CN117229206B - A method for preparing polysubstituted 2-quinolinone compounds by base catalysis - Google Patents
A method for preparing polysubstituted 2-quinolinone compounds by base catalysis Download PDFInfo
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Abstract
The invention provides a high-efficiency preparation method for preparing polysubstituted 2-quinolinone by using 2-aminobenzophenone compounds and monoethyl malonate acyl chloride through the action of alkali, which mainly comprises the steps of adding 2-aminobenzophenone compounds and imidazole into corresponding solvents, slowly dripping monoethyl malonate acyl chloride into the reaction system under low-temperature stirring, heating to react for several hours, adding water to quench the reaction, extracting with ethyl acetate, separating liquid, drying, filtering, concentrating, and separating by column chromatography to obtain the product. The preparation and synthesis method is simple and effective in operation, mild in reaction condition, high in yield and easy to amplify production, does not need inert gas protection, can well solve the technical problem that the existing polysubstituted 2-quinolinone compound has a complicated preparation route, and can provide an efficient synthesis method for preparing natural products or medicines containing a 2-quinolinone skeleton.
Description
Technical Field
The invention belongs to the field of medicinal chemistry and active heterocyclic compounds, and particularly relates to a preparation method for synthesizing a polysubstituted 2-quinolinone compound by an imidazole-promoted one-pot method.
Background
2-Quinolinone is an important class of nitrogen-containing heterocyclic compounds, and is widely used for synthesis of drug molecules and various functional materials due to its unique parent skeleton structure. The nitrogenous heterocyclic compounds generally have good pharmaceutical activity, such as anticancer, antibacterial, antimalarial and Alzheimer disease treatment, schizophrenia treatment and the like. In addition, 2-quinolinone compounds are also important organic synthesis intermediates for the synthesis of fused heterocyclic compounds.
At present, the synthesis method of the 2-quinolinone compound is mainly reported to be a method such as a serial cyclization reaction (scheme 1 a) of aniline and alkyne, an intramolecular Houben-Hoesch reaction (scheme 1 b), pd catalyzed carbonyl insertion (scheme 1 c), stepwise amidation condensation, a strong base promoted intramolecular addition cyclization reaction (scheme 1 d) and the like. Although the method enriches the synthetic approaches of the 2-quinolinone compound, the method still has the defects of harsh reaction conditions, expensive catalyst or substrate, complicated steps and the like. Therefore, the development of a method for preparing the 2-quinolinone compound has the advantages of simple operation, mild condition, high yield and good substrate universality.
Aiming at the problems, the invention aims to design the efficiency and the method for constructing the diversity of the 2-quinolinone skeleton structure by starting from 2-aminobenzophenone and reacting with monoethyl malonate acyl chloride under the promotion of alkali without inert gas protection and directly synthesizing the 2-quinolinone compound by a one-pot method (the prior synthetic methods 1a-1d and the conception route 1e are shown in the following figures).
The condensation, addition and cyclization of the alkali-promoted 2-aminobenzophenone and the monoethyl malonate acyl chloride under mild conditions are the high-efficiency synthesis method which is feasible in theory, has obvious step economy and is in accordance with the green chemistry concept. The invention uses proper amount of alkali finally through optimized screening, has the functions of alkali and intramolecular aldol condensation catalyst, can promote amidation reaction and intramolecular addition cyclization reaction under mild conditions, and finally realizes the technical route of preparing polysubstituted 2-quinolinone compounds by an imidazole-promoted high-efficiency 'one-pot method'.
Disclosure of Invention
Aiming at the defects and drawbacks existing in the prior art, the invention discovers that under the mild condition, some alkali can promote the condensation, addition and cyclization 'one-pot method' reaction of 2-aminobenzophenone and monoethyl malonate acyl chloride under the mild condition, and can smoothly prepare the polysubstituted 2-quinolinone compound, thereby providing an efficient synthesis method of the polysubstituted 2-quinolinone compound promoted by the alkali, further developing a more efficient and convenient synthesis technical route, and the method has the characteristics of good substrate adaptability, low price and easy availability of used alkali, simple operation, mild reaction condition, easy scale-up production and the like.
The technical scheme provided by the invention is as follows:
A preparation method for synthesizing polysubstituted 2-quinolinone compounds by base catalysis is characterized by comprising the following steps:
1) Adding the 2-aminobenzophenone compound and alkali into a corresponding solvent methylene dichloride according to a molar ratio of 1:1.5, so that the solute concentration of the 2-aminobenzophenone compound reaches 0.5mol/L;
2) Slowly dropwise adding monoethyl malonate acyl chloride into the solution under the condition of stirring and cooling at low temperature, wherein the dosage of the monoethyl malonate acyl chloride is 110% of the molar dosage of the 2-aminobenzophenone compound according to the acyl chloride equivalent which can be provided by the monoethyl malonate acyl chloride;
3) After the dripping of the monoethyl malonate acyl chloride is finished, heating the reaction system to 20-60 ℃, stirring and reacting for 2-24 hours, and then adding water to quench and react;
4) Extracting with ethyl acetate, separating, drying, filtering, concentrating, and purifying to obtain product;
The reaction formula for preparing the polysubstituted 2-quinolinone compounds is as follows:
wherein the number of R 1-R3 substituents may be 0 to 4.
Preferably, the R 1-R3 substituent is one or more selected from F, br, cl, I, CN, CO 2Et、CO2Me、Ac、ArCO、CF3、NO2, C1-8 alkyl, C1-8 alkoxy, et, n-Pr, i-Pr, bu and CH 2 = CH, OMe, OEt, OPr, ph, ar, further, the R 1-R3 substituent is one or more selected from F, br, cl, I, CN, CO 2Et、CO2Me、Ac、ArCO、CF3、NO2, and further, the R 1-R3 substituent is one or more selected from Me, et, n-Pr, i-Pr, bu and CH 2 = CH, OMe, OEt, OPr, ph, ar.
Preferably, the base in step 1) may be selected from KOH, naOH, K 2CO3,Na2CO3,Cs2CO3, DBU, triethylamine, imidazole, N-methylimidazole, further, the base may be preferably imidazole.
Preferably, the stirring speed of the step 2) is 200-500r/min, and further, the stirring speed of the step 2) is 300r/min.
Preferably, the cryogenically cooled conditions in step 2) may be selected from ice baths.
Preferably, the heating temperature in the step 3) is 40-60 ℃, and further, the heating temperature in the step 3) can be selected to be 50 ℃ or 60 ℃.
The preparation method for synthesizing the polysubstituted 2-quinolinone compound by the 'one-pot method' base catalysis has the following beneficial effects:
1. The 'one-pot method' is used for efficiently constructing the polysubstituted 2-quinolinone parent skeleton, greatly simplifying the operation, shortening the synthetic technical route, overcoming the defects of noble metal catalysis, harsh reaction conditions, complicated multi-step synthesis and the like.
2. The equivalent imidazole is used as a base catalyst, and the raw materials are cheap and easy to obtain. Imidazole not only can be used as a catalyst for catalyzing aldol condensation in molecules, but also can be used as an amidation acid-binding agent, and finally, the purpose of synthesizing the 2-quinolinone compound by a one-pot method is achieved conveniently.
3. The method has the characteristics of good substrate applicability, mild reaction conditions, no need of inert gas protection, simple synthesis steps, less side reaction, good product yield, short time consumption, simple and convenient operation, easy amplification, good safety and reliability and the like.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum 1H-NMR(400MHz ind6 -DMSO of product 3a of example 1
FIG. 2 is a nuclear magnetic resonance spectrum 13C-NMR(400MHz in d6 -DMSO of product 3a of example 1
FIG. 3 is a nuclear magnetic resonance hydrogen spectrum 1H-NMR(400MHz in d6 -DMSO of product 3b of example 2
FIG. 4 is a nuclear magnetic resonance spectrum 13C-NMR(400MHz in d6 -DMSO of product 3b of example 2
FIG. 5 is a nuclear magnetic resonance hydrogen spectrum 1H-NMR(400MHz in d6 -DMSO of product 3c of example 3
FIG. 6 is a nuclear magnetic resonance spectrum 13C-NMR(400MHz in d6 -DMSO of product 3c of example 3
FIG. 7 is a nuclear magnetic resonance hydrogen spectrum 1H-NMR(400MHz in d6 -DMSO of product 3d of example 4
FIG. 8 is a nuclear magnetic resonance spectrum 13C-NMR(400MHz in d6 -DMSO of the product 3d of example 4
FIG. 9 is a nuclear magnetic resonance hydrogen spectrum 1H-NMR(400MHz in d6 -DMSO of product 3e of example 5
FIG. 10 is a nuclear magnetic resonance spectrum 13C-NMR(400MHz in d6 -DMSO of product 3e of example 5
FIG. 11 is a nuclear magnetic resonance hydrogen spectrum 1H-NMR(400MHz in d6 -DMSO of product 3f of example 6
FIG. 12 is a nuclear magnetic resonance spectrum 13C-NMR(400MHz in d6 -DMSO of product 3f of example 6
FIG. 13 is a nuclear magnetic resonance hydrogen spectrum 1H-NMR(400MHz ind6 -DMSO of the product of example 1, 3g
FIG. 14 is a nuclear magnetic resonance spectrum 13C-NMR(400MHz in d6 -DMSO of 3g of the product of example 1
FIG. 15 is a nuclear magnetic resonance hydrogen spectrum 1H-NMR(400MHz in d6 -DMSO of the product of example 2, 3h
FIG. 16 is a nuclear magnetic resonance spectrum 13C-NMR(400MHz in d6 -DMSO of the product of example 2, 3h
FIG. 17 is a nuclear magnetic resonance hydrogen spectrum 1H-NMR(400MHz in d6 -DMSO of product 3i of example 3
FIG. 18 is a nuclear magnetic resonance spectrum 13C-NMR(400MHz in d6 -DMSO of product 3i of example 3
FIG. 19 is a nuclear magnetic resonance hydrogen spectrum 1H-NMR(400MHz in d6 -DMSO of product 3j of example 4
FIG. 20 is a nuclear magnetic resonance spectrum 13C-NMR(400MHz in d6 -DMSO of product 3j of example 4
FIG. 21 is a nuclear magnetic resonance hydrogen spectrum 1H-NMR(400MHz in d6 -DMSO of product 3k of example 5
FIG. 22 is a nuclear magnetic resonance spectrum 13C-NMR(400MHz in d6 -DMSO of the product 3k of example 5
FIG. 23 is a nuclear magnetic resonance hydrogen spectrum 1H-NMR(400MHz in d6 -DMSO of product 3l of example 6
FIG. 24 is a nuclear magnetic resonance spectrum 13C-NMR(400MHz in d6 -DMSO of the product 3l of example 6
Detailed Description
The reaction parameter conditions of examples 1-12 and the amplification reactions 1-1 to 1-9 are selected according to the invention by setting different alkali types, solvent conditions, heating temperatures and reaction substrate concentrations on the basis of the reactant raw materials of example 1, and searching and comparing the obtained materials with the reference table 1. The separation yields of examples 1-12 and the amplification reaction are all higher than 70%, which shows that the condensation, addition and cyclization 'one-pot method' reaction of the imidazole-promoted 2-aminobenzophenone and the malonic acid monoethyl ester acyl chloride obtained by the invention under mild conditions is very efficient, and the synthesis method for preparing the polysubstituted 2-quinolinone compound has very good conversion application value.
Example 1
The specific preparation method of the compound 4-phenyl-2-quinolinone-3-carboxylic acid ethyl ester (3 a) comprises the following steps:
2-aminobenzophenone (1.0 mmol) and imidazole (1.5 mmol) were added to the corresponding solvents dichloromethane (2.0 mol/L), and monoethyl malonate acyl chloride (1.1 eq.) was slowly added dropwise to the reaction system under stirring and cooling at low temperature. After the acid chloride is added dropwise, heating under the air without inert gas protection and keeping the temperature of 50 ℃ for reacting for 12 hours, adding 10mL of water for quenching reaction after TLC inspection until the reaction is complete, extracting (10 mL of 3) with ethyl acetate, drying, filtering and concentrating after liquid separation to obtain a crude product, separating and purifying by column chromatography to obtain a pure product 3a, and separating and producing MHz,DMSO-d6)δ165.1,158.6,148.5,138.7,134.1,131.6,129.0,128.6,128.5,127.1,126.7,122.5,118.3,115.8,60.6,13.6ppm, As shown in FIG. 2, HRMS (ESI) m/z calcd for C 18H15NO3Na[M+Na]+:316.0950, found:316.0942.
Example 1-1 (amplification reaction)
The compound 4-phenyl-2-quinolinone-3-carboxylic acid ethyl ester (3 a) is amplified by the following preparation method:
2-aminobenzophenone (10 mmol) and imidazole (15 mmol) were added to the corresponding solvents dichloromethane (2.0 mol/L), and after cooling at low temperature under stirring, monoethyl malonate acid chloride (1.1 eq.) was slowly added dropwise to the reaction system. After the acid chloride is added dropwise, the mixture is heated and kept at 50 ℃ for reaction for 12 hours under the protection of inert gas without the protection of air, 100mL of water is added for quenching reaction after TLC inspection until the reaction is complete, ethyl acetate is used for extraction (100 mL of 3), the mixture is separated, dried, filtered and concentrated to obtain a crude product, and the crude product is separated and purified by column chromatography to obtain a pure product 3a (2.78 g, separation yield is 95%).
Example 2
The specific preparation method of the compound 6-chloro-4-phenyl-2-quinolinone-3-carboxylic acid ethyl ester (3 b) is as follows:
2-amino-5-chlorobenzophenone (1.0 mmol) and imidazole (1.5 mmol) were added to the corresponding solvents dichloromethane (2.0 mol/L), and after cooling at low temperature with stirring, monoethyl malonate acid chloride (1.1 eq.) was slowly added dropwise to the reaction system. After the acid chloride is added dropwise, the method does not need to be inert And structural characterization data as follows ：1H NMR(400MHz,DMSO-d6)δ12.44(s,1H),7.63(dd,J＝8.8,2.4Hz,1H),7.54(dd,J＝5.0,1.7Hz,3H),7.42(d,J＝8.8Hz,1H),7.34(dd,J＝6.6,3.0Hz,2H),7.00(d,J＝2.3Hz,1H),3.95(q,J＝7.1Hz,2H),0.84(t,J＝7.1Hz,3H)ppm, and ;13C NMR(100MHz,DMSO-d6)δ164.7,158.4,147.4,137.5,133.4,131.5,129.3,128.7,128.6,127.7,126.4,125.8,119.6,117.9,60.8,13.5ppm, are shown in FIG. 3 and FIG. 4, HRMS (ESI) m/z calcd for C 18H14ClNO3Na[M+Na]+:350.0560, found:350.0561.
Example 2-1 (amplification reaction)
The compound 4-phenyl-2-quinolinone-3-carboxylic acid ethyl ester (3 b) is amplified by the following preparation method:
2-amino-5-chlorobenzophenone (10 mmol) and imidazole (15 mmol) were added to the corresponding solvents dichloromethane (2.0 mol/L), and after cooling at low temperature with stirring, monoethyl malonate acid chloride (1.1 eq.) was slowly added dropwise to the reaction system. After the acid chloride is added dropwise, the mixture is heated and kept at 50 ℃ for reaction for 12 hours under the protection of inert gas without the protection of air, 100mL of water is added for quenching reaction after TLC inspection until the reaction is complete, ethyl acetate is used for extraction (100 mL of 3), the mixture is separated, dried, filtered and concentrated to obtain a crude product, and the crude product is separated and purified by column chromatography to obtain a pure product 3b (2.95 g, separation yield 90%).
Example 3
The specific preparation method of the compound 6-chloro-4- (2' -fluorophenyl) -2-quinolinone-3-carboxylic acid ethyl ester (3 c) is as follows:
2-amino-5-chloro-2' -fluorobenzophenone (1.0 mmol) and imidazole (1.5 mmol) were added to the corresponding solvents dichloromethane (2.0 mol/L), and after cooling at low temperature under stirring, monoethyl malonate acyl chloride (1.1 eq.) was slowly added dropwise to the reaction system. After the acid chloride is added dropwise, heating under the air without inert gas protection and keeping the temperature of 50 ℃ for reacting for 12 hours, adding 10mL of water for quenching reaction after TLC inspection until the reaction is complete, extracting (10 mL of 3) with ethyl acetate, separating liquid, drying, filtering and concentrating to obtain a crude product, separating and purifying by column chromatography to obtain a pure product 3C, separating and purifying ;13C NMR(101MHz,DMSO-d6)δ164.7,159.1(d,J＝247.5Hz),158.6,142.7,137.8,132.6(d,J＝8.0Hz),132.4,131.2(d,J＝2.0Hz),129.4,127.2,125.6,125.5(d,J＝3.0Hz),121.3(d,J＝17.2Hz),119.6,118.5,116.4(d,J＝20.2Hz),61.4,14.0ppm, Shown in FIG. 5 is shown in FIG. 6 ;HRMS(ESI)m/z calcd for C18H13ClFNO3Na[M+Na]+:368.0466,Found:368.0461.
Example 3-1 (amplification reaction)
The compound 6-chloro-4- (2 '-fluorophenyl) -2-quinolinone-3-carboxylic acid ethyl ester (3 c) was amplified by adding 2-amino-5-chloro-2' -fluorobenzophenone (10 mmol) and imidazole (15 mmol) to the corresponding solvent dichloromethane (2.0 mol/L), cooling under stirring at low temperature, and then slowly dropping malonic acid monoethyl ester acyl chloride (1.1 eq) to the reaction system. After the acid chloride is added dropwise, the mixture is heated and kept at 50 ℃ for reaction for 12 hours under the protection of inert gas without the protection of air, after TLC inspection is carried out until the reaction is complete, 100mL of water is added for quenching reaction, ethyl acetate is used for extraction (100 mL of 3), the mixture is separated, dried, filtered and concentrated to obtain a crude product, and the crude product is separated and purified by column chromatography to obtain a pure product 3C (2.87 g, separation yield is 83%).
Example 4
The specific preparation method of the compound 4- (4' -fluorophenyl) -2-quinolinone-3-carboxylic acid ethyl ester (3 d) is as follows:
2-amino-4' -fluorobenzophenone (1.0 mmol) and imidazole (1.5 mmol) were added to the corresponding solvents dichloromethane (2.0 mol/L), and after cooling at low temperature with stirring, monoethyl malonate acid chloride (1.1 eq.) was slowly added dropwise to the reaction system. After the acid chloride is added dropwise, the reaction is carried out for 12 hours under the condition of heating and keeping the temperature of 50 ℃ in the air without the protection of inert gas, after TLC inspection is carried out until the reaction is complete, 10mL of water is added for quenching the reaction, and then NMR(101MHz,DMSO-d6)δ165.5,δ162.9(d,J＝246.0Hz),159.0,148.1,139.2,132.2,131.5(d,J＝8.4Hz),130.9(d,J＝3.1Hz),127.5,127.5,123.1,118.8,116.2(d,J＝14.9Hz),116.0,61.2,14.1ppm, As shown in FIG. 8, HRMS (ESI) M/z calcd for C 18H14FNO3 Na [ M+Na ] +:334.0855, found:334.0852.
Example 4-1 (amplification reaction)
The compound 4- (4 '-fluorophenyl) -2-quinolinone-3-carboxylic acid ethyl ester (3 d) was amplified by adding 2-amino-4' -fluorobenzophenone (10 mmol) and imidazole (15 mmol) to the corresponding solvent dichloromethane (2.0 mol/L), cooling under stirring at low temperature, and then slowly adding malonic acid monoethyl ester acyl chloride (1.1 eq.) dropwise to the reaction system. After the acid chloride is added dropwise, the mixture is heated and kept at 50 ℃ for reaction for 12 hours under the protection of inert gas without the protection of air, 100mL of water is added for quenching reaction after TLC inspection until the reaction is complete, ethyl acetate is used for extraction (100 mL of 3), the mixture is separated, dried, filtered and concentrated to obtain a crude product, and the crude product is separated and purified by column chromatography to obtain a pure product 3d (2.80 g, separation yield 90%).
Example 5
The specific preparation method of the compound 6-bromo-4-phenyl-2-quinolinone-3-carboxylic acid ethyl ester (3 e) is as follows:
2-amino-5-bromobenzophenone (1.0 mmol) and imidazole (1.5 mmol) were added to the corresponding solvents dichloromethane (2.0 mol/L), and after cooling under stirring at low temperature, monoethyl malonate acid chloride (1.1 eq.) was slowly added dropwise to the reaction system. After the acid chloride is added dropwise, the reaction is carried out for 12 hours under the condition of heating and keeping the temperature of 50 ℃ in the air without the protection of inert gas, after TLC inspection is carried out until the reaction is complete, 10mL of water is added for quenching the reaction, and then (d,J＝1.4Hz,1H),7.54(d,J＝2.2Hz,2H),7.38–7.33(m,3H),7.14(d,J＝2.2Hz,1H),3.95(q,J＝7.1Hz,2H),0.85(t,J＝7.1Hz,3H)ppm, ;13C NMR(100MHz,DMSO-d6)δ164.7,158.3,147.3,137.8,134.2,133.4,129.3,128.8,128.7,128.6,127.7,120.1,118.1,114.2,60.8,13.5ppm, As shown in FIG. 9 and FIG. 10, HRMS (ESI) m/z calcd for C 18H14BrNO3Na[M+Na]+:394.0055, found:394.0047.
Example 5-1 (amplification reaction)
The amplification reaction of ethyl 6-bromo-4-phenyl-2-quinolinone-3-carboxylate (3 e) was carried out by adding 2-amino-5-bromobenzophenone (10 mmol) and imidazole (15 mmol) to the corresponding solvent dichloromethane (2.0 mol/L), cooling under stirring at low temperature, and slowly adding malonic acid monoethyl ester acyl chloride (1.1 eq.) dropwise to the reaction system. After the acid chloride is added dropwise, the mixture is heated and kept at 50 ℃ for reaction for 12 hours under the protection of inert gas without the protection of air, after TLC inspection is carried out until the reaction is complete, 100mL of water is added for quenching reaction, ethyl acetate is used for extraction (100 mL of 3), the mixture is separated, dried, filtered and concentrated to obtain a crude product, and the crude product is separated and purified by column chromatography to obtain a pure product 3e (2.83 g, separation yield is 76%).
Example 6
The specific preparation method of the compound 5, 7-dibromo-2-quinolinone-3-carboxylic acid ethyl ester (3 f) is as follows:
2-amino-4, 6-dibromobenzaldehyde (1.0 mmol) and imidazole (1.5 mmol) were added to the corresponding solvent dichloromethane (2.0 mol/L), and after cooling at low temperature under stirring, monoethyl malonate acyl chloride (1.1 eq) was slowly added dropwise to the reaction system. After the acid chloride is added dropwise, the reaction is carried out for 12 hours under the condition of heating and keeping the temperature of 50 ℃ in the air without the protection of inert gas, after TLC inspection is carried out until the reaction is complete, 10mL of water is added for quenching reaction, 1H) 8.15 (s, 1H), 8.14 (s, 1H), 4.29 (q, J=7.1 Hz, 2H), 1.30 (t, J=7.1 Hz, 3H) ppm, ;13C NMR(100MHz,DMSO-d6)δ163.3,157.9,142.0,137.0,131.0,128.1,124.9,120.2,116.2,113.5,60.8,13.7ppm, as shown in FIG. 11 and FIG. 12 ;HRMS(ESI)m/z calcd for C12H9Br2NO3Na[M+Na]+:395.8847,Found:395.8841.
Example 6-1 (amplification reaction)
The compound 5, 7-dibromo-2-quinolinone-3-carboxylic acid ethyl ester (3 f) was amplified by adding 2-amino-4, 6-dibromobenzaldehyde (10 mmol) and imidazole (15 mmol) to the corresponding solvent dichloromethane (2.0 mol/L), cooling under stirring at low temperature, and then slowly adding malonic acid monoethyl ester acyl chloride (1.1 eq) dropwise to the reaction system. After the acid chloride is added dropwise, the mixture is heated and kept at 50 ℃ for reaction for 12 hours under the protection of inert gas without the protection of air, 100mL of water is added for quenching reaction after TLC inspection until the reaction is complete, ethyl acetate is used for extraction (100 mL of 3), the mixture is separated, dried, filtered and concentrated to obtain a crude product, and the crude product is separated and purified by column chromatography to obtain a pure product 3f (3.30 g, separation yield is 88%).
Example 7
The specific preparation method of the compound 4- (4' -chlorophenyl) -2-quinolinone-3-carboxylic acid ethyl ester (3 g) is as follows:
2-amino-4' -chlorobenzophenone (1.0 mmol) and imidazole (1.5 mmol) were added to the corresponding solvents dichloromethane (2.0 mol/L), and after cooling at low temperature under stirring, monoethyl malonate acid chloride (1.1 eq.) was slowly added dropwise to the reaction system. After the acid chloride is added dropwise, the reaction is carried out for 12 hours under the condition of heating and keeping the temperature of 50 ℃ in the air without the protection of inert gas, after TLC inspection is carried out until the reaction is complete, 10mL of water is added for quenching the reaction, and then the reaction is carried out by using ethyl acetate DMSO-d 6) delta 163.3,157.9,142.0,137.0,131.0,128.1,124.9,120.2,116.2,113.5,60.8,13.7ppm, FIG. 12, FIG. ;HRMS(ESI)m/z calcd for C12H9Br2NO3Na[M+Na]+:395.8847,Found:395.8841.1H NMR(400MHz,DMSO-d6)δ12.33(s,1H),7.63–7.56(m,3H),7.41(d,J＝8.2Hz,1H),7.38–7.34(m,2H),7.18–7.13(m,1H),7.10(dd,J＝8.2,1.4Hz,1H),3.98(q,J＝7.1Hz,2H),0.90(t,J＝7.1Hz,3H)ppm,, FIG. 13, FIG. ;13C NMR(101MHz,DMSO-d6)δ165.0,158.4,147.4,138.7,133.9,132.9,131.8,130.6,128.7,127.037,126.8,122.7,118.1,115.9,60.819,13.6ppm,, FIG. 14, HRMS (ESI) m/z calcd for C 18H14ClNO3Na[M+Na]+:350.0560, found:350.0561.
Example 7-1 (amplification reaction)
The compound 4- (4 '-chlorophenyl) -2-quinolinone-3-carboxylic acid ethyl ester (3 g) was amplified by adding 2-amino-4' -chlorobenzophenone (10 mmol) and imidazole (15 mmol) to the corresponding solvents dichloromethane (2.0 mol/L), cooling under stirring at low temperature, and then slowly dropping malonic acid monoethyl ester acyl chloride (1.1 eq) into the reaction system. After the acid chloride is added dropwise, the mixture is heated and kept at 50 ℃ for reaction for 12 hours under the protection of inert gas without the protection of air, 100mL of water is added for quenching reaction after TLC inspection until the reaction is complete, ethyl acetate is used for extraction (100 mL of 3), the mixture is separated, dried, filtered and concentrated to obtain a crude product, and 3g (2.30 g, 70% of isolated yield) of the pure product is obtained through separation and purification of column chromatography.
Example 8
The specific preparation method of the compound 6-chloro- (2' -chlorophenyl) -2-quinolinone-3-carboxylic acid ethyl ester (3 h) is as follows:
2-amino-5, 2' -dichlorobenzophenone (1.0 mmol) and imidazole (1.5 mmol) were added to the corresponding solvents methylene chloride (2.0 mol/L), and after cooling at low temperature under stirring, monoethyl malonate acid chloride (1.1 eq.) was slowly added dropwise to the reaction system. After the acid chloride is added dropwise, the reaction is carried out for 12 hours under the condition of heating and keeping the temperature of 50 ℃ under the air without the protection of inert gas, after TLC inspection is carried out until the reaction is complete, 10mL of water is added for quenching reaction, ethyl acetate is used for extraction (10 mL of 3), the solution is separated, dried, filtered and concentrated, the crude product is obtained, and the pure product is obtained after separation and purification by column chromatography for 3 hours, the separation yield is 71 percent, the white solid is obtained, and the temperature is mp 218-219 ℃. The structural formula and structural characterization data are shown as follows 1H NMR(400MHz,DMSO-d6) delta
131.8,131.3,130.1,128.6,128.1,127.2,125.6,119.4,118.5,61.3,14.0Ppm as shown in FIG. 16 ;HRMS(ESI)m/z calcd for C18H13Cl2NO3Na[M+Na]+:384.0170,Found:384.0164.
Example 8-1 (amplification reaction)
The compound 6-chloro- (2 '-chlorophenyl) -2-quinolinone-3-carboxylic acid ethyl ester (3 h) was amplified by adding 2-amino-5, 2' -dichlorobenzophenone (10 mmol) and imidazole (15 mmol) to the corresponding solvent dichloromethane (2.0 mol/L), cooling under stirring at low temperature, and then slowly adding malonic acid monoethyl ester acyl chloride (1.1 eq.) dropwise to the reaction system. After the acid chloride is added dropwise, the mixture is heated and kept at 50 ℃ for reaction for 12 hours under the protection of inert gas without the protection of air, 100mL of water is added for quenching reaction after TLC inspection until the reaction is complete, ethyl acetate is used for extraction (100 mL of 3), the mixture is separated, dried, filtered and concentrated to obtain a crude product, and the crude product is separated and purified by column chromatography to obtain a pure product for 3h (2.72 g, separation yield is 75%).
Example 9
The specific preparation method of the N-methyl-6-chloro-phenyl-2-quinolinone-3-carboxylic acid ethyl ester (3 i) is as follows:
N-methyl-2-amino-5-chlorobenzophenone (1.0 mmol) and imidazole (1.5 mmol) were added to the corresponding solvents dichloromethane (2.0 mol/L), and after cooling at low temperature under stirring, monoethyl malonate acyl chloride (1.1 eq.) was slowly added dropwise to the reaction system. After the acid chloride is added dropwise, heating under the air without inert gas protection and keeping the temperature of 50 ℃ for reacting for 12 hours, adding 10mL of water for quenching reaction after TLC inspection until the reaction is complete, extracting (10 mL of 3) with ethyl acetate, drying, filtering and concentrating after liquid separation to obtain a crude product, separating and purifying by column chromatography to obtain a pure product 3i, Chloroform-d)δ165.4,158.8,147.0,138.5,133.8,131.7,129.3,128.9,128.7,128.2,127.9,127.8,121.6,116.0,61.6,30.0,13.8ppm, As shown in FIG. 18, HRMS (ESI) m/z calcd for C 19H16ClNO3Na[M+Na]+:364.0716, found:364.0711.
Example 9-1 (amplification reaction)
N-methyl-6-chloro-phenyl-2-quinolinone-3-carboxylic acid ethyl ester (3 i) was amplified by adding N-methyl-2-amino-5-chlorobenzophenone (10 mmol) and imidazole (15 mmol) to the corresponding solvents dichloromethane (2.0 mol/L), cooling under stirring at low temperature, and then slowly dropping malonic acid monoethyl ester acyl chloride (1.1 eq.) into the reaction system. After the acid chloride is added dropwise, the mixture is heated and kept at 50 ℃ for reaction for 12 hours under the protection of inert gas without the protection of air, 100mL of water is added for quenching reaction after TLC inspection until the reaction is complete, ethyl acetate is used for extraction (100 mL of 3), the mixture is separated, dried, filtered and concentrated to obtain a crude product, and the crude product is separated and purified by column chromatography to obtain a pure product 3i (3.04 g, separation yield is 89%).
Example 10
The specific preparation method of the compound 4-phenyl-2-quinolinone-3-carboxylic acid methyl ester (3 j) comprises the following steps:
2-aminobenzophenone (1.0 mmol) and imidazole (1.5 mmol) were added to the corresponding solvents dichloromethane (2.0 mol/L), and after cooling at low temperature under stirring, monomethyl malonate acid chloride (1.1 equivalent) was slowly added dropwise to the reaction system. After the acid chloride is added dropwise, heating under the air without inert gas protection and keeping the temperature of 50 ℃ for reacting for 12 hours, adding 10mL of water for quenching reaction after TLC inspection until the reaction is complete, extracting (10 mL of 3) with ethyl acetate, drying, filtering and concentrating after liquid separation to obtain a crude product, separating and purifying by column chromatography to obtain a pure product 3j, wherein the separation yield is NMR(101MHz,DMSO-d6)δ165.9,158.6,148.7,138.76,134.1,131.7,129.1,128.6,128.5,127.2,126.6,122.6,118.3,115.9,52.0ppm, As shown in FIG. 20, HRMS (ESI) m/z calcd for C 16H20NO3S[M+H]+:162.1163, found:162.1164.
Example 11
The compound methyl 6-chloro-4-phenyl-2-quinolinone-3-carboxylate (3 k) was specifically prepared by adding 2-amino-5-chlorobenzophenone (1.0 mmol) and imidazole (1.5 mmol) to the corresponding solvents dichloromethane (2.0 mol/L), cooling under stirring at low temperature, and then slowly adding monomethyl malonate acyl chloride (1.1 eq.) dropwise to the reaction system. After the acid chloride is added dropwise, the reaction is carried out for 12 hours under the condition of heating and keeping the temperature of 50 ℃ under the air without the protection of inert gas, after TLC inspection till the reaction is complete, 10mL of water is added for quenching the reaction, and acetic acid is used for1H) 3.48 (s, 3H) ppm, ;13C NMR(101MHz,DMSO-d6)δ165.4,158.4,147.5,137.8,134.3,133.4,129.4,128.9,128.8,128.5,127.6,120.1,118.2,114.2,52.1ppm, as shown in FIG. 21 and FIG. 22, HRMS (ESI) m/z calcd for C 17H12NO3NaBr[M+Na]+:379.9904, found:379.9898.
Example 12
The specific preparation method of the compound 6-bromo-4-phenyl-2-quinolinone-3-carboxylic acid methyl ester (3 l) is as follows: Taking (10 ml. Times.3), drying, filtering and concentrating after separating liquid, obtaining crude product, separating and purifying by column chromatography to obtain pure product 3l, wherein the separation yield is 99%, white solid, mp 233-234 ℃. The structural formula and structural characterization data are ：1H NMR(400MHz,DMSO-d6)δ12.48(s,1H),7.66(dd,J＝8.8,2.4Hz,1H),7.55(d,J＝1.7Hz,1H),7.54(d,J＝2.0Hz,2H),7.43(d,J＝8.8Hz,1H),7.37–7.33(m,2H),7.01(d,J＝2.3Hz,1H),3.48(s,3H)ppm, as shown in FIG. 23 and ;13C NMR(101MHz,DMSO-d6)δ165.5,158.4,147.5,137.5,133.4,131.7,129.4,128.8,128.5,127.6,126.4,125.9,119.6,118.0,52.1ppm, as shown in FIG. 24, HRMS (ESI) m/z calcd for C 17H12NO3NaCl[M+Na]+:336.0402, found:336.0403.
Optimized screening test for reaction conditions
Using example 1 as the test base, the test parameters were adjusted according to the test parameters shown in Table 1 below to investigate the different base conditions, solvent conditions, heating temperature conditions and reaction concentration conditions, and the yield-level comparison data was isolated, and the test results were as follows:
TABLE 1 comparison of isolated yields of 4-phenyl-2-quinolinone-3-carboxylic acid ethyl ester (3 a) under different experimental parameters
From the comparison result of the test, the solvent is dichloromethane, the alkali is imidazole, the temperature is 50 ℃, and the reaction concentration is 2.0mol/L, so that the product yield of the reaction is optimal under the reaction condition. From this experimental data, it was demonstrated that the inventive intent of the present invention could be achieved without selecting conventional base types, conventional solvents, or setting conventional temperature conditions in the synthetic process of the present invention.
It should be understood that while the present description has been described in terms of embodiments, such description is for clarity only, and that the description as a whole should be construed by those skilled in the art to form other embodiments that will be apparent to those skilled in the art, and should also fall within the scope of the invention.
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| CN1203598A (en) * | 1995-12-08 | 1998-12-30 | 詹森药业有限公司 | Farnesyl protein transferase inhibiting (imidazol-5-yl) methyl-2-quinolinone derivatives |
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| PL196955B1 (en) * | 1998-12-04 | 2008-02-29 | Bristol Myers Squibb Co | 3-substituted-4-arylquinolin-2-one derivatives as potassium channel modulators |
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| "Design, synthesis, and biological evaluations of novel quinolones as HIV-1 non-nucleoside reverse transcriptase inhibitors";David Ellis等;Bioorganic & Medicinal Chemistry Letters;20061231;第16卷(第16期);第4246-4251页 * |
| Amandine Carrer等."Synthesis of 3,4-disubstituted quinolin-2-(1H)-ones via palladium-catalyzed decarboxylative arylation reactions".Advanced Synthesis & Catalysis.2013,第355卷(第10期),第2044-2054页. * |
| Chinh T. Bui."One-pot microwave-assisted synthesis of 3,4-disubstituted 2-quinolinones".Synthetic Communications.2014,第44卷(第8期),第1122-1127页. * |
| 刘怡阳等;刘怡阳等;延安大学学报（自然科学版）;20230920;第42卷(第3期);第7-12页 * |
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