Quinolinone derivative and preparation method thereof
Through the combination method of Vilsmeier-Haack Formoylation and cycloaddition reaction, the existing quinolinone derivative synthesis methods are solved, and the efficient and green synthesis of quinolinone derivatives is achieved, and the wide range of pharmacological application prospects are achieved.
Patent Information
- Application Number
- CN202510039788.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-01-10
- Publication Date
- 2025-06-06
AI Technical Summary
The existing quinolinone derivative synthesis methods have problems such as cumbersome steps, harsh reaction conditions, many by-products, low yields, heavy metals and not environmentally friendly.
Using the combination of Vilsmeier-Haack Formoylation and cycloaddition reaction, 3-phenyl-6,7-dimethoxyisoquinoline-1(2H)-one and 3-phenyl-6,7-dimethoxyquinoline-2(1H)-one derivatives were prepared through specific reaction steps step by step.
It has achieved efficient, green and simple synthesis of quinolinone derivatives, with mild reaction conditions, simple operation and broad application prospects.
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Figure CN120097912A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the field of biomedical materials, and particularly relates to a quinolinone derivative and a preparation method thereof. Background Art
[0002] Quinolinone is a class of heterocyclic compounds containing quinoline or isoquinoline and keto groups. It is widely present in nature, has diverse chemical molecular structures and significant biological activities, and its derivatives have shown important pharmacological effects in the fields of antibacterial, antiviral, antitumor, anti-inflammatory, and antimalarial. The molecular diversity, synthesis methods, and biological activity research of quinolinone derivatives have received attention in recent years. The biological activity of quinolinone derivatives is mainly related to the quinoline skeleton in its molecular structure. The skeleton can be modified by different substituents to give the compound specific pharmacological properties. For example, CeMMEC13 (structural formula see Figure 6 ) can selectively inhibit the second bromodomain of TAF1; SAR407899 (structural formula see Figure 6 ) is a selective, ATP-competitive ROCK inhibitor; Vesnarinone (Arkin) (structural formula see Figure 6 ) can inhibit phosphodiesterase III activity, increase calcium flux and decrease potassium flux.
[0003] At present, the synthesis methods of quinolinone derivatives mainly include: cyclization reaction, substitution reaction and transformation of other heterocyclic compounds. However, the above synthesis methods have the problems of cumbersome steps, harsh reaction conditions, many by-products, low yield, the need to use heavy metals (catalysts), and environmental pollution. Therefore, it is urgent to develop a new method for synthesizing quinolinone derivatives that is efficient, green and simple. Summary of the invention
[0004] In view of the problems existing in the prior art, the present invention aims to provide a quinolinone derivative and a preparation method thereof.
[0005] In order to achieve the above object, the present invention adopts the following technical solution: The first aspect of the present invention provides quinolinone derivatives, which include 3-phenyl-6,7-dimethoxyisoquinolin-1(2H)-one derivatives and 3-phenyl-6,7-dimethoxyquinolin-2(1H)-one derivatives having the general structural formulas shown in formula (I) and (II):
[0006] Wherein, R represents any substituent, including but not limited to C1-C4 alkyl, C1-C4 alkoxy, aromatic group, heteroaryl group, amino group, halogen, nitrile group, ester group, hydroxyl group, trifluoro-substituted alkyl group, etc.
[0007] The second aspect of the present invention provides a method for preparing the above-mentioned quinolinone derivative, wherein the quinolinone derivative is a 3-(3-fluorophenyl)-6,7-dimethoxyisoquinolin-1(2H)-one derivative, and the preparation method comprises the following steps: S1, 1,2-dimethoxy-4-toluene and POCl 3 Dissolve in an organic solvent and carry out Vilsmeier-Haack formylation reaction under protective gas to obtain 4,5-dimethoxy-2-methylbenzaldehyde; S2. Dissolve 4,5-dimethoxy-2-methylbenzaldehyde, substituted benzonitrile, and potassium tert-butoxide (tBuOK) in cyclopentyl methyl ether (CPME), stir to react, and then add lithium bis(trimethylsilylamide) (LiHMDS) to carry out a cycloaddition reaction to obtain a 3-(substituted phenyl)-6,7-dimethoxyisoquinolin-1(2H)-one derivative.
[0008] Preferably, in step S1, the Vilsmeier-Haack formylation reaction temperature is 95-100° C., and the reaction time is 10-20 h.
[0009] Preferably, in step S2, the stirring reaction temperature is 60-70° C., and the reaction time is 6-8 h.
[0010] Preferably, in step S2, the temperature of the cycloaddition reaction is 110-130° C., and the reaction time is 7-9 h.
[0011] Preferably, in step S1, the 1,2-dimethoxy-4-toluene and POCl 3 The equivalent ratio is 1:4~5.
[0012] Preferably, in step S2, the equivalent ratio of the 4,5-dimethoxy-2-methylbenzaldehyde, substituted benzonitrile, potassium tert-butoxide (tBuOK), and lithium bistrimethylsilylamide (LiHMDS) is 1:1.5:1.5:1.5~2. The third aspect of the present invention provides a method for preparing the above-mentioned quinolinone derivative, wherein the quinolinone derivative is a 3-phenyl-6,7-dimethoxyquinolin-2(1H)-one derivative, and the preparation method comprises the following steps: A1. 4,5-dimethoxy-2-nitrobenzaldehyde and NH 4 Cl is dissolved in a mixed solvent of ethanol and water, and then iron powder is added and stirred to react to obtain 2-amino-4,5-dimethoxybenzaldehyde; A2, 2-amino-4,5-dimethoxybenzaldehyde, substituted phenylacetic acid, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and triethylamine (Et3 N) is dissolved in an organic solvent and subjected to acylation reaction to obtain 2-(substituted phenyl)-N-(2-formyl-4,5-dimethoxyphenyl)acetamide; A3, 2-(3-fluorophenyl)-N-(2-formyl-4,5-dimethoxyphenyl)acetamide and K 2 CO 3 Dissolve in organic solvent and replace N 2 , a cyclization reaction was carried out to obtain a 3-phenyl-6,7-dimethoxyquinolin-2(1H)-one derivative.
[0013] Preferably, in step A1, the stirring reaction temperature is 60-70° C., and the stirring reaction time is 2-5 h.
[0014] Preferably, in step A1, the 4,5-dimethoxy-2-nitrobenzaldehyde, NH 4 The equivalent ratio of Cl and iron powder is 1:0.5~1:4~5.
[0015] Preferably, in step A2, the acylation reaction is carried out at room temperature and the reaction time is 7 to 9 hours.
[0016] Preferably, in step A2, the equivalent ratio of 2-amino-4,5-dimethoxybenzaldehyde, substituted phenylacetic acid, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) and triethylamine is 1.2:1.3:2-3.
[0017] Preferably, in step A3, the temperature of the cyclization reaction is 60-70° C., and the reaction time is 1-3 h. Preferably, in step A3, the 2-(3-fluorophenyl)-N-(2-formyl-4,5-dimethoxyphenyl)acetamide and K 2 CO 3 The equivalent ratio is 0.1:2~3.
[0018] The present invention has the following beneficial effects: The present invention provides quinolinone derivatives, specifically 3-phenyl-6,7-dimethoxyisoquinolin-1(2H)-one derivatives and 3-phenyl-6,7-dimethoxyquinolin-2(1H)-one derivatives. Among them, the 3-phenyl-6,7-dimethoxyisoquinolin-1(2H)-one derivative (the general structural formula is shown in formula (I)) is synthesized by Vilsmeier-Haack formylation reaction to first synthesize 4,5-dimethoxy-2 -methylbenzaldehyde, which is then reacted with substituted benzonitrile in the presence of potassium tert-butylate (tBuOK) and lithium bis(trimethylsilyl)amide (LiHMDS) for a cycloaddition reaction to obtain the product; 3-phenyl-6,7-dimethoxyquinolin-2(1H)-one derivatives (the general structural formula is shown in formula (II)) are first synthesized by nitro reduction of 2-amino-4,5-dimethoxybenzaldehyde, which is then reacted with substituted phenylacetic acid in the presence of a condensing agent 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) for an acylation reaction to obtain 2-(substituted phenyl)-N-(2-formyl-4,5-dimethoxyphenyl)acetamide, which is then reacted with the obtained 2-(substituted phenyl)-N-(2-formyl-4,5-dimethoxyphenyl)acetamide in the presence of potassium tert-butylate (tBuOK) and lithium bis(trimethylsilyl)amide (LiHMDS) for a cycloaddition reaction to obtain the product; 3-phenyl-6,7-dimethoxyquinolin-2(1H)-one derivatives (the general structural formula is shown in formula (II)) are first synthesized by nitro reduction of 2-amino-4,5-dimethoxybenzaldehyde, which is then reacted with substituted phenylacetic acid in the presence of a condensing agent 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) for an acylation reaction to obtain 2-(substituted phenyl)-N-(2-formyl-4,5-dimethoxyphenyl)acetamide. 2 CO 3 The preparation method of the present invention has the characteristics of mild reaction conditions, simple operation, high efficiency, green and environmental protection, and thus has broad application prospects. BRIEF DESCRIPTION OF THE DRAWINGS
[0019] In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings required for use in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.
[0020] Figure 1 The chemical structural formula of the 3-phenyl-6,7-dimethoxyisoquinoline-1(2H)-one derivative and the 3-phenyl-6,7-dimethoxyquinoline-2(1H)-one derivative provided by the present invention; Figure 2 A synthetic route diagram of 3-(3-fluorophenyl)-6,7-dimethoxyisoquinolin-1(2H)-one provided by the present invention; Figure 3 A synthetic route diagram of 3-(3-fluorophenyl)-6,7-dimethoxyquinoline-2(1H)-one provided by the present invention; Figure 4 is the nuclear magnetic spectrum of 3-(3-fluorophenyl)-6,7-dimethoxyisoquinolin-1(2H)-one prepared in Example 1; Figure 5is the NMR spectrum of 3-(3-fluorophenyl)-6,7-dimethoxyquinolin-2(1H)-one prepared in Example 2; Figure 6 The structural formulas of CeMMEC13, SAR407899 and Vesnarinone. DETAILED DESCRIPTION
[0021] In the following description, for the purpose of illustration rather than limitation, specific details such as specific system structures and technologies are provided to provide a thorough understanding of the embodiments of the present invention. However, it should be clear to those skilled in the art that the present invention may also be implemented in other embodiments without these specific details.
[0022] Example 1 Reference Figure 2 , synthesize 3-phenyl-6,7-dimethoxyisoquinolin-1(2H)-one derivatives (the general structure is shown in Figure 1 ), specifically 3-(3-fluorophenyl)-6,7-dimethoxyisoquinolin-1(2H)-one, the steps are as follows: (1) Synthesis of 4,5-dimethoxy-2-methylbenzaldehyde: Add POCl into a three-necked flask. 3 (4.03 g, 4 eq) and 1,2-dimethoxy-4-toluene (1 g, 1 eq) were heated at 80 °C and N 2 The mixture was stirred under protective conditions, and DMF (1.92 g, 4 eq) was added dropwise. The temperature was then raised to 98°C and stirred for 12 h. The reaction was monitored by TLC. After the reaction was completed, ice water and ethyl acetate were added and stirred. The organic phase was collected and the solvent was removed to obtain 4,5-dimethoxy-2-methylbenzaldehyde. 1 HNMR (400 MHz, CDCl 3 ) δ10.22 (s, 1H), 7.35 (s, 1H), 6.69 (s, 1H), 3.94 (d, J = 12.7 Hz, 7H), 2.64(s, 3H), 1.61 (s, 3H), 1.39-1.27 (m, 1H), 1.26 (s, 3H), 0.87 (dd, J = 15.5,9.4 Hz, 1H). MS m / z(ESI):181.0 [M+H]; (2) Synthesis of 3-(3-fluorophenyl)-6,7-dimethoxyisoquinolin-1(2H)-one: 4,5-Dimethoxy-2-methylbenzaldehyde (0.2 g, 1 eq), 3-fluorobenzonitrile (0.2 g, 1.5 eq), 0.19 g potassium tert-butoxide (tBuOK) (0.19 g, 1.5 eq) and 8 mL cyclopentyl methyl ether (CPME) were added into a 10 mL Schlenk tube, stirred at 60 °C for 6 h, and the reaction was monitored by TLC. The temperature was then lowered to room temperature, and lithium bis(trimethylsilyl)amide (LiHMDS) (2.22 mL, 2 eq) was added. After the addition was complete, N 2 , the temperature was raised to 120°C, stirred for reaction for 8 hours, then slowly cooled to room temperature, dichloromethane and sodium chloride aqueous solution were added for extraction, the organic phase was collected, anhydrous sodium sulfate was added, stirred and dried, the organic phase was vacuum-reduced to remove the solvent, and purified by silica gel column chromatography to obtain 3-(3-fluorophenyl)-6,7-dimethoxyisoquinolin-1(2H)-one with a yield of 53%. The NMR spectrum is shown in Figure 4 . 1 HNMR (400 MHz, CDCl 3 ) δ 10.48 (s, 1H), 7.74 (s, 1H), 7.52-7.35 (m,3H), 7.12-6.97 (m, 1H), 6.91 (s, 1H), 6.70 (s, 1H), 3.96 (d, J = 5.7 Hz, 6H). MSm / z(ESI):300.1 [M+H].
[0023] Example 2 Reference Figure 3 , synthesize 3-phenyl-6,7-dimethoxyquinolin-2(1H)-one derivatives (the general structure is shown in Figure 1 ), specifically 3-(3-fluorophenyl)-6,7-dimethoxyquinolin-2(1H)-one, the steps are as follows: (1) Synthesis of 2-amino-4,5-dimethoxybenzaldehyde: 4,5-dimethoxy-2-nitrobenzaldehyde (1g, 1eq), NH 4 Cl (0.13 g, 0.5 eq), ethanol and water were added to a three-necked flask and heated to 65 °C and stirred for 5 min. At this time, the solution changed from turbid to clear. Fe powder (4 eq) was added in two batches to react. The solution changed from yellow to green. The reaction was stirred for 2 h. After the reaction was completed, the mixed solution was filtered, the solvent was removed, and saturated NaHCO was added. 3 The mixture was extracted with aqueous solution and DCM, and the organic phases were combined, added with anhydrous sodium sulfate, dried, filtered, and purified by silica gel column chromatography to obtain 2-amino-4,5-dimethoxybenzaldehyde. 1 H NMR (600 MHz, CDCl 3) δ 9.70 (s,1H), 6.88 (s,1H), 6.12 (s,1H), 3.90 (s,3H), 3.85 (s,3H). MS m / z(ESI):182.0[M+H]; (2) Synthesis of 2-(3-fluorophenyl)-N-(2-formyl-4,5-dimethoxyphenyl)acetamide: 2-Amino-4,5-dimethoxybenzaldehyde (0.1 g, 1 eq), 3-fluorophenylacetic acid (0.1 g, 1.2 eq), 2-(7-azabenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU) (0.27 g, 1.3 eq) and triethylamine (Et 3 N) (0.14 g, 2.5 eq) was added into a three-necked flask, and then 8 mL of dichloromethane was added as a solvent. After stirring at room temperature for 8 h, the reaction was completed, and dichloromethane and sodium chloride aqueous solution were added for extraction. Anhydrous sodium sulfate was added to the organic phase, stirred and dried, and then filtered. The organic phase was evaporated under reduced pressure and purified by silica gel column chromatography to obtain 2-(3-fluorophenyl)-N-(2-formyl-4,5-dimethoxyphenyl)acetamide. 1 HNMR (400 MHz, CDCl 3 ) δ 11.32 (s, 1H), 9.63 (s,1H), 8.40 (s,1H), 7.33-7.25(m,1H), 7.19(s,1H), 7.09(d,J=7.7Hz,1H), 7.06-7.00(m,1H), 6.95(s,1H), 3.90(s,3H), 3.86-3.82(m,3H), 3.70(s,2H). MS m / z(ESI):318.1 [M+H]; (3) Synthesis of 3-(3-fluorophenyl)-6,7-dimethoxyquinolin-2(1H)-one: 2-(3-Fluorophenyl)-N-(2-formyl-4,5-dimethoxyphenyl)acetamide (0.1 g, 1 eq), K 2 CO 3 (0.087 g, 2 eq) and 5 mL of dichloromethane were added into a three-necked flask, and then N 2 , heated to 65 ° C and stirred for 2 h, the reaction was monitored by TLC (petroleum ether: ethyl acetate = 1: 1), the pH was adjusted to 9.6, dichloromethane and sodium chloride aqueous solution were added for extraction, the organic phase was dried over anhydrous sodium sulfate and filtered, the organic phase was rotary evaporated, and purified by silica gel column chromatography to obtain 3-(3-fluorophenyl)-6,7-dimethoxyquinolin-2(1H)-one with a yield of 55%. The NMR spectrum is shown in Figure 5 . 1HNMR (400 MHz, DMSO- d 6 ) δ 11.84 (s,1H),8.13 (s,1H), 7.73-7.57 (m,2H), 7.46 (q, J = 7.6 Hz,1H), 7.27 (s,1H), 7.17 (td, J =8.6,2.9 Hz,1H), 6.89 (s,1H), 3.84 (s,3H), 3.81 (s,3H). MS m / z(ESI):300.1 [M+H].
[0024] Example 3
[0025] (1) 2-amino-4,5-dimethoxybenzaldehyde (0.1 g, 1 eq), m-trifluoromethylphenylacetic acid (1.2 eq), 2-(7-azabenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU) (0.27 g, 1.3 eq) and triethylamine (Et 3 N) (0.14 g, 2.5 eq) was added into a three-necked flask, and then 8 mL of dichloromethane was added as solvent. After stirring at room temperature for 8 h, the reaction was completed, and dichloromethane and sodium chloride aqueous solution were added for extraction. Anhydrous sodium sulfate was added to the organic phase, stirred and dried, and then filtered. The organic phase was evaporated under reduced pressure and purified by silica gel column chromatography to obtain N-(2-formyl-4,5-dimethoxyphenyl)-2-(3-(trifluoromethyl)phenyl)acetamide.
[0026] (2) N-(2-formyl-4,5-dimethoxyphenyl)-2-(3-(trifluoromethyl)phenyl)acetamide (1 eq) and K 2 CO 3 (0.087 g, 2 eq) and 5 mL of dichloromethane were added into a three-necked flask, and then N 2 , heated to 65°C, stirred for 2 h, monitored the reaction by TLC (petroleum ether: ethyl acetate = 1:1), adjusted the pH to 9.2, added dichloromethane and sodium chloride aqueous solution for extraction, dried the organic phase over anhydrous sodium sulfate, filtered, rotary evaporated the organic phase, purified by silica gel column chromatography, and obtained compound a as shown in the chemical formula (a), with a yield of 53%. MS m / z (ESI): 350.1 [M+H].
[0027] Example 4
[0028] (1) 2-amino-4,5-dimethoxybenzaldehyde (0.1 g, 1 eq), p-methylphenylacetic acid (1.2 eq), 2-(7-azabenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU) (0.27 g, 1.3 eq) and triethylamine (Et 3 N) (0.14 g, 2.5 eq) was added into a three-necked flask, and then 8 mL of dichloromethane was added as solvent. The reaction was stirred at room temperature for 7 h. After the reaction was completed, dichloromethane and sodium chloride aqueous solution were added for extraction. Anhydrous sodium sulfate was added to the organic phase, stirred and dried, and then filtered. The organic phase was evaporated under reduced pressure and purified by silica gel column chromatography to obtain N-(2-formyl-4,5-dimethoxyphenyl)-2-(p-tolyl)acetamide.
[0029] (2) N-(2-formyl-4,5-dimethoxyphenyl)-2-(p-tolyl)acetamide (1 eq), K 2 CO 3 (0.087 g, 2 eq) and 5 mL of dichloromethane were added into a three-necked flask, and then N 2 , heated to 65°C and stirred for 2 h, the reaction was monitored by TLC (petroleum ether: ethyl acetate = 1:1), the pH was adjusted to 9.6, dichloromethane and sodium chloride aqueous solution were added for extraction, the organic phase was dried over anhydrous sodium sulfate and filtered, the organic phase was rotary evaporated, and purified by silica gel column chromatography to obtain compound b shown in the chemical formula (b), with a yield of 62%. MS m / z (ESI): 296.1 [M+H].
[0030] Example 5
[0031] (1) 2-amino-4,5-dimethoxybenzaldehyde (0.1 g, 1 eq), 3-cyano-phenylacetic acid (1.2 eq), 2-(7-azabenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU) (0.27 g, 1.3 eq) and triethylamine (Et 3 N) (0.118 g, 2 eq) was added into a three-necked flask, and then 8 mL of dichloromethane was added as a solvent. The reaction was stirred at room temperature for 8 h. After the reaction was completed, dichloromethane and sodium chloride aqueous solution were added for extraction. Anhydrous sodium sulfate was added to the organic phase, stirred and dried, and then filtered. The organic phase was evaporated under reduced pressure and purified by silica gel column chromatography to obtain 2-(3-cyanophenyl)-N-(2-formyl-4,5-dimethoxyphenyl)acetamide.
[0032] (2) 2-(3-cyanophenyl)-N-(2-formyl-4,5-dimethoxyphenyl)acetamide (1 eq) and K 2 CO 3(0.087 g, 2 eq) and 5 mL of dichloromethane were added into a three-necked flask, and then N 2 , heated to 65°C and stirred for 2 h, the reaction was monitored by TLC (petroleum ether: ethyl acetate = 1:1), the pH was adjusted to 9.5, dichloromethane and sodium chloride aqueous solution were added for extraction, the organic phase was dried over anhydrous sodium sulfate and filtered, the organic phase was rotary evaporated, and purified by silica gel column chromatography to obtain compound c as shown in the chemical formula (c), with a yield of 49%. MS m / z (ESI): 307.1 [M+H].
[0033] Example 6
[0034] (1) 2-amino-4,5-dimethoxybenzaldehyde (0.1 g, 1 eq), 3-methoxyphenylacetic acid (1.2 eq), 2-(7-azabenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU) (0.27 g, 1.3 eq) and triethylamine (Et 3 N) (0.168 g, 3 eq) was added into a three-necked flask, and then 8 mL of dichloromethane was added as a solvent. The reaction was stirred at room temperature for 9 h. After the reaction was completed, dichloromethane and sodium chloride aqueous solution were added for extraction. Anhydrous sodium sulfate was added to the organic phase, stirred and dried, and then filtered. The organic phase was evaporated under reduced pressure and purified by silica gel column chromatography to obtain N-(2-formyl-4,5-dimethoxyphenyl)-2-(3-methoxyphenyl)acetamide.
[0035] (2) N-(2-formyl-4,5-dimethoxyphenyl)-2-(3-methoxyphenyl)acetamide (1 eq), K 2 CO 3 (0.087 g, 2 eq) and 5 mL of dichloromethane were added into a three-necked flask, and then N 2 , heated to 70°C, stirred for 1 h, monitored the reaction by TLC (petroleum ether: ethyl acetate = 1:1), adjusted the pH to 10, added dichloromethane and sodium chloride aqueous solution for extraction, dried the organic phase over anhydrous sodium sulfate, filtered, rotary evaporated the organic phase, purified by silica gel column chromatography, and obtained compound d as shown in the chemical formula (d), with a yield of 52%. MS m / z (ESI): 312.1 [M+H]. Example 7
[0036] (1) 2-amino-4,5-dimethoxybenzaldehyde (0.1 g, 1 eq), 3-chlorophenylacetic acid (1.2 eq), 2-(7-azabenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU) (0.27 g, 1.3 eq) and triethylamine (Et 3N) (0.14 g, 2.5 eq) was added into a three-necked flask, and then 8 mL of dichloromethane was added as a solvent. After stirring at room temperature for 8 h, the reaction was completed, and dichloromethane and sodium chloride aqueous solution were added for extraction. Anhydrous sodium sulfate was added to the organic phase, stirred and dried, and then filtered. The organic phase was evaporated under reduced pressure and purified by silica gel column chromatography to obtain 2-(3-chlorophenyl)-N-(2-formyl-4,5-dimethoxyphenyl)acetamide. (2) 2-(3-chlorophenyl)-N-(2-formyl-4,5-dimethoxyphenyl)acetamide (1 eq) and K 2 CO 3 (0.087 g, 2 eq) and 5 mL of dichloromethane were added into a three-necked flask, and then N 2 , heated to 65°C and stirred for 2 h, the reaction was monitored by TLC (petroleum ether: ethyl acetate = 1:1), the pH was adjusted to 9.1, dichloromethane and sodium chloride aqueous solution were added for extraction, the organic phase was dried over anhydrous sodium sulfate and filtered, the organic phase was rotary evaporated, and purified by silica gel column chromatography to obtain compound e shown in the chemical formula (e), with a yield of 57%. MS m / z (ESI): 317.1 [M+H].
[0037] Example 8
[0038] 4,5-Dimethoxy-2-methylbenzaldehyde (0.2 g, 1 eq), 3-hydroxybenzonitrile (1.5 eq), 0.19 g potassium tert-butoxide (tBuOK) (1.5 eq) and 8 mL cyclopentyl methyl ether (CPME) were added into a 10 mL Schlenk tube and stirred at 60 °C. After 6 h, the reaction was monitored by TLC. The temperature was then lowered to room temperature and lithium bis(trimethylsilyl)amide (LiHMDS) (2.22 mL, 2 eq) was added. After the addition was complete, N 2 , heated to 120°C, stirred for reaction for 8h, then slowly cooled to room temperature, added dichloromethane and sodium chloride aqueous solution for extraction, collected the organic phase, added anhydrous sodium sulfate, stirred and dried, the organic phase was vacuum-reduced to remove the solvent, and purified by silica gel column chromatography to obtain compound f with structural formula (f), with a yield of 55%. MS m / z (ESI): 296.1 [MH].
[0039] Example 9
[0040] 4,5-Dimethoxy-2-methylbenzaldehyde (0.2 g, 1 eq), 3-(pyridin-3-yl)benzonitrile (1.5 eq), 0.19 g potassium tert-butoxide (tBuOK) (1.5 eq) and 8 mL cyclopentyl methyl ether (CPME) were added into a 10 mL Schlenk tube and stirred at 60 °C. After 6 h, the reaction was monitored by TLC. The temperature was then lowered to room temperature and lithium bis(trimethylsilyl)amide (LiHMDS) (2.22 mL, 2 eq) was added. After the addition was complete, N 2 , heated to 110°C, stirred for reaction for 9 hours, then slowly cooled to room temperature, added dichloromethane and sodium chloride aqueous solution for extraction, collected the organic phase, added anhydrous sodium sulfate, stirred and dried, the organic phase was vacuum-reduced to remove the solvent, and purified by silica gel column chromatography to obtain compound g with the structural formula (g), with a yield of 60%. MS m / z (ESI): 359.1 [M+H].
[0041] Example 10
[0042] 4,5-dimethoxy-2-methylbenzaldehyde (0.2 g, 1 eq), p-aminobenzonitrile (1.5 eq), 0.19 g potassium tert-butoxide (tBuOK) (1.5 eq) and 8 mL cyclopentyl methyl ether (CPME) were added into a 10 mL Schlenk tube and stirred at 60 °C. After 6 h, the reaction was monitored by TLC. The temperature was then lowered to room temperature and lithium bis(trimethylsilyl)amide (LiHMDS) (2.22 mL, 2 eq) was added. After the addition was complete, N 2 , heated to 130°C, stirred for reaction for 7h, then slowly cooled to room temperature, added dichloromethane and sodium chloride aqueous solution for extraction, collected the organic phase, added anhydrous sodium sulfate, stirred and dried, the organic phase was vacuum-reduced to remove the solvent, and purified by silica gel column chromatography to obtain compound h shown in the structural formula (h), with a yield of 51%. MS m / z (ESI): 295.1 [MH].
[0043] The present invention is not limited to the above-mentioned specific implementation modes. Various changes made by ordinary technicians in this field based on the above-mentioned concepts without creative work are all within the protection scope of the present invention.
Claims
1. A quinolinone derivative, characterized in that: The quinolinone derivatives include 3-phenyl-6,7-dimethoxyisoquinolin-1(2H)-one derivatives and 3-phenyl-6,7-dimethoxyquinolin-2(1H)-one derivatives having the following general structural formulas: Here, R represents a substituent.
2. The quinolinone derivative according to claim 1, characterized in that The R is selected from any one of a C1-C4 alkyl group, a C1-C4 alkoxy group, an aromatic group, a heteroaromatic group, an amino group, a halogen group, a nitrile group, an ester group, a hydroxyl group, and a trifluoro-substituted alkyl group.
3. A method for preparing a quinolinone derivative as claimed in claim 1, wherein the quinolinone derivative is a 3-(3-fluorophenyl)-6,7-dimethoxyisoquinolin-1(2H)-one derivative, characterized in that: The following steps are involved: S1, dissolving 1,2-dimethoxy-4-toluene and POCl3 in an organic solvent, and performing a Vilsmeier-Haack formylation reaction under a protective gas to obtain 4,5-dimethoxy-2-methylbenzaldehyde; S2. Dissolve 4,5-dimethoxy-2-methylbenzaldehyde, substituted benzonitrile and potassium tert-butoxide in cyclopentyl methyl ether, stir to react, then add lithium bis(trimethylsilyl)amide to carry out cycloaddition reaction to obtain 3-(substituted phenyl)-6,7-dimethoxyisoquinolin-1(2H)-one derivatives.
4. The method for preparing the quinolinone derivative according to claim 3, characterized in that: In step S1, the temperature of the Vilsmeier-Haack formylation reaction is 95-100° C., and the reaction time is 10-20 h; the equivalent ratio of 1,2-dimethoxy-4-toluene and POCl 3 is 1:4-5.
5. The method for preparing the quinolinone derivative according to claim 3, characterized in that: In step S2, the temperature of the cycloaddition reaction is 110-130° C., and the reaction time is 7-9 hours; the equivalent ratio of the 4,5-dimethoxy-2-methylbenzaldehyde, substituted benzonitrile, potassium tert-butoxide, and lithium bistrimethylsilylamide is 1:1.5:1.5:1.5-2.
6. A method for preparing a quinolinone derivative as claimed in claim 1, wherein the quinolinone derivative is a 3-phenyl-6,7-dimethoxyquinolin-2(1H)-one derivative, characterized in that: The following steps are involved: A1, dissolving 4,5-dimethoxy-2-nitrobenzaldehyde and NH4Cl in a mixed solvent of ethanol and water, then adding iron powder, stirring and reacting to obtain 2-amino-4,5-dimethoxybenzaldehyde; A2, dissolving 2-amino-4,5-dimethoxybenzaldehyde, substituted phenylacetic acid, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and triethylamine in an organic solvent, and performing an acylation reaction to obtain 2-(substituted phenyl)-N-(2-formyl-4,5-dimethoxyphenyl)acetamide; A3. Dissolve 2-(3-fluorophenyl)-N-(2-formyl-4,5-dimethoxyphenyl)acetamide (0.1 g, 1 eq) and K2CO3 in an organic solvent, replace N2, and perform a cyclization reaction to obtain a 3-phenyl-6,7-dimethoxyquinoline-2(1H)-one derivative.
7. The method for preparing a quinolinone derivative according to claim 6, characterized in that: In step A1, the stirring reaction temperature is 60-70°C, and the stirring reaction time is 2-5h; the equivalent ratio of the 4,5-dimethoxy-2-nitrobenzaldehyde, NH4Cl and iron powder is 1:0.5-1:4-5.
8. The method for preparing a quinolinone derivative according to claim 6, characterized in that: In step A2, the temperature of the acylation reaction is room temperature, and the reaction time is 7 to 9 hours; the equivalent ratio of the 2-amino-4,5-dimethoxybenzaldehyde, substituted phenylacetic acid, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and triethylamine is 1:1.2:1.3:2 to 3.
9. The method for preparing a quinolinone derivative according to claim 6, characterized in that: In step A3, the temperature of the cyclization reaction is 60-70° C., and the reaction time is 1-3 h; the equivalent ratio of the 2-(3-fluorophenyl)-N-(2-formyl-4,5-dimethoxyphenyl)acetamide to K2CO3 is 0.1:2-3.