Alkali-promoted 4-(1H)-quinolone derivative as well as synthesis method and application thereof

Abstract

The invention provides an alkali-promoted 4-(1H)-quinolone derivative and a synthetic method and application thereof, and the synthetic method comprises the following steps: step 1, adding a certain amount of an o-amino acetylenic ketone compound into a reaction container, then adding a ketone compound and an alkali catalyst in proportion, and then adding a reaction solvent; step 2, after the charging process in the step 1 is finished, sealing the reaction container, placing the reaction container under a certain temperature condition, and stirring and reacting for 1-24 hours; 3, after the reaction is finished, water is added for quenching, organic phases are extracted and combined, and a pure target product 4-(1H)-quinolones derivative is obtained through column separation. The synthesis method is simple and convenient to operate and has good universality.

Description

Technical Field

[0001] The present invention belongs to the technical field of 4-(1H)-quinolone derivatives and their synthesis, and particularly relates to an alkali-promoted 4-(1H)-quinolone derivative, its synthesis method and application. Background Art

[0002] Quinolones, also known as pyridonecarboxylic acids or pyridinonecarboxylic acids, are a class of synthetic antibacterial drugs containing the basic structure of 4-quinolone. The quinolone skeleton is widely present in antibiotics, anti-tumor drugs and bioactive natural products, showing various activities such as antibacterial, antiviral, anti-anxiety, anti-tumor, anti-angiogenesis, etc., and has received extensive attention from medicinal / synthetic and natural product chemists. The first 4-quinolone analogue to enter the market was the antibacterial drug nalidixic acid more than 50 years ago. Since then, 4-quinolone skeleton compounds with 6-fluoro and 3-carboxylic acid modifications have evolved into several generations of antibacterial drugs, and the most famous example is ciprofloxacin 1. Novel 3-substituted-4-quinolone derivatives, such as ivacaftor, marbofloxacin and etravirine, are drugs used to treat cystic fibrosis, veterinary and HIV infections (I).

[0003]

[0004] In addition to these synthetic quinolone drugs, it has been reported for many years that some 2-substituted-4-quinolone natural products have a wide range of biological activities. Among these quinolone alkaloids, 4-(1H)-quinolones are less common. Pseudances III-XII, graveoline and waltherione F containing the 4-quinolone skeleton are recently added compounds, which have attracted the attention of the synthetic chemistry community due to their good biological activities (II).

[0005]

[0006]

[0007] In view of the wide range of drug properties of N-substituted 4-quinolone drugs, many methods have been developed to obtain compounds containing this skeleton, including classical cyclization reactions (such as Conrad-Limpach, Niementowski and Camps) and various metal-catalyzed reactions, etc. Compared with the reports on the synthesis of N-substituted 4-quinolones, the direct synthesis of 2-substituted-4-(1H)-quinolone drugs is relatively less reported. Although there are already some methods for synthesizing 4-quinolone derivatives, some reaction conditions are often relatively harsh, the yields are not high, and some methods also have to use expensive catalysts, etc., which are not satisfactory. Therefore, there is an urgent need to develop a simple and effective new method for synthesizing 4-quinolone. Summary of the Invention

[0008] One of the objectives of the present invention is to provide an alkali-promoted 4-(1H)-quinolone derivative having a structure shown in Formula (I) or Formula (II):

[0009]

[0010] Wherein,

[0011] R 1 is hydrogen, chlorine or fluorine;

[0012] R 2 is phenyl, 4-methylphenyl, 4-bromophenyl, 3-fluorophenyl, 3-chlorophenyl or benzo[d][1,3]dioxol-5-yl;

[0013] R 3 is phenyl, 4-methylphenyl or 4-chlorophenyl;

[0014] R 4 is phenyl or cyano.

[0015] As a preferred embodiment, the alkali-promoted 4-(1H)-quinolone derivative includes the following compounds:

[0016]

[0017] Another objective of the present invention is to provide a synthesis method of the 4-(1H)-quinolone derivative as described above. In a certain amount of solvent, the starting material o-aminoynamide compound and the ketone compound are reacted under the action of an alkali catalyst to synthesize the 4-(1H)-quinolone derivative.

[0018] As a preferred embodiment, in Step 1, a certain amount of o-aminoynamide compound is first added to the reaction vessel, then the ketone compound and the alkali catalyst are added in proportion, and then the reaction solvent is added;

[0019] In Step 2, after the feeding process in Step 1 is completed, the reaction vessel is sealed and placed under stirring at a certain temperature for 1 - 24 h;

[0020] In Step 3, after the reaction is completed, water is added for quenching, the organic phase is extracted and combined, and the pure target product 4-(1H)-quinolone derivative is obtained by column separation.

[0021] As a preferred embodiment, in the above Step 1, the molar ratio of o-aminoynamide compound:ketone compound:alkali catalyst is 1:1 - 2:2.

[0022] As a preferred embodiment, the o-aminoynamide compound is an ynamide with an electron-withdrawing group or an electron-donating group attached to the benzene ring.

[0023] As a preferred embodiment, in the first step, the base catalyst is one of Cs2CO3 or t-BuOK.

[0024] As a preferred embodiment, in the first step, the reaction solvent is one of N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide.

[0025] As a preferred embodiment, in the first step, the ketone compound is 3-oxo-3-phenylpropanenitrile or 3-oxo-3-(p-tolyl)propanenitrile.

[0026] The third object of the present invention is to provide the application of the above-mentioned 4-(1H)-quinolone derivatives in the synthesis of the organic molecule graveoline.

[0027] To achieve the above object and solve the above problems existing in the prior art, for the 4-(1H)-quinolone derivatives prepared by the raw materials and methods of the present invention, the reaction mechanism is illustrated as follows: The present invention uses o-aminoynamones and benzoylacetonitriles as raw materials, and undergoes an intramolecular nucleophilic addition reaction under the action of a base to generate an allene intermediate A. Intermediate A undergoes an intramolecular nucleophilic attack to generate a four-membered ring intermediate B. Under the action of ring strain, the four-membered ring opens to generate an eight-membered ring intermediate C. Intermediate C undergoes an intramolecular nucleophilic addition to obtain intermediate D, and finally D dehydrates to generate the end product 1-3a. The reaction mechanism process is shown in the following formula:

[0028]

[0029] The present invention has the following beneficial effects:

[0030] First, the 4-(1H)-quinolone derivatives synthesized by the present invention have potential biological activities; there are carbonyl, cyano and N-H in the products, which can be used as organic synthesis intermediates.

[0031] Second, the present invention optimizes the synthesis process of 4-(1H)-quinolone derivatives. The raw materials used are simple and easily available; the synthesis process system only needs a cheap base to promote the reaction, which is more green and economical; and this synthesis process reaction can be carried out at room temperature, and the method is easy to operate; this method has good generality. By strictly controlling the process and process parameters, substrates with electron-donating or electron-withdrawing groups can all obtain 4-(1H)-quinolone derivatives in good yields. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 It is the structural general formula of the 4-(1H)-quinolone derivatives in the present invention;

[0033] Figure 2 It is the reaction general formula of the 4-(1H)-quinolone derivatives in the present invention;

[0034] Figure 3 Schematic diagram of the reaction mechanism in the present invention;

[0035] Figure 4 1H NMR spectrum of product 1-3a in Example 1 of the present invention;

[0036] Figure 5 13C NMR spectrum of product 1-3a in Example 1 of the present invention;

[0037] Figure 6 1H NMR spectrum of product 1-3b in Example 8 of the present invention;

[0038] Figure 7 13C NMR spectrum of product 1-3b in Example 8 of the present invention;

[0039] Figure 8 1H NMR spectrum of product 1-3c in Example 9 of the present invention;

[0040] Figure 9 13C NMR spectrum of product 1-3c in Example 9 of the present invention;

[0041] Figure 10 1H NMR spectrum of product 1-3d in Example 10 of the present invention;

[0042] Figure 11 13C NMR spectrum of product 1-3d in Example 10 of the present invention;

[0043] Figure 12 1H NMR spectrum of product 1-3e in Example 11 of the present invention;

[0044] Figure 13 1H NMR spectrum of product 1-3f in Example 12 of the present invention;

[0045] Figure 14 13C NMR spectrum of product 1-3f in Example 12 of the present invention;

[0046] Figure 15 1H NMR spectrum of product 1-3g in Example 13 of the present invention;

[0047] Figure 16 13C NMR spectrum of product 1-3g in Example 13 of the present invention; Detailed implementation manners

[0048] To make the technical means, creative features, achieved purposes and beneficial effects of the present invention easy to understand, the present invention will be further described below in conjunction with specific implementation manners.

[0049] In addition, for better illustration of the present invention, numerous specific details are provided in the following specific embodiments. Those skilled in the art should understand that the present invention can still be implemented without some of these specific details. In some other embodiments, methods, means, equipment, and steps well-known to those skilled in the art are not described in detail to highlight the gist of the present invention.

[0050] The present invention provides a 4-(1H)-quinolone derivative having a structure shown in Formula (I) or Formula (II):

[0051]

[0052] Wherein;

[0053] R 1 is hydrogen, chlorine or fluorine;

[0054] R 2 is phenyl, 4-methylphenyl, 4-bromophenyl, 3-fluorophenyl, 3-chlorophenyl or benzo[d][1,3]dioxol-5-yl;

[0055] R 3 is phenyl, 4-methylphenyl or 4-chlorophenyl;

[0056] R 4 is phenyl or cyano.

[0057] The specific preparation steps of the above-mentioned 4-(1H)-quinolone derivative are as follows: Using a Schlenk tube as the reaction device, first add an o-aminoynamide compound, then add a ketone compound, and then add a catalyst; the catalyst can be selected from one of K2CO3, Cs2CO3 or t-BuOK; preferably, Cs2CO3 is selected; then add a reaction solvent, which is one of N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile or dimethyl sulfoxide, preferably dimethyl sulfoxide. After the addition is completed, seal the reaction tube and stir the reaction at room temperature or under the condition of 100 °C for 1-24 h, preferably for 1-3 h at room temperature. After the reaction is completed, add water to quench the reaction, extract with ethyl acetate three or more times, combine the organic phases, dry with anhydrous sodium sulfate, rotary evaporate, and separate by column chromatography to obtain a pure product. The reaction formula is shown in Formula (III) below:

[0058]

[0059] Wherein, R 1 is hydrogen, chlorine or fluorine;

[0060] R 2 is phenyl, 4-methylphenyl, 4-bromophenyl, 3-fluorophenyl, 3-chlorophenyl or benzo[d][1,3]dioxol-5-yl;

[0061] R3 is phenyl, 4-methylphenyl or 4-chlorophenyl;

[0062] R 4 is phenyl or cyano.

[0063] Preferably, the molar ratio of the ortho-aminopropargyl ketone compound: the ketone compound: the base catalyst is 1:1 - 2:2.

[0064] Example 1

[0065]

[0066] Using a Schlenk tube as the reaction device, first add 0.3 mmol of 1-(2-aminophenyl)-3-(p-tolyl)prop-2-yn-1-one and 0.36 mmol of 3-oxo-3-phenylpropanenitrile, then add 0.6 mmol of the catalyst Cs2CO3, and then add 3 ml of the dry reaction solvent dimethyl sulfoxide. After the addition, seal the reaction tube and stir at room temperature for 1 h. After the reaction, quench the reaction with water, extract three times with 10 ml of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, rotary evaporate, and column chromatograph with petroleum ether: ethyl acetate = 2:1 to obtain the target product (1-3a), a light yellow solid, 79.0 mg, Z:E = 2:3, with a separation yield of 73%.

[0067] NMR data: 1 H NMR (400 MHz, DMSO-d6) δ 2.27 (s, 2H), 2.30 (s, 3H), 5.70 (s, 1H), 6.30 (s, 1H), 7.06 - 7.09 (m, 1H), 7.14 - 7.17 (m, 2H), 7.20 - 7.22 (m, 1H), 7.38 - 7.44 (m, 10H), 7.70 - 7.72 (m, 1H), 7.74 - 7.76 (m, 1H), 7.83 - 7.86 (m, 1H), 8.11 - 8.14 (m, 2H), 12.05 (s, 1H), 12.11 (s, 1H); 13 C NMR (100 MHz, DMSO-d6) δ 174.5, 157.1, 150.1, 149.5, 139.9, 138.8, 134.3, 133.9, 132.2, 129.8, 129.6, 129.2, 128.7, 128.6, 128.2, 127.8, 126.8, 125.1, 124.5, 124.3, 123.8, 118.7, 116.7, 99.0, 98.2.

[0068] Example 2

[0069]

[0070] Using a Schlenk tube as the reaction device, first add 0.3 mmol of 1-(2-aminophenyl)-3-(p-tolyl)prop-2-yn-1-one and 0.30 mmol of 3-oxo-3-phenylpropanenitrile, then add 0.6 mmol of the catalyst Cs2CO3, and then add 3 ml of the dry reaction solvent dimethyl sulfoxide. After the addition is completed, seal the reaction tube and stir at room temperature for 1 h. After the reaction is completed, quench the reaction with water, extract three times with 10 ml of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, evaporate by rotary evaporation, and column chromatograph with petroleum ether:ethyl acetate = 2:1 to obtain the target product (1-3a), a light yellow solid, 73.3 mg, with a separation yield of 68%.

[0071] Example 3

[0072]

[0073] Using a Schlenk tube as the reaction device, first add 0.3 mmol of 1-(2-aminophenyl)-3-(p-tolyl)prop-2-yn-1-one and 0.45 mmol of 3-oxo-3-phenylpropanenitrile, then add 0.6 mmol of the catalyst Cs2CO3, and then add 3 ml of the dry reaction solvent dimethyl sulfoxide. After the addition is completed, seal the reaction tube and stir at room temperature for 1.5 h. After the reaction is completed, quench the reaction with water, extract three times with 10 ml of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, evaporate by rotary evaporation, and column chromatograph with petroleum ether:ethyl acetate = 2:1 to obtain the target product (1-3a), a light yellow solid, 96.9 mg, with a separation yield of 89%.

[0074] Example 4

[0075]

[0076] Using a Schlenk tube as the reaction device, first add 0.3 mmol of 1-(2-aminophenyl)-3-(p-tolyl)prop-2-yn-1-one and 0.60 mmol of 3-oxo-3-phenylpropanenitrile, then add 0.6 mmol of the catalyst Cs2CO3, and then add 3 ml of the dry reaction solvent dimethyl sulfoxide. After the addition is completed, seal the reaction tube and stir at room temperature for 1 h. After the reaction is completed, quench the reaction with water, extract three times with 10 ml of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, evaporate by rotary evaporation, and column chromatograph with petroleum ether:ethyl acetate = 2:1 to obtain the target product (1-3a), a light yellow solid, 92.2 mg, with a separation yield of 85%.

[0077] Example 5

[0078]

[0079] Using a Schlenk tube as the reaction apparatus, first add 0.3 mmol of 1-(2-aminophenyl)-3-(p-tolyl)prop-2-yn-1-one and 0.36 mmol of 3-oxo-3-phenylpropanenitrile, then add 0.6 mmol of the catalyst t-BuOK, and then add 3 ml of the dry reaction solvent dimethyl sulfoxide. After the addition is completed, seal the reaction tube and stir at room temperature for 1 h. After the reaction is completed, quench the reaction with water, extract three times with 10 ml of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, evaporate by rotary evaporation, and column chromatograph with petroleum ether:ethyl acetate = 2:1 to obtain the target product (1-3a), a light yellow solid, 32.3 mg, with a separation yield of 30%.

[0080] Example 6

[0081]

[0082] Using a Schlenk tube as the reaction apparatus, first add 0.3 mmol of 1-(2-aminophenyl)-3-(p-tolyl)prop-2-yn-1-one and 0.36 mmol of 3-oxo-3-phenylpropanenitrile, then add 0.6 mmol of the catalyst Cs2CO3, and then add 3 ml of the dry reaction solvent N,N-dimethylformamide. After the addition is completed, seal the reaction tube and stir at room temperature for 3 h. After the reaction is completed, quench the reaction with water, extract three times with 10 ml of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, evaporate by rotary evaporation, and column chromatograph with petroleum ether:ethyl acetate = 2:1 to obtain the target product (1-3a), a light yellow solid, 38.3 mg, with a separation yield of 35%.

[0083] Example 7

[0084]

[0085] Using a Schlenk tube as the reaction apparatus, first add 0.3 mmol of 1-(2-aminophenyl)-3-(p-tolyl)prop-2-yn-1-one and 0.36 mmol of 3-oxo-3-phenylpropanenitrile, then add 0.6 mmol of the catalyst Cs2CO3, and then add 3 ml of the dry reaction solvent N,N-dimethylacetamide. After the addition is completed, seal the reaction tube and stir at room temperature for 3 h. After the reaction is completed, quench the reaction with water, extract three times with 10 ml of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, evaporate by rotary evaporation, and column chromatograph with petroleum ether:ethyl acetate = 2:1 to obtain the target product (1-3a), a light yellow solid, 20.9 mg, with a separation yield of 19%.

[0086] Example 8

[0087]

[0088] Using a Schlenk tube as the reaction device, first add 0.3 mmol of 1-(2-aminophenyl)-3-(p-tolyl)prop-2-yn-1-one and 0.45 mmol of 3-oxo-3-(p-tolyl)propanenitrile, then add 0.6 mmol of the catalyst Cs2CO3, and then add 3 ml of the dry reaction solvent dimethyl sulfoxide. After the addition is completed, seal the reaction tube and stir at room temperature for 1.5 h. After the reaction is completed, quench the reaction with water, extract three times with 10 ml of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, rotary evaporate, and column chromatograph with petroleum ether:ethyl acetate = 2:1 to obtain the target product (1-3b), a light yellow solid, 92.3 mg, Z:E = 1:1.3, with a separation yield of 82%.

[0089] NMR data: 1 H NMR(400MHz,DMSO-d6)δ2.27(s,3H),2.31(s,3H),2.31(s,3H),2.33(s,3H),5.66(s,1H),6.29(s,1H),6.90-6.93(m,1H),7.07-7.10(m,1H),7.14-7.17(m,2H),7.21-7.26(m,6H),7.28-7.33(m,5H),7.36-7.42(m,5H),7.69-7.76(m,5H),8.07-8.12(m,2H),11.96(s,1H),12.03(s,1H); 13 C NMR(100MHz,DMSO-d6)δ174.5,174.4,157.8,150.0,149.5,140.0,139.9,139.6,139.5,139.3,138.9,135.4,134.3,132.2,131.4,131.1,129.2,128.7,128.7,128.6,128.6,128.1,127.8,126.8,125.2,125.1,124.5,124.2,123.7,119.3,118.6,118.6,118.2,116.6,98.9,98.0,20.9,20.8.

[0090] Example 9

[0091]

[0092] Using a Schlenk tube as the reaction device, first add 0.3 mmol of 1-(2-amino-5-fluorophenyl)-3-phenylprop-2-yn-1-one and 0.45 mmol of 3-oxo-3-phenylpropanenitrile, then add 0.6 mmol of the catalyst Cs2CO3, and then add 3 ml of the dry reaction solvent dimethyl sulfoxide. After the addition is completed, seal the reaction tube and stir at room temperature for 1.5 h. After the reaction is completed, quench the reaction with water, extract three times with 10 ml of ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, rotary evaporate, and column chromatograph with petroleum ether:ethyl acetate = 2:1 to obtain the target product (1-3c), a light yellow solid, 71.2 mg, Z:E = 1:5, and the separation yield is 65%.

[0093] Nuclear magnetic data: 1 H NMR(400MHz,DMSO-d6)δ5.82(s,0.2H),6.37(s,1H),7.23-7.27(m,1H),7.30-7.34(m,1H),7.34-7.37(m,1H),7.37-7.42(m,5H),7.42-7.45(m,1H),7.46-7.49(m,2H),7.64-7.71(m,1H),7.74-7.79(m,1H),7.81-7.85(m,1H),12.22(s,0.2H),12.29(s,1H); 13 C NMR(100MHz,DMSO-d6)δ173.7,159.9,157.5,157.4,149.8,137.0,136.6,133.7,130.1,130.0,128.7,128.6,128.2,128.2,128.0,127.9,126.9,125.4,121.6,121.6,121.3,121.1,118.2,116.0,109.3,109.1,99.5.

[0094] Example 10

[0095]

[0096] Using a Schlenk tube as the reaction device, first add 0.3 mmol of 1-(2-aminophenyl)-3-(4-bromophenyl)prop-2-yn-1-one and 0.45 mmol of 3-oxo-3-phenylpropanenitrile, then add 0.6 mmol of the catalyst Cs2CO3, and then add 3 ml of the dry reaction solvent dimethyl sulfoxide. After the addition is completed, seal the reaction tube and stir at room temperature for 1.5 h. After the reaction is completed, quench the reaction with water, extract three times with 10 ml of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, evaporate by rotary evaporation, and column chromatograph with petroleum ether:ethyl acetate = 2:1 to obtain the target product (1-3d), a light yellow solid, 90.7 mg, Z:E = 1:3, and the separation yield is 71%.

[0097] Nuclear magnetic data: 1 H NMR (400 MHz, DMSO-d6) δ 5.81 (s, 0.4H), 5.85 (s, 1H), 7.24 - 7.26 (m, 1H), 7.38 - 7.41 (m, 4H), 7.43 - 7.44 (m, 2H), 7.45 - 7.46 (m, 1H), 7.69 - 7.71 (m, 2H), 7.71 - 7.73 (m, 1H), 7.74 - 7.76 (m, 1H), 8.11 - 8.14 (m, 2H), 12.06 (s, 0.3H), 12.11 (s, 1H); 13 C NMR (100 MHz, DMSO-d6) δ 174.3, 155.8, 150.6, 139.4, 134.2, 132.3, 131.0, 129.9, 129.7, 128.8, 128.3, 128.0, 127.9, 125.3, 124.6, 124.0, 122.3, 118.7, 118.7, 100.4.

[0098] Example 11

[0099]

[0100] Using a Schlenk tube as the reaction device, first add 0.3 mmol of 1-(2-aminophenyl)-3-(p-tolyl)prop-2-yn-1-one and 0.45 mmol of 3-oxo-3-phenylpropanenitrile, then add 0.6 mmol of the catalyst Cs2CO3, and then add 3 ml of the dry reaction solvent dimethyl sulfoxide. After the addition is completed, seal the reaction tube and stir at 100 °C for 1.5 h. After the reaction is completed, quench the reaction with water, extract three times with 10 ml of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, evaporate by rotary evaporation, and column chromatograph with petroleum ether:ethyl acetate = 2:1 to obtain the target product (1-3e), a light yellow solid, 58.4 mg, and the separation yield is 83%.

[0101] Nuclear magnetic data:1 1H NMR (400 MHz, DMSO-d6) δ 2.41 (s, 3H), 6.32 (s, 1H), 7.30 - 7.35 (m, 1H), 7.39 - 7.41 (m, 2H), 7.64 - 7.69 (m, 1H), 7.73 - 7.78 (m, 3H), 8.07 - 8.10 (m, 1H), 11.63 (s, 1H).

[0102] Example 12

[0103]

[0104] Using a Schlenk tube as the reaction device, first add 0.3 mmol of 1-(2-aminophenyl)-3-(3-chlorophenyl)prop-2-yn-1-one and 0.45 mmol of 3-oxo-3-phenylpropanenitrile, then add 0.6 mmol of the catalyst Cs2CO3, and then add 3 ml of the dry reaction solvent dimethyl sulfoxide. After the addition is completed, seal the reaction tube and stir at 100 °C for 1.5 h. After the reaction is completed, quench the reaction with water, extract three times with 10 ml of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, rotary evaporate, and column chromatograph with petroleum ether:ethyl acetate = 2:1 to obtain the target product (1-3f), a light yellow solid, 56.1 mg, with a separation yield of 73%.

[0105] NMR data: 1 1H NMR (400 MHz, DMSO-d6) δ 6.38 (s, 1H), 7.33 - 7.37 (m, 1H), 7.59 - 7.71 (m, 3H), 7.73 - 7.77 (m, 1H), 7.80 - 7.82 (m, 1H), 7.93 (s, 1H), 8.09 - 8.15 (m, 1H), 11.75 (s, 1H); 13 13C NMR (100 MHz, DMSO-d6) δ 170.3, 133.7, 131.9, 130.9, 130.2, 127.1, 126.3, 124.7, 123.4, 118.7, 107.7.

[0106] Example 13

[0107]

[0108] Using a Schlenk tube as the reaction device, first add 0.3 mmol of 1-(2-aminophenyl)-3-(benzo[d][1,3]dioxol-5-yl)prop-2-yn-1-one and 0.45 mmol of 3-oxo-3-phenylpropanenitrile, then add 0.6 mmol of the catalyst Cs2CO3, and then add 3 ml of the dry reaction solvent dimethyl sulfoxide. After the addition is completed, seal the reaction tube and stir at 100 °C for 1.5 h. Then add 0.3 mmol of NaH and 0.6 mmol of iodomethane to the above Schlenk tube and stir at room temperature for 2 h. After the reaction is completed, quench the reaction with water, extract three times with 10 ml of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, evaporate by rotary evaporation, and column chromatograph with petroleum ether:ethyl acetate = 5:1 to obtain the target product (1 - 3 g). 1 - 3 g is the known graveoline, a light yellow solid, 52.6 mg, with a separation yield of 63%.

[0109] NMR data: 1 1H NMR (400 MHz, CDCl3) δ 3.63 (s, 1H), 6.07 (s, 2H), 6.28 (s, 1H), 6.85 - 6.93 (m, 3H), 7.38 - 7.43 (m, 1H), 7.53 - 7.56 (m, 1H), 7.68 - 7.73 (m, 1H), 8.47 - 8.50 (m, 1H); 13 13C NMR (100 MHz, CDCl3) δ 177.5, 154.3, 148.7, 147.9, 141.9, 132.3, 129.4, 126.8, 126.7, 123.6, 122.7, 116.0, 112.6, 109.0, 108.6, 101.7, 37.3.

[0110] Comparative Example 1

[0111]

[0112] Using a Schlenk tube as the reaction device, first add 0.3 mmol of 1-(2-aminophenyl)-3-(p-tolyl)prop-2-yn-1-one and 0.36 mmol of 3-oxo-3-phenylpropanenitrile, then add 0.6 mmol of the catalyst K2CO3, and then add 3 ml of the dry reaction solvent dimethyl sulfoxide. After the addition is completed, seal the reaction tube and stir at room temperature for 24 h. After the reaction is completed, detect the reaction and only obtain a trace amount of the target product of Formula 1-3a.

[0113] Comparative Example 2

[0114]

[0115] Using a Schlenk tube as the reaction device, first add 0.3 mmol of 1-(2-aminophenyl)-3-(p-tolyl)prop-2-yn-1-one and 0.36 mmol of 3-oxo-3-phenylpropanenitrile, then add 0.6 mmol of the catalyst DABCO, and then add 3 ml of the dry reaction solvent dimethyl sulfoxide. After the addition is completed, seal the reaction tube and stir at room temperature for 24 h. After the reaction is completed, detect the reaction. No reaction occurred and the target product 1-3a was not obtained.

[0116] Comparative Example 3

[0117]

[0118] Using a Schlenk tube as the reaction device, first add 0.3 mmol of 1-(2-aminophenyl)-3-(p-tolyl)prop-2-yn-1-one and 0.36 mmol of 3-oxo-3-phenylpropanenitrile, then add 0.6 mmol of the catalyst Cs2CO3, and then add 3 ml of the dry reaction solvent acetonitrile. After the addition is completed, seal the reaction tube and stir at room temperature for 23 h. After the reaction is completed, detect the reaction. Only a trace amount of the target product 1-3a was obtained.

[0119] As described above, it is only the preferred embodiments of the present invention, and there is no limitation to the present invention in any form. Although the present invention has been disclosed above with the preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some changes or modifications to equivalent embodiments by using the disclosed technical content within the scope of the technical solution of the present invention. However, as long as it does not depart from the content of the technical solution of the present invention, any simple modification, equivalent change and modification made to the above embodiments according to the technical essence of the present invention still fall within the scope of the technical solution of the present invention.

Claims

1. A base-promoted 4-(1H)-quinolone derivative, characterized in that: Having a structure as shown in formula (I) or formula (II): in, R 1 is hydrogen, chlorine or fluorine; R 2 is phenyl, 4-methylphenyl, 4-bromophenyl, 3-fluorophenyl, 3-chlorophenyl or phenyldioxolane; R 3 is phenyl, 4-methylphenyl or 4-chlorophenyl; R 4 is phenyl or cyano.

2. A base-promoted 4-(1H)-quinolone derivative according to claim 1, characterized in that: These compounds include:

3. A method for synthesizing a 4-(1H)-quinolone derivative according to claim 1 or 2, characterized in that: In a certain amount of solvent, raw materials o-amino alkynyl ketone compounds and ketone compounds are synthesized under the action of a base catalyst to obtain the 4-(1H)-quinolone derivatives.

4. The method for synthesizing 4-(1H)-quinolone derivatives according to claim 3, characterized in that: Step 1: first add a certain amount of o-amino alkynyl ketone compound into a reaction vessel, then add a ketone compound and a base catalyst in proportion, and then add a reaction solvent; After the addition process of step 2 and step 1 is completed, the reaction vessel is sealed and placed at a certain temperature for stirring and reacting for 1-24 hours; Step 3: After the reaction is completed, water is added to quench the mixture, and the organic phases are extracted and combined, and then separated by column to obtain the pure target product 4-(1H)-quinolone derivatives.

5. A method for synthesizing a 4-(1H)-quinolone derivative according to claim 3 or 4, characterized in that: In the step 1, the molar ratio of the o-amino alkynyl ketone compound: the ketone compound: the base catalyst is 1:1-2:

2.

6. A method for synthesizing a 4-(1H)-quinolone derivative according to claim 3 or 4, characterized in that: The o-amino alkynone compound is an alkynone with an electron-withdrawing group connected to the benzene ring or an alkynone with an electron-donating group connected to the benzene ring.

7. A method for synthesizing a 4-(1H)-quinolone derivative according to claim 3 or 4, characterized in that: In the step 1, the base catalyst is one of Cs2CO3 or t-BuOK.

8. A method for synthesizing a 4-(1H)-quinolone derivative according to claim 3 or 4, characterized in that: In the step 1, the reaction solvent is one of N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide.

9. A method for synthesizing a 4-(1H)-quinolone derivative according to claim 3 or 4, characterized in that: In the step 1, the ketone compound is 3-oxo-3-phenylpropionitrile or 3-oxo-3-(p-tolyl)propionitrile.

10. Use of the 4-(1H)-quinolone derivative according to claim 1 or 2 in the synthesis of the organic molecule graveoline.

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