CN110003187B - 一种多氟烷基取代苯并呋喃类化合物及其制备方法 - Google Patents
一种多氟烷基取代苯并呋喃类化合物及其制备方法 Download PDFInfo
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- CN110003187B CN110003187B CN201910387303.6A CN201910387303A CN110003187B CN 110003187 B CN110003187 B CN 110003187B CN 201910387303 A CN201910387303 A CN 201910387303A CN 110003187 B CN110003187 B CN 110003187B
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- methyl
- perfluorobutyl
- polyfluoroalkyl
- reaction
- imidazole
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- -1 benzofuran compound Chemical class 0.000 title claims abstract description 56
- IANQTJSKSUMEQM-UHFFFAOYSA-N benzofuran Natural products C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- 239000007795 chemical reaction product Substances 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 16
- 238000004440 column chromatography Methods 0.000 claims abstract description 13
- 239000000654 additive Substances 0.000 claims abstract description 9
- 239000003054 catalyst Substances 0.000 claims abstract description 9
- 150000001907 coumarones Chemical class 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 9
- 238000012546 transfer Methods 0.000 claims abstract description 9
- 230000000996 additive effect Effects 0.000 claims abstract description 8
- 239000003513 alkali Substances 0.000 claims abstract description 8
- 230000002195 synergetic effect Effects 0.000 claims abstract description 8
- 238000001035 drying Methods 0.000 claims abstract description 7
- 238000002156 mixing Methods 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 7
- 238000005406 washing Methods 0.000 claims abstract description 7
- 238000003756 stirring Methods 0.000 claims abstract description 6
- 238000001514 detection method Methods 0.000 claims abstract description 3
- 238000004809 thin layer chromatography Methods 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical group [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 8
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical group [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 7
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- XHLHPRDBBAGVEG-UHFFFAOYSA-N 1-tetralone Chemical compound C1=CC=C2C(=O)CCCC2=C1 XHLHPRDBBAGVEG-UHFFFAOYSA-N 0.000 claims description 6
- CHIFTAQVXHNVRW-UHFFFAOYSA-N 1h-indole-3-carbonitrile Chemical compound C1=CC=C2C(C#N)=CNC2=C1 CHIFTAQVXHNVRW-UHFFFAOYSA-N 0.000 claims description 6
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 claims description 6
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 6
- BVIAOQMSVZHOJM-UHFFFAOYSA-N N(6),N(6)-dimethyladenine Chemical compound CN(C)C1=NC=NC2=C1N=CN2 BVIAOQMSVZHOJM-UHFFFAOYSA-N 0.000 claims description 6
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methylaniline Chemical compound CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 claims description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
- BZRRQSJJPUGBAA-UHFFFAOYSA-L cobalt(ii) bromide Chemical group Br[Co]Br BZRRQSJJPUGBAA-UHFFFAOYSA-L 0.000 claims description 5
- 239000003208 petroleum Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- LDZYRENCLPUXAX-UHFFFAOYSA-N 2-methyl-1h-benzimidazole Chemical compound C1=CC=C2NC(C)=NC2=C1 LDZYRENCLPUXAX-UHFFFAOYSA-N 0.000 claims description 4
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 claims description 4
- 239000012964 benzotriazole Substances 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- KASJZXHXXNEULX-UHFFFAOYSA-N 1,5,6,7-tetrahydroindol-4-one Chemical compound O=C1CCCC2=C1C=CN2 KASJZXHXXNEULX-UHFFFAOYSA-N 0.000 claims description 3
- KHHSXHXUQVNBGA-UHFFFAOYSA-N 1-(1h-pyrrol-3-yl)ethanone Chemical compound CC(=O)C=1C=CNC=1 KHHSXHXUQVNBGA-UHFFFAOYSA-N 0.000 claims description 3
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 3
- KWTCVAHCQGKXAZ-UHFFFAOYSA-N 1H-indazole-3-carboxylic acid methyl ester Chemical compound C1=CC=C2C(C(=O)OC)=NNC2=C1 KWTCVAHCQGKXAZ-UHFFFAOYSA-N 0.000 claims description 3
- ZBFZXENHYIJZGA-UHFFFAOYSA-N 2,3,4,4a-tetrahydrocarbazol-1-one Chemical compound C1=CC=C2C3CCCC(=O)C3=NC2=C1 ZBFZXENHYIJZGA-UHFFFAOYSA-N 0.000 claims description 3
- BWOVACANEIVHST-UHFFFAOYSA-N 2-(1h-benzimidazol-2-yl)acetonitrile Chemical compound C1=CC=C2NC(CC#N)=NC2=C1 BWOVACANEIVHST-UHFFFAOYSA-N 0.000 claims description 3
- FFYTTYVSDVWNMY-UHFFFAOYSA-N 2-Methyl-5-nitroimidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1 FFYTTYVSDVWNMY-UHFFFAOYSA-N 0.000 claims description 3
- AYPSHJCKSDNETA-UHFFFAOYSA-N 2-chloro-1h-benzimidazole Chemical compound C1=CC=C2NC(Cl)=NC2=C1 AYPSHJCKSDNETA-UHFFFAOYSA-N 0.000 claims description 3
- QHCCOYAKYCWDOJ-UHFFFAOYSA-N 2-ethyl-1h-benzimidazole Chemical compound C1=CC=C2NC(CC)=NC2=C1 QHCCOYAKYCWDOJ-UHFFFAOYSA-N 0.000 claims description 3
- VRWJZGHUCOFGPZ-UHFFFAOYSA-N 2-{[4-(4-pyridin-4-yl-1h-pyrazol-3-yl)phenoxy]methyl}quinoline Chemical compound C=1C=C2C=CC=CC2=NC=1COC(C=C1)=CC=C1C1=NNC=C1C1=CC=NC=C1 VRWJZGHUCOFGPZ-UHFFFAOYSA-N 0.000 claims description 3
- UDKYMMQGPNFWDA-UHFFFAOYSA-N 3-iodo-2h-indazole Chemical compound C1=CC=CC2=C(I)NN=C21 UDKYMMQGPNFWDA-UHFFFAOYSA-N 0.000 claims description 3
- UBOOKRVGOBKDMM-UHFFFAOYSA-N 3h-imidazo[4,5-c]pyridine Chemical compound C1=NC=C2NC=NC2=C1 UBOOKRVGOBKDMM-UHFFFAOYSA-N 0.000 claims description 3
- LJUQGASMPRMWIW-UHFFFAOYSA-N 5,6-dimethylbenzimidazole Chemical compound C1=C(C)C(C)=CC2=C1NC=N2 LJUQGASMPRMWIW-UHFFFAOYSA-N 0.000 claims description 3
- PZBQVZFITSVHAW-UHFFFAOYSA-N 5-chloro-2h-benzotriazole Chemical compound C1=C(Cl)C=CC2=NNN=C21 PZBQVZFITSVHAW-UHFFFAOYSA-N 0.000 claims description 3
- RUKDVLFJSMVBLV-UHFFFAOYSA-N 5-iodo-1h-pyrazole Chemical compound IC1=CC=NN1 RUKDVLFJSMVBLV-UHFFFAOYSA-N 0.000 claims description 3
- LRUDIIUSNGCQKF-UHFFFAOYSA-N 5-methyl-1H-benzotriazole Chemical compound C1=C(C)C=CC2=NNN=C21 LRUDIIUSNGCQKF-UHFFFAOYSA-N 0.000 claims description 3
- PZKFSRWSQOQYNR-UHFFFAOYSA-N 5-methyl-1h-1,2,4-triazole Chemical compound CC1=NC=NN1 PZKFSRWSQOQYNR-UHFFFAOYSA-N 0.000 claims description 3
- MARUHZGHZWCEQU-UHFFFAOYSA-N 5-phenyl-2h-tetrazole Chemical compound C1=CC=CC=C1C1=NNN=N1 MARUHZGHZWCEQU-UHFFFAOYSA-N 0.000 claims description 3
- GEDVWGDBMPJNEV-UHFFFAOYSA-N 6-bromo-1h-benzimidazole Chemical compound BrC1=CC=C2N=CNC2=C1 GEDVWGDBMPJNEV-UHFFFAOYSA-N 0.000 claims description 3
- WMKDUJVLNZANRN-UHFFFAOYSA-N 6-bromo-1h-indazole Chemical compound BrC1=CC=C2C=NNC2=C1 WMKDUJVLNZANRN-UHFFFAOYSA-N 0.000 claims description 3
- XPAZGLFMMUODDK-UHFFFAOYSA-N 6-nitro-1h-benzimidazole Chemical compound [O-][N+](=O)C1=CC=C2N=CNC2=C1 XPAZGLFMMUODDK-UHFFFAOYSA-N 0.000 claims description 3
- 239000002947 C09CA04 - Irbesartan Substances 0.000 claims description 3
- SAXFVEHGPKAUGE-UHFFFAOYSA-N CC1=C(CCC(C1=O)C(C(C(C(F)(F)F)(F)F)(F)F)(F)F)C1=CC=CC=C1 Chemical compound CC1=C(CCC(C1=O)C(C(C(C(F)(F)F)(F)F)(F)F)(F)F)C1=CC=CC=C1 SAXFVEHGPKAUGE-UHFFFAOYSA-N 0.000 claims description 3
- 229910019131 CoBr2 Inorganic materials 0.000 claims description 3
- LSGKMZLPZFPAIN-UHFFFAOYSA-N Oxime-1H-Indole-3-carboxaldehyde Natural products C1=CC=C2C(C(=O)N)=CNC2=C1 LSGKMZLPZFPAIN-UHFFFAOYSA-N 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- YTLQFZVCLXFFRK-UHFFFAOYSA-N bendazol Chemical compound N=1C2=CC=CC=C2NC=1CC1=CC=CC=C1 YTLQFZVCLXFFRK-UHFFFAOYSA-N 0.000 claims description 3
- LZCZIHQBSCVGRD-UHFFFAOYSA-N benzenecarboximidamide;hydron;chloride Chemical compound [Cl-].NC(=[NH2+])C1=CC=CC=C1 LZCZIHQBSCVGRD-UHFFFAOYSA-N 0.000 claims description 3
- XOUHVMVYFOXTMN-UHFFFAOYSA-N ethyl 1h-indole-3-carboxylate Chemical compound C1=CC=C2C(C(=O)OCC)=CNC2=C1 XOUHVMVYFOXTMN-UHFFFAOYSA-N 0.000 claims description 3
- OLNJUISKUQQNIM-UHFFFAOYSA-N indole-3-carbaldehyde Chemical compound C1=CC=C2C(C=O)=CNC2=C1 OLNJUISKUQQNIM-UHFFFAOYSA-N 0.000 claims description 3
- NBKQRVSGHYZUOR-UHFFFAOYSA-N indoline-3-carbaldehyde Natural products C1=CC=C2C(C=O)CNC2=C1 NBKQRVSGHYZUOR-UHFFFAOYSA-N 0.000 claims description 3
- YCPOHTHPUREGFM-UHFFFAOYSA-N irbesartan Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2[N]N=NN=2)C(CCCC)=NC21CCCC2 YCPOHTHPUREGFM-UHFFFAOYSA-N 0.000 claims description 3
- 229960002198 irbesartan Drugs 0.000 claims description 3
- WJHHIVYNOVTVGY-UHFFFAOYSA-N methyl 3h-benzimidazole-5-carboxylate Chemical compound COC(=O)C1=CC=C2N=CNC2=C1 WJHHIVYNOVTVGY-UHFFFAOYSA-N 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- SVDVKEBISAOWJT-UHFFFAOYSA-N n-methylbenzenesulfonamide Chemical compound CNS(=O)(=O)C1=CC=CC=C1 SVDVKEBISAOWJT-UHFFFAOYSA-N 0.000 claims description 3
- XAUGWFWQVYXATQ-UHFFFAOYSA-N n-phenylbenzenesulfonamide Chemical compound C=1C=CC=CC=1S(=O)(=O)NC1=CC=CC=C1 XAUGWFWQVYXATQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000005003 perfluorobutyl group Chemical group FC(F)(F)C(F)(F)C(F)(F)C(F)(F)* 0.000 claims description 3
- ZSKGQVFRTSEPJT-UHFFFAOYSA-N pyrrole-2-carboxaldehyde Chemical compound O=CC1=CC=CN1 ZSKGQVFRTSEPJT-UHFFFAOYSA-N 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 2
- PQTPYRHWJTWVLU-UHFFFAOYSA-N CC1=C(CCC(C1=O)C(C(C(C(F)(F)F)(F)F)(F)F)(F)F)C1=CC=C(C=C1)C Chemical compound CC1=C(CCC(C1=O)C(C(C(C(F)(F)F)(F)F)(F)F)(F)F)C1=CC=C(C=C1)C PQTPYRHWJTWVLU-UHFFFAOYSA-N 0.000 claims description 2
- KPAIDITXXLXPRR-UHFFFAOYSA-N CC=1CCC(C(C=1C1=CC=C(C=C1)C#N)=O)C(C(C(C(F)(F)F)(F)F)(F)F)(F)F Chemical compound CC=1CCC(C(C=1C1=CC=C(C=C1)C#N)=O)C(C(C(C(F)(F)F)(F)F)(F)F)(F)F KPAIDITXXLXPRR-UHFFFAOYSA-N 0.000 claims description 2
- UGLVFWUGDDXDLO-UHFFFAOYSA-N CC=1CCC(C(C=1C1=CC=CC=C1)=O)C(C(C(C(F)(F)F)(F)F)(F)F)(F)F Chemical compound CC=1CCC(C(C=1C1=CC=CC=C1)=O)C(C(C(C(F)(F)F)(F)F)(F)F)(F)F UGLVFWUGDDXDLO-UHFFFAOYSA-N 0.000 claims description 2
- TXTGRQHTEAQHFX-UHFFFAOYSA-N ClC1=CC=C(C=C1)C1=C(C(C(CC1)C(C(C(C(F)(F)F)(F)F)(F)F)(F)F)=O)C Chemical compound ClC1=CC=C(C=C1)C1=C(C(C(CC1)C(C(C(C(F)(F)F)(F)F)(F)F)(F)F)=O)C TXTGRQHTEAQHFX-UHFFFAOYSA-N 0.000 claims description 2
- TUWUXMXIPLTYOL-UHFFFAOYSA-N FC(C(C(C(F)(F)F)(F)F)(F)F)(C1C(C2=C(SC=C2)CC1)=O)F Chemical compound FC(C(C(C(F)(F)F)(F)F)(F)F)(C1C(C2=C(SC=C2)CC1)=O)F TUWUXMXIPLTYOL-UHFFFAOYSA-N 0.000 claims description 2
- 239000003480 eluent Substances 0.000 claims description 2
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- LXBGSDVWAMZHDD-UHFFFAOYSA-N 2-methyl-1h-imidazole Chemical compound CC1=NC=CN1 LXBGSDVWAMZHDD-UHFFFAOYSA-N 0.000 claims 2
- UYVCRAVATMDGNZ-UHFFFAOYSA-N 2,4-diethyl-5-methyl-1h-imidazole Chemical compound CCC1=NC(CC)=C(C)N1 UYVCRAVATMDGNZ-UHFFFAOYSA-N 0.000 claims 1
- NELFWLUXURRZAY-UHFFFAOYSA-N 4-ethyl-2,5-dimethyl-1h-imidazole Chemical compound CCC=1N=C(C)NC=1C NELFWLUXURRZAY-UHFFFAOYSA-N 0.000 claims 1
- 229950000900 bendazol Drugs 0.000 claims 1
- 239000004305 biphenyl Substances 0.000 claims 1
- 239000007805 chemical reaction reactant Substances 0.000 claims 1
- 229940056729 sodium sulfate anhydrous Drugs 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 230000004071 biological effect Effects 0.000 abstract description 2
- 230000000144 pharmacologic effect Effects 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 28
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
- 125000000217 alkyl group Chemical group 0.000 description 12
- 125000001624 naphthyl group Chemical group 0.000 description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 8
- 229910052736 halogen Inorganic materials 0.000 description 8
- 150000002367 halogens Chemical group 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- 238000012360 testing method Methods 0.000 description 5
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 4
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- UFMZWBIQTDUYBN-UHFFFAOYSA-N cobalt dinitrate Chemical compound [Co+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O UFMZWBIQTDUYBN-UHFFFAOYSA-N 0.000 description 4
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 4
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 4
- PSCMQHVBLHHWTO-UHFFFAOYSA-K indium(iii) chloride Chemical compound Cl[In](Cl)Cl PSCMQHVBLHHWTO-UHFFFAOYSA-K 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 4
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- ZCCUUQDIBDJBTK-UHFFFAOYSA-N psoralen Chemical compound C1=C2OC(=O)C=CC2=CC2=C1OC=C2 ZCCUUQDIBDJBTK-UHFFFAOYSA-N 0.000 description 4
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 4
- 125000001544 thienyl group Chemical group 0.000 description 4
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000004293 19F NMR spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 230000005526 G1 to G0 transition Effects 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000007789 sealing Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- FCICNMFOICNGHZ-UHFFFAOYSA-N 2-phenylpropanethioic s-acid Chemical compound SC(=O)C(C)C1=CC=CC=C1 FCICNMFOICNGHZ-UHFFFAOYSA-N 0.000 description 2
- VXGRJERITKFWPL-UHFFFAOYSA-N 4',5'-Dihydropsoralen Natural products C1=C2OC(=O)C=CC2=CC2=C1OCC2 VXGRJERITKFWPL-UHFFFAOYSA-N 0.000 description 2
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 2
- JQFHQCMGGLBEJC-UHFFFAOYSA-N C1=CC=C2C(=O)C(OC=3C4=CC=CC=C4C(O)=C(C4=3)OC)=C4C(=O)C2=C1 Chemical compound C1=CC=C2C(=O)C(OC=3C4=CC=CC=C4C(O)=C(C4=3)OC)=C4C(=O)C2=C1 JQFHQCMGGLBEJC-UHFFFAOYSA-N 0.000 description 2
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 2
- 229910021580 Cobalt(II) chloride Inorganic materials 0.000 description 2
- 229910021590 Copper(II) bromide Inorganic materials 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 229910005258 GaBr3 Inorganic materials 0.000 description 2
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/92—Naphthofurans; Hydrogenated naphthofurans
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种多氟烷基取代苯并呋喃类化合物及其制备方法。本发明通过往多氟烷基取代酮类化合物与含氮杂环化合物按摩尔比1：(1～3)混合得到反应原料中加入催化剂、相转移添加剂、碱协同促进剂以及溶剂，在空气氛围、25～110℃温度条件下搅拌反应10～48小时，TLC检测确定反应进程，反应结束后得到反应产物；将反应产物洗涤、萃取和干燥，再通过柱层析分离得到多氟烷基取代苯并呋喃类化合物。本发明制备方法所用原料廉价易得，有效节约了合成成本，反应条件简单、温和，并且还具有反应、高效操作便捷、绿色环保等特点，所合成的一系列多氟烷基苯并呋喃类化合物有潜在生物和药理活性，产率最高大于99％。
Description
技术领域
本发明属于有机化学及药物化学领域，尤其涉及一种多氟烷基取代苯并呋喃类化合物及其制备方法。
背景技术
苯并呋喃衍生物是最为重要的一类杂环有机化合物，其骨架不仅广泛存在于天然产物、药物活性分子中，也可以作为先进材料和金属配体，还是重要的有机合成中间体。
多取代苯并呋喃类化合物在生物医药方面应用的极其广泛，例如：补骨脂素(Psoralen)，一种天然苯并呋喃衍生物，广泛存在于无花果、芹菜、欧芹、西印度沙丁木等植物体中，常用于治疗银屑病和其他真皮疾病；半枝莲素(Rubicordifolin)，是由茜草科植物茜草(Rubiaceae Cordifolia)生产的天然产物，在体外具有细胞毒性，可做药；Balsaminone A，从凤仙花科植物凤仙的种子中提取，具有一定的抗肺癌活性。
从目前已有文献来看，最常用的合成苯并呋喃类衍生物的方法包括：
(1)邻卤代苯酚类化合物和炔烃的Sonogashira偶联环化反应(Tetrahedron,2010，66,2235；Org.Lett.,2005,7,1545)；
(2)联烯炔化合物同卡宾类化合物的偶联-环化串联反应(Org.Lett.,2000，2,1267)；
(3)杂环化反应构建苯并呋喃化合物骨架(Adv.Heterocycl.Chem.2015,117,261)。
然而，这些方法往往需要用到强碱或强酸，或者在很苛刻的反应条件(无水、无氧)下进行，或者底物的范围非常局限，同时往往有较多的副产物生成，这些缺点都严重的制约着该方法的实际运用。此外，已报道的方法并不能在构建苯并呋喃化合物骨架的同时引入多氟烷基基团。在目标分子中定向引入氟及多氟烷基官能团往往能显著改变其物理和化学性能。因此，苯并呋喃类化合物的新型合成方法的开发一直是有机化学及药物化学的热点研究领域。新的多氟烷基苯并呋喃化合物方法的建立对于此类分子的合成及进一步用于药物合成或材料研究都具有重要意义。
发明内容
本发明的首要目的在于提供一种多氟烷基取代苯并呋喃类化合物。
本发明的再一目的在于提供上述多氟烷基取代苯并呋喃类化合物的制备方法，该方法所需原料廉价易得，反应温和、高效。
本发明是这样实现的，一种多氟烷基取代苯并呋喃类化合物，该化合物的化学结构式如下式所示：
上式中，R1为包括氢、甲基、乙基、丁基、戊基或异丙基在内的C1～C10烷基基团，苄基，Cl～C5烷基取代苄基，苯基，Cl～C5烷基取代的苯基，Cl～C5烷氧基取代的苯基，卤素取代的苯基，氰基取代的苯基，硝基取代的苯基，烷氧羰基取代的苯基，萘基，Cl～C5烷基取代的萘基，卤素取代的萘基，噻吩基，包括2-吡啶基的芳基基团；
R2为包括氢、甲基、乙基、丁基、戊基或异丙基在内的C1～C10烷基基团，苄基，Cl～C5烷基取代苄基，苯基，Cl～C5烷基取代的苯基，Cl～C5烷氧基取代的苯基，卤素取代的苯基，氰基取代的苯基，硝基取代的苯基，烷氧羰基取代的苯基，萘基，Cl～C5烷基取代的萘基，卤素取代的萘基，噻吩基，包括2-吡啶基的芳基基团；
R3为包括氢、甲基、乙基、丁基、戊基或异丙基在内的C1～C10烷基基团，苄基，Cl～C5烷基取代苄基，苯基，Cl～C5烷基取代的苯基，Cl～C5烷氧基取代的苯基，卤素取代的苯基，氰基取代的苯基，硝基取代的苯基，烷氧羰基取代的苯基，萘基，Cl～C5烷基取代的萘基，卤素取代的萘基，噻吩基，包括2-吡啶基的芳基基团；
R4为包括氢、甲基、乙基、丁基、戊基或异丙基在内的C1～C10烷基基团，苄基，Cl～C5烷基取代苄基，苯基，Cl～C5烷基取代的苯基，Cl～C5烷氧基取代的苯基，卤素取代的苯基，氰基取代的苯基，硝基取代的苯基，烷氧羰基取代的苯基，萘基，Cl～C5烷基取代的萘基，卤素取代的萘基，噻吩基，包括2-吡啶基的芳基基团；
R5、R6为氮杂环化合物取代基；
n为不小于2的自然数。
优选地，所述氮杂环化合物取代基包括但不限于2-甲基苯并咪唑、2-乙基苯并咪唑、苯并咪唑、5-溴苯并咪唑、5-甲氧羰基苯并咪唑、5-硝基苯并咪唑、5，6-二甲基苯并咪唑、1H-咪唑[4,5-C]吡啶、咪唑、2-醛基咪唑、2-甲基-4-硝基咪唑、1H-吲唑-3-羧酸甲酯、3-碘吡唑、吡唑、3,5-二甲基-4-碘吡唑、3-碘吲唑、6-溴吲唑、苯并三氮唑、5-氯苯并三氮唑、5-甲基苯并三氮唑、3-甲基-1H-1,2,4-三唑、5-苯基四氮唑、3-乙氧羰基吲哚、3-乙酰基吡咯、2-醛基吡咯、1,5,6,7-四氢-4H-吲哚-4-酮、3-醛基吲哚、3-氰基吲哚、四氢咔唑酮、咔唑、6-二甲基氨基嘌呤、苯胺、N-甲基苯胺、N-苯磺酰基苯胺、N-甲基苯磺酰胺、哌啶、地巴唑、2-正丙基-4-甲基-6-(1'-甲基苯并咪唑-2-基)苯并咪唑、甲基(S)-2-(1,3-二氧异吲哚-2-基)-3-(1H-咪唑-4-基)丙酸酯、厄贝沙坦、2-氯苯并咪唑、2-氰甲基苯并咪唑和苄脒盐酸盐；
n为2～10。
本发明公开了上述多氟烷基取代苯并呋喃类化合物的制备方法，该方法包括以下步骤：
(1)往由多氟烷基取代酮类化合物与含氮杂环化合物混合而成的反应原料中加入催化剂、相转移添加剂、碱协同促进剂以及溶剂，在空气氛围、25～110℃温度条件下搅拌反应10～48小时，TLC检测确定反应进程，反应结束后得到反应产物；其中，所述多氟烷基取代酮类化合物与含氮杂环化合物的摩尔比1mmol：(1～3)mmol混合得到；
(2)将反应产物洗涤、萃取和干燥，再通过柱层析分离得到多氟烷基取代苯并呋喃类化合物。
优选地，在步骤(1)中，所述催化剂为CoCl2、Co(OAc)2、Co(acac)2、Co(acac)3、Co(NO3)2、NiBr2、AlCl、InCl3、CuBr2、FeCl3、GaBr3、ZnBr、BiCl3中的任意一种；
所述相转移添加剂为四丁基溴化铵、四丁基氯化铵、四丁基碘化胺、四丁基硫酸氢铵、四丁基醋酸铵、苄基三乙基溴化铵、十六烷基三甲基溴化铵、甲基三辛基氯化铵中的任意一种；
所述碱协同促进剂为碳酸铯、碳酸钾、碳酸铵、磷酸钾、醋酸钠、氢氧化钠、氢氧化锂、三乙烯二胺、二异丙胺、三乙胺、二异丙胺基钠中的任意一种。
优选地，在步骤(1)中，所述催化剂为溴化钴CoBr2，所述相转移添加剂为四丁基溴化铵，所述碱协同促进剂为碳酸铯，所述溶剂为二甲亚砜。
优选地，在步骤(1)中，所述多氟烷基取代酮类化合物、催化剂、相转移添加剂、碱协同促进剂、溶剂的摩尔体积比为0.3mmol：(0.02～0.04)mmol：(0.2～0.4)mmol：0.75mmol：(1～3)mL。
优选地，在步骤(1)中，所述反应原料为多氟烷基取代酮类化合物与含氮杂环化合物按摩尔比1：2混合得到；
所述温度为25℃。
优选地，在步骤(2)中，所述洗涤为水洗，所述萃取为乙酸乙酯萃取，所述干燥为无水硫酸钠干燥；
所述柱层析分离以乙酸乙酯和石油醚按体积比1：(1～500)为洗脱剂，用2cm直径柱层析。
优选地，在步骤(1)中，所述多氟烷基取代酮类化合物为2-全氟丁基四氢萘酮、2-全氟丁基-7-甲氧基四氢萘酮、2-全氟丁基-6-甲氧基四氢萘酮、2-全氟丁基-5-甲氧基四氢萘酮、2-全氟丁基-6-苄氧基四氢萘酮、2-全氟丁基-7-甲基四氢萘酮、2-全氟丁基-7-氟取代四氢萘酮、2-全氟丁基-7-氯取代四氢萘酮、2-全氟丁基-7-溴取代四氢萘酮、2-全氟丁基-5-对甲苯磺酸酯基四氢萘酮、2-全氟丁基-4-甲基四氢萘酮、2-全氟丁基-4-(3，4-二氯苯基)四氢萘酮、5-(全氟丁基)-6,7-二氢苯并[b]硫酚-4(5H)-酮、2-甲基-4-(全氟丁基)-5,6-二氢-[1,1'-联苯基]-3(4H)-酮、2,4'-二甲基-4-(全氟丁基)-5,6-二氢-[1,1'-联苯基]-3(4H)-酮、4'-氯-2-甲基-4-(全氟丁基)-5,6-二氢-[1,1'-联苯基]-3(4H)-酮、2-甲基-3-(1-萘基)-6-(全氟丁基)-环己烯基-1-酮、6-甲基-3-(全氟丁基)-4,5-二氢-[1,1'-联苯基]-2(3H)-酮、6'-甲基-2'-氧-3'-(全氟丁基)-2',3',4',5'-四氢-[1,1'-联苯基]-4-腈、3-甲基-6-(全氟丁基)-2-(2-赛噻吩基)环己烯酮、5-甲基-2-(全氟丁基)-1,6-二氢-[1,1'-联苯基]-3(2H)-酮、5-((邻溴苯基)硫)-2-(全氟丁基)-1,6-二氢-[1,1'-联苯基]-3(2H)-酮、2-全氟癸基四氢萘酮、2-全氟壬基四氢萘酮、2-全氟辛基四氢萘酮、2-全氟庚基四氢萘酮、2-全氟己基四氢萘酮、2-全氟戊基四氢萘酮和2-全氟丙基四氢萘酮中的一种。
优选地，在步骤(1)中，所述含氮杂环化合物为2-甲基苯并咪唑、2-乙基苯并咪唑、苯并咪唑、5-溴苯并咪唑、5-甲氧羰基苯并咪唑、5-硝基苯并咪唑、5，6-二甲基苯并咪唑、1H-咪唑[4,5-C]吡啶、咪唑、2-醛基咪唑、2-甲基-4-硝基咪唑、1H-吲唑-3-羧酸甲酯、3-碘吡唑、吡唑、3,5-二甲基-4-碘吡唑、3-碘吲唑、6-溴吲唑、苯并三氮唑、5-氯苯并三氮唑、5-甲基苯并三氮唑、3-甲基-1H-1,2,4-三唑、5-苯基四氮唑、3-乙氧羰基吲哚、3-乙酰基吡咯、2-醛基吡咯、1,5,6,7-四氢-4H-吲哚-4-酮、3-醛基吲哚、3-氰基吲哚、四氢咔唑酮、咔唑、6-二甲基氨基嘌呤、苯胺、N-甲基苯胺、N-苯磺酰基苯胺、N-甲基苯磺酰胺、哌啶、地巴唑、2-正丙基-4-甲基-6-(1'-甲基苯并咪唑-2-基)苯并咪唑、甲基(S)-2-(1,3-二氧异吲哚-2-基)-3-(1H-咪唑-4-基)丙酸酯、厄贝沙坦、2-氯苯并咪唑、2-氰甲基苯并咪唑和苄脒盐酸盐中的一种。
本发明克服现有技术的不足，提供一种多氟烷基取代苯并呋喃类化合物及其制备方法与应用，本发明将多氟烷基取代酮类化合物与含氮杂环化合物混合，在溴化钴为催化剂、四丁基溴化铵为添加剂和碳酸铯为碱的协同促进下，将混合物在空气氛围、二甲亚砜(DMSO)为溶剂以及室温条件下搅拌反应12～48小时，TLC检测，水洗、乙酸乙酯萃取、无水硫酸钠干燥，最后再通过柱层析分离得到多氟烷基取代苯并呋喃类化合物。本发明多氟烷基取代苯并呋喃类化合物的制备反应方程式如下：
本发明制备方法的条件筛选过程中，对不同的催化剂，如：CoCl2、Co(OAc)2、Co(acac)2、Co(acac)3、Co(NO3)2、NiBr2、AlCl、InCl3、CuBr2、FeCl3、GaBr3、ZnBr、BiCl3均能得到预期结果，但CoBr2效果最优；多氟烷基取代酮类化合物与含氮杂环化合物之间不同的比例1：(1～3)之间，以1：2最优；不同的相转移添加剂，如：四丁基溴化铵、四丁基氯化铵、四丁基碘化胺、四丁基硫酸氢铵、四丁基醋酸铵、苄基三乙基溴化铵、十六烷基三甲基溴化铵、甲基三辛基氯化铵均能得到预期结果，但四丁基溴化铵效果最优；不同的碱，如：碳酸铯、碳酸钾、碳酸铵、磷酸钾、醋酸钠、氢氧化钠、氢氧化锂、三乙烯二胺、二异丙胺、三乙胺、二异丙胺基钠，均能得到预期结果，但碳酸铯效果最优；25～110℃范围内的不同温度下均能得到目标产物，25℃最优。
相比于现有技术的缺点和不足，本发明具有以下有益效果：
(1)本发明制备方法所用原料廉价易得，有效节约了合成成本；
(2)本发明在空气氛围、室温条件下即可进行催化反应，反应条件简单、温和；
(3)本发明反应过程中完成了C-F碱的连续切断，反应所得的苯并呋喃化合物中成功引入了多氟烷基和含氮杂环片段，该发明具有反应、高效操作便捷的特点；
(4)本发明制备方法具有合成路线短、催化体系绿色环保的特点；
(5)本发明能够合成一系列有潜在生物和药理活性的多氟烷基苯并呋喃类化合物，产品产率最高大于99％。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。
实施例1
称取0.3mmol的2-全氟丁基四氢萘酮(0.1093克)，0.6mmol的2-甲基苯并咪唑(0.0793克)，0.03mmol的溴化钴(0.0066克)，0.3mmol的四丁基溴化铵(0.0967克)，0.75mmol的碳酸铯(0.2444克)，于10mL的试管反应管中，加2mL二甲亚砜(DMSO)作溶剂，封口密闭，25℃下搅拌反应10小时；反应结束后，反应液依次经过水、乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1：6→1：3，得到0.0887克反应产物。
对上述反应产物进行表征，结果为：
无色液体；
IR(KBr)(＝3063,1625,1538,812,744cm-1；1H NMR(400MHz,CDCl3):δ＝8.46(d,J＝8.2Hz,1H),7.98(d,J＝8.1Hz,1H),7.84(d,J＝8.0Hz,1H),7.77–7.70(m,2H),7.67–7.63(m,1H),7.32(td,J＝7.8,1.1Hz,1H),7.23–7.18(m,1H),7.14(d,J＝8.7Hz,1H),7.03(d,J＝8.0Hz,1H),2.52(s,3H)ppm；19F NMR(376MHz,CDCl3):δ＝-83.36(t,J＝4.0Hz,3F),-113.83–-116.67(m,2F)ppm；13C NMR(100MHz,DMSO-D6):δ＝151.7,150.7,142.6,136.4,135.5(t,J＝31.0Hz),133.0,128.8,128.1,127.9,126.6,123.0,122.7,122.6,120.2,120.0,119.5,118.9,116.5,109.7,13.2ppm。
根据表征数据可知，制得的反应产物为2-甲基-1-(2-(全氟丁基)萘并[1,2-b]呋喃-3-基)-1H-苯并咪唑纯品(纯度＞95％)；对产品产率进行计算，结果为71％。
实施例2
称取0.3mmol的2-全氟丁基四氢萘酮(0.1093克)，0.6mmol的3-醛基吲哚(0.0871克)，0.03mmol的溴化钴(0.0066克)，0.3mmol的四丁基溴化铵(0.0967克)，0.75mmol的碳酸铯(0.2444克)，于10mL的试管反应管中，加2mL二甲亚砜(DMSO)作溶剂，封口密闭，25℃下搅拌反应10小时；反应结束后，反应液依次经过水、乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:6→1:3，得到0.0734克反应产物。
对上述反应产物进行表征，结果为：
白色固体；M.p.150.5～152.2℃；
IR(KBr):(＝3104,1676,1626,1611,805,755cm-1；1H NMR(400MHz,CDCl3):δ＝10.16(s,1H),8.48–8.42(m,2H),8.00(d,J＝8.1Hz,1H),7.90(s,1H),7.79–7.72(m,2H),7.71–7.65(m,1H),7.44–7.38(m,1H),7.36–7.30(m,1H),7.26(d,J＝8.7Hz,1H),7.18(d,J＝8.2Hz,1H)ppm；19F NMR(376MHz,CDCl3):δ＝-83.45(t,J＝4.0Hz,3F),-112.29–-115.94(m,2F)ppm；13C NMR(100MHz,CDCl3):δ＝185.0,150.9(t,J＝1.0Hz),139.2,138.4,135.7(t,J＝31.7Hz),133.2,128.6,127.9,127.7,126.2,125.1,125.0,124.6(t,J＝1.6Hz),123.8,122.4,121.0,120.7,120.3,119.9,116.7,110.8ppm。
根据表征数据可知，制得的反应产物为1-(2-(全氟丁基)萘并[1,2-b]呋喃-3-基)-1H-吲哚-3-醛纯品(纯度＞95％)；对产品产率进行计算，结果为57％。
实施例3
称取0.3mmol的2-甲基-4-(全氟丁基)-5,6-二氢-[1,1'-联苯基]-3(4H)-酮(0.1213克)，0.6mmol的苯并三氮唑(0.0715克)，0.03mmol的溴化钴(0.0066克)，0.3mmol的四丁基溴化铵(0.0967克)，0.75mmol的碳酸铯(0.2444克)，于10mL的试管反应管中，加2mL二甲亚砜(DMSO)作溶剂，封口密闭，25℃下搅拌反应10小时；反应结束后，反应液依次经过水、乙酸乙酯、无水硫酸钠干燥和柱层析分离(柱层析分离条件：固定相为300～400目硅胶粉，流动相为乙酸乙酯(A)和石油醚(B)，流动相变化程序(A:B)为1:6→1:3，得到0.0734克反应产物。
对上述反应产物进行表征，结果为：
白色固体；M.p.120.1～120.6℃；
IR(KBr):(＝3103,1686,1611,805cm-1；1H NMR(400MHz,CDCl3):δ＝8.25–8.19(m,1H),7.62–7.56(m,1H),7.53–7.45(m,4H),7.44–7.36(m,3H),7.33(d,J＝8.2Hz,1H),7.23(d,J＝8.2Hz,1H),2.57(s,3H)ppm；19F NMR(376MHz,CDCl3):δ＝-83.11(t,J＝3.1Hz,3F),-114.92(s,2F)ppm；13C NMR(100MHz,CDCl3):δ＝153.8(t,J＝1.1Hz),145.6,142.5,139.8,136.8(t,J＝32.0Hz),134.2,129.4,128.9,128.4,127.6,127.6,124.7,122.0(t,J＝1.0Hz),121.9,121.0,120.4,117.1,109.6,12.5ppm。
根据表征数据可知，制得的反应产物为1-(7-甲基-2-(全氟丁基)-6-苯基苯并呋喃-3-基)-1H-苯并[d][1,2,3]三氮唑纯品(纯度＞95％)；对产品产率进行计算，结果为60％。
实施例4/5
实施例4/5与实施例1基本相同，差别之处如下表1所示：
表1实施例4～5
实施例6～30
实施例6～30与实施例1基本相同，差别之处在于如下表2所示：
表2实施例6～30
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。
Claims (4)
1.一种多氟烷基取代苯并呋喃类化合物的制备方法，其特征在于，该方法包括以下步骤：
(1)往由多氟烷基取代酮类化合物与含氮杂环化合物混合而成的反应原料中加入催化剂、相转移添加剂、碱协同促进剂以及溶剂，在空气氛围、25～110℃温度条件下搅拌反应10～48小时，TLC检测确定反应进程，反应结束后得到反应产物；
所述多氟烷基取代酮类化合物的结构通式为：
所述含氮杂环化合物的结构通式为：
所述反应产物的结构通式为：
其中，所述多氟烷基取代酮类化合物与含氮杂环化合物的摩尔比1mmol：(1～3)mmol混合得到；
在步骤(1)中，所述催化剂为溴化钴CoBr2；
所述相转移添加剂为四丁基溴化铵；
所述碱协同促进剂为碳酸铯；
在步骤(1)中，所述多氟烷基取代酮类化合物为2-全氟丁基四氢萘酮、2-全氟丁基-7-甲氧基四氢萘酮、2-全氟丁基-6-甲氧基四氢萘酮、2-全氟丁基-5-甲氧基四氢萘酮、2-全氟丁基-6-苄氧基四氢萘酮、2-全氟丁基-7-甲基四氢萘酮、2-全氟丁基-7-氟取代四氢萘酮、2-全氟丁基-7-氯取代四氢萘酮、2-全氟丁基-7-溴取代四氢萘酮、2-全氟丁基-5-对甲苯磺酸酯基四氢萘酮、2-全氟丁基-4-甲基四氢萘酮、2-全氟丁基-4-(3，4-二氯苯基)四氢萘酮、5-(全氟丁基)-6,7-二氢苯并[b]硫酚-4(5H)-酮、2-甲基-4-(全氟丁基)-5,6-二氢-[1,1'-联苯基]-3(4H)-酮、2,4'-二甲基-4-(全氟丁基)-5,6-二氢-[1,1'-联苯基]-3(4H)-酮、4'-氯-2-甲基-4-(全氟丁基)-5,6-二氢-[1,1'-联苯基]-3(4H)-酮、2-甲基-3-(1-萘基)-6-(全氟丁基)-环己烯基-1-酮、6-甲基-3-(全氟丁基)-4,5-二氢-[1,1'-联苯基]-2(3H)-酮、6'-甲基-2'-氧-3'-(全氟丁基)-2',3',4',5'-四氢-[1,1'-联苯基]-4-腈、3-甲基-6-(全氟丁基)-2-(2-赛噻吩基)环己烯酮、5-甲基-2-(全氟丁基)-1,6-二氢-[1,1'-联苯基]-3(2H)-酮、5-((邻溴苯基)硫)-2-(全氟丁基)-1,6-二氢-[1,1'-联苯基]-3(2H)-酮、2-全氟癸基四氢萘酮、2-全氟壬基四氢萘酮、2-全氟辛基四氢萘酮、2-全氟庚基四氢萘酮、2-全氟己基四氢萘酮、2-全氟戊基四氢萘酮和2-全氟丙基四氢萘酮中的一种；
在步骤(1)中，所述含氮杂环化合物为2-甲基苯并咪唑、2-乙基苯并咪唑、苯并咪唑、5-溴苯并咪唑、5-甲氧羰基苯并咪唑、5-硝基苯并咪唑、5，6-二甲基苯并咪唑、1H-咪唑[4,5-C]吡啶、咪唑、2-醛基咪唑、2-甲基-4-硝基咪唑、1H-吲唑-3-羧酸甲酯、3-碘吡唑、吡唑、3,5-二甲基-4-碘吡唑、3-碘吲唑、6-溴吲唑、苯并三氮唑、5-氯苯并三氮唑、5-甲基苯并三氮唑、3-甲基-1H-1,2,4-三唑、5-苯基四氮唑、3-乙氧羰基吲哚、3-乙酰基吡咯、2-醛基吡咯、1,5,6,7-四氢-4H-吲哚-4-酮、3-醛基吲哚、3-氰基吲哚、四氢咔唑酮、咔唑、6-二甲基氨基嘌呤、苯胺、N-甲基苯胺、N-苯磺酰基苯胺、N-甲基苯磺酰胺、哌啶、地巴唑、2-正丙基-4-甲基-6-(1'-甲基苯并咪唑-2-基)苯并咪唑、甲基(S)-2-(1,3-二氧异吲哚-2-基)-3-(1H-咪唑-4-基)丙酸酯、厄贝沙坦、2-氯苯并咪唑、2-氰甲基苯并咪唑和苄脒盐酸盐中的一种；
(2)将反应产物洗涤、萃取和干燥，再通过柱层析分离得到多氟烷基取代苯并呋喃类化合物。
2.如权利要求1所述的多氟烷基取代苯并呋喃类化合物的制备方法，其特征在于，在步骤(1)中，所述多氟烷基取代酮类化合物、催化剂、相转移添加剂、碱协同促进剂、溶剂的摩尔体积比为0.3mmol：(0.02～0.04)mmol：(0.2～0.4)mmol：0.75mmol：(1～3)mL。
3.如权利要求1所述的多氟烷基取代苯并呋喃类化合物的制备方法，其特征在于，在步骤(1)中，所述反应原料为多氟烷基取代酮类化合物与含氮杂环化合物按摩尔比1：2混合得到；
所述温度为25℃。
4.如权利要求1所述的多氟烷基取代苯并呋喃类化合物的制备方法，其特征在于，在步骤(2)中，所述洗涤为水洗，所述萃取为乙酸乙酯萃取，所述干燥为无水硫酸钠干燥；
所述柱层析分离以乙酸乙酯和石油醚按体积比1：(1～500)为洗脱剂，用2cm直径柱层析。
Priority Applications (1)
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