CN113372275A - Synthetic method of 3, 5-diaryl-4-trifluoromethyl pyrazole derivative - Google Patents
Synthetic method of 3, 5-diaryl-4-trifluoromethyl pyrazole derivative Download PDFInfo
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- 238000010189 synthetic method Methods 0.000 title description 2
- 239000002904 solvent Substances 0.000 claims abstract description 64
- 238000006243 chemical reaction Methods 0.000 claims abstract description 60
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 38
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 21
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000000758 substrate Substances 0.000 claims abstract description 15
- 239000003513 alkali Substances 0.000 claims abstract description 6
- 238000003756 stirring Methods 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 120
- 239000000706 filtrate Substances 0.000 claims description 64
- 238000001035 drying Methods 0.000 claims description 36
- 239000000047 product Substances 0.000 claims description 29
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 21
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 21
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 21
- 238000001914 filtration Methods 0.000 claims description 21
- 239000000741 silica gel Substances 0.000 claims description 21
- 229910002027 silica gel Inorganic materials 0.000 claims description 21
- 239000003480 eluent Substances 0.000 claims description 20
- 238000005406 washing Methods 0.000 claims description 18
- -1 aryl aldehyde Chemical class 0.000 claims description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 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 7
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 6
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 6
- 230000002194 synthesizing effect Effects 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 4
- 235000011009 potassium phosphates Nutrition 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 3
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 3
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 3
- 239000012044 organic layer Substances 0.000 claims description 3
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 3
- 238000002390 rotary evaporation Methods 0.000 claims description 3
- 238000010828 elution Methods 0.000 claims description 2
- 239000010410 layer Substances 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000001308 synthesis method Methods 0.000 abstract description 4
- 238000005265 energy consumption Methods 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 abstract description 3
- 150000003934 aromatic aldehydes Chemical class 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 38
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 29
- 239000003208 petroleum Substances 0.000 description 19
- 238000004809 thin layer chromatography Methods 0.000 description 19
- 238000001816 cooling Methods 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- 239000012295 chemical reaction liquid Substances 0.000 description 16
- FZFLTDNAHASQQC-RVDMUPIBSA-N n-[(e)-benzylideneamino]-4-methylbenzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N\N=C\C1=CC=CC=C1 FZFLTDNAHASQQC-RVDMUPIBSA-N 0.000 description 14
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 10
- 238000004293 19F NMR spectroscopy Methods 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- QXOVAGGCYWLSOP-UHFFFAOYSA-N 3,5-diphenyl-4-(trifluoromethyl)-1H-pyrazole Chemical compound FC(F)(F)c1c(n[nH]c1-c1ccccc1)-c1ccccc1 QXOVAGGCYWLSOP-UHFFFAOYSA-N 0.000 description 9
- KDEJQUNODYXYBJ-UHFFFAOYSA-N 4-(trifluoromethyl)-1h-pyrazole Chemical class FC(F)(F)C=1C=NNC=1 KDEJQUNODYXYBJ-UHFFFAOYSA-N 0.000 description 8
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 150000003217 pyrazoles Chemical class 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- HMAHQANPHFVLPT-UHFFFAOYSA-N 1,3,3-trifluoroprop-1-yne Chemical compound FC#CC(F)F HMAHQANPHFVLPT-UHFFFAOYSA-N 0.000 description 2
- VCKMQVMCOLQVOG-UHFFFAOYSA-N 5-(4-methoxyphenyl)-3-phenyl-4-(trifluoromethyl)-1H-pyrazole Chemical compound COc1ccc(cc1)-c1[nH]nc(c1C(F)(F)F)-c1ccccc1 VCKMQVMCOLQVOG-UHFFFAOYSA-N 0.000 description 2
- PYXNITNKYBLBMW-UHFFFAOYSA-N 5-(trifluoromethyl)-1h-pyrazole Chemical compound FC(F)(F)C1=CC=NN1 PYXNITNKYBLBMW-UHFFFAOYSA-N 0.000 description 2
- 229940126062 Compound A Drugs 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- IXRSTROMJFVSEH-UHFFFAOYSA-N FC(C1=C(C2=CC=CC=C2)NN=C1C(C=C1)=CC=C1Br)(F)F Chemical compound FC(C1=C(C2=CC=CC=C2)NN=C1C(C=C1)=CC=C1Br)(F)F IXRSTROMJFVSEH-UHFFFAOYSA-N 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 150000008049 diazo compounds Chemical class 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- OZDXFYDFLJPTAZ-UHFFFAOYSA-N 1-(2-chloro-3,3,3-trifluoroprop-1-enyl)-2-methylbenzene Chemical compound CC1=CC=CC=C1C=C(C(F)(F)F)Cl OZDXFYDFLJPTAZ-UHFFFAOYSA-N 0.000 description 1
- IPWGTQUIODPMCM-UHFFFAOYSA-N 1-(2-chloro-3,3,3-trifluoroprop-1-enyl)-3-methylbenzene Chemical compound CC1=CC(=CC=C1)C=C(C(F)(F)F)Cl IPWGTQUIODPMCM-UHFFFAOYSA-N 0.000 description 1
- GXJKGDWVLGKJNU-UHFFFAOYSA-N 1-(2-chloro-3,3,3-trifluoroprop-1-enyl)-4-methoxybenzene Chemical compound COC1=CC=C(C=C(Cl)C(F)(F)F)C=C1 GXJKGDWVLGKJNU-UHFFFAOYSA-N 0.000 description 1
- UYHTVWCKANUOED-UHFFFAOYSA-N 1-bromo-4-(2-chloro-3,3,3-trifluoroprop-1-enyl)benzene Chemical compound FC(F)(F)C(Cl)=CC1=CC=C(Br)C=C1 UYHTVWCKANUOED-UHFFFAOYSA-N 0.000 description 1
- YCOLGQXHSARNHD-UHFFFAOYSA-N 5-(2-methylphenyl)-3-phenyl-4-(trifluoromethyl)-1H-pyrazole Chemical compound Cc1ccccc1-c1[nH]nc(c1C(F)(F)F)-c1ccccc1 YCOLGQXHSARNHD-UHFFFAOYSA-N 0.000 description 1
- WKJPYDKAUDWKKO-UHFFFAOYSA-N 5-(4-fluorophenyl)-3-phenyl-4-(trifluoromethyl)-1H-pyrazole Chemical compound Fc1ccc(cc1)-c1[nH]nc(c1C(F)(F)F)-c1ccccc1 WKJPYDKAUDWKKO-UHFFFAOYSA-N 0.000 description 1
- NTTHOVXUOOXMMP-UHFFFAOYSA-N 5-(4-methylphenyl)-3-phenyl-4-(trifluoromethyl)-1H-pyrazole Chemical compound Cc1ccc(cc1)-c1[nH]nc(c1C(F)(F)F)-c1ccccc1 NTTHOVXUOOXMMP-UHFFFAOYSA-N 0.000 description 1
- KLXFXPNYTCIHLD-UHFFFAOYSA-N CC1=CC(C2=NNC(C3=CC=CC=C3)=C2C(F)(F)F)=CC=C1 Chemical compound CC1=CC(C2=NNC(C3=CC=CC=C3)=C2C(F)(F)F)=CC=C1 KLXFXPNYTCIHLD-UHFFFAOYSA-N 0.000 description 1
- WGEQPJXRQIBSAH-UHFFFAOYSA-N FC(C1=C(C(C=C2)=CC=C2Cl)NN=C1C1=CC=CC=C1)(F)F Chemical compound FC(C1=C(C(C=C2)=CC=C2Cl)NN=C1C1=CC=CC=C1)(F)F WGEQPJXRQIBSAH-UHFFFAOYSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001361 allenes Chemical class 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- 229940111134 coxibs Drugs 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 238000007033 dehydrochlorination reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 150000002429 hydrazines Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- TTZNQDOUNXBMJV-UHFFFAOYSA-N mavacoxib Chemical compound C1=CC(S(=O)(=O)N)=CC=C1N1C(C=2C=CC(F)=CC=2)=CC(C(F)(F)F)=N1 TTZNQDOUNXBMJV-UHFFFAOYSA-N 0.000 description 1
- 229950007241 mavacoxib Drugs 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000010327 methods by industry Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- BPJBUIWCUYKVNL-UHFFFAOYSA-N n-[(4-bromophenyl)methylideneamino]-4-methylbenzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NN=CC1=CC=C(Br)C=C1 BPJBUIWCUYKVNL-UHFFFAOYSA-N 0.000 description 1
- HAYVMYJAVSRNGS-UHFFFAOYSA-N n-[(4-chlorophenyl)methylideneamino]-4-methylbenzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NN=CC1=CC=C(Cl)C=C1 HAYVMYJAVSRNGS-UHFFFAOYSA-N 0.000 description 1
- OMBDHPYMTXWALU-UHFFFAOYSA-N n-[(4-fluorophenyl)methylideneamino]-4-methylbenzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NN=CC1=CC=C(F)C=C1 OMBDHPYMTXWALU-UHFFFAOYSA-N 0.000 description 1
- RTARYTGUYUAXBK-UHFFFAOYSA-N n-[(4-methoxyphenyl)methylideneamino]-4-methylbenzenesulfonamide Chemical compound C1=CC(OC)=CC=C1C=NNS(=O)(=O)C1=CC=C(C)C=C1 RTARYTGUYUAXBK-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 238000010957 regioselective [3+2] cycloaddition Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000001291 vacuum drying Methods 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
- C07D231/12—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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a synthesis method of a 3, 5-diaryl-4-trifluoromethyl pyrazole derivative, which comprises the following steps: aromatic aldehyde p-toluenesulfonylhydrazone and 2-chloro-3, 3, 3-trifluoroarylpropene are used as reaction substrates, potassium tert-butoxide is used as alkali, tetrahydrofuran is used as a solvent, and the reaction is carried out for 12 hours at 70 ℃ by stirring. The method has the advantages of simple and easily obtained raw materials, relatively mild reaction conditions, wide substrate universality, novel preparation process, less pollution, low energy consumption and the like.
Description
Technical Field
The invention relates to a preparation method of a 3, 5-diaryl-4-trifluoromethyl pyrazole derivative.
Background
Pyrazole is an important five-membered heterocyclic ring containing N atoms, pyrazole derivatives are important heterocyclic compounds, fluorine-containing pyrazole compounds are particularly widely applied to synthesis of natural products, medicaments, medicament intermediates, pesticides, materials and dyes, and particularly, the fluorine-containing pyrazole compounds are important motifs in bioactive compounds, so the fluorine-containing pyrazole compounds have important application and research values. For example, SC-560 as a lung cancer inhibitor, Celecoxib and Mavacoxib as COX-2 inhibitors: (Angew. Chem. Int. Ed. 2017, 568823-Org. Lett. 2020, 22(3), 809-813). Therefore, it is highly developedThe strategy of efficiently and conveniently constructing fluorine-containing pyrazole structures is receiving wide attention. With respect to the synthesis of 3-trifluoromethylpyrazole, it was reported early that acetylene or allene and a diazo compound were reacted as a substrate and metallic silver was reacted as a catalyst (Angew. Chem. Int. Ed. 2013, 526255-6258) or with 1, 3-diketones or alkynones as substrates, catalyzed by metallic copper, with hydrazines (Angew. Chem. Int. Ed. 2017, 568823-8827) to produce the series of 3-trifluoromethylpyrazoles. For the synthesis of 4-trifluoromethylpyrazole compounds, only the Tsui project group reports that alkyne hydrazone is first generated in situ by using alkyne aldehyde or alkyne ketone as a reaction substrate, and then is self-cyclized under the catalytic condition of metallic copper to generate 4-trifluoromethylpyrazole compounds (Org. Lett.2017, 19, 658-661). The method has the defects of multi-step reaction, complex operation, low metal catalytic economy and the like. There is therefore a great need for a versatile method for synthesizing them from readily available, simple compounds.
Disclosure of Invention
Aiming at the defects existing in the prior stage, the invention provides a synthesis method of a 3, 5-diaryl-4-trifluoromethyl pyrazole derivative by using aryl aldehyde p-toluenesulfonylhydrazone and 2-chloro-3, 3, 3-trifluoroarylpropene as reaction raw materials, and the synthesis method has the advantages of wide substrate application range, easily obtained raw materials, simple operation, high economy, safety and no pollution.
In order to achieve the purpose, the invention adopts the technical scheme that:
a method for synthesizing 3, 5-diaryl-4-trifluoromethyl pyrazole derivatives comprises the following steps: taking aryl aldehyde p-toluenesulfonylhydrazone and 2-chloro-3, 3, 3-trifluoroarylpropene as reaction substrates, potassium phosphate, cesium carbonate, potassium carbonate, sodium carbonate or potassium tert-butoxide as alkali, tetrahydrofuran, N-dimethylformamide, toluene, 1, 4-dioxane or dimethyl sulfoxide as a solvent, stirring at 70 ℃ for reaction for 12 hours, wherein the chemical reaction formula is as follows:
the-Ar is one of phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-bromophenyl, 2-methylphenyl and 3-methylphenyl;
and the-R is one of phenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorphenyl and 4-bromophenyl.
The preparation method adopted by the invention is that the aryl aldehyde p-toluenesulfonylhydrazone and the 2-chloro-3, 3, 3-trifluoroarylpropene react to synthesize the 4-trifluoromethylpyrazole derivative under the promotion of alkali, the process is simple, no special instrument or mode is needed, the method is very suitable for the operation of people in the field, and the method has the advantages of simple and convenient operation, easy product obtaining, safety, reliability and the like.
In a further embodiment of the invention, the base is potassium tert-butoxide.
In a further embodiment of the invention, the amount of potassium tert-butoxide is 3 equivalents.
In a further embodiment of the present invention, the solvent is tetrahydrofuran.
According to a further development of the invention, the molar ratio of the two substrates is 1: 1.2.
The method is further provided, after the reaction is finished, filtering is carried out, filtrate is washed by saturated sodium chloride solution, ethyl acetate is used for extracting and then dried by anhydrous magnesium sulfate, a combined organic layer is subjected to rotary evaporation by using a rotary evaporator, the solvent is removed to obtain a remainder, the remainder is subjected to column layer separation by using a silica gel column, elution is carried out by eluent, effluent containing a target product is collected, the effluent is combined, and the solvent is removed by vacuum concentration to obtain the target product.
The method can directly synthesize the target product, does not need to separate intermediate products, can obtain the target product only by stirring and reacting under normal pressure, greatly simplifies the process engineering, reduces the energy consumption and has excellent yield; in addition, the waste solution is less in the reaction process, and other polluted gases and liquid are not discharged, so that the method reduces the discharge of the waste solution, and has the advantages of protecting the environment and ensuring the health of operators; in addition, a series of 4-trifluoromethyl pyrazole derivatives can be prepared, and the method has better substrate universality. Therefore, the invention supplements the method for preparing the 4-trifluoromethyl pyrazole derivative at the present stage, promotes the development of the polysubstituted 4-trifluoromethyl pyrazole derivative and provides a powerful guarantee for developing the medicament containing the 4-trifluoromethyl pyrazole derivative.
The mechanism of the invention is as follows: first, dehydrochlorination of the substrate 1 under alkaline conditions leads to trifluoropropyne 3. At the same time, tosylhydrazone 2 decomposes in the presence of a base to form the diazonium compound A. Then, the diazo compound A and trifluoropropyne 3 undergo regioselective [3+2] cycloaddition reaction to obtain an intermediate B. And finally, carrying out 1, 3-hydrogen migration twice on the intermediate B to obtain a target product, wherein a possible reaction mechanism has the following chemical reaction formula:
Detailed Description
The invention discloses a synthesis method of a 3, 5-diaryl-4-trifluoromethyl pyrazole derivative, which takes aryl aldehyde p-toluenesulfonylhydrazone and 2-chloro-3, 3, 3-trifluoro aryl propylene as reaction substrates, potassium phosphate, cesium carbonate, potassium carbonate, sodium carbonate or potassium tert-butoxide as alkali, tetrahydrofuran, N-dimethylacetamide, toluene, 1, 4-dioxane or dimethyl sulfoxide as a solvent, and the reaction is stirred at 70 ℃ for 12 hours, wherein the chemical reaction formula is as follows:
the-Ar is one of phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-bromophenyl, 2-methylphenyl and 3-methylphenyl;
and the-R is one of phenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorphenyl and 4-bromophenyl.
After the reaction, filtration was performed, the filtrate was washed with a saturated sodium chloride solution, extracted with ethyl acetate and dried over anhydrous magnesium sulfate, and the combined organic layers were subjected to rotary evaporation using a rotary evaporator to remove the solvent to obtain a residue. Eluting the residue with silica gel column with petroleum ether and ethyl acetate at volume ratio (v: v), collecting eluate according to actual gradient, detecting by TLC, mixing eluates containing target product, removing solvent by rotary evaporator, and vacuum drying to obtain target product.
The first embodiment is as follows: 41.2 mg (0.2 mmol) of 2-chloro-3, 3, 3-trifluorophenylene, 65.8 mg (0.24 mmol) of benzaldehyde p-toluenesulfonylhydrazone, 67.3 mg (0.6 mmol) of potassium tert-butoxide are added to 3 ml of tetrahydrofuran as a solvent. The reaction was stirred at 70 ℃ for 12 hours. And cooling after the reaction is finished, filtering the reaction liquid to obtain a filtrate, washing the filtrate with a saturated sodium chloride solution, extracting with ethyl acetate, drying with anhydrous magnesium sulfate, removing the solvent from the filtrate by using a rotary evaporator to obtain a residue, eluting the residue through a silica gel column by using an eluent prepared from petroleum ether and ethyl acetate according to the volume ratio of 10:1, collecting the effluent according to the actual gradient, detecting by TLC (thin layer chromatography), combining the effluent containing the target product, removing the solvent from the combined effluent by using the rotary evaporator in a rotating manner, and drying in vacuum to obtain 40.3 mg of white solid 3, 5-diphenyl-4- (trifluoromethyl) -1H-pyrazole, wherein the yield is 70%.1H NMR (400 MHz, Acetone-d 6): δ 13.03 (s, 1H), 7.68 (d, J = 6.0 Hz, 4H), 7.52 - 7.50 (m, 6H); 13C NMR (125 MHz, Acetone-d 6): δ 148.2, 129.9, 129.7, 129.5, 129.3, 124.8 (q, J CF = 265.0 Hz), 107.1 (q, J CF = 35.6 Hz); 19F NMR (376 MHz, Acetone-d 6): δ -51.92 (s, 3F)。
The second embodiment is as follows: 44 mg (0.2 mmol) of 1- (2-chloro-3, 3, 3-trifluoro-1-propenyl) -4-toluene, 65.8 mg (0.24 mmol) of benzaldehyde p-toluenesulfonylhydrazone, 67.3 mg (0.6 mmol) of potassium tert-butoxide, are added to 3 ml of tetrahydrofuran as a solvent. The reaction was stirred at 70 ℃ for 12 hours. Cooling after the reaction is finished, filtering the reaction solution to obtain filtrate, washing the filtrate with saturated sodium chloride solution, extracting with ethyl acetate, drying with anhydrous magnesium sulfate, removing the solvent from the filtrate with a rotary evaporator to obtain residue, eluting the residue with an eluent prepared from petroleum ether and ethyl acetate according to the volume ratio of 10:1 through a silica gel column, collecting the effluent according to actual gradient, detecting by TLC, combining the effluent containing the target product, and purifying the eluate with a chromatographic columnThe combined effluents were rotary evaporated to remove the solvent and dried in vacuo to give 41 mg of 5-phenyl-3- (p-tolyl) -4- (trifluoromethyl) -1H-pyrazole as a white solid in 68% yield.1H NMR (400 MHz, Acetone-d 6): δ 12.84 (s, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.56 - 7.50 (m, 5H), 7.34 (d, J = 8.0 Hz, 2H), 2.41(s, 3H); 13C NMR (125 MHz, Acetone-d 6): δ 148.9, 139.9, 131.9, 129.9, 129.8, 129.6(1), 129.6(0), 129.5(1), 129.5(0), 129.2, 124.8 (q, J CF = 265.0 Hz), 106.8 (q, J CF= 36.2 Hz), 21.2; 19F NMR (376 MHz, Acetone-d 6): δ -51.92 (s, 3F)。
The third concrete embodiment: 44 mg (0.2 mmol) of 1- (2-chloro-3, 3, 3-trifluoro-1-propenyl) -2-methylbenzene, 65.8 mg (0.24 mmol) of benzaldehyde p-toluenesulfonylhydrazone, 67.3 mg (0.6 mmol) of potassium tert-butoxide are added to 3 ml of tetrahydrofuran as a solvent. The reaction was stirred at 70 ℃ for 12 hours. And cooling after the reaction is finished, filtering the reaction liquid to obtain a filtrate, washing the filtrate with a saturated sodium chloride solution, extracting with ethyl acetate, drying the filtrate with anhydrous magnesium sulfate, removing the solvent from the filtrate by using a rotary evaporator to obtain a residue, eluting the residue by using a silica gel column with an eluent prepared from petroleum ether and ethyl acetate according to the volume ratio of 10:1, collecting the effluent according to an actual gradient, detecting by TLC (thin layer chromatography), combining the effluent containing the target product, removing the solvent from the combined effluent by using the rotary evaporator in a rotating way, and drying in vacuum to obtain 37 mg of white solid 5-phenyl-3- (o-tolyl) -4- (trifluoromethyl) -1H-pyrazole, wherein the yield is 61%.1H NMR (500 MHz, Acetone-d 6): δ 12.87 (s, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.54 - 7.47 (m, 3H), 7.42 - 7.36 (m, 3H), 7.33 - 7.29 (m, 1H), 2.28 (s, 3H); 13C NMR (125 MHz, Acetone-d 6): δ 148.8, 146.9, 138.2, 132.1, 131.1, 130.8, 130.2, 129.7, 129.4, 129.4, 129.2, 126.3, 124.6 (q, J CF = 265.0 Hz), 108.3 (q, J CF = 35.0 Hz), 19.8; 19F NMR (376 MHz, Acetone-d 6): δ -53.07 (s, 3F)。
The fourth concrete embodiment: 44 mg (0.2 mmol) of 1- (2-chloro-3, 3, 3-trifluoro-1-propenyl) -3-methylbenzene, 65.8 mg (0.24 mmol) of benzaldehyde p-toluenesulfonylhydrazone, 67.3 mg (0.6 mmol) of potassium tert-butoxide are added to 3 ml of tetrahydrofuran as a solvent. The reaction was stirred at 70 ℃ for 12 hours. And cooling after the reaction is finished, filtering the reaction liquid to obtain a filtrate, washing the filtrate by using a saturated sodium chloride solution, extracting by using ethyl acetate, drying the filtrate by using anhydrous magnesium sulfate, removing the solvent from the filtrate by using a rotary evaporator to obtain a residue, eluting the residue by using a silica gel column by using an eluent prepared by using petroleum ether and ethyl acetate according to the volume ratio of 10:1, collecting effluent according to an actual gradient, combining the effluent containing the target product by TLC detection, rotatably removing the solvent from the combined effluent by using the rotary evaporator, and drying in vacuum to obtain 33 mg of white solid 5-phenyl-3- (m-tolyl) -4- (trifluoromethyl) -1H-pyrazole, wherein the yield is 54%.1H NMR (500 MHz, Acetone-d 6): δ 13.07 (s, 1H), 7.71-7.70 (m, 2H), 7.53-7.47 (m, 5H), 7.43-7.38 (m, 1H), 7.32-7.32 (m, 1H), 2.42 (s, 3H); 13C NMR (125 MHz, Acetone-d 6): δ 149.3, 148.9, 138.8, 131.3, 130.6, 130.2, 129.8, 129.6, 129.6, 129.2, 129.1, 126.8, 124.7 (q, J CF = 265.0 Hz), 107.0 (q, J CF = 36.3 Hz), 21.3; 19F NMR (376 MHz, Acetone-d 6): δ -51.88 (s, 3F)。
The fifth concrete embodiment: 47.2 mg (0.2 mmol) of 1- (2-chloro-3, 3, 3-trifluoro-1-propenyl) -4-methoxybenzene, 65.8 mg (0.24 mmol) of benzaldehyde p-toluenesulfonylhydrazone, 67.3 mg (0.6 mmol) of potassium tert-butoxide are added to 3 ml of tetrahydrofuran as a solvent. The reaction was stirred at 70 ℃ for 12 hours. Cooling after the reaction is finished, filtering the reaction solution to obtain filtrate, washing the filtrate with saturated sodium chloride solution, extracting with ethyl acetate, drying with anhydrous magnesium sulfate, removing the solvent from the filtrate with a rotary evaporator to obtain residues, eluting the residues with an eluent prepared from petroleum ether and ethyl acetate according to the volume ratio of 10:1 through a silica gel column, collecting the effluent according to the actual gradient, detecting by TLC, combining the effluent containing the target product, removing the solvent from the combined effluent by rotating the rotary evaporator, and drying in vacuum to obtain white pigment36 mg of 5-phenyl-3- (p-methoxyphenyl) -4- (trifluoromethyl) -1H-pyrazole as a colored solid in 56% yield.1H NMR (400 MHz, Acetone-d 6): δ 12.82 (s, 1H), 7.67 (d, J = 7.2 Hz, 2H), 7.60 (d, J = 8.8 Hz, 2H), 7.52-7.46 (m, 3H), 7.08 (d, J = 8.8 Hz, 2H), 3.87 (s,3H); 13C NMR (125 MHz, Acetone-d 6): δ 161.4, 149.2, 148.1, 132.1, 130.9, 129.7, 129.6, 129.2, 124.8 (q, J CF = 265.0 Hz), 123.3, 114.7, 106.6 (q, J CF = 35.0 Hz), 55.6; 19F NMR (376 MHz, Acetone-d 6): δ -51.99 (s, 3F)。
The sixth specific embodiment: 57 mg (0.2 mmol) of 1- (2-chloro-3, 3, 3-trifluoro-1-propenyl) -4-bromobenzene, 65.8 mg (0.24 mmol) of benzaldehyde p-toluenesulfonylhydrazone, 67.3 mg (0.6 mmol) of potassium tert-butoxide are added to 3 ml of tetrahydrofuran as a solvent. The reaction was stirred at 70 ℃ for 12 hours. And cooling after the reaction is finished, filtering the reaction liquid to obtain a filtrate, washing the filtrate with a saturated sodium chloride solution, extracting with ethyl acetate, drying the filtrate with anhydrous magnesium sulfate, removing the solvent from the filtrate with a rotary evaporator to obtain a residue, eluting the residue with an eluent prepared from petroleum ether and ethyl acetate according to the volume ratio of 10:1 through a silica gel column, collecting the effluent according to the actual gradient, detecting by TLC (thin layer chromatography), combining the effluent containing the target product, removing the solvent from the combined effluent by rotating the rotary evaporator, and drying in vacuum to obtain 35 mg of white solid 5-phenyl-3- (p-bromophenyl) -4- (trifluoromethyl) -1H-pyrazole, wherein the yield is 48%.1H NMR (500 MHz, Acetone-d 6): δ 13.08 (s, 1H), 7.72 - 7.62 (m, 6H), 7.55 - 7.48 (m, 3H); 13C NMR (125 MHz, Acetone-d 6): δ 148.6, 148.5, 132.5, 131.6, 131.0, 130.3, 130.2, 129.8, 129.4, 124.7 (q, J CF = 265.0 Hz), 123.8, 107.2 (q, J CF = 36.3 Hz); 19F NMR (376 MHz, Acetone-d 6): δ -52.04 (s, 3F)。
The seventh specific embodiment: 41.2 mg (0.2 mmol) of 2-chloro-3, 3, 3-trifluorophenylene, 73 mg (0.24 mmol) of p-methoxybenzaldehyde p-toluenesulfonylhydrazone, 67.3 mg (0) were added.6 mmol) of potassium tert-butoxide, in 3 ml of tetrahydrofuran as solvent. The reaction was stirred at 70 ℃ for 12 hours. And cooling after the reaction is finished, filtering the reaction liquid to obtain a filtrate, washing the filtrate by using a saturated sodium chloride solution, extracting by using ethyl acetate, drying by using anhydrous magnesium sulfate, removing the solvent from the filtrate by using a rotary evaporator to obtain a residue, eluting the residue by using a silica gel column by using an eluent prepared from petroleum ether and ethyl acetate according to the volume ratio of 10:1, collecting the effluent according to the actual gradient, detecting by using TLC (thin layer chromatography), combining the effluent containing the target product, removing the solvent from the combined effluent by using the rotary evaporator in a rotating way, and drying in vacuum to obtain 33 mg of white solid 3-phenyl-5- (p-methoxyphenyl) -4- (trifluoromethyl) -1H-pyrazole, wherein the yield is 52%.1H NMR (400 MHz, Acetone-d 6): δ 12.83 (s, 1H), 7.66 (d, J = 6.8 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.51 - 7.43 (m, 3H), 7.08 (d, J = 8.4 Hz, 2H), 3.87 (s, 3H); 13C NMR (125 MHz, Acetone-d 6): δ 161.4, 149.1, 147.9, 132.0, 130.9, 129.7, 129.6, 129.2, 124.8 (q, J CF = 264.8 Hz), 123.2, 114.7, 106.6 (q, J CF = 35.0 Hz), 55.6; 19F NMR (376 MHz, Acetone-d 6): δ -52.0 (s, 3F)。
The eighth embodiment: 41.2 mg (0.2 mmol) of 2-chloro-3, 3, 3-trifluorophenylene, 70 mg (0.24 mmol) of p-fluorobenzaldehyde p-toluenesulfonylhydrazone, and 67.3 mg (0.6 mmol) of potassium tert-butoxide were added to 3 ml of tetrahydrofuran as a solvent. The reaction was stirred at 70 ℃ for 12 hours. And cooling after the reaction is finished, filtering the reaction liquid to obtain a filtrate, washing the filtrate with a saturated sodium chloride solution, extracting with ethyl acetate, drying the filtrate with anhydrous magnesium sulfate, removing the solvent from the filtrate with a rotary evaporator to obtain a residue, eluting the residue with an eluent prepared from petroleum ether and ethyl acetate according to the volume ratio of 10:1 through a silica gel column, collecting the effluent according to the actual gradient, detecting by TLC (thin layer chromatography), combining the effluent containing the target product, removing the solvent from the combined effluent by rotating the rotary evaporator, and drying in vacuum to obtain 31 mg of white solid 3-phenyl-5- (p-fluorophenyl) -4- (trifluoromethyl) -1H-pyrazole, wherein the yield is 50%.1H NMR (400 MHz, Acetone-d 6): δ 13.00 (s, 1H), 7.74 - 7.66 (m, 4H), 7.52 - 7.48 (m, 3H), 7.32 - 7.26 (m, 2H); 13C NMR (125 MHz, Acetone-d 6): δ 164.1 (d, J CF = 246.0 Hz), 148.0, 131.8, 131.8, 130.7, 130.1, 129.7, 129.3, 127.8, 124.7 (q, J CF = 265.1 Hz), 116.2 (d, J CF = 21.6 Hz), 107.2 (q, J CF = 35.8 Hz); 19F NMR (376 MHz, Acetone-d 6): δ -52.1 (s, 3F), -115.04 (m, 1F)。
The specific embodiment is nine: 41.2 mg (0.2 mmol) of 2-chloro-3, 3, 3-trifluorophenylene, 74 mg (0.24 mmol) of p-chlorobenzaldehyde p-toluenesulfonylhydrazone, and 67.3 mg (0.6 mmol) of potassium tert-butoxide were added to 3 ml of tetrahydrofuran as a solvent. The reaction was stirred at 70 ℃ for 12 hours. And cooling after the reaction is finished, filtering the reaction liquid to obtain a filtrate, washing the filtrate with a saturated sodium chloride solution, extracting with ethyl acetate, drying the filtrate with anhydrous magnesium sulfate, removing the solvent from the filtrate with a rotary evaporator to obtain a residue, eluting the residue with an eluent prepared from petroleum ether and ethyl acetate according to the volume ratio of 10:1 through a silica gel column, collecting the effluent according to an actual gradient, detecting by TLC (thin layer chromatography), combining the effluent containing the target product, removing the solvent from the combined effluent by rotating the rotary evaporator, and drying in vacuum to obtain 33 mg of white solid 3-phenyl-5- (p-chlorophenyl) -4- (trifluoromethyl) -1H-pyrazole, wherein the yield is 51%.1H NMR (400 MHz, Acetone-d 6): δ 13.01 (s, 1H), 7.70 - 7.65 (m, 4H), 7.56 - 7.51 (m, 5H); 13C NMR (125 MHz, Acetone-d 6): δ 148.4, 147.7, 135.5, 131.2, 131.0, 130.6, 130.2, 129.7, 129.4, 129.3, 124.6 (q, J CF = 265.1 Hz), 107.2 (q, J CF = 36.0 Hz); 19F NMR (376 MHz, Acetone-d 6): δ -52.1 (s, 3F)。
The specific embodiment ten: 41.2 mg (0.2 mmol) of 2-chloro-3, 3, 3-trifluorophenylene, 84.5 mg (0.24 mmol) of p-bromobenzaldehyde p-toluenesulfonylhydrazone, and 67.3 mg (0.6 mmol) of potassium tert-butoxide were added to 3 ml of tetrahydrofuran as a solvent. The reaction was stirred at 70 ℃ for 12 hours. Cooling after the reaction is finished, and filtering the reaction liquid to obtainWashing the filtrate with saturated sodium chloride solution, extracting with ethyl acetate, drying with anhydrous magnesium sulfate, removing the solvent from the filtrate with a rotary evaporator to obtain a residue, eluting the residue with an eluent prepared from petroleum ether and ethyl acetate according to a volume ratio of 10:1 through a silica gel column, collecting the effluent according to an actual gradient, detecting by TLC, combining the effluent containing the target product, removing the solvent from the combined effluent by rotating the rotary evaporator, and drying in vacuum to obtain 35 mg of white solid 3-phenyl-5- (p-bromophenyl) -4- (trifluoromethyl) -1H-pyrazole, wherein the yield is 48%.1H NMR (400 MHz, DMSO-d 6): δ 13.99(s, 1H), 7.72 (d, J = 7.6 Hz, 2H), 7.59 - 7.51 (m, 7H); 13C NMR (125 MHz, Acetone-d 6): δ 148.2, 147.8, 132.4, 131.6, 131.5, 130.5, 130.2, 129.7, 129.4, 124.6 (q, J CF = 265.1 Hz), 123.7, 107.2 (q, J CF = 35.8 Hz); 19F NMR (376 MHz, Acetone-d 6): δ -52.06 (s, 3F)。
The first specific embodiment: 41.2 mg (0.2 mmol) of 2-chloro-3, 3, 3-trifluorophenylene, 65.8 mg (0.24 mmol) of benzaldehyde p-toluenesulfonylhydrazone, 67.3 mg (0.6 mmol) of potassium tert-butoxide are added to 3 ml of a solvent, N-dimethylformamide. The reaction was stirred at 70 ℃ for 12 hours. And cooling after the reaction is finished, filtering the reaction liquid to obtain a filtrate, washing the filtrate with a saturated sodium chloride solution, extracting with ethyl acetate, drying with anhydrous magnesium sulfate, removing the solvent from the filtrate by using a rotary evaporator to obtain a residue, eluting the residue through a silica gel column by using an eluent prepared from petroleum ether and ethyl acetate according to the volume ratio of 10:1, collecting the effluent according to the actual gradient, detecting by TLC (thin layer chromatography), combining the effluent containing the target product, removing the solvent from the combined effluent by using the rotary evaporator in a rotating manner, and drying in vacuum to obtain 25.9 mg of white solid 3, 5-diphenyl-4- (trifluoromethyl) -1H-pyrazole, wherein the yield is 45%.
The specific example twelve: 41.2 mg (0.2 mmol) of 2-chloro-3, 3, 3-trifluorophenylene, 65.8 mg (0.24 mmol) of benzaldehyde p-toluenesulfonylhydrazone, 67.3 mg (0.6 mmol) of potassium tert-butoxide are added to 3 ml of dimethyl sulfoxide as a solvent. The reaction was stirred at 70 ℃ for 12 hours. And cooling after the reaction is finished, filtering the reaction liquid to obtain a filtrate, washing the filtrate with a saturated sodium chloride solution, extracting with ethyl acetate, drying with anhydrous magnesium sulfate, removing the solvent from the filtrate by using a rotary evaporator to obtain a residue, eluting the residue through a silica gel column by using an eluent prepared from petroleum ether and ethyl acetate according to the volume ratio of 10:1, collecting the effluent according to the actual gradient, detecting by TLC (thin layer chromatography), combining the effluent containing the target product, removing the solvent from the combined effluent by using the rotary evaporator in a rotating manner, and drying in vacuum to obtain 27.6 mg of white solid 3, 5-diphenyl-4- (trifluoromethyl) -1H-pyrazole, wherein the yield is 48%.
The specific example thirteen: 41.2 mg (0.2 mmol) of 2-chloro-3, 3, 3-trifluorophenylene, 65.8 mg (0.24 mmol) of benzaldehyde p-toluenesulfonylhydrazone, 67.3 mg (0.6 mmol) of potassium tert-butoxide are added to 3 ml of toluene as a solvent. The reaction was stirred at 70 ℃ for 12 hours. And cooling after the reaction is finished, filtering the reaction liquid to obtain a filtrate, washing the filtrate with a saturated sodium chloride solution, extracting with ethyl acetate, drying with anhydrous magnesium sulfate, removing the solvent from the filtrate by using a rotary evaporator to obtain a residue, eluting the residue through a silica gel column by using an eluent prepared from petroleum ether and ethyl acetate according to the volume ratio of 10:1, collecting the effluent according to the actual gradient, detecting by TLC (thin layer chromatography), combining the effluent containing the target product, removing the solvent from the combined effluent by using the rotary evaporator in a rotating manner, and drying in vacuum to obtain 30.0 mg of white solid 3, 5-diphenyl-4- (trifluoromethyl) -1H-pyrazole, wherein the yield is 52%.
The specific embodiment fourteen: 41.2 mg (0.2 mmol) of 2-chloro-3, 3, 3-trifluorophenylene, 65.8 mg (0.24 mmol) of benzaldehyde p-toluenesulfonylhydrazone, 67.3 mg (0.6 mmol) of potassium tert-butoxide are added to 3 ml of a solvent, 1, 4-dioxane. The reaction was stirred at 70 ℃ for 12 hours. And cooling after the reaction is finished, filtering the reaction liquid to obtain a filtrate, washing the filtrate with a saturated sodium chloride solution, extracting with ethyl acetate, drying the filtrate with anhydrous magnesium sulfate, removing the solvent from the filtrate with a rotary evaporator to obtain a residue, eluting the residue with an eluent prepared from petroleum ether and ethyl acetate according to the volume ratio of 10:1 through a silica gel column, collecting the effluent according to the actual gradient, detecting by TLC (thin layer chromatography), combining the effluent containing the target product, removing the solvent from the combined effluent by rotating the rotary evaporator, and drying in vacuum to obtain 25.3 mg of white solid 3, 5-diphenyl-4- (trifluoromethyl) -1H-pyrazole, wherein the yield is 44%.
The specific embodiment fifteen: 41.2 mg (0.2 mmol) of 2-chloro-3, 3, 3-trifluorophenylene, 65.8 mg (0.24 mmol) of benzaldehyde p-toluenesulfonylhydrazone, 63.6 mg (0.6 mmol) of sodium carbonate were added to 3 ml of tetrahydrofuran solvent. The reaction was stirred at 70 ℃ for 12 hours. And cooling after the reaction is finished, filtering the reaction liquid to obtain a filtrate, washing the filtrate with a saturated sodium chloride solution, extracting with ethyl acetate, drying the filtrate with anhydrous magnesium sulfate, removing the solvent from the filtrate with a rotary evaporator to obtain a residue, eluting the residue with an eluent prepared from petroleum ether and ethyl acetate according to the volume ratio of 10:1 through a silica gel column, collecting the effluent according to the actual gradient, detecting by TLC (thin layer chromatography), combining the effluent containing the target product, removing the solvent from the combined effluent by rotating the rotary evaporator, and drying in vacuum to obtain 19.0 mg of white solid 3, 5-diphenyl-4- (trifluoromethyl) -1H-pyrazole, wherein the yield is 33%.
The specific embodiment is sixteen: 41.2 mg (0.2 mmol) of 2-chloro-3, 3, 3-trifluorophenylene, 65.8 mg (0.24 mmol) of benzaldehyde p-toluenesulfonylhydrazone, and 82.9 mg (0.6 mmol) of potassium carbonate were added to 3 ml of tetrahydrofuran solvent. The reaction was stirred at 70 ℃ for 12 hours. And cooling after the reaction is finished, filtering the reaction liquid to obtain a filtrate, washing the filtrate with a saturated sodium chloride solution, extracting with ethyl acetate, drying with anhydrous magnesium sulfate, removing the solvent from the filtrate by using a rotary evaporator to obtain a residue, eluting the residue through a silica gel column by using an eluent prepared from petroleum ether and ethyl acetate according to the volume ratio of 10:1, collecting the effluent according to the actual gradient, detecting by TLC (thin layer chromatography), combining the effluent containing the target product, removing the solvent from the combined effluent by using the rotary evaporator in a rotating manner, and drying in vacuum to obtain 20.7 mg of white solid 3, 5-diphenyl-4- (trifluoromethyl) -1H-pyrazole, wherein the yield is 36%.
Specific example seventeen: 41.2 mg (0.2 mmol) of 2-chloro-3, 3, 3-trifluorophenylene, 65.8 mg (0.24 mmol) of benzaldehyde p-toluenesulfonylhydrazone, and 127.4 mg (0.6 mmol) of potassium phosphate were added to 3 ml of tetrahydrofuran solvent. The reaction was stirred at 70 ℃ for 12 hours. And cooling after the reaction is finished, filtering the reaction liquid to obtain a filtrate, washing the filtrate with a saturated sodium chloride solution, extracting with ethyl acetate, drying the filtrate with anhydrous magnesium sulfate, removing the solvent from the filtrate with a rotary evaporator to obtain a residue, eluting the residue with an eluent prepared from petroleum ether and ethyl acetate according to the volume ratio of 10:1 through a silica gel column, collecting the effluent according to the actual gradient, detecting by TLC (thin layer chromatography), combining the effluent containing the target product, removing the solvent from the combined effluent by rotating the rotary evaporator, and drying in vacuum to obtain 21.9 mg of white solid 3, 5-diphenyl-4- (trifluoromethyl) -1H-pyrazole, wherein the yield is 38%.
The specific embodiment eighteen: 41.2 mg (0.2 mmol) of 2-chloro-3, 3, 3-trifluorophenylene, 65.8 mg (0.24 mmol) of benzaldehyde p-toluenesulfonylhydrazone, and 195.5 mg (0.6 mmol) of cesium carbonate were added to 3 ml of tetrahydrofuran solvent. The reaction was stirred at 70 ℃ for 12 hours. And cooling after the reaction is finished, filtering the reaction liquid to obtain a filtrate, washing the filtrate with a saturated sodium chloride solution, extracting with ethyl acetate, drying with anhydrous magnesium sulfate, removing the solvent from the filtrate by using a rotary evaporator to obtain a residue, eluting the residue through a silica gel column by using an eluent prepared from petroleum ether and ethyl acetate according to the volume ratio of 10:1, collecting the effluent according to the actual gradient, detecting by TLC (thin layer chromatography), combining the effluent containing the target product, removing the solvent from the combined effluent by using the rotary evaporator in a rotating manner, and drying in vacuum to obtain 25.9 mg of white solid 3, 5-diphenyl-4- (trifluoromethyl) -1H-pyrazole, wherein the yield is 45%.
In the embodiment of the invention, 2-chloro-3, 3, 3-trifluoroarylpropene and aryl aldehyde p-toluenesulfonylhydrazone are used as reaction substrates, potassium tert-butoxide is used as alkali, tetrahydrofuran is used as a solvent, and the reaction is carried out for 12 hours at 70 ℃ by stirring. In the first to sixth examples, Ar in 2-chloro-3, 3, 3-trifluoroarylpropene is substituted by different substituents as variables, and in the seventh to tenth examples, R in arylaldehyde p-toluenesulfonylhydrazone is substituted by different substituents as variables, it is noted that the substituent with strong electron-withdrawing property and alkyl on phenyl can be well used by the method of the present invention. Examples eleven to fourteen are variables of solvent; examples fifteen to eighteen are with base as variable.
According to the invention, the intermediate product does not need to be separated, the target product can be directly synthesized by simple raw materials, the process is simplified, the energy consumption is low, the waste solution discharge is reduced, the environmental pollution is reduced, and the yield reaches 70% at most; in the above examples, 2-chloro-3, 3, 3-trifluoroarylpropene containing different substituents is selected to react with aryl aldehyde p-toluenesulfonylhydrazone to prepare a series of 4-trifluoromethylpyrazole derivatives, and the method has certain substrate universality and operation simplicity. The present invention is not limited to the above embodiments, and those skilled in the art can implement the present invention in other embodiments according to the disclosure of the present invention, or make simple changes or modifications on the design structure and idea of the present invention, and fall into the protection scope of the present invention.
Claims (6)
1. A method for synthesizing 3, 5-diaryl-4-trifluoromethyl pyrazole derivatives comprises the following steps: taking aryl aldehyde p-toluenesulfonylhydrazone and 2-chloro-3, 3, 3-trifluoroarylpropene as reaction substrates, potassium phosphate, cesium carbonate, potassium carbonate, sodium carbonate or potassium tert-butoxide as alkali, tetrahydrofuran, N-dimethylformamide, toluene, 1, 4-dioxane or dimethyl sulfoxide as a solvent, stirring at 70 ℃ for reaction for 12 hours, wherein the chemical reaction formula is as follows:
the-Ar is one of phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-bromophenyl, 2-methylphenyl and 3-methylphenyl;
and the-R is one of phenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorphenyl and 4-bromophenyl.
2. The method for synthesizing 3, 5-diaryl-4-trifluoromethylpyrazole derivatives according to claim 1, wherein: the base is potassium tert-butoxide.
3. The process for producing a 3, 5-diaryl-4-trifluoromethylpyrazole derivative according to claim 2, wherein: the amount of the potassium tert-butoxide used is 3 equivalents.
4. The method for synthesizing 3, 5-diaryl-4-trifluoromethylpyrazole derivatives according to claim 1, wherein: the solvent is tetrahydrofuran.
5. The process for producing a 3, 5-diaryl-4-trifluoromethylpyrazole derivative according to claim 1, wherein: the molar ratio of the two substrates was 1: 1.2.
6. The method for synthesizing 3, 5-diaryl-4-trifluoromethylpyrazole derivatives according to claim 1, wherein: and after the reaction is finished, filtering, washing the filtrate by using a saturated sodium chloride solution, extracting by using ethyl acetate, drying by using anhydrous magnesium sulfate, carrying out rotary evaporation on the combined organic layers by using a rotary evaporator to remove the solvent to obtain a residue, carrying out column layer separation on the residue by using a silica gel column, carrying out elution by using an eluent, collecting an effluent containing the target product, combining the effluent, and removing the solvent by vacuum concentration to obtain the target product.
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| CN115010575A (en) * | 2022-06-15 | 2022-09-06 | 温州大学 | Synthesis method of 2-trifluoromethyl naphthalene derivative |
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