CN116675643A - Synthesis method of polysubstituted pyrazole compound - Google Patents
Synthesis method of polysubstituted pyrazole compound Download PDFInfo
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- CN116675643A CN116675643A CN202310540837.4A CN202310540837A CN116675643A CN 116675643 A CN116675643 A CN 116675643A CN 202310540837 A CN202310540837 A CN 202310540837A CN 116675643 A CN116675643 A CN 116675643A
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- -1 polysubstituted pyrazole compound Chemical class 0.000 title claims abstract description 73
- 238000001308 synthesis method Methods 0.000 title claims abstract description 6
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical class O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 19
- 238000000926 separation method Methods 0.000 claims abstract description 17
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 238000000746 purification Methods 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 138
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 95
- 238000006243 chemical reaction Methods 0.000 claims description 70
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 52
- 239000002904 solvent Substances 0.000 claims description 52
- 239000003208 petroleum Substances 0.000 claims description 46
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 31
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 26
- 238000001704 evaporation Methods 0.000 claims description 24
- 238000010898 silica gel chromatography Methods 0.000 claims description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 6
- 125000003609 aryl vinyl group Chemical group 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 239000000741 silica gel Substances 0.000 claims description 4
- 229910002027 silica gel Inorganic materials 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 238000004440 column chromatography Methods 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 238000011068 loading method Methods 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- 238000001179 sorption measurement Methods 0.000 claims description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 abstract description 25
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 239000000758 substrate Substances 0.000 abstract description 4
- 239000003054 catalyst Substances 0.000 abstract description 3
- 229910052751 metal Inorganic materials 0.000 abstract description 3
- 239000002184 metal Substances 0.000 abstract description 3
- 238000006555 catalytic reaction Methods 0.000 abstract 1
- 230000007613 environmental effect Effects 0.000 abstract 1
- 239000000047 product Substances 0.000 description 47
- 239000003480 eluent Substances 0.000 description 44
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 43
- 238000002360 preparation method Methods 0.000 description 26
- 150000001875 compounds Chemical class 0.000 description 23
- 238000004809 thin layer chromatography Methods 0.000 description 23
- 239000012300 argon atmosphere Substances 0.000 description 22
- 239000012043 crude product Substances 0.000 description 22
- 238000004821 distillation Methods 0.000 description 22
- 230000008020 evaporation Effects 0.000 description 22
- 239000007788 liquid Substances 0.000 description 22
- 239000000463 material Substances 0.000 description 22
- 238000003756 stirring Methods 0.000 description 22
- 238000012512 characterization method Methods 0.000 description 21
- 150000003217 pyrazoles Chemical class 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 6
- 125000003226 pyrazolyl group Chemical group 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 238000005658 halogenation reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 101000851058 Homo sapiens Neutrophil elastase Proteins 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 230000002921 anti-spasmodic effect Effects 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000011918 double bond oxidative cleavage Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 102000052502 human ELANE Human genes 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 201000005249 lung adenocarcinoma Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- PQKSGWWAKCJGLT-UHFFFAOYSA-N phenyl(pyrazol-1-yl)methanone Chemical class C1=CC=NN1C(=O)C1=CC=CC=C1 PQKSGWWAKCJGLT-UHFFFAOYSA-N 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 description 1
- 239000003368 psychostimulant agent Substances 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- LDYNSPRLHCXFQC-UHFFFAOYSA-N styrene;sulfane Chemical compound S.C=CC1=CC=CC=C1 LDYNSPRLHCXFQC-UHFFFAOYSA-N 0.000 description 1
- ISXOBTBCNRIIQO-UHFFFAOYSA-N tetrahydrothiophene 1-oxide Chemical compound O=S1CCCC1 ISXOBTBCNRIIQO-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C07D231/16—Halogen atoms or nitro radicals
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a synthesis method of a polysubstituted pyrazole compound, and belongs to the field of organic synthesis. According to the invention, the pyrazole compound shown in the formula IV is obtained by using alkenyl sulfonium salt shown in the formula I, pyrazole shown in the formula II and halogenated succinimide (NIS, NBS, NCS) shown in the formula III as raw materials without metal catalysis. The method has the advantages of cheap and easily obtained raw materials, no need of using metal catalysts, environmental protection, no pollution, wide substrate range, higher yield, simple operation, easy separation and purification of products and the like.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a synthesis method of a polysubstituted pyrazole compound.
Background
Pyrazole is an important five-membered nitrogen-containing heterocyclic compound, widely exists in a plurality of natural products, bioactive molecules and drug molecules, and is also an important organic synthesis intermediate. Pyrazole has a variety of physiological effects including analgesic, anti-inflammatory, antipyretic, antiarrhythmic, sedative, muscle relaxing, psychostimulant, antispasmodic, antidiabetic and antibacterial effects. In recent years, it has been found that pyrazole compounds exhibit excellent anticancer activity, and that pyrazole amide compounds A and B shown below have excellent inhibitory effects on human colon cancer cells, breast cancer cells and lung adenocarcinoma cells, and N-benzoylpyrazole compounds C as small molecule inhibitors of human neutrophil elastase (NE inhibitors) (reference Igor A. Schepetkin, et al Journal of Medicinal Chemistry,2007, vol.50, no. 20). In view of the extremely important biological activity exhibited by pyrazoles, the development of efficient and mild methods for synthesizing pyrazoles has been a focus of attention of organic chemistry and pharmaceutical and agrochemical workers, and in particular, the creation of novel drugs and pesticides based on pyrazoles structures and the innovation of production process routes still have great potential and development space.
Furthermore, since the first synthesis of pyrazole compounds in 1883, synthetic routes to pyrazole rings are continually being developed. To date, there are two main strategies for the synthesis of pyrazoles: firstly, various pyrazole compounds are constructed through cyclization reaction, and then, direct functionalization on pyrazole rings is carried out. There is a great room for development of the latter, in particular for N-alkenylation-4-halogenation of the pyrazole ring, in comparison with the former. And N-alkenylation-4-halogenated pyrazole can be further derivatized through some classical reactions to obtain various polysubstituted pyrazole compounds such as pyrazole amides and pyrazole amine derivatives shown above.
Disclosure of Invention
Aiming at the condition that the existing synthetic route needs to pass through a complex process and reaction flow, the invention aims to provide a method for synthesizing an N-alkenylation-4-halogenated pyrazole compound, which is low in cost, environment-friendly, simple and convenient to operate, free of pollution and catalyst, wide in applicable substrate range, high in yield, simple to operate, easy to separate products and the like.
In order to achieve the above purpose, the invention adopts the following technical scheme:
an inorganic base-promoted synthesis method of a polysubstituted pyrazole compound, which takes aryl vinyl sulfonium salt shown in a formula I, a pyrazole compound shown in a formula II and halogenated succinimide (NIS, NBS, NCS) shown in a formula III as raw materials, and the polysubstituted pyrazole compound shown in a formula IV is obtained by reaction under the action of base;
wherein R is substituted or unsubstituted aryl, substituted by one or two substituents, and the substituents are: halogen, -SMe, C1-4 alkyl, halogenated C1-4 alkyl; r is R 1 Is H or phenyl; r is R 2 H, br, cl, phenyl; r is R 3 H, methyl and phenyl; r is R 4 Halogen (Cl, br, I).
In one embodiment of the invention, the aryl group is a benzene ring or a naphthalene ring.
In one embodiment of the invention, R is specifically selected from:
in one embodiment of the invention, the reaction is carried out in an organic solvent, in particular any one or more of toluene, acetonitrile, tetrahydrofuran.
In one embodiment of the invention, the base comprises potassium hydroxide, sodium hydride, cesium carbonate, or potassium t-butoxide.
In one embodiment of the present invention, the reaction temperature is 0℃to 60℃and the reaction time is 12 to 24 hours. The temperature of the further optional reaction is room temperature, and the time is 12-16 h.
In one embodiment of the invention, the ratio of the amounts of the aryl vinyl sulfonium salt shown in formula I, the pyrazole compound shown in formula II and the halogenated succinimide shown in formula III is 1.0 (1.0-2.0): 1.0-2.0.
In one embodiment of the present invention, the ratio of the amount of the arylvinyl sulfonium salt represented by formula I to the amount of the base substance is 1.0 (1.0 to 2.0).
In one embodiment of the invention, the amount of the organic solvent added is 2-10 mL/mmol based on the amount of the substance of the aryl vinyl sulfonium salt shown in formula I.
In one embodiment of the invention, the product is purified after the reaction using silica gel column chromatography separation.
The purification method comprises the following steps: after the reaction is finished, adding column chromatography silica gel, distilling under reduced pressure to remove the solvent, spin-drying until the silica gel adsorption product is in powder form, loading the powder on the column, eluting with (petroleum ether: ethyl acetate=20:1), collecting the powder, and evaporating and concentrating the powder to obtain the pyrazole compound.
The beneficial effects are that:
the invention aims to solve the problem that the prior art cannot effectively realize direct N-alkenylation-4-halogenation of a pyrazole ring, and the pyrazole compound is prepared by a method without a metal catalyst by using raw materials with low price and simple preparation. The method has the advantages of good position selectivity and high yield, and the prepared pyrazole compound has higher purity.
The N-alkenyl-4-halogenated polysubstituted pyrazole compound obtained by the invention can be used as an intermediate for derivatization to prepare a plurality of drug molecules with excellent biological activity. Such as NE inhibitors.
Detailed Description
The styrene sulfonium salt substrate related by the invention is prepared by the following steps:
25mL of methylene chloride, tetramethylene sulfoxide (11.0 mmol,1.1 g) was added to a 100mL reaction flask under argon or nitrogen, and the mixture was stirred at-40℃for 5 minutes, and then the corresponding substituted styrenic substrate (10.0 mmol) and trifluoromethanesulfonic anhydride (11.0 mmol,3.1 g) were added to the reaction system, followed by further reaction at-40℃for 30 minutes, and then the temperature was raised to 0℃for reaction, followed by TLC plate monitoring. After the reaction was completed, the solvent was removed under reduced pressure. Recrystallizing with dichloromethane and diethyl ether to obtain white solid, which is the corresponding styryl sulfonium salt.
The gram-grade synthesis route is as follows:
wherein R is:
example 1:
the pyrazole compound prepared in the example has the following structure:
the preparation method comprises the following steps: stirring magnet, styryl sulfonium salt (0.2 mmol,68.0 mg), pyrazole (0.3 mmol,20.5 mg), iodinated succinimide (0.24 mmol,54.0 mg), cesium carbonate (0.24 mmol, 78.4 mg) and 2mL THF solvent were sequentially added to a 10mL reaction tube under argon atmosphere, and reacted at room temperature for 12 hours. After the reaction, the solvent is removed by reduced pressure distillation, the crude product is subjected to silica gel column chromatography and separated, petroleum ether and ethyl acetate (petroleum ether: ethyl acetate=20:1) are used for eluting, a TLC (thin layer chromatography) plate is used for tracking and detecting, the eluent containing the target product is collected, the eluent containing the target product is combined, and the compound shown in the formula is obtained by evaporation and concentration, so that the yield is 83%. The material was a colorless oily liquid.
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 for C 11 H 10 N 2 I(M+H) + 296.9883,found 296.9880.
example 2:
the pyrazole compound prepared in the example has the following structure:
the preparation method comprises the following steps: stirring magnet, styryl sulfonium salt (0.2 mmol,77.8 mg), pyrazole (0.3 mmol,20.5 mg), iodinated succinimide (0.24 mmol,54.0 mg), cesium carbonate (0.24 mmol, 78.4 mg) and 2mL THF solvent were sequentially added to a 10mL reaction tube under argon atmosphere, and reacted at room temperature for 12 hours. After the reaction is finished, the solvent is removed by reduced pressure distillation, the crude product is subjected to silica gel column chromatography separation, petroleum ether and ethyl acetate (petroleum ether: ethyl acetate=20:1) are used for eluting, a TLC (thin layer chromatography) plate is used for tracking and detecting, the eluent containing the target product is collected, the eluent containing the target product is combined, and the compound shown in the formula is obtained by evaporation and concentration, so that the yield is 74%. The material was a colorless oily liquid.
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.HRMS m/z(ESI)calcd for C 12 H 11 N 2 ClI(M+H) + 344.9650,found 344.9653.
example 3:
the pyrazole compound prepared in the example has the following structure:
the preparation method comprises the following steps: stirring magnet, styryl sulfonium salt (0.2 mmol,74.7 mg), pyrazole (0.3 mmol,20.5 mg), iodinated succinimide (0.24 mmol,54.0 mg), cesium carbonate (0.24 mmol, 78.4 mg) and 2mL THF solvent were sequentially added to a 10mL reaction tube under argon atmosphere, and reacted at room temperature for 12 hours. After the reaction is finished, the solvent is removed by reduced pressure distillation, the crude product is subjected to silica gel column chromatography separation, petroleum ether and ethyl acetate (petroleum ether: ethyl acetate=20:1) are used for eluting, a TLC (thin layer chromatography) plate is used for tracking and detecting, the eluent containing the target product is collected, the eluent containing the target product is combined, and the compound shown in the formula is obtained by evaporation and concentration, so that the yield is 85%. The material was a colorless oily liquid.
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). 13 C 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 H 9 N 2 ClI(M+H) + 330.9493,found 330.9494.
example 4:
the pyrazole compound prepared in the example has the following structure:
the preparation method comprises the following steps: stirring magnet, styryl sulfonium salt (0.2 mmol,83.8 mg), pyrazole (0.3 mmol,20.5 mg), iodinated succinimide (0.24 mmol,54.0 mg), cesium carbonate (0.24 mmol, 78.4 mg) and 2mL THF solvent were sequentially added to a 10mL reaction tube under argon atmosphere, and reacted at room temperature for 12 hours. After the reaction is finished, the solvent is removed by reduced pressure distillation, the crude product is subjected to silica gel column chromatography separation, petroleum ether and ethyl acetate (petroleum ether: ethyl acetate=20:1) are used for eluting, a TLC (thin layer chromatography) plate is used for tracking and detecting, the eluent containing the target product is collected, the eluent containing the target product is combined, and the compound shown in the formula is obtained by evaporation and concentration, so that the yield is 75%. The material is colorless oily liquid
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 for C 11 H 9 N 2 BrI(M+H) + 374.8988,found 374.8990.
example 5:
the pyrazole compound prepared in the example has the following structure:
the preparation method comprises the following steps: stirring magnet, styryl sulfonium salt (0.2 mmol,93.3 mg), pyrazole (0.3 mmol,20.5 mg), iodinated succinimide (0.24 mmol,54.0 mg), cesium carbonate (0.24 mmol, 78.4 mg) and 2mL THF solvent were sequentially added to a 10mL reaction tube under argon atmosphere, and reacted at room temperature for 12 hours. After the reaction is finished, the solvent is removed by reduced pressure distillation, the crude product is subjected to silica gel column chromatography separation, petroleum ether and ethyl acetate (petroleum ether: ethyl acetate=20:1) are used for eluting, a TLC (thin layer chromatography) plate is used for tracking and detecting, the eluent containing the target product is collected, the eluent containing the target product is combined, and the compound shown in the formula is obtained by evaporation and concentration, so that the yield is 80%. The material was a colorless oily liquid.
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 for C 12 H 9 N 2 I 2 (M+H) + 422.8850,found 422.8845.
example 6:
the pyrazole compound prepared in the example has the following structure:
the preparation method comprises the following steps: stirring magnet, styryl sulfonium salt (0.2 mmol,81.6 mg), pyrazole (0.3 mmol,20.5 mg), iodinated succinimide (0.24 mmol,54.0 mg), cesium carbonate (0.24 mmol, 78.4 mg) and 2mL THF solvent were sequentially added to a 10mL reaction tube under argon atmosphere, and reacted at room temperature for 12 hours. After the reaction is finished, the solvent is removed by reduced pressure distillation, the crude product is subjected to silica gel column chromatography separation, petroleum ether and ethyl acetate (petroleum ether: ethyl acetate=20:1) are used for eluting, a TLC (thin layer chromatography) plate is used for tracking and detecting, the eluent containing the target product is collected, the eluent containing the target product is combined, and the compound shown in the formula is obtained by evaporation and concentration, so that the yield is 35%. The material was a colorless oily liquid.
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 for C 12 H 9 N 2 F 3 I(M+H) + 364.9757,found 364.9756.
example 7:
the pyrazole compound prepared in the example has the following structure:
the preparation method comprises the following steps: stirring magnet, styryl sulfonium salt (0.2 mmol,77.3 mg), pyrazole (0.3 mmol,20.5 mg), iodinated succinimide (0.24 mmol,54.0 mg), cesium carbonate (0.24 mmol, 78.4 mg) and 2mL THF solvent were sequentially added to a 10mL reaction tube under argon atmosphere, and reacted at room temperature for 12 hours. After the reaction is finished, the solvent is removed by reduced pressure distillation, the crude product is subjected to silica gel column chromatography separation, petroleum ether and ethyl acetate (petroleum ether: ethyl acetate=20:1) are used for eluting, a TLC (thin layer chromatography) plate is used for tracking and detecting, the eluent containing the target product is collected, the eluent containing the target product is combined, and the compound shown in the formula is obtained by evaporation and concentration, so that the yield is 75%. The material was a colorless oily liquid.
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 for C 12 H 12 N 2 IS(M+H) + 342.9760,found 342.9762.
example 8:
the pyrazole compound prepared in the example has the following structure:
the preparation method comprises the following steps: stirring magnet, styryl sulfonium salt (0.2 mmol,74.7 mg), pyrazole (0.3 mmol,20.5 mg), iodinated succinimide (0.24 mmol,54.0 mg), cesium carbonate (0.24 mmol, 78.4 mg) and 2mL THF solvent were sequentially added to a 10mL reaction tube under argon atmosphere, and reacted at room temperature for 12 hours. After the reaction, the solvent is removed by reduced pressure distillation, the crude product is subjected to silica gel column chromatography and separated, petroleum ether and ethyl acetate (petroleum ether: ethyl acetate=20:1) are used for eluting, a TLC (thin layer chromatography) plate is used for tracking and detecting, the eluent containing the target product is collected, the eluent containing the target product is combined, and the compound shown in the formula is obtained by evaporation and concentration, so that the yield is 81%. The material was a colorless oily liquid.
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 H 9 N 2 ClI(M+H) + 330.9493,found 330.9491.
example 9:
the pyrazole compound prepared in the example has the following structure:
the preparation method comprises the following steps: stirring magnet, styryl sulfonium salt (0.2 mmol,70.9 mg), pyrazole (0.3 mmol,20.5 mg), iodinated succinimide (0.24 mmol,54.0 mg), cesium carbonate (0.24 mmol, 78.4 mg) and 2mL THF solvent were sequentially added to a 10mL reaction tube under argon atmosphere, and reacted at room temperature for 12 hours. After the reaction is finished, the solvent is removed by reduced pressure distillation, the crude product is subjected to silica gel column chromatography separation, petroleum ether and ethyl acetate (petroleum ether: ethyl acetate=20:1) are used for eluting, a TLC (thin layer chromatography) plate is used for tracking and detecting, the eluent containing the target product is collected, the eluent containing the target product is combined, and the compound shown in the formula is obtained by evaporation and concentration, so that the yield is 73%. The material was a colorless oily liquid.
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). 13 C 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 N 2 I(M+H) + 311.0040,found 311.0041.
example 10:
the pyrazole compound prepared in the example has the following structure:
the preparation method comprises the following steps: stirring magnet, styryl sulfonium salt (0.2 mmol,83.9 mg), pyrazole (0.3 mmol,20.5 mg), iodinated succinimide (0.24 mmol,54.0 mg), cesium carbonate (0.24 mmol, 78.4 mg) and 2mL THF solvent were sequentially added to a 10mL reaction tube under argon atmosphere, and reacted at room temperature for 12 hours. After the reaction is finished, the solvent is removed by reduced pressure distillation, the crude product is subjected to silica gel column chromatography separation, petroleum ether and ethyl acetate (petroleum ether: ethyl acetate=20:1) are used for eluting, a TLC (thin layer chromatography) plate is used for tracking and detecting, the eluent containing the target product is collected, the eluent containing the target product is combined, and the compound shown in the formula is obtained by evaporation and concentration, so that the yield is 73%. The material was a colorless oily liquid.
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 for C 11 H 9 N 2 Br(M+H) + 374.8988,found 374.8988.
example 11:
the pyrazole compound prepared in the example has the following structure:
the preparation method comprises the following steps: stirring magnet, styryl sulfonium salt (0.2 mmol,73.7 mg), pyrazole (0.3 mmol,20.5 mg), iodinated succinimide (0.24 mmol,54.0 mg), cesium carbonate (0.24 mmol, 78.4 mg) and 2mL THF solvent were sequentially added to a 10mL reaction tube under argon atmosphere, and reacted at room temperature for 12 hours. After the reaction is finished, the solvent is removed by reduced pressure distillation, the crude product is subjected to silica gel column chromatography separation, petroleum ether and ethyl acetate (petroleum ether: ethyl acetate=20:1) are used for eluting, a TLC (thin layer chromatography) plate is used for tracking and detecting, the eluent containing the target product is collected, the eluent containing the target product is combined, and the compound shown in the formula is obtained by evaporation and concentration, so that the yield is 79%. The material was a colorless oily liquid.
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)calcd for C 13 H 14 N 2 I(M+H) + 325.0196,found 325.0195.
example 12:
the pyrazole compound prepared in the example has the following structure:
the preparation method comprises the following steps: stirring magnet, styryl sulfonium salt (0.2 mmol,90.5 mg), pyrazole (0.3 mmol,20.5 mg), iodinated succinimide (0.24 mmol,54.0 mg), cesium carbonate (0.24 mmol, 78.4 mg) and 2mL THF solvent were sequentially added to a 10mL reaction tube under argon atmosphere, and reacted at room temperature for 12 hours. After the reaction is finished, the solvent is removed by reduced pressure distillation, the crude product is subjected to silica gel column chromatography separation, petroleum ether and ethyl acetate (petroleum ether: ethyl acetate=20:1) are used for eluting, a TLC (thin layer chromatography) plate is used for tracking and detecting, the eluent containing the target product is collected, the eluent containing the target product is combined, and the compound shown in the formula is obtained by evaporation and concentration, so that the yield is 73%. The material was a colorless oily liquid.
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 N 2 I(M+H) + 409.1135,found 409.1132.
example 13:
the pyrazole compound prepared in the example has the following structure:
the preparation method comprises the following steps: stirring magnet, styryl sulfonium salt (0.2 mmol,81.9 mg), pyrazole (0.3 mmol,20.5 mg), iodinated succinimide (0.24 mmol,54.0 mg), cesium carbonate (0.24 mmol, 78.4 mg) and 2mL THF solvent were sequentially added to a 10mL reaction tube under argon atmosphere, and reacted at room temperature for 12 hours. After the reaction, the solvent is removed by reduced pressure distillation, the crude product is subjected to silica gel column chromatography and separated, petroleum ether and ethyl acetate (petroleum ether: ethyl acetate=20:1) are used for eluting, a TLC (thin layer chromatography) plate is used for tracking and detecting, the eluent containing the target product is collected, the eluent containing the target product is combined, and the compound shown in the formula is obtained by evaporation and concentration, so that the yield is 81%. The material was a colorless oily liquid.
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 H 8 N 2 Cl 2 I(M+H) + 364.9104,found 364.9108.
example 14:
the pyrazole compound prepared in the example has the following structure:
the preparation method comprises the following steps: stirring magnet, styryl sulfonium salt (0.2 mmol,78.1 mg), pyrazole (0.3 mmol,20.5 mg), iodinated succinimide (0.24 mmol,54.0 mg), cesium carbonate (0.24 mmol, 78.4 mg) and 2mL THF solvent were sequentially added to a 10mL reaction tube under argon atmosphere, and reacted at room temperature for 12 hours. After the reaction, the solvent is removed by reduced pressure distillation, the crude product is subjected to silica gel column chromatography and separated, petroleum ether and ethyl acetate (petroleum ether: ethyl acetate=20:1) are used for eluting, a TLC (thin layer chromatography) plate is used for tracking and detecting, the eluent containing the target product is collected, the eluent containing the target product is combined, and the compound shown in the formula is obtained by evaporation and concentration, and the yield is 71%. The material was a colorless oily liquid.
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 N 2 I(M+H) + 347.0040,found 347.0039.
example 15:
the pyrazole compound prepared in the example has the following structure:
the preparation method comprises the following steps: stirring magnet, styryl sulfonium salt (0.2 mmol,83.2 mg), pyrazole (0.3 mmol,20.5 mg), iodinated succinimide (0.24 mmol,54.0 mg), cesium carbonate (0.24 mmol, 78.4 mg) and 2mL THF solvent were sequentially added to a 10mL reaction tube under argon atmosphere, and reacted at room temperature for 12 hours. After the reaction is finished, the solvent is removed by reduced pressure distillation, the crude product is subjected to silica gel column chromatography separation, petroleum ether and ethyl acetate (petroleum ether: ethyl acetate=20:1) are used for eluting, a TLC (thin layer chromatography) plate is used for tracking and detecting, the eluent containing the target product is collected, the eluent containing the target product is combined, and the compound shown in the formula is obtained by evaporation and concentration, so that the yield is 73%. The material was a colorless oily liquid.
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 N 2 I(M+H) + 373.0196,found 373.0194.
example 16:
the pyrazole compound prepared in the example has the following structure:
the preparation method comprises the following steps: stirring magnet, styryl sulfonium 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 2mL THF solvent were sequentially added to a 10mL reaction tube under argon atmosphere, and reacted at room temperature for 12 hours. After the reaction is finished, the solvent is removed by reduced pressure distillation, the crude product is subjected to silica gel column chromatography separation, petroleum ether and ethyl acetate (petroleum ether: ethyl acetate=20:1) are used for eluting, a TLC (thin layer chromatography) plate is used for tracking and detecting, the eluent containing the target product is collected, the eluent containing the target product is combined, and the compound shown in the formula is obtained by evaporation and concentration, so that the yield is 68%. The material was a colorless oily liquid.
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 for C 11 H 10 N 2 Br(M+H) + 249.0022,found 249.0018.
example 17:
the pyrazole compound prepared in the example has the following structure:
the preparation method comprises the following steps: stirring magnet, styryl sulfonium 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 2mL of THF solvent were sequentially added to a 10mL reaction tube under argon atmosphere, and reacted at room temperature for 12 hours. After the reaction is finished, the solvent is removed by reduced pressure distillation, the crude product is subjected to silica gel column chromatography separation, petroleum ether and ethyl acetate (petroleum ether: ethyl acetate=20:1) are used for eluting, a TLC (thin layer chromatography) plate is used for tracking and detecting, the eluent containing the target product is collected, the eluent containing the target product is combined, and the compound shown in the formula is obtained by evaporation and concentration, so that the yield is 48%. The material was a colorless oily liquid.
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 for C 11 H 10 N 2 Cl(M+H) + 205.0527,found 205.0523.
example 18:
the pyrazole compound prepared in the example has the following structure:
the preparation method comprises the following steps: stirring magnet, styryl sulfonium salt (0.2 mmol,43.3 mg), pyrazole (0.3 mmol,20.5 mg), iodinated succinimide (0.24 mmol,54.0 mg), cesium carbonate (0.24 mmol, 78.4 mg) and 2mL THF solvent were sequentially added to a 10mL reaction tube under argon atmosphere, and reacted at room temperature for 12 hours. After the reaction, the solvent is removed by reduced pressure distillation, the crude product is subjected to silica gel column chromatography and separated, petroleum ether and ethyl acetate (petroleum ether: ethyl acetate=20:1) are used for eluting, a TLC (thin layer chromatography) plate is used for tracking and detecting, the eluent containing the target product is collected, the eluent containing the target product is combined, and the compound shown in the formula is obtained by evaporation and concentration, so that the yield is 81%. The material was a colorless oily liquid.
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). 13 C 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 N 2 I(M+H) + 373.0196,found 373.0196.
example 19:
the pyrazole compound prepared in the example has the following structure
The preparation method comprises the following steps: stirring magnet, styryl sulfonium salt (0.2 mmol,44.1 mg), pyrazole (0.3 mmol,20.5 mg), iodinated succinimide (0.24 mmol,54.0 mg), cesium carbonate (0.24 mmol, 78.4 mg) and 2mL THF solvent were sequentially added to a 10mL reaction tube under argon atmosphere, and reacted at room temperature for 12 hours. After the reaction, the solvent is removed by reduced pressure distillation, the crude product is subjected to silica gel column chromatography and separated, petroleum ether and ethyl acetate (petroleum ether: ethyl acetate=20:1) are used for eluting, a TLC (thin layer chromatography) plate is used for tracking and detecting, the eluent containing the target product is collected, the eluent containing the target product is combined, and the compound shown in the formula is obtained by evaporation and concentration, so that the yield is 91%. The material was a colorless oily liquid.
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 H 9 N 2 BrI(M+H) + 374.8988,found 374.8986.
example 20:
the pyrazole compound prepared in the example has the following structure:
the preparation method comprises the following steps: stirring magnet, styryl sulfonium salt (0.2 mmol,43.8 mg), pyrazole (0.3 mmol,20.5 mg), iodinated succinimide (0.24 mmol,54.0 mg), cesium carbonate (0.24 mmol, 78.4 mg) and 2mL THF solvent were sequentially added to a 10mL reaction tube under argon atmosphere, and reacted at room temperature for 12 hours. After the reaction, the solvent is removed by reduced pressure distillation, the crude product is subjected to silica gel column chromatography and separated, petroleum ether and ethyl acetate (petroleum ether: ethyl acetate=20:1) are used for eluting, a TLC (thin layer chromatography) plate is used for tracking and detecting, the eluent containing the target product is collected, the eluent containing the target product is combined, and the compound shown in the formula is obtained by evaporation and concentration, wherein the yield is 84%. The material was a colorless oily liquid.
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 for C 12 H 11 N 2 BrI(M+H) + 388.9145,found 388.9144.
example 21:
the pyrazole compound prepared in the example has the following structure:
the preparation method comprises the following steps: stirring magnet, styryl sulfonium salt (0.2 mmol,66.1 mg), pyrazole (0.3 mmol,20.5 mg), iodinated succinimide (0.24 mmol,54.0 mg), cesium carbonate (0.24 mmol, 78.4 mg) and 2mL THF solvent were sequentially added to a 10mL reaction tube under argon atmosphere, and reacted at room temperature for 12 hours. After the reaction is finished, the solvent is removed by reduced pressure distillation, the crude product is subjected to silica gel column chromatography separation, petroleum ether and ethyl acetate (petroleum ether: ethyl acetate=20:1) are used for eluting, a TLC (thin layer chromatography) plate is used for tracking and detecting, the eluent containing the target product is collected, the eluent containing the target product is combined, and the compound shown in the formula is obtained by evaporation and concentration, so that the yield is 32%. The material was a colorless oily liquid.
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)calcd for C 23 H 18 N 2 I(M+H) + 449.0509,found 449.0509.
example 22: influence of temperature
Referring to example 1, the temperature was merely replaced with other temperatures in table 1, and the results of the corresponding reactions are shown in table 1.
TABLE 1 influence of temperature on the preparation of pyrazoles
| Temperature (temperature) | Yields of pyrazoles |
| Room temperature (example 1) | 83％ |
| 60℃ | 60％ |
| 80℃ | ＜10％ |
Example 23: influence of alkali
Referring to example 1, cesium carbonate was merely replaced with other bases shown in table 2, and the other bases were unchanged, and the results of the corresponding reactions are shown in table 1.
TABLE 2 Effect of base on preparation of pyrazoles
| Alkali | Yields of pyrazoles |
| Cesium carbonate (example 1) | 83％ |
| t BuOK | 55％ |
| NaOH | 40％ |
Example 24: influence of solvent
Referring to example 1, only the solvent was replaced with tetrahydrofuran, and the other solvents shown in table 3 were replaced, and the results of the corresponding reactions were shown in table 3.
TABLE 3 influence of solvent selection on the preparation of pyrazoles
| Solvent(s) | Yields of pyrazoles |
| THF (example 1) | 83％ |
| DMF | trace |
| Toluene | 75％ |
Example 25: expansion of reaction atmosphere
Referring to example 1, the atmosphere was replaced with oxygen and air, respectively, and the results of the corresponding reactions were shown in table 4.
TABLE 4 influence of the reaction atmosphere on the preparation of pyrazoles
| Reaction atmosphere | Yields of pyrazoles |
| Argon (example 1) | 83％ |
| Air | 55％ |
| O 2 | 72％ |
Example 26: amplification reaction
Referring to example 1, stirring magnet, styryl sulfonium 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 50mL of THF solvent were sequentially added to a 100mL reaction tube under argon atmosphere, and reacted at room temperature for 12 hours. After the reaction, the solvent is removed by reduced pressure distillation, the crude product is subjected to silica gel column chromatography and separated, petroleum ether and ethyl acetate (petroleum ether: ethyl acetate=20:1) are used for eluting, a TLC (thin layer chromatography) plate is used for tracking and detecting, the eluent containing the target product is collected, the eluent containing the target product is combined, and the target compound is obtained by evaporation and concentration, so that the yield of the target compound is 79%. The material was a colorless oily liquid.
The N-alkenyl-4-halogenated polysubstituted pyrazole compound prepared by the method can be used as an intermediate to perform catalytic double bond oxidative cleavage to prepare the NE inhibitor shown in the corresponding formula V, and the process is as follows:
finally, it is noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications and equivalents may be made thereto without departing from the spirit and scope of the technical solution of the present invention, which is intended to be covered by the scope of the claims of the present invention.
Claims (10)
1. The synthesis method of the polysubstituted pyrazole compound promoted by inorganic alkali is characterized in that aryl vinyl sulfonium salt shown in a formula I, pyrazole compound shown in a formula II and halogenated succinimide shown in a formula III are taken as raw materials, and the polysubstituted pyrazole compound shown in a formula IV is obtained by reaction under the action of alkali;
wherein R is substituted or unsubstituted aryl, substituted by one or two substituents, and the substituents are: halogen, -SMe, C1-4 alkyl, halogenated C1-4 alkyl; r is R 1 Is H or phenyl; r is R 2 H, br, cl, phenyl; r is R 3 H, methyl and phenyl; r is R 4 Is halogen.
2. The method of claim 1, wherein the aryl group is a benzene ring or a naphthalene ring.
3. The method according to claim 1, wherein R is specifically selected from:
4. the process according to claim 1, wherein the reaction is carried out in an organic solvent, in particular any one or more of toluene, acetonitrile, tetrahydrofuran.
5. The method of claim 1, wherein the base comprises potassium hydroxide, sodium hydride, cesium carbonate, or potassium t-butoxide.
6. The method according to claim 1, wherein the reaction temperature is 0 ℃ to 60 ℃ and the reaction time is 12 to 24 hours.
7. The method according to claim 1, wherein the ratio of the amounts of the arylvinyl 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 to 2.0): 1.0 to 2.0.
8. The method according to claim 1, wherein the ratio of the amount of the aryl vinyl sulfonium salt represented by formula I to the amount of the base substance is 1.0 (1.0-2.0).
9. The method according to claim 1, wherein the amount of the organic solvent added is 2-10 mL/mmol based on the amount of the substance of the arylvinyl sulfonium salt represented by formula i.
10. The method of claim 1, wherein the product is purified after the reaction using silica gel column chromatography separation; the purification method comprises the following steps: and after the reaction is finished, adding column chromatography silica gel, distilling under reduced pressure to remove the solvent, spin-drying until the silica gel adsorption product is in a powder form, loading the powder into a column, eluting with petroleum ether and ethyl acetate, collecting the mixture, and evaporating and concentrating the mixture to obtain the pyrazole compound.
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