Synthesis method of quinoline compound
The [4+2] circular reaction was performed in organic solvents through compounds and compound 2 in organic solvents. Synthesis, high yield and economy economy.
Patent Information
- Application Number
- CN202411450924.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-17
- Publication Date
- 2025-01-21
- Estimated Expiration
- 2044-10-17
AI Technical Summary
The existing quinoline compound synthesis methods have problems such as the use of catalysts and acid-base reagents, the reaction conditions are not green, and the scope of application is narrow.
The compound 1 and compound 2 are carried out in organic solvents. The [4+2] circular reaction is generated. The intermediate is generated by high temperature conditions and inter -inter -inter -inter -inter -messed. The dehydration is dehydrated to obtain the target pyrine -type compound, and no catalyst and acid and alkali reagent are required.
The green synthesis of pyrine -like compounds has a mild response conditions, the raw materials are easy to be available and the price is low, and the yield is as high as 90%.
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Figure CN119330879A_ABST
Abstract
Description
Technical Field
[0001] The 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 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. The current methods for synthesizing quinoline include 2-aminoaryl ketone and N, N-dimethylenamine enamine in toluenesulfonic acid as a catalyst to generate quinoline, or zinc chloride as a catalyst to synthesize quinoline. These methods have the disadvantages of narrow application range, reaction conditions requiring acid, base or metal participation, 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 at 90-110° C. in an organic solvent, and the target quinoline compounds are obtained after purification. The synthetic route is as follows:
[0005]
[0006] Where R is H, halogen, -OC 1-3 Any one of .
[0007] Enaminone generates an intermediate under high temperature conditions, and then the intermediate reacts with reactant 1 to obtain a new intermediate, which is then subjected to 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 is reduced to a hydroxyl group in ethanol, and after the reaction is completed, the reaction is quenched with water and compound 4 is obtained by extraction;
[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 the 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 and compound 2 react in one step, the reaction is green and does not require any additives and 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 quinoline derivatives 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 The H-NMR spectrum of (4-methoxyphenyl)(4-phenylquinolin-3-yl)methanone synthesized in Example 1;
[0028] Figure 3 The NMR carbon spectrum of (4-methoxyphenyl)(4-phenylquinolin-3-yl)methanone synthesized in Example 1;
[0029] Figure 4 The 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 The H-NMR spectrum of (4-chlorophenyl)(4-phenylquinolin-3-yl)methanone synthesized in Example 3;
[0032] Figure 7 The NMR carbon spectrum of (4-chlorophenyl)(4-phenylquinolin-3-yl)methanone synthesized in Example 3;
[0033] Figure 8 The H-NMR spectrum of (4-bromophenyl)(4-phenyl-1,4-dihydroquinolin-3-yl)methanone synthesized in Example 4;
[0034] Fig. 9 The NMR carbon spectrum of (4-bromophenyl)(4-phenyl-1,4-dihydroquinolin-3-yl)methanone synthesized in Example 4;
[0035] Fig.10 The H-NMR spectrum of (4-fluorophenyl)(4-phenyl-1,4-dihydroquinolin-3-yl)methanone synthesized in Example 5;
[0036] Fig.11 The carbon 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 is further described below in conjunction with embodiments.
[0038] Example 1
[0039] The quinoline compound of the present invention, R is -OMe, its chemical name is (4-methoxyphenyl) (4-phenylquinolin-3-yl) ketone, and its structure is as follows:
[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 mixture was heated to 70° C. for reaction for 3 hours. After the reaction was completed, water was added to quench the mixture, and the mixture was 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 (400 MHz, DMSO-d 6 )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] Add p-methoxyacetophenone (16.6 mmol), N,N-dimethylformamide dimethyl acetal (49.9 mmol) and toluene (21.2 mL) into a 100 mL reaction flask and reflux for 48 hours. Cool to room temperature and evaporate the solvent. Wash with petroleum ether and air dry.
[0050] The NMR data of the compound are: 1H NMR (400MHz, CDCl 3)δ7.90(d,J=8.8Hz,2H),7.78(d,J=12.4Hz,1H),6.90(d,J=8.8Hz,2H),5.70(d,J=12.4Hz,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, and 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, and the eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 10:1; 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-methoxyphenyl)(4-phenylquinolin-3-yl)methanone.
[0054] like Figure 2 The H NMR data of the compound are as follows: 1H NMR (400MHz, CDCl 3 )δ8.94(s,1H),8.21(d,J=8.3Hz,1H),7.80-7.75(m,2H),7.63-7.59(m,2H),7.52 (ddd,J=8.3,6.9,1.2Hz,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, CDCl 3 )δ195.2,163.9,148.8,148.5,146.7,135.1,132.4(d,J=9.9Hz),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, R is Ph, its chemical name is [1,1'-biphenyl]-4-yl (4-phenylquinoline-3-yl)methanone, and its structural formula is as follows:
[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 mixture was heated to 70° C. for reaction for 3 hours. After the reaction was completed, water was added to quench the mixture, and the mixture was 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 (400 MHz, DMSO-d 6 )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] Add p-phenylacetophenone (16.6 mmol), N,N-dimethylformamide dimethyl acetal (49.9 mmol) and toluene (21.2 mL) into a 100 mL reaction flask and reflux for 48 hours. Cool to room temperature and evaporate the solvent. Wash with petroleum ether and air dry.
[0068] The NMR data of the compound are as follows: 1H NMR (400MHz, CDCl3 )δ7.99(d,J=8.0Hz,2H),7.83(d,J=12.4Hz,1H),7.67-7.61(m,4H),7.45(t,J=7. 5Hz,2H),7.36(t,J=7.3Hz,1H),5.76(d,J=12.4Hz,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, and 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, and the eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 10:1; 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 [1,1'-biphenyl]-4-yl(4-phenylquinoline-3-yl)methyl ketone.
[0072] like Figure 4 , the H NMR spectrum data of the compound is: 1 H NMR (400 MHz, CDCl 3 )δ9.02(s,1H),8.25(d,J=8.3Hz,1H),7.84-7.78(m,2H),7.71-7.68(m,2H),7.5 8-7.50(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 (101 MHz, CDCl 3 )δ196.4,148.6,146.0,139.8,136.1,135.1,132.0,130.6(d,J=12.8Hz),130.2,1 29.9, 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, R is -Cl, its chemical name is (4-chlorophenyl) (4-phenylquinoline-3-yl) ketone, and its structural formula is as follows:
[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 mixture was heated to 70° C. for reaction for 3 hours. After the reaction was completed, water was added to quench the mixture, and the mixture was 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 (400 MHz, DMSO-d 6 )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] Add p-chloroacetophenone (16.6 mmol), N,N-dimethylformamide dimethyl acetal (49.9 mmol) and toluene (21.2 mL) into a 100 mL reaction flask and reflux for 48 hours. Cool to room temperature and evaporate the solvent. Wash with petroleum ether and air dry.
[0086] The NMR data of this compound are: 1 H NMR (400 MHz, CDCl 3 )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, and finally 1 mL of dimethyl sulfoxide was added to react at 100° 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 10:1; 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-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 (400 MHz, CDCl 3 )δ8.97(s,1H),8.22(d,J=8.3Hz,1H),7.81-7.76(m,2H),7.55-7.50(m,3 H),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 (101 MHz, CDCl 3 )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, R is -Br, its chemical name is (4-bromophenyl) (4-phenylquinoline-3-yl) ketone, and its structural formula is as follows:
[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 mixture was heated to 70° C. for reaction for 3 hours. After the reaction was completed, water was added to quench the mixture, and the mixture was 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 (400 MHz, DMSO-d 6 )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] Add p-bromoacetophenone (16.6 mmol), N,N-dimethylformamide dimethyl acetal (49.9 mmol) and toluene (21.2 mL) into a 100 mL reaction flask and reflux for 48 hours. Cool to room temperature and evaporate the solvent. Wash with petroleum ether and air dry.
[0104] like Figure 8 , the NMR data of the compound are: 1 H NMR (400 MHz, CDCl 3 )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 stirring magnetic bar was added, and 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, and the eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 10:1; 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-bromophenyl)(4-phenylquinolin-3-yl)methanone.
[0108] like Fig. 9 , the H NMR spectrum data of the compound is: 1 H NMR (400 MHz, CDCl 3 )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 Fig.10 , the NMR carbon spectrum data of the compound is: 13 CNMR (101MHz, CDCl 3)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-phenylquinoline-3-yl) (p-fluoro) ketone, and has the structural formula:
[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 mixture was heated to 70° C. for reaction for 3 hours. After the reaction was completed, water was added to quench the mixture, and the mixture was 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 (400 MHz, DMSO-d 6 )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] Add p-fluoroacetophenone (16.6 mmol), N,N-dimethylformamide dimethyl acetal (49.9 mmol) and toluene (21.2 mL) into a 100 mL reaction flask and reflux for 48 hours. Cool to room temperature and evaporate the solvent. Wash with petroleum ether and air dry.
[0122] The NMR data of this compound are: 1 H NMR (400 MHz, CDCl 3 )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, and 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, and the eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 10:1; 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-phenylquinolin-3-yl)(p-fluoro)ketone.
[0126] like Fig.10 , the H NMR spectrum data of the compound is: 1 H NMR (400 MHz, CDCl 3 )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 Fig.11 , the NMR carbon spectrum data of the compound is: 13 C NMR (101 MHz, CDCl 3)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, and the target quinoline compound is obtained after purification. The synthetic route is as follows: Where R is H, halogen, -OC 1-3 Any one of .
2. The synthetic method of quinoline compounds according to claim 1, characterized in that, The molar ratio of the compound 2 to the compound 1 is 1:1.1-2.
3. The synthetic method of quinoline compounds according to claim 1, characterized in that, The solvent for the reaction is dimethyl sulfoxide, dichloromethane or ethanol.
4. The method for synthesizing quinoline compounds according to claim 1, characterized in that: The purification method comprises: adopting column chromatography to separate, 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 method for synthesizing quinoline compounds according to claim 1, characterized in that: The volume ratio of petroleum ether to ethyl acetate is 1 to 10:
1.
6. The method for synthesizing quinoline compounds according to claim 1, characterized in that: The synthesis method of compound 1 is: (1) The carbonyl group of compound 3 is reduced to a hydroxyl group in ethanol, and 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 a substitution reaction to obtain compound 1. The synthetic route is as follows:
7. The method for synthesizing quinoline compounds according to claim 6, characterized in that: In step (1), the reducing agent of the reduction reaction is sodium borohydride, which is first added at -10 to 10°C, and then heated to 60 to 100°C for reaction.
8. The method for synthesizing quinoline compounds according to claim 1, characterized in that: In step (2), during the substitution reaction, the reaction temperature is 60 to 100°C.
9. The method for synthesizing quinoline compounds according to claim 1, characterized in that: The synthesis method of the compound 2 is: 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, characterized in that: The reaction temperature is 80-120°C.
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Method for preparing quinoline derivative
CN120271504A