A method for synthesizing a 3-benzoylquinoxalin-2(1h)-one compound

Abstract

The application relates to a synthesis method of a 3-benzoylquinoxalin-2(1H)-one compound, which comprises the following steps: in a glove box, a photosensitizer fac-Ir(ppy)3 and a substrate quinoxalin-2(1H)-one are accurately weighed by using an analytical balance and added into a reaction tube, then a syringe is used to add a solvent into the reaction tube, a rubber plug is plugged, the reaction tube is shaken and taken out of the glove box; in the reaction tube containing the above-mentioned medicine, benzoic chloride and an organic base N,N-diisopropylethylamine are continuously added by using a micro-sampler; the reaction mixture is placed in a 20W blue LED light reaction generating device for reaction, the reaction is completed, the reaction liquid is concentrated by reduced pressure distillation to obtain a crude product, and the pure product is obtained by separation and purification; the application adopts a photo-oxidation and reduction catalysis strategy, uses cheap and easily obtained acyl chloride as an acyl source, can realize quinoxalin-2(1H)-one C-3 acylation reaction without the action of an oxidant, greatly reduces the cost of 3-benzoylquinoxalin-2(1H)-one synthesis, and has remarkable social and economic benefits.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of a 3-benzoylquinoxaline-2(1H)-one compound. BACKGROUND

[0002] In the experiment, under the catalysis of visible light, single electron transfer (SET) occurs between benzoyl chloride and the reductive excited state photosensitizer to generate benzoyl radicals, which then react with quinoxaline-2(1H)-one and other benzene-containing nitrogen heterocycles.

[0003] 3-acylquinoxaline-2(1H)-one is an important pharmacophore, which not only exhibits many new biological activities, but also has certain fluorescence applications. Therefore, relevant research has been widely concerned by people, and the synthesis of such compounds has attracted a large number of researchers to compete for research. At present, the traditional method for synthesizing such compounds mainly includes two types, namely, oxidation method and acyl radical method. The traditional oxidation method is divided into direct oxidation of benzyl quinoxaline ketone, Kornblum oxidation and oxidation ring contraction of benzodiazepine compounds. In the traditional preparation method, not only the experimental conditions are harsh, but also the cost of the raw materials required for synthesis is high.

[0004] However, people have found that acyl radical reaction is also an important means for synthesizing such carbonyl compounds, and the source of acyl radicals is particularly extensive. In addition to obtaining CO and alkyl radicals by carbonylation, acyl radicals can also be obtained from some conventional acylating reagents such as carboxylic acids, aldehydes and acid anhydrides. Compounds based on the quinoxaline-2(1H)-one skeleton have extremely wide biological activity, and quinoxaline-2-ketone pharmacophore drugs or bioactive molecules have also entered clinical trials. Compared with other functional group methods such as C3 arylization, alkylation and amination of quinoxaline-2(1H)-one, the research on the acylation reaction of the C3 site is still relatively less. SUMMARY

[0005] In view of the above problems, the application provides a synthesis method of a 3-benzoylquinoxaline-2(1H)-one compound.

[0006] The specific technical scheme is as follows: a synthesis method of a 3-benzoylquinoxaline-2(1H)-one compound, comprising the following steps:

[0007] Step 1: taking quinoxaline-2(1H)-one as a starting material, fac-Ir(ppy)3 and the substrate quinoxaline-2(1H)-one are accurately weighed in a glove box by using an analytical balance and added to a reaction tube, then a syringe is used to add a solvent, a rubber plug is inserted, the reaction tube is shaken uniformly, and then the reaction tube is taken out of the glove box;

[0008] Step 2: continue to add benzoyl chloride and organic base N,N-diisopropyl ethylamine into the reaction tube containing the above-mentioned medicine by using a micro-sampler respectively;

[0009] Step 3: place the reaction mixture in a 20 W blue LED light reaction device for reaction; monitor by thin layer chromatography (TLC) until the reaction is complete, and then concentrate the reaction liquid by reduced pressure distillation to obtain a crude product, which is then separated and purified by column chromatography to obtain a corresponding pure product;

[0010] The reaction formula is as follows:

[0011]

[0012] Further, the molecular structure of the quinoxaline-2(1H)-one is:

[0013]

[0014] Further, the amount ratio of the quinoxaline-2(1H)-one to the photosensitizer in step 1 is 25:1.

[0015] Further, the photosensitizer fac-Ir(ppy)3 in the synthesis method is 0.004 mmol, the quinoxaline-2(1H)-one is 0.1 mmol, the solvent is 1 mL, the benzoyl chloride is 0.2 mmol, and the organic base N,N-diisopropyl ethylamine is 0.2 mmol.

[0016] Further, the solvent in step 1 is acetonitrile MeCN.

[0017] Advantages of the present application:

[0018] (1) The present application adopts the strategy of photo-oxidation and reduction catalysis, uses cheap and easily available acyl chloride as the acyl source, and realizes the C-3 acylation of quinoxaline-2(1H)-one without the action of oxidants, greatly reducing the cost of synthesis of 3-benzoyl quinoxaline-2(1H)-one compounds, and having significant social and economic benefits.

[0019] (2) The catalytic conditions adopted by the present application are mild, the catalytic system is simple, and the reaction selectivity is very high.

[0020] (3) The present application is simple to operate and relatively green and environmentally friendly. BRIEF DESCRIPTION OF DRAWINGS

[0021] Figure 1 is the nuclear magnetic hydrogen spectrum of the product of Example 1;

[0022] Figure 2 is the nuclear magnetic hydrogen spectrum of the product of Example 2;

[0023] Figure 3is the product of Example 3 nuclear magnetic hydrogen spectrum;

[0024] Figure 4 is the product of Example 4 nuclear magnetic hydrogen spectrum;

[0025] Figure 5 is the product of Example 5 nuclear magnetic hydrogen spectrum;

[0026] Figure 6 is the product of Example 6 nuclear magnetic hydrogen spectrum;

[0027] Figure 7 is the product of Example 7 nuclear magnetic hydrogen spectrum. Embodiment

[0028] In order to make the technical problems solved by the present application, the technical solutions more clearly, in the following, the present application is further described in detail in combination with the drawings and examples. It should be understood that the specific examples described herein are only used to explain the present application, and are not used to limit the present application. Example

[0029] As Figure 1 shown, the present embodiment provides a synthesis method of 3-benzoylquinoxaline-2(1H)-one compound, comprising the following steps:

[0030] Step 1: In the glove box, the photosensitizer fac-Ir(ppy)3 (2.6 mg, 0.004 mmol) and 1-benzylquinoxaline-2(1H)-one (23.6 mg, 0.1 mmol) are accurately weighed by an analytical balance, and then added into a reaction tube with a stirrer, and then acetonitrile solvent (1 mL) is added by a pipette, and then the reaction tube is taken out of the glove box after being shaken up and being plugged with a rubber plug;

[0031] Step 2: Continue to use a micro-syringe to suck p-fluorobenzoyl chloride (0.2 mmol) and organic base N,N-diisopropylethylamine (0.2 mmol) respectively and add them into the above reaction tube and shake up;

[0032] Step 3: The reaction mixture is placed in a 20 W blue LED light reaction device for reaction; the reaction is monitored by thin layer chromatography (TLC) until the reaction is complete, and then the reaction liquid is concentrated by reduced pressure distillation to obtain a crude product, which is then separated and purified by column chromatography to obtain a corresponding pure product;

[0033]

[0034] The reaction formula is as follows:

[0035] .

[0036] Example 2

[0037] As Figure 2As shown, this embodiment provides a method for synthesizing a 3-benzoylquinoxaline-2(1H)-one compound, comprising the following steps:

[0038] Step 1: In the glove box, accurately weigh the photosensitizer fac-Ir(ppy)3 (2.6 mg, 0.004 mmol) and 1-benzylquinoxaline-2(1H)-one (23.6 mg, 0.1 mmol) using an analytical balance, and put them into a reaction tube with a stir bar. Then, use a pipette to add 1 mL of acetonitrile solvent, stopper the tube with a rubber stopper, shake well, and then send the reaction tube out of the glove box.

[0039] Step 2: Continue to use a microsyringe to add p-bromobenzoyl chloride (0.2 mmol) and the organic base N,N-diisopropylethylamine (0.2 mmol) to the above reaction tube and shake well;

[0040] Step 3: Place the reaction mixture in a 20 W blue LED light reaction generator and react; monitor the reaction by thin-layer chromatography (TLC) until the reaction is complete, concentrate the reaction solution by vacuum distillation to obtain crude product, and then purify it by column chromatography to obtain the corresponding pure product;

[0041]

[0042] The reaction formula is as follows:

[0043] . Example

[0044] like Figure 3 As shown, this embodiment provides a method for synthesizing a 3-benzoylquinoxaline-2(1H)-one compound, comprising the following steps:

[0045] Step 1: In the glove box, accurately weigh the photosensitizer fac-Ir(ppy)3 (2.6 mg, 0.004 mmol) and 1-benzylquinoxaline-2(1H)-one (23.6 mg, 0.1 mmol) using an analytical balance, and put them into a reaction tube with a stir bar. Then, use a pipette to add 1 mL of acetonitrile solvent, stopper the tube with a rubber stopper, shake well, and then send the reaction tube out of the glove box.

[0046] Step 2: Continue to use a microsyringe to add p-chlorobenzoyl chloride (0.2 mmol) and the organic base N,N-diisopropylethylamine (0.2 mmol) to the above reaction tube and shake well;

[0047] Step 3: Place the reaction mixture in a 20 W blue LED light reaction generator and react; monitor the reaction by thin-layer chromatography (TLC) until the reaction is complete, concentrate the reaction solution by vacuum distillation to obtain crude product, and then purify it by column chromatography to obtain the corresponding pure product;

[0048]

[0049] The reaction formula is as follows:

[0050] .

[0051] Example 4

[0052] As shown in the Figure 4 , the embodiment provides a synthesis method of a 3-benzoylquinoxalin-2(1H)-one compound, comprising the following steps:

[0053] Step 1: In the glove box, the photosensitizer fac-Ir(ppy)3 (2.6 mg, 0.004 mmol) and 1-benzylquinoxalin-2(1H)-one (23.6 mg, 0.1 mmol) were accurately weighed by an analytical balance, and were loaded into a reaction tube with a stirrer. Then acetonitrile solvent (1 mL) was added by a pipette, and the reaction tube was taken out of the glove box after being shaken up and being plugged with a rubber plug.

[0054] Step 2: The p-tolyl benzoyl chloride (0.2 mmol) and the organic base N,N-diisopropyl ethylamine (0.2 mmol) were continuously sucked into the above reaction tube by a micro-syringe, and were shaken up;

[0055] Step 3: The reaction mixture was placed in a 20 W blue LED light reaction device for reaction. The reaction was monitored by thin layer chromatography (TLC) until the reaction was complete. The reaction liquid was concentrated by reduced pressure distillation to obtain a crude product, which was separated and purified by column chromatography to obtain a corresponding pure product;

[0056]

[0057] The reaction formula is as follows:

[0058] .

[0059] Example 5

[0060] As shown in the Figure 5 , the embodiment provides a synthesis method of a 3-benzoylquinoxalin-2(1H)-one compound, comprising the following steps:

[0061] Step 1: In the glove box, the photosensitizer fac-Ir(ppy)3 (2.6 mg, 0.004 mmol) and 1-benzylquinoxalin-2(1H)-one (23.6 mg, 0.1 mmol) were accurately weighed by an analytical balance, and were loaded into a reaction tube with a stirrer. Then acetonitrile solvent (1 mL) was added by a pipette, and the reaction tube was taken out of the glove box after being shaken up and being plugged with a rubber plug.

[0062] Step 2: Continue to use micro-syringe to suck benzoyl chloride (0.2 mmol) and organic base N,N-diisopropyl ethylamine (0.2 mmol) respectively into the above reaction tube and shake well;

[0063] Step 3: Put the reaction mixture into a 20 W blue LED light reaction device for reaction; monitor by thin layer chromatography (TLC) until the reaction is complete, and then concentrate the reaction liquid by reduced pressure distillation to obtain a crude product, which is then separated and purified by column chromatography to obtain a corresponding pure product;

[0064] The reaction is as follows: .

[0065] Example 6

[0066] As shown in the following scheme, the present embodiment provides a synthesis method of a 3-benzoylquinoxaline-2(1H)-one compound, which comprises the following steps: Figure 6 Step 1: In a glove box, accurately weigh photosensitizer fac-Ir(ppy)3 (2.6 mg, 0.004 mmol) and 1-benzyl-6,7-dichloroquinoxaline-2(1H)-one (30.5 mg, 0.1 mmol) using an analytical balance, and then add acetonitrile solvent (1 mL) into the reaction tube with a stirrer, and shake well after plugging the rubber plug, and then take the reaction tube out of the glove box;

[0067] Step 2: Continue to use micro-syringe to suck benzoyl chloride (0.2 mmol) and organic base N,N-diisopropyl ethylamine (0.2 mmol) respectively into the above reaction tube and shake well;

[0068] Step 3: Put the reaction mixture into a 20 W blue LED light reaction device for reaction; monitor by thin layer chromatography (TLC) until the reaction is complete, and then concentrate the reaction liquid by reduced pressure distillation to obtain a crude product, which is then separated and purified by column chromatography to obtain a corresponding pure product;

[0069]

[0070] The reaction is as follows:

[0071]

[0072] . Example 7

[0073] As shown in the following scheme, the present embodiment provides a synthesis method of a 3-benzoylquinoxaline-2(1H)-one compound, which comprises the following steps:

[0074] Figure 7

[0075] ​​Step 1: In a glove box, accurately weigh photosensitizer fac-Ir(ppy)3(2.6 mg, 0.004 mmol) and 1-benzyl-6,7-dimethylquinoxalin-2(lH)-one (30.5 mg, 0.1 mmol) using an analytical balance, load into a reaction tube with a stir bar, then add acetonitrile solvent (1 mL) using a pipette, shake well after plugging the rubber plug, and then take the reaction tube out of the glove box;

[0076] Step 2: Continue to use a microsyringe to add benzoyl chloride (0.2 mmol) and organic base N,N-diisopropylethylamine (0.2 mmol) into the above reaction tube respectively, and shake well;

[0077] Step 3: Put the reaction mixture into a 20 W blue LED light reaction device for reaction; monitor by thin layer chromatography (TLC) until the reaction is complete, then concentrate the reaction liquid by reduced pressure distillation to obtain a crude product, and then purify by column chromatography to obtain a corresponding pure product;

[0078]

[0079] The reaction is as follows:

[0080] .

[0081] The present application is described in detail above through specific and preferred examples, but those skilled in the art should understand that the present application is not limited to the above-mentioned examples, and any modification, equivalent replacement, etc. made within the spirit and principles of the present application should be included in the protection scope of the present application.

Claims

1. A method for synthesizing a 3-benzoylquinoxaline-2(1H)-one compound represented by formula (2), characterized in that, Includes the following steps: Step 1: Using quinoxaline-2(1H)-one as the starting material, accurately weigh photosensitizer fac-Ir(ppy)3 and quinoxaline-2(1H)-one substrate as shown in formula (1) in the glove box using an analytical balance and add them to the reaction tube. Then, add acetonitrile solvent (MeCN) to it using a pipette, stopper it with a rubber stopper, shake it well, and send the reaction tube out of the glove box. Step 2: Add benzoyl chloride and N,N-diisopropylethylamine, an organic base, to the reaction tube containing the reagents using a microsyringe. Step 3: Place the reaction mixture in a 20 W blue LED light reaction generator and react; monitor the reaction by thin-layer chromatography (TLC) until the reaction is complete, concentrate the reaction solution by vacuum distillation to obtain crude product, and then purify it by column chromatography to obtain the corresponding pure product; The reaction formula is as follows: 。 2. The method for synthesizing a 3-benzoylquinoxaline-2(1H)-one compound according to claim 1, characterized in that, The molecular structure of the 3-benzoylquinoxalin-2(1H)-one compound obtained by the method is as follows: 。 3. The method for synthesizing a 3-benzoylquinoxaline-2(1H)-one compound according to claim 1, characterized in that, The molar ratio of quinoxaline-2(1H)-one to the photosensitizer in step 1 is 25:

1.

4. The method for synthesizing a 3-benzoylquinoxaline-2(1H)-one compound according to claim 1, characterized in that, The photosensitizer fac-Ir(ppy)3 in the synthesis method is 0.004 mmol, quinoxaloline-2(1H)-one is 0.1 mmol, acetonitrile solvent is 1 mL, benzoyl chloride is 0.2 mmol, and organic base N,N-diisopropylethylamine is 0.2 mmol.

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