A method for synthesizing polysubstituted pyrazole compounds

Abstract

This invention discloses a method for synthesizing polysubstituted pyrazole compounds, belonging to the field of organic synthesis. The method utilizes an alkenyl sulfonium salt represented by Formula I, a pyrazole represented by Formula II, and a halogenated succinimide (NIS, NBS, NCS) represented by Formula III as raw materials, without the need for metal catalysis, to produce the pyrazole compound represented by Formula IV. This method utilizes readily available, inexpensive raw materials, eliminates the need for metal catalysts, and is environmentally friendly and pollution-free. It also boasts a wide substrate range, high yield, simple operation, and easy product separation and purification. #imgabs0#

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing a polysubstituted pyrazole compound. Background Art

[0002] Pyrazole is an important five-membered nitrogen-containing heterocyclic compound, which is widely present in many natural products, bioactive molecules and drug molecules, and is also an important organic synthesis intermediate. Pyrazole has a variety of physiological effects, including analgesia, anti-inflammatory, antipyretic, antiarrhythmic, sedative, muscle relaxant, mental excitement, anticonvulsant, antidiabetic and antibacterial effects. Recent studies have also found that pyrazole compounds show good anticancer activity, as shown below. Pyrazole amide compounds A and compound B have good inhibitory effects on human colon cancer cells, breast cancer cells and lung adenocarcinoma cells, as well as N-benzoylpyrazole compound C as a small molecule inhibitor of human neutrophil elastase (NE inhibitor) (reference Igor A. Schepetkin, etc. Journal of Medicinal Chemistry, 2007, Vol. 50, No. 20). Given that pyrazole compounds exhibit extremely important biological activities, the development of efficient and mild methods to synthesize pyrazole compounds has always been a hot topic of concern for organic chemistry, pharmacy and pesticide researchers. In particular, the creation of new drugs and pesticides based on pyrazole structures and the innovation of production process routes still have huge potential and room for development.

[0003]

[0004] Furthermore, since the first synthesis of pyrazole compounds in 1883, synthetic pathways related to the pyrazole ring have continued to evolve. To date, there are two main strategies for the synthesis of pyrazole compounds: one is to construct various pyrazole compounds through cyclization reactions, and the other is direct functionalization of the pyrazole ring. Compared to the former, the latter still has considerable room for development, especially for the N-alkenylation-4-halogenation of the pyrazole ring, which has not been well addressed. Furthermore, N-alkenylation-4-halogenated pyrazoles, as excellent intermediates, can be further derivatized through classic reactions to yield various types of polysubstituted pyrazole compounds, such as the pyrazoleamide and pyrazoleamine derivatives shown above. Summary of the Invention

[0005] In view of the fact that existing synthetic routes require complex processes and reaction flows, the purpose of the present invention is to provide a cheap and environmentally friendly method for synthesizing N-alkenylated-4-halogenated pyrazole compounds. The method is simple, convenient and easy to operate, pollution-free, catalyst-free, and has a wide range of applicable substrates, high yield, simple operation, and easy product separation.

[0006] To achieve the above object, the present invention adopts the following technical solutions:

[0007] A method for synthesizing polysubstituted pyrazole compounds promoted by an inorganic base, comprising using an aryl vinyl sulfonium salt represented by formula I, a pyrazole compound represented by formula II, and a halogenated succinimide (NIS, NBS, NCS) represented by formula III as raw materials, and reacting in the presence of a base to obtain a polysubstituted pyrazole compound represented by formula IV.

[0008]

[0009] Wherein, R is a substituted or unsubstituted aryl group, the substitution is mono- or di-substituted, and the substituents are: halogen, -SMe, C1-4 alkyl, halogenated C1-4 alkyl; R1 is H, phenyl; R2 is H, Br, Cl, phenyl; R3 is H, methyl, phenyl; R4 is halogen (Cl, Br, I).

[0010] In one embodiment of the present invention, the aryl group is a benzene ring or a naphthalene ring.

[0011] In one embodiment of the present invention, R is specifically selected from:

[0012] In one embodiment of the present invention, the reaction is carried out in an organic solvent, specifically any one or more of toluene, acetonitrile, and tetrahydrofuran.

[0013] In one embodiment of the present invention, the base comprises potassium hydroxide, sodium hydride, cesium carbonate, or potassium tert-butoxide.

[0014] In one embodiment of the present invention, the reaction temperature is 0°C to 60°C, and the reaction time is 12 to 24 hours. Alternatively, the reaction temperature can be room temperature, and the reaction time can be 12 to 16 hours.

[0015] In one embodiment of the present invention, the molar ratio of the aromatic vinyl sulfonium salt represented by Formula I, the pyrazole compound represented by Formula II and the halogenated succinimide represented by Formula III is 1.0:(1.0-2.0):(1.0-2.0).

[0016] In one embodiment of the present invention, the molar ratio of the arylvinyl sulfonium salt represented by Formula I to the base is 1.0:(1.0-2.0).

[0017] In one embodiment of the present invention, the amount of the organic solvent added is 2 to 10 mL / mmol based on the amount of the arylvinyl sulfonium salt represented by Formula I.

[0018] In one embodiment of the present invention, after the reaction, the product is purified by silica gel column chromatography.

[0019] The purification method comprises the following steps: after the reaction is completed, adding column chromatography silica gel, distilling under reduced pressure to remove the solvent, spinning to dryness until the silica gel adsorbs the product into powder, applying the sample to the column, eluting with (petroleum ether:ethyl acetate=20:1), collecting the product, and evaporating and concentrating to obtain the pyrazole compound.

[0020] Beneficial effects:

[0021] The present invention aims to address the existing problem of ineffective direct N-alkenylation-4-halogenation of pyrazole rings. It uses inexpensive, easily prepared raw materials and a metal-catalyst-free method to prepare a pyrazole compound. This method offers the advantages of good positional selectivity and high yield, and the resulting pyrazole compound is of high purity.

[0022] The N-alkenylated-4-halogenated multi-substituted pyrazole compounds obtained in the present invention can be used as intermediates to derive many drug molecules with excellent biological activities, such as NE inhibitors. DETAILED DESCRIPTION

[0023] The styrene sulfonium salt substrate of the present invention is prepared by the following process:

[0024] Under argon or nitrogen, add 25 mL of dichloromethane and tetramethylene sulfoxide (11.0 mmol, 1.1 g) to a 100 mL reaction flask and stir at -40°C for 5 minutes. Then, add the corresponding substituted styrene substrate (10.0 mmol) and trifluoromethanesulfonic anhydride (11.0 mmol, 3.1 g) to the reaction system. After continuing to react at -40°C for 30 minutes, the temperature was raised to 0°C and the reaction was monitored by TLC. After completion of the reaction, the solvent was removed under reduced pressure. Recrystallization from dichloromethane and diethyl ether yielded a white solid, the corresponding styrene sulfonium salt.

[0025] The gram-scale synthesis route is:

[0026]

[0027] Where R is:

[0028]

[0029]

[0030] Example 1:

[0031] The structure of the pyrazole compound prepared in this example is as follows:

[0032]

[0033] Preparation: Under argon, a stirring magnet, styrylsulfonium salt (0.2 mmol, 68.0 mg), pyrazole (0.3 mmol, 20.5 mg), iodosuccinimide (0.24 mmol, 54.0 mg), cesium carbonate (0.24 mmol, 78.4 mg), and 2 mL of THF were added to a 10 mL reaction tube and allowed to react at room temperature for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 20:1). TLC spot plate tracking was used. The eluates containing the target product were collected, combined, and evaporated to obtain the compound represented by the above formula in an 83% yield. This substance is a colorless oily liquid.

[0034] Characterization data: 1 H NMR (400MHz, Chloroform-d) δ7.68(s,1H),7.54(s,1H),7.43–7.39(m,3H),7.38–7.35(m,2H),5.60(s,1H),5.20(s,1H). 13 C NMR(101MHz,Chloroform-d)δ145.7,145.3,135.2,133.9,129.53,128.6,128.0,105.5,57.8.HRMS m / z(ESI)calcd forC 11 H 10 N2I(M+H) + 296.9883, found 296.9880.

[0035] Example 2:

[0036] The structure of the pyrazole compound prepared in this example is as follows:

[0037]

[0038] Preparation: Under argon, a stirring magnet, styrylsulfonium salt (0.2 mmol, 77.8 mg), pyrazole (0.3 mmol, 20.5 mg), iodosuccinimide (0.24 mmol, 54.0 mg), cesium carbonate (0.24 mmol, 78.4 mg), and 2 mL of THF were added to a 10 mL reaction tube and allowed to react at room temperature for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 20:1). TLC spot plate tracking was used. The eluates containing the target product were collected, combined, and evaporated to obtain the compound represented by the above formula in a 74% yield. This substance is a colorless oily liquid.

[0039] Characterization data: 1 H NMR (400MHz, Chloroform-d) δ7.67(s,1H),7.56(s,1H),7.43(d,J=8.2Hz,2H),7.36(d,J=8.3Hz,2H),5.58(s,1H),5.22(s,1H),4.61(s,2H). 13 C NMR(101MHz,Chloroform-d)δ145.8,144.8,138.8,135.2,133.9,128.8,128.3,106.0,58.0,45.5.HRMSm / z(ESI)calcd for C 12 H 11 N2ClI(M+H) + 344.9650, found 344.9653.

[0040] Example 3:

[0041] The structure of the pyrazole compound prepared in this example is as follows:

[0042]

[0043] Preparation: Under argon, a stirring magnet, styrylsulfonium salt (0.2 mmol, 74.7 mg), pyrazole (0.3 mmol, 20.5 mg), iodosuccinimide (0.24 mmol, 54.0 mg), cesium carbonate (0.24 mmol, 78.4 mg), and 2 mL of THF were added to a 10 mL reaction tube and allowed to react at room temperature for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the crude product was separated by silica gel column chromatography using petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 20:1) as eluents. TLC spot detection was performed, and the eluents containing the target product were collected, combined, and concentrated by evaporation to obtain the compound represented by the above formula in an 85% yield. This substance is a colorless oily liquid.

[0044] Characterization data: 1 H NMR (400MHz, Chloroform-d) δ7.67(s,1H),7.56–7.52(m,3H),7.25–7.21(m,2H),5.56(s,1H),5.21(s,1H). 13C NMR(101MHz,Chloroform-d)δ145.9,144.4,134.0,133.9,131.8,129.5,123.8,106.0,58.2.HRMS m / z(ESI)calcd for C 11 H9N2ClI(M+H) + 330.9493,found 330.9494.

[0045] Example 4:

[0046] The structure of the pyrazole compound prepared in this example is as follows:

[0047]

[0048] Preparation method: Under argon, a stirring magnet, styrenesulfonium salt (0.2mmol, 83.8mg), pyrazole (0.3mmol, 20.5mg), iodosuccinimide (0.24mmol, 54.0mg), cesium carbonate (0.24mmol, 78.4mg) and 2mL of THF solvent were added to a 10mL reaction tube in sequence and reacted at room temperature for 12 hours. After the reaction, the solvent was removed by distillation under reduced pressure, and the crude product was separated by silica gel column chromatography, eluted with petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 20:1), and detected by TLC spot plate tracking. The eluents containing the target product were collected, combined, and evaporated to obtain the compound shown in the above formula with a yield of 75%. This substance is a colorless oily liquid.

[0049] Characterization data: 1 H NMR (400MHz, Chloroform-d) δ7.67(s,1H),7.56(s,1H),7.39–7.36(m,2H),7.31–7.26(m,2H),5.56(s,1H),5.20(s,1H). 13 C NMR(101MHz,Chloroform-d)δ145.9,144.3,135.6,133.9,133.6,129.3,128.9,106.0,58.2.HRMS m / z(ESI)calcd forC 11 H9N2BrI(M+H) + 374.8988, found 374.8990.

[0050] Example 5:

[0051] The structure of the pyrazole compound prepared in this example is as follows:

[0052]

[0053] Preparation: Under argon, a stirring magnet, styrylsulfonium salt (0.2 mmol, 93.3 mg), pyrazole (0.3 mmol, 20.5 mg), iodosuccinimide (0.24 mmol, 54.0 mg), cesium carbonate (0.24 mmol, 78.4 mg), and 2 mL of THF were added to a 10 mL reaction tube and allowed to react at room temperature for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 20:1). TLC spot plate tracking was used. The eluates containing the target product were collected, combined, and evaporated to obtain the compound represented by the above formula in an 80% yield. This substance is a colorless oily liquid.

[0054] Characterization data: 1 H NMR (400MHz, Chloroform-d) δ7.75–7.72(m,2H),7.67(s,1H),7.56(s,1H),7.11–7.08(m,2H),5.56(s,1H),5.21(s,1H). 13 C NMR(101MHz,Chloroform-d)δ145.9,144.5,137.8,134.6,133.8,129.6,106.0,95.7,58.2.HRMS m / z(ESI)calcd forC 12 H9N2I2(M+H) + 422.8850, found 422.8845.

[0055] Example 6:

[0056] The structure of the pyrazole compound prepared in this example is as follows:

[0057]

[0058] Preparation: Under argon, a stirring magnet, styrylsulfonium salt (0.2 mmol, 81.6 mg), pyrazole (0.3 mmol, 20.5 mg), iodosuccinimide (0.24 mmol, 54.0 mg), cesium carbonate (0.24 mmol, 78.4 mg), and 2 mL of THF were added to a 10 mL reaction tube and allowed to react at room temperature for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the crude product was separated by silica gel column chromatography using petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 20:1) as eluents. TLC spot detection was performed, and the eluents containing the target product were collected, combined, and concentrated by evaporation to obtain the compound represented by the above formula in a 35% yield. This substance is a colorless oily liquid.

[0059] Characterization data: 1 H NMR (400MHz, Chloroform-d) δ7.69–7.66 (m, 3H), 7.59 (s, 1H), 7.49 (d, J = 8.1Hz, 2H), 5.64 (s, 1H), 5.30 (s, 1H). 13 C NMR (101MHz, Chloroform-d) δ146.2, 144.3, 138.6, 131.5 (d, J = 32.7Hz), 128.3, 125.6 (q, J = 3.7Hz), 123.8 (d, J = 272.4Hz), 107.3, 58.43. 19 F NMR(376MHz,Chloroform-d)δ-62.81.HRMS m / z(ESI)calcd forC 12 H9N2F3I(M+H) + 364.9757, found 364.9756.

[0060] Example 7:

[0061] The structure of the pyrazole compound prepared in this example is as follows:

[0062]

[0063] Preparation: Under argon, a stirring magnet, styrylsulfonium salt (0.2 mmol, 77.3 mg), pyrazole (0.3 mmol, 20.5 mg), iodosuccinimide (0.24 mmol, 54.0 mg), cesium carbonate (0.24 mmol, 78.4 mg), and 2 mL of THF were added to a 10 mL reaction tube and allowed to react at room temperature for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 20:1). TLC spot plate tracking was used. The eluates containing the target product were collected, combined, and evaporated to obtain the compound represented by the above formula in a 75% yield. This substance is a colorless oily liquid.

[0064] Characterization data: 1 H NMR (400MHz, Chloroform-d) δ7.66(s,1H),7.55(s,1H),7.26–7.24(m,4H),5.52(s,1H),5.17(s,1H),2.49(s,3H). 13 C NMR(101MHz,Chloroform-d)δ145.7,144.9,140.7,133.9,131.6,128.3,126.0,105.1,57.9,15.4.HRMS m / z(ESI)calcd forC 12 H 12 N2IS(M+H) + 342.9760,found 342.9762.

[0065] Example 8:

[0066] The structure of the pyrazole compound prepared in this example is as follows:

[0067]

[0068] Preparation: Under argon, a stirring magnet, styrylsulfonium salt (0.2 mmol, 74.7 mg), pyrazole (0.3 mmol, 20.5 mg), iodosuccinimide (0.24 mmol, 54.0 mg), cesium carbonate (0.24 mmol, 78.4 mg), and 2 mL of THF were added to a 10 mL reaction tube and allowed to react at room temperature for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 20:1). TLC spot plate tracking was used. The eluates containing the target product were collected, combined, and evaporated to obtain the compound represented by the above formula in an 81% yield. This substance is a colorless oily liquid.

[0069] Characterization data: 1 H NMR (400MHz, Chloroform-d) δ7.68(s,1H),7.56(s,1H),7.40–7.33(m,3H),7.24–7.22(m,1H),5.59(d,J=1.0Hz,1H),5.23(d,J=0.9Hz,1H). 13 C NMR(101MHz,Chloroform-d)δ146.0,144.1,136.9,134.6,133.9,129.9,129.6,128.0,126.0,106.6,58.3.HRMS m / z(ESI)calcd for C 11 H9N2ClI(M+H) + 330.9493,found 330.9491.

[0070] Example 9:

[0071] The structure of the pyrazole compound prepared in this example is as follows:

[0072]

[0073] Preparation: Under argon, a stirring magnet, styrylsulfonium salt (0.2 mmol, 70.9 mg), pyrazole (0.3 mmol, 20.5 mg), iodosuccinimide (0.24 mmol, 54.0 mg), cesium carbonate (0.24 mmol, 78.4 mg), and 2 mL of THF were added to a 10 mL reaction tube and allowed to react at room temperature for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 20:1). TLC spot plate tracking was used. The eluates containing the target product were collected, combined, and evaporated to obtain the compound represented by the above formula in a 73% yield. This substance is a colorless oily liquid.

[0074] Characterization data: 1 H NMR (400MHz, Chloroform-d) δ7.68(s,1H),7.41–7.37(m,2H),7.35–7.27(m,3H),5.90(s,1H),4.94(s,1H),2.11(s,3H). 13C NMR(101MHz,Chloroform-d)δ145.8,144.2,137.1,134.7,132.7,130.5,130.4,129.6,126.1,104.0,58.0,19.2.HRMS m / z(ESI)calcd for C 12 H 12 N2I(M+H) + 311.0040,found 311.0041.

[0075] Example 10:

[0076] The structure of the pyrazole compound prepared in this example is as follows:

[0077]

[0078] Preparation: Under argon, a stirring magnet, styrylsulfonium salt (0.2 mmol, 83.9 mg), pyrazole (0.3 mmol, 20.5 mg), iodosuccinimide (0.24 mmol, 54.0 mg), cesium carbonate (0.24 mmol, 78.4 mg), and 2 mL of THF were added to a 10 mL reaction tube and reacted at room temperature for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 20:1). TLC spot plate tracking was performed. The eluates containing the target product were collected, combined, and evaporated to obtain the compound represented by the above formula in a 73% yield. This substance is a colorless oily liquid.

[0079] Characterization data: 1 H NMR (400MHz, Chloroform-d) δ7.64(s,1H),7.46–7.38(m,3H),7.37–7.33(m,2H),5.87(s,1H),5.01(s,1H). 13 C NMR(101MHz,Chloroform-d)δ145.9,142.4,134.1,133.9,132.7,131.9,130.8,130.0,127.1,105.6,58.2.HRMS m / z(ESI)calcd forC 11 H9N2Br(M+H) + 374.8988,found 374.8988.

[0080] Example 11:

[0081] The structure of the pyrazole compound prepared in this example is as follows:

[0082]

[0083] Preparation: Under argon, a stirring magnet, styrylsulfonium salt (0.2 mmol, 73.7 mg), pyrazole (0.3 mmol, 20.5 mg), iodosuccinimide (0.24 mmol, 54.0 mg), cesium carbonate (0.24 mmol, 78.4 mg), and 2 mL of THF were added to a 10 mL reaction tube and allowed to react at room temperature for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 20:1). TLC spot plate tracking was used. The eluates containing the target product were collected, combined, and evaporated to obtain the compound represented by the above formula in a 79% yield. This substance is a colorless oily liquid.

[0084] Characterization data: 1 H NMR (400MHz, Chloroform-d) δ7.67(s,1H),7.53(s,1H),7.06(s,1H),6.97(s,2H),5.55(s,1H),5.14(s,1H),2.33(s,6H). 13 C NMR(101MHz,Chloroform-d)δ145.7,145.5,138.2,135.1,133.9,131.2,125.8,105.1,57.7,21.3.HRMS m / z(ESI)calcdfor C 13 H 14 N2I(M+H) + 325.0196,found 325.0195.

[0085] Example 12:

[0086] The structure of the pyrazole compound prepared in this example is as follows:

[0087]

[0088] Preparation: Under argon, a stirring magnet, styrylsulfonium salt (0.2 mmol, 90.5 mg), pyrazole (0.3 mmol, 20.5 mg), iodosuccinimide (0.24 mmol, 54.0 mg), cesium carbonate (0.24 mmol, 78.4 mg), and 2 mL of THF were added to a 10 mL reaction tube and reacted at room temperature for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 20:1). TLC spot plate tracking was performed. The eluates containing the target product were collected, combined, and evaporated to obtain the compound represented by the above formula in a 73% yield. This substance is a colorless oily liquid.

[0089] Characterization data: 1 H NMR (400MHz, Chloroform-d) δ7.69(s,1H),7.55(s,1H),7.50(s,1H),7.20(s,2H),5.61(s,1H),5.15(s,1H),1.34(s,18H). 13 C NMR(101MHz,Chloroform-d)δ151.1,146.2,145.6,134.4,134.0,123.7,122.5,104.6,57.6,34.9,31.4.HRMS m / z(ESI)calcd for C 19 H 26 N2I(M+H) + 409.1135, found 409.1132.

[0090] Example 13:

[0091] The structure of the pyrazole compound prepared in this example is as follows:

[0092]

[0093] Preparation: Under argon, a stirring magnet, styrylsulfonium salt (0.2 mmol, 81.9 mg), pyrazole (0.3 mmol, 20.5 mg), iodosuccinimide (0.24 mmol, 54.0 mg), cesium carbonate (0.24 mmol, 78.4 mg), and 2 mL of THF were added to a 10 mL reaction tube and allowed to react at room temperature for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 20:1). TLC spot plate tracking was used. The eluates containing the target product were collected, combined, and evaporated to obtain the compound represented by the above formula in an 81% yield. This substance is a colorless oily liquid.

[0094] Characterization data: 1 H NMR (400MHz, Chloroform-d) δ7.63(s,1H),7.47(d,J=1.7Hz,1H),7.42(s,1H),7.38–7.32(m,2H),5.82(d,J=1.1Hz,1H),5.02(d,J=1.1Hz,1H). 13 C NMR(101MHz,Chloroform-d)δ146.0,141.6,136.2,134.7,132.65,132.60,132.56,130.0,127.5,106.0,58.5.HRMS m / z(ESI)calcd for C 11 H8N2Cl2I(M+H) + 364.9104,found364.9108.

[0095] Example 14:

[0096] The structure of the pyrazole compound prepared in this example is as follows:

[0097]

[0098] Preparation: Under argon, a stirring magnet, styrylsulfonium salt (0.2 mmol, 78.1 mg), pyrazole (0.3 mmol, 20.5 mg), iodosuccinimide (0.24 mmol, 54.0 mg), cesium carbonate (0.24 mmol, 78.4 mg), and 2 mL of THF were added to a 10 mL reaction tube and reacted at room temperature for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 20:1). TLC spot plate tracking was performed. The eluates containing the target product were collected, combined, and evaporated to obtain the compound represented by the above formula in a 71% yield. This substance is a colorless oily liquid.

[0099] Characterization data: 1 H NMR (400MHz, Chloroform-d) δ7.88–7.84(m,4H),7.72(s,1H),7.59(s,1H),7.56–7.50(m,2H),7.43(dd,J=8.6,1.7Hz,1H),5.68(s,1H),5.33(s,1H). 13 C NMR(101MHz,Chloroform-d)δ145.8,145.4,134.1,133.7,133.0,132.5,128.4,127.7,127.0,126.7,125.1,106.1,57.9.HRMS m / z(ESI)calcd for C 15 H 12 N2I(M+H) + 347.0040,found347.0039.

[0100] Example 15:

[0101] The structure of the pyrazole compound prepared in this example is as follows:

[0102]

[0103] Preparation: Under argon, a stirring magnet, styrylsulfonium salt (0.2 mmol, 83.2 mg), pyrazole (0.3 mmol, 20.5 mg), iodosuccinimide (0.24 mmol, 54.0 mg), cesium carbonate (0.24 mmol, 78.4 mg), and 2 mL of THF were added to a 10 mL reaction tube and allowed to react at room temperature for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 20:1). TLC spot plate tracking was used. The eluates containing the target product were collected, combined, and evaporated to obtain the compound represented by the above formula in a 73% yield. This substance is a colorless oily liquid.

[0104] Characterization data: 1 H NMR (400MHz, Chloroform-d) δ7.78(s,1H),7.44(s,1H),7.39–7.35(m,3H),7.25–7.21(m,5H),7.00(s,1H),6.86–6.84(m,2H). 13 C NMR(101MHz,Chloroform-d)δ145.9,137.5,137.1,135.9,133.8,129.1,128.8,128.6,128.5,128.4,126.1,125.4,57.5.HRMS m / z(ESI)calcd for C 17 H 14 N2I(M+H) + 373.0196, found 373.0194.

[0105] Example 16:

[0106] The structure of the pyrazole compound prepared in this example is as follows:

[0107]

[0108] Preparation: Under argon, a stirring magnet, styrylsulfonium salt (0.2 mmol, 42.7 mg), pyrazole (0.3 mmol, 20.5 mg), bromosuccinimide (0.24 mmol, 54.0 mg), cesium carbonate (0.24 mmol, 78.4 mg), and 2 mL of THF were added to a 10 mL reaction tube and allowed to react at room temperature for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 20:1). TLC spot plate tracking was used. The eluates containing the target product were collected, combined, and evaporated to obtain the compound represented by the above formula in a 68% yield. This substance is a colorless oily liquid.

[0109] Characterization data: 1 H NMR (400MHz, Chloroform-d) δ7.68(s,1H),7.54(s,1H),7.43–7.39(m,3H),7.38–7.35(m,2H),5.60(s,1H),5.20(s,1H). 13 C NMR(101MHz,Chloroform-d)δ145.7,145.3,135.2,133.9,129.53,128.6,128.0,105.5,57.8.HRMS m / z(ESI)calcd forC 11 H 10 N2Br(M+H) + 249.0022,found 249.0018.

[0110] Example 17:

[0111] The structure of the pyrazole compound prepared in this example is as follows:

[0112]

[0113] Preparation: Under argon, a stirring magnet, styrylsulfonium salt (0.2 mmol, 32 mg), pyrazole (0.3 mmol, 20.5 mg), chlorosuccinimide (0.24 mmol, 54.0 mg), cesium carbonate (0.24 mmol, 78.4 mg), and 2 mL of THF were added to a 10 mL reaction tube and allowed to react at room temperature for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 20:1). TLC spot plate tracking was used. The eluates containing the target product were collected, combined, and evaporated to obtain the compound represented by the above formula in a 48% yield. This substance is a colorless oily liquid.

[0114] Characterization data: 1 H NMR(500MHz,Chloroform-d)δ7.61(s,1H),7.48(s,1H),7.44–7.40(m,3H),7.39–7.35(m,2H),5.59(s,1H),5.21(s,1H). 13 C NMR(126MHz,Chloroform-d)δ145.5,139.4,135.1,129.6,128.6,128.0,127.5,111.3,105.5.HRMS m / z(ESI)calcd forC 11 H 10 N2Cl(M+H) + 205.0527,found 205.0523.

[0115] Example 18:

[0116] The structure of the pyrazole compound prepared in this example is as follows:

[0117]

[0118] Preparation: Under argon, a stirring magnet, styrylsulfonium salt (0.2 mmol, 43.3 mg), pyrazole (0.3 mmol, 20.5 mg), iodosuccinimide (0.24 mmol, 54.0 mg), cesium carbonate (0.24 mmol, 78.4 mg), and 2 mL of THF were added to a 10 mL reaction tube and allowed to react at room temperature for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 20:1). TLC spot plate tracking was used. The eluates containing the target product were collected, combined, and evaporated to obtain the compound represented by the above formula in an 81% yield. This substance is a colorless oily liquid.

[0119] Characterization data: 1 H NMR (500MHz, Chloroform-d) δ7.96–7.94(m,2H),7.58(s,1H),7.53–7.33(m,8H),5.76(s,1H),5.22(s,1H). 13C NMR(126MHz,Chloroform-d)δ153.1,145.1,136.2,135.1,132.3,129.5,128.6,128.5,128.23,128.20,128.16,105.4,58.3.HRMS m / z(ESI)calcd for C 17 H 14 N2I(M+H) + 373.0196,found 373.0196.

[0120] Example 19:

[0121] The structure of the pyrazole compound prepared in this example is as follows

[0122]

[0123] Preparation: Under argon, a stirring magnet, styrylsulfonium salt (0.2 mmol, 44.1 mg), pyrazole (0.3 mmol, 20.5 mg), iodosuccinimide (0.24 mmol, 54.0 mg), cesium carbonate (0.24 mmol, 78.4 mg), and 2 mL of THF were added to a 10 mL reaction tube and allowed to react at room temperature for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 20:1). TLC spot plate tracking was used. The eluates containing the target product were collected, combined, and evaporated to obtain the compound represented by the above formula in a 91% yield. This substance is a colorless oily liquid.

[0124] Characterization data: 1 H NMR(400MHz,Chloroform-d)δ7.46–7.32(m,6H),5.65(s,1H),5.18(s,1H). 13 C NMR(101MHz,Chloroform-d)δ144.8,135.9,134.8,134.4,129.8,128.8,128.1,106.0,64.7.HRMS m / z(ESI)calcd for C 11 H9N2BrI(M+H) + 374.8988, found 374.8986.

[0125] Example 20:

[0126] The structure of the pyrazole compound prepared in this example is as follows:

[0127]

[0128] Preparation: Under argon, a stirring magnet, styrylsulfonium salt (0.2 mmol, 43.8 mg), pyrazole (0.3 mmol, 20.5 mg), iodosuccinimide (0.24 mmol, 54.0 mg), cesium carbonate (0.24 mmol, 78.4 mg), and 2 mL of THF were added to a 10 mL reaction tube and allowed to react at room temperature for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 20:1). TLC spot plate tracking was used. The eluates containing the target product were collected, combined, and evaporated to obtain the compound represented by the above formula in an 84% yield. This substance is a colorless oily liquid.

[0129] Characterization data: 1 H NMR (400MHz, Chloroform-d) δ7.37–7.32(m,3H),7.21–7.16(m,2H),5.79(s,1H),5.44(s,1H),2.13(s,3H). 13 C NMR(101MHz,Chloroform-d)δ145.0,144.0,135.2,133.1,129.5,128.8,125.9,113.4,67.3,13.5.HRMS m / z(ESI)calcd forC 12 H 11 N2BrI(M+H) + 388.9145, found 388.9144.

[0130] Example 21:

[0131] The structure of the pyrazole compound prepared in this example is as follows:

[0132]

[0133] Preparation: Under argon, a stirring magnet, styrylsulfonium salt (0.2 mmol, 66.1 mg), pyrazole (0.3 mmol, 20.5 mg), iodosuccinimide (0.24 mmol, 54.0 mg), cesium carbonate (0.24 mmol, 78.4 mg), and 2 mL of THF were added to a 10 mL reaction tube and allowed to react at room temperature for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 20:1). TLC spot plate tracking was performed. The eluates containing the target product were collected, combined, and evaporated to obtain the compound represented by the above formula in a 32% yield. This substance is a colorless oily liquid.

[0134] Characterization data: 1 H NMR(400MHz,Chloroform-d)δ7.99–7.96(m,2H),7.51–7.47(m,2H),7.45–7.40(m,1H ),7.39–7.32(m,5H),7.30–7.25(m,3H),7.24–7.21(m,2H),5.64(s,1H),5.36(s,1H). 13 C NMR(101MHz,Chloroform-d)δ152.6,146.8,145.6,136.1,132.8,130.0,129.9,128.9,128.6,128.4,128.3,128.2,128.1,126.3,113.2,62.4.HRMS m / z(ESI)calcdfor C 23 H 18 N2I(M+H) + 449.0509,found 449.0509.

[0135] Example 22: Effect of Temperature

[0136] Referring to Example 1, only the temperature was replaced with other temperatures in Table 1, and the other conditions remained unchanged. The results of the corresponding reactions are shown in Table 1.

[0137] Table 1 Effect of temperature on the preparation of pyrazole compounds

[0138] temperature Yield of pyrazole compounds Room temperature (Example 1) 83％ 60℃ 60％ 80℃ ＜10％

[0139] Example 23: Effect of Base

[0140] Referring to Example 1, only cesium carbonate was replaced by other bases shown in Table 2, and the other conditions remained unchanged. The results of the corresponding reactions are shown in Table 1.

[0141] Table 2 Effect of base on the preparation of pyrazole compounds

[0142] alkali Yield of pyrazole compounds Cesium carbonate (Example 1) 83％ <![CDATA[ t Full]]> 55％ NaOH 40％

[0143] Example 24: Effect of Solvent

[0144] Referring to Example 1, only the solvent was replaced from tetrahydrofuran to other solvents shown in Table 3, and the other conditions remained unchanged. The results of the corresponding reactions are shown in Table 3.

[0145] Table 3 Effect of solvent selection on the preparation of pyrazole compounds

[0146] solvent Yield of pyrazole compounds THF (Example 1) 83％ DMF trace Toluene 75％

[0147] Example 25: Reaction atmosphere expansion

[0148] Referring to Example 1, the atmosphere was replaced by oxygen and air respectively, while other conditions remained unchanged. The results of the corresponding reactions are shown in Table 4.

[0149] Table 4 Effect of reaction atmosphere on the preparation of pyrazole compounds

[0150] Reaction atmosphere Yield of pyrazole compounds Argon (Example 1) 83％ Air 55％ <![CDATA[O2]]> 72％

[0151] Example 26: Amplification reaction

[0152] Referring to Example 1, under argon, a stirring magnet, styrylsulfonium salt (5.0 mmol, 1.7 g), pyrazole (7.5 mmol, 510.6 mg), chlorosuccinimide (6.0 mmol, 1.35 g), cesium carbonate (6.0 mmol, 1.96 g), and 50 mL of THF solvent were added to a 100 mL reaction tube in sequence and reacted at room temperature for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 20:1). TLC spot plate tracking was performed, and the eluents containing the target product were collected, combined, and evaporated to obtain the target compound in a yield of 79%. This substance is a colorless oily liquid.

[0153] The N-alkenylated-4-halogenated polysubstituted pyrazole compounds prepared by the above method can be used as intermediates to carry out catalytic double bond oxidative cleavage to prepare the corresponding NE inhibitor represented by formula V. The process is as follows:

[0154]

[0155] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not limiting. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the purpose and scope of the technical solutions of the present invention, which should all be included in the scope of the claims of the present invention.

Claims

1. A method for synthesizing a polysubstituted pyrazole compound promoted by a base, characterized in that: Using an arylvinyl sulfonium salt represented by formula I, a pyrazole compound represented by formula II, and a halogenated succinimide represented by formula III as raw materials, in the presence of a base, a reaction is performed to obtain a polysubstituted pyrazole compound represented by formula IV; Wherein, R is a substituted or unsubstituted aryl group, the substitution is mono- or di-substituted, and the substituents are: halogen, -SMe, C1-4 alkyl, halogenated C1-4 alkyl; R1 is H, phenyl; R2 is H, Br, Cl, phenyl; R3 is H, methyl, phenyl; R4 is halogen; The aryl group is a benzene ring or a naphthalene ring.

2. The method according to claim 1, characterized in that R is specifically selected from:

3. The method according to claim 1, characterized in that The reaction is carried out in an organic solvent, which is any one or more of toluene, acetonitrile and tetrahydrofuran.

4. The method according to claim 1, wherein The base is potassium hydroxide, sodium hydride, cesium carbonate, or potassium tert-butoxide.

5. The method according to claim 1, characterized in that The reaction temperature is 0°C to 60°C, and the reaction time is 12 to 24 hours.

6. The method according to claim 1, characterized in that The molar ratio of the aryl vinyl sulfonium salt represented by formula I, the pyrazole compound represented by formula II and the halogenated succinimide represented by formula III is 1.0:(1.0-2.0):(1.0-2.0).

7. The method according to claim 1, characterized in that The molar ratio of the arylvinyl sulfonium salt represented by Formula I to the base is 1.0:(1.0-2.0).

8. The method according to claim 1, characterized in that The amount of the organic solvent added is 2 to 10 mL / mmol based on the amount of the arylvinyl sulfonium salt represented by Formula I.

9. The method according to claim 1, characterized in that After the reaction, the product is purified by silica gel column chromatography separation; the purification method is as follows: after the reaction is completed, column chromatography silica gel is added, the solvent is removed by reduced pressure distillation, the product is spin-dried until the silica gel adsorbs the product in a powdery state, and then the product is loaded onto a column, eluted with a mixture of petroleum ether and ethyl acetate, and evaporated and concentrated to obtain a pyrazole compound.

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