CN112920133A - (E) -4-methyl-2- (4- (trifluoromethyl) styryl) oxazole compound and preparation method and application thereof - Google Patents
(E) -4-methyl-2- (4- (trifluoromethyl) styryl) oxazole compound and preparation method and application thereof Download PDFInfo
- Publication number
- CN112920133A CN112920133A CN202110122263.XA CN202110122263A CN112920133A CN 112920133 A CN112920133 A CN 112920133A CN 202110122263 A CN202110122263 A CN 202110122263A CN 112920133 A CN112920133 A CN 112920133A
- Authority
- CN
- China
- Prior art keywords
- trifluoromethyl
- methyl
- styryl
- reaction
- oxazole
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 68
- 125000005504 styryl group Chemical group 0.000 title claims abstract description 65
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 title claims abstract description 65
- -1 oxazole compound Chemical class 0.000 title claims abstract description 45
- 150000001875 compounds Chemical class 0.000 claims abstract description 30
- 239000003814 drug Substances 0.000 claims abstract description 10
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 8
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 8
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims abstract description 8
- 125000001424 substituent group Chemical group 0.000 claims abstract description 8
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims abstract description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 4
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 104
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 52
- 239000007787 solid Substances 0.000 claims description 30
- 238000004809 thin layer chromatography Methods 0.000 claims description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- 238000001704 evaporation Methods 0.000 claims description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 238000012544 monitoring process Methods 0.000 claims description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 17
- 238000004440 column chromatography Methods 0.000 claims description 15
- ANRMAUMHJREENI-ZZXKWVIFSA-N (E)-4-(trifluoromethyl)cinnamic acid Chemical compound OC(=O)\C=C\C1=CC=C(C(F)(F)F)C=C1 ANRMAUMHJREENI-ZZXKWVIFSA-N 0.000 claims description 12
- BPRFEFAHXYCKRO-ZZXKWVIFSA-N (e)-3-[4-(trifluoromethyl)phenyl]prop-2-enamide Chemical compound NC(=O)\C=C\C1=CC=C(C(F)(F)F)C=C1 BPRFEFAHXYCKRO-ZZXKWVIFSA-N 0.000 claims description 12
- RIYDEYWRFIHXBD-ZZXKWVIFSA-N (e)-3-[4-(trifluoromethyl)phenyl]prop-2-enoyl chloride Chemical compound FC(F)(F)C1=CC=C(\C=C\C(Cl)=O)C=C1 RIYDEYWRFIHXBD-ZZXKWVIFSA-N 0.000 claims description 12
- SUNMBRGCANLOEG-UHFFFAOYSA-N 1,3-dichloroacetone Chemical compound ClCC(=O)CCl SUNMBRGCANLOEG-UHFFFAOYSA-N 0.000 claims description 12
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 12
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 11
- 238000000967 suction filtration Methods 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 239000012065 filter cake Substances 0.000 claims description 8
- 239000012453 solvate Substances 0.000 claims description 8
- 239000002552 dosage form Substances 0.000 claims description 7
- 238000000605 extraction Methods 0.000 claims description 7
- BEOBZEOPTQQELP-UHFFFAOYSA-N 4-(trifluoromethyl)benzaldehyde Chemical compound FC(F)(F)C1=CC=C(C=O)C=C1 BEOBZEOPTQQELP-UHFFFAOYSA-N 0.000 claims description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 6
- 239000012295 chemical reaction liquid Substances 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 150000002916 oxazoles Chemical class 0.000 claims description 5
- FHOQUVWQBVOKEJ-JXMROGBWSA-N FC(C1=CC=C(/C=C/C2=NC(CNC(C=CC=C3)=C3Br)=CO2)C=C1)(F)F Chemical compound FC(C1=CC=C(/C=C/C2=NC(CNC(C=CC=C3)=C3Br)=CO2)C=C1)(F)F FHOQUVWQBVOKEJ-JXMROGBWSA-N 0.000 claims description 4
- BOFFROCKPXQEEH-DHZHZOJOSA-N FC(C1=CC=C(/C=C/C2=NC(CNC3=CC=CC=C3)=CO2)C=C1)(F)F Chemical compound FC(C1=CC=C(/C=C/C2=NC(CNC3=CC=CC=C3)=CO2)C=C1)(F)F BOFFROCKPXQEEH-DHZHZOJOSA-N 0.000 claims description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 150000004677 hydrates Chemical class 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- VXWVFZFZYXOBTA-UHFFFAOYSA-N 5-bromo-1h-indole Chemical compound BrC1=CC=C2NC=CC2=C1 VXWVFZFZYXOBTA-UHFFFAOYSA-N 0.000 claims description 3
- UJQWOFFGNHVFHG-IZZDOVSWSA-N CC(C=C1)=CC=C1NCC1=COC(/C=C/C2=CC=C(C(F)(F)F)C=C2)=N1 Chemical compound CC(C=C1)=CC=C1NCC1=COC(/C=C/C2=CC=C(C(F)(F)F)C=C2)=N1 UJQWOFFGNHVFHG-IZZDOVSWSA-N 0.000 claims description 3
- YEPXWQYPHRMSJL-DHZHZOJOSA-N CC(C=CC=C1)=C1NCC1=COC(/C=C/C2=CC=C(C(F)(F)F)C=C2)=N1 Chemical compound CC(C=CC=C1)=C1NCC1=COC(/C=C/C2=CC=C(C(F)(F)F)C=C2)=N1 YEPXWQYPHRMSJL-DHZHZOJOSA-N 0.000 claims description 3
- JCKROJPFLFDBOF-JXMROGBWSA-N CC1=CC=CC(NCC2=COC(/C=C/C3=CC=C(C(F)(F)F)C=C3)=N2)=C1 Chemical compound CC1=CC=CC(NCC2=COC(/C=C/C3=CC=C(C(F)(F)F)C=C3)=N2)=C1 JCKROJPFLFDBOF-JXMROGBWSA-N 0.000 claims description 3
- BHBAKAMXKOEGOS-NYYWCZLTSA-N COC(C=C1)=CC=C1NCC1=COC(/C=C/C2=CC=C(C(F)(F)F)C=C2)=N1 Chemical compound COC(C=C1)=CC=C1NCC1=COC(/C=C/C2=CC=C(C(F)(F)F)C=C2)=N1 BHBAKAMXKOEGOS-NYYWCZLTSA-N 0.000 claims description 3
- RRVAAWPXOPHXBC-DHZHZOJOSA-N COC(C=CC=C1)=C1NCC1=COC(/C=C/C2=CC=C(C(F)(F)F)C=C2)=N1 Chemical compound COC(C=CC=C1)=C1NCC1=COC(/C=C/C2=CC=C(C(F)(F)F)C=C2)=N1 RRVAAWPXOPHXBC-DHZHZOJOSA-N 0.000 claims description 3
- NWJRFCIKVOWJED-JXMROGBWSA-N COC1=CC=CC(NCC2=COC(/C=C/C3=CC=C(C(F)(F)F)C=C3)=N2)=C1 Chemical compound COC1=CC=CC(NCC2=COC(/C=C/C3=CC=C(C(F)(F)F)C=C3)=N2)=C1 NWJRFCIKVOWJED-JXMROGBWSA-N 0.000 claims description 3
- OIOZIHCKXDQTLW-XCVCLJGOSA-N FC(C1=CC=C(/C=C/C2=NC(CNC(C=C3)=CC=C3Br)=CO2)C=C1)(F)F Chemical compound FC(C1=CC=C(/C=C/C2=NC(CNC(C=C3)=CC=C3Br)=CO2)C=C1)(F)F OIOZIHCKXDQTLW-XCVCLJGOSA-N 0.000 claims description 3
- GOGJVDDXUNCEQZ-XCVCLJGOSA-N FC(C1=CC=C(/C=C/C2=NC(CNC(C=C3)=CC=C3Cl)=CO2)C=C1)(F)F Chemical compound FC(C1=CC=C(/C=C/C2=NC(CNC(C=C3)=CC=C3Cl)=CO2)C=C1)(F)F GOGJVDDXUNCEQZ-XCVCLJGOSA-N 0.000 claims description 3
- LQTGHMBQDOQFCW-XCVCLJGOSA-N FC(C1=CC=C(/C=C/C2=NC(CNC(C=C3)=CC=C3F)=CO2)C=C1)(F)F Chemical compound FC(C1=CC=C(/C=C/C2=NC(CNC(C=C3)=CC=C3F)=CO2)C=C1)(F)F LQTGHMBQDOQFCW-XCVCLJGOSA-N 0.000 claims description 3
- NTCNXENEFGFCKG-JXMROGBWSA-N FC(C1=CC=C(/C=C/C2=NC(CNC(C=CC=C3)=C3Cl)=CO2)C=C1)(F)F Chemical compound FC(C1=CC=C(/C=C/C2=NC(CNC(C=CC=C3)=C3Cl)=CO2)C=C1)(F)F NTCNXENEFGFCKG-JXMROGBWSA-N 0.000 claims description 3
- VSNMAFGMOIYXIQ-JXMROGBWSA-N FC(C1=CC=C(/C=C/C2=NC(CNC(C=CC=C3)=C3F)=CO2)C=C1)(F)F Chemical compound FC(C1=CC=C(/C=C/C2=NC(CNC(C=CC=C3)=C3F)=CO2)C=C1)(F)F VSNMAFGMOIYXIQ-JXMROGBWSA-N 0.000 claims description 3
- OYSDICXGXOLSBP-RMKNXTFCSA-N FC(C1=CC=C(/C=C/C2=NC(CNC3=CC(Br)=CC=C3)=CO2)C=C1)(F)F Chemical compound FC(C1=CC=C(/C=C/C2=NC(CNC3=CC(Br)=CC=C3)=CO2)C=C1)(F)F OYSDICXGXOLSBP-RMKNXTFCSA-N 0.000 claims description 3
- JEASCNMPAUREFQ-RMKNXTFCSA-N FC(C1=CC=C(/C=C/C2=NC(CNC3=CC(Cl)=CC=C3)=CO2)C=C1)(F)F Chemical compound FC(C1=CC=C(/C=C/C2=NC(CNC3=CC(Cl)=CC=C3)=CO2)C=C1)(F)F JEASCNMPAUREFQ-RMKNXTFCSA-N 0.000 claims description 3
- RFLDKDRBFRIRBR-RMKNXTFCSA-N FC(C1=CC=C(/C=C/C2=NC(CNC3=CC(F)=CC=C3)=CO2)C=C1)(F)F Chemical compound FC(C1=CC=C(/C=C/C2=NC(CNC3=CC(F)=CC=C3)=CO2)C=C1)(F)F RFLDKDRBFRIRBR-RMKNXTFCSA-N 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 239000002243 precursor Substances 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 230000000259 anti-tumor effect Effects 0.000 abstract description 9
- 239000002246 antineoplastic agent Substances 0.000 abstract description 8
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 6
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- 238000011160 research Methods 0.000 abstract description 4
- 238000012827 research and development Methods 0.000 abstract description 3
- 230000000144 pharmacologic effect Effects 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 92
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 23
- 238000005160 1H NMR spectroscopy Methods 0.000 description 23
- 239000000047 product Substances 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 6
- 210000004881 tumor cell Anatomy 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 3
- 230000005918 in vitro anti-tumor Effects 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 2
- 229960005420 etoposide Drugs 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- KZDCMKVLEYCGQX-UDPGNSCCSA-N 2-(diethylamino)ethyl 4-aminobenzoate;(2s,5r,6r)-3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid;hydrate Chemical group O.CCN(CC)CCOC(=O)C1=CC=C(N)C=C1.N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 KZDCMKVLEYCGQX-UDPGNSCCSA-N 0.000 description 1
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
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- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
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- 238000000338 in vitro Methods 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
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- 239000000865 liniment Substances 0.000 description 1
- 229940040145 liniment Drugs 0.000 description 1
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- 239000011159 matrix material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 230000035407 negative regulation of cell proliferation Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
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- 230000035755 proliferation Effects 0.000 description 1
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- 239000002994 raw material Substances 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
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- 229960005322 streptomycin Drugs 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
The invention belongs to the technical field of medicines, relates to a compound with a specific chemical structure and antitumor activity, and particularly relates to a (E) -4-methyl-2- (4- (trifluoromethyl) styryl) oxazole compound and a preparation method and application thereof. The structural general formula of the compound is as follows:
wherein: r1The substituent of the group is fluorine atom, methyl, chlorine atom, methoxyl, mono-substituted in 2, 3 or 4 positions,A bromine atom or an unsubstituted group; r2The substituent of the group is methoxy group which is mono-substituted at 2, 3 or 4 position, chlorine atom or unsubstituted group. Pharmacological research shows that the compound has certain inhibitory activity on human non-small cell lung cancer A549 cells, can be used for preparing antitumor drugs, and opens up a new way for the deep research and development of the future antitumor drugs. The preparation method provided by the invention is simple and feasible, has high yield and is easy for large-scale production.
Description
Technical Field
The invention belongs to the technical field of medicines, relates to a compound with a specific chemical structure and antitumor activity, and particularly relates to an (E) -4-methyl-2- (4- (trifluoromethyl) styryl) oxazole antitumor compound and a preparation method and application thereof.
Background
Malignant tumors are still difficult diseases to treat today and are a serious global public health problem. The current anti-tumor drugs on the market have side effects of different degrees and also have defects in drug selectivity. Therefore, the synthesis of novel high-efficiency anticancer drugs is one of the hot spots in modern pharmaceutical chemistry research. Therefore, the novel anti-tumor compound is designed and synthesized, the effective active group of the xylitinib is reserved, and meanwhile, the structures of the indole and the aniline are introduced, so that a novel compound with a better anti-tumor effect is obtained.
Disclosure of Invention
In view of the problems in the prior art, the invention aims to provide an (E) -4-methyl-2- (4- (trifluoromethyl) styryl) oxazole antitumor compound, and a preparation method and application thereof. The prepared compound shows good results in-vitro antitumor activity tests. Pharmacological research shows that the compound has certain inhibitory activity on human non-small cell lung cancer A549 cells.
In order to achieve the above purpose, the invention adopts the following technical scheme.
A (E) -4-methyl-2- (4- (trifluoromethyl) styryl) oxazole compound has the following structural general formulas I and II:
wherein: r1The substituent of the group is fluorine atom, methyl, chlorine atom, methoxyl, bromine atom or unsubstituted group which is monosubstituted at 2 position, 3 position or 4 position; r2The substituent of the group is methoxy group which is mono-substituted at 2, 3 or 4 position, chlorine atom or unsubstituted group.
The (E) -4-methyl-2- (4- (trifluoromethyl) styryl) oxazole compound has the general formulas I and II, and pharmaceutically acceptable salts, hydrates, solvates or precursors thereof, and the structure of the compound is selected from any one of the following compounds:
(E) -N- ((2- (4- (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline (a 1);
(E) -2-fluoro-N- ((2- (4- (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline (a 2);
(E) -3-fluoro-N- ((2- (4 (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline (a 3);
(E) -4-fluoro-N- ((2- (4 (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline (a 4);
(E) -2-chloro-N- ((2- (4- (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline (a 5);
(E) -3-chloro-N- ((2- (4- (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline (a 6);
(E) -4-chloro-N- ((2- (4- (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline (a 7);
(E) -2-bromo-N- ((2- (4- (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline (A8);
(E) -3-bromo-N- ((2- (4- (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline (a 9);
(E) -4-bromo-N- ((2- (4- (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline (a 10);
(E) -2-methyl-N- ((2- (4- (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline (a 11);
(E) -3-methyl-N- ((2- (4- (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline (a 12);
(E) -4-methyl-N- ((2- (4- (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline (a 13);
(E) -2-methoxy-N- ((2- (4- (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline (a 14);
(E) -3-methoxy-N- ((2- (4- (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline (a 15);
(E) -4-methoxy-N- ((2- (4- (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline (a 16);
(E) -4- ((5-phenyl-1H-indol-1-yl) methyl) -2- (4- (trifluoromethyl) styryl) oxazole (B1);
(E) -4- ((5- (2-chlorophenyl) -1H-indol-1-yl) methyl) -2- (4- (trifluoromethyl) styryl) oxazole (B2);
(E) -4- ((5- (3-chlorophenyl) -1H-indol-1-yl) methyl) -2- (4- (trifluoromethyl) styryl) oxazole (B3);
(E) -4- ((5- (4-chlorophenyl) -1H-indol-1-yl) methyl) -2- (4- (trifluoromethyl) styryl) oxazole (B4);
(E) -4- ((5- (2-methoxyphenyl) -1H-indol-1-yl) methyl) -2- (4- (trifluoromethyl) styryl) oxazole (B5);
(E) -4- ((5- (3-methoxyphenyl) -1H-indol-1-yl) methyl) -2- (4- (trifluoromethyl) styryl) oxazole (B6);
(E) -4- ((5- (4-methoxyphenyl) -1H-indol-1-yl) methyl) -2- (4- (trifluoromethyl) styryl) oxazole (B7);
the preparation method of the (E) -4-methyl-2- (4- (trifluoromethyl) styryl) oxazole compound specifically comprises the following steps.
Step 1, adding 1 time (molar amount) of 4- (trifluoromethyl) benzaldehyde, 2 times of pyridine, 1.5 times of malonic acid, a small amount of piperidine and a proper amount of isopropanol into a reaction bottle, and monitoring the reaction process by using a thin-layer chromatography; after the reaction is finished, decompressing and evaporating to remove isopropanol, adding water into the reaction liquid, adjusting the pH value to be acidic, standing to precipitate solid, and performing suction filtration to obtain the (E) -3- (4- (trifluoromethyl) phenyl) acrylic acid.
Step 2, adding 1 time of (E) -3- (4- (trifluoromethyl) phenyl) acrylic acid, a proper amount of dichloromethane serving as a solvent, 2 times of thionyl chloride and a small amount of DMF (dimethyl formamide) serving as a catalyst into a reaction bottle, reacting at normal temperature, and monitoring the reaction process by thin-layer chromatography; after the reaction is finished, decompressing and evaporating to obtain (E) -3- (4- (trifluoromethyl) phenyl) acryloyl chloride.
Step 3, adding 4 times of ammonia water into a reaction bottle, and slowly adding 1 time of (E) -3- (4- (trifluoromethyl) phenyl) acryloyl chloride into the reaction bottle by using a dropping funnel; after the dropwise addition, the mixture is filtered by suction, and the filter cake is (E) -3- (4- (trifluoromethyl) phenyl) acrylamide.
Step 4, adding 1 time of (E) -3- (4- (trifluoromethyl) phenyl) acrylamide, 1.5 times of 1, 3-dichloroacetone and a proper amount of toluene as a solvent into a reaction bottle, reacting at 110 ℃, and monitoring the reaction process by thin-layer chromatography; after the reaction is finished, adding a proper amount of water, extracting with ethyl acetate, drying the extract, evaporating under reduced pressure, and purifying by column chromatography to obtain (E) -4-methyl-2- (4- (trifluoromethyl) styryl) oxazole.
And 5, adding 1 time of aniline substituted by R group, a proper amount of DMF (dimethyl formamide) as a solvent and 1 time of (E) -4-methyl-2- (4- (trifluoromethyl) styryl) oxazole into a reaction bottle, reacting at 50 ℃, and monitoring the reaction process by thin-layer chromatography. After the reaction is finished, water is added for extraction, the extract liquid is dried, decompressed and evaporated, and then the target compound is obtained through column chromatography purification.
The preparation method of the (E) -4-methyl-2- (4- (trifluoromethyl) styryl) oxazole compound and the preparation method of the compound in the general formula II concretely comprise the following steps.
Step 1, adding 1 time (molar amount) of 4- (trifluoromethyl) benzaldehyde, 2 times of pyridine, 1.5 times of malonic acid, a small amount of piperidine and a proper amount of isopropanol into a reaction bottle, and monitoring the reaction process by using a thin-layer chromatography; after the reaction is finished, decompressing and evaporating to remove isopropanol, adding water into the reaction liquid, adjusting the pH value to be acidic, standing to precipitate solid, and performing suction filtration to obtain the (E) -3- (4- (trifluoromethyl) phenyl) acrylic acid.
Step 2, adding 1 time of (E) -3- (4- (trifluoromethyl) phenyl) acrylic acid, a proper amount of dichloromethane serving as a solvent, 2 times of thionyl chloride and a small amount of DMF (dimethyl formamide) serving as a catalyst into a reaction bottle, reacting at normal temperature, and monitoring the reaction process by thin-layer chromatography; after the reaction is finished, decompressing and evaporating to obtain (E) -3- (4- (trifluoromethyl) phenyl) acryloyl chloride.
Step 3, adding 4 times of ammonia water into a reaction bottle, and slowly adding 1 time of (E) -3- (4- (trifluoromethyl) phenyl) acryloyl chloride into the reaction bottle by using a dropping funnel; after the dropwise addition, the mixture is filtered by suction, and the filter cake is (E) -3- (4- (trifluoromethyl) phenyl) acrylamide.
Step 4, adding 1 time of (E) -3- (4- (trifluoromethyl) phenyl) acrylamide, 1.5 times of 1, 3-dichloroacetone and a proper amount of toluene as a solvent into a reaction bottle, reacting at 110 ℃, and monitoring the reaction process by thin-layer chromatography; after the reaction is finished, adding a proper amount of water, extracting with ethyl acetate, drying the extract, evaporating under reduced pressure, and purifying by column chromatography to obtain (E) -4-methyl-2- (4- (trifluoromethyl) styryl) oxazole.
And step 5, adding 1 time of 5-bromoindole, 1.2 times of sodium bicarbonate and a small amount of DMF (dimethyl formamide) as a solvent into a reaction bottle, and reacting at room temperature. A large amount of bubbles are generated in the reaction, when the bubbles are not generated in the reaction, 1 time of (E) -4-methyl-2- (4- (trifluoromethyl) styryl) oxazole is slowly added, the reaction is carried out at the temperature of 50 ℃, and the reaction process is monitored by thin layer chromatography. After the reaction is finished, water is added for extraction, the extract liquid is dried, decompressed and evaporated, and then (E) -4- ((5-bromo-1H-indol-1-yl) methyl) -2- (4- (trifluoromethyl) styryl) oxazole is obtained by column chromatography.
Step 6, adding 1 time of (E) -4- ((5-bromo-1H-indol-1-yl) methyl) -2- (4- (trifluoromethyl) styryl) oxazole, 1.2 times of phenylboronic acid, 2 times of potassium carbonate, dioxane and water in a reaction bottle, wherein the weight ratio of (E) -4- ((5-bromo-1H-indol-1-yl) methyl) -2- (4- (trifluoromethyl) styryl) oxazole is 1: 3 as solvent, a small amount of Pd (pph)3)4The reaction is carried out at 85 ℃ under the protection of nitrogen for the catalyst, and the reaction progress is monitored by thin layer chromatography. After the reaction is finished, adding water for extraction, drying the extract liquor, evaporating under reduced pressure, and thenAnd purifying by column chromatography to obtain the target compound.
A pharmaceutical composition comprises the (E) -4-methyl-2- (4- (trifluoromethyl) styryl) oxazole compound, the pharmaceutically acceptable salt, the hydrate or the solvate thereof and a pharmaceutically acceptable carrier.
The (E) -4-methyl-2- (4- (trifluoromethyl) styryl) oxazole compound, isomer or pharmaceutically acceptable salt, hydrate or solvate thereof or the pharmaceutical composition is applied to the preparation of antitumor drugs.
Further, the tumor is non-small cell lung cancer.
Further, the dosage form of the drug is a pharmaceutically therapeutically acceptable dosage form.
Further, the dose of the drug is a pharmaceutically therapeutically acceptable dose.
The anti-tumor drug is a drug for resisting human non-small cell lung cancer cells (A549).
The invention also includes prodrugs of the derivatives of the invention. Prodrugs of the derivatives of the invention are derivatives of formula I and formula ii which may themselves be less active or even inactive, but which, upon administration, are converted to the corresponding biologically active form under physiological conditions (e.g., by metabolism, solvolysis, or otherwise).
The invention can contain (E) -4-methyl-2- (4- (trifluoromethyl) styryl) oxazole compounds with general formulas I and II, and pharmaceutically acceptable salts and solvates thereof as active ingredients, and the active ingredients are mixed with pharmaceutically acceptable carriers or excipients to prepare a pharmaceutical composition and prepare a clinically acceptable dosage form, wherein the pharmaceutically acceptable excipients refer to any diluents, auxiliary agents and/or carriers which can be used in the pharmaceutical field. The derivatives of the present invention may be used in combination with other active ingredients as long as they do not produce other adverse effects, such as allergic reactions.
The pharmaceutical composition of the present invention can be formulated into several dosage forms containing some excipients commonly used in the pharmaceutical field. The above-mentioned several dosage forms can adopt the dosage forms of injection, tablet, capsule, aerosol, suppository, membrane, dripping pill, external liniment and ointment, etc.
Carriers for the pharmaceutical compositions of the present invention are of the usual type available in the pharmaceutical art, including: binder, lubricant, disintegrating agent, cosolvent, diluent, stabilizer, suspending agent, pigment-free, correctant, antiseptic, solubilizer, matrix, etc.
The invention comprises the application of any (E) -4-methyl-2- (4- (trifluoromethyl) styryl) oxazole compound, isomer, pharmaceutically acceptable salt, hydrate and pharmaceutical composition in preparing anti-tumor medicaments; the pharmaceutical composition comprises any one of the (E) -4-methyl-2- (4- (trifluoromethyl) styryl) oxazole compounds, pharmaceutically acceptable salts, hydrates or solvates thereof and pharmaceutically acceptable carriers.
Compared with the prior art, the invention has the following beneficial effects.
The compound (E) -4-methyl-2- (4- (trifluoromethyl) styryl) oxazole compound provided by the invention has a remarkable effect in an in vitro anti-tumor activity test. In the design process of the invention, the (E) -4-methyl-2- (4- (trifluoromethyl) styryl) oxazole antitumor compound is designed and synthesized, the antitumor effect is greatly improved, and the compound is found to have excellent antiproliferative capability on human non-small cell lung cancer A549 cells. In the synthesis process, the preparation method of the compound is simple and feasible, has better yield and is suitable for industrial production.
Detailed Description
The present invention is further illustrated by the following specific examples, which are intended to be illustrative only and not to limit the scope of the invention.
A (E) -4-methyl-2- (4- (trifluoromethyl) styryl) oxazole compound has the following structural general formulas I and II:
wherein: r1The substituent of the group is fluorine atom, methyl, chlorine atom, methoxyl, bromine atom or unsubstituted group which is monosubstituted at 2 position, 3 position or 4 position; r2The substituent of the group is methoxy group which is mono-substituted at 2, 3 or 4 position, chlorine atom or unsubstituted group.
Example 1 preparation of (E) -N- ((2- (4- (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline (a 1).
Preparation of (E) -3- (4- (trifluoromethyl) phenyl) acrylic acid.
A500 mL reaction flask was charged with 1-fold (molar amount) amount of 4- (trifluoromethyl) benzaldehyde (30g, 0.17mol), 2-fold amount of pyridine (27.26g,0.34mol), 1.5-fold amount of malonic acid (26.89g,0.25mol), 10mL of piperidine, and 200mL of isopropanol as a solvent, and reacted at 90 ℃ with monitoring the progress of the reaction by thin layer chromatography. After the reaction is finished, decompressing and evaporating to remove isopropanol, adding water into the reaction liquid, adjusting the pH value to 2, standing to precipitate a solid, and performing suction filtration to obtain a filter cake as a product, wherein the yield is as follows: 93.5 percent.
Preparation of (E) -3- (4- (trifluoromethyl) phenyl) acryloyl chloride.
A500 mL reaction flask was charged with 1-fold amount of (E) -3- (4- (trifluoromethyl) phenyl) acrylic acid (25g, 0.11mol), 200mL of dichloromethane as a solvent, 2-fold amount of thionyl chloride (27.52g, 0.23mol), and a small amount of DMF as a catalyst, and reacted at room temperature, followed by monitoring the progress of the reaction by thin layer chromatography. After the reaction is finished, the product is obtained after reduced pressure evaporation, and the yield is as follows: 100 percent.
Preparation of (E) -3- (4- (trifluoromethyl) phenyl) acrylamide.
A500 mL reaction flask was charged with 4 times the mass of 25% aqueous ammonia (59.75g, 0.42mol), and 1 time the mass of (E) -3- (4- (trifluoromethyl) phenyl) acryloyl chloride (25g, 0.10mol) was slowly added via a dropping funnel. After dripping, performing suction filtration to obtain a filter cake as a product, wherein the yield is as follows: 90.3 percent.
Preparation of (E) -4-methyl-2- (4- (trifluoromethyl) styryl) oxazole.
A500 mL reaction flask was charged with 1-fold amount of (E) -3- (4- (trifluoromethyl) phenyl) acrylamide (20g, 0.09mol), 1.5-fold amount of 1, 3-dichloroacetone (17.70g,0.13mol), and 200mL of toluene as a solvent, and reacted at 110 ℃ for 9 hours, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is finished, adding 250mL of water, extracting with ethyl acetate, drying the extract, evaporating under reduced pressure, and purifying by column chromatography to obtain a product with the yield: 80.2 percent. Preparation of (E) -N- ((2- (4- (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline.
A500 mL reaction flask was charged with 1-fold amount of aniline (4.86g,0.05mol), 20mL of DMF as a solvent, and 1-fold amount of (E) -4-methyl-2- (4- (trifluoromethyl) styryl) oxazole (15g, 0.05mol), reacted at 50 ℃ and the progress of the reaction was monitored by thin layer chromatography. After the reaction is finished, adding water for extraction, drying the extract, evaporating under reduced pressure, and purifying by column chromatography to obtain a product, namely a white solid, with the yield: 75.2 percent.
1HNMR(600MHz,DMSO-d6)δ7.97(s,1H),7.89(d,J＝6.9Hz,2H),7.71(d,J＝8.0Hz,2H),7.54(d,J＝16.4Hz,1H),7.31(d,J＝10.4Hz,1H),7.08(t,J＝7.4Hz,2H),6.67(d,J＝7.7Hz,2H),6.55(t,J＝7.1Hz,1H),6.05(s,1H),4.19(s,2H)；13CNMR(150MHz,DMSO-d6)δ160.24,160.08,148.20,140.66,139.50,139.08,136.64,136.14,133.59,128.65,127.75,125.39,116.42,115.93,112.20,46.13；MS(ESI,m/z):345.1209[M+H]+。
Example 2 preparation of (E) -2-fluoro-N- ((2- (4- (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline (a 2).
The preparation method is the same as (A1).
White solid, yield: 78.2 percent.1HNMR(600MHz,DMSO-d6)δ7.97(s,1H),7.92(d,J＝8.0Hz,2H),7.74(d,J＝8.0Hz,2H),7.55(d,J＝16.5Hz,1H),7.29(d,J＝16.4Hz,1H),7.02(dd,J＝12.1,8.2Hz,1H),6.95(t,J＝7.7Hz,1H),6.77(t,J＝8.5Hz,1H),6.56(d,J＝5.2Hz,1H),5.88(s,1H),4.27(d,J＝5.9Hz,2H)；13CNMR(150MHz,DMSO-d6)δ160.11,151.78,149.89,140.43,139.13,136.26,136.14,136.04,133.66,127.81,125.43,124.49,116.46,115.77,114.24,114.09,112.20,38.76；MS(ESI,m/z):363.1122[M+H]+。
Example 3 preparation of (E) -3-fluoro-N- ((2- (4 (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline (a 3).
The preparation method is the same as (A1).
White solid, yield: 73.1 percent.1HNMR(600MHz,DMSO-d6)δ7.97(s,1H),7.89(d,J＝6.9Hz,2H),7.71(d,J＝8.0Hz,2H),7.54(d,J＝16.4Hz,1H),7.31(d,J＝10.4Hz,1H),7.08(t,J＝7.4Hz,1H),6.67(d,J＝7.7Hz,2H),6.55(t,J＝7.1Hz,1H),6.05(s,1H),4.19(s,2H)；13CNMR(150MHz,DMSO-d6)δ160.31,160.17,150.23,140.15,139.04,136.75,136.27,133.70,130.02,127.79,125.41,116.39,108.42,101.95,101.78,98.46,98.26,45.97；MS(ESI,m/z):363.1113[M+H]+
Example 4 preparation of (E) -4-fluoro-N- ((2- (4 (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline (a 4).
The preparation method is the same as (A1).
White solid, yield: 74.6 percent.1HNMR(600MHz,DMSO-d6)δ7.96(s,1H),7.87(d,J＝5.4Hz,2H),7.69(d,J＝7.3Hz,2H),7.53(d,J＝16.4Hz,1H),7.26(d,J＝16.4Hz,1H),6.91(d,J＝8.5Hz,2H),6.67(d,J＝4.4Hz,2H),5.98(s,1H),4.17(s,2H)；13CNMR(150MHz,DMSO-d6)δ160.26,160.10,155.32,144.87,140.54,139.35,139.03,136.66,136.12,133.60,127.70,125.35,125.01,116.36,115.08,114.90,113.00,46.60；MS(ESI,m/z):363.1115[M+H]+。
Example 5 preparation of (E) -2-chloro-N- ((2- (4 (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline (a 5).
The preparation method is the same as (A1).
Brown solid, yield: 77.5 percent.1HNMR(600MHz,DMSO-d6)δ7.95(s,1H),7.86(d,J＝7.9Hz,2H),7.68(d,J＝8.0Hz,2H),7.51(d,J＝16.4Hz,1H),7.26(t,J＝11.8Hz,2H),7.11(t,J＝7.7Hz,1H),6.78(d,J＝8.2Hz,1H),6.59(t,J＝7.5Hz,1H),5.80(s,1H),4.34(d,J＝5.6Hz,2H)；13CNMR(150MHz,DMSO-d6)δ160.19,143.49,140.13,139.07,136.25,133.69,128.80,128.62,127.79,127.48,125.40,125.04,122.87,117.87,116.74,116.41,111.47,38.85；MS(ESI,m/z):379.0812[M+H]+。
Example 6 preparation of (E) -3-chloro-N- ((2- (4 (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline (a 6).
The preparation method is the same as (A1).
Brown solid, yield: 72.1 percent.1HNMR(600MHz,DMSO-d6)δ8.00(s,1H),7.91(d,J＝7.0Hz,2H),7.72(d,J＝8.7Hz,2H),7.53(d,J＝7.5Hz,1H),7.31(d,J＝9.5Hz,1H),7.07(t,J＝8.0Hz,1H),6.68(s,1H),6.61(d,J＝8.1Hz,1H),6.55(d,J＝7.5Hz,1H),6.42(s,1H),4.19(d,J＝4.8Hz,2H)；13CNMR(150MHz,DMSO-d6)δ160.35,160.19,149.70,140.11,138.99,136.75,136.27,133.81,133.73,133.45,130.12,127.79,125.41,116.39,115.28,111.40,110.75,45.96；MS(ESI,m/z):379.0816[M+H]+。
Example 7 preparation of (E) -4-chloro-N- ((2- (4 (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline (a 7).
The preparation method is the same as (A1).
Brown solid, yield: 80.4 percent.1HNMR(600MHz,DMSO-d6)δ7.98(s,1H),7.89(d,J＝4.9Hz,2H),7.72(d,J＝8.4Hz,2H),7.52(d,J＝6.9Hz,1H),7.31(d,J＝8.8Hz,1H),7.09(d,J＝7.8Hz,2H),6.66(d,J＝7.9Hz,2H),6.28(s,1H),4.17(d,J＝4.5Hz,2H)；13CNMR(150MHz,DMSO-d6)δ160.30,160.15,147.10,140.25,139.10,136.72,136.23,133.77,133.68,128.35,127.78,125.41,119.24,116.39,114.18,113.53,46.18；MS(ESI,m/z):379.0809[M+H]+。
Example 8 preparation of (E) -2-bromo-N- ((2- (4 (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline (A8).
The preparation method is the same as (A1).
Brown solid, yield: 72.3 percent.1HNMR(600MHz,DMSO-d6)δ7.97(s,1H),7.92(d,J＝8.0Hz,2H),7.73(d,J＝7.9Hz,2H),7.55(d,J＝16.5Hz,1H),7.41(d,J＝7.8Hz,1H),7.30(d,J＝16.4Hz,1H),7.16(t,J＝7.7Hz,1H),6.76(d,J＝8.1Hz,1H),6.54(t,J＝7.5Hz,1H),5.61(s,1H),4.33(d,J＝5.6Hz,2H)；13CNMR(150MHz,DMSO-d6)δ160.22,144.45,140.04,139.09,136.26,133.74,132.08,128.36,127.81,125.42,125.04,122.88,117.44,116.42,111.65,108.53,59.55；MS(ESI,m/z):423.0302[M+H]+。
Example 9 preparation of (E) -3-bromo-N- ((2- (4 (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline (a 9).
The preparation method is the same as (A1).
Yellow solid, yield: 78.6 percent.1HNMR(600MHz,DMSO-d6)δ8.00(s,1H),7.92(d,J＝6.8Hz,2H),7.74(s,2H),7.60(d,J＝16.7Hz,1H),7.31(d,J＝10.8Hz,1H),7.01(t,J＝8.0Hz,1H),6.82(s,1H),6.68(d,J＝7.6Hz,1H),6.64(d,J＝8.2Hz,1H),6.39(s,1H),4.19(d,J＝5.3Hz,2H)；13CNMR(150MHz,DMSO-d6)δ169.86,160.46,149.87,140.10,138.07,136.28,134.26,133.75,130.47,127.88,127.81,125.44,122.11,118.17,116.41,116.16,114.34,111.04,57.24；MS(ESI,m/z):423.0321[M+H]+。
Example 10 preparation of (E) -4-bromo-N- ((2- (4 (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline (a 10).
The preparation method is the same as (A1).
White solid, yield: 74.2 percent.1HNMR(600MHz,DMSO-d6)δ7.98(s,1H),7.91(d,J＝7.9Hz,2H),7.73(d,J＝8.1Hz,2H),7.55(d,J＝16.4Hz,1H),7.28(d,J＝16.4Hz,1H),7.20(d,J＝8.4Hz,2H),6.62(d,J＝8.4Hz,2H),6.31(s,1H),4.17(d,J＝5.6Hz,2H)；13CNMR(150MHz,DMSO-d6)δ160.15,147.46,140.21,139.09,136.25,133.71,131.16,128.66,127.80,125.42,125.04,122.88,116.41,114.12,106.60,46.13；MS(ESI,m/z):423.0308[M+H]+。
Example 11 preparation of (E) -2-methyl-N- ((2- (4 (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline (a 11).
The preparation method is the same as (A1).
Brown solid, yield: 75.8 percent.1HNMR(600MHz,DMSO-d6)δ7.92(s,1H),7.90(d,J＝7.7Hz,2H),7.72(d,J＝7.7Hz,2H),7.54(d,J＝16.3Hz,1H),7.29(d,J＝16.4Hz,1H),6.97(d,J＝7.6Hz,2H),6.58(d,J＝7.9Hz,1H),6.52(t,J＝7.3Hz,1H),5.32(s,1H),4.27(d,J＝5.4Hz,2H),2.13(s,3H)；13CNMR(150MHz,DMSO-d6)δ160.04,145.79,140.98,139.12,136.13,133.53,129.60,127.75,126.47,125.42,125.39,125.04,122.88,121.84,116.48,116.00,109.42,59.54,17.41；MS(ESI,m/z):359.1369[M+H]+。
Example 12 preparation of (E) -3-methyl-N- ((2- (4 (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline (a 12).
The preparation method is the same as (A1).
White solid, yield: 74.3 percent.1HNMR(600MHz,DMSO-d6)δ7.95(s,1H),7.88(d,J＝5.3Hz,2H),7.71(d,J＝8.2Hz,2H),7.51(d,J＝6.7Hz,1H),7.30(d,J＝8.8Hz,1H),6.96(t,J＝7.7Hz,1H),6.49–6.46(m,2H),6.38(d,J＝7.3Hz,1H),5.93(s,1H),4.18(d,J＝5.4Hz,2H),2.18(s,3H)；13CNMR(150MHz,DMSO-d6)δ160.22,160.06,148.19,140.77,139.59,139.08,137.63,136.59,136.07,133.56,128.52,127.73,125.37,116.92,116.42,112.91,109.45,46.15,21.11；MS(ESI,m/z):359.1381[M+H]+。
Example 13 preparation of (E) -4-methyl-N- ((2- (4 (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline (a 13).
The preparation method is the same as (A1).
White solid, yield: 78.2 percent.1HNMR(600MHz,DMSO-d6)δ7.95(s,1H),7.91(d,J＝7.5Hz,2H),7.74(d,J＝7.9Hz,2H),7.53(d,J＝6.4Hz,1H),7.30(d,J＝7.3Hz,1H),6.89(d,J＝7.9Hz,2H),6.56(d,J＝8.0Hz,2H),5.80(s,1H),4.14(s,2H),2.14(s,3H)；13CNMR(150MHz,DMSO-d6)δ160.16,160.03,145.92,140.83,139.64,139.13,136.65,136.13,133.67,133.59,129.11,127.81,125.44,116.47,113.05,112.37,46.38,19.88；MS(ESI,m/z):359.1380[M+H]+。
Example 14 preparation of (E) -2-methoxy-N- ((2- (4 (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline (a 14).
The preparation method is the same as (A1).
White solid, yield: 74.2 percent.1HNMR(600MHz,DMSO-d6)δ7.97(s,1H),7.92(d,J＝7.7Hz,2H),7.74(d,J＝7.4Hz,2H),7.55(d,J＝16.4Hz,1H),7.31(d,J＝16.5Hz,1H),6.82(d,J＝7.8Hz,1H),6.76(t,J＝7.6Hz,1H),6.59(dd,J＝19.2,7.8Hz,2H),5.25(s,1H),4.23(d,J＝5.7Hz,2H),3.79(s,3H)；13CNMR(150MHz,DMSO-d6)δ160.13,146.39,140.52,139.14,138.12,137.34,137.05,136.13,134.27,133.64,127.90,127.81,125.46,120.80,116.47,115.98,109.67,109.54,55.15,20.41；MS(ESI,m/z):375.1325[M+H]+。
Example 15 preparation of (E) -3-methoxy-N- ((2- (4 (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline (a 15).
The preparation method is the same as (A1).
Brown solid, yield: 75.8 percent.1HNMR(600MHz,DMSO-d6)δ7.98(s,1H),7.90(d,J＝7.5Hz,2H),7.72(d,J＝8.1Hz,2H),7.55(d,J＝16.4Hz,1H),7.31(d,J＝11.2Hz,1H),6.97(t,J＝8.0Hz,1H),6.27(d,J＝7.9Hz,1H),6.23(s,1H),6.07(d,J＝5.4Hz,1H),5.06(s,1H),4.17(d,J＝5.5Hz,2H),3.66(s,3H)；13CNMR(150MHz,DMSO-d6)δ160.15,160.08,149.56,140.62,139.08,136.63,136.15,133.61,129.37,127.77,125.41,116.42,106.69,105.25,101.48,101.28,98.04,54.42,46.23；MS(ESI,m/z):375.1317[M+H]+。
Example 16 preparation of (E) -4-methoxy-N- ((2- (4 (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline (a 16).
The preparation method is the same as (A1).
Brown solid, yield: 75.4 percent.1HNMR(600MHz,DMSO-d6)δ7.96(s,1H),7.92(d,J＝7.7Hz,2H),7.74(d,J＝7.6Hz,2H),7.55(d,J＝16.4Hz,1H),7.30(d,J＝16.4Hz,1H),6.72(d,J＝7.9Hz,2H),6.52(d,J＝7.9Hz,2H),5.63(s,1H),4.13(s,2H),3.63(s,3H)；13CNMR(150MHz,DMSO-d6)δ160.02,150.87,150.55,142.40,142.12,140.93,139.13,136.11,133.59,127.79,125.44,116.47,114.81,114.41,114.35,113.33,55.12,46.92；MS(ESI,m/z):375.1334[M+H]+。
Example 17 preparation of (E) -4- ((5-phenyl-1H-indol-1-yl) methyl) -2- (4- (trifluoromethyl) styryl) oxazole (B1).
Preparation of (E) -3- (4- (trifluoromethyl) phenyl) acrylic acid.
A500 mL reaction flask was charged with 1-fold (molar amount) amount of 4- (trifluoromethyl) benzaldehyde (30g, 0.17mol), 2-fold amount of pyridine (27.26g,0.34mol), 1.5-fold amount of malonic acid (26.89g,0.25mol), 10mL of piperidine, and 200mL of isopropanol as a solvent, and reacted at 90 ℃ with monitoring the progress of the reaction by thin layer chromatography. After the reaction is finished, decompressing and evaporating to remove isopropanol, adding water into the reaction liquid, adjusting the pH value to 2, standing to precipitate a solid, and performing suction filtration to obtain a filter cake as a product, wherein the yield is as follows: 93.5 percent.
Preparation of (E) -3- (4- (trifluoromethyl) phenyl) acryloyl chloride.
A500 mL reaction flask was charged with 1-fold amount of (E) -3- (4- (trifluoromethyl) phenyl) acrylic acid (25g, 0.11mol), 200mL of dichloromethane as a solvent, 2-fold amount of thionyl chloride (27.52g, 0.23mol), and a small amount of DMF as a catalyst, and reacted at room temperature, followed by monitoring the progress of the reaction by thin layer chromatography. After the reaction is finished, the product is obtained after reduced pressure evaporation, and the yield is as follows: 100 percent.
Preparation of (E) -3- (4- (trifluoromethyl) phenyl) acrylamide.
A500 mL reaction flask was charged with 4 times the mass of 25% aqueous ammonia (59.75g, 0.42mol), and 1 time the mass of (E) -3- (4- (trifluoromethyl) phenyl) acryloyl chloride (25g, 0.10mol) was slowly added via a dropping funnel. After dripping, performing suction filtration to obtain a filter cake as a product, wherein the yield is as follows: 90.3 percent.
Preparation of (E) -4-methyl-2- (4- (trifluoromethyl) styryl) oxazole.
A500 mL reaction flask was charged with 1-fold amount of (E) -3- (4- (trifluoromethyl) phenyl) acrylamide (20g, 0.09mol), 1.5-fold amount of 1, 3-dichloroacetone (17.70g,0.13mol), and 200mL of toluene as a solvent, and reacted at 110 ℃ for 9 hours, and the progress of the reaction was monitored by thin layer chromatography. After the reaction is finished, adding 250mL of water, extracting with ethyl acetate, drying the extract, evaporating under reduced pressure, and purifying by column chromatography to obtain a product with the yield: 80.2 percent; preparation of (E) -4- ((5-bromo-1H-indol-1-yl) methyl) -2- (4- (trifluoromethyl) styryl) oxazole.
A250 mL reaction flask was charged with 1-fold amount of 5-bromoindole (10.22g, 52.14mmol), 1.2-fold amount of 60% by mass sodium hydrogen (2.50g, 62.57mmol) and DMF25 mL as a solvent, and reacted at room temperature. A large amount of bubbles are generated in the reaction, when the bubbles are not generated in the reaction, 1 time of (E) -4-methyl-2- (4- (trifluoromethyl) styryl) oxazole (15g, 52.14mmol) is slowly added for reaction at the temperature of 50 ℃, and the reaction process is monitored by thin layer chromatography. After the reaction is finished, adding 300mL of water, extracting with ethyl acetate, drying the extract, evaporating under reduced pressure, and purifying by column chromatography to obtain a product, namely a yellow solid, with the yield: 80.6 percent.
Preparation of (E) -4- ((5-phenyl-1H-indol-1-yl) methyl) -2- (4- (trifluoromethyl) styryl) oxazole.
A100 mL reaction flask was charged with 1-fold amount of (E) -4- ((5-bromo-1H-indol-1-yl) methyl) -2- (4- (trifluoromethyl) styryl) oxazole (1g, 2.24mmol), 1.2-fold amount of phenylboronic acid (0.32g, 2.68mmol), 2-fold amount of potassium carbonate (0.61g, 4.47mmol), 5mL of dioxane, 15mL of water as a solvent, and a small amount of Pd (pph)3)4The reaction is carried out at 85 ℃ under the protection of nitrogen for the catalyst, and the reaction progress is monitored by thin layer chromatography. After the reaction is finished, adding 100mL of water, extracting with ethyl acetate, separating liquid to obtain an organic layer, drying the extract liquid with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by column chromatography to obtain a product, namely a white solid, with the yield: 85.3 percent.
1HNMR(600MHz,DMSO-d6)δ8.11(s,1H),7.87(d,J＝7.9Hz,2H),7.74(s,1H),7.70(d,J＝8.0Hz,2H),7.65(d,J＝8.2Hz,1H),7.58(d,J＝8.7Hz,1H),7.50(d,J＝6.1Hz,2H),7.47–7.37(m,3H),7.34(d,J＝7.2Hz,1H),7.27(s,1H),7.25(d,J＝8.6Hz,1H),6.47(s,1H),5.35(s,2H)；13CNMR(150MHz,DMSO-d6)δ160.48,138.26,136.79,134.32,134.11,133.92,130.21,129.97,129.79,129.16,128.57,127.82,127.22,127.14,126.55,125.38,123.43,122.48,116.20,115.09,111.98,111.74,100.56,59.55；MS(ESI,m/z):445.1529[M+H]+。
Example 18 preparation of (E) -4- ((5- (2-chlorophenyl) -1H-indol-1-yl) methyl) -2- (4- (trifluoromethyl) styryl) oxazole (B2).
The preparation method is the same as (B1).
Yellow solid, yield: 78.5 percent.1HNMR(600MHz,DMSO-d6)δ8.19(s,1H,),7.89(d,J＝7.9Hz,2H),7.71(d,J＝8.0Hz,2H),7.67(d,J＝8.5Hz,1H),7.59(s,1H),7.55–7.50(m,3H,),7.42(d,J＝6.8Hz,1H,),7.38(t,J＝7.5Hz,1H),7.34(t,J＝7.4Hz,1H),7.29(d,J＝16.5Hz,1H),7.21(d,J＝8.4Hz,1H),6.53(s,1H),5.39(s,2H)；13CNMR(150MHz,DMSO-d6)δ160.48,140.93,138.99,138.47,136.85,134.95,134.09,131.74,131.54,129.89,129.54,129.47,128.70,128.18,127.93,127.84,127.09,125.43,125.03,122.87,122.56,121.01,116.27,109.57,101.24,41.20；MS(ESI,m/z):479.1135[M+H]+
Example 19 preparation of (E) -4- ((5- (3-chlorophenyl) -1H-indol-1-yl) methyl) -2- (4- (trifluoromethyl) styryl) oxazole (B3).
The preparation method is the same as (B1).
Yellow solid, yield: 84.2 percent.1HNMR(600MHz,DMSO-d6)δ8.16(s,1H,),7.90(d,J＝7.8Hz,2H),7.87(s,1H),7.73(s,1H),7.71(d,J＝6.1Hz,2H),7.68(d,J＝9.0Hz,1H),7.63(d,J＝7.6Hz,1H),7.52(d,J＝17.1Hz,2H),7.46(m,2H),7.34(d,J＝7.9Hz,1H),7.28(d,J＝16.7Hz,1H),6.54(s,1H),5.38(s,2H)；13CNMR(150MHz,DMSO-d6)δ160.48,140.93,138.99,138.47,136.85,134.95,134.09,131.74,131.54,129.89,129.54,129.47,128.70,128.18,127.93,127.84,127.09,125.43,125.03,122.87,122.56,121.01,116.27,109.57,101.24,41.20；MS(ESI,m/z):479.1137[M+H]+。
Example 20 preparation of (E) -4- ((5- (4-chlorophenyl) -1H-indol-1-yl) methyl) -2- (4- (trifluoromethyl) styryl) oxazole (B4).
The preparation method is the same as (B1).
Yellow solid, yield: 84.6 percent.1HNMR(600MHz,DMSO-d6)δ8.11(s,1H,),7.87(d,J＝7.9Hz,2H),7.74(s,1H),7.70(d,J＝8.0Hz,2H),7.67(d,J＝9.0Hz,2H),7.58(d,J＝8.7Hz,1H),7.50(m,4H),7.27(s,1H),7.23(d,J＝7.6Hz,1H),6.46(s,1H),5.35(s,2H)；13CNMR(150MHz,DMSO-d6)δ160.46,142.40,139.00,138.53,136.87,134.72,134.58,134.09,132.38,129.98,129.79,129.62,129.24,128.94,128.07,127.86,127.05,126.41,125.55,125.45,122.46,120.46,116.29,109.52,101.03,59.57；MS(ESI,m/z):479.1139[M+H]+。
Example 21 preparation of (E) -4- ((5- (2-methoxyphenyl) -1H-indol-1-yl) methyl) -2- (4- (trifluoromethyl) styryl) oxazole (B5).
The preparation method is the same as (B1).
White solid, yield: 86.3％。1HNMR(600MHz,DMSO-d6)δ8.15(s,1H),7.90(d,J＝7.9Hz,2H),7.72(d,J＝8.0Hz,2H),7.62(s,1H),7.59(d,J＝8.5Hz,1H),7.53(d,J＝16.7Hz,1H),7.47(d,J＝1.6Hz,1H),7.31–7.24(m,4H),7.08(d,J＝8.4Hz,1H),7.01(t,J＝7.3Hz,1H),6.49(s,1H),5.36(s,2H),3.74(s,3H)；13CNMR(150MHz,DMSO-d6)δ160.45,156.11,139.01,138.61,136.76,134.67,134.07,131.14,130.53,129.26,128.99,128.70,128.01,127.85,127.74,125.44,123.42,122.95,122.47,120.90,120.50,116.29,111.54,109.27,101.10,55.25,41.20；MS(ESI,m/z):475.1632[M+H]+。
Example 22 preparation of (E) -4- ((5- (3-methoxyphenyl) -1H-indol-1-yl) methyl) -2- (4- (trifluoromethyl) styryl) oxazole (B6).
The preparation method is the same as (B1). White solid, yield: 84.5 percent.
1HNMR(600MHz,DMSO-d6)δ8.13(s,1H),7.87(d,J＝8.0Hz,2H),7.84(s,1H),7.70(d,J＝8.1Hz,2H),7.66(d,J＝8.6Hz,1H),7.49(d,J＝3.5Hz,2H),7.46(d,J＝8.6Hz,1H),7.34(t,J＝7.9Hz,1H),7.28(d,J＝6.3Hz,1H),7.25–7.22(m,1H),7.20(s,1H),6.87(d,J＝8.0Hz,1H),6.54(s,1H),5.36(d,J＝10.5Hz,2H),3.82(s,3H)；13CNMR(150MHz,DMSO-d6)δ160.46,159.55,143.07,138.98,138.55,136.76,135.28,134.07,131.58,129.57,129.48,128.68,127.82,125.42,125.03,122.87,122.48,120.50,118.96,118.51,116.25,112.13,111.69,110.28,101.39,54.86,41.26；MS(ESI,m/z):475.1627[M+H]+。
Example 23 preparation of (E) -4- ((5- (4-methoxyphenyl) -1H-indol-1-yl) methyl) -2- (4- (trifluoromethyl) styryl) oxazole (B7).
The preparation method is the same as (B1).
White solid, yield: 82.3 percent.1HNMR(600MHz,DMSO-d6)δ8.13(s,1H),7.89(d,J＝7.9Hz,2H),7.75(s,1H),7.71(d,J＝7.9Hz,2H),7.63(d,J＝8.5Hz,1H),7.58(d,J＝8.1Hz,2H),7.56–7.46(m,3H),7.39(d,J＝8.5Hz,1H),7.28(d,J＝16.2Hz,1H),6.99(d,J＝8.2Hz,2H),6.50(s,1H),5.36(s,2H),3.78(s,3H)；13CNMR(150MHz,DMSO-d6)δ160.46,142.40,139.00,138.53,136.87,134.72,134.58,134.09,132.38,129.98,129.79,129.62,129.24,128.94,128.07,127.86,127.05,126.41,125.55,125.45,122.46,120.46,116.29,109.52,101.03,59.57,41.17；MS(ESI,m/z):475.1629[M+H]+。
Example 24 inhibition of tumor cell proliferation assay.
The compound of the invention is subjected to tumor cell proliferation inhibition experiments, and the test method adopts a conventional MTT method.
Culturing of tumor cells: the cell selection was carried out in A549 (human non-small cell lung carcinoma cell) McCoy's5A + 10% FBS + double antibody (penicillin 100 units/mL, streptomycin 100. mu.g/mL).
Sample preparation: after dissolution in DMSO (Merck), media (-) was added to make a 1000. mu.g/mL solution or homogeneous suspension, which was then diluted with DMSO-containing media (-). The final concentrations were: 50. mu.M, 25. mu.M, 12.5. mu.M, 6.25. mu.M, 3.125. mu.M. Etoposide (Etoposide) was used as a control.
Test methods for inhibition of cell proliferation: the adding concentration of each hole of the 96-hole plate is 4-5 multiplied by 104Cell suspension 100. mu.L/mL, at 37 ℃ in 5% CO2In the incubator. After 24 hours, the sample solution and the control solution were added, respectively, at 10. mu.L/well, in duplicate wells, at 37 ℃ with 5% CO2The reaction was carried out for 24 hours. Adding 20 μ L of 5mg/mL MTT (3- (4, 5-dimethylthiazol-2-yl) -2, 5-diphenyltetrazolium bromide) solution into each well, reacting for 4 hr, adding DMSO solution into each well, placing in incubator, dissolving, measuring 570nm OD value with MK-2 full-automatic enzyme standard instrument, and calculating inhibitory concentration IC50。
The results are shown in Table 1.
TABLE 1 in vitro proliferation inhibitory Activity of samples on human tumor cells IC50The value is obtained.
The experimental data show that most of the compounds in the invention have better in-vitro anti-tumor activity, have more value in further research and development of new anti-tumor drugs, and provide a wider idea for research and development of new drugs. The invention proves that the compound has the function of inhibiting the tumor activity according to the tumor cell line test (human non-small cell lung cancer cells). The compound provided by the invention has easily available raw materials, and experiments prove that the compound has good anticancer effect and good application prospect in the field of design and research of antitumor drugs.
Claims (9)
1. The (E) -4-methyl-2- (4- (trifluoromethyl) styryl) oxazole compound is characterized in that the structural general formulas I and II of the compound are as follows:
wherein: r1The substituent of the group is fluorine atom, methyl, chlorine atom, methoxyl, bromine atom or unsubstituted group which is monosubstituted at 2 position, 3 position or 4 position; r2The substituent of the group is methoxy group which is mono-substituted at 2, 3 or 4 position, chlorine atom or unsubstituted group.
2. The (E) -4-methyl-2- (4- (trifluoromethyl) styryl) oxazole compound of claim 1 wherein the compounds of formula I and II, isomers and pharmaceutically acceptable salts, hydrates, solvates or precursors thereof, have a structure selected from any one of the following:
(E) -N- ((2- (4- (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline;
(E) -2-fluoro-N- ((2- (4- (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline;
(E) -3-fluoro-N- ((2- (4 (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline;
(E) -4-fluoro-N- ((2- (4 (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline;
(E) -2-chloro-N- ((2- (4- (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline;
(E) -3-chloro-N- ((2- (4- (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline;
(E) -4-chloro-N- ((2- (4- (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline;
(E) -2-bromo-N- ((2- (4- (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline;
(E) -3-bromo-N- ((2- (4- (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline;
(E) -4-bromo-N- ((2- (4- (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline;
(E) -2-methyl-N- ((2- (4- (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline;
(E) -3-methyl-N- ((2- (4- (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline;
(E) -4-methyl-N- ((2- (4- (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline;
(E) -2-methoxy-N- ((2- (4- (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline;
(E) -3-methoxy-N- ((2- (4- (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline;
(E) -4-methoxy-N- ((2- (4- (trifluoromethyl) styryl) oxazol-4-yl) methyl) aniline;
(E) -4- ((5-phenyl-1H-indol-1-yl) methyl) -2- (4- (trifluoromethyl) styryl) oxazole;
(E) -4- ((5- (2-chlorophenyl) -1H-indol-1-yl) methyl) -2- (4- (trifluoromethyl) styryl) oxazole;
(E) -4- ((5- (3-chlorophenyl) -1H-indol-1-yl) methyl) -2- (4- (trifluoromethyl) styryl) oxazole;
(E) -4- ((5- (4-chlorophenyl) -1H-indol-1-yl) methyl) -2- (4- (trifluoromethyl) styryl) oxazole;
(E) -4- ((5- (2-methoxyphenyl) -1H-indol-1-yl) methyl) -2- (4- (trifluoromethyl) styryl) oxazole;
(E) -4- ((5- (3-methoxyphenyl) -1H-indol-1-yl) methyl) -2- (4- (trifluoromethyl) styryl) oxazole;
(E) -4- ((5- (4-methoxyphenyl) -1H-indol-1-yl) methyl) -2- (4- (trifluoromethyl) styryl) oxazole.
3. The method for preparing (E) -4-methyl-2- (4- (trifluoromethyl) styryl) oxazole compounds according to claim 1 wherein the method for preparing the compound of formula I comprises the steps of:
step 1, adding 1 time (molar amount) of 4- (trifluoromethyl) benzaldehyde, 2 times of pyridine, 1.5 times of malonic acid, a small amount of piperidine and a proper amount of isopropanol into a reaction bottle, and monitoring the reaction process by using a thin-layer chromatography; after the reaction is finished, decompressing and evaporating to remove isopropanol, adding water into the reaction liquid, adjusting the pH value to acidity, standing to precipitate a solid, and performing suction filtration to obtain (E) -3- (4- (trifluoromethyl) phenyl) acrylic acid;
step 2, adding 1 time of (E) -3- (4- (trifluoromethyl) phenyl) acrylic acid, a proper amount of dichloromethane serving as a solvent, 2 times of thionyl chloride and a small amount of DMF (dimethyl formamide) serving as a catalyst into a reaction bottle, reacting at normal temperature, and monitoring the reaction process by thin-layer chromatography; after the reaction is finished, decompressing and evaporating to obtain (E) -3- (4- (trifluoromethyl) phenyl) acryloyl chloride;
step 3, adding 4 times of ammonia water into a reaction bottle, and slowly adding 1 time of (E) -3- (4- (trifluoromethyl) phenyl) acryloyl chloride into the reaction bottle by using a dropping funnel; after the dropwise adding is finished, carrying out suction filtration to obtain a filter cake which is (E) -3- (4- (trifluoromethyl) phenyl) acrylamide;
step 4, adding 1 time of (E) -3- (4- (trifluoromethyl) phenyl) acrylamide, 1.5 times of 1, 3-dichloroacetone and a proper amount of toluene as a solvent into a reaction bottle, reacting at 110 ℃, and monitoring the reaction process by thin-layer chromatography; after the reaction is finished, adding a proper amount of water, extracting with ethyl acetate, drying the extract, evaporating under reduced pressure, and purifying by column chromatography to obtain (E) -4-methyl-2- (4- (trifluoromethyl) styryl) oxazole;
and 5, adding 1 time of aniline substituted by R group, a proper amount of DMF (dimethyl formamide) as a solvent and 1 time of (E) -4-methyl-2- (4- (trifluoromethyl) styryl) oxazole into a reaction bottle, reacting at 50 ℃, and monitoring the reaction process by thin-layer chromatography. After the reaction is finished, water is added for extraction, the extract liquid is dried, decompressed and evaporated, and then the target compound is obtained through column chromatography purification.
4. The method for preparing (E) -4-methyl-2- (4- (trifluoromethyl) styryl) oxazole compounds according to claim 1 wherein the method for preparing the compounds of formula II comprises the steps of:
step 1, adding 1 time (molar amount) of 4- (trifluoromethyl) benzaldehyde, 2 times of pyridine, 1.5 times of malonic acid, a small amount of piperidine and a proper amount of isopropanol into a reaction bottle, and monitoring the reaction process by using a thin-layer chromatography; after the reaction is finished, decompressing and evaporating to remove isopropanol, adding water into the reaction liquid, adjusting the pH value to acidity, standing to precipitate a solid, and performing suction filtration to obtain (E) -3- (4- (trifluoromethyl) phenyl) acrylic acid;
step 2, adding 1 time of (E) -3- (4- (trifluoromethyl) phenyl) acrylic acid, a proper amount of dichloromethane serving as a solvent, 2 times of thionyl chloride and a small amount of DMF (dimethyl formamide) serving as a catalyst into a reaction bottle, reacting at normal temperature, and monitoring the reaction process by thin-layer chromatography; after the reaction is finished, decompressing and evaporating to obtain (E) -3- (4- (trifluoromethyl) phenyl) acryloyl chloride;
step 3, adding 4 times of ammonia water into a reaction bottle, and slowly adding 1 time of (E) -3- (4- (trifluoromethyl) phenyl) acryloyl chloride into the reaction bottle by using a dropping funnel; after the dropwise adding is finished, carrying out suction filtration to obtain a filter cake which is (E) -3- (4- (trifluoromethyl) phenyl) acrylamide;
step 4, adding 1 time of (E) -3- (4- (trifluoromethyl) phenyl) acrylamide, 1.5 times of 1, 3-dichloroacetone and a proper amount of toluene as a solvent into a reaction bottle, reacting at 110 ℃, and monitoring the reaction process by thin-layer chromatography; after the reaction is finished, adding a proper amount of water, extracting with ethyl acetate, drying the extract, evaporating under reduced pressure, and purifying by column chromatography to obtain (E) -4-methyl-2- (4- (trifluoromethyl) styryl) oxazole;
and step 5, adding 1 time of 5-bromoindole, 1.2 times of sodium bicarbonate and a small amount of DMF (dimethyl formamide) as a solvent into a reaction bottle, and reacting at room temperature. A large amount of bubbles are generated in the reaction, when the bubbles are not generated in the reaction, 1 time of (E) -4-methyl-2- (4- (trifluoromethyl) styryl) oxazole is slowly added, the reaction is carried out at the temperature of 50 ℃, and the reaction process is monitored by thin layer chromatography. After the reaction is finished, adding water for extraction, drying the extract, evaporating under reduced pressure, and performing column chromatography to obtain (E) -4- ((5-bromo-1H-indol-1-yl) methyl) -2- (4- (trifluoromethyl) styryl) oxazole;
step 6, adding 1 time of (E) -4- ((5-bromo-1H-indol-1-yl) methyl) -2- (4- (trifluoromethyl) styryl) oxazole, 1.2 times of phenylboronic acid, 2 times of potassium carbonate, dioxane and water in a reaction bottle, wherein the weight ratio of (E) -4- ((5-bromo-1H-indol-1-yl) methyl) -2- (4- (trifluoromethyl) styryl) oxazole is 1: 3 as solvent, a small amount of Pd (pph)3)4The reaction is carried out at 85 ℃ under the protection of nitrogen for the catalyst, and the reaction progress is monitored by thin layer chromatography. After the reaction is finished, water is added for extraction, the extract liquid is dried, decompressed and evaporated, and then the target compound is obtained through column chromatography purification.
5. A pharmaceutical composition comprising (E) -4-methyl-2- (4- (trifluoromethyl) styryl) oxazole compound of claim 1, a pharmaceutically acceptable salt, hydrate or solvate thereof and a pharmaceutically acceptable carrier.
6. Use of (E) -4-methyl-2- (4- (trifluoromethyl) styryl) oxazole compounds, isomers or pharmaceutically acceptable salts, hydrates or solvates thereof according to claim 1 or a pharmaceutical composition according to claim 5 for the preparation of a medicament for the treatment of tumors.
7. The use of claim 6, wherein the tumor is non-small cell lung cancer.
8. The use of claim 6, wherein the medicament is in a pharmaceutically-therapeutically acceptable dosage form.
9. The use of claim 6, wherein the dose of the medicament is a pharmacotherapeutically acceptable dose.
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| WO2002051849A1 (en) * | 2000-12-26 | 2002-07-04 | Daiichi Pharmaceutical Co., Ltd. | Cdk4 inhibitors |
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| CN111886234A (en) * | 2017-11-03 | 2020-11-03 | 蒙特利尔大学 | Heterocyclic mitochondrial activity inhibitors and uses thereof |
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| WO2002051849A1 (en) * | 2000-12-26 | 2002-07-04 | Daiichi Pharmaceutical Co., Ltd. | Cdk4 inhibitors |
| CN1780830A (en) * | 2003-04-30 | 2006-05-31 | 霍夫曼-拉罗奇有限公司 | Aniline derivatives, their manufacture and use as pharmaceutical agents |
| JP2005023007A (en) * | 2003-06-30 | 2005-01-27 | Takeda Chem Ind Ltd | Heterocyclic compound and its use |
| WO2005095388A1 (en) * | 2004-03-05 | 2005-10-13 | F. Hoffmann-La Roche Ag | Pentafluorosulfanyl compounds, their manufacture and use as pharmaceutical agents |
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