CN113801119B - Synthesis method of pyrazolo [1,3,5] triazine compound - Google Patents
Synthesis method of pyrazolo [1,3,5] triazine compound Download PDFInfo
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Abstract
The invention discloses a synthetic method of pyrazolopyrimidine compounds, and belongs to the technical field of organic synthesis. The technical scheme provided by the invention has the key points that: the aromatic aldehyde compound, the 3-amino pyrazole compound and ammonium iodide are dissolved in a solvent, then an oxidant is added, and then the mixture reacts at the temperature of 130-150 ℃ to prepare the target product pyrazolo [1,3,5] triazine compound. The synthetic process is simple and efficient, the pyrazolo [1,3,5] triazine compound is directly prepared in one step through one-pot series reaction, a catalyst and an additive are not needed in the synthetic process, the operation is convenient, the raw materials are simple, the reaction condition is mild, and the application range of the substrate is wide.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthetic method of a pyrazolo [1,3,5] triazine compound.
Background
Studies have shown that pyrazolo [1,3,5] triazines are isosteres of purines and can be used to target signal receptors and enzymes of purines. Therefore, pyrazolo [1,3,5] triazine derivatives have various biological activities, such as corticotropin releasing factor (CRF1) receptor antagonists, cannabinoid (CB1) receptor antagonists, adenosine (a) receptor antagonists, anti-Thymidine Phosphorylase (TP) inhibitors, casein kinase II (CK2) inhibitors, cyclin-dependent kinase (CDK2) inhibitors, phosphodiesterase (PDE4, PDE10) inhibitors, Tyrosine Threonine Kinase (TTK) inhibitors, antitumor, antibacterial, antiviral, anticonvulsive, antimigraine, antidepressant and anxiolytic effects, and have important application values in the fields of biology and medicine. Meanwhile, the synthesis method of pyrazolo [1,3,5] triazine compounds reported in related documents at present mainly depends on the condensation reaction of 3-aminopyrazole and a pre-prepared nitrogen-containing 1, 3-amphiphilic reagent and the heterocyclic reaction of N-pyrazolyl amidine. Although these methods are generally reliable, many of them involve disadvantages of requiring a preliminary preparation of a substrate, a narrow substrate range, harsh reaction conditions, cumbersome post-treatment, etc., which largely limits the application of such synthetic methods in practical production. Therefore, research and development of a method for efficiently synthesizing pyrazolo [1,3,5] triazine compounds by using cheap reagents as raw materials through simple operation steps have certain theoretical significance and important application value.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a synthesis method of pyrazolo [1,3,5] triazine compounds, which is characterized in that a target product of pyrazolo [1,3,5] triazine compounds is prepared by one-pot series reaction from simple raw materials, the synthesis process is convenient to operate, the reaction conditions are mild, the substrate application range is wide, and the method is suitable for industrial production.
The invention adopts the following technical scheme for solving the technical problems, and the synthesis method of the pyrazolo [1,3,5] triazine compound is characterized by comprising the following specific steps: dissolving aromatic aldehyde compounds 1, 3-amino pyrazole compounds 2 and ammonium iodide in a solvent, adding an oxidant, and reacting at 130-150 ℃ to obtain a target product pyrazolo [1,3,5] triazine compound 3, wherein the reaction equation in the synthesis method is as follows:
wherein R1 is phenyl, substituted phenyl, 2-naphthyl, thienyl, pyridyl or quinolyl, the substituted phenyl is 3, 4-dimethylphenyl, 2, 4-dichlorophenyl or mono-substituted phenyl, and the substituent on the benzene ring of the mono-substituted phenyl is methyl, tert-butyl, methoxy, ethoxy, thiomethyl, fluorine, chlorine, bromine, trifluoromethylFluoromethoxy, cyano, carbomethoxy, methylsulfonyl or nitro, R 2 Is hydrogen, an ethyl ester group, a methyl ester group or a cyano group, R 3 Hydrogen or methyl, chlorobenzene, iodobenzene, bromobenzene, o-dichlorobenzene or o-xylene as solvent, and di-tert-butyl peroxide (DTBP), tert-butyl peroxybenzoate (TBPB), dimethyl sulfoxide (DMSO), oxygen or air as oxidant.
More preferably, when the oxidant is di-tert-butyl peroxide, tert-butyl peroxybenzoate or dimethyl sulfoxide, the feeding molar ratio of the aldehyde compound 1, the 3-aminopyrazole compound 2, ammonium iodide and the oxidant is 2:1:1:3, and the feeding ratio of the aldehyde compound 1 and the solvent is 1mmol:4 mL.
Further preferably, when the oxidant is di-tert-butyl peroxide, tert-butyl peroxybenzoate, dimethyl sulfoxide or oxygen, the synthesis process is carried out under a sealed condition; when the oxidant is air, the synthesis process is carried out under open conditions.
Further preferably, the pyrazolo [1,3,5] triazine compound is one of the following compounds:
compared with the prior art, the invention has the following advantages and beneficial effects: 1. the synthesis process of the invention is a one-pot series reaction, the process is simple and efficient, and simultaneously, the resource waste and the environmental pollution caused by the use of various reagents in multi-step reactions, purification treatment of reaction intermediates in each step and the like are avoided; 2. the raw materials are cheap and easy to obtain; 3. the reaction condition of the invention does not need catalyst, does not need additive, and is simple and convenient to operate; 4. the substrate has wide application range. Therefore, the invention provides a novel method which is economical, practical, green and environment-friendly for synthesizing the pyrazolo [1,3,5] triazine compound.
Detailed Description
The present invention is described in further detail below with reference to examples, but it should not be construed that the scope of the above subject matter of the present invention is limited to the following examples, and that all the technologies realized based on the above subject matter of the present invention belong to the scope of the present invention.
Example 1
A35 mL reaction flask was charged with benzaldehyde 1a (106mg,1mmol), 3-aminopyrazole-4-carboxylic acid ethyl ester 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol) and o-dichlorobenzene (2mL), and the mixture was left to react with open stirring at 140 ℃ for 8 h. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution and the saturated brine were successively washed, and dried over anhydrous sodium sulfate. Filtration, spin-drying and isolation on silica gel (petrol ether/ethyl acetate 30/1, v/v) gave product 3a as a pale yellow solid (161.7mg, 94%). The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ(ppm)8.89–8.82(m,2H),8.75–8.68(m,2H),8.65(s,1H),7.74–7.69(m,1H),7.68–7.62(m,2H),7.60–7.51(m,3H),4.48(q,J＝7.2Hz,2H),1.50(t,J＝7.2Hz,3H)； 13 C NMR(100MHz,CDCl 3 ):δ(ppm)162.2,160.7,154.7,151.1,149.2,135.4,133.6,132.3,131.5,129.9,129.3,128.7,128.6,103.0,60.6,14.5；HRMS(ESI):m/z[M+Na] + calcd for C 20 H 16 N 4 NaO 2 :367.1165；found:367.1163。
example 2
To a 35mL sealed tube were added 1a (106mg,1mmol), 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol), di-t-butyl peroxide (219mg,1.5mmol) and o-dichlorobenzene (2mL), and the reaction was stirred in a metal bath at 140 ℃ for 8 h. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petrol ether/ethyl acetate 30/1, v/v) gave product 3a as a pale yellow solid (135.9mg, 79%).
Example 3
1a (106mg,1mmol), 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol), tert-butyl peroxybenzoate (291mg,1.5mmol) and o-dichlorobenzene (2mL) were added to a 35mL sealed tube, and the reaction was stirred in a metal bath at 140 ℃ for 8 h. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 30/1, v/v) afforded product 3a (134.1mg, 78%) as a pale yellow solid.
Example 4
To a 35mL sealed tube were added 1a (106mg,1mmol), 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol), dimethyl sulfoxide (117mg,1.5mmol) and o-dichlorobenzene (2mL), followed by stirring in a metal bath at 140 ℃ for 8 h. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 30/1, v/v) afforded product 3a (58.5mg, 34%) as a pale yellow solid.
Example 5
A50 mL Schlenk tube was charged with 1a (106mg,1mmol), 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol) and O-dichlorobenzene (2mL), followed by O 2 The mixture is placed in a metal bath at 140 ℃ under the atmosphere and stirred for reaction for 8 hours. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 30/1, v/v) afforded product 3a (141mg, 82%) as a pale yellow solid.
Example 6
A35 mL reaction flask was charged with 1a (106mg,1mmol), 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol), and chlorobenzene (2mL), and then placed in a 140 ℃ metal bath to react with open stirring for 8 h. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and thenNa with mass concentration of 10% is used for the organic phase 2 S 2 O 3 The solution was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel column (petroleum ether/ethyl acetate 30/1, v/v) gave product 3a as a pale yellow solid (146.2mg, 85%).
Example 7
A35 mL reaction flask was charged with 1a (106mg,1mmol), 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol), and iodobenzene (2mL), and placed in a 140 deg.C metal bath with open stirring for reaction for 8 h. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution and the saturated brine were successively washed, and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 30/1, v/v) afforded product 3a (142.8mg, 83%) as a pale yellow solid.
Example 8
A35 mL reaction flask was charged with 1a (106mg,1mmol), 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol), and bromobenzene (2mL), and then placed in a 140 deg.C metal bath with open stirring for 8 h. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 30/1, v/v) afforded product 3a (147.9mg, 86%) as a pale yellow solid.
Example 9
A35 mL reaction flask was charged with 1a (106mg,1mmol), 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol), and o-xylene (2mL), and then placed in a 140 ℃ metal bath to react with open stirring for 8 h. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 30/1, v/v) afforded product 3a (141mg, 82%) as a pale yellow solid.
Example 10
At 35A mL reaction flask was charged with 1a (106mg,1mmol), 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol) and o-dichlorobenzene (2mL), and the reaction was left to stir open in a metal bath at 130 ℃ for 8 h. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petrol ether/ethyl acetate 30/1, v/v) gave product 3a as a pale yellow solid (135.9mg, 79%).
Example 11
A35 mL reaction flask was charged with 1a (106mg,1mmol), 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol) and o-dichlorobenzene (2mL) and placed in a 150 ℃ metal bath with open stirring for reaction for 8 h. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petrol ether/ethyl acetate 30/1, v/v) gave product 3a as a pale yellow solid (158.2mg, 92%).
Example 12
A35 mL reaction flask was charged with 1b (120mg,1mmol), 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol), and o-dichlorobenzene (2mL), and placed in a 140 ℃ metal bath with open stirring for reaction for 8 h. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 20/1, v/v) gave product 3b (176.7mg, 95%) as a white solid. The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ(ppm)8.75(d,J＝8.4Hz,2H),8.60(s,1H),8.56(d,J＝8.4Hz,2H),7.40(d,J＝8.0Hz,2H),7.31(d,J＝8.0Hz,2H),4.47(q,J＝7.2Hz,2H),2.48(s,3H),2.44(s,3H),1.49(t,J＝7.2Hz,3H)； 13 C NMR(100MHz,CDCl 3 ):δ(ppm)162.3,160.7,154.4,151.2,148.9,144.5,142.8,132.7,131.5,129.3,129.2,127.1,102.5,60.4,21.8,21.7,14.5；HRMS(ESI):m/z[M+Na] + calcd for C 22 H 20 N 4 NaO 2 :395.1478；found:395.1477。
example 13
A35 mL reaction flask was charged with 1c (162mg,1mmol), 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol), and o-dichlorobenzene (2mL), and then placed in a 140 ℃ metal bath with open stirring for reaction for 8 h. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 20/1, v/v) gave product 3c (191.5mg, 84%) as a pale yellow solid. The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ(ppm)8.78–8.74(m,2H),8.65–8.60(m,3H),7.68–7.64(m,2H),7.58–7.54(m,2H),4.47(q,J＝7.2Hz,2H),1.49(t,J＝7.2Hz,3H),1.41(s,9H),1.39(s,9H)； 13 C NMR(100MHz,CDCl 3 ):δ(ppm)162.4,160.8,157.4,155.8,154.6,151.1,149.0,132.8,131.3,129.1,127.1,125.6,102.6,60.5,35.2,35.0,31.2,31.0,14.5；HRMS(ESI):m/z[M+Na] + calcd for C 28 H 32 N 4 NaO 2 :479.2417；found:479.2416。
example 14
A35 mL reaction flask was charged with 1d (136mg,1mmol), 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol), and o-dichlorobenzene (2mL), and then placed in a 140 ℃ metal bath with open stirring for reaction for 8 h. Adding 50mL of water to quench the reaction, and using ethyl acetateThe ester was extracted (50 mL. times.3), after which the organic phase was treated with 10% by mass Na 2 S 2 O 3 The solution and the saturated brine were successively washed, and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 10/1, v/v) afforded product 3d (171.7mg, 85%) as a yellow solid. The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ(ppm)8.98–8.91(m,2H),8.67–8.62(m,2H),8.59(s,1H),7.12–7.07(m,2H),7.05–7.00(m,2H),4.46(q,J＝7.2Hz,2H),3.94(s,3H),3.91(s,3H),1.49(t,J＝7.2Hz,3H)； 13 C NMR(100MHz,CDCl 3 ):δ(ppm)；163.9,163.0,162.5,160.3,153.7,151.4,148.8,133.8,131.1,128.2,122.2,113.9,102.1,60.4,55.6,55.4,14.5.HRMS(ESI):m/z[M+Na] + calcd for C 22 H 20 N 4 NaO 4 :427.1377；found:427.1378。
example 15
A35 mL reaction flask was charged with 1e (150mg,1mmol), 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol), and o-dichlorobenzene (2mL), and then placed in a 140 ℃ metal bath with open stirring for reaction for 8 h. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 10/1, v/v) afforded product 3e (187.9mg, 87%) as a yellow solid. The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ(ppm)8.95–8.90(m,2H),8.65–8.60(m,2H),8.58(s,1H),7.10–7.05(m,2H),7.03–6.98(m,2H),4.46(q,J＝7.2Hz,2H),4.19–4.11(m,4H),1.51–1.44(m,9H)； 13 C NMR(100MHz,CDCl 3 ):δ(ppm)163.3,162.5,162.4,160.4,153.7,151.4,148.7,133.8,131.1,128.0,122.0,114.3(3),114.3(1),102.0,63.9,63.6,60.4,14.7,14.6,14.5；HRMS(ESI):m/z[M+Na] + calcd for C 24 H 24 N 4 NaO 4 :455.1690；found:455.1689。
example 16
A35 mL reaction flask was charged with 1f (152mg,1mmol), 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol), and o-dichlorobenzene (2mL), and placed in a 140 ℃ metal bath with open stirring for 8 h. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution and the saturated brine were successively washed, and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 15/1, v/v) gave product 3f (146.1mg, 67%) as a yellow solid. The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ(ppm)8.87–8.82(m,2H),8.62–8.55(m,3H),7.44–7.39(m,2H),7.37–7.32(m,2H),4.47(q,J＝7.2Hz,2H),2.58(s,3H),2.57(s,3H),1.49(t,J＝7.2Hz,3H)； 13 C NMR(100MHz,CDCl 3 ):δ(ppm)162.3,160.2,153.9,151.2,148.9,147.1,144.5,131.8,131.7,129.5,125.7,125.3,124.8,102.5,60.5,14.9,14.7,14.5；HRMS(ESI):m/z[M+Na] + calcd for C 22 H 20 N 4 NaO 2 S 2 :459.0920；found:459.0919。
example 17
A35 mL reaction flask was charged with 1g (124mg,1mmol), 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol), and o-dichlorobenzene (2mL), and then placed in a 140 ℃ metal bath with open stirring for reaction for 8 h. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtering, spin-drying, and separating with silica gel column (petroleum ether/ethyl acetate 15/1, v/v) to obtain white solid3g (161.5mg, 85%) of the product. The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ(ppm)8.99–8.93(m,2H),8.70–8.64(m,2H),8.62(s,1H),7.34–7.28(m,2H),7.23–7.17(m,2H),4.47(q,J＝7.2Hz,2H),1.49(t,J＝7.2Hz,3H)； 13 C NMR(100MHz,CDCl 3 ):δ(ppm)167.3,166.9,164.7,164.3,162.1,159.5,153.4,151.0,149.2,134.4,134.3,131.6,131.5(0),131.4(7),131.4,125.9(3),125.9(0),116.0,115.9,115.8,115.7,102.9,60.6,14.4；HRMS(ESI):m/z[M+Na] + calcd for C 20 H 14 F 2 N 4 NaO 2 :403.0977；found:403.0975。
example 18
A35 mL reaction flask was charged with 1h (140.5mg,1mmol), 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol) and o-dichlorobenzene (2mL) and placed in a 140 deg.C metal bath with open stirring for reaction for 8 h. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel column (petroleum ether/ethyl acetate 30/1, v/v) gave the product as a white solid for 3h (190mg, 92%). The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ(ppm)8.87–8.81(m,2H),8.61(s,1H),8.58–8.52(m,2H),7.62–7.54(m,2H),7.50–7.44(m,2H),4.46(q,J＝7.2Hz,2H),1.48(t,J＝7.2Hz,3H)； 13 C NMR(100MHz,CDCl 3 ):δ(ppm)161.9,159.4,153.5,150.9,149.2,140.3,138.7,133.6,132.9,130.4,128.9(3),128.9(1),128.0,103.1,60.6,14.4；HRMS(ESI):m/z[M+Na] + calcd for C 20 H 14 C l2 N 4 NaO 2 :435.0386；found:435.0389。
example 19
A35 mL reaction flask was charged with 1i (185mg,1mmol), 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol) and o-dichlorobenzene (2mL) and placed in a 140 deg.C metal bath with open stirring for reaction for 8 h. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petrol ether/ethyl acetate 30/1, v/v) gave the product 3i as a pale yellow solid (225.9mg, 90%). The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ(ppm)8.79–8.73(m,2H),8.63(s,1H),8.54–8.46(m,2H),7.79–7.73(m,2H),7.67–7.62(m,2H),4.46(q,J＝7.2Hz,2H),1.48(t,J＝7.2Hz,3H)； 13 C NMR(100MHz,CDCl 3 ):δ(ppm)161.9,159.6,153.7,150.9,149.3,134.1,132.9,131.9,130.6,129.2,128.5,127.5,103.2,60.7,14.4；HRMS(ESI):m/z[M+Na] + calcd for C 20 H 14 Br 2 N 4 NaO 2 :524.9356；found:524.9353。
example 20
A35 mL reaction flask was charged with 1j (174mg,1mmol), 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol), and o-dichlorobenzene (2mL), and then placed in a 140 ℃ metal bath with open stirring for reaction for 8 h. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 20/1, v/v) afforded product 3j (223.2mg, 93%) as a pale green solid. The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ(ppm)8.96(d,J＝8.0Hz,2H),8.74(d,J＝8.0Hz,2H),8.66(s,1H),7.90(d,J＝8.4Hz,2H),7.77(d,J＝8.4Hz,2H),4.47(q,J＝7.2Hz,2H),1.49(t,J＝7.2Hz,3H)； 13 C NMR(100MHz,CDCl 3 ):δ(ppm)161.7,158.9,153.5,150.7,149.6,138.2,135.1,134.8,133.9,133.6,132.8,131.9,129.4,125.6(8),125.6(5),125.6(1),125.5(7),125.5(5),125.5(1),125.4(8),125.4,125.2,124.8,122.5,122.1,103.8,60.8,14.4；HRMS(ESI):m/z[M+Na] + calcd for C 22 H 14 F 6 N 4 NaO 2 :503.0913；found:503.0913。
example 21
A35 mL reaction flask was charged with 1k (190mg,1mmol), 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol), and o-dichlorobenzene (2mL), and then placed in a 140 ℃ metal bath with open stirring for reaction for 8 h. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petrol ether/ethyl acetate 30/1, v/v) gave the product 3k (225.3mg, 88%) as a pale yellow solid. The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ(ppm)9.00–8.93(m,2H),8.72–8.65(m,2H),8.64(s,1H),7.46(d,J＝8.4Hz,2H),7.35(d,J＝8.4Hz,2H),4.46(q,J＝7.2Hz,2H),1.48(t,J＝7.2Hz,3H)； 13 C NMR(100MHz,CDCl 3 ):δ(ppm)161.9,159.2,153.3,153.0,152.3,150.8,149.4,133.7,133.5,131.0,127.8,121.6(4),121.5(9),120.5,120.2,119.1,119.0,103.3,60.7,14.4；HRMS(ESI):m/z[M+Na] + calcd for C 22 H 14 F 6 N 4 NaO 4 :535.0811；found:535.0811。
example 22
A35 mL reaction flask was charged with 1l (131mg,1mmol), 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5 m)mol) and o-dichlorobenzene (2mL), and then placed in a metal bath at 140 ℃ to react for 8h with open stirring. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution and the saturated brine were successively washed, and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petrol ether/ethyl acetate 5/1, v/v) gave 3l (159.6mg, 81%) of the product as a yellow solid. The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ(ppm)9.03(d,J＝8.4Hz,2H),8.79(d,J＝8.4Hz,2H),8.73(s,1H),7.96(d,J＝8.4Hz,2H),7.86(d,J＝8.4Hz,2H),4.50(q,J＝7.2Hz,2H),1.50(t,J＝7.2Hz,3H)； 13 C NMR(100MHz,CDCl 3 ):δ(ppm)161.6,158.5,153.2,150.6,149.9,138.9,133.4,132.5,132.2,132.0,129.6,118.3,117.7,117.0,115.6,104.2,60.9,14.4；HRMS(ESI):m/z[M+Na] + calcd for C 22 H 14 N 6 NaO 2 :417.1070；found:417.1073。
example 23
A35 mL reaction flask was charged with 1m (164mg,1mmol), 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol) and o-dichlorobenzene (2mL) and placed in a 140 deg.C metal bath with open stirring for reaction for 8 h. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution and the saturated brine were successively washed, and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel column (petroleum ether/ethyl acetate 8/1, v/v) gave the product 3m (188.6mg, 82%) as a pale yellow solid. The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ(ppm)8.93(d,J＝8.4Hz,2H),8.72(d,J＝8.4Hz,2H),8.67(s,1H),8.28(d,J＝8.4Hz,2H),8.18(d,J＝8.4Hz,2H),4.48(q,J＝7.2Hz,2H),4.01(s,3H),3.98(s,3H),1.50(t,J＝7.2Hz,3H)； 13 C NMR(100MHz,CDCl 3 ):δ(ppm)166.5,166.0,161.8,159.4,153.8,150.8,149.5,139.0,134.3,133.4,133.2,131.5,129.8,129.5,129.1,103.7,60.7,52.6,52.4,14.4；HRMS(ESI):m/z[M+Na] + calcd for C 24 H 20 N 4 NaO 6 :483.1275；found:483.1278。
example 24
A35 mL reaction flask was charged with 1n (184mg,1mmol), 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol), and o-dichlorobenzene (2mL), and then placed in a 140 ℃ metal bath with open stirring for reaction for 8 h. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel column (petroleum ether/ethyl acetate 1/1, v/v) gave the product 3n (162.5mg, 65%) as a pale yellow solid. The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ(ppm)9.07(d,J＝8.4Hz,2H),8.89(d,J＝8.4Hz,2H),8.75(s,1H),8.25(d,J＝8.4Hz,2H),8.15(d,J＝8.4Hz,2H),4.50(q,J＝7.2Hz,2H),3.17(s,3H),3.15(s,3H),1.50(t,J＝7.2Hz,3H)； 13 C NMR(100MHz,CDCl 3 )δ(ppm):161.6,158.6,153.4,150.6,150.0,144.8,143.6,139.9,134.4,132.5,130.1,127.8,127.6,104.4,61.0,44.4(3),44.3(7),14.4；HRMS(ESI):m/z[M+Na] + calcd for C 22 H 20 N 4 NaO 6 S 2 :523.0716；found:523.0718。
example 25
A35 mL reaction flask was charged with 1o (120mg,1mmol), 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol), and o-dichlorobenzene (2mL), and then placed in a 140 ℃ metal bath with open stirring for reaction for 8 h. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution and the saturated brine were successively washed, and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel column (petroleum ether/ethyl acetate 30/1, v/v) gave the product 3o as a white solid (133.9mg, 72%). The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ(ppm)8.61(s,1H),8.34(d,J＝8.0Hz,1H),7.75(d,J＝8.0Hz,1H),7.57–7.51(m,1H),7.45–7.39(m,3H),7.37–7.32(m,2H),4.46(q,J＝7.2Hz,2H),2.89(s,3H),2.38(s,3H),1.46(t,J＝7.0Hz,3H)； 13 C NMR(100MHz,CDCl 3 ):δ(ppm)162.9,162.3,157.1,149.5,149.2,139.8,137.7,134.8,132.1,131.8,131.7,131.2,131.1,129.7(8),129.7(6),126.0,125.9,103.6,60.6,22.8,20.2,14.4；HRMS(ESI):m/z[M+Na] + calcd for C 22 H 20 N 4 NaO 2 :395.1478；found:395.1482。
example 26
A35 mL reaction flask was charged with 1p (124mg,1mmol), 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol), and o-dichlorobenzene (2mL), and then placed in a 140 ℃ metal bath with open stirring for reaction for 8 h. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution and the saturated brine were successively washed, and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petrol ether/ethyl acetate 15/1, v/v) gave the product 3p as a pale yellow solid (106.4mg, 56%). The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ(ppm)8.65(s,1H),8.41(td,J＝7.6,1.6Hz,1H),8.01–7.96(m,1H),7.72–7.66(m,1H),7.57–7.51(m,1H),7.42(td,J＝7.6,0.8Hz,1H),7.37–7.32(m,1H),7.32–7.28(m,1H),7.27–7.21(m,1H),4.47(q,J＝7.2Hz,2H),1.47(t,J＝7.2Hz,3H)； 13 C NMR(100MHz,CDCl 3 ):δ(ppm)163.4,162.0,161.9,160.8,159.4,159.3(4),159.2(9),153.4,149.5,134.6,134.5,133.6,133.5,132.5,131.7(2),131.7(0),124.5(5),124.5(1),124.3,124.2,124.0(4),123.9(6),118.6,118.4,117.4,117.2,116.8,116.6,104.1,60.8,14.4；HRMS(ESI):m/z[M+Na] + calcd for C 20 H 14 F 2 N 4 NaO 2 :403.0977；found:403.0977。
example 27
A35 mL reaction flask was charged with 1q (120mg,1mmol), 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol), and o-dichlorobenzene (2mL), and then placed in a 140 ℃ metal bath and left to stir open for 8 h. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petrol ether/ethyl acetate 20/1, v/v) gave the product 3q as a pale yellow solid (163.7mg, 88%). The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ(ppm)8.61(s,1H),8.60–8.55(m,2H),8.51–8.44(m,2H),7.53–7.45(m,2H),7.43–7.34(m,2H),4.47(q,J＝7.2Hz,2H),2.51(s,3H),2.47(s,3H),1.49(t,J＝7.0Hz,3H)； 13 C NMR(100MHz,CDCl 3 ):δ(ppm)162.2,160.7,154.7,151.0,148.9,138.3,138.2,135.2,134.3,133.0,131.7,129.8,129.6,128.6,128.4,128.3,126.5,102.7,60.4,21.5,21.4,14.4；HRMS(ESI):m/z[M+Na] + calcd for C 22 H 20 N 4 NaO 2 :395.1478；found:395.1476。
example 28
A35 mL reaction flask was charged with 1r (136mg,1mmol), 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol), and o-dichlorobenzene (2mL), and then placed in a 140 ℃ metal bath with open stirring for reaction for 8 h. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-drying and silica gel column separation (petroleum ether/ethyl acetate 10/1, v/v) gave the product 3r as a pale yellow solid (161.6mg, 80%). The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ(ppm)8.62(s,1H),8.43(dd,J＝7.6,0.8Hz,1H),8.40–8.37(m,1H),8.29–8.23(m,1H),8.21–8.15(m,1H),7.54–7.48(m,1H),7.45–7.38(m,1H),7.24–7.19(m,1H),7.12–7.06(m,1H),4.46(q,J＝7.2Hz,2H),3.93(s,3H),3.92(s,3H),1.49(t,J＝7.0Hz,3H)； 13 C NMR(100MHz,CDCl 3 ):δ(ppm)162.2,160.2,159.8,159.4,154.2,150.9,149.1,136.7,131.0,129.6,129.5,123.9,121.8,119.4,118.6,116.5,113.5,102.9,60.5,55.5,55.3,14.4；HRMS(ESI):m/z[M+Na] + calcd for C 22 H 20 N 4 NaO 4 :427.1377；found:427.1377。
example 29
A35 mL reaction flask was charged with 1s (124mg,1mmol), 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol) and o-dichlorobenzene (2mL), and then placed in a 140 deg.C metal bath with open stirring for reaction for 8 h. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution and the saturated brine were successively washed, and dried over anhydrous sodium sulfate. Filtration, spin-drying and silica gel column separation (petroleum ether/ethyl acetate 20/1, v/v) gave the product 3s as a pale yellow solid (148.2mg, 78%). The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ(ppm)8.70(d,J＝8.0Hz,1H),8.64(s,1H),8.63–8.59(m,1H),8.43(d,J＝8.0Hz,1H),8.34–8.27(m,1H),7.64–7.56(m,1H),7.52–7.45(m,1H),7.40(td,J＝8.1,2.2Hz,1H),7.28–7.21(m,1H),4.47(q,J＝7.2Hz,2H),1.49(t,J＝7.2Hz,3H)； 13 C NMR(100MHz,CDCl 3 ):δ(ppm)164.2,163.5,161.9,161.8,161.1,159.2,159.1,153.2(3),153.2(0),150.8,149.4,137.5,137.4,131.6,131.5,130.2(3),130.2(1),130.1(5),130.1,127.4,127.3,124.8(4),124.8(2),120.9,120.7,119.3,119.1,118.6,118.4,116.0,115.7,103.4,60.7,14.4；HRMS(ESI):m/z[M+Na] + calcd for C 20 H 14 F 2 N 4 NaO 2 :403.0977；found:403.0976。
example 30
A35 mL reaction flask was charged with 1t (140.5mg,1mmol), 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol) and o-dichlorobenzene (2mL), and the reaction was left to open to the atmosphere in a metal bath at 140 ℃ for 8 h. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-drying and silica gel column separation (petroleum ether/ethyl acetate 20/1, v/v) gave the product 3t as a pale yellow solid (175.5mg, 85%). The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ(ppm)8.83(t,J＝1.8Hz,1H),8.78–8.72(m,1H),8.62(s,1H),8.56(t,J＝1.8Hz,1H),8.49(dt,J＝7.6,1.6Hz 1H),7.67–7.63(m,1H),7.55(t,J＝7.8Hz,1H),7.52–7.48(m,1H),7.43(t,J＝7.8Hz,1H),4.46(q,J＝7.2Hz,2H),1.49(t,J＝7.2Hz,3H)； 13 C NMR(100MHz,CDCl 3 ):δ(ppm)161.8,158.9,153.2,150.7,149.4,136.8,134.8,134.7,133.7,132.2,131.3,131.2,129.9,129.8,129.6,129.0,127.2,103.4,60.7,14.4；HRMS(ESI):m/z[M+Na] + calcd for C 20 H 14 C l2 N 4 NaO 2 :435.0386；found:435.0387。
example 31
A35 mL reaction flask was charged with 1u (185mg,1mmol), 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol), and o-dichlorobenzene (2mL), and placed at 140 deg.C in goldThe reaction is carried out for 8 hours in the bath with open stirring. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel column (petroleum ether/ethyl acetate 15/1, v/v) gave the product 3u as a pale yellow solid (218.3mg, 87%). The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ(ppm)8.97(t,J＝1.6Hz,1H),8.78(d,J＝8.0Hz,1H),8.71(t,J＝1.6Hz,1H),8.62(s,1H),8.53(d,J＝8.0Hz,1H),7.84–7.76(m,1H),7.68–7.63(m,1H),7.48(t,J＝8.0Hz,1H),7.37(t,J＝7.8Hz,1H),4.46(q,J＝7.2Hz,2H),1.49(t,J＝7.2Hz,3H)； 13 C NMR(100MHz,CDCl 3 ):δ(ppm)161.8,158.8,153.1,150.6,149.4,137.0,136.6,135.1,134.1,131.9,131.3,130.1(2),130.0(7),130.0,127.7,122.9,122.6,103.4,60.7,14.4；HRMS(ESI):m/z[M+Na] + calcd for C 20 H 14 Br 2 N 4 NaO 2 :524.9356；found:524.9365。
example 32
A35 mL reaction flask was charged with 1v (174mg,1mmol), 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol), and o-dichlorobenzene (2mL), and then placed in a 140 ℃ metal bath with open stirring for reaction for 8 h. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel column (petroleum ether/ethyl acetate 20/1, v/v) gave the product 3v (204mg, 85%) as a pale yellow solid. The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ(ppm)9.18(s,1H),9.07(d,J＝8.0Hz,1H),8.88(s,1H),8.80(d,J＝8.0Hz,1H),8.66(s,1H),7.96(d,J＝8.0Hz,1H),7.79(dd,J＝14.8,7.2Hz,2H),7.66(t,J＝7.8Hz,1H),4.46(q,J＝7.2Hz,2H),1.50(t,J＝7.2Hz,3H)； 13 C NMR(100MHz,CDCl 3 ):δ(ppm)161.8,158.8,153.3,150.6,149.7,135.8,134.7,132.2,131.4(5),131.4(0),131.1(3),131.0(7),130.3(2),130.2(5),130.2(2),130.1(8),130.1(5),129.3,129.2,128.8(2),128.7(9),128.7(5),128.7,128.5(3),128.4(9),128.4(5),128.4(1),125.9(0),125.8(6),125.8(2),125.7(8),125.2,124.9,122.5,122.2,103.7,60.8,14.3；HRMS(ESI):m/z[M+Na] + calcd for C 22 H 14 F 6 N 4 NaO 2 :503.0913；found:503.0915。
example 33
A35 mL reaction flask was charged with 1w (151mg,1mmol), 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol) and o-dichlorobenzene (2mL), and then placed in a 140 ℃ metal bath with open stirring for reaction for 8 h. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution and the saturated brine were successively washed, and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on a silica gel column (petroleum ether/ethyl acetate 8/1, v/v) gave the product 3w (160.6mg, 74%) as a yellow solid. The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ(ppm)9.85(s,1H),9.47(s,1H),9.27(d,J＝8.0Hz,1H),9.03(d,J＝7.6Hz,1H),8.76(s,1H),8.60(d,J＝8.0Hz,1H),8.45(d,J＝8.0Hz,1H),7.92(t,J＝8.0Hz,1H),7.78(t,J＝8.0Hz,1H),4.50(q,J＝7.2Hz,2H),1.53(t,J＝7.2Hz,3H)； 13 C NMR(100MHz,CDCl 3 ):δ(ppm)161.6,158.1,152.8,150.5,150.1,148.8,148.3,137.0,136.7,134.7,131.0,130.0,128.2,126.7(7),126.7(6),124.0,104.3,61.0,14.4；HRMS(ESI):m/z[M+Na] + calcd for C 20 H 14 N 6 NaO 6 :457.0867；found:457.0866。
example 34
A35 mL reaction flask was charged with 1X (134mg,1mmol), 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol), and o-dichlorobenzene (2mL), and placed in a 140 ℃ metal bath with open stirring for 8 h. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 15/1, v/v) afforded the product 3x (168.1mg, 84%) as a pale brown solid. The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ(ppm)8.60(s,1H),8.58–8.53(m,2H),8.47–8.39(m,2H),7.36(d,J＝8.4Hz,1H),7.28(d,J＝7.6Hz,1H),4.47(q,J＝7.2Hz,2H),2.42(s,3H),2.39(s,3H),2.39(s,3H),2.36(s,3H),1.50(t,J＝7.0Hz,3H)； 13 C NMR(100MHz,CDCl 3 ):δ(ppm)162.4,160.9,154.7,151.2,148.8,143.2,141.6,137.0,136.9,133.1,132.2,130.2,130.0,129.8,129.1,127.5,126.9,102.4,60.4,20.2,20.1,20.0,19.9,14.4；HRMS(ESI):m/z[M+Na] + calcd for C 24 H 24 N 4 NaO 2 :423.1791；found:423.1789。
example 35
A35 mL reaction flask was charged with 1y (175mg,1mmol), 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol), and o-dichlorobenzene (2mL), and placed in a 140 deg.C metal bath with open stirring for 8 h. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution and the saturated brine were successively washed, and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 15/1, v/v) afforded product 3y (175.9mg, 73%) as a white solid. The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ(ppm)8.65(s,1H),8.12(d,J＝8.4Hz,1H),7.72(d,J＝8.0Hz,1H),7.67–7.56(m,2H),7.51(dd,J＝8.4,2.0Hz,1H),7.41(dd,J＝8.4,2.0Hz,1H),4.46(q,J＝7.2Hz,2H),1.44(t,J＝7.2Hz,3H)； 13 C NMR(100MHz,CDCl 3 ):δ(ppm)161.7,160.1,154.3,149.8,148.9,138.8,137.5,134.8,134.6,133.7,133.1,132.0,131.2,130.5,127.8,127.6,127.3,104.7,60.9,14.4；HRMS(ESI):m/z[M+Na] + calcd for C 20 H 12 C l4 N 4 NaO 2 :502.9607；found:502.9604。
example 36
A35 mL reaction flask was charged with 1z (156mg,1mmol), 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol), and o-dichlorobenzene (2mL), and the reaction was left to stir open in a 140 deg.C metal bath for 8 h. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on a silica gel column (petroleum ether/ethyl acetate 15/1, v/v) gave the product 3z as a yellow solid (175.4mg, 79%). The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ(ppm)9.62(s,1H),9.22(s,1H),8.79(dd,J＝8.4,1.6Hz,1H),8.73(dd,J＝8.4,1.6Hz,1H),8.66(s,1H),8.10(d,J＝7.6Hz,1H),8.04(d,J＝8.4Hz,2H),7.94(t,J＝8.8Hz,2H),7.87(d,J＝7.6Hz,1H),7.67–7.51(m,4H),4.50(q,J＝7.2Hz,2H),1.53(t,J＝7.0Hz,3H)； 13 C NMR(100MHz,CDCl 3 ):δ(ppm)162.3,160.5,154.3,151.2,149.1,135.6,135.3,134.2,133.0,132.8,132.4,130.4,130.0,129.5,129.0,128.3,128.2,127.9,127.8,127.7,127.0,126.8,126.5,126.3,125.3,102.9,60.6,14.5；HRMS(ESI):m/z[M+Na] + calcd for C 28 H 20 N 4 NaO 2 :467.1478；found:467.1479。
example 37
A35 mL reaction flask was charged with 1aa (112mg,1mmol), 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol), and o-dichlorobenzene (2mL), and then placed in a 140 ℃ metal bath with open stirring for reaction for 8 h. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel column (petroleum ether/ethyl acetate 20/1, v/v) gave the product 3aa (103.2mg, 58%) as a pale yellow solid. The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ(ppm) 1 H NMR(400MHz,CDCl 3 ):δ(ppm)9.00(d,J＝3.2Hz,1H),8.63(s,1H),8.25(d,J＝2.8Hz,1H),7.91(d,J＝4.4Hz,1H),7.66–7.59(m,1H),7.35(t,J＝4.6Hz,1H),7.22(t,J＝4.2Hz,1H),4.46(q,J＝7.2Hz,2H),1.49(t,J＝7.0Hz,3H)； 13 C NMR(100MHz,CDCl 3 ):δ(ppm)162.3,157.4,150.4,149.6,149.2,141.3,137.8,136.8,132.5,132.1,131.8,128.8,128.6,102.6,60.6,14.4；HRMS(ESI):m/z[M+Na] + calcd for C 16 H 12 N 4 NaO 2 S 2 :379.0294；found:379.0295。
example 38
A35 mL reaction flask was charged with 1ab (107mg,1mmol), 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol), and o-dichlorobenzene (2mL), and then placed in a 140 ℃ metal bath and left to react with open stirring for 8 h. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 1/1, v/v) gave the product 3ab (74.4mg, 43%) as a yellow solid. The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ(ppm)9.01(dd,J＝4.8,1.6Hz,2H),8.89(dd,J＝4.4,1.2Hz,2H),8.76(s,1H),8.73(dd,J＝4.4,1.6Hz,2H),8.50(dd,J＝4.4,1.6Hz,2H),4.50(q,J＝7.2Hz,2H),1.51(t,J＝7.2Hz,3H)； 13 C NMR(100MHz,CDCl 3 ):δ(ppm)161.6,158.6,153.3,150.8,150.7,150.5,150.0,142.2,136.7,124.3,122.4,104.5,61.0,14.4；HRMS(ESI):m/z[M+H] + calcd for C 18 H 15 N 6 O 2 :347.1251；found:347.1254。
example 39
A35 mL reaction flask was charged with 1ac (107mg,1mmol), 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol) and o-dichlorobenzene (2mL), and placed in a 140 ℃ metal bath with open stirring for reaction for 8 h. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 3/1, v/v) gave the product 3ac (72.7mg, 42%) as a yellow solid. The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ(ppm)10.07(d,J＝1.6Hz,1H),9.89(d,J＝1.6Hz,1H),9.29–9.22(m,1H),9.00–8.89(m,2H),8.83(dd,J＝4.8,1.6Hz,1H),8.73(s,1H),7.64–7.59(m,1H),7.53–7.50(m,1H),4.49(q,J＝7.2Hz,2H),1.50(t,J＝7.2Hz,3H)； 13 C NMR(100MHz,CDCl 3 ):δ(ppm)161.9,158.9,154.0,152.9,152.3,150.8,149.8,138.9,136.4,130.9,130.8,128.8,126.0,123.6,123.3,103.9,60.9,14.5；HRMS(ESI):m/z[M+Na] + calcd for C 18 H 14 N 6 NaO 2 :369.1070；found:369.1074。
example 40
A35 mL reaction flask was charged with 1ad (157mg,1mmol), 2a (77.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol) and o-dichlorobenzene (2mL), and placed at 14The reaction is carried out for 8 hours in a metal bath at the temperature of 0 ℃ with open stirring. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 3/1, v/v) gave the product 3ad (120.5mg, 54%) as a yellow solid. The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ(ppm)9.63(dd,J＝8.4,0.8Hz,1H),9.23(d,J＝4.4Hz,1H),9.11(d,J＝4.4Hz,1H),8.71(s,1H),8.48(d,J＝4.4Hz,1H),8.32(d,J＝8.4Hz,1H),8.26(dd,J＝8.4,0.8Hz,1H),8.03(d,J＝4.4Hz,1H),7.91(d,J＝8.4Hz,1H),7.89–7.81(m,2H),7.78–7.72(m,1H),7.66–7.61(m,1H),4.54(q,J＝7.2Hz,2H),1.54(t,J＝7.2Hz,3H)； 13 C NMR(100MHz,CDCl 3 ):δ(ppm)161.7,160.5,154.8,150.3,150.0,149.6,149.5,149.0,148.9,138.8,134.4,130.7,130.5,130.4,129.7,128.3,126.2,125.5,124.5,124.3,123.9,122.3,105.4,61.1,14.5；HRMS(ESI):m/z[M+Na] + calcd for C 26 H 18 N 6 NaO 2 :469.1383；found:469.1381。
EXAMPLE 41
A35 mL reaction flask was charged with 1a (106mg,1mmol), 2b (70.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol), and o-dichlorobenzene (2mL), and then placed in a 140 ℃ metal bath with open stirring for reaction for 8 h. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 15/1, v/v) afforded the product 3ae as a white solid (151.8mg, 92%). The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ(ppm)8.85–8.79(m,2H),8.70–8.64(m,2H),8.62(s,1H),7.70–7.65(m,1H),7.63–7.57(m,2H),7.56–7.49(m,3H),4.00(s,3H)； 13 C NMR(100MHz,CDCl 3 ):δ(ppm)162.5,160.6,154.5,150.9,149.1,135.2,133.5,132.2,131.4,129.8,129.2,128.6,128.4,102.6,51.7；HRMS(ESI):m/z[M+Na] + calcd for C 19 H 14 N 4 NaO 2 :353.1009；found:353.1008。
example 42
A35 mL reaction flask was charged with 1a (106mg,1mmol), 2c (54mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol) and o-dichlorobenzene (2mL), and then placed in a 140 ℃ metal bath and stirred open to the atmosphere for 8 h. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 The solution was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petrol ether/ethyl acetate 30/1, v/v) gave the product 3af (69.8mg, 47%) as a white solid. The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ(ppm)8.88–8.84(m,2H),8.73–8.69(m,2H),8.47(s,1H),7.77–7.73(m,1H),7.69–7.64(m,2H),7.63–7.55(m,3H)； 13 C NMR(100MHz,CDCl 3 ):δ(ppm)161.2,154.8,153.9,148.4,134.7,134.1,132.8,131.6,129.5,129.3,128.9,128.7,112.3,83.0；HRMS(ESI):m/z[M+Na] + calcd for C 18 H 11 N 5 Na:320.0907；found:320.0907。
example 43
A35 mL reaction flask was charged with 1a (106mg,1mmol), 2d (48.6mg,0.5mmol), ammonium iodide (72.5mg,0.5mmol), and o-dichlorobenzene (2mL), and then placed in a 140 ℃ metal bath with open stirring for reaction for 8 h. The reaction was quenched with 50mL of water, extracted with ethyl acetate (50 mL. times.3), and the organic phase was then quenched with 10% by weight Na 2 S 2 O 3 Solution and saturated saline solutionWashed twice and dried by anhydrous sodium sulfate. Filtration, spin-drying and separation on silica gel (petroleum ether/ethyl acetate 8/1, v/v) afforded the product 3ag (104.4mg, 73%) as a white solid. The characterization data for this compound are as follows: 1 H NMR(400MHz,CDCl 3 ):δ(ppm)11.73(s,1H),8.68–8.61(m,2H),7.92–7.86(m,2H),7.62–7.57(m,3H),7.56–7.48(m,3H),2.51(s,3H)； 13 C NMR(100MHz,CDCl 3 ):δ(ppm)163.2,161.8,157.3,143.3,137.7,137.6,130.8,130.4,129.7,128.8,128.6,128.4,109.6,16.0；HRMS(ESI):m/z[M+H] + calcd for C 18 H 15 N 4 :287.1291；found:287.1292。
the foregoing embodiments illustrate the principles, principal features and advantages of the invention, and it will be understood by those skilled in the art that the invention is not limited to the foregoing embodiments, which are merely illustrative of the principles of the invention, and that various changes and modifications may be made therein without departing from the scope of the principles of the invention.
Claims (1)
1. A synthetic method of pyrazolo [1,3,5] triazine compounds is characterized by comprising the following steps:
adding 1mmol of benzaldehyde 1a, 0.5mmol of 3-aminopyrazole-4-ethyl formate 2a, 0.5mmol of ammonium iodide and 2mL of o-dichlorobenzene into a 35mL reaction bottle, and then placing the mixture in a metal bath at 140 ℃ to react for 8 hours with open stirring; adding 50mL of water to quench the reaction, extracting with ethyl acetate for 3 times (50mL each time), and then using 10% Na by mass as the organic phase 2 S 2 O 3 Washing the solution and saturated salt solution in turn, and drying the solution by anhydrous sodium sulfate; filtering, spin-drying, separating with silica gel column to obtain pyrazolo [1,3,5]The triazine compound 3a has the following reaction process:
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