CN108395404B - Synthesis method of polysubstituted pyrazole compound - Google Patents
Synthesis method of polysubstituted pyrazole compound Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention discloses a method for synthesizing a polysubstituted pyrazole compound by adopting
Is used as a reaction raw material and is obtained by reaction under the action of Lewis base
Wherein R is1、R2、R3And R4All are any of alkyl, aryl or heterocyclic. The method has the advantages of simple reaction operation, mild reaction conditions and high yield, and is suitable for large-scale industrial production.
Description
Technical Field
The invention relates to the technical field of organic compound process application, in particular to a synthesis method of a polysubstituted pyrazole compound.
Background
The pyrazole compounds are very important pharmaceutical and chemical intermediates and have very high application value. Many drugs and biologically active molecules, such as Fipronil, Anti-diabetic agent, Celebrex and Doramapimod, have a pyrazole backbone.
The conventional method for synthesizing pyrazole compounds is mainly prepared by metal-catalyzed cycloaddition reaction. However, in this method, the use of heavy metals causes serious environmental pollution, and the application of this method is restricted.
Therefore, the research on a novel method for simply and efficiently preparing the polysubstituted pyrazole compound in an environment-friendly manner is a problem which needs to be solved by the technical personnel in the field.
Disclosure of Invention
In view of the above, the invention provides a novel method for simply and efficiently preparing a multi-substituted pyrazole compound, which is environment-friendly, and can efficiently realize the conversion of the reaction by using Lewis base as a catalyst.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method for synthesizing a polysubstituted pyrazole compound comprises the following steps:
step 1), mixing a reaction raw material compound (1) and a compound (2) and adding the mixture into a reactor,
step 2), adding a Lewis base catalyst, and then adding a reaction solvent for reaction at the reaction temperature of 20-80 ℃ for 72 hours to obtain a multi-substituted pyrazole compound;
wherein the chemical formula of the compound (1) is:
the chemical formula of the compound (2) is:
(ii) a The chemical formula of the polysubstituted pyrazole compound is
R1, R2, R3 and R4 are all any of alkyl, aryl or heterocyclic.
The invention has the beneficial effects that: the pyrazole compound is obtained by reacting simple and easily-obtained ketone and nitrilimine as reaction raw materials under the action of Lewis base. The reaction operation is simple, the reaction condition is mild, the yield is high, and the method is suitable for large-scale industrial production.
Preferably, the reaction raw materials of compound 1 and compound 2 are mixed and added into the reactor, and air is exchanged with nitrogen three times; after the compound 1, the compound 2 and the catalyst are added into a reactor, evacuating and replacing nitrogen, and adding a reaction solvent in a nitrogen atmosphere; after the reaction is finished, adding silica gel into the reactor, and performing spin-drying column chromatography to obtain the polysubstituted pyrazole compound. The reaction operation is simple, the reaction condition is mild, the yield is high, and the method is suitable for large-scale industrial production.
Preferably, the reaction solvent is one or more of dichloromethane, toluene, chloroform, tetrahydrofuran, DMA, 1, 2-dichloroethane, THF, chlorobenzene, 1, 4-dioxane, DMF, DMSO and acetonitrile. The solvents used in the invention are common commercial reagents, and have stable performance and mild reaction.
Preferably, the molar ratio of compound 1 to compound 2 is 1: 2. The invention has high molar ratio yield of the two raw materials and is suitable for large-scale industrial production.
Preferably, the Lewis base catalyst is used in an amount of 1 to 100 mol% based on the compound 1.
Preferably, the Lewis base catalyst is used in an amount of 20 to 30 mol% based on the molar amount of the compound (1). More preferably 10 mol%.
Preferably, the lewis base catalyst is DMAP and/or triethylamine. Wherein DMAP is 4-dimethylaminopyridine. The catalyst adopted in the invention is a common commercial reagent, has stable performance, can better promote the reaction and improve the reaction efficiency.
Preferably, the reaction temperature after the addition of the reaction solvent is 20 to 80 ℃ and the reaction time is 72 hours. More preferably at room temperature (23 ℃ to 26 ℃). The reaction condition is mild, easy to control and high in yield.
Preferably, the synthesis method of the polysubstituted pyrazole compound comprises the following steps:
R1is H, R2Is an aromatic radical, R3Is phenyl, R4Is phenyl, the reaction steps are asThe following:
step 1), reacting raw materials
Mixing and adding the mixture into a reactor, and adding the mixture into the reactor,
step 2), adding Lewis base catalyst, adding reaction solvent for reaction at the temperature of 20-80 ℃ for 72 hours to obtain
According to the technical scheme, compared with the prior art, the synthesis method disclosed by the invention has the advantages that all raw materials used are very simple, are all industrial commodities, are simple and easily available, have wide sources and very stable performance, and do not need special storage conditions. The catalyst used in the invention is also a common commercial reagent and has stable performance. Conventional methods for synthesizing spirocyclic polysubstituted pyrazole compounds are generally accomplished using metal-catalyzed cycloaddition reactions. However, the use of heavy metals causes serious environmental pollution and great limitation to industrial production. Therefore, the pyrazole compound is obtained by adopting simple and easily obtained ketone and nitrilimine as reaction raw materials and reacting under the action of Lewis base. The reaction operation is simple, the reaction condition is mild, the yield is high, and the method is suitable for large-scale industrial production. The synthesized pyrazole compound is a core skeleton of a plurality of natural products and active drug molecules, and a reaction route innovatively designed by the invention provides a widely applicable preparation method for synthesizing the compound.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The embodiment of the invention discloses a novel method for simply and efficiently preparing a polysubstituted pyrazole compound, which is green and environment-friendly.
Example 1
The synthesis method of the polysubstituted pyrazole compound comprises the following steps:
exchanging air 3 times with nitrogen in a 25mL tube reactor; will be provided with
(0.05mmol，8.9mg)，
(0.10mmol, 23.0mg), triethylamine (0.10mmol, 10.1mg) and DMAP (0.005mmol, 1.2mg) were weighed in order into a reaction tube, evacuated to exchange nitrogen, and 0.3mL of dichloromethane was added under nitrogen atmosphere; reacting the reaction system at room temperature for 72 hours; after the TCL detection reaction is finished, directly adding silica gel, and performing spin-drying column chromatography to obtain a white solid
(yield 87%).
1H NMR(CDCl3,500MHz):δ(ppm)7.72-7.70(m,2H),7.53-7.50(m,6H),7.48-7.46(m,1H),7.26-7.25(m,5H),7.07-7.06(m,1H),2.67(s,3H).13C NMR(CDCl3125 MHz. delta. (ppm)162.1,150.2,144.3,138.7,137.9,132.3,129.5,129.3,129.3,129.0,128.9,128.7,125.7,124.0,119.4,114.0,12.4.HRMS (ESI). calculated as M+(C30H20N3O) requires m/z 354.1601, with an actual value of 354.1591.
Example 2
The synthesis method of the polysubstituted pyrazole compound comprises the following steps:
exchanging air 3 times with nitrogen in a 25mL tube reactor; will be provided with
(0.05mmol，8.9mg)，
(0.10mmol, 24.4mg), triethylamine (0.10mmol, 10.1mg) and DMAP (0.005mmol, 1.2mg) were weighed in order into a reaction tube, evacuated to exchange nitrogen, and 0.3mL of dichloromethane was added under nitrogen atmosphere; reacting the reaction system at room temperature for 72 hours; after the TCL detection reaction is finished, directly adding silica gel, and performing spin-drying column chromatography to obtain a white solid
(yield 95%).
1H NMR(CDCl3,500MHz):δ(ppm)7.60(d,J＝10.0Hz,2H),7.53-7.50(m,4H),7.46-7.44(m,1H),7.35(s,1H),7.31(d,J＝5.0Hz,2H),7.28-7.27(m,4H),7.07-7.06(m,1H),2.66(s,3H),2.44(s,3H).13CNMR(CDCl3125 MHz. delta. (ppm)162.2,150.2,144.2,139.3,138.8,138.0,129.7,129.3,129.2,128.9,128.6,125.7,124.0,119.6,113.9,21.4,12.5.HRMS (ESI) calculated as M+(C24H22N3O) requires m/z368.1757, with an actual value of 368.1751.
Example 3
The synthesis method of the polysubstituted pyrazole compound comprises the following steps:
exchanging air 3 times with nitrogen in a 25mL tube reactor; will be provided with
(0.05mmol，8.9mg)，
(0.10mmol, 26.0mg), triethylamine (0.10mmol, 10.1mg) and DMAP (0.005mmol, 1.2mg) were weighed in order into a reaction tube, evacuated to exchange nitrogen, and 0.3mL of dichloromethane was added under nitrogen atmosphere; reacting the reaction system at room temperature for 72 hours; after the TCL detection reaction is finished, directly adding silica gel, and performing spin-drying column chromatography to obtain a white solid
(yield 98%).
1H NMR(CDCl3,500MHz):δ(ppm)7.64(d,J＝10.0Hz,2H),7.51-7.48(m,4H),7.46-7.44(m,1H),7.39(s,1H),7.31-7.28(m,3H),7.27-7.25(m 1H),7.08-7.05(m,1H),7.03(d,J＝5.0Hz,2H),3.86(s,3H),2.64(s,3H).13CNMR(CDCl3125 MHz. delta. (ppm)162.2,160.4,149.9,144.2,138.8,138.0,130.8,129.2,128.9,128.6,125.7,124.5,124.0,119.5,114.4,113.8,55.4,12.4.HRMS (ESI) calculated as M+(C24H22N3O2) requires m/z 384.1707, actual value 384.1698.
Example 4
The synthesis method of the polysubstituted pyrazole compound comprises the following steps:
exchanging air 3 times with nitrogen in a 25mL tube reactor; will be provided with
(0.05mmol，8.9mg)，
(0.10mmol, 24.8mg), triethylamine (0.10mmol, 10.1mg) and DMAP (0.005mmol, 1.2mg) were weighed in order into a reaction tube, evacuated to exchange nitrogen, and 0.3mL of dichloromethane was added under nitrogen atmosphere; reacting the reaction system at room temperature for 72 hours; after the TCL detection reaction is finished, directly adding silica gel, and performing spin-drying column chromatography to obtain a white solid
(yield 92%).
1H NMR(CDCl3,500MHz):δ(ppm)7.72-7.70(m,2H),7.54-7.45(s,5H),7.32-7.27(m,4H),7.23(s,1H),7.20-7.17(m,2H),7.10-7.07(m,1H),2.63(s,3H).13CNMR(CDCl3125MHz) δ (ppm)163.3 (J990.0 Hz),162.0,149.1,144.1,138.7,137.8,131.2 (J30.0 Hz),129.3,129.0,128.8,128.3 (J10.0 Hz),125.6,124.2,119.5,116.1 (J85.0 Hz),114.2,12.3 hrms (esi) calculated as M+(C23H19FN3O) requires m/z 372.1507, with an actual value of 372.1511.
Example 5
The synthesis method of the polysubstituted pyrazole compound comprises the following steps:
exchanging air 3 times with nitrogen in a 25mL tube reactor; will be provided with
(0.05mmol，8.9mg)，
(0.10mmol, 24.4mg), triethylamine (0.10mmol, 10.1mg) and DMAP (0.005mmol, 1.2mg) were weighed in order into a reaction tube, evacuated to exchange nitrogen, and 0.3mL of dichloromethane was added under nitrogen atmosphere; reacting the reaction system at room temperature for 72 hours; after the TCL detection reaction is finished, directly adding silica gel, and performing spin-drying column chromatography to obtain a white solid
(yield 90%).
1H NMR(CDCl3,500MHz):δ(ppm)754-7.48(m,6H),7.47-7.44(m,1H),7.42-7.38(m,1H),7.35(s,1H),7.32-7.31(m,1H),7.28-7.26(m,4H),7.07-7.05(m,1H),2.67(s,3H),2.41(s,3H).13CNMR(CDCl3125 MHz. delta. (ppm)162.1,150.3,144.3,138.9,138.7,138.0,132.2,130.1,130.1,129.2,128.9,128.9,128.6,126.6,125.7,124.0,119.4,113.9,21.4,12.5.HRMS (ESI) calculated as M+(C24H22N3O) requires m/z368.1757, with an actual value of 368.1748.
Example 6
The synthesis method of the polysubstituted pyrazole compound comprises the following steps:
exchanging air 3 times with nitrogen in a 25mL tube reactor; will be provided with
(0.05mmol，8.9mg)，
(0.10mmol, 30.8mg), triethylamine (0.10mmol, 10.1mg) and DMAP (0.005mmol, 1.2mg) were weighed in order into a reaction tube, evacuated to exchange nitrogen, and 0.3mL of dichloromethane was added under nitrogen atmosphere; reaction system in chamberReacting for 72 hours at the temperature; after the TCL detection reaction is finished, directly adding silica gel, and performing spin-drying column chromatography to obtain a white solid
(yield 83%).
1H NMR(CDCl3,500MHz):δ(ppm)7.78(d,J＝5.0Hz,1H),7.61(d,J＝10.0Hz,1H),7.53-7.50(m,5H),7.48-7.46(m,1H),7.42-7.39(m,1H),7.26-7.23(m,2H),7.18(d,J＝10.0Hz,2H),7.09(s,1H),7.09-7.04(m,1H),2.72(s,3H).13CNMR(CDCl3125 MHz. delta. (ppm)161.6,149.1,144.1,138.6,137.9,134.0,133.4,132.4,131.2,129.2,128.9,128.7,128.0,125.6,124.7,124.0,119.6,114.7,12.6.HRMS (ESI). calculated as M+(C23H19BrN3O) requires m/z 434.0686, with an actual value of 434.0674.
Example 7
The synthesis method of the polysubstituted pyrazole compound comprises the following steps:
exchanging air 3 times with nitrogen in a 25mL tube reactor; will be provided with
(0.05mmol，8.9mg)，
(0.10mmol, 28.0mg), triethylamine (0.10mmol, 10.1mg) and DMAP (0.005mmol, 1.2mg) were weighed in order into a reaction tube, evacuated to exchange nitrogen, and 0.3mL of dichloromethane was added under nitrogen atmosphere; reacting the reaction system at room temperature for 72 hours; after the TCL detection reaction is finished, directly adding silica gel, and performing spin-drying column chromatography to obtain a white solid
(yield 90%).
1H NMR(CDCl3,500MHz):δ(ppm)8.25(s,1H),7.97(d,J＝15.0Hz,1H),7.92-7.88(m,2H),7.82(d,J＝10.0Hz,1H),7.56-7.54(m,6H),7.48-7.47(m,1H),7.36(s,1H),7.21(m,4H),7.05-7.04(m,1H),2.68(s,3H).13CNMR(CDCl3125 MHz. delta. (ppm)162.2,150.0,144.4,138.8,137.8,133.4,133.3,129.6,129.3,128.9,128.7,128.4,127.8,126.9,126.7,126.6,125.7,124.1,119.7,114.2,12.4.HRMS (ESI). calculated as M+(C27H22N3O) requires m/z 404.1757, with an actual value of 404.1749.
Example 8
The synthesis method of the polysubstituted pyrazole compound comprises the following steps:
exchanging air 3 times with nitrogen in a 25mL tube reactor; will be provided with
(0.05mmol，8.9mg)，
(0.10mmol, 22.0mg), triethylamine (0.10mmol, 10.1mg) and DMAP (0.005mmol, 1.2mg) were weighed in order into a reaction tube, evacuated to exchange nitrogen, and 0.3mL of dichloromethane was added under nitrogen atmosphere; reacting the reaction system at room temperature for 72 hours; after the TCL detection reaction is finished, directly adding silica gel, and performing spin-drying column chromatography to obtain a white solid
(yield 67%).
1H NMR(CDCl3,500MHz):δ(ppm)8.37(s,1H),7.26(s,1H),7.57(d,J＝10.0Hz,2H),7.53-750(m,2H),7.48-7.46(m,3H),7.37-7.34(m,2H),7.14-7.11(m,1H),6.88-6.87(m,1H),6.58(s,1H),2.61(s,3H).13CNMR(CDCl3125 MHz. delta. (ppm). delta. (161.62,146.86,144.51,142.97,140.46,138.52,138.17,129.3,129.1,128.9,125.8,124.2,119.7,114.2,111.9,110.7, 12.5.HRMS (ESI). calculated as M+(C21H18N3O2) requires m/z 344.1394, actual value 344.1385.
Example 9
The synthesis method of the polysubstituted pyrazole compound comprises the following steps:
exchanging air 3 times with nitrogen in a 25mL tube reactor; will be provided with
(0.05mmol，8.9mg)，
(0.10mmol, 30.2mg), triethylamine (0.10mmol, 10.1mg) and DMAP (0.005mmol, 1.2mg) were weighed in order into a reaction tube, evacuated to exchange nitrogen, and 0.3mL of dichloromethane was added under nitrogen atmosphere; reacting the reaction system at room temperature for 72 hours; after the TCL detection reaction is finished, directly adding silica gel, and performing spin-drying column chromatography to obtain a white solid
(yield 72%).
1H NMR(CDCl3,500MHz):δ(ppm)7.70-7.67(m,2H),7.52-7.49(m,4H),7.33-7.30(m,2H),7.28-7.25(m,4H),7.1-7.15(m,1H),7.08-7.05(m,1H),2.69(s,3H).13CNMR(CDCl3125MHz) δ (ppm) δ 163.7,161.8 (J55.0 Hz),150.5,144.3,140.0 (J40.0 Hz),137.8,132.1,130.5 (J35.0 Hz),129.5,129.4,129.1,128.9,124.1,121.1 (J10.0 Hz),119.5,115.7 (J85.0 Hz),114.5,113.3 (J95.0 Hz),12.5 hrms (esi) calculated as M+(C23H19FN3O) requires m/z 372.1507, with an actual value of 372.1498.
Example 10
The synthesis method of the polysubstituted pyrazole compound comprises the following steps:
exchanging air 3 times with nitrogen in a 25mL tube reactor; will be provided with
(0.05mmol，9.6mg)，
(0.10mmol, 23.0mg), triethylamine (0.10mmol, 10.1mg) and DMAP (0.005mmol, 1.2mg) were weighed in order into a reaction tube, evacuated to exchange nitrogen, and 0.3mL of dichloromethane was added under nitrogen atmosphere; reacting the reaction system at room temperature for 72 hours; after the TCL detection reaction is finished, the reaction is continuedAdding silica gel, and performing spin-drying column chromatography to obtain white solid
(yield 80%).
1H NMR(CDCl3,500MHz):δ(ppm)7.71(d,J＝10.0Hz,2H),7.52-7.49(m,7H),7.47-7.45(m,1H),7.21(s,1H),7.15(d,J＝10.0Hz,2H),7.07(d,J＝5.0Hz,2H),2.66(s,3H),2.29(s,3H).13CNMR (CDCl3,125MHz) < delta > (ppm) < delta > 162.0,150.1,144.1,138.8,135.3,133.6,132.4,129.4,129.4,129.3,129.0,128.6,125.7,119.5,114.1,20.8,12.4.HRMS (ESI) < calculated M+(C24H22N3O) requires m/z368.1757, with an actual value of 368.1748.
Example 11
The synthesis method of the polysubstituted pyrazole compound comprises the following steps:
exchanging air 3 times with nitrogen in a 25mL tube reactor; will be provided with
(0.05mmol，10.4mg)，
(0.10mmol, 23.0mg), triethylamine (0.10mmol, 10.1mg) and DMAP (0.005mmol, 1.2mg) were weighed in order into a reaction tube, evacuated to exchange nitrogen, and 0.3mL of dichloromethane was added under nitrogen atmosphere; reacting the reaction system at room temperature for 72 hours; after the TCL detection reaction is finished, directly adding silica gel, and performing spin-drying column chromatography to obtain a white solid
(yield 74%).
1H NMR(CDCl3,500MHz):δ(ppm)7.71(d,J＝10.0Hz,2H),7.52-7.49(m,6H),7.47-7.45(m,1H),7.20-7.16(m,3H),6.81(d,J＝10.0Hz,2H),3.77(s,3H),2.65(s,3H).13CNMR(CDCl3125 MHz. delta. (ppm)162.0,156.2,150.1,144.0,138.8,132.4,131.0,129.4,129.3,129.0,128.6,125.7,121.2,114.1,55.5,12.4.HRMS (ESI) calculated as M+(C24H22N3O2) requires m/z 384.1707, actual value 384.1698.
Example 12
The synthesis method of the polysubstituted pyrazole compound comprises the following steps:
exchanging air 3 times with nitrogen in a 25mL tube reactor; will be provided with
(0.05mmol，10.3mg)，
(0.10mmol, 23.0mg), triethylamine (0.10mmol, 10.1mg) and DMAP (0.005mmol, 1.2mg) were weighed in order into a reaction tube, evacuated to exchange nitrogen, and 0.3mL of dichloromethane was added under nitrogen atmosphere; reacting the reaction system at room temperature for 72 hours; after the TCL detection reaction is finished, directly adding silica gel, and performing spin-drying column chromatography to obtain a white solid
(yield 78%).
1H NMR(CDCl3,500MHz):δ(ppm)7.98(d,J＝10.0Hz,1H),7.70(d,J＝10.0Hz,2H),7.52-7.51(m,4H),7.48-7.44(m,4H),7.10(s,1H),7.01(d,J＝10.0Hz,1H),6.87(s,1H),2.66(s,3H),2.26(s,3H),1.60(s,3H).13CNMR(CDCl3125 MHz. delta. (ppm)162.1,150.2,144.1,138.8,133.9,133.5,132.6,131.0,129.6,129.3,129.3,129.1,128.6,127.6,127.2,125.7,121.6,114.4,20.8,16.7,12.4.HRMS (ESI) calculated as M+(C25H24N3O) requires m/z 382.1914, with an actual value of 382.1906.
Example 13
The synthesis method of the polysubstituted pyrazole compound comprises the following steps:
exchanging air 3 times with nitrogen in a 25mL tube reactor; will be provided with
(0.05mmol，9.6mg)，
(0.10mmol, 23.0mg), triethylamine (0.10mmol, 10.1mg) and DMAP (0.005mmol, 1.2mg) were weighed in order into a reaction tube, evacuated to exchange nitrogen, and 0.3mL of dichloromethane was added under nitrogen atmosphere; reacting the reaction system at room temperature for 72 hours; after the TCL detection reaction is finished, directly adding silica gel, and performing spin-drying column chromatography to obtain a white solid
(yield 86%).
1H NMR(CDCl3,500MHz):δ(ppm)8.17(d,J＝5.0Hz,1H),7.70(d,J＝5.0Hz,2H),7.52(s,4H),7.49-7.45(m,4H),7.22-7.21(m,1H),7.16(s,1H),7.05-7.04(m,1H),6.99-6.98(m,1H),2.67(s,3H),1.60(s,3H).13CNMR(CDCl3125 MHz. delta. (ppm)162.1,150.2,144.3,138.7,136.1,132.5,130.3,129.6,129.3,129.3,129.1,128.7,127.3,126.7,125.7,124.2,121.3,114.3,16.6,12.5.HRMS (ESI) calculated as M+(C24H22N3O) requires m/z368.1757, with an actual value of 368.1749.
Example 14
The synthesis method of the polysubstituted pyrazole compound comprises the following steps:
exchanging air 3 times with nitrogen in a 25mL tube reactor; will be provided with
(0.05mmol，10.4mg)，
(0.10mmol, 23.0mg), triethylamine (0.10mmol, 10.1mg) and DMAP (0.005mmol, 1.2mg) were weighed in order into a reaction tube, evacuated to exchange nitrogen, and 0.3mL of dichloromethane was added under nitrogen atmosphere; reacting the reaction system at room temperature for 72 hours; after the TCL detection reaction is finished, directly adding silica gel, and performing spin-drying column chromatography to obtain a white solid
(yield 77%).
1H NMR(CDCl3,500MHz):δ(ppm)8.53(d,J＝5.0Hz,1H),7.99(s,1H),7.70-7.69(m,2H),7.51(s,4H),7.46-7.45(m,4H),7.00-6.94(m,2H),6.73(d,J＝5.0Hz,1H),3.44(s,3H),2.66(s,3H).13CNMR(CDCl3125 MHz. delta. (ppm)162.1,150.5,147.8,144.0,138.8,132.3,129.6,129.2,128.8,128.7,128.6,127.9,125.7,123.3,120.9,119.4,114.6,109.7,55.3,12.4.HRMS (ESI) calculated as M+(C24H22N3O2) requires m/z 384.1707, actual value 384.1699.
Example 15
The synthesis method of the polysubstituted pyrazole compound comprises the following steps:
exchanging air 3 times with nitrogen in a 25mL tube reactor; will be provided with
(0.05mmol，10.6mg)，
(0.10mmol, 23.0mg), triethylamine (0.10mmol, 10.1mg) and DMAP (0.005mmol, 1.2mg) were weighed in order into a reaction tube, evacuated to exchange nitrogen, and 0.3mL of dichloromethane was added under nitrogen atmosphere; reacting the reaction system at room temperature for 72 hours; after the TCL detection reaction is finished, directly adding silica gel, and performing spin-drying column chromatography to obtain a white solid
(yield 74%).
1H NMR(CDCl3,500MHz):δ(ppm)8.57(d,J＝10.0Hz,1H),7.86(s,1H),7.68(d,J＝10.0Hz,2H),7.53-7.52(m,4H),7.47-7.44(m,4H),7.27-7.21(m,2H),2.67(s,3H).13CNMR (CDCl3,125MHz) < delta > (ppm)162.2,150.6,144.4,138.7,135.0,132.0,129.6,129.3,129.3,129.1,129.0,128.7,127.5,125.7,124.1,122.3,121.0,114.1,12.5 HRMS (ESI) < calculated value M+(C23H19ClN3O) requires m/z388.1211, practical value 388.1204。
Example 16
The synthesis method of the polysubstituted pyrazole compound comprises the following steps:
exchanging air 3 times with nitrogen in a 25mL tube reactor; will be provided with
(0.05mmol，12.0mg)，
(0.10mmol, 23.0mg), triethylamine (0.10mmol, 10.1mg) and DMAP (0.005mmol, 1.2mg) were weighed in order into a reaction tube, evacuated to exchange nitrogen, and 0.3mL of dichloromethane was added under nitrogen atmosphere; reacting the reaction system at room temperature for 72 hours; after the TCL detection reaction is finished, directly adding silica gel, and performing spin-drying column chromatography to obtain a white solid
(yield 90%).
1H NMR(CDCl3,500MHz):δ(ppm)7.87(d,J＝10.0Hz,2H),7.49-7.44(m,3H),7.40-7039(m,5H),7.32-7.31(m,5H),7.24-7.19(m,4H),7.11(s,1H),7.06-7.04(m,1H).13CNMR(CDCl3125 MHz. delta. (ppm)161.6,151.0,144.1,139.2,137.7,132.1,130.2,129.4,128.9, 128.8,128.7, 127.9,125.4,124.2,119.7,116.2 HRMS (ESI) calculated as M+(C28H22N3O) requires m/z416.1757, with an actual value of 416.1746.
Example 17
The synthesis method of the polysubstituted pyrazole compound comprises the following steps:
exchanging air 3 times with nitrogen in a 25mL tube reactor; will be provided with
(0.05mmol，11.2mg)，
(0.10mmol, 23.0mg), triethylamine (0.10mmol, 1)0.1mg) and DMAP (0.005mmol, 1.2mg) were sequentially weighed into a reaction tube, evacuated to exchange nitrogen, and 0.3mL of dichloromethane was added under nitrogen atmosphere; reacting the reaction system at room temperature for 72 hours; after the TCL detection reaction is finished, directly adding silica gel, and performing spin-drying column chromatography to obtain a white solid
(yield 97%).
1H NMR(CDCl3,500MHz):δ(ppm)7.76(d,J＝5.0Hz,2H),7.63(d,J＝5.0Hz,2H),7.35-7.32(m,6H),7.27-7.26(m,3H),7.21-7.18(m,7H).13CNMR(CDCl3125 MHz. delta. (ppm)192.7,151.9,144.5,139.3,137.8,132.9,132.2,130.1,129.9,128.9, 128.3,128.2,128.1,127.8,125.4,119.9 HRMS (ESI): calculated M+(C28H21N2O) requires m/z 401.1648, with an actual value of 401.1642.
Example 18
The synthesis method of the polysubstituted pyrazole compound comprises the following steps:
exchanging air 3 times with nitrogen in a 25mL tube reactor; will be provided with
(0.05mmol，5.0mg)，
(0.10mmol, 23.0mg), triethylamine (0.10mmol, 10.1mg) and DMAP (0.005mmol, 1.2mg) were weighed in order into a reaction tube, evacuated to exchange nitrogen, and 0.3mL of dichloromethane was added under nitrogen atmosphere; reacting the reaction system at room temperature for 72 hours; after the TCL detection reaction is finished, directly adding silica gel, and performing spin-drying column chromatography to obtain a white solid
(yield 79%).
1H NMR(CDCl3,500MHz):δ(ppm)7.55(d,J＝5.0Hz,2H),7.51-7.49(m,4H),7.46-7.44(m 4H),2.56(s,3H),2.13(s,3H).13CNMR(CDCl3,125MHz is delta (ppm)195.9, 153.3, 143.7, 138.5, 133.7, 129.4, 129.2, 128.7,128.4, 127.0, 125.7, 120.5, 30.8, 12.8 HRMS (ESI)+(C18H17N2O) requires m/z 277.1335, with an actual value of 277.1329.
Example 19
The synthesis method of the polysubstituted pyrazole compound comprises the following steps:
exchanging air 3 times with nitrogen in a 25mL tube reactor; will be provided with
(0.05mmol，10.3mg)，
(0.10mmol, 23.0mg), triethylamine (0.10mmol, 10.1mg) and DMAP (0.005mmol, 1.2mg) were weighed in order into a reaction tube, evacuated to exchange nitrogen, and 0.3mL of dichloromethane was added under nitrogen atmosphere; reacting the reaction system at room temperature for 72 hours; after the TCL detection reaction is finished, directly adding silica gel, and performing spin-drying column chromatography to obtain a white solid
(yield 92%).
1H NMR(CDCl3,500MHz):δ(ppm)7.72(d,J＝10.0Hz,2H),7.54-7.49(m,3H),7.48-7.46(m,2H),7.44-7.41(m,3H),7.29-7.28(m,4H),7.19(s,1H),7.09(s,1H),3.33-3.27(m,1H),1.43(s,3H),1.41(s,3H).13CNMR(CDCl3125 MHz. delta. (ppm)162.9,151.9,150.0,139.5,137.9,132.2,129.2,129.1,128.9,128.8,128.8,128.8,126.8,124.3,119.8,113.8,26.7,21.1.HRMS (ESI) calculated as M+(C25H24N3O) requires m/z 382.1914, with an actual value of 382.1907.
The embodiments in the present description are described in a progressive manner, each embodiment focuses on differences from other embodiments, and the same and similar parts among the embodiments are referred to each other. The device disclosed by the embodiment corresponds to the method disclosed by the embodiment, so that the description is simple, and the relevant points can be referred to the method part for description.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (2)
1. A method for synthesizing a polysubstituted pyrazole compound is characterized by comprising the following steps:
step 1), reacting the starting compound (1)
And compound (2) is
、
、
Or
Mixing and adding the mixture into a reactor, and adding the mixture into the reactor,
step 2), adding Lewis base catalyst, adding solvent for reaction at the reaction temperature of 20-80 ℃ for 72 hours to obtain
、
、
、
；
The Lewis base catalyst is DMAP and triethylamine;
the molar ratio of the compound (1) to the compound (2) is 1: 2;
the amount of DMAP is 10mol% of the molar amount of the compound (1), the amount of triethylamine is 2 times of the molar amount of the compound (1), and the solvent is dichloromethane.
2. The method for synthesizing multi-substituted pyrazole compounds according to claim 1,
mixing the reaction raw material compound (1) and the compound (2) and adding the mixture into a reactor, and exchanging air with nitrogen for three times; after the compound (1), the compound (2) and the Lewis base catalyst are added into the reactor, evacuating and exchanging nitrogen, and adding a reaction solvent in a nitrogen atmosphere; after the reaction is finished, adding silica gel into the reactor, and performing spin-drying column chromatography to obtain the polysubstituted pyrazole compound.
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| An Efficient Entry to Perfluoroalkyl Substituted Azoles Starting from β-Perfluoroalkyl-β-dicarbonyl Compounds;Pierfrancesco Bravo et al.;《Tetrahedron》;19941231;第50卷(第29期);第8827-8836页 * |
| Reaction of benzonitrilium N-phenylimide with (Z)-4-arylmethyleneimidazol-5(4H)-ones;Abdallah M. A. et al.;《Indian Journal of Chemistry》;20010331;第40B卷;第187-190页 * |
| Regioselective [3+2]-annulation of hydrazonyl chlorides with 1,3-dicarbonyl compounds for assembling of polysubstituted pyrazoles;Kun Liu et al.;《Organic &Biomolecular Chemistry》;20181011;第16卷;第7811-7814页 * |
| The Regioselectivity in the Formation of Pyrazolines and Pyrazoles from Nitrile Imines;Hassaneen H.M. et al.;《J. Heterocyclic Chem.》;19841231;第21卷;第1013-1016页 * |
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