CN114349703B - Trifluoromethyl-4-cyano pyrazole compound, and preparation method and application thereof - Google Patents
Trifluoromethyl-4-cyano pyrazole compound, and preparation method and application thereof Download PDFInfo
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- CN114349703B CN114349703B CN202210066364.4A CN202210066364A CN114349703B CN 114349703 B CN114349703 B CN 114349703B CN 202210066364 A CN202210066364 A CN 202210066364A CN 114349703 B CN114349703 B CN 114349703B
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- trifluoromethyl
- pyrazole
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- mmol
- nmr
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- -1 Trifluoromethyl-4-cyano pyrazole compound Chemical class 0.000 title claims abstract description 146
- 238000002360 preparation method Methods 0.000 title claims description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 47
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 23
- 239000003814 drug Substances 0.000 claims abstract description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 55
- 239000002585 base Substances 0.000 claims description 34
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 33
- 229910021607 Silver chloride Inorganic materials 0.000 claims description 33
- 239000003054 catalyst Substances 0.000 claims description 33
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 claims description 33
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 20
- KYPOHTVBFVELTG-UPHRSURJSA-N (z)-but-2-enedinitrile Chemical compound N#C\C=C/C#N KYPOHTVBFVELTG-UPHRSURJSA-N 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 18
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 claims description 18
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 235000011056 potassium acetate Nutrition 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 229910052751 metal Inorganic materials 0.000 claims description 9
- 239000002184 metal Substances 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 9
- 229910001923 silver oxide Inorganic materials 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 6
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 claims description 6
- 229940071536 silver acetate Drugs 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 claims description 4
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 4
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 4
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 4
- 229910001958 silver carbonate Inorganic materials 0.000 claims description 4
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 claims description 4
- 229940096017 silver fluoride Drugs 0.000 claims description 4
- REYHXKZHIMGNSE-UHFFFAOYSA-M silver monofluoride Chemical compound [F-].[Ag+] REYHXKZHIMGNSE-UHFFFAOYSA-M 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- WLXALCKAKGDNAT-UHFFFAOYSA-N diazoethane Chemical compound CC=[N+]=[N-] WLXALCKAKGDNAT-UHFFFAOYSA-N 0.000 claims description 3
- 238000006722 reduction reaction Methods 0.000 claims description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
- 238000005694 sulfonylation reaction Methods 0.000 claims description 3
- HNIRANRLHUHUOS-UHFFFAOYSA-N 5-(trifluoromethyl)-1h-pyrazole-4-carbonitrile Chemical class FC(F)(F)C=1NN=CC=1C#N HNIRANRLHUHUOS-UHFFFAOYSA-N 0.000 claims description 2
- 238000006193 diazotization reaction Methods 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 19
- 125000003118 aryl group Chemical group 0.000 abstract description 16
- 230000000694 effects Effects 0.000 abstract description 9
- 125000003358 C2-C20 alkenyl group Chemical group 0.000 abstract description 7
- 239000000758 substrate Substances 0.000 abstract description 5
- 238000012216 screening Methods 0.000 abstract description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 abstract description 4
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 116
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 72
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 60
- 238000003786 synthesis reaction Methods 0.000 description 56
- 230000015572 biosynthetic process Effects 0.000 description 55
- 238000004293 19F NMR spectroscopy Methods 0.000 description 52
- 238000005160 1H NMR spectroscopy Methods 0.000 description 52
- 238000005481 NMR spectroscopy Methods 0.000 description 52
- 238000004458 analytical method Methods 0.000 description 52
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 48
- 239000002904 solvent Substances 0.000 description 45
- 238000003756 stirring Methods 0.000 description 33
- 239000007787 solid Substances 0.000 description 26
- 235000019439 ethyl acetate Nutrition 0.000 description 25
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- 239000012265 solid product Substances 0.000 description 24
- QAHCLVUOQJKFGJ-UHFFFAOYSA-N (3z)-3-diazo-1,1,1-trifluoropropane Chemical compound FC(F)(F)CC=[N+]=[N-] QAHCLVUOQJKFGJ-UHFFFAOYSA-N 0.000 description 23
- 239000012074 organic phase Substances 0.000 description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
- 238000003760 magnetic stirring Methods 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- 229910052786 argon Inorganic materials 0.000 description 12
- 239000003208 petroleum Substances 0.000 description 12
- 238000010898 silica gel chromatography Methods 0.000 description 12
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 12
- 238000004809 thin layer chromatography Methods 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 239000003480 eluent Substances 0.000 description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- 229940079593 drug Drugs 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- WFQDTOYDVUWQMS-UHFFFAOYSA-N 1-fluoro-4-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(F)C=C1 WFQDTOYDVUWQMS-UHFFFAOYSA-N 0.000 description 6
- 102100027456 Cytochrome c oxidase subunit 2 Human genes 0.000 description 6
- 101000725401 Homo sapiens Cytochrome c oxidase subunit 2 Proteins 0.000 description 6
- 101000605127 Homo sapiens Prostaglandin G/H synthase 2 Proteins 0.000 description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 6
- 230000003110 anti-inflammatory effect Effects 0.000 description 6
- 229910052736 halogen Inorganic materials 0.000 description 6
- 150000002367 halogens Chemical class 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- QGFRHGWFBFTLKH-UHFFFAOYSA-N CC(C=C1)=CC=C1C(N(C(C=C1)=CC=C1N)N=C1C(F)(F)F)=C1C#N Chemical compound CC(C=C1)=CC=C1C(N(C(C=C1)=CC=C1N)N=C1C(F)(F)F)=C1C#N QGFRHGWFBFTLKH-UHFFFAOYSA-N 0.000 description 4
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 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 4
- 229960000590 celecoxib Drugs 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000001308 synthesis method Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- KZUAIXBYZSYVLG-UHFFFAOYSA-N COC(C=CC(C(N(C(C=C1)=CC=C1N)N=C1C(F)(F)F)=C1C#N)=C1)=C1F Chemical compound COC(C=CC(C(N(C(C=C1)=CC=C1N)N=C1C(F)(F)F)=C1C#N)=C1)=C1F KZUAIXBYZSYVLG-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 239000002158 endotoxin Substances 0.000 description 3
- 125000004185 ester group Chemical group 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 229920006008 lipopolysaccharide Polymers 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 239000011148 porous material Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 description 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 2
- 101710088172 HTH-type transcriptional regulator RipA Proteins 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 2
- 239000006180 TBST buffer Substances 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 229940124599 anti-inflammatory drug Drugs 0.000 description 2
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 239000002274 desiccant Substances 0.000 description 2
- 239000012973 diazabicyclooctane Substances 0.000 description 2
- 238000009509 drug development Methods 0.000 description 2
- 238000001962 electrophoresis Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000010413 mother solution Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000003531 protein hydrolysate Substances 0.000 description 2
- 238000010814 radioimmunoprecipitation assay Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- YWUIUNGMQOICND-UHFFFAOYSA-N (2z)-2-diazo-1,1,1-trifluoroethane Chemical compound FC(F)(F)C=[N+]=[N-] YWUIUNGMQOICND-UHFFFAOYSA-N 0.000 description 1
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 description 1
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 1
- 125000006729 (C2-C5) alkenyl group Chemical group 0.000 description 1
- 125000006736 (C6-C20) aryl group Chemical group 0.000 description 1
- SKKOKOMEGRDZMU-UXBLZVDNSA-N (Z)-2-(4-methoxyphenyl)but-2-enedinitrile Chemical compound COC1=CC=C(C(=C\C#N)\C#N)C=C1 SKKOKOMEGRDZMU-UXBLZVDNSA-N 0.000 description 1
- NRPLCRUPAMRDRX-XYOKQWHBSA-N (Z)-2-(4-tert-butylphenyl)but-2-enedinitrile Chemical compound CC(C)(C)c1ccc(cc1)C(=C\C#N)\C#N NRPLCRUPAMRDRX-XYOKQWHBSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 description 1
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
- IJMBFOPCPHVSRS-UHFFFAOYSA-N 3-(4-chlorophenyl)pyrrole-2,5-dione Chemical compound C1=CC(Cl)=CC=C1C1=CC(=O)NC1=O IJMBFOPCPHVSRS-UHFFFAOYSA-N 0.000 description 1
- PYXNITNKYBLBMW-UHFFFAOYSA-N 5-(trifluoromethyl)-1h-pyrazole Chemical class FC(F)(F)C1=CC=NN1 PYXNITNKYBLBMW-UHFFFAOYSA-N 0.000 description 1
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 description 1
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 1
- 101150071146 COX2 gene Proteins 0.000 description 1
- 101100114534 Caenorhabditis elegans ctc-2 gene Proteins 0.000 description 1
- ULXPBGAKCBEWOK-VMPITWQZSA-N ClC1=C(C=CC=C1)/C(/C#N)=C/C#N Chemical compound ClC1=C(C=CC=C1)/C(/C#N)=C/C#N ULXPBGAKCBEWOK-VMPITWQZSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 238000006736 Huisgen cycloaddition reaction Methods 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical group [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 101150000187 PTGS2 gene Proteins 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- NDBRTVDQRLEFAM-LREOWRDNSA-N S1C=C(C=C1)/C(/C#N)=C/C#N Chemical compound S1C=C(C=C1)/C(/C#N)=C/C#N NDBRTVDQRLEFAM-LREOWRDNSA-N 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical group [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
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- 125000003342 alkenyl group Chemical group 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
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- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
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- 125000005842 heteroatom Chemical group 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
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- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 description 1
- 239000012160 loading buffer Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
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- 230000002503 metabolic effect Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000000751 protein extraction Methods 0.000 description 1
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- 235000020183 skimmed milk Nutrition 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Plural Heterocyclic Compounds (AREA)
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Abstract
The invention provides a trifluoromethyl-4-cyano pyrazole compound shown as a formula (I) or a formula (II); wherein R 1 is selected from substituted or unsubstituted C6-C30 aryl, substituted or unsubstituted C2-C20 carboxyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C3-C30 heterocyclic; r 2 is selected from H, C-C10 alkyl, substituted or unsubstituted C6-C30 aryl, and substituted or unsubstituted C3-C30 heterocyclic group. Compared with the prior art, the trifluoromethyl-4-cyano pyrazole compound provided by the invention contains trifluoromethyl and pyrazole heterocyclic structures, can be used as a medicament, can be used as a core structural unit for synthesizing the medicament, is used for screening the activity of the medicament, and has the advantages of higher conversion rate, excellent regioselectivity, wide substrate universality and the like.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a trifluoromethyl-4-cyano pyrazole compound, a preparation method and application thereof.
Background
Pyrazole is one of the most popular heterocycles in bioactive compounds and has a wide range of applications in fields including pharmaceuticals and agrochemicals (Taylor, r.d.; macCoss, m.; lawson, a.d. g.j.med.chem.2014,57,5845). Because of the strength and polarity of the C-F bond, the incorporation of fluorine atoms or fluoroalkyl groups into the organic molecule is typically used to fine tune its physicochemical properties: changing the pKa value of the functional group, increasing metabolic stability, affecting lipophilicity, enhancing potency and selectivity, etc. (O' Hagan, D.Chem.Soc.Rev.2008,37,308;Meanwell,N.A.J.Med.Chem.2018,61,5822). Therefore, the introduction of fluorine atoms and fluorine-containing groups into the pyrazole can greatly improve the medicinal value, wherein the trifluoromethyl heterocycle is a core structural unit of medicinal molecules and functional materials and plays an irreplaceable role in the aspects of biological physiological activity and special functionality (Purser,S.;Moore,P.R.;Swallow,S.;Gouverneur,V.Chem.Soc.Rev.2008,37,320;Liu,H.et al.Chem.Rev.2016,116,422;Müller,K.;Faeh,C.;Diederich,F.Science 2007,317,1881).
In recent years, the synthesis of 3-trifluoromethyl pyrazole compounds has attracted extensive attention from researchers of synthetic chemistry and pharmaceutical chemistry, and the synthesis method mainly comprises the condensation reaction of 1, 3-dicarbonyl compounds and hydrazine, the [3+2] cycloaddition reaction of trifluoro diazoethane and alkene, alkyne and other unsaturated systems, and the like (Fustero,S.;Sánchez-Roselll,M.;Barrio,P.;Simln-Fuentes,A.Chem.Rev.2011,111,6984;Mykhailiuk,P.K.Chem.Rev.2020,120,12718;Mykhailiuk,P.K.Chem.Rev.2021,121,1670;Li,F.;Nie,J.;Sun,L.;Zheng,Y.;Ma,J.-A.Angew.Chem.,Int.Ed.2013,52,6255;Chen,Z.;Zheng,Y.;Ma,J.-A.Angew.Chem.,Int.Ed.2017,56,4569). is remarkable, and meanwhile, the synthesis method for introducing trifluoromethyl and cyano functional groups into pyrazole heterocycle is very rare, particularly the synthesis method of 3-trifluoromethyl-4-cyano pyrazole compounds still has the defects of low regioselectivity, harsh reaction conditions, poor substrate universality and the like (Lee, S.et al.Bioorg.Med.Chem.Lett.2017,27,4383;Beller,M.et al.Nat.Commun.2014,5,4123) because only few reports at present need to pass through complicated functional group conversion reactions. Therefore, the development of a novel 3-trifluoromethyl-4-cyano pyrazole compound and a practical synthesis method thereof are very significant in theoretical research and potential application value.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide a trifluoromethyl-4-cyanopyrazole compound, a preparation method and application thereof, wherein the preparation method has high conversion rate, excellent regioselectivity and wide substrate universality, and the obtained target compound contains a trifluoromethyl pyrazole heterocycle structure, and can be used as a drug or a core structural unit for drug synthesis for screening of pharmaceutical activity.
The invention provides a trifluoromethyl-4-cyano pyrazole compound shown as a formula (I) or a formula (II):
Wherein R 1 is selected from substituted or unsubstituted C6-C30 aryl, substituted or unsubstituted C2-C20 carboxyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C3-C30 heterocyclic;
R 2 is selected from H, C-C10 alkyl, substituted or unsubstituted C6-C30 aryl, and substituted or unsubstituted C3-C30 heterocyclic group.
The invention also provides a preparation method of the trifluoromethyl-4-cyano pyrazole compound, which comprises the following steps:
The method comprises the steps of (1) reacting maleonitrile shown in a formula (III), a metal catalyst, alkali and 2, 2-trifluoro diazoethane in an organic solvent to obtain a trifluoromethyl-4-cyano pyrazole compound shown in the formula (I) in which R 2 is hydrogen;
Carrying out N-functional group conversion reaction on a trifluoromethyl-4-cyano pyrazole compound shown in a formula (I) in which R 2 is hydrogen to obtain a trifluoromethyl-4-cyano pyrazole compound shown in a formula (I) or a formula (II) in which R 2 is not hydrogen;
Wherein R 1 is selected from substituted or unsubstituted C6-C30 aryl, substituted or unsubstituted C2-C20 carboxyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C3-C30 heterocyclic;
R 2 is selected from H, C-C10 alkyl, substituted or unsubstituted C6-C30 aryl, and substituted or unsubstituted C3-C30 heterocyclic group.
The invention also provides application of the trifluoromethyl-4-cyano pyrazole compound in preparing anti-inflammatory drugs.
The invention also provides application of the trifluoromethyl-4-cyano pyrazole compound in preparing medicines for inhibiting COX2 protein.
The invention provides a trifluoromethyl-4-cyano pyrazole compound shown as a formula (I) or a formula (II); wherein R 1 is selected from substituted or unsubstituted C6-C30 aryl, substituted or unsubstituted C2-C20 carboxyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C3-C30 heterocyclic; r 2 is selected from H, C-C10 alkyl, substituted or unsubstituted C6-C30 aryl, and substituted or unsubstituted C3-C30 heterocyclic group. Compared with the prior art, the trifluoromethyl-4-cyano pyrazole compound provided by the invention contains trifluoromethyl and pyrazole heterocyclic structures, can be used as a medicament, can be used as a core structural unit for synthesizing the medicament, is used for screening the activity of the medicament, and has the advantages of higher conversion rate, excellent regioselectivity, wide substrate universality and the like.
Drawings
FIG. 1 is a graph of the protein bands of compounds inhibiting protein COX 2.
Detailed Description
The technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The invention provides a trifluoromethyl-4-cyano pyrazole compound shown as a formula (I) or a formula (II):
wherein R 1 is a substituted or unsubstituted C6-C30 aryl group, a substituted or unsubstituted C2-C20 carboxyl group, a substituted or unsubstituted C2-C20 alkenyl group, or a substituted or unsubstituted C3-C30 heterocyclic group; preferably a substituted or unsubstituted C6-C20 aryl group, a substituted or unsubstituted C2-C15 carboxyl group, a substituted or unsubstituted C2-C15 alkenyl group, a substituted or unsubstituted C3-C20 heterocyclic group, more preferably a substituted or unsubstituted C6-C15 aryl group, a substituted or unsubstituted C2-C10 carboxyl group, a substituted or unsubstituted C2-C10 alkenyl group, a substituted or unsubstituted C3-C15 heterocyclic group, still more preferably a substituted or unsubstituted C6-C10 aryl group, a substituted or unsubstituted C2-C5 carboxyl group, a substituted or unsubstituted C2-C5 alkenyl group, or a substituted or unsubstituted C3-C10 heterocyclic group.
R 2 is H, C to C10 alkyl, substituted or unsubstituted C6 to C30 aryl, substituted or unsubstituted C3 to C30 heterocyclyl, preferably H, C to C8 alkyl, substituted or unsubstituted C6 to C20 aryl, substituted or unsubstituted C3 to C20 heterocyclyl, more preferably H, C to C5 alkyl, substituted or unsubstituted C6 to C15 aryl, substituted or unsubstituted C3 to C15 heterocyclyl, still more preferably H, C to C3 alkyl, substituted or unsubstituted C6 to C10 aryl, substituted or unsubstituted C3 to C10 heterocyclyl.
In the present invention, the substituent of the substituted C6-C30 aryl group, the substituted C2-C20 carboxyl group, the substituted C2-C20 alkenyl group and the substituted C3-C30 heterocyclic group is preferably one or more of halogen, hydroxyl, nitro, amino, sulfonylamino, azido, cyano, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 alkoxy, phenyl and C2-C10 ester group, more preferably one or more of halogen, hydroxyl, nitro, amino, sulfonylamino, azido, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, phenyl and C2-C8 ester group, still more preferably one or more of halogen, hydroxyl, nitro, amino, sulfonylamino, azido, cyano, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C1-C5 alkoxy, phenyl and C2-C10 ester group, more preferably one or more of halogen, hydroxyl, nitro, amino, sulfonylamino, phenyl and C1-C3-C8 ester, most preferably one or more of substituted or unsubstituted C1-C5 alkoxy, amino, 3-C5 ester, nitro, amino and 3-C5 ester.
Wherein, the substituent groups in the substituted C1-C10 alkyl and the substituted C1-C10 alkoxy are preferably one or more of halogen, hydroxyl, nitro, amino, sulfonamido, azido and phenyl.
The heteroatoms in the heterocyclic group are preferably one or more of O, S and N.
According to the present invention, most preferably, R 1 is one of the formulas (1) to (21):
According to the present invention, most preferably, R 2 is H, -CH 3 or one of the formulas (22) to (25):
further preferably, the trifluoromethyl-4-cyanopyrazole compound is one of the formulae L-1 to L-52:
The trifluoromethyl-4-cyano pyrazole compound provided by the invention contains trifluoromethyl and pyrazole heterocyclic structures, can be used as a medicament, can be used as a core structural unit for synthesizing the medicament, is used for screening the medicament activity, and has the advantages of higher conversion rate, excellent regioselectivity, wide substrate universality and the like.
The invention also provides a preparation method of the trifluoromethyl-4-cyano pyrazole compound, which comprises the following steps: the method comprises the steps of (1) reacting maleonitrile shown in a formula (III), a metal catalyst, alkali and 2, 2-trifluoro diazoethane in an organic solvent to obtain a trifluoromethyl-4-cyano pyrazole compound shown in the formula (I) in which R 2 is hydrogen; carrying out N-functional group conversion reaction on a trifluoromethyl-4-cyano pyrazole compound shown in a formula (I) in which R 2 is hydrogen to obtain a trifluoromethyl-4-cyano pyrazole compound shown in a formula (I) or a formula (II) in which R 2 is not hydrogen;
Wherein R 1 is a substituted or unsubstituted C6-C30 aryl group, a substituted or unsubstituted C2-C20 carboxyl group, a substituted or unsubstituted C2-C20 alkenyl group, or a substituted or unsubstituted C3-C30 heterocyclic group; r 2 is H, C-C10 alkyl, substituted or unsubstituted C6-C30 aryl, substituted or unsubstituted C3-C30 heterocyclic group.
The sources of all raw materials are not particularly limited, and the raw materials are commercially available; the R 1 and R 2 are the same as described above, and are not described in detail herein.
In the present invention, the metal catalyst is preferably a silver-based catalyst, more preferably one or more of silver oxide, silver carbonate, silver acetate, silver chloride and silver fluoride; the alkali is preferably one or more of N, N, N ', N' -tetramethyl ethylenediamine, potassium acetate, potassium dihydrogen phosphate, triethylene diamine and 4-dimethylaminopyridine; the organic solvent is preferably one or more of tetrahydrofuran, 1, 4-dioxane, acetonitrile, N-dimethylformamide and toluene; the molar ratio of the maleonitrile, the metal catalyst, the base and the 2, 2-trifluorodiazoethane represented by formula (III) is preferably 1: (0.05-1.5): (0.5-4): (3-6); in the embodiment provided by the invention, the molar ratio of the maleonitrile shown in the formula (III), the metal catalyst, the alkali and the 2, 2-trifluoro-diazoethane is specifically 1:0.05:3: 5. 1:1:0.5: 6. 1:1.5:0.5: 6. 1:0.1:4: 3. 1:0.1:3: 5. 1:0.2:3:4.
In the present invention, it is preferable that the maleonitrile represented by the formula (III), the metal catalyst and the base are mixed and then 2, 2-trifluorodiazoethane is added to react with the organic solvent; the temperature of the reaction is preferably 0-50 ℃; the reaction time is preferably 10 to 50 hours, more preferably 12 to 48 hours. The reaction formula is as follows:
After the reaction is finished, preferably adding a saturated ammonium chloride aqueous solution and then extracting with an organic solvent; the organic solvent is not particularly limited as long as it is an organic solvent well known to those skilled in the art, and ethyl acetate is preferable in the present invention.
After extraction, the extracted organic phase is preferably dried by a desiccant and purified by silica gel column chromatography to obtain a trifluoromethyl-4-cyanopyrazole compound shown in the formula (I) with R 2 as hydrogen; the drying agent is preferably anhydrous magnesium sulfate; the mobile phase used for the silica gel column chromatography is preferably petroleum ether and ethyl acetate; the silica gel column chromatography is preferably gradient elution, and the elution program is that the volume ratio of petroleum ether to ethyl acetate is 20:1 to 10:1.
Carrying out N-functional group conversion reaction on a trifluoromethyl-4-cyano pyrazole compound shown in a formula (I) in which R 2 is hydrogen to obtain a trifluoromethyl-4-cyano pyrazole compound shown in a formula (I) or a formula (II) in which R 2 is not hydrogen; the N-functional group conversion reaction preferably includes one or more of a nucleophilic substitution reaction, a reduction reaction, a diazotization reaction, and a sulfonylation reaction.
The N-functional group conversion reaction is preferably specifically: carrying out nucleophilic substitution reaction on trifluoromethyl-4-cyano pyrazole compound shown in a formula (I) in which R 2 is hydrogen and X-R 2 in the presence of an alkaline compound; the X is halogen, preferably I or F; the basic compound is preferably one or more of cesium carbonate, lithium t-butoxide, potassium carbonate, potassium phosphate, triethylamine, cesium fluoride, 4-dimethylaminopyridine, triethylenediamine or N, N-diisopropylethylamine.
After nucleophilic substitution reaction, the product can be purified by silica gel column chromatography; the eluent of the silica gel column chromatography is preferably petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate can be selected according to the polarity of the product; in the invention, the ratio of petroleum ether to ethyl acetate eluent is 5: 1-20: 1.
After nucleophilic substitution reaction, reduction reaction, diazo reaction or sulfonylation reaction can be performed, and the kind of substituent in R 2 can be changed.
The invention also provides application of the trifluoromethyl-4-cyano pyrazole compound in preparing anti-inflammatory drugs.
The invention also provides application of the trifluoromethyl-4-cyano pyrazole compound in preparing medicines for inhibiting COX2 protein.
The trifluoromethyl-4-cyano pyrazole compound provided by the invention has good inhibition effect on key protein COX2 protein in a rheumatoid arthritis model, has good anti-inflammatory activity, and can be used as an anti-inflammatory analgesic drug for drug development.
In order to further illustrate the present invention, the following examples are provided to describe in detail a trifluoromethyl-4-cyanopyrazole compound, its preparation method and application.
The reagents used in the examples below are all commercially available and are used directly without further purification treatment unless otherwise specified. All parts and percentages are parts by weight and percentages by weight, and the temperatures are degrees celsius unless otherwise indicated; 200-300 target quasi-silica gel for Qingdao ocean chemical industry for rapid column chromatography; qingdao ocean chemical 0.20mm standard plate for thin layer chromatography; nuclear magnetic resonance spectrum data (NMR) were obtained using Bruker 400 Mr, with tetramethylsilane as the internal standard and deuterated chloroform as the solvent (s for singlet, d for triplet, t for triplet, q for quartet, and m for multiplet).
Example 1: preparation of 5- (p-tolyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile
2-Partolylmaleonitrile (0.2 mmol,33.6 mg), agCl (0.01 mmol,1.4 mg) and TMEDA (69.7 mg,0.6 mmol) were added to a dry 10mL Schlenk flask, and a solution of CF 3CHN2 in N, N dimethylformamide (1.0 mmol,0.5M,2 mL) was added to the system and stirred at room temperature for 12 hours. After the completion of the TLC detection reaction, saturated aqueous ammonium chloride was added and extracted with ethyl acetate (3 x 6 ml), the organic phases were combined and dried over anhydrous MgSO 4, silica gel column chromatography (eluent petroleum ether/ethyl acetate=20/1 to 10/1 in 1 hour), gradient elution, and the target product 5- (p-tolyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile was obtained in 94% yield.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,DMSO-d6)δ14.86(s,1H),7.71(d,J=7.8Hz,2H),7.35(d,J=7.7Hz,2H),2.34(s,3H);19F NMR(376MHz,DMSO-d6)δ-61.56.
Example 2: preparation of 5- [4- (tert-butyl) phenyl ] -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile
In a similar manner to example 1, using silver chloride as the catalyst, TMEDA as the base and DMF as the solvent, the molar ratios of 2-p-tert-butylphenylmaleonitrile, silver chloride, TMEDA and 2, 2-trifluoromethyldiazoethane were 1:0.05:3:5, 5- [4- (tert-butyl) phenyl ] -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile was synthesized in 92% yield after 48 hours of reaction at zero degrees.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,DMSO-d6)δ14.93(s,1H),7.78(d,J=8.2Hz,2H),7.62(d,J=8.3Hz,2H),1.30(s,9H);19F NMR(376MHz,DMSO-d6)δ-61.38.
Example 3: synthesis of 5- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile
In a similar manner to example 1, using silver oxide as a catalyst, potassium acetate as a base, and tetrahydrofuran as a solvent, the molar ratio of 2-p-methoxyphenyl-maleonitrile, silver oxide, potassium acetate, and 2, 2-trifluoromethyl diazoethane was 1:0.05:3:5, synthesis of 5- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile at room temperature for 12 hours in 95% yield
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,DMSO-d6)δ14.79(s,1H),7.79(d,J=8.3Hz,2H),7.14(d,J=8.4Hz,2H),3.83(s,3H);19F NMR(376MHz,DMSO-d6)δ-61.47.
Example 4: synthesis of 5- (3, 4-dimethoxyphenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile
In a similar manner to example 1, using silver oxide as a catalyst, potassium acetate as a base, and tetrahydrofuran as a solvent, the molar ratio of 2- (3, 4-dimethoxyphenyl) maleonitrile, silver oxide, potassium acetate and 2, 2-trifluoromethyl diazoethane was 1:0.05:3:5, 5- (3, 4-dimethoxyphenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile was synthesized in a yield of 90% by reacting at room temperature for 12 hours.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,DMSO-d6)δ14.70(s,1H),7.49(d,J=8.3Hz,2H),7.10(s,1H),3.83(s,3H),3.82(s,3H);19F NMR(376MHz,DMSO-d6)δ-62.47.
Example 5: synthesis of 5- (3-benzyloxy-4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile
In a similar manner to example 1, using silver oxide as a catalyst, potassium acetate as a base, and tetrahydrofuran as a solvent, the molar ratio of 2- (3-benzyloxy-4-methoxyphenyl) maleonitrile, silver oxide, potassium acetate, and 2, 2-trifluoromethyl diazoethane was 1:0.05:3:5, 5- (3-benzyloxy-4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile was synthesized in 85% yield after 12 hours at room temperature.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,DMSO-d6)δ14.70(s,1H),7.45-7.35(m,4H),7.25-7.15(m,3H),7.10(s,1H),5,25(s,2H),3.82(s,3H);19F NMR(376MHz,DMSO-d6)δ-62.40.
Example 6: synthesis of 5- [ (1, 1' -biphenyl) -4-yl ] -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile
In a similar manner to example 1, using silver carbonate as catalyst, potassium dihydrogen phosphate as base and DMF as solvent, the molar ratio of 2-4-biphenylmaleonitrile, silver carbonate, potassium dihydrogen phosphate and 2, 2-trifluoromethyl diazoethane was 1:0.05:3:5, 5- [ (1, 1' -biphenyl) -4-yl ] -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile was synthesized in 83% yield at 40℃for 12 hours.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,DMSO-d6)δ15.02(s,0H),7.96–7.84(m,4H),7.74–7.70(m,2H),7.50–7.44(m,2H),7.42–7.36(m,1H);19F NMR(376MHz,DMSO-d6)δ-61.35.
Example 7: synthesis of 5- (4-fluorophenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile
In a similar manner to example 1, using silver acetate as catalyst, triethylenediamine (DABCO) as base and DMF as solvent, the molar ratio of 2-p-fluorophenyl-maleonitrile, silver acetate, triethylenediamine and 2, 2-trifluoromethyl diazoethane was 1:0.05:3:5, 5- (4-fluorophenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile was synthesized in 92% yield by reacting at 50℃for 12 hours.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,DMSO-d6)δ14.93(s,1H),7.94–7.77(m,2H),7.40(t,J=8.6Hz,2H);19F NMR(376MHz,DMSO-d6)δ-61.66,-108.85.
Example 8: synthesis of 5- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile
In a similar manner to example 1, using silver fluoride as a catalyst, potassium acetate as a base, DMF as a solvent, and molar ratios of 2-p-chlorophenyl maleimide, silver fluoride, potassium acetate and2, 2-trifluoromethyl diazoethane were 1/0.05/3/5, and reacted at room temperature for 12 hours to synthesize 5- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile, the yield was 87%.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,DMSO-d6)δ15.02(s,1H),7.83(d,J=8.3Hz,2H),7.65(d,J=8.3Hz,2H);19F NMR(376MHz,DMSO-d6)δ-61.49.
Example 9: synthesis of 5- (3-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile
In a similar manner to example 1, using silver chloride as catalyst, 4-Dimethylaminopyridine (DMAP) as base and DMF as solvent, the molar ratio of 2- (3-chlorophenyl) -maleonitrile, silver chloride, 4-dimethylaminopyridine and 2, 2-trifluoromethyl diazoethane was 1:0.5:2:3, 5- (3-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile was synthesized in 76% yield by reacting at room temperature for 24 hours.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,DMSO-d6)δ15.06(s,1H),7.88(s,1H),7.82–7.76(m,1H),7.70–7.58(m,2H);19F NMR(376MHz,DMSO-d6)δ-61.63.
Example 10: synthesis of 5- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile
In a similar manner to example 1, using silver chloride as the catalyst, TMEDA as the base and DMF as the solvent, the molar ratio of 2- (2-chlorophenyl) -maleonitrile, silver chloride, TMEDA and 2, 2-trifluoromethyl diazoethane was 1:1:0.5:6, 5- (2-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile was synthesized in 71% yield after 12 hours at room temperature.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,DMSO-d6)δ15.08(s,1H),7.78–7.70(m,3H),7.66(td,J=7.8,1.6Hz,2H),7.62–7.55(m,2H);19F NMR(376MHz,DMSO-d6)δ-61.21.
Example 11: synthesis of 5- (3, 4-dichlorophenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile
In a similar manner to example 1, using silver chloride as a catalyst, TMEDA as a base, toluene as a solvent, the molar ratio of 2- (3, 4-dichlorophenyl) maleonitrile, silver chloride, TMEDA and 2, 2-trifluoromethyl diazoethane was 1:1.5:0.5:6, 5- (3, 4-dichlorophenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile was synthesized in 74% yield by reacting at room temperature for 12 hours.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,DMSO-d6)δ15.04(s,1H),7.98(s,1H),7.75(q,J=8.4Hz,2H);19F NMR(376MHz,DMSO-d6)δ-61.59.
Example 12: synthesis of 5- (4-bromophenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile
In a similar manner to example 1, using silver chloride as the catalyst, TMEDA as the base, and acetonitrile as the solvent, the molar ratio of 2-p-bromophenyl-maleic nitrile, silver chloride, TMEDA and 2, 2-trifluoromethyl diazoethane was 1:0.1:4:3, 5- (4-bromophenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile was synthesized in 80% yield by reacting at room temperature for 12 hours.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,DMSO-d6)δ15.02(s,1H),7.82–7.67(m,4H);19F NMR(376MHz,DMSO-d6)δ-61.51.
Example 13: synthesis of 3- (trifluoromethyl) -5- [4- (trifluoromethyl) phenyl ] -1H-pyrazole-4-carbonitrile
In a similar manner to example 1, using silver oxide as a catalyst, TMEDA as a base and DMF as a solvent, the molar ratios of 2-p-trifluoromethylphenylmaleonitrile, silver chloride, TMEDA and 2, 2-trifluoromethyldiazoethane were 1:0.1:3:5, 3- (trifluoromethyl) -5- [4- (trifluoromethyl) phenyl ] -1H-pyrazole-4-carbonitrile was synthesized in a yield of 84% by reacting at room temperature for 12 hours.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,DMSO-d6)δ15.18(s,1H),8.03(d,J=7.9Hz,2H),7.94(d,J=7.9Hz,1H);19F NMR(376MHz,DMSO-d6)δ-61.64,-62.07.
Example 14: synthesis of 5- (4-cyanophenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile
In a similar manner to example 1, using silver chloride as the catalyst, TMEDA as the base and DMF as the solvent, the molar ratios of 2-p-cyanophenyl maleonitrile, silver chloride, TMEDA and 2, 2-trifluoromethyl diazoethane were 1:0.2:3:4, 5- (4-cyanophenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile was synthesized in 75% yield by reacting at room temperature for 12 hours.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,DMSO-d6)δ15.21(s,1H),8.06(d,J=8.2Hz,2H),7.98(d,J=8.2Hz,2H);19F NMR(376MHz,DMSO-d6)δ-61.46.
Example 15: synthesis of 5- (4-nitrophenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile
In a similar manner to example 1, using silver chloride as the catalyst, TMEDA as the base and DMF as the solvent, the molar ratios of 2-p-nitrophenylmaleonitrile, silver chloride, TMEDA and 2, 2-trifluoromethyl diazoethane were 1:0.05:3:5, 5- (4-nitrophenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile was synthesized in 80% yield by reacting at room temperature for 12 hours.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,DMSO-d6)δ15.27(s,1H),8.45(d,J=8.9Hz,2H),8.09(d,J=8.9Hz,2H);19F NMR(376MHz,DMSO-d6)δ-61.33.
Example 16: synthesis of 5- (naphthalen-2-yl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile
In a similar manner to example 1, using silver chloride as the catalyst, TMEDA as the base, 1, 4-dioxane as the solvent, and 2- (naphthalen-2-yl) maleonitrile as the solvent, the molar ratio of maleonitrile, silver chloride, TMEDA and 2, 2-trifluoromethyl diazoethane was 1:0.05:3:5, 5- (naphthalen-2-yl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile was synthesized in 91% yield by reacting at room temperature for 12 hours.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,DMSO-d6)δ15.12(s,1H),8.42(s,1H),8.14(d,J=8.6Hz,1H),8.07–7.97(m,2H),7.90(dd,J=8.6,1.7Hz,1H),7.64(td,J=6.6,5.8,3.6Hz,2H);19F NMR(376MHz,DMSO-d6)δ-61.25.
Example 17: synthesis of 5- (naphthalen-1-yl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile
In a similar manner to example 1, 5- (naphthalen-1-yl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile was synthesized in a molar ratio of 1/0.05/3/5 of 2- (naphthalen-1-yl) maleonitrile, silver chloride, TMEDA and 2, 2-trifluoromethyl diazoethane using silver chloride as a catalyst, TMEDA as a base and toluene as a solvent at room temperature for 12 hours in a yield of 92%.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,DMSO-d6)δ15.16(s,1H),8.22(d,J=8.2Hz,1H),8.17–8.08(m,1H),7.84(d,J=7.2Hz,2H),7.78–7.61(m,3H);19F NMR (376MHz,DMSO-d6)δ-61.10.
Example 18: synthesis of 5- (thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile
In a similar manner to example 1, using silver chloride as the catalyst, TMEDA as the base and DMF as the solvent, the molar ratios of 2- (thiophen-2-yl) maleonitrile, silver chloride, TMEDA and 2, 2-trifluoromethyl diazoethane were 1:0.05:3:5, 5- (thiophen-2-yl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile was synthesized in 91% yield by reacting at room temperature for 12 hours.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,DMSO-d6)δ15.04(s,1H),7.90(d,J=4.7Hz,1H),7.77(d,J=3.0Hz,1H),7.31–7.26(m,1H);19F NMR(376MHz,DMSO-d6)δ-61.49.
Example 19: synthesis of 5- (thiophen-3-yl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile
In a similar manner to example 1, using silver chloride as catalyst, TMEDA as base and DMF as solvent, the molar ratio of 2- (thiophen-3-yl) -maleonitrile, silver chloride, TMEDA and 2, 2-trifluoromethyl diazoethane was 1:0.05:3:5, 5- (thiophen-3-yl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile was synthesized in 93% yield by reacting at room temperature for 12 hours.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,DMSO-d6)δ14.87(s,1H),8.20–8.15(m,1H),7.78(dd,J=5.0,2.9Hz,1H),7.69–7.59(m,1H);19F NMR(376MHz,DMSO-d6)δ-61.52.
Example 20: synthesis of 5- (furan-2-yl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile
In a similar manner to example 1, using silver chloride as the catalyst, TMEDA as the base and DMF as the solvent, the molar ratios of 2- (furan-2-yl) maleonitrile, silver chloride, TMEDA and 2, 2-trifluoromethyl diazoethane were 1:0.05:3:5, 5- (furan-2-yl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile was synthesized in 94% yield after 12 hours at room temperature.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,DMSO-d6)δ15.08(s,1H),8.25–7.73(m,1H),7.14(d,J=3.5Hz,1H),6.74(dd,J=3.5,1.8Hz,1H);19F NMR(376MHz,DMSO-d6)δ-61.55.
Example 21: synthesis of 4-cyano-3- (trifluoromethyl) -1H-pyrazole-5-carboxylic acid ethyl ester
In a similar manner to example 1, using silver chloride as the catalyst, TMEDA as the base and DMF as the solvent, the molar ratio of 2- (ethyl formate) maleonitrile, silver chloride, TMEDA and 2, 2-trifluoromethyl diazoethane was 1:0.05:3:5, 4-cyano-3- (trifluoromethyl) -1H-pyrazole-5-carboxylic acid ethyl ester was synthesized in 82% yield after 12 hours at room temperature.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,Chloroform-d)δ12.11(s,1H),4.55(q,J=7.1Hz,2H),1.48(t,J=7.1Hz,3H);19F NMR(376MHz,Chloroform-d)δ-62.46.
Example 22: synthesis of 4-cyano-1-methyl-3- (trifluoromethyl) -1H-pyrazole-5-carboxylic acid ethyl ester
3-Cyano-5- (trifluoromethyl) -1H-pyrazole-4-carboxylic acid ethyl ester (233 mg,1mmol, example 21) was dissolved in 5mL DMF, K 2CO3 (276 mg,2mmol,2 equiv) was added as base, reacted with MeI (213 mg,1.5mmol,1.5 equiv) at room temperature for 5 hours to give 5-cyano-1-methyl-3- (trifluoromethyl) -1H-pyrazole-4-carboxylic acid ethyl ester, which was purified by silica gel column chromatography, rf=0.14 (PE/EtOAc=10:1), petroleum ether/ethyl acetate=20/1 as eluent, gradient elution gave the title compound as a white solid in 70% yield.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,Chloroform-d)δ4.34(q,J=7.1Hz,2H),4.11(s,3H),1.34(t,J=7.1Hz,3H);19F NMR(376MHz,Chloroform-d)δ-62.28.
Example 23: synthesis of 4-cyano-1-methyl-5- (trifluoromethyl) -1H-pyrazole-3-carboxylic acid ethyl ester
3-Cyano-5- (trifluoromethyl) -1H-pyrazole-4-carboxylic acid ethyl ester (233 mg,1mmol, example 21) was dissolved in 5mL DMF, K 2CO3 (276 mg,2mmol,2 equiv) was added as base, and reacted with MeI (213 mg,1.5mmol,1.5 equiv) at room temperature for 5 hours to give 4-cyano-1-methyl-5- (trifluoromethyl) -1H-pyrazole-3-carboxylic acid ethyl ester, which was purified by silica gel column chromatography, rf=0.14 (PE/EtOAc=10:1), petroleum ether/ethyl acetate=20/1 as eluent, gradient elution gave the title compound as a white solid, yield 10%.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,Chloroform-d)δ4.36(q,J=7.2Hz,2H),4.14(s,3H),1.35(t,J=7.2Hz,3H);19F NMR(376MHz,Chloroform-d)δ-62.38.
Example 24: (E) Synthesis of-5-styryl-3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile
In a similar manner to example 1, using silver chloride as the catalyst, TMEDA as the base and DMF as the solvent, the molar ratio of 2- [ (E) -5-styryl ] -maleonitrile, silver chloride, TMEDA and 2, 2-trifluoromethyl diazoethane was 1:0.05:3:5, synthesis of (E) -5-styryl-3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile at room temperature for 12 hours in a yield of 90%.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,DMSO-d6)δ14.74(s,1H),7.63(d,J=6.9Hz,2H),7.54(d,J=16.7Hz,1H),7.41(ddt,J=14.1,10.0,4.5Hz,3H),7.11(d,J=16.7Hz,1H);19F NMR(376MHz,DMSO-d6)δ-61.40.
Example 25: synthesis of 5- (3-fluoro-4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile
In a similar manner to example 1, using silver acetate as catalyst, triethylenediamine (DABCO) as base, DMF as solvent, and 2- (3-fluoro-4-methoxyphenyl) maleonitrile, silver acetate, triethylenediamine and 2, 2-trifluoromethyl diazoethane in a molar ratio of 1:0.05:3:5, 5- (3-fluoro-4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile was synthesized in 82% yield by reacting at 50℃for 12 hours.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,DMSO-d6)δ13.90(s,1H),7.54–7.45(m,1H),7.32(d,J=8.0Hz,2H);19F NMR(376MHz,DMSO-d6)δ-62.66,-109.85.
Example 26: synthesis of isopropyl 2-chloro-5- [ 4-cyano-3- (trifluoromethyl) -1H-pyrazol-5-yl ] -4-fluorobenzoate
In a similar manner to example 1, using silver chloride as the catalyst, TMEDA as the base, THF as the solvent, and the molar ratio of 2- (2-fluoro-4-chloro-5-carboxylic acid isopropyl-phenyl) maleonitrile, silver chloride, TMEDA and 2, 2-trifluoromethyl diazoethane was 1:0.05:3:5, synthesis of isopropyl 2-chloro-5- [ 4-cyano-3- (trifluoromethyl) -1H-pyrazol-5-yl ] -4-fluorobenzoate in 76% yield after 12 hours of reaction at room temperature.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,DMSO-d6)δ15.23(s,1H),8.26(d,J=7.7Hz,1H),7.95(d,J=10.1Hz,1H),5.17(p,J=6.2Hz,1H),1.33(d,J=6.3Hz,6H);19F NMR(376MHz,DMSO-d6)δ-61.27,-105.62(t,J=8.9Hz).
Example 27: synthesis of isopropyl 2-chloro-5- [ 1-methyl-4-cyano-3- (trifluoromethyl) -1H-pyrazol-5-yl ] -4-fluorobenzoate
Starting from isopropyl 2-chloro-5- [ 4-cyano-3- (trifluoromethyl) -1H-pyrazol-5-yl ] -4-fluorobenzoate (375 mg,1mmol,1equiv, example 26) in DMF (8 mL) as solvent and potassium carbonate (276 mg,2mmol,2 equiv) as base, the reaction with methyl iodide (213 mg,1.5mmol,1.5 equiv) at room temperature for 5 hours gave the title product in 30% yield.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,Chloroform-d)δ7.98(d,J=7.5Hz,1H),7.45(d,J=9.3Hz,1H),5.26(p,J=6.3Hz,1H),3.88(s,3H),1.38(d,J=6.3Hz,6H);19F NMR(376MHz,Chloroform-d)δ-62.36,-105.22(t,J=8.6Hz).
Example 28: synthesis of isopropyl 2-chloro-5- [ 1-methyl-4-cyano-5- (trifluoromethyl) -1H-pyrazol-3-yl ] -4-fluorobenzoate
Starting from isopropyl 2-chloro-5- [ 4-cyano-3- (trifluoromethyl) -1H-pyrazol-5-yl ] -4-fluorobenzoate (375 mg,1mmol,1equiv, example 26) in DMF (8 mL) as solvent and potassium carbonate (276 mg,2mmol,2 equiv) as base, the reaction with methyl iodide (213 mg,1.5mmol,1.5 equiv) at room temperature for 5 hours gave the title product in 40% yield.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,Chloroform-d)δ8.18(d,J=7.7Hz,1H),7.36(d,J=9.7Hz,1H),5.27(p,J=6.3Hz,1H),4.13(s,3H),1.38(d,J=6.3Hz,6H);19F NMR(376MHz,Chloroform-d)δ-60.01,-105.75(t,J=8.6Hz).
Example 29: synthesis of 1- (4-nitrophenyl) -5- (p-tolyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile
In a dry 25mL Schlenk tube, add magnetic stirring bar, add 5- (p-tolyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile (0.5 mmol, example 1), potassium carbonate (0.75 mmol) and p-fluoronitrobenzene (0.75 mmol), add 3mL DMF as solvent, react for 12 hours at 120℃TLC check reaction, wash with saturated NaCl solution and extract with EtOAc, dry the organic phase with anhydrous sodium sulfate, concentrate the organic phase under vacuum and purify the residue by silica gel column chromatography (petroleum ether/ethyl acetate=20:1 as eluent) to give the target product 1- (4-nitrophenyl) -5- (p-tolyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile in 63% yield.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,Chloroform-d)δ8.28(d,J=9.0Hz,2H),7.55(d,J=9.0Hz,2H),7.34–7.25(m,4H),2.45(s,3H);19F NMR(376MHz,Chloroform-d)δ-62.62.
Example 30: synthesis of 1- (4-aminophenyl) -5- (p-tolyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile
In a dry 25 mL-sealed tube, add magnetic stirring bar, add 1- (4-nitrophenyl) -5- (p-tolyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile (0.5 mmol, example 23), iron powder (2.5 mmol), and add 5mL of additional volume ratio AcOH: the mixture was stirred for 2 hours at 70 degrees celsius with H 2 o=1:10:10, monitored by TLC, after completion of the reaction of the starting materials, the mixture was diluted with ethyl acetate (15 mL), washed with saturated aqueous NH 4 Cl (2×15 mL), the organic phase was dried over anhydrous sodium sulfate, the organic phase was concentrated in vacuo and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5:1 as eluent) to give the target product 1- (4-aminophenyl) -5- (p-tolyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile in 95% yield.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,DMSO-d6)δ7.41–7.20(m,4H),7.03(d,J=8.7Hz,2H),6.59(d,J=8.7Hz,2H),5.58(s,2H),2.32(s,3H);19F NMR(376MHz,DMSO-d6)δ-61.44.
Example 31: synthesis of 1- (4-azidophenyl) -5- (p-tolyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile
In a dry 25mL round bottom flask, add magnetic stirring bar, dissolve 1- (4-aminophenyl) -5- (p-tolyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile (3 mmol, example 24) completely in 15mL EtOH, drop HBF 4 (6 mmol) at 0deg.C, continue stirring for 5min, slowly drop t BuONO (6 mmol), continue stirring for 30min, precipitate a solid, filter under vacuum, wash the solid residue twice with 5mL diethyl ether, and then put the solid product into the next reaction. 25mL of Schlenk tube was taken, a magnetic stirring bar was added, the above solid product (0.5 mmol), naN 3 (0.5 mmol), tetrabutylammonium bromide (1.0 equiv,0.5 mmol) was added sequentially, CH 3CN:H2 O=1:2 (v/v) solvent 1.5mL under argon, and stirred at 80℃for 12 hours. After completion of the reaction by TLC, the mixture was diluted with ethyl acetate (15 mL), washed with saturated aqueous NH 4 Cl (2×15 mL), the organic phase was dried over anhydrous sodium sulfate, concentrated in vacuo, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=20:1 as eluent) to give the target product 1- (4-azidophenyl) -5- (p-tolyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile in 71% yield.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,Chloroform-d)δ7.40–7.21(m,6H),7.08(d,J=8.8Hz,2H),2.44(s,3H);19F NMR(376MHz,Chloroform-d)δ-62.40.
Example 32: synthesis of 4- [ 4-cyano-5- (p-tolyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] benzenesulfonamide
In a dry 25mL round bottom flask, add magnetic stirring bar, dissolve 1- (4-aminophenyl) -5- (p-tolyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile (3 mmol, example 25) completely in 15mL EtOH, drop HBF 4 (6 mmol) at 0deg.C, continue stirring for 5min, slowly drop t BuONO (6 mmol), continue stirring for 30min, precipitate a solid, filter under vacuum, wash the solid residue twice with 5mL diethyl ether, and then put the solid product into the next reaction. 25mL of Schlenk tube was taken, a magnetic stirring bar was added, the above solid product (0.5 mmol), ru (bpy) 3Cl2 (0.005equiv, 0.0025 mmol) was added, 2mL of CH 3 CN as solvent was added in place of argon, SOCl 2/H2 O=1:1 (0.5 mmol) was added, and stirring was carried out for 12 hours at 20℃under blue LED light conditions at 450 nm. After completion of the reaction of the starting materials by TLC, the reaction was monitored, washed with saturated aqueous NaCl, extracted with ethyl acetate (3X 15 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and the organic phase was spin-dried to give a sulfonyl chloride intermediate. After the reaction of the starting materials was completed by TLC monitoring after adding 6mL of NH 3·H2 O to the above sulfonyl chloride intermediate and stirring at room temperature for 18 hours, the organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=3:1 as eluent) to give the objective 4- [ 4-cyano-5- (p-tolyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] benzenesulfonamide in 69% yield.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,Chloroform-d)δ7.94(d,J=8.6Hz,2H),7.45(d,J=8.6Hz,2H),7.31–7.16(m,4H),5.10(s,2H),2.41(s,3H);19F NMR(376MHz,Chloroform-d)δ-62.56.
Example 33: synthesis of 1- (4-nitrophenyl) -5- (p-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile
Prepared in analogy to example 29, starting from 5- (p-methoxy) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile (0.5 mmol, example 3) and p-fluoronitrobenzene (0.75 mmol) potassium carbonate (0.75 mmol) as base and 3mL DMF as solvent in a reaction at 120 ℃ for 12H in 50% yield.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,Chloroform-d)δ8.38(d,J=8.8Hz,2H),7.96(d,J=8.9Hz,2H),7.45–7.35(m,2H),7.15–7.05(m,2H);19F NMR(376MHz,Chloroform-d)δ-62.40,-108.60.
Example 34: synthesis of 1- (4-aminophenyl) -5- (p-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile
Prepared in analogy to example 30, as 1- (4-nitrophenyl) -5- (p-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile (0.5 mmol, example 33), iron powder (2.5 mmol) was added and a further 5mL volume of mixed solvent of AcOH: etOH: H 2 o=1:10:10 was added, stirred at 70 ℃ for 2 hours in 80% yield.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,DMSO-d6)δ7.42(d,J=8.6Hz,2H),7.35(d,J=8.6Hz,2H),7.0-6.9(m,4H),5.52(s,2H);19F NMR(376MHz,DMSO-d6)δ-63.46,-108.60(s).
Example 35: synthesis of 1- (4-azidophenyl) -5- (p-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile
Prepared in analogy to example 31, using 1- (4-aminophenyl) -5- (p-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile (3 mmol, example 34) was completely dissolved in 15mL of EtOH, HBF 4 (6 mmol) was added dropwise at 0 degrees celsius, stirring was continued for 5min, t BuONO (6 mmol) was slowly added dropwise, stirring was continued for 30min, solids precipitated, filtered off under vacuum, the solid residue was washed twice with 5mL of diethyl ether and the solid product was subsequently taken up in the next reaction. 25mL of Schlenk tube was taken, a magnetic stirring bar was added, the above solid product (0.5 mmol), naN 3 (0.5 mmol), tetrabutylammonium bromide (1.0 equiv,0.5 mmol) was added sequentially, CH 3CN:H2 O=1:2 (v/v) solvent 1.5mL under argon, and stirred at 80℃for 12 hours, yielding 60%.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,Chloroform-d)δ7.68(d,J=8.8Hz,2H),7.45(d,J=8.6Hz,2H),7.25–7.10(m,4H);19F NMR(376MHz,Chloroform-d)δ-63.20,-109.10.
Example 36: synthesis of 4- [ 4-cyano-5- (p-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] benzenesulfonamide
Prepared in analogy to example 32, using 1- (4-aminophenyl) -5- (p-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile (3 mmol, example 35) was completely dissolved in 15mL of EtOH, HBF 4 (6 mmol) was added dropwise at 0 degrees celsius, stirring was continued for 5min, t BuONO (6 mmol) was slowly added dropwise, stirring was continued for 30min, solids precipitated, filtered off under vacuum, the solid residue was washed twice with 5mL of diethyl ether and the solid product was then taken up in the next reaction. 25mL of Schlenk tube was taken, a magnetic stirring bar was added, the above solid product (0.5 mmol), ru (bpy) 3Cl2 (0.005equiv, 0.0025 mmol) was added, 2mL of CH 3 CN as solvent was added in place of argon, SOCl 2/H2 O=1:1 (0.5 mmol) was added, and stirring was carried out for 12 hours at 20℃under blue LED light conditions at 450 nm. After completion of the reaction of the starting materials by TLC, the reaction was monitored, washed with saturated aqueous NaCl, extracted with ethyl acetate (3X 15 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and the organic phase was spin-dried to give a sulfonyl chloride intermediate. 6mL of NH 3·H2 O was added to the sulfonyl chloride intermediate, and the mixture was stirred at room temperature for 18 hours, with a yield of 55%.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,Chloroform-d)δ7.80(d,J=8.6Hz,2H),7.74(d,J=8.8Hz,2H),7.35(d,J=8.6Hz,2H),7.15–7.10(m,2H),5.60(s,2H);19F NMR(376MHz,Chloroform-d)δ-63.36(s),-108.10(s).
Example 37: synthesis of 1- (4-nitrophenyl) -5- (3, 4-dimethoxyphenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile
Prepared in analogy to example 29, starting from 5- (3, 4-dimethoxyphenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile (0.5 mmol, example 4) and p-fluoronitrobenzene (0.75 mmol) potassium carbonate (0.75 mmol) as base and 3mL DMF as solvent in 120 ℃ for 12H in 45% yield.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,Chloroform-d)δ8.35(d,J=8.8Hz,2H),7.95(d,J=8.8Hz,2H),7.30–7.20(m,3H);19F NMR(376MHz,Chloroform-d)δ-63.40,-109.10.
Example 38: synthesis of 1- (4-aminophenyl) -5- (3, 4-dimethoxyphenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile
Prepared in analogy to example 30, as 1- (4-nitrophenyl) -5- (3, 4-dimethoxyphenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile (0.5 mmol, example 37) was added iron powder (2.5 mmol) and then 5mL of acoh:etoh in volume ratio of: h 2 o=1:10:10, and stirred at 70 ℃ for 2 hours in 75% yield.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,DMSO-d6)δ7.40(d,J=8.6Hz,2H),7.31(d,J=8.6Hz,2H),7.10-6.90(m,3H),5.60(s,2H);19F NMR(376MHz,DMSO-d6)δ-62.40,-109.25(s).
Example 39: synthesis of 1- (4-azidophenyl) -5- (3, 4-dimethoxyphenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile
Prepared in analogy to example 31, using 1- (4-aminophenyl) -5- (3, 4-dimethoxyphenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile (3 mmol, example 38) was completely dissolved in 15mL of EtOH, HBF 4 (6 mmol) was added dropwise at 0 degrees celsius, stirring was continued for 5min, t BuONO (6 mmol) was slowly added dropwise, stirring was continued for 30min, solid precipitated, filtered off under vacuum and the solid residue was washed twice with 5mL of diethyl ether and the solid product was subsequently taken up in the next reaction. 25mL of Schlenk tube was taken, a magnetic stirring bar was added, the above solid product (0.5 mmol), naN 3 (0.5 mmol), tetrabutylammonium bromide (1.0 equiv,0.5 mmol) was added sequentially, CH 3CN:H2 O=1:2 (v/v) solvent 1.5mL under argon, and stirred at 80℃for 12 hours in 55% yield.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,Chloroform-d)δ7.65(d,J=8.6Hz,2H),7.35(d,J=8.5Hz,2H),7.24–7.05(m,3H);19F NMR(376MHz,Chloroform-d)δ-63.28,-109.15.
Example 40: synthesis of 4- [ 4-cyano-5- (3, 4-dimethoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] benzenesulfonamide
Prepared in analogy to example 32, using 1- (4-aminophenyl) -5- (3, 4-dimethoxyphenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile (3 mmol, example 39) was completely dissolved in 15mL of EtOH, HBF 4 (6 mmol) was added dropwise at 0 degrees celsius, stirring was continued for 5min, t BuONO (6 mmol) was slowly added dropwise, stirring was continued for 30min, solid precipitated, filtered off under vacuum and the solid residue was washed twice with 5mL of diethyl ether and the solid product was then taken up in the next reaction. 25mL of Schlenk tube was taken, a magnetic stirring bar was added, the above solid product (0.5 mmol), ru (bpy) 3Cl2 (0.005equiv, 0.0025 mmol) was added, 2mL of CH 3 CN as solvent was added in place of argon, SOCl 2/H2 O=1:1 (0.5 mmol) was added, and stirring was carried out for 12 hours at 20℃under blue LED light conditions at 450 nm. After completion of the reaction of the starting materials by TLC, the reaction was monitored, washed with saturated aqueous NaCl, extracted with ethyl acetate (3X 15 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and the organic phase was spin-dried to give a sulfonyl chloride intermediate. 6mL of NH 3·H2 O was added to the sulfonyl chloride intermediate, and the mixture was stirred at room temperature for 18 hours, with a yield of 50%.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,Chloroform-d)δ7.82(d,J=8.6Hz,2H),7.70(d,J=8.8Hz,2H),7.20–7.05(m,3H),5.80(s,2H);19F NMR(376MHz,Chloroform-d)δ-63.27(s),-108.40(s).
Example 41: synthesis of 1- (4-nitrophenyl) -5- (3-hydroxy-4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile
Prepared in analogy to example 29, starting from 5- (3-hydroxy-4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile (0.5 mmol, example 5) by first removing the benzyl protecting groups under Pd/C-hydrogen (10 mol% Pd/C,5atmH 2) and filtering, washing the reaction mixture and concentrating it before use in the next reaction; the crude product of the previous step is subjected to nucleophilic substitution reaction with p-fluoronitrobenzene (0.75 mmol), potassium carbonate (0.75 mmol) is taken as alkali, 3mL of DMF is taken as solvent, the reaction is carried out for 12 hours at 120 ℃, and the yield of the two steps is 35%.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,Chloroform-d)δ9.50(s,1H),8.36(d,J=8.8Hz,2H),7.96(d,J=8.8Hz,2H),7.20–7.05(m,3H);19F NMR(376MHz,Chloroform-d)δ-63.30,-109.20.
Example 42: synthesis of 1- (4-aminophenyl) -5- (3-hydroxy-4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile
Prepared in analogy to example 30, as 1- (4-nitrophenyl) -5- (3-hydroxy-4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile (0.5 mmol, example 41) was added iron powder (2.5 mmol) and a further 5mL volume of mixed solvent of AcOH: etOH: H 2 o=1:10:10 was added stirring at 70 ℃ for 2 hours in 65% yield.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,DMSO-d6)δ9.62(s,1H),7.42(d,J=8.6Hz,2H),7.21(d,J=8.6Hz,2H),7.08-6.85(m,3H),5.65(s,2H);19F NMR(376MHz,DMSO-d6)δ-62.45,-109.50(s).
Example 43: synthesis of 1- (4-azidophenyl) -5- (3-hydroxy-4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile
Prepared in analogy to example 31, using 1- (4-aminophenyl) -5- (3-hydroxy-4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile (3 mmol, example 42) was completely dissolved in 15mL of EtOH, HBF 4 (6 mmol) was added dropwise at 0 degrees celsius, stirring was continued for 5min, t BuONO (6 mmol) was slowly added dropwise, stirring was continued for 30min, solids precipitated, filtered under vacuum, the solid residue was washed twice with 5mL of diethyl ether and the solid product was then taken up in the next reaction. 25mL of Schlenk tube was taken, a magnetic stirring bar was added, the above solid product (0.5 mmol), naN 3 (0.5 mmol), tetrabutylammonium bromide (1.0 equiv,0.5 mmol) was added sequentially, CH 3CN:H2 O=1:2 (v/v) solvent 1.5mL under argon, and stirred at 80℃for 12 hours in 45% yield.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,Chloroform-d)δ9.68(s,1H),7.70(d,J=8.6Hz,2H),7.30(d,J=8.5Hz,2H),7.14–7.01(m,3H).19F NMR(376MHz,Chloroform-d)δ-63.48,-109.95.
Example 44: synthesis of 4- [ 4-cyano-5- (3-hydroxy-4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] benzenesulfonamide
Prepared in analogy to example 32, using 1- (4-aminophenyl) -5- (3-hydroxy-4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile (3 mmol, example 43) was completely dissolved in 15mL of EtOH, HBF 4 (6 mmol) was added dropwise at 0 degrees celsius, stirring was continued for 5min, t BuONO (6 mmol) was slowly added dropwise, stirring was continued for 30min, solids precipitated, filtered under vacuum, the solid residue was washed twice with 5mL of diethyl ether and the solid product was then taken up in the next reaction. 25mL of Schlenk tube was taken, a magnetic stirring bar was added, the above solid product (0.5 mmol), ru (bpy) 3Cl2 (0.005equiv, 0.0025 mmol) was added, 2mL of CH 3 CN as solvent was added in place of argon, SOCl 2/H2 O=1:1 (0.5 mmol) was added, and stirring was carried out for 12 hours at 20℃under blue LED light conditions at 450 nm. After completion of the reaction of the starting materials by TLC, the reaction was monitored, washed with saturated aqueous NaCl, extracted with ethyl acetate (3X 15 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and the organic phase was spin-dried to give a sulfonyl chloride intermediate. 6mL of NH 3·H2 O was added to the sulfonyl chloride intermediate, and the mixture was stirred at room temperature for 18 hours, with a yield of 44%.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,Chloroform-d)δ7.80(d,J=8.6Hz,2H),7.68(d,J=8.8Hz,2H),7.15–7.02(m,3H),5.90(s,2H);19F NMR(376MHz,Chloroform-d)δ-63.16(s),-108.65(s).
Example 45: synthesis of 1- (4-nitrophenyl) -5- (p-fluorophenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile
Prepared in analogy to example 29, starting from 5- (p-fluorophenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile (0.5 mmol, example 7) and p-fluoronitrobenzene (0.75 mmol) potassium carbonate (0.75 mmol) as base and 3mL DMF as solvent at 120 ℃ for 12 hours in 60% yield.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,Chloroform-d)δ8.48(d,J=9.0Hz,2H),7.95(d,J=9.0Hz,2H),7.74–7.65(m,2H),7.34–7.25(m,2H);19F NMR(376MHz,Chloroform-d)δ-62.42,-108.40.
Example 46: synthesis of 1- (4-aminophenyl) -5- (p-fluorophenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile
Prepared in analogy to example 30, as 1- (4-nitrophenyl) -5- (p-fluorophenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile (0.5 mmol, example 45) was added iron powder (2.5 mmol) and then 5mL volumes of acoh:etoh: h 2 o=1:10:10, and stirred at 70 ℃ for 2 hours in 90% yield.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,DMSO-d6)δ7.82(d,J=8.5Hz,2H),7.45(d,J=8.6Hz,2H),7.30(s,2H),7.0–6.9(m,2H),5.50(s,2H);19F NMR(376MHz,DMSO-d6)δ-63.16,-108.40(s).
Example 47: synthesis of 1- (4-azidophenyl) -5- (p-fluorophenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile
Prepared in analogy to example 31, using 1- (4-aminophenyl) -5- (p-fluorophenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile (3 mmol, example 46) was completely dissolved in 15mL EtOH, HBF 4 (6 mmol) was added dropwise at 0 degrees celsius, stirring was continued for 5min, t BuONO (6 mmol) was slowly added dropwise, stirring was continued for 30min, solids precipitated, filtered off under vacuum, the solid residue was washed twice with 5mL diethyl ether and the solid product was subsequently taken up in the next reaction. 25mL of Schlenk tube was added to the solid product (0.5 mmol), naN 3 (0.5 mmol), tetrabutylammonium bromide (1.0 equiv,0.5 mmol) was added sequentially, CH 3CN:H2 O=1:2 (v/v) solvent 1.5mL under argon and stirred at 80℃for 12 hours in 65% yield.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,Chloroform-d)δ7.78(d,J=8.8Hz,2H),7.48(d,J=8.6Hz,2H),7.30–7.21(m,4H);19F NMR(376MHz,Chloroform-d)δ-62.80,-109.50.
Example 48: synthesis of 4- [ 4-cyano-5- (p-fluorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] benzenesulfonamide
Prepared in analogy to example 32, using 1- (4-aminophenyl) -5- (p-fluorophenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile (3 mmol, example 47) was completely dissolved in 15mL EtOH, HBF 4 (6 mmol) was added dropwise at 0 degrees celsius, stirring was continued for 5min, t BuONO (6 mmol) was slowly added dropwise, stirring was continued for 30min, solids precipitated, filtered off under vacuum, the solid residue was washed twice with 5mL diethyl ether and the solid product was subsequently taken up in the next reaction. 25mL of Schlenk tube was taken, a magnetic stirring bar was added, the above solid product (0.5 mmol), ru (bpy) 3Cl2 (0.005equiv, 0.0025 mmol) was added, 2mL of CH 3 CN as solvent was added in place of argon, SOCl 2/H2 O=1:1 (0.5 mmol) was added, and stirring was carried out for 12 hours at 20℃under blue LED light conditions at 450 nm. After completion of the reaction of the starting materials by TLC, the reaction was monitored, washed with saturated aqueous NaCl, extracted with ethyl acetate (3X 15 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and the organic phase was spin-dried to give a sulfonyl chloride intermediate. 6mL of NH 3·H2 O was added to the sulfonyl chloride intermediate, and the mixture was stirred at room temperature for 18 hours, with a yield of 60%.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,Chloroform-d)δ7.85(d,J=8.6Hz,2H),7.78(d,J=8.8Hz,2H),7.45(d,J=8.6Hz,2H),7.31–7.26(m,2H),5.12(s,2H);19F NMR(376MHz,Chloroform-d)δ-63.26(s),-108.80(s).
Example 49: synthesis of 1- (4-nitrophenyl) -5- (3-fluoro-4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile
Prepared in analogy to example 29, starting from 5- (3-fluoro-4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile (0.5 mmol, example 25) and p-fluoronitrobenzene (0.75 mmol) potassium carbonate (0.75 mmol) as base and 3mL DMF as solvent at 120 ℃ for 12H in 50% yield.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,Chloroform-d)δ8.42(d,J=8.8Hz,2H),7.90(d,J=8.8Hz,2H),7.50–7.30(m,3H);19F NMR(376MHz,Chloroform-d)δ-62.70,-108.80.
Example 50: synthesis of 1- (4-aminophenyl) -5- (3-fluoro-4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile
Prepared in analogy to example 30, as 1- (4-nitrophenyl) -5- (3-fluoro-4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile (0.5 mmol, example 49) was added iron powder (2.5 mmol) and a further 5mL volume of mixed solvent of AcOH: etOH: H 2 o=1:10:10 was added stirring at 70 ℃ for 2 hours in 80% yield.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,DMSO-d6)δ7.51–7.45(m,3H),7.32(d,J=8.7Hz,2H),6.55(d,J=8.7Hz,2H),5.52(s,2H),3.80(s,3H);19F NMR(376MHz,DMSO-d6)δ-61.44,-109.40(s).
Example 51: synthesis of 1- (4-azidophenyl) -5- (3-fluoro-4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile
Prepared in analogy to example 31, using 1- (4-aminophenyl) -5- (3-fluoro-4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile (3 mmol, example 50) was completely dissolved in 15mL of EtOH, HBF 4 (6 mmol) was added dropwise at 0 degrees celsius, stirring was continued for 5min, t BuONO (6 mmol) was slowly added dropwise, stirring was continued for 30min, solids precipitated, filtered under vacuum, the solid residue was washed twice with 5mL of diethyl ether and the solid product was then taken up in the next reaction. 25mL of Schlenk tube was taken, a magnetic stirring bar was added, the above solid product (0.5 mmol), naN 3 (0.5 mmol), tetrabutylammonium bromide (1.0 equiv,0.5 mmol) was added sequentially, CH 3CN:H2 O=1:2 (v/v) solvent 1.5mL under argon, and stirred at 80℃for 12 hours, yielding 60%.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,Chloroform-d)δ7.75(d,J=8.6Hz,2H),7.45–7.30(m,3H),7.20(d,J=8.6Hz,2H);19F NMR(376MHz,Chloroform-d)δ-62.90,-109.80.
Example 52: synthesis of 4- [ 4-cyano-5- (3-fluoro-4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] benzenesulfonamide
Prepared in analogy to example 32, using 1- (4-aminophenyl) -5- (3-fluoro-4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazole-4-carbonitrile (3 mmol, example 51) was completely dissolved in 15mL of EtOH, HBF 4 (6 mmol) was added dropwise at 0 degrees celsius, stirring was continued for 5min, t BuONO (6 mmol) was slowly added dropwise, stirring was continued for 30min, solids precipitated, filtered under vacuum, the solid residue was washed twice with 5mL of diethyl ether and the solid product was then taken up in the next reaction. 25mL of Schlenk tube was taken, a magnetic stirring bar was added, the above solid product (0.5 mmol), ru (bpy) 3Cl2 (0.005equiv, 0.0025 mmol) was added, 2mL of CH 3 CN as solvent was added in place of argon, SOCl 2/H2 O=1:1 (0.5 mmol) was added, and stirring was carried out for 12 hours at 20℃under blue LED light conditions at 450 nm. After completion of the reaction of the starting materials by TLC, the reaction was monitored, washed with saturated aqueous NaCl, extracted with ethyl acetate (3X 15 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and the organic phase was spin-dried to give a sulfonyl chloride intermediate. 6mL of NH 3·H2 O was added to the sulfonyl chloride intermediate, and the mixture was stirred at room temperature for 18 hours, with a yield of 55%.
Analysis of the sample by nuclear magnetic resonance to obtain 1H NMR(400MHz,Chloroform-d)δ7.85(d,J=8.4Hz,2H),7.85(d,J=8.6Hz,2H),7.45(s,1H),7.31–7.26(m,2H),3.80(s,3H);19F NMR(376MHz,Chloroform-d)δ-63.66(s),-108.20(m).
Anti-inflammatory Activity assay
The compounds obtained in compound examples 29 to 52 were selected for anti-inflammatory activity test.
1) Cell culture: RAW264.7 cells were cultured in high-sugar DMEM complete medium containing 10% fbs, and when the cell density reached 80 to 90%, the cells were scraped off with a disposable cell scraper and were cultured in accordance with 1: passaging was performed at 3 density.
2) Cell plating: cells were added to six well plates at a density of 4X 10 7 per well and placed in a 37℃incubator at 5% CO 2 overnight.
3) Cell modeling and drug administration: a medium containing LPS (lipopolysaccharide) at a concentration of 1. Mu.g/mL was prepared as a mother solution for use. The compound was dissolved in DMSO and prepared to a concentration of 1mM as a stock solution for use. The culture medium mother solution containing LPS is used as a diluent, and the compound example and the positive control celecoxib are dissolved according to a certain concentration. The final concentration of the dissolved celecoxib is 10 mu M and 5 mu M. The final concentration of compound dissolved was 10. Mu.M, 5. Mu.M, 1. Mu.M, 0.1. Mu.M.
The prepared solutions are respectively added into corresponding pore plates, placed in a 37 ℃ incubator and incubated for 48 hours with 5% CO 2, and then taken out.
4) Protein extraction and Western Blot: taking out the pore plate, washing the pore plate once with PBS, adding 200 mu L of protein lysate RIPA, performing low-temperature reaction for 30 minutes, sucking and adding the protein lysate RIPA into a centrifuge tube, centrifuging at 14000rpm for 10 minutes, sucking the supernatant, quantifying protein, preparing the protein into a corresponding loading volume after the protein concentration is leveled, adding loading buffer for boiling, and placing the sample into a refrigerator at 4 ℃ for later use.
Preparing corresponding lower glue according to the size of the protein, adding newly prepared electrophoresis liquid into the inner layer, adding recovered electrophoresis liquid into the outer layer, and converting into 120V after 20min, wherein 90min is the time. The transfer conditions were 240mA for 120 minutes. The membrane is taken out and placed in 5% concentration skimmed milk powder, and after shaking for 1 hour in a shaker, the corresponding antibody is added. Placed in a refrigerator at 4 ℃ overnight. The membrane was then removed and washed three times with TBST for 15 minutes each. Adding secondary antibody, shaking at room temperature for 1 hr, taking out, and washing the membrane with TBST three times for 15 min each time.
Results of activity test:
As shown in table 1 and in fig. 1. FIG. 1 is a graph showing the bands of the inhibitor of the compounds against protein COX2, which are the compounds obtained in examples 30,31, 32, 29, respectively.
According to the optimal dosage concentration of the positive drug celecoxib, the concentration of 10 mu M and 5 mu M are adopted, the concentration of 10 mu M, 5 mu M, 1 mu M and 0.1 mu M are selected in compound examples, the positive drug is not obviously regulated downwards compared with the protein of the compound of the administration group, and the compound obtained by the invention can inhibit protein COX2 at a lower concentration, wherein the inhibition effect of compound example 30 on protein COX2 is most obvious.
TABLE 1 anti-inflammatory Activity test results
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The results of the table show that the obtained N-aryl-3 trifluoromethyl-4 cyano pyrazole compound has good inhibition effect on key protein COX2 in a rheumatoid arthritis model through a preliminary anti-inflammatory activity test, has better effect than a positive control drug celecoxib, and has good potential for further drug development.
Claims (7)
1. A trifluoromethyl-4-cyanopyrazole compound shown in formula (I) or formula (II):
R 1 is selected from one of the formulas (1) to (5), formula (7), formula (20) and formula (21):
R 2 is selected from one of the formulas (22) to (25):
2. The trifluoromethyl-4-cyanopyrazole compound according to claim 1, wherein the compound is represented by one of the formulae L-29 to L31 and L33 to L-52:
3. a method for preparing trifluoromethyl-4-cyanopyrazole compounds, which is characterized by comprising the following steps:
The method comprises the steps of (1) reacting maleonitrile shown in a formula (III), a metal catalyst, alkali and 2, 2-trifluoro diazoethane in an organic solvent to obtain a trifluoromethyl-4-cyano pyrazole compound shown in the formula (I) in which R 2 is hydrogen;
Carrying out N-functional group conversion reaction on a trifluoromethyl-4-cyano pyrazole compound shown in a formula (I) in which R 2 is hydrogen to obtain a trifluoromethyl-4-cyano pyrazole compound shown in a formula (I) or a formula (II) in which R 2 is not hydrogen;
Wherein, R 1 is selected from one of the formulas (1) to (5), (7), (20) and (21):
R 2 is selected from one of the formulas (22) to (25):
4. The process according to claim 3, wherein the molar ratio of the maleonitrile of formula (III), the metal catalyst, the base and the 2, 2-trifluorodiazoethane is 1: (0.05-1.5): (0.5-4): (3-6).
5. The method of claim 3, wherein the metal catalyst is selected from one or more of silver oxide, silver carbonate, silver acetate, silver chloride, and silver fluoride;
The alkali is selected from one or more of N, N, N ', N' -tetramethyl ethylenediamine, potassium acetate, potassium dihydrogen phosphate, triethylene diamine and 4-dimethylaminopyridine;
The organic solvent is selected from one or more of tetrahydrofuran, 1, 4-dioxane, acetonitrile, N-dimethylformamide and toluene;
the reaction temperature is 0-50 ℃.
6. The method of claim 3, wherein the N-functional group conversion reaction comprises one or more of a nucleophilic substitution reaction, a reduction reaction, a diazotization reaction, and a sulfonylation reaction.
7. Use of a trifluoromethyl-4-cyanopyrazole compound according to any one of claims 1 to 2 or a trifluoromethyl-4-cyanopyrazole compound prepared by a preparation method according to any one of claims 3 to 6 in the preparation of a medicament for treating rheumatoid arthritis.
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