CN108976173A - 一种4-芳基-2-(2-(硫三氟甲基)芳基)喹唑啉的制备方法 - Google Patents
一种4-芳基-2-(2-(硫三氟甲基)芳基)喹唑啉的制备方法 Download PDFInfo
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- CN108976173A CN108976173A CN201810895951.8A CN201810895951A CN108976173A CN 108976173 A CN108976173 A CN 108976173A CN 201810895951 A CN201810895951 A CN 201810895951A CN 108976173 A CN108976173 A CN 108976173A
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- Prior art keywords
- quinazoline
- aryl
- trifluoromethyl
- sulphur trifluoromethyl
- phenyl
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- 125000003118 aryl group Chemical group 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 title claims description 20
- 229910052717 sulfur Inorganic materials 0.000 title abstract 4
- 239000011593 sulfur Substances 0.000 title abstract 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 44
- -1 quinazoline compound Chemical class 0.000 claims abstract description 43
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 28
- 239000003054 catalyst Substances 0.000 claims abstract description 27
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims abstract description 22
- 150000003246 quinazolines Chemical class 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 10
- 238000010499 C–H functionalization reaction Methods 0.000 claims abstract description 4
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims abstract description 3
- 229910052709 silver Inorganic materials 0.000 claims abstract description 3
- 239000004332 silver Substances 0.000 claims abstract description 3
- 239000000758 substrate Substances 0.000 claims abstract description 3
- 239000005864 Sulphur Substances 0.000 claims description 75
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 50
- 239000003960 organic solvent Substances 0.000 claims description 25
- 125000003963 dichloro group Chemical group Cl* 0.000 claims description 21
- WQIQNKQYEUMPBM-UHFFFAOYSA-N pentamethylcyclopentadiene Chemical compound CC1C(C)=C(C)C(C)=C1C WQIQNKQYEUMPBM-UHFFFAOYSA-N 0.000 claims description 21
- PZSJYEAHAINDJI-UHFFFAOYSA-N rhodium(3+) Chemical compound [Rh+3] PZSJYEAHAINDJI-UHFFFAOYSA-N 0.000 claims description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- IDTLIHPSZJWDAC-UHFFFAOYSA-N FC(F)(F)[Ag].[S] Chemical compound FC(F)(F)[Ag].[S] IDTLIHPSZJWDAC-UHFFFAOYSA-N 0.000 claims description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 238000006471 dimerization reaction Methods 0.000 claims description 2
- 150000003949 imides Chemical class 0.000 claims description 2
- 125000002346 iodo group Chemical group I* 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 5
- 238000007086 side reaction Methods 0.000 abstract description 3
- 230000035484 reaction time Effects 0.000 abstract description 2
- QVLTVILSYOWFRM-UHFFFAOYSA-L CC1=C(C)C(C)([Rh](Cl)Cl)C(C)=C1C Chemical class CC1=C(C)C(C)([Rh](Cl)Cl)C(C)=C1C QVLTVILSYOWFRM-UHFFFAOYSA-L 0.000 abstract 1
- 238000006555 catalytic reaction Methods 0.000 abstract 1
- 239000000539 dimer Substances 0.000 abstract 1
- 238000000746 purification Methods 0.000 abstract 1
- 238000000926 separation method Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 108
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 39
- 239000000047 product Substances 0.000 description 27
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 19
- 238000010521 absorption reaction Methods 0.000 description 19
- 239000012043 crude product Substances 0.000 description 19
- 230000026045 iodination Effects 0.000 description 19
- 238000006192 iodination reaction Methods 0.000 description 19
- 239000000741 silica gel Substances 0.000 description 19
- 229910002027 silica gel Inorganic materials 0.000 description 19
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 18
- 238000004293 19F NMR spectroscopy Methods 0.000 description 18
- 238000005160 1H NMR spectroscopy Methods 0.000 description 18
- 239000003921 oil Substances 0.000 description 18
- 239000002904 solvent Substances 0.000 description 17
- 238000010898 silica gel chromatography Methods 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 238000002156 mixing Methods 0.000 description 13
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 12
- 229910052731 fluorine Inorganic materials 0.000 description 10
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 6
- 229910020323 ClF3 Inorganic materials 0.000 description 5
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 5
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 5
- 239000011737 fluorine Substances 0.000 description 5
- 229910052710 silicon Inorganic materials 0.000 description 5
- 239000010703 silicon Substances 0.000 description 5
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 125000001153 fluoro group Chemical group F* 0.000 description 4
- 238000006692 trifluoromethylation reaction Methods 0.000 description 4
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 150000002391 heterocyclic compounds Chemical class 0.000 description 3
- 239000000575 pesticide Substances 0.000 description 3
- XEEQGYMUWCZPDN-DOMZBBRYSA-N (-)-(11S,2'R)-erythro-mefloquine Chemical compound C([C@@H]1[C@@H](O)C=2C3=CC=CC(=C3N=C(C=2)C(F)(F)F)C(F)(F)F)CCCN1 XEEQGYMUWCZPDN-DOMZBBRYSA-N 0.000 description 2
- HIISVQYDQWJITQ-UHFFFAOYSA-N 1h-pyrrole;quinoline Chemical class C=1C=CNC=1.N1=CC=CC2=CC=CC=C21 HIISVQYDQWJITQ-UHFFFAOYSA-N 0.000 description 2
- NGLJTEMOTTVIEA-UHFFFAOYSA-N 2-(2-methylphenyl)-4-(4-methylphenyl)quinazoline Chemical compound C1(=C(C=CC=C1)C1=NC2=CC=CC=C2C(=N1)C1=CC=C(C=C1)C)C NGLJTEMOTTVIEA-UHFFFAOYSA-N 0.000 description 2
- ZRNSSRODJSSVEJ-UHFFFAOYSA-N 2-methylpentacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCC(C)C ZRNSSRODJSSVEJ-UHFFFAOYSA-N 0.000 description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 description 2
- 239000005780 Fluazinam Substances 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 230000001644 anti-hepatocarcinoma Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 description 2
- 229960003804 efavirenz Drugs 0.000 description 2
- UZCGKGPEKUCDTF-UHFFFAOYSA-N fluazinam Chemical compound [O-][N+](=O)C1=CC(C(F)(F)F)=C(Cl)C([N+]([O-])=O)=C1NC1=NC=C(C(F)(F)F)C=C1Cl UZCGKGPEKUCDTF-UHFFFAOYSA-N 0.000 description 2
- 238000003682 fluorination reaction Methods 0.000 description 2
- 229960002949 fluorouracil Drugs 0.000 description 2
- 230000000855 fungicidal effect Effects 0.000 description 2
- 239000000417 fungicide Substances 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 229960001962 mefloquine Drugs 0.000 description 2
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- PFFIDZXUXFLSSR-UHFFFAOYSA-N 1-methyl-N-[2-(4-methylpentan-2-yl)-3-thienyl]-3-(trifluoromethyl)pyrazole-4-carboxamide Chemical compound S1C=CC(NC(=O)C=2C(=NN(C)C=2)C(F)(F)F)=C1C(C)CC(C)C PFFIDZXUXFLSSR-UHFFFAOYSA-N 0.000 description 1
- MSCWFMYBYQEEGV-UHFFFAOYSA-N 2,4-bis(2-methylphenyl)quinazoline Chemical compound C1(=C(C=CC=C1)C1=NC2=CC=CC=C2C(=N1)C1=C(C=CC=C1)C)C MSCWFMYBYQEEGV-UHFFFAOYSA-N 0.000 description 1
- SLZKSEMOXRULHQ-UHFFFAOYSA-N 2-(2-methylphenyl)quinoline Chemical compound CC1=CC=CC=C1C1=CC=C(C=CC=C2)C2=N1 SLZKSEMOXRULHQ-UHFFFAOYSA-N 0.000 description 1
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 1
- OJQTVSGHMGXMOV-UHFFFAOYSA-N 4-(2-methylphenyl)quinazoline Chemical compound CC1=CC=CC=C1C1=NC=NC2=CC=CC=C12 OJQTVSGHMGXMOV-UHFFFAOYSA-N 0.000 description 1
- IPKFDHOTYYPLRE-UHFFFAOYSA-N 4-(4-fluorophenyl)-2-(2-methylphenyl)quinazoline Chemical compound FC1=CC=C(C=C1)C1=NC(=NC2=CC=CC=C12)C1=C(C=CC=C1)C IPKFDHOTYYPLRE-UHFFFAOYSA-N 0.000 description 1
- PLBAPWNXCCHIFU-UHFFFAOYSA-N 4-(4-methoxyphenyl)-2-(2-methylphenyl)quinazoline Chemical compound COC1=CC=C(C=C1)C1=NC(=NC2=CC=CC=C12)C1=C(C=CC=C1)C PLBAPWNXCCHIFU-UHFFFAOYSA-N 0.000 description 1
- LRPOWONLCIWBTQ-UHFFFAOYSA-N 5-chloro-2,4-bis(2-methylphenyl)quinazoline Chemical compound ClC1=C2C(=NC(=NC2=CC=C1)C1=C(C=CC=C1)C)C1=C(C=CC=C1)C LRPOWONLCIWBTQ-UHFFFAOYSA-N 0.000 description 1
- OLQCEFPOEVRPBN-UHFFFAOYSA-N 5-chloro-2-(2-methylphenyl)-4-(4-methylphenyl)quinazoline Chemical compound ClC1=C2C(=NC(=NC2=CC=C1)C1=C(C=CC=C1)C)C1=CC=C(C=C1)C OLQCEFPOEVRPBN-UHFFFAOYSA-N 0.000 description 1
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- OGHJWHOAQQRDGC-UHFFFAOYSA-N C1(=C(C=CC=C1)C1=C(C=CC(=C1)C1=NC2=CC=CC=C2C=N1)C)C Chemical compound C1(=C(C=CC=C1)C1=C(C=CC(=C1)C1=NC2=CC=CC=C2C=N1)C)C OGHJWHOAQQRDGC-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- VSGNZYVGIJDNHM-UHFFFAOYSA-N FC1=CC=C(C=C1)C=1C=C2C=NC(=NC2=CC1)C1=C(C=CC=C1)C Chemical compound FC1=CC=C(C=C1)C=1C=C2C=NC(=NC2=CC1)C1=C(C=CC=C1)C VSGNZYVGIJDNHM-UHFFFAOYSA-N 0.000 description 1
- UDSJPFPDKCMYBD-UHFFFAOYSA-N Metsulfovax Chemical compound S1C(C)=NC(C)=C1C(=O)NC1=CC=CC=C1 UDSJPFPDKCMYBD-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 239000005816 Penthiopyrad Substances 0.000 description 1
- 239000005818 Picoxystrobin Substances 0.000 description 1
- 241000224016 Plasmodium Species 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 230000001399 anti-metabolic effect Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- 208000019065 cervical carcinoma Diseases 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- IBSNKSODLGJUMQ-SDNWHVSQSA-N picoxystrobin Chemical compound CO\C=C(\C(=O)OC)C1=CC=CC=C1COC1=CC=CC(C(F)(F)F)=N1 IBSNKSODLGJUMQ-SDNWHVSQSA-N 0.000 description 1
- UBZJXAQDXUGXIZ-UHFFFAOYSA-N quinazoline;quinoline Chemical compound N1=CC=CC2=CC=CC=C21.N1=CN=CC2=CC=CC=C21 UBZJXAQDXUGXIZ-UHFFFAOYSA-N 0.000 description 1
- 229940127224 quinoline drug Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000003335 steric effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/74—Quinazolines; Hydrogenated quinazolines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2282—Unsaturated compounds used as ligands
- B01J31/2295—Cyclic compounds, e.g. cyclopentadienyls
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
- C07F1/08—Copper compounds
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- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Catalysts (AREA)
Abstract
本发明公开了一种4‑芳基‑2‑(2‑(硫三氟甲基)芳基)喹唑啉类化合物及其制备方法。采用2，4‑二芳基喹唑啉作为反应底物，在80℃条件下，与NIS在二氯(五甲基环戊二烯基)合铑(III)二聚体/六氟锑酸银的催化作用反应后，与硫三氟甲基化试剂，以碘化亚铜为催化剂，反应温度为85℃，反应时间为7～10小时，经碳氢键活化过程，从而得到4‑芳基‑2‑(2‑(硫三氟甲基)芳基)喹唑啉类化合物。本发明的制备方法反应条件温和、操作简便、成本较低、副反应少、产品纯度高、便于分离提纯，可适合于较大规模的制备，所得产物具有良好药物活性，具有非常好的潜在应用前景。
Description
技术领域
本发明涉及含氟喹唑啉类化合物的合成方法，具体地指一种4-芳基-2-(2-(硫三氟甲基)芳基)喹唑啉的制备方法。
背景技术
在有机化合物的结构中引入氟原子会导致其物理、化学性质和生物活性产生很大的变化。含氟有机分子因其优异的性能在药物化学、天然产物化学和农药等领域扮演着重要角色。相关文献报道，最新注册的医药中大约20％含一个或者多个氟原子，40％以上的农药是含氟化合物。比如：fluazinam(氟啶胺，一种农药，杀菌剂)、picoxystrobin(啶氧菌酯,一种广谱杀菌剂)、celecoxib(塞内昔布，治疗宫颈癌的药物)、efavirenz(依法韦仑，一种抗病毒药)、5-fluorouracil(5-氟尿嘧啶，抗代谢抗肿瘤药)、mefloquine(甲氟喹，防疟药，亦用于耐药疟原虫的治疗)、penthiopyrad(吡噻菌胺，在农药上用作杀菌剂)等药物分子(Scheme1)都是含有氟原子的杂环化合物。因此，把氟元素引入到杂环化合物的研究备受重视。
Scheme1含氟杂环药物
由于氟原子的特性，合成含氟的芳烃和杂环芳烃通常具有很大的挑战性。因为亲电氟化反应通常没有选择性，亲核氟化反应由于氟负离子存在强的氢键作用和高的水合能，导致反应复杂，含水的氟化物亲核性低，干燥的氟化物又存在强的碱性。过渡金属催化的C—F键的形成，很困难的部分原因还在于金属离子与氟负离子之间的强离子键作用。
喹唑啉类化合物作为一类具有较高药用价值的杂环化合物，对其改性具有明显的现实意义。
如上所述，为了开发新型喹唑啉药物，本发明人通过对文献的调研和实验探索而旨在提供4-芳基-2-(2-(硫三氟甲基)芳基)喹唑啉化合物及其制备方法。
发明内容
本发明目的在于提供一种4-芳基-2-(2-(硫三氟甲基)芳基)喹唑啉化合物及其制备方法，该方法反应条件温和、操作简便、成本较低、副反应少、产品纯度高、便于分离提纯，可适合于较大规模的制备。
本发明提供如通式I所示的4-芳基-2-(2-(硫三氟甲基)芳基)喹唑啉类化合物，通式I如下：
其中，R1、R2为选自H、CH3、OCH3、F、Cl或CF3；
Ar为苯基或卤取代的苯基或萘基。
本发明中，所述通式I的4-芳基-2-(2-(硫三氟甲基)芳基)喹唑啉类化合物特别优选下列化合物中的一种，但这些化合物并不意味着对本发明的任何限制：
2-(2-甲基-6-(硫三氟甲基)苯基)-4-对甲苯基喹唑啉、
2-(2-氯-6-(硫三氟甲基)苯基)-6-甲氧基-4-邻甲苯基喹唑啉、
6-甲氧基-2-(2-甲基-6-(硫三氟甲基)苯基)-4-邻甲苯基喹唑啉、
6-甲氧基-2-(2-甲基-6-(硫三氟甲基)苯基)-4-对甲苯基喹唑啉、
4-(4-氟苯基)-6-甲氧基-2-(2-甲基-6-(硫三氟甲基)苯基)喹唑啉、
4-(4-氟苯基)-2-(2-甲基-6-(硫三氟甲基)苯基)喹唑啉、
4-(4-甲氧基苯基)-2-(2-甲基-6-(硫三氟甲基)苯基)喹唑啉、
6-氯-2-(2-甲基-6-(硫三氟甲基)苯基)-4-对甲苯基喹唑啉、
6-氯-2-(2-甲基-6-(硫三氟甲基)苯基)-4-(萘-1-基)喹唑啉、
6-氯-4-(4-氟苯基)-2-(2-甲基-6-(硫三氟甲基)苯基)喹唑啉、
2-(5-甲基-2-(硫三氟甲基)苯基)-4-苯基喹唑啉、
2-(2-甲基-6-(硫三氟甲基)苯基)-4-(萘-1-基)喹唑啉、
2-(2-甲基-6-(硫三氟甲基)苯基)-4-甲苯基喹唑啉、
2-(2-甲基-6-(硫三氟甲基)苯基)-4-间甲苯基喹唑啉、
2-(2-甲基-6-(硫三氟甲基)苯基)-4-邻甲苯基喹唑啉、
6-甲氧基-2-(2-甲基-6-(硫三氟甲基)苯基)-4-间甲苯基喹唑啉、
6-氯-2-(2-甲基-6-(硫三氟甲基)苯基)-4-邻甲苯基喹唑啉、
6-氯-2-(2-甲基-6-(硫三氟甲基)苯基)-4-间甲苯基喹唑啉。
本发明还提供了上述4-芳基-2-(2-(硫三氟甲基)芳基)喹唑啉类化合物的制备方法，其特别之处在于：所述方法采用2,4-二芳基喹唑啉为反应底物，在80℃下，与碘代丁二酰亚胺和有机溶剂在催化剂作用下反应1～4小时，所述2,4-二芳基喹唑啉与碘代丁二酰亚胺的摩尔比为1.0:1.5，反应体系所用有机溶剂为二氯甲烷、1,2-二氯乙烷、甲苯、N,N-二甲基甲酰胺、1,4-二氧六环或乙腈，所用催化剂为二氯(五甲基环戊二烯基)合铑(III)二聚体/六氟锑酸银；然后，以碘化亚铜为催化剂，与硫三氟甲基化试剂在85℃下反应7～10小时，经碳氢键活化过程，得到4-芳基-2-(2-(硫三氟甲基)芳基)喹唑啉类化合物；反应所使用的硫三氟甲基化试剂为1-(硫三氟甲基)吡咯烷-2,5-二酮、2-(硫三氟甲基)二氢吲哚-1,3-二酮或硫三氟甲基银，所述2,4-二芳基喹唑啉与硫三氟甲基化试剂的摩尔比为1.0:2.0；反应方程式如下：
本发明中，所述硫三氟甲基化试剂优选为硫三氟甲基银。
本发明中，所述有机溶剂优选为1,2-二氯乙烷。
本发明优选的具体操作为：
将2-邻甲苯基-4-对甲苯基喹唑啉(0.3mmol)、碘化试剂碘代丁二酰亚胺(NIS)(0.45mmol，1.5equiv)、催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(0.006mmol，0.02equiv)和六氟锑酸银(0.024mmol，0.08equiv)溶于有机溶剂1,2-二氯乙烷中，在80℃下于空气中搅拌反应1～4小时，后加入AgSCF3(0.6mmol，2.0equiv)，CuI(0.03mmol，10％equiv),在85℃反应3～4小时，TLC检测至反应完全。处理时加少量硅胶吸附粗产物并将溶剂旋干，直接经硅胶柱层析分离得纯净的产物2-(2-甲基-6-(硫三氟甲基)苯基)-4-对甲苯基喹唑啉。
本发明的催化体系创新之处在于：(一)对2,4-二芳基喹唑啉进行硫三氟甲基化；(二)硫三氟甲基化的位点在2位芳基的邻位，并没有在4位芳基上或者喹唑啉母环上发生；(三)本发明方法硫三氟甲基化具有典型的区域位阻效应，比如实例11。
本发明的有益效果在于：利用喹唑啉母环作为导向基团，经碳氢键活化2位芳基的邻位，用NIS碘化形成中间体后，进而以AgSCF3将硫三氟甲基引入，一锅法合成4-芳基-2-(2-(硫三氟甲基)芳基)喹唑啉类化合物。该项目的研究内容主要是基于具有潜在生物活性的类天然产物骨架分子的合成，为开发新药奠定良好的基础。本发明首次对2,4-二芳基喹唑啉进行硫三氟甲基化反应，所得产物均是新化合物。
本发明的制备方法具有以下特点：收率较高；
反应化学选择性：只发生在2位芳基的邻位；
反应条件温和：温度85度，不需要氮气保护，反应时间短不需要过夜反应；
操作简单：只需要将原料和AgSCF3及催化剂按照计量关系投入，柱层析方便，快捷；
副反应少：反应除反应产物外无其它反应发生；
产品纯度高：所分离的产品核磁数据纯净，图谱干净；
便于分离提纯：利用柱层析方便快捷，成本低。
本发明所得产物具有良好的生物活性，在医药领域，具有非常好的潜在应用前景。
具体实施方式
为了更好地解释本发明，以下结合具体实施例对本发明作进一步的详细说明，但它们不对本发明构成限定。
实例1
将2-邻甲苯基-4-对甲苯基喹唑啉(0.3mmol)、碘化试剂NIS(0.45mmol，1.5equiv)、催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(0.006mmol，0.02equiv)和六氟锑酸银(0.024mmol，0.08equiv)溶于有机溶剂1,2-二氯乙烷中，在80℃下于空气中搅拌反应1～4小时后，加入AgSCF3(0.6mmol,2.0equiv)，CuI(0.03mmol,10％equiv),在85℃反应3～4小时，TLC检测至反应完全。处理时加少量硅胶吸附粗产物并将溶剂旋干，直接经硅胶柱层析分离得纯净的产物2-(2-甲基-6-(硫三氟甲基)苯基)-4-对甲苯基喹唑啉(3a)。
Yellow oil(91％)
1H NMR(400MHz,CDCl3)δ8.14(d,J＝8.0Hz,1H),8.06(d,J＝8.4Hz,1H),7.87–7.83(m,1H),7.65(d,J＝8.0Hz,2H),7.61–7.54(m,2H),7.33–7.27(m,4H),2.37(s,3H),2.22(s,3H).13C NMR(100MHz,CDCl3)δ168.3,161.8,151.0,144.9,140.3,138.1,134.1,133.9,133.8,132.7,130.1,129.4(q,1JC-F＝307Hz),129.3,129.1,128.9,127.8,127.2,124.0,121.3,21.4,20.5；19F NMR(376MHz,CDCl3)δ；-41.514.HRMS(ESI):m/z[M+H]+calcd forC23H18F3N2S+:411.1143；found:411.1145.
实例2
将2-(2-氯苯基)-6-甲氧基-4-邻甲苯基喹唑啉(0.3mmol)、碘化试剂NIS(0.45mmol，1.5equiv)、催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(0.006mmol，0.02equiv)和六氟锑酸银(0.024mmol，0.08equiv)溶于有机溶剂1,2-二氯乙烷中，在80℃下于空气中搅拌反应1～4小时后，加入AgSCF3(0.6mmol,2.0equiv)，CuI(0.03mmol,10％equiv),在85℃反应3～4小时，TLC检测至反应完全。处理时加少量硅胶吸附粗产物并将溶剂旋干，直接经硅胶柱层析分离得纯净的产物2-(2-氯-6-(硫三氟甲基)苯基)-6-甲氧基-4-邻甲苯基喹唑啉(3b)。
Yellow oil(88％)
1H NMR(400MHz,CDCl3)δ7.99(d,J＝8.8Hz,1H),7.65(d,J＝8.0Hz,1H),7.53–7.50(m,2H),7.33–7.23(m,5H),6.85(d,J＝2.8Hz,1H),3.68(s,3H),2.11(s,3H)；13C NMR(100MHz,CDCl3)δ168.3,159.0,158.0,146.8,144.2,136.4,136.1,134.8,134.6,132.0,130.6,130.4,129.8,129.3,129.1(q,1JC-F＝307Hz),128.9,127.1,126.2,125.8,123.6,104.1,55.6,19.6；19F NMR(376MHz,CDCl3)δ；-41.259.HRMS(ESI):m/z[M+H]+calcd forC23H17ClF3N2OS+:461.0702；found:461.0706.
实例3
将6-甲氧基-2,4-二-邻甲苯基喹唑啉(0.3mmol)、碘化试剂NIS(0.45mmol，1.5equiv)、催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(0.006mmol，0.02equiv)和六氟锑酸银(0.024mmol，0.08equiv)溶于有机溶剂1,2-二氯乙烷中，在80℃下于空气中搅拌反应1-4小时后，加入AgSCF3(0.6mmol，2.0equiv)，CuI(0.03mmol，10％equiv),在85℃反应3～4小时，TLC检测至反应完全。处理时加少量硅胶吸附粗产物并将溶剂旋干，直接经硅胶柱层析分离得纯净的产物6-甲氧基-2-(2-甲基-6-(硫三氟甲基)苯基)-4-邻甲苯基喹唑啉(3c)。
Yellow oil(69％)
1H NMR(400MHz,CDCl3)δ8.07(d,J＝9.2Hz,1H),7.66(d,J＝7.6Hz,1H),7.61(dd,J＝9.2,2.8Hz,1H),7.43–7.33(m,6H),6.92(d,J＝2.8Hz,1H),3.78(s,3H),2.27(s,3H),2.20(s,3H)；13C NMR(100MHz,CDCl3)δ168.2,160.0,158.8,146.8,145.2,138.1,136.6,135.9,134.2,132.7,130.6,130.4,129.4(q,1JC-F＝307Hz),129.2,129.0,128.9,127.0,125.8,123.9,123.3,104.1,55.7,20.3,19.7；19F NMR(376MHz,CDCl3)δ；-41.609.HRMS(ESI):m/z[M+H]+calcd for C24H20F3N2OS+:441.1248；found:441.1251.
实例4
将6-甲氧基-2-邻甲苯基-4-对甲苯基喹唑啉(0.3mmol)、碘化试剂NIS(0.45mmol，1.5equiv)、催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(0.006mmol，0.02equiv)和六氟锑酸银(0.024mmol，0.08equiv)溶于有机溶剂1,2-二氯乙烷中，在80℃下于空气中搅拌反应1～4小时，加入AgSCF3(0.6mmol，2.0equiv)，CuI(0.03mmol，10％equiv),在85℃反应3～4小时，TLC检测至反应完全。处理时加少量硅胶吸附粗产物并将溶剂旋干，直接经硅胶柱层析分离得纯净的产物6-甲氧基-2-(2-甲基-6-(硫三氟甲基)苯基)-4-对甲苯基喹唑啉(3d)。
Yellow oil(72％)
1H NMR(400MHz,CDCl3)δ8.05(d,J＝9.2Hz,1H),7.74(d,J＝8.0Hz,2H),7.67(d,J＝7.6Hz,1H),7.60(dd,J＝9.2,2.8Hz,1H),7.48(d,J＝2.8Hz,1H),7.41-3.62(m,4H),3.87(s,3H),2.46(s,3H),2.30(s,3H)；13C NMR(100MHz,CDCl3)δ166.6,159.9,158.7,147.3,144.9,140.0,138.2,134.6,133.8,132.6,131.1,130.4,129.7,129.5(q,1JC-F＝307Hz),129.4,128.9,126.5,122.2,104.5,55.7,21.4,20.5；19F NMR(376MHz,CDCl3)δ；-41.527.HRMS(ESI):m/z[M+H]+calcd for C24H20F3N2OS+:441.1248；found:441.1247.
实例5
将4-(4-氟苯基)-6-甲氧基-2-邻甲苯基喹唑啉(0.3mmol)、碘化试剂NIS(0.45mmol，1.5equiv)、催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(0.006mmol，0.02equiv)和六氟锑酸银(0.024mmol，0.08equiv)溶于有机溶剂1,2-二氯乙烷中，在80℃下于空气中搅拌反应1～4小时后，加入AgSCF3(0.6mmol，2.0equiv)，CuI(0.03mmol，10％equiv),在85℃反应3-4小时，TLC检测至反应完全。处理时加少量硅胶吸附粗产物并将溶剂旋干，直接经硅胶柱层析分离得纯净的产物4-(4-氟苯基)-6-甲氧基-2-(2-甲基-6-(硫三氟甲基)苯基)喹唑啉(3e)。
Yellow oil(68％)
1H NMR(400MHz,CDCl3)δ7.98(d,J＝9.2Hz,1H),7.75(dd,J＝8.4,5.6Hz,2H),7.59(d,J＝7.6Hz,1H),7.52(dd,J＝9.2,2.8Hz,1H),7.32–7.26(m,3H),7.19-7.15(m,2H),3.78(s,3H),2.20(s,3H)；13C NMR(100MHz,CDCl3)δ165.4,163.8(d,1JC-F＝249Hz),159.9,158.9,147.4,144.8,138.2,133.9,133.5(d,2JC-F＝32Hz),132.7,131.7(d,3JC-F＝9Hz),130.6,129.5(q,1JC-F＝307Hz),129.0,126.7,124.2,122.1,115.9(d,2JC-F＝22Hz),104.1,55.6,20.4；19F NMR(376MHz,CDCl3)δ；-41.552，-110.574.HRMS(ESI):m/z[M+H]+calcd forC23H17F4N2OS+:445.0998；found:445.0996.
实例6
将4-(4-氟苯基)-2-邻甲苯基喹唑啉(0.3mmol)、碘化试剂NIS(0.45mmol，1.5equiv)、催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(0.006mmol，0.02equiv)和六氟锑酸银(0.024mmol，0.08equiv)溶于有机溶剂1,2-二氯乙烷中，在80℃下于空气中搅拌反应1-4小时后，加入AgSCF3(0.6mmol，2.0equiv)，CuI(0.03mmol，10％equiv)，在85℃反应3～4小时，TLC检测至反应完全。处理时加少量硅胶吸附粗产物并将溶剂旋干，直接经硅胶柱层析分离得纯净的产物4-(4-氟苯基)-2-(2-甲基-6-(硫三氟甲基)苯基)喹唑啉(3f)。
Yellow oil(84％)
1H NMR(400MHz,CDCl3)δ8.17(d,J＝8.4Hz,2H),7.95(ddd,J＝8.4,7.0,1.2Hz,1H),7.86–7.83(m,2H),7.70–7.65(m,2H),7.43–7.37(m,2H),7.28–7.24(m,2H),2.31(s,3H)；13C NMR(100MHz,CDCl3)δ167.1,163.9(d,1JC-F＝249Hz),161.8,151.2,144.8,138.1,134.1,134.0,133.1(d,2JC-F＝32Hz),132.8,132.1(d,3JC-F＝9Hz),129.4(q,1JC-F＝307Hz),129.1,129.0,128.1,126.8,124.0,121.2,115.7(d,2JC-F＝22Hz),20.4；19F NMR(376MHz,CDCl3)δ；-41.524，-110.280.HRMS(ESI):m/z[M+H]+calcd for C22H15F4N2S+:415.0892；found:415.0890.
实例7
将4-(4-甲氧基苯基)-2-邻甲苯基喹唑啉(0.3mmol)、碘化试剂NIS(0.45mmol，1.5equiv)、催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(0.006mmol，0.02equiv)和六氟锑酸银(0.024mmol，0.08equiv)溶于有机溶剂1,2-二氯乙烷中，在80℃下于空气中搅拌反应1-4小时后，加入AgSCF3(0.6mmol，2.0equiv)，CuI(0.03mmol，10％equiv),在85℃反应3～4小时，TLC检测至反应完全。处理时加少量硅胶吸附粗产物并将溶剂旋干，直接经硅胶柱层析分离得纯净的产物4-(4-甲氧基苯基)-2-(2-甲基-6-(硫三氟甲基)苯基)喹唑啉(3g)。
Yellow oil(61％)
1H NMR(400MHz,CDCl3)δ8.16(d,J＝8.4Hz,1H),8.05(d,J＝8.4Hz,1H),7.86–7.82(m,1H),7.75–7.73(m,2H),7.61–7.54(m,2H),7.33–7.27(m,2H),7.00(d,J＝8.8Hz,2H),3.80(s,3H),2.22(s,3H)；13C NMR(101MHz,CDCl3)δ167.7,161.8,161.3,151.2,144.9,138.1,133.9,133.7,132.7,131.8,129.6,129.5(q,1JC-F＝307Hz),129.0,128.9,127.7,127.2,124.1,121.3,114.1,55.4,20.5；19F NMR(376MHz,CDCl3)δ；-41.498.HRMS(ESI):m/z[M+H]+calcd for C23H18F3N2OS+:427.1092；found:427.1090.
实例8
将6-氯-2-邻甲苯基-4-对甲苯基喹唑啉(0.3mmol)、碘化试剂NIS(0.45mmol，1.5equiv)、催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(0.006mmol，0.02equiv)和六氟锑酸银(0.024mmol，0.08equiv)溶于有机溶剂1,2-二氯乙烷中，在80℃下于空气中搅拌反应1-4小时后，加入AgSCF3(0.6mmol，2.0equiv)，CuI(0.03mmol，10％equiv),在85℃反应3～4小时，TLC检测至反应完全。处理时加少量硅胶吸附粗产物并将溶剂旋干，直接经硅胶柱层析分离得纯净的产物6-氯-2-(2-甲基-6-(硫三氟甲基)苯基)-4-对甲苯基喹唑啉(3h)。
Yellow oil(90％)
1H NMR(400MHz,CDCl3)δ8.21(d,J＝2.0Hz,1H),8.09(d,J＝8.8Hz,1H),7.86(dd,J＝9.2,2.4Hz,1H),7.71(dd,J＝16.4,8.0Hz,3H),7.42–7.36(m,4H),2.46(s,3H),2.30(s,3H)；13C NMR(100MHz,CDCl3)δ167.6,162.1,149.7,144.7,140.7,138.2,134.8,134.2,133.7,133.6,132.8,130.7,130.0,129.6,129.5(q,1JC-F＝307Hz),129.2,126.1,124.1(q,J＝1.8Hz),121.9,21.5,20.5；19F NMR(376MHz,CDCl3)δ；-41.529.HRMS(ESI):m/z[M+H]+calcd for C23H17ClF3N2S+:445.0753；found:445.0754.
实例9
将6-氯-4-(萘-1-基)-2-邻甲苯基喹唑啉(0.3mmol)、碘化试剂NIS(0.45mmol，1.5equiv)、催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(0.006mmol，0.02equiv)和六氟锑酸银(0.024mmol，0.08equiv)溶于有机溶剂1,2-二氯乙烷中，在80℃下于空气中搅拌反应1～4小时后，加入AgSCF3(0.6mmol，2.0equiv)，CuI(0.03mmol，10％equiv)，在85℃反应3～4小时，TLC检测至反应完全。处理时加少量硅胶吸附粗产物并将溶剂旋干，直接经硅胶柱层析分离得纯净的产物6-氯-2-(2-甲基-6-(硫三氟甲基)苯基)-4-(萘-1-基)喹唑啉(3i)。
Yellow oil(91％)
1H NMR(400MHz,CDCl3)δ8.16(d,J＝8.8Hz,1H),8.06(d,J＝8.0Hz,1H),7.97(d,J＝8.0Hz,1H),7.90(dd,J＝8.8,2.4Hz,1H),7.70–7.61(m,4H),7.54(t,J＝8.0Hz,2H),7.45–7.37(m,3H),2.31(s,3H)；13C NMR(100MHz,CDCl3)δ168.5,162.3,149.3,144.8,138.0,135.5,134.4,133.9,133.8,133.6,132.9,131.4,130.7,130.2,129.4(q,1JC-F＝307Hz),129.3,128.5,127.9,127.0,126.5,126.0,125.3,125.0,123.8,123.7,20.45；19FNMR(376MHz,CDCl3)δ；-41.579.HRMS(ESI):m/z[M+H]+calcd for C26H17ClF3N2S+:481.0753；found:481.0751.
实例10
将6-氯-4-(4-氟苯基)-2-邻甲苯基喹唑啉(0.3mmol)、碘化试剂NIS(0.45mmol，1.5equiv)、催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(0.006mmol，0.02equiv)和六氟锑酸银(0.024mmol，0.08equiv)溶于有机溶剂1,2-二氯乙烷中，在80℃下于空气中搅拌反应1～4小时后，加入AgSCF3(0.6mmol，2.0equiv)，CuI(0.03mmol，10％equiv),在85℃反应3～4小时，TLC检测至反应完全。处理时加少量硅胶吸附粗产物并将溶剂旋干，直接经硅胶柱层析分离得纯净的产物6-氯-4-(4-氟苯基)-2-(2-甲基-6-(硫三氟甲基)苯基)喹唑啉(3j)。
Yellow oil(90％)
1H NMR(400MHz,CDCl3)δ8.15–8.10(m,2H),7.90–7.82(m,3H),7.70(d,J＝6.8Hz,1H),7.44–7.38(m,2H),7.30–7.25(m,2H),2.30(s,3H)；13C NMR(100MHz,CDCl3)δ166.2,164.1(d,1J＝250Hz),162.1,149.7,144.5,138.1,135.0,134.2,133.9,132.8,132.5(d,2J＝32Hz),132.1(d,3J＝9Hz),130.8,129.4(q,1JC-F＝307Hz),129.3,125.6,123.9(q,J＝1.8Hz),121.78,116.0(d,2J＝22Hz),20.4；19F NMR(376MHz,CDCl3)δ；-41.575,-109.566ppm.HRMS(ESI):m/z[M+H]+calcd for C22H14ClF4N2S+:449.0502；found:449.0505.
实例11
将4-苯基-2-间甲苯基喹唑啉(0.3mmol)、碘化试剂NIS(0.45mmol，1.5equiv)、催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(0.006mmol，0.02equiv)和六氟锑酸银(0.024mmol，0.08equiv)溶于有机溶剂1,2-二氯乙烷中，在80℃下于空气中搅拌反应1～4小时后，加入AgSCF3(0.6mmol，2.0equiv)，CuI(0.03mmol,10％equiv),在85℃反应3～4小时，TLC检测至反应完全。处理时加少量硅胶吸附粗产物并将溶剂旋干，直接经硅胶柱层析分离得纯净的产物2-(5-甲基-2-(硫三氟甲基)苯基)-4-苯基喹唑啉(3k)。
Yellow oil(86％)
1H NMR(400MHz,CDCl3)δ8.20–8.17(m,2H),8.04(d,J＝1.2Hz,1H),7.95–7.86(m,3H),7.74(d,J＝8.0Hz,1H),7.64–7.58(m,4H),7.31(dd,J＝8.0,1.6Hz,1H),2.45(s,3H)；13C NMR(101MHz,CDCl3)δ168.1,160.8,151.2,142.2,139.5,137.2,133.9,133.6(q,J＝1.2Hz),132.0,130.9,130.2,130.1,129.9(q,1JC-F＝308Hz),128.9,128.6,127.8,127.1,123.1,121.2,21.1；19F NMR(376MHz,CDCl3)δ；-41.476.HRMS(ESI):m/z[M+H]+calcd forC23H17ClF3N2S+:397.0896；found:397.0896.
实例12
将2-邻甲苯基-4-(萘-1-基)喹唑啉(0.3mmol)、碘化试剂NIS(0.45mmol，1.5equiv)、催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(0.006mmol，0.02equiv)和六氟锑酸银(0.024mmol，0.08equiv)溶于有机溶剂1,2-二氯乙烷中，在80℃下于空气中搅拌反应1～4小时后，加入AgSCF3(0.6mmol，2.0equiv)，CuI(0.03mmol,10％equiv),在85℃反应3～4小时，TLC检测至反应完全。处理时加少量硅胶吸附粗产物并将溶剂旋干，直接经硅胶柱层析分离得纯净的产物2-(2-甲基-6-(硫三氟甲基)苯基)-4-(萘-1-基)喹唑啉(3l)
Yellow oil,85％yield.
1H NMR(400MHz,CDCl3)δ8.21(d,J＝8.4Hz,1H),8.02(dd,J＝6.8,2.0Hz,1H),7.96-7.92(m,2H),7.71-7.48(m,7H),7.41-7.34(m,3H),2.32(s,3H).13C NMR(101MHz,CDCl3)δ169.2,162.1,150.7,145.1,138.1,134.4,134.3,134.2,133.6,132.8,131.6,129.8,129.4(q,1JC-F＝307Hz),129.1,128.9,128.3,128.0,127.6,127.4,126.8,126.3,125.6,125.0,123.8(q,J＝1.8Hz),123.1,20.4.19F NMR(376MHz,CDCl3)δ；-41.481.HRMS(ESI):m/z[M+H]+calcd for C26H18F3N2S+:447.1143；found:447.1141.
实例13
将2-邻甲苯基-4-甲苯基喹唑啉(0.3mmol)、碘化试剂NIS(0.45mmol，1.5equiv)、催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(0.006mmol，0.02equiv)和六氟锑酸银(0.024mmol，0.08equiv)溶于有机溶剂1,2-二氯乙烷中，在80℃下于空气中搅拌反应1～4小时后，加入AgSCF3(0.6mmol,2.0equiv)，CuI(0.03mmol,10％equiv),在85℃反应3～4小时，TLC检测至反应完全。处理时加少量硅胶吸附粗产物并将溶剂旋干，直接经硅胶柱层析分离得纯净的产物2-(2-甲基-6-(硫三氟甲基)苯基)-4-甲苯基喹唑啉(3m)。
Yellow oil,90％yield.
1H NMR(400MHz,CDCl3)δ8.21-8.15(m,2H),7.95(t,J＝8.0Hz,1H),7.84-7.82(m,2H),7.70-7.64(m,2H),7.59-7.56(m,3H),7.43-7.36(m,2H),2.31(s,3H).13C NMR(100MHz,CDCl3)δ168.3,161.8,151.1,144.9,138.1,137.0,134.0,132.7,131.0,130.0,129.9,129.5(q,1JC-F＝307Hz),129.1,129.0,128.6,128.0,127.1,124.1,121.3,20.4.19F NMR(376MHz,CDCl3)δ；-41.511.HRMS(ESI):m/z[M+H]+calcd for C22H16F3N2S+:397.0986；found:397.0986.
实例14
将2-邻甲苯基-4-间甲苯基喹唑啉(0.3mmol)、碘化试剂NIS(0.45mmol，1.5equiv)、催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(0.006mmol，0.02equiv)和六氟锑酸银(0.024mmol，0.08equiv)溶于有机溶剂1,2-二氯乙烷中，在80℃下于空气中搅拌反应1～4小时后，加入AgSCF3(0.6mmol,2.0equiv)，CuI(0.03mmol,10％equiv),在85℃反应3～4小时，TLC检测至反应完全。处理时加少量硅胶吸附粗产物并将溶剂旋干，直接经硅胶柱层析分离得纯净的产物2-(2-甲基-6-(硫三氟甲基)苯基)-4-间甲苯基喹唑啉(3n)。
Yellow oil,85％yield.
1H NMR(400MHz,CDCl3)δ8.21(d,J＝8.4Hz,1H),8.15(d,J＝8.4Hz,1H),7.94(t,J＝8.4Hz,1H),7.70-7.60(m,4H),7.47-7.36(m,4H),2.46(s,3H),2.31(s,3H).13C NMR(100MHz,CDCl3)δ168.6,161.8,151.0,145.0,138.5,138.1,137.0,134.0,133.9,132.7,130.7,130.6,129.5(q,1JC-F＝307Hz),129.0,128.9,128.4,127.9,127.3,127.2,124.0,121.4,21.5,20.48.19F NMR(376MHz,CDCl3)δ；-41.507.HRMS(ESI):m/z[M+H]+calcd forC23H18F3N2S+:411.1143；found:411.1145.
实例15
将2-邻甲苯基-4-邻甲苯基喹唑啉(0.3mmol)、碘化试剂NIS(0.45mmol，1.5equiv)、催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(0.006mmol，0.02equiv)和六氟锑酸银(0.024mmol，0.08equiv)溶于有机溶剂1,2-二氯乙烷中，在80℃下于空气中搅拌反应1～4小时后，加入AgSCF3(0.6mmol,2.0equiv)，CuI(0.03mmol,10％equiv),在85℃反应3～4小时，TLC检测至反应完全。处理时加少量硅胶吸附粗产物并将溶剂旋干，直接经硅胶柱层析分离得纯净的产物2-(2-甲基-6-(硫三氟甲基)苯基)-4-邻甲苯基喹唑啉(3o)。
Yellow oil,87％yield.
1H NMR(400MHz,CDCl3)δ8.17(d,J＝8.4Hz,1H),7.98-7.92(m,1H),7.73(d,J＝8.4Hz,1H),7.67(d,J＝8.0Hz,1H),7.62-7.58(m,1H),7.44-7.32(m,6H),2.28(s,3H),2.18(s,3H).13C NMR(100MHz,CDCl3)δ170.1,162.0,150.6,145.2,138.0,136.4,136.0,134.3,134.2,32.7,130.5,129.4(q,1JC-F＝307Hz)129.3,129.1,129.0,128.9,128.0,127.1,125.7,123.8,122.3,20.3,19.7.19F NMR(376MHz,CDCl3)δ；-41.596.HRMS(ESI):m/z[M+H]+calcd for C23H18F3N2S+:411.1143；found:411.1144.
实例16
将6-甲氧基-2-邻甲苯基-4-间甲苯基喹唑啉(0.3mmol)、碘化试剂NIS(0.45mmol，1.5equiv)、催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(0.006mmol，0.02equiv)和六氟锑酸银(0.024mmol，0.08equiv)溶于有机溶剂1,2-二氯乙烷中，在80℃下于空气中搅拌反应1～4小时后，加入AgSCF3(0.6mmol,2.0equiv)，CuI(0.03mmol,10％equiv),在85℃反应3～4小时，TLC检测至反应完全。处理时加少量硅胶吸附粗产物并将溶剂旋干，直接经硅胶柱层析分离得纯净的产物6-甲氧基-2-(2-甲基-6-(硫三氟甲基)苯基)-4-间甲苯基喹唑啉(3p)。
Yellow oil,63％yield.
1H NMR(400MHz,CDCl3)δ8.06(d,J＝9.2Hz,1H),7.69-7.58(m,4H),7.46-7.35(m,5H),3.87(s,3H),2.46(s,3H),2.30(s,3H).13C NMR(100MHz,CDCl3)δ166.8,159.9,158.7,147.2,145.0,138.6,138.2,137.3,133.9,132.7,130.6,130.4,130.3,128.9,128.4,126.7,126.6,124.2,122.3,104.5,55.6,21.5,20.4.19F NMR(376MHz,CDCl3)δ；-41.525.HRMS(ESI):m/z[M+H]+calcd for C24H20F3N2OS+:441.1248；found:441.1247.
实例17
将6-氯-2-邻甲苯基-4-邻甲苯基喹唑啉(0.3mmol)、碘化试剂NIS(0.45mmol，1.5equiv)、催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(0.006mmol，0.02equiv)和六氟锑酸银(0.024mmol，0.08equiv)溶于有机溶剂1,2-二氯乙烷中，在80℃下于空气中搅拌反应1～4小时后，加入AgSCF3(0.6mmol,2.0equiv)，CuI(0.03mmol,10％equiv),在85℃反应3～4小时，TLC检测至反应完全。处理时加少量硅胶吸附粗产物并将溶剂旋干，直接经硅胶柱层析分离得纯净的产物6-氯-2-(2-甲基-6-(硫三氟甲基)苯基)-4-邻甲苯基喹唑啉(3q)。
Yellow oil,63％yield.
1H NMR(400MHz,CDCl3)δ8.06(d,J＝9.2Hz,1H),7.69-7.58(m,4H),7.46-7.35(m,5H),3.87(s,3H),2.46(s,3H),2.30(s,3H).13C NMR(100MHz,CDCl3)δ166.8,159.9,158.7,147.2,145.0,138.6,138.2,137.3,133.9,132.7,130.6,130.4,130.3,128.9,128.4,126.7,126.6,124.2,122.3,104.5,55.6,21.5,20.4.19F NMR(376MHz,CDCl3)δ；-41.525.HRMS(ESI):m/z[M+H]+calcd for C24H20F3N2OS+:441.1248；found:441.1247.
实例18
将6-氯-2-邻甲苯基-4-间甲苯基喹唑啉(0.3mmol)、碘化试剂NIS(0.45mmol，1.5equiv)、催化剂二氯(五甲基环戊二烯基)合铑(III)二聚体(0.006mmol，0.02equiv)和六氟锑酸银(0.024mmol，0.08equiv)溶于有机溶剂1,2-二氯乙烷中，在80℃下于空气中搅拌反应1～4小时后，加入AgSCF3(0.6mmol,2.0equiv)，CuI(0.03mmol,10％equiv),在85℃反应3～4小时，TLC检测至反应完全。处理时加少量硅胶吸附粗产物并将溶剂旋干，直接经硅胶柱层析分离得纯净的产物6-氯-2-(2-甲基-6-(硫三氟甲基)苯基)-4-间甲苯基喹唑啉(3r)。
Yellow oil,91％yield.
1H NMR(400MHz,CDCl3)δ8.18(d,J＝2.0Hz,1H),8.10(d,J＝9.2Hz,1H),7.86(dd,J＝9.2,2.4Hz,1H),7.69(d,J＝7.2Hz,1H),7.64-7.57(m,2H),7.48-7.36(m,4H),2.47(s,3H),2.30(s,3H).13C NMR(101MHz,CDCl3)δ167.9,162.2,149.7,144.8,138.8,138.2,136.5,134.9,134.2,133.8,132.9,131.1,130.7,130.5,129.5(q,1JC-F＝307Hz),129.3,128.6,127.2,126.1,124.1(q,J＝1.8Hz),122.0,21.5,20.5.19F NMR(376MHz,CDCl3)δ；-41.509.HRMS(ESI):m/z[M+H]+calcd for C23H17ClF3N2S+:445.0753；found:445.0754。
本发明产物抗肝癌作用
HepG2细胞的培养基为DMEM培养基，并加入2mM的L-谷氨酸、20U/ml青霉素、20μg/ml链霉素及10％热失活的牛血清蛋白，在37℃、5％CO2的条件下培养72h，随后用0.025％的胰蛋白酶溶液将细胞制血成悬浮状态。将HepG2细胞接种于96孔板中，在相同条件下继续培养24h，随后分别加入8.6、15.6、31.3、62.5、125、250及500μg/ml产物溶液，以空白培养基为阴性对照。48h时各个产物的IC50见表一：
表1本发明产物的抗肝癌IC50值
由此可见，本发明化合物具有具有显著的抗肝癌作用。
Claims (4)
1.一种4-芳基-2-(2-(硫三氟甲基)芳基)喹唑啉类化合物，其特征在于，所述化合物为选自下列化合物中的一种：
2-(2-甲基-6-(硫三氟甲基)苯基)-4-对甲苯基喹唑啉、
2-(2-氯-6-(硫三氟甲基)苯基)-6-甲氧基-4-邻甲苯基喹唑啉、
6-甲氧基-2-(2-甲基-6-(硫三氟甲基)苯基)-4-邻甲苯基喹唑啉、
6-甲氧基-2-(2-甲基-6-(硫三氟甲基)苯基)-4-对甲苯基喹唑啉、
6-氯-2-(2-甲基-6-(硫三氟甲基)苯基)-4-对甲苯基喹唑啉、
2-(2-甲基-6-(硫三氟甲基)苯基)-4-甲苯基喹唑啉、
2-(2-甲基-6-(硫三氟甲基)苯基)-4-间甲苯基喹唑啉、
2-(2-甲基-6-(硫三氟甲基)苯基)-4-邻甲苯基喹唑啉、
6-甲氧基-2-(2-甲基-6-(硫三氟甲基)苯基)-4-间甲苯基喹唑啉、
6-氯-2-(2-甲基-6-(硫三氟甲基)苯基)-4-邻甲苯基喹唑啉、
6-氯-2-(2-甲基-6-(硫三氟甲基)苯基)-4-间甲苯基喹唑啉。
2.一种根据权利要求1所述的4-芳基-2-(2-(硫三氟甲基)芳基)喹唑啉类化合物的制备方法，其特征在于：所述方法采用2,4-二芳基喹唑啉为反应底物，在80℃下，与碘代丁二酰亚胺和有机溶剂在催化剂作用下反应1～4小时，所述2,4-二芳基喹唑啉与碘代丁二酰亚胺的摩尔比为1.0:1.5，反应体系所用有机溶剂为二氯甲烷、1,2-二氯乙烷、甲苯、N,N-二甲基甲酰胺、1,4-二氧六环或乙腈，所用催化剂为二氯(五甲基环戊二烯基)合铑(III)二聚体/六氟锑酸银；然后，以碘化亚铜为催化剂，与硫三氟甲基化试剂在85℃下反应7～10小时，经碳氢键活化过程，得到4-芳基-2-(2-(硫三氟甲基)芳基)喹唑啉类化合物；反应所使用的硫三氟甲基化试剂为1-(硫三氟甲基)吡咯烷-2,5-二酮、2-(硫三氟甲基)二氢吲哚-1,3-二酮或硫三氟甲基银，所述2,4-二芳基喹唑啉与硫三氟甲基化试剂的摩尔比为1.0:2.0；反应方程式如下：
3.根据权利要求2所述4-芳基-2-(2-(硫三氟甲基)芳基)喹唑啉的制备方法，其特征在于：所述硫三氟甲基化试剂为硫三氟甲基银。
4.根据权利要求2所述4-芳基-2-(2-(硫三氟甲基)芳基)喹唑啉的制备方法，其特征在于：所述有机溶剂为1,2-二氯乙烷。
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| CN114057634A (zh) * | 2021-08-13 | 2022-02-18 | 江西师范大学 | 一种5-三氟甲硫基烟酸酯系列物的制备方法 |
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| CN111303029B (zh) * | 2020-03-17 | 2023-01-20 | 辽宁石油化工大学 | 一种4-氰基-2-三氟甲基取代的喹啉类化合物及合成方法 |
| CN111620824B (zh) * | 2020-06-24 | 2023-08-22 | 武汉理工大学 | 一种以芳香醛为底物合成喹唑啉类化合物的方法 |
| CN111704587B (zh) * | 2020-06-29 | 2023-04-07 | 遵义医科大学 | 一种三氟甲基化1,3-噁嗪类化合物的合成方法 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2014210769A (ja) * | 2013-04-03 | 2014-11-13 | 株式会社ヤクルト本社 | チアゾリジン誘導体又はその塩を有効成分とするＰｉｍ阻害剤 |
| WO2015040425A1 (en) * | 2013-09-23 | 2015-03-26 | Vernalis (R&D) Limited | Resorcinol n-aryl amide compounds, for use as pyruvate dehydrogenase kinase inhibitors |
| CN105418516A (zh) * | 2015-12-21 | 2016-03-23 | 信阳师范学院 | 一种喹唑啉类化合物及其制备方法 |
| WO2016118565A1 (en) * | 2015-01-20 | 2016-07-28 | Millennium Pharmaceuticals, Inc. | Quinazoline and quinoline compounds and uses thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB201316823D0 (en) * | 2013-09-23 | 2013-11-06 | R & D Vernalis Ltd | New Chemical Entities |
-
2016
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2014210769A (ja) * | 2013-04-03 | 2014-11-13 | 株式会社ヤクルト本社 | チアゾリジン誘導体又はその塩を有効成分とするＰｉｍ阻害剤 |
| WO2015040425A1 (en) * | 2013-09-23 | 2015-03-26 | Vernalis (R&D) Limited | Resorcinol n-aryl amide compounds, for use as pyruvate dehydrogenase kinase inhibitors |
| WO2016118565A1 (en) * | 2015-01-20 | 2016-07-28 | Millennium Pharmaceuticals, Inc. | Quinazoline and quinoline compounds and uses thereof |
| CN105418516A (zh) * | 2015-12-21 | 2016-03-23 | 信阳师范学院 | 一种喹唑啉类化合物及其制备方法 |
Non-Patent Citations (6)
| Title |
|---|
| HWANGSEO PARK ET AL.,: "Identification of Novel Inhibitors of Tropomyosin-Related Kinase A through the Structure-Based Virtual Screening with Homology-Modeled Protein Structure", 《J. CHEM. INF. MODEL.》 * |
| JI YEA KIM ET AL.,: "Effects of Tropomyosin-Related Kinase A Inhibitors on the Proliferation of Human Lung Cancer Cells", 《BULL. KOREAN CHEM. SOC.》 * |
| SMITA NAHAR ET AL.: "Anti-cancer therapeutic potential of quinazoline based small molecules via global upregulation of miRNAs", 《CHEM. COMMUN.》 * |
| 刘瑶等: "miR-141 表达异常对人肝癌细胞恶性生物学表型的影响", 《中国病理生理杂志》 * |
| 彭以元等: "2，4-二芳基喹唑啉区域选择性的硫三氟甲基化反应", 《中国化学会第十四届全国氟化学会议论文集》 * |
| 李才 主编: "《疾病模型与实验病理学》", 31 March 2005, 吉林大学出版社 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112159363A (zh) * | 2020-10-28 | 2021-01-01 | 兰州大学 | 一种制备1,3-苯并噁嗪三氟甲基化官能化衍生物的方法 |
| CN112159363B (zh) * | 2020-10-28 | 2023-05-02 | 兰州大学 | 一种制备1,3-苯并噁嗪三氟甲基化官能化衍生物的方法 |
| CN114057634A (zh) * | 2021-08-13 | 2022-02-18 | 江西师范大学 | 一种5-三氟甲硫基烟酸酯系列物的制备方法 |
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