Synthesis method of dihydroquinoline compound
Through the metal-free [4+2] cyclization reaction method, the synthesis efficiency and yield of dihydroquinoline compounds were successfully improved, and the problems of difficult raw materials and harsh reaction conditions in the existing technology were solved, thus achieving high efficiency , economical green synthesis process.
Patent Information
- Application Number
- CN202411378741.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-30
- Publication Date
- 2025-01-03
AI Technical Summary
The existing synthesis method of dihydroquinoline compounds has problems such as difficult to obtain starting materials, expensive catalysts, narrow application range of substrates, harsh reaction conditions and low yields.
Using the [4+2] cyclization reaction method without metal and catalyst participation, Compound 1 and Compound 2 undergo cyclization reaction in organic solvents, the product is purified by column chromatography, and a mixture of petroleum ether and ethyl acetate is used as the elution. The reaction temperature is controlled at 60-100°C, the reaction time is 15 hours, and the molar ratio of compound 2 and compound 1 is 1:1.1-1:2, and tetrahydrofuran, dichloromethane or ethanol are used as the organic solvent.
Green and mild reaction conditions are achieved, raw materials are easily obtained and cheap, substrate tolerance is good, and yield is as high as 90%, which solves the shortcomings of resource and economic efficiency in the original method.
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Figure CN119241430A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of synthesis methods of quinoline compounds, and in particular to a synthesis method of dihydroquinoline compounds. Background Art
[0002] Dihydroquinoline compounds are widely present in natural products and synthetic drugs with broad-spectrum biological activities and have attracted widespread attention. Quinoline and its derivatives have certain biological activities in antimalarial, anticancer, antioxidant, anti-inflammatory and anti-SARS-CoV-2. These literature methods have the disadvantages of difficult to obtain starting materials, use of expensive catalysts, narrow substrate application range, harsh reaction conditions and low yield, which greatly limits the scope of application of this type of synthesis method. Summary of the invention
[0003] Technical problems to be solved: In view of the technical problems in the prior art such as difficulty in obtaining starting materials, use of expensive catalysts, narrow substrate application range, harsh reaction conditions and low yield, a method for synthesizing dihydroquinoline compounds is provided, which does not involve metals and catalysts and has green and mild reaction conditions.
[0004] Technical solution:
[0005] The present invention discloses a method for synthesizing a dihydroquinoline compound. The method comprises the following steps: a compound 1 and a compound 2 undergo a [4+2] cyclization reaction in an organic solvent, and after the reaction, a product is purified by column chromatography, wherein the eluent is a mixture of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 10:1 to 1:1, to obtain a target quinoline compound. The synthesis route is as follows:
[0006]
[0007] Where R 1 For H, R 2 is H or Br, R 3 It is H, CF3, Cl or Br.
[0008] Furthermore, in the synthesis method of the dihydroquinoline compound, the reaction temperature is 60-100° C., the reaction time is 15 h, the molar ratio of compound 2 to compound 1 is 1:1.1-1:2; and the organic solvent is tetrahydrofuran, dichloromethane or ethanol.
[0009] Further, the purification method is:
[0010] Column chromatography was used for separation, wherein the column chromatography solid phase was column chromatography silica gel, and the mobile phase was a mixture of petroleum ether and ethyl acetate; the volume ratio of petroleum ether to ethyl acetate was 3:1.
[0011] Furthermore, the synthesis method of compound 1 is:
[0012] Step 1: The carbonyl group of compound 3 is reduced to a hydroxyl group in a reaction solvent, and after the reaction is completed, the reaction is quenched with water, and then purified to obtain compound 4;
[0013] Step 2: Compound 4 and triphenylphosphine hydrobromide were dissolved in acetonitrile and refluxed at 80°C for 12 hours to obtain compound 1; the synthetic route is as follows:
[0014]
[0015] Furthermore, the reducing agent for the reduction reaction in the first step 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 for 3 hours; the molar volume ratio of compound 3, reaction solvent, reducing agent, triphenylphosphine hydrobromide and acetonitrile is 10mmol:30mL:40mmol:10mmol:30mL, and the reaction solvent is ethanol or dichloromethane; the purification method of compound 4 is: extraction with ethyl acetate.
[0016] Furthermore, the purification method is specifically as follows: after the reduction reaction is completed, water is added for quenching, extraction is performed three times with 50 mL of ethyl acetate, and washing is performed with saturated brine. After completion, anhydrous sodium sulfate is added for drying, and the solvent is removed by rotary evaporation to obtain (2-aminophenyl)(phenyl)methanol or its derivatives.
[0017] Furthermore, after the second step reflux reaction is completed, the product is fully washed with ether until white and dried.
[0018] Furthermore, the synthetic route of compound 2 is as follows:
[0019]
[0020] Where R 1 For H, R 2 is H or Br, R 3 It is H, CF3, Cl or Br.
[0021] Furthermore, in the synthesis of compound 2, the reaction temperature is 80-120° C., and the reaction solvent is toluene; the purification method of compound 2 is: separation by column chromatography, wherein the column chromatography solid phase is column chromatography silica gel, and the mobile phase is petroleum ether and / or ethyl acetate.
[0022] Furthermore, the molar volume ratio of compound 5, compound 6 and toluene is 16.6 mmol:49.9 mmol:21.2 mL, and compound 5, compound 6 and toluene are kept in reflux at 80-120° C. for 48 hours. After cooling to room temperature, the solvent is evaporated, washed with mobile phase, and air-dried to obtain compound 2.
[0023] Beneficial effects:
[0024] (1) The reaction is green and does not require any additives or catalysts, and the reaction conditions are mild;
[0025] (2) The raw materials for the reaction are readily available and inexpensive;
[0026] (3) The reaction has good substrate tolerance;
[0027] (4) The yield of dihydroquinoline derivatives obtained by this reaction is as high as over 90%;
[0028] (5) Currently, there are few methods for synthesizing dihydroquinoline. The synthesis method of the present application does not involve metals and catalysts, and the reaction conditions are green and mild. BRIEF DESCRIPTION OF THE DRAWINGS
[0029] Figure 1 The reaction route of the synthesis method of this application;
[0030] Figure 2 This is the H NMR spectrum of phenyl (4-phenyl-1,4-dihydroquinolin-3-yl)methanone synthesized in Example 1 of the present application;
[0031] Figure 3 This is the NMR carbon spectrum of phenyl (4-phenyl-1,4-dihydroquinolin-3-yl)methanone synthesized in Example 1 of the present application;
[0032] Figure 4 This is the H NMR spectrum of (3-bromophenyl)(4-phenyl-1,4-dihydroquinolin-3-yl)methanone synthesized in Example 2 of the present application;
[0033] Figure 5 This is the NMR carbon spectrum of (3-bromophenyl)(4-phenyl-1,4-dihydroquinolin-3-yl)methanone synthesized in Example 2 of the present application;
[0034] Figure 6 This is the H NMR spectrum of (4-chlorophenyl)(4-phenyl-1,4-dihydroquinolin-3-yl)methanone synthesized in Example 3 of the present application;
[0035] Figure 7 This is the NMR carbon spectrum of (4-chlorophenyl)(4-phenyl-1,4-dihydroquinolin-3-yl)methanone synthesized in Example 3 of the present application;
[0036] Figure 8 This is the H NMR spectrum of (4-bromophenyl)(4-phenyl-1,4-dihydroquinolin-3-yl)methanone synthesized in Example 4 of the present application;
[0037] Fig. 9 This is the NMR t carbon spectrum of (4-bromophenyl)(4-phenyl-1,4-dihydroquinolin-3-yl)methanone synthesized in Example 4 of the present application;
[0038] Fig.10 This is the H NMR spectrum of (4-trifluoromethylphenyl)(4-phenyl-1,4-dihydroquinolin-3-yl)methanone synthesized in Example 5 of the present application;
[0039] Fig.11 This is the carbon NMR spectrum of (4-trifluoromethylphenyl)(4-phenyl-1,4-dihydroquinolin-3-yl)methanone synthesized in Example 5 of the present application. DETAILED DESCRIPTION
[0040] The technical solution of the present invention will be further described below in conjunction with embodiments.
[0041] All raw materials in the examples of this application are commercially available.
[0042] Example 1
[0043] A method for synthesizing a dihydroquinoline compound, wherein the method comprises: a [4+2] cyclization reaction of compound 1 and compound 2 occurs in an organic solvent, and after the reaction, the target quinoline compound is purified by column chromatography. The synthetic route is as follows:
[0044]
[0045] Where R 1 For H, R 2 For H, R 3 The dihydroquinoline compound is named phenyl (4-phenyl-1,4-dihydroquinoline-3-yl) ketone, and its structural formula is: The compound synthesis method comprises the following steps:
[0046] Step 1: Preparation of 2-[(bromotriphenyl-5-phosphino)phenylmethyl]aniline
[0047]
[0048] (1) Add 10 mmol of compound 3 (2-aminobenzophenone) and 30 mL of ethanol as a reaction solvent to a 100 mL reaction flask. After compound 3 is fully dissolved in ethanol, add 40 mmol (added in four times, 10 mmol each time) of sodium borohydride at 0° C., raise the temperature to 70° C. and react for 3 hours. After the reaction is completed, add water to quench, extract with ethyl acetate (50 mL x 3), and wash with saturated brine. After the reaction is completed, add anhydrous sodium sulfate to dry, and remove the solvent by rotary evaporation to obtain (2-aminophenyl)(phenyl)methanol;
[0049] (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.
[0050] The NMR data of this compound are: 1 HNMR(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).
[0051] Step 2: Preparation of (E)-3-(dimethylamino)-1-phenyl-2-propene-1-one
[0052] Acetophenone (16.6 mmol), N,N-dimethylformamide dimethyl acetal (49.9 mmol) and toluene (21.2 mL) were added to a 100 ml reaction flask and kept under reflux for 48 hours. The mixture was cooled to room temperature and the solvent was evaporated. The mixture was washed with petroleum ether and air-dried.
[0053]
[0054] The NMR data of this compound are: 1 HNMR (400MHz, CDCl3) δppm: 7.92-7.84(m,2H),7.79(d,J=12.4Hz,1H),7.48-7.35(m,3H),5.70(d,J=12.4Hz,1H),3.11(s,3H),2.90(s,3H).
[0055] Step 3: Preparation of phenyl (4-phenyl-1,4-dihydroquinolin-3-yl)methanone
[0056]
[0057] 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, and finally 1 mL of tetrahydrofuran was added, and the reaction was carried out at 60° C. for 15 hours; after the reaction, the product was purified by column chromatography, and the eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 3:1; with the help of TLC elution tracking detection, the eluate containing the target product was collected, the eluate of the target product was combined, and evaporated and concentrated to obtain phenyl (4-phenyl-1,4-dihydroquinolin-3-yl) ketone.
[0058] like Figure 2 The H NMR data of the compound are: 1H NMR (400 MHz, DMSO-d6) δ9.61 (d, J = 6.2 Hz, 1H), 7.48–7.41 (m, 5H), 7.31–7.20 (m, 6H), 7.13–7.06 (m, 2H), 6.97–6.88 (m, 2H), 5.32 (s, 1H). Figure 3 , the NMR carbon spectrum data of the compound is: 13 C NMR (101MHz, DMSO-d6) δ192.4,148.4,142.7,140.2,135.5,130.0,129.9,128.3,128.2,128.0,127.1,125.9,125.4,123.5,115.7,111.0,40.9.
[0059] Example 2
[0060] A method for synthesizing a dihydroquinoline compound, wherein the method comprises: a [4+2] cyclization reaction of compound 1 and compound 2 occurs in an organic solvent, and after the reaction, the target quinoline compound is purified by column chromatography. The synthetic route is as follows:
[0061] Where R 1 For H, R 2 Br, R 3 The dihydroquinoline compound is named phenyl (3-bromophenyl) (4-phenyl-1,4-dihydroquinolin-3-yl) ketone, and its structural formula is: The compound synthesis method comprises the following steps:
[0062] Step 1: Preparation of 2-[(bromotriphenyl-5-phosphino)phenylmethyl]aniline
[0063]
[0064] (1) Add 10 mmol of compound 3 (2-aminobenzophenone) and 30 mL of ethanol as a reaction solvent to a 100 mL reaction flask. After compound 3 is fully dissolved in ethanol, add 40 mmol (added in four times, 10 mmol each time) of sodium borohydride at 0° C., raise the temperature to 70° C. and react for 3 hours. After the reaction is completed, add water to quench, extract with ethyl acetate (50 mL x 3), and wash with saturated brine. After the reaction is completed, add anhydrous sodium sulfate to dry, and remove the solvent by rotary evaporation to obtain (2-aminophenyl)(phenyl)methanol;
[0065] (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.
[0066] The NMR data of this compound are: 1 HNMR(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).
[0067] Step 2: Preparation of (E)-1-(3-bromophenyl)-3-(dimethylamino)prop-2-en-1-one
[0068] In a 100 ml reaction flask, m-bromoacetophenone (16.6 mmol) and N,N-dimethylformamide dimethyl acetal (49.9 mmol) were added and the solution in toluene (21.2 mL) was kept under reflux for 48 hours. The mixture was cooled to room temperature and the solvent was evaporated. The mixture was washed with petroleum ether and air-dried.
[0069]
[0070] The NMR data of the compound are: 1H NMR (400MHz, CDCl3) δppm: 8.00 (t, J = 1.8Hz, 1H), 7.84-7.78 (m, 2H), 7.56 (ddd, J = 7.9, 2.1, 1.1Hz, 1H), 7.27 (t, J = 7.8Hz, 1H), 5.63 (d, J = 12.4Hz, 1H), 3.16 (s, 3H), 2.93 (s, 3H).
[0071] Step 3: Preparation of (3-bromophenyl)(4-phenyl-1,4-dihydroquinolin-3-yl)methanone
[0072]
[0073] 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, and finally 1 mL of tetrahydrofuran was added, and the reaction was carried out at 60° C. for 15 hours; after the reaction, the product was purified by column chromatography, and the eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 3:1; with the help of TLC elution tracking detection, the eluate containing the target product was collected, the target product eluate was combined, and evaporated and concentrated to obtain (3-bromophenyl)(4-phenyl-1,4-dihydroquinolin-3-yl)methanone.
[0074] like Figure 4 , the H NMR spectrum data of the compound is: 1 HNMR (400MHz, DMSO-d6) δ9.74(d,J=6.2Hz,1H),7.68(dt,J=7.7,1.7Hz,1H),7.55(t,J=1.8Hz,1H),7.40(dt,J=15. 3,7.6Hz,2H),7.31(dd,J=6.6,5.0Hz,3H),7.25–7.19(m,3H),7.12–7.07(m,2H),6.98–6.90(m,2H),5.30(s,1H). Such as Figure 5 The nuclear magnetic carbon spectrum data of this compound are: 13C NMR (101MHz, DMSO-d6) δ190.4, 148.3, 143.4, 142.5, 135.3, 132.8, 130.5, 130.4, 129.9, 128.4, 127.2, 127.1, 126.0, 125.5, 123.7, 121.6, 115.8, 110.7, 40.9.
[0075] Example 3
[0076] A method for synthesizing a dihydroquinoline compound, wherein the method comprises: a [4+2] cyclization reaction of compound 1 and compound 2 occurs in an organic solvent, and after the reaction, the target quinoline compound is purified by column chromatography. The synthetic route is as follows:
[0077] Where R 1 For H, R 2 For H, R 3 The dihydroquinoline compound is -Cl, and the name of the dihydroquinoline compound is (4-chlorophenyl) (4-phenyl-1,4-dihydroquinoline-3-yl) ketone, and its structural formula is: The compound synthesis method comprises the following steps:
[0078] Step 1: Preparation of 2-[(bromotriphenyl-5-phosphino)phenylmethyl]aniline
[0079]
[0080] (1) Add 10 mmol of compound 3 (2-aminobenzophenone) and 30 mL of ethanol as a reaction solvent to a 100 mL reaction flask. After compound 3 is fully dissolved in ethanol, add 40 mmol (added in four times, 10 mmol each time) of sodium borohydride at 0° C., raise the temperature to 70° C. and react for 3 hours. After the reaction is completed, add water to quench, extract with ethyl acetate (50 mL x 3), and wash with saturated brine. After the reaction is completed, add anhydrous sodium sulfate to dry, and remove the solvent 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 HNMR(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] In a 100 ml reaction flask, p-chloroacetophenone (16.6 mmol) and N,N-dimethylformamide dimethyl acetal (49.9 mmol) were added and the solution in toluene (21.2 mL) was kept under reflux for 48 hours. The mixture was cooled to room temperature and the solvent was evaporated. The mixture was washed with petroleum ether and air-dried.
[0085]
[0086] The NMR data of this compound are: 1HNMR (400MHz, CDCl3) δppm: 7.85-7.80 (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-phenyl-1,4-dihydroquinolin-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, and finally 1 mL of tetrahydrofuran was added, and the reaction was carried out at 60° C. for 15 hours; after the reaction, the product was purified by column chromatography, and the eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 3:1; with the help of TLC elution tracking detection, the eluate containing the target product was collected, the eluate of the target product was 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 HNMR (400MHz, DMSO-d6) δ9.70 (d, J=6.2Hz, 1H), 7.47 (q, J=8.5Hz, 4H), 7.30 (d, J= 6.2Hz,3H),7.24–7.19(m,3H),7.12–7.07(m,2H),6.98–6.90(m,2H),5.31(s,1H).
[0091] like Figure 7 , the NMR carbon spectrum data of the compound is: 13 C NMR (101MHz, DMSO-d6) δ190.9,148.3,142.9,138.9,135.4,134.7,129.9,128.3,127.1,127.0,125.9,125.4,123.6,115.7,110.8,40.9.
[0092] Example 4
[0093] A method for synthesizing a dihydroquinoline compound, wherein the method comprises: a [4+2] cyclization reaction of compound 1 and compound 2 occurs in an organic solvent, and after the reaction, the target quinoline compound is purified by column chromatography. The synthetic route is as follows:
[0094] Where R 1 For H, R2 For H, R 3 It is -Br, and its name is (4-chlorophenyl)(4-phenyl-1,4-dihydroquinolin-3-yl)methanone, and its structural formula is: The compound synthesis method comprises the following steps:
[0095] Step 1: Preparation of 2-[(bromotriphenyl-5-phosphino)phenylmethyl]aniline
[0096]
[0097] (1) Add 10 mmol of compound 3 (2-aminobenzophenone) and 30 mL of ethanol as a reaction solvent to a 100 mL reaction flask. After compound 3 is fully dissolved in ethanol, add 40 mmol (added in four times, 10 mmol each time) of sodium borohydride at 0° C., raise the temperature to 70° C. and react for 3 hours. After the reaction is completed, add water to quench, extract with ethyl acetate (50 mL x 3), and wash with saturated brine. After the reaction is completed, add anhydrous sodium sulfate to dry, and remove the solvent by rotary evaporation to obtain (2-aminophenyl)(phenyl)methanol;
[0098] (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.
[0099] The NMR data of this compound are: 1 HNMR(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).
[0100] Step 2: Preparation of (E)-1-(4-bromophenyl)-3-(dimethylamino)prop-2-en-1-one
[0101] In a 100 ml reaction flask, p-bromoacetophenone (16.6 mmol) and N,N-dimethylformamide dimethyl acetal (49.9 mmol) were added and the solution in toluene (21.2 mL) was kept under reflux for 48 hours. The mixture was cooled to room temperature and the solvent was evaporated. The mixture was washed with petroleum ether and air-dried.
[0102]
[0103] The NMR data of this compound are: 1 H NMR (400MHz, CDCl3) δppm: 7.83 (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).
[0104] Step 3: Preparation of (4-bromophenyl)(4-phenyl-1,4-dihydroquinolin-3-yl)methanone
[0105]
[0106] 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, and finally 1 mL of tetrahydrofuran was added, and the reaction was carried out at 60° C. for 15 hours; after the reaction, the product was purified by column chromatography, and the eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 3:1; with the help of TLC elution tracking detection, the eluate containing the target product was collected, the target product eluate was combined, and evaporated and concentrated to obtain (4-bromophenyl)(4-phenyl-1,4-dihydroquinolin-3-yl)methanone.
[0107] like Figure 8 , the H NMR spectrum data of the compound is: 1 HNMR (400MHz, DMSO-d6) δ9.69(d,J=6.2Hz,1H),7.63(d,J=8.3Hz,2H),7.38(d,J=8.4Hz,2H ),7.31–7.28(m,3H),7.24–7.19(m,3H),7.12–7.07(m,2H),6.97–6.90(m,2H),5.30(s,1H).
[0108] like Fig. 9 , the NMR carbon spectrum data of the compound is: 13 C NMR(101MHz,DMSO-d6)δ191.1,148.3,142.9,139.3,135.4,131.2,130.1,1 29.9,128.3,127.1,127.0,125.9,125.4,123.6,123.5,115.7,110.8,40.8.
[0109] Example 5
[0110] A method for synthesizing a dihydroquinoline compound, wherein the method comprises: a [4+2] cyclization reaction of compound 1 and compound 2 occurs in an organic solvent, and after the reaction, the target quinoline compound is purified by column chromatography. The synthetic route is as follows:
[0111] Where R 1 For H, R 2 For H, R 3 It is -CF3, named (4-chlorophenyl)(4-phenyl-1,4-dihydroquinolin-3-yl)methanone, and its structural formula is: The compound synthesis method comprises the following steps:
[0112] Step 1: Preparation of 2-[(bromotriphenyl-5-phosphino)phenylmethyl]aniline
[0113]
[0114] (1) Add 10 mmol of compound 3 (2-aminobenzophenone) and 30 mL of ethanol as a reaction solvent to a 100 mL reaction flask. After compound 3 is fully dissolved in ethanol, add 40 mmol (added in four times, 10 mmol each time) of sodium borohydride at 0° C., raise the temperature to 70° C. and react for 3 hours. After the reaction is completed, add water to quench, extract with ethyl acetate (50 mL x 3), and wash with saturated brine. After the reaction is completed, add anhydrous sodium sulfate to dry, and remove the solvent by rotary evaporation to obtain (2-aminophenyl)(phenyl)methanol;
[0115] (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.
[0116] The NMR data of this compound are: 1 HNMR(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).
[0117] Step 2: Preparation of (E)-1-(4-trifluoromethylphenyl)-3-(dimethylamino)prop-2-en-1-one
[0118]
[0119] In a 100 ml reaction flask, add p-trifluoromethylacetophenone (16.6 mmol) and N,N-dimethylformamide dimethyl acetal (49.9 mmol) and a solution in toluene (21.2 mL) and keep it in reflux for 48 hours. Cool to room temperature and evaporate the solvent. Wash with petroleum ether and air dry.
[0120] The NMR data of this compound are: 1 HNMR (400MHz, CDCl3) δppm: 7.97 (d, J = 8.0Hz, 2H), 7.85 (d, J = 12.4Hz, 1H), 7.66 (d, J = 8.0Hz, 2H), 5.68 (d, J = 12.4Hz, 1H), 3.18 (s, 3H), 2.95 (s, 3H).
[0121] Step 3: Preparation of (4-trifluoromethylphenyl)(4-phenyl-1,4-dihydroquinolin-3-yl)methanone
[0122]
[0123] 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, and finally 1 mL of tetrahydrofuran was added, and the reaction was carried out at 60° C. for 15 hours; after the reaction, the product was purified by column chromatography, and the eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 3:1; with the help of TLC elution tracking detection, the eluate containing the target product was collected, the target product eluate was combined, and evaporated and concentrated to obtain (4-trifluoromethylphenyl)(4-phenyl-1,4-dihydroquinolin-3-yl)methanone.
[0124] like Fig.10 , the H NMR spectrum data of the compound is: 1 H NMR (400MHz, DMSO-d6) δ9.75(d,J=6.3Hz,1H),7.79(d,J=8.4Hz,2H),7.62(d,J=7.7Hz,2H), 7.33–7.29(m,3H),7.23(t,J=7.7Hz,3H),7.13–7.08(m,2H),7.00–6.91(m,2H),5.34(s,1H).
[0125] like Fig.11 , the NMR carbon spectrum data of the compound is: 13C NMR(101MHz,DMSO-d6)δ190.9,148.3,144.1,143.5,135.3,130.1,129.9,129.7,1 28.7,128.3,127.1,127.0,125.9,125.5,125.2,123.7,122.7,115.8,110.9,40.7.
[0126] Finally, it is understood that the above embodiments are merely exemplary embodiments used to illustrate the principles of the present invention, but the present invention is not limited thereto. For those of ordinary skill in the art, various modifications and improvements can be made without departing from the principles and essence of the present invention, and these modifications and improvements are also considered to be within the scope of protection of the present invention.
Claims
1. A method for synthesizing a dihydroquinoline compound, characterized in that: The synthesis method is as follows: Compound 1 and Compound 2 undergo a [4+2] cyclization reaction in an organic solvent, and after the reaction, the product is purified by column chromatography, and the eluent is a mixture of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 10:1 to 1:1, to obtain the target quinoline compound. The synthesis route is as follows: Where R 1 For H, R 2 is H or Br, R 3 It is H, CF3, Cl or Br.
2. The method for synthesizing a dihydroquinoline compound according to claim 1, characterized in that: In the synthesis method of the dihydroquinoline compound, the reaction temperature is 60-100° C., the reaction time is 15 hours, the molar ratio of compound 2 to compound 1 is 1:1.1-1:2; and the organic solvent is tetrahydrofuran, dichloromethane or ethanol.
3. The method for synthesizing a dihydroquinoline compound according to claim 1, characterized in that: The purification method is: Column chromatography was used for separation, wherein the column chromatography solid phase was column chromatography silica gel, and the mobile phase was a mixture of petroleum ether and ethyl acetate; the volume ratio of petroleum ether to ethyl acetate was 3:
1.
4. The method for synthesizing dihydroquinoline compounds according to claim 1, characterized in that: The synthesis method of compound 1 is: Step 1: The carbonyl group of compound 3 is reduced to a hydroxyl group in a reaction solvent, and after the reaction is completed, the reaction is quenched with water, and then purified to obtain compound 4; Step 2: Compound 4 and triphenylphosphine hydrobromide were dissolved in acetonitrile and refluxed at 80°C for 12 hours to obtain compound 1; the synthetic route is as follows:
5. The method for synthesizing dihydroquinoline compounds according to claim 4, characterized in that: The reducing agent for the reduction reaction in the first step 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 for 3 hours; the molar volume ratio of compound 3, reaction solvent, reducing agent, triphenylphosphine hydrobromide and acetonitrile is 10mmol:30mL:40mmol:10mmol:30mL, and the reaction solvent is ethanol or dichloromethane; the purification method of compound 4 is: extraction with ethyl acetate.
6. The method for synthesizing dihydroquinoline compounds according to claim 5, characterized in that: The purification method specifically comprises the following steps: after the reduction reaction is completed, water is added for quenching, extraction is performed three times with 50 mL of ethyl acetate, and the mixture is washed with saturated brine. After the reaction is completed, anhydrous sodium sulfate is added for drying, and the solvent is removed by rotary evaporation to obtain (2-aminophenyl)(phenyl)methanol or a derivative thereof.
7. The method for synthesizing dihydroquinoline compounds according to claim 4, characterized in that: After the second step reflux reaction, the product is fully washed with ether until white and dried.
8. The method for synthesizing dihydroquinoline compounds according to claim 1, characterized in that: The synthetic route of compound 2 is as follows: Where R 1 For H, R 2 is H or Br, R 3 It is H, CF3, Cl or Br.
9. The method for synthesizing dihydroquinoline compounds according to claim 8, characterized in that: The reaction temperature in the synthesis of compound 2 is 80-120° C., and the reaction solvent is toluene. The purification method of compound 2 is: separation by column chromatography, wherein the column chromatography solid phase is column chromatography silica gel, and the mobile phase is petroleum ether and / or ethyl acetate.
10. The method for synthesizing dihydroquinoline compounds according to claim 9, characterized in that: The molar volume ratio of compound 5, compound 6 and toluene is 16.6 mmol: 49.9 mmol: 21.2 mL. Compound 5, compound 6 and toluene are kept in reflux at 80-120° C. for 48 hours. After cooling to room temperature, the solvent is evaporated, washed with mobile phase, and air-dried to obtain compound 2.