,108.5, 73.7, 26.2, 24.8; HRMS (ESI): m / z [M + Na] + calcd for C 10 H 11 NO2Na,200.0682; found, 200.0689. Although the embodiments of the present invention have been disclosed above, they are not limited to the applications listed in the specification and embodiments. The above description is only a part of the embodiments of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing a 3-hydroxylated quinoline-2,4-dione compound, characterized in that: In the presence of oxidant and solvent, N-o-cyanoarylacrylamide compounds were used as substrates and reacted with stirring at 80-120℃. The reaction products were separated and purified to obtain 3-hydroxylated quinoline-2,4-dione compounds. ； In the formula R 1 Selected from H, halogen, methyl, methoxy, thiophene heterocycle; R 2 Selected from H, butyl, benzyl, methyl, propyl, ethoxymethyl; R 3 Selected from benzyl, phenyl, methyl, and ethyl.

2. The method for preparing 3-hydroxylated quinoline-2,4-dione compounds according to claim 1, characterized in that: The oxidant is selected from potassium persulfate complex salt, ammonium persulfate, and the molar ratio of N-o-cyanoarylacrylamide compound to oxidant is 1:4-6.

3. The method for preparing 3-hydroxylated quinoline-2,4-dione compounds according to claim 1, characterized in that: The solvent is selected from acetone, tetrahydrofuran, acetone-hexafluoroisopropanol-tetrahydrofuran mixed solvent, acetone-isopropanol-tetrahydrofuran mixed solvent, and acetone-N,N-dimethylformamide-tetrahydrofuran mixed solvent.

4. The application of the 3-hydroxylated quinoline-2,4-dione compounds prepared by the method of claim 1 as organic synthesis intermediates.

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