CN113801119B - A kind of synthetic method of pyrazolo[1,3,5]triazine compound - Google Patents

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

A kind of synthetic method of pyrazolo[1,3,5]triazine compound

technical field

The invention belongs to the technical field of organic synthesis, in particular to a method for synthesizing pyrazolo[1,3,5]triazine compounds.

Background technique

Studies have shown that pyrazolo[1,3,5]triazines are isosteres of purines and can be used to target purine signaling receptors and enzymes. 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, phosphodiesterases (PDE4, PDE10) Inhibitors, tyrosine threonine kinase (TTK) inhibitors, antitumor, antibacterial, antiviral, anticonvulsant, antimigraine, antidepressant and anxiolytic effects, have important application value in the fields of biology and medicine. However, the synthesis methods of pyrazolo[1,3,5]triazine compounds reported in related literatures mainly rely on the condensation reaction of 3-aminopyrazole with a pre-prepared nitrogen-containing 1,3-dielectrophile and N - Heterocyclization of pyrazolyl amidines. Although these methods are generally reliable, many of them involve the disadvantages of pre-preparation of substrates, narrow substrate range, harsh reaction conditions, and cumbersome post-processing, which largely limit the practical use of such synthetic methods in practical production. Applications. Therefore, the research and development of a method for the efficient synthesis of pyrazolo[1,3,5]triazine compounds using cheap reagents as raw materials and simple operation steps not only has certain theoretical significance, but also has important application value.

SUMMARY OF THE INVENTION

The technical problem solved by the present invention is to provide a method for synthesizing pyrazolo[1,3,5]triazine compounds. The method starts from simple raw materials and obtains the target product pyrazolo by one-pot series reaction in one step. The [1,3,5]triazine compound has the advantages of convenient synthesis process, mild reaction conditions and wide application range of substrates, and is suitable for industrial production.

In order to solve the above technical problems, the present invention adopts the following technical scheme, a method for synthesizing pyrazolo[1,3,5]triazine compounds, characterized in that the specific steps are: the aromatic aldehyde compounds 1, 3-aminopyridine The azole compound 2 and ammonium iodide are dissolved in a solvent, and then an oxidant is added, and then the target product pyrazolo[1,3,5]triazine compound 3 is obtained by reacting at 130-150 ° C. The reaction in the synthesis method The equation is:

wherein R1 is phenyl, substituted phenyl, 2-naphthyl, thienyl, pyridyl or quinolyl, and the substituted phenyl is 3,4-dimethylphenyl, 2,4-dichlorophenyl or Mono-substituted phenyl, the substituents on the benzene ring of mono-substituted phenyl are methyl, tert-butyl, methoxy, ethoxy, thiomethyl, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy group, cyano group, carbomethoxy group, methylsulfonyl group or nitro group, R ² is hydrogen, ethyl ester group, carbomethoxy group or cyano group, R ³ is hydrogen or methyl group, the solvent is chlorobenzene, iodobenzene, bromobenzene , o-dichlorobenzene or o-xylene, and the oxidant is di-tert-butyl peroxide (DTBP), tert-butyl peroxybenzoate (TBPB), dimethyl sulfoxide (DMSO), oxygen or air.

Further preferably, when the oxidant is di-tert-butyl peroxide, tert-butyl peroxybenzoate or dimethyl sulfoxide, the feeding of aldehydes 1, 3-aminopyrazoles 2, ammonium iodide and oxidant The molar ratio is 2:1:1:3, and the feeding ratio of the aldehyde compound 1 to the solvent is 1 mmol: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 sealed conditions; when the oxidant is air, the synthesis process is carried out in the open conditions.

Further preferably, the pyrazolo[1,3,5]triazine compound is one of the following compounds:

Compared with the prior art, the present invention has the following advantages and beneficial effects: 1. The synthesis process of the present invention is a one-pot series reaction, which is simple and efficient, and simultaneously avoids the use of various reagents in the multi-step reaction and the reaction of each step. Resource waste and environmental pollution caused by the purification of intermediates, etc.; 2. The raw materials of the present invention are cheap and easy to obtain; 3. The reaction conditions of the present invention do not require catalysts, do not require additives, and are easy to operate; 4. The substrates of the present invention have a wide range of applications . Therefore, the present invention provides a new economical, practical and green method for the synthesis of pyrazolo[1,3,5]triazine compounds.

Detailed ways

The above-mentioned content of the present invention is described in further detail below through the examples, but it should not be understood that the scope of the above-mentioned subject matter of the present invention is limited to the following examples, and all technologies realized based on the above-mentioned content of the present invention belong to the scope of the present invention.

Example 1

Into a 35 mL reaction flask were added benzaldehyde 1a (106 mg, 1 mmol), 3-aminopyrazole-4-carboxylic acid ethyl ester 2a (77.6 mg, 0.5 mmol), ammonium iodide (72.5 mg, 0.5 mmol) and o-dichlorobenzene (2mL), and then placed in a metal bath at 140°C and stirred for 8h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-dried, and separation by silica gel column (petroleum ether/ethyl acetate=30/1, v/v) to obtain the product 3a as a pale yellow solid (161.7 mg, 94%). The characterization data for this compound are as follows: ¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.89–8.82 (m, 2H), 8.75–8.68 (m, 2H), 8.65 (s, 1H), 7.74–7.69 ( ^13C 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

In a 35 mL sealed tube were added 1a (106 mg, 1 mmol), 2a (77.6 mg, 0.5 mmol), ammonium iodide (72.5 mg, 0.5 mmol), di-tert-butyl peroxide (219 mg, 1.5 mmol) and o-dichloride Benzene (2 mL) was then placed in a metal bath at 140°C and stirred for 8 h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-dried, and separation by silica gel column (petroleum ether/ethyl acetate=30/1, v/v) to obtain the product 3a as a pale yellow solid (135.9 mg, 79%).

Example 3

To a 35 mL sealed tube were added 1a (106 mg, 1 mmol), 2a (77.6 mg, 0.5 mmol), ammonium iodide (72.5 mg, 0.5 mmol), tert-butyl peroxybenzoate (291 mg, 1.5 mmol) and o-dichloride Benzene (2 mL) was then placed in a metal bath at 140°C and stirred for 8 h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-dried, and separation by silica gel column (petroleum ether/ethyl acetate=30/1, v/v) to obtain the product 3a as a pale yellow solid (134.1 mg, 78%).

Example 4

In a 35 mL sealed tube were added 1a (106 mg, 1 mmol), 2a (77.6 mg, 0.5 mmol), ammonium iodide (72.5 mg, 0.5 mmol), dimethyl sulfoxide (117 mg, 1.5 mmol) and o-dichlorobenzene (2 mL). ), and then placed in a metal bath at 140 °C and stirred for 8 h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filter, spin dry, and separate through silica gel column (petroleum ether/ethyl acetate=30/1, v/v) to obtain light yellow solid product 3a (58.5 mg, 34%).

Example 5

1a (106 mg, 1 mmol), 2a (77.6 mg, 0.5 mmol), ammonium iodide (72.5 mg, 0.5 mmol) and o-dichlorobenzene ( ₂ mL) were added to a 50 mL Schlenk tube, and then placed under O atmosphere. The reaction was stirred in a metal bath at 140°C for 8h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-dried, and separation by silica gel column (petroleum ether/ethyl acetate=30/1, v/v) to obtain the product 3a (141 mg, 82%) as a light yellow solid.

Example 6

1a (106 mg, 1 mmol), 2a (77.6 mg, 0.5 mmol), ammonium iodide (72.5 mg, 0.5 mmol) and chlorobenzene (2 mL) were added to a 35 mL reaction flask, and then placed in a 140°C metal bath with open stirring The reaction was carried out for 8 hours. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-dried, and separation by silica gel column (petroleum ether/ethyl acetate=30/1, v/v) to obtain light yellow solid product 3a (146.2 mg, 85%).

Example 7

1a (106 mg, 1 mmol), 2a (77.6 mg, 0.5 mmol), ammonium iodide (72.5 mg, 0.5 mmol) and iodobenzene (2 mL) were added to a 35 mL reaction flask, and then placed in a metal bath at 140°C and stirred openly The reaction was carried out for 8 hours. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-dried, and separation by silica gel column (petroleum ether/ethyl acetate=30/1, v/v) to obtain the product 3a as a pale yellow solid (142.8 mg, 83%).

Example 8

1a (106 mg, 1 mmol), 2a (77.6 mg, 0.5 mmol), ammonium iodide (72.5 mg, 0.5 mmol) and bromobenzene (2 mL) were added to a 35 mL reaction flask, and then placed in a metal bath at 140 °C and stirred openly The reaction was carried out for 8 hours. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-dried, and separation by silica gel column (petroleum ether/ethyl acetate=30/1, v/v) to obtain the product 3a as a pale yellow solid (147.9 mg, 86%).

Example 9

1a (106 mg, 1 mmol), 2a (77.6 mg, 0.5 mmol), ammonium iodide (72.5 mg, 0.5 mmol) and o-xylene (2 mL) were added to a 35 mL reaction flask, and then placed in a metal bath at 140 °C to expose The reaction was stirred for 8h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-dried, and separation by silica gel column (petroleum ether/ethyl acetate=30/1, v/v) to obtain the product 3a (141 mg, 82%) as a light yellow solid.

Example 10

1a (106 mg, 1 mmol), 2a (77.6 mg, 0.5 mmol), ammonium iodide (72.5 mg, 0.5 mmol) and o-dichlorobenzene (2 mL) were added to a 35 mL reaction flask, and then placed in a 130 ℃ metal bath to expose The reaction was stirred for 8h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-dried, and separation by silica gel column (petroleum ether/ethyl acetate=30/1, v/v) to obtain the product 3a as a pale yellow solid (135.9 mg, 79%).

Example 11

1a (106 mg, 1 mmol), 2a (77.6 mg, 0.5 mmol), ammonium iodide (72.5 mg, 0.5 mmol) and o-dichlorobenzene (2 mL) were added to a 35 mL reaction flask, and then placed in a 150 ℃ metal bath to expose The reaction was stirred for 8h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filter, spin dry, and separate through silica gel column (petroleum ether/ethyl acetate=30/1, v/v) to obtain the product 3a (158.2 mg, 92%) as a light yellow solid.

Example 12

1b (120 mg, 1 mmol), 2a (77.6 mg, 0.5 mmol), ammonium iodide (72.5 mg, 0.5 mmol) and o-dichlorobenzene (2 mL) were added to a 35 mL reaction flask, and then placed in a 140 ℃ metal bath to expose The reaction was stirred for 8h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-dried, and separation by silica gel column (petroleum ether/ethyl acetate=20/1, v/v) to obtain white solid product 3b (176.7 mg, 95%). Characterization data for this compound are as follows: ¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.75 (d, J=8.4 Hz, 2H), 8.60 (s, 1H), 8.56 (d, J=8.4 Hz, 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=7.2 Hz, 3H); ¹³ C NMR (100 MHz, 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 _C22H20N4NaO2 : 395.1478; found: 395.1477.

Example 13

1c (162 mg, 1 mmol), 2a (77.6 mg, 0.5 mmol), ammonium iodide (72.5 mg, 0.5 mmol) and o-dichlorobenzene (2 mL) were added to a 35 mL reaction flask, and then placed in a 140 ℃ metal bath to expose The reaction was stirred for 8h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-dried, and separation by silica gel column (petroleum ether/ethyl acetate=20/1, v/v) to obtain the product 3c (191.5 mg, 84%) as a light yellow solid. The characterization data for this compound are as follows: ¹ H NMR (400 MHz, 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

1d (136 mg, 1 mmol), 2a (77.6 mg, 0.5 mmol), ammonium iodide (72.5 mg, 0.5 mmol) and o-dichlorobenzene (2 mL) were added to a 35 mL reaction flask, and then placed in a 140 ℃ metal bath to expose The reaction was stirred for 8h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-dried, and separation by silica gel column (petroleum ether/ethyl acetate=10/1, v/v) to obtain yellow solid product 3d (171.7 mg, 85%). The characterization data for this compound are as follows: ¹ H NMR (400 MHz, 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 (100 MHz, CDCl ₃ ): δ (ppm); .HRMS(ESI): m/z[ _{M +} Na] ⁺ calcd for _C22H20N4NaO4 : _427.1377 ; found: 427.1378.

Example 15

1e (150 mg, 1 mmol), 2a (77.6 mg, 0.5 mmol), ammonium iodide (72.5 mg, 0.5 mmol) and o-dichlorobenzene (2 mL) were added to a 35 mL reaction flask, and then placed in a 140 ℃ metal bath to expose The reaction was stirred for 8h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-dried, and separation by silica gel column (petroleum ether/ethyl acetate=10/1, v/v) to obtain yellow solid product 3e (187.9 mg, 87%). The characterization data for this compound are as follows: ¹ H NMR (400 MHz, 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 _C24H24N4NaO4 : _455.1690 ; found: _455.1689 .

Example 16

1f (152 mg, 1 mmol), 2a (77.6 mg, 0.5 mmol), ammonium iodide (72.5 mg, 0.5 mmol) and o-dichlorobenzene (2 mL) were added to a 35 mL reaction flask, and then placed in a 140 ℃ metal bath to expose The reaction was stirred for 8h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-dried, and separation by silica gel column (petroleum ether/ethyl acetate=15/1, v/v) to obtain yellow solid product 3f (146.1 mg, 67%). Characterization data for this compound are as follows: ¹ H NMR (400 MHz, 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 _{C22H20N4NaO2S2} : _459.0920 ; found: _459.0919 .

Example 17

1g (124mg, 1mmol), 2a (77.6mg, 0.5mmol), ammonium iodide (72.5mg, 0.5mmol) and o-dichlorobenzene (2mL) were added to a 35mL reaction flask, and then placed in a 140°C metal bath to expose The reaction was stirred for 8h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filter, spin dry, and separate through silica gel column (petroleum ether/ethyl acetate=15/1, v/v) to obtain 3 g (161.5 mg, 85%) of white solid product. The characterization data for this compound are as follows: ¹ H NMR (400 MHz, 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=7.2 Hz, 2H), 1.49 (t, J=7.2 Hz, 3H); ¹³ C NMR (100 MHz, 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 _{C20H14F2N4NaO2} : _403.0977 ; found: _403.0975 .

Example 18

1h (140.5mg, 1mmol), 2a (77.6mg, 0.5mmol), ammonium iodide (72.5mg, 0.5mmol) and o-dichlorobenzene (2mL) were added to a 35mL reaction flask, and then placed in a metal bath at 140°C The reaction was stirred openly for 8h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filter, spin dry, and separate through silica gel column (petroleum ether/ethyl acetate=30/1, v/v) to obtain a white solid product for 3h (190 mg, 92%). The characterization data for this compound are as follows: ¹ H NMR (400 MHz, 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=7.2 Hz, 2H), 1.48 (t, J=7.2 Hz, 3H); ¹³ C NMR (100 MHz, 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 _{C20H14C12N4NaO2} : _435.0386 ; found: _435.0389 .

Example 19

1i (185 mg, 1 mmol), 2a (77.6 mg, 0.5 mmol), ammonium iodide (72.5 mg, 0.5 mmol) and o-dichlorobenzene (2 mL) were added to a 35 mL reaction flask, and then placed in a 140 ℃ metal bath to expose The reaction was stirred for 8h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-dried, and separation by silica gel column (petroleum ether/ethyl acetate=30/1, v/v) to obtain the product 3i (225.9 mg, 90%) as a pale yellow solid. The characterization data for this compound are as follows: ¹ H NMR (400 MHz, 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=7.2 Hz, 2H), 1.48 (t, J=7.2 Hz, 3H); ¹³ C NMR (100 MHz, 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 H14Br2N4NaO2 : 524.9356} ; found: _524.9353 .

Example 20

1j (174 mg, 1 mmol), 2a (77.6 mg, 0.5 mmol), ammonium iodide (72.5 mg, 0.5 mmol) and o-dichlorobenzene (2 mL) were added to a 35 mL reaction flask, and then placed in a 140 ℃ metal bath to expose The reaction was stirred for 8h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-dried, and separation by silica gel column (petroleum ether/ethyl acetate=20/1, v/v) to obtain light green solid product 3j (223.2 mg, 93%). Characterization data for this compound are as follows: ¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.96 (d, J=8.0 Hz, 2H), 8.74 (d, J=8.0 Hz, 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 (100 MHz, 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 _{C22H14F6N4NaO2} : _{503.0913 ;} found: 503.0913.

Example 21

1k (190 mg, 1 mmol), 2a (77.6 mg, 0.5 mmol), ammonium iodide (72.5 mg, 0.5 mmol) and o-dichlorobenzene (2 mL) were added to a 35 mL reaction flask, and then placed in a 140 ℃ metal bath to expose The reaction was stirred for 8h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filter, spin dry, and separate through silica gel column (petroleum ether/ethyl acetate=30/1, v/v) to obtain the product 3k as a pale yellow solid (225.3 mg, 88%). The characterization data for this compound are as follows: ¹ H NMR (400 MHz, 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 _{C22H14F6N4NaO4} : _{535.0811 ;} found: _535.0811 .

Example 22

1l (131 mg, 1 mmol), 2a (77.6 mg, 0.5 mmol), ammonium iodide (72.5 mg, 0.5 mmol) and o-dichlorobenzene (2 mL) were added to a 35 mL reaction flask, and then placed in a 140 ℃ metal bath to expose The reaction was stirred for 8h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-dried, and separation by silica gel column (petroleum ether/ethyl acetate=5/1, v/v) to obtain yellow solid product 3l (159.6 mg, 81%). Characterization data for this compound are as follows: ¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 9.03 (d, J=8.4 Hz, 2H), 8.79 (d, J=8.4 Hz, 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 (100 MHz, 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 _C22H14N6NaO2 : _{417.1070 ;} found: 417.1073.

Example 23

1m (164mg, 1mmol), 2a (77.6mg, 0.5mmol), ammonium iodide (72.5mg, 0.5mmol) and o-dichlorobenzene (2mL) were added to a 35mL reaction flask, and then placed in a 140°C metal bath to expose The reaction was stirred for 8h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-drying, and separation by silica gel column (petroleum ether/ethyl acetate=8/1, v/v) to obtain a pale yellow solid product 3m (188.6 mg, 82%). Characterization data for this compound are as follows: ¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.93 (d, J=8.4 Hz, 2H), 8.72 (d, J=8.4 Hz, 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=7.2 Hz, 3H); ¹³ C NMR (100 MHz, 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

Into a 35mL reaction flask was added 1n (184mg, 1mmol), 2a (77.6mg, 0.5mmol), ammonium iodide (72.5mg, 0.5mmol) and o-dichlorobenzene (2mL), then placed in a 140 ℃ metal bath to expose The reaction was stirred for 8h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filter, spin dry, and separate through silica gel column (petroleum ether/ethyl acetate=1/1, v/v) to obtain the product 3n (162.5 mg, 65%) as a pale yellow solid. Characterization data for this compound are as follows: ¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 9.07 (d, J=8.4 Hz, 2H), 8.89 (d, J=8.4 Hz, 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=7.2 Hz, 3H); ¹³ C NMR (100 MHz, 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

1o (120 mg, 1 mmol), 2a (77.6 mg, 0.5 mmol), ammonium iodide (72.5 mg, 0.5 mmol) and o-dichlorobenzene (2 mL) were added to a 35 mL reaction flask, and then placed in a 140 ℃ metal bath to expose The reaction was stirred for 8h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filter, spin dry, and separate through silica gel column (petroleum ether/ethyl acetate=30/1, v/v) to obtain white solid product 3o (133.9 mg, 72%). Characterization data for this compound are as follows: ¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.61 (s, 1H), 8.34 (d, J=8.0 Hz, 1H), 7.75 (d, J=8.0 Hz, 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=7.0 Hz, 3H); ¹³ C NMR (100 MHz, 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 _20N4NaO2 : _395.1478 ; found: _395.1482 .

Example 26

1p (124 mg, 1 mmol), 2a (77.6 mg, 0.5 mmol), ammonium iodide (72.5 mg, 0.5 mmol) and o-dichlorobenzene (2 mL) were added to a 35 mL reaction flask, and then placed in a 140 ℃ metal bath to expose The reaction was stirred for 8h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filter, spin dry, and separate through silica gel column (petroleum ether/ethyl acetate=15/1, v/v) to obtain the product 3p (106.4 mg, 56%) as a pale yellow solid. Characterization data for this compound are as follows: ¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.65 (s, 1H), 8.41 (td, J=7.6, 1.6 Hz, 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 (100 MHz, 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 _{C20H14F2N4NaO2 : 403.0977 ;} found: _403.0977 .

Example 27

1q (120 mg, 1 mmol), 2a (77.6 mg, 0.5 mmol), ammonium iodide (72.5 mg, 0.5 mmol) and o-dichlorobenzene (2 mL) were added to a 35 mL reaction flask, and then placed in a 140 ℃ metal bath to expose The reaction was stirred for 8h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-dried, and separation by silica gel column (petroleum ether/ethyl acetate=20/1, v/v) to obtain the product 3q (163.7 mg, 88%) as a pale yellow solid. The characterization data for this compound are as follows: ¹ H NMR (400 MHz, 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) _The ^_ 102.7, 60.4, 21.5, 21.4, 14.4; HRMS (ESI): m/z [ _{M +} Na] ⁺ _calcd for _C22H20N4NaO2 : 395.1478; found: 395.1476.

Example 28

1r (136 mg, 1 mmol), 2a (77.6 mg, 0.5 mmol), ammonium iodide (72.5 mg, 0.5 mmol) and o-dichlorobenzene (2 mL) were added to a 35 mL reaction flask, and then placed in a 140 ℃ metal bath to expose The reaction was stirred for 8h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filter, spin dry, and separate through silica gel column (petroleum ether/ethyl acetate=10/1, v/v) to obtain 3r (161.6 mg, 80%) as a pale yellow solid product. Characterization data for this compound are as follows: ¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.62 (s, 1H), 8.43 (dd, J=7.6, 0.8 Hz, 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=7.2 Hz, 2H), 3.93 (s, 3H), 3.92 (s, 3H), 1.49 (t, J=7.0 Hz, 3H); ¹³ C NMR (100 MHz, 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 ; HRMS (ESI): m/z [M+Na] ⁺ calcd for C ₂₂ H ₂₀ N ₄ NaO ₄ : 427.1377; found: 427.1377.

Example 29

1s (124 mg, 1 mmol), 2a (77.6 mg, 0.5 mmol), ammonium iodide (72.5 mg, 0.5 mmol) and o-dichlorobenzene (2 mL) were added to a 35 mL reaction flask, and then placed in a 140 ℃ metal bath to expose The reaction was stirred for 8h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filter, spin dry, and separate through silica gel column (petroleum ether/ethyl acetate=20/1, v/v) to obtain 3s (148.2 mg, 78%) as a pale yellow solid product. Characterization data for this compound are as follows: ¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.70 (d, J=8.0 Hz, 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 (100 MHz, 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

1t (140.5 mg, 1 mmol), 2a (77.6 mg, 0.5 mmol), ammonium iodide (72.5 mg, 0.5 mmol) and o-dichlorobenzene (2 mL) were added to a 35 mL reaction flask, and then placed in a metal bath at 140 °C The reaction was stirred openly for 8h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filter, spin dry, and separate through silica gel column (petroleum ether/ethyl acetate=20/1, v/v) to obtain 3t (175.5 mg, 85%) as a pale yellow solid product. Characterization data for this compound are as follows: ¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.83 (t, J=1.8 Hz, 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 Cl 2 N ₄ NaO ₂ : _435.0386 ; found: 435.0387.

Example 31

1u (185mg, 1mmol), 2a (77.6mg, 0.5mmol), ammonium iodide (72.5mg, 0.5mmol) and o-dichlorobenzene (2mL) were added to a 35mL reaction flask, and then placed in a 140°C metal bath to expose The reaction was stirred for 8h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filter, spin dry, and separate through silica gel column (petroleum ether/ethyl acetate=15/1, v/v) to obtain 3u (218.3 mg, 87%) as a pale yellow solid product. Characterization data for this compound are as follows: ¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.97 (t, J=1.6 Hz, 1H), 8.78 (d, J=8.0 Hz, 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 _{C20H14Br2N4NaO2} : _524.9356 ; found: _524.9365 .

Example 32

1v (174 mg, 1 mmol), 2a (77.6 mg, 0.5 mmol), ammonium iodide (72.5 mg, 0.5 mmol) and o-dichlorobenzene (2 mL) were added to a 35 mL reaction flask, and then placed in a 140 ℃ metal bath to expose The reaction was stirred for 8h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filter, spin dry, and separate through silica gel column (petroleum ether/ethyl acetate=20/1, v/v) to obtain the product 3v as a pale yellow solid (204 mg, 85%). Characterization data for this compound are as follows: ¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 9.18 (s, 1H), 9.07 (d, J=8.0 Hz, 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 (100 MHz, 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] ⁺ calcdfor C ₂₂ H ₁₄ F ₆ N _4NaO2 : _503.0913 ; found:503.0915.

Example 33

1w (151 mg, 1 mmol), 2a (77.6 mg, 0.5 mmol), ammonium iodide (72.5 mg, 0.5 mmol) and o-dichlorobenzene (2 mL) were added to a 35 mL reaction flask, and then placed in a 140 ℃ metal bath to expose The reaction was stirred for 8h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filter, spin dry, and separate through silica gel column (petroleum ether/ethyl acetate=8/1, v/v) to obtain yellow solid product 3w (160.6 mg, 74%). Characterization data for this compound are as follows: ¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 9.85 (s, 1H), 9.47 (s, 1H), 9.27 (d, J=8.0 Hz, 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=8.0 Hz, 1H), 4.50 (q, J=7.2 Hz, 2H), 1.53 (t, J=7.2 Hz, 3H); ¹³ C NMR (100 MHz, 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

1x (134 mg, 1 mmol), 2a (77.6 mg, 0.5 mmol), ammonium iodide (72.5 mg, 0.5 mmol) and o-dichlorobenzene (2 mL) were added to a 35 mL reaction flask, and then placed in a 140 ℃ metal bath to expose The reaction was stirred for 8h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-drying, and separation through silica gel column (petroleum ether/ethyl acetate=15/1, v/v) gave the product 3x (168.1 mg, 84%) as a light brown solid. The characterization data for this compound are as follows: ¹ H NMR (400 MHz, 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 (100 MHz, 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 _{C24H24N4NaO2 : 423.1791} ; found: _423.1789 .

Example 35

1y (175 mg, 1 mmol), 2a (77.6 mg, 0.5 mmol), ammonium iodide (72.5 mg, 0.5 mmol) and o-dichlorobenzene (2 mL) were added to a 35 mL reaction flask, and then placed in a 140 ℃ metal bath to expose The reaction was stirred for 8h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-drying, and separation through silica gel column (petroleum ether/ethyl acetate=15/1, v/v) to obtain the white solid product 3y (175.9 mg, 73%). Characterization data for this compound are as follows: ¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 8.65 (s, 1H), 8.12 (d, J=8.4 Hz, 1H), 7.72 (d, J=8.0 Hz, 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=7.2 Hz, 3H); ¹³ C NMR (100 MHz, 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

1z (156 mg, 1 mmol), 2a (77.6 mg, 0.5 mmol), ammonium iodide (72.5 mg, 0.5 mmol) and o-dichlorobenzene (2 mL) were added to a 35 mL reaction flask, and then placed in a 140 ℃ metal bath to expose The reaction was stirred for 8h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-dried, and separation by silica gel column (petroleum ether/ethyl acetate=15/1, v/v) to obtain yellow solid product 3z (175.4 mg, 79%). Characterization data for this compound are as follows: ¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 9.62 (s, 1H), 9.22 (s, 1H), 8.79 (dd, J=8.4, 1.6 Hz, 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 CNMR (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, 127.9.2, 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

1aa (112 mg, 1 mmol), 2a (77.6 mg, 0.5 mmol), ammonium iodide (72.5 mg, 0.5 mmol) and o-dichlorobenzene (2 mL) were added to a 35 mL reaction flask, and then placed in a 140 ℃ metal bath to expose The reaction was stirred for 8h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filter, spin dry, and separate through silica gel column (petroleum ether/ethyl acetate=20/1, v/v) to obtain the product 3aa as a pale yellow solid (103.2 mg, 58%). Characterization data for this compound are as follows: ¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) ¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 9.00 (d, J=3.2 Hz, 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=4.2 Hz, 1H), 4.46 (q, J=7.2 Hz, 2H), 1.49 (t, J=7.0 Hz, 3H); ¹³ C NMR (100 MHz, 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 _{12N4NaO2S2 : 379.0294} ; found: _379.0295 .

Example 38

1ab (107 mg, 1 mmol), 2a (77.6 mg, 0.5 mmol), ammonium iodide (72.5 mg, 0.5 mmol) and o-dichlorobenzene (2 mL) were added to a 35 mL reaction flask, and then placed in a 140 ℃ metal bath to expose The reaction was stirred for 8h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-dried, and separation by silica gel column (petroleum ether/ethyl acetate=1/1, v/v) to obtain 3ab as a yellow solid product (74.4 mg, 43%). Characterization data for this compound are as follows: ¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 9.01 (dd, J=4.8, 1.6 Hz, 2H), 8.89 (dd, J=4.4, 1.2 Hz, 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=7.2 Hz, 3H); ¹³ C NMR (100 MHz, 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

1ac (107 mg, 1 mmol), 2a (77.6 mg, 0.5 mmol), ammonium iodide (72.5 mg, 0.5 mmol) and o-dichlorobenzene (2 mL) were added to a 35 mL reaction flask, and then placed in a 140 ℃ metal bath to expose The reaction was stirred for 8h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-dried, and separation by silica gel column (petroleum ether/ethyl acetate=3/1, v/v) to obtain yellow solid product 3ac (72.7 mg, 42%). Characterization data for this compound are as follows: ¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 10.07 (d, J=1.6 Hz, 1H), 9.89 (d, J=1.6 Hz, 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 (100 MHz, 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

1ad (157 mg, 1 mmol), 2a (77.6 mg, 0.5 mmol), ammonium iodide (72.5 mg, 0.5 mmol) and o-dichlorobenzene (2 mL) were added to a 35 mL reaction flask, and then placed in a 140 ℃ metal bath to expose The reaction was stirred for 8h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-dried, and separation by silica gel column (petroleum ether/ethyl acetate=3/1, v/v) to obtain yellow solid product 3ad (120.5 mg, 54%). Characterization data for this compound are as follows: ¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) 9.63 (dd, J=8.4, 0.8 Hz, 1H), 9.23 (d, J=4.4 Hz, 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 (100 MHz, CDCl ₃ ): δ (ppm) 161.7, 160.5, 154.8, 150.3 HRMS(ESI) z[M+Na] ⁺ calcd for C ₂₆ H ₁₈ N ₆ NaO ₂ : 469.1383; found: 469.1381.

Example 41

1a (106 mg, 1 mmol), 2b (70.6 mg, 0.5 mmol), ammonium iodide (72.5 mg, 0.5 mmol) and o-dichlorobenzene (2 mL) were added to a 35 mL reaction flask, and then placed in a 140 ℃ metal bath to expose The reaction was stirred for 8h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-dried, and separation by silica gel column (petroleum ether/ethyl acetate=15/1, v/v) to obtain the product 3ae (151.8 mg, 92%) as a white solid. The characterization data for this compound are as follows: ¹ H NMR (400 MHz, 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 (100 MHz, 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

1a (106 mg, 1 mmol), 2c (54 mg, 0.5 mmol), ammonium iodide (72.5 mg, 0.5 mmol) and o-dichlorobenzene (2 mL) were added to a 35 mL reaction flask, and then placed in a metal bath at 140 °C to expose The reaction was stirred for 8h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filter, spin dry, and separate through silica gel column (petroleum ether/ethyl acetate=30/1, v/v) to obtain 3af (69.8 mg, 47%) as a white solid product. The characterization data for this compound are as follows: ¹ H NMR (400 MHz, 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 (100 MHz, 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

1a (106 mg, 1 mmol), 2d (48.6 mg, 0.5 mmol), ammonium iodide (72.5 mg, 0.5 mmol) and o-dichlorobenzene (2 mL) were added to a 35 mL reaction flask, and then placed in a 140 ℃ metal bath to expose The reaction was stirred for 8h. 50 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), and the organic phase was washed successively with 10% Na ₂ S ₂ O ₃ solution and saturated brine, and dried over anhydrous sodium sulfate. Filtration, spin-dried, and separation by silica gel column (petroleum ether/ethyl acetate=8/1, v/v) to obtain 3ag (104.4 mg, 73%) as a white solid product. The characterization data for this compound are as follows: ¹ H NMR (400 MHz, 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 (100 MHz, 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 above embodiments describe the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above embodiments. The above embodiments and descriptions only describe the principles of the present invention. Without departing from the scope of the principles of the present invention, the present invention may have various changes and improvements, and these changes and improvements all fall within the protection scope of the present 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: