A method for synthesizing quinoline compounds
Quinoline compounds are synthesized in an organic solvent through a [4+2] cyclization reaction, which solves the problem of the participation of catalysts and acid-base reagents in the existing technology and achieves high-yield and low-cost synthesis of quinoline compounds.
Patent Information
- Application Number
- CN202411450924.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-17
- Publication Date
- 2025-09-30
- Estimated Expiration
- 2044-10-17
AI Technical Summary
The existing synthesis methods of quinoline compounds involve catalysts and acid-base reagents, resulting in harsh reaction conditions, a narrow scope of application, and high costs.
The [4+2] cyclization reaction is carried out in an organic solvent. Compound 1 and compound 2 react to generate an intermediate, which is then dehydrated to obtain the target product. A green synthesis route without catalysts and acid-base reagents is used, and the purification method is column chromatography.
The method achieves high-yield synthesis of quinoline compounds, has mild reaction conditions, readily available and inexpensive raw materials, and has a wide range of applications.
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Figure CN119330879B_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to a method for synthesizing a compound, in particular to a method for synthesizing a quinoline compound. Background Art
[0002] Quinoline compounds are widely found in natural products and synthetic drugs with a broad spectrum of biological activities and have attracted widespread attention. Quinoline and its derivatives have demonstrated certain biological activities in antimalarial, anticancer, antioxidant, anti-inflammatory, and anti-SARS-CoV-2 activities. Current methods for synthesizing quinoline include the use of 2-aminoaryl ketones and N,N-dimethylenamine enamine in the presence of p-toluenesulfonic acid as a catalyst, or the use of zinc chloride as a catalyst. These methods have drawbacks such as a narrow scope of application, the requirement of acid, base, or metal in the reaction conditions, and the use of expensive catalysts. Summary of the Invention
[0003] Purpose of the invention: The purpose of the present invention is to provide a method for synthesizing quinoline compounds without the participation of catalysts and acid-base reagents and with green and mild reaction conditions.
[0004] Technical solution: The method for synthesizing quinoline compounds of the present invention comprises the following steps: Compound 1 and Compound 2 undergo a [4+2] cyclization reaction in an organic solvent at 90-110°C, and the target quinoline compound is obtained after purification. The synthetic route is as follows:
[0005]
[0006] Wherein, R is H, halogen, -OC 1-3 Any one of them.
[0007] Enaminone generates an intermediate under high temperature conditions, and then the intermediate reacts with reactant 1 to obtain a new intermediate, which then undergoes intermolecular cyclization and dehydration to obtain the target product.
[0008] Preferably, the molar ratio of compound 2 to compound 1 is 1:1.1-2.
[0009] Preferably, the solvent for the reaction is dimethyl sulfoxide, dichloromethane or ethanol.
[0010] Preferably, the purification method is: separation by column chromatography, wherein the column chromatography solid phase is column chromatography silica gel, and the mobile phase is a mixture of petroleum ether and ethyl acetate.
[0011] Preferably, the volume ratio of petroleum ether to ethyl acetate is 1 to 10:1.
[0012] Preferably, the synthesis method of compound 1 is:
[0013] (1) The carbonyl group of compound 3 undergoes a reduction reaction in ethanol to a hydroxyl group. After the reaction is completed, the reaction is quenched with water and extracted to obtain compound 4;
[0014] (2) Compound 4 and triphenylphosphine hydrobromide undergo a substitution reaction to obtain compound 1. The synthetic route is as follows:
[0015]
[0016] Preferably, in step (1), the reducing agent for the reduction reaction is sodium borohydride, and sodium borohydride is first added at -10 to 10°C, and then the temperature is raised to 60 to 100°C for reaction.
[0017] Preferably, in step (2), during the substitution reaction, the reaction temperature is 60-100°C.
[0018] Preferably, in the reduction reaction of step (1), the purification method of compound 4 is: extraction with ethyl acetate.
[0019] Preferably, the synthesis method of compound 2 is: compound 5 and compound 6 undergo a substitution reaction to obtain compound 2. The synthesis route is as follows:
[0020]
[0021] Preferably, the reaction temperature is 80-120°C.
[0022] Preferably, the solvent for the reaction is toluene.
[0023] Preferably, the purification method of the compound 2 in the reaction is separation by column chromatography, wherein the column chromatography solid phase is column chromatography silica gel, and the mobile phase is a mixture of petroleum ether and ethyl acetate.
[0024] Reactants 5 and 6 were from Adams reagents purchased from the Discovery Platform.
[0025] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: (1) In the synthesis method, compound 2 and compound 2 react in one step, the reaction is green and does not require any additives or catalysts, and the reaction conditions are mild; (2) the raw materials of the reaction are easily available and inexpensive; (3) the substrate tolerance of the reaction is good; (4) the yield of the quinoline derivative obtained by the reaction is as high as more than 90%. BRIEF DESCRIPTION OF THE DRAWINGS
[0026] Figure 1 The reaction route of the synthesis method of the present invention;
[0027] Figure 2 H NMR spectrum of (4-methoxyphenyl)(4-phenylquinolin-3-yl)methanone synthesized in Example 1;
[0028] Figure 3 The C-NMR spectrum of (4-methoxyphenyl)(4-phenylquinolin-3-yl)methanone synthesized in Example 1;
[0029] Figure 4 H NMR spectrum of [1,1'-biphenyl]-4-yl(4-phenylquinolin-3-yl)methanone synthesized in Example 2;
[0030] Figure 5 The C-NMR spectrum of [1,1'-biphenyl]-4-yl(4-phenylquinolin-3-yl)methanone synthesized in Example 2;
[0031] Figure 6 H NMR spectrum of (4-chlorophenyl)(4-phenylquinolin-3-yl)methanone synthesized in Example 3;
[0032] Figure 7 C NMR spectrum of (4-chlorophenyl)(4-phenylquinolin-3-yl)methanone synthesized in Example 3;
[0033] Figure 8 H NMR spectrum of (4-bromophenyl)(4-phenyl-1,4-dihydroquinolin-3-yl)methanone synthesized in Example 4;
[0034] Figure 9 C NMR spectrum of (4-bromophenyl)(4-phenyl-1,4-dihydroquinolin-3-yl)methanone synthesized in Example 4;
[0035] Figure 10 H NMR spectrum of (4-fluorophenyl)(4-phenyl-1,4-dihydroquinolin-3-yl)methanone synthesized in Example 5;
[0036] Figure 11 C NMR spectrum of (4-fluorophenyl)(4-phenyl-1,4-dihydroquinolin-3-yl)methanone synthesized in Example 5. DETAILED DESCRIPTION
[0037] The technical solution of the present invention will be further described below in conjunction with embodiments.
[0038] Example 1
[0039] The quinoline compound of the present invention, wherein R is -OMe, has a chemical name of (4-methoxyphenyl)(4-phenylquinolin-3-yl)methanone, and has the following structure:
[0040]
[0041] The compound synthesis method comprises the following steps:
[0042] Step 1: Preparation of 2-[(bromotriphenyl-5-phosphino)phenylmethyl]aniline
[0043]
[0044] (1) 10 mmol of 2-aminobenzophenone was added to a 100 mL reaction flask, and 30 mL of ethanol was added to fully dissolve the mixture. 40 mmol (added in four portions, 10 mmol each time) of sodium borohydride was added at 0°C, and the temperature was raised to 70°C for reaction for 3 hours. After the reaction was completed, the mixture was quenched with water and extracted with ethyl acetate (50 mL x 3), and washed with saturated brine. After the reaction was completed, anhydrous sodium sulfate was added to dry the mixture, and the solvent was removed by rotary evaporation to obtain (2-aminophenyl)(phenyl)methanol.
[0045] (2) Transfer (2-aminophenyl)(phenyl)methanol to a 100 mL reaction flask, add 10 mmol of triphenylphosphine hydrobromide, use 30 mL of acetonitrile to fully dissolve the reactants, and reflux at 80°C for 12 hours. After the reaction, wash thoroughly with ether until the product turns white and air-dry.
[0046] The NMR data of this compound are: 1 H NMR(400MHz, DMSO-d6)δ7.92-7.87(m,3H),7.73(td,J=7.9,3.7Hz,7H),7.64(dd,J=12.0,7.5Hz,6H), 7.40-7.22(m,6H),7.06(t,J=7.6Hz,1H),6.79(d,J=8.2Hz,1H),6.67-6.56(m,2H),6.41-6.35(m,1H).
[0047] Step 2: Preparation of (E)-3-(dimethylamino)-1-(4-methoxyphenyl)prop-2-en-1-one
[0048]
[0049] In a 100 mL reaction flask, add p-methoxyacetophenone (16.6 mmol), N,N-dimethylformamide dimethyl acetal (49.9 mmol), and toluene (21.2 mL). Reflux for 48 hours. Cool to room temperature, evaporate the solvent, wash with petroleum ether, and air-dry.
[0050] The NMR data of this compound are: 1H NMR (400 MHz, CDCl 3 ) δ 7.90 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 12.4 Hz, 1H), 6.90 (d, J = 8.8 Hz, 2H), 5.70 (d, J = 12.4 Hz, 1H), 3.84 (s, 3H), 3.10 (s, 3H), 2.90 (s, 3H).
[0051] Step 3: Preparation of (4-methoxyphenyl)(4-phenylquinolin-3-yl)methanone
[0052]
[0053] 0.2 mmol of the product synthesized in the second step was dissolved in a Schlenk tube, 0.3 mmol of the compound prepared in the first step was added, and a stirring magnetic bar was added. Finally, 1 mL of dimethyl sulfoxide was added, and the reaction was carried out at 100° C. for 12 hours. After the reaction, the product was purified by column chromatography using a mixture of petroleum ether and ethyl acetate in a volume ratio of 10:1 as the eluent. The eluate containing the target product was collected and detected by TLC elution tracking. The target product eluates were combined and concentrated by evaporation to obtain (4-methoxyphenyl)(4-phenylquinolin-3-yl)methanone.
[0054] like Figure 2 The H NMR data of this compound are: 1H NMR (400 MHz, CDCl 3 ) δ 8.94 (s, 1H), 8.21 (d, J = 8.3 Hz, 1H), 7.80-7.75 (m, 2H), 7.63-7.59 (m, 2H), 7.52 (ddd, J = 8.3, 6.9, 1.2 Hz, 1H), 7.31-7.26 (m, 5H), 6.78-6.74 (m, 2H), 3.78 (s, 3H).
[0055] like Figure 3 , the NMR carbon spectrum data of the compound is: 13 CNMR(101MHz, CDCl3)δ195.2,163.9,148.8,148.5,146.7,135.1,132.4(d,J=9.9 Hz), 130.4, 130.1, 129.9, 128.6, 128.3, 127.5, 126.7 (d, J = 17.4Hz), 113.7, 55.6.
[0056] Example 2
[0057] The quinoline compound of the present invention, wherein R is Ph, has a chemical name of [1,1'-biphenyl]-4-yl (4-phenylquinolin-3-yl)methanone, and has the following structural formula:
[0058]
[0059] The compound synthesis method comprises the following steps:
[0060] Step 1: Preparation of 2-[(bromotriphenyl-5-phosphino)phenylmethyl]aniline
[0061]
[0062] (1) 10 mmol of 2-aminobenzophenone was added to a 100 mL reaction flask, and 30 mL of ethanol was added to fully dissolve the mixture. 40 mmol (added in four portions, 10 mmol each time) of sodium borohydride was added at 0°C, and the temperature was raised to 70°C for reaction for 3 hours. After the reaction was completed, the mixture was quenched with water and extracted with ethyl acetate (50 mL x 3), and washed with saturated brine. After the reaction was completed, anhydrous sodium sulfate was added to dry the mixture, and the solvent was removed by rotary evaporation to obtain (2-aminophenyl)(phenyl)methanol.
[0063] (2) Transfer (2-aminophenyl)(phenyl)methanol to a 100 mL reaction flask, add 10 mmol of triphenylphosphine hydrobromide, use 30 mL of acetonitrile to fully dissolve the reactants, and reflux at 80°C for 12 hours. After the reaction, wash thoroughly with ether until the product turns white and air-dry.
[0064] The NMR data of this compound are: 1 H NMR(400MHz, DMSO-d6)δ7.92-7.87(m,3H),7.73(td,J=7.9,3.7Hz,7H),7.64(dd,J=12.0,7.5Hz,6H), 7.40-7.22(m,6H),7.06(t,J=7.6Hz,1H),6.79(d,J=8.2Hz,1H),6.67-6.56(m,2H),6.41-6.35(m,1H).
[0065] Step 2: Preparation of (E)-1-([1,1'-biphenyl]-4-yl)-3-(dimethylamino)prop-2-en-1-one
[0066]
[0067] In a 100 mL reaction flask, add p-phenylacetophenone (16.6 mmol), N,N-dimethylformamide dimethyl acetal (49.9 mmol), and toluene (21.2 mL). Reflux for 48 hours. Cool to room temperature, evaporate the solvent, wash with petroleum ether, and air-dry.
[0068] The NMR data of this compound are: 1H NMR (400 MHz, CDCl 3 ) δ 7.99 (d, J = 8.0 Hz, 2H), 7.83 (d, J = 12.4 Hz, 1H), 7.67-7.61 (m, 4H), 7.45 (t, J = 7.5 Hz, 2H), 7.36 (t, J = 7.3 Hz, 1H), 5.76 (d, J = 12.4 Hz, 1H), 3.14 (s, 3H), 2.93 (s, 3H).
[0069] Step 3: Preparation of [1,1'-biphenyl]-4-yl (4-phenylquinolin-3-yl)methanone
[0070]
[0071] 0.2 mmol of the product synthesized in the second step was dissolved in a Schlenk tube, 0.3 mmol of the compound prepared in the first step was added, and a stirring magnetic bar was added. Finally, 1 mL of dimethyl sulfoxide was added, and the reaction was carried out at 100° C. for 15 hours. After the reaction, the product was purified by column chromatography using a mixture of petroleum ether and ethyl acetate in a volume ratio of 10:1 as the eluent. With the help of TLC elution tracking detection, the eluates containing the target product were collected, the target product eluates were combined, and evaporated and concentrated to obtain [1,1'-biphenyl]-4-yl(4-phenylquinolin-3-yl)methyl ketone.
[0072] like Figure 4 , the H NMR spectrum data of the compound is: 1 H NMR (400MHz, CDCl3) δ9.02 (s, 1H), 8.25 (d, J = 8.3Hz, 1H), 7.84-7.78 (m, 2H), 7.71-7.68 (m ,2H),7.58-7.50(m,5H),7.46-7.41(m,2H),7.40-7.35(m,1H),7.30(q,J=2.4,1.7Hz,5H).
[0073] like Figure 5 , the NMR carbon spectrum data of the compound is: 13 C NMR (101MHz, CDCl3) δ196.4,148.6,146.0,139.8,136.1,135.1,132.0,130.6(d,J=12.8Hz) ,130.2,129.9,129.1,128.7,128.4(d,J=7.0Hz),127.6,127.3,126.9(d,J=10.7Hz),126.6.
[0074] Example 3
[0075] The quinoline compound of the present invention, wherein R is -Cl, has a chemical name of (4-chlorophenyl)(4-phenylquinolin-3-yl)methanone and has the following structural formula:
[0076]
[0077] The compound synthesis method comprises the following steps:
[0078] Step 1: Preparation of 2-[(bromotriphenyl-5-phosphino)phenylmethyl]aniline
[0079]
[0080] (1) 10 mmol of 2-aminobenzophenone was added to a 100 mL reaction flask, and 30 mL of ethanol was added to fully dissolve the mixture. 40 mmol (added in four portions, 10 mmol each time) of sodium borohydride was added at 0°C, and the temperature was raised to 70°C for reaction for 3 hours. After the reaction was completed, the mixture was quenched with water and extracted with ethyl acetate (50 mL x 3), and washed with saturated brine. After the reaction was completed, anhydrous sodium sulfate was added to dry the mixture, and the solvent was removed by rotary evaporation to obtain (2-aminophenyl)(phenyl)methanol.
[0081] (2) Transfer (2-aminophenyl)(phenyl)methanol to a 100 mL reaction flask, add 10 mmol of triphenylphosphine hydrobromide, use 30 mL of acetonitrile to fully dissolve the reactants, and reflux at 80°C for 12 hours. After the reaction, wash thoroughly with ether until the product turns white and air-dry.
[0082] The NMR data of this compound are: 1 H NMR(400MHz, DMSO-d6)δ7.92-7.87(m,3H),7.73(td,J=7.9,3.7Hz,7H),7.64(dd,J=12.0,7.5Hz,6H), 7.40-7.22(m,6H),7.06(t,J=7.6Hz,1H),6.79(d,J=8.2Hz,1H),6.67-6.56(m,2H),6.41-6.35(m,1H).
[0083] Step 2: Preparation of (E)-1-(4-chlorophenyl)-3-(dimethylamino)prop-2-en-1-one
[0084]
[0085] In a 100 mL reaction flask, add p-chloroacetophenone (16.6 mmol), N,N-dimethylformamide dimethyl acetal (49.9 mmol), and toluene (21.2 mL). Reflux for 48 hours. Cool to room temperature, evaporate the solvent, wash with petroleum ether, and air-dry.
[0086] The NMR data of this compound are: 1 H NMR (400MHz, CDCl3) δ7.85-7.80(m,3H),7.36(d,J=8.5Hz,2H),5.66(d,J=12.4Hz,1H),3.15(s,3H),2.92(s,3H)
[0087] Step 3: Preparation of (4-chlorophenyl)(4-phenylquinolin-3-yl)methanone
[0088]
[0089] 0.2 mmol of the product synthesized in the second step was dissolved in a Schlenk tube, 0.3 mmol of the compound prepared in the first step was added, and a stirring magnetic bar was added. Finally, 1 mL of dimethyl sulfoxide was added and the reaction was carried out at 100°C for 15 hours. After the reaction, the product was purified by column chromatography using a mixture of petroleum ether and ethyl acetate in a volume ratio of 10:1 as the eluent. With the help of TLC elution tracking detection, the eluates containing the target product were collected, the target product eluates were combined, and evaporated and concentrated to obtain (4-chlorophenyl)(4-phenyl-1,4-dihydroquinolin-3-yl)methanone.
[0090] like Figure 6 , the H NMR spectrum data of the compound is: 1 H NMR (400MHz, CDCl3) δ8.97 (s, 1H), 8.22 (d, J = 8.3Hz, 1H), 7.81-7.76 (m, 2H), 7.55- 7.50(m,3H),7.28(dt,J=4.9,2.1Hz,3H),7.25(d,J=2.2Hz,1H),7.24-7.19(m,3H).
[0091] like Figure 7 , the NMR carbon spectrum data of the compound is: 13 C NMR (101MHz, CDCl3) δ195.8,149.0,148.5,147.1,139.8,135.8,134.9,131 .7–130.6(m),130.1(d,J=23.8Hz),129.1–128.2(m),127.8,126.8,126.4.
[0092] Example 4
[0093] The quinoline compound of the present invention, wherein R is -Br, has a chemical name of (4-bromophenyl)(4-phenylquinolin-3-yl)methanone, and has the following structural formula:
[0094]
[0095] The compound synthesis method comprises the following steps:
[0096] Step 1: Preparation of 2-[(bromotriphenyl-5-phosphino)phenylmethyl]aniline
[0097]
[0098] (1) 10 mmol of 2-aminobenzophenone was added to a 100 mL reaction flask, and 30 mL of ethanol was added to fully dissolve the mixture. 40 mmol (added in four portions, 10 mmol each time) of sodium borohydride was added at 0°C, and the temperature was raised to 70°C for reaction for 3 hours. After the reaction was completed, the mixture was quenched with water and extracted with ethyl acetate (50 mL x 3), and washed with saturated brine. After the reaction was completed, anhydrous sodium sulfate was added to dry the mixture, and the solvent was removed by rotary evaporation to obtain (2-aminophenyl)(phenyl)methanol.
[0099] (2) Transfer (2-aminophenyl)(phenyl)methanol to a 100 mL reaction flask, add 10 mmol of triphenylphosphine hydrobromide, use 30 mL of acetonitrile to fully dissolve the reactants, and reflux at 80°C for 12 hours. After the reaction, wash thoroughly with ether until the product turns white and air-dry.
[0100] The NMR data of this compound are: 1 H NMR(400MHz, DMSO-d6)δ7.92-7.87(m,3H),7.73(td,J=7.9,3.7Hz,7H),7.64(dd,J=12.0,7.5Hz,6H), 7.40-7.22(m,6H),7.06(t,J=7.6Hz,1H),6.79(d,J=8.2Hz,1H),6.67-6.56(m,2H),6.41-6.35(m,1H).
[0101] Step 2: Preparation of (E)-1-(4-bromophenyl)-3-(dimethylamino)prop-2-en-1-one
[0102]
[0103] In a 100 mL reaction flask, add p-bromoacetophenone (16.6 mmol), N,N-dimethylformamide dimethyl acetal (49.9 mmol), and toluene (21.2 mL). Reflux for 48 hours. Cool to room temperature, evaporate the solvent, wash with petroleum ether, and air-dry.
[0104] like Figure 8 , the NMR data of the compound are: 1 H NMR (400MHz, CDCl3) δ7.83(d,J=12.2Hz,1H),7.78-7.75(m,2H),7.56-7.51(m,2H),5.66(d,J=12.4Hz,1H),3.16(s,3H),2.93(s,3H).
[0105] Step 3: Preparation of (4-bromophenyl)(4-phenylquinolin-3-yl)methanone
[0106]
[0107] 0.2 mmol of the product synthesized in the second step was dissolved in a Schlenk tube, 0.3 mmol of the compound prepared in the first step was added, and a magnetic stirring bar was added. Finally, 1 mL of dimethyl sulfoxide was added, and the reaction was carried out at 100° C. for 12 hours. After the reaction, the product was purified by column chromatography using a mixture of petroleum ether and ethyl acetate in a volume ratio of 10:1 as the eluent. The eluate containing the target product was collected and detected by TLC elution tracking. The target product eluates were combined and concentrated by evaporation to obtain (4-bromophenyl)(4-phenylquinolin-3-yl)methanone.
[0108] like Figure 9 , the H NMR spectrum data of the compound is: 1 H NMR(400MHz, CDCl3)δ8.96(s,1H),8.22(d,J=8.3Hz,1H),7.81-7.76(m,2H),7.53(ddd,J=8.3,6.9,1.2Hz, 1H),7.45-7.41(m,2H),7.3-7.36(m,2H),7.28(dt,J=4.8,1.9Hz,3H),7.25(s,1H),7.22(d,J=2.3Hz,1H)..
[0109] like Figure 10 , the NMR carbon spectrum data of the compound is: 13CNMR (101MHz, CDCl3) δ195.9,149.1,148.5,147.1,136.2,134.9,131.6,131.4 ,131.2,130.8,130.2,129.9,128.8,128.5(d,J=12.7Hz),127.8,126.8,126.3.
[0110] Example 5
[0111] The quinoline compound of the present invention, R is F, is named (4-phenylquinolin-3-yl)(p-fluoro)methanone, and its structural formula is
[0112]
[0113] The compound synthesis method comprises the following steps:
[0114] Step 1: Preparation of 2-[(bromotriphenyl-5-phosphino)phenylmethyl]aniline
[0115]
[0116] (1) 10 mmol of 2-aminobenzophenone was added to a 100 mL reaction flask, and 30 mL of ethanol was added to fully dissolve the mixture. 40 mmol of sodium borohydride was added in batches at 0°C, and the temperature was raised to 70°C for reaction for 3 hours. After the reaction was completed, the mixture was quenched with water and extracted with ethyl acetate (50 mL x 3), and washed with saturated brine. After the reaction was completed, anhydrous sodium sulfate was added to dry the mixture, and the solvent was removed by rotary evaporation to obtain (2-aminophenyl)(phenyl)methanol.
[0117] (2) Transfer (2-aminophenyl)(phenyl)methanol to a 100 mL reaction flask, add 10 mmol of triphenylphosphine hydrobromide, use 30 mL of acetonitrile to fully dissolve the reactants, and reflux at 80°C for 12 hours. After the reaction, wash thoroughly with ether until the product turns white and air-dry.
[0118] The NMR data of this compound are: 1 H NMR(400MHz, DMSO-d6)δ7.92-7.87(m,3H),7.73(td,J=7.9,3.7Hz,7H),7.64(dd,J=12.0,7.5Hz,6H), 7.40-7.22(m,6H),7.06(t,J=7.6Hz,1H),6.79(d,J=8.2Hz,1H),6.67-6.56(m,2H),6.41-6.35(m,1H).
[0119] Step 2: Preparation of (E)-1-(4-methylphenyl)-3-(dimethylamino)prop-2-en-1-one
[0120]
[0121] In a 100 mL reaction flask, add p-fluoroacetophenone (16.6 mmol), N,N-dimethylformamide dimethyl acetal (49.9 mmol), and toluene (21.2 mL). Reflux for 48 hours. Cool to room temperature, evaporate the solvent, wash with petroleum ether, and air-dry.
[0122] The NMR data of this compound are: 1 H NMR (400MHz, CDCl3) δ7.95-7.88(m,2H),7.85(d,J=12.4Hz,1H),7.07(t,J=8.7Hz,2H),5.67(d,J=12.4Hz,1H),3.16(s,3H),2.94(s,3H).
[0123] Step 3: Preparation of (4-phenylquinolin-3-yl)(p-fluoro)ketone
[0124]
[0125] 0.2 mmol of the product synthesized in the second step was dissolved in a Schlenk tube, 0.3 mmol of the compound prepared in the first step was added, and a stirring magnetic bar was added. Finally, 1 mL of dimethyl sulfoxide was added, and the reaction was carried out at 100°C for 15 hours. After the reaction, the product was purified by column chromatography using a mixture of petroleum ether and ethyl acetate in a volume ratio of 10:1 as the eluent. The eluate containing the target product was collected and detected by TLC elution tracking. The target product eluates were combined and concentrated by evaporation to obtain (4-phenylquinolin-3-yl)(p-fluoro)ketone.
[0126] like Figure 10 , the H NMR spectrum data of the compound is: 1 H NMR (400MHz, CDCl3) δ8.97(s,1H),8.22(d,J=8.6Hz,1H),7.78(t,J=8.6Hz,2H),7 .63-7.50(m,3H),7.33-7.26(m,3H),7.24(d,J=4.3Hz,2H),6.91(t,J=8.4Hz,2H).
[0127] like Figure 11 , the NMR carbon spectrum data of the compound is: 13C NMR(101MHz,CDCl3)δ195.4,149.0,148.5,146.9,134.9,133.9,132.4(d,J=9.5Hz),131.6,130.7,130.2,129.9,128.8,128.4,127.7,126.8,126.4,115.7,115.4。
Claims
1. A method for synthesizing a quinoline compound, characterized in that: The following steps are involved: Compound 1 and compound 2 undergo a [4+2] cyclization reaction in an organic solvent at 90-110°C. After purification, the target quinoline compound is obtained. The synthetic route is as follows: ； Wherein, R is H, halogen, -OC 1-3 Any one of them.
2. The synthetic method of quinoline compounds according to claim 1, wherein The molar ratio of compound 2 to compound 1 is 1:1.1~2.
3. The synthetic method of quinoline compound according to claim 1, wherein The solvent for the reaction is dimethyl sulfoxide.
4. The synthetic method of quinoline compounds according to claim 1, wherein The purification method comprises the following steps: separation by column chromatography, wherein the column chromatography solid phase is column chromatography silica gel, and the mobile phase is a mixture of petroleum ether and ethyl acetate.
5. The synthetic method of quinoline compound according to claim 4, wherein The volume ratio of petroleum ether to ethyl acetate is 1-10:
1.
6. The method for synthesizing quinoline compounds according to claim 1, wherein The synthesis method of compound 1 is: (1) The carbonyl group of compound 3 undergoes a reduction reaction in ethanol and is reduced to a hydroxyl group. After the reaction is completed, the reaction is quenched with water and compound 4 is obtained by extraction; (2) Compound 4 and triphenylphosphine hydrobromide undergo substitution reaction to obtain compound 1. The synthetic route is as follows: 。 7. The method for synthesizing quinoline compounds according to claim 6, wherein In step (1), the reducing agent of the reduction reaction is sodium borohydride, which is first added at -10~10°C, and then the temperature is raised to 60~100°C for reaction.
8. The method for synthesizing quinoline compounds according to claim 6, wherein In step (2), during the substitution reaction, the reaction temperature is 60-100°C.
9. The method for synthesizing quinoline compounds according to claim 1, wherein The synthesis method of compound 2 is as follows: Compound 5 and compound 6 undergo a substitution reaction to obtain compound 2. The synthesis route is as follows: 。 10. The method for synthesizing quinoline compounds according to claim 9, wherein The reaction temperature is 80-120°C.