A method for preparing polysubstituted 2-quinolinone compounds by base catalysis
By reacting 2-aminobenzophenone with monoethyl malonic acid chloride in one pot under the promotion of alkali, using imidazole as a catalyst, the reaction conditions in the existing 2-quinolinone synthesis method are solved and harsh and harsh reaction conditions are used in the existing 2-quinolinone synthesis method and The steps are complicated, and the synthesis of multiple substituted 2-quinolinone compounds under efficient and mild conditions has been achieved, with high yield and good substrate applicability.
Patent Information
- Application Number
- CN202311204082.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-09-18
- Publication Date
- 2025-01-03
- Estimated Expiration
- 2043-09-18
AI Technical Summary
The existing synthesis methods of 2-quinolinone compounds have insufficient reaction conditions, expensive catalysts, cumbersome steps, and lack methods with simple operation, mild conditions, high yields, and universal substrates.
Under the promotion of the alkali, 2-aminobenzophenone and monoethyl malonic acid chloride undergo a one-pot condensation, addition and cyclization reaction under mild conditions, using imidazole as the base catalyst to achieve multiple substitutions of 2-quine under mild conditions. Highly efficient synthesis of linone compounds.
The synthesis route is simplified, and the use of precious metal catalysis is reduced. The reaction conditions are mild, the yield is high, the substrate is suitable for easy operation, and it is suitable for large-scale production.
Smart Images
Figure CN117229206B_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the field of medicinal chemistry and active heterocyclic compounds, and specifically relates to a preparation method for synthesizing polysubstituted 2-quinolinone compounds in a one-pot manner promoted by imidazole. Background Art
[0002] 2-Quinolinone is an important class of nitrogen-containing heterocyclic compounds, which are widely used in the synthesis of drug molecules and various functional materials due to their unique parent skeleton structure. This class of nitrogen-containing heterocyclic compounds usually has good drug activity, such as anti-cancer, anti-bacterial, anti-malarial, and treatment of Alzheimer's disease and schizophrenia. In addition, 2-quinolinone compounds are also an important organic synthesis intermediate for the synthesis of fused heterocyclic compounds.
[0003] At present, the reported synthesis methods of 2-quinolinone compounds mainly include the tandem cyclization reaction of aniline and alkyne (scheme 1a), intramolecular Houben-Hoesch reaction (scheme 1b), Pd-catalyzed carbonyl insertion (scheme 1c), step-by-step amidation condensation and strong base-promoted intramolecular addition cyclization reaction (scheme 1d), etc. Although the above methods have enriched the synthetic pathways of 2-quinolinone compounds, there are still shortcomings such as harsh reaction conditions, expensive catalysts or substrates, and cumbersome steps. Therefore, it is of great significance to develop a method for preparing 2-quinolinone compounds with simple operation, mild conditions, high yield, and good substrate universality.
[0004] In view of the above problems, the present invention intends to design a one-pot method to efficiently synthesize 2-quinolinone compounds starting from 2-aminobenzophenone, under the promotion of base, with ethyl malonate chloride, without the need for inert gas protection, and further improve and optimize the efficiency and method of constructing the diversity of 2-quinolinone skeleton structures (the existing synthesis methods 1a-1d and the inventive concept route 1e are shown in the figure below).
[0005]
[0006] The base-promoted condensation, addition and cyclization "one-pot" reaction of 2-aminobenzophenone and ethyl malonate chloride under mild conditions is a theoretically feasible and efficient synthesis method with obvious step economy and in line with the concept of green chemistry. After optimization and screening, the present invention finally uses an appropriate amount of base, which has both alkalinity and intramolecular aldol condensation catalyst functions, and can promote the amidation reaction and intramolecular addition and cyclization reaction under mild conditions, and finally realizes the technical route of preparing polysubstituted 2-quinolinone compounds by the efficient "one-pot" method promoted by imidazole. Summary of the invention
[0007] In view of the shortcomings and drawbacks existing in the prior art, the present invention has found through experimental exploration that under mild conditions, some bases can promote the condensation, addition and cyclization "one-pot" reaction of 2-aminobenzophenone and monoethyl malonate chloride under mild conditions, and can smoothly prepare polysubstituted 2-quinolinone compounds. Based on this, a high-efficiency synthesis method of polysubstituted 2-quinolinone compounds promoted by a base is provided, thereby developing a more efficient and convenient synthesis technology route, and the method has the characteristics of good substrate adaptability, cheap and easily available bases, simple operation, mild reaction conditions, and easy large-scale production.
[0008] The technical solution provided by the present invention is specifically as follows:
[0009] A method for preparing polysubstituted 2-quinolinone compounds by base catalysis, characterized in that it comprises the following steps:
[0010] 1) adding a 2-aminobenzophenone compound and a base into a corresponding solvent, dichloromethane, at a molar ratio of 1:1.5, so that the solute concentration of the 2-aminobenzophenone compound reaches 0.5 mol / L;
[0011] 2) under stirring, slowly adding ethyl malonate chloride to the above solution under low temperature cooling, wherein the amount of ethyl malonate chloride used is 110% of the molar amount of the 2-aminobenzophenone compound according to the acyl chloride equivalent it can provide;
[0012] 3) After the addition of the ethyl malonate chloride is complete, the reaction system is heated to 20-60° C., stirred for 2-24 hours, and then water is added to quench the reaction;
[0013] 4) extracting with ethyl acetate, drying after separation, filtering, concentrating, and purifying to obtain the product;
[0014] The reaction formula for preparing the polysubstituted 2-quinolinone compounds is:
[0015]
[0016] The number of R1-R3 substituents can be 0-4.
[0017] Preferably, the types of the R1-R3 substituents can be selected from one or more of F, Br, Cl, I, CN, CO2Et, CO2Me, Ac, ArCO, CF3, NO2, C1-8 alkyl, C1-8 alkoxy, Et, n-Pr, i-Pr, Bu, CH2=CH, OMe, OEt, OPr, Ph, Ar; further, the R1-R3 substituents can be selected from one or more of F, Br, Cl, I, CN, CO2Et, CO2Me, Ac, ArCO, CF3, NO2; further, the R1-R3 substituents can be selected from one or more of Me, Et, n-Pr, i-Pr, Bu, CH2=CH, OMe, OEt, OPr, Ph, Ar.
[0018] Preferably, in step 1), the base can be selected from KOH, NaOH, K2CO3, Na2CO3, Cs2CO3, DBU, triethylamine, imidazole, N-methylimidazole, and further, the base can be preferably imidazole.
[0019] Preferably, the stirring rate of step 2) is 200-500 r / min, and further, the stirring rate of step 2) is 300 r / min.
[0020] Preferably, the low temperature cooling condition in step 2) can be an ice bath.
[0021] Preferably, the heating temperature in step 3) is 40-60°C, and further, the heating temperature in step 3) can be selected to be 50°C or 60°C.
[0022] The 'one-pot' base-catalyzed synthesis method for preparing polysubstituted 2-quinolinone compounds proposed in the present invention has the following beneficial effects:
[0023] 1. The one-pot method is used to efficiently construct the polysubstituted 2-quinolinone parent skeleton, which greatly simplifies the operation, shortens the synthesis technology route, and overcomes the shortcomings of the need for precious metal catalysis, harsh reaction conditions, and cumbersome multi-step synthesis.
[0024] 2. Using an equivalent amount of imidazole as a base catalyst, the raw material is cheap and readily available. Imidazole can not only act as a catalyst for catalyzing intramolecular aldol condensation, but also as an acid-binding agent for amidation, ultimately achieving a convenient one-pot synthesis of 2-quinolinone compounds.
[0025] 3. This method has good substrate applicability, mild reaction conditions, and no need for inert gas protection. The reactions involved in synthesizing the target product have the characteristics of simple synthesis steps, few side reactions, good product yield, short time consumption, simple operation, easy scale-up, good safety and reliability, etc. BRIEF DESCRIPTION OF THE DRAWINGS
[0026] Figure 1 This is the H NMR spectrum of product 3a in Example 1 1 H-NMR (400MHz ind6-DMSO)
[0027] Figure 2 The NMR carbon spectrum of the product 3a in Example 1 is 13 C-NMR (400MHz in d6-DMSO)
[0028] Figure 3 This is the H NMR spectrum of product 3b of Example 2 1 H-NMR (400MHz in d6-DMSO)
[0029] Figure 4 The NMR carbon spectrum of the product 3b of Example 2 is 13 C-NMR (400MHz in d6-DMSO)
[0030] Figure 5 This is the H NMR spectrum of product 3c of Example 3 1 H-NMR (400MHz in d6-DMSO)
[0031] Figure 6 The NMR carbon spectrum of the product 3c of Example 3 is 13 C-NMR (400MHz in d6-DMSO)
[0032] Figure 7 This is the H NMR spectrum of product 3d of Example 4 1 H-NMR (400MHz in d6-DMSO)
[0033] Figure 8 The NMR carbon spectrum of the product 3d of Example 4 is 13 C-NMR (400MHz in d6-DMSO)
[0034] Fig. 9 This is the H NMR spectrum of the product 3e of Example 5 1 H-NMR (400MHz in d6-DMSO)
[0035] Fig.10 The NMR carbon spectrum of the product 3e of Example 5 is 13 C-NMR (400MHz in d6-DMSO)
[0036] Fig.11 This is the H NMR spectrum of the product 3f of Example 6 1 H-NMR (400MHz in d6-DMSO)
[0037] Fig.12This is the NMR carbon spectrum of the product 3f of Example 6 13 C-NMR (400MHz in d6-DMSO)
[0038] Fig.13 This is the H NMR spectrum of product 3g of Example 1 1 H-NMR (400MHz ind6-DMSO)
[0039] Fig.14 The NMR carbon spectrum of the product 3g of Example 1 is 13 C-NMR (400MHz in d6-DMSO)
[0040] Fig.15 This is the H NMR spectrum of the product 3h in Example 2 1 H-NMR (400MHz in d6-DMSO)
[0041] Fig.16 This is the NMR carbon spectrum of the product 3h in Example 2 13 C-NMR (400MHz in d6-DMSO)
[0042] Fig.17 This is the H NMR spectrum of product 3i of Example 3 1 H-NMR (400MHz in d6-DMSO)
[0043] Fig.18 The NMR carbon spectrum of the product 3i of Example 3 is 13 C-NMR (400MHz in d6-DMSO)
[0044] Fig.19 This is the H NMR spectrum of product 3j of Example 4 1 H-NMR (400MHz in d6-DMSO)
[0045] Fig. 20 The NMR carbon spectrum of the product 3j of Example 4 is 13 C-NMR (400MHz in d6-DMSO)
[0046] Fig.21 This is the H NMR spectrum of the product 3k of Example 5 1 H-NMR (400MHz in d6-DMSO)
[0047] Fig. 22 This is the NMR carbon spectrum of the product 3k of Example 5 13 C-NMR (400MHz in d6-DMSO)
[0048] Fig.23This is the H NMR spectrum of product 31 of Example 6 1 H-NMR (400MHz in d6-DMSO)
[0049] Fig.24 The NMR carbon spectrum of the product 31 of Example 6 is 13 C-NMR (400MHz in d6-DMSO) DETAILED DESCRIPTION
[0050] The reaction parameter conditions of Examples 1-12 and amplified reactions 1-1 to 1-9 provided in the present invention are selected based on the reactant raw materials of Example 1, by setting different base types, solvent conditions, heating temperatures and reaction substrate concentrations, and are explored and compared, as shown in Table 1. The separation yields of Examples 1-12 and amplified reactions are all higher than 70%, indicating that the condensation, addition and cyclization "one-pot" reaction of 2-aminobenzophenone and ethyl malonate chloride promoted by imidazole obtained in the present invention under mild conditions to prepare polysubstituted 2-quinolinone compounds is very efficient and has very good conversion application value.
[0051] Example 1
[0052] The specific preparation method of the compound 4-phenyl-2-quinolinone-3-carboxylic acid ethyl ester (3a) is as follows:
[0053] 2-Aminobenzophenone (1.0mmol) and imidazole (1.5mmol) were added to the corresponding solvent dichloromethane (2.0mol / L), and ethyl malonate chloride (1.1 equivalents) was slowly added dropwise to the reaction system under stirring and low temperature cooling conditions. After the addition of the acyl chloride was completed, the reaction was heated and maintained at 50°C under air without inert gas protection for 12 hours. After TLC inspection to see that the reaction was complete, 10mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (10mL*3). After separation, the mixture was dried, filtered, and concentrated to obtain a crude product, which was separated and purified by column chromatography to obtain pure product 3a. 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, such as Figure 2 As shown; HRMS (ESI) m / z calcd for C 18 H 15 NO3Na[M+Na] + :316.0950,Found:316.0942.
[0054] Example 1-1 (Amplification reaction)
[0055] The amplified reaction of the compound 4-phenyl-2-quinolinone-3-carboxylic acid ethyl ester (3a) is as follows:
[0056] 2-Aminobenzophenone (10mmol) and imidazole (15mmol) were added to the corresponding solvent dichloromethane (2.0mol / L), and after cooling under stirring, ethyl malonate chloride (1.1 equivalents) was slowly added dropwise to the reaction system. After the addition of the acyl chloride was completed, the reaction was heated and maintained at 50°C under air for 12 hours without the protection of inert gas. After TLC was checked to see that the reaction was complete, 100mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (100mL*3). After separation, the mixture was dried, filtered, and concentrated to obtain a crude product, which was separated and purified by column chromatography to obtain pure product 3a (2.78g, 95% separation yield).
[0057] Example 2
[0058] The specific preparation method of the compound 6-chloro-4-phenyl-2-quinolinone-3-carboxylic acid ethyl ester (3b) is as follows:
[0059] 2-amino-5-chlorobenzophenone (1.0 mmol) and imidazole (1.5 mmol) were added to the corresponding solvent dichloromethane (2.0 mol / L), and after low temperature cooling under stirring, ethyl malonate chloride (1.1 equivalents) was slowly added dropwise to the reaction system. The structural characterization data are as follows: 1 H 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=8.8 Hz,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, such as Figure 3 As shown; 13 CNMR (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, such as Figure 4 As shown; HRMS (ESI) m / z calcd for C 18 H 14 ClNO3Na[M+Na] +:350.0560,Found:350.0561.
[0060] Example 2-1 (Amplification reaction)
[0061] The amplified reaction of the compound 4-phenyl-2-quinolinone-3-carboxylic acid ethyl ester (3b) is as follows:
[0062] 2-amino-5-chlorobenzophenone (10mmol) and imidazole (15mmol) were added to the corresponding solvent dichloromethane (2.0mol / L), and after cooling under stirring, ethyl malonate chloride (1.1 equivalents) was slowly added dropwise to the reaction system. After the addition of the acyl chloride was completed, the reaction was heated and maintained at 50°C under air without inert gas protection for 12 hours. After TLC inspection to complete the reaction, 100mL of water was added to quench the reaction, and ethyl acetate was used for extraction (100mL*3). After separation, the crude product was dried, filtered, and concentrated to obtain the pure product 3b (2.95g, 90% separation yield) by column chromatography.
[0063] Example 3
[0064] The specific preparation method of the compound 6-chloro-4-(2'-fluorophenyl)-2-quinolinone-3-carboxylic acid ethyl ester (3c) is as follows:
[0065] 2-amino-5-chloro-2'-fluorobenzophenone (1.0mmol) and imidazole (1.5mmol) were added to the corresponding solvent dichloromethane (2.0mol / L), and after cooling at low temperature with stirring, ethyl malonate chloride (1.1 equivalents) was slowly added dropwise to the reaction system. After the addition of the acyl chloride was completed, the reaction was heated and maintained at 50°C under air without inert gas protection for 12 hours. After TLC inspection to see that the reaction was complete, 10mL of water was added to quench the reaction, and ethyl acetate (10mL*3) was used for extraction. After separation, the crude product was dried, filtered, and concentrated to obtain the pure product 3c. The crude product was separated and purified by column chromatography. Figure 5 As shown; 13 C 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=2.0H z), 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, such as Figure 6 HRMS (ESI) m / z calcd for C 18H 13 ClFNO3Na[M+Na] + :368.0466,Found:368.0461.
[0066] Example 3-1 (Amplification reaction)
[0067] The amplified reaction of compound 6-chloro-4-(2'-fluorophenyl)-2-quinolinone-3-carboxylic acid ethyl ester (3c) is as follows: 2-amino-5-chloro-2'-fluorobenzophenone (10mmol) and imidazole (15mmol) are added to the corresponding solvent dichloromethane (2.0mol / L), and after low temperature cooling under stirring, malonic acid monoethyl ester chloride (1.1 equivalents) is slowly added dropwise to the reaction system. After the addition of the acyl chloride is completed, the reaction is heated and maintained at 50°C under air without inert gas protection for 12 hours. After TLC is checked to see that the reaction is complete, 100mL of water is added to quench the reaction, and ethyl acetate is extracted (100mL*3). After separation, the crude product is dried, filtered, and concentrated to obtain the pure product 3c (2.87g, isolated yield 83%).
[0068] Example 4
[0069] The specific preparation method of the compound 4-(4'-fluorophenyl)-2-quinolinone-3-carboxylic acid ethyl ester (3d) is as follows:
[0070] 2-amino-4'-fluorobenzophenone (1.0 mmol) and imidazole (1.5 mmol) were added to the corresponding solvent dichloromethane (2.0 mol / L), and after cooling under stirring, ethyl malonate chloride (1.1 equivalents) was slowly added dropwise to the reaction system. After the addition of the acyl chloride was completed, the reaction was heated and maintained at 50°C under air for 12 hours without the protection of inert gas. After the reaction was complete by TLC, 10 mL of water was added to quench the reaction, and the reaction was continued with 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 Figure 8 HRMS (ESI) m / z calcd for C 18 H 14 FNO3Na[M+Na]+:334.0855,Found:334.0852.
[0071] Example 4-1 (Amplification reaction)
[0072] The amplified reaction of the compound 4-(4'-fluorophenyl)-2-quinolinone-3-carboxylic acid ethyl ester (3d) is as follows: 2-amino-4'-fluorobenzophenone (10mmol) and imidazole (15mmol) are added to the corresponding solvent dichloromethane (2.0mol / L), and after low temperature cooling under stirring, malonic acid monoethyl ester chloride (1.1 equivalents) is slowly added dropwise to the reaction system. After the addition of the acyl chloride is completed, the reaction is heated and maintained at 50°C under air without inert gas protection for 12 hours. After TLC is checked to see that the reaction is complete, 100mL of water is added to quench the reaction, and ethyl acetate is extracted (100mL*3). After separation, the crude product is dried, filtered, and concentrated to obtain the pure product 3d (2.80g, 90% separation yield) by column chromatography.
[0073] Example 5
[0074] The specific preparation method of the compound 6-bromo-4-phenyl-2-quinolinone-3-carboxylic acid ethyl ester (3e) is as follows:
[0075] 2-amino-5-bromobenzophenone (1.0 mmol) and imidazole (1.5 mmol) were added to the corresponding solvent dichloromethane (2.0 mol / L), and after cooling under stirring, ethyl malonate chloride (1.1 equivalents) was slowly added dropwise to the reaction system. After the addition of the acyl chloride was completed, the reaction was heated and maintained at 50°C under air for 12 hours without the protection of inert gas. After the reaction was complete by TLC, 10 mL of water was added to quench the reaction, and the reaction was carried out with (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, such as Fig. 9 As shown; 13 C NMR (100 MHz, DMSO-d6) δ 164.7, 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, 13.5 ppm, as Fig.10 HRMS (ESI) m / z calcd for C 18 H 14 BrNO3Na[M+Na] + :394.0055,Found:394.0047.
[0076] Example 5-1 (Amplification reaction)
[0077] The amplified reaction of ethyl 6-bromo-4-phenyl-2-quinolinone-3-carboxylate (3e) is as follows: 2-amino-5-bromobenzophenone (10 mmol) and imidazole (15 mmol) are added to the corresponding solvent dichloromethane (2.0 mol / L), and after cooling at low temperature under stirring, ethyl malonate chloride (1.1 equivalents) is slowly added dropwise to the reaction system. After the addition of the acyl chloride is completed, the reaction is heated and maintained at 50°C under air without inert gas protection for 12 hours. After TLC is checked to see that the reaction is complete, 100 mL of water is added to quench the reaction, and the mixture is extracted with ethyl acetate (100 mL*3). After separation, the mixture is dried, filtered, and concentrated to obtain a crude product, which is separated and purified by column chromatography to obtain the pure product 3e (2.83 g, 76% separation yield).
[0078] Example 6
[0079] The specific preparation method of compound 5,7-dibromo-2-quinolinone-3-carboxylic acid ethyl ester (3f) is as follows:
[0080] 2-amino-4,6-dibromobenzaldehyde (1.0mmol) and imidazole (1.5mmol) were added to the corresponding solvent dichloromethane (2.0mol / L), and after cooling under stirring, ethyl malonate chloride (1.1 equivalents) was slowly added dropwise to the reaction system. After the addition of the acyl chloride was completed, the reaction was heated and maintained at 50°C under air for 12 hours without the protection of inert gas. After the reaction was complete by TLC, 10mL of water was added to quench the reaction. 1H), 8.15(s,1H), 8.14(s,1H), 4.29(q,J=7.1Hz,2H), 1.30(t,J=7.1Hz,3H)ppm, such as Fig.11 As shown; 13 C NMR (100 MHz, DMSO-d6) δ 163.3, 157.9, 142.0, 137.0, 131.0, 128.1, 124.9, 120.2, 116.2, 113.5, 60.8, 13.7 ppm, as Fig.12 HRMS (ESI) m / z calcd for C 12 H9Br2NO3Na[M+Na] + :395.8847,Found:395.8841.
[0081] Example 6-1 (Amplification reaction)
[0082] The amplified reaction of compound 5,7-dibromo-2-quinolinone-3-carboxylic acid ethyl ester (3f) is as follows: 2-amino-4,6-dibromobenzaldehyde (10mmol) and imidazole (15mmol) are added to the corresponding solvent dichloromethane (2.0mol / L), and after low temperature cooling under stirring, malonic acid monoethyl ester chloride (1.1 equivalents) is slowly added dropwise to the reaction system. After the addition of the acyl chloride is completed, the reaction is heated and maintained at 50°C under air without inert gas protection for 12 hours. After TLC is checked to see that the reaction is complete, 100mL of water is added to quench the reaction, and ethyl acetate is extracted (100mL*3). After separation, the crude product is dried, filtered, and concentrated to obtain the pure product 3f (3.30g, isolated yield 88%).
[0083] Example 7
[0084] The specific preparation method of the compound 4-(4'-chlorophenyl)-2-quinolinone-3-carboxylic acid ethyl ester (3g) is as follows:
[0085] 2-amino-4'-chlorobenzophenone (1.0 mmol) and imidazole (1.5 mmol) were added to the corresponding solvent dichloromethane (2.0 mol / L), and after cooling under stirring, ethyl malonate chloride (1.1 equivalents) was slowly added dropwise to the reaction system. After the addition of the acyl chloride was completed, the reaction was heated and maintained at 50°C under air for 12 hours without the protection of inert gas. After the reaction was complete by TLC, 10 mL of water was added to quench the reaction, and ethyl acetate was used to obtain the reaction mixture. 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, such as Fig.12 HRMS (ESI) m / z calcd for C 12 H9Br2NO3Na[M+Na] + :395.8847,Found:395.8841. 1 H NMR (400 MHz, DMSO-d6) δ12.33 (s, 1H), 7.63–7.56 (m, 3H), 7.41 (d, J = 8.2 Hz, 1H), 7.38–7.34 (m, 2H), 7.18–7.13 (m, 1H), 7.10 (dd, J = 8.2, 1.4 Hz, 1H), 3.98 (q, J = 7.1 Hz, 2H), 0.90 (t, J = 7.1 Hz, 3H) ppm, as Fig.13 As shown; 13C NMR (101 MHz, DMSO-d6) δ 165.0, 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, 13.6 ppm, as Fig.14 HRMS (ESI) m / z calcd for C 18 H 14 ClNO3Na[M+Na] + :350.0560,Found:350.0561.
[0086] Example 7-1 (Amplification reaction)
[0087] The amplified reaction of the compound 4-(4'-chlorophenyl)-2-quinolinone-3-carboxylic acid ethyl ester (3g) is as follows: 2-amino-4'-chlorobenzophenone (10mmol) and imidazole (15mmol) are added to the corresponding solvent dichloromethane (2.0mol / L), and after low temperature cooling under stirring, malonic acid monoethyl ester chloride (1.1 equivalents) is slowly added dropwise to the reaction system. After the addition of the acyl chloride is completed, the reaction is heated and maintained at 50°C under air without inert gas protection for 12 hours. After TLC is checked to see that the reaction is complete, 100mL of water is added to quench the reaction, and ethyl acetate is extracted (100mL*3). After separation, the crude product is dried, filtered, and concentrated to obtain a pure product 3g (2.30g, separation yield 70%).
[0088] Example 8
[0089] The specific preparation method of the compound 6-chloro-(2'-chlorophenyl)-2-quinolinone-3-carboxylic acid ethyl ester (3h) is as follows:
[0090] 2-amino-5,2'-dichlorobenzophenone (1.0mmol) and imidazole (1.5mmol) were added to the corresponding solvent dichloromethane (2.0mol / L), and after cooling at low temperature under stirring, ethyl malonate chloride (1.1 equivalents) was slowly added dropwise to the reaction system. After the addition of the acyl chloride was completed, the reaction was heated and maintained at 50°C under air without inert gas protection for 12 hours. After TLC inspection to complete the reaction, 10mL of water was added to quench the reaction, and ethyl acetate was used for extraction (10mL*3). After separation, the crude product was dried, filtered, and concentrated to obtain a pure product 3h after column chromatography separation and purification, with a separation yield of 71%, a white solid, and mp 218-219°C. Its structural formula and structural characterization data are as follows: 1 H NMR (400 MHz, DMSO-d6)δ
[0091] 131.8,131.3,130.1,128.6,128.1,127.2,125.6,119.4,118.5,61.3,14.0ppm, e.g. Fig.16 HRMS (ESI) m / z calcd for C 18 H 13 Cl2NO3Na[M+Na] + :384.0170,Found:384.0164.
[0092] Example 8-1 (Amplification reaction)
[0093] The amplified reaction of the compound 6-chloro-(2'-chlorophenyl)-2-quinolinone-3-carboxylic acid ethyl ester (3h) is as follows: 2-amino-5,2'-dichlorobenzophenone (10mmol) and imidazole (15mmol) are added to the corresponding solvent dichloromethane (2.0mol / L), and after low temperature cooling under stirring, malonic acid monoethyl ester chloride (1.1 equivalents) is slowly added dropwise to the reaction system. After the addition of the acyl chloride is completed, the reaction is heated and maintained at 50°C under air without inert gas protection for 12 hours. After TLC is checked to see that the reaction is complete, 100mL of water is added to quench the reaction, and ethyl acetate is extracted (100mL*3). After separation, the crude product is dried, filtered, and concentrated to obtain the pure product 3h (2.72g, separation yield 75%).
[0094] Example 9
[0095] The specific preparation method of N-methyl-6-chloro-phenyl-2-quinolinone-3-carboxylic acid ethyl ester (3i) is as follows:
[0096] N-methyl-2-amino-5-chlorobenzophenone (1.0mmol) and imidazole (1.5mmol) were added to the corresponding solvent dichloromethane (2.0mol / L), and after cooling at low temperature with stirring, ethyl malonate chloride (1.1 equivalents) was slowly added dropwise to the reaction system. After the addition of the acyl chloride was completed, the reaction was heated and maintained at 50°C under air without the protection of inert gas for 12 hours. After TLC was checked to see that the reaction was complete, 10mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate (10mL*3). After separation, the mixture was dried, filtered, and concentrated to obtain a crude product, which was separated and purified by column chromatography to obtain 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, such as Fig.18As shown; HRMS (ESI) m / z calcd for C 19 H 16 ClNO3Na[M+Na] + :364.0716,Found:364.0711.
[0097] Example 9-1 (Amplification reaction)
[0098] The amplified reaction of N-methyl-6-chloro-phenyl-2-quinolinone-3-carboxylic acid ethyl ester (3i) is as follows: N-methyl-2-amino-5-chlorobenzophenone (10mmol) and imidazole (15mmol) are added to the corresponding solvent dichloromethane (2.0mol / L), and after low temperature cooling under stirring, ethyl malonate chloride (1.1 equivalents) is slowly added dropwise to the reaction system. After the addition of the acyl chloride is completed, the reaction is heated and maintained at 50°C under air without inert gas protection for 12 hours. After TLC is checked to see that the reaction is complete, 100mL of water is added to quench the reaction, and ethyl acetate is extracted (100mL*3). After separation, the crude product is dried, filtered, and concentrated to obtain the pure product 3i (3.04g, isolated yield 89%).
[0099] Example 10
[0100] The specific preparation method of the compound 4-phenyl-2-quinolinone-3-carboxylic acid methyl ester (3j) is as follows:
[0101] 2-Aminobenzophenone (1.0mmol) and imidazole (1.5mmol) were added to the corresponding solvent dichloromethane (2.0mol / L), and after cooling at low temperature with stirring, malonic acid monomethyl ester chloride (1.1 equivalents) was slowly added dropwise to the reaction system. After the addition of the acyl chloride was completed, the reaction was heated and maintained at 50°C under air without inert gas protection for 12 hours. After TLC inspection to see that the reaction was complete, 10mL of water was added to quench the reaction, and ethyl acetate (10mL*3) was used for extraction. After separation, the crude product was dried, filtered, and concentrated to obtain the pure product 3j, which was separated and purified by column chromatography. The separation yield was 2.37%. 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, such as Fig. 20 As shown; HRMS (ESI) m / z calcd for C 16 H 20 NO3S[M+H] + :162.1163,Found:162.1164.
[0102] Embodiment 11
[0103] The specific preparation method of the compound 6-chloro-4-phenyl-2-quinolinone-3-carboxylic acid methyl ester (3k) is as follows: 2-amino-5-chlorobenzophenone (1.0 mmol) and imidazole (1.5 mmol) are added to the corresponding solvent dichloromethane (2.0 mol / L), and after low temperature cooling under stirring, malonic acid monomethyl ester chloride (1.1 equivalents) is slowly added dropwise to the reaction system. After the addition of the acyl chloride is completed, the reaction is heated and maintained at 50°C under air without inert gas protection for 12 hours. After TLC is checked to see that the reaction is complete, 10 mL of water is added to quench the reaction, and acetic acid is used to precipitate the mixture. 1H), 3.48 (s, 3H) ppm, such as Fig.21 As shown; 13 C NMR (101 MHz, DMSO-d6) δ 165.4, 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, 52.1 ppm, as Fig. 22 HRMS (ESI) m / z calcd for C 17 H 12 NO3NaBr[M+Na] + :379.9904,Found:379.9898.
[0104] Example 12
[0105] The specific preparation method of the compound 6-bromo-4-phenyl-2-quinolinone-3-carboxylic acid methyl ester (31) is as follows: Take (10mL*3), separate the liquids, dry, filter and concentrate to obtain the crude product, which is separated and purified by column chromatography to obtain pure product 31 with an isolation yield of 99%, white solid, mp 233-234°C. Its structural formula and structural characterization data are as follows: 1 H 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, such as Fig.23 As shown; 13C NMR (101 MHz, DMSO-d6) δ 165.5, 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, 52.1 ppm, as Fig.24 HRMS (ESI) m / zcalcd for C 17 H 12 NO3NaCl[M+Na] + :336.0402,Found:336.0403.
[0106] Optimization and screening test of reaction conditions
[0107] Taking Example 1 as the experimental basis object, the experimental parameters were adjusted according to the experimental parameters described in Table 1 below to explore the high and low separation yield comparison data under different alkali conditions, solvent conditions, heating temperature conditions and reaction concentration conditions. The experimental results are as follows:
[0108] Table 1 Comparison of the separation yield of ethyl 4-phenyl-2-quinolinone-3-carboxylate (3a) under different experimental parameters
[0109]
[0110]
[0111] From the above test comparison results, when dichloromethane is selected as the solvent, imidazole is selected as the base, 50°C is selected as the temperature, and the reaction concentration is 2.0 mol / L, the product generation rate of this type of reaction under these reaction conditions is optimal. This test data proves that the parameter setting in the synthesis method of the present invention is not to select conventional base types, conventional solvents, or set conventional temperature conditions to achieve the invention intent of the present invention.
[0112] It should be understood that although the present specification is described in terms of implementation methods, this narrative style of the specification is only for the sake of clarity, and those skilled in the art should take the specification as a whole to form other implementation methods that can be understood by those skilled in the art, which should also fall within the scope of protection of the present invention.
Claims
1. A method for preparing a polysubstituted 2-quinolinone compound by base catalysis, characterized in that: The steps include: 1) adding a 2-aminobenzophenone compound and a base in a molar ratio of 1:1.5 to a corresponding solvent, dichloromethane, so that the solute concentration of the 2-aminobenzophenone compound reaches 2 mol / L; the base is imidazole; 2) under stirring, slowly adding ethyl malonate chloride to the solution in step 1) under low temperature cooling, wherein the amount of ethyl malonate chloride used is 110% of the molar amount of the 2-aminobenzophenone compound provided by the ethyl malonate chloride; the low temperature cooling condition is an ice bath; 3) After the addition of the ethyl malonate chloride is complete, the reaction system is heated to 40-60° C., stirred for 2-24 hours, and then water is added to quench the reaction; 4) extracting with ethyl acetate, drying after separation, filtering, concentrating, and purifying to obtain the product; The reaction formula for preparing the polysubstituted 2-quinolinone compounds is: ； wherein the number of R1-R3 substituents is 0-4; The type of the R1 substituent is selected from one or more of F, Br, Cl, I, CF3, and C1-8 alkyl; The type of the R2 substituent is selected from one or more of F, Br, Cl, I, CF3, and C1-8 alkyl; The type of the R3 substituent is selected from one or more of CH3, Et, and n-Pr.
2. The preparation method according to claim 1, characterized in that: C1-8 alkyl is Et, n-Pr, i-Pr or Bu.
3. The preparation method according to claim 1, characterized in that: The stirring rate of step 2) is 200-500 r / min.
4. The preparation method according to claim 3, characterized in that: The stirring rate of step 2) is 300 r / min.
5. The preparation method according to any one of claims 1 to 4, characterized in that: The heating temperature in step 3) is selected to be 50°C or 60°C.